IE50596B1 - Penem compounds - Google Patents

Description

The present invention relates to certain novel 2substituted and 2,6-disubstituted penem compounds which possess potent antibiotic activity. Also provided are Various novel intermediates useful in preparing the bio5 logically active penem derivatives and various processes for the production of the intermediates and active compounds The penem ring system has the formula and systematically can be designated as 7-oxo-410 thia-l-azabicyclo(3.2.0Jhept-2-ene. For the sake of - 2 simplicity, it is named 2-penem in the present application and the numbering system used is as follows: 505ββ There is thus provided by the present invention 5 the novel penem compounds having the formula I wherein Z is hydrogen or an easily removable ester-forming protecting group; X is (a) a radical of the formula (i) -OR in which R is hydrogen; d ci (ii) -ORjj in which is 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, di20 (lower)alkylamino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or mo're (preferably 1 or 2) of hydroxy, - 3 (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkylamino , di (lower)alkylamino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or (iii) -OCORc in which Rc is amino, (lower)alkylamino, di(lower)alkylamino or optionally substituted (lower)alkyl in which the substituents are as defined under (ii); or (b) a substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower) aliphatic radical or a ring-substituted phenyl phenyl(lower)alkyl, heterocyclic, heterocyclic (lower)alkyl or heterocyclicthio(lower)alkyl radical, substituents for the above-mentioned aliphatic, cycloaliphatic, phenyl or heterocyclic groups being NR. li 1 (i) -CNR2R3 or -N=C-NR2R3 in which R^ is hydrogen, R, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzyl; (ii) -OR^ in which R^ is amino, (lower)alkylamino, di (lower)alkylamino, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic or heterocyclic (lower)alkyl, the substituents on the alkyl, phenyl or heterocyclic groups being as defined-under (a) (ii); - 4 50586 except that they are not amino,(lower)alkylamino or di(lower) alkylamino when -x is substituted C-|-C2 alkyl and Rg is substituted Cg-C^ alkyl; (iii) -O(CH2)nORr in which n is an integer 5 from 1 to 6 and is optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl, phenyl or heterocyclic groups being as defined under (a)(ii); (iv) -OCOR,' in which Rr' is amino, (lower)alkylamino, di(lower)alkylamino or Rj., wherein R' is as defined above, with the proviso that R 1 may not be unsubstituted (lower)alkyl; (v) -OSO3H; + (vi) -OP(OH)2; (vii) -OSO2Rr in which Rr is as defined under (b) (iii) ; t (viii) -OP(ORe)(0Rr) in which Re is (lower)alkyl and R*. is as defined under (b) (iii) ; (ix) -s(°)nRa which n is 0, 1 or 2 and is as defined under (b) (ii) with the exception of (lower) alkyl substituted by one or more halogen atoms or NR, a Ί ., is in the case where n=O,“C-NRgRg in which R^ is hydrogen or (lower) alkyl and Rg and Rg are each independently hydrogen or (lower)alkyl, with the proviso that Rd may not be unsubstituted phenyl; (x) -CORf in which Rf is amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, -NHNHg, -NR1? Ν(«18)2. - 5 50586 -NHOR19, -S-R17, -0(CH2)n-A-Re or -NReRg in which R-^θ and Rg are (lower) alkyl, Rig is hydrogen or (lower)alkyl, A is 0, S, NH or NCH3 and n is as defined under (b) (iii) an<i Rg is an Rf 9rouP> (xi) -PO(ORw)2 in which Rw is hydrogen or (lower)alkyl; (xii) -ΝΗΕ^ in which R^ is optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -SO^H, -OH, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, -C-NR.R. in which R_ and Ro are each / o / o independently (lower)alkyl, phenyl or NH II phenyl(lower)alkyl, -C-Rg in which Rg is (lower)alkyl, phenyl or phenyl(lower)O II alkyl, or -C-R^ in which R^ is ammo (lower)alkyl, -NH.,, (lower) alkylamino, di (lower)20 alkylamino, O II -NH-C-R1q in which R10 is (lower)alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being defined NH II under (a)(ii), -NH-C-NH2, (lower)alkoxy, - 6 50580 -O(CH2)2Si(CHg)3; II (xiii) -S-C-R.^ in which R11 is (lower)alkyl substituted by amino, (lower)alkylamino or di (lower)alkylamino ; (xiv) -NR R. in which R. is (lower)alkyl and κ 3 R. is (lower)alkyl, (lower)alkoxy, K 0 II heterocyclic, amino, or -C-R^ in which R^ is as defined under (b)(xii) or, when taken together with the nitrogen, W R. and R. represent J Λ „ , providing that when Rj, is amino or -CH2CH2NH2, Rj is methyl and also providing that Rj and may not both be (lower)alkyl; (xv) -NR.'R. ' in which 8,* is (lower)alkoxy 3 J and RjJ is (lower)alkyl, heterocyclic, amino (lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)- fi alkyl or -C-R^ in which R^ is as defined under (b)(xii) or, when taken together with the nitrogen, R. * and R. ’ represent J K - 7 50599 Θ (xvi) -NR. R R in which R. , R and R are each l m n 1 m n independently (lower)alkyl or when taken together with the nitrogen, represent (xvii) -N=CH-Rx in which Rx 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=CRxRy in which R^ is (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being as defined under (a)(ii), and Rx is as defined under (b)(xvii); (xlx) =N_Rp in which Rp is hydroxy, (lower)alkoxy, amino, di(lower)alkylamino or (xx) -C- (CH2) nNRi5Rig i*1 which n is an integer from 1 to 6 and R^g and R^g are each in20 dependently hydrogen or (lower)alkyl; and Y is hydrogen or a radical selected from the group consisting of (a) optionally substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic, the substituents being one or more of hydroxy, (lower)alkoxy, optionally substituted phenyloxy, optionally substituted heterocyclicoxy, optionally substituted (lower)alkylthio, optionally substituted phenylthio, optionally substituted 0596 heterocyclicthio, mercapto, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoyloxy, (lower)alkanoylarnino, optionally substituted phenyl, optionally substituted heterocyclic, carboxy, carb(lower)alkoxy, carbamoyl, N-(lower)alkylcarbamoyl, N,N-di (lower)alkylcarbamoyl, halo, cyano, oxo, thioxo, -SO^H, -OSO^H, -SO?-(lower)alkyl, (lower)alkylsulfinyl, nitro, phosphono + or -OP(OR )(OR ) in which R and R are as defined above, the substitutents on the (lower)alkylthio group being one or more of halo, hydroxy, (lower)alkoxy, amino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the phenyl or heterocyclic substituents above being one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methane15 sulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lower) all-snoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo(lower)alkyl; (b) -OK in which R is optionally substituted (lower)alkyl S S or (lower)alkanoyl or optionally substituted phenyl or heteiocyclic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)alkoxy, (lower)alkylamino, di(lower)alkylamino, amino, oxo, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic being one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo (lower)alkyl, methanesulfonyl, (lower)alkylthio, (lower)alkylamino, di (lower)alkylamino, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; • 50596 (c) -S(O)nRg in which n is 0, 1 or 2 and Rg is as defined above; (d) halo; and (e) optionally substituted phenyl or heterocyclic in which the substituents are one or .more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo(lower)alkyl, methanesulfonyl, (lower)aIky1thio, amino, (lower)alkylamino, di (lower)alkylamino, (lower)alkanoylamino, (Icwer)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or a pharmaceutically acceptable salt thereof , with the proviso that when Y is hydrogen, X may not be The compounds of formula I wherein Z is hydrogen (and their pharmaceutically acceptable salts and 15 physiologically hydrolyzed esters) are potent antibacterial agents. The remaining compounds are useful intermediates for prepai fion of the biologically active penems.

Substituent groups disclosed above for the 2and 6-positions of the penem ring may be further defined as follows .(a) Halo includes chlorine, bromine, fluorine and iodine. Preferred halo substituents are chlorine and fluorine; (b) (Lower)alkyl includes both straight and branched chain saturated aliphatic hydrocarbon radicals having from 1-6 carbon atoms inclusive, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc. Preferred (lower)alkyl substituents have from 1-4 carbons and most preferably 1-2 carbons; 50SB6 (c) (Lower,aliphatic is intended to include acyclic straight and branched chain saturated and unsaturated hydrocarbon radicals having from 1-6 carbon atoms inclusive. The unsaturated radicals may contain one or more double or triple bonds, but preferably contain either one double bond or one triple bond. Examples of (lower)aliphatic are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-2-propenyl, ethynyl' and 2-propynyl.

The most preferred aliphatic radicals are (lower)alkyl as in (b); (d) (Lower)cycloaliphatic is intended to represent alicyclic saturated and unsaturated hydrocarbon radicals having from 3-8 ring carbon atoms, preferably '3-6 carbon atoms. The unsaturated ring may contain one or more (preferably one) double bond. Examples of this group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopentenyl, 1,3-cyclohexadienyl and cyclohexenyl; (e) (Lower)cycloaliphatic(lower)aliphatic represents cycloaliphatic-aliphatic radicals having 3-8 carbon atoms (preferably 3-6) in the cycloaliphatic ring and 1-6 carbon atoms (preferably 1-4 and most preferably 1-2) in the aliphatic Π portion. Examples include cyclopropylmethyl, cyclopropylethyl, cyclopropylpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cyclopentenylethyl, cyclopropylethenyl, cyclopropylethynyl, etc. The most preferred groups of this type are cycloalkyl-alkyl in which the cycloalkyl portion contains 3-6 carbons and the alkyl portion contains 1-2 carbons; (f) by the term (Lower)alkoxy is meant C^-Cg alkoxy groups, the alkyl portion of which being defined as in (b). Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy. Preferred groups are alkoxy and most preferred are alkoxy; (g) by the term(Lower)alkylthio is meant C-j-Cg alkylthio; groups in which the alkyl portion is as defined under (b). Examples include methylthio, ethylthio and n-butylthio; (h) ty the term (Lower) alkylamino is meant C-j-Cg alkylamino groups in which the alkyl portion is as under (b). Examples are methylamino, ethylamino, n-propylamino and ^-butylamino; (i) by the term mdi(lower)alkylamino is meant di ^-Cg alkylamino in which each alkyl is as defined under (b), Examples are dimethylamino and diethylamino; 50586 (j) by the tern (Lower)alkanoyloxy is meant groups of 0 H the formula (lower) alkyl-C-O- in which alkyl is as defined under (b); (k) by the term(Lower)alkanoylanrino is meant groups of II the formula (lower)alkyl-C-NH- in which alkyl is as under (b); II (l) by the term Carb(lower)alkoxy is meant -C-(lowerJalkoxy 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 n is 1-6; (o) by the term Carboxy (lower) alkyl is meant -(CH2)nCOOH in which n is 1-6; (p) by the term Phenyl (lower) alkyl is meant -(CH2)n in which n is 1-6; (q) by the term “(Lower)alkylamino(lower)alkyl is meant -(CH2)nNH-(lower)a1kyl in which £ is 1-6 and alkyl is as defined in (b); (r) by the term Di(lower)alkylamino(lower)alkyl is meant ^,(lower)alkyl -(CH2)nN in which n is 1-6 (lower)alkyl and each alkyl is as defined under (b); ll (s) by the term (LowerJalkanoyl” is meant (lower)alkyl-C25 in which alkyl is as under (b); (t) by the term 11N-(Lower )al kyl carbamoyl is meant II (lower)alkyl-HN-C- in which alkyl is as defined in (b); (u) by the term N,N-Di (lower)alkyl carbamoyl” is meant (lower)alkyl^ in which each (lower)alkyl is as (lower)alkyl defined in (b); (v) by the term Amino(lower)alkyl is meant -(Ο^^ΝΙ^ in which n is 1-6; (w) by the term Hydroxyamino(lower)alkyl“ is meant -(CHg)nNHOH in which £ is 1-6; θ (x) by the term (Lower)alkylsulfinyl is meant -S-(lower)alky1 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 2-6 carbon atoms inclusive, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl.

By the term heterocyclic as used herein is meant heteromonocyclic and heterobicyclic residues of aromatic character as well as appropriate partially or wholly saturated residues, said heterocyclic residues 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 * 50586 50686 Similarly, the terms heterocyclic-(lower)alkyl, heterocyclicthio-(lower)alkyl, heterocyclicoxy and heterocyclic-thio represent -(CH2)n~Heterocyclic, -(CHj)n~S-Heterocyclic, -Ο-Heterocyclic and -S-Heterocyclic, respectively, in which n is 1-6 (preferably 1 or 2).

Since an asymmetric carbon atom is present in the 2-substituted compounds of formula I, such compounds may exist either in the form of racemic mixtures (R,S form) or as the individual dextrorotatory and levorotatory (Rand S— forms) optical isomers. Preferred are the compounds in which the configuration of the 5-oarbon atom corresponds to that of natural penicillin (5R-configuration), Substituents at the 5- and 6-positions of the 2,6-disubstituted penems may be in the cis or trans position in relation to one another. Where the penem 6-substituent contains an asymmetric carbon atom, the resulting isomers are identified herein as i some) η, B, C and. D (see Example 34 for stereochemistry) , The preferred isomer in compounds of this type is isomer B. Separation of the various optical and geometric isomers may be carried out by conventional separation and resolution procedures well-known to those skilled in the art.

The present invention is intended to include the compounds of formula I in the form of isomer mixtures and also in the 'form of the individual separated and resolved isomers .

I The pharmaceutically acceptable salts referred to above include the nontoxic carboxylic acid salts, e.g. nontoxic metallic salts such as sodium, potassium, calcium, aluminum and magnesium, the ammonium salt and salts with nontoxic amines such as trialkylamines (triethylamine), (1596 procaine, dibenzylamine, N-benzyl-6-phenethylamine, 1ephenamine, Ν,Ν'-dibenzylethylenediamine, N-alkylpiperidine and other amines which have been used to form salts of penicillins and cephalosporins. When a basic group is present, the present invention also includes the pharmaceutically acceptable acid addition salts, e.g. salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric or with suitable organic carboxylic acids or sulfonic acids such as trifluoroacetic, [θ p-toluenesulfonic, «aieic, acetic, citric, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic and malic. Compounds containing an acid group and a basic group can also be in the form of inner salts, i.e. a zwitterion. Preparation of the ibove-described salts may be carried cut according io conve ional. procedures for forming salts of S-lactam antibiotics such as penicillins and cephalosporins.

The terra 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 20 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. Kr.cwn ester protecting groups include 2,2,2-trichloroethyl, tertiary alkyl of from 4-6 carbon atoms, tertiary alkenyl of from 5-7 carbon atoms, tertiary alkynyl of from 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl of from 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, o-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethyl silyl and β-triraethylsily lethyl· 50696 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 β10 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, glycyloxymcihyl, pheny Iglycyloxymethyl, thienylglyoyloxymethy1 or acyloxymethyl of the formula II -CH2c-Y' in which Y1 is C^-C^ alkyl or phenyl. Particularly preferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

It will be appreciated that the compounds of formula I may exist in various states of solvation and the anhydrous as well as solvated (including hydrates) forms are intended to be within the scope of the invention.

S0S96 With respect to the compounds of formula I, the preferred compounds are those wherein Y is hydrogen or (lower)alkyl optionally substituted (preferably at the α-earbon) by hydroxy. More preferred compounds within the above group are those wherein Y is ethyl or α-hydroxyethyl. Still more preferred compounds of formula I are those wherein Y is hydrogen or a-hydroxyethyl. The most preferred compounds are those wherein Y is α-hydroxyethyl. Λ preferred embodiment of the present invention consists of the compounds of formula I wherein substituent X is a substituted (iower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic radical or a ringsubstituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthiotlowerl alkyl radical, the subs+ituents for the above-named aliphatic, cycloaliphatic· - iphatic-attphatic, phenyl, phenylalkyl, heterocyc is , heterocyclic-alkyl and heterocyclicthioaIky1 rad 5< 'Is t, NR.

II 1 - ('NR ,ί· •ng R is hydrogen, (lowerjalkyl or phenyl and R. and R- are χ ·ώ y each indep< fdent) ·.· hydrogen, (lower) al kyl, phenyl w seBrn. Within th1n o]«5 the . referred compounds are these whereir Y is hydrog-n, ·*« i»yi .... α-hydroxyethyl, especially those wherein Y is hydr -ger ;r α-hydroxyethyl and most espentilv those whe.cin Y a hyaroxyethyl. 50586 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 heterocyclicthio. 10 alkyl radicals being -COR f in which Rg is amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di (lower) alkylamino (lower) alkyl, -NHNHg, -NR^tRjgJgj Rg and ire (lower)alkyl, Rgg 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 a-hydroxyethyl.

Still another preferred embodiment of the present invention consists of the compounds of formula I wherein in which n is an an integer from 1 to 6, preferably 1 to 4; (b) -(CHgJjjNHOH in which n is an integer from 1 to 6, preferably 1 to 4; - 20 50586 (ο) -(CH,)ηΡΟ(O-C^-Cg alkyl), in which n is an integer from 1 to 6, preferably 1 to 4 and alkyl is preferably methyl, ethyl or isopropyl; ll“ in which n is an Cj^-Cg alkyl integer from 1 to 6, preferably 1 to 4, and alkyl is preferably methyl or ethyl; ,NH? in which n is an integer from (d) NH -(CH2)nNH10 (e) -(CH,) N=C z n \ H to 6, preferably 1 to 4; II AB (f) -(CH2)nOC(CH2)mNRR° 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) -(rH2) NHC-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 -(CH2)m-0 λ 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.

The intermediates of the following formulae are claimed in our copending patent application No. 8215252: III wherein Y is hydrogen or as defined above in regard to '5 compounds of formula I, Q is phenyl or (lower)alkyl, R is an easily removable ester 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; (B) in which Y, Q and R are as defined above under (A); and wherein Y is as defined above in regard to compounds of formula I, Q is phenyl or (lower)alkyl,- R is an easily 50586 removable ester-forming protecting group and T is 6H5 0 1 H or -C-X- wherein X is as defined above in C6H5 regard to compounds of formula I.

Reactive functional groups such as mercapto, amino and hydroxy 5 in substituents Y and X may be protected by conventional blocking groups during conversion of the intermediate to biologically active end-products.

Compound I may be prepared by one or more of the reaction routes discussed below. The various synthetic routes may be divided into three main processes depending on the -stage of incorporation of the 6-substituent, i.e. Y. Thus, in Process 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 0 acylation of mercaptide intermediate III or IIIa shown below since these procedures have been found to be the most generally useful.

The steps of Process I may be seen from the following scheme: SO506 Ο II Ac = CHgC0 = c6h524 Process I (Variation 2): Late incorporation of 2-substituent n Y-CH=CH-OAc CSI ______ ti CH^C-SNa pH 7.5 X-C- © = acylating agent MA = heavy metal salt 50586 Process I (Variation 3)' Late incorporation of 2-substituent - 26 50586 In Process I a vinyl ester (Y = H or a radical as defined in connection with compounds I) containing the desired 6-substituent is converted to the optionally 1substituted 4-acetoxy-2-azetidinone by a cycloaddition reaction with chloro sulfonyl isocyanate (CSI) followed by reduction with an organic reducing agent such as sodium sulfite. The CSI reaction is conveniently carried out in an inert organic solvent such as diethyl ether at a temperature of O’C or below. The reduction step may be conducted in an aqueous or aqueous-organic reaction mixture at a temperature of 0° or below and at a slightly basic pH.

Following formation of the 4-acetoxy-2azetidinone, Process I may be separated into three different paths. In one route (Variation 1) the azetidinone is reel II acted with a thiolic acid X-C-SH wherein X is as defined in connection with compounds I, or a salt thereof, in a suitable 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-azetidinor.e into the 4-acetylthio-2-azetidinone and 4-tritylthio-2azetidinone products, respectively, by nucleophic displacement with thioacetic acid or triphenyImethyl mercaptan (or a salt thereof such as the sodium salt), respectively.

The 4-thio azetidinone is next reacted with a 0 11 glyoxylate ester HC-COjR 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, POC1.J, PCl5, and the like) in an inert organic solvent (e.g. tetrahydrofuran, diethyl ether, methylen·. 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 -10°C. 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 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 cycliza'tion 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 50586 wherein Q is preferably phenyl or (lower)alkyl, x is 1 or 2 and M is Cu(II), Pb(II) or Hg(II) when x is 2 or Ag(I) when x is 1. Mercaptide formation is accomplished by reaction of the pbosohorane with a salt of Hg(II), Pb(II), Cu(II) or -\g(I) ir with (methoxycarbonyl)mercury(II) acetate in a methanol-containing solvent and in the pre10 sence of an organic or inorganic base such as aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate, and the like. A preferred base is pyridine.

The reaction may be carried out at room temperature or, if desired, with moderate cooling or heating. The anion (A) of the heavy metal salt may be any anion which gives a soluble salt in the selected solvent, e.g. NO^ , CH^COO , BF^-, F~, C1O4, flO2', CNO~, etc. The mercaptide intermediate is then reacted with an acylating agent capable of introducing the moiety X-C- wherein X is the desired penem 50586 2-substituent. The acylating agent (X-C- © ) may be the acid 0 ll 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 N,Ν'-dicyclohexylcarbodiimide.

Acylation of .the mercaptide can be achieved over a wide temperature range, but is preferably carried out from about -20 to +25C. 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 50586 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 S-trimethylsilylethyl group, 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 below: Process II (Variation 1): Early incorporation of 2-substituent -OAc ch2=ch-oac CSI o' II XC-SNa pH 7.5 ' Process II (Variation 2); Late incorporation of 2-substituent CH2=CH-OAc .SAc -> SOCl, Process II (Variation 3 )j Late incorporation of 2-substituent -OAC 03CSNa ch2=ch-oac _csi> I I* -^775 <0 50586 As can be seen Process II is substantially the same as Process I (except that Y must be H) up through the thermal cyclization step which produces the 2-substituted penem. A 6-substituent, however, if desired, is now in5 corporated at this stage by reaction of the 2-penem with a suitable electrophile in an inert solvent (e.g. tetrahydrofuran, diethyl ether, dimethoxyethane, and the like) and in the presence of a strong base. In this procedure the 2penem can be reacted in the form of the free acid (obtained by de-blocking as described above) in the presence of about two equivalents of base or, alternatively, a suitable 2penem ester may be used in the presence of about one equivalent of base. Any ester inert to anion chemistry (the reaction involves anion formation with base followed by reaction of the electrophile with the penem anion) may be employed, e.g. (lower)alkyl such as methyl, ethyl, n-propyl or t-butyl, phenyl, trichloroethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl, and the like. Penem esters having activated methylene groups such as p-nitrobenzyl are not suitable and, if the 2-penera 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 dimethylamide or lithium di-isopropylamide (LDA) is used. 50586 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. Br2I2), an alkyl halide (e.g. CH3I) or a similar halide such as an aliphatic, cycloaliphatic, cycloaliphatic5 aliphatic, phenyl-(lower)alkyl, heterocyclic, heterocyclic-thio, heterocyc1ic-thio(lower)alkyl, or heterocyclic-(lower)alkyl, halide, a tosylate or mesylate (e.g. »o CH3CH20S02Ό*”,Δ). an aldehyde (e.g. CHgCHO, CgHgCHgCHO) CH3CH20S02CH3, JiCHgCHgCHgOSOgCHj, etc.), an epoxide (e.g episulfide (e.g. Δ,. an a ketone (e.g. CH3C0CH3, or an ester (e.g. CH3CH2C00CH3 or CgHgCOOCHg). Representative examples of other suitable electrophiles are shown below: CH2=CH-CH2Br \Δ· II CH3CCH=CH2 a..

Br ι CH3CH-CH3 /-Cl pCHgBr HCHO 0C®CCH2Br 1 T CH,SCH,C1 ch3sso2ch, POCHgCl 0CH=CHCHO Ο II CH3CCH2C1 0^/ C-CH-C1. II 2 0 A most preferred electrophile is acetaldehyde which gives rise to the hydroxyethyl 6-substituent. Introduction of the 6-substituent by this process is preferably carried out with cooling (e.g. -80° to 0°C.) according to the general procedure described in Canadian Journal of Chemistry, 50 (19), 3196-3201 (1972).

After formation of the desired 2,6-disubstituted penem, any -18 ester-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 111 (Variations 1 and 2): SC03 O' SC03 base de-protect - 38 50586 SC0, ψΗΟ C02R V © CC^R de-protect -”· SC-X CHO J/S0C12 MA/base - 39 SO 59 β de-protect Ψ Β = blocking group for ring nitrogen - 40 50596 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 da-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-disubstituted 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 mercapti.de, acylation of the mercaptide with 0 X-C- © , thermal cyclization of the resulting phosphorane to give the 2,6-penem ester and removal of the carboxylprotecting group. Reaction conditions for these steps are as disclosed in connection with Process II (Variation 3).

An alternative route involves the steps of converting the N-protected azetidinone to a heavy metal mercaptide, acylating the mercaptide with the moiety 0 X-C- © , removing the N-protecting group, reacting the - 41 5.0 58 6 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-disubstituted 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.

Additionally, it is possible in compounds of formula I to functionally modify the 2- and/or 2,6substituents during or at the conclusion of the reaction procedures according to known processes to obtain other substituents included within the scope of the present invention. Thus, for example, carbonyl groups can be reduced to alcohol groups, unsaturated aliphatic groups can be halogenated, amino groups can be alkylated or acylated, nitro groups can be converted to hydroxyamino and amino groups, hydroxyl groups can be etherified or esterified, etc.

The penem free acid compounds may be converted to pharmaceutically acceptable salts thereof or to easily - 42 S0SB6 cleavable esters thereof (particularly physiologically cleavable esters). Salts may be formed by reaction of the free acid with a stoichiometric amount of a suitable nontoxic acid or base in an inert solvent followed by recovery of the desired salt as by lyophilization or precipitation. Esters (in particular physiologically cleavable esters) may be prepared in an analogous manner to preparation of the corresponding esters of penicillins and cephalosporins. Resulting mixtures of isomers can be separated into the individual isomers according to known methods. Mixtures of diastereomeric isomers, for example, can be separated by fractional crystallization, adsorption chromatography (column or thin-layer) or other suitable separation methods. Resulting racemates can be resolved into the antipodes in ]5 the customary manner, for example by forming a mixture of diastereomeric salts with optically active salt-forming reagents, separating the diasteromeric salts and converting the salts into tlie ree compounds, or by fractional crystallization from optically active solvents.

Accordingly, the present invention also provides for a process for the preparation of the compounds of formula I which comprises cyclizing a compound of the formula - 43 50586 wherein Q is phenyl or (lower)alkyl, R is an easily removable ester-forming protecting group and X and Y are as defined above in an inert organic solvent at the reflux temperature of the solvent; optionally removing by methods known per se the removable ester-forming group and other protecting groups; and if desired, converting a compound of formula I wherein Y is a hydrogen atom to any other desired product where Y is a substituent as defined above other than a hydrogen atom by treating the product with a corresponding electrophile in an inert solvent in the presence of a strong base.

By the expression methods known per se is meant any method which is used, or is described in the literature, for removing ester-forming groups and is suitable for preparation of the compounds of the invention.

The free acid penem compounds provided by the present invention and pharmaceutically acceptable salts S0586 and physiologically cleavable esters of said acids have been found to be potent broad-spectrum antibacterial agents useful in the treatment of infectious diseases in animals, including man, caused by both Gram-negative and Gram-positive organisms. The compounds are also of value as nutritional supplements in animal feeds and as agents for the treatment of mastitis in cattle.

The 2-penem acids (and physiologically cleavable esters and pharmaceutically acceptable salts thereof) projq vided according to the present invention (i.e. compounds of general formula 1' wherein Y = H) possess antibacterial activity per se and are also useful intermediates (preferably in their carboxyl-protected form) for preparing the 2,6disubstituted penems 1 via anion formation and reaction with an electrophile, The active compounds provided by the present invention may be formulated as pharmaceutical compositions comprising, in addition to the active ingredient, a pharmaceutically acceptable carrier or diluent. The compounds 20 may be administered both orally and parenterally. The pharmaceutical preparations may be in solid form such as capsules, tablets or dragees, or in liquid form such as solutions, suspensions or emulsions. In the treatment of bacterial infections in man, the active compounds of this - 45 50586 invention may be administered orally or parenterally in an amount of from about 5 to 200 mg./kg/day and preferably about 5 to 20 mg/kg/day in divided dosage, e.g. three or four times a day. They are administered in dosage units containing, for example, 125, 250 or 500 mg. of active ingredient with suitable physiologically acceptable carriers or diluents.

Illustrative examples of the preparation of starting material and end-products of the present invention follow. All temperatures are in degrees Centrigrade. For the sake of convenience, certain abbreviations are employed in the examples. Definitions of the less obvious of these abbreviations are as follows: CSI pet. ether b.p. n.m.r. h ether chloro sulfonyl isocyanate petroleum ether boiling point nuclear magnetic resonance hour 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(c6h5)3 Me ch3- THF tetrahydrofuran Ph phenyl DMF dimethylformamide TEA triethylamine PNBG p-nitrobenzylglyoxylate THP tetrahydropyranyl TFA trifluoroacetic acid HMPT (or HMPA) hexamethylphosphorus triamide EtOAc ethyl acetate DMSO dimethylsulfoxide Ac ch3co- Ms CH3SO2- DMAP 4-dimethylaminopyridine Py pyridine LDA lithium diisopropyl amide LDCA lithium dicyclohexyl amide Of the Examples Nos. 2-10, 13-14 (part), 15, 16 (part), 17-21, (part), 33-42 and 44-52 do not fall within the scope of the invention but are nevertheless useful as illustrative preparations analogous to those of the invention or intermediates. 30586 EXAMPLE 1 21 -(2'-Diethylphospnono-1’-ethyl)penent-3-carboxylic Acid EtO) 2-P- (CH.,) 2CO.,CH3 -¼ (EtO) fi- (CH2) 2CO2H (EtO) 2P- (CHp 2COC1 (EtO) 2-P-CH2) 2COSH A mixture of _1 (11.2 g, 50 mmoles) and sn HaOH (10 ml) was stirred and cooled (ice-bath) for 15 min and at room tempe1q raCure for 15 min. The mixture was extracted with ether and the extract discarded. The aqueous solution was acidified with >N 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, m) 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 (COC1)2 were removed azeotropically with benzene to give 2.4 g (quantitative yield) of crude 3.IP. V C 1800; 1735 cm . nmr <5 4.3 (4H, m), 3.0 - 3.7 XC1 (2H, m) 2.0 - 3.0 (2H, m), 1.4 (6H, m). This was treated 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).

To _i (1-9 9, 8.4 mmoles) was added under N2 IM solution of NaHCOg (10 ml), followed by addition of £ (0.813 g, 6.3 mnoles) in H20 (3 ml). The pH of the mixture was adjusted to 7-8 by adding more NaHCOg. 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. 64-67°, nmr 6 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,) 2>/Et)2 - rfsV 4— Ns. ΌΗ fCH2)2-P-(cEt).

COjPNB 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 /, 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, m) 1.7-2.5 (2H, ra) 1.3 (6H, A crude / (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 SCC12 in THF (0.9 ml) ind Ihr mixture was stirred in the cold for 15 min and at room temperature for 40 min. To it was added benzene (10 ml), and the solid was filtered off. The filtrate was concentrated in vacuo to give 463 mg (quantitative yield) of crude 8, nmr 5 8.3 (2H, d), 7.6 (2H, d), 6.1 (1H, s), 5.7 (IH, m) , 5.3 (2H, d) , 4.2 (4H) , 1.8-3.6 (6)1, m) 1.3 (611), 2>/-(oEt)2 > co2pnb CO2PNB To a solution of crude £ (463 mg, 0.88 mmole) in THF (4 ml) was added triphenylphosphine (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 filtered, the filtrate concentrated and the residual oil chromatographed on a silica gel column with ethyl acetate-2* EtOH as eluent, to give 203 rag (30.6*) of oil 9., which solidified on standing, m.p. 126-128eC.

S, 0' co2pnb Λ 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 -1 (56%) of 10 as oil, IR 1795, 1710 cm . ]5 nmr δ 8,3 (2H, d) 7.7 (2H, d) 5.7 (lH, ra) , 5.38 (2H, d) 4.1 (4H) 1.8-3.8 (6H, 1.35 (6H).

CO^NB CO2H To a solution of 10 (59 mg, 0.126 mmole) in THF (3 ml) and ether (1 ml) was added NaHCO(9 mg, 0.107 mmole) , water (1 ml) and 10% Pd/celite (60 mg) and the mixture hydrogenated at 30 psi for 2 h. The product was isolated as usual to give 36 mg (86%) of U as oil, IR (CHC13) 1798, 1730, 1710 cm1, nmr (5 9.0 (COjH) , 5.6 (IH, m) 4.4 (4H), 3.6 (IH, q) , 3.15 (IK, q) 1.7-3.0 (4H, m) , 1.3 (6H) . 50886 Example 2 6-Acetoxymethyl-2-methylpenem-3-carboxylic Acid Preparation of 1,3-diacetoxypropene 1_ 5 (Ref. L.W. McTeer U.S. 2,866,813. CA 53 9063) Ac^O CH «CH-CHO —----> AcOCil-CK-CH-OAe + CH =Ci!-CH(OAc) OCl t · 2 2 2 Preparation of catalyst: A solution of boric acid (6.2 g) and 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 - 53 S Ο 5 9 3 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 (13.06¾) 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: υ 1770, 1750, υ___ 1680. c=o c-o AcOCH2CH=CH-OAc AcO' lAc NH 2a 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 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 NaHCO3 was added to keep pH at 7-8. The layers 2q 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 undistilled 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 nmr) as colourless oil. NMR: 7.25 (H, NH), 6.0 (O.25H, d, J = 4.3), 5.8 (0.75H, d, J = 15.), 4.5 (0.5H, d, J = 6.5), 4.4 (l.SH, d, J =, 4.5), 3.8 (0.25H, m) , 3.5 (0.75H, m) , 2.13 (3H, s) , 2.1 (3H, s) .

XR: v 1780, 1740. 3a 3b 3c PROCEDURE: Sodium thioacetate was prepared by addition of thioacetic acid (2.22 ml, 2.363 g) to a solution of IM NaHCO^ (31.0 ml) under nitrogen. This was added to a cooled (ice bath) solution of (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 bentene-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 (ά 5.55, d, J = 4.3) to which structure 3c was tentatively assigned. NMR: 6.78 (Η,ΝΗ), 5.52 (0.17H, d, J = 4.3), 5.18 (O.83H, d, J = 1.5), 4.37 (2H, d, J = 4,5). 3.45 (Η, m), 2.35 (3H, s) , 2.05 (3H, s) . IR: V 1765, 1740, 1600 οζή1 c=o PROCEDURE: A mixture of crude _3 (2.17 g; 10 mmoles) and p-nitrobenzyl glyoxylate hydrate (2.5 g; ii mmoles) in benzene (200 mi) was refluxed 20 h under a Dean Stark water collector followed by 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. 4 5 PROCEDURE: To a cooled (ice-bath) solution of crude 5. (3.3 g; 7.75 nmoles) and pyridine (0.67 g; 8.5 mmoles) in benzene (20 ml) was added dropwise thionyl chloride (1-01 g; 8.5 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 solid 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: 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 6 PROCEDURE: ft mixture of crude £ (.1.90 g; 4.2 7 mmoles) • 10 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.

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 SiO (30 g) and eluted with benzene to give 0.4 g of 7_ (57¾).

Anal. Calc'd for C 52.04; H 4.11; N 7.14. PoMd; C 51.77; K 4.03; N 7.30.

Separation of the cis and trans isomers was achieved through careful chromatography on silica gel (60 g) CH ) , 2.0 (3H, s, CH CO) . eluting with benzene. cis-isomer: 6 (ppm, CDCl^): 7.5-8.5 (4H, 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, -1 1770, 1740, 1730 cm trans isomer: δ (ppm, CDCl^): 7.5-8.5 (411, aromatics) , 5.53 (IH, d, J = 2, H-5), 5.30 (2h, A3 quartet, Leuzyl), 4.32 (2ii, d, AcOCH ), 4.27 (IH, dt, J = 5, J - 2, H-6). 2.31 (3H, s. —2 CH_3) , 2.0 (3H, s, CH3CO) v 1770, 1740, 1730 cm c=o To a solution of trans 7. (119 mg; 0.3 mmole) ir. ethyl acetate (15 ml) and water (7 ml) was added NaHCOj (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 acueous layer was washed with ether and then lyophilized to give 40 mg of solid 8_ (48%) . '»c=o 1765, 1740, 1600 cm'1. d (ppm, DjO) s 5.52 (IH, ((-5), 4.85 (2H, AcOCHp, 4.0 (IH, Ii-6, , 2.65 (3H, CHg) , 2.40 (3H, CHjCO) .

