IE50597B1 - Azetidinones - Google Patents

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 certain novel azetidinones which are useful as intermediates in the preparation of certain penem compounds possessing antibiotic activity.

In a first aspect of the present invention there are provided 5 compounds of the formula wherein Y is a hydrogen atom or a group selected from (a) an optionally substituted (lower) aliphatic, (lower) cycloaliphatic or (lower) cycloaliphatic (lower) aliphatic group, the substituents being one or more of a 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)alkyl-carbamoyl, halo, cyano, oxo, thioxo, -SOgH, -OSOgH, -S02 -(lowerJalkyl, (lower)alkylsulfinyl, nitro, phosphono or 0 A -OP(ORe) (0Rr) group in which Rg and Rf are as defined above; the substituents on the (lower)alkylthio group being one or more of a halogen atom, a hydroxy (lower)alkoxy, amino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic group and the phenyl or heterocyclic substituents above being one or more of a halogen atom, a hydroxy, (lower)-alkoxy, (lower)alkyl, halo(lower)alkyl, methane-sulfopyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lowerJalkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; (b) -0Rg in which Rs is an optionally substituted (lower) alkyl or (lower)alkanoyl group or an optionally substituted phenyl or heterocyclic group, the substituents on the alkyl and alkanoyl being one or more of a halogen atom, a hydroxy (lowerJalkoxy, (lower)alkylamino, di(lower)alkylamino, amino, oxo, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic group and the substituents on the phenyl or heterocyclic being one or more of a halogen atom, a hydroxy (lower)alkoxy, (lower)alkyl, ha1o(lower)alkyl, methanesulfonyl, (lower)alkylthio, (lower)alkylamino, di(lower)alkylamino, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl group; (c) -S(0) R in which n is 0, 1 or 2 and R is as defined above; n s “ s (d) a halogen atom; and (e) an optionally substituted phenyl or heterocyclic group in which the substituents are one or more of a halogen atom a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkylamino di(lower)alkylamino, (lower)alkanoylami no, (lower)-alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl group, Qis a phenyl or (lower)alkyl group, R is an easily removable ester10 forming protecting group, 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.

In a second aspect of the present invention there are provided compounds of the formula Ilia P(Q)3 '2' in which Y, Q and R are as defined in claim 1.

In a third aspect of the present invention there are provided compounds of the formula: wherein Y, Q and T is CfiH,I65 -f-C6H5 ^6^5 R“ are as defined in claim 1, and ll or -C-X wherein X is (a) a radical of the formula (i) -0Ra in which Ra is hydrogen; (ii) -CORb in which Rfa is hydrogen, hydroxy, optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl group being one or more (preferably 1 or 2) of halo, hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower)alkyl ami no, di-(lower)alkylamino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or more (preferably 1 or 2) of hydroxy, (lower)alkoxy, halo, (lower) alkyl, halo(lower)alkyl, methanesulfonyl, oxo, (lower)alkyl thio, amino, (lower)alkyl ami no, di(lower)alkylamino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or (a) (iii) -OCORc in which Rc is an amino, (lower)alkyl ami no, di(lower)alkyl ami no or optionally substituted (lower)alkyl group in which the substituents are as defined in (a) (ii); or (b) a substituted (lower)aliphatic, (lower)-cycloaliphatic or (lower)cycloaliphatic (lower)-aliphatic group or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl group, substituents for the aliphatic, cycloaliphatic, phenyl or heterocyclic groups being NR, (i) -cnrzr3or -n-J-nr2r3 inwhichR1 R.| is a hydrogen atom, a (lower)alkyl or phenyl group and Rz and R3 are each independently a hydrogen atom, a (lower)alkyl, phenyl or benzyl group; (ii) -ORj in which R^ is an amino, (lower)alkylamino di(lower)alkyl ami no, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic or heterocyclic(lower)alkyl group, the substituents on the alkyl, phenyl and heterocyclic groups being as defined under (a) (ii) except that they are not amino, (lower)alkylamino or di(lower)alkylamino when X is substituted C-|-C2 alkyl and R^ is substituted Cg-C^ alkyl S0597 (iii) -0(CH2)n0Rr in which n is an integer from 1 to 6 and Rf is optionally substituted (lower)alkyl or optionally ringsubstituted phenyl or heterocyclic group; the substituents on the alkyl, phenyl or heterocyclic groups being as defined under (a) (ii) with the proviso that X is not -CH2 OCHg CH2 OCH3 when Y is hydrogen; (iv) -OCORr' in which Rr' is an amino, (lower)-alkylamino, di(lower)alkylamino or Rf group, wherein Rf is as defined above, with the proviso that R 1 may not be an unsubstituted (lower)alkyl group; (V) -oso2h 0 Φ (vi) -0P(0H)2 (vii) -0S02Rr in which Rr is as defined under (b) (iii); (viii) -oT(ORe) (0Rr) in which Rg is a (lower)alkyl group and Rr is as defined under (b) (iii); (ix) -S(O)nRd in which n is 0, 1 or 2 and Rd is as defined under (b) (ii) or is in the case where NR. lj 4 n=O-C-NRgRg in which R^ is a hydrogen atom or a (lower)alkyl group and Rg and Rg are each independently a hydrogen atom or a (lower)-alkyl group, with the proviso that Rd may not be an unsubstituted phenyl group; (x) -C0Rf in which Ry is an amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)-alkylamino(lower) alkyl, -NHNH2, -NR17N(R18)2, -NHORlg> -S-R1?, -O(CH2,n-A-Re or NRgRg in which Rp, Rp and Rg are (lower)alkyl groups, Rig is a hydrogen atom or a (lower)alkyl group, A is 0, S, NH or NCHg and n is as defined under (b) (iii) and Rg is an Rf group; (xi) -PO(ORw)2 in which Rw is a hydrogen atom or a (lower)alkyl group; (xii) -NHRh in which R^ is an optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -SOgH, -OH, (lower)alkoxy, amino, (lower)alkylami no, di(lower)alkylami no, -NHCOCH 3’ -CS2CH3, -so2ch3 - so, -C—NRyRg in which Ry and Rg are each independently (lower)alkyl, phenyl or NH II phenyl(lower)alkyl, -C—Rg in which Rg is (lower)alkyl, phenyl or phenyl(lower)- alkyl, or 0 II -C-R. in which R^ is amino (lower)-alkyl, -NH2, (lower)alkylamino, di(lower)alkylamino, O' II -NH—C — R]0 in which R^q is (lower)alkyl or optionally substituted phenyl or heterocyclic group, the phenyl and heterocyclic substituents being defined under NH II (a) (ii) in claim 1, -NH-C—NH2> (lower)alkoxy, -OCH -0CH2no2 or -O(CH2)2Si(CH3)3; _$_*{_ R in which Rn is a (lower)alkyl group substituted by an amino, (lower)alkylamino or di(lower)alkyl ami no group; (xiv) -NR.-Rr, in which R. is a (lower)alkyl group and J K J Rk is a (lower)alkyl, (lower)alkoxy, heterocyclic amino, or 0 -C—Rq group in which R^ is as defined under (b) (xii) or, when taken together with the nitrogen, R. and R represent J k providing that when is an amino or -CH2CH2NH2, Rj is methyl and also providing that Rj and Rk may not both be (lower)alkyl; 50587 (xv) -NR.‘R. ' in which R,' is (lower)alkoxy and J K j Rk' is (lower)alkyl, heterocyclic, amino(lower)alkyl, (1ower)a1ky1 ami no(1ower) a1ky1, di (1ower)a1 kylami no(1ower)0 il alkyl or -C-R^ in which R. is as defined under (b) (xii) or, when taken together with the nitrogen, R.' and R^1 represent (xvi) 'nRiRmRn in which Ri’ and Rn are each independently (lower)alkyl or when taken together with the nitrogen, represent (xvii) -N=CH-RX in which βχ is (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the phenyl or heterocyclic ring being as defined under (a)(ii); (xviii) -N=CR R in which R is (lower)alkyl or optionally ring** y y substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being as defined under (a)(ii), and Rx is as defined under (b) (xvii); (xix) =N-Rp in which Rp is hydroxy, (lower)alkoxy, amino, di (lowerjalkylamino or — NH or NOH ιι (xx) -C — (CH2^n^R15R15 in w*”ch n 's an integer from 1 to 6 and R-j 5 and Rj6 are each independently hydrogen or (lowerJalkyl.

The substituent groups of the azetidinones are further defined 5 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 (lowerJalkyl is meant both straight and branched chain saturated aliphatic hydrocarbon groups having from 1 to 6 carbon atoms inclusive, e.g. methyl, ethyl, ηι-propyl, isopropyl, ιι-butyl, ι sobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl. Preferred (lower)alkyl substituents have from l to 4 carbon atoms and roost preferably 1 or 2 carbon atoms; (c) by the term (lower)aliphatic” is meant acrylic straight and branched chain saturated or unsaturated hydrocarbon groups having from 1 to 6 carbon atoms inclusive. The unsaturated 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 groups are methyl, ethyl, ri-propyl, isopropy!, ji-butyl, t-butyl, sec-butyl, ji-pentyl, i sobutyl, vinyl, 1-propenypl, 2-propenyl, isopropenyl, 2-methyl-2-propenyl, ethynyl, and 2-propynyl. The most preferred aliphatic radicals are (lower)alkyl as in (b); (d) by the term (Iower)cycloaliphatic is meant alicyclic saturated and unsaturated hydrocarbon groups having from 3 to 8 ring carbon atoms, preferably 3 to 6 ring carbon atoms. The unsaturated ring may contain one or more (preferably one) double bond. Examples of this group include cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, cycioheptyl, cyclooctyl, cyclopropenyl, cyclopententyl, 1,3-cyclohexadienyl and cyclohexenyl; (e) by the term '‘(lower)cycloaliphatic(lower)aliphatic is meant cycloaliphatic-aliphatic groups having from 3 to 8 carbon atoms (preferably 3 to 6 carbon atoms) in the cycloaliphatic ring and to 6 carbon atoms (preferably 1 to 4 and most preferably 1 or 2 carbon atoms in the aliphatic portion. Examples include cyclopropylmethyl, cyclopropylethyl, cyclopropylpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cyclopentenylethyl, cyclopropylethenyl and cyclopropylethynyl.

The most preferred groups of this type are cycloalkyl-alkyl groups in which the cycloalkyl portion contains 3 to 6 carbon atoms and the alkyl portion contains 1 or 2 carbon atoms; (f) by the term (lower)alkoxy is meant C^-Cg alkoxy groups, the alkyl portion of which is defined as in (b). Examples include methoxy, ethoxy, ji-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and n-pentyloxy. Preferred groups are Cg-C4 alkoxy and the most preferred are C^-C2 alkoxy; (g) by the term {lowerjalkylthio is meant C-j-Cg alkylthio groups in which the alkyl portion is as defined in (b). Examples include methylthio, ethylthio and n-butylthio; (h) by the term (lower)alkylamino1,is meant C-j-Cg alkylamino radicals in which the alkyl portion is defined as in (b).

Examples are methylamino, ethylamino, n-propylamino and £-b.uty 1 ami no; (i) by the term di(lower)alkylamino is meant di C^-Cg alkylamino in which each alkyl group is as defined in (b). Examples are dimethylamino and diethylamino; (j) by the term (lower)alkanoyloxy'1 is meant groups of the formula 0 ll (lower)alkyl-C-O in which alkyl is as defined in (b); (k) by the term (lower)alkanoylami no is meant groups of the formula (lower)alkyl-C-NH- in which alkyl is as defined in (b); (1) by the term carb(lower)alkoxy is meant ii -C-(lower)alkoxy in which (lower)alkoxy is as defined in (f); (m) by the term halo(lower)alkyl is meant alkyl groups as defined in (b) in which one or more hydrogen atoms are replaced by a halogen atom; (n) by the term sulfo(lower)alkyl is meant -(CH2)nS03H in which £ is 1 to 6; (o) by the term carboxy(1ower)alkyl is meant -(CH2)nC00H in which £ is 1 to 6; (p) by the term phenyl(lower)alkyl is meant -(CH2) in which £ is 1 to 6; (q) by the term (lower)alkylamino(lower)alkyl is meant -(CH2)nNH-(lower)alkyl in which £ is 1 to 6 and alkyl is as defined in (b); (r) by the term di(lower)alkylamino(lower)alkyl is meant (lower)alkyl (CH2^nN ™ - 1S 1 t0 6 and eacb a1kyl (lower)alkyl is as defined in (b); 0 (s) by the term (lowerjalkanoyl” is meant (lower)alkyl -C- in which alkyl is as defined in (b); jO (t) by the term N-(lower)alkylcarbamoyl” is meant (lower)alkyl-HN-Cin which (lower)alkyl is as defined in (b); (u) by the term “N,N-di(1ower)a1kylcarbamoyl is meant (lower)alkyl^ θ N-C— in which each (lower) alkyl is as defined in (b); (lower) alkyl (v) by the term amino(lower)alkyl is meant -(CH2)nNH2 in which £ is 1 to 6; (w) by the term hydroxyaminotlowerjalkyl is meant -(CH2)nNH0H in which ti is 1 to 6; (x) by the term (lower)alkylsulfinyl11 is meant -!>-(lower)alkyl in which (lower)alkyl is as defined in (b); and (y) by the term (lower)alkenyl is meant a straight or branched unsaturated aliphatic hydrocarbon group containing one double bond and having from 2 to 6 carbon atoms inclusive, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl.

The term heterocyclic as used herein is meant heteromonocyclic and heterobicyclic residues of aromatic character as well as appropriate partially or wholly unsaturated residues, the heterocyclic residues containing at least one heteroatom selected from oxygen, sulfur and nitrogen and being bonded to the adjacent group 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 heterocyclic radicals are the following: H 30597 Similarly, by the terms heterocyclic-(lower)alkyl, heterocyclicthio-(lower)alkyl, heterocyclicoxy and heterocyclicthio are meant -(CHg^-Heterocyclic, -(Cl^n'S-Heterocyclic, -C-Heterocyclic and -S-Heterocyclic, respect ively, in which n is 1 to 6 (preferably 1 or 2).

The term easily removable ester-forming protecting group is one which has acquired a definite meaning within the β-lactam and peptide art. Many such groups are known which are used to protect the carboxyl group during subsequent 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 -7 carbon atoms, alkoxymethyl, alkanoylmethyl of from 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl and β -trimethylsilylethyl.

Choice of an ester-forming protecting group is dependent on the 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. For use as a chemical intermediate the most preferred ester is the p-nitrobenzyl ester which can be readily removed by catalytic hydrogenation. For preparation of compounds containing functional groups reducible under such removal conditions, a preferred alternative is the ΒΊΟ trimethylsilylethyl ester removable by treatment with fluoride ions. Also included within the scope of easily removable ester protecting groups are physiologically cleavable esters, i.e. those esters known in the penicillin and cephalosporin art to be easily cleaved within the body to the parent acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl, thienylglycyloxymethyl or acyloxymethyl of the formula ll -cH2c-y in which Y' is alkyl or phenyl. Particularly preferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

The azetidinones of the present invention are useful as intermediates in the preparation of 2-substituted and 2, 6-disubstituted penem compounds of the formula I, which are claimed in our Irish Patent Specification No. 2461/79.

Some of the compounds of formula I are potent antibacterial agents, while others are useful intermediates for the preparation of the biologically active compounds.

In the compounds of the invention Q is preferably 10 phenyl, R is preferably p-nitrobenzyl and Y is preferably 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 ethyl or α-hydroxyethyl. Still more preferred compounds are those wherein Y is hydrogen or α-hydroxyethyl. The most preferred compounds are those wherein Y is α-hydroxyethyl. 8059 A preferred embodiment of the present invention consists of the compounds of formula IV wherein X is a substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic radical or a ring5 substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic (lower)alkyl or heterocyclicthio(lower)alkyl radical, the substituents for the above-named aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenylalkyl, heterocyclic, heterocyclic-alkyl and heterocyclicthio alkyl radicals being NR.

II ! -CNR2R3 or -N»C-NR2R3 in which «1 R1 is hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzyl. Within this class, the preferred compounds are those wherein Y is hydrogen, ethyl or α-hydroxyethyl, especially those wherein Y is hydrogen or α-hydroxyethyl and most especially those wherein Y is a-hydroxyethyl.

Another preferred embodiment of the present invention consists of the compounds of formula I wherein X is a substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic radical or a ring5 substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl radical, the substituents on the above-mentioned aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenylalkyl, heterocyclic, heterocyclic-alkyl or heterocyclicthio10 alkyl radicals being -CORf in which R^ is amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, -NHNH_, -NR,, N<R181 -NHORig, -SR17, —O(CH2)n-A~Rg or -NReRg in which R1?, Rlg>2 Rg and Rg are (lower)alkyl, R^g is hydrogen or (lower)alkyl, A is 0, S, NH or NCHg and n is an integer from 1 to 6.

Within this class, the preferred compounds are those wherein Y is hydrogen, ethyl or α-hydroxyethyl, especially those wherein Y is hydrogen or α-hydroxyethyl and most especially those wherein Y is α-hydroxyethyl.

Still another preferred embodiment of the present invention consists of the compounds of formula I wherein (a) (CH2)n in which n is an an integer from 1 to 6, preferably 1 to 4; (b) -(CH2)nNHOH in which n is an integer from 1 to 6, preferably 1 to 4; 50587 (c) -(CH,)nPO(O-Cj-Cg alkyl)2 in which n is an integer from 1 to 6, preferably 1 to 4 and alkyl is preferably methyl, ethyl or isopropyl; ™ (d) -(CH2)nNH-C^ in which n is an C^-Cg alkyl integer from 1 to 6, preferably 1 to 4, and alkyl is preferably methyl or ethyl; /NH2 (e) -(CH2)nN=C in which n is an integer from H to 6, preferably 1 to 4; II a B (f) -'(CH2)nOC{CH2)mNR R in which n and m are A B each independently 1 or 2 and R and R are each independently hydrogen or (lower)alkyl; or (g) -(CH2)nNHC-RC in which n is an integer of NH to 6, preferably 1 to 4, and Rc is C^-C^ alkyl (preferably methyl or ethyl), phenyl or (CH,) z ra in which m is 1 or 2.

Within this class of compounds, the preferred members are those wherein Y is hydrogen, ethyl or a-hydroxyethyl, preferably those wherein Y is hydrogen or a-hydroxyethyl and most preferably those wherein Y is a-hydroxyethyl, 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 I, 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 general, it is preferred to incorporate substituent Y in mid-synthesis and to incorporate substituent X by aclyation of mercaptide intermediate III or IHa shown below since these procedures have been found to be the most generally useful.

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

The steps of Process I may be seen from the following scheme: Ο II Ac = CH3C0 =C6H525 Process I (Variation 2): Late incorporation of 2-substituent co2r X-C- © = acylating agent MA = heavy metal salt Process I (Variation 3): Late incorporation of 2-substituent Y-CH=CH-OAc _CSI_> 0,CSNa -> pH 7.5 X CHO I CO R P0-. base C02R -> SOC12 χ-C- @ -> CO2R - 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 0°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 re0 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 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.

The 4-thio azetidinone is next reacted with a glyoxylate ester HC-CC^R wherein R is an easily removable ester-forming 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 reagent (e.g. SOC12, POC13, PClg, 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) in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 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. As used herein dimethoxyethane is to be understood to refer to 1,2-dimethoxyethane.

At this stage the process again diverges into two routes. In Variation I (where the 2-substituent has 1 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, 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 C09Rhί X III or SHgCOOCH. 4-tk J?(Q) C02R 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(l) when x is 1. Mercaptide formation is accomplished by reaction of the phosphorane with a salt of Hg(II), Pb(II), TO Cu(II) or Ag(I) or with (methoxycarbonyl)mercury (II) acetate in a methanol-containing solvent and in the presence 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 , BP4“, F~, C1O4~, N02“, CNO-, etc. The mercaptide inter20 mediate is then reacted with an acylating agent capable of introducing the moiety X-C- wherein X is the desired penem 31 2-substituent. The acylating agent (X-C- © ) may be the acid 0 II 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 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 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 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 a carboxylic acid salt. Removal of the 6-trimethylsilylethyl ester, another useful protecting group, is conveniently achieved by treatment with a source of fluoride ions. Other ester-forming 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 belows Process II (Variation 1): Early incorporation of 2-substituent ch2=ch-oac CSI II XC-SNa pH 7.5 ' 50587 Process II (Variation 2 )_· Late incorporation of 2-substituent CH2=CH-OAc CSI AcSNa Process II (Variation 3) : Late incorporation of 2-substituent 50S97 CH2=CH-OAc CSI 03CSNa pH 7.5 50587 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 incorporated 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 lithium dicyclohexylamide (LDCA), lithium diethylamide, lithium dime thylamide 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. CHgI) or a similar halide such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenylflower) alkyl, heterocyclic, heterocyclic-thio, heterocyclicthio- (lower) alkyl, or heterocyclic-(lower)alkyl, halide, a tosylate or mesylate (e.g. -θ-SO,, CH3CH2OSO2-^~^-CH3 , CH3CH2OSO2CH3 0CH2CH2CH2OSO2CH3, etc.), an epoxide (e.g. Ζλ ) , an S episulfide (e.g. / \). an aldehyde (e.g. CHgCHO, CgHgCHjCHO) r^r° a ketone (e.g. CHgCOCHg, I j ) or an ester (e.g.

CH3CH2COOCH3 or CgHgCOOCHg). Representative examples of other suitable electrophiles are shown below: CH2=CH-CH2Br Br ch3cch=ch2 Br Br I CHgCH-CHg <0>cl 0CH2Br HCHO Q° CHgSSOjCHg 0CECCH2Br ch2sch2ci 0och2ci 0CH=CHCHO Ο II 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 O’C.) according to the general procedure described in Canadian Journal of Chemistry, 50 (19), 3196-3201 (1972).

After formation of the desired 2,6-disubst1tuted penem, any ester10 forming 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); Υ, IM tpHO C02Rn V ο ιι Λ X-C- © _^sc03 co2r soci V de-protect II ^SC-X 0>-νχη · CHO C02R ο II ^SC-X C02R SOC12 ψ de-protect Ψ de-protect Ψ Β = blocking group for ring nitrogen 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-penem 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 χ-c- © , thermal cyclization of the resulting phosphorane tc give the 2,6-disubstituted 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 50587 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-substituted 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. -.s 50587 Illustrative examples of the preparation of compounds of the invention and their subsequent conversion with the penem compounds of formula I 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: CSI chloro sulfonyl isocyanate pet. ether petroleum ether b.p. boiling point n.m.r nuclear magnetic resonance h 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 EtC2H5 Tr -c(o6h5)3 Me ch3- THF tetrahydrofuran Ph phenyl DMF dimethylformamide TEA triethylamine PNBG p-nitrobenzylglyoxylate THP tetrahydropyranyl TFA trifluoroacetic acid HMPT (or HMPA) hexamethylphosphorus triamide EtOAc ethyl acetate DMSO dimethylsulfoxide Ac ch3co- Ms ch3so2- DMAP 4-dimethylaminopyridine py pyridine LDA lithium diisopropyl amide Of the Examples Nos. 2, 10-11 (part), 15, 16 (part) 33, 38 and 41-44 do not fall within the scope of the invention but are nevertheless useful in illustrating the preparation of analogous compounds.

Example Ί ' -12'-Diethylpliosphono-l1-ethyl)penem-3-carboxylic Acid (EtO) -P- (CH2) 2CO2CH3 -V· (EtO> (CH2) 2CO2H -*· A 2 (EtO) J-(CH ) COCI -> (EtO) -^-CH,),COSH 2 2 2 2 2 A A A mixture of 1^ (11.2 g, 50 mmoles) and sh HaOH (10 ml) was stirred and cooled (ice-bath) for 15 min and at room tempe10 rature for 15 min. The mixture was extracted with ether and the extract discarded. The aqueous solution was acidified with 5N HCl and extracted wht CH2C12 to give after drying and evaporation of solvent 10.0 g (95%) of oil 2, nmr δ (CDCl^J, 4.1 (4H, m) , 1.8 - 2.9 (4H, sn) 1.2 (6H, t) .

To a cooled (ice-bath) solution of 2 (2.26 g, 10.76 mmoles) was added dropwise oxalyl chloride (2.74 g, 1.88 ml, 21.5 mmoles).

The mixture was kept at room temperature for 6 h and then it was evaporated to dryness. The traces of (C0C1) 2 were removed azeotropically with benzene to give 2.4 g (quantitative yield) of crude _3.IP. v 1800; 1735 cm \ nmr fi 4.3 (4H, m) , 3.0 - 3.7 'Cl (2H, m) 2.0 - 3.0 (2H, m), 1.4 (6H, m). This was treated 5 with H2S/TEA in a standard procedure to give 1.9 g (80%) of oil 4 estimated to be 80% pure. Nmr: fi 4.1 (4H, q), 2.7 - 3.5 (2H, m), 1.7 - 2.5 (2H, m) 1.33 (6H, t).

OAc ff ff _ ~ JCH,) tEtO)2B-(CH2)^S pf 2Ρ<°Ευ2 To £ (1.9 g, 8.4 mmoles) was added under N2 IM solution of NaHCO(10 ml), followed by addition of £ (0.813 g, 6.3 nmoles) in H^O (3 ml). The pH of the mixture was adjusted to 7-8 by adding more NaHCQ^. After standing for 4 h the mixture was extracted with CHCl^ to give after drying and con15 centration 1.05g (56.4% based on 5) of solid 6, m.p. 64-67e, nmr fi 7.7 (NH), 5.3 (IH q), 4.2 <4H,) 3.8 (IH q) 3.5 (IH, q,, 2.6-3.2 (2H, m) 1.7-2.4 (2H, m), 1.3 (6H.) A mixture of 6 (260 mg, 0.88 mmole) and p-nitrobenzyl glyoxalate (198 mg, 0.88 mmole) was refluxed in benzene (6 ml) under a Dean Stark apparatus for 16 h to give after evaooration of benzene 453 mg of heavy oil Ί_, nmr δ 8.3 (2H, d) 7.6 (2H, d) .3-5.7 (4H,) 4.9 (OH), 4.2 (4H,) 3.55 (IH g), 3.4 (IH, g), 2.5-3.2 (2H, ra) 1.7-2.5 (2H, m) 1.3 (6H) A crude 2 (504 mg, 0.88 mmole) was dissolved in IM 10 solution of pyridine in THF (0.9 ml). To this was added dropwise with stirring and cooling (ice-bath) IM solution of SCClj in THF (0.9 ml) and the mixture was stirred in the cold for 15 rain and at room temperature for 40 min. To it was added benzene (10 ml), and the solid was filtered off. The filtrate v;as concentrated in vacuo to give 463 mg (quantitative yield) of crude 8, nmr δ 8.3 (2H, d), 7.6 (2H, d) , 6.1 (IH, s), 5.7 (IH, m) , 5.3 (2H, d) , 4.2 (4H) , 1.8-3.6 (6H, m) 1.3 (6H). 5059 To a solution of crude 8 (463 mg, 0.88 mmole) in THF (4 ml) was added triphenyIphosphine (236 mg, 0.9 mmole) and 2,6 lutidine (96 mg, 0.9 mmole) and the mixture was allowed to stand at room temperature for 65 h. Then it was fil5 tered, the filtrate concentrated and the residual oil chromato graphed on a silica gel column with ethyl acetate-2* EtOH as eluent, to give 203 mg (30.6¾) of oil 9., which solidified on standing, m.p. 126-128’C.

A solution of 9. (470 mg, 0.635 mmole) in toluene (30 ml) was refluxed for 5 h followed by concentration and chromatography on silica gel-ethyl acetate to give 167 mg (56*) of 10 as oil, XR 1795, 1710 cm 1. nmr δ 8,3 (2H, d) 7.7 (2H, d) 5.7 (IH, m), 5.38 (2H, d) 4.1 (4H) 1.8-3.8 (6H, 1.35 (6H).

To a solution of JO (59 mg, 0.126 nmole) in THF (3 ml) and ether (1 ml) was added NaHC03 (9 mg, 0.107 mmole), water (1 ml) and 10$ Pd/celite (60 mg) and the mixture hydrogenated at 30 psi for 2 hours. The product was isolated as usual to give mg (86%) of 1^ as oil, IR (CHC13) 1798, 1730, 1710 cm'1, nmr δ 9.0 (COgH), 5.6 (IH, m) 4.4 (4H), 3.6 (IH, q), 3.15 (IH, q) 1.7-3.0 (4H, m), 1.3 (6H).

Example 2 6-Acetoxymethyl-2-methylpenem-3-carboxylic Acid Preparation of 1,3-diacetoxypropene 1_ (Ref. L.W. McTeer U.S. 2,866,813. CA 5J 9063) CH =CH-CHO ----+ AcOCH,CH=CH-OAC + CH-Ctl-CH(OAo) Cat. 2 22 Preparation of catalyst: A solution of boric acid (6.2 g) and 15 oxalic acid (12.6 g) in water (44 ml) was evaporated to dryness to give the solid catalyst.

Procedure: Acrolein (140 g; 2.5 mol) was mixed with acetic anhydride (256 g, 2.5 mol) at r.t. A 5 ml portion of this mixture was transferred to a one-liter Erlenmeyer flask and treated with a few drops of catalyst, prepared by dissolving 1.0 g of solid Catalyst in 5 ml acetic anhydride. A vigorous exothermic reaction set in and the reaction mixture was kept at a temperature of 40 - 60’ (controlled by cooling with ice-bath), and the rest of the acroleinacetic anhydride mixture was introduced into the flask in portions of 10 to 15 ml followed by a few drops of catalyst. The resulting mixture was distilled to remove unreacted starting materials followed by 1,1-diacetoxy-propene. The product 51.6 g (13.06%) was obtained next, b.p. 54 - 57“C/ 1.2 mm. NMR: δ (ppm, CDCl^), 7.4 (H, d, J = 12), 5.3 - 5.8 (H, m), 4.5 (2H, d, J - 7), 2.16 (3H, s), 2.05 (3H, s). IR: ν,_θ 1770, 1750, 1680.

AcOCH2CH=CH-OAc Ac Λ™ 2b PROCEDURE: CSI (16.92 g,- 0.12 mol) was added dropwise to cooled (ice salt bath, -15’C) 1 (18.96 g; 0.12 mol). The pale yellow mixture was kept at 5* for 5 h whereby it changed to deep yellow. This was diluted with ethyl acetate (20 ml) , cooled to -30°C, and added in portions to a cooled (ice salt bath) mixture of water (3.4 ml); ice (17.0 g) NaHCO3 (0.3 g) and Na2SC>3 (3.4 g) . .After addition, the resulting mixture was stirred vigorously for 20 min and some additional NaHC03 was added to keep pH at 7-8. The layers were separated, and aqueous layer was extracted with ethyl acetate (2 x 50 ml,. The combined organic phase was dried (Na SO ; NaHCO: 4 3 1:1). It was filtered and evaporated to give 17.4 g of an oil.

This was distilled under high vacuum (0.01-0.05 mm) in a hot air bath. (temp. 55· - 85°) to remove 1^. The undistillcd light brown oil was cooled, taken up in ether and filtered over celite-charcoal to give, after evaporation to dryness 5.28 g (22%) of 4-.1 mixture of 2a and 2b (determined by runr) as colourless oil. NMR: 7.25 (H, NH) , 6.0 (0.25H, d, J = 4.3), 5.8 (0.75H, d, J = 15.), 4.5 (0.5H, d, J = 6.5), 4.4 (1.5H, d, J =, 4.5), 3.8 (0.25H, m) , 3.5 (0.75H, m, , 2.13 (3H, s) , 2.1 (3H, s) . 3a 3b 3c PROCEDURE: Sodium thioacetate was prepared by addition of thioacetic acid (2.22 ml, 2.363 g) to a solution of IM NaHCO3 (31.0 ml) under nitrogen. This was added to a cooled (ice bath) solution of 2. (5.2 g; 25.9 mmoles) in water (20 ml) and stirred for 4 h at room temperature. Some acetone ( 20 ml) was added to render the reaction mixture homogeneous. The mixture was concentrated in vacuo to remove acetone and then extracted with methylene chloride. The extract was dried and evaporated to give 5-6 g of a mixture of isomers (83.14%) of 3a and 3b. The NMR spectrum of the crude oil showed that there were one trans and two cis compounds present in the mixture. A sample (550 mg) was chromatographed on silica gel (30 g, 10% H^O) and eluted with benzene-ether-methanol to give 200 mg of a mixture of 3a and 3b in the ratio of 7:1, followed by 150 mg of an unknown cis compound (6 5.55, d, J = 4.3) to 50587 uhich structure 3c was tentatively assigned. NMR: 6.78 (Η,ΝΗ), 5.52 (0.17H, d, J = 4.3) , 5.18 (0.83H, d, J » l.S) , 4.37 (2H, d, J = 4.5 ) . 3.45 (H, m), 2.35 (3H, s), 2.05 (3H, s) . IR: v 1765, 1740, 1600 cm?1 c=o PROCEDURE: A mixture of crude 2 (2.1V g; 10 mmoles) and p-nitrobenzyl glyoxylate (2.5 g; 11 mmoles) in benzene (200 ml) was refluxed 20 h under a Dean Stark water collector followed by 10 concentration in vacuo to give 3.4 g of crude £ as oil. -This was used as such without further purification. NMR: δ 7.5 - 8-5 (4H), 5.2 - 5.8 (4H), 3.4 - 5.1 (4H), 2 - 2.4 (6H). IR: V 1665, c=o 1740, 1740, 1730, 1700.

PROCEDURE: To a cooled (ice-bath) solution of crude 5. (3.3 g; 7.75 mmoles, and pyridine (0.67 g; 8.5 mmoles) in benzene (20 ml) was added dropwise thionyl chloride (1.01 g; 3.5 mmoles) in benzene (10 ml) and the mixture stirred at the above temperature for 15 min. and at r.t.for 15 min. The benzene solution was decanted, and the residual semi solia washed three times with 15 ml portions of benzene. The combined benzene solution was evaporated to give 1.90 g of crude 5. (55%). NMR: δ 7,5 - 8.5 (4H) , 6.12 and 6.2 (IH) , 5.66 (IH, m), 5.4 (2H, d, J = 6), 4.3 - 4.7 (2H, m) , 3.63 (H, m) 2.4 (3H, d), 2.1 (3H, s).

IR: V 1765, 1740, 1730, 1700. c=o PROCEDURE: A mixture of crude £ (1.90 g; 4.27 mmoles) triphenylphosphine (1.572 g: 6 mmoles) and 2,6-lutidine (0.642 g; 6 mmoles) in dioxane (20 ml) was heated at 55° for h. It was cooled, filtered and evaporated to give 3.8 g of a crude dark oil. This was chromatographed on silica gel to give 1.2 g (42%) of 6.

Ac< SAc -ρ=Ρ(Φ) 3 CO PNB 2 PROCEDURE: A solution of crude £ (1.20 g; 1.79 mmoles) in toluene (15 ml) was refluxed for 5 h. It was cooled and evaporated to give an oil which was chromatographed on Sic (30 g) and eluted with benzene to give 0.4 g of 7 (57%).

Anal, calc'd for C17H16N2°7S· C 52.04: H 4.11: N 7.14. Found: C 51.77; H 4.08; N 7.30.

Separation of the cis and trans isomers was 5 achieved through careful chromatography on silica gel (60 g) eluting with benzene. cis-isomer: δ (ppm, CDCip: 7.5-8.5 (4K, aromatics), 5.67 (IH, d, J » 5, H-5), 5.28 (2H, AB quartet benzyl), 4.33 (2H, d, AcOCH2>, 4.20 (IH, dt, H-6), 2.31 (3H, s, CH ), 2.0 (3H, s, CH CO). v '1770, 1740, 1730 cm-1.

J —-j CeO trans isomer: δ (ppm, CDCl^): 7.5-8.5 (411, aromatics), 5.53 (IH, d, J - 2, H-5,, 5.30 (2H, AB quartet, benzyl), 4.32 (2H, d, AcOCH2), 4.27 (IH, dt, J « 5, J - 2, H-6,, 2.31 (3H, s, CH ) , 2.0 (3H, s, CH CO). v 1770, 1740, 1730 cm1. —3 —3 c-o PROCEDURE: To a solution of trans 7 (119 mg; 0.3 mmole) in ethyl acetate (15 ml) and water (7 ml) was added NaHCO(25.2 mg, 0.3 mmole) and Pd/C (110 mg) and this was hydrogenated 4.5 h at psi. The mixture was filtered and layers separated. The aqueous layer was washed with ether and then lyophilized to give 40 mg of solid £) (48%) . 597 vc=o 1765, 1740, 1600 cm 1. 6 (ppm, D2O): 5.52 (IH, H-5), 4.85 (2H, AcOCH2), 4.0 (IH, H-6), 2.65 (3H, CI^), 2.40 (3H, CHjCO).

PROCEDURE: To a solution of crude trans 8 (100 mg) in cold water (2 ml) was acidified with cold IN HCl and extracted with CHCl^. The extract was dried (Na^O^) and evaporated to give 30 mg of a pale yellow solid. M.P. 111-113° with decomposition. XR V 1780, 1750, 1680. (Neat). IR: (KBr): υ _ 1775 (Strong), c=o c_o 1745, 1670.

Treatment of cis paranitrobenzyl 6-acetoxymethyl2-methyl-penem-3-carboxylate according to the above procedure gives the cis sodium salt and free acid.

EXAMPLE 3 l-tp-Nitrobenzyloxycarbonylmethyltriphenylohosphoranyl·)^(silver mercaptidyl)-2-azetidinone co2pnb OAc STr TrSH --► NaOMe A methanol (90cc) suspension of triphenylmethyl mercaptan (13.8 g, 0.05 mmole) was degassed for 0-5 hour with a nitrogen stream. The mixture was cooled down at 0’ and sodium hydride (2.4 g, 0.05 mole, 50% oil dispersion) was 10 added portionwise. The resulting solution was stirred for min and 4-acetoxyazetidinone (7.7 g, 0.059 mole) in water (55 cc)· was added rapidly. Precipitation of 4-triphenyl methyl mercaptoazetidinone ii) 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 MgSOd (89.8%, m.p.: 146.5 - 147,5°C) Anal. Calc'd for C^H NOS: C, 76.49; H, 5.54; N, 4.05; S, 9.28 Found: C, 7.54; H, 5.60; N, 4.00; S, 9.36. 6(ppm, CDCip 7.60 - 7.10 (15H, m, H-trityl) , 4.62 (IH, bs, NH) , 4.40 (IH, dd, J43 fcrans = 3.0, J4_3 c.s = 5, H-4), 3.24 (IH, ddd. %em = 15' Jg-4 cis = S' ™ = H’31 ' 2‘81 J. . = 3.0, J 3-4 trans 3-NH 3-NH 1.2, H-3) Vo (CHC13) 1760' VNH 3340« STr OTO C0_l PNB STr 0Χ-Ϊγ>0Η PNB = 15, Hydrated p-nitrobenzyl glyoxylate (4.54 g, 0.02 mole) and azetidinone 2_ (6.90, 0.02 mole) were refluxed in benzene o 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 HCl, water, aqueous % NaHCO 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 (CH2Cl2-ether 6:4) Isomer A: Rf = 0.87, m.p. = 170.5- 171.5° δ(ρρπι, CDClj) 8.07 (2Η, d, J=9, Hm aromatic), 7.45 (part of d, Ho aromatic) , 7.40-7.00 (15H, m, Trityl), 5.25 (2H, s, CH^PNB) , 4.75 (IH, s, H-C-O), 4.37 (IH, dd, J, , = 3, J . = 4, H-3), 3-4 trans 3-4 cis 2.83 (IH, dd, J = 16, J, , . = 4, H-4), 2-10 (IH, dd, J = 16, gem 4-3 cis gem 5 J a i = 3' H-4’’ 1·42 (b-s·' θΗ>· 4-3 trans υ (CHCl) 1770, 1760 (shoulder), V,A 1525, 3475. cso 3 NO^ θ** Isomer B: Rf = 0.75, m.p. = 152 - 153’ t δ (ppm, CDC13), 8.13 (2H, d, J = 9, Hm aromatic), 7.47 (2H, d, J - 9, Ho aromatic), 7.40 - 7.00 (1SH, m, trityl), 5.30 (3H, s, CHj-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 (CHCl ) 1767, 1755 (shoulder), V 1525, V 3500. c=o 3 NO A cold (-15“) THF (150 cc, dried over molecular sieves) solution of azetidinone _3 (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 min at -15’. The precipitate was filtered off and washed with benzene. Evaporation of solvent gave a residue which was 59 taken up in benzene and treated with activated charcoal (11.7 g, 94%, crystallized out from chloroform). 6(ppm, CDCl^) 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, CH2-PNB), 4.81 (IH, m, H-4), 3.27 - 2.40 (2H, m, H-3) V (KBr film) 1785, 1770 V 1525. c=o NC>2 A THF (100 cc, distilled over LAH) solution of chloroazetidinone 4. (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 solventgave 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 _H AN0 SP: 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. υ (CHCl ) 1740, u phosohorane (1620, 1610), υ 1525. c=o 3 - N0_ • 4-Tritylmercapto azetidinone 5, (1.6 g, 2 mmoles) was dissolved in CK2C12 (20 cc) and the solvent was flushed down at 55°-60°. Phosphorane A 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) . )0 The warming bath was then immediately removed. The mixture was stirred at room temperature for 2 h and at 0°C for 1 h. The silver mercaptide 6 was filtered off, washed twice with cold (0°, methanol and three times with ether. (1.12 g, 84.5%, m.p.: 130-135 dec.).

