Catalytic enantioselective synthesis of a spriofused azetidinone

A process for producing a compound of the formula ##STR1## comprises the following sequence of steps: ##STR2## wherein the various radicals are as defined in the specification.

BACKGROUND 
Asymmetric spiro-fused azetidinones are useful pharmaceutical compounds. 
Thus, any efficient process for producing these compounds in high yield 
would be a welcome contribution to the art. This invention provides such a 
contribution. 
SUMMARY OF THE INVENTION 
This invention provides a catalytic enantioselective aldol synthesis of 
spiro-fused azetidinones. 
Thus, this invention provides a process for producing a compound of the 
formula: 
##STR3## 
wherein: 
R.sup.1, R.sup.2 and R.sup.3 are each independently selected from: 
(a) H; 
(b) halo; 
(c) --OR.sup.5 wherein R.sup.5 is selected from: H, C.sub.1 to C.sub.6 
alkyl, aryl, aralkyl, alkaryl, heteroaryl, C.sub.2 to C.sub.6 alkenyl, 
C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.7 cycloalkyl, C.sub.3 to 
C.sub.7 cycloalkenyl, or --C(O)R.sup.6 (wherein R.sup.6 is selected from 
C.sub.1 to C.sub.6 alkyl, aryl, or --OR.sup.7 wherein R.sup.7 is C.sub.1 
to C.sub.6 alkyl or aryl); or 
(d) --C(O)R.sup.8 wherein R.sup.8 is selected from C.sub.1 to C.sub.6 
alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, --OR.sup.9 (wherein R.sup.9 
is selected from C.sub.1 to C.sub.6 alkyl or aryl), or --N(R.sup.10).sub.2 
(wherein each R.sup.10 is independently selected from H, C.sub.1 to 
C.sub.6 alkyl or aryl); 
R.sup.4 is selected from H or --OH; 
said process comprising: 
(a) reacting, in a suitable organic solvent, a compound of formula: 
##STR4## 
with an enolization base and a silylation reagent to produce a compound of 
the formula: 
##STR5## 
wherein n is 1 or 2, R.sup.11 is a C.sub.1 to C.sub.4 alkyl group, and 
R.sup.12 is a C.sub.1 to C.sub.4 alkyl group; 
(b) reacting, in a suitable organic solvent, the compound of Formula 3.0 
with a chiral catalyst and a compound of the formula: 
##STR6## 
wherein R.sup.2 is as defined above, with the proviso that R.sup.2 is not 
OH, and then reacting the resulting product with a deprotecting reagent to 
remove the --Si(R.sup.12).sub.3 protecting group thereby forming a 
compound of the formula: 
##STR7## 
(or an enantiomeric mixture of 5.0 or 5.1); said chiral catalyst being a 
complex with borane and a compound of the formula: 
##STR8## 
wherein R.sup.13 is selected from aryl or fused aryl, and R.sup.14 
represents an amino acid bound to the sulfur of Formula 6.0 through the 
nitrogen of the amino acid --C(H)(NH.sub.2)COOH group; 
(c) reacting a compound of Formula 5.0 or 5.1 (or an enantiomeric mixture 
of 5.0 and 5.1), in a suitable organic solvent, with a compound of the 
formula: 
##STR9## 
wherein R.sup.1 is as defined above, with the proviso that R.sup.1 is not 
OH, with a Lewis acid and with a strong acid, to produce a compound of the 
formula: 
##STR10## 
(or an enantiomeric mixture of 8.0 and 8.1); 
(d) reacting a compound of Formula 8.0 or 8.1 (or enantiomeric mixtures 
thereof), in a suitable solvent, with a reagent that converts a --OH group 
into a leaving group, with a strong base, and with a phase transfer 
catalyst, to produce a compound of the formula: 
##STR11## 
(e) reacting a compound of Formula 9.0, in a suitable solvent, with a 
compound of the formula: 
##STR12## 
wherein R.sup.3 is as defined above, with the proviso that R.sup.3 is not 
OH, to produce a compound of the formula: 
##STR13## 
with the proviso that R.sup.1, R.sup.2 and R.sup.3 am not --OH; 
(f) when R.sup.1, R.sup.2, and/or R.sup.3 (i.e., when one or more of 
R.sup.1, R.sup.2, and R.sup.3) in Formula 1.0 in (e) above is --OR.sup.5, 
wherein R.sup.5 is an aralkyl group, optionally hydrogenating said 
compound of Formula 1.0 in a suitable alkanol solvent with a hydrogenation 
catalyst and a suitable Lewis acid, thereby convening said --OR.sup.5 to 
--OH; and 
(g) when R.sup.4 is --OH, optionally converting said --OH R.sup.4 
substituent to H by heating a compound of Formula 1.0 (wherein R.sup.4 is 
--OH) with an acid to produce a dehydrated compound of Formula 1.2: 
##STR14## 
and then hydrogenating the compound of Formula 1.2 in a C.sub.1 to C.sub.6 
alkanol solvent using a hydrogenation catalyst to produce a compound of 
Formula 1.0 wherein R.sup.4 is H. 
This invention also provides a process for producing a compound of the 
formula: 
##STR15## 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, end 
with the proviso that at least one of R.sup.1, R.sup.2 and R.sup.3 is OH, 
said process comprising: hydrogenating a compound of Formula 1.0 in a 
suitable alkanol solvent, wherein at least one of R.sup.1, R.sup.2 and 
R.sup.3 is --OR.sup.5, respectively, said R.sup.5 substituent being an 
aralkyl protecting group, with a hydrogenation catalyst and a suitable 
Lewis acid (such as, for example. MgX.sub.2, TiX.sub.4, or ZnX.sub.2, 
wherein X is Cl or Br, with ZnX.sub.2 being preferred and ZnBr.sub.2 being 
most preferred), thereby converting said --OR.sup.5 to --OH. Step (g), 
described above, can then be carried out to convert an R.sup.4 --OH group 
to an R.sup.4 H. 
This invention further provides a process for producing a compound of the 
formula: 
##STR16## 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, and 
with the proviso that at least one of R.sup.1, R.sup.2 and R.sup.3 is OH 
and at least one of the remaining R.sup.1, R.sup.2 and R.sup.3 is halo, 
said process comprising: hydrogenating a compound of Formula 1.0 in an a 
suitable alkanol solvent, wherein at least one of R.sup.1, R.sup.2 and 
R.sup.3 is --OR.sup.5, said R.sup.5 substituent being an aralkyl 
protecting group, with a hydrogenation catalyst and a suitable Lewis acid 
(such as, for example, MgX.sub.2, TiX.sub.4, or ZnX.sub.2, wherein X is Cl 
or Br, with ZnX.sub.2 being preferred and ZnBr.sub.2 being most 
preferred), thereby converting said --OR.sup.5 to --OH. Step (g), 
described above, can then be carried out to convert an R.sup.4 --OH group 
to an R.sup.4 H. 
In addition this invention also provides a process for producing a compound 
of the formula: 
##STR17## 
(or an enantiomeric mixture of 5.0 and 5.1) wherein n and R.sup.2 are as 
defined above, with the proviso that R.sup.2 is not OH, by reacting, in a 
suitable organic solvent, the compound of Formula 3.0 with a chiral 
catalyst and a compound of the formula: 
##STR18## 
wherein R.sup.2 is defined above, with the proviso that R.sup.2 is not OH, 
and then reacting the resulting product with a deprotecting reagent to 
remove the --Si(R.sup.12).sub.3 protecting group; said chiral catalyst 
being a complex with boron and a compound of the formula: 
##STR19## 
wherein R.sup.13 is selected from aryl or fused aryl, and R.sup.14 
represents an amino acid bound to the sulfur of Formula 6.0 through the 
nitrogen of the amino acid --C(H)(NH.sub.2)COOH group.