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

Treatment of cis paranitrobenzyl 6-acetoxymethyl2-raethyl-penera-3-carboxylate according to the above procedure gives the cis sodium salt and free acid. 50396 Example 3 Potassium 6-(21-Hydroxyisopropyl)-2-methylpenem-3-carboxylate (anion process) A solution of acid 1 (116 mg, 0.627 mmoles) in anhydrous THF (4cc, freshly distilled over LAH) was added dropwise at -78°C to a THF (2cc) solution of LDA (from diisopropylamine, 70.7 mg, 98 pi, 0.699 mmoles, and n BuLi 1.6 M, 0.440cc, 0.704 mmole stirred at -78°C for 30 min). The mixture was stirred for 5 min. followed by successive addition of diisopropylamine (70.7 mg, 98 pi, 0.699 mmole) and 1.6 Μ n BuLi (0.440cc, 0.704 mmole) at -78°. It was then stirred for 10 min. at -78° and treated rapidly with acetone (5.cc) . The ]5 mixture was allowed to react with acetone for 10 rain. It was acidified (pH=2) with 1% HCl, diluted with ethyl acetate (40 cc) and washed with brine (3 x 20 cc). It was dried over Na_SO,. Solvent evaooration 2 4 gave a crude residue (3a) which was taken up in CH^l^ (crude yield 90 mg). The crude acid was dissolved in cold MIBK (2 cc) and 2q treated dropwise with potassium 2-ethyl hexanoate. It gave two batches of potassium salt (36.4 mg, 26%) as a cis and trans mixture, the trans isomer being predominant. 80586 δ (ppm, DMSOd,) 5.60 J5-6 trans “ 2* H5)' 3·93 <1H' d' J6-5 cis’ 4‘ H~6)' 3’62 (IH, d. Jg_5 > 2, H-6), 3.50 (b.s.,0H), 2.34 (3H, s, CH^) . 1.47, 1.40 (6H, 2s, 2CH3), 1.35, 1.32 (6H, 2s, 2CH.j) c V (%ijol mull) 1765, 1582, V 3600 - 3100 u c-o OH UV (EtOH) λ 257 (ε = 3920), 300 (ε = 4020). max *nujol is a trade mark Example 4 Potassium 6-Hydroxybenzyl-2-methylpenem-3-carboxylate (anion process) A solution of acid 1 (100 mg, 0.540 mmole) in anhydrous THF (6 cc, distilled over LAH) was added dropwise to a cold (-78’) ]5 THF (2cc) solution of LDA made from diisopropylamine (84 pi, 60.6 mg, 0.599 mmole) and 1.6 H η-BuLi (0.380 cc, 0.608 mmole). The mixture was stirred for 5 min, followed by successive addition of diisopropyl amine (84 pi, 60.6 mg, 0.599 mmole) and 1.6· M η-BuLi (0.380 cc, 0.608 mmole). It was then stirred for 7 min at -78’ and treated rapidly with benz20 aldehyde (300 pi).. The mixture was allowed to react at -78’ for 20 min. Xt was acidified with 1% HCl (pH=2) , diluted with ethyl acetate (40 cc), washed with 1:1 H20-brine (3 x 20 cc) and brine (1 x 20cc) It was dried over Na/0^. Solvent evaporation gave a residue which was dissolved in MI3K (2cc). It was treated dropwise with potassium 2-ethyl Kexanoate. It gave 4b (35 ag) in 20% yield as a diastereoisomeric mixture. 6: (ppm, DMSOd^) 7.95 (5H, s, H-aromatic) 5.57 (d, Jg_g trans = 1.5, H-5) , 5.45 (d, J ·, „ = 1.5, H-5) 5.35 (d, J- , .= 4. H-5), -o trans 5-6 cis .0 (m, C-H hydroxybenzyl), 4.25 (dd, Jf._5 = 4, J._C_K hydroxy ben2yl = 10, H-6), 3.90 (m, H-6), 3.65 (b.s., OH), 2.35 (3H, 2s, CH3, V (nujolmull) 1760, 1590, υ 3600 - 3100. UV (HnO) λ 252 (C = 5,100), c=o J OH 2 max 296 (ε = 3,300) .

Example 5 Potassium 6-Thiomethyl-2-methylpenem-3-carboxylate (anion process) 4c A solution of acid 1 (100 mg, 0.540 mmole) in anhydrous THF (See, distilled over LAH) was added dropwise to a cold (-78°) THF (2cc) solution of LDA made from diisopropylamine (84 Ul, 60.6 mg, 0.599 mmole) and 1.6 M n-Butyl lithium (0.380 cc, 0.608 mmole).

The mixture was stirred for 7-8 min, followed by successive addition of diisopropylamine (84 01, 60.6 mg, 0.599 mmole)· and 1.6 Ά n-3utyl lithium (0.380 cc, 0.60B mmole). It was then stirred for ' .T.m at -78° and treated rapidly with methylthio methyl sulfone (CH3SS02CH3)300 pi, excess). The mixture was allowed to react at -78° for min. It was acidified with 1% HCl (pH=2), diluted with ethyl acerare (40 cc), washed with 1:1 H2O-brine (3 x 20 cc) and bt.ne (20 cc). 50396 The organic solution was dried over Na^SO^. Solvent evaporation gave a residue which was dissolved in cold MIBK (2cc). The cold solution was treated dropwise with potassium 2-ethylhexanoate. It gave 4c (40 mg) in 28% yield as a 8:3 mixture of cis and trans isomers (decomp.) 120*) δ (ppm, CMSOd ) 5.85 (IH, d, c . = 4, H-5), 5.57 (IH, d, O CJLS J c = 1.5, H-5), 4.87 (IH, d, J , . = 4, H-6). 4.72 (1H, d, - 6 trans 6-5 cis J c _ » 1.5, H-6), 3.42 (b.s., OH), 2.37 (s, SCHJ, 2.33 (s, CH,) , 6- 5 trans 3 J 2.25 (s, SCH J . V ' (nujol mull) 1770, 1600, UV (HO) λ 252 (ε=4200) c—ο < max 7 297 (ε = 3700) Example 6 1- (p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone 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 added portionwise. The resulting solution was stirred for 5 min and 4-acetoxyazetidinone <7.7 g, 0.059 mole) in water (55 cc) was added rapidly. Precipitation of 4-triphenyl methyl mercaptoazetidinone (2} occurred immediately. The’ S038S 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, agueous sodium bicarbonate water and brine and dried over MgSO^ (89.8%, m.p.: 146.5 - 147.5”Ci Anal, calc'd for C22H19NOS·· 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. δ(ppm, CDC13> 7.60 - 7.10 (15H, ra, H-trityl), 4.62 (IH, bs, NH), 4.40 (IH, dd, 1., = 3.0 4-3 trans ' J4-3 cis = 5' H-4), 3.24 (IH, ddd, J gemJ3-4 cis = 5' J3-NH = 1.8, H-3), 2, .81 (IH, ddd, J = 15, gem 10 j 3-4 trans ” 3'°' J3-NH ~ 1'2, H-3) V c=o (CHCI ) 1760, 3340.

Hydrated p-nitrobenzyl glyoxylate (4.54 g, 0.02 mole) and azetidinone £ (6.90, 0.02 mole) were refluxed in benzene 0 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 5% NaHCO^ water and brine. It was dried over MgSO^ (12 g, quantitative A small fraction of the epimeric mixture was separated on a silica gel plate (CH2Cl2-ether 6:4) I somer a·’ Rf = 0.87, m.p, = 170.5- 171.5® 50586 6(ppm, CDCI3, 8.07 (2H, d, J=9, Hm aromatic), 7.45 (part of d,.

Ho aromatic), 7.40-7.00 (15H, m. Trityl), 5.25 (2H, s, CH^PNB), 4.75 (IH, s, H-C-0), 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, 3 = 16, gem 4-3 cis gem 5 J4.3trans-3. H-4), 1.42 (b.s.,OH).

V (CHC1-) 1770, 1760 (shoulder), 1525, υ„ 3475. c-o 3 NO^ Isomer B: Rf = 0.75, m.p. = 152 - 153* δ (ppm, CDC13), 8.13 (2H, d, J - 9, Hm aromatic), 7.47 (2H, d, J = 9, Ho aromatic), 7.40 - 7.00 (15H, m, trityl), 5.30 (3H, s, CK -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 OH (5 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 45 min at -15*. The precipitate was filtered off and washed with benzene. Evaporation of solvent gave a residue which was 65 taken up in benzene and treated with activated charcoal (11.7 g, 94%, crystallized out from chloroform). 6(ppm, CDC13) 8.17 (2H, d, J = 8, Hm aromatic), 7.67 - 7.00 (17H, m, Ho aromatic, Tr-H), 5.80 (s, H-C-Cl)- 5.37, 5.33 (2s, H-C-Cl, CHj-PNB), 4.81 (IH, ra, H-4), 3.27 - 2.40 (2H, m, H-3) v (.KBr film) 1785, 1770 V 1525. c=o NOj A THF (100 cc, distilled over LAH) solution of IQ chloroazetidinone £ (11.6 g, 20.2 mmoles) was treated with triphenyl phosphine (7.86 g, 30.0 mmoles) and 2,6-lutidine (2.36 g, 2.56 cc, 22.0 mmoles). The mixture was refluxed for h. The precipitate was filtered off and washed with ether.

The organic solution was washed with 2% aqueous HCl and 5%15 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 0<οΗ,.Ν05Ρ: C, 73.57,- H, 5.04; N, 3.50; S, 4.01. 4U z o Found: C, 73.58; H, 4.91; N, 3.44; S, 3.87.

V (CHC1 ) 1740, V phosohorane (1620, 1610), υ 1525. c=o 3 N0„ 5059 4-Tritylmercapto azetidinone £ 11.6 g, 2 mmoles) was dissolved in CI^Cl^ (20 cc) and the solvent was flushed down at S5’-60’. Phosphorane at 55 - 60° was dissolved in preheated (55-60*) methanol (32 cc). Immediately . fter the obteution 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, 1?8μ1, 2.2 mmoles, 1.1 eq) The warming bath was then immediately removed. The mixture was stirred at room temperature for 2 h and at O’C for 1 h. The silver mercaptide 6 was filtered off, washed twice with cold (0°) methanol and three times with ether. (1.12 g, 84.5%, m.p.: 130-135 dec.), \) (CHC1,) 1795, 1725 (shoulder), V.phosphorane (1620, 1605), c=o 3 Example 7 1-(p-Mitrobenzyloxyearbonylmethyltriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone xt .SCOCH3 COOPNB COOPNB θ A solution of phosphorane Ί_ (1.796 g, 3.0 mmoles) in chloroform (3 ml) was diluted with methanol (90 ml) , cooled at 0°C under nitrogen atmosphere and treated successively with silver nitrate (0.51 g, 3.0 mmoles) and potassium carbonate (0.33 g, 2.4 mmoles). The reaction mixture (prot,.. t erom light) was stirred at 0eC for 15 min., then the cooling bath was removed and stirring was continued for 3 h. The reaction nixture 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) a'1: 1748, 1620 and 1605. An analytical sample was obtained by preparative TLC (ethyl acetate); M.P.: 140 - 5°C dec, calc'd for C30H24N2O5SPAg: C' 54·31; H' 3-65: N* 4'22; S' 4·θ3- Found: c< 54.11; H, 3.48; N, 3.92; S, 4.62.

Example 8 1-(o-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4(silver mercaptidyl)-2-azetidinone Use o? aniline as base scoch3 Aniline, AgNC>3 MeOH yPPh3 COOPNE _^SAg Λ ° ?=PPh3 COOPNB A solution of phosphorane j? (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 all, 16.5 mmoles). The reaction mixture (protected from licht) 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)cmidentical to compound of Example 7.

Silver-l- (paranitrobenzyl 2'-triphenyIpiiosphotanylidetiu 2'-acetai:e)2-azetidinone-4-thiolate B. Use of U-dimethylaminopyridine (DMAP) as base o CC^PNB AgNO /DMAP -i-> ch2«2/ch3oh CO PNB 2 A solution of the above S-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. The residue was redissolved in the minimum amount of dichloromethane and added dropwise, with stirring to cold methanol (300 ml). The precipitated silver salt was collected by filtration, washed with ether and dried; 18.1 g (91%); ir (CHC1 ) V : 1745 (C=O of β-lactam) and 1607 cm 1 (C=0 of ester). 3 max Silvcr-l- (paranitrobenzyl 2' - tr ipheny lphosplior any lidene-2-ace tate) -2C. Use of 1,8-diazabicyclo|^5.4.^ under-7~ene (DBU) as base AgNO _..5*9 DBU, MeOH CO2PN3 S~acetylphosphorane (36.0 g, 0.060 mol) was chloride 120 ml. The solvent was evaporated dissolved in methylene 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 ccwn (ice bath) and a DBU (8.96 ml, 0.060 int ’·.! solu’ on in methanol (20 ml) was added over a 5 min period. The mixture -as stirred for 5 min. The solid was filtered, washed once with cold (0°C) methanol and ether and dried under vacuum; 37.0 g (93%) ,- ir (nujol mull) \) (c=O) and 1600 cm 1 max (phosphorane) j. Use of pyrrolidine as base Silver 1- (paranitrobenzyl 2'-triphenylphosphoranylidene-21'-acetate) 2-azetidinone-4-th scoch3 C=PPh3 toOPNB To a cold (0°C) solution of 4-acetylthio-l-(paranitro20 benzyl 2’’-triuhenylphosphoranylidene-2-acetate) -2-azetidinone (0.60 g, 1.0 mmol) in CH2C12 {2 ml) was added MeOH (4 ml), a solution of AgNO^ in MeOH (G.14N, 7-36 ml, 1.1 mmol) and a solution of pyrrol- lolate Pyrrolidine AgNO SAg 'x-C=PPh_ I 3 COOPNB 5059 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 -10°C, stirred for 0.25 h and filtered. The solid was washed with cold MeOH and dried in vacuo; 0.548 g, m.p. 115’C, 82.4%. ir (nujol) V : 1755 (C=0) and 1600 cm 1 (aromatics).

Example 9 Mercuric (II)-[2,-Triphenylphosphoranylidene-21-acetate]-2-azetidinone 4-thiolate Hg(0Ac)„ X COjPNB II A solution of I (2.4 g, '1 mmoles} in dichloromethane (15 ml) was cooled to S’C and treated with a solution of mercuric acetate (0.525 g, 1.65 mmole) dissolved in methanol (15 ml) . After stirring at 5’C for 2 h, the solvent was evaporated and the residue redissolved in dichloromethane and washed with cold water. The organic solution after being dried (MgSO^) and treated with charcoal, was evaporated to give a foam which crystallized when triturated in ether. Yield: 1.73 g (91%) M.P. 123’ - 127’C, I.R. (CHCl,) 1745 cm1 (V β-lactam) c—o 1608 cm 1 (phenyl) 50586 Example 10 2-MethyInenem-3-p-nitrobenzyl-carboxylate (from mercaptide intermediate) /S,2h9 J-N PPh CT 3 CC^PNB _/SCOCH3 pyridine PPh.

CO2PNB II III A solution of II (262 mg, 0.2 mmo) r-) , 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 (V β-lactam) 1692 (V„„„„„ ) 1620 (phenyl).

C=O SCOCH72 50386 III Phosphorane III (75 mg, 0.126 mmole) in toluene (10 co) was refluxed over a 2.5 h period under nitrogen 5 atmosphere. Solvent evaporation and purification of the residu6 afforded a crystalline derivative (25 mg, 63%) whose physical and spectral data were in complete agreement with those of the title product.

Product iv may if desired be subjected to 10 catalytic hydrogenation (30% Pd on celite) to produce the corresponding 3-carboxylic acid product.

Example 11 2-Aminomethylpenem-3-carboxylic Acid (from mercaptide intermediate) CH2NH IH ,SAg C1COCH N COCH2N3 “A f=PPh3 COOPNB |··=?ΡΗ3 COOPN3 A solution of silver mercaptide _1 (1.25 g, 1.99 nmole) in dichloromethane (15 ml) kept under nitrogen atmosphere was cooled at 0°C and treated dropwise with a 2M solution of azido— acetyl chloride in dichloromethane (1.13 ml, 2.26 nmoles). 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 chromatography (30 g of silica gel 60, eluate; ether-2% ethyl acetate S0S96 (200 al), 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%.

Toluene ch2n3 COOPNB phosphorane 2 (0.593 q, 0.93 mmole, in A solution of 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 ml) benzene-2» ether (100 ml) and ben2ene-4% ether·fraction 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 (CDCl,) δ 8.22 (2H, d, J „ = 8.8 Hz, Ho * Ho, Hm of p-nitrobenzyl), 7.60 (2H, d, J „ - 8.8 H2, Hra of p-nitroHm, Ho benzyl), 5.71 (IH. dd, cis - 3.6 Hz, = 2.1 Hz.

H-5), 5.33 (2H, center of ABq, Ja -D= 14-0 Hz, CH2 of p-nitrobenzyl) , ' 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, r . = 2.1 Hz, J = 16.5 Hz, H-6 trans). 6,5 trans gem I.R. (Nujol) cm”1: 2115 and 2090 (N3) , 1780 (c=o of (3-lactam) and 1685 (c=o of p-nitrobenzyl ester,· An analytical sample was obtained by preparative T.L.C.; M.P. 127-8°C, calc'd for C,.H,,N,O,S: C, 46.54; H, 3.07; N, 19.37; S, 8.87. Found: 11 5 5 C, 46.43; H, 3.08; N, 19.37; S, 8.90. 5CS96 COOPNB % Pd/celite ( THF, ether, H.,0 ch2nh2 COOH To a solution of penem _3 (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 <1. [Water and ether insoluble comoound 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 ^1- NMR (DMSO d-S) 5: 5.7 (dd, J_ , . - 3.5 Hz, Jr , _ = 1.5 Hz, H-5). X.R.(nujol) ' -6 cis 5-6 trans cm 1775 (c=o of β-lactam) and 1615, 1585. U.V. λ 2 mp: (£=2320) msx and 307 (£=2685) .

Title product 4. was also obtained from intermediate 3 by the following route; 'COOPNB H2,Pd/D.E. THF, Ether, «2° COOH To a solution of penem 3^ (2.4 g, 6.89 mmoles) in tetrahydrofuran-ether-uater mixture (1:1:1, 165 ml) was added % palladium on diatomaceous earth (4.8 g). The reaction mixture was hydrogenated under 45 p.s.i. at 23°C for 2.5 h and. filtered over celite pad. The filtrate and washings were combined, washed twice with ether, centrifugated and filtered several times to give a clear solution which was lyophilized; 0.622 g, 45%. The crystallization of the compound was induced by the addition of water (0.8 ml); the suspension was centrifuged and the water was removed leaving an orange solid. This solid was washed twice with water and a slightly yellow solid was H2° obtained after drying: 0.273 mg, 19.8%. UV λ 307 (8=4318) and 257 (8=2650). Some crude starting material· (1.2 g, 50%) was recovered. The compound (50 mg) can also be purified by column chromatography *Sephadex G10, column size: 1.6 x 100 cm, flow rate: 10 ml/h, elvent: distilled water, fraction volume: V 1.5 ml, detector: refractive index)·. UV λ : 307 (8=3597) and max 255 (8=2424). lhe stability of the compound in aqueous solution was checked by: UV: 6 h 21 h 28 h 46 h 307 307 307 307 (8=3545) (8=3467) (8=3337) (8=3259) and 255 (8=2773) (8=2411 (8=2398) (8=2398) and and and 255 254 254 20 70 h 307 (8=3076) 94 h 307 (8=2842) 170 h 307 (8=1900) A sample of compound £ was kept at 23°C for 3 days H2° and the UV was taken: UV λ : 307 (8=3055) and 255 (8=2008). max Compound £ was converted as described below to two additional 2-penem derivatives.

*Sephadex is a trade mark NaHCC>3,H2O CH C-OEt CH -N=C 2 \ COI 'CH.

A suspension of compound 4 (50 mg, 0.25 mmole) in distilled water (0.5 ml) was treated with one equivalent of sodium bicarbonate (21 mg) followed by the addition of ethyl acetimidate (21.8 mg, 0.024 ml). The reaction mixture was stirred at 23°C for 20 min ano Lyophilized giving 52 mg of a yellow solid. NMR (D^O) S: 5,7 (m, H-5) and 2.23 (b.s., CH3 of amidine) I.R. (KBr) cm f'72 (c=o ot β-lactam). in DO iv U.V. λ 2 mu: 305 (£=3116) and 253 (£=2525). The comoound 5 was max * — applied on a column (Sephadex G10, column size: 1,6 x 100 cm \ Eluent: H20, detector: I.R. fraction size: 3.6 ml) and lyophilization of appropriate fractions gave 23 mg 45% of slightly yellow Η O powder. U.V. 12 . mil: 303 (£=296'·' and 248 (£=2885), max jX h2nh3 oj NaHC03,H 0 H-HC1 -OEt :η,ν=/ + 6NaCl 2 NW COoQa© Ά suspension of compound ^4 {50 mg, 0.25 mmole) in distilled water (0.5 ml) was treated with sodium bicarbonate (21 mg, 0.25 mole) and stirred for 1.5 min before the addition {2 min) of a mixture of sodium bicarbonate (126 mg, 1-5 mmole) and ethyl for— mimidate hydrochloride {164 mg, 1.5 mmole). The reaction mixture was stirred for 10 min at 23°C and lyophilized giving an orange H ° oowder. U.V. λ 4 mp: 304 (C—2300). max 80596 Example 12 Sodium 2-Hydroxyam inopropylpeneni-3-carboxylat e 1) NaOH 5% To a cold 5% aqueous solution of sodium hydroxide (320 ml) was added ester 1_ (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%). 50S96 02N' -co2h + SOCK 3 A solution of acid 2^ (13.2 g, 0.1 mole) in SOC12 (25 ml) was stirred for 2 hours at 30°C. After evaporation of thionyl chloride, the residue was distilled under vacuum T = 76-78°C (P = 0.2 mm Hg).

Yield 8.8 g (58.3%) as a colourless liquid: n.m.r. (CDClg) ppm: 2.40 (2H,m, g-CH2); 3.15 (2H, t, a*CH2); 4.50 (2H, t, y-CH2) i.r. (neat): 1550 cm'1 (v^); 1790 cm'1 (\>c=(p acid chloride). o2n COCI 1) 2) H2S/Et3N 0^ ΚΗ Π no2 4 A solution of 3 (19.46 g, 0.128 mole) in methylene chloride (200 ml) was added rapidly to a cold (0J0°) stirred solution of thiethyl amine (36 ml, 0.256 mole) in methylene chloride (500 ml) which had been saturated at 0-5° with H2S. The mixture was stirred at -10° for 1 hour and then a stream of nitrogen was passed through the solution to eliminate the excess of HgS. The mixture was washed with 10% HCI, the organic extract was concentrated to about 150 ml and then sodium bicarbonate (10.9 g) and water (500 ml) was added. The pH was adjusted to about 7.5 with NaHCOg or HCI.

The resulting mixture was cooled to 0°C and 4-acetoxy-2-azetidinone (16.8 g, 0.13 mole) in water (20 ml) was added with vigorous stirring.

After 4 hours 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 (Si02; eluent: ether then ether-ethyl acetate 5%) giving an oil which crystallized in ethyl acetate-hexanes yielding 4 (3.5 g, 12.5%) as a white powder. (m.p. 45-47’C).

A mixture of azetidinone 4 (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 o 4A molecular sieves for 18 h. Evaporation of the solvent gave the glyoxylate adduct 5 (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 O’C and SOC12 (0.5 ml, 7 mmoles) was slowly added. The mixture was stirred 1 h at O’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%). 0 596 ί 2 To a solution of chloroazetidinone (6.2 g, mmoles) in THF (300 ml) was added triphenyl phosphine 5 (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 3 silica gel column and eluted with dichlcrcmerhane and dichlc) romethane-ethylacetate (1:1). Evaporation of eluent gave a white solid (2.9 g, 30%). ί Phosphorane T_ (2.0 g, 3 mmoles) in toluene 15 (ISO 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 white solid (0.82 g, 40.7%).

» Pd/OE NO, ______ Z THF-ETHER-H O-NaHCO » lpnb IHOH O' COjNa To a solution of ester £! {50 mg, 0.127 mmole) 5 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 rag). 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. Aqueous solution was lyophilized yielding a yellow powder (30 mg) of hygroscopic compound.

Example 13 6-Ethyl-2-aninomethylpenein-3-carboxylic Acid (cis and trans Isomers) a. Silver cis and trans 3-ethyl-l-(p-nitrobenzyl-21triphenylphosphoranylidene-2'-acetate)-2-azetidinone4-thiolates A solution of cis and trans 3-ethyl-l-(p-nitrobenzyl20 2' -phosphoranvlidene-2'-acetate)-4-acetylthio-2-azetidinones (1.88 g., 3.0 mmoles) in chloroform (4 ml.) was diluted with methanol (90 ml.), cooled to 0° ar.d treated successively with finely powdered silver nitrate (0.51 g., 3.0 mmoles) and potassium carbonate (0.33 g., 2.4 mmoles). The mixture was stirred vigorously 15 min. at O’, 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=Q 1750, 1620, 1605. b. Cis and trans 3-ethvl-l-(p-nitrobenzyl-21-phosphoranylidene2 ' -acetate)-4-azidoacetvlthio-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 ° 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 washes 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 rag. υ (CDCl^) ; 2105, 1760, 1690, 1621 cm-1. c. Cis and trans p-nitrobenzvl-2-azidonethyl-6-ethylper.em-3carboxvlates A solution of the above crude phosphorane (0.60 g) in toluene (30 ml) was kept at 105* for 1 h, cooled and concentrated to leave an oily residue which was purified by column cnromatography 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, A3 quartet, J = 15.0, CH2-N3), 3.4 (IH, m, H-6), 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3). trans isomer: δ (ppm, CDC13) : 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, A3 quartet, J = 14.0, benzyl), 4.58 (2H, AB quartet, J = 15.0, CH2~N3), 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. vc=o 1775, 1615 cra~\ = 306 (ε = 3465). δ (ppm, D.O-DMSO): 5.40 (IH, d, J = 2.0, H-5), 2.0 (2H, m, CH2CH3) , 1.1 (3H, t, J = 7.4, CH2CH’3) . e · cis 2-j\minomethyl-6-ethylpenem-3-carboxylic Acid Reduction of the cis-p-nitrobenzvl ester as described above for the trans-ester gave the cis-acid as a yellowish hygroscopic power (13¾) v 1775, 1615 era'1. λ 304 t-o max (£ = 3563). S (ppm, DjO-DMSO): 5.75 (111, d, J = 4.0, H-5) , 2.0 :2h. m, CH2CH3), 1.1 (3H, t, J = 7.4,cH2CH3). Example 14 The following compounds may he prepared by procedures Similar to the general procedure of Example 13. Y S- s Π > X o C0- i Acylatinq Agent Y z (SOCH2COC1 -CH3 -CH2O0 Na, HM3(CH2J 2C0C1 -ch3 -2)2nh2 HN3lCH2)3C0Cl -ch3 -(ch2)3nh2 H 15 nc(ch2)2coci -ch3 -ich2)3nh2 H o2n(ch2) 3cocl -ca3 -(CH2)3WHOH Na, F)3 (CHj1 4C0C1 -ch3 -(ch2)4nh2 HN3lCH2’2°CH2C0C1 -ch3 -CH2O(CH2)2«H2 HN32)2SCH2COC1 -ch3 -CH2S(CH2)2NH2 K 20 AcMH(CH2)2CO2CO2Ec -ch3 -(CH2)2NHAc Us, (SOCHjCOCl tL^coci -C2H5 -c2h5 -CHjOP Λ Ha, Na,ii3lCil21 2C°C1 -C2«5 -(CH2)2NH2 ii NjlCHj) jCOCI -c2h5 -(cu2)3nh2 H 25 °2Ν(Ο12) -jCOCI -c,H5 -(ch2)3nhoh Na, h3(ch2)4coci -C2H5 -(ch2)4nh2 H 596 N3CH2COC1 iso-C3H7 -ch2nh2 H N3(CH2)2COC1 iso-C3Hy -(ch2)2nh2 H N3(CH2)3COC1 iso-C3Hy -(ch2)3nh2 K 02N(CH2)3C0Cl iso-C3Hy -2)3nhoh Na, H. Example 15 cis- and trans-6-Acetoxymethyl -2-ami nomethylpenem-3-carboxyl a) 3-Acetoxymethyl-4-tritylthio-2-azetidiones (cis and transisomers) A solution of a mixture of cis and trans 4-acetoxy-3-acetoxymethyl 10 -2-azetidinone (4.7 g, 25 mmoles) (Example 2, structure 2b) in water (200 ml) was added rapidly to a vigorously stirred solution of sodium triphenylmethyl mercaptide (from triphenylmethyl mercaptan, 55.2 g; and sodium hydride, 9.6 g, in methanol, 300 ml). The mixture was stirred at room temperature for 4 hours and the solids were collected by filtration, washed with water, and dissolved in dichloromethane.

The solution 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-Acetoxymethyl-l-(p-nitrobenzyl-2'-hydroxy20 2'-acetate)-4-tri thylthi o-2-azeti di ones A solution of the above azetidinone (8.0 g, 20 mmoles) and p-nitrobenzyl glyoxylate (4.54 g, 20 nmoles) were refluxed in benzene (100 ml) through a Dean-Stark water separator filled 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 concentrated 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 (2.3d 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) crs and trans 3-Acetoxymethyl-1-(p-nitrobenzyl-21-tripheny)pnosohoranylidene-21-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 sodium 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%). υ 1740, v 1620, c—o c=P03 1610, 1525 cm-1.

NQ2 e) Silver cis and trans 3-Acetoxymethy1-1-(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 (2.04 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%, melts with decomposition). v_ „ 1745, 1740, 1625 cm f) cis and trans 3-AcetoxymethyI-4-azidoacetvithio-)-fp-m'trobenzyl) 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 13 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: 5 (ppm, CDCl^): 3.5-7.5 (4H, aromatics), 5.67 (IK, d, J = 5, H-5), 5.31 (2H, AB quartet, CH-j-benzyl) , 4.50 (2H, AB quartet, CH^) , 4.33 (2H, d, AcOCH2), 4.26 (IH, dt, H-6), 2.0 (3H, s, CH3). trans isomer: 5 (ppm, CDCl^): 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 N ), 4.27 (2H, d, AcOCH2), 2.0 (3H, s, CH3). h) trans 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic Acid Hydrogenation of the above trans isomer by the procedure described in Example 13 gave the title compound. vc=o 1775, 1740, 1616 cm-1. Amajj. 304 (ε = 3192). i) cis 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic Acid Hydrogenation of the corresponding cis isomer as described in Example 13 gave the title compound as an unstable hygroscopic semi-solid. 50586 Example 16 The following compounds may be prepared by procedures similar to the general procedure of Example 15.

Acylating Agent χ X Z N3(CH2)2COC1 -ch2oa -CH2)2NHz H N3(CH2)3COC1 -CH20Ac -(CH2)3NH2 H N3(CH2)4COC1 -CH20Ac -(CH2)4NH2 H O2N(CH2)3COC1 -CH20Ac -(CH2)3NH0H H N3CH2COC1 -(CH2)20Ac -ch2nh2 H N3(CH2)2COC1 -(CH2)20Ac -(CHz)2NH2 H N3(CH2)3COC1 -(CH2)20Ac -(CH2)3NH2 H n3 ch2 coci CH, 1) 0 -CH-OAc -ch2nh2 H Example 17 cis and trans 6-(1'-Hydroxy-l'-ethyl)-2-methylpenem-3carboxylic Acid, Sodium Salts OH il (Y = -CH-CH3; X=-CH3) To a solution of 2-methylpenem-3-carboxylic acid (100 mg, 0.54 mmoles) in THF (8 ml) was added di isopropylamine (0.08 ml, 0.57 mmoles) at 0° and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78°. After stirring for 2 minutes at -78°, freshly distilled acetylaldehyde (0.5 ml) was added and stirring was continued for 10 minutes. The reaction mixture was 50586 quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer was acidified with 0.IN hydrochloric acid (18 ml) and extracted with ethyl acetate (3 x 20 ml). Concentration of the dried ethyl acetate phases left an oil (49 mg). The oil was dissolved in methyl isobutyl ketone and treated with an excess of sodium 2-methylhexanoate in the same solvent. Addition of ether precipitated the title compounds as a white amorphous solid (25 mg), δ (ppm, DgO): 5.6-5.83 (IH, m, H-5, cis and trans), 2.27 (3H, s, CHg), 1.22 and 0.90 (3H, 2d, CHg).

Example 18 cis 6-(T-Hydroxy-1'-ethyl)-2-methylpenem-3-carboxylic Acid, Sodium Salt (isomer D) 2-Methylpenem-3-carboxylic acid (100 mg) was treated with LDCA and acetaldehyde in a procedure analogous to that of Example 17. The residue (58 mg) obtained after concentration of the dried ethyl acetate phases, was extracted with ether and the ether solution concentrated to an oil (48 mg). This oil was converted to a sodium salt with sodium 2methyl hexanoate as described in Example 33. This yielded 29 mg of a white solid which was identified as ci s-6-(1'-h.ydroxy-1'-ethyl )-220 methyl penem-3-carboxylic acid, sodium salt, contaminated with a little sodium 5-methyl-1,3-thiazole-4-carboxylate. 6(ppm, DMSO-dg): .5 (IH, d, J=4.1, H-5), 2.22 (3H, s, CHg), 1.02 (3H, d, J=5.5, CHg). 50586 Example 19 cis and trans 6-(2'-Hydroxy-21-propyl)-2-ethylpenem-3-carboxyl Acids, Potassium Salts (Y = (CH3)2C-; X = -C2H5) OH Substitution in the general procedure of Example 3 for the 2-methylpenem-3-carboxylic acid used therein of an equimolar amount of 2-ethylpenem-3-carboxylic acid gave a mixture of potassium salts. 4 (ppm, DMSQdfi): 5.60 and 5.56 (IH, 2d, J = 4 and J = 2, H-5), 3.92 and 1 60 (IH, 2d, J = 4 and J = 2, H -6), 2.88 and 2.86 (2H, 2q, CH^- CH3), 1.47, 1.41, 1.36 and 1.32 (6H, 4s, CH-j) , 1, ? •md 1.4 ( 3H 2t, CH_CK_J . Z J λ v 257 (e = 3705) and 302 (ε = 3815). ΓΠαΧ Example 20 cis and trans 6-(l'-Kydroxy-l'-ethyl)-2-methoxymethylpenem-3carboxylic Acid, Sodium Salts To a solution of 2-mpthoxyinethylpenem-3-carboxylic acid (116 mg, 0.55 mmoles) in THF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) at 0’ and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78°. After stirring 2 min at -78 freshly distilled acetaldehyde (0.5 ml) was added and stirring was continued for 10 min. The reaction mixture was quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (0.1N, 18 ml) and extracted with ethyl acetate (3 x 20 ml). Concentration of the dried ethyl acetate phases left an oil (53 mg) which was converted to a mixture of the sodium salts of the title compounds as described in Example 17. White amorphous hygro scopic powder (21 mg). δ (ppm, D20): 5.7-5.85 (IH, m, H-5, cis and trans) 3.38 (3H, 2s, OCH^), 1.22 and 0.92 (3H, 2d, CH,). υ 1770, 1600 cm-1.

C=O Example 21 cis and trans 6-Acetyl-2-methvlpenem-3-carboxylic Acid, Sodium Salts if (Y = -C-Cli3; X =-CH3) To a solution of 2-methylpenem-3-carboxylie acid (100 mg, 0.54 mmoles) in THF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) at 0° and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78°. After stirring for 2 min at -78’, ethyl acetated ml) was added and stirring was continued for 10· min.

