Derivatives of 1-azatricyclo[7.2.03,8]undec-2-ene-2-carboxyclic acid

The invention relates to heterocyclic derivatives having antibacterial activity, to processes for their preparation, to compositions containing them, and to their medicinal uses. The derivatives according to the invention have the following general formula: ##STR1##

This invention relates to heterocyclic derivatives having antibacterial 
activity, to processes for their preparation, to compositions containing 
them, and to their use in medicine. 
Thus the present invention provides compounds of the general formula (I) 
##STR2## 
in which R.sub.1 represents a hydrogen atom or a hydroxyl protecting 
group; 
R.sub.2 represents a hydrogen atom, a carboxyl protecting group or a cation 
derived from an inorganic base or an organic base; 
R.sub.3 represents a hydrogen atom, a hydroxyl, hydroxylmethyl or C.sub.1-3 
alkyl group, or a group XR.sub.4 in which X represents an oxygen atom or 
the group S(O)n in which n is zero or the integer 1 or 2 and R.sub.4 
represents a C.sub.1-5 alkyl, C.sub.3-7 cycloalkyl, or phenyl group, or 
when X is an oxygen or sulphur atom then R.sub.4 may also represent the 
group AlkNR.sub.5 R.sub.6 in which Alk represents a C.sub.2-6 straight or 
branched alkylene chain, and R.sub.5 and R.sub.6 each independently 
represent a hydrogen atom or a C.sub.1-4 alkyl group or R.sub.5 represents 
a formyl, acetyl or iminomethyl group and R.sub.6 represents a hydrogen 
atom or R.sub.5 and R.sub.6 together with the nitrogen atom to which they 
are attached form a pyrrolidino or piperidino ring, or the group R.sub.3 
represents the group (CH.sub.2).sub.m NR.sub.7 R.sub.8 in which m is zero 
or one and R.sub.7 and R.sub.8 independently each represent a hydrogen 
atom or a C.sub.1-4 alkyl group or R.sub.7 represents a formyl, acetyl or 
iminomethyl group and R.sub.8 represents a hydrogen atom or the group 
R.sub.3 and the carbon atom to which it is attached represents a keto 
group or a ketal derivative thereof; and metabolically labile esters, 
salts and solvates thereof. 
When the group R.sub.3 contains a basic centre acid addition salts of such 
compounds and internal salts formed with the carboxylic acid grouping 
(R.sub.2 .dbd.H) are also included in the invention. 
In addition to the fixed stereochemical arrangement as defined in formula 
(I) the molecule contains a further asymmetric carbon atom at the 
8-position, and another at the 4-position, when R.sub.3 is other than a 
hydrogen atom or when R.sub.3 and the carbon atom to which it is attached 
forms a keto group or a ketal derivative thereof. It will be appreciated 
that all stereoisomers including mixtures thereof arising from these 
additional asymmetric centres, are within the scope of the compounds of 
formula (I). 
The compounds of formula (I) are antibacterial agents and/or of use as 
intermediates for the preparation of other active compounds within the 
general formula (I). Compounds wherein R.sub.1 represents a hydroxyl 
protecting group and/or wherein R.sub.2 represents a carboxyl protecting 
group are in general intermediates for the preparation of other compounds 
of formula (I). 
Suitable hydroxyl protecting groups R.sub.1 and carboxyl protecting groups 
R.sub.2 include those which may be removed by hydrolysis under buffered 
conditions or under non-aqueous conditions. 
When the group OR.sub.1 is a protected hydroxyl group this is conveniently 
an ether or an acyloxy group. Examples of particularly suitable ethers 
include those in which R.sub.1 is a hydrocarbylsilyl group such as 
trialkylsilyl, e.g. trimethylsilyl or t-butyldimethylsilyl. When the group 
OR.sub.1 represents an acyloxy group then examples of suitable groups 
R.sub.1 includes alkanoyl e.g. acetyl, pivaloyl; alkenoyl e.g. 
allylcarbonyl; aroyl e.g. p-nitrobenzoyl; alkoxycarbonyl e.g. 
t-butoxcarbonyl; haloalkoxycarbonyl e.g. 2,2,2-trichloroethoxycarbonyl, or 
1,1,1-trichloro-2-methyl-2-propoxycarbonyl; aralkyloxycarbonyl e.g. 
benzyloxycarbonyl or P-nitrobenzyloxycarbonyl; or alkenyloxycarbonyl e.g. 
allyloxycarbonyl. 
A particularly convenient protecting group R.sub.1 is t-butyldimethylsilyl. 
Examples of suitable carboxyl protecting groups include arylmethyl groups 
such as benzyl, p-nitrobenzyl or trityl, or alkenyl groups such as allyl 
or substituted allyl, t-butyl, haloalkyl e.g. trichloroethyl or 
trialkylsilylalkyl e.g. trimethylsilylethyl. Preferred protecting groups 
R.sub.2 include arylmethyl e.g. benzyl or allyl. 
When the group R.sub.3 together with the carbon atom to which it is 
attached represents a ketal group then the ketal is conveniently that 
derived from a C.sub.1-3 alkanol e.g. methanol or a 1,2 or 1,3 alkane diol 
such as glycol or propane 1,3-diol. 
Particularly useful compounds of formula (I) for use in medicine as 
antibacterial agents are those in which the group R.sub.1 represents a 
hydrogen atom and R.sub.2 represents a hydrogen atom or a physiologically 
acceptable cation, or an internal salt thereof. These compounds exhibit 
antibacterial activity against a wide range of gram positive and gram 
negative, aerobic and anaerobic pathogenic microorganisms. 
Where R.sub.2 is a physiologically acceptable cation, suitable cations 
include those of alkali metals (e.g. sodium or potassium), alkaline earth 
metals (e.g. calcium), amino acids (e.g. lysine and arginine) and organic 
bases (e.g. procaine, phenylbenzylamine, dibenzylethylenediamine, 
ethanolamine, diethanolamine, and N-methyl glucosamine). 
Where R.sub.2 is a cation that is not physiologically acceptable then such 
compounds may be useful as intermediates for the preparation and/or 
isolation of other compounds of the invention. 
Metabolically labile esters of the compounds of formula (I) include alkyl 
esters for example C.sub.1-4 alkyl esters such as methyl ethyl or 
isopropyl esters or alkenyl esters such as allyl or substituted allyl 
esters. 
The general formula (I) as drawn includes at least 4 stereoisomers and 
mixtures thereof and these may be represented by the formulae (1a, 1b, 1c 
and 1d). 
##STR3## 
The wedge shaped bond indicates that the bond is above the plane of the 
paper. The broken bond indicates that the bond is below the plane of 
the paper. 
The configuration shown for the carbon atom at the 8-position in formulae 
1a and 1b is hereinafter referred to as the .beta. configuration and in 
formulae 1c and 1d as the .alpha. configuration. 
The configuration shown for the carbon at the 4 position in formulae 1b and 
1d is hereinafter referred to as the .alpha. configuration and in formulae 
1a and 1c as the .beta. configuration. 
In general, in the specific compounds named below, the .beta.-configuration 
at the 8-position corresponds to the S isomer and the .beta.-configuration 
at the 4-position to the R isomer. The .alpha. configuration at the 
8-position corresponds to the R isomer and the .alpha.-configuration at 
the 4-position corresponds to the S isomer. The assignment of the R or S 
configuration at the 4- and 8- positions have been made according to the 
rules of Cahn. Ingold and Prelog, Experientia 1956, 12, 81. 
A preferred group of compounds of formula I are those in which the carbon 
atom at the 8- position is in the .beta. configuration. Within this group 
those compounds in which the carbon atom at the 4-position is in the 
.alpha. configuration are particularly preferred. 
A further preferred group of compounds of the invention are those in which 
the group R.sub.3 represents a hydrogen atom or more particularly an 
amino, aminomethyl, methylamino, hydroxy, hydroxylmethyl, methyl, 
cyclopentyloxy, ethoxy, isopropoxy, methoxy, aminoethoxy, phenylthio, 
methylthio or methylsulphinyl group or together with the carbon atom to 
which it is attached form a keto group or its dimethylketal. 
A particularly preferred group of compounds of formula (I) are those in 
which the carbon atom at the 8- position is in the .beta. configuration 
and and the carbon atom at the 4-position in the .alpha. configuration, 
R.sub.1 represents a hydrogen atom, R.sub.2 represents a hydrogen atom or 
a physiologically acceptable cation and R.sub.3 represents an amino, 
methylamino, aminomethyl, ethoxy, methoxy, isopropoxy, aminoethoxy, 
phenylthio, methylthio, methylsulphinyl, hydroxy or hydroxymethyl group, 
and metabolically labile esters, salts and solvates thereof. 
Specific preferred compounds include 
(4S,8S,9R,10S,12R)-4-methoxy-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo 
[7.2.0.0.sup.3,8 ] undec-2-ene-2-carboxylic acid and salts thereof e.g. 
sodium or potassium salt. 
(4S,8S,9R,10S,12R)-4-methylthio-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7. 
2.0.0.sup.3,8 ]undec-2-ene-2-carboxylic acid and salts thereof e.g. 
potassium or sodium salt. 
(4S,8S,9R,10S,12R)-4-methylsulphinyl-10-(1-hydroxyethyl)-11-oxo-1-azatricyc 
lo[7.2.0.0.sup.3,8 ]undec-2-ene-2-carboxylic acid and salts thereof e.g. 
potassium or sodium salt. 
(4S,8S,9R,10S,12R)-4-amino-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo[7.2.0.0 
.sup.3,8 ]undec-2-ene-2-carboxylic acid and salts thereof. 
Compounds according to the invention not only exhibit a broad spectrum of 
antibacterial activity against a wide range of pathogenic microorganisms 
but also have a very high resistance to all .beta.-lactamases. Compounds 
of the invention are also relatively stable to renal dehydropeptidase. 
Compounds of the invention have been found to exhibit useful levels of 
activity against strains of Staphylococcus aureus, Streptococcus faecalis, 
Escherichia coli, Pseudomonas aeruginosa, Clostridium perfringens and 
Bacteriodes fragilis. 
The compounds of the invention may therefore be used for treating a variety 
of diseases caused by pathogenic bacteria in human beings and animals. 
Thus, according to another aspect of the present invention, we provide a 
compound of formula (I) for use in the therapy or prophylaxis of systemic 
or topical bacterial infections in a human or animal subject. 
According to a further aspect of the invention we provide the use of a 
compound of formula (I) for the manufacture of a therapeutic agent for the 
treatment of systemic or topical bacterial infections in a human or animal 
body. 
According to a yet further aspect of the invention we provide a method of 
treatment of the human or non-human animal body to combat bacterial 
infections which method comprises administering to the body an effective 
amount of a compound of formula (I). 
The compounds of the invention may be formulated for administration in any 
convenient way for use in human or veterinary medicine and the invention 
therefore includes within its scope pharmaceutical compositions comprising 
a compound of the invention adapted for use in human or veterinary 
medicine. Such compositions may be presented for use in conventional 
manner with the aid of one or more suitable carriers or excipients. The 
compositions of the invention include those in a form especially 
formulated for parenteral, oral, buccal, rectal, topical, implant, 
ophthalmic, nasal or genito-urinary use. 
The compounds according to the invention may be formulated for use in human 
or veterinary medicine by injection (e.g. by intravenous bolus injection 
or infusion or via intramuscular, subcutaneous or intrathecal routes) and 
may be presented in unit dose form, in ampoules, or other unit-dose 
containers, or in multi-dose containers, if necessary with an added 
preservative. The compositions for injection may be in the form of 
suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may 
contain formulatory agents such as suspending, stabilising, solubilising 
and/or dispersing agents. Alternatively the active ingredient may be in 
sterile powder form for reconstitution with a suitable vehicle, e.g. 
sterile, pyrogen-free water, before use. 
The compounds of the invention may also be presented for human or 
veterinary use in a form suitable for oral or buccal administration, for 
example in the form of solutions, gels, syrups, mouth washes or 
suspensions, or a dry powder for constitution with water or other suitable 
vehicle before use, optionally with flavouring and colouring agents. Solid 
compositions such as tablets, capsules, lozenges, pastilles, pills, 
boluses, powder, pastes, granules, bullets or premix preparations may also 
be used. Solid and liquid compositions for oral use may be prepared 
according to methods well known in the art. Such compositions may also 
contain one or more pharmaceutically acceptable carriers and excipients 
which may be in solid or liquid form. 
The compounds of the invention may also be administered orally in 
veterinary medicine in the form of a liquid drench such as a solution, 
suspension or dispersion of the active ingredient together with a 
pharmaceutically acceptable carrier or excipient. 
The compounds of the invention may also, for example, be formulated as 
suppositories e.g. containing conventional suppository bases for use in 
human or veterinary medicine or as pessaries e.g. containing conventional 
pessary bases. 
The compounds according to the invention may be formulated for topical 
administration, for use in human and veterinary medicine, in the form of 
ointments, creams, gels, lotions, shampoos, powders, (including spray 
powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g. eye ear 
or nose drops) or pour-ons. 
Aerosol sprays are conveniently delivered from pressurised packs, with the 
use of a suitable propellant, eg dichlorodifluoromethane, 
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other 
suitable gas. 
For topical administration by inhalation the compounds according to the 
invention may be delivered for use in human or veterinary medicine via a 
nebuliser. 
The pharmaceutical compositions for topical administration may also contain 
other active ingredients such as corticosteroids or antifungals as 
appropriate. 
The compositions may contain from 0.01-99% of the active material. For 
topical administration, for example, the composition will generally 
contain from 0.01-10%, more preferably 0.01-1% of the active material. 
