IE49876B1

IE49876B1 - Azetidinones

Info

Publication number: IE49876B1
Application number: IE2462/79A
Authority: IE
Original assignee: Bristol Myers Co
Priority date: 1978-12-18
Filing date: 1979-12-18
Publication date: 1986-01-08
Also published as: DK161520B; CH643846A5; IE49877B1; YU43280B; YU42125B; ES487034A0; SE8405813L; AU3288484A; AU563015B2; IL58576A; SE8405812L; FI793905A; YU215782A; DK237690D0; AU5378779A; AU3240884A; IL58804A0; ZA796812B; GR74491B; DK161520C

Abstract

This invention relates to 2-substituted and 2,6disubstituted penem compounds of the formula wherein Y is hydrogen, halo or certain organic substituents and X represents certain organic substituents. Also included in the invention are pharmaceutically acceptable salts of the above compounds and derivatives of the above compounds in which the carboxyl group at the 3-position is protected as by an easily removable ester protecting group. The compounds of the present invention are potent antibacterial agents or are of use as intermediates in the preparation of such agents.

Description

The present invention relates to novel azetidinones which are useful as intermediates in preparing certain 2-substituted and 2,6-disubstituted penem compounds which possess antibiotic activity.

More specifically the present invention comprises novel compounds 5 of the formula ll wherein Q is phenyl or (lower)alkyl; R is an easily removable esterforming protecting group; X is -(Alk)-A-(Alk' )-R2C)· wherein Alk represents a C^-Cg alkylene group optionally substituted by a C.J-C4 alkyl radical; A is 0, S, SO, S02 or NR2^ in which R2^ is hydrogen, (lower)alkyl, phenyl or phenyl(lower)alkyl ; Alk' is a C2-C4 alkylene group; R2(J is a polar substituent selected from the group consisting of azide, -HHOH, -NR22R23 in which R22 and R^ are each independently hydrogen or (lower)alkyl and -N02; and Y is a hydrogen or a radical selected from the group consisting of (a) optionally substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic, the substituents being one or more of hydroxy, (lower)alkoxy, optionally substituted phenyloxy, optionally substituted heterocyclicoxy, optionally substituted (lower)alkylthio, optionally substituted phenylthio, optionally substituted heterocyclicthio, mercapto, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoyloxy, (lower)alkanoylamino, optionally substituted phenyl, optionally substituted heterocyclic, carboxy, carb(lower)alkoxy, carbamoyl, N-(lower)alkylcarbamoyl, N,N-di(lower)alkylcarbamoyl, halo, cyano, oxo, thioxo, -SO3H, -OSO^H, -SO2-(lower)alkyl, (lower)alkylsulfinyl, nitro, phosphono O + or -OP(ORe)(ORr) the substitutents on'the (lower)alkylthio group being one or more of halo, hydroxy, (lower)alkoxy, amino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the phenyl or heterocyclic substituents above being one or «-.ore of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower) alkyl, sulfo or sulfo(lower)alkyl; Rg being a (lower)alkyl group and Rf being an optionally substituted (lower)alkyl group or optionally ring-substituted phenyl or heterocyclic group, the substituents on the alkyl group being one or more of a halogen atom, a hydroxy oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino and (lower)alkanoylamino group, and the substituents on the phenyl or heterocyclic rings being one or more of a halogen atom, a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkyl amino, (lower)alkanoylami no, / Ί a».»a ν» \ a 1 L· a n a ν Τ η ν v ra»*Knvu Lui ciiI^a av» i wiwi f ** » nuiiuj t wssjr y ww» wwnj y vmi w wajt < y fc» » rxj ι y m « » w y w ι sulfo(lower)alkyl group. - 3 (b) -ORS in which R$ is optionally substituted (lower)alkyl or (lower)alkanoyl or optionally substituted phenyl or heterocyclic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)alkoxy, (lower)alkylamino, di(lower)alkylamino, amino, oxo, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic being one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, * halo(lower)alkyl, methenesulfonyl, (lower)alkylthio, (lower)alkylamino, di(lower)alkylamino, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; (c) -S(0) R„ in which n is 0, 1 or 2 and R, is as defined above; ns — s (d) halo; and (e) optionally substituted phenyl or heterocyclic in which the substituents are one or more of hydroxy, (lower)alkoj(y, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or a pharmaceutically acceptable salt thereof.

The compounds of fonnula I wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolyzable esters) are potent antibacterial agents. The remaining compounds are useful intermediates for preparation of the biologically active penems. » Substituent groups disclosed above for the 2- and 6-positions of the penem ring may be further defined as follows: « (a) by the term halogen is meant chlorine, bromine, fluorine, and iodine. Preferred halogen substituents are chlorine and fluorine; (b) by the term (lower)alkyl is meant both straight and branched chain saturated aliphatic hydrocarbon radicals having from 1-6 carbon atoms inclusive, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc. Preferred (lower)alkyl substituents are from 1-4 carbons atoms and most preferably 1-2 carbon atoms; (c) by the term (lower)aliphatic is meant acyclic straight and branched chain saturated and unsaturated hydrocarbon groups having from 1-6 carbon atoms inclusive. The un5 saturated · groups may contain one or more double or triple bonds, but preferably contain either one double bond or one triple bond. Examples of (lower)aliphatic are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, 1-propenyl, 2-propenyl, jsopropenyl, 2-methyl-2-propenyl, ethynyl and 2-propynyl.

The most preferred aliphatic radicals are (lower)alkyl as in (b); (d) by the term (lower)cycloaliphatic is meant alieyelie saturated and unsaturated hydrocarbon groups having from 3-8 ring carbon atoms, preferably 3-6 carbon atoms. The unsaturated ring may contain one or more (preferably one) double bond. Examples of this group include cyclopropyl, cyclobutyl, cyclopentyl, cyelohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopentenyl, 1,3-cyclohexadienyl and cyclohexenyl; (e) ty the term (lower)cycloaliphatic (lower)aliphatic is meant cycloaliphatic-aliphatic groups having 3-8 carbon atoms (preferably 3-6) in the cycloaliphatic ring and 1-6 carbon atoms (preferably 1-4 and most preferably 1-2) in the aliphatic - 5 10 portion. Examples include cyclopropylmethyl, cyclopropylethyl, cyclopropyIpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cycloperitenylethyl, cyclopropylethenyl, cyclopropylethynyl, etc. The most preferred groups of this type are cycloalkyl-alkyl groups in which the cycloalkyl portion contains 3-6 carbon atoms and the alkyl portion contains 1-2 carbon atoms; (f) by the term (lower)alkoxy is meant CyCg alkoxy groups, the alkyl portion of which is defined as in (b) . Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, etc. Preferred groups are C1~C4 alkoxy and most preferred are C3~C2 alkoxy; (9) by the term (lower)alkylthio is meant C^-Cg alkylthio groups i.n which the alkyl portion is as defined under (b). Examples include methylthio, ethylthio and n-butylthio; (b) by the term (lower) alkyl ami no is meant C^-Cg alkylamino radicals in which the alkyl portion is as under (b). Examples are methylamino, ethylamino, n-propylamino and n-butylamino; (i) by the term di (lower Jal kyl ami nd' is meant di C-j-Cg alkylamino in which each alkyl is as defined under (b). Examples are dimethylamino and diethylamino; I tf tf 7 Ο (j) by the term (lower)alkanoyloxy is meant groups of the formula n (lower)alkyl-C-O- in which alkyl is as defined under (b); (k) by the term (lower)alkanoylamino is meant groups of the fonnula II (lower)alkyl-C-NH- in which alkyl is as under (b); (l) by the term carb(lower)alkoxy is meant ii -C-(lower)alkoxy in which (lower)alkoxy is as under (f); (m) by the term halo(lower)alkyl is meant alkyl groups as defined under (b) in which one or more hydrogen atoms are replaced by a halogen atom; (n) by the term sulfo(lower)alkyl is meant -(CHgJgSO-jH in which n is 1-6; (o) by the term carboxy(lower)alkyl is meant -(CHg^COOH in which n is 1-6; (p) by the term phenyl (lower)alkyl is meant in which n is 1-6; it (q) by the term (lowerJalkanoyl is meant (lower)alkyl-Cin which alkyl is as under (b); (r) by the term N-(lower)alkylcarbamoyl is meant ll (lower)alkyl-HN-C- in which alkyl is as under (b); (s) by the term N,N-Di(lower)carbamoyl is meant (lower Jalkyl^ 0 N-C- in which each alkyl is as under (b); (1ower)alkyl/ (t) by the term (lower)alkylsulfinyl is meant -S-(lower)alkyl in which (lower)alkyl is as defined above under (b). - 7 By the term heterocyclic as used herein is meant heteromonocyclic and heterobicyclic residues of aromatic character as well as appropriate partially or wholly saturated residues, said heterocyclic residues con5 taining at least one heteroatom selected from oxygen, sulfur and nitrogen and being bonded to the penem ring carbon atom via a ring carbon atom. The preferred heterocyclic groups are either 5- or 6-membered monocyclic radicals or fused 6,6 or 5,6 bicyclic radicals. Illustrative of suitable Ιθ heterocyclic radicals are the following: ζΤ Q tj Q- (J H Similarly, by the terms heterocyclic-(lower)alkyl, heterocyclicthio-dower) alkyl, heterocyclicoxy and heterocyclic-thio are meant -iCH-1 -Heterocyclic, -(CH,)_-S-Heterocyclic, --- - - £ n - 4, *1 -O-Heterocyclic and -S-Heterocyclic, respectively, in which n is 1-6 (preferably 1 or 2).

The term easily removable ester-forming protecting group is one which has acquired a definite meaning within the 8-lactam and peptide art. Many such groups are known which are used to protect the carboxyl group during sub5 sequent chemical reactions and which may later be removed by standard methods to give the free carboxylic acid. Known ester protecting groups include 2,2,2-trichloroethyl, tertiary alkyl of from 4-6 carbon atoms, tertiary alkenyl of from 5-7 carbon atoms, tertiary alkynyl of from 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl of from 2-7 carbon atoms, phthalimidomethyl, benzovlmethy1, halobenzoylmethyl, benzyl, D-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethvlsilyl, triethylsilyl, 3-trimethvlsilylethyL· Choice of an ester-forming protecting group is dependent on the 15 subsequent reaction conditions the group must withstand and the conditions desired for removing it. Selection of a suitable group is well within the ability of one skilled in the art. The most preferred ester is the p-nitrobenzyl ester which can be readily removed by catalytic hydrogenation. For preparation of 2o compounds containing functional groups reducible under such removal conditions, a preferred alternative is the 8trimethylsilylethyl ester removable by treatment with fluoride ions.

The azetidinones of the Invention are useful in the preparation of novel 2-substituted or 2,6-disubstituted penems having the formula wherein Z is hydrogen or an easily cleavable ester-forming protecting group. 5 These penems are claimed in our Irish Patent Specification No.

The penem ring system has the formula and systematically can be designated as 7-oxo-4-thia-l-azabicyclof3.2.o]hept-2-ene. For the sake of simplicity, it is named 2-penem in the present application and the numbering system used is as follows: The preferred compounds of the present invention are those wherein Y is hydrogen or (lower)alkyl optionally substituted (preferably at the α-carbon) by hydroxy. More preferred compounds within the above group are those wherein Y is hydrogen, ethyl or α-hydroxyethyl.

Still more preferred compounds of fonnula II are those wherein Y is hydrogen or α-hydroxyethyl. The most preferred compounds are those wherein Y is α-hydroxyethyl.

A preferred embodiment of the present invention consists of the compounds of fonnula II wherein X is -(Alk)-O-(Alk’)-R are as defined above. Examples of in which Alk, Alk1 and R2q substituents included within this class include -ch2och2ch2nh2-, -ch2och2ch2n(ch3)2 -ch2och2ch2nhc3h7, -CH2OCH2CH2CH2CH2NH2, -CH2OCH2CH2CH2CH2N(CH3)2 -CH2CH2OCH2CH2N(CH3)2, -ch2ch2och2ch2ch2nhch3, CH2OCH2CH2NHCH3, -CH2OCH2CH2N(C2H5)2, -ch2och2ch2ch2nh2, -CH2CH2OCH2CH2NH2, -CH2OCH2CH2NHC2H5, -CH20CH2CH2N(C3H7)2, -CH2OCH2CH2CH2CH2NHCH3, -CH2CH20CH2CH2NHCH3, -ch2och2ch2ch2nh2, -CH2CH20CH2CH2CH2N(CH3)2 -CH2CH-0CH2CH2NH2, -CH2CH-0CH2CH2NHCH3, CH3 -CH2CH-OCH2CH2CH2N(CH3)2, C3H7 -CH2CH2OCH2CH2NHOH, -CH2CH20CH2CH2N02, -ch2choch2ch2nhoh, CH, -CH20CH2CH2NH0H, -CH2OCH2CH2CH2NHO -CH2OCH2CH2NO2, CH, -CH20CH2CH2CH2CH2N02, -CH2CH0CH2CH2N02C2H5 and -CH2OCH2CH2CH2NHOH.

Within this class of compounds, the preferred members are those wherein Y is hydrogen, ethyl or o-hydroxyethyl. Most preferred members have Y= hydrogen or a-hydroxyethyl and especially Υ» ahydroxyethyl.

Another preferred embodiment of the present invention consists of the compounds of formula H wherein X is -(Alk)-S-(Alk')-R20 in which Alk, Alk' and R2Q are as defined above. Examples of substituents within this class include -CHjSCHjCHjNHj, -ch2ch2sch2ch2nh2, -ch2sch2ch2ch2nh2, -ch2sch2ch2ch2ch2nh2, -CH2SCH2CH2NHCH3, -CH2SCH2CH2N(CH3)2, -CH2SCH2CH2NHC2H5, -CH2SCH2CH2N(C2H5)2, -CH2SCH2CH2NHC4H9, -CH2SCH2CH2N(C4H9)2, -CH2SCH2CH2CH2NHCH3 , -CH2SCH2CH2CH2N(CH3)2, -CH2SCH2CH2CH2N(C3H7)2, -CH2SCH2CH2CH2CH2NHCH3, -CH2CH2SCH2CH2CH2NH2, -CH2CH2SCH2CH2NH2, -CH2CHSCH2CH2NH2, CH3 -CH2SCH2CH2NHOH, -CH2SCH2CH2CH2NHOH, -ch2sch2ch2ch2ch2nhoh, -CH2CH2SCH2CH2NHOH, -CH2CH2SCH2CH2CH2NHOH, -CH2CHSCH2CH2NHOH, C3H7 -CH2SCH2CH2NO2, -CH2SCH2CH2CH2NO2, -ch2sch2ch2ch2ch2no2, -CH2CH2SCH2CH2NO2 and -CH2CH2SCH2CH2CH2NC>2. Within this class of compounds, the preferred members are those wherein Y is hydrogen, ethyl or a-hydroxyethyl. Most preferred members have Y= hydrogen or α-hydroxyethyl and especially Y= a-hydroxyethyl.

An especially preferred embodiment of the present invention consists of the following compounds included within formula II: (a) Υ = Η; X = CH20CH2CH2NH2; (b) Υ = α-hydroxyethyl; X = CH2OCH2CH2NH2; (c) Y = Η; X = CH2OCH2CH2NHOH; (d) Y = a-hydroxyethyl; X = CH20CH2CH2NH0H; (e) Y = Η; X = CH2SCH2CH2NH2; (f) Y = a-hydroxyethyl; X - CH2SCH2CH2NH2; (g) γ = Η; X = CH2SCH2CH2NHOH; (h) Y = a-hydroxyethyl; X = CH2SCH2CH2NH0H; II (i) Y = Η; X = CH2SCH2CN2NH2; H (j) Y = a-hydroxyethyl; X = CH2SCH2CH2NH2 (k) Y = Η; X = CH2SCH2CH2NHOH; II (l) Y = a-hydroxyethyl; X = CH2SCH2CH2NHOH; (m) Y = Η; X = CH20CH2CH2N02; (η) Y = a-hydroxyethyl; X = CH20CH2CH2N02; (ο) Y = Η; X = CH2SCH2CH2NO2; (ρ) Y = a-hydroxyethyl; X = CH2SCH2CH2N02; ο (q) Y = Η; X = CH2SCH2CH2NO2; and II (r) Y = a-hydroxyethyl; X = CH2SCH2CH2NO2· Most preferred compounds of the present invention are those where Y = hydrogen or, more preferably, a-hydroxyethyl, and X is -CHgOCHgCHzNHg, most especially the free acids, pharmaceutically acceptable salts thereof and physiologically cleavable esters thereof.

In the intermediates of formula II, reactive functional groups such as mercapto, amino and hydroxy in substituents X and Y may be protected by conventional blocking groups during conversion of the intermediates to biologically active end-products.

Compound I may be prepared by one or more of the reaction routes discussed below. The various synthetic routes may be divided into three main processes depending on the stage of incorporation of the 6-substituent, i.e. Y. Thus, in Process 1, the 6-substituent is incorporated in the basic starting material; Process II involves incorporation of Y at the end of the synthesis and in Process III substituent Y is incorporated in mid-synthesis. Each of the three main processes in turn can vary in the procedure for incorporating the desired 2-substituent, i.e. X in the schemes shown below. In general, it is preferred to incorporate substituent Y in mid-synthesis and to incorporate substituent X by acylation of the mercaptide intermediates III or IIIa shown below since these procedures have been found to be the most generally useful.

The steps of Process I may be seen from the following scheme: Process I (Variation 1): Early incorporation of 2-substituent ll Ac = CH3CC6H5Κ. ••90 I Ό Process I (Variation 2 ) : Late incorporation of 2-substituent Y-CH=CH-OAc CSI II CH,C-SNa pH 7.5 -> CHO I co2r base co2r X-C- © = acylating agent MA = heavy metal salt Process I (Variation 3)·' Late incorporation of 2-substituent - 18 4987 In Process I a vinyl ester (Y = H or a radical as defined in connection with compounds I) containing the desired 6-substituent is converted to the optionally 1substituted 4-acetoxy-2-azetidinone by a cycloaddition reaction with chloro sulfonyl isocyanate (CSI) followed by reduction with an organic reducing agent such as sodium sulfite. The CSI reaction is conveniently carried out in an inert organic solvent such as diethyl ether at a temperature of O’C or below. The reduction step may be conducted in an aqueous or aqueous-organic reaction mixture at a temperature of 0’ or below and at a slightly basic pH.

Following formation of the 4-acetoxy-2azetidinone, Process I may be separated into three different paths. In one route (Variation 1) the azetidinone is reel II acted with a thiolic acid X-C-SH wherein X is as defined in connection with compounds I, or a salt thereof, in a suit able solvent (e.g. aqueous or aqueous organic). Displacement of the acetoxy group results in incorporation of the desired 2-substituent in the azetidinone at this 2o stage. The displacement reaction is preferably carried out at room temperature or below and at a slightly basic pH (^7.5). When Y / H, cis and trans isomers of the resulting azetidinone are preferably separated (e.g. by chromatography) at this point in the process. Variations 2 and 3 depicted above convert the 4-acetoxy-2-azetidinone into the 4-acetylthio-2-azetidinone and 4-tritylthio-2azetidinone products, respectively, by nucleophic displacement with thioacetic acid or triphenylmethyl mercaptan (or a salt thereof such as the sodium salt), respectively.

I The 4-thio azetidinone is next reacted with a 0 ll glyoxylate ester HC-CO2R wherein R is an easily removable ester protecting group such as p-nitrobenzyl or trimethylsilylethyl, or a reactive oxo derivative thereof such as a hydrate, in an inert organic solvent (e.g. benzene, toluene, xylene, and the like) and preferably at an elevated temperature (e.g. 50*C. up to most preferably reflux temperature). When a hydrate of the ester is employed, resulting water may be removed azeotropically or with molecular sieves.

The hydroxy ester product is formed as a mixture of epimers which can be optionally purified as by chromatography or used directly in the next step.

Conversion of the hydroxy ester to the corresponding chloro ester is achieved by reaction with a chlorinating re15 agent (e.g. SOC12, POCl3, PC15, and the like) in an inert organic solvent (e.g. tetrahydrofuran, diethyl ether, methylene chloride, dioxane, and the like) in the presence or absence of a base, preferably an aliphatic tertiary amine (e.g. triethylamine) or a heterocyclic tertiary amine (e.g. pyridine or collidine). The reaction is advantageously run at from about -10eC. to room temperature. Chloro ester product is obtained as a mixture of epimers which can optionally be purified before use in the next step.

The phosphorane intermediate may be obtained by reaction of the chloro ester with a suitable phosphine (preferably triphenylphosphine or a tri(lower)alkyl phosphine such as triethylphosphine or tri-n-butyl phosphine) - 20 •Λ 9 Ο · Μ in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,2-dimethoxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. hexane, cyclohexane, benzene, toluene, and the like) in the presence of a base, preferably an organic tertiary amine such as triethylamine, pyridine or 2,6-lutidine. The reaction is advantageously carried out at temperatures from room temperature to the reflux temperature of the solvent system. )0 At this stage the process again diverges into two routes. In Variation I (where the 2-substituent has already been incorporated), the phosphorane intermediate is converted to the desired penem by thermally cyclizing in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent system. Most conveniently, the cyclization is carried out under reflux conditions. Suitable inert organic solvents include aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, tetrahydofuran, 1,2-dimethoxyethane), carboxylic acid amides (e.g. dimethylformamide), di C^-Cg alkylsulfoxides (e.g. dimethylsulfoxide) or a C^-Cg alkanol (e.g. methanol, ethanol, t-butanol), or a mixture thereof.

In variations 2 and 3 the phosphorane is converted to a heavy metal mercaptide of the formula CO-R _ z x III rf or SHgCOOCH.

P(Q) CO2R Ilia wherein Q is preferably phenyl or (lower)alkyl, x is 1 or 2 and M is Cu(II), Pb(II) or Hg(II) when x is 2 or Ag(I) when x is 1. Mercaptide formation is accomplished by reaction of the phosphorane with a salt of Hg(II), Pb(II), Cu(II) or Ag(I) or with (methoxycarbonyl)mercury(II) acetate in a methanol-containing solvent and in the pre10 sence of an organic or inorganic base such as aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate, and the like. A preferred base is pyridine.

The reaction may be carried out at room temperature or, if desired, with moderate cooling or heating. The anion (A) of the heavy metal salt may be any anion which gives a soluble salt in the selected solvent, e.g. NO^-, CH^COO , BF4“, F“, C1O4, NO2“, CNO-, etc. The mercaptide intermediate is then reacted with an acylating agent capable of U introducing the moiety X-C- wherein X is the desired penem _ 00 2-substituent. The acylating agent (X-C- © ) may be the acid U X-C-OH or a reactive functional derivative thereof such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed acid anhydride, active ester, active thioester, etc. Acylation is conducted in an inert solvent (e.g. a halogenated hydrocarbon such as methylene chloride or an ether such as dioxane, tetrahydrofuran or diethyl ether) and, when an acid derivative is used, in the presence of an acid acceptor such as a tri (lower)alkylamine (e.g. triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine.

When the free acid is employed, the acylation is conducted in the presence of a suitable, condensing agent, for example a carbodiimide such as Ν,Ν'-dicyclohexylcarbodiimide.

Acylation of the mercaptide can be achieved over a wide temperature range, but is preferably carried out from about -20° to +25’C. Following acylation, the resulting phosphorane is cyclized as described above to give the desired penem ester.

Formation of the phosphorane via the mercaptide intermediate (Variations 2 and 3) has been found to result in product of much better purity than that obtained by the more conventional route of Variation 1.

