Process for the diastereoselective reductive pinacol coupling of homochiral .alpha.-aminoaldehydes

Process for the diastereoselective reductive pinacol coupling of homochiral .alpha.-aminoaldehydes A process for the preparation of optically pure symmetrical compounds of the formula I ##STR1## is described in which R.sup.1, R.sup.2 and R.sup.3 are explained in the description, with simultaneous control of the four centers of chirality marked by *.

The invention relates to a process for the preparation of optically pure 
symmetrical compounds of the formula I 
##STR2## 
in which R.sup.1, R.sup.2 and R.sup.3 are explained in greater detail 
below, with simultaneous control of the four centers of chirality marked 
by *. 
The preparation of compounds of the above type using McMurry reagent 
[TiCl.sub.3 /Zn(Cu)] is described in EP-A 0,402,646, which is a 
counterpart of U.S. Pat. No. 5,142, 056 to Kempf et al., and D. J. Kempf 
et al. [J. Med. Chem. 33, 2687 (1990)]. This reductive coupling method 
gives mixtures which are difficult to separate. As reported in the 
publications cited above, the three diastereomers are formed in 
approximately equal amount and in poor yield. 
E. J. Roskamp et al. [J. Am. Chem. Soc. 109, 3152 (1987) and 109, 6551 
(1987)] described the fact that synaminoaldehydes can be synthesized 
diastereoselectively using the niobium (III) or niobium (IV) complexes 
NbCl.sub.3 (DME) and NbCl.sub.4 (THF) in the reductive cross-coupling of 
achiral aldehydes with achiral iminoaldehydes or diastereoselective 
syn-diamines can be formed in the reductive coupling of iminoaldehydes. 
The aim of the present invention is to find a simpler and stereoselective 
process for the preparation of the abovementioned compounds (I), which 
does not have the known disadvantages. 
The aim is achieved by the process for the preparation of compounds of the 
formula I 
##STR3## 
in which 
R.sup.1 is a side-chain radical of a natural or unnatural .alpha.-amino 
acid; 
R.sup.2 and R.sup.3 are identical or different and are 
a) - hydrogen 
b) - a radical of the formula 
EQU D-(E).sub.n -(F).sub.o -(G).sub.p (II) 
where E, F and G independently of one another are a natural or unnatural 
amino acid, aza amino acid or imino acid; 
n, o and p independently of one another are 0 or 1; 
D is R.sup.4 or a radical of the formula III, IV or V 
##STR4## 
in which R.sup.4 is 
b.sub.1) - hydrogen, 
- carboxyl, 
- (C.sub.1 -C.sub.18) -alkyl which is optionally monounsaturated or 
diunsaturated and which is optionally substituted by up to 3 identical or 
different radicals selected from the group comprising 
- mercapto, 
- hydroxyl, 
- (C.sub.1 --C.sub.7)-alkoxy, 
- carbamoyl, 
- (C.sub.1 --C.sub.8)-alkanoyloxy, 
- carboxyl, 
- (C.sub.1 -C.sub.7)-alkoxycarbonyl, 
- F, Cl, Br or I, 
- amino, 
- amidino which can optionally be substituted by one, two or three (C.sub.2 
-C.sub.8)-alkyl radicals, 
- guanidino which can optionally be substituted by one or two 
benzyloxycarbonyl radicals or by one, two, three or four (C.sub.1 
-C.sub.8)-alkyl radicals, 
- (C.sub.1 -C.sub.7)-alkylamino, 
- di-(C.sub.1 -C.sub.7)-alkylamino, 
- (C.sub.1 -C.sub.6)-alkoxycarbonylamino, 
- (C.sub.7 -C.sub.15)-aralkoxycarbonyl, 
- (C.sub.7 -C.sub.15)-aralkoxycarbonylamino, 
- phenyl-(C.sub.1 -C.sub.4)-alkoxy, 
- 9-fluorenylmethoxycarbonylamino, 
- (C.sub.1 -C.sub.6)-alkylsulfonyl, 
- (C.sub.1 -C.sub.6)-alkylsulfinyl, 
- (C.sub.1 -C.sub.6)-alkylthio, 
- hydroxamino, 
- hydroximino, 
- sulfamoyl, 
- sulfo, 
- carboxamido, 
- formyl, 
- hydrazono, 
- imino, 
- a radical CONR.sup.9 R.sup.10, 
- by up to six hydroxyl or 
- by up to five (C.sub.1 -C.sub.8)-alkanoyloxy; 
- mono-, bi- or tricyclic (C.sub.3 -C.sub.18)-cycloalkyl, 
- (C.sub.3 -C.sub.18)-cycloalkyl-(C.sub.1 -C.sub.6)-alkyl, where the 
cycloalkyl moiety is in each case optionally substituted by one or two 
identical or different radicals selected from the group comprising 
- F, Cl, Br or I, 
- carboxyl, 
- carbamoyl, 
- carboxymethoxy, 
- hydroxyl, 
- (C.sub.1 -C.sub.7)-alkoxy, 
- (C.sub.1 -C.sub.7)-alkyl, 
- (C.sub.1 -C.sub.7)-alkoxycarbonyl, 
- amino, 
- (C.sub.1 -C.sub.6)-alkylamino-(C.sub.1 -C.sub.6)-alkyl, 
- di-(C.sub.1 -C.sub.6)-alkylamino-(C.sub.1 -C.sub.6)-alkyl, 
- amidino, 
- hydroxamino, 
- hydroximino, 
- hydrazono, 
- imino, 
- guanidino, 
- (C.sub.1 -C.sub.6)-alkoxysulfonyl, 
- (C.sub.1 -C.sub.6)-alkoxysulfinyl, 
- (C.sub.1 -C.sub.6)-alkoxycarbonylamino, 
- (C.sub.6 -C.sub.6)-aryl-(C.sub.1 -C.sub.4)-alkoxycarbonylamino, 
- (C.sub.1 -C.sub.7)-alkylamino, 
- di-(C.sub.1 -C.sub.7)-alkylamino and 
- trifluoromethyl; 
- (C.sub.6 -C.sub.14)-aryl, 
- (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkyl, 
- (C.sub.6 -C.sub.14)-aryloxy-(C.sub.1 -C.sub.6)-alkyl or 
- (C.sub.6 -C.sub.14)-aryl-(C.sub.3 -C.sub.8)-cycloalkyl, in which the aryl 
moiety is in each case optionally substituted by one, two or three 
identical or different radicals selected from the group comprising 
- F, Cl, Br or I, 
- hydroxyl, 
- mono, di- or trihydroxy-(C.sub.1 -C.sub.4)-alkyl, 
- trifluoromethyl, 
- formyl, 
- carboxamido, 
- mono- or di- (C.sub.1 -C.sub.4)-alkylaminocarbonyl, 
- nitro, 
- (C.sub.1 -C.sub.7)-alkoxy, 
- (C.sub.1 -C.sub.7)-alkyl, 
- (C.sub.1 -C.sub.7)-alkoxycarbonyl, 
