Novel aminediol compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds in inhibiting retroviral protease, particularly useful in the treatment and/or prevention of HIV infection (AIDS).

FIELD OF THE INVENTION 
The present invention relates to novel aminediol compounds, to 
pharmaceutical compositions containing these compounds, and to methods of 
using these compounds in inhibiting the replication of retroviruses. The 
present invention particularly relates to novel aminediol compounds useful 
in the treatment and/or prevention of Acquired Immunodeficiency Syndrome 
(AIDS). 
SUMMARY OF THE INVENTION 
The present invention provides compounds of the following formula I: 
##STR1## 
where A.sup.a, A.sup.b and A.sup.c are independently: 
(1) hydrogen; 
(2) alkyl, especially lower alkyl; 
##STR2## 
D.sup.a and D.sup.b are independently selected from groups of the formula: 
##STR3## 
where D.sup.a and D.sup.b are bonded to the groups A.sup.a and A.sup.b, 
respectively, through the moiety --E--N(R.sup.8)--, where E is a single 
bond or a peptide chain containing 1 to 4 amino acids, the N-terminus of 
which is bonded to A.sup.a when E is part of D.sup.a or to A.sup.b when E 
is part of D.sup.b ; 
R.sup.1 and R.sup.2 are independently: 
(1) hydrogen; 
(2) alkyl, especially lower alkyl; 
(3) alkenyl, especially lower alkenyl; 
(4) aryl; 
(5) heterocyclo; or 
(6) carbocyclo, such as cycloalkyl; 
R.sup.3 and R.sup.4 are independently: 
(a) hydrogen; 
(b) alkyl, especially lower alkyl; 
(c) aryl; 
(d) heterocyclo; 
(e) carbocyclo, such as cycloalkyl; 
(f) when R.sup.3 and R.sup.4 are bonded to a common nitrogen atom, R.sup.3 
and R.sup.4 may be joined, together with that nitrogen atom, to form a 
heterocyclic ring system, such as a 5 to 7 membered heterocyclic ring; or 
(g) when E is a single bond and R.sup.3 is part of A.sup.a or A.sup.b, 
R.sup.3 may, together with R.sup.8, form an alkylene group, for example, 
having one to five carbons, such as wherein R.sup.3 and R.sup.8, together 
with the atoms to which they are bonded, form the cyclic moiety: 
##STR4## 
R.sup.5, R.sup.6 and R.sup.7 are independently: (a) hydrogen; 
(b) alkyl, especially lower alkyl; 
(c) aryl; 
(d) carbocyclo, such as cycloalkyl; 
(e) fluorenyl; 
(f) heterocyclo; 
(g) R.sup.5, R.sup.6 and R.sup.7 may, independently, be joined, together 
with the carbon atom to which they are bonded, to form a mono-, bi- or 
tricyclic carbocyclic ring system, especially wherein each ring contains 3 
to 7 carbon atoms, or a mono-, bi- or tricyclic heterocyclic ring system; 
(h) alkynyl; 
(i) alkenyl; or 
(j) when E is a single bond and R.sup.5, R.sup.6 and R.sup.7 are part of 
A.sup.a or A.sup.b, one of R.sup.5, R.sup.6, or R.sup.7 may, together with 
R.sup.8, form an alkylene group, for example, having one to three carbons, 
such as wherein R.sup.5 and R.sup.6 are methyl and R.sup.7 and R.sup.8, 
together with the atoms to which they are bonded, form the cyclic moiety: 
##STR5## 
R.sup.8 is: (a) hydrogen; 
(b) alkyl, especially unsubstituted lower alkyl or aryl-lower alkyl; 
(c) R.sup.8 and R.sup.9 may be joined, together with the atoms to which 
they are bonded, to form a heterocyclic ring system, for example, a 5 to 7 
membered monocyclic heterocyclic ring; 
(d) R.sup.8 may be joined together with R.sup.5, R.sup.6 or R.sup.7 as 
described above; 
(e) R.sup.8 may be joined together with R.sup.3 as described above; or 
(f) R.sup.8 and R.sup.11 may be joined, together with the atoms to which 
they are bonded, to form a heterocyclic ring system, such as where R.sup.8 
and R.sup.11 together are an alkylene group; 
R.sup.9 and R.sup.9' are independently: 
(a) hydrogen; 
(b) alkyl, especially lower alkyl; 
(c) alkenyl, especially lower alkenyl; 
(d) alkynyl; 
(e) aryl; 
(f) heterocyclo; 
(g) carbocyclo, such as cycloalkyl; 
(h) R.sup.9 may be joined together with R.sup.8 as described above; or 
(i) R.sup.9 and R.sup.9' may be joined, together with the carbon atom to 
which they are bonded, to form a carbocyclic group, such as 5- or 
6-membered carbocyclic ring; 
R.sup.10 is: 
(a) hydrogen; 
(b) alkyl, such as unsubstituted lower alkyl or hydroxy-lower alkyl, 
cycloalkyl-lower alkyl, aryl-lower alkyl or heterocyclo-lower alkyl; 
(c) alkenyl, especially lower alkenyl; 
(d) alkynyl; 
(e) carbocyclo, such as cycloalkyl; 
(f) aryl; or 
(g) R.sup.10 and R.sup.11 taken together may form a a bond to give a keto 
(C.dbd.O) group; 
R.sup.11 is: 
(a) hydrogen; 
(b) a hydroxyl protecting group, such as alkyl; 
(c) R.sup.11 may be joined together with R.sup.8 as described above; or 
(d) R.sup.11 may, together with R.sup.10, form a bond to give a keto group 
as described above; 
Z is oxygen or sulfur; and 
p and q are, independently, integers from 0 to 4; and 
salts, preferably pharmaceutically acceptable salts, thereof. 
The compounds of the present invention inhibit the replication of 
retroviruses. The present invention thus also provides methods, and 
pharmaceutical compositions, for the treatment and/or prevention of 
diseases caused by such pathogenic organisms.

DETAILED DESCRIPTION OF THE INVENTION 
The terms "alk" or "alkyl", as employed herein alone or as part of another 
group, denote both straight and branched chain, optionally substituted 
saturated radicals, for example, containing 1 to 12 carbons, most 
preferably 1 to 8 carbons, in the normal chain. It is understood, 
therefore, that throughout this specification the terms "alk" and "alkyl" 
denote both unsubstituted groups such as methyl, ethyl, n-propyl, 
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 
1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, n-hexyl and the like, as 
well as substituted groups such as phenylmethyl and the like. Exemplary 
substituents may include one or more, such as 1, 2 or 3, of the following: 
(1) hydroxy (or protected hydroxy); 
(2) oxo (i.e. .dbd.o), with the proviso that the carbon bearing the oxo 
group is not adjacent to a heteroatom; 
(3) carboxy; 
(4) halo (especially to form trihaloalkyl, particularly trifluoromethyl); 
(5) alkoxy, such as phenyl-lower alkoxy or 
EQU R.sup.16 --[O--(CH.sub.2).sub.m ].sub.n --O-- 
where m is an integer from 2 to 5; n is an integer from 1 to 5; and 
R.sup.16 is: 
(a) hydrogen; 
(b) alkyl, especially unsubstituted lower alkyl or alkoxy-lower alkyl; 
(c) aryl; or 
(d) heterocyclo; 
(6) aryloxy; 
(7) alkoxycarbonyl; 
##STR6## 
where R.sup.12 and R.sup.13 are independently: 
(a) hydrogen; 
(b) alkyl, especially lower alkyl; 
(c) aryl; 
(d) heterocyclo; 
(e) carbocyclo, such as cycloalkyl; 
(f) R.sup.12 and R.sup.13 may be joined, together with the nitrogen atom to 
which they are bonded, to form a 5 to 7 membered heterocyclic ring; 
(9) (R.sup.12) (R.sup.13) N--, such as amino (H.sub.2 N--); 
##STR7## 
where R.sup.14 is: 
(a) hydrogen; 
(b) alkyl, especially lower alkyl; 
(c) aryl; 
(d) heterocyclo; 
(e) carbocyclo, such as cycloalkyl; or 
(f) R.sup.14 and R.sup.15 may be joined to form an alkylene group of three 
to five carbon atoms; and 
R.sup.15 is: 
(a) hydrogen; 
(b) alkyl, especially lower alkyl; 
(c) alkenyl, especially lower alkenyl; 
(d) aryl; 
(e) heterocyclo; 
(f) carbocyclo, such as cycloalkyl; 
##STR8## 
wherein R.sup.5, R.sup.6 and R.sup.7 are, independently, those groups (a) 
through (i) recited for R.sup.5, R.sup.6 and R.sup.7 above; or 
(h) R.sup.15 may be joined together with R.sup.14 as described above; 
##STR9## 
(12) carbocyclo, such as cycloalkyl; 
(13) heterocyclo; 
(14) heterocyclooxy; 
(15) aryl; 
(16) alkylcarbonyloxy, such as lower alkylcarbonyloxy; 
(17) arylcarbonyloxy; 
(18) cyano; 
(19) mercapto; 
(20) alkenyl; 
(21) alkynyl, such as ethynyl (e.g., forming a propargyl group); 
(22) alkylthio; 
(23) arylthio; 
(24) trialkylsilyl, such as trimethylsilyl; 
(25) azo (i.e., R.sup.16 O--N.dbd. where R.sup.16 is as defined above, 
preferably hydrogen (to form an oxime group (HO--N.dbd.)) or unsubstituted 
alkyl (to form an unsubstituted alkoxyimino group (alkyl--O--N.dbd.)); or 
(26) (R.sup.12)(R.sup.13)N--C(O)--O--, where R.sup.12 and R.sup.13 are as 
defined above. 
The term "alkoxy" denotes an alkyl group bonded through an oxygen bridge 
(--O--); the term "alkylthio" denotes an alkyl group bonded through a 
sulfur bridge (--S--); the term "alkoxycarbonyl" (also referred to as 
"carboalkoxy") denotes an alkoxy group attached to a carbonyl group to 
form an ester; the term "alkylcarbonyloxy" denotes an alkyl group bonded 
to a carbonyl group which is in turn bonded through an oxygen bridge; the 
term "aminocarbonyloxy" denotes an amino group bonded through a carbonyl 
group which is, in turn, bonded through an oxygen bridge; the term 
"alkylaminocarbonyloxy" denotes an alkyl group bonded through an 
aminocarbonyloxy group as described above; the term "alkylaminocarbonyl" 
denotes an alkyl group bonded through an amino group which is, in turn, 
bonded through a carbonyl group; and the term "alkylene" denotes a 
divalent alkyl group. With respect to exemplary alkyl groups which are 
substituted, the term "alkoxy-alkyl" specifically denotes an alkoxy group 
bonded through an alkyl group; the term "aryl-alkyl" specifically denotes 
an aryl group bonded through an alkyl group; the term "heterocyclo-alkyl" 
specifically denotes a heterocyclo group bonded through an alkyl group; 
the term "cycloalkyl-alkyl" specifically denotes a cycloalkyl group bonded 
through an alkyl group; and the term "hydroxy-alkyl" specifically denotes 
one or more hydroxyl groups attached to an alkyl group. In each of the 
aforementioned terms, "alkyl" may be further substituted, or 
unsubstituted, as defined above. Likewise, "fluorenylalkyl" specifically 
denotes a fluorenyl group bonded through alkyl. Similarly, the terms 
"arylalkoxy", "alkoxyalkoxy", "hydroxyalkoxy", "heterocycloalkoxy", 
"aminoalkoxy", "aminocarbonyloxyalkoxy", "heterocyclocarbonylalkoxy", 
"heterocyclooxyalkoxy", alkoxycarbonylalkoxy" and "carboxyalkoxy" 
specifically denote alkoxy substituted by aryl, alkoxy, hydroxy, 
heterocyclo, amino, aminocarbonyloxy, heterocyclocarbonyl, heterocyclooxy, 
alkoxycarbonyl and carboxy, respectively. 
The term "lower alkyl", as employed herein alone or as part of another 
group, denotes optionally substituted groups as described above for alkyl 
containing 1 to 6 carbon atoms in the normal chain. Lower alkyl groups are 
preferred alkyl groups. 
The term "alkenyl", as employed herein alone or as part of another group, 
denotes both straight and branched chain, optionally substituted radicals, 
for example, containing 2 to 12 carbons in the normal chain, most 
preferably 2 to 8 carbons, which contain at least one carbon to carbon 
double bond and which are directly attached through one of the carbons 
composing the double bond. It is understood, therefore, that throughout 
this specification, the term "alkenyl" denotes both unsubstituted groups 
such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like, as 
well as substituted groups. Exemplary substituents may include one or 
more, such as 1, 2 or 3, of the following: 
(1) alkyl, especially lower alkyl; 
(2) aryl; 
(3) carbocyclo, such as cycloalkyl; 
(4) heterocyclo; 
(5) carboxy; 
(6) halo; 
##STR10## 
(8) cyano; 
(9) alkoxycarbonyl; 
(10) trialkylsilyl; or 
(11) alkynyl. 
The term "lower alkenyl", as employed herein alone or as part of another 
group, denotes optionally substituted groups as described above for 
alkenyl containing 2 to 6 carbon atoms in the normal chain. Lower alkenyl 
groups are preferred alkenyl groups. 
The term "alkynyl", as employed herein alone or as part of another group, 
denotes both straight and branched chain, optionally substituted radicals, 
for example, containing 2 to 12 carbons in the normal chain, most 
preferably 2 to 8 carbons, which contain at least one carbon to carbon 
triple bond and which are directly attached through one of the carbons 
composing the triple bond. It is understood, therefore, that throughout 
this specification, the term "alkynyl" denotes both unsubstituted groups 
such as ethynyl, methyl-ethynyl, and the like, as well as substituted 
groups. Exemplary substituents may include one or more, such as 1, 2 or 3, 
of the following: 
(1) alkyl, especially lower alkyl; 
(2) aryl; 
(3) carbocyclo, such as cycloalkyl; 
(4) heterocyclo; 
(5) carboxy; 
##STR11## 
(7) cyano; 
(8) alkoxycarbonyl; 
(9) alkenyl; or 
(10) trialkylsilyl. 
The terms "carbocyclo", "carbocyclic" or "carbocyclic ring system", as 
employed herein alone or as part of another group, denote an optionally 
substituted, saturated or partially unsaturated, homocyclic carbon ring 
system, such as a cycloalkenyl ring system, which is partially 
unsaturated, or most preferably, a cycloalkyl ring system, which is fully 
saturated, wherein the aforementioned cycloalkenyl and cycloalkyl ring 
systems are, according to the above definition, optionally substituted. 
Such cyclic groups preferably contain from 1 to 3 rings and from 3 to 12, 
most preferably from 3 to 7, carbons per homocyclic ring. It is 
understood, therefore, that throughout this specification the terms 
"carbocyclo", "carbocyclic" and "carbocyclic ring system" denote both 
unsubstituted groups exemplified by monocyclic groups such as cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; bicyclic groups such 
as octahydropentalenyl, decalin, norbornyl, spirocycloheptyl (e.g., 
spiro[2.4]heptyl), spirocyclooctyl (e.g., spiro[3.4]octyl), 
spirocyclononyl (e.g. spiro[4.4]nonyl), and the like; and tricyclic groups 
such as adamantyl, as well as substituted groups. Exemplary substituents 
may include one or more, such as 1, 2 or 3, of the following: 
(1) alkyl, especially lower alkyl; 
(2) hydroxy (or protected hydroxy); 
(3) halo; 
(4) mercapto; 
(5) cyano; 
(6) carboxy; 
(7) alkoxycarbonyl; 
##STR12## 
(9) alkylcarbonyloxy, such as lower alkylcarbonyloxy; 
(10) arylcarbonyloxy; 
(11) (R.sup.12) (R.sup.13)N--, such as amino (H.sub.2 N--); 
(12) alkoxy; 
(13) aryl, such as where said aryl group is bonded through a single bond or 
is fused to said carbocyclo group (e.g. to form a tetrahydronaphthyl, 
indanyl or indenyl group), and wherein, in each case, the aryl-carbocyclo 
moiety so formed is bonded through the carbocyclo group; 
(14) heterocyclo; 
(15) heterocyclooxy; 
(16) oxo (.dbd.O); 
(17) aryloxy; 
(18) alkylthio; 
(19) arylthio; 
##STR13## 
(21) alkenyl; 
(22) alkynyl; or 
(23) trialkylsilyl. 
The terms "ar" or "aryl", as employed herein alone or as part of another 
group, denote homocyclic, optionally substituted aromatic groups, 
preferably monocyclic or bicyclic groups containing from 6 to 12 carbons 
in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, 
biphenyl and the like. It is understood, therefore, that throughout this 
specification, the terms "ar" and "aryl" denote unsubstituted as well as 
substituted groups. Exemplary substituents may include on or more, such as 
1, 2 or 3, of the following: 
(1) alkyl, especially lower alkyl; 
(2) alkoxy; 
(3) hydroxy (or protected hydroxy); 
(4) halo; 
(5) (R.sup.12)(.sup.13)N--, such as amino (H.sub.2 N--) ; 
(6) alkylthio; 
(7) mercapto; 
(8) nitro; 
(9) cyano; 
(10) carboxy; 
(11) carboalkoxy; 
(12) carbocyclo, such as where said carbocyclo group is bonded through a 
single bond, or is fused to said aryl group (e.g. to form a 
tetrahydronaphthyl, indanyl or indenyl group), and wherein, in each case, 
the carbocyclo-aryl moiety so formed is bonded through the aryl group; 
##STR14## 
where R.sup.17 is: 
(a) hydrogen; 
(b) alkyl, especially lower alkyl; 
(c) aryl; 
(d) heterocyclo; 
(e) carbocyclo, such as cycloalkyl; or 
(f) R.sup.17 may, together with R.sup.3, form an alkylene group of three to 
five carbons; 
##STR15## 
(17) phenyl; 
(18) alkylcarbonyloxy, such as lower alkylcarbonyloxy; 
(19) arylcarbonyloxy; 
(20) arylthio; 
(21) heterocyclooxy; 
(22) aryloxy; 
(23) alkylthio; or 
(24) alkenyl. 
The terms "arylcarbonyloxy" or "aroyloxy" denote an aryl group which is 
bonded through a carbonyl group which is, in turn, bonded through an 
oxygen bridge; the term "aryloxy" denotes on aryl group bonded through an 
oxygen bridge; the term "arylcarbonyl" denotes an aryl group bonded 
through a carbonyl group; the term "arylaminocarbonyl" denotes an aryl 
group bonded through an amino group which is, in turn, bonded through a 
carbonyl group; and the term "arylthio" denotes an aryl group bonded 
through a sulfur bridge. 
The terms "halogen" or "halo", as employed herein alone or as part of 
another group, refer to chlorine, bromine, fluorine and iodine. 
The terms "heterocyclo", "heterocyclic" or "heterocyclic ring system", as 
employed herein alone or as part of another group, denote an optionally 
substituted, fully saturated or unsaturated, aromatic or nonaromatic 
cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 
membered bicyclic, or 10 to 15 membered tricyclic ring system, which has 
at least one heteroatom in at least one carbon atom-containing ring. Each 
ring of the heterocyclo group containing a heteroatom may have 1, 2 or 3 
heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, 
where the nitrogen and sulfur heteroatoms may optionally be oxidized and 
the nitrogen heteroatoms may optionally be quaternized. The heterocyclo 
group may be attached at any heteroatom or carbon atom. 
Exemplary monocyclic heterocyclo groups include pyrrolidinyl, pyrrolyl, 
pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, 
imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazoyl, 
thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, 
furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, 
azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 
tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl 
sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and 
tetrahydro-1,1-dioxothienyl, and the like. 
Exemplary bicyclic heterocyclo groups include indolyl, benzothiazolyl, 
benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, 
tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, 
indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, 
quinoxalinyl, indazolyl, pyrrolopyridyl, dihydroindazolyl such as the 
group: 
##STR16## 
furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or 
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 
3,4-dihydro-4-oxo-quinazolinyl), and the like. 
Exemplary tricyclic heterocyclo groups include carbazolyl, benzindolyl, 
phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like. 
It is understood that throughout this specification the terms 
"heterocyclo", "heterocyclic" and "heterocyclic ring system" denote both 
unsubstituted as well as substituted groups. Exemplary heterocyclo 
substituents may include one or more, such as 1, 2 or 3, of the following: 
(1) alkyl, especially lower alkyl; 
(2) hydroxy (or protected hydroxy); 
(3) halo; 
(4) oxo (i.e. .dbd.O); 
(5) (R.sup.12)(R.sup.13)N--, such as amino (H.sub.2 N--); 
(6) alkoxy; 
(7) carbocyclo, such as cycloalkyl; 
(8) carboxy; 
(9) heterocyclooxy; 
(10) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl; 
##STR17## 
(12) mercapto; 
(13) nitro; 
(14) cyano; 
(15) carboalkoxy; 
(16) (R.sup.12)(R.sup.13)N--SO.sub.2 --; 
##STR18## 
(19) aryl; 
(20) alkylcarbonyloxy; 
(21) arylcarbonyloxy; 
(22) arylthio; 
(23) aryloxy; 
(24) alkylthio; or 
(25) formyl. 
The term "heterocyclooxy" denotes a heterocyclo group bonded through an 
oxygen bridge; and the term "heterocyclocarbonyl" denotes a heterocyclo 
group bonded through a carbonyl group. 
The term "hydroxyl protecting group", as used herein, denotes any group 
known as or capable of functioning as a hydroxyl protecting group, such as 
those groups so described in "Protective Groups in Organic Synthesis" by 
T. W. Greene, John Wiley and Sons, 1991, or Fieser & Fieser. Exemplary 
hydroxyl protecting groups include benzyl, trialkylsilyl, acetate and 
benzoate. 
The term "carboxy", as used herein alone or as part of another group, 
denotes the carboxylic acid group --COOH. 
The term "amino acid", as used herein alone or as part of another group, 
preferably denotes the group: 
##STR19## 
where R.sup.18 and R.sup.19 are independently: 
(1) hydrogen; 
(2) alkyl, especially lower alkyl; 
(3) alkenyl, especially lower alkenyl; 
(4) aryl; 
(5) heterocyclo; 
(6) carbocyclo, such as cycloalkyl; 
(7) R.sup.18 and R.sup.19 may be joined, together with the carbon atom to 
which they are bonded, to form a carbocyclo group, such as a 4- to 
7-membered cycloalkyl ring; or 
(8) R.sup.18 and R.sup.20 may be joined as described in the definition of 
R.sup.20 following; 
R.sup.20 is: 
(1) hydrogen; 
(2) alkyl, especially lower alkyl; 
(3) aryl; 
(4) heterocyclo; 
(5) carbocyclo, such as cycloalkyl; or 
(6) R.sup.18 and R.sup.20 may be joined, together with the atoms to which 
they are bonded, to form a heterocyclic group, such as a 4 to 7 membered, 
saturated monocyclic heterocyclic ring which may be unsubstituted or 
substituted by groups such as: 
(i) hydrogen; 
(ii) alkyl, especially lower alkyl; 
(iii) alkenyl, especially lower alkenyl; 
(iv) aryl, for example, where said aryl group is bonded through a single 
bond, or is fused to said monocyclic heterocyclic ring to form an 
unsaturated bicyclic heterocyclic ring system; 
(v) heterocyclo; 
(vi) mercapto; 
(vii) alkoxy; 
(viii) carbocyclo, such as cycloalkyl, for example, where said cycloalkyl 
group is bonded through a single bond, or is fused or spirofused to said 
monocyclic heterocyclic ring to form a saturated bicyclic heterocyclic 
ring system; 
(ix) hydroxyl (or protected hydroxyl); 
(x) aryloxy; 
(xi) alkylthio; 
(xii) arylthio; or 
(xiii) oxo. 
The amino acid moiety described above includes, for example, such moieties 
as may be found in D and L alanine, asparagine, aspartic acid, arginine, 
cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, 
leucine, lysine, methionine, phenylalanine, serine, homoserine, threonine, 
tryptophan, tyrosine, valine, hydroxyvaline, norleucine, norvaline, 
phenylglycine, cyclohexylalanine, t-butylglycine (t-leucine), 
hydroxy-t-butylglycine, amino butyric acid, ornithine, and cycloleucine, 
and preferably, when R.sup.18 and R.sup.20 are joined, together with the 
atoms to which they are bonded, proline, 4-hydroxyproline, pyroglutamic 
acid, azetidine carboxylic acid, pipecolinic acid, indoline-2-carboxylic 
acid, tetrahydro-3-isoquinoline carboxylic acid, 
##STR20## 
The term "peptide chain", as used herein, denotes two or more amino acids 
as described above bonded through a peptide linkage 
##STR21## 
The "N-terminus" of the above-described amino acid(s) denotes the 
--N(R.sup.20)-- group. 
The term "salt(s)", as employed herein, denotes acidic and/or basic salts 
formed with inorganic and/or organic acids and bases. Zwitterions 
(internal or inner salts) are included within the term "salt(s)" as used 
herein, as are quaternary ammonium salts such as alkylammonium salts. The 
nontoxic, pharmaceutically acceptable salts are preferred, although other 
salts may be useful, for example, in isolation or purification steps which 
may be employed during preparation. 
Exemplary acid addition salts include acetate, adipate, alginate, 
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, 
camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, 
dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, 
glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, 
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, 
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pectinate, 
persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, 
tartrate, thiocyanate, tosylate, and undecanoate. 
Exemplary basic salts include ammonium salts, alkali metal salts such as 
sodium, lithium, and potassium salts, alkaline earth metal salts such as 
calcium and magnesium salts, salts with organic bases such as 
dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such 
as arginine, lysine and so forth. The basic nitrogen-containing groups may 
be quaternized with agents such as lower alkyl halides (e.g. methyl, 
ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl 
sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long 
chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, 
bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl 
bromides), and others. 
The present invention contemplates all compounds containing the moiety: 
##STR22## 
particularly such compounds capable of inhibiting retroviral, preferably 
HIV, protease. 
Prodrugs and solvates of the inventive compounds are also contemplated 
herein. The term "prodrug", as employed herein, denotes a compound which, 
upon administration to a subject, undergoes chemical conversion by 
metabolic or chemical processes to yield a compound of the formula I, or a 
salt and/or solvate thereof. See H. Bundgaard, "Drugs of the Future", 16 
(5), 443-458 (1991); and H. Bundgaard (Ed), "Design of Prodrugs" 1985 
Elsevier (Amsterdam), both incorporated herein by reference. 
Solvates of the compounds of formula I are preferably hydrates. Tautomers 
of the inventive compounds are also contemplated, such as hemiketals of 
hydroxyketones, the enol form of ketones, and the like. 
The initial definition provided for a group or term herein applies to that 
group or term throughout the present specification, unless otherwise 
indicated. It is to be understood that "exemplary" groups recited herein 
are illustrative and not limiting. It is particularly advantageous to 
employ those groups preceded by the terms "especially" or "preferably". 
Throughout this specification, groups and substituents thereof may be 
chosen to provide stable moieties and compounds. 
All stereoisomers of the present compounds are contemplated within the 
scope of this invention. Individual stereoisomers of the compounds of the 
invention may, for example, be substantially free of other isomers, or may 
be admixed, for example, as racemates or with all other, or other 
selected, stereoisomers. The chiral centers of the present invention can 
have the S or R configuration as defined by the IU 1974 
Recommendations. 
A description of exemplary methods for obtaining the compounds of the 
present invention follows. The reaction conditions of these methods, such 
as temperature, amount of reagent, pressure, reaction time, atmosphere and 
solvent employed may readily be ascertained by one of ordinary skill in 
the art. 
In the following Reaction Schemes: 
Q.sup.1 and Q.sup.2 are independently: 
##STR23## 
The above Q.sup.1 and Q.sup.2 groups are preferably employed where 
indicated as they render the nitrogen atoms to which they are bonded 
non-basic. Where compounds of the invention are desired in which A.sup.a 
and/or A.sup.b are one of the above groups (1) to (7), the Q.sup.1 or 
Q.sup.2 groups of the following Reaction Schemes need not be removed. 
Where compounds of the invention are desired in which A.sup.a and/or 
A.sup.b are other than the above groups (1) to (7), Q.sup.1 or Q.sup.2, 
for example, can be: 
##STR24## 
(especially t-butoxycarbonyl (Boc) or carbobenzyloxy (Cbz)), forming amide 
and carbamate groups, respectively. These latter groups can be removed, 
and replaced with the desired A.sup.a and/or A.sup.b groups, by methods 
known in the art. With the exception of the conditions used for their 
optional removal, Q.sup.1 and Q.sup.2 groups are chosen that are stable to 
the conditions used in the following Reaction Schemes. 
Q.sup.3 is: 
(1) hydrogen; or 
(2) alkyl. 
The above Q.sup.3 groups are preferably employed where indicated as they 
render the nitrogen atom to which they are bonded basic. Exemplary Q.sup.3 
groups are hydrogen, unsubstituted lower alkyl, alkenyl-lower alkyl, and 
aryl-lower alkyl. Where compounds of the invention are desired in which 
A.sup.c is one of the above groups (1) or (2), the Q.sup.3 group employed 
in the following Reaction Schemes need not be removed. Where compounds of 
the invention are desired in which A.sup.c is other than the above groups 
(1) or (2), Q.sup.3 can, for example, be a benzyl group. The benzyl group 
may be removed and replaced by the desired A.sup.c group by methods known 
in the art. With the exception of the conditions used for their removal, 
Q.sup.3 groups are chosen that are stable to the conditions used in the 
following Reaction Schemes. 
In the following Reaction Schemes, where it is desired to remove Q.sup.1, 
Q.sup.2 and/or Q.sup.3 groups and to couple the amine groups so formed 
with another of the groups of A.sup.a, A.sup.b and/or A.sup.c, methods 
known to those of ordinary skill in the art may be employed (as 
exemplified by Methods (D), (E) and (F) of Reaction Scheme 11). For 
examples of amine protecting groups and their removal see Greene, 
"Protective Groups in Organic Synthesis," John Wiley (1991). 
##STR25## 
Intermediate materials for the preparation of compounds of the formula I 
may be prepared by Methods (A) or (B) as shown in Reaction Scheme 1 above. 
Starting compounds II may readily be prepared by one of ordinary skill in 
the art by known methods, such as those described in Greene. 
In Method (A), an N-protected amino acid II is converted to a reactive 
intermediate (not shown), such as to an acid chloride by reaction with 
thionyl chloride or oxalyl chloride, or to a mixed anhydride by reaction 
with a chloroformate of the formula Cl--C(O)--OR.sup.21 where R.sup.21 is 
an unsubstituted lower alkyl group, and then treated with diazomethane to 
give the diazoketone III. Treatment of III with HCl gives the 
.alpha.-chloroketone IV, which may be converted to the chlorohydrin V by 
reduction, and then to the epoxide VI by reaction with a base by methods 
known in the art (see Handa et al., Eur. Pat. Appl. 346,847; Rich et al., 
J. Med. Chem., 34, 1222 (1991)). For example, the .alpha.-chloroketone IV 
may be reduced with a hydride reducing agent such as lithium aluminum 
hydride, sodium borohydride, lithium and/or potassium-selectride, 
potassium borohydride, diisobutylaluminum hydride, and the like to give 
the chlorohydrin V, which can be converted to the epoxide VI by treatment 
with a base such as sodium or potassium hydroxide, sodium or potassium 
hydride, or an alkylamine base such as triethylamine. Compound III may, 
alternatively, be treated with HBr to give the .alpha.-bromoketone 
corresponding to .alpha.-chloroketone IV. The corresponding 
.alpha.-bromoketone may be prepared or employed wherever the 
.alpha.-chloroketone IV is prepared or employed in the present Reaction 
Schemes (for example, to prepare the bromohydrin corresponding to 
chlorohydrin V). 
An alternate procedure, Method (B), based upon methods known in the art 
(see Desolms et al., European Patent 356,223) may also be employed. This 
method involves reduction of the protected amino acid II to the alcohol 
VII using a reagent such as lithium aluminum hydride or borane (Brown et 
al., J. Amer. Chem. Soc., 82, 3866 (1960)) or via reduction of a mixed 
anhydride intermediate (formed as described above) with a hydride reducing 
agent such as sodium borohydride (Corey et al., J. Amer. Chem. Soc., 98, 
6417 (1976)). The alcohol VII can be oxidized to the aldehyde VIII with a 
chromium (VI) reagent (Evans et al., J. Org. Chem., 47, 3016 (1982)), or 
via a Moffatt (Albright et al., J. Org. Chem., 30, 1107 (1965)) or Swern 
(Swern et al., J. Org. Chem., 43, 2480 (1978)) procedure. The aldehyde 
VIII may be converted directly to the epoxide VI via reaction with a 
sulfonium or arsonium ylide (Corey et al., J. Amer. Chem. Soc., 87, 1353 
(1965); Still et al., J. Amer. Chem. Soc., 103, 1283 (1981)), or 
indirectly by a Wittig or Peterson (Peterson, J. Org. Chem., 33, 780 
(1968)) reaction to give the olefin IX, followed by epoxidation with a 
reagent such as meta-chloroperbenzoic acid (mCPBA), peracetic acid, or the 
like. 
In Method (B), the aldehyde VIII may also be produced from a carboxylic 
acid ester of the acid II (not shown) by reduction with diisobutylaluminum 
hydride (Ito et al., Chem. Pharm. Bull., 23, 3081 (1975)), or via 
reduction of the methyl hydroxamate with lithium aluminum hydride (Castro 
et al., Synthesis, 676 (1983)), and the aldehyde VIII converted to the 
epoxide VI as described above. 
##STR26## 
Reaction Scheme 2 above illustrates Methods (A) through (F), which may be 
used to prepare compounds of the formula I where A.sup.a is the same as 
A.sup.b and D.sup.a is the same as D.sup.b ("symmetrical" compounds). 
Method (A) begins by treating two equivalents of the epoxide VI with one 
equivalent of Q.sup.3 --NH.sub.2, where Q.sup.3 is preferably hydrogen, 
unsubstituted lower alkyl, alkenyl-lower alkyl (e.g. allyl) or aryl-lower 
alkyl (e.g. benzyl), particularly benzyl as described above, and heating 
in a solvent such as methanol or dimethylformamide (Parker et al., Chem. 
Rev., 59, 737 (1959); for alternative conditions, see Posner et al., J. 
Amer. Chem. Soc., 99, 8208 (1977); Overman, J. Org. Chem., 50, 4154 
(1985); Tetrahedron Lett., 27, 2451 (1986)), giving the aminediol X. 
The terminal groups Q.sup.1 of the aminediol X may optionally be removed by 
methods known to the skilled artisan (Greene), and the resulting bis-amine 
XI coupled to an N-protected amino acid or peptide chain (prepared using 
standard solid or solution phase techniques as described in Bodanszky and 
Bodanszky, The Practice of Peptide Chemistry; pp. 89-150, Springer-Verlag, 
1984, where Q.sup.2 is described above and is compatible with the 
conditions used in the coupling reaction), using a coupling reagent such 
as dicyclohexylcarbodiimide (DCC), 
3-ethyl-3'-(dimethylamino)propylcarbodiimide (EDCI), 
bis-(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl), 
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate 
(BOP reagent), diphenylphosphoryl azide (DPPA) and the like, to give the 
aminediol XII. (For other methods see Bodanszky, Principles of Peptide 
Synchesis, pp. 9-58, Springer-Verlag (1984)). In the N-protected amino 
acid or peptide chain, v is an integer from 1 to 4. Where, in the 
bis-amine XI, Q.sup.3 is hydrogen, the central nitrogen atom to which it 
is bonded ("central amine") may optionally be protected. Here, and in the 
following Reaction Schemes where appropriate, the central amine may be 
protected by nitrogen protecting groups known in the art, for example, by 
an aryl-alkyl group such as benzyl or trityl, an alkenyl-alkyl group such 
as allyl, as well as groups forming, together with the central nitrogen 
atom, a carbamate or amide group. 
Methods (B) through (F), described following, illustrate alternate routes 
for obtaining compound X, which may optionally be further treated as 
described above in Method (A). 
In Method (B), the process may be carried out in a step-wise fashion by 
treatment of one equivalent of the epoxide VI with one equivalent or an 
excess of the primary amine or ammonia (Q.sup.3 --NH.sub.2) to give the 
amino alcohol XIII, which in turn may be coupled again to the epoxide VI 
to give X. 
In Method (C), the process may be carried out by reaction of two 
equivalents of the chloroketone IV (or the corresponding bromoketone) with 
one equivalent of the aforementioned primary amine or ammonia (Q.sup.3 
--NH.sub.2, where Q.sup.3 is preferably benzyl), to form the diketoamine 
XIV, which may be reduced to the aminediol X with a hydride reducing agent 
such as lithium aluminum hydride, sodium or potassium borohydride, lithium 
or potassium selectride (i.e., lithium or potassium 
tri-sec-butylborohydride), diisobutylaluminum hydride, and the like. 
In Method (D), a step-wise procedure can be carried out by coupling the 
aforementioned amino alcohol XIII with the chloroketone IV (or the 
corresponding bromoketone) (Gordon et al., J. Org. Chem., 51, 3073 (1986)) 
to give the ketohydroxyamine XV, which may be reduced by methods described 
above. 
In Method (E), the epoxide VI may be opened with azide anion, such as by 
treatment with sodium azide, to give the azidoalcohol XVI (Ingham et al., 
J. Org. Chem., 21, 373 (1956); Rosenberg et al., J. Med. Chem., 32, 1371 
(1989); Saito et al., Tetrahedron Lett., 30, 4153 (1989)). The azido 
moiety may be reduced to the amine by, for example, hydrogenation over 
Pd/C or by treatment with triphenylphosphine (Vaultier et al., Tetrahedron 
Lett., 24, 763 (1983)). The resulting aminoalcohol XVII can be coupled to 
the epoxide VI, or to the chloroketone IV (or the corresponding 
bromoketone) followed by reduction, as described above to give the 
aminodiol XVIII. The central amine may optionally be protected as 
described above, and the Q.sup.1 groups optionally removed and the 
resulting amines coupled to amino acids or peptide chains, also as 
described above. 
In Method (F), the aminoaldehyde VIII can be reacted with a vinyl 
organometallic reagent of the formula CH.sub.2 .dbd.CH(M), where M is a 
metal-containing moiety, such as vinyl lithium, vinyl magnesium bromide 
and the like to give the allylic alcohol XIX. The olefin moiety may be 
oxidatively cleaved to the aldehyde by ozonolysis, or the compound XIX 
converted to the corresponding diol (not shown) with osmium tetraoxide or 
potassium permanganate, followed by cleavage of the diol with sodium 
periodate (Lemieux et al., J. Org. Chem., 21, 478 (1956)) to form the 
aldehyde. The aldehyde XX can then be reacted with the aminoalcohol XIII 
under reductive amination conditions (for example, hydrogenation over Pd/C 
or reaction with sodium cyanoborohydride where Q.sup.3 is hydrogen or 
benzyl; see Hudlicky, Reductions in Organic Chemistry, pp. 134-136, John 
Wiley, 1984) to give compound X. 
##STR27## 
Reaction Scheme 3 above illustrates Methods (A) through (C), which may be 
used to prepare compounds of the formula I where A.sup.a differs from 
A.sup.b and/or D.sup.a differs from D.sup.b ("asymmetrical" compounds) by 
procedures analogous to those of Reaction Scheme 2. In Reaction Scheme 3, 
and hereinafter, the symbols "a" or "b" added to a moiety (e.g. R.sup.9a) 
denote those groups ultimately forming a part of the moiety A.sup.a 
-D.sup.a - or A.sup.b -D.sup.b -, respectively, in the compounds of 
formula I, or, in the case of Q.sup.1a or Q.sup.2a and Q.sup.1b or 
Q.sup.2b, denote those groups on the corresponding side of the molecule. 
Moieties to which the symbols "a" or "b" are added are otherwise defined 
as above (e.g., R.sup.9a is defined as for R.sup.9), although said 
moieties may be defined independently of each other (e.g., R.sup.9a may be 
defined independently of R.sup.9b). 
Method (A) of Reaction Scheme 3 begins by coupling the aminoalcohol XIII to 
the epoxide XXI (see Method (A) of Reaction Scheme 1 for preparation of 
epoxide XXI), or to the chloroketone XXII (see Method (A) of Reaction 
Scheme 1 for preparation of chloroketone XXII; the corresponding 
bromoketone may also be prepared and employed as described therein) 
followed by reduction, to give the asymmetric aminediol XXIII. Optionally, 
the groups Q.sup.1a and Q.sup.1b may be sequentially removed and the 
resulting amines coupled to N-protected amino acids or peptide chains to 
give the compound XXV. Where Q.sup.3 is hydrogen, the central amine to 
which it is bonded may optionally be protected as described above. 
Such compounds as are prepared above may also be prepared by employing 
Methods (B) or (C) of Reaction Scheme 3 using procedures analogous to 
those of Reaction Scheme 2. In particular, Method (B) of Reaction Scheme 3 
may be carried out by procedures analogous to those of Method (E) of 
Reaction Scheme 2; Method (C) of Reaction Scheme 3 may be carried out by 
procedures analogous to those of Method (F) of Reaction Scheme 2. The 
asymmetrical diols XXVI and XXIII may optionally be deprotected and 
coupled as described above. Where Q.sup.3 is hydrogen, the central amine 
group no which it is bonded may, in each case, be optionally protected as 
described above. 
##STR28## 
Reaction Scheme 4 above illustrates Methods (A) to (D) which may be used to 
prepare compounds of the formula I where R.sup.1 and/or R.sup.2 are not 
hydrogen. 
As shown above in Method (A), selective removal of the protecting group 
(Pro) of compound XXVIII (which compound may be prepared by methods 
analogous to those employed in the preparation of compound XIII described 
above) is conducted, where (Pro) is independently chosen from those groups 
defined for Q.sup.1, followed by coupling of the resulting amine XXIX with 
epoxide VI, or chloroketone IV (or corresponding bromoketone) followed by 
reduction, giving the aminediol XXX. Optionally, where A.sup.c is 
hydrogen, the central amine group to which it is bonded may be protected 
as described above, and the Q.sup.1a and/or Q.sup.1b N-terminal groups may 
then be sequentially or simultaneously removed and the resulting amines 
coupled to N-protected amino acids or peptide chains by methods described 
above. 
Alternatively, as shown in Method (B), the aldehyde XXXIII (see Method (B) 
of Reaction Scheme 1 for preparation) may be converted to the olefin XXXIV 
by Wittig or Peterson methodology, and the olefin XXXIV in turn epoxidized 
by methods analogous to those described above (see Reaction Scheme 1, 
Method (B)) to yield compound XXXV. The epoxide XXXV may be coupled with 
the amine XXIX to give the aminediol XXXVI, which optionally may be 
protected at the central amine when A.sup.c is hydrogen as described 
above, and the Q.sup.1a and/or Q.sup.1b N-terminal groups may be 
sequentially or simultaneously deprotected and coupled to N-protected 
amino acids or peptide chains to give aminediol XXXVIII. 
The aminediol XXXVIII may also be prepared as shown in Method (C) by 
reaction of the aldehyde XXXIII with the vinyl organometallic reagent 
XXXIX, where M is a metal-containing moiety such as magnesium bromide, 
lithium, CeCl.sub.2, and the like, to give the allylic alcohol XL. The 
double bond may then be oxidatively cleaved by methods described above to 
give the ketone XLI, which can then undergo reductive amination in the 
presence of the amine XXIX, by methods also described above, to give 
compound XXXVI. The compound XXXVI may be converted to the aminediol 
XXXVIII by the methods described above in Method (B). The reagent XXXIX 
employed above in Method (C) may be prepared from the corresponding 
acetylene XLII via the vinyl bromide XLIII (Poller et al., Syn. Commun., 
10, 805 (1980); Suzuki et al., Tetrahedron Lett., 24, 731 (1983)). 
Alternatively, as shown in Method (D), the ketone XLI may undergo reductive 
amination by methods described above, in the presence of ammonia, to give 
the aminoalcohol XLIV, which in turn can undergo reductive amination in 
the presence of the ketone XLV (see Method (C) for a method for 
preparation thereof) to give the aminediol XLVI. The aminediol XLVI may 
then be optionally protected, and sequentially deprotected and coupled to 
N-protected amino acids or peptide chains as described above in Method (B) 
to give compound XLVII. 
##STR29## 
Reaction Scheme 5 above illustrates Methods (A) to (D), which may be used 
to prepare compounds of the formula I where R.sup.10 is not hydrogen. 
In Method (A), the protected amino acid II can be converted to the ketone 
XLVIII by methods known in the art (see, e.g., Gordon et al., Tetrahedron 
Lett., 28, 1603 (1987)). For example, conversion of amino acid II to an 
intermediate pyridyl ester or methyl hydroxamate (Weinreb et al., 
Tetrahedron Lett., 22, 3815 (1981)) (not shown), followed by reaction with 
an organolithium or organomagnesium reagent provides ketone XLVIII. The 
ketone obtained may then be converted to the olefin XLIX via a Wittig or 
Peterson reaction, which can be followed by epoxidation using methods as 
described above. The epoxide L so formed may be coupled with the 
aminoalcohol XXVII to give the aminediol LI. Optionally, the Q.sup.1 
groups may then be sequentially or simultaneously deprotected and coupled 
to N-protected amino acids or peptide chains using methods as described 
above to give compound LII. 
Alternatively, as shown in Method (B), the olefin XLIX may be converted 
directly to the cis diol LIII using osmium tetraoxide or potassium 
permanganate (Kochi et al., Metal Catalyzed Oxidations of Organic 
Compounds, pp. 162-171, 294-296, Academic Press (1981)), and the diol LIII 
in turn oxidized to the aldehyde LIV by methods described above. The 
aldehyde LIV may then undergo reductive amination in the presence of the 
aminoalcohol XXVII to give the aminediol LI, and the latter compound 
converted to the aminediol LII, by methods described above. 
Another route is shown in Method (C). In Method (C), the epoxide L may be 
coupled to a primary amine or ammonia Q.sup.3 -NH.sub.2 by methods 
described above to give the aminoalcohol LV, which can be coupled to the 
epoxide LVI (see Method (A) for preparation thereof), to give the 
aminediol LVII. As described above, the Q.sup.1 protecting groups may 
optionally be sequentially or simultaneously removed and the resulting 
amino groups coupled to N-protected amino acids or peptide chains to give 
compound LVIII. 
Alternatively, as shown in Method (D), the aminoalcohol LV may undergo 
reductive amination in the presence of the aldehyde LIX (see Method (B) 
for preparation) by methods described above to give compound LVII, and the 
latter converted to compound LVIII by methods also described above, for 
example, in Method (C). 
##STR30## 
Reaction Scheme 6 above illustrates Methods (A), (B) and (C) which may be 
used to prepare compounds of the formula I where R.sup.8 is not hydrogen. 
In Method (A), the aminoalcohol XVII can be protected as shown yielding 
compound LX (Bergmann, Chem. Rev., 53, 309 (1953)) and the non-basic 
nitrogen alkylated (Benoiton et al., Can. J. Chem., 49, 1968 (1971)) by 
treatment with a base such as sodium or potassium hydride, sodium or 
potassium hexamethyldisilazide, or the like, followed by, for example, an 
alkylating agent such as an alkyl iodide, bromide, chloride, rosylate, 
triflate, or the like. Q.sup.1a is an activating group which renders the 
hydrogen on the nitrogen atom to which it is bonded acidic and easily 
removed with a base as described above, such as a group forming, together 
with --N(R.sup.8a), a carbamate or amide group. The aminoalcohol LXI 
formed can then be deprotected to form compound LXII, and the latter 
coupled to an epoxide XXI, or to a chloroketone XXII (the corresponding 
bromoketone may be employed as described above) followed by reduction, by 
methods described above to give an aminediol LXIII, which optionally may 
be protected at the central amine and the Q.sup.1 groups sequentially or 
simultaneously deprotected and coupled to N-protected amino acids or 
peptide chains to give LXIV. 
Alternatively, as shown in Method (B), an aminediol such as XXIIIa (which 
may be prepared from aminediol XXIII by methods known to one of ordinary 
skill in the art) may be monodeprotected at Q.sup.1a or Q.sup.1b and the 
resulting amine reacted under reductive amination conditions in the 
presence of a compound of the formula R.sup.22a --CHO where R.sup.22a is 
hydrogen or alkyl, by methods described above to give LXV. Q.sup.4 is 
defined to include alkyl and those groups included in the definition of 
Q.sup.1. The resulting amine may be optionally coupled by methods 
described above to give compound LXVI. A similar process may optionally be 
carried out at the other end of the molecule to produce an aminediol such 
as LXVII. 
In Method (C), compounds where R.sup.8 is a methyl group may be prepared by 
deprotecting an aminediol XXIIIa, where Q.sup.4 is not formyl; formylating 
the deprotected amine; and reducing the resulting formamide to the 
methylated amine using borane-dimethyl sulfide complex (Krishnamurthy, 
Tetrahedron Lett., 22, 3315 (1982)). The methylated amine LXV (R.sup.22a 
.dbd.H) may optionally be coupled to an N-protected amino acid or peptide 
chain to give the compound LXVI (R.sup.22a =H), and the compound LXVI 
converted to compound LXVII (R.sup.22 =H) as described above. 
##STR31## 
Reaction Scheme 7 above illustrates Methods (A) to (E), which may be used 
to prepare compounds of the formula I where p and/or q are not zero. 
In Method (A), the protected amino ester LXVIII (R.sup.23 may be 
unsubstituted lower alkyl, aryl or aryl-lower alkyl) where p.sub.a =1-4 
and q=0 can be alkylated via its enolate anion (formed by treatment of the 
ester with a base such as lithium diisopropylamide, lithium 
bis(trimethylsilyl)amide or the like) with R.sup.9a - X, where X is 
halogen, rosylate, mesylate or the like to give the ester LXIX. The ester 
may be reduced directly to the aldehyde LXX with diisobutylaluminum 
hydride or in two steps by conversion to the primary alcohol with a 
hydride reducing agent and then oxidation to the aldehyde as described 
above. The aldehyde can be converted directly to the epoxide LXXI via 
reaction with a sulfonium or arsonium ylide or by a Wittig or Peterson 
reaction to give the corresponding olefin (not shown), followed by 
epoxidation as described above. The epoxide may be coupled to the amino 
alcohol XXVII to give the aminediol LXXII, which optionally may then be 
sequentially or simultaneously deprotected and coupled to N-protected 
amino acids or peptide chains as described above to give the compound 
LXXIII. The starting ester LXVIII of Method (A) may be obtained by methods 
known to those skilled in the art such as those methods described in J. 
March, "Advanced Organic Chemistry", John Wiley (1985) (see pages 
1157-1158). 
Method (B) illustrates a method for obtaining compounds where both p.sub.a 
and p.sub.b &gt;zero. In this method, the epoxide LXXI is reacted with 
ammonia or a primary amine Q.sup.3 --NH.sub.2 to give the compound LXXIV, 
followed by coupling with the epoxide LXXV (which may be prepared by a 
method analogous to that for preparing the epoxide LXXI above) to give 
compound LXXVI. The compound LXXVI may optionally then be sequentially or 
simultaneously deprotected and coupled to N-protected amino acids or 
peptide chains as described above. 
Method (C) illustrates a method for obtaining compounds where q.sub.a =2-4 
and p=zero. In Method (C), Wittig reaction of the hydroxyphosphorane 
LXXVII with the protected amino aldehyde XXXIII gives the olefin LXXVIII 
which can be reduced to the saturated alcohol LXXIX under catalytic 
hydrogenation conditions. Oxidation of the alcohol LXXIX to the aldehyde 
LXXX may be followed by conversion to the epoxide LXXXI, the latter 
achieved by a Wittig reaction followed by treatment with 
m-chloroperoxybenzoic acid (mCPBA). The epoxide LXXXI is then coupled with 
the amino alcohol XXVII to give the aminediol LXXXII as described above. 
The aminediol may then optionally and sequentially be deprotected and 
coupled to N-protected amino acids or peptide chains to give compound 
LXXXIII. The hydroxyphosphorane starting material LXXVII may be prepared 
by reaction of the appropriate haloalcohol with triphenylphosphine under 
standard conditions. 
Method (D) illustrates a method where compounds in which q.sub.a and 
q.sub.b are both &gt;1 and p=0 may be prepared by reaction of the epoxide 
LXXXI with ammonia or a primary amine Q.sup.3 --NH.sub.2 to give compound 
LXXXIV. The latter compound may then be coupled with the epoxide LXXXV 
(prepared, e.g., by the method employed above for preparation of the 
epoxide LXXXI) to yield the aminediol LXXXVI. The aminediol LXXXVI may 
optionally then be sequentially or simultaneously deprotected and coupled 
to N-protected amino acids or peptide chains as described above. 
Method (E) illustrates a method for preparing intermediate compounds which 
may be employed in preparing aminediols where q=1 and p=0. In Method (E), 
the intermediate aldehyde LXXXVIII may be prepared by an Arndt-Eistert 
reaction (Meier and Zeller, Angew. Chem. Int. Ed. Engl., 14, 32 (1975)) on 
the diazoketone III to give the carboxylic acid LXXXVII. Conversion of the 
carboxylic acid to the aldehyde may be conducted by reduction and 
oxidation as described above. The aldehyde may then be converted to the 
desired aminediol as described in Methods (C) and (D). 
##STR32## 
Reaction Scheme 8 illustrates a method for the preparation of compounds of 
the formula I where R.sup.9' is not hydrogen. 
An N-protected amino acid II may be converted into an acetal LXXXIX where 
R.sup.24 and R.sup.25 are independently hydrogen or unsubstituted lower 
alkyl as shown. Treatment of the acetal LXXXIX with a base such as lithium 
diisopropyl amide, followed by reaction with a compound R.sup.9' -Y where 
Y may be Cl, Br, I or triflate, and hydrolysis of the acetal gives the 
.alpha.-substituted amino acid XC. The amino acid XC may be converted to 
amine diols of the formula I by those methods described in Schemes 1 to 7 
above. Unnatural, optically active .alpha.-amino acids can be prepared by 
methods such as those described in Evans et al., J. Am. Chem. Soc., 112, 
4011 (1990); and Oppolzer et al., Tetrahedron Lett., 30, 5603, 6009 
(1989). Alternative methods are also described in Williams, R. M., 
Synthesis of Optically Active .alpha.-Amino Acids, Pergamon Press: Oxford 
(1989). 
##STR33## 
Intermediate materials for the preparation of compounds of the formula I 
may alternatively be prepared by Methods (A) to (F) as shown in Reaction 
Scheme 9 above. 
In this regard, the present invention provides a novel method for the 
preparation of a halohydrin of the following formula: 
##STR34## 
where Q.sup.1, E, R.sup.2, R.sup.8, R.sup.9, R.sup.9' and R.sup.10 are as 
defined above, particularly where R.sup.9 is not the same as R.sup.9' 
(most preferably, where one of R.sup.9 or R.sup.9' is hydrogen), and 
X.sub.hal is chloro or bromo, comprising the step of contacting an olefin 
of the following formula: 
##STR35## 
with the compound HOX.sub.hal. 
The compound HOX.sub.hal may be formed in situ for use in the method of the 
present invention, such as by contacting N-chlorosuccinimide, 
N-bromosuccinimide, Br.sub.2 or Cl.sub.2 with water. Preferred molar 
ratios of the compound HOX.sub.hal to the olefin starting material are 
from about 1:1 to about 3:1. 
In a preferred embodiment, the novel method of the present invention 
comprises the optional further step of preparing an epoxide of the 
following formula: 
##STR36## 
by contacting the above halohydrin with a base. 
The base employed may be any basic compound providing conversion of the 
halohydrin to the epoxide, such as alkali metal (e.g., sodium or 
potassium) hydroxides, alkali metal (e.g., sodium or potassium) hydrides, 
alkali metal (e.g., sodium or potassium) carbonates, or amine bases (e.g., 
trialkylamines). Preferred molar ratios of the base to the halohydrin are 
from about 1:1 to about 5:1. 
The temperature employed during the above steps for halohydrin and, 
optionally, epoxide formation is preferably from about -78.degree. C. to 
about 50.degree. C. The steps are preferably conducted in an organic 
solvent such as dioxane or tetrahydrofuran. An alcohol (for example, 
methanol) is preferably employed during epoxide formation, such as by 
addition to the aforementioned organic solvent when a single pot is 
employed, particularly where the base is other than an amine base. Times 
employed are those sufficient for halohydrin and, optionally, epoxide 
formation. 
The above novel method of the present invention preferentially (that is, in 
a greater than 1:1 molar ratio) provides halohydrins of the following 
relative stereoconfiguation: 
##STR37## 
relative to the corresponding stereoisomers thereof: 
##STR38## 
Thus, the above method of the present invention comprising the preferred 
further step of epoxide formation is particularly advantageous where 
epoxides having the following relative stereoconfiguration are sought: 
##STR39## 
as such compounds are formed preferentially (that is, in a greater that 
1:1 molar ratio) relative to the corresponding stereoisomers thereof: 
##STR40## 
The starting olefins may be prepared by methods such as those described by 
Luly et al., J. Org. Chem., 52, 1487-1482 (1987). 
Method (A) illustrates the novel method of the present invention. In Method 
(A), olefin IX is converted to the halohydrin (not shown) by treatment 
with aqueous bromine or N-bromo-succinimide or N-chlorosuccinimide, and 
then treated with base, such as potassium carbonate or potassium or sodium 
hydroxide or the like to give epoxide VI. 
As shown in Method (B), olefin IX may be converted to the diol XCI by 
treatment with osmium tetroxide or potassium permanganate, or other 
methods known in the art (Kochi, et al., Metal Catalyzed Oxidations of 
Organic Compounds, pp. 162-171, 294-296, Academic Press (1981); Jacobsen, 
et al., J. Am. Chem. Soc., 110, 1968 (1988); Sharpless, et al., J. Org. 
Chem., 57, 2768 (1992)). Diol XCI may be treated with a sulfonyl chloride 
(e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride; Ar denotes 
aryl) to give the sulfonate XCII; or, alternatively, the primary hydroxyl 
group of XCI may be selectively protected (see Greene, Protective Groups 
in Organic Synthesis), and the secondary hydroxyl group sulfonylated, 
followed by deprotection of the primary hydroxyl group, to give XCIII. The 
sulfonate esters XCII or XCIII may be independently converted to the 
epoxide VI by treatment with base, such as sodium or potassium hydroxide, 
or an alkylamine base such as triethylamine; the latter reaction from 
XCIII occurs with inversion of the configuration of the secondary hydroxyl 
group. 
In Method (C) (see Thompson, et. al., J. Am. Chem. Soc., 115, 801 (1993) 
and Bennett, et. al., JCS Chem. Commun., 737 (1993)), the olefin XCIV may 
be converted to the epoxide XCV by asymmetric epoxidation (Gao, et al., J. 
Am. Chem. Soc., 109, 5765 (1987)). Starting olefin XCIV may readily be 
prepared by one of ordinary skill in the art by known methods (e.g., 
Witrig reaction, March, Advanced Organic Reactions, pp 839-841 and pp 
845-854 (Third Edition)). Epoxide XCV can be converted to the azidodiol 
XCVI by treatment with azide anion, such as treatment with sodium azide 
and titanium bisisopropoxide (Caron, et al., J. Org. Chem., 53, 5185 
(1988); Omaka, et al., Chem. Lett., 1327 (1986)). The azidodiol can be 
reduced by methods described above in Reaction Scheme 2, Method (E) to 
give the aminodiol XCVII. Protection of the amine by methods known in the 
art, such as those described in Greene, Protective Groups in Organic 
Synthesis, may provide Compound XCI. 
Alternatively, as described in Method (D), azidodiol XCVI may be converted 
to the mixture of haloacetates XCVIII and XCIX by treatment with 
2-acetoxyisobutyryl halide, or treatment with trimethyl orthoacetate and 
PPTs followed by acetyl halide (e.g., acetyl bromide) or trimethylsilyl 
halide (e.g., trimethylsilyl chloride) (Russel, et al., J. Am. Chem. Soc., 
95, 4025 (1973); Thompson, et al., ibid, 115, 801 (1993); Kolb, et al, 
Tetrahedron, 48, 10515 (1992)). The haloacetates XCVIII and XCIX may be 
treated with base such as sodium methoxide or sodium or potassium 
carbonate, to give the azidoepoxide C. Reduction of the azidoepoxide C to 
the aminoepoxide CI followed by protection of the amine by methods known 
in the art provides epoxide VI. 
Alternatively, as shown in Method (E), the azidodiol XCVI may be converted 
to the epoxide C by methods analogous to those described above (Reaction 
Scheme 9, Method (B)). 
In Method (F), diol XCI may be converted to the cyclic sulfate CXXIV by 
treatment, first with thionyl chloride to give the cyclic sulfite 
(structure not shown), and then oxidation with potassium permanganate or 
ruthenium trichloride/sodium periodate, and the like (Lohray, Synthesis, 
1035 (1992); Gao, et al., J. Am. Chem. Soc., 110, 7538 (1988)). Compound 
CXXIV, or the intermediate sulfite, may be converted to aminediols by 
methods described above for the conversion of epoxides VI and/or XXI. 
##STR41## 
Reaction Scheme 10 above illustrates Methods (A) through (C), which may be 
used to prepare compounds of the formula I where A.sup.a is the same as 
A.sup.b and D.sup.a is the same as D.sup.b ("symmetrical" compounds. 
In Method (A), one equivalent of the bis-amine CXXIV (prepared as for XI 
where A.sup.c replaces Q.sup.3) is coupled to a carboxylic acid (prepared 
by standard techniques, where R.sup.3 is described above and is compatible 
with the conditions used in the coupling reaction), using a coupling 
reagent such as DCC, EDCI, BOP reagent, BOP-C1, DPPA, and the like, as 
described earlier (for alternative coupling conditions see Bodanszky, 
"Principles of Peptide Synthesis"; pp. 9-58, Springer-Verlag, (1984)) to 
give the aminediol CII. Where, in the bis-amine CXXIV, A.sup.c is 
hydrogen, the central amine to which it is bonded may optionally be 
protected as described above. 
In Method (B), the process may be carried out in a step-wise fashion. The 
groups Q.sup.1a and Q.sup.1b in CXXV (prepared as for XXIII where A.sup.c 
replaces Q.sup.3) may be sequentially removed and the resulting amines 
coupled to a carboxylic acid to give the compound CII. Where A.sup.c is 
hydrogen, the central amine to which it is bonded may optionally be 
protected as described above. 
Method (C) begins with removal of the group Q.sup.1a and coupling of the 
resulting amine with a carboxylic acid to give the azidoalcohol CIII. The 
azido moiety may be reduced and the resulting aminoalcohol CIV can be 
coupled to the epoxide XXI or the haloketone XXII, followed by reduction, 
to give the aminediol CV (see Reaction Scheme 3). The central amine may 
optionally be protected with A.sup.c. Removal of the group Q.sup.1b and 
coupling with a carboxylic acid as described above gives CII. 
##STR42## 
Reaction Scheme 11 above illustrates Methods (A) through (F) which may be 
used to prepare compounds of the formula I where A.sup.a differs from 
A.sup.b and/or D.sup.a differs from D.sup.b ("non-symmetrical" compounds). 
According to Methods (A) and (B), non-symmetrical compounds may be prepared 
by procedures analogous to those of Scheme 10. In Method (A), the groups 
Q.sup.1a and Q.sup.1b may be sequentially removed and the resulting amines 
coupled to carboxylic acids to give Compound CVI. Where A.sup.c is 
hydrogen, the central amine to which it is bonded may optionally be 
protected as described above. Such compounds may also be prepared by 
employing Method (B), starting from azidoalcohol XVI and using procedures 
analogous to those of Method (C) of Reaction Scheme 10. 
According to Method (C), non-symmetrical compounds may be prepared by 
procedures analogous to those of Reaction Schemes 2, 3 and 10. The method 
begins by removing the group Q.sup.1a and coupling the resulting amine to 
N-protected amino acids or peptide chains to give the compound CIX. The 
azido moiety may be reduced and the resulting aminoalcohol CX can be 
coupled to the epoxide XXI, or to the haloketone XXII followed by 
reduction, as described in Methods (C) through (E) of Reaction Scheme 2, 
to give the aminodiol CXI. Optionally, the central amine may be protected 
and the Q.sup.1b group may be removed and the resulting amine coupled to a 
suitable carboxylic acid by procedures analogous to those of Method (A) of 
Reaction Scheme 10 to give the aminodiol CXII. 
Method (D) starts from compound CXIII (prepared as for XXIV where A.sup.c 
replaces Q3) where w=0-4. The hydroxyl groups may optionally be protected 
such as with an ethoxyethyl group as described in Greene, Protective 
Groups in Organic Synthesis (P.sub.hyd denotes a hydroxyl protecting 
group). The Q.sup.2b group may then be removed and the resulting amine 
CXIV coupled with a chloroformate to afford, after removal of the hydroxyl 
protecting groups, the carbamate CXV. Where A.sup.c is hydrogen, the 
central amine to which it is bonded may be protected as described above. 
In Method (E), the amine CXIV may be coupled with an isocyanate compound or 
a carbamoyl chloride to provide, after removal of the hydroxyl protecting 
groups, the urea CXVI. Where A.sup.c is hydrogen, the central amine to 
which it is bonded may be protected as described above. 
In Method (F), the amine CXIV may be coupled with a carboxylic acid, using 
methods described in Scheme 10, to give, after removal of the hydroxyl 
protecting groups, the amide CXVII. Where A.sup.c is hydrogen, the central 
amine to which it is bonded may optionally be protected as described 
above. 
##STR43## 
Reaction Scheme 12 above illustrates Methods (A) and (B) which may be used 
to prepare compounds of the formula I where R.sup.9 is a substituted 
(hydroxyphenyl)methyl group. 
Compound CXVIII in which the nitrogens bear P.sup.1a or P.sup.1b (P.sup.1 
denotes a nitrogen protecting group) and in which the hydroxyl groups are 
protected (P2 denotes a hydroxyl protecting group) of Method (A) may be 
prepared by methods described in Greene, Protective Groups in Organic 
Synthesis. In particular, the aforementioned nitrogen and hydroxyl oxygen 
may be connected by a one carbon linker to form an oxazolidine ring. The 
phenol may then be reacted with a suitable alcohol CXIX (where R.sup.26 is 
a lower alkyl group) in the presence of a phosphine (e.g., 
triphenylphosphine) and a reagent, such as diethyl- or 
diisopropylazodicarboxylate to give, after deprotection, the substituted 
phenol CXXI (Mitsunobu, Synthesis, 1 (1981); Varasi, et al., J. Org. 
Chem., 52, 4235 (1987)). Alternatively, phenol CXVIII may be treated with 
a base, such as potassium carbonate, sodium or potassium hydride, sodium 
or potassium bis(trimethylsilyl)amide, or the like, and a suitable 
activated alkyl compound CXX where X can be a halogen, such as bromo, 
chloro, or iodo, or a sulfonate ester such as trifluoromethyl sulfonate 
(i.e. --O--SO.sub.2 --CF.sub.3) to give CXXI. Compound CXX can be prepared 
by methods known to those skilled in the art. 
The aminediol CXXI may also be prepared as shown in Method (B). Procedures 
analogous to those of Method (A) above may be used to convert phenol CXXII 
(see Reaction Scheme 1 and Methods (A) and (B) of Reaction Scheme 9 for 
preparation) to epoxide CXXIII. Compound CXXIII may be converted to 
aminediol CXXI by procedures analogous to those of Methods (A), (B) and 
(E) of Reaction Scheme 2 and Methods (A) and (B) of Reaction Scheme 3. 
Compounds of the formula I where R.sup.11 is not hydrogen may be obtained, 
for example, by methods known in the art for adding a hydroxyl protecting 
group, such as those described in Greene (referred to above). 
Modifications to the processes of the above Reaction Schemes 1 to 12 may be 
made by one of ordinary skill in the art to obtain any of the compounds of 
the present invention. For example, protection and deprotection of groups 
may be suitably employed during such preparation. 
PREFERRED COMPOUNDS 
Preferred compounds of the formula I are those compounds containing the 
preferred groups described following. 
A.sup.a and A.sup.b are preferably, independently, 
(A) hydrogen; 
(B) alkyl such as unsubstituted lower alkyl or hydroxyalkyl; 
(C) the group: 
##STR44## 
where Z is sulfur or, most preferably, oxygen; R.sup.3 is preferably alkyl 
such as unsubstituted lower alkyl (e.g., methyl or tert-butyl), arylalkyl 
(e.g., benzyl), or heterocycloalkyl (e.g., pyridylmethyl or 
benzimidazolylmethyl); and 
R.sup.4 is preferably alkyl such as unsubstituted lower alkyl (e.g., 
methyl) or, most preferably, R.sup.4 is hydrogen; 
(D) the group: 
##STR45## 
where R.sup.5 is preferably hydrogen; carbocyclo (e.g., indenyl); alkyl 
such as unsubstituted lower alkyl (e.g., methyl, ethyl or tert-butyl) or 
alkyl which is substituted by one or more of amino, substituted amino 
(e.g., amino substituted by formyl, phenyl, benzyl or benzyloxycarbonyl), 
halo (e.g., fluoro), aryl (e.g., phenyl), hydroxy (e.g., mono or 
dihydroxy) or protected hydroxy, heterocyclo (e.g., dihydroindazolyl 
(optionally substituted by oxo and/or benzyl)), alkoxy (such as 
unsubstituted lower alkoxy (e.g., methoxy) or arylalkoxy (e.g., 
benzyloxy)), aryloxy (e.g., phenoxy), or arylaminocarbonyl (e.g., 
phenylaminocarbonyl); aryl (e.g., phenyl or biphenyl); heterocyclo (e.g., 
imidazolyl (optionally substituted by trityl and/or phenyl), oxazolyl 
(optionally substituted by phenyl), 2- furo[2,3-c]pyridinyl, 2-furo 
[3,2-b]pyridinyl, 2-furo[2,3-b]pyridinyl, quinoxalinyl, benzothiazolyl, 
quinolinyl, benzimidazolyl (optionally substituted by benzyloxymethyl), 
pyridyl, indolyl, oxazolidinyl (optionally substituted by oxo), 
dihydroisoindolyl (optionally substituted by oxo), 1,3-dioxolane 
(optionally substituted by methyl groups), dihydroquinazolinyl (optionally 
substituted by oxo), or benzoxazolyl); or alkynyl (e.g., phenylalkynyl); 
R.sup.5 is most preferably hydrogen, alkyl (unsubstituted or substituted, 
in the latter case preferably hydroxyalkyl), aryl or heterocyclo; 
R.sup.6 and R.sup.7 are preferably hydrogen, or alkyl such as unsubstituted 
lower alkyl (e.g., methyl) or hydroxyalkyl; or 
two of R.sup.5, R.sup.6 and R.sup.7, together with the carbon atom to which 
they are bonded, form a carbocyclo group (e.g., cyclobutyl or cyclopentyl 
(optionally substituted by hydroxy), or indanyl (optionally further 
substituted by hydroxy or protected hydroxy)), or a heterocyclo group 
(e.g., oxetanyl, tetrahydrofuryl (optionally substituted by hydroxy), 
tetrahydro-1,1-dioxothienyl, tetrahydropyranyl, or benzimidazolyl 
(optionally substituted by methyl)); 
(E) the group: 
##STR46## 
where z is sulfur or, most preferably, oxygen; 
R.sup.3 is preferably hydrogen; aryl (e.g., phenyl or naphthyl); alkyl 
which is unsubstituted (e.g., ethyl or tert-butyl) or substituted by one 
or more of oxo, hydroxy (e.g., mono- or dihydroxy) or protected hydroxy, 
aryloxy (e.g., phenoxy or naphthyloxy), alkoxy (e.g., methoxy, benzyloxy, 
or benzimidazolylpropoxy), aryl (e.g., phenyl ), heterocyclo (e.g., 
benzimidazolyl, 1,3-dioxolane (optionally substituted by methyl groups) , 
indolyl, pyridyl, or dihydroindazolyl (optionally substituted by oxo)), 
oxime, alkoxyimino (e.g., methoxyimino), amino or substituted amino (e.g., 
benzyloxycarbonylamino), alkylaminocarbonyl (e.g., N-methylaminocarbonyl), 
arylaminocarbonyl (e.g., phenylaminocarbonyl), alkylaminocarbonyloxy 
(e.g., N-methylaminocarbonyloxy), or fluoro (e.g., to form 
trifluoromethyl); carbocyclo (e.g., cyclopentyl or cyclohexyl (optionally 
substituted by methyl and/or hydroxy groups), or indanyl (optionally 
further substituted by hydroxy); or heterocyclo (e.g., quinolinyl, 
pyrrolidinyl (optionally substituted by methyl and/or oxo groups), 
oxazolidinyl (optionally substituted by methyl and/or oxo groups), 
dihydroisoindolyl (optionally substituted by formyl), tetrahydrofuryl 
(optionally substituted by hydroxy and/or methyl groups), or 
benzimidazolyl); R.sup.3 is most preferably carbocyclo or alkyl wherein 
the carbocyclo or alkyl groups are substituted, particularly by one or 
more of hydroxy, aryl, heterocyclo, alkylaminocarbonyl or fluoro 
(especially to form trifluoromethyl); or 
(F) the groups: 
R.sup.3 --SO.sub.2 --or 
R.sup.3 --SO-- 
where R.sup.3 is alkyl, especially unsubstituted lower alkyl. 
The above groups (C), (D) and (E) are most preferred as A.sup.a or A.sup.b 
substituents. 
A.sup.c is most preferably hydrogen. Where A.sup.c is other than hydrogen, 
preferred A.sup.c groups are alkyl--O--C(O)--, such as 
trialkylsilylalkyl--O--C(O)-- (e.g., trimethylsilylethoxycarbonyl), 
fluorenylalkyl--O-C(O)-- (e.g., fluorenylmethoxycarbonyl) or 
arylalkyl--O--C(O)-- (e.g., benzyloxycarbonyl); arylalkyl (e.g., benzyl); 
or unsubstituted lower alkyl (e.g., methyl). 
E is preferably a single bond or a peptide chain containing 1 or 2 amino 
acids. Preferred amino acids are those wherein, in the formula: 
##STR47## 
R.sup.18 is hydrogen or unsubstituted lower alkyl (e.g., methyl); R.sup.19 
is hydrogen, aryl (e.g., phenyl) , or, most preferably, R.sup.19 is lower 
alkyl which is unsubstituted (e.g., methyl, isopropyl, or tert-butyl) or 
which is substituted, particularly by one or more of hydroxy (or protected 
hydroxy), amino, aminocarbonyl, fluoro (e.g., to form trifluoromethyl), 
phenyl, or hydroxyphenyl; or 
R.sup.18 and R.sup.19, together with the carbon atom to which they are 
bonded, form a cycloalkyl group (e.g., cyclopentyl); and 
R.sup.20 is hydrogen or unsubstituted lower alkyl (e.g., methyl). 
R.sup.1 and R.sup.2 are most preferably hydrogen. Where R.sup.1 and R.sup.2 
are other than hydrogen, preferred R.sup.1 and R.sup.2 groups are 
arylalkyl (e.g., benzyl). 
R.sup.8 is preferably hydrogen; alkyl, especially unsubstituted lower 
alkyl(e.g., methyl); R.sup.8 and R.sup.9, together with the atoms to which 
these groups are bonded, form a heterocyclo group (e.g., pyrrolidinyl or 
tetrahydroisoquinolinyl); R.sup.8 and R.sup.11, together with the atoms to 
which these groups are bonded, form a heterocyclo group (e.g., 
2,2-dimethyloxazolidinyl); or R.sup.8 and A.sup.a or A.sup.b (as described 
above), together with the atoms to which these groups are bonded, form a 
heterocyclo group (e.g., 5,5-dimethyl-2-oxo-oxazolidinyl). R.sup.8 is most 
preferably hydrogen. 
R.sup.9 is most preferably alkyl, especially unsubstituted lower alkyl 
(e.g., sec-butyl or isobutyl); or substituted lower alkyl, particularly: 
(A) cycloalkylalkyl (e.g., cyclohexylmethyl); 
(B) heterocycloalkyl, especially heterocyclomethyl (e.g., indolylmethyl, 
pyridylmethyl, or quinolinylmethyl); 
(C) arylalkenylalkyl, particularly where aryl is substituted by a group 
Ar(sub) defined below; or 
(D) arylalkyl, for example, phenylethyl, or, especially, a group of the 
formula: 
##STR48## 
where Ar (sub) is: 
(i) hydrogen; 
(ii) hydroxy; 
(iii) alkenyl (e.g., ethenyl); 
(iv) unsubstituted lower alkyl (e.g., ethyl); or 
(v) alkoxy, especially: 
unsubstituted lower alkoxy (e.g., methoxy); 
alkoxyalkoxy (e.g., methoxyethoxy, methoxybutoxy, benzyloxyethoxy, or 
benzyloxypropoxy); 
hydroxyalkoxy (e.g., hydroxyethoxy, hydroxypropoxy, or hydroxybutoxy); 
arylalkoxy (e.g., benzyloxy); 
heterocycloalkoxy (e.g., morpholinylpropoxy, morpholinylethoxy, 
3-oxo-morpholinylethoxy, pyridylethoxy, benzoxazolylmethoxy, 
benzoxazolylpropoxy, imidazolylethoxy, 2-oxo-oxazolidinylethoxy, 
3-methyl-2-oxoimidazolidinylethoxy, 2-hydroxy-2-pyridylethoxy); 
aminoalkoxy (e.g., aminoethoxy) or aminocarbonyloxyalkoxy (e.g., 
aminocarbonyloxyethoxy), especially where the amino moiety is 
unsubstituted or mono- or disubstituted by alkyl (e.g., methyl) or aryl 
(e.g., tolyl); 
heterocyclocarbonylalkoxy (e.g., morpholinylcarbonylethoxy, 
morpholinylcarbonylmethoxy or piperidinylcarbonylmethoxy); 
heterocyclooxyalkoxy (e.g., pyridyloxyethoxy); 
alkoxycarbonylalkoxy (e.g., ethoxycarbonylmethoxy); or 
carboxyalkoxy (e.g., carboxymethoxy). 
Where R.sup.9 is other than alkyl, preferred R.sup.9 groups are hydrogen; 
aryl; alkenyl; carbocyclo; or R.sup.9 and R.sup.8, together with the atoms 
to which these groups are bonded, form aheterocyclo group (e.g., 
pyrrolidinyl or tetrahydroisoquinolinyl). 
R.sup.9' is preferably hydrogen. 
R.sup.10 is most preferably hydrogen. Where R.sup.10 is other than 
hydrogen, preferred R.sup.10 groups are arylalkyl (e.g., benzyl); 
unsubstituted lower alkyl (e.g., methyl); or R.sup.10 and R.sup.11 
together form a keto group. 
R.sup.11 is most preferably hydrogen. Where R.sup.11 is other than 
hydrogen, preferred R.sup.11 groups are alkoxyalkyl (e.g., ethoxyethyl); 
unsubstituted lower alkyl (e.g., methyl); R.sup.11 and R.sup.8, together 
with the atoms to which these groups are bonded, form a heterocyclo group 
(e.g., 2,2-dimethyloxazolidinyl); or R.sup.11 and R.sup.10 together form a 
keto group. 
p and q are preferably 0. 
Particularly preferred compounds of the present invention are the following 
compounds, and salts and/or stereoisomers thereof, prepared as the title 
compounds of the following Examples of this specification: 2, 21, 76, 93, 
104, 162, 175, 178, 209, 224, 226, 234, 246, 257, 262, 271, 282, 293, 297, 
298, 304, 308, 311, 322, 327, 331, 333, 334, 336, 339, 344, 352, 355, 356, 
359, 366, 368, 377 and 383. 
PREFERRED UTLIITY 
Proteases are enzymes which cleave proteins at specific peptide bonds and, 
in living systems, mediate or control a broad spectrum of biological 
functions, such as cleaving precursors to form active proteins in 
post-translational processing of polypeptides. For example, retroviral 
proteases cleave large precursor polypeptides, produced in infected cells, 
into smaller protein components, or subunits, which are subsequently 
assembled to form functional virus structures. As proteases encoded by the 
viral genome play a critical role in the replication of a virus, these 
enzymes represent targets for therapeutic agents. 
Retroviruses are viruses which contain two copies of their RNA genome, each 
of which is copied into a double strand of DNA using a retroviral enzyme 
reverse transcriptase (RT). A second retroviral enzyme, ribonuclease H, is 
part of the RT protein and facilitates the synthesis of the DNA:DNA 
duplex. A third retroviral enzyme called integrase splices the double 
stranded DNA copy of the virus into the chromosome of the host cell. A 
fourth retroviral enzyme cell protease is critical to the process of viral 
replication by cleaving polypeptide precursors into required enzymes and 
structural proteins. 
The compounds of the present invention inhibit retroviral proteases, 
thereby inhibiting viral replication, and are thus especially useful in 
the treatment and/or prevention of retroviral infections caused by such 
pathogenic organisms. 
Exemplary protease-encoding retroviruses, the replication of which may be 
inhibited by the compounds of the present invention include the human 
T-cell lymphotrophic viruses, HTLV-I and HTLV-II, the human 
immunodeficiency viruses, for example, HIV-1, HIV-2 or mutants thereof 
(AIDS pathogens), feline leukemia virus and simian immunodeficiency virus. 
Protease inhibition may be assayed by methods such as those described 
below in the Examples section of the present specification. The compounds 
of the present invention may, of course, be used to simultaneously inhibit 
the replication of two or more retroviruses, as well as to inhibit the 
replication of a single retrovirus. 
The compounds of the present invention are particulary useful in the 
inhibition of human immunodeficiency virus (HIV) protease, and thus in the 
prevention and/or treatment of infection by HIV viruses (HIV-1, HIV-2, and 
mutants thereof), including the treatment of consequent pathological 
conditions such as AIDS. 
HIV protease is a retroviral protease which processes the gag polyprotein 
precursor into core proteins and the pol polyprotein precursor into 
reverse transciptase, integrase, and the protease itself. HIV protease is 
essential for the correct processing of these polyproteins and the 
production of infectious viral particles, as evidenced by the fact that 
mutations of the protease gene result in non-infectious viral particles 
with an immature morphology. Inhibition of HIV protease is thus a highly 
attractive target for anti-HIV therapy. 
Use of the compounds of the present invention in inhibiting HIV protease 
includes, but is not limited to, treating a wide range of states of HIV 
infection such as treating or preventing AIDS or ARC (AIDS related 
complex), treating both symptomatic and asymptomatic HIV-infected 
patients, and treating actual or potential exposure to HIV. For example, 
the compounds of this invention are useful in treating infection by HIV 
after suspected past exposure to HIV by, e.g., blood transfusion, 
accidental needle stick, or exposure to patient blood during surgery. 
As indicated above, the compounds of the present invention may also be 
useful in the treatment and/or prevention of infections caused by other 
retroviruses. Exemplary retroviruses that are pathogenic in man in 
addition to the human immunodeficiency viruses are HTLV-1 and HTLV-2. 
Exemplary viruses pathogenic in other species are feline leukemia virus 
and simian immunodeficiency virus. 
The present invention also provides pharmaceutical compositions comprising 
at least one of the inventive compounds capable of inhibiting retroviral 
protease in an amount effective therefor, and a pharmaceutically 
acceptable vehicle or diluent. The compositions of the present invention 
may be formulated, for example, by employing conventional solid or liquid 
vehicles or diluents, as well as pharmaceutical additives of a type 
appropriate to the mode of desired administration. The compounds may, for 
example, be administered orally, such as in the form of tablets, capsules, 
granules or powders; parenterally, such as by subcutaneous, intravenous, 
intramuscular, or intrasternal injection or infusion techniques (e.g. as 
sterile injectable aqueous or non-aqueous solutions or suspensions); 
nasally such as by inhalation spray; or rectally such as in the form of 
suppositories; in dosage unit formulations containing non-toxic, 
pharmaceutically acceptable vehicles or diluents. The present compounds 
may, for example, be administered liposomally. 
When administered orally, the compositions may be prepared according to 
techniques well known in the art of pharmaceutical formulation. As a 
suspension they may, for example, contain microcrystalline cellulose for 
imparting bulk, alginic acid or sodium alginate as a suspending agent, 
methylcellulose as a viscosity enhancer, and sweeteners or flavoring 
agents known in the art. As immediate release tablets, the present 
compositions may contain microcrystalline cellulose, dicalcium phosphate, 
starch, magnesium stearate and/or lactose and/or other excipients, 
binders, extenders, disintegrants, diluents and lubricants known in the 
art. 
When administered by nasal aerosol or inhalation, the compositions may be 
prepared according to techniques well known in the art of pharmaceutical 
formulation and may be prepared as solutions in saline, employing benzyl 
alcohol or other suitable preservatives, absorption promoters to enhance 
bioavailability, and/or other solubilizing or dispersing agents known in 
the art. 
When administered as injectable solutions or suspensions, the present 
compositions may be formulated according to techniques well known in the 
pharmaceutical art, using suitable non-toxic, parenterally acceptable 
diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's 
solution, an isotonic sodium chloride solution, or other suitable 
dispersing or wetting and suspending agents, including synthetic mono- or 
diglycerides, and fatty acids, including oleic acid. 
When rectally administered in the form of suppositories, these compositions 
may be prepared by techniques well known in the pharmaceutical art by 
mixing the drug with a-suitable non-irritating excipient, such as cocoa 
butter, synthetic glyceride esters or polyethylene glycols, which are 
solid at ordinary temperatures, but liquify and/or dissolve in the rectal 
cavity to release the drug. 
The pharmaceutical compositions of the present invention may contain an 
amount of the inventive compound(s) effective for the inhibition of 
retroviral replication, and preferably an amount effective for the 
treatment and/or prevention of infection by HIV. The effective amount of a 
compound of the present invention may be determined by one of ordinary 
skill in the art, and includes amounts such as those from about 1 to 150 
mg/kg of body weight of active compound per day. It will be understood 
that the specific dose level and frequency of dosage for any particular 
subject may be varied and will depend upon a variety of factors including 
the activity of the specific compound employed, the metabolic stability 
and length of action of that compound, the species, age, body weight, 
general health, sex and diet of the subject, the mode and time of 
administration, rate of excretion, drug combination, and severity of the 
particular condition. 
Viral hosts which are preferred subjects for treatment and/or prevention of 
retroviral infections include animals, most preferably mammalian species 
such as humans, and domestic animals such as dogs, cats and the like. A 
dose for adult humans is preferably between about 10 and about 50 mg/kg of 
body weight per day, which may be administered in a single dose or in the 
form of individual divided doses, such as from 1-4 times per day. 
The compounds of the present invention may be employed alone or in 
combination with other suitable therapeutic agents useful in the treatment 
of retroviral infections such as AIDS, such as other antiviral agents, 
immunomodulators, antibiotics or vaccines. 
Other therapeutic agents may include, but are not restricted to the 
following: antivirals exemplified by AL-721, interferon beta, 
polymannoacetate, ganciclovir, DDC (dideoxycytidine), d4T, DDI 
(dideoxyinosine), Foscarnet (trisodium phosphonoformate), HPA-23, 
eflornithine, Peptide T (octapeptide sequence), Reticulose 
(nucleophosphoprotein), AZT, ansamycin LM 427, trimetrexate, UA-001, 
ribavirin, .alpha.-interferon, acyclovir, 3TC, PMEA, nevirapine, 
pyridinones (e.g. L-697,661), BHAPs (e.g. U-90152), alpha-APA derivatives 
(e.g. R 18893), TIBO derivatives (e.g. R 82913), and Ro 31-8959; 
immunomodulators exemplified by bropirimine, Ampligen (mismatched RNA), 
Anti-human alpha interferon antibody, Colony Stimulating Factor (GM-CSF), 
CL246,738, IMREG-1, IMREG-2, diethyl dithio carbamate, interleukin-2, 
inosine pranobex, methionine enkephalin, MTP-PE (muramyl-tripeptide), 
Thymypentin (TP-5) (thymic compound), recombinant erythoropoietin, 
naltrexone, TNF (tumor necrosis factor); and antibiotics exemplified by 
Pentam 300 (pentamidine isethionate). 
In particular, the HIV protease inhibitors of the present invention may be 
used in combination with other anti-retroviral therapies for the treatment 
of AIDS. Such combined therapies may include, but are not limited to, a 
compound of the present invention in combination with: other (e.g., those 
other than inhibitors of the present invention) HIV protease inhibitors 
(e.g. Ro 31-8959); nucleoside and non-nucleoside reverse transcriptase 
inhibitor(s), preferably nucleoside reverse transcriptase inhibitors such 
as AZT, DDI, d4T, DDC, 3TC or PMEA, and non-nucleoside reverse 
transcriptase inhibitors such as nevirapine, pyridinones (e.g. L-697,661), 
BHAPs (e.g. U-90152), alpha-APA derivatives (e.g., R 18893), and TIBO 
derivatives (e.g. R 82913); inhibitor(s) of tat such as RO24-7429; drug(s) 
which inhibit binding of the virus to CD.sub.4 receptors; inhibitor(s) of 
RNase, integrase, or rev; and immunomodulator(s) such as IFN-.alpha. 