For systemic administration the daily dose as employed for adult human 
treatment will range from 5-100 mg/kg body weight, preferably 10-60 mg/kg 
body weight, which may be administered in 1 to 4 daily doses, for example, 
depending on the route of administration and the condition of the patient. 
When the composition comprises dosage units, each unit will preferably 
contain 200 mg to 1 g of active ingredient. 
The duration of treatment will be dictated by the rate of response rather 
than by arbitrary numbers of days. 
The compounds of formula (I) may be prepared by the cyclisation of a 
compound of formula (II) 
##STR4## 
in which the group R.sub.3a has the meansings defined above for R.sub.3 or 
is a group convertible thereto, and Y is an oxygen atom or a phosphine 
group, and the groups R.sub.1a and R.sub.2a are hydroxy and carboxyl 
protecting groups as defined for R.sub.1 and R.sub.2 and if required or 
desired subjecting the resulting compound prior to or subsequent to any 
separation into its stereochemical isomers, to one or more of the 
following operations 
(a) removal of one or more protecting groups. 
(b) conversion of the group R.sub.3a into the group R.sub.3. 
(c) conversion of a compound in which R.sub.2 is a hydrogen atom or a 
carboxyl protecting group into a salt of an inorganic or organic base. 
The cyclisation of a compound of formula (II) in which Y is oxygen is 
conveniently carried out by heating in the presence of an organic 
phosphite. The reaction is preferably carried out in a solvent or mixture 
of solvents at a temperature within the range 60.degree.-200.degree.. 
Suitable solvents include hydrocarbons with an appropriate boiling point, 
for example aromatic hydrocarbons, such as toluene or xylene. 
Suitable organic phosphites include acyclic and cyclic trialkylphosphites, 
triarylphosphites and mixed alkylarylphosphites. Particularly useful 
organic phosphites are the trialkylphosphites e.g. triethylphosphite or 
trimethylphosphite. 
The cyclisation of a compound of formula (II) in which Y is a phosphine 
grouping is preferably carried out in a solvent at a temperature between 
40.degree.-200.degree. C. Suitable solvents include hydrocarbons such as 
aromatic hydrocarbons, for example xylene or toluene, aliphatic 
hydrocarbons and halogenated hydrocarbons such as dichloromethane, 
chloroform and trichloroethane. Examples of suitable phosphine groups are 
triarylphosphines e.g. triphenyl phosphine, or trialkylphosphines e.g. 
tri-t-butylphosphine. 
The hydroxyl and carboxyl protecting groups R.sub.1a and R.sub.2a may be 
removed by conventional procedures and in any order. More preferably 
however the hydroxyl protecting group R.sub.1a is removed prior to the 
removal of the carboxyl protecting group. Such removal of the protecting 
groups is a further feature of the invention. 
The hydroxyl protecting groups may be removed by well known standard 
procedures such as those described in Protective Groups in Organic 
Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973). For 
example when R.sub.1a is a t-butyldimethylsilyl group, this may be removed 
by treatment with tetrabutylammonium fluoride and acetic acid. This 
process is conveniently carried out in a solvent such as tetrahydrofuran. 
Similarly when R.sub.1a is a trichloroethoxycarbonyl group this may be 
removed by treatment with zinc and acetic acid. 
The carboxyl protecting group R.sub.2a may also be removed by standard 
processes such as those described in Protective Groups in Organic 
Chemistry, pages 192-210, Edited by J F W McOmie (Plenum Press 1973). For 
example when R.sub.2a represents an arylmethyl group this may be removed 
by conventional procedures using hydrogen and a metal catalyst e.g. 
palladium. When the group R.sub.2a represents an allyl or substituted 
allyl group then this is preferably removed by treatment with an allyl 
acceptor in the presence of tetrakis(triphenylphosphine) palladium and 
optionally in the presence of triphenylphosphine. Suitable allyl acceptors 
include sterically hindered amines such as tertbutylamine, cyclic 
secondary amines such as morpholine or thiomorpholine, tertiary amines 
such as triethylamine, aliphatic or cycloaliphatic .beta.-dicarbonyl 
compounds such as acetylacetone, ethyl acetoacetate or dimedone, or 
alkanoic acids or alkali metal salts thereof such as acetic acid, 
propionic acid or 2-ethyl hexanoic acid or the potassium or sodium salt 
thereof. 
A particularly useful allyl acceptor is 2-ethylhexanoic acid and more 
especially the sodium or potassium salts thereof. 
The reaction is preferably carried out in an inert solvent such as an ether 
e.g. diethyl ether or tetrahydrofuran, an alkanol e.g. ethanol, an ester 
e.g. ethyl acetate or a halohydrocarbon e.g. methylene chloride, or 
mixtures thereof. The reaction is conveniently carried out in the 
temperature range 0.degree.-40.degree. more particularly at room 
temperature. 
Compounds of the invention in which the group R.sub.2 is a physiologically 
acceptable cation may be prepared from compounds of the invention in which 
R.sub.2 is hydrogen by treatment with a suitable base. Conveniently the 
salt is formed in solution and then if required precipitated by the 
addition of a non-solvent e.g. a non polar aprotic solvent. Alternatively 
the sodium or potassium salt may be prepared by treating a solution of a 
compound of formula (I) in which R.sub.2 represents a hydrogen atom with a 
solution of sodium or potassium 2-ethylhexanoate in a non-polar solvent 
such as diethyl ether. 
For the preparation of compounds of formula I in which R.sub.3 represents a 
hydroxyl or hydroxymethyl group the cyclisation reaction is conveniently 
carried out using an intermediate of formula (II) in which R.sub.3a is a 
protected hydroxyl or protected hydroxymethyl group. Suitable protected 
hydroxyl groups include trihydrocarbyl silyl ethers such as the 
trimethylsilyl or t-butyldimethylsilyl ether. The hydroxyl protecting 
group may then be removed at any subsequent stage in the synthesis, for 
example at the same time as the removal of the hydroxyl protecting group 
R.sub.1a. 
For the preparation of compounds of formula (I) in which R.sub.3 represents 
a primary or secondary amino grouping or is a substituent containing such 
an amino grouping, the cyclisation is conveniently carried out with an 
intermediate of formula (II) in which the amino group present in R.sub.3a 
is in protected form, e.g. such as an allyloxycarbonylamino group. The 
amino protecting group may then be removed by conventional procedures. 
Thus for example if R.sub.3a is the allyloxycarbonylamino, 
allyloxycarbonylaminoethoxy or allyloxycarbonylaminomethyl group these may 
be converted into the amino, aminoethoxy or aminomethyl group using the 
conditions described above for converting an allyl ester into the 
corresponding carboxylic acid. 
Compounds of formula (I) may be converted into other compounds of formula 
(I). Thus compounds of formula (I) wherein the group R.sub.2 is a carboxyl 
protecting group and R.sub.3 represents the group SOR.sub.4 may be 
prepared by oxidation of the corresponding compound of formula (I) wherein 
R.sub.3 represents the group SR.sub.4. The oxidation is preferably carried 
out using a peracid e.g. a peroxybenzoic acid such as 
m-chloroperoxybenzoic acid in an organic solvent such as a halogenated 
hydrocarbon e.g. methylene chloride. Preferably the reaction is carried 
out at a low temperature e.g. -78.degree. C. to -20.degree. C. 
Compounds of formula (I) wherein the group R.sub.3 and the carbon atom to 
which it is attached represents a keto group and the groups R.sub.1 and 
R.sub.2 represent protecting groups may be prepared by hydrolysis of the 
corresponding ketal of formula (I). For example a compound of formula (I) 
wherein R.sub.3 and the carbon atom to which it is attached represents a 
dimethyl ketal may be converted into the corresponding ketone by treatment 
with silica in the presence of an aqueous acid such as aqueous oxalic acid 
or aqueous sulphuric acid. The reaction is conveniently carried out in the 
presence of a solvent such as a halohydrocarbon e.g. methylene chloride. 
Compounds of formula (I) wherein the group R.sub.3 represents an hydroxyl 
group may be prepared by the reduction of compounds of formula (I) wherein 
the group R.sub.3 and the carbon atom to which it is attached represent a 
keto group. The reduction may be carried out using a borohydride reducing 
agent, such as sodium borohydride, sodium cyanoborohydride, or a 
trialkylborohydride such as lithium trisamyl borohydride or lithium 
tri-sec-butylborohydride. The reaction is carried out in a solvent such as 
an alkanol e.g. methanol or an ether e.g. tetrahydrofuran or an aromatic 
hydrocarbon e.g. toluene. Thus for example the reduction may be carried 
out using sodium borohydride in aqueous methanol and preferably the pH of 
the reaction medium is maintained between 4 and 7 by the addition of a 
suitable acid e.g. hydrochloric acid. 
Compounds of formula (I) in which R.sub.1 is a hydroxyl protecting group, 
R.sub.2 is a carboxyl protecting group and R.sub.3 is an alkoxy group e.g. 
methoxy may be prepared by 0-alkylation of the corresponding compound of 
formula (I) in which R.sub.3 is a hydroxyl group. The reaction may be 
carried out using an appropriate alkyltrifluoromethanesulphonate in the 
presence of a suitable base such as potassium bis (trimethylsilyl)amide. 
Compounds of formula (II) in which Y.dbd.0 may be prepared by treating a 
compound of formula (III) in which the group R.sub.1a and R.sub.3a have 
the meanings given above with an activated derivative of the acid (IV) in 
which R.sub.2a has the meanings defined above. 
##STR5## 
Suitable activated derivatives of the acid (IV) includes the corresponding 
acid halides e.g. acid chloride. 
When the acid halide is used as the activated derivative of the acid (IV) 
then the reaction is preferably carried out in the presence of an acid 
acceptor such as a tertiary organic base for example pyridine or a 
trialkylamine in an aprotic solvent such as dichloromethane. 
The compound of formula (II) in which Y is a phosphine group may be 
prepared by treating the intermediate (V) in which L is a leaving group 
such as a halogen e.g. chlorine 
##STR6## 
with the corresponding phosphine e.g. triphenylphosphine in the presence 
of a base. The reaction is conveniently carried out in a solvent such as 
dioxan in the presence of a tertiary organic base, e.g. 2,6 lutidine. The 
compounds of formula (II) are novel compounds and as such form a further 
aspect of the invention. 
The compounds of formula (V) may be prepared from the corresponding hydroxy 
derivative (VI) by conventional means for converting hydroxyl groups into 
leaving groups. 
##STR7## 
Thus for example a compound of formula (V) in which L is a chlorine atom 
may be prepared by treating a compound of formula (VI) with thionyl 
chloride in an aprotic solvent such as dioxan or tetrahydrofuran and in 
the presence of a tertiary organic base e.g. 2,6-lutidine. Compounds of 
formula (VI) may be prepared from the reaction of a compound of formula 
(III) with glyoxylic ester (VII; CHOCO.sub.2 R.sub.2a) preferably in the 
form of its hydrate or hemiacetal. The reaction is preferably carried out 
in an aprotic solvent such as toluene and in the presence of an activated 
molecular sieve. Compounds of formula (VI) may also be prepared by 
reduction of a compounds of formula (II) in which Y.dbd.O. Suitable 
reducing agents include zinc/acetic acid. 
Alternatively compounds of formula (II) in which Y.dbd.O, may be prepared 
by oxidation of a compound of formula (VI), using for example manganese 
dioxide. 
Compounds of formula (III) may be prepared by treating the azetidinone 
(VIII) with the enolate ion of the ketone (IX). 
##STR8## 
The reaction is preferably carried out at a low temperature e.g. 
-78.degree. C. in a solvent such as tetrahydrofuran. 
The enolate ion of the ketone (IX) is conveniently generated in situ by 
treatment with a suitable base such as lithium bis(trimethyl silyl)amide. 
Alternatively compounds formula (III) in which R.sub.3a is a hydrogen atom 
may be prepared from the reaction of azetidinone (VIII) with the enol 
ether (X) 
##STR9## 
The reaction may be carried out in a solvent such as methylene chloride or 
acetonitrile in the presence of an activated ester of 
trifluoromethanesulphonic acid e.g. the trimethylsilyl ester or a Lewis 
acid such as stannic chloride. Compounds of formula (III) may also be 
prepared by reduction of a compound of formula (XI) 
##STR10## 
The reduction may be effected using hydrogen and a metal catalyst e.g. 
palladium on a suitable support e.g. carbon or alumina. The reaction is 
carried out in a solvent such as an ester e.g. ethyl acetate. 
The compound of formula (XI) may be prepared from the reaction of the 
azetidinone (VIII) with the ketone (XII) or the enol ether (XIII) using 
the conditions described above for preparing compounds of formula (III) 
from the ketone (IX) and the enol ether (X). 
##STR11## 
Compounds of formula (III) may also be prepared by oxidation of the alcohol 
of formula (XIV) 
##STR12## 
in which the groups R.sub.1a and R.sub.3a have the meanings defined above. 
The oxidation may be carried out using conventional oxidising agents known 
in the art for converting a secondary alcohol such as a cyclohexanol into 
a ketone such as a cyclohexanone. Thus for example the oxidation may be 
carried out using pyridinium chlorochromate or oxalyl chloride and 
dimethylsulphoxide. The reactions are preferably carried out in a solvent 
such as methylene chloride. 
The alcohol (XIV) may be prepared by reduction of the .alpha.-.beta. 
unsaturated ketone (XI). This reduction is conveniently carried out in a 
two stage reaction. The first stage is the reduction of the ketone to the 
alcohol using a suitable metal hydride such as sodium borohydride. The 
resultant .alpha.-.beta. unsaturated alcohol is then reduced to the 
required alcohol (XIV) using hydrogen and a metal catalyst as described 
above for the preparation of the ketone (III) from the .alpha.-.beta. 
unsaturated ketone (XI). 