- amino, 
- (C.sub.1 -C.sub.7)-akylamino, 
- di- (C.sub.1 -C.sub.7)-alkylamino, 
- carboxyl, 
- carboxymethoxy, 
- amino- (C.sub.1 -C.sub.7)-alkyl, 
- (C.sub.1 -C.sub.7)-alkylamino-(C.sub.1 -C.sub.7)-alkyl, 
- di- (C.sub.1 -C.sub.7) -alkylamino- (C.sub.1 -C.sub.7)-alkyl, 
- (C.sub.1 -C.sub.7)-alkoxycarbonylmethoxy, 
- carbamoyl, 
- sulfamoyl, 
- (C.sub.1 -C.sub.7)-alkoxysulfonyl, 
- (C.sub.1 -C.sub.8)-alkylsulfonyl, 
- sulfo- (C.sub.1 -C.sub.6)-alkyl, 
- guanidino- (C.sub.1 -C.sub.8)-alkyl and 
- (C.sub.1 -C.sub.6)-alkoxycarbonylamino; 
- het, 
- het- (C.sub.1 -C.sub.6)-alkyl, 
- het- (C.sub.3 -C.sub.8)-cycloalkyl, 
- het- (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl, 
- het- (C.sub.3 -C.sub.8)-cycloalkoxy-(C.sub.1 -C.sub.4)-alkyl, 
- het-thio- (C.sub.1 -C.sub.6)-alkyl, 
- het-thio- (C.sub.3 -C.sub.8)-cycloalkyl, 
- het-thio- (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl, where 
het in each case is the radical of a 5- to 7-membered monocyclic or 8- to 
10- membered bicyclic ring system which can be benzo-fused, aromatic, 
partly or completely hydrogenated, which as hetero elements can contain 
one, two, three or four different radicals from the group comprising N, O, 
S, NO, SO and SO.sub.2, which can be substituted by 1 to 6 hydroxyl and 
which is optionally defined as in the case of (C.sub.6 -C.sub.14)-aryl in 
b.sub.1) and/or is mono-, di- or trisubstituted by oxo, or is a radical 
NR.sup.6 -C.sup.10, or 
b.sub.2) - a radical of the formula VI 
EQU R.sup.4a - W (VI) 
in which R.sup.4a is defined as R.sup.4 in b.sub.1) and W is --CO--, 
--CS--, --O--CO--, --SO.sub.2 --, --SO--, --S--, --NHSO.sub.2 --, 
--NHCO--, --CH(OH)--, --N(OH)-- or --CO--V--, where V is a peptide having 
altogether 1 to 10 amino-, imino- and/or aza amino acids; 
or in which R.sup.4 together with R.sup.8 and the atoms carrying them, form 
monocyclic or bicyclic, saturated or partially unsaturated ring systems 
having 5-12 ring members, which, apart from carbon, can also contain 1 
sulfur atom which can optionally be oxidized to the sulfoxide or sulfone; 
b.sub.3) - a glycosyl radical, preferably a glucofuranosyl or 
glucopyranosyl radical which is derived from naturally occurring 
aldotetroses, aldopentoses, aldohexoses, ketopentoses, ketohexoses, 
deoxyaldoses, aminoaldoses and oligosaccharides and their stereoisomers; 
or 
b.sub.4) - an amino protective group; 
R.sup.5 is - hydrogen or 
- (C.sub.1 -C.sub.8)-alkyl, or 
- together with R.sup.6 and the atoms carrying this radical forms mono- or 
bicyclic, saturated or partially unsaturated ring systems having 5-12 ring 
members; 
R.sup.6 is - defined as R.sup.4 in b.sub.1); 
- hydroxyl or (C.sub.1 -C.sub.4)-alkanoyloxy; or 
- together with R.sup.7 and the atoms carrying this radical, forms a 
saturated or partially saturated ring system having 3 to 12 ring members; 
or 
- together with R.sup.8 and the atoms carrying this, forms a mono- or 
bicyclic, saturated or partially saturated ring system having 5-12 ring 
members which, apart from carbon, can also contain one sulfur atom which 
can optionally be oxidized to the sulfoxide or sulfone; or can contain one 
nitrogen atom, where the ring system can optionally be substituted by 
amino; 
R.sup.7 is - hydrogen or 
- (C.sub.1 -C.sub.6)-alkyl; 
R.sup.6 is - hydrogen 
- hydroxyl, 
- (C.sub.1 -C.sub.4)-alkanoyloxy or 
- (C.sub.1 -C.sub.8)-alkyl; 
R.sup.9 and R.sup.10 are 
- hydrogen, 
- (C.sub.1 -C.sub.8)-alkyl which can be substituted by 
- amino, 
- (C.sub.1 -C.sub.4)-alkylamino, 
- di-(C.sub.1 -C.sub.4)-alkylamino, 
- mercapto, 
- carboxyl, 
- hydroxyl or 
- (C.sub.1 -C.sub.4)-alkoxy, 
- (C.sub.3 -C.sub.7)-cycloalkyl, 
- (C.sub.1 -C.sub.4)-alkoxycarbonyl, 
- (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 
-C.sub.4)-alkoxycarbonyl which can be substituted in the aryl moiety as 
described in the case of R.sup.4, 
- het or 
- het-(C.sub.1 -C.sub.4)-alkyl, where het is defined as described in the 
case of R.sup.4, or where 
R.sup.9 and R.sup.10, together with the nitrogen atom carrying them, form 
monocyclic or bicyclic, saturated, partially unsaturated or aromatic ring 
systems which as ring members in addition to carbon also contain 1 or 
additionally 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and can be 
substituted by (C.sub.1 -C.sub.4)-alkyl, where in the above compounds of 
the formula I one or more amide groups (--CONH--) of the main chain can be 
replaced by --CH.sub.2 NR.sup.11 --, --CH.sub.2 S--, --CH.sub.2 O--, 
--OCH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH-- (cis and trans), 
--COCH.sub.2 --, --CH(OH)CH.sub.2 --, --CH.sub.2 SO--, --CH.sub.2 SO.sub.2 
--, --COO--, --(PCO) (OR.sup.12)CH.sub.2 -- and --P(O) (OR.sup.12)NH--, or 
alternatively by an amide group of reverse polarity (--NHCO--); 
in which R.sup.11 and R.sup.12 independently of one another are 
- hydrogen or 
- (C.sub.1 -C.sub.4)-alkyl; 
and their enantiomers and physiologically acceptable salts, which comprises 
treating homochiral .alpha.-aminoaldehydes of the formula VII 
##STR5## 
in which R.sup.1, R.sup.2 l and R.sup.3 are defined as above, with the 
NbCl.sub.3 -dimethoxyethane complex [NbCl.sub.3 (DME)], simultaneous 
control over all four centers of chirality existing. 