DETAILED DESCRIPTION OF THE INVENTION 
The following terms, as used herein, have the following meanings, unless 
indicated otherwise: 
alkyl--represents straight and branched carbon chains and contains from one 
to twenty carbon atoms, preferably one to six carbon atoms; 
alkaryl--represents an aryl group, as defined below, in which an alkyl 
group, as defined above, is substituted for one of the aryl H atoms 
alkenyl--represents straight of branched carbon chains having at least one 
carbon to carbon double bond and preferably having from 2 to 6 carbon 
atoms; 
alkynyl--represents straight or branched carbon chains having at least one 
carbon to carbon triple bond and preferably having from 2 to 6 carbon 
atoms; 
aralkyl--represents an alkyl group, as defined above, in which an aryl 
group as defined below Is substituted for one of the alkyl H atoms, e.g., 
benzyl, 4-nitrobenzyl, 4-methoxybenzyl, and 4-chlorobenzyl; 
aryl (including substituted aryl)--represents a carbocyclic group 
containing from 6 to 15 carbon atoms and having at least one aromatic ring 
(e.g., aryl is a phenyl ring), with all available substitutable carbon 
atoms of the carbocyclic group being intended as possible points of 
attachment, said carbocyclic group being optionally substituted (e.g., 1 
to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF.sub.3, 
amino, alkylamino, dialkylamino, or --NO.sub.2 ; 
cycloalkyl--represents a saturated carbocyclic ring having from 3 to 8 
carbon atoms; 
cycloalkenyl--represents a carbocyclic ring having from 3 to 8 carbon atoms 
and at least one carbon to carbon double bond in the ring; 
--C(O)-represents the structure 
##STR20## 
fused aryl--represents one or more aryl rings, as defined above, fused 
together, e.g., a radical of naphthalene, such as an .alpha.-naphthyl or 
.beta.-naphthyl (such as a 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-naphthyl), or 
a radical of anthracene (such as 1-, 2-, 3-, 4- or 9-anthryl), or a 
radical of phenanthrene (such as 1-, 2-, 3-, 4: of 10-phenanthryl); 
halo (halogen)--represents Cl, F, Br and I; 
heteroaryl--represents cyclic groups having at least one (i.e., one or 
more) heteroatoms, selected from O, S or N, interrupting a carbocyclic 
ring structure and having a sufficient number of delocalized pi electrons 
to provide aromatic character, with the aromatic heterocyclic groups 
preferably containing from 2 to 14 carbon atoms, e.g., 2-, 3- or 
4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- 
or 5-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 
4-pyridazinyl, 3-, 5- or 6-[1,2,4-triazinyl], 3- or 5-[1,2,4-thiadizolyl], 
2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 
4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, etc. Preferred heteroaryl groups 
are pyridyl, 2- or 3-furyl, or 3-thienyl, 2-, 4- or 5-imidazolyl or 
7-indolyl; and 
substituted aryl, substituted benzyl, substituted phenyl, or substituted 
heteroaryl - an aryl, benzyl, phenyl or heteroaryl, repectively, wherein 
one or more aromatic hydrogens are replaced by the same or different 
substituents independently selected from hydroxy, alkyl having from 1 to 6 
carbon atoms, halogen, nitro, alkoxy having from 1 to 6 carbon atoms, 
trifluoromethyl, cyano, cycloalkyl having from 3 to 7 carbon atoms, 
alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having from 3 to 6 
carbon atoms, S(O).sub.p R.sup.a (wherein p is 0, 1 or 2 and R.sup.a is 
alkyl having from 1 to 6 carbon atoms). 
Each reaction of the processes of the invention takes place at suitable 
temperature or within a suitable temperature range. A suitable temperature 
is a temperature (or temperature range) that allows the reaction to 
proceed at a reasonable rate without the formation of an excessive amount 
of by-products and without the production of an excessive amount of 
degradation products. 
A suitable solvent is a solvent in which the reactants are suitably soluble 
in or in which the reactants are in sufficient contact with each other, to 
allow the reaction to proceed at a reasonable rate. The solvents used 
herein are used in amounts suitable to provide a reaction medium which 
allows the reaction to proceed at a reasonable rate. 
Those reactions which are not disclosed as being carried out under an inert 
atmosphere (e.g., nitrogen), can, if desired, be carried out under an 
inert atmosphere. Those skilled in the art will appreciate that it is 
desirable to carry out a reaction under an inert atmosphere when reagents 
are used which are known to be unstable when exposed to air (e.g., 
(CH.sub.3).sub.3 Al and the Grignard reagent). 
Preferably, the compounds produced by the processes of this invention 
contain the R.sup.1, R.sup.2, and R.sup.3 substituents in the para 
position of their respective phenyl rings. Thus, this invention preferably 
provides a process for producing a compound of the formula: 
##STR21## 
To produce the compounds of Formula 1.1 by the processes of the invention, 
compounds of the formulas: 
##STR22## 
are used instead of compounds of Formulas 4.0, 7.0 and 10.0, respectively. 
In so doing, intermediate compounds of formulas: 
##STR23## 
(or an enantiomeric mixture of 5.2 and 5.3) are produced instead of 
Formulas 5.0 or 5.1, respectively. Preferably, n is 1; therefore, 
intermediate compounds of formulas: 
##STR24## 
(or an enantiomeric mixture of 5.4 and 5.5) are preferably produced. 
Intermediate compounds of the formulas: 
##STR25## 
(or an enantiomeric mixture of 8.2 and 8.3) am produced instead of Formulas 
8.0 and 8.1, respectively. Also, intermediate compounds of the formula: 
##STR26## 
are produced instead of Formula 9.0. 
Those skilled in the art will appreciate that when n is 1, the intermediate 
##STR27## 
is produced from starting reactant 
##STR28## 
Preferably, for the compounds of Formulas 1.0 and 1.1, R.sup.1 is, as 
stated above, in the para position of the phenyl ring, and is selected 
from H, halo, or --OR.sup.5 wherein R.sup.5 is selected from H, C.sub.1 to 
C.sub.6 alkyl or aralkyl. Most preferably, R.sup.1 is selected from H, Cl, 
F or --OR.sup.5 wherein R.sup.5 is C.sub.1 to C.sub.6 alkyl; more 
preferably, H, Cl, F or --OCH.sub.3 ; still more preferably, H or F; and 
even more preferably, F. 
Preferably, for the compounds of Formulas 1.0 and 1.1, R.sup.2 is, as 
stated above, in the para position of the phenyl ring, and is selected 
from H, halo, or --OR.sup.5 wherein R.sup.5 is selected from H, C.sub.1 to 
C.sub.6 alkyl or aralkyl. Most preferably, R.sup.2 is selected from H, 
--OH or --OR.sup.5 wherein R.sup.5 is C.sub.1 to C.sub.6 alkyl or aralkyl; 
more preferably, H, --OH, benzyloxy (i.e., --OCH.sub.2 C.sub.6 H.sub.5), 
4-chlorobenzyloxy, 4-nitrobenzyloxy, 4-methoxybenzyloxy or --OCH.sub.3 ; 
still more preferably, --OH or --OCH.sub.3 ; and even more preferably, 
--OH. 
Preferably, for the compounds of Formulas 1.0 and 1.1, R.sup.3 is, as 
stated above, in the pare position of the phenyl ring, and is selected 
from H, halo, or --OR.sup.5 wherein R.sup.5 is selected from H, C.sub.1 to 
C.sub.6 alkyl or aralkyl. Most preferably, R.sub.3 is selected from H, Cl, 
F or --OR.sup.5 wherein R.sup.5 is C.sub.1 to C.sub.6 alkyl; more 
preferably, H, Cl, F or --OCH.sub.3 ; and still more preferably, Cl. 