(.alpha.-interferon). 
The above compounds to be employed in combination with the compounds of the 
present invention will be used, for example, in amounts as indicated in 
the Physicians' Desk Reference (PDR) or as otherwise determined by one of 
ordinary skill in the art. The aforementioned combined therapies may, for 
example, be conducted simultaneously or sequentially. 
The instant invention also provides methods for the inhibition of 
retroviral proteases by contacting said protease with a compound of the 
present invention capable of said inhibition, and particularly for the 
treatment and/or prevention of retroviral infections. Treatment and/or 
prevention of infection by the human imunodeficiency viruses is preferred. 
The methods of the present invention preferably comprise the step of 
administering to a subject in need thereof one or more of the present 
compounds capable of treatment and/or prevention of retroviral infection 
in an amount effective therefor. Other therapeutic agents such as those 
described above may be employed with the inventive compounds in the 
present methods. 
The compounds of the present invention are also useful in the preparation 
of other compounds of the formula I. Thus, for example, one compound of 
the present invention may be employed in the preparation of another 
compound of the present invention, where the latter compound has greater 
potency against the same or a different retrovirus than the former. 
The following Examples will serve to illustrate the preparation of 
compounds of the present invention, and are not intended to limit the 
scope or spirit of the instant claims. The following abbreviations are 
employed in the Examples: 
Abbreviations 
Ph=phenyl 
Bn=benzyl 
t-Bu=tertiary-butyl 
Me=methyl 
Et=ethyl 
Ts=tosyl (p-toluenesulfonyl) 
Bz=benzoyl 
Phe=phenylalanine 
Val=valine 
TMS=trimethylsilyl 
TBS or TBDMS=tert-butyldimethylsilyl 
FMOC=fluorenylmethoxycarbonyl 
Teoc=trimethylsilylethoxycarbonyl 
Boc=tert-butoxycarbonyl 
Cbz or Z=carbobenzoxy (or carbobenzyloxy or benzyloxycarbonyl) 
THF=tetrahydrofuran 
Et.sub.2 O=diethylether 
EtOAc=ethyl acetate 
DMF=dimethylformamide 
MeOH=methanol 
EtOH=ethanol 
i-PrOH=iso-propanol 
t-BuOH=tert-butanol 
DMSO=dimethylsulfoxide 
DME=1,2-dimethoxyethane 
HMPA=hexamethylphosphoric triamide 
HOAc or AcOH=acetic acid 
TFA=trifluoroacetic acid 
i-Pr.sub.2 NEt=diisopropylethylamine 
Et.sub.3 N=triethylamine 
DMAP=4-dimethylaminopyridine 
MeLi=methyl lithium 
n-BuLi=n-butyllithium 
s-BuLi=sec-butyllithium 
n-Bu.sub.4 NF.multidot.nH.sub.2 O=tetra-n-butylammonium fluoride hydrate 
n-Bu.sub.4 NBr=tetra-n-butylammonium bromide 
n-Bu.sub.4 NI=tetra-n-bunylammonium iodide 
EDC (or EDC.multidot.HCl) or EDCI (or 
EDCI.multidot.HCl)=3-ethyl-3'-(dimethylamino)propylcarbodiimide 
hydrochloride (or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride) 
HOBT or HOBT.multidot.H.sub.2 O=1-hydroxybenzotriazole hydrate 
KN(TMS).sub.2 =potassium bis (trimethylsilyl)amide 
NaN (TMS).sub.2 =sodium bis (trimethylsilyl)amide 
Boc-ON=[2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile] 
AcCl=acetyl chloride 
BOP-C1=Bis(2-oxo-3-oxazolidinyl)phosphinic chloride 
BOP reagent=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium 
hexafluorophosphate 
PPh.sub.3 =triphenylphosphine 
DEAD=diethylazodicarboxylate 
Me.sub.2 S=dimethylsulfide 
Ti(i-Pro).sub.4 =titanium(IV) isopropoxide 
KOAc=potassium acetate 
Dibal or DIBAL-H=diisobutylaluminum hydride 
Cbz-C1=carbobenzoxy chloride (benzyl chloroformate) 
PMA=phosphomolybdic acid 
min=minute(s) 
h or hr=hour(s) 
L=liter 
ml or mL=milliliter 
.mu.l or .mu.L=microliter 
g=gram(s) 
mg=milligram(s) 
mol=mole(s) 
mmol=millimole(s) 
RT=room temperature 
sat. or sat'd.=saturated 
aq.=aqueous 
TLC=thin layer chromatography 
HPLC=high performance liquid chromatography 
UV=ultraviolet 
MS or Mass Spec.=mass spectrometry 
NMR=nuclear magnetic resonance 
mp=melting point 
hex=hexane 
Tf=triflate 
NaHB(OAc).sub.3 =sodium triacetoxyborohydride 
p-TsOH=p-toluenesulfonic acid 
m-CPBA=metachloroperbenzoic acid 
DCC=dicyclohexylcarbodiimide 
NBS=N-bromosuccinimide 
PPTs=Pyridinium p-tosylate 
PCC=pyridinium chlorochromate 
BF.sub.3 .multidot.Et.sub.2 O=boron trifluoride etherate 
Compounds in the following Examples are referred to by the step and number 
of the Example in which they are prepared. For example, "Compound 1c" 
denotes the compound prepared in step (c) of Example 1; "Compound 39" 
denotes the compound prepared in Example 39, which Example contains a 
single step. 
EXAMPLE 1 
Preparation of [1S-[1R*, 2S* (2S*, 
3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbuty 
l](phenylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 1c) 
(a) Compound 1a(iv) 
##STR49## 
(i) Diazomethane-Et.sub.2 O solution 
To the mixture of 40% aqueous KOH (75 ml) and Et.sub.2 O (255 ml) cooled at 
0.degree. C. was added 1-methyl-3-nitro-1-nitrosoguanidine (23.85 g, 162.2 
mmol) portionwise. The mixture was swirled several times during each 
addition. After 10 min, the resulting yellow Et.sub.2 O layer was decanted 
over KOH pellets at 0.degree. C. and dried for 2.0 h at 0.degree. C. 
(ii) Compound 1a(ii) 
##STR50## 
To the solution of N-Boc-L-phenylalanine (14.34 g, 54.05 mmol) in dry THF 
(80 ml) cooled at -20.degree. C. to -25.degree. C. (dry ice-CCl.sub.4 
bath) was added isobutyl chloroformate (7.01 ml, 54.05 mmol) over 5 min, 
followed by 4-methylmorpholine (5.94 ml, 54.05 mmol) and the mixture was 
stirred for 20 min. The white precipitate was removed by filtration under 
argon atmosphere and washed with ca. 70 ml of dry THF. The combined THF 
solution of mixed anhydride was cooled to -5.degree. C. and poured into 
the above prepared diazomethane in Et20 solution at 0.degree. C. The 
resulting yellow solution was kept at 0.degree. C. for 2.0 h, then RT 
overnight. N.sub.2 was then bubbled through the light-yellow solution for 
30 min, and Et.sub.2 O (400 ml) then added. The solution was washed with 
H.sub.2 O (400 ml), saturated NaHCO.sub.3 (300.ml) and brine (300 ml), and 
was dried over anhydrous MgSO.sub.4. Concentration in vacuo afforded a 
yellow residue, which was triturated with hexane to give, after drying 
over P.sub.2 O.sub.5 overnight under high vacuum, 14.72 g (94%) of the 
title .alpha.-diazoketone as a pale yellow solid. This material was used 
immediately in the reaction of the next step without further purification. 
(iii) Compound 1a (iii) 
##STR51## 
To the solution of the crude .alpha.-diazoketone prepared above (14.72 g, 
50.87 mmol) in dry Et.sub.2 O (500 ml) cooled at 0.degree. C. was added, 
dropwise, a solution of 4N HCl in dioxane (12.72 ml, 50.87 mmol) while 
maintaining the temperature below 5.degree. C. The reaction mixture was 
then stirred at 0.degree. C. for 1.0 h. TLC (hexane-EtOAc 4:1) showed 
trace amounts of the starting .alpha.-diazoketone remained. Additional 4N 
HCl in dioxane (636 .mu.l, 0.05 eq., 2.54 mmol) was added and the mixture 
was stirred at 0.degree. C. for one additional hour. 
Concentration in vacuo gave a residue which was dissolved in hot Et.sub.2 O 
(60 ml). Hexane (200 ml) was slowly added and the mixture allowed to stand 
for 2.0 h at 5.degree. C. The solid was filtered and dried over P.sub.2 
O.sub.5 under high vacuum to afford 9.58 g (first crop) of the title 
.alpha.-chloroketone. The filtrate was concentrated to dryness and the 
residue was again recrystallized from Et.sub.2 O-hexane to give an 
additional 4.41 g (second crop) of the above .alpha.-chloroketone. Total 
yield: 13.99 g (92%). 
(iv) Compound 1a(iv) 
NaBH.sub.4 (1.59 g; 42 mmol) was added to a solution of the 
.alpha.-chloroketone prepared above (5 g; 16.8 mmol) in 84 ml of THF and 9 
ml of H.sub.2 O at 0.degree. C. After stirring at 0.degree. C. for 45 min 
the reaction mixture was concentrated to dryness. The residue was stirred 
at 0.degree. C. with EtOAc (150 ml) and H.sub.2 O (25 ml) while saturated 
KHSO3 solution was carefully added until the pH was .about.1.5. This 
mixture was then diluted with 350 ml of EtOAc and the layers were 
separated. The organic layer was washed with H.sub.2 O (100 ml) and brine 
(100 ml). After drying over MgSO.sub.4, the organic layer was concentrated 
to a white solid. A portion of this solid (4.89 g) was recrystallized from 
70 ml of hot EtOAc to afford 2.47 g (50%) of Compound la(iv) as a white 
solid containing a few percent of its diastereomer, the following Compound 
1a(v): 
##STR52## 
(b) Compound 1b(i) 
##STR53## 
0.71M KOH in EtOH (14.7 ml; 10.4 mmol) was added to a suspension of 
Compound 1a(iv) (2.6 g; 8.67 mmol) in 87 ml of EtOH at RT. The reaction 
was stirred 1.5 h at RT, during which time the thick suspension became a 
fine powdery one. At this time, the EtOH was removed in vacuo and the 
residue was partitioned between EtOAc (200 ml) and H.sub.2 O (200 ml). The 
organic layer was washed with saturated NH.sub.4 Cl solution (2.times.100 
ml), H.sub.2 O (2.times.100 ml), and brine (100 ml). After drying over 
MgSO.sub.4, the EtOAc was removed in vacuo and the solid white residue was 
recrystallized by dissolving in 10 ml of refluxing EtOAc and adding 190 ml 
of hexane. The resulting crystalline suspension was allowed to cool to 
-40.degree. C. and stand overnight. Filtration, rinsing with hexane, and 
drying under high vacuum for two hours afforded 1.92 g (84%) of Compound 
1b(i) as a colorless crystalline solid. This material was 99.1% 
diastereomerically pure by HPLC. 
Compound 1b(ii) 
##STR54## 
The diastereomeric epoxide 1b(ii) is prepared by a procedure analogous to 
the one used for 1b(i) starting from the minor diastereomeric chlorohydrin 
isolated by column chromatography from 1a(iv) above. 
Alternatively, to a solution of the compound: 
##STR55## 
(for preparation, see Luly et al., J. Org. Chem., 52, 1487-1492 (1987)) in 
dioxane at 0.degree. C. was added a suspension of NBS in H.sub.2 O. After 
5 min, the reaction mixture was warmed to RT and stirred for 2.0 h. The 
reaction mixture was then diluted with MeOH and K.sub.2 CO.sub.3 was 
added. After 3.0 h, the volatiles were removed in vacuo and the residue 
was partitioned between CH.sub.2 Cl.sub.2 and H.sub.2 O. The organic layer 
was concentrated in vacuo to give a mixture of Compounds 1b(i) and 1b(ii) 
(3:1 mixture, 1b(i): 1b(ii)) as a colorless solid. 
(c) Compound 1c 
##STR56## 
A DMF (2.5 mL) solution of Compound 1b(i) (1.97 g, 7.48 mmol) and benzyl 
amine (0.41 mL, 3.74 mmol) was heated under argon for 7 h at 
105.degree.-108.degree. C., then stirred overnight at RT. After heating an 
additional 1.5 h at 105.degree.-108.degree. C., the volatiles were 
evaporated in vacuo. The resulting residue was co-evaporated twice with 
MeOH/CH.sub.2 Cl.sub.2 and purified by flash column chromatography (silica 
gel, 5 by 19 cm) , eluting with 0.5, 1,2,3,4,7, and then 10% MeOH:CH.sub.2 
Cl.sub.2 to give Compound 1c (1.39 g, yield) as a colorless solid. Anal. 
Calc. for C.sub.37 H.sub.51 N.sub.3 O.sub.5 .multidot.1.63 H.sub.2 O: 
C, 68.68; H, 8.45; N, 6.49 Found: C, 68.35; H, 8.10; N, 6.82 
EXAMPLE 2 
Preparation of [1S-[1R*, 2S* (2S*, 
3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbuty 
l]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl 
ester (Compound 2) 
##STR57## 
To an EtOH (5 mL) solution of Compound 1c (90 mg, 0.142 mmol) and. 
cyclohexene (2.5 mL) at RT was added Pd(OH).sub.2 (41 mg, 20% on carbon). 
The reaction mixture was refluxed at 90.degree. C. for 1 h, filtered hot 
through Celite, and the volatiles were removed in vacuo to leave a 
colorless solid (74 mg). The residue was purified by flash chromatography 
(silica gel, 1 by 12.5 cm), eluting with 0.5, 2, 4, 8, and then 9% 
MeOH:CH.sub.2 Cl.sub.2 to give the title Compound 2 (53 mg, 69% yield) as 
a colorless solid. m.p. 178.degree.-179.5.degree. C.; [.alpha.].sub.D 
=-7.07.degree. (c 0.1, MeOH ) . MS: 544 (M+H). Anal. Calc. for C.sub.30 
H.sub.45 N.sub.3 O.sub.6 .multidot.0.8 H.sub.2 O: 
C, 64.57; H, 8.42; N, 7.53 Found: C, 64.53; H, 8.30; N, 7.57 
EXAMPLE 3 
Preparation of [1S-[1R*, 2R*(2R*, 
3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbuty 
l]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl 
ester (Compound 3) 
##STR58## 
Compound 1b(ii) was converted to the title Compound 3 by procedures 
analogous to those described for Compounds 1c and 2. m.p. 
140.degree.-141.degree. C.; [.alpha.]D.sup.25 =-42.38.degree. (c 0.29, 
MeOH). MS: 544 (M+H). Anal. Calc. for C.sub.30 H.sub.45 N.sub.3 O.sub.6 
.multidot.1.45 H.sub.2 O: 
C, 63.24; H, 8.47; N, 7.37 Found: C, 63.25; H, 8.36; N, 7.36 
EXAMPLE 4 
Preparation of [1S-[1R*, 2S*(2R*, 
3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbuty 
l](phenylmethyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 4b) 
(a) Compound 4a 
##STR59## 
A DMF (0.4 mL) solution of Compound 1b(i) (75 mg, 0.285 mmol) and benzyl 
amine (0.025 mL, 0.229 mmol) was heated for 18 h at 85.degree. C. and the 
volatiles were evaporated in vacuo at 30.degree. C. The solid residue (100 
mg) was purified by flash column chromatography (silica gel, 1.5 by 11 
cm), eluting with 0.5, 4, and then 8% MeOH:CH.sub.2 Cl.sub.2 to give 
Compound 4a (50 mg, 41% yield) as a colorless solid. 
(b) Compound 4b 
##STR60## 
A DMF (0.3 mL) solution of Compound 4a (48 mg, 0.11 mmol) and Compound 
1b(ii) (55 mg, 0.21 mmol) was heated for 7 h at 105-.degree.110.degree. 
C., then stored at -40.degree. C. overnight. After warming to RT, the 
volatiles were evaporated in vacuo at 30.degree. C. The oily-solid residue 
(120 mg) was purified by flash column chromatography (silica gel, 1 by 16 
cm), eluting with 0.5, 1, 1.5, and then 2% MeOH:CH.sub.2 Cl.sub.2 to give 
Compound 4b (74 mg, .about.100% yield) as a colorless solid. R.sub.f =0.69 
(7% MeOH:CH.sub.2 Cl.sub.2). 
EXAMPLE 5 
Preparation of 
[1S-[1R*,2S*(2R*,3R*)]][3-[[3-[[(1,1-Dimethylethoxy)carbonyl[amino]-2-hydr 
oxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 5) 
##STR61## 
Compound 4b was deprotected using a procedure analogous to that for 
Compound 2 to give the title Compound 5. m.p. 151.degree.-153.degree. C.; 
[.alpha.].sub.D.sup.25 =-22.93.degree. (c 0.23, MeOH). MS: 544 (M+H). 
Anal. Calc. for C.sub.30 H.sub.45 N.sub.3 O.sub.6 .multidot.0.67 H.sub.2 
O: 
C, 64.83; H, 8.40; N, 7.56 Found: C, 64.84; H, 8.37; N, 7.55 
EXAMPLE 6 
Preparation of 
(2S)-2,2'-[(Phenylmethyl)imino-bis[1-hydroxy-2,1-ethanediyl]bis-1-pyrrolid 
ine-carboxylic acid], bis(1,1-dimethylether) ester, single isomer (A) 
(Compound 6b) 
(a) Compounds 6a(i) and 6a(ii) 
##STR62## 
Compound 6a(i) faster moving isomer Compound 6a(ii) slower moving isomer 
Compounds 6a (i) and 6a (ii) (unknown stereochemistry) were prepared by a 
procedure analogous to the synthesis of Compounds 1b(i) and 1b(ii) in 
which Boc-(L)-proline was employed in place of N-Boc-L-phenylalanine. 
(b) Compound 6b 
##STR63## 
Compound 6a(ii) was converted to the title Compound 6b by opening with 
benzyl amine and then reacting with another molecule of 6a(ii) analogous 
to the two-step procedure used for the preparation of Compound 4b. R.sub.f 
=0.36 (3:1 EtOAc/hexane) (oil). 
EXAMPLE 7 
Preparation of 
(2S)-2,2'-[Iminobis(1-hydroxy-2,1-ethanediyl]bis-(1-pyrrolidinecarboxylic 
acid), bis(1,1-dimethylether)ester, single isomer (A) (Compound 7) 
##STR64## 
A suspension of 0.069 g (0.13 mmol) of Compound 6b and 10 mg of Pd(OH)2 in 
1.5 ml of MeOH was stirred under a H.sub.2 atmosphere (balloon) at RT 
overnight. The mixture was filtered through a micropore fritted funnel 
(MeOH wash) and evaporated. The crude product was purified by flash 
chromatography (20 mm.times.6"; 10% MeOH/CH.sub.2 Cl.sub.2 +1% NH.sub.4 
OH) to give 41 mg (&lt;72%) of slightly impure material. This material was 
combined with 41 mg of material from a previous reaction and 
recrystallized from EtOAc/Hexane to give 32 mg of the title Compound 7 as 
a white solid. m.p.=181.degree.-184.degree. C.; [.alpha.].sub.D.sup.25 
=-86.degree. (c 0.1, MeOH). MS: 444 (M+H). Anal. Calc. for C.sub.22 
H.sub.41 N.sub.3 O.sub.6 .multidot.0.52 H.sub.2 O: 
C, 58.34; H, 9.35; N, 9.28; Found: C, 58.39; H, 9.44; N, 9.23. 
EXAMPLE 8 
Preparation of 
[S-(R*,R*)]-2-[2-[[[S-(R*,S*)]-1-[1-[(1,1-Dimethylethoxy)carbonyl]-pyrroli 
dinyl], 2-hydroxyethyl]amino]-hydroxyethyl]-1-pyrrolidine-carboxylic acid, 
(1,1-dimethylethyl) ester (Compound 8) 
##STR65## 
Compounds 6a(i) and 6a(ii) were converted to the title Compound 8 (white 
solid) by procedures analogous to those used for the synthesis of Compound 
7 except that epoxide 6a(ii) was opened with 2 equivalents of benzyl amine 
and the resulting product was reacted with epoxide 6a(i) by a procedure 
analogous to that used for Compound 4b. m.p. 44.degree.-48.degree. C.; 
[.alpha.].sub.D =-67.3.degree. (c 0.26, CHCl.sub.3) Mass Spec. 444 (M+H) 
Anal. Calc. for C.sub.22 H.sub.41 N.sub.3 O.sub.6 .multidot.0.56 H.sub.2 
O: 
C, 58.24; H, 9.36; N, 9.26 Found: C, 58.50; H, 9.63; N, 9.00 
EXAMPLE 9 
Preparation of [S-(R*, 
R*)]-3,3-[[(Phenylmethyl)imino]bis(1-hydroxy-2,1-ethanediyl)]bis[2(1H)-iso 
quinolinecarboxylic acid, bis(1,1-dimethylethyl) ester (Compound 9b) 
(a) Compound 9a(i) 
##STR66## 
and 
Compound 9a(ii) 
##STR67## 
Compounds 9a(i) (major) and 9a(ii) (minor) were prepared by a procedure 
analogous to the synthesis of Compounds 1b(i) and 1b(ii) in which 
Boc-(L)-tetrahydroisoquinoline-2-carboxylic acid (see J. Am. Chem. Soc., 
70, 180 (1948); ibid 84, 4487 (1962)) was employed in place of 
N-Boc-L-phenylalanine. 
(b) Compound 9b 
##STR68## 
Compound 9a(i) was converted to the title Compound 9b (light-yellow oil) by 
opening with 2 equivalents of benzyl amine and then reacting with another 
molecule of 9a(i) analogous to the two-step procedure used for the 
preparation of Compound 4b. 
.sup.1 H NMR (CD.sub.3 OD): .delta.1.43-1.46 (brs's, 18H), 2.45 (m, 4H), 
2.61 (m, 2H), 2.87 (m, 2H), 3.43 (m, 1H), 3.55 (m, 3H), 4.22 (m, 4H), 4.71 
(m, 2H), 7.00-7.25 (m, 13H). 
EXAMPLE 10 
Preparation of 
[S-(R*,R*)]-3,3'-[Iminobis(1-hydroxy-2,1-ethanediyl)]-bis[2(1H)-isoquinoli 
necarboxylic acid], bis(1,1-dimethylethyl) ester (Compound 10) 
##STR69## 
Compound 9b was deprotected by a procedure analogous to that used for 
Compound 7 to give the title Compound 10 (white solid). mp 
70.degree.-76.degree. C.; [.alpha.].sub.D +33.6.degree. (c 0.25, MeOH); 
Mass Spec: 568 (M+H) Analysis calc. for C.sub.32 H.sub.45 N.sub.3 O.sub.6 
.multidot.0.69H.sub.2 O: 
C, 66.25; H, 8.06; N, 7.24; Found: C, 66.45; H, 7.96; N, 7.04. 
EXAMPLE 11 
Preparation of [R-(R* 
,R*)]-3,3'[Iminobis(1-hydroxy-2,1-ethanediyl)]-bis[2(1H)-isoquinolinecarbo 
xylic acid], bis(1,1-dimethyethyl) ester (Compound 11) 
##STR70## 
Compound 11 (white solid) was prepared from Compound 9a(ii) by procedures 
analogous to those used for the synthesis of Compound 10. mp 
68.degree.-76.degree. C.; [.alpha.].sub.D =+34.0.degree. (c 0.05, MeOH). 
Mass Spec.: 568 (M+H) Analysis calc. for C.sub.32 H.sub.45 N.sub.3 O.sub.6 
.multidot.0.91H.sub.2 O: 
C, 65.81; H, 8.08; N, 7.19; Found: C, 65.96; H, 8.15; N, 7.04. 
EXAMPLE 12 
Preparation of 
[S-(R*,R*)]-3-[2-[[[S-(R*,S*)]-2-[2-[(1,1-Dimethylethoxy)carbonyl]-1,2,3,4 
-tetrahydro-3-isoquinolinyl]-2 
-hydroxyethyl]amino]-1-hydroxyethyl]-3,4-dihydro-2(1H)-isoquino-linecarbox 
ylic acid, (1,1-dimethylethyl) ester (Compound 12) 
##STR71## 
Compounds 9a(i) and 9a(ii) were converted to the title Compound 12 (white 
solid) by procedures analogous to those used for the synthesis of Compound 
10 except that epoxide 9a(i) was opened with benzyl amine and the 
resulting product was reacted with epoxide 9a(ii) by a procedure analogous 
to that used for Compound 4b. mp 65.degree.-72 .degree. C.; 
[.alpha.].sub.D =+20.5.degree. (c 0.19, MeOH). Mass Spec.: 568 (M+H) 
Analysis calc. for C.sub.32 H.sub.45 N.sub.3 O.sub.6 19 1.13H.sub.2 O: 
C, 65.35; H, 8.10; N, 7.15; Found: C, 65.68; N, 7.94; N, 6.82. 
EXAMPLE 13 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(1-methylpropyl)-3,1-propanediyl]]bis-ca 
rbamic acid, 1,1 -dimethylethyl ester (Compound 13) 
##STR72## 
Starting from N-Boc-L-isoleucine in place of N-Boc-L-phenylalanine, the 
title Compound 13 (colorless oil) was prepared using procedures analogous 
to those described for Compounds 1b(i), 4b, and 7. TLC, Rf=0.10, CH.sub.2 
Cl.sub.2 :MeOH:NH.sub.4 OH, 95.5:4.9:0.1, (PMA). .sup.13 C NMR (CD.sub.3 
OD): 812.1, 16.7, 24.1, 28.8, 36.1, 52.8, 59.6, 69.6, 80.1, 158.9. Mass 
Spec. (M+H).sup.+ @476 
EXAMPLE 14 
Preparation of 
[R-(R*,S*)]-[Iminobis[-1(Cyclohexyl-methyl)-2-hydroxy-3,1-propanediyl]]-bi 
scarbamic acid, bis(1,1dimethylethyl) ester (Compound 14) 
##STR73## 
Starting from N-Boc-L-cyclohexylalanine in place of N-Boc-L-phenylalanine, 
the title Compound 14 (white solid) was prepared using procedures 
analogous to those described for Compounds 1b(i), 4b, and 7. 
[.alpha.].sub.D =-33.7.degree. (c 0.18, MeOH). .sup.13 C NMR (CDCl.sub.3): 
.delta.26.1, 26.4, 26.5, 28.4, 32.3, 34.2, 34.3, 38.1, 51.0, 51.6, 72.7, 
79.5, 156.4. Mass Spec. (M+H ).sup.+ @556. High Resolution FAB; exact mass 
calcd. for C.sub.30 H.sub.58 O.sub.6 N.sub.3 (M+H).sup.+, 556,4325; Found 
556.4304. 
EXAMPLE 15 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)1]-[3-[[4-Cyclohexyl-3-[[(1,1-dimethylethoxy)carbonyl 
]-amino]-2-hydroxybutyl]amino-2-hydroxy-1(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 15) 
##STR74## 
Compound 4a and the epoxide prepared in Example 14 (i.e., in the step 
analogous to that for Compound 1b(i)) were converted to the title Compound 
15 by procedures analogous to those used for Compounds 4b and 7. mp 
120.degree.-125.degree. C.; [.alpha.].sub.D =-15.0.degree. (c 0.10, MeOH). 
Mass Spec. (M+H).sup.+ @550. Analysis calc. for C.sub.30 H.sub.51 N.sub.3 
O.sub.6 .multidot.0.32H.sub.2 O: 
C, 64.99; H, 9.20; N, 7.58; Found: C, 65.08; H, 9.46; N, 7.49. 
EXAMPLE 16 
Preparation of [2S-[2R*,1S*(2S*,3R* 
)]]-[1-Hydroxy-3-[[(1,1-dimethylethoxy)carbonylamino]-2-hydroxy-4-phenylbu 
tyl]amino]ethyl-2-methylbutyl]carbamic acid, phenylmethyl ester (Compound 
16c) 
(a) Compound 16a 
##STR75## 
Compound 16a was prepared by procedures analogous to those used for the 
synthesis of Compound 1b(i) in which N-Cbz-L-isoleucine was employed in 
place of N-Boc-L-phenylalanine. 
(b) Compound 16b 
##STR76## 
Compound 1b(i) (15.0 g; 56.96 mmol) dissolved in 350 ml of EtOH was added, 
with stirring, over 1 h to 350 ml of concentrated NH.sub.4 OH at 0.degree. 
C. NH.sub.3 gas was bubbled through the reaction mixture during the 
addition and for 1 h after. The reaction was then warmed to RT and stirred 
overnight. The resulting slurry was diluted with 800 ml EtOAc and the 
organic layer washed repeatedly with brine. The organic extracts were 
dried (MgSO.sub.4) and concentrated to give a white solid which was 
triturated with 10% i-PrOH/EtOAc to give 4.37 g of Compound 16b. The 
mother liquors were evaporated and triturated again as above to give an 
additional 5.73 g of Compound 16b (total yield: 10.1 g; 63%). 
(c) Compound 16c 
##STR77## 
Compounds 16a and 16b were reacted by a procedure analogous to that used 
for the preparation of Compound 4b to give the title Compound 16c. mp 
155.degree.-157.degree. C.; [.alpha.].sub.D =+1.3 6.degree. (c 0.22, 
MeOH). Mass Spec. (M+H).sup.+ @544. Analysis calc. for C.sub.30 H.sub.45 
N.sub.3 O.sub.6 .multidot.0.38H.sub.2 O 
C, 65.46 H, 8.38 N, 7.63 Found: C, 65.48 H, 8.29 N, 7.61 
EXAMPLE 17 
Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3- [[3-[[(1,1 
Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1- 
[[4-(phenylmethoxy)phenyl]methyl]propyl]carbamic acid, phenylmethyl ester 
(Compound 17b) 
(a) Compound 17a 
##STR78## 
Compound 17a was prepared by procedures analogous to those used for the 
synthesis of Compound 1b(i) where N-Cbz-O-benzyl-L-tyrosine was employed 
in place of N-Boc-L-phenylalanine. 
(b) Compound 17b 
##STR79## 
Compounds 17a and 16b were reacted by a procedure analogous to that used 
for the preparation of Compound 4b to give the title Compound 17b. m.p.: 
154.degree.-155.5.degree. C. [.alpha.].sub.D =-19.09.degree. (c 0.24, 
DMSO). MS (FAB): 684.sup.+ (M+H).sup.+. Anal. Calc. for C.sub.40 H.sub.49 
N.sub.3 O.sub.7 .multidot.0.87H.sub.2 O: C, 68.68; H, 7.31; N, 6.01. 
Found: C, 68.84; H, 7.18; N, 5.85. 
EXAMPLE 18 
Preparation of [1S-[1R*, 
2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-ph 
enylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-[[4- 
(phenylmethoxy)phenyl]methylpropyl]carbamic acid, phenylmethyl ester 
(Compound 18) 
##STR80## 
To the mixture of Compound 17b (342 mg, 0.5 retool) and i-Pr.sub.2 NEt (140 
.mu.l, 0.8 retool) in dry DMF (3.8 ml) cooled at 0.degree. C. was added 
2-trimethylsilylethyl chloroformate (125 .mu.l, 0.55 retool). The mixture 
was stirred at 0.degree. C. for 1.0 hr and diluted with EtOAc (70 ml). 
H.sub.2 O (50 ml) was added and the mixture was extracted with additional 
EtOAc (2.times.20 ml). The combined organic layers were washed with 
saturated NaHCO.sub.3 (40 ml) and brine (40 ml) and dried over anhydrous 
Na.sub.2 SO.sub.4. Concentration in vacuo followed by flash chromatography 
(100% CHCl.sub.3 to 2:1 CHCl.sub.3 -EtOAc) afforded 401 mg (97%) of 
Compound 18 as a white foam. .sup.1 H-NMR (400 MHz, CDCl.sub.3): 7.17-7.44 
(m, 15H), 7.08 (d, J=8.12, 2H), 6.85 (d, J=8.12, 2H), 4.99 (s, 2H), 4.58 
and 4.72 (bs, 2H), 4.14 (t, J=8.77, 2), 3.70-4.00 (m, 4H), 3.15-3.55 (m, 
4H), 2.70-3.00 (m, 4H), 1.32 (s, 9H), 0.94 (m, 2H), 0.00 (s, 9H). 
EXAMPLE 19 
Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-Amino-2 
-hydroxy-4-(4-hydroxyphenyl)butyl][[2-(trimethylsilyl)ethoxy]carbonyl]amin 
o]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethyl-ethyl ester 
(Compound 19) 
##STR81## 
To the solution of Compound 18 (401 mg, 0.485 mmol) in 17 ml of 100% EtOH 
was added 200 mg of Pd(OH).sub.2. The mixture was stirred under a H.sub.2 
atmosphere overnight (&gt;16 hrs). The catalyst was removed by filtration 
through a small plug of Celite and washed several times with MeOH. 
Concentration in vacuo afforded an oily residue, which after 
recrystallization from CHCl.sub.3 (2.0 ml) and hexane (25 ml) gave 272 mg 
(93%) of Compound 19 as an off-white solid. This material was immediately 
used in the next Example. 
EXAMPLE 20 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-(4-hydroxyphenyl)butyl][[2-(trimethylsilyl)-ethoxy]carbonyl]amino]-2-hy 
droxy-1-(phenylmethylpropyl]carbamic acid, 1,1 -dimethylethyl ester 
(Compound 20) 
##STR82## 
To the solution of Compound 19 (121 mg, 0.20 mmol) in 1,4 -dioxane-water ( 
1: 1, 0.6 ml ) was added Et.sub.3 N (42 .mu.l, 0.30 mmol), followed by 
Boc-ON (59 mg, 0.24 mmol). The mixture was stirred at RT overnight. The 
reaction mixture was diluted with EtOAc (25 ml) and washed with H.sub.2 O 
(2.times.10 ml). The aqueous layer was extracted with EtOAc (2.times.25 
ml). The combined organic layers were washed with saturated NaHCO.sub.3 
(20 ml) and brine (20 ml) and dried over anhydrous Na.sub.2 SO.sub.4. 
Concentration in vacuo followed by flash chromatography (100% CHCl.sub.3 
to 95:5 CHCl.sub.3 -MeOH) on a silica gel column (190.times.20 mm) 
afforded 132 mg of Compound 20 as a glassy solid, which was triturated 
with hexane to give 126 mg (94%) of Compound 20 as a white solid. MS 
(FAB): 704.sup.+ (M+H).sup.+. 
EXAMPLE 21 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-3-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydro 
xy-4-(4-hydroxyphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester (Compound 21) 
##STR83## 
The mixture of Compound 20 (124 mg, 0.176 mmol) and solid n-Bu.sub.4 
NF.multidot.nH.sub.2 O (138 mg, 0.529 mmol) in dry THF (0.75 ml) was 
heated at 50.degree. C. for 4.0 hrs. After cooling to room temperature, 
Celite (1.0 g) was added and the solvent was removed under reduced 
pressure. Flash chromatography (100% CHCl.sub.3 to CHCl.sub.3 
-MeOH-NH.sub.4 OH: 92:8:0.8) on silica gel column (20.times.200 mm) 
afforded 79 mg (81%) of Compound 21 as a white solid. m.p.: 
151.0.degree.-152.5.degree. C. [.alpha.].sub.D =-1.53.degree. (c 0.196, 
CHCl.sub.3). MS (FAB): 560.sup.+ (M+H).sup.+. Anal. Calc. for C.sub.30 
H.sub.45 N.sub.3 O.sub.7 .multidot.0.70H.sub.2 O: C, 62.96; H, 8.17; N, 
7.34. Found: C, 63.03; H, 8.08; N, 7.27. 
EXAMPLE 22 
Preparation of [1S-[1R*, 
2S*(2S,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phe 
nylbutyl]amino]-2-hydroxy-1-[(1H-indol-3-yl)methyl]propyl]carbamic acid, 
phenylmethyl ester (Compound 22b) 
(a) Compound 22a 
##STR84## 
Compound 22a was prepared by procedures analogous to those used for the 
synthesis of Compound 1(i) in which N-Cbz-L-tryptophan was employed in 
place of N-Boc-L-phenylalanine. 
(b) Compound 22b 
##STR85## 
Compounds 22a and 16b were reacted by a procedure analogous to that used 
for the preparation of Compound 4b to give the title Compound 22b (white 
solid). Elemental Analysis (%) C.sub.35 H.sub.44 N.sub.4 O.sub.6 
.multidot.0.89 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 67.62 67.53 
H 7.22 7.14 
N 9.01 9.10 
______________________________________ 
m.p. 170.degree.-171.degree. C. [.alpha.].sub.D =21.1.degree. (c 0.48, 
MeOH) 
EXAMPLE 23 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(1H-indol-3-ylmethyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]c 
arbamic acid, 1,1-dimethylethyl ester (Compound 23) 
##STR86## 
Compound 22b was converted to the title Compound 23 (white solid) using 
procedures analogous to those for the synthesis of Compounds 18 through 21 
(di-tert-butyldicarbonate was used instead of BOC-ON to put on the Boc 
group). Elemental Analysis (%) for C.sub.32 H.sub.46 N.sub.4 O.sub.6 
.multidot.1.09 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.24 65.31 
H 7.99 8.18 
N 9.51 9.44 
______________________________________ 
m.p. 168.degree.-169.degree. C. [.alpha.].sub.D =-14.4.degree. (c=0.21, 
MeOH) 
EXAMPLE 24 
Preparation of 
[1S-[1R*,2S*((2S*,3R*)]]-[3-[[3-[[1,1-Dimethylethoxy)carbonyl]amino-2-hydr 
oxy-4-phenylbutyl]amino]-2-hydroxy-1-(2-phenylethyl)propyl]carbamic acid, 
phenylmethyl ester (Compound 24b) 
(a) Compound 24a 
##STR87## 
Compound 24a was prepared by procedures analogous to those used for the 
synthesis of Compound 1b(i), in which N-Cbz-L-homophenylalanine was 
employed in place of N-Boc-L-phenylalanine. 
(b) Compound 24b 
##STR88## 
Compounds 24a and 16b were reacted by a procedure analogous to that used 
for the preparation of Compound 4b to give the title Compound 24b. mp 
150.degree.-151.degree. C. [.alpha.].sub.D =-9.1.degree. (c 0.2, MeOH). 
Mass Spec. [M+H].sup.+ =592. Analysis calc. for C.sub.34 H.sub.45 N.sub.3 
O.sub.6 .multidot.0.43 H.sub.2 O: 
C, 68.13; H, 7.71; N, 7.01; Found: C, 68.15; H, 7.58; N, 6.99. 
EXAMPLE 25 
Preparation of 
[1S-[1R*,2S*(2S,2R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydr 
oxy-4-phenylbutyll]amino]-2-hydroxy-1-(2-phenylethyl))propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 25) 
##STR89## 
Compound 24b was converted to the title Compound 25 using procedures 
analogous to those for the synthesis of Compounds 18 through 21. mp 
145.degree.-148.degree. C.; [.alpha.].sub.D =-6.degree. (c 0.3, MeOH). 
Mass Spec: Fab (M+H).sup.+ : 558. Analysis calculated for C.sub.31 
H.sub.47 N.sub.3 O.sub.6 .multidot.0.44H.sub.2 O: 
C; 65.82; H; 8.53; N; 7.43; Found: C; 65.69: H; 8.40; N; 7.56. 
EXAMPLE 26 
Preparation of 
[1R-[1R*,2R*(2R*,3S*)]]-3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2 
-hydroxy-4-phenylbutyl]amino]-2hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 26b(i)) and 
Preparation of [1R-[1R*,2S* 
(2R*,3S*)]]-3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenyl 
butyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 26b(ii)) 
(a) Compound 26a (i) 
##STR90## 
and 
Compound 26a(ii) 
##STR91## 
Compounds 26a(i) and 26a(ii) were prepared by procedures analogous to those 
used for the synthesis of Compounds 1b(i) and 1b(ii), in which 
N-Boc-D-phenylalanine was employed in place of N-Boc-L-phenylalanine. 
(b) Compound 26b(i) 
##STR92## 
and 
Compound 26b(ii) 
##STR93## 
A mixture of Compounds 26a(i) and 26a(ii) were reacted with Compound 16b by 
a procedure analogous to that used for the preparation of Compound 4b 
(except that MeOH at 55.degree. was used in place of DMF) to give, after 
separation by silica gel chromatography the title Compounds 26b(i) and 
26b(ii). 
Compound 26b (i ) m.p. 158.degree.-160.degree. C.; [.alpha.].sub.D.sup.25 
=+14.9.degree. (c 0.35, MeOH). MS: (CI/NH.sub.3): 544 (M+H). Anal. Calc. 
for C.sub.30 H.sub.45 N.sub.3 O.sub.6 .multidot.0.67 H.sub.2 O 
C, 64.84; H, 8.40; N, 7.56 Found: C, 64.66; H, 8.25; N, 7.74 
Compound 26b(ii) m.p. 200.degree.-201.degree. C.; [.alpha.].sub.D.sup.25 
=+6.0.degree. (c 0.1, DMSO). MS: (FAB): 544 (M+H). Anal. Calc. for 
C.sub.30 H.sub.45 N.sub.3 O.sub.6 .multidot.0.32 H.sub.2 O 
C, 65.58; H, 8.37; N, 7.65 Found: C, 65.44; H, 8.38; N, 7.79 
EXAMPLE 27 
Preparation of 
[1S-[1R*,2R*(3S*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy 
-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid 
1,1,dimethylethyl ester (Compound 27b) 
(a) Compound 27a 
##STR94## 
Compound 1b(ii) was converted to Compound 27a by a procedure analogous to 
the one used for the preparation of Compound 16b. 
(b) Compound 27b 
##STR95## 
A mixture of Compounds 26a(i) and 26a(ii) were reacted with Compound 27a by 
a procedure analogous to that used for the preparation of Compound 4b 
(except that MeOH at 55.degree. was used in place of DMF) to give the 
title Compound 27b as a mixture of diastereomers. m.p. 
156.degree.-159.degree. C.; MS: (CI/NH.sub.3): 544 (M+H). Anal. Calc. for 
C.sub.30 H.sub.45 N.sub.3 O.sub.6 .multidot.0.16 H.sub.2 O 
C, 65.91; H, 8.36; N, 7.69 Found: C, 65.89; H, 8.34; N, 7.71 
EXAMPLE 28 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-[[3-(phenylmethoxy)phenyl]methyl]pro 
pyl]carbamic acid, 1,1-dimethylethyl ester (Compound 28g) 
(a) Compound 28a 
##STR96## 
SOCl.sub.2 (1.28 ml) was added dropwise to a solution of DL-meta-tyrosine 
(3.2 g, 17.7 mmol) in 4.4 ml MeOH at -15.degree. C. and the resulting 
solution was stirred at 0.degree. C. for 2 h, and at RT overnight. The 
reaction mixture was concentrated in vacuo and the residue was washed with 
Et.sub.2 O, filtered, and dried in vacuo to yield 3.2 g (94%) of the HCl 
salt of methyl ester Compound 28a. 
(b) Compound 28b 
##STR97## 
Compound 28a (1.54 g, 6.65 mmol) in 70 ml of 0.2N NaHCO.sub.3 was added to 
a 100 ml aqueous solution of Subtilisin (protease type VIII from baccilus 
licheniformis, 3.8 mg) and the reaction mixture was stirred slowly at RT 
for 40 min. The pH of this solution was maintained at pH 8.0 with the 
occasional addition of 1N NaOH. Unreacted methyl ester of D-m-tyrosine was 
extracted 5.times. with 100 ml portions of EtOAc. The aqueous solution was 
acidified with 1N HCl to pH 6.0 and concentrated to 5 ml. The resulting 
solid was filtered, washed with 1 ml of cold H.sub.2 O and dried to yield 
0.45 g of Compound 28b. The filtrate was passed through 20 ml of Dowex 
AG50 in H.sup.+ form, followed by the elution of desired material with 2% 
pyridine in H.sub.2 O to yield an additional 0.14 g of Compound 28b (total 
0.59 g, 98%). This crude product was carried on to the next step. 
(c) Compound 28c 
##STR98## 
Compound 28b (0,473 g, 2.61 mmol) was reacted with BOC-anhydride (0.613 g, 
2.81 mmol) in 20 ml of absolute EtOH overnight at RT. The reaction mixture 
was concentrated in vacuo, and the residue was dissolved in EtOAc (400 ml) 
and washed with H.sub.2 O, brine, dried (Na.sub.2 SO.sub.4), filtered and 
concentrated in vacuo. The crude product was chromatographed through 80 g 
of silica gel using a (2:1:97) MeOH:HOAc:CHCl.sub.3 solvent system. The 
resulting product was crystallized from CHCl.sub.3 (15 ml) to yield 0.41 g 
(59%) of Compound 28c. [.alpha.].sub.D =+10.8.degree. (MeOH, c=1.0) 
(d) Compound 28d 
##STR99## 
Compound 28c (0.41 g, 1.46 mmol), benzyl bromide (0.51 g,,2.98 mmol) and 
Cs.sub.2 CO.sub.3 (0.97 g, 2.96 mmol) were stirred in DMF (2.5 ml) 
overnight. The reaction mixture was diluted with 200 ml of EtOAc and the 
organic solution was washed with water, brine, dried (Na.sub.2 SO.sub.4) 
and concentrated in vacuo. The product was crystallized from 10 ml of 
(1:1) Et.sub.2 O:hexane to yield 0.54 g (81%) of Compound 28d. 
(e) Compound 28e 
##STR100## 
Compound 28d (1.147 g; 2.49 mmol) was dissolved in 2.5 ml of THF and 2.5 ml 
of 1N LiOH and stirred at RT for 20 min. An additional 2.0 ml of THF was 
added and the reaction was stirred for 40 more min. The reaction mixture 
was neutralized with 2.5 ml of 1N HCl at 0.degree. C. and concentrated in 
vacuo to 4 ml. The product was extracted with EtOAC and this solution was 
washed with brine, dried (Na.sub.2 SO.sub.4), and concentrated in vacuo. 
The residue was redissolved in 50 ml of saturated NaHCO.sub.3 and washed 
with Et.sub.2 O (3.times.). The bicarbonate solution was neutralized with 
1N HCl and the product was extracted with EtOAc. The organic extracts were 
washed with brine, dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to 
yield Compound 28e (0.84 g, 91%). 
(f) Compound 28f 
##STR101## 
Compound 28e was converted into Compound 28f by procedures analogous to 
those used for the synthesis of Compound 1b(i). 
(g) Compound 28g 
##STR102## 
Compounds 28f and 16b were reacted by a procedure analogous to that used 
for the preparation of Compound 4b to give the title Compound 28g. 
mp=125.degree.-145.degree. C. High Resolution mass spec: (M+H).sup.+ 
=650.3802; theory=650.3805. 
EXAMPLE 29 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino],2-hyd 
roxy-4-(3-hydroxyphenyl)butyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl]carb 
amic acid, 1,1-dimethylethyl ester (Compound 29) 
##STR103## 
The benzyl group of Compound 28 g (0.177 mmol) was removed by 
hydrogenolysis (MeOH, cat. Pd(OH).sub.2, H.sub.2) by a procedure analogous 
to that used for the preparation of Compound 7 to give, after silica gel 
chromatography, 53 mg (51%) of the title Compound 29. 
m.p.=193.degree.-196.degree. C., [.alpha.].sub.D =-5.65.degree. (MeOH, 
c=0.23) High Resolution mass spec: (M+H).sup.+ 560.3343 theory=560.3336. 
EXAMPLE 30 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(4-pyridinylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 30g) 
(a) Compound 30a 
##STR104## 
Boc-L-serine (4.03 g, 19.6 mmol) and benzyl bromide (3.35 g, 19.6 mmol) 
were stirred with Cs.sub.2 CO.sub.3 (7.5 g, 23.0 mmol) in 20 ml of DMF at 
5.degree. C. for 4 h. The reaction was diluted with Et.sub.2 O (500 ml) 
and the resulting mixture was washed with H.sub.2 O, brine, dried 
(Na.sub.2 SO.sub.4) and concentrated in vacuo. The resulting residue 
solidified and was triturated with hexane, filtered, and dried in vacuo to 
yield Compound 30a as a white solid (mp 62.degree.-64.degree. C., 5.02 g, 
86%). 
(b) Compound 30b 
##STR105## 
Compound 30a (5.0 g, 16.9 mmol) was dissolved in 10 ml of pyridine, and the 
reaction was cooled to -10.degree. C. Tosyl chloride (3.24 g, 17.0 mmol) 
was added portionwise and the reaction mixture was stirred at -10.degree. 
C. for 4 h. Crushed ice was added to the reaction mixture which was 
stirred until the product solidified. The solid was filtered and washed 
thoroughly with water and finally dried over P.sub.2 O.sub.5 overnight to 
give Compound 30b (mp 88.degree.-90.degree. C., 6.8 g, 80%). 
(c) Compound 30c 
##STR106## 
Compound 30b (5.0 g, 11.12 mmol) was partially dissolved in 26 ml of 
acetone. NaI (1.9 g, 12.75 mmol) was added and the reaction mixture was 
stirred for 48 h. The reaction mixture was filtered and the filtrate was 
concentrated in vacuo. The resulting residue was chromatographed on 200 g 
of silica gel using (5:95) acetone:hexane 3.6 g, 82%) to give Compound 30c 
as a white solid (mp 78.degree.-80.degree. C., 
(d) Compound 30d 
##STR107## 
Three grams of zinc dust and 3 g of copper (II) acetate monohydrate were 
suspended in 6 ml of glacial HOAc and this mixture was stirred until it 
solidified (15 min). The mixture was triturated with Et.sub.2 O and 
transferred to a filter funnel under a stream of argon. The solid was 
washed with Et.sub.2 O (200 ml) followed by benzene (50 ml). The resulting 
Zn/Cu couple reagent was dried in vacuo over P.sub.2 O.sub.5 for 2 h; 0.54 
g of it was suspended in 3 ml of benzene and 0.6 ml of dimethylacetamide, 
and sonicated while a solution of Compound 30c (1.82 g, 4.06 mmol) in 7 ml 
of benzene was added slowly. The reaction mixture was sonicated for 45 min 
and then diluted with 4 ml of benzene. 4-Bromopyridine (0.64 g, 4.06 mmol) 
and Pd((Ph).sub.3 P).sub.2 Cl .sub.2 (0.23 g) was added and the reaction 
mixture was stirred at 40.degree. C. for 1 h. The reaction mixture was 
diluted with EtOAc (200 ml) and filtered. The filtrate was stirred with 50 
ml of 0.1N HCl then neutralized with saturated NaHCO.sub.3. The organic 
layer was separated, washed with H.sub.2 O brine, dried (Na.sub.2 
SO.sub.4) and concentrated. The crude product was chromatographed on 80 g 
of silica gel using (2:8) acetone:hexane to give Compound 30d (0.71 g, 
49%). 
(e) Compound 30e 
##STR108## 
Compound 30d (1.2 mmol) was saponified with aqueous LiOH (1.3 ml of 1N 
solution) in 1.2 ml THF using a procedure analogous to the one used for 
Compound 28e to give 0.28 g of the title Compound 30e (m.p.=218.degree. 
C.). 
(f) Compound 30f 
##STR109## 
Compound 30e was converted into Compound 30f by procedures analogous to 
those used for the synthesis of Compound 1b(i). 
(g) Compound 30g 
##STR110## 
Compounds 30f and 16b were reacted by a procedure analogous to that used 
for the preparation of Compound 4b to give the title Compound 30g. 
High Resolution mass spec(M+H).sup.+ 545.3347.sup.+ Theoretical 
(M+H).sup.+ 545.3339.sup.+ .sup.1 H (CD.sub.3 OD, 300 MHz, 50.degree. 
C.): .delta. 8.39-8.37 (m, 2H) , 7.31-7.14 (m, 7H), 3.76-3.59 (m, 4H), 
3.05-3.27 (m, 2H), 2.60-2.85 (m, 6H), 1.29 (br s, 9H). 
EXAMPLE 31 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino-2-hydroxy-1-(6-quinolinylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester 
(Compound 31i) 
(a) Compound 31a 
##STR111## 
6-Methylquinoline (7.0 g, 49 mmol) and selenium oxide (6.0 g, 54 mmol) were 
heated at 150.degree. C. for 1 h and at 220.degree. C. for 30 min. The 
reaction mixture was cooled to RT and the residue was triturated with MeOH 
and filtered. The filtrate was concentrated in vacuo, and the crude 
product was chromatographed on 250 g of silica gel using 3:7 EtOAc:Hexane. 
The appropriate fractions were combined and concentrated to yield 3.8 g 
(49%) of Compound 31a as a white solid. m.p. 93.degree.-95.degree. C. 
(b) Compound 31b 
##STR112## 
Compound 31a (1.65 g, 10.5 mmol) was dissolved in 50 ml of MeOH, cooled to 
5.degree. C. and NaBH.sub.4 (0.397g, 10.5 mmol) was added and the reaction 
mixture was stirred for 15 min. After the addition of 10 ml saturated 
NH.sub.4 Cl, the reaction mixture was concentrated to 10 ml and extracted 
with EtOAc. The organic layer was washed with H.sub.2 O, brine, dried 
(Na.sub.2 SO.sub.4), and concentrated in vacuo to yield a viscous oil 
which on standing solidified (74.degree.-78.degree. C.). This material was 
dissolved in Et.sub.2 O and 4N HCl was added until acidic. The HCl salt 
that precipitated was filtered and dried to yield 1.56 g (76%) of Compound 
31b as its hydrochloride salt. 
(c) Compound 31c 
##STR113## 
SOCl.sub.2 (4.5 ml) was added to Compound 31b (1.46 g, 7.5 mmol). The 
reaction mixture was heated at 110.degree. C. for 1 h, and excess 
SOCl.sub.2 was distilled off. The residue was dissolved in H.sub.2 O and 
1N KOH was added until basic (pH 12). The product was extracted with EtOAc 
and this solution was washed with H.sub.2 O, brine, dried (Na.sub.2 
SO.sub.4) and concentrated to yield Compound 31c (1.22 g, 91%) as a 
crystalline solid. m.p. 65.degree.-68.degree. C. 
(d) Compound 31d 
##STR114## 
Diethylaminomalonate (4.23 g, 20 mmol), di-tert-butyldicarbonate (4.4 g, 20 
mmol) and Et.sub.3 N (2.8 ml, 20 mmol) were dissolved and stirred in 150 
ml of absolute EtOH for 24 h. The reaction mixture was concentrated in 
vacuo and the residue was dissolved in EtOAc (300 ml). This was washed 
with aqueous KHSO.sub.4 (10%), brine, dried (Na.sub.2 SO.sub.4), filtered 
and concentrated in vacuo to yield Compound 31d (4.3 g, 78%) as an oil. 
(e) Compound 31e 
##STR115## 
Sodium ethoxide (4.27M in EtOH, 3.0 ml, 12.8 mmol) was added to an EtOH (5 
ml) solution of Compound 31d (3.52 g, 12.8 mmol), followed by the addition 
of Compound 31c (1.13 g, 6.4 mmol). The reaction mixture was refluxed for 
3.5 h. Celite (2 g) was added and the mixture was concentrated and 
chromatographed on 80 g of Merck silica gel to yield Compound 31e (2.03 g, 
76%) as a crystalline solid. m.p. 110.degree.-113.degree. C. 
(f) Compound 31f 
##STR116## 
Compound 31e (0.8 g, 1.9 mmol) was dissolved in 1 ml of THF and 2.2 ml of 
1N LiOH. The reaction mixture was stirred at 40.degree. C. for 4 hr, 
concentrated down to 2 ml and HOAc was added until pH 4 was reached. The 
mono-acid precipitated and was filtered. Without further purification this 
material was suspended in dioxane and the reaction mixture was heated at 
reflux for 2 hr. The reaction was concentrated and the resulting residue 
was chromatographed on 50 g of Merck silica gel using (3:7) acetone:hexane 
to afford Compound 31f (0.52 g, 80%). m.p. 92.degree.-95.degree. C. 
(g) Compound 31g 
##STR117## 
Compound 31f (1.8 g, 5.2 mmol) in 45 ml of DMF was added dropwise to 700 ml 
of H.sub.2 O containing 10 mg of Subtlisin protease VII and 50 ml of 0.2N 
NaHCO.sub.3. After the addition, the pH was maintained at 7.5 to 8.0 with 
the occasional addition of 0.1N NaOH. After 2.5 h the solution was 
extracted with EtOAc and the aqueous layer was acidified to pH 4 with 
HOAc. The aqueous layer was concentrated in vacuo and the crude product 
was chromatographed on 80 g of Merck silica gel using 16:1.5:0.25 CH.sub.2 
Cl.sub.2 :MeOH:HOAc to afford Compound 31 g (0.82 g, 90%). m.p. 
184.degree.-189.degree. C. (dec) [.alpha.].sub.D =+29.0.degree. (c 0.77, 
MeOH) 
(h) Compound 31h 
##STR118## 
Compound 31h was prepared from Compound 31g by a multi-step procedure 
analogous to that used for the conversion of N-Boc-L-phenylalanine to 
Compound 1b(i). m.p. 136.degree.-140.degree. C. 
(i) Compound 31i 
##STR119## 
Compound 31h (100.9 mg, 0.321 mmol) was reacted with Compound 16b (90 mg, 
0.321 mmol) by a procedure analogous to that of Example 4b to afford the 
title Compound 31i (0.113 g; 59%) as a white solid. m.p. 
105.degree.-112.degree. C.; [.alpha.].sub.D =+4.55.degree. (C 0.88, MeOH) 
. 
EXAMPLE 32 
Preparation of 
[2R-(2R*,3S*)]-1,1'-(Phenylmethyl)iminobis(3-amino-4-phenyl-2-butanol)hydr 
ochloride salt 
(Compound 32) 
##STR120## 
To neat Compound 1c (117 mg, 0.185 mmol) at 0.degree. C. was added HCl in 
dioxane (2.0 mL, 4M). The reaction mixture was stirred at 0.degree. C. for 
15 min and then 1.15 h at RT. The volatiles were then removed in vacuo and 
the residue co-evaporated with dry Et.sub.2 O. The resulting solid was 
dried under high vacuum (P.sub.2 O.sub.5) for 4 h to give the title 
Compound 32 as a colorless solid (91 mg), which was used without further 
purification as the tri-HCl salt. R.sub.f =0.53 (20:7:80, MeOH:NH.sub.4 
OH:CHCl.sub.3) 
EXAMPLE 33 
Preparation of 
[S-(1R*,2S*)]-N,N'-[(Phenylmethyl)iminobis[2-hydroxy-1-(phenylmethyl)-3,1- 
propanediyl]]bis-[N.sup.2 -[(1,1-dimethylethoxy)carbonyl]-L-valinamide] 
(Compound 33) 
##STR121## 
To a solution of Compound 32 (.ltoreq.0.185 mmol) and Boc-(L)-valine (87 
mg, 0.40 mmol) in CH.sub.2 Cl.sub.2 (2.0 mL) at 0.degree. C. under argon 
was added EDCI (85 mg, 0.44 mmol), HOBT (93 mg, 0.69 mmol), and 
4-methylmorpholine (0.065 mL). After 20 min at 0.degree. C., the reaction 
mixture was stirred at RT for 68 h. The reaction mixture was partitioned 
between EtOAc and saturated NaHCO.sub.3. The organic layer was extracted 
with brine, dried over Na.sub.2 SO.sub.4, and the volatiles were 
evaporated in vacuo to give an oily-solid residue. This residue (140 mg) 
was purified by flash column chromatography (silica gel, 2.5 by 13 cm), 
eluting with 0.5, 1, 2, 3, 4 and then 12% MeOH:CH.sub.2 Cl.sub.2 to give 
the title Compound 33 (29.6 mg, 19% yield for the 2 steps) as a colorless 
solid. R.sub.f =0.59 (15% MeOH:CH.sub.2 Cl.sub.2). 
EXAMPLE 34 
Preparation of 
[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]b 
is[N.sup.2 -[(1,1-dimethylethoxy)carbonyl]-L-valinamide] 
(Compound 34) 
##STR122## 
Compound 33 was converted to the title Compound 34 by a procedure analogous 
to the one used for the synthesis of. Compound 7. 
m.p. 216.degree.-222.degree. C.; [.alpha.].sub.D.sup.25 =-28.55.degree. (c 
0.16, MeOH) . MS: 742 (M+H ) . Anal. Calc. for C.sub.40 H.sub.63 N.sub.5 
O.sub.8 . 0.27 H.sub.2 O: C, 64.32; H, 8.58; N, 9.38 Found: C, 63.90; H, 
8.49; N, 9.80 
EXAMPLE 35 
Preparation of 
[S-(1R*,2S*)]-N,N'-[[(Phenylmethyl)imino]bis[2-hydroxy-1-(phenylmethyl)-3, 
1-propanediyl]]bisbenzamide 
(Compound 35) 
##STR123## 
To a suspension of Compound 32 (.ltoreq.0.168 mmol) in CH.sub.2 Cl.sub.2 
(1.5 mL) was added i-Pr.sub.2 NEt (0.09 mL), resulting in a homogeneous 
solution. To the stirring reaction mixture at 0.degree. C. was added 0.04 
ml of benzoyl chloride. A second portion of CH.sub.2 Cl.sub.2 (1.5 mL) and 
i-Pr.sub.2 NEt (0.09 mL) was added after 30 min at 0.degree. C. and the 
reaction mixture was stirred at RT for 1.5 h. At 0.degree. C., the 
reaction mixture was quenched with saturated NaHCO.sub.3 and the aqueous 
layer was saturated with NaCl and extracted with EtOAc and CH.sub.2 
Cl.sub.2. The combined organic layers were dried (Na.sub.2 SO.sub.4) and 
the volatiles were evaporated in vacuo to a slightly yellow solid residue 
which was purified by silica gel chromatography (2 by 10 cm), eluting with 
8:2 EtOAc:CH.sub.2 Cl.sub.2, then EtOAc to give the title Compound 35 (96 
mg, 93% yield) as a colorless solid. R.sub.f =0.60 (20:7:80 MeOH:NH.sub.4 
OH:CHCl.sub.3). 
EXAMPLE 36 
Preparation of 
[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]b 
isbenzamide 
(Compound 36) 
##STR124## 
A mixture of Compound 35 (96 mg, 0.157 mmol) and Pd(OH).sub.2 (45 mg, 20% 
on carbon) in aqueous HOAc (3 mL, 90%) at RT was stirred under a H.sub.2 
atmosphere. After 7 h, a second portion of Pd(OH).sub.2 (6 mg) was added. 
The reaction mixture was stirred for an additional 45 min and filtered 
through Celite, washing the filter pad thoroughly with aqueous HOAc. The 
volatiles were removed in vacuo to give a colorless solid which was 
triturated twice with hot Et.sub.2 O and once with hot EtOAc. The 
resulting residue was purified by flash chromatography (silica gel, 1 by 
11 cm), eluting with MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2 (1:0.1:9) to give 
the title Compound 36 (50 mg, 58% yield) as a colorless solid. 
m.p. dec. 227.degree.-231.degree. C.; [.alpha.].sub.D.sup.25 
=-83.95.degree. (c 0.21, DMSO); MS: 552 (M+H). Anal. Calc. for C.sub.34 
H.sub.37 N3O.sub.4 : C, 74.02; H, 6.76; N, 7.62 Found: C, 73.88; H, 6.90; 
N, 7.62 
EXAMPLE 37 
Preparation of 
[S-(1R*,2S*)]-[[(Phenylmethyl)imino]bis[2-hydroxy-1-(phenylmethyl)-3,1-pro 
panediyl]]bisiminobis[N.sup.2 
-[(1,1-dimethylethoxy)carbonyl]-L-phenylalaninamide] 
(Compound 37) 
##STR125## 
Compound 32 was coupled with Boc-L-phenylalanine by a procedure analogous 
to the one used for the synthesis of Compound 33 (1:1 CH.sub.2 Cl.sub.2 
:DMF was used) to give the title Compound 37. R.sub.f =0.78 (10% 
MeOH:CH.sub.2 Cl.sub.2). 
EXAMPLE 38 
Preparation of [S-(1R*,2S*)]-[Iminobis[2 
-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]-bisimino-bis[N.sup.2 
-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alaninamide] 
(Compound 38) 
##STR126## 
Compound 37 was converted to the title Compound 38 by a procedure analogous 
to the one used for the synthesis of Compound 36. 
m.p. dec. 206.degree.-212.degree. C.; [.alpha.].sub.D.sup.25 
=-14.28.degree. (c 0.13, DMSO); MS: (CI/NH.sub.3): 838 (M+H). Anal. Calc. 
for C.sub.48 H.sub.63 N.sub.5 O.sub.8 . 1.07 H.sub.2 O: C, 67.24; H, 7.66; 
N, 8.17 Found: C, 67.23; H, 7.26; N, 8.18 
EXAMPLE 39 
Preparation of 
[S-(1R*,2S*)]-N,N'-[[[(9H-Fluoren-9-ylmethoxy)carbonyl]imino]-bis[2-hydrox 
y-1-(phenylmethyl)-3,1-propanediyl]biscarbamic acid, bis 
(1,1-dimethylethyl)ester 
(Compound 39) 
##STR127## 
To a mixture of Compound 2 (192 mg, 0.354 mmol) in i-Pr.sub.2 NEt (0.08 mL) 
and DMF (2 mL) at 0.degree. C. was added 9-fluorenylmethyl chloroformate 
(100 mg, 0.386 mmol). After 1 h at 0.degree. C., the reaction mixture was 
stirred at RT for 2 h, quenched at 0.degree. C. with saturated 
NaHCO.sub.3, and extracted with EtOAc. The organic layer was dried 
(Na.sub.2 SO.sub.4) and the volatiles removed in vacuo to leave an 
oily-foam which was purified by flash chromatography (silica gel, 2.5 by 
12 cm), eluting with 30% EtOAc:CH.sub.2 Cl.sub.2 to give the title 
Compound 39 (251 mg, containing 8% by weight of EtOAc by 1H NMR analysis, 
85% yield) as an oily foam. R.sub.f =0.33 (35:65, EtOAc:CH.sub.2 
Cl.sub.2). 
EXAMPLE 40 
Preparation of [R-(R*,S*)]-N,N-Bis(3-amino-2-hydroxy-4-phenylbutyl)carbamic 
acid, 9H-fluoren-9-ylmethyl ester, hydrochloride salt 
(Compound 40) 
##STR128## 
Compound 39 was converted to the title Compound 40 by a procedure analogous 
to the one used for the synthesis of Compound 32. R.sub.f =0.56 (20:6:80, 
MeOH:NH.sub.4 OH:CHCl.sub.3). 
EXAMPLE 41 
Preparation of [S-(1S*,2R*)]-N,N'- 
[[[(9H-Fluoren-9-ylmethoxy)carbonyl]imino]bis-[2-hydroxy-1-(phenylmethyl)- 
3,1-propanediyl]bis [N.sup.2 -[(phenylmethoxy)carbonyl]-L-valinamide] 
(Compound 41) 
##STR129## 
Compound 40 was coupled with Cbz-L-valine by a procedure analogous to the 
one used for the synthesis of Compound 33 (DMF was used) to give the title 
Compound 41. R.sub.f =0.69 (1:9, MeOH:CH.sub.2 Cl.sub.2). 
EXAMPLE 42 
Preparation of 
[1S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]b 
is [N.sup.2 -[(phenylmethoxy)carbonyl]-L-valinamide] 
(Compound 42) 
##STR130## 
To a mixture of Compound 41 (110 mg, 0.107 mmol) in DMF (4 mL) at RT was 
added piperidine (0.20 mL). After 50 min, the reaction mixture was diluted 
with H.sub.2 O and the resulting solid was collected by filtration and 
washed with H.sub.2 O and hexanes. The resulting residue was purified by 
flash chromatography (silica gel, 2 by 13 cm), eluting with MeOH:NH.sub.4 
OH:CH.sub.2 Cl.sub.2 (7:0.7:92.3, 8:0.8:91.2, and then 9:0.9:90.1) to give 
the title Compound 42 (65 mg, 75% yield) as a colorless solid. 
m.p. dec. 217.degree.-221.degree. C.; [.alpha.].sub.D.sup.25 
=-14.14.degree. (c 0.21, DMSO); MS: 810 (M+H) . Anal. Calc. for C.sub.46 
H59N.sub.5 O.sub.8 . 0.56 H.sub.2 O: C, 67.37; H, 7.39; N, 8.54 Found: C, 
67.43; H, 7.17; N, 8.48 
EXAMPLE 43 
Preparation of 
[S-(1S*,2R*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]b 
is-L-valinamide 
(Compound 43) 
##STR131## 
A mixture of Compound 42 (65 mg, 81 .mu.mol) and Pd(OH).sub.2 (23 mg) in 
aqueous HOAc (3 mL, 90%) at RT was stirred under an H.sub.2 for 2.5 h, 
filtered through Celite, washing the filter pad with aqueous HOAc, and the 
volatiles were removed in vacuo. The resulting oily-residue was 
co-evaporated with dry Et.sub.2 O to give a colorless solid (60 mg). This 
residue was dissolved in H.sub.2 O, basified to pH 9-10 with saturated 
aqueous K.sub.2 CO.sub.3 and purified by CHP-20P resin chromatography, 
eluting with H.sub.2 O, then CH.sub.3 CN:NH.sub.4 OH:H.sub.2 O and the 
column flushed with MeOH:NH.sub.4 OH:H.sub.2 O to give the title Compound 
43 (29 mg, .about.62% yield) as a slightly colored solid. m.p. 
115.degree.-116.degree. C. MS: 542 (M+H) . 
EXAMPLE 44 
Preparation of 
[R-(R*,S*)]-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbam 
ic acid, bis(phenylmethyl) ester 
(Compound 44c) 
(a) Compound 44a) 
##STR132## 
Compound 44a was prepared by procedures analogous to those used for the 
synthesis of Compound 1b(i), in which N-Cbz-L-phenylalanine was employed 
in place of N-Boc-L-phenylalanine. 
(b) Compound 44b 
##STR133## 
Compound 44a was converted into Compound 44b by a procedure analogous to 
the one used for the synthesis of Compound 16b except that the reaction 
was done in MeOH saturated with NH.sub.3 at 55.degree. C. for 40 h in a 
sealed bottle. 
(c) Compound 44c 
##STR134## 
Compounds 44a and 44b (1 equivalent of each) were reacted by a procedure 
analogous to that used for the preparation of Compound 4b to give the 
title Compound 44c (white solid). 
mp 167.degree.-171.degree. C.; [.alpha.].sub.D =-27.7.degree. (C 0.13, 
AcOH). Mass Spec. 612 (M+H). Analysis Calc. for C.sub.36 H.sub.41 N.sub.3 
O.sub.6.1.43H.sub.2 O: C, 67.82; H, 6.93; N, 6.59; Found: C, 68.12; H, 
6.56; N, 6.29. 
EXAMPLE 45 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy1-(phenylmethyl)-3,1-propandiyl]biscarbamic 
acid, 1,1-dimethylethyl phenylmethyl ester 
(Compound 45) 
##STR135## 
To a solution of lithium perchlorate (16.4 g, 0.155 mol) in 500 ml CH.sub.3 
CN was added Compound 16b (43.5 g, 0.155 mol) as a solid followed by 
Compound 44a (41.2 g, 0.139 mole) in 150 ml CH.sub.3 CN. The resulting 
mixture was stirred at 30.degree. C. for 2 h and at 40.degree. C. for 30 h 
at which point it was cooled to RT then added to 1.5 L of H.sub.2 O. The 
resulting precipitate was filtered and triturated with i-PrOH followed by 
1:1 EtOAc:i-PrOH (2.times.) to give 42.1 g (52%) of Compound 45 as a white 
solid. 
m.p. 169.degree.-173.degree.; [.alpha.].sub.D =-13.9.degree. (c 1.3, MeOH). 
EXAMPLE 46 
Preparation of 
[R-(R*,S*)]-N,N"-[[(9H-Fluoren-9-ylmethoxy)carbonyl]iminobis-[2-hydroxy-1- 
(phenylmethyl)-3,1-propanediyl]]bis[N'-(1,1-dimethylethyl)urea] 
(Compound 46) 
##STR136## 
To a suspension of Compound 40 (59 mg, 92 .mu.mmol) in CH.sub.2 Cl.sub.2 (1 
mL) was added Et.sub.3 N (40 .mu.L) followed by tert-butylisocyanate (20 
mg, 0.201 mmol). After 3 h, a second portion of tert-butylisocyanate (4.3 
mg, 0.044 mmol) was added and after a further 2 h the volatiles were 
removed in vacuo to leave a colorless solid. The residue was purified by 
flash chromatography (silica gel, 1 by 14 cm), eluting with 0.5, 3, and 
then 4% MeOH:CH.sub.2 Cl.sub.2 to give the title Compound 46 (55 mg, 79% 
yield) as a colorless solid. R.sub.f =0.56 (10:90, MeOH:CH.sub.2 Cl.sub.2) 
(PMA); Mass Spec. (FAB): 764 (M+H) . 
EXAMPLE 47 
Preparation of 
[R-(R*,S*)]-N,N"-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]-bi 
s [N'-(1,1-dimethylethyl)urea] 
(Compound 47) 
##STR137## 
Compound 46 was converted to the title Compound 47 by a procedure analogous 
to the one used for the synthesis of Compound 42. 
m.p. 108.degree.-110.degree. C.; [.alpha.].sub.D.sup.25 =+1.93.degree. (c 
0.19, MeOH). MS: (CI): 542 (M+H). Anal. Calc. for C.sub.30 H.sub.47 
N.sub.5 O.sub.4 . 0.84 H.sub.2 O: C, 64.70; H, 8.81; N, 12.58 Found: C, 
64.85; H, 8.71; N, 12.43 
EXAMPLE 48 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[3-Amino-2-hydroxy-4-phenylbutyl)-[[2-(trimethy 
lsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1.1-dimethylethyl ester 
(Compound 48) 
##STR138## 
Compound 45 was converted to the title Compound 48 by a two-step procedure 
analogous to the coversion of Compound 17b to Compound 19 (MeOH was used 
in removing the carbobenzyloxy group). 
.sup.1 H NMR (CD.sub.3 OD): .delta. 0.05 (s, 9H), 1.03 (m, 2H), 1.30 (s, 
9H), 2.60 (m, 2H), 3.00 (m, 3H), 3.21 (m, 1H) , 3.45-3.82 (m's, 6H), 4.12 
(m, 2H) , 7.11-7.28 (m, 10H). 
EXAMPLE 49 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]carbonyl]amino] 
-2-hydroxy-4-phenylbutyl][2-(trimethylsilyl)ethoxy]carbonyl]amino]- 
2-hydroxy]-1-(phenylmethyl]propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 49) 
##STR139## 
Compound 48 was converted to the title Compound 49 by a procedure analogous 
to that used for the synthesis of Compound 46. 
.sup.1 H NMR (CD.sub.3 OD): .delta. 0.05 (s, 9H), 0.98 (m, 2H), 1.20 (s, 
9H), 1.27 (s, 9H), 2.65 (m, 2H), 3.05 (m, 2H), 3.25 (m, 2H), 3.60-3.85 
(m's, 6H), 4.15 (m, 2H), 7.10-7.30 (m, 10H) . 
EXAMPLE 50 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]carbonyl]amino] 
-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester 
(Compound 50) 
##STR140## 
Compound 49 was deprotected by a procedure analogous to the one used for 
the synthesis of Compound 21 to give the title Compound 50. 
mp 110.degree.-112.degree. C.; [.alpha.].sub.D =-3.5.degree. (c 0.2, MeOH) 
. Mass Spec.: 543 (M+H) . Analysis calc. for C.sub.30 H.sub.46 
N4O.sub.5.1.39H.sub.2 O: C, 63.46; H, 8.66; N, 9.87; Found: C, 63.78; H, 
8.21; N, 9.55. 
EXAMPLE 51 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino]-2-hydroxy-1- 
(phenylmethyl)propyl]-N.sup.2 -[(phenylmethoxy)carbonyl-L-valinamide 
(Compound 51) 
##STR141## 
EDC (44 mg; 0.23 mmol) was added to a solution of Cbz-valine (54 mg; 0.23 
mmol) and HOBT (35 mg; 0.23 mmol) in 1 ml of DMF at 0.degree. C. After 
stirring at 0.degree. C. for 1 h, Compound 48 (124 mg; 0.21 mmol) was 
added, followed by N-methylmorpholine (28 ml; 0.25 mmol ) . The reaction 
mixture was allowed to warm to RT and stir for 20 h, after which time it 
was partitioned between EtOAc (30 ml) and H.sub.2 O (30 ml). The organic 
layer was washed with saturated aqueous KHSO.sub.4 (2.times.), H.sub.2 O, 
1N NaOH (2.times.), H.sub.2 O and brine. The organic layer was dried 
(MgSO.sub.4), concentrated, and the resulting residue purified by silica 
gel column chromatography (2.5.times.12 cm), eluting with 1:1 EtOAc:hexane 
to afford 137 mg (80%) of Compound 51 as a white foam. 
Mass Spec.: 821 (M+H). 
EXAMPLE 52 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 52) 
##STR142## 
Compound 51 was deprotected by a procedure analogous to the one used for 
the synthesis of Compound 21 to give the title Compound 52 (white solid) . 
mp 202.degree.-204.degree. C.; [.alpha.].sub.D =-31.4.degree. (c 0.07, 
AcOH). Mass Spec.: 677 (M+H) . Analysis calc. for C.sub.38 H.sub.52 
N.sub.4 O.sub.7.0.22H.sub.2 O: C, 67.04; H, 7.76; N, 8.23; Found: C, 
67.01; H, 7.79; N, 8.26. 
EXAMPLE 53 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2- 
hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)-carbonyl]-L-aspartamide 
(Compound 53) 
##STR143## 
The title Compound 53 was prepared from Compound 48 by a two-step procedure 
analogous to that used for the synthesis of Compound 52 except that 
Cbz-asparagine was used. 
mp 182.degree.-185.degree. C.; [.alpha.].sub.D =-26.7.degree. (C 0.4, AcOH) 
High Resolution mass spec.(M+H): 692.3665; calc'd for C.sub.37 H.sub.50 
N.sub.5 O.sub.8 : 692.3659. 
EXAMPLE 54 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)amino]-2-hydro 
xy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 54) 
##STR144## 
A suspension of 1.0 g (1.73 mmol) of Compound 45 in 12 ml of EtOH and 6 ml 
of cyclohexene along with 0.1 g of Pd(OH).sub.2 /C was stirred at reflux 
(oil bath temp.=85.degree.) for 1 h. The reaction mixture was cooled to RT 
and filtered through a plug of Celite on a nylon-66 filter and the 
filtrate evaporated to dryness to give 0.705 g (92%) of a white solid 
containing the title Compound 54. .sup.1 H NMR (CD.sub.3 OD): .delta. 1.30 
(s, 9H), [1.18-rotamer], 2.45-2.64 (m, 2H), 2.65-2.84 (m, 4H), 2.93-3.15 
(m, 3H), 3.56-3.73 (m, 3H), 7.10-7.36 (m, 10H). 
EXAMPLE 55 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4 
-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-phenylalaninamide 
(Compound 55) 
##STR145## 
EDC (38.4 mg, 0.20 mmol) was added to a solution of Cbz-phenylalanine (57.0 
mg, 0.19 mmol) and HOBT (33.0 mg, 0.24 mmol) in CH.sub.2 Cl.sub.2 (0.8 mL) 
at 0.degree. C. under argon. After stirring at 0.degree. C. for 1 hr, 
Compound 54 (77.0 mg, 0.17 mmol) was added in dry DMF (1.0 mL). The 
reaction mixture was allowed to warm to RT and stirred overnight. The 
reaction was diluted with CH.sub.2 Cl.sub.2 (40 mL) and washed with 
saturated NaHCO.sub.3 solution (15 mL), H.sub.2 O (15 mL), and brine (15 
mL), dried over MgSO.sub.4, filtered, and concentrated. The crude material 
was purified by flash chromatography (silica gel; 1.5.times.15 cm) eluting 
with CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH (gradient from 98.9:1:0.1 to 
89:9:1) to give 76 mg of the title Compound 55 (62%). 
mp 185.degree.-188.degree. C.; [.alpha.].sub.D =-27.8.degree. (C 0.2, MeOH) 
High Resolution mass spec. (M+H).sup.+ : 725.3906; Calc'd for C.sub.42 
H.sub.53 N.sub.4 O.sub.7 : 725.3914. 
EXAMPLE 56 
Preparation of [S-[1R*,2S*(2S*,3R*)]-N.sup.2 
-[(1,1-Dimethylethoxy)carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]am 
ino]-2-hydroxy-4-phenylbutyl]-amino]-2-hydroxy-1-(phenylmethyl 
)-propyl]-L-phenylalaninamide 
(Compound 56) 
##STR146## 
The title Compound 56 was prepared from Compound 54 and Boc-phenylalanine 
by a procedure analogous to that used for the synthesis of Compound 55. 
mp 179.degree.-182.degree. C.; [.alpha.].sub.D =-14.4.degree. (C 0.6, MeOH) 
Mass Spec.: (M+H)=691 Analysis calculated for C.sub.39 H.sub.54 N.sub.4 
O.sub.7.0.47 H.sub.2 O: C, 66.90 H, 7.92 N, 8.01 Found: C, 67.00 H, 7.64 
N, 7.99 
EXAMPLE 57 
Preparation of 
[1R*,2S*(2S*,3R*)]-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[[(phenylmethyl)am 
ino]carbonyl]amino]butyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester 
(Compound 57) 
##STR147## 
The title Compound 57 was prepared from Compound 48 by a two-step procedure 
analogous to the one used for the synthesis of Compound 50 except that 
benzylisocyanate was used in place of tert-butylisocyanate. 
mp 161.degree.-165.degree. C.; [.alpha.].sub.D =-11.9.degree. (c 0.5, 
MeOH). Mass Spec. (M+H) 577 Analysis calculated for C.sub.33 H.sub.44 
N.sub.4 O.sub.5.0.40 H.sub.2 O C, 67.88; H, 7.73; N, 9.60; Found: C, 
67.90; H, 7.59; N, 9.58. 
EXAMPLE 58 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(1,1-dimethylethoxy)carbonyl]-L-valinamide 
(Compound 58) 
##STR148## 
The title Compound 58 (white solid) was prepared from Compound 48 by a 
two-step procedure analogous to that used for the synthesis of Compound 52 
except that Boc-valine was used. 
mp 182.degree.-187.degree. C.; [.alpha.].sub.D =-11.7.degree. (c 0.06, 
AcOH). Mass Spec.: 642 (M+H) . Analysis calc. for C.sub.35 H.sub.54 
N.sub.4 O.sub.7. 0.26H.sub.2 O: C, 64.93; H, 8.49; N, 8.65; Found: C, 
64.80; H, 8.35; N, 8.78. 
EXAMPLE 59 
Preparation of 
[S-[1R*,2S*(2S*,3R*)-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydr 
oxy-4 -phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide 
(Compound 59) 
##STR149## 
The title Compound 59 (white solid) was prepared from Compound 52 by a 
procedure analogous to the one used for the preparation of Compound 43. mp 
131.degree.-137.degree. C.; [.alpha.].sub.D =+6.0.degree. (C 0.2, MeOH). 
Mass Spec.: 543 (M+H) . Analysis calc. for C.sub.30 H.sub.46 N.sub.4 
O.sub.5.1.14H.sub.2 O: C, 63.97; H, 8.64; N, 9.95; Found: C, 63.96; H, 
8.39; N, 9.96. 
EXAMPLE 60 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethyl-1-oxybutyl)amino]-2-hydroxy- 
4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester 
(Compound 60) 
##STR150## 
The title Compound 60 was prepared from Compound 48 by a two-step procedure 
analogous to that used for the synthesis of Compound 52 except that 
tert-butylacetic acid was used in place of Cbz-valine (CH.sub.2 Cl.sub.2 
replaced DMF and no N-methyl morpholine was used in the EDC coupling). 
mp 153.degree.-156.degree. C.; [.alpha.].sup.rt.sub.D =-3.3.degree. (C 0.1, 
MeOH) . Mass Spec.: 542 (M+H) . Analysis calc. for C.sub.31 H.sub.47 
N.sub.3 O.sub.5.0.54 H.sub.2 O: C, 67.52; H, 8.79; N, 7.62; Found: C, 
67.88; H, 8.80; N, 7.26. 
EXAMPLE 61 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-h 
ydroxy-4-phenylbutyl][[2-(trimethylsilyl) 
ethoxy]carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valinamide 
(Compound 61) 
##STR151## 
A suspension of Compound 51 (385 mg; 0.47 mmol) and 110 mg of Pd(OH).sub.2 
/C in 5 ml of MeOH was stirred at RT under a H.sub.2 atmosphere for 1.5 h. 
The reaction mixture was filtered through a Nylon-66, 0.45 micron filter 
to remove the catalyst and the filtrate was concentrated to dryness. The 
residue was chromatographed on a 2.5.times.20 cm silica gel column, using 
5% MeOH/CH.sub.2 Cl.sub.2 as the mobile phase to afford 306 mg (95%) of 
the title Compound 61 as a white foam. .sup.1 H NMR (DMSO-d.sup.6 ; 
60.degree. C.): .delta. 0.02 (s, 9H), 0.56 (J=7 Hz, 3H), 0.74 (d, J=7 Hz, 
3H), 0.95 (t, J=7.5, 9.5 Hz, 2H), 1.25 (s, 9H), 1.48 (brs, 2H), 1.80 (m, 
1H), 2.62 (m, 2H), 2.87 (d, J=4.5 Hz, 1H), 2.97 (m, 2H), 3.59 (m, 3H), 
3.69 (m, 2H), 3.94 (m, 1H), 4.06 (dd, J=7.5, 14.5 Hz, 2H), 4.87 (m, 1H), 
4.97 (m, 1H), 6.37 (brs, 1H), 7.14 (m, 2H), 7.20 (m, 10H), 7.57 (d, J=9 
Hz, 1H). 
EXAMPLE 62 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]-N-[3S-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-h 
ydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-phenylalanyl]-L-valinamide 
(Compound 62) 
##STR152## 
The title Compound 62 (white solid) was prepared from Compound 61 and 
Cbz-phenylalanine by a two-step procedure analogous to that used for the 
conversion of Compound 48 to Compound 52. 
mp 215.degree.-218.degree. C.; [.alpha.].sub.D =-20.7.degree. (C 0.15, 
AcOH) . Mass Spec.: (M+H=824). Analysis calc. for C.sub.47 H.sub.61 
N.sub.5 O.sub.8.0.90 H.sub.2 O: C, 67.19; H, 7.53; N, 8.33; Found: C, 
67.25; H, 7.25; N, 8.27. 
EXAMPLE 63 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1-naphthalenyloxy)ac 
etyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester 
(Compound 63) 
##STR153## 
The title Compound 63 was prepared from Compound 48 by a two-step procedure 
analogous to that used for the synthesis of Compound 52 except that 
(1-naphthoxy)acetic acid was used. 
m.p. 182.degree.-185.degree. C.; [.alpha.].sub.D =-58.5.degree. (c=0.19, 
MeOH). High Resolution Mass Spec: (M+H=628.3397; C.sub.37 H.sub.46 N.sub.3 
O.sub.6 ; 1.7 ppm error). 
EXAMPLE 64 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(2-naphthalenylcarbony 
l)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester 
(Compound 64) 
##STR154## 
The title Compound 64 was prepared from Compound 48 by a two-step procedure 
analogous to that used for the synthesis of Compound 52 except that 
2-naphthoic acid was used. 
m.p. 188.degree.-192.degree. C.; [.alpha.].sub.D =-64.1.degree. (c=0.19, 
MeOH). High Resolution Mass Spec: (M+H=598.3292; C.sub.36 H.sub.44 N.sub.3 
O.sub.5 ; 1.8 ppm error). 
EXAMPLE 65 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[(2-quinolinyl 
carbonyl)amino]butyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester 
(Compound 65) 
##STR155## 
The title Compound 65 was prepared Compound 48 by a two-step procedure 
analogous to that used for the synthesis of Compound 52 except that 
quinaldic acid was used. 
m.p. 192.degree.-196.degree. C.; [.alpha.].sub.D =-67.2.degree. (c=3.75, 
MeOH). High Resolution Mass Spec: (M+H=599.3257; C.sub.35 H.sub.43 N.sub.4 
O.sub.5 ; 4 ppm error). 