Compounds of the formula I are preferably prepared in which 
R.sup.1 is a side-chain radical of the .alpha.-amino acids Gly, Ala, Val, 
Leu, Ile, Ser, Thr, Cys, Met, Pro, Lys, Arg, His, Asp, Asn, Glu, Gln, Phe, 
Tyr, Trp or Cha; 
R.sup.2 and R.sup.3 are identical or different and are 
a) - hydrogen 
b) - a radical of the formula II 
in which o and p=0, 
n=0 or 1 and 
E is one of the abovementioned a-amino acids, 
D is R.sup.4 or a radical of the formula III or IV, in which R.sup.4 is 
b.sub.1) - hydrogen 
- (C.sub.1 -C.sub.9)-alkyl which is optionally monounsaturated or 
diunsaturated and which is optionally substituted by up to 3 identical or 
different radicals selected from the group comprising 
- hydroxyl, 
- (C.sub.1 -C.sub.7)-alkoxy, 
- carbamoyl, 
- (C.sub.1 -C.sub.8)-alkanoyloxy, 
- (C.sub.1 -C.sub.7)-alkoxycarbonyl, 
- F or Cl, 
- amino, 
- (C.sub.1 -C.sub.7)-alkylamino, 
- di- (C.sub.1 -C.sub.7)-alkylamino, 
- (C.sub.1 -C.sub.6)-alkoxycarbonylamino, 
- (C.sub.7 -C.sub.15)-aralkoxycarbonyl, 
- (C.sub.7 -C.sub.15)-aralkoxycarbonylamino, 
- phenyl- (C.sub.1 -C.sub.4)-alkoxy, 
- 9-fluorenylmethoxycarbonylamino, 
- (C.sub.1 -C.sub.6)-alkylsulfonyl, 
- (C.sub.1 -C.sub.6)-alkylsulfinyl, 
- (C.sub.1 -C.sub.6)-alkylthio, 
- (C.sub.6 -C.sub.14)-aryl, 
- (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkyl or 
- (C.sub.6 -C.sub.14)-aryloxy-(C.sub.1 -C.sub.6)-alkyl, in which the aryl 
moiety can in each case be optionally substituted by one or two or three 
identical or different radicals selected from the group of the 
abovementioned preferred substituents of (C.sub.1 -C.sub.9)-alkyl, 
b.sub.2) - a radical of the formula VI, in which 
R.sup.4a is defined as R.sup.4 in b.sub.1) and W is --CO--, O--CO--, 
--SO.sub.2 --, --SO--, --S--, --NHCO--, --CH(OH)--; 
b.sub.4) - an amino protective group Fmoc, Z or Boc, 
R.sup.5 and R.sup.7 are hydrogen, 
R.sup.6 is - defined as R.sup.4 and 
R.sup.8 is - hydrogen, 
- hydroxyl, 
- (C.sub.1 -C.sub.4)-alkanoyloxy or 
- (C.sub.1 -C.sub.6)-alkyl. 
Preferred compounds of the formula I are further those in which one of the 
radicals R.sup.2 or R.sup.3 is hydrogen. 
Furthermore, compounds of the formula I with the SRRS-configuration (when 
aldehydes of the formula VII with the S-configuration are employed) or 
compounds of the formula I with the RSSR-configuration (when aldehydes of 
the formula VII with the (R)-configuration are employed) are preferred. 
Very particularly preferred compounds of the formula I are those in which 
R.sup.1 is - a side-chain radical of the .alpha.-amino acids Ala, Val, Leu, 
Ile, Pro, Phe, Cha or Tyr, 
R.sup.2 and R.sup.3 are identical or different and are 
a) - hydrogen 
b) - a radical of the formula II in which 
o and p=0, 
n is 0 or 1 and 
E is Ala, Val, Leu, Ile, Pro, Phe, Cha or Tyr; 
D is R.sup.4 or a radical of the formula IV where R.sup.4 is 
b.sub.1) - hydrogen, 
- (C.sub.1 -C.sub.4)-alkyl, 
- phenyl or naphthyl, 
- phenylmethyl or naphthylmethyl, 
b.sub.2) - a radical of the formula VI in which R.sup.4a is defined as in 
b.sub.1) and W is --CO--, --O--CO--, --SO.sub.2 --, --SO--, --S--, 
--NHCO--, --CH(OH)--, or 
b.sub.4) - an amino protective group Fmoc, Z or Boc, 
R.sup.5, R.sup.7 and R.sup.8 are hydrogen, and 
R.sup.6 is defined as R.sup.4 in b.sub.1). 
Additionally preferred compounds are the example compounds of European 
Patent Application 0,428,849, which is a counterpart of Canadian 
Application No. 2,026,382. 
Very particularly preferably, compounds of the formula I with the 
SRRS-configuration are furthermore obtained using aldehydes of the formula 
VII with the (S)-absolute configuration. This statement only applies under 
the condition that the group R.sup.1 has lower Cahn-Ingold prolog priority 
than the group --CH(OH)--CH(OH)--. 