Compounds of formula (III) in which R.sub.3a represents an alkyl thio group 
may be prepared by treating the corresponding compound of formula (III) in 
which R.sub.3a represents a hydrogen atom with an alkali metal base e.g. 
lithium bis(trimethylsilyl)amide and the corresponding alkylthio 
methanesulphonate. 
In this reaction an alkylthio group is introduced on to the N-nitrogen atom 
of the azetidinone group and thus it is necessary to use two equivalents 
of the base lithium bis(trimethylsilyl)amide and the corresponding 
alkylthio methanesulphonate. If the reaction is carried out stepwise, such 
that the alkylthio group is introduced on the azetidinone nitrogen before 
the second equivalent of base and alkylthio reagent is added, then the 
reaction gives predominantly one stereoisomer at the 4-position. If 
however the 2 equivalents of base and alkylthio ester are added together 
then the reaction gives an approximately even mixture of the two 
stereoisomers at the 4-position. The alkylthio group on the azetidinone 
nitrogen atom may be removed by treatment with a suitable nucleophile e.g. 
2-mercaptopyridine in the presence of an additional tertiary organic base 
such as triethylamine, to give the required compound of formula (III) in 
which R.sub.3 represents an alkylthio group. 
In a modification of this process the compound of formula (III) in which 
R.sub.3a represents hydrogen may be first converted into an alternative 
N-protected derivative e.g. the N-trimethylsilyl derivative by 
conventional means and then the alkylthio group R.sub.3a introduced using 
the conditions described above followed by subsequent removal of the 
N-protecting group. 
Compounds of formula (III) in which the group R.sub.3a has the meaning 
SR.sub.4 may also be prepared from a corresponding compound in which 
R.sub.3a represents hydrogen, via a corresponding halo derivative. Thus 
for example reaction of a compound of formula (III) in which R.sub.3a is 
hydrogen with a suitable base such as sodium or lithium 
bis(trimethylsilyl) amide in a solvent such as hexane and/or 
tetrahydrofuran followed by reaction with iodine and then sodium sulphite 
gives the corresponding iodo derivative (III; R.sub.3a .dbd.I). Treatment 
of the iodide with the thiol R.sub.4 SH in aqueous methylene chloride in 
the presence of a suitable base such as a phase transfer catalyst e.g. 
tetrabutylammonium hydroxide gives the required compound (III: R.sub.3a 
--SR.sub.4). 
The alcohol of formula (XIV) in which R.sub.3a is an alkoxy group may be 
prepared by reacting the corresponding epoxide (XV) with the corresponding 
alcohol R.sub.3a OH in the presence of an acid catalyst such as p-toluene 
sulphonic acid. 
##STR13## 
The alcohol of formula (XIV) in which R.sub.3a is an azido group may be 
prepared by treating the expoxide (XV) with an alkali metal azide. The 
reaction may be carried out in a solvent such as an alkanol e.g. methanol. 
The compounds of formula (III) in which the group R.sub.3a is an amino 
group may be prepared by reducing a compound of formula (III) in which the 
group R.sub.3 is azido. The reduction may be carried out using hydrogen 
and a metal catalyst in a solvent such as ethyl acetate. 
Compounds of formula (III) in which R.sub.3a is or contains a protected 
amino group may be prepared from the corresponding primary amino compound 
by conventional means for example by reaction with a suitable acid 
chloride such as allyloxycarbonyl chloride. 
The alcohol of formula (XIV) in which R.sub.3a is the group NR.sup.7 
R.sup.8 wherein R.sub.7 is a hydrogen atom or a C.sub.1-4 alkyl group and 
R.sub.8 represents a C.sub.1-4 alkyl group may be prepared by from the 
reaction of the epoxide (XV) with the corresponding amine R.sub.7 R.sub.8 
NH. The reaction is preferably carried out in a solvent such as an alkanol 
e.g. ethanol or aqueous ethanol and in the presence of an ammonium salt. 
The alcohol of formula (XIV) in which R.sub.3a is a protected secondary 
amino group may be prepared from the corresponding secondary amino group 
--NHR.sub.8 by conventional means, such as for example reaction with a 
suitable acid chloride e.g. allyloxycarbonylchloride. 
The epoxide of formula (XV) may be prepared by epoxidation of the 
cycloalkene of formula (XVI) 
##STR14## 
in which R.sub.1a has the meanings given above. The epoxidation may 
conveniently be carried out by treating the cycloalkene of formula (II) 
with a peracid. Suitable peracid include optionally substituted perbenzoic 
acids such as perbenzoic acid or meta chloroperbenzoic acid, and 
peralkanoic acids such as peracetic acid and trifluoroperacetic acid. The 
reaction may be carried out in a solvent such as a halohydrocarbon e.g. 
dichloromethane and conveniently at a temperature within the range 
-30.degree. to +30.degree. C. 
The cycloalkene of formula (XVI) may be prepared by treating the 
corresponding tosylhydrazone (XVII) 
##STR15## 
in which R.sup.1 is a hydroxyl protecting group with a base, such as 
methyl or butyl lithium or lithium diisopropylamide. The reaction is 
conveniently carried out in an aprotic solvent such as an ether e.g. 
tetrahydrofuran and at a temperature between -50.degree. C. to 0.degree. 
C. 
The tosylhydrazone (XVII) may be prepared by treating the cyclohexanone 
derivative (III) in which R.sub.1a is a hydroxyl protecting group and 
R.sub.3a is hydrogen 
##STR16## 
with tosylhydrazide (XVIII) in a suitable solvent such as glacial acetic 
acid. 
Compounds of formula (III) in which R.sub.3a is an hydroxyl group may be 
prepared from the silylenol ether (XIX) by reaction with a peracid such as 
metachloroperbenzoic acid followed by hydrolysis of the silylenol ether 
and the N-silyl protecting group. 
##STR17## 
The silylenolether (XIX) may be prepared from the corresponding ketone 
(XX) by reaction with a halo trialkylsilane in the presence of a strong 
base such as potassium or lithium bis (trimethylsilyl) amide. 
The ketone (XX) may be prepared from the reaction of the N-protected 
azetidinone (XXI) with the enol ether (X) in the presence of an activated 
ester of trifluoromethyl sulphonic acid e.g. the trimethylsilyl ester or a 
Lewis acid such as stannic chloride. 
##STR18## 
The N-protected azetidinone (XXI) may be prepared from the azetidinone 
(VIII) by reaction with an appropriate trihydrocarbylsilylhalide in the 
presence of a tertiary organic base such as triethylamine and in an 
aprotic solvent e.g. dichloromethane. 
In any of the formulae (I) to (XX) shown above when there is an asymmetric 
carbon atom and no specific configuration is shown then the formula 
includes all possible configurations. 
Specific stereoisomers of the compounds of formula (I) as defined in 
formulae 1a, 1b, 1c and 1d, essentially free of the other stereoisomers 
may be prepared by using the general processes described above starting 
with the appropriate stereoisomer of formula (III). 
The processes described above for preparing the compounds of formula (III) 
will in general give a mixture of stereoisomers. 
The individual stereoisomers of the compounds of formula (III) may be 
separated from each other by conventional techniques such as fractional 
crystallisation or more particularly by column chromatography, using for 
example a silica column, as illustrated in the relevant examples. 
The compounds of formulae (III), (XI) and (XIV) are novel compounds and 
these compounds and the individual stereoisomers thereof form a further 
aspect of the invention. 
Alternatively the synthesis may be carried out starting with a mixture of 2 
or more stereoisomers of formula (III) and the required specific 
stereoisomer separated at by conventional techniques at another stage in 
the synthesis. Thus the compounds may be separated by fractional 
crystallisation and or column chromatography. 
In the synthesis of compounds of formula (I) or the intermediates therefore 
it may be necessary to protect functional groupings within the group 
R.sub.3. Such protection and deprotection steps are conventional and are 
within the scope of the invention. For example when the group is a primary 
or secondary amine or contains such a group then it may be desirable to 
protect these during the synthesis using conventional nitrogen protecting 
groups. 
The compounds of formulae (VIII), (IX), (X), (XII) and (XIII) are either 
known compounds or may be prepared by analogous methods to those used for 
known compounds. 
In order that the invention may be more fully understood the following 
examples are given by way of illustration only. 
In the Preparations and Examples, unless otherwise stated: 
Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus and 
are uncorrected. All temperatures refer to .degree.C. 
Infrared spectra were measured in chloroform-d.sub.1 solutions on a FT-IR 
instrument. Proton Magnetic Resonance (1H-NMR) spectra were recorded at 
300 MHz as solutions in chloroform-d.sub.1. Chemical shifts are reported 
in ppm downfield (.delta.) from Me.sub.4 Si, used as an internal standard, 
and are assigned as singlets (s), doublets (d), doublet of doublets (dd) 
or multiplets (m). 
Column chromatography was carried out over silica gel (Merck AG Darmstadt, 
Germany). 
Solutions were dried over anhydrous sodium sulphate. 
"Petrol" refers to petroleum ether, b.p. 40.degree.-60.degree. C. 
Methylene chloride was redistilled over calcium hydride; tetrahydrofuran 
was redistilled over sodium; ethyl ether was redistilled over sodium; 
xylene was redistilled over phosphorus pentoxide and ethyl acetate was 
dried over activated molecular sieves. 
The following abbreviations are used in the tables and text. EA=ethyl 
acetate, CH=cyclohexane, P=petroleum ether 40.degree.-60.degree. C., 
THF=tetrahydrofuran, MC=methylene chloride, EE=ethyl ether. Tlc refers to 
thin layer chromatography on silica plates. 
Intermediate 1 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-2'-(1'-oxocyclohexy 
l)]azetidin-2-one (1a) and 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-2'-(1'-oxocyclohex 
yl)]azetidin-2-one (1b) 
Method A 
1-Trimethylsilyloxycyclohexene (11 g) was dissolved in methylene chloride 
(400 ml) under nitrogen. (3R,4R)-4-Acetoxy-3((R)-(t-butyldimethylsilyloxy) 
ethyl)-2-azetidinone (9.28 g; intermediate A) was added to the solution, 
the mixture stirred at 23.degree. and trimethylsilyl 
trifluoromethanesulphonate (0.66 g) was added. The mixture was stirred 
under nitrogen for 2 hr and then poured into an ice cold 1% solution of 
sodium hydrogen carbonate (300 ml). The organic layer was separated, 
washed with water (300 ml) and brine (300 ml). The oily residue obtained, 
after evaporating the solvent under reduced pressure was chromatographed 
(gradient elution with EE/P) to give the title compound (1a; 2.6 g) as a 
white solid m.p. 70.degree.-80.degree. (t.l.c. P/EA 4/6; Rf 0.5) and the 
title compound (1b; 2.63 g) as a white solid m.p. 100.degree. (t.l.c. P/EA 
4/6; Rf 0.45). 
Method B 
A 1M solution of lithium bis(trimethylsilyl)amide in hexane (250 ml) was 
added to tetrahydrofuran (250 ml), the mixture stirred under nitrogen, 
cooled to -78.degree. and cyclohexanone (15.2 g) was added over 20 min. 
The temperature was allowed to rise to -55.degree. for 10 min and then the 
mixture cooled to -78.degree. for 40 min. Intermediate A (34 g) was added 
and the resulting mixture stirred for 30 min at -78.degree.. The reaction 
mixture was poured into a saturated ammonium chloride solution (200 ml) 
and the resulting mixture extracted with ethyl acetate (3.times.200 ml). 
The combined organic layers were washed with brine, dried and evaporated 
under reduced pressure. The oily residue was chromatographed (gradient 
elution with CH/EA) to give the title compound (1a; 11.6 g) as a white 
solid m.p. 70-80 and the title compound (1b; 12 g) as a white solid m.p. 
100.degree. C. 
Using Method A 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4((S)-6'-(1'-oxocyclohex- 
2'-enyl)-azetidin-2-one (1c; 12.7 g), m.p. 125.degree. was prepared from 
2-trimethylsilyloxycyclohex-1,3-diene (19.2 g) and intermediate A (14.34 
g) except that the reaction time was 18 hr and the crystalline product was 
obtained from the oily residue by crystallisation from EE/P in place of 
the chromatographic purification step. 