Once the carboxyl-protected penem is formed, the protecting group may be removed by conventional deblocking procedures (e.g. hydrolysis, hydrogenation or photolysis) to give the de-blocked penem. Removal of the p-nitrobenzyl ester, for example, may be achieved by _ 01 catalytic hydrogenation in the presence of a noble metal catalyst such as palladium or rhodium, including derivatives thereof such as oxides, hydroxides or halides, said catalyst being optionally supported on a conventional carrier such 5 as carbon or diatomaceous earth. A non-reducible aqueous or non-aqueous inert solvent such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ether or dioxane is used. Hydrogenation may be conducted at atmospheric or elevated pressure and is conveniently run 10 at room temperature for a period of from about 1-5 hours depending on the solvent and catalyst used. If an equivalent weight of a base such as an alkali metal or alkaline earth metal hydroxide or an amine is employed during the hydrogenation, the product may be recovered in the form of 15 a carboxylic acid salt. Removal of the 8-trimethylsilylethyl ester, another useful protecting group, is conveniently achieved by treatment with a source of fluoride ions. Other ester protecting groups can be similarly removed by methods well-known to those skilled in the art.

In a second main process (Process II), the reaction sequence is as shown below: 48876 Process II (Variation 1): Early incorporation of 2-substituent CH2=CH-OAc CSI II XC-SNa pH 7.1 -> SOC12 - 25 of 2-substituent Process II (Variation .2J.: Late incorporation --> de-protect N // CO2H Process II (Variation 3 ) = Late incorporation of 2-substituent ch2=ch-oac __csi_> 03CSNa pH 7.5 -> SOCl 2 MA --> base O CO2H As can be seen Process II is substantially the same as Process I (except that Y must be H) up through the thermal cyclization step which produces the 2-substituted penem. A 6-substituent, however, if desired, is now in5 corporated at this stage by reaction of the 2-penem with a suitable electrophile in an inert solvent (e.g. tetrahydrofuran, diethyl ether, dimethoxyethane, and the like) and in the presence of a strong base. In this procedure the 2penem can be reacted in the form of the free acid (obtained by de-blocking as described above) in the presence of about two equivalents of base or, alternatively, a suitable 2penem ester may be used in the presence of about one equivalent of base. Any ester inert to anion chemistry (the reaction involves anion formation with base followed by reaction of the electrophile with the penem anion) may be employed, e.g. (lower)alkyl such as methyl, ethyl, n-propyl or t-butyl, phenyl, trichloroethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl, and the like. Penem esters having activated methylene groups such as p-nitrobenzyl are not suitable and, if the 2-penem ester is of this type, it must be first de-blocked and either used as the free acid or converted to a suitable ester. The particular base used is not critical and the usual strong bases such as sodium hydride, phenyl lithium or butyl lithium are suitable. Most preferably, however, a lithium disilylamide or a lithium dialkylamide such as 1 xthiUIu di- cyclohexylamide (LDCA), lithium diethylamide, lithium dimethylamide or lithium di-isopropylamide (LDA) is used.

The electrophile is selected so as to generate the desired Y-substituent upon reaction with the anion and may be, for example, a halogen (e.g. Br2, I2) , an alkyl halide (e.g. CH^I) or a similar halide such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyldower) alkyl, heterocyclic, heterocyclic-thio, heterocyclic thio-(lower)alkyl, or heterocyclic-(lower)alkyl, halide, a tosylate or mesylate (e.g.

CH3CH2OSO2-^~~^-CH3, CH3CH2OSO2CH3 , I^^Loso2 0CH2CH2CH2OSO2CH3, etc.), an epoxide (e.g. A ) , an S episulfide (e.g. / \ ) . an aldehyde (e.g. CH3CHO, CgHgCH2CHO), a ketone (e.g. CH3COCH3, I J ) or an ester (e.g.

CH3CH2COOCH3 or CgHgCOOCH-j) . Representative examples of other suitable electrophiles are shown below: CH2=CH-CH2Br Br I? ch3cch=ch Br Br I CH3CH-CH3 <0>cl 0CH2Br HCHO 0οξο<:η2βγ G° ch2sch2ci CH3SSO2CH3 0OCH2C1 . 90 . 0CH=CHCHO Ο ch3cch2ci A most preferred electrophile is acetaldehyde which gives rise to the hydroxyethyl 6-substituent. Introduction of the 6-substituent by this process is preferably carried out with cooling (e.g. -80° to 0°C.) according to the general procedure described in Canadian Journal of Chemistry, 50(19), 3196-3201 (1972).

After formation of the desired 2,6-penem, any 10 ester protecting group may be removed as discussed above to give the de-protected product.

The third main reaction process (Process III) can be understood from the following scheme: Process III (Variations 1 and 2): ΓΤ SC0, ,SC00' base de-protect MA/base SC0Υ. Π, Ο Β 2r ο ιι Λ x-c- © Υνν»«_p-SC-X Ν\ ο X de-protect II ^sc-x MA/base Cl CO2R l· de-protect Ψ B = blocking group for ring nitrogen - 32 The 4-tritylthio-2-azetidinone of Process III is formed as described in Process II (Variation 3). The ring nitrogen of the azetidinone is then protected by a conventional easily removable blocking group such as triorganosilyl (e.g. trimethylsilyl or t-butyldimethylsilyl), methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, and the like. Introduction of the desired Y-substituent at the 1-position of the azetidinone is then achieved by reaction of an appropriate electrophile with the N-protected azetidinone in the presence of a strong base (reaction conditions as described above in connection with Process II).

At this point the process diverges into two routes depending on the time of de-blocking the azetidinone.

In one route the N-protected intermediate is de-blocked by conventional procedures (e.g. acid hydrolysis) and then converted to the 2,6-penera via ester formation, chlorination of the hydroxy ester, conversion of the chloro ester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with 0 X-C- © , thermal cyclization of the resulting phosphorane to give the 2,6-penem ester and removal of the carboxylprotecting group. Reaction conditions for these steps are as disclosed in connection with Process II (Variation 3) .

An alternative route involves the steps of converting the N-protected azetidinone to a heavy metal mercaptide, acylating the mercaptide with the moiety 0 X-C- © , removing the N-protecting group, reacting the - 33 de-protected azetidinone with the glyoxylate ester, chlorinating, reacting the chloro ester with the phosphine to give the phosphorane, cyclizing the phosphorane to give the penem ester and removing the carboxyl-protecting group to give the 2,6-penem. Reaction conditions for these steps are as disclosed previously.

In preparing the 2-disubstituted penem or 2,6-disubstituted penem compounds according to the above processes, free functional groups in substituents X or Y which do not participate in the reaction may be temporarily protected in a manner which is itself known, such as free amino groups by acylation, tritylation or silylation, free hydroxyl groups, for example, by etherification or esterification, mercapto groups by esterification, and free carboxyl or sulfo groups, for example, by esterification, including silylation. After the reaction has taken place, these groups can, if desired, be liberated, individually or jointly, in a manner.which is itself known.

Additionally, it is possible in compounds of formula I to functionally modify the 2- and/or 2,620 substituents during or at the conclusion of the reaction procedures according to known processes to obtain other substituents included within the scope of the present invention. Thus, for example, carbonyl groups can be reduced to alcohol groups, unsaturated aliphatic groups can be halogenated, amino groups can be alkylated or acylated, nitro groups can be converted to hydroxyamino and amino groups, hydroxyl groups can be etherified or esterified, etc Illustrative examples of the preparation of starting materials and end-products of the preedit invention follow.

All temperatures are in degrees Centigrade. For the sake of convenience, certain abbreviations are employed in the examples. Definitions of the less obvious of these abbreviations are as follows: CS1 pet. ether b.p. n.m.r. chloro sulfonyl isocyanate petroleum ether boiling point nuclear magnetic resonance hour ether diethyl ether (unless otherwise indicated) Celite Trademark of Johns-Manville Products Corporation for diatomaceous earth psi pounds per square inch r. t. room temperature PNB p-nitrobenzyl m.p. melting point LAH lithium aluminum hydride n-BuLi n-butyl lithium MIBK methyl isobutyl ketone EtC2Hs- Tr -c(c6h5)3 Me ch3- THF tetrahydrofuran Ph phenyl DMF dimethylformamide TEA triethylamine PNBG p-nitrobenzylglyoxylate THP tetrahydropyranyl TFA trifluoroacetic acid HMPT (or HMPA) hexamethylphosphorus triamide LDA lithium diisopropyl amide AC ch3co- Ms ch3so2- DMAP 4-dimethylaminopyridine - 36 Preparation of Starting Materials Preparation of 4-Tritylthio-2-azetidinone Intermediates 1. 1-(Trimethylsilyl)-4-tritylthio-2-azetidinone A solution of 4-tritylthio-2-azetidinone (345 mg, mmole), 1,1,1, 3,3,3,-hexamethyldisilazane (80 mg, 0.5 mmole) and chlorotrimethylsilane (55 mg, 0.5 mmole) in dichloromethane (20 ml) was heated under reflux for 18 h. Concentration of the reaction mixture left virtually pure title compound. (ppm, CDCl^): 7.32 (15H, m, aromatics), 4.22 (IH, dd, H-4), 2.67 (IH, dd, J = 4.1, J = 16, H-3), 2.22 (IH, dd, J = 2.2, J = 16, H-3), 0.3 (9H, s, CHj). 2. 1-(t-Butyldimethylsilyl)-4-tritylthio-2-azetidinone Triethylamine (1.62 ml, 11.6 mmoles) was added dropwise in 5 min to a cooled (0“) and stirred solution of 4-tritylthio-2-azetidinone (3.5 g, 10.1 mmoles) and chloro-tbutyldimethylsilane (1.68 g, 12.7 mmoles) in DMF (35 ml). The reaction mixture was stirred at room temperature for 18 h , diluted with water (250 ml) and ether (200 ml). The organic phase was washed with water (3 x 50 ml), dried and concentrated to leave an oil (4.33 g). Crystallization from pentane gave a total of 4.1 g(89%) of the title compound as a white solid, m.p. 113-4°. δ (ppm, CDCl^): 7.45 (15H, m, aromatics), 4.2 (IH, dd, H-4), 2.63 (IH, dd, J - 4, J - 16, H-3), 2.13 (IH, dd, J = 2, J = 16, H-3), 1.0 (9H, s, t-Bu), 0.35 (6H, s, Me).

V 1735 cm-1. Anal, calc'd for C„aH NOSSi: C, 73.15; H, 7.24; c=o 28 33 N, 3.05; S, 6.97%. Found; C, 73.27; H, 7.32; N, 2.97; S 6.94%. 3. l-Methoxymethyl-4-trltylthio-2-azetidinone A solution of 4-tritylthio-2-azetidinone (1.38 g, 4.0 mmoles) in THF (10 ml) was added to a well stirred suspension of sodium hydride (200 mg of commercial 50%, 4.1 mmoles, washed with pentane) in THF (10 ml) maintained at -15°.

Methanol (12 drops) was added and the mixture was stirred at -15° for 0.5 h. Methoxymethyl bromide (0.58 g, 4.6 mmoles) was added and the mixture was stirred for 2h, diluted with ether, washed with water and brine, dried and concentrated to leave an oil (1.72 g). Crystallization from pentane gave a white solid (1.41 g) m.p. 72-76' δ (ppm, CDClj): 7.3 (15H, m, aromatics), 4.4 (3H, m, NCH_,O and H-4), 3.22 (3H, s, CH^), 2.76 (2H, m, H-3). - 38 4. l-(2-Methoxyethoxymethyl)-4-tritylthio-2-azetidinone To a suspension of tetrabutylammonium bromide (322 mg, mmole) and potassium hydroxide (85%, 70 mg, 1.1 mmole) in dichloromethane (10 ml) cooled to 5’ was added with vigorous stirring 4-tritylthio-2azetidinone (345 mg, 1 mmole) and methoxyethoxymethyl chloride (187 mg, 1.5 mmole). The mixture was stirred at room temperature for 2 h, the solvent was evaporated and the residue partitioned between water and ethyl acetate. The dried organic phase was concentrated to leave a viscous oil (415 mg,. Purification by column chromatography on silica gel eluting with ether (5%)-dichloromethane gave the title compound (206 mg, 48%) as an oil. δ (ppm, CDCl^): 7.30 (15H, m, aromatics), 4.57 (2H, AB quartet, N-CH„O), 4.46 (IH, dd, H-4), 3.50 (4H, s, OCH^CH^, , 3.30 (3H, s, CH^, 2.75 (2H, m, H-3). . 1-(21-Tetrahydropyranyl)-4-tritylthio-2-azetidinone n-Butyl lithium (1.6M, 1.6 ml, 2.56 mmoles) was added dropwise to a solution of 4-tritylthio-2-azetidinone (863 mg, 2.5 mmoles) in THF maintained at -78’.

After stirring for 15 min, 2-chlorotetrahydropyran (560 mg, 4.7 mmoles) was added and the reaction mixture was allowed to come to room temperature in 1-5 h. The reaction solution was diluted with ethylacetate, washed with brine, dried and concentrated to leave an oil (635 mg). Column chromatography on silica gel eluting with dichloromethane-ether gave a mixture of the isomeric title compounds contaminated with a little starting material, δ (ppm, CDCl^): 7.28 (15H, m, aromatics), 4.4 (H, dd, H-4), 2.9-2.2 (2H, m, H-3), 4.1-3.2 and 2.2-0.7 (tetrahydropyranyl).

. Preparation of ti-Tritylthio-l-(p-nitrohenzyl-21-triphenylphosphoranylidene-21-acetate)-2-azet i dinone CO PNB 2 1-(l'-carboxy-l'-hydroxymethyl)-4-tritylthio-2-azetidinone . triethylamine salt _..STr CHO !θ2Η -**2° TEA STr Mol. sieves THF (ΑΝγΟΗ TEA co2h To a solution of 4-tritylthio-2-azetidinone (3.5 g, 10.15 mmol) in tetrahydrofuran (8 ml) was added triethylamine (1.42 ml, 10.15 mmol) and glyoxylic acid hydrate (1.02 g, 10.15 mmol). The mixture was stirred at room temperature with 4A mol. sieves* (volume of 8 ml) for 1 h and allowed to stand at room temperature overnight. The solidified mixture was diluted with methylene chloride and filtered; the filtrate ZU was evaporated and the residue crystallized from pentane to give 5.18 g (98%) of title compound as a white solid mp 112-5eC; ir V : 3100-3600, and 1755 cm1; ’Hmr (CDC13) δ: 7.3 (15Η, m), 4.92 and 5.10 (1Η, 2s), 4.50 (IH, dd, J=8Hz, J=3Hz), 3.0 (1Η, dd, J=15Hz, J=7Hz), 3.1 (6Η, q.

J=7H2), 2.70 (IH, dd, J=15Hz, J=3Hz), 2.0-3.5 (2H, m) and 1.21 ppm (9H, t, J=7Hz).

* Mol. sieves were dried at 150’C for 18 h. 1-(1·-carboxy-1'-chloromethyl)-4-tritylthio-2-azetidinone STr 3 γ .TEA + SOC1. «Λ .STr co2h CO H 2 A cooled (ice bath) solution of the triethylamine salt of 1-(1’-carboxy-1'-hydroxymethyl)-4-tritylthio-2-azetidinone (1.04 g, 2.0 mmol) in methylene chloride (5 ml) was treated dropwise, under N2, with thionyl chloride (0.16 ml, 2.2 mmol) in methylene chloride (2 ml).

The solution was stirred at room temperature for 20 min and concentrated. The residue was diluted with benzene and filtered over a Celite/charcoal bed. The filtrate was evaporated in vacuo to give 870 mg (quantitative, of the title compound as an amorphous solid. It was used in the next step without further purification, ir 1775 cm ; 'Hmr (CDCl^) 5: 9.22 (IH, bs), 7.27 (15H, m), 5.3 and 5.2 (IH, 2d, J=2Hz), 4.6 (IH, m) and 2.8 ppm (2H, m). Ι-d'-carbo-p-nitrobenzyloxy-1'-chloromethyl)-4-tritylthio-2-azetidinone STr JZT Cl + PNB-OH Θ?Θ Me2N=CH Cl ,STr CHC1. co2h O' IM pyridine/THF * J—-Cl co2pnb To a cooled (ice bath) solution of DM? (0.17 ml, 2.2 mmol) in ’chloroform (4.4 ml) was added dropwise oxalyl chloride (0.19 ml, 2.2 mmol). The mixture was stirred 5 min in ice, then 20 min at room temperature. The solution was cooled in an ice bath and treated dropwise with l-d'-carboxy-l'-chromethyD^-tritylthio^azetidinone (854 ag, 2 mmol) in chloroform (2 ml) followed by a IM solution of pyridine in tetrahydrofuran (2.2 ml, 2.2 mmol); the solution was stirred at room temperature for 30 min, cooled to 0°C and treated dropwise with paranitrobenzyl alcohol (370 mg, 2.2 mmol) in tetrahydrofuran/chloroform (1:1, 2 ml) and triethylamine (0.31 ml, 2.2 mmol). The solution was stirred at room temperature for 30 min, then evaporated. The residue was diluted with benzene and filtered over a Celite/charcoal bed and the filtrate was evaporated in vacuo.

IQ The crude chloro ester was purified on a silica gel pad (5 g) and eluted with methylene chloride to give 790 mg (70%) of the title compound as a beige powder. Trituration in ether gave a white solid, mp 168-9°C. ir V : 1780, 1760 cm1; ’Hmr (CDC1,) 6: 8.15 (2H, d, c max J j=9Hz). 7.49 (2H, d, J=9Hz), 7.3 (15H, m) , 5.75 and 5.35 (IK, 2s), .3 (2H, s), 4.55 (IH, m), 2.8 (2H, m). This compound was identical to an authentic sample prepared by reaction of 4-tritylthio-2azetidinone with p-nitrobenzyl glyoxylate followed by a thionyl chloride treatment. ft * chloroform was left on mol sieves· (3A> for 18 h before reaction (to remove any trace of alcohol) - 42 Example 1 1- (p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4(silver mercaptldyl)-2-azetidinone i COjPNB .OAc STr TrSH -» NaOMe A methanol (90cc) suspension of triphenylmethyl mercaptan (13.8 g, 0.05 mmole) was degassed for °·5 hour with a nitrogen stream. The mixture was cooled down at 0° and sodium hydride (2.4 9, 0.05 mole, 50% oil dispersion) was added portionwise. The resulting solution was stirred for 5 min and 4-acetoxyazetidinone (7.7 g, 0.059 mole) in water (55 cc) was added rapidly. Precipitation of 4-triphenyl methyl mercaptoazetidinone (2) occurred immediately. The mixture was stirred for 4 h at room temperature. The solid was filtered off, washed with water and dissolved in methylene chloride.

The methylene chloride solution was washed with diluted HCl, water, aqueous sodium bicarbonate water and brine and dried over MgSO4 (89.8%, m.p.: 146.5 - 147.5’C) Anal. Calc'd for C22HigNOS: C, 76.49; H. 5.54 Found: C, 7.54; K, 5.60; N, 4.00; S, 9.36. δ(ρριη, CDC13) 7.60 - 7.10 (15H, m, H-trityl) , 4.40 (IH, dd, J4_3 - 3.0, J4_3 c.s = 5, N, 4.05; S, 9.28 4.62 (IH, bs, NH), H-4), 3.24 (IH, ddd, Jgem ’ 15' J3-4 cis 5' J3-NH = 1‘8' H~3)' 2’81 (1H' ddd' J___ = 15· gem J3-4 trans = 3‘°' J3-NH “ X*2' H’3> Vc=o {OiC13> 1760' VNH 3340‘ STr .PNB STr JV CO,PN STr J— .OH CO.PNB Hydrated p-nitrobenzyl glyoxylate (4.54 g, 0.02 mole) and azetidinone _2 (6.90, 0.02 mole) were refluxed in benzene « through a Dean Stark condenser filled with 3A molecular sieves for 24 h. Further glyoxylate (2 x 454 mg, 2 mmoles) was added with reflux period (18 h) after each addition. The mixture was diluted with ether, washed with 5% aqueous HCI, water, aqueous % NaHCOg water and brine. It was dried over MgSO4 (12 g, quantitative) A small fraction of the epimeric mixture was separated on a silica gel plate (CH^Clj-ether 6:4) Isomer aRf = 0.87, m.p. = 170.5- 171.5’ δ(ppm, CDC13) 8.07 (2H, d, J=9, Hm aromatic), 7.45 (part of d,.

Ho aromatic), 7.40-7.00 (15H, m. Trityl), 5.25 (2H, s, CHj-PNB) , 4.75 (IH, S, H-C-O), 4.37 (IH, dd, J>4 = 3, J3_4 cis = 4. H-3), 2.83 (IH, dd, 3 - 16, J . = 4, H-4), 2.10 (IH, dd, J = 16, 4-3 trans gem 4-3 cis 3, H-4), 1.42 (b.s., OH).

Isomer B: Rf a 0.75, m.p. = 152 - 153 c=o V___ (CHC1,) 1770, 1760 (shoulder), υΝ0 1525, \>QH 3475 δ (ppm, CDC13), 8.13 (2H, d, J => 9, Hm aromatic), 7.47 (2H, d, J = 9, Ho aromatic), 7.40 - 7.00 (15H, m, trityl), 5.30 (3H, s, CH2-PNB, H-C-O), 4.45 (IH, t, J = 3.5, H-4), 2.90 - 2.70 (2H, AB part of ABX, H-4), 1.55 (b.s., OH).

V (CHC1,) 1767, 1755 (shoulder), V 1525, V 3500. c«o 3 wv2 A cold (-15°) THF (150 cc, dried over molecular sieves) solution of azetidinone J) (12 g, 21.7 mmoles) was treated with pyridine (1.9 g, 24.1 mmoles, 1.94 cc) and dropwise with thionyl chloride (2.86 g, 24 mmoles, 1.88 cc, under a nitrogen atmosphere. The mixture was stirred for 45 min at -15°. The precipitate was filtered off and washed with benzene. Evaporation of solvent gave a residue which was taken up in benzene and treated with activated charcoal (11.7 g, 94%, crystallized out from chloroform). δ (ppm, CDClj) 8.17 (2H, d, J « 8, Hm aromatic), 7.67 - 7.00 (17H, m. Ho aromatic, Tr-H), 5.80 (s, H-C-Cl), 5.37, 5.33 (2s, H-C-Cl, CHj-PNB), 4.81 (IH, m, H-4), 3.27 - 2.40 (2H, m, H-3) V (KBr film) 1785, 1770 1525. c=o NO^ A THF (100 cc, distilled over LAH) solution of chloroazetidinone £ (11,6 g, 20.2 mmoles) was treated with triphenyl phosphine (7.86 g, 30.0 mmoles) and 2,6-lutidine (2.36 g, 2.56 cc, 22.0 mmoles). The mixture was refluxed for h. The _precipitate was filtered off and washed with ether.

The organic solution was washed with 2% aqueous HCl and 5%· aqueous bicarbonate and dried over MgSO^. Evaporation of solvent gave a residue which was purified through silica gel pad (200 g) The desired phosphorane was eluted with 30,40 and 50% ether-benzene (11.4 g, 70.4%, m.p.: 201-202’).