.alpha.-Amino acids can be present, if chiral, in the S- or R- form. They 
correspond to the formula VIII below 
##STR6## 
and differ only in the radical R.sup.1 of the side chain. By way of 
example, some natural and unnatural .alpha.-amino acids are mentioned 
below in the three-letter code: 
Aad, Abu, ABz, 2ABz, Ach, Acp, Adpd, Ahb, Aib, Ala, Alg, All, Ama, Amt, 
Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cha, Cit, Cys, 
(Cys).sub.2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, 
Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, 
hMet, hPhe, hPro, hSer, hThr, hTrp, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, 
Lant, Lcn, Leu, Lsg, Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, 
Pec, Pen, Phe, Phg, Pic, Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, 
Ser, Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Nal, Tbg, 
Npg, Chg, Thia, Cha (see, for example, Houben-Weyl, "Methoden der 
organischen Chemie" (Methods of Organic Chemistry", volume XV/1 and 2, 
Stuttgart 1974). If not stated otherwise in individual compounds, the 
abbreviation of an amino-acid radical without a stereodescripter 
represents the radical in the L-form, which customarily corresponds to the 
S-configuration. 
An imino acid is generally understood as meaning natural or unnatural amino 
acids whose amino group is monosubstituted. Compounds which are 
substituted by (C.sub.1 -C.sub.8)-alkyl may particulary be mentioned in 
this connection. Heterocycles of the following group are further suitable: 
pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; 
decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic 
acid; decahydroquinoline-2-carboxylic acid; 
octahydrocylcopenta[b]pyrrole-2-carboxylic acid; 
2-azabicyclo[2.2.21octane-3-carboxlic acid; 
2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 
2-azabicyclic[3.1.0]hexane-3-carboxylic acid; 
2-azaspiro[4.4]nonane-3-carboxylic acid; 
2-azaspiro[4.5]decane-3-carboxylic acid; 
spiro[(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid]; 
spiro[(bicyclo[2.2.21octane)-2,3-pyrrolidine-5-carboxylic acid]; 
2-azatricyclo[4.3.0.1.sup.6,9 ]decane-3-carboxylic acid; 
decahydrocyclohepta[b]pyrrole-2-carboxylic acid; 
decahydrocycloocta[b]pyrrole-2-carboxylic acid; 
octahydrocyclopenta[c]pyrrole-2-carboxylic acid; 
octahydroisoindole-1-carboxylic acid; 
2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 
2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid; 
tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; 
pyrazolidine-3-carboxylic acid; hydroxyproline-2-carboxylic acid, all of 
which can be optionally substituted: 
##STR7## 
Aza amino acids are derived from natural or unnatural amino acids, the 
central component --CHR-- or --CH.sub.2 -- being replaced by --NR-- or 
--NH--. 
An overview of the syntheses, in particular of the unnatural optically 
active .alpha.-amino and imino acids is given by R. M. Williams in 
"Synthesis of Optically Active .alpha.-Aminoacids", Pergamon Press, Oxford 
1989. 
The nomenclature used in this description follows the general practice with 
amino acids, i.e. the amino group is on the left and the carboxyl group on 
the right of each amino acid. The same applies to imino acids and aza 
amino acids. 
Amino protective groups are described in R. Geiger and W. Konig "The 
Peptides" Volume 3 "Protection of Functional Groups in Peptide Synthesis", 
E. G. Gross, J. Meienhofer Edit., Academic Press, New York (1981), in 
particular pages 7-46. Some are given below by way of example: 
______________________________________ 
HCO For 
CF.sub.3CO Pfa 
##STR8## Pht 
CH.sub.3COCH.sub.2CO Aca 
##STR9## Maleoyl 
ClCH.sub.2CO Cla 
##STR10## 
##STR11## 
##STR12## Dts 
Cysteic acid Cys(O.sub.3 H) 
##STR13## 
X = H Z 
2-Cl 2Cz 
4-Cl 4Cz 
4-Br 4Bz 
3-Cl 3Cz 
4-NO.sub.2 4Nz 
4-(C.sub.6 H.sub.5NN) Paz 
4-(CH.sub.3 OC.sub.6 H.sub.5NN) 
Mpaz 
4-CH.sub.3 Mez 
4-CH.sub.3 O Moz 
4-CH.sub.3 COO 4Acz 
4-(HO).sub.2 B Dobz 
2-CON(CH.sub.3).sub.2 2-Di- 
methyl- 
amino- 
carbonyl-Z 
2,4-di-Cl 2,4-Dcz 
3,4-di-Cl 3,4-Dcz 
3,5-di-OCH.sub.3 3,5-Dmoz 
2-NO.sub.2 -4,5-di-OCH.sub.3 
2N-3,5- 
Dmoz 
##STR14## Tsc 
CH.sub.3SO.sub.2CH.sub.2CH.sub.2OCO 
Msc 
##STR15## Bic 
Ph.sub.3 PCH.sub.2CH.sub.2OCO 
Pec 
##STR16## Fmoc 
CH.sub.3 SCH.sub.2CH.sub.2OCO 
Mtc 
##STR17## Foc 
##STR18## Inc 
BrCH.sub.2CH.sub. 2OCO Bec 
ICH.sub.2CH.sub.2OCO Iec 
Cl.sub.3 CCH.sub.2OCO Tcc 
H.sub.2 CCHOCO Voc 
(iPr.sub.2).sub.2CHOCO Dmc 
##STR19## Cpc 
##STR20## -- 
##STR21## Ibc 
Cholesteryl-OCO Coc 
Ph.sub.2 CHOCO Doc 
##STR22## Dpc 
(CH.sub.3).sub.3 OCO Boc 
CH.sub.3CH.sub.2C(CH.sub.3).sub.2OCO 
Aoc 
##STR23## Adc 