Using method B 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-((S)-2'-((R)-6'-methyl-1 
'-oxocyclohexyl))azetidin-2-one (1d; 0.5 g) m.p. 117.degree. and a mixture 
(intermediate 1e; 3.15 g) of 
(3R,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-((S)-2'((S)-6'-methyl-1 
'-oxocyclohexyl))azetidin-2-one and 
(3R,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-((R)-2'-((S) 
-6'-methyl-1'-oxocyclohexyl))azetidin-2-one were prepared from 
intermediate A (14.35 g) and 2-methyl-1-oxo-cyclohexane 13.2 g. 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-2'-(6',6'-dimethoxy 
-1'-cyclohexyl))azetidin-2-one (1f; 0.97 g) from intermediate A (1.8 g) and 
2,2-dimethoxy-1-oxocyclohexane (2.0 g) except that the chromatography 
eluants were EE and P. 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-6'-(2-methoxy-1'-ox 
ocyclohex-2'-enyl))]azetidin-2-one (1 g) and 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-6'-(2'-methoxy-1'- 
oxo-cyclohex-2'-enyl))]azetidin-2-one (1h) 
2-Methoxy-2-cyclohexenone (11.9 g) was added dropwise to a stirred mixture 
of anhydrous tetrahydrofuran (200 ml) and a 1M solution of lithium 
bis(trimethylsilyl)amide in hexane (200 ml) cooled to -78.degree. and 
under nitrogen. The temperature was maintained at -78.degree. for a 
further 30 min, intermediate A (15 g) added and the reaction mixture kept 
at -78.degree. for an additional 15 min. The reaction mixture was poured 
into a cold saturated solution of ammonium chloride (100 ml) and then 
extracted with ether. The organic layer was washed with a cold 1% solution 
of hydrochloric acid (50 ml) and a cold saturated solution of sodium 
hydrogen carbonate, dried and then evaporated under reduced pressure. The 
residue was dissolved in the minimum amount of ethyl acetate and petroleum 
ether (200 ml) added to give the title compound (1h; 7.9 g) as a white 
solid m.p. 170.degree. (t.l.c. Rf 0.25; CH/EA 4/6). The mother liquors 
were evaporated under reduced pressure and submitted to flash 
chromatography to give the title compound (1g; 2.9 g) (t.l.c. Rf 0.20; 
CH/EA 4/6). 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-6'-(2'-ethoxy-1'-ox 
ocyclohex-2'-enyl))]azetidin-2-one (1i) and 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4((S)-6'-(2'-ethoxy-1'-ox 
o-cyclohex-2'-enyl)]azetidin-2-one (1j) 
A solution of 2-ethoxy-2-cyclohexenone (24 g) in anhydrous tetrahydrofuran 
was added to a mixture of anhydrous tetrahydrofuran (160 ml) and a 1M 
solution of lithium bis(trimethylsilyl)amide in hexane (200 ml) cooled to 
-78.degree. and under nitrogen and with the resultant mixture kept at 
-78.degree. for 1 h. A solution of intermediate A (26.3 g) in 
tetrahydrofuran (80 ml) was then added over 10 min. A cold saturated 
solution of ammonium chloride (320 ml) was added followed by a 10% 
solution of hydrochloric acid (70 ml). The resultant mixture was extracted 
with ether (3.times.150 ml) washed with cold 10% hydrochloric acid (50 
ml), brine and then dried. Removal of the solvent under reduced pressure 
gave an oily residue which was purified by flash chromatography (eluants 
CH/EA) to give a 1:1 mixture of the title compounds (20 g) and pure title 
compound (1j; 1.3 g) (t.l.c. Rf 0.36; CH/EA 1/1). The mixture was 
dissolved in the minimum amount of ethyl acetate, diluted with cyclohexane 
and chilled to give the title compound (1i; 4 g) as a white solid (t.l.c. 
Rf 0.38; CH/EA 1/1). 
Intermediate 1K 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-2'-(1'-oxo-cyclohex 
yl)]azetidin-2-one and 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-2'-(1'-oxocyclohex 
yl)]azetidin-2-one 
1-Trimethylsilyloxycyclohexene (11 g) was dissolved in methylene chloride 
(400 ml) under nitrogen. 
(3R,4R)-4-Acetoxy-3((R)-(t-butyldimethylsilyloxy)ethyl)-2-azetidinone 
(9.28 g; intermediate A) was added to the solution, the mixture stirred at 
23.degree. and trimethylsilyl trifluoromethanesulphonate (0.66 g) was 
added. The mixture was stirred under nitrogen for 2 hr and then poured 
into an ice cold 1% solution of sodium hydrogen carbonate (300 ml). The 
organic layer was separated, washed with water (300 ml) and brine (300 
ml). Evaporation of the solvent under reduced pressure gave a mixture of 
the title compounds as an oil. 
Intermediate 2 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4[(R)-2'-((S)-6'-methoxy-1 
'-oxocyclohexyl))]azetidin-2-one (2a) and 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4[(R)-2'-((R)-6'-methoxy- 
1'-oxocyclohexyl)]]azetidin-2-one (2b) 
10% Palladium on charcoal (1.8 g) was added to a solution of intermediate 
(1g: 2.2 g) in ethyl acetate (200 ml) and the mixture was hydrogenated at 
1 atmosphere for 2 hr. The catalyst was removed by filtration and the 
filtrate evaporated under reduced pressure. The oily residue was 
chromatographed (eluants EA/CH 9/1) to give the title compound 2a (0.6 g) 
(t.l.c. Rf 0.8; EA/CH 9/1) as a light yellow oil. Further elution gave the 
title compound 2b (1.1 g) (t.l.c. Rf 0.4; EA/CH 9/1) as an oil. 
In a similar manner: 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-2'-((S)-6'-methoxy- 
1'-oxocyclohexyl))]azetidin-2-one (2c; 2.1 g) was obtained from 
intermediate 1h (2.2 g); 
(3S,4R)-3-[(R)-1-(t-Butyldimethyisilyloxy)ethyl)-4((R)-2'-((S)-6'-ethoxy-1' 
-oxocyclohexyl))]azetidin-2-one (2d; 0.95 g) (t.l.c. Rf 0.57; eluants EA/CH 
1/1) and 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-2'-((R)-6'-ethoxy-1 
-oxocyclohexyl))]azetidin-2-one (2e; 3 g) (t.l.c. Rf 0.35 eluants EA/CH 
1/1) from intermediate 1i (4.4 g). 
Intermediate 3 
(3S,4R)-3-[(R)-1-(t-Butylidmethylsilyloxy)ethyl]-4-((R)-2'-(1-oxocyclohexyl 
))]-1-methylthioazetidin-2one 
Intermediate 1a (9.56 g) was dissolved in tetrahydrofuran (60 ml) under 
nitrogen and cooled to -78.degree. C. Lithium bis(trimethylsilyl)amide 
(32.3 ml 1M solution in hexane) was added in 8 min from a dropping funnel 
and the reaction stirred at -78.degree. for 30 min. Methylthio methane 
sulphonate (4.08 g) was added, the mixture kept at -78.degree. for 30 min. 
and then warmed to -30.degree.C. Ethyl ether (20 ml) was added and the 
mixture was maintained at -30.degree. C. for 30 min and poured in to a 
saturated solution of ammonium chloride (100 ml). The organic layer was 
washed with a 1% solution of cold hydrochloric acid (2.times.50 ml) then 
with brine (50 ml). The oil obtained after evaporation of the organic 
solvent was chromatographed (eluants E/P) to yield the title compound 
(5.15 g). 
IR (CDCl.sub.3) .nu..sub.max (cm.sup.-1) 1765 (.beta.-lactam), 1709 
(C.dbd.0), 2850 and 1300 (--S--CH.sub.3) H.sup.1 -NMR (CDCl.sub.3): 4.307 
(dd), 4.22 (m), 2.992 (t), 2.61 (m), 2.46 (m), 2.395 (s), 2.407 (m), 2.105 
(m), 1.935 (m), 1.70 (m), 1.49 (m), 1.19 (d), 0.86 (s), 0.064 (s), 0.048 
(s). 
Intermediate 4 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-2'-((S)-6'-methylth 
io-1'-oxocyclohexyl))]-1-methylthioazetidin-2-one 
A 1M solution in hexane of lithium bis(trimethylsilyl)amide (18 ml) was 
cooled at -78.degree. and a solution of intermediate 3 (5.15 g) in 
tetrahydrofuran (20 ml) added over 4 min. The resulting mixture was 
stirred for 30 min the methylthiomethanesulphonate (2.27 g) was added. The 
reaction mixture was kept at -78.degree. for 30 min then at -30.degree. C. 
for 10 min. Diethyl ether (50 ml) was added and the mixture was poured 
into a saturated solution of ammonium chloride (200 ml). The organic layer 
was washed with cold 1% hydrochloric acid (2.times.100 ml) then with brine 
(100 ml). The organic layer was dried, evaporated under reduced pressure 
and purified by flash chromatography (eluants EE/P) to obtain the title 
compound (3.72 g) as a yellow oil. 
IR (CDCl.sub.3) .nu..sub.max (cm.sup.-1) 1757 (.beta.-lactam), 1699 
(C.dbd.0) 
H.sup.1 -NMR (CDCl.sub.3): 4.396 (m), 4.18 (m), 3.5 (m), 3.03 (dd), 2.42 
(s), 2.2 (m), 2.068 (s), 2.1-1.6 (m), 1.47 (d), 1.21 (d), 0.86 (s), 0.077 
(s), 0.065 (s). 
Intermediate 5 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-2'-((R)-6'-methylth 
io-1'-oxocyclohexyl))-1-methylthioazetidin-2-one (5a) and 
(3S,4R)-3-[(R)-1-(t-Butylmethylsilyloxyethyl]-4((S)-2'-((S)-6'-methylthio- 
1'-oxo-cyclohexyl)-1-methylthioazetidin-2-one (5b) 
A 1M solution in hexane of lithium bis(trimethylsilyl)amide (18 ml) was 
cooled at -78.degree. under nitrogen and a solution of intermediate 1b (2 
g) in tetrahydrofuran (20 ml) was added. 
During the addition the temperature rose to -70.degree.C. The reaction 
mixture was kept under stirring at -78.degree. for 30 min then 
methylthiomethaneulsphonate (2 ml) was carefully added over 5 min. After a 
further 15 min under stirring the mixture was allowed to warm to 
-30.degree.C. for 1 h and then diluted with anhydrous diethylether (40 
ml). The mixture was poured into a saturated aqueous solution of ammonium 
chloride (200 ml). The organic layer was washed with a 1% cold solution of 
hydrochloric acid (2.times.50 ml) then with brine (50 ml) and dried. The 
organic layer was evaporated and the residue purified by flash 
chromatography (eluting with petroleum ether/diethylether) to give the 
title compound 5a (1 g). (t.l.c. Rf=0.7 eluants P/EE 3/7). Further elution 
gave the title compound 5b (0.84 g) as a yellow oil (t.l.c. Rf 0 0.35 
eluants P/EE 3/7). 
Intermediate 5a 
IR (CDCl.sub.3) .nu..sub.max (cm.sup.-1) 1757 (.beta.-lactam), 1725 
(C.dbd.O) H.sup.1 -NMR (CDCl.sub.3): 4.4 (dd), 4.2 (m), 3.6 (m), 2.9 (dd), 
2.6 (m), 2.45 (m), 2.4 (s), 2.11 (s), 2.0-1.7(m), 1.9 (m), 1.2 (d), 0.8 
(s), 0.04 (s) 
Intermediate 5b 
IR (CDCl.sub.3) .nu..sub.max (cm.sup.-1) 1755 (.beta.-lactam), 1707 
(C.dbd.0) H.sup.1 -NMR (CDCl.sub.3): 4.31 (dd), 4.24 (m), 3.52 (m), 3.33 
(dd), 2.96 (dd), 2.45 (s). 2.17 (m), 2.12 (s), 2.1-1.9 (m), 1.75 (m), 1.46 
(m), 1.18 (d), 0.86 (s), 0.06 (s). 
Intermediate 6 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyoxy)ethyl]-4-((R)-2'-((S)-6'-methylthi 
o-1'-oxocyclohexyl))azetidin-2-one 6a 
2-Mercaptopyridine (1.63 g) and triethylamine (1.49 g) were added to a 
solution of intermediate 4 (5.60 g) in methylene chloride under nitrogen 
and cooled at 0.degree.. The reaction mixture was stirred at 23.degree. 
for 2 hrs and then poured into cold 2% hydrochloric acid (200 ml). The 
organic layer was separated, washed with dilute hydrochloric acid 
(2.times.200 ml) and then with water (2.times.200 ml). The residue 
obtained after evaporating the solvent was purified by flash 
chromatography (eluants EE/P) to give the title compound 6a (3.87 g) as a 
light yellow oil. 
H.sup.1 NMR (CDCl.sub.3) ppm. H.sub.3 2.88(dd), H.sub.4 4.16(m). 
In a similar manner 
(3S,4R)-3-((R)-1-(t-Butyldimethylsilyloxy)ethyl-4-((S)-2'-((S)-6'-methylth 
io-1'-oxocyclohexyl))azetidine-2-one (6b; 0.6 g) H.sup.1 NMR (CDCl.sub.3) 
ppm. H.sub.3 2.70 (m) H.sub.4 3.68 (dd) was prepared from Intermediate 5b 
(0.84 g), and 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-2'-((R)-6'-methylt 
hio-1'-oxocyclohexyl))azetidin-2-one (6c; 0.5 g) H.sup.1 NMR (CDCl.sub.3) 
ppm H.sub.3 2.73(m), H.sub.4 3.59(dd) was prepared from Intermediate 5a 
(0.7 g). 
Intermediate 7 
(3S,4R)-1-(t-butyldimethylsilyl-4-acetoxy-3[(R)-(t-butyldimethylsilyloxy)et 
hyl]azetidin-2-one 
To a stirred ice-cold solution of the 
(3S,4R)-4-acetoxy-3((R)-t-butyldimethylsilyloxy)ethyl)-2-azetidinone (112 
g) in dichloromethane (800 ml), t-butyldimethylchlorosilane (73 g) and 
triethylamine (80 ml) were added. The mixture was stirred at room 
temperature for 20 hours then washed with water (1 l) and brine (300 ml). 
The organic layer was dried and evaporated to give an oil (160 g) which 
was dissolved in a mixture of cyclohexane/ethyl acetate (95/5) (1600 ml) 
and treated with silica gel (480 g). The suspension was stirred for 15 min 
then filtered. The solid was washed with cyclohexane/ethyl acetate 
(95/5:4.81) and the solvent evaporated to give the title compound (110 g) 
as a pale yellow oil. (Rf=0.85 Petrol/Diethyl ether=2/1) 
IR(CDCl.sub.3)V.sub.max (cm.sup.-1): 1747(C.dbd.O) 
H.sup.1 -NMR a (CDCl.sub.3):6.14(d), 4.15(m), 3.07(dd), 2.03(s), 1.2(d), 
0.9(s), 0.84(s), 0.22(s), 0.055(s), 0.35(s), 0.005(s)ppm. 