EXAMPLE 66 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl)amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-methyl-N.sup.2 [(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 66b ) 
(a) Compound 66a 
##STR156## 
To a solution of N-Cbz-L-valine (2.51 g, 10.0 mmol) and CH.sub.3 I (5.0 mL, 
80.0 mmol) in dry THF (30 mL) cooled at 0.degree. C. was added Nail (0.90 
g of 80% dispersion in mineral oil, 30.0 mol) in portions. After the 
addition, the suspension was stirred at RT for 12 h at which time 
additional CH.sub.3 I (1.5 mL, 24.0 mmol) was added, followed by 0.25 g of 
NaH (80%, 8.3 mmol). After the suspension was stirred 
for an additional 24 h, EtOAc (50 mL) was added. The mixture was stirred 
for 30 min at RT, and then cooled down to 0.degree. C. H.sub.2 O was added 
dropwise to destroy NaH. The solvents were removed in vacuo, the oily 
residual partitioned between H.sub.2 O and Et.sub.2 O, and the aqueous 
layer extracted with Et.sub.2 O. The combined Et.sub.2 O solution was 
extracted with 40% aqueous NaHCO.sub.3 and the combined aqueous phase 
acidified with 4N HCl to pH 2 and extracted with EtOAc. The EtOAc extracts 
were washed with H.sub.2 O, 5% aqueous NaS.sub.2 O.sub.3, H.sub.2 O, dried 
over MgSO.sub.4 and evaporated in vacuo to dryness to give a pale yellow 
oil, which was crystallized from Et.sub.2 O and pentane to afford white 
crystalline Compound 66a. 
(2.97 g, 97%). mp. 66.degree.-67.degree. C. 
(b) Compound 66b 
##STR157## 
The title Compound 66b was prepared from Compounds 54 and 66a by a 
procedure analogous to the one used for the synthesis of Compound 55 (1 
eq. of N-methylmorpholine was added along with Compound 54). 
mp 67.degree.-70.degree. C.; [.alpha.].sup.rt.sub.D =-59.3.degree. (c 0.8, 
MeOH). Mass Spec. FAB [M+H].sup.+ : 691. Analysis calc. for C.sub.39 
H.sub.54 N.sub.4 O.sub.7.1.15 H.sub.2 O: C, 65.84; H, 7.97; N, 7.87; 
Found: C, 65.94; H, 7.62; N, 7.77. 
EXAMPLE 67 
Preparation of [S-[1R*,2S*(2S*,3R*)]]-N.sup.2 
-[[2,3-Dihydro-1H-inden-1-yl)oxy]carbonyl-N-[3-[[3-[[(1,1-dimethylethoxy)c 
arbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)pro 
pyl]-L-valinamide 
(Compound 67c) 
(a) Compound 67a 
##STR158## 
To a solution of 537 mg (4.00 mmol) of (.+-.)-1-indanol in 20 ml of dry 
CH.sub.2 Cl.sub.2 at 0.degree. C. were added 1.01 g (5.00 mmol) of 
p-nitrophenyl chloroformate and 0.70 mL of Et.sub.3 N. The mixture was 
stirred for 2 h at 0.degree. C. and for 2 h at RT. The reaction mixture 
was diluted with 100 mL of CH.sub.2 Cl.sub.2, and washed with 5% 
KHSO.sub.4 (50 mL), 0.1N NaOH (2.times.50 mL) and saturated NaCl (50 mL). 
The organic layer was dried over Na.sub.2 SO.sub.4, filtered, and 
concentrated in vacuo. Flash chromatography of the residue on silica gel 
(CC-7; buffered, pH=7), eluting with 0-10% EtOAc-hexane, provided 1.24 g 
(.about.100%) of Compound 62a, as a white solid. 
(b) Compound 67b 
##STR159## 
A suspension of 117 mg (1.00 mmol) of L-valine in 1 mL of 1.0N NaOH was 
stirred for 30 min and then treated with a solution of 299 mg (1.00 mmol) 
of Compound 67a in 2 mL of t-butanol and 1 mL of dioxane. The reaction 
mixture was stirred at RT overnight. 0.2 mL of Et.sub.3 N was added to the 
mixture to increase the rate of the reaction and stirring was continued 
for 48 h. The reaction mixture was diluted with 50 mL of EtOAc, and washed 
with 5% KHSO.sub.4 (2.times.25 mL), and saturated NaCl (25 mL). The 
organic layer was dried over Na.sub.2 SO.sub.4, filtered, and concentrated 
in vacuo to provide 355 mg of crude acid. Flash chromatography on silica 
gel, eluting with 50% EtOAc-hexane and then 50% EtOAc-hexane with 0.5% 
HOAc, afforded 209 mg (75%) of Compound 67b, as a white solid. 
(c) Compound 67c 
##STR160## 
The title Compound 67c was prepared as a mixture of diastereomers from 
Compound 54 and Compound 67b by a procedure analogous to that used for the 
synthesis of Compound 55. 
mp 202.degree.-206.degree. C.; [.alpha.].sup.20.sub.D =-15.degree. 
(c=0.071, CH.sub.3 OH) Mass Spec. 703 (M+H).sup.+ Elemental Analysis (%) 
C.sub.40 H.sub.54 N.sub.4 O.sub.7 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 68.35 68.13 
H 7.74 7.84 
N 7.97 7.70 
______________________________________ 
EXAMPLE 68 
Preparation of [S-[1R*,2S*(2S*,3R*)]]-N.sup.2 
-[(1,1'-Biphenyl]-4-ylmethoxy]carbonyl-N-[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]-L-valinamide 
(Compound 68) 
##STR161## 
The title Compound 68 was prepared from Compound 54 by a three-step 
procedure analogous to that used for the synthesis of Compound 67c except 
that 4-biphenylmethanol was used in the first step and 1.1 eq. of Et.sub.3 
N (no t-BuOH) was used in the second step. 
mp 208.degree.-211.degree. C.; [.alpha.].sup.20.sub.D =-19.degree. (c=0. 
077, CH.sub.3 OH) Mass Spec. 753 (M+H).sup.+ Elemental Analysis (%) 
C.sub.44 H.sub.56 N.sub.4 O.sub.7 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 70.19 69.91 
H 7.50 7.48 
N 7.44 7.23 
______________________________________ 
EXAMPLE 69 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-2-Hydroxy-3-[[2-hydroxy-3-[[[methyl(phenylmethyl)a 
mino]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester 
(Compound 69) 
##STR162## 
The title Compound 69 (white solid) was prepared from Compound 48 and 
N-benzyl-N-methyl carbamoyl chloride (Bull. Chem. Soc. Jpn., 50, 1872 
(1977)) by a two-step procedure analogous to that used for the synthesis 
of Compound 50. 
mp 97.degree.-99.degree. C.; [.alpha.].sub.D =-18.8.degree. (C 0.5, 
CH.sub.3 OH). Mass Spec.(FAB) (M+H).sup.+ =591 Analysis calc. for C.sub.34 
H.sub.46 N.sub.4 O.sub.5.0.89H.sub.2 O: Calculated C, 67.31; H, 7.94; N, 
9.23; Found: C, 67.42; H, 7.83; N, 9.12. 
EXAMPLE 70 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylothoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(2-pyridinylmethoxy)carbonyl]-L-valinamide 
(Compound 70d) 
(a) Compounds 70a(i) and 70a(ii) 
##STR163## 
To a solution of L-valine methyl ester hydrochloride (2.5 g; 14.9 mmol) in 
14.9 mL of dry dioxane was added trichloromethyl chloroformate (1.5 g; 7.6 
mmol) at RT. The mixture was heated at 60.degree. C. for 3.5 h. The clear 
solution was cooled to RT and concentrated in vacuo to give an oil, which 
was azeotroped from dry toluene (2.times.10 mL) to give Compounds 70a(i) 
and 70a(ii). 
(b) Compound 70b 
##STR164## 
To a solution of the crude Compounds 70a(i) and 70a(ii) (2.3 g; 14.9 mmol) 
in 48 mL of dry toluene was added 1.6 g (14.9 mmol) of 2-pyridylcarbinol. 
The mixture was heated to reflux for 12 h and then concentrated in vacuo 
to a residue. Purification by flash chromatography (silica gel; 25% 
acetone-hexane) afforded 1.08 g (27% over two steps) of Compound 70b. 
(c) Compound 70c 
##STR165## 
To a solution of Compound 70b (223 mg; 0.83 mmol) in 3.3 mL of dry dioxane 
was added 3.0 mL of 0.5M LiOH. After 12 h at RT, the reaction mixture was 
acidified with 1N HCl (1.5 ml) and then evaporated to dryness. Further 
drying over P.sub.2 O.sub.5 under vacuum at RT gave 300 mg (.about.100%) 
of a brown residue containing Compound 70c. 
(d) Compound 70d 
##STR166## 
The title Compound 70d was prepared from Compounds 54 and crude 70c by a 
procedure analogous to that used for the synthesis of Compound 55 (1 eq. 
of N-methylmorpholine was used). 
m.p. 175.degree.-178.degree. C.; [(.alpha.].sup.rt.sub.D =-16.0.degree. (c 
0.13, MeOH). Mass spec. (M+H) 678 Elemental Analysis (%) C.sub.37 H.sub.51 
N.sub.5 O.sub.7.2.90 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 60.87 60.84 
H 7.54 7.30 
N 9.59 9.57 
______________________________________ 
EXAMPLE 71 
Preparation of 
[R-[1S*,2R*(2R*,3S*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-phenylmethyl) propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-D-valinamide 
(Compound 71) 
##STR167## 
The title Compound 71 was prepared from Compounds 54 and N-Cbz-D-valine by 
a procedure analogous to that used for the synthesis of Compound 55. 
mp 185.degree.-187.degree. C.; [.alpha.].sup.rt.sub.D =+16.25.degree. (c 
0.16, MeOH ) . Mass Spec. FAB [M+H].sup.+ : 677. Analysis calc. for 
C.sub.38 H.sub.52 N.sub.4 O.sub.7. 1.63 H.sub.2 O: C, 64.63; H, 7.89; N, 
7.93; Found: C, 64.63; H, 7.70; N, 8.12. 
EXAMPLE 72 
Preparation of 1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2 
-hydroxy-3-[(phenoxyacetyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)pro 
pyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 72) 
##STR168## 
The title Compound 72 (white solid) was prepared from Compounds 54 and 
phenoxyacetic acid by a procedure analogous to that used for the synthesis 
of Compound 55 (1 eq. of N-methylmorpholine was used). 
mp 162.degree.-165.degree. C.; [.alpha.].sub.D =-17.6.degree. (C 0.5, 
CH.sub.3 OH). Mass Spec.(FAB) (M+H).sup.+ =578 Analysis calc. for C.sub.33 
H.sub.43 N.sub.3 O.sub.6 : Calculated C, 68.61; H, 7.50; N, 7.27; Found: 
C, 68.59; H, 7.58; N, 7.33. 
EXAMPLE 73 
Preparation of 
[(S,R)-3-[[(R,S)-3-[[2-[[(Phenylmethoxy)carbonyl)amino]-2,3-dimethyl 
-1-oxybutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethy 
l)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 73d ) 
(a) Compound 73a 
##STR169## 
A suspension of N-Cbz-L-Valine (2.51 g, 10.0 mmol), paraformaldehyde (2.0 
g) and p-toluene-sulfonic acid (0.2 g) in 200 mL of toluene was heated to 
reflux for 2 h. After being cooled down to RT, the reaction mixture was 
washed with saturated NaHCO.sub.3, brine and dried over MgSO.sub.4. The 
filtrate was concentrated in vacuo to afford 2.32 g (88%) of Compound 73a 
as a light yellow solid. 
(b) Compound 73b 
##STR170## 
To a solution of crude Compound 73a (0.76 g; 2.88 mmol) in 10 ml of dry THF 
cooled at -78.degree. C. was added 6.62 ml (3.31 mmol) of KN(TMS).sub.2 
(0.5M solution in toluene) dropwise over 15 min. The reaction mixture was 
stirred at the same temperature for 15 min, then CH.sub.3 I (0.216 ml, 
3.46 mmol) was added dropwise. The mixture was stirred at -78.degree. C. 
for 20 min, -20.degree. C. for 20 min, then at 0.degree. C. for 1 h. The 
reaction was quenched with 10 ml pH 7 buffer, and extracted with CH.sub.2 
Cl.sub.2 (2.times.50 ml). The combined organics were washed with H.sub.2 
O, brine and dried over MgSO.sub.4. The filtrate was concentrated to 
dryness and the oily residue purified by flash chromatography (silica 
gel), using 20% EtOAc/hexane as the mobile phase to afford 0.487 g (61%) 
of Compound 73b as a colorless oil. 
(c) Compound 73c 
##STR171## 
A solution of Compound 73b (0.46 g, 1.66 mmol) in 5 ml of MeOH and 5 ml of 
1N NaOH was heated at 55.degree. C. for 30 min. After removal of MeOH, the 
aqueous phase was acidified to pH 1-2 with 1N HCl and extracted with 
CH.sub.2 Cl.sub.2 (2.times.30 ml). The combined CH.sub.2 Cl.sub.2 phase 
was washed with water, brine and dried over MgSO.sub.4 to give after 
concentrating in vacuo 0.44 g (100%) of Compound 73c as a colorless oil. 
(d) Compound 73d 
##STR172## 
The title Compound 73d was prepared as a 1:1 mixture of diastereomers from 
Compounds 54 and 73c by a procedure analogous to that used for the 
synthesis of Compound 55. 
mp 66.degree.-68.degree. C.; [.alpha.].sup.rt.sub.D =-5.6.degree. (c 0.25, 
MeOH). Mass Spec. [M+H].sup.+ : 691. Analysis calc. for C.sub.39 H.sub.54 
N.sub.4 O.sub.7. 0.46 H.sub.2 O: C, 67.00; H, 7.92; N, 8.01; Found: C, 
66.88; H, 7.88; N, 8.13. The diastereomers (at position indicated by an 
asterisk) were then separated by HPLC. 
EXAMPLE 74 
Preparation of [[R-(R*,S*)]-1,1'-Iminobis (3-amino-4-phenyl-2-butanol), 
trihydrochloride 
(Compound 74) 
##STR173## 
The title Compound 74 was prepared from Compound 2 by a procedure analogous 
to that used for the synthesis of Compound 32. R.sub.f =0.054 (20:2:78 
MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2). 
EXAMPLE 75 
Preparation of 
[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bi 
s [N.sup.2 -[[methyl(2-pyridinylmethyl)amino]carbonyl]L-valinamide 
(Compound 75f) 
(a) Compound 75a 
##STR174## 
To a solution of di-tert-butyldicarbonate (63 g, 0.29 mole) in 600 ml of 
CH.sub.2 Cl.sub.2 at 0.degree. C. was added a solution of 
2-(aminomethyl)pyridine (31.36 g, 0.29 mole) in 150 ml of CH.sub.2 
Cl.sub.2 in a dropwise manner. After the addition was complete the mixture 
was allowed to slowly warm to RT and stir overnight. The reaction was 
washed with H.sub.2 O (3.times.800 ml), brine (800 ml) and dried (Na.sub.2 
SO.sub.4) to give, after concentration, 58.6 g (97%) of Compound 75a as a 
pale yellow oil. 
(b) Compound 75b 
##STR175## 
Compound 75a was converted to Compound 75b by a procedure analogous to that 
used for the synthesis of Compound 66a except that DMF was used in place 
of THF. 
(c) Compound 75c 
##STR176## 
Compound 75b was converted to Compound 75c by a procedure analogous to that 
used for the synthesis of Compound 32 except that the reaction was run at 
40.degree. C. 
(d) Compound 75d 
##STR177## 
Compound 75c was converted to Compound 75d by a procedure analogous to that 
used for the synthesis of Compound 70b except that CH.sub.2 Cl.sub.2 
replaced toluene and 2.5 eq. of N-methylmorpholine was added. 
(e) Compound 75e 
##STR178## 
Compound 75d was converted to Compound 75e by a procedure analogous to that 
used for the synthesis of Compound 70c (the reaction was quenched with one 
equivalent of 1N HCl). 
(f) Compound 75f 
##STR179## 
A mixture of Compound 74 (136 mg, 0.25 mmol), HOBT (84 mg, 0.55 mmol), and 
Compound 75e (148 mg, 0.55 mmol) in 0.6 ml of dry DMF was cooled to 
0.degree. C. EDCI (108 mg, 0.55 mmol) was added followed by 6 eq. of 
N-methylmorpholine (167 mg, 3.3 mmol). The mixture was stirred at 
0.degree. C. for several hours and was then allowed to slowly warm to RT 
and stir overnight. The DMF was removed in vacuo and the residue was 
partitioned between saturated NaHCO.sub.3 (10 ml) and EtOAc (15 ml). The 
EtOAc layer was washed with additional saturated NaHCO.sub.3, brine, dried 
over MgSO.sub.4 and evaporated to give a crude yellow solid which purified 
on a 30 ml silica column (CC-7, pH 6.8) eluting with 5%-10% MeOH/CH.sub.2 
Cl.sub.2 +0.1% NH.sub.4 OH to afford 86 mg (41%) of the title Compound 75f 
as a colorless solid. 
m.p. 178.degree.-182.degree. C.; [.alpha.].sub.D =-22.4.degree. (c,0.25, 
MeOH) Analysis calc. for C.sub.46 H.sub.63 N.sub.9 O.sub.6. 2.0 H.sub.2 O: 
C, 63.21; H, 7.73; N, 14.42; Found: C, 63.51; H, 7.52; N, 14.12. 
EXAMPLE 76 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4 -phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
[[methyl(2-pyridinylmethyl)amino]carbonyl]-L-valinamide 
(Compound 76) 
##STR180## 
To a solution of Compound 54 (111 mg, 0.25 mmol), HOBT (42 mg, 0.275 mmol), 
and Compound 75e (74 mg, 0.275 mmol) in dry DMF (0.5 ml) at 0.degree. C. 
was added EDCI (53 mg, 0.275 mmol) followed immediately by 
N-methylmorpholine (91 .mu.l, 83 mg, 0.825 mmol). The reaction was stirred 
several hours at 0.degree. C. and was then slowly warmed to RT and stirred 
overnight. The DMF was removed in vacuo and the resulting residue was 
partitioned between EtOAc (10 ml) and H.sub.2 O (10 ml). The organic layer 
was washed with saturated NaHCO.sub.3 and brine, dried over MgSO.sub.4 and 
concentrated to give a crude product which was purified on a 20 ml CC-7 
silica column (Silica pH 6.8) eluting with 3%.fwdarw.10% MeOH/CH.sub.2 
Cl.sub.2 +0.1% NH.sub.4 OH to afford a glasslike residue. Lyophilization 
from dioxane/H.sub.2 O gave 48 mg (28%) of Compound 76 as a colorless 
solid. 
m.p. 184.degree.-188.degree. C.; [.alpha.].sub.D =-16.4.degree. (c=0.2, 
MeOH) High Resolution Mass Spec. (FAB): C.sub.38 H.sub.55 N.sub.6 O.sub.6 
=691.4183; .DELTA.=0.35 ppm. 
EXAMPLE 77 
Preparation of [S-[1R*,2S*[2S*,3R*,N.sup.2 -R*]]-N-[3-[[3 
-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hy 
droxy-1-(phenylmethyl)propyl]-N.sup.2 
-(2-hydroxy-1-oxo-3-phenylpropyl)-L-valinamide 
(Compound 77) 
##STR181## 
The title Compound 77 (white solid) was prepared from Compound 61 and 
L-phenyllactic acid by a two-step procedure analogous to that used for the 
conversion of Compound 48 to Compound 52. 
mp 176.degree.-178.degree. C.; [.alpha.].sub.D =-49.5.degree. (C 0.16, 
MeOH). Mass Spec. FAB+ ion: (M+H)=691. Analysis calc. for C.sub.39 
H.sub.54 N.sub.4 O.sub.7.0.61 H.sub.2 O: C, 66.75; H, 7.93; N, 7.98; 
Found: C, 66.81; H, 7.69; N, 7.92. 
EXAMPLE 78 
Preparation of [S-[1R*,2S*[2S*,3R*,N.sup.2 
-S*[-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbuty 
l]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(2-hydroxy-1-oxo-3-phenylpropyl)-L-valinamide 
(Compound 78) 
##STR182## 
The title Compound 78 (white solid) was prepared from Compound 61 and 
D-phenyllactic acid by a two-step procedure analogous to that used for the 
conversion of Compound 48 to Compound 52. 
mp 188.degree.-194.degree. C.; [.alpha.].sub.D =+7.6.degree. (c 0.17, 
MeOH). Mass Spec. FAB+ ion: (M+H)=691. Analysis calc. for C.sub.39 
H.sub.54 N.sub.4 O.sub.7.1.42 H.sub.2 O: C, 65.38; H, 8.00; N, 7.82; 
Found: C, 65.26; H, 7.84; N, 7.94. 
EXAMPLE 79 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(2-naphthalenylcarbonyl)-L-valinamide 
(Compound 79) 
##STR183## 
The title Compound 79 was prepared from Compound 61 and 2-naphthoic acid by 
a two-step procedure analogous to that used for the conversion of Compound 
48 to Compound 52. 
m.p. 192.degree.-196.degree. C.; [.alpha.].sub.D =-12.6.degree. (C=0.18, 
MeOH) Analysis: calc. for C.sub.41 H.sub.52 N.sub.4 O.sub.6.0.6 H.sub.2 O: 
C, 69.59; H, 7.58; N, 7.92; Found: C, 69.64; H, 7.59; N, 7.87. 
EXAMPLE 80 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(2-quinolinylcarbonyl)-L-valinamide 
(Compound 80) 
##STR184## 
The title Compound 80 was prepared from Compound 61 and quinaldic acid by a 
two-step procedure analogous to that used for the conversion of Compound 
48 to Compound 52. 
m.p. 192.degree.-194.degree. C.; [.alpha.].sub.D =-14.5.degree. (c=0.24, 
MeOH) Analysis calc. for C.sub.40 H.sub.51 N.sub.5 O.sub.6. 0.64 H.sub.2 
O: C, 67.73; H, 7.43; N, 9.87; Found: C, 67.98; H, 7.56; N, 9.62. 
EXAMPLE 81 
Preparation of [2R-[2R*(2S*,3S*),3S*]]-1,1'-Iminobis 
(3-amino-4-phenyl-2-butanol)hydrochloride 
(Compound 81) 
##STR185## 
The title Compound 81 was prepared as a tri-HCl salt from Compound 5 by a 
procedure analogous to that used for the synthesis of Compound 32. 
R.sub.f =0.07 (15:1.5:84.5 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2). 
EXAMPLE 82 
Preparation of 
[S-[1R*,2R*(2S*,3R*)]]-N-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[[N-(phenylm 
ethoxy)carbonyl]-L-valyl]amino]butyl]amino]-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 82) 
##STR186## 
The title Compound 82 was prepared from Compound 81 and Cbz-L-valine by a 
procedure analogous to that used for the synthesis of Compound 75f. 
m.p. 216.degree.-219.degree. C.; [.alpha.].sub.D.sup.25 =-34.8.degree. (c 
0.28, DMSO). Mass Spec.: (FAB): 810 (M+H). Anal. Calc. for C.sub.46 
H.sub.59 N.sub.5 O.sub.8 : C, 68.21; H, 7.34; N, 8.65 Found: C, 67.88; H, 
7.50; N, 8.64 
EXAMPLE 83 
Preparation of 
[R-(R*,S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bisb 
enzeneacetamide 
(Compound 83) 
##STR187## 
The title Compound 83 was prepared from Compound 74 and phenylacetic acid 
by a procedure analogous to that used for the synthesis of Compound 75f. 
m.p dec. 216.degree.-221.degree. C; [.alpha.].sub.D.sup.25 =+11.4.degree. 
(c 0.22, DMSO). MS: (CI/NH.sub.3): 580 (M+H) . Anal. Calc. for C.sub.36 
H.sub.41 N.sub.3 O.sub.4.0.3 H.sub.2 O: C, 73.90; H, 7.17; N, 7.18 Found: 
C, 73.88; H, 7.03; 7.20 
EXAMPLE 84 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2- 
hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl)-L-valyl]-L-p 
henylalanamide, fumarate (2:3) salt 
##STR188## 
A solution of Compound 62 (153 mg; 0.185 mmol) in 2 ml of HOAc was stirred 
for 1 h over 20% Pd(OH).sub.2 /C (50 mg) at RT under a H.sub.2 atmosphere 
(balloon). The catalyst was removed by filtration through a 0.45 micron 
Nylon-66 filter and the filtrate was concentrated to dryness. The residue 
was dissolved in 5 ml of MeOH and fumaric acid (43 mg; 0.370 mmol) was 
added as a solution in hot MeOH. The MeOH was removed in vacuo and the 
residual HOAc was azeotroped with heptane. After drying under high vacuum 
for several hours, the solid was dissolved in .about.2 ml of MeOH and 
Et.sub.2 O (.about.12 ml) was added dropwise with rapid stirring. The 
resulting suspension was filtered and dried under high vacuum at 
60.degree. C. for 48 h to give 149 mg (93%) of Compound 84 as a white 
powder. 
mp 125.degree.-136.degree. C.; [.alpha.].sub.D =-20.7 (c 0.15, MeOH). Mass 
Spec. FAB+ions: M+H=690. Analysis calc. for C.sub.39 H.sub.55 N.sub.5 
O.sub.6. 1.5 C.sub.4 H.sub.4 O.sub.4. 0.52 H.sub.2 O: C, 61.89; H, 7.16; 
N, 8.02; Found: C, 61.91; H, 7.23; N, 8.00. 
EXAMPLE 85 
Preparation of [S-(1R*,2S*,3R*)]-N.sup.2 
-[3-[[(Phenylmethoxy)carbonyl]amino]-1-oxo-3-phenylpropyl)-N-[3-[[3-[[(1,1 
-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenyl-butyl]amino]-2-hydroxy-1 
-(phenylmethyl)-propyl]-L-valinamide 
(Compound 85b ) 
(a) Compound 85a 
##STR189## 
Benzylchloroformate (1.0 ml; 6.70 mmol) and 2N NaOH (3.1 ml; 6.2 mmol) were 
alternately added over 5 min to a vigorously stirred solution of 
3-amino-3-phenylpropionic acid (1.0 g; 6.05 mmol) in 3.05 ml of 2N NaOH at 
0.degree. C. The mixture was stirred for 30 min at 0.degree. C. and 30 min 
at RT. 1N NaOH (10 ml) and water (50 ml) were added and the reaction 
mixture was washed with Et.sub.2 O (3.times.50 ml). After acidifying the 
aqueous layer to pH&lt;1 with 6N HCl, it was extracted with Et.sub.2 O. The 
Et.sub.2 O layer was washed with H.sub.2 O and brine, dried over 
MgSO.sub.4, and concentrated to a white solid which was recrystallized 
from EtOAc:hexane, 1:1 to afford 1.02 g (61% ) of Compound 85a. 
(b) Compound 85b 
##STR190## 
The title Compound 85b (white solid) was prepared as a mixture of 
diastereomers (at carbon marked with an asterisk) from Compounds 61 and 
85a by a two-step procedure analogous to that used for the conversion of 
Compound 48 to Compound 52. .sup.1 H NMR (DMSO-d.sup.6 ; 70.degree. C.): 
.delta. 0.57 (d, J=7 Hz, 1.5H), 0.63 (d, J=7 Hz, 1.5H) , 0.69 (d, J=7 Hz, 
1.5H) , 0.72 (d, J=7 Hz, 1.5H), 1.25 (s, 9H), 2.56 (m, 8H), 2.95 (m, 2H), 
3.43 (m, 2H), 3.57 (m, 1H), 3.91 (m, 1H), 4.04 (m, 2H), 4.55 (brs, 1H), 
4.97 (m, 3H), 6.33 (brs, 1H), 7.25 (m, 20H), 7.50 (m, 2H), 7.56 (d, 8.5 
Hz, 1H). 
EXAMPLE 86 
Preparation of [S-[1R*,2S*(2S*,3R*)]-N.sup.2 
-(3-Amino-1-oxo-3-phenylpropyl)-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]am 
ino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-val 
inamide, fumarate (2:3) salt 
(Compound 86) 
##STR191## 
Compound 85b was converted to the title Compound 86 (white solid) by a 
procedure analogous to that used for the synthesis of Compound 84. 
mp 138.degree.-146.degree. C.; [.alpha.].sub.D =-13.0 (c 0.2, MeOH). Mass 
Spec. FAB+ ion: (M+H)=690. Analysis calc. for C.sub.39 H.sub.55 N.sub.5 
O.sub.6.1.5 C.sub.4 H.sub.4 O.sub.4.0.92 H.sub.2 O: C, 61.98; H, 7.15; N, 
8.03; Found: C, 61.95; H, 7.21; N, 8.06. 
EXAMPLE 87 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[[1-[[(phenylmethoxy)c 
arbonyl]amino]cyclopentyl]carbonyl]amino]-4-phenylbutyl]-amino]-1-(phenylme 
thyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 87b ) 
(a) Compound 87a 
##STR192## 
Compound 87a was prepared from 1-aminocyclopentanecarboxylic acid 
(cycloleucine) by a procedure analogous to that used for the synthesis of 
Compound 85a. 
(b) Compound 87b 
##STR193## 
The title Compound 87b was prepared from Compounds 54 and 87a by a 
procedure analogous to that used for the synthesis of Compound 55. 
mp 70.degree.-73.degree. C.; [.alpha.].sub.D =+9.degree. (c 0.2, MeOH); 
Mass Spec: FAB (M+H)+: 689. Analysis calculated for C.sub.38 H.sub.52 
N.sub.4 O.sub.7.0.65H.sub.2 O C, 66.87; H, 7.67; N, 8.00; Found: C, 66.82; 
H, 7.58; N, 8.05. 
EXAMPLE 88 
Preparation of 
[1S-[1R*-[1R*,2S*(2S*,3R*)]]]-2,2-Dimethyl-1-[[[3-[[3-[[(1,1-Dimethylethox 
y)carbonylamino]-2-hydroxy-4-phenylbutyl]amino]- 
2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamic acid, 
phenylmethyl ester 
(Compound 88b) 
(a) Compound 88a 
##STR194## 
Compound 88a was prepared from L-tert-leucine by a procedure analogous to 
that used for the synthesis of Compound 85a. 
(b) Compound 88b 
##STR195## 
The title Compound 88b was prepared from Compounds 54 and 88a by a 
procedure analogous to that used for the synthesis of Compound 55 (DMF 
only was used along with 1 equivalent of N-methylmorpholine). 
m.p. 144.degree.-147.degree.; [.alpha.].sub.D.sup.25 =-14.8.degree. (c 
0.15, MeOH) {[.alpha.].sub.365 =-62.7.degree. (c 0.15, MeOH)}. Mass Spec.: 
(FAB/SIMS): 691 (M+H) . Analysis Calc. For C.sub.39 H.sub.54 N.sub.4. 0.13 
H.sub.2 O: C,67.58; H,7.89; N,8.08 Found: C,67.32; H,7.76; N,8.34 
EXAMPLE 89 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-lysinamide 
(Compound 89b ) 
(a) Compound 89a 
##STR196## 
Compound 89a was prepared from .alpha.-N-Cbz-L-lysine and 
trimethylsilylethylchloroformate by a procedure analogous to that used for 
the synthesis of Compound 85a. 
(b) Compound 89b 
##STR197## 
The title Compound 89b (white solid) was prepared from Compounds 48 and 89a 
by a two-step procedure analogous to that used for the synthesis of 
Compound 52 (6 equivalents of n-Bu.sub.4 NF was used). 
mp 129.degree.-131.degree. C.; [.alpha.].sub.D =-19.4.degree. (c 0.35, 
MeOH). Mass Spec. FAB+ion: (M+H)=706. Analysis calc. for C.sub.39 H.sub.55 
N.sub.5 O.sub.7.1.49H.sub.2 O: C, 63.93; H, 7.98; N, 9.56; Found: C, 
64.01; H, 7.68; N, 9.48. 
EXAMPLE 90 
Preparation of 
[S-(1R*,2S*]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bi 
s [L-valinamide], trihydrochloride 
(Compound 90) 
##STR198## 
The title Compound 90 was prepared from Compound 34 by a procedure 
analogous to that used for the synthesis of Compound 32. R.sub.f =0.29 
(20:2:78 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2) . 
EXAMPLE 91 
Preparation of 
[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]b 
is [N.sup.2 -[N-[(1,1-dimethoxyethyl)carbonyl]-L-phenylalanyl]-L-valinamide 
] 
(Compound 91) 
##STR199## 
The title Compound 91 was prepared from Compound 90 and Boc-L-phenylalanine 
by a procedure analogous to that used for the synthesis of Compound 75f. 
R.sub.f =0.31 (10:1:89 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2). MS: (FAB): 
1036 (M+H). 
EXAMPLE 92 
Preparation of 
[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bi 
s [N.sup.2 -(L-phenylalanyl)-L-valinamide], trihydrochloride 
(Compound 92) 
##STR200## 
Compound 91 (81 mg; 78.2 .mu.mol) was stirred with methanolic HCl (1 ml of 
2.09M solution) at 0.degree. C. for 30 min and at RT for 2 h. The 
volatiles were removed and the residue evaporated from Et.sub.2 O and 
dried under high vacuum overnight. The resulting solid was dissolved in 
MeOH and precipitated with Et.sub.2 O after which it was triturated with 
Et.sub.2 O and EtOAc to give 62 mg (86%) of a light-orange colored solid. 
m.p. dec. 180.degree.-187.degree. C.; [.alpha.].sub.D.sup.25 =-16.5.degree. 
(c 0.12, MeOH); MS: (FAB): 836 (M+H) . Anal. Calc. for C.sub.48 H.sub.68 
C.sub.13 N.sub.7 O.sub.6 . 2.58 H.sub.2 O: C, 58.13; H, 7.43; N, 9.88 
Found: C, 58.20; H, 7.33; N, 9.81 
EXAMPLE 93 
Preparation of [S-[1R*,2S*(2S*,3R*)]]-N, 
[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy 
-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(1H-benzimidazol-2-ylmethoxy) carbonyl]-L-valinamide 
(Compound 93f ) 
(a) Compound 93a 
##STR201## 
A mixture of 3.24 g (30.0 mmol) of .sigma.-phenylenediamine and 3.42 g 
(45.0 mmol) of glycolic acid in 30 mL of 4N HCl was heated at reflux for 
45 min. The resulting solution was cooled to RT and basified (pH=8) with 
NH.sub.4 OH. The resulting suspension was cooled in an ice bath, and the 
solid filtered, rinsed with cold H.sub.2 O and recrystallized from H.sub.2 
O to afford 2.70 g (61%) of Compound 93a as a tan solid. 
(b) Compound 93b 
##STR202## 
To a solution of 500 mg (3.37 mmol) of Compound 93a in 5 mL of DMF were 
added 357 mg (3.37 mmol) of Na.sub.2 CO.sub.3 and 0.58 mL (3.37 mmol; 80% 
pure) of benzyl chloromethyl ether. The mixture was stirred at 0.degree. 
C. for 1 h and at RT for 24 h. The mixture was partitioned between EtOAc 
and H.sub.2 O, and the combined organic extracts dried over Na.sub.2 
SO.sub.4, filtered, and concentrated in vacuo to give 945 mg of crude 
material. Flash chromatography on silica gel (25-100% EtOAc-hexane; then, 
5% CH.sub.3 OH-EtOAc) provided 339 mg (39%) of Compound 93b. 
(c) Compound 93c 
##STR203## 
To a solution of 260 mg (1.01 mmol) of Compound 93b in 3 mL of CH.sub.2 
Cl.sub.2 and 1.5 mL of pyridine at 0.degree. C. was added 214 mg (1.06 
mmol) of p-nitrophenylchloroformate in 1.5 mL of CH.sub.2 Cl.sub.2. The 
mixture was stirred at 0.degree. C. for 1 h and at RT for 3 h, diluted 
with 100 mL of EtOAc and washed with 1M NaOH (3.times.25 mL), H.sub.2 O 
(2.times.25 mL), and brine (25 mL). The organic layer was dried over 
MgSO.sub.4, filtered, and concentrated in vacuo affording 396 mg of 
Compound 93c. 
(d) Compound 93d 
##STR204## 
To a solution of 105 mg (0.893 mmol) of L-valine in 0.9 mL of 1.0N NaOH was 
added a solution of 387 mg (0.893 mmol) of Compound 93c in 3 mL of dioxane 
and 0.2 mL of Et.sub.3 N. The mixture was stirred at RT for 18 h and 
partitioned between EtOAc and H.sub.2 O. The aqueous layer was acidified 
to pH=4 with 5% KHSO.sub.4 and extracted with EtOAc (2.times.25 mL). The 
combined organic extracts were dried over Na.sub.2 SO.sub.4, filtered, and 
evaporated in vacuo to provide 0.79 g of crude acid. Flash chromatography 
on silica gel, eluting with 50% EtOAc-hexane and then 10% MeOH-CHCl.sub.3, 
afforded 151 mg (41%) of Compound 93d. 
(e) Compound 93e 
##STR205## 
To a solution of 242 mg (0.588 mmol) of Compound 93d in 3 mL of MeOH was 
added a solution of HCl (0.74 mmol) in 5 mL of MeOH and 200 mg of 
Pd(OH).sub.2. The mixture was stirred under a H.sub.2 atmosphere (balloon) 
for 4 h at which time an additional 0.1 mL of 1N HCl and 50 mg of 
Pd(OH).sub.2 was added. The mixture was stirred under a H.sub.2 atmosphere 
for another 2.5 h and then filtered and evaporated in vacuo. 
Re-evaporation in vacuo from CHCl.sub.3 /Et.sub.2 O afforded 326 mg of 
crude Compound 93e as an HCl salt. 
(f) Compound 93f 
##STR206## 
To a solution of 270 mg (.about.0.488 mmol; ca. 60% pure, contaminated with 
solvent) of Compound 93e in 3 mL of dry DMF at 0.degree. C. were added 228 
mg (0.488 mmol) of Compound 54, 99 mg (0.73 mmol) of HOBT, 110 .mu.L of 
N-methylmorpholine, and 104 mg (0.54 mmol) of EDC. The mixture was stirred 
at RT for 18 h, diluted with 100 mL of EtOAc, and washed with saturated 
NaHCO.sub.3, H.sub.2 O, and brine. The organic layer was dried over 
Na.sub.2 SO.sub.4, filtered and evaporated in vacuo to give 0.41 g of 
crude material. Flash chromatography on silica gel (5% CH.sub.3 
OH/CHCl.sub.3, then 5-7.5% CH.sub.3 OH/CHCl.sub.3 with 0.5% NH.sub.4 OH) 
followed by precipitation from hot MeOH with Et.sub.2 O provided 150 mg of 
the title Compound 93f. 
mp 161.degree.-165.degree. C.; Mass Spec. 717 (M+H).sup.+ 
EXAMPLE 94 
Preparation of 
[1S-[[1R*[1R*,2S*(2S*,3R*)]]]-[2-[[3-[[3[[(1,1-Dimethylethoxy)carbonyl]ami 
no]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]- 
2-oxo-1-phenylethyl]carbamic acid, phenylmethyl ester 
(Compound 94) 
##STR207## 
The title Compound 94 was prepared from Compound 54 and Cbz-L-phenylglycine 
by a procedure analogous to that used for the preparation of Compound 55 
(DMF only used along with 2 eq. N-methyl morpholine). 
m.p. 203.5.degree.-205.degree. C.; [.alpha.].sub.D =+16.2.degree. (c 0.22, 
AcOH) Elemental Analysis (%) for C.sub.41 H.sub.50 N.sub.4 O.sub.7 . 0.24 
H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 68.86 68.98 
H 7.11 7.13 
N 7.83 7.71 
______________________________________ 
Example 95 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-valinamide 
(Compound 95) 
##STR208## 
The title Compound 95 was prepared from Compound 61 and Cbz-alanine by a 
procedure analogous to that used for the two-step conversion of Compound 
48 to Compound 52. 
EXAMPLE 96 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(L-alanyl)-L-valinamide, fumarate salt 
(Compound 96) 
##STR209## 
Compound 95 was converted into Compound 96 by a procedure analogous to the 
one used for the synthesis of Compound 84. 
mp 168.degree.-174.degree. C.; [.alpha.].sub.D.sup.22 =-19.degree. (c 0.15, 
CH.sub.3 OH) High Resolution Mass Spec. (FAB): C.sub.33 H.sub.52 N.sub.5 
O.sub.6 =614.3908.sup.+ ;.DELTA.=1.6 ppm. 
EXAMPLE 97 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valinamide 
(Compound 97) 
##STR210## 
The title Compound 97 was prepared from Compound 61 and Cbz-L-leucine by a 
procedure analogous to that used for the two-step conversion of Compound 
48 to Compound 52. 
EXAMPLE 98 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(L-leucyl)-L-valinamide, fumarate salt 
(Compound 98) 
##STR211## 
Compound 97 was converted into Compound 98 by a procedure analogous to the 
one used for the synthesis of Compound 84. 
mp 184.degree.-190.degree. C.; [.alpha.].sub.D.sup.22 =-12.degree. (c 0.16, 
CH.sub.3 OH) High Resolution Mass Spec. (FAB): C.sub.36 H.sub.57 N.sub.5 
O.sub.6 =656.4382.sup.+ ; .DELTA.=0.8 ppm. 
EXAMPLE 99 
Preparation of 
[S-(1R*,2S*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]] 
bis[N.sup.2 -[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]-L-valinamide] 
(Compound 99) 
##STR212## 
The title Compound 99 was prepared from Compound 90 and Boc-glycine by a 
procedure analogous to the one used for the synthesis of 75f. 
m.p. 212.degree.-215.degree. C.; [.alpha.].sub.D =-26.2.degree. (c 0.1, 
AcOH) Elemental Analysis (%) for C.sub.44 H.sub.69 N.sub.7 O.sub.10 . 0.78 
H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 60.74 60.81 
H 8.17 8.08 
N 11.27 11.20 
______________________________________ 
EXAMPLE 100 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-threoninamide 
(Compound 100) 
##STR213## 
The title Compound 100 (white solid) was prepared from Compound 54 and 
Cbz-L-threonine by a procedure analogous to that used for the synthesis of 
55 (DMF only used). 
m.p. 150.degree.-155.degree. C.; [.alpha.].sub.D =-17.8.degree. (C 0.18, 
MeOH) Mass Spec.: 679 (M+H) Elemental Analysis (%) for C.sub.37 H.sub.50 
N.sub.4 O.sub.8 . 0.75 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 64.20 64.25 
H 7.50 7.34 
N 8.09 8.04 
______________________________________ 
EXAMPLE 101 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy- 1-(phenylmethyl) propyl]-N.sup.2 
-[(1H-benzimidazol-2-yl)carbonyl]-L-valinamide] 
(Compound 101b) 
(a) Compound 101a 
##STR214## 
To a solution of 0.500 g (3.37 mmol) of Compound 93a in 10 mL of boiling 
H.sub.2 O was added 10 drops of 3M NaOH. The resulting solution was kept 
at 100.degree. C. during the addition (10 min) of a solution of 0.8 g 
(5.05 mmol) of KMnO.sub.4 in 50 mL of water. Heating at 100.degree. C. was 
continued for 30 min. The hot mixture was filtered through celite, cooled 
to RT and acidified with HOAc. The white precipitate was collected by 
suction filtration and recrystallized from H.sub.2 O to afford 185 mg 
(34%) of Compound 101a. 
mp 170.degree.-172.degree. C. (--CO.sub.2). 
(b) Compound 101b 
##STR215## 
The title Compound 101b was prepared from Compounds 61 and 101a by a 
two-step procedure analogous to that used for the conversion of Compound 
48 to Compound 52. 
m.p. 210.degree.-215.degree. C.; [.alpha.].sup.20.sub.D =-30.degree. (c 
0.32, CH.sub.3 OH) Mass Spec. 687 (M=H).sup.+ Elemental Analysis (%) 
C.sub.38 H.sub.50 N.sub.6 O.sub.6 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.45 66.53 
H 7.34 7.38 
N 12.24 12.21 
______________________________________ 
EXAMPLE 102 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2- 
hydroxy-4-phenylbutyl]amino]-2-hydroxy -1-(phenylmethyl)propyl]-N.sup.2 
-[phenylmethoxy)carbonyl]-L-prolinamide 
(Compound 102) 
##STR216## 
The title Compound 102 (white solid) was prepared from Compound 54 and 
Cbz-L-proline by a procedure analogous to that used for the synthesis of 
Compound 55 (used DMF only). 
m.p. 142.degree.-146.degree. C.; [.alpha.].sub.D =-31.7.degree. (C 0.81, 
MeOH) Mass Spec. 675 (M+H) Elemental Analysis (%) for C.sub.38 H.sub.50 
N.sub.4 O.sub.7 . 0.69 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.42 66.29 
H 7.53 7.41 
N 8.15 8.28 
______________________________________ 
EXAMPLE 103 
Preparation of [S-[1R*,2S*(2S*,3R*)]-N.sup.2 
-[3-(1H-Benzimidazol-2-yl)-1-oxo-propyl]-N-[3-[[3-[[(1,1-dimethylethoxy)ca 
rbonyl]amino-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valin 
amide 
(Compound 103b) 
(a) Compound 103a 
##STR217## 
A mixture of .sigma.-phenylenediamine (2.70 g, 25 mmol) and succinic acid 
(5.02 g, 42.5 mmol) was heated at reflux in 150 ml of 5N HCl for 3 hrs. 
The mixture was allowed to stand overnight at RT, filtered and then the pH 
was adjusted to 5 with 5N NaOH. The aqueous mixture was saturated with 
NaOAc and stored overnight at 0.degree. C. The crude product precipitated 
as a tan solid and was crystallized from H.sub.2 O/EtOH (9:1) affording 
968 mg (20%) of the Compound 103a. See Chemical Abstracts CA: 19953 g 
(1961); French Patent 1,179,933 (May 29, 1959). 
(b) Compound 103b 
##STR218## 
The title Compound 103b was prepared from Compounds 61 and 103a by a 
two-step procedure analogous to that used for the conversion of Compound 
48 to Compound 52. 
mp 182.degree.-185.degree. C.; [.alpha.].sub.D.sup.22 =-20.degree. (c 0.25, 
CH.sub.3 OH) Analysis. calc. for C.sub.40 H.sub.54 N.sub.6 O.sub.6 . 2.5 
mole H.sub.2 O: C, 63.22; H, 7.80; N, 11.06; Found: C, 63.06; H, 7.47; N, 
10.90. 
EXAMPLE 104 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy]-1-(phenylmethyl)propyl]-N.sup.2 
-[(1H-indol-2-ylmethoxy)carbonyl]-L-valinamide 
(Compound 104e ) 
(a) Compound 104a 
##STR219## 
A solution of LiBH.sub.4 (1.6M in THF, 2.4 mL, 3.8 mmol) was added at 
-78.degree. C. to a stirred solution of 1.0 g, 3.5 mmol, of 
2-formyl-1-phenylsulfonyl indole (Saulnier et al., J. Org. Chem., 47, 757 
(1982)) in 30 mL of Et.sub.2 O. The mixture was allowed to come to RT and 
stirred for 30 min. The reaction mixture was carefully quenched by adding 
sat. NaHCO.sub.3, diluted with EtOAc and stirred for 30 min. The organic 
layer was separated, dried over MgSO.sub.4 and concentrated to afford 
0.975 g (97%) of Compound 104a. 
(b) Compound 104b 
##STR220## 
To a solution of Compound 104a (0.97 g, 3.38 mmol) in 15 mL 
2-methoxyethanol was added 3 mL 20% aq. KOH. The mixture was heated under 
reflux for 3 h, allowed to come to RT and partitioned between EtOAc and 
brine. The organic layer was washed with brine, dried over sodium sulfate 
and concentrated to afford a crude brown oil which was purified by flash 
chromatography (silica gel/hexane-EtOAc 5:1 to 1:1) giving 0.45 g (91%) of 
Compound 104b as a yellow solid. 
(c) Compound 104c 
##STR221## 
Trichloromethyl chloroformate (1.08 mL) was added to a stirred suspension 
of L-valine methyl ester hydrochloride (3.0 g, 17.9 mmol) in 10 mL dry 
dioxane. The mixture was refluxed for 1.5 h, concentrated, and the residue 
flash distilled (bath temperature 100.degree.-125.degree. C., 0.5 mm 
vacuum) to afford 1.0 g of L-valine methyl ester isocyanate. A solution of 
0.55 g (3.5 mmol) of L-valine methyl ester isocyanate in 7.5 mL dry 
toluene was treated with 4M HCl in dioxane (79 mL, 0.315 mmol) at RT and 
stirred for 5 min. The resulting mixture was treated with 1.0 g solid 
K.sub.2 HPO.sub.4 for 5 min, followed by the addition of Compound 104b 
(0.464 g, 3.15 mmol). The mixture was refluxed for 9 h, diluted with EtOAc 
and washed with sat. NaHCO.sub.3 followed by brine. The organic phase was 
dried (MgSO.sub.4), concentrated, and the crude product purified by flash 
chromatography (silica gel/hexane to EtOAc-hexane 1:9 to 1:4, stepwise 
gradient) to afford 0.51 g (53%) of Compound 104c as a yellow gummy solid. 
(d) Compound 104d 
##STR222## 
To a solution of Compound 104c (0.5 g, 1.64 mmol) in 7 mL dioxane was added 
0.54 M aq. LiOH (3.05 mL, 1.64 mmol), stirred at RT for 12 h, concentrated 
and the residue chased 3 times with toluene. The resulting off-white Li 
salt (0.5 g) of the acid was used as such for the next step. 
(e) Compound 104e 
##STR223## 
To a solution of Compound 104d (0.15 g, 0.51 mmol) and HOBT (0.101 g, 0.66 
mmol) in 1.5 mL dry DMF at 0.degree. C. was added EDC (0.108 g, 0.56 mmol) 
and N-methyl morpholine (0.111 mL, 1.02 mmol), and the resulting mixture 
was stirred at 0.degree. C. for 1 h. The mixture was treated with Compound 
54 (0.226 g, 0.51 mmol), and stirred at RT for 12 h, concentrated, and the 
residue partitioned between EtOAc and sat. NaHCO.sub.3. The organic layer 
was washed with brine, dried over MgSO.sub.4, concentrated, and the crude 
product was purified by flash chromatography (silica gel/CHCl.sub.3 
-MeOH-NH.sub.4 OH 99:1:0.5 to 90:10:1) followed by preparative HPLC 
(Waters Prep Nova-Pack HR C18, 6 micron, 30.times.300 mm; eluent: 
MeOH-H.sub.2 O-TFA 75:25:0.05 to 80:20:0.05; UV 254 nm). The desired 
fractions were made basic with sat. NaHCO.sub.3, concentrated, and the 
residue partitioned between EtOAc/1:1 brine-sat. NaHCO.sub.3. The organic 
phase was dried over MgSO.sub.4, concentrated and the resulting white 
solid was triturated from 10:1 hexane-Et.sub.2 O to afford 0.181 g (50%) 
of the title Compound 104e as a white solid. 
[.alpha.].sub.D =+3.0.degree. (c=0.5, CH.sub.2 Cl.sub.2); m.p. 
115.degree.-120.degree. C. 
High Resolution Mass Spectrum: (M+H).sup.+ =716.4010, .DELTA. 1.8 ppm error 
(theoretical: (M+H).sup.+ : 716.5023). 
EXAMPLE 105 
Preparation of 
S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydr 
oxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]-N.sup.2 
-(1H-benzimidazol-2-ylacetyl)-L-yalinamide 
(Compound 105) 
##STR224## 
The title Compound 105 was prepared from Compound 61 and 
2-benzimidazoleacetic acid (Copeland et al., J. Am. Chem. Soc., 65, 1072 
(1943)) by a two-step procedure analogous to that used for the conversion 
of Compound 48 to Compound 52. 
m.p. 177.degree.-182.degree. C.; Mass spec (FAB) 701 (M+H) 
Elemental Analysis 
Calc. for C.sub.39 H.sub.52 N.sub.6 O.sub.6 .multidot.0.78 H.sub.2 O C, 
65.52; H, 7.55; N, 11.75 
Found C, 65.52; H, 7.40; N, 11.68 
EXAMPLE 106 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-3-[[3-[[3,3-Dimethyl-1-oxo-2-(phenylmethoxy)butyl] 
amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenyl-methyl)propyl]car 
bamic acid, 1,1-dimethylethyl ester 
(Compound 106e) 
(a) Compound 106a 
##STR225## 
A solution of 1.18 g (10 mmoles) of 3,3-dimethyl-2-hydroxy-1-butanol and 
3.1 g of triphenylmethyl chloride in 25 ml of pyridine was stirred at RT 
overnight. The reaction mixture was evaporated to dryness and the residue 
diluted with EtOAc and washed with 1N HCl, brine, saturated NaHCO.sub.3 
and brine. After drying (MgSO.sub.4), removal of solvent gave an oily 
residue which was purified by flash chromatography on a 400 cc column of 
silica gel. Elution with 5% ether-hexane afforded 3.0 g (8.5 mmoles, 85% 
yield) of Compound 106a as a clear colorless oil which crystallized on 
standing. 
(b) Compound 106b 
##STR226## 
To a solution of 750 mg (2.1 mmoles) of Compound 106a in 9 ml of dry THF, 
at -10.degree. C. was added dropwise 4.6 ml (2.3 moles) of 0.5M 
KN(TMS).sub.2 in toluene. Cooling was removed and the clear solution 
stirred for 0.5 hr. The reaction was ice cooled and 309 .mu.l (2.6 mmoles) 
of benzyl bromide was added dropwise, neat. Stirring was continued at RT 
for 1 hr. The reaction was diluted with brine and extracted with EtOAc. 
The extracts were washed with brine, dried (MgSO.sub.4) and the solvent 
evaporated to yield an oily residue which was purified by flash 
chromatography on a 450 cc column of silica gel. Elution with 20% CH.sub.2 
Cl.sub.2 -hexane gave 880 mg (1.95 mmoles, 94% yield) of Compound 106b as 
a colorless oil. 
(c) Compound 106c 
##STR227## 
A solution of 0.8 g (1.8 mmoles) of Compound 106b and 40 mg of 
p-toluenesulfonic acid in 20 ml of MeOH was stirred at RT for 3 hr. The 
reaction was evaporated to dryness and the residue placed on a 400 cc 
column of silica gel. Elution with 20% Et.sub.2 O-hexane, followed by 30% 
Et.sub.2 O-hexane gave 233 mg (1.12 mmole, 63%) of Compound 106c as a 
clear colorless oil. 
(d) Compound 106d 
##STR228## 
To a solution of 5.8 g (16.8 mmoles) of pyridinium dichromate in 8 ml of 
DMF at RT was added dropwise a solution of 1.0 g (4.8 mmoles) of Compound 
106c in 2 ml of DMF. The dark solution was stirred overnight, poured into 
80 ml of ice/water and extracted with Et.sub.2 O. The extracts were 
filtered through a Celite-MgSO.sub.4 mixture and extracted with saturated 
NaHCO.sub.3, and H.sub.2 O. The combined aqueous fractions were washed 
once with Et.sub.2 O, acidified with 6N HCl, and extracted with Et.sub.2 
O. The combined extracts were washed with brine, dried (MgSO.sub.4) and 
the solvent removed to yield 480 mg of clear colorless oil. Distillation 
(kugelrohr, 140.degree. C., 0.05 mm) gave 410 mg (1.8 mmoles, 38%) of 
Compound 106d as a clear colorless oil. 
(e) Compound 106e 
##STR229## 
The title Compound 106e was prepared as a white solid from Compounds 54 and 
106d by a procedure analogous to that used for the synthesis of Compound 
55 (DMF only; 2 eq. of N-methylmorpholine used). 
m.p. 114.degree.-117.degree. C.; Mass spec. (M+H) 648 
Elemental Analysis 
Calc. for C.sub.38 H.sub.53 N.sub.3 O.sub.6 : C, 70.45; H, 8.25; N, 6.49 
Found: C, 70.09; H, 8.27; N, 6.57 
EXAMPLE 107. 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-(p 
henylmethyl)propyl]carbamic acid, phenylmethyl ester 
(Compound 107) 
##STR230## 
Compound 45 was converted to the title Compound 107 by a procedure 
analogous to the one used for the synthesis of Compound 39. 
.sup.1 H NMR (CD.sub.3 OD): .delta.1.23 (m, 9H), 2.42 (m, 1H), 2.59 (m, 
1H), 2.91 (m, 1H), 3.07 (m, 1H), 3.18 (m, 1H), 3.28 (m, 1H), 3.44-3.88 
(m's, 6H), 4.27 (m, 1H), 4.52 (m, 2H), 4.87 (m, 2H), 7.05-7.47 (m's, 19H), 
7.64 (m, 2H), 7.78 (m, 2H). 
EXAMPLE 108 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)-[(9H-fluoren 
-9-yl-methoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester 
(Compound 108) 
##STR231## 
Compound 107 was converted to the title Compound 108 by a procedure 
analogous to that used for the synthesis of Compound 61 (EtOH was employed 
in place of MeOH). Compound 108 was used without further purification in 
the preparation of Compound 109 following. 
EXAMPLE 109 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)carbonyl]-amino]-2 
-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 109) 
##STR232## 
Compound 108 was coupled with Cbz-valine by a procedure analogous to that 
used for the preparation of Compound 51 to give the title Compound 109. 
Mass Spec. (FAB): 899 (M+H).sup.+. 
EXAMPLE 110 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)-[(9H-fluore 
n-9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-valinamide, monohydrochloride 
(Compound 110) 
##STR233## 
Acetyl chloride (39.8 uL, 56.0 mmol, 10 eq.) was added at 0.degree. C. to 
MeOH (560 uL) followed by Compound 109 (50 mg, 0.56 mmol). The viscous 
solution was diluted with 1 mL MeOH and an additional solution of acetyl 
chloride (39.8 uL) in MeOH (2 mL) was added. The white turbid mixture was 
allowed to warm to RT, stirred for 4 hrs, and then gently warmed to 
40.degree. C. After 1 h, the volatiles were removed in vacuo to yield 46 
mg (99%) of Compound 110 which was used without further purification. 
EXAMPLE 111 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[N-[(phenylm 
ethoxy)-carbonyl]-L-valyl]amino]butyl][(9H- fluoren-9 
-yl-methoxy)carbonyl]amino]-1-(phenylmethyl)propyl]-N.sup.2- 
[(phenylmethoxy)carbonyl]-L-asparaginamide 
(Compound 111) 
##STR234## 
Compound 110 and Cbz-L-asparagine were reacted by a procedure analogous to 
that used for the preparation of Compound 51 to give the title Compound 
111. 
Mass Spec.: (FAB): 1047.5 (M+H).sup.+. 
EXAMPLE 112 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[2-Hydroxy-3-[[2-hydroxy-4-phenyl-3-[[N-[(phenylm 
ethoxy)carbonyl]-L-valyl]amino]butyl]amino]-1-(phenylmethyl)propyl]-N.sup.2 
[(phenylmethoxy)-carbonyl]-L-asparaginamide, monohydrochloride 
(Compound 112) 
##STR235## 
Compound 111 was converted to the title Compound 112 by a procedure 
analogous to that used for the synthesis of Compound 42. Compound 112 was 
isolated as the HCl salt which was recrystallized from MeOH/Et.sub.2 O. 
mp 198.degree.-200.degree. C.; [.alpha.].sub.D =-31.degree. (c 0.2, AcOH) . 
Mass Spec.: (FAB): 825 (M+H).sup.+. 
Analysis calculated for C.sub.45 H.sub.56 N.sub.6 O.sub.9.HCl.2.30H.sub.2 
O: C, 59.93; H, 6.77; N, 9.32; 
Found: C, 60.26; H, 6.56; N, 8.99; 
EXAMPLE 113 
Preparation of 
[1S-[1R*,2S*(2R*,3R*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydr 
oxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
phenylmethyl ester 
(Compound 113c) 
(a) Compound 113a 
##STR236## 
Compound 113a was prepared during the reduction procedure in which Compound 
44a above was prepared and isolated. 
(b) Compound 113b 
##STR237## 
Compound 113b was prepared from Compound 113a by a procedure analogous to 
that used for the synthesis of Compound 1b(ii). 
(c) Compound 113c 
##STR238## 
Compounds 113b and 16b (1 eq. of each) were reacted by a procedure 
analogous to that used for the synthesis of Compound 4b to give the title 
Compound 113c (white solid). 
.sup.1 H NMR (CD.sub.3 OD): .delta.1.29 (s, 9H), 2.56 (dd, J=10.5, 14 Hz, 
1H), 2.66 (m, 2H), 2.80 (m, 3H), 2.91 (dd, J=5.5, 13.5 Hz, 1H), 3.09 (dd, 
J=3.5, 14 Hz, 1H), 3.60 (m, 2H), 3.80 (m, 1H), 3.86 (m, 1H), 4.99 (m, 2H), 
7.20 (m, 15H). 
EXAMPLE 114 
Preparation of 
[1S-[1R*,2S*(2R*,3R*)]-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)amino]-2-hydro 
xy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 114) 
##STR239## 
Compound 113c was converted to the title Compound 114 (white foam) using 
conditions analogous to those used for the synthesis of Compound 7. 
.sup.1 H NMR (CD.sub.3 OD): .delta.1.29 (s, 9H), 2.54 (dd, J=10.5, 14 Hz, 
1H), 2.63 (dd, J=7.5, 12 Hz, 1H), 2.71 (m, 2H), 2.85 (dd, J=9.5, 12.5 Hz, 
1H), 2.91 (m, 2H), 3.10 (m, 2H), 3.62 (m, 3H), 7.28 (m, 10H). 
EXAMPLE 115 
Preparation of 
[S-[1R*,2R*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)-carbonyl]-L-valinamide 
(Compound 115) 
##STR240## 
Compound 114 and Cbz-valine were reacted by a procedure analogous to that 
used for the synthesis of Compound 55 (DMF only as solvent) to give the 
title Compound 115. 
mp 183.degree.-186.degree. C.; [.alpha.].sub.D =-38.7.degree. (c 0.23, 
MeOH). 
Mass Spec. FAB: M+H=677. 
Analysis calc. for C.sub.38 H.sub.52 N.sub.4 O.sub.7 .multidot.0.81 H.sub.2 
O: C, 66.01; H, 7.82; N, 8.10; 
Found C, 65.95; H, 7272; N, 8.16. 
EXAMPLE 116 
Preparation of 
[S-(R*,R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbam 
ic acid, 1,1-dimethylethyl phenylmethyl ester 
(Compound 116) 
##STR241## 
Compounds 27a and 113b (1 eq. of each) were reacted by a procedure 
analogous to that used for the synthesis of Compound 4b to give the title 
Compound 116 (white foam). 
.sup.1 H NMR (CD.sub.3 OD): .delta.1.34 (s, 9H), 2.52 (m, 4H), 2.75 (m, 
2H), 2.87 (m, 2H), 3.69 (m, 3H), 3.82 (m, 1H), 4.98 (s, 2H), 7.22 (m, 
15H). 
EXAMPLE 117 
Preparation of 
[S-[1R*,2R*(2R*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)-carbonyl]-L-valinamide 
(Compound 117) 
##STR242## 
Compound 116 was converted to the title Compound 117 by a two-step 
procedure analogous to that used for the synthesis of Compound 115 
(removal of the Cbz group using conditions analogous to those for Compound 
7, and coupling of the resulting product with Cbz-valine analogous to 
Compound 55 [DMF only]). 
mp 170.degree.-175.degree. C.; [.alpha.].sub.D =-51.5.degree. (c 0.20, 
MeOH). 
Mass Spec. FAB+ions: M+H=677. 
Analysis calc. for C.sub.38 H.sub.52 N.sub.4 O.sub.7 .multidot.0.59 H.sub.2 
O: C, 66.38; H, 7.80; N, 8.15; 
Found C, 66.25; H, 7.61; N, 8.28. 
EXAMPLE 118 
Preparation of [S-(R*,R*)]-1,1'-Iminobis(3-amino-4-phenyl-2-butanol) 
(Compound 118) 
##STR243## 
Compound 3 was converted to the title Compound 118 (which was used without 
further purification in the following Example as the tri-HCl salt) by a 
procedure analogous to that used for the synthesis of Compound 32. R.sub.f 
=0.035 (20:2:78 MeOH:NH.sub.4 OH:CHCl.sub.3). 
EXAMPLE 119 
Preparation of 
[S-(1R*,2R*)]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]b 
is[N.sup.2 -[phenylmethyloxy)carbonyl]-L-valinamide] 
(Compound 119) 
##STR244## 
Compound 118 and Cbz-L-valine were reacted by a procedure analogous to that 
used for the synthesis of Compound 75f to give the title Compound 119. 
m.p. dec. 206.degree.-208.degree. C.; [.alpha.].sub.D.sup.25 =-42.8.degree. 
(c 0.14, DMSO). 
MS: (FAB): 810 (M+H). 
Anal. Calc. for C.sub.46 H.sub.59 N.sub.5 O.sub.8 .multidot.1.08 H.sub.2 O: 
C, 66.62; H, 7.43; N, 8.44 
Found: C, 66.71; H, 7.33; N, 8.35 
EXAMPLE 120 
Preparation of [S-[1R*,2S* 
(2S*,3R*)]]-N-[3-[(3-Amino-2-hydroxy-4-phenylbutyl)amino]-2-hydroxy-1-(phe 
nylmethyl)-propyl]-N.sup.2 -[(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 120) 
##STR245## 
Compound 52 was converted to the title Compound 120 (used without further 
purification in the next Example) by a procedure analogous to that used 
for the synthesis of Compound 110. 
.sup.1 H NMR (CD.sub.3 OD): .delta.0.52 (d, J=6.6 Hz, 3H), 0.56 (d, J=6.6 
Hz, 3H), 1.70 (m, 1H), 2.70 (m, 1H), 2.95 (m, 1H), 3.05 (m, 4H), 3.17 (m, 
2H), 3.57 (d, J=7.2 Hz, 1H), 3.72 (m, 1H), 3.80 (m, 1H), 4.07 (m, 1H), 
4.28 (m, 1H), 5.11 (s, 2H), 7.12-7.42 (m's, 15H). 
EXAMPLE 121 
Preparation of [S-[1R*,2S*(2S*,3R*)]]-N.sup.2 
-[(1,1-Dimethylethoxy)carbonyl]-N-[2-hydroxy-3-[[2-hydroxy-4-phenyl-3-[[N- 
[(phenylmethoxy)carbonyl]-L-valyl]amino]butyl]amino]-1-(phenylmethyl)propyl 
]-L-asparacinamide 
(Compound 121) 
##STR246## 
Compound 120 was reacted with Boc-L-asparagine by a procedure analogous to 
that used for the synthesis of Compound 55 (DMF only; 2 eq. of 
N-methylmorpholine added) to give the title Compound 121. 
mp 199.degree.-202.degree. C.; [.alpha.].sub.D =-31.degree. (c 0.2, AcOH). 
Mass Spec.: FAB (M+H).sup.+ 791. 
Analysis calculated for C.sub.42 H.sub.58 N.sub.6 O.sub.9.0.61H.sub.2 O: C, 
62.90; H, 7.44; N, 10.48; 
Found: C, 63.04; H, 7.33; N, 10.34. 
EXAMPLE 122 
Preparation of [R-(R*,S*)]-[[(Phenylmethyl)-imino]bis 
[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarbamic acid, bis 
(1-methylethylester 
(Compound 122) 
##STR247## 
To a solution of Compound 32 (165 mg; 0.35 mmol) and 0.27 mL (1.56 mmol) of 
i-Pr.sub.2 NEt in 0.35 mL of dry DMF at 0.degree. C. was added 0.78 mL 
(0.78 mmol) of isopropyl chloroformate. The reaction mixture was stirred 
at RT for 72 h, at which point it was quenched with saturated aqueous 
NaHCO.sub.3 and extracted with Et.sub.2 O. The organic layer was washed 
with brine and dried (Na.sub.2 SO.sub.4). The salts were filtered and the 
solvents removed in vacuo to give a residue, which was purified on silica 
gel (gradient of 75:25 to 50:50 hexane:EtOAc) to give 100 mg of Compound 
122 (white solid). 
.sup.1 H NMR (CDCl.sub.3): .delta.1.11 (d, 6H), 1.70 (1H), 1.17 (d, 6H), 
2.50-2.59 (m, 4H), 2.70-2.83 (m, 4H), 3.40-3.51 (m, 2H), 3.60-3.83 (m, 
5H), 4.69 (m, 2H), 4.76-4.82 (m, 2H), 7.13-7.35 (m, 15H). 
EXAMPLE 123 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propandiyl]biscarbami 
c acid, bis(1-methylethyl)ester 
(Compound 123) 
##STR248## 
Compound 122 was converted to the title Compound 123 by a procedure 
analogous to that used for the synthesis of Compound 2. 
m.p. 195.degree.-200.degree. C.; [.alpha.].sub.D =-13.2.degree. (c, 0.09, 
MeOH) 
Mass spec. (CI) (M+H) 516 
Elemental Analysis (%) 
C.sub.28 H.sub.41 N.sub.3 O.sub.6 .multidot.0.63 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.22 64.00 
H 8.01 7.88 
N 8.15 7.80 
______________________________________ 
EXAMPLE 124 
Preparation of 
[1S-[1R*,2R*(2S*,3R*)]]-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenvlbutvl]amino]-2-hydroxy-1-(phenyl-methyl)propyl]carbamic acid, 
phenylmethyl ester 
(Compound 124) 
##STR249## 
Compounds 27a and 44a (1 eq. of each) were reacted by a procedure analogous 
to that used for the synthesis of Compound 4b (white powder) to give the 
title Compound 124. 
.sup.1 H NMR (DMSO-d.sup.6): .delta.1.30 (s, 9H), 2.57 (m, 6H), 2.80 (dd, 
J=5.5, 13.5, 1H), 3.01 (d, J=11 Hz, 1H), 3.41 (m, 1H), 3.50 (m, 1H), 3.60 
(m, 1H), 3.70 (m, 1H), 4.73 (m, 1H), 4.85 (m, 1H), 4.88 (d, J=13 Hz, 1H), 
4.93 (d, J=13 Hz, 2H), 6.40 (d, J=9 Hz, 1H), 7.27 (m, 15H). 
EXAMPLE 125 
Preparation of 
[S-[1R*,2S*(2R*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
[(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 125) 
##STR250## 
Compound 124 was converted to the title Compound 125 by a two-step 
procedure analogous to that used for the synthesis of Compound 115 
(removal of Cbz group using conditions analogous to those used for 
Compound 7 (AcOH used in place of MeOH), and coupling of the resulting 
product with Cbz-valine analogous to Compound 55 (DMF only). 
mp 175.degree.-180.degree. C.; [.alpha.].sub.D =-26.0.degree. (c 0.15, 
MeOH). 
Mass Spec. FAB+ions: M+H=677. 
Analysis calc. for C.sub.38 H.sub.52 N.sub.4 O.sub.7 .multidot.0.95 H.sub.2 
O: C, 65.77; H, 7.83; N, 8.07; 
Found C, 65.55; H, 7.59; N, 8.29. 
EXAMPLE 126 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethylbutyl)amino]-2-hydroxy-4-phen 
ylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]-amino]-2-hydroxy-1-(phenylmeth 
yl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 126) 
##STR251## 
To a solution of Compound 48 (300 mg, 0.51 mmol) in 1.55 mL MeOH (adjusted 
to pH 6 with AcOH) was added 3,3-dimethylbutylraldehyde (70 .mu.l, 0.56 
mmol, 1.1 eq. ) and a small amount of pulverized 4 .ANG. molecular sieves. 
To this mixture at RT was added NaCNBH.sub.3 (48 mg, 0.77 mmol) in two 
portions. The reaction was quenched after 2 h with 10 mL saturated 
NaHCO.sub.3 solution and extracted with CH.sub.2 Cl.sub.2. The combined 
extracts were washed with brine, dried over MgSO.sub.4, filtered, 
concentrated, and dried in vacuo to yield 330 mg crude oil. The residue 
was purified by chromatography on a 3.times.16 cm silica gel column, 
eluting with CH.sub.2 Cl.sub.2, then 98.9:1:0.1 and 97.8:2:0.2 CH.sub.2 
Cl.sub.2 :MeOH:NH.sub.4 OH to afford 238 mg (69%) of Compound 126. 
Mass Spec: 672 (M+H).sup.+ 
EXAMPLE 127 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3.3-Dimethylbutyl)amino]-2-hydroxy-4-phen 
ylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester 
(Compound 127) 
##STR252## 
Compound 126 was converted to the title Compound 127 by a procedure 
analogous to the one used for the synthesis of Compound 21. 
mp 89.degree.-91.degree. C.; [.alpha.].sub.D =+9.degree. (c 0.24, MeOH). 
Mass Spec: Fab (M+H).sup.+ : 528. C, 68.82; H, 9.40; N, 7.77; 
Found: C, 68.51; H, 9.16; N, 8.02. 
EXAMPLE 128 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-Amino-2-hydroxy-4-phenylbutyl][(9H-fluoren- 
9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester, monoacetate salt 
(Compound 128) 
##STR253## 
A solution of 1.69 g (2.1 mmoles) of Compound 107 and 2.0 ml of 
1,4-cyclohexadiene in 60 ml of EtOH containing 225 mg of 10% Pd/C catalyst 
was stirred under a hydrogen atmosphere for 3.5 hr. The catalyst was 
removed by filtration through Celite and 0.5 ml of HOAc added. Evaporation 
to dryness gave 1.8 g (assumed 100% yield) of Compound 128 as a white 
solid. [TLC: R.sub.f =0.38, 10% MeOH-CH2Cl.sub.2 ]. 
Mass Spec. 666 (M+H). 
EXAMPLE 129 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[(9H-Fluoren-9-ylmethoxy)carbonyl][3-(formylam 
ino)-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbam 
ic acid, 1,1-dimethylethyl ester 
(Compound 129) 
##STR254## 
Formic acetic anhydride was prepared by the addition of 260 .mu.l of formic 
acid to 745 .mu.l of acetic anhydride at 0.degree. C. and the resulting 
solution then heated at 50.degree. C. for 2 h. The anhydride was dissolved 
in 5 ml of THF and added to a slurry of 1.8 g (assumed 2.1 mmoles) of 
Compound 128 in 20 ml of THF. The reaction was stirred at 0.degree. C. for 
30 min, then at RT for 30 min, and then evaporated to dryness to yield the 
crude product as a white foam. This material was purified by flash 
chromatography on a 75 cc column of silica gel. Elution with 50% 
EtOAc-hexane, followed by 100% EtOAc gave 1.16 g (1.67 mmole, 80% yield 
over two steps) of Compound 129 as a solid white foam. [TLC: R.sub.f 
=0.29, EtOAc] 
Mass Spec. 694 (M+H). 
EXAMPLE 130 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[(9H-Fluoren-9-ylmethoxy)carbonyl][2-hydroxy-3 
-(methylamino)-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbam 
ic acid, 1,1-dimethylethyl ester, monoacetate salt 
(Compound 130) 
##STR255## 
To a solution of 785 mg (1.13 mmoles) of Compound 129 in 10 ml of THF at 
0.degree. C. was added dropwise 2.85 ml of 2M borane-methyl sulfide in 
THF. After foaming ceased the reaction mixture was heated at 50.degree. C. 
for 1 h then cooled to 0.degree. C. and excess borane hydrolyzed by the 
dropwise addition of approx. 10 ml of MeOH. After reaction ceased, 0.5 ml 
of HOAc was added and the solution heated at 50.degree. C. for 6 h to 
destroy the amine-boron complex. The solution was evaporated to dryness 
and the residue purified by flash chromatography on a 35 cc column of 
silica gel (elution with 100% EtOAc, 10% MeOH-EtOAc, and 20% MeOH-EtOAc). 
After the appropriate fractions were combined, 0.5 ml of HOAc was added 
and the solvent removed to yield 625 mg (0.84 mmole, 75% yield) of 
Compound 130 as a solid white foam. This material contained approximatly 3 
equivalents of HOAc by .sup.1 H NMR. [TLC: R.sub.f =0.43, 10% 
MeOH-CH.sub.2 Cl.sub.2 ]. 
Mass Spec. 690 (M+H). 
EXAMPLE 131 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)-carbonyl]amino]-2-hydroxy-1-(p 
henyl-methyl)propyl]methylcarbamic acid, 1,1-dimethylethyl ester 
(Compound 131) 
##STR256## 
To a solution of 160 mg (0.166 mmole, based on 3 eq of HOAc) of Compound 
130 and 137 mg (0.63 mmole) of di-t-butyl dicarbonate in 1 ml of DMF at 
0.degree. C. was added, dropwise, 146 .mu.l of Et.sub.3 N. After 30 min an 
additional 65 mg of di-t-butyl dicarbonate and 75 .mu.l of Et.sub.3 N were 
added and stirring continued for an additional 30 min. The reaction was 
diluted with EtOAc and washed with water and brine, dried (MgSO.sub.4), 
and the solvent removed to yield a residue which was purified by flash 
chromatography on a 20 cc column of silica gel (elution with 25% 
EtOAc/hexane, followed by 50% EtOAc/hexane) to give 129 mg (0.166 mmole, 
89% yield) of Compound 131 as a solid white foam. [TLC: R.sub.f =0.30, 50% 
EtOAc/Hexane] 
Mass Spec. 780 (M+H). 
EXAMPLE 132 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-3-[[-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]methylcarbamic 
acid, 1,1-dimethylethyl ester 
(Compound 132) 
##STR257## 
Compound 131 was converted to the title Compound 132 by a procedure 
analogous to the procedure used for the synthesis of Compound 42 (CH.sub.2 
Cl.sub.2 used in place of DMF). 
[.alpha.].sub.D =-19.6.degree. (c=0.6, MeOH); MS: (M+H).sup.+ =558; MW=557 
Anal. Calc. for C.sub.31 H.sub.47 N.sub.3 O.sub.6 .multidot.0.33 H.sub.2 
O: C, 66.06; H, 8.52; N, 7.46. Found: C, 66.00; H, 8.47; N, 7.52. 
EXAMPLE 133 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]-amino]-2-h 
ydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxy-1-( 
phenylmethyl)propyl]-N-methyl-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 133) 
##STR258## 
To a solution of 75 mg (0.087 mmole) of Compound 130 in 0.5 ml of MeOH was 
added a solution of 6.2 .mu.l (0.087 mmole) of AcCl in 1 ml of MeOH. The 
solution was evaporated to dryness and the residue co-evaporated from 
toluene to remove traces of HOAc. The residue was dried under high vacumn 
for 2 h to give 68 mg of the hydrochloride salt as a white solid. This 
material was diluted with 1 ml of CH.sub.2 Cl.sub.2, cooled to 0.degree. 
C. and 44 mg (0.174 moles) Cbz-L-valine and 49 mg (0.192 mmole) of BOP-Cl 
added as solids, followed by 46 .mu.l (0.261 mmole) of i-Pr.sub.2 NEt. The 
solution was stirred at 0.degree. C. for 4.5 hr and then placed directly 
on a 16 cc column of silica gel (elution with 50% EtOAc/hexane afforded 70 
mg (0.077 mmole, 88% yield) of the title Compound 133 as a white foam. 
[TLC: R.sub.f =0.27, 50% EtOAc-hexane]. 
Mass Spec.: 913 (M+H). 
EXAMPLE 134 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]-N-methyl-N.su 
p.2 -[(phenylmethoxy)carbonyl]-L-valinamide 
(Compound 134) 
##STR259## 
Compound 133 was converted to the title Compound 134 (solid white foam) by 
a procedure analogous to the procedure used for the synthesis of Compound 
42 (CH.sub.2 Cl.sub.2 used in place of DMF). 
[.alpha.].sub.D =-35.6.degree. (c 0.82, MeOH). 
Mass Spec.: 691 (M+H). 
Elemental Analysis (%) 
for C.sub.39 H.sub.54 N.sub.4 O.sub.7 .multidot.0.36 H.sub.2 O C; 67.18; H; 
7.91; N; 8.03 
Found: C; 67.12; H; 7.83; N; 8.09 
EXAMPLE 135 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]-carbonyl]methy 
lamino]-2-hydroxy-4-phenylbutyl][(9H-fluoren-9-ylmethoxy)-carbonyl]amino]-2 
-hydroxy-1(phenylmethyl)propyl]-carbamic acid, 1,1-dimethylethyl ester 
(Compound 135) 
##STR260## 
A solution of 110 mg of Compound 130 (0.13 mmole, material contained 3 eq. 
of HOAc by NMR) and 14.5 .mu.l (0.16 mmole) of t-butyl isocyanate in 2 ml 
of CH.sub.2 Cl.sub.2 was stirred at RT for 3 hr. An additional 7 .mu.l of 
t-butyl isocyanate was added and stirring continued for 2.5 hr. The 
solution was evaporated to dryness to give 112 mg of a white foam which 
was combined with material from a similar reaction (total 130 mg) and 
purified by flash chromatography on a 20 cc column of silica gel (elution 
with 50% EtOAc/hexane) to afford 110 mg (0.14 mmole, 88% yield) of the 
title Compound 135 as a solid white foam. [TLC: R.sub.f =0.66, 100% 
EtOAc]. 
Mass Spec. 799 (M+H). 
EXAMPLE 136 
Preparation of 
[1S-[1R*,2S*(2S,3R*)]]-[3-[[3-[[(1,1-Dimethylethyl)amino]carbonyl]methylam 
ino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl))propyl]carba 
mic acid, 1,1-dimethylethyl ester 
(Compound 136) 
##STR261## 
Compound 135 was converted to the title Compound 136 (solid white foam) by 
a procedure analogous to the procedure used for the synthesis of Compound 
42 (CH.sub.2 Cl.sub.2 used in place of DMF). TLC: R.sub.f =0.31, CH.sub.2 
Cl.sub.2 -MeOH-NH.sub.4 OH, 90:10:1] 
[.alpha.].sub.D =-15.2.degree. (c=0.27, MeOH) 
Mass Spec.: 557 (M+H) . 
Calc. for C.sub.31 H.sub.48 N.sub.4 O.sub.5 .multidot.0.28 H.sub.2 O 
(561.79): C,66.28; H, 8.71, N, 9.97. 
Found: C, 66.40; H, 8.59, N, 9.85. 
EXAMPLE 137 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)amino]thioxomethyl]am 
ino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy1-(phenylmethyl))propyl]carbam 
ic acid, 1,1-dimethylethyl ester 
(Compound 137) 
##STR262## 
Compound 48 was converted to the title Compound 137 (white solid) by a 
two-step procedure analogous to that used for the preparation of Compound 
50 (t-butylisothiocyanate used in place of t-butylisocyanate). 
m.p. 85.degree.-87.degree. C. ("softening" at 75.degree.-85.degree. C.). 
[.alpha.].sub.D =-12.8.degree. (c=0.40, MeOH) 
Compound 138 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propandiyl]]biscarbam 
ic acid, bis(1,1-dimethylpropyl)ester 
(Compound 138b) 
(a) Compound 138a 
##STR263## 
Compound 138a was obtained as a white solid by reaction of Compound 32 with 
di-tertamyldicarbonate using conditions analogous to those used for the 
synthesis of Compound 131 (i-Pr.sub.2 NEt used instead of Et.sub.3 N). 
Mass Spec. 662 (M+H) 
(b) Compound 138b 
##STR264## 
Compound 138a was converted to Compound 138b (white solid) by a procedure 
analogous to that used for the preparation of Compound 2. 
m.p. 161.degree.-163.degree. C.; [.alpha.].sub.D =+147.degree. (c=0.2, 
CH.sub.2 Cl.sub.2) 
Elemental Analysis (%) 
for C.sub.32 H.sub.49 N.sub.3 O.sub.6 .multidot.0.52 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.13 66.42 
H 8.68 8.73 
N 7.23 6.94 
______________________________________ 
EXAMPLE 139 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisca 
rbamic acid, bis(2,2-dimethylpropyl)ester 
(Compound 139) 
##STR265## 
Compound 139 was obtained as a solid by reaction of Compound 32with 
neopentyl chloroformate (J. Org. Chem. 49, 1174 (1984)), and subsequent 
deprotection analogous to the two step procedure used for the synthesis of 
Compound 123. 
m.p. 152.degree.-154.degree. C.; [.alpha.].sup.20.sub.D =-12.5.degree. 
(c=0.1, CH.sub.3 OH) 
TLC:Rf=0.43 (silica gel); Solvent:90:9:1 
CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH. 
EXAMPLE 140 
Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3- 
[[3-(5,5-Dimethyl-2-oxo-3-oxazolidinyl)-2-hydroxy-4-phenylbutyl]amino]-2-h 
ydroxy-1-(phenylmethyl)-propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 140f) 
(a) Compound 140a 
##STR266## 
To a solution of the Cbz-intermediate formed during the first step of the 
synthesis of Compound 48 (100 mg, 0.138 mmol) in dry CH.sub.2 Cl.sub.2 (1 
mL) at 0.degree. C. was added ethyl vinyl ether (300 .mu.L, 3.14 mmol), 
followed by pyridinum p-toluene sulfonate (10.7 mg, 0.042 mmol) and the 
reaction stirred at RT for 18 h. The reaction mixture was diluted with 
EtOAc and washed with saturated NaHCO.sub.3. The combined organic extracts 
were dried (MgSO.sub.4), filtered and concentrated in vacuo to yield a 
gummy white solid which was purified by silica gel chromatography, eluting 
with EtOAc (10 to 40%)/hexane to afford 105 mg of Compound 140a (88% 
yield) as a white residue. TLC (silica gel/Hexanes:EtOAc 1:1): R.sub.f 
=0.7 
(b) Compound 140b 
##STR267## 
Compound 140a was converted to Compound 140b (colorless oil) by a procedure 
analogous to that used for the synthesis of Compound 54. 
Mass Spec.: 732 (M+H) 
(c) Compound 140c 
##STR268## 
To a solution of Compound 140b (175 mg, 0.24 mol) in EtOH (2 mL) in a 
pressure tube was added isobutylene oxide (0.66 mL, 7.17 mmol) and the 
tube sealed under argon and heated at 110.degree. C. for 4 h, and then at 
150.degree. C. for 2 h. The solvents were removed in vacuo, and the oily 
residue purified by silica gel chromatography, eluting with CH.sub.3 OH (1 
to 10%)/CHCl.sub.3 to give 138 mg of Compound 140c (71% yield) as a 
colorless gummy residue. 
Mass Spec. 805 (M+H) 
(d) Compound 140d 
##STR269## 
To a solution of Compound 140c (103 mg, 0.13 mmol) in dry CH.sub.2 Cl.sub.2 
(375 .mu.L) at 0.degree. C. was added pyridine (125 .mu.L, 1.54 mmol), 
followed by 20% COCl.sub.2 in toluene (166 .mu.L, 1.93 M) and the mixture 
stirred at 0.degree. C. for 25 min. The reaction mixture was quenched with 
saturated NaHCO.sub.3, extracted with EtOAc, the organic phase dried 
(MgSO.sub.4), filtered and concentrated in vacuo to afford 98 mg of 
Compound 140d (ca. 91% crude yield) as yellow foamy residue. 
TLC (silica gel/CHCl.sub.3 : MeOH 98:2 ): R.sub.f =0.26 
(e) Compound 140e 
##STR270## 
To a solution of Compound 140d (98 mg, 0.12 mmol) in 1.5 mL acetone was 
added pyridinum p-toluene sulfonate (98 mg, 0.12 mmol) and the yellow 
solution stirred at RT for 18 h. The solvent was removed and the residue 
taken into EtOAc (10 mL) and washed with saturated NaHCO.sub.3. The 
organic extracts were dried (anhydrous Na.sub.2 SO.sub.4), filtered and 
concentrated to dryness.: The crude product was purified by silica gel 
chromatography, eluting with CH.sub.3 OH (1 to 10%)/CHCl.sub.3 to afford 
68 mg of Compound 140e (81% yield) as a yellow residue. 
Mass Spec. 686 (M+H) 
(f) Compound 140f 
##STR271## 
Compound 140e was converted to the title Compound 140f (yellow solid) by a 
procedure analogous to that used for the synthesis of Compound 21. 
m.p. 55.degree.-58.degree. C., [.alpha.].sub.D =-3.96.degree. (c=0.2, 
CH.sub.2 Cl.sub.2). 