Preferably, R.sup.4 is --OH 
Examples of compounds produced by the processes of this invention include: 
##STR29## 
Additional examples are disclosed in WO 94/17038, published Aug. 4, 1994, 
the disclosure of which is Incorporated herein by reference thereto. 
The starting reactant, Formula 2.0, can be produced by methods well known 
in the art. For example, catalytic hydrogenation of a (C.sub.1 to C.sub.4 
alkyl) 4-hydroxy benzoate (Formula 15.0) with 5% Rh on alumina gives the 
(C.sub.1 to C.sub.4 alkyl) 4-hydroxy cyclohexanoate (Formula 16.0). 
Oxidation of Formula 16.0 with bleach yields the ketone ester (17.0). The 
protection of the ketone group is achieved with ethylene glycol (when n is 
1 in Formula 2.0) or propylene glycol (when n is 2 in Formula 2.0) in the 
presence of an acid catalyst (e.g., p-CH.sub.3 C.sub.6 H.sub.4 SO.sub.2 H 
or HCl). The reaction sequence can be represented as: 
##STR30## 
Step 1 represents reaction with H.sub.2 /5% Rh on alumina; Step 2 
represents reaction with bleach (i.e., aqueous sodium hypochlorite) and 
acetic acid; and Step 3 represents reaction with ethylene glycol (or 
propylene glycol) with p-toluenesulfonic acid in a suitable organic 
solvent such as toluene. Preferably, n is I (i.e., ethylene glycol is 
used) so that a compound of Formula 2.1 is produced. Most preferably, n is 
I and R.sup.11 is ethyl so that a compound of formula: 
##STR31## 
is obtained. 
In reaction Step (a), a compound of Formula 2.0 is reacted, under an inert 
atmosphere such as nitrogen, with an enolization base and a silylation 
reagent to produce a compound of Formula 3.0. Preferably, as stated above, 
n is 1 so a Formula of 3.1 is produced. Most preferably, n is 1, R.sup.11 
is ethyl, and R.sup.12 is methyl so that a compound of formula: 
##STR32## 
is obtained. Examples of suitable organic solvents include but are not 
limited to: hexane, THF (tetrahydrofuran), pentane, toluene and mixtures 
thereof. When mixtures of solvents are used, THF is mixed with pentane or 
hexane, or toluene is mixed with pentane or hexane. The ratio of solvents, 
(THF or toluene):(pentane or hexane) is about 1:0.4 to about 1:0.9, with 
about 1:0.6 to about 1:0.9 being preferred, and about 1:0.8 being most 
preferred. Preferably, THF/hexane (i.e., a mixture) is used as the 
solvent. The reaction is conducted at a temperature of about -78.degree. 
to about 0.degree. C. with about -50.degree. to about -10.degree. C. being 
preferred, and about -30.degree. to about -15.degree. C. being most 
preferred. 
The enolization base in Step (a) is used in an amount of about 1.0 to about 
1.5 equivalents, with about 1.0 to about 1.4 equivalents being preferred, 
and about 1.1 to about 1.3 equivalents being most preferred. Examples of 
suitable enolization bases include but are not limited to: 
LiN(R.sup.15).sub.2, KO-t-C.sub.4 H.sub.9, NaH.sub.2, sec-butyl lithium, 
t-butyl lithium, and lithium bis(trimethylsilyl)amide (i.e., 
((CH.sub.3).sub.3 Si).sub.2 NLi). Each R.sup.15 is independently selected 
from a C.sub.1 to C.sub.6 alkyl, and preferably each R.sup.15 is i-C.sub.3 
H.sub.7. Preferably, the enolization base is selected from LiN(i-C.sub.3 
H.sub.7).sub.2 or KO-t-C.sub.4 H.sub.9, with LiN(i-C.sub.3 H.sub.7)2 being 
most preferred. 
The silylation reagent in Step (a) is used in an amount of about 1.0 to 
about 2.0 equivalents, with about 1.2 to about 1.8 equivalents being 
preferred, and about 1.4 to about 1.6 equivalents being most preferred. 
Suitable silylation reagents are represented by the formula 
(R12)3SiR.sup.16 wherein R.sup.12 is a C.sub.1 to C.sub.4 alkyl group 
(e.g., methyl, ethyl or t-butyl), and R.sup.16 is Cl, Br, or I. 
Preferably, R.sup.12 is methyl and R.sup.16 is Cl. Examples of silylation 
reagents include but are not limited to: (CH.sub.3).sub.3 SiCl, (C.sub.2 
H.sub.5).sub.3 SiCl, (t-C.sub.4 H.sub.9)(CH.sub.3).sub.2 SiCl, and 
CH.sub.3 C(.dbd.NSi(CH.sub.3).sub.3)OSi(CH.sub.3).sub.3. Preferably, 
(CH.sub.3).sub.3 SiCl is used. 
Preferably, the reaction product from Step (a) is isolated before 
proceeding to Step (b). For example, the reaction mixture is vacuum 
distilled to obtain the reaction product of Step (a). 
In Step (b) a compound of Formula 3.0 (or 3.1 or 3.2) is reacted, 5 under 
an inert atmosphere such as nitrogen, with a compound of Formula 4.0 (or 
4.1) in the presence of a chiral catalyst to produce the intermediates: 
##STR33## 
(or an enantiomeric mixture of 5.0A and 5.1A). When the preferred 
substituents are used, intermediates of the formulas: 
##STR34## 
(or an enantiomeric mixture of 5.4A and 5.5A) am obtained. Further 
reaction with a deprotecting reagent removes the silyl protecting group 
(--Si(R.sup.12).sub.3) to produce a compound of Formula 5.0, 5.1, 5.2, 
5.3, 5.4, or 5.5 (or the enantiomeric mixture of 5.0 and 5.1, 5.2 and 5.3, 
or 5.4 and 5.5). 
Suitable organic solvents for the reaction in Step (b) include but are not 
limited to: propionitrile, nitromethane, acetonitrile, benzonitrile, 
nitrobenzene and CH.sub.2 Cl.sub.2. Preferably, propionitrile, 
nitromethane or acetonitrile is used, and most preferably propionitrile is 
used. The reaction of a compound of Formula 3.0 with a compound of Formula 
4.0 followed by deprotection of the resulting product in Step (b) is 
conducted at a temperature of about -80.degree. to about -30.degree. C. 
with about -80.degree. to about -50.degree. C. being preferred, and about 
-78.degree. to about -65.degree. C. being most preferred. 
In Step (b), a compound of Formula 4.0 is used in an amount of about 0.8 to 
about 1.2 equivalents, with about 0.9 to about 1.1 equivalents being 
preferred, and about 1.0 to about 1.05 equivalents being most preferred. 
The chiral catalyst is a complex formed from borane and a compound of 
Formula 6.0. The complex used can be an individual enantiomer or the 
mixture of enantiomers formed when the borane reagent is reacted with the 
compound of Formula 6.0 to produce the complex. The complex can be formed 
before addition to the reaction mixture or can be formed in situ in the 
reaction mixture. Preferably, the complex is formed in situ. The complex 
is formed by mixing (reacting) a borane reagent (e.g., BH.sub.3.THF, 
BH.sub.3.(CH.sub.3).sub.2 S or B.sub.2 H.sub.6) with a compound of Formula 
6.0. When the complex is formed in situ, the compound of Formula 6.0 is 
added to the reaction mixture and then the borane reagent is added to the 
reaction mixture. Preferably, BH.sub.3.THF or BH.sub.3.(CH.sub.3).sub.2 S 
is used, with BH.sub.3.THF being most preferred. The boron reagent is used 
in an amount of about 0.8 to about 1.2 equivalents, preferably about 0.9 
to about 1.1 equivalents and most preferably about 0.9 to about 1.0 
equivalents. 