V (CHC1) 1795, 1725 (shoulder) c=o 3 V.phosphorane (1620, 1605), NO, 1530.

' Example 4 1-(p-Hitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone SCOCH. (f=PPh3 COOPNB K?CO3,A9NO3 MeOH _/SAg x ^(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 0eC under nitrogen atmosphere and treated successively with I 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 0°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 1: 1748, 1620 and 1605. An analytical sample was obtained by preparative TLC (ethyl acetate); M.P.: 140 - 5°C dec, calc'd for C H NO SPAg: C, 54.31: H, 3.65; N, 4.22; S, 4.83. Found: C, 54.11; 24 2 5 H, 3.48; N, 3.92; S, 4.62.

Example 5 1- (p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4( silver mercaptidyl)-2-azetidinone A. Use of aniline as base Aniline, AgNO -3-► MeOH A solution of phosphorane / (1.8 g, 3.0 mmoles) in chloroform (4 ml) was diluted with methanol (90 ml), cooled to -15’C under nitrogen atmosphere and treated successively with silver nitrate (0.56 g, 3.3 mmoles) and aniline (1.5 jnl, 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 7.

Silver-1-(paranitrobenzyl 2'-triphenylphosphoranylidene-21-acetate)2-azetidinone-4-thiolate B. Use of lt-dimethylaminopyridlne (DMAP) as base AgNO/DHAP ch2ci2/ch3oh CO PNB 2 A solution of the above Ξ-acetyl phosphorane (17.96 g, mmol) in methanol and dichloromethane (1:2, 450 ml) was purged with nitrogen (5-10 min), cooled to 5’C and treated successively 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 1 h. The colored reaction mixture was treated with charcoal, filtered and evaporated. Tiie 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 (CHCl ) V : 1745 (C=O of β-lactam) and 1607 cm 1 (C=O of ester). max .xX SCOCH_ CO.PNB C.

Silver-1- (paranitrobenzyl 2‘-triphenylphosphoranylidene-2-acetate)-2Use nf l,8-diazabicyclo[5.4.o[ undec-7-ene (DBU) as base DBU, MeOH AgNO _ ' SAg J_n W T CO PNB 2 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 naill) V (c=O) and 1600 cm max (phosphorane) D. Use of pyrrolidine as base Silver 1-(paranitrobenzyl 2'-triphenylphosphoranylidene-2-acetate)2-azetidinone-4-thiolate ri SCOCH, Pyrrolidine AgNO, SAg C=PPh L OOPNB xC=PPh„ I 3 COOPNB To a cold (0°C) solution of 4-acetylthio-l-(paranitro2o benzyl 2-triphenylphosphoranylidene-2-acetate)- 2-azetidinone (0.60 g, 1.0 mmol) in CHjClj (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 pyrrol64 * idine (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 -10eC, stirred for 0.25 h and filtered. The solid was washed with cold MeOH and dried in vacuo; 0.548 g, m.p. 115°C, 82.4%. ir (nujol) V : 1755 (C=0) and 1600 cm 1 (aromatics). max Example 6 Mercuric (II)-[2*-Triphenylphosphoranylidene-2’-acetate]-2-azetidinone4-thiolate Hg(OAc)2 S)2Hg PPh, r COjPNB II A solution of I (2.4 g, 3 mmoles) in dichloromethane (15 ml) was cooled to 5“C and treated with a solution )5 of mercuric acetate (0.525 g, 1.65 mmole) dissolved in methanol (15 ml) . After stirring at 5eC 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 cm”1 (V β-lactam) c=o 1608 cm 1 (phenyl) Example 7 2-Methylnenem-3-p-nitrobenzyl-carboxylate (from mercaptide intermediate) /9)2«9 J-N PPh. '-γ' _/SCOCH pyridine PPh.

CO2PNB CO2PNB II III A solution of II (262 mg, 0.2 mmole), acetyl chloride (35 mg, 0.44 mmole) and 2 drops of pyridine in 10 ml of dichloromethane was stirred at 5°C for 1 h. The precipitated mercuric chloride was then filtered off and the filtrate washed successively with cold dilute hydrochloric acid, sodium hydroxide and finally brine. The organic solution was submitted to a stream of hydrogen sulfide for 2 minutes at 5°C and stirred at that temperature for an additional 10 minutes in order to precipitate the last traces of mercuric salts. Some charcoal was added to the black mixture which was then filtered through a pad of celite. Evaporation of the clear filtrate left 193 mg (80.7%) of III as a foamy material.

I.R. (CHCI ) 1755 (u β-lactam) 1692 (V,_____ ) 1620 (phenyl).

C—O SCOCH phosphorane III (75 mg, 0.126 mmole) in toluene (10 cc, was refluxed over a 2.5 h period under nitrogen atmosphere. Solvent evaporation and purification of the residue afforded a crystalline derivative (25 mg, 63%, whose physical and spectral data were in complete agreement with those of the title product.

Productiv may if desired be subjected to catalytic hydrogenation (30% Pd on celite) to produce the corresponding 3-carboxylic acid product. 597 Example 8 2-AminomethyIpenem-3-carboxylie Acid (from mercaptide intermediate) A solution of silver mercaptide _1 (1.25 g, 1.99 mmole) in dichloromethane (15 ml) kept under nitrogen atmosphere was cooled at 0°C and treated dropuise with a 2M solution of azido10 acetyl chloride in dichloromethane (1.13 ml, 2.26 mmoles). The reaction mixture was stirred at 0°C for lh; the cooling bath was removed and stirring was continued for 5 h. The reaction mixture was filtered over a celite pad and the solids were washed with dichloromethane (35 ml). The filtrate and washings were combined, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to an orange syrup which was purified by column chromato-, graphy ( 30 9 of silica gel 60, eluate; e ther - 2% ethyl acetate (200 mllj ether -6% ethyl acetate (200 ml) and ether-20* ethyl acetate (500 ml), fraction size: 10 ml). The combination and evaporation of fractions 49-80 gave a yellow powder; 0.73 g, M.P. 61-70’, 60.8%. ά Toluene COOPNB A solution of phosphorane 2 (0-593 g, 0.93 mmole) in toluene (20 ml) was heated at 105“C for 1 h, cooled to 23°C and concentrated to a semi-crystalline compound which was purified by column chromatography (12 g of silica gel 60, Eluate: benzene (100 ral)< benzene-2* ether (100 ml) and benzene-4* etherjfraction size: ml). The combination and evaporation of fractions 18 - 26 gave a yellow syrup which crystallized on standing; 0.18 g, M.P.: 127-8“C, 53.7*. NMR (CDC1 ) δ 8.22 (2H, d, J „ = 8.8 Hz, Ho * HO, nm of p-nitrobenzyl), 7.60 (2H, d, J = 8.8 Hz, Hm of p-nitronlTl, HO benzyl), 5.71 (IH, dd, cis = 3.6 Hz, = 2.1 Hz, H-5), 5.33 (2H, center of ABq, J . = 14.0 Hz, CH of p-nitrobenzyl), Ά fO i 4.58 (2H, center of ABq, = 15.0 Hz, CH2on C-2) 3.88 (IH, dd, J . = 3.6 Hz, J = 16.5 Hz, H-6 cis) and 3.55 (IH, dd, 6,5 cis gem J , = 2.1 Hz, J - 16.5 Hz, H-6 trans). 6,5 trans gem I.R. (Nujol) cm”1: 2115 and 2090 (H ) , 1780 (c=o of β-lactam) and 1685 (c=o of ρ-nitrobenzyl ester)· An analytical sample was obtained by preparative T.L.C.; M.P. 127-8°C, calc'd for Ο,,Η,,Ν O S: C, 46.54; H, 3.07; N, 19.37; S, 8.87. Found: 14 11 5 5 C, 46.43; H, 3.08; N, 19.37; S, 8.90. 597 rf COOPNB % Pd/celite , THF, ether, H2O To a solution of penem £ (0.18 g, 0.5 mmole) in tetrahydrofuran (6 ml) was successively added ether (6 ml), water (6 ml) and 30% palladium on celite (0.18 g) . The reaction mixture was hydrogenated under 30,p.s.i. at 23°C for 2.5 h and filtered over celite pad; the pad was washed with water and the filtrate and washings were combined, washed with ether-THF mixture and lyophilized to give 30 mg, 30%, of compound 4_. [Water ana echer insoluble compound were dissolved in chloroform and the organic solution was washed with water and dried over anhydrous sodium sulfate. The evaporation of solvent under reduced pressure gave 77 mg (42.8%) of starting material £). NMR (DMSO d-6) 6: 5.7 (dd, Jc , . - 3.5 Hz, J -6 cis 5-6 trans 1.5 Hz, H-5) . I.R.(nujol) cm 1: 1775 (c-o of β-lactam) and 1615, 1585. U.V. λΗ2° πψ: (£=2320) max and 307 (ε=2685) Example 9 Sodium 2-Hydroxyaminopropylpenem-3-carboxylate I 2 To a cold 5% aqueous solution of sodium hydroxide (320 ml) was added ester £ (21.6 g, 0.134 mole). The resulting mixture was stirred at room temperature for 2 h and then concentrated to 250 ml and acidified with concentrated HCl. The mixture was extracted with ethyl acetate (4 x 200 ml) and the organic extracts were dried over sodium sulfate. Concentration on rotary evaporator left an oil. Yield 13.2 g (75%).

+ SOC12 -¼ Ο COCI A solution of acid j2 (13.2 g, θ-l mole) in SOC12 (25 ral) was stirred for 2.h at 30°C. After evaporation of thionyl chloride» the residue was distilled under vacuum T = 76-78°C (P=0.2 mm Hg). Yield 8.8g (58.3%) as a colourless liquid: n.m.r. (CDCl.^ 6ppm:2.40 (2H,m,; 3.IS (2H, t, a-CH2) ; 4.SO (2H, t, y-CH^ i.r. (neat,: 1550 cm 1 (v.JQ ); J'iQ cm 1 (V , acid chloride) . c=o 4 A solution of 2 (19.46 g, 0.128 mole) in methylene chloride (200 ml) was added rapidly to a cold (0-10°, stirred solution of triethylamine (36 ml, 0.256 mole) in methylene chloride (500 ml) which had been saturated at 0-5° with The mixture was stirred at -10° for 1 h and then a stream of nitrogen was passed through the solution to eliminate the excess of H2S. The mixture was washed with 10% HCl, the organic extract was concentrated to about 150 ml and then sodium bicar20 bunate ( 10.9 g) and uater (500 ml) was audwd. The pH was j.)justed to about 7.5 with NaHCOg or HCl. The resulting mixture cooled to 0°C and 4-acetoxy-2-azetidinone (16.8 g, 0.13 mole) xn water (20 ml) was added with vigourous stirring. After 4 h the mixture was extracted with ethyl acetate. The extracts were washed with 10% HCl, sat. NaHCO3, brine, dried (Na2SO4, and evaporated.

The residue was purified by column chromatography (SiC>2; eluent: ether then ether-ethyl acetate 5%) giving an oil which crystallized in ethyl acetate-hexanes yielding £ (3.5 g, 12.5%) as a white powder. (m.p. 45-47“C).

A mixture of azetidinone £ (1.09 g. 5 mmoles) and p-nitrobenzyl glyoxylate hydrate (1.2 g, 5.25 mmoles) in benzene (100 ml) was heated at reflux with a Dean-Stark trap filled with β 4A molecular sieves for 18 h. Evaporation of the solvent gave the glyoxylate adduct £ (2.1 g) as an oil.

Azetidinone glyoxylate £ (2.1 g) was dissolved in tetrahydrofuran (50 ml) and pyridine (0.57 ml, 7 mmoles) was added to the solution. The mixture was cooled to 0°C and SOC12 (0.5 ml, 7 mmoles) was slowly added. The mixture was stirred 1 h at 0°C and then filtered before evaporation to dryness. Filtration of this material over a pad of silica gel with CH2C1? gave a foam; yield 1.9 g (85%).

To a solution of chloroazetidinone (6.2 g, mmoles) in THF (300 ml) was added triphenyl phosphine (5.5 g, 0.02 mole) and 2,6-lutidine (2.4 ml, 0.02 mole). The mixture was heated at 45°C for 20 hours. Lutidine hydrochloride was filtered off and washed with ether. The filtrate was then evaporated. The residue was purified by chromatography through a silica gel column and eluted with dichloromethane and dichlo10 romethane-ethylacetate (1:1). Evaporation of eluent gave a white solid (2.9 g, 30%).

:=P3 :o2pnb no2 A Toluene ___-a, ~ :o2pnb io Phosphorane _7 (2.0 g, 3 mmoles) in toluene 15 (150 ml) was refluxed for 2.5 h. Evaporation of solvent afforded an oil which was purified by chromatography through a silica gel column and eluted with dichloromethane and dichloromethane-ethylacetate (9:1). Evaporation of the solvent gave a syrup which crystallized in ethylacetate-hexanes as a 20 white solid (0.82 g, 40.7%).

To a solution of ester £ (50 mg, 0.127 mmole) in tetrahydrofuran-ether mixture (2:3, 25 ml) was added water (10 ml), sodium bicarbonate (10 mg, 0.127 mmole) and 30% palladium on diatomaceous earth (50 mg). The reaction mixture was hydrogenated under 50 p.s.i. for 3 h at 25’C, filtered over a celite pad and washed with ether. Acueous solution was lyophilized yielding a yellow powder (30 mg) Example 10 6-Ethyl-2-aminomethylpenem-3-carbo>iylic Acid (cis and trans isomers) a. Silver cis and trans 3-ethyl-l-(n-nitrobenzyl-21 15 triphenylnhosphoranylidene-21-acetate)-2-azetidinone4-thiolates A solution of cis and trans 3-ethyl-l-(p-nitrobenzvl2'-phosphoranylidene-21-acetate)-4-acetylthio-2-azetidinones -4-thiolates. Λ solution of cis ana trans 3-ethy1-l-(p-nitrobenzyl-2'-phosphorany)idene21-acetate)-4-acety1thi o-2-azeti di nones (1.88 g., 3.0 mmoles) in chloroform (4 ml.) was diluted with methanol (90 ml.i, cooled to 0° and treated successively with finely powdered silver nitrate (0.51 g., 3.0 mmoles) and potassium carbonate (0.33 a., 2.4 moles). The mixture was stirred vigorously 15 min. at 0°, 3 h at room temperature and 1 h at -10°C. The precipitated silver mercaptide was collected by filtration, washed with methanol and with ether and dried in a vacuum.

The title product was obtained as a greyish solid, m.p. 112-135 · d. vc=0 1750, 1620, 1605. t b. Cis and trans 3-ethvl-l-(p-nitrobenzyl-21-phosphoranylidene2’-acetate)-4-azidoacetylthio-2-azetidinones A solution of the above crude mercaptide (1.31 g,.2 mmoles) in dichloromethane (15 ml) was cooled to 0° and treated, under a nitrogen atmosphere, with a 2M solution of azidoacetyl , chloride in dichloromethane (1.13 ml, 2.26 mmoles). The mixture was stirred at 0° for 1 h and at room temperature for 5 h. The insoluble silver salts were removed by filtration over Celite and washed with dichloromethane. The combined filtrates were washed with dilute sodium bicarbonate solution and water, dried and concentrated. The oily residue was purified by chromatography over silica gel (35 g) eluting with ether-ethyl acetate. The pertinent fractions were concentrated to give a mixture of cis and trans acylated compounds as a semi-solid; 0.62 mg. v (CDCl^): 2105, 1760, 1690, 1621 cm-1. c. Cis and trans p-nitrobenzyl-2-azidomethyl-6-ethylpenem-3carboxvlates A solution of the above crude phosphorane (0.60 g) in 76 toluene (30 ml) was kept at 105’ for 1 h, cooled and concentrated to leave an oily residue which was purified by column crtromatography over silica gel (20 g) eluting with increasing proportions of ether in benzene. The pertinent fractions were concentrated to give both the cis and trans isomers. cis isomer: δ (ppm, CDCl^): 8.25 (2H, d, J = 8.8, Ho of paranitrobenzyl), 7.65 (2H, d, Hm), 5.93 (IH, d, J = 4.1, H-5), 5.38 (2H, AB quartet, J = 14.0, benzyl), 4.68 (2H, AB quartet, J = 15.0, CH2-a3), 3.4 (IH, m, H-6), 2.0 (2H, ra, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3). trans isomer: δ (ppm, CDClj) : 8.18 (2H, d, J = 8.8, Ho), 7.59 (2H, d, Hm), 5.52 (IH, d, J = 1.4, H-5), 5.33 (2H, AB quartet, J = 14.0, benzyl), 4.58 (21i, AB quartet, J = 15.0, ΟΗ,,-Mj) , 3.7 (IH, dt, J = 1.4, J = 7.4, H-6), 1.9 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3). d. Trans 2-Aminomethyl-6-ethylpenem-3-carboxylic Acid A mixture of the above trans p-nitro benzyl ester (0.20 g, 0.5 mmole), THF (6 ml), ether (6 ml), water (12 ml) and 30% palladium on celite (0.20 g) was reduced at 23° for 2.5 h at an initial hydrogen pressure of 30 psi. The catalyst was removed by filtration over celite and washed with water. The combined filtrates were washed with ether-THF and lyophilized to give the crude trans acid (12 mg). Chromatography over a column of Sephadex G-10 eluting witn water gave the pure trans acid (6 mg) as a hygroscopic powder. 1775, 1615 cm λ = 306 (ε => 3465). δ (ppm, D-O-DMSO): 5.40 (IH, d, J = HlciX Z 2.0, H-5), 2.0 (2H, ra, CH_2CH3) , 1.1 (3K, t, J = 7.4, CII2CH'3) . 50587 e. (cis 2-Ami nomethyl-6-ethylpenem-3-carboxylic Acid Reduction of the cis-p-nitrobenzyl ester as described, above for the trans-ester gave the cis-acid as a yellowish hydroscopic power (13%) γθ 1775, 1615 cm'1, λ , 304 (e=35631. 5 (ppm, D-O-DMSO): 5.75 (IH, d, J = 4.0, H-5), ίΠαΧ ' 2 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J=7.4, CH2CH3).

Example 11 The following compounds may be prepared by procedures similar to the general procedure of Example 10.

Y C02Z Acylating Agent Y X z 0OCH2COC1 -ch3 -CH2O0 Na, N3(CH2)2COC1 -ch3 -(CH2)zNH2 N3(CH2)3COC1 -ch3 -(CH2)3NH2 NC(CH2)2COC1 -ch3 -(CH2)3NH2 O2N(CH2)3COC1 -CH3 -(CH2)3NH0H Na, N3(CH2)4C001 -CH3 (CHgl/JNHg N3(CH2)20CH2C0Cl -ch3 -CH2O(CH2)2NH2 N3(CH2)2SCH2C0Cl -ch3 -CH2S(CH2)2NH2 AcNH(CH2)2CO2CO2Et -ch3 -(CH2)2NHAc Na, 0OCH2COC1C2H5 -CH2O0 Na, |\ COCI -CoHn Z1 Na, N3(CH2)2COC1 2 5 -c2h5 -(CH2)2NH2 N3(CH2)3COC1 'C2H5 -(CH2)3NH2 O2N(CH2)3COC1 -C2H5 -(CH2)3NH0H Na, 1 N3(CH2)4COC1C2H5 -(ch2)4nh2 1 N3CH2COC1 1SO-CgHy -ch2nh2 1 N,(CH2)2COC1 i SO-C-jHy -(ch2)2nh2 1 N3fCH,)5cOCl lSO-CjHy -(CH2)3NH2 i o2n;ci2i.coci iso-C3H7 -(CH2)3NH0H Na, I Example 12 ^^.an^trans^e^Acetoxymeth^l^^aminOTiethylgenan-S^carboxybic Acid a) 3-Acetoxymethyl-4-tritylthio-2-azetidinones (cis and trans isomers) A solution of a mixture of cis and trans 4-acetoxy3-acetoxymethyl-2-azetidinone (4.7 g, 25 mmoles) (Example 2, structure 26) in water (200 ml) was added rapidly to a vigorously stirred solution of sodium triphenyImethyl mercaptide (from tripheny Imethyl mercaptan, 55.2 g; and sodium hydride, 9.6 g, in methanol, 300 ml). The mixture was stirred at room temperature for 4 h and the solids were collected by filtration, washed with water, and dissolved in dichloromethane. The solu15 tion was washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, dried and concentrated to leave 85% of a solid which was used as such in the next experiment. b) cis and trans 3-Acefcoxymethyl-l-(p-nitrobenzyl-2'-hydroxy21-acetate)-4-tritylthio-2-azetidinones 2q A solution of the above azetidinone (8.0 g, 20 mmoles) and p-nitrobenzyl glyoxylate (4.54 g, 20 mmoles) were refluxed in benzene (100 ml) through a Dean-Stark water separator filled 597 with 3A molecular sieves. After 24 h a second quantity of pnitrobenzyl glyoxylate (4.54 g) was added and the reflux continued for a further 24 h. The mixture was diluted with ether, washed with 5% aqueous hydrochloric acid, water, aqueous 5% sodium bicarbonate and water. Drying and concentrating left 100% of the crude isomeric mixture as an oil. c) cis and trans 3-Acetoxymethy1-1-p-nitrobenzy1-2'-chloro21-acetate)-4-tritylthio-2-azetidinones A solution of azetidinones from part b (12.2 g, 20 mmoles) and pyridine (1.9 g, 24 mmoles) in dried THF (150 ml) was cooled to -15° and treated dropwise with thionyl chloride (2.86 g, 24 mmoles) under a nitrogen atmosphere. The mixture was stirred 45 min at -15°, the precipitate was removed by filtration and washed with benzene, and the filtrates were concentrated to leave a semi-solid (95%) . d) cis and trans 3-Acetoxymethy1-1-(p-nitrobenzyl-21-triphenylphosphoranylidene-2 1-acetate)-4-tritylthio-2-azetidinones A mixture of azetidinones from step c (12. 6 g, 20 mmoles), triphenylphosphine (7.8 g, 30 mmoles) and 2,6-lutidine (2.6 cc, 22 mmoles) in THF (100 ml) was heated under reflux for 80 h. The insoluble material was removed by filtration and washed with ether. The filtrates were washed with 2% aqueous hydrochloric acid, 5% aqueous sodiuin bicarbonate and water, dried and concentrated. The residue was dissolved in benzene, filtered slowly through a pad of silica gel (250 g) and the pad was eluted with increasing proportions of ether in benzene. Concentration of the pertinent fractions gave a mixture of the title compounds (65%). vc=o 1740, ',c_p0 1620, 1610, 1525 cm-1. e) Silver cis and trans 3-Acetoxymethyl-l-(p-nitrobenzyl-2 triphenylphosphoranylidene-21-acetate)-2-azetidinone-4thiolates The crude azetidinones from step d (8.5 g, 10 mmoles) were dissolved in hot methanol (55-60°). A hot solution (55-60°) of silver nitrate (2.0.4 g;12mmoles) and pyridine (0.87 g, 11 mmoles) in methanol (80 ml) was added. The mixture was allowed to cool down to room temperature in 2 h and stirred a further 1 h at 0°. The silver mercaptide was collected by filtration, washed with ice-cold methanol and then with ether. (5.7 g, 82%z melts with decomposition). \>c^_o 1745, 1740, 1625 cm \ f) cis and trans 3-Acetoxymethyl-4-azidoacetvlthio-l-(p-nitrobenzyl 2'-triphenylphosphoranylidene-21-acetate)-2-azetidinones The above silver mercaptide (from step e; 1.4 g, 2 15 mmoles) in dichloromethane (15 ml) treated as described in Example 28 with azidoacetylchloride (2.3 mmoles) gave 0.78 g of a yellow powder, g) cis and trans 6-Acetoxymethyl-2-azidomethylpenem-3carboxylic Acid p-Nitrobenzyl Esters 20 A solution of the above crude phosphorane (0.70 mg) in toluene (35 ml) was kept at 105° for 1 h, cooled and concentrated to leave an oil which was purified by chromatography over silica gel (25 g) eluting with increasing proportions of ether in benzene. The pertinent fractions were concentrated to give the cis and trans-isomers of the title compound. cis isomer: δ (ppm, CDClg): 8.5-7.5 (4H, aromatics), 5.67 (IH, d, J = 5, H-5), 5.31 (2H, AB quartet, CHj-benzyl), 4.50 (2H, AB quartet, CH^) , 4.33 (2H, d, AcOCH2), 4.26 (IH, dt, H-6), 2.0 (3H, s, CHg). trans isomer: δ (ppm, CDClg): 8.5-7.5 (4H, aromatics), .62 (IH, d, J = 2, H-5), 5.33 (2H, A3 quartet, CH2-benzyl), 4.40 (IH, dt, H-6), 4.50 (2H, AB quartet, CH^Ng), 4.27 (2H, d, AcOCH2), 2.0 (3H, s, CHg). h) trans 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic 1q Acid Hydrogenation of the above trans isomer by the procedure described in Example 28 gave the title compound. v „ 1775, 1740, 1616 cm-1. v 304 (ε = 3192).

C-·Ο 'IiIgjC i) cis 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic Acid Hydrogenation of the corresponding cis isomer as described in Example 28 gave the title compound as an unstable hygroscopic semi-solid.

Example 13 S0597 The following compounds may be prepared by procedures the general procedure of Example 12. similar to Acylating Agent Y X z ii3(CH2)2C0Cl -CH20Ac -(ch2)2nh2 H n3(ch2)3coci -CH20Ac -(ch2)3nh2 H n3(ch2)4coci -CH20Ac -(ch2)4nh2 Fi o2n(ch2)3coci -CH20Ac -(CHz)3NH0H H 10 N3CH2COC1 -(CH2)20Ac -ch2nh2 H N3(CH2)2c0Ci -(CH2)20Ac -(CH2)2NH2 H N3(CH2)3C0Cl -(CH2)20Ac -(CH2)3NH2 H n3ch2coci fH3 -CH- OAc -ch2nh2 H Example 16 2-(4'-Phthalimido-l·'-butyl)penem-3-carboxylic Acid To a solution of triethylamine hydrosuifide, previously prepared by bubbling HjS gas through a methylene chloride (200 ml) solution of triethylamine (8.8 ml, 63.7 mmoles), was added dropwis° a methylene chloride (75 ml) solution of £ (Gabriel Ber. 41, 2010) (10.65 g, 40.2 mmoles), at 0°C over a 30 min period. The mixture was stirred at 0°C for 15 min and 2 h at room temperature. The Organic solution was diluted with methylene chloride (125 ml) and washed with IN HCl (2 x 15 ml), water (2 x 15 ml) and brine. It was dried over MgSO^ and the solvent was flashed down to give 10.5 g (100%) of £ as a white solid, m.p.: 93-94’C n.m.r. (CDCl^) fi 7.5 - 8 (4H, m), 4.47 (IH, broad s), 3.5 - 3.9 (2H, m), 2.5 - 2.9 (2H, m), 1.4 - 1.9 (4H, m). Anal, calc'd for C13H13NO3S: c> 59.29; H, 4.97; N, 5.32; S, 1217. Found: C, 58.92; H, 4.91, N, 5.42; S, 12.31. 50587 A suspension of 2. (3.04 g, 11.6 mmoles) in a solution of IM sodium bicarbonate (11.6 ml) wAs stirred at room temperature under nitrogen for 15 min. TO it was added 3^ (1.5 g, 11.6 mmoles) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture wes diluted with water and extracted with methylene chloride. The organic phase was dried and evaporated in vacuo to give 3.82 g of solid 4; m.p.: 95 - 96’C; i.r. (CHC13) 1775, 1710 cm-1. n.r>-r- δ 7.8 (4H, d, J = 2Hz), 7.05 (IH, broad s) , 5.25 (IH, dd, = SHZ, = 3Hz) , 3.5 - 3.0 (2H, m), 1.5 - 2.0 (4H, m) Anal, .alc'd for: C^H^N^S: C, 57.62; H, 4.85; N, 8.43,- S, 9.64. Found C, 57.43; H, 4.82; N, 8.44; S, 9.71.

A benzene solution (30 ml) of 4. (3.0 g, 9.04 5 mmoles) and p-nitrobenzyl glyoxalate (2.22 g, 9.8 mmoles) Θ was refluxed under a Dean-Stark condenser filled with 3A molecular sieves for 21 h· Evaporation of the solvent afforded 5.4 g of 5 as an oil (100%). i-r. (neat) 3200 - 3600, 1770, 1710, 1525 cm1 n.m.r. (CDCl^ δ 8.21 (2H, d J = 9Hz), 7.75 (4H, d J = 2Hz), 7.52 (2H, d, J = 9Hz, 5.52 (IH, broad s), .32 (3H, 2s), 4.55 (IH, broad s), 3.5 - 3.7 (2H, m), 3.45 (IH, dd J = 15Hz, J . = 5Hz) 3.02 (IH, dd, J = 15Hz, 3 gem cis trans Azetidinone glyoxalate J5 (4.9 g, 9.05 mmoles) was treated at 0°C with thionyl chloride (15 ml) at 0°C for 0.5 h and at room temperature for 1 h. The excess of thionyl chloride was codistilled with benzene in vacuo to afford 6 as a yellow syrup (5.0 g, 100*, n.m.r. (COCL/ δ 8.2 (2H, d, J » 9Hz), 7.72 (4H, broad s) , 7.60 (2H, d, J = 9Hz) , 6.1 (IH, broad s), 5.50 - 5.85 (IH, m), .32 (2H, 2s), 3.4 - 4.0 (2H, m) , 3.1 - 3.3 (1H, m) , 2.8 5 3.05 (IH, m), 2.50 - 2.85 (2H, m) , 1.5 - 1.9 (4H, m).

A solution of 6 (21.6 g, 38.8 mmoles) in tetrahydrofuran (85 ml, distilled over IAH) was treated with triphenyl phosphine (10.2 g, 38.8 mmoles) and 2.6lutidine (5.0 ml, 42.9 mmoles) for 18 h at 40°C. The K) mixture was diluted with benzene-ether 1:1 (30 ml), washed with water, IN HCl, saturated NaHCOg, brine and dried over MgSO^. Evaporation of the solvent afforded a dark brown oil.

It was passed through a silica gel (700 g) column (benzene ether) to give 16.0 g (53*) of 7. as a thick oil. NHR (CDCl^) δ 8.2 (2H, d, J = 9Hz), 7.8 (8H, d, J = 2Hz), 7.52 (16H, broad s), 5.2 (IH, broad s) 4.78 (IH, 2s), 4.30 - 4.52 (IH, m), 3.5 - 3.8 (2H, m), 2.8 - 3.S (2H, m,, 2.1 - 2.9 (4H, m), 1.5 - 1.9 (4H, m) A solution of phosphorane T_ (5.0 g, 6.4 mmoles) in toluene (35 ml) was refluxed for 3 h. Evaporation of the solvent gave a residue which was passed through a silica gel (100 g) column. Elution with benzene followed by ether gave 600 mg of the ester £ as oil i.r. (neat 1790, 1710, 1520 cm 1 n.m.r. (CDC13) δ 8.22 (2H, d, J = 9Hz), 7.82 (4H, d, J = 2Hz), 7.65 (2H, d, J = 9Hz), 5.69 (IH, dd, J . = 4Hz, J = 2Hz), cis trans .35 (2H, 2s), 4.12 (IH, dd, J = 16Hz, J . = 4Hz), 3.50 gem cis (IH, dd, J = 16Hz, J = 2Hz), 3.1 - 3.8 (2H, m) , 2.5 - 3.0 gem trans 10 (2H, m), 1.4 - 2.0 (4H, m) .

A two phase mixture made of ester £ (196 mg, 0.39 mmole) in ether (2 ml),tetrahydrofuran (4 ml) and sodium bicarbonate (32 mg, 0.39 mmoles) in water (2 ml) was hydrogenated on 30% Palladium on Diatomaceous earth (190 mg) in a Parr shaker at 40 p.s.i. H2_ After 4.5 h it was filtered over celite pad and the pad was washed with water and tetrahydrofuran.

The filtrate and washings were combined and the organic phase was 88 50587 separated. The aqueous solution was washed with ether, acidified with IN hydrochloric acid (3 x 0.4 ml) and extracted (after each acid portion added) with ethyl acetate (4x2 ml).

The organic extracts were washed with brine, dried over MgSO^ and the solvent was removed by evaporation to afford the acid 9., 67 mg (47%), as a yellow solid. i.r. (nujol) 1775, 1705, 1690 cm n.m.r. (DMSO, δ 7.92 (4H, s), 5.71 (IH, dd, J . - 4Hz, J cis crons = 2Hz), 3.90 (IH, dd, J » 16 Hz, J . - 4Hz), 3.47 (IH, dd, gem cis J » 16 Hz, J « 2Hz), 3.3 - 4.3 (3H, m), 2.7 - 3.05 2H, m) , gem trans 1.5 - 2.0 (4H, m).

Example 17 Sodium 2-(Acetonylmethyl oxime)-penem-3-carboxylate Ketal 2 (2.0 g, 4.54 mmoles) was treated at 0“ with 95% TFA (20 cc) for 15 min. The mixture was diluted with brine and extracted with methylene chloride (4 x 30 cc). The methylene chloride extracts were washed with water-brine (3 times) and brine, and dried over MgSO^ (1.44 g, 80%). δ(ppm, CDCl ) 8.27 (2H, d, J = 9, Hm aromatic), 8.60 (2H, d, OC X J = 9, Ilo aromatic), 5.70 - 5.25 (a, CHURNS, H-C-O, H-i.^OC^) , 4.75 (IH, bs, OH), 3.76 (center of ABq, CH^CO) , 3.47 (part of a dd, J . = 5, H-3), 3.05 (2H, 2dd, J = 15, J, Λ u ' “3_4 cis gem 3-4 trans = 3, H-3), 2.30, 2.28 (1.67H, 2s, CH^ , 1.98 (1.33 H, s, CHg) V (CHCl ) 1780, 1755, V 1525. c=o 3 NOg A methylene chloride (50 cc) solution of ketone 2 — (1.44 g, 3.63 mmoles) was treated at 0° under nitrogen atmosphere with methoxyi amine hydrochloride (334 mg, 1.1 eq) .

Triethyl amine (367 mg, 0.51 cc, 1 eq) was then g added dropwise to the mixture. It was then stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride, washed with water-brine (2 times) , brine and dried over MgSO^ (1.52 g, 98%). 0(ppm, CDC13) 8.12 (2H, d, J=8, Hm aromatic), 8.40 (2H, d, J = 8 10 Ho aromatic), 5.50-5.05 (4H, m, CHj-PNB, H-4, H-C-O), 3.80-3.60 (m, OCH3> part of H-3 cis, part of OH), 3.55-270 (m, part of H-3 cis, H-3 trans, CH2CO, part of OH), 1.97, 1.90, 1.88 (3H, 3s, CH3) U (CHCI ) 1770, 1750, 1690.

C=O 3 SOC1Z pyridine A cold (-15’C) THF (20 cc, distilled over LAH, solution of azetidinone 3 (1.52 g, 3.57 mmoles) was treated dropwise with pyridine (325 mg, 0.332 cc, 4.10 mmoles, 1.15 eq) and thionyl chloride (488 mg, 0.299 cc, 4.10 nmoles, 1.15 eq) under nitrogen atmosphere. The mixture was stirred for 15 min at -15°. The solid was filtered off and washed with benzene. The resulting solution was evaporated down. The residue was taken upon benzene and treated with charcoal (1.2 g, 76%) 6{ppm, coci3) 8.23 (2H, d, Hm aromatic), 7.80 (2H, d, Ho aromatic), 6.12, 6.08 (IH, 2s, H-C-Cl), 5.75 - 5.55 (IH, m, H-4), 5.40, .30 (2H, 2s, CH2-PNB) , 3.95 - 3.80 (3H, 3s, OCt^) , 3.80 - 2.95 (4Η, m, 2H-3, CH^CO) , 2.00 - 1.85 (3H, 4s, CH3). v (CHCl ) 1790, 1765 (shoulder), 1700, V 1530. co □ HO N—OCH II 3 N—OCH, II > A THF (20 cc, distilled over LAH) solution of chloroazetidinone 4_ (1.2 g, 2.70 mmoles) was treated with triphenyl phosphine (1.06 g, 4.05 mmoles 1.5 eq) and 2,6lutidine (318 mg, 0.346 cc, 2.97 mmoles, 1.1 eq). The mixture was stirred for 4 days at room temperature under nitrogen atmosphere. It was diluted with ethyl acetate, washed with 2% aqueous HCI. H2O. 2% aqueous HaliCOj, water and brine. The solution was then dried over MgSO^ and the solvent was evaporated. Crude _5 was purified on silica gel (10 times by weight) column (ethyl acetate, 770 mg, 45%) .

V (CHCl,) 1755, 1695, V 1630 - 1610, V 1525. c=o 3 NO Toluene N~OCH ch2-c-ch3 co2pnb Phosphorane J5 (700 mg, 1.05 mmole) was refluxed in toluene for 4.5 h. Toluene evaporation afforded a residue which was passed through a silica gel (1:15 ratio) column (4% ether-benzene). It gave 6 as a crystalline material (251 mg, 62%, m.p. 116-125).

Anal, calc'd for C^H 17N3°6S: c> 52.17; H, 4.38; N, 10.74. Found: C, 51.15; H, 4,18; N, 10.33. 6(ppm, CDC13) 7.70 (2H, d, Hm aromatic), 7.12 (2H, d. Ho aromatic), 5.00 (2H, s, CH^NB) , 4,85 (IH, m, H-5), 3.75 - 2.70 (7H, m, CH3O, CH2, H-6), 1.77, 1.72, 1.65 (3H, s, CH^.

U (CHC1 ) 1787, 1742, 1705, U 1530. c=o 3 NC>2 A mixture of ester 6 (151 mg, 0.386 mmole) in THF (20 cc), ether (40 cc) and NaHC03 (32 mg, 0.381 mmole) in water (20 cc) was shaken in a Parr hydrogenator for 3 h at 35 p.s.i. Hj, using 30% Pd on celite (200 mg) as catalyst.

The catalyst was filtered off and washed with water and ether.

The resulting aqueous mixture was washed with ether (3 x 60 cc) and lyophilized (32 mg, 30%). δ (ppm, DMSO, S.50 (m, H-5), 3.75 (s, OCH,,, 0.77 (s, CH,,. 3 V (nujol mull) 1770, 1600, 1400. c=o U.V. (Η,Ο) λ 300 (E = 2,800), 255 (E = 2,400). max Example 18 597 The following 2-penem compounds may be prepared by acylation of 1-(p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl)-2-azetidinone with the appropriate acylating agent followed by cyclization and deblocking steps. The general reaction scheme is shown below: 0 ll II 1. RC-O-C-O-iBu or 2. RCOC1 -SCOR P0: co2pnb for variation 1: use RCO2H + iBuCOCl for variation 2: use HCl + PClg + RC02H 5059 Acylating Agent Method 0CH2OCONH-{CH2,4-CO2U 1 CH, I 3 0CU2OCONH-CH-CQ2H 1 (both D and L, CH-CH, I 2 3 0CH2OCONH-CH-CO2H 1 (both D and L) CH, I 3 CII-CH, I 3 0CH2OCONH-CH-CO2H 1 (both D and L) 0CH2OCQNH-CH-CO2H 1 (both D and L) py 0CU2OCONH-CH-CO2H 1 (both D and L) CH,OCH,0-NO,-p I 2 2^ 2 r S3CH2OCONH-CI1-C02H 1 (both D and L) ch2co2ch20-no2-p 0CH2OCONH-CH-CO2H 1 (both D and L) CH,C0NH, I 2 2 0CH2OCOHH-CH-CO2H 1 (both D and L) CH-CH,SCH, I 2 2 3 0CH2OCONH-CH-CO2H 1 ι (both D and L) (ch2)4nhco2ch20 0CH2OCONH-CH-CO2H 1 (both D and L) ?H3 0CH2OCONCH2CO2H ι CH, I J «;!ι OCUICH .CIt,CO ,li 1 Product 2-(4-Aminobutyl,penem-3carboxylic acid 2-(1-Aminoethyl,penem-3carboxylic acid 2-(1-Aminopropyl)penem-3carboxylic acid 2-(l-Amino-2-methylpropyl)penem-3-carboxylic acid 2-(1-Aminobenzyl)penem-3carboxylic acid 2-(l-Amino-2-phenylethyl)penem-3-carboxylic acid 2-(l-Amino-2-hydroxyethyl)penem-3-carboxylic acid 2-(l-Amino-2-carboxyethyl)penem-3-carboxylie acid 2-(l-Amino-2-carbamoylethyl)penem-3-carbcxylic acid 2-(1-Amino-3-methylthiopropyl) penem-3-carboxylic acid 2- (1,5-Diaminopentyl)penem3- carboxylic acid 2- [(Methylamino)methyl)penem3- carboxylic acid 2-Γ2- (Methylamino)ethyl)pener.-3-carboxyHc acid.