Analysis for: C.sub.30 H.sub.43 N.sub.3 O.sub.6 .multidot.2.19 H.sub.2 O 
Calculated: C, 62.00; H, 8.22; N, 7.23; 
Found: C, 62.25; H, 7.63; N, 6.98. 
EXAMPLE 141 
Preparation of [S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1 
-Dimethylethoxy)carbonyl]methylamino]-2 
-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)-carbonyl]-L-valinamide] 
(Compound 141e ) 
(a) Compound 141a 
##STR272## 
Compound 129 was converted to Compound 141a (yellow solid) by a procedure 
analogous to that used for the synthesis of Compound 32. 
(b) Compound 141b 
##STR273## 
Compound 141a was converted to Compound 141b (white solid) by a procedure 
analogous to that used for the synthesis of Compound 51 (CH.sub.2 Cl.sub.2 
was used as solvent). TLC: R.sub.f =0.21, 100% EtOAc. 
(c) Compound 141c 
##STR274## 
Compound 141b was converted to Compound 141c (white foam) by a procedure 
analogous to that used for the synthesis of Compound 130. TLC: R.sub.f 
=0.42, CH.sub.2 Cl.sub.2 -MeOH-NH.sub.4 OH, 90:10:1. 
(d) Compound 141d 
##STR275## 
Compound 141c was converted to Compound 141d (white foam) by a procedure 
analogous to that used for the synthesis of Compound 131. 
(e) Compound 141e 
##STR276## 
Compound 141d was converted to Compound 141e (white foam) by a procedure 
analogous to that used for the synthesis of Compound 42. TLC: Rf =0.38, 
CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH, 90:10:0.1 (UV detection). 
[.alpha.].sub.D =-27.9.degree. (c 0.72, MeOH) 
Elemental Analysis (%) 
C.sub.39 H.sub.54 N.sub.4 O.sub.7 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 67.80 67.51 
H 7.88 7.94 
N 8.11 8.14 
______________________________________ 
EXAMPLE 142 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[9-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-methoxy-1-(phenylmethyl)propyl]carbamic acid 
1,1-dimethyl-ethyl ester 
(Compound 142d) 
(a) Compound 142a 
##STR277## 
A solution of 300 mg (1.14 mmole) of Compound 1b(i), 186 mg (2.85 mmoles) 
of NaN.sub.3 and 111 mg (2.05 mmoles) of NH.sub.4 Cl in 6 ml of MeOH was 
stirred at reflux overnight. The white solid residue obtained on removal 
of solvent was dissolved in EtOAc and washed with H.sub.2 O and brine. 
Drying (MgSO.sub.4) and concentration gave 300 mg (0.98 mmole, 86%) of 
Compound 142a as a white solid. TLC: R.sub.f =0.21, 25% EtOAc-hexane. 
(b) Compound 142b 
##STR278## 
To a suspension of 48 mg (1.2 mmoles) of 60% NaH (hexane washed) in 1 ml of 
dry THF at RT was added a solution of 295 mg (0.96 mmole) of Compound 142a 
in 4 ml of THF. The reaction was stirred for 2 hr at which time 89 .mu.l 
(1.44 moles) of methyl iodide was added. Stirring was continued for 1 hr 
then the reaction was diluted with EtOAc and washed with H.sub.2 O, 10% 
Na.sub.2 S.sub.2 O.sub.3, and brine. After drying (MgSO.sub.4), removal of 
solvent gave a white solid residue which was purified by flash 
chromatography on a 130 cc column of silica gel (elution with 20% 
EtOAc/hexane) to give 206 mg (0.64 mmole, 67%) of Compound 142b as a white 
solid. TLC: R.sub.f =0.55, 25% EtOAc-hexane. 
(c) Compound 142c 
##STR279## 
A solution of 150 mg (0.47 mmole) of Compound 142b in 3 ml of MeOH 
containing 45 mg of 10% Pd/C was hydrogenated at RT for 1.5 hr (balloon). 
The reaction was diluted with additional MeOH, 0.5 ml of NH.sub.4 OH was 
added, and stirring was continued for 15 min. The catalyst was removed by 
filtration through Celite (MeOH wash) and the filtrate concentrated. The 
residue was taken up in CH.sub.2 Cl.sub.2, dried (MgSO.sub.4), and the 
solvent evaporated to afford 122 mg (0.41 mmole, 88%) of Compound 142c as 
a white solid. TLC: R.sub.f =0.28, CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH, 
(90:10:1). 
(d) Compound 142d 
##STR280## 
Compounds 142c and 1b(i) were reacted by a procedure analogous to that used 
for the synthesis of Compound 4b to give the title Compound 142d (white 
foam). TLC: Rf=0.37, CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH, 90:10:0.1 
[.alpha.].sub.D =-3.9.degree. (c 0.67, MeOH) 
Elemental Analysis (%) 
C.sub.31 H.sub.47 N.sub.3 O.sub.6 .multidot.0.78 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.11 64.75 
H 8.56 8.22 
N 7.35 7.71 
______________________________________ 
EXAMPLE 143 
Preparation of 
[1S-[1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]bis[2-hydroxy-1 
-(phenylmethyl)-3,1-propanediyl]biscarbamic acid, 
1,1-dimethylethyl2,3-dihydro-1H-inden-1-yl ester 
(Compound 143) 
##STR281## 
To a solution of 53 mg (0.0924 mmol) of Compound 48 in 200 .mu.L of 
CH.sub.3 CN at RT were added 29 mg of Compound 67a and 26 .mu.L of 
Et.sub.3 N. After 22 h, an additional 3 mg of Compound 67a and 5 .mu.L of 
Et.sub.3 N were added to the reaction mixture. After 48 h, the mixture was 
diluted with 50 mL of CH.sub.2 Cl.sub.2 and washed with 10% citric acid 
and saturated NaHCO.sub.3. The organic layer was dried over Na.sub.2 
SO.sub.4, filtered and concentrated in vacuo. Flash chromatography on 
silica gel eluting with 10-50% EtOAc-hexane provided 57 mg (84%) of 
Compound 143. 
EXAMPLE 144 
Preparation of 
[1S-(1R*,2S)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]-bis[c 
arbamic acid], 1,1-dimethylethyl-2,3-dihydro-1H-inden-1-yl ester 
Compound 144) 
##STR282## 
Compound 143 was converted to the title Compound 144 by a procedure 
analogous to that used for the synthesis of Compound 21. (1:1 mixture R:S 
at *) 
mp 157.degree.-166.degree. C.; [.alpha.].sup.20.sub.D =-11.degree. (c=0.35, 
CH.sub.3 OH) 
Mass Spec. 604 (M+H).sup.+ 
Elemental Analysis (%) 
C.sub.35 H.sub.45 N.sub.3 O.sub.6 .multidot.0.71 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 68.18 68.40 
H 7.59 7.55 
N 6.81 6.59 
______________________________________ 
EXAMPLE 145 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]bisca 
rbamic acid, 1,1-dimethylethyl(R)-2,3-dihydro-1H-inden-1-yl ester 
(Compound 145) 
##STR283## 
Compound 48 was converted to the title Compound 145 by a two-step procedure 
analogous to that used for the synthesis of Compound 144 except that the 
p-nitrophenyl carbonate of R-(-)-indanol was used. 
mp 187.degree.-190.degree. C.; [.alpha.].sup.20.sub.D =-4.9.degree. 
(c=0.35, DMSO) 
Mass Spec. 604 (M+H).sup.+ 
Elemental Analysis (%) 
C.sub.35 H.sub.45 N.sub.3 O.sub.6 +0.51 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 68.58 68.24 
H 7.57 7.29 
N 6.86 7.20 
______________________________________ 
EXAMPLE 146 
Preparation of [1S-(1R*, 
2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbamic 
acid, 1,1-dimethylethyl(S)-2,3-dihydro-1H-inden-1-yl ester 
(Compound 146) 
##STR284## 
Compound 48 was converted to the title Compound 146 by a two-step procedure 
analogous to that used for the synthesis of Compound 144 except that the 
p-nitrophenyl carbonate of S-(+)-indanol was used. 
mp 175.degree.-178.degree. C.; [.alpha.].sup.20.sub.D =-26.degree. (c=0.12, 
CH.sub.3 OH) 
Mass Spec. 604 (M+H).sup.+ 
Elemental Analysis (%) 
C.sub.35 H.sub.45 N.sub.3 O.sub.6 .multidot.0.25 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 69.12 68.96 
H 7.54 7.62 
N 6.91 7.07 
______________________________________ 
EXAMPLE 147 
Preparation of 
[1S-(1R*,2S*)]-[[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisc 
arbamic acid, 1,1-dimethylethyl 
2,3-dihydro-2-[(1,1-dimethylethyl)dimethylsilyl]oxy]-1H-inden-1-yl ester, 
1:1 mixture of 1R,2R- and 1S,2S-diastereomers on indane ring 
(Compound 147d) 
(a) Compound 147a 
##STR285## 
To a solution of 200 mg of OsO.sub.4 in 100 mL of dry CH.sub.2 Cl.sub.2 
were added 14.6 g (125 mmol) of N-methylmorpholine oxide and 15.2 g (125 
mmol) of phenylboronic acid. To the resulting solution was added a 
solution of 11.6 g of indene in 200 mL of CH.sub.2 Cl.sub.2 over 10 min. 
The resulting orange solution was stirred at RT for 45 min and the 
reaction quenched with 10% sodium thiosulfate (RT, 1 hr). The mixture was 
diluted with EtOAc, washed with brine and the organic layer dried over 
Na.sub.2 SO.sub.4, filtered, and concentrated to give 27 g of a 
phenylboronate intermediate. The solid was dissolved in 250 mL of THF and 
300 mL of 2N NaOH was added. The mixture was cooled to 0.degree. C. and 
treated dropwise with 200 mL of 30% H.sub.2 O.sub.2. The mixture was 
stirred at RT for 2 h and at 50.degree. C. for 1h. After cooling to RT, 
the aqueous layer was saturated with NaCl, diluted with 500 mL of EtOAc 
and the organic layer separated and concentrated in vacuo. The aqueous 
layer was extracted with EtOAc and the combined organics washed with 
brine. The organic layer was dried over Na.sub.2 SO.sub.4, filtered, and 
concentrated in vacuo to give 13.3 g of a residue. Flash chromatography of 
the residue on silica gel, eluting with 10-100% EtOAc-hexane, provided 
6.64 g (44%) of Compound 147a. 
(b) Compound 147b(i) 
##STR286## 
and 
Compound 147b(ii) 
##STR287## 
To a solution of the diol Compound 147a in 70 mL of DMF were added 6.4 g 
(42 mmol) of t-butyldimethylsilyl chloride and 3.6 g (53 mmol) of 
imidazole. The mixture, containing Compounds 147b(i) and 147b(ii), was 
stirred at RT for 24 h and the solvent removed in vacuo. The residue was 
taken up in Et.sub.2 O and washed with saturated NaHCO.sub.3. The organic 
layer was dried over Na.sub.2 SO.sub.4, filtered, and concentrated in 
vacuo to give 9.27 g of a colorless oil. Flash chromatography on silica 
gel, eluting with 0-10% Et.sub.2 O-hexane, provided 1.38 g (26%) of 
Compound 147b(i) as a colorless oil. 
(c) Compound 147c 
##STR288## 
Compound 147b(i) was converted to Compound 147c by a procedure analogous to 
that used for the synthesis of Compound 67a [pyridine was used as base and 
co-solvent (3:1 CH.sub.2 Cl.sub.2 /pyridine)]. 
(d) Compound 147d 
##STR289## 
To a solution of 211 mg (0.476 mmol) of Compound 54 in 2 mL DMF at RT were 
added 0.26 mL of i-Pr.sub.2 NEt and then a solution of 225 mg (0.523 mmol) 
of Compound 147c in 2 mL of CH.sub.2 Cl.sub.2. The mixture was stirred at 
RT for 72 h then diluted with EtOAc and washed with 0.1N NaOH and brine. 
The organic layer was dried over Na.sub.2 SO.sub.4, filtered and 
concentrated in vacuo to give 381 mg of crude material. Flash 
chromatography on silica gel, eluting with 95:5:0.25 CHCl.sub.3 /CH.sub.3 
OH/NH.sub.4 OH, provided 144 mg (41%) of the title Compound 147d. 
EXAMPLE 148 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]bisca 
rbamic acid, 1,1-dimethylethyl2,3-dihydro-2-hydroxy-1H-inden-1-yl ester 
(Compound 148) 
##STR290## 
To a solution of 143 mg (0.195 mmol) of Compound 147d in 1.0 mL of dry THF 
at 0.degree. C. was added 5 mL of a cold (0.degree. C.) HF-pyridine 
solution (prepared by adding 1 mL of HF-pyridine to an ice cold solution 
of 2 mL pyridine in 7 mL of dry THF). The resulting solution was stirred 
at 0.degree. C. for 2 h and at RT for 2 h. The mixture was diluted with 
CHCl.sub.3 and washed with saturated NaHCO.sub.3 and brine. The organic 
layer was dried over Na.sub.2 SO.sub.4, filtered, and concentrated in 
vacuo to give 123 mg (.about.100%) of the title Compound 148. The compound 
was triturated with Et.sub.2 O and lyophilized from dioxane. 
mp 135.degree.-140.degree. C. (soft at 75.degree. C.); 
[.alpha.].sup.20.sub.D=- 3.degree. (c 0.20, CH.sub.3 OH) 
Mass Spec. 620 (M+H).sup.+ 
Elemental Analysis (%) 
C.sub.35 H.sub.45 N.sub.3 O.sub.7 .multidot.0.054 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.78 66.86 
H 7.38 7.28 
N 6.67 6.59 
______________________________________ 
EXAMPLE 149 
Preparation of 
[1S-(1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]bis-[2-hydroxy- 
1-(phenylmethyl)-3,1-propanediyl]]biscarbamic acid, 
1,1-dimethylethyl1,1-dimethyl-4-[[(phenylmethoxy) carbonyl]amino]butyl 
ester 
(Compound 149e ) 
(a) Compound 149a 
##STR291## 
Compound 149a was prepared from 4-aminobutyric acid using a procedure 
analogous to that used for the synthesis of Compound 85a. 
(b) Compound 149b 
##STR292## 
Thionyl chloride (2.91 ml; 40 mmol) was added dropwise to a solution of 
Compound 149a (4.74 g; 20 mmol) in 65 ml of MeOH at -20.degree. C. After 
warming to RT, the reaction mixture was stirred for 18 hr then diluted 
with Et.sub.2 O and the resulting organic layer washed with saturated 
NaHCO.sub.3 and brine. After drying over MgSO.sub.4, the organic layer was 
concentrated to afford 4.475 g (89%) of crude Compound 149b as a colorless 
oil. A 3.5 g portion of this material was chromatographed on a 5.times.15 
cm silica gel column using hexane:EtOAc, 85:15 and hexane:EtOAc, 75:25 as 
the mobile phase to afford 3.28 g (84% yield) of Compound 149b as a 
colorless liquid. 
(c) Compound 149c 
##STR293## 
A solution of Compound 149b (500 mg; 2 mmol) in 4 ml of THF was added to a 
solution of MeLi (5.7 ml 1.4M in Et.sub.2 O; 8 mmol) in 6 ml of THF at 
-78.degree. C. After stirring 5 h at -78.degree. C., the reaction mixture 
was quenched with saturated NH.sub.4 Cl and the resulting mixture 
extracted with Et.sub.2 O. The organic layer was washed with H.sub.2 O and 
brine. After drying over MgSO.sub.4, the organic layer was concentrated 
and the resulting liquid purified on a 2.5.times.25 cm silica gel column 
using hexane:EtOAc, 6:4 as the mobile phase to afford 294 mg (59%) of 
Compound 149c as a colorless liquid. 
(d) Compound 149d 
##STR294## 
4-Nitrophenylchloroformate (350 mg; 1.70 mmol) in 1 ml of CH.sub.2 Cl.sub.2 
was added dropwise to a solution of Compound 149c (280 mg; 1.11 mmol) in 
2.5 ml of CH.sub.2 Cl.sub.2 and 0.5 ml pyridine. After stirring for 2 h at 
0.degree. C., an additional 0.25 ml of pyridine and 
4-nitrophenylchloroformate (225 mg; 1.10 mmol) were added. The reaction 
mixture was stirred an additional 2 h at 0.degree. C. after which time 75 
ml of Et.sub.2 O was added. The organic layer was washed with H.sub.2 O, 
0.1N NaOH, H.sub.2 O, 5% cupric sulfate solution, H.sub.2 O, and brine. 
Drying (MgSO.sub.4) and concentration afforded a solid residue which was 
purified on a 2.5.times.20 cm silica gel column using hexane:EtOAc, 75:25 
to afford 370 mg (80%) of Compound 149d as a light yellow oil. 
(e) Compound 149e 
##STR295## 
A mixture of Compound 48 (447 mg; 0.76 mmol) , Compound 149 d (357 mg; 0.84 
mmol) and i-Pr.sub.2 NEt (0.29 ml; 1.70 mmol) in 1.5 ml of CH.sub.3 CN was 
stirred 72 h at RT. An additional quantity of i-Pr.sub.2 NEt (0.15 ml; 
0.86 mmol) was added and the reaction mixture was heated to 45.degree. C. 
for 18 h. The volatiles were removed in vacuo and the residue was 
partitioned between EtOAc and H.sub.2 O. The organic layer was washed with 
H.sub.2 O, 0.1N NaOH, H.sub.2 O, saturated aq. KHSO.sub.4, H.sub.2 O, and 
brine. Dying (MgSO.sub.4) and concentration afforded a residue which was 
purified on a 2.5.times.15 cm silica gel column using 4% MeOH/CH.sub.2 
Cl.sub.2 to afford 540 mg (82%) of Compound 149e as a white foamy solid. 
.sup.1 H NMR (DMSO-d.sup.6 ; 70.degree. C.): .delta.0.01 (s, 9H)0.93 (t, 
J=8, 8.5 Hz, 2H), 1.19 (s, 6H), 1.23 (s, 9H), 1.32 (m, 2H), 1.53 (m, 2H), 
2.56 (m, 2H), 3.15 (m, 2H), 3.57 (m, 4H), 3.68 (m, 2H), 4.07 (m, 2H), 4.79 
(m, 2H), 5.00 (s, 2H), 6.27 (brs, 2H), 6.90 (brs, 1H), 7.11 (m, 2H), 7.18 
(m, 8H), 7.31 (m, 5H). 
EXAMPLE 150 
Preparation of [1S-(1R*,2S*)], 
[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-promanediyl)]biscarbamic acid, 
1,1-dimethylethyl1,1-dimethyl-4-[[(phenylmethoxy)carbonyl]amino]butyl 
ester 
(Compound 150) 
##STR296## 
Compound 149e was converted to the title Compound 150 (white solid) by a 
procedure analogous to that of Example 21. 
mp 153.degree.-155.degree. C.; [.alpha.].sub.365 =-18.0.degree. (c 0.10, 
MeOH). 
Mass Spec. FAB+ion: (M+H)=721. 
Analysis calc. for C.sub.40 H.sub.56 N.sub.4 O.sub.8 : C, 66.64; H, 7.83; 
N, 7.77; 
Found: C, 66.36; H, 7.81; N, 7.75. 
EXAMPLE 151 
Preparation of 
[1S-(1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]-bis[[2-hydroxy 
-1-(phenylmethyl)-3,1-proponediyl]]biscarbamic acid, 1,1-dimethylethyl 
4-amino-1,1-dimethylbutyl ester 
(Compound 151) 
##STR297## 
Compound 149e was converted to the title Compound 151 (colorless oil) using 
conditions analogous to those used for the synthesis of Compound 7. 
.sup.1 H NMR (DMSO-d.sup.6 ; 70.degree. C.): .delta.0.01 (s, 9H), 0.93 (t, 
J=9, 8 Hz, 2H), 1.20 (s, 6H), 1.22 (m; buried under large singlets, 2H), 
1.23 (s, 9H), 2.43 (m, 2H), 2.55 (m, 2H), 2.93 (dd, J=3.5, 14 Hz, 2H), 
3.05 (m, 4H), 3.53 (m, 4H), 3.65 (m, 2H), 4.02 (m, 2H), 6.23 (brs, 2H), 
7.12 (m, 10H). 
EXAMPLE 152 
Preparation of 
[1S-(1R*,2S*)]-[[[[2-(Trimethylsilyl)ethoxy]carbonyl]imino]-bis[[2-hydroxy 
-1-(phenylmethyl)-3,1-propanediyl]]biscarbamic acid, 1,1-dimethylethyl 
1,1-dimethyl-4-[(phenylmethyl)amino]butyl ester 
(Compound 152) 
##STR298## 
NaHB(OAc).sub.3 (57 mg; 0.26 mmol) was added to a solution of Compound 151 
(125 mg; 0.178 mmol) and benzaldehyde (18 .mu.l; 0.178 mmol) in 
1,2-dichloroethane at RT. After stirring for 3 h the solvent was removed 
in vacuo and the residue was partitioned between EtOAc and saturated 
NaHCO.sub.3. The organic layer was washed with H.sub.2 O and brine, dried 
over MgSO.sub.4 and concentrated to afford a crude residue which was 
purified on a 2.5.times.8 cm silica gel column, using CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, 94.5:5.0:0.5 to give 125 mg (86%) of the title Compound 
152 as a white foam. 
.sup.1 H NMR (DMSO-d.sup.6 ; 70.degree. C.): .delta.0.01 (s, 9H), 0.93 (t, 
J=9, 8 Hz, 2H), 1.21 (S, 6H), 1.23 (s, 9H), 1.33 (m, 2H), 1.58 (m, 2H), 
2.48 (m, 2H), 2.57 (m, 2H), 2.94 (dd, J=3, 14 Hz, 2H), 3.15 (m, 2H), 3.54 
(m, 4H), 3.68 (m, 2H), 3.72 (s, 2H), 4.05 (m, 2H), 4.80 (m, 2H), 6.26 
(brs, 2H), 7.17 (m, 10H), 7.30 (m, 5H). 
EXAMPLE 153 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscar 
bamic acid, 1,1-dimethylethyl 1,1-dimethyl-4-[(phenylmethyl)-amino]butyl 
ester 
(Compound 153) 
##STR299## 
Compound 152 was converted to the title Compound 153 (white solid) by a 
procedure analogous to that used for the synthesis of Compound 21. 
mp 128.degree.-132.degree. C.; [.alpha.].sub.D =-4.8.degree. (c 0.42, 
MeOH). 
Mass Spec. FAB+ion: (M+H)=677. 
Analysis calc. for C.sub.39 H.sub.56 N.sub.4 O.sub.6 .multidot.0.52 H.sub.2 
O: C, 68.27; H, 8.38; N, 8.16; 
Found: C, 68.14; H, 8.25; N, 8.29. 
EXAMPLE 154 
Preparation of 
[R-(R*,S*)]-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarbam 
ic acid, 1,1-dimethylethyl 1,1-dimethyl-2-phenylethyl ester 
(Compound 154) 
##STR300## 
.alpha.,.alpha.-Dimethylphenethyl alcohol was converted to the title 
Compound 154 (white solid) by a three-step procedure analogous to that 
used for the conversion of Compound 149c to Compound 150 (Et.sub.3 N and 
DMF used in the coupling of the p-nitrophenyl carbonate to Compound 48). 
m.p. 161.degree.-164.degree. C. 
EXAMPLE 155 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarb 
amic acid, 1,1-dimethylethyl 1,1-dimethyl-5-phenyl-2-pentynyl ester 
(Compound 155b) 
(a) Compound 159a 
##STR301## 
To a -78.degree. C. solution of 4-phenyl-1-butyne (1.00 g, 7.68 mmol) in 
THF (4.40 mL) was added dropwise a solution of n-BuLi/hexane (3.24 mL of a 
2.49 M solution) and the resulting solution stirred at -78.degree. C. for 
1 h. A solution of acetone (0.59 mL, 8.07 mmol) in THF (1.0 mL) was added 
dropwise at -78.degree. C. and the resulting solution stirred at 
-78.degree. C. for 3 h at which point a solution of aqueous NH.sub.4 Cl (9 
mL of a 1 M solution) was added. The aqueous layer was extracted with 
EtOAc and the combined organic extracts dried (anhydrous Na.sub.2 
SO.sub.4) and concentrated in vacuo to give a yellow oil. This crude 
material was chromatographed on silica gel (100 mL) eluting with 10:1 
hexane:EtOAc to give Compound 155a (1.36 g, 94%) as a clear colorless oil. 
(b) Compound 155b 
##STR302## 
Compound 155a was converted to the title Compound 155b (white solid) by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (DMF used in the coupling of the p-nitrophenyl 
carbonate to Compound 48). 
m.p. 140.degree.-142.degree. C.; .alpha..sub.D =+2.0.degree. (c=0.2, MeOH) 
Elemental Analysis (%) 
for C.sub.39 H.sub.51 N.sub.3 O.sub.6 .multidot.0.87 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 69.55 69.40 
H 7.89 7.73 
N 6.24 6.39 
______________________________________ 
EXAMPLE 156 
Preparation of 
[1S-(1R*,2S*)]-2hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbamic acid, 
1,1-dimethylethyl-1-methyl-1-phenylethyl ester 
Compound 156) 
##STR303## 
Dimethylphenyl carbinol was converted to the title Compound 156 (white 
solid) by a three-step procedure analogous to that used for the conversion 
of Compound 149c to Compound 150 (Et.sub.3 N and DMF used in the coupling 
of the p-nitrophenyl carbonate to Compound 48). 
m.p. 89.degree.-92.degree. C. 
EXAMPLE 157 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]bisca 
rbamic acid, 1,1-dimethylethyl 1,1-dimethyl-2(phenylmethoxy)-ethyl ester 
(Compound 157b) 
(a) Compound 157a) 
##STR304## 
Compound 157a was prepared from benzyloxyacetyl chloride by a procedure 
analogous to that used for the synthesis of Compound 149c. 
(b) Compound 157b 
##STR305## 
Compound 157a was converted to the title Compound 157b (white solid) by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (DMF used in the coupling of the p-nitrophenyl 
carbonate to Compound 48). 
m.p. 129.degree.-135.degree. C.; [.alpha.].sup.20.sub.D =-3.5.degree. (c 
0.5, CH.sub.3 OH) 
Elemental Analysis (%) 
Calculated for C.sub.37 H.sub.51 N.sub.3 O.sub.7 .multidot.1.37 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.89 65.52 
H 8.03 7.64 
N 6.23 6.60 
______________________________________ 
EXAMPLE 158 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscar 
bamic acid, 1,1-dimethylethyl 1,1-dimethyl-3-(phenylmethoxy)-propyl ester 
(Compound 158b) 
(a) Compound 158a 
##STR306## 
To a solution of 3M MeMgCl in THF (5 mL, 15 mmol) at -20.degree. C. was 
added 5 mL of THF and a solution of 4-benzyloxy-2-butanone (1.735 mL, 10 
mmol) in 5 mL of THF. After the addition was complete, the reaction 
mixture was warmed to RT and quenched with 10 mL of water. The mixture was 
extracted with CH.sub.2 Cl.sub.2 and the organic phase was separated, 
dried (MgSO.sub.4) and concentrated to provide the Compound 158a (1.8 g, 
92%) as a colorless oil. 
(b) Compound 158b 
##STR307## 
Compound 158a was converted to the title Compound 158b (white solid) by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (Et.sub.3 N and DMF used in the coupling of the 
p-nitrophenyl carbonate to Compound 48). 
m.p. 122.degree.-125.degree. C.; [.alpha.].sup.20.sub.D =-4.8.degree. 
(c=0.5, CH.sub.3 OH) 
Elemental Analysis (%) 
Calculated for C.sub.38 H.sub.53 N.sub.3 O.sub.7 .multidot.1.30 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.41 66.58 
H 8.15 7.89 
N 6.11 5.94 
______________________________________ 
EXAMPLE 159 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis-[ 
carbamic acid], 1,1-dimethylethyl 1-methyl-cyclopentyl ester 
(Compound 159) 
##STR308## 
1-Methyl-1-cyclopentanol was converted to the title Compound 159 by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (DMF used in the coupling of the p-nitrophenyl 
carbonate to Compound 48). 
m.p. 160.degree.-162.degree. C.; [.alpha.].sub.D =-4.3.degree. (c 0.21) 
Elemental Analysis (%) 
for C.sub.32 H.sub.47 N.sub.3 O.sub.6 .multidot.1.54 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 64.34 64.15 
H 8.45 8.03 
N 7.03 7.22 
______________________________________ 
EXAMPLE 160 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[c 
arbamic acid], 1,1-dimethylethyl-1-methylcyclopentyl ester 
(Compound 160) 
##STR309## 
1-Methyl-1-cyclobutanol was converted to the title Compound 160 (white 
solid) by a three-step procedure analogous to that used for the conversion 
of Compound 149c to Compound 150 (Et.sub.3 N and DMF used in the coupling 
of the p-nitrophenyl carbonate to Compound 48). 
m.p. 179.degree.-182.degree. C. 
Elemental Analysis (%) 
C.sub.31 H.sub.45 N.sub.3 O.sub.6 .multidot.0.47 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.00 65.89 
H 8.21 8.00 
N 7.45 7.56 
______________________________________ 
EXAMPLE 161 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarba 
mic acid, 1,1-dimethylethyl 
2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1,1-dimethylethyl ester 
(Compound 161g) 
(a) Compound 161a 
##STR310## 
A mixture of Compound 44a (1.0 g, 3.36 mmol) and 5% Pd on CaCO.sub.3, 
poisoned with Pb (0.1 g, Aldrich) in 40 mL of MeOH was stirred under 1 atm 
H.sub.2 for 2 h. The catalyst was filtered off through a pad of Celite and 
the filtrate concentrated. The crude product was purified by 
chromatography on a column of silica gel (2.5.times.35 cm) eluting with a 
gradient of CH.sub.2 Cl.sub.2 -MeOH-aqueous NH.sub.4 OH (98.0-1.8-0.2 to 
95.0-4.5-0.5) to afford 170 mg (31% yield) of Compound 161a as a clear 
oil. 
(b) Compound 161b 
##STR311## 
To 26.25 mL of 0.1M HClO.sub.4 was slowly added 9.45 g (0.131 mol) of 
isobutylene oxide and the reaction mixture stirred at RT for 30 mins. 
Water from the reaction mixture was distilled off first, followed by the 
product which distilled at 80.degree. C. (10 mm Hg). Collection of pure 
distillate afforded Compound 161b as a colorless oil (6.4 g, 54%). 
(c) Compound 161c 
##STR312## 
To a cooled (0.degree. C.) solution of Compound 161b (2.0 g, 22.22 mmol) in 
10 mL of CH.sub.2 Cl.sub.2 was added Et.sub.3 N (6.2 mL, 44.44 mmol) 
followed by t-butyldimethylsilyl chloride (3.684 g, 24.44 mmol). The 
reaction mixture was warmed to RT and after 2 h of stirring, 
N,N-dimethylaminopyridine (0.056 g, 0.44 mmol) was added. After stirring 
the reaction mixture overnight, it was diluted with EtOAc and washed with 
saturated NaHCO.sub.3 followed by brine. The organic phase was dried 
(MgSO.sub.4) and concentrated. The crude product obtained was 
chromatographed on silica gel eluting with a stepwise gradient of hexane 
to 50% EtOAc-hexane to afford Compound 161c (4.2 g, 92%) as a colorless 
oil. 
(d) Compound 161d 
##STR313## 
To a solution of Compound 161c (1.0 g, 4.9 mmol) in 10 mL of dry CH.sub.2 
Cl.sub.2 cooled to 0.degree. C. was added 5.0 mL of pyridine followed by 
slow addition of a solution of p-nitrophenylchloroformate (1.185 g, 5.88 
mmol) in 6 mL of CH.sub.2 Cl.sub.2. The resulting suspension was stirred 
at 5.degree. C. overnight. The reaction mixture was diluted with EtOAc and 
washed with saturated NaHCO.sub.3 and brine. The organic phase was dried 
(MgSO.sub.4) and concentrated to obtain the crude product which was flash 
chromatographed on silica gel eluting with a stepwise gradient of hexane 
to 10% EtOAc-hexane to afford Compound 161d (1.05 g, 58%) as a viscous 
oil. 
(e) Compound 161e 
##STR314## 
A solution of Compound 161a (70 mg, 0.429 mmol), Compound 161d (174 mg, 
0.472 mmol), and i-Pr.sub.2 NEt (90 .mu.L, 66.5 mg, 0.515 mmol) in 0.5 mL 
DMF was stirred at RT for 72 h. The crude mixture was combined with the 
crude mixture of a second, similar reaction run on exactly twice the 
scale. The combined crude mixture was concentrated and chromatographed on 
a column of silica gel (2.5.times.30 cm) eluting with 10% EtOAc-hexane to 
afford 423 mg (83% yield) of Compound 161e as a clear oil. 
(f) Compound 161f 
##STR315## 
A stream of NH.sub.3 was bubbled into a 5.degree. C. solution of Compound 
161e (420 mg, 1.07 mmol) in 5 mL EtOH and 5 mL 30% aqueous NH.sub.4 OH for 
30 min. The resulting solution was stirred at 5.degree. C. for 15 min and 
then at RT for 18 h. Argon was bubbled through the mixture for a few 
minutes and the solvents were removed. The crude product was 
chromatographed on a column of silica gel (2.5.times.15cm) eluting with a 
gradient of CH.sub.2 Cl.sub.2 -MeOH-aqueous NH.sub.4 OH (98.0-1.8-0.2 to 
92.0-7.2-0.8) to afford 373 mg (85% yield) of Compound 161f as a white 
solid. 
(g) Compound 161g 
##STR316## 
A solution of Compound 161f (223 mg, 0.543 mmol) and Compound 1b(i) (129 
mg, 0.489 mmol) was stirred in 1 mL of DMF at 115.degree. C. for 3.5 h. 
The mixture was cooled to RT, concentrated to remove the bulk of the DMF, 
and the crude product was chromatographed on a column of silica gel 
(2.5.times.25cm) eluting with a gradient of CH.sub.2 Cl.sub.2 
-MeOH-aqueous NH.sub.4 OH (98.0-1.8-0.2 to 92.0-7.2-0.8) to afford 176 mg 
(53% yield) of Compound 161g as a white solid. 
EXAMPLE 162 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbam 
ic acid, 1,1-dimethylethyl-2-hydroxy-1,1-dimethylethyl ester 
(Compound 162) 
##STR317## 
To a solution of Compound 161g (170 mg, 0.252 mmol) in 1 mL THF was added 3 
mL HOAc followed by 1 mL of H.sub.2 O. The resulting mixture was stirred 
at RT for 32 h. Solvents were removed and the crude product was 
chromatographed on a column of silica gel (2.5.times.25 cm) eluting with a 
gradient of CH.sub.2 Cl.sub.2 -MeOH-aqueous NH.sub.4 OH (98.0-1.8-0.2 to 
92.0-7.2-0.8) to afford 107 mg (76% yield) of the title Compound 162 as a 
white solid. (Alternatively, Compound 157b was converted to Compound 162 
by a procedure analogous to that used for the synthesis of Compound 2.) 
m.p. 153.degree.-155.degree. C.; [.alpha.].sub.D =-6.5.degree. (c 0.54) 
Elemental Analysis (%) 
for C.sub.30 H.sub.45 N.sub.3 O.sub.7 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 64.38 64.07 
H 8.10 8.16 
N 7.51 7.91 
______________________________________ 
EXAMPLE 163 
Preparation of 
[R-(R*,S*)]-[[[(Trimethylsilyl)-ethoxy]carbonyl]iminobis[2-hydroxy-1-(phen 
ylmethyl)-3,1-propanediyl]]biscarbamic acid, 
1,1-dimethylethyl2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-1,1-dimethylet 
hyl ester 
(Compound 163) 
##STR318## 
Compounds 161d and 48 were reacted by a procedure analogous to that used 
for the synthesis of Compound 143 (i-Pr.sub.2 NEt used as base) to give 
the title Compound 163 (white solid). 
.sup.1 H NMR (CD.sub.3 OD) .delta.7.23-7.08 (m, 10H) 4.13 (m, 2H) 3.81-3.60 
(m, 6H) 3.5-3.36 (m, 2H) 3.30 (m, 2H) 3.03 (m, 2H) 2.59 (m, 2H) 1.30-1.08 
(15H) 0.98 (m, 2H). 
Mass Spec (FAB)-(M+H)+=704 
EXAMPLE 164 
Preparation of 
[R-(R*,S*)]-[[[(Trimethylsilyl)-ethoxy]carbonyl]iminobis[2-hydroxy-1-(phen 
ylmethyl)-3,1-propanediyl]]biscarbamic acid, 
1,1-dimethylethyl2-hydroxy-1,1-dimethylethyl ester 
(Compound 164) 
##STR319## 
Compound 163 was converted to the title Compound 164 (white foam) by a 
procedure analogous to that used for Compound 162. TLC (SiO.sub.2) R.sub.f 
=0.22 (50% EtOAc/Hexanes-PMA). Compound 164 was converted to Compound 162 
in 20% yield by a procedure analogous to that used for Compound 21. 
EXAMPLE 165 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbam 
ic acid, bis(2-hydroxy-1,1-dimethylethyl) ester 
(Compound 165c) 
(a) Compound 165a 
##STR320## 
Compounds 32 and 161d (2 eq.) were reacted by a procedure analogous to that 
used for the synthesis of Compound 161e to give Compound 165a. 
(b) Compound 165b 
##STR321## 
Compound 165a was converted into Compound 165b (white solid) by a procedure 
analogous to that used for the synthesis of Compound 2. 
(c) Compound 165c 
##STR322## 
Compound 165b was converted to Compound 165c by a procedure analogous to 
that used for the synthesis of Compound 162. 
mp 140.degree.-142 .degree. C.; [.alpha.].sub.D =-2.3.degree. (c=0.2, 
CH.sub.3 OH). 
Mass Spec. (FAB) (M+H).sup.+ =576; 
Analysis calc. for C.sub.30 H.sub.45 N.sub.3 O.sub.8 .multidot.1.42 H.sub.2 
O: 
Calculated C, 59.93; H, 8.02; N, 6.99; 
Found: C, 60.14; H, 7.68; N, 6.78. 
EXAMPLE 166 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[c 
arbamic acid], 1,1-dimethylethyl-4-methyltetrahydropyran-4-yl-ester 
(Compound 166b) 
(a) Compound 166a 
##STR323## 
Tetrahydro-4H-pyran-4-one was converted to Compound 166a by a procedure 
analogous to that used for the synthesis of Compound 149c. 
(b) Compound 166b 
##STR324## 
Compound 166a was converted to the title Compound 166b (white solid) by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (DMF used in the coupling of the p-nitrophenyl 
carbonate to Compound 48). 
m.p. 144.degree.-146.degree. C. 
Elemental Analysis (%) 
C.sub.32 H.sub.47 N.sub.3 O.sub.7 .multidot.0.54 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 64.55 64.64 
H 8.14 8.02 
N 7.06 6.97 
______________________________________ 
EXAMPLE 167 
Preparation of 
[1S-(1R*,2S))]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscar 
bamic acid, 1,1-dimethylethyl 1,1-dimethyl-5-phenyl-3-pentynyl ester 
(Compound 167b) 
(a) Compound 167a 
##STR325## 
To a -78.degree. C. solution of 3-phenyl-1-propyne (4.00 g; 34.4 mmol) in 
THF (16 mL) was added a solution of n-BuLi (14.10 mL of a 2.52M solution 
in hexanes) followed 30 min later by BF.sub.3 .multidot.Et.sub.2 O (4.24 
mL; 34.5 mmol). The resulting solution was stirred at -78.degree. C. for 1 
h at which point a solution of isobutylene oxide (2.55 g; 35.4 mmol) in 
THF (5 mL) was added. After 2 hr, a saturated aqueous NaHCO.sub.3 solution 
was added and the mixture was allowed to warm to RT. The mixture was 
partitioned between H.sub.2 O and Et.sub.2 O and the combined organic 
extracts washed with H.sub.2 O and brine, dried (anhydrous Na.sub.2 
SO.sub.4) and concentrated in vacuo to give an orange-yellow oil. This 
material was chromatographed on silica gel (200 mL) using 10:1 
hexane:EtOAc as eluent to give Compound 167a (4.32 g; 67%) as a pale 
yellow oil. 
(b) Compound 167b 
##STR326## 
Compound 167a was converted to the title Compound 167b (white solid) by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (DMF used in the coupling of the p-nitrophenyl 
carbonate to Compound 48). 
m.p. 120.degree.-124.degree. C.; [.alpha.].sub.D =3.2.degree. (c 0.25, 
MeOH) 
Mass spec (CI) 658 (M+H) 
EXAMPLE 168 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)biscarbam 
ic acid, 1,1-dimethylethyl2-methoxy-1,1-dimethylethyl ester 
(Compound 168b) 
(a) Compound 168a 
##STR327## 
Methylmethoxy acetate was converted to Compound 168a by a procedure 
analogous to that used for the synthesis of Compound 149c. 
(b) Compound 168b 
##STR328## 
Compound 168a was converted to the title Compound 168b (white solid) by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (DMF used in the coupling of the p-nitrophenyl 
carbonate to Compound 48). 
m.p. 151.degree.-155.degree. C.; [.alpha.].sub.D =-5.8.degree. (c 0.32, 
MeOH) 
Mass spec (CI) 574 (M+H) 
EXAMPLE 169 
Preparation of 
[1S-(1R*,2S*)]-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscar 
bamic acid, 1,1-dimethylethyl-3-hydroxy-1,1-dimethylpropyl ester 
(Compound 169) 
##STR329## 
Compound 169 was obtained as a white solid from Compound 158b by a 
procedure analogous to that used for the synthesis of Compound 2. 
m.p. 133.degree. C.; [.alpha.].sup.20.sub.D =-5.0.degree. (c 0.2, CH.sub.3 
OH) 
Elemental Analysis (%) 
Calculated for C.sub.31 H.sub.47 N.sub.3 O.sub.7 .multidot.0.95 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 63.02 62.98 
H 8.34 8.18 
N 7.11 7.15 
______________________________________ 
EXAMPLE 170 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydromy-1-(phenylmethyl)-propyl]-N.sup.2 
-[[(1-methyl-1H-benzimidazol-2-yl)-methoxy]carbonyl]-L-valinamide 
(Compound 170b) 
(a) Compound 170a 
##STR330## 
A mixture of 2-hydroxymethylbenzimidazole (500 mg, 3.38 mmol), anhydrous 
K.sub.2 CO.sub.3 (467 mg, 3.38 mmol) and MeI (210 .mu.l, 3.38 mmol) in 5 
ml of DMF was heated at 50.degree. C. for 6 hr. The reaction was diluted 
with H.sub.2 O and extracted with EtOAc. The extracts were washed with 
brine, dried (Na.sub.2 SO.sub.4) and concentrated. The crude product was 
purified on a 30 ml silica column eluting with MeOH:EtOAc (1:9) to give 
146 mg (27%) of Compound 170a. 
(b) Compound 170b 
##STR331## 
Compound 170a was converted into the title Compound 170b by a three-step 
sequence analogous to that used for the synthesis of Compound 67c 
(pyridine was used in the formation of the p-nitrophenyl carbonate; no 
t-BuOH was used in the coupling of the p-nitrophenyl carbonate with 
L-valine; and no CH.sub.2 Cl.sub.2 was used in the reaction of the 
resulting acid with Compound 54). 
m.p. 148.degree.-152.degree. C.; [.alpha.].sub.D =-18.6.degree. (c=0.22, 
MeOH) 
High Res. Mass Spec. (FAB): C.sub.40 H.sub.55 N.sub.6 O.sub.7 
=731.4142.sup.+ ; .DELTA.=1.4 ppm. 
EXAMPLE 171 
Preparation of S-[1R*,2S*(2S*,3R*)]-N.sup.2 
-[[(2-Benzoxazolyl)methoxy]carbonyl]-N-[3-[[3-[[(1,1-dimethyl 
ethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylm 
ethyl)-propyl]-L-valinamide, 
(Compound 171b) 
(a) Compound 171a 
##STR332## 
To a mixture of 2.50 g (22.9 mmol) of o-aminophenol and 1.74 g (22.9 mmol) 
of glycolic acid in 50 mL of toluene was added 150 mg of p-toluenesulfonic 
acid. The mixture was heated at reflux for 18 h with azeotropic removal of 
water. The resulting solution was cooled to RT, diluted with EtOAc and 
washed with 1N NaOH. The organic layer was dried (Na.sub.2 SO.sub.4), 
filtered through a pad of silica gel, and concentrated in vacuo to give 
1.57 g (47%) of an orange solid which was recrystallized from EtOAc-hexane 
to afford 647 mg of Compound 171a (yellow solid). (b) Compound 171b 
##STR333## 
Compound 171a was converted into the title Compound 171b by a three-step 
sequence analogous to that used for the synthesis of Compound 67c 
(pyridine was used in the formation of the p-nitrophenyl carbonate; no 
t-BuOH was used in the coupling of the p-nitrophenyl carbonate with 
L-valine; and no CH.sub.2 Cl.sub.2 was used in the reaction of the 
resulting acid with Compound 54). 
m.p. 186.degree.-188.degree. C. 
Elemental Analysis 
Calc. for C.sub.39 H.sub.51 N.sub.5 O.sub.8 .multidot.0.82 H.sub.2 O C, 
63.93; H, 7.24; N, 9.56 
Found C, 64.02 H, 7.13 N, 9.47 
Mass spec (FAB) 718 (M+H) 
EXAMPLE 172 
Preparation of 
[4S-4.alpha.,5.alpha.(4R*,5S*)]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-4-[ 
(4-hydroxyphenyl)-methyl]-2,2-dimethyl-5-oxazolidinyl]methyl][[2-(trimethyl 
silyl)ethoxy]carbonyl]amino]methyl]-2,2-dimethyl-4-(phenylmethyl)-3-oxazoli 
dinecarboxylic acid, 1,1-dimethylethyl ester 
(Compound 172) 
##STR334## 
The mixture of Compound 20 (211 mg, 0.30 mmol), 2,2-dimethoxypropane (250 
mg, 2.4 mmol) and p-TsOH (1.5 mg) in dry benzene (1.6 ml) was refluxed for 
3.0 hrs with azeotropic removal of H.sub.2 O, then stirred at RT 
overnight. The mixture was diluted with EtOAc then washed with saturated 
NaHCO.sub.3 and brine and dried over anhydrous Na.sub.2 SO.sub.4. 
Concentration in vacuo followed by flash chromatography (hexane/ETOAc 10:1 
to 6:1) on a silica gel column (190.times.20 mm) afforded 230 mg (98%) of 
Compound 172 as a white foam. .sup.1 H-NMR (400 MHz, CDCl.sub.3): 
6.65-7.40 (m, 11H), 4.04-4.38 (m, 6H), 3.20-3.64 (m, 4H), 2.81-3.06 (m, 
4H), 1.25-1.94 (m, 30H), 0.95 (m, 2H), 0.00 (s, 9H). 
EXAMPLE 173 
Preparation of [4S-4 .alpha.,5.alpha.(4R*, 
5S*)]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-2,2-dimethyl-4-[[4-[2-(4-morp 
holinyl)ethoxy]phenyl]methyl]-5-oxazolidinyl]methyl][[2-(trimethylsilyl)eth 
oxy]carbonyl]-amino]methyl]-2,2-dimethyl-4-(phenylmethyl)-3-oxazolidinecarb 
oxylic acid, 1,1-dimethylethyl ester (Compound 173) 
##STR335## 
The mixture of Compound 172 (200 mg, 0.255 mmol), 4-(2 
-chloroethyl)morpholine (191 mg, 1.28 mmol) and K.sub.2 CO.sub.3 (88 mg, 
0.638 mmol) in dry DMF (1.0 ml) was heated at 100.degree. C. for 14 hrs. 
The mixture was diluted with EtOAc then washed with water, saturated 
NaHCO.sub.3 and brine and dried over anhydrous Na.sub.2 SO.sub.4. 
Concentration in vacuo followed by flash chromatography (100% CHCl.sub.3 
to CHCl.sub.3 --MeOH--NH.sub.4 OH: 99:1:0.1) on a silica gel column 
(200.times.20 mm) afforded 163 mg (71%) of Compound 173 as a colorless 
oil. .sup.1 H-NMR (400 MHz, CDCl.sub.3): 7.10-7.40 (m, 7H), 6.84 (m, 2H), 
4.02-4.39 (m, 8H), 3.76 (t, J=4.70, 4H), 3.20-3.60 (m, 4H), 2.73 -3.03 (m, 
6H), 2.60 (m, 4H), 1.24-1.83 (m, 30H), 0.95 (m, 2H), 0.00 (s, 9H). 
EXAMPLE 174 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydr 
oxy-4-[4-[2-(4-morpholinyl)ethoxy]phenyl]butyl][[2-(trimethylsilyl)ethoxy]c 
arbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 174) 
##STR336## 
To Compound 173 (160 mg, 0.178 mmol) was added pre-cooled (10.degree. C.) 
96% formic acid (8.0 ml). The mixture was stirred at 5.degree. C. for 15 
min then was frozen (dry ice-acetone) and lyophilized overnight. The 
residue was taken into CHCl.sub.3 and washed with saturated NaHCO.sub.3 
and dried over anhydrous Na.sub.2 SO.sub.4. Concentration in vacuo 
followed by flash chromatography (100% CHCl.sub.3 to CHCl.sub.3 
--MeOH--NH.sub.4 OH: 98:2:0.2) on a silica gel column afforded 112 mg 
(77%) of Compound 174 as a colorless oil. .sup.1 H-NMR (400 MHz, CD.sub.2 
Cl.sub.2): 7.10-7.30 (m, 7H), 6.78 (m, 2H), 4.45-4.85 (m, 3H), 4.13 (t, 
J=8.76, 2H), 4.00 (t, J=5.77, 2H), 3.55-3.90 (m, 4H), 3.63 (t, J=4.70, 
4H), 3.10-3.55 (m, 4H), 2.60-2.95 (m, 4H), 2.70 (t, J=5.77, 2H), 2.48 (m, 
4H), 1.31 and 1.30 (both s, 18H), 0.96 (m, 2H), 0.00 (s, 9H). 
EXAMPLE 175 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(4-[2-(4-morpholinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylm 
ethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 175e) 
(a) Compound 175a 
##STR337## 
To a solution of N-Boc-o-benzyl-L-tyrosine (25 g, 67.3 mmol) in dry THF (90 
ml) cooled at -20.degree. C. to -25.degree. C. was added isobutyl 
chloroformate (8.7 ml, 67.3 mmol) followed by 4-methylmorpholine (6.8 ml, 
67.3 mmol) and the mixture was stirred for 20 min. The precipitate was 
filtered and washed with dry THF. The filtrate was cooled to -5.degree. C. 
and poured into a diazomethane in ether solution (prepared from 
1-methyl-3-nitro-1-nitrosoguanidine (29.7 g, 202 mmol) as described in 
Example 1a(i)) at 0.degree. C. The resulting yellow solution was kept at 
0.degree. C. for 2.0 h, then at RT overnight. Nitrogen was then bubbled 
through the solution for 30 min, the solution diluted with Et.sub.2 O (500 
ml) and then washed with H.sub.2 O, sat'd NaHCO.sub.3, and brine, and 
dried (MgSO.sub.4). Concentration in vacuo afforded a yellow residue, 
which was triturated with hexane (500 ml) to give 24.5 g (92%) of the 
corresponding .alpha.-diazoketone as an off-white solid. A solution of 48% 
aqueous HBr (5.8 ml, 51.4 mmol) was added dropwise to the 
.alpha.-diazoketone (20.3 g, 51.4 mmol) in 500 ml of 1,4-dioxane-DME (2:1) 
cooled at -5.degree. C. After 30 min, saturated NaHCO.sub.3 was added 
until pH=7.0 and the solvent was removed under reduced pressure. The 
mixture was diluted with H.sub.2 O and extracted with EtOAc. The combined 
organic extracts were washed with H.sub.2 O and brine and dried (Na.sub.2 
SO.sub.4). Concentration in vacuo followed by recrystallization from 
EtOAc-hexane gave 20.9 g (91%) Compound 175a as an off-white solid. 
(b) compound 175b 
##STR338## 
To a solution of Compound 175a (23.3 g, 50.0 mmol) in 250 ml of MeOH-THF 
(1:1) cooled at -5.degree. C. was added, portionwise, NaBH.sub.4 (2.0 g, 
50.0 mmol). After 1 h, 10% KHSO.sub.4 (75 ml) was added at 0.degree. C. 
and the mixture was allowed to warm to RT. The mixture was extracted with 
hot EtOAc and the combined organic extracts were washed with H.sub.2 O and 
brine, and dried (Na.sub.2 SO.sub.4). Concentration in vacuo followed by 
recrystallization from EtOAc (350 ml) afforded 14.5 g (62%) of the syn 
bromohydrin as a white solid. HPLC analysis showed the diastereomeric 
ratio as 95:5. To a solution of the syn bromohydrin, prepared as above 
(115.2 g. 0.256 mole), in 1.5 L of THF and 1.5 L of 100% EtOH was added a 
solution of KOH (17.2 g of 87.6% pellets, 0.269 mole) in 300 mL of 100% 
EtOH at RT. After 15 min, 1 L of sat. aq. NH.sub.4 Cl was added and the 
mixture then diluted with 6 L of H.sub.2 O to give a precipitate. The 
solid was filtered, washed with H.sub.2 O, and extracted into 1 L of 
EtOAc. The organic phase was dried (Na.sub.2 SO.sub.4) and concentrated in 
vacuo to give a solid which was triturated with 1 L of hexane, to afford 
79.3 g (84%) of Compound 175b as a white solid. 
(c) Compound 175c 
##STR339## 
The mixture of Compound 175b (5.0 g, 13.5 mmol) and Pd(OH).sub.2 (500 mg) 
in 100 ml EtOH and 25 ml of EtOAc was stirred under hydrogen atmosphere 
for 4.5 hrs. The catalyst was removed by filtration and the filter cake 
was washed with EtOH, MeOH, and EtOAc. The combined washes were 
concentrated in vacuo to give a 3.8 g (99%) of Compound 175c as a white 
solid. 
(d) Compound 175d 
##STR340## 
To the mixture of Compound 175c (150 mg, 0.54 mmol), 
4-(2-hydroxyethyl)morpholine (141 mg, 1.07 mmol) and PPh.sub.3 (282 mg, 
1.07 mmol) in 1.5 ml of dry THF was added DEAD (169 .mu.l, 1.07 mmol). The 
resulting mixture was stirred at RT overnight. Concentration in vacuo 
followed by flash chromatography (CHCl.sub.3 --i--PrOH--NH.sub.4 OH: 
99:1:0.1 to 2:0.2) afforded 190 mg (90%) of Compound 175d as a white foam. 
(e) Compound 175e 
##STR341## 
A mixture of Compound 175d (126 mg, 0.32 mmol) and Compound 16b (90 mg, 
0.32 mmol) in 0.64 ml of dry DMF was heated at 100.degree. C. for 4.0 hrs. 
Concentration in vacuo followed by flash chromatography (CHCl.sub.3 
--MeOH--NH.sub.4 OH: 99:1:0.1 to 96:4:0.4) afforded, after trituration 
with chloroform/hexane, 90 mg (44%) of Compound 175e. m.p.: 
140.0.degree.-141.0.degree. C.; [.alpha.].sub.D =-3.25.degree. (c 0.246, 
MeOH). MS (FAB): 673.sup.+ (M+H).sup.+. Anal. Calc. for C.sub.36 H.sub.56 
N.sub.4 O.sub.8 .multidot.0.42H.sub.2 O: C, 63.55; H, 8.42; N, 8.24. 
Found: C, 63.73; H, 8.43; N, 8.06. 
Alternatively, Compound 175e was prepared as follows. Compound 174 was 
converted to the title Compound 175e by a procedure analogous to that used 
for the synthesis of Compound 21. Flash chromatography (100% CHCl.sub.3 to 
CHCl.sub.3 --MeOH--NH.sub.4 OH: 0:4.5:0.5) on a silica gel column gave 
Compound 175e as a white solid which was lyophilized from 1,4-dioxane to 
give a white lyophilate. 
EXAMPLE 176 
Preparation of [4S-4.alpha., 
5.alpha.(4R*,5S*)]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-2,2-dimethyl-4-p 
henylmethyl-5-oxazolidinyl]methyl][[2-(trimethylsilyl)ethoxy]carbonyl]amino 
]methyl]-2,2-dimethyl-4-[[4-[2-(2-pyridinyl)ethoxy]phenyl]methyl]]-3-oxazol 
idinecarboxylic acid, 1,1-dimethylethyl ester (Compound 176) 
##STR342## 
To the mixture of Compound 172 (184 mg, 0.235 mmol), 
2-(2-hydroxyethyl)pyridine (40 .mu.l, 0.352 mmol) and PPh.sub.3 (93 mg, 
0.352 mmol) in dry THF (0.5 ml) was added DEAD (55 .mu.l, 0.352 retool). 
The resulting yellow solution was stirred at RT overnight. Concentration 
in vacuo followed by flash chromatography (hexane/EtOAc 4:1) on a silica 
gel column afforded 143 mg (69%) of Compound 176 as a colorless oil. 
.sup.1 H-NMR (400 MHz, CD.sub.3 OD): 8.49 (d, J=5.13, 1H), 7.79 (m, 1H), 
7.44 (d, J=7.69, 1H), 7.13-7.38 (m, 8H), 6.87 (d, J=7.69, 1H), 4.34 (t, 
J=6.41, 2H), 4.03-4.35 (m, 6H), 3.30-3.55 (m, 4H), 3.26 (t, J=6.41, 2H), 
2.75-3.00 (m, 4H) , 1.30-1.79 (m, H), 0.93 (m, 2H), 0.00 (s, 9H). 
EXAMPLE 177 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl][[2-(trimethylsilyl)ethoxy]carbonyl]-amino]-2-hydroxy-1- 
[[4-2-(2-pyridinyl)ethoxy]-phenyl]methyl]propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 177) 
##STR343## 
a) Removal of bis-acetonide 
To Compound 176 (143 mg, 0.161 mmol) was added pre-cooled (10.degree. C.) 
96% formic acid (4.0 ml). The mixture was stirred at 5.degree. C. for 15 
min then was frozen (dry ice-acetone) and lyophilized overnight to give an 
oily residue. 
b) The above residue was dissolved in MeOH (2.3 ml). To this solution was 
added Et.sub.3 N (40 .mu.l, 0.242 mmol) and di-t-butyldicarbonate (20 
.mu.l, 0.08 mmol). The mixture was stirred at RT overnight. Concentration 
in vacuo followed by flash chromatography (100% CHCl.sub.3 to CHCl.sub.3 
--MeOH--NH.sub.4 OH: 97:3:0.3) on a silica gel column afforded 106 mg 
(81%) of Compound 177 as a white foam. .sup.1 H-NMR (400 MHz, CD.sub.3 
OD): 8.42 (m, 1H), 7.72 (m, 1H), 7.36 (m, 1H), 7.03-7.25 (m, 8H), 6.75 (d, 
J=7.69, 2H), 4.24 (t, J=6.41, 2H), 4.12 (t, J=8.55, 2H), 3.50-3.80 (m, 
6H), 3.17 (t, J=6.41, 2H), 2.88-3.30 (m, 4H), 2.35-2.64 (m, 2H), 1.25 (s, 
18H), 0.99 (t, J=8.55, 2H), 0.00 (s, 9H). 
EXAMPLE 178 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(4-[2-(2-pyridinyl)ethoxy]phonyl]butyl]amino]-2-hydroxy-1-(phenylmet 
hyl)propyl]carbamic acid, 1,1-dimethyl-ethyl ester (Compound 178) 
##STR344## 
A mixture of Compound 177 (0.106 g; 0.131 mmol) and solid n-Bu.sub.4 
NF.multidot.nH.sub.2 O (0.103 g; 0.393 mmol) in 0.56 ml THF was stirred at 
50.degree. C. for 4 h. After cooling to RT, 1 g of celite was added and 
the solvent removed in vacuo. Flash chromatography (CHCl.sub.3 
--MeOH--NH.sub.4 OH: 98:2:0.2 to 95:5:0.5) on a silica gel column followed 
by trituration with Et.sub.2 O-hexane gave 0.04 g of Compound 178 as a 
light yellow solid. m.p.: 125.0.degree.-126.5.degree. C.; [.alpha.].sub.D 
=-4.84.degree. (c 0.248, MeOH). MS (FAB): 665.sup.+ (M+H).sup.+. Anal. 
Calc. for C.sub.37 H.sub.52 N.sub.4 O.sub.7 .multidot.0.53H.sub.2 O: 
C, 65.89; H, 7.93; N, 8.13. Found: C, 66.07; H, 7.85; N, 8.13. 
EXAMPLE 179 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-(phenylmethoxy)-phenyl]methyl]pro 
pyl]carbamic acid, 1,1-dimethylethyl ester (Compound 179c) 
(a) Compound 179a 
##STR345## 
Compound 18 was converted to Compound 179a in 27% yield by a procedure 
analogous to that used for the synthesis of Compound 19 except that the 
reaction was only allowed to proceed to partial completion. 
(b) Compound 179b 
##STR346## 
Compound 179a was converted to Compound 179b by a procedure analogous to 
that used for the synthesis Compound 131 except that MeOH was used in 
place of DMF and the reaction was run at RT overnight. 
(c) Compound 179c 
##STR347## 
Compound 179c was obtained as a white solid from Compound 179b by a 
procedure analogous to that used for the synthesis of Compound 21. m.p. 
159.degree.-161.degree. C.; [.alpha.].sub.D =-8.97.degree. (c 0.245, DMSO) 
M.S. (FAB): 650.sup.+ (M+H).sup.+. 
EXAMPLE 180 
Preparation of 
[1S-(1R,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]biscarb 
amic acid, 4-amino-1,1-dimethylbutyl 1,1-dimethylethyl ester, fumarate 
(2:3) salt (Compound 180) 
##STR348## 
Compound 180 was obtained as a white powder from Compound 150 by a 
procedure analogous to that used for the synthesis of Compound 84. mp 
123.degree.-130.degree. C.; [.alpha.].sub.365 =-12.7 (c 0.15, MeOH). Mass 
Spec. FAB+ions: (M+H)=587. Analysis calc. for C.sub.32 H.sub.50 N.sub.4 
O.sub.6 .multidot.1.5 C.sub.4 H.sub.4 O.sub.4 .multidot.2.96 H.sub.2 O: 
C, 56.06; H, 7.66; N, 6.88; Found: C, 56.21; H, 7.42; N, 6.73. 
EXAMPLE 181 
Preparation of 
[1S,[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethylpropyl)sulfonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 181b) 
(a) Compound 181a 
##STR349## 
To a stirred solution of Compound 48 (300 mg, 0.51 retool) in 2 ml of dry 
CH.sub.3 CN at -20.degree. C. under argon was added 
2,2-dimethylpropyl-1-sulfonylchloride (Synthesis, 489 (1974)) (96 mg, 0.56 
mmol) followed by i--Pr.sub.2 NEt (79 mg, 0.61 mmol). After approximately 
2 hr at -5.degree. C., additional sulfonylchloride (48 mg, 0.28 retool) 
and i--Pr.sub.2 NEt (40 mg, 0.31 retool) was added at -20.degree. C. The 
mixture was re-warmed to ca. -5.degree. C. and stirred at that temperature 
for 4 hr, at which time the solution was adsorbed onto celite and 
chromatographed on a column (2.5.times.30 cm) of silica gel eluting with a 
gradient of hexane and EtOAc to afford 101 mg (27% yield) of Compound 181a 
as a clear solid foam. 
(b) Compound 181b 
##STR350## 
Compound 181b was obtained as a white lyophilate from Compound 181a by a 
procedure analogous to that used for the synthesis of Compound 21. m.p. 
134.degree.-137.degree. C. ("shrinkage" at 65.degree.-134.degree. C.); 
[.alpha.].sub.D =-11.0.degree. (c 0.77, MeOH) Elemental Analysis (%) Calc. 
for C.sub.30 H.sub.47 N.sub.3 O.sub.6 S.multidot.0.7 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 61.03 61.05 
H 8.26 8.17 
N 7.12 7.10 
______________________________________ 
Example 182 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[(1,1-Dimethylethyl)-sulfinyl]amino-2-hydroxy- 
4-phenylbutyl]amino]2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 182c) 
(a) Compound 182a 
##STR351## 
To a solution of t-butyl disulfide (4.8 mL, 25 mmol) in 25 mL of HOAc at 
0.degree. C. was added 3.18 mL (31.25 mmol) of 30% aqueous H.sub.2 
O.sub.2. The reaction mixture was stirred at 5.degree. C. for 24 h and 
then poured into 100 mL of ice water. The product was extracted with 
CH.sub.2 Cl.sub.2 and the combined extracts washed with sat. NaHSO.sub.3, 
sat. NaHCO.sub.3 and H.sub.2 O. The organic phase was dried (MgSO.sub.4) 
and concentrated to obtain a colorless oil. Cl.sub.2 gas (1.93 g, 27.18 
mmol) was condensed at -78.degree. C. and cannulated into a cooled 
solution (0-10.degree. C.) of the above oil in 25 mL of dry CH.sub.2 
Cl.sub.2. The resulting yellow solution was allowed to warm to RT and 
concentrated to obtain a dark yellow oil which was distilled at 
47.degree.-48.degree. C. (9 mm Hg) to obtain pure Compound 182a (0.72 g, 
20%) as a colorless oil. 
(b) Compound 182b 
##STR352## 
Compound 182a was converted to Compound 182b by a procedure analogous to 
that used for the synthesis of Compound 181a except that Et.sub.3 
N/CH.sub.2 Cl.sub.2 was used. 
(c) Compound 182c 
##STR353## 
Compound 182c was prepared as a white solid from Compound 182b by a 
procedure analogous to that used for Compound 21. m.p. 
152.degree.-155.degree. C. ("shrinkage" at 55.degree.-70.degree. C.) 
EXAMPLE 183 
Preparation of 
[1S-[1R*,25*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethylethyl)sulfonyl]amino]-2-hydr 
oxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester. (Compound 183b) 
(a) Compound 183a 
##STR354## 
To a solution of Compound 182b (0.22 g, 0.318 mmol) in 2.5 mL of CH.sub.2 
Cl.sub.2 cooled to 0.degree. C. was added 1.5 mL of saturated aq. 
NaHCO.sub.3. The suspension was vigorously stirred and a solution of 75% 
(80 mg, 0.35 mmol) in 2.5 mL of CH.sub.2 Cl.sub.2 was added dropwise. The 
reaction mixture was stirred for 90 min after which time it was warmed to 
RT, diluted with CH.sub.2 Cl.sub.2 and washed with sat. NaHSO.sub.3 
followed by sat. NaHCO.sub.3. The organic phase was dried (MgSO.sub.4) and 
concentrated. The crude material was flash chromatographed of silica 
eluting with a step-wise gradient of 25% EtOAc-hexane to 80% EtOAc-hexane 
to obtain 0.193 g (85%) of Compound 183a as a white solid. 
(b) Compound 183 b 
##STR355## 
Compound 183b was prepared as a white solid by a procedure analogous to 
that used for the synthesis of Compound 21. m.p. 86.degree.-90.degree. C. 
("softening" at 75.degree.-86.degree. C.); [.alpha.].sup.20.sub.D 
=-18.7.degree. (c=0.2, CH.sub.3 OH). 
EXAMPLE 184 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[[(1,1-Dimethylethyl)thio)carbonyl]amino]- 
2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 184b) 
(a) Compound 184a 
##STR356## 
Compound 184a was prepared from t-butyl mercaptan by a procedure analogous 
to that used for the synthesis of Compound 67a (pyridine was used). 
(b) Compound 184b 
##STR357## 
Compounds 184a and 54 were reacted by a procedure analogous to that used 
for the synthesis of Compound 147d to afford Compound 184b as a white 
solid. m.p. 140.degree.-141.degree. C. ("softening" at 
134.degree.-140.degree. C.); [.alpha.].sup.20.sub.D =-20.0.degree. 
(c=0.05, CH.sub.3 OH). 
EXAMPLE 185 
Preparation of 
[2S-[2R*,3S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino-2-hydr 
oxy-4-phenylbutyl]amino-2-hydroxy-4-phenylbutyl]carbamic acid, phenylmethyl 
ester (Compound 185d ) 
(a) Compound 185a 
##STR358## 
A 3:2 mixture of Compounds 26a(i) and 26a(ii) was converted into Compound 
185a by a procedure analogous to that used for the synthesis of Compound 
16b (except that the reaction was performed in NH.sub.3 saturated MeOH at 
50.degree.-60.degree. C. in a sealed vessel). 
(b) Compound 185b 
##STR359## 
Compound 185a was reacted with Cbz chloride by a procedure analogous to 
that used for the synthesis of Compound 122 to give Compound 185b 
(CH.sub.2 Cl.sub.2 used in place of DMF). 
(c) Compound 185c 
##STR360## 
Compound 185b was converted to Compound 185c by a procedure analogous to 
that used for the synthesis of Compound 32. 
(d) Compound 185d 
##STR361## 
Compounds 185c and 1b(i) were reacted by a procedure analogous to that used 
for the synthesis of Compound 4b to give the title Compound 185d as a 
white solid after silica gel chromatography (28 g) eluting the column with 
a stepwise gradient of CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH (98.9:1.0:0.1) 
to CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH (94.5:5.0:0.5), using 1% increments 
for MeOH and 0.1% increments for NH.sub.4 OH and trituration with Et.sub.2 
O to separate the isomers. MS: (M+H).sup.+ @ 578.sup.+. mp 
120.degree.-121.degree. C.; [.alpha.].sub.D =-5.0.degree. (c 0.10, MeOH). 
Analysis calc. for C.sub.33 H.sub.43 N.sub.3 O.sub.6 .multidot.0.01H.sub.2 
O: 
C, 68.59; H, 7.50; N, 7.27; Found: C, 68.52; H, 7.65; N, 7.34. 
EXAMPLE 186 
Preparation of 
[3S-[3R*,2(R*,S*)[2S*,3R*)]-3-[[3-(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-4-phenylbutyl]carbamic acid, 
phenylmethyl ester (Compound 186) 
##STR362## 
Compound 186 was prepared as a colorless solid from a 1:1 mixture of 1b(i) 
and 1b(ii) by a procedure analogous to that used for the synthesis of 
Compound 185d. mp 90.degree.-95.degree. C.; [.alpha.].sub.D =-4.0.degree. 
(c 0.10, MeOH). MS: (M+H).sup.+ @578.sup.+ Analysis calc. for C.sub.33 
H.sub.43 N.sub.3 O.sub.6. 0.9 6H.sub.2 O: 
C, 68.40; H, 7.81; N, 7.25; Found: C, 68.39; H, 7.57; N, 7.26. 
EXAMPLE 187 
Preparation of 
[2S-[2R*,3S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-4-phenylbutyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 187) 
##STR363## 
Compound 187 was obtained as a white solid from the (S)-hydroxyl 
diastereomer of Compound 185d by removing the Cbz group using reaction 
conditions analogous to those used for the synthesis of Compound 7 and 
putting on the Boc group using a procedure analogous to that used for the 
synthesis of Compound 20 (CH.sub.2 Cl.sub.2 /DMF used as solvent). m.p. 
143.degree. C.-144.degree. C.; [.alpha.].sub.D =-4.0.degree. (c=0.09, 
MeOH) Elemental Analysis (%) C.sub.33 H.sub.45 N.sub.3 O.sub.6, calculated 
for 0.44 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.31 65.09 
H 8.38 8.22 
N 7.62 7.83 
______________________________________ 
EXAMPLE 188 
Preparation of 
[3S-[3R*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy 
-4-phenyl-butyl]amino]-2-hydroxy-4-phenylbutyl]carbamic acid, 
1,1-dimethylethyl ester, 2:1 diastereomer mixture (Compound 188) 
##STR364## 
Compound 188 was obtained as a white solid from Compound 186 by removing 
the Cbz group using reaction conditions analogous to those used for the 
synthesis of Compound 7 and putting on the Boc group using a procedure 
analogous to that used for the synthesis of Compound 20 (CH.sub.2 Cl.sub.2 
/DMF used as solvent ) . m.p. 93.degree. C.-94.degree. C.; [.alpha.].sub.D 
=+4.0.degree. (c=0.10, MeOH) Elemental Analysis (%) C.sub.30 H.sub.45 
N.sub.3 O.sub.6, calculated for 0.2 moles H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.84 65.74 
H 8.36 8.39 
N 7.68 7.78 
______________________________________ 
EXAMPLE 189 
Preparation of 
[2R-[2R*,3R*(2R*,3S*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-4-phenylbutyl]-carbamic acid, 
phenylmethyl ester (Compound 189) 
##STR365## 
Compound 189 was obtained as a white solid from the (R)-hydroxyl 
diastereomer of Compound 185a by a procedure analogous to that of Example 
185d. m.p. 112.degree. C.-113.degree. C.; [.alpha.].sub.D =+3.0.degree. 
(c=0.09, MeOH) Elemental Analysis (%) C.sub.33 H.sub.43 N.sub.3 O.sub.6, 
calculated for 0.27 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 68.03 67.94 
H 7.53 7.35 
N 7.21 7.30 
______________________________________ 
EXAMPLE 190 
Preparation of 
[2R-[2R*,3R*(2R*,3S*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenyl-butyl]amino]-2-hydroxy-4-phenylbutyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 190) 
##STR366## 
Compound 190 was obtained as a white solid from Compound 189 by a two-step 
procedure analogous to that used for the synthesis of Compound 187. m.p. 
132.degree. C.-134.degree. C.; [.alpha.].sub.Hg =+1.0.degree. (c=0.08, 
MeOH) Elemental Analysis (%) C.sub.30 H.sub.45 N.sub.3 O.sub.6 calculated 
for 1.34 moles H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.63 65.27 
H 7.96 7.83 
N 6.96 7.32 
______________________________________ 
EXAMPLE 191 
Preparation of 
[1S-(1R*,2S*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-2-(p 
henylmethyl)propyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethyl-ethyl ester (Compound 191e) 
(a) Compound 191a 
##STR367## 
Compound 191a was prepared from epoxypropyl benzene by a procedure 
analogous to that used for the synthesis of Compound 16b except that 
NH.sub.3 saturated MeOH was used at 90.degree. C. in a sealed vessel. 
(b) Compound 191b 
##STR368## 
Compound 191b was prepared from Compound 191a by a procedure analogous to 
that used for the synthesis of Compound 131 (THF/H.sub.2 O used). 
(c) Compound 191c 
##STR369## 
DMSO (0.17 ml, 2.40 mmol) was added to a stirred solution of (COCl).sub.2 
(0.104 ml, 1.20 mmol) in dry CH.sub.2 Cl.sub.2 (5.0 ml) at -78.degree. C. 
After 15 min, a solution of Compound 191b (0.10 g, 0.40 mmol) in CH.sub.2 
Cl.sub.2 (5.0 ml) was added. The reaction mixture remained at -78.degree. 
C. for 40 min before adding Et.sub.3 N (0.39 ml, 2.80 mmol), and warming 
to 0.degree. C. for 4 min. The yellow reaction mixture was then quenched 
with saturated NH.sub.4 Cl and the aqueous layer extracted with EtOAc. The 
organic layer was washed with saturated NaHCO.sub.3, dried (Na.sub.2 
SO.sub.4) and concentrated in vacuo to afford 0.109 g of Compound 191c as 
a yellow oil. 
(d) Compound 191d 
##STR370## 
To a solution of Compound 191c (0.10 g, 0.40 mmol) in THF (30 ml) was added 
the ylide (0.60 ml, 0.962M) freshly prepared by refluxing 
trimethylsulfoxonium chloride (3.75 g, 29.16 mmoles) and NaH (0.693 g, 
28.88 mmol, 60% oil dispersion washed with hexane) in dry THF (30 ml) for 
3.5 h. After stirring at 0.degree. C. for 75 seconds, saturated 
NaHCO.sub.3 was added and the reaction mixture was partitioned between 
EtOAc and NaHCO.sub.3 solution. The volatiles were evaporated to afford a 
yellow oil which is a mixture of Compounds 191c and 191d (1:1). The oil 
was dried by azeotroping with toluene three times and placing under high 
vacuum, then resubmitting to the reaction conditions. The isolated crude 
material was purified on a silica gel column (10 g), eluting the column 
with CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH (98.9:1.0:0.1, 97.8:2.0:0.2 and 
96.7:3.0:0.3) to afford 0.69 g (66%) of Compound 191d as a yellow oil. 
(e) Compound 191e 
##STR371## 
Compounds 191d and 16b were reacted by a procedure analogous to that of 
Example 4b (except in MeOH at 50.degree. C.) to give Compound 191e as a 
colorless foam. m.p. 65.degree.-67.degree. C.; [.alpha.].sub.D 
=-3-0.degree. (c 0.10, MeOH) Calculated for C.sub.30 H.sub.45 N.sub.3 
O.sub.6 .multidot.0.35 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.52 65.36 
H 8.37 8.42 
N 7.64 7.80 
______________________________________ 
EXAMPLE 192 
Preparation of 
[1S-[1R*,2S*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy 
-2-methyl-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carba 
mic acid, 1,1-dimethylethyl ester (Compound 192c) 
(a) Compound 192a 
##STR372## 
KN(TMS).sub.2 (6.08ml, 3.04 mmol) was added dropwise to a mixture of 
MePPh.sub.3 +Br.sup.- (1.19 g, 3.34 mmol) in toluene (8 ml) at -78.degree. 
C. After 5 min, the mixture was warmed to RT and stirred for 15 min. After 
recooling the reaction to -78.degree. C., a solution of 
3S-3-[(1,1-dimethylethoxycarbonyl)amino]-4-phenyl-2-butanone [Godfrey et 
al., Tetrahedron Letters, 28, 1603 (1987)](0.40 g, 1.52 mmol) in toluene 
(2 ml) was added. The reaction was quenched after 35 min with pH 7 buffer 
and the aqueous layer extracted with EtOAc. The combined extracts were 
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to afford 0.159 g of 
Compound 192a as a white solid (42% yield). 
(b) Compound 192b 
##STR373## 
m-CPBA (0.13 g, 0.61 mmole) was added to a stirred solution of Compound 
192a (0.16 g, 0.61 mmol) in CH.sub.2 Cl.sub.2 (2 ml) at 0.degree. C. After 
30 min, the reaction mixture was warmed to RT and stirred for an 
additional 30 min before quenching with pH 7 buffer and partitioning 
between aq. NaHCO.sub.3 and EtOAc. The organic extracts were dried 
(Na.sub.2 SO.sub.4) and concentrated in vacuo to afford 0.17 g of a white 
solid. This crude material was purified by silica gel chromatography (20 
g), eluting the column with 10% EtOAc/hexane to afford 0.129 g of Compound 
192b as a white solid (87% yield). 
(c) Compound 192c 
##STR374## 
Compounds 192b and 16b were reacted by a procedure analogous to that of 
Example 4b (except that the reaction was run in MeOH at 50.degree. C.) to 
give the title Compound 192c as a colorless foam. m.p. 
63.degree.-66.degree. C.; [.alpha.].sub.D =-3.0.degree. (c 0.10, MeOH) 
Elemental Analysis (%) Calc. for C.sub.31 H.sub.47 N.sub.3 O.sub.6 
.multidot.0.42 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 65.98 66.15 
H 8.37 8.52 
N 7.45 7.28 
______________________________________ 
EXAMPLE 193 
Preparation of 
[1S-[1R*,2S*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-oxo-4-p 
henylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 193b) 
(a) Compound 193a 
##STR375## 
To a solution of Compound 1a(iii) (197 mg, 0.68 mmol), Compound 4a (250 mg, 
0.66 mmol), and NaI (99 mg, 0.66 mmol) in DMF (1.8 mL) was added 
NaHCO.sub.3 (200 mg, 2.38 mmol). The suspension was stirred at RT for 18.5 
h and then partitioned between EtOAc and H.sub.2 O. The organic extracts 
were dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to give an 
oily-solid residue which was purified by flash chromatography (silica gel, 
3 by 11 cm), eluting with MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2 
(0.5:0.05:99.45 and then 1:0.1:98.9) to give Compound 193a (130 mg, 31% 
yield) as a colorless solid. R.sub.f =0.36 (4:0.4:95.6; MeOH:NH.sub.4 
OH:CH.sub.2 Cl.sub.2); Mass Spec. (FAB): 632 (M+H). 
(b) Compound 193b 
##STR376## 
Compound 193b was prepared as a colorless solid from Compound 193a by a 
procedure analogous to that of Example 7 (1:1 THF:MeOH used). m.p. dec. 
116.degree.-120.degree. C. Mass Spec. (CI/NH.sub.3): 542 (M+H). Anal. 
Calc. for C.sub.30 H.sub.43 N.sub.3 O.sub.6 .multidot.0.26 H.sub.2 O: 
C, 65.94; H, 8.03; N, 7.69 Found: C, 66.00; H, 8.05; N, 7.63 
EXAMPLE 194 
Preparation of 
[2S-(2R*,2R*)]-[[(Phenylmethyl)-imino]bis[2-hydroxy-4-phenyl-3,1-butanediy 
l]]bis-carbamic acid, bis(1,1-dimethylethyl)ester (Compound 194b) 
(a) Compound 194a 
##STR377## 
Compound 194a was prepared from 1 eq. of benzyl amine and 2.2 eq. of 
Compound 1a(iii) by a procedure analogous to that used in Example 193a. 
(b) Compound 194b 
##STR378## 
Compound 194b was prepared as a white foam from Compound 194a by a 
procedure analogous to that used for the synthesis of Compounds 1a(iv) and 
1a(v) except that 95% EtOH was used. m.p. 60.0.degree.-62.0.degree. C. 
Elemental Analysis (%) C.sub.37 H.sub.51 N.sub.3 O.sub.6 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 70.11 69.67 
H 8.11 8.05 
N 6.63 6.43 
______________________________________ 
EXAMPLE 195 
Preparation of 
[1S-[1R*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-p 
henylbutyl]-(phenylmethyl)amino]-2-oxo-1-(phenylmethyl)propyl]-carbamic 
acid, 1,1-dimethylethyl ester. (Compound 195) 
##STR379## 
Compound 195 was also isolated as a white solid from the reaction mixture 
of Example 194b. m.p. (161.0.degree. C. softens) 
176.0.degree.-177.0.degree. C. Elemental Analysis (%) C.sub.37 H.sub.49 
N.sub.3 O.sub.6 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 70.34 69.85 
H 7.82 7.86 
N 6.65 6.77 
______________________________________ 
EXAMPLE 196 
Preparation of 
(3S,3S')-[[(Phenylmethyl)nitrilo]-bis(2-hydroxy-5-methyl-3,1-hexandiyl)]-b 
iscarbamic acid, bis(1,1-dimethylethyl)ester (Compound 196b) 
(a) Compound 196a 
##STR380## 
Compound 196a was prepared from Boc-L-leucine by a procedure analogous to 
that used for the synthesis of Compound 1a(iii). 
(b) Compound 196b 
##STR381## 
Compound 196b was prepared as a white foam by a two-step procedure 
analogous to that of Example 194b. m.p. 54.0.degree.-55.0.degree. C. 
Elemental Analysis (%) C.sub.31 H.sub.55 N.sub.3 O.sub.6 .multidot.0.53 
H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 64.72 64.63 
H 9.82 9.27 
N 7.30 7.39 
______________________________________ 
EXAMPLE 197 
Preparation of [1S-[1R*(2S*,3R*)]]-[3 
-[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl]-methy 
lamino]-2-oxo-1-phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 197b) 
(a) Compound 197a 
##STR382## 
Compound 197a was prepared from Compound 1b(i) and MeNH.sub.2 by a 
procedure analogous to that used for the synthesis of Compound 4a except 
that the reaction was run in EtOH at RT. 
(b) Compound 197b 
##STR383## 
Compound 197b was prepared as a white foam from Compounds 197a and la(iii) 
by a procedure analogous to that of Example 193a. m.p. 
120.0.degree.-122.0.degree. C. Elemental Analysis (%) C.sub.31 H.sub.45 
N.sub.3 O.sub.6 19 0.40 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.14 66.01 
H 8.20 8.08 
N 7.46 7.28 
______________________________________ 
EXAMPLE 198 
Preparation of 
[1S-[1R*,2S*(3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydrox 
y-4-phenylbutyl]-methylamino]-2-hydroxy-1-(phenylmethyl)propyl-carbamic 
acid, 1,1-dimethylethyl ester (Compound 198) 
##STR384## 
Compound 198 was prepared as a white foam from Compound 197b by a procedure 
analogous to that used for the synthesis of Compounds 1a(iv) and 1a(v) 
except that 95% EtOH was used. m.p. 62.0.degree.-70.0.degree. C. Elemental 
Analysis (%) C.sub.31 H.sub.47 N.sub.3 .multidot.0.18 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 66.76 66.37 
H 8.49 8.70 
N 7.53 7.27 
______________________________________ 
EXAMPLE 199 
Preparation of [1S-[1R*(2R*,3R*)]]-3- 
[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-4-phenylbutyl]-methyl 
amino]-2-oxo-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 199) 
##STR385## 
Compound 199 was prepared as a white foam from Compound 1b(ii) by a 
procedure analogous to that of Example 197b. m.p. 
72.0.degree.-80.0.degree. C. Elemental Analysis (%) C.sub.31 H.sub.45 
N.sub.3 O.sub.6 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 67.00 66.84 
H 8.16 8.14 
______________________________________ 
EXAMPLE 200 
Preparation of 
[1S-[1R*,2R*(1R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydrox 
y-4-phenylbutyl]-methylamino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic 
acid, 1,1-dimethylethyl ester (Compound 200). 
##STR386## 
Compound 200 was prepared as a white foam from Compound 199 by a procedure 
analogous to that used for the synthesis of Compounds 1a(iv) and 1a(v) 
except that 95% EtOH was used. m.p. 70.0.degree.-75.0.degree. C. Elemental 
Analysis (%) C.sub.31 H.sub.47 N.sub.3 O.sub.6 .multidot.0.85 H.sub.2 O 
______________________________________ 
Calc. 
Found 
______________________________________ 
C 64.98 65.31 
H 8.57 8.30 
N 7.33 7.00 
______________________________________ 
EXAMPLE 201 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[3-(4-morpholinyl)propoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenyl 
methyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 201d) 
(a) Compound 201a 
##STR387## 
Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of 
morpholine (2.20 ml; 25 mmol) and Na.sub.2 CO.sub.3 (2.78 g; 26 mmol) in 
4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at 
reflux. After cooling to RT and filtering, the filtrate was concentrated 
and the residue was dissolved in H.sub.2 O. The pH was adjusted to 
.about.1.5 with saturated KHSO.sub.4 and the acidic mixture was washed 
with Et.sub.2 O. Solid K.sub.2 CO.sub.3 was added to the aqueous layer 
until a pH of .about.9 was reached. The basic mixture was extracted with 
CH.sub.2 Cl.sub.2, dried (MgSO.sub.4) and concentrated to afford 4.75 g 
(100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a 
colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of 
Et.sub.2 O was added to a suspension of LiAlH.sub.4 (400 mg; 10 mmol) in 
80 ml of Et.sub.2 O at 0.degree. C. After stirring for 30 min at 0.degree. 
C., the reaction was quenched by the careful addition of 0.42 ml of 
H.sub.2 O followed by 0.42 ml of 15% NaOH and 1.26 ml of H.sub.2 O. 
MgSO.sub.4 was added and the suspension was filtered and concentrated to 
afford 531 mg (73%) of Compound 201a as a colorless liquid. 
(b) Compound 201b 
##STR388## 
Compounds 172 and 201a were reacted by a method analogous to that described 
in Example 176 to give Compound 201b. 
(c) Compound 201c 
##STR389## 
Compound 201b was converted into Compound 201c (white foam) by the method 
described for Compound 177. 
(d) Compound 201d 
##STR390## 
Compound 201c was converted to the title Compound 201d (white solid) by the 
method described in Example 21. mp 122.degree.-124.degree. C.; 
[.alpha.].sub.D =-4.7.degree. (c 0.30, MeOH). Mass Spec. FAB+ions: 
M+H=687. Analysis calc. for C.sub.37 H.sub.58 N.sub.4 O.sub.8 
.multidot.0.39H.sub.2 O: 
C, 64.05; H, 8.54; N, 8.07; Found: C, 64.10; H, 8.50; N, 8.02. 