The reaction mixture was quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer was carefully acidified at 0° with 0.1N hydrochloric acid and extracted rapidly with ethyl acetate (3 x 20 ml). Concentration of the dried extracts left an oil (36 mg) which was converted to the title compounds as described in Example 33 ί (ppm, D2O) : 5.90-6.10 (IH, 2d. J = 4, J = 2, H-5), 3.8 (IH, m, H-ό cis and trans) ,- 2.34 and 2.27 (3H, 2s, CH3) , 2.12 and 2.0 ?3H, 2s, CH3). 50S86 Example 22 The following compounds may be prepared according to the general procedure of Example 3· X Y z -CH2O0 OH -CH-C»3 Na -CH2O0 OH -CH-0 K -CH2O0 OH 1 -ch(ch3)2 K Example 23 2-(4*-Phthalimido-l'-butyl)pcnera-3-carboxylic Acid 50536 To a solution of triethylamine hydrosuifide, previously prepared by bubbling gas through a methylene 5 chloride (200 ml) solution of triethylamine (8.8 ml, 63.7 mmoles), was added dropwise a methylene chloride (75 ml) solution of 1 (Gabnel Der. 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 10 methylene chloride (125 nl) 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 2^ as a white solid, m.p.: 93-94°C n.m.r. (CDC13) δ 7.5 - 8 (4H, m), 4.47 (IH, broad s) , 3.5 - 3.9 (2H, m) , 2.5 - 2.9 (2H, in), 1.4 - 1.9 (4H, m). Anal, calc'd for CX3H13NO3S: c> 59-29; H, 4.97; N, 5.32; S, 1217. Found: C, 58.92; H, 4.91, N, 5.42; S, 12.31. of IM sodium ture under ni A suspension of ϊ_ (3.04 g, 11.6 mmoles) in a solution bicarbonate (11.6 ml) was stirred at room temperatrogen for 15 min. To it was added 3^ (1.5 g, 11.6 mmoles) and the resulting mixture «-as stirred at room temperature for 1.5 h. The reaction mixture vas diluted with water and extracted with methylene chloride. The organic phase was dried and evaporated in vacuo to give 3.^2 9 of solid 4} m.p.: 95 - 96aC; i.r. (CHCl3) 1775, 1710 cm*1. n.Rl.r. 3 7.8 (4H, d, J = 2Hz) , 7.05 (IH, broad s) , 5.2S (1H, dd, Jcis = 5Hz, Jfcrans = 3Hz) , 3.5 - 3.0 (2H, m), 1.5 - 2.0 (4H, ra) Anal, talc'd for: CjgHggNjO 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-nitrobenzylglyoxylate hydrate (2.22 g, 9.8 ramoles) o was refluxed under a Dean-Stark condenser filled with 3A molecular sieves for 21 h. Evaporation of the solvent afforded .4 g of5 as an oil (100%). i.r. (neat) 3200 - 3600, 1770, 1710, 1525 cm'1 n.m.r. (CDC1J δ 8.21 (2H, d J = 9Hz) , 10 7.75 (4H, d J = 2Hz) , 7.S2 (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, J.. gem cis gem trans Azetidinone glyoxalate _5 (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 £ as a yellow syrup (5.0 g, 100%, n.m.r. (CDCL^, , 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 (IH, 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 LAH) 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 mixture was diluted with benzene-ether 1:1 (30 ml), washed with water, IN HCl, saturated NaHCC>3, brine and dried over MgSO^. Evaporation of the solvent afforded a dark brown oil.

It was passed through a silica gel (700 g) column (benzeneether) to give 16.0 g (53%, of 7 as a thick oil. NMR (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 - 3.5 (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 8_ as oil i.r. (neat 1790, 1710, 1520 cm 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, 0 . = 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 (2H, n) , 1.4 - 2.0 (4H, m).

A two phase mixture made of ester 8^ (195 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 Dad and the pad was washed with water and tetrahydrofuran.

The filtrate and washings were combined.and the organic phase was 100 50586 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 {4 x 2 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 ilH, dd, - 4Hz, Jtrans = 2Hz), 3.90 (IH, dd, J » 16 Hz, J . = 4Hz) , 3.47 (IH, dd, gen cxs J = 16 Hz, J = 2Hs), 3.3 - 4.3 (3H, ro), 2.7 - 3.05 2H, m), gem trans 1.5 - 2.0 (4H, m). 101 Example 24 Sodium 2-(Acetonylmethyl oxirae)-penem-3-carboxylate Ketal 1^ (2.0 g, 4.54 mmoles) was treated at Ο with 95% TFA (20 cc) for Ϊ5 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%) . 6(ppm, CDCl ) 8.27 (2H, d, J = 9, Hm aromatic), 8.60 (2H, d, OC J = 9, Ho aromatic), 5.70 - 5.25 (m, CH -PNB, H-C-O, H-4, 7C=C^ ) H OH 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, . _ ' 3-4 cis gem 3-4 trans = 3, H-3), 2.30, 2.28 (1.67H, 2s, CH^ , 1.98 (1.33 H, s, CH.p V (CHCl,) 1780, 1755, υ 1525. c=o 3 KO2 N-OCH, 102 A methylene chloride (50 cc, solution of ketone £ (1.44 g, 3.63 mmoles) was treated at 0“ under nitrogen atmosphere with methoxyl amine hydrochloride {334 mg, 1.1 eq).

Triethyl amine (367 mg, 0.51 cc, 1 eq) was then 5 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%). 6(ppm, CDCl3) 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-0), 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, CH^ V (CHC1 ) 1770, 1750, 1690. c=o 3 SOC12 pyridine A cold (-15*0 THF (20 cc, distilled over LAH, solution of azetidinone 2 (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 mmoles, 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 benze; and treated with charcoal (1.2 g, 76%) 6(ppm, CDC13) 8.23 (2H, d, Hm aromatic), 7.80 (2H, d, Ho aromatic 25 6.12, 6.08 (IH, 2s, H-C-Cl), 5.75 - 5.55 (IH, m, H-4), 5.40, 103 50396 .30 (2H, 2s, CH2~PNB), 3.95 - 3.80 (3H, 3s, OCH^), 3.80 - 2.95 (4H, m, 2H-3, CH2-CO) , 2.00 - 1.85 (3H, 4s, CH.^. vc_o (CHCl^) 1790, 1765 (shoulder), 1700, V 1530.

N—OCH, N—OCH, ' II 3 A THF (20 cc, distilled over LAH) solution of chloroazetidinone (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% acueous HCl, H^O. 2% aqueous MaHCO^, 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 (CKC1,) 1755, 1695, V 1630 - 1610, V„„ 1525. c=o 3 NO 104 50586 Phosphorane _S (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 _N,O,S: C, 52.17,· H, 4.38; N, 10.74, Found: C, 51.15; H, 4.18; N, 10.33.

S(ppm, CDCl^) 7.70 (2H, d, Hra aromatic), 7.12 (2H, d. Ho aromatic), 5.00 (2H, s, CH^PNB), 4.85 (IH, in, H-5), 3.75 - 2.70 10 (7H, m, CH3O, CH2, H-6), 1.77, 1.72, 1.65 (3H, s, C·^).

V (CHC1 ) 1787, 1742, 1705, V.,„ 1530. c=o 3 N0_ A mixture of ester £ (151 mg, 0.386 mmole) in THF (20 cc)f 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. H2, using 30% Pd on celite (200 mg) as catalyst.

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

The resulting agueous mixture was washed with ether (3 x 60 cc) and lyophilized (32 mg, 30%). (ppm, DMSO) 5.50 (m, H-5), 3.75 (s, OCH^ , 0.77 (s, CH3).

V (nujol mull) 1770, 1600, 1400. c=o O.V. (HO) λ 300 (ε = 2,800), 255 (e = 2,400). mdx 105 Example 25 The following 2-penem compounds may be prepared by acylation of l-(p-nitrobenzyloxycarbonylmethyltriphenylpnosphoranyl)-4-(silver mercaptidyl)-2-azetidinone with the appropriate acylating agent followed by cyclization and deblocking steps. The general reaction scheme is shown below: 1. RC-O-C-O-iBu or 2. RCOC1 ^SCOR co2pnb H_/30% Pd/diatomaceous earth -> CO2PNB RCO - may be the acyl group of any one of the acylating agents listed below, for variation 1: use RCO2H + iBuCOCl for variation 2-. use HCl + PCl^ + RCO2H 106 S0S96 Acvlating Agent Method Product 3ch2oconh- (cii2) 4-co2h 1 2-(4-Aminobutyl)penem-3carboxylic acid ch3 0CH2OCONH-CH-CO2H 1 2-(1-Arainoethyl)penem-3- (both D and L) carboxylic acid CH-CH, 1 2 3 0ch2oconh-ch-co2h 1 2-(1-Aminopropyl)penem-3- (both D and L) carboxylic acid CH, 1 3 CH-CH, 0CH 2OCONH-CH-CO2 H (both D and L) 0CH2OCONH-CH-CO2H 1 2-(l-Amino-2-methylpropyl)penem-3-carboxylic acid 1 2-(1-Aminobenzyl)penem-3- (both D and L) carboxylic acid fH20 0CH2OCONH-CH-CO2H 1 2-(l-Amino-2-phenylethyl)- (both D and L) penem-3-carboxylic acid ch2och20-no2-p 0CH2OCOHH-CH-CO2H 1 2-(l-Amino-2-hydroxyethyl)- (both D and L) penem-3-carboxylic acid CH,CO_,CH.,0-NO7-p 0CH2OCONH-CH-CO2H 1 2- (l-Amino-'2-carboxyethyl) - (both D and L) penem-3-carboxylic acid. CH.CONH, 0CH2OCONH-CH-CO2H 1 2-(l-Amino-2-carbamoylethyl)- (both D and L) penem-3-carboxylic acid CH,CH,SCH, ,22 3 0CH2OCONH-CH-CO2H 1 2-(l-Amino-3-methylthiopropyl)- (both D and L) penem-3-carboxylic acid (CH,)4NHCO7CH,0 0CH2OCONK-CH-CO2H 1 2-(1,5-Diaminopentyl)penem- (both D and L) 3-carboxylic acid ™3 0CH2OCONCH2CO2H 1 2- ((Methylamino)methyl]penem- 3- carboxylic acid ?H3 0CH2 OCONCH2 CH 2 CO2H 1 2-(2-(Methylamino)ethyl]penem-3-carboxylic acia 107 Acylating Agent CH, I 3 0ch2oconch2ch2ch2co2h CH, I 3 0ch2oconch2ch2ch2ch2co2h C,H«. 0CH2OCONCH2CO2H C,H, 0CH2OCONCH2CH2CO2H C,H, I 2 5 0CK2OCONCH2CH2CH2CO2H C,H,I 2 5 0CH2OCONCH2CH2CH2CH2CO2H 0CH2OCONCH2CO2H ? 0CH2OCONCH2CH2CO2H 0CH2OCONCH2CH2CH2CO2H f 0CH2OCONCH2CH2CH2CH2CO2H CH3CONHCH2CO2H CH3CONHCH2CH2CO2H ch3conhch2ch2ch2co2h Product 2-[3-(Methylamino)propyl] penem-3-carboxylic acid 2-[4- (methylamino)butyl]penem-3-carboxylic acid 2- [(Ethylamino)methyl]penem 3- carboxylic acid 2- [2- (Ethy lamino) ethyllpenem3- carboxylic acid 2-[3-(ethylamino)propyl]penem-3-carboxylic acid 2-[4-(Ethylamino)butyl]penem-3-carboxylic acid 2-[(Phenylamino)methyl]penem-3-carboxylic acid 2-(2-(Phenylamino)ethyl) penem-3-carboxylic acid 2-[3-(Phenylamino)propyl] penem-3-carboxylic acid 2-[4-(Phenylamino)butyl]penem-3-carboxylic acid 2-[(Acetylamino)methyl]penem-3-carboxylic acid 2-(2-(Acetylamino)ethyl]penem-3-carboxylic acid 2-(3-(Acetylamino)propyl]penem-3-carboxylie acid 108 Acylatinq Agent Method Product ch3conhch2ch2ch2ch2co2h 1 2-(4-(Acetylamino)butylj * penem-3-carboxylic acid C.H-C0NHCH-C0.H 0 0 4 4 1 2- ((Benzoylamino) methyl] penem-3-carboxylic acic C6H5CONHCH2CH2CO2H 1 2- [2-(Benzoylamino) ethyl] penem-3-carboxylic acid C^H-CONHCH-CH-CH-CO-jH bo 2 2 2 2 1 2-(3- (Benzoylamino) propyl] penem-3-carboxylic acid CrH-CONHCH-CH-CH-CH.CO-H 0 o 2 2 2 2 2 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 0CH2OCONHCH2CONHCH2CH2CH2CO2 H 1 2- [ 3- (Glycinamido) propyl] penem-3-carboxylic acid 0CH2OCONHCH2CONHCH2CH2CH2- CH2CO2H 1 2-(4-(Glycinamido)butyl]penem-3-carboxylic acid H2-N’CONHCH2CO2H 1 2-(Ureidomethyl)penem-3 carboxylic acid H2NCONHCH2CH2CO2H 1 2-{2-Ureidoethyl)penemcarboxylic acid H2NCONHCH2CH2CH2CO2H 1 2-(3-Ureidopropyl)penemcarboxylic acid H2NCONHCH2CH2CH2CH2CO2H 109 1 2-(4-Ureidobutyl)penem-: carboxylic acid Acylating Agent Method Product ch3nhconhch2co2h 1 2- ((Methylcarbamoylamino) methylJpenem-3-carboxylie acid CH3NHCONHCH2CH2CO2H 1 2-[2-(Methylcarbamoylamino)methyl]penera-3-carboxylic acid CH3NHCONHCH2CH2CH2CO2H 1 2-(3-(Mefchylcarbamoylamino, propyl]penem-3-carboxylic acid CH3NHCONHCH2CH2CH2CH2C02H 1 2-(4- (Methylcarbamoylamino)butyl]penem-3-carboxylie acid 0NHCONHCH2COoH 1 2-[(Phenylcarbamoylamino)methyl]penem-3-carboxylie acid 0NHCONHCH2CH2CO2H 1 2-[2-Phenylcarbamoylamino)ethyl]penem-3-carboxylic acid 0HHCONHCH2CH2CH2CO2H 1 2-(3-(Phenylcarbamoylamino)propyl]penem-3-carboxylie acid 0NHCONHCH2CH2CH2CH2CO2H 1 2-[4-(Phenylcarbamoylamino) butyl]penem-3-carboxylie acid CH3CONHCONHCH2CO2H 1 2-((Acetylcarbamoylamino)methyl]penem-3-carboxylic acid CH3CONHCONHCH2CH2CO2H 1 2-(2-(Acetylcarbamoylamino)ethyl]penem-3-carboxylie acid CH3CONHCONHCH2CH2CH2CO2H 1 2-(3-(Acetylcarbamoylamino) propyl]penem-3-carboxylie acid CH3CONHC0NHCH2CH2CH2CH2CO2H 1 2-(4-Acetylcarbamoylamino)butyl] penem-3.-carboxylie ac·^ 0CONHCONHCH2CO2H 1 no 2-[(Benzoylcarbamoylamino) · methyl]penem-3-carboxylie acid Acylating Agent Method Product 0conhconhch2ch2co2h 1 0COHHCONHCH2CH2CH2CO2H 1 0COtJHCONHCH2CH2CH2CH2CO2H 1 CH3OCONHCONHCH2CO2H 1 CH3OCONHCONHCH2CH2C02H 1 CH3OCONHCONHCH2ai2CH2CO2H 1 CH3OCONHCONHCH2CH2CH2CH2C02H 1 (CH3)3Si(CH2)2OCONHCONHCH2CO2H 1 (CH3)3Si(CH2)2OCONHCONHCH2- 1 CHnCO_H A. £.

(CH3)3Si(CH2)2OCONKCONHCH2- 1 ch2ch2co2h 2-[2-(Benzoylcarbamoylaminoethylj penem-3-carboxylic acid 2-[3-(Benzoylcarbamoylamino- propyl]penem-3-carboxylie acid 2- (4- (Benzoy lcarbamoy laminobutyl]-penem-3-carboxylic acid 2- [ (Carbomethoxycarbamoyl·' amino)methyl]penem-3carboxylic acid 2-[2-'Carbomethoxycarbamoyl amino)ethyl]penem-3carboxylic acid 2-(3-(Carbomethoxycarbamoylamino)propyl]penem-3carboxylic acid 2-(4-(Carbomethoxy carbamoyl amino)butyl]penem-3carboxylic acid 2-((2-trimethylsilylethylqylcarbonylcarbamoylamino)methyl]penem-3-carboxylic acid 2-(2-(2-trimethylsilylethyl oxycarbonylcarbamoylamino)ethyl]penem-3-carboxylic acid 2-[3-(2-trimethylsilylethyl oxycarbonylcarbamoylamino)propyl]penem-3-carboxylic acid 111 Acylating Agent Method Product (CH3)3Si(CH2)2OCONHCQNHCH2CH2CH2CH2CO2H 1 2-[4-(2-Trimethylsilylethyloxycarbonylcarbamoylamino)butyl]penera-3-carboxylie acid CH3S2CNHCH2CO2H 1 2-I(Methylthiothiocarbonylamino )me thy1]penem-3carboxylic acid CH3S2CNHCH2CH2CO2H 1 2-(2-(Methylthiothiocarbonyiamino)ethyl]penem-3carboxylic acid CH3S2CNHCH2CH2CH2CO2H 1 2-(3-(Methyl thiothiocarbonylamj no)propyl]penem-3carboxylie acid CH3S2CNHCH2CH2CH2CH2CO2H 1 2- [ 4- (Methyl thiothiocarbonylamino) butyl]penem-3carboxylic acid CH SO NHCH2CO2H 1 2-[(Methanesulfonylamino)methyl]penem-3-carboxylie acid CH3SO2NHCH2CH2CO2H 1 2-[2-(Methanesulfonylamino)ethyl]penem-3-carboxylic acid CH3SO2NHCH2CH2CH2C02H 1 2-[3-(Methanesulfonylamino)propyl]penem-3-carboxylie acid CH3S02NHCH2CH2CH2CH2C02U 1 2- [4- (Methanesulfonylamino) butyl]penem-3-carboxylie acid 0SO2NHCH2CO2H 1 2-[(Benzenesulfonylamino)methyl]penem-3-carboxylie acid 112 50586 Acylatinq Agent 113CHHCNHCH2CH2CO2H s il H CNHCNHCH2CH CH2CO2H s II H CNHCNHCH2CH2CH2CH2CO2H 0NKOJHCH2CO2H s II 0NHCNHCH2CH2co2h s II 0NHCNHCH2CH2CH2CO2H s I! 0NHCNHCH2CH2CH2CH2CO2H Method Product 2-(2-(N-Methylthioearbamoyl amino)ethyl]penem-3carboxylic acid 2-(3-(N-Methylthiocarbamoyl amino)propyl]penem-3carboxylic acid 2- (4- (N-Methylthiocarbamoyl· amino)butyl!penera-3carboxylic acid 2-((N-Phenylthiocarbamoylamino)methyl]penem-3~ carboxylic acid 2-[2-(I'i-Phenylthiocarbamoylamino)ethyl]penem-3carboxylic acid 2-(3-(N-Phenylthiocarbamoyiamino)propyl]penem-3carboxvlic acid 2-[4-(N-Phenylthiocarbamoylamino)butyl]penem-3carboxylic acid HO A, 0' -NHCH2CO2H 2-((Guanylamino)methyl]penera-3-carboxylic acid N-jj—NHCH2CH2CO2H N H0^°X 2-[2-(Guanylamino)ethyl]penem-3-carboxylic acid O' HHCH CH2CH2CO2H 2-[3-(Guanylamino) propyl]penem-3-carboxylic acid 113 Acylating Agent Method 1 Product 2-(4- (Guanylamino)butyl] - N jj N UCH2 CH 2 CH CH 2 CO H Ji N hcA0 penem-3-carboxylic acid ,-O\ 0 N J 1 2-({Acetimidoylamino)methyl]- J]-N-CH, CO ,H H C penem-3-carboxylic acid -ch2ch2co2h 1 2- (2- (Acetimidoylamino) ethy§penem-3-carboxylic acid · ” -CH2CH2CH2CO2H 1 2- [ 3- (Acetimidoy lamino) propyl)penem-3-carboxylic acid -CH2CH2CH2CH2CO2H 1 2-[4-(Acetimidoylamino)butyljpenem-3-carboxylic acid ;fY l!_N- CH2CO2H 1 2-[(Formimidoylamino)methyl]penem-3-carboxylic acid “ -CH2CH2CO2H 1 2-(2-(Formimidoylamino)ethyl]penem-3-carboxylic acid -CH2CH2CH2CO2H 1 2-(3- (Formimidoylamino) propyl] ~ penem-3-carboxylic acid -CH2CH2CH2CH2CO2H 1 2-(4-(Formimidoylamino)butyl]penem-3-carboxylic acid O2NCH2CO2H 1 2-[(Hydroxyamino)methyl]penem-3-carfaoxylic acid O2NCH2CH2CO2H 1 2-(2-(Hydroxyamino)ethyl]penem-3-carboxylic acid O2NCH2CH2CH2CH2CO2H 1 2-(4-(Hydroxyamino)butyl]penem-3-carboxylic acid 114 Acylating Agent OCH.

I 3 (CH3)3Si(CH,)2OCON-CH2CO2H OCH, I 3 (CH3) Si(CH2) OCON-CH2CH2C02H OCH, I 3 (CH3)3Si(CH2)2OCONCH2CH2CH2CO2H OCK3 (CH3) 3Si.(CH2) 2 OCONCH2CH2CH2CH2CO2H NH, I 2 (CH3) Si (CH2) 2O CONCH COjH nh2 (CH3).3Si (CH2) 2 OCONCH2CH2CO2H NH, I 2 (CH3) 3Si (CH2) 2 OC0NCH2CH2CH2CO2H NH, I 2 (CH3) 3Si (CH2) 2 OCONCH2CH2CH2CH2CO2H n(ch3)2 (CH3) 3Si (CH2) 2 OC0NCH2CO2H n(ch3)2 (CH,) 3Si (CH2) 2 OCONCH2CH2CO2H N(ch3)2 (CK3) 3Si (CH2) 2 OCONCH2CH2CH2CO2H N(CH,), I 3 2 (CH.) 3Si (CH2) 2 OCONCH2CH2CH2CH2CO2H * 2 2-(4-(2,2-Dimethylhydrazino)· Method Product * 1 2-[ (MethoxyaminoJmethyDpenem-S-carboxylic acid * 1 2-[2-(Methoxyamino)ethyl)penem-3-carboxylic acid * 1 2-(3-(Methoxyamino)propyl]penem-3-carboxylic acid * 1 2-[4-(methoxyamino)butyljpenem-3-carboxylic acid * 2 2-((Hydrazino)methyl]penem3-carboxylic acid * 2 2-(2-(Hydrazino)ethyl]penem3-carboxylic acid * 2 2-(3-(Hydrazino)propyl]penem 3-carboxylic acid * 2 2-[4-(Hydrazino)butyl]penem3-carboxylic adid * 2 2-((2,2-Dimethylhydrazino).methyl]penem-3-carboxylic * 2 2-(2-(2,2-Dimethylhydrazino) -ethyl]penem-3-carboxylic acid * 2 2-(3-(2,2-Dimethylhydrazino)· -propyl]penem-3-carboxylic acid * use trimethylsilylethyl instead of PNB in azetidinone intermediate and deblock with F . - butyl]penem-3-carboxylie acid 1)5 Acylating Agent Method Product ch3conhnhch2co2h * 2 . 2-[(2-Acetylhydrazino)methyl] penem-3-carboxylic acid ch3conhnhch2ch2co2h ★ 2 2-[2-(2-Acetylhydrazino)ethyl]penem-3-earboxylie acid CH3CONHNHCH2CH2CH2CO2H k 2 2-[3-(2-Acetylhydrazino)propyl]penem-3-carboxylie acid CH3CONHNHCH2CH2CH2CH2CO2H k 2 2-[4-(2-Acetylhydrazino) butyl]penem-3—carboxylic 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 CH1 3 CH3CONCH2CO2H 1 2-[(N-Methylacetamido)methylJpenem-3-carboxylic acid ?H3 CH3CONCH CH2CO2H 1 2- [2- (N-Methylacetamido) ethyl]· penem-3-carboxylic acid ?3 CH3CONCH2CH2CH2CO2H 1 2-(3-(n-Methylacetamido)propyl penem-3-carboxylic acid ?3 CH3CONCH2CH2CH2CH2CO2H 1 2-(4-(N-Methylacetamido)butyl penem-3-carboxylic acid 116 Acylating Agent CH CO H 2 2 Method Product -ch2ch2ch2ch2co2h 2- 1(Phthalimido)methyl)penem 3- carboxylic acid 2-(2-(Phthalimido)ethyl]penem-3-carboxylic acid 2-(3-(Phthalimido)propyl]penem-3-carboxylic acid 2-(4-(Phthalimido)butyl]penem-3-carboxylic acid 0CH2OCONHCH2CH2OCH2CO2H 2-((2-Aminoethoxy)roethylJpenem-3-carboxylic acid 0ch2oconhch2ch2sch2co2h 1 fO2CH20 0CH2OCONHCH2CH2NCH2CO2H 1 CH, I 3 0CH2OCONHCH2CH2NCH2CO2H 2 2-((2~Aminoethylthio)methyi]penem-3-carboxylic acid 2-( (2-Aminoethylamino) methyl] penem-3-carboxylic acid 2-[N-(2-Aminoethyl)-Nmethy1amino]methyIpenem-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 117 Acylating Agent Method Product 2-(o-Aminophenyl)penem-3carboxylic acid 2-[p-(Aminomethyl)phenyl] penem-3-carboxylic acid 2-[ra-(Aminomethyl)phenyl] penem-3-carboxylic acid 2-[o-(Aminomethyl)phenyl] penem-3-carboxylic acid 118 50586 Example 26 The 2-penem products listed below as the triethylamine salts are treated with (CH3)3N’SO3 in CH^Clj solution at 0°. Addition of sodium 2-ethylhexanoate in 1-butanol to the reaction solution results in precipitation of the indicated products as disodium salts.

Starting Material -S.

\.,CB2>n®2 CO2N(C2H5)3 Product •NHS03Na Exp. A Exp. B Exp. C Exp. D n = 1 n = 2 n = 3 n = 4 A. n = 1 Β. n = 2 C. n = 3 D. n = 4 Example 27 The following 2-penem products may be prepared 15 from the indicated starting materials by the procedure ck3i CO2PNB CO2PNB 119 S0596 Starting Material Exp. A n = 1 Exp. Β n = 2 Exp. C n = 3 Exp. D n = 4 A. n = 1 Β. n = 2 C. n = 3 D. n = 4 Example 28 The following 2-penem products may be prepared from the indicated starting materials by the procedure + CKCH.,) COCI 2 Π -JL n) Cl 2 n Ο CO2PNB 120 Starting Material Product Exp. A n = 1 Exp. Β n = 2 Exp. C n = 3 Exp. D n = 4 A. n = 1 Β. n = 2 C. n = 3 □ . n = 4 Example 29 The following 2-penem products may be prepared from the indicated starting materials by the procedure 121 Ο °\ ? SC-(CH2)m-C-R TFA CO2Z Η2ΝΒ Β I 0 V II 11 SC-(CH2)m-C-R Ν .OH co2z m = 0-2 R = H, CH3 Ζ = -(CH2)2Si(CH3)3 Β = -O(CH2)2Si(CH3)3 122 Starting Material 0 H 1—1 \ >> ,_^SC-(CH2) ΠΤ. 0 Kz® CO2PNB m-C-R Exp. A R = H, m = 0 Exp. B R = H, m = 1 Exp. C R = H, m = 2 Exp. D R = CH3, m = 0 Exp. E R= CH3, m - 1 Exp. F R = CH3, m = 2 Product OH ι N , II (CH_) -C-R i m co2h A. R = H, ra = 0 B. R = H, ra - 1 C. R = H, ra = 2 D. R = CH3, m = 0 E. R = CH3, m = 1 P. R = CH3, ra = 2.

Substitution in the above procedure of H2NOCH3 for the H2NO(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 ra = 2, R = H Exp. D m = 0, R = CH Exp. E m = 1, R = CH Exp. F m 2, R = CH. 123 50386 Substitution in the above procedure of (CH3)3Si(CH2) 2^ΟΝΗΝΗ2 ^or HjNO (CHj) 2θϊ (CHg) jUsed therein results in formation of the following products, Exp. A m = 0, R = H Exp. B m = 1, R = H Exp. C m = 2, R = H Exp. D in = 0, R = CH3 Exp. E m = 1, R = Cii3 Exp. F m = 2, R = CH3 Substitution in the above procedure of (CH3)2NNH2 for the H2NO(CH2)2Si{CH3)3 used therein results in formation of the following products: nn(Ch3)2 H2)m-C-R CO2H Exp. A m = 0, R = H Exp. B in 1, R = H Exp. C in = 2, R = H Exp. D m = 0, R = CH Exp. E m = 1, R = CH. Exp. F m = 2, R = CH 124 Substitution in the above procedure of (CHg)3Si(CH2)2OCON-NH2 for the H2NO(CH2)2Si(CHg)3 used therein results in formation of the following products: Exp. B m = 1, R = H Exp. C m = 2, R = H Exp. D ra = 0, R = CHg Exp. E m - 1, R = CH3 Exp. P m = 2, R = CHg. 125 50506 Example. 3η s. (ο-<)2 'CO Η 2 , 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 HCI (5 ml), water (5 ml), IM MaHCO^ (5 ml) and brine, and then dried (MgSO^l 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 (CHClj) 1755, 1690 cm ig NMR (CDCl^) 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) . 126 5059 A mixture of III (1.3 g, 2 mmoles) and IV (0.65 ml, 3 mmoles) was heated at 80°C fox 4 h. The reaction mixture was diluted with methylene chloride (10 ml) and washed with water (2 : 5 ml) . Organic layer was dried (MgSO^) and evaporated in vacuo to give V, 1.4 g (90%), as an amorphous solid.

It was used in the next step without further purification. 1r (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 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 127 (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 (1H, dd, J = 4 Hz, £Xcins 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 (lH, d«l, J - 13 Hz, gem trans gem J . = 2 Hz,, 2.8-3.3 (2H, m) , 1.4 (6H, s), 1.28 (6H, s). cis VI VII 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) ami 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 HCl (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 (CHC13) 1790, 1710 cm-1. NMR (CDC^) δ 9.5 (IH, ws) , 5.65 (IH, dd, J = 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). 128 Example 31 CO.PNB l^CHj. ί(αΑ>2 +. C1C(CH2)3P(OC2HS),, CO t?NB 2 To a cooled (ice bath) mixture of _1 (1.324 g, 2 mmoles) and 2_ (0,54 g, 2.2 mmoles, crude) in CHjClj (15 ml) was added dropwise 1 M solution pyridine /CH^Cl^ (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, Hf), 0.5 M NaHC03 and brine. Xt 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 SiO2 U0* HjO) and eluted with ethylacetate to give 0.5 g of J3. (32.8%). NMS 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) . 129 (0.4 <3, 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^Ρ=Ο. This was chromatographed on SiO2 (10% H20) and eluted with EtOAc to give 0.1 g of pure 4, followed by 0.15 g of 3 and 4. NMR δ (ppm,CDCl ) 8.3 (2b, 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 1 (β-lactam) 1710 cm 1 (ester).

A mixture of _4 (θ-l 9, 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 ^2^^2 an<^ (MgSO^) . The CH^Clj solution was evaporated to give 48 mg of 2 (66.5%). IR spectrum 5 1790 (β-lactam) δ 1700 (-C-OH). 130 Example 32 (OMe), CO2Na I 0 + (MeO) f „Λ-»υ»ι31 -p ?φ3 (OMe) _ ί COjPNB I co2pnb A mixture of 1. (1.07 g, 1.66 mmole) and £ (0,42 g, 5 3 mmoles) in CH2C12 (3 ml) was heated at 80’ for 5 h. The crude oil was chromatographed on SiO2 (3% H2<>) and eluted with ether, ether-ethylacetate (1:1) and ethyl acetate: % EtOH to give 1.0 g of 3 (82%). The oil crystallized on standing, M.P. (ether) 138-40“.

NMR δ (ppm, CDClj) 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 ic SiO (3% H O) and eluted with Et O: EtOAc (1:1) followed by 10 2 2 2 EtOAc: 10% EtOH to give 0.18 g of 4 (58%). NMR δ (ppm, CDClj), 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). -. 131 0 5 9 6 A mixture of 4_ (50 mg, 0.112 mmole) , NaHCO^ (9.125 mg) 5 and 30% Pd/celite (50 mg) in THF (5 ml), Et2O <2.5 ml) and water (2.5 ml) was hydrogenated at an initial pressure of 40 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 cm'1 (-COO~). 132 5059 Example 33' (1'R.5R,6r) and (l'S,5S,6s) 6-(1'-Hydroxy-1'-ethyl)-2-methylpenem-3carboxylic Acid (isomer D) (illustrates most preferred process of introducing 6-substltutent in mid-synthesis A. Preparation of 4-Tritylthio-2-azetidinone Intermediates 1. 1-(Trimethylsilyl)-4-tritylthio-2-azetidinone 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, ό (ppm, CDC13): 7.32 (15H, m, aromatics), 4.22 (IH, dd, H-4), 15 2.67 (IH, dd, J = 4.1, J = 16, H-3), 2.22 (IH, dd, J = 2.2.

J = 16, H-3), 0.3 (9H, s, CH3). 133 2· 1— (t-Butyldimethylsilyl)-4-tritylthio-2-azetidinone SC03 £ι J-L. ch3 '''Si—CH, I 3 c(ch3)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 mmole's) 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(89¾) of the title compound as a white solid, m.p. 113-4°. δ (ppm, CDC13): 7.45 (15H, m, aromatics), 4.2 (IH, dd, H-4), 2.63 (IH, dd, J = 4, J = 16, H-3), 2.13 (IH, dd, J = 2, J = 16, H-3), 1.0 (9H, s, t-Bu), 0.35 (6H, s. Me). 15 V 1735 cm 1 c=o . Anal, calc'd for C.H NOSSi: C, 2o 33 73.15,- H, 7.24 N, 3.05; S, 6. 97%. Found: C, 73.27; H, 7.32; N, 2.97,- S 6.94%. 134 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 suspension of sodium hydride (200 mg of commercial. 504, 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, NCH2O and H-4), 3.22 (3H, s, CH}) , 2.76 (2H, m, H-3). 4. 1-(Methoxyethoxymethyl)-4-tritylthio-2-azetidinone To a suspension of tetrabutylammonium bromide (322 mg, mmole) and potassium hydroxide (85%, 70 mg, 1.1 mmole) in dichloromethane (10 ml, cooled to 5” was added with vigorous stirring 4-tritylthio-2azetidinone (345 mg, 1 mmole) and methoxyethoxymethyl chloride (187 mg, 1.5 mmole). The mixture was stirred at room temperature for 2 h, the 135 50598 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 cel eluting with ether (5%)-dichlororaethane gave the title compound (206 mg, 48%) as an oil. δ (ppm, CDC13>: 7.30 (15H, m, aromatics), 4.57 (2H, AB quartet, N-CH20), 4.46 (IH, dd, H-4), 3.50 (4H, s, OCH^CH^) , 3.30 (3H, s, CH3) , 2.75 (2H, m, H-3) . . 1-(21-Tetrahydropyranyl)-4-tritylthio-2-azetidinone /SC^3 X. - r/c*3 n-Butyl lithium (1.6M, 1.6 ml, 2.56 nmoles) was added dropwise to a solution of 4-tritylthio-2-azeti— dinone (863 mg, 2.5 mmoles) in THF maintained at -78°.

After stirring for 15 min, 2-chlorotetrahydropyran (560 mg, 4.7 mmoles) was added and the reaction mixture was allowed to come to room temperature in 1.5 h. The reaction solution was diluted with ethylacetate, washed with brine, dried and concentrated to leave an oil (635 mg,. Column chromatography on silica gel eluting with dichloromethane-ether gave a mixture of the isomeric title compounds contaminated with a little starting material, δ (ppm, CDC13>: 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). 136 5059 3. Preparation of 3-(l*-Hydroxy-11 -ethyl)-l-methoxymethyl-lt-tritylthio-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 iranol). After 30 min a solution of l-methoxymethyl-4-tritylthio-2-azetidinone (491 mg, 1.42 mmol) in THF (6 ml) was added dropwise and the solution was stirred for 15 min. Acetaldehyde (3.0 ml) was added dropwise, followed, after 20 min, by water (30 ml). The mixture was acidified to pH 3 with 2% HCl and extracted with ethyl acetate (5 x 20 ml). The combined organic phases were washed with brine, dried and concentrated to leave an oi which crystallized upon trituration with ether: 440 mg, 80%, mp 188.5-9°C; ’ffinr (CDCly δ: 7.3- (15H, m, aromatics), 4.37 (2H, ABq, N-CH^O), 4.32 (IH, d, J=2, H-4), 3.17 (3H, s, OCHg), 3.32-2. 70 (2H, ra, H-3 and H-5), and 1.12 ppm (3H, d, J=7, CH,); Anal, calcd for C,cH,,NOS: 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 iranol) 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 iranol) and diisopropyl amine 137 50586 (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 organi 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 ch· >matography 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 (CH_C1_) V : 3600 (OH), 1760 cm”1 (C=0); ’ftair (CDC1,) δ;6.9-7.5 (15H, m, aromatics), 4.2 (2H, center of ABq, 0=11.5, CH^-O-CH^), 4.28 (lH, d, J=2.0, 4-H), 3.65 (IH, center of a broad sextet, H-l'), 3.3 (IH, dd, J3 4 trans=2-5' J3,i'=5·5' h3> ' 3·15 <3H> s' 1·55 (IH, broad s, OH-1'), 1.05 (3H, d, J=6.5, H-2'); Anal, calcd for C,,H._NO,S: C 72.02, H 6.28, N 3.23, S 7.39; found: C 71.77, H 6.36, 27 3 N 3.15, S 7.43%. 138 50586 C. Preparation of trans 3-Acetyl-l-methoxymethyl-4-tritylthio-2-azetidinone . O Lithium diisopropylamide was prepared under a nitrogen 5 atmosphere at -78°C in the usual manner from diisopropylamine (0.34 ml, 2.4 ιηικ,Ί) 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 nmol) in THF (3 ml) was added dropwise and, after stirring at -78°C for 20 min, ethylacetate 10 (0.53 g, 6 mmol) was added in one portion and stirring continued ior 0.75 h at - 78’C. he reaction mixture was diluted with ether and washed with an anmonium 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 15 amounts of ether in benzene. The pertinent fractions were concentrated to give the title material as a colorless oil (0.32 g, 37%); 1Hmr (CDC13) 6:7.7-6.8 (15H, aromatics), 4.85 (IH, d, J=2, H-4), 4.5 (2H, s, N-CH2-0), 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. max 139 D. Preparation of trans 3-Acetyl-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone LDA -—> EtOAc u CH?-. c/-N\s/'EUV(CH3’2 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) IO 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 !Hmr (CDC1,) 6: 8-7.1 (15H, m, aromatics), max 3 4.83 (IH, a, 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, CH.^).