Intermediate 8 
(3S,4R)-1-(t-butyldimethylsilyl-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4- 
[2'-(1'-oxo-cyclohexyl)]azetidin-2-one 
Stannic chloride (35.4 ml) was added dropwise to stirred acetonitrile (400 
ml) under nitrogen atmosphere at -40.degree. C., a white solid formed 
together with white fumes which were eliminated by nitrogen flushing. The 
obtained suspension was allowed to rise to -10.degree. C. then a solution 
of 1-trimethylsilyloxycyclohexene (60.6 ml) and of Intermediate 7 (110 g) 
in acetonitrile (300 ml) was added in 10 minutes. The yellow solution was 
stirred at 0.degree. C. for 10 min then poured into a stirred, ice-cold, 
mixture of a 10% aq solution of sodium hydroxide (1 l), diethyl ether (1 
l) and ice (500 g). The organic layer was separated, washed again with 
sodium hydroxide (500 ml) and then with a saturated solution of ammonium 
chloride, dried and evaporated to give a yellow solid (117.7 g). The solid 
was dissolved at 40.degree. C. in isopropanol (300 ml) then cooled at room 
temperature, water (300 ml) was added slowly under stirring to obtain a 
solid which was stirred at 0.degree. C. for 30 min then filtered, washed 
with a 1 to 1 mixture of isopropanol/water (100 ml) and dried under vacuum 
at 40.degree. C. for 15 hr. to afford the title compound (76 g) as a 
mixture of 2'R and 2'S isomers in a ratio of 70% to 30% (the ratio between 
the two isomers was determined by HPLC using hexane/ethanol (99/1) as 
eluant). 
Intermediate 9 
(3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4 
-[6'-trimethylsilyloxycyclohex-1'-enyl)]azetidin-2-one 
A 1M solution of lithium bis(trimethylsilyl)amide in hexane (70 ml) was 
added to tetrahydrofuran (150 ml), the mixture stirred under nitrogen, 
cooled to -70.degree. C. and then a solution of the compound of 
Intermediate 8 (15.5 g) in tetrahydrofuran (70 ml) was added over 20 min. 
The obtained solution was stirred for 30 min then chlorotrimethylsilane 
(10 ml) was added over 10 min. The reaction temperature was allowed to 
rise to -20.degree. C. then the mixture was poured into a saturated 
ammonium chloride solution (500 ml) and the resulting mixture extracted 
with diethyl ether (300 ml). The organic layer was washed with water (200 
ml), a 2% ice-cold solution of hydrochloric acid (300 ml), aqueous 
solution of sodium hydrogen carbonate and brine, dried and evaporated 
under reduced pressure to give the title compound as a mixture of 6'R and 
6'S isomers. 
Intermediate 10 
(3S,4R)-3-[(R)-1(t-butyldimethylsilyloxy)ethyl]-4-[(R)-[2'-((S)-6'-hydroxy- 
1'-oxocyclohexyl)]azetidin-2-one 
The compound of Intermediate 9 was dissolved at -10.degree. C. in 
dichloromethane (300 ml) and treated with sodium hydrogen carbonate (2.85 
g). To the obtained suspension, 3-chloroperoxybenzoic acid (8.5 g) was 
added portionwise over 30 min. The reaction mixture was stirred at 
0.degree. C. for 1.5 h and at room temperature for 1 h then solid sodium 
sulphite (5 g) was added. After stirring for 30 min the solid was filtered 
and washed with dichloromethane (100 ml). The organic layer was washed 
with a 3% aqueous sodium sulphite solution (100 ml) followed by an 
ice-cold 3% aqueous sodium hydrogen carbonate solution (3.times.150 ml) 
and water, dried and evaporated to give a yellow oil which was dissolved 
in methanol (250 ml). Potassium fluoride (6 g) was added and the obtained 
solution stirred at room temperature for 30 min then poured into a 
saturated solution of ammonium chloride (500 ml) and the resulting mixture 
extracted with ethyl acetate (3.times.200 ml). The combined organic layers 
were washed with brine, dried and evaporated to give a white foam (12 g). 
Crystallisation from a mixture of petrol and diethyl ether (8/2) (25 ml) 
afforded the title compound (4.4 g) as a white solid m.p. 
145.degree.-147.degree. C. 
IR(CDCl.sub.3)V.sub.max (cm.sup.-1): 3501(OH), 3414(NH), 1763(C.dbd.O), 
1713(C.dbd.O) 
H.sup.1 -NMR a (CDCl.sub.3): 6.29(m), 4.20(m), 4.02(dd), 3.51(d), 2.93(m), 
2.81(m), 2.40(m), 2.0-1.8(m), 1.73-1.6(m), 1.03(d), 0.87(s), 0.0(s)ppm. 
Intermediate 11 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-2'-((S)6'-trimethyl 
silyloxy-1'-oxocycxlohexyl)]azetidin-2-one 
The compound of Intermediate 10 (4.4 g) was dissolved in dry 
dichloromethane (100 ml) at room temperature. Trimethylsilyl chloride (7.5 
ml) followed by triethylamine (11 ml) were added and the mixture was 
stirred for 1 h, then poured into water (200 ml). The organic layer was 
separated and washed with water (2.times.200 ml), dried and evaporated to 
give a yellow oil containing traces of triethylamine. The oil was 
dissolved in methanol (100 ml), silica gel (10 g) added and the suspension 
was stirred for 1 h then filtered. The silica gel was washed with ethyl 
acetate (2.times.100 ml) and the combined organic layers evaporated under 
reduced pressure at 25.degree. C. The obtained oil was dissolved with 
ethyl acetate (150 ml), washed with brine, dried and evaporated to give a 
yellow foam which was chromatographed on silica gel using a mixture of 
petroleum and diethyl ether (1/1) as eluant (Rf) 0.25) to afford the title 
compound (3.5 g) as a white foam. 
IR(CDCl.sub.3) V.sub.max (cm.sup.-1): 3418(NH), 1755(C.dbd.O) 1717(C.dbd.O) 
H.sup.1 -NMR a (CDCl.sub.3): 5.77(s), 4.16(m), 4.01(m), 3.95(m), 3.20(m), 
2.86(dd), 2.1(m), 1.4(m), 1.25(d), 0.86(s), 0.10(s), 0.07(s), 0.05(s)ppm. 
Intermediate 12 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[[(R)-1'-(4-methylphenyl 
sulfono)hydrazono]-cyclohex-2'-yl]-azetidin-2-one(12a) and 
(3S,4R)-3-[R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[[(S)-1'-(4-methylphenyl 
sulfono)hydrazono]-cyclohex-2'-yl]-azetidin-2-one(12b) 
To a solution of intermediate (1K 12.1 g) in glacial acetic acid (120 ml) 
tosylhydrazide (6.9 g) was added at room temperature. The reaction was 
stirred for 3 hrs., then diluted with dichloromethane (250 ml) and washed 
with brine (2.times.250 ml), then with a 5% solution of sodium hydrogen 
carbonate until pH 7, and with brine again (2.times.150 ml). The organic 
layer was dried and the solvent evaporated under reduced pressure. The 
obtained foam was stirred with diethyl ether (60 ml) for 2 hrs at room 
temperature to give the title compound 12b as a white powder, after 
filtration and drying under vacuum (6 g; m.p. 187.degree.-189.degree. C.; 
t.l.c. diethyl ether Rf=0.13). IR (CDCl.sub.3) V.sub.max (CM.sup.1) 
3416(N--H), 3304(NNHSO.sub.4), 1753 (lactam), 1599(C.dbd.N; C.dbd.C) 
H.sup.1 -NMR (CDCl.sub.3): 7.80 (d) 7.38 (bm), 7.34(d), 5.65 (bs), 4.15 
(m) 3.58 (dd) 2.63(m), 2.62(m), 2.44(s), 2.3(m), 2.08(m), 1.92(m), 
1.78(d), 1.4(m), 1.20(m), 1.185(d), 0.9(s), 0.077(s), 0.067(s). 
The organic layer, which contained the title compound 12a in presence of a 
small amount of the title compound 12b (by t.l.c.), was concentrated and 
the residue was purified by flash chromatography (eluant dithyl 
ether/petroleum ether 7:3) to give the title compound 12a as a white 
powder (7.6 g; m.p. 95.degree.-96.degree. C.; t.l.c. diethyl ether 
Rf-0.37) 
IR (CDCl.sub.3)V.sub.max (cm.sup.1) 3410(N--H), 3306(NNHSO.sub.2), 
1755(lactam), 1599 (C--N; C.dbd.C) H.sup.1 -NMR (CDCl.sub.3): 7.81(d), 
7.40(m), 7.33(d), 5.60(bs) 4.09(m) 4.00(m), 2.81(dd), 2.52(m), 2.44(s), 
2.3(m), 2.0-1.8(m), 1.6-1.4(m), 1.04(d) 0.87(s) 0.06(s), 0.03(s). 
Intermediate 13 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(S)-3'-cyclohex-1'-enyl 
]azetidin-2-one 
A solution of the Intermediate (12a 1.12 g) in anhydrous tetrahydrofuran 
(20 ml) was slowly added, at -40.degree. C., to a stirred solution of 
diisopropylamide (prepared from anhydrous diisopropylamine (1.35 ml) and a 
1.6M solution of n-butyllithium in hexane (5.7 ml). The reaction was 
slowly warmed to -20.degree./0.degree. C. and maintained at 
-20.degree./0.degree. C. for 1 h. The reaction mixture was added to a 
precooled 5% solution of hydrochloric acid (20 ml) and extracted with 
ethyl acetate (2.times.40 ml). The organic layer was washed with a 5% 
solution of sodium hydrogen carbonate (20 ml) and brine (20 ml), dried and 
evaporated. The crude product was purified by flash chromatography (eluant 
diethyl ether/petroleum ether 1/1) to give the title compound as a white 
powder (0.45 g, m.p. 104.degree.-06.degree. C.; t.l.c. diethyl ether 
Rf=0.73) IR (CDCl.sub.3) V.sub.max (CM.sup.1) 3416(N--H), 1753 (lactam), 
1603(C.dbd.C) H.sup.1 -NMR (CDCl.sub.3): 5.82(bs),. 5.81(m), 5.60(dd), 
4.14(m), 3.46(dd), 2.85(m), 2.2.4(m), 2.00(m), 1.85-1.70(m), 1.54(m), 
1.27(m) 1.23(d), 0.86(s), 0.064(s), 0.054(s). 
Intermediate 14 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1'R,2'S,3'R)-1'2'-epox 
ycyclohex-3'-yl]-azetidin-2-one 
A solution of metachloroperbenzoic acid (3.76 g; assay 55%) in 
dichloromethane (50 ml) was added dropwise, at 0.degree. C., to a solution 
of the intermediate 13 in methylene chloride (50 ml). The solution was 
warmed to room temperature and stirred for 3 hrs. The reaction mixture was 
added to a 10% solution of sodium sulphite (50 ml), the washed with a 5% 
solution of sodium hydrogen carbonate (2.times.50 ml) and brine (50 ml). 
The solution was dried and the solvent was evaporated. The crude product 
was purified by flash chromatography (eluant ethyl acetate/cyclohexane 
3/7) to obtain the title compound as a white powder (1.53 g; m.p. 
134.degree.-136.degree. C.; t.l.c. diethyl ether Rf=0.3)IR (CDCl.sub.3) 
V.sub.max (cm.sup.-1) 3413(N--H), 1757 (Lactam) H.sup.1 -NMR CDCl.sub.3. 
5.85(bm), 4.22(m), 3.77(dd), 3.16(t), 3.12(m), 3.01(m), 2.00-1.7(m), 
1.55(m), 1.4(m), 1.24(d), 1.22(m), 0.87(s), 0.67(s). 
Intermediate 15 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-6'-((S)-2'-azido-1' 
(R)-hydroxycyclohex-6'-yl)]azetidin-2-one 
To a solution of the intermediate 14 (1.5 g) in methanol (150 ml) under 
nitrogen, magnesium sulphate heptahydrate (1.135 g) and sodium azide (0.9 
g) were added. The resulting mixture was refluxed overnight, poured into 
water (150 ml) and extracted with dichloromethane (3.times.150 ml) dried 
and evaporated to give the title compound (1.49 g), m.p. 
124.degree.-125.degree. C.; t.l.c. cyclohyexane/ethyl acetate 3/7(Rf 
0.68); IR:V.sub.max (CDCl.sub.3) 3600, 3416, 2101, 1755 cm.sup.1 ; 1H-NMR 
(300 MHZ, CDCl.sub.3) 6.02(bs) 4.16(m), 3.78(m), 3.72(m), 3.60(dd), 
2.99(m), 2.27(bm), 2.0-1.4(m), 1.24(m), 1.28(d), 0.89(s), 0.098(s), 
0.092(s)ppm. 
Intermediate 16 
(3S,4R)-3-[R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-6'-((S)-2'-azido-1'- 
oxocylohex-6'-yl)]azetidin-2-one 
To a mixture of pyridinium chlorochromate (6.67 g) in dry dichloromethane 
(50 ml), under nitrogen, a solution of the intermediate 15 in 
dichloromethane (200 ml) was added. The mixture was stirred at room 
temperature overnight, filtered through florisil and the resulting 
solution evaporated under reduced pressure. The oily residue was 
chromatographed on silica gel using a cyclohexane/ethylacetate (1/1) 
mixture as eluant to afford the title compound (4 g; m.p. 