##STR24## McBoc 
##STR25## Mch 
PhC(CH.sub.3).sub.2OCO Poc 
PhC.sub.6 h.sub.4C(CH.sub.3).sub.2OCO 
Bpoc 
##STR26## Ddz 
##STR27## Mpc 
##STR28## -- 
##STR29## -- 
(CH.sub.3).sub.2 NCH.sub.2CH.sub.2CPh.sub.2OCO 
-- 
(CH.sub.3).sub.2 NCOCH.sub.2CH.sub.2C(CH.sub.3).sub.2OCO 
-- 
PhNNC.sub.6 H.sub.4C(CH.sub.3 ).sub.2OCO 
Azc 
NCCH.sub.2C(CH.sub.3).sub.2OCO 
Cyc 
##STR30## -- 
(CH.sub.3).sub.2 NOCO -- 
CH.sub.3C.sub.6 H.sub.4SO.sub.2NHCO 
Tac 
##STR31## Nps 
CH.sub.3C.sub.6 H.sub.4SO.sub.2 
Tosyl 
(XC.sub.6 H.sub.4CH.sub.2O).sub.2PO 
Dbp 
Ph.sub.2 P(O) Dpp 
Ph.sub.2 P(S) Ppt 
Ph.sub.3 C Trityl 
PhCH -- 
RCOCHC(CH.sub.3) 
R = CH.sub.3 Amv 
C.sub.6 H.sub.5 Bmv 
OC.sub.2 H.sub.5 -- 
NH.sub.2 -- 
##STR32## Dim 
______________________________________ 
Functional groups in the side chains of the amino-, imino- or aza amino 
acids can be protected, for example, as follows: 
a) the guanidino group (for example of arginine) can be protected according 
to Geiger/Konig in E. Gross, J. Meienhofer ("The Peptides-Protection of 
Functional Groups in Peptide Synthesis", Academic Press, New York, 1981), 
pp. 60-70; 
b) the amino nitrogen (for example of lysine) can be protected according to 
pp. 7-49; 
c) the imidazole nitrogen (for example of histidine) can be protected 
according to pp. 70-80; 
d) the pyrazolyl nitrogen (for example of .beta.-3-pyrazolylalanine) can be 
protected according to pp. 81-82; 
e) the indole nitrogen (for example of tryptophan) can be protected 
according to pp. 82-84; 
f) the carboxyl group (for example of aspartic acid) can be protected 
according to pp. 102-132; 
g) the sulfhydryl group (for example of cysteine) can be protected 
according to pp. 137-169; 
h) the hydroxyl group (for example of serine, threonine or tyrosine) can be 
protected according to pp. 170-201; 
i) if R.sup.2 corresponds to a peptide group, peptide amide nitrogens can 
be protected, where necessary, according to pp. 52-59. 
Glycosyl radicals as described above are derived, in particular, from 
natural D- or L-monosaccharides occurring in microorganisms, plants, 
animals or humans, such as ribose (Rib), arabinose (Ara), xylose (Xyl), 
lyxose (Lyx), allose (All), altrose (Alt), glucose (Glc), mannose (Man), 
gulose (Gul), idose (Ido), galactose (Gal), talose (Tal), erythrose (Ery), 
threose (Thr), psicose (Psi), fructose (Fru), sorbose (Sor), tagatose 
(Tag), xylulose (Xyu), fucose (Fuc), rhamnose (Rha), olivose (01i), oliose 
(Olo), mycarose (Myc), rhodosamine (RN), N-acetylglucosamine (GlcNAc), 
N-acetylgalactosamine (GalNAc), N-acetylmannosamine (ManNAc) or 
disaccharides such as maltose (Mal), lactose (Lac), cellobiose (Cel), 
gentiobiose (Gen), N-acetyllactosamine (LacNAc), chitobiose (Chit), 
.beta.-galactopyranosyl-(1,3)-N-acetylgalactosamine and 
.beta.-galactopyranosyl-(1-3)- or (1-4)-N-acetylglucosamine, and their 
synthetic derivatives, such as 2-deoxy-, 2-amino-, 2-acetamido- or 
2-halo-, preferably bromo- and iodo sugars. 
Alkyl can be straight-chain or branched. The same applies to radicals 
derived therefrom, such as, for example, alkoxy, alkylthio, alkylamino, 
dialkylamino, alkanoyl and aralkyl. 
Cycloalkyl is understood as also meaning alkylsubstituted radicals, such 
as, for example, 4-methylcyclohexyl or 2,3-dimethylcyclopentyl. 
(C.sub.6 -C.sub.14)-aryl is, for example, phenyl, naphthyl, biphenylyl or 
fluorenyl; phenyl and naphthyl are preferred. The same applies to radicals 
derived therefrom, such as, for example, aryloxy, aroyl, aralkyl and 
aralkoxy. Aralkyl is understood as meaning an unsubstituted or substituted 
(C.sub.6 -C.sub.14)-aryl radical which is linked to (C.sub.1 
-C.sub.6)-alkyl, such as, for example, benzyl, 1- and 2-naphthylmethyl, 
aralkyl, however, not being restricted to said radicals. 
Radicals het within the meaning of the above definition are pyrrolyl, 
furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 
isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, 
isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, 
quinazolinyl, cinnolinyl, .beta.-carbolinyl, or a benzo-fused, 
cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. 
These heterocycles can be substituted on a nitrogen atom by oxido; (C.sub.1 
-C.sub.7)-alkyl, for example methyl or ethyl; phenyl; phenyl-(C.sub.1 
-C.sub.4)-alkyl, for example benzyl; and/or on one or more carbon atoms by 
(C.sub.1 -C.sub.4)-alkyl, for example methyl; phenyl; phenyl-(C.sub.1 
-C.sub.4)-alkyl, for example benzyl; halogen; hydroxyl; (C.sub.1 
-C.sub.4)-alkoxy, for example methoxy; phenyl-(C.sub.1 -C.sub.4)-alkoxy, 
for example benzyloxy; or by oxo and are partially or completely 
saturated. 