Preferably, R.sup.13 is a substituted phenyl group or a naphthyl group. The 
naphthyl group is bound to the sulfur atom through a .beta. carbon, i.e., 
R.sup.13 is a 2-, 3-, 6- or 7-naphthyl group. Examples of R.sup.13 include 
but are not limited to: 4-nitrophenyl, 2,4,6-trimethlyphenyl and 
2-naphthyl. 
R.sup.14 represents a radical of an amino acid (i.e., an .alpha.-amino 
carboxylic acid) wherein the radical is bound to the sulfur through the 
.alpha.-amino group of the amino acid, i.e., R.sup.14 represents 
##STR35## 
wherein R.sup.17 represents the remaining portion of the amino acid. The 
amino acids useable in the processes of the invention do not include those 
containing a second carboxylic group or a second basic group (e.g., 
amino). Thus, the acidic amino acids and the basic amino acids are 
excluded. Suitable amino acids include but are not limited to: valine, 
3,3-dimethyl-2-amino-butanoic acid, tryptophan, phenylglycine and 
phenyl-alanine. Preferably, valine, phenylglycine or tryptophan are used. 
Examples of compounds of Formula 6.0 include but are not limited to: 
##STR36## 
Preferably, 18.0, 19.0, 20.0, 21.0 or 22.0 is used. Most preferably, 18.0 
is used. 
The compounds of Formula 6.0 can be obtained in high yield and high purity 
by reacting at a suitable temperature, in a suitable solvent, the amino 
acid with R.sup.13 SO.sub.2 Cl with a mild base. The reaction mixture is 
then acidified with an acid such as aqueous HCl, H.sub.2 SO.sub.4, acetic 
acid or H.sub.3 PO.sub.4, with aqueous HCl being preferred. After 
acidification, the compound of Formula 6.0 can be filtered and recovered, 
or the compound of Formula 6.0 can be extracted into a suitable ether 
solvent such as t-butyl methyl ether or diethyl ether. The compound of 
Formula 6.0 is then obtained by concentration of the ether solutions, 
crystallization (by techniques well known in the art) and filtration. 
The reaction producing the compound of Formula 6.0 is conducted at a 
temperature of about -20.degree. to about 40.degree. C., with about 
-10.degree. to about 30.degree. C. being preferred, and about 5.degree. to 
about 25.degree. C. being most preferred. Suitable bases include, for 
example, (CH.sub.3).sub.3 N, (C.sub.2 H.sub.5).sub.3 N and NaHCO.sub.3, 
with (C.sub.2 H.sub.5).sub.3 N being preferred. Suitable solvents include, 
for example, mixtures of THF/H.sub.2 O, CH.sub.3 CN/H.sub.2 O and 
acetone/H.sub.2 O, with THF/H.sub.2 O being preferred. The ratio of 
organic solvent (e.g., CH.sub.3 CN or THF) to water is about 1:1.5 to 
about 1:3.5, with about 1:2.0 to about 1:3.0 being preferred, and about 
1:2.5 being most preferred. 
In the reaction producing compound 6.0, about 0.9 to about 1.2 equivalents 
of amino acid is used, with about 0.95 to about 1.1 equivalents being 
preferred, and about 1.0 to about 1.05 equivalents being most preferred. 
The reactant R.sup.13 SO.sub.2 Cl is used in amounts of about 0.9 to about 
1.2 equivalents, with about 0.95 to about 1.1 equivalents being preferred, 
and about 1.0 to about 1.05 equivalents being most preferred. 
The compound of Formula 6.0, to form the complex with the borane reagent, 
is used in an amount of about 0.8 to about 1.1 equivalents, preferably 
about 0.9 to about 1.05 equivalents, and most preferably about 0.9 to 
about 0.95 equivalents. 
The complex is formed between the nitrogen of the amino group and the --OH 
of the carboxylic group of Formula 6.0 thus producing a five membered 
ring: 
##STR37## 
Examples of the boron complexes used as chiral catalysts include: 
##STR38## 
After the aldol condensation is complete, the protected intermediate 5.0A 
or 5.1A (e.g., 5.4A or 5.5A) is produced. Before deprotection of the 
intermediate, the reaction mixture is quenched with an aqueous NaHCO3 
solution (preferably a saturated solution). Quenching the reaction mixture 
converts the chiral catalyst (borane complex) to the sodium salt of a 
compound of Formula 6.0, i.e., 
##STR39## 
The aqueous layer containing the sodium salt is separated from the organic 
layer containing a compound of Formula 5.0 or 5.1. Acidification of the 
aqueous layer with acid produces the compound of 6.0, or extraction with 
an ether (e.g., (C.sub.2 H.sub.5).sub.2 O, (CH.sub.3).sub.2 O or 
(t-C.sub.4 H.sub.9)O(CH.sub.3), and preferably (t-C.sub.4 
H.sub.9)O(CH.sub.3)) produces the compound of 6.0, i.e., a compound of the 
formula: 
##STR40## 
After catalyst recovery, the protecting silyl group, --S(R.sup.12).sub.3, 
is removed (i.e, the intermediate is deprotected) by the addition of a 
deprotecting reagent selected from: tetrabutylammonium fluoride, NaF or 
benzyltrimethylammonium fluoride. Preferably, tetrabutylammonium fluoride 
is used. The deprotecting reagent is mixed with a suitable organic solvent 
before addition to the reaction mixture. Suitable organic solvents 
include, for example, THF, toluene or methylene chloride. Preferably, THF 
is used. The deprotection reaction is conducted at a temperature of about 
0.degree. to about 30.degree. C., with about 10.degree. to about 
25.degree. C. being preferred, and about 20.degree. to about 25.degree. C. 
being most preferred. The deprotecting reagent is used in an an amount of 
about 0.5 to about 1.0 equivalents, with about 0.6 to about 0.9 
equivalents being preferred, and about 0.7 to about 0.8 equivalents being 
most preferred. 
Preferably, the reaction product of Step (b) is isolated before proceeding 
to Step (c). For example, the reaction product of Step (b) can be 
crystallized out of solution using a suitable organic solvent such as 
toluene or ethyl acetate. 
Suitable organic solvents for Step (c) include, for example, methylene 
chloride, hexane, toluene and mixtures thereof. Preferably, methylene 
chloride is used. 
The reaction in Step (c) is conducted at a temperature of about 20.degree. 
to about 100.degree. C., with about 40.degree. to about 80.degree. C. 
being preferrred, and about 50.degree. to about 60.degree. C. being most 
preferred. 
The compound of Formula 7.0 (or 7.1) is used in an amount of about 1.5 to 
about 6.0 equivalents, with about 2.0 to about 5.0 equivalents being 
preferred, and about 3.0 to about 4.0 equivalents being most preferred. 
Examples of Lewis acids useable in Step (c) include but are not limited to: 
(CH.sub.3).sub.3 Al, (C.sub.2 H.sub.5).sub.3 Al and Cl.sub.3 Al, with 
(CH3)3Al being preferred. The Lewis acid is used in an amount of about 1.0 
to about 6.0 equivalents, with about 2.0 to about 5.0 equivalents being 
preferred, and about 3.0 to about 4.0 equivalents being most preferred. 
Examples of strong acids suitable for use in Step (c) include, for example, 
HCl, H.sub.2 SO.sub.4, CF.sub.3 CO.sub.2 H and CH.sub.3 SO.sub.3 H. 