E. Preparation of trans-1-(t-Butyldimethylsilyi)-3-formyl-4-tritylthio-2-azetidinone εφ, To a cooled (-78°C) solution of diisopropylamine (0.34 ml, 2.4 mmol) in tetrahydrofuran (5 ml) was added dropwise, under Nj, a Si(CH3)2 t-Bu 140 50886 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) g 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 (MgSO^), evaporated and crystallized from pentane to give 810 mg (76%) of formate as a white solid mp 132-3eC; ir (CHCl^) 1n V : 1760, 1715 cm”1; ’«mr (CDC1,) δ: 9.0 (IH, d, J=1.25 Hz), 7.30 10 max 3 (15H, m), 4.7 (IH, d, J’l.SHz) and 3.5 ppm (IH, t, J=1.5 Hz).

NOTE; a) diisopropyl am.i.'e was distilled over CaH and stored on KOH b) tetrahydrofuran was distilled over L/A.H. and stored on o molecular sieves 3A c) ethyl formate was stirred at room temperature with K2CO2 ’ then distilled over P^Og d) η-BuLi was titr. ted with IN hydrochloric acid F. Preparation of 1- (t-Butyldimethylsilyl)-j-(1'-hydroxy-11-ethyl)-4-tritylthio-220 azetidinones. (4 isomers). n-Butyllithium (1.6M, 3.4 ml, 5.44 mnol) 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 l-(t25 butyldimethylsilyl,4-trity.lthio-2-azetidinone (2.0 g, 4.4 mmol, in THF (20 ml) was added; after 15 min acetaldehyde (10 ml) was 141 added in one portion: after another 15 min water (100 ml) was added.

The mixture was acidified (pH 5-6) with dilute hydrochloric acid and extracted with ethyl acetate (3 x 30 ml). The organic phases were washed with brine, dried and concentrated to leave an oil which was found to consist of a mixture of four isomers by 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 chro10 matography (Waters, 500) of the above solid and mother-liquors. The relative proportions were: A, 17%; B, 32%; C, .39%; D, 12%. In the above reaction, when ether was substituted for THF and the reaction quenched after 1 min at -78^0, 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 .Wl 31%.

Isomer Λ.- This isomer possesses a cis-stereochemistry at Cj-C^. It is a racemic mixture composed of the (l'S, 3R, 4R) and the (1*R, 3S, 4S) enantiomers. Compounds later derived from compound A are referred to as Isomer A. They consist of an enantiomeric mixture and possess the same configuration at C^, , Cj 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 C3 mp 152-3°C; ’Hmr (CDClj) δ: 8.0-6.8 (15H, m, aromatics), 4.30 (IH, d, J=5.5, H-4), 3.78 (IH, m, H-l'), 3.10 (IH, dd, J=5.5, J=10, H-3,, 1.22 (3H, d, J=6.5, CHj), 0.95 (9H, s, Bu), 0.27 (6H, 2s, CHj). Anal, calcd for: C30H37N°2Si' C 71·52' H 7·40' N 2·7Θ< S 6·36%· found: C 71.28, H 7.41, N 2.48, S 6.19%. 142 50586 Isomer B: This isomer posseses a trans-stereochemistry at c3-c4- Ifc 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^,, C^ and C^ are referred to as Isomer B”; ir (CHC1) V : 1745 cm (£=0); mp 3 IuclA 158-9“C; ’Hmr (CDClj) δ: 7.60-7.10 (15H, m, aromatics), 4.02 (IH, d, J=0.8 H-4), 3.32 (IH, dd, J=3.0, J=0.8, H-3), 3.55-3.15 (IH, m, H-l'), 0.88 (12H, CH3, and t-Bu), 0.16 (6H, S, CHj); Isomer Cs This isomer possesses a trans-stereochemistry at c3-c4· It is a racemate formed of the (l'S,3S,4R) and the (l'R,3R,4S) )0 enantiomers. Compounds with the same configuration at C^,, C3 and C^ are referred to as Isomer C. mp 134-6°C; ’Hmr (CDC13) δ: 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, 3=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=O>. 13 max Isomer D: This isomer possesses a cis-stereochemistry at C^-C^.

It is a racemate composed of the (l'R,3R,4R) and the (l‘S,3S,4S) enantiomers. Compounds with the same configuration at C ,, C3 and are referred to as Isomer D”. mp 171-2’C; Hmr (CDC13) : 7.8020 6.90 (15H, m, aromatics), 4.70 (IH, d, J=4.5, H-4), 3.02 (IH, dd, J=4.5, J=0.5, H-3), 2.39 (IH, dq, J=0.5, J=6.5, H-l'), 1.0 (3H, d, J=6.5, CH3), 0.97 (9H, s, t-Bu), 0.32 (6H, s, CH ). 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%. 143 N\s.ztBu 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 ]q 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%.

OH 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 st-ί rred 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 144 and the organic phase was washed with a IM solution of ammonium chloride (3x5 ml) and then brine and dried over sodium sulfate. Filtration and evaporation gave alcohol, isomer B, which crystallized from warm pentane to yield 1.6 g (65%), mp 160-1’C; ir (CHCl^) 1730 cm ·,. ς IHmr (CDC1,) δ: 7.32 (15H, m), 4.05 (IH, s), 3..4 UH, d, J=3HZ, 3.25J 3 3.55 (IH, m), 1.6 (IH, s), 0.9 (12H, s) and 0.1 ppm (6H, s).

NOTE: a) tetrahydrofuran and ether were distilled over L.A.H. b) methyl lithium was titrated with IN hydrochloric acid c) copper (I) iodide was purified by continuous extraction with anhydrous tetrahydrofuran in a Soxhlet extractor for h, then dried under vacuum in a dessicator (P2°5^ for MethyImagnesium iodide (0.1 ml, 0.1 mmol) was added dropwise to a cooled (0’C) and stirred solution of trans 1-(t-butyldimethylsilyl)-3-formyl-4-tritylthio-2-a2etidinone (25 mg, 0.05 mmol) in THF (2 ml). The solution was stirred 1.5 h at 0’C, poured onto an ammonium chloride solution, acidified with a hydrochloric acid solution (IN) and extracted with ether. Drying and concentration of the organic extracts left an oil consisting of starting material and a small amount of a mixture of the two trans title compounds with isomer B predominating. 145 50586 F, Preparation of (l'S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-trimethylsilyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (isomer C) x A solution of (l'S,3S,4R and l'R,3R,4S) 1-(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 stirred at room tenperature until disappearance of the starting material (15 min). Purification of the reaction mixture by column chromatography (silica gel, gave the desired compound as a white solid (128 mg, 74%) mp 144-46°C. ’Hmr (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-21), 0.27 (6H, s, CHJ, -0.10 <9H, s, -O-SiiCH,),; ir (CHC1_) V : 1736 cm”1 (C=O) . j j J max G. Preparation of (l'S,3R,4R and l'R,3S,4S) l·1(t-Butyldimethylsilyl)-3-(l'-methoxymethoXy ether-11-ethyl)-4-tritylthio-2-azetidinone (isomer A).

Xt-Bu n-Butyllithium (ca 12.5 ml of 1.6M solution in hexane, 20 20 mmol; just enough to obtain a permanent pink coloration) was added dropwise to a solution of (1*S,3R,4R and 1*R,3S,4S) l-(t-Butyl· dimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer A) (10.1 g, 20 mmol) in THF (100 ml) maintained at -78°. 146 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 5 (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»). 1Hmr (CDClj) δ: 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, Ο-CHj), 1.37 (3H, d, J=6.5, CHj), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CHj).

K, Preparation of (1*S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-formyloxy-l1ethyI)-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-bromobenzenesulfonylehloride (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-CHj). 147 I. Preparation of (l'R,3S,4R and l'S,3R,4S) 1'(t-Butyldimethylsllyl)-3-l'-acetoxyl'-ethyl)-4-tritylthio-2-azetidlnone (Isomer B) Ac2° Pyridine OAc A solution of (l'R,3S,4S and l'S 3R 4S) 1-(t-butyldimethylsilyl) -3- (11-hydroxy-1'-ethyl)-4-trity lthio-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 (.T>h m, ff 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 (3H, d, J=6, Cli,) , 0.88 (9H, s, t-butyl), 0.12 (6H, s, CHg); ir (CHC1,) v : 1775, 1740 cm”1 (C=O) max J. Preparation of 1—(t-Butyldimethylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl)-11ethyl)-4-tritylthio-2-azetidinone. (4 isomers) Isomer C n-Butyllithium (8.8 ml of 1.6 M solution in hexane, 14 mmol; just enough to obtain a permanent pink coloration) was 148 50586 added dropwise to a solution of Isomer C of 1-(t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl)-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 118-9°C (ether); 'Hmr (CDCl^) 6: 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.S, J=2, H-l'), 3.10 (IH, dd, J=2, J=1.8, H-3), 1.2 (3fI, d, J=6.5, CH3), 1.0 (9H, s, Bu) and 0.30 ppm (6H, 2s, CH ),- ir (CHCl ) υ .· 1745 cm'1 (C=O); Anal, calcd 3 «ί ΣΠ3Χ ” for C„„H,„N OSiS: 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 l-(t-butyldimethylsilyl)-3-(l'hydroxy-1'-ethyl (-4-tritylthio-2-azetidinone, treated as described above gave pure Isomer fi of l-(t-butyldiraethylsilyl)-3-(l'-paranitrobenzyldioxycarbonyi-1'-ethyl)-4-tritylthio-2-azetidinone as a foam, 95%. ’Hmr (CDC13) 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=S.8, H-3), 1.1 (3H, d, CI^), 0.7 (9H, s; Bu and 0.2 ppm (6H, s, CH ); ir (film) V : 1755, 1740 cm 1 C=O.

ReLX Isomer A The Isomer A” of 1- (t-butyldimethylsilyl-3-(1'-hydroxyl'-ethyl)-4-tritylthio-2-azetidinone, treated as described above gave pure Isomer A of l-(t-butyldimethylsilyl-3-(l'-paranitrobenzyldioxycarbony1-1'-ethyl)-4-tritylthio-2-azetidinone as an oil. 95% *Hmr (CDCl J S: 8.3-6.7 (19H,m, aromatics), 4.95 (2H, ABq, benzyl), 149 4.53 (IH, p, J=7.5, J=7.5, H-l'_, 4.31 (IH, d, J=6, H-4), 3.32 (IH, dd, J=6, J=7.5, H-3), 1.44 (3H, d, J=6.5), 0.95 (9H, s, tBu) and 0.2 ppm (6H, 2s, CH^).

Isomer D Likewise Isomer D of 1-(t-butyldimethylsilyl-3-(1'5 hydroxy-1’-ethyl)-4-tritylthio-2-azetidinone, gave pure Isomer D of 1-(t-butyldimethylsilyl)-3-(1'-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), 1-03 (3H, d, J=6.5, CH^), 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH^ mp 130-2°C. Anal, calcd for C 66.83, H 6.20, N 4.10, S 4.70,- found: C 66.56, H 6.28, N ;.96, S 4.89.

K. Preparation of (l'S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-methane15 sulf ony loxy-l‘-ethyl)-4-tritylthio-2-azetidinone (Isomer C) OH sc3 J_N V \si -X-(CH3)2 t-Bu OMs 3Ϊ(ΟΗ3)2 t-Bu A solution of (1'9,3S,4R.and l'R,3R,4S)-1-(t-butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (2.0 g, 4 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 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 120-22^0,- 'flmr (CDC13) d: 7.13-7.61 150 (15H, m, aromatics), 4.50 (IH, d, J=2, H-4), 3.62 (IH, dq, J=6.5, 2, H-l'), 2.96 (IH, dd, J»2, 2, H-3), 2.84 (3H, s, methanesulfonyl), 1.22 (3H, d, J=6.5, H-2'), 0.99 (9H, s, Si-t-Bu) and 0.30 ppm (6H, s, Si-(CH ) ); ir V (CHCl,): 1746 (C=O), 1343 and 1180 cm1 (SO,).

J x SI£LX J x L. Preparation of (l'R,3S,4R and l'S,3R,4S) l-(t-Butyldimethylsilyl)-3-(l'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) » «SO Λ XSi X A solution of (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethyl]Q silyl)-3-(l-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) (5.03 g, 1C· :nmol), 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 (MgSO^) and evaporated to leave a residue which crystallized as a white solid when triturated in ether (5.40 g, 93%) mp 127-31°C. lHmr (CDClj) δ: 7.20-7.63 (15H, m, aromatics), 4.51 (IH, dq, J=5.0-6.2, H-l·), 4.10 (IH, d, 02.0, H-4), 3.60 (IH, dd, 05.0-2.0, H-3), 2.03 (3H, s, -CH3), 1.01 (3H, d, 06.2, H-2'), 0.90 (9H, s, t-Bu), 0.12 (6H, s, -CH,),· ir (CHCl,) υ ; 1745 cm1 (OO)., J max 151 50386 M. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(l'-p-Bromobenzenesulfonyloxy-l'-ethyl)1-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) A solution of (l’S,3S,4R and l'R,3R,4S) 1-(t-butyldimethyl silyl)-3-(l'-hydroxy-l'-ethyl)-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 nmol) dissolved in THF 10 was added dropwise. The solution was stirred at -78°C for 3 h and then allowed to come to room temperature. Then the solvent was evaporated and the desired product purified by column chromatography (silica gel, CH2C12) (3.36 g, 94.6%) rap 142-44°C; ’Hmr (CDC13) δ: 7.68 (4H, s, benzenefulsonyl), 7.28-7.60 (15H, m, aromatics), 4.59 (IH, d, J=1.8, H-4), 3.68 (lH, 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-21), 1.08 (9H, s, t-Bu), 0.40 and 0.38 (6H, 2S, -CH,); ir (CHC1J V : 1749 cm1 (C=0). 3 max 152 S0586 Tr. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(ll-Methoxymethyl-ll-ethyl)-4-tritylthio-2azetidinone (isomer A).

OCH5OCH3 t-Bu A cold (O’C) HMPA-HgO (116 ml-13 ml) solution of Isomer A of 1-(t-butyldimethylsilyl)-3-(1'-methoxymethy1-11-ethyl)4-tritylthio-2-azetidinone (11 g, 20 mmol) was treated with sodium azide (2.7 g, 42 nunol). 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 (CDClg) δ; 7.10-7. (1SH, m, aromatics), 4.85 (2H, ABq, J=7.4, O-CHg-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 cm1 (C=O). 0. Preparation of (l’S,3S,4R and l’R,3R,4S) 3-(l'4 A cold (dry ice-acetone bath) solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-(l’-hydroxy-l,-ethyl)-4tritylthio-2-azetidinone (5.03 g, 10 mmol) in THF (50 ml, distilled over IAH) was treated dropwise with a 1.6M solution of n-butyl 153 50586 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 (MgSO^) and concentrated to give crude (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldimethyIsilyl)-3-(11-methoxymethyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (5.83 g, 100%) which was deprotected as described below: ]Q A cold (ice bath) solution of the above derivative (5.83 g, 10 mmol) in HMPA-H?O (90 ml-10 ml) was treated with sodium azide (1.365 y, 21 mmol). The cooling bath was removed and the mixture was stirred at room temperature for a 2 h period. It was then poured slowly into ice cold water (900 ml) and stirred for 30 min. The precipi15 tate was collected by filtration and redissolved in methylene chloride.

The solution was washed with water and brine and dried (MgSO^) to give the title coigwimd (3.0 y. 69.3%), mp 172-2.5 (ethyl acetate-hexane); ir (CHClj) Vmax! 3400 (N_H) 3410 1760 011,-1 <c=°b (CDClj) 5.- 7.67-7.12 (15H, m, H aromatics), 4.63 (2H, center of ABq, J=6, O-CHj-O), 4.49 (IH, s, N-H), 4.40 (IH, d, 0>3, H-4), 4,25-3.80 (IH, m, H-l'), 3.35-3.15 and 3.26 (4H, s + m, CH and H-3) and 1.30 ppm (3H, d, J=6, CH ) « 3 154 S0596 P. Preparation of (l‘R,3S,4R and l'S,3R,4S) 3-(1'-Formyloxy-l1-ethyl)-4-tritylthio-2azetidinone (Isomer B) A solution of (l'S,3S,4R and l'R,3R,4S) 3-(l'-p-bromobenzenesulfonyloxy-1'-e thyl)-1-(t-butyldimethylsilyl)-4-tritylthio. 2-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 H^O and extracted with ether. The ethereal extracts were IQ washed with brine, dried (MgSO^) and evaporated. The title compound was obtained as white crystals after purification by column chromatography (silica gel, 5% Ct^CN-CH^Cl^) (2 mg, 4.8%) mp 131-32°C; ’Hmr (CDC13) δ: 8.07 (III, s, CHO), 7.24-7.56 (15H, m, aromatics), .23 (IH, dq, J=6.4, 7, H-l’), 4.38 (IH, dm J=2.4, H-4), 4.25 (IH, s, NH), 3.20 (IH, dd, J'=7, 2.4, H-3), 1.43 (3H, d, J=6.4, H-2'); ir (CHC1 ) V : 3400 (NH) , 1765 (C=O), 1725 cm1 (C=0,. max Q. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l,-Acetoxy-ll-ethyl)-4-tritylthio-2azetidinone (isomer B) Pure derivative (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethylsilyl) -3-(1’-acetoxy-1'-ethyl)-4-tritylthio-2-azetidinone (5.77 g, 10.57 mmol) was dissolved in warm HMPT-water (60 ml, 10 ml). 155 The solution was cooled down at room temperature and NaN3 (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 C^Clj, washed with water (twice) and brine and dried over MgSO . Solvent 4 evaporation left a foam which crystallized out from ether-petroleum ether (4.90 g, 96.5%, mp 143-44.5°C). ir (CH,C1,)V : 3395 (N-H), 1772, 1738 on1 (C=O). *Hmr (CDC1,) 2. 2 max 3 fi : 7.9-6.8 (15H, m, H aromatic), 5.12 (IH, center of dq, J=6.5, 7.5, H-l'), 4.3.3 (IH, d, J=2.8, H-4), 4.20 (IH, bs, N-H), 3.17 (1H, ddd, J3-l'=7·5' J3-4=2'8' J3-NH=1' H_3)' 2-1 i3H' S' CH3C0)' 1'35 (3H' d' J-6.5, CH3).

R. Preparation of 3-(1'-Hydroxy-1’-ethyl)-4-tritylthio-2-azetidinone. Mixture of four ibunusia/ sci, LDA ^Si(CH3)3 ch3cho A solution prepared at -78°C in drv of lithium diisopropyl amide1(0.74 mmol) was tetrahydrofuran (5 ml) from diisopropyl 20 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-trimethvlsilyl-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 155 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 silicagel (10 g, elution CgHgzEtOAc, 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 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)* hi t-Butyldimetyl silyl derivatives The mixture of alcohols (0.121 g, 0.34 mmol) was treated with t-butyl dimethylchlorosilane (0.117 g, 0.776 mmol) and triethyl amine (0.10 ml, 7.14 mmol) in dry dimethylformamide (1 ml) for 36 h at room temperature. After dilution with ethyl acetate, the solution was washed with saturated ammonium chloride and dried over anhydrous magnesium sulfate. Evaporation gave an oil (0.716 g) which contains 4 components by HPLC. a = 3,7%; b = 60.6%; c = 31.1%; <3 = 4.6% (the identity of each one has not been established)* NOTE: '.Butyl lithium and lithium hexamethyl disilazane wexe ineffective z0rder of increasing polarity ’Acetylation of the product derived from l-t-butyldimethylsilyl-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 = 5.21; t; = 41.3%; c 48%; <3 = 4.6% 157 50586 S. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l'-Eenzoxy-l'-ethy1)-4-tritylthio-2azetidinone (Isomer B) A solution of (l'S,3S,4R and l’R,3R,4S) 3-(l'-methanesulfonyloxy-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 and extracted with ethyl acetate. The organic )Q extracts were washed with brine, dried (MgSO^) and evaporated.

The residue, purified by column chromatography (silica gel, S% CH^ CN-CH2C12) gave the title compound as a white solid (108 mg, 23.2%) mp 158°C. ’him (CDCI^) 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 (CHCip V . : 3400 (N-H), 1765 (C-0), 1715 cm-1 (C=0).

DlclX.

T. Preparation of 3—d1 -Paranitrobenzyldioxycarbony 1-1 *-ethyl) -4-tritylthio-2azetidinone (4 isomers) Isomer C a) A solution of Isomer C” of 1-(t-butyldimethylsilyl ) -3- ( 1 1 -parani trobe nzyldioxycarbonyl-1’-ethyl)-4-trity1thio-2-azetidinone (1.3 g) in a mixture of TFA (5 ml), water 158 (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 g water, dried and concentrated to leave an oil. Crystallization from ether gave the pure title compound (902 mg), mp 78-S0°C; 'Hmr (CDCl^J : 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.j); ir (CHCl ) V : 3390 (N-H), 1765 and 1745 (shoulder) (C=O, and 1525 3 max cm-1 (NO2). b) A cold (O’C) HMPT-H2O (90 ml - 19 ml) solution of Isomer C of l-(t-butyidimethylsilyl)-3-(l'-paranitrobenzyldioxycarboxyl-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 vater (I. 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 comoound 4 ι 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'-paranitrobenzyldioxycarbony1l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the Isomer C; 92%; mp 155.5-6’C (ether); 1Hmr (CDCl^) 6: 8.25-6.80 (19H, m, aromatics), 5.20 (2H, s, benzyl), 4.95 (IH, m, H-l'), 4.35 (IH, cl, 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 (CHCl,) V i 3480, 3390 (N-H), 1772, 1750 (C=O), and 1525 cm1 max (NO,). Anal, calcd for C,,H,oN,0,S: C 67.59, H 4.96, N 4.93, —— J2 2o 2 O S 5.64; found: C 67.48, H 4.98, N 4.92, S 5.67. 159 Isomer A Isomer A of 3-(l'-paranitrobenzyldioxycarbonyll'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the Isomer C; mp 205-6°C. ’Hmr (CDClg) <5: 8.2-6.7 5 (19H, m, aromatics), 5.22 (2H, ABq, benzyl), 5.57-4.85 (IH, m, H-l'), 4.65 (IH, N-H), 4.50 (IH, d, J=6.5, H-4), 3.65 (IH, dd, J=6.5, 12, JN-H=1' H_3> 1-52 ΡΡΠ1 <3H' d' J=7'5)· Isomer D Isomer D of 3-(l'-paranitrobenzyldioxycarbonyΙΙΟ l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for Isomer C”; ’Hmr (CDClg) 5; 8.15-6.70 (19H, m, 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), ).42 (IH, J=5.5, 3, H-3 and 1.5 ppm (3H, d, J=6.5, CHg). (J value for H-3 taken after DgO- exchange).

U. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l'-methanesulfonyloxy-l1-ethy1)-4tritylthio-2-azetidinone (isomer B) A solution of (l'R,3S,4R and l'S,3R,4S) 1-(t-butyldimethyl 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% HgO-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. lHmr (CDClg) δ: 7.20-7.62 (15H, m, aromatics), 4.97 (IH, dq, J=6.4, 6.1, H-l'), 4.56 (IB, d, 1=-2.8, H-4), 4.22 (IH, m, N-H), 3.27 (IH, dd, 1=6.1, 2.8, H-3), 3.0 (3H, s, -CHg), 1.63 (3H, d, 1=6.4, H-2'); on ir (nujol) V : 3195 (n-H), 1768 cm 1 (C=O). 160 V. Preparation of (l'S,3S,4R and 1'R,3R,4S)3-(1'-methanesulfonyloxy-1'-ethyl)-4-trltylthio2-azetidinone, (Isomer C) A solution of (l'S,3S,4R and l'R,3R,4S)1-(t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer C) (2.85 g; 4.9 mmol) in 10» aqueous HMPA (25 ml) was treated with sodium azide (0.65 g, 10 mmol) and stirred at 25°C for 0.5 h. By diluting the solution with water (250 mi), the reaction product 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%; ’iJn. (CDClj) 4: 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 V : 3395 (N-H), 1768 cm1 (C=0); max Anal, calcd for C. Jk.NO.6. C 64.22, H 5.39, N 3.00; found: C 63.93, H 5.39, - 2b 2b 4 N 3.24».

W. Preparation of (l'S,35,4R and l'R,3R,4S) 3-(l'-p-Bromobenzenesulfonyloxy-l'-ethyl)20 4-trltylthio-2-azetidinone (Isomer C) A solution of (l’S,3S,4R and l'R,3R,4S) 3-(l'-p-bromobenzenesulfoxyloxy-1'-ethyl)-1-(t-butyldimethylsilyl)-4-tritylthio-2azetidinone (Isomer C) (1.42 g, 2 mmol) and sodium benzoate (0.865 g, 161 mmol) in 10% H^O-HMPA (40 ml) was stirred at room temperature for 1 h. Then the solution was diluted with H^O (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 (CDCip fi: 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 (CHCI,) V : 3400 cm”1 (N-H), '1770 cm 1 3 max (c=o).

X, Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(l'-Hydroxy-l'-ethyl)-4-tritylthio-2~ azetidinone (Isomer B) To a warm solution of (l'S,3S,4R and l'R,3R,4S) 3-(l’-pbromobenzenesulfonyloxy-11-ethyl)-1-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) in HMPA (5 ml) was added dropwise l_nl of H^O. The reaction mixture was kept at 90’C for 20 h, then diluted with ether and washed 4 times with brine. The organic solution was dried (MgSO^), evaporated and the crude title compound purified by column chromatography (silica gel, 15% CH^CN-CH^C^).

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. 162 B0598 Υ. Preparation of 3-(1'-Hydroxy-1'-ethyl)-4-trltylthio-2-azetidinone Both isomers, (l'S,3S,4R and l'R,3R,4S) 3-(l'-hydroxy5 1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) and (l'R,3S,4R and 11S,3R,4S) 3-(1'-hydroxy-l'-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, 2 mmol) and sodium benzoate (0.865 g, 6 mmol) in 10% HjO - DMF (40 ml) was stirred at room temperature for 18 h. Then the reaction mixture was diluted with HjO and extracted with ether. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude title compound was crystallized from cold ether (0.47 g, 61%) mp 134-35OC. ’nmr (CDCl^) 6: 7.12-7.56 (15H, m, aromatics), 4.48 (IH, S, N-H), 4.28 (1H, d, 0=2.8, H-4), 2.94 (IH, dq, J=6.5, 6.2, H-l'), 3.06 (IH, dd, 0=6.2, 2.8, H-3), 2.18 (IH, s, -OH), 1.30 (3H, d, 0=6.5, H-2');ir (CHCl,) V : 3400 (n-H), 1760 cm”1 (C=0). max Similarly (l'R,35,4R and 1*S,3R,4S) 1—(t-butyldimethylsilyl)-320 (1*-hydroxy-1 '-ethyl)-4-tritylthio-2-azetidinone (Isomer B) mp 190-92’C. ’Hmr (CDC^J δ: 7.10-7.55 (15H, m, aromatics), 4.45 (IH, d, 0=2.5, H-4), 4.28 (IH, s, NH), 4.10 (IH, dq, 0=6.4, .3, H-l'), 3.08 (IH, dd, 0=5.3, 2.5, H-3), 1.50 (IH, s, -OH), 1.30 (3H, d, 0=6.4, H-2');ir (CHCl ) V : 3400 (N-H), 1760 cm1 j max (C=O) 163 Z. Preparation of (l'S,3R,4R and l'R,3S,4S) 3-(l’-Methoxyniethyl-l'-ethyl)-l-(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinones (Isomer A) A mixture of Isomer A of 3-(I'-methoxymethyl-l’-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 0 for 1 h in a Dean and Stark apparatus filled with 3A molecular sieves.

The solution was cooled in ice and triethylamine (0.24 ml, 1.7 mmol) was added dropwise. The mixture was stirred for 1 h, washed with diluted hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give tne title compound as a foam (10.5 g, 94%). ’Hmr (CDClj) 5: 8.25-6.84 (19H, m, aromatics), 5.24 (2H, s, benzyls), 4.674.83 (3H, m, υ-ΓΗ 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 (K3r) v : 3360 (OH', 1770 (C=O of β-lactam), 1735 (C=O of ester) and 1605 cm 1 max (aromatics).

AA. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(1'-Ϊ4ethoxyniethoxyri'-ethyl)-1-(paranitro2q benzyl 2-hydroxy-2''-acetate)-4-tritylthio-2-azetidinone (Isomer C) OCH.OCH, A—rSTr CHO co2pnb OCH2OCH3 STr oh 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-1125 154 ethyl)-4-tritylthio-2-azetidinone (3.0 g, 6.93 mmol) and the mixture uas refluxed for 2 h more. The mixture was cooled to room temperature, triethyl amine (70 mg, 97 Ul, 0.69 mmol) was added and it was stirred for 2 h. The reaction mixture was diluted with ether, washed with 1% aqueous HCI, water, 1% aqueous NaHCOy water and brine, dried (MgSO4> and concentrated to give the title compound (4.60 g, 100%); ir (CHCl^) V :3530-3100 (0-H), 1765, 1750 (C=0) and 1525 cm1 (NO.); lHmr (CDCl ) max 2 4 δ: 8.22, 8.18 (2H, 2d, J-=8, Hm aromatics), 7.67-7.0 (17H, m, H-aromatics), .3 (2H, bs, CHj-PNB), 5.30-5.02 (ra, 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-CHj-O), 4.1-3.67 (IH, ra, H-1‘), 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 1S.3R.45) 3-(1‘-Acetoxy-1’-ethyl)-1-(paranitrobenzyl15 2-hyproxy-2-acetate)4-tritylthio-2-azetidinone CO.PNB Isomer B A solution of hydrated p-nitrobenzyl glyoxylate (triturated with ether) (1.82 g, 30 mol) was refluxed in benzene o through a Dear. Stark condenser filled with 3A molecular sieves for 2 h. To that kss 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 b more. The solution was cooled at room temperature and triethyl amine (0.35 ml, 2.5 mmol was added . It was tnen stirred for 2 h; the reaction progression being followed by tic. ’Solvent evaporation afforded a white 165 50596 foam in quantitative yield (100%, mixture of epimers) ‘Alternatively the solution can be acid and base washed. ir (CH3C12) vmaa: 3520 (OH), 1775, 1745 cm-1 (C=O); JHmr [CDC1 ) fi: 8.2, 8.18 (2H, 2d, 7=8, Ho aromatic). 7.80-6.90 (17H, m, H-aromatic), 5.28, 5.17 (2H, 24, CH^-PNB, 4.89 (0.67H, fi, .3=7.2, CHO), 4.80 (center of m, H-l'), 4.38 (0.33 H, 2d, 7=8.8, CHO), 4.22 (D.33H, d, J43=2.5, H-4). 4.09 (0.67H, <3, J4_3= 2.1, H-4), 3.65 (D.67H. dd, 7^,=5.8, H3} ' 3‘47 (°-33H' dd, J3 ,=5.5 J3 4=2.5. H-3), 3.33 (0.3311, d, 7=8.8, OH), 3.23 (0.67H, d, 7=7.5, OH), 1.38, 1.86 (3H, 2s, CH^CD), 1.10, 1.06 (3H, 2d, 7=5.8, 6.3, C«3) CC. Preparation of 3-(11-paranitrobenzyldioxycarbonyl-11-ethyl)-1-(paranitrobenzyl 2-hydroxy-2''-acetate) 4-tritylthio-2-azetidinone (4 isomers).

OCO.PNB I 2 SC<^ 3— N. OH ο γ co2pnb 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 0 Stark apparatus filled with 3A molecular sieves. The cooled solution was washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound (2.1 g) as an epimeric mixture at carbon-2. Purification was effected by chromatography over silica gel. Alternatively the title compound could be prepared by using a catalytic amount of triethyl 166 S0596 amine. Less polar epimer at 2: lHmr (CDClj) 6: 8.25-6.80 (23H, m, aromatics), 5.30 and 3.12 (4H, 2s, benzyls), 4.65 (IH, d, J=9, H-2), 4.45 (IH, d, J=2.5, H-4), 4.45-4.10 (IH, ra, H-l'), 3.50 (IH, d, J=9, 2-OH), 3.28 (IH, dd, J=2.5, J=2.5, H-3) and 1.23 ppm (3H, d, J=6.5, CHj); ir (CHClj) 3530 to 3200 (D-H), 1765, 1750 (C=O, and 1525 cm1 (NOj). More polar isomer at C-2”: ’Hmr (CDClj) 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, 0=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, CHj); ir (CHCip 3520 to 3200 (O-H), 1755 (C=O) and 1525 cm1 (NOj).

Isomer B A mixture of hydrated paranitrobenzylglyoxylate (1.74 g, 7.66 mmol) and (l'R,3S,4R and l'S,3R,4S) 3-(1'-paranitrobenzyldioxycarbony 1-1' -ethyl) -4-trity lthio-2-azetidinone (3.63 g, 6.38 mmol) was refluxed in toluene (70 ml) on a Dean Stark condenser filled with σ 3A molecular sieves for 3h. The solution was cooled down to room temperature and triethvl 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 NaHCOj, 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 (CHCl.) V ; 3500 (O-H), 1772, -, -r*^ .... ,,, . 3 max 1750 (C=0) 1525 cm1 (N0?); ’ffinr (CDClj) 6:8.30-8.0 and 7.65-6.80, (23H, ro, 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.) V 3480 (O-H) -*-*- 3 max: 1772, 1750 (C=O) and 1525 cm_1(N02); ’Hmr (CDClj) δ: 8.35-6.90 (23H, ra, aromatics), 5.15 (4H, benzyls), 4.72 (IH, d, J=7.5, H-20),4.90167 4.50 (IH, m, 7=6.5, 6.5, H-l*), 4.10 (IH, d, 7=2, H-4), 3.68 (IH, c 7=2, 6.5, H-3), 3.28 (IH, d, 7=6.5, O-H) and 1.15 ppm (3H, d, J=6.E ch3) .

Isomer A The Isomer A” of 3-(l'-paranitrobenzyldioxycarbonyll'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of Isomer A” of S-d'-paranitrobenzyldioxycarbonyl-l'-ethyD-l(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinones. 'Hmr (CDC13) 5: 8.3-6.7 (23H, m, aromatics), 5.17 (2H, benzyls), )0 5.0 (IH, m, H-l'), 4.9 and 4.8 (IH, 2d, 7=6, H-4, two epimers), 4.32 and 3.96 (IH, 2s, H-2”, two epimers) 3.68 ilfl, dd, 7=6, 6, H-3( and 1.47 ppm (3H, 2d, J=6.5, CHy two epimers).

Isomer D The “Isomer D of 3-(l'-paranitrobenzyldioxycarbonyl15 1'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of Isomer D of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinones. 'Hmr (CDC13) 5: 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, ra, 0-H), 1.37 and 1.30 ppm (3H, 2d, CH3).

DD. Preparation of (l’S,3S,4R and 1’R,3R,4S)3-(l'-Methanesulfonyloxy-l1-ethyl)-1-(paranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinone (isomer C) (epimers at C2).