EXAMPLE 202 
Preparation of [[1R*,2S*(2S*,3R*)], N.sup.2 -(R*)]-N.sup.2 
-[(2,3-Dihydroxypropoxy)carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl] 
amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-v 
alinamide (Compound 202e) 
(a) Compound 202a 
##STR391## 
(R)-2,2-Dimethyl-1,3-dioxolane-4-methanol was converted to Compound 202a 
(pale yellow oil) by a method analogous to that of Example 161d. 
(b) Compound 202b 
##STR392## 
Compound 202a and valine methyl ester hydrochloride were reacted by a 
method analogous to that described for Example 161e to give Compound 202b 
(yellow oil). 
(c) Compound 202c 
##STR393## 
Crude Compound 202b was dissolved in a solution of glacial HOAc (10 mL) and 
H.sub.2 O (2.50 mL) and heated at 40.degree.-45.degree. C. in an oil bath 
for 3 h. Volatiles were removed in vacuo to afford an orange oil, which 
was chromatographed on silica gel (100 mL) using a gradient from 1:1 
hexane:EtOAc to 100% EtOAc as eluent to afford Compound 202c (0.552 g, 74% 
over 2 steps) as a pale yellow oil. 
(d) Compound 202d 
##STR394## 
Compound 202c was converted to Compound 202d (white solid) by a method 
analogous to that used for the preparation of Compound 70c (THF used as 
solvent). 
(e) Compound 202e 
##STR395## 
Compounds 54 and 202d were reacted by a method analogous to that described 
for Compound 55 (2 eq. N-methylmorpholine added; DMF only used) to give 
the title Compound 202e. This material was purified by preparative HPLC on 
a Waters Delta Prep 4000, with a Waters Novapak C-18 (6 .mu.m particle 
size; 30.times.300 mm) column using as eluent a gradient from 50:50 A:B to 
100% A (A=90:10:0.05 MeOH:H.sub.2 O:TFA; B=90:10:0.05 H.sub.2 O:MeOH:TFA) 
to give 47 mg (21%) of pure Compound 202e as a white powder. 
m.p.=167.degree.-170.degree. C.; [.alpha.].sub.D =-15.9.degree. (c=0.23; 
MeOH) High resolution MS (FAB): Calculated (M+H).sup.+ (for C.sub.34 
H.sub.53 O.sub.9 N.sub.4)=661.3813; Observed (M+H).sup.+ =661.3798 
.DELTA.=2.3 ppm 
EXAMPLE 203 
Preparation of 
[1R*,2S*(2S*,3R*)1-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy- 1-(phenylmethyl)propyl]-N.sup.2 
-[[2-(phenylamino)ethoxy]carbonyl]-L-valinamide (Compound 203e) 
(a) Compound 203a 
##STR396## 
2-Anilinoethanol, benzaldehyde and NaCNBH.sub.3 were reacted by a method 
analogous to that of Example 126 (MeOH/1% HOAc used) to give Compound 203a 
(clear oil). 
(b) Compound 203b 
##STR397## 
Compound 203a was converted to Compound 203b (yellow oil which solidified 
upon standing) by a method analogous to that described in Example 161d. 
(c) Compound 203c 
##STR398## 
Compounds 203b and 61 were reacted by a method analogous to that described 
in Example 161e to give 238 mg of Compound 203c (white solid). 
(d) Compound 203d 
##STR399## 
Compound 203c was converted into Compound 203d (white solid) by a method 
analogous to that described in Example 21. 
(e) Compound 203e 
##STR400## 
Compound 203d was converted into the title Compound 203e (white solid) by a 
method analogous to that of Example 2. mp 162.degree.-167.degree. C. 
("softening" at 150.degree.-162.degree. C.); [.alpha.].sub.D 
=-15.5.degree. (c=0.69, MeOH) Mass spectrum (FAB): 706 (M+H.sup.+) 
Analysis calculated for C.sub.39 H.sub.55 O.sub.7 N.sub.5 
.multidot.1.85H.sub.2 O: 
C, 63.37 H, 8.00 N, 9.47 Found: C, 63.32 H, 7.91 N, 9.52 
EXAMPLE 204 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[[1,4-dioxo-4-(phenylamino)butyl]-L-valinamide (Compound 204b) 
(a) Compound 204a 
##STR401## 
Compound 204a was prepared by a procedure analogous to that described in 
Liebigs Ann. Chem., 306, 326 (1899). 
(b) Compound 204b 
##STR402## 
Compound 204b (white solid) was prepared starting from Compounds 61 and 
204a by a two-step method analogous to that used for the conversion of 
Compound 48 to Compound 52. mp 218.degree.-220.degree. C. ("softening" at 
210.degree.-218.degree. C.); [.alpha.].sub.D =-3.7.degree. (c=0.47 , MeOH) 
mass spectrum (FAB): 718 (M+H.sup.+); Analysis calculated for C.sub.40 
H.sub.55 O.sub.7 N.sub.5 .multidot.0.94H.sub.2 O: 
C, 65.38 H, 7.80 N, 9.53 Found: C, 65.44 H, 7.65 N, 9.47. 
EXAMPLE 205 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-allothreoninamide (Compound 205b) 
(a) Preparation of Cbz-L-allothreonine (Compound 205a) 
Benzylchloroformate (0.35 ml; 2.3 mmol) was added to a mixture of 
L-allothreonine (0.25 g; 2.1 mmol) and NaHCO.sub.3 (435 mg; 5.18 mmol) in 
2.5 ml of H.sub.2 O at RT. After 3 h, the reaction mixture was partitioned 
between Et.sub.2 O and H.sub.2 O. The aqueous layer was washed with Et20, 
acidified to pH &lt;2 with 6N HCl, and extracted with CH.sub.2 Cl.sub.2. The 
organic layer was dried (MgSO.sub.4) and concentrated to afford 320 mg 
(63%) of Cbz-L-allothreonine. 
(b) Compound 205b 
##STR403## 
Compounds 205a and 54 were reacted by a method analogous to that described 
in Example 55 (DMF only) to give the title Compound 205b (white solid). mp 
155.degree.-157.degree. C.; [.alpha.].sub.D =-21.0.degree. (c 0.45, MeOH). 
Mass Spec. FAB+ions: M+H=679. Analysis calc. for C.sub.37 H.sub.50 N.sub.4 
O.sub.8 .multidot.0.61 H.sub.2 O: 
C, 64.43; H, 7.48; N, 8.12; Found C, 64.46; H, 7.35; N, 8.09. 
EXAMPLE 206 
Preparation of [4S- 
[4.alpha.,5.alpha.(4R*,5S*)]]-5-[[[[3-[(1,1-Dimethylethoxy)carbonyl]-4-[[4 
-[2-(phenyl-methoxy)ethoxy]phenyl]methyl]-2,2-dimethyl-5-oxazolidinyl]methy 
l][[2-(trimethylsilyl)ethoxy]-carbonyl]]amino]methyl]-2,2-dimethyl-4-(pheny 
l-methyl)-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester (Compound 
206) 
##STR404## 
To a mixture of Compound 172 (250 mg, 0.32 mmol), 2-benzyloxyethanol (91 
.mu.l, 0.64 mmol) and Ph.sub.3 P (167 mg, 0.64 mmol) in dry THF (0.64 ml) 
was added DEAD (100 .mu.l, 0.64 mmol). The mixture was stirred at RT 
overnight. Concentration in vacuo followed by flash chromatography 
(hexane/EtOAc 10:1 to 8:1) afforded 251 mg (86%) of Compound 206 as a 
white foam. .sup.1 H NMR (400 MHz, CDCl.sub.3): 7.10-7.55 (m, 12H), 6.85 
(m, 2H), 4.66 (s, 2H), 4.02-4.38 (m, 8H), 3.85 (m, 2H), 3.20-3.60 (m, 4H), 
2.70-3.05 (m, 4H), 1.20-1.80 (m, 30H), 0.92 (m, 2H), 0.00 (s, 9H). 
EXAMPLE 207 
Preparation of 
[1R*,2S*(2S*,3R*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy- 
4-[4-[2-(phenylmethoxy)ethoxy]phenyl]butyl][[2-(trimethyl-silyl)ethoxy]carb 
onyl]]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 207 ) 
##STR405## 
To Compound 206 (251 mg, 0,274 mmol) was added pre-cooled (10.degree. C.) 
96% formic acid (6.0 ml). The mixture was stirred at 5.degree. C. for 20 
min and then frozen (dry ice-acetone) and lyophilized (overnight). The 
residue was taken into MeOH (5 ml). To this solution was added Et.sub.3 N 
(115 .mu.l, 0.822 mmol), followed by di-tert-butyldicarbonate (60 mg, 
0.274 mmol). The mixture was stirred at RT overnight. Concentration in 
vacuo followed by flash chromatography (100% CHCl.sub.3 to CHCl.sub.3 
--MeOH--NH.sub.4 OH: 95:5:0.5) afforded 219 mg (97%) of Compound 207 as a 
white foam. .sup.1 H NMR (400 MHz, CD.sub.3 OD): 7.05-7.35 (m, 12H), 6.79 
(d, J=8.12, 2H), 4.55 (s, 2H), 4.12 (m, 2H), 4.06 (t, J=4.70, 2H), 3.75 
(t, J=4.70, 2H), 3.54-3.85 (m, 6H), 3.10-3.30 (m, 2H, N--CH.sub.2), 2.54 
and 3.00 (both m, 4H), 1.25 and 1.26 (both s, 18H), 0.99 (m, 2H), 0.00 (s, 
9H). 
EXAMPLE 208 
Preparation of 
[1R*,2S*(2S*,3R*)]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy- 
4-[4-(2-hydroxyethoxy)phenyl]butyl][[2-(trimethylsilyl)ethoxy]carbonyl]]ami 
no]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 208) 
##STR406## 
To a solution of Compound 207 (219 mg, 0.265 mmol) in 4.0 ml of MeOH was 
added 75 mg Pd(OH).sub.2. The mixture was stirred under a H.sub.2 
atmosphere overnight. The catalyst was removed by filtration and the 
filtrate was concentrated under reduced pressure to give 195 mg of 
Compound 208 as a colorless oil, which was used immediately for the next 
Example. .sup.1 H NMR (400 MHz, CD.sub.3 OD): 7.05-7.25 (m, 7H), 6.79 (d, 
J=7.69, 2H), 4.12(m, 2H), 3.95 (t, J=4.91, 2H), 3.79 (t, J=4.91, 2H), 
3.50-3.80 (m, 6H), 3.10-3.32 (m, 2H), 2.52 and 3.00 (both m, 4H), 1.25 and 
1.27 (both s, 18H), 0.99 (t, J=8.55, 2H), 0.00 (s, 9H). 
EXAMPLE 209 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-(2-hydroxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)pr 
opyl]carbamic acid, 1,1-dimethylethyl ester (Compound 209) 
##STR407## 
A mixture of Compound 208 (195 mg, 0.265 mmol) and solid n-Bu.sub.4 
NF.multidot.nH.sub.2 O (208 mg, 0.795 mmol) in dry THF (1.2 ml) was heated 
at 50.degree. C. for 4.0 h. After cooling to RT, Celite (1.0 g) was added 
and the solvent was removed under reduced pressure. Flash chromatography 
(100% CHCl.sub.3 to CHCl.sub.3 --MeOH--NH.sub.4 OH: 94:6:0.6) on silica 
gel afforded 122 mg (76%) of Compound 209 as a white solid. M.P.: 
152.degree.-154.degree. C.; [.alpha.].sub.D =-2.9.degree. (C 0.49, MeOH). 
MS (FAB): 604.sup.+ (M+H).sup.+. Anal. Calc. for C.sub.32 H.sub.49 N.sub.3 
O.sub.8 .multidot.1.16H.sub.2 O: 
C, 61.52; H, 8.28; N, 6.73. Found: C, 61.44; H, 7.90; N, 6.81. 
EXAMPLE 210 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisca 
rbamic acid, 1,1-dimethylethyl-4-(phenylmethoxy)-1,1-dimethylbutyl ester 
(Compound 210b) 
(a) Compound 210a 
##STR408## 
Compound 210a (viscous oil) was prepared from 5-benzyloxy-2-pentanone 
(Jiang et al., J. Org. Chem, 48, 2001 (1983)) by a procedure analogous to 
that described in Example 158a. 
(b) Compound 210b 
##STR409## 
Compound 210a was converted into Compound 210b (white solid) by a 
three-step procedure analogous to that used for the conversion of Compound 
149c to Compound 150 (DMF used in the coupling of the p-nitrophenyl 
carbonate with Compound 48). mp 139.degree.-142.degree. C. ("shrinkage" at 
120.degree.-135.degree. C.); [.alpha.].sub.D =-3.4.degree. (c 0.23, 
CH.sub.3 OH). Mass Spec. (High Res.) (M+H).sup.+ =678. 4092 
(.DELTA.ppm=3.8) 
EXAMPLE 211 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(2-hydroxyphenylalanyl)-L-valinamide, fumarate (2:3) salt (Compound 211c 
) 
(a) Compound 211a 
##STR410## 
DL-o-Tyrosine was converted to Compound 211a (colorless solid) by a method 
analogous to that described in Example 85a. 
(b) Compound 211b 
##STR411## 
Compounds 211a and 61 were converted to Compound 211b (colorless solid) by 
a two-step procedure analogous to that used for the conversion of Compound 
48 to Compound 52. 
(c) Compound 211c 
##STR412## 
Compound 211b was converted into Compound 211c (colorless solid) by a 
method analogous to that described in Example 84. High Res. Mass Spec. 
(FAB): C.sub.39 H.sub.56 N.sub.5 O.sub.7 (M+H).sup.+ =706.4180.sup.+ 
.DELTA.=3.7 ppm. [.alpha.].sub.D =-12.degree. (c=0.2, MeOH). 
EXAMPLE 212 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-FN-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-L-valyl]-L-seri 
namide, fumarate (2:3) salt (Compound 212b) 
(a) Compound 212a 
##STR413## 
Compound 61 and N-Cbz-L-serine were converted to Compound 212a (colorless 
solid) by a two-step procedure analogous to that used for the conversion 
of Compound 48 to Compound 52. 
(b) Compound 212b 
##STR414## 
Compound 212a was converted into Compound 212b (colorless solid) by a 
method analogous to that described in Example 84. m.p. 
178.degree.-184.degree. C. High Res. Mass Spec. (FAB): C.sub.33 H.sub.52 
N.sub.5 O.sub.7 (M+H).sup.+ =30.3850.sup.+ ; .DELTA.=2.7 ppm. 
EXAMPLE 213 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethyl-1,2-dioxobutyl)amino]-2-hydr 
oxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 213c) 
(a) Compound 213a 
##STR415## 
7 ml of 1N aqueous KOH was added to 600 mg (3.8 mmoles) of t-butyl ethyl 
oxylate [J. Org. Chem, 35, 3726 (1970)] in 7 ml of MeOH. After 3 h, the 
reaction was evaporated to near dryness and the residue dissolved in 
H.sub.2 O and washed with Et.sub.2 O. The aqueous layer was acidified to 
pH 1, saturated with solid NaCl and extracted with Et.sub.2 O. The 
combined extracts were washed with brine, dried (MgSO.sub.4) and the 
solvent evaporated to yield a colorless oil residue. Distillation 
(kugelrohr, 165.degree.-175.degree. C., 50 mm) afforded 427 mg (86% yield) 
of Compound 213a as a colorless oil which crystallized on standing. 
(b) Compound 213b 
##STR416## 
1 eq. of HCl/MeOH was added to Compound 128 in MeOH. Filtration and 
evaporation gave the hydrochloride salt which was reacted with Compound 
213a by a procedure analogous to that described in Example 51 to give 
Compound 213b as a viscous foam. 
(c) Compound 213c 
##STR417## 
Compound 213b was converted to Compound 213c (white solid) by a procedure 
analogous to that described in Example 42. m.p. 133.degree.-134.degree. 
C.; [.alpha.].sub.D =-14.3.degree. (c 0.96, MeOH) Mass Spec.: 556 (M+H) 
Anal. Calc. for C.sub.31 H.sub.45 N.sub.3 O.sub.6 (555.7): 
C, 67.00; H, 8.16; N, 7.56. Found: C, 66.87; H, 8.01; N, 7.37. 
EXAMPLE 214 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,3-Dimethyl-1,2-dioxobutyl)amino]-2-hydr 
oxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 214b) 
(a) Compound 214a 
##STR418## 
Compound 106d was converted to Compound 214a (white solid) by a procedure 
analogous to that described in Example 7 (ETOH used). 
(b) Compound 214b 
##STR419## 
Compounds 54 and 214a were reacted by a procedure analogous to that 
described in Example 55 (2 eq. of N-methylmorpholine was added; DMF only 
used) to give the title Compound 214b (white foam). Anal. Calc. for 
C.sub.31 H.sub.47 N.sub.3 O.sub.6 .multidot.1.75 H.sub.2 O: C, 63.20; H, 
8.64; N, 7.13. Found: C, 63.71; H, 8.36; N, 6.62. HRMS: (M+H).sup.+ 
=558.3533.sup.+ 
EXAMPLE 215 
Preparation of 
[1S-(1R*,2S*)(trans)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl 
)]biscarbamic acid, 1,1-dimethylethyl 2,3-dihydro-2-hydroxy-1H-inden-1-yl 
ester (Compound 215d) 
(a) Compound 215a 
##STR420## 
To a solution of indene (1 ml, 8.57 mmol) in CH.sub.2 Cl.sub.2 (2 8 mL ) 
was added m-CPBA (2.1 g, 9.13 mmol). After stirring for 21.5 h, the 
mixture was filtered and the volatiles evaporated in vacuo. The resulting 
residue was partitioned between CH.sub.2 Cl.sub.2 and saturated 
NaHCO.sub.3, the aqueous layer back-extracted with CH.sub.2 Cl.sub.2, and 
the combined organic layers dried (Na.sub.2 SO.sub.4). Evaporation in 
vacuo gave an oil containing Compounds 215a(i) and 215a(ii) (1.9 g total) 
which was used in the next reaction. 
(b) Compound 215b 
##STR421## 
To a cloudy solution of crude Compounds 215a(i) and 215a(ii) (&lt;1.9 g, 
.ltoreq.6.89 mmol) in MeOH (50 mL) was added NaOMe (1.9 mL, 8.31 mmol, 25% 
in MeOH). The solution was stirred at RT for 1 h, the volatiles removed in 
vacuo, and the residue partitioned between EtOAc and brine. The combined 
organic layers were dried (Na.sub.2 SO.sub.4) and concentrated in vacuo. 
The residue was purified by flash chromatography (silica gel, 5 by 17 cm), 
eluting with EtOAc:CH.sub.2 Cl.sub.2 (3:2 then 2:1) to give Compound 215b 
(140 mg) as a colorless solid. A somewhat contaminated fraction of 
Compound 215b was crystallized from hot EtOAc to give a further 74 mg (214 
mg, 20.7% total). 
(c) Compound 215c 
##STR422## 
Compound 215b was converted to Compound 215c by a procedure analogous to 
that used for the synthesis of Compound 161d. Compound 215c was separated 
from its regioisomer by flash chromatography (silica gel, 5.times.10 cm) 
eluting with Et.sub.2 O:pentane (1:1 then 3:2). 
(d) Compound 215d 
##STR423## 
Compounds 215c and 54 were reacted by a procedure analogous to that used in 
Example 147d (DMF only used) to give Compound 215d (colorless solid). m.p. 
131.degree.-133.degree. C.; [.alpha.].sub.D =-12.3.degree. [c 0.20, MeOH]. 
MS: (CI): 620 (M+H). Anal. Calc. for C.sub.35 H.sub.45 N.sub.3 O.sub.7 
.multidot.1.42 H.sub.2 O: 
C,65.14; H,7.47; N,6.51 Found: C,65.22; H,7.10; N,6.43. 
EXAMPLE 216 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisca 
rbamic acid, 2-amino-1,1-dimethylethyl-1,1-dimethylethyl ester (Compound 
216e) 
(a) Compound 216a 
##STR424## 
Isobutylene oxide was reacted with benzyl amine by a procedure analogous to 
that used in Example 4a except that MeOH at 105.degree. C. was used 
(sealed tube). 
(b) Compound 216b 
##STR425## 
Compound 216a was reacted with carbobenzyloxy chloride using a procedure 
analogous to that of Example 122 (except that CH.sub.2 Cl.sub.2 was used 
and the reaction was run at RT) to give Compound 216b. 
(c) Compound 216c 
##STR426## 
Compound 216b was converted to Compound 216c by a two-step procedure 
analogous to that used for the conversion of Compound 149c to 149e (DMF 
was used in coupling of p-nitrophenyl carbonate to Compound 48). 
(d) Compound 216d 
##STR427## 
Compound 216c was converted to Compound 216d by a procedure analogous to 
that of Example 54. 
(e) Compound 216e 
##STR428## 
Compound 216d was converted to the title Compound 216e (white solid) by a 
procedure analogous to that of Example 21. m.p. 118.degree.-120.degree. C. 
Analysis calculated for: C.sub.30 H.sub.46 N.sub.4 O.sub.6 .multidot.1.12 
H.sub.2 O 
C, 62.24; H, 8.40; N, 9.68. Found: C, 62.65; H, 8.19; N, 9.27. 
EXAMPLE 217 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[2-methyl(4-methylphenyl)amino]-ethoxy]phenyl]butyl]amino]-2-hydr 
oxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 
217b) 
(a) Compound 217a 
##STR429## 
A mixture of N-methyl-p-toluidine (3.5 g; 29 mmol) and ethylene carbonate 
(4 g) was heated to 100.degree. C. for 3 h and 150.degree. C. for 10 h. 
After cooling to 0.degree. C., 15 ml of 4N HCl was added and the resulting 
mixture was partitioned between CH.sub.2 Cl.sub.2 and 4N HCl. After 
adjusting the pH of the aqueous layer to .about.9 with solid K.sub.2 
CO.sub.3, the aqueous layer was extracted with CH.sub.2 Cl.sub.2, dried 
(MgSO.sub.4) and concentrated to dryness. The residue was chromatographed 
on a 5.times.20 cm silica gel column, using 25% EtOAc/Hex as the mobile 
phase to afford 2.63 g (55%) of Compound 217a as a light yellow liquid. 
(b) Compound 217b 
##STR430## 
Compound 217a and Compound 172 were reacted by a four-step procedure 
analogous to that used for the conversion of Compound 172 to Compound 178 
to give the title Compound 217b (white solid). mp 120.degree.-127 .degree. 
C.; [.alpha.].sub.D =-5.6.degree. (c 0.27, MeOH). Mass Spec. FAB+ions: 
M+H=707 Analysis calc. for C.sub.40 H.sub.58 N.sub.4 O.sub.7 
.multidot.1.27 H.sub.2 O: 
C, 65.83; H, 8.36; N, 7.68; Found: C, 66.05; H, 8.09; N, 7.46. 
EXAMPLE 218 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(2-hydroxyethoxy)carbonyl]-L-valinamide (Compound 218c) 
(a) Compound 218a 
##STR431## 
Benzyloxyethanol and valine methyl ester hydrochloride were converted to 
Compound 218a by a two-step procedure analogous to that used for the 
conversion of Compound 161c to Compound 161e. 
(b) Compound 218b 
##STR432## 
Compound 218a was converted to Compound 218b by a procedure analogous to 
that of Example 2. 
(c) Compound 218c 
##STR433## 
Compounds 218b and 54 were converted to the title Compound 218c (white 
solid) by a two-step procedure analogous to that used for the conversion 
of Compound 202c to Compound 202e. m.p.=174.degree.-179.degree. C.; 
[.alpha.].sub.D =-16.1.degree. (c =0.23; MeOH) High resolution MS (FAB): 
Calculated (M+H).sup.+ (for C.sub.33 H.sub.51 N.sub.4 O.sub.8)=631.3707; 
Observed (M+H).sup.+ =631.3709 .DELTA.=0.3 ppm 
EXAMPLE 219 
Preparation of [[1R*,2S*(2S*,3R*)],N.sup.2 -(S*)]-N.sup.2 
-[(2,3-Dihydroxypropoxy)carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbonyl] 
-amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-4-(phenylmethyl)propyl]-L- 
valinamide (Compound 219) 
##STR434## 
Starting from (S)-(+)-2,2 dimethyl-1,3-dioxolane-4-methanol, the title 
Compound 219 (white solid) was prepared by a procedure analogous to that 
used for the preparation of Compound 202e. m.p.=200.degree.-205.degree. C. 
(decomposes); [.alpha.].sub.D =3.3.degree. (c=0.30; MeOH). High resolution 
MS (FAB): Calculated (M+H).sup.+ (for C.sub.34 H.sub.53 O.sub.9 
N.sub.4)=661.3831; Observed (M+H).sup.+ =661.3798 .DELTA.=2.3 ppm 
EXAMPLE 220 
Preparation of 
[1R*,2S*(2S*,3R*)]-N2-[[(2-Benzimidazolyl)methoxy]carbonyl]-N-[3-[[3-[[(1, 
1-dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1 
-(phenylmethyl)propyl]-L-alaninamide (Compound 220d) 
(a) Compound 220a 
##STR435## 
Compound 93a and 2-(trimethylsilyl)-ethoxymethyl chloride was converted to 
Compound 220a by a procedure analogous to that of Example 93b (reaction 
was run at 70.degree. C.). 
(b) Compound 220b 
##STR436## 
Compound 220a and alanine were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 93b to Compound 93d to give 
Compound 220b. 
(c) Compound 220c 
##STR437## 
Compound 220b in a 4M HCl/dioxane solution (23 ml) was stirred at 
50.degree. C. for 2.5 h then cooled to RT and stirred overnight. The 
reaction was concentrated and the resulting yellow foam was purified by 
silica gel chromatography, eluting the column with a stepwise gradient of 
EtOAc, EtOAc:AcOH (98:2), and EtOAc:MeOH:AcOH (78:20:2) to afford 0.498 g 
(70%) of Compound 220c. 
(d) Compound 220d 
##STR438## 
Compounds 220c and 54 were reacted by a procedure analogous to that used 
for the preparation of Compound 93f to give the title Compound 220d (white 
solid). m.p. 106-108.degree. C.; [.alpha.].sub.D =-1.0.degree. (c, 0.10 
MeOH). Mass Spec. FAB: (M+H).sup.+ @689.sup.+. Analysis calc. for C.sub.37 
H.sub.48 N.sub.6 O.sub.7 .multidot.0.65H.sub.2 O: 
C, 63.63; H, 6.83; N, 12.03; Found: C, 63.66; H, 7.13; N, 11.99. 
EXAMPLE 221 
Preparation of 
[1S-[[1R*,2S*(2S*,3R*)],N.sup.2,(S*)]]-N-[3-[[3-[[(1,1-Di-methylethoxy)car 
bonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propy 
l]-N.sup.2 -(2-hydroxy-1-oxo-propyl)-L-valinamide (Compound 221) 
##STR439## 
Compound 61 and D-lactic acid were reacted by a two-step procedure 
analogous to that used for the conversion of Compound 48 to Compound 52 to 
give the title Compound 221 (white solid). mp 213.degree.-219.degree. C.; 
[.alpha.].sub.D =-56.8.degree. (c 0.19, AcOH). Mass Spec. FAB+ion: 
M+H=615. Analysis calc. for C.sub.33 H.sub.50 N.sub.4 O.sub.8 
.multidot.1.34 H.sub.2 O: 
C, 62.04; H, 8.31; N, 8.77; Found: C, 62.02; H, 7.87; N, 8.79. 
EXAMPLE 222 
Preparation of [1R*, 2S*(2S*,3R*)]-N.sup.2 
-[[(3,4-Dihydro-4-oxo-2-quinazolidyl)methoxy1carbonyl]-N-[3-[[3-[[(1,1-dim 
ethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phe 
nylmethyl)propyl]-L-valinamide (Compound 222d) 
(a) Compound 222a 
##STR440## 
Compound 222a was prepared according to the procedure of Bergman et al., 
Tetrahedron, 46, 1296 (1990). 
(b) Compound 222b 
##STR441## 
Compound 222a and L-valine methyl ester hydrochloride were reacted by a 
two-step procedure analogous to that used for the conversion of Compound 
161c to Compound 161e to give Compound 222b. 
(c) Compound 222c 
##STR442## 
Compound 222b was converted to Compound 222c by a procedure analogous to 
that of Example 70c. 
(d) Compound 222d 
##STR443## 
Compounds 222c and 48 were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 48 to Compound 52 (no 
N-methylmorpholine was used in the EDCI coupling step) to give the title 
Compound 222d (white solid). m.p. 105.degree.-107.degree. C. 
[.alpha.].sub.D +-1.8.degree. (c=0.5, MeOH). High Res Mass Spectrum: 
(M+H).sup.+ =745.3925, theoretical: (M+H).sup.+ =745.3925 (.DELTA.0.0 ppm 
error). 
EXAMPLE 223 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,3-Dihydro-3-oxo-1H-isoindol-1-yl)carbo 
nyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl] 
carbamic acid, 1,1-dimethylethyl ester (Compound 223b) 
(a) Compound 223a 
##STR444## 
To a MeOH (50 mL) solution of 2-carboxybenzaldehyde (5.0 g, 0.033 tool ) in 
a cool water bath (.about.18.degree. C.) was added NH.sub.3 gas for 15 
min, and the solution stirred at RT for 1 h. Aqueous NaCN (1.63 g, 0.033 
mol in 50 mL H.sub.2 O) was then added dropwise over 15 min. After 1 h, 
the volatiles were concentrated in vacuo and the resulting yellow solution 
was treated with 6N HCl (40 mL). A precipitate formed after several mls of 
HCl had been added and the reaction slowly became homogeneous. The 
reaction mixture was heated at 00.degree. C. for 1.45 h, then placed in a 
cool water bath (.about.18.degree. C.). A yellow solid quickly formed and 
was removed by filtration, washing with H.sub.2 O and acetone. The 
filtrate was allowed to stand at RT for several days and the resulting 
solid was collected by filtration, washing with H.sub.2 O and acetone to 
give slightly impure Compound 223a (2.2 g, .about.38% yield). A portion 
(670 mg) of this material was crystallized from hot H.sub.2 O, washing the 
solid with more H.sub.2 O and drying in vacuo to give Compound 223a (359 
mg) as a colorless solid. 
(b) Compound 223b 
##STR445## 
Compounds 223a and 54 were reacted by a procedure analogous to that of 
Example 93f to give the title Compound 223b (colorless solid). m.p. dec. 
141.degree.-152.degree. C.; [.alpha.].sub.D.sup.25 =-1.2.degree. (c 0.16, 
AcOH). MS: (FAB): 603 (M+H). Anal. Calc. for C.sub.34 H.sub.42 N.sub.4 
O.sub.6 .multidot.0.82 H.sub.2 O: 
C, 66.14; H, 7.12; N, 9.07 Found: C, 66.10; H, 6.88; N, 9.11. 
EXAMPLE 224 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-(2-methoxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)pr 
opyl]carbamic acid, 1,1-dimethylethyl ester (Compound 224c) 
(a) Compound 224a 
##STR446## 
To a mixture of Compound 172 (250 mg, 0.32 mmol), 2-methoxyethanol (50 
.mu.l, 0.64 mmol) and PPh.sub.3 (167 mg, 0.64 mmol) in dry THF (0.64 ml) 
was added DEAD (100 .mu.l, 0.64 mmol). The mixture was stirred at RT 
overnight. Concentration in vacuo followed by flash chromatography 
(hexane/EtOAc 10:1 to 7:1) afforded 225 mg (84%) of Compound 224a as a 
white foam. 
(b) Compound 224b 
##STR447## 
To Compound 224a (225 mg, 0.267 mmol) was added pre-cooled (10.degree. C.) 
96% formic acid (5.0 ml). The mixture was stirred at 5.degree. C. for 20 
min and was then frozen (dry ice-acetone) and lyophilized (overnight) . 
The residue was taken into MeOH (5 ml) and Et.sub.3 N (112 .mu.l, 0.80 
mmol) was added followed by di-tert-butyldicarbonate (88 mg, 0.40 mmol). 
The mixture was stirred at RT overnight. Concentration in vacuo followed 
by flash chromatography (100% CHCl.sub.3 to CHCl.sub.3 --MeOH--NH.sub.4 
OH: 96:4:0.4) afforded 203 mg (100%) of Compound 224b as a white foam. 
(c) Compound 224c 
##STR448## 
A mixture of Compound 224b (203 mg, 0.27 mmol) and solid n-Bu.sub.4 
NF-nH.sub.2 O (223 mg, 0.85 mmol) in dry THF (1.3 ml ) was heated at 
50.degree. C. for 4.0 h. After cooling to RT, Celite (1.0 g) was added and 
the solvent was removed under reduced pressure. Flash chromatography (100% 
CHCl.sub.3 to CHCl.sub.3 --MeOH--NH.sub.4 OH: 94:6:0.6) on silica gel 
afforded 128 mg (73%) of the title Compound 224c as a gel, which upon 
trituration with Et.sub.2 O-hexane afforded the product as a white solid. 
m.p.: 136.degree.-138.degree. C.; [.alpha.].sub.D =-2.3.degree., 
[.alpha.]Hg(436)=-6.1.degree. , [.alpha.]Hg(365)=-14.2.degree., (c 0.53, 
MeOH). Mass Spec. (FAB): 618.sup.+ (M+H).sup.+. Anal. Calc. for C.sub.33 
H.sub.51 N.sub.3 O.sub.8 .multidot.0.83H.sub.2 O: C, 62.65; H, 8.39; N, 
6.64. Found: C, 62.52; H, 8.12; N, 6.77. 
EXAMPLE 225 
Preparation of [1S-[[1R*,2S*(2S*,3R*)],N.sup.2 
-(R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbu 
tyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]N.sup.2 
-(2-hydroxy-1-oxo-propyl)-L-valinamide (Compound 225 ) 
##STR449## 
Compound 61 and L-lactic acid were reacted by a two-step procedure 
analogous to that used for the conversion of Compound 48 to Compound 52 to 
give the title Compound 225 (white solid). m.p. 210.degree.-214.degree. 
C.; [.alpha.].sub.D =-24.8.degree. (c 0.31, MeOH). Mass Spec. (FAB+ion): 
M+H=615. Analysis calc. for C.sub.33 H.sub.50 N.sub.4 O.sub.8 
.multidot.1.00 H.sub.2 O: 
C, 62.63; H, 8.28; N, 8.85; Found: C, 62.37; H, 7.84; N, 8.74. 
EXAMPLE 226 
Preparation of 
[1S-[1S*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(4-[2-(4-morpholinyl)-2-oxo-ethoxy]phenyl]butyl]amino]-2-hydroxy-1-( 
phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 226b) 
(a) Compound 226a 
##STR450## 
NaH (48 mg, 60% dispersion in mineral oil, 1.2 mmol) was washed twice with 
hexane and suspended in 1.0 ml of dry DMF. The suspension was cooled to 
0.degree. C. and a solution of Compound 175c (280 mg, 1.0 mmol) in 1.5 ml 
of dry DMF was added. The mixture was stirred at 0.degree. C. for 30 min 
and then 4-(2-bromoacetyl)morpholine (J. Med. Chem., 35, 1685 (1992); 270 
mg, 1.3 mmol) was added in one portion, followed by n-Bu.sub.4 NI (185 mg, 
0.5 mmol). The resulting mixture was stirred at RT overnight. After 
cooling to 10.degree. C., H.sub.2 O was added and the mixture extracted 
with EtOAc. The combined extracts were washed with H.sub.2 O and brine, 
dried (NaHCO.sub.3) and concentrated in vacuo to give a crude product 
which was purified by flash chromatography (hexane-EtOAc: 1:1 to 1:4) on 
silica gel to give 392 mg (96%) of Compound 226a as a white solid. 
(b) Compound 226b 
##STR451## 
A mixture of Compounds 226a (407 mg, 1.0 mmol) and 16b (280 mg, 1.0 mmol) 
in 1.0 ml of dry DMF was heated at 100.degree. C. for 4.0 h. Concentration 
in vacuo followed by flash chromatography (CHCl.sub.3 --MeOH--NH.sub.4 OH: 
98:2:0.2 to 95:5:0.5) on silica gel afforded 501 mg (73%) of Compound 226b 
as a white solid. m.p. 118.degree.-120.degree. C.; [.alpha.].sub.D 
=-4.7.degree., [.alpha.].sub.365(Hg) =-23.6.degree.(c 1.0, MeOH). Mass 
Spec. (FAB): 687.sup.+ (M+H).sup.+. Anal. Calc. for C.sub.36 H.sub.54 
N.sub.4 O.sub.9 .multidot.0.30H.sub.2 O: 
C, 62.46; H, 7.95; N, 8.09. Found: C, 62.46; H, 7.91; N, 8.28. 
EXAMPLE 227 
Preparation of 
[1S-(1R*,2S*),(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]] 
biscarbamic acid, 2,3-dihydroxy-1,1-dimethylpropyl 1,1-dimethylethyl ester 
(Compound 227c) 
(a) Compound 227a 
##STR452## 
Methyl (S)-(-)-2,2-dimethyl-1,3-dioxolane-4-carboxylate was converted to 
Compound 227a by a procedure analogous to that of Example 158a. 
(b) Compound 237b 
##STR453## 
Compound 227a was converted to Compound 227b by a three-step procedure 
analogous to that used for the conversion of Compound 149c to Compound 150 
(DMF was used in the coupling of the p-nitrophenyl carbonate with Compound 
48). 
(c) Compound 227c 
##STR454## 
Compound 227b was converted to Compound 227c (white solid) by a procedure 
analogous to that of Example 202c. m.p. 104.degree.-105.degree. C. High 
Res Mass Spectrum: (M+H).sup.+ =590.3463, theoretical: (M+H).sup.+ 
=590.3441 (.DELTA.4 ppm error). 
EXAMPLE 228 
Preparation of 
[1S-(1R*,2S*),(S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]] 
biscarbamic acid, 2,3-dihydroxy-1,1-dimethylpropyl1,1-dimethylethyl ester 
(Compound 228) 
##STR455## 
Methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate was converted to 
the title Compound 228 (white solid) by a procedure analogous to that used 
for the synthesis of Compound 227c. m.p. 69.degree.-72.degree. C.; 
[.alpha.].sub.D =-6.0.degree. (c=0.2, CD.sub.3 OD) Analysis Calculated 
for:C.sub.31 H.sub.47 N.sub.3 O.sub.8 .multidot.1.03 H.sub.2 O 
C, 61.20; H, 8.13; N, 6.91. Found: C, 61.26; H, 7.93; N, 6.85. 
EXAMPLE 229 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarba 
mic acid, 4-hydroxy-1,1-dimethyl-butyl 1,1-dimethylethyl ester (Compound 
229) 
##STR456## 
Compound 210b was converted to the title Compound 229 (white solid) by a 
procedure analogous to that of Example 2. m.p. 80.degree.-84.degree. C.; 
[.alpha.]D.sub.=-2.6 .degree. (c 0.2, CH.sub.3 OH). High Res Mass Spec 
(M+H).sup.+ =588.3649 (.DELTA.ppm=1.2) Analysis calc. for C.sub.32 
H.sub.49 N.sub.3 O.sub.7 .multidot.2.69H.sub.2 O: Calculated C, 60.42; H, 
8.61; N, 6.60; Found: C, 60.46; H, 8.22; N, 6.56. 
EXAMPLE 230 
Preparation of 
[1S-(1R*,2S*),(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]] 
biscarbamic acid, 2,3-dihydroxypropyl 1,1-dimethylethyl ester (Compound 
230) 
##STR457## 
(R)-2,2-Dimethyl-1,3-dioxolane-4-methanol was converted to the title 
Compound 230 (white solid) by a three-step procedure analogous to that 
used for the conversion of Compound 149c to Compound 150 (DMF was used in 
the coupling of the p-nitrophenyl carbonate with Compound 48). 
m.p.=151.degree.-154.degree. C. (decomposes); [.alpha.].sub.D =-5.3.degree. 
(c=0.30; MeOH). 
High resolution MS (FAB): Calculated (M+H).sup.+ (for C.sub.29 H.sub.44 
O.sub.8 N.sub.3)=562.3128; Observed (M+H).sup.+ =562.3147 .DELTA.=3.4 ppm 
Analysis for C.sub.29 H.sub.43 N.sub.3 O.sub.8.1.31 H.sub.2 O: Calculated: 
C, 59.51; H, 7.86; N, 7.48 Found: C, 59.19; H, 7.47; N, 7.18. 
EXAMPLE 231 
Preparation of [1S-(1R*,2S*), 
(S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamic 
acid, 2,3-dihydroxypropyl 1,1-dimethylethyl ester (Compound 231) 
##STR458## 
(S)-2,2-Dimethyl-1,3-dioxolane-4-methanol was converted to the title 
Compound 231 (white solid) by a three-step procedure analogous to that 
used for the conversion of Compound 149c to Compound 150 (DMF was used in 
the coupling of the p-nitrophenyl carbonate with Compound 48). 
m.p.=157.degree.-160.degree. C.; [.alpha.].sub.D =-8.7.degree. (c=0.31; 
MeOH) 
High resolution MS (FAB): Calculated (M+H).sup.+ (for C.sub.29 H.sub.44 
O.sub.8 N.sub.3)=562.3128; Observed (M+H).sup.+ =562.3127; .DELTA.=0.2 ppm 
Analysis for C.sub.29 H.sub.43 N.sub.3 O.sub.8.0.45 H.sub.2 O: Calculated: 
C, 61.13; H, 7.77; N, 7.38 Found: C, 60.94; H, 7.62; N, 7.57 
EXAMPLE 232 
Preparation of [1S-(1R*, 2S*), 
(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamic 
acid, 1,1-dimethylpropyl 2-hydroxy-1,1-dimethylpropyl ester (Compound 
232d) 
(a) Compound 232a 
##STR459## 
To a solution of 0.5 g (0.48 ml; 4.23 mmol) of (S)-Ethyl lactate in 8.5 ml 
of CH.sub.2 Cl.sub.2 at 0.degree. C. was added 1.13 ml (1.2 eq; 5.07 mmol) 
of 2,6-di-t-butylpyridine followed by 1.16 ml (1.2 eq; 5.07 mmol) of 
t-butyldimethylsilyl triflate. After 1 h at 0.degree. C., Et.sub.2 O and 
1N HCl were added and the organic layer washed with H.sub.2 O, saturated 
NaHCO.sub.3, and brine. The extracts were dried=(MgSO.sub.4) and 
evaporated in vacuo to give a crude liquid which was purified by flash 
chromatography (25 mm.times.7"; elution with 2% EtOAc/Hexanes then 5% 
EtOAc/Hexanes) to give 0.89 g (90%) of Compound 232a as a colorless 
liquid. 
(b) Compound 232b 
##STR460## 
Compound 232a was converted to Compound 232b by a procedure analogous to 
that used in Example 149c. 
(c) Compound 232c 
##STR461## 
Compound 232b was converted to Compound 232c by a two-step procedure 
analogous to that used for the conversion of Compound 147b(i) to Compound 
147d. 
(d) Compound 232d 
##STR462## 
Compound 232c was converted to Compound 232d (white solid) by a procedure 
analogous to that of Example 162. 
m.p. 129.degree.-131.degree. C. (softens at 90.degree. C.); [.alpha.].sub.D 
=-20.9.degree. (c 0.32, MeOH). 
Mass Spec.: FAB+ions: M+H=574. 
Analysis calc. for C.sub.31 H.sub.47 N.sub.3 O.sub.7.0.15 H.sub.2 O: C, 
64.59; H, 8.27; N, 7.29; Found: C, 64.47; H, 8.25; N, 7.41. 
EXAMPLE 233 
Preparation of [1S-[1R*, 2S* (2S*, 3R*)]]-[[3- 
[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-hydroxyphenyl)but 
yl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
2-hydroxy-1,1-dimethylethyl ester (Compound 233c) 
(a) Compound 233a 
##STR463## 
Compounds 19 and 161d were reacted by a procedure analogous to that of 
Example 143 (i-Pr.sub.2 NEt and DMF were used) to give Compound 233a. 
(b) Compound 233b 
##STR464## 
Compound 233a was converted to Compound 233b by a procedure analogous to 
that of Example 162. 
(c) Compound 233c 
##STR465## 
Compound 233b was converted to Compound 233c (white solid) in 28% yield by 
a procedure analogous to that of Example 21. 
m.p. 135.degree.-137.degree. C.; [.alpha.]D=-4.9.degree. (c 0.55, MeOH). 
MS: (M+H).sup.+ 576.3290.sup.+ (High res). 
Anal. Calc for C.sub.30 H.sub.45 N.sub.3 O.sub.8 : C, 62.59; H, 7.88; N, 
7.30. Found: C, 62.20; H, 7.86; N, 7.38. 
EXAMPLE 234 
Preparation of [1S-[1R*,2S*(2S*,3R*), 
(R*)]]-[3-[[3-[[3,3-Dimethyl-2-(formylamino)-1-oxobutyl]amino]-2-hydroxy-4 
-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 234c) 
(a) Compound 234a 
##STR466## 
To a mixture of Compound 88b (286 mg, 0.414 mmol) and i-Pr.sub.2 NEt (94 
.mu.l, 0.538 mmol) in 2.5 ml of dry DMF at 0.degree. C. was added 
9-fluorenylmethyl-chloroformate (124 mg, 0.48 mmol). The mixture was 
stirred at 0.degree. C. for 1.0 hr and H.sub.2 O was added. The mixture 
was extracted with EtOAc and the extracts were washed with sat'd 
NaHCO.sub.3 and brine and dried over Na.sub.2 SO.sub.4. Concentration in 
vacuo followed by flash chromatography (hexane/EtOAc 4:1 to 1:1) on a 
silica gel column afforded 341 mg (90%) of Compound 234a as a white solid. 
TLC(SiO.sub.2)Rf=0.51. 
(CHCl.sub.3 - MeOH 95:5 - PMA). 
(b) Compound 234b 
##STR467## 
A mixture of Compound 234a (341 mg, 0.374 mmol), 1,4-cyclohexadiene (356 
.mu.l) and 10% Pd-C (40 mg) in 11 ml of EtOH was stirred under a H.sub.2 
atmosphere for 2 h. An additional 25 mg of 10% Pd-C was added after 2 and 
4 h. After 6 h total, the catalyst was removed by filtration through a 
short pad of Celite. 90 .mu.l of HOAc was added to the filtrate and the 
mixture was evaporated to dryness to yield 308 mg of the amine acetate 
salt as a white solid. 
Formic acetic anhydride was prepared by addition of 46.3 .mu.l of HCO.sub.2 
H to 133 .mu.l of ice-cooled Ac.sub.2 O. The solution was then stirred at 
50.degree. C. for 2 h. This material dissolved in 1 ml of dry THF was 
added to an ice-cooled solution of 308 mg of the amine acetate salt in 2.5 
ml of dry THF. The mixture was stirred at 0.degree. C. for 1.0 h and then 
at RT for 15 min. The reaction mixture was partitioned between H.sub.2 O 
and EtOAc and the organic extracts were washed with brine and dried 
(Na.sub.2 SO.sub.4). Concentration in vacuo followedby purification by 
prep HPLC (Nova-Pak HR silica 60 .ANG.) with 60% EtOAc in hexane as 
eluent, afforded 123 mg (41% for two steps) of Compound 234b as a white 
solid. 
TLC(SiO.sub.2)R.sub.f =0.17. 
(CHCl.sub.3 -MeOH 95:5 - PMA). 
(c) Compound 234c 
##STR468## 
To a solution of Compound 234b (123 mg, 0.152 mmol) in 2.7 ml of dry 
CH.sub.2 Cl.sub.2 was added piperidine (132 .mu.l, 1.34 mmol). The mixture 
was stirred at RT for 1.5 h. Concentration in vacuo followed by flash 
chromatography (CHCl.sub.3 -MeOH-NH.sub.4 OH: 99:1:0.1 to 92:8:0.8) on 
silica gel gave, after trituration with CHCl.sub.3 -hexane, 84 mg (94%) of 
the title Compound 234c as a white solid. 
m.p.: 166.degree.-168.degree. C.; [.alpha.].sub.D =-23.8.degree., 
[.alpha.].sub.436(Hg) =-54.8.degree. (c 0.21, MeOH). 
Mass Spec. (FAB): 585.sup.+ (M+H).sup.+. 
Anal. Calc. for C.sub.32 H.sub.49 N.sub.4 O.sub.6.0.34H.sub.2 O: C, 64.93; 
H, 8.46; N, 9.47. Found: C, 64.99; H, 8.20; N, 9.41. 
EXAMPLE 235 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(E)]]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2- 
hydroxy-6-(4-hydroxyphenyl)-5-hexenyl]amino]-2-hydroxy-1-(phenylmethyl)prop 
yl] carbamic acid, 1,1-dimethylethyl ester (Compound 235e) 
(a) Compound 235a 
##STR469## 
Compound 235a was prepared according to the procedure of Oppolzer et al., 
Tetrahedron Lett., 30 (44), 6009 (1989). 
(b) Compound 235b 
##STR470## 
To a solution of n-BuLi (4.4 ml; 11.0 mmol; 2.5M in hexanes) in 25 ml of 
dry THF cooled at -78.degree. C. was added a solution of Compound 235a 
(3.77 g; 10.0 mmol) in 15 ml of dry THF. The mixture was stirred at 
-78.degree. C. for 1 h, followed by addition of a solution of 
4-t-butyldiphenylsilyloxycinnamyl bromide (Young et al., J. Med. Chem., 
35, 1702 (1992)); 6.8 g, 15.0 mmol) in 10 ml of 1:1 THF-HMPA, dropwise 
over 10 min. n-Bu.sub.4 NI (200 mg) was then added and the reaction was 
warmed from -78.degree. C. to RT over 2 hours. The reaction mixture was 
cooled back to -20.degree. C. and H.sub.2 O was added. The mixture was 
extracted with EtOAc and the combined extracts washed with H.sub.2 O and 
brine and dried over MgSO.sub.4. Concentration in vacuo gave an oily 
residue which was purified by flash chromatography (10:1 hexane-chloroform 
to 100% chloroform) on silica gel to afford 5.2 g (69%) of Compound 235b 
as a colorless oil which solidified upon standing. 
(c) Compound 235c 
##STR471## 
To a solution of Compound 235b (14.7 g, 19.7 mmol) in 280 ml of THF and 125 
ml of DME was added a solution of 1.0 N HCl (125 ml). The homogeneous 
mixture was then heated at 40.degree. C. overnight. H.sub.2 O (200 ml) was 
added and the pH was adjusted to 12 with 6N KOH. The mixture was extracted 
with EtOAc and the combined organic extracts washed with H.sub.2 O, 
saturated NaHCO.sub.3, brine and dried over Na.sub.2 SO.sub.4. Removal of 
solvent under reduced pressure afforded 13.9 g of crude amine as an 
off-white foam which was used without further purification. 
To the suspension of the crude amine (13.9 g) in 85 ml of dry CH.sub.3 CN 
cooled at 0.degree. C. was added di-t-butyl dicarbonate (7.7 g, 32.5 
mmol). The reaction mixture was stirred at RT overnight. The solvent was 
removed under reduced pressure and the residue was purified by flash 
chromatography (hexane-EtOAc: 4:1) on silica gel to afford 13.7 g of the 
N-Boc carbamate as an off-white foam. 
To a solution of LiOH.H.sub.2 O (1.5 g, 36.8 mmol) in H.sub.2 O (36 ml) 
cooled at 0.degree. C. was added a solution of 30% H.sub.2 O.sub.2 (11.3 
ml, 110 mmol). The mixture was stirred at 0.degree. C. for 1 h and added 
at 0.degree. C. to a solution of the above prepared N-Boc carbamate (13.7 
g, 18.4 mmol) in 380 ml of 3:1 THF-H.sub.2 O. The reaction mixture was 
stirred at 0.degree. C. for 15 min and a solution of 1.5N Na.sub.2 
SO.sub.3 (85 ml) was added. After stirring for another 30 min, the mixture 
was acidified to pH=2 with 3N HCl and extracted with EtOAc. The combined 
extracts were washed with brine and dried over Na.sub.2 SO.sub.4. 
Concentration in vacuo followed by flash chromatography (CHCl.sub.3 
-MeOH-AcOH: 95:5:1) on silica gel afforded 7.74 g (77%) of Compound 235c 
as a white solid. 
(d) Compound 235d 
##STR472## 
Compound 235c was converted to Compound 235d by a procedure analogous to 
that used for the preparation of Compound 175b. 
(e) Compound 235e 
##STR473## 
Compounds 235d and 16b were reacted by a procedure analogous to that used 
for the synthesis of Compound 4b to give the title Compound 235e 
(off-white solid). 
m.p.: 110.degree.-112.degree. C.; [.alpha.].sub.D =+1.6.degree. (c 0.25, 
MeOH). 
Mass Spec. (FAB): 586.sup.+ (M+H).sup.+. 
Anal. Calc. for C.sub.32 H.sub.47 N.sub.3 O.sub.7.0.82 H.sub.2 O: C, 64.00; 
H, 8.16; N, 7.00. Found: C, 64.15; H, 8.05; N, 6.85. 
EXAMPLE 236 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisca 
rbamic acid, 2-(formylamino)-1,1-dimethylethyl 1,1-dimethylethyl ester 
(Compound 236b) 
(a) Compound 236a 
##STR474## 
Compound 216d was reacted with formylacetic anhydride in THF by a procedure 
analogous to that of Example 129 to give Compound 236a. 
(b) Compound 236b 
##STR475## 
Compound 236a was converted to the title Compound 236b (white solid) by a 
procedure analogous to that of Example 21. The final product was purified 
by reverse phase HPLC (19.times.300 mm C18 column) eluted with a 
continuous gradient (30:70 A:B to 80:20 A:B; A=90% CH.sub.3 OH/H.sub.2 
O+0.05% TFA; B=10% CH.sub.3 OH/H.sub.2 O+0.05% TFA). The resulting foamy 
white solid was lyophlized from CH.sub.3 OH/H.sub.2 O. 
m.p. 78.degree.-81.degree. C.; [.alpha.].sub.D =-7.8.degree. (C=0.2, 
CH.sub.3 OH). 
Analysis calculated for:C.sub.31 H.sub.46 N.sub.4 O.sub.7.1.89 H.sub.2 O C, 
59.98; H, 8.08; N, 9.02. Found: C, 60.45; H, 7.73; N, 8.55. 
EXAMPLE 237 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(trans)]]]-[3-[[3-[[(2,3-Dihydro-2-hydroxv-1H-inden-1- 
yl)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl 
)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 237c) 
(a) Compounds 237a (i) and 237a (ii) 
##STR476## 
To a mixture of NaBH.sub.4 (230 mg, 6.08 mmol) in aqueous EtOH (30 mL, 95% 
) at 0.degree. C. was added 1-carboethoxy-2-indanone (0.62 g, 3.03 mmol, 
prepared as in J. Chem. Soc., 121, 1562-1571 (1922)). After stirring for 1 
h, solid NH.sub.4 Cl (140 mg, 2.61 mmol) was added and the mixture was 
brought to RT. More solid NH.sub.4 Cl (440 mg, 8.22 mmol) was added after 
2 h, followed by NaBH.sub.4 (59 mg, 1.56 mmol). Further amounts of 
NH.sub.4 Cl (995 mg over 11.5 h), and then NaBH.sub.4 (573 mg over 11.5 
h), were added periodically over the next 11.5 h. The mixture was 
evaporated in vacuo, the resulting residue suspended in saturated NH.sub.4 
Cl and extracted with EtOAc. The combined organic layers were dried 
(Na.sub.2 SO.sub.4) and evaporated in vacuo to an oil which was purified 
by flash chromatography (silica gel, 3 by 20 cm), eluting with 
EtOAc:CH.sub.2 Cl.sub.2 (1, 2, 3, and then 5% EtOAc) to give Compounds 
237a(i) and 237a(ii) (350 mg, 3:2 ratio by .sup.1 H NMR, 56% yield) as a 
colorless oil. 
(b) Compound 237b 
##STR477## 
To neat Compounds 237a(i) and 237a(ii) (350 mg, 1.70 mmol) was added IN 
NaOH (3 mL, 3 mmol). After 1.5 h, the solution was brought to pH 1 with 1N 
HCl. The resulting solution was extracted with Et.sub.2 O, the combined 
organic layers dried over Na.sub.2 SO.sub.4 and concentrated in vacuo to 
give an oily solid. This residue was dissolved in hot EtOAc, diluted with 
hot pentane and allowed to slowly cool. After storing overnight at 
-20.degree. C., the solid was triturated twice with cold pentane/EtOAc 
(4:1) to give after drying in vacuo Compound 237b (219 mg, 72% yield) as a 
slightly orange colored solid. 
(c) Compound 237c 
##STR478## 
Compounds 237b and 54 were reacted by a procedure analogous to that of 
Example 55 (DMF only used) to give the title Compound 237c (colorless 
solid). 
m.p. (shrink 141.degree. C.) dec. 161.degree.-165.degree. C.; 
[.alpha.].sub.D =+10.degree.-7.degree. (c 0.41, HOAc). 
MS: (CI): 604 (M+H). 
Anal. Calc. for C.sub.35 H.sub.45 N.sub.3 O.sub.6.0.51 H.sub.2 O C, 68.58; 
H, 7.57; N, 6.86 Found: C, 68.53; H, 7.41; N, 6.91 
EXAMPLE 238 
Preparation of 
[1S-[1R*,2*(2S*,3R*)]]-[3-[[3-[[2-[3-(2-Benzimidazoly)propoxy]-3,3-dimethy 
l-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethy 
l)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 238e) 
(a) Compound 238a 
##STR479## 
The triflate of 4-pentene-1-ol was prepared by the addition of 5.5 ml (33 
mmol) of triflic anhydride in 50 ml of CH.sub.2 Cl.sub.2, over a period of 
1 hr, to a solution of 3.1 g (30 mmol) of 4-pentene-1-ol and 3.6 ml (45 
mmol) of pyridine in 150 ml of CH.sub.2 Cl.sub.2, at -10.degree. C. After 
the addition was complete, the cold reaction was washed twice with 1N HCl, 
twice with brine, sat NaHCO.sub.3, and twice with brine. The solution was 
dried (MgSO.sub.4) and the solvent removed to yield 6.6 g (assumed 30 
mmol, 100%) of the triflate as a pale yellow oil. This material was used 
immediately in the next step. 
To a suspension of 1.7 g (15 mmol) of 35% KH suspension (hexane washed) in 
50 ml of THF, at RT was added dropwise a solution of 4.8 g (13.3 mmoles) 
of Compound 106a in 25 ml of THF. After 2 h the solution was ice cooled 
and diluted with 75 ml of DMF. To this solution was added a solution of 
the freshly prepared pre-cooled (-78.degree. C.) 4-pentene-1-ol triflate 
in 10 ml of THF. After stirring for 0.5 h at 0.degree. C. and RT for 1 h, 
the reaction was diluted with brine and extracted twice with Et.sub.2 O. 
The extracts were washed with brine, dried (MgSO.sub.4), the solvent 
removed and the resulting oil purified by flash chromatography on a 400 cc 
column of silica gel (elution with 25% CH.sub.2 Cl.sub.2 /hexane) to 
afford 2.9 g (51%) of Compound 238a as a colorless oil. 
(b) Compound 238b 
##STR480## 
A solution of 1.7 g (4 mmoles) of Compound 238a, 1.9 g (12 mmoles) of 
KMnO.sub.4, and 75 mg of n-Bu.sub.4 NBr in 20 ml of toluene, 20 ml of 
H.sub.2 O and 4 ml of HOAc was stirred for 2 h. To the resulting slurry 
was added sat. NaHSO.sub.3 with stirring until the reaction became 
colorless. The suspension was extracted with EtOAc and the combined 
extracts washed with brine, dried (MgSO.sub.4) and the solvent removed to 
yield a crude product which was purified by flash chromatography on a 125 
cc column of silica gel (elution with 25% EtOAc/hexane) to afford 1.1 g 
(62%) of Compound 238b as a colorless oil. 
(c) Compound 238c 
##STR481## 
To a solution of 1.0 g (2.2 mmol) of Compound 238b and 0.42 ml (3 mmol) of 
Et.sub.3 N in 10 ml of THF, at -10.degree. C. was added dropwise 0.32 ml 
(2.5 mmol) of i-butylchloroformate. After 0.5 h, a solution of 270 mg (2.5 
mmol) of o-phenylenediamine in 5 ml of THF was then added. After 1.5 h at 
-10.degree. C., the reaction was diluted with EtOAc and washed with 
H.sub.2 O, sat. NaHCO.sub.3, and brine, dried (MgSO.sub.4) and the solvent 
removed to give 1.3 g of a white foam. This material was dissolved in 25 
ml of HOAc and heated at 65.degree. C. for 3.5 hr. After cooling, the 
solution was evaporated to dryness. The residue was taken into EtOAc and 
washed with sat NaHCO.sub.3 and brine. After drying (MgSO.sub.4), removal 
of solvent gave a residue which was purified by flash chromatography on a 
125 cc column of silica gel (elution with 100% EtOAc) to give 266 mg (44%) 
of Compound 238c as a solid foam. 
(d) ComDound 238d 
##STR482## 
75 mg (0.27 mmol) of Compound 238c was converted to the corresponding 
aldehyde by a procedure analogous to that of Example 191c. To 50 mg of the 
intermediate aldehyde in 0.5 ml of THF and 0.9 ml (1.8 mmoles) of a 2M THF 
solution of 2-methyl-2-butene was added dropwise a solution of 23 mg (0.2 
mmol) of sodium chlorite (80%) in 0.5 ml of pH 3.95 acetate buffer. After 
1 h, the reaction was evaporated to dryness and the residue taken into 1 
ml of H.sub.2 O saturated with solid NaCl and the pH adjusted to 5.0 by 
the addition of HOAc. After extraction with EtOAc, the combined organic 
layers were washed once with minimal brine, dried (MgSO.sub.4), and the 
solvent removed to give a crude product which was purified by flash 
chromatography on a 15 cc column of silica gel (elution with 5%, 10% and 
20% MeOH/CHCl.sub.3) to afford 35 mg (45%) of Compound 238d as a white 
solid. 
(e) Comoound 238e 
##STR483## 
Compounds 238d and 54 were reacted by a procedure analogous to that of 
Example 93f to give the title Compound 238e (solid foam) as a 1:1 mixture 
of diastereomers. 
High Res Mass Spec.: (M+H).sup.+ =716.4375; calc. 716.4387. 
Calc. for C.sub.41 H.sub.57 N.sub.5 O.sub.6.H.sub.2 O (733.9): C, 67.09; H, 
8.10; N, 9.54. Found: C, 67.01; H, 8.00; N, 9.21. 
EXAMPLE 239 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(5,5-Dimethyl-2-oxo-4-oxazolidinyl)carbon 
yl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]c 
arbamic acid, 1,1-dimethylethyl ester, isomer A (Compound 239d) 
(a) Compound 239a 
##STR484## 
Dimethylacrylic acid and sodium tungstate were suspended in H.sub.2 O (0.67 
ml/g acid) the pH of which was adjusted to 6.5 with aq. NaOH. At RT, 35% 
aq. H.sub.2 O.sub.2 (4.1 mol eq.) was added dropwise maintaining the pH 
with additional aq. NaOH. After the addition was complete, the reaction 
was stirred for 1 h at 40.degree. C. at which time Na.sub.2 SO.sub.3 was 
added to destroy excess peroxide. Benzylamine was added (1.2 eq.) and the 
resulting mixture stirred at reflux for 2 h. The reaction was partially 
concentrated and then brought to pH 6 with concentrated HCl. The reaction 
was cooled to RT and the solid product Compound 239a filtered off and 
washed with cold H.sub.2 O and EtOH (28%). 
(b) Compound 239b 
##STR485## 
Compound 239a was stirred in MeOH (10 ml/g) along with 10% Pd/C under a 
H.sub.2 atmosphere for 1 h (35.degree. C.). After filtering off the 
catalyst, the reaction was partially concentrated and then cooled to 
0.degree. C. Acetone (7 ml/g Compound 239a) was added and the resulting 
solid Compound 239b filtered and washed with acetone (100%). 
(c) Compound 239c 
##STR486## 
To a solution of Compound 239b (1.33 g, 10.0 mmol) in 12.5% aq. KOH (37 ml) 
cooled at 0.degree. C. was added a solution of phosgene (1.93M) in toluene 
(11.7 ml). The mixtureswas stirred at 0.degree. C. for 1.0 h and the 
toluene layer was separated. The aqueous layer was washed with Et.sub.2 O, 
acidified to pH=3 with 3N HCl and concentrated in vacuo to afford a solid 
residue. This residue was extracted into hot methanol (200 ml) and the 
solid removed by filtration. The filtrate was concentrated in vacuo and 
then partitioned between 5% KHSO.sub.4 and EtOAc. The aqueous layer was 
extracted with hot EtOAc and the combined organic layers were dried 
(Na.sub.2 SO.sub.4) and concentrated to afford 1.38 g (87%) of Compound 
239c as an off-white solid. 
(d) Compound 239d 
##STR487## 
Compounds 54 and 239c were reacted by a procedure analogous to that of 
Example 93f to give Compound 239d along with its diastereomer Compound 240 
as a 1:1 mixture. HPLC purification (S-10 C18; 120 .ANG. ODS; MeOH-H.sub.2 
O-TFA 60:40:0.1) gave the title Compound 239d (white solid) as the slower 
moving isomer. 
m.p. 108.degree.-110.degree. C.; [.alpha.].sub.D -5.0.degree. (c 0.2, 
MeOH). 
Mass Spec. (FAB): 585.sup.+ (M+H).sup.+. 
Analysis Calc. for C.sub.31 H.sub.44 N.sub.4 O.sub.7 : C, 63.68; H, 7.58; 
N, 9.51. Found: C, 63.75; H, 7.79; N, 9.51. 
EXAMPLE 240 
Preparation of [1S-[1R*,2S* 
(2S*,3R*)]]-[3-[[3-[[(5.5-Dimethyl-2-oxo-4-oxazolidinyl)carbonyl]amino]-2- 
hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester, isomer B (Compound 240) 
##STR488## 
Compound 240 (white solid) was isolated by preparative HPLC (the faster 
moving isomer) as described in Example 239. 
m.p. 120.degree.-122.degree. C.; [.alpha.].sub.D =-18.3.degree. (c 0.25, 
MeOH). 
Mass Spec. (FAB): 585.sup.+ (M+H).sup.+. 
Analysis Calc. for C.sub.31 H.sub.44 N.sub.4 O.sub.7.1.08H.sub.2 O: C, 
61.63; H, 7.70; N, 9.27. Found: C, 61.70; H, 7.62; N, 9.20. 
EXAMPLE 241 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarba 
mic acid, 1,1-dimethylethyl-2-hydroxyethyl ester (Compound 241c) 
(a) Compound 241a 
##STR489## 
Benzyloxyethanol was converted to Compound 241a by a procedure analogous to 
that of Example 161c. 
(b) Compound 241b 
##STR490## 
Compound 241a was converted to Compound 241b by a procedure analogous to 
that of Example 7. 
(c) Compound 241c 
##STR491## 
Compounds 241b and 48 were converted to the title Compound 241c (white 
solid) by a three-step procedure analogous to that used for the conversion 
of Compound 149c to Compound 150 (DMF was used as the solvent in the 
coupling reaction of Compound 48 with the p-nitrophenyl carbonate of 
Compound 241b). 
m.p.=168.degree.-172.degree. C.; [.alpha.].sub.D =-8.3.degree. (c=0.32; 
MeOH) 
MS (FAB): (M+H).sup.+ =532; 
Elemental Analysis: (for C.sub.28 H.sub.41 N.sub.3 O.sub.7.0.27 H.sub.2 O) 
Calculated: C, 62.68; H, 7.80; N, 7.83 Found: C, 62.69; H, 7.68; N, 7.82. 
EXAMPLE 242 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[4-[4-[(2-Benzoxazolyl)methoxylphenyl]-3-[[(1, 
1-dimethylethoxy)carbonyl]amino]-2-hydroxybutyl]amino]-2-hydroxy-1-(phenylm 
ethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 242) 
##STR492## 
Compounds 171a and 172 were reacted by a four-step procedure analogous to 
that used for the conversion of Compound 172 to Compound 178 to give the 
title Compound 242 (white solid). 
mp 145.degree.-150.degree. C.; [.alpha.].sub.365 =-21.7.degree. (c 0.27, 
MeOH). 
Mass Spec. FAB+ions: M+H=691 
Analysis calc. for C.sub.38 H.sub.50 N.sub.4 O.sub.8.1.09 H.sub.2 O: C, 
64.24; H, 7.40; N, 7.89; Found: C, 64.16; H, 7.14; N, 7.97. 
EXAMPLE 243 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-alaninamide (Compound 243) 
##STR493## 
Compound 54 and N-carbobenzyloxy-L-alanine were reacted by a procedure 
analogous to that of Example 55 (DMF only used) to give the title Compound 
243 (white solid). 
mp 156.degree.-157.degree. C., [.alpha.].sub.D =-10.degree. (c 0.10, MeOH). 
Mass Spec. IONSPRAY+ion; (M+H).sup.+ =649.sup.+. 
Analysis calc. for C.sub.36 H.sub.48 N.sub.4 O.sub.7 .multidot.0.25H.sub.2 
O: C, 66.18; H, 7.48; N, 8.58; Found: C, 66.21; H, 7.47; N, 8.55. 
EXAMPLE 244 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[3-[(2-benzoxazolyl)-propoxy]phenyl]butyl]amino]-2-hydroxy-1-(phe 
nylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 244b) 
(a) Compound 244a 
##STR494## 
A mixture of o-aminophenol (2.5 g; 23 mmol), 4-pentenoic acid (2.33 ml; 23 
mmol) and p-toluenesulfonic acid (150 mg) in 50 ml of toluene was refluxed 
with azeotropic removal of H.sub.2 O for 30 hours. After cooling to RT, 
the reaction mixture was partitioned between EtOAc and 1N NaOH and the 
organic layer washed with 1N NaOH, H.sub.2 O and brine. After drying over 
MgSO.sub.4 and decolorizing over charcoal (Darco), the organic layer was 
filtered and concentrated to afford 793 mg (20%) of the intermediate, 
benzoxazole-2-prop-3-ene, as a yellow liquid. Ozone was bubbled through a 
solution of this intermediate (492 mg; 2.8 mmol) in 13 ml of MeOH at 
-78.degree. for -3 min. The reaction was stopped when starting material 
was consumed by TLC (EtOAc:Hex, 1:1). After purging with oxygen, the 
reaction mixture was warmed to -35.degree. C. and 1.5 ml of H.sub.2 O, 
followed by NaBH.sub.4 (163 mg; 4.2 mmol), was added. The reaction mixture 
was warmed to 0.degree. C. over 1 h, at which time saturated aqueous 
NH.sub.4 Cl (3 ml) was added. Most of the MeOH was removed in vacuo and 
the residue was partitioned between EtOAc and saturated aqueous NH.sub.4 
Cl. The organic layer was washed with saturated aqueous NH.sub.4 Cl and 
brine. After drying over MgSO.sub.4 and concentrating, the residue was 
chromatographed on a 2.5.times.5 cm silica gel column using EtOAc as the 
mobile phase to afford 400 mg (81%) of Compound 244a as an orange solid. 
(b) Compound 244b 
##STR495## 
Compounds 244a and 172 were reacted by a four-step procedure analogous to 
that used for the conversion of Compound 172 to Compound 178 to give the 
title Compound 244b (white solid). 
mp 121.degree.-126.degree. C.; [.alpha.].sub.365 =-3.6.degree. (c 0.48, 
MeOH). 
Mass Spec. FAB+ions: M+H=719 
Analysis calc. for C.sub.40 H.sub.54 N.sub.4 O.sub.8.1.28 H.sub.2 O: C, 
64.75; H, 7.68; N, 7.55; Found: C, 64.59; H, 7.43; N, 7.71. 
EXAMPLE 245 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy -1-(phenylmethyl)propyl]-N.sub.2 
-[[(1H-benzimidazol-1-yl-methyl)methylamino]carbonyl]-L-valinamide 
(Compound 245d) 
(a) Compound 245a 
##STR496## 
To a 40% aqueous solution of methylamine (100 ml) cooled to 0.degree. C. 
was slowly added 2-chloromethyl benzimidazole (6.0 g, 36 mmol). After 1 
additional h at 0.degree. C. the reaction was diluted with H.sub.2 O and 
extracted with CH.sub.2 Cl.sub.2. The combined extracts were dried 
(Na.sub.2 SO.sub.4) and the solvent was evaporated in vacuo to give a 
crude product which was purified on a silica column eluting with a 
gradient from 5 to 10% MeOH/CH.sub.2 Cl.sub.2 +0.1% NH.sub.4 OH to afford 
680 mg (12%) Compound 245a as a colorless solid. 
(b) Compound 245b 
##STR497## 
Pyridine (1.19 g; 15 mmol) was added to a suspension of L-valine methyl 
ester hydrochloride (1 g; 6 mmol) in CH.sub.2 Cl.sub.2 at 0.degree. C. 
p-Nitrophenyl-chloroformate (1.33 g; 6.6 mmol) was added and the mixture 
stirred at 0.degree. C. for 2 h and at RT for 1 h. The reaction was 
diluted with EtOAc and washed with 10% KHSO.sub.4, sat. NaHCO.sub.3, 
H.sub.2 O and brine. The organic layer was dried (Na.sub.2 SO.sub.4) and 
concentrated to afford 1.4 g (80%) of Compound 245b as a pale-yellow 
solid. 
(c) Compound 245c 
##STR498## 
A mixture of Compound 245a (282 mg, 1.75 mmol), Compound 245b (518 mg, 1.75 
mmol), and Et.sub.3 N (354 mg, 3.5 mmol) in 9 ml of dry CH.sub.3 CN was 
stirred overnight at RT. The volatiles were evaporated to give a crude 
product which was purified on a silica column eluting with a gradient from 
2 to 5% MeOH/CH.sub.2 Cl.sub.2 +0.1% NH.sub.4 OH to afford 136 mg (24%) of 
Compound 245c as a colorless solid. 
(d) Compound 245d 
##STR499## 
Compounds 245c and 54 were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 70b to Compound 70d (DMF only; no 
N-methyl morpholine was added) to give the title Compound 245d (colorless 
solid). 
m.p. 184.degree.-188.degree.C. (dec); [.alpha.].sub.D =-18.5.degree. 
(c=0.25, MeOH) 
High Res. Mass Spec. (FAB): (M+H).sup.+ =730.4292.sup.+ ; C.sub.40 H.sub.56 
N.sub.7 O.sub.6 .DELTA.=1.5 ppm. 
EXAMPLE 246 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 246b) 
(a) Compound 246a 
##STR500## 
To a 0.degree. C. solution of (L)-t-leucine (0.600 g, 4.57 mmol) in aqueous 
NaOH (2.80 mL of a 2.0N solution) were added in alternate portions methyl 
chloroformate (0.388 mL, 5.03 mmol) and aqueous NaOH (2.20 mL of a 2.0N 
solution) over 5 min. The solution was stirred at 0.degree. C. for 30 min 
and for 1 h at RT. The aqueous solution was washed with Et.sub.2 O, 
acidified with aqueous 3M HCl solution to pH 1 and extracted with EtOAc. 
The combined organic extracts were dried (Na.sub.2 SO.sub.4) and 
concentrated in vacuo to give the Compound 246a (0.867 g, .ltoreq.100%) as 
a colorless glass, which was used in the next step without purification. 
(b) Compound 246b 
##STR501## 
To a 0.degree. C. solution of Compound 246a (0.094 g, 0.496 mmol) and 
HOBT.H.sub.2 O (0.114 g, 0.744 mmol) in DMF (1.0 mL) was added EDC (0.095 
g, 0.496 mmol). The solution was stirred at 0.degree. C. for 1 h. Compound 
54 (200 mg, 0.451 mmol) in 1 ml DMF was added followed by N-methyl 
morpholine (0.165 mL, 1.50 mmol). The solution was allowed to warm to RT 
and and stir for 36 h at which time volatiles were removed in vacuo. The 
residue was partitioned between aqueous 50% NaHCO.sub.3 and EtOAc. The 
combined organic extracts were washed with brine, dried (Na.sub.2 
SO.sub.4), and concentrated in vacuo to give solid, which was 
chromatographed on silica gel (100 mL) using a gradient from 99:1:0.1 to 
90:10:1 CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH as eluent to afford Compound 
246b as a white solid (135 mg; 49%). 
m.p.=153.degree.-156.degree. C.; [.alpha.].sub.D =-16.1.degree. (c=0.33; 
MeOH) MS (FAB): (M+H).sup.+ =615; 
Elemental Analysis: (for C.sub.33 H.sub.50 N.sub.4 O.sub.7.1.09 H.sub.2 O) 
Calculated: C, 62.48; H, 8.29; N, 8.83 Found: C, 62.48; H, 8.06; N, 8.83. 
EXAMPLE 247 
Preparation of [1R*, 2S*, 
3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]- 
2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl) propyl]-N.sup.2 
-(methoxycarbonyl)-L-valinamide (Compound 247) 
##STR502## 
Compound 54 and L-valine were converted into the title Compound 247 (white 
solid) by a two-step procedure analogous to that of Example 246. 
m.p. 202.degree.-205.degree. C.; [.alpha.].sub.D =-33.3.degree. (C 0.06, 
MeOH) 
Analysis Calc. for C.sub.32 H.sub.48 O.sub.7 N.sub.4. 0.28 H.sub.2 O C, 
63.44; H, 8.08; N, 9.25 Found: C, 63.51; H, 8.03; N, 9.18. 
EXAMPLE 248 
Preparation of [1R*, 2S*, (2S*, 
3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbut 
yl]amino]-2-hydroxy-1-(phenylmethyl) propyl]-N.sup.2 
-(1-oxopropyl)-L-valinamide (Compound 248) 
##STR503## 
Compound 61 and propionic acid were converted into the title Compound 248 
(white solid) by a two-step procedure analogous to that used for the 
conversion of Compound 48 to Compound 52. 
m.p. 222.degree.-225.degree. C.; [.alpha.].sub.D =-28.5.degree. (c 0.07, 
MeOH) 
Analysis Calc. for C.sub.32 H.sub.50 O.sub.6 N.sub.4. 0.64 H.sub.2 O: C, 
64.95; H, 8.47; N, 9.18 Found: C, 64.90; H, 8.31; N, 9.23. 
EXAMPLE 249 
Preparation of [1R*,2S* 
(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phen 
ylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(1H-imidazol-2-ylmethoxy)carbonyl]-L-valinamide, acetate (2:3) salt 
(Compound 249c) 
(a) Compound 249a 
##STR504## 
To a solution containing 1-trityl-2-formyl imidazole (1.54 g, 4.55 mmol; J. 
Org. Chem., 43, 4381 (1978)) in a mixture of 12 mL of THF and 12 mL of 
EtOH cooled to 0.degree. C. was added portionwise NaBH.sub.4 (300 mg, 7.93 
mmol). After 45 min at 0.degree. C., the cold reaction mixture was 
quenched with pH 4 phosphate buffer and extracted with CH.sub.2 Cl.sub.2. 
The combined organic extracts were washed with brine, dried (MgSO.sub.4) 
and concentrated in vacuo to afford 1.47 g of Compound 249a as a waxy 
solid (95%, crude yield). 
(b) Compound 249b 
##STR505## 
Compound 249a and 61 were converted into Compound 249b by a three-step 
procedure analogous to that used for the conversion of Compound 149c to 
Compound 150 (Et.sub.3 N was used in the coupling of Compound 61 with the 
p-nitrophenyl carbonate of Compound 249a). 
(c) Compound 249c 
##STR506## 
Compound 249b (250 mg, 0.275 mmol) was dissolved in a mixture of 3 mL of 
absolute EtOH and 12 mL of HOAc. The reaction mixture was heated at 
40.degree. C. for 3.5 h in a stoppered flask, then concentrated in vacuo 
and triturated with CH.sub.2 Cl.sub.2 -hexanes to afford the title 
Compound 249c (180 mg, 83% ) as a white solid. 
m.p. (softens 129.degree. C.), 135.degree.-152.degree. C.; [.alpha.].sub.D 
=+1.2.degree. (c=0.21, MeOH). 
MS (FAB): (M+H).sup.+ =667.sup.+ 
Elemental Analysis: Calcd for C.sub.35 H.sub.50 N.sub.6 O.sub.7 
.multidot.1.5 C.sub.2 H.sub.4 O.sub.2 .multidot.1.8 H.sub.2 O: C, 57.82; 
H, 7.61; N, 10.65. Found: C, 57.77; H, 7.27; N, 11.04. 
EXAMPLE 250 
Preparation of [1R*,2S*(2S*,3R*)]-N.sub.2 
-[3-Dihydro-3-oxo-2H-indazol-2-yl)-1-oxopropyl]-N-[3-[[3-[[(1,1-dimethylet 
hoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmeth 
yl)propyl]-L-valinamide (Compound 250e) 
(a) Compound 250a 
##STR507## 
To a solution of 0.380 mg (16,5 mmol) of Na metal in 25 mL of anhydrous 
EtOH was added 2.01 g (15.0 mmol) of indazolinone. The resulting 
suspension was heated at reflux for 15 min at which point 1.9 mL (16.5 
mmol) of benzyl chloride was added over 15 min. The resulting mixture was 
heated at reflux for 7 h, cooled to RT, concentrated in vacuo, and the 
residue diluted with 150 mL of 1N NaOH. The mixture was extracted with 
Et.sub.2 O. The aqueous layer was acidified to pH=5 with HOAc and then 
extracted with Et.sub.2 O. The Et.sub.2 O extracts were dried (Na.sub.2 
SO.sub.4), filtered, and concentrated in vacuo and the solid 
recrystallized from H.sub.2 O/MeOH to give 990 mg (29%) of Compound 250a. 
(b) Compound 250b (i) 
##STR508## 
To a solution of 0.253 mg (11.0 mmol) of Na metal in 20 mL of anhydrous 
EtOH was added 2.29 g (10.2 mmol) of Compound 250a. The mixture was heated 
at reflux for 15 min at which point 1.13 mL (12.0 mmol) of 3-bromopropanol 
in 5 mL of toluene was added over 10 min. After 4 h, an additional 0.38 mL 
(1.1 mmol; 21% wt in ethanol) of sodium ethoxide and 0.1 mL of 
3-bromopropanol were added. The mixture was heated at reflux for 2 h, and 
then stirred at RT for 12 h. The cooled mixture was concentrated in vacuo, 
and the residue was diluted with 150 mL of 1N NaOH. The mixture was 
extracted with Et.sub.2 O and the extracts washed with brine dried 
(Na.sub.2 SO.sub.4), filtered, and concentrated in vacuo. Flash 
chromatography on silica gel (10-50% EtOAc-CH.sub.2 Cl.sub.2 ; then, 5% 
CH.sub.3 OH-CH.sub.2 Cl.sub.2) provided 634 mg (22%) of Compound 250a(i) 
[TLC Rf=0.10 (10% EtOAc-CH.sub.2 Cl.sub.2)] and 2 g of Compound 250b(ii) 
[TLC Rf=0.37 (10% EtOAc-CH.sub.2 Cl.sub.2)]. 
(c) Compound 250c 
##STR509## 
To a solution of 200 mg (0.708 mmol) of Compound 250b(i) in 3.5 mL of dry 
DMF was added 1.03 g (2.73 mmol) of pyridinium dichromate. The mixture was 
stirred at RT for 18 h then poured into 1:1 H.sub.2 O/brine (100 mL) and 
extracted with Et.sub.2 O. The organic layer was dried (Na.sub.2 
SO.sub.4), filtered, and evaporated in vacuo to give 130 mg (62%) of 
Compound 250c. 
(d) Compound 250d 
##STR510## 
To a solution of 238 mg (0,439 mmol) of Compound 59, 130 mg (0.439 mmol) of 
Compound 250c, and 119 mg (0.88 mmol) of HOBT in 2.5 mL of dry DMF at 
0.degree. C. was added 93 mg (0.483 mmol) of EDCI. The mixture was stirred 
at 0.degree. C. for 3 h and at RT for 18 h then concentrated in vacuo. The 
residue was diluted with EtOAc, and washed with saturated NaHCO.sub.3, 
H.sub.2 O, and brine. The organic layer was concentrated in vacuo, and 
purified by flash chromatography on silica gel [2-10% CH.sub.3 OH/CH.sub.2 
Cl.sub.2 with 1.0% NH.sub.4 OH] to provide 265 mg [74% yield (88% pure by 
HPLC)] of Compound 250d. 
(e) Compound 250e 
##STR511## 
A solution of 185 mg (0.225 mmol) of Compound 250d in 12 mL of hot MeOH was 
cooled to RT, and treated with 100 mg of 10% Pd/C. The mixture was stirred 
under a H.sub.2 atmosphere for 24 h then an additional 100 mg of 10% Pd/C 
was added and the mixture was stirred under a H.sub.2 atmosphere for 
another 12 h. The mixture was filtered, rinsed with hot MeOH, and 
evaporated in vacuo. Flash chromatography of the residue on silica gel [2% 
CH.sub.3 OH/CH.sub.2 Cl.sub.2, then 3-10% CH.sub.3 OH/CH.sub.2 Cl.sub.2 
(with 0.3-1.0% NH.sub.4 OH)] provided 81 mg (49%) of the title Compound 
250e (colorless solid). 
mp 187.degree.-192.degree. C. (dec.); [.alpha.].sub.D =-22.degree. (c 0.32, 
CH.sub.3 OH) 
Mass Spec: 731 (M+H).sup.+ 
Elemental Analysis: Calcd for C.sub.40 H.sub.54 N.sub.6 O.sub.7.0.32 
H.sub.2 O: C, 65.21; H, 7.48; N, 11.41. Found: C, 65.31; H, 7.53; N, 
11.31. 
EXAMPLE 251 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarba 
mic acid, 1,1-bis(hydroxymethyl)ethyl 1,1-dimethylethyl ester (Compound 
251d) 
(a) Compound 251a 
##STR512## 
Compound 251a was prepared by the method described in Curran et al., 
Synthetic Comm. 20, 3575 (1990). 
(b) Compound 251b 
##STR513## 
To a slurry of (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) 
(3.8 g, 8.96 mmol) in 10 mL of dry CH.sub.2 Cl.sub.2 was added t-BuOH 
(0.929 mL, 9.856 mmol). The mixture was cooled to 0.degree. C. and a 
solution of Compound 251a (1.434 g, 4.48 mmol) in 5 mL of CH.sub.2 
Cl.sub.2 was added. The reaction mixture was warmed to RT and stirred for 
2 h after which time the mixture was diluted with 75 mL of EtOAc and 90 mL 
of 1:1:1 sat. NaHCO.sub.3 -10% Na.sub.2 SO.sub.3 -brine was added. The 
mixture was stirred vigorously for 1 h, the two phases separated and the 
organic phase washed with brine, dried (MgSO.sub.4) and concentrated. The 
crude residue was purified by flash chromatography on silica, eluting with 
a stepwise gradient of hexane to 50% EtOAc-hexane to obtain Compound 251b 
(0.775 g, 54%) as a colorless oil. 
(c) Compound 251c 
##STR514## 
To 1.95 mL (2.681 mmol) of a 1.4M MeLi solution in Et.sub.2 O was added 5 
mL of THF. The solution was cooled to -78.degree. C. and a solution of 
Compound 251b (0.775 g, 2.437 mmol) in 5 mL of THF was slowly added. An 
additional 1 mL of MeLi solution was added twice at intervals of 1 h and 
the mixture slowly warmed to -40.degree. C. After 1 additional h, the 
reaction was quenched by adding 0.4 mL of HOAc in 5 mL of THF, warmed to 
RT and diluted with H.sub.2 O. The mixture was extracted with EtOAc and 
the extracts washed with sat. NaHCO.sub.3 and brine, dried (MgSO.sub.4) 
and concentrated. The crude residue was purified by flash chromatography 
on silica gel eluting with a stepwise gradient of hexane to 75% 
EtOAc-hexane to afford Compound 251c (0.475 g, 58%) as a colorless oil. 
(d) Compound 251d 
##STR515## 
Compounds 161a and 251c were reacted by a five-step procedure analogous to 
that used for the conversion of Compound 161c to Compound 162 (Et.sub.3 N 
was used in the coupling of the p-nitrophenyl carbonate of Compound 251c 
with Compound 161a) to give the title Compound 251d (off-white solid). 
High Res. Mass Spec. (M+H).sup.+ =576.3285 (.DELTA..sub.ppm =2.2). 
EXAMPLE 252 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bisca 
rbamic acid, 2-fluoro-1,1-dimethylethyl 1,1-dimethylethyl ester (Compound 
252d) 
(a) Compound 252a 
##STR516## 
Compound 48 and 2-methyl-1-fluoro-2-propanol (Bergmann et al., J. Chem. 