Radicals of this type are, for example, 2- or 3-pyrrolyl; phenylpyrrolyl, 
for example 4- or 5-phenyl-2-pyrrolyl; 2-furyl; 2-thienyl; 4-imidazolyl; 
methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl; 
1,3-thiazol-2-yl; 2-, 3- or 4-pyridyl; 2-, 3- or 4-pyridyl N-oxide; 
2-pyrazinyl; 2-, 4- or 5-pyrimidinyl; 2-, 3- or 5-indolyl; substituted 
2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 
5-chloro- or 4,5-dimethyl-2-indolyl; 1- benzyl-2- or -3-indolyl; 
4,5,6,7-tetrahydro-2-indolyl; cyclohepta[b]-5-pyrrolyl; 2-, 3- or 
4-quinolyl; 1-, 3- or 4-isoquinolyl; 1-oxo-l,2-dihydro-3-isoquinolyl, 
2-quinoxalinyl; 2-benzofuranyl; 2-benzoxazolyl; benzothiazolyl; 
benz[e]indol-2-yl or .beta.-carbolin-3-yl. 
Partially hydrogenated or completely hydrogenated heterocyclic rings are, 
for example, dihydropyridinyl, pyrrolidinyl, for example 2-, 3- or 
4-N-methylpyrrolidinyl; piperazinyl; morpholino; thiomorpholino; 
tetrahydrothiophenyl; benzodioxolanyl. 
Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or 
chlorine. 
Salts of compounds of the formula (I) are particularly understood as 
meaning pharmaceutically utilizable or nontoxic salts. 
Such salts are formed, for example, from compounds of the formula (I) which 
contain acid groups, for example carboxyl, with alkali metals or alkaline 
earth metals such as, for example, Na, K, Mg and Ca, and with 
physiologically tolerable organic amines, such as, for example, 
triethylamine and tris(2-hydroxyethyl)amine. 
Compounds of the formula (I) which contain basic groups, for example an 
amino group or a guanidino group, form salts with inorganic acids, such 
as, for example, hydrochloric acid, sulfuric acid or phosphoric acid and 
with organic carboxylic or sulfonic acids, such as, for example, acetic 
acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid 
and p-toluenesulfonic acid. 
An embodiment of the process according to the invention comprises 
dimerizing aldehydes of the formula VII by stereoselective reductive 
treatment with the niobium (III) complex NbCl.sub.3 (DME) in inert 
solvents in the temperature range from -78.degree. C. to the boiling point 
of the reaction mixture to give the compounds of the formula I. 
The abovementioned niobium complex is isolated from the reaction of 
NbCl.sub.5 with Bu.sub.3 SnH (J. Am. Chem. Soc. 109, 6551 (1987)); it is 
additionally commercially available (for example Aldrich Chemie GmbH, 
Steinheim). 
A preferred embodiment for preparing the compounds of the formula I with 
the abovementioned preferred configurations comprises initially 
introducing NbCl.sub.3 (DME) into a protective gas-flushed apparatus (for 
example N.sub.2 or argon) in inert solvents, such as cyclic or acyclic 
dialkyl ethers, aromatic or alkyl hydrocarbons, or halogenated 
hydrocarbons, in particular dichloromethane, di-, tri- or 
tertachloroethane, toluene or THF at temperatures from -78.degree. C. to 
the boiling point of the solvent, preferably from 0.degree. C. to the 
boiling point of the solvent, and, relative to the niobium (III) complex, 
treating with 0.3 to 1.0, preferably 0.7 to 0.9, equivalents of aldehyde 
of the formula VII and stirring under a protective gas atmosphere (for 
example N.sub.2 or argon) at the respective starting temperature until 
reaction is complete according to TLC checking. The reaction takes place 
stereoselectively to a particular extent when using the solvent THF. 
For working up, the reaction temperature is preferably adjusted to room 
temperature and the mixture is treated with the aqueous solution of a 
complexing agent, preferably 10-30% strength aqueous citric acid or 
tartrate solution. After separation of the phases, the aqueous phase is 
extracted with the solvent used in the reaction mixture or as an 
alternative with a water-immiscible organic solvent, the combined organic 
phases are washed successively with aqueous base, aqueous acid and water, 
washed, dried, filtered and evaporated to dryness, after which the crude 
products is obtained in yields of 20% to 90% of theory. Purification is 
preferably carried out by crystallization or chromatography on a silica 
gel column or is unnecessary owing to the adequate purity of the crude 
product obtained. 
The particularly preferred compounds of the formula I in the 
SRRS-configuration are obtained in particularly high yield from the 
.alpha.-aminoaldehydes of the formula VII with the S-configuration by 
reaction according to the invention at room temperature to the boiling 
point of the reaction mixture, in particular at the boiling point of the 
reaction mixture. 
Optically pure .alpha.-aminoaldehydes of the formula VII are obtained from 
amino acids in a simple manner known from the literature, for example as 
explained in more detail below. 
Commercially available or self-synthesized compounds of the formula IX 
##STR33## 
in which 
R.sup.13 is H, (C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.14)-aryl or 
(C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.6)-alkyl, in particular methyl, 
ethyl or benzyl and 
R.sup.1 and R.sup.2 are as defined above (Houben Weyl 15/1 and 2, 
Stuttgart, 1974; V. Teetz, R. Geiger, H. Gaul, Tetrahedron Letters 
25/(40), 4479 (1984), A. Pictet, T. Spengler, Chem. Ber. 44, 2030 (1911); 
R. M. Williams, "Synthesis of Optically Active .alpha.-Aminoacids", 
Pergamon Press, Oxford, 1989) are introduced analogously to methods known 
from the literature (M. W. Drewes, "The Syntheses and Stereoselective 
Reactions of .alpha.-Aminoaldehydes", Inaugural Dissertation, Department 
of Chemistry of Philipps University, Marburg/Lahn 1988; and literature 
cited therein; N. G. Gaylord, "Reduction with Complex Metal Hydrides", 
Interscience Publishers, NY London, 1956; H. Schenker, Angew. Chemie 73, 
81 (1961); C. F. Stanfield, J. E. Parker, P. Kanellis, J. Org. Chem. 46 
4797 and 4799 (1981); K. E. Rittle, C. F. Homnick, B. E. Evans, J. Org. 
Chem. 47, 3016 (1982); K. Haaf, C. Ruchardt, Chem. Ber. 123,635 (1990)) 
for example with NaBH.sub. 4 (N. G. Gaylord, see above), BH.sub.3.THF (K. 
