CA1268183C - Phosphorane intermediates for use in preparing penem antibiotics - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to phosphorane compounds of the formula

Description

1~i8i~3 The present invention relates to certain novel 2-substituted and 2,6-disubstituted penem compounds which possess potent antibiotic activity. Also provided are various novel intermediates useful in preparing the bio-logically active penem derivatives and various processes for the production of the intermediates and active compounds.
The penem ring system has the formula ~S~

~ N ~

and systematically can be designated as 7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene. For the sake of .~.

simplicity, it is named "2-penem" in the present application and the numbering system used is as follows:

~ S~
,~L N _~

There is thus provided by the present invention the novel penem compounds having the formula Y S
I ~X

o~ ~ N ~

wherein Z is hydrogen or an easily removable ester protecting group; X is (a) a radical of the formula (i) ~ORa in which Ra is hydrogen;
(ii) -CORb in which Rb is hydrogen, hydroxy, optionally substituted (lower) alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl group being one or more (preferably 1 or 2) of halo, hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower) alkylamino, di-(lower)alkylamino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or more (preferably 1 or 2) of hydroxy, 12~

(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 jNIRl (i) -CNR2R3 or -N=C-NR2R3 in which R1 is Rl hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzyl;
(ii) -ORd in which Rd 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 and heterocyclic groups being as defined under (a) (ii);
(iii) -O(CH2)nORr in which n is an integer from 1 to 6 and Rr 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) -OCORr' in which Rr~ is amino, (lower)-alkylamino, di(lower)alkylamino or Rr,with the proviso that Rrl may not be unsubstituted (lower)alkyl;
(v) -OSO3H;
$

(vi) -OP(OH)2;
(vii) -OSO2Rr in which Rr is as defined under (b) ( i ii ) ;
o (viii) -OP (ORe) (ORr) in which Re is (lower)alkyl and Rr is as defined under (b) (iii);
(ix) -S(O)nRd in which n is 0, 1 or 2 and Rd is as defined under (b)(ii) or is in the case where NR
n=O -C-NR5R6 in which R4 is hydrogen or (lower) alkyl and R5 and R6 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, -NHNH2, -NR17NR18, -NHR19~ -S-R17, ~0(CH2)n-A-Re or ~NReRg in which R17, R18 and Re are (lower)alkyl~ R19 is hydrogen or (lower)alkyl, A is 0, S, NH or NCH3 and n and Rg ar~ as defined under (b) (iii) and (b)(viii);
(xi) -PO(ORw)2 in which RW i8 hydrogen or (lower)alkyl;
(xii) -NHRh in which Rh is optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH~ -S03H, -OH, (lower)alkoxy, amino, (lower) alkylamino, di(lower)alkylamino, -NHCOCH3, -CS2CH3, -SO2CH3' -S2 -S02NH2 -CNH2, -;CNHCH3, -C-NH

NH
-C-NR7R8 in which R7 and R8 are each independently (lower) alkyl, phenyl or NH NH
NH
phenyl(lower)alkyl, -C-Rg in which Rg is (lower)alkyl, phenyl or phenyl(lower)- alkyl, or -C-Ri in which Ri is amino(lower)- alkyl, -NH2, (lower)alkylamino, di(lower)-alkylamino, -NH ~ , -NH-C-Rlo in which R1o is (lower)alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being NH
defined under (a)(ii), -NH-C-NH2, (lower)alkoxy, ~`

-OCH2 ~ , -OCH2 ~ NO2 or -o~cH2)2si(cH3)3;
O
(xiii) -S-~-R11 in which R11 is (lower)alkyl substituted by amino, (lower) alkylamino or di(lower) alkylamino;
(xiv) -NRjRk in which Rj is (lower)alkyl and Rk is (lower)alkyl, (lower) alkoxy, heterocyclic, o amino, or -C-R1 in which Ri is as defined under (b)(xii) or, when taken together with the nitrogen, Rj and Rk represent o -~ ~ ~ , providing that when Rk is amino or -CH2CH2NH2, Rj is methyl and also providing that R~ and Rk may not both be (lower)alkyl;
(xv) -NRj'Rk' in which Rj' i8 tlower)alkoxy and Rk' i8 (lower) alkyl, heterocyclic, amino(lower) alkyl, (lower) alkylamino-(lower)alkyl, di(lower)alkylamino(lower)-o alkyl or -C-Ri in which Ri i8 as defined under (b)(xii) or, when taken together with the nitrogen, Rj' and Rk' represent -N~
o l;~ti~

(xvi) -NRlRmRn in which Rl, Rm and Rn are each independently (lower)alkyl or when taken together with the nitrogen, represent ~ ~
-N ~ ;

(xvii) -N=CHXRx 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 Ry 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);
(xix) =N-Rp in which Rp is hydroxy, (lower)alkoxy, amino, di(lower)alkylamino or -NH~ ; or N OH
(xx) ~C-(CH2)nNR15R16 in which n is an integer from 1 to 6 and R15 and R16 are each independently hydrogen or (lower)alkyl; and Y is hydrogen or a radical selected from the group consisting of (a) optionally substituted (lower)aliphatic, (lower)cyclo-aliphatic 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 ~.~

18;~

heterocyclicthio, mercapto, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoyloxy, (lower)alkanoylamino, optionally substituted phenyl, optionally substituted heterocyclic, carboxy, carb (lower)alkoxy, carbamoyl, N- (lower)alkylcarbamoyl, N,N-ditlower)alkylcarbamoyl, halo, cyano, oxo, thioxo, -S03H, -OS03H, -S02-(lower)alkyl, t (lower)alkylsulfinyl, nitro, phosphono or -OP
(ORe)(ORr) in whioh Re and Rr are as defined above the substituent6 on the (lower)alkylthio group being one or more of halo, hydroxy, (lower)alkoxy, amino, (lower)alkanoylamino or optionally sub6tituted phenyl or heterocyclic and the phenyl or heterocyclic 6ubstituents above being one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo (lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or 6ulfo(10wer)alkyl;
(b) -ORS in which Rs is optionally sub6tituted (lower)alkyl or (lower) alkanoyl or optionally substituted phenyl or heterocyclic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)alkoxy, (lower)alkylamino, di (lower)alkylamino, amino, oxo, (lower)alkanoyIamino or optionally 6ubstituted 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;

.~

81~3~
(c) S(O)nRS in which n is 0, l or 2 and Rs is as defined above;
(d) halo; and (e) optionally substituted phenyl or heterocyclic in which the substituents are one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo (lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower)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 -CH2OCH2CH2OCH3.
The compounds of formula I wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolyzed esters) are potent antibacterial agents. The remaining compounds are useful intermediates for preparation of the biologically active penems.
Substituent groups disclosed above for the 2- and 6-positions of the penem ring may be further defined as follows:
(a) 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;

....... .

" .

12~
(c) (Lower)aliphatic is intended to include acyclic straight and branched chain saturated and unsaturated hydocarbon 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, l-propenyl, 2-propenyl, isopropenyl, 2-methyl-2-propenyl, ethynyl and 2-propenyl. 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 cyclohexienyl (e) (Lower)cycloaliphatic (lower)aliphatic represents cycloaliphatic-aliphatic radicals having 3-8 carbon atoms (preferably 3-6) in the cyclo-aliphatic ring and 1-6 carbon atoms (preferably l-4 and most preferably 1-2) in the aliphatic ~`

lZ~
portion. Examples include cyclopropylmenthyl, cyclopropylethyl, cyclopropylpentyl, cyclo-butylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cyclopentenylethyl, cyclopropylethenyl, cyclopropylethynyl, etc. The most preferred radicals of this type are cycloalkyl-alkyl in which the cycloalkyl portion contains 3-6 carbons and the alkyl portion contains 1-2 carbons;
(f) (Lower)alkoxy includes Cl-C6 alkoxy radicals, the alkyl portion of which being defined as in (b).
Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, etc. Preferred are Cl-C4 alkoxy and most preferred are Cl-C2 alkoxy;
(g) ~Lower)alkylthio includes Cl-C6 alkylthio radicals in which the alkyl portion is as defined under (b). Examples include methylthio, ethylthio and n-butylthio;
(h) (Lower)alkylamino includes Cl-C6 alkylamino radicals in which the alkyl portion is as under (b). Examples are methylamino, ethylamino, n-propylamino and n-butylamino;
(i) Di(lower)alkylamino represents di Cl-C6 alkylamino in which each alkyl is as defined under (b).
Examples are dimethylamino and diethylamino;

~2~i81~3 (j) (Lower)alkanoyloxy represents radicals of the l formula (lower)alkyl-C-O- in which alkyl is as defined under (b);
(k) (Lower)alkanoylamino includes radicals of the formula (lower)alkyl-C-NH- in which alkyl is as under (b);

(1) Carb(lower)alkoxy represents -C-(lower)alkoxy in which (lower)alkoxy is as under (f);
(m) Halo(lower)alkyl represents alkyl radicals in which one or more hydrogen atoms are replaced by a halogen atom;
(n) Sulfo(lower)alkyl represents - (CH2)nSO3H in which n is 1-6;
(o) Carboxy(lower)alkyl represents - (CH2)nCOOH in which n is 1-6; /---(p) Phenyl (lower)alkyl represents -(CH2) in which n is 1-6;
(q) (Lower)alkylamino(lower)alkyl represents -(CH2)nNH-(lower)alkyl in which n is 1-6 and alkyl is as defined under (b);
(r) Di(lower)alkylamino(lower)alkyl represents ~ (lower)alkyl - (CH2)nN in which n is 1-6 (lower) alkyl and each alkyl is as defined under (b);
O
(s) (Lower)alkanoyl represents (lower)alkyl-C-in which alkyl is as under (b);
(t) N-(Lower)alkylcarbamoyl represents O
(lower)alkyl-HN-C- in which alkyl is as under (b);

i81~

(u) N,N-Di(lower)carbamoyl repre6ents (lower)alkyl O
N-C- in which each alkyl is (lower)alkyl S as under (b);
(v) Amino(lower)alkyl represents -(CH2)nNH2 in which n is 1-6;
(w) Hydroxyamino (lower)alkyl represents - (CH2)nNHOH
in which n is 1-6;
$
(x) (Lower)alkylsulfinyl represents -S- (lower)alkyl in which (lower)alkyl is as defined above under (b); and (y) (lower)alkenyl represents 6 traight or branched unsaturated aliphatic hydrocarbon radicals con-taining one double bond and having from 2-6 carbon atoms inclusive, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl.
The term "heterocyclic" aæ u6ed herein is intended to include heteromonocyclic and heterobicyclic residues of aromatic character as well as appropriate partially or wholly saturated residues, said heterocyclic residues con-taining at least one heteroatom selected from oxygen, sulfur and nitrogen and being bonded to the penem ring carbon atom via a ring carbon atom. The preferred heterocyclic groups are either 5- or 6-membered monocyclic radicals or fused 6,6 or 5,6 bicyclic radicals. Illustrative of suitable heterocyclic radlcals are the following:

' 12~81~3 H

~( ~H 2 ~,N! ~J [~N~ ~

~S~ N

H H
N ~

N 1 ~ ~ ~ I

O ~ ~ `S

~N ~,~

( ~ and ~2~ 3 Similarly, the terms heterocyclic-(lower) alkyl, heterocyclic-thio-(lower)alXyl, heterocyclicoxy and heterocyclic-thio represent - (CH2)n-Heterocyclic, (CH2)n-S-Heterocyclic, -0-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 (R- and S- forms) optical isomers. Preferred are the compounds in which the configuration of the 5-carbon atom corresponds to that of natural penicillin (SR-configuration). Sub-stituents 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 isomers A, B, C and D (see Example 58 for stereochemistry). ~he 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.
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), procaine, dibenzylamine, N-benzyl-~-phenethylamine, 1-ephenamine, N,N'-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, p-toluenesulfonic, maleic, 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 above-described salts may be carried out according to conventional procedures for forming salts of ~-lactam antibiotics such as penicillins and cephalosporins.
The term "easily removable ester protecting group"
is one which has acquired a definite meaning within the ~-lactam and peptide art. Many such groups are known which are used to protect the carboxyl group during subsequent chemical reactions and which may later be removed by standard methods to give the free carboxylic acid. Known ester protecting groups include 2,2,2-trichloroethyl, tertiary alkyl of from 4-6 carbon atoms, tertiary alkenyl of from 5-7 carbon atoms, tertiary alkynyl of from 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl of from 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl, ~-trimethylsilylethyl, and the like.