Anal. Calc'd for C„QHNOSP: C, 73.57; H, 5.04; N, 3.50; S, 4.01. 40 2 5 Found: C, 73.58; H, 4.91; N, 3.44; S, 3.87. ic u (CHC1) 1740, υ phosphorane (1620, 1610), υ 1525. 1J c=o 3 NO, 4-Tritylmercapto azetidinone 5^ (1.6 g, 2 mmoles) was dissolved in CK2C12 (20 cc) and the solvent was flushed down at 55“-60e. Phosphorane S at 55 - 60° was dissolved in preheated (55-60’) methanol (32 cc). Immediately after the obtention of a methanolic solution of 6 it was treated with a preheated (55 - 60°) mixture of methanolic 0.15 M silver nitrate solution (16 cc, 1.2 eq) and pyridine (174 mg, 178μ1, 2.2 mmoles, 1.1 eq) . The wanning bath was then immediately removed. The mixture was stirred at room temperature for 2 h and at O’C for 1 h. The silver mercaptide .6 was filtered off, washed twice with cold (O’) methanol and three times with ether. (1.12 g, 84.5%, m.p.: 130-135 dec.). v (CHC1 ) 1795, 1725 (shoulder), V.phosphorane (1620, 1605), C=O 3 V 1530.

NOn Example 2 - (p-Mi trobenz yloxycarbonyImethy ltriphenylphosphoranyl) - 4 (silver mercaptldyl)-2-azetidinone 3 COOPNB K2CO3,A9N°3 MeOH SAg '(j=PPh3 COOPNB A solution of phosphorane _7 (1.796 g, 3.0 mmoles) in chloroform (3 ml) was diluted with methanol (90 ml) , cooled at O’C under nitrogen atmosphere and treated successively with silver nitrate (0.51 g, 3.0 mmoles) and potassium carbonate (0.33 g, 2.4 mmoles). The reaction mixture (protected from light) was stirred at O’C for 15 min., then the cooling bath was removed and stirring.was continued for 3 h. The reaction mixture was cooled down to —10’C, stirred for 1 h and filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.91 g. M.P.: 138 - 145’C dec, 96%. I.R. (*nujol) cm 1748, 1620 and 1605. An analytical sample was obtained by preparative TLC (ethyl acetate); M.P.: 140 - 5’C dec, calc d for c Η K o SPAg: C, 54.31; H, 3.65; N, 4.22; S, 4.83. Found: C, 54.11; 3U 24 2 5 H, 3.48; N, 3.92; S, 4.62.

Example 3 (p-NitrobenzyloxycarbonyImethyItripheny1phosphoranyl)-4(silver mercaptidyl)-2-azetidinone A. Use of aniline as base scoch3 Aniline, AgNO ---2-, MeOH pPh3 COOPNB SAg >PPh3 _OOPNB i A solution of phosphorane J7 (1.8 g, 3.0 mmoles) in chloroform (4 ml) was diluted with methanol (90 ml), cooled to -15eC under nitrogen atmosphere and treated successively with silver nitrate (0.56 g, 3.3 mmoles) and aniline (1.5 ml, 16.5 mmoles). The reaction mixture (protected from lioht) was stirred at -15°C for 0.5 h and then the cooling bath was removed and stirring was continued for 24 h. The reaction mixture was cooled to -10°C and stirred for 1 h before being filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.55 g, M.P. 114-5’C dec. 77.9%. IR (nujol)cm 1; identical to compound of Example 2.

Silver 1-(11-paranitrobenzyloxycarbonyl-11-tri phenyl phosphoranyl methyl)2-azetidinone-4-thio1ate B. Use of ^-dimethylaminopyridine (DMAP) as base SCOCH, rf J-N .Pd> ox = AgNO^/DMAP CH^CiyCH^OH SAg COjPNB COOPNB mmol) in methanol and dichloromethane (1:2, 450 ml) uas purged with nitrogen (5-10 min), cooled to 5°C and treated successively rf J—»x A solution of the above S-acetyl phosphorane (17.96 g. with silver nitrate (5.35 g, 31.5 mmol) and 4-dimethylaminopyridine (3.85 g, 31.5 mmol). The ice-bath was removed and the solution refluxed vigorously for 2 h and then stirred at room temperature for.l h. The colored reaction mixture was treated with charcoal, filtered and evaporated. The residue was redissolved in the minimum amount of dichloromethane and added dropwise, with stirring to cold methanol (300 ml). The precipitated silver salt was collected by filtration, washed with ether and dried; 18.1 g (91%); ir (CHC1,) V : 1745 (C=0 of β-lactam) and 1607 cm 1 (C=O of ester). max Silver-1- (paranitrobenzyl 2'-triphenylphosphoranylidene-2-acetate)-2azetidinone-4-thiplate.

C. Use of 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) as base SCOCH DBU, MeOH > PNB The above S-acetylphosphorane (36.0 g, 0.060 mol) was dissolved in methylene chloride 120 ml. The solvent was evaporated in order to obtain an oil. The resulting oily residue was dissolved in warm ( 35°C) methanol (240 ml) and treated rapidly with a methanolic (420 ml) solution of silver nitrate (10.68 g, 0.0628 mol). The resulting solution (or suspension) was stirred at room temperature for 5 min, cooled down (ice bath) and a DBU (8.96 ml, 0.060 mol) solution in methanol (20 ml) was added over a 5 min period. The mixture was stirred for 5 min. The solid was filtered, washed once with cold (0°C) methanol and ether and dried under vacuum; 37.0 g (93%); ir (nujol mull) v (c=0) and 1609 cm 1 max (phosphorane) - 49 D. Use or pyrrolidine as base Silver 1-(1'-paranitrobenzyloxycarbonyl —1‘-triphenylphosphoranylmethyl) -2-azetidinone-4-thiolate SAg x'C=PPh I 3 COOPNB SCOCH J Pyrrolidine AgNC>3 C=PPh I 3 COOPNB To a cold (0°C) solution of 4-acetyl thi o-l -(parani trobenzyl oxycarbonyl-1* 1-tri phenylphosphorany1 methyl)-2-azeti di none (0.60 g. 1.0 mmol) in CH2C12 (2 ml) was added MeOH (4 ml), a solution of AgNO3 in MeOH (0.14N, 7.86 ml. 1.1 mmol) and a solution of pyrrolidine (0.92 ml, 1.1 mmol) in MeOH (2 ml). The cooling bath was removed and the reaction mixture was stirred for 1.75 h, cooled to -10°C, stirred for 0.25 h and filtered. The solid was washed with cold MeOH and dried in vacuo; 0.548 g, m.p. llS’C, 82.4%. ir (nujol) V : 1755 (C=O) and 1600 cm 1 (aromatics). nidx Example Mercuric (11)-β'-p-nitrobenzyloxycarbonyl-l‘-triphenylphosphoranylmethyl] -2-azetidmone-4-thiolate STr Hg(OAc)2 'C=PPh, I 3 C02pNB A-^PPh3 CO2PNB ri A solution of I (2.4 g, 3 mmoles) in dichloromethane (15 ml) was cooled to 5°C and treated with a solution of mercuric acetate {0.525 g, 1.65 mmole) dissolved in methanol (15 ml). After stirring at 5®C for 2 h, the solvent was evaporated and the residue redissolved in dichloromethane and washed with cold water. The organic solution after being dried (MgSO^) and treated with charcoal, was evaporated to give a foam which crystallized when triturated in ether. Yield: 1.73 g (91%) M.P. 123® - 127®C, I.R. (CHC1,) 1745 cm1 (V β-lactam) c=o 1608 cm 2 (phenyl) Example 5 Ιθ A. Preparation of 3-(1'-Hydroxy-1'-ethyl)-l-methoxymethyl-b-tritylthio-2azetidinones a) (l'S,3S,4R and 1'R,3R,4S)isomer (isomer C) A solution of lithium diisopropyl amide was prepared in THP (5 ml) at -78°C from n-butyl lithium (1.6M, 1.0 ml, 1.6 mmol) and diisopropylamine (0.25 ml, 1.84 mmol). After 30 min a solution of l-methoxyroethyl-4-tritylthio-2-azetidinone (491 mg, 1.42 mmol) in THF (6 ml) was added dropwise and the solution was stirred for 15 min. Acetaldehyde (3.0 ml) was added dropwise, followed, after 20 min, by water (30 ml). The mixture was acidified to pH 3 with 2% HCl and extracted with ethyl acetate (5 x 20 ml). The combined organic phases were washed with brine, dried and concentrated to leave an oil which crystallized upon trituration with ether: 440 mg, 80%, mp 188.5-9°C; ’Hmr (CDCl^ δ:7.3- (15H, m, aromatics), 4.37 (2H, ABq, N-CH^O), 4.32 (IH, d, J=2, H-4), 3.17 (3H, s, OCH.,), 3.32-2.70 (2H, m, H-3 and H-5), and 1.12 ppm (3H, d, J=7, CH3); Anal, calcd for C^H^NOjS: C 72.02, H 6.28, N 3.23, S 7.39; found: C 71.99, H 6.02, N 3.21, S 7.40%. b) (l'S,3S,4R and l'R,3R,4S) and (l'R,3S,4R and l'S,3R,4S) (isomers C and B).

A solution of lithium diisopropyl amide (0.482 mmol) is prepared at —78eC in dry ether (3 ml) from butyl lithium 0.191 ml of 2.52 M solution in hexane, 0.482 mmol) and diisopropyl amine (0.067 ml, 0.482 mmol). After 20 min, a solution of (4R and 45) l-methoxymethyl-4-tritylthio-2-azetidinone (0.171 g, 0.439 mmol) in a mixture of dry ether (1ml) and dry THF (1 ml, was added dropwise and the. resulting clear solution was stirred at -78“C for 15 min.

A solution of tetrabutyl ammonium fluoride (0.96 ml of a 0.5M solution in THF, 0.48 mmol) was then added. A precipitate was formed with the generation of a slight pink colour. After 5 min at -78°C, the reaction mixture was quenched with freshly distilled acetaldehyde (0.2 ral, excess), and the stirring continued for 15 more min.

The work-up was done by adding to a saturated solution of ammonium chloride and extracting with ethyl acetate (2 x 25 ml). The combined organic phases were washed with brine and dried over anhy20 drous magnesium sulfate. Evaporation of the solvent under vacuum gave an oil (0.228 g) which was chromatographed on 10 g of silica gel A mixture of benzene and ethyl acetate (6:4)gave 0.106 g (62% recovery) of substrate and a mixture of the two isomer alcohols which were separated by chromatography on thick layer plates (same solvent25 system). The alcohol with the high Rf (0.033 g, 17 %) was identical to the above isomer (isomer C): mp 188.5-189OC (Ether-dichloromethane); The alcohol with low Rf (0.030 g, 16%) (isomer 5), was obtained as an oil which crystallized with difficulty from hexanes: mp 94-95°C. ir (CHC1J V : 3600 (OH), 1760 cm1 (C=O) ; ’itar (CDC1,) 5:6.9-7.5 2 2 rosx 4 (15H, m, aromatics), 4.2 (2H, center of ABq, «7=11.5, CH^-0-CH.p , 4.28 (IH, d, j=2.0, 4-H), 3.65 (IH, center of a broad sextet, H-l'), 3.3 (IH, dd. J3 4 trans=2-5. J3,l·-5·5’ 3·15 (3H’ Sr ^55 (IH, broad s, OH-1’), 1.05 (3H, d, J=6.5, H-2'); Anal, calcd for C H NO S: C 72.02, H 6.28, N 3.23, S 7.39; found: C 71.77, H 6.36, 26 27 3 N 3.15, S 7.43%.

B . Preparation of trans 3-Acetyl-l-methoxymethyl-4-tritylthio-2-azetidinone LDA EtOAc Lithium diisopropylamide was prepared under a nitrogen atmosphere at -78°C in the usual manner from diisopropylamine (0.34 ml, 2.4 mmol) and n-butyl lithium (1.1 ml of a 2.2M solution in hexane, 2.4 mmol) in THF (3 ml). A solution of 1-methoxymethyl4-tritylthio-2-azetidinone (0.78 g, 2 mmol) in THF (3 ml) was added dropwise and, after stirring at -78“C for 20 min, ethylacetate (0.53 g, 6 mmol) was added in one portion and stirring continued for 0.75 h at -78°C. The reaction mixture was diluted with ether and washed with an ammonium chloride solution, water and brine, dried and concentrated to give an oil (0.7 g). Purification was achieved by chromatography over silica gel (20 g) eluting with increasing amounts of ether in benzene. The pertinent fractions were concen’Hmr (CDC13) 5:7.7-6.8 (15H, aromatics), 4.85 (IH, d, J=2, H-4), 4.5 (2H, s, N-CH2-O), 3.9 (IH, d, J=2, H-3), 3.22 (3H, s,. CH ) and 2.0 ppm (3H, s, CH,); ir V : 1770, 1710 cm1, j max C. Preparation of trans 3-Acetyl-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone >εφ3 '‘“Λ LDA EtOAc Diisopropy! lithium amide was prepared in the usual manner from diisopropylamine (0.18 ml, 1.24 mmol) and n-butyllithium (0.78 ml of a 1.6M solution in hexane, 1.24 mmol) in THF (8 ml). A solution of 1-(t-butyldimethylsilyl)-4-tritylthio-2azetidinone (0.46 g, 1 mmol) in THF (8 ml) was added dropwise at -78’C. After a 5 min stirring period, ethyl acetate (1 ml) IQ was added in one portion and the mixture was stirred 3 h at -78°C.

The mixture was acidified with cold hydrochloric acid (0.5N) to pH 6 and extracted with ethyl acetate (2 x 20 ml). The combined organic phases were dried and concentrated to give an oil (0.5 g) which crystallized from pentane: 200 mg total, 40%; mp 122-4°C; ir V : 1750, 1710 cm”1; ’Hmr (CDCl,) 6: 8-7.1 (ISH, m, aromatics), max 3 4.83 (IH, d, J=2,H-4), 3.38 (IH, d, J=2, H=3), 1.80 (3H, s, CH3), 0.92 (9H, s, Bu and 0.3 ppm (6H, s, CH^).

D. Preparation of trans-1-(t-Butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone ri SC.

•Si(CH3)2 t-Bu To a cooled (-78*0 solution of diisopropylamine (0.34 ml 2.4 mmol) in tetrahydrofuran (5 ml) was added dropwise, under N2, a 48876 solution of 1.5 M n-BuLi (1.6 ml, 2.4 mmol). After stirring for 30 min, a solution of 1-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (1.0 g, 2.18 mmol) in tetrahydrofuran (5 ml) was added dropwise and stirring was maintained for 30 min. Ethyl formate (0.8 ml, 9.9 mmol) was added and the cooled solution was stirred for 10 min. The reaction mixture was washed successively with cold IN hydrochloric acid (5 ml), 1M sodium bicarbonate (6 ml), water (10 ml) and brine. The organic layer was dried (MgSO^), evaporated and crystallized from pentane to give 810 mg (76%) of formate as a white solid mp 132-3“C; ir (CHCl^) V : 1760, 1715 cm”1; ’Hmr (CDC1,) δ: 9.0 (IH, d, J=1.25 Hz), 7.30 max 3 (15H, m), 4.7 (IH, d, J=1.5Hz) and 3.5 ppm (IH, t, J=1.5 Hz).

NOTE: a) diisopropyl amine was distilled over CaH and stored on KOH b) tetrahydrofuran was distilled over L.A.H. and stored on ό molecular sieves 3A c) ethyl formate was stirred at room temperature with ’ then distilled over p2°5 d) n-BuLi was titrated with IN hydrochloric acid E. Preparation of 1-(t-Butyldimethylsilyl)-3-(1 *-hydroxy-1’-ethyl)-4-tritylthio-220 azetidinones. (4 isomers). a) .SC$> Bu (Me). n-Butyllithium (1.6M, 3.4 ml, 5.44 mmol) was added in min to a solution of diisopropylamine (0.847 ml, 6.23 mmol) in THF (30 ml) maintained at -78’C. After 0.5 h a solution of 1-(t25 butyldimethylsilyl) 4-tritylthio-2-azetidinone (2.0 g, 4.4 mmol) in THF (20 ml) was added; after 15 min acetaldehyde (10 ml) was II II III I IM added in one portion; after another 15 min water (100 ml) was added.

The mixture was acidified (pH 5-6) with dilute hydrochloric acid and extracted with ethyl acetate (3 x 30 ml). The organic phases were washed with brine, dried and concentrated to leave an oil which was found to consist of a mixture of four isomers by flc (labelled isomers A,B,C,D by decreasing order of polarity).

Crystallization of the oily residue in ethyl acetate-pentane gave isomers B and C as a white solid and left A and 0 in the motherliquors. The four pure compounds were obtained by preparative chro10 matography (Waters, 500) of the above solid and mother-liquors. The relative proportions were: A, 17%; B, 32%; C, 39%; D, 12%. In the above reaction, when ether was substituted for THF and the reaction quenched after 1 min at -78’C, the relative proportions of A,B,C, and D were: 12.9, 30.5, 38.2 and 18.4%. In ether, when the reaction was allowed to come to 20eC in 2 h before quenching, the proportions were: 13.4, 24.6, 44, and 18%. When one molar equivalent of anhydrous magnesium bromide was added to the reaction mixture, the proportions changed to: 19.2, 19.7, 30.1 and 31%.

Isomer A: This isomer possesses a cis-stereochemistry at C^-C^. It 2Q is a racemic mixture composed of the (l'S, 3R, 4R) and the (l’R, 3S, 4S) enantiomers. Compounds later derived from compound A are referred to as Isomer A. They consist of an enantiomeric mixture and possess the same configuration at C^,, C^ and C^. Compounds derived from compound A, through a reaction that proceeds with inversion of configuration, will be referred to as Isomer D if the inversion takes place at and as isomer C for the inversion, at C3 mp 152-3’C; ’Hmr (CDC13) δ: 8.0-6.8 (15H, m, aromatics), 4.30 (IH, d, J=5.5, H-4), 3.78 (IH, m, H-l’), 3.10 (IH, dd, J=5.5, J=10, H-3), 1.22 (3H, d, J=6.5, CH3), 0.95 (9H, S, Bu), 0.27 (6H, 2s, CH3>. Anal, calcd for: C30H37N°2Si: C 71·52' H 7·40· N 2·78' S 6·36'· found: C 71.28» H 7.41, N 2.48, S 6.19%.

BBS aaa76 Isomer B: This isomer posseses a trans-stereochemistry at C3-C4> It is a racemic mixture composed of the (l'R,3S,4R) and the (I'S,3R,4S) enantiomers. Compounds with the same configuration at C^, C3 and C4 are referred to as Isomer B”; ir (CHC13) 1745 cm1 (C=0) ; mp 5 158-9’C; lHmr (CDC13) δ: 7.60-7.10 (15H, ra, aromatics), 4.02 (IH, d, J=0.8 H-4), 3.32 (IH, dd, J=3.0, J=0.8, H-3), 3.55-3.15 (IH, m, H-l ), 0.88 (12H, CHy and t-Bu) , 0.16 (6H, s, CH.j) ; Isomer C: This isomer possesses a trans-stereochemistry at C„-C„. - 3 4 It is a racemate formed of the (l'S,3S,4R) and the (l'R,3R,4S) enantiomers. Compounds with the same configuration at C^,, C3 and C. are referred to as Isomer C. mp 134-6’C; ’Hmr (CDC1) δ: 7.604 3 7.10 (15H, m, aromatics), 4.32 (1H, d, J=1.8, H-4), 3.02 (IH, dd, J=2.7, J=1.8, H-3), 3.0-2.5 (IH, dq, J=2.7, J=6, H-l'), 1.02 (3H, d, J=6, CH3), 0.95 (9H, s, t-Bu) , 0.27 (6H, s, CH.j) ; ir (CHCl^ V : 1735 cm-1 (C=O).

J max Isomer D: This isomer possesses a cis-stereochemistry at C3~C4· It is a racemate composed of the (I'R,3R,4R) and the (I'S,3S,4S) enantiomers. Compounds with the same configuration at C^,, C3 and C4 are referred to as Isomer D. mp 171-2°C; Hmr (CDClj) : 7.8020 6.90 (15H, m, aromatics), 4.70 (IH, d, J=4.5, H-4), 3.02 (IH, dd, J=4.5, J=0.5, H-3), 2.39 (IH, dq, J=0.5, J=6.5, H-l'), I.O (3H, d, J=6.5, CH3), 0.97 (9H, s, t-Bu), 0.32 (6H, s, CH3). Anal, calcd for c30H37NO2ssi: C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71.27, H 7.43, N 2.51, S 6.31%. - 57 OH trans isomers A solution of trans 3-acetyl-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (1.0 g, 2 mmol) in THF (30 ml) was added dropwise, under a nitrogen atmosphere, to a cooled 5 (O’) and stirred suspension of sodium borohydride (0.38.g, mmol) in THF (120 ml). The ice bath was removed and the mixture was stirred at room temperature for 4 h. It was poured into ice-cold hydrochloric acid (IN, pH 6), stirred for 15 min and extracted with ether (3X) , The combined ether extracts were ]Q dried and concentrated to give an oil (1.04 g) which was crystallized in pentane to give the title compounds as a 70:30 mixture of the C and B isomers, mp 119-121’C; 84%. c) t-Bu Isomer B A suspension of cuprous iodide (4.78 g, 15 mmol) in ether (50 ml) was cooled to 0’C and treated under Nj, with a 1.9 M solution of methyl lithium (26 ml, 50 mmol). The brown solution was stirred at 0eC for 10 min and then cooled to -60°C and treated dropwise with the trans 1-,(t-butyl dimethylsilyl)-3-formyl-420 tritylthio-2-azetidinone (2.43 g, 5.0 mmol) in a mixture of tetrahydrofuran (10 ml)/ether (40 ml). Stirring was continued for 3 h.

The solution was warmed up to -40°C and treated carefully with a IH solution of ammonium chloride. The mixture was filtered over Celite and the organic phase was washed with a 1M solution of airanonium chloride (3x5 ml) and then brine and dried over sodium sulfate. Filtration and evaporation gave alcohol, isomer B, which crystallized from warm pentane to yield 1.6 g (65%), mp 160-leC; ir (CHCl^) 1730 cm ;.

’Hmr (CDC13) δ« 7.32 (15H, m), 4.05 (IH, s), 3.4 (IH, d, J=3HZ, 3,25-: 3.55 (IH, m), 1.6 (IH, s), 0.9 (12H, s) and 0.1 ppm (6H, s,.

NOTE: a) tetrahydrofuran and ether were distilled over L.A.H. b) methyl lithium was titrated with IN hydrochloric acid c) copper (I, iodide was purified by continuous extraction Ιθ with anhydrous tetrahydrofuran in a Soxhlet extractor for h, then dried under vacuum in a dessicator H.

Jkl |xSC?0J-^si'Me2 - tBu A.

CH, 'Si Me. ''tBu Methylmagnesium iodide (0.1 ml, 0.1 mmol) was added dropwise to a cooled (0“C) and stirred solution of trans 1-(t-butyl15 dimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (25 mg, 0.05 mmol) in THF (2 ml). The solution was stirred 1.5 h at 0°C, poured onto an ammonium chloride solution, acidified with a hydrochloric acid solution (IN) and extracted with ether. Drying and concentration of the organic extracts left an oil consisting of starting material and a small amount of a mixture of the two trans title compounds with isomer B predominating. - 59 F. Preparation of (1*S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-trimethylsilyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer C) A solution of (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldimethylsilyl)-3-(1 *-hydroxy-11-ethyl)-4-tritylthio-2-azetidinone (15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in dry THF (6 ml) was stirred at room temperature until disappearance of the starting material (15 min). Purification of the reaction mixture by column chromatography (silica gel, CH^Cl^ gave the desired compound as a white solid (128 mg, 74%) mp 144-46’C. ’Hmr (CDCl^) δ; 7.10-7.60 (ISH, m, aromatics), 4.30 (IH, d, J=1.5, H-4), 2.25-2.89 (2H, m, H-3, H-l1), 0.82-1.07 (12H, m, t-Bu, H-2'), 0.27 (6H, s, CH,), -0.10 (9H, s, -O-Si(CH-) ; ir (CHC1,) υ : 1736 cm1 (C=0).