Preferably, aqueous HCl, H.sub.2 SO.sub.4, or CF.sub.3 CO.sub.2 H is used, 
with aqueous HCl being most preferred. In Step (d), the product of Step 
(c) is reacted, in a suitable solvent, with a reagent that converts a 
hydroxy group into a leaving group, a strong base and a phase transfer 
reagent to produce the intermediate compound of Formula 9.0. The solvent 
used is a mixture of water with a solvent selected from, for example, 
methylene chloride, toluene or t-butyl methyl ether. The ratio of water to 
solvent is about 1:1 to about 1:8, with about 1:2 to about 1:6 being 
preferred, and about 1:3 to about 1:5 being most preferred, and about 1:4 
being even more preferred. Preferably, methylene chloride mixed with water 
is used as the solvent. 
The reaction in Step (d) is conducted at a temperature of about 0.degree. 
to about 60.degree. C., with about 20.degree. to about 50.degree. C. being 
preferred, and about 30.degree. to about 40.degree. C. being most 
preferred. 
Examples of the reagents that convert a hydroxy group into a leaving group 
in Step (d) include, for example, the Mitsunobu reagents (a 
triarylphosphine or a trialkylphosphine mixed with 
diethylazodi-carboxylate, such as triphenylphosphine mixed 
diethylazodicarboxylate), (C.sub.2 H.sub.5 O).sub.2 P(O)Cl, 
2,4,6-trichlorobenzoyl chloride, 2,6-dichlorobenzoyl chloride, CH.sub.3 
SO.sub.2 Cl and p-toluenesulfonyl chloride (TsCl). Preferably, (C.sub.2 
H.sub.5 O).sub.2 P(O)Cl, 2,4,6-trichlorobenzoyl chloride, or 
2,6-dichlorobenzoyl chloride are used, with (C.sub.2 H.sub.5 O).sub.2 
P(O)Cl being most preferred. The reagent that converts a hydroxy group 
into a leaving group is used in an amount of about 1.0 to about 2.0 
equivalents, with about 1.2 to about 1.8 equivalents being preferred, and 
about 1.3 to about 1.6 equivalents being most preferred. 
Strong bases utilizable in Step (d) include, for example, NaOH, 
NaOCH.sub.2, KOH, KOCH.sub.3, KO-t-C.sub.4 H.sub.9 and NaO-t-C.sub.4 
H.sub.9. Preferably, NaOH, NaOCH.sub.2, KOH, KOCH.sub.3, or KO-t-C.sub.4 
H.sub.9 is used, with NaOH being preferred. The base is used in an amount 
of about 10 to about 50 equivalents, with about 20 to about 40 equivalents 
being preferred, and about 25 to about 30 equivalents being most 
preferred. 
In Step (d), a phase transfer catalyst is used in an amount of about 0.01 
to about 1.0 equivalents, with about 0.05 to about 0.6 equivalents being 
preferred, and about 0.1 to about 0.3 equivalents being most preferred. 
Examples of useable phase transfer catalysts include but are not limited 
to: C.sub.6 H.sub.5 CH.sub.2 N(C.sub.2 H.sub.5).sub.3 Cl, C.sub.6 H.sub.5 
CH.sub.2 N(C.sub.2 H.sub.5).sub.3 Br, tetrabutyl-ammonium sulfate, 
tetrabutylammonium acetate, tetrabutylammonium chloride, 
tetrabutylammonium iodide, benzyltributylphosphorous chloride, 
tetrabutylammonium hydroxide, and tetraphenylphosphorous iodide. 
Preferably, C.sub.6 H.sub.5 CH.sub.2 N(C.sub.2 H.sub.5).sub.3 Cl 
(benzyltriethylammonium chloride), C.sub.6 H.sub.5 CH.sub.2 N(C.sub.2 
H.sub.5).sub.3 Br (benzyltriethylammonium bromide), tetrabutyl-ammonium 
sulfate, tetrabutylammonium acetate or tetrabutylammonium chloride is 
used, with C.sub.6 H.sub.5 CH.sub.2 N(C.sub.2 H.sub.5).sub.3 Cl being most 
preferred. 
The reaction mixture in Step (d) is quenched into an ice-cold HCl solution, 
and extracted With a suitable organic solvent, such as ethyl acetate, 
CH.sub.2 Cl.sub.2, toluene, or (C.sub.2 H.sub.5).sub.2 O, with ethyl 
acetate or toluene being preferred, and ethyl acetate being most 
preferred. Concentration of the organic solvent solution followed by 
addition of (C.sub.2 H.sub.5).sub.2 O or t-butyl methyl ether, preferably 
(C.sub.2 H.sub.5).sub.2 O, produces the compound of Formula 9.0. 
Generally, the compound of Formula 9.0 is obtained as crystals. 
In Step (e), the intermediate from Step (d) is reacted with a compound of 
10.0 or 10.1. This reaction is a diasteroselective reverse Grignard 
addition. In this reaction the ketone intermediate (9.0 or 9.1) from Step 
(d) is added slowly (e.g., dropwise) to the Grignard reagent of Formula 
10.0 or 10.1. The dropwise addition usually is done at a rate of about 10 
to about 60 ml/minute, preferably about 20 to about 50 ml/minute and most 
preferably about 30 to about 40 ml/minute. The Grignard reagent (10.0 or 
10.1) is used in an amount of about 1.0 to about 2.0 equivalents, with 
about 1.2 to about 1.8 equivalents being preferred, and about 1.4 to about 
1.6 equivalents being most preferred. The product from Step (d) (9.0 or 
9.1) is used in an amount of about 1.0 equivalent. The reaction is 
conducted at a temperature of about 10.degree. to about 80.degree. C., 
with about 20.degree. to about 70.degree. C. being preferred, and about 
40.degree. to about 60.degree. C. being most preferred. 
The reaction mixture in Step (e) is quenched into ice-cold HCl solution and 
extracted with a suitable organic solvent. Examples of suitable organic 
solvents include, for example, ethyl acetate, toluene, and (C.sub.2 
H.sub.5).sub.2 O, with ethyl acetate being most preferred. Concentration 
of the solvent yields the product of Step (e), i.e., a compound of Formula 
1.0 (or 1.1). If desired, such as if Step (f) will not be carried out, the 
product of Step (e) can be isolated by techniques well known in the art. 
For example, the product of Step (e) can be isolated using silica gel 
column chromatography with a solvent to elute the desired product. 
R.sup.1, R.sup.2 and R.sup.3 in the compounds of Formulas 1.0 and 1.1 
produced in Step (e) are not --OH. For one or more (i.e., at least one) of 
R.sup.1, R.sup.2 and R.sup.3 to be --OH in the final product, the 
corresponding R.sup.1, R.sup.2 and/or R.sup.3 group in the reactants of 
Formulas 7.0, 4.0 and/or 10.0 is a protected --OH group, i.e., an 
--OR.sup.5 group wherein R.sup.5 is aralkyl. Compounds of Formula 1.0 or 
1.1 with these protected hydroxy groups are reacted according to the 
process of Step (f) to produce the corresponding compound of Formula 1.0 
or 1.1 with the desired --OH group or groups. In the process of Step (f), 
when one or more of the remaining R.sup.1, R.sup.2 and R.sup.3 groups are 
halo (e.g., Cl or F), dehalogenation does not take place when the 
protected hydroxy group is subjected to hydrogenation. Those skilled in 
the art will apprecitate that because there is hydrogenation in this step, 
any substituents containing unsaturation will also be hydrogenated. Thus, 
it is desirable to avoid having one or more of the remaining R.sup.1, 
R.sup.2 and R.sup.3 groups be an --OR.sup.5 group wherein R.sup.5 is 
alkenyl, alkynyl or cycloalkenyl. 
Suitable aralkyl groups for R.sup.5 in Step (f) include benzyl, 
4-methoxybenzyl, 4-Cl-benzyl, and 4-NO.sub.2 -benzyl, with benzyl being 
preferred. 