~`

12~ 33 Choice of an ester 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 pre-ferred 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 ~-trimethylsilylethyl ester removable by treatment with fluoride ions. Also included within the scope of easily removable ester protecting groups are physiologically cleavable esters, i.e. those esters known in the penicillin and cephalosporin art to be easily cleaved within the body to the parent acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl, thienylglycyloxymethyl or acyloxymethyl of the formula O
-CH2C-Y ' in which Y' is Cl-C4 alkyl or phenyl. Particularly pre-ferred 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 tincluding hydrates) forms are intended to be within the scope of the invention.

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 ~-carbon) by hydroxy. More preferred compounds within the above group are those wherein Y is hydroxy, ethyl or -hydroxyethyl. Still more preferred compounds of formula I are those wherein Y is hydrogen or -hydroxyethyl.
The most preferred compounds are those wherein Y is a-hydroxyethyl.
A preferred embodiment of the present invention consists of the compounds of formula I wherein substituent X is 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, the substituents for the above-named aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenyl-alkyl, heterocyclic, heterocyclic-alkyl and heterocyclicthio-alkyl radicals being INI Rl -CNR2~3 or -N=C-NR2R3 in which Rl Rl is hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzyl.
Within this class, the preferred compounds are those wherein Y is hydrogen, etnyl or -hydroxyethyl, esoecially those wnerein Y is hydrogen or Q-hydroxyethyl and most especially those wherein Y is ~-hydroxyethyl.

81~

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)c~cloaliphatic(lower)aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocvclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl radical, t-.- substituents on the above-mentioned aliphatic, cycloaliphatic, cycloaliphatic-allphatic, phenyl, phenyl-alkyl, heterocyclic, heterocyclic-alkyl or heterocyclicthio-alkyl radicals being -CORf in which Rf is amino(lower)alkyl, (lower)alkylamino(lower)-alkyl, di(lower)alkylamino(lower)alkyl, -NHNH2, -NR17NR18, 19 17 ( 2)n A Re or ~NReRg in which Rl , R
Re and Rg are (lower)alkyl, Rlg is hydrogen or (lower)alkyl, A is O, S, NH or NCH3 and n is an integer from 1 .o 6.
Within this class, the preferred com?ounds are those wherein Y is hydrogen, ethyl or ~-hydroxyethyl, especially those wherein Y is hydrogen or ~-hydroxyethyl and most es?ecially those wherein Y is ~-hydroxyethyl.
Still another prefer-ed embodiment of the present invention consists of the compounds of formula I wherein X is ~ ~
(a) ~(CH2)n~ ~ in which n is an an integer .rom 1 to 6, preferably 1 to 4;
(b) -(CH2)nNHOH in which n is an inteaer from 1 to 6, preferably 1 to 4;

_ Iq ~
;~

1~i8i~

(c) -(CH2)nPO(O-Cl-C6 alkyl)2 in which n is an integer from 1 to 6, preferably 1 to 4 and alkyl is preferably methyl, ethyl or iso-propyl; NH

(d) (CH2)n \ in which n is an Cl-C6 alkyl integer from 1 to 6, preferably 1 to 4, and alkyl is preferably methyl or ethyl;

(e) (C 2)n \ in which n is an integer from 1 to 6, preferably 1 to 4;

(f) -(CH2)nOC(CH2)mNR R in which n and m are each independently 1 or 2 and RA and RB
are each independently hydrogen or (lower)-alkyl; or (g) -(CH2)nNHC-RC in which n is an integer of NH
1 to 6, preferably 1 to 4, and Rc is Cl-C4 alkyl (preferably methyl or ethyl), phenyl or (CH2)m ~ in which m is 1 or 2.

Within this class of compounds, the preferr2d members a-e those wherein Y is hydrosen, ethyl or ~-hydroxyethyl, preferably those wherein Y is hydrogen or ~-hvdroxyethyl and most preferably those wherein Y is a-hydroxyethyl.

~ 3 Other preferred embodiments of the present invention include the intermediates of the formulae:

~N ~ P(Q~31 M

C02R x III
wherein Y is hydrogen or as defined above in regard to compounds of formula I, Q is phenyl or (lower)al~yl, R"
is an easily removable ester protec~ing group, X is l or 2 and M is Cu(II), Pb(II) or Hg(II) when x is 2 or Ag(I) when x is l;

(B) Y ~ SHgCOOCH3 CO2R" IIIa in which Y, Q and R" are as defined above under (A); and (C) y ~ -T
N ~ P(Q)3 C2R"
IV

wherein Y is as defined above in regard to compounds of formula I, Q is pnenyl or (lower)al~vl,.R" is an easily removable ester protecting group and T is C 6H~ 11 -7-C6H5 or -C-X wnerein X is as defined above in regard to compounds of formula I.
In the intermediates of formulae III, IIIa and IV, Q is preferably phenyl, R" is preferably p-nitrobenz-l and X and Y are preferably those substituent groups mentioned as being preferred in connection with the compounds of for~ula I. Reactive functional sroups such as mercapto, amino and hydroxy in substiluents Y and X may be protected by conventional blocking groups during con-version of the intermediates to biologically active end-products.
Compound I may be prepared bv 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 incor-porated in the basic starting material; Process II invol~es incorporation of Y at the end of the synthesis and in Process III substituent Y is incorporated in mid-svnthesis.
Fach 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 subatituent Y in mid-synthesis and to incor?orate substituent X by acylation of mercaptide intermediate III or IIIa snown below since these procedures have been ~ound ~o be the most senerally useful.
The steps of Process I may be seen f_om the following scheme~

12~ 3 Process I (Variation 1): Early incor?orat on or 2-substituent ~ OAc XC-SNa Y-CH=CR-OAc CSI ~ ~ N~ pH 7.5 >
O H

O O
Y ~,,SC-X ~ Y~,SC-X
I l CHO l l SOCl~
N~ C2R" ~

C2R"

Y~sc-~ P0 Y~SC-X ~

N ~ Cl base N ~ P~3 C02R" ' C2R"

~U ~ de-p~otect ~N

Ac = CH3C---.23--~ 83 Process I (Variation 2) ~ate incor?oration of 2-substituent ~ OAc cH3c-sNa Y-CH=CH-OAc CSI > ~ N~ pH 7.5 >
O H

Y SAc ~ Y ~ SAc >
CHO l l SOCl2 N~ C2R" ~

C2R"

Y ~ SAc P03 , ~~~ ~ SAc MA
N ~ Cl base ~ N ~ P~3 base C2R" C2 SM Y ~ SC-X

CO2R" CO2R"

de-protect ~ ~CO
o X-C- ~ = acvlating agent ~A - heavy metal salt ~ 3 Process I (Variation 3): Late incorporation of 2-substituent ~ OAc 03CS~a Y-CH=CH-OAc CSI > ~ I >
O H

SC03 CHO ~ sc03 SOCl~
o~~N~H , 1 02R' co2~l Y~ ~ SC03 P03 ` ~ SC~3 .~A >
~ N ~ Cl base ~ N ~ P03 base C2R" C2R"

~sl~ ~ Y~,SC-X a O~ 3 O ~

C2R" C2R"

~1 ~ de -pro tect r, -~5--1;~ti~183 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 l-substituted ~-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 0C 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-2-azetidinone, Process I may be separated into three different paths. In one route (Variation l), the o azetidinone is reacted 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-azetidinone into the 4-acethylthio-2-azetidinone and 4-tritylthio-2-azetidinone products, respectively, by nucleophic dis-placement with thioacetic acid or triphenylmethyl mercaptan (or a salt thereof such as the sodium salt), respectively.

12~8~3 The 4-thio azetidinone is next reacted with a o glyoxylate ester HC-C02R~ wherein R" is an easily removable ester protecting group such as p-nitrobenzyl or trimethyl-silylethyl, or a reactive oxo derivative thereof such as ahydrate, in an inert organic solvent te.g. benzene, toluene, xylene, and the like) and preferably at an elevated temperature (e.g. 50C. up to most preferably reflux temperature). When a hydrate of the ester iB 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 re-agent (e.g. SOC12, POC13, PC15, and the like) in an inert organic solvent (e.g. tetrahydrofuran, diethyl ether, methylene chloride, dioxane, and the like) in the presence or absence of a base, preferably an aliphatic tertiary amine (e.g. triethylamine) or a heterocyclic tertiary amine (e.g. pyridine or collidine). The reaction is advantageously run at from about -10C. to room temperature.
Chloro ester product is obtained as a mixture of epimers which can optionally be purified before use in the next step.
~ he 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) i81~;~

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.
At this stage the process again diverges into two routes. In Variation I (where the 2-substituent has already been incorporated), the phosphorane intermediate is converted to the desired penem by thermally cyclizing in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent system. Most conveniently, the cyclization is carried out under reflux conditions. Suitable inert organic solvents include aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane), carboxylic acid amides (e.g. dimethylformamide), di C1-C6 alkylsulfoxides (e.g.
dimethylsulfoxide) or a Cl-C6 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 .~

~268183 I S ~

~ 0 ~ P(Q)3 _ M

2 x III
or / SHgCOOCH3 n N ~f~P ( Q ) 3 IIIa 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 i8 accomplished by reaction of the phosphorane with a salt of Hg(II), Pb(II), Cu(II) or Ag(I) or with (methoxycarbonyl)mercury(II) acetate in a methanol-containing solvent and in the presence of an organic or inorganic base such as aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate, and the like. A preferred base is pyridine. The reaction may be carried out at room temperature or, if desired, with moderate cooling or heating. The anion (A) of the heavy metal salt may be any anion which gives a soluble salt in the selected solvent, e.g. N03 , CH3C00 , BF4 , F , C104 , N02 , CN0 , etc. The mercaptide intermediate i8 then 35 reacted with an acylating agent capable of introducing the moiety X-C- wherein X i8 the desired penem 12~18~

2-substituent. The acylating agent tx-C-O) may be the acid S O
X-~-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 thioe6ter, etc. Acylation is conducted in an inert solvent (e.g. a halogenated hydrocarbon such as methylene chloride or an ether 6uch 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 condenslng agent, for example a carbodiimide such as N,N'-dicyclohexylcarbodiimide. Acylation of the mercaptide can be achieved over a wide temperature range, but is preferably carried out from about -20 to l25C.
Following acylation, the resulting phosphorane is cyclized as described above to give the desired penem ester.
Formation of the phosphorane via the mercaptide intermediate (Varlations 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 12~i~18~

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-a~ueous 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 ~eriod of from about 1-; hours depending on the solvent and catalyst used. I- an eaui-valent weight of a base such as an alkali metal or alkaline earth metal hydroxide or an amine is emploved during .;~e hvdrogenation, the product may be recovered in the form of a carboxylic acid salt. Removal o' the ~-trimethylsilyl-ethvl ester, another useful ?rotectina g~ou?, is conveniently ach eved by trea'~ment with a source of -luorice ions. Other ester ~rotecting groups can be simila~ly removed bv methods ~ell-known to those skilled in the art.
In a second main p~ocess (~rocess II), the reaction seauence is as shown below:

12t~8183 Process II (Variation~ Early incorporation of 2-substituent - O
OAc 11 r~~~' XC-SNa CH2=c~-oAc CSI ~ ~ N~ pH 7.5 >
0 ~1 O O
Il 11 ~SC-X ~ ~ SC-X >
CY.O l SOC12 N~ C2R" o N ~ OH

C2R"

SC-X p~ ~S 11 -X ~, N ~ Cl base N ~ P~3 C2R" C2R"

~X Y > ~,T,~`

~S

de-Drotect O ~X

co2 -3~

~2681~

Process II (Variation 2): Late incor~oration of 2-substituent OAC
CH2=CH-OAc CSI ~ ~N--~ AcSNa >

~SAc CHO n~SAc SOC12 N~ C02R" \~

~SAC P~3 ~ n' S~c MA
N ~ Cl base ~ N Y ?~3 base C2R" C02 SM X-C- ~ ~ ~ SC-X a C~2R" C2R"

~N ~ base ~ ~ ~ X

C2R Co2R"

de-protect ~ ~

12~i8183 Process II (Variation_3 ): Late incorporation of 2-substituent OAc 03CSNa CH2=cH-oAc CSI 3 ~ pH 7 . 5 >
O H

~SC03 CHO ~ SC~3 SOC12 ~N~ co2R o N~,,OH

C2R"

bC~ ~p03 C02R'' o 2 ~SM ~ ~

C2R" C2R"

~N ~ base ~N ~

C 2 C2R"

> ~ ~X
de -pro tec t --3't-1~6t31~3 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, ir desired, is now in-corporated at this stage by reaction of the 2-penem with a suitable electrophile in an inert solvent (e.g. tetrahydro-furan, diethyl ether, dimethoxyethane, and the liXe) and in the presence of a strong base. In this procedure the 2-penem can be reacted in the form of the free acid (obtained by de-blocking as described above) in the presence of about t~o equivalents of base or, alternatively, a suitable 2-penem ester may be used in the presence o about one equi-valent o` base. Any ester inert to anion chemistry (the reaction involves anion formation with base followed by reaction of the electro?hile with the penem anion) may be em?loyed, e.g. (lower)alkyl such as methyl, ethyl, n-propvl or t-butyl, pnenyl, trichloroethyl, methoxvmethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl, and the like. Penem esters :aving activated methylene groups such as p-nitrobenzyl are not suitable and, if the 2-penem ester is of this ty?e, it must be first de-bloc.ced 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 hvdride, phenyl lithium or butyl lithium are suitable. .~ost prererably, however, a lithium disilylami~e or a lithium dialkylamice such as lithium Zi-cyclohexylamide (LDCA), lithium di-thylamide, lithi-lm di-methylamide or lithium di-isopropvlamide (LD~) is used, ~2~i8183 The electxophile is selected so as to generate the-desired Y-substituent upon reaction with the anion and ~ay be, for example, a halogen (e.g. Br2, I2), an alkyl halide (e.g. CH3I) or a similar halide such as an aliphatic, cycloaliphatic, cvcloaliphatic-aliphatic, phenyl-(lower)alkyl, heterocvclic, heterocyclic-thio, heterocyclic-thio-(lower)alkyl, or heterocyclic-~lower)alkyl, halide, a tosylate or ~esylate (e.g.

CH3CH2 2 ~ CH3, CH3CH20502CH3' ~ 52 ~ SO2, 2 2CH20SO2CH3, etc.), an e?oxide (e.g. ~ ) an pisul,ide (e.g. ~ ), an aidehyde (e.a. CH3CHO, C6H5CH2CHO), ~0 a ketone (e.g. CH3COCH3, ~ ) or an ester (e.g.

CH3CH2COOCH3 or C6H5COOCH3). Representatlve examples o other suitable electrophiles are shown below:

CH2=CH-CH2~3r ~ 11 Br CH3CCH=CH2 Br Br CH3CH-CH3 ~ Cl ~cH2Br HCHO 0C CCH2Br Gco CH3SSO2cH3 ~0CH2Cl ~2~ 83 ~CH=C~CHO 0 ~

CH3CCH2Cl ~L Icl CH2Cl A most preferred electropnile 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 0C.) according to the general procedure described in Canadian Journal of Chemistrv, 50(19), 3196-3201 (1972).
After fQrmation o- the desired 2,6-~e?em, any ester protecting group may be remove~ as discussed above to give the de-protected p.oduct.
The third main reaction process (Process III) can be understood from the following scheme:

Process III (Variations 1 and 2):

~ SC03 SC03 ~H N~B

y ~ Y~SC~3 base N~B

ce-protect / \ .U~/base 12~i81~;~

S C0 3 Y~CNf M

O H O ~B

¦, co2R" ¦~x, 1~) Y~SC03 Y~SC-X
O N~OH \B

\ SOC12 ~ / de-protect Y~,SC03 Y~SC-X
O N~

C2R"
p03 \ ~ base \ ~CCHOo2R~l , SC03 SC-X
l~sP03 ~N~f,OH

C2R~ C2R~I

~!~ MA/base ~ SOC12 -3~-12~

Y~ _~ S~ ~,sc-x 0~ ~N~P~3 ~ N ~ Cl C2R" C02R"

~3 ~1~ X-C- ~ base Y ~ ,SC-X Y SC-X

N~P~Z53 C2R" C2R"

y --~ Y ~--~

C2R" C2R"

j~de-protect ~¦~de-protect ~X ~X
O O
CO 2~ CO 2 .
B = blocking group for ring nitrosen 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 bloc~ing group such as triorganosilyl (e.g. trimethylsilvl or t-butyldimethylsilyl), methoxymethyl, methoxvethoxymethyl, tetrahydropyranyl, and the like. Introduction of the desired Y-substituent at the l-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 con-ditions as described above in connection with ~rocess II).
At this point the process diverses into two routes depending on the time of de-blocking the azetidinone.

In one route the N-protected intermediate is de-blocked by conventional procedurés (e.g. acid hydrolysis) and then converted to the 2,6-penem via ester formation, chlorination of the hydroxy ester, conversion of the chloro ester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with X-C- ~ , thermal cyclization of the resulting ?hos?horane to give the 2,6-penem ester and removal of the carboxyl-protecting group. Reaction conditions for these steps are as disclosed in connection with Process II (Varlation 3).
Ar. alternative route involves the s.eps of converting the ~-protected azetidinone to a ;.eavy metal mercaptide, acylating the mercaptide with the ~oiety X-C- ~ , removing the N-?rotecting sroup, reacting the '~

1~i81~

de-protected azetidinone with the glvoxylate ester, chlorinating, reacting the chloro ester with the phosphine to give the phos?horane, cyclizing the phos?horane to give the penem ester and removing the carboxyl-protecting group to give the 2,6-penem. Reaction conditions for these steps are as disclosed previously.
In preparing the 2-penem or 2,6-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 esteri-Lication, and free carboxyl or sulfo groups, for example, oy esterification, including silylation. After the reaction has taken place, these grou~s 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 2,6-substituents during or at the conclusion of the reaction ?rocedures according to known processes to obtaln other substituents incluced within the scope of the ?resent invention. Thus, 'or e~ample, carbonyl sroups can be re-duced to alcohol groups, unsaturated ali?hatic crou?s can be halogenated, amino groups can be alXylated or acylated, nitro groups can be converted to hyd-o~yamino and amino groups, hydroxyl groups can be etheri~ied or este~ified, etc.
The ~enem free acid compounds may be converted to pharmaceutically acceptable salts the=eof or to easily ~~/~

12~i8~3 removable esters thereof (particularly physiologically cleavable esters). Salts may be 'ormed by reaction of the free acid with a stoichiometric amount of a suitable non-toxic 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. Ml~tures of diastereomeric isomers, ror examole, can be seoarated by fractional crystallization, adsorption chromatograpny (column or thin-laver) or other suitable separation methods.
Resulting racemates can be resolved into the antipodes in 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 the free compounds, or by fractional crystal-lization 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 y s--C-X

0 ~ ~ ~(Q)3 C2R"

12~8~83 wherein Q is phenyl or (lower~alkyl, Rll is an easily removable ester group and X and Y are as defined above in an inert organic solvent at a temperature of from just above room temperature to the re~lux temperature of the solvent: removing by methods knswn per se the removable ester group and,optionally, other protecting groupss and, if Y is hydrosen and when desired, converting the product to any other desired product where Y is not hydrogen by treating said product with a corsesponding electrophile in an inert solvent in the presence of a strong base.
The present invention also comprises those ~m-bodiments according to which.compounds used as intermedlate products are used as starting materials and the remaining process steps are carried out with these, or the process is discontinued at any stage, Furthermore, starting materials can be used in the form of derivatives or can be formed during the reaciton.
The free acid penem compounds provided by the present invention and pharmaceutically acceptable salts , ~ . .
-~3-and physiologically cleavable esters of said acids have been found to be potent broad-spectrum antibacterial agents usefu~ in the treatment of infectious diseases in animals, including man, caused by both Gram-negative and Gram-positive organisms. The compounds are also of ~alue 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) pro-vided according to the present invention (i.e. compounds of general formula I wherein Y = H) possess antibacterial activity per se and are also useful inter,mediates (preferably in their carboxyl-protected form) for preparing the 2,6-disubstituted penems I via anion formation and reaction witn an electrophile.

The active compounds provided by the present in-vention may be formulated as pharmaceutical compositions comprising, in addition to the active ingredient, a pha~a-ceutically acceptable carrier or diluent, The compounds may be administered both orally and parenterally. The pharmaceutical preparations may be in solid form such as capsules, tablets or dragees, or in li~uid fo~ such as solutions, suspensions or emulsions. In the treatment of bacterial infections in man, the active compounds of this 1~681~3 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 ~g./Xg./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 in-gredient with suitable physiologically acceptable carriers or diluents.
The present invention also provides a method of combatting bacterial infections in animals, particularly warm-blooded animals, which comprises administering an acid of formula I or a physiologically cleavable ester thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to an infected host in an amount sufficient to com~at such infection.
Illustrative examples of the preparation of starting materials and end-products of the present invention follow. All temperatures are in degrees Centigrade, For the sake of convenience, certain abbreviations are employed in the examples. Definitions of the less obvious of these abbreviaticns are as follows:
CSI chloro sulfonyl isocyanate pet. ether petroleum ether b.p. boiling point n.m.r. nuclear magnetic resonance h hour ether diethyl ether (unless otherwise indica.ed`) ~5-`" 12~i81~1 "CELIT~'* 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 Et C2H5-Tr -C(c6H5)3 Me CH3-THF tetrahydrofuran Ph phenyl DMF dimethylformamide TEA triethylamine PNBG p-nitrobenzylglyoxylate THP tetrahydropyranyl TFA trifluoroacetic acid H~PT (or HMPA) hexamethylphosphorus triamide EtOAc ethyl acetate DMSO dimethylsulfoxide Ac CH3CO-Ms CH3SO2-DMAP 4-dimethylaminopyridine Py pyridine LDA lithium diisoproDyl amide sl6- `

*Trade Mark 126~83 \

2'-~2'-Diethylphos~hono-l'-ethvl)~enem-3-carboxylic Acid n ' ~ (CH2)2P-(OEt)2 N _~

O O
(EtO)2-P-(cH2)2co2cH3 ) (~tO)2P-(CH2)2C02H

Il 11 [Eto)2p-(cH2)2cocl ~ (EtO)2-P-CH2)2COSH

A mixture of 1 (11.2 g, 50 mmoles) and 5N NaOH (10 ml) was stirred and cooled (ice-bath) for 15 min and at room temperature for 15 min. The mixture was extracted with ether and the extract discarded. The aqueous solution was acidified with 5N HCl and extracted wht CH2C12 to give after drying and evaporation of solvent 10.0 g (95%) of oil ~, nmr ~ (CDC13), 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 mmoleg) 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 t~

evaporated to dryness. The traces of (COCl)2 were removed azeo-tropically with benzene to give 2.4 g (quantitati~e yield) of c ude 3.~. v C 1800; 1?35 cm . n~r ~ 4.3 (4H, m!, 3.Q ~ '.7 ~Cl (2H, m) 2.0 - 3.0 (2H, m), 1.4 (6H, m). This was treated with H25/TEA in a standard procedure to g~ve 1.9 g (80%) of oil 4 estimated to be 803 pure. Nmr: ~ 4.1 (4H, q), 2.7 - 3.5 (2H, m), 1.7 - 2.5 ~2ff, m) 1.33 (6H, .).