Acylating Agent Method Product CH, ι 3 0ch2oconch2ch2ch2co2h 1 2-[3-(Methylamino)propyl]penem-3-carboxylic acid CH, 1 3 0CH2OCONCH2CH2CH2CH2CO2H 1 2-(4-(methylamino)butyl] penem-3-carboxylic acid Ϊ2Η5 0CH2OCONCH2CO2H 1 2- [(Ethylamino)methyl]penem- 3- carboxylic acid<f2H5 0CH2OCONCH2CH2CO2H 1 2- [2-(Ethylamino)ethyl]penem 3- carboxylic acid C,H, 1 2 5 0CH2OCONCH2CH2CH2CO2H 1 2-[3-(ethylamino)propyl]penem-3-carboxylic acid C,H. |2 5 0CH2OCONCH2CH2CH2CH2CO2H 0CH2OCONCH2CO2H 1 2-[4-(Ethylamino)butyl]penem-3-carboxylic acid 1 2-[(Phenylamino)methyl]penem-3-carboxylic acid ΐ 0CH7OCONCH7CH,CO7H 1 2-[2-(Phenylamino)ethyl]penem-3-carboxylic acid 0CH7OCONCH7CH7CH7CO7H 1 2-[3-(Phenylamino)propyl]penem-3-carboxylie acid ? 0CH 7 OCONCH 7 CH 7 CH 7 CH 7 CO,H 1 2-(4-(Phenylamino)butyl]penem-3-carboxylic acid ch3conhch2co2h 1 2-[(Acetylamino)methyl]penem-3-carboxylic acid ch3conhch2ch2co2h 1 2-(2-(Acetylamino)ethyl]penem-3-carboxylic acid CH3CONHCH2CH2CH2CO2H 1 2-(3-(Acetylamino)propyl]penem-3-carboxylic acid 96 Acylating Agent Method Product ch3conhch2ch2ch2ch2co2h 1 2-(4-(Acetylamino)butyl]penem-3-carboxylic acid CgH5CONHCH2CO2H 1 2-((Benzoylamino)methyl]penem-3-carboxylie acid CgHsCONHCH2CH2CO2H 1 2-[2-(Benzoylamino)ethyl]penera-3-carboxylic acid CgH5CONHCH2CH2CH2CO2H 1 2-(3-(Benzoylamino)propyl] penem-3-carboxylic acid CgH5CONHCH2CH2CH2CH2CO2H 1 2-(4-Benzoylamino)butyl]penem-3-carboxylic acid 0ch2oconhch2conhch2co2h 1 2-((Glycinamido)methyl]penem-3-carboxylic acid 0CH2OCONHCH2CONHCH2CH2CO2H 1 2-(2-(Glycinamido)ethyl]penem-3-carboxylic acid 0CH2OCONHCH2CONHCH2CH2CH2CO2H 1 2-[3-(Glycinamido)propyl]penem-3-carboxylic acid 0CH2OCONHCH2CONHCH2CH2CH2- CH2CO2H 1 2-(4-(Glycinamido)butyl]penem-3-carboxylic acid H2NCONHCH2CO2H 1 2-(Ureidomethyl)penem-3carboxylic acid H2NCONHCH2CH2CO2H 1 2-(2-Ureidoethyl)penem-3carboxylic acid H2NCONHCH2CH2CH2CO2H 1 2-(3-Ureidopropyl)penem-3carboxylic acid H2NCONHCH2CH2CH2CH2CO2H 97 1 2-(4-Ureidobuty1)penem-3carboxylic acid - Acylating Agent Method Product CH gNHCONHCHg COgH 1 2-[(Methylcarbamoylamino)methyl]penem-3-carboxylic acid CHgNHCONHCHgCHgCOgH 1 2-(2-(Methylcarbamoylamino)methyl]penem-3-carboxylie acid 5 CHgNHCONHCHgCHgCHgCOgH 1 2-(3-(Methylcarbamoylamino)propyl]penem-3-carboxylic acid CHgNHCONHCHgCHgCHgCHgCOgH 1 2-[4-(Methylcarbamoylamino)butyl]penem-3-carboxylie acid 10 0hhconhch2co2h 1 2-[(Phenylcarbamoylamino)methyl]penem-3-carboxylie acid 0nhconhck2ch2co2h 1 2-(2-Phenylcarbamoylamino)ethyl]penem-3-carboxylic acid 0NHCONHCH2CH2CH2CO2H 1 2-(3-(Phenylcarbamoylamino)propyl]penem-3-carboxylie acid 15 0NHCONHCH2CH2CH2CH2CO2H 1 1 2-(4-(Phenylcarbamoylamino)butyl]penem-3-carboxylie acid CHgCONHCONHCH2CO2H 1 2-((Acetylcarbamoylamino)methyl]penem-3-carboxylie acid 20 ch3conhconhch2ch2co2h 1 2-(2-(Acetylcarbamoylamino)ethyl]penem-3-carboxylie acid CH3CONHCONHCH2CH2CH2CO2H 1 2-(3-(Acetylcarbamoylamino)propyl]penem-3-carboxylie acid CH3CONHCONHCH2CH2CH2CH2CO2H 1 2-[4-Acetylcarbamoylamino)butyl]penem-3rcarboxylie acid 25 0CONH CONH CH 2 CO2 H 1 98 2-((Benzoylcarbamoylamino)methyl]penem-3-carboxylio acid Acylating Agent Method 0CONHCONHCH2CH2CO2H 1 0COHHCONHCH2CH2CH2CO2H 1 Product 2-[2-(Benzoylcarbamoylamino ethyl]penem-3-carboxylie acid 2-[3-(Benzoylcarbamoylamino)propyl]penem-3-carboxylic acid 0conhconhch2ch2ch2ch2co2h 2-[4-(Benzoylcarbamoylamino)butyl]-penem-3-carboxylie acid ch3oconhconhch2co2h 2-[(Carbomethoxycarbamoylamino) methyl]penem-3carboxylic acid io ch3oconhconhch2ch2co2h 2-(2-(Carhomethoxycarbamoylamino)ethyl]penem-3carboxylic acid ch3oconhconhch2ch2ch2co2h 2-[3-(Carbomethoxycarbamoylamino) propyl]penem-3carboxylic acid ch3oconhconhch2ch2ch2ch2co2h 1 (ch3)3si(cH2)2oconhconhch2co2h 1 (CH3)3Si(CH2)2OCONHCONHCH2- 1 CH2CO2H 2-[4-(Carbomethoxycarbamoylamino) butyl]penem-3carboxylic acid 2-((2-trimethylsilylethyloxycarbonylcarbamoylamino)methyl]penem-3-carboxylic acid 2- [2-(2-trimethylsilylethyloxycarbonylcarbamoylamino)ethyl]penem-3-carboxylie acid (ch3)3si(ch2)2oconhconhch2- 1 ch2ch2co2h 2-[3-(2-trimethylsilylethyloxycarbonylcarbamoylamino)propyl]penem-3-carboxylic acid Acylating Agent Method Product (ch3)3si(ch2)2oconhconhch2ch2ch2ch2co2h 1 2-[4-(2-Trimethylsilylethyloxycarbonylcarbamoylamino)butyl]penem-3-carboxylie acid CH3S2CNHCH2CO2H 1 2-[(Methylthiothiocarbonylamino) me thy1]penem-3- carboxylic acid CH3S2CNHCH2CH2CO2H 1 2-[2-(Methyl thiothiocarbonylamino) ethyl]penem-3- carboxylic acid CH3S2CNHCH2CH2CH2CO2H 1 2-[3-(Methylthiothiocarbonylamino)propy1]penem-3- carboxylic acid CH3S2CNHCH2CH2CH2CH2CO2H 1 2-[4-(Methylthiothiocarbonylamino)butyl]penem-3carboxylic acid CH3SO2NHCH2CO2K 1 2-[(Methanesulfonylamino)methyl]penem-3-carboxylic acid CH3SO2NHCH2CH2CO2H 1 2-(2-(Methanesulfonylamino)ethyl]penem-3-carboxylic acid CH3SO2NHCH2CK2CH2CO2H 1 2-[3-(Methanesulfonylamino)propyl]penem-3-carboxylic acid CH3SO2NHCH2CH2CH2CH2CO2H 1 2-[4-(Methanesulfonylamino)butyl]penem-3-carboxylie acid 0SO2NHCH2CO2H 100 1 2-[(Benzenesulfonylamino)methyl]penem-3-carboxylic acid 5059? Acylating Agent S ll H CNHCNHCH CH CO H H3CNHCNHCH2CH2CH2CO2H s II H CNHCNHCH2CH2CH2CH2CO2H s II 0NHCNHCH2CO2H s II 0NHCNHCH2CH2CO2H 0NHCNHCH2CH2CH2CO2H 0NHCNHCH2CH2CH2CH2CO2H N-π-NHCH2CO2H HO fl N A-n/ HO n—jj—nhcii2ch2co2h Jl N _Ά.Ο/ N-n—NHCH2CH2CH2CO2H HO Λ N An/ Method Product 2-(2-(ίΙ-Methy lthiocarbamoylamino)ethyl]penem-3carboxylic acid 2-[3-(N-Methylthiocarbamoylamino)propyl]penem-3carboxylic acid 2-[4-(N-Methylthiocarbamoylamino)butyl]penem-3carboxylic acid 2-[(N-Phenylthiocarbamoylamino)methyllpenem-3carboxylic acid 2-[2-(N-Phenylthiocarbamoylamino)ethyl]penem-3carboxylic acid 2-(3-(N-Phenylthiocarbamoylamino)propyl]penem-3carboxylic acid 2-(4-(N-Phenylthiocarbamoylamino)butyl]penem-3carboxylic acid 2-[(Guanylamino)methyl]penem-3-carboxylic acid 2-[2-(Guanylamino)ethyl]penem-3-carboxylic acid 2-[3-(Guanylamino)propyl]penem-3-carboxylic acid 101 Acylating Agent Method Product N-NHCH2CH2CH2CH2CO2H 1 2-[4-(Guanylamino)butyl]HO O' penem-3-carboxylic acid h3c ,-0 ii f -N-CH2CO2H -CH2CH2CO2H -ch2ch2ch2co2h 2-[(Acetimidoylamino)methyl]penem-3-carboxylic acid 2-[2-(Acetimidoylamino)ethyl]penem-3-carboxylic acid 2-[3-(Acetimidoylamino)propyl] penem-3-carboxylic acid -CH2CH2CH2CH2CO2H 1 2-(4-(Acetimidoylamino)butyl]penem-3-carboxylie acid .N- CH2CO2H -ch2ch2co2h -CH2CH2CH2CO2H -ch2ch2ch2gh2co2h o2nch2co2h o2nch2ch2co2h o2nch2ch2ch2ch2co2h 2-[(Formimidoylamino)methyl] penem-3-carboxylic acid 2-[2-(Formimidoylamino)ethyl]penem-3-carboxylic acid 2-[3-(Formimidoylamino)propyl] penem-3-carboxylic acid 2-[4-(Formimidoylamino)butyl] · penem-3-carboxylic acid 2-[(Hydroxyamino)methyl] penem-3-carboxylic acid 2-[4-(Hydroxyamino)butyl] penem-3-carboxylic acid 2-[2-(Hydroxyamino)ethyl] penem-3-carboxylic acid 102 Acylating Agent OCH, Method Product (CH3)3Si(CH2)2OCON-CH2CO2H OCH3 * 1 2-1(Methoxyamino)methyl]penem-3-carboxylic acid (CH3)3Si(CH2)2OCON-CH2CH2CO2H OCH, * 1 2-(2-(Methoxyamino)ethyl]penem-3-carboxylic acid (CH3)3Si(CH2)2OCONCH2CH2CH2CO2H OCH, * 1 2-(3-(Methoxyamino)propyli penem-3-carboxylie acid 5 (CH3)3Si(CH2) 2OCONCH2CH2CH2CH2CO2H NH, 1 2 ★ 1 2-(4-(methoKyamino)butyl]· penem-3-carboxylic acid (CH3)3Si(CH2) 2O CONCH2CO2H Nn_ ★ 2 2- ((Hydrazino)methyl]penera- 3- carboxylic acid (CH3)3Si(CH2) 2 OCONCH2CH2CO2H NH2 * 2 2- [2-(Hydrazine)ethyl]penem- 3- carboxylic acid (CH3)3Si(Cri2) 2 OCONCH2CH2CH2CO2H * 2 2- (3-(Hydrazino)propyl] penem 3- carboxylic acid 103 Acylating Agent Method Product ch 3conhnhch 2co2h * 2 . 2-((2-Acetylhydrazino)methyl]penem-3-carboxylic acid CH3CONHNHCH2CH2CO2H * 2 2-[2-(2-Acetylhydrazino)ethyl]penem-3-carboxylic acid CH3CONHNHCH2CH2CH2CO2H * 2 2-(3-(2-Acetylhydrazino)propyl]penem-3-carboxylie acid CH 3 CONHNHCH 2 CH2 CH 2 CH 2 CO2H * 2 2-[4-(2-Acetylhydrazino)butyl]penem-3-carboxylie acid (ch3)2nch2co2h 2 2- [ (Dimethylamino)methyl]penem-3-carboxylic acid (CH3)2NCH2CH2CO2H 2 2-[2-(Dimethylamino)ethyl]penem-3-carboxylic acid (CH3)2NCH2CH2CH2CO2H 2 2-(3-(Dimethylamino)propyl]penem-3-carboxylic acid (CH3)2NCH2CH2CH2CH2CO2H 2 2-[4-(Dimethylamino)butyl]penem-3-carboxylic acid CH, I 3 CH3CONCH2CO2H 1 2-[(N-Methylacetamido)methyl]penem-3-carboxylic acid CH, 1 3 CH3CONCH2CH2CO2H 1 2-(2-(N-Methylacetamido)ethyl]penem-3-carboxylic acid CH, 1 3 CH3CONCH2CH2CH2CO2H 1 2-(3-(n-Methylacetamido)propyl]penem-3-carboxylic acid CH, 1 3 CH3CONCH2CH2CH2CH2CO2H 1 104 2- [4-(N-Methylacetamido)butyl]penem-3-carboxylic acid Method Product 2- ((Phthalimido)methyl]penem3- carboxylic acid 2-(2-(Phthalimido)e thy1]penem-3-carboxylie acid 2-(3-(Phthalimido)propyl]penem-3-carboxylic acid 2-[4-(Phthalimido)butyl]penem-3-carboxylic acid 2-((2-Aminoethoxy)methy1)penem-3-carboxylic acid 0ch2oconhch2ch2sch2co2h 1 Ϋ°2<:η20 0CH2OCONHCH2CH2NCH2CO2H 1 CH, I 3 0CH2OCONHCH2CH2NCH2CO H 2 2-((2-Aminoethylthio)methyl]penem-3-carboxylic acid 2-((2-Aminoethylamino)methyl]penem-3-carboxylic acid 2-[N-(2-Aminoethyl)-Nme thylamino]me thyIpenem-3carboxylic acid 2-(p-Aminobenzyl)penem-3carboxylic acid 2-(o-Aminobenzyl)penem-3carboxylic acid 2-(p-Aminophenyl)penem-3carboxylic acid 2-(m-Aminophenyl)penem-3carboxylic acid 105 Method Product Acylating Agent 2-(o-Aminophenyl)penem-3carboxylic acid 2-[p-(Aminomethyl)phenyl] penem-3-carboxylic acid 2-[m-(Aminomethyl)phenyl] penem-3-carboxylic acid 2- (o-(Aminomethyl)phenyl] penem-3-carboxylic acid EXAMPLE 19 The following 2-penem products may be prepared from the indicated starting materials by the procedure + Cl(CH-) COCI 2 n rSC0(C!L·) Cl ζ n P0, CO2PNB 106 deblocking V .2© Starting Material Product Exp. A n = 1 A. n = 1 Exp. B n = 2 B. n = 2 Exp. C n =3 3 C. n 3 Exp. □ n » 4 D. n = 4 Example 20 The following 2-penem products may be prepared from the indicated starting materials by the procedure 107 30597 I ζ = -(CH2)2Si(CH3) Β = -0(CH2)2Si(CH3) 108 50537 Starting Material I—1 Λ Product o II SC-(CH-) -C-R ι m 2'm OH I N II •C-R co2h CO2PNB Exp. A R a H, m a 0 A. R =s H, m - 0 Exp. B R a H, m = 1 B. R = H, m 1 Exp. C R = H, m ss 2 C. R = H, m = 2 Exp. D R 3» ch3, m SS 0 D. R ch3, m = 0 Exp. E R as ch3, m ss 1 E. R = ch3, m = 1 Exp. F R as ch3, m a 2 F. R = ch3, m = 2.

Substitution in the above procedure of H_,NOCH3 for the H2N0(CH2)2Si(CH3)3 used therein results in formation of the following products.

Exp. A m = 0, R = H Exp. B ra = 1, R = H Exp. C m = 2, R = H Exp. D m = 0» R = CH Exp. E m = 1, R = CH Exp, F tn = 2, R = CH- 109 Substitution in the above procedure of (CH^J-jSi(CH2)2OCONHNH2 for the H2NO(CHf2Si(CHg)3used therein results in formation of the following products, Exp. A IU = 0, R = H Exp. B m = 1, R = H Exp. C ra = 2, R = H Exp, D IU = o, R = ch3 Exp. E m = 1, R = ch3 Exp. F IU = 2, R = ch3 Substitution in the above procedure of (CH3)2NNH2 for the H2NO(CH2)2Si(CH3)3 used therein results in formation I of the following products: Exp. A IU = 0, R H Exp. B m a 1, R = H Exp. C ra = 2, R H Exp. D m = 0, R = CH Exp. E in = 1, R = CH Exp. F ra = 2, R = CH 110 Substitution in the above procedure of therein results in formation of the following products: co2h Exp. A m = 9, R = H Exp. B m = 1, R = H Exp. C ra » 2, R = H Exp. D ra = 0, R = CH3 Exp. E m = 1, R = CH3 Exp. F m = 2, R = CH3.

Ill Example 21 O' /SAg COjPNB CO H 2 (0-O2 co2pnb II III A solution of I (1.1 g, 1.6 mmole) and II (0.16 ml, 1.6 mmole) in methylene chloride (30 ml) was cooled in an ice bath and treated dropwise with IM solution of pyridine in methylene chloride (1.7 ml, 1.7 mmole). The resulting reaction mixture was stirred at room temperature for 1 h and then filtered over celite and washed with methylene .chloride. The filtrate and washings were combined and washed successively with IN HCl (5 ml), water (5 ml), IM NaHCOg (5 ml) and brine, and then dried (MgS04> and evaporated in vacuo to give III 900 mg (87%) as an amorphous solid. It was used in the next step without further purification. IR (CHClg) 1755, 1690 cm NMR (CDClg) δ 8.22 (2H, d, J=9 Hz), 7.55 (15H, m) , 6.72 (2H, d, J=9 Hz), 5.7 (IH, m), 5.0 (2H, 2s), 3.55 (2H, 2s), 2.8 (4H, m). 112 V A mixture of III (1.3 g, 2 mmoles) and IV (0.65 ml, 3 mmoles) was heated at 60°C for 4 h. The reaction mixture was diluted with methylene chloride (10 ml) and washed with water (2x5 ml). Organic layer was dried (MgSO^) and evaporated in vacuo to give V, 1.4 g (90¾), as an amorphous solid.

It was used in the next step without further purification. ίκ (CHC13) 1755, 1690 cm1 NMR (CDC13> δ 8.25 (2H, d, J=9 Hz), 7.55 (15 H, m), 6.8 (2H, d, J=9 Hz), 5.7 (IH, m), 5.1 (2H, 2s), 4.72 (2H, dg J=12 Hz, J=6 Hz), 2.6 (4H,m), 1.4 (6H, s), 1.28 (6H, s) .

CO PNB 2 VI A solution of V (1.6 g, 2.06 mmoles) in toluene (60 ml) was heated under reflux for 5 h.

The solvent was evaporated in vacuo and the residual oil was chromatographed on silica gel column 113 (30 g). Elution with benzene followed by ether removed first unpolar material and then ethyl acetate gave VI, 620 mg (62%) as a white solid, m.p.: 83-4°C from ether.

IR (CHC13) 1790, 1710 cm'1 NMR: (CDCl ) δ 8.2 (2H, d, J=9 Hz), 7.6 (2H, d, J=9 Hz) 7.5 (2H, s) 5.65 (IH, dd, Jtrans = 4 Hz, J . = 2 Hz), 5.22 (2H, 2s), 4.75 (2H, dq J=12 Hz, J=6 Hz), 3.85 cis (IH, dd, J = 15 Hz, J = 4 Hz), 3.5 (IH, dd, J = 15 Hz, gem trans gem J . = 2 Hz), 2.8-3.3 (2H, m), 1.4 (6H, s), 1.28 (6H, s).

To a solution of VI (200 mg, 0.4 mmole) in tetrahydrofuran (8 ml) and ether (4 ml) was added sodium bicarbonate (34 mg, 0.4 mmole), water (4 ml) and 30% Pd/Celite (200 mg) followed by hydrogenation 2h at 40 p.s.i. The mixture was filtered and layers were separated. The aqueous phase, after washing with methylene chloride (2x5 ml), was cooled with ice, acidified with IN HCI (1 ml), and extracted with chloroform (5x5 ml) . Organic extracts were dried (MgSO^) and evaporated in vacuo to give VII, 76 mg (52%) , as an oil. IR (CHCl3) , 1790, 1710 cm-1, NMR (CDCl ) δ 9.5 (IH, ws) , 5.65 (IH, dd, = 4Hz, J . = 2 Hz) , 4.72 (2H, dq J=12 Hz, J=6 Hz), 4.2trans cis .1 (2H, m), 3.4-4.1 (2H, m) , 2.7-3.4 (2H, m), 1.35 (6H, s) , 1.25 (6H, s). 114 50S97 Example 22 _S. (0C2H5’2 co2h To a cooled (ice bath) mixture of 1^ (1.324 g, 2 mmoles) and .2 (0,54 g, 2.2 mmoles, crude) in CH2C12 (15 ml) was added dropwise 1 M solution pyridine /CH2C12 (2.2 ml, 2.2 mmoles).

The mixture was stirred at r.t. for 1 h and filtered over celite. The filtrate was washed successively with 0.5N HCl, HjO, 0.5 M NaHCO^ and brine. It was dried (MgSO^) and filtered over celite charcoal to give after evaporation to dryness 0.9 g of an oil. The oil was chromatographed on SiOj (10% H^O) and eluted with ethylacetate to give 0.5 g of (32.8%). NMR δ (ppm, CDC13) 7.0-8.4 (m, 19H), 4.8-5.8 (3H, m,, 4.1 (4H, q), 3.3-4.2, (2H. m) 2.7 (2H, m), 1.9 (2H, m) , 1.3 (6H, t) . 115 597 CO.PNB (0.4 g, 0.52 mmole) in toluene (35 ml) was refluxed for 4 h and evaporated to dryness to give an oil which contained 3, 4 and φ P=O. This was chromatographed on SiO (10¾ HO) — — 3 2 4 and eluted with EtOAc to give 0.1 g of pure £, followed by 0.15 g of 3 and £. NHR δ (ppm, CDCl ). 8.3 (2H, d) , 7.67 (2H, d), 5.7 (H, q), 5.33 (2H, d) , 4.2 (4H, q) , 3.83 (H, q) , 3.4 (H, q), 2.9 (2H, m), 1.9 (2H, m), 1.3 (6H, t). IR (neat) 1790 cm 3 (β-lactam) 1710 cm (ester).

A mixture of £ (0.1 g, 0.207 mmole), 30% Pd/celite (0.1 g) and NaHCO^ (17 mg, 0.207 mmole) in THF (10 ml), ether (5 ml) and water (5 ml) was hydrogenated at an initial pressure of 40 psi for 2 h. It was filtered over celite and the layers separated. Basic aqueous layer was washed well with ethylacetate and acidified with 1NHC1. It was extracted with CH2C12 and dr%ed (MgSO^). The CH2C12s°Tution was evaporated to give 48 mg of 2 (66.5%). IR spectrum δ 1790 (β-lactam) δ 1700 (-C-OHJ. 116 g A mixture of £ (1.07 g, 1.66 mmole) and £ (0.42 g, mmoles, in CHjC^ (3 ml) was heated at 80’ for 5 h. The crude oil was chromatographed on Sic>2 (3% H20) and eluted with ether, ether-ethylacetate (1:1, and ethyl acetate: % EtOH to give 1.0 g of £ (82%). The oil crystallized on standing, M.P. (ether) 138-40°.

NMR δ (ppm, CDC13) 8.2 (2H, d) 7.0-8.0 (17H, m), 4.6-5.5 (3H, m), 3.8 (3H, s), 3.6 (3H, s), 1.5-3.5 (6H, m). £ (0.5 g, 0.69 mmole) in toluene (30 ml) was refluxed for 4 h. It was evaporated to dryness, chromatographed on SiO2(3% H2O) and eluted with EtjO: EtOAc (1:1) followed by EtOAc: 10% EtOH to give 0.18 g of 4 (58%). NMR δ (ppm, CDC13), 8.25 (2H, d), 7.6 (2H, d,, 5.65 (H, q), 5.3 (2H, d), 3.8 (3H, s) 3.6 (3H, s), 2.7-3.6 (2H, m) . 1.5-2.5 (4H, m). 117 A mixture of £ (50 mg, 0.112 mmole), NaHCOg (9.125 mg) 5 and 30% Pd/celite (50 mg) in THF (5 ml), E^O (2.5 ml) and water (2.5 ml) was hydrogenated at an initial pressure of psi (for 2 h). It was filtered over celite, and the layers separated. The basic aqueous layer was washed well with EtOAc and lyophilized under high vacuum to give 28 mg of 5.. (75.9%) (hygroscopic). IR (KBr) 1770 cm 1 (β-lactam), 1610 cm1 (-COO). 118 Example 24 (l'R,5R,6R) and (l'S,5S.6S) 6-(l'-Bydroxy-l'-ethyl)-2-methylpeneiii-3carboxylic Acid (isomer D) (illustrates most preferred process of introducing 6-substitutent in mid-synthesis OH COgHa, K A. Preparation of 4-Tritylthio-2-azetidinone Intermediates 1. 1-(Trimethylsilyl)-4-tritylthio-2-azetidinone A vA-A _sc3 Si (Me).

A solution of 4-tritylthio-2-azetidinone (345 mg, 10 1 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, CDC13): 7.32 (15H, m, aromatics), 4.22 (IH, dd, H-4), 2.67 (IH, dd, J = 4.1, J = 16, H-3), 2.22 (lH, dd, J = 2.2, J = 16, H-3), 0.3 (9H, s, CH3, . Π9 2· 1-(t-Butyldimethylsilyl)-4-tritylthio-2-azetidinone __5C*3 rf D 0 ch3 '‘Si—-CH, c3)3 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 (15Η, 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 (6Η, s, Me). v 1735 cm 1 c=o . Anal, calc'd for C^H^NOSSi: C, 73.15; H, 7.24; N, 3.05; S, 6. 97%. Found: C, 73.27; H, 7.32; N, 2.97; S 6.94%. 120 3. l-Methoxymethyl-4-tritylthio-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 sus5 pension 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, CDCl^) : 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). 4. 1-(Methoxyethoxymethyp-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, 2Q 1.5 mmole). The mixture was stirred at room temperature for 2 h, the 121 υ 5 1) 7 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, CDClg): 7.30 (15H, m, aromatics), 4.57 (2H, AB quartet, N-CH.O), 4.46 (IH, dd, H-4), 3.50 (4H, s, OCH^CHgO), 3.30 (3H, s, CHg), 2.75 (2H, m, H-3) . . 1-(2'-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 gav.e a 20 mixture of the isomeric title compounds contaminated with a little starting material, δ (ppm, CDClg): 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). '22 B. Preparation of 3-(1'-Hydroxy-l1-ethyl )-l-tnethoxymethyl-1i-tribylthio-2azetidinones a) (l'S,3S,4R and l'R,3R,4S)isomer (isomer C) A solution of lithium diisopropyl amide was prepared in THF (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-methoxymethyl-4-tritylthio-2-azetidinone (491 mg, 1.42 mmol) in THF (5 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 15 ether: 440 mg, 80%, mp 188.5-9°C; ’Hmr (CDCly δ:7.3- (15H, m, aromatics), 4.37 (2H, ABq, N-Ct^O), 4.32 (IH, d, J=2, H-4), 3.17 (3H, s, OCH3), 3.32-2.70 (2H, m, H-3 and H-5), and 1.12 ppm (3H, d, J=7, CH,); Anal, calcd for C_,H,,NO,S: 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 -78°C in dry ether (3 ml) from butyl lithium 0.191 ml of 2.52 M solution in hexane, 0.482 mmol) and diisopropyl amine 123 (0.067 ml, 0.482 mmol). After 20 min, a solution of (4R and 4S) 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 ml, 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 anhydrous 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 solventsystem) . The alcohol with the high Rf (0.033 g, 17 %) was identical to the above isomer (isomer C) :( mp 188.5-189°C (Ether-dichloromethane); The alcohol with low Rf (0.030 g, 16%) (isomer Β), was obtained as an oil which crystallized with difficulty from hexanes: mp 94-95°C. ir CCHC1) y : 3600 (OH), 1760 cm1 (C=0); ‘Hmr (CDCl ) 5:6.9-7.5 2 2 max 3 (15H, m, aromatics), 4.2 (2H, center of ABq, J=11.5, CH.-O-CH^), 4.28 (IH, d, 0=2.0, 4-H), 3.65 (IH, center of a broad sextet, H-l'), 3.3 (IH, dd, 0 . . .=2.5, 0 .,=5.5, H ), 3.15 (3H, s, O-CH,), 1.55 (IH, broad s, OH-1'), 1.05 (3H, d, 0=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, zb z / 3 N 3.15, S 7.43%. 124 C. Preparation of trans 3-Acetyl-l-methoxymethyl-4-tritylthio-2-azetidinone Lithium diisopropylamide was prepared under a nitrogen 5 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 anraonium 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 concentrated to give the title material as a colorless oil (0.32 g, 37%); '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 cm”1.

J max 125 597 D. Preparation of trans 3-Acetyl-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone t-Bu LDA EtOAc u OA .-sc3)2 Diisopropyl 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) 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 υ : 1750, 1710 cm S 'Hmr'(CDCl,) δ: 8-7.1 (15H, m, aromatics), max 3 4.83 (IH, d, J=2,H-4), 3.38 (IH, d, J=2, H=3), 1.80 (3H, s, CH.^ , 0.92 (9H, s, Bu and 0.3 ppm (6H, s, CH3).

E.

Preparation of trans-1- (t- Butyldimethylsilyl)-3-foimiyl-4-tritylthio-2-azetidinone •ttt Si(CH3)2 t-Bu To a cooled (-78°C) solution of diisopropylamine (0.34 ml, 2.4 mmol) in tetrahydrofuran (5 mi) was added dropwise, under N^, a 126 50897 solution of 1.5 M η-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), IM sodium bicarbonate (6 ml), water (10 ml) and brine. The organic layer was dried (MgSO4>, evaporated and crystallized from pentane to give 810 mg (76%) of formate as a white solid mp 132-3°C; ir (CHClj) in υ ! 1760, 1715 cm1; ‘Hmr (CDCl.) δ: 9.0 (IH, d, J=1.25 Hz), 7.30 1u 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 0 molecular sieves 3A lg c) ethyl formate was stirred at room temperature with K2CO3 ’ then distilled over P_0_ □ d) η-BuLi was titrated with IN hydrochloric acid F. Preparation of 1-(t-Butyldimethylsilyl)-3-(11-hydroxy-1'-ethyl)-4-trity1thio-22Q azetidinones. (4 isomers). n-Butyllithium (1.6M, 3.4 ml, 5.44 mmol) was added in 5 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- (t— butyldimethylsilyl,4-tritylthio-2-azetidinone (2.0 g, 4.4 mmol) in THF (20 ml) was added; after 15 min acetaldehyde (10 ml, was 127 added in one portion; after another 15 min water (100 ml) was added.

The mixture was acidified (pH 5-5) 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 tic (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 D in the motherliquors. The four pure compounds were obtained by preparative chromatography (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 20°C 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 CyC^. It is a racemic mixture composed of the (l’S, 3R, 4R) and the (l'R, 3Ξ, 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^,, Cg 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 C^, and as isomer C for the inversion, at Cg mp 152-3°C; ’Hmr (CDClg) 6: 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, CHg), 0.95 (9H, s, Bu), 0.27 (6H, 2s, CHg). Anal, calcd for: C30H37N°2Si: c 71-52- p 7·40’ N 2-78’ s 6.36%. found: C 71.28, H 7.41, N 2.48, S 6.19%. 128 0 597 Isomer B: This isomer posseses a trans-stereochemistry at C3~C4· is a racemic mixture composed of the (l'R,3S,4R) and the (l'S,3R,4S) enantiomers. Compounds with the same configuration at C^,, and are referred to as Isomer B; ir (CHCip 1745 cm (C=0,; mp 158-9-C; 'Hmr (CDClj) δ: 7.60-7.10 (15H, m, aromatics), 4.02 (IH, d, J=0.S 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, CH3); Isomer C: This isomer possesses a trans-stereochemistry at C -C .

It is a racemate formed of the (l'S,3S,4R) and the (l'R,3R,4S) lg enantiomers. Compounds with the same configuration at C^,, C3 and are referred to as Isomer C. mp 134-6’C; 'Hmr (CDCl^) 5: 7.607.10 (15H, m, aromatics), 4.32 (IH, 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, CH3); ir (CHC13> V : 1735 cm1 (C=0). max Isomer D: This isomer possesses a cis-stereochemistry at c3“c4· It is a racemate composed of the (l'R,3R,4R) and the (1’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 (CDC13) : 7.8020 6-90 (ISH, 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'), 1.0 (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%. 129 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 (0°) 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 10 and extracted with ether (3X) . The combined ether extracts were 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%. t-Bu 3 Isomer B A suspension of cuprous iodide (4.78 g, 15 mmol) in ether (50 ml) was cooled to O’C and treated under N2, with a 1.9 M solution of methyl lithium (26 ml, 50 mmol). The brown solution was stirred at O’C for 10 min and then cooled to -60°C and treated dropwise with the trans 1-1(t-butyl dimethylsilyl)-3-formyl-4tritylthio-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 IM solution of ammonium chloride. The mixture was filtered over Celite 130 and the organic phase was washed with a IM solution of ammonium chloride (3 x 5 ml) and then brine and dried over sodium sulfate. Filtration and evaporation gave alcohol, isomer B, which crystallized from ‘Hmr (CDC13) δ: 7.32 (15H, m), 4.05 (IH, s), 3.4 tlH, d, J=3HZ, 3.253.S5 (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 with anhydrous tetrahydrofuran in a Soxhlet extractor for 18 h, then dried under vacuum in a dessicator (P^Og) for 18 h d) ' tBu CH. ''tBu Methylmagnesium iodide (0.1 ml, 0.1 mmol) was added dropwise to a cooled (O’C) and stirred solution of trans l-(t-butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (25 mg, 0.05 iranol) in THF (2 ml). The solution was stirred 1.5 h at O’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. 131 F. Preparation of (l'S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-trimethylsi1yloxy-1*-ethyl)-4-tritylthio-2-azetidinone (isomer C) -5 A solution of (l'S,3S,4R and l'R,3R,4S) l-{t-butyldimethylsilyl)-3-(1'-hydroxy-1‘-ethyl)-4-tritylthio-2-azetidinone (15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in dry THF (6 ml) was 3tirred 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. lHmr (CDCl^) 5: 7.10-7.60 (15H, m, aromatics), 4.30 (IH, d, J=1.5, H-4), 2.25-2.89 (2H, m, H-3, H-l'), 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 cm”1 (C=O). 3 3 3 max G. Preparation of (1’5,3R,4R and l'R,3S,4S) 1'(t-Butyldimethylsilyl)-3-(1‘-methoxymethoxy ether-1’-ethyl)-4-tritylthio-2-azetidinone (isomer A). n-Butyllithium (ca 12.5 ml of 1.6H 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 (isomer A) (10.1 g, 20 mmol) in THF (100 ml) maintained at -78°. 132 50587 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 temperature 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 (CDClj) 5: 7.1-7.5 (15H, m, aromatics), 4.47 (IH, d, H-4), 4.23 (2H, ABq, J=7, O-CHj-O), 3.1-3.4 (2H, m, H-3 et H-l'), 3.23 (3H, s, O-CH.*) , 1.37 (3H, d, J=6.5, CHj), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH3).

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- (l'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (isomer c) (50 mg, 0.1 mmol), p-bromobenzenesulfonylchloride (100 mg, 0.4 mmol) and 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 (CDClj) 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), 1.18 (3H, d, J=6.5, H-2'), 1.0 (9H, s, t-Bu), 0.31 (6H, s, di-CH3>. 133 I. Preparation of (l'R,3S,4R and l'S,3R,4S) 1'(t-Butyldimethylsilyl)-3-l'-acetoxy1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) A solution of (l'R,3S,4S and l'S 3R 4Ξ) 1-(t-butyldimethylsilyl)-3-(1'-hydroxy-l'-ethy1)-4-tritylthio-2-azetidinone (13.85 g, 27.5 mmol) in pyridine (75 ml) acetic anhydride (50 ml) (prepared at 0°) 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%). ’Hmr (CDClg 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, CHgCO), 0.98 I (3H, d, J=6, CHg), 0.88 (9H, s, t-butyl), 0.12 (6H, s, CHg); ir (CHCl,) V : 1775, 1740 cm1 (C=0) max J. Preparation of 1-(t-Butyldimethylsilyl)-3-(1‘-paranitrobenzyldioxycarbony!)-1'ethyl)-4-tritylthio-2-azetidinone. (4 isomers) Isomer C n-Butyllithium (8.8 ml of 1.6 M solution in hexane, mmol; just enough to obtain a permanent pink coloration) was 134 50587 added dropwise to a solution of Isomer C of 1-(t-butyldimethylsilyl) -3-{1'-hydroxy-1*-ethy 1)-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 chloroformate (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 118-9Ο (ether); 'Hmr (CDCl^) δ: 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, CH.*), 1.0 (9H, s, Bu) and 0.30 ppm (6H, 2s, CH ); ir (CHC1 ) U : 1745 cm 1 (C=O); Anal, calcd J «3 max for C„_H.JJjrSiS: C 66.83, H 6.20, N 4.10, S 4.69; found: C 66.90, 42 2 6 H 6.26, N 4.11, S 4.59.

Isomer B The Isomer B of 1-(t-butyldimethyIsilyl)-3-(1'hydroxy-l'-ethyl(-4-tritylthio~2-azetidinone, treated as described above gave pure Isomer B of l-(t-butyldimethylsilyl)-3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone as a foam, 95%. 'Hmr (CDCl^ δ: 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, Cfi^ , 0.7 (9H, s; Bu and 0.2 ppm (6H, s, CH,); ir (film) V : 1755, 1740 cm 1 C=O. max Isomer A The Isomer A” of 1-(t-butyldimethylsily1-3-(1'-hydroxyl'-ethyl)-4-tritylthio-2-azetidinone, treated as described above gave pure Isomer A of l-(t-butyldimethylsilyl-3-(l'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-tritylthio-2-azetidinone as an oil. 95% 'Hmr (CDCl.*) δ: 8.3-6.7 (19H,m, aromatics), 4.95 (2H, ABq, benzyl), 4.53 (111, p, J=7.5, J-7.5, H-l4.31 (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, CH^).

Isomer D Likewise Isomer D of 1-(t-butyIdimethylsily1-3-(1'5 hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone, gave pure Isomer D of 1-(t-butyldimethylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'ethyl)-4-tritylthio-2-azetidinone, 90%. ’Hmr (CDCl^) 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), io 1.03 (3H, d, J=6.5, CH^), 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH^ mp 13O-2°C. Anal, calcd for C 66.83, H 6.20, N 4.10, S 4.70; found: C 66.56, H 6.28, N 3.96, S 4.89.

K. Preparation of (i'S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1*-methane1 - sulfonyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) A solution of (1'3,3S,4R.and l'R, 3R,4S)-1- (t-butyldimethylsilyl) -3-(1'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (2.0 g, 4 mmol) in dichloromethane (80 ml) was treated at 5°C, with 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 N.,, 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 120-22°C; ’Hmr (CDC13) δ: 7.13-7.61 136 (15H, m, aromatics), 4.50 (IH, d, J»2, H-4), 3.62 (IH, dq, J=6.5, 2, H-l'), 2.96 (XH, 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 (CHCl ): 1746 (C=O), 1343 and 1180 cm”1 (SO ) . 2 max 3 2 L. Preparation of (l'R,3S,4R and l'S,3R,4S) l-(t-Butyldimethylsilyl)-3-(l'-methanesulfonyloxy-11-ethyl)-4-tritylthio-2-azetidinone (Isomer B) A solution of (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethyl10 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 was stirred at 5°C for 1 h. Then the solution was washed with brine, dried (MgSO4) and evaporated to leave a residue which crystallized as a white solid when triturated in ether (5.40 g, 93%) mp 127-31°C.

'Hmr (CDCl ) 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, -CHj), 1.01 (3H, d, J=6.2, H-2'), 0.90 (9H, s, t-Bu), 0.12 (6H, s, -CH,); ir (CHCl ) υ : 1745 cm”1 (C=O). 3 max 137 M. Preparation of (l'S,3S,4R and l'R,3R,4S) S-d'-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-butyldimethyl silyl)-3-(1'-hydroxy-1'-ethy1)-4-tritylthio-2-azetidinone (Isomer 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, CH Cl > (3.36 g, 94.6%) mp 142-44’C; ’Hmr (CDC13) δ: I 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 (CHCl.) V : 1749 cm”1 (C=O). 3 max 138 Ν. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(1'-Methoxymethyl-1'-ethyl)-4-tritylthio-2azetidinone (isomer A).