OMs sap^ OMs XL JT sc3 OH CC 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 168 (1* S,3S,4R and 1' R, 3R, 4S) 3- (1'-methanesulfonyloxy-l'-ethyl)-4-tritylthio2-azetidinone (16.62 g, 35.5 mmol) and the reflux maintained for an additional 0.5 h. Then the reaction mixture was cooled to room temperature, treated with triethylamine (0.5 ml; 3.5 mmol) and stirred for 3 h in order to complete the reaction. Evaporation of the solvent left a white foam which was used as such in the next step. ,*Hmr (CDCl^) δ: 8.12 (2H, d, J=9, Hm aromatic), 7.28 (17H, part of d,Ho aromatic, trityl), 5.28 (2H, s, -CH^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, 0=6 Hz, H-2');ir M :3520 (O-H), 1775 (C=O) and 1765 cm-1 (C=0). 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-azetidinone (Isomer A) Pyridine (1.1 ml, 14.2 mmol) was added dropwise to a solution of Isomer A of 3-(1’-methoxymethyl-1'-ethyl)-1-(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 henzene and the solution treated with activated charcoal, filtered and concentrated to leave to title compound as an oil (6.5 g, 90%), ’Hmr (CDCl^) δ: 6.65-8.35 (19H, m, aromatics), 5.24 (2H, s, benzyl), 3.43 (3H, s, OCH^) and 1.42 ppm (3H, d, J=6, CHj). 169 FF. Preparation of (1'5,3S,4R and l'R,3R,4S) 3—fl’— ethoxymethyloxy-l'~ethyl)-l-(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) j-d'-methoxymethyloxy-l'-ethyl)1-oaranitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinone (4.25 g, 6.62 mmol) was treated dropwise with pyridine <0.696 ml, 6.61 mmol) and thionyl chloride (0.530 ml, 8.61 mmol). The mixture was stirred for 30 min at -15°C. The precipitate was. collected ny 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. Removal of charcoal on a Celite pad and subsequent benzene evaporation afforded the title compound 5 ¢4.86 g, 100%); ir (CHC1,) V .- 1770 (C=0) and 1525 cro_1 (NO,); ’Hmr max 2 (CDC13) 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 in, O-CH2-O, H-l'), 3.5-2.8 (m, H-3), 3.12, 3.08 (3H, 2s, O-CH^, and 1.30-0.96 ppm (3H, m, CH^). 170 50586 GG. Preparation of (l'R, 3S,4R and l'S,3R,4S) 3-(l‘-Acetoxy-l'-ethyl)-l-(paranitrobenzyl 2-chloro-2acetate)-4-tritylthio-2-azetldinc.ne Isomer B A THF (distilled over LAH) solution of (l.’R,3S,4R and l'S, 3R,4S) 3-(1 '-acetoxy-1 '-ethyl)-l-(paranitrobf.':Zyl-2-hyil>;oxy-2--.»cetate) 4-tritylthio-2-azetidinone (from 10.88 g of Ν-H) was treated at -1.5°C (ice-methanol bath) under nitrogen atmosphere with pyridine (2.19 g, 2.24 ml, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol). The mixture was stirred for 20 min at -15®. The salt was filtered off and washed with benzene. Solvent (THF + benzene) evaporation afforded a residue which was taken up in benzene (warm) and treated with charcoal. The suspension was filtered through a celite pad and solvent evaporation left a foam; ir (CH.C1.) V : 1780, 1740 cm1 (C=O) lHmr (CDCl δ: 2 max 3 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, CH^PNB, CHCl), 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, C^CO), 1.12 20 1.07 (3H, J=6.5, CH3). 171 HH. 3- (1*- faranitrobenzyldioxycarbonyl-1'-ethyl)-l-(paranitrobenzyl 2''-chloro2‘'-acetate)-4-tritylthio-2-azetidinones (mixture of epimers at C2).

Isomer C“ g Pyridine (58 mg, 0.73 mmol) was added dropwise to a solution of Isomer C of 3-(l’-paxanitrobenzy)dioxycarhonyl-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 (CDClj) δ: 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 (CHClj) V ; 1780, 1750 (C=O) and 1525 cm1 (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 (CDClj) 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 -5 and 4.S7 (IH, 2s, H-2), 4.36 and 4.31 (IH, 2d, 3=2.5, H-4), 3.63 (IH, m, 3=2.5, J=6.5, H-3), 1.25 and 1.18 ppm (JH, 2d, J=6.5, CHj); ir (CHC1 ) : 1780, 1750 (C=O), and 1525 cm1 (NO ). max - 2 172 80596 Isomer A Isomer A of 3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)1'· (paranitrobenzyl 2-chloro-2-acetate)-4-tritylthio-2-azetidinones ('mixture of C-2” epimers,. ’Hmr (CDClg) fi: 8.30-6.80 (23H, m, aromatics), . 5.45-4.80 (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, CHg).

Isomer D Isomer D of 3-(l-paraniti nbenzyldioxycarbony1-1'-ethyl10 1’-(paranitrobenzyl 2-chloro-2-acetate)-4-tritylthio-'2-azetidinones (mixture of C-2 epimers,. ’Hmr (CDClg) (5: 8.30-6.70 (23H, m, aromatics), 5.32-5.10 (4H, m, benzyls), 5.48 and 5.30 ll :. 2s, R 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, CHg); ir CHClg) 1780, 1750 (C=O) and 1525 cm 1 (NOg) II. Preparation of (l'S,3S,4R and l'R,3R,4S)3-(I'-Methanesulfonyloxy-l'-ethyl)-!-(paranitrobenzyl 2-chloro-2-acetate(-4-tritylthio-2-azetidinone (isomer C) (epimers at C2).

To a cold solution (5°C) of (l‘S,3S,4R and l'R,3R,4S)3(11-methanesulfonyloxy-1'-ethyl)-1-(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 (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. 173 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. *Ηπιτ (CDCl^) 6: 8.18 (2H, d, J=9, Hm aromatic), 7.72 (17H, m, part of d. Ho aromatic, trityl), 5.57 and 5.12 (IH, s, H-2), 5.28 (2H, s, -CH PNB), 4.73 (IH, 2d, H-4), 3.21 (IH, 2dq, H-3), 2.78 (3H, 2s, mesylate and 1.21 ppm (3H, 2d, H-6H2; H-2'),· ir 1779 cm’1 (C=O) CJ. rrecaration of (l'S,3R,4R and l'R,3S,4S) 3-(1 '-Methoxymethoxy-1'-ethyD-l-(paranitro10 benzyl 2''-triphenylphosphoranylidene-2''-acetate)-4-tritylthio-2-azetidinone (Isomer A) A mixture of Isomer A of 3-(l'-methoxymothoxy-l'-ethyl)-1(parani trobenzy1-2-chloro-2-acetate)-4-tritylthio-2-azetidinone 15 (6.6 g, 10 mmol), triphenylphosphine (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% HCI), 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 (X3r) \) : 1750 (C=O) and 1660-1650 cm 1 (C=C, aromatics). max 174 50586 KK. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(l'-Methoxymethyloxy-l'-ethyl)-l-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone (Isomer C).

A dioxane (X00 ml, distilled over LAH) solution of (1'S, ,4R and l'R,3R,4S) 3-(1'-methoxyraethyloxy-1'-ethy1)-i-(paranitrobenzyl2-chlcro-2-acetate)-4-tritylthio-2-azetidinone (4.8 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 HCl, water, 10% aqueous NaHCO^, water and brine and dried (MgSO^). The solution was concentrated and the residue filtered ttrough a silica gel (65 g) column (5%, 10% and 20% ether-benzene) to give the title compound (2.8 g, 48%). ir (CHC1,) V : 1795 (C=O), 1620 and 1605 (phosphorane) max and 1515 cm 1 (NO2).

LL. (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) OAc ___x_> Λ 2,6-lutidine ] I (X-Ν'Ύ*ρΦ3 CO,PNB 2 A dioxane (100 ml, freshly distilled over LAH, solution of crude (l'R,3S,4R and l'S,3R,4S) 3-(1*-acetoxy-1'-ethyl,-1-(paranitro375 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 in methylene chloride. The resulting solution was successively washed with diluted HCl, H^O, diluted aqueous NaHCO^t^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 (CH Cl ) \) : 1750 (C=O) and 1620, 1610 cm1 (phosphorane). 2 MM. 3-(I'-Paranitrobenzyldioxycarbonyl-l'-ethyl)-!-(paranitrobenzyl-2triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone.

ISOMER B A mixture of (l'R,3S,4R and l'S,3R,4S) 3-(l'-paranitro15 benzyl-dioxycarbonyl-1'-ethyl)-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 176 5059 residue which was passed through a silica gel (10 times its weight, column (10% ether-benzene, ether, and ethyl acetate). The title compound was obtained as a crystalline solid (3.1 g, 49%), mp 189-190° (ether); ir (CHClj) νπ|3χ: 1750 (C=O), 1620, 1605 (phosphorane; und 1522 cm 1 (no2).

ISOMER C Isomer C of B-d'-paranitrobenzyldioxycarbonyl-l'-ethyl)1- (paranitrobenzyl-2-triphenylphosphoranylidene-2-acetate)-4-tritylthio2- azetidinone was prepared as described above for isomer B. ir (CHCl^, V : 1750 (C=O), 1610, 1620 (phosphorane) and 1520 cm 1 (NO ) ) 'Hmr ΓΠ3Χ 2 (CDClj) fi: 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-nitrobenzyldioxycarbonyl15 1'-ethyl)-1-(p-nitrobenzyl 2-chloro-2“-aoetate)-4-tritylthio-2-azetidinone (4.598 g, 4.45 mmol; purity 77%, nixture of epimers at C-2), triphenylphosphine (1.425 g, 5.44 nmol; Aldrich) and 2,6-lutidine (0.63 ml, 580 mg, 5.40 mmol,- Anachemia) in dioxane (65 ml; distilled from LAH) was heated at gentle reflux under Nj for 41 h, monitoring the reaction by tic (benzene :ether=3:1). The dark reaction mixture was cooled, diluted with EtOAc and washed successively with 0.1 NHC1, water, 2% NaHC03 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 (CDC13) fi: 1.08 (d, J=6Hz, l'-CH^); ir (neat) V : 1745 cm“l (s, C=O). max 177 NM. Preparation of (l’S,3S,4R and 11R,3R,4S)3- (1'- Methanesulfonyloxy-11-ethyl)-1-(pananitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone (isomer C) A solution of (l'S,3S,4R and l‘R,3R,4S)3-(l'-methanesulfonyloxy-1'-ethyl)-1- (paranitrobenzyl 2-chlon-2-acetate)-4-tritylt'nio-2~ azetid-inone (24.7 g, 35.5 mmol), triphenylphor-'iiine (11.2 g, 42.7 mmol) and 2.6-lutidine (4.2 g, 39.1 mmol) in dry dioxane (350 ml) was refluxed under nitrogen for 19 h. The solvent was evaporated and the crude product redissolved in ethyl acetate and washed successively with dilute HCl, NaHCOj and brine. Purification was completed by chromatography on a silica gel column (8.5 x 12 cm). Elution with 10% ether-dichloromethane (1.5 £j and then ether (1.5 £) gave the purified phosphorane; 12.36 g (40%). 'Hmr (COClj) δ: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir 1749 and 1620 cm”1 (C=O) 00. Preparation of (I'R,3S,4R and l'S,3R,4S) 3-(l'-Hydroxy-l'-ethyl)-1-(paranitrobenzyl2-triphenylphosphoranylidene-2-acetate) 4-tritylthio-2-azetidinone 20 (Isomer B).

A solution of phosphorane (l’R,3S,4R and l'S,3R,4s) 3(1 -acetoxy-l’-ethyl)-l-(paranitrobenzyl 2-triphenylphosphoranylidene-2 -acetate)-4-tritylthio-2-azetidinone (4.43 g, 5.00 mmol) 178 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, HjO, aqueous NaHCO3, H^O 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.Cl.) V : 1745 (C=O, and 1620 cm”1 (phosphorane) 2 ]J)dX *Heating the mixture increased the reaction rati'.

PP. Preparation of (l‘S,3R,4R and l'R,3S,4S) Silver 3-(11-incthoxymetl;; 1-1’-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone-4thiolate (Isomer A) Silver 3-(1'-methoxymethyl-1'-ethyl)-1-(paranitrobenzyl 15 -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 Vmax! 1745 e’’’1 (C=0)179 50S96 Preparation of l'S,3S,4R and l'R,3R,4S) Silver 3- (1*-methoxymethyloxy-1’-ethyl)-1(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate) -2-azetidinone 4-thiolate (Isomer C) (l'S,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1’-ethyl)-1-(paranitrobenzyl 2-triphenylphosphor nylidene-2-acetate)-4-tritylthio-2azetidinor,. (88/ 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-) V : 1745 (C=O), 1605 (phosphorane) and 1520 3 UlcLX cm 1 (NOg).

Prenaration of Silver 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzvl 2-triphenylPhosphoranylidene-2-acetate)-2-azetidinone-4-thiolate. (l'R,3S,4R and l'S,3R,4S) 3-(l’-paranitrobenzylcarbonyldioxy-1'-ethyl)-1-(paranitrobenzy1-2-triphenylphosphoranylidene-2acetate) -4-trithio-2-azetidinone (1.02 g, 1 mmol) was first dissolved in 180 CH2C12 (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) V : 1745 (C=O), 1600 (phosphorane) and 1517 cm 1 (NO ). max a Isomer C Silver 3-(1'-paranitroben, ldioxyearbonyl-l’-ethyl) -1- (paranitrobenzyl 2“-triphenylphosphoranyiidene-2-· triphenylphosphoranylidene-2-acetate)-2-azetidinone-4-thioli.ir.. Isomer C”, was prepared as described above for the Isomer B) ix >nujol) V : 1745 (C-O) arid ltlrl X 1600 cm 1 (phosphorane).

Isomer D A solution of Isomer D of 3-(l'-p-nitrobenzylcarbonyldioxy-1'-ethyl)-1-(p-nitrobenzyl 2-triphenyiphosphojaaylidene-2acetate)-4-tritylthio-2-azetidinone (145 mgr 0.142 mmol) was prepared by first dissolving it in CH2C12 (5 ml), removing the CH2C12 at 55’60’ and adding hot MeOH (4 ml). To the above solution was added a hot solution of AgNO^ in MeOH (0.15 M, 1.14 ml, 0.17 mmol, 1.2 eq), followed by pyridine (14 Jll, 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 O’. 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 181 59 6 SS. Preparation Of (l'R,3S,4R and l’S,3R,4S) Silver 3-(I'-hydroxy-l'-etliyl)-l-)paranitrobenzy1-2-triphenylphosphoranylidene-2-acetate)-2-azetidinone-4thiolate (Isomer B) OH AgNO, co2pnb A solution* of (1·Κ,3£,4Η and l'S,3R,4S) 3-(l'nydroxy-1'-ethyl)-1-(paranitrobenzyl-2-triphenylphosphoranylidene-2acetate)-4-tritylth:o-2-azetjdinone (lg, 1.1? mmol) tn MeOH (10 ml), was treated with pyridine (124 μί, 121.3 mg, 1.53 mmol) and at 10°C 10 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) \) : 3500-3400 (0-H), 1752 (C=0) 1595 (phosphorane) and 1525 cm 1 (NO,) max 2 *The crystalline material was first dissolved in ΟΗ,^ΟΙ.,Prenaration of (l‘R,3R,4R and l'S,3S,4S) 4-Acetylthio-3-(1'-p-nitrobenzyldioxycarbonyl20 1'-ethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate) -2azetidinone (Isomer D) oco2pnb ,SAc CH COCl-Pyr -3---> CH2C12 co2pnb To a stirred solution of silver 3-(1'-paranitrobenzyl-dioxycarbonyl- 182 50586 11-ethyl)-1-(p-ni trobenzyl-2-tri phenylphosphoranyli dene2“-acetate)-2-azetidinone-4-thiolate (isomer D) (85 mg, 0.095 mmol) in CH2C12 (5 ml) containing pyridine (30 Pl,» 0.37 mmol; Fisher, was added at 0-5eC CH3COC1 (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 CHjClj. The filtrate and washings were combined, washed successively with brine, diluted HCl, saturated NaHCO3 and then brine, dried (Na2SC>4, and evaporated yielding 75 mg (0.091 mmol, crude yield 95%) of the title compound as a syrup: ’Hmr (CDC1-) 5: 2.33 (s, -SOCOCH.); ir (neat) V : 1750 (β-lactam, ester), J max 1695 (thioester), 1520 and 1350 cm 1 (-NOj).

UU. Preparation of (l'R,5R,6R and l'S,5S,6S) cis p-Nitrobenzyl 2-methy1-6-(I1-p-nitrobenzvldioxycarbonylmethyl-penem-3-carboxylate (Isomer D) A solution of the above acetylthioazetidinone (74 mg, 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:l) 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 CHgCl^-fether: ^Hmr (CDCl^) δ: 1.40 (3H, d, J=6.5 Hz, l'-CH,), 2.38 (3H, s, 2-CH,), 4.07 (IH, dd, J =4Hz, 3 3 j,o Jg 3=9Hz, 6-H), 5.05-5.30-5.34-5.59 (2H, AB type, 3-CO2CH2~Ar), 5.30 (2H, s, l'-OCO -CH„-Ar), 5.1-5.6 (IH, m, l’-H), 5.68 (IH, d, J. =4Hz, ~~2 31 & -H), 7.49-7.64-8.18-8.33 (4H, A2'B2', 1'-aromatic Hs), 7.53-7.68-8.188.33 (4H, A 'B ’, 3-aromatic Hs); ir (neat) V : 1780 (β-lactam), 2 max 1750 (-0C02-), 1710 (ester), 1520 and 1350 cm”1 (-NOj). 183 59 6 W, 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) , H2O (5 ml) , phosphate buffer (1.00 ml, 0.05 molar pH 7.00: Fisher) and 30% 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 separated, washed with ether and lyophilized yielding 12 mg of the title mixture of sodium and potassium salts . as a white powder: ’Hmr (D^O) δ: 1.23 (3H, d, J=6Hz, l'-CH^), 2.27 (3H, s, 2-CH,), 3.85 (IH, dd, =4Hz, J, =9Hz, 6-H), 4.3 (IH, m, l’-H) and /O Ο/ X .65 ppm (IH, d, J, =4Hz, 5-H); ir (Nujol) V : 1755 ( -lactam) and 5,0 Z&HX 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) 184 Example 34 (1'5,5Ri6S and l'R,5S,6R) 6-l;-Hydroxy-l'-ethyl)-l;l--methylpenctn-3-cartioxylic Acid (isomer C) OH AA: CO„H Method A: Ό,ΡΝΒ SAC H „OH 9CO2PNB CC^PNB A ^AC Ay* PNB 185 • S Ο 5 9 6 METHOD A 1) (l'S,3S,4R and l'R,3R,4s) 4-Acetylthio-3-(l'-paranitrobenzyldioxycarbonyl-l1 -ethyl)-l- (paranitrobenzyl 2-triphenylphosphoranylidene2”-acetate)-2-azetidinone (isomer C) COjPNB CHjCOCl C5H5N A cold (ice-MeOH bath) solution of l'S,3S,4R and l'R,3R,4S) silver 3- (1* -paranitrobenzyl-dioxycarbonyl-1 '-ethy I.) -1-(paranitrobenzyl 2-triphenylphospr.oranylidene-2-acetale) - azeticlj.iiono-4-thiolate (isomer C) (1.14 g, 1.30 mmol) in CHjCl^ ((,0 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 NallCO , water and brine and dried (MgSO^). The residue upon solvent evaporation U was triturated in ether (895 mg, 83.7%, mp 184-5“C dec); ir (CHClj) V : 1755, 1695 (C=O), 1620 and 1605 cm 1 (phosphorane). Anal, calcd max —. for CHN O 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. 186 2) (l'S,5R,6S and l'RtSS.eR) Paranitrobenzy 1 2-ntethyl-6-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-penem-3-carboxylate (isomer C) A solution of (l'S,3S,4R and l'R,3R,4S) 4-acetylthio5 3- (1'-paranitrobenzyldioxycarbony1-1'-ethyl) Ί- (paranitrobenzyl 2triphenylphosphoranylidene-2-acetate)-2-azetidinone (isomer C) (855 mg, 1.04 nmol) in toluene (60 ml) was heated under reflux for 4.5 h. The residue upon concentration of tbe solution was passed through a silica gel (10 g) column (1% ether in benzene) to give 10 the pure title compound (393 mg, 69.6%), mp 157-158°C (CHCl^-ether); ir (CHCl ) u : 1785, 1745, 1710 (C=O) and 1525 cm1 (NO,); 'Hmr (CDC13) 6: 8.30-7.2 (8H, m, H-aromatics) 5.46 (IH, d, J=1.8, H-5), 5.40-5.0 (5H, m, z CH2-PNB and H-l'), 3.95 (IH, dd, J=1.8, J=5.4, H-6), 2.35 (3H, s, CH ) and 1.43 ppm (3H, d, J=5.4, CH3); Anal, calcd for C24H21N3°ioS: C 53‘04' H 3·89’ N 7·73- found c ^2.76, H 3.86, N 7.69. 3) (l'S,5R,6S and l'R,5S,6R) 6-(1*-Hydroxy-1'-ethyl)-2-methyl penem-3carboxylic acid (isomer C) A mixture made of (l'S,5R,6S and l’R,5S,6R> paranitrobenzyl 2-methyl-6-(1'-paranitrobenzyldioxycarbony1-1'-ethyl)penem-3-carboxylate (206 mg, 0.379 mmol), THF-ether-H2O (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 H2 on a Parr shaker 187 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 HCl 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) V : 3580-3300 (O-H), 1755 and max 1660 cm1 (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, CHg) and 1.23 ppm (3H, d, CHg).

METHOD B 1) Silver (l'S,3S,4R and l'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(1'-paranitrobenzy ldioxycarbonyl-1*-ethyl)-2-azetidinone-4-thiolate (isomer C) ' 3 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 20 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 v : 1735 cm 1 (C=0). max 188 50886 2) (l’S,3S,4R and l'R,3R,4S) 4-Acetylthio-1-(t-butyldimethylsllyl-3(Γ-paranitrobenzyldioxycarbonyl-1'-ethyl)-2-azetidinone (isomer C) To a solution of isomer C of silver :-(t-butyldi5 methylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-2-azetidinone-4—thiolate (880 mg, in dichloromethane (40 ml) stirred at 0’C was added pyridine (0.57 ml) followed, dropwise, by acetyl chloride (0.49 ml). The mixture was stirred 0.5 h at 0°, 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). JHmr (CDC13) 2.32 (3H, s, CH3), 1.40 (3H, d, J=6.5, CH3), 0.95 OH, s, t-Bu) and 0.2 ppm (6H, CHj,. 3) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(1*-paranitrobenzyldioxycarbonyl-1 '-ethyl) -2-azetidinone. (isomer C) Isomer C of the above S-acetyl N-t-butylaethyl-silyl-azetidinone 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 189 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 ICDCl^j S: 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, s, CH3) and 1.42 ppm (3H, d, J=6.5, CH3); ir 1780, 1750, 1695 cm-1 (C=O). 4) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(I'-paranitrohenzyldioxycarbonyl-11-ethyl)-1-(paranitrobenzyl 2-hydroxy-2-acetate)-2-azetidinones (epimers at C-2). (isomer C) A mixture of isomer C of 4-?cetylthio-3-(l'-paranitrobenzyldioxycarbony1-1'-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 (CDC13) 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^. 190 ) (l'S,3S,4R and l'R,3R,4S) 4-acetylthio-3-(l'-paranitrobenzyldioxycarbony1-1'-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene2-acetate)2-azetidinone (isomer C) Isomer C of 4-acetylthio-3-(l'-paranitrobenzyldioxycarbonyl-1'-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 i'-he solution.

The solution was cooled to 0® and thionyl chloride (143 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 ch.nro compound.

It was dissolved in THF (20 ml), triphenylphosphine (314 mg, 1.2 mmol) 15 1 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 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 34 (Method A). 191 0 5 9 6 (1'P,5R,6S and 1'S,5S,6r) 6-(l'-Hydroxy-l'-ethyl)-2-methylpeneni-3-carboxylic Acid Example 35 (isomer B) OH METHOD B SAg J— Ν Ρφ ? τ PNB DTMS/TEA 2) AcCl pyridine 3) H 0+ METHOD A 1) (l'R,3S,4R and l'S,3R,4S) 4-Acethylthio-3-(11-paranitrobenzy1-dioxycarbonyl-11-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2acetate)-2-azetidinone, (isomer B) OCO.PNB J 2 5Ag AcCl CO^NB co2pnb A solution of (l'R,3S,4R and l'S,3R,4S) silver 3-(l'paranitrobenzyldioxycarbony1-1'-ethyl) 1'-paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone-4-thiolate (isomer B) (917 mg, 1.03 mmol) in CH2C12 (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 192 50896 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 3 4 evaporation crystallized from ether (710 mg, 80%, mp 183-185°C; ir (CHCl^) 5 Vmax! 1755' 1695 (C“0)' 1620' 1605 (Phosphorane) and 1625 cm-1 (1K>2) ; 2) (l’R,SR,6S and l‘S,5R,6R) Paranifcrobenzyl 2-methyl-6-(l'-paranitro- benzyldioxycarbonyl-l'-ethyl)-enem-3-carboxylate. (isomer B) A solution of (l'R,3S,4R and l'S,3R,4S) 4-acetylthio-3(1'-paranitrobenzyldioxycaxbonyl-1'-ethyl)-1 (paranitrobenzyl 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, (CHjCl^-ether); ir (CHCI,) V. : 1785, 1745, 1705 (C=O) and 1525 cm”1 (NO,); lHmr (CDC1,) fi: 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, CH^); Anal, calcd for c,4h21N3°10S: c 53.04, H 3.89, N 7.73, S 5.90; found: C 53.05, H 3.98, N 7.63, S 6.02. 193 3) (l'R,5R,6S and l'S,5S,6R) 6-(11-Hydroxy-1'-ethyl)-2-methyl penem -3-carboxylic acid (isomer B) 50586 A mixture of (l'R,5R,6S an-1 l'S,5S,6R) paranitrobenzyl 5 2-methy1-6-(1'-paranitrobenzyldioxycarbonyl-I'-ethyl,-penem-3-carboxylate (isomer B) (65 mg, 0.12 mmol), 0.05 M pH 7 buffer solution (1.06 eg), HgO-THF-ether (10 ml, 10 ml, 25 ml) was shaken on a Parr hydrogenator using 30% Pd on Celite (200 mg for L6 li -it 50 psi 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 ethyl acetate. 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) V : 3500 (O-H), 1785, 1672 cm_1 (C=O); uv (EtOH) QL3X 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, O-H), 3.65 (IH, dd, J=6.5, J=1.5, H-6), 2.28 (3H, s, CHg) and 1.15 ppm (3H, d, J=6, CHg). 194 βοβββ METHOD Β 1) (l'R,3S,4R and l'S,3R,4S) 4-Acetylthio-3-(l'-trimethylsilyloxy-l'ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylldene-2-acetate) -2-azetidinone (isomer B) A suspension of (l'R,3B,4); and l'S,.5R,4S) silver 3-(l'hydroxy-l'-ethyl)-l(paranitrobenzyl 2 -tr .|,i:enyiphosphoranylidene-2'‘acetate)-2-azetidinone-4-thiolate (505 mg, 0.715 nmol) in THF (25 ml) was cooled to -15“C (ice-MeOH bath), treated dropwise with triethyl 10 amine (289 mg, 398 μΐ, 2.86 mmol), trimethyl chlorosilane (310 mg, 362 μΐ, 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 ali quot showed absence of hydroxyl group). The mixture was cooled to -15°C, diluted with CH2C12 (20 ml), treated with pyridine (226 mg, 231 μΐ, 2.86 mmol) and acetylchloride (168 mg, 152 μΐ, 2.14 mmol), stirred for 0.5 h, diluted with ether, washed with dilute aqueous HCl, water % aqueous 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) υ : 1750, 1790 (C=O), max 1620 (phosphorane) and 1518 cm 1 (NOj). 195 2) (l'R,3S,4R and I'S,3R,4S) 4-Acetylthio-3-(I'-hydroxy-1'-ethyl)-1(paranltrobenzyl 2-trlphenylphosphoranylldene-2-acetate)-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-triphenylphosphoranylidene-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 (MgSO4). Solvent evaporation afforded the title compound (334 mg, 100%); ir (CHCl^) v : 1755, 1690 (C=O), 1620, 1605 (phosphorane and 1520 cm 1 (NO,,, max 4 3) (l'R,5R,6S and l'S,5S,6R) Paranitrobenzy! 2-methyl-6-(1'-hydroxy-1'15 ethyl)-penem-3-carboxylate (isomer B) OH OH Λ ,n>-. 'contra A solution of (l'R,3S,4R and l’S,3R,4S) 4-acetylthio3-(1'-hydroxy-1’-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 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 (CDCip 3600, 3500-3400 (OH), 1780, 1608 (c=0) and 1525 cm-1 (NO2) ; JHmr (CDCl^) 6: 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, CH2-PNB), 4.2 (IH, dq, J=7, J=6, H-l'), 3.67 (IH, dd, J=7, J=2, H-6,, 196 S0596 2.33 (3H, s, CHg) and 1.33 ppm (3H, d, J=6, CHg); Anal, calcd for C26H16N2°6S: C 52·74' H 4·43' N 7·69, s θ·8θ; found: c 52.67, H 4.41, JJ 7.71, s 8.96. ) (l‘R,5R,6S and l’S,5S,6R) e-il’-Hydroxy-l'-ethyD-Z-methyl penem -3-carboxylic acid (isomer B) A mixture of (1', 5R, 6S and l'S,5S,6R) paranitrobenzyl 6- (1 '-hydroxy-l' -ethyl}-2-methylpenem-3 arboxylate '39 mg, 0.244 mmol), THF-H^Ο-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 Hg. A work-up identical to the one previously described gave title compound (32 mg, 57%).

Example 36 (Ι'Ξ,οΗ,έΗ and l’R,5S,6s) 6-(l'-Hydroxy-l,-ethyl)-2-methylpenem-3-carboxylic Acid (isomer A) 1) (1'5,3R,4R and l‘R,3S,4S) 4-A cetylthio-3-(1'-methoxyrnethoxy-l'-ethyl)-1(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone (isomer A) COgPNB 197 Isomer A of 4-acetylthio-3-(1‘-methoxymethoxy-l’-ethyl) -1-(paranitrobenzyl-2-triphenylphosphoranylidene-2~acetate)-2-azetidinone was prepared as described elsewhere for isomer C of the paranitrobenzyl dioxycarbonyl derivative, yield 85%. ir (neat) v s 1750 and max 1690 cm”1 (C=0). 2) (l'S,3R,4S and l'R,3S,4S) 4-Acetylthio-3-(1'-hydroxy-11-ethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2-azetidinone, (isomer A) 1q Isomer A of 4-ace ty lthio-3-(1'-me thoxyme thoxy-1 '-ethyl) 1-(paranitrobenzyl-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) 3400 (OH), 1745 and 1690 cm 1 (C=0). 198 3) (l'S,5R,6R and l'R,5S,6S) Paranitrobenzyl 6-(1'-hydroxy-1'-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, CH3), 2.31 (IH, s, OH), and 1.42 ppm (3H, d, J=6, CH,); ir (CHCl ) V : 31003600 (OH), 1780 and 1710 cm1 (C=0). !s) (l'S,5R/6R and l'R,5S,6S) 6-(l'-Hydroxy-l'-ethyl)-2-methyl penem-3- A mixture of isomer A of paranitrobenzyl 6-(1'-hydroxy1'-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 SSO-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 199 triturated in ether to give a white solid (20 mg, 44%). ir (nujol) V : 3500 (OH), 1765 and 1665 cm1 (C=O); uv (EtOH) λ : 301 (E 5922), max 260 (£ 4280).

Example 37 (l'R,5R,6S and 1'S,5S,6r) 2-Aminomethyl-6-(l'-hydroxy-1'-ethyl)-penem-3-eart)Oxyiic Acid (isomer B) (l'R,35,4R and l'S,3R,4S) 4-azidoacetylthio-3-(11-hydroxy-1 ethyl) -1- (paranitrobenzyl 2-triphenylphosphorar-\ lidene-2acetate)-2-azetidinone (isomer B) A cold (ice-MeOH bath) suspension of (l'R,3S,4R and l'S,3R,4S) silver 3-(1'-hydroxy-l'-ethyl)-1-(paranitrobenzyl 2triphenyl phosphoranylidene-2”-acetate)-2- azetxdinone-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 tinder 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% agueous HCl, water, 1% aqueous NaHCOj, water and brine and dried (MgSO^). The residue 200 S0586 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 (MgSO4). The residue was passed through a silica gel (8 times its weight) column (benzene ether 1:1, ether and ethylacetate-ether 1:1) to give the title compound (565 mg, 69.8%): ir (film) V : 3500-3200 (O-H), DIOA 2100 (N3), 1755, 1609 (C=O), 1620-1605 (phosphorane) and 1518 cm-1 (NO2). (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-azidoacetylthio-3-(1'-hydroxy-1'-ethyl)-1-(paranitrobenzyl 2-tripheny1phosphoranylidene-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 title compound (193 mg, 65.1%) as a yellowish solid ’Hmr (COC13) δ: 8.13 (2H, d. Ho aromatic), 7.52 (2H, d, Hra aromatic), .59 (IH, d, J=1.8, H-5), 5.27 (2H, center of ABq, J=13.5, CH^PNB) , 4.50 (2H, center of ABq, J=16, CH2~N3), 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=0) j j max 3 and 1520 cm 1 (N02), 201 S0S86 (l'R,5R,6S and l’S,5S,6R) 2-aminomethyl-6-(11-hydroxy-1'-ethyl)penem-3-carobxylic acid (isomer B) A solution of (l’R,5R,6S and l'S,5S,6R) paranitro benzyl 2-azidomethy1-6-(1'-hydroxy-1'-ethyl)-penera-3-carboxylate (25 mg, 0.062 mmol) in THF-ether-water (P ml, 6 ml 15 ml) was shaken on a Parr hydrogenator for 2.5 h at 40 psi 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 (0 (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-l'), 4.02 (IH, dd, J=6.5, J=2, H-6) and 1.37 ppm (JH, d, J=6-5, CH ),· ir (nujol mull) V : 3550-2450 (0-H, N-H), 1765 (C=O) and 3 ΙΠ2Χ 1600 cm1 (CO ®); uv (HO) , λ : 309 (ε 3650), 255 (e 2815) . 2 SlcOC 202 Example 38 ll’R,5R,6s and 1'S,5S,6R l-g-fKArainobutyl )-6-(1'-hydroxy-ethyl )-penem-3-carboxylic Acid (isomer B) OH (ch214nh2 H (l'R,3S,5R and i'S,3R,4S) 4-(fi-azidopentanavlthio)-3-(1'-hydroxyethyl) -1-(paranitrubenzyl. 2·triphenylphosphoranylidene-2-acetate)-2azetidinone Ϊ.

SAg THSC1 ^«PPhj COOPNB TEA, Im.

N3(CH2)4COC1 c5h5n h20 ^_^-^CH2>4N3 C=PPh3 COOPNB A solution of (l'R,3S,4R and l'S,3R,4S) silver 3] (1' -hydroxyetliyl) -1- (paranitrobenzyl 2-triphenylphosphoranylidene2-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), trimethylchiorosilane (2.18 ml, 17.12 mmol) and imidazole (0.10 g, 1.47 mmol). The reaction mixture was stirred at -25’C for 0.25 h, the cooling bath was 203 removed, and the stirring was continued for 16 h. The reaction mixture was cooled to 0°C and diluted with CH^Cl^ (55 ml); it was then treated successively with pyridine (0.73 ml, 9.0 mmol) and with a solution of 4-aminopentanoyl chloride (1.36 g, 8.56 mmol) in CH^Cl^ (10 ml). The reaction mixture was stirred at O’C for 1 h and filtered through a Celite pad. The pad was washed with CH^Clj (25 ml); the filtrate and washings were combined and diluted with EtOAc (300 ml). The organic solution was washed with IN HCI solution, HjO, saturated NaHCO3 solution and HjO, dried over anhydrous MgSO4 and concentrated on a rotary evaporator to an orange syrup {3.33 g).

The syrup was dissolved in CH^Clj (75 ml) and water (4 ml) and’TFA (0.2 ml) were added; tin! reaction mixture was stirred at 23’C for 1.5 h, washed with NaHCOj and H2O, dried over anhydrous Na.,S04 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 CHjClp 10% -* 75%). Evaporation of the appropriate fractions gave nn oil; 7.14 g, 67.7%. Anal, calcd for C ,Η Ν 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. (l'R,5R,6S and 3’S,5S,6R) paranitrobenzyl 2-(6-azidobutyl)-6-(1'-hycroxy20 ethyl)-penem-3-carboxylate COOPNB A solution of (l'R,3S,4R and l'S,3K,4S) 4-(6-azidopentanoyl thio)3- (1'-hydroxy-1' -ethyl)-1- (paranitrobenzy 1-2”-triphenylphosphoranylidene-2-acetate)-2-azetidinone (2.04 g, 2.81 mmol) in a toluene-CH2Cl2 mixture (30:1, 310 ml) was refluxed for 9 h under a 204 50586 nitrogen atmosphere (The CHjCl^ 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 CinHN 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 (Ν.), 1770 (C=0, β-lactam) and 1705 cm 1 (C=0, PNB ester); uv JBdX 3 (HO 23’C, λ : 268 (e 13757), 316 (ε9826). ’Hmr (CDCl,) ¢: 1.36 (d, max 3 J ,.. .. ,..=5·3 «ζ, 3H, methyl), 1.52-1.77 (m, 4H, H-2’, H-3'), 2.57-3.00 H-2 -H-l (m, 2H, H-4'), 3.00-3.42 (m, 2H, H-l'), 3.72 (dd, JH_6_H_5=l-6 Hz, 15 ί „ ,«“6.4 Hz, H-6), 4.02-4.42 (m, IH, H-l), 5.32 (ABq, J =13.6 Hz, H—A 3—D 2H, CH2 of PNB ester), 5.60 (d, JH_5.H_6=1·6 Hz. lH,H-5), 7.61 (d, ^_Ηο ==3.13 Hz, 28, Mm of PNB ester) and 8.21 ppm (d, JjjQ-jjn,”8·8 IIz< 2H' 90 of PNB ester). (l'R,5R,6S and l'S,5S,6R) 2-(4-aminobutyl)-6-(l'-hydroxyethyl)-penem3-carboxylic acid % Pd/C DME: Et20, 1^0 OH >cooh benzyl 2-(6-azidobutyl)-6-(l'-hydroxyethyl)-penem-3-carboxylate (0.54 g, 1.21 mmol) in dimethoxyethane (50 ml) 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 23°C for 3 h. The reaction 205 50598 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: 1760 'c=0' B~lactam) and 1565 cm 1 (C-O, carboxylate),- *Hmr (DgO) δ 1-32 (d, JCH3_H_r.=6>4 HZ( 3Hf CH )r 1.45-1.85 (m, 4H, Η-Ι',Η-3'J, 2.50-3.20 (m, 4H, H-l’, H-4’), 3.84 (dd, J„ , „ ,,.=6.1 Hz, , „ c n—Q—ri” X H-o-H-b =1.4 Hz, 1-H, H-6), 4.00-4.45 (m, IH, H-l- and 5.62 ppm (d, J _ „ r H—5-H-6 =1.4 Hz, IH, H-5); uv (H_O) λ : 260 (ε 4240), 302 (ε 5480). max .