Soc., 2259 (1958)) were converted to Compound 252a by a two-step procedure 
analogous to that used for the conversion of Compound 149c to 149e. 
(b) Compound 252b 
##STR517## 
Compound 252a was converted to Compound 252b by a procedure analogous to 
that of Example 140a. 
(c) Compound 252c 
##STR518## 
Compound 252b was converted to Compound 252c by a procedure analogous to 
that of Example 21. 
(d) Compound 252d 
##STR519## 
Compound 252c was converted to the title Compound 252d (white solid) by a 
procedure analogous to that of Example 140e except that the reaction was 
run at RT for 18 h and at reflux for 2 h. 
m.p. 174.degree.-176.degree. C.; [.alpha.].sub.D =-6.0.degree. (c=0.2, 
CH.sub.3 OH) 
Analysis calculated for:C.sub.30 H.sub.44 N.sub.3 O.sub.6 F C, 64.15; H, 
7.90; N, 7.48; F, 3.38. Found: C, 63.99; H, 7.96; N, 7.81; F, 3.35. 
EXAMPLE 253 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarba 
mic acid, 1,1-dimethylethyl(4-phenyl-1H-imidazol-2-yl)methyl ester 
(Compound 253e) 
(a) Compound 253a 
##STR520## 
4-Phenylimidazole (2.5 g, 17.3 mmol) was stirred with trityl chloride (4.8 
g, 17.2 mmol) in acetone (37 ml) and Et.sub.3 N (2.9 ml, 20.8 mmol) for 3 
h. The mixture was concentrated, dissolved in CH.sub.2 Cl.sub.2 and washed 
with H.sub.2 O, brine, dried (Na.sub.2 SO.sub.4) and concentrated. The 
product crystallized and was dried in vacuo to yield Compound 253a (6.49 
g, 97%, mp 185.degree.-188.degree. C.). 
(b) Compound 253b 
##STR521## 
Compound 253a (2.0 g, 5.17 mmol) in 50 ml of dry THF was cooled to 
-45.degree. C. and tert-butyl lithium (1.7M in hexanes, 6.1 ml, 10.34 
mmol) was added dropwise and the reaction was stirred for 30 min. DMF (1.9 
ml, 25.85 mmol) was added and the reaction was stirred for 1.5 h at which 
point saturated aq. NH.sub.4 Cl was added and product was extracted with 
EtOAc. The EtOAc solution was washed with H.sub.2 O, brine, dried 
(Na.sub.2 SO.sub.4), and concentrated in vacuo to yield crystalline 
Compound 253b (2.09 g, 94%, mp 185.degree.-188.degree. C.). 
(c) Compound 253c 
##STR522## 
Compound 253b (2.09 g, 5.0 mmol) was dissolved in THF:EtOH:CHCl.sub.3 (15 
ml:15 ml:20 ml), cooled to 0.degree. C. and NaBH.sub.4 (0.33 g, 8.57 mmol) 
was added portionwise. After 1 h, the reaction mixture was diluted with 
CH.sub.2 Cl.sub.2 and washed with H.sub.2 O, brine, dried (Na.sub.2 
SO.sub.4) and concentrated. The product crystallized from Et.sub.2 O to 
yield Compound 253c (1.8 g, 86%, mp 183.degree.-190.degree. C.). 
(d) Compound 253d 
##STR523## 
Compounds 253c and 48 were reacted by a three-step procedure analogous to 
that used for the conversion of Compound 149c to 150 (Et.sub.3 N and DMF 
were used in the reaction of the p-nitrophenyl carbonate of Compound 253c 
with Compound 48) to give Compound 253d. 
(e) Compound 253e 
##STR524## 
Compound 253d was dissolved in EtOH (4.7 mL) and HOAc (19 mL) and the 
reaction mixture was stirred at 40.degree. C. for 2 h, concentrated in 
vacuo and the residue triturated with Et.sub.2 O. The resulting solid was 
chromatographed through 80 g of silica gel eluting with CHCl.sub.3 
:MeOH:NH.sub.4 OH (89:10:1) to afford the title Compound 253e (0.12 g, 
54%) as a white solid. 
m.p. 109.degree.-115.degree. C.; [.alpha.].sub.D =-5.6.degree. (c=0.85, 
MeOH). 
Analysis Calc. for C.sub.36 H.sub.45 N.sub.5 O.sub.6.1.13 H.sub.2 O: C, 
65.11;H, 7.17; N, 10.55 Found: C, 65.12;H, 6.99; N, 10.54 
EXAMPLE 254 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 -(3,4 
-dihydroxy-1-oxobutyl)-L-valinamide (Compound 254f) 
(a) Compound 254a 
##STR525## 
To a 0.degree. C. solution of diazomethane/Et.sub.2 O (see Compound 1a(i) 
for preparation) was added dropwise 3-butenoic acid (4.94 mL, 58.0 mmol) 
over 5 min. The solution was swirled until colorless, then washed with 
aqueous NaHCO.sub.3 and dried (Na.sub.2 SO.sub.4). The Et.sub.2 O was 
distilled off to give Compound 254a (4.32 g, 74%). 
(b) Compound 254b 
##STR526## 
To a solution of Compound 254a (4.25 g, 42.4 mmol) and N-methylmorpholine 
N-oxide (8.07 mL of a 60% solution by weight in H.sub.2 O) in acetone (30 
mL) and H.sub.2 O (20 mL) was added OsO.sub.4 (70.0 mg, 0.275 mmol) and 
the resulting solution stirred at RT for 18 h. A solution of NaHSO.sub.3 
(0.50 g in 5 mL H.sub.2 O) was then added, the resulting black solution 
stirred at RT for 30 min, then filtered through Celite (acetone wash). The 
volatiles were removed and the residual aqueous solution was saturated 
with NaCl and extracted with EtOAc. The combined organic extracts were 
dried (Na.sub.2 SO.sub.4), concentrated and purified on silica gel (150 
mL) using a gradient from 1:1 hexane:EtOAc to 100% EtOAc to give Compound 
254b (3.15 g, 55%) as a slightly yellow oil. 
(c) Compound 254c 
##STR527## 
To a solution of Compound 254b (1.00 g, 7.46 mmol) in acetone (10 mL) and 
2,2-dimethoxypropane (10 mL) was added p-toluenesulfonic acid hydrate (7 
mg, 0.037 mmol) and the solution was stirred at RT for 18 h. Saturated 
aqueous NaHCO.sub.3 solution was added and the mixture was concentrated in 
vacuo. The residue was partitioned between H.sub.2 O and EtOAc and the 
combined organic extracts were washed with H.sub.2 O, dried (Na.sub.2 
S0.sub.4), and concentrated in vacuo. The oil was purified on silica gel 
(150 mL) using 10:1 hexane:EtOAc to give Compound 254c (1,260 g, 97%) as a 
colorless oil. 
(d) Compound 254d 
##STR528## 
Compound 254c was converted to Compound 254d by a procedure analogous to 
that of Example 70c (THF used as solvent). 
(e) Compound 254e 
##STR529## 
Compounds 254d and 61 were reacted by a two step procedure analogous to 
that used for the conversion of Compound 48 to Compound 52 to give 
Compound 254e (white foam). 
(f) Compound 254f 
##STR530## 
Compound 254e was converted to the title Compound 254f (white solid; 
mixture of diastereomers at *) by a procedure analogous to that of Example 
202c. 
m.p.=156.degree.-160.degree. C.; [.alpha.].sub.D =-11.1.degree. (c=0.28; 
MeOH) 
High resolution Mass Spec. (FAB): Calculated (M+H).sup.+ (for C.sub.34 
H.sub.53 N.sub.4 O.sub.8)=645.3861; 
Observed (M+H).sup.+ =645.3862 .DELTA.=0.2 ppm 
EXAMPLE 255 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(3,4-Dihydroxy-1-oxo-butyl)amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 255b) 
(a) Compound 255a 
##STR531## 
Compounds 254d and 48 were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 48 to 52 to give Compound 255a 
(white solid). 
(b) Compound 255b 
##STR532## 
Compound 255a was converted to the title Compound 255b (white solid; 
mixture of diastereomers) by a procedure analogous to that of Example 
202c. 
m.p.=145.degree.-150.degree. C.; [.alpha.].sub.D =+5.0.degree. (c=0.20; 
MeOH) 
Mass Spec. (FAB): (M+H).sup.+ =546; 
Elemental Analysis: (for C.sub.29 H.sub.43 N.sub.3 O.sub.7.1.19 H.sub.2 O) 
Calculated: C, 61.42; H, 8.07; N, 7.41 Found: C, 61.20; H, 7.83; N, 7.63 
EXAMPLE 256 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarba 
mic acid, 1,1-dimethylethyl-3-pyridinylmethyl ester (Compound 256) 
##STR533## 
3-Pyridine carbinol and Compound 48 were converted to the title Compound 
256 (colorless solid) by a three-step procedure analogous to that used for 
the conversion of Compound 149c to 150 (DMF was used in the coupling of 
the p-nitrophenyl carbonate of 3-pyridine carbinol to Compound 48). 
m.p. 167.degree.-170.degree. C.; [.alpha.].sub.D =-16.degree. (c 0.24, 
CH.sub.3 OH) 
Mass Spec. 579 (M+H).sup.+ 
Analysis Calc. for C.sub.32 H.sub.42 N.sub.4 O.sub.6.0.37 H.sub.2 O: C, 
65.66; H, 7.36;N, 9.57 Found: C, 65.65; H, 7.39;N, 9.58 
EXAMPLE 257 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]-amino]-2-hydroxy-1-(phenylmethyl)propy 
l]amino]-carbonyl]propyl]carbamic acid, (2-benzoxazolyl)methyl ester 
(Compound 257c) 
(a) Compound 257a 
##STR534## 
To a solution of 350 mg (2.35 mmol) of Compound 171a in 5 mL of CH.sub.2 
Cl.sub.2 and 2.5 mL of pyridine at 0.degree. C. was added 475 mg (2.35 
mmol) of p-nitrophenylchloroformate in 2.5 mL of CH.sub.2 Cl.sub.2. The 
mixture was stirred at 0.degree. C. for 2 h. The mixture was diluted with 
EtOAc and washed with 1M NaOH, H.sub.2 O, and brine. The organic layer was 
dried (Na.sub.2 SO.sub.4), filtered, and concentrated in vacuo. Flash 
chromatography of the residue (20-40% EtOAc-hexane) afforded 567 mg (77%) 
of Compound 257a. 
(b) Compound 257b 
##STR535## 
To neat tert-L-leucine (146 mg, 1.11 mmol) was added aqueous 1N NaOH (1.1 
mL). After stirring for several minutes, a dioxane (3 mL) solution of 
Compound 257a (140 mg, 2.61 mmol) was added, followed by Et.sub.3 N (0.23 
mL, 1.65 mmol) . The reaction mixture was stirred for 26 h, diluted with 
H.sub.2 O, and brought to pH 4 with 5% KHSO.sub.4. The aqueous solution 
was extracted with EtOAc, the aqueous layer brought back to pH 3 with more 
5% KHSO.sub.4 and extracted with EtOAc. The combined organic layers were 
dried (Na.sub.2 SO.sub.4) and evaporated in vacuo to an oil. The residue 
was purified by flash chromatography (silica gel, 3 by 15 cm), eluting 
with EtOAc: CH.sub.2 Cl.sub.2 (1:1), then 10%MeOH: CH.sub.2 Cl.sub.2 to 
give Compound 257b (227.7 mg, 67% yield) as a colorless oily solid. 
(c) Compound 257c 
##STR536## 
To a solution of Compound 257b (152 mg, 0.50 mmol) in DMF (2.5 mL) at 
0.degree. C. under argon was added HOBT (105 mg, 0.78 mmol), and then EDCI 
(95 mg, 0.50 mmol). After 45 min, solid Compound 54 (226 mg, 0.51 mmol) 
was added and the mixture was brought to RT. After stirring 24 h, the 
reaction mixture was partitioned between EtOAc and saturated NaHCO.sub.3. 
The combined organics were dried (Na.sub.2 SO.sub.4) and evaporated in 
vacuo to give an oily solid which was purified by flash chromatography 
(silica gel, 3 by 15 cm), eluting with MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2 
(5:0.5:94.5, 6:0.6:93.4, and then 7:0.7:92.3) to give the title Compound 
257c (151 mg, 42% yield) as a colorless solid. m.p. 
149.degree.-159.degree. C.; [.alpha.].sub.D.sup.25 =-18.2.degree. (c 0.28, 
MeOH). 
Mass Spec.: (FAB): 732 (M+H). 
Anal. Calc. for C.sub.40 H.sub.53 N.sub.5 O.sub.8 C, 65.64; H, 7.30; N, 
9.57 Found: C, 65.79; H, 7.54; N, 9.66 
EXAMPLE 258 
Preparation of [R- (R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl) 
-3,1-propanediyl)]biscarbamic acid, 1,1-dimethylethyl-1-(3-pyridinyl)ethyl 
ester (Compound 258b) 
(a) Compound 258a 
##STR537## 
To a solution of 536 mg (5.00 mmol) of 3-pyridinecarboxaldehyde in 16.5 mL 
of dry THF at -78.degree. C. was added 3.4 mL (5.5 mmol) of methyllithium 
(1.6M in Et.sub.2 O) (internal temperature&lt;-55.degree. C.). The resulting 
yellow solution was warmed to 0.degree. C. and quenched by the addition of 
30 mL of saturated NH.sub.4 Cl. The reaction mixture was extracted with 
Et.sub.2 O and the organic layer dried (Na.sub.2 SO.sub.4), filtered, and 
concentrated in vacuo to provide 458 mg of Compound 258a. The aqueous 
layer was saturated with NaCl and extracted with Et.sub.2 O. Concentration 
in vacuo provided an additional 74 mg (total 532 mg) of product. 
(b) Compound 258b 
##STR538## 
Compounds 258a and 48 were converted to the title Compound 258b (colorless 
solid) by a three-step procedure analogous to that used for the conversion 
of Compound 149c to 150 (DMF was used in the coupling of the p-nitrophenyl 
carbonate of Compound 258a to Compound 48). 
m.p. 161.degree.-170.degree. C.; [.alpha.].sub.D =-14.degree. (c 0.21, 
CH.sub.3 OH) 
Mass Spec. 593 (M+H).sup.+ 
Anal. Calc. for C.sub.33 H.sub.44 N.sub.4 O.sub.8 C, 66.87; H, 7.48; N, 
9.45 Found: C, 66.54; H, 7.64; N, 9.28 
EXAMPLE 259 
Preparation of [1R*, 2S* (2S*, 
3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbut 
yl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(hyroxyacetyl)-L-valinamide (Compound 259) 
##STR539## 
Compound 61 and glycolic acid were reacted by a two-step procedure 
analogous to that used for the conversion of Compound 48 to Compound 52 to 
afford the title Compound 259 (white solid). 
m.p. 208.degree.-210.degree. C. 
Mass Spec. High resolution 601.3595, error 1.0 ppm, theory 601.3601 
Analysis Calc. for C.sub.32 H.sub.48 O.sub.7 N.sub.4.1.34 H.sub.2 O: C, 
61.50; H, 8.17; N, 8.97 Found: C, 61.77; H, 8.15; N, 8.70 
EXAMPLE 260 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[3-(1H-indol-3-yl)-1-oxo-propyl]-L-valinamide (Compound 260) 
##STR540## 
Compound 61 and 3-indolpropionic acid were reacted by a two-step procedure 
analogous to that used for the conversion of Compound 48 to Compound 52 to 
afford the title Compound 260 (white solid). 
m.p. 212.degree.-214.degree. C.; [.alpha.].sub.D =-38.1.degree. (c=0.2, 
CH.sub.3 OH) 
Analysis for:C.sub.41 H.sub.55 N.sub.5 O.sub.8.0.65 H.sub.2 O Calculated:C, 
67.86; H, 7.82; N, 9.65. Found: C, 67.95; H, 7.77; N, 9.56. 
EXAMPLE 261 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(R*)]]]-[3-[[3-[(2-Hydroxy-2,3,3-trimethyl-1-oxobutyl) 
amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carb 
amic acid, 1,1-dimethylethyl ester (Compound 261c) 
(a) Compound 261a 
##STR541## 
A solution of t-butyl magnesium chloride (2M in Et.sub.2 O, 21.55 mL, 43.1 
mmol) was added to a stirred solution of ethyl pyruvate (5 g, 43.1 mmol) 
in THF (75 mL) at -78.degree. C. The reaction mixture was stirred at 
-78.degree. C. for 15 min, RT for 1 h, diluted with EtOAc, and washed with 
1N HCl followed by sat. NaHCO.sub.3. The organic layer was dried 
(MgSO.sub.4), concentrated, and the resulting oil was fractionally 
distilled under vacuum affording 3.5 g (47%) of Compound 261a as a 
colorless oil (b.p. 45.degree.-50.degree. C. at 1.2 mm). 
(b) Compound 261b 
##STR542## 
A 0.5M aq. solution of LiOH (10.64 mL) was added to a solution of Compound 
261a (1.0 g, 5.75 mmol), stirred at 75.degree. C. for 8 h, concentrated in 
vacuo, and the residue concentrated from toluene. The residue was 
triturated from Et.sub.2 O to afford 0.9 g (ca. 100% ) o f Compound 261b. 
(c) Compound 261c 
##STR543## 
To a solution of Compound 261b (0.114 g, 0.75 mmol), HOBT monohydrate 
(0.135 g, 0.88 mmol) in 2 mL dry DMF at 0.degree. C. was added N-methyl 
morpholine (0.1634 mL, 1.49 mmol), EDCI hydrochloride (0.1434 g, 0.75 
mmol) and the resulting mixture was stirred at 0.degree. C. for 15 min. 
The mixture was treated with Compound 54 (0.3 g, 0.68 mmol) and stirred at 
RT for 20 h, concentrated, and the residue partitioned between EtOAc and 
sat. NaHCO.sub.3. The organic layer was dried (MgSO.sub.4), concentrated, 
and the crude product was subjected to flash chromatography (silica 
gel/CH.sub.2 Cl.sub.2 -MeOH-NH.sub.4 OH 95:5:0.5) affording 0.193 mg (50%) 
of a mixture of the two diastereomeric products. This mixture was 
subjected to prep. HPLC (Waters Prep Nova-Pack HR C18, 6 micron, 
30.times.300 mm; eluent: MeOH-water-TFA 30:70:0.05 to 90:10:0.05; UV 254 
nm). The fractions from the slower moving isomer were made basic with sat. 
NaHCO.sub.3, concentrated, and the residue partitioned between EtOAc/1:1 
brine-sat. NaHCO.sub.3. The organic phase was dried (MgSO.sub.4), 
concentrated, the resulting white solid was triturated from 10:1 
hexane-Et.sub.2 O to afford 19 mg (5%) of the title Compound 261c as a 
white solid. 
m.p. 97.degree.-100.degree. C.; [.alpha.].sub.D =-5.2.degree. (c=0.91, 
MeOH). 
High resolution Mass Spec.: (M+H).sup.+ =572.3688, theoretical: (M+H).sup.+ 
=572.3699 (.DELTA. 1.9 ppm error). 
Similar work-up of the fractions from the faster moving peak afforded 23 mg 
(6%) of Compound 262f. 
EXAMPLE 262 
Preparation of [1S-[1R*,2S*[2S*,3R* 
(S*)]]]-[3-[[3-[(2-Hydroxy-2,3,3-trimethyl-1-oxobutyl)amino]-2-hydroxy-4-p 
henylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 262f) 
(a) Compound 262a 
##STR544## 
A 70% solution of t-butyl hydroperoxide in water (340.5 ml, 2.38 mol) was 
extracted with 300 ml CH.sub.2 Cl.sub.2. The organic layer was added to a 
stirred mixture of SeO.sub.2 (3.67 g, 33.1 mmol) and benzoic acid (8.1 g, 
66.2 mmol) in 50 ml CH.sub.2 Cl.sub.2. The mixture was cooled to 0.degree. 
C. and 2,3,3-trimethylbutene (65 g, 0.662 mol) was added and the mixture 
stirred at RT for 14 h. The mixture was washed with 5% aq. KOH, brine and 
dried (MgSO.sub.4). The volatiles were removed by distillation and the 
residue was cooled to ca. 0.degree. C. 100 ml HOAc was added followed by 
100 ml Me.sub.2 S added dropwise over 15 min. The reaction was stirred at 
RT for 3 h, cooled to 0.degree. C. and made basic with 20% aq. K.sub.2 
CO.sub.3. The mixture was extracted with Et.sub.2 O and the organic 
extracts washed with sat. NaHCO.sub.3, dried (MgSO.sub.4), and the solvent 
removed by distillation at atmospheric pressure followed by distillation 
of the product (90.degree.-100.degree. C., 25 mm) to afford 20 g (26.5%) 
of Compound 262a. 
(b) Compound 262b 
##STR545## 
Diethyl D-tartrate (618 mg, 3 mmol) and Ti(iPrO).sub.4 (0.744 ml, 2.5 mmol) 
were added to a stirred suspension of 4 .ANG. activated powdered molecular 
sieves in 175 ml dry CH.sub.2 Cl.sub.2 at 0.degree. C. The mixture was 
cooled to -20.degree. C. and a 5.5M solution of t-butyl hydroperoxide in 
2,2,4-trimethylpentane (18.2 ml, 100 mmol) was added. After 20 min, a 
solution of Compound 262a (5.7 g, 50 mmol) in 25 ml CH.sub.2 Cl.sub.2 was 
added and the mixture stirred at -20.degree. C. for 14 h. After warming to 
0.degree. C., 15 ml H.sub.2 O was added, the mixture stirred at RT for 30 
min, 30% aq. NaOH saturated with NaCl (3 ml) was added and the reaction 
stirred at RT for 25 min. The aqueous layer was extracted with CH.sub.2 
Cl.sub.2, the combined extracts dried (MgSO.sub.4) and concentrated by 
distillation at atmospheric pressure followed by distillation of Compound 
262b (105.degree.-107.degree. C., 25 mm; 4.75 g, 73%). 
(c) Compound 262c 
##STR546## 
A solution of Compound 262b (2.3 g, 17.7 mmol) in 10 ml Et.sub.2 O was 
added to a suspension of LiAlH.sub.4 (1.477 g, 38.9 mmol) in 100 ml 
Et.sub.2 O at -5.degree. C. and stirred at RT for 30 min. The mixture was 
cooled to 0.degree. C., and quenched with 10% aq. H.sub.2 SO.sub.4 
saturated with Na.sub.2 SO.sub.4. The aqueous layer was extracted with 
EtOAc and the combined extracts washed with sat. NaHCO.sub.3 and brine and 
dried (MgSO.sub.4). Concentration in vacuo followed by recrystallization 
from hexane gave 1.5 g (64%) of Compound 262c as a white solid. 
(d) Compound 262d 
##STR547## 
A solution of DMSO (2.578 ml, 36.3 mmol) in 3 ml CH.sub.2 Cl.sub.2 was 
added dropwise at -78.degree. C. to a stirred solution of oxalyl chloride 
(1.585 ml, 18.2 mmol) over 5 min. and stirred at -78.degree. C. for 10 
min. A solution of Compound 262c (2.18 g, 16.5 mmol) in 25 ml CH.sub.2 
Cl.sub.2, was added dropwise and stirred for 15 min. at -78.degree. C. 
Et.sub.3 N (11.51 ml, 82.6 mmol) was added and the reaction allowed to 
come to RT. The mixture was diluted with additional CH.sub.2 Cl.sub.2, 
washed with 10% H.sub.2 SO.sub.4, the combined aqueous phase extracted 
with CH.sub.2 Cl.sub.2, and the combined organic layer washed with sat. 
NaHCO.sub.3, dried (MgSO.sub.4), and concentrated by distillation at 
atmospheric pressure to afford 2.15 g (100%) of Compound 262d as a pale 
gummy solid. 
(e) Compound 262e 
##STR548## 
NaClO.sub.2 (1.81 g, 20 mmol) and sulfamic acid (1.94 g, 20 mmol) were 
added in succession to a stirred solution of Compound 262d (2.0 g, 15.4 
mmol) in 30 ml 1:1 THF-water at 0.degree. C. The mixture was allowed to 
warm to RT, stirred for 30 min., diluted with CH.sub.2 Cl.sub.2 and ca. 1 
ml Me.sub.2 S was added followed by a small quantity of H.sub.2 O. The 
organic layer was separated, the aqueous layer was extracted with CH.sub.2 
Cl.sub.2, the combined organic layer was dried (MgSO.sub.4) and 
concentrated to afford a yellow gummy solid which was recrystallized from 
hexanes to afford 1.45 g (64.5%) of Compound 262e as a pale solid. 
(f) Compound 262f 
##STR549## 
N-methylmorpholine (0.037 ml, 0.34 mmol) and BOP-reagent (150 mg, 0.34 
mmol) were added at RT in succession to a stirred mixture of Compound 262e 
(45 mg, 0.31 mmol) and Compound 54 (137 mg, 0.31 mmol) in 0.5 ml dry DMF. 
The mixture was stirred at RT for 60 h, concentrated in vacuo, the residue 
partitioned between EtOAc and sat. NaHCO.sub.3, and the organic layer 
dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by 
flash chromatography (1".times.12" silica gel/CH.sub.2 Cl.sub.2 to 
CH.sub.2 Cl.sub.2 :MeOH:aq. NH.sub.4 OH 99:1:0.1 stepwise to 
92.5:7.5:0.75) to afford 120 mg (68%) of the title Compound 262f as a 
white solid. 
m.p. 204.degree.-205.degree. C. 
Anal. Calcd. for C.sub.32 H.sub.49 N.sub.3 O.sub.6.1.22 H.sub.2 O: C, 
64.73; H, 8.73; N, 7.08 Found: C, 64.73; H, 8.42; N, 7.10. 
EXAMPLE 263 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(methylamino)carbonyl]-3-methyl-L-valinamide (Compound 263d) 
(a) Comoound 263a 
##STR550## 
Compounds 88a and 48 were reacted by a procedure analogous to that of 
Example 51 to give Compound 263a (white foam). 
(b) Compound 263b 
##STR551## 
Compound 263a was converted to Compound 263b (white foam) by a procedure 
analogous to that of Example 61. 
(c) Compound 263c 
##STR552## 
Compound 263b and methyl isocyanate were reacted by a procedure analogous 
to that of Example 46 to give Compound 263c (colorless oil). 
(d) Compound 263d 
##STR553## 
Compound 263c was converted to the title Compound 263d (white solid) by a 
procedure analogous to that of Example 21. 
m.p.=174.degree.-178.degree. C.; [.alpha.].sub.D =-15.0 .degree. (c=0.28; 
MeOH) 
High resolution Mass Spec. (FAB): Calcualted (M+H).sup.+ (for C.sub.33 
H.sub.52 O.sub.6 N.sub.5)=614.3917; 
Observed (M+H).sup.+ =614.3936 .DELTA.=3.1 ppm. 
EXAMPLE 264 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(phenylmethoxy)carbonyl]-L-homoserinamide (Compound 264d) 
(a) Compound 264a 
##STR554## 
To a solution of L-homo-serine (596 mg, 5.0 mmol) and NaHCO.sub.3 (420 mg, 
5.0 mmol) in 14 ml of H.sub.2 O-acetone (1:1) was added 
N-benzyloxycarbonyloxy succinimide (1.25 g, 5.0 mmol). The mixture was 
stirred overnight at RT. Acetone was removed under reduced pressure. The 
aqueous solution was washed with CH.sub.2 Cl.sub.2 and then acidified to 
pH 2.5 with 6N HCl solution and extracted with EtOAc. The combined 
extracts were washed with H.sub.2 O and brine and dried (Na.sub.2 
SO.sub.4). Concentration in vacuo afforded 980 mg (77%) of Compound 264a. 
(b) Compound 264b 
##STR555## 
To a stirred solution of Compound 264a (506 mg, 2.0 mmol) in 10 ml of dry 
DMF was added tert-butyldimethylsilyl chloride (1.81 g, 12.0 mmol), 
followed by imidazole (1.63 g, 24.0 mmol). The mixture was stirred for 24 
h at RT. CH.sub.3 OH (35 ml) was added and the mixture was stirred for 
another 14 h. The solvent was removed under reduced pressure and the 
residue was dissolved in EtOAc. The organic layer was washed with 10% 
citric acid and brine and dried over Na.sub.2 SO.sub.4. Concentration in 
vacuo followed by flash chromatography (CHCl.sub.3 -EtOAc-HOAc: 60:40:1) 
afforded 638 mg (87%) of Compound 264b as a colorless oil. 
(c) Compound 264c 
##STR556## 
Compounds 54 and 264b were reacted by a procedure analogous to that of 
Example 93f to give Compound 264c. 
(d) Compound 264d 
##STR557## 
Compound 264c was converted to the title Compound 264d (white solid) by a 
procedure analogous to that of Example 162. 
m.p. 168.degree.-170.degree. C.; [.alpha.].sub.D =-25.6.degree. (C 0.36, 
MeOH). 
Mass Spec. (FAB): 679.sup.+ (M+H).sup.+. 
Analysis Calc. for C.sub.37 H.sub.50 N.sub.4 O.sub.8.0.20H.sub.2 O: C, 
65.12; H, 7.44; N, 8.21. Found: C, 65.04; H, 7.48; N, 8.29. 
EXAMPLE 265 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[[(4-phenyl-1H-imidazol-2-yl)methoxy]carbonyl]-L-valinamide (Compound 
265b) 
(a) Compound 265a 
##STR558## 
Compounds 253c and 61 were reacted by a three-step procedure analogous to 
that used for the conversion of Compound 149c to 150 (Et.sub.3 N and DMF 
were used in the reaction of the p-nitrophenyl carbonate of Compound 253c 
with Compound 61) to give Compound 265a. 
(b) Compound 265b 
##STR559## 
Compound 265a was converted to Compound 265b (white solid) by a procedure 
analogous to that of Example 253e. 
m.p. 140.degree.-145.degree. C.; [.alpha.].sub.D =-1.8.degree. (MeOH, 
c=0.5) 
Analysis Calc. for C.sub.41 H.sub.54 N.sub.6 O.sub.7.1.61H.sub.2 O: C, 
63.80; H, 7.47; N, 10.89. Found: C, 63.75; H, 7.39; N, 10.94. 
EXAMPLE 266 
Preparation of [1S-[1R*,2S* 
(2S*,3R*)]]-[3-[[3-[[(3,3-Dimethyl-5-oxo-2-pyrrolidinyl)carbonyl]amino]-2- 
hydroxy-4-phenylbutyl]amino]-2-hydrxmy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 266c) 
(a) Compound 266a 
##STR560## 
Compound 266a was prepared by the method of Yamazaki et al., Chem. Pharm. 
Bull., 24, 3011 (1976). 
(b) Compound 266b 
##STR561## 
Compound 266a was converted to Compound 266b by a procedure analogous to 
that of Example 70c (except THF:H.sub.2 O:DME (2:1:0.5) was used). 
(c) Compound 266c 
##STR562## 
Compounds 266b and 54 were reacted by a procedure analogous to that of 
Example 93f to give the title Compound 266c along with its diastereomer 
Compound 267 (1:1). Compound 266c (white lyophilate) was isolated by flash 
chromatography (CHCl.sub.3 -MeOH-NH.sub.4 OH 95:5:0.5 to 90:10:1) on 
silica gel followed by preparative HPLC (CH.sub.3 CN-H.sub.2 O-TFA 
62:38:0.1) purification (YMC SH ODS-365-10, S-10 column). 
.sup.1 H-NMR (400 MHz, CD.sub.3 OD): .delta. 7.10-7.30 (m, 10H), 4.27 (m, 
1H), 3.70 (s, 1H), 3.58-3.75 (m, 3H), 3.14 (m, 2H), 2.50-2.84 (m, 6H), 
2.26 (d, J=16.7, 1H), 1.93 (d, J=16.7, 1H), 1.29 (s, 9H), 0.79 (s, 3H), 
0.76 (s, 3H). 
High resolution Mass Spec. Calc. for C.sub.32 H.sub.47 N.sub.4 O.sub.6 : 
583.3496; Found: 583.3506, .DELTA.=1.7 ppm. 
EXAMPLE 267 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(3,3-Dimethyl-5-oxo-2-pyrrolidinyl)carbon 
yl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]c 
arbamic acid, 1,1-dimethylethyl ester (Compound 267) 
##STR563## 
Compound 267, the diastereomer of Compound 266c, was isolated by 
preparative HPLC as described in Example 266c. 
.sup.1 H-NMR (400 MHz, CD.sub.3 OD):.delta. 7.10-7.30 (m, 10H), 4.16 (m, 
1H), 3.63 (s, 1H), 3.56-3.73 (m, 3H), 3.10 (m, 2H), 2.63-2.80 (m, 5H), 
2.58 (m, 1H), 2.47 (d, J=16.7, 1H), 2.38 (d, J=16.7, 1H), 1.29 (s, 9H), 
0.97 (s, 3H), 0.93 (s, 3H). 
High resolution Mass Spec. Calc. for C.sub.32 H.sub.47 N.sub.4 O.sub.6 : 
583.3496; Found: 583.3505, .DELTA.=1.7 ppm. 
EXAMPLE 268 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]biscarba 
mic acid, (1H-imidazol-2-yl)-methyl 1,1-dimethylethyl ester (Compound 268b) 
(a) Compound 268a 
##STR564## 
Compounds 249a and 48 were reacted by a three-step procedure analogous to 
that used for the conversion of Compound 149c to 150 (Et.sub.3 N and DMF 
were used in the reaction of the p-nitrophenyl carbonate of Compound 249a 
with Compound 48) to give Compound 268a. 
(b) Compound 268b 
##STR565## 
Compound 268a was converted to Compound 268b (white solid) by a procedure 
analogous to that of Example 253e. 
m.p. 143.degree.14 147.degree. C. (dec.); [.alpha.].sub.D 
=-5.degree.-9.degree. (c=0.16, MeOH). 
Analysis Calcd. for C.sub.30 H.sub.41 N.sub.5 O.sub.6.0.45 H.sub.2 O 
(575.79): C, 62.58; H, 7.34; N, 12.16. Found: C, 62.57; H, 7.35; N, 12.08. 
Mass Spec. (FAB): (M+H).sup.+ =568.sup.+ 
EXAMPLE 269 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(2,2-Dimethyl-1-oxo-propyl)amino]-2-hydrox 
yl-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 269) 
##STR566## 
Compound 54 and trimethylacetic acid were converted to the title Compound 
269 (white solid) by a procedure analogous to that of Example 262f except 
that a mixture of DMF and CH.sub.2 Cl.sub.2 was used and no 
N-methylmorpholine was added. 
m.p. 100.degree.-104.degree. C. ("softening" at 84.degree.-99.degree. C.); 
[.alpha.].sub.D =+10.1.degree. (c=0.8.5 , MeOH). 
High resolution Mass Spec. 528.3 428.sup.+ for C.sub.30 H.sub.46 O.sub.5 
N.sub.3 (calc. 528.3437.sup.+) .DELTA.=1.7 ppm. 
EXAMPLE 270 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2-Formyl-2,3-dihydro-1-isoindol-1-yl)car 
bonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propy 
l]carbamic acid, 1.1-dimethylethyl ester (Compound 270g) 
(a) Compound 270a 
##STR567## 
A solution of benzoyl peroxide (97%; 0.043 g), N-bromosuccinimide (11.74 g, 
0.066 mol) and o-tolylacetic acid (10.0 g, 0.066 mol) in CCl.sub.4 (600 
ml) was heated at 90.degree. C. for 3.5 h. Upon cooling, the reaction was 
filtered to remove a yellow precipitate, and the filtrate was concentrated 
in vacuo to a yellow solid. This solid was recrystallized from CCl.sub.4 
to afford 9.20 g (64%) of Compound 270a as a white crystalline solid. 
(b) Compound 270b 
##STR568## 
After heating a solution of Compound 270a (9.0 g, 0.04 mol) in SOCl.sub.2 
(9.0 ml) at 50.degree. C. for 3 h, the excess reagent was removed at 
reduced pressure, and the resulting yellow oil heated to 80.degree. C. 
under a 250 watt lamp. Br.sub.2 (2.5 ml) was added and the reaction 
continued at 80.degree. C. for 4 h before cooling and removing the excess 
reagent under reduced pressure. The resulting brown residue was stirred in 
MeOH for 30 min at RT then concentrated in vacuo to an orange oil which 
was chromatographed on a silica gel column, eluting the column with 
toluene to afford 8.0 g (65%) of Compound 270b as a yellow oil. 
(c) Compound 270c 
##STR569## 
Benzylamine (2.04 ml, 18.69 mmol) was added to a stirred solution of 
Compound 270b (2.0 g, 6.23 mmol) in toluene (13 ml) at 0.degree. C. The 
reaction was warmed to RT where it remained for 72 h before filtering off 
a yellow precipitate under Ar. The solid was washed thoroughly with 
toluene and the filtrate diluted with a solution of anhydrous Et.sub.2 O 
saturated with HCl gas. The mother liquor was decanted and the remaining 
yellow gum dried under high vacuum to afford 1.35 g (50%) of Compound 270c 
as a green foam. 
(d) Compound 270d 
##STR570## 
Compound 270c was converted to Compound 270d by a procedure analogous to 
that of Example 2. 
(e) Compound 270e 
##STR571## 
Compound 270d was converted to Compound 270e by a procedure analogous to 
that of Example 129 (except 1.1 eq. of N-methylmorpholine was also added 
to the reaction mixture). 
(f) Compound 270f 
##STR572## 
A solution of aqueous NaOH (0.736 ml, 1N) was added at RT to a rapidly 
stirred solution of Compound 270e in THF (lml). After 20 min, the solution 
was concentrated in vacuo then dried under high vacuum to afford 0.136 g 
(51%) of Compound 270f as a brown/green solid. 
(g) Compound 270g 
##STR573## 
Compounds 270f and 54 were reacted by procedure analogous to that of 
Example 55 (DMF only used) to give the title Compound 270 g as a mixture 
ofdiastereomers. 
m.p. 174.degree.-176.degree. C.; [.alpha.].sub.D =-30.degree. (c 0.1, MeOH) 
Mass spec: HRMS C.sub.35 H.sub.45 O.sub.6 N.sub.4 : 617.3328+: calculated 
617.3339+, .DELTA.=1.8 ppm. 
EXAMPLE 271 
Preparation of [1S-[1R*,2S*(2S*,3R*)]]- 
[2-Hydroxy-1-(phenylmethyl)-3-[[2-hydroxy-4-phenyl-3-[(3,3,3-trifluoro-2-h 
ydroxy-1-oxopropyl)amino]butyl]amino]propyl]carbamic acid, 
1,1-dimethylethyl ester (isomer A) (Compound 271) 
##STR574## 
To a solution of trifluorolactic acid (0.107 g, 0.75 mmol, prepared as 
described in Burstein, Can. J. Chem., 39, 1848 (1961)), HOBT monohydrate 
(0.135 g, 0.88 mmol) in 2.1 mL dry DMF at RT was added in succession 
N-methylmorpholine (0.163 mL, 1.49 mmol), Compound 54 (0.3 g, 0.68 mmol) 
and EDCI hydrochloride (0.143 g, 0.75 mmol). The resulting mixture was 
stirred at RT for 16 h, concentrated, and the residue partitioned between 
EtOAc and sat. NaHCO.sub.3. The organic layer was dried (MgSO.sub.4), 
concentrated, and the crude product was purified by flash chromatography 
(silica gel/CH.sub.2 Cl.sub.2 to CH.sub.2 Cl.sub.2 -MeOH-NH.sub.4 OH 
90:10:1, stepwise gradient) affording 0.21 g (54%) of a mixture of the two 
diastereomeric products. This mixture was subjected to preparative HPLC 
(Waters Prep Nova-Pack HR C18, 6 micron, 30.times.300 mm; eluent: 
MeOH-water-TFA 20:80:0.05 to 90:10:0.05; UV 254 nm). The desired fractions 
containing the faster eluting component on C18 were made basic with sat. 
NaHCO.sub.3, concentrated, and the residue partitioned between 
EtOAc/brine. The organic phase was dried (MgSO.sub.4), concentrated, and 
the resulting solid was triturated from 5:1 pentane-Et.sub.2 O to afford 
51 mg (13%) of the title Compound 271 as a white solid. 
m.p. 160.degree.-163.degree. C.; [.alpha.].sub.D =+2.25.degree. (c=0.2, 
MeOH). 
High resolution Mass Spec.: (M+H).sup.+ =570.2809, theoretical: (M+H).sup.+ 
=570.2791 (.DELTA. 3.1 ppm error). 
EXAMPLE 272 
Preparation of [1S- 
[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-1-(phenylmethyl)-9-[[2-hydroxy-4-phenyl-3-[ 
(3,3,3-trifluoro-2-hydroxy-1-oxopropyl)amino]butyl]amino]propyl]carbamic 
acid, 1,1-dimethylethyl ester (isomer B) (Compound 272) 
##STR575## 
Compound 272 (white solid), the diastereomer of Compound 271, was isolated 
by preparative HPLC (work up of the fraction from the slower moving peak) 
as described in Example 271. 
m.p. 127.degree.-130.degree. C.; [.alpha.].sub.D =+5.0.degree. (c=0.3, 
MeOH). 
High resolution mass spectrum: (M+H).sup.+ =570.2786, theoretical: 
(M+H).sup.+ =570.2791 (.DELTA. 0.9 ppm error). 
EXAMPLE 273 
Preparation of [1R*,2S*(2S*,3R*)]-N.sup.2 
-[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-N-[3-[[3-[[(1,1-dimethyleth 
oxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethy 
l)propyl]-L-valinamide (Compound 273b) 
(a) Compound 273a 
##STR576## 
2-Aminomethylbenzimidazole and Compound 245b were reacted by a procedure 
analogous to that of Example 245c to give Compound 273a. 
(b) Compound 273b 
##STR577## 
Compounds 273a and 54 were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 70b to Compound 70d (DMF only; no 
N-methylmorpholine was added) to give the title Compound 273b (white 
solid) along with its valine diastereomer Compound 274. The diastereomers 
were separated on a 30 ml silica column eluting with 2-8% MeOH/CH.sub.2 
Cl.sub.2 which was increased in 0.5% units with 0.1% NH.sub.4 OH. TLC 
(SiO.sub.2)R.sub.f =0.40 (CH.sub.2 Cl.sub.2 :MeOH: NH.sub.4 OH 90:10:1) 
m.p. 182.degree.-186.degree. C. (dec); [.alpha.].sub.D =-22.degree. 
(c=0.25, MeOH) 
Analysis Calcd. for: C.sub.39 H.sub.53 N.sub.7 O.sub.6 .multidot.2.5 
H.sub.2 O C, 61.57 H, 7.68 N, 12.89 Found: C, 61.23 H, 7.33 N, 12.78. 
EXAMPLE 274 
Preparation of [1S*,2R*(2R*,3S*)]-N.sub.2 
-[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-N-[3-[[3-[[(1,1-dimethyleth 
oxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethy 
l)propyl]-D-valinamide (Compound 274) 
##STR578## 
Compound 274 (white solid) was isolated as the slower moving isomer by the 
procedure described in Example 273b. 
TLC(SiO.sub.2)R.sub.f =0.35 (CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH 90:10:1) 
m.p. 186.degree.-189.degree. C. (dec); [.alpha.].sub.D =-10.5.degree. 
(c=0.25, MeOH) 
Analysis Calcd. for: C.sub.39 H.sub.53 N.sub.7 O.sub.6 .multidot.2.4 
H.sub.2 O C, 61.77 H, 7.67 N, 12.93 Found: C, 61.54 H, 7.28 N, 13.03 
EXAMPLE 275 
Preparation of [1S-(1R*,2S*), 
(S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarbamic 
acid, 1,1-dimethylethyl 2-hydroxy-1,1-dimethylpropyl ester (Compound 275h) 
(a) Compound 275a 
##STR579## 
Compound 275a was prepared from (R)-methyl lactate by a procedure analogous 
to that of Example 232a. 
(b) Compound 275b 
##STR580## 
Compound 275a was converted to Compound 275b by a two-step procedure 
analogous to that used for the conversion of Compound 149b to Compound 
149d. 
(c) Compound 275c 
##STR581## 
Compound 16b was reacted with benzylchloroformate by a procedure analogous 
to that used in Example 122 (reaction run at 0.degree. C. for 2 h) to give 
Compound 275c. 
(d) Compound 275d 
##STR582## 
Solid Compound 275c (1.21 g; 2.91 mmol) was added to a saturated solution 
of HCl gas in 45 ml of EtOAc at 0.degree. C. The reaction was stoppered 
and stirred for 3 h at 0.degree. C. The solution was purged with N.sub.2 
for 15 min and the volatiles were removed in vacuo to afford 1.03 g 
(.about.100%; contained trace solvent) of Compound 275d as a white solid. 
(e) Compound 275e 
##STR583## 
Compounds 275b and 275d were reacted by a procedure analogous to that of 
Example 161e to give Compound 275e. 
(f) Comoound 275f 
##STR584## 
Compound 275e was converted to Compound 275f by a procedure analogous to 
that of Example 61. 
(g) Compound 275q 
##STR585## 
Compounds 1b(i) and 275f were reacted by a procedure analogous to that of 
Example 4b to give Compound 275g. 
(h) Compound 275h 
##STR586## 
Compound 275g was converted to the title Compound 275h (white solid) by a 
procedure analogous to that of Example 162. 
m.p. 77.degree.-87.degree. C. (dec.); [.alpha.]D.sup.=-8.5 .degree. (c 
0.27, MeOH). 
Mass Spec. FAB: M+H=574 (M+H) 
Analysis calc. for C.sub.31 H.sub.47 N.sub.3 O.sub.7 .multidot.0.64 H.sub.2 
O: C, 63.62; H, 8.31; N, 7.18; Found: C, 63.57; H, 8.33; N, 7.23. 
EXAMPLE 276 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-6-[4-[2-(4-morpholinyl)-2-oxoethoxy]phenyl]-5-hexenyl]amino]-2-hydroxy 
-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethl ester (Compound 
276d) 
(a) Compound 276a 
##STR587## 
Compound 235e was converted to Compound 276a by a procedure analogous to 
that of Example 18. 
(b) Compound 276b 
##STR588## 
Compound 276a and 4-(2-bromoacetyl)-morpholine (J. Med. Chem., 35, 1685 
(1992)) were converted to Compound 276b by a two-step procedure analogous 
to that used for the conversion of Compound 20 to Compound 173. 
(c) Compound 276c 
##STR589## 
Compound 276b was converted to Compound 276c by a two-step procedure 
analogous to that of Example 177. 
(d) Compound 276d 
##STR590## 
Compound 276c was converted to the title Compound 276d (white solid) by a 
procedure analogous to that of Example 21. 
m.p. 115.degree.-116.degree. C.; [.alpha.]Hg (365)=-27.1.degree. (c 0.14, 
MeOH ). 
Mass Spec. (FAB): 713.sup.+ (M+H).sup.+. 
Analysis Calcd. for C.sub.38 H.sub.56 N.sub.4 O.sub.9 : C, 64.00; H, 7.92; 
N, 7.86. Found: C, 63.78; H, 7.93; N, 8.08. 
EXAMPLE 277 
Preparation of [R-(R*, 
S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanedyl)]biscarbamic 
acid, 1,1-dimethylethyl-2-hydroxy-1-(3-pyridinyl)ethyl ester (Compound 
277e) 
(a) Compound 277a 
##STR591## 
To a 0.degree. C. solution of vinyl magnesium bromide (41.0 mL of a 1.0M 
solution in THF) was added dropwise over 1 h a solution of pyridine 
3-carboxaldehyde (4.00 g, 37.3 mmol) in THF (50 mL). The resulting 
orange-yellow solution was allowed to warm to RT and stirred for 24 h 
under argon. The reaction mixture was cooled to 0.degree. C., then was 
quenched by slow addition of aqueous NH.sub.4 Cl (55 mL of a 1M solution). 
EtOAc was added and the resulting emulsion was filtered through Celite in 
a sintered glass funnel under vacuum. The aqueous layer was extracted with 
EtOAc and the combined organic extracts were dried (Na.sub.2 SO.sub.4) and 
concentrated in vacuo to give a red oil which was purified on silica gel 
(500 mL) using a stepwise gradient from 1:1 to 1:5 hexanes:ethyl acetate 
as eluent to give Compound 277a (3.89 g; 77%) as a pale yellow oil. 
(b) Compound 277b 
##STR592## 
Ozone was bubbled through a solution of 1.00 g (7.40 mmol) of Compound 277a 
in 25 mL of CH.sub.3 OH at -78.degree. C. for 20 min. After purging with 
N.sub.2 and warming to 0.degree. C., the reaction mixture was diluted with 
3 mL of H.sub.2 O and NaBH.sub.4 (420 mg, 11.1 mmol) was added. The 
mixture was stirred for 30 min at 0.degree. C. and for 1 h at RT then 
quenched by the addition of 10 mL of saturated NH.sub.4 Cl. The pH was 
adjusted to 4 with 20 mL of 1M HCl, and the reaction mixture was 
concentrated in vacuo. Flash chromatography on silica gel [2% CH.sub.3 
OH/CH.sub.2 Cl.sub.2, then 3-10% CH.sub.3 OH/CH.sub.2 Cl.sub.2 (with 1.0% 
NH.sub.4 OH)]provided 717 mg (70%) of Compound 277b. 
(c) Compound 277c 
##STR593## 
To a solution of 677 mg (4.86 mmol) of Compound 277b in 20 mL of dry 
CH.sub.2 Cl.sub.2 at 0.degree. C. were added 0.75 mL (5.4 mmol) of 
Et.sub.3 N, 30 mg DMAP, and 769 mg (5.10 mmol) of 
t-butyldimethylsilylchloride. The reaction mixture was warmed to RT over 4 
h and then stirred for 4 days. The reaction mixture was diluted with 75 mL 
of EtOAc, and washed with saturated NaHCO.sub.3 and brine. The organic 
layer was dried (Na.sub.2 SO.sub.4), filtered, and concentrated in vacuo 
to provide, after flash chromatography on silica gel (25-100% 
EtOAc-hexane), 1.12 g (91%) of Compound 277c. 
(d) Compound 277d 
##STR594## 
Compounds 277c and 54 were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 147b to Compound 147d to give 
Compound 277d. 
(e) Compound 277e 
##STR595## 
Compound 277d was converted to the title Compound 277e (white solid) by a 
procedure analogous to that of Example 162. 
m.p. 75.degree.-85.degree. C.; [.alpha.].sub.D =-13.degree. (c 0.28, 
CH.sub.3 OH) 
Mass Spec. 609 (M+H).sup.+ 
Analysis Calcd. for C.sub.33 H.sub.44 N.sub.4 O.sub.7 .multidot.1.03 
H.sub.2 O: C, 63.18; H, 7.40; N, 8.93. Found: C, 63.28; H, 7.28; N, 8.83. 
EXAMPLE 278 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(2-hydroxy-2-methyl-1- 
oxopropyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester (Compound 278) 
##STR596## 
Compound 54 and 2-hydroxyisobutyric acid were reacted by a procedure 
analogous to that of Example 269 to give the title Compound 278 (white 
solid). m.p. 162.degree.-166.degree. C. ("softening" at 
156.degree.-161.degree. C.); [.alpha.].sub.Hg 365=-2.9.degree. (c=0.99, 
CH.sub.3 OH). 
Mass Spec. (FAB), 530 (M+H.sup.+) 
Analysis Calcd. for C.sub.29 H.sub.43 N.sub.3 O.sub.6 .multidot.0.48 
H.sub.2 O: C, 64.70; H, 8.23; N, 7.81. Found: C, 64.72; H, 8.32; N, 7.79. 
EXAMPLE 279 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-(hydroxymethyl)-2-m 
ethyl-1-oxopropyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbam 
ic acid, 1,1-dimethylethyl ester (Compound 279) 
##STR597## 
Compound 54 and 2,2-dimethyl-3-hydroxypropionic acid were reacted by a 
procedure analogous to that of Example 269 (CH.sub.2 Cl.sub.2 only used) 
to give the title Compound 279 (white solid). 
m.p. 73.degree.-76.degree. C. ("softening" at 66.degree.-72.degree. C.); 
[.alpha.].sub.D =+3.6.degree.; (c=0.76, CH.sub.3 OH). 
Mass Spec. (FAB), 544 (M+H.sup.+) 
Analysis Calcd. for C.sub.30 H.sub.45 N.sub.3 O.sub.6 .multidot.0.29 
H.sub.2 O: C, 65.64; H, 8.37; N, 7.65. Found: C, 65.64; H, 8.33; N, 7.81. 
EXAMPLE 280 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[[(1H-inden-2-yl)methoxy]carbonyl]-L-valinamide (Compound 280b) 
(a) Compound 280a 
##STR598## 
A solution of 2-carboethoxyindene (1.0 g, 6.24 mmol; see Treibs, Chem. 
Ber., 93, 545 (1960)) in 15 ml of dry toluene was treated with 4 eq. of a 
1M solution of diisobutylaluminum hydride in toluene (24.96 ml) at RT. 
After 4 h at RT, the reaction was cooled in an ice-bath and MeOH was 
added. The mixture was filtered and the solvents evaporated yielding the 
crude product as a colorless oil which was purified by chromatography on 
silica column eluting with 60% EtOAc/hexane to afford 593 mg (77%) of 
Compound 280a as a colorless solid. 
(b) Compound 280b 
##STR599## 
L-Valine and Compounds 280a and 54 were reacted by a three-step procedure 
analogous to that described for the conversion of Compound 171a to 
Compound 257c to give the title Compound 280b (colorless solid). 
m.p. 148.degree.-154.degree. C. (dec); [.alpha.].sub.D =-18.5.degree. (c 
0.22, MeOH) 
Mass Spec. (FAB) :715.sup.+ (M+H).sup.+ 
Analysis Calcd. for: C.sub.41 H.sub.54 N.sub.4 O.sub.7 +0.75 H.sub.2 O: C, 
67.61; H, 7.68; N, 7.69 Found: C, 67.62; H, 7.52; N, 7.68. 
EXAMPLE 281 
Preparation of 
[1R*,2S*(2S*,3R*)]]-N-[3-[[1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4- 
phenylbutyl]amino]- 2-hydroxy-1-(phenylmethyl)-propyl]-N.sup.2 
-[(2-quinolinylmethoxy)carbonyl]-L-valinamide (Compound 281c) 
(a) Compound 281a 
##STR600## 
A solution of 7.25 mL (7.25 mmol; 1.0M in Et.sub.2 O) of LiAlH.sub.4 was 
diluted with 4 mL of dry Et.sub.2 O and cooled to -60.degree. C. To this 
was added, over 30 min, a solution of 1.15 g of methyl quinaldate in 7 mL 
of dry Et.sub.2 O. The mixture was warmed to -25.degree. C., stirred for 
15 min, and treated with 10 mL of Et.sub.2 O which was saturated with 
H.sub.2 O. The mixture was warmed to 0.degree. C. and quenched by the 
addition of a solution of 360 mg of NaOH in 2 mL of H.sub.2 O. The mixture 
was diluted with 100 mL of Et.sub.2 O and washed with H.sub.2 O and brine. 
The organic layer was dried (Na.sub.2 SO.sub.4), filtered, and 
concentrated in vacuo to give crude material which was purified by flash 
chromatography on silica gel (25-100% EtOAc-hexane) to afford 445 mg (46%) 
of Compound 281a. 
(b) Compound 281b 
##STR601## 
Compound 281a and L-valine were reacted by a two-step procedure analogous 
to that described for the conversion of Compounds 70a(i) and 70a(ii) to 
Compound 70c to give Compound 281b. 
(c) Compound 281C 
##STR602## 
Compounds 281b and 54 were reacted by a procedure analogous to that of 
Example 55 (DMF only used) to give the title Compound 281c (white solid). 
m.p. 177.degree.-190.degree. C. (dec.); [.alpha.].sub.D =-12.degree. (C 
0.33, CH.sub.3 OH) 
Mass Spec. 728 (M=H).sup.+ 
Analysis Calcd. for: C.sub.41 H.sub.53 N.sub.5 O.sub.7 .multidot.0.85 
H.sub.2 O: C, 66.25; H, 7.42; N, 9.42 Found: C, 66.10; H, 7.28; N, 9.57 
EXAMPLE 282 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-[2-(2-pyridinyl)ethoxy]phenyl]met 
hyl]propyl]carbamic acid, 2-hydroxy-1,1-dimethylethyl ester (Compound 282g) 
(a) Compound 282a 
##STR603## 
To a suspension of Compound 175c (400 mg, 1.43 mmol) in THF (1.5 mL) was 
added PPh.sub.3 (0.564 g, 2.15 mmol), followed by 
2-(2-hydroxyethyl)pyridine (256.5 mg, 2.15 mmol) and DEAD (0.374 g, 2.15 
mmol). The resulting solution was stirred at RT for 18 h. The reaction 
mixture was concentrated in vacuo and purified by silica gel 
chromatography, eluting with EtOAc (10% to 100%)-hexane to afford Compound 
282a (0.254 g, 45% yield). 
(b) Compound 282b 
##STR604## 
To a solution of Compound 282a (200 mg, 0.52 mmol) in MeOH (ca. 8 mL) was 
added NaN.sub.3 (101.45 mg, 1.56 mmol) and NH.sub.4 Cl (50 mg, 0.93 mmol) 
and the mixture heated at reflux for 18 h. The solution was cooled to RT, 
and the solvent removed under vacuum. The residue was taken in EtOAc and 
washed with H.sub.2 O and brine. The combined organic phase was dried 
(MgSO.sub.4), and concentrated in vacuo to yield Compound 282b (187 mg, 
71%) as a gummy white residue. 
(c) Compound 282c 
##STR605## 
Compound 282b (180 mg, 0.421 mmol) in 4M HCl in dioxane (3.36 mL) was 
stirred at RT for 1 h, and concentrated in vacuo to yield a yellow residue 
which was azeotroped from CHCl.sub.3 and then toluene to yield Compound 
282c as a foamy yellow solid (197 mg, ca. 100% yield, crude). 
(d) Compound 282d 
##STR606## 
To Compound 282c (195 mg, 0.595 mmol) in DMF (0.5 mL) was added i-Pr.sub.2 
NEt (0.72 mL, 4.16 mmol), followed by a solution of the Compound 161d (242 
mg, 0.655 mmol) in DMF (ca. 0.5 mL) and the mixture stirred at RT for 18 
h. The reaction mixture was concentrated in vacuo and the residue taken in 
EtOAc and washed with 1:1 saturated NaHCO.sub.3 :brine. The combined 
organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo 
to yield a yellow gummy residue which was purified by flash 
chromatography, eluting with CH.sub.3 OH (1% to 30%)-CH.sub.2 Cl.sub.2 to 
afford Compound 282d (250 mg, 75% yield) as a yellow solid. 
(e) Compound 282e 
##STR607## 
To a solution of Compound 282d (235 mg, 0.421 mmol) in THF (2.5 mL) was 
added H.sub.2 O (12 .mu.L), followed by triphenylph0sphine (122 mg, 0.463 
mmol) and the mixture stirred at RT for 18 h. The reaction mixture was 
concentrated in vacuo, and purified on silica gel, eluting with CH.sub.2 
Cl.sub.2 :CH.sub.3 OH:aq. NH.sub.4 OH (99:1:0.02 to 85:15:0.1) to afford 
Compound 282e (145 mg, 65% yield) as a gummy white solid. 
(f) Compound 282f 
##STR608## 
To a solution of Compound 282e (134 mg, 0.252 mmol) in DMF (0.5 mL ) was 
added the Compound 1b(i) (66.36 mg, 0.252 mmol) and the mixture heated at 
110.degree. C. for 6 h, and concentrated in vacuo. The crude product was 
purified by silica gel chromatography, eluting with CH.sub.2 Cl.sub.2 
:CH.sub.3 OH:aq. NH.sub.4 OH (99:1:0.02 to 90:10:1) to afford Compound 
282f (114 mg, 57% yield) as a white residue. 
TLC(SiO.sub.2) R.sub.f =0.22 (9:1:0.1 CH.sub.2 Cl.sub.2 :MeOH:aq. NH.sub.4 
OH - Rydon) 
(g) Compound 282g 
##STR609## 
Compound 282f (114 mg, 0.143 mmol) in a mixture of HOAc:THF:H.sub.2 O 
(3:1:1, 1.5 mL) was stirred at RT for 40 h, and then heated at 50.degree. 
C. for 4 h. The reaction mixture was concentrated in vacuo and the residue 
purified by silica gel chromatography, eluting with CH.sub.2 Cl.sub.2 
:CH.sub.3 OH:aq. NH.sub.4 OH (97.5:2.5:0.025 to 90:10:1) to afford the 
title Compound 282 g (50 mg, 51% yield) as a foamy white solid. 
m.p. 106.degree.-108.degree. C.; [.alpha.].sub.D =-4.0.degree. (c=0.2, 
CH.sub.3 OH). 
Analysis for: C.sub.37 H.sub.52 N.sub.4 O.sub.8 .multidot.0.84 H.sub.2 O 
Calculated: C, 63.85; H, 7.77; N, 8.05. Found: C, 63.86; H, 7.58; N, 8.04. 
EXAMPLE 283 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-phenylbutyl]amino]-2-hydroxy-1-[[4-(2-methoxyethoxy)phenyl]methyl]pr 
opyl]carbamic acid, 2-hydroxy-1,1-dimethylethyl ester (Compound 283) 
##STR610## 
Compound 175c and 2-methoxyethanol were converted to the title Compound 283 
(white solid) by a seven-step procedure analogous to that used in Example 
282. 
m.p. 118.degree.-120.degree. C.; [.alpha.].sub.D =-3.90.degree. (c=0.2, 
CH.sub.3 OH). 
Analysis for: C.sub.33 H.sub.51 N.sub.3 O.sub.9 .multidot.0.38 H.sub.2 O 
Calculated: C, 61.87; H, 8.14; N, 6.56. Found: C, 61.88; H, 8.0.8; N, 
6.55. 
EXAMPLE 284 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4- 
phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(N-formyl-L-alanyl)-3-methyl-L-valinamide (Compound 284d) 
(a) Compound 284a 
##STR611## 
Compound 263b and N-carbobenzyloxy-L-alanine were reacted by a procedure 
analogous to that of Example 51 to give Compound 284a. 
(b) Compound 284b 
##STR612## 
Compound 284a was converted to Compound 284b by a procedure analogous to 
that of Example 61 (EtOH was used instead of MeOH). 
(c) Compound 284c 
##STR613## 
Compound 284b was reacted with formic acetic anhydride by a procedure 
analogous to that of Example 129 to give Compound 284c. 
(d) Compound 284d 
##STR614## 
Compound 284c was converted to the title Compound 284d (white solid) by a 
procedure analogous to that of Example 21. 
m.p. 167.degree.-170.degree. C., [.alpha.].sub.D =-25.7.degree. (MeOH, 
C=0.6). 
Mass Spec. 656 (M+H).sup.+ 
EXAMPLE 285 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4- 
phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(N-formyl-L-phenylalanyl)-3-methyl-L-valinamide (Compound 285) 
##STR615## 
Compound 263b and N-carbobenzyloxy-L-phenylalanine were converted to the 
title Compound 285 (white solid) by a four-step procedure analogous to 
that described in Example 284. 
m.p. 117.degree.-119.degree. C., [.alpha.].sub.D =-9.6.degree. (MeOH, c 
1.12). 
Mass Spec. 732 (M+H).sup.+ 
EXAMPLE 286 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy-4- 
phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(N-formylglycyl)-3-methyl-L -valinamide (Compound 286b) 
(a) Compound 286a 
##STR616## 
Compound 263b and N-formylglycine were reacted by a procedure analogous to 
that of Example 51 to give Compound 286a. 
(b) Compound 286b 
##STR617## 
Compound 286a was converted to the title Compound 286b (white solid) by a 
procedure analogous to that of Example 21. 
m.p. 180.degree.-183.degree. C. 
EXAMPLE 287 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[3,3-Dimethyl-2-[[(methylamino)carbonyl]ox 
y]-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmeth 
yl)propyl]-carbamic acid, 1,1-dimethylethyl ester (Compound 287d) 
(a) Compound 287a 
##STR618## 
Vinyl magnesium bromide was added to pivaldehyde by a procedure analogous 
to that of Example 277a to give Compound 287a as a yellow-orange oil. 
(b) Compound 287b 
##STR619## 
To a 0.degree. C. suspension of THF-washed Nail (0.116 g of an 80% oil 
dispersion) in anhydrous THF (5 mL) was added dropwise a solution of 
Compound 287a (0.400 g; 3.50 mmol) in THF (10 mL). The reaction mixture 
was allowed to warm to RT and stirred for 1 h. After recooling to 
0.degree. C., a solution of methyl isocyanate (0.25 mL; 4.20 mmol) in THF 
(1.5 mL) was added dropwise. The reaction was allowed to warm to RT and 
stirred for 4 h. Aqueous NH.sub.4 Cl (10 mL of a 1M solution) and EtOAc 
(20 mL) were added. The aqueous layer was saturated with NaCl and 
extracted with EtOAc. The combined organic extracts were dried (Na.sub.2 
SO.sub.4) and concentrated in vacuo to give Compound 287b (0.302 g; 50%) 
as a yellow oil. 
(c) Compound 287c 
##STR620## 
Compound 287b was converted to Compound 287c by a procedure analogous to 
that of Example 238b. 
(d) Compound 287d 
##STR621## 
Compound 287c was converted to the title Compound 287d (white solid) by a 
procedure analogous to that of Example 93f. 
m.p.=85.degree.-89.degree. C. (softens at 65.degree.-70.degree. C.); 
[.alpha.].sub.D =-5.8.degree. (c 0.12, MeOH) 
Mass Spec. (M+H).sup.+ =615 
Analysis Calculated for C.sub.33 H.sub.50 N.sub.4 O.sub.7.0.80 H.sub.2 O: 
C, 63.00; H, 8.27; N, 8.91 Found: C, 63.00; H, 8.20; N, 8.63 
EXAMPLE 288 
Preparation of [1R*,2S*(2S*,3R*)]-N.sup.2 
-[[(2Benzoxazolyl)methoxy]carbonyl]-N-[3-[[3-[[(1,1-dimethylethoxy)carbony 
l]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-[(4-hydroxyphenyl)methy 
l]propyl]-L-valinamide (Compound 288f) 
(a) Compound 288a 
##STR622## 
Compound 175b was converted to Compound 288a by a two-step procedure 
analogous to that described for the conversion of Compound 282a to 
Compound 282c. 
(b) Compound 288b 
##STR623## 
Compound 288a was converted to Compound 288b by a procedure analogous to 
that of Example 122 except that benzylchloroformate was used. 
(c) Compound 288c 
##STR624## 
Compounds 288b and 1b(i) were converted to Compound 288c by a two-step 
procedure analogous to that used for the conversion of Compound 282d to 
Compound 282f (except that the second step was performed in i-PrOH at 
80.degree. C.). 
(d) Compound 288d 
##STR625## 
Hydrogenation (balloon) of 120 mg (0.175 mmole) of Compound 288c in 10 ml 
of MeOH over 30 mg of 10% Pd/C catalyst afforded 80 mg (0.174 mmole, 100%) 
of Compound 288d as a solid foam. 
(e) Compound 288e 
##STR626## 
Compound 288e was prepared as described in Example 171. 
(f) Compound 288f 
##STR627## 
Compounds 288d and 288e were reacted by a procedure analogous to that of 
Example 93f to give the title Compound 288f (white solid). 
m.p. 175.degree.-177.degree. C.; [.alpha.].sub.D =-20.1 (c. 0.92, MeOH) 
Mass Spec.: (M+H).sup.+ 734.sup.+ 
Analysis Calc. for C.sub.39 H.sub.51 N.sub.5 O.sub.9 .multidot.0.33 H.sub.2 
O: C, 63.32; H, 7.04; N, 9.47. Found: C, 63.32; H, 7.03, N, 9.27. 
EXAMPLE 289 
Preparation of 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3.1-propanediyl)]biscarba 
mic acid, (1H-benzimidazol-2-yl)methyl 1,1-dimethylethyl ester (Compound 
289e) 
(a) Compound 289a 
##STR628## 
Compounds 93c and 48 were reacted by a procedure analogous to that of 
Example 149e (DMF used) to give Compound 289a. 
(b) Compound 289b 
##STR629## 
Compound 289a was converted to Compound 289b by a procedure analogous to 
that of Example 140a. 
(c) Comoound 289c 
##STR630## 
Compound 289b was converted to Compound 289c by a procedure analogous to 
that of Example 21. 
(d) Compound 289d 
##STR631## 
Compound 289c was converted to Compound 289d by a procedure analogous to 
that of Example 140e. 
(e) Compound 289e 
##STR632## 
Compound 289d was converted to the title Compound 289e (white solid) by a 
procedure analogous to that of Example 7 (1 eq. of hydrazine monohydrate 
was added). 
m.p. 95.degree.-105.degree. C.; [.alpha.].sub.D =-9.3.degree. (c=0.2, 
CH.sub.3 OH). 
Mass Spec. (FAB) (M+H).sup.+ =618 
Analysis calc. for C.sub.34 H.sub.43 N.sub.5 O.sub.6 .multidot.1.02H.sub.2 
O: C, 64.19; H, 7.14; N, 11.01; Found: C, 64.39; H, 6.89; N, 10.81. 
EXAMPLE 290 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[2-(1H-imidazol-1-yl)-ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phe 
nylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 290d) 
(a) Compound 290a 
##STR633## 
A mixture of imidazole (2 g; 29 mmol), ethyl bromoacetate (3.2 ml; 29 mmol) 
and K.sub.2 CO.sub.3 (8.1 g; 58 mmol) in 30 ml of DMF was heated to 
65.degree. C. for 18 h. After cooling to RT, the reaction mixture was 
filtered through a glass-fritted funnel and the filtrate was concentrated 
in vacuo. The residue was purified on a 5.times.15 cm silica gel column, 
using 5% MeOH/CH.sub.2 Cl.sub.2 as the mobile phase to afford 2.10 g (49%) 
of Compound 290a as a light orange oil. 
(b) Compound 290b 
##STR634## 
Compound 290a was converted to Compound 290b by a procedure analogous to 
that of Example 281a. 
(c) Compound 290c 
##STR635## 
Compounds 290b and 175c were reacted by a procedure analogous to that of 
Example 282a to give Compound 290c. 
(d) Compound 290d 
##STR636## 
Compounds 290c and 16b were reacted by a procedure analogous to that of 
Example 226b to give the title Compound 290d (white solid). 
m.p. 130.degree.-135.degree. C. (dec); [.alpha.].sub.365 =-14.1.degree. 
(0.33, MeOH). 
Mass Spec. CI: (M+H) 654 
Analysis calc. for C.sub.35 H.sub.51 N.sub.5 O.sub.7 .multidot.0.52 H.sub.2 
O; C, 63.38; H, 7.91; N, 10.56; Found: C, 63,31; H, 7,97; N, 10.63. 
EXAMPLE 291 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(4-hydroxy-2,2-dimethy 
l-1-oxobutyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 291d) 
(a) Compound 291a 
##STR637## 
Compound 291a was prepared as described in U.S. Pat. No. 4,732,902. 
(b) Compound 291b 
##STR638## 
To a solution of Compound 291a (2.0 g, 11.76 mmol) in DMF was added 
t-butyldimethylsilyl chloride (10.635 g, 70.56 mmol) and imidazole (8.006 
g, 117.6 mmol). The resulting mixture was stirred at RT for 24 h. MeOH 
(100 mL) was added and the reaction mixture was stirred at RT for 24 h. 
The mixture was diluted with EtOAc and washed with 10% citric acid (until 
aqueous phase had pH=2) followed by H.sub.2 O and brine. The organic phase 
was separated, dried (MgSO.sub.4) and concentrated. The crude residue was 
purified by flash chromatography on silica gel eluting with 90:9:1 
followed by 80:19:1 hexane-EtOAc-HOAc to afford Compound 291b (1.8 g, 62%) 
as a colorless oil. 
(c) Compound 291c 
##STR639## 
Compounds 291b and 54 were reacted by a procedure analogous to that of 
Example 55 to give Compound 291c. 
(d) Compound 291d 
##STR640## 
Compound 291c was converted to Compound 291d (white solid) by a procedure 
analogous to that of Example 162. 
m.p. 70.degree.-74.degree. C. (softening at 60.degree.-65.degree. C.); 
[.alpha.].sub.D =-1.2.degree. (c=1.0, CH.sub.3 OH). 
Mass Spec. (FAB) (M+H).sup.+ =558 
Analysis calc. for C.sub.31 H.sub.47 N.sub.3 O.sub.6 .multidot.0.35H.sub.2 
O: Calculated C, 66.01; H, 8.52; N, 7.45; Found: C, 65.91; H, 8.55; N, 
7.55. 
EXAMPLE 292 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy 
-1-(phenylmethyl)propyl]amino]carbonyl]propyl]carbamic acid, 
(2-benzothiazolyl)methyl ester (Compound 292b) 
(a) Compound 292a 
##STR641## 
2-Aminothiophenol and glycolic acid were reacted by a procedure analogous 
to that of Example 171a to give Compound 292a. 
(b) Compound 292b 
##STR642## 
Compound 292a and L-tert-leucine were reacted by a three-step procedure 
analogous to that used for the conversion of Compound 171a to Compound 
257c to give the title Compound 292b (colorless solid). 
m.p. 148.degree.-154.degree. C. (dec); [.alpha.].sub.D =-14.5.degree. 
(c=0.25, MeOH). 
Mass Spec. (FAB): (M+H).sup.+ =748.sup.+ 
Analysis Calcd. for C.sub.40 H.sub.53 N.sub.5 SO.sub.7 .multidot.1.78 
H.sub.2 O: C, 61.60; H, 7.31; N, 8.98; S, 4.11 Found: C, 61.62; H, 6.96; 
N, 8.96; S, 4.01 
EXAMPLE 293 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[2-hydroxy-1-oxo-2-(trifluoromethyl)p 
ropyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethylester (isomer A) (Compound 293b) 
(a) Compound 293a 
##STR643## 
1,1,1-Trifluoroacetone cyanohydrin (5 g, 39.4 mmol) was added to 5 mL conc. 
H.sub.2 SO.sub.4 with stirring at RT. The mixture was heated at 
120.degree. C. for 15 min and 20 mL ice cold water was added. After 
refluxing for 15 h, the reaction was cooled to RT, saturated with Na.sub.2 
SO.sub.4 and extracted with Et.sub.2 O. The combined Et.sub.2 O extracts 
were dried (MgSO.sub.4), the Et.sub.2 O distilled off with a vigruex 
column at atmospheric pressure and the residue sublimed (0.5 mm at 
150.degree.-200.degree. C.) to afford 4.3 g (69%) of the Compound 293a as 
a white solid. 
(b) Compound 293b 
##STR644## 
To a solution of Compound 293a (117.5 mg, 0.75 mmol) and HOBT monohydrate 
(0.135 g, 0.88 mmol) in 2 mL dry DMF at RT was added in succession 
Compound 54 (0.3 g, 0.68 mmol), N-methylmorpholine (0.1634 mL, 1.49 mmol), 
and EDCI hydrochloride (0.1434 g, 0.75 mmol). The resulting mixture was 
stirred at RT for 14 h, concentrated, and the residue partitioned between 
EtOAc and sat. NaHCO.sub.3. The organic layer was dried over MgSO.sub.4, 
concentrated, and the crude product was purified by flash chromatography 
(silica gel/CH.sub.2 Cl.sub.2 to CH.sub.2 Cl.sub.2 -MeOH-NH.sub.4 OH 
90:10:1, continuous gradient) affording 0.3 g (76%) of a mixture of the 
two diastereomeric products (at *). This mixture was subjected to prep. 
HPLC (Waters Prep Nova-Pack HR C18, 6 micron, 40.times.300 mm; eluent: 
MeOH-water-TFA 50:50:0.05 to 100:0:0.05; UV 254 nm). The desired fractions 
containing the faster eluting component were made basic with sat. 
NaHCO.sub.3, concentrated, and the residue partitioned between EtOAc/1:1 
brine-sat. NaHCO.sub.3. The organic phase was dried (MgSO.sub.4) and 
concentrated to afford 100 mg (25%) of the title Compound 293b (single 
diastereomer) as a white solid. 
m.p. 203.degree.-204.degree. C.; [.alpha.].sub.D =+1.5.degree. (c=1.2, 
MeOH). 
Mass Spec. 584 (M+H).sup.+. 
Analysis calcd. for C.sub.29 H.sub.40 N.sub.3 O.sub.6 F.sub.3.0.55H.sub.2 
O: C, 58.69; H, 6.98; N, 7.08; F, 9.60. Found: C, 58.55; H, 6.81; N, 7.22; 
F, 10.04. 
EXAMPLE 294 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[2-hydroxy-1-oxo-2-(trifluoromethyl)p 
ropyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethylester (isomer B) (Compound 294) 
##STR645## 
Preparative HPLC separation as described in Example 293b and work up of the 
fraction from the slower moving peak afforded 95 mg (24%) of the title 
Compound 294 (single diastereomer) as a white solid. 
m.p. 92.degree.-95.degree. C.; [.alpha.].sub.D =-2.5.degree. (c 0.75, 
MeOH). 
Mass Spec. 584 (M+H).sup.+. 
Analysis calcd. for C.sub.29 H.sub.40 N.sub.3 O.sub.6 F.sub.3.1.23H.sub.2 
O: C, 57.50; H, 7.06; N, 6.94; F, 9.41. Found: C, 57.70; H, 6.70; N, 6.74; 
F, 9.67. 
EXAMPLE 295 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-(hydroxyimino)-3,3- 
dimethyl-1-oxobutyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl]propyl]carb 
amic acid, 1,1-dimethylethyl ester (Compound 295) 
##STR646## 
A solution of Compound 213c (60 mg, 91% pure, 0.10 mmol) , hydroxylamine 
hydrochloride (22.5 mg, 0.324 mmol) and 3 drops of pyridine in 1.0 ml 
absolute EtOH was stirred at RT for 2 h. The reaction mixture was 
concentrated in vacuo to provide an oily residue which was purified by 
chromatography on a silica gel column (11 mm.times.20 cm) eluting with 
CH.sub.2 Cl.sub.2 -MeOH-aq. NH.sub.4 OH in a gradient from 98-1.8-0.2 to 
92-7.2-0.8 to provide 36 mg (63% yield) of Compound 295 (white solid) as a 
single isomer (oxime geometry not determined). 
m.p. 100.degree.-104.degree. C. ("softening" at 87.degree.-100.degree. C.); 
[.alpha.].sub.D =-12.4.degree.; (c=1.1, CH.sub.3 OH) 
Mass Spec. (FAB): 571 (M+H.sup.+) 
Analysis calc. for C.sub.31 H.sub.46 N.sub.4 O.sub.6 .multidot.0.87H.sub.2 
O: C, 63.49; H, 8.21; N, 9.55 Found: C, 63.47; H, 8.02; N, 9.57 
EXAMPLE 296 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-(methoxyimino)-3,3- 
dimethyl-1-oxobutyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carb 
amic acid, 1,1-dimethylethyl ester (Compound 296) 
##STR647## 
Compound 213c was reacted with methoxyamine hydrochloride by a procedure 
analogous to that of Example 295 to give the title Compound 296 (white 
solid). 
m.p. 199.degree.-201.degree. C. ("softening" at 175.degree.-198.degree. 
C.); [.alpha.].sub.D =-13.5.degree.; (c=0.38, CH.sub.3 OH) 
Mass Spec. (FAB): 585 (M+H.sup.+) 
EXAMPLE 297 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-[[4-[2-(2-pyridinyl)ethoxy]phenyl]methyl 
]propyl]-N.sup.2 -(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 297g) 
(a) Compound 297a 
##STR648## 
A solution of Compound 282c (410 mg, 1.25 mmol) in CH.sub.2 Cl.sub.2 (40 
mL) and CH.sub.3 OH (5 mL) was stirred with K.sub.2 CO.sub.3 (3 g) at RT 
for 1 h, filtered, and the filtrate concentrated in vacuo to yield the 
free amine (390 mg, ca. 95% yield) as a gummy yellow residue. This 
material was coupled to Compound 88a (350 mg, 1.31 mmol) in 2 mL DMF, 
along with 251 mg (1.31 mmol) EDCI, 177 mg (1.31 mmol) HOBT and 170 .mu.l 
(1.55 mmol) N-methylmorpholine, using a procedure analogous to that 
described in Example 93f, to give Compound 297a (421 mg, 61%). 
(b) Compound 297b 
##STR649## 
Compound 297a (420 mg, 0.729 mmol) was treated with triphenylphosphine 
(210.5 mg, 0.802 mmol) in THF (4.5 mL) and water (20 .mu.L), using a 
procedure analogous to that of Example 282e to afford Compound 297b (318 
mg, 79%) as a gummy residue. 
(c) Compound 297c 
##STR650## 
Compound 297b (314 mg, 0.571 mmol) was taken in DMF (1.0 mL) and heated 
with the Compound 1b(i) (150.2 mg, 0.571 mmol) using a procedure analogous 
to that of Example 282f to afford Compound 297c (296 mg, 63% yield) as a 
yellow residue. 
TLC(SiO.sub.2) R.sub.f =0.28 (9:1:0.1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH: aq. 
NH.sub.4 OH-Rydon) 
(d) Compound 297d 
##STR651## 
To a solution of Compound 297c (291 mg, 0.358 mmol) in DMF (1 mL), was 
added i-Pr.sub.2 NEt (130 .mu.L, 0.752 mmol) and 
2-trimethylsilylethylchloroformate (72 mg, 0.394 mmol) at 0.degree. C., 
and the mixture stirred for 2.5 h. The reaction mixture was diluted with 
EtOAc and poured into a 1:1 mixture of saturated NaHCO.sub.3 :H.sub.2 O. 
The organic layer was washed with brine, dried (MgSO.sub.4) and 
concentrated under vacuum to yield a gummy residue which was purified by 
silica gel chromatography, eluting with CH.sub.3 OH (3% to 8%)-CH.sub.2 
Cl.sub.2 to afford Compound 297d (305 mg, 89% yield) as a foamy white 
residue. 
TLC(SiO.sub.2) R.sub.f =0.53 (8% CH.sub.3 OH-CH.sub.2 Cl.sub.2 -Rydon) 
(e) Compound 297e 
##STR652## 
Compound 297d (303 mg, 0.316 mmol) in EtOH (4 mL) was treated with 20% 
Pd(OH).sub.2 /C (104 mg) under a H.sub.2 atmosphere for 18 h. The catalyst 
was filtered and the filtrate concentrated. The crude product was purified 
by silica gel chromatography, eluting with CH.sub.3 OH (2.5% to 
7.5%)-CH.sub.2 Cl.sub.2, to afford Compound 297e (185 mg, 71% yield) as a 
yellow solid. 
TLC(SiO.sub.2) R.sub.f =0.27 (8% CH.sub.3 OH-CH.sub.2 Cl.sub.2 -Rydon) 
(f) Compound 297f 
##STR653## 
To a solution of Compound 297e (85 mg, 0.103 mmol) in p-dioxane (0.8 mL) 
was added a 1:1 mixture of saturated NaHCO.sub.3 :H.sub.2 O (400 uL), 
followed by methyl chloroformate (0.114 mmol, 8.7 uL) and the mixture 
stirred at RT for 30 min. Additional methyl chloroformate was added (3.3 
eq.; 27 .mu.l total in small portions), and stirred at RT for a total of 
3.5 h. The reaction mixture was diluted with EtOAc and washed with 
saturated NaHCO.sub.3 and brine and the organic layer was dried and 
concentrated in vacuo to yield crude Compound 297f (86 mg, 94% yield) as 
as gray solid. TLC(SiO.sub.2) R.sub.f =0.25 (5% CH.sub.3 OH/CH.sub.2 
Cl.sub.2 -PMA) 
(g) Compound 297g 
##STR654## 
To a solution of Compound 297f (86 mg, 0.097 mmol) in dry THF (1 mL) was 
added n-Bu.sub.4 NF (76.6 mg, 0.293 mmol) and the reaction mixture heated 
at 45.degree. C. for 4 h. The mixture was concentrated in vacuo and 
chromatographed on silica gel, eluting with CH.sub.3 OH (2.5% to 
6.5%)-CH.sub.2 Cl.sub.2 with aq. NH.sub.4 OH (0.25% to 0.6%) to afford the 
title Compound 297g (44 mg, 62%) as a white solid 
m.p. 127.degree.-130.degree. C.; [.alpha.].sub.D =-16.degree. (c=0.2, 
CH.sub.3 OH). 
Analysis Calc. for C.sub.40 H.sub.57 N.sub.5 O.sub.8 .multidot.0.52 H.sub.2 
O Calculated: C, 64.46; H, 7.85; N, 9.40 Found: C, 64.31; H, 7.49; N, 9.55 
EXAMPLE 298 
Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[2 
Hydroxy-3-[[2-hydroxy-3-[[(2-hydroxy-1,1-dimethylethoxy)carbonyl]amino]-4- 
phenylbutyl]amino]-1-[[4-[2- 
(2-pyridinyl)ethoxy]phenyl]methyl]propyl]carbamic acid, 1,1-dimethylethyl 
ester (Compound 298e) 
(a) Compound 298a 
##STR655## 
To a solution of 1.4 g (4.6 mmol) of Compound 142a in 10 ml of dioxane was 
added 10 ml of 4N HCl in dioxane and stirred at RT for 4 hr. Removal of 
solvent afforded 1.24 g (.ltoreq.100%) of Compound 298a as a white foam. 
(b) Compound 298b 
##STR656## 
A solution of 381 mg (1.57 mmol) of Compound 298a, 579 mg (1.57 mmol) of 
Compound 161d, and 1.48 ml (8.65 mmol) of i-pR.sub.2 NEt in 10 ml of dry 
DMF was stirred at RT for 5 days. After removal of solvent the residue was 
taken into EtOAc and washed with 1N HCl and brine. The oil residue 
obtained after drying (MgSO.sub.4) and removal of solvent was purified by 
flash chromatography on silica gel (10% EtOAc-hexane) to afford 589 mg 
(86%) of Compound 298b as a white solid. 
(c) Compound 298c 
##STR657## 
A solution of 550 mg (1.26 mmol) of Compound 298b was hydrogenated 
(balloon) over 55 mg 10% Pd/C catalyst in 10 ml of MeOH at RT for 2 hr. 
After filtration of catalyst through Celite, removal of solvent gave 423 
mg (82%) of Compound 298c as a white foam. 
(d) Compound 298d 
##STR658## 
A solution of 184 mg (0.45 mmol) of Compound 298c and 165 mg (0.43 mmol) of 
Compound 282a in 1 ml of dry DMF was heated at 100.degree. C. for 7 h. 
After removal of solvent, the residue was purified by flash chromatography 
on a 35 cc column of silica gel. Elution with CHCl.sub.3 :MeOH:NH.sub.4 OH 
(95:5:0.5) afforded 113 mg (33%) of Compound 298d as a solid foam. 
TLC(SiO.sub.2) R.sub.f =0.32 CHCl.sub.3 :MeOH:NH.sub.4 OH 90:10:1) 
(e) Compound 298e 
##STR659## 
A solution of 110 mg (0.14 mmol) of Compound 298d in 1 ml HOAc:H.sub.2 
O:THF (3:1:1) was stirred at RT for 48 h. After removal of solvent, the 
residue was purified by flash chromatography on a 35 cc column of silica 
gel. Elution with CHCl.sub.3 :MeOH:NH.sub.4 OH (95:5:0.5) afforded 67 mg 
of material which was further purified by trituration with Et.sub.2 O to 
afford 60 mg (63%) of the title Compound 298e as a white powder; m.p. 
125.degree.-126.degree. C.; [.alpha.].sub.D =-3.4.degree. (c 0.82, MeOH) 
Mass Spec: (M+H).sup.+ 681.sup.+ 
Analysis Calc. for C.sub.37 H.sub.52 N.sub.4 O.sub.8 .multidot.0.87 H.sub.2 
O: C, 63.81; H, 7.78; N, 8.04. Found: C, 63.88; H, 7.53; N, 8.04. 
EXAMPLE 299 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy- 
4-[4-(2-methoxyethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl] 
carbamic acid, 1-(hydroxymethyl)-1-methylethyl ester (Compound 299b) 
(a) Compound 299a 
##STR660## 
To a solution of 200 mg (0.72 mmol) of Compound 175c, 113 .mu.l (1.44 mmol) 
of 2-methoxyethanol and 377 mg (1.44 mmol) of PPh.sub.3 in 3 ml of dry THF 
at RT, was added 226 .mu.l (1.44 mmol) of DEAD. Stirring was continued 
overnight. After removal of solvent, flash chromatography of the oil 
residue on silica gel (25 % EtOAc-hexane) afforded 198 mg (81%) of 
Compound 299a as a white solid. 