R

~ (EtO)2P_(cH2)2cs ~ S ~ (CH2)2PIOE')2 To 4 (1.9 9, 8.4 mmoles) was adced ~nce; N2 1:1 solution of NaHCO3 (10 ml), followed by addition o' 5 (0.8i3 9, 6.3 .mmoles) in H20 (3 ml). The oH of the mixtu-e W2S adjusted to 7-8 by acding more NaHCO3. After standing for 4 h the mixture was extracted with CHC13 to give after drying and con-centration 1.05g (56.4~ based on 5) of solid 6, m.p. 64-67, nmr ~ 7.7 (~H), 5.3 (lH ~), 4.2 (4H,) 3.8 (1~ q) 3.5 (lH, q), 2.6-3.2 (2H, m) 1.7-2.4 (2~., m), 1.3 (6R,) S (CH2)2~(OEt)2 5 (C~2)2-$~(-~)2 NH ~- N ~ H

_~g~

A mixture of 6(260 mg, 0.88 mmole) and ?-nitroben~yl glyoxalate (198 mg, 0.88 mmole) was refluxed in benzene (6 ml) under a Dean Stark a~paratus for 16 h to give after evaDoration of benzene 453 ms of heavyoil 7, nmr ~ 8.3 (2~, d) 7.6 (2H, c) 5.3-5.7 (4H,) 4.9 (OH), 4.2 (4H,) 3.55 (lH 9), 3.A (~H, gj / Z.5-3.2 (2H, m) 1.7-2.5 (2H, m) 1.3 (6H) 5 ~ (C~2)2~(OEt)2 (cH2)2J~-(OEt)2 ~N ~ H O N ~ Cl O
l :O2PNB 2 A crude 7 (504 mg, 0.88 ~mole) W25 cissolved in LM
solution of pyridine in THF (0.9 ml). To this was added dropwise with stirring and cooling (ice-bath) lM solution of sCC12 in T~F (0-9 ~1) and the mixture was stirred in the cold for 15 min and at room te~Derature for 40 min. mO it was added benzene (10 ml), anà ~he solid was filtered off. The eiltrate was concentr~ted in vacuo to give 463 mg (quantitative yielc.) o' c~ude 8, r~r ~ 8.3 (2H, c.), /.o (2H, d), 6.1 (lH, s), 5.7 (lH, ~), 5.3 (2H, d), 4.2 (4H), 1.8-3.6 (6H, m) 1.3 (6H), Crl2)2~-(OEt)2 s ~C~2)2~ t)2 t N ~ 1 ~

, llq-1~,818;~

To a solution of crude 8 (463 mg, 0.88 mmole) in T~ (4 ml) was added tri~henylphospl~ine (236 mg, 0.9 ~;r~ole) and 2,6 lutidine (96 mg, 0.9 mmole) and the mixture was al-lowed to stand at room temperature for 65 h. Then it was fil-tered, the filtrate concentrated and the residual oll chromato-graphed on a silica gel column with ethyl acetate-29s EtOH as sluent, to give 203 ~g t30.6%) of oil 9, which solidified on standing, m.p. 126-128C.

~S ~ CH2)2~(OEt)2 ~ ~(C~12)2P(OFt)2 CO PNB

A solution of 9 (470 mg, 0.635 mmole) in toluene (30 ml) was refluxed for 5 h followed }~y concentration and chromatography on silica gel-ethyl acetate to give 167 mg t56%) of 10 as oil, IR 1795, 1710 cm nmr ~ 8,3 (2H, d) 7.7 t2~, d) 5.7 (lH, m), ;.38 (2H, d) 4.1 t4H) 1.8-3.8 (6H, 1.35 t6H), ~Nf ~tCH2)2-~ ~~ )2o~N - - ~ (C'2).-( - )2 12~81~
;

To a solution of 10 (59 mg, 0.126 mmole) in THF
~3 ml) and et~er (1 ml) was added NaHC03 (9 mg, 0.107 mmole~, water (1 ml) and 10~ 2dA~ELITE~ 60 mg)and the miY.ture hydrogenated at 30 psi for 2 h. The product was isolated as usual to ~ive 36 mg (86.) of 11 as oil, IR (C~C13) 1798, 1730, 1710 C.T. l;
nmr ~ 9.0 (C02H), 5.6 (lH, m) 4.4 (4H), 3.6 (lH, q), 3.15 (lH, ~) 1.7-3.0 (4H, mj, 1.3 (6~).

*Trade Mark 5 1 81~33 ExamDle 2 6-Acetoxymethyl-2-methylDenç~-3-carboxvlic Acid AcO ~ ~ CH3 N ~

Preparation of 1,3-diaeetoxypropene (Ref. L.W. McTeer U.S. 2,866,813. CA $3 9063) Ac~O
CH2=CH-CHO )ACOCH2CH=CH-OAc + CH2=CH-CH(OAC)2 Cat.

Preparation of catalyst: A ~olution of boric acid (6.2 g) and oxalie aeid (12.6 g) in water (44 ml) wa6 evaporated to dryness to give the solid eatalyst.
Proeedure: Acrolein (140 g; 2.5 mol) was mixed with aeetic anhydride (256 g, 2.5 mol) at r.t. A 5 ml portion of this mixture wa6 transferred to a one-liter Erlenmeyer flask and treated with a few drops of eatalyst, prepared by dissolving 1.0 g of solid eatalyst in 5 ml aeetic anhydride. A vigorous exothermic reaction set in ~i 12~

and the reaction mixture was kept at a temperature of 40 -60 (controlled by cooling with ice-bath), and the rest of the acroleinacetic anhydride mixture was introduced into the flask in portions of 10 to 15 ml followed by a few drops of catalyst. The resulting mixture was distilled to remove unreacted starting materials followed by 1,1-diacetoxy-propene. The product 51.6 g (13.06%) was obtained next, b.p. 54 - 57C/ 1.2 mm. NMR: ~ (ppm, CDC13) 7.4 (H, d, J = 121, 5.3 - 5.8 (H, m), 4.5 (2H, d, J = 7) 2.16 (3H, s), 2.05 (3H, s). IR: vc=O 1770, 1750, vc=O 1680.

CSI / ~ OAc ~ OAc AcOCH2CH=CH-OAc - ) Aco ~ AcO
+ NH
~ NH ~
1 0 ~ 2b PROC~DUR~:
CSI (16.92 g; 0.12 mol) was added dropwise to cooled (ice salt bath, -15C) 1 (18.96 g; 0.12 mol). The pale yellow mixture was kept at 5 for 5 h whereby it changed to . 25 deep yellow. This was diluted with ethyl acetate (20 ml) , cooled to -30C, and added in portions to a cooled (ice salt bath) mixture of water (3.4 ml); ice (17.0 g) NaHC03 (0.3g) and Na2 S03 (3.4 g). After addition, the resulting mixture was stirred vigorously for 20 min and some additional NaHC03 was added to keep pH at 7-8. The layers ware separated, and aqueous layer was extracted with ethyl acetate (2 x 50 ml).
The combined organic phase waæ dried (Na2S04; NaHC03; 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 i 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, .L~

1~i8~8~3 after evaporation to dryne~6 5. 28 g (22%) of 4: 1 mixture of 2a and 2b (determined by nmr) as colourle6s oil. NM~: 7. 25 (H, NH), 6. 0 (0. 25H, d, J = 4.3), 5. 8 (0. 75H, d, J = 15. ), 4. 5 (0. 5H, d, J = 6. 5), 4. 4 (1. 5H, d, J = 4.5), 3. 8 (0.25H, m), 3.5 (0.75H, m), 2.13 (3H, s), 2.1 (3H, 8).
IR: c=o 1780, 1740.

AcO ~ 3 o~
2 AcO ~ Ac ~ SAcAcS ~ OAc O ~ O ~ 0~ NH

3a 3b 3c ~ROCEDURE:
Sodium thioacetate was prepared by addition of thioacetic acid (2.22 ml, 2.363 g) to a solution of IM
NaHC03 (31.0 ml) under nitrogen. This was added to a cooled (ice bath) 601ution of 2 (5.2 g; 25.9 mmoles) in water (20 ml) and stirred for 4 h at room temperature. Some acetone (20 ml) was added to render the reaction mixture homogeneous. The mixture was concentrated in vacuo to remove acetone and then extracted with methylene chloride. The extract was dried and evaporated to give 5.6 g of a mixture of isomers (83.14%) of 3a and 3b. The NMR
spectrum of the crude oil showed that there were one trans and two Ci8 compounds pre6ent in the mixture. A sample (550 mg) was chromatographed on silica gel (30 g, 10% H20) and eluted with benzene-ether-methanol to give 200 mg of a mixture of 3a and 3b in the ratio 7:1, followed by 150 mg of an unknown ci6 compound (~ 5.55, d, J = 4.3) to ~.~

~Z6~3183 which structure 3c was tentatively assigned. NMR: 6.78 (H,NH), 5.52 (0.17H, d, J = 4.3), 5.18 (0.83H, d, J = 1.5) 4.37 (2H, d, J = 4.5), 3.45 (H, m), 2.35 (3H, s), 2.05 (3H,s). IR: Vc=O 1765, 1740, 1600 cm.-l Ac0 ~ 02N ~ 0H2C02CH(0H)2 ~ SAc N ~ N - C H - O H
O O
3 4 Co2PNg PROCEDURE:

A mixture of crude 3 (2.17 g; 10 mmoles) and p-nitrobenzyl glyoxylate (2.5 g; 11 mmoles) in benzene (200 ml) was refluxed 20 h under a Dean Stark water collector followed by concentration in vacuo to give 3.4 g of crude 4 as oil. This was used as such without further purification.
NMR: ~ 7-5 - 8.5 (4H), 5.2 - 5.8 (4H), 3.4 - 5.1 (4H), 2 -2.4 (6H). IR: VC=O 1665, 1740, 1740, 1730, 1700.
Ac0 ~ SAc S0C12 Ac0 ~ SAc ,~N-CH-OH .~.N-CH-C1 PROCEDURE:
To a cooled (ice-bath) solution of crude 5 (3.3 g; 7.75 mmoles) and pyridine (0.67 g; 8.5 mmoles) in benzene (20 ml) was added dropwise thionyl chloride 30 (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 -`~ 126818~
times with 15 ml portions of benzene. The combined benzene solution was evaporated to give 1.90 g of crude 5 (5S~).
NMR: ~ 7.5 - 8.5 (4H), 6.12 and 6.2 (lH), 5.66 (lH, 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: Vc=O 1765, 1740, 1730, 1700.