Example 39 (lR,5R,6s and l'S,5S,6r)-2-(trans-31-Amino-1 '-cyclobutyl)-6-(l-hydroxy-lethyl)penem-3-carboxylic Acid (isomer B) OH (1R, 3S,4K and 1S,.?R,4S) 4-(trans-3' -azidocyclobutanoylthio) -315 (I-hydroxy-l-ethyl)-1-(paranitrobenzyl 2” idene-2ra -acetate)-2-azetidinone -triphenylphosphoranyl- SAg C=PPh..

TMSC1 , TEA, Im ' C5H5 COOPNB A solution of (l'R,3S,4R and l'S,3R,4S) silver 3-(l'hydroxyethyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2acetate)-2· azetidinene-4-thiolate (1.01 g, 1.43 mmol) in dry THF 20 (25 ml), kept under a nitrogen atmosphere, was cooled to -40°C and successively treated with triethylamine (0.80 ml, 5-7^ 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 CHgClg (25 ml); it was 206 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 nmol) 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. Tbe filtrate was diluted with EtOAc (100 ml) and washed with IN HCl, HjO, saturated NaHCOj 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 CH^Clj (50 ml) was added H^O (2 ml) and TEA (0.2 ml). The reaction mixture was stirred at 23°C for 2 h, washed with saturated NaHCOj solution and HO, dried ovet anhydrous Na SO and concentrated to an orange 2 2 4 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, 74.4¾ ir (neat) V ί 3440 (OH), 2100 (N,) , 1755 max (C-0 β-laui.Hi), 1735 (C-0), 1680 (C=0) and 1625 cm 1 (aromatics). (1R,5R,6S and 1S,5S,6R) paranitrobenzyl 2-(trans-3'-azidocyclobutyl) -6-(l-hydroxy-1-ethyL)penem-3-carboxylate A solution of (1R,3S,4R and 1S,3R,4S) 4-(trans3' -azidocyclobutanoylthio)-3-(l-hydroxy-l-ethyl)-1-(paranitrobenzyl2·-triphenylphosphoranylidene-2™ -acetate)-2-azetidinone (2.27 g, 3.14 mmol) in CIIClj (40 ml) was diluted with toluene (300 ml) and refluxed under a nitrogen atmosphere for 6 h. The first 60 ml of solution (CHClj + toluene) were removed with a Dean-Stark trapp. The reaction.mixture was cooled to 23°C and the solvent was evaporated 207 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, 0.38 g, mp 134-5^0, 27.3%. Anal calcd for c^gH19N5°6S: 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) \J : 2110 (N,) , 1765 C=0 β-lactam), 1690 (C=0 PNB max 3 ester), 1510 (NO2) and 1355 cm”1 (N02); 'Hmr (CDC13) δ: Γ. 36 (d, J „ „ ,,,=6.3 Hz, 3H, CH ) , 2.0-2.75 (m, 4H, H-2·, H-4'), 3.67 (dd, CH -H-I 3 J = „ c=l-5 Hz' A = „ ,..=6-5 Hz, IH, H-6), 3,8-4.55 (m, 3H, H-l', H-3' H—6~H—5 H-6-u-l and H-l-, 5.30 (ABq, Ja_b=13.6 Hz, 2H, Ci^-Ph-NO^ , 5.60 (d, JH_5_H_S= 1.5 Hz, IH, H-5), 7.59 (d, J„ „ =8.8 Hz, 2H, H-m of PNB) and 8.20 HO-fim Id, J =8.8 Hz, 2H, H-0 of PNB). uv (CHCl,, 23°C) λ : 266 (ε 13050) Hm-Ho 3 max and 322 ppm (e 10008). The unreacted phosphorane was recovered mixed with PhjP-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%. :i''R,5R,6S and 1“S,5S,6R) --2- (trans-3'-amino-1'-cyclobutyl (-6-(1“hydroxyethyl)penem-3-carboxylie acid To a solution of (1R,5R,6S and 1S,5S,6R) parani20 trobenzyl 2-(trans-3'-azidocyclobutyl)-6-!l-hydroxyethyl)-penem-3carboxylate (0.33 g, 0.74 mmol) in dimethoxyethane (U0 ml) was added ether C-0 ml) and 10% Palladium on charcoal (0.33 g). The reaction mixture was hydrogenated under 45 psi of H2 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) ar.d 306 (e 3613). The crude material was triturated 208 50586 with water and the white solid was filtered and dried over p2°s under high vacuum for 5 h, 84 rog, 40%; ’Hmr (DjO) 6: 1.34 (d, Jh-2”-h-1=6'3 Kz' 3H, H-2-), 2.3-2.7 (m, 4H, H-2', H-4'), 3.90 (dd, JH_6_H_5«1.5 Hz, IH, H-6) and 5.68 (d, ·*η_5-η-6=1·5 Hz' 1H* h_5); uv (H2°' 23“c) λ ; 258 (ε 4738) and 306 (ε 6318,. The filtrate was purified by hplc, tnax mg; uv (H.O, 23’C) λ ; 257 (ε 3580) and 306 (ε 5033). ' wax 209 50586 Example 40 (l'S,5R,6S and l'R,?S,6R) g-Trimethylsilylethyl-SQ'-acetoxy-l'-ethyl)2-methyIpenem-3-carboxylate (Isomer C) 3-(l'-hydroxy-l'-ethyl)-1-(β-trimethylsilylethyl 2-triphenylphosphoranyl· 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) wi>I- stirring. After 5 min, a solution of 1^(β-trimethylsilylethyl 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 rain, freshly distilled acetaldehyde il 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 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 20 absorbed from methylene chloride onto 7 g of silica gel and placed (dry) on a 28 g silica gel column. The column was eluted with ether (100 ml) an 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 210 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 5 in vacuo to give partially purified title compound, 440 mg (33%); ir υ : 3400 (OH) and 1750 cm*1 (β-lactam and ester); ’Hmr (CHC1.) 6: max 4 too poorly resolved to make peak assignments other than aromatics and trimethylsilyl.

Silver 3-(l'-hydroxy-l’-ethyl)-l-(g-trimethylsilylethyl 2“-triphenyl10 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 vmax: 3400 (OH) and 1750 cm 1 (β-lactam and ester). 211 4-Acetylthio-3-(1'-acetoxy-l·' -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 0°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 acid and 0.1 M sodium bicarbonate (10 ml each). The solvent was evaporated in vacuo to give the title compound, 153 mg (59%); ir vroax! 3450 (OH), j’53 (β-lactam and ester) and 1690 cm 1 (thioester); lHmr (CDC13) 6: 7.5-8.2 (m, 15H, Ph), 5.85 (br, IH, H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH,. H-3), 2.0-2.6 (3 singlets; 6H, OAc, SAC), 0.9-1.7 (m, 5H, CH3, CH^Si) and 0.20 ppm (s, 9H, SiMe3). (l'S,5R,65 and l‘R,5S,6R) β-trimethylsilylethyl 6-(1'-acetoxy-l'-ethyl)2-methylpenem-3-carboxylate (isomer C) SiMe, A solution of the above phosphorane (150 mg, 0.23 mmol) 20 in toluene (15 ml) was heated under reflux for 2 h. The solution 212 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 solventf gave the title compound , 65 ng (76%) as a waxy solid, ir 1790 (β-lactam) , 1740 (ester) and 17C0 cm-1 (OAc); ’Hmr (CDClj) δ: (d, J=2Hz, IH, H-5), 5.4 (m, IH, H-l'), 4.3 (m, 2H, OCHj), 3.90 (q, J=2Hz, 4Hz, IH, H-7), 2.37 (s, 3H, 2-CHj), 2.11 (s, 3H, OAc), 1.42 (d, J=6.5, Hz, 3H, 2'-CH3), 1.1 (η, 2K. CHjSi) and 0.05 ppm (s, 9H, SiMep . The product was found to be a single isomer.

Example 41 (l'R,5R,6S and 1'S,5S,6r) 6-l'-Aaino-l’-etbyl)-2-methylpenes-3-carcox:.-l-:c Acid Procedure A (l'R,3S,4R and 1' S,3R,4S)3-(I1-azido-1'-ethyl·)-!-(paranitrobenzyl 215 triphonylphosphoranylidene-2-acetate)-4-tritylthio-2-azeticlnone (isomer B) A solution of (lfS,3S,4R and 1*R,3R,4S)3-(1-methanesulfonyloxy-1' -ethyl) -1- (paranitrobenzyl 2“-triphenylphosphoranylic’er.e· 2-acetate)-4-tritylthio-2-azetidinone (isomer C) (12.36 g, 13.4 mmol) in 10% HjO-HMPA (135 ml) was heated at 85’C for 7 h in the presence oi sodium azide (1.75 g 27.o mmol) The solution was then poured into 213 80596 cold water (1 ί} and 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 V (CHCl ): 2100 (N ), 1740 and 1610 cm r max 3 3 (C=O). (l'R, 3S,4R and 1'Ξ,3R,4S)4-acetylthio-3-(1'-azido-l‘-ethy1)-1-(paranitrobenzyl 2ll-triphenylphosphoranylidene-2-acetate)-2-azetidinone >t_/SC0CH3 COPNB 2 A cooled solution (5°C) of (l'R,3S,4R and l'S,3R,4S)3(1'-azido-1' -c t hy 1) -1· (pa rani trobenzyl 2-triphenylphosphoranylidine2-acetate)-4- : itylth i. · '>. - izetidinone (8.9 g, 10.25 mmol) in dichloromethane (30 ml) was treated with a solution of mercuric acetate (2.12 g, 6.66 nunol) in methanol 130 ml). After stirring at 5°C for 0.5 h and room temperatui-.. for ). '' h, the solvent was evaporated and the crude mercuric salt re.lissolved in dichloromethane and washed with dilute SaHCO^ 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 q, 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, NaHCOg and 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) 214 50586 and 15% acetonitrile-dichloroinethane: 5.1 9 (74.6%); ’Hmr (CDClj) δ: 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 V (CHC1,): 2115 (N ), 1758, 1693 and 1620 max 3 3 cm-1 (C=O) (1'R,5R,6S and l'S,5S,6R)paranitrobenzyl 6-(l'azido-l·'-ethy1)-2-methyl penem-3-carboxylate (isomer B) A solution of (l'R,5R,6S and l'S,5S,6R)4-acetylthio-2(I'-azido-l'-ethyl)-l-paranitrobenzyl 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 (further elution with 10% ether-dichloromethane allowed to recover 1.82 g of unreacted phosphoranel: 1.21 g (40.6%) mp 132-34’C; ’Hmr (CDClj) δ: 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, CH.^, 1.46 (3H, d, J=6.4 Hz, H-2'),· ir υ (CDCl ): 2123 (Ν,) , 1788 and 1712 cm-1 (c=0). 215 S0596 (l'R,5R,6S and 1*S,Ss,6R)6-(1’amino-1’-ethyl)-2-methyl penem-3carboxylic acid (isomer B) CO-PNB CO,H 2 A solution of (l’R,5R,6S and l'S,5S,6R) paranitrobenzyl 5 6-(l'azido-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 amin' acid (100 mg) was purified by hplc: 19.5 mg ’Hmr (DgO) 6: 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 υ (Nujol): max 1767, 1576 cm”1 (C=0),- uv (HO) λ : 300 mp (ε5326). max Procedure B (l'R,3S,4S and l'S,3R,4S) 3-(l'-azido-l'-ethyl)-4-tritylthio-215 azetidinone (Isomer B) A solution of (l'S,3S,4R and l'R,3R,4S) 1-(t-butyldime thylsilyl)-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 lo% HgO:HMPA (15 ml) was heated under Ng 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. 216 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 6: 7.23-7.78 (15H, m, aromatics,, 4.43 (IH, 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 5 (3H, d, J=6.5, H-2'); ir (CHC13): 3410 (n-H,, 2123 (^) and 1765 cm1 (C=O). (l'R,3S,4R and l'S,3R,4S) 3-(1*-amino-1'-ethyl)-4-trltylthio-2azetidinone (Isomer B) A suspension of (l'R,3S,4R and l'S,3R,4S) 3-(l'-azido1'-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 ]5 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. *Hmr (CDClj) 6: 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, NH.,). 217 (l'R,3S,4R and l'S,3R,4S) 3-(1'-p-nitrobenzyloxycarhonylamino-1'-ethyl)4-tritylthio22^azetidinone_(Isomer_B) A solution of (l'R,3S,4R and l'S,3R,4S) 3-(11-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 (CDC13) 5 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, 7=2.2, 8 H-3) and 1.23 ppm (3H, d, J=6, H-2'); ir υ max (CHC13): 3395 (N-H), 1765 and 1724 cm1 (C=0). (l'R,5R,65 and l'S,5S,6R) p-nitrobenzyl 2-methyl 6-(l'-p-nitrobenzyloxycarbonylamino-1'-ethyl) penem-3-carboxylate (Isomer B) The title product was prepared from (l'R,5R,6S and 20 1 S, 5S, 6R) 3- (1' -p-nit.robenzyloxycarbonylamino-1' -ethyl) -4-tritylthio2-azetidinone (isomer B) by the standard procedure; mp 108-110°C. 'Hmr (CDCip 5: 7.50-8.40 (8H, ra, aromatics), 5.58 (IH, d, J=1.20, H-5), 218 B0596 .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, CHj),- ir V^: 3435 (n-H), 1777 and 1717 era1 (C=O).

The p-nitrobenzyl ester may be .subjected to catalytic hydrogenation as by the procedure of Example 41 (Procedure A) to provide the corresponding carboxylic acid.

Example 42 6-Dimethylaminomethyl-2-methylpenem-3-carboxylic Acid A «ζ CH, \»2h 1- (t-butyldiinothylsixyl)-3-dimethylaminomethyl-4-tritylthio-2azetidinone (cis and trans). k;^t-Bu Me2NH NaBH^CN ^t-Bu To s solution of dimethylamine (18.5 ml of a 2N solution in methanol, 36.9 mmoles) in methanol (8C ml) was added a solution of hydrochloric acid in methane.’ (2.5 ml of a 5N solution in methanol) followed by trans l-(t-butyldimethylsxlyl)-3-formyl-4-tri tylthio-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.S h, poured 20 onto ice-hydrochloric acid (pH=2) and made basic with sodium 219 50586 hydroxide (IN NaOH, pH =9). The mixture was extracted with ether and the ether phase was washed with brine, dried and evaporated io give the title compound as a crude oil (3.0g). cis and trans 3-dimethylaminomethyl-4-tritylthio-2-azetidinone \l-Bu A solution of the above crude compound (3.0 g, o mmoles) i · hexamethyI phosphorous 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) mcl 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); 20 δ (ppm, CDCl^) : 6.8-7.8 (15fi, m, aromatics), 4.5 (IH, 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, CH3).

Cis isomer: 0.5 g, m.p. 132-3°C (ether-pentane); δ (ppm, CDC13): 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), 2.8S-2.3S (2H, m, H-l’), 2.31 (6H, s, CH^ .

The cis to trans ratio can be varied by changes in conditions. 220 cis and trans 6-dimethylaminotnethyl-2-methylpenem-3-carboxylic acid The title compound was prepared from cis and trans 3-dimethylaminomethyl-4-tritylthio-2-azetidinone by the procedure of Example 33. (ppm, CDClj): 5.5 (IH, 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). 221 50SS6 Example 43 2-Ar.inoacetoxymethyl-penem-3-carboxylic Acid (via mercaptide intermediate) 4-Azidoacetoxyacetylthio-l-(paranitrobenzyl 2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone A cold (ice-MeOH bath) solution of 4-hydroxyacetylthio-l(paranitrobenzyl 2'-triphenylphosphoranylidene-2'-acetate)-2-azetidincne (586 mg, 0.954 mmol) in methylene chloride (15 ml) was treated successively with azido acetyl chloride (240 mg, 2.01 mmol) and cropwise with 222 pyridine (226 mg, 231 ml, 3.0 mmol) in methylene chloride (10 ml) ; At the end of the addition tic showed disappearance of starting, material The mixture was diluted with ether, washed successively with dilute HCI, water, dilute agueous 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 (CHCip : 1763, 1702 (C=0), 1625 (C=P$3), 1522 (N02, and 2110 cm-1 (N ). (0 paranitrobenzyl 2-azidoace toxymethyIpenem-3-carboxylate COjPNB 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 5: 8.21 (2H, d, Hm aromatic), 7.57 (2H, d, Ho aromatic), 5.68 (IH, dd, j . =4, j , =2, H-5), 5.43 (2H, center of ABq, J=16, CH,-PN3), -6 cis 5-6 trans ·* .39 (2H, CH20), 3.93 (2H, s, CHj-Nj), 3.72 (part of dd, Jg_5 cis“4, H-6,, and 3.50 ppm (IH, dd, Jgem“17, Jg_5 ^=2, H-6); ir (CHC^): 1795, 1755, 1710 (C=O), 1525 (NOj), 2110 cm1 (N3>. 223 2-Aminoacetoxymethylpenem-3-carboxylic acid AX' COgPNB (16 ml)-ether (30 ml) and water (16 ml) was shaken on a Parr hydro10 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 (8 mg, 6.7%) as a white powder. lHmr (DgO) δ: 5.72 (IH, dd, J- , . =3.5, J, , . =2, H-5), 5.37 (2H, center of ABq, -6 cis 5-6 trans J=13.5, CH -O), 3.96 (2H, s, CH-NH,), 3.87 (IH, dd, J =16.5, J , . 2-2 gem 6—5 cis = 3.5, H-6) and 3.49 Nmr (IH, dd, J =16.5, A c , =2, H-6),- ir gem 6-5 trans max (nujol): 1775, 1755 and 1600 cm”1 (C=O),- uv (Η,Ο) λ 306 (ε4900), max 256 (ε3000). 224 50396 Example 44' Silver 1-( S-Trimethyls ilylethyl-2' -triphenylphosphoranylidene^.aeetatel-g-azetidlnone-k-thiolate di-g-trimethylsilylethyl fumarate To a cold <-10°C) ether (20 ml, solution of 2-trimethylsilyl ethanol (4.73 g, 004 mmol) (H. Gerlach Helv. Chim. Acta 60, 3039 (1977)) and pyridine (5.66 ml, 0.07 mol), under nitrogen, was added dropwise (15 min) fumaxyl 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 tha 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 225 SO 59 6 a brown solid. This compound was purified on a silica gel pad (30 g, 4x5 cm) with benzene (300 ml) as eluent to give an oil (4.855 g, 77%) which solidified on standing: mp 33-34’C. Anal, calcd for C,H„O Si„: C 53.12, H 8.91; found: C 53.35, H 8.91. ’Hmr (CDC1J 5: 14 28 4 2 3 6.78 (2H, s, C—CH), 4.26 (4H, m, CH^O), 1.03 (4H, m, CH^Si) and 0.06 ppm (18H, s, (CHJ,Si); ir (CHCl.) V : 1710 (C=0 of ester), 3 max 1643 (C=C), 1267, 1258, 862 and 840 an”1 (Si-C).

Trimethylsilylethyl glyoxylate hydrate Si(CH3)3 (CH^Si· > 2) (CH3)2S 1q λ solut >n ot' di-B-trimethylsilylethyl fumarate (37 g, 0.117 mmol) in methylene chloride (1.1 £) was ozonized at -78“C until a blue color persisted. The excess ozone was purged with nitrogen and dimethyl sulfide (2.57 ml, 0.351 mol) was added.

The solution was allowed to gradually warm to 23°C. The reaction mix.ure was diluted wi'h carbon tetrachloride to 2 liters and washed with 1% aqueous solution of sodium carbonate (500 ml). The organic phase was dried over 'iudium sulfate, filtered on Celite and evaporated (~ 25“C) to dry· .ss to give 43.9 g of the title compound (97%); ir meat) V : 3450 ' OH), 1740 (ester, 1255, 860 and 840 cm 1 (Si-C). max 1- (f-trimethylsilyleth/l 21-hydroxy-21-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 1:. 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 226 chloride (1:19) until the title compound started to come out (—1.5 £) and then with ethylacetate: methylene chloride (1:9, £). The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of the title compound. ’Hmr (CDC13, fi: 7.80 to 6.70 (15H, m, trityl), 5.23 and 4,90 (IH, 2s, H-C-O), 4.50 to 4.10 (3H,m, H-3 and O-CHj), 2.60 (2H, m, H-2), 0.95 (2H, m, CH2-Si and 0.1 ppm (9H, s, Si-CH^ ; ir (CHC1 ) V : 3520 (-0H), 1765 (C=0 of β-lactam), 1740 (C=0 of 3 max ester), 1595 (C-H, aromatic), 1257, 860 and 840 cm 1 (C-Si) 1-(β-trimethylsilylethyl 2,-chloro-2'-acetate)-4-tritylthio-2-azetidinone ' SOCl _2_ pyridine 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-215 azetidinone (4.9 g, 9.37 mmol), pyridine (0.84 ml, 10.38 mmol) and dry THF (40 ml) at -Xi’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 £). Evaporation of the pertinent fractions gave 4.64 g of the title compound (92%).

’Hmr (CDC13) fi: 7.30 (15H, m, aromatic H), 5.77 and 5.43 (lH, 2s, CH-C1), 4.7 to 4.2 (3H, m, H-4 and 0^-0), 2.85 to 2.50 (2H, ra, H-3), 1.15 (2H, m, CHj-Si) and 0.06 ppm (9H, s, Si-CH,^); ir (neat) \i : 1760 (CO), 860 and 840 cm1 (C-Si). max 227 1-(S-trimethylsilylethyl-21-triphenylphosphoranylidene-2'-acetate)-4tritylthio-2-azetidinone A dioxane (20 ml) solution of the above chloroazeti5 dinone (4.12 g, 7.568) was treated with triphenylphosphine (2.209 g, 8,424 mmol) and 2,6-lutidine (0.98 ml, 8.424 mmol). The mixture was refluxed for 3.5 h. The cooled solution was filtered and the white solid washed with THF. The filtrate was evaporated to dryness. The residue was purified on a silica gel column (200 g, 4 x 31 cm) using ethylacetate-hexane (3:7, 1 Z; 7:3, 1 Z) to give the title phosphorane (4.836 g, 83%). ir (film) V : 1755 (C=O), max 1615 (phosphorane), 850 and 830 cm 1 (Si-C). Anal, calcd for C NO PSSl: C 73.89, H 6.07, N 1.81; found: C 72.18, H 6.08, 46 3 N 1.83 Silver 1-(8-trimethylsilylethyl 2l-triphenylphosphoranylidene-2'acetate)-2-azetidinona -4-thiolate 4- AgNOg Si(ch3)3 (nBu)gN + CFgCOgH 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, 228 OSS 6 0.2 mmol) in ether (20 ml). The mixture was mechanically stirred forl9 iWiutes. 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 (CHCL3) Max; 1862 (C=0, 1630 (Phosphorane), 860 and 840 CM -1 (Sl-C).

Example 45 6-Fonnamidomethyl-2-methylpenem-3-carboxylic acid, sodium and potassium trans 1-(t-butyldimethylsilyl) -3- methanesulfonyloxymethyl-4-tritylthio-2-azetidinone A solution of trans-1-(t-butyldimethylsilyl)-3-bydroxy15 methyl-4-tritylthio-2-azetidinone (8.0 g, 16.36 mmol) in dichloromethane (50 ml) was treated at S’C with methanesulfonyl chloride (1.4 ml, mmol, in dichloromethane (10 ml) apd triethylamine (2.5 ml, 13 mmol,. Stirring was maintained for 1 h under Then the solution was washed 229 successively with cold IN hydrochloric acid, IM sodium bicarbonate and brine, dried (MgSO^) and evaporated in vacuo. The residue (mixture 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 mp 167-168°C; ir (neat) U : 1755 cm-1; *Hmr (CDCl,) δ: 7.3 (15H, 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 Η H λ, £ SC(j) HscY'·sc3 \i(CH3>2 t -Bu A solution of trans -1-(t-butyldimethylsilyl)-3-methanesulfonylmethyl 4-trityithio-2-azetidinone (21.0 g, 37.0 mmol) in HMPA (90 ml) was cooled in an ice bath and treated with sodium azide (2.7 g, 41.2 mmol) in Η,,Ο (10 ini) . The reaction mixture was stirred at room temperature for 1 h, diluted with ethyl acetate, washed with H^O (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 H^O (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 a white solid. The analytical sample was recrystallized from CH^Cl^/ ether mp 174-5°C; Anal, calcd for 40S: C 88-97' H 5.03, N 13.99: 230 found C 68.78, H 5.00, N 14.16; ir (nujol) 2100, 1765 cm : *Hmr (CDClj) <5: 7.35 (15H, m), 4.75 (IH, bs), 4.4 (IH, d J=2Hz) , and 3.1-3./ ppm (3H, »). trans-3-aminomethyl-4-tritylthio-2-azetidinone To a solution of trans 3-azidomethyl-4-tritylthio-2azetidinone (10.0 g, 47.5 iranol) 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 10 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 warhed with brine, dried (MgSO^) and evaporated in vacuo. The crude amine crystallised from ether, 14.05 g (79%); rnp 139-9eC; Anal, calcd for C23H22N2°C1' 1/Λ1 at2C12: C 70'56' H s·73' N 7.08; Found; C 70.68, (I 5.94, N 7.27; ir (CHCI ) V : 3400 and 3 max 1760 cm1,· hirar (CDC13) fi: 7.35 (15H, m), 5.15 (IH, m), 4.3 (IH, bs), 2.7-3.5 (3H, m) and 1.3 ppm (2H, m). 231 50536 trans 3-phthalimidomethy1-4-tritylthio-2-azetidinone Ά?-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 72-78, H 4.79, N 5.55, found: C 73.32, H 4.UZ, N 5.49; ir (CHCl,) 0 : 1770 and 1715 cm-1; max lHmr (CDC1 ) 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, ra). trans 3-phthaIimidomethyl-l-(paranitrobenzyl 2'-hydroxy-2'-acetate)4-trity lthio-..- 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 glyoxylate derivative (25 g, quantitative) as an amorphous solid. 232 50586 It was used in the next step -without further purification, ir (CHCl^) U : 1770 and 1715 cm”1; *Hmr (CDCl,) δ: β.1 (2H, d, J=9Hz), 7.55 max J (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-(paranltrobenzyl-2'-chloro-2'-acetate)4-tritylthio-2-azetldinone To a cooled (ice bath, 0°C) solution of trans-3-phthal,'raidomethyl 1- (parani trohenzyl-21 -hydroxy-21 -acetate) -4-tritylthio10 2-azetidinone (25 g, 35 mmol) in tetrahydrofuran (150 ml) was added dropwise a IM solution of thionyl chloride in tetrahydrofuran (46 ml, mmol) followed by a IM solution of pyridine in tetrahydrofuran (46 ml, 46 mmol). The reaction mixture was stirred at room temperature for 20 inin, 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 (CHCl^) \> : 1775 and 1720 cm*1. ’Hmr (CDCl,) δ: 8.12 (2H, d, J=9Hz), 7.60 max 3 (2H, d, J»9Hz), 7.3 (19H, m), 5.25 <2H, m), 4.7-5.4 (1H, m), 4.55 20 (IH, bs) and 3.3-4.0 ppm (3H, m). 233 trans-3-phthalimidomethyl-l- (paranitrobenzyl-2' -triphenylphosphoranylidene-2*-acetate)-4-tritylthio-2-azetidinone „C1 Η H CO PNB 2 A mixture of trans-3-phthaliraidomethyl-l-(paranitrobenzyl-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.i 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 IQ (21 g, 62%) as a white solid, ir (CHCl^ 1750 and 1710 cm .

'Hmr (CDC1,) fi: 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 droowise with sodium sulfide (4.97 g, 20.7 mmol) in acetone/water 1:1 (30 ml) and heated to reflux tor 8 h. The reaction mixture was diluted with water, acidified with IN hydrochloric acid and extracted with dichlo234 50586 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 1; ’Hmr max (CDC13) δ: 7.4 (38H, m) and 3.3-5.5 ppm (8H, m). tran3-3-phthalisoiniidomethyl-l- (paranitrobenzyl-21 -triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone A solution of trans-3-phthalimidomethyl-l-(paranitrobenzyl10 2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone <17.1 g, 17.54 mmol) in dichloromethane (125 ml) was treated dropwise at room tenperature with Ν,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) v : 2110, 1755 and 1710 cm \ ’Hmr (CDC1,) δ: BAX j 7.5 (38H, m), 4.6-5.3 (4H, m) and 3.9 ppm (2H, bs). 235 trans-3-aminomethyl-l- (paranitrobenzyl-2'-triphenylphosphoranylidene 21-acetate)-4-tritylthio-2-azetidinone A solution of trans-3-phthalisoimidomethyl)-l-(parani5 trobenzy1-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2azetidinone (5.9 g, 5.16 mmol) in tetrahydrofuran (40 tnl) , cooled to -20°C, was treated dropwise under N^ 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 a silica gel column (60 g) eluting with ether to ethyl acetate to give 3.38 g (66%) o' the amino phosphorane as an amorphous solid. ir (CHC1_) V : 1730, 1710 cm1; 'Hmr (CDC1,) ά: 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-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2 1-acetate)-4-tritylthio-2-azetidinone To a cooled (ice bath) solution of trans 3-(aminomethyl1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-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 236 80886 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 (MgSO4), 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 Ihe formamide as an amorphous solid, ir (CHCl ) V : 1740, 1685 and 1620 cm ; ’Hmr 3 nsx (CDClg) δ: 6.6-8.2 (35H, m), and 2.5-5.3 ppm (7H, m). trans silver 3-foraamidomethyl-l-(paranitrobenzy1-2'-triphenylphos10 phoranylldene-21-acetate)-2-azetidinone-4-thiolate A solution of trans 3-formamidomethy1-1-(paranitrobenzyl-2 ‘-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2azetidinone (550 mg, 0.64 mmol) in dichloromethane (10 ml) was IS evaporated to dryness and diluted with hot methanol (20 ml). The solution was stirred at 60eC 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 for 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. 237 505S6 trans 4-acetylth3.o-3-formaniidoinethyI.-l- (paranitrobenzyl-21 tr iphenylphosphoranylidene-21-acetate)-2-azetidinone To a cooled (ice bath) solution of trans silver 35 formamidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene2’-acetate)-2-azetidinone-4-thiolate (800 mg, 1.11 mmol) in dichloromethane (10 ml) was added dropwise under N2 a solution of IM acetyl chloride 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% methanol in ethyl acetate to give 450 mg (62%) of the title compound: ir (CHCl.) V : 1755, 1685 and 1620 cm \ 3 max lHmr (CDCl^) 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 (lH, ra), 3.0 (IH, m) and 2.2 ppm (3H, two s). 238 paranitrobenzyl 6—formamidomethyl—2—methylpenem-3—carboxylate co2pnb A solution of trans 4-acetylthio-3-formamidomethyl—1(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-25 azetidinone (450 mg, 0.686 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 (CHC13> υ: 1780 and 1690 cm1; 'Hmr (CDClj) δ: 8.2 (2H, d, J=9Hz), 8.2 (IH, s), 1° 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 A mixture of paranitrobenzyl 6-formidomethyl-2-methylpenem-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. 239 505S6 The crude solid was purified by hplc to give l8 mg of a mixture of the sodium and potassium salts. uv (Η 0) λ : 299 (ε 4933) , 259 (e 4094); ir (nujol) max υ : 3100-3650 and 1755 cm1; 'Hmr (D,0) 5: 8.15 (IH, s), 5.53 (IH, d, max 4 J=1.4Hz), 4,0 (1H, m), 3.74 (2H, d, J=5Hz), 3.25-4.25 (IH, m) and 5 2.27 ppm (3H, s).

Example 46 (l'S,5R,6S, and 1'R,5S,6r) 6-(l'-Hydroxy-l'-propyl)-2-methylpenea-3carboxylic acid, sodium salt (isomer C) (1(7^ Xb CO2Na trans l-t-Butyldimethylsilyl-3-propionyl-4-tritylthio-2-azetidinor.ss + LDA + CHCH C-OCH 3 2 3 SiMe + 2 -t- 2 PROCEDURE: n-BuLi (37.50 ml, 1.6M/hexane, 60 mmol) was added dropwise under N., to a cooled (dry ice-acetone bath) and stirred solution of diisopropylamine (8.50 ml, 60 mmol) in dry THF (200 ml). The mixture was stirred in the cold and l-t-butyldimethylsilyl-U-tritylthic2-azetidincne (22.9 g, 50 mmol) in dry THF (100 ml) was added. After min, methyl propionate (40 ml, excess) was added and the reaction mixture was kept at -78° for 4 h. Then the cooling bath was removed 20 and the internal temperature was allowed to come to 0“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 240 (NagSO^). 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) V : 1710 (-?-), 1750 cm1 (e-lactam). l-t-Butyldimethylsilvl-3-(1'-hydroxy-l’-propyl)-4-tritylthio-2azetidinones PROCEDURE: A solution of l-t-butyldimethylsilyl-3-propionyl-h-tritylthio1q 2-azetidinone (26 g, 50 mmol) and sodium borohydride (7.6 g, 200 mmol) in THF (400 ml) was stirred at room temperature for 18 n. 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 SiOg (ACT. 1, 400 g) and eluted first with CHgClg to give 10.8 g of l-t-bucyldimethylsilyl-4-tritylthio-2-azetidinone. Elution with 20% ether in CHgClg 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 CHgClg as eluent. Isomer C, white solid, 3.8 g; mp (pet. ether) 134-36’C.

’Hmr (CDClg) S-. 7.1-7.8 (1SH, m, STr), 4.35 (H, d), 3.1 (H, dd) , 2.5 (H, m), 0.7-1.7 (SH, m), 0.97 (9H, s) and 0.25 ppm (6H, s). Anal, calcd for c3lH39N°2SSi: c Ί-91» H 7.59, N 2·71ί 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 (CDClg) 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). 241 5GS96 97-99°C. ’Hmr (CDC1 ) δ: 7.1-7.8 (15H, ro, STr), 4.15 (H, d) , 3.4 (H, dd), 3.2 (H, m), 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%. (l'S,3S,4R and l’R,3R,4S) l-t-butyldimethylsilyl-3-(l'-paranitrobenzyl dioxycarbonyl-11-propyl)-4-tritylthio-2-azetidinone (isomer C).

PROCEDURE: To a cooled (dry ice-acetone bath) solution of (l'S,3S, 4R and l'R,3R,4S) 1-t-butyldimethylsilyl-3-(1'-hydroxy-11-propyl)4-tritylthio-2-azetidinone (isomer C) (3.1 g, 6 mmol) in dry THF (20 ml) was added dropwise under N2 a solution of 1.6M n-BuLi/hexane (4.88 ml, 7.0 mmol) stirred at -78°C for 25 rain . 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 HH^Cl solution and brine. The organic phase was dried (Na^O^) and evaporated to dryness to give 4.2 g of title compound (Quantative yield). ’Hmr (CDCip 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, ra) , 0.9 (9H, s) and 0.25 ppm (6H, d). 242 (1'5.35,4Η and l'R,3R,4S) B-d'-paranitrobenzyldioxycarbonyl-l'-propyl) -4-tritylthio-2-azetidinone (isomer C) 50586 oco2pnb 'ύΧ.

STr SiMe.

+ HMPT (10% HjO) + NaN.