(b) Compound 299b 
##STR661## 
Compounds 298c and 299a were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 298c to Compound 298e to give the 
title Compound 299b (white solid). 
m.p. 128.degree.-130.degree. C.; [.alpha.].sub.D =-4.0.degree. (c 0.89, 
MeOH) 
Mass Spec.: (M+H).sup.+ 634.sup.+ 
Analysis Calc. for C.sub.33 H.sub.51 N.sub.3 O.sub.9 .multidot.0.42 H.sub.2 
O: C, 61.81; H, 8.15; N, 6.55. Found: C, 61.88; H, 8.21; N, 6.48. 
EXAMPLE 300 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)-carbonyl]amino]-2-hy 
droxy-4-[4-(4-methoxybutoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)p 
ropyl]carbamic acid, 1,1-dimethylethyl ester (Compound 300d) 
(a) Compound 300a 
##STR662## 
4-Penten-1-ol (1.80 ml; 17.5 mmol) was added dropwise over 1 h to a 
suspension of pentane washed NaH (770 mg 60% in oil; 19.2 mmol) in 35 ml 
of DMF at 0.degree. C. After stirring at 0.degree. C. for 30 min, methyl 
iodide (1.40 ml; 21.8 mmol) was added dropwise over 15 min and the 
reaction mixture was allowed to warm to RT. After stirring 18 h at RT, the 
excess methyl iodide was pumped off (dry ice trap). H.sub.2 O was then 
added and the mixture was extracted with Et.sub.2 O. The organic layer was 
washed with H.sub.2 O and brine, dried (MgSO.sub.4) and most of the 
Et.sub.2 O was removed at atmospheric pressure to give a concentrated 
solution of Compound 300a in Et.sub.2 O which was used without further 
purification. 
(b) Compound 300b 
##STR663## 
Compound 300a was converted to Compound 300b by a procedure analogous to 
that of Example 277b. 
(c) Compound 300c 
##STR664## 
Compounds 175c and 300b were reacted by a procedure analogous to that of 
Example 282a to give Compound 300c. 
(d) Compound 300d 
##STR665## 
Compounds 300c and 16b were reacted by a procedure analogous to that of 
Example 226b to give the title Compound 300d (white solid). 
m.p. 118.degree.-125.degree. C.; [.alpha.].sub.D =+1.4.degree. (0.59, 
MeOH). 
Mass Spec. FAB: M+H=646. 
Analysis calc. for C.sub.35 H.sub.55 N.sub.3 O.sub.8 .multidot.1.39 H.sub.2 
O: C, 62.67; H, 8.68; N, 6.26; Found: C, 62.50; H, 8.43; N, 6.43. 
EXAMPLE 301 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl] 
-2-hydroxy-2-methylpropyl]carbamic acid, phenylmethyl ester, isomer A 
(Compound 301b) 
(a) Compound 301a 
##STR666## 
Compound 239b was converted to Compound 301a by a procedure analogous to 
that of Example 205a. 
(b) Compound 301b 
##STR667## 
Compounds 301a and 54 were reactedby a procedure analogous to that of 
Example 55 (DMF only used) to give the Compound 301b along with its 
diastereomer (at .cndot.) Compound 302. Flash chromatography (silica gel, 
5 by 10.5 cm), eluting with a step-wise gradient of MeOH:NH.sub.4 
OH:CH.sub.2 Cl.sub.2 (5:0.5:94.5 to 8:0.8:91.2) followed by trituration of 
the faster moving isomer with hot Et.sub.2 O gave the title Compound 301b 
(53 mg, 17% yield) as a colorless solid. 
R.sub.f =0.39 (10:1:89 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2); m.p. 
164.degree.-166.degree. C.; [.alpha.].sub.D =+7.89.degree. (c 0.34, MeOH). 
Anal. Calc. for C.sub.38 H.sub.52 N.sub.4 O.sub.8 .multidot.0.58 H.sub.2 O 
C, 64.90; H, 7.62; N, 7.97 Found: C, 64.97; H, 7.55; N, 7.90 
EXAMPLE 302 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl] 
-2-hydroxy-2-methylpropyl]carbamic acid, phenylmethyl ester, isomer B 
(Compound 302) 
##STR668## 
Flash chromatography of the diastereomeric mixture described in Example 301 
followed by trituration of the slower moving isomer with hot Et.sub.2 O 
and with hot EtOAc gave Compound 302 (48 mg, 15% yield) as a colorless 
solid. R.sub.f =0.33 (10:1:89 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2); m.p. 
185.degree.-189.degree. C.; [.alpha.].sub.D =-17.3.degree. (c 0.15, MeOH). 
Anal. Calc. for C.sub.38 H.sub.52 N.sub.4 O.sub.8 .multidot.0.26 H.sub.2 O 
C, 65.44; H, 7.59; N, 8.03 Found: C, 65.54; H, 7.53; N, 7.93 
EXAMPLE 303 
Preparation of [1S-(1R*,2S*)]-[Iminobis[2-hydroxy 
-1-(phenylmethyl)-3,1-propanediyl]]bis[[carbamic acid], 
1-(hydroxymethyl)cyclobutyl 1,1-dimethylethyl ester (Compound 303e) 
(a) Compound 303a 
##STR669## 
Compound 303a was prepared as described in J. Am. Chem. Soc., 71, 3925 
(1949). 
(b) Compound 303b 
##STR670## 
Compound 303a was converted to Compound 303b by a procedure analogous to 
that of Example 277c. 
(c) Compound 303c 
##STR671## 
Compounds 303b and 48 were converted to Compound 303c by a two-step 
procedure analogous to that used for the conversion of Compound 149c to 
Compound 149e (DMF was used in the coupling of the p-nitrophenylcarbonate 
of Compound 303b with Compound 48). 
(d) Compound 303d 
##STR672## 
Compound 303c was converted to Compound 303d by a procedure analogous to 
that of Example 162. 
(e) Compound 303e 
##STR673## 
Compound 303d was converted to the title Compound 303e (light-brown solid) 
by a three-step procedure analogous to that used for the conversion of 
Compound 289a to Compound 289d. 
m.p. 139.degree.-145.degree. C.; [.alpha.].sub.D =-5.1.degree. (c 0.2, 
CH.sub.3 OH). 
Mass Spec.(FAB) (M+H).sup.+ =572 
Analysis calc. for C.sub.31 H.sub.45 N.sub.3 O.sub.7 .multidot.2.05H.sub.2 
O: C, 61.17; H, 8.13; N, 6.90; Found: C, 60.95; H, 7.70; N, 7.12. 
EXAMPLE 304 
Preparation of 
[1S-[1R*,2S*(2S,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydr 
oxy-4-[4-[2-(3-pyridinyloxy)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(phenylm 
ethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 304c) 
(a) Compound 304a 
##STR674## 
To a 0.degree. C. suspension of 3-hydroxypridine (1.00 g; 10.5 mmol), 
Ph.sub.3 P (7.08 g; 27.0 mmol), and bromoethanol (1.91 mL; 27.0 mmol) in 
anhydrous THF (30 mL) was added dropwise DEAD (4.25 mL; 27.0 mmol) over 15 
min, The resulting yellow solution was allowed to warm to RT and stirred 
for 36 h, Volatiles were removed in vacuo to give a yellow-brown residue, 
which was dissolved in EtOAc and Et.sub.2 O (1:1). This solution was 
extracted with aqueous 1N HCl and the aqueous extracts basified at 
0.degree. C. with excess 1M aq, NaOH, Extraction with EtOAc followed by 
drying (MgSO.sub.4) and evaporation in vacuo gave an oil which was 
purified on silica gel (150 mL) using a stepwise gradient from 3:1 to 1:2 
hexanes:EtOAc to afford Compound 304a (1.27 g; 60%) as a yellow oil. 
(b) Compound 304b 
##STR675## 
To a 0.degree. C. suspension of NaH (0.032 g of a 60% suspension in oil) in 
anhydrous DMF (1.0 mL) was added dropwise a solution of Compound 175c 
(0.200 g; 0.716 mmol) in DMF (1.0 mL), The solution was stirred at RT for 
1 h, then recooled to 0.degree. C. A solution of Compound 304a (0.167 g; 
0.827 mmol), n-Bu.sub.4 NI (0.015 g; 0.039 mmol) and 15-crown-5 (0.159 mL; 
0.80 mmol) in DMF (1.0 mL) was added dropwise. The reaction was stirred at 
RT for 24 h. Volatiles were removed in vacuo, and the residue was 
partitioned between H.sub.2 O and EtOAc. The organic extracts were washed 
with H.sub.2 O, dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to 
give an oil, which was purified on silica gel (100 mL) using a gradient 
from 3:1 to 1:3 hexane:EtOAc as eluent to give Compound 304b (0.168 g; 
59%) as a white solid. 
(c) Compound 304c 
##STR676## 
Compound 304b (0.160 g; 0.400 mmol) was reacted with Compound 16b (0.112 g; 
0.400 mmol) in DMF at 100.degree. C. for 5 h. Volatiles were removed in 
vacuo and the residue was chromatographed on silica gel (100 mL) using as 
eluent a stepwise gradient from 99:1:0.1 to 90:10:1 CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH to afford a white solid (0.125 g, 46%). This material 
was further purified by preparative HPLC on a C-18 column (6 .mu.m- 
30.times.300 cm; using a stepwise gradient from 50:50 to 75:25 A:B; 
A=90:10:0.05 MeOH:H.sub.2 O:TFA; B=90:10:0.05 H.sub.2 O:MeOH:TFA) followed 
by basification with saturated aq. NaHCO.sub.3, extraction with EtOAc, 
concentration and lyphilization from dioxane-H.sub.2 O to afford the title 
Compound 304c (0.091 g; 34%) as a white solid. 
m.p.=127.degree.-130.degree. C.; [.alpha.].sub.D =-3.5.degree. (c=0.34; 
MeOH) 
Mass Spec. (CI): (M+H).sup.+ =681; 
Analysis calc. for C.sub.37 H.sub.52 N.sub.4 O.sub.8.0.80 H.sub.2 O: C, 
63.92; H, 7.77; N, 8.06 Found: C, 64.24; H, 7.72; N, 7.74 
EXAMPLE 305 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1.1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)probyl]-N.sup.2 
-[(dimethylamino)carbonyl)-3-methyl-L-valinamide (Compound 305b) 
(a) Compound 305a 
##STR677## 
To a 0.degree. C. solution of Compound 263b (0.271 g; 0.387 mmol) in 
anhydrous CH.sub.2 Cl.sub.2 (4.0 mL) was added dimethyl carbamyl chloride 
(0.050 g; 0.464 mmol) dropwise, followed by dry Et.sub.3 N (0.129 mL, 
0.930 mmol). The reaction was allowed to warm to RT and stirred for 24 h. 
Additional dimethyl carbamyl chloride (0.040 g; 0.372 mmol) and Et.sub.3 N 
(0.100 mL; 0.718 mmol) were added and the reaction was stirred for another 
24 h. Aqueous NaHCO.sub.3 (10 mL of a 50% saturated solution) was added 
and extracted with CH.sub.2 Cl.sub.2. The combined organic extracts were 
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to give an oil, which 
was chromatographed on silica gel (150 mL) with a stepwise gradient from 
2:1 to 1:4 hexanes:EtOAc to afford Compound 305a (0.193 g; 65%) as a white 
foam. 
(b) Compound 305b 
##STR678## 
Compound 305a was converted to the title Compound 305b (white solid) by a 
procedure analogous to that of Example 21. 
m.p.=146.degree.-150.degree. C. (dec.); [.alpha.].sub.D =-12.5.degree. 
(c=0.20; MeOH). 
Mass Spec. (FAB): (M+H).sup.+ =628. 
EXAMPLE 306 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]-[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxy- 
4-[4-(2-hydroxypropoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]carbamic acid, 1,1-dimethylethyl ester (Compound 306e) 
(a) Compound 306a 
##STR679## 
To a 0.degree. C. suspension of THF-washed NaH (1.0 g of a 60% suspension 
in oil) was added dropwise a solution of methyl lactate (2.10 mL; 22.0 
mmol) in 10 mL of dry THF over 15 min. The reaction mixture was allowed to 
warm to 20.degree. C. and stirred for 30 min. The solution was cooled to 
0.degree. C. and benzyl bromide (2.97 mL;25 mmol) in 5 mL of dry THF was 
added, followed by Bu.sub.4 NI (0.092 g; 0.25 mmol). The reaction solution 
was allowed to warm to RT and stirred for 24 h. The reaction mixture was 
partitioned between H.sub.2 O and EtOAc and the combined organic extracts 
were washed with H.sub.2 O and brine and dried over Na.sub.2 SO.sub.4. 
Volatiles were removed in vacuo to give an oil, which was-purified on 
silica gel using a gradient from hexane to 10% EtOAc/hexane to afford 
Compound 306a (2.46 g; 57%) as a clear, colorless oil. 
(b) Compound 306b 
##STR680## 
Compound 306a was converted to Compound 306b by a procedure analogous to 
that of Example 281a (reaction was run at 0.degree. C. to RT). 
(c) Compound 306c 
##STR681## 
Compounds 306b and 175c were reacted by a procedure analogous to that of 
Example 282a to give Compound 306c. 
(d) Compound 306d 
##STR682## 
Compounds 306c and 16b were reacted by a procedure analogous to that of 
Example 226b to give the Compound 306d. 
(e) Compound 306e 
##STR683## 
To a suspension of 10% Pd/C (60 mg) in MeOH (2.5 mL) was added Compound 
306d (64 mg; 0.09 mmol) followed by aq. HCl (900 .mu.L of a 0.1N solution) 
and the reaction was placed under an atmosphere of H.sub.2. After 1 h, the 
reaction mixture was neutralized with 900 .mu.L of 0.1N NaOH, filtered 
through a Celite plug and concentrated in vacuo. The crude product was 
purified on silica gel using a stepwise gradient from 98:2:0.2 to 92:8:0.8 
CH.sub.2 Cl.sub.2 :MeOH: NH.sub.4 OH to afford Compound 306e (35 mg; 65%) 
as a white solid. 
m.p.=145.degree.-147.degree. C. 
Mass Spec. (CI): (M+H)=618 
Analysis calc. for C.sub.33 H.sub.51 N.sub.3 O.sub.8 .multidot.0.94 H.sub.2 
O C, 62.44; H, 8.40; N, 6.62 C, 62.89; H, 8.17; N, 6.17 
EXAMPLE 307 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]- 
2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)-propyl]amino]carb 
onyl]-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-2.2-dimethylpropyl]carbami 
c acid, phenylmethyl ester, isomer A (Compound 307e) 
(a) Compound 307a 
##STR684## 
To a solution of dihydro-4,4-dimethyl-2,3-furandione (0.5 g, 3.76 mmol) in 
HOAc (20 mL) was added KOAc (1.0 g, 0.01 mol) and then H.sub.2 NOH.HCl 
(0.70 g, 0.01 mol). After 1.2 h, the reaction mixture was partitioned 
between EtOAc and H.sub.2 O, and the aqueous layer extracted with EtOAc. 
The combined organic extracts were dried (Na.sub.2 SO.sub.4) and 
evaporated in vacuo to give Compound 307a (1.28 g, 89% yield) as a 
colorless solid. 
(b) Compound 307b 
##STR685## 
A solution of Compound 307a (710 mg, 4.96 mmol) in EtOH (3 mL) was added to 
a suspension of 180 mg of 5% Pd/C in EtOH(10 mL) and 2N HCl (5 mL) and the 
mixture stirred under a H.sub.2 atmosphere. After 4 h, the reaction 
mixture was filtered through a Nylon plug and the filtrate evaporated in 
vacuo to give Compound 307b (826 mg, .ltoreq.100% crude yield) as an oily 
solid after co-evaporation from MeOH. 
(c) Compound 307c 
##STR686## 
To a 0.degree. C. solution of Compound 307b (.ltoreq.0.82 g, .ltoreq.3.47 
mmol) in aqueous 0.83M NaHCO.sub.3 (10 mL) was added Cbz-Cl (0.50 mL, 3.26 
mmol). After 15 min, the reaction mixture was brought to RT for 3 h and a 
second portion of Cbz-rCl (0.10 mL, 0.65 mmol) was added. After a total of 
5 h, the reaction mixture was filtered, washing the solid with H.sub.2 O 
and hexanes. The solid residue was purified by flash chromatography 
(silica gel, 5 by 10 cm), eluting with 2% EtOAc:CH.sub.2 Cl.sub.2 to give 
Compound 307c (567 mg, 61% yield for the 2 steps) as a colorless solid. 
(d) Compound 307d 
##STR687## 
To a solution of Compound 307c (500 mg, 1.90 mmol) in THF (15 mL) was added 
an aqueous solution of LiOH (80 mg, 1.91 mmol). After 1.45 h the volatiles 
were evaporated in vacuo to give the lithium salt (826 mg, .ltoreq.100% 
crude yield) as an oily solid after co-evaporation with dry THF and with 
dry DMF. The crude residue (.ltoreq.1.90 mmol) was dissolved in DMF (7 mL) 
and imidazole (320 mg, 4.7 mmol) and then t-butyldimethylsilyl chloride 
(630 mg, 4.18 mmol) was added. After stirring 23 h, MeOH (8 mL) was added 
and the mixture was stirred for 21 h, then stored at -80.degree. C. After 
warming, the volatiles were removed in vacuo and the oily residue was 
partitioned between EtOAc and saturated NH.sub.4 Cl. The combined organic 
extracts were dried over Na.sub.2 SO.sub.4 and concentrated in vacuo to 
give an oil which was purified by flash chromatography (silica gel, 5 by 9 
cm), eluting with EtOAc:CH.sub.2 Cl.sub.2 (6, 7 and then 20% EtOAc 
containing 1% AcOH) to give Compound 307d (450 mg, 60% yield for the 2 
steps) as an oily solid after co-evaporation with heptane. 
(e) Compound 307e 
##STR688## 
To a solution of Compound 307d (345 mg, 0.873 mmol) and Compound 54 (410 
mg, 0.925 mmol) in DMF (6 mL) at 0.degree. C. under argon was added HOBT 
(190 mg, 1.41 mmol), EDCI (170 mg, 0.887 mmol), and then 
N-methylmorpholine (0.1 mL, 0.91 mmol). The mixture was allowed to come to 
RT and stirred for 20 h. The reaction mixture was partitioned between 
EtOAc and saturated NaHCO.sub.3, and the combined organic extracts were 
washed with brine, dried over Na.sub.2 SO.sub.4 and evaporated in vacuo to 
leave an oil. The residue was purified by flash chromatography (silica 
gel, 5 by 10 cm), eluting with a gradient of MeOH:NH.sub.4 OH:CH.sub.2 
Cl.sub.2 (2:0.2:97.8, 3:0.3:96.7, 3.5:0.35:96.15, 4:0.4:95.6, 
4.5:0.45:95.05, 0 5:0.5:94.5, and then 6:0.6:93.4) to give the title 
Compound 307e (170 mg, 47%) as a colorless glass (single isomer). R.sub.f 
(SiO.sub.2)=0.45 (10:1:89 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2); Compound 
309a was also isolated. 
EXAMPLE 308 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl] 
-2-(hydroxymethyl)-2-methylpropyl]carbamic acid, phenylmethyl ester, isomer 
A (Compound 308) 
##STR689## 
A solution of Compound 307e (162 mg, 0.197 mmol) in AcOH:THF:H.sub.2 O (5 
mL, 3:1:1) was stirred at RT for 59.5 h and the volatiles were removed in 
vacuo. The oily residue was co-evaporated once with heptane and then twice 
with heptane/CH.sub.2 Cl.sub.2 to leave an oily solid residue. The residue 
was purified by flash chromatography (silica gel, 2.5 by 18 cm), eluting 
with MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2 (6:0.6:93.4 and then 7:0.7:92.3) 
to give the title Compound 308 (98 mg, 70%) as a colorless solid. 
R.sub.f (SiO.sub.2)=0.29 (10:1:89 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2); m.p. 
68.degree.-70.degree. C.; [.alpha.].sub.D =-19.8.degree. (c 0.19, MeOH). 
(FAB): 707 (M+H). 
Analysis Calc. for C.sub.39 H.sub.54 N.sub.4 O.sub.8 .multidot.0.46 H.sub.2 
O: C, 65.51; H, 7.74; N, 7.83 Found: C, 65.45; H, 7.62; N, 7.89 
EXAMPLE 309 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbonyl] 
-2-(hydroxymethyl)-2-methylpropyl]carbamic acid, phenylmethyl ester, isomer 
B (Compound 309b) 
(a) Compound 309a 
##STR690## 
Flash chromat, ography o#the reaction mixture from Example 307e gave 
Compound 309a, the diastereomer at .cndot. of Compound 307e. R.sub.f 
(SiO.sub.2)=0.43 (10:1:89 MeOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2). 
(b) Compound 309b 
##STR691## 
Compound 309a was converted to the title Compound 309b (colorless solid) by 
a procedure analogous to that, of Example 308. 
R.sub.f (SiO.sub.2)=0.35 (10:1:89 M:eOH:NH.sub.4 OH:CH.sub.2 Cl.sub.2); 
m.p. 72.degree.-76.degree. C.; [.alpha.].sub.D =-9.72.degree. (c 0.26, 
ACOH). 
Mass Spec.: (FAB): 707 (M+H). 
Anal. Calc. for C.sub.39 H.sub.54 N.sub.4 O.sub.8 .multidot.0.47 H.sub.2 O: 
C, 65.49; H, 7.74; N, 7.83 Found: C, 65.50; H, 7.64; N, 7.82 
EXAMPLE 310 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)3,1-propanediyl]]bis[ca 
rbamic acid], 3-tetrahydrofuranyl 1,1-dimethylethyl ester (Compound 310) 
##STR692## 
3-Hydroxytetrahydrofuran and Compound 48 were reacted by a three-step 
procedure analogous to that used for the conversion of Compound 149c to 
Compound 150 (DMF was used in the coupling of the p-nitrophenylcarbonate 
with Compound 48) to give the title Compound 310 (white solid). 
m.p. 200.degree.-203.degree. C.; [.alpha.].sub.D =-11.degree. (c=0.2, 
CH.sub.3 OH) 
Analysis calc. for C.sub.30 H.sub.43 N.sub.3 O.sub.7 .multidot.0.26 H.sub.2 
O: C, 63.84; H, 8.13; N, 7.44 Found: C, 63.89; H, 7.70; N, 7.39 
EXAMPLE 311 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[(1,1-dimethylethoxy)carbonyl 
]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]ami 
nocarbonyl]propyl]carbamic acid, (2-auinoxalinyl)methyl ester (Compound 
311c) 
(a) Compound 311a 
##STR693## 
A solution of 2-hydroxymethyl quinoxaline (Lindquist, J. Chem. Soc., 2052-8 
(1956)) (160.2 mg, 1.0 mmol) in 4 ml of CH.sub.2 Cl.sub.2 was cooled to 
0.degree. C. and pyridine (87 mg, 1.1 mmol) was added followed by the 
addition of p-nitrophenylchloroformate (222 mg, 1.1 mmol) in 2 ml of 
CH.sub.2 Cl.sub.2. The mixture was stirred at 0.degree. C. for 3 h and 
slowly warmed to RT and stirred overnight. The reaction was diluted with 
EtOAc and washed with H.sub.2 O and brine. After drying over Na.sub.2 
SO.sub.4 the solvents were evaporated yielding the crude product as a 
yellow solid. The product was purified by chromatography on CC-7 (buffered 
silica, pH 6.8) eluting with EtOAc/hexane (1:1) to afford 304 mg (93%) of 
Compound 311a as a colorless solid. 
(b) Compound 311b 
##STR694## 
L-tert-Leucine (112 mg, 0.85 mmol) was dissolved in 0.85 ml of 1N NaOH and 
a solution of Compound 311a (275 mg, 0.85 mmol) in 1.5 ml of dioxane was 
added at RT followed by the addition of Et.sub.3 N (91 mg, 1.55 mmol). The 
reaction was stirred overnight, diluted with 5% KHSO.sub.4 and extracted 
with EtOAc. The combined EtOAc extracts were washed with H.sub.2 O and 
brine and the solvents evaporated yeilding the crude product as a plae 
yellow solid. The crude material was purified ona silica column eluting 
with 5-10% MeOH/CH.sub.2 Cl.sub.2 to afford 198 mg (73%) of the Compound 
311b as a colorless solid. 
(c) Compound 311c 
##STR695## 
A mixture of Compound 54 (273 mg, 0.6 mmol), Compound 311b (195 mg, 0.6 
mmol) and HOBT (94 mg, 0.6 mmol) was dissolved in 2 ml of dry DMF and the 
mixture cooled to 0.degree. C. EDCI (118 mg, 0.6 mmol) was added and the 
mixture stirred at 0.degree. C. for 3 h and then slowly allowed to warm to 
RT and stir overnight. The reaction was diluted with EtOAc and washed with 
5% KHSO.sub.4, NaHCO.sub.3, H.sub.2 O and brine. The solvents were 
evaporated and the crude residue was pruified ona silica column eluting 
with 3-5% MeOH/CH.sub.2 Cl.sub.2 +0.1% NH.sub.4 OH to afford 198 mg (44%) 
od the title Compound 311c as a colorless solid. 
m.p. 178.degree.-184.degree. C. (dec); [.alpha.].sub.D =14.5.degree. 
(c=0.25, MeOH). 
Mass Spec. (FAB): (M+H).sup.+ =743.sup.+ 
Analysis Calcd. for C.sub.14 H.sub.54 N.sub.6 O.sub.7 .multidot.0.45 
H.sub.2 O: C, 65.58 H, 7.37 N, 11.1 Found C, 65.62 H, 7.41 N, 11.15 
EXAMPLE 312 
Preparation of [1S-[1R*,2S*(2S*, 
3R*)]]-[3-[[3-[[2-(1,1-Dimethylethyl)-4-hydroxy-1-oxobutyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester, isomer A (Compound 312d) 
(a) Compound 312a 
##STR696## 
Compound 312a was prepared as described in Chem. Ber. 123, 2167-2172 
(1990). 
(b) Compound 312b 
##STR697## 
Compound 312a was converted to Compound 312b by a procedure analogous to 
that of Example 291b. 
(c) Compound 312c 
##STR698## 
To a 5.degree. C. mixture of Compound 312b (250 mg, 0.91 mmol) and HOBT 
hydrate (149 mg, 1.1 mmol) in CH.sub.2 Cl.sub.2 (1 mL ) and DMF (0.5 mL ) 
was added EDCI hydrochloride (192 mg, 1.0 mmol). The mixture was allowed 
to warm to RT and was stirred overnight. The mixture was concentrated to 
remove most of the DMF and the residue was partitioned between EtOAc and 
sat'd. aq. NaHCO.sub.3. The combined organic extracts were washed with 
H.sub.2 O and brine, dried (Na.sub.2 SO.sub.4) and concentrated to afford 
a crude residue which was purified by column chromatography on silica gel 
eluting with EtOAc-hexane (80-20) to afford 324 mg (91% yield) of Compound 
312c as a white solid. 
(d) Compound 312d 
##STR699## 
A mixture of Compound 54 (365 mg, 0.82 mmol) and Compound 312c (269 mg, 
0.69 mmol) in 1.2 mL dry DMF was heated at 75.degree.-80.degree. C. for 4 
hr. The mixture was cooled to RT and concentrated to remove most of the 
DMF. This residue was dissolved in EtOAc and the solution was washed with 
sat'd. aq. NaHCO.sub.3, H.sub.2 O, and brine, and was dried over Na.sub.2 
SO.sub.4. The solution was concentrated to afford 600 mg of a semisolid 
which was dissolved in 3 mL THF and 3 mL H.sub.2 O followed by the 
addition of 9 mL HOAc. The clear solution was stirred overnight at RT. The 
reaction mixture was concentrated and the crude product was purified by 
chromatography on silica gel eluting with a gradient of CH.sub.2 Cl.sub.2 
-MeOH-aq. NH.sub.4 OH (98:1.8:0.2 to 92:7.2:0.8) to afford the semipure 
diastereomers (at *) Compounds 312d and 313. The faster moving 
diastereomer was repurified by preparative TLC on silica gel eluting with 
CH.sub.2 Cl.sub.2 -MeOH-aq. NH.sub.4 OH (90:9:1) to afford 57 mg (14% 
yield) of the title Compound 312d (white solid). 
TLC R.sub.f (SiO.sub.2)=0.19 (CH.sub.2 Cl.sub.2 -MeOH-aq. NH.sub.4 OH 
90:9:1); 
m.p. 158.degree.-162.degree. C. ("softening" at 150.degree.-157.degree. 
C.); [.alpha.].sub.D =-0.57.degree.; (C=1.23, CH.sub.3 OH) 
Mass Spec. (FAB), 586 (M+H.sup.+) 
Analysis calc. for C.sub.33 H.sub.51 N.sub.3 O.sub.6 .multidot.0.05H.sub.2 
O: C, 67.56; H, 8.78; N, 7.16; Found: C, 67.45; H, 8.69; N, 7.27. 
EXAMPLE 313 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-(1,1-Dimethytethyl)-4-hydroxy-1-oxobuty 
l]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]ca 
rbamic acid, 1,1-dimethylethyl ester, isomer B (Compound 313) 
##STR700## 
Compound 313 (white solid) was prepared as the slower moving isomer as 
described in Example 312. 
TLC R.sub.f (SiO.sub.2)=0.13 (CH.sub.2 Cl.sub.2 -MeOH-aq. NH.sub.4 OH 
90:9:1); 
mp 140.degree.-143.degree. C.; [.alpha.].sub.D =-5.62.degree.; (c=1.30, 
CH.sub.3 OH) 
Mass Spec. (FAB), 586 (M+H.sup.+) 
Analysis calc. for C.sub.33 H.sub.51 N.sub.3 O.sub.6 .multidot.0.52H.sub.2 
O: C, 66.61; H, 8.81; N, 7.06; Found: C, 66.53; H, 8.87; N, 7.14. 
EXAMPLE 314 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-promanediyl]]bis[c 
arbamic acid], 1,1-dimethylethyl-3-methyl-3-tetrahydrofuranyl ester 
(Compound 314c) 
(a) Compound 314a 
##STR701## 
To the suspension of pyridinium chlorochromate (32 g, 0.15 mol) and 
activated 4 .ANG. molecular sieves (40 g, powder) in 200 ml of dry 
CH.sub.2 Cl.sub.2 cooled at 10.degree. C. was added a solution of 
3-hydroxytetrahydrofuran (8.9 g, 0.1 mol) in 50 ml of dry CH.sub.2 
Cl.sub.2. The mixture was stirred at RT for 2.5 h and then filtered 
through a short column of Florisil. The filtrate was evaporated by careful 
distillation of the solvent. Short-path distillation of the residue (bp: 
136.degree.-137.degree. C.) afforded 4.9 g (56%) of Compound 314a as a 
colorless liquid. 
(b) Compound 314b 
##STR702## 
Compound 314a was converted to Compound 314b by a procedure analogous to 
that of Example 258a. 
(c) Compound 314c 
##STR703## 
Compounds 314b and 48 were converted to the title Compound 314c (white 
solid) by a three-step procedure analogous to that used for the conversion 
of Compound 149c to Compound 150 (DMF was used in the coupling of the 
p-nitrophenyl carbonate of Compound 314b with Compound 48). 
m.p.: 166.degree.-167.degree. C. 
Mass Spec. (FAB): 572.sup.+ (M+H).sup.+. 
Analysis Calc. for C.sub.31 H.sub.45 N.sub.3 O.sub.7.0.18H.sub.2 O: C, 
64.75; H, 7.95; N, 7.31. Found: C, 64.77; H, 8.00; N, 7.29. 
EXAMPLE 315 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]amino]carbonyl]propyl]carbamic acid, (2-oxo-4-oxazolidinyl)methyl ester 
(Compound 315b) 
(a) Compound 315a 
##STR704## 
To a stirring solution of 2-amino-1,3-propanediol (1.58 g, 0.017 mol) in 
aqueous 1.73M KOH at 0.degree. C. (20 mL) was added a toluene solution of 
phosgene (11 mL, 0.021 mol). After warming to RT slowly overnight, the 
reaction mixture was extracted with hexanes and the aqueous layer 
evaporated at -30.degree. C. to give an oily solid residue. The residue 
was repeatedly washed with hot EtOAc and the combined washes were 
evaporated in vacuo. The resulting solid residue was co-evaporated with 
heptane to afford Compound 315a as a colorless solid (1.28 g, 63%). 
(b) Compound 315b 
##STR705## 
tert-Leucine and Compounds 315a and 54 were reacted by a three-step 
procedure analogous to that used for Example 257a through 257c to give the 
title Compound 315b (colorless solid). 
m.p. 104.degree.-114.degree. C.; [.alpha.].sub.D =-16.6.degree. (c 0.22, 
MeOH). 
Mass Spec.: (FAB): 700 (M+H). 
Analysis Calc. for C.sub.36 H.sub.53 N.sub.5 O.sub.9 : C, 61.78; H, 7.63; 
N, 10.01 Found: C, 61.62; H, 7.91; N, 9.65. 
EXAMPLE 316 
Preparation of [1S-(1R*,2S*), 
(3S-trans)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carb 
amic acid], 4-hydroxy-3-tetrahydrofuranyl 1,1-dimethylethyl ester (Compound 
316) 
##STR706## 
1,4-Anydro-L-threitol was converted to its mono-p-nitrophenyl carbonate 
which was reacted with Compound 48 by a procedure analogous to that used 
for the conversion of Compound 149c to 150 (DMF was used in the coupling 
of the p-nitrophenyl carbonate with Compound 48) to give the title 
Compound 316 (white solid). 
m.p.: 183.degree.-184.degree. C.; [.alpha.].sub.365 =-27.2.degree. (c 0.2, 
MeOH) 
Mass Spec. (FAB): 574.sup.+ (M+H).sup.+. 
Analysis Calc. for C.sub.30 H.sub.43 N.sub.3 O.sub.8 : C, 62.81; H, 7.55; 
N, 7.32. Found: C, 62.77; H, 7.72; N, 7.25. 
EXAMPLE 317 
Preparation of [1S-(1R*,2S*), 
(3R-trans)]-[Iminobis[2-hydroxy-11-(phenylmethyl)-3,1-propanediyl]]bis[car 
bamic acid], 4-hydroxy-3-tetrahydrofuronyl 1,1-dimethylethl ester (Compound 
317) 
##STR707## 
1,4-Anydro-D-threitol (prepared from D-threitol [Terfort, Synthesis, 951 
(1992)] according to Otey et al., J. Org. Chem., 26, 1673 (1961)) was 
converted to its mono-p-nitrophenyl carbonate which was reacted with 
Compound 48 by a procedure analogous to that used for the conversion of 
Compound 149c to 150 (DMF was used in the coupling of the p-nitrophenyl 
carbonate with Compound 48) to give the title Compound 317 (white solid). 
m.p.: 181.degree.-182.degree. C.; [.alpha.].sub.D =-31.3.degree. (c 0.63, 
MeOH). 
Mass Spec. (FAB): 574.sup.+ (M+H).sup.+. 
Analysis Calc. for C.sub.30 H.sub.43 N.sub.3 O.sub.8.0.45 H.sub.2 O: C, 
61.93; H, 7.61; N, 7.22. Found: C, 62.01; H, 7.55; N, 7.14. 
EXAMPLE 318 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]bis[c 
arbamic acid], 1,1-dimethylethyl-3-tetrahydropyranyl ester 
(Compound 318) 
##STR708## 
3-Hydroxytetrahydropyran (Zweifel et al., J. Org. Chem., 35, 898-902 
(1970)) and Compound 48 were reacted by a procedure analogous to that used 
for the conversion of Compound 149c to 150 (DMF was used in the coupling 
of the p-nitrophenyl carbonate with Compound 48) to give the title 
Compound 318 (colorless solid). 
m.p. 185.degree.-187.degree. C.; [.alpha.].sub.D =-1.80.degree. (c 0.36, 
CHCl.sub.3). 
MS: (FAB): 572 (M+H). 
Anal. Calc. for C.sub.31 H.sub.45 N.sub.3 O.sub.7 . 0.09 H.sub.2 O C, 
64.95; H, 7.94; N, 7.35 Found: C, 64.68; H, 8.00; N, 7.33. 
EXAMPLE 319 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)3,1-propanediyl)]bis[ca 
rbamic acid], 1,1-dimethylethyl 4-oxetanyl ester 
(Compound 319c) 
(a) Compound 319a 
##STR709## 
Compound 319a was prepared as described in Baum et al., J. Org. Chem., 48, 
2953-2956 (1983). 
Compound 319b 
##STR710## 
To a solution of Compound 319a (670 mg, 4.58 mmol) in MeOH (7 mL) was added 
pyridinium p-tosylate (277 mg, 5 mmol). After 4 h NaHCO.sub.3 (150 mg) was 
added and the volatiles were evaporated in vacuo to give an oily solid 
residue which was purified by flash chromatography (silica gel, 3 by 15 
cm), eluting with MeOH:CH.sub.2 Cl.sub.2 (3 and then 3.5% MeOH) to give 
Compound 319b (148 mg, 44%) as an oil. 
(c) Compound 319c 
##STR711## 
Compounds 319b and 48 were reacted by a procedure analogous to that used 
for the conversion of Compound 149c to 150 (DMF was used in the coupling 
of the p-nitrophenyl carbonate with Compound 48) to give the title 
Compound 319c (colorless solid). 
m.p. 196.degree.-199.degree. C.; [.alpha.].sub.D =-9.06.degree. (c 0.23, 
MeOH). 
Mass Spec.: (FAB): 544 (M+H). 
Analysis Calc. for C.sub.29 H.sub.41 N.sub.3 O.sub.7 : C, 64.07; H, 7.60; 
N, 7.73 Found: C, 63.99; H, 7.74; N, 7.63. 
EXAMPLE 320 
Preparation of 
[S-[1R*,2S*,(2S*,3R*)]-[2,2-Dimethyl-1-[[[3-[[3-(1,1-dimethylethoxy)carbon 
yl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]a 
mino]carbonyl]propyl]methylcarbamic acid, methyl ester 
(Compound 320c) 
(a) Compound 320a 
##STR712## 
Compound 246a was converted to Compound 320a by a procedure analogous to 
that of Example 66a. 
(b) Compound 320b 
##STR713## 
Compound 320a was converted to Compound 320b by a procedure analogous to 
that of Example 70c (no acid work-up). 
(c) Compound 320c 
##STR714## 
Compounds 320b and 54 were reacted by a procedure analogous to that of 
Example 93f to give the title Compound 320c (white solid). 
m.p.=78.degree.-81.degree. C. 
Mass Spec. (CI): (M+H)=629 
Analysis Calc. for C.sub.34 H.sub.52 N.sub.4 O.sub.7 . 1.35 H.sub.2 O: C, 
62.52; H, 8.44; N, 8.58 Found: C, 62.74; H, 8.27; N, 8.36. 
EXAMPLE 321 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclopentyl)carbony 
l]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]ca 
rbamic acid, 1,1-dimethylethyl ester, isomer A 
(Compound 321d) 
(a) Compound 321a 
##STR715## 
A suspension of anhydrous cerium (III) chloride (4.25 g; 17 mmol) in 
freshly distilled THF was stirred at RT for 2 h. After cooling this 
suspension to -78.degree. C., vinylmagnesium bromide (17 ml 1.0M in THF; 
17 mmol) was added dropwise over .about.15 min. The resulting light orange 
suspension was stirred at -78 .degree. C. for 1.5 h. After this time 
2,2-dimethylcyclopentanone (1.27 g; 11 mmol) was added and the reaction 
mixture was stirred for 1.5 h at -78.degree. C. Saturated NH.sub.4 Cl 
solution (50 ml) was added and the mixture was allowed to warm to RT with 
stirring. The mixture was partitioned between Et.sub.2 O and H.sub.2 O. 
The organic layer was washed with H.sub.2 O and brine, dried (MgSO.sub.4), 
and most of the solvent removed in vacuo to afford 3.38 g of a light 
yellow liquid. This liquid was .about.50% by wt. a solution of Compound 
321a in THF and was used in the subsequent step without further 
purification. 
(b) Compound 321b 
##STR716## 
Ozone/oxygen was bubbled through a solution of Compound 321a (1.6 g; 50% by 
wt. in THF; 5.6 mmol) and NaHCO.sub.3 (42 mg) in 50 ml of MeOH at 
-78.degree. C. for .about.10 min. After purging the solution for 15 min, 
Me.sub.2 S (4.5 ml) was added. After warming to RT, the mixture was 
stirred for 1 h and the volatiles removed in vacuo. The residue was 
partitioned between Et.sub.2 O and H.sub.2 O and the organic layer washed 
with brine and dried (MgSO.sub.4). Concentration afforded 760 mg (96%) of 
Compound 321b as a colorless liquid. 
(c) Compound 321c 
##STR717## 
Sodium chlorite (746 mg; 6.6 mmol; 80% pure) was added to a rapidly 
stirring mixture of Compound 321b (720 mg; 5.06 mmol) and sulfamic acid 
(641 mg; 6.6 mmol) in 5 ml of H.sub.2 O and 5 ml of THF at 0.degree. C. 
After stirring at 0.degree. C. for 30 min, 0.5 ml of Me.sub.2 S was added 
followed by 20 ml of 1N NaOH. This mixture was extracted with Et.sub.2 O 
and the aqueous layer acidified to pH .about.1.5 with saturated 
KHSO.sub.4, saturated with NaCl, and extracted with EtOAc. The combined 
organic extracts were washed with brine and dried (MgSO.sub.4). 
Concentration afforded a solid which was recrystallized from hexane to 
afford 456 mg (57%) of Compound 321c as a colorless solid. 
(b) Compound 321d 
##STR718## 
BOP-reagent (265 mg; 0.60 mmol) was added in one portion to a solution of 
Compound 321c (90 mg; 0.569 mmol), Compound 54 (252 mg; 0.569) and 
N-methylmorpholine (66 .mu.l; 0.60 mol) at 0.degree. C. in 1 ml of DMF. 
The reaction mixture was allowed to warm to RT and stir 16 h. After 
diluting with EtOAc, the organic phase was washed with H.sub.2 O, 
saturated aq. NaHCO.sub.3 and brine. After drying (MgSO.sub.4), the 
solvent was removed in vacuo. The residue was chromatographed on a 
5.times.12 cm silica gel column eluting with 2% MeOH/CH.sub.2 Cl.sub.2 
followed by a gradient of 3-7% MeOH/CH.sub.2 Cl.sub.2 +0.3-0.7% NH.sub.4 
OH in 0.5% and 0.05% increments respectively. The slower moving isomer (at 
*) was rechromatographed on a 2.5.times.15 cm silica gel column with 
elution as above followed by trituration with Et.sub.2 O which afforded 23 
mg (7%) of Compound 321d as a white solid. 
R.sub.f =0.25, CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA 
detection); m.p. 108.degree.-111.degree. C.; [.alpha.].sub.D 
=-15.2.degree. (c 0.25, MeOH). 
Mass Spec. FAB: M+H=584. 
Analysis calc. for C.sub.33 H.sub.49 N.sub.3 O.sub.6.0.57 H.sub.2 O: C, 
66.73; H, 8.51; N, 7.07; Found C, 66.66; H, 8.44; N, 7.14. 
EXAMPLE 322 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclopentyl)carbony 
l]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]ca 
rbamic acid, 1,1-dimethylethyl ester, isomer B 
(Compound 322) 
##STR719## 
The faster moving isomer from Example 321d was rechromatographed on a 
2.5.times.25 cm silica gel column using 1% MeOH/CH.sub.2 Cl.sub.2 followed 
by 2% MeOH/CH.sub.2 Cl.sub.2 then 2.5% MeOH/CH.sub.2 Cl.sub.2 and finally 
a gradient of 3-5% MeOH/CH.sub.2 Cl.sub.2 +0.3-0.5% NH.sub.4 OH in 0.25% 
and 0.025% increments respectively. Concentration and trituration with 
Et.sub.2 O afforded 41 mg (12%) of Compound 322 as a white solid. 
R.sub.f =0.28, CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA 
detection); m.p. 185.degree.-190.degree. C.; [.alpha.].sub.D 
=+15.5.degree. (c 0.33, MeOH). 
Mass Spec. FAB: M+H=584. 
Analysis calc. for C.sub.33 H.sub.49 N.sub.3 O.sub.6.1.17 H.sub.2 O: C, 
65.53; H, 8.56; N, 6.95; Found C, 65.45; H, 8.25; N, 7.03. 
EXAMPLE 323 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]amino]carbonyl]propyl]carbamic acid, (2-furo[3,2-b]pyridinyl)methyl ester 
(Compound 323f) 
(a) Compound 323a 
##STR720## 
Compound 323a was prepared as described in Shiotani et al., J. Het. Chem., 
23, 665 (1986). 
(b) Compound 323b 
##STR721## 
Compound 323a was converted to Compound 323b by the method described in 
Morita et al., J. Heter. Chem. 24, 373, (1987). 
(c) Compound 323c 
##STR722## 
To a solution of Compound 323b (1.5 g, 10.195 mmol) in 100 mL of 3:3:4 
THF-EtOH-CHCl.sub.3 cooled to 0.degree. C. was added NaBH.sub.4 (0.675 g, 
17.841 mmol) in portions. After the addition was complete, the mixture was 
stirred at 0.degree. C. for 30 min, diluted with H.sub.2 O and extracted 
with CH.sub.2 Cl.sub.2. The combined extracts were dried (MgSO.sub.4) and 
concentrated. The crude residue was flash chromatographed on silica gel 
eluting with a stepwise gradient of 25% to 100% EtOAc-hexane to afford 
Compound 323c (1.42 g, 93%) as a beige solid. 
(d) Compound 323d 
##STR723## 
To a solution of Compound 323c (0.745 g, 5 mmol) in 30 mL of CH.sub.2 
Cl.sub.2 cooled to 0.degree. C. was added 2 mL of pyridine followed by 
p-nitrophenylchloroformate (1.008 g, 5 mmol) as a solid. The reaction 
mixture was stirred for 16 h at RT, diluted with EtOAc and washed with 
sat. NaHCO.sub.3 and brine. The organic phase was dried (MgSO.sub.4) and 
concentrated to obtain Compound 323d (1.56 g, 99%; crude yield) containing 
traces of p-nitrophenylchloroformate and p-nitrophenol. 
(e) Compound 323e 
##STR724## 
Compound 323d (0.75 g; 2.38 mmol) in 5 mL of dioxane was added to a 
solution of L-tert-leucine (0.314 g; 2.38 mmol) in 2.4 mL of 1N NaOH at RT 
followed by the addition of Et.sub.3 N (365 .mu.L; 2.62 mmol). After 5 h 
at RT, the reaction mixture was diluted with 10% KHSO.sub.4 and extracted 
with EtOAc. The organic extracts were washed with H.sub.2 O and brine, 
dried (MgSO.sub.4) and concentrated. Flash chromatography on silica gel of 
the crude residue (CH.sub.2 Cl.sub.2 followed by 5% then 10% MeOH/CH.sub.2 
Cl.sub.2 +0.5% HOAc) afforded 0.28 g (38%) of Compound 323e as a beige 
solid. 
(f) Compound 323f 
##STR725## 
To a 0.degree. C. solution of Compound 323e (0.173 g; 0.56 mmol) in 3 mL of 
CH.sub.2 Cl.sub.2 was added HOBT (0.115 g; 0.84 mmol) followed by EDCI 
(0.114 g; 0.59 mmol). After 30 min, Compound 54 (0.25 g; 0.56 mmol) was 
added followed by 0.5 mL of DMF. The reaction mixture was stirred at 
0.degree. C. for 30 min and at RT for 40 h, at which time it was diluted 
with CH.sub.2 Cl.sub.2, and washed with H.sub.2 O, sat. aq. NaHCO.sub.3 
and brine. The organic extracts were dried (MgSO.sub.4), concentrated, and 
the resulting residue purified by flash chromatography on silica gel, 
eluting with a gradient of 98.9:1:0.1 to 89:10:1 CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, to afford 0.26 g (65%) of the title Compound 323f as a 
white solid. 
m.p. 108.degree.-112.degree. C. (softening at 95.degree.-105.degree. C.); 
[.alpha.].sub.D =-16.5.degree. (c=0.2, CH.sub.3 OH). 
Mass Spec. (FAB) (M+H).sup.+ =732 
Analysis calc. for C.sub.40 H.sub.53 N.sub.5 O.sub.8 . 1.77 H.sub.2 O: C, 
62.91; H, 7.46; N, 9.17; Found: C, 62.91; H, 7.17; N, 9.17. 
EXAMPLE 324 
Preparation of 
1S-(1S*,2R*)-N,N'-Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]bis( 
imino)bis[1-(1,1-dimethylethyl)-2-oxo-2,1-ethanediyl]]biscarbamic acid, 
dimethyl ester 
(Compound 324) 
##STR726## 
Compounds 74 and 246a were reacted by a procedure analogous to that of 
Example 75f to give the title Compound 324 (colorless solid). 
m.p. 98.degree.-102.degree. C.; [.alpha.].sub.D =-37.7.degree. (c 0.25, 
CHCl.sub.3). 
Mass Spec.: (FAB): 686 (M+H). 
Anal. Calc. for C.sub.36 H.sub.55 N.sub.5 O.sub.8 . 0.73 H.sub.2 O C, 
61.86; H, 8.14; N, 10.02 Found: C, 61.86; H, 8.09; N, 10.06 
EXAMPLE 325 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[(2-methoxy-3,3-dimethy 
l-1-oxobutyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester 
(Compound 325b) 
(a) Compound 325a 
##STR727## 
Through a solution of 4,4-dimethyl-3-methoxy-1-pentene (J. Am. Chem. Soc., 
109, 3353, (1987); 0.512 g, 4 mmol) in 10 mL of CH.sub.2 Cl.sub.2 cooled 
to -78.degree. C. was bubbled O.sub.3 for a period of 2 h until a light 
blue color persisted. To the mixture was added Me.sub.2 S (1.468 mL, 20 
mmol) and the yellow solution stirred at RT for 2 h at which point most of 
the solvent was distilled off. The resulting aldehyde was then converted 
to Compound 325a by a procedure analogous to that of Example 262e. 
(b) Compound 325b 
##STR728## 
Compounds 325a and 54 were reacted by a procedure analogous to that of 
Example 55 to give the title Compound 325b (white solid). 
m.p. 153.degree.-162.degree. C.; 
Mass Spec. (FAB) (M+H).sup.+ =572 
Analysis calc. for C.sub.32 H.sub.49 N.sub.3 O.sub.6.0.58 H.sub.2 O: C, 
66.02; H, 8.68; N, 7.22; Found: C, 65.99; H, 8.56; N, 7.25. 
EXAMPLE 326 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]amino]carbonyl]propyl]carbamic acid, (2-phenyloxy)ethyl ester 
(Compound 326) 
##STR729## 
2-Phenoxyethanol was converted to its p-nitrophenyl carbonate which was 
reacted with tert-leucine and the resulting product coupled with Compound 
54 by a three-step procedure analogous to that used for Example 257a 
through 257c to give the title Compound 326 (colorless solid). 
m.p. 138.degree.-140.degree. C. (shrinks 120.degree. C.); [.alpha.].sub.D 
=-20.4.degree. (c 0.3, CHCl.sub.3). 
Mass Spec.: (FAB): 721 (M+H). 
Anal. Calc. for C.sub.36 H.sub.53 N.sub.5 O.sub.9 . 0.31 H.sub.2 O C, 
66.13; H, 7.86; N, 7.71 Found: C, 66.09; H, 7.85; N, 7.75. 
EXAMPLE 327 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-[4-[2-(2-pyridinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-phenylmethyl) 
propyl]-N.sup.2 -(methoxycarbonyl)-3-methyl-L-valinamide 
(Compound 327c) 
(a) Compound 327a 
##STR730## 
To an ice cooled solution, under argon, of 608 mg (2.5 mmol) of Compound 
298a, 520 mg (2.75 mmol) of Compound 246a, 371 mg (2.75 mmol) of HOBT and 
905 .mu.l of N-methylmorpholine in 12.5 ml of DMF was added 528 mg (2.75 
mmol) of EDCI. Stirring was continued with cooling for 1 h, then at RT 
overnight. The solution was evaporated to dryness (30.degree. C., high 
vacuum) and the residue taken into EtOAc and washed with brine, 1N HCl, 
brine, sat. NaHCO.sub.3, and brine. After drying (MgSO.sub.4), removal of 
solvent afforded 1.03 g of Compound 327a as a solid white foam. 
(b) Compound 327b 
##STR731## 
A solution of 250 mg (0.66 mmol) of Compound 327a in 8 ml of EtOH, 
containing 25 mg of 10% Pd on carbon catalyst, was stirred under an 
atmosphere of H.sub.2 for 4 h. After removal of catalyst by filtration 
through Celite, removal of solvent gave a solid foam residue which was 
recrystallized from CHCl.sub.3 to afford 108 mg (47% yield over 2 steps) 
of Compound 327b as a white powder. 
(c) Compound 327c 
##STR732## 
A solution of 246 mg (0.70 mmol) of Compound 327b and 250 mg (0.65 mmol) of 
Compound 282a in 1 ml of DMF, under argon, was heated at 100.degree. C. 
for 5 h. The solvent was removed (30.degree. C., high vacuum) and the 
residue purified by flash chromatography on a 130 cc column of silica gel. 
Elution with CHCl.sub.3 :MeOH:NH.sub.4 OH (95:5:0.5) followed by 
recrystallization from hot EtOAc afforded 170 mg of Compound 327c as a 
white solid. 
m.p. 139.degree.-141.degree. C.; [.alpha.].sub.D =-15.9.degree. (c 0.92, 
MeOH) 
Mass Spec.: (M+H).sup.+ 736.sup.+ 
Analysis Calc. for C.sub.40 H.sub.57 N.sub.5 O.sub.8 . 0.46 H.sub.2 O: C, 
64.56; H, 7.84; N, 9.41. Found: C, 64.82; H, 7.87; N, 9.41. 
EXAMPLE 328 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2 
-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]-2-oxo 
-1-(trifluoromethyl)ethyl]carbamic acid, phenylmethyl ester 
(Compound 328b) 
(a) Compound 328a 
##STR733## 
Compound 328a was prepared from D,L-trifluoromethyl alanine by a procedure 
analogous to that of Example 85a. 
(b) Compound 328b 
##STR734## 
Compounds 328a and 48 were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 48 to 52 to give the title 
Compound 328b (white solid). 
m.p. 166.degree.-169.degree. C.; [.alpha.].sub.D =-5.7.degree. (c=0.21, 
CH.sub.3 OH) 
Analysis calculated for: C.sub.36 H.sub.45 N.sub.4 O.sub.7 F.sub.3 . 1.21 
H.sub.2 O C, 59.68; H, 6.60; N, 7.73; F, 7.87 Found: C, 59.74; H, 6.47; N, 
7.67; F, 7.81 
EXAMPLE 329 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1-Amino-2,2,2-trifluoroethyl)carbonyl]am 
ino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbam 
ic acid, 1,1-dimethylethyl ester 
(Compound 329) 
##STR735## 
Compound 328b was converted to the title Compound 329 by a procedure 
analogous to that of Example 19. 
m.p. 152.degree.-155.degree. C. 
EXAMPLE 330 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-hydroxy-3-[[2-hydroxy-3-[[(tetrahydro-3-hydroxy 
-3-furanyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carb 
amic acid, 1,1-dimethylethyl ester 
(Compound 330b) 
(a) Compound 330a 
##STR736## 
To a solution of Compound 314a (2.02 g, 23.46 mmol) in CH.sub.2 Cl.sub.2 
(2.5 mL) was added trimethylsilyl cyanide (4.06 mL, 30.50 mmol), ZnI.sub.2 
(0.22 g, 0.70 mmol) and the solution stirred at RT for 18 h. The reaction 
mixture was purged with a stream of nitrogen, concentrated in vacuo and 
taken in concentrated HCl (6 mL) and heated at reflux for 2 h. After 
cooling to RT, the mixture was saturated with Na.sub.2 SO.sub.4 and 
extracted with EtOAc, dried (MgSO.sub.4) and concentrated in vacuo to 
yield a brown gummy oil. The crude product was combined with another batch 
(1.06 g, 12.3 mmol) of similar crude material and partially purified by 
silica gel chromatography, eluting with CH.sub.3 OH (5% to 60%)--CH.sub.2 
Cl.sub.2 (with 1 to 2% HOAc). The product was taken in 3N NaOH and washed 
with Et.sub.2 O. The aqueous layer was acidified to pH ca. 2 by addition 
of 6N HCl, saturated with Na.sub.2 SO.sub.4, and extracted repeatedly with 
EtOAc. The combined organic layer was dried (MgSO.sub.4), and concentrated 
in vacuo to afford Compound 330a (2.5 g, 52% overall yield) as a brown 
oil. 
(b) Compound 330b 
##STR737## 
Compounds 330a and 54 were reacted by a procedure analogous to that of 
Example 262f to give the title Compound 330b. 
m.p. 119.degree.-122.degree. C.; [.alpha.].sub.D =-3.5.degree. (c=0.2, 
CH.sub.3 OH) 
Analysis calculated for: C.sub.30 H.sub.43 N.sub.3 O.sub.7 . 0.45 H.sub.2 O 
C, 63.68; H, 7.82; N, 7.43 Found: C, 63.63; H, 7.79; N, 7.48 
EXAMPLE 331 
Preparation of 
[1S-(1R*,2S*,3R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]b 
is[carbamic acid], 3-tetrahydrofuranyl 1,1-dimethylethyl ester 
(Compound 331c) 
(a) Compound 331a 
##STR738## 
To a solution of (S)-(+)-3-hydroxytetrahydrofuran (441 mg, 5.0 mmol) in 15 
mL of CH.sub.2 Cl.sub.2 -pyridine (5:1) cooled at 0.degree. C. was added a 
solution of para-nitrophenylchloroformate (1.0 g, 5.0 mmol) in 12.5 mL of 
CH.sub.2 Cl.sub.2. The reaction was stirred at 0.degree. C. for 1.0 h, 
then at RT overnight. The reaction mixture was diluted with EtOAc and the 
organic layer was washed with sat. aq. NaHCO.sub.3 and brine, and dried 
(Na.sub.2 SO.sub.4). Flash chromatography (hexane-EtOAc: 10:1 to 2:1) on 
silica gel afforded 1.25 g (99%) of Compound 331a as a colorless liquid. 
(b) Compound 331b 
##STR739## 
To a solution of Compound 48 (200 mg, 0.340 mmol) in 0.25 mL DMF was added 
i-Pr.sub.2 NEt (220 mg; 1.7 mmol), followed by Compound 331a (112 mg, 
0.442 mmol) in DMF (0.3 mL). After stirring overnight at RT, the reaction 
was concentrated in vacuo and diluted with EtOAc. After washing with aq. 
1N NaOH, sat. aq. NaHCO.sub.3 and brine, the organic phase was dried 
(MgSO.sub.4) and concentrated in vacuo. The crude material was purified by 
flash chromatography on silica gel, eluting with a gradient from 0.5-5% 
MeOH/CH.sub.2 Cl.sub.2 to afford 0.2 g (83%) of a yellow foam. 
Mass Spec. (Fab): (M+H).sup.+ 702.sup.+. 
(c) Compound 331c 
##STR740## 
To Compound 331b (200 mg, 0.284 mmol) in THF (2 mL) was added solid 
n-Bu.sub.4 NF.nH.sub.2 O (223 mg, 0.854 mmol) and the mixture stirred at 
50.degree. C. for 5 h. The reaction was concentrated in vacuo, the residue 
dissolved in EtOAc, and washed with sat. aq. NaHCO.sub.3 and brine. The 
organic phase was dried (MgSO.sub.4) and concentrated in vacuo to give a 
solid which was purified by flash chromatography on silica gel, eluting 
with a gradient from 98.5:1.5:0.15 to 92.5:7.5:0.75 CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, to afford the title Compound 331c (102 mg, 64%) as a 
white solid. 
m.p. 200.degree.-202.degree. C.; [.alpha.].sub.D =-14.5.degree. (c=0.2, 
CH.sub.3 OH) 
Mass Spec. (CI): (M+H).sup.+ 558. 
Analysis calculated for: C.sub.30 H.sub.43 N.sub.3 O.sub.7 . 1.70 H.sub.2 O 
C, 61.08; H, 7.96; N, 7.12. Found: C, 61.10; H, 7.45; N, 7.10. 
EXAMPLE 332 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[2-oxo-2-(1-tetrahydropyranyl)ethoxy]phenyl]butyl]amino]-2-hydrox 
y-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 332c) 
(a) Compound 332a 
##STR741## 
Bromoacetyl bromide (0.87 g, 10 mmol) was added dropwise to a stirring 
solution of piperidine (2.03 ml, 20.60 mmol) in anhydrous Et.sub.2 O (21 
ml) at 0.degree. C. After 20 min, the reaction was filtered, and the solid 
washed with Et.sub.2 O. The filtrate was concentrated in vacuo and the 
crude material chromatographed on a CC.sub.7 column, eluting with EtOAc, 
to afford 1.27 g (62%) of Compound 332a as a yellow oil. 
(b) compound 332b 
##STR742## 
Compounds 175c and 332a were reacted by a procedure analogous to that of 
Example 226a to give Compound 332b. 
(c) Compound 332c 
##STR743## 
Compounds 16b and 332b were reacted by a procedure analogous to that of 
Example 226b to give the title Compound 332c (colorless solid). 
m.p. 116.degree.-118.degree. C.; [.alpha.].sub.D =-6.0.degree. (c, 0.10 
MeOH). 
Mass spec.: (M+H) 685. 
Analysis calc. for C.sub.37 H.sub.56 N.sub.4 O.sub.8 . 0.53 H.sub.2 O. C, 
64.00; H, 8.28; N, 8.07; Found: C, 64.05; H, 8.43; N, 8.02. 
EXAMPLE 333 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-Hydroxy-2,3,3-trimethyl-1-oxobutyl) 
amino]-2-hydroxy-4-phenylbutyl]amino-2-hydroxy-1-(phenylmethyl)propyl]carba 
mic acid, 2-hydroxy-1,1-dimethylethyl ester 
(Compound 333d) 
(a) Compound 333a 
##STR744## 
To a solution of Compound 298c (380 mg, 0.93 mmol) in DMF (0.5 mL) was 
added Compound 44a (276 mg, 0.93 mmol) and the solution heated at. 
100.degree. C. for 4 h. The reaction mixture was cooled to RT and DMF 
removed in vacuo. Purification by silica gel chromatography, eluting with 
a stepwise gradient from 99.5:0.5:0.05 to 90:10:1 CH.sub.2 Cl.sub.2 
:CH.sub.3 OH:aq.NH.sub.4 OH afforded Compound 333a (367 mg, 55% yield) as 
a white residue. 
Mass Spec: (M+H).sup.+ =708. 
(b) Compound 333b 
##STR745## 
To a solution of Compound 333a (365 mg, 0.52 mmol) in EtOH (14 mL) and 
EtOAc (3.5 mL) was added 20% Pd(OH).sub.2 /C (110 mg total added in three 
portions over the reaction) and the slurry stirred under a H.sub.2 
atmosphere overnight. Filtration, evaporation, and trituration of the 
resulting solid gave Compound 333b (230 mg, 77% yield) as a white solid. 
Mass Spec: (M+H).sup.+ =574 
(c) Compound 333c 
##STR746## 
To a solution of Compound 333b (127 mg, 0.22 mmol) in DMF (0.25 mL) was 
added a solution of Compound 262e (35.6 mg, 0.243 mmol) in 0.25 mL DMF, 
followed by BOP reagent (107.5 mg, 0.243 mmol) and N-methylmorpholine 
(53.45 .mu.L) and the reaction stirred for 36 h. The DMF was evaporated in 
vacuo and the residue dissolved in EtOAc which was washed with satd. 
NaHCO.sub.3 and brine and dried (MgSO.sub.4). Silica gel chromatography 
eluting with a stepwise gradient from 98:2:0.2 to 90:10:1 CH.sub.2 
Cl.sub.2 :CH.sub.3 OH:aq.NH.sub.4 OH afforded Compound 333c (105 mg, 67% 
yield) as a solid. 
Mass Spec: (M+H).sup.+ =702 
(d) Compound 333d 
##STR747## 
To a solution of Compound 333c (103 mg, 0.146 mmol) in THF (1.5 mL) was 
added H.sub.2 O (0.5 mL) and HOAc (0.5 mL) and the reaction mixture 
stirred at RT for 2 d. Evaporation to dryness, azeotroping with H.sub.2 O 
and purification by silica gel chromatography eluting with a stepwise 
gradient from 98:2:0.2 to 90:10:1 CH.sub.2 Cl.sub.2 :CH.sub.3 
OH:aq.NH.sub.4 OH afforded the title Compound 333d (74 mg, 86% yield) as a 
white solid. 
m.p. 185.degree.-188.degree. C.; [.alpha.].sub.D =+19.5.degree. (c=0.2, 
CH.sub.3 OH) 
Mass spec. (CI): (M+H).sup.+ 588.sup.+. 
Analysis calc. for: C.sub.32 H.sub.49 N.sub.3 O.sub.7 . 0.75 H.sub.2 O C, 
63.93; H, 8.47; N, 6.99 Found: C, 63.93; H, 8.32; N, 7.11 
EXAMPLE 334 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-Hydroxy-3,3-dimethyl-1-oxobutyl)ami 
no]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester 
(Compound 334) 
##STR748## 
To an ice cooled solution of 73 mg (0.55 mmol) of 
(R)-3,3-dimethyl-2-hydroxybutanoic acid (Ito et al., Synthesis, 137 
(1993)), 244 mg (0.55 mmol) of Compound 54, 111 mg (0.83 mmol) of HOBT and 
121 .mu.l (1.1 mmol) of N-methylmorpholine was added 105 mg (0.55 mmol) of 
EDCI as a solid. Stirring was continued with cooling for 1 h, then at RT 
overnight. The resulting solution was then added with stirring to an 
ice-sat. NaHCO.sub.3 mixture. The resulting precipitate was filtered and 
washed with H.sub.2 O. The crude product was taken into CH.sub.2 Cl.sub.2, 
dried (MgSO.sub.4), and the solution placed on a 50 cc column of silica 
gel. Elution with CHCl.sub.3 :MeOH:NH.sub.4 OH (95:5:0.5) afforded impure 
product. This material was recrystallized from CH.sub.2 Cl.sub.2 and then 
rechromatographed on a 100 cc column of silica gel. A gradient elution 
with CHCl.sub.3 :MeOH:NH.sub.4 OH (95:5:0.1 to 0.5) afforded 20 mg of 
Compound 334 as a white powder. 
m.p. 175.degree.-176.degree. C.; [.alpha.].sub.D =+1.1.degree. (c 0.08, 
MeOH). 
Mass. Spec.: (M+H).sup.+ 558.sup.+ 
Analysis Calc. for C.sub.31 H.sub.47 N.sub.3 O.sub.6 . 0.25 H.sub.2 O: C, 
66.23; N, 8.52; N, 7.47. Found: C, 66.23, H, 8.46; N, 7.39. 
EXAMPLE 335 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(R*)]]]-[3-[[3-[(2-Hydroxy-3,3-dimethyl-1-oxobutyl)ami 
no]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester 
(Compound 335) 
##STR749## 
Compound 335 (white solid) was prepared from 
(S)-3,3-dimethyl-2-hydroxybutanoic acid and Compound 54 by a procedure 
analogous to that of Example 334. 
m.p.: 92.degree.-96.degree. C.; [.alpha.].sub.D =-2.7.degree. (c 0.81, 
MeOH). 
Mass. Spec.: (M+H).sup.+ 558.sup.+ 
Analysis Calc. for C.sub.31 H.sub.47 N.sub.3 O.sub.6 . 1.0 H.sub.2 O: C, 
64.60; N, 8.58; N, 7.29. Found: C, 64.60; H, 8.57; N, 7.02. 
EXAMPLE 336 
Preparation of 
N,N'-[Iminobis[(1S,2R)-2-Hydroxy-1-(Phenylmethyl)-3,1-propanediyl]]bis-[1- 
hydroxy-2,2-dimethylcyclopentanecarboxamide], isomer A 
(Compound 336b) 
(a) Compound 336a 
##STR750## 
A solution of Compound 321d (115 mg; 0.197 mmol) in 3 ml of HCl saturated 
EtOAc was stirred 1 h at 0.degree. C. The volatiles were removed in vacuo 
to afford 109 mg (99%) of Compound 336a as an off-white solid. 
.sup.1 H NMR (CD.sub.3 OD): .delta. 0.82 (s, 3H), 0.94 (s, 3H), 1.65 (m, 
5H), 2.05 (m, 1H), 2.80 (dd, J=10.5, 13.5 Hz, 1H), 2.91 (dd, J=8.5, 14.5 
Hz, 1H), 3.04 (m, 3H), 3.22 (m, 3H), 3.70 (m, 1H), 3.90 (m, 1H), 4.03 (m, 
1H), 4.25 (m, 1H), 7.33 (m, 10H). 
(b) Compound 336b 
##STR751## 
BOP-reagent (89 mg; 0.200 mmol) was added in one portion to a solution of 
Compound 336a (105 mg; 0.189 mmol), Compound 321c (30 mg; 0.190) and 
N-methylmorpholine (65 ml; 0.580 mol) at 0.degree. C. in 0.5 ml of DMF. 
The reaction mixture was allowed to warm to RT and stir 18 h. After 
diluting with EtOAc, the organic phase was washed with H.sub.2 O, 
saturated NaHCO.sub.3 solution and brine. After drying (Na.sub.2 
SO.sub.4), the solvent was removed in vacuo. The residue was preabsorbed 
on celite and chromatographed on a 2.5.times.15 cm silica gel column 
eluting with CH.sub.2 Cl.sub.2 ; 1% MeOH/CH.sub.2 Cl.sub.2 ; 2% 
MeOH/CH.sub.2 Cl.sub.2 ; 2.5% MeOH/CH.sub.2 Cl.sub.2 ; then 3-5% 
MeOH/CH.sub.2 Cl.sub.2 +0.3-0.5% NH.sub.4 OH in 0.25% and 0.025% 
increments respectively to afford 14.4 mg (12%) of Compound 336b (white 
solid) as a single symmetrical isomer of undetermined absolute 
configuration. 
m.p. 135.degree.-145.degree. C.; R.sub.f =0.25, CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA detection); [.alpha.].sub.D 
=+28.2.degree. (c 0.38, MeOH). 
Mass Spec.: M+H=624. 
EXAMPLE 337 
Preparation of 
N,N'-[Iminobis[(1S,2R)-2-Hydroxy-1-(Phenylmethyl)-3,1-propanediyl]]bis-[1- 
hydroxy-2,2-dimethylcyclopentanecarboxamide], isomer B 
(Compound 337) 
##STR752## 
Compound 337 was isolated as the more polar isomer from the reaction 
described in Example 336. Recrystallization from ether/hexane gave 18 mg 
(15%) of a white solid. 
m.p. 109.degree.-112.degree. C.; R.sub.f =0.19, CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA detection); [.alpha.].sub.365 
=+25.7.degree. (c 0.33, MeOH). 
Mass Spec.: M+H=624. 
Analysis Calc. for C.sub.36 H.sub.53 N.sub.3 O.sub.6 . 1.35 H.sub.2 O: C, 
66.71; N, 8.66; N, 6.48. Found: C, 66.52, H, 8.52; N, 6.67. 
EXAMPLE 338 
Preparation of 
[1S-(1R*,2S*),(R*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]] 
bis[carbamic acid], bis(3-tetrahydrofuranyl)ester 
(Compound 338b) 
(a) Compound 338a 
##STR753## 
Compound 32 was reacted with 3 eq. of Compound 331a and 10 eq. of iPr.sub.2 
NEt by a procedure analogous to that of Example 149e (DMF was used in 
place of CH.sub.3 CN) to give Compound 338a. 
(b) Example 338b 
##STR754## 
Compound 338a was converted to the title Compound 338b (white solid) by a 
procedure analogous to that of Example 2. 
m.p. 230.degree.-231.degree. C.; [.alpha.].sub.D =-23.5.degree. (c 0.2, 
HOAc). 
Mass Spec. (FAB): 572.sup.+ (M+H).sup.+. 
Analysis Calc. for C.sub.30 H.sub.41 N.sub.3 O.sub.8 : C, 63.03; H, 7.23; 
N, 7.35. Found: C, 63.19; H, 7.33; N, 7.04. 
EXAMPLE 339 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]amino]carbonyl]propyl]carbamic acid, (2-furo[2,3-c]pyridinyl) methyl ester 
(Compound 339f) 
(a) Compound 339a 
##STR755## 
Compound 339a was prepared as described in Shiotani et al. , J. Heter. 
Chem., 19, 1207 (1982). 
(b) Compound 339b 
##STR756## 
Compound 339b was prepared from Compound 39a as described in Shiotani et 
al., J. Heter. Chem., 24, 373 (1987). 
(c) Compound 339c 
##STR757## 
To a solution of Compound 339b (0.66 g, 4.49 mmol) in 50 mL of 3:3:4 
THF-EtOH-CHCl.sub.3 cooled to 0.degree. C. was added NaBH.sub.4 (0.298 g, 
7.86 mmol) in portions. After addition was complete, the mixture was 
stirred at 0.degree. C. for 30 min, diluted with H.sub.2 O and extracted 
with CH.sub.2 Cl.sub.2. The combined extracts were dried (MgSO.sub.4) and 
concentrated. The crude residue was flash chromatographed on silica gel 
eluting with a stepwise gradient of 25% to 100% EtOAc-hexane to afford 
Compound 339c (0.555 g, 83%) as a white solid. 
(d) Compound 339d 
##STR758## 
To a solution of Compound 339c (0.298 g, 2 mmol) in 15 mL of CH.sub.2 
Cl.sub.2 cooled to 0.degree. C. was added 1 mL of pyridine followed by 
p-nitrophenylchloroformate (0.403 g, 2 mmol) as a solid. The reaction 
mixture was stirred for 16 h at RT, diluted with EtOAc and washed with 
sat. NaHCO.sub.3 and brine. The organic phase was dried (MgSO.sub.4) and 
concentrated to obtain Compound 339d (0.6 g, 95%; crude yield) containing 
traces of p-nitrophenylchloroformate and p-nitrophenol. 
(e) Compound 339e 
##STR759## 
Compound 339d (0.6 g; 1.91 mmol) in 5 mL of dioxane was added to a solution 
of L-tert-leucine (0.25 g; 1.91 mmol) in 1.92 mL of 1N NaOH at RT followed 
by the addition of Et.sub.3 N (293 .mu.L; 2.1 mmol). After 24 h at RT, the 
reaction mixture was diluted with 10% KHSO.sub.4 and extracted with EtOAc. 
The aqueous phase was brought to pH 3.5 with 2N NaOH and extracted with 
EtOAc. The organic extracts were washed with brine, dried (MgSO.sub.4) and 
concentrated to afford 0.5 g (85%) of Compound 339e as an off-white solid. 
(f) Compound 339f 
##STR760## 
To a 0.degree. C. solution of Compound 339e (0.173 g; 0.56 mmol) in 3 mL of 
CH.sub.2 Cl.sub.2 was added HOBT (0.115 g; 0.84 mmol) followed by EDCI 
(0.114 g; 0.59 mmol). After 30 min, Compound 54 (0.25 g; 0.56 mmol) was 
added followed by 0.5 mL of DMF. The reaction mixture was stirred at 
0.degree. C. for 30 min and at RT for 16 h, at which time it was diluted 
with CH.sub.2 Cl.sub.2, and washed with H.sub.2 O, sat. aq. NaHCO.sub.3 
and brine. The organic extracts were dried (MgSO.sub.4), concentrated, and 
the resulting residue purified by flash chromatography on silica gel, 
eluting with a gradient of 96.7:3:0.3 to 89:10:1 CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, to afford 0.135 g (33%) of the title Compound 339f as 
an off-white solid. 
m.p. 95.degree.-105.degree. C.; [.alpha.].sub.D =-19.4.degree. (c=0.2, 
CH.sub.3 OH). 
Mass. Spec. (FAB) (M+H).sup.+ =732 
Analysis calc. for C.sub.40 H.sub.53 N.sub.5 O.sub.8.1.39 H.sub.2 O: C, 
63.42; H, 7.43; N, 9.25 Found: C, 63.33; H, 7.23; N, 9.34. 
EXAMPLE 340 
Preparation of 
[1S*,2R*(2R*,3S*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-(2-methoxycarbonyl)-3-methyl-D-valinamide 
(Compound 340) 
##STR761## 
(D)-t-Leucine and Compound 54 were converted to the title Compound 340 by 
the two-step procedure described in Example 246. 
m.p. 135.degree.-143.degree. C.; [.alpha.].sub.D =+13.4.degree. (c=0.2, 
CH.sub.3 OH). 
Mass Spec. (FAB) (M+H).sup.+ =615 
Analysis calc. for C.sub.40 H.sub.53 N.sub.5 O.sub.8.1.39 H.sub.2 O: C, 
61.95; H, 8.31; N, 8.76 Found: C, 61.95; H, 8.12; N, 8.93. 
EXAMPLE 341 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-[[4-[2-(4-morpholinyl)-2-oxoethoxy]pheny 
l]methyl]propyl]-N.sup.2 -(2-methoxycarbonyl)-3-methyl-L-valinamide 
(Compound 341e) 
(a) Compound 341a 
##STR762## 
Compound 226a was converted to Compound 341a by a two-step procedure 
analogous to that used for the conversion of Compound 282a to Compound 
282c. 
(b) Compound 341b 
##STR763## 
Compound 341a was converted to Compound 341b by a procedure analogous to 
that of Example 122 except that carbobenzyloxy chloride was used. 
(c) Compound 341c 
##STR764## 
Compounds 341b and 1b(i) were converted to Compound 341c by a two-step 
procedure analogous to that used for the conversion of Compound 282d to 
Compound 282f. 
(d) Compound 341d 
##STR765## 
Compound 341c was converted to Compound 341d by a procedure analogous to 
that of Example 19. 
(e) Compound 341e 
##STR766## 
Compounds 341d and 246a were reacted by a procedure analogous to that of 
Example 246b to give the title Compound 341e (white solid). 
m.p. 128.degree.-130.degree. C.; [.alpha.].sub.D =-12.degree. (c=0.07, 
MeOH). 
Mass spec.: 758.sup.+ (M+H).sup.+. 
Analysis calc. for C.sub.39 H.sub.59 N.sub.5 O.sub.10 . 0.9 H.sub.2 O: C, 
60.51; H, 7.92; N, 9.05; Found: C, 60.79; H, 8.01; N, 8.65. 
EXAMPLE 342 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydrox 
y-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-N.sup.2 
-[(methylamino)carbonyl]-N.sup.2 -3-dimethyl-L-valinamide 
(Compound 342f ) 
(a) Compound 342a 
##STR767## 
Compound 88a was converted to Compound 342a by a procedure analogous to 
that of Example 66a (except that DMF was used as solvent instead of THF). 
(b) Compound 342b 
##STR768## 
Compound 342a was converted to Compound 342b by a procedure analogous to 
that of Example 70c except that the reaction was not acidified before 
evaporation. 
(c) Compound 342c 
##STR769## 
To a 0.degree. C. solution of Compound 48 (200 mg; 0.34 mmol) and Compound 
342b (102 mg; 0.35 mmol) in anhydrous DMF (0.68 mL) were successively 
added BOP reagent (0.154 g; 0.350 mmol) and N-methyl morpholine (0.188 mL; 
1.71 mmol). The solution was allowed to warm to RT and stirred for 36 h. 
Volatiles were removed in vacuo and the residue was partitioned between 
saturated aqueous NaHCO.sub.3 and EtOAc. The combined organic extracts 
were washed with brine, dried (Na.sub.2 SO.sub.4), and concentrated in 
vacuo to give a viscous oil, which was chromatographed on silica gel using 
a gradient from 10% EtOAc-hexane to 50% EtOAc-hexane to furnish Compound 
342c (233 mg; 81%) as a white solid. 
(d) Compound 342d 
##STR770## 
Compound 342c was converted to Compound 342d (white solid) by a procedure 
analogous to that of Example 19. 
(e) Compound 342e 
##STR771## 
Compound 342d and methyl isocyanate were reacted by a procedure analogous 
to that of Example 46 to give Compound 342e (colorless oil). 
(f) Compound 342f 
##STR772## 
Compound 342e was converted to the title Compound 342f (white solid) by a 
procedure analogous to that of Example 21. 
m.p. 87.degree.-90.degree. C. 
Mass Spec. (FAB): (M+H)=628 
EXAMPLE 343 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hy 
droxy-4-[4-[2-(2-oxo-3-oxazolidinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1- 
(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 343c) 
(a) Compound 343a 
##STR773## 
Diethanolamine was converted to Compound 343a by a procedure analogous to 
that of Example 315a. 
(b) Compound 343b 
##STR774## 
Compounds 175c and 343a were reacted by a procedure analogous to that of 
Example 282a to give Compound 343b. 
(c) Compound 343c 
##STR775## 
Compounds 16b and 343b were reacted by a procedure analogous to that of 
Example 226b (except that the reaction was run in MeOH at 60.degree. C.) 
to afford the title Compound 343c (colorless solid). 
m.p. 130.5.degree.-133.5.degree. C.; [.alpha.].sub.D =-3.1.degree. (c 0.27, 
MeOH). 
Mass Spec.: (FAB): 673 (M+H). 
Anal. Calc. for C.sub.35 H.sub.52 N.sub.4 O.sub.9 . 0.25 H.sub.2 O C, 
62.07; H, 7.81; N, 8.27 Found: C, 62.04; H, 7.84; N, 8.29. 
EXAMPLE 344 
Preparation of 
[2R-[R*(R*,S*)]]-N,N'-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl 
]]bis[2-hydroxy-2,3,3-trimethylbutaneamide] 
(Compound 344) 
##STR776## 
BOP reagent (308 mg, 0.7 mmol) was added to a stirred mixture of Compound 
74 (0.15 g, 0.33 mmol), Compound 262e (0.102 g, 0.7 mmol) and 
N-methylmorpholine (0.254 mL, 2.32 mmol) in 0.75 mL dry DMF. The mixture 
was stirred at RT for 14 h, concentrated and the residue partitioned 
between EtOAc and sat. NaHCO.sub.3. The organic phase was dried 
(MgSO.sub.4), concentrated, and the residue purified by flash 
chromatography (silica gel/CH.sub.2 Cl.sub.2 stepwise to 95:5:0.5 CH.sub.2 
Cl.sub.2 --MeOH-aq NH.sub.4 OH) followed by preparative HPLC (column: 
Polymer Labs. PLRP-S 100 .ANG. 10 .mu.m 25.times.300 mm; eluent: 1:1 A:B, 
eluent A=H.sub.2 O--CH.sub.3 CN--NH.sub.4 OH 90:10:0.2, eluent B=H.sub.2 
O--CH.sub.3 CN--NH.sub.4 OH 10:90:0.2; UV 254 nm) to afford 100 mg (50%) 
of the title Compound 344 as a white solid. 
m.p. 159.degree.-160.degree. C.; [.alpha.].sub.D +43.8.degree. (c 0.48, 
MeOH). 
Mass. Spec.: 600 (M+H).sup.+. 
Analysis calc. for C.sub.34 H.sub.53 N.sub.3 O.sub.6.0.59 H.sub.2 O: C, 
66.90; H, 8.95; N, 6.88. Found: C, 66.89; H, 8.90; N, 6.89. 
EXAMPLE 345 
Preparation of 
[S-(1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[1,1-dimethylethoxy)carbo 
nyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl] 
amino]carbonyl]propyl]carbamic acid, (4-phenyl-2-oxazolyl)methyl ester 
(Compound 345b) 
(a) Compound 345a 
##STR777## 
A solution of 4-phenyloxazole (Whitney, J. Org. Chem., 55, 929-935 (1990)) 
(2.15 g; 14.8 mmol) and 2,2,4,4-tetramethylpiperidine (250 .mu.l; 1.48 
mmol) in 30 ml of distilled THF at -78.degree. C. was added 1.3M s-BuLi in 
cyclohexane (13.7 ml). The mixture was stirred for 30 min at -78.degree. 
C. and then warmed to 0.degree. C. Formaldehyde gas (from 
paraformaldehyde) was bubbled through the mixture for 5 min and it was 
allowed to warm to RT and stir overnight. The reaction was quenched with 
1N HCl and extracted with CH.sub.2 Cl.sub.2. The extracts were washed with 
brine and dried (Na.sub.2 SO.sub.4). Evaporation and purification on a 
silica gel column eluting with EtOAc/hexane (1:3) and EtOAc/hexane (1:1) 
gave 1.75 g (68%) Compound 345a. 
(b) Compound 345b 
##STR778## 
Compound 345a was converted to its p-nitrophenyl carbonate which was 
reacted with tert-leucine and the resulting product coupled with Compound 
54 by a three-step procedure analogous to that used for Example 257a 
through 257c to give the title Compound 345b (colorless solid). 
m.p. 178.degree.-184.degree. C. (dec).; [.alpha.].sub.D =-11.degree. 
(c=0.25, MeOH). 
Analysis calcd. for: C.sub.42 H.sub.55 N.sub.5 O.sub.8 . 0.5 H.sub.2 O: C, 
65.73; H, 7.36; N, 9.12 Found: C, 65.73; H, 7.30; N, 9.12 
Mass Spec. (FAB): (M+H).sup.+ =758.sup.+. 
EXAMPLE 346 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[4-[4-(Carboxymethoxy)phenyl)-3-[[3-[[1,1-dimethyl 
ethoxy)carbonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl)carbamic acid, 
1,1-dimethylethyl ester 
(Compound 346c) 
(a) Compound 346a 
##STR779## 
To a 0.degree. C. solution of Compound 175c (0.080 g; 0.286 mmol) in DMF 
(0.60 ml) was added a solution of NaN(TMS).sub.2 in THF (0.30 ml of a 1.0M 
solution; 0.30 mmol). The solution was stirred at 0.degree. C. for 1 h, 
then ethyl bromoacetate in DMF (0.30 mL of a 1.0M solution; 0.30 mmol) was 
added dropwise, followed by Bu.sub.4 NI (0.011 g; 0.029 mmol). The 
solution was allowed to warm to RT and stirred for 18 h. Volatiles were 
removed in vacuo, and the residue was partitioned between H.sub.2 O and 
EtOAc. The combined organic extracts were washed with H.sub.2 O, dried 
(Na.sub.2 SO.sub.4) and concentrated in vacuo to give, after 
chromatography on silica gel (50 mL) using a gradient from 10:1 to 1:2 
hexane:EtOAc as eluent, Compound 346a (0.100 g; 95%) as a white solid. 
(b) Compound 346b 
##STR780## 
Compounds 346a and 16b were reacted by a procedure analogous to that of 
Example 226b to give Compound 346b. 
Mass Spec. (CI): (M+H).sup.+ =646 
(c) Compound 346c 
##STR781## 
Compound 346b was converted to the title Compound 346c (white solid) by a 
procedure analogous to that of Example 70c (THF was used instead of 
dioxane). 
m.p.=182.degree.-187.degree. C. (dec) 
Mass Spec. (FAB): (M+H).sup.+ =618. 
EXAMPLE 347 
Preparation of 
[S-(1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[1,1-dimethylethoxy)carbo 
nyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl] 
amino]carbonyl]propyl]carbamic acid, (5-phenyl-2-oxazolyl)methyl ester 
(Compound 347b) 
(a) Compound 347a 
##STR782## 
5-Phenyloxazole-2-carboxylic acid ethyl ester (Saito, J. Pharm. Soc. Japan, 
76, 305 (1956)) was converted to Compound 347a by a procedure analogous to 
that of Example 281a (except that the reaction was run at 0.degree. C. to 
RT). 
(b) Compound 347b 
##STR783## 
Compound 347a was converted to its p-nitrophenyl carbonate which was 
reacted with tert-leucine and the resulting product coupled with Compound 
54 by a three-step procedure analogous to that used for Example 257a 
through 257c to give the title Compound 347b (colorless solid). 
m.p. 168.degree.-174.degree. C. (dec).; [.alpha.].sub.D =-12.5.degree. 
(c=0.25, MeOH). 