E. Rittle, see above) or LiAlH.sub.4 (K. Haaf, see above) in inert 
solvents, or lower alcohols, or alcoholic/aqueous mixtures to give the 
aminoalcohols of the formula X 
##STR34## 
in which 
R.sup.1 and R.sup.2 are as defined above. The compounds of the formula X 
thus obtained are then reacted by known methods (Houben-Weyl, see above; 
E. Gross, J. Meienhofer, Ed., "The Peptides - Protection of Functional 
Groups in Peptide Synthesis", Academic Press, New York, 1981; T. W. 
Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, NY 
Chichester Brisbane Toronto Singapore, 1980; Proceedings of European 
Peptide Symposium, Platja D'Aro, September 1990) to give the compounds of 
the formula XI 
##STR35## 
with said meanings for R.sup.1 -R.sup.3 and then reacted without 
racemization with pyridinium dichromate (C. F. Stanfield, see above), 
CrO.sub.3 pyridine (K. E. Rittle, see above), but in particular with 
(COCl).sub.2 and DMSO and by the Swern Method to give the aldehydes of the 
formula VII 
##STR36## 
in which R.sup.1, R.sup.2 and R.sup.3 are as defined above (K. Omura, A. 
K. Sharma, D. Swern, J. Org. Chem. 41, 957 (1976); D. Swern, S. L. Huang, 
A. J. Mancuso, J. Org. Chem. 43, 2480 (1978); A. J. Mancuso, D. Swern, 
Synthesis, 165 (1981)). 
A second variant consists in reacting compounds of the formula IX 
analogously to the abovementioned syntheses known from the literature to 
give compounds of the formula XII 
##STR37## 
in which 
R.sup.1, R.sup.2 and R.sup.3 and R.sup.13 are as defined above, and 
reacting these--after possible prior hydrolysis, without racemization, of 
an ester of the formula XII where R.sup.13 .noteq.H--for example by the 
method of Weinreb (S. Nahm, S. M. Weinreb, Tetrahedron Letters 22, 3815 
(1981)) with N, O-dimethylhydroxylamine to give the compounds of the 
formula XIII 
##STR38## 
in which R.sup.1, R.sup.2 and R.sup.3 are as defined above. The amides of 
the formula XIII are converted directly and without racemization, for 
example by the method of Castro (J. A. Fehrentz, B. Castro, Synthesis, 676 
(1983); J. A. Fehrentz, B. Castro, Int. J. Peptide Protein Res. 26,236 
(1985)) by reduction with LiAlH.sub.4 to said aldehydes of the formula 
VII. 
In a third variant, carboxylic acids of the formula XII (R.sup.13 =H) are 
derivatized with thionyl chloride or other suitable halogenating agents to 
the corresponding carbonyl halides of the formula XIV 
##STR39## 
in which 
R.sup.1 -R.sup.3 corresponds to the above definitions and 
R.sup.14 is Cl, Br, I or radicals of mixed carbonic anhydrides, 
and subsequently reduced without racemization with H.sub.2 /Pd/BaSO.sub.4 
to give the aldehydes of the formula VII (analogously to: R. L. Johnson, 
J. Med. Chem. 25, 605 (1982)). In principle, aldehydes can also be 
prepared from carboxylic acids and their derivatives using other methods, 
for example by reaction with simple and complex metal hydrides, metal 
carbonyl complexes, silanes, alkali metals, formates or photochemically 
(Houben Weyl 7E3, 418ff, Stuttgart, 1983). 
In contrast to the couplings described in Roskamp et al. using niobium 
complexes (J. Amer. Chem. Soc. 109, 3152 (1987) and 109, 6551 (1987)) 
reactions without iminoaldehyde components are carried out in the present 
process, and in addition simultaneous control over four stereocenters is 
exercized in the present process. When using optically active starting 
materials, optically active coupling products are obtained in high yield. 
A further advantage of the process described here is the greater 
selectivity of the reductant for the activated aldehyde function, which 
leads to greater compatibility with other functional groups. As described 
by J. E. McMurry (Chem. Rev. 89, 1513 (1989), in particular Table 2, p. 
1515), the McMurry reagent is only partially compatible with functional 
groups such as, for example, amide, carboxylic acid, ester, ketone and is 
incompatible with functional groups such as nitro, oxime, sulfoxide, 
epoxide and 1,2-diol. On the other hand, the niobium complex, for example, 
is completely compatible with the amide function and other non-activated 
carboxyl functions also do not react at a significant rate (J. Am. Chem. 
Soc. 109, 6551 (1987)). 
Abbreviations used: 
Cha cyclohexylalanine 
Chg cyclohexylglycine 
DABCO 1,4-diazabicyclo[2.2.21octane 
DME dimethoxyethane 
DMF diemethylformamide 
DMSO dimethyl sulfoxide 
EDTA ethylenediaminetetraacetic acid 
HMPA hexamethylphosphoramide 
MTB methyl tert-butyl 
Nal 1- and 2-naphthylalanine 
Npg neopentylglycine 
Tbg tert-butylglycine 
THF tetrahydrofuran 
Thia 2-thienylalanine 
TMEDA N,N,N',N'-tetramethylethylenediamine 
The process according to the invention is further illustrated by the 
following examples and actual procedure variants are described. These 
examples and procedure variants do not limit the subject of the invention 
either with respect to the structural range of the .alpha.-aminoaldehydes 
VII dimerized by diastereoselective reduction in this manner, nor with 
respect to the process conditions (reagent preparation, physical 
parameters of reductive dimerization, solvents, reaction time, working up, 
purification and analysis of the reaction products).

EXAMPLE 1: 
N-(tert-Butoxycarbonylamino)-(S)-phenylalanine-N-methoxy-N-methylamide 
88.1 g (332 mmol) of (S)-phenylalanine are dissolved in 1.2 1 of 
dichloromethane and treated under a nitrogen atmosphere at a constant 
internal temperature of 20.degree. C. (cooling by ice-bath) with 268 ml 
(2.1 mol) of ethylmorpholine and 43.7 g (445 mmol) of 
N,O-dimethylhydroxylamine hydrochloride. The reaction mixture is cooled to 
-10.degree. C. and a solution of 252 ml of propanephosphonic anhydride in 
250 ml of ethyl acetate is added dropwise. Complete conversion of the 
reactants is achieved by additional stirring (1 h at 0.degree. C., then 2 
h at room temperature). The mixture is washed with 1 of 3 N HCl, 800 ml of 
saturated, aqueous NaHCO.sub.3 solution and 800 ml of saturated, aqueous 
NaCl solution, and the organic phase is dried over Na.sub.2 SO.sub.4. 