OCOjPNB >STr Xi PBOCEDORE: θ To a cooled (ice bath) solution of (l'S,3S,4R and l'R,3R,4S> l-t-butyldimethylsilyl-3-(1'-paranitrobenzyldioxycarbony 1-1' -propyl) -4-trity lthio- 2-azetidinone (isomer C) (4.2 g, 6 mmol) in HMPT (40 ml) containing 10% H2O was added sodium azide (0.78 g, 12 mmol). The mixture was stirred at room tempe10 rature 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 (NajSO^) 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 (CDC13) δ: 8.2 (2H, d) , 7-7.7 (17H, n), S.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). 243 505S6 (l‘S,3S,4R and l'R,3R,4S) S-Cl'-paranitrobenzyldioxycarbonyl-l'propyl)-1-(paranitrobenzyl 2-hydroxy-2-hydroxy-2-acetate)-4tritylthio-2-azetidinone (isomer C) PROCEDURE: To a solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-1 1-propyl)-4-tritylthio-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 (4 drops) and Na^SO^ (to absorb H2O 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 (CDCl^) 6: 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, ra), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t). (l'S,3S,4R and l'R,3R,4S) 3-(11-paranitrobenzyldioxycarbonyl-1'— propyl)-1-(paranitrobenzyl 2-chloro-2-acetate(-4-tritylthio-2azetidinone (isomer C) Py/THF SOC12/THF COjPNB To a cooled (ice salt bath) solution of the above glyoxylate (4.35 g, 5.5 mmol) in dry THF (30 ml) was added IM py/THF (7 ml, 7 mmol) followed by dropwise addition of IM SOC12/THF (7 ml, 7 mmol). The re244 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 (CDC13) δ: 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, ra) and 0.9 ppm (3H, t). (l'S,3S,4R and l'R,3R,4S) 3-(l'-paranitrobenzyldioxycarbonyl-l*propyl)-!-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate) -4-tritylthio-2-azetldinone (isomer C) PROCEDURE: To a solution of the above chloro compound (3.7 g, 4.568 mmol) in dioxane (35 ml) was added 3P (1.197 g, 5 mmol) and lutidine (0.54 g, 5 mmol). The mixture was heated in an oil hath at 100“ C fox 3 days. It was cooled, diluted with ether and washed successively with IN HCl, IM NaHC03 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 245 (l‘S,3S,4R and l’R,3R,4S) 4-acetylthio-3-(l'paranitrobenzyldioxycarbonyl1'-propyl)-I-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)2-azetidinone (isomer C) 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 AgNO^ (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 0°C for 2 h.

It was filtered, and the solid washed well with cold MeOH and ether, 1.2 g quantitative yield); ”P H3-llSeC (d): ir (nujol) 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 mmol) in CH2C12 (15 ml) was added acetyl chloride (0.1l8 g, 0.10Ϊ ml, 1.5 mmol) in CHgClg (2 ml) followed by pyridine (0.119 g, 0.122 ml, 1.5 mmol) in CH2C12 (2 ml). The mixture was stirred at C°C for 30 min. It was filtered over Celite to remove silver salt and the filtrate was washed successively with HCl (0.5N), HjO, NaHCO^ (0.5 M) and brine. The CH2C12 solution was dried (MgSO^) and evaporated to dryness to give 0.94 g of title compound as an amorphous solid. (83.4%) ir (neat) υ : 1750 cm 1 (broad). max 246 (1*S,5R,6S and l'R,5S,6R) paranitrobenzyl 6-(l'-paranitrobenzyldioxycarbonyl-l*-propyl)-2-methylpenem-3-carboxylate (isomer C) PROCEDURE; 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 (CDClj) 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 (JH, t,. (l'S,5R,6S and l'R,5S,6R) 6-(1*-hydroxy-1*-propyl)-2-methylpenem-315 carboxylic acid (isomer C), sodium salt.

% Pd-Celite (100 mg) in THF (10 ml), Et2O (20 ml), HjO (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) V : 1750 (β-lactam), and 1600 max 1650 cm 1 (broud, -CO, ); uv λ , ; 258 (ε 1105) and 305 (e 1244). mdX 247 Example.47 (l'R,$R,6S and 1'S,5S,6r) 6-(l'-Hydroxy-l’-Tiropyl)-2-methylpenem-3carboxylic acid, sodium and potassium salts (isomer B) CH.

J · WgH (l'R,3S,4R and l'S,3R,4S) 1-t'-Butyldimethylsilyl-3-(l'-formyloxy-1 propyl)-4-tritylthio-2-azetidinone (isomer B) STr HCOgH, EtgN DMAP, ACgO OCHO Si Me + I ?iKe2 4-Dimethylaminopyridine (DMAP) was prepared according to a) H.C. Brown eX aZ. Org. Synth. Collect. Vol. 5, 977 (1973) Ιθ and b) Helmet Vorbruggen it aZ. Angew. Chem. Int. Ed., 17, 569, (1978), PROCEDURE: To a cooled ( 0°C) solution of (l'R,3S,4R and l'S,3R,4S) 1-t-butyldiniet hy < silyl-3 i).' -hydroxy-l-' -propyl) -4-tritylthio-2-azetidinone (isomer B) (3.612 g, 7 mmol) in CHgClg (50 ml) was added Et^N (4.48 al, mmol), HC0„H (0.63 ml, l6.8 mmol) and DMAP (O.S54 g, 7 mmol) followed by dropwise addition of acetic anhydride (7.14 g, 70 mmol). The clear yellow solution was stirred at -40°C and milky mixture. It was poured onto ice-ΙΝ HCl (pH 6) and the layers were separated. The CHgClg solution was washed with IM NaHCOg and brine. It was dried (Na^SO^) 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 BI3X 1750 cm-1 (β-lactam); ’Hmr (CDClg) 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 CggHggNOgSSi: C 70.42; H 7.20; N 2.57; found: C 70.20; H 7.33, N 2.73. 248 (l'R,3S,4R and l'S,3R,4S) 3-(1'-formyloxy-l’-propyl)-4-tritylthio-2azetidinone (isomer B) OCHO OCHO PROCEDURE: To a cooled (ice bath) solution of l-t-butyldimethylsilyl-3-(l'5 formyloxy-1'-propyl)-4-tritylthio-2-azit1dinone (3.7 g, 6.77 mmol) in HMPT (40 mi) containing 10% HjO was added NaN^ (0.91 g, 14 mmol).

The mixture was stirred at room temperature for 1.5 h. It was poured onto ice water (200 mi) and extracted with ether (4 x 40 ml). The ether solution was diluted with pet-ether and washed extensively with water and brine to remove HMPT. It was dried (Na„S0.) and 2 4 evaporated to dryness to give 2.92 g of a thick colorless oil. (quantitative yield) . 'Hmr (CDCl3) 6: 8.1 (Η, Η-^-,δ), 7.1-7.7 (15H, ra, -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).

PROCEDURE: A mixture azetidinone (isomer B), mmol), Et,N (5 drops) IS (l'R,3S,4R and l'S,3R,4S) 3-(11-formyloxy-1'-ethyl)-1-(paranitrobenzyI 2-hydroxy-2-acetate)-4-tritylthio-2-azetidlnone (isomer B) PNB GLYOXYLATE Et^/THF co2pnb of 3-(1'-formyloxy-1'-propyl)-4-tritylthio-2(2.9 g, 6.77 mmol), PNB glyoxylate (1.59 g, and NajSO^ (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 (CDC13) δ: 8.2 (2H, d), 7.1-7.8 (18H, m), 5.2 '249 (2H, d) , 4.9 (H, m), 4.65 and 4.3 (tt, 4.65 (1/2 H,s) 4.3 (1/2 H, s) 1, 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-(1'-formyloxy-11-propyl)-1-(paranitrobenzyl 2-chloro-2-acetate)-4-tritylthio-2-azetidinone (isomer B) XL yc1 OCHO _ - STr Py/THF — soci2/thf C02?N3 PROCEDURE: To a cooled (ice salt bath) solution of the above glyoxylate derivative (4.3 g, 6.77 mmol) and IM Py/THF (8 ml, 8 mmol) in dry THF (30 ml) was added dropwise IM SOCl,/py (8 ml, 8 mmol). The resulting solid mixture was ) stirred at the cove temperature for 1 h. It was diluted with benzene (30 ml) and stirring was continued for 20 min. It was filtered over Celite-charcoal and the filtrate was evaporated to dryness to give 4.1 g of an amorphous solid (92%). ir (neat) v : 1720 fH—2—), 1750 max (-C-OPNB) and 1780 an”1 (β-lactam); ’Hmr (CDCl ) δ: 8.25 (2H, d), 7.3 ? (H, s, H-C-), 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). 250 (l’R,3S,4R and l’S,3R,4S) 3-(l'-formyloxy-l*-propyl)-1-(paranitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-tritylthio-2-azetidinone (isomer B) OCHO CO,PNB 0jP dioxane lutidine OCHO co2pnb PROCEDURE: A mixture of the above chloro compound (4.0 g, 6.07 mmol) φ^Ρ (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 NaHCOj and brine. The organic solution was dried (Na2SO4) 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) 1720 (H-^-0-) , and 1750-1760 cm* ’ (~co2pnb ar.d β-lactam). (l'R,3S,4R and l'S,3R,4S) 4-acetylthio-3-(I’-formyloxy-l*-propyl)-1(paranitrobenzyl 2H-triphenylphosphoranylidene-2-acetate)-2-azetidinone (isomer B).

PROCEDURE: A warm solution (60°C) of 0.15 M AgNO^-CH^OH (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 251 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 CH^Cl^ (10 ml) was added dropwise CH^COCl (01079 g, 1 mmol) in CHyCl^ (5 ml). After stirring at 0’C for 1 h, it was filtered.

The filtrate was washed well with a cold solution of 0.5M HCl, 0.5M NaHCO and brine. It was dried (Na.SO ) and evaporated to dryness 3 A *i )0 to give 0.43 g of an oj.L. (63%); ir (neat) V : 1700-1760 cm _ max o (broad -C and β-lactam-. (l'R,3S,4R and 1'5,3R,4S) and acetylthio-3-(l'-hydroxy-l'-propyl-l(paranitrobenzyl 2-trl·phenylphosphoranyl·ide-2'l-acetate) -2-azetidinone (isomer B) OCHO PH HCl/MeOH U, _ rf , CO2PNB formate (1.0 u. 1.45 mmol) in THF (10 ml) The abo 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^SO^). It was evaporated to give 0.9 g of crude title compound. This was chromatographed on SiO., 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 (CDCl^) fi: 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). .252 (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 6-(1'-hydroxy-1'-propyl)-2methylpenem-3-carboxylate (isomer B).

PROCEDURE; g 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 S.iO2 and eluted with ether to give 0.1 g of title compound as a white solid. (87%); mp (pentane) 133-135°C; 'Hmr (CDCl^ 5: 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, C«3), 2.2 (H, OH), 1.7 (2H, m) and 1.05 ppm (3H, t). (l'R,5R,6S and l'S,5S,.R) 6-1'-hydroxy-1'-propyl)-2-methylpenem-3carboxylic ac id (isomer Β), mixed K and Na salts (0.07 g, 0.185 mmol), 30% 7, 4 ml) in THF (15 ml, A mixture of the above ester Pd-Celite (150 mg) and buffer solution (pH 2o 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) V : 1780 (β- lactam) and 1650 cm 1 (broad, -CO ); uv max 2 HO λ ; 255 (ε 983) and 300 (ε 1092). max 253 Example 48 (l'R,5R,6S and 1'S,5S,6r) 6-(1'-Hydroxy-2'-phenylethyl)-2-methyIpenea3-carhoxylic acid (isomer B) IH trans 1-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio-2azetidinone l-t-Butyldimethylsilyl-4-tritylthio-2-azetidinone (18.32 g, 40 mmol) in dry THF (100 ml) was added dropwise 1q under to a cooled (-78°C) LDA solution [prepared under 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 'l'HF (150 mi) 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 .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 20 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^ δ: 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) . 254 1- (t-butyldimethylsilyl-3- (1'-hydroxy-2'-phenylethyl) -4-trity It'nio2- azetidinone (2 trans diastereomers).

OH trans 1-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio5 2-azetidinone (28.8 g, 50 innol) and NaBH^ (0.5 g, 0.25 mole) in TH? (200 ml) were stirred at room temperature for 18 h. The mixture was poured onto ice-ΙΝ HCl and extracted with CH^Clj. The CHjCl^ solution was washed with brine and dried (Na^SO^). It was evaporated 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 (l4.4 g) which was found to he 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 (CDCip fi: 7-7.7 (20H, m) , 4.37 (1/2H, d), 4.18 (1/2H, d) , 3.3-3.8 (H, ra), 3.45 (1/2H, dd), 3.1 (1/2H, dd), 2.7 (2H, Bl), 0.87 (9H, d) and 0.25 ppm (6K, s). 1-(t-butyldimethylsilyl)-3-(1'-formyloxy-21-phenylethyl)-4-tritylthio- 2~azetidinone OH To a cooled (-40“C) solution of the above mixture of alcohols (14.4 g, 24.9 mmol) in CH2C12 '25° m1’ was added Et3N (15.93 ml, 125 mmol), HCO..H (2.24 ml, 59.76 mmol) and DMA? (3.04 g. 255 Sosas 2h.9 mmol). After stirring for 5 min acetic anhydride (2.35 =1, 249 mmol) was added dropwise. The clear solution was stirred at -40°C for 15 min whereby it turned into a white cloudy mixture. It was kept at -40°C for another 45 min (total time 1 h).

It was poured onto ice-IN HCl, and the layers separated. The CH Cl, solution was washed well with cold IN HCl,HO, IM NaHCO 2 2 2 3 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 (CDC13) δ: 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 (CDC13) δ: 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- (l'-formyloxy-2'-phenylethyl)-4-tritylthio-2-azetidinone (l'R,3S,4R and l’S,3K,4S enantromers) of the above formate water (50 ml) was 2q To a cooled (ice bath) solution (5.9 g, 9.375 mmol) in HMPT containing 10% added NaN3 (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^SO^) and evaporated to give a solid residue. This was treated with 256 petroleum ether and filtered to give 4.4 g of a white solid (92%) mp 169-71eC. Anal, calcd for C^H^NO Ss C 75.43, H 5.51, N 2.84; found: C 75.04, H 5.64, N 2.78. 'Hmr (CDC1 ) 5: 7.9 (H, s), 7.1-7.6 (20H, ro), 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-(1'-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl 2-hydroxy-2“acetate)4-trltylthio-2-azetidinone (l'R,3S,4R and l'S,3R,4S enantiomers) co2pnb A suspension of PNB glyoxylate (2.37 g, 1C.16 mmol) in dry benzene (100 ml) was refluxed under a Dean Stark c 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 J 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^) δ: 8.0-8.3 (2H, two doublets), 7.5 and 7.6 (H, two singlets), 7.0-7.4 (20H, ra), 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, ra). 257 3-(11-formyloxy-2’-phenylethyl)-1-(paranitrobenzyl 2-chloro-2acetate)-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 derivative (6.0 g, 8.537 mmol) 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 min. It was filtered over Celite-charcoal and evaporated to dryness to give 6.0 g of an amorphous solid (98%): 'ffinr (CDC13) 5: 8.2 (2H, m), 7-7.7 (23H, ro), 5.8 (H, s), 5.25 (2H, s), 4.35 (H, d). 3.5-4.0 (H, ro), 3.3 (H, m) and 2.9 ppm 15 (2H, d). 3-(11-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl 2-triphenylphosphor any lidene-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 nnol), (2.489 g, 0.5 mmol) and lutidine (1.0165 g, 1.1 ml, 9.5 mmol) 258 in dioxane (50 ml) was heated at 110’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, HgO, IM NaHCOg and brine. It was dried (NagSO^) and evaporated to give 8.0 g of a crude product. This was chromatographed on SiOg 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”1, max 4-acetylthlo-3-(l'-formyloxy-2'-phenylethyl)-1-(paranitrobenzyl ]Q 2-triphenylphosphoranylidene-211 -acetate) -2-azetidinone (1'R,3S,4R and l'S,3R|4S enantiomers) To a refi-uxing solution of tlie above phosphorane (3.6 g, 3.8 mmol) and pyridine (0.33 g, 4.2 nmol) in CHgClg (30 ml) and MeOH (30 ml) was added dropwise a 0.15M AgNOg/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 (CHgClg (20 ml) was treated dropwise with CHgCOCl (0.27 g, 3.5 mmol) in CHgClg (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, HgO, IM NaHCO. and brine. It was dried (MgSO.) and evaporated to dryness 3 4 to give 1.0 g of an amorphous solid (89.8%). ’Hmr (CDClg). δ: 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). 259 50586 4-acetylthio-3- (1'-hydroxy-2’-phenyiethyl)-1-(paranitrobenzyl 2triphenylphosphoranylidene 2-acetate)-2-azetidinone (l'R,35,4R and l'S,3R,4S enantiomers). Λ solution of the above phosphorane (1.8 g, 2.415 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 CHCl^. The CHCl^ 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 (CDCl^) δ: 8.2 (2H, d), &.J-8.0 (22)), m), 4.0-6.0 (5H. m), 2.5-3.5 (3H, m) and 2.2 ppm !3H, SAc). paranitrobenzyl 6-(11 -hydroxy-2*-phenyiethyl)-2—methylpenem—3— carboxylate (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 260 (CDClg) δ: 8.2 (2H, d) , 7.6 (2Η, d), 5.4 (Η, d), 5.2-5.4 (2Η, d), 4.0-4.5 (Η, π), 3.7-4.0 (Η, dd), 3.0 (2Η, d) and 2.3 ppm (3Η, s). 6-(1'-hydroxy-2'-phenylethyl)-2-methylpenem-3-carboxylic acid (l'R,5R,6S and l'S,5S,6R enantiomers) 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 ?oinbin>eC; ir (nujol) 3580 (OH, Sharp), 1660 and 1760 cm1; uv (MeOH) λ t 310 (ε 5490) and 254 (e 4880). 261 Example 49 (t'R,5R,6S and 1>'S,5S,6r) 6-(2',2l-Dimethyl-l',3'-dioxolan-4,-yl)-2methyIpenem-3-carboxylic Acid (Isomer C) (4'R,3S,4R and 4'S,3R,4S) and (4‘S,3S,4R and 4'R,3R,4SJ 1-(t-Butyldimethylsilyl)-3-(2',2’-dimethyl-1'3'-dioxolan4'-yl)-4-tritylthio-2-a2etidinone (“Isomer C and Isomer B) 262 1) 50586 Ethyl 0—(2-methoxy-2-propyl)glycolate “VA OEt poci3 )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) 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 K2CO3· ftfter 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 (CC14) δ: 1.25 (3H, t, J-7Hz -CHjCl·^), 1.28 (6H, s, Me^, 3.12 (3H, s, -OCllj), 3.88 (2H, s, -OC^CO-), 4.10 (2H, q, J=7Hz, -CH^^); ir (neat) υ 1760 and 1.735 cm 1 (ester). max 1) J. Meinwald et ai., Tet. Lett., 4327 (1978) 2) M.S. Newman and M.C. Vander Zwan, J. Org. Chaa.,38, 2910 (1973). (3S,4R and 3R,45) l-(t-Butyldimethylsilyl)-3-(l'-keto-2'-(2-methoxy2M-isopropy loxy)-!'-ethyl)-4-tritylttiio-2-azetidinone To a stirred solution of diisopropylamine (18.5 ml, 0.134 mol) in THF (400 mi; freshly distilled from LAH) at -78’C was added n-butyllithium (1.6M in hexane, 90 ml, 0.144 mol) under 263 50S96 N2 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 Etj0 13 x TOO ml). The combined organic extracts were washed with brine, dried (Na^O^) and evaporated yielding 60.95 g (0.103 mol, crude yield 94.6%) of the title compound as a crude orange oil. This crude material was used in the next reaction. A pure sample was obtained by column chromatography (SiO^, eluent: 2% Et2O in benzene); lHmr (CDC13) δ: 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 cem 17Hz), 3.77 (1H, d, J=*1.6Hz, H-3), 3,97 {1H, B of AB, J =17Hz), 4.83 gem (IH, d, J=1.6Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs); ir (neat) v : max 1750, 1725, 1710 cm1 (C=O) ; tic, Rf 0.53 (benzene; Ε^0=4:1), Rf 0.61 (hexane: EtOAc = 2:1). (3S,4R and 3R.4S) 1-(t-Butyldimethylsilyl)-3-(1'-hydroxy-2'-methcxyisopropyloxyethyl)-4-tritylthio-2-a2etidinone (mixture of epimers at C-l1) A solution of crude l-(t-butyldimethylsilyl)-3-(l,-keto-2' (2-methoxy-2-isopropyloxy)-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 mol). The mixture was stirred at room temperature for 2 h and 254 quenched by slow addition of brine (280 ml). The mixture was extracted with EtjO (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 Cl. (500 ml). This was dried (Na,S0J 2 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: ’fimr (CDCl^) δ: 0.17 (s, SiCH3), 0.80, 0.87 (2s, Si-tBu), 1.22, 1.25 (2s, CHj), 3.03 (s, OCH ), 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,3S,4R and 4,S,3R,4S) and (4'S,3S,4R and 4'R,3R,4S) l-(t-Butyldimethylsily 1) -3- (2', 2'-dimethyl-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-d'-hydroxy-?' metho-i-'isopropyloxyethyl)-4-tritylthio-2-azetidinone (mixture of diastereomevs at C-l' (57.1 g, 0.0966 mol; crude, in CHjCl^ (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. NaHCO3 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=8il) 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) δ: 0.27 (6H, s, Si-CHj), 0.95 (9H, s, Si-tBu), 1.15 (6H, s. 265 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 Ks) ir (nujol) \) : 1750 (C=O) and 1595 era 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^) 6: 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, J3 4=1.5Hz, J3_4,=S.0Hz, H-3), 3.93 (IH, d, J4_3=1.5Hz, H-4), 7.1-7.7 (15H, m, aromatic Hs),- ir (nujol) vmax: 1650 (C=O) and 1595 cm 1 (aromatics); IQ Rf 0.37 (hexanes: EtOAc =4:1). Anal calcd for C jH NOjSSi: C 70.80, H 7.38, N 2.50, Ξ 5.73; found: (Isomer C) C 70.23, H 7.30, H 7.3-,M 2.41, S 5.53 and (Isomer B) C 70.52, H 7.31, N 2.40, S 5.05. 266 B. Preparation of the Penem Product (Isomer C) (4'R,3S,4R and 4'S,3R,4S) 3-(21,2'-Dimethyl-Γ ,3'-dioxolan-4'-yl)4-trltylthio-2-azetidinone (Isomer C) HMPT-HgO To a stirred solution of (4'R,3S,4R and 4's,3R,4S) l-(tbutyl-dimethylsilyl)-3-(2 *,2'-dimethy1-1',3'-dioxolan-4’-yl)-4-tritylthio-2-azetidinone (Isomer C) )14.3 g, 25.6 mmol) in hexamethylphosphorie triamide (230.4 ml) was added slowly ( in 20 min) at 0-5°C a solution of sodium azxde (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 BO 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 (CDClg)6:1.33, 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, ra, aromatic Hs) ,· ir (nujol) 3220 (NH), 1760 (C=O) and 1950 cm 1 (aromatics); Rf 0.31 (hexanes: EtOAc = 3:2). 267 (4’R,3S,4R and 4'S,3R,4S) 3-(21,2'-Dimethyl-1',3'-dioxolan-4'-yl)1-(p-nitrobenzyl 2-hydroxy-2-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2'1) (Isomer C) CH(0H)2 PNB Et^N/THF A suspension of p-nitrobenzyl glyoxylate hydrate (6.57 g, 28.95 mmol; 1.15 eq) in henzene (500 ml) was heated at reflux with Dean-Stark trap for 2 h. Evaporation of the solvent gave p-nitrobenzyl ytyoxylate as an oil. A mixture of this oil and (4’R,3S,4R and 4'S,3R,4S) 3-(2',2,-dimethyl-l'-3'-dioxolan10 4'-yl)-4-tritylthio-2-azetidinone (Isomer C) (11.2 g, 25.2 mmol) in THE (350 ml, distilled from LAH) was treated with triethylamine (289 mg, 2.86 mmol) at room temperature under Ng for 18 h (overnight).

After evaporation o the solvent, the residue diluted with CH2C12 (200 ml) was washed successively with brine containing IN HCl (2.9 ml) sat. NaHCO^ and brine, dried (Na^O^) and evaporated after addition of EtjO (30 mi) to g.ve 17.2 g (26.3 mmol, crude yield 100%; purity 95.8%) of the title compound as a white foam: Rf 0.40 and 0.30 (benzene: Et2O=2:2). Each isomer was separated by hplc (SiO2< eluent, benzene: Et2O=3:2) and purified by crystallization from CHjClj-E^O. Isomer I: Rf 0.40 (benzene: Et20=3:2); mp 153-4’C, ’Hmr (CDC13) δ: 1.20 (6H, s, di-Me), 3.1 (2H, m, H-3 and OH), 3.5-4.? (3!(, ra, H-4' and H-5’), 4.55 (IH, d, J=2Hz, H-4), .12 (IH, br, H-2), 5.30 (2H, s, OCHjAr) and 7.1-8.3 ppm (19H, ra, 268 aromatic Hs); ir (nujol) V : 3370 (OH), 1775 (β-lactam) and 1745 cm max (ester); Anal, calcd for C,,H,,N,0oS: C 66.04, H 5.23, N 4.28, found: 2 o C 65.85, H 5.64, N 4.11. Isomer II: Rf 0.30 (benzene: Et2O=3:2); mp 164-5’C; ’Hmr (CDC13) d: 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, -OOHjAr), and 7.1-8.3 ppm (19H, m, aromatic Hs); ir (nujol) V : 3340 (OH), 1765 (β-lactam) and 1740 cm 1 (ester); max Anal, calcd for c36H341,20gS: c 66-04, H 5.23, N 4.28, S 4.90, found:.

C 66.01, H 5.34, N 4.28, 3 4.75.

U'P.K.ffl and 3’S.3R.4S) 3-(2*,2’-Pimethvl-l',31-dioxolan-4'-vl)-1(p-nitrobenzvl 2-chloro-2''-acetate)-4-tritvlthio-2-azetidinone (mixture of epimers at C-2) (Isomer C) To a ;i.ii;red solution of (3*R,3S,4R and 4'S,3R,4S) 3- (2', 2' -dimethy1-1', 3' -dioxolan-4 ’ -yl) -1- (p-nitrobenzyl 2-hydroxy15 2-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 -15’C under 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 (CDCip δ: 269 1.20 (6H, s, diMe), 3.17 (IH, 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, OCH^Ar), 5.33 (s, H-2) and 7.1-8.3 ppm (19 H, m, aromatic Hs); ir (neat) V : 1770 cm 1 (g-lactam and ester). This material was used in the next step without purification. (4'R,35,4R and 4'S,3R,45) 3-(2',2'-Dimethyl-1‘,3'-dioxolan-4'-yl)-1(p-nitrobenzyl 2-tripheny lphosphoranylidene-2’’-acetate)-4-tri tyl thio2-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-chloro-2-acetate)-4-tritylthio2-azetidinone (Isomer u) i!7.87 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 for 40 '1. Evaporation of the solvent in vacuo gave 29.5 g 15 of dark oil which was purified by column chromatography (SiO2330 9- eluent -50% Et2O in benzene), yielding 10.5 g of yellowish solid. This solid was rinsed with Et2O to give 7.49 g (8.33 mmol, yield 33.3%) of the title compound as slightly yellow crystals: ’HmrtCDCip δ: 1.07 (s, di-Me) and 7.1-8.2 ppm (m, aromatic Hs); ir (nujol) vmax5 1760 cm 1 (C=O). An analytical sample was obtained by crystallization from CH2Cl2~Et2O: mp 231-2°C; Anal, calcd for CHN 0 PS: C 72.14, H 5.27, N 3.12, S 3.57; -- 54 47 2 7 found: C 72.18, H 5.43, N 2.98, S 3.41; Rf 0.17 (benzene: Et2O=l:l). 270 50586 (4'R,3S,4R and 4'S,3R,4S) Silver 3-(21,2'-dimethyl-1',3'-dioxolan4'-yl)-l-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-2azetidinone-4-thiolate (Isomer C) A solution of (4'R,3S,4R and 4'S,3R,4S) 3-(21,2'-dimethy11',3'-dioxolan-4'-yl)-1- (p-nitrobenzyl 2”-triphenylphosphoranylidene-2acetate)-4-tritylthio-2-azetidinone (Isomer C) (319 mg, 0.355 nmol) in Ci52C12 m1' was evaP°rated to yield an oily residue which was redissolved in hot methanol (8 ml; 60°). To this solution was added at 60® a hot solution of AgNO^ in MeOH (0.15M, 4.0 ml, 0.60 mmol) and then pyridine (29 μΐ, 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 methar.ol and then cold i't.O, yielding Λ. 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). max (4'R,3S,4R and 4'S,)R,4S) 3-(2' ,2'-Dimethyl-1',3'-dioxoIar.-4’-yl)1-(p-nitrobenzyl 2-tr iphenylphosphoranylidene-2,,-acetate) -4-acetylthio-2-azetidinone (Isomer C) To a solution of (4'R,3S,4R and 4'S,3R,4S) silver 3-(2',2'-dimethyl-11,3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2“triphenylphosphoranylidene-2-acetate-2-azetidinone-4-thiolate (Isomer C) (254 mg, 0.333 mmol) in CHgClg (15 ml) containing 271 pyridine (100 pi, 1.24 mmol; 3.72 eq) was added at 0-5°C acetyl chloride (71 pi, 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. NaHCO^ and then brine, dried (Na^O^) 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 (CDC13) δ: 1.23 (s, di-Me), 2.20, 2.33 (2s,-SAc) and 7.2-8.3 ppm (m, aromatic Hs): ir (nujol) V : 1750 (β-lactam and max ester) and 1690 cm 1 (thioester). An analytical sample was obtained by crystallization ί rom CH2Cl2-Et2O: mp 177-8’C; Anal, calcd for C ,H CN O PS: C 63.60, <1 5.05, N 4.01, S 4.59; found: C 63.34, H 5.32, J i 2 o N 3.83, S 4.31; Rf 0.62 (EtOAc) (4'R,5R,6S and 4'S,4S,bR) p-Nitrobenzyl 6-(2’,2'-dimethyl-11,3'5 dioxolan-4’-yl)-2-mcthylpenem-3-carboxylate (Isomer C) A suspension of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'dimethy1-1',3'-dioxolan-4'-yl)-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 9< eluent 10% Et.,0 in benzene) yielding 247 mg (0.587 mmol, yield 92.7%) of the title compound as white solid: ’Hmr (CDC13) δ: 1.42 (6H, s, di-Me), 2.38 (3H, s, 2-CHp 3.8-4.5 (4H, m, H-6, H-4* and H-5’), 5.02-5.25-5.33-5.57 (2H, AB type. 272 50896 -OCH2Ar), 5.57 (IH, d, J“1.8 Hz, H-5) and 7.52-7.67-8.12-8.27 ppm (4H, A2'B2', aromatic Hs); ir (nujol) 1760 (β-lactam) and 1700 cm”1 (ester). An analytical sample was obtained by crystallization from CH„Cl,-Et„O: mp 167-8’C; uv (EtOH) λ : 265 (ε 14,000) and 314 mp 2 2 2 max (ε 10,000); Anal, calcd for c19H20N2°7S: c 54-28> 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-l',3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylic acid (Isomer C) A solution of (4'R,5R,6S and 4'S,5S,6R) p-nitrobenzyl 6-(2', 2'-dimethyl-1’,3‘-dioxolan-4-yl)-2-methylpenem-3-carboxylate (Isomer C) (195 mg, 0.464 mmol) in THF (20 ml) was mixed with EtjO (20 ml), HjO (20 ml), NaHCO^ (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 39 mg (0.31 mmoL, yield 67%) of the title compound as yellowish solid: mp 132-3’C; Rf 0.60 (Acetone: HOAc=5: 0.7); 'Hmr (CDC1 ) δ: 1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-CH.p, 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) V : 1760 (β-lactam) and 1660 cm”1 (CO H); uv (EtOH) λ : 309 (ε 6300) and 2 wax 263 rap (ε 3800). 273 50586 Example 50 (h’S,5R,6s and 4'R,5S,6B) 6-(21 ,2'-Dimethyl-l' ,3'-dioxolan-4 '-yl)-2methylpenem-3-carboxylic Acid (Isomer B) (4'S,3S,4R and 4'R,3R,4S) 3-(2*,21-Diraethyl-1',3'-dioxolan-41-yl)4-trityithio-2-azetidinone (Isomer B) The title compound was prepared as described in Exp-nw q qg for the Isomer C from (4'S,3S,4R and 4’R,3R,4S) l-(t-butyldimethyisiJy.i i-3- (2' ,2 dimethyl-1' , S'-dioxolan-S'-yD^-trityllO thio-2-azolidinone (Isomer B) (14.4 g, 25.8 mmol): yield 10.8 g, 24.3 nwto), ‘M. 1%; mp 155°σ (CH Cl -EtjO) ,· Rf 0.24 (hexanes: EtOAc=2:3); Hmr (CDCl^) : 1.37, 1.40 (6H, 2s, di-Me), 3.23 (IH, dd, 03-4=2.5 Hz, J3_4,=5Hz, H-3), 3.7-4.5 (4H, m, H-4',H-5',N-H), 4.50 (IU, d, J=2.5Hz, H-4) and 7.1-7.S ppm (15H, m, aromatic Hs),ir (nujol) 3170 (NH) and 1745 cm1 (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. 274 50S96 (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethy1-1',3'-dioxolan-4'-yl·)1- (p-nitrobenzyl 2'*-hydroxy-2'’-acetate) -4-tritylthxo-2-azetidinone (mixture of epimers at C-2) (Isomer B) g The title compound was prepared as described in Exaaple 49 for the Isomer C from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl1',3'-dioxolan-4'-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: EtjO+l.-l); JHmr (CDC1 ) 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, OCH2Ar) and 7.1-8.3 ppm (m, aromatic Hs); ir (neat) υ : 3440 (br, OH), 1760 (C=O), 1520, 1350 max cm 1 (N02). (4'S,3S,4R and 4'R,3R,4S) 3-(2*,2'-Dimethyl-11,3'-dioxolan-4'-yl)]5 l-(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 Exanple 49 for the “Isomer CB from (4’S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1',3'20 1' ,3'-dioxolan-4'-yI)-l-(p-nitrobenzyl 2-hydroxy-2''-acetate) -4tritylthio-2-azetidinone (Isomer B) (14.9 g, 22.8 mmol; mixture of 275 epimers at C-2); yield 14.1 g, 20.9 mmol, 91.9%; yellowish foam; Rf 0.52 (benzene: Ε^Ο=3:2); ’Hmr (CDCl.^ 5: 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=3H2, 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-(21,2'-Dimethyl-1',3'-dioxolan-4 y1)-1-(p-nitrobenzyl 2-triphenylphosphoranilidene-2-acetate)-4tritylthio-2-azetidinone (Isomer B) -1 The title compound was prepared as described in Example ag for the Isomer C from ;4'S,3S,4R and 3'R,3R,4S) 3-(2',2'-dimethyl1',3 ' -dioxolan-4 '-yl) -1- (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 190^95^0 (dec., CH.Cl2-Et2O); ’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 Cl ) \) : 1750 cm 1 (β-lactam 2 m&x ester); Anal, calcd for C^H^N O^S: C 72.14, H 5.27, N 3.12, S 3.57; found: C 71.90, H 5.57, N 3.07, S 3.56; Rf 0.21 (benzene: Et 0=1:1). 276 50586 (4'S,3S,4R and 4'R,3S,4R) Silver 3-(2',2'-dimethyl-11,3'-dioxolan4'-yl)-1- (p-nitrobenzyl 2-triphenylphosphoranylldene-2-acetate)2-azetidlnone-4-thiolate (Isomer B) COjPNB AgNO -pyr MeOH co2?nb The title compound was prepared as described in Exaaple for the Isomer C from (4'S,3S,4R and 4'R,3S,4R) 3(2',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) υ : 1745 cm 1 (β-lactam, ester), max (4'S,3S,4R and 4'R,3R,4S) 3-(2',2’-Dimethyl-11,3'-dioxolan-4’-yl)1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer B) The title cbmpound was prepared as described in Exanple 4g for the Isomer C from (4’S,3S,4R and 4'R,3R,4S) silver 3-(2',2'dimethyl-1',3'-dioxolan-4'-y1)-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 (SiO2 • 277 g, eluent 10%-50% EtOAc in CH2Cl2=l:l); ‘Hmr (CDCl^ 6: 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) υ 1755 (β-lactam, ester) and 1695 cm 7 {thioester). max (4'S,5R,6S and 4'R,5S,6R) p-Nitrobenzyl 6-(2‘,2'-dimethyl-11,3'5 dioxolan-4’-yl)-2-methylpenem-3-carboxylate (Isomer B) The title compound was prepared as described in Example 49 for the Isomer C from (4’S,3S,4R and 4'R,3R,4S) 3-(2*,2'-dimethyl-11, ’-dioxolan-4 '-yl)-1- (p-nitrobenzyl 2-triphenylphosphoranylidene-2acetate)-4-acetylthio-2-azetidinone (Isomer B) (200 mg, 0.286 mmol): yield 64 mg, 0.15 mmol, 53%; mp 151-2’C (CH2Cl2/Et2O); Rf 0.67 (benzene: Et 0=1:1); ’llnu (CDCi3) fi: 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=l.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 2 max (ester); uv (EtOH) λ : 266 (ε 13,300) and 314 mp (ε 9,700); Anal, calcd max C19H20N2°7S: 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. 278 (4'S,5R,6S and 4'R,5S,6R) 6-(2',2'-Dimethyl-l*,3'-dioxolan-41-yl)2-methylpenem-3-carboxylie acid (Isomer B) The title compound was prepared as described in Exaaple 49 5 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-methylpenem-3-carboxylate (Isomer B) (79 mg, 0.19 mmol): yield after reerystallization from CHjCl^pentane 9 mg, 0.032 mmol, 17%; Rf 0.54 (Acetone: HOAc=5:0.5); 'Hmr (CDClj) δ: 1.35, 1.44 (6H, 2s, di-Me), 2.37 {3H, s, 2-CH.j) , 3.6-4.5 jQ (4H, m, H-6, H-4',H-5*) and 5.56 ppm (IH, brs, H-5); ir (neat) 1785 cm1 (β-lactam) ,· uv (EtOH) λ : 307 (ε 4300) and 262 mp (E 3700) . max Example 51 (l'R,5R,6s and 1'S,5S,6r) 6-(l'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-2ethyl)-2-methylpenem-3-carhoxylic acid (Isomer C) (l'R,35,4R and l'S,3R,4S) 3-(1',2'-dihydroxyethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-3-acetate)-4-acetylthio-2-azetidinone (Isomer C) J—'k.