Mass Spec. (FAB): (M+H).sup.+ =758.sup.+ 
Analysis calcd. for: C.sub.42 H.sub.55 N.sub.5 O.sub.8 . 0.68 H.sub.2 O: C, 
65.50; H, 7.38; N, 9.09 Found: C, 65.46; H, 7.29; N, 9.13. 
EXAMPLE 348 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[2-(phenylmethoxy)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)prop 
yl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 348d) 
(a) Compound 348a 
##STR784## 
D,L-o-Tyrosine was resolved into the (L) enantiomer, Compound 348a, by the 
procedure described in Can. J. Biochem., 49, 877 (1971). 
(b) Compound 348b 
##STR785## 
Compound 348a was converted to Compound 348b by a three-step procedure 
analogous to that used for the conversion of Compound 28b to Compound 28e. 
(c) Compound 348c 
##STR786## 
Compound 348b was converted into Compound 348c by procedures analogous to 
those used for the synthesis of Compound 1b(i). 
(d) Compound 348d 
##STR787## 
Compounds 348c and 16b were reacted by a procedure analogous to that of 
Example 226b to give the title Compound 348d (colorless solid). 
m.p. 146.degree.-152.degree. C.; [.alpha.].sub.D =-4.degree. (c 0.8, HOAc) 
Mass Spec. (CI): (M+H).sup.+ =650.sup.+ 
Analysis calcd. for: C.sub.37 H.sub.51 N.sub.3 O.sub.7 . 1.5 H.sub.2 O: C, 
65.65; H, 8.04; N, 6.41 Found: C, 65.49 H, 7.72; N, 6.66. 
EXAMPLE 349 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-1,1-Dimethylethoxy)-carbonyl]amino]-2-hydro 
xy-4-(2-methoxyphenyl)butyl]-amino]-2-hydroxy-1-(phenylmethyl)propyl]carbam 
ic acid, 1,1-dimethylethyl ester 
(Compound 349c) 
(a) Compound 349a 
##STR788## 
Compound 348c was converted to Compound 349a by a procedure analogous to 
that of Example 175c. 
(b) Compound 349b 
##STR789## 
A solution of Compound 349a (70 mg, 0.25 mmol) in 0.5 ml of dry DMF was 
cooled to 0.degree. C. and 250 .mu.l of a 1M solution of sodium 
bis(trimethylsilyl)amide in THF (46 mg, 0.25 mmol) was added. After 
stirring for 15 min, 10 eq. of CH.sub.3 I (0.15 ml, 2.5 mmol) was added 
and the resulting mixture was stirred at 0.degree. C. for 1 h and then 
allowed to warm to RT and stir overnight. The DMF was evaporated and the 
crude product purified on a 20 ml silica gel column eluting with 15% 
EtOAc/hexane yielding 68 mg (93%) of Compound 349b. 
(c) Compound 349c 
##STR790## 
Compounds 349b and 16b were reacted by a procedure analogous to that of 
Example 226b to give the title Compound 349c (colorless solid). 
m.p. 136.degree.-140.degree. C.; [.alpha.].sub.D =-3.5.degree. (c 0.5, 
HOAc) 
Mass Spec. (CI): (M+H).sup.+ =574.sup.+ 
Analysis calcd. for: C.sub.31 H.sub.47 N.sub.3 O.sub.7 . 1.45 H.sub.2 O: C, 
62.07; H, 8.38; N, 7.01 Found: C, 61.92; H, 8.08; N, 7.16. 
EXAMPLE 350 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(2-hydroxyphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carba 
mic acid, 1,1-dimethylethyl ester 
(Compound 350) 
##STR791## 
Compound 348d was converted to the title Compound 350 (colorless solid) 
using conditions analogous to those of Example 43. 
m.p. 156.degree.-160.degree. C.; [.alpha.].sub.D =-5.2.degree. (c 0.5, 
HOAc) 
Mass Spec. (CI): (M+H).sup.+ =560.sup.+ 
Analysis calcd. for: C.sub.30 H.sub.45 N.sub.3 O.sub.7 . 1.18 H.sub.2 O: C, 
62.03; H, 8.22; N, 7.23 Found: C, 61.95; H, 7.79; N, 7.31. 
EXAMPLE 351 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino-2-hydroxy-1-(phenylmethyl)propyl] 
amino]carbonyl]propyl]carbamic acid, 2-(phenylmethoxy)ethyl ester 
(Compound 351) 
##STR792## 
2-Benzyloxyethanol was converted to its p-nitrophenyl carbonate which was 
reacted with tert-leucine and the resulting product coupled with Compound 
54 by a three-step procedure analogous to that used for Example 257a 
through 257c to give the title Compound 351 (white solid). 
m.p. 99.degree.-101.degree. C.; [.alpha.].sub.D =-13.degree. (c 0.11, 
MeOH). 
Mass spec.: 735.sup.+ (M+H).sup.+. 
Analysis calc. for C.sub.41 H.sub.58 N.sub.4 O.sub.8 . 1.61 H.sub.2 O: C, 
64.46; H, 8.08; N, 7.33; Found: C, 64.15; H, 7.83; N, 7.51. 
EXAMPLE 352 
Preparation of 
[S-[1R*,2S*(2S*,3R*)]]-[2,2-Dimethyl-1-[[[3-[[3-[[(1,1-dimethylethoxy)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]amino]carbonyl]propyl]carbamic acid, (2-furo[2,3-b]pyridinyl)methyl ester 
(Compound 352h) 
(a) Compound 352a 
##STR793## 
Compound 352a was prepared as described in Sliwa, Bull Soc. Chim. Fr. 631 
(1970). 
(b) Compound 352b 
##STR794## 
Compound 352a was converted to Compound 352b by the procedure described in 
Morita et al., J. Heter. Chem., 23, 1465 (1986). 
(c) Compound 352c 
##STR795## 
Compound 352b was converted to Compound 352c by the procedure described in 
Sliwa, Bull Soc. Chim. Fr. 646 (1970). 
(d) Compound 352d 
##STR796## 
Compound 352c was converted to Compound 352d by the procedure described in 
Morita et al., J. Heter. Chem., 23, 1465 (1986). 
(e) Compound 352e 
##STR797## 
To a solution of Compound 352d (0.26 g, 1.769 mmol; ca. 75% pure) in 20 mL 
of 3:3:4 THF-EtOH-CHCl.sub.3 cooled to 0.degree. C. was added NaBH.sub.4 
(0.117 g, 3.095 mmol) in portions. After addition was complete, the 
mixture was stirred at 0.degree. C. for 30 min, diluted with H.sub.2 O and 
extracted with CH.sub.2 Cl.sub.2. The combined extracts were dried 
(MgSO.sub.4) and concentrated. The crude residue was flash chromatographed 
on silica gel eluting with a stepwise gradient of 25% to 100% EtOAc-hexane 
to afford Compound 352e (0.16 g, 80%) as a white solid. 
(f) Compound 352f 
##STR798## 
To a solution of Compound 352e (0.160 g, 1.073 mmol) in 8 mL of CH.sub.2 
Cl.sub.2 cooled to 0.degree. C. was added 0.5 mL of pyridine followed by 
p-nitrophenylchloroformate (0.216 g, 1.073 mmol) as a solid. The reaction 
mixture was stirred for 20 h at RT, diluted with EtOAc and washed with 
sat. NaHCO.sub.3 and brine. The organic phase was dried (MgSO.sub.4) and 
concentrated to obtain Compound 352f (0.336 g, crude yield) containing 
traces of p-nitrophenylchloroformate and p-nitrophenol. 
(g) Compound 352g 
##STR799## 
Compound 352f (0.336 g; 1.07 mmol) in 5 mL of dioxane was added to a 
solution of L-tert-leucine (0.154 g; 1.177 mmol) in 1.17 mL of 1N NaOH at 
RT followed by the addition of Et.sub.3 N (179 .mu.L; 1.284 mmol). After 
stirring overnight at RT, the reaction mixture was diluted with 10% 
KHSO.sub.4 and the pH adjusted to 2.0 with 1N NaOH. The mixture was 
extracted with EtOAc and the combined extracts were washed with brine, 
dried (MgSO.sub.4) and concentrated. Flash chromatography on silica gel of 
the crude residue (CH.sub.2 Cl.sub.2 followed by a stepwise gradient from 
2% to 10% MeOH/CH.sub.2 Cl.sub.2 +0.5% HOAc) afforded 0.23 g (ca. 80% 
pure) of Compound 352g. 
(h) Compound 352h 
##STR800## 
To a 0.degree. C. solution of Compound 352g (0.15 g; 0.40 mmol based on 80% 
pure material) in 3 mL of CH.sub.2 Cl.sub.2 was added HOBT (0.092 g; 0.676 
mmol) followed by EDCI (0.091 g; 0.474 mmol). After 30 min, Compound 54 
(0.20 g; 0.451 mmol) was added followed by 0.5 mL of DMF. The reaction 
mixture was stirred at 0.degree. C. for 30 min and at RT for 16 h, at 
which time it was diluted with EtOAc, and washed with H.sub.2 O, sat. aq. 
NaHCO.sub.3 and brine. The organic extracts were dried (MgSO.sub.4), 
concentrated, and the resulting residue purified by flash chromatography 
on silica gel, eluting with a gradient of 98.9:1:0.1 to 90.1:9:0.9 
CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH, to afford 0.238 g (72%) of the title 
Compound 352h as an off-white solid. 
m.p. 99.degree.-106.degree. C.; [.alpha.].sub.D =-15.2.degree. (c=0.2, 
CH.sub.3 OH). 
Mass Spec. (FAB) (M+H).sup.+ =732 
Analysis calc. for C.sub.40 H.sub.53 N.sub.5 O.sub.8 . 1.28 H.sub.2 O: C, 
63.64; H, 7.42; N, 9.28 Found: C, 63.54; H, 7.37; N, 9.38. 
EXAMPLE 353 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[(2-Hydroxy-1-oxo-2-phenylpropyl)amino] 
-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethyl ethyl ester 
(Compound 353) 
##STR801## 
To a solution of Compound 54 (100 mg, 0.225 mmol) in DMF (0.4 ml) was added 
a solution of (R)-2-hydroxy-2-phenylpropionic acid (41 mg, 0.247 mmol) in 
0.3 ml DMF, followed by BOP reagent (109 mg, 0.247 mmol) and 
N-methylmorpholine (54 .mu.l; 0.49 mmol) to afford 55 mg (41%) the title 
Compound 353 using a procedure analogous to that of Example 262f. 
m.p. 161.degree.-163.degree. C.; [.alpha.].sub.D =+2.5.degree. (c 0.2, 
CH.sub.3 OH) 
Mass spectrum (Fab): (M+H).sup.+ 592.sup.+. 
Analysis Calc. for: C.sub.34 H.sub.45 N.sub.3 O.sub.6 . 0.51 H.sub.2 O: C, 
67.95; H, 7.72; N, 6.99 Found: C, 67.92; H, 7.48; N, 7.02. 
EXAMPLE 354 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[3,3-Dimethyl-2-[(methylamino)carbonyl]-1- 
oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)pr 
opyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 354d) 
(a) Compound 354a 
##STR802## 
2-tert-Butyl-diethylmalonate was saponified with KOH/EtOH to afford 
Compound 354a as described in Bajwa et al. J. Amer. Chem. Soc., 104, 6385 
(1982). 
(b) Compound 354b 
##STR803## 
A solution of Compound 354a (1.0 g, 5.31 mmol) in 0.775 ml (10.62 mmol) of 
SOCl.sub.2 was refluxed for 2 h. The excess SOCl.sub.2 was removed in 
vacuo and the residue was dissolved in 20 ml dry Et.sub.2 O. Anhydrous 
CH.sub.3 NH.sub.2 was bubbled into the reaction until no more precipitate 
formed. The precipitate was filtered off and the filtrate was concentrated 
to afford 865 mg (81%) of Compound 354b. 
(c) Compound 354c 
##STR804## 
Compound 354c was prepared from Compound 354b by a procedure analogous to 
that used for the preparation of Compound 354a. 
(d) Compound 354d 
##STR805## 
Compound 354d (white solid) was prepared as a 1:1 mixture of diastereomers 
from Compounds 354c and 54 by a procedure analogous to that of Example 
334. 
m.p. 117.degree.-120.degree. C. ("softening" at 114.degree.-117.degree. C.) 
Mass Spec. (FAB), 599 (M+H.sup.+) 
Analysis Calc. for: C.sub.31 H.sub.50 N.sub.4 O.sub.6 . 0.16 H.sub.2 O: C, 
65.87; H, 8.43; N, 9.31 Found: C, 65.84; H, 8.55; N, 9.34. 
EXAMPLE 355 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[2-hydroxy-2-(3-pyridinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1- 
(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester, Isomer A 
(Compound 355f) 
(a) Compound 355a 
##STR806## 
Pyridine 3-carboxaldehyde (4.0 g; 37.3 mmol) in THF (50 mL) was reacted 
with vinyl magnesium bromide (41.0 mL of a 1.0M solution in THF; 41.0 
mmol), first at 0.degree. C. then at RT for 24 h. The reaction mixture was 
cooled to 0.degree. C. and aqueous NH.sub.4 Cl (55 mL of a 1M solution) 
was slowly added, followed by EtOAc (200 mL). The resulting mixture was 
filtered through Celite and the aqueous layer extracted with EtOAc. The 
combined organic extracts were dried (Na.sub.2 SO.sub.4) and concentrated 
in vacuo to give an oil, which was purified by flash chromatography (500 
mL SiO.sub.2 ; stepwise gradient from 1:1 to 1:5 hexanes:EtOAc) to give 
Compound 355a (3.89 g; 77%) as a pale yellow oil. 
(b) Compound 355b 
##STR807## 
To a 0.degree. C. solution of Compound 355a (0.40 g; 2.96 mmol) in 
anhydrous DMF (3.0 mL) were successively added tert-butyldimethylsilyl 
chloride (0.535 g; 3.55 mmol), Et.sub.3 N (0.467 g; 4.62 mmol) and DMAP 
(0.036 g; 0.296 mmol). The mixture was allowed to warm to RT and stirred 
for 24 h. Volatiles were removed in vacuo and the residue was partitioned 
between aqueous NaHCO.sub.3 (20 mL of a 50% saturated solution) and EtOAc 
(20 mL). The aqueous layer was extracted with EtOAc and the combined 
organic extracts were washed with H.sub.2 O, dried, and concentrated in 
vacuo to give an oil. Flash chromatography (SiO.sub.2 ; 100 mL) using as 
eluent 10:1 hexane:EtOAc furnished Compound 355b (0.744; 100%) as a pale 
yellow oil. 
(c) Compound 355c 
##STR808## 
A stream of O.sub.3 was bubbled into a -78.degree. C. solution of Compound 
355b (0.650 g; 2.61 mmol) in CH.sub.2 Cl.sub.2 (10.0 mL) for 15 min until 
the solution was faintly blue. After stirring for a further 30 min at 
-78.degree. C., N.sub.2 was bubbled into the solution for 15 min to 
discharge the blue color. DIBAL-H (10.4 mL of a 1.0M solution in hexane; 
10.4 mmol) was added dropwise over 5 min, followed by 10 mL of dry hexane. 
The solution was stirred at -78.degree. C. for 1 h, then at -20.degree. C. 
for 2 h. The solution was then recooled to -78.degree. C. and MeOH (3.0 
mL) was added dropwise. The solution was allowed to warm to RT and brine 
(5.0 mL), Et.sub.2 O (100 mL) and MgSO.sub.4 (15 g) were added. The 
mixture was stirred for 2 h, filtered, and concentrated in vacuo to give a 
yellow oil, which was flash chromatographed (SiO.sub.2 ; 100 mL) using a 
stepwise gradient from 1:1 to 1:4 hexane:EtOAc to give Compound 355c 
(0.234g; 35%) as a slightly yellow oil. 
(d) Compound 355d 
##STR809## 
Compound 355c (0.331 g; 1.31 mmol) and Compound 175c (0.183 g; 0.655 mmol) 
were reacted with DEAD (0.228 g; 1.31 mmol) and Ph.sub.3 P (0.343 g; 1.31 
mmol) in THF for 24 h at RT. The solution was concentrated in vacuo and 
adsorbed onto Celite. Flash chromatography (100 mL SiO.sub.2) using a 
gradient from 95:5 to 1:1 hexane:EtOAc gave Compound 355d (0.301 g; 
contaminated with 1,2-dicarbethoxyhydrazine; only one of two possible 
diastereomers was isolated) as a pale yellow viscous oil. 
(e) Compound 355e 
##STR810## 
Compound 355d (0.301 g) was dissolved in anhydrous THF and n-Bu.sub.4 
NF.H.sub.2 O (0.204 g; 0.779 mmol) was added at RT. The yellow solution 
was stirred for 1.5 h. Volatiles were removed in vacuo and the residue was 
purified by flash chromatography (SiO.sub.2, 100 mL) using a gradient from 
1:1 to 1:10 hexane:EtOAc to give Compound 355e (0.096 g; 37% for 2 steps) 
as a white solid. 
(f) Compound 355f 
##STR811## 
Compound 355e (0.030 g; 0.075 mmol) and Compound 16b (0.025 g; 0.090 mmol) 
were heated in MeOH (0.20 mL) at 60.degree. C. for 4 h. Volatiles were 
removed in vacuo and the residue was purified by flash chromatography on 
SiO.sub.2 (100 mL) using as eluent a stepwise gradient from 99:1:0.1 to 
92:8:0.8 CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH to afford a white solid 
(0.026 g, 52%). This material was further purified by preparative HPLC 
(Polymer Labs PLRP-S column, 25.times.300 mm, 10 .mu.m particle size, 
stepwise gradient from 70:30 to 40:60 A:B; A=90:10:0.2 H.sub.2 O: MeCN: 
NH.sub.4 OH, B=90:10:0.2 MeCN:H.sub.2 O:NH.sub.4 OH) and then lyophilized 
from dioxane-H.sub.2 O to give the title Compound 355f (0.021 g; 41%) as a 
white solid (single diastereomer of undetermined configuration). 
m.p.=68.degree.-72.degree. C. (dec.); [.alpha.].sub.D =-4.0.degree. 
(c=0.10, MeOH) 
Mass Spec. (FAB): (M+H).sup.+ =681. 
EXAMPLE 356 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(2,4-Dihydroxy-2,3,3-trimethyl-1-oxobutyl) 
amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carb 
amic acid, 1,1-dimethylethyl ester, isomer A 
(Compound 356b) 
(a) Compound 356a 
##STR812## 
A solution of CH.sub.3 MgCl (3M in THF, 14.32 mL, 43 mmol) was added to a 
solution of dihydro-4,4-dimethyl-2,3-furandione (5 g, 39 mmol) in 30 mL 
THF at -78.degree. C. The mixture was allowed to warm to RT, diluted with 
Et.sub.2 O and dilute HCl was added. The organic layer was washed with 
sat. NaHCO.sub.3, dried (MgSO.sub.4) and concentrated to afford 3.5 g of a 
colorless oil. This material was dissolved in 50 mL THF, and a solution of 
LiOH (583.4 mg, 24.3 mmol) in 25 mL water was added and the mixture was 
refluxed for 24 h. The mixture was concentrated, the residue dissolved in 
30 mL water, washed with Et.sub.2 O, and the aqueous phase lyophilized to 
afford 3.0 g of a pale solid. This solid (1.0 g) was dissolved in 5 mL 
water which was acidified with 10% HCl, extracted with EtOAc, and the 
organic phase dried (MgSO.sub.4), concentrated, and the residue purified 
by flash chromatography (silica gel/hexane-EtOAc 1:1) to afford 0.815 g of 
Compound 356a as a colorless oil. 
(b) Compound 356b 
##STR813## 
A mixture of Compound 54 (200 mg, 0.45 mmol) and Compound 356a (129.8 mg, 
0.90 mmol) in 1 mL dry DMF was heated at 100.degree. C. for 14 h and 
145.degree. C. for 2 h, concentrated, and the residue purified by flash 
chromatography to afford a ca. 1:1 mixture of the two diastereomeric (at 
*) products. This material was subjected to preparative TLC (0.5 mm silica 
gel plates/CH.sub.2 Cl.sub.2 --MeOH--NH.sub.4 OH 9:1:0.1, developed twice) 
to afford, as the faster moving isomer, the title Compound 356b (11 mg, 
4.1%) as a white solid. 
m.p. 73.degree.-75.degree. C.; [.alpha.].sub.D +8.degree. (c=0.15, MeOH); 
R.sub.f (SiO.sub.2)=0.23 (CH.sub.2 Cl.sub.2 --MeOH--NH.sub.4 OH 8:2:0.2). 
Mass Spec.: 588 (M+H).sup.+. 
EXAMPLE 357 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[(2,4-Dihydroxy-2,3,3-trimethyl-1-oxobutyl) 
amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carb 
amic acid, 1,1-dimethylethyl ester, isomer B 
(Compound 357) 
##STR814## 
Compound 357 (white solid) was isolated as the slower moving isomer by 
preparative TLC as described in Example 356b. 
m.p. 71.degree.-75.degree. C., R.sub.f (SiO.sub.2)=0.20 (CH.sub.2 Cl.sub.2 
--MeOH--NH.sub.4 OH 8:2:0.2). 
Mass Spec. 588 (M+H).sup.+. 
EXAMPLE 358 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-(2-hydroxy-2-methylpropoxy)phenyl]butyl]amino]-2-hydroxy-1-(pheny 
lmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 358b) 
(a) Compound 358a 
##STR815## 
Compound 346a was reacted with CH.sub.3 MgBr by a procedure analogous to 
that of Example 158a to give Compound 358a. 
(b) Compound 358b 
##STR816## 
Compounds 358a and 16b were reacted by a procedure analogous to that of 
Example 226b to give the title Compound 358b (white solid). 
m.p. 85.degree.-88.degree. C.; [.alpha.].sub.D =-4.5.degree. (c=0.11, 
CH.sub.3 OH) 
Mass Spec. (FAB): (M+H)=632. 
EXAMPLE 359 
Preparation of 
[1R*,2S*(2S*,3R*)]-N-[2-Hydroxy-3-[[2-hydroxy-3-[[(2-hydroxy-1,1-dimethyle 
thoxy)carbonyl]amino]-4-phenylbutyl]amino-1-(phenylmethyl)propyl]-N.sup.2 
-(2-methoxycarbonyl)-3-methyl-L-valinamide 
(Compound 359b) 
(a) Compound 359a 
##STR817## 
To a 0.degree. C. solution of Compound 246a (0.036 g, 0.191 mmol) in 3 mL 
of CH.sub.2 Cl.sub.2 was added HOBT-hydrate (0.035 g, 0.261 mmol) followed 
by EDCI (0.037 g, 0.191 mmol). The mixture was stirred at 0.degree. C. for 
0.5 h and Compound 333b (0.1 g, 0.174 mL) was added followed by 
N-methylmorpholine (0.058 mL, 0.522 mmol) and 0.5 mL of DMF. The resulting 
solution was stirred at RT for 20 h. The mixture was diluted with EtOAc 
and washed with sat. NaHCO.sub.3 and brine. The organic phase was dried 
(MgSO.sub.4) and concentrated in vacuo. The residue obtained was flash 
chromatographed on silica gel eluting with a stepwise gradient of 
98.9:1:0.1 to 89:10:1 CH.sub.2 Cl.sub.2 --MeOH--NH.sub.4 OH to afford 
Compound 359a (0.096 g, 74%) as a white solid. 
Mass Spec (FAB)--(M+H).sup.+ =745. 
(b) Compound 359b 
##STR818## 
A solution of Compound 359a (0.095 g, 0.127 mmol) in 3 mL of 3:1:1 
HOAc-THF-H.sub.2 O was stirred at RT for 16 h. The mixture was 
concentrated in vacuo and flash chromatographed twice on silica gel 
eluting with a stepwise gradient of 98.9:1:0.1 to 89:10:1 CH.sub.2 
Cl.sub.2 --MeOH--NH.sub.4 OH to obtain a solid which was triturated twice 
with Et.sub.2 O to afford Compound 359b (0.07 g, 87%) as a white solid. 
m.p. 93.degree.-104.degree. C.; [.alpha.].sub.D =-21.2.degree. (c=0.2, 
CH.sub.3 OH). 
Mass Spec. (FAB): (M+H).sup.+ =631 
Analysis calc. for C.sub.33 H.sub.50 N.sub.4 O.sub.8 . 3.03 H.sub.2 O: C, 
57.83; H, 8.24; N, 8.18 Found: C, 57.92; H, 7.66; N, 8.09. 
EXAMPLE 360 
Preparation of 
[1S-(1R*,2S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl)]bis[c 
arbamic acid], 1,1-dimethylethyl tetrahydro-1,1-dioxo-3-thienyl ester 
(Compound 360c) 
(a) Compound 360a 
##STR819## 
Compound 360a was prepared from tetrahydrothiophene-3-one in two steps 
employing the procedure described in Dodd et al., J. Heterocyclic. Chem., 
27, 1453 (1990). 
(b) Compound 360b 
##STR820## 
Compound 360a was converted to Compound 360b by a procedure analogous to 
that of Example 149d. 
(c) Compound 360c 
##STR821## 
Compounds 360b and 54 were converted to the title Compound 360c (white 
solid) in 13% yield by a procedure analogous to that of Example 147d (DMF 
only used). 
m.p. 197.degree.-201.degree. C. 
Mass Spec. (FAB): 606 (M+H.sup.+) 
Analysis calc. for C.sub.30 H.sub.43 N.sub.3 O.sub.8 S: C, 59.49; H, 7.15; 
N, 6.94; S, 5.29 Found: C, 59.44; H, 7.17; N, 7.07; S, 5.23. 
EXAMPLE 361 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclohexyl)carbonyl 
]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]car 
bamic acid, 1,1-dimethylethyl ester, isomer A 
(Compound 361b) 
(a) Compound 361a 
##STR822## 
2,2-Dimethylcyclohexanone was converted to Compound 361a by a three-step 
procedure analogous to that used for the preparation of Compound 321c. 
(b) Compound 361b 
##STR823## 
Compounds 361a and 54 were reacted by a procedure analogous to that of 
Example 321d. The crude product was chromatographed on a 2.5.times.25 cm 
silica gel column as follows: 1% MeOH/CH.sub.2 Cl.sub.2 ; 2% MeOH/CH.sub.2 
Cl.sub.2 ; 2.5% MeOH/CH.sub.2 Cl.sub.2 ; 3-4.75% MeOH/CH.sub.2 Cl.sub.2 
+0.3-0.75% NH.sub.4 OH in 0.25% and 0.025% increments respectively. The 
faster moving isomer was further purified by preparative HPLC (UV 220; YMC 
S-10 ODS (C-18) 30.times.500 mm column; stepwise gradient from 76-86% 
MeOH/H.sub.2 O+0.1% TFA) followed by chromatography on a 2.5.times.5 cm 
silica gel column using 5% MeOH/CH.sub.2 Cl.sub.2 +0.5% NH.sub.4 OH to 
give 59 mg (17%) of the title Compound 361b as a white solid. 
m.p 175.degree.-180.degree. C.; R.sub.f =0.20, CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA detection); [.alpha.].sub.D 
=+6.2.degree. (C 0.42, MeOH). 
Mass Spec. CI+ions: M+H=598. 
Analysis calc. for C.sub.34 H.sub.51 N.sub.3 O.sub.6 : C, 68.31; H, 8.60; 
N, 7.03; Found C, 68.38; H, 8.80; N, 7.08. 
EXAMPLE 362 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2,2-Dimethyl-1-hydroxycyclohexyl)carbonyl 
]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]car 
bamic acid, 1,1-dimethylethyl ester, isomer B 
(Compound 362) 
##STR824## 
The slower moving isomer of Example 361b was further purified by 
preparative HPLC (UV 220; YMC S-10 ODS (C-18) 30.times.500 mm column; 
stepwise gradient from 76-86% MeOH/H.sub.2 O+0.1% TFA) followed by 
chromatography on a 2.5.times.5 cm silica gel column using 5% 
MeOH/CH.sub.2 Cl.sub.2 +0.5% NH.sub.4 OH to afford 50 mg (15%) of Compound 
362 as a white solid. 
m.p. 101.degree.-105.degree. C.; R.sub.f =0.17, CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA detection); [.alpha.].sub.D 
=-4.1.degree. (C 0.49, MeOH). 
Mass Spec. FAB+ions: M+H=598. 
Analysis calc. for C.sub.34 H.sub.51 N.sub.3 O.sub.6.0.28 H.sub.2 O: C, 
67.74; H, 8.62; N, 6.97; Found C, 67.70; H, 8.57; N, 7.01. 
EXAMPLE 363 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[2-(3-methyl-2-oxo-1-imidazolidinyl)ethoxy]phenyl]butyl]amino]-2- 
hydroxy-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester 
(Compound 363d) 
(a) Compound 363a 
##STR825## 
To a solution of Compound 343a (750 mg; 5.72 mmol) in 572 .mu.L of dry 
benzene was added SOCl.sub.2 (417 .mu.L; 5.72 mmol). The solution was 
heated to reflux for 3 h at which time an additional amount of SOCl.sub.2 
(83 .mu.L; 1.14 mmol) was added to the reaction. After 30 min, NaHCO.sub.3 
(576 mg) was added and the mixture was filtered. The solid residue was 
washed with 50 mL of benzene. The filtrate was treated with charcoal and 
filtered. The filtrate was concentrated in vacuo to afford Compound 363a 
as a clear brown oil (580 mg; 68%). 
(b) Compound 363b 
##STR826## 
Compound 363a (424 mg; 2.83 mmol) and methylamine (1.95 mL; 56.6 mmol; 40% 
weight solution in H.sub.2 O) were stirred at RT for 6 d. The reaction 
mixture was concentrated in vacuo and purified on silica gel using a 
stepwise gradient of 2% to 8% MeOH:CH.sub.2 Cl.sub.2 to afford Compound 
363b (333 mg; 82%) as a green oil. 
(c) Compound 363c 
##STR827## 
Compounds 175c and 363b were reacted by a procedure analogous to that of 
Example 282a to afford Compound 363c. 
(d) Compound 363d 
##STR828## 
Compounds 363c and 16b were reacted by a procedure analogous to that of 
Example 226b to give the title Compound 363d as a white solid. 
m.p. 63.degree.-66.degree. C.; [.alpha.].sub.D =+2.5.degree. (c 0.12, 
CH.sub.3 OH) 
Mass Spec. (FAB): (M+H)=686 
EXAMPLE 364 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[tetrahydro-3-hydroxy-4,4-dimethyl-3 
-furanyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)-propyl]carba 
mic acid, 1,1-dimethylethyl ester, Isomer A 
(Compound 364f) 
(a) Compound 364a 
##STR829## 
(D,L)-Pantolactone was converted to Compound 364a by a procedure analogous 
to that of Example 306a. 
(b) Compound 364b 
##STR830## 
To a -78.degree. C. solution of Compound 364a (7.50 g; 34.0 mmol) in 
anhydrous toluene and CH.sub.2 Cl.sub.2 (75 mL each) was added a solution 
of DIBAL-H (40.90 mL of a 1.0M solution in hexanes; 40.9 mmol) over 1 h. 
The solution was stirred at -78.degree. C. for 2 h. MeOH (9.0 mL) was 
added dropwise. The resulting suspension was allowed to warm to RT. Brine 
(31 mL) and Et.sub.2 O (1 L) were added, followed by MgSO.sub.4 (70 g). 
The suspension was stirred for 1.5 h, and then filtered. The solids were 
washed with EtOAc and the combined filtrates were concentrated in vacuo to 
give a viscous oil, which solidified on standing to give Compound 364b 
(7.11 g; 94%; 5.4:1 mixture of anomers) as a white solid. 
(c) Compound 364c 
##STR831## 
To a -78.degree. C. solution of Compound 364b (5.97 g; 26.8 mmol) in 
anhydrous CH.sub.2 Cl.sub.2 were successively added Et.sub.3 SiH (12.84 
mL, 80.4 mmol), and BF.sub.3.OEt.sub.2 (3.63 mL; 29.5 mmol) dropwise. The 
solution was stirred at -78.degree. C. for 2 h, then slowly warmed to 
0.degree. C. and stirred for 1 h, then cooled to -78.degree. C. 
NaHCO.sub.3 (9.0 g) was added and the mixture was stirred at -78.degree. 
C. for 15 min. Saturated aq. NaHCO.sub.3 was added, and the mixture was 
allowed to warm to RT over 1 h. The aqueous layer was extracted with EtOAc 
and the combined organic extracts were dried (MgSO.sub.4), concentrated in 
vacuo, and purified by flash chromatography (SiO.sub.2 ; 200 mL) using a 
stepwise gradient from 99:1 to 90:10 hexanes:Et.sub.2 O to give Compound 
364c (4.89g; 88%) as a colorless oil. 
(d) Compound 364d 
##STR832## 
Compound 364c was converted to Compound 364d by a procedure analogous to 
that described in Example 19. 
(e) Compound 364e 
##STR833## 
Compound 364d was converted to Compound 364e by a procedure analogous to 
that of Example 314a. 
(f) Compound 364f 
##STR834## 
Compounds 364e and 54 were converted to the title Compound 364f by a 
four-step procedure analogous to that described in Example 321. Flash 
chromatography (100 mL SiO.sub.2 ; stepwise gradient from 99:1:0.1 to 
90:10:1 CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH) followed by preparative HPLC 
(Polymer Labs PLRP-S column, 25.times.300 mm, 10 .mu.m particle size, 
stepwise gradient from 70:30 to 45:55 A:B (where A=90:10:0.2 H.sub.2 
O:MeCN:NH.sub.4 OH and B=90:10:0.2 MeCN:H.sub.2 O:NH.sub.4 OH)), and 
lyophilization from dioxane-H.sub.2 O gave 19 mg of Compound 364f as a 
white solid. 
m.p.=84.degree.-87.degree. C.; [.alpha.]=+6.8.degree. (c=0.20, MeOH); 
R.sub.f (SiO.sub.2)=0.29 (90:10:1 CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH). 
Mass Spec. (CI): (M+H).sup.+ =586 
Analysis calc. for C.sub.32 H.sub.47 N.sub.3 O.sub.7.0.78 H.sub.2 O: C, 
64.07; H, 8.16; N, 7.01 Found: C, 63.99; H, 7.97; N, 7.09. 
EXAMPLE 365 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[tetrahydro-3-hydroxy-4,4-dimethyl-3 
-furanyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)-propyl]carba 
mic acid, 1,1-dimethylethyl ester, Isomer B 
(Compound 365) 
##STR835## 
Flash chromatography followed by preparative HPLC as described in Example 
364f gave 17 mg of the title Compound 365 (white solid). 
m.p.=82.degree.-85.degree. C.; [.alpha.]=-13.7.degree. (c=0.16, MeOH); 
R.sub.f (SiO.sub.2)=0.19 (90:10:1 CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH). 
Mass Spec. (CI): (M+H).sup.+ =586 
Analysis calc. for C.sub.32 H.sub.47 N.sub.3 O.sub.7.0.69 H.sub.2 O: C, 
64.25; H, 8.15; N, 7.02. Found: C, 64.24; H, 8.02; N, 7.03. 
EXAMPLE 366 
Preparation of [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3 
-[[2-Hydroxy-2-(hydroxymethyl)-3,3-dimethyl-1-oxobutyl]amino]-2-hydroxy-4- 
phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester, isomer A (Compound 366d) 
(a) Compound 366a 
##STR836## 
To a solution of 80% m-CPBA (8.5 g, 39.41 mmol) in 160 mL CH.sub.2 Cl.sub.2 
was added Compound 262a (3 g, 26.27 mmol) in 30 mL CH.sub.2 Cl.sub.2 (40 
mL) and the mixture stirred at RT for 20 h. The reaction mixture was 
cooled to 0.degree. C. and quenched by addition of Me.sub.2 S (6 mL) and 
washed with 10% aq. Na.sub.2 CO.sub.3. The aqueous phase was extracted 
with CH.sub.2 Cl.sub.2, and the combined organic layer dried (Na.sub.2 
SO.sub.4), filtered and the solvent removed by distillation. Fractional 
distillation (10-23 mm, 70.degree.-90.degree. C.) of the residue afforded 
Compound 366a (2.63 g, 77% yield) as a light yellow liquid. 
(b) Compound 366b 
##STR837## 
To Compound 366a (2.47 g, 18.97 mmol) in CH.sub.3 CN (65 mL), was added 
0.85 mL H.sub.2 O, followed by NaIO.sub.4 (12.17 g, 56.92 mmol) and 
RuCl.sub.3 (86.5 mg, 0.417 mmol) and the slurry stirred at RT for 2-3 min, 
after which another 0.85 mL H.sub.2 O was added and the mixture stirred at 
RT for 2 h. The reaction mixture was diluted with Et.sub.2 O, filtered 
through celite and the filtrate concentrated in vacuo. The resulting 
residue was dissolved in 1N NaOH (pH ca. 12), extracted with Et.sub.2 O 
and the aqueous layer separated and acidified (pH 3.0) by addition of 3N 
HCl. Saturation of the aqueous phase with Na.sub.2 SO.sub.4, and 
extraction with EtOAc afforded Compound 366b (1.58 g, 58% yield) as a 
brown oil. 
(c) Compound 366c 
##STR838## 
To Compound 366b (1.58 g, 10.97 mmol) in H.sub.2 O (55 mL), was added 10% 
H.sub.2 SO.sub.4 (25 mL) and the mixture heated at 100.degree.-105.degree. 
C. for 8 h. The mixture was cooled to RT, saturated with Na.sub.2 SO.sub.4 
and extracted with EtOAc. The organic layer was separated, dried 
(MgSO.sub.4) and concentrated in vacuo. The residue was purified by silica 
gel chromatography, eluting with 80:20:0.2 to 0:100:1 hexane:EtOAc:HOAc to 
afford Compound 366c (276 mg, 16% yield) as a white solid. 
(d) Compound 366d 
##STR839## 
To a solution of Compound 54 (300 mg, 0.676 mmol) in DMF (1.5 mL) was added 
a solution of Compound 366c (120 mg, 0.743 mmol) in 0.3 mL DMF, followed 
by BOP reagent (329 mg, 0.743 mmol) and N-methylmorpholine (164 .mu.L, 
1.48 mmol) at 0.degree. C. The mixture was heated at 50.degree. C. for 24 
h, and then stirred at RT for another 24 h. DMF was removed in vacuo and 
the residue dissolved in EtOAc, washed with saturated NaHCO.sub.3 and then 
with brine. The organic layer was separated, dried (MgSO.sub.4) and 
concentrated in vacuo to afford the crude product as a mixture of 
diastereomers. Combination with material from a prior reaction (0.113 mmol 
scale reaction) and chromatography on silica gel, eluting with 99:1:01 to 
92:8:0.8 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. NH.sub.4 OH gave Compound 366d 
as the faster moving isomer. Further purification by preparative HPLC 
(Polymer Labs PLRP-S 100 .ANG., 10.mu. column, stepwise gradient [65:35 
C:D to 55:45 C:D (1 h); C=10% CH.sub.3 CN/H.sub.2 O+0.2% aq. NH.sub.4 OH; 
D=90% CH.sub.3 CN/H.sub.2 O+0.2% aq. NH.sub.4 OH]) gave the title Compound 
366d (13 mg, 3%) as a white solid. 
m.p. 83.degree.-85.degree. C.; R.sub.f (SiO.sub.2)=0.4 (90:10:1 CH.sub.2 
Cl.sub.2 :MeOH:NH.sub.4 OH). 
Mass spectrum (Fab): (M+H).sup.+ 588.sup.+. 
EXAMPLE 367 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-Hydroxy-2-(hydroxymethyl)-3,3-dimethyl- 
1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl) 
propyl]carbamic acid, 1,1-dimethylethyl ester, isomer B (Compound 367) 
##STR840## 
The slower moving isomer from Example 366d was purified by preparative HPLC 
in analogy to Compound 366d to afford Compound 367 as a white solid. 
m.p. 84.degree.-86.degree. C.; R.sub.f (SiO.sub.2)=0.3 (90:10:1 CH.sub.2 
Cl.sub.2 :MeOH:NH.sub.4 OH). 
Mass spectrum (Fab): (M+H).sup.+ 588.sup.+. 
EXAMPLE 368 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethyl-1-hydroxycyclopentyl)carbon 
yl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]c 
arbamic acid, 2-hydroxy-1,1-dimethylethyl ester, isomer A (Compound 368f) 
(a) Compound 368a 
##STR841## 
To an ice cooled solution of 1.75 g (3 mmol) of Compound 45 and 1.03 ml (6 
mmol) of i-Pr.sub.2 NEt in 10 ml of DMF was added dropwise 470 .mu.l (3.3 
mmoles) of benzyl chloroformate, neat. Stirring was continued with cooling 
for 0.5 h, then at RT overnight. The solution was evaporated to dryness 
and the residue purified by flash chromatography on a 1250 cc column of 
silica gel. Elution with 40% EtOAc - hexane afforded 2.0 g (94%) of 
Compound 368a as a white solid. 
TLC (SiO.sub.2) R.sub.f =0.14 (1:1 EtoAc/Hexane). 
(b) Compound 368b 
##STR842## 
To 1.88 g (2.64 mmol) of Compound 368a at 0.degree. C. was added 10 ml of 
4N HCl-dioxane. The reaction was stirred with cooling until solution was 
obtained, then at RT for an additional 3 h. The reaction mixture was 
evaporated to dryness and the residue evaporated twice from MeOH to afford 
1.54 g (90%) of Compound 368b as a white solid. 
TLC (SiO.sub.2) R.sub.f =0.33 (10% MeOH/CHCl.sub.3). 
(c) Compound 368c 
##STR843## 
A solution of 1.38 g (2.13 mmol) of Compound 368b, 0.86 g (2.34 mmol) of 
Compound 161d, and 2.2 ml of i-Pr.sub.2 NEt in 10 ml of DMF was stirred at 
RT for 5 d. The solution was evaporated to dryness and the residue 
dissolved in EtOAc. The solution was washed with 1N HCl, brine, 1N NaOH, 
and brine and dried (MgSO.sub.4). After removal of solvent, the residue 
was purified by flash chromatography on a 500 cc column of silica gel. 
Elution with 25% EtOAc - hexane, followed by 50% EtOAc - hexane afforded 
1.36 g (76%) of Compound 368c as a solid white foam. 
TLC (SiO.sub.2) R.sub.f =0.25 (1:1 EtOAc/hexane). 
(d) Compound 368d 
##STR844## 
A solution of 1.0 g (1.19 mmol) of Compound 368c in 20 ml of EtOH was 
hydrogenated over 100 mg of 20% Pd(OH).sub.2 /C catalyst for 2 h at RT. To 
the reaction was added 1 ml of NH.sub.4 OH and stirring was continued for 
0.5 h. The catalyst was removed by filtration through Celite and the 
filtrate evaporated to dryness to give 717 mg (100%) of Compound 368d as a 
solid foam. 
TLC (SiO.sub.2) R.sub.f =0.21 (CHCl.sub.3 :MeOH:aq. NH.sub.4 OH 90:10:1). 
(e) Compound 368e 
##STR845## 
To a solution of 700 mg (1.22 mol) of368d, 193 mg (1.22 mol) of Compound 
321c, and 148 .mu.l (1.35 mol) of N-methylmorpholine in 5 ml of DMF, with 
ice cooling, was added 597 mg (1.35 mol) of BOP reagent. Stirring was 
continued with cooling for 2 h, then at RT overnight. After removal of the 
DMF (high vac, 30.degree. C.) the residue, in EtOAc, was washed with brine 
and dried (MgSO.sub.4). The solvent was removed and the residue purified 
by flash chromatography on a 125 cc column of silica gel. Elution with 
CHCl.sub.3 :MeOH:NH.sub.4 OH (95:5:0.5) afforded 737 mg (85%) of Compound 
368e as a white foam. 
TLC(SiO.sub.2) R.sub.f =0.39 and 0.34 (CHCl.sub.3 :MeOH:aq. NH.sub.4 OH 
90:10:1). 
(f) Compound 368f 
##STR846## 
A solution of 720 mg (1 mmol) of Compound 368e in 10 ml HOAc:H20:THF 
(3:1:1) was stirred at RT for 48 h. The reaction was evaporated to dryness 
and the clear colorless oil residue dissolved in EtOAc and washed with 
sat. aq. NaHCO.sub.3 and with brine and dried (MgSO.sub.4). Removal of 
solvent gave 654 mg of crude material which was purified by flash 
chromatography on a 125 cc column of silica gel. Elution with CHCl.sub.3 
:MeOH:NH.sub.4 OH (95:5:0.5) afforded, as the faster moving isomer, 
Compound 368f, which was triturated with CHCl.sub.3 to afford 161 mg (0.27 
mmole) of the title Compound 368f as a white powder. 
m.p. 178.degree.-179.degree. C.; [.alpha.].sub.D =+16.0.degree. (c 0.73, 
MeOH) 
R.sub.f (SiO.sub.2)=0.20 (CHCl.sub.3 :MeOH:NH.sub.4 OH, 90:10:1). 
Mass Spec.: (M+H).sup.+ 600.sup.+. 
Analysis calc. for C.sub.33 H.sub.49 N.sub.3 O.sub.7.0.85 H.sub.2 O: C, 
64.45; H, 8.31; N, 6.83. Found: C, 64.20; H, 8.09; N, 7.08. 
EXAMPLE 369 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,2-Dimethyl-1-hydroxycyclopentyl)carbon 
yl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]c 
arbamic acid, 2-hydroxy-1,1-dimethylethyl ester, isomer B (Compound 369) 
##STR847## 
The slower moving isomer from Example 368f was further purified by 
preparative HPLC on a YMC S-10 ODS (30.times.500 mm) column. Gradient 
elution from 60-90% MeOH-H.sub.2 O+0.1% TFA afforded a white foam which 
was passed through a short column of silica gel (elution with CHCl.sub.3 
:MeOH:NH.sub.4 OH, 90:10:1) to give 71 mg of Compound 369 as a solid white 
foam. 
m.p. 90.degree.-100.degree. C. (softening at 80.degree.); [.alpha.].sub.D 
=-12.9.degree. (c 0.79, MeOH). 
R.sub.f (SiO.sub.2)=0.17 (CHCl.sub.3 :MeOH:NH.sub.4 OH, 90:10:1). 
Mass Spec.: (M+H).sup.+ 600.sup.+. 
Analysis calc. for C.sub.33 H.sub.49 N.sub.3 O.sub.7.0.40 H.sub.2 O: C, 
65.30; H, 8.27; N, 6.92. Found: C, 65.39; H, 8.32; N, 6.83. 
EXAMPLE 370 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(2-ethenylphenyl)butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carba 
mic acid, 1,1-dimethylethyl ester (Compound 370c) 
(a) Compound 370a 
##STR848## 
A solution of Compound 349a (1.9 g, 6.8 mmol) in 100 ml of CH.sub.2 
Cl.sub.2 was cooled at 0.degree. C. and N-phenyltriflimide (2.67 g, 7.47 
mmol) was added follwed by Et.sub.3 N (1.15 ml, 8.25 mmol). The reaction 
was stirred at 0.degree. C. for 2.5 h and then allowed to warm to RT and 
stir overnight. Additional quantities of N-phenyltriflimide (800 mg, 2.24 
mmol) and Et.sub.3 N (345 ml, 2.48 mmol) were added. Stirring was 
continued for an additional 6 h at RT. The reaction was diluted with 
Et.sub.2 O and washed with H.sub.2 O, 1N NaOH, H.sub.2 O, and brine. After 
drying (Na.sub.2 SO.sub.4), the solvents were removed and the crude 
material was purified on a 250 ml silica column eluting with EtOAc/hexanes 
(1:4) to afford 1.6 g (68%) of Compound 370a as a colorless solid. 
(b) Compound 370b 
##STR849## 
To a solution of the Compound 370a (610 mg, 1.5 mmol) in 10 ml of 
1-methyl-2-pyrrolidinone was added LiCl (190 mg, 4.5 mmol) and 
triphenylarsine (90 mg, 0.3 mmol) and the reaction mixture was degassed 
with argon. Tris(dibenzylideneacetone)dipalladium (0) (138 mg, 0.15 mmol) 
was added and the mixture stirred for 5 min. Vinyltributyltin (0.520 ml, 
560 mg, 1.8 mmol) was added and the reaction mixture was then stirred for 
2.5 h at RT and heated at 55.degree. C. overnight. An additional 20% of 
triphenylarsine (18mg), Pd.degree. (28 mg) and vinyltributyltin (104 ml) 
were added and heating was continued for an additional 6 h. The mixture 
was poured into 1:1 sat. NaHCO.sub.3 /H.sub.2 O and extracted with EtOAc. 
The combined EtOAc extract was washed with H.sub.2 O and brine and dried 
(Na.sub.2 SO.sub.4). The solvent was removed and the crude material was 
purified on a 100 ml silica column eluting with 10 to 20% EtOAc/hexane 
gradient to afford 190 mg (44%) of Compound 370b as a colorless solid. 
(c) Compound 370c 
##STR850## 
Compounds 370b and 16b were reacted by a procedure analogous to that of 
Example 304c to afford the title Compound 370c (colorless solid). 
m.p. 173.degree.-176.degree. C. (dec); [.alpha.].sub.D =-6.0.degree. (c 
0.5, MeOH) 
Mass Spec.: (M+H).sup.+ 570.sup.+. 
Analysis calc. for C.sub.32 H.sub.47 N.sub.3 O.sub.6.1.5 H.sub.2 O: C, 
64.40; H, 8.40; N, 7.05. Found: C, 64.21; H, 8.03; N, 7.00. 
EXAMPLE 371 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-(2-ethylphenyl)butyl]amido]-2-hydroxy-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester (Compound 371) 
##STR851## 
A solution of Compound 370c (68 mg, 0.12 mmol) in 3 ml of MeOH containing 7 
mg of 10% Pd/C catalyst was stirred under a hydrogen atmosphere (balloon) 
for 12 h. The reaction was filtered and the MeOH evaporated to afford 66 
mg (98%) of Compound 371 as a colorless solid. 
m.p. 178.degree.-181.degree. C. (dec); [.alpha.].sub.D =-5.6.degree. (c 
0.5, MeOH) 
Mass Spec.: (M+H).sup.+ 572.sup.+. 
Analysis calc. for C.sub.32 H.sub.49 N.sub.3 O.sub.6.1.75 H.sub.2 O: C, 
63.61; H, 8.91; N, 7.08. Found: C, 63.71; H, 8.77; N, 6.97. 
EXAMPLE 372 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[4-[4-[2-[[(Dimethylamino)carbonyl]oxy]ethoxy] 
phenyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxybutyl]amino]-2-hyd 
roxy-1-(phenylmethyl)propyl]carbamic acid (Compound 372d) 
(a) Compound 372a 
##STR852## 
To a stirred solution of phosgene in toluene (8.5 mL of a 1.93M solution; 
16.4 mmol) at -60.degree. C. was added a solution of 2-benzyloxyethanol 
(467 .mu.L, 3.28 mmol) and pyridine (583 .mu.L, 7.22 mmol) in 3 mL 
CH.sub.2 Cl.sub.2. After adding 20 mL more CH.sub.2 Cl.sub.2, the 
temperature of the reaction mixture was allowed to rise to 15.degree. C. 
and was then cooled to -20.degree. C. Excess N,N-dimethylamine was bubbled 
through the turbid mixture which was stirred at RT overnight. The solution 
was washed with H.sub.2 O, dried (Na.sub.2 SO.sub.4), and concentrated to 
afford the crude product which was purified by chromatography on a column 
(5 cm.times.15 cm) of silica gel eluting with EtOAc-hexane (20-80 to 
25-75) to afford 490 mg (67%) of Compound 372a. 
(b) Compound 372b 
##STR853## 
Compound 372a was converted to Compound 372b by a procedure analogous to 
that of Example 208 (EtOH was used instead of MeOH). 
(c) Compound 372 c 
##STR854## 
Compounds 372b and 175c were converted to Compound 372c by a procedure 
analogous to that of Example 282a. 
(d) Compound 372d 
##STR855## 
Compounds 372c and 16b were reacted by a procedure analogous to that of 
Example 304c to give the title Compound 372d (white solid). 
m.p. 128.degree.-132.degree. C.; [.alpha.].sub.D =-3.1.degree. (c 0.52, 
MeOH) 
Mass Spec. (FAB), 675 (M+H).sup.+. 
Analysis calc. for C.sub.35 H.sub.54 N.sub.4 O.sub.9.0.54 H.sub.2 O: C, 
61.41; H, 8.11; N, 8.18. Found: C, 61.40; H, 7.95; N, 8.19. 
EXAMPLE 373 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]- 
2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbo 
nyl]-1,2-dimethylpropyl]carbamic acid, methyl ester, isomer A (Compound 
373d) 
(a) Compound 373a 
##STR856## 
Compound 373a was prepared as described in Obrecht et al., Helv. Chim. 
Acta, 75, 1666 (1992). 
(b) Compound 373b 
##STR857## 
A solution of 1.2 g (7.1 mmol) of 373a in 25 ml of concentrated HCl was 
heated at 130.degree. C., in a pressure vessel, for 7 d. After cooling to 
RT, the solution was evaporated to dryness to yield a solid residue which 
was taken into H.sub.2 O, washed with CH.sub.2 Cl.sub.2, and again 
evaporated to dryness to yield 1.6 g of Compound 373b as a tan solid. 
(c) Compound 373c 
##STR858## 
Compound 373b was converted to Compound 373c by a procedure analogous to 
that of Example 246a. 
(d) Compound 373d 
##STR859## 
Compounds 373c and 54 were converted to the title Compound 373d by a 
two-step procedure analogous to that employed for the synthesis of 
Compound 312d (CH.sub.2 Cl.sub.2 only used for reaction of HOBT with 
Compound 373c). The crude product was purified by flash chromatography on 
a 45 cc column of silica gel. Elution with CHCl.sub.3 :MeOH:NH.sub.4 OH 
(95:5:0.5) afforded 140 mg of a mixture of isomers which were separated by 
preparative HPLC on a YMC S-10 ODS (30.times.500 mm) column. Isocratic 
elution with 70% MeOH-H.sub.2 O+0.1% TFA, gave as the faster moving isomer 
on C-18, Compound 373d, which was passed through a short column of silica 
gel (elution with CHCl.sub.3 :MeOH:NH.sub.4 OH (90:10:1)) and triturated 
with Et.sub.2 O to afford 42 mg (16%) of the title Compound 373d as a 
white solid. 
m.p. 120.degree.-122.degree. C.; [.alpha.].sub.D =-0.9.degree. (c 0.66, 
MeOH) 
Mass Spec.: (M+H).sup.+ 629.sup.+. 
Analysis calc. for C.sub.34 H.sub.52 N.sub.4 O.sub.7 : C, 64.94; H, 8.33; 
N, 8.91. Found: C, 64.54; H, 8.13; N, 8.57. 
EXAMPLE 374 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[1-[[[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]- 
2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]amino]carbo 
nyl]-1,2-dimethylpropyl]carbamic acid, methyl ester, isomer B (Compound 
374) 
##STR860## 
The slower moving isomer on C-18 was isolated by preparative HPLC as 
described in Example 373d followed by passage through a short column of 
silica gel (elution with CHCl.sub.3 :MeOH:NH.sub.4 OH (90:10:1)) and 
trituration with Et.sub.2 O to afford 54 mg (20%) of Compound 374 as a 
white solid. 
m.p. 168.degree.-170.degree. C.; [.alpha.].sub.D =-21.5.degree. (c 0.75, 
MeOH) 
Mass Spec.: (M+H).sup.+ 629.sup.+. 
Analysis calc. for C.sub.34 H.sub.52 N.sub.4 O.sub.7 : C, 64.94; H, 8.33; 
N, 8.91. Found: C, 64.75; H, 8.33; N, 8.68. 
EXAMPLE 375 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,3-Dihydro-1-hydroxy-1H-inden-1-yl)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]carbamic acid, 1,1-dimethylethyl ester, isomer A (Compound 375) 
##STR861## 
1-Indanone was converted to a 1:1 mixture of Compounds 375 and 376 by a 
four-step procedure analogous to that used for the synthesis of Compounds 
321 and 322. Compound 375 (while solid) was isolated as the faster moving 
isomer by silica gel chromatography, eluding with 99:1:0.1 to 94:6:0.6 
CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. NH.sub.4 OH. 
m.p. 189.degree.-192.degree. C.; [.alpha.].sub.D =-15.7.degree. (c 0.2, 
CH.sub.3 OH) R.sub.f (SiO.sub.2)=0.32 (99:1:0.1 CH.sub.2 Cl.sub.2 
:CH.sub.3 OH:aq. NH.sub.4 OH) 
Mass Spec. (Fab): (M+H).sup.+ 604. 
Analysis calc. for C.sub.35 H.sub.45 N.sub.3 O.sub.6 : C, 69.63; H, 7.51; 
N, 6.96. Found: C, 69.28; H, 7.5; N, 6.97. 
EXAMPLE 376 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(2,3-Dihydro-1-hydroxy-1H-inden-1-yl)carb 
onyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl 
]carbamic acid, 1,1-dimethylethyl ester, isomer B (Compound 376) 
##STR862## 
Compound 376 (white solid) was isolated as the slower moving isomer as 
described in Example 375. 
m.p. 100.degree.-102.degree. C.; [.alpha.].sub.D =+15.0.degree. (c 0.22, 
CH.sub.3 OH) 
R.sub.f (SiO.sub.2)=0.25 (99:1:0.1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. 
N.sub.4 OH) 
Mass Spec. (Fab): (M+H).sup.+ 604. 
EXAMPLE 377 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(S*)]]]-[3-[[3-[2-Hydroxy-1-oxo-2-phenylethyl)amino]-2 
-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 377) 
##STR863## 
To a solution of (R)-mandelic acid (100 mg, 0,225 mmol) in DMF (0.5 mL) was 
added Compound 54 (37.6 mg, 0.247 mmol), followed by BOP reagent (241 mg, 
0.545 mmol) and N-methylmorpholine (132 .mu.L, 1.20 mmol) at 0.degree. C. 
The mixture was stirred at RT for 16 h. DMF was removed in vacuo and the 
residue dissolved in EtOAC, washed with saturated aq. NaHCO.sub.3 and then 
with brine. The organic layer was separated, dried (MgSO.sub.4) and 
concentrated in vacuo and the residue purified by silica gel 
chromatography, eluting with 99:1:0.1 to 91.5:8.5:0.85 CH.sub.2 Cl.sub.2 
:CH.sub.3 OH:aq. NH.sub.4 OH to afford Compound 377 (94 mg, 72%) as a 
white solid. 
m.p. 125.degree.-127.degree. C.; [.alpha.].sub.D =-13.0.degree. (c 0.2, 
CH.sub.3 OH) 
Mass Spec. (Fab): (M+H).sup.+ 578.sup.+. 
Analysis calc. for: C.sub.33 H.sub.43 N.sub.3 O.sub.6.0.80 H.sub.2 O C, 
66.93; H, 7.59;N, 7.10. Found: C, 66.76; H, 7.55; N, 7.27. 
EXAMPLE 378 
Preparation of 
[1S-[1R*,2S*[2S*,3R*(R*)]]]-[3-[[3-2-Hydroxy-1-oxo-2-phenylethyl)amino]-2- 
hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic 
acid, 1,1-dimethylethyl ester (Compound 378) 
##STR864## 
(S)-Mandelic acid and Compound 54 were reacted by a procedure analogous to 
that of Example 377 to afford the title Compound 378 (white solid). 
m.p. 135.degree.-138.degree. C.; [([.alpha.].sub.D =+9.1.degree. (c 0.22, 
CH.sub.3 OH) 
Mass Spec. (Fab): (M+H).sup.+ 578.sup.+. 
Analysis calc. for: C.sub.33 H.sub.43 N.sub.3 O.sub.6.0.63 H.sub.2 O C, 
67.28; H, 7.57; N, 7.13. Found: C, 67.12; H, 7.54; N, 7.29. 
EXAMPLE 379 
Preparation of [1S-(1R*,2S*) 
(trans)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]bis[carbami 
c acid], 1,1-dimethylethyl 2-hydroxy-1-methylcyclopentyl ester (Compound 
379e) 
(a) Compound 379a 
##STR865## 
A solution of NaOH (600 mg; 15 mmol) and KMnO.sub.4 (2.81 g; 17.8 mmol) in 
95 ml of H.sub.2 O precooled to 0.degree. C. was added to a slurry of 
1-methylcyclopentene (1 g; 12 mmol), t-BuOH (120 ml), H.sub.2 O (25 ml) 
and ice (60 g) at -10.degree. C. The resulting mixture was stirred 10 min 
at -10.degree. C. Sodium sulfite (2.3 g) was added and the mixture was 
filtered through celite. The filtrate was concentrated to .about.30 ml by 
distillation of the solvents at atmospheric pressure. Solid NaCl was added 
to saturation and the mixture was extracted with EtOAc. After drying 
(MgSO.sub.4), the organic layer was concentrated to afford 1.03 g (74%) of 
racemic Compound 379a. 
(b) Compound 379b 
##STR866## 
Compound 379a was converted into racemic Compound 379b by a procedure 
analogous to that of Example 264b. 
(c) Compound 379c 
##STR867## 
Compound 379b was converted into racemic Compound 379c by a procedure 
analogous to that of Example 161d. 
(d) Compound 379d 
##STR868## 
Compounds 379c and 298a were reacted by a two-step procedure analogous that 
that used for the conversion of Compound 282c to Compound 282e to afford 
Compound 379d. 
(e) Compound 379e 
##STR869## 
Compounds 379d and 1b(i) were reacted by a two-step procedure analogous to 
that used for the conversion of Compound 282e to Compound 282g to afford 
the title Compound 379e (white solid). 
m.p. 102.degree.-113.degree. C. ("shrinkage at 68.degree.-87.degree. C.); 
Mass Spec. (FAB) (M+H).sup.+ =586. 
Analysis calc. for C.sub.32 H.sub.46 N.sub.3 O.sub.7.0.98H.sub.2 O: C, 
63.81; H, 8.02; N, 6.98 Found: C, 63.81; H, 8.17; N, 6.98. 
EXAMPLE 380 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[2-(3-oxo-4-morpholinyl)ethoxy]phenyl]butyl]amino]-2-hydroxy-1-(p 
henylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (Compound 380d) 
(a) Compound 380a 
##STR870## 
To a 0.degree. C. solution of diethanolamine (2.10 g; 20.0 mmol) in 40 mL 
of dry CH.sub.2 Cl.sub.2 was added dry Et.sub.3 N (4.2 mL; 30.0 mmol) and 
bromoacetyl bromide (2.1 mL; 24.0 mmol). The reaction mixture was stirred 
at 5.degree. C. for 3 h, then at RT overnight. Volatiles were removed in 
vacuo and the residue was purified on silica using 100% EtOAc to afford 
1.5 g of pure Compound 380a (33%). 
(b) Compound 380b 
##STR871## 
To a suspension of Nail (260 mg; 6.63 mmol; 60% in mineral oil) in 1.0 mL 
of dry DMF at 0.degree. C. was added a solution of Compound 380a (1.5 g; 
6.63 mmol) in 5.5 mL of dry DMF. The solution was allowed to warm to RT. 
After 6 h another 260 mg (6.63 mmol) of Nail was added and the mixture was 
stirred overnight. The reaction was quenched with H.sub.2 O and 
concentrated in vacuo to give crude material which was purified on silica 
gel using a stepwise gradient from 2% to 8% MeOH:CH.sub.2 Cl.sub.2 :0.1% 
NH.sub.4 OH to afford Compound 380b (600 mg; 62%). 
(c) Compound 380c 
##STR872## 
Compounds 175c and 380b were reacted by a procedure analogous to that of 
Example 282a to give Compound 380c. 
(d) Compound 380d 
##STR873## 
Compounds 16b and 380c were reacted by a procedure analogous to that of 
304c to give the title Compound 380d (white solid). 
m.p. 108.degree.-111.degree. C.; [.alpha.].sub.D =-3.3.degree. (c 0.03, 
CH.sub.3 OH) 
Mass Spec. (FAB): (M+H)=687. 
EXAMPLE 381 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-hydroxy-1-oxo-2-(2- 
pyridinyl)propyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester, isomer A (Compound 381b) 
(a) Compound 381a 
##STR874## 
ZnI.sub.2 (96 mg; 0.3 mmol) was added to a solution of 2-acetylpyridine 
(1.10 ml; 9.8 mmol) and trimethylsilylcyanide (1.70 ml; 12.7 mmol) in 20 
ml of CH.sub.2 Cl.sub.2 at 20.degree. C. After stirring at RT for 3 h, the 
solvent was removed in vacuo and the residue was stirred in .about.4 ml of 
concentrated HCl at RT for 40 h. After cooling to 0.degree. C., the pH of 
the reaction mixture was adjusted to 9 with 6N NaOH. The basic mixture was 
washed with EtOAc, concentrated to .about.15 ml and loaded onto an HP-20 
column, eluting with water, to afford 940 mg (50%) of Compound 381a as a 
white solid. 
(b) Compound 381b 
##STR875## 
Compounds 54 and 381a were reacted by a procedure analogous to that 
described in Example 321d to afford a 1:1 mixture of Compounds 381b and 
382. The diastereomers were separated by preparative HPLC [YMC S-10 ODS 
(C-18) 30.times.500 mm column; stepwise gradient from 56-74% MeOH/H.sub.2 
O+0.1% TFA]. Final isolation of the faster moving isomer by chromatography 
on a 2.5.times.10 cm silica gel column using 5% MeOH/CH.sub.2 Cl.sub.2 
+0.5% NH.sub.4 OH as the mobile phase gave 88 mg (33%) of the title 
Compound 381b as a white solid. 
m.p. 114.degree.-117.degree. C. (softens at 92.degree. C.); R.sub.f 
(SiO.sub.2)=0.25, CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA 
detection); [.alpha.].sub.D =-7.8 (c 0.32, MeOH). 
Mass Spec. FAB: M+H=593. 
Analysis calc. for C.sub.33 H.sub.44 N.sub.4 O.sub.6.0.49 H.sub.2 O: C, 
65.90; H, 7.54; N, 9.31; Found C, 66.10; H, 7.45; N, 9.11. 
EXAMPLE 382 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-hydroxy-1-oxo-2-(2- 
pyridinyl)propyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester isomer B (Compound 382) 
##STR876## 
Compound 382 (white solid) was isolated as the slower moving isomer by 
preparative HPLC followed by silica gel chromatography as described in 
Example 381b. 
m.p. 92.degree.-96.degree. C.; R.sub.f (SiO.sub.2)=0.06, CH.sub.2 Cl.sub.2 
:MeOH:NH.sub.4 OH, 90:9:1 (UV and PMA detection); [.alpha.].sub.D 
=-5.7.degree. (c 0.30, MeOH). 
Mass Spec. FAB: M+H=593. 
Analysis calc. for C.sub.33 H.sub.44 N.sub.4 O.sub.6.0.26 H.sub.2 O: C, 
66.34; H, 7.51; N, 9.38; Found C, 66.46; H, 7.65; N, 9.26. 
EXAMPLE 383 
Preparation of 
[1R*,2S*[2S*,3R*(S*)]]-N-[2-Hydroxy-3-[[2-hydroxy-3-[(2-hydroxy-2,3,3-trim 
ethyl-1-oxobutyl)amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]-N.sup. 
2 -(2-methoxycarbonyl)-3-methyl-L-valinamide (Compound 383e) 
(a) Compound 383a 
##STR877## 
To a solution of Compound 298a (500 mg, 2.42 mmol) in 0.5 mL DMF was added 
Compound 246a (505 mg, 2.66 mmol), followed by HOBT hydrate (360 mg, 2.66 
mmol), N-methylmorpholine (318 mg, 3.15 mmol) and EDCI hydrochloride (510 
mg, 2.66 mmol) an 0.degree. C., and the mixture stirred at RT for 21 h. 
DMF was removed in vacuo and the residue dissolved in EtOAc, washed with 
sat. NaHCO.sub.3 and then brine. The organic layer was separated, dried 
(MgSO.sub.4) and concentrated to yield a residue which was purified by 
silica gel chromatography, eluting from 99.5:0.5:0.05 to 96.5:3.5:0.35 
CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. NH.sub.4 OH to afford Compound 383a 
(604 mg, 66%) as a white solid. 
TLC (SiO.sub.2), R.sub.f =0.41 (9:1:0.1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. 
NH.sub.4 OH - Rydon). 
(b) Compound 383b 
##STR878## 
To Compound 383a (604 mg, 1.60 mmol) in THF (7 mL) and H.sub.2 O (43 .mu.L) 
was added Ph.sub.3 P (462 mg, 1.76 mmol) and the solution stirred at RT 
for 18 h. The solvent was removed in vacuo and the resulting residue 
purified by flash chromatography on silica gel, eluting with a step wise 
gradient from 99:1:0.1 to 87:13:1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. 
NH.sub.4 OH to afford Compound 383b (478 mg, 85%) as a white solid. 
TLC (SiO.sub.2) R.sub.f =0.15 (9:1:0.1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. 
NH.sub.4 OH - Rydon). 
(c) Compound 383c 
##STR879## 
To a solution of Compound 383b (468 mg, 1.33 mmol) in DMF (0.6 mL) was 
added Compound 44a (396 mg, 1.33 mmol) and the mixture heated at 
100.degree. C. for 7 h. DMF was removed in vacuo and the residue purified 
by flash chromatography on silica gel, eluting with a step wise gradient 
from 99:1:0.1 to 82:12:1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. NH.sub.4 OH to 
afford Compound 383c (377 mg, 43%) as a white solid. 
TLC (SiO.sub.2) R.sub.f =0.28 (9:1:0.1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. 
NH.sub.4 OH/Rydon). 
(d) Compound 383d 
##STR880## 
To a solution of Compound 383c (366 mg, 0.564 mmol) in EtOH (12 mL) and 
EtOAc (4 mL) was added 20% Pd(OH).sub.2 /C (108 mg) and the slurry stirred 
under a H.sub.2 (g) atmosphere for 18 h. The reaction mixture was filtered 
and the filtrate concentrated in vacuo. The residue was purified by flash 
chromatography on silica gel, eluting with a step wise gradient from 
97.5:2.5:0.25 to 87:13:1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. NH.sub.4 OH to 
afford Compound 383d (209 mg, 7 6% ) as a white solid. 
TLC (SiO.sub.2) R.sub.f =0.14 (9:1:0.1 CH.sub.2 Cl.sub.2 :CH.sub.3 OH:aq. 
NH.sub.4 OH/Rydon). 
(e) Compound 383e 
##STR881## 
To a solution of Compound 383d (105 mg, 0.204 mmol) in DMF (0.5 mL ) was 
added Compound 262e (34.5 mg, 0.236 mmol), followed by BOP reagent (104 
mg, 0.236 mmol) and N-methylmorpholine (52 .mu.L, 0.473 mmol) and the 
mixture stirred at RT for 18 h. DMF was removed in vacuo, the residue 
dissolved in EtOAc and washed with sat. NaHCO.sub.3 and then brine. The 
organic layer was separated, dried (MgSO.sub.4) and concentrated in vacuo. 
Purification was achieved by flash chromatography on silica gel, eluting 
with a step wise gradient from 97.5:2.5:0.25 to 87:13:1 CH.sub.2 Cl.sub.2 
: CH.sub.3 OH:aq. NH.sub.4 OH to afford the title Compound 383e (70 mg, 
54% yield) as a white solid. 
m.p. 94.degree.-96.degree. C.; [.alpha.].sub.D =+4.54.degree. (c 0.22, 
CH.sub.3 OH) 
Mass Spec. (Fab): (M+H).sup.+ 643.sup.+. 
Analysis calcd. for C.sub.35 H.sub.54 N.sub.4 O.sub.7.1.00 H.sub.2 O C, 
63.62; H, 8.54; N, 8.72. Found: C, 63.70; H, 8.43; N, 8.40. 
EXAMPLE 384 
Preparation of [1S 
-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-Hydroxy-3,3-dimethyl-2-[(methylamino)carbo 
nyl]-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(phenylme 
thyl)propyl]carbamic acid, 1,1-dimethylethyl ester, isomer A (Compound 
384d) 
(a) Compound 384a 
##STR882## 
Diazomethane in Et.sub.2 O (prepared from 5.45 g of 
1-methyl-3-nitro-1-nitrosoguanidine as described in Example 1a(i)) was 
added to a suspension of Compound 366c (3.0 g, 18.5 mmol) in 50 mL of 
Et.sub.2 O at 0.degree. C. The resulting mixture was quenched with few 
drops of HOAc and concentrated in vacuo to afford Compound 384a (oil; 3.26 
g, 100% crude yield). 
(b) Compound 384b 
##STR883## 
Compound 384a was converted to Compound 384b by a two-step procedure 
analogous to that used for the synthesis of Compound 262e. 
(c) Compound 384c 
##STR884## 
A mixture of methylamine (ca. 5 g) and Compound 384b (0.9 g, 4.74 mmol) in 
10 mL of MeOH was heated in a sealed tube at 150.degree. C. for 3 h and 
concentrated in vacuo. The residue was dissolved in CH.sub.2 Cl.sub.2, 
washed with 20% aq. sulfuric acid, the combined aqueous phase was 
extracted with CH.sub.2 Cl.sub.2, and the combined organic phase was dried 
(MgSO.sub.4) and concentrated to afford the Compound 384c (0.55 g, 61%) as 
a colorless oil. 
(d) Compound 384d 
##STR885## 
Compounds 384c and 54 were converted to the title Compound 384d and its 
diastereomer Compound 385 by a two-step procedure analogous to that 
employed for the synthesis of Compound 312d (CH.sub.2 Cl.sub.2 only was 
used for the reaction of HOBT with Compound 384c). The mixture was 
purified by flash chromatography (silica gel/CH.sub.2 Cl.sub.2 
--MeOH--NH.sub.4 OH 99:1:0.1 to 95:5:0.5) to afford 115 mg of a 1:1 
mixture of diastereomers which were separated by preparative HPLC (column: 
Polymer Labs. PLRP-S 100 A 10 .mu.m 25.times.300 mm; eluent: 30:70 step 
wise to 1:1 A:B, eluent A=H.sub.2 O--CH.sub.3 CN--NH.sub.4 OH 90:10:0.2, 
eluent B=H.sub.2 O--CH.sub.3 CN--NH.sub.4 OH 10:90:0.2) to afford the 
title Compound 384d (faster moving isomer on polymer column) as a white 
solid (25 mg, 9% yield). 
R.sub.f =0.37 (silica gel/CH.sub.2 Cl.sub.2 --MeOH--NH.sub.4 OH 9:1:0.1), 
m.p. 77.degree.-78.degree. C., [.alpha.].sub.D =-7.5.degree. (c 0.6 MeOH). 
Mass Spec.: 615 (M+H).sup.+. 
Analysis calcd for C.sub.33 H.sub.50 N.sub.4 O.sub.7.0.77 H.sub.2 O: C, 
63.05; H, 8.26; N, 8.91. Found: C, 63.24; H, 8.17; N, 8.91. 
EXAMPLE 385 
Preparation of 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[2-Hydroxy-3,3-dimethyl-2-[(methylamino)ca 
rbonyl]-1-oxobutyl]amino]-2-hydroxy-4-phenylbutyl]amino]-2-hydroxy-1-(pheny 
lmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester, isomer B (Compound 
385) 
##STR886## 
Compound 385 (white solid) was isolated (slower moving isomer on polymer 
column) by preparative HPLC as described in Example 384d. 
R.sub.f =0.37 (silica gel/CH.sub.2 Cl.sub.2 --MeOH--NH.sub.4 OH 9:1:0.1), 
m.p. 76.degree.-77.degree. C.; [.alpha.].sub.D =-15.1.degree. (c 0.55 
MeOH). 
Mass Spec.: 615 (M+H).sup.+. 
Other compounds contemplated by the present invention include the following 
compounds: 
1. 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarba 
mic acid, 1,1-dimethylethyl 3,3,3-trifluoro-2-hydroxy-1,1-dimethylpropyl 
ester. 
2. 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarba 
mic acid, 1,1-dimethylethyl (R,R:S, S)-2-hydroxy-1-methylcyclopentyl ester. 
3. 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarba 
mic acid, 1,1-dimethylethyl (R,S:S,R)-tetrahydro-4-hydroxy-3-furanyl ester. 
4. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1-hydroxy-2,2-dimeth 
ylcyclobutyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]ca 
rbamic acid, 1,1-dimethylethyl ester. 
5. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(4-hydroxyspiro[2.4]h 
ept-4-yl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbam 
ic acid, 1,1-dimethylethyl ester. 
6. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(5-hydroxyspiro[3.4]o 
ct-5-yl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester. 
7. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(6-hydroxyspiro[4.4]n 
on-6-yl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carbami 
c acid, 1,1-dimethylethyl ester. 
8. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(octahydro-1-hydroxy- 
1-pentalenyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]ca 
rbamic acid, 1,1-dimethylethyl ester. 
9. 
[R-(R*,S*)]-[Iminobis[2-hydroxy-1-(phenylmethyl)-3,1-propanediyl]]biscarba 
mic acid, 1,1-dimethylethyl tetrahydro-4,4-dimethyl-3-furanyl ester. 
10. 
[1S-[1R*,2S*(2S*,3R-*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1,5-dihydroxy-2,2-d 
imethylcyclopentyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)pro 
pyl]carbamic acid, 1,1-dimethylethyl ester. 
11. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[(1,4-dihydroxy-2,2-di 
methylcyclopentyl)carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)prop 
yl]carbamic acid, 1,1-dimethylethyl ester. 
12. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-hydroxy-1-oxo-2-(3- 
pyridinyl)propyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propy 
l]carbamic acid, 1,1-dimethylethyl ester. 
13. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2,3,3-trimethyl-2-[(m 
ethylamino)carbonyl]-1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phe 
nylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester. 
14. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-cyano-2,3,3-trimeth 
yl-1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]c 
arbamic acid, 1,1-dimethylethyl ester. 
15. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[2-cyano-3,3-dimethyl- 
1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino]-1-(phenylmethyl)propyl]carb 
amic acid, 1,1-dimethylethyl ester. 
16. 
[1S-[1R*,2S*(2S*,3R*)]]-[2-Hydroxy-3-[[2-hydroxy-3-[[4-hydroxy-2-[(methoxy 
carbonyl)amino]-3,3-dimethyl-1-oxobutyl]carbonyl]amino]-4-phenylbutyl]amino 
]-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester. 
17. 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[2-(hydroxymethyl)phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)prop 
yl]carbamic acid, 1,1-dimethylethyl ester. 
18. 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[2-(2-hydroxyethyl) 
phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester. 
19. 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[2-(3-hydroxypropyl) 
phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid, 
1,1-dimethylethyl ester. 
20. 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[[(4-morpholinylcarbonyl)oxy]methyl]phenyl]butyl]amino]-2-hydroxy 
-1-(phenylmethyl)-propyl]carbamic acid, 1,1-dimethylethyl ester. 
21. 
[1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hyd 
roxy-4-[4-[3-(4-morpholinyl)-3-oxopropyl]phenyl]butyl]amino]-2-hydroxy-1-(p 
henylmethyl)propyl]-carbamic acid, 1,1-dimethylethyl ester. 
The above compounds correspond (by number) to the following structures: 
##STR887## 
HIV Protease Assay 
An HIV protease standard assay was performed in a 60 .mu.l reaction medium 
containing 50 mM sodium acetate, pH 5.5, 100 .mu.g/ml bovine serum 
albumen, 450 .mu.M substrate (H.sub.2 
N-Val-Ser-Gln-Asn-(.beta.-naphthylalanine)-Pro-Val-Ile-OH), and purified 
protease. The reaction medium was incubated for 30 minutes at 37.degree. 
C., quenched by the addition of 140 .mu.l 5% H.sub.3 PO.sub.4, then 
analyzed by reverse phase HPLC using UV.sub.220 detection. In a typical 
control assay, 7% of the substrate was hydrolyzed. Aminediol inhibitors of 
the present invention, listed in the following Table 1, were then employed 
in the assay, for which purpose they were prepared as a 0.5 mM solution in 
DMSO, then diluted to 30 .mu.M with 50 mM sodium acetate/bovine serum 
albumen. This working stock was then diluted three-fold into the protease 
reaction medium, for a final concentration of 10 .mu.M inhibitor and 4% 
DMSO. The results obtained from the assay are shown in the following Table 
1. 
Cell Culture 
Anti-HIV Activity 
The antiviral activity of aminediol inhibitors of the present invention was 
evaluated by a microculture method which determines the increase in cell 
viability of an infected culture when a drug is added. The assay depends 
on the metabolic reduction of tetrazolium reagent by viable cells to yield 
a soluble colored formazan product. 
The assay was performed as follows: suspensions of CEM-SS cells (5000/well) 
were infected with the RF strain of HIV at a multiplicity of infection at 
0.04 in a 96-well plate. The compounds of the present invention listed in 
the following Table 1, serially diluted in half-log fashion, were added to 
the infected and uninfected control cells. Untreated (infected and 
uninfected) cells were included as controls. Following incubation for 6 
days at 37.degree. C., viable cells in each well were quantitated by the 
visible light absorbance at 450 nm. 
The IC.sub.50 was calculated as the concentration of drug that increased 
the formazan production in virally infected cells to 50% of that produced 
by uninfected cells in the absence of drug. The results obtained in the 
assay are shown in the following Table 1. 
TABLE 1 
______________________________________ 
HIV Protease HIV (CEM Cells) 
Compound % Inhibition at 10 .mu.M 
IC.sub.50 (.mu.M) 
______________________________________ 
2 100 0.09 
3 0 &gt;3.2 
5 41 2.8 
7 8 ND 
8 2 ND 
10 1 ND 
11 0 &gt;6 
12 1 ND 
13 45 5.3 
14 100 1.1 
15 98 0.38 
16 83 .gtoreq.2.3 
17 84 &gt;1.5 
21 99 0.09 
22 90 &gt;1.8 
23 98 0.45 
24 78 4.5 
25 98 0.53 
26i 57 ND 
26ii 41 ND 
27 19 ND 
28 100 0.09 
29 100 0.1 
30 97 0.5 
31 100 0.03 
34 20 &gt;9 
36 36 &gt;8 
38 3 &gt;4 
42 100 0.6 
43 21 ND 
44 58 &gt;5 
45 87 0.5 
47 81 1.1 
50 97 0.22 
52 100 0.2 
53 99 0.54 
55 91 0.7 
56 47 ND 
57 46 ND 
58 57 1.0 
59 45 ND 
60 78 1.2 
62 98 0.05 
63 53 ND 
64 72 &gt;5 
65 11 ND 
66 99 0.27 
67 100 0.04 
68 99 0.11 
69 11 ND 
70 100 0.5 
71 58 1.2 
72 51&gt; 3.2 
73 99 0.6 
75 100 5.0 
76 100 0.6 
77 99 0.2 
78 99 0.16 
79 99 0.4 
80 98 0.3 
82 94 &gt;3 
83 19 ND 
84 99 1.2 
86 78 1.8 
87 92 &gt;0.88 
88 100 0.03 
89 23 ND 
92 100 39 
93 100 0.18 
94 80-99 ND 
96 100 &gt;7.6 
98 100 1.3 
99 99 &gt;100 
100 99 0.23 
101 99 0.14 
102 47 ND 
103 98 1.7 
104 99 0.03 
105 99 1.6 
106 71 ND 
112 100 &gt;8.6 
115 58 ND 
117 14 ND 
119 10 ND 
121 73 &gt;0.3 
123 65 1.0 
125 71 &gt;1.5 
127 15 ND 
132 65 &gt;3 
134 87 &gt;5 
136 73 ND 
137 92 &gt;2.6 
138 98 &gt;0.8 
139 73 ND 
140 61 ND 
141 77 &gt;2.3 
142 30 ND 
144 88 1.0 
145 95 &gt;2.2 
146 98 .gtoreq.3.0 
148 88 2.0 
150 93 &gt;4.0 
153 65 &gt;0.55 
154 96 &gt;1.2 
155 95 &gt;0.2 
156 85 &gt;6.0 
157 90 ND 
158 97 &gt;1.8 
159 100 1.3 
160 99 0.08 
164 99 0.04 
165 100 0.62 
166 89 1.7 
167 97 &gt;1.8 
168 61 1.4 
169 97 0.2 
170 100 0.1 
171 99 0.05 
175 99 0.03 
178 99 0.03 
179 99 0.17 
180 73 ND 
181 46 ND 
182 41 ND 
183 35 ND 
184 99 1.3 
185 5 ND 
186 0 ND 
187 28 ND 
188 21 ND 
189 23 ND 
190 &lt;16 ND 
191 13 ND 
192 85 ND 
193 66 ND 
194 0 &gt;5.0 
195 0 ND 
196 6 ND 
197 10 &gt;10 
198 10 &gt;14 
199 3 &gt;17 
200 5 &gt;15 
201 99 0.04 
202 95 16 
203 98 0.2 
204 99 0.17 
205 98 0.07 
209 99 0.03 
210 81 &gt;5 
211 99 0.9 
212 99 3.8 
213 98 0.17 
214 97 0.05 
215 66 ND 
216 49 ND 
217 100 0.48 
218 96 1.6 
219 86 3 5 
220 100 0.77 
221 96 1.1 
222 98 0.38 
223 89 1.4 
224 98 0.04 
225 99 0.5 
226 98 0.05 
227 99 0.9 
228 98 0.7 
229 82 0.6 
230 92 4.9 
231 83 ND 
232 99 0.05 
233 100 1.0 
234 100 0.08 
235 97 0.35 
236 89 0.7 
237 54 ND 
238 64 2.3 
239 37 ND 
240 99 2.0 
241 95 0.28 
242 99 0.11 
243 99 0.08 
244 100 1.5 
245 100 1.8 
246 100 0.04 
247 99 0.1 
248 99 0.23 
249 100 0.84 
250 100 1.5 
251 98 ND 
252 99 0.06 
253 85 ND 
254 98 17 
255 86 ND 
256 88 1.5 
257 99 0.03 
258 91 1.5 
259 99 5.0 
260 100 0.29 
261 94 1.1 
262 100 0.03 
263 98 0.34 
264 99 0.16 
265 100 2.6 
266 69 ND 
267 97 0.18 
268 94 ND 
269 61 ND 
270 27 ND 
271 99 0.06 
272 87 ND 
273 100 1.7 
274 99 ND 
275 95 0.45 
276 97 0.13 
277 67 ND 
278 94 0.84 
279 54 ND 
280 100 0.05 
281 100 0.29 
282 100 0.06 
283 100 0.11 
284 100 4.4 
285 100 0.65 
286 99 5.0 
287 89 ND 
288 100 0.47 
289 53 ND 
290 99 0.06 
291 73 ND 
292 99 0.17 
293 99 0.03 
294 89 ND 
295 82 ND 
296 37 ND 
297 100 0.05 
298 100 0.06 
299 99 0.24 
300 99 0.03 
301 95 2.4 
302 99 0.25 
303 98 0.07 
304 99 0.03 
305 100 0.2 
306 100 0.06 
308 100 0.02 
309 100 1.8 
310 100 0.18 
311 100 0.05 
312 95 3.5 
313 65 ND 
314 100 0.12 
315 100 1.6 
316 97 0.62 
317 85 ND 
318 100 0.1 
319 93 1.37 
320 100 0.22 
321 100 0.2 
322 100 0.02 
323 100 0.014 
324 100 0.22 
325 90 1.54 
326 99 0.03 
327 99 0.05 
328 99 054 
329 84 ND 
330 92 0.85 
331 99 0.06 
332 100 0.07 
333 100 0.15 
334 99 0.05 
335 89 ND 
336 100 0.04 
337 99 0.29 
338 99 0.93 
339 99 0.012 
340 56 ND 
341 99 2.1 
342 99 0.07 
343 99 0.05 
344 99 0.03 
345 99 0.33 
346 98 &gt;50 
347 99 0.05 
348 99 ND 
349 98 0.37 
350 98 0.5 
351 99 0.08 
352 99 0.1 
353 98 1.1 
354 99 0.12 
355 99 0.07 
356 99 0.12 
357 99 0.11 
358 99 0.1 
359 99 0.56 
360 96 0.45 
361 97 ND 
362 98 ND 
363 99 0.04 
364 98 0.22 
365 72 ND 
366 99 0.009 
367 50 ND 
368 98 0.017 
369 96 ND 
370 96 ND 
371 98 ND 
372 98 ND 
373 85 ND 
374 28 ND 
375 98 ND 
376 63 ND 
377 95 ND 
378 27 ND 
379 98 ND 
380 97 ND 
381 60 ND 
382 89 ND 
383 99 ND 
384 99 ND 
385 99 ND 
______________________________________ 
ND = Not Determined