In the process of Step (f), a compound of Formula 1.0 or 1.1, having one or 
more of the protected hydroxy groups described above, is hydrogenated in a 
suitable alkanol solvent using a suitable hydrogenation catalyst, 
hydrogen, and a suitable Lewis acid to produce a compound of Formula 1.0 
or 1.1 having one or more corresponding hydroxy groups. The hydrogenation 
reaction is generally conducted at room temperature (i.e., about 
20.degree. to about 25.degree. C.). The compound of Formula 1.0 or 1.1 
(having one or more protected hydroxy groups) is used in an amount of 
about 1.0 equivalent. Suitable alkanol solvents include the C.sub.1 to 
C.sub.6 alkanols, such as, for example, ethanol, methanol, n-propanol, 
iso-propanol, and n-butanol. Preferably, ethanol is used. 
Suitable hydrogenation catalysts include, for example, Pd/C, Pt/C, Ni/C, 
Raney Nickel and PtO. Preferably, Pd/C, Pt/C or Ni/C is used, and most 
preferably Pd/C is used. The catalyst is used in an amount of about 5 to 
about 40 w/w %, with about 10 to about 20 w/w % being preferred. 
Hydrogenation is carried out at a pressure of about 5 to about 70 psi, 
with about 20 to about 60 psi being preferred, and about 40 to about 60 
psi being most preferred. 
In process Step (f), a Lewis acid is used. Without wishing to be bound by 
theory, it is believed that the presence of the Lewis acid prevents the 
dehalogenation of any of the remaining R.sup.1, R.sup.2 and R.sup.3 groups 
which are halo. Examples of suitable Lewis acids include but are not 
limited to ZnX.sub.2, MgX.sub.2 or TiX.sub.4, wherein X is Cl or Br. 
Preferably, a Lewis acid of the formula ZnX2 wherein X is Cl or Br, 
preferably Br, is used. The Lewis acid is used in an amount of about 0.2 
to about 1.0 equivalents, with about 0.4 to about 0.9 equivalents being 
preferred, and about 0.7 to about 0.8 equivalents being most preferred. 
Other Lewis Acids which may prove useful include AlCl.sub.3, MgBr.sub.2 
and MnBr.sub.2. 
In the above process compounds of Formula 1.0 are usually produced wherein 
R.sup.4 is is --OH. Compounds wherein R.sup.4 is --OH can be dehydrated 
using techniques well known in the art to produce compounds of Formula 1.0 
wherein R.sup.4 is H. Thus, the R.sup.4 --OH group can be converted to H 
by heating a compound of Formula 1.0 (wherein R.sup.4 is --OH) with an 
acid to produce a compound of Formula 1.2: 
##STR41## 
and preferably a compound of Formula 1.3: 
##STR42## 
Suitable temperatures for the dehydration step are within the range of 
about 40.degree. to about 100.degree. C., with about 60.degree. to about 
90.degree. C. being preferred, and about 70.degree. to about 90.degree. C. 
being most preferred. Examples of acids useable in the dehydration Step 
include, for example, sulfuric acid, HCl, p-toluenesulfonic acid and 
trifluoroacetic acid. 
The compound of Formula 1.2 or 1.3 is then hydrogenated at room temperature 
(i.e., about 20.degree. to about 25.degree. C.), in a suitable alkanol 
solvent with a suitable hydrogenation catalyst to produce a compound of 
Formula 1.0 or 1.1, respectively, wherein R.sup.4 is H. The alkanol 
solvent, hydrogenation catalyst, amounts and pressure used are as 
described above for the hydrogenation in Step (f). 
The product of Step (f) can be isolated by techniques known in the art. For 
example, the product of Step (f) can be crystallized from solution using 
an organic solvent such as, for example, methylene chloride, 
ethanol/hexane (i.e., a mixture), or ethyl acetate/hexane (i.e., a 
mixture). If the conversion of R.sup.4 from --OH to H is to be made, the 
product of Step (f) does not have to be isolated before performing the 
conversion step (Step (g)). If conversion to the R.sup.4 H compound is 
carried out, the product so formed can be isolated as described for the 
isolation of the product of Step (f). 
Those skilled in the art will appreciate that, unless stated otherwise, the 
compounds produced in the various process steps can, if desired, be 
separated from their reaction mixtures, isolated and purified by 
techniques well known in the art. For example, separation can be 
accomplished by precipitation, chromatography (e.g., column), phase 
separation (extraction) and distillation. The desired product can then be 
dried and purified by recrystallization. 
The example that follows is intended to exemplify the claimed Invention, 
and such example should not be construed as limiting the disclosure or the 
claimed invention. 
EXAMPLE 1 
All reactions described below were carried out under nitrogen. 
Chromatography was carried out using 230-400 mesh silica gel. The .sup.1 H 
NMR spectra (300 or 400 MHz) were recorded in ppm and referred to 
(CH.sub.3).sub.4 Si unless otherwise noted. All starting materials were 
purchased commercially and used without further purification, except the 
4-benzyl-oxybenzaldehyde (Formula 37.0) which was recrystallized from 
toluene. The HPLC chiral assays of the hydroxy ester of Formula 34.0, the 
.beta.-lactam of Formula 39.0, and the compound of Formula 11.0 were 
carried out on a Chiralcel ODH column (0.46 cm ID.times.25 cm) with a 
mobile phase of hexane:i-propanol (84:16) and a flow rate of 1.0 mL/min. 
For chemical purities a reversed phase HPLC was employed using 
.mu.-Bondapak Phenyl column (0.39 cm.times.30 cm) and H.sub.2 O:CH.sub.3 
CN (1:1) as a mobile phase. UV detectors at 225 nm were used for both of 
the above HPLC. 
Step 1: Ethyl 4-hydroxycyclohexanecarboxylate (32.0) 
##STR43## 
To a 1-L Pyrex pressure bottle were added sequentially 50 g of ethyl 
4-hydroxybenzoate, 300 mL of methanol, and 5 g of 5% Rh on Al.sub.2 
O.sub.3. The sealed bottle was flashed with nitrogen and hydrogenated at 
50 psi until .sup.1 H NMR indicated complete reaction (about 8 to about 16 
hrs). Filtration of the reaction mixture followed by concentration gave 50 
g of the compound of Formula 32.0 as a mixture of trans and cis-isomers 
with a ratio of 78:22 as determined by GLC. The crude pale-yellow liquid 
was used directly in the oxidation step (Step 2 below) without further 
purification. HRMS: 173.1178 (MH.sup.+); calculated: 173.1171; .sup.1 H 
NMR (CDCl.sub.3) trans: 4.12 (q, J=7.2 Hz, 2H), 3.89 (m, 1H), 2.36 (m, 
1H), 2.04-1.90 (m, 3H), 1.70-1.60 (m, 5H), 1.24 (t, J=7.2 Hz, 3H). IR: 
1730 cm.sup.--1. 
Step 2: Ethyl 4-oxocyclohexanecarboxylate (33.0) 
##STR44## 
To a 3-L 3-neck flask equipped with a mechanical stirrer, a thermometer, 
and an addition funnel were added 50 g (292 mmol) of the compound of 
Formula 32.0 from Step 1, 33 mL (584 mmol) of acetic acid and 145 mL of 
commercial bleach (5.25% NaOCl). To the cooled reaction mixture, at 
5.degree. C., was added dropwise 479 mL of more bleach. The reaction was 
allowed to warm to room temperature for 1 hour and then was extracted with 
3.times.400 mL ethyl acetate. The combined extract was washed with water, 
dried over MgSO.sub.4, and concentrated to give 49 g of crude 33.0 as an 
oil which was used without purification. The spectrum data are identical 
to that of literature (see Sanchez, I. H.; Ortega, A.; Garcia, G.; 
Larraza, M. I.; Flores, H. J. Synthetic comm. 1985, 15, 141). 