TFA-HjO HC< ^5Ac co2pnb COjPNB A solution of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'dimethyl-1',3'-dioxolan-4 '-yl)Ί-(p-nitrobenzyl 2-triphenylphos279 phoranylidene-2”-acetate)-4-acetylthio-2-azetidinone (Isomer C) (472 mg, 0.676 mmol) in trifluoroacetic acid (1.0 ml) and H2<0 (0.1 ml) was left at room temperature for 30 min. The mixture was added dropwise to a cold solution of NaHCO^ (2.5 g) in H20 (50 ml) and extracted with CH2C12 (20 ml x 3). The extracts washed with sat.

NaHCO^ and then brine were dried (Na^O^) and evaporated yielding 458 mg (0.695 mmol, crude yield 100%; purity 97.3%) of the crude title compound as yellowish foam: 'Hmr (CDCl^) δ: 2.20, 2.32 (2s, SAc) and 7.2-8.3 ppm (m, aromatic Hs); ir (neat) 'Jmax: 3420 (OH), 1745 (β-lactam, ester) and 1690 cm 1 (thioester) ,· Rf 0.16 EtOAc). (l'K,3S,4R and l’S,3R,4S) 3-(1'-Hydroxy-2'-methoxymethoxy-l’-ethyl)1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer C) CO,P.:s ch2ci OH BrCH2OCH3~dimethylaniline co2pnb To a solution of (l'R,3S,4R and l'S,3R,4S) 3-{l',2'dihydroxyethyl)-1-(p-ni trobenzy1 2-triphenylphosphoranylidene-2”acetate)-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 CH2C12 (8 ml) was added at 0°C, Ν,Ν'-dimethylaniline (58.8 mg, 0.483 mmol; 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 CH2C12 was washed successively with IN HCl, sat. NaHCO^ and brine, dried (Na2SO4> and evaporated. The crude residue was purified by hole (SiOj, eluent EtOAc) collecting (31 mg, 0.186 mmol, yield 42.2%) of the title compound as an oil: Rf 0.24 (EtOAc); 'Hmr (CDC13) δ: 2.20, 2.32 (2s, SAc), 3.30 (s, OCHp , 4.52 (s,-OCH2O-) and 7.4-8.3 ppm (m, aromatic Hs); ir (neat) V : 3420 (OH), 1755 (br, β-lactam and ester) and 1690 cm 1 max (thioester). 280 (l‘R,5R,6S and l'S,5S,6R) p-Nitrobenzyl 6-(l'-hydroxy-2'-methoxymethoxy-21-ethyl)-2-methyIpenem-3-carboxylate OH A solution of (l'R,3S,4R and l'S,3R,4S) 3-(l'-hydroxy5 2'-methoxymethoxy-1'-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 N2 for 8 h. Evaporation of Lhe sol · ani in vacuo gave oily residue which was purified by hplc (SiOj, 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: Et2O=l:l); ’Hmr (CDC13) δ: 2.38 (3H, S, 2-CH3), 3.35 (IH, br, OH), 3.40 (3H, s, 0CH3), 3.6-3.8 (2H, m, H-2’), 3.90 (IH, dd, J65=2Hz, Jg_1,=4Hz, H-6), 4.18 (IH, m, H-l'), 4.67 (2H, S, -OCH 0-), 5.03-5.27-5.38-5.62 (2H, ABq, OCH^r) , .65 (IH, d, J=2Hz, H-5) and 7.55-7.70-8.15-8.30 ppm (4H, A2'B2', aromatic Hs); ir (neat) V : 3450 (OH), 1785 (β-lactam), 1710 (ester) and 1520 cm 1 max (NO.,); uv (EtOH) λ : 26ο (ε 13000, and 313 mil (ε 9100); Anal, calcd for 2 max C,_H_„N„O„S: C 50.94, Ii 4.75, N 6.60; found: C 51.13, H 4.77, N 6.36. 2 8 281 (l'R,5R,6S and 1’S,5S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)2-methylpenem-3-carboxylic acid (Isomer C) OH OH A solution of (l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl 6-(11 -.hydroxy-2' -methoxymethoxy-2'-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 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 0°C with 0.1N HCl (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 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-d,) δ: 2.28 (3H, s, 2-CH.), 3.27 (3H, s, OCH.), 3.49(2H, d, J o J=6.2HZ, 2'-H), 3.87 (IH, dd, J =1.7Hz, < ,,=3.3Hz, 6-H), 4.58 6-5 0-1 (2H, s, -OCHgO-) and 5.55 ppm (IH, d, J=1.7 Hz, 5-H); ir (KBr) 3410 (OH), 1755 (β-lactam) and 1655 cm1 (COgH); uv (EtOH) 308 (ε 6800) and 262 mp (ε 4200), mp 137-8’C (dec.). 282 Example 52 (1'S,5R,6S and 1'R,5S,6r) S-Cl'-Hydroxy-O'-methoxymethoxy-S'-cthyl)-.?methylpenem-3-carboxylic acid (Isomer B) (1*S,3S,4R and l‘R,3R,4S) 3-(11,2'-dihydroxyethyl)-1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer B) thf-H2O > The title compound was prepared as described in Example 51 for the 10 “Isomer C front (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 (CDC13> 6: 2.20, 2.32 (2s, -SAc) and 7,3-8.2 ppm (ra, aromatic Hs): ir (neat) V : 3410 (°H’' 1730 (β-lactam, ester) and 1690 cm 1 (thioester): Rf 0.16 (EtOAc). 283 S Ο 59 6 (l'S,3S,4R and l'R,3R,4S) 3-(11-Hydroxy-2'-methoxymethoxy-1'-ethyl)1-(p-nitrobenzyl 2-triphenylphosphoranylidene-2-acetate)-4-acetylthio-2-azetidinone (Isomer B) The title compound was prepared as described in Example 51 for the Isomer C from (l's,3S,4R and l'R,3R,4S) 3-(1'.2'-dihydroxyethyl) -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 (CDC13) δ: 2.22, 2.33 (2s, SAc), 3.32 (s, OCH3), 4.57 (s,-OCH2O-> and 7.2-8.3 ppm (m, aromatic ir (neat) υ : 3420 (OH), 1755 (β-lactam, ester) and 1690 (thioestep max Rf 0. 32 (EtOAc) . 'l'S,5R,6S and l’R,5S,6R) p-Nitrobenzyl 6-(1'-hydroxy-l'-methoxymethoxy-2' -ethyl) -2-me thylpenem-3-carboxylate toluene-HQ for the Isomer C from (l'S,3S,4R and l'R,3R,4S) 3-(1'-hydroxy-2*me thoxyme thoxy-1' -ethyl) -1- (p-nitrobenzyl 2-triphenylphosphorany1idene-2-acetate)-4-acetylthio-2-azetidinone (Isomer B) (205 mg, 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 (CDCl^ δ: 2.37 (3H, s. 2-CH3), 3.40 (3H, s, OCH^, 3.4-3.9 (3H, m, H-6, H-2), 284 4.15 tin, m, H-l'), 4.67 (2H, s, -OCH2O-), 5.10-5.27-5.39-5.56 (2H, ABq, -0CH2Ar), 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,C1, mull) v : 3370 (OH), 22 3 2 2 max 1785 (β-lactam) and 1700 cm 1 (ester); uv (THF-EtOH=l:l) λ : 265 max (ε 10400) and 314 mp (£ 7800). (l'S,5R,6S and l'R,5S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2‘-ethyl)2-methylpeneni-3-carboxylic acid (Isomer B) OH OH CH, H2/Pd-C COjPNB co2h The title compound was prepared as described in Example 5) ]0 for the Isomer C from (l’S,5R,6S and l'R,5S,SR) p-nitrobenzyl 6(1’-hydroxy-2'-methoxymethoxy-21-ethyl)-2-methylpenem-3-carboxylate (Isomer B) (36 mg, 0.085 mmol): yield 7.5 mg, 0.026 mmol, 30%; yellowish crystals; ’Hair (CDCl^) fi: 2.36 (3H, s, 2-CH^), 3.39 (3H, s, OCH3), 3.6-1.9 (JH, m, H-6, H-2'), 4.15 (IH, m, H-l'), 4.66 (2H, s, OCHjO) and 5.67 ppm (IH, d, 0=1.4 Hz, H-5); ir (CH2C12) 1785 (β-lactam) and 1675 cm'1 (CO„H); uv (EtOH) λ : 308 (ε 2900) max and 263 mp (ε2900). 285 Example 53 2-Benzylimidoyl ami nomethylpenem-3-carboxylic Acid To a suspension of 0.38 g (0.0015 mole) of sodium 3-benzyl-l,2,4-oxadiazol-5-oneE-acetate (I)1 iu 10 ml of methyl chloride, containing 2 drops of D’-iF, was added at room temperature 0.13 ml (0.0015 mole) of oxalyl chloride, causing the mixture to effei-vesce. The reaction mixture was stirred at room temperature fcr 1 hour. 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.

Ber. 103, 2330 (l9?0). 1. K. Takacs and K. Harsanyi, Β. (II) SAg (III) 02PNB A solution of 1.0 g (0.0015 mole) of (III) and 0.12 ml (0.015 mole) of pyridine in 10 ml of methylene chloride under a nitrogen atmosphere was cooled to 1»°. The acid chloride (II) solution was added all at once to the solution of (ill) and the reaction mixture was stirred at h° for 5 minutes, then at rooa 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 0.1N hydrochloric acid, 80 ml of 1? sodium bicarbonate and 80 ml of water. The methylene chloride phase was dried over magnesium sulfate. The solvent was removed at 286 50586 reduced pressure and the residual oil chromatographed on Mallinckrodt 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 V, C.

(XV) toluene . reflux A solution of 0.4 g (0.00045 mole) of IV in 50 ml of toluene was heated at reflux for 4 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 C Hj^O S: C, 55.86; K, 3-67; N, 11.33.

Found: C, 56.17; H, 3.76; N, 11.23.

A solution of 0.135 g (0.00027 mole) of V in 4o ml of tetrahydrofuran and 4o ml of anhydrous diethyl ether was added to a slurry of 10? palladium on carbon catalyst in 4o 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 4.5 psi. The catalyst was removed by filtration, washing the filter pad well with water. . Additional diethyl ether uas 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 r,uc^ea’* 287 SO 59 6 magnetic resonance spectra vere consistent for the desired product.

Anal. Calcd for N 0 S-1.5H2O: C, 52.31; H, 5-27; N, 12.20.

Found: C, 51.61»; h, h.95; N, 12.31.

Example 54 2-PhenylimidoylaminoniethyIpenem-3-carboxylic Acid COOH Following the procedure of Example 53 but using an equimolar amount of sodium 3-pheny1-1,2,4-wxadiazol-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.

Biological Data Representative compounds of the present invention were subjected to in vitro antibiotic screening against a variety of microorganisms. Samples of the indicated compounds a-ter solu— tion in water and dilution with Nutrient Broth were found to exhibit the following Minimum Inhibitory Concentration (MIC) in meg./ml. versus the indicated microorganisms as determined by overnight incubation at 37°c. by the tube dilution method. 288 50S9 Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staohylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus Mirabilis A9716 Proteus morganii A15153 Proteus rettceri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Sacteroides fragilis A20931 Bacteroides fragilis A2°929 289 H.l.C. in mcg/inl Compound ( Example 1 ' 125 >125 125 125 125 >125 No Organism Streptococcus pneumoniae A9585 Compound (Example Ko.) 2 1 3 1 Streptococcus pyogenes A9604 2 4 Staphylococcus aureus A9537 8 2 Staph aureus +50% Serum A9537 >63 >63 Staphylococcus aureus A96O6 4 4 Staphylococcus aureus A15097 8 32 Streptococcus faecalis A20688 63 125 Escherichia coli A15119 32 63 Escherichia coli A20341-1 32 63 Klebsiella pneumoniae A15130 63 125 Klebsiella species A20468 >125 >125 Proteus mirabilis A9900 63 63 Proteus vulgaris A9716 63 32 Proteus morganii A15153 63 125 Providencia stuartii A21205 32 63 Serratia marcescens A20019 125 63 Enterobacter cloacae A9659 125 125 Enterobacter cloacae A9656 >125 125 Pseudomonas aeruginosa A9843A >125 >125 Pseudomonas aeruginosa A21213 >125 >125 Hemophilus influenzae A9833 — Haemophilus influenzae A21522 — Bacteroides fragilis A20931 Bacteroides fragilis A20929 •A. - - 290 M.I.C. in mcg/ml Compound (Example Organism 4 5 Streptococcus pneumoniae A958S τ 75 Streptococcus pyogenes A9604 4 4 Staphylococcus aureus A9S37 8 4 Staph aureus +50% Serum A9537 >63 >63 Staphylococcus aureus A9606 4 9 Staphylococcus aureus A15097 125 .63 Streptococcus faecalis A20688 125 125 Escherichia coli A15119 >125 63 Escherichia coli A20341-1 >125 125 Klebsiella pneumoniae A15130 >125 63 Klebsiella species A20468 >125 >125 Proteus mirabilis A9900 63 63 Proteus vulgaris A9716 63 32 Proteus morganii A15153 125 125 Providencia stuartii A21205 126 32 Serratia marcescens A20019 >125 63 Enterobacter cloacae A9659 >125 125 : Enterobacter cloacae A9656 >125 125 Pseudomonas aeruginosa A9843A - >125 Pseudomonas aeruginosa A21213 * >125 Hemophilus influenzae A9833 - - Haemophilus influenzae A21522 - - Bacteroides fragilis A20931 - - Bacteroides fragilis A20929 - - 291 M.I.C. in mcg/ml .(Example No. Compound Organism Streptococcus pneumoniae A958S 5(n; 1 6(11) Streptococcus pyogenes A96O4 2 4 Staphylococcus aureus A9537 4 4 Staph aureus +50% Serum A9537 32 63 Staphylococcus aureus A9606 32 125 Staphylococcus aureus ' A15097 63 63 Streptococcus faecalis A20688 >63 125 Escherichia coli A15119 16 16 Escherichia coli A20341-1 >63 125 Klebsiella pneumoniae A15130 63 125 Klebsiella species A20468 >63 >125 Proteus mirabilis A9900 8 16 Proteus vnliarii A21559 63 32 Proteus morganii A15153 16 32 Proteus rettgeri A21203 32 32 Serratia marcescens A20019 32 63 Enterobacter cloacae A9659 63. 63 Enterobacter cloacae A9656 63 63 Pseudomonas aeruginosa A9843A 16 32 Pseudomonas aeruginosa A21213 32 >125 Hemophilus influenzae A9833 - Haemophilus influenzae A21522 Bacteroides fragilis A2O931 - — Bacteroides fragilis A20929 292 M.I.C.

Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mjrabilis A9900 Proteus vulgaris A9710 Proteus morganii A151S3 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9 833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 in mcg/ml Compound (Example No.) “ _12 .016 .06 .13 125 .5 >125 125 125 293 0 596 Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A9555 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9 833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 294 M.I.C. in mcg/ml Compound (Example No.) 32 38 24 725 725 7016 8 2 .25 8 4 .03 32 63 63 16 4 16 63 16 >125 >125 125 16 63 4 63 >125 16 >125 125 32 >125 >125 125 >125 63 16 32 125 16 - - 125 32 32 63 32 - 63 32 16 125 32 >125 125 63 125 125 125 >125 125 125 >125 - - - - - - - - - - M.l.C. in mcg/ml Compound (Example No.) Organism 32 13 Pseudomonas A20599 Pseudomonas A9925 Pseudomonas A20229 Proteus species A20543 Proteus mirabilis A9716 Providencia stuartii A21205 aeruginosa aeruginosa aeruginosa 295 M.I.C.

Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A2Q468 Proteus mirabilis A9900 Proteus vulgaris A9716 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9 833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 296 in mcg/ml Compound (Example No.) 25 >63 >125 >125 125 >125 >125 >125 125 125 >125 >125 >125 125 125 50S96 M.I.C. in mcg/ml Compound (Example Mo.) Organism 25 Pseudomonas aeruginosa A20599 Pseudomonas aeruginosa A9925 Pseudomonas aeruginosa A20229 Proteus species A20543 Proteus mirabilis 63 A9716 Proteus mirabilis A9555 297 M.I.C. in mcg/ml Compound (Example No.) Organism 31 Streptococcus pneumoniae -A9585 63 Streptococcus pyogenes A9604 125 Staphylococcus aureus A9537 32 Staph aureus +50% Serum A9537 32 Staphylococcus aureus A9606 >125 Staphylococcus aureus A15097 63 Streptococcus faecalis A20688 63 Escherichia coli A1S119 63 Escherichia coli A20341-1 32 Klebsiella pneumoniae A15130 >125 Klebsiella species A20468 63 Proteus mirabilis A990P 125 Proteus vulgari : A9555 ' >125 Proteus morganii A1S153 125 Proteus rettgeri A21203 125 Serratia marcescens A2OO19 125 Enterobacter cloacae A9659 125 Enterobacter cloacae A9656 , 32 Pseudomonas aeruginosa A9843A 125 Pseudomonas aeruginosa A21213 . 125 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 298 M.I.C.

Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A1S097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A9555 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 in mcg/ml Compound (Example No.) 34 .06 • .13 2 1 4 16 63 125 4 >125 16 125 125 16 4 >125 16 125 ' 32 >125 125 8 16 63 16 32 32 16 32 63 32 125 32 63 63 125 125 125 125 - - - - Bacteroides fragilis A20929 299 50593 M.l.C. in mcg/ml Compound (Example No.) Organism 35 36 40 Streptococcus pneumoniae 7Σ5 ~ ;σο4 A9585 32 .25 .008 Streptococcus pyogenes 125 1 .004 A9604 125 1 .008 Staphylococcus aureus - - .008 A9537 >125 2 .008 Staph aureus +50% - .06 Serum A9537 >63 8 .06 Staphylococcus aureus - . .06 A9606 >125 4 .06 Staphylococcus aureus - - .06 A15097 >125 8 .25 Streptococcus faecalis >125 63 .5 A20688 >125 63 .5 Escherichia coli >125 16 .13 A15119 >125 16 .25 Escherichia coli >125 16 <.25 A20341-1 >125 16 .13 Klebsiella pneumoniae >125 16 <,25 A15130 >125 16 .5 Klebsiella species >125 16 .5 A20468 >125 16 .5 Proteus mirabilis >125 32 <•25 A99OO >125 16 .25 Proteus vulaans >125 16 <•25 A21559 >125 16 ' .25 Proteus morganii >125 32 1 A151S3 >125 16 1 Proteus rettgeri >125 16 <<25 A21203 > 125 16 .5 Serratia marcescens > 125 16 • 5 A20019 >125 16 .5 Enterobacter cloacae >125 32 4 A9659 > 125 ” 2 Enterobacter cloacae > 125 16 .5 A9656 > 125 - .5 Pseudomonas aeruginosa >125 >125 16 A9843A >125 16 Pseudomonas aeruginosa > 125 >125 125 A21213 > 125 — 63 Hemophilus influenzae - - - A9 8 33 — Haemophilus influenzae - - - A21522 • Bacteroides fragilis - - - A20931 Bacteroides fragilis - - - A20929 - - - 300 5058 M.X.C. in mcg/ml Compound (Example No.) Organism 37 33 39 Streptococcus pneumoniae A9585 .03 .03 .016 Streptococcus pyogenes A9604 .06 .5 .03 Staphylococcus aureus A9537 .5 .03 .06 Staph aureus +50% Serum A9537 4 .25 .13 Staphylococcus aureus Ά9606 1 .25 .13 Staphylococcus aureus A15097 2 .5 .25 Streptococcus faecalis A20688 2 32 4 Escherichia coli A1S119 2 8 2 Escherichia coli A20341-1 8 8 2 Klebsiella pneumoniae A15130 8 16 4 Klebsiella species A20468 63 32 4 Proteus mirabilis A9900 2 2 4 Proteus vn'loa.ris A21559 4 2 2 Proteus morganii A15153 8 2 4 Proteus rettgeri A21203 2 2 4 Serratia marcescens A20019 a 16 4 Enterobacter cloacae A9659 8 32 4 Enterobacter cloacae A9656 32 1 16 Pseudomonas aeruginosa A9843A 63 2 16 Pseudomonas aeruginosa A21213 - - - Hemophilus influenzae A9833 ·- - - Haemophilus influenzae A21522 - - - Bacteroides fragilis A20931 - - - Bacteroides fragilis A20929 - - - 301 M.I.C.

Organism Streptococcus pneumoniae A958S Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A21559 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9 8 33 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 in mcg/ml Compound (Exampl >63 >63 >63 >32 >63 >63 >63 >63 >63 >63 >63 >63 >63 >63 >63 . >63 >63 >63 >63 >63 M.I.C. in mcg/ml Compound (Example Mo.) Organism 45 Streptococcus pneumoniae A9585 2 Streptococcus pyogenes A9604 16 Staphylococcus aureus A9S37 32 Staph aureus +50% Serum A9537 >32 Staphylococcus aureus A9606 2 Staphylococcus aureus A15097 , 8 Streptococcus faecalis A20688 63 Escherichia coli A151X9 2 Escherichia coli A20341-1 32 Klebsiella pneumoniae A15130 8 Klebsiella species A20468 >63 Proteus mirabilis A9900 4 Proteus vulgaris A21559 16 Proteus morganii A15153 8 Proteus rettgeri A21203 8 Serratia marcescens A20019 8 Enterobacter cloacae A9659 8 Enterobacter cloacae A9656 8 Pseudomonas aeruginosa A984 3A 63.

Pseudomonas aeruginosa A21213 >63 Hemophilus influenzae A9833 Haemophilus A21522 Bacteroides A20931 Bacteroides A20929 influenzae fragilis fragilis 303 SOS06 M.I.C. in meg/ml Compound (Example No.) Organism Streptococcus pneumoniae —— A9585 .5 Streptococcus pyogenes A9604 .5 Staphylococcus aureus A9537 3 Staph aureus +50% Serum A9537 32 Staphylococcus aureus A9606 16 Staphylococcus aureus A15097 32 Streptococcus faecalis A20688 >63 Escherichia coli A15119 32 Escherichia coli A20341-1 32 Klebsiella pneumoniae A15130 . 63 Klebsiella species A204S8 63 Proteus mirabilis A9900 32 Proteus vuloaris A21559 ' 32 Proteus morganii A15153 63 Proteus rettgeri A21203 32 Serratia marcescens A20019 63 Enterobacter cloacae A9659 63 Enterobacter cloacae A9656 63 Pseudomonas aeruginosa A9843A >63 Pseudomonas aeruginosa A21213 >63 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A2O931 Bacteroides fragilis A20929 304 M.I.C.

Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vo.lgari* A21559 Proteus morganii A151S3 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9 833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 in mcg/ml Compound (Example No.) 48 49 50 >125 1 32 >125 16 32 >125 32 125 >63 >63 >63 >125 32 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 >125 - - - - - - - - - - M.I.C.

Organism Streptococcus pneumoniae A95 85 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia coli A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulaaris A21559 Proteus morganii A15153 Proteus rettgeri A21203 Serratia marcescens A20019 Enterobacter cloacae A9 659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 in mcg/ml Compound (Example Mo.) 51 52 53 54 63 16 4 32 63 32 4 32 >63 63 >8 63 >32 >32 >32 >32 >63 63 63 >63 >63 63 >63 >63 >63 63 >63 >63 >63 >63 63 63 >63 >63 63 63 >63 >63 63 >63 >63 >63 >63 >63 63 >63 >63 63 >63 >63 >63 >63 >63 >63 >63 >63 >63 63 32 63 >63 . >63 >63 63 >63 >63 63 >63 >63 >63 63 63 63 63 63 63 63 63 63 63 - - - - - - - - - - - - 306 M.I.C.

Organism Streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 Staphylococcus aureus A9537 Staph aureus +50% Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus A15097 Streptococcus faecalis A20688 Escherichia cold A15119 Escherichia coli A20341-1 Klebsiella pneumoniae A15130 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vuloaris A2155S Proteus morganii, A15153 Proteus rettger.i A21203 Serratia marcescens A20019 Enterobacter cloacae A9 659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9843A Pseudomonas aeruginosa A21213 Hemophilus influenzae A9833 Haemophilus influenzae A21522 Bacteroides fragilis A20931 Bacteroides fragilis A20929 in mcg/ml Compound (Example No, 55 56 .5 .25 .5 .25 .5 .25 16 16 32 16 >63 >125 >63 125 63 63 >63 >125 >63 125 >63 >125 65 63 63 125 63 63 63 63 63 125 >63 125 63 125 .63 63 63 125 - - - - 307 S0S96 Representative compounds of the present invention were also tested in vivo in mice and their Ρϋ^θ (dose of compound in mg/kg required to protect 50% of the treated mice against an otherwise lethal infection of a microS organism) values determined with respect to the test organisms shown below. 308 S. aureus A9537 Compound # of infecting organisms of , S. aureus # of A 9537 treatments Treatment routePD50 (mg/kg/treatment. Compound of EX. 40 • 7.8 χ 105 2 IH 0.12 Compound of EX. 36 6.6 x 10s 2 IM 7.7 Mouse blood levels after intramuscular administration of representative compounds of the present invention were determined and are reported in the table below.

*Mouse Blood Levels in mcg/ml After intramuscular Administration of 40 mg/kg Body Weight Compound Minutes After Administration 30 45 60 90 120 Compound of Ex. 40 44.7 34.4 23.7 17.6 9.8 3.6 1 *Average of 6 mice 310 CLAIMS 1. A compound having the formula wherein 1 is hydrogen atom or an easily removable ester-forming protecting group; X is (a) a group of the formula (i) -OR, in which R is a hydrogen atom; a 3 (ii) -0Rb in which Rfa is a hydroxy, optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic group, the substituents on the alkyl group being one or more of a halogen atom, a hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkyl, amino, (lower)alkyl amino, di(1ower)alkylamino, (lower)-alkanoylamino, or optionally substituted phenyl or heterocyclic group and the substituents on the phenyl or heterocyclic rings being one or more of a halogen atom, a hydroxy, (lower)-alkoxy, (lower)alkyl, halo(lower)-alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkylamino, di(lower)-alkylamino, (lower)alkanoylamino, (lower)-alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl group; or 311 (iii) -OCORc in which Rc is an amino, (lower)-alkylamino, di(lower)alkylamino or optionally substituted (lower)alkyl group in which the substituents are as defined under(ii); or (b) a substituted (lower)aliphatic, (lower)-cycloaliphatic or 5 (lower)cycloaliphatic(lower)-aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl group the substituents for the above-mentioned aliphatic, cycloaliphatic, phenyl or heterocyclic groups being NR, II 1 (i)-CNR2R3 or N=C-NR2R3 «1 in which R^ is a hydrogen atom, a (lower)alkyl or phenyl group and R2 and R3 are each independently a hydrogen atom a (lower)alkyl, phenyl or benzyl group; (ii) -0Rd in which Rd is an amino, (lower)alkylamino, di(lower)alkylamino, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyl (lower)alkyl, heterocyclic or heterocyclic (lower)alkyl, the substituents on the alkyl, phenyl or heterocyclic groups being as defined under (a) (ii); except that they are not ami no,( lower) alkyl ami no or di (lower) alkyl ami no when - x is substituted C-j-Cg alkyl and Rd is substituted C2-C4 alkyl; (iii) -0(CH2)n0Rr in which n is an integer from 1 to 6 and Rr is an optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl, phenyl or heterocyclic groups being as defined under (a) (ii); (iv) -OCORr' in which R^' is an amino (lower)-alkylamino, di(lower)alkylamino or R group, wherein Rf is as defined above, with the proviso that Rf may not be an unsubstituted (lower)alkyl group; 312 (ν) -0S03H; Φ (vi) -0Ρ(0Η)2; (vii) -0S02Rr in which Rp is as defined in (b) (iii); * (viii) -OP(ORe)(ORr) in which Rg is a (lower)alkyl group and Rp is as defined in (b) (iii); (ix) -S(O)nRd in which n is 0, 1 or 2 and Rd is as defined in (b) (ii) with the exception of (lower) alkyl substituted by one or more halogen atoms or is in the case where n=0, nr4 II 4 -C-NR5R6 in which R4 is a hydrogen atom or a (lower)alkyl group and 10 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) -COR^ in which Rf is an amino(lower)alkyl, (lower)alkyl amino(lower) alkyl, di(lower)alky1amino(lower)alkyl, -NHNH2, -NR17N(R18)2, NHOR1g, -S-Rp, -0(CH2)n-A-Re or -NReRg in which R17, R^g and Rgare (lower)alkyl groups, R^g is a hydrogen atom or a (lower)alkyl group, A is 0, S, NH or NCHg and £ is as defined in (b) (iii) and Rg is an Rp group; (xi) -P0(0Rw)2 in which Rw is a hydrogen or a (lower)alkyl group; (xii) - r(HRh in which R^ is an optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -SOgH, -OH, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, 313 50386 NH II -C-NRyRg in which R? and Rg are each independently (lower)alkyl, phenyl or 5 phenyl (lower)alkyl, NH II -C-Rg in which Rg is (lower)alkyl, phenyl or phenyl(lower)-alkyl or II -C-R. in which Ri is amino (lower)-alkyl, -NH,, (lower)alkylamino, di(lower)-a1kylamino, Z HN- , in which is (lower)alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being as defined under (a) (ii), NH II NH-C-NHg, (lower)alkoxy, -OCH, :-OCH2-( Vn02 or -0(CH2)2Si(CHg)3 group; 314 II (xiii) -S-C-R^ in which R^ is a (lower)alkyl group substituted by an amino, (lower)alkylamino or di(lower)alkylamino group; (xiv) -NRjRfc in which Rj is a (lower)aikyi group and Rk is a (iower)alkyi, (lower)alkoxy, heterocyclic, amino, or II -C-R] group in which R1 is as defined in (b) (xii) or, when taken together with the nitrogen, Rj and Rk represent providing that when Rk is an amino or -CH2CH2NH2 group, Rj is a methyl group and also providing that Rj and Rk may not both be a (lower)alkyl group; (xv) -NR-'Rp' in which R.' is a (lower)alkoxy group and J K j Rk' is a (lower)alkyl, heterocyclic, amino(1ower)alkyl, (lower)alkylamino-(lower)alkyl, di(lower)alkylamino(lower)-alkyl or group in which P( is as defined under {bj (xii) or, when taken together with the nitrogen, Rj' and Rk' represent 315 S0S86 © (xvi) -NR-.R R in which R,, Rm and Rn are each independently a ' ' ι m η I m n (lower)alkyl group or when taken together with the nitrogen, represent _y % (xvii) -N=CH-Rx in which R* is a (lower)alkyl or optionally ringsubstituted phenyl or heterocyclic group, the substituents on the phenyl or heterocyclic ring being as defined in (a) (ii); (xviii) -N=CRxRy in which Ry is a (lower)alkyl or optionally ringsubstituted phenyl or heterocyclic group, the phenyl and heterocyclic substituents being as defined in (a) (ii), and Rx is as defined in (b) (xvii); (xix) = N-Rp in which Rp is a hydroxy,(lower)alkoxy, amino, di(lower)alkylamino || (xx) -c-(CH2)nNR15R16 316 $0596 in which n is an integer from 1 to 5 and R·^ and R^ are each independently a hydrogen atom or a (lower)alkyl group; and Y is a hydrogen atom or a group selected from (a) an optionally substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic group, the substituents being one or more of a hydroxy, (lower)alkoxy, optionally substituted phenyloxy, optionally substituted heterocyclicoxy, optionally substituted (lower)alkyl thio, optionally substituted phenylthio, optionally substituted heterocyclicthio, mercapto, amino, (lower)alkylamino, di(lower)alkylamino, (lowerJalkanoyloxy, (lower)alkanoylamino, optionally substituted phenyl, optionally substituted heterocyclic, carboxy, carb(lower)alkoxy, carbamoyl, N-(lower)alkylcarbamoyl, N,N-di(lower)alkylcarbamoyl, halo, cyano, oxo, thioxo, -SO^H, -OSO^H, -S02-(lower)alkyl, (lower)alkylsulfinyl, nitro, phosphono or ΐ -OP(ORe)(ORr) group in which Rg and Rr are as defined above, the substituents on the (lower)alkylthio group being one or more of a halogen atom, a hydroxy, (lower)alkoxy, amino, (lowerJalkanoylamino or optionally substituted phenyl or heterocyclic group and the phenyl or heterocyclic substituents above being one or more of a halogen atom, a hydroxy, (lower)-alkoxy, (lower)alkyl, halo(lower)alkyl, methane-sulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; 317 (b) -0Rs in which R$ 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,(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, methanesulfonyl, (lower)alkylthio, (lower)alkylamino, di(lower)alkylamino, amino, (lower)alkanoylamino, (lower)alkanoyloKy, carboxy, carboxy(1ower)alkyl, sulfo or sulfo(lower)alkyl group; (c) “S(O)nRs in which n is 0, 1 or 2 and Rs is as defined above; (d) a halogen atom; and; (e) an optionally substituted phenyl or heterocyclic group in which

Claims (13)

1. 5 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)alkanoylamino, (lower)-alkanoyloxy, carboxy, carboxy(lower) alkyl, sulfo or sulfo(lowerjalkyl group, with the proviso that 20 when Y is a hydrogen atom then X may not be -CHgOCHgCHgOCHg.

2. A compound as claimed in claim 1 wherein Y is a hydrogen atom.

3. A compound as claimed in claim 1 wherein Y is a C^-Cg alkyl group optionally substituted by a hydroxy group. 25

4. A compound as claimed in claim 1 wherein Y is an α-hydroxyethyl group.

5. A compound as claimed in any one of claims 1 to 4 wherein X is 318 (b) -(CHg^NHOH in which £ is an integer from i to

6. ; (c) -(CH 2 ) n P0(0-C^-Cgalkyl) 2 in which n is an integer from 1 to 6; NH II (d) -(CH 2 ) n NH-C-C^-Cg alkyl in which n is an integer from 1 to 6; NH, I 2 (e) -(CH 2 ) n N=CH in which ji is an integer from 1 to 6; 11 AB (f) -(CH2) n 0C(CH2) ra NR”R B in which ji and m are each A B independently 1 or 2 and R and R are each independently a hydrogen atom or a (lower)alkyl group; or 10 (g -ch 2 NHC-R c ί n „ NH in which ji is an integer from 1 to 6 and R c is a C-j-C^ alkyl, phenyl or -< C AA // group in which m is 1 or 2. 319 5. A compound as claimed in claim 1 as specifically defined in any one of the foregoing specific Examples.

7. A pharmaceutically acceptable salt of a compound as claimed in any one of the preceding claims. 5

8. A process for the preparation of a compound as claimed in any one of the preceding claims which process comprises cyclizing a compound of the formula: ,S - C-X N-. CO 2 R wherein Q is a phenyl or (lower)alkyl group, R is an easily removable ester group and X and Y are as defined in claim 1 in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent; removing by methods known per se the removable ester-forming protecting group and other protecting groups; and 15 if desired, converting a compound of formula I where Y is a hydrogen atom, to any other desired product where Y is a substituent as defined in claim 1 other than a hydrogen atom by treating the product with a corresponding electrophile in an inert solvent in the presence of a strong base. 20

9. A process as claimed imclaim 8 substantially as hereinbefore described.

10. A compound as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 8 or 9. 320

11. A pharmaceutical composition which comprises as active ingredient at least one compound as claimed in any one of claims 1 to 6, or claim 10, or a pharmaceutically acceptable salt thereof as claimed in claim 7, together with a pharmaceutically acceptable diluent 5 or carrier, ,

12. A process for the preparation of a compound as claimed in any of claims 1 to 6 substantially as described herein with reference to the Examples.

13. A compound as claimed in any of claims 1 to 6 whenever 10 prepared by a process as claimed in claim 12. Dated this 18th day of December 1979, (signed)