AcO ~ (~)3p Ac0 ~ SAc ~ N-fHCl Dioxane ~ CO PNB

PROCEDURE:

A mixture of crude 5 (1.90 G; 4.27 mmoles) triphenylphosphine (1.572 g; 6 mmoles) and 2,6-lutidine (0.642 g; 6 mmoles) in dioxane (20 ml) was heated at 55 for 18 h. It was cooled, filtered and evaporated to give 3.8 g of a crude dark oil. This was chromatographed on 20 silica gel to give 1.2 g (42%) of 6.
Ac~S Ac ~ ~

¦ 25 CO2PNB 7 O2PNB

PROCEDURE:
A solution of crude 6 (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 sio2 ~ 1268:L8~
(30 g) and eluted with benzene to give 0.4 g of 7 (57%) .
Anal. Calc'd for C17H16N207S. C 52.04; H 4.11; N 7.14.
Found: C 51.77; H 4.08; N 7.30.
Separation of the cis and trans isomers was achieved through careful chromatography on silica gel (60 g) eluting with benzene. cis-isomer: ~ (ppm, CDC13): 7.5-8.5 (4H, aromatics), 5.67 (lH, d, J = 5, H-5), 5.28 (2H, AB quartet, benzyl), 4.33 (2H, d, AcOCH2), 4.20 (lH, dt, H-6), 2.31 (3H, s, CH3), 2.0 (3H, s, CH3CO). VC=O 1770, 1740, 1730 10 cm~l.
trans isomer: ~ (ppm, CDC13): 7.5-8.5 (4H, aromatics), 5.53 (lH, d, J = 2, H-5), 5.30 (2H, AB quartet, benzyl), 4.32 (2H, d, AcoCH2), 4.27 (lH, dt, J = 5, J - 2, H - 6), 2.31 (3H, s, CH3), 2-0 (3H, s, CH3CO)- VC=O 1770~ 1740~ 1730 cm~l.

Ac ~ ~ C~ H2Pd/C ~ ~ ~ c~3 O N NaHCO3 C2Na CO2PN~ 8 PROCEDURE:
To a solution of trans 7 ~119 mg; 0.3 mmole) in ethyl acetate (15 ml) and water (7 ml) was added NaHCO3 (25.2 mg, 0.3 mmole), and Pd/C (110 mg) and this was hydrogenated 4.5 h at 30 psi. The mixture was filtered and layers separated. The aqueous layer was washed with ether and then lyophilized to give 40 mg of solid 8 (48%).

12~3183 ~J 1765, 1740, 1600 cm . ~ (ppm, D2O): 5.52 (lH, H-5), 4.85 (2H, AcOCIi2), 4.0 tl}'., }i-6), 2.65 (3.i, C1~3), 2.40 t3~i, C H 3 C O ) Ac~ ~f S\ ~cO~
CH 3 ~. O
C2Na C02H

PROC''DUR_:
To a solution or crude trans 8 (100 mc~ in cold .~rater t2 ml) was acidified with cold lN HCl and extracted with CHC13. The ext~act was dried (Na2SO4) a;ld evaoorater? to give 30 mg of a pale yellow solid. M.P. 111-113 with decomposition. I~:
v O 1780, 1750, 1680. (Neat) . IR: (~r): v 1775 (S.rong), 1745, 1670.

Treatment of cis paranitrobenzyl 6-acetoxymethyl-2-methyl-penem-3-carboxylate according to tne above procedu-P
gives the cis sodiu~t salt ~md free acid.

- 5~-Exam~le 3 ?otassium 6-(2'-H,vdroxviso~ro~yl)-2-methYl~enem-3-car~oxvlate (anion process) .

C02~C

CH3 LDA H0 ~ ~ CH

0zH + CO

1 4a A solution of acid 1 (116 mg, 0.627 m~oles) in anhycrous THF (4cc, freshly distille~ over L~H) was added dropwise at -78C
to a rHP (2cc3 solution of LDA (from diiso?ro?ylamine, 70.7 m5, 98 ~1, 0.699 mmoles, and n BuLi 1.6 ~l, 0.440cc, 0.704 ~mcle stirred at -78C for 30 min). The mixture was stirred for 5 min. followed by successive addition of diisop~opylamine (70.7 mg, 98 ~1, 0.699 r~T~ole) and 1.6 M n 3uLi (0.440cc, 0.704 ~mole) at -78. It was then sti--e~
for 10 min. at -78 and treated raDidly with acetone (~cc). .he mixture was allowed to react with acetone for 10 min. It w2s acic,i_ied (pH=2) with 1% HCl, diluted with ethvl acetate (40 cc) and washed with brine (3 x 20 cc). It was dried ove~ Na2S04. Solvent eva?o~ation gave a crude residue (3a) which was ta~en u~ in CH2C12 (c_ude yield 90 mg). The c-ude acid was dissolvec in cold MIa;~ (2 cc) and treated dropwise with ?otassiu~ 2-ethyl he,Yanoat- It s2ve ~-~o batches of ~otassium salt (36.4 mg, 26~) as a cis and .rans mixturo, the trans isomer being ~redominant.

- 5q -6) 5-60 (lH~ d~ Js-6 CiS = 4~H-5)~ 5-55 (lH~ d J = 2~ H-5), 3-93 (lH~ d~ J6-5 ~is 4, H j, (lH, d, J6-5 trans = 2, H-6), 3.50 (b.s. ,OH), 2-34 (3H~ s, CH3), 1.47, 1.40 (6H, 25, 2CH3), 1.35, 1.32 (6H, 25, 2CH3) Vc=o ("NUJOLMWLL'~ 1765~ 1582, VOH 3600 ~ 3100 W (EtOH) ~ 257 (E = 3920), 300 (E = 4020).
max ExamDle 4 Potassium 6-Hydroxvbenzvl-2-methvl?en em-3-carboxylate (anion ?rocess) ~xH

~H

CH3 ~CHO ~ CH3 1 4b A solution of acid 1 (100 mg, 0.540 mmole) in anhvc-ous T$F (6 CC, di5.illed over LAH) was added dropwise to a ccld (-78) ~HF (2cC) solution of LDA made from diisopropyla~ine (84 ~1, 60.6 mg, 0.599 ~ole) and 1.6 M n-3uLi (0.380 cc, 0.608 mmole). .~.e mixture was stirred for 5 min, followed by sUcCessive acdition Oc cd_isoproDv!
amine (84 ~1, 60.6 mg, 0.599 ~mole) and 1.6~.~ n-3uLi (0.380 c_, 0.608 m~ole). It was then s_i-red 'or 7 min at -78 and treated ra?iclv with ~er.~-aldehvde ~300 Ul). The mixture was allowed to -eact at -78 for 20 min. It was acidified wi~h 1~ HCl (pH-2), dilute~ w~th et;~v~
acetate (40 cc), washed with 1:1 H2O-brine (3 x 20 CC) anc ~rine (1 X 20Cc~
It was dried over Na25O4. Solvent evaporation gave a residue which was dissolved in MI3~ (2cC). It ~as treated dropwise with po_assi~m '-elh~

*Trade Mark ~ 1268183 hexanoate. It gave 4b (35 mg) in 20~ yield as a diastereoisomeric mixture. ~ : (ppm, DMSOd6) 7.9S (5H, s, H-aromatic) 5.57 (d, J5-6 trans = 1.5, H-5), 5.45 (d, J
5-6 trans = 1.5, H-5) 5-35 (d, J5-6 cis = 4~ H 5)~ 5-0 (m~
C-H hydroxybenzyl), 4-25 (dd, J6-5 cis = 4, J 6-C-H
hydroxy benzyl = 10, H-6), 3.90 (m, H-6), 3.65 (b.s., OH), 2.35 (3H, 2s, CH3) Vc=O ("NUJOL MULL")* 1760, 1590, vOH
3600 - 3100. UV (H2O) max 252 ( ~ = 5,100), 296 (~ =
3,300)-Exam~le 5 Potassium 6-Thiomethyl-2-methvlpenem-3-carboxylate ranion ~rocess) SMe ~ ~ CH3 S SMe S
~ H 3 LDA ~ CH3 20~ N ~ 3 2 3 o N ~

1 4c A solution of acid 1 (100 mg, 0.540 mmole) in anhydrous THF (5cc, distilled over LAH) was added dropwise to a cold (-78) THF (2cc) solution of LDA made from diisopropylamine (84 1, 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 6uccessive addition of diisopropylamine (84 ~l, 60.6 mg, 0.599 mmole) and 1.6 M
n-Butyl lithium (0.380 cc, 0.608 mmole). It was then stirred for 7 min at -78 and treated rapidly, with methyl thiomethylsulfonate (300 ~ l, excess). The mixture was allowed to react at -78 for 5 min. It was acidified with 1%
HC1 (pH-2), diluted with ethyl acetate (40 cc) , washed with 1:1 H2O-brine (3 x 20 cc) and brine (2~ cc).
*Trade Mark -~ lZ681~;~

The organic solution was dried over Na2S04. Solvent evaporation gave a residue which waæ dis601ved in cold MIBK
(2cc). The cold 601ution was treated dropwise with potassium 2-ethylhexanoate. It gave 4c (40 mg)in 28~ yield as a 8:3 mixture of cis and trans isomer6 (decomp.) 115 120) ~ (ppm, DMSOd6 ) 5.85 (lH, d, J5-6 cis = 4~ H 5) ~
5-57 (lH~ d~ J5-6 trans = 1-5, H-5), 4.87 (lH, d, J6-5 cis =
4, H-6), 4.72 (lH, d, J6-s trans = 1.5, H-6), 3.42 (b.s., OH), 2.37 (s, SCH3), 2.33 (s, CH3), 2.25 (6, SCH3). Vc=O
("NUJOL MULL)* 1770, 1600, Uv (H20) ~max 252 ( F = 4200), 297 ( ~= 3700) Example 6 1-(~-Nitrobenzyloxycarbonylmethyltriphenylphos~horanvl)-4-(silver merca~tidvl)-2-azetidinone ~ SAg O ~ ~ P~3 STr OAc TrSH ~ `H

O H

A methanol (9Occ) 6uspen6ion of triphenylmethyl mercaptan (13.8 g, 0.05 mmole) was degas6ed for O . 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 (~) occurred immediately. The * Trade Mark mixture wa6 8 tirred for 4 h at room temperature. The 6olid was filtered off, washed with water and di6~01ved in methylene chloride. The methylene chloride 601ution was washed with diluted HC1, water, aqueou6 sodium bicarbonate water and brine and dried over MgS04, (89.8%, m.p.: 146.5 - 147.5C) Anal. Calc~d for C22HlgNOS: 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.
~ (ppm, CDC13) 7.60 - 7.10 (15H, m, H-trityl), 4.62 (lH, b8, NH), 4-40 (lH~ dd~ J4_3 tran6 = 3 ~ J4-3 ci6 = 5~ H-4)~3-24 (lH~
ddd~ Jgem = 15~ J3_4 ci6 = 5~ J3-NH = 1.8, H-3), 2.81 (lH, ddd~ Jgem = 15~ J3_4 tran6 = 3 ~ J3-NH = 1-2~ H-3) Vc=O (CHC13) 1760, VNH 3340 F1'\H CHO ~Tr ~STr C02PNB C02P~B

Hydrated p-nitrobenzyl glyoxylate (4.54 g, 0.02 mole) and azetidinone 2 (6.90, 0.02 mole) were refluxed in benzene through a Dean Stark condenser filled with 3A
molecular sieves for 24 h. Further glyoxylate (2 x 454 mg, 2 mmoles) was added with reflux period (18 h) after each addition. The mixture was diluted with ether, washed with 5~ aqueous HC1, water, aqueous 5~ NaHC03 water and brine. It was dried over MgS04 (12 g, quantitative) A 6mall fraction of the epimeric mixture was separated on a 6ilica gel plate (CH2C12- ether 6:4) Isomer A:
Rf = 0.87, m.p. = 170.5 - 171.5 ^~' 126818~

~ (ppm, CDC13) 8.07 (2H, d, J=9, Hm aromatic), 7.45 (part of d, Ho aromatic), 7.40-7.00 (15H, m, Trityl), 5.25 (2H, s, CH2-PNB), 4.75 (lH, s, H-C-O), 4-37 (lH, dd, J3-4 trans= 3 J3-4 cis = 4, H-3), 2.83 (lH, dd, Jgem = 16, J4-3 Ci8 = 4 H-4), 2.10 (lH, dd, Jgem = 16, J4-3 trans 3, H 4), (b. B., OH).
c=o (CHC13 1770, 1760 (shoulder), vNO2 1525, vOH 3475.