J 3 4 OULX g. Preparation of (l‘S,3R,4R and l'R,3S,4S) 1’(t-Butyldimethylsilyl)-3-(1'-methoxymethgxy ether-l'-ethyl)-4-tritylthio-2-azetidinone (isomer A). n-Butyllithium (ca 12.5 ml of 1.6M solution in hexane, mmol; just enough to obtain a permanent pink coloration) was added dropwise to a solution of (l'S,3R,4R and l'R,3S,4S) l-(t-Butyldimethylsilyl)-3- (1’-hydroxy-1 * -ethyl)-4-tritylthio-2-azetidinone t;---tin l a. 20 mmol) in THF (100 ml) maintained at -78°.

After a 15 min stirring period a solution of bromomethoxymethyl ether (2 ml, 24 mmol) in THF (30 ml) was added dropwise · The mixture was stirred 1 h at -78° and 2 h at room tenperature and poured into an ammonium chloride solution (200 ml). Extraction with ethyl acetate (3 x 200 ml), washing with brine, drying with sodium sulfate and concentration gave the crude title compound which was purified by chromatography on silica gel eluting with increasing amounts of ether in benzene (10.4 g 95%). ’Hmr (CDCl^) ¢: 7.1-7.5 (15H, m, aromatics), 4.47 (IH, d, H-4), 4.23 (2H, ABq, J=7, O-O^-O) , 3.1-3.4 (2H, m, H-3 et H-l'), 3.23 (3H, s, 0-CH.p , 1.37 (3H, d, J=6.5, CH3), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CHj).

H. Preparation of (l‘S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-formyloxy-1 ethyl)-4-tritylthio-2-azetidinone (isomer C) A solution of (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldimethylsilyl) -3- (1'-hydroxy-1 ’-ethyl)-4-tritylthio-2-azetidinone (isomer c) (50 mg, 0.1 mmol,, p-bromobenzenesulfonylchloride (100 mg, 0.4 mmol) and 4- dimethylaminopyridine (24 mg, 0.2 mmol, in DMF (3 ml) was stirred at room temperature until disappearance of starting material (0.5 h).

Then the reaction mixture was diluted with water and extracted with ether. The organic extracts were washed with brine, dried (MgSO^) and evaporated. The title compound was purified by column chromatography. ’Hmr (CDC13) δ: 7.80 (IH, s, CHO), 7.20-7.66 (15H, m, aromatics), 3.90-4.36 (IH, m, H-l*), 4.07 (IH, d, J»2, H-4), 3.22 (IH, broad s, H-3, , I. Preparation of (l'R,3S,4R and l‘S,3R,4S) l'(t-Butyldimethylsilyl)-3-l'-acetoxy1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OAc ac2o Pyridine ‘''-•Μ5 A solution of (l'R,3S,4S and l'S 3R 4S) 1-(t-butyldi· methylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (13.85 g, 27.5 mmol) in pyridine (75 ml) acetic anhydride (50 ml) (prepared at O’) was stirred at room temperature for 40 h. The reagents were evaporated off (the last traces being removed azeotropically with toluene 3 times) leaving a nearly white solid.

Crude derivative was crystallized from an ether-petroleum ether mixture to give pure title compound (97.5%). ’ffinr (CDCl^ δ: 7.64-7.03 (15H, m, H aromatic), 4.60 (IH, m, J»6, H-l'), 3.92 (IH, d, J=2, H-4), 3.55 (IH, dd, J=2, J=6, H-3), 1.79 (3H, s, CH^O), 0 (3H, d, J=6, CH3), 0.88 (9H, s, t-butyl), 0.12 (6H, s, CH3>; ir (CHCl,) V : 1775, 1740 cm 1 (C=O) max J. Preparation of l- (t-BUtyldimethylsilyl)-3-(1' -paranitrobenzylyycarbonyloxy)-!1ethyl)-4-tritylthio-2-azetidinone. (4 isomers) Isomer C n-Butyllithium (8.8 ml of 1.6 M solution in hexane, 14 mmol; just enough to obtain a permanent pink coloration) was added dropwise to a solution of Isomer C” of 1- (t-butyldimethylsilyl)-3- (1*-hydroxy-1'-e thyl)-4-tritylthio-2-azetidinone (6.55 g, 13 mmol) in THF (70 ml) maintained at -78°C. After a 15 min stirring period a solution of paranitrobenzyl chloro5 formate (3.2 g, 14.8 mmol) in THF (30 ml) was added dropwise.

The mixture was stirred 1 h at -78’C and poured into an ammonium chloride solution (100 ml) . Extraction with ethyl acetate (3 x 100 ml) washing with brine, drying and concentration left 11 g of crude material. The pure title compound was obtained by chromatography on silica gel (220 g) eluting with increasing amounts of ether in benzene. 93%, mp 118—9°C (ether); ^Hmr (CDCl^) : 8.35-7 (19H, m, aromatics), 5.12 (2H, s, benzyl), 4.08 (IH, d, J=1.8, H-4), 4-3.5 (IH, dq, J=6.5, J=2, H-l'), 3.10 (IH, dd, J=2, J=1.8, H-3), 1.2 (3H, d, J=6.5, CH3), 1.0 (9H, s, Bu) and 0.30 ppm (6H, 2s, CH,); ir (CHC1,) V : 1745 cm 1 (C=O); Anal, calcd 3 uloX for C,aH _N 0 SiS: C 66.83, H 6.20, N 4.10, S 4.69; found: C 66.90, 42 2 o H 6.26, N 4.11, S 4.59.

Isomer B The Isomer B of 1-(t-butyldimethylsilyl)-3-(1'hydroxy-1'-ethyl (-4-tritylthio-2-azetidinone, treated as described above gave pure Isomer B of 1-(t-butyldimethylsilyl)-3-(1'paranitrobenzyloxycarbonyloxy-1'-ethyl)-4-tritylthio-2-azetid1none as a foam, 95%. *Hmr (CDC13) 5: 8.32-6.90 (19H, m, aromatics), 5.1 (2H, s, benzyl), 4.65-4.20 (IH, m, H-l'), 3.97 (IH, d, J=»1.5, H-4), 3.58 (IH, dd, J=1.5, J=5.8, H-3), 1.1 (3H, d, CH3), 0.7 (9H, s, Bu oc and 0.2 ppm (6H, s, CH ); ir (film) V : 1755, 1740 cm 1 C=O.

Isomer A The “Isomer A of l-(t-butyldimethylsilyl-3-(l'-hydroxy1'-ethyl)-4-tritylthio-2-azetidinone, treated as described above gave pure Isomer A of 1-(t-butyldimethylsilyl-3-(1'-paranitrobenzyloxycarbonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone as an oil. 95% ’Hmr (CDC13) 5: 8.3-6.7 (19H,m, aromatics), 4.95 (2H, ABq, benzyl), 4.53 (IH, p, J=7.5, J=7.5, 4.31 (IH, d, J=6, H-4), 3.32 (IH, dd, J=6, J=7.5, H-3), 1.44 (3H, d, J-6.5), 0.95 (9H, s, tBu) and 0.2 ppm (6H, 2s, CH3).

Isomer D” Likewise Isomer D of 1-(t-butyldimethylsilyl-3-(1'5 hydroxy-1’-ethyl)-4-tritylthio-2-azetidinone, gave pure Isomer D of 1- (t-butyldimethylsilyl) -3-(1' -paranitrobenzyloxycarbonyl oxy-1' ethyl)-4-tritylthio-2-azetidinone, 90%. ’Hmr (CDC13) δ: 8.3-6.7 (19H, m, aromatics), 5.20 (2H, ABq, benzyl), 4.72 (IH, d, J=5, H-4), 3.50 (IH, dq, J=6.5, J=0.5, H-l’), 2.85 (IH, dd, J=0.5, J=5, H-3), 1.03 (3H, d, J=6.5, CH3), 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH^), mp 130-2®c. Anal, calcd for C^gll^l^OgSlS C 66.83, H 6.20, N.4.10, S 4.70 found: C 66.5b». π b.28, N 3.96, S 4,89.

K. Preparation of (l‘S,3S,4R and l'R,3R,4S) l-(t-Butyldimethylsilyl)-3-(l'-methane1 c sulfonyloxy-l*-ethyl)-4-tritylthio-2-azetidinone (Isomer C) A solution of (l'S,3S,4R.and l’R,3R, 4S)-1-(t-butyldimethylsilyl) -3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (2.0 g, 4 mnol) in dichloromethane (80 ml) was treated at 5’C, with 20 methanesulfonyl chloride (0.99 g, 8.6 mmol) and triethylamine (0.87 g, 8.6 mmol). After stirring at that temperature for 1 h under No, the solution was washed with brine, dried (MgSO^) and evaporated to dryness. After crystallization from ether-pet-ether, 1.9 g (81.9%) of mesylate was obtained, mp 120-22eC; JHmr (CDC13) δ: 7.13-7.61 (15Η, m, aromatics), 4.50 (IH, d, J=2, H-4), 3.62 (IH, dq, J=6.5, 2, H-l*), 2.96 (IH, dd, J»2, 2, H-3), 2.84 (3H, s, methanesulfonyl), 1.22 (3H, d, J=6.5, H-2*), 0.99 (9H, s, Si-t-Bu) and 0.30 ppm (6H, s, Si-(CH)); ir V (CHC1,): 1746 (C=-O), 1343 and 1180 cm”1 (SO ). 2 max 3 4, L. Preparation of (l'R,3S,4R and l‘S,3R,4S) l-(t-Butyldimethylsilyl)-3-(l'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OH sc*3 MsO A solution of (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethyΙΙΟ silyl)-3-(l*-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) (5.03 g, 10 mmol), methanesulfonylchloride (2.52 g, 22.0 mmol) and triethylamine (2.23 g, 22.0 mmol) in CH2C12 (200 ml) was stirred at 5’C for 1 h. Then the solution was washed with brine, dried (MgSO^) and evaporated to leave a residue which crystallized as a ]5 white solid when triturated in ether (5.40 g, 93%) mp 127-31°C.

'Hmr (CDClj) δ: 7.20-7.63 (15H, m, aromatics), 4.51 (IH, dq, J=5.0-6.2, H-l’), 4.10 (IH, d, J=2.0, H-4), 3.60 (IH, dd, J=5.0-2.0, H-3), 2.03 (3H, s, -CH3>, 1.01 (3H, d, J=6.2, H-2'), 0.90 (9H, s, t-Bu), 0.12 (6H, s, -CH,); ir (CHC1,) V : 1745 cm-1 (C=O). 3 max - 65 Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(l'-p-Bromobenzenesulfonyloxy-l'-ethyl)1-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) A solution of (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldimethylsily1)-3-(1’-hydroxy-1’-ethyl)-4-tritylthio-2-azetidinone (Isoiner C) (2.5 g, 5 mmol) in dry THF (100 ml) was cooled to -78’C and treated with 2.52M butyllithium/hexane (2.38 ml, 6 mmol). After 3-4 min p-bromobenzenesulfonylchloride (1.53 g, 6 mmol) dissolved in THF was added dropwise. The solution was stirred at -78’C for 3 h and then allowed to come to room temperature. Then the solvent was evaporated and the desired product purified by column chromatography (silica gel, CH2C12) (3.36 g, 94.6%) mp 142-44’C; ’Hinr (CDC13) δ: 7.68 (4H, s, benzenefulsonyl), 7.28-7.60 (15H, m, aromatics), 4.59 (IH, d, J=1.8, H-4), 3.68 (IH, dq, J=6.2, H-l'), 2.99 (IH, dd, J=1.8, 2.0, H-3), 1.18 (3H, d, J=6.2, H-2'), 1.08 (9H, s, t-Bu), 0.40 and 0.38 (6H, 2S, -CH,); ir (CHC1,) U__; 1749 cm1 (C=0). j j max - 66 49876 N. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(1'-MethoxymethylOXy-Γ-ethyl)-4-tr1 tylthio-2- OCHoOCH-j V' A cold (O’C) HMPA-H2O (116 ml-13 ml) solution of Isomer A of 1- (t-butyldimethylsilyl)-3- (l'-methoxymethyloxy-l '-ethyl )4-tritylthio-2-azetidinone (11 g, 20 mmol) was treated with sodium azide (2.7 g, 42 mmol). The cold bath was removed and the mixture was stirred for 30 min. It was then poured into cold water (1.3 i) and dried. The title compound recrystallized from ethyl acetate-hexanes (7.2 g, 83%) as a white solid mp 173-174’C. ’Hmr (CDC13) δ; 7.10-7. (15H, m, aromatics), 4.85 (2H, ABq, J=7.4, O-CH^O) , 4.53 (IH, d, J=5.2, H-4), 4.42 (IH, s, N-H), 4.15 (IH, m, H-l'), 3.5 (IH, m, H-3), 3.47 (3H, s, O-CH ), 1.5 (3H, d, J=6, CH_). ir (KBr) V : 3400-3500 -> 3 max (N-H) and 1760 cm-1 (c=O). 0. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(1'-M ethoxymethyloxy-l*-ethyl)-4-tritylthio2-azetidinone (Isomer C) OCH2OCH3 STr -•s,-BrCH2OCH3 sT-4x. Π' NaN OCH OCH J ΛΓί STr A cold (dry ice-acetone bath.) solution of (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4tritylthio-2-azetidinone (5.03 g, 10 mmol) in THF (50 ml, distilled over LAH) was treated dropwise with a 1.6M solution of n-butyl lithium in hexane (13.0 ml) until a pink coloration persisted.

A THF (20 ml) solution of bromomethyl methylether (1.49 g, 0.97 ml, 1.19 mmol) was added dropwise. The mixture was stirred at -78’C for 30 min and for a 3 h period at O’C. It was poured in an ice cold ammonium chloride solution and extracted with ether. The ether extracts were combined, washed with water, dried (MgSO^) and concentrated to give crude (l'S,3S,4R and 1*R,3R,4S) 1-(t-butyldimethylsilyl)-3-(l'-methoxymethyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (5,83 g, 100%) which was deprotected as described below: A cold (ice bath) solution of the above derivative (5.83 g, 10 mmol) in ΗΜΡΑ-Ηγ (90 ml-10 ml) was treated with sodium azide (1.365 g, 21 mmol). The cooling bath was removed and the mixture was stirred at room temperature for a 2 h period. It was then poured slowly into ice cold water (900 ml) and stirred for 30 min. The precipi15 tate was collected by filtration and redissolved in methylene chloride.

The solution was washed with water and brine and dried (MgSO^) to give the title compound (3.0 g, 69.3%), mp 172-2.5 (ethyl acetate-hexane); ir (CHC13) Vmax: 3400 H) and 1760 Cm_1 (C=O); 1Hmr (CDC13) ά: 7.67-7.12 (15H, m, H aromatics), 4.63 (2H, center of ABq, J=6, O-CHj-O), 4.49 (IH, s, N-H), 20 4.40 (IH, d. J=3, H-4). 4.25-3.80 (IH, m, H-l'), 3.35-3.15 and 3.26 (4H, s+m, CH3 and H-3) and 1.30 ppm (3H, d, J=6, CH3), - 68 ·* σ ο < Ο Ρ. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l'-Formyloxy-l'-ethyl)-4-tritylthio-2azetidinone (Isomer B) A solution of (l'S,3S,4R and 1*R,3R,4S) 3-{l'-p-bromobenzenesulfonyloxy-l'-ethyl)-l- (t-butyldimethylsilyl) -4-tritylthio2-azetidinone (Isomer C) in DMF (3 ml) was heated at 50°C for 48 h and then at 100°C for 4 h. The reaction mixture was then diluted with HjO and extracted with ether. The ethereal extracts were washed with brine, dried (MgSO ) and evaporated. The title compound was obtained as white crystals after purification by column chromatography (silica gel, 5% O^CN-CH^l^) (2 mg, 4.8%) mp 131-32°C; ’Hmr (CDC13) 5: 8.07 (IH, s, CHO), 7.24-7.56 (15H, m, aromatics), .23 (IH, dq, J=6.4, 7, H-l'), 4.38 (IH, dm J=2.4, H-4), 4.25 (IH, s, NH), 3.20 (IH, dd, J=7, 2.4, H-3), 1.43 (3H, d, J=6.4, H-2'); ir (CHC1 ) U : 3400 (NH) , 1765 (C=O) , 1725 cm1 (C=0) . max Q. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l’-Acetoxy-l'-ethyl)-4-tritylthio-2azetidinone (isomer B)' OAc STr NaN3 HMPT KtBDMS Pure derivative (1*R.,3S,4R and l’S,3R,4S) l-(t-butyldimethylsilyl)-3- (1'-acetoxy-1'-ethyl)-4-tritylthio-2-azetidinone ‘ The solution was cooled down at room temperature and NaN^ (1.2 g was added in. It was stirred for 45 min (reaction progression was followed by tic) and poured slowly in stirred cold water (800 ml).

The mixture was stirred for 20 more min. The crystalline material was collected and washed with water. It was redissolved in CH^Cl^ washed with water (twice) and brine and dried over MgSO,. Solvent 4 evaporation left a foam which crystallized out from ether-petroleum ether (4.90 g, 96.5%, mp 143-44.5’C). ir (CH,C1 )\> : 3395 (N-H), 1772, 1738 cm'1 (C=O). ’Hmr (CDCl,) 2 TOQX 3 δ : 7.9-6.8 (15H, m, H aromatic), 5.12 (IH, center of dq, J=6.5, 7.5, H-l’), 4.33 (IH, d, J=2.8, H-4), 4.20 (IH, bs, N-H), 3.17 (IH, ddd, J ,,=7.5, J, =2.8, J, =1. H-3), 2.1 (3H, s, CH,CO), 1.35 (3H, d, 3-1 3—4 J—Mn J J-6.5, CH3).

Preparation of 3-(1’-Hydroxy-1'-ethy1)-4-tritylthio-2-azetidinone. Mixture of four A solution of lithium diisopropyl amide1(0.74 mmol) was prepared at -78“C in dry tetrahydrofuran (5 ml) from diisopropyl amine (0.103 ml, 0.74 mmol) and BuLi (0.29 ml of a 2.52 M in hexane).

After 30 min at -78C, a solution of the (R and S) l-trimethylsilyl-4tritylthio-2-azetidinone (0.292 g, 6.99 mmol) in dry tetrahydrofurane (2 ml) was added dropwise. After 5 min, excess of freshly distilled acetaldehyde (0.2 ml) was added all at once. After 20 min at -78®C, tic indicated complete disappearance of starting materials and the reaction mixture was quenched by adding to a saturated solution of ammonium chloride. Extraction with ethyl acetate (2 x 25 ml) followed by washing of the combined organic phases with saturated NH^Cl, brine and drying on anhydrous magnesium sulfate gave, after evaporation of the solvent, a yellow oil. Filtration of this oil on silica gel (10 g, elution C,H.:EtOAc, 6:4) gave a mixture of alcohols (0.215 g, 80%j . This 6 o mixture (lHmr) cannot be separated either by hplc or by tic. a: Acetylation Acetylation of an aliquot of the mixture (0.065 g) with IQ excess acetic anhydride (1.0 ml) and pyridine (1.4 ml) gave a mixture of acetates, hplc Analysis indicated four components2: a) 34:6%; b) 17.4%; c) 30.1%; d) 17.9%. Compound a) was identical to the isomer B by direct comparison (hplc). * b: t-Butyldimetyl silyl derivatives The mixture of alcohols (0.121 g, 0.34 mmol) was treated with t-butyl dimethylchlorosilane (0.117 g, 0.776 mmol) and triethyl amine (0.10 ml, 7.14 mmol, in dry dimethylformamide (1 ml) for 36 h at room temperature. After dilution with ethyl acetate, the solution was washed with saturated ammonium chloride and dried over anhydrous magnesium sulfate. Evaporation gave an oil (0.716 g) which contains 4 components by HPLC. a = 3.7%; b — 60.6%; £ = 31.1%; <3 = 4.6% (the identity of each one has not been established)* NOTE: rButyl lithium and lithium hexamethyl disilazane were ineffective 20rder of increasing polarity ’Acetylation of the product derived from l-t-butyldimethylsilyI-4tritylthio-2-azetidinone gave the following ratio: d = 29.5%; £ = 24.1%; b =· 33.8%; a = 12.6% ''Reaction of a mixture of alcohols derived from (R and S) :- ;*--Hi,»-«i.4'imoi-hvlsilvl)-4-tritvlthio-2-azetidinone gave the S. Preparation of (l'R,3s,4R and i'S,3R,4S) 3-(l‘- Benzyloxy-1 ‘-ethyl)-4-tritylthio-2azetidinone (Isomer B) A solution of (1*S,3S,4R and l'R,3R,4S) 3-(l’-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (035 mg, mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H2O-DMF (10 ml) was heated at 90®C for 7.5 h. Then the reaction mixture was diluted with R^O and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO^) and evaporated.

The residue, purified by column chromatography (silica gel, 5% CH^ CN-CH2C12) gave the title compound as ,·» white solid (108 mg, 23.2%) mp 158°C. ’Hmr (Cix:i3) δ: 7.03-8.25 (20H, m, aromatics), 5.32 (IH, dq, J=6.1, 9, H-l'), 4.40 (IH, d, J=2.5, H-4), 4.30 (IH, s, N-H), 3.40 (IH, dd, J=9, 2.5, H-3), 1.50 (3H, d, J=6.1, H-2');ir (CHC13) V : 3400 (N-H), 1765 (C-0), 1715 cm1 (C=O). max T. Preparation of 3- (l'-Faranitrobenzyl oxycarbonyl oxy-11 -ethyl )-4-tritylthio-2azetidinone (4 isomers).

Isomer C a) A solution of Isomer C“ of 1-(t-butyldimethylsi lyl) -3- (l·-parani trobenzyl oxycarbonyloxy-1 '-ethyl)-4-tri tyl ivf-nre of TFA (5 ml), water (5 ml), dichloromethane (20 ml) and methanol (30 ml) was stirred for 2 days at room temperature. The solution was diluted with water and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with sodium bicarbonate and water, dried and concentrated to leave an oil. Crystallization from ether gave the pure title compound (902 mg), mp 78-80eC; 'Hmr (CDCl^) : 8.25-6.75 (19H, m, aromatics), 5.21 (2H, s, benzyl), .05 (IH, m, H-l'), 4.40 (IH, s, N-H), 4.27 (IH, d, J=2.8, H-4), 3.37 (IH, dd, J=5.3, 2.8, H-3) and 1.37 ppm (3H, d, J=6.5, CH3); in ir (CHC1 ) V : 3390 (N-H), 1765 and 1745 (shoulder) (C=O, and 1525 lu 3 max cm 1 (NO^)b) A cold (0eC) HMPT-H2O (90 ml - 19 ml) solution of Isomer C” of 1-(t-butyldimethylsilyl)-3-(l'-paranitrobenzyl oxycarbonyloxy-l’-ethyl)-4-tritylthio-2-azetidinone (9.11 g, 13.3 mmol) was treated with sodium azide (1.82 g, 27.9 mmol). The cold bath was removed and the mixture was stirred for 30 min. It was then poured into water (1 £) and extracted with ether (5 x 200 ml).

The ether fractions were combined and washed with water (5 x 200 ml), brine and dried over MgSO . Alternatively since the title compound precipitated out on water dilution, it was filtered off and recrystallized from ether; 7.22 g,. 89%, mp 78-80°C.