Step 3: Cyclicketal ester (2.2) 
##STR45## 
To a 2-L one-neck flask was added 307.5 g (1.968 mole) of the compound of 
Formula 33.0, 131.7 mL (2.362 mole) of ethylene glycol, and 3.74 g (19.68 
mmol) of p-toluenesulfonic acid. With a distillation head attached, water 
produced was removed via an azotropical distillation. When the 
distillation slowed down, 75 mL of toluene was charged and the 
distillation was continued until about 4% starting material was left as 
determined by GLC. The cooled reaction was quenched portionwise into 450 
mL ice cold saturated NaHCO.sub.3 solution and extracted with 3.times.300 
mL of ethyl acetate. The combined extract was washed with brine, dried 
with MgSO.sub.4, and concentrated. The residue was distilled at 
115.degree. to 125.degree. C./0.3 mmHg to give 319 g (81%) of the compound 
of Formula 2.2. HRMS: 215.1283 (MH.sup.+); calculated: 215.1292. .sup.1 H 
NMR (CDCl.sub.3) 4.13 (q, J=7.0 Hz, 2H), 3.96 (s, 4H), 2.4-2.3 (m, 1H), 
2.0-1.9 (m, 2H), 1.9-1.75 (m, 4H), 1.65-1.5 (m, 2H), 1.26 (t, J=7.0 Hz, 
3H). IR: 1730 cm.sup.-1. 
Step 4: Cyclicketal TMSenolether (3.2) 
##STR46## 
To a dry 1-L 3-neck flask equipped with a mechanical stirrer, an addition 
funnel, and a thermometer was added 130 mL of THF and 23.3 mL (166 mmol) 
of diisopropylamine. The mixture was cooled to -20.degree. C. and 104 mL 
(166 mmol) of 1.6 M butyl lithium in hexane was added dropwise. After 30 
minutes agitation at -20.degree. C., a solution of 29.6 g (138 mmol) of 
the compound of Formula 2.2 in 30 mL of THF was added dropwise and the 
resulting mixture was stirred at -20.degree. C. for 1 hour. To the enolate 
formed, at -20.degree. C., was added dropwise 26.3 mL (207 retool) of 
(CH.sub.3).sub.3 SiCl (TMSCl). The mixture was stirred at -20.degree. C. 
for 30 minutes and then allowed to warm to room temperature for 1 hour. 
The THF was distilled off and the residue was transferred into a smaller 
flask via a Schlenk air-free filter. High vacuum distillation at 
87.degree.-92.degree. C./0.3 mmHg produced 38.9 g (94%) of the compound of 
Formula 3.2. HRMS: 285.1522 (MH.sup.+); calculated: 285.1512. .sup.1 H NMR 
(CDCl.sub.3) 3.89 (s, 4H), 3.71 (q, J=7.0 Hz, 2H),2.25-2.20 (m, 2H), 
2.19-2.10 (m, 2H), 1.48-1.40 (m, 4H), 1.15 (t, J-7.0 Hz, 3H), 0.13 (s, 
9H). 
Step 5: Hydroxy ester (34.0) 
(A) N-(2-naphthalenesulfonyl) D-valine (18.1) 
##STR47## 
To a 12-L 3-neck flask with a mechanical stirrer, an addition funnel, and a 
thermometer were added 400 g (3.414 mol) of D-valine (36.0), 3 L of water, 
380 mL of THF, and 1190 mL (8.572 mol) of triethylamine (TEA). To this 
solution was added dropwise at 5.degree.-10.degree. C. a solution of 774 g 
(3.414 mol) of 2-naphthalenesulfonyi chloride (35.0) in 800 mL THF. The 
mixture was allowed to warm to room temperature and stirred for 2 hours. 
Evaporation of THF followed by quenching into 4 L of 3 N HCl precipitated 
crude product. Crystallization of the crude product from t-butyl methyl 
ether gave 910 g (87%) of 18.1. M.p: 170.degree.-172.degree. C. 
(literature gives the m.p. as 170.degree.-172.degree. C.-see Kiyooka, S.; 
Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M. J. Org. Chem., 1991, 56, 
2276.). The spectrum data are identical to that of the literature. 
(B) Hydroxy Ester (34.0) formation 
##STR48## 
To a dry 50 mL 2-neck flask with a magnetic stirrer and thermometer were 
added 1.23 g (4.0 retool) of N-(2-naphthalenesulfonyl) D-valine (18.1) and 
5 mL of propionitrile (dried over 3.ANG. molecular sieves). To the cooled 
mixture at 5.degree. C. was added dropwise 4.0 mL (4.0 mmol) of 1.0M 
BH.sub.3.THF to produce in situ the chiral catalyst: 
##STR49## 
The resulting mixture was cooled to -78.degree. C. and 3.15 g (11 mmol) of 
the TMSenol ether (Formula 3.2) was added dropwise. To the resulting 
mixture was added dropwise, in 2 hours using a syringe pump, a solution of 
2.12 g (10 retool) 4-benzyloxybenzaldehyde (37.0) 
##STR50## 
in 4 mL propionitrile. After stirring at -78.degree. C. for another hour, 
the reaction was quenched into 50 mL of ice cold saturated NaHCO.sub.3 and 
extracted with 3.times.50 mL of ethyl acetate. The combined extract was 
washed with NaHCO.sub.3 4 times to remove any catalyst, dried over 
MgSO.sub.4, and concentrated to a small volume. The residue was 
redissolved in a small amount of THF (about 4 ml) and 0.7 equivalents of 
1.0M (C.sub.4 H.sub.9).sub.4 NF in THF was added dropwise to remove the 
trimethylsilyl (TMS) group. Concentration of the THF was followed by 
quenching into brine. The product was extracted with toluene, washed with 
brine, dried over MgSO.sub.4, and concentrated to a small volume. 
Crystallization gave 3.21 g (75%) of the compound of Formula 34.0 with an 
89% e.e. (enantiomer excess). M.p: 83.degree.-85.degree. C. HRMS: 449.1940 
(MNa.sup.+); calculated: 449.1942. .sup.1 H NMR (CDCl.sub.3) 7.40-7.25 (m, 
5H), 7.07 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H),4.99 (s, 2H), 4.56 (d, 
J=5.6 Hz, 1H), 4.15-4.0 (m, 2H), 3.85 (s, 4H), 2.80 (d, J=5.6 Hz, 1H), 
2.3-2.2 (m, 1H), 2.0-1.9 (m, 1H), 1.7-1.4 (m, 6H), 1.14 (t, J=7.1 Hz, 3H). 
IR: 1720 cm.sup.-1. 
Step 6: Hydroxy amide (38.0) 
##STR51## 
To a dry 2-L 3-neck flask with a mechanical stirrer, an addition funnel, 
and a thermometer was added 41.3 mL (436 mmol) of 4-fluoro-aniline and 120 
mL of CH.sub.2 Cl.sub.2. To the mixture was added 218 mL (436 mmol) of 
2.0M (CH.sub.3)3Al in hexane. After agitation at room temperature for 30 
minutes, a solution of 46.7 g (109 mmol) of hydroxy ester (34.0) in 110 mL 
of CH.sub.2 Cl.sub.2 was added dropwise and the resulting mixture was 
heated at 50.degree. to 55.degree. C. for 2 days. The cooled reaction was 
quenched dropwise into a mixture of 700 mL of 3N HCl and 400 mL of toluene 
and extracted with 2.times.400 mL of ethyl acetate. The combined ethyl 
acetate extract was washed with 2.times.300 mL of 3N HCl, 300 mL brine, 
and concentrated. The residue was redissolved in 250 mL of THF and then 
hydrolyzed at room temperature for 3 days with the addition of 300 mL of 3 
N HCl. After removal of the THF, the crude product was filtered and 
slurried with saturated NaHCO.sub.3 to give 40.9 g (38.0) which was used 
for the cyclization (Step 7 below) without purification. An analytical 
sample was recrystallized from ethyl acetate/hexane. M.p: 
173.degree.-175.degree. C. HRMS: 448.1924 (MH.sup.+); calculated: 
448.1920. .sup.1 H NMR (CDCl.sub.3) 8.88 (s, 1H), 7.48 (dd, J=8.9, 4.8 Hz, 
2H), 7.40-7.30 (m, SH), 7.13 (d, J=8.6 Hz, 2H), 7.04 (t, J=8.6 Hz, 2H), 
6.87 (d, J=8.6 Hz, 2H), 5.00 (s, 2H), 4.56 (s, 1H), 3.16 (bs, 1H), 
2.85-2.75 (m, 1H), 2.75-2.65 (m, 1H), 2.45-2.32 (m, 2H), 2.27 (dm, J=15.8 
Hz, 1H), 2.15-2.05 (m, 1H), 1.93 (td, J=13.4, 5.3 Hz, 1H), 1.55 (td, 
J=13.4, 5.3 Hz, 1H). IR: 1700, 1640 cm.sup.-1. 