After evaporating the solvent, 100 g of a colorless oil remain, which can 
be subjected without further purification to the reduction to give the 
corresponding aminoaldehyde. 
EXAMPLE 2: 
N- (tert-Butoxycarbonyl)-(S)-phenylalaninal 
4.36 g of lithium aluminum hydride are initially introduced at 0.degree. C. 
under a nitrogen atmosphere into 875 ml of dry diethyl ether and a 
solution of 26.9 g of 
N-(tert-butoxycarbonylamino)-(S)-phenylalanine-N-methoxy-N-methylamide in 
73 ml of diethyl ether is added with stirring. The mixture is stirred at 
0.degree. C. for 30 min and then treated with 450 ml of 5% strength cold 
aqueous KHSO.sub.4 solution. The phases are separated, and the organic 
phase is washed successively with 300 ml of 0.5N HCl, 600 ml of saturated 
aqueous NaHCO.sub.3 solution and 600 ml of saturated aqeous NaCl solution, 
and finally dried over Na.sub.2 SO.sub.4. After evaporation of the 
solvent, 20.9 g (96.3%) of white crystals remain, which can be employed 
without further purification for the reductive coupling. 
EXAMPLE 3: 
(N-(tert-Butoxycarbonylvalinyl)amino)-(S)-phenylalaninal 
2.1 ml (25 mmol) of oxalyl chloride are dissolved in 125 ml of dry 
dichloromethane under an inert gas atmosphere. 2.4 ml (33.4 mmol) of DMSO 
are added dropwise at -70.degree. C. with stirring and a solution of 5.85 
g (16.7 mmol) of N-(tert-butoxycarbonyl)-(S)-valyl-(S)-phenylalaninol in a 
mixture of 4 ml of DMSO and 30 ml of dichloromethane is slowly added after 
a waiting time of 15 min. The reaction mixture is additionally stirred at 
-70.degree. C. for 30 min and 9.4 ml (66.8 mmol) of triethylamine are then 
added dropwise, the temperature rising to -60.degree. C. After a further 
15 min at -60.degree. C. the mixture is hydrolyzed with 200 ml of 15% 
strength aqueous citric acid and the phases are separated. The organic 
phase is washed successively in each case with 200 ml of saturated aqueous 
bicarbonate solution, with water and finally with saturated aqueous sodium 
chloride solution and dried over sodium sulphate. After evaporating the 
solvent, 4.4 g of white crystals remain, which are subjected to the 
dimerization without further purification steps. 
General experimental procedure for the reductive coupling: 
1.4 eq. of trichloro(dimethoxyethane)niobium (III) are initially introduced 
into 10 ml of dry solvent under an inert gas atmosphere and treated with 1 
eq. of aldehyde in 2 ml of dry solvent and the reaction temperature is 
adjusted. When the temperature is stable, the reaction conversion is 
monitored by means of TLC checking. After the reaction has taken place, 
extraction by shaking at room temperature with aqueous sodium tartrate 
solution and aqueous citric acid solution, successive washing of the 
organic phase with aqueous base solution, aqueous acid and water, drying 
of the organic phase over Na.sub.2 SO.sub.4, filtering off of the drying 
agent and removal of the solvent yields an oily or solid residue which is 
optionally purified by chromatography on silica gel and/or by 
crystallization. 
EXAMPLE 4: 
N,N'-bis(tert-Butoxycarbonyl)-2S,5S-diamino-1,6-diphenylhexane-3R,4R-diol 
Starting from 2.5 g of N-(tert-butoxycarbonyl)-(S)-phenylalaninal, 1.5 g of 
crystals of the title compound are obtained analogously to the general 
procedure (solvent: THF; reaction temperature: reflux). 
MS (FAB): 507 (M+Li.sup.+), 401, 352,307 
EXAMPLE 5: 
(2S, 3R, 4R, 5S)-2,5-(N,N'-((tert-Butoxycarbonyl)-(S)-valinyl) 
amino)-3,4-dihydroxy-1,6-diphenylhexane 
Starting from 3.5 g of N-(tert-butoxycarbonyl)-(S)-valinyl-phenylalaninal, 
1.9 g of oil of the title compound are obtained analogously to the general 
procedure. 
(Solvent: THF; reaction temperature: reflux). 
MS (FAB): 705 (M+Li.sup.+), 699 (M+H.sup.+), 667,605,599. 
EXAMPLE 6:l 
1,2-Bis 
[N-{2(S)-(1,1-dimethylethylsulfonylmethyl)-3-(1-naphthyl)propionyl}-(S)-va 
lyl]-(S)-1, 2, 3, 4-tetrahydroisoquinolin-3-yl]ethane-1(R),2(R)-diol 
Starting from 2.5 g of 
N-[{(S)-2-(1,1-dimethylethylsulfonylmethyl)-3-(1-naphthyl)propionyl}-(S)-v 
alyl]-(S)-1,2,3,4-tetrahydroisoquinoline-3-carbaldehyde, 0.8 g of yellowish 
crystals of the title compound are obtained analogously to the 
experimental procedure with in situ preparation of the coupling reagent 
(complexing agent: 1,3-dimethylimidazolidin-2one). 
MS (FAB): 1162 (M+Li.sup.+), 1156 (M+H.sup.+), 741, 388. 
EXAMPLE 7: 
N,N'-Bis[{(S)-2-(1,1-diemthylethylsulfonylmethyl)-3-(1-naphthyl)-propionyl} 
-(S)-valyl]-2(S) ,5(S)-diamino-1,6-diphenylhexane-3(R),4(R)-diol 
##STR40## 
Starting from 2.0 g of 
N-[{(S)-2-(1,1-dimethylethylsulfonylmethyl)-3-(1-naphthyl)propionyl}-(S)-v 
alyl]-(S)-phenylalaninal, 0.8 g of crystals of the title compound are 
obtained analogously to the general procedure. 
(Solvent: THF; reaction temperature: reflux). 
MS (FAB): 1154 (M+Na.sup.+), 1132 (M+H.sup.+), 716, 567.