Isomer B Isomer B of 3-(l'-paranitrobenzylOXycarbonyloxy1'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the Isomer C; 92%; mp 155.5-6°C (ether); ’Hmr (CDClj) 0: 8.25-6.80 (19K, ra, aromatics), 5.20 (2H, s, benzyl), 4.95 (IH, m, H-l'), 4.3S (IH, d, J=2.9, H-4), 4.17 (IH, s, N-H), 3.20 (IH, dd, J=10.8, J=2.9, H-3) and 1.40 ppm (3H, d, J=7.5, CH3) .· ir (CHC1,) V ; 3480, 3390 (N-H), 1772, 1750 (C=O). and 1525 can1 3 max (NO ) . Anal, calcd for C,,H Ν O S: C 67.59, H 4.96, N 4.93, ——— j2 20 2 o Isomer A' Isomer A of 3-(1'-paranitrobenzyl oxycarbonyloxy1’-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the Isomer Cn; mp 205-6’C. *Ηιητ (CDC13> δ: 8.2-6.7 (19H, m, aromatics), 5.22 (2H, ABq, benzyl), 5.57-4.85 (IH, m, H-l1), 4.65 (IH, N-H), 4.50 (IH, d, J=6.5, H-4), 3.65 (IH, dd, J=6.5, 12, J =1, H-3) and 1.52 ppm (3H, d, J=7.5).

N~n Isomer P Isomer D of 3-(l'-paranitrobenzyloxycarbonyloxy10 1'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for Isomer C”; 1Hmr (CPC13) δ: 8.15-6.70 (19H, m, aromatics), .23 (2H, ABq, benzyl), 5.20 (IH, m, H-l*), 4.75 (IH, NH), 4.52 (IH, d, J=5.5, H-4), 3.42 (IH, J=5.5, 3, H-3 and 1.5 ppm (3H, d, J=6.5, CH3). (J value for H-3 taken after DjO· exchange).

U. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l·'- ethanesulfonyloxy-1'-ethyl)-4tritylthio-2-azetidinone (isomer B) MsO A solution of (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethyΙΣΟ silyl)-3- (1'-me thane sul fony loxy-1 '-ethyl) -4-trithylthio-2-azetidinone. (Isomer B) (4.95 g, 8.5 mmol) and sodium azide (1.11 g, 17.0 mmol) in 10% HjO-HMPA (50 ml) was stirred at room temperature for 30 min. Then the solution was diluted with water (250 ml) and extracted with ether. The organic extracts were washed with brine, dried (MgSO^) and evaporated. Crystallization of the residue (ether-petether) gave the title compound (3.33 g, 83.8%). mp 130-31’C. ’Hmr (CDC13) δ: 7.20-7.62 (15H, m, aromatics), 4.97 (IH, dq, J=6.4, 6.1, H-l'), 4.56 (IH, d, J»2.8, H-4), 4.22 (IH, m, N-H), 3.27 (IH, dd, J=6.1, 2.8, H-3), 3.0 (3H, s, -CH3), 1.63 (3H, d, J=6.4, H-2'); ir (nujol) V : 3195 (n-H), 1768 cm”1 (C=O). max «9070 V. Preparation of (l’S,3S,4R and 1 *R,3R,4S) 3-(1'-Methanesulfonyloxy-1'-ethyl)-4-tritylthio2-azetidinone. (Isomer C) A solution of (l’S,3S,4R and l'R,3R,4S)1-(t-butyldimethylsilyl)-3- (1' -methanesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer C) (2.85 g; 4.9 mmol) in 10% aqueous HMPA (25 ml) was treated with sodium azide (0.65 g, 10 mmol) and stirred at 25°C for 0.5 h. By diluting the solution with water (250 ml), the reaction product was ΊΟ forced to crystallize out. The crude mesylate was redissolved in dichloromethane, washed with brine, dried (MgSO^) and evaporated.

Trituration in ether gave the title compound as white crystals mp 155-60’C; 1.80 g; 78.6%; JHmr (CDC13) δ; 7.43 (15H, ra, aromatic), 5.02 (IH, dq, J=6.9, 4.9, H-l'), 4.55 (IH, s, N-H), 4.95 (IH, d, J=3, H-4), 3.33 (IH, dd, J=4.9, 3, H-3), 1.51 (3H, d, J=6.9, H-2'); ir V : 3395 (N-H), 1768 cm1 (C=O); max Anal, calcd for C,cH Ν0„S. C 64.22, H 5.39, N 3.00; found: C 63.93, H 5.39, - 25 25 4 N 3.24%.

W. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(1'-p-Bromobenzenesulfonyloxy-1'-ethyl)4-tritylthio-2-azetidinone (Isomer C) OSO^Br / οεο,φΒΓ H A solution of (l'S,3S,4R and l'R,3R,4S) 3-(l'-p-bromobenzenesulfoxyloxy-1' -ethyl)-1- (t-butyldimethylsilyl)-4-tritylthio-2— — Λ ή ««m 9 o a ♦ A Q . τ -g^agaai mmol) in 10» H^O-HMPA (40 ml) was stirred at room temperature for 1 h. Then the solution was diluted with HjO (100 ml) and extracted with ether. The ether extracts were washed with brine, dried (MgSO^) and evaporated. The crude crystalline title compound was triturated in a small volume of ether and collected by filtration (0.92 g, 77») mp 125-26’C. 1Hmr (CDC13> 5: 7.80 (4H, s, benzenesulfonyl), 7.30-7.65 (15H, m, aromatics), 5.13 (IH, dq, J=6.5, 4.0, H-l'), 4.50 (IH, d, J=2.9, H-4), 4.40 (IH, s, N-H), 3.40 (IH, dd, J=4.0, 2.9, H-3), 1.50 (3H, d, J=6.5, H-2');ir (CHC1,) V : 3400 cm”1 (N-H), 1770 cm 1 3 ITtcLX (C=0).

X. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(1’-Hydroxy-1’-ethyl)-4-tritylthio-2azetidinone (Isomer B) To a warm solution of (l’S,3S,4R and l’R,3R,4S) 3-(l'-pbromobenzenesulfonyloxy-1*-ethyl)-1-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) in HMPA (5 ml) was added dropwise ljnl of H2O. The reaction mixture was kept at 90’C for 20 h, then diluted with ether and washed 4 times with brine. The organic solution was dried (MgSO^), evaporated and the crude title compound purified by column chromatography (silica gel, 15» CHjCN-CHjCl^).

A white solid was obtained (122 mg, 44.5%) mp 187-189’C which was found to be identical to a sample of the title compound prepared by another method. - 76 :sbs » w V, o Y. Preparation of 3-(1'-Hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone Both isomers, (l'S,3S,4R and l'R,3R,4S) 3-(1'-hydroxy5 1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) and (l'R,3S,4R and l'S,3R,4S) 3-(1*-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) were prepared by the same method. For exanple, a solution of (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldimethylsilyl)-3(l'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (1.0 g, Ιθ 2 mmol) and sodium benzoate (0.865 g, 6 mmol) in 10% HjO - DMF (40 ml) was stirred at room temperature for 18 h. Then the reaction mixture was diluted with H20 and extracted with ether. The organic extracts were washed with brine, dried (MgSO^) and evaporated. The crude title compound was crystallized from cold ether (0.47 g, 61%) mp 134-35’C. ’Hmr (CDCl^ δ: 7.12-7.56 (15H, m, aromatics), 4.48 (IH, s, N-H), 4.28 (IH, d, J=2.8, H-4), 2.94 (IH, dq, J=6.5, 6.2, H-l'), 3.06 (IH, dd, J=6.2, 2.8, H-3), 2.18 (IH, s, -OH), 1.30 (3H, d, J=6.5, H-2');ir (CHC1) V : 3400 (n-H), 1760 cm”1 (C=O). max Similarly C1'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethylsilyl)-320 (l'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) mp 190-92’C. *Hmr (CDCl^ δ: 7.10-7.55 (15H, m, aromatics), 4.45 (IH, d, «7=2.5, H-4), 4.28 (IH, s, NH), 4.10 (IH, dq, J=6.4, .3, H-l'), 3.08 (IH, dd, J=5.3, 2.5, H-3), 1.50 (IH, s, -OH), 1.30 (3H, d, J=6.4, H-2');ir (CHC1 ) U : 3400 (N-H), 1760 cm”1 3 max (C=O) - 77 Z. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(l'-MethoxymethylQxy-1 ‘-sthyl )-1-(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinones (Isomer A) A mixture of Isomer A of 3-(1*-methoxymethyloxy-1 '-ethyl )-4tritylthio-2-azetidiiione (7.5 g, 17.3 mmol), paranitrobenzyl glyoxylate hydrate (4.7 g, 20.8 mmol) and toluene (300 ml) was heated under reflux 0 for 1 h in a Dean and Stark apparatus filled with 3A molecular sieves.

The solution was cooled in ice and triethylamine (0.24 ml, 1.7 mmol) was added dropwise. The mixture was stirred for 1 h, washed with diluted hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound as a foam (10.5 g, 94%). ’Hmr (CDC13) δ: 8.25-6.84 (19H, m, aromatics), 5.24 (2H, s, benzyls), 4.674.83 (3H, m, O-CH2 and H-4), 4.34-4.55 (IH, ra, H-2), 4.02 (IH, m, H-l'), 3.54 (IH, m, H-3), 3.40 (3H, s, O-CH^, 1.38 (3H, d, J=6.5, CH3); ir (KBr) V : 3360 (OH), 1770 (C=O of β-lactam), 1735 (OO of ester) and 1605 cm 3 max (aromatics).

AA.

Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(1'-M ethoxymethoxy-1'-ethyl)-1- (T-paranitrObenzyloxycarbonyl-l '-hydroxy-methyl )-4-tritylthio-2-azetidinone (Isomer C) CHO co2pnb -» A solution of hydrated paranitrobenzyl glyoxylate (1.73 9, 7.11 mmol) was refluxed in toluene (90 ml) using a Dean Stark condenser filled with 3A molecular sieves for a 2 h period. To the boiling solution was added (1*S,3S,4R and l‘R,3R,4S) 3-(1'-methoxymethyloxy-11- ethyl)-4-tritylthio-2-azeticli.none (3.0 g, 6.93 mmol) and the mixture was refluxed for 2 h more. The mixture was cooled to room temperature, triethyl amine (70 mg, 97 JJl, 0.69 mmol) was added and it was stirred for 2 h. The reaction mixture was diluted with ether, washed with 1% aqueous HCI, water, 1% aqueous NaHCOg, water and brine, dried (MgSO^) and concentrated to give the title compound (4.60 g, 100%); ir (CHCl^) V :3530-3100 (O-H), 1765, 1750 (C=O) and 1525 cm'1 (NO ); ’Hmr (CDC1,) max 2 3 δ: 8.22, 8.18 (2H, 2d, J=8, Hm aromatics), 7.67-7.0 (17H, m, H-aromatics), .3 (2H, bs, CH2-PNB), 5.30-5.02 (m, H-2), 4.89-4.52 (m, H-l' and O-H), 4.63, 4.59 (IH, 2d, J=2, H-4), 4.33, 4.30 (2H, 2 center of 2 ABq, J=7, J=7, O-CH2-O), 4.1-3.67 (IH, m, H-l'), 3.2 (IH, H-3), 3.1, 3.6 (3H, 2s, CH^-O), and 1.15 ppm (3H, d, J=6.5, CH^) .

BB. Preparation of (l'R,3S,4R and 1S,3R,4S) 3- (1 ’-^cetoxy-1 · -ethyl) -1 - (parani trobenzyl oxycarbonyl -11-hydroxy-methyl)4-tritylthio-2-azetidinone OAc STr Isomer B A solution of hydrated p-nitrobenzyl glyoxylate (triturated with ether) (1.82 g, 30 mol) was refluxed in benzene through a Dean Stark condenser filled with 3A molecular sieves for 2 h. To that was added azetidinone (1*R,3S,4R and l'S,3R,4S) 3-(1'-acetoxy-l1-ethyl)-4-tritylthio-2-azetidinone (10.88 g, 25.2 mmol) and the mixture was refluxed for 1 h more. The solution was cooled at room temperature and triethyl amine (0.35 ml, 2.5 mmol) was added .

It was then stirred for- 2 h; the reaction progression being followed by tic. Solvent evaporation afforded a white foam in quantitative yield (100%, mixture of epimers) ’Alternatively the solution can be acid and base washed. ir (CH^Clj) vmax: 3520 (OH), 1775. 1745 cm'1 (C=O); 2 Hmr (CQC1 ) <5= 8.2, 8.18 (2H. 2d, J=8, Ho aromatic). 7.80-6.90 (1?H. m, H-aroma t i c), 5.28, 5.17 (2H, 24, CH^PNB, 4.89 (0.67H, o, J=7.2, CHO), 4.80 (center of m, H-l'), 4.38 (0.33 H, 2d, J=8.8, CHO). 4.22 (D.33H, d, J43=2.S, H-4), 4.09 (0.67H, d, $4_3« 2.1, H-4), 3.65 (D.67H, dd, J, ,,=5.8, J, ,=2.1, H-3), 3.47 (O.33H, 3-1 3-4 dd, J, ,,=5.5 J, =2.5, H-3), 3.33 (0.33H, d, 3=8.8. OH), 3.23 (0.67H, 3-1 3-4 d, J=7.5, OH), 1.38, 1.36 (3H, 2s, CH^D) , 1.10, 1.06 (3H, 2d. J=5.8, 6.3, CH3) .

CC. Preparation of 3-(1'-Paranitrobenzyloxycarbonyloxy-l'-ethyl )-1-(paranitrobenzyloxycarbonvl11-hydroxy-methyl)-4-tritylthio-2-azetidi none (4 isomers).

OCOjPNB sc4>_ Isomer C A mixture of Isomer C“ of 3-(1'-paranitrobenzyloxycarbonyloxy-Γ-ethyl)-4-tritylthio-2-azetidinone (1.70 g, 0.3 mmol), paranitrobenzyl glyoxylate hydrate (815 mg, 3.6 mmol) and toluene (50 ml) was heated under reflux 7 days in a Dean and Stark apparatus filled with 3A molecular sieves. The cooled solution was washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound (2.1 g) as an epimeric mixture at carbon-2. Purification was effected by chromatography over silica gel. Alternatively the title compound could be prepared by using a catalytic amount of triethyl amine. Less polar epimer at 2: ’Hmr (CDC13) 5: 8.25-6.80 (23H, m, aromatics), 5.30 and 3.12 (4H, 2s, benzyls), 4.65 (IH, d, J=9, H-2), 4.45 (IH, d, J=2.5, H-4), 4.45-4.10 (IH, ra, H-l'), 3.50 (IH, d, J=9, 2-0H), 3.28 (IH, dd, J=2.5, J=2.5, H-3) and 1.23 ppm (3H, d, J=6.5, CH,); ir (CHCl,) V : 3530 to 3200 (D-H), 1765, 1750 (C=O) and 1525 cm-1 3 max (N02). More polar isomer at C-2: 1Hmr (CDC13) 5: 8.25-6.85 (23H, m, aromatics), 5.25 and 5.08 (4H, 2s, benzyls), 5.05 (IH, d, J=7, H-2), 4.35 (IH, d, J=2.5, H-4), 4.40-4.05 (IH, m, H-l’), 3.42 (IH, J=7, 2n-0H), 3.33 (IH, dd, J=2.5, 2.5, H-3), 1.23 (3H, d, ,1=6.5., CH^; ir (CHC13) y' : 3520 to 3200 (O-H), 1755 (C=O) and 1525 cm1 (NO,). max 2 Isomer B A mixture of hydrated paranitrobenzylglyoxylate (1.74 g, 7.66 mmol) and (1*R,3S,4R and l'S,3R,4S) 3-(l*-paranitrobenzyldxyearbonyloxy —1’-ethyl)-4-tritylthio-2-azetidinone (3.63 g, 6.38 mmol) was refluxed in toluene (70 ml) on a Dean Stark condenser filled with o 3A molecular sieves for 3h. The solution was cooled down to room temperature and triethyl amine (64.5 mg, 89 ml, 0.639 mmol) was added. It was then stirred for 4 h, diluted with ether and washed with 2% aqueous HCl, water, 2% aqueous NaHCOy water and brine. It was dried and concentrated to give pure title compound (5.02 g, 100%). Separation of the 2 epimers was effected on preparative silica gel plate. Less polar epimer at 2: ir (CHClj) vmax: 3500 (O-H), 1772, 1750 (C=O) 1525cm-1 (N02); ’Hmr (CDC13) 6:8.30-8.0 and 7.65-6.80, (23H, m, aromatics), 5.27 and 5.13 (4H, 2s, benzyls), 4.71 (IH, m, -5 j=6.5, 6.5, H-l’), 4.28 (IH, d, J=2.2, H-4), 4.23 (IH, d, J=8.7, H-2), 3.50 (IH, dd, J=2.2, 6.5, H-3), 3.28 (IH, d, J=8.7, O-H) and 1.18 ppm (3H, d, J=6.5, CH ). More polar epimer: ir (CHCl ) V 3480 (0-K) — J ΠιοίΧ · 1772, 1750 (C=O) and 1525 cm_1(NO2); lHmr (CDC13) δ: 8.35-6.90 (23H, m, aromatics), 5.15 (4H, benzyls), 4.72 (IH, d, J=7.5, H-20), 4.90- 81 i 4.SO (IH, m, 3=6.5, 6.5, H-l’), 4.10 (IH, d, 3=2, H-4). 3.68 (IH, dd, J=2, 6.5, H-3), 3.28 (IH, d, J=6.5, 0-H) and 1.15 ppm (3H, d, 3=6.5, ch3).

Isomer A” The Isomer A of 3-(l'-paranitrobenzy loxycarbony loxyl'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of Isomer A of 3-(l'-paranitrobenzy)Oxycarbonyloxy-l'-ethyl)-l-(l'paranitrobenzyloxycarbonyl-1'-hydroxymethyl)-4-tritylthio-2-azetidi nones. ’Hmr (CDC13) δ: 8.3-6.7 (23H, m, aromatics), 5.17 (2H, benzyls), .0 (IH, m, H-l'), 4.9 and 4.8 (IH, 2d, J=6, H-4, two epimers), 4.32 and 3.96 (IH, 2s, H-2, two epimers), 3.68 (IH, dd, 3=6, 6, H-3( and 1.47 ppm (3H, 2d, J=6.5, CHy two epimers).

Isomer D The Isomer D of 3-(1'-paranitrobenzyloxycarbonyl oxy15 1' -ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of Isomer D of 3- (1' -paranitrobenzyl°kycarbonyloxy-l -ethyl )-1-(1 parani trobenzyloxycarbonyl-11-hydroxymethyl)-4-tri tylthi o-2-azeti di nones. ’Hmr (CDC13) δ: 8.30-6.60 (23H, m, aromatics), 5.20 (4H, m, benzyls), 4.83 (IH, 2d, 3=5, H=4), 5.50-4.30 (2H, m, H-l' and H-2)., 3.48 20 (IH, m, H-3), 3.15 (IH, m, 0-H), 1.37 and 1.30 ppm (3H, 2d, CH}).

DD. Preparation of (l'S,3S,4R and l'R,3R,4S)3-(1'-Methanesulfonyloxy-1'-ethyl)->(1 'paranitrobenzyloxycarbonyl-1'-hydroxy-methyl)-4-tritylthio-2-azetidinone (Isomer C) (epimers at C21').

A solution of paranitrobenzylglyoxylate hydrate (9.72 g; 42.6 mmol) in benzene (350 ml) was refluxed for 2 h, removing the water azeotropically in a Dean-Stark trap. To that solution was added the » Μ Ο β (11S, 3S,4R and 1' R, 3R, 4S) 3- (1 ’-methanedulfonyloxy-1’-ethyl)-4-tri ty1thio2-azetidinone (16.62 g, 35.5 mmol) and the reflux maintained for an additional 0.5 h. Then the reaction mixture was cooled to room temperature, treated with triethylamine (0.5 ml; 3.5 mmol) and stirred for 3 h in order to complete the reaction. Evaporation of the solvent left a white foam which was used as such in the next step. 1Hmr (CDCl^) δ: 8.12 (2H, d, J=9, Hm aromatic), 7.28 (17H, part of d,Ho aromatic, trityl), 5.28 (2H, s, -CH2~ PNB), 4.88 (0.5 H, s, H-l), 4.62 (1.5H, m, H-2 and H-4), 4.00 (2H, m, H-l’, -OH), 3.15 (IH, m, H-3), 2.73 (3H, s, mesylate and 1.30 ppm (3H, d, Js6 Hz, H-2·); ir V :3520 (O-H), 1775 (C=O) and 1765 cm 1 (C=O). max p.p, Preparation of (1'S,3R,4R and i'R,3s,4S) 3-(i-Methoxymethyloxy-T-ethyl)-1 -(T-paranitrobenzyl oxycarbonyl-l'-chloromethyl)-4-tritylthio-2-azetidinone (Isomer A) Pyridine (1.1 ml, 14.2 mmol) was added dropwise to a solution of Isomer A of 3- (1'-methoxymethyl0\y-l'-ethyl )-1-(T - parani trobenzy 1 oxycarbonyl -1' -hydroxy ethyl) -4-tri tyl thio-2-azeti di none (7 g, 10.9 mmol) in THF (350 ml) cooled to -15“C. Immediately after thionyl chloride (1.0 ml, 14.0 mmol) was added dropwise and the mixture was stirred at -15’ for 0.5.h. The precipitate was removed by filtration and washed with benzene. The combined filtrates vers cone entrated, the residue dissolved in fresh benzene and the solution treated with activated charcoal, filtered and concentrated to leave to title compound as an oil (6.5 g, 90%), 1Hmr (CDCl^) δ: 6.65-B.35 (19H, m, aromatics), 5.24 (2H, s, benzyl), 3.43 (3H, s, ΟΟψ 'ani 1.42 ppm (3H, d, J=6, CH^).

FF. Preparation of (l'S,3S,4R and l'R,3R,4S) 3—(1*— ethoxymethyloxy-1'-ethyl)-1-( 1 ' paranitrobenzyloxycarbonyl-1'-chloromethyl)-4-tritylthio-2-azetidi none (Isomer C) co2pnb co2pnb A cold (ice-MeOH bath) THF (60 ml, distilled over LAH) solution of (l'S,3S,4R and l'R,3R,4S) 3~(l'-methoxymethyloxy-l'-ethyl) _1(1'-paranitrobenzyloxycarbonyl-T -hydroxymethyl)-4-tritylthio-2-azetidinone (4.25 g, 6.62 mmol) was treated dropwise with pyridine (0.696 ml, 8.61 mmol) and thionyl chloride (0.530 ml, 8.61 mmol). The mixture was stirred for 30 min at -15’C. The precipitate was collected by filtration and washed with benzene. The THF-benzene solution was concentrated and the residue was dissolved again in benzene. The resulting solution was treated with charcoal. Ranoval of charcoal on a Celite pad and subsequent benzene evaporation afforded the title compound 5 (4.86 g, 100%); ir (CHC13) Vmay: 1770 (C=O) and 1525 cm1 (NO2); 3 Hmr (CDClj) δ: 8.15, 8.12 (2H, 2d, H-aromatics), 7.70-7.00 (17H, m, H-aromatics), 5.62, 5.02 (IH, 2s, H-2), 5.27 (2H, s, CH^PNB) , 4.7 (IH, d, H-4), 4.7-3.7 (m, O-CH2-O, H-l'), 3.5-2.8 (m, H-3), 3.12, 3.08 (3H, 2s, Ο-CHj), and 1.30-0.96 ppm (3H, m, CHj). _ Q/l _ GG. Preparation of (l'R, 3S,4R and l'S,3R,4S) 3-(l'-Acetoxy-l’-ethyl)-l-(paranitrobenzyloxycarbonyl-1‘-chloromethyl)-4-tritylthio-2-azetidinone Isomer B A THF (distilled over LAH) solution of (l'R,3S,4R and l'S, 3R, 4S) 3- (1' -acetoxy-l' -ethyl) -1-(1'-paranitrobenzyl oxycarbonyl -1' -hydroxymethyl )4-tritylthio-2-azetidinone (from 10.88 g of N-H) was treated at -15°C (ice-methanol bath) under nitrogen atmosphere with pyridine (2.19 g, 2.24 ml, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol. The mixture was stirred for 20 min at -15°. The salt was filtered off and washed with benzene. Solvent (THF + benzene) evaporation afforded a residue which was taken up in benzene (warm) and treated with charcoal. The suspension was filtered through a celite pad and solvent evaporation left a foam; ir (CH.Cl ) V : 1780, 1740 cm1 (C=O) ’Hmr (CDC1 δ: 2 DlfilX 3 8.17, 8.21 (2H, 2d, J=8, Ho aromatic) 7.76-6.88 (17H, m, H-aromatic), .31, 5116, 5.12, 4.73 (3H, 4s, CH2~PNB, CHC1), 5.12-4.55 (IH, m, H-l'), 4.35-4.25 (IH, m, H-4), 3.80-3.45 (IH, m, H-3) 1.90 (3H, s, CH^O) , 1.12 1.07 (3H, J=6.5, CH3). - 85 HH. 3-(1'-Paranitrobenzyloxycarbonyloxy-1‘-ethyl )-1-(11-paranitrobenzyl oxycarbony1-V-chloroniethyl)-4-tritylthio-2-azetidiones (mixture of epimers at C2) Isomer C Pyridine (58 mg, 0.73 mmol) was added dropwise to a solution of Isomer C of 3-(l'-paranitrobenzy!oxycarbonyloxy-l '-ethyl )-1(T-paranitrobenzyl oxycarbonyl-1 *-chloromethyl)-3-tritylthio-2-azetidinones (470 mg, 0.6 mmol; mixture of epimers at C-2) in THF (15 ml) cooled to -15C. Immediately after thionyl chloride (86.5 mg, 0.73 mmol) was added dropwise and the mixture was stirred at -15°C for 0.5 h.