134.degree.-135.degree. C. dec; t.l.c. diethyl ether Rf 0.68); 
IR:V.sub.max (CDCl.sub.3)3416, 2104, 1759, 1720cm.sup.1 ; .sup.1 H-NMR 
(300 MHZ. CDCl.sub.3) 5.77 (bs), 0.2(m), 4.04(m), 3.00(m), 2.9(m), 
2.15-1.3(m), 1.21(d), 0.87(s), 0.074(s), 0.065(s)ppm. 
Intermediate 17 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-6'-((S)-2'-allyloxy 
carbonylamino-1'-oxocyclohex-6'-yl)]azetidin-2-one 
The Intermediate 16 (4 g) was dissolved in ethyl acetate (300 ml), 10% 
palladium on charcoal (3 g) added and the mixture hydrogenated at 3 atm 
for 2 hrs. A further amount of the catalyst (1 g) was added and the 
hydrogenation was continued for 2 hrs. The mixture was filtered through a 
pad of celite and the resulting solution treated with allyl chloroformate 
(1.7 g) and pyridine (1.12 g). The reaction mixture was kept under 
stirring for 30 min at room temperature, then poured into a saturated aq. 
solution of ammonium chloride (350 ml). The organic layer was washed with 
a 1% solution of hydrochloric acid (2.times.150 ml), then with a 5% 
solution of sodium hydrogen carbonate (2.times.150 ml) and brine (200 ml), 
dried and evaporated in vacuo. The residue was purified by flash 
chromatography on a silica column, using a cyclohexane-ethyl acetate (1/1) 
mixture to obtain the title compound as an oil (2 g; t.l.c. 
cyclohexane/ethyl acetate 3/7 Rf=0.4). IR: V.sub.max (CDCl.sub.3) 3414, 
1765, 1709 cm.sup.1 ; .sup.1 H-NMR (300 MHZ, CDCl.sub.3) 6.05(s), 5.9(m) 
5.64(bd), 5.26(m), 4.56(m), 4.4-41(m), 4.05(dd), 2.9(m), 2.75(m), 2.60(m), 
2.0-1.2(m), 1.02(d), 0.86(s), 0.06(s). 
Intermediate 18 
(3S,4R)-3-[(R)-1'-(t-Butyldimethylsilyloxy)ethyl]-4-[(1"S,2"R,6"R)-1"-hydro 
xy-2"-cyano-cyclohex-6"-yl]azetidin-2-one 
Intermediate 14 (2.4 g) was dissolved into a mixture of dimethylformamide 
(80 ml) and water (40 ml), potassium cyanide (1 g) was added the mixture 
was warmed at 60 C. for 8 hours, diluted with ether (150 ml) and washed 
twice with water (150 ml). The organic layer was dried and evaporated 
under reduced pressure to give a crude oil which was purified by flash 
chromatography on silica gel (eluent ether/ethyl acetate 8/2Rf=0.4) to 
afford the title compound (1.7 g) as a white solid. 
IR(cm.sup.-1): 3611 (OH), 3416(NH), 1755 (CO); 
NMR (ppm): 6.12(bs), 4.18-4.16(m), 3.60(dd), 3.0(dd), 2.94(m), 2.74(bs), 
2.0-1.87(m), 1.85-1.6(m), 1.6-15(m), 1.29(d), 0.89(s), 0.09(s). 
Intermediate 19 
(3S,4R)-3-[(R)-1'(t-Butyldimethylsilyloxy)ethyl]-4-[(1"R,2"R,6"R)-1"-hydrox 
y-2"-(allyloxycarbonylaminomethyl)cyclohex -6"-yl]azetidin-2-one 
Intermediate 18 (1.7 g) was dissolved in acetic acid (15 ml) and platinum 
dioxide (40 mgr.) was added, the mixture was hydrogenated (1 atm) for 3.5 
hours then filtered on a celite pad and the solvent was evaporated under 
reduced pressure. The residue was redissolved with dry dichloromethane (80 
ml) at 0.degree. C., N-ethyl-piperdine (1.8 ml) and allyl chloroformate 
(0.55 ml) were added and the resulting mixture was stirred for 16 hrs. The 
solvent was evaporated under reduced pressure to give a crude material 
which was redissolved with ethyl acetate (100 ml) and washed twice with 
brine (50 ml). The organic layer was dried and evaporated under reduced 
pressure to give an oil which was purified by flash chromatography on 
silica gel (eluants cyclohexane/ethylacetate 60/40 Rf=0.5) to afford the 
title compound (0.7 g) as a white solid. 
IR(cm.sup.-1): 3454(NH), 3416(NH), 1751(CO), 1720(CO); 
NMR (ppm) 6.32(s), 5.9(m), 5.06(t), 4.55(m), 4.18(m), 3.78-3.6(m), 3.26(m), 
3.07-2.7(m), 1.89(m), 1.83-1.2(m), 1.28(d), 0.88(s), 0.1(s), 0.09(s). 
Intermediate 20 
(3S,4R)-3-[(R)-1'(t-Butyldimethylsilyloxy)ethyl]-4-[(2"R,6"R)-1"-oxo-2"-(al 
lyloxycarbonylaminomethyl)cyclohex-6"-yl]-azetidin-2-one 
Intermediate 19 (0.7 g) was dissolved in methylene chloride (50 ml) and 
pyridinium chlorochromate (1.1 g) was added under vigorous stirring. After 
2.5 hours the mixture was filtered on a celite pad diluted with methylene 
chloride (150 ml) was washed with cold 5% hydrochloric acid (20 ml), and 
then with aqueous sodium hydrogen carbonate (20 ml). The organic layer was 
dried and evaporated under reduced pressure to give an oil which was 
purified by flash chromatography on silica gel (eluants cyclohexane/ethyl 
acetate 30/70 Rf=0.3) to afford the title compound (0.48 g) as a white 
sold. 
IR V.sub.max cm.sup.-1): 3456 and 3439 (NH), 1759 (CO), 1720 and 1718 (CO), 
1603(C.dbd.C); 
NMR (d ppm) 6.02(bs), 5.98 (m), 5.23(m), 5.12(bt), 4.5(m), 4.21(m), 
4.05(m), 13.35(m), 2.92(bs), 2.68(m), 2.58(m), 2.1-1.55(m), 1.32-1.2(m), 
1.04(d), 0.87(s), 0.06(s). 
Intermediate 21 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-6'-(2'-isopropoxy-1' 
-oxocyclohex-2'-enyl))azetidin-2-one (21a) and 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-6'-(2'-isopropoxy-1 
'-oxocyclohex-2'-enyl))azetidin-2-one (21b) 
To a mixture of 1M solution of Lithium bis(trimethylsilyl)amide in hexane 
(486 ml) and anhydrous THF (300 ml), under inert atmosphere and cooled to 
-78.degree. C., a solution of 2-isopropoxy-2-cyclohexenone (30 g) in 
anhydrous THF (100 ml), was added dropwise. The temperature was maintained 
at -78.degree. C. for further 30', then a solution of (3R, 
4R)-4-Acetoxy-3-((R)-t-Butyldimethylsilyloxy)ethyl-2-azetidinone (46.59 g) 
in anhydrous THF (100 ml) was added dropwise. The reaction was kept at 
-78.degree. C. for 10 min then poured in to a cold saturated solution of 
ammonium chloride (300 ml), and extracted with diethyl ether. The organic 
layer, after washing with a cold 1% solution of hydrochoric acid (150 ml) 
and with a cold saturated solution of sodium hydrogen carbonate, dried and 
evaporated under reduced pressure. The yellow oily residue was treated 
with petroleum ether. After filtration, the title compound 21a was 
obtained as a white solid (8.4 g); m.p. 130.degree. C. dec.; t.l.c. 
cyclohexane/ethyl acetate 4/6 Rf 0.21; IR (Nujol), V.sub.max (Cm.sup.- 1): 
3233 (NH), 1759(C.dbd.O .sub..beta. -lactam), 1680(C.dbd.O); H.sub.1 -MNR, 
(CDCl.sub.3): 5.92(t), 575(bs), 4.29(m), 4.2(m), 2.99(dd), 2.59(m), 
2.09(m) 1.9(m), 1.27(d), 1.25(d), 1.23(d), 0.86(s), 0.06(s) p.p.m. 
The mother liquors were evaporated under reduced pressure and submitted to 
flash chromatography to obtain the title compound 21b as an oil (9.2 g; 
t.l.c. cyclohexane/ethyl acetate 4/6 Rf 0.21); IR (Nujol), V.sub.max 
(cm.sup.-1) 3425(NH), 1755 (C.dbd.O .rho.-lactam), 1684 (C.dbd.O), 
1684(C.dbd.O), 1624 (C.dbd.C). 
H.sup.1 -NMR, (CDCl.sub.3): 6.35(bs), 5.95(m), 4.2(m), 3.6(dd), 2.75(m), 
2.5(m), 2.44(m), 2.07(m), 1.7(m), 1.27(d), 1.25(d), 0.86(s), 0.07(s), 
0.057(s) ppm. 
Intermediate 22 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-6'-(2'-isopropoxy-1' 
-hydroxycyclohex-2'-enyl))azetidin-2-one 
To an ice-cold solution of intermediate 21a (5.7) in methanol (100 ml) and 
water (30 ml), sodium borohydride (560 mg) was added in ten portions in 
1.5 hrs. During the additions the pH was maintained between 5 and 7.5 with 
a 5% solution of hydrochloric acid. At the end dichloromethane (200 ml) 
and water (100 ml) were added. The organic layer, after washing with 
water, was dried and evaporated under reduced pressure to give the title 
compound 22 as a white foam (5.5 g). 
Intermediate 23 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[((R)-2'-((S)-6'-isopropo 
xy-1'-oxocyclohexyl))]azetidin-2-one (23a) 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[((R)-2'-((R)-6'-isoprop 
oxy-1'-oxocyclohexyl))]azetidin-2-one (23b) 
The intermediate 22 (5.5 g) was dissolved in ethanol (100 ml). Then 10% 
palladium on charcoal (0.5 g) was added and the mixture was hydrogenated 
at 3 atm for 4 hrs. The catalyst was filtered off and the solution was 
evaporated under reduced pressure. The oily residue (5 g) was dissolved in 
anhydrous dichloromethane (150 ml) and pyridinium chlorochromate (4.2 g) 
was added. The reaction mixture was stirred at 20.degree. C. for 6 hrs, 
then more pyridinium chlorochromate (2.8 g) was added. The reaction was 
stirred for further 4 hrs. then diluted with diethyl ether (100 ml) and 
decanted from black gum, which was washed twice with diethyl ether. The 
organic solutions were combined and evaporated under reduced pressure; the 
oily residue was chromatographed using a mixture ethyl acetate/cyclohexane 
9/1) to obtain the title compound 23a as a white solid (0.8 g; t.l.c. 
ethyl acetate/cyclohexane 1/1 Rf 0.5); IR(CDCl.sub.3), V.sub.max 
(cm.sup.-1): 3416(NH), 1755(C.dbd.O .beta. lactam), 1705(C.dbd.O ketone). 
H.sup.1 -NMR(CDCl.sub.3): 5.89(bs), 4.17(m), 3.97(m), 3.78(m), 3.53(m), 
3.15(m), 2.86(dd), 2.13(m), 2.10(m), 1.8-1.4(m), 1.24(d), 1.13(d), 
0.88(s), 0.08(s), 0.06(s)ppm. 
Further elution gave the title compound 23b as a white solid (1 g; m.p. 
121.degree. C.; t.l.c. ethyl acetate/cyclohexane 1/1 Rf 0.28); 
IR(CDCl.sub.3), V.sub.max (Cm.sup.-1): 3416(NH), 1759(C.dbd.O .rho. 
lactam), 1722C.dbd.O). 
H.sup.1 NMR(CDCl.sub.3): 5.7(bs), 4.18(m), 4.09(m), 3.97(dd), 3.6(m), 
2.8(dd) 2.55(m), 2.3(m), 2.1(m), 1.98(m), 1.8-1.6(m), 1.22(d), 1.14(d), 
0.8(s), 0.07(s), 0.06(s) ppm. 
Intermediate 24 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((R)-6'-(2'-cyclopentylox 
y-1'-oxocyclohex-2'-enyl))azetidin-2-one (24a) and 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((S)-6'-(2'-cyclopentylo 
xy-1'-oxocyclohex-2'-enyl))azetidin-2-one (24b) 
To a mixture of a 1M solution of Lithium bis(trimethylsilyl)amide in hexane 
(140 ml) and anhydrous THF (70 ml) under inert atmosphere and cooled to 
-78.degree., 2-cyclophenthyloxy-2-cyclohexenone (8.5 g) dissolved in 
anhydrous THF (70 ml), was added. 
The temperature was kept at -78.degree. for 40 minutes, then a cooled 
solution of 
(3R,4R)-4-acetoxy-3-((R)-t-Butyldimethylsilyloxy)ethyl-2-azetidinone 
(11.25 g) in anhydrous THF (70 ml) was added. The reaction mixture was 
kept at -78.degree. for 5 minutes then it was poured into a cooled mixture 
of diethyl ether (225 ml), 10% solution of hydrochloric acid (63 ml), 
water (180 ml) and a saturated solution of ammonium sulphate (180 ml). The 
organic layer was washed with 10% solution of hydrochloric acid 
(2.times.70 ml) and brine (3.times.70 ml), dried and evaporated under 
reduced pressure. The residue was chromatographed on silica gel using a 
mixture of cyclohexane/ethyl acetate 9/1 to 8/2 to obtain an equimolar 
mixture of the two title compounds 24a and 24b (6.82 g). 