Isomer B:
Rf 0.75, m.p. = 152 - 153 ~ (ppm, CDC13), 8.13 (2H, d, J = 9, Hm aromatic), 7.47 (,2H, d, J = 9, Ho aromatic), 7.40 - 7.00 (lSH, M, trityl), 5.30 (3H, 8, CH2-PNB, H-C-0), 4.45 (lH, t, J = 3.5, H-4), 2.90 -lS 2.70 (2H, AB part of ABX, H-4), l.SS (b.s., OH).
vc=o (CHC13) 1767, 1755 (shoulder), vNO2 1525, CH

STr SOC12 ~,~STr ~ pyridine 0 L N~f~

3 . 4 A cold (-15) THF (150 CC, dried over molecular sieves) solution of azetidinone 3 (12 g, 21. 7 mmoles) was treated wlth 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 stirrQd for 45 min at -15. The precipitate was filtered off and washed with benzene. Evaporation of solvent gave a residue which was taken up in benzene and treated with activated charcoal (11.7 g, 94%, crystallized out from chloroform).
~(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, CH2-PNB), 4.81 (lH, m, H-4), 3.27 - 2.40 (2H, m, H-3) c=o (KBr film) 1785, 1770 vN0 1525.

STr ~STr 2,6-Lutidine ~ P~3 0 N ~ ~
C02PNB C02P~B

A THF (100 cc, distilled over LAH) solution of chloroazetidinone 4 (11.6 g, 20.2 mmoles) was treated with triphenyl phosphine (7.86 g, 30.0 mmoles) and 2,6-lutidine (2.36 g, 2.56 cc, 22.0 mmoles). The mixture was refluxed for 72 h. The precipitate was filtered off and washed with ether. The organic solution was washed with 2% aqueous HCl and 5% aqueous bicarbonate and dried over MgSO4.
Evaporation of solvent gave a residue which was purified through silica gel pad (200 g). The desired phosphorane was eluted with 30,40 and 50% ether-benzene (11.4 g, 70.4%, m.p.: 201-202).
Anal. Calc'd for C49H40N2O5$P: C, 73.57; H, 5.04; N, 3.50;
S, 4.01.
Found: C, 73.58; H, 4.91; N, 3.44; S, 3.87.
~c=o (CHC13 1740, ~phosphorane (1620, 1610), VNO 1525.

~26818;~

T. S
~5 AgN03 _~ Ag d-- I P~3 pyridineo~N~f ~3 4-Tritylmercapto azetidinone 5 (1.6 g, 2 mmoles) was dissolved in CH2C12 (20 cc) and the solvent was flushed down at 55-60. Phosphorane 5 at 55 - 60 was dissolved in preheated (55-60) methanol (32 cc). Immediately after the obtention of a methanolic solution of 6 it wa6 treated with a preheated (55 - 60) mixture of methanolic 0.15 M silver nitrate solution (16 ~o, 1.2 eq) and pyridine (174 mg, 178 1, 2.2 mmoles, 1.1 eq). The warming bath wa~ then immedlately removed. The mixture was stirred at room temperature for 2 h and at OC for 1 h. The silver mercaptide 6 was filtered off, washed twice with cold (O) methanol and three time6 with ether. (1.12 g, 84.5%, m.p.:
130-135 dea.).

va=o (CHC13) 1795, 1725 (shoulder), v phosphorane (1620, 1605), VN02 1530.

.r~

12681~
Example 7 1-(p-NitrobenzyloxycarbonylmethYltri~henvl~hos~horanyl)-4-tsilver mercaptidyl)-2-azetidinone) SCOCH3 K2C03,AgN03 SAg 1~' ~ 1~
O ~ C=PPh3 MeOHo~N~ C=PPh3 lOCOOPNB COOPNB

-A solution of phosphorane 7 (1.796 g, 3.0 mmoles) in chloroform, (3ml) was diluted with methanol (90 ml), cooled at 0C under nitrogen atmosphere and treated successively with silver nitrate (0.51 g, 3.0 mmoles) and potassium, carbonate (0.33 g, 2.4 mmoles). The reaction mixture (protected from light) was stirred at 0C for 15 min., then the cooling bath was removed and stiring was continued for 3 h. The reaction mixture was cooled down to -10C, stirred for 1 h and filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.91 g, M.P.: 138 - 145C dec, 96%. I.R. ("NUJOL")* cm~l: 1748, 1620 and 1605. An analytical sample was obtained by, preparative TLC (ethyl acetate); M.P.: 140 - 5C dec, calc'd for C30H24N205SPAg: C, 54.31; H, 3.65; N, 4.22; S, 4.83.
Found: C, 54.11; H, 3.48; N, 3.92; S, 4.62.
Example 8 1-t~-NitrobenzyloxycarbonYlmethyltriphenvlphos~horanyl-4 lsilver mercaptidvl)-2-azetidinone A. ~se of aniline as base -SCOCH3 Aniline, AgN03 SAg n' ~ I~' ~ N MeOH ~ N ~
35 0 ~ C=PPh3 C=PPh3 COOPNB COOPNB

* Trademark , 12~81~3 A solution of phosphorane 1 (1.8 g, 3. 0 mmoles ) in ohloroform (4 ml) was diluted with methanol (90 ml ), cooled to -15C under nitrogen atmo6phere and treated successively with silver nitrate (0.56 g, 3.3 mmoles) and anilins (1.5 ml, 16.5 mmoles). ~he reaction mixture (protected from light) was stirred at -15C for 0.5 h and then the cooling bath was removed and stirring was continued for 24 h. The reaction mixture was cooled to -10C
and 6 tirred for 1 h before being filtered; the silver mercaptide was ~uccessively washed with cold methanol and ether; 1.55 g, M. P. 114-5C dec. 77.9%. IR (~NUJOL~ )*cm 1;
identical to compound of Example 7.

Silver-l-(Paranitrobenzyl 2'-tri~henvlpho6phoranvlidene-2'-acetate)-2-azetidinone-4-thiolat_ B. Use of 4-dimethylaminopvridine (DMAP) as base SC0CH SAg 3 AgNo3lDMAp I P~3 ~ I P~3 0~ - N ~ CH2C12/CH3H 0~ N ~

A solution of the above S-acetyl phosphorane (17.96 g, 30 mmol) in methanol and dichloromethane (1:2, 450 ml) was purged with nitrogen (5-10 min), cooled to 5C
and treated succe6sively with silver nitrate (5.35 g, 31.5 mmol) and 4-dimethylaminopyridine (3.85 g, 31.5 mmol). The lce-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 (CHC13) vmax 1745 (C=0 of B-lactam) and 1607 cm~1 (C=0 of ester).
* Trademark 12~81~

Silye~ (paranitl;~)ben2.vl 2' -tri~henyll;hos~horanylidene -2"-~o~t~t~-2-C.Use of dia~ ycloundecene (DBU) as base 5r~' AgN03 ~SAg ~ Dsu, MeOH ~- N ~p~3 The above S-acetylphosphorane (36. 0 g, O. 060 mol) 10 was dissolved in methylene chloride 120 ml. The solvent was evaporated in order to obtain an oil. The resulting oily residue was dissolved in warm (35C) methanol (240 ml) and treated rapidly with a methanolic (420 ml) solution of silver nitrate (10-68 g. O. 0628 mol). I~he resulting solution 15 (or 6uspen6ion) wa6 stirred at room temperature for 5 min, cooled down (ice-bath) and a D3U (8. 96 ml, O. 060 mol) 601ution in methanol (20 ml) was added over a 5 min period.
The mixture was stirred for 5 min. The solid was filtered, washed once with cold (0C) methanol and ether and 20 dried under vacuum; 37. 0 g (93%); ir ("NVJOL NAILL")* `~max (c=O) and 1600 cm 1 (phosphorane) D. Use of pyrrolidine as base Silver 1-(paranitrobenzyl 2' -triphenylpho6phoranvl-idene-2"-acetate)-2-azetidinone-4-thiolate SCOCH
SAg I_ / Pyrrol id ine_~
~L AgNO3 ¦

C- PPh 3 b. PPh 3 COOPNB COOPNB
To a cold(0C) solution of 4-acetylthio -1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate) -2-azetidinone (O. 60 g, 1. 0 mmol) in CH2C12 (2 ml) was 35 added MeOH (4 ml), a solution of AgN03 in MeOH (O. 14N, 7. 86 ml, 1. 1 mmol) and a solution:. of pyrrol-*Trade Mark idine tO.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 -10C, stirred for 0.25 h and filtered. The 601id was washed with cold MeOH and dried in vacuo; 0.548 g, m.p.
115C, 82.4%. ir ("NUJOL")* vmax: 1775 (C=O) and 1600 cm 1 (aromatics).
Example 9 Mercuric (II~-~2'-TriphenylphosphQranylidene-2'-ace~tel -2-azetidinone-4-thiolate STr H g ( OAc ) 2 2 n N \C
=PPh3 / )2 g ~ PPh3 II Co2PNB

A solution of I (2.4 g, 3 mmoles) in dichloromethane (15 ml) was cooled to 5C and treated with a solution of mercuric acetate (0.52S g, 1.65 mmole) dissolved in methanol (15 ml). After stirring at 5 for 2 h, the solvent was evaporated and the residue redissolved in dichloromethane and washed with cold water. The organic solution after being dried (MgS04) and treated with charcoal, was evaporated to give a foam which crystalized when triturated in ether. Yield: 1.73 g (91~) M.P. 123 -127C, I.R. (CHC13) 1745 cm 1 (vc=O B lactam) 1608 cm 1 (phenyl) *Trade Mark ~2ti81~

Exam~le 1 0 2-Methyl~enem-3-p-nitxobenzyl-carboxylate tfrom mercaptide inte~mediatel S ) 2 H g n' PPh 2CH COCl ¦~/COCH3 ,~N 3 3 ~ 2PPh pyridine ~ N ~ 3 II III

A solution of 11 (262 mg, 0.2 mmole), acetyl chloride (35 mg, 0.44 mmole) and 2 drops of pyridine in 10 ml of dichloromethane wa~ stirred at 5C for 1 h. The precipitated mercuric chloride was then filtered off and the filtrate washed succes~ively with cold dilute hydrochloric acid, sodium hydroxide and finally brine. The organic solution was submitted to a stream of hydrogen 25 sulfide for 2 minutes at 5C 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 LII as a foamy material.
I.R. (CHCl3) 1755 (, Vc=O 3-lactam) 1692 (v ) 1620 (phenyl). SCOCH3 12~i81~33 A t ~ ~ C53 Phosphorane ILl (75 mg, 0.126 mmole) in toluene (10 ac) was refluxed over a 2.5 h period under nitrogen atmosphere. Solvent evaporation and purification of the residue afforded a crystalline derivative (25 mg, 63%) whose physical and spectral data were in complete agreement with those of the title product.
Product IV may if desired be sub~ected to catalytic hydrogenation (30% Pd on "CELITE")* to produce the corresponding 3-carboxylic acid product.
*Trade Mark 12~ 3 Exam~lell 2-Aminomethyl~enem-3-aa~Q,~,ylic Acid from merca~tide intermediate,), ~f~ CH2NH2 COOH
1 0 . . .