The precipitate was removed by filtration and washed with benzene.

The combined filtrates were concentrated, the residue dissolved in fresh benzene and the solution treated with activated charcoal, filtered and concentrated to leave the title compound as an oil. 530 mg; 100%.

’Hmr (CDC13) 6; 8.7-6.8 (23H, m. aromatic), 5.53 (IH, s, H-2), 5.30 and 5.17 (4H, 2s, benzyls), 4.52 (IH, d, J=2, H-4), 4.20-3.70 (IH, m, H-l'), 3.31 (IH, dd, H-3), 1.27 and 1.21 ppm (3H, 2d, J=6.5); ir (CHC13) V : 1780, 1750 (C=0) and 1525 cm1 (NO_). max 2 Isomer B Isomer B of 3- (1-paranitrobenzyloxycarbonyloxy-l '-ethyl )-1(1'-paranitrobenzyloxycarbonyl -11-chioromethyl>4-tritylthio-2-azetidi nones (mixture of C-2 epimers) was prepared as described above for the Isomer C in quantitative yield. ’Hmr (CDC13) 6: 8.25-6.90 (23H, m, aromatics), 5.40—5.0 (4H, m, benzyls), 5.40—4.45 (IH, m. Η—1'), 4.82 and 4.57 (IH, 2s, H-2), 4.36 and 4.31 (IH, 2d, J=2.5, H-4), 3.63 (IH, m, J=2.5, J=6.5, H-3), 1.25 and 1.18 ppm (3H, 2d, J=6.5, CH3); ir (CHC1 ) : 1780, 1750 (C=0) , and 1525 cm1 (NO ). max * naaEsaaiEMr τ.

Isomer A Isomer A of 3-(1'-paranitrobenzyloxycarbonyloxy-1'-ethyl)-1'(1'-paranitrobenzyloxycarbonyl-l'-chloromethyl-4-tri tylthio-2-azeti di nones ('mixture of C-2 epimers). ‘Hmr (CDC13) δ: 8.30-6.80 (23H, m, aromatics), .45-4.80 (IH, m, H-l'), 5.18 and 5.21 (4H, 2s, benzyls), 4.87 (IH, 2d, H-4), 4.22 and 3.87 (IH, 2s, H-2), 4.05-3.40 (IH, m, H-3), 1.57 and 1.50 ppm (3H, 2d, CH^ .

Isomer D Isomer D of 3-(l-parani trobenzy Joxycarbonyl oxy-Γ-ethyl-1'(11-paranitrobenzyloxycarbonyl-1'-chloromethyl)-4-tritylthio-2-azetidi nones (mixture of C-2 epimers). ’Hmr (CDC13) δ: 8.30-6.70 (23H, m, aromatics), .32-5.10 (4H, m, benzyls), 5.48 and 5.30 (IH, 2s, H-2), 4.82 (IH, d, J=5, H-4), 5.30-5.20 (IH, m, H-l'), 3.15 (IH, m, H-3), 1.40 and 1.30 ppm (3H, 2d, J=6.5, CH,); ir CHC1,) V : 1780, 1750 (C=O) and 1525 cm 1 3 3 ΠιβΛ (NO2) II. Preparation of (l'S.3S,4R and l'R,3R.4S)3-(1'-Methanesulfonyloxy-1'-ethyl)-1-(paranitrobenzyloxycarbonyl-1'-chloromethyl)-4-tritylthio-2-azetidinone (Isomer C) (epimers at C2).

To a cold solution (5’C) of (l'S,3S,4R and 1'R,3R,4S)3-< {1* — methanssulforsyloxy— 1 * —ethyl) — 1— (paranitrobenzyl oxycarbonyl-1 —hydroxymethyl) -4-tritylthio-2-azetidinone (24.0 g, 35.5 nmol) in dry tetrahydrofuran (350 ml) was added pyridine (3.65 g, 46.2 mmol) and thionyl chloride 25 (5.5 g, 46.2 mmol) dropwise. After stirring for 45 min, ether (100 ml) was added to precipitate the hydrochloride salt which was filtered off.

The filtrate was evaporated and the residue redissolved in benzene (200 ml) and treated with charcoal. Evaporation of the solvent left a nearly white foam which was used as such in the next step. >Hmr (CDCip 6: 8.18 (2H, d, J=9, Hm aromatic), 7.72 (17H, m, part ofd,Ho aromatic, trityl), 5.57 and 5.12 (IH, s, H-2), 5.28 (2H, s, -CH^NB) , 4.73 (IH, 2d, H-4), 3.21 (IH, 2dq, H-3), 2.78 (3H, 2s. mesylate and 1.21 ppm (3H, 2d, H-6H2; H-2’); ir 1779 cm-1 (C=O) JJ. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(11 -Methoxymethoxy-1'-ethyl)-1-(T-paranltro1q benzyloxycarbonyl-!'-triphenylphosphoranylmethyl)-4-tritylthio-2-azetidinone (Isomer A) A mixture of Isomer A of 3-(1'-methoxymethoxy-1'-ethyl)-1(Γ-paranitrobenzyloxycarbonyl-l'-chloromethyl)-4-tritylthio-2-azetidinone (6.6 g, 10 mmol), triphenylphosphine (3.3 g, 12.5 mmol), 2,6-lutidine (1.3 mi; 11 mmol) and dioxane (140 ml) was heated under reflux for 2 days. The solution was diluted with ether, washed with dilute acid (5% HCl), water, dilute sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 10% ether in benzene. Concentration of the pertinent fractions left the title compound as a foam (1.4 g, 13.7%) ir (KBr) V : 1750 (C=O) and 1660-1650 cm 1 (C=C, aromatics). max - 88 KK. Preparation of (1 * S, 3S, 4R and l'R,3R,4S) 3-(l'-Methoxymethyloxy-l'-ethyl)-l-(l'-paranitrobenzy1oxycarbony1-11-tri phenylphosphoranylmethy1)-fl-tri tylthi o-2-azetidi none (Isomer C). oo^ootj ρφ3 -> A dioxane (100 ml, distilled over LAH) solution of (l'S, 3S,4R and J'R ’R.4S) 3-(1*-methoxyraethyloxy-1’-ethyl)-1-( Γ-parani trobenzyloxycarbonyl-1'-chloromethyl-4-tritylthio-2-azetidinone (4.86 g, 6.62 mmol), triphenylphosphine (2.60 g, 9.93 mmol) and 2,6-lutidine (770 mg, 0.837 ml, 10 7.20 mmol) was heated under reflux for 4 h and kept in a hot bath (100C) for 16 h. The mixture was diluted with ether, washed with 1% aqueous HCl, water, 10% aqueous NaHCOg water and brine and dried (MgSC>4) . The solution was concentrated and the residue filtered through a silica gel (65 g) column (5%, 10% and 20% ether-benzene) to give the title compound (2.8 g, 48%). ir (CHClj) 1795 (C=O), 1620 and 1605 (phosphorane) and 1515 cm 1 (NOj)· LL. (l'R,3S,4R and l's,3R,4S) 3-(l'-ACetoxy-l'-ethyl)-l- (.1 '-paranitrobenzyloxycarbonyl-T-triphenylphosphoranylmethyl)-4-tritylthio-2-azetidinone (Isomer B) A dioxane (100 ml, freshly distilled over LAH) solution of crude (1’R.3S.4R) and TS.3R.4S) 3-(l'-acetoxv-l‘-ethvl)-1-(1'-Daranitrorefluxed (oil bath 130’, the residue was redissolved solution was successively aqueous NaHCO_,H,O and brine. with 2,6-lutidine (2.97 g, 3.23 ml, 27.72 mmol) and triphenyl phosphine (9.91 g, 37.8 mmol). The mixture was 18 h. The solvent was evaporated and in methylene chloride. The resulting 5 washed with diluted HCI, H^O, diluted Drying and solvent evaporation left the title compound as.a solid which was triturated with ether and collected by filtration (14.6 g, 65.9%); ir (CH„C1,) υ : 1750 (C=O) and 1620, 1610 cm 1 (phosphorane). 2 max MM. 3-(1'-Paranitrobenzyloxycarbonyloxy-1'-ethyl )-1-(1'-paranitrobenzyloxy1Q carbonyl-1'-tri phenylphosphoranylmethyl)-4-tritylthio-2-azetidinone.

OCO.PNB ISOMER B A mixture of (l'R,3S,4R and 1*S,3R,4S) 3-(1'-paranitrobenzyloxycarbonyloxy-1'-ethyl)-1-(1 *-paranitrobenzyloxycarbonyl-1'-chloromethyl) -4-tritylthioazetidinone (isomer B) (4.96 g, 6.22 mmol, mixture of epimers at C-2), triphenyl phosphine (2.47 g, 9.42 mmol) and 2,6lutidine (740 mg, 0.80 ml, 6.91 mmol) was refluxed in dioxane (freshly distilled over LAH) for 30 h. The solution was diluted with ether and ethyl acetate, washed with 5% aqueous HCI, water, 10% aqueous NaHCOg, water and brine and dried (MgSO4>. Solvent evaporation afforded a - 90 10 residue which was passed through a silica gel (10 times its weight) column (10% ether-benzene, ether, and ethyl acetate). The title compound was obtained as a crystalline solid (3.1 g, 49%), mp 189-I9O0 (ether); ir (CHC1 ) V : 1750 (C=O), 1620, 1605 (phosphorane) and 1522 cm 3 max (N02).

ISOMER C Isomer C of 3-(1'-paranitrobenzyloxycarbonyloxy-l'-ethyl )-1(1'-paranitrobenzyloxycarbonyl-l'-triphenylphosphoranylmethyl )-4-tritylthio2-azetidinone was prepared as described above for isomer B. if (CHCl^) V : 1750 (C=O), 1610, 1620 (phosphorane) and 1520 cm 1 (NO )lHmr max 2 (CDCl^) 6: 8.6=6.7 (H, aromatics), 5.22 and 4.95 (benzyls), 4.70 (H-4), 2.6 (H-3), 1.19 and 1.07 ppm (Οψ.

ISOMER D A mixture of Isomer D of 3-(1'-p-nitrobenzyloxycarbonyloxy-V-ethyl)15 1-(1 '-p-nitrobenzyloxycarbonyl-l '-chloromethyl-4-tritylthio-2-azetidinone (4.593 g, 4.45 mmol; purity 77%, mixture of epimers at C-2”), triphenylphosphine (1.425 g, 5.44 mmol; Aldrich) and 2,6-lutidine (0.63 ml, 580 mg, 5.40 mmol; Anachemia) in dioxane (65 ml; distilled from LAH) was heated at gentle reflux under N2 for 41 h, monitoring the reaction by tic (benzene:ether=3:1) · The dark reaction mixture was cooled, diluted with EtOAc and washed successively with 0.1 NHC1, water, 2% NaHCO^ and then brine. Drying (Na2SO4) and evaporation of the solvents gave 4.18 g of a dark coloured oil which was purified by column chromatography (SiOj, 88 g; eluent 10-25% ether in benzene), yielding 1.108 g (1.08 mmole, yield 24.3%) of the title compound as a yellowish foam: *Hmr (CDCl^) 6: 1.08 (d, J=6Hz, l'-CH^); ir (neat) vmax: 1745 cm 1 (s, C=O).

NN. Preparation of (l'S,3S,4R and l'R,3R,4S)3-(1'-Methanesulfonyloxy-1'-ethyl)-1~(i paranitrobenzyloxycarbonyi-l‘-tri phenylphosphoranyimethyl)-4-tritylthio-2azetidinone (isomer C) A solution of (l'S,3S,4R and l'R,3R,4S)3-(l'-methanesulfbnyloxy1'-ethyl )-1-(1'-paranitrobenzyloxycarbonyl-l'-chloromethyl)-4-tritylthio-2azetidinone (24.7 g, 35.5 mmol), triphenylphosphine (11.2 g, 42.7 mmol) and 2.6-lutidine (4.2 g, 39.1 mmol) in dry dioxane (350 ml) was refluxed under nitrogen for 19 h. The solvent was evaporated and the crude product redissolved in ethyl acetate and washed successively with dilgte HCl, NaHCOg and brine. Purification was completed by chromatography on a silica gel column (8.5 x 12 cm). Elution with 10% ether-dichloromethane (1.5 Zl. and then ether (1.5 Z) gave the purified phosphorane; 12.36 g (40%).

’Hmr (QDC13) δ: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir 1749 and 1620 cm'1 (C=O) 00. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(1'-Hvdroxy-1'-ethyl)-1-1' paranitrobenzyioxycarbonyl-1'-tri phenylphosphoranylmethyl)-4-tritylthio -2-azetidinone A solution of phosphorane (l'R,3S,4R and l'S,3R,4S) 3(l'-acetoxy-l'-ethyl)-l-(l'-paranitrobenzyloxycarbonyl-1 'tri nhpnvl nhncnhnranvlmpfhvl )-4-tri tvl thin-?-A7Pt irlinnnp (4 43 n. 5 Π0 mmnl 1 in methanol (10 ml) THF (60 ml) was treated at room temperature with 1% aqueous NaOH (1 eq, 200 mg in 20 ml H20). The reaction progression was followed by tic*. The mixture was diluted with ether-ethyl acetate and washed with HCI, HjO, aqueous NaHCOg, H2O and brine. Solvent evaporation afforded a residue which was crystallized from benzene-ether (3.7 g, 87.7%) mp 169.5-170.5’C. ir (CH_C1_) V : 1745 (C=O) and 1620 cm”1 (phosphorane). 2 max ‘Heating the mixture increased the reaction rate.

PP. Preparation of (l‘S,3R,4R and l'R,3S,4S) Silver 3-(1'-methoxymethyl-1'-ethyl)-1-1'paranitrobenzyloxycarbonyl-1'-tri phenylphosphoranylmethyl)-2-azetidinone4-thiolate (Isomer A) Silver 3- (1'-methoxymethyl-1'-ethyl) -1-(1 '-paranitrobenzyloxy1'-tri phenylphosphoranylmethyl)-3-tritylthio-2-azetidinone (isomer A), was prepared as described elsewhere for the isomer C of the paranitrobenzyldioxy carbonyl derivative. Yield 50%. ir (neat V' : 1745 cm-1 (C=O). max - 93 aseEr SE QQ. Preparation of l'S,3S,4R and l'R,3R,4S) Silver 2-(1*-methoxymethyloxy-1’-ethyl)-1(1'-paranitrobenzyloxycarbonyl-1'-tri phenylphosphoranylmethyl)-2azetidinone-4-thiolate (Isomer C).

AgNO3 OCH2OCH3 CO2PNB (l'S,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-ethyl)-l-(11 paranitrobenzyloxycarbonyl-1'-triphenylphosphoranylmethyl)-4-tritylthio-2azetidinone (887 mg, 1.0 mmol) was first dissolved in hot ( 40°C) methanol (30 ml), treated with pyridine(103 mg, 0.105 ml, 1.3 mmol) and, after cooling, was treated with a 0.15 M methanol solution of silver nitrate (8.7 ml, 1.3 mmol). The mixture was stirred for 1 h at 23’C, cooled (ice bath) and stirred for 20 min. The salt was filtered and washed successively with cold methanol and ether (3 times, 671 mg, 87%). ir (CHC13) vfnax: 1745 (C=O), 1605 (phosphorane) and 1520 cm 1 (NO2).

RR Preparation of Silver 3- (1’-paranitrobenzyioxycarbonyloxy-l '-ethyl )-1-(1 paranitrobenzyloxycarbonyl-11-tri phenylphosphoranylmethyl)-2-azetidinone-4thiolate. -4-tritylthio-2-azetidinone (1.02 g, 1 mmol) was first dissolved in (l’R,3S,4R and l’S,3R,4S) 3-(1'-paranitrobenzyloxycarbonyl oxy-1'-ethyl )-1-(11-paranitrobenzyloxycarbonyl-1'-tri phenylphosphoranylmethyl) CH2C12 (3 ml) and diluted with hot (55eC) MeOH (20 ml). The hot solution was treated first with pyridine (120 ml, 117 mg, 1.48 mmol, and a hot (55°C) 0.15M methanolic solution of silver nitrate (8 ml, 1.2 mmol).

The mixture was stirred at room temperature for 15 min, then at 0’C for 2 h. It was then concentrated to a 10% solution on the rotary evaporator (no bath). The mercaptide was filtered and washed twice with cold (-15°C) methanol and three times with ether. (917 mg, 100%). ir (nujol mull) V : 1745 (C=O), 1600 (phosphorane) and 1517 cm 1 (NO ). max * Isomer C Ιθ Silver 3-(l’-paranitrobenzylOxycarbonyloxy-l '-ethyl )1-(1'-paranitrobenzyloxycarbonyl-1'-triphenylphosphoranylmethyl) -2-azetidinone-4-thiolate, Isomer C, was prepared as described above for the Isomer B”J ir (nujol) V : 1745 (C=O) and ulaX 1600 cm 1 (phosphorane)15 Isomer D A solution of Isomer D of 3-(l'-p-nitrobenzylOxycarbonyloxy -1'-ethyl )-1-(1'-p-nitrobenzyloxycarbonyltriphenylphosphoranylmethyl ) - 4_tritylthio-2-azetidinone (145 mg, 0.142 mmol) was prepared by first dissolving it in CH2C12 (5 ml), removing the CH2C12 at 55°20 60 and adding hot MeOH (4 ml). To the above solution was added a hot solution of AgNO^ in MeOH (0.15 M, 1.14 ml, 0.17 mmol, 1.2 eq), followed by pyridine (14 pi, 0.17 mmol, 1.2 eq). The silver mercaptide started to precipitate immediately. The mixture was stirred 2 h at room temperature and 1 h at 0. The mercaptide was collected by filtration and washed with ice-cold MeOH and ether, yielding 99 (0.11 nunol, 78%) of the title compound as a brownish solid: ir (Nujol) V : 1750 cm-1 (s, C=O). max - 95 ‘“V SS. Preparation of (l'R,3S,4R and l’S,3R,4S) Silver 3-(1'-hydroxy-1'-ethyl)-1-.( Tparan i trobenzyloxycarbonyl-1' -tri phenylphosphoranylmethyl)-2-azeti di none-4-thiolate (Isomer B) OH AgNO c5h5n OH co2pnb A solution* of Π'ρ. 3S,4R and l’S,3R,4S) 3—{l'— hydroxy-1'-ethyl)-1- (1 '-paranitrobenzyloxycarbonyl-l '-tri phenyl phosphoranyl methyl)—4-tritylthio-2-azetidinone (lg, 1.19 mmol) in MeOH (10 ml), was treated with pyridine (124 pi, 121.3 mg, 1.53 mmol) and at 10°C with a O.15M solution of silver nitrate in MeOH (15 ml, 2.25 mmol or until no more precipitation of the silver mercaptide occurred). The mixture was stirred for 1 h and concentrated on the rotary evaporator (no bath) to approximatively 10% concentration. The solvent was filtered off. The cake was washed once with MeOH and 3 times with ether, and pumped under high vacuum (954 mg, 100%). ir (Nujol mull) V : 3500-3400 (O-H), 1752 (C=O) 1595 (phosphorane) and 1525 cm 1 (NO ) max ‘The crystalline material was first dissolved in CH2C12. - 96 10 Example 6 l'R,5R,6S and l'S,?S,6R) 6-(1'-Hydroxyethyl)-2-(2-aminoethoxymethyl)penea-3carboxyllc Acid (isomer B) (l'R,3S.4R andl'S,3R,4S) 4-(2-Azidoethoxy)acetylthio-3-(11-hydroxyethyl )-1-(1'-p-nitrobenzyloxycarbonyl-l'-triphenylphosphoranylmethyl)-2azetidinone (Isomer B) SAg L ρφ Im/THF Me SiCl/Et N J J .