A cold (0°C) HMPA-H2O (116 ml-13 ml) solution of Isomer A of 1-(t-butyldimethylsilyl)-3-(1'-methoxymethyl-1'-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 (CDCip δ: 7.10-7. (15H, m, aromatics), 4.85 (2H, ABq, J=7.4, O-CI^-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 3 max (N-H) and 1760 cm'1 (C=O). 0. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(l'-M ethoxymethyloxy-1'-ethyl)-4-tritylthio2-azetidinone (Isomer C) A cold (dry ice-acetone bath) solution of (l'S,3S,4R and 1’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 139 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 0°C. It was poured in an ice cold ammonium chloride solution and extracted with ether. The ether extracts were combined, washed with water, dried (MgSO4) and concentrated to give crude (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldimethylsilyl)-3-(1'-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 HMPA-H2O (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 precipitate was collected by filtration and redissolved in methylene chloride.

The solution was washed with water and brine and dried (MgSO4) to give the title compound (3.0 g, 69.3%), mp 172-2.5 (ethyl acetate-hexane); ir (CHCl^) Vx: 3400 >- llimr (CDCl ) 5:7.67-7.12 (15H, m, H aromatics), 4.63 (2H, center of ABq, J=6, O-CH^O), 4.49 (IH, s, N-H), 4.40 (IH, d, J=3, H-4), 4.25-3.80 (lH, 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, CH.^ 140 P, Preparation of (l'R,3S,4R and 1'5,3R,4S) 3-(11-Formyloxy-11-ethyl)-4-tritylthio-2azetidinone (Isomer B) osn (hBr otho A solution of (l'S,3S,4R and l'R,3R,4S) 3-(l'-p-bromobenzenesulfonyloxy-1'-ethyl)-1-(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 HgO 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% CHgCN-CHgClg) (2 mg, 4.8%) mp 131-32°C; ’Hmr (CDClg) δ: 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 (CHCl,) V : 3400 (NH), 1765 (C=O), 1725 cm'1 (C=O). max Q, Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l'-Acetoxy-l'-ethyD^-tritylthio^azetidinone (isomer B) Pure derivative (l'R,3S,4R and l'S,3R,4S) l-(t-butyldimethylsilyl)-3-(l’-acetoxy-l1-ethyl)-4-tritylthio-2-azetidinone ' (5.77 g, 10.57 mmol) was dissolved in warm HMPT-water (60 ml, 10 ml). 141 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.C1., 2 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.Cl.JV : 3395 (N-H), 1772, 1738 cm”1 (C=0) . ’Hmr (CDCl ) 2 2 max 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, J3^.=7.5, J3_4=2.8, J3_nh=1, H-3), 2.1 (3H, s, CH^O), 1.35 (3H, d, J-6.5, CH3>.

R. Preparation of 3-(1'-Hydroxy-i'-ethyl)-4-tritylthio-2-azetidinone. Mixture of four A solution of lithium diisopropyl amide1(0.74 mmol) was 25 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 -78°C, 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 142 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 CgHgtEtOAc, 6:4) gave a mixture of alcohols (0.215 g, 80%). This mixture (’Hmr) cannot be separated either by hplc or by tic. a: Acetylation Acetylation of an aliquot of the mixture (0.065 g) with ]Q 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).1’ b; t-Butyldimetyl silyl derivatives ,. The mixture of alcohols (0.121 g, 0.34 mmol) was treated (5 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 aranonium chloride and dried over anhydrous magnesium sulfate. Evaporation gave an oil (0.716 g) which contains components by HPLC. a 3.7%; 1; = 60.6%; £ = 31.1%; £ = 4.6% (the identity of each one has not been established)* NOTE: lButyl lithium and lithium hexamethyl disilazane were ineffective 2Order of increasing polarity ’Acetylation of the product derived from 1-t-butyIdimethylsily1-4tritylthio-2-azetidinone gave the following ratio: d = 29.5%; c = 24.1%; b = 33.8%; a = 12.6% ''Reaction of a mixture of alcohols derived from (R and S) 1-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone gave the following proportions: a = 5.2%; b = 41.3%; £ =1 48%; d = 4.6% 143 S. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(1'-Benzoxy-1'-ethyl)-4-tritylthio-2azetidinone (Isomer B) A solution of (l'S,3S,4R and l'R,3R,4S) 3-(l'-methanesulfo nyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (035 mg, mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H^O-DMF (10 ml) was heated at 90°C for 7.5 h. Then the reaction mixture was diluted with 1^0 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 a white solid (108 mg, 23.2%) mp 158°C. ‘Hmr (CDC13) 6: 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 (CHCl^ 15 V i 3400 (N-H), 1765 (C-0), 1715 cm”1 (C=O).

T. Preparation of 3-(1' -Paranitrobenzyldioxycarbonyl-11-ethyl)-4-tritylthio-2azetidinone (4 isomers). •tBu Isomer C a) A solution of Isomer C of 1-(t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-tritylthio- 2-azetidinone (1.3 g) in a mixture of TFA (5 ml), water 144 (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 78-80°C; 'Hmr (CDC13) : 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, CH^; ir (CHCI ) V : 3390 (N-H), 1765 and 1745 (shoulder) (C=O, and 1525 max cm 1 (NO2). b) A cold (0°C) HMPT-H20 (90 ml - 19 ml) solution of Isomer C of l-(t-butyldimethylsilyl)-3-(l*-paranitrobenzyldioxycarboxy1-1'-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 Z) 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'-paranitrobenzyldioxycarbonyll'-ethyl)-4-tritylthio-2-azetidinone was prepared as described 25 above for the “Isomer C; 92%; mp 155.5-6’C (ether); *Hmr (CDCip δ: 8.25-6.80 (19H, m, aromatics), 5.20 (2H, s, benzyl), 4.95 (IH, m, H-l'), 4.35 (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 (CHCI ) V : 3480, 3390 (N-H), 1772, 1750 (C=0), and 1525 cm'1 3 max (NO2). Anal, calcd for C32H28N2°6S: C 67·59' H 4-96’ N 4·93' S 5.64; found: C 67.48, H 4.98, N 4.92, S 5.67. 145 Isomer A Isomer A of 3-(l'-paranitrobenzyldioxycarbonyl1'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the Isomer C; mp 2O5-6°C. 'Hmr (CDCl^) δ: 8.2-6.7 (19H, m, aromatics), 5.22 (211, ABq, benzyl), 5.57-4.B5 (III, m, H-l'), 4.65 (IH, N-H), 4.50 (IH, d, J=6.5, H-4), 3.65 (lH, dd, J=6.5, 12, JN_H=1, H-3) and 1.52 ppm (3H, d, J=7.5).

Isomer D Isomer D of 3-(l'-paranitrobenzyldioxycarbonylig l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for Isomer C; 'Hmr (CDC13> δ: 8.15-6.70 (19H, ro, aromatics), 5.23 (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, CH ). (J value for H-3 taken after D20- exchange).

(J, Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(1'-methanesulfonyloxy-1'-ethyl)-4tritylthio-2-azetidinone (isomer B) MsO MsO A solution of (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethyl 2Q silyl)- 3-(1'-methanesulfonyloxy-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% H2O-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 25 (MgSO^) and evaporated. Crystallization of the residue (ether-petether) gave the title compound (3.33 g, 83.8%). mp 130-31°C. 'Hmr (CDC1 ) 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, -CH ), 1.63 (3H, d, J=6.4, H-2'); ir (nujol) υ : 3195 (n-H), 1768 cm 1 (C=0). jv max 146 V. Preparation of (l'S,3S,4R and l'R,3R,4S)3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio2-azetldinone. (Isomer C) A solution of (l'S,3S,4R and 1'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 produot was 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%; 'Hmr (CDC1 ) δ: 7.43 (15H, m, 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 3395 (N-H), 1768 cm1 (C=0) ; Anal, calcd for C_eH, NO„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)20 4-tritylthio-2-azetidinone (Isomer C) A solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-p-bromobenzenesulfoxyloxy-1'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2azetidinone (Isomer C) (1.42 g, 2 mmol) and sodium benzoate (0.865 g, 147 mmol) in 10% H2O-HMPA (40 ml, was stirred at room temperature for 1 h. Then the solution was diluted with H2O (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. 'Hmr (CDCl^ δ: 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 ) U : 3400 cm”1 (N-H), 1770 cm 1 3 max (C=O).

X. Preparation of (i'R,3S,4R and l'S,3R,4S) 3-(l'-Hydroxy-l'-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 l_ml of HO. '’'h® reacti°n mixture was kept at 90°C for 20 h, then diluted with ether and washed 4 times with brine. The organic 20 solution was dried (MgSO^), evaporated and the crude title compound purified by column chromatography (silica gel, 15% CH^CN-CH^l^ .

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. 148 Preparation»of 3- (I1-Hvdroxv-11-ethyl)-4-tritvlthio-2-azetidinone δΟφ, Both isomers, (l'S,3S,4R and l'R,3R,4S) 3-(l'-hydroxy1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) and (l'R,3S,4R and 1’S,3R,4S) 3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) were prepared by the same method. For example, 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, mmol) and sodium benzoate (0.865 g, 6 mmol) in 10% H^O - 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 (CDC13) 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 (CHCl,) V : 3400 (n-H), 1760 cm 1 (C=O). max Similarly (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethylsilyl)-3(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, J»2.5, H-4), 4.28 (IH, s, NH), 4.10 (IH, dq, J=6.4, 5.3, 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 (CHCl,) V : 3400 (N-H), 1760 cm”1 3 max (C=O) 149 Z. Preparation of (l'S,3R.4R and l'R,3S,4S) 3-(1'-Methoxymethyl-1'-ethyl)-1-(paranitrobenzyl Z-hydroxy-2’’-acetate)-4-tritylthio-2-azetidinones (Isomer A) A mixture of Isomer A of 3-(1'-methoxyraethy1-1’-ethyl)-4tritylthio-2-azetidinone (7.5 g, 17.3 mmol), paranitrobenzyl glyoxylate hydrate (4.7 g, 20.8 mmol) and toluene (300 ml) was heated under reflux o 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, m, 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, CH^; ir (KBr) V : 3360 (OH), 1770 (C~0 of β-lactam), 1735 (C=O of ester) and 1605 cm max (aromatics).

AA. Preparation of (l'S,3S,4R and l'R,3R,4S) l-d'-Methoxymethoxyrl'-ethyD-l-tparanitro20 benzyl 2-hydroxy-2''-acetate)-4-tritylthio-2-azetidinone (Isomer C) OCH2OCH3 Γί STr CHO CO PNB 2 OCH OCH 2 3 I STr J— ». ™ CO2PNB A solution of hydrated paranitrobenzyl glyoxylate (1.73 g, 7.11 mmol) was refluxed in toluene (90 ml) using a Dean Stark condenser 0 filled with 3A molecular sieves for a 2 h period. To the boiling solution was added (l'S,3S,4R and l'R,3R,4S) 3-(1'—methoxymethyloxy-1 150 50587 ethyl)-4-tritylthio-2-azetidinone (3.0 g, 6.93 iranol) and the mixture was refluxed for 2 h more. The mixture was cooled to room temperature» triethyl amine (70 mg, 97 μί, 0.69 iranol) was added and it was stirred for 2 h. The reaction mixture was diluted with ether, washed with 1% aqueous HCl, water, 1% aqueous NaHCOy water and brine, dried (MgSO4) and concentrated to give the title compound (4.60 g, 100%); ir (CHC13) V :3530-3100 (O-H), 1765, 1750 (C=O) and 1525 cm1 (NO,); ’Hmr (CDCl ) max 2 3 i: 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 0-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, CH3~O), and 1.15 ppm (3H, d, J=6.5, CHj).

BB. Preparation of (l'R.3S,4R and IS.3R.4S) 3-(1'-Acetoxy-1'-ethyl)-1- (paranitrobenzyl2-hydroxy-2-a eg ta te)4-tri ty 1 th i o-2-azeti di none OAc A.

STr CHO CO PNB 2 -N 0' H TEA OAc /A STr CO PNB 2 Isomer B A solution of hydrated p-nitrobenzyl glyoxylate (triturated with ether) (1.82 g, 30 mol) was refluxed in binzene o through a Dear. Stark condenser filled with 3A molecular sieves for 2 h. To that was added azetidinone (l'R,3S,4R and l'S,3R,4S) 3-(1'-acetoxy-I'-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 inmol was added , jt ,..as then stirred for 2 h; tbe reaction progression being followed by tic. ‘Solvent evaporation afforded a white 151 foam in quantitative yield (100%, mixture of epimers) «Alternatively the solution can be acid and base washed., ir (CH3C12) 3520 (OH), 1775, 1745 cm 1 (C=0) ; 1 Hmr (COCl^ δ: 8.2, 8.18 (2H, 2d, J=8, Ho aromatic), 7.8C-6.90 (17H, m, H-aromatic), 5.28, 5.17 (2H, 24, CH^PNB, 4.89 (0.67H, d, 0=7.2, CHO), 4.80 (center of m, H-l'), 4.38 (0.33 H, 2d, 0=8.8, CHO), 4.22 (D.33H, d, 04_3=2.5, H-4), 4.09 (0.67H, d, J4_3= 2.1, H-4), 3.65 (D.67H, dd, J31,=S.8, J3-4=2-1, H-3) ' 3-47 (°-33H· dd, 0 ,=5-5 0 =2.5, H-3), 3.33 (0.3311, d, 0=8.8, OH), 3.23 (0.67H, 3-1 3-4 d, 0=7.5, OH), 1.38, 1.36 (3H, 2s, CH^D) , 1.10, 1.06 (3H, 2d, 0=5.8, 6.3, cn3) CC. Preparation of 3-(11-paranitrobenzyldioxycarbonyl-!1-ethyl)-1-(paranitrobenzyl 2'’-hydroxy-2-acetate) 4-tritylthio-2-azetidinone (4 isomers) . 0C0 PNB OCO.PNB ΓΛλ COPNB Isomer C“ A mixture of Isomer C of 3-(1'-paranitrobenzyldioxycarbony1-1'-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 o 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 25 compound could be prepared by using a catalytic amount of triethyl 152 50S97 amine. Lean polar epimer at 2: ’Hmr (CDClg) δ: 0.25-6.HO (23H, tn, 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, m, H-l*), 3.50 (IH, >3, 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 3 max (NOg). More polar isomer at C-2; ’Hmr (CDClg) δ: 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, 2-OH), 3.33 (IH, dd, J=2.5, 2.5, H-3), 1.23 (3H, d, J=6.5, CHg); ir (CHClg) V -· 3520 to 3200 (O-H), 1755 (C=0) and 1525 cm'1 (NO ) . max 2 Isomer B A mixture of hydrated paranitrobenzylglyoxylate (1.74 g, 7.66 mmol) and (l'R,3S,4R and l'S,3R,4S) 3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (3.63 g, 6.38 mmol) was refluxed in toluene (70 ml, on a Dean Stark condenser filled with 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 NaHCOg, 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 (CHClg) vmax: 3500 (O-H), 1772, 1750 (C=O, 1525 cm1 (NOg); ’Hmr (CDClg) δ:8.30-8.0 and 7.65-6.80, (23H, m, aromatics,, 5.27 and 5.13 (4H, 2s, benzyls), 4.71 (IH, m, 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.) υ 3480 (O-H) -*-—— j max: 1772, 1750 (C=O) and 1525 cm1 (NOg)’, ’Hmr (CDClg) δ: 8.35-6.90 (23H, m, aromatics), 5.15 (4H, benzyls), 4.72 (IH, d, J=7.5, H-2O),4.9O153 4.50 (IH, m, J=6.5, 6.5, H-l'), 4.10 (IH, d, J=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, J=6.5, ch3) .

Isomer A The Isomer A of 3-(1'-paranitrobenzyldioxycarbony 15 l'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of Isomer A of 3-(I1-paranitrobenzyldioxycarbony1-1'-ethyl)-1(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinones. ’Hmr (CDClj) 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, J=6, 6, H—3 ( and 1.47 ppm (3H, 2d, J=6.5, CHy two epimers).

Isomer D The Isomer D of 3-(1'-paranitrobenzyldioxycarbony1l'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of Isomer D of 3-(1'-paranitrobenzyldioxycarbony1-1'-ethyl)-1(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinones. ’Hmr (CDC13) δ: 8.30-6.60 (23H, m, aromatics), 5.20 (4H, m, benzyls), 4.83 (IH, 2d, J=5, H=4), 5.50-4.30 (2H, m, H-l' and H-2), 3.48 (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·)-!-(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinone (isomer C) (epimers at Cz).

OMs OMs OH ti PNB 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 154 (11S,3S,4R and 1' R, 3R,4S)3- (1'-methanesulfonyloxy-1*-ethyl)-4-tritylthio”” 2-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 iranol) and stirred for 3 h in order g to complete the reaction. Evaporation of the solvent left a white foam which was used as such in the next step. lHmr (CDCl^) δ: 9.12 (2H, d, J=9, Hm aromatic), 7.20 (17H, part of d,Ho aromatic, trityl), 5.28 (2H, s, 'CHj- 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, J=i6 Hz, M :3520 (O-H), 1775 (C=0) and 1765 cm1 (C=O) . max EE. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(1-Methoxymethy1-1'-ethyl)-1-(paranitrobenzyl 2-chloro-2-acetate)-4-tritylthio-2-azetidlnone (Isomer A) Pyridine (1.1 ml, 14.2 mmol) was added dropwise to a solution of Isomer A of 3-(l'-methoxymethyl-l'-ethyl)-l-(paranitrobenzyl-2-hydroxy-2-acetate)-4-tritylthio-2-azetidinone (7 g, .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 were concentrated, 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%), ’Hmr (CDClf δ: 6.65-8.35 -5 (19H, m, aromatics), 5.24 (2H, s, benzyl), 3.43 (3H, s, OCH^) and 1.42 ppm (3H, d, J=6, CHj). 155 FF. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(l'~ ethoxymethyloxy-1'-ethyl)-1-(paranitrobenzyl 2-chloro-2-acetate)-4-tritylthio-2-azetidinone (Isomer C) A cold (ice-MeOH bath) THF (60 ml, distilled over LAH) solution of (l’S,3S,4R and l'R,3R,4S) 3“(1'-methoxymethyloxy-1'-ethyl)1-paranitrobenzyl 2-hydroxy-2-acetate)-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 10 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. Renoval of charcoal on a Celite pad and subsequent benzene evaporation afforded the title compound (4.86 g, 100%); ir (CHC1 ) U : 1770 (C=O) and 1525 cm1 (NO ); 'Hmr max ί I (CDCl^) 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, O-CH3>, and 1.30-0.96 ppm (3H, m, CH.^ . 156 GG. Preparation of (l'R, 3S,4R and l'S,3R,4S) 3-(I1-Acetoxy-1'-ethyl)-1-(paranitrobenzyl 2-chloro-2acetate)-4-trltylthlo-2-azetidinone Isomer B A THF (distilled over IAH, solution of (l'R,3S,4R and l'S, 3R,4S) 3-(11-acetoxy-11-ethyl)-l-(paranitrobenzyl-2-hydroxy-2-acetate)~ 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, io 2.24 ml, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 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 1 which was taken up in benzene (warm) and treated with charcoal. The 15 suspension was filtered through a celite pad and solvent evaporation left a foam; ir (CHjClj) V^.· 1780, 1740 cm1 (C=O, ‘Hmr (CDC13 δ: 8.17, 8.21 (2H, 2d, J=8, Ho aromatic) 7.76-6.88 (17H, m, H-aromatic), 5.31, 5.16, 5.12, 4.73 (3H, 4s, C^-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). 157 HH. 3-(I1- Taranitrobenzyldioxycarbonyl-l'-ethyD-l-(paranitrobenzyl 2-chloro2-acetate)-4-tritylthio-2-azetidinones (mixture of epimers at C2).. 597 Isomer C Pyridine (58 mg, 0.73 mmol) was added dropwise to a solution of Isomer C of 3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)1-(paranitrobenzyl 2“-hydroxy-2”-acetate)-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 (CHCl.j) U : 1780, 1750 (C=O) and 1525 cm-1 (NO ). max 2 Isomer B Isomer B of 3-(l-paranitrobenzyldioxycarbonyl-l'-ethyl)1- (paranitrobenzyl 2-chloro-2-acetate) -4-tritylthio-2-azetidinones (mixture of C-2 epimers) was prepared as described above for the Isomer C in quantitative yield. ‘Hmr (CDC13) δ: 8.25-6.90 (23H, m, aromatics), 5.40-5.0 (4H, m, benzyls), 5.40-4.45 (IH, m, H-l'), 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, 0=6.5, H-3), 1.25 and 1.18 ppm (3H, 2d, J=6.5, CHJ; ir (CHCI ) : 1780, 1750 (C=0), and 1525 cm1 (NO ). max 4 158 Isomer A' Isomer A of 3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)1'· (paranitrobenzyl 2-chloro-2'*-acetate)-4-tri tylthio-2-azetidinones ('mixture of C-2” epimers). lHmr (CDCip 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-paranitrobenzyldioxycarbonyl-1'-ethyl10 1'-(paranitrobenzyl 2-chloro-2-acetate )-4-tritylthio-2-azetidinones (mixture of C-2 epimers). lHmr (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,) U : 1780, 1750 (C=0) and 1525 cm 1 3 3 max (No2) II. Preparation of (l'S,3S,4R and l'R,3R,4S)3-(l'-M3thanesulfonyloxy-l'-ethyl)-l-(paranitroI benzyl 2-chloro-2''-acetate (-4-trity lthio-2-azetidinone (isomer C) (epimers at C;).

To a cold solution (5“C) of (l'S,3S,4R and l'R,3R,4S)3(1'-methanesulfonyloxy-l'-ethyl)-l-(paranitrobenzyl 2-hydroxy-2-acetate)4-tritylthio-2-azetidinone (24.0 g, 35.5 mmol) 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. 159 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. lHmr (CDClg) 5: 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, -CHgPNB), 4.73 (IH, 2d, H-4), 3.21 (IH, 2dq, H-3), 2.78 (3H, 2s, mesylate and 1.21 ppm (3H, 2d, H-6H ; H-2’,; ir V 1779 cm”1 (C=0) max JJ. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(1'-Methoxymethoxy-1'-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone (Isomer A) A mixture of Isomer A of 3-(l'-methoxymethoxy-l'-ethyl)-lί (paranitrobenzyl-2-chloro-2”-acetate)-4-tritylthio-2-azetidinone )5 (6.6 g, 10 mmol), triphenyIphosphine (3.3 g, 12.5 mmol), 2,6-lutidine (1.3 ml, 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 20 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 cm1 (C=C, aromatics). 160 KK. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(l’-Methoxymethyloxy-l1-ethyl)-!-(paranitrobenzyl 2-triphenylphosphoranylidene-2l'-acetate) -4- trityl thio-2-azetidinone (Isomer C).

A dioxane (100 ml, distilled over LAH) solution of (l'S, 3S,4R and l'R,3R,4S) 3-(l'-methoxymethyloxy-l'-ethyl)-l-(paranitrobenzyl2“-chloro-2,'-acetate)-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, 7.20 mmol) was heated under reflux for 4 h and kept in a hot bath (100°C) for 16 h. The mixture was diluted with ether, washed with 1% aqueous HCI, water, 10% aqueous NaHCO^, water and brine and dried (MgSO^). 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 q, 48%). ir (CHCl ) V : 1795 (C=O), 1620 and 1605 (phosphorane) ’ 3 max and 1515 cm 1 (NO^). (l'R,3S,4R and l'S,3R,4S) 3-(l'-Acetoxy-l'-ethyl)-l-(paranitrobenzyl2”-triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azeditinone (Isomer B) A dioxane (100 mi, freshly distilled over LAH) solution of crude (l'R,3S,4R and l'S,3R,4S) 3-(l'-acetoxy-l'-ethyl)-1-(paranitro161 benzyl 2-chloro-2-acetate)-4-tritylthio-2-azetidinone was treated 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 refluxed (oil bath 130°) for h. The solvent was evaporated and the residue was redissolved 5 in methylene chloride. The resulting solution was successively washed with diluted HCl, H^O, diluted aqueous NaHCO^.H^O and brine. 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 (CH2C12) 1750 (C=O) and 1620, 1610 cm 1 (phosphorane).

MM· 3-(l'-Paranitrobenzyldioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl-2triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone.

ISOMER B A mixture of (l'R,3S,4R and l'S,3R,4S) 3-(1'-paranitrobenzy 1-dioxy carbonyl- 1' -ethy 1)-1- (paranitrobenzyl-2-chloro-2-acetate) -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 HCl, water, 10% aqueous NaHCO^, water and brine and dried (MgSO^). Solvent evaporation afforded a 162 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%), np 189-190° (ether); ir (CHCI,) u : 1750 (C=0), 1620, 1605 (phosphorane) and 1522 cm 1 (NOj).

ISOMER C Isomer C of 3-(11-paranitrobenzyldioxycarbonyl-1’-ethyl)1- (paranitrobenzyl-2-triphenylphosphoranylidene-2-acetate)-4-tritylthio2- azetidinone was prepared as described above for isomer B. ir (CHCl^) V : 1750 (C=0), 1610, 1620 (phosphorane) and 1520 cm'1 (NO,); 'Hmr max 2 (CDClj) 5: 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 (CHj).

ISOMER D A mixture of Isomer D of 3-(l'-p-nitrobenzyldioxycarbonyl1’-ethyl)-1-(p-nitrobenzyl 2-chloro-2-acetate)-4-tritylthio-2-azetidinone (4.598 g, 4.45 nmol; 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 wnol; 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 ·Ί) · The dark reaction mixture was cooled,'diluted with EtOAc and washed successively with 0.1 NHC1, water, 2% NaHCO^ and then brine. Drying (Na^O^) and evaporation of the solvents gave 4.18 g of a dark coloured oil which was purified by column chromatography (SiO2, 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^) δ: 1.08 (d, J=6Hz, l’-CH^); ir (neat) \) : 1745 cm 1 (s, C=O). max 163 S0S97 NN. Preparation of (l’S,3S,4R and 1'R,3R,4S)3-(!'-Methanesulfonyloxy-1'-ethyl)-1-(pananitrobertzyl 2-triphenylphosphoranylidene-2-acetate)-4-trityithio-2-azetidinone (isomer C) A solution of (l'S,3S,4R and l'R,3R,4S) 3-d'-methanesulfonyloxy-1'-ethyl)-1-(paranitrobenzyl 2-chloro-2-acetate)-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 )Q under nitrogen for 19 h. The solvent was evaporated and the crude product redissolved in ethyl acetate and washed successively with dilute HCl, NaHCO and brine. Purification was completed by chromatography on a silica gel column (8.5 x 12 cm). Elution with 10% ether-dichloromethane (1.5 Zj and then ether (1.5 £) gave the purified phosphorane; 12.36 g (40%). i: ‘Hmr (CDC1 ) δ: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir V : 1749 and 1620 ι -j 3 max cm’1 (C=0) 00. Preparation of (l'R,3S,4R and l'S,3R,4S) 3- d1 -Hydroxy-1' -ethyl) -1- (paranitrobenzyl2-triphenylphosphoranylidene-2-acetate) 4-tritylthio-2-azetidinone og (Isomer B).

A solution of phosphorane d'R,3S,4R and l'S,3R,4S) 3(1'-acetoxy-1'-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone (4.43 g, 5.00 mmol) 164 in methanol (10 ml) THF (60 ml) was treated at room temperature with 1% aqueous NaOH (1 eq, 200 mg in 20 ml H2O). The reaction progression was followed by tic*. The mixture was diluted with ether-ethyl acetate and washed with HCl, H2O, aqueous NaHCO^, HjO 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,) υ : 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 i'R,3S,4S) Silver 3-(l'-roethoxymethyl-l'-ethyl)-l-(paranitrobenzyl 2-triphenylphosphoranylidene-2''-acetate)-2-azetidinone-4thiolate (Isomer A) OCH2OCH3 och2och3 co2pnb Silver 3-il'-methoxymethyl-1'-ethyl)-1-(paranitrobenzyl -2-triphenylphosphoranylidene-2-acetate)-3-tritylthio-2-azetidinone (isomer A), was prepared as described elsewhere for the isomer C of the paranitrobenzyldioxy carbonyl derivative. Yield 50%. ir (neat 165 QQ. Preparation of l'S,3S,4R and l'R,3R,4S) Silver 2-(1'-methoxymethyloxy-1'-ethyl)-1(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone 4-thiolate (Isomer C).

OCH-OCH. och2och3 , STr AgNO ο' CO2PNB CO PNB 2 (l'S,3S,4R and l'R,3R,4S) 3-(11-methoxymethyloxy-1'-ethyl)-l-(parani trobenzy1 2-triphenylphosphoranylidene-2-acetate)-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 (CHC1,) υ : 1745 (C=O), 1605 (phosphorane) and 1520 J max cm'1 (NO ).

RR. Preparation of Silver 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2-tnphenylphosphoranylidene-2-acetate)-2-azetidinone-4-thiolate. (l’R,3S,4R and l'S,3R,4S) 3-(l'-paranitrobenzylcarbonyl— dioxy-1'-ethyl)-1-(paranitrobenzyl-2-triphenylphosphoranylidene-2acetate)-4-trithio-2-azetidinone ().02 g, 1 mmol) was first dissolved in CHgClg (3 ml) and diluted with hot (55’C) 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 O’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) \) : 1745 (C=O) , 1600 (phosphorane) and 1517 cm 1 (NO ) .

Isomer C Silver 3-(11-paranitrobenzyldioxycarbony1-1'-ethyl) -1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-triphenylphosphoranylidene-2-acetate)-2-azetidinone-4-thiolate, Isomer C, was prepared as described above for the Isomer B,‘ ir (nujol) V : 1745 (C=0) and indx 1600 cm 1 (phosphorane).

Isomer D A solution of Isomer D of 3-(1'-p-nitrobenzylcarbonyldioxy-1'-ethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2acetate)-4-tritylthio-2-azetidinone (145 mg, 0.142 mmol) was prepared by first dissolving it in CHgClg (5 ml), removing the CHgClg at 55°60° and adding hot MeOH (4 ml). To the above solution was added a hot solution of AgNOg in MeOH (0.15 M, 1.14 ml, 0.17 mmol, 1.2 eq), followed by pyridine (14 μΐ, 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 mg (0.11 mmol, 78%) of the title compound as a brownish solid: ir (Nujol) V : 1750 cm 1 (s, C=O). max 167 5059 7 r’icpnrntloii ol' (l'R,3S,4R and l'S,3R,4S) Silver 3-(l'-hydroxy-l'-ethyl)-l-)paranitrobcnzyl-2-tr ipliony lphosphoi any lideno-2-acel:ato) -2-azotidinon A solution* of (l'R,3S,4R and l’S,3R,4S) 3-(l'hydroxy-1' -ethyl) -1- (paranitrobenzyl-2’’-triphenylphosphoranylidene-2acetate)-4-tritylthio-2-azetidinone (lg, 1.19 mmol) in MeOH (10 ml), was treated with pyridine (124 μί, 121.3 mg, 1.53 mmol) and at 10°C with a 0.15M 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 (0-H), 1752 (C=O) 1595 (phosphorane) and 1525 cm 1 (NO ) max 2 ‘The crystalline material was first dissolved in CH^l^· TT, Preparation of (l'R,3R,4R and l'S,3S,4S) 4-Acetylthio-3-(1'-p-nitrobenzyldioxycarbonyl1'-ethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2azetidinone (Isomer D) CH COCl-Pyr -J-:—--t CHCI 2 2 OCOPNB V , θ/“Νγ?*3 ,SAc CO2PNB To a stirred solution of silver 3-(1'-paranitrobenzyl 2-triphenylphosphoranylidene-2”-acetate)-2-azetidinone-4-thiolate 168 · (isomer D, (85 mg, 0.095 mmol) in CH2C12 <5 containing pyridine (30 Ul,«0.37 mmol; Fisher) was added at 0-5’C CHgCOCl (20 pi, 0.28 mmol) and the mixture was stirred at 0-5’C for 30 min. The precipitate which formed was filtered and washed with CH^Clj. The filtrate and washings were combined, washed successively with brine, diluted HCl, saturated NaHCO, and then brine, dried (Na.SO.) and evaporated yielding 75 mg 3 2 4 (0.091 mmol, crude yield 95») of the title compound as a syrup: ’Hmr (COC13) δ: 2.33 (s, -SOCOCH3); ir (neat) 1750 (β-lactam, ester), 1695 (thioester), 1520 and 1350 cm”1 (-NO2). ]θ UU. Preparation of (l'R,5R,6R and l'S,5S,6S) cis p-Nitrobenzyl 2-methyl-6-(l'-p-nitrobenzyldioxycarbonyImethy1-penem-3-carboxylate (Isomer D) A solution of' the above acetylthioazetidinone (74 mg, 15 0.09 mmol) in toluene (30 ml) was heated at reflux under N2 atmosphere for 7 h. After evaporation of the solvent, the residue was purified by hplc (SiO2; eluent, benzene:ether=3:1) yielding 24 mg (0.044 mmol, yield 49%) of the penem ester as a syrup. (Note: this oil could be crystallized from THF-ether or CHgClg-ether: (CDCl^) δ: 1.40 (3H, d, J=6.5 Hz, l'-CH,), 2.38 (3H, s, 2-CH,), 4.07 (IH, dd, J =4Hz, J i? / D Jg χ=9Ηζ, 6-H), 5,05-5.30-5.34-5.59 (2H, AB type, 3-CO,CH,-Ar), 5.30 (2H, s, I'-OCO -CH,-Ar), 5.1-5.6 (IH, m, l'-H), 5.68 (IH, d, J. =4Hz, i 3,6 -H), 7.49-7.64-8.18-8.33 (4H, A 'B ', l'-aromatic Hs ), 7.53-7.68-8.188.33 (4H, A'B ', 3-aromatic Hs); ir (neat) V : 1780 (β-lactam), 2 HlflX 25 1750 (-0CO2-), 1710 (ester), 1520 and 1350 cm1 (-N02). 169 VV. Preparation of (l'R,5R,6R and l'S,5S,6S) Potassium and sodium 6-(l'-hydroxyethyl)~ 2-methylpenem-3-carboxylate (isomer D).

A solution of the above penem ester (24 mg, 0.044 mmol) in THF (5 ml) was mixed with ether(10 ml), H^O (5 ml), phosphate buffer (1.00 ml, 0.05 molar pH 7.00: Fisher) and 304 Pd-Celite (50 mg, Engelhard) This mixture was hydrogenated at 35 psi for 21.5 h at room temperature.

After removal of the catalyst (over Celite), the aqueous layer was Ό separated, washed with ether and lyophilized yielding 12 mg of the title mixture of sodium and potassium salts as a white powder; lHmr (D20) δ: 1.23 (3H, d, J=6Hz, I'-CH^), 2.27 (3H, s, 2-CH,), 3.85 (IH, dd, .=4Hz, J =9Hz, 6-H), 4.3 (IH, m, 1*-H) and ,6 6,1 .65 ppm (1H, d, J =4Hz, 5-H); ir (Nujol) υ : 1755 ( -lactam) and 5 , Ο ΖΠαΧ 1570 cm_1 (-CO®); uv (H,0) λ : 297 (ε 2300, calcd as K-salt), 258 2 max (ε 1900, calcd as K-salt). This material was identical to a sample of title compound prepared by an aldol condensation of acetaldehyde with the dianion of 2-methylpenem-3-carboxylic acid.(’Hmr, ir, uv) 170 Example 25 U'S,5R,6S and I'R'SS^R) 6-l;-Hydroxy-l'-ethyl)-2-niethylpenem-3-carboxylic Acid (Isomer C) OH co2h Method A: OH CO, H 1 Method B: qco2pnb -A co2pnb PNB 171 METHOD A 1) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(1'-paranitrobenzyldioxycarbonyl-1' -ethyl·) -1- (paranitrobenzyl 2-triphenylphosphoranylidene2-acetate)-2-azetidinone(isomer C).

OCO PNB -SAg OCO2PNB CH3COC1 C5V CO2PNB CO2PNB A cold (ice-MeOH bath) solution of l'S,3S,4R and l'R,3R,4S) silver 3—(1'-paranitrobenzyl-dioxycarbonyl-11-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone-4-thiolate (isomer C) (1.14 g, 1.30 mmol) in CH2C12 (60 ml) was treated with pyridine (0.6 ml, 0.74 mmol) and dropwise with acetyl chloride (236 mg, 0.213 ml, 3.00 mmol). The reaction mixture was stirred for 1 h at -15°C. The precipitate was filtered and washed with ether. The filtrate was washed with 2% aqueous HCl, water, 2% aqueous NaHCOy water and brine and dried (MgSO^). The residue upon solvent evaporation was triturated in ether (895 mg, 83.7%, mp 184-5°C dec); ir (CHCl^) υ : 1755, 1695 (C=O), 1620 and 1605 cm 1 (phosphorane). Anal, calcd max for C _H N 0 SSi: C 61.38, H 4.42, N 5.11, S 3.90; found: C 61.26, 36 3 11 H 4.49, N 4.88, S 4.26. 172 50587 2) (l'S,5R,6S and l'R,5S,6R) Paranitrobenzyl 2-methyl-6-(1'-paranitrobenzyldioxycarbonyl-1 '-ethyl)-penem-3-carboxy late (isomer C) A solution of (l'S,3S,4R and l'R,3R,4S) 4-acetylthlo5 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2triphenylphosphoranylidene-2“-acetate)-2-azetidinone (isomer C) (855 mg, 1.04 mmol) in toluene (60 ml) was heated under reflux for 4.5 h. The residue upon concentration of the solution was passed through a silica gel (10 g) column (1% ether in benzene) to give the pure title compound (393 mg, 69.6%), mp 157-158’C (chci3· -ether); ir (CHCI ) V i 1785, 1745, 1710 (C=O) 3 UlclX and 1525 cm1 (NO,); ’nmr 2 (CDC13) δ: 8.30-7.2 (8H, m, H-aromatics) 5.46 (IH, d. J=1.8, H-5) , .40-5.0 (5H, m, z CH^PNB and H-l'), 3.95 (IH, dd, J=1.8, J=5.4, H-6), 2.35 (3H, s, CH3) and 1.43 ppm (3H, d, J=5.4, CHj); Anal, calcd for C24H21N3°10S: C 53·04' H 3 *·89' N 7-73; found c 52.76, H 3.86, N 7.69. 3) (l'S,5R,65 and l'R,5S,6R) 6-(l'-Hydroxy-l’-ethyl)-2-methyl penem-3carboxylic acid (isomer C) A mixture made of (l'S,5R,6S and l'R,5S,6R) paranitrobenzyl 2-methy1-6-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)penem-3-carboxylate (206 mg, 0.379 mmol), THF-ether-H^O (30 ml, 40 ml, 20 ml), a 0.05 M pH 7 buffer solution (7.64 ml, 0.382 mmol) and 30% Pd on Celite (500 mg) was hydrogenated at 42 psi on a Parr shaker 173 597 for 16 h. The catalyst was filtered and washed with water. The aqueous phase was washed with ether (3 times), acidified portionwise with cold 1% aqueous HCI to pH 2.5 and extracted with ethyl acetate (15 x 20 ml) between each hCl addition. The ethyl acetate extracts were combined and washed with brine (3 x 30 ml). Evaporation of the solvent and trituration of the residue with ether gave the title compound (57 mg, 65.6%), ir (KBr) vmax: 3580-3300 (O-H), 1755 and 1660 cm-1 (C=0); uv (EtOH) λ 311 (ε 6538), 262 (ε 3672); ’Hmr max (DMSO-d ) δ: 5.57 (IH, d, J=1.7, H-5), 4.02 (IH, m, H-l'), 3.75 6 (IH, dd, J=1.7, J=3.5, H-6), 2.23 (3H, s, CH.^ and 1.23 ppm (3H, d, ch3> .

METHOD B 1) Silver (1*Ξ,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-parani trobenzyldioxycarbony1-1’-ethyl)-2-azetidinone-4-thiolate (isomer C) Isomer C of 1'-(t-butyldimethylsilyl) -3(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-tritylthio-2-azetidinone (1 g, 143 mmol) was dissolved by stirring in hot (40°C) methanol (12 ml). A solution of silver nitrate (0.59 g) in methanol (12 ml) was added followed by pyridine (0.13 ml). The mixture was stirred vigorously 1 h at room temperature and 2 h at 0°. The solid silver mercaptide was collected by filtration and washed with ether, 352 mg (46%). ir υ : 1735 cm 1 (C=O). max 174 2) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-l-(t-butyldimethylsilyl-3(1'-paranitrobenzyldioxycarbony1-1'-ethyl)-2-azetidinone (isomer C) XtBu To a solution of isomer C of silver 1-(t-butyldi5 methylsilyl)-3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone-4-thiolate (880 mg) in dichloromethane (40 ml) stirred at O’C was added pyridine (0.57 ml) followed, dropwise, by acetyl chloride (0.49 ml). The mixture was stirred 0.5 h at O’, the solids removed by filtration and the filtrates diluted with 10 ether, washed with aqueous hydrochloric acid (2%), water, sodium bicarbonate (2%) and brine, dried and concentrated to leave the title material as an oil. (610 mg). lHmr (CDClg) ¢: 8.2 and 7.48 (4H, 2d, aromatics), 5.40 (IH, d, J=2.2, H-4), 5.2 (2H, s, benzyl), 5.3-4.9 (IH. IB, H-l'), 3.42 (IH, dd, J=2, H-3), 2.32 (3H, s, CHg), 1.40 (3H, d, J=6.5, CHg), 0.95 (9H, s, t-Bu) and 0,2 ppm (6H, CHg). 3) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone. (Isomer C) ^tBu 2q Isomer C of the above S-acetyl N-t-butylmethyl-silyl-asetidinone derivative (1.4 g) was dissolved in a mixture of TFA (0.5 ml), water (0.5 ml), methanol (3 ml) and dichloromethane (2 ml) and stirred at room temperature for 48 h.