The title compound 24a was obtained by crystallation from THF/Petroleum 1/5 
(2.1 g, m.p. 111-113; t.l.c. cyclohexane/ethyl acetate 1/1 Rf 0.29) IR 
(CDCl.sub.3), V.sub.max (CM.sup.-1): 3412 (NH); 1757 (C.dbd.O beta 
lactam); 1688 (C.dbd.)); 1626 (C.dbd.C). 
H.sup.1 -NMR (CDCl.sub.3): 5.85(t), 5.67(sa), 4.4(m), 4.3(dd), 4.2(m), 
2.98(dd), 2.57(m), 2.50(m), 2.1(m), 1.9(m), 1.5(m), 1.22(d), 0.83(s), 
0.05(s). The mother liquors were evaporated under reduced pressure to give 
the title compound 24b containing a small amount of the compound 24a (2.45 
g; t.l.c. cyclohexane/ethyl acetate 1/1 Rf 0.29) IR (CDCl.sub.3), 
V.sub.max (cm.sup.-1): 3425 (NH), 1757 (C.dbd.O .beta. lactam), 1684 
(C.dbd.O), 1624 (C.dbd.C). H.sup.1 -NMR (CDCl.sub.3) 6.38(sa), 5.87(m), 
4.41(m), 4.17(m), 3.60(dd), 2.75(m), 2.49(m), 1.20(m), 1.7-1.6(m), 
1.235(d), 0.86(s), 0.068(s), 0.054(s). 
Intermediate 25 
(3S,4R)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[((2'R,6,'S)-6'-(2'-cyclo 
pentyloxy-1'-oxocyclohex-6'-yl))azetidin-2-one 
The intermediate 24b (3.2 g) was dissolved in ethyl acetate (290 ml) 10% 
Palladium on charcoal (1.35 g) was added and the mixture was hydrogenated 
at 3 atm for 1 hr. The catalyst was filtered off through a pad of celite, 
and the solution was evaporated under reduced pressure. The residue was 
chromatographed on silica gel, using a mixture of ethyl 
acetate/cyclohexane 9/1 to 7/3 to obtain the title compound as a white 
foam (1.2 g); t.l.c. cyclohexne/ethyl acetate 1/1 Rf 0.45) IR 
(CDCl.sub.3), V.sub.max (cm.sup.-1): 3418 (NH), 1755 (C.dbd.O .beta. 
lactam), 1722(C.dbd.O). 
H.sup.1 -NMR (CDCl.sub.3): 6.097(sa), 4.15(m), 4.01(m), 3.905(m), 3.67(dd), 
2.69(m), 2.43-2.22(m), 2.10(m), 2.00-1.90(m), 1.83-1.50(m), 1.33(m), 
1.22(d), 0.86(s), 0.075(s), 0.049(s). 
Intermediate 26 
2-(t-Butyldimethylsilyloxymethyl)-cyclohexanone 
2-hydroxymethyl cyclohexanone (8.8 g) tert-Butyldimethylsilyl-chloride (10 
g) and Imidazole (4.6 g) were dissolved in DMF (100 ml) at room 
temperature. 
The resulting mixture was stirred for 2 hours, then poured into petroleum 
ether (200 ml). The organic layer was washed twice with cold 10% sodium 
hydrogen carbonate (60 ml), dried, evaporated under reduced pressure and 
purified by flash chromatography (eluants cyclohexane/ethyl acetate 95/5 
Rf=0.7) to obtain the title compound (13.6 g) as a yellow oil. 
IR: (V.sub.max cm.sup.-1): 3670 and 1703; 
NMR (d ppm): 3.96(dd), 3.555(dd), 2.47(m), 2.4-2.2(m), 2.04(m), 1.89(m), 
1.65(m), 1.40(m), 0.87(s), 0.048(s), 0.044(s). 
Intermediate 27 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(2"R,6"R)-2"-(t-Butyldi 
methylsilyloxymethyl)1"-oxocyclohex-6"-yl]azetidin-2-one 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(2"S,6"R)-2"-(t-Butyldi 
methylsilyloxymethyl)1"-oxocyclohex-6"-yl]azetidin-2-one 
2,2,6,6-Tetramethyl piperidine (28.3 ml) was added dropwise to a stirred 
solution of butyl lithium 1.6M in hexane (125 ml) in dry THF (150 ml) 
under nitrogen and cooled at -50.degree.. The resulting mixture was warmed 
at 5.degree. C. for 10 min cooled at -78.degree. C., and intermediate 26 
(23 g) in dry THF (100 ml) was added dropwise at -70.degree. C. After 1 
hour, 
(3R,4R)-4-Acetoxy-3-((R)-(tertbutyldimethylsilyloxy)ethyl-2-azetidinone 
(27.5 g) was added and the resulting mixture was stirred for 40 min at 
-78.degree. C. The reaction mixture was poured into a saturated solution 
of ammonium chloride (300 ml), extracted twice with ethyl acetate (250 
ml), the organic layer was dried and evaporated under reduced pressure. 
The oil obtained was purified by flash chromatography (eluants 
cyclohexane/ethyl acetate 90/10 Rf=0.3) to give a mixture of the title 
compound (17 g) as a yellow solid. 
IR: (V.sub.max cm.sup.1) 3582, 1755(CO p-lactam), 1612 
NMR: (d ppm): 6.1-5.7 (bs+bs+bs). 4.18(m), 4.06(m), 3.97(m), 3.90(m), 
3.51(m), 3.74(m), 2.86(m), 2.7-2.5(m), 2.40(m), 2.14(m), 2.1-1.6(m), 
1.32(m), 1.24(d), 1.17(d), 0.87(s+s+s), 0.05(m). 
Intermediate 28 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((2'S)-((6'R,S)-6'-iodo- 
1'-oxocyclohex-2'-yl]azetidin-2-one 
To a stirred 1M solution of lithium bis (trimethylsilyl) amide i hexane 
(48.7 ml), dissolved in anhydrous THF (70 ml) cooled to -78 C. under 
nitrogen atmosphere a solution of intermediate 1a (7.2 g) in THF (70 ml) 
was added. The resulting mixture was stirred at -70 for 1.5 hrs, cooled to 
-78 C. and a solution of iodine (7.4 g) in anhydrous THF (20 ml) was 
slowly added. The reaction was stirred for further 10 min then brine (250 
ml) was added at -78 C. The resulting mixture was extracted twice with 
ether (150 ml); the organic layer was washed twice with a saturated 
solution of sodium sulphite (100 ml) and with water (100 ml). The organic 
layer was dried, evaporated under reduced pressure and the crude material 
(9.5 g) was used without any further purification. 
Intermediate 29 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((2'S)-((6'S)-6'-phenylt 
hio-1'-oxocyclohex-2'-yl)]azetidin-2-one 29a 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-((2'S)-2'((6'R)-6'-pheny 
lthio-1'-oxocyclohex-2'-yl)]azetidin-2-one 29b 
Thiophenol (7.424 g) was dissolved into a solution of potassium hydroxide 
(5.33 g) in water (740 ml) under stirring. To the resultin solution 
tetrabutyl ammonium bromide (1.52 g) was added followed by a solution of 
intermediate 28 (15.2 g) in methylene chloride (500 ml). The resulting 
mixture was stirred for 16 hrs. The organic layer was separated and the 
aqueous phase was extracted with methylene chloride. The organic layer was 
dried, and evaporated under reduced pressure. The residue was 
chromatgraphed (elutants cyclohexane/ethyl acetate 7/3) to give thiophenol 
(4.9 g) and a mixture (5.34 g) of the title compounds 29a and 29b and 
intermediate 1A. The mixture was chromatographed using petroleum ether 
40-60/diethyl ether 9/1 as elutant to give title compound 29a (0.1 g) as 
the first eluted material and a mixture of title compounds 29a and 29b 
(1.1 g) as the second eluted material. The second eluted material was 
further purified by HPLC (silica, n-hexane/ethyl acetate 8/2, 10 ml/min, 
uv detection set at 275) to give the title compound 29a (0.7 g) as a white 
solid (m.p. 116-7 from cyclohexane) and title compound 29b (0.12 g) as a 
light yellow solid m.p. 65.degree.-7.degree.. 
Title Compound 29A 
.sup.1 H-NMR (ppm) 7.4-7.2(m), 5.8 (bs); 4.13(m); 3.9(m); 3.8(m); 3.46(m); 
2.75 (dd); 2.3(m); 2.2(m); 2.00(m); 1.8(m); 1.6(m); 1.18(d); 0.8(s); 
0.019(s). 
Title compound 29B 
.sup.1 H-NMR (ppm) 7.4-7.3(m); 5.77(bs); 4.17(m); 4.11(m); 3.95(m); 
2.8(dd); 2.6(m); 2.4(m); 2.2(m); 2.00(m); 1.7(m); 1.4(m); 1.23(d); 
0.86(s); 0.06(s); 0.055(s). 
Intermediate 30 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(2'S,6'R)-2'-methoxy-1' 
-hydroxycyclohex-6'-yl)]azetidin-2-one 
To a solution of the intermediate 14 (0.1 g) in methanol (10 ml) 
p-toluenesesulfonic acid mononhydrate (10 mg) was added at 0.degree.. The 
resulting mixture was stirred at 22.degree. for 2 hrs, poured into diethyl 
ether (30 ml), washed with brine (2.times.50 ml), dried and evaporated to 
give the crude title compound as a white powder (70 mg; t.l.c. diethyl 
ether Rf 0.20); IR (CDCl.sub.3) V.sub.max (cm.sup.-1) 3700, 3609, 3418, 
1753; .sup.1 H-NMR (300 MHZ, CDCl.sub.3) 5.85(bs), 4.18(m), 3.88(bm), 
3.64(dd), 3.34(s), 3.30(m), 2.95(m), 1.8(m), 1.8-1.4(m), 1.27(d), 0.88(s), 
0.08(s). 
Intermediate 31 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(2'S,6'R)-2'-methoxy-1' 
-oxocyclohex-6'-yl)]azetidin-2-one 
To a solution of the intermediate 30 (70 mg) in dry dichloromethane (8 ml) 
a mixture of pyridiniumchlorochromate (80 ml) in dry dichloromethane was 
added, under nitrogen. The resulting mixture was stirred at 22.degree. for 
4 hrs, then diluted with diethyl ether (30 mg), decanted from black gum 
and filtered through florisil. The organic solution was evaporated under 
reduced pressure to give the title compound as a pale yellow powder (30 
mg; t.l.c. cyclohexane/ethyl acetate 4/6 Rf 0.43); IR (CDCl.sub.3), 
V.sub.max (cm.sup.-1): 3418, 1757, 1718; .sup.1 H-NMR (300 MHZ, 
CDECl.sub.3) 5.84(sa), 4.18(m), 3.99(m), 3.57(m), 3.28(s), 3.10(m), 
2.876(dd), 2.24(m), 2.08(m), 1.98(m), 1.68(m), 1.56(m), 1.248(d), 0.87(s), 
0.075(s), 0.063(s). 
Intermediate 32 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(1'S,2'S,6'R)-2'-methyl 
amino-1'-hydroxycyclohex-6'-yl]-azetidin-2-one 
To a solution of the intermediate 14 (5 g) in 96% ethanol (150 ml) and 
water (50 ml) ammonium chloride (1.67 g) and methylamine (40 wt % solution 
in water; 30 ml) were added. The resulting mixture was refluxed for 15 
hrs, then poured into a mixture of dichloromethane (150 ml) and brine (400 
ml). The aqueous layer was extracted with dichloromethane (2.times.120 ml) 
and the organic layer washed with brine (150 ml), dried and evaporated to 
give the title compound as a white foam (5.2 g; t.l.c. CH.sub.2 Cl.sub.2 
/MeOH/NH.sub.4 OH 23/7/0.5 Rf 0.75); IR (CDCl.sub.3) V.sub.max 
(cm.sup.-1)3416, 1753; .sup.1 H-NMR (300 MHZ, CDCl.sub.3) 6.26(bs), 
4.20(m), 3.80(m), 3.72(dd), 3.13(m), 2.67(m), 2.49(s), 2.02(m), 
1.7-1.2(m), 1.31(d), 0.91(s), 0.12(s). 
Intermediate 33 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(1'S,2'S,6'R)-2'-(N-all 
yloxycarbonyl-N-methylamino)-1'-hydroxycyclohex-6'-yl]azetidin-2-one 
To a solution of the intermediate 32 (5.2 g) in dry dichloromethane (120 
ml), under nitrogen at 0.degree., allyl chloroformate (2.2 ml) and 
2,2,6,6-tetramethylpiperidine (3.5 ml) were added. The reaction mixture 
was stirred for 10 min at 0.degree., then diluted with dichloromethane (60 
ml) and washed with a saturated aq. solution of ammonium chloride 
(2.times.100 ml), a 5% solution of sodium hydrogen carbonate (100 ml), 
brine (100 ml), dried, and evaporated in vacuo. The residue was purified 
by trituration in diethyl ether (30 ml), to obtain the title compound as a 
white powder (4.54 g; m.p. 159.degree.-161.degree.; t.l.c. 
dichloromethane/methanol 9/1 Rf=0.64). 
IR: V.sub.max (CDCl3) 3414, 1753, 1688 cm.sup.-1 ; .sup.1 H-NMR (300 MHZ 
CDCl3) 6.2(bs), 5.9(m), 5.2(m), 4.6(m), 4.2(m), 4.04(m), 3.87(dd), 3.8(m), 
3.17(dd), 2.86(s), 2.26(m), 1.8-1.2(m), 1.30(d), 0.89(s), 0.10(s), 
0.09(s). 