OSiMej Λ SSiMe3 Cl 111 2) COjPNB COjPNB ,/pyr OH A. >s TFA COjPNB To a stirred solution of (l'R)3S,4R and l'S,3R,4S) silver 3- (1' -hydroxyethy 1)-1-( 11 -p-ni trobenzyloxycarbonyl-11 -tri phenylphosphoranylmethyl,-2-azetidinone-4-thiolate (Isomer B) (820 mg, 1.16 mmol) THP (20 ml) was added at -15° (MeOH-ice bath) under N2 atmosphere successively triethylamine (01648 ml, 4.66 imnol, 4.02 eq), chlorotrimethyl silane (0.589 ml, 4.64 mmol, 4.00 eq) and imidazole (81.2 mg, 1.12 mmol). The mixture was stirred at room temperature for 18 h (overnight) and then cooled to -10- -15*. To this was added pyridine (0.220 ml, 2.72 mmol) and then a solution of 2-azidoethoxyacetyl chloride (372 mg, 2.27 mmol, 1.96 eq, in CHjCl^ (20 ml). It was stirred in - 97 at room temperature for 1 h. After filtration of the precipitate, the filtrate, diluted with EtOAc, was washed successively with IN HCI, brine, saturated NaHCO3 and brine, dried (Na^O^) and evaporated yielding 748 mg an oil. This oil dissolved in wet CH2C12 (20 ml with 3 drops of water) was treated with trifluoroacetic acid (2 drops) at room temperature for min. The mixture was washed with saturated NaHCOg and then brine, dried (Na2SO4) and evaporated yielding 695 mg of a crude oil. This oil was purified by column chromatography (Si02 15 g, eluent EtOAc; CH2C32=1:1^ collecting 538 mg (0.739 mmol, yield 63.7%) of the title compound as a yellowish oil: ’Hmr (CDC13) δ: 1.22 (d, J=6Hz, 0^-1'), 5.6 (2d, H-4) and 7.3=8.4 ppm (aromatic Hs); ir (neat) V : 3420 (OH), 2100 (-N ), * max o 1750 (C=O) and 1690 cm1 (thioester); Rf 0.20 (CH2C12: EtOAc =1:1). (l’R,5R,6S and 1*S,5S,6R) p-Nitrobenzyl 6-(1'-hydroxyethyl)-2(2-azidoethoxymethyl)penem-3-carboxylate (Isomer B) A solution of (l'R,3S,4R and l'S,3R,4S) 4-(2-azidoethoxy) acetylthio>-3-(l’-hydroxyethyl)- 1-(T-p-nitrobenzyloxycarbonyl-11 triphenylphosphoranylmethyl)-2-azetidinone, (Isomer B) (490 mg, 0.673 mmol) in toluene (80 ml) was heated at gentle reflux for 3 h. Evaporation of the solvent in vacuo gave an oily residue which was purified by column chromatography (SiO2, 10 g; eluent 5-10% EtOAc in CHjClj) followed by crystallization from CH2Cl2- ether to obtain 202 mg (0.449 mmol, yield 66.8%) of the title compound as light yellow crystals: ’Hmr (COC13) δ: 1-35 (3H, d, J=6.5Hz, CH -1'), 2.18 (IH, br, OH), 3.2-3.9 Qfi 20 (5H, m, -CH2- and H-6), 3.9-4.5 (IH, m, H-l'), 4.45-4.72-4.75-5.02 (2H, AB type, CH2-2,, 5.02-5.25-5.35-5.57 (2H, AB type,-CH2Ax), 5.62 (IH, d, J=lHz, H-5) and 7.42-7.65-8.13-8.28 ppm (4H, aromat^c Hs); ir (nujol) V : 3460 (-OH), 2110 (-N ), 1765 (β-lactam) and 1680 cm 1 CT3X 3 (ester). An analytical sample was obtained by further crystallization: mp 107-8“C (CH,Cl -ether uv (EtOH) λ : 264 (ε 12000) and 323 my 2 2 max (ε 9200); Rf 962 (CH,C1,: EtOAc=l: 1); Anal.calcd for C_QH,QN,0,S: 2 — xy 5 f C 48.10, H 4.26, N 15.88, S 7.13; found: C 47.81, H 4.18, N 15.00, S 7.16 (l‘R,5R,6S abd l'S,5S,6R) 6-1'-hydroxyethyl)-2-(2-azidoethoxymethyl) penem-3-carboxylic acid (Isomer B) X.

CHOCHCHNH 2 2 2 2 CH20CH2CH2N3 co2pnb A solution of (l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl 6-(1'-hydroxyethyl)-2-(2-azidoethoxymethyl) penem-3-carboxylate (Isomer B) (180 mg, 0.400 mmol) in THF (18 ml) was mixed with ether (19 ml), HgO )5 (18 ml) and 10% Pd-C (180 mg). It was hydrogenated (Hg, 55 psi) at room temperature for 2.5 h. After filtering off the catalyst the aqueous filtrate was washed with EtOAc and lyophilized to yield 84.4 mg (0.293 mmol, crude yield 73.2%, of the title compound as a crude yellowish powder: uv (Η,Ο) λ : 305.5 (ε 4800) and 255 mp (ε 3800). This 2 max powder was purified by hplc (Waters C,o Micro Bondapack Reverse Phase 1“ cm x 10 mm; eluent 1% CT^CN in H2O) to give 44.7 mg (0.155 mmol, yield 38.8%) of the title compound as white powder: 'Hmr (DgO) δ: 1.34 (3H, d, J=6.4 Hz, CH3-1·), 3.26 (2H, m, -CHgN), 3.82 (2H, m, -OCHgCHg-) , 3.94 (IH, dd, J, ,,=6.2Hz, J -1.4 Hz, H-6), 4.2-4.4 (IH, m, H-l'), 4.520—1 ο—o 4.70-4.84-5.02 (2H, AB type, CHg-2) and 5.71 ppm (IH, d, J=1.3 Hz, H-5); ir (KBr disc) V : 3420 (OH), 3000-2600 (br, COH), 1765 (β-lactam) and max 2 1575 cm”1 (-CO H); uv (Η,Ο) λ : 306 (ε 5300) and 258 mp (ε 3600). 2 max Example 7 2-(2-Aminoethoxymethyl)penem-3-carboxylic Acid (via mercaptide intermediate) Ethyl 2-chloroethoxyacetate ClCH2CO2Et + TEAB 150-160eC A mixture of ethyl chloroacetate (24.5 g, 0.200 mol), ethyleneoxide (8.80 g, 0.300 mol) and tetraethylammonium bromide (0.40 g, 1.9 mmol; dried in vacuo) was heated in a bomb at 10 150-160°C for 6 h. After cooling, the reaction mixture was distilled under reduced pressure collecting 6.66 g (54.4 mmol, 27.2%) of ethyl chloroacetate, bp 22-24’C (0.5 mmHg) and 8.39 g (50.4 mmol, .2%) of ethyl 2-chloroethoxyacetate as a colourless oil; bp 49-53eC (0.1 mmhg); *Hmr (CDC13) δ: 1.28 (3H, t, J=7Hz,-CH.^ , 3.5-4.0 (4H, m, A^,-CHjCH -Cl), 4.15 (2H, s, -COCH^-), 4.25 ppm (2H, q, J=7Hz,-OCH,CH,); ir (neat)V : 1740 cm1 (C=0 ester). ~3 max Procedure of D. Klamann eX aZ, Jastus Liebig Ann., 710, 59 (1967) (Reported: yield 42%, bp 55.5’/0.35 mmHg).

Ethyl 2-azidoethoxyacetate A mixture of ethyl 2-chloroethoxyacetate (7.71 g, 36.3 mmol) and sodium azide (3.31 g, 50.9 mmol, in DMF (100 ml) was heated at 80-90eC for 3.5 h by which time tic (hexane; ether 1:1) indicated that the reaction was complete, The cooled mixture was poured into H2O (1 Z) and extracted with ether (250 ml x 3) . The extracts washed with H20 (x 2) and brine • 49876 (χ 1, were dried (MgSO^) and evaporated yielding 7.16 g (41.4 mmol 89.4%) of ethyl 2-azidoethoxyacetate as a yellowish oil: ’Hmr (CDC13) 6: 1.30 (3H, t, J=»7Hz, -OCH2CH3) , 3.3-4.0 (4H, m, -OCH2 CH2N3), 4.13 (2H, S, -COCH2O-), 4.23 ppm (2H, q, J=7Hz, -OCH^CH^; ir (neat) υ : 2100 (N,) and 1750 an1 (C=0 ester). This material max 3 was used in the next step without further purification. 2-Azidoethoxyacetic acid NaOH H2O-MeOH O To a solution of ethyl 2-azidoethoxyacetate (6.56 g, 10 37.9 mmol) in MeOH (80 ml) was added IN aq. NaOH (80 ml) and the mixture was stirred at room temperature overnight (17 h) . After removing the insoluble material, the methanol was evaporated in vacuo and this was saturated with sodium chloride and washed withether (30 ml x 3), The aqueous layer acidified with 3N HCl 15 (30 ml) was extracted withether (40 ml x 4). The ether extracts were washed with brine, dried (MgSO^) and evaporated to yield 4.25 g (29.3 mmol, 77.3%) of 2-azidoethoxyacetic acid as a colourless oil: ’Hmr (CDC13) δ: 3.3-4.0 (4H, m, -OCH^H^) , 4.22 (2H, s, -COCH2O-), 9.52 ppm (IH, s, -CO2H, exchanged with D^); ir (neat) V : 2600-3300 (br,-CO,H) 2100 (azide) and 1740 cm1 max 2 C=O-CO2H). This material was used in the next step without further purification. 2-Azidoethoxyacetyl chloride A solution of 2-azidoethoxyacetic acid (2.09 g, 14.4 mmol) in thionyl chloride (5 ml) was stirred at room temperature for 4 h. The excess thionyl chloride was removed under the vacuum of the water aspirator and the residue dissolved in benzene (10 ml, dried over molecular sieves) was evaporated in vacuo. The oil so obtained was dried in vacuo (water pump) over NaOH for 1 h yielding 2.23 g (13.6 mmol, 94.4%) of 2-azidoethoxyacetyl chloride as a colourless oil: ’Hmr (CDCl.j) 5: 3.43 (2H, 5 br. t, J=5Hz, -CH2O-) 3.78 (2H, br. t, J=5Hz, -CH^) and 4.50 ppm (2H, s, -COCHO-); ir (neat) V : 2100 (azide) and 1800 cm 1 (-COC1). 2 max This material was used in the next reaction without any purification. 4-(2'-azidoethoxyacetylthio)-l- (1'-paranitrobenzy1oxycarbonyl-1 tri pheny)phosphoranylmethyl) -2-azeti di none CO-PNB CO PNB 2 To a stirred solution of silver 1.-(1'-paranitrobenzyloxycarbonvl1'-tri phenylphosphoranylmethyl)-2-azeti di none-4-thiolate (7.96 g, 12.0 mmol) in CH2C12 (100 ml) containing pyridine (1.94 ml, 24.0 mmol) was added at 0-5“C under a nitrogen atmosphere a solution of 2-azidoethoxyacetyl chloride (2.23 g, 13.6 mmol) in CH2C12 (20 ml) and the mixture was stirred at room temperature for 2 h. After filtration of the precipitate, the filtrate was evaporated and the residual oil was purified by column chromatography (SiO2« 160 g; eluent, EtOAc: CH2C12=1:1) collecting 4.216 g (6.17 mmol, 51.4%) of the title phosphorane as a yellowish foam.

This foam was used in the next step. An analytical sample was obtained by crystallization from CH2Cl2-ether(1:9): mp 128-9eC (dec.); ir (nujol) V : 2090 (-N_), 1755 (β-lactam) and 1690 can 1 max 3 (thioester); Anal, calcd for C,.H, N,O_PS: C 59.74, H 4.42, N 10.26, - 34 30 5 7 S 4.69; found: C 59.33, H 4.49, N 9.69, S 5.19; tic (EtOAc) Rf=0.55. - 102 p-Nitrobenzyl 2- (2-azidoethoxy)methyl-penem-3-carboxylate A solution (cloudy) of the above phosphorane (4.13 g. 6.04 mmol) in toluene (200 ml) was heated under reflux under a nitrogen atmosphere for 1.5 h. After removal of the insoluble material, the solvent was evaporated in vacuo and the residual oil was purified by column chromatography (SiO2, 80 g, eluent 5% ether in benzene) collecting 2.44 g (6.02 mmol, 99.6%) of title compound as a yellowish oil. This oil was used in the next step. Crystallization from CH^C^-ether (1:9) gave an analytical sample: mp 88-89.5°C; 'Hmr (CDC13) δ: 3.35 (2H, t, J=5Hz,-OCH2~), 3.47 (IH, dd, J =16Hz, J. =2Hz, C-H), 3.67 (2H, t, J=5Hz,-CH,N>, gem trans 6 2 3 3.85 (IH, dd, J =16Hz, J . =3.5 Hz, C-H), 4.73 (2H, ABq, J=16, 19 gem cis o C-CH ), 5.30 (2H, ABq, J=13.5, 9, -OCHjAr) , 5.63 (IH, dd, Jtrans= 2Hz, J . =3.5 Hz, C-H), 7.50-7.63-8.12-8.27 ppm (4H, A *B ’, CIS 5 ii aromatic Hs); ir (nujol) V : 2100 (-N,), 1785 (β-lactam) and 1695 cm 1 max 3 (ester) uv (EtOH) λ : 263 mp (612000), 320.5 mp (69600) tic (benzene: max ether=l:l) Rf=0.60 2- (2-Aminoethoxy)methyl-penem-3-carboxylic acid H2/Pd-C ,2och2ch2nh2 ^2« mmol) in dimethoxyethane (50 ml) was mixed with ether (50 ml), HjO (50 ml) and 10% Pd-C (1.62 g; Engelhard) and hydrogenated at temperature (H^ 55 psi) for 2.5 h. After filtration of the room catalyst, the aqueous layer was washed with ether (50 ml x 2) and then EtOAc (50 ml x 1). The aqueous solution was lyophilized to give 817 mg (3.34 mmol, 83.6%) of the title amino-acid as a yellowish powder: uv (H20) A^^: 304 mp (ε5000). This material was purified by hplc (Waters, Micro Bondapak Reverse Phase 30 cm x mm; eluent 1% CH3CN in H20) to give 432 mg (1.77 mmol, 44.2%) of the title amino-acid as a white powder: ’Hmr (D2O) δ: 3.19-3.9 (4H, m, -OCH2CH2NH2), 3.54 (IH, dd, Jgem=16·9 Hz, Hz, C6_H> ' 3.88 (IH, dd, J =16.8 Hz, J . =3.7 Hz, C -H), 4.52-4.70-4.83-5.01 (2H, gen cis o AB type, C2-CH2O-) and 5.77 ppm (IH, dd, Jcj,s=3·6 Hz> Jtrans=19 C5-H^' ir (KBr disc) v : 1770 (β-lactam) and 1580 cm 1 (-CO H); uv (HO) max 2 2 A : 104 mp (65400), 256 mp (63100). max Example 8 2-(2-Aminoethylthiomethyl)penem-3-carboxylic Acid (via mercaptide intermediate) 2-Azidoethyl methanesulfonate BrCHCH OH -► NCHCHOMs 2 3 2 2 A solution of 2-bromoethanol (7.5 g, 60.0 mmol) and sodium azide (5.0 g, 76.9 mmol) in HMPT (30 ml) was heated at 2θ 115°C for 2.5 h. The reaction mixture was cooled to 23°C and diluted with CH2C12 (100 ml). The solids were removed by filtratipn and the CH2C12 was evaporated on the rotary evaporator leaving a yellow liquid which was cooled to 0°C and successively treated with mesylchloride (5.57 ml, 72.0 mmol, and triethylamine (10.0 ml, 72.0 mmol). The reaction mixture was stirred at 0°C for 1 h, then at 23°C for 6 h, and poured into H20 (300 ml). The aqueous solution was extracted with ether (1 x 200 ml, 4 x 100 ml); the ether extracts were combined, - 104 washed with IN HCI solution, HjO saturated NaHCOg solution and H20, dried over anhydrous MgSO^ and concentrated on a rotary evaporator to an orange liquid which was distilled under high vacuum bp 95-100°C.0.3 torr, 5.8 g, 58.5%; ir (neat) υ : 2005 max (s, N3), 1345 (s, SO2-O), 1175 (m, SC^-O) cm1. ’Hmr (CDC13) δ; 3.03 (s, 3H, OCH3), 3.43-3.76 (m, 2H, H-2) and 4.2-4.46 ppm (m, 2H, H-l). 2'-Azidoethylthioglycolic acid 1. Δ N CH CH OMs + NaSCH COONa --—► N CH CH SCH COOH 2 2 2 + 3 2 2 2 Thioglycolic acid (3.14 g, 34.1 mmol) was treated with IN NaOH solution (68 ml, 68.0 mmol) and the resulting solution was stirred at 23eC for 0.5 h and treated with a solution of 2*-azidoethyl methanesulfonate (5-3 g, 32.1 mmol) in 1,2 dimethoxyethane (15 ml). The reaction mixture was stirred at 1»5°C for 22 h, cooled to 23°C, washed with C«2C12 (3 x 20 ml), acidified with 6N HCI solution and extracted with CH2C12 (7 x 40 ml).

The CH_C1_ extracts were combined, dried over anhydrous Na SO. 2 4 “ and concentrated on a rotary evaporator to an oil which was distilled under high vacuum bp 117-22°C/0.27 torr, 4.2 g, 81.2%. ir (neat) υ ·· 2100 (s, N ) , 1708 (s, C=O) cm 1. ’Hmr (CDC1,) δ: 2.7-3.07 (m, 2H, H-l'), 3.35 (s, 2H, H-l), 3.30-3.73 (m, 2H, H-2') and 11.81 ppm (s, IH, COOH). 2'-Azidoethylthioacetyl chloride (COCI)2 n 3ch 3ch 3sch 3cooh N3CH2CH2SCH2COC1 To a solution of 2-azidoethylthio glycolic acid (3.33 g, 20.7 mmol) in CH2C12 (5° m1^ was added °xalyi chloride (3.9 ml) and DMF (one drop). The reaction mixture was stirred at 23“C for 1.5 h and the solvent was removed on a rotary evaporator leaving a yellow liquid, ir(neat) υ : 2100 (s, N ), 1785 (bs, C=O). lHmr (CDC1.) 6: 2.6-3.0 max 3 3 (ra, 2H, H-l’), 3-37-3.73 (m, 2H, H-2'), and 3.82 ppm (s, 2H, H-l). 4-(2*-azidoethylthioacetylthio)-1-() '-paranitrobenzyloxycarbonyl-1 5 triphenylphosphoranylmethyl)-2-azetidinone COOPNB CICCH.SCH CH N 2 2 2 3 -¼ COOPNB A solution of silver 1-(1'-paranitrobenzyl 1'-triphenylphosphoranylmethyl)-2-azetidinone-4-thiolate (15.7 mmol) and pyridine (1.6 ml, 19.8 mmol) in CH2C12 ^200 ml> was treated dropwise (0.25 h) with a solution of 2'-azidoethylthioacetyl chloride (3.64 g, 20.3 mmol) in CH2C12 (50 ml,. The reaction mivt-nre was stirred at 23’C for 1.5 h and filtered; the solids were washed with CH2C12. The filtrate and washings were combined and washed with 0.1N HCl solution, H2O, saturated NaHCO3 solution and H2O, dried over anhydrous Na2SO4 and concentrated on a rotary evaporator to an orange syrup. A column chromatography (300 g of silica gel G-60, eluent; EtOAc in CH2C12, 0-40%) of crude compound gave after evaporation of solvent a white powder, 7.7 g, 70%. An analytical sample was obtained after a recrystallization 2Q from CH Cl -ether-pet. ether, mp 150-1’C dec. Anal, calcd for C Η N 0 S P: C 58.36, H 4.32, N 10.01, S 9.17; found: C 58.64, 5 6 2 H 4.36, N 10.03, S 9.25. ir. (KBr) 2100 (s, N3) , 1750 (s, C=O of β-lactam), 1675 (s, C=0,, 1655 (s, C=O), 1610 (s, aromatics), and 1440 an 1 (s, P-Ph). - 106 49876 paraNitrobenzyl 2-aminoethylthiomethylpenem-3-carboxylate -SCCH SCH CH N rf -N. o x-j:=pph3 COOPNB o ch2sch2ch2n3 COOPNB A suspension of 4-(2’-azidoethylthioacetylthio)-l(1'-paranitrobenzyloxycarbonyl-l'-triphenylphosphoranylmethyl)-2-azetidin10 one (4.5 g, 6.43 mmol) in toluene (375 ml) was stirred at 110°C for 2.25 h under a nitrogen atmosphere. The reaction mixture was cooled to 23eC and the evaporation of solvent on a rotary evaporator gave an orange syrup. The purification of crude material was done on a silica gel column (90 g of silica gel G-60, eluent: ether-pet-ether, 1:1-3:2).- the pure material was obtained as a yellow syrup, 2.2 g, 81%). ir (neat) 2100 (s, N3), 1785 (s, C=O of β-lactam), 1705 cm 1 (s, C=O of PNB); ’Hmr (CDC13) δ: 2.53-2.90 (m, 2H, H-l), 3.30-3.67 (m, 3H, H02, H-6 trans), 3.98 (ABq, J =14.8Hz, 2H, H-l'), 5.32 (ABq, Ja_b=13.0Hz, 2H, CH -PhNOp, 5.66 (dd, JH_5,H_6 cis=3-6 Hz' J . u . „ =1-9 Hz, 1-H, H-5), 7.58 (d, J =8.8Hz, 2H, Ho H-5,H-6 trans Ho-Hm PNB) and 8.19 ppm (d, J „ =8.8Hz, 2H, Hm PNB,. Hxn-nO 2-Aminoe thy lthiomethy lpenem-3-carboxy lie acid PP ch2sch2ch2n3 COOPNB h2sch2ch2nh3 0(0 To a solution of p-nitrobenzyl 2-azidoethylthiomethylpenem3-carboxylate (1*5 mg, 0.11 mmol) in 1,2-dimethoxyethane (5 ml) were added ether (5 ml), water (5 ml) and 10% Pd/C (1*5 mg, 0.11 mmol).

The reaction mixture was hydrogenated at 23°C under 45 psi of hydrogen for 3.0 h and filtered over a*Celite pad. The pad was washed with water and the filtrate and washings were combined *Celite is a Trade Mark and diluted with ether. The water phase was separated and ' washed with ether and lyophylized. The crude compound (20 mg) was purified by hplc: 5 mg, 18%; ir (KBr) ',’max: 1765 (C-O) , 1600 cm-1 (b, COO_); *Hmr (DjO) δ: 2.70-3.00 (ra, 2H, H-l”), 3.15-3.45 (m, 2H, H-2), 3.49 (dd, Jgen)-16.8Hz, g trans*l·7H*' H-6 trans), 3.85 (dd, Jgenl“16-8Hz' J6.5cisw3.4Hz, H-6 cis), 4.05 (ABq, J -14.6Hz, 2H, H-l) and 5.74 ppm (dd, J. , . -3.4Hz, a-o 5-o cis J r -1.7Hz, IH, H-5); uv λ : 307 (e 4330), 250 (ε 3282). -6 trans max EXAMPLE 9 silver i-(8-Trimethylsilylethyjoxycarbonyl-T’tripheny1phosphorany1inethyl)2-azetidinone-4-thiolate _✓SAg J— , /CH3 CO CH CH Si—CH3 2 xch3 di-8-trimethylsilylethyl fumarate O ‘ Cl Cl HO ,Si (CH3)3 pyridine (CH3)3Si i(CH3)3 To a cold (-10*0 ether (20 ml) solution of 2-trimethyl15 silyl ethanol (4.73 g, 0.04 mmol) (H. Gerlach Helv. Chim. Acta 60, 3039 (1977)) and pyridine (5.66 ml, 0.07 mol), under nitrogen, was added dropwise (15 min) fumaryl chloride (3.78 ml, 0.035 mol) dissolved in ether (10 ml). The black mixture was stirred five 2Q minutes at -10’C and ten at room temperature. Charcoal was added and the reaction mixture filtered on a Celite pad. The filtrate was washed with sodium bicarbonate 1% - brine (1:1, 150 ml). The aqueous phase was back extracted with ether (30 ml). The ether solutions were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give - 108 49876 a brown solid. This compound was purified on a silica gel pad (30 g, 4x5 cm) with benzene (300 ml) as eluent to give an oil (4.855 g, 77%) which solidified on standing: mp 33-34’C. Anal, calcd for C H 0 Si : C 53.12, H 8.91; found: C 53.35, H 8.91. ’Hmr (CDCl.) 6: 14 28 4 2 3 6.78 (2H, s, C=CH,, 4.26 (4H, m, CHg-O), 1.03 (4H, m, CHg-Si) and 0.06 ppm (18H, s, (CH) Si); ir (CHCl,) V: 1710 (C=O of ester), 3 3 max 1643 (C=C), 1267, 1258, 862 and 840 cm 1 (Si-C).

TrimethylsilyIethyl glyoxylate hydrate (CH3)3Si Si(CH3)3 2) (CH3)2S ;h(oh) 3i (CH3) A solution of di-S-trimethylsilyIethyl fumarate (37 g, 0.117 mmol) in methylene chloride (1.1 £) was ozonized at -78“C until a blue color persisted. The excess ozone was purged with nitrogen and dimethyl sulfide (2.57 ml, 0.351 mol) was added.