The solution was diluted with water (100 ml) and extracted with dichloromethane (4 x 20 ml). The combined organic extracts were 175 — washed with sodium bicarbonate (2%) and brine, dried and concentrated to leave the crude title compound as an oil. Purification was done by chromatography over silica gel (30 g) eluting with 5% ether in benzene; (650 mg). Crystallization from benzene gave a white solid. ’Hmr (CDClf δ: 8.15 and 7.45 (4H, 2d, aromatics), 6.18 (IH, N-H), 5.19 (2H, s, benzyl), 5.05 (2H, m, H-4 and H-l'), 3.35 (IH, dd, J=2.5, 4.5, H-3), 2.34 (3H, Ξ, αγ and 1.42 ppm (3H, d, J=6.5, CH ); ir U : 1780, 1750, 1695 cm 1 (C=0). 1,) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(Γ-paranitrobenzyldioxycar10 bonyl-l'-ethy1)-1-(paranitrobenzyl 2-hydroxy-2-acetate)-2-azetidinones (epimers at C-2). (isomer C) A mixture of isomer C of 4-acetylthio-3-(l'-paranitrobenzyldioxycarbonyl-1'-ethyl)-2-azetidinone (750 mg), paranitrobenzylglyoxylate hydrate (525 mg) and benzene (50 ml) was heated under reflux for 3 days over a Dean and Stark apparatus filled with 3A molecular sieves. A second portion of glyoxylate (52 mg) was added and reflux was continued for 2 more days. The mixture was diluted with ether, washed with hydrochloric acid (2%), water, sodium bicarbonate (2%) and water, dried and concentrated to leave an oily residue (975 mg). Chromatography on silica gel, eluting with benzene-ether (85=15) gave the pure title compounds. ’Hmr (CDCl^) δ: 8.25-6.75 (8H, m, aromatics), 5.30 and 5.12 (4H, 2s, benzyls), 5.05-4.70 (IH, H-2), 4.45-4.35 (IH, 2d, H-4), 4.50-4.10 (IH, m, H-l'), 3.30 (IH, m, H-2 and 1.25 ppm (3H, 2d, CH ). 176 ) (l'S,3S,4R and l'R,3R,4S) 4-acetylthio-3-(1*-paranitrobenzyldioxycarbonyl-1 1 -ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene2-acetate)2-azetidinone (isomer C) Isomer C of 4-acetylthio~3-(l'-paranitrobenzyldioxycarbonyl-11-ethyl)-1-(paranitrobenzyl 2-hydroxy-2-acetate) -2-azetidinone (577 mg, 1 mmol) was dissolved in anhydrous THF (10 ml) and pyridine (95 mg, 1.2 mmol) was added to the solution.

The solution was cooled to 0’ and thionyl chloride (lb3 mg, 1,2 mmol) was added slowly. The mixture was stirred 30 min at 0°, diluted with a little ether and the insoluble salts removed by filtration and washed with ether. The combined filtrates were concentrated to give the crude mixture of epimers of the C-2 chloro compound.

It was dissolved in THF (20 ml), triphenylphosphine (314 mg, 1.2 mmol) and 2,6-lutidine (129 mg, 1.2 mmol) were added and the solution was stirred at 45’C for 4 days. The solids were removed by filtration, washed with benzene and the combined filtrates were concentrated to leave an oil whose spectral characteristics and tic behaviour were identical to a sample of the title compound prepared by acylation 2Q of the corresponding silver thiolate.

The desired penem product may be produced by reacting the title compound according to the method of steps 2 and 3 of Example 25 (Method A). 177 597 Example 26 (l’R,5R,6S and 1'S,5S,6r) 6-(1'-Hydroxy-1'-ethyl)-2-methylpenem-3-carboxylic Aeid (isomer B) OH METHOD B 1) (l’R,3S,4R and l'S,3R,45) 4-Acethylthio-3-(l'-paranitrobenzyl-dioxycarbonyl-11 -ethyD-l- (paranitrobenzyl 2-triphenylphosphoranylidene-2acetate)-2-azetidinone, (isomer B) nm ΡΗϋ CO PNB AcCl C5H5N A solution of (l'R,3S,4R and l'S,3R,4S) silver 3-(l·'15 paranitrobenzyldioxycarbonyl-1'-ethyl) 1'-paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone-4-thiolate (isomer B) (917 mg, 1.03 mmol) in CH^Cl^ (20 ml) was treated at -15°C (ice-MeOH bath) with pyridine (242 pi, 247 mg, 3.13 mmol) and dropwise with acetyl chloride (lh2 pi, 157 mg, 2.0 mmol). The mixture was stirred 178 S0597 for 15 min at -15°C and the solid was filtered and washed with ether.

The organic solution was washed with 2% aqueous HCl, water, 2% aqueous NaHCO^, water and brine and dried over MgSO^. The residue upon solvent evaporation crystallized from ether (710 mg, 80%, mp 183-185°C; ir (CHCl^) υ : 1755, 1695 (C=O), 1620, 1605 (phosphorane) and 1625 cm'1 (NO,); max / 2) (l'R,5R,6S and 1'5,5R,6R) Paranitrobenzyl 2-methyl-6-(l'-paranitro. benzyldfoxycarbonyl-l'-ethyD-enem-3-carboxylate. (isomer B) OCO PNB A solution of (l'R,3S,4R and l'S,3R,4S) 4-acetylthio-310 (1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-lfparanitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone (650 mg, 0.791 mmol) was refluxed in toluene for 7 h. The concentrated solution upon solvent evaporation was passed through a silica gel column (10 times its weight) and the title compound (0.5% ether-benzene to 2% ether-benzene) was obtained as a white solid; 329 mg, 77%, mp 134-135’C, (CH2Cl2-ether); ir (CHCI,) V : 1785, 1745, 1705 (C=O) and 1525 cm'1 (NO,); ’Hmr (CDCl ) δ: 3 max 2 3 8.20 (2H, d, Ho aromatic), 7.60 (2H, d, Hm aromatic), 5.55 (IH, d, J=1.5, H-s), 5.5-4.75 (5H, m, 2CH2-PNB, H-l'), 3.86 (IH, dd, J=7.8, J=1.5, H-6), 2.38 (3H, s, CHj) and 1.50 ppm (3H, d, J=6.3, CH3>; Anal, calcd for C24H21N3°10S: C 53·Π4' H 3·89' N 7·73' Ξ 5·9θ! found: c 53.05, H 3.98, N 7.63, S 6.02 179 50S97 3) (l'R,5R,6S and l'S,5S,6R) 6-(1'-Hydroxy-11-ethyl)-2-methyl penem -3-carboxylic acid (isomer B) A mixture of (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 2-methy1-6-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-penem-3-carboxylate (isomer B) (65 mg, 0.12 mmol), 0.05 M pH 7 buffer solution (1.06 eq) , H^-THF-ether (10 ml, 10 ml, 25 ml) was shaken on a Parr hydrogenator using 30% Pd on Celite (200 mg) for 16 h at 50 psi H^.

The catalyst was filtered and washed with small volumes of water. The aqueous layer was washed with ether (3 times), acidified portionwise with 1% cold aqueous HCl, extracted with ethyl acetate between each addition of HCl, and saturated with brine and extracted throughly with ethylacetate. The ethyl acetate extracts were combined, washed with brine (5 times) and dried (MgSO^). Solvent evaporation afforded a solid residue which was triturated with methylene chloride (19.4 mg, 71%). ir (nujol) υ : 3500 (0-H), 1785, 1672 cm”1 (C=O); uv (EtOH) max λ : 260 (ε 3450), 309 (ε 6400); ‘Hmr (DMSO d,) δ: 5.54 (IH, d, max 6 J=1.5, H-5), 3.88 (IH, m, H-l'), 4.2-3.5 (2H, bs, 0-H), 3.65 (IH, dd, J=S.5, J=1.5, H-6), 2.28 (3H, s, CH^ and 1.15 ppm (3H, d, J=6, CH3>. 180 5059 METHOD Β 1) (l'R,3S,4R and l'S^R^S) 4-Acetylthio-3-(1 ’-trimethylsilyloxy-l ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate) -2-azetidinone (isomer B) TMSC1 -% TEA AcCl c5h5h OTMS J, >SAC XV CO2PNB A suspension of (l'R,3S,4R and l'S,3R,4S) silver 3—(l'— hydroxy-1’-ethyl)-1(paranitrobenzyl 2”-triphenylphosphoranylidene-2acetate)-2-azetidinone-4-thiolate (505 mg, 0.715 mmol) in THF (25 ml) was cooled to -15’C (ice-MeOH bath), treated dropwise with triethyl 10 amine (289 mg, 398 pi, 2.86 mmol), trimethyl chlorosilane (310 mg, 362 Ul, 2.85 mmol) and finally with imidazole (50 mg, 0.734 mmol), stirred for 3 h at -15”C and at room temperature for 16 h. (ir of an all quot showed absence of hydroxyl group). The mixture was cooled to -15°C, diluted with CH^Cl^ (20 ml)) treated with pyridine (226 mg, 231 ul, 2.86 mmol) and acetylchloride (168 mg, 152 Ul, 2.14 mmol), stirred for 0.5 h, diluted with ether, washed with dilute aqueous HCl, water 5% agueous NaHCO^ water and brine and dried. The solvent was removed on the rotary evaporator and the residue purified by filtration through a silica gel column (1:10 ratio, 3% to 10% ether in benzene) to give the title compound (360 mg, 84.2%) mixed with a little of the desilylated derivative (30 mg, 7.8%). ir (liquid film) V a ’ 1750, 1790 (C=O), 1620 (phosphorane) and 1518 cm 1 (NOj). 181 o) (l'R, 3S,-1R and l'S,3R.4S) 4-Acetylthio-3-(1 ,-liydroxy-l/_-»JJ1YIJ.~L· (paranitrobenzyl 2”-triphenylphosphoranylidene-2-,icrtiite)-2-azetidinone (isomer B) A solution of (l'R,3S,4R and l'S,3R,4S) 4-acetylthio-3 1'-trimethylsilyloxy-1'-ethyl)-1(paranitrobenzyl 2—triphenylphosphorany lidene-2-acetate) -2-azetidinone (360 mg, 0.504 mmol) was treated with TFA (3 drops) and stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate, washed with water, dilute aqueous NaHCOg, water and brine and dried (MgSO^). Solvent evaporation afforded the title compound (334 mg, 100%); ir (CHClg) v : 1755, 1690 (C=O), 1620, 1605 (phosphorane and 1520 cm 1 (NO ). max (l 4 3) (l'R,5R,6S and l'S,5S,6R) Paranitrobenzyl 2-roethyl-6-(1'-hydroxy-l'ethyl)-penem-3-carboxylate (isomer B) A solution of (l'R,3S,4R and l'S,3R,4S) 4-acefcylthio3-(1'-hydroxy-l'-ethyl)-1(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone (410 mg, 0.638 mmol) in toluene (40 ml) was refluxed for a 7 h period. Toluene was partially evaporated. The residue was passed through a silica gel (1 to 12 ratio) column (3%, 4% and 5% ether in benzene) to give the title compound (151 mg, 65%) as a white solid mp 161-161.5°C; ir (CDCl ) v : 3600, 3500-3400 (OH), 1780, 1608 (c=0) and 1525 cm1 J max (NOg); ‘Hmr (CDClg) δ: 8.20 (2H, d, J=7, Ho aromatic), 7.60 (2H, d aromatic), 5.57 (IH, d, J=2, H-5), 5.29 (2H, center of ABq, J=15, CHg-PNB), 4.2 (IH, dq, J=7, J=6, H-l'), 3.67 (IH, dd, J=7, J=2, H-6), 182 2.33 (3H, s, CHj) and 1.33 ppm (3H, d, J=6, CH^); Anal, calcd for cleH,cN,°^S: C 52.74, H 4.43, N 7.69, S 8.80; found: C 52.67, H 4.41, lb 10 2 o N 7.71, s 8.96. 4) (l'R,5R,6S and l'S,5S,6R) 6-(1'-Hydroxy-1'-ethyl)-2 -methyl penem -3-carboxy11c acid (isomer B) A mixture of (1*, 5R, 6S and l'S,5S,6R) paranitrobenzyl 6-(1'-hydroxy-1’-ethyl)-2-methylpenem-3-carboxylate (89 mg, 0.244 mmol), THF-HjO-ether (15 ml, 10 ml, 30 ml), a 0,05 M pH 7 buffer solution (5.06 ml, 0.253 mmol) and 30% Pd on Celite (250 mg) was shaken on a Parr hydrogenator for 3.5 h at 45 psi H^. A work-up identical to the one previously described gave title compound (32 mg, 57%).

Example 27 (1'S,5R,6r and l'R,5S,6S) 6-(11 -Hydr'oxy-1 '-ethyl)-2-methylpenem-3-carboxylxc Aeid (isomer A) 1) (l'S,3R,4R and l'R,3S,4S) 4-Acetylthio-3-(l'-methoxymethoxy-l'-ethyl)-l(paranitrobenzyl 2-triphenylphosphoranyIidene-2-acetate)-2-azetidinone (isomer A) 183 Isomer A of 4-acetylthio-3-(l'-methoxymethoxy-l'-ethyl) -1-(paranitrobenzy1-2”-triphenylphosphoranylidene-2-acetate)-2-azetidinone was prepared as described elsewhere for isomer C of the paranitrobenzyl dioxycarbonyl derivative, yield 85%. ir (neat) υ : 1750 and max 1690 cm 1 (C=0). 2) (l’S,3R,4S and l'R,3S,4S) 4-Acetylthio-3-(1'-hydroxy-l1-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone, (isomer A) Isomer A of 4-acety lthio-3- (1' -me thoxyme thoxy-1 '-ethyl) 1-(paranitrobenzy1-2-triphenylphosphoranylidene-2-acetate)-2-azetidinone (500 mg, 0.68 mmol) was added to a cooled solution (0°C) of trifluoroacetic acid (50 ml) and water (10 ml) and stirred for 15 min in ice and 3 h at room temperature. The reaction mixture was concen15 trated, dichloromethane was added and the solution was washed with sodium bicarbonate, water, and brine, dried and concentrated to give the title compound (450 mg, 96%); ir (neat) δ : 3400 (OH) , 1745 max and 1690 cm 1 (C=O). 184 S0597 3) (l'S,5R,6R and l'R,5S,6S) Paranitrobenzyl 6-(l’-hydroxy-l'-ethyl)-2methyl penem-3-carboxylate (isomer A).

Prepared as described for isomer C of the paranitro5 benzyl dioxycarbonyl derivative, yield 45%, ’Hmr (CDC13) δ: 7.93 (4H, ABq, aromatics), 5.68 (IH, d, J=4.0, H-5), 5.33 (2H, ABq, benzyl), 4.3 (IH, m, H-l'), 3.8 (IH, dd, J=4.0, H-6), 2.41 (3H, s, CHf, 2.31 (IH, s, OH), and 1.42 ppm (3H, d, J=6, CH,); ir (CHCI,) V : 31003 3 max 3600 (OH,, 1780 and 1710 cm1 (C=0), it) (l'S.5R,6R and l'R,5S,6S) 6-(1'-Hydroxy-1'-ethyl)-2-methyl penem-3- A mixture of isomer A of paranitrobenzyl 6-(1'-hydroxy*l‘-ethyl)-2-methyl penem-3-carboxylate (82 mg, 0.2 mmol), palladium on Celite (30%, 400 mg), THF (10 ml), ether (25 ml), water (10 ml) and buffer (0.05 M, pH=7, Fisher #S0-B-108) (4 ml) was hydrogenated on a Parr shaker at an initial hydrogen pressure of 45 psi for 4 h. The catalyst was removed by filtration on Celite and washed with water.

The filtrates were washed with ether and the aqueous layer was acidified in the cold hydrochloric acid (0.25 M) and extracted with ethyl acetate (5 x 10 ml). The combined organic extracted were washed with brine, dried and concentrated. The foamy solid was 185 triturated in ether to give a white solid (20 mg, 44%). ir (nujol) υ : 3500 (OH), 1765 and 1665 cm 1 (C=O); uv (EtOH) λ : 3°1 5922), max 260 (E 4280).

Example 28 (l'R,5R,65 and l'S.SS^R) S-Aminomethyl-6-(l'-hydroxy-l'-ethyl)-penem-3-carboxylic Acid (isomer B) (1'R,3S,4R and I'S,3R,4S) 4-azidoacetylthio-3-(1'-hydroxy-1'ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2acetate)-2-azetidinone (isomer B) OH A X.sAgΝ^ΡΦ3 CO2PNB TMSC1 TEA c1coch2n3 A cold (ice-MeOH bath) suspension of (l'R,3S,4R and l'S,3R,4S) silver 3-(1'-hydroxy-1'-ethyl)-l-(paranitrobenzyl 2triphenyl phosphoranylidene-2-acetate)-2- azetidinone-4-thiolate (970 mg, 1.37 mmol, from 1 g of the corresponding trityl) in THF (40 ml) was treated dropwise with trimethylchlorosilane (0.695 ml, 595 mg, 5.48 mmol), triethyl amine (0.765 ml, 555 mg, 5.49 mmol) and imidazole (50 mg, 0.734 mmol). The mixture was stirred under N2 for 17 h, then cooled to -15°C (ice-MeOH bath) and azidoacetyl chloride (406 mg, 3.40 mmol) was added in. It was stirred for 30 min (the reaction progression being followed by tic). The solid was filtered and washed with ether. The filtrate was diluted with more ether, washed with 1% aqueous HCI, water, 1% aqueous NaHC03, water and brine and dried (MgSO^). The residue 186 upon solvent evaporation was taken up in moist CH2C12 (50 ml) and treated with TFA (3 drops, cleavage of TMS-ether being followed by tic). The methylene chloride solution was then washed with 1% aqueous NaHCOy water and brine and dried (MgSO^). The residue was passed through a silica gel (8 times its weight) column (benzeneether 1:1, ether and ethylacetate-ether 1:1) to give the title compound (565 mg, 69.8%); ir (film) vmax: 3500-3200 (O-H), 2100 (N3), 1755, 1609 (C=O), 1620-1605 (phosphorane) and 1518 cm”1 (NO ). (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 2-azidomethyl-6-(l'-hydroxy1'-ethyl)-penem-3-carboxylate (isomer B) A solution of (l'R,3S,4R and l'S,3R,4S) 4-azido15 acetylthio-3-(1'-hydroxy-1'-ethyl)-1-(paranitrobenzyl 2-triphenyl) phosphoranylidene-2-acetate!-2-azetidinone (500 mg, 0.731 mmol) in toluene 100 ml was refluxed under N2 for 30 min. The solution was concentrated under vacuum and the residue was passed through a silica gel (5 g) column (3.5-4% ether-benzene) and yielded the 2q title compound (193 mg, 65.1%) as a yellowish solid ’Hmr (CDC13) δ: 8.13 (2H, d. Ho aromatic), 7.52 (2H, d, Hm aromatic), .59 (IH, d, J=1.8, H-5), 5.27 (2H, center of ABq, J=13.5, CH2-PNB) , 4.50 (2H, center of ABq, J=16, CHj-^), 4.15 (IH, m, H-l'), 3.73 (IH, dd, J=6.3, J=1.8, H-6), 1.92 (IH, d, J=4, O-H) and 1.33 ppm (3H, d, J=6.3 CH,); ir (CHCl,) V : 2110 (N ), 1785, 1705 (C=O) J j max 3 and 1520 cm”1 (NO2). 187 S0597 (l'R,5R,6S and l'S,5S,6R) 2-aminomethyl-6-(1 '-hydroxy-1 ’-ethyl)penem-3-carobxylie acid (isomer B) A solution of (l'R,5R,6S and l'S,5S,6R) paranitro benzyl 2-azidomethyl-6-(1'-hydroxy-1'-ethyl)-penem-3-carboxylate (25 mg. 0.062 mmol) in THF-ether-water (6 ml, 6 ml, 15 ml) was shaken on a Parr hydrogenator for 2.5 h at 40 psi H2 using 10% Pd on carbon (100 mg). The catalyst was filtered and washed with small volumes of water. The aqueous layer was washed with ether (3 times) and lyophilized to give the title compound (11 mg, 73%).

‘Hmr (D20) δ: 5.75 (IH, d, J=2, H-5), 4.30 (IH, center of m, J=6.5 H-1'J, 4.02 (IH, dd, J=6.5, J=2, H-6) and 1.37 ppm (3H, d, J=6.5, CH ); ir (nujol mull) \) : 3550-2450 (O-H, N-H) , 1765 (C=0) and max 1600 cm-1 (CO®) ; uv (H O) , λ : 309 (ε 3650), 255 (ε 2815) . 2 max 188 50587 Example 29 (1'R.gR.oS and l'S,5S,6R)-2-(t-Aminobutyl)-6-( I'-hydroxy-ethyl)-penem-3-carboxylic Acid (Isomer B) OH (l'R,3S,5R and l'S,3R.4Si 4-(6-azidobutanoylthio)-3-(J.'-hydroxye thyl) -1- (paranitrobenzyl 2’‘-triphenylphosphoranylidene-Z-acetate) -2azetidinone SAg rJ—N\„ CT THSC1 TEA, Im.

PPh3 COOPNB N (CH_) COCI _3__2_ac5h5n h2o =PPh3 COOPNB A solution of (l'R,3S,4R and l'S,3R,4S) silver 3(1'-hydroxyethyl)-1-(paranitrobenzyl 2“-triphenyiphosphoranylidene2-acetate)-2-azetidinone-4-thiolate (3.03 g, 4.28 mmol) in dry THF (55 ml) kept under a nitrogen atmosphere was cooled to -25°C and successively treated with triethylamine (2.39 ml, 17.12 mmol), trimethylchlorosilane (2.18 ml, 17.12 mmol) and imidazole (0.10 g, 1.47 mmol). The reaction mixture was stirred at -25’C for 0.23 h, the cooling bath was 189 removed, and the stirring was continued for 16 h. The reaction mixture was cooled to 0°C and diluted with CHjClj (55 ml); it was then treated successively with pyridine (0.73 ml, 9.0 mmol) and with a solution of 4-aminobutanoyl chloride (1.36 g, 8.56 mmol) in t CH.C1. (10 ml). The reaction mixture was stirred at 0°C for 1 h J 2 2 and filtered through a Celite pad. The pad was washed with CH2C12 (25 ml); the filtrate and washings were combined and diluted with EtOAc (300 ml). The organic solution was washed with IN HCl solution, HjO, saturated NaHCOsolution and HjO, dried over anhydrous MgSO^ and concentrated on a rotary evaporator to an orange syrup (3.83 g).

The syrup was dissolved in CH^Cl^ (75 ml) and water (4 ml) and TFA (0.2 ml) were added; the reaction mixture was stirred at 23°C for 1.5 h, washed with NaHCO3 and H^O, dried over anhydrous Na^SO^ and concentrated to an orange syrup (3.4 g). Purification of the syrup was achieved by a column chromatography (silica gel G 60, 80 g; eluent: EtOAc in CHjCl^ 10% -> 75%). Evaporation of the appropriate fractions gave an oil; 2.14 g, 67.7%. Anal, calcd for C,,H N O_SP: C 61.23, H 5.00, N 9.65, S 4.42; found: C 61.17, H 5.10, N 10.02, S 3.71. 2Q (l'R,5R,6s and 1'5,5S,6R) paranitrobenzy! 2-(δ-azidobutyl)-6-(l'-hydroxyethyl)-penem-3-carboxylate A solution of (l'R,3S,4R and l'S,3K,4S) 4-[fi-azidobutanoy1thio) -3-(1'-hydroxy-1’-e thyl)-1-(parani trobenzy1-2-triphenyl25 phosphoranylidene-2-acetate)-2-azetidinone (2.04 g, 2.81 mmol) in a toluene-CHjClj mixture (30:1, 310 ml) was refluxed for 9 h under a 190 nitrogen atmosphere (The CHjClj was removed at the beginning of reflux). The reaction mixture was cooled to 23’C and the toluene was removed in vacuo leaving an orange residue which was purified by column chromatography (silica gel 60, 45 g; eluent, ether in pet. ether, 1:1 + 9:1). The appropriate fractions were combined and concentrated to a syrup which was crystallized from an ether-pet.ether mixture, 0.443 g, mp 85°C, 35.2%. Anal, calcd for C,nH..N.O,S: C 51.00, H 4.73, N 15.65, S 7.17,· found: C 51.05, H 4.86, N 15.86, S 7.19. The fractions corresponding to unreacted starting material were cyclized as described above to give an additional quantity (0.276 mg, 21.9%) of title compound.

V : 2100 (N_), 1770 (C=0, β-lactam) and 1705 cm”1 (C=0, PNB ester); uv max 3 (H,0 23°C) λ : 268 (e 13757), 316 (£9826). 'Hmr (CDC1,) 6: 1.36 (d, max 3 J, H-2-H-l' ,=6.3 Hs, 3Η, methyl), 1.52-1.77 (m, 4H, H-2', H-3'), 2.57-3.00 (m, 2H, H-4'), 3.00-3.42 (ra, 2H, H-l'), 3.72 (dd, J, H-6-H-5 =1.6 Hz, J, H-6-H-1' „=6.4 Hz, H-6), 4.02-4.42 (m, IH, H-l), 5.32 (ABq, Ja_b=13.6 Hz 2H, CH2 of PNB ester), 5.60 (d, ή H-5-H-6 .=1.6 Hz, lH,H-5), 7.61 (d, =8.8 Hz, 2H, Hm of PNB ester) and 8.21 ppm (d, ^θ.^8·8 Hz' 2H' Ho of PNB ester). (i'R,SR,6S and l'S,5S,6R) 2-(4-aminobutyl)-6-(1'-hydroxyethyl)-penem3-carboxylic acid OH OH % Pd/C :ooh To a solution of (I'R, 5R,6S and l'S,5S,6R) paranitrobenzyl Z-(d-azidobutyl)-6-(Γ-hydroxyethyl)-penem-3-carboxylate (0.54 g, 1,21 mmol) in diaethoxyethane (50 mi) was added ether (50 ml), water (50 ml) and 10% Palladium on charcoal (0.54 g). The reaction mixture was hydrogenated under 45 psi of hydrogen at 23OC for 3 h. The reaction 191 mixture was filtered over a Celite pad and the filtrate was diluted with ether. The aqueous phase was separated, washed with ether and lyophylized. The crude title compound was purified by hplc. ir (KBr) Vmax: 37θθ (C=O, β-lactam) and 1565 cm 1 (C-0, carboxylate); 'Hmr (D2O) δ 1.32 (d, JCH3_H_r.=6<4 HZ) 3H( CHp( 1.45-1.35 (m, 4H, H-l',H-3’), 2.50-3.20 (m, 4H, H-l', H-4'), 3.84 (dd, JH_s_H_in=6·1 Hz- JH_6_H_5 =1.4 Hz, 1-H, H-6), 4.00-4.45 (m, IH, H-l- and 5.62 ppm (d, J , „ , H—5—H-6 =1.4 Hz, IH, H-5); uv (H.O) λ : 260 (ε 4240), 302 (Ε 5480). max Example 30 (1R,5R,6S and l'S,$S,6R)-2-(trans-3'-Amino-1'-cyclobutyl)-6-(l-hydroxy-l~ ethyl)penem-3-carboxylic Acid (isomer B) NH OH XQO COOH (1R,3S,4R and 1S,3R,4S) 4-(trans-3'-azidocyclobutanoylthio)-3(l-hydroxy-l-ethyl)-1-(paranitrobenzyl 2' -triphenylphosphoranylidene-2' -acetate) -2-azetidinone OH SAg TMSC1 C1?A>'N3 h+ 7:.-O« C=PPh.

I 3 COOPNB TEA, Im -¼ C5H5 h2° ^3 COOPNB A solution of (l'R,3S,4R and l'S,3R,4S) silver 3-(l'hydroxyethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2acetate)-2-azetidinone-4-thiolate (1.01 g, 1.43 mmol) in dry THF (25 ml), kept under a nitrogen atmosphere, was cooled to -40°C and sue20 cessively treated with triethylamine (0.80 ml, 5-74 mmol) trimethylchlorosilane (0.726 ml, 5.72 mmol) and imidazole (0.10 g, 1.47 mmol).

The reaction mixture was warmed to -15°C, stirred for 3 h, the cooling bath was removed and the stirring was continued for 18 h. The reaction mixture was cooled to -15°C and diluted with CH2C12 (25 ml); it was 392 then treated with pyridine (0.15 ml, 1.85 mmol) and trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The cooling bath was removed and the solution was stirred for 1 h and treated with pyridine (0.15 ml, 1.85 mmol) and trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The reaction mixture was stirred at 23’C for 1 h and filtered through a Celite pad. The filtrate was diluted with EtOAc (100 ml) and washed with IN HCI, HjO, saturated NaHCO^ solution and HjO, dried over anhydrous MgSO^ and concentrated on a rotary evaporator to an orange syrup (1.47 g). To a solution of the syrup in CH2C1Z (50 ml) was added H2O (2 ml) and TFA (0.2 ml). The reaction mixture was stirred at 23C for 2 h, washed with saturated NaHCO^ solution and HO, dried over anhydrous Na SO and concentrated to an orange 2 '24 syrup (1.1 g). Purification of the syrup was achieved by column chromatography (silica gel 60, 20 g: eluent EtOAc-ether 35% ♦ 70%).

Evaporation of the appropriate fractions gave the title compound as an oil; 0.77 g, 74.4% ir (neat) υ : 3440 (OH), 2100 (N_), 1755 (C-O β-lactam), 1735 (C=O), 1680 (C-O) and 1625 cm 1 (aromatics). (1R,5R,6S and 1S,5S,6R) paranitrobenzyl 2-(trans-31-azidocyclobutyl) -6-(l-hydroxy-l-ethyl)penem-3-carboxylate A solution of (1”R,3S,4R and 1S,3R,4S) 4-(trans3'-azidocyclobutanoylthio)-3-(l-hydroxy-l-ethyl)-l-(paranitrobenzyΙΕ' -triphenylphosphoranylidene-2 -acetate)-2-azetidinone (2.27 g, 3.14 mmol) in CHCl^ (40 ml) was diluted with toluene (300 ml) and refluxed under a nitrogen atmosphere for 6 h. The first 60 ml of solution (CHC13 + toluene) were removed with a Dean-Stark trapp. The reaction mixture was cooled to 23’C and the solvent was evaporated 193 under a reduced pressure leaving an orange syrup which was purified by a silica gel column (silica gel 60, 35 g, eluent, ether-benzene, * 6%) . Evaporation of the appropriate fractions gave the title compound, 0.3Θ g, mp 134-5°C, 27,3%. Anal calcd for C Η N OS: C 51.24, H 4.30, N 15.73, S 7.20; found: C 50.98, H 4.20, N 15.83, S 7.10; ir (KBr) υ : 2110 (N ), 1765 C=O β-lactam), 1690 (C=O PNB max 3 ester), 1510 (NOg) and 1355 cm”1 (NOg); ’Hmr (CDClg) δ: 1.36 (d, „ ,..=6-3 HZ, 3H, CH,), 2.0-2.75 (m, 4H, H-2', H-4'), 3.67 (dd, 3 J„ = „ c=1--5 Hz, J„ , „ ,,,=6-5 Hz, IH, H-6), 3.8-4.55 (m, 3H, H-l', H-3' fi“o—H—j H-o-H-1 and H-l”-, 5.30 (ABq, J =13.6 Hz, 2H, CH,-Ph-NO,), 5.60 (d, J = 1,5 Hz, IH, H-5), 7.59 (d, J„ „ =8.8 Hz, 2H, H-m of PNB) and 8.20 Ho-Hro (d, J =8.8 Hz, 2H, H-0 of PNB). uv (CHCl,, 23°C) λ : 266 (ε 13050) Hm-Ho 3 max and 322 ppm (ε 10008). The unreacted phosphorane was recovered mixed with Ph^P-0 and cyclized as described before to give an additional quantity of title compound: 0.145 g, 10.4% for a total yield of 37.7%. (l”Rf5R,6S and 1S,5S,6R)-2-(trans-31-amino-l1-cyclobutylf-6-{!hydroxye thyl)penem-3-carboxylie acid l % Pd/C DME, ether, H^O COOH To a solution of (1R,5R,6S and 1S,5S,6R) paranitrobenzyl 2-(trans-3'-azidocyclobutyl)-6-(l-hydroxyethyl)-penem-3carboxylate (0.33 g, 0.74 mmol) in dimethoxyethane (ho ml) was added ether (1)0 ml) and 10% Palladium on charcoal (0.33 g). The reaction mixture was hydrogenated under 45 psi of Hg for 3 h and filtered over a Celite pad. The pad was washed with water and the filtrate and washings were combined and diluted with ether. The aqueous phase was separated, washed withether and lyophylized, 0.20 g, 95%, uv (H 0, 23°C) λ : max 258 (ε 2725) and 306 (ε 3613). The crude material was triturated 194 with water and the white solid was filtered and dried over p2°g under high vacuum for 5 h, 84 mg, 40%; ’Hmr (DjO) δ: 1.34 (d, jh_2.._h_^.i=6.3 Hz' 3H, H-2-, 2.3-2.7 (m, 4H, H-2', H-4’), 3.90 'dd, JH_6_H.5=1·5 ttz' jh_6_h-i »6.1 Hz, IH, H-6) and 5.68 (d, JH_5_H_6»1.5 Hz, IH, H-5); uv (H20, 23°C) A : 258 (ε 4738) and 306 (ε 6318). The filtrate was purified by hplc, max mg; uv (Hn0, 23**C) λ : 257 (e 3580) and 306 (ε 5033). max (The next Example is No. 32) 195 Example 32 (l'S,5R,6S and l'R,5S,6R) B-Trimethylsilylethyl-6(l'-acetoxy-l'-ethyl)2-methylpenem-3-carboxylate (Isomer C) / -Si3-(1'-hydroxy-1'-ethyl)-1-(β-trimethylsilylethyl 2-triphenyiphosphoranyl5 idene-2-acetate)-4-tritylthio-2-azetidinone To a solution of diisopropylamine (185 mg, 1.84 mmol) in tetrahydrofuran (5 ml) at -78°C was added n-butyl lithium (1.3 ml, 2.0 mmol) with stirring. After 5 min, a solution of l-(6-trimethyllO silylethyl 2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2azetidinone (1.27 g, 1.67 mmol) in tetrahydrofuran (15 ml) was added dropwise over 20 min with stirring. After 2 min, freshly distilled acetaldehyde (1 ml) was added and the solution was stirred for 5 min.

Hydrochloric acid (12.6 ml of 0.3M) was added and the mixture was 15 allowed to warm to 23°C. Water and ethyl acetate (20 ml each) were added, shaken, and separated. The organic phase was washed with water and saturated sodium chloride (20 ml each), dried and the solvent was evaporated in vacuo to give crude product, 1.37 g. The product was absorbed from methylene chloride onto 7 g of silica gel and placed (dry) on a 28 g silica gel column. Ths column was eluted with ether (100 ml) and then with ether/ethyl acetate 1:1 (50 ml). The first 20 ml of column fractions were discarded. The rest were combined and the solvent was 196 evaporated in vacuo to give a product, 1.03 g. This product was absorbed from ether onto a 50 g silica gel column (wet). The column was eluted with ether (680 ml) and then with ethyl acetate (200 ml). Later fractions were combined (major low Rf spot on tic) and the solvent was evaporated in vacuo to give partially purified title compound, 440 mg (33%); ir V : 3400 (OH) and 1750 cm 1 (β-lactam and ester); lHmr (CHCl ) δ: max 3 too poorly resolved to make peak assignments other than aromatics and trimethylsilyl.

Silver 3-(11-hydroxy-11-ethyl)-1-(β-trimethylsilylethyl 2-triphenyl]Q phosphoranylidene-2-acetate)-2-azetidinone-4-thiolate.

A solution of silver nitrate (425 mg, 2,5 mmol). pyridine (79 mg, 1.0 mmol) and water (10 ml) was added to a solution of the above compound (403 mg, 0.50 mmol) in ether (10 ml).

The mixture was stirred vigorously for 1 h. The precipitate was collected by filtration and washed with water and ether to give the title mercaptide 267 mg (80%) - ir \) : 3400 (OH) and 1750 cm 1 Π13Χ (S-lactam and ester). 197 4-Acetylthio-3-(1'-acetoxy-11-ethyl)-1-(β-trimethylsilylethyl 2-triphenylphosphoranylidene-2 -acetate) -2-azetidinone A solution of acetyl chloride (70 mg, 0.88 mmol) in methylene chloride (1 ml) was added dropwise to a solution of the above silver mercaptide (267 mg, 0.40 mmol) and pyridine (70 mg, 0.88 mmol) in methylene chloride (5 ml) at O’C. The mixture was stirred at 0°C for 1.5 h and then at 23°C for 15 min. The precipitate was filtered off and the solution was washed with 0.1 M hydrochloric β acid and 0.1 M sodium bicarbonate (10 ml each). The solvent was evaporated in vacuo to give the title compound, 153 rag (59%); ir vmax: 3450 (OH), 1750 (β-lactam and ester) and 1690 cm 1 (thioester); ’Hmr (CDCip δ: 7.5-8.2 (m, 15H, Ph), 5.85 (br, IH, H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH2> H-3), 2.0-2.6 (3 singlets; 6H, OAc, SAc), 0.9-1.7 (m, 5H, CH3< CH2Si) and 0.20 ppm (s, 9H, SiMe3). (l'S,5R,6S and l'R,5S,6R) β-trimethylsilylethyl 6-(1*-acetoxy-1'-ethyl)2-methylpenem-3-carboxylate (isomer C) OAc X ^SAc AY Ox-Azph3 X/^SiMe3 Me OAc .A* A A solution of the above phosphorate (150 mg, 0.23 mmol) in toluene (15 ml I was heated under reflux for 2 h. The solution 198 ,SiMe, S0597 was mixed with 1 g of silica gel and the solvent was evaporated in vacuo. The silica was placed on a 4 g silica gel column (dry) and eluted with ether. The first 5 ml fraction (single high Rf spot on tic), on evaporation of the solvent, gave the title compound, 65 mg (76%) as a waxy solid, ir υ : 1790 (β-lactam,, 1740 (ester) and max 1700 cm-1 (OAc); lHmr (CDC13) δ: (d, J=2Hz, IH, H-5), 5.4 (m, 1Η, H-l’), 4.3 (m, 2H, OCH2), 3.90 (q, J=2Hz, 4Hz, IH, H-7), 2.37 (s, 3H, 2-CH3), 2.11 (s, 3H, OAc), 1.42 (d, J=6.5, Hz, 3H, 2'-CH3), 1.1 (m, 2H, CH2Si) and 0.05 ppm (s, 9H, SiMe3). The product was found to be a single isomer.