S A g 2 3 ~

~ ~ CH2C12 oJ~ PPh O C=PPh3 COOPNB COOPNB

A solution of silver mercaptide 1 (1.25 g, 1.99 mmole) in dichloromethane (15 ml) kept under nitrogen atmosphere was cooled at 0C and treated dropwi6e with a 2M
solution of azidoacetyl chloride in dichloromethane ~1.13 ml, 2.26 mmoles). The reaction mixture was stirred at 0C
for lh; the cooling bath was removed and stirring was continued for S 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 *Trade Mark 12~8i~;~

t200 ml), ~ther -6~ ethyl acetate (200 ml) and ether-20%
ethyl aoetate (500 ml), fraction size: 10 ml). The oombination and evaporation of fraction6 49-80 gave a yellow powder; 0.73 g, M.P. 61-70, 60.8%.
s ~ 2 3 ~ ~ ~ CH 2~3 0,~ N~ 'roluene N_~
~-PPh3 COOPNB
COOPNB

A solution of phosphorane 2 (0.593 9, 0.93 mmole) in toluene (20 ml) was heated at 105C for 1 h, cooled to 23C
and concentrated to a semi-crystalline compound which was purified by column chromatography t12 g of silica gel 60, Eluate: benzene (100 ml), benzene-2% ether (100 ml) and benzene-4~ ether; fraction size: 10 ml). The combination and evaporation of fractions 18 - 26 gave a yellow syrup which crystallized on standing; 0.18 g, M.P.: 127-8C, 53.7%. NMR
(CDC13, ~ 8.22 (2H, d, JHO, Hm = 8-8 Hz, Ho of p nitrobenzYl), 7.60 (2H, d, JHm, Ho = 8-8 Hz~ Hm of p nitrobenzyl), 5.71 (lH, dd, J5,6 CiB = 3-6 Hz~ J5,6 trans = 2.1 Hz, H-5), 5.33 (2H, center of ABq, Ja b = 14.0 Hz, CH2 of p-nitrobenzyl), 4.58 (2H, center of ABq, Ja b =
15.0 Hz, CH2on C-2) 3-88 (lH, dd, J6,s Ci8 = 3-6 Hz~ Jgem =
16.5 Hz, H-6 CiB) and 3-55 (lH, dd, J5,6 trans = 2-1 hz~
Jgem=16 5 Hz, ~-6 trans) I.R. ("NUJOL")* cm 1 2115 and 2090 (N3), 1780 (c=o of B-lactam) and 1685 (c=o of p-nitrobenzyl ester).
An analytical sample was obtained by preparative T.L.C.;
M.P. 127-8C, calc'd for C14H11N5O5S: C, 46.54; H, 3.07; N, 19.37; S, 8.87. Found: C, 46.43; H, 3.08; N, 19.37; S, 8.90.

*Trade Mark i2~

s CH N 30~ Pd~ "~ITE" ~ ~ CH2NH2 ~ h~ 2 3 TH~, e~er, ~2 ~ N

COOPNB

To a solution of penem 3 (0.18 g, O. 5 mmole) in tetrahydrofuran (6 ml) was successively added ether (6 ml), water (6 ml) and 30% palladium on ~CE~ITE~* (0.18 g). The reaction mixture was hydrogenated under 30 p. 8. i. at 23C
for 2.5 h and filtered over "CELITE"* pad; the pad was washed with water and the filtrate and washings were combined, washed with ether-THF mixture and lyophilized to give 30 mg, 30%, of compound 4. lWater and ether insoluble compound were dis601ved in chloroform and the organic 601ution was wa6hed with water and dried over anhydrous sodium sulfate. The evaporation of solvent under reduced pressure gave 77 mg (42.8%) of starting material 3]. NMR
(DMSO d-6) ~:5.7 (dd, J5-6ci8 - 3-5 Hz, J5-6trans = 1-5 Hz~
H-5). I. R. ("NUJOL")* cm 1 1775 (c=o of B-lactam) and 1615, 1585. U.V. ~H20 m : (E =2320) and 307 (s=2685).
max Title product 4 was also obtained from intemediate 3 by the following route:

rr CH2N3 H2,Pd/D.E. rl~ CH2 H2 ~ N ~ ~HF, Ether, o~N ~~
COOPNB COOH

To a solution of penem 3 (2.4 g, 6.89 mmoles) in tetrahydrofuran-ether-water mixture (1:1:1, 165 ml) was added 30% palladium on diatomaceous earth (4.8 g). The reaction mixture was hydrogenated under 45 p.s.i. at 23C
for 2.5 h and *Trade Mark i81~;~
~ .

filtered over celite pad. The filtrate and washings were combined, wa~hed 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 wa~ induced by the addition of water (0.8 ml); the 6uspension was centrifuged and the water was removed leaving an orange 601id. This solid wa6 washed twice with water and a slightly yellow 601id was obtained after drying: 0.273 mg, 19.8%. W ~ : 307 (~ =4318) and 257 max (~ =2650). Some crude 6tarting material (1.2 g, 50%) was recovered. The compound (50 mg) can al60 be purified by column chromatography ["SEPHADEX" *GI0, column 6ize: 1.6 x 100 cm, flow rate: 10 ml/h, eluent: di6tilled water, fraction volume: 1.5 ml, detector: refractive index].

UV~ : 307 (~=3597) and 255 (E=2424).
max The stability of the compound in aqueous solution was checked by:
W: 6 h 307 (~=3545 and 255 (~=2773) 21 h 307 (=3467) and 255 (~=2411) 28 h 307 (F =3337) and 254 (~=2398) 46 h 307 (E =3259) and 254 (~=2398) 70 h 307 (F=3076) 94 h 307 (F =2842) 170 307 (~=1900) 30 A 6ample of compound 4 was kept at 23C for 3 days and the UV was taken: W ~ :307 ( =3055) and ( =2008).
max Compound 4 was converted a6 described below to two additional 2-penem derivative6.

*Trade Mark \
1.
5 ~3 NaHC03,H20 ~5 ,~H2 4 --~OG(~) ~H ~ C;:)GQ,1a(3 A su6pen~ion of compound 4 (50 mg, 0.25 mmole) in di6tilled water ~0.5 ml) was treated with one equivalent of sodium bicarbonate (21 mg) followed by the addition of ethyl acetimidate (21. 8 mg, O. 024 ml). The reaction mixture was stirred at 23C for 20 min and lyophilized 10 giving 52 mg of a yellow solid. NMR (D20) ~: 5.7 (m, H-5) and 2.23 (b.s., CH3 of amidine). I.R. (RBr)cm 1 1772 (c=o of B-lactam). U.V. AD20 m~ : 305 ~=3116) and 253 max 15 ( =2525). The compound ~ wa6 applied on a column ("SEPHADEX")*G10, column size: 1.6 x 100 cm 1 Eluent: H20, detector: I.R. fraction size: 1.6 ml) and lyophilization of appropriate fraction6 gave 23 mg 45% of slightly yellow 20 powder U.V.A 2 m~: 303 (E =2960) and 248 (E =2885).
max 2 . ~ (3 NaHCO , H O S H
~:H NH 3 2 ~ CH2N=C +6NaCl ~ N----~C 2 3 ~H HCl o~ ~4~ (~ (3 NH2 4 o ~ H- -OEt 6 c A suspension of compound 4 (50 mg, 0.25 mmole) in distilled water (0-5 ml) was treated with sodium bicarbonate (21 mg, 0.25 mmole) and stirred for 1.5 min before the addition (2 min) of a mixture of sodium bicarbonate (126 mg, 1.5 mmole) and ethyl formimidate hydrochloride (164 mg, 1.5 mmole). The reaction mixture was stirred for 10 min at 23C and lyophilized giving an orange powder. U.V. A 2 m~: 304 (E =2300).
*Trade Mark max ~2~

E x a m p 1 e 12 Sodium 2-Hydroxyaminopropylpenem-3-carboxylate ~ NHC~
C2Na 1) NaOH 5~
2 O2E~ 2) HCl conc 2 C02H

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 wilh 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%).

12~
.

2 CO2H + SOCl2 2 COCl A solution of acid 2 (13.2 g, 0.1 mole) in SOC12 (25 ml) was 6tirred for 2 h at 30C. After evaporation of thionyl chloride, the residue was distilled under vacuum T =
76-78C (P=0.2 mm Hg). Yield 8.8g (58. 3%) as a colourless liquid: n.m.r. (CDC13) ~ ppm:2.40 (2H,m,B-CH2); 3. 15 t2H, t, a -CH2); 4. 50 (2H, t, Y-CH2) i.r. (neat): 1550 cm 1 (VNo ); 1790 cm 1 (~c=o~ acid chloride).
S ~ N0 '----\ 2~ N H~03/F~ ~
-A solution of 3 (19. 46 g, 0. 128 mole) in methylene chloride (200 ml) was added rapidly to a cold (0-10) stirred solution of triethylamine (36 ml, 0. 256 mole) in methylene chloride (500 ml) which had been saturated at 0-51 with H2S. The mixture was stirred at -10 for 1 h and then a stream of nitrogen was passed throuqh the solution to eliminate the excess of H2S. The mixture was washed with 10% HC1, 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 NaHC03 or HC1. The resulting mixture was cooled to 0C and 4-acetoxy-2-azetidinone (16. 8 g, 0.13 mole) in water (20 ml) was added with vigourous stirring. After 4 h the mixture was extracted with ethyl, acetate. The extracts were washed wlth 10% HCl, sat. NaHC03, brine, dried (Na2S04) and evaporated. The residue was purified by column chromatography (SiO2 ; eluent: ether then ether-ethyl acetate 5%) giving an oil which crystallized in ethyl acetate-hexanes yielding ~ (3.5 g, 12.5%) as a white powder. (m.p. 45-47,C).

~ ~ 2 2 ~ s ~ ~2 10 0 H o ~H OH

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 o filled with 4A molecular sieves for 18 h. Evaporation of the solvent gave the glyoxylate adduct 5 (2.1 g) as an oil.

~ S ~ 2 SOC12 ~ ~ ~2 25 o N~CB PY 2 Azetidinone glyoxylate 5 (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 0C and SOCl2 (0.5 ml, 7 mmoles) was slowly added. The mixture was stirred 1 h at 0C and then filtered before evaporation to dryness. Filtration of this material over a pad of silica gel with CH2Cl2 gave a foam; yield 1.9 g (85%).

~1 S ~ N2 P~3 ~ ~ 2 F 2,6-lutidine C=2~
C02PN8 c02PNB

To a solution of chloroazetidinone (6.2 g, 14 mmoles) in THF (300 ml) waQ added triphenyl pho6phine (5.5 g, 0.02 mole) and 2,6-lutidine (2.4 ml, 0.02 mole). The mixture was heated at 45C for 20 hours. Lutidine hydrochloride was filtered off and washed with ether. The filtrate was then evaporated. The residue was purified by chromatography through a silica gel column and eluted with dichloromethane and dichloromethane-ethylacetate (1:1). Evaporation of eluent gave a white solid (2. 9 g, 30%.) F~ N2 ~ ~--NO 2 Cl=P~3 co2PNs 7 a Phosphorane 1 (2.0 g, 3 mmoles) in toluene (150 ml) was refluxed for 2.5 h. Evaporation of solvent afforded an oil which was purified by chromatography through a 6ilica gel column and eluted with dichloromethane and dichloromethane-ethylacetate (9: 1) - Evaporation of the 601vent gave a 6yrup which cry6tallized in ethylacetate-hexane6 a6 a white 601id (0. 82 g, 40. 7%) ~S~ ~NO 30~ Pd/DE
J_N_~2 THF-ET~E~-~2o-NaHco3 15 3 D~l S~y N H C H
o N ~
C2Na To a 601ution of ester 8 t50 mg, 0. 127 mmole) in a tetrahydrofuran-ether mixture (2: 3, 25 ml) was added water (10 ml), sodium bicarbonate (10 mg, 0. 127 mmole) and 30%
palladium on diatomaceous earth (50 mg). The reaction mixture was hydrogenated under S0 p.s.i. for 3 h at 25C, filtered over a celite pad and washed with ether. Aqueous solution was lyophilized yielding a yellow powder (30 mg) of hydroscopic compound.

12~
.