The solution was allowed to gradually warm to 23°C. The reaction mixture was diluted with carbon tetrachloride to 2 liters and washed with 1% aqueous solution of sodium carbonate (500 ml). The organic phase was dried over sodium sulfate, filtered on Celite and evaporated (~ 25°C) to dryness to give 43.9 g of the title compound (97%); ir (neat) V : 3450 (-OH), 1740 (ester, 1255, 860 and 840 cm 1 (Si-C). max l-(f^g-trimethylsily1ethyToxycarbony1-l'-hydroxymethyl)-4-tritylthio-2-azetidi none rr CO./ 2-Trimethylsilylethyl glyoxylate hydrate (4.000 g, 11.6 mmol) and the 4-tritylthio-2-azetidinone (4.8 g, 24.96 mmol) were refluxed in benzene (25 ml) through a Dean Stark condenser, under nitrogen for 24 h. The solvent was evaporated under a vacuum. The product was chromatographed on a silica gel column (450 g, 8.5 x 14.5 cm) and eluted with ethyl acetate: methylene ^Si(CH3) chloride (1:19, until the title compound started to come out (—1.5 £, and then with ethylacetate: methylene chloride (1:9, t). The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of the title compound. lHmr (CDCl^) 6: 7.80 to 6.70 (15H, m, trityl), 5.23 and 4.90 (IH, 2s, H-C-O), 4.50 to 4.10 (3H, m, H-3 and O-CH2), 2.60 (2H, m, H-2), 0.95 (2H, m, CH^Si and 0.1 ppm (9H, s, Si-CH.^ ; ir (CHC1,) V : 3520 (-0H), 1765 (C=O of β-lactam), 1740 (C=O of 3 max ester), 1595 (C-H, aromatic), 1257, 860 and 840 cm (C-Si) 1-(1'-β-trimethylsilylethyloxycarbonyl-l'-chloromethyl)-4-tritylthio-2-azetidinone A solution of thionyl chloride (0.74 ml, 10.37 mmol) in dry THF (9 ml) was added dropwise with stirring to a solution of 1-(11β-trimethylsilylethyloxycarbonyl'l'-hydroxymethyl)-4-tri tylthio-2azetidinone (4.9 g, 9.37 Rgnol), pyridine (0.84 ml, 10.38 mmol) and dry THF (40 ml) at -15°C under a nitrogen atmosphere. The mixture was stirred at -15°C for 2 h. The precipitate was removed by filtration on a Celite pad and washed with benzene (50 ml) . The filtrate was evaporated in vacuo at 30°C. The residue was dissolved in benzene (100 ml), treated with charcoal and filtered through a Celite pad. Evaporation of the solvent gave a residue which was purified through a silica gel pad (100 g, 4.7 x 11 cm): hexanebenzene (1:1, 400 ml), ether-benzene (1:19, 1 i). Evaporation of the pertinent fractions gave 4.64 g of the title compound (92%). 1 Hmr (CDCl^) δ: 7.30 (15H, m, aromatic Ή), 5.77 and 5.43 (IH, 2s, CH-C1) , 4.7 to 4.2 (3H, m, H-4 and CH^O) , 2.85 to 2.50 (2H, m, H-3), 1.15 (2H, ra, CH^Si) and 0.06 ppm (9H, s, Si-CH.*) ; ir (neat) V : 1760 (C=0), 860 and 840 cm1 (C-Si). max - 110 THEE 1-(l'-B-triir,ethy1si1y1ethyloxycarbonyl-T-triphenylphosphoranylmethyl)-4tritylthio-2-azetidinone STr A dioxane (20 ml) solution of the above chloroazeti5 dinone (4.12 g, 7.568) was treated with triphenylphosphine (2.209 g, 8,424 mmol) and 2,6-lutidine (0.98 ml, 8.424 mmol). The mixture was refluxed for 3.5 h. The cooled solution was filtered and the white solid washed with THF. The filtrate was evaporated to dryness. The residue was purified on a silica gel column (200 g, 4 x 31 can) using ethylacetate-hexane (3:7, 1 Z; 7:3, 1 Z) to give the title phosphorane (4.836 g, 83%). ir (film) u : 1755 (C=0), ΙΠαΧ 1615 (phosphorane), 850 and 830 cm 1 (Si-C). Anal, calcd for C _H NO PSSi: C 73.89, H 6.07, N 1.81; found: C 72.18, H 6.08, 46 3 N 1.83 Silver 1-(1'-β-trimethylsilylethyloxycarbonyl-l ις triphenylphosphoranylmethyl)-2-azetidinone-4-thiolate STr + AgNOj (nBu)3N + CF3CO2H ether/HgO ♦ Si(CH3)3 1-(1'-β-trimethylsilylethyloxycarbonyl-l'-triphenylphosphoranylmethyl -2'-azetate) -2-azetidinone (7.64 g, 10 mmol) was dissolved in ether (60 ml).

An aqueous solution of silver nitrate (0.5M, 80 ml, 40 mmol) was added followed by a rapid addition ( 1 min) of a solution of tributylamine (3 ml, 12.58 mmol) and trifluoroacetic acid (0.154 ml. 0.2 mmol) in ether (20 ml). The mixture was mechanically stirred for 19 min. The precipitate was filtered, rinsed with ether (200 ml), triturated in water (70 ml), filtered again and rinsed with ether (100 ml). The light brown solid was dried under vacuum (water aspirator min and pump 65 min) to give the title compound (6.42 g). ir (CHC13) u : 1862 (C=0, 1630 (phosphorane), 860 and 840 cm (Si-C) . max Example 10 Silver 3-(l'-Hydroxy-l'-ethyl)'-^trimethylsiTylethyloxycarbonyl -11-triphenylphosphoranylmethyl)-2-azetidinone-4-thio1ate OH X /SAg Vie | Π j — N >L/siMe3 C°2 trans 3-acetyl-l-(l' -β-trimethylsilylethyloxycarbonyl-1'- tri phenylphosDhoranylmethyl)-4-tritylthio-2-azetidinone To a solution of diisopropylamine (0.80 ml, 5.5 mmol) in tetrahydrofuran (25 ml) at -78’C was added n-butyl lithium (4.0 ml, 6.0 mmol) with stirring. After 3 min, a solution of 1-(1'“S“ trimethylsilylethyloxycarbonyl-l1-triphenylphosphoranylmethyl)-4-tri tylthio-2azetidinone (3.82 g, 5.00 mmol) in tetrahydrofuran (40 ml) was added dropwise over 20 min with stirring. After 2 min, 2.5 ml (25 mmol) of ethyl acetate was added and the solution was stirred for 10 min. The «asgjgiga cooling bath was removed and 0.2M hydrochloric (58 ml) acid was added with vigorous stirring. Water and ethyl acetate were added (65 ml each), shaken and separated. The organic phase was washed with water and saturated sodium chloride (60 ml each), dried and the solvent was eva5 porated in vacuo to give the crude product, 4.1 g. The product was absorbed from methylene chloride onto 20 g of silica gel and placed (dry) on a 120 g silica gel column. The column was eluted with ether/ hexane 1:1 (200 ml) then with ether (500 ml). Evaporation of the solvent from the appropriate fractions gave partially purified title compound, 2.17 g (53%); ir υ : 1755 (β-lactam and ester) and 1710 cm 1 max (ketone); *Hmr (CDCl^) 6: 1.67 and 1.87 peaks for CH^C-, trimethylsilyl and aromatic peaks; remainder poorly resolved. 3-(11-hydroxy-1 '-ethyl )-1-(1 '-β-trimethylsi lyl ethyl oxycarbonyl' triphenylphosphoranylmethyl)-4-tritylthio-2-azetidinone. hydride (160 mg, 4.3 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at 23°C for 4 h. Water (30 ml) was added followed by the slow addition of 1M hydrochloric acid until pH 3 was reached.

The mixture was extracted with ethyl acetate (50 ml) . The organic phase was washed with 50 ml each of 0.1 M sodium bicarbonate, diluted sodium chloride and saturated sodium chloride then dried and the solvent was evaporated in vacuo to give the crude product, 2.22 g.

The product was absorbed from methylene chloride onto 11 g of silica gel and placed (dry) on a 44 g silica gel column. The column was eluted with ether. Evaporation of the solvent from the appropriate fractions gave partially purified title compound, 1.43 g (68%); ?H ’Hmr (CDCl ): peaks around δ 1 for CH CH-, trimethylsilyl and *3 aromatic peaks; remainder poorly resolved.

Silver 3-()'-hydroxy-Ί'-ethyl)-l-(T-g-trimethylsilylethyloxycarbonyl-l'triphenyIphosphoranylmethyl)-2-azetidinone-4-thiolate A solution of silver nitrate (1.43 g, 8.4 mmol) in water (40 ml) and a solution of pyridine (0.27 ml, 3.35 mmol) and the above phosphorane (1.35 g, 1.67 mmol) in ether (40 ml) were stirred together vigorously at 23°C for 1 h. The precipitate was collected by filtration, washed with water and ether and dried to give crude title compound 1.24 g (100%); ir v : 3420 (OH) and max 1750 cm 1 (β-lactam and ester). - 114 Example 11 (l'R,5R,6s and 1'S,$S,6r) 6-(1'-Hydroxyethyl)-2-(2-aminoethoxymethyl)penem-3-carboxylic Acid (isomer B) - Alternate Procedure g (Isomer B) (l'R,3S,4R and l'S,3R,4S)4-(2-azidoethoxyacetylthio)-3-(1'-hydroxyethyl) -l-(l'-8-trimethylsilylethyloxycarbonyl-T-triphenylphosphoranylmethyl)2-azetidinone Trimethylsilyl chloride (1.54 ml, 11.8 mmol) was added to a stirred io Slurry of silver 3-(1'-hydroxyethyl)-1-(1 '-8-trimethylsilylethyloxycarbonyll'-triphenylphosphoranylmethyl)-2-azetidinone-4-thiolate (isomer B) (2.48 g, 3.34 mmol), imidazole (136 mg, 2.0 mmol) and triethylamine (1.64 ml, 11.8 mmol) in THF (60 ml) at 0°C. The mixture was stirred at 23° for 18 h. Methylene chloride (60 ml) was added, the mixture cooled to -15’C, pyridine (1.32 ml, 16.4 mmol) and β-azidoethoxyacetyl chloride (1.43 g, 8.70 mmol) - 115 49B7b added and the mixture stirred at -15°C for 0.5 h. Ether (60 ml), ethyl acetate (60 ml) and 1 M hydrochloric acid (20 ml) were added. The precipitate was removed by filtration and the organic phase was washed with 0.1 M hydrochloric acid (100 ml), 1% sodium bicarbonate (100 ml), and saturated sodium chloride. Concentration of the dried solution gave crude title compound as an oil. 85%. ir V : 1755 and 1695 cm \ r max (l'R,5R,6S and l'S,5S,6R) B-trimethylsilylethyl 2-B-azidoethoxymethyl-6(1'-hydroxyethy!)-penem-3-carboxylate (Isomer B) (200 ml) was heated under reflux for 3 h. Concentration of the solvent on a rotary evaporator gave the crude title compound.

Chromatography on silica gel (40 g) eluting with increasing proportions of ether in hexane gave crystalline title compound, 65%. ir v : 1760 and 1700 cm S ’Hmr indicated contamination Π1&Χ with a second isomer. (l'R,5R,6S and l'S,5S,6R)-2-g-azidoethoxymethy1-6-(11-hydroxyethyl)- 1.5 mmol) in THF was added to a solution of the above ester (155 mg, 0.37 mmol) in THF (2 ml) at 0eC. After 5 min at 0eC, water (10 ml) and ethyl acetate (10 ml) were added, the mixture was acidified to pH 3 (1 M hydrochloric acid) and the phases separated. The organic phase n ns m sodium bicarbonate, the aqueous extracts -J acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried, concentrated on the rotary evaporator and the residue triturated in ether to give the crude title compound as a solid, 27 mg, 28%. ir V : 3500, 1785, 1670 cm1; ’Hmr (CDC1,) δ: 1.30 (3H, d, max 3 J=6.5, CH -1’), 2.22 (IH, OH), 3.1-3.9 (5H, m, C»2 and H-6), 3.9-4.4 (IH, m, H-l*), 5.60 (IH, d. J=l, H-5). (l’R,5R.6s and 1'S.5S,6r) 6-(l,-Hydroxyethyl)-2-(2-aainoethoxymethyl)penem-3-carboxylic acid (isomer B) A solution of the above azidocompound (150 mg) in THF (15 ml) , ether (15 ml) and water (15 ml) was hydrogenated in a Parr shaker in the presence of 10% Pd/C (150 mg) at an initial H2 pressure of 60 psi. After 3 h the catalyst was removed by filtration over Celite and the aqueous phase vas washed vith ethyl acetate and lyophilized to give the crude title compound. Purification by hplc (Waters, C 1“ Micro Bondapack Reverse Phase) gave 46.7 mg of pure title compound identical to a previously prepared sample prepared by hydrogenation/ hydrogenolysis of the corresponding azido p-nitrobenzyl derivative. - 117 <* » Ο < Ο Example 12 6-Ethyl-g-(2-aminoethoxymethyl)penem-3-carboxylie Acid mixture of cis and trans Bedoukian, J. Am. Chem.

The 1-butenylacetate (about 1 isomers) was prepared according to P.Z.

Soc. 66 1325(1944) .

To cooled (-15°C) I (50'ml) was added dropwise 10 ml (11 g, 78 mmoles) of CSI. The mixture was allowed to warm up gradually 10 during 30 min. to O’C. It was cooled to -20“C and poured carefully onto a mixture of water (8 ml) ice (35 g), NaHCOg (18.4 g) and Na2SO3 (6.4 g). This was stirred vigorously at O’C for 30 min., treated with pet. ether (250 ml) and cooled to -40’C. The solvent was decanted and the residue was treated with another 100 ml of pet. ether in the same way. The combined pet. ether extracts were washed with water (30 ml) and dried (Na^O^) for recycling of I.

The aqueous phases were combined and extracted with ethylacetate (5 x 40 ml). The extract was dried (Na2SO4) and concentrated in vacuo to give 7.0 g (57%, of a mixture of 28% II and 72% III, 118 4 3 βϊ b b.p. 82-85’C (0.01 nun); n.m.r. δ (ppm, CDC13) 7.3 (ΙΗ,ΝΗ) 5.92 (0.72 H, d, J = 4.4, II-H-3), 3.3 (0.28 H, d, J = 1.4, III-H-4),3.3 (IH, m, H-3), 2.24 (3H, s), 2.72 (2H, two q, J = 7), 1.1 (3H, two t, J = 7).

V 1775, 1755 cm1 Anal, calcd. for C,H,,NO, C 53.49, H 7.05, N 8.91. c=o / 11 3 Found C 53.12, H 6.93, H 8.85.

OCOCH.

NaSCOCH. -π; S-COCH.

II + III IV Sodium thioacetate was prepared by addition of thioacetic acid (0.8 ml, 850 mg, 11.2 mmoles) to a cooled (ice-bath) IN sodium hydroxide solution (11.2 ml) under nitrogen. This was added to a cooled solution of II and III (1.57 g 10 mmoles) in water (5 ml) under N2· The mixture was stirred for 1 h at room temperature. Since an oil was separating, acetone (9 ml) was added and stirring continued for 1.5 h. The mixture was concentrated in vacuo to remove acetone and then extracted with methylene chloride. The extract was dried and concentrated in vacuo to give 1.65 g (95%) of crude mixture of 85% trans IV and 15% cis IV bp 105-110’ (0.02 mm), 7.1 (ΙΗ,ΝΗ) 5.53 (0.24H, d, J=4.5, cis-H-4), 5.12 (0.8H, d, J = 2.4 trans -H-4) 3.34 (lH, two t, J = 7) 2.48 (3H) 1.9 (IH, two q, J = 7) 1.15 (3H, two t, J=7. oc 1700 1765 cm1. Anal, calcd for C,H,,N C 48.53, H 6.40, N 8.07. co ' 7 11 Found C 48.18, H 6.47, N 7.77 A mixture of IV (1.25 g, 7.2 mmole) and p-nitrobenzyl glyoxylatehydrate (1.6 g, 7.5 mmole) in benzene (80 ml) was refluxed 20 h under a Dean Stark water collector followed by concentration in vacuo to give 3.01 g of crude product. This was filtered over a small amount of silica in chloroform to give 2.8 g (quantitative yield) of slightly yellow oil V containing some solvent, δ 7.9 (4H, m) 5.3 (4H,m> 4.8 (IH, OH) 3.2 (IH, m) 3.37 and 3.33 (3H, two s) 1.8 (2H, m) 1.05 (3H, m) v^o 1765,1700 cn f This product was used in the next step without further purification.

To a cooled (ice-bath) stirred solution of (2.1 g, .5 mmole) in dry benzene (10 ml) was added thionyl chloride (3 ml) and the mixture kept at 5’C for 2 h followed by evaporation in vacuo at room temperature. The excess thionyl chloride was removed by repeated addition and evaporation of benzene’ and the product was purified by filtration of the benzene solution over a small amount of silica gel, to give after concentration 1.7 a (77%) of crude slightly yellow oil VI, δ 7.9 ' 43876 (4H, m) 6.0 (1H, s) 5.3 (3H. m) 3.3 (IH, m) 2.7 and 2.3 (3H, two s) 1.75 (3H, m) 1.0 (3H, mJ V 1700, 1775 cm'1. The product was ' * * c=o used in the next step without further purification. co2pnb VI VII A mixture of VI (1.7 g, 4.2 nancies), triphenylphosphine (1.57 g 6.0 mmoles) and 2,6-lutidine (5.35 mg, 5 mmoles, in dry dioxane (20 ml) was heated at 55’ for 19 h, followed by concentration in vacuo. The dark-red residue was chromatographed on a silica gel column (35 g). Elution with benzene-ether gave Ιθ 2.3 g (87%) of crude VII as light red oil, which was used in the next step without further purification. γ ✓ s-coch3 γΡ03 J-Nv AgN03 base COOPNB VII Mercaptide VIII is prepared from VII by the general procedure of Example 3. - 121 Cl VIII CO2PNB >IX S'. \ z/-ch2och2ch2n3 ^CC^PNB H2/Pd-C Reaction of mercaptide VIII vith 2-azidoethoxyacetyl chloride according to the procedure of Example 6 gives intermediate IX which nay be cyclized and reduced as in Example c to give the title product.

Claims

1. A compound of the formula: U wherein Q is phenyl or (lower)alkyl; R is an easily removable ester5 forming protecting group; X is -(Alk)-A-(Alk 1 )-Rgg' wherein Alk represents a C-j-C? alkylene group optionally substituted by a C-|-C 4 alkyl radical; A is 0, S, SO, S0 2 or NR 2 ^ in which is hydrogen, (lower)alkyl, phenyl or phenyl(lower)alkyl; Alk' is a C 2 ~C 4 alkylene group; R 2Q is a polar substituent selected 10 from the group consisting of -NHOH, “^22^23 10 ^22 an< ^ ^23 are each independently hydrogen or (lower)alkyl and -l^; and Y is hydrogen or a radical selected from the group consisting of (a) optionally substituted (lower)aliphatic, (lower)cycloaliphatic or (1ower)cycloaliphatic(lower)aliphatic, the substituents being one or more 15 of hydroxy, (lower)alkoxy, optionally substituted phenyloxy, optionally substituted heterocyclicoxy, optionally substituted (lower)alkylthio, optionally substituted phenylthio, optionally substituted heterocyclicthio, mercapto, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoyloxy, (lower)alkanoylamino, optionally substituted phenyl, 20 optionally substituted heterocyclic, carboxy, carb(lower)alkoxy, carbamoyl, N-(lower)alkylcarbamoyl, N,N-di(lower)alkylcarbamoyl, halo, cyano, oxo, thioxo, -SO3H, -0S0 3 H, -S0 2 (lower)alkyl, (lower)alkylsulfinyl, nitro, phosphono or - 123 ο -OP(OR e )(OR r ), the substituents on the (lower)alkylthio group being one or more of halo, hydroxy, (lower)alkoxy, amino, (lowerJalkanoylamino or optionally substituted phenyl or heterocyclic and the phenyl or heterocyclic substituents 5 above being one or more of hydroxy, (lower)-alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo, or sulfo(lower)alkyl, R g being a (lower)alkyl group and R p being an optionally substituted 10 (lower)alkyl group or optionally ring-substituted phenyl or heterocyclic group, the substituents on the alkyl group being one or more of a halogen atom, a hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino group, and the substituents on the phenyl or 15 heterocyclic rings being one or more of a halogen atom, a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkyl ami no, di(lower)alkylami no, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo, or su1fo(lower)alkyl group. 20 (b) -OR in which R is optionally substituted (lower)alkyl or s s 4 (lower)alkanoyl or optionally substituted phenyl or heterocyclic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)alkoxy, (loweralkylamino, di(lower)alkylamino, amino, oxo, ' (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and 25 the substituents on the phenyl or heterocyclic being one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, (lower)alkylamino, di(lower)alkylamino, amino, (lower)alkanoylami no, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; - 124 (c) -S(0) n R $ in which n is 0, 1 or 2 and R g is as defined above; (d) halo; and (e) optionally substituted phenyl or heterocyclic in which the substituents are one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkyl ami no, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl.

2. A compound as claimed in claim 1 wherein an ethyl or α-hydroxyethyl group.

3. A compound as claimed in claim 1 or claim Alk is C.| alkylene, A is 0, S or S=0, Alk' R 2q is amino.

4. A compound as claimed in claim 1 wherein X is -CH 2 OCH 2 CH 2 NH 2 .

5. A compound as claimed in claim 1 wherein and X is -CH 2 OCH 2 CH 2 NHOH.

6. A compound as claimed in claim 1 wherein X is -CH 2 SCH 2 CH 2 NH 2 .

7. A compound as claimed in claim 1 wherein and X is -CH 2 SCH 2 CH 2 NHOH.

8. A compound as claimed in claim 1 wherein and X is θ ll -ch 2 sch 2 ch 2 nh 2 . Y is a hydrogen atom, 2 wherein is C 2 alkylene and Y is a hydrogen atom and Y is a hydrogen atom Y is a hydrogen atom and Y is a hydrogen atom Y is a hydrogen atom

9. and A compound as claimed in claim 1 wherein Y is a hydrogen atom is 0 -ch 2 sch 2 ch 2 nhoh.

10. A compound as claimed in claim 1 wherein Y is a hydrogen atom and X is -CH 2 OCH 2 CH 2 NO 2 · - 125 η. X is 12. χ is la. group 14. group 15. group 16. group 17. group 18. group 19. group 20. group 21. A compound as claimed in claim 1 -ch 2 sch 2 ch 2 no 2 . A compound as claimed in claim 1 -ch 2 sch 2 ch 2 no 2 . wherein Y is a hydrogen atom and wherein Y is a hydrogen atom and A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl and X is -CH 2 OCH 2 CH 2 NH 2 · A compound as claimed in claim 1 and X is -CH 2 OCH 2 CH 2 NHOH. A compound as claimed in claim 1 and X is -CH 2 SCH 2 CH 2 NH 2 . wherein Y is an a-hydroxyethyl wherein Y is an a-hydroxyethyl A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl and X is -CH 2 SCH 2 CH 2 NHOH. A compound as claimed in claim 1 and X is θ wherein Y is an a-hydroxyethyl -ch 2 sch 2 ch 2 nh 2 . A compound as claimed in claim 1 and X is ? wherein Y is an a-hydroxyethyl -ch 2 sch 2 ch 2 nhoh. A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl and X is -CH 2 0CH 2 CH 2 N0 2 · A compound as claimed in claim 1 wherein Y is an a-hydroxyethyl and X is-CH 2 SCH 2 CH 2 NO 2 . A compound as claimed in claim 1 0 wherein Y is an a-hydroyethyl group and X is -ch 2 sch 2 ch 2 no 2 .