Example 33' (l'R,5R,65 and l'S,5S,6R) 6-1'-Amino-1’-ethyl)-2-methylpenem-3-carboxylic Acid Procedure A (l'R,3S,4R and 1'S, 3R, 4S) 3-(Γ-aaiido-l'-ethyl)-1-(paranitrobenzyl 2triphonylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone (isomer B) A solution of (l'S,3S,4R and l'R,3R,4S)3-(1-methanesulfonyloxy-1'-ethyl)-1-(paranitrobenzyl 2”-triphenylphosphoranylidene2-acetate)-4-tritylthio-2-azetidinone (isomer C) (12.36 g, 13.4 mmol) in 10% H2O-HMPA (135 ml) was heated at θδ’Ο for 7 h in the presence of sodium azide (1.75 g 27.0 mmol). The solution was then poured into 199 597 coLil watei (1 f) ond the reaction product which crystallized out was collected by filtration. Redissolution in dichloromethane, washing with brine and drying (MgSO^ gave the azido phosphorane as a yellow foam after evaporation of the solvent; 11.5 g (98.9%). It was used as such for the next step, ir \) (CHC1 ): 2100 (N ), 1740 and 1610 cm max 3 3 (C=0). (1'R,35,4R and 1'S,3R,4S)4-acetylthio-3-(11-azido-11-ethyl)-1-(paranitrobenzyl 2-tripheny lphosphoranylidene-2'l-acetate) -2-azetidinone A cooled solution (5°C) of (l'R,3S,4R and l'S,3R,4S)3(1'-azido-1'-e thyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidine2”-acetate)-4-tritylthio-2-azetidinone (8.9 g, 10.25 mmol) in dichloromethane (30 ml) was treated with a solution of mercuric acetate (2.12 g, 6.66 mmol) in methanol (30 ml). After stirring at 5°C for 0.5 h and room temperature for 1.5 h, the solvent was evaporated and the crude mercuric salt redissolved in dichloromethane and washed with dilute NaHCO^ and brine. After drying (MgSO^) the solution was cooled to 5°C and treated directly with pyridine (1.66 g, 21 mmol) and dropwise with acetyl chloride (1.65 g, 21 mmol). The reaction mixture was stirred at 5°C for h. The precipitated mercuric chloride was filtered off and the filtrate washed successively with dilute HCl, NaHCOand brine. Then the organic solution was saturated at 5°C with hydrogen sulfide in order to precipitate the remaining mercuric impurities as mercuric sulfide. The crude thioester obtained after evaporation of the solvent was purified on a silica gel column (8.5 x 9 cm), eluting with dichloromethane (500 ml) 200 and 15% acetonitrilenlichloromethane: 5.1 g (74.6%); ‘llrnr (CDCl^) ά: 3.70 (IH, m, H-l'), 2.98 (IH, m, H-3), 2.33 and 2.20 (3H, 2s, acetyl), 1.28 (3H, d, J=6.2 Ha, H-2’); ir (CHClj): 2115 (Nj), 1758, 1693 and 1620 cm”1 (C=O) (I1R,5R,6S and l'S,5S,6R)paranitrobenzyl 6-(l'azido-l1-ethy1)-2-methyl penem-3-carboxylate (isomer B) A solution of (l'R,5R,6S and l’S,5S,6R)4-acetylthio-2(1'-azido-1'-e thyl)-1-parani trobenzyl 2-triphenylphosphoranylidene10 2”-acetate)-2-azetidinone (5.1g, 13.1 mmol) in toluene (100 ml) was refluxed for 2 h under nitrogen. The solvent was evaporated and the reaction mixture purified by chromatography on a silica gel column (7x5 cm). The azido penem was eluted with dichloromethane I (further elution with 10% ether-dichloromethane allowed to recover 15 1.82 g of unreacted phosphoranel: 1.21 g (40.6%) mp 132-34°C; ‘Hmr (CDClj) ά: 8.21 (2H, d, Hm aromatic), 7.60 (2H, d. Ho aromatic), 5.51 (IH, d, J=1.6 Hz, H-5), 5.33 (2H, ABq, H-benzyl), 3.92 (IH, dq, J=8, 6.4 Hz, H-l'), 3.67 (IH, dd, J=1.6, 8 Hz, H-6), 2.37 (3H, s, CHj), 1.46 (3H, d, J=6.4 Hz, H-2’); ir V (CDCl ): 2123 (N ), 1788 and 1712 max 3 3 2θ cm 1 (C=O) 201 (l'R,5R,6S and 1'S,5S,6R)6-(11 amino-1'-ethyl)-2-methyl penem-3carboxylic acid (isomer B) N » NH CH A solution of (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 6-(l'a2ido-l'-ethyl)-2-methyl penem-3-carboxylate (440 mg, 1.13 mmol) in THF-ether-water (1:1:1) (120 ml) was hydrogenated at 50 psi for h in the presence of 10% Pd-C (440 mg). The catalyst was filtered off, the filtrate extracted with ether and the aqueous phase lyophilized. The crude amino acid (100 mg) was purified by hplc: 19.5 mg ‘Hmr (D20) δ: 5.69 (IH, d, J=0.9 Hz, H-5), 3.94 (2H, m, H-6, H-l'), 2.28 (3H, s, CH,), 1.50 (3H, d, J=6.4 Ha, H-2'); ir V (Nujol): max 1767, 1576 cm”1 (C=O); uv (HO) λ : 300 my (ε5326). max Procedure B (l'R,3S,4S and 1'5,3R,4S) 3-(1'-azido-11-ethyl)-4-tritylthio-2azetidinone (Isomer B) ' t-Bu 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) (1.75 g, 3 mmol) and sodium azide (0.39 g, 6 mmol) in 10% HjOlHMPA (15 ml) was heated under N2 at 75°-80°C for 3 h. Then the reaction mixture was diluted with ethyl acetate and washed several times with brine. The organic phase was dried (MgSO^) and evaporated to leave an oil which crystallized spontaneously. 202 Trituration in ether and filtration gave 951 mg (76.5%) of the azido compound as a white solid mp 185-90’C, dec. !HMR (CDCip δ: 7.23-7.78 (15H, m, aromatics), 4.43 (1H, d, J=3, H-4), 4.37 (IH, s, N-H), 3.89 (IH, dq, J=7, 6.5, H-l'), 3.16 (IH, dd, J=7, 3, H-3), 1.50 (3H, d, J=6.5, H-2’); ir \) (CHCl ): 3410 (n-H), 2123 (N_) 'and max J 3 1765 cm1 (C=O). (l'R,3S,4R and l'S,3R,4S) 3-(1‘-amino-1'-ethyl)-4-tritylthio-2azetidinone (Isomer B).

A suspension of (l'R,3S,4R and l'S,3R,4S) 3-(l'-azido11-ethyl)-4-tritylthio-2-azetidinone (Isomer B) (1.0 g, 2.41 mmol) and platinum oxide (100 mg) in ethyl acetate (100 ml) was hydrogenated for 1 h at a pressure of 50 psi. Since the reaction was incomplete, 200 mg of platinum oxide was added and the mixture hydrogenated for one additional hour. Finally, 200 mg of platinum oxide was again added and the reaction continued for 2,5 h. Total catalyst: 500 mg. Total time: 4.5 h. Then the catalyst was filtered off and the solvent evaporated. The crude amine crystallized from ether: 700 mg (80%). mp 128’-30’C. lHmr (CDClj) δ: 7.13-7.63 (15H, m, aromatics), 4.40 (IH, d, J=2.5, H-4), 4.30 (IH, broad, H-l), 3.30 (IH, dq, J=5.1, 6.3, H-l'), 3.03 (IH, dd, J=5.1, 2.5, H-3), 1.20 (3H, d, J=6.3, H-2') and 1.0-1.80 ppm (2H, broad, NH2). 203 (l'R,35,4R and l'S,3R,4S) 3-(1'-p-nitrobenzyloxycarbonylamino-1'-ethyl)4-tritylthio-2-azetidinone (Isomer B) A solution of (l'R,3S,4R arid l'S,3R,4S) 3-(1'-amino-1'5 ethyl)-4-tritylthio-2-azetidinone (Isomer B) (1.00 g, 2.57 mmol) in dichloromethane (100 ml) was cooled to 5°C and treated with p-nitrobenzylchloroformate (0.61 g, 2.83 mmol) and pyridine (0.22 g, 2.83 mmol). After stirring at 5°C for 45 min and at room temperature for 2.25 h, the reaction mixture was washed with dilute HCl, brine, dried (MgSO^) and finally evaporated to dryness. The crude carbamate was crystallized from ether: 1.03 g (70.5%). mp 147-50°C. 'Hmr (CDCip δ 7.10-8.33 (19H, m, aromatics), 5.23 (2H, s, benzyl), 5.08 (IH, N-H), 4.40 (IH, s, N-H), 4.29 (IH, d, J=2.2, H-4), 4.10 (IH, dq, J=8, 6, H-l'), 3.18 (IH, dd, J=2.2, 8, H-3) and 1.23 ppm (3H, d, J=6, H-2'); ir V max (CHC1 ): 3395 (N-H), 1765 and 1724 cm”1 (C=O). (l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl 2-methyl 6-(1'-p-nitrobenzy1oxycarbonylamino-11-ethyl) penem-3-carboxylate (Isomer B) NHCO PNB SC03 NHCO2PNB > it? CO.PNB ί The title product was prepared from (l'R,5R,6S and 20 1'S,5S,6R) 3-(1'-p-nitrobenzyloxycarbonylamino-1'-ethyl)-4-tritylthio2-azetidinone (isomer B) by the standard procedure; mp 108-110°C. 'Hmr (CDCip δ: 7.50-8.40 (8H, m, aromatics). 5.58 (IH, d, J=1.20, H-5), 204 50S97 .35 (2H, ABq, benzyl ester), 5.20 (2H, s, benzyl carbamate), 4.90 (IH, broad N-H), 4.20 (IH, dq, J=6, 8, H-l’), 3.80 (IH, dd, J=1.2, 8.0, H-6), 2.40 (3H, s, (CH.^, 1.40 (3H, d, J=6, Ci^); ir 3435 (n-H), 1777 and 1717 cm1 (C=0).

The p-nitrobenzyl ester may be subjected to catalytic hydrogenation as by the procedure of Example 31 (Procedure A) to provide the corresponding carboxylic acid.

Example 34 e-Dimethylaminomethyl^-methylpenem-l-carboxylic Acid CH CH, l-(t-butyldimethylsilyl)-3-dimethylaminomethy1-4-tritylthio-210 azetidinone (cis and trans). ;c$ a-W*2 '''t-Bu MeNH NaBH^CN To a solution of dimethylamine (18.5 ml of a 2N solution in methanol, 36.9 mmoles) in methanol (BC ml) was added a solution of hydrochloric acid in methane.' (2.5 ml of a 5N solution in methanol) followed by trans 1-(t-butyldimethylsilyl) -3- formyl-4-tritylthio-2-azetidinone (3.0 g, 6.16 mmoles) and by sodium cyanoborohydride (0.27 g, 4.31 mmoles).

The mixture was stirred at room temperature for 3.5 h, poured onto ice-hydrochloric acid (pH=2) and made basic with sodium 205 hydroxide (IN NaOH, pH =9) . The mixture was extracted with ether and the ether phase was washed with brine, dried and evaporated to give the title compound as a crude oil (3.0g). cis and trans 3-dimethylaminomethyl-4-tritylthio-2-azetidinone V-Bu A solution of the above crude compound (3.0 g, mmoles) in hexamethylphosphorous triamide (HMPT, 16 ml) containing water (10%) was cooled (5°) and treated with sodium azide (0.78 g, 12 mmol). The mixture was stirred 1.5 h at room temperature, poured onto ice-water and extracted with ether (5 x 30 ml). The organic phases were extracted with hydrochloric acid (IN) and the acidic extracts washed well with ether to remove the HMPT. The acidic phase was made basic (IN, NaOH) and extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the title compounds as an amorphous white solid (1.5 g, 62.5% overall). The mixture of isomers was separated on a Waters Prep 500, eluting with methanol (5%), ammonia (0.2%), ethyl acetate (95%) . Trans isomer: 1.0 g, m.p. 129-131°C (pentane); δ (ppm, CDClg): 6.8-7.8 (15H, m, aromatics), 4.5 (1H, N-H), 4.28 (IH, d. J=2.5, H-4), 3.35 (IH, m, H-3), 2.75-2.1 (2H, m, H-l’), 2.3 (6H, s, CHg).

Cis isomer: 0.5 g, m.p. 132-3°C (ether-pentane); δ (ppm, CDClg): 7.7-6.7 (15H, m, aromatics), 4.72 (IH, N-H), 4.5 (IH, d, J=5.3, H-4), 3.5 (IH, m, H-3), 2.85-2.35 (2H, m, H-l'), 2.31 (6H, s, CHg).

The cis to trans ratio can be varied by changes in conditions. 206 cis and trans e-dimethylaminomethyl^-methyipenem-S-carboxylic acid The title compound was prepared from cis and trans 3-dimethylaminomethyl-4-tritylthio-2-azetidinone by the procedure of Example 22. (ppm, CDC13): 5.5 (1H, d, J»1.3), 3.7 (IH, dt, J-1.3, J=8), 2.8 (2H, d, J=8), 2.35 (6H, s), 2.3 (3H, s).

Example .35 g-Aminoacetoxymethyl-penem-3-carboxylic Acid (via mercaptide intermediate) h200ch2nh2 co2h 4-Agidoacetoxyacetylthio-i-(paranitrobenzyl 2'-triphenylphosphoranylidene-2 '-ace tate) -2-azetidinone A cold (xce-MeOH bath) solution of 4-hydroxyacetylthio-l(paranitrobenzy1 2'-triphenylphosphoranylidene-2’-acetate)-2-azetidinone (586 mg, 0.954 mmol) in methylene chloride (15 ml) was treated successively with azido acetyl chloride (240 mg, 2.01 mmol) and dropwise with 207 pyridine (226 mg, 231 ml, 3.0 mmol) in methylene chloride (10 ml)J At the end of the addition tic showed disappearance of starting material The mixture was diluted with ether, washed successively with dilute HCl, water, dilute aqueous sodium bicarbonate, water and brine. It was dried over sodium sulfate. Purification of the residue was performed on a silica gel (10 g) column, eluting with 20% ether in benzene, ether, and 30% ethyl acetate in ether. Concentration of the pertinent fraction gave the title compound as a foam; 533 mg, 80.1%; ir V : max (CHC13): 1763, 1702 (C=O) , 1625 (C=P<|>3), 1522 (NOp and 2110 cm-1 (N ). paranitrobenzyl 2-azidoacetoxymethylpenem-3-carboxylate co2pnb heated under reflux in toluene (90 ml) for 0.5 h using a catalytic amount of hydroquinone. The solvent was concentrated on the evaporator and the concentrated solution was passed through a silica gel (10 g) column. (benzene: ether, 48:2). It gave the title compound (236 mg, 73.7%) as an oil. This oil was found to be unstable at room temperature. It was kept at -78°C until needed. 'Hmr (CDCip δ: 8.21 (2H, d, Hm aromatic), 7.57 (2H, d, Ho aromatic), 5.68 (IH, dd, . -:-=4=2, H-5), 5.43 (2H, center of ABq, J=16, CH^PNB) , '5-6 cis 5-6 trans .39 (2H, CH20), 3.93 (2H, s, CH2-N3), 3.72 (part of dd, J and 3.50 ppm (IH, dd, J =17, J =2, H-6); ir V gem 6-5 trans max 1755, 1710 (C=0), 1525 (NO ), 2110 cm”1 (^), c - . =4, H-6), 6-5 cis (CHC1 ): 1795, 208 50S97 2-Aminoacetoxymethylpenem-3-carboxyiic acid (16 ml,-ether (30 ml) and water (16 ml) was shaken on a Parr hydrog genator for 2.25 h at 50 psi of using 10% Pd/C (240 mg) as catalyst.

The catalyst was filtered off and washed with water and ether. The aqueous phase was washed with ether (3 x 30 ml) and lyophilized. The crude powder was purified on a reversed phase hplc column and gave the title compound (Θ mg, 6.7%) as a white powder. lHmr (DjO) 5: 5.72 (IH, dd, J, , , =3.5, J =2, H-5), 5.37 (2H, center of ABq, -o cis 5-6 trans 3=13.5, CH -0), 3.96 (2H, s, CH -NH ), 3.87 (IH, dd, J =16.5, J , . 22 gem 6-5 cis =3.5, H-6) and 3.49 Nmr (IH, dd, J =16.5, J, „ =2, H-6); ir V gem 6-5 trans max (nujol): 1775, 1755 and 1600 cm 1 (C=0); uv (Η,Ο) λ 306 (£4900), max 256 (£3000). 209 Example 36 Silver 1-( B-Tr imethy Is ilylethyl-2'-tripheny lphosphoranylidene-2^ acetate) -2-a&etidinone-4-thiola-te _^SAg J— 0 y 3 /*3 CO.CH CH Si—CH3 — — CH, di-B-trimethylsilylethyl fumarate To a cold l-lO’C) ether (20 ml) solution of 2-trimethyl 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 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 210 5059 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 C14H28°4Si2! c 53·12' H 8-91; found: c 53.35, H 8.91. ’Hmr (CDC13) 6: 6.78 (2H, s, C=CH), 4.26 (4H, m, CH2-O), 1.03 (4H, m, CHj-Si) and 0.06 ppm (18H, s, (CH , Si); ir (CHCl,) V : 1710 (OO of ester), j j j max 1643 (OC), 1267, 1258, 862 and 840 cm”1 (Si-C) .

Trlmethylsilylethyl glyoxylate hydrate A solution of di-B-trimethylsilylethyl fumarate (37 g, 0.117 mmol) in methylene chloride (1.1 Z) 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 (-0H), 1740 (ester, 1255, 860 and 840 cm1 (Si-C). max 1-(β-trimethylsilylethyl 2’-hydroxy-2’-acetate)-4-tritylthio-2-azetidinone 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, 25 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 211 597 chloride (1:19) until the title compound started to come out (—1.5 Z) and then with ethylacetate: methylene chloride (1:9, Z). The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of the title compound. 'ffinr (CDCl^) 2), 2.60 (2H, m, H-2), 0.95 (2H, m, Cf^-Si and 0.1 ppm (9H, s, Si-CH^; ir (CHCI ) U : 3520 (-OH) , 1765 (C=O of β-lactam), 1740 (C=0 of 3 max ester), 1595 (C-H, aromatic), 1257, 860 and 840 cm 1 (C-Si) 1-(8-trimethylsilylethyl 2’-chloro-2'-acetate)-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-(β-trimethylsilylethyl 2'-hydroxy-2’-acetate)-4-tritylthio-2azetidinone (4.9 g, 9.37 mmol), 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 Z). Evaporation of the pertinent fractions gave 4.64 g of the title compound (92%).

'Hmr (CDCip δ: 7.30 (15H, m, aromatic Η) , 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, m, CH^Si) and 0.06 ppm (9H, s, Si-CH^); ir (neat) V : 1760 (C=O), 860 and 840 cm”1 (C-Si). max 212 l-(B-trimethylsilylethy1-2'-triphenylphosphoranylidene-2'-acetate)-4tritylthio-2-azetidinone A dioxane (20 ml) solution of the above chloroazetidinone (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, x 31 cm) using ethylacetate-hexane (3:7, it; 7:3, 1 Z) to give the title phosphorane (4.836 g, 83%). ir (film) U _ 1755 (C=O), 1615 (phosphorane), 850 and 830 cm max (Si-C). Anal, calcd for CHNOPSSi: C 73.89, H 6.07, N 1.81; found: C 72.18, H 6.08, 47 46 3 N 1.83 Silver 1-(β-trimethylsilylethyl 2'-triphenylphosphoranylidene-2'acetate)-2-azetidinone-4-thiolate + AgNOj (nBu)3N + CF3CO2H ether/HgO * ,SAg 1-(β-trimethylsilylethyl 2'-triphenyl phosphoranylidene-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, 213 0.2 mmol) in ether (20 ml). The mixture was mechanically stirred for 19 minutes. 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 10 min and pump 65 min) to give the title compound(6.42 g). IR (CHCL31 'Max: 1862 (0=0).1630 (Phosphorane), 860 and 840 cm-1 (SI-C).

Example 37 6-Formafflidomethyl-2-niethylpenem-3-cartioxy3.ic acid, sodium and potassium salts HCN H c 'C0_Qa®and -CH trans 1-(t-butyldimethylsilyl) -3-methanesulfonyloxymethyl-4-tritylthio-2-a2etidinone OH MsO J— \i(CH3>2 t-Su se(CH3>2 t-Bu A solution of trans-1-(t-butyldimethylsilyl)-3-hydroxy15 methyl-4-tritylthio-2-azetidinone (8.0 g, 16.36 mmol) in dichloromethane (50 ml) was treated at 5°C with methanesulfonyl chloride (1.4 ml, mmol) in dichloromethane (10 ml) and triethylamine (2.5 ml, 18 mmol). Stirring was maintained for 1 h under Nj. Then the solution was washed 214 S0S97 successively with cold IN hydrochloric acid, IM sodium bicarbonate and brine, dried (MgSO.) and evaporated in vacuo. The residue (mixture 4 of hydroxy and mesylate cpd) was treated a second time as before, to give the mesylate (90 g, 97%, as an amorphous solid. It was used as such in the next step without further purification. The analytical sample was recrystallized from methylene chloride n$> 167-168’C; ir (neat) V : 1755 cm”1,· 'Hmr (CDC1„) δ: 7.3 (ISH, m), 4.4 (IH, d, J=2Hz), max 3 3.9 (IH, dd, J=8Hz, 4Hz), 3.2 (2H, bs), 2.8 (3H, s), 0.95 (9H, s) and 0.3 ppm (6H, s). trans 3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone and trans3-azidomethyl)-4-tritylthio-2-azetidinone Y-3'2 t-Bu A solution of trans -1-(t-butyldimethylsilyl)-3-methanesulfonylmethyl-4-tritylthio-2-azetidinone (21.0 g, 37.0 mmol) in HMPA 15 (90 ml) was cooled in an ice bath and treated with sodium azide (2.7 g, 11.2 mmol) in H20 (10 ml). The reaction mixture was stirred at room temperature for 1 h, diluted with ethyl acetate, washed with H20 (5 x 100 ml), dried (MgSO^) and evaporated in vacuo. The trans-3methanesulfonyloxymethyl-4-tritylthio-2-azetidinone was diluted with HMPA (90 ml), treated at room temperature with sodium azide (2.7 g, 41.2 mmol) in H20 (10 ml), heated at 60’C for 2 h and triturated with cold water. The crude azide was diluted with benzene-ether (5:1) and washed with water (5 x 20 ml). Evaporation of the solvent followed by crystallization from ether gave 18.0 g (77%) of azide as 25 a white solid. The analytical sample was recrystallized from CH2C12/ ether mp 174-5’C; Anal, calcd for C23H20N4OS: c 6θ·97, H 5.03, N 13.99; 215 found C 63.78, H 5.00, N 14.16; ir (nujol) 2100, 1765 cm : ‘Hmr (CDC1 ) δ: 7.35 (15H, m), 4.75 (IH, bs), 4.4 (IH, d J=2Hz), and 3.1-3.7 ppm (3H, m). trans-3-aminomethyl-4-tritylthio-2-azetidinone To a solution of trans 3-azidomethyl-4-tritylthio-2azetidinone (10.0 g, 47.5 mmol) in dry methanol (500 ml) was added ammonium chloride (19.0 g) and zinc powder (1.0 g) and the suspension was stirred at room temperature for 5 h. The reaction mixture was ]Q filtered and evaporated. The residue was partitioned between IN hydrochloric acid and benzene. The aqueous layer was basified with IM sodium bicarbonate and extracted with methylene chloride.

The extracts were washed with brine, dried (MgSO^) and evaporated in vacuo. The crude amine crystallized from ether, 14.05 g (79%); mp 139-9’C; Anal, calcd for ,C23H22N2°C1'1/>4 CH2C12: C 7O’5&' H 5·73' N 7.08; Found: C 70.68, H 5.94, N 7.27; ir (CHC1) V : 3400 and 3 ΓΠ3Χ 1760 cm”1: 'Hmr (CDC1 ) δ: 7.35 (15H, m), 5.15 (IH, m), 4.3 (IH, bs), 2.7-3.5 (3H, m) and 1.3 ppm (2H, m). 216 trans' 3-phthalimidomethyl-4-tritylthio-2-azetidinone A solution of trans 3-aminomethyl-4-tritylthio-2azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimide (8.3 g, 37.9 mmol) in benzene (200 ml) was heated under reflux for 15 h. The solvent was evaporated in vacuo and the residue crystallized from ether to give 17.4 g (93%) of the title compound; mp 172-3°C; Anal, calcd for C31H24N2°3S: C 73·78' H 4.79, N 5·55' found: C 73.92, H 4.87, N 5.49; ir (CHC1,) V : 1770 and 1715 cm1; max lHmr (CDClj) δ: 7.8 (4H, m), 7.3 (15H, m), 4.45 (IH, d, J=2Hz), 3.34.1 (3H, m) and 3.3-4.6 ppm (IH, m). trans 3-phthalimidomethy1-1-(paranitrobenzyl 2’-hydroxy-2'-acetate)4-tritylthio-2-azetidinone A mixture of trans-3-phthalimidomethyl-4-tritylthio-2azetidinone (17.4 g, 34.52 mmol), paranitrobenzylglyoxylate hydrate (9.4 g, 41.4 mmol) and triethylamine (4.8 ml, 34.5 mmol) in tetrahydrofuran (250 ml) was stirred at room temperature for 20 h. The reaction mixture was evaporated in vacuo and the residue was treated with charcoal in benzene. Evaporation of the solvent yielded the crude hydroxyglyoxylate (25 g, quantitative) as an amorphous solid. 217 It was used in the next step without further purification, ir (CHC13> v : 1770 and 1715 cm”1; *Hmr (CDCl ) δ: 8.1 (2H, d, J=9Hz), 7.55 max (3H, d, J=9Ha), 7.3 (19H, m), 5.0-5.4 (2H, bs), 4.3-5.0 (2H, m) and 2.8-3.8 ppm (4H, m). trans-3-phthalimidomethyl-l-(paranitrobenzyl-21-chloro-2'-acetate)4-tritylthio-2-azetidinone To a cooled (ice bath, 0°C) solution of trans-3-phthalimidomethyl-1-(paranitrobenzyl-2'-hydroxy-2'-acetate)-4-tri tylthio1 2-azetidinone (25 g, 35 mmol) in tetrahydrofuran (150 ml) was added dropwise a IM solution of thionyl chloride in tetrahydrofuran (46 ml, 46 mmol) followed by a IB solution of pyridine in tetrahydrofuran (46 ml, 46 mmol). The reaction mixture was stirred at room temperature for 20 min, diluted with pet-ether (50 ml) and filtered over a Celite/charcoal bed. The solvent was evaporated in vacuo to give the chloro azetidinone (26 g,.quantitative) as an amorphous solid.

It was used in the next step without further purification, ir (CHC13) V : 1775 and 1720 cm”1. ‘Hmr (CDCl,) 6: 8.12 (2H, d, J=9Hz), 7.60 max 3 (2H, d, J=9Hz), 7.3 (19H, ra), 5.25 (2H, m), 4.7-5.4 (IH, m), 4.55 (IH, bs) and 3.3-4.0 ppm (3H, m). 218 trans-3-phthalimidomethyl-l-(paranitrobenzy1-21-triphenylphosphorany lidene-2 '-acetate)-4-tri tylthio-2-azetidinone H H C0, .Cl CO.PNB A mixture of trans-3-phthalimidomethyl-l-(paranitro5 benzyl-2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone (26 g, .5 mmol), triphenylphosphine (10.25 g, 39.1 mmol) and 2.6 lutidine (4.6 ml, 39.1 mmol) in dioxane (200 ml) was heated at 100°C for 20 h. The reaction mixture was filtered over Celite and evaporated. The residue was chromatographed on a silica gel column (350 g) eluting with benzene to benzene/ether (1:1) to yield the phosphorane (21 g, 62%) as a white solid, ir (CHCl.) V s 1750 and 1710 cm 1. ’Hmr (CDClg) δ: 7.4 (38H, m), 4.8-5.4 (3H, m), 4.6 (2H, m) and 3.7 ppm (IH bs). trans-3-phthalamidomethyl-l-, (paranitrobenzyl-21 -triphenylphosphoranylidene-2’-acetate)-4-tritylthio-2-azetidinone A cooled (ice bath) suspension of trans-3-phthalimidomethy1-1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)4-tritylthio-2-azetidinone (18.02 g, 18.83 mmol) in tetrahydrofuran (30 ml), water (30 ml) and acetone (30 ml) was treated dropwise with sodium sulfide (4.97 g, 20.7 mmol) in acetone/water 1:1 (30 ml) and heated to reflux for 8 h. The reaction mixture was diluted with water, acidified with IN hydrochloric acid and extracted with dichlo219 romethane. The organic extracts were washed with brine and evaporated in vacuo to give 17.1 g (88%) of the title compound as an amorphous light yellow solid. It was used in the next step without further purification, ir (neat) V : 3150-3600, 1750 and 1700 cm S ’Hmr max (CDC1 ) δ: 7.4 (38H, m) and 3.3-5.5 ppm (8H, m). trans-3-phthalisoimidomethyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2 '-ace tate )-4- tri tylthio- 2-azetidinone A solution of trans-3-phthalimidomethyl-l-(paranitrobenzyl21-triphenylphosphoranylidene-21-acetate)-4-tritylthio-2-azetidinone (17.1 g, 17.54 mmol) in dichloromethane (125 ml) was treated dropwise at room temperature with N,Ν'-dicyclohexylcarbodiimide (3.62 g, 17.54 mmol) in dichloromethane (30 ml). The solution was filtered over Celite and evaporated to give the title compound (18.23 g, quantitative) as an oil. It was used in the next step without further purification, ir (neat) \) : 2110, 1755 and 1710 cm \ ’Hmr (CDC1,) δ max 3 7.5 (38H, m), 4.6-5.3 (4H, m) and 3.9 ppm (2H, bs). 220 tran5-3-aminomethyl-l-(paranitrobenzyl-21-triphenylphosphoranylidene2'-acetate)-4-tritylthio-2-azetidinone CO PNB 2 A solution of trans-3-phthalisoimidomethyl)-l-(paranitrobenzyl-2 '-triphenylphosphoranylidene-21-acetate)-4-tritylthio-2azetidinone (5.9 g, 6.16 mmol) in tetrahydrofuran (40 ml), cooled to -20°C, was treated dropwise under Ng with hydrazine (0.2 ml, 6.16 mmol) and stirring was maintained for 30 min. The reaction mixture was acidified with IN hydrochloric acid and washed with ether; the aqueous phase was basified with IM sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine, dried (MgSO ) and evaporated. The residue was purified on 4 a silica gel column (60 g) eluting with ether to ethyl acetate to give 3.38 g (66%) of the amino phosphorane as an amorphous solid. ir (CHCl ) V : 1730, 1710 cm1; ’Hmr (CDCl,) 5: 6.5-8.1 (34H, m), max 3 3.8-5.3 (6H, m) and 0.9-1.9 ppm (2H, m) . trans 3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphoranylidene-21-acetate)-4-tritylthio-2-azetidinone To a cooled (ice bath) solution of trans 3-(aminomethyl1-(paranitrobenzyl-21-triphenylphosphoranylidene-21-acetate)-4tritylthio-2-azetidinone (5.0 g, 6.04 mmol) in dichloromethane (50 ml) was added dropwise under Ng a solution of acetic formic anhydride (600 mg, 6.8 mmol) in dichloromethane (5 ml) followed by 221 50587 a solution of triethylamine (1 ml, 7 mmol) in dichloromethane (2 ml,.

Stirring was continued for 30 min. The solution was washed successively with IN hydrochloric acid, water, IM sodium bicarbonate and brine. The organic layer was dried (MgSO^), evaporated and the residue was chromatographed on a silica gel column (50 g). Elution with ether to ethyl acetate yielded 2.0 g (39%). of the formamide as an amorphous solid, ir (CHC1„) V : 1740, 1685 and 1620 cm , 'Hmr c 3 max (CDCip fi: 6.6-8.2 (35H, m) , and 2.5-5.3 ppm (7H, m) . trans silver 3-formamidomethyl-I-(paranitrobenzyl-2’-triphenylphos33 2 benzy1-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2azetidinone (550 mg, 0.64 mmol) in dichloromethane (10 ml) was evaporated to dryness and diluted with hot methanol (20 ml). The solution was stirred at 60°C and treated with a pre-heated (60°C) solution of 0.15 M silver nitrate in methanol (5.7 ml, 0.86 mmol) followed by a solution of 1.5 M pyridine in methanol (0.57 ml, 0.86 mmol). The creamy solution was stirred at room temperature f°r 30 min, then in an ice bath for 2 h. The solid was filtered washed with cold methanol and ether, and dried to give 300 mg (65%) of the silver salt as a beige solid. It was used in the next step without further purification. 222 505 trans 4-acetylthio-3-formamidomethy1-1-(paranitrobenzyl-2'triphenylphosphoranylidene-21-acetate)-2-azetidinone To a cooled (ice bath) solution of trans silver 35 formamidoraethyl-1-(paranitrobenzyl-2'-triphenylphosphoranylidene2'-acetate)-2-azetidinone-4-thiolate (800 mg, 1.11 mmol) in dichloromethane (10 ml) was added dropwise under a solution of IM acetylchloride in dichloromethane (1.33 ml, 1.33 mmol) followed by a solution of IM pyridine in dichloromethane (1.33 ml, 1.33 mmol). The solution was stirred in a cold bath for 1 h, and was then filtered over Celite. The filtrate was washed successively with IN hydrochloric acid, water, IM sodium bicarbonate and brine and the organic layer was dried (MgSO^) and evaporated.

The residue was purified on a silica gel column (5.0 g) and eluted with ethyl acetate to 10% mpthanol in ethyl acetate to give 450 mg (62%) of the title compound: ir (CHC1,) V : 1755, 1685 and 1620 cm 3 max ‘Hmr (CDClj) δ: 8.18 (2H, d, J=9Hz), 7.0-8.0 (20H, m), 6.75 (2H, d, J=9 Hz), 6.3 (IH, m), 5.5 (IH, m), 5.2 (2H, bs), 4.9 (IH, bs), 3.6 (IH, m), 3.0 (IH, m) and 2.2 ppm (3H, two s). 223 navani trnhenzvi fi-formamidomethv 1-2-methvlpenem-3-carboxylate co2pnb A solution of trans 4-acetylthio-3-formamidomethyl-l(paranitrobenzy1-2'-triphenylphosphoranylidene-2'-acetate)-25 azetidinone (450 mg, 0.636 mmol) in toluene (10 ml) was heated under reflux for 12 h. Concentration and purification on a silica gel column eluting with ether to 10% methanol in ether gave 100 mg (39%) of the penem as an amorphous solid, ir (CHCl^) Vmax: 1780 and 1690 cm-1; “Hmr (CDCl ) δ: 8.2 (2H, d, J=9Hz), 8.2 (IH, s), 7.6 (2H, d, J=9Hz), 6.9 (IH, m), 5.55 (IH, s), 5.35 (2H, 2s), 3.34.1 (3H, m) and 2.33 ppm (3H, s). 6-formamidoinethyl-2-methylpenem-3-carboxylic acid sodium and potassium salts of paranitrobenzyl 6-formidomethyl-2-methylCO PNB 2 A mixture penem-3-carboxylate (80 mg, 0.21 mmol), palladium on Celite (30%, 100 mg), tetrahydrofuran (10 ml), ether (25 ml) and 0.05 M buffer solution pH 7 (4.46 ml, 0.223 mmol) was hydrogenated on a Parr shaker at an initial hydrogen pressure of 45 psi for 3 h. The catalyst was removed by filtration on Celite and washed with water.

The filtrate and washings were combined and the phases separated. The aqueous phase was washed with ether (3 x 15 ml) and lyophylized 224 The crude solid wa3 purified by hplc to give 18 mg of a mixture of the sodium and potassium salts. uv (H„O) λ : 299 (ε 4933) , 259 (e 4094); ir (nujol) max υ : 3100-3650 and 1755 cm1; 'Hmr (D.O) fi: 8.15 (IH, s), 5.53 (IH, d, max 2 J=1.4Hz), 4.0 (IH, m), 3.74 (2H, d, J=5Hz), 3.25-4.25 (IH, m) and 2.27 ppm (3H, s).

Example 38 (l'S,gR,6S, and 1'R,5S,6r) 6-(l'-Hydroxy-l'-propyl)-2-methylpenem-3carboxylic acid, sodium salt (isomer C) trans l-t-Butyldimethylsilyl-3-propionyl-4-tritylthio-2-azetidinones was added dropwise stirred solution 4F i200 mil - The mixPROCEDURE: n-BuLi (37.50 ml, 1.6M/hexane, 60 mmol) under N2 to a cooled (dry ice-acetone bath) and of diisopropylamine (8.50 ml, 60 mmol) in dry Tl ture was stirred in the cold and 1-t-butyldimethylsilyl-ii-tritylthio2-azetidincne (22.9 g, 50 mmol) in dry THF (100 ml) was added. After 15 min, methyl propionate (40 ml, excess) was added and the reaction 20 mixture was kept at -78’ for 4 h. Then the cooling bath was removed and the internal temperature was allowed to come to O’C (-40 min).

It was poured over ice-HCl (pH ~ 6) and extracted with ether. The layers were separated and the aqueous layer was extracted with ether.

The combined ether solution was washed with water and brine and dried 225 (Na2SO4). It was evaporated in vacuo to give an oil in quantitative yield. This contained a mixture of starting material and title compound. It was used as such and purified in the next step, ir (Neat) \) ; 1710 (-^-), 1750 cm 1 (β-lactam). max 1-t-ButyIdimethylsily1-3-(1'-hydroxy-l'-propyl)-4-tritylthio-2azetidinones SiMe -r 2 + NaBH.

PROCEDURE: A solution of 1-t-buty Idimethylsily 1-3-propionyl-H-tritylthio2-azetidinone (26 g, 50 mmol) and sodium borohydride (7.6 g, 200 mmol) in THF (400 ml) was stirred at room temperature for 18 h. It was poured onto ice-HCl (IN) (pH 6) and extracted with ether. The acidic phase was extracted several times with ether and the combined ether solution was washed with brine, dried (Na SO^) and evaporated to give an amorphous solid, 25.0 g. This crude product was chromatographed on SiO2 (ACT. 1, 400 g) and eluted first with CH Cl to give 10.8 g of 1-t-butyIdimethylsilyl-4-tritylthio-2-azetidinone. Elution with 20% ether in CH/1^ gave 10.3 g of the title compound as a mixture of two isomeric trans alcohols. This was separated by hplc (Water Associates, System 500), and using 10% EtOAc in CH2C12 as eluent. Isomer C, white solid, 3.8 g; mp (pet. ether) 134-36°C.

’Hmr (CDC13) δ: 7.1-7.8 (15H, m, STr), 4.35 (H, d), 3.1 (H, dd), 2.5 (H, m), 0.7-1.7 (5H, m), 0.97 (9H, s) and 0.25 ppm (6H, s). Anal, calcd for c31H39NO2SSi: C 7Τ·91, H 7.59, N 2.71; found: C 71.51, H 7.60, N 2.96. Isomer B, white solid, 5.4 g; mp (pentane-pet. ether) 97-99°C. 'Hmr (CDCl^ δ; 7.1-7.8 (15H, m, STr), 4.15 (H, d) , 3,4 (H, dd), 3.2 (H, m), 0.7-1.7 (5H, m), 0.85 (9H, s) and 0.1 ppm (6H, s). 226 97-99’C. ’Hmr (CDClj) &: 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (Η, ra), 0.7-1.7 (SH, m), 0.85 (9H, s) and 0.1 ppm (6H, s). Total yield of these two alcohols (based on recovered starting material was 67.5%. (i'S,35,4R and l'R,3R,4S) l-t-butyldimethylsilyl-3-(l’-paranitrobenzyldioxycarbonyl-1'-propyl)-4-tritylthio-2-azetldinone(isomer C).

PROCEDURE: To a cooled (dry ice-acetone bath) solution of (l'S,3S, 4R and l'R,3R,4S) l-t-butyldimethylsilyl-3-(l'-hydroxy-l'-propyl)4-tritylthio-2-azetidinone (isomer C) (3.1 g, 6 mmol) in dry THF (20 ml) was added dropwise under a solution of 1.6M n-BuLi/hexane (4.88 ml, 7.8 mmol) stirred at -78’C for 25 min . Paranitrobenzyl chloroformate (1.56 g, 7.2 mmol) in dry THF (10 ml) was then added dropwise and the resulting mixture was stirred at -78’C for 4 h.

It was diluted with ether and washed with NH^Cl solution and brine.

The organic phase was dried (Na.SOJ and evaporated to dryness to 2 4 give 4.2 g of title compound (Quantative yield). ’Hmr (CDC13) δ: 8.2 (2H, d), 7.0-7.7 (17H, m), 5.13 (2H, s), 4.05· (H, d), 3.75 (H, dt), 3.25 (dd), 0.55-1.8 (5H, m), 0.9 (9H, s) and 0.25 ppm (6H, d). 227 (l'S,3S,4R and l'R,3R,4S) 3-(l'-paranitrobenzyldioxycarbonyl-l'-propyl) -4-tritylthio-2-azetidinone (isomer C) OCOnPNB A 'STr OCOgPNB xA-,_STr 'SiMe, + 2 + HMPT + NaN (10% HgO) 3 PROCEDURE: To a cooled (ice bath) solution of (l‘S,3S,4R and 1’R,3R,4S) l-t-butyldimetbylsilyl-3-(l'-paranitrobenzyldioxycarbonyl-1'-propyl)-4-tritylthio-2-azetidinone (isomer C) (4.2 g, 6 mmol) in HMPT (40 ml) containing 10% HgO was added sodium azide (0.78 g, 12 mmol). The mixture was stirred at room temperature for 1 h. It was diluted with water (100 ml) and extracted with benzene: pet. ether (1:1) (4 x 15 ml). The organic phase was washed several times with water (6 x 30 ml) and brine. It was dried (NagSO4) and evaporated to dryness to give 3.5 g of a solid (quantitative yield). It was treated with pentane and filtered to give 3.4 g of a pale yellow solid, mp 84-86°C; *Hmr (CDClg) 6: 8.2 (2H, d), 7-7.7 (17H, η), 5.2 2H, s), 4.95 (H, dt), 4.4 (NH), 4.25 (H, d), 3.4 (H, dd), 1.7 (2H, m) and 0.95 ppm (3H, t). 228 (1*5,35,41% and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-11 propyl)-1-(paranitrobenzyl 2-hydroxy-2-hydroxy-2-acetate)-4tritylthio-2-azetidinone (Isomer C). j: o2pnb STr PNB glyoxalate THF TEA COjPNB PROCEDUREi To a solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-paranitrobenzy ldioxycarbony 1-1 ' -propyl) -4-tri tyl thio-2-azetidinone (isomer C) (3.2 g, 5.5 mmol) and paranitrobenzyl glyoxylate hydrate (1.362 g, mmol) in dry THF (50 ml) was added a catalytic amount of TEA IQ (4 drops) and Na2SO4 (to absorb HjO formed). The resulting mixture was stirred at room temperature for 6 h. It was filtered and evaporated to dryness to give 4.35 g of an amorphous solid (quantitative yield). lHmr (CDClj) S: 8.25 (4H, dd), 7-7.9 (19H, m), 5.28 (2H, s), 5.1 (2H, s), 4.8 (H, d), 4.4 (H, dd), 4.1 (H, dt), 3.4 (H, m), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t). (l'S,3S,4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-11propyl)-1-(paranitrobenzy! 2-chloro-2-acetate(-4-tritylthio-2azetidinone (isomer C) Py/THF SOClj/THF CO2PNB To a cooled (ice salt bath) solution of the above glyoxylate (4.35 g, 5.5 mmol) in dry THF (30 mi) was added IM py/THF (7 ml, 7 mmol) followed by dropwise addition of IN SOC12/THF (7 ml, 7 mmol). The re 229 suiting mixture was stirred at the above-indicated temperature for 1 h It was diluted with benzene (30 ml), stirred in the cold (ice water bath) for 30 min and filtered over Celite-charcoal. The filtrate was evaporated to dryness to give 3.8 g of an amorphous solid (85.3%); ’Hmr (CDClg) 6; 8.15 (4H, d), 6.75-7.7 (19H, m), 5.65 (H, s), 5.2 (2H, s), 5.1 (2H, s), 4.5 (H, m), 3.85 (H, m), 3.4 (H, m), 1.25-2.0 (2H, m) and 0.9 ppm (3H, t). (l'S,3S,4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-11propyl)-1-(paranitrobenzy! 2-triphenylphosphoranylidene-2-acetate) -4-tritylthio-2-azetidinone (isomer C) PROCEDURE: To a solution of the above chloro compound (3.7 g, 4.568 mmol) in dioxane (35 ml) was added φ^Ρ (1.197 g, 5 mmol) and lutidine (0.54 g, 5 mmol). The mixture was heated in an oil bath at 100° C for 3 days. It was cooled, diluted with ether and washed successively with IN HCl, IM NaHCOg and brine.