Intermediate 34 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(2'S,6'R)-2'-N-allyloxy 
carbonyl-N-methylamino-1-'-oxocyclohex-6'-yl)]azetidin-2-one 
Method A 
To a solution of the intermediate 33 (1.8 g) in dry dichloromethane (50 ml) 
pyridiniumchlorochromate (2.2 g) was added under nitrogen. The reaction 
mixture was stirred at 22.degree. for 5 hrs, then filtered through 
florisil, washing with ethylacetate (200 ml), and the resulting solution 
evaporated under pressure. The oily residue was chromatographed on silica 
gel, using a cyclohexane/ethylacetate 1/1 mixture as elutant to, afford 
the title compound as a white powder (1.0 g; m.p. 
140.degree.-142.degree.). 
Method B 
To a solution of oxalyl chloride (3.35 ml) in dry dichloromethan (15 ml), 
under nitrogen at -70.degree., a solution of dimethyl sulfoxide (3.35 ml) 
in dry dichloromethane (40 ml) was added dropwise in 15 min. After 15 min, 
a solution of the intermediate 33 (4.34 g) in dry dichloromethane (35 ml) 
was added dropwise in 20 min and the solution was stirred at -70.degree. 
for 2 hr, then triethylamine (14 ml) was added with warming to -40.degree. 
in 10 min. The solution was washed with a saturated solution of ammonium 
chloride (2.times.100 ml), brine (2.times.100 ml), dried, and evaporated. 
The crude product was triturated with a mixture of petroleum ether (40 ml) 
and diethyl ether (10 ml) to give the title compound as a white powder 
(3.71 g; m.p. 140.degree.-142.degree.; t.l.c. diethyl ether Rf 0.3;); IR: 
V.sub.max (CDCl.sub.3) 3414, 1763, 1718, 1691 cm.sup.-1 ; .sup.1 -H-NMR 
(300 MHZ, CDCl.sub.3) 6.08(bs), 5.92(m), 5.3-5.1(m), 4.55(m), 4.20(m), 
4.03(dd), 2.99(m), 2.85(s), 2.66(m), 2.08-1.8(m), 1.06(bd), 0.86(s), 
0.06(s) ppm. 
Intermediate 35 
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(2'S,6'R)-2'-(N-allylox 
ycarbonyl-N-methylamino)-1-oxocyclohex-6'-yl)-1-allyloxalyl]-azetidin-2-one 
To a solution of the intermediate 34 (3.77 g) in dry dichloromethane (50 
ml), solid potassium carbonate (0.15 g), then allyloxalylchloride (3 ml) 
were added at 22.degree., under nitrogen. Triethylamine (6 ml) was then 
added dropwise over 5 min. The reaction mixture was stirred at 22.degree. 
for 45 min, then washed with a saturated solution of ammonium chloride 
(2.times.90 ml), brine (2.times.90 ml), dried, and evaporated. The residue 
was chromatographed on silica gel, using a petroleum ether/diethyl ether 
1/1 mixture as eluant, to afford the title compound as a colourless oil 
(4.0 g; t.l.c. diethyl ether Rf 0.76) 
IR: V.sub.max (CDCl.sub.3) 1809, 1753, 1703, cm.sup.-1 ; .sup.1 H-NMR (300 
MHZ, CDCl.sub.3) 5.97(m), 5.3(m), 5.25(m), 4.79(m), 4.65(m), 4.55(m), 
4.54(m), 4.30(m), 3.24(m), 2.87(m), 2.87(s), 2.2-1.8(m), 1.1(d), 0.84(s), 
0.06(s)ppm. 
Intermediate 36 
2-(2-benzyloxyethoxy)-cyclohexanone 
A mixture of dimeric 2-hydroxycyclohexanone (13.7 g), 2 benzyloxyethanol 
(20 g) and p-toluensulphonic acid (2 g) were dissolved in xylene (500 ml) 
in a round bottom flask fitted with a Dean Stark apparatus and reluxed for 
10 hrs. The resulting solution was cooled, washed with sodium hydrogen 
carbonate (3.times.50 ml) dried and concentrated under reduced pressure. 
The crude oil was then purified by flash chromatography using 
cyclohexane/ethyl acetate 60/40 as eluant yielding 20 g of the title 
compound (Rf=0.5). 
IR, CDCl.sub.3, (cm.sup.-1): 1722 (C.dbd.O), 1603(C.dbd.C). 
.sup.1 H-NMR, 300 MHz, CDCl.sub.3, chemical shift (ppm, TMS): 7.32(m), 
4.55(dd), 3.92(m), 3.83(m), 3.64(m), 3.60(m), 2.48(m), 2.24(m), 1.93(m), 
1.8-1.55(m). 
Intermediate 37 
(3S,4R)3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)2'-[(S)6'-(2-benzylox 
yethoxy)-1'-oxocyclohexyl]]azetidin-2-one 
2,2,6,6-tetramethylpiperidine (12.7 g) was dropped to a solution of 
n-butyllithium 2.5M in hexane (33 ml) in tetrahydrofuran (150 ml) at -70 
C. under a nitrogen atmosphere. The reaction mixture was then warmed to 10 
C., recooled to -70 and intermediate 36 (18.72 g) was slowly added 
maintaining the temperature below -70 C. After the addition was completed, 
the solution was maintained at that temperature for 15 min and then 
intermediate A (11.48 g), dissolved in THF (200 ml) was added over 30 mins 
maintaining the temperature below -70 C. The reaction was quenched after 5 
minutes using a mixture of ammonium chloride (100 ml saturated solution) 
and hydrochloric acid (200 ml 10% solution) and extracted with ethyl 
acetate. The organic layer was washed with brine, dried, concentrated 
under reduced pressure and purified by flash chromatography using 
cyclohexane/ethyl acetate 85/15 to 30/70 as eluant, title compound (2.2 
g., RF=0.65). 
IR, CDCl.sub.3 (cm.sup.-1): 3418(NH), 1757(C.dbd.O lactam), 1718 (C.dbd.O), 
1603 (C.dbd.O). 
.sup.1 H-NMR 300 MHz CDCl.sub.3, chemical shift (ppm, TMS): 7.32(m), 5.71 
(s broad), 4.56 (s+m), 4.18(m), 3.99(m), 3.73(m), 3.6-3.5(m), 3.15(m), 
2.87(dd), 2.30(m), 2.10(m), 1.80-1.50(m), 1.19(d), 0.86(s), 0.07(s+s); 
Intermediate 38 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)2'-[(S)6'-(2-azidoet 
hoxy)-1'-oxocyclohexyl]]azetidin-2-one 
To a stirred solution of the intermediate 37 (3.7 g) in anhydrous 
dimethylformamide (20 ml), triphenylphosphine (2.6 g) and sodium azide 
(1.8 g) were added. Carbon tetrabromide 3.4 g) was then added over 10 min. 
After 2 hr. the resulting mixture was diluted with diethyl ether (50 ml) 
and washed three times with water (30 ml). The organic layer was dried and 
evaporated in vacuo. The residue was chromatographed on silica gel, using 
a ethyl acetate/cyclohexane 7/3 mixture as eluant, to afford the title 
compound as a colourless oil (2.6 g t.l.c. ethyl acetate/cyclohexane 
9/1Rf=0.8). 
IR (CDCl.sub.3 V.sub.max (cm.sup.-1) 3161 (N--H), 1759 (lactam), 1707 
(C.dbd.O) 
H.sup.1 -NMR (CDCl.sub.3): 5.84 (sa), 4.18(m), 4.00(m), 3.71(t), 3.60(m), 
3.49(m), 3.35(m), 3.12(m), 2.88(dd), 2.25(m), 2.20-2.00(m), 1.6(m), 
1.22(d), 0.86(s), 0.06(s), 0.05(s). 
Intermediate 39 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)2'-[(S)6'-(2-azidoet 
hoxy)-(R/S)-1'-hydrocyclohexyl]]azetidin-2-one 
To a solution of the intermediate 38 (2.6 g) in methyl alcohol (70 ml) at 
-10 C., sodium borohydride (0.4 g) was added in 15 min. then, after 1 hr 
the mixture was quenched with a saturated solution of ammonium chloride 
(100 ml) and ethyl acetate (2.times.150 ml). The organic layer was dried 
and evaporated to afford the title compound (2.8 g) as a mixture of two 
diastereoisomers (t.l.c. Rf 0.6 ethyl acetate/cyclohexane 95/5). 
IR (CDCl.sub.3 V.sub.max (cm.sup.-1) 3416 (N--H OH), 2108 (N.sub.3) 1753 
(lactam) 
H.sup.1 -NMR (CDCl.sub.3): 6.32(sa), 6.08(sa), 6.04(sa), 5.96(sa), 4.14(m), 
4.00-3.00(m), 3.21(dd), 2.10-1.0(m), 1.32(d), 1.26(s), 0.90(s), 0.12(s). 
Intermediate 40 
(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)2'-[(S)6'-(2-allylox 
ycarbonlyaminoethoxy)-1'-oxocyclohexyl]]azetidin-2-one 
To a solution of the intermediate 39 in anhydrous tetrahydrofuran (100 ml), 
triphenyl phosphine (1.6 g) was added, the mixture stirred at room 
temperature for 36 hr. and then water (0.09 ml) was added. After 12 hr the 
mixture was cooled at -5 C..degree., and N-ethylpiperidine (0.9 ml) and 
allylchloroformate (0.8 ) were added. After 3 hr the mixture was diluted 
with ethyl acetate (100 ml) and washed with a cooled 5% solution of 
hydrochloric acid (2.times.30 ml). The organic layer was dried, evaporated 
and purified on silica gel using a ethyl acetate/cyclohexane 6/4 mixture 
as eluant. The material so obtained was dissolved in dichloromethane (30 
ml), pyridinium chlorochromate (2.6 g) was added over 40 min and the 
mixture was refluxed. After 4 hr the mixture was filtered on celite and 
washed with a cooled 5% solution of hydrochloric acid (2.times.20 ml). The 
organic layer was dried and chromatographed on silica gel, using a ethyl 
acetate/cyclohexane 2/8 as eulant to afford the title compound as a 
colourless oil (0.75 g) t.l.c. ethyl acetate/cyclohexane 9/1 Rf=0.4) 
IR (CDCl.sub.3 V.sub.max (cm.sup.-1) 3458 and 3418(N--H) 1757(lactam), 
1718(C.dbd.O), 1603(C.dbd.C). 
H.sup.1 -NMR (CDCl.sub.3): 5.92(m), 5.25(m), 5.10(sa), 4.56(m), 4.18(m), 
3.98(m), 3.80-3.20(m), 3.05(m), 2.88(m), 2.40-1.10(m), 1.22(d), 0.87(s), 
0.07(s), 0.06(s). 
Intermediate 41 
Benzyl 
2-[(3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(2'S,6'R)-2'-mehoxy 
-1"-oxocyclohex-6"-yl]azetidin-2-on-1-yl]-2-hydroxyacetate 
To a solution of the intermediate 2a (0.6 g) in dry toluene (5 ml) benzyl 
glyoxylate (0.83 g) and 3A molecular sieves were added. The resulting 
mixture was refluxed for 3 hrs with the use of a Dean Stark trip to remove 
water, then concentrated under reduced pressure. The oily residue was 
chromatographed on silica gel, using a cyclohexane/ethyl acetate 8/2 
mixture as eluant, to afford the title compound as a mixture of two 
isomers (0.67 g; t.l.c. cyclohexane/ethyl acetate 1/1; Rf=0.61 and 0.72). 
IR (CDCl.sub.3 V.sub.max (cm.sup.-1) 3490(O--H), 1753(C.dbd.O .beta. 
lactam), 1713(C.dbd.O ester); 
.sup.1 H-NMR(300 MHZ, CDCl.sub.3): 7.4-7.30(m), 5.54(d) 5.46(d), 5.34(d), 
5.16(d), 4.80(d), 4.21(m), 4.05(m), 4.05-3.90(m), 3.55(d), 3.53(m), 
3.48(m), 3.24(s), 3.23(s), 3.2-3.0(m), 2.94-2.86(dd), 2.15-1.40(m), 
1.26(d). 
Intermediate 42 
Ethyl 
2-[(3'S,4'R)-3'-[(R)-1"-(t-butyldimethylsilyloxy)ethyl]-4'-[(2'"S,6'"R)-2'- 
methoxy-1'"-oxocyclohex-6'"-y-]azetidine-2'on-1'-yl]-2-hydroxyacetate 
To a solution of 
(3S,4R)-3-[(R)-1"(t-butyldimethylsilyloxy)ethyl]-4-[(2S",6R")-2-methoxy-1" 
oxocyclohex-6"-yl]azetidin-2-one (0.1 g) in dry tetrahydrofuran (5 ml), 
ethyl glyoxylate (0.5 g), N,N,N-triethylamine (0.02 ml) and 3A molecular 
sieves were added. The resulting mixture was stirred at 22.degree. for 17 
hrs, then diluted with ethyl acetate (30 ml), washed with brine 
(3.times.70 ml), dried and concentrated under vacuum. The crude product 
was chromatographed on silica gel, using diethyl ether/light petroleum 3/7 
as eluant, to afford the title compound as a colourless oil (0.1 g) (1/1 
mixture of isomers at 2 position; t.l.c. diethyl ether; Rf=0.63 nd 0.51). 
IR(CDCl.sub.3)V.sub.max cm.sup.-1 ; 3524(O--H), 1747(C.dbd.O .beta. 
lactam), 1715(C.dbd.O ester);