Step 7: Ketone .beta.-Lactam (39.0) 
##STR52## 
To a 2-L 3-neck flask with a mechanical stirrer, an addition funnel, and a 
thermometer were added 39.3 g of the crude hydroxy amide (38.0), 1.0 liter 
of CH.sub.2 Cl.sub.2 and 4 g of C.sub.6 H.sub.5 CH.sub.2 N(C.sub.2 
H.sub.5).sub.3 Cl. To the mixture was added slowly through the addition 
funnel 232 g of 50% NaOH and 19 mL (132 mmol) of (C.sub.2 H.sub.5 O).sub.2 
P(O)Cl in 20 minutes. The resulting mixture was stirred at room 
temperature for 2 hours, then quenched slowly into 2 L of ice cold 3N HCl 
with agitation, and then extracted with 3.times.500 mL of ethyl acetate. 
The combined extract was washed with brine, dried over MgSO.sub.4, and 
concentrated. Addition of 200 mL of (C.sub.2 H.sub.5).sub.2 O to the 
residue precipitated 23.4 g (59% over two steps) of the compound of 
Formula 39.0. The enantiomer excess was determined to be 99.8%. M.p: 
127.degree.-129.degree. C. HRMS: 430.1818 (MH.sup.+); calcd: 430.1805. 
.sup.1 H NMR (CDCl.sub.3) 7.34-7.17 (m, 7H), 7.09 (d, J=8.6 Hz, 2H), 
6.90-6.96 (m, 4H), 4.95 (s, 2H), 4.80 (s, 1H), 2.80-2.75 (m, 1H), 2.5-2.45 
(m, 3H), 2.25-2.15 (m, 1H), 1.95-1.80 (m, 2H), 1.52-1.42 (m, 1H). IR: 
1735, 1720 cm.sup.-1. 
Step 8: Hydroxy .beta.-lactam (40.0) 
##STR53## 
To a dry 12-L 3-neck flask with a mechanical stirrer, an addition funnel, 
and a thermometer was added 1750 mL of 1.0M 4-ClC.sub.6 H.sub.4 MgBr. The 
mixture was heated to 48.degree. to 52.degree. C. and a solution of 500 g 
(1.164 mmol) of the compound of Formula 39.0 in 2 L toluene was added 
dropwise in 1 hour. The resulting mixture was stirred for another 30 
minutes at the same temperature, cooled to room temperature, quenched 
slowly into 6 L ice cold 3N HCl, and extracted with 3.times.3 L of ethyl 
acetate. The combined extract was washed with 2.times.3 L of 3N HCl and 
brine, dried over MgSO.sub.4, and concentrated to give 567 g of crude 
product as a mixture of two diastereomers 40.0 and 40.1 (ratio 94:6 of 
40.0 to 40.1). The crude mixture was used directly in hydrogenation Step 9 
below. HRMS: 541.1820 (M.sup.+); calculated 541.1816. .sup.1 H NMR 
(CDCl.sub.3, major isomer only) 7.50-7.20 (m, 8H), 7.00 (d, J=8.6 Hz, 2H), 
6.93 (t, J=8.6 Hz, 2H), 5.04 (s, 2H), 4.86 (s, 1H), 2.60-2.50 (m, 1H), 
2.16 (td, J=13.8, 4.3 Hz, 1H), 2.05-1.90 (m, 3H), 1.63 (rim, J=13.8 Hz, 
1H), 1.32 (dm, J=14.3 Hz, 1H), 1.10 (td, J=13,8, 4.3 Hz, 1H). IR: 1730 
cm.sup.-1. 
Step 9: Hydrogenation to produce Formula 11.0 
##STR54## 
To a 2-L Pyrex pressure bottle were charged 35 g of 10% Pd/C, 350 g (about 
645 mmol) of the crude mixture of 40.0 and 40.1, and 145 g (645 mmol) of 
ZnBr.sub.2. The bottle was sealed with a rubber septum, evacuated, and 
flashed with nitrogen 3 times. To the sealed bottle was added through a 
cannula 1100 mL of ethanol. The mixture was hydrogenated at 50 to 55 psi 
for 16 hours at ambient temperature, filtered through a pad of celite, and 
concentrated. The palladium was covered with sand. The residue was 
redissolved in 1 L of ethyl acetate, quenched slowly into 1 L of ice cold 
saturated NaHCO.sub.3, and extracted with 2.times.300 mL of ethyl acetate. 
The combined extract was washed with saturated NH.sub.4 Cl and brine, 
dried over MgSO.sub.4, and concentrated. Addition of 1 L of CH.sub.2 
Cl.sub.2 precipitated 178 g (63% over 2 steps) of the compound of Formula 
11.0. M.p: 235.degree.-236.degree. C. Elemental analysis: C, 69.16; H, 
5.42; N, 3.19; Cl, 7.75; F, 4.30. calculated for C.sub.26 H.sub.23 
CIFNO.sub.3 : C, 69.10; H, 5.13; N, 3.10; Cl, 7.86; F, 4.21. [a].sup.25 
=+50.9 (8.33 mg/2 mL CH.sub.3 OH). Chiral HPLC: 99.9% e.e. .sup.1 H NMR 
(DMSO-d.sub.6) 9.57 (s, 1H), 7.40-7.15 (m, 10H), 6.80 (d, J=8.5 Hz, 2H), 
5.14 (s, 1H), 5.04 (s, 1H), 2.30 (td, J=12.8, 3.5 Hz, 1H), 2.05 (td, 
J=13.6 Hz, 3.5 Hz, 1H), 1.96 (td, J=13.6, 3.9 Hz, 1H), 1.87 (rim, J=13.6 
Hz, 1H), 1.72 (rim, J=13.6 Hz, 1H), 1.48 (dm, J=13.6 Hz, 1H), 1.13 (din, 
J=12.8 Hz, 1H), 0.84 (td, J=13.6, 3.5 Hz, 1H). .sup.13 C NMR 
(DMSO-d.sub.6, ppm) 170.6, 158.1 (d, J=240 Hz), 157.4, 149.4, 134.1 (d, 
J=2.3 Hz), 130.9, 130.0, 126.6, 125.4, 118.6 (d, J=8.0 Hz), 116.0 (d, J=23 
Hz),115.6, 70.2, 64.9, 58.5, 34.8, 33.4, 27.5, 21.7. IR: 1730 cm.sup.-1. 
While the present invention has been described in conjunction with the 
specific embodiments set forth above, many alternatives, modifications and 
variations thereof will be apparent to those of ordinary skill in the art. 
All such alternatives, modifications and variations are intended to fall 
within the spirit and scope of the present invention.