It was dried (Na SO ) and filtered over Celite-charcoal. The 2 4 filtrate was evaporated to dryness to give 3.6 g of an oil.

This was chromatographed on SiO^ (120 g) and eluted with benzene, benzene-ether to give 1.45 g of title compound as an amorphous solid (31%); ir (neat) V : 1750 cm”1 (broad). max 230 (l'S,3S,4R and l'R,3R,4S) 4-acetylthio-3-(l'paranitrobenzyldioxycarbonyl1'-propyl)-1-(paranitrobenzyl 2-triphenylphosphoranylldene-2-acetate)2-azetidinone (isomer C) OCO PNB Cf--ΝΧγ*Ρψ AgNO3 Py/MeOH co2pnb PROCEDURE: To a hot solution (60’C) of the above phosphorane (1.4 g, 1.35 mmol) in MeOH (40 ml) was added with stirring a hot solution of AgNO3 (0.3 g, 1.76 mmol) in MeOH (10 ml) followed by pyridine (0.107 g, 0.11 ml, 1.76 mmol). The silver mercaptide began to precipitate immediately. The mixture was stirred at room temperature for 15 min and at O’C for 2 h.

It was filtered, and the solid washed well with cold MeOH and ether, 1.2 g quantitative yield); »P 113-115’C (d); ir (nujol) V^: 1740-1760 cm 1 (broad). This solid was used as such. To a cooled (ice bath) solution of the above mercaptide (1.2 g, 1.35 οποί) in CH2C12 Was added acetyl chloride (0.118 g, 0.107 ml, 1.5 mmol) in CH^ (2 ml) followed by pyridine (0.119 g, 0.122 ml, 1.5 mmol) .in CH2C12 (2 ml). The mixture was stirred at O’C for 30 min. It was filtered over Celite to remove silver salt and the filtrate was washed successively with HCl (0.5N), H20, NaHC03 (0.5 M) and brine. The CHjClj solution was dried (MgSO4> and evaporated to dryness to give 0.94 g of title compound as an amorphous solid. (83.4%) ir (neat) V : 1750 cm-1 (broad). max 231 (l'S,5R,6S and l'R,5S,6R) paranitrobenzyl 6-(I1-paranitrobenzyldioxycarbonyl-1 '-propyl) -2-methy lpenem-3-carboxy late (isomer C) PROCEDURE: g A solution of the above phosphorane (0.4 g, 1.077 mmol) in toluene (35 ml) was heated to reflux and 5 ml of toluene was distilled off. The yellow solution was refluxed for 7.5 h. It was evaporated to dryness to give 0.76 g of a thick oil. This was chromatographed on SiO., (ACT 1.30 g) and eluted with benzene and benzene-ether to give the title compound as a solid, 0.32 g (53.4%); mp (pentane) 160-162°C; ‘Hmr (CDCl^) δ: 7.3-8.4 (8H, m, aromatic), .4 (H,d), 5.3 (4H, benzyls, m), 5.0 (H, dt), 4.0 (H, dd), 2.35 (6H, s), 0.8 (2H, dq) and 1.0 ppm (3H, t). (l'S,5R,6S and l'R,5S,6R) 6-(1'-hydroxy-1*-propyl)-2-methylpenem-3] 5 carboxylic acid (isomer C), sodium salt.

A mixture of the above ester (48 mg, 0.086 mmol) and % Pd-Celite (100 mg) in THF (10 ml), E^O (20 ml), H2O (10 ml) and phosphate buffer (pH7, 2 ml) was hydrogenated at an initial pressure of 50 psi for 23 h. It was filtered over Celite and the layers separated. The organic layer was washed with H20 (2x5 ml) and the combined water layer was washed with EtOAc (2 x 10 ml). The aqueous layer was then lyophilized to give the title campound as a white salt, 30 mg; ir (KBr) \) : 1750 (β-lactam) , and 1600 ΙΠΗΧ 1650 cm1 (broad, -CO,); uv λ : 258 (ε 1105) and 305 (ε 1244). max 232 Exanple 39 (l'R,5R,6S and l'S,55,6R) 6-(l*-Hydroxy-l'-propyl)-2-methylpenem-3carboxylic acid, sodium and potassium salts (isomer B) λ CO2H CH. (l'R,3S,4R and l'S,3R,4S) 1-t*-Butyldimethylsilyl-3-(11-formyloxy-1'propyl)-4-tritylthlo-2-azetidlnone (isomer B).

OH STr HCO2H, EtjN DMAP, Ac/ OCHO xJ··, '''SiMe. ch2ci2 χ/ SiMe + .2 4-Dimethylaminopyridine (DMAP) was prepared according to a) H.C. Brown &£ aZ. Org. Synth. Collect. Vol. 5, 977 (1973) and b) Helmet Vorbruggen it aZ. Angew. Chem. Int. Ed., 17, 569, (1978).

PROCEDURE: To a cooled ( O’C) solution of (l'R,3S,4R and l'S,3R,4S) l-t-butyldimethylsilyl-3(1'-hydroxy-l’-propyl)-4-tritylthio-2-azetidinone (isomer B) (3.612 g, 7 mmol) in CH2C12 (50 ml) was added Et^N (E.lt8 ml, 35 mmol), HCO^H (0.63 ml, 16.8 mmol) and DMAP (O.85E g, 7 mmol) followed by dropwise addition of acetic anhydride (7.11* g, 70 mmol) The clear yellow solution was stirred at -40’c and after 20 minutes it changes to a milky mixture. It was poured onto ice-ΙΝ HCl (pH 6) and the layers were separated. The CH2C12 solution was washed with IM NaHCO3 and brine. It was dried (Na^O^) and evaporated to dryness to give 3.8 g of a solid residue. This was treated with pentane and filtered to give 3.7 g of a white solid (96.8%); mp 125-27’C; ir (neat) v : 1720 (H-) and -1 ί 1750 cm (β-lactam); *Hmr (CDClj) δ: 7.1 (H, s, H-C-) 6.8-7.7 (15H, m), 4.8 (H, m), 4.05 (H, d, J=1.5), 3.7 (H, m, J=1.5, J=7), 1.4 (2H, m), 0.95 (9H, s), 0.8 (3H, t) and 0.1 ppm (6H, s); Anal, calcd for c32H39N°3SSf! C 70.42; H 7.20; N 2.57; found: C 70.20; H 7.33, N 2.73. 233 (l'R,3S,4R and l'S,3R,4S) 3-(1'-formyloxy-1'-propyl)-4-tritylthio-2azetidinone (isomer B) OCHO PROCEDURE: OCHO To a cooled (ice bath) solution of (3.7 g, 6.77 mmol) in HMPT (40 ml) containing 10% H^O was added NaNg (0.91 g, 14 mmol). The mixture was stirred at room temperature for 1.5 h. It was poured onto ice water (200 ml) and extracted with ether (4 x 40 ml). The ether solution was diluted with pet-ether and washed extensively in with water and brine to remove HMPT. It was dried (Na„SO.) and 2 4 evaporated to dryness to give 2.92 g of a thick colorless oil. (quantitative yield). ’Hmr (CDClg, δ: a.l (H, H-^-.S), 7.1-7.7 (15H, m, -STr), 5.23 (H, m, J=7), 4.38 (H, d, J=2.5), 4.3 (H, -NH), 3.35 (H, dd J=2.5, J=7), 1.75 (2H, m) and 1.0 ppm (3H, t). (l'R,3S,4R and l'S,3R,4S) 3-(1'-formyloxy-11-ethyl)-1-(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinone (isomer B) OCHO γΓ PNB GLYOXYLATE , OCHO c/- EtgN/THF COPNB PROCEDURE: A mixture of 3-(1‘-formyloxy-1’-propyl)-4-tritylthio-2azetidinone (isomer B), (2.9 g, 6.77 mmol), PNB glyoxylate (1.59 g, mmol), EtgN (5 drops) and Na^SO^ (anhydrous, 5.0 g) in THF (50 ml) was stirred at room temperature for 18 h. It was filtered and evaporated to dryness to give an amorphous solid in quantitative yield (4.33 g); ’Hmr (CDClg) δ: 8.2 (2H, d), 7.1-7.8 (18H, m), 5.2 234 (2H, d), 4.9 (H, m), 4.65 and 4.3 W, 4.65 (1/2 H,s) 4.3 (1/2 H, s)J , 4.2-4.3 (H, d, 1/2 H at 4.2, 1/2 H at 4.3), 3.65 (H, m), 1.4 (2H, m) and 0.8 ppm (3H, t). (l'R,3S,4R and l'S,3R,4S) 3-(l'-formyloxy-l'-propyD-l-(paranitrobenzyl 2-chloro-2-acetate)-4-tritylthio-2-azetldinone (isomer B) Py/THF -w SOCI /THF OCHO COgPNB PROCEDURE: To a cooled (ice salt bath) solution of the above glyoxylate (4.3 g, 6.77 mmol) and IM Py/THF (8 ml, 8 imnol) in dry THF (30 ml) was added dropwise IM SOCl^/py (8 ml, 8 mmol). The resulting solid mixture was stirred at the above temperature for 1 h. It was diluted with benzene (30 ml) and stirring was continued for 20 min. It was filtered over I Celite-charcoal and the filtrate was evaporated to dryness to give 4.1 g of an amorphous solid (92%). ir (neat) v : 1720 (H-^-), 1750 max (-C-OPNB) and 1780 cm-1 (β-lactam); ’Hmr (CDClg) ¢: 8.25 (2H, d), 7.8 15 (H, s, H-?-), 7-7.75 (17H, m), 5.25 (2H, d), 5.0 (H, m), 4.6 (H, s), 4.4 (H, d), 3.7 (H, m), 1.6 (2H, ra) and 0.9 ppm (3H, t). 235 (l’R,3S,4R and l’S,3R,4S) 3-(l'-formyloxy-l'-propyl)-1-(paranitrobenzyl 2-tr ipheny lphosphorany lidene-2-ace tate)-4-tri tyl thio-2-azetidi.none (isomer B) OCHO jSTr ΤΪ' o^ γα CO2PNB dioxane lutidine OCHO co2pnb PROCEDURE; A mixture of the above chloro compound (4.0 g, 6.07 mmol) φ P (1.834 g, 7 mmol) and lutidine (0.749 g, 7 mmol) in dioxane (40 ml) was heated at 100°C (oil bath) for 2 days. It was cooled, diluted with ether and washed successively with cold solution of IN HCl, IM NaHCO^ and brine. The organic solution was dried (Na^O^) and filtered over Celite-charcoal. It was evaporated to dryness to give an oil which was chromatographed on SiO2 (Act. 1, 200 g) and eluted with benzene and benzene-ether to give 2.60 g of the title compound as an amorphous solid (48.45%); ir (neat) υ : 1720 (H-^-0-), and max 1750-1760 cm1 (-COjPNB and β-lactam). (1'R,3S,4R and l'S,3R,4S) 4-acetylthio-3-(1'-formyloxy-1'-propyl,-1(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone (isomer B).

PROCEDURE: A warm solution (60°C) of 0.15 M AgNOyCHjOH (8.7 ml, 1.3 mmol) was added to a mixture of the above phosphorane (0.88 g. mmol) and pyridine (0.103 g, 1.3 mmol) in MeOH (5 ml) warmed 236 to 60’C. The mixture was stirred at room temperature for 15 min and at 0’C for 2 h. It was filtered and washed with cold MeOH to give 0.53 g of the silver mercaptide as a yellow solid (71%) which was used as such. To a cooled (ice bath) mixture of the above mercaptide (0.53 g, 0.71 mmol) and pyridine (0.079 g, 1 mmol) in CH2C12 '10 WaS added dr°Pwisa CHjCOCl (0.079 g, 1 mmol) in CH2C12 (5 ml). After stirring at 0’C for 1 h, it was filtered.

The filtrate was washed well with a cold solution of O.SM HCl, 0.5M NaHCO, and brine. It was dried (Na,SO.) and evaporated to dryness 3 2 4 to give 0.43 g of an oil. (63%); ir (neat) v : 1700-1760 cm max (broad -C and β-lactam). (l'R,3S,4R and l'S,3R,4S) and acetylthio-3-(l'-hydroxy-l'-propyl-l(paranitrobenzyl 2-triphenylphosphoranylide-2-acetate)-2-azetidinone (isomer B) PROCEDURE: The above formate (1.0 g, 1.45 mmol) in THF (10 ml) was treated at room temperature with HCl/MeOH (10 ml, prepared from ml concentrated HCl and diluted with MeOH to a volume of 24 ml).

The mixture was kept at room temperature for 0.5 h. It was basified with IM NaHCO , extracted with EtOAc solution, washed with brine and dried (Na^O^). It was evaporated to give 0.9 g of crude title compound. This was chromatographed on Si02 and eluted with ether and ether: EtOAc (1:1) to give 0.6 g of pure title compound as an amorphous solid (62.5%); ‘Hmr (CDClj) 6: 8.25 (2H, d), 7.3-8.1 (17H, m, aromatic), 5.6 (H, m), 5.2 (2H), 4.9 (H), 4.4 (H, m), 2.3 (3H, SAc), 1.5 (2H, m) and 0.9 ppm (3H, t). 237 (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 6-(l'-hydroxy-l'-propyl)-2methylpenem-3-carboxyIate (isomer B).

PROCEDURE: The above phosphorane (0.2 g, 0.3 mmol) in toluene (45 ml) was heated to reflux and 5 ml of toluene was distilled off.

The resulting solution was refluxed for 6 h. It was cooled and evaporated to dryness to give 0.2 g of an oil. This was chromatographed on SiO2 and eluted with ether to give 0.1 g of title compound as a white solid. (87%); mp (pentane) 133-135’C; 'Hmr (CDC13> δ: 8.3 (2H, d), 7.6 (2H, d) , 5.6 (H, d), 5.35 (2H, d) , 4.15 (H, m) , 3.8 (H, m), 2.4 (3H, s, CH^ , 2.2 (H, OH), 1.7 (2H, m) and 1.0S ppm (3H, t). (l’R,5R,6S and l'S,5S,6R) 6-1 ’-hydroxy-1 '-propyl)-2-methylpenem-315 carboxylic ac id (isomer B) , mixed K and Na salts -——► CO ‘ (Ha+K) A mixture of the above ester (0.07 g, 0.185 mmol), 30% Pd-Celite (150 mg) and buffer solution (pH 7, 4 ml) in THE (15 ml, Et2O (25 ml) and deionized water (15 ml was hydrogenated at an initial pressure of 48 psi for 4 h. It was filtered over Celite and the layers were separated. The aqueous layer was washed with ethylacetate and then lyophilized to give 91 mg of a solid; ir (KBr) υ : 1780 (β-lactam) and 1650 cm 1 (broad, -CO ); uv max 2 Η 0 λ : 255 (ε 983) and 300 (ε 1092). max 238 Example 40 (l'R,5R,6S and l'S,5S,6R) 6-(l'-Hydroxy-2'-phenylethyl)-2-inethylpenem3-carboxylic acid (isomer B) H, IH trans 1-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthlo-2azetidinone 1-t-Butyldimethylsily1-4-tritylthio-2-azetidinone (18.32 g, 40 mmol) in dry THF (100 ml) was added dropwise 10 under n2 to a cooled (-78’C) LDA solution (prepared under N2, at -78’C from dropwise addition of 1.6 M η-BuLi (101.25 ml, 162 mmol) to diisopropyl amine (22.95 ml, 162 mmol) in dry THF (150 ml) and stirred at -78’C for 30 min). The mixture was stirred at -78C for 30 min and ethyl phenylacetate (15.66 g, 15.12 ml lg 15.12 ml, 93.6 mmol) in dry THF (50 ml) was added and the reaction mixture was stirred at -78’C for 2 h. It was poured onto ice1N HCl (pH 5-6) and extracted with ether several times. The ether solution was washed with brine and dried (Na.SO,). It was 2 4 evaporated to dryness to give 33.7 g of a crude solid. This was dissolved in ether (10 ml) and triturated with pentane (200 ml,.

The solid was filtered and washed several times with pentane to give 18.3 g of a white solid (79.6%) mp 141-143. ‘Hmr (CDCl^ 6: 7.0 - 7.6 (20H, m), 4.8 (H, d), 3.7 (H, d), 3.53 (H, s), 3.43 (H, s) 1.5 (9H, s) and 0.3 ppm (6H, s). 239 1- (t-butyldime thy1s1ly1-3-(1'-hydroxy-21-phenyle thyl)-4 -tritylthio2- azetidinone (2 trans diastereomers). trans 1-(t-butyldimethylsilyl)-3-phenylacety1-4-tritylthio 2-azetidinone (28.8 g, 50 mmol) and NaBH^ (0.5 g, 0.25 mole) in THF (200 ml) were stirred at room temperature for 18 h. The mixture was poured onto ice-IN HCI and extracted with CH^Cl^. The CH^Clg solution was washed with brine and dried (Na SO ). It was evapo2 4 rated to give an amorphous solid (27.7 g). A portion of the solid (23.0 g) was chromatographed on SiO^ and eluted with hexane: ether to give off-white solid (lU.lt g) which was found to be a mixture of (l'R,3S,4R and l'S,3R,4S) and (l'S,3S,4R and l'R,3R,4S) isomers in the ratio of 1:1 (60%). ’Hmr (CDCl^) δ: 7-7.7 (20H, m), 4.37 (1/2H, d), 4.18 (1/2H, d) , 3.3-3.8 (H, m) , 3.45 (1/2H, dd), 3.1 (1/2H, dd), 2.7 (2H, m), 0.’87 (9H, d) and 0.25 ppm (6H, s) . 1-(t-butyldimethylsilyl)-3-(I’-formyloxy-2*-phenylethyl)-4-tritylthio- 2- azetidinone To a cooled (-40°C) solution of the above mixture of alcohols (14.4 g, 24.9 mmol) in CHgClg (250 ml) was added Et^N (15.93 ml, 125 mmol), HCOgH (2.24 ml, 59.76 mmol) and DMAP (3.0U g, 240 50S97 24.9 mmol). After stirring for 5 min acetic anhydride (2.35 ml, 249 mmol) was added dropwise. The clear solution was stirred at -4O°C for 15 min whereby it turned into a white cloudy mixture. Xt was kept at -40eC for another 45 min (total time 1 h).

It was poured onto ice-ΙΝ HCl, and the layers separated. The CH^Clj solution was .washed well with cold IN HC1,H2O, IM NaHCOj and brine. It was dried (MgSO^) and evaporated to give 14.0 g of an amorphous solid. This was separated by hplc (Water Associates, System 500) to give: Isomer B“ 6.0 g, mp 172-73“C and Isomer C 6.0 g mp 188-89“C. Total yield of pure compound 12.0 g (73.2%).

Isomer C: *Hmr (CDClj) 5: 6.8-7.7 (21H, m), 5.05 (H, dt), 4.05 (CH, d) 3.65 and 3.75 (H, two doublets), 2.7-2.9 (2H, d), 0.88 (9H, s) and 0.2 ppm (6H, s). Isomer B: *Hmr (CDClj) fi: 7.75 (H, s), 6.9-7.5 (20H, m), 4.3 (H, dt), 3.95 (H, d), 3.37 (H, dd), 2.95 (H, s), 2.85 (H, s), 0.9 (9H, s) and 0.2 ppm (6H, s). 3-(I1-formyloxy-2'-phenylethyl)-4-tritylthio-2-azetidinone (11R,3S,4R and l‘S,3R,4S enantiomers) To a cooled (ice bath) solution of the above formate (5.9 g, 9.375 mmol) in HMPT containing 10% water (50 ml) was added NaN^ (1.3 g, 20 mmol). The mixture was stirred at room temperature for 1.5 h. It was poured onto ice water (300 ml) and extracted with ether (3 x 100 ml). The ether solution was washed well with water and brine. It was dried (Na^O^) and evaporated to give a solid residue. This was treated with petroleum ether and filtered to give 4.4 g of a white solid (92%) mp 169-71’C. Anal, calcd for C31H27NO3S: c 75·43' H 5-sl< N 2.84: found: C 75.04, H 5.64, N 2.78. 'Hmr (CDClj) 6: 7.9 (H, s), 7.1-7.6 (20H, m), 5.4 (H, m), 4.6 (H, NH), 4.2 (H, d) , 3.3 (H, dd), 3.15 (H, s) and 3.0 (H, s). 3-(l'-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl 2-hydroxy-2~ acetate)4-tritylthio-2-azetidinone (l'R,3S,4R and l'S,3R,4S enantiomers) A suspension of PNB glyoxylate (2.37 g, 10.16 mmol) in dry benzene (100 ml) was refluxed under a Dean Stark o apparatus (packed with molecular sieve 3A) for 2 h. Then the above N-H compound (4.2 g, 8.537 mmol) was added and refluxing continued for 1 more h. It was cooled to room temperature Et^N (0.12 ml, 0.85 mmol) was added and the mixture was stirred at room temperature for 1.5 h. It was evaporated to dryness to give the title compound in quantitative yield as a mixture of two isomeric alcohols. 'Hmr (CDCl^) 5: 8.0-8.3 (2H, two doublets), 7.5 and 7.6 (H, two singlets), 7.0-7.4 (20H, m), 5.25 (2H, d), 4.9 (H, OH), 4.25 and 4.35 (H, two doublets), 3.5-4.5 (H, m, broad), 3.1-3.3 (H, m) and 2.9 ppm (2H, m). 242 S0597 3-(1*-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl 2-chloro-2~ acetate)-4-tritylthio-2-azetidinone (l'R,3S,4R and l'S,3R,4S enantiomers) To a cold (ice salt bath) solution of the above glyoxylate (6.0 g, 8.537 nmol) in dry THF (30 ml) was added a IM solution of pyridine in THF (10 ml, 10 mmol) followed by the dropwise addition of a IM solution of thionyl chloride in THF (10 ml, 10 mmol). After 1 h at the above temperature it was diluted with benzene (30 ml) and stirring was continued in the cold for 30 rain. It was filtered over Celite-charcoal and evaporated to dryness to give 6.0 g of an amorphous solid (98%): ’Hmr (CDClg) δ: 8.2 (2H, m), 7-7.7 (23H, m), 5.8 (H, s), 5.25 (2H, s), 4.35 (H, d), 3.5-4.0 (H, m), 3.3 (H, m) and 2.9 ppm (2H, d). 3-(1'-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl 2“-triphenylphosphoranylldene-2-acetate)-4-tritylthio-2-azetidinone (1'R,3S,4R and 1S,3R,4S enantiomers).

A mixture of the above chloro compound (6.0 g, 8.333 nmol), $gP (2.489 g, 0.5 mmol) and lutidine (1.0165 g, 1.1 ml, 9.5 mmol) 243 in dioxane (50 ml) was heated at HO’C (bath temp) for 18 h.

It was cooled and filtered over Celite. The filtrate was diluted with ethyl acetate and washed with cold IN HCl. Η Ο, IM 2 NaHCOand brine. It was dried (Na^SO^) and evaporated to give 5 8.0 g of a crude product. This was chromatographed on SiO^ and eluted with ether: hexane (1:1) and ether to give 4.0 g of the title compound, mp (needless from ether) 235-37°C (d). (51%); ir (film) V : 1720, 1750 cm \ max 4-acetylthio-3-(1'-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone (l'R,3S,4R and l'S,3R,4S enantiomers) To a refluxing solution of the above phosphorane (3.6 g, 3.8 mmol) and pyridine (0.33 g, 4.2 mmol) in CH^C^ (30 ml) and MeOH (30 ml) was added dropwise a 0.15M AgNO^/MeOH solution (28 ml, 4.2 mmol) The mixture was stirred at room temperature for 2.15 h. It was concentrated to a small volume (-10 ml), cooled and filtered to give the silver mercaptide as a yellow solid (2.3 g, 77%). This mercaptide and pyridine (0.277 g, 3.5 mmol) in ice-cold (CH^Cl^ (20 ml) was treated dropwise with CH^COCl (0.27 g, 3.5 mmol) in CU^Cl^ (5 ml).

The mixture was stirred at room temperature for 3 h. It was filtered over Celite and the filtrate was washed with cold IN HCl, H2O, IM NaHCO^ and brine. It was dried (MgSO^) and evaporated to dryness to give 1.0 g of an amorphous solid (89.8%). ‘Hmr (CDCl^) 6: 8.2 (2H, d), 7.0-8.0 (23H, m), 4.5-5.7 (4H, m), 2.6-3.3 (3H, m), and 2.3 ppm (2H, d, SAc). 244 i-.icetyl thio-l- (1 '-hydrnxy-3'-phenyiethyl)-1- (par.inil rnbenzyl triphenylphosphoranylidene 2-acetate)-2-azetidinone (l'R,3S.4R and l'S,3R,4S enantiomers).

A solution of the above phosphorane (1.8 g, 2.416 mmol) in THF (10 ml) was treated with IN HCl/MeOH (10 ml) and the mixture was stirred at room temperature for 4h. It was concentrated to remove methanol, diluted with cold water, basified with IM NaHCO^ and extracted with CHC13- The CHClj solution was dried (MgSO^) and evaporated to give 1.65 g of an amorphous solid. This was chromatographed on SiO2 and eluted with ether: ethyl acetate to give 1.30 g of the title compound (75%). !Hmr (CDClj) δ: 8.2 (2H, d), 6.7-8.0 (22H, m), 4.0-6.0 (5H, ra), 2.5-3.5 (3H, m) and 2.2 ppm (3H, SAc). paranitrobenzyl 6-(11-hydroxy-2'-phenyiethyl)-2-methylpenem-3carboxylate (l’R,5R,6S and l'S,5S,6R enantiomers) A solution of the above phosphorane (1.2 g, 1.67 mmol) in toluene (80 ml) was heated to reflux (10 ml was distilled off to remove moisture and low boiling point solvent present) for 6 h.

It was evaporated to dryness and the crude product was chromatographed on SiO2· The title compound was obtained by eluting the column with ether to give 0.65 g of amorphous solid (89%). ’Hmr 245 (CDCl ) δ: 8.2 (211, d) , 7.6 (.211, d) , 5.4 (11, d) , 5.2-5.4 (2H, d) , 4.0-4.5 (H, m) , 3.7-4.0 (Η, dd), 3.0 (211, d) and 2.3 ppm (3H, s) . 6-(1'-hydroxy-2'-phenylethyl)-2-methyIpenem-3-carboxylic acid (l'R,5R,6S and l'S,5S,6R enantiomers) H., H OH CH, COgH A mixture of the paranitrobenzyl ester (0.33 g, 0.75 mmol), 0.05 M Buffer solution (pH 7, 17.4 ml), THF (30 ml), EtgO (30 ml), distilled HgO (60 ml), and 30% Pd/Celite (0.69 g) was hydrogenated at an initial pressure of 50 psi for 24 h. It was filtered over Celite and the organic layer washed with water.

The combined water layer was washed several times with EtOAc and it was lyophilized for 18 h to give the title compound as a yellow solid salt. This was treated with a small amount of water, acidified with cold IN HCI and extracted well with CHCly The CHCl^ solution was dried (MgSO4> and evaporated to give a solid residue. This was treated with ether and filtered to give 30 mg of a white solid (13.2%), mp 165-167°C; ir (nujol) V : 3580 (OH, Sharp), 1660 and ΠΙ&Χ 1760 cm uv (MeOH) λ 310 (ε 5490) and 254 (e 4880). 246 Example 41 (lt'R,5R,6S end »i'S,5P.6R) 6-(2* ,2'-Dimethyl-l1 ,3'-dioxoIan-li '-5'1 )-2roethylpenerc-3-carboxylic Acid (Isomer C) (4'R,3S,4R and 4'S,3R,4S) and (4·5,35,4Κ and 4'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(2',2'-dimethyl-1’-,3'-dioxolan4'-yl)-4-tritylthio-2-azetidinone (Isomer C and Isomer B) 247 1) Ethyl 0-(2-methoxy-2-propyl)glycolate IK OEt z° POClj >Et To a solution of ethyl glycolate (15.6 g, 0.150 mol; freshly distilled) and 2-methoxypropene (16.4 g, 0.216 mol; 95% pure)2’ in CH2C12 (150 ml) was added at 0-5° phosphorus oxychloride (3 drops, 35 mg, 0.23 mmol) and the mixture was stirred at 0-5° for 15 min and at room temperature for 1.5 h. This was then quenched with pyridine (30 drops), stirred 45 min and the solvent evaporated. The residue diluted with pentane (150 ml) was dried over K2C°3’ A^ter filtration, the solvent was evaporated yielding 27.89 g (0.158 mol, 100%; 94.9% pure) of the title compound as a colourless oil 'Hmr (CC1„) 6: 1.25 (3H, t, J=7Hz -CHCH), 1.28 (6H, s. Me,), 3.12 4 2—3 2 (3H, s, -OCHp, 3.88 <2H, s, -OCF^CO-), 4.10 (2H, q, J=7Hz, -Ci^CHp ; ir (neat) v : 1760 and 1735 cm (ester). max 1)0. Meinwald et at., Tet. Lett., 4327 (1978) 2) M.S. Newman and M.C. Vander Zwan, J. Org. Chem.,38, 2910 (1973). (3S,4R and 3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-keto-2(2-methoxy2-isopropyloxy)-11-ethyl)-4-tritylthio-2-azetldinone STr Ϊ Τ.ΠΑ /THF STr -s/ / X To a stirred solution of diisopropylamine (18.5 ml, 0.134 mol) in THF (400 ml; freshly distilled from LAH) at -78“C was added n-butyllithium (1.6M in hexane, 90 ml, 0.144 mol) under 248 0 5 9 7 Nj atmosphere. After 30 min, a solution of 1-(t-butyldimethylsilyl) 4-tritylthio-2-azetidinone (50.0 g, 0.109 mol) in THF (100 ml) was added dropwise over 10 min and the mixture was stirred for 5 min.

To this pink solution was added ethyl 0-(2-methoxy-2-propyl)glycolate (23.94 g, 0.136 mol) and the mixture was stirred for 1 h. After removing the dry-ice bath saturated NH^Cl solution (200 ml) was added followed by brine (100 ml). The aqueous phase was extracted with Et^O (3 x 100 ml). The combined organic extracts were washed with brine, dried (NajSO^) and evaporated yielding 60.95 g (0.103 mol, crude yield 94.6%) of the title oompound as a crude orange oil. This crude material was used in the next reaction. A pure sample was obtained by column chromatography (SiO2, eluent: 2% Et^O in benzene); ‘Hmr (CDC13) fi: 0.30 (6H, s, Si-CH3>, 0.95 (9H, S, t-Bu), 1.12 (3H, s, CH,), 1.15 (3H, s, CH,), 3.15 (3H, s, OCH,), 3.57 (IH, A of AB, J 33 3 gem 17Hz), 3.77 (IH, d, J=1.6Hz, H-3), 3.97 (IH, B of AB, J =17Hz), 4.83 gem (IH, d, J=1.6Hz, H-4), 7.1-7.6 (15H, tn, aromatic Hs); ir (neat) υ : ' max 1750, 1725, 1710 cm’1 (C=O); tic, Rf 0.53 (benzene; Et20=4:l), Rf 0.61 (hexane: EtOAc = 2:1). (3S,4R and 3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-hydroxy-2'-methoxy20 isopropyloxyethyl)-4-tritylthio-2-azetidinone (mixture of epimers at C-l') A solution of crude l-(t-butyldimethylsilyl)-3-(l'-keto-2' (2''-me thoxy-2-isopropy loxy )-1 ’-ethyl) -4-tritylthio-2-azetidinone (60.95 g, 0.103 mol) in THF (100 ml) was diluted with abs.EtOH (350 ml) and to this solution was added at 0’C NaBH (4.88 g, 0.156 4 mol). The mixture was stirred at room temperature for 2 h and 249 0 5 9 7 quenched by slow addition of brine (280 ml). The mixture was extracted with Et^O (3 x 150 ml) and the extracts were washed with brine, dried (Na^SO^) and evaporated to yield a yellow residue which was redissolved in CH„C1_ (500 ml). This was dried (Na,SO.) 2 2 4 again and evaporated yielding 57.1 g (0.0966 mol, crude yield 93.8%) of the title compound as a crude yellow foam: ’Hmr (CDCl^) 5: 0.17 (s, SiCHg), 0.80, 0.87 (2s, Si-tBu), 1.22, 1.25 (2s, CHg), 3.03 (s, OCHg), 4.32 (d, J=2Hz, H-4), 7.0-7.7 (m, aromatic Hs); ir (neat) V 3460 (OH), max 1745 (C=O), 1595 (aromatics): Rf 0.47 and 0.42 (hexanes: EtOAc=2:l).

This crude material was used in the next step without purification. (4'R,35,4R and 4'S,3R,4S) and (4‘S,3S,4R and 4'R,3R,4S) l-(t-Butyldimethylsilyl)-3-(2',2'-dimethy1-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone.

(Isomer C and Isomer B) A solution of (3S,4R and 4R,4S) 1-(t-butyldimethylsilyl)3-(1'-hydroxy-21-methoxyisopropyloxyethyl)-4-tritylthio-2-azetidinone (mixture of diastereomers at C-l' (57.1 g, 0.0966 mol; crude) in CHgClg (500 ml) was treated at room temperature with p-toluenesulfonic acid monohydrate (200 mg) and 2,2-dimethoxypropane (20 ml) and then stirred for 1 h. It was washed with sat. NaHCOg and then brine, dried (Na^SO^) and evaporated yielding 49.64 g (0.0888 mol, crude yield 91.9%) of a mixture of the title compounds (Isomer B and Isomer C) as yellowish foam. This was purified by HPLC (Waters 500 Silicagel; eluent, hexane: EtOAc=9:l) and by crystallization yielding 14.28 g (25.5 mmol, 26.4%) of the title compound (Isomer C) as white crystals; mp 146-7’C (pentane); ‘Hmr (CC14) 6: 0.27 (6H, s, Si-CHg), 0.95 (9H, s, Si-tBu), 1.15 (6H, s, 250 di-Me), 2.5-2.9 (IH, m, H-4'), 2.97 (IH, t, J=1.8 Hz, H-3), 3.25-3.9 (2H, m, H-5'), 4.27 (IH, d, J=1.8Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs); ir (nuiol) υ : 1750 (C=O) and 1595 cm 1 (aromatics); Rf 0.45 (hexanes: max EtOAc=4:l) and 14.50 g (25.9 mmol, yield 25.9%) of the title compound 5 (Isomer B) as white crystals: mp 144-5’C (Et2O-pentane); 'Hmr (CCl^) ¢: 0.02 (6H, s, SiMe), 0.833 (9H, s, Si-tBu), 1.13, 1.18 (6H, 2s, diMe), 2.5-2.8 (IH, m, H-4'), 3.3-4.1 (2H, m, H-5'), 3.48 (IH, dd, J, =1.5Hz, J3_4,“5.0Hz, H-3), 3.93 (IH, d, J4_3=1.5Hz, H-4), 7.1-7.7 (15H, m, aromatic Hs); ir (nujol) \) : 1650 (C=O) and 1595 cm 1 (aromatics); max Rf 0.37 (hexanes: EtOAc =4:1). Anal calcd for C_.HNO.SSi: C 70.80, - 33 41 3 H 7.38, N 2.50, S 5.73; found: (Isomer C) C 70.23, H 7.30, H 7.3-; N 2.41, S 5.53 and (Isomer B) C 70.52, H 7.31, N 2.40, S 5.05. 251 B. Preparation of the Penem Product (Isomer C) (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Dimethyl-l·',3'-dioxolan-4'-yl)4-tritylthio-2-azetidlnone (Isomer C) To a stirred solution of (4'R,3S,4R and 4's,3R,4S) l-(tbutyl-dimethyls ily1)-3-(2',2 *-dimethyl-1',3'-dioxolan-4'-yl)-4-trity1thio-2-azetidinone (Isomer C) )14.3'g, 25.6 mmol) in hexamethylphosphoric triamide (230.4 ml) was added slowly ( in 20 min) at 0-5°C a solution of sodium azide (2.50 g, 38.4 mmol; 1.5 eq) in HgO (25.6 ml).

The mixture was stirred at room temperature for 2 h and poured into cold water (2.5 Z) . The white precipitate formed was collected, washed with HgO and dried yielding 11.26 g (25.3 mmol, crude yield 98.8%) of the title compound as a white solid. A pure material was obtained by crystallization from CHgClg-EtgO: mp 192-3°C (dec.); lHmr (CDCl )0:1.33, 1.37 (6H, 2s, di-Me), 3.27 (IH, t, J=3Hz, H-3), 3.8-4.4 (3H, m, H-4' and H-5'), 4.40 (IH, d, J=3Hz, H-4), 4.47 (IH, br, NH, DgO exchanged) and 7.1-7.7 ppm (15H, m, aromatic Hs); ir (nujol) υ[η3χ: 3220 (NH), 1760 (C=O) and 1950 cm 1 (aromatics); Rf 0.31 (hexanes: EtOAc = 3:2). 252 (4»R,3S,4R and 4'S,3R,4S) 3-(2^2^0^^1-1^3^3^01^-4^71)1-(p-nitrobenzyl 2H-hydroxy-2H-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2H) (Isomer C) CH(0H)2 co2pnb Et^N/THF A suspension of p-nitrobenzyl glyoxylate hydrate (6.57 g, 28.95 mmol; 1.15 eq) in benzene (500 ml) was heated at reflux with Dean-Stark trap for 2 h. Evaporation of the solvent gave p-nitrobenzyl glyoxylate as an oil. A mixture of this oil and <4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1'-3'-dioxolan)0 4'-yl)-4-tritylthio-2-azetidinone (Isomer C) (11.2 g, 25.2 mmol) in THF (350 ml, distilled from LAH) was treated with triethylamine (289 mg, 2.86 mmol) at room temperature under N2 for 18 h (overnight). After evaporation of the solvent, the residue diluted with Ct^Clj (200 ml) was washed successively with brine containing IN HCl (2.9 ml) sat. NaHCOg and brine, dried (Na^O^) and evaporated after addition of Et2O (30 ml) to give 17.2 g (26.3 mnol, crude yield 100%; purity 95.8%) of the title compound as a white foam: Rf 0.40 and 0.30 (benzene: Et2O=3:2) Each isomer was separated by hplc (SiO2, eluent, benzene: Et2O=3:2) and purified by crystallization from CH2Cl2-Et2O. Isomer I: Rf 0.40 (benzene: Et2O=3:2); mp 153-4’C; 'Hmr (CDCl3) δ: 1.20 (6H, s, di-Me), 3.1 (2H, m, H-3 and OH), 3.5-4.2 (3H, m, H-4' and H-5'), 4.55 (IH, d, J=2Hz, H-4), .12 (IH, br, H-2), 5.30 (2H, s, OCH^r) and 7.1-8.3 ppm (19H, m. 253 aromatic Hs); ir (nujol) υ : 3370 (OH), 1775 (β-lactam) and 1745 cm max (ester); Anal, calcd for C N 0 S: C 66.04, H 5.23, N 4.28, found: jo 34 2 o C 65.85, H 5.64, N 4.11. Isomer II: Rf 0.30 (benzene: £^0^3:2) ; mp 164-5°C; 'Hmr (CDCip δ: 1.17 (6H, s, di-Me), ~3.2 (2H, m, H-3 and OH) 3.4-4.0 (3H, m, H-4' and H-5'), 4.57 (IH, d, J=2Hz, H-4), 5.23 (IH, br, -2”), 5.27 (2H, s, -OCH^Ar), and 7.1-8.3 ppm (19H, m, aromatic Hs); ir (nujol) υ : 3340 (OH), 1765 (β-lactam) and 1740 cm 1 (ester); max Anal, calcd for c36H34N2°gS: C 66.04, H 5.23, N 4.28, S 4.90, found: C 66.01. H 5.34, N 4.28, S 4.75.

U'P.n.W And TS.3R.4S) 3-(2'.2'-Dimethyl-l1,31-dioxolan-4'-yl)-1(p-nitrobenzvl 2 -ch loro-2 '‘-acetate)-4-tri ty lthio-2-azetidinone (mixture of epimers at C-2) (Isomer C) To a stirred solution of (3'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-l',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2-hydroxy2-acetate)-4-tritylthio-2-azetidinone (Isomer C) (17.13 g, 25.07 mmol; mixture of epimers at C-2) in THF (250 ml) was added at -150C under n2 pyridine (2.84 ml, 35.1 mmol) and then immediately afterwards thionyl chloride (2.20 ml, 30.1 mmol; Anachemia). The mixture was stirred for 20 min at -15° and then the white precipitate was filtered off. After washing with benzene, the filtrates and washings were combined and concentrated. The residue dissolved in benzene (250 ml) was treated with activated charcoal, filtered and evaporated, yielding 17.94 g (26.65 mmol, crude yield 100%; purity 94.1%) of the crude title compound as white foam: Rf 0.76 (benzene: Et2O»3:2); ’Hmr (CDCl^) δ: 254 1.20 (6H, s, diMe), 3.17 (HI, m, H-3), 3.4-3.9 (3H, m, H-4' and H-5*), 4.67, 4.72 (IH, 2d, J=2.5 Hz, H-4), 5.30 (2H, s, OCHgAr), 5.83 (s, H-2) and 7.1-8.3 ppm (19 H, m, aromatic Hs); ir (neat) vmax: 1770 cm 1 (β-lactam and ester). This material was used in the next step without purification. (4'R,3S,4R and 4’S,3R,4S) 3-(21,2'-Dimethy1-1’,3’-dioxolan-4'-yl)-1(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-tritylthio2-azetidinone (Isomer C) A mixture of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl10 1',3’-dioxolan-4'-yl)-l-(p-nitrobenzyl 2-ohloro-2-acetate)-4-tritylthio2-azetidinone (Isomer C) (17.87 g, 25.0 mmol; purity 94.1% mixture of epimers at C-2), triphenylphosphine (7.27 g, 27.5 mmol) and 2,6-lutidine (3.19 ml, 27.5 mmol) in dioxane (350 ml; distilled from LAH) was heated at reflux under Ng for 40 h. Evaporation of the solvent in vacuo gave 29.5 g of dark oil which was purified by column chromatography (SiOg 330 g; eluent -50% EtgO in benzene), yielding 10.5 g of yellowish solid. This solid was rinsed with EtgO to give 7.49 g (8.33 mmol, yield 33.3%) of the title compound as slightly yellow crystals: ’HmrtCDClg) 6: 1.07 (s, di-Me) and 7.1-8.2 ppm (m, aromatic Hs); ir (nujol) \) : Π60 cm 1 (C=0) . An analytical sample was obtained by crystallization from CHgCl,-EtgO: mp 231-2’C; Anal, calcd for C54H47N2O7PS! C 72·14’ H 5·27' N 3-12' s 3·57· found: C 72.18, H 5.43, N 2.98, S 3.41; Rf 0.17 (benzene: EtgO=l.-l). 255 (4'1ί. 35.4K .mil 4'S,3R,4S) Silver 3-(2',2'-dimethyl-1' , I'-dioxoIan4 ’-yl) -1- (p-nitrobenzyl 2-tripheny lphosphorany lldene-2''-aceta te)-2azetidinone-4-thiolate (Isomer C) A solution of (4'R,3S,4R and 4'S,3R,4S) 3-(21,21-dimethy1 1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl 2''-triphenylphosphoranylidene-2acetate)-4-tritylthio-2-azetidinone (Isomer C) (319 mg, 0.355 mmol) in CH^C12 (10 ml) was evaporated to yield an oily residue which was redissolved in hot methanol (8 ml; SO). To this solution was added ]q at 60° a hot solution of AgNO^ in MeOH (0.15M, 4.0 ml, 0.60 mmol) and then pyridine (29 yl, 0.36 mmol). The mixture was stirred at room temperature for 5 h and at 0°C for 1 h. The precipitate was collected and washed with ice-cold methanol and then cold E^O, yielding 255 mg (0.334 mmol, yield 94.1%) of the title compound as a brownish solid: ir (nujol) V : 1750 cm 1 (s, C=O).

IR3X (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Oimethyl-l’,3'-dioxolan-4*-yl)1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer C) CO2PN3 CH^OCl/pyr CHjCl To a solution of (4'R,3S,4R and 4'S,3R,4S) silver 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2triphenylphosphoranylidene-2-acetate-2-azetidinone-4-thiolate (Isomer C) (254 mg, 0.333 mmol) in CH2C12 ^15 m1’ containin9 256 pyridine (100 μΐ, 1.24 mmol; 3.72 eq) was added at 0-5’C acetyl chloride (71 Ul, 1.0 mmol; 3.0 eq). The mixture was stirred at 0-5*C for 40 min. After filtration of the precipitate over Celite the filtrate was washed successively with brine containing IN HCl (1.25 ml), sat. NaHCOj and then brine, dried (Na^SO^) and evaporated, yielding 200 mg of an oil which was crystallized from EtjO to give 155 mg (0.222 mmol, yield 66.7%) of the title compound as white crystals: *Hmr (CDClj) δ: 1.23 (s, di-Me), 2.20, 2.33 (2s,-SAc) and 7.2-3.3 ppm (m, aromatic Hs): ir (nujol) υ : 1750 (β-lactam and max ester) and 1690 cm 1 (thioester). An analytical sample was obtained 1 by crystallization from CH2Cl2-Et2O: mp 177-8’C; Anal. calcd for C37H35N20gPS: C 63.60, H 5.05, N 4.01, S 4.59; found: C 63.34, H 5.32, N 3.83, S 4.31; Rf 0.62 (EtOAc) · (4'R,5R,6S and 4’S,4S,6R) p-Nitrobenzyl 6-(2',2'-dimethyl-l'.3'dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer C) A suspension of (4'R,3S,4R and 4'S,3R,4S) 3-(2’,2’dimethyl-1',3 *-dioxolan-4’-y1)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer C) (443 mg, 0.634 mmol) in toluene (70 ml) was heated at reflux under N2 for 6 h. Evaporation of the solvent gave white solid which was purified by column chromatography (SiO2 10 g,- eluent 10% Et2O in benzene) yielding 247 mg (0.587 mmol, yield 92.7%) of the title compound as White solid: lHmr (CDClj) δ: 1.42 (6H, s, di-Me), 2.38 (3H, s, 2-CHj), 3.8-4.5 (4H, m, H-6, H-4' and H-5'), 5.02-5.25-5.33-5.57 (2H, AB type, 257 -OCH^r), 5.57 (IH, d, J=1.8 Hz, H-5) and 7.52-7,67-8.12-8.27 ppm (4H, A2B2‘' aromatic Hs); ir (nu5o1) vmax: 1760 (B_lactara) and 1700 on’1 (ester). An analytical sample was obtained by crystallization from CH Cl -Et 0: mp 167-8°C; uv (EtOH) λ : 265 (ε 14,000) and 314 mp 2 2 2 max (e 10,000); Anal, calcd for c39H20N2°7S! C ^4.28, H 4.79, N 6.66, S 7.63; found: C 54.15, H 4.78, N 6.54, S 7.64; Rf 0.62 (benzene-Et2O=l:1). (4'R,5R,6S and 4'S,5S,6R) 6-(2',2’-Dimethyl-11,3'-dioxolan-4’-yl) -2-methylpenem-3-carboxylie acid (Isomer C) A solution of (4'R,5R,6S and 4’S,5S,6R) p-nitrobenzyl 6-(2',2'-dimethy1-1',3'-dioxolan-4-yl)-2-methylpenem-3-carboxylate (Isomer C) (195 mg, 0.464 mmol) in THF (20 ml) was mixed with E^O (20 ml), H2O (20 ml), NaHCO3 (39 mg, 0.46 mmol) and 10% Pd-C (200 mg, Engelhard). This mixture was hydrogenated at 35 psi for 4 h at room temperature. After removal of the catalyst (over Celite), the aqueous layer was washed with EtOAc (x2), saturated with NaCl, acidified with IN HCl (0.47 ml) and immediately extracted with EtOAc (20 ml x 3). The extracts washed with brine were dried (Na^O^) and evaporated yielding 94 mg of yellowish solid which was rinsed with pentane to give 89 mg (0.31 mmol, yield 67%) of the title compound as yellowish solid: mp 132-3°C; Rf 0.60 (Acetone: H0Ac=5: 0.7),- *Hmr (CDClj) 6: 1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-01 ), 3.9-4.6 (4H, m, H-6, H-4' and H-5') and 5.59 ppm (IH, d, J=1.7 Hz, H-5); ir (nujol) ; 1760 (S-lactam) and 1660 cm-1 (CO^); uv (EtOH) λ^^.- 309 (e 6300) and 263 mp (ε 3800). 258 Example 42 (4,S,5R,6s and L'R,5S,6r) 6-(g' ,2'-Dimethyl-11 .S'-dioxolan-k'-yl)-gmethylpenem-3-carboxylic Acid (Isomer B) CH. (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl-1',3’-dioxolan-4'-yl)4-tritylthio-2-azetidinone (Isomer B) The title compound was prepared as described in Example 39 for the Isomer C from (4'S,3S,4R and 4'R,3R,4S) l-(t-butyl10 dimethylsilyl)-3-(2',2'-dimethyl-1’,3'-dioxolan-3'-yl>-4-tritylthio- 2-azetidinone (Isomer B) (14.4 g, 25.8 mmol): yield 10.8 g, 24.3 nmol, 94.1%) mp 155C (CHgClyEtgO); Rf 0.24 (hexanes: EtOAc=2:l): Hmr (CDClg) : 1.37, 1.40 (6H, 2s, di-Me), 3.23 (IH, dd, J3-4=2.5 Hz, J3_4,=5Hz, H-3), 3.7-4.5 (4H, m, H-4',H-5',N-H), 15 4.50 (IH, d, J«2.5Hz, H-4) and 7.1-7.6 ppm (15H, m, aromatic Hs); ir (nujol) 3170 (NH) and 1745 cm-1 (C=O); Anal, calcd for C27H27NO3S: C 72.78, H 6.11, N 3.14, S 7.20; found: C 72.16, H 6.11, N 3.14, S 7.17. 259 (4'S,3S,4R and 4'R,3R,4S) 3-(2‘,2'-Dimethyl-l',3'-dioxolan-4'-yl)1-(p-nitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2) (Isomer B) iSTr CH(0H)2 COgPNB EtgN/THF g The title compound was prepared as described in Example d9 for the Isomer C from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl1',3 ' -dioxolan-4 1 -yl) -4-tritylthio- 2-azetidinone (Isomer B) (10.8 g, 24.3 mmol): yield 15.8 g, 24.1 mmol, 99.3%); yellowish foam; Rf 0.29 and 0.22 (benzene: Et2O+l:l); ‘Hmr (CDClg) δ: 1.28, 1.34 (2s, di-Me), 3.4-4.4 (m, H-3, H-4',H-5’, H-2,OH), 4.39, 4.53 (2d, J=2Hz, H-4), 5.15, 5.25 (2s, OCHgAr) and 7.1-8.3 ppm (m, aromatic Hs); ir (neat) V : 3440 (br, OH), 1760 (C=O), 1520, 1350 max cm 1 (NOg). (4'S,3S,4R and 4'R,3R,4S) 3-(2',21-Dimethyl-l·',3'-dioxolan-41-yl)15 I-(p-nitrobenzyl 2-chloro-2-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2) (Isomer B) The title compound was prepared as described in Example 39 for the Isomer C from (4'S,3S,4R and 4'R,3R,4S) 3-(2’,2’-dimethyl-l’,3'20 1 *,31-dioxolan-4'-yl)-1-(p-nitrobenzyl 2-hydroxy-2-acetate)-4tritylthio-2-azetidinone (Isomer B) (14.9 g, 22.8 mmol; mixture of 260 S0S97 epimers at C-2); yield 14.1 g, 20.9 mmol, 91.9%; yellowish Foam; Rf 0.52 (benzene; Et2O=3:2); 'llmr (CBCl^ δ: 1.30, 1.38 (6H, 2s, di-Me), 3.4-4.5 (4H, m, H-3, H-4',H-5'), 4.57 (IH, d, J=3Hz, H-4), .13 (s, H-2), 5.27 (s, OCHjAr) and 7.1-8.3 ppm (19H, m, aromatic Hs); ir (neat) v : 1780 cm 1 (β-lactam, ester). max (4's,3S,4R and 4'R,3R,4S) 3-(21 ^'-Dimethyl-l'^'-dioxolan^'yl) -1- (p-nitrobenzyl 2,,-triphenylphosphoranilidene-2-acetate) -4tritylthio-2-azetidinone (Isomer B) Ίθ The title compound was prepared as described in Example 39 for the Isomer C from (4‘S,3S,4R and 3’R,3R,4S) 3-(2',2'-dimethyl1’,3’-dioxolan-4'-yl)-l-(p-nitrobenzyl 2“-chloro-2”-acetate)-4tritylthio-2-azetidinone (Isomer B) (14,0 g, 20.8 mmol; mixture of epimers at C-2): yield 4.64 g, 5.16 mmol, 24.8%; mp 190“-95°C (dec., CH Cl -EtjO); ‘Hmr (CDCl^ δ: 1.12, 1.20, 1.27, 1.35 (4s, di-Me) and 7.0-8.1 ppm (m, aromatic Hs); ir (CH_C1.) V : 1750 cm 1 (β-lactam 2 2 max ester); Anal, calcd for C^H^N^PS: C 72.14, H 5.27, N 3.12, S 3.57; found: C 71.90, H 5.57, M 3.07, S 3.56; Rf 0.21 (benzene: Et 01:1). 261 50S97 (4'S,3S,4R and 4'R,3S,4R) Silver 3-(2',2'-dimethyl-l',3'-dioxolan4'-yl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)2-azetidinone-4-thiolate (Isomer B) AgNO^-pyr MeOH co2pnb co2pnb The title compound was prepared as described in Example for the Isomer C from (4'S>3S,4R and 4'R,3S,4R) 3(21,2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2”-acetate)-4-tritylthio-2-azetidinone (Isomer B) (1.00 g, 1.12 mmol): yield 580 mg, 0.760 mmol, 67.8%; mp 129-135“C (dec); ir (nujol) V : 1745 cm 1 (β-lactam, ester). (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl-l·'.3'-dioxolan-4'-yl)1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acety1thro-2-azetidinone (Isomer B) The title compound was prepared as described in Example 35 for the Isomer C from (4'S,3S,4R and 4'R,3R,4S) silver 3-(2‘,2'dimethyl-1',3’-dioxolan-4'-yl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2“-acetate)-2-azetidinone-4-thiolate (Isomer B) (2.46 g, 3.22 mmol): yield after purification by column chromatography (SiO., g, eluent 10»-50% EtOAc in CH^l^l: 1); ’llmr (CDCl^ δ: 1.23, 1.27, 1.30 (3s, di-Me), 2.22, 2.33 (2s, SAc) and 7.3-8.3 ppm (m, aromatic Hs); ir (neat) u 1755 (β-lactam, ester) and 1695 cm 1 (thioester!. max (4'S,5R,6S and 4'R,SS,6R) p-Nltrobenzyl 6-(21,2'-dimethyl-l',3'5 dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer B) CO2PNB The title compound was prepared as described in Example 39 for the Isomer C” from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1', 3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2-triphenylphosphoranylidene-210 acetate)-4-acetylthio-2-azetidinone (Isomer B) (200 mg, 0.286 mmol): yield 64 mg, 0.15 mmol, 53%; mp 15l-2eC (CH2C12/Et2 Rf 0.67 (benzene: Et2O=l:l); ’Hmr (CDCl^ 6: 1.29, 1.38 (6H, 2s, di-Me), 2.30 (3H, S, 2-CH3), 3.6-4.4 (4H, m, H-6, H-4',H-5'), 5.00-5.18-5.28-5.46 (4H, ABq, -0CH2Ar), 5.47 (IH, d, J»1.5Hz, H-5) and 7.42-7.55-8.05-8.15 ppm (4H, A_'B aromatic Hs); ir (neat) V : 1785 cm 1 (β-lactam) and 1710 cm 1 2 max (ester): uv (EtOH) λ : 266 (ε 13,300) and 314 my (ε 9,700); Anal, calcd max ~ ” C19H20N207S! C 54·28, H 4·79’ N 6·66' S 7·63*' found: C 54.00, H 4.75, N 6.68, S 7.61. 263 (4'S,5R,6S and 4'R,5S,6R) 6-(2',2'-Dimethy1-1',3'-dioxolan-4'-yl)2-methylpenem-3-carboxylic acid (Isomer B) The title compound was prepared as described in Example for the Isomer C: from (4'S,5R,6S and 4'R,5S,6R) p-nitrobenzyl 6(2',2'-dimethyl-1',3‘-dioxolan-4’-yl)-2-methyIpenem-3-carboxylate < (Isomer B) (79 mg, 0.19 mmol): yield after recrystallization from CH^C^-pentane 9 mg, 0.032 mmol, 17%; Rf 0.54 (Acetone: HOAc=5:0.5); ’Hmr (CDC13) δ: 1.35, 1.44 (6H, 2s, di-Me), 2.37 (3H, s, 2-CH^), 3.6-4.5 ]Q (4H, m, H-6, H-4',H-5') and 5.56 ppm (IH, brs, H-5),- ir (neat) 1785 cm”1 (β-lactam); uv (EtOH) λ : 307 (ε 4300) and 262 mp (ε 3700). max Example ¢3 (l'R,5R,6s and 1'S,5S,6r) g-tl'-Hydroxy-B'-methoxymethoxy-g'-ethyll-gethyl)-2-methyIpenem-3-carhoxylic acid (isomer C) (l'R,3S,4R and l'S^R^S) 3- (11,2‘-dihydroxyethyl)-I-(p-nitrobenzyl· 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone OH hc rf CO2PNB A solution of (4’R,3S,4R and 4'S,3R,4S) 3-{2',2’ dimethy1-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2-triphenylphostfa-h2o iSAc 264 phoranyliden<:-2“-ace tate)-4-acety Ith io-2-azetidi none (isomer C) (472 mg, 0.676 mmol) in trifluoroacetic acid (1.0 ml) and H^O (0.1 ml) was left at room temperature for 30 min. The mixture was added dropwise to a cold solution of NaHCOg (2.5 g) in H^O (50 ml) and extracted with CHgClg (20 ml x 3). The extracts washed with sat.

NaHCO, and then brine were dried (Na.SO.) and evaporated yielding 458 mg (0.695 mmol, crude yield 100%; purity 97.3%) of the crude title compound as yellowish foam: lHmr (CDClg) δ: 2.20, 2.32 (2s, SAc, and 7.2-8.3 ppm (m, aromatic Hs); ir (neat, υ : 3420 (OH), 1745 max (β-lactam, ester) and 1690 cm 1 (thioester); Rf 0.16 (EtOAc).

I (l'R,3S,4R and l'S,3R,4S) 3-(11-Hydroxy-2'-methoxymethoxy-11-ethyl)1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer C) OH OH BrCH2OCH3-dimethylaniline CHCl 2 CO PNB 2 To a solution of (l'R,3S,4R and l'S.SR.AS) 3-(l',2*dihydroxyethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2acetate)-4-acetylthio-2-azetidinone (Isomer C) (291 mg, 0.430 mmol; purity 97.3%) and bromomethylmethylether (55.2 mg, 0.442 mmol; 4 drops) in CHgClg (8 ml) was added at O’C, N,Ν'-dimethylaniline (58.8 mg, 0.483 nmol; drops) and the mixture was stirred at room temperature for 20 h. Additional bromomethylmethylether (2 drops) and Ν,Ν'-dimethylaniline (2 drops) were added and it was stirred for another 4 h. The mixture diluted with CHgClj was washed successively with IN HCl, sat. NaHCOg and brine, dried (Na^SO^) and evaporated. The crude residue was purified by hplc (SiOg, eluent EtOAc) collecting (31 mg, 0.186 mmol, yield 42.2%) of the title compound as an oil: Rf 0.24 (EtOAc); ’Hmr (CDClg) δ: 2.20, 2.32 (2s, SAc), 3.30 (s, OCHg), 4.52 (s,-OCHgO-) and 7.4-8.3 ppm (m, aromatic Hs); ir (neat) 3420 (OH), 1755 (br, β-lactam and ester) and 1690 cm 1 (tflioester) 265 597 ll'R,SR,6S and l'S,5S,6R) p-Nitrobenzyl 6-(1'-hydroxy-2'-methoxymethuxy-2' -ethyl) -2-methylpenem-3-carboxylate OH SAc 0J— Ν^ρΦ-, OH CO.PNB A solution of (l'R,3S,4R and l'S,3R,4S) 3-(1'-hydroxy21-methoxymethoxy-11-ethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2”~acetate)-4-acetylthio-2-azetidinone (Isomer C) (167 mg, 0.238 mmol) in toluene (30 ml) was heated at reflux under Nj for 8 h.

Evaporation of the solvent in vacuo gave oily residue which was purified by hplc (SiO2, eluent EtOAc) to give 68 mg (0.16 mmol, yield 67%) of the title compound as an oil: Rf 0.61 (EtOAc), 0.15 (benzene: Et 0=1:1); !Hmr (CDC1 ) 6: 2.38 (3H, s, 2-CH^ , 3.35 (IH, br, OH), 3.40 (3H, Ξ, OCH}), 3.6-3.8 (2H, m, H-2'), 3.90 (IH, dd, J. =2Hz, J ,,=4Hz, H-6), 4.18 ο—o b—1 (IH, m, H-l'), 4.67 (2H, s, -OC^O-) , 5.03-5.27-5.38-5.62 (2H, ABq, OCH^r) .65 (lH, d, J=2Hz, H-5) and 7.55-7.70-8.15-8.30 ppm (4H, A2'B2'' aroraatic Hs) ,· ir (neat) V : 3450 (OH), 1785 (β-lactam) , 1710 (ester) and 1520 cm 1 max (NO ); uv (EtOH) λ : 266 (ε 13000) and 313 mp (ε 9100); Anal, calcd for 2 max C Η Ν 0 Ξ: C 50.94, H 4.75, N 6.60; found: C 51.13, H 4.77, N 6.36. 2 8 266 S05S7 (l'R,5R,6S and l'S,5S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)2-methylpenem-3-carboxylic acid (Isomer C) OH A solution of (l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl 6-(1'-hydroxy-2'-methoxymethoxy-21-ethyl)-2-methylpenem-3-carboxylate (Isomer C) (51 mg, 0.12 mmol) in THF (10 ml) was mixed with EtgO (10 ml), HgO (10 ml), NaHCOg (10 mg, 0.12 mmol) and 10% Pd-C (50 mg; Engelhard). It was hydrogenated at room temperature at 32 psi for 3 h. After filtration of the catalyst over Celite, the aqueous layer separated was washed with EtgO (x 3) and saturated with NaCl.

The aqueous phase acidified at O’C with O.lN HCI (1.2 ml) was immediately extracted with EtOAc (15ml x 3). The extracts were washed with brine, dried (Na.SO.) and evaporated yielding 22 mg of yellowish 2 4 solid which was rinsed with a small amount of EtgO to give 20 mg (0.069 mmol, yield 58%) of the title compound as slightly yellow solid: ’Hmr (DMSO-dg) δ: 2.28 (3H, s, 2-CHg), 3.27 (3H, s, OCHj), 3.49(2H, d, J=6.2HZ, 2'-H), 3.87 (IH, dd, J, =1.7Hz, J ,,-3.3Hz, 6-H), 4.58 (2H, s, -OCHgO-) and 5.55 ppm (IH, d, J«1.7 Hz, 5-H); ir (KBr) 3410 (OH), 1755 (β-lactam) and 1655 cm”1 (COgH); uv (EtOH) 308 (ε 6800) and 262 mU (ε 4200), mp 137-8“C (dec.). 267 Example 44 (l'S,5R,6s and l'R,5S,6R) 6-(l'-Hydroxy-2'-methoxyTnethoxy-2'-ethyl)-2methylpenem-3-carboxylic acid (Isomer B) OH CH, °2h (1'S,3S,4R and l'R,3R,4S) 3-(1',2'-dihydroxyethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer B) The title compound was prepared as described in Example 41 for the IQ Isomer C from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1',3'dioxolan-4’-yl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2acetate)-4-acetylthio-2-azetidinone (Isomer B) (1.03 g, 1.47 mmol): yield 970 mg, 1.47 mmol, 100%; yellowish foam: ‘Hmr (CDCl3) δ: 2.20, 2.32 (2s, -SAc) and 7.3-8.2 ppm (m, aromatic Hs); ir (neat) v : 3410 (OH), 1750 (β-lactam, ester) and 1690 cm 1 (thioester): max Rf 0.16 (EtOAc)· 268 (l'S,3S,4R and l'R,3R,4S) 3-(l'-Hydroxy-2'-methoxymethoxy-l’-ethyl)1-(p-nitrobenzyl 2-trlphenylphosphoranylldene-2-acetate)-4-acetylthio-2-azetidlnone (Isomer B) The title compound was prepared as described in Example 41 for the Isomer C from (l's,3S,4R and l'R,3R,4S) 3-(1',2'-dihydroxyethy1)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4acetylthio-2-azetidinone (Isomer B) (485 mg, 0.736 mmol): yield 205 mg, 0.292 mmol, 39.6%: oil; *Hmr (CIXlj) 5: 2.22, 2.33 (2s, SAc), 3.32 (s, OCHj), 4.57 (s.-OCHjO-) and 7.2-8.3 ppm (m, aromatic ir (neat) υ : 3420 (OH), 1755 (β-lactam, ester) and 1690 (thioester) max Rf 0.32 (EtOAc). (l'S,5R,6S and l'R,SS,6R) p-Nltrobenzyl 6-(1*-hydroxy-1'-methoxymethoxy- 2 '-ethyl)-2-methylpenem-3-carboxylate The title compound was prepared as described in Example 41 for the Isomer C from (l'S,3S,4R and l'R,3R,4S) 3-(1'-hydroxy-2'methoxymethoxy-11-ethyl)-1-(p-nitrobenzyl 2“-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer B) (205 mg, q 0.292 mmol) and hydroquinone (10 mg, 0.09 mmol): yield 38 mg, 0.090 mmol, 31%; 152-4‘C; Rf 0.23 (benzene: Et2O»l:l); ‘Hmr (CDC13> 5: 2.37 (3H, s, 2-CHj), 3.40 (3H, s, OCHj), 3.4-3.9 (3H, m, H-6, H-2), 269 υ 5 !) 7 4.15 (ΙΗ, ra, H-l'), 4.57 (2H, s, -OCi^O-) , 5.10-5.27-5.39-5.56 (2H, ABq, -OCH2Ar), 5.67 (IH, d, J=1.5 Hz, H-5) and 5.55-5.16-8.158.27 ppm (4H, A 'B ', aromatic H,; ir (CH Cl„ mull) υ : 3370 (OH), 2 2 3 2 2 max 1785 (β-lactam) and 1700 cm 1 (ester); uv (THF-EtOH=l:l) λ ; 265 max . (£ 10400) and 314 mU (E 7800). (l'S,5R,6S and l’R,5S,6R) 6-(l'-Hydroxy-2'-methoxymethoxy-2’-ethyl)2-methylpenem-3-carboxyllc acid (Isomer B) The title compound was prepared as described in Example -41 ]Q for the Isomer C” from (l'S,5R,6S and l'R,5S,6R) p-nitrobenzyl 6(1'-hydroxy-2'-methoxymethoxy-2'-ethyl)-2-methylpenem-3-carboxylate (Isomer B) (36 mg, 0.085 mmol): yield 7.5 mg, 0.026 mmol, 30%; yellowish crystals; ’Hmr (CDCl^) S: 2.36 (3H, s, 2-CH^), 3.39 (3H, s, OCH3), 3.6-3.9 (3H, m, H-6, H-2'), 4.15 (IH, m, H-l'), 4.66 (2H, s, OCH2O) and 5.67 ppm (IH, d, J=1.4 Hz, H-5); ir (CH2C12) Ύχ: 1785 (β-lactam) and 1675 cm”1 (CO H); uv (EtOH) λ : 308 (e 2900) max and 263 my (£2900). 270 Example 45 2-Benzimidoylaminomethylpenem-3-carboxylic Acid To a suspension of 0.38 g (0.0015 mole) of sodium 3-benzyl-l,2,b-oxadiazol-5-one4-acetate (i)1 in 10 ml of methyl chloride, containing 2 drops of DMF, was added at room temperature 0.13 ml (0.0015 mole) of oxalyl chloride, causing the mixture to effervesce. The reaction mixture was stirred at room temperature for 1 hour.

IQ The NaCl that had formed was removed by filtration and the filter cake was washed with several small portions of methylene chloride. The solution of acid chloride (II), was used directly. 1. K. Takacs and K. Harsanyi, Ber. 103, 2330 (1970).

A solution of 1.0 g (0.0015 mole) of (ill) and 0.12 ml (0.015 mole) of pyridine in 10 ml of methylene chloride under a nitrogen atmosphere was cooled to 4°. The acid chloride (II) solution was added all at once to the solution of (ill) and the reaction mixture was stirred at 4° for 5 minutes, then at room temperature for 1.5 hrs. A thick precipitate formed in the reaction mixture. The mixture was filtered and the filtrate diluted with methylene chloride to a volume to 7090 ml. The organic phase was then washed successively with 70 ml of Q.lii hydrochloric Bcid, 80 ml of if sodium bicarbonate and 80 ml of water. The methylene chloride phase was dried over magnesium sulfate. The solvent was removed at 271 reduced pressure and the residual oil chromatographed on Mallinckroft SilicAR CC-7 silica gel using chloroform as the eluant, giving 0.4 g (30.5%) of (IV) as an oil The infrared and nuclear magnetic resonance spectra were consistent for (IV) A solution of 0.1» g (O.OOOU5 mole) of IV in 50 ml of toluene was heated at reflux for U hrs. The solvent was removed at reduced pressure and the residue chromatographed on Mallinckrodt SilicAR CC-7 silica gel, using 5# ethyl acetate in methylene chloride as eluant, affording 0.15 g (66.6#) of V as an oil which solidified. The infrared and nuclear magnetic resonance spectra were consistent for V Anal. Calcd for θ23Ηΐ8Ν1»°7δ: C’ 55'86; Η» 3’67; H> u·33· Found: C, 56.17; H, 3-76; N, 11.23.

A solution of 0.135 g (0.00027 mole) of V in Uo nl of tetrahydrofuran and l»0 ml of anhydrous diethyl ether was added to a slurry of 10# palladium on carbon catalyst in 1*0 ml of water under a nitrogen atmosphere. The resultant mixture was hydrogenated in a Parr hydrogenation apparatus at room*temperature at an initial hydrogen pressure of 52 psi for 3.5 hrs. Hydrogen uptake was It.5 psi.

The catalyst was removed by filtration, washing the filter pad well with water. . Additional diethyl ether was added to the filtrate and the phases were separated The aqueous phase was extracted 3x with diethyl ether. The aqueous phase was then concentrated to dryness at reduced pressure. The residue was chromatographed, using the high pressure liquid chromatography technique, to afford 0.050 g (58#) of the title penem acid; decomp 156-173°. The infrared and nuclear 272 magnetic resonance spectra were consistent for the desired product.

Anal. Calcd for C H^ll^S· 1.51^0: C, 52.31; H, 5-27; M, 12.20.

Found: C, 51-6^, H, h.95; N, 12.31.

Example 46 2-Phenylimidoylaminomethylpenem-3-carboxylic Acid COOH Following the procedure of Example 45 but using an equimolar amount of sodium 3-phenyl-l,2,4-oxadiazol-5one-4-acetate as the starting material in place of the sodium 3-benzyl-l,2,4-oxadiazol-5-one-4-acetate used therein, there was produced the title product.

Claims (9)

1. I. A compound of the formula X wherein Y is a hydrogen atom or a group selected from 5 (a) an optionally substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic group, the substituents being one or more of a hydroxyl(lower)alkoxy, optionally substituted phenyloxy, optionally substituted heterocyclicoxy, optionally substituted (lower)alkyl thio, optionally substituted 10 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)a1kyl-carbamoyl, halo, 15 cyano, oxo, thioxo, -SO^H, -OSO^H, -S02-(lower)alkyl, (1ower)alkylsulfiny1, nitro, phosphono or -OP(OR e )(OR r ) group in which R g and R f are as defined above, the substitLents on tbe (lower)alkylthio group being one or more of a halogen atom, a hydroxy, (lower)alkoxy, amino, (lower)alkanoylamino or 274 optionally substituted phenyl or heterocyclic group and the phenyl or heterocyclic substituents above being one or more of a halogen atom, a hydroxy, (lower)-alkoxy, (lower)alkyl, halo(lower)alkyl, methane-sulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, 5 (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; (b) -OR S in which R g is an optionally substituted (lower)alkyl or (lower)alkanoyl group, or an optionally substituted phenyl or heterocyclic group, the substituents on the alkyl and alkanoyl being TO one or more of a halogen atom, a hydroxy (lower)alkoxy, (lower)alkylamino, di(lower)alkylamino, amino, oxo, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic group and the substituents on the phenyl or heterocyclic being one or more of a halogen atom, a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alkyl, 15 nethanesulfonyl, (lower)alkyl thio, (lower)alkylamino, di(lower)alkylamino, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl group; (c) -S(O) n R s in which n is 0, 1 or 2 and R s is as defined above; (d) a halogen atom; and 20 (e) an optionally substituted phenyl or heterocyclic group in which the substituents are one or more of a halgoen atom a hydroxy, (lower)alkoxy, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkyl ami no, di(lower)alkylamino, (lower)alkanoylamino, (lowerJalkanoyloxy, 25 carboxy, carboxy(1ower)alkyl, sulfo or sulfo(lower)alkyl group Q is a phenyl or (lower)alkyl group, R is an easily removable ester-forming protecting group, X is 1 or 2 and M is 275 Cu(II), Pb(II) or Hg(II) when X is 2 or Ag(I)

2. a compound of the formula when X is 1 C0 2 R' in which Y, Q and R are as defined in claim 1. 5

3. A compound of the formula: wherein Y, Q and R are as defined in claim 1, and 276 ιι T is C c H c or -C-X wherein X is i 65 C-CgHg I CgHg (a) a radical of the formula (i) -OR in which R, is hydrogen; α a (ii) CORg in which Rg is hydrogen, hydroxy, optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl group being one or more (preferably 1 or 2) of halo, hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower)alkylamino, di-(lower)alky1amino, (lower)alkanoylamino, or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or more (preferably 1 or 2) of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkyl amino, di(lower)alkylamino, (lower)alkanoylami no, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or (a) (iii) -OCOR c in which R c is an amino, (lower)alkylami no, di(lower)alky1amino or optionally substituted (lower)alkyl group in which the substituents are as defined in (a) (ii); or (b) a substituted (lower)aliphatic, (lower)-cycloaliphatic or (lower)cycloaliphatic(lower)-aliphatic group or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl group, substituents for the aliphatic, cycloaliphatic, phenyl or heterocyclic groups being 277 NR, II 1 (i) -CNRgRg or -N=C-NR 2 R 3 in which Rj is a hydrogen atom, R 1 a (lower)alkyl or phenyl group and R 2 and R 3 are each independently a hydrogen atom, a (lower)alkyl, phenyl or benzyl group; (ii) -0R d in which R d is an amino, (lower)alkylamino, 5 di(lower)alkylamino, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic or heterocyclic(lower)alkyl group, the substituents on the alkyl, phenyl and heterocyclic groups being as defined under (a)(ii), except that they are not amino, ]q (lower)alkyl ami no or di(lower) alkylamino when X is substituted C^-Cg alkyl and R d is substituted Cg-C^ alkyl, (iii) -0(CH 2 ) n 0R r in which £ is an integer from 1 to 6 and R f is optionally substituted (lower)alkyl or optionally ringsubstituted phenyl or heterocyclic group; the substituents on the 15 alkyl, phenyl or heterocyclic groups being as defined under (a) (ii) with the proviso that X is not -CH 2 0CH 2 CH 2 OCHg when Y is hydrogen; (iv) -OCOR r ' in which R r ' is an amino, (lower)-alkylamino, ui(lower)alkylamino or R f group, wherein R r is as defined 2o above, with the proviso that R 1 may not be an unsubstituted (lower)alkyl group; (v) -OSO 3 H P (vi) -ot(OH) 2 ; (vii) -0S0 2 R r in which R p is as defined under (b) (iii); 278 (viii) -ot(OR fi )(0R p ) in which R g is a (lower)alkyl group and R f is as defined under (b) (iii); (ix) -SfO^Rg in which n is 0, 1 or 2 and Rg is as defined under (b) (ii) or is in the case where nr 4 I 4 £=0-C—NRgRg in which R^ is a hydrogen atom or a (lower)alkyl group and Rg and Rg are each independently a hydrogen atom or a (lower)-alkyl group, with the proviso that Rg may not be an unsubstituted phenyl group; (x) -COR f in which R f is an amino(lower)alkyl, 10 (lower)alkylamino(lower)alkyl, di(lower)-alkylamino(lower)alkyl, -NHNH 2 , -NR 17 H(R ]8 ) z , -NHOR 1g , -S-R 17 , -O(CH 2 ) n -A-R e or NR e Rg in which Rp, R^ and R fi are (lower)alkyl groups, R^ g is a hydrogen atom or a (lowtr)alkyl group, A is 0, S, NH or NCH^ and £ is as defined under (b) (iii) and R q is an R r group; 15 (xi) -P0(0P w ) 2 in which R^^ is a hydrogen atom or a (lower)alkyl group; (xii) -NHR h in which R^ is an optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -SO-jH, -OH, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, 279 NH II -C- NRyRg in which Ry and R g are each independently (lower)alkyl, phenyl or NH II phenyl(lower)alkyl, -C—R g in which Rg is (lower)alkyl, phenyl or phenyl(lower)-alkyl, or 0 ii 5 -C-R. in which R^ is anrino(lower)-alkyl, -NH 2 , (lower) alkylamino di(lower)-alkylamino, R lo is (lower)alkyl or optionally substituted phenyl or heterocyclic group, the phenyl and heterocyclic substituents being defined under NH II (a) (ii), -NH-C -NH 2 , (lower)alkoxy, -O(CH 2 ) 2 Si(CH 3 ) 3 ; (xiii) -S-cJ-R^ in which is a (lower)alkyl group substituted by an amino, (lower)alkylamino or di(lower)alkyl amino group; (xiv) -NR.R., in which R. is a (lower)alkyl group and J K J R k is a (lower)alkyl, (lower)alkoxy, haterocyclic amino, or -C-R.j group in which R^ is as defined under (b) (xii) or, when taken together with the nitrogen, 280 R. and R. represent j K when R^ is an amino or -CHgCHgNHg group, R. is a methyl group and also providing that R. and R. may not J J K 5 both be a (lower)alkyl group; (xv) -NRj'Rj. 1 in which Rj ‘ is a (lower)alkoxy group and R k * is a (lower)alkyl, heterocyclic, amino(lower)alkyl, (lower)alkyl ami no- (lower)alkyl, di(1ower)alkylamino(lower)0 II alkyl or -C-R^ group in which R^ is as defined under (b) (xii) © 10 (xvi) -NR-jR m R n inwhich R·,, R ffl and R n are each independently a (lower)alkyl group or when taken together with the nitrogen, represent (xvii) -N=CH-R x in which R x is (lower)alkyl or optionally ringsubstituted phenyl or heterocyclic, the substituents on the phenyl or heterocyclic ring being as defined under (a) (ii); 281 50397 (xviii) 'N=CR x Ry in which R y is (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being as defined under (a) (ii), and R x is as defined under (b) (xvii); (xix) =N-R p in which is hydroxy, (lower)alkoxy, amino, di(lower)alkyl ami no or NH or NOH ll (xx) -C — (Cf^^NR^gRig in which n is an integer from 1 to 6 and R 15 and R 16 are each independently hydrogen or (lower)alkyl.

4. A compound as claimed in claim 3 wherein Y is a hydrogen atom, an ethyl or α-hydroxyethyl group and T is il -C-X. 5. A compound as claimed in claim 3 wherei n atom 0 a -C-X or an α-hydroxyethyl group and T is in which X is a group of the formula Y is a hydrogen in which n is an integer 282 (b) -(CHgJ^HOH in which n is an integer from i to 6; (c) -(Cil.,) n P0(0-C|-C 6 alkyl) 2 in which n is an integer from 1 to 6; NH H (d) -(CH 2 ) n NH-C-(C^-Cg)alkyl in which n is an integer from 1 to 6; ««2 (e) -(CH 2 ) n N=CH in which ni is an integer from 1 to 6; II a β

5. (f) -(CH 2 ) n 0C(CH 2 ) m NRR in which n and m are each independently A B 1 or 2 and R and R are each independently hydrogen or (lower)alkyl; or (g) -(CH 2 ) n NHCR c in which n is an integer from 1 to

6. And NR R c is C^-C^ alkyl, phenyl or m is 1 or 2. / w group in which 10 6. A compound as claimed in any one of claims 1 to 3 wherein Y is a hydrogen atom.

7. A compound as claimed in any one of claims 1 to 3 wherein Y is a Cj~Cg alkyl group optionally substituted by a hydroxy group.

8. A compound as claimed in claim 7 wherein Y is an 15 α-hydroxyethyl group.

9. A compound as claimed in any one of claims 1 to 3 as hereinbefore described in any one of the Examples.