Example 13 6-Ethyl-2-aminomethylpenem-3-carboxylic Acid_(cis and trans isomersL

~ ~ ~ CU2N 2 ~ o2HH2NH2 a. Silver cis and trans 3-ethvl-1-rp-nitrobenzyl-2'-tri~henylphosphoranylidene-2'-acetate)-2-azetidinone-4-thiolates A solution of cis and trans 3-ethyl-1-(p-nitrobenzyl-2'-phosphoranylidene-2'acetate)-4-acetylthio-2-azetidinones `8~ 3 (1.8a g., 3.0 mmoles; ~Y~ample 1, structure 7) in chlorofor~
(4 ml.) was diluted with ~ethanol (90 ml.), cooled to 0 and treated successively with finely powdered silver nitrate (O.Sl g., 3.0 mmoles) and potassium carbona~e (0.33 g., 2.4 ~moles). The mi;;ture was stirred vigorouslv 15 mi~.
at 0~, 3 h at room temperature and 1 h at -10C. The ~recipitated silver mercaptide was collected by filtration, washed with methanol and with ether and dried in a vacuum.
The title product was obtained as a grevish solid, m.p.
112-135 ~. ~C=O 1750, 1620, 1605.

b. Cis and trans 3-ethvl~ -nit-obenzvl-2'-~hosDhoranvlidene-2'-acetate)-4-azidoacetvlthio-2-azetidir.ones A solution of the above crude mercaptide (1.31 g, 2 ~moles) in dichloromethane (15 ml) was cooled to 0 and treated, under a nitrogen atmosphe_e, with a 2r1 solution of azidoacetyl chloride in dichloromethane (1.13 ml, 2.26 ~moles). The m-x-ture was stirred at 0 for 1 h and at room te~perature for 5 h. The insoluble silver salts were removed by filt-ation over"~ITE~* and washed with dichloromethane. The combined filtrates were washed with dilute sodium bicar~onate solution anc water, dried and concentrated. The oilv residue was purified by chro~atography ove_ silica gel (35 g) eluting with ether-ethyl acetate. The pertinent fractions ~lere concentrated to give a mi~ture of cis and trans acvlated com~ounds as a se.mi-solid; 0.62 mg. v (CDC13): 2105, 1760, 15~, 1621 c.~ 1.
c. Cis and t_ans ~-nit-obenzvl-2-azido~et~vl-6-etnylper.em-3-carboxvlates ~ solution of the above crude phosphorane (0.60 g) in *~ade ~ k ~

toluene (30 ml) was ~ept at 105 for 1 ;~, cooled and concentrate~
to leave an oily residue wnich was puri-ieZ ~y col~nn cnromato-graphy over silica gel (20 g) eluting wit.~ increasiny ~ropor-tions of etn~r in benzene. T~e ~ertinent fractions were concentrated to give both the cis and trans isomers.
cis isomer: ~ (ppm, CDC13): 8.25 ~2}i, d, J = 8.8, ~o of paranitrobenzyl), 7.65 (2~, d, Hm), 5.93 (lH, d, J = 4.1, H-;), 5.38 (2~, ~3 ~uartet, J = 14.0, benzyl), 4.68 (2~, A~ quartet, J = 15.0, C-H2-.~3), 3.4 (1~1, m, h-6), 2.0 (2H, m, CH2CH3), 1.1 (3~, t, J = 7.4, CH2CH3)-trans isomer: ~ (ppm, CDC13): 8.18 (2H, d, J = 8.8, Ho), 7.59 (2H, d, Hm), 5.52 (lH, d, J = 1.4, ~-5), 5.33 (2H, ~ ~uartet, J = 14.0, benzyl), 4.58 (2H, A3 quartet, J = 15.0, CH2-~3), 3.7 (lH, dt, J = 1.4, J = 7.4, ~-6), 1.9 (2~, m, CH2C~3), 1.1 (3H, t, J = 7.4, CH2C~3).

d. Trans 2-~minomethyl-6-ethvl~enem-3-carDoxylic Acid A mixture of the above trans p-nit~o benzyl ester (0.20 ~, 0.5 mmole), THF (6 ml), etner (6 ml), water (12 ml) and 30% palladium on "G~lTE"*(0.20 g) was reduced at 23 for 2.5 h at an initial hydrogen pressure of 30 ?si. Tl~e catalyst was removed by filtration over "~,TTEI'* and washed with ~ater. The combined filtrates were washed with etner-THF and lyopnilized to give the crude trans acid (12 mg). C~romatosr2?hy over a column oflls~Ex G-lO"eluting wi~n water gave t;ne ?ure trans acid (o mg) as a nygroscopic powcer. ~c=o 1715, lolS cm 1 A = 306 (E = 3465). ~ (p~m, D 0-3MSO): 5.40 (lH, d, J =
max - 2 2.0, ~-5), 2.0 (~H, m, CH2CH3), 1.1 (3~, t, J = 7.4, C112C;.3).

*~ade ~k ~ 8~ -e. cis 2-.~mlnometh~1-6-ethvl~enem-3-carboxvlic ~cid .
~ eduction of the cis-p-nitrobenzvl ester as described above for the trans-ester ga~e the cis-acid as a ~ellowish h~.~groscopic power (13~ =O 1775, 1615 cm 1, ~ma~ 304 (c=3563). ~(ppm, D2O-DMSO): 5.75 (lH, d, J = 4.0, Y-5), 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3).

ExamDle ~
The following com?ounds may De prepared accordins to tne general procedure of Example ~ S
Or~ ~

~cvlatins Agent Y X Z
CH3COcl -CH3 -c~3 ~.ta, ~
Ac2O -CH3 -CH3 ~a, H
3 2 2 3 -c~3 -c~3 ~a, H
C2H5COC1 -CH3 -C2~5 Na, 'i H2cocl -CH3 -CH2~ ~a, n ~OCH2COCl -CH3 2 ~ Na, ;i COCl -CH3 ~ ~a, H
COCl -C~3 ~ ~a~ ~-(CF3CO)2O -CH3 -CF3 `.ta 2 ; 2 - C~ 3 -CO 2 E t rl a COCl 3 ~ ~ ~ Na, H

- ~6 -1~i81~

Acyla_ing A~ent Y X 2 CEI2COCl -CH3 CH2 ~ Na, 3(CH2)2COCl -CH3 -(CH2)2N~2 ~3(CH2)3COCl -CH3 -(CH2)3NH2 NC ( CH2 ) 2Ccl-CEI 3 (CH2)3~ 2 H
02N(CH2)3C -CH3 -(CH2)3~HO~ Na, H
3(CH2)4COCl -CE~3 (CH2) 4 2 H
N3 (CH2) 20CH2COCl -CE13 -CH20 (CH2) 2NH2 N3(CH2)2 C 2 -CH3 -CH25(CH2)2NH2 ACNH(cEl2)2co2co2Et -CH3 -(CH2)2~HAC Na, H

CH3COCl C2 5 -CH3 ~la, H
C2 5C C2H5 C2 ; ~a, H
COCl -C2xS -C~2~ Na, H
00CH2COcl C2 5 CH2~ Na, H
~COCl -C2H5 a Na, H
N3(CH2) 2 C2H5 (CH2) 2' ~2 1~
N3 (CEi2) 3COCl-C2H5 - (CH2) 3NH2 H

02N(C 2)3 C2 5 -(CH2) 3NH~ Na, Ei N3(CH2)4C -C2H5 -(CEi2)4~E12 CH3COCliso-C3H7 -CE~3 Na, H

C2H5COC1iso-C3~7 -C2Hi Na, ~
COCl iso-C3H7 ~ ~a, H
COCliso-C3H7 ~ Na, ;~

¢~COCl iso-C3H7 ~ l~la, H
S S~

0cH2cocliso-C3H7 -CH2~ Na, H
N3C 2C iso-C H -C~2~iH2 -~7 -N3~CH232COCl iso-C3H7 ~(C~2)2~2 ~3(C~2)3COCl iso-C H7 -(CH2)3~H2 O2N(CH2)3COCl iso-C3H7 -(CH2)3~HO~ ~a, Exam~le ~

cis- and trans-6-Acetoxymethyl-2-aminomethyl~enem-3-carboxvlic Acid AcO ~ ~ C~2~H2 a) 3-Acetoxvmethvl-4-tritvlthio-2-azetidinones (cis and trans isomers) A solution of a mixture of cis and trans 4-acetoxy-3-acetoxymethyl-2-azetidinone (4.7 g, 25 mmoles) (Exzm~le 2, structure 26) 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, 3.6 g, in methanol, 300 ml). The mixture was stirred at room tempera-ture for 4 h and the solids were collected by filtration, washed with water, and dissolved in dichloromethane. The solu-tion was washed wi~h dilute hydrocnhloric acid, water, aqueous sodium bicarbonate and water, dried and concentrated to leave 85% of a solid which was used as such in the next experi~ent.

b3 cis and trans 3-~cetoxvmethvl-1-(o-nitrobenzvl-2'-hvdroxy-2'-acetate)-4-tritvlthio-2-azetidinones A solution of the above azetidinone (8.0 g, 20 ~oles) and p-nitrobenzyl glyoxylate (4.54 g, 20 mmoles) were refluxed in benzene (100 ml) through a Dean-Star~ ~-ater separator filled with 3A molecular sieves. After 24 h a second quantity of p-nitroDenzyl 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. D~ins and concentratior lPft 100% of the crude isomeric mixture as an oil.

C) cis and trans 3-AcetoxYmethvl-l-p-nitroDenzyl-2'-chloro-2'-acetate)-4-tritylthio-2-azetidinones A solution of azetidinones from ~art b (12.2 g, 20 mmoles) and pyridine (1.9 g, 24 mmoles) in dried THF (150 ml) was cooled to -15 and treated droowise witn tnionyl cnloride (2.86 g, 24 mmoles) under a nitrogen atmosphere. The mixture was stirred 45 min at -15, the precipitate was removed by filtration and washed with Denzene, and the filtrates were concentrated to leave a semi-solid (95%).

d) cis and trans 3-AcetoxYmethy~ -nitrobenzyl-2~-tri~r~en phosohoranvlidene-2'-acetate)-4-tritvlthio-2-azetidinones A mixture of azetidinones from step c (12. 6 g, 20 ~moles), triphenylphosphine (7.8 g, 30 mmoles) and 2,6-lutiaine (2.6 cc, 22 mmoles) in TH~ (100 ml) was heated under reflux for 80 h. The insoluble material was removed by filtration and washed wi~h ether. The filtrates were washed with 2~
aqueous hydroc~loric acid, 5% aqueous sodium ~icar~onate and water, dried and concentrated. Tne residue was dissolved in benzene, filtered slowly through a pad of silica ~el (250 5) and the ?ad was eluted with inc-easing pro?ortions of etner in benzene. Concentration of the pertinent fractions save a mixture of the title compounds (65~). vC=O 1740, vc=p~ 1620, 1610~ V;~O2 1525 cm ~ 81~3 e) Silver cis and trans 3-Acetoxymethvl-l-(~-nitrobenzYl-2'-triohenYlphosphoranYlidene-2'-acetate)-2-azetidinone-4-thiolates 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 (2.0a g;l2mmoles) 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 furtner 1 h at 0. The silver mercaptide was collected bv filtration, washed with ice-cold metha~ol an- then wit;n etner (5.7 g, 82%~
melts with decomposition). vC=O 1745, 1740, 1625 cm l.

f) cis and trans 3-Acetoxvmethyl-4-azidcecetvl~:~ic-1-(o-nitrobenzvl -2'-triphenYl?hosohoranvlidene-2l-acetate)-2-azetidinones The above silver mercaptide (from s'ep e; 1.4 g/ 2 mmoles) in dichloromethane (15 ml) treated as descri~ed in Example 28 with azidoacetylchloride (2.3 mmoles) gave 0.78 g of a yellow powder.

g) cis and trans 6-Acetoxvmethvl-2-azidomethvl3enem-3-_ carboxYlic Acid ~-NitroDenzvl Esters -A solution of ~e above crude ?hos?horane (0.70 ~g) in toluene (3; ml) was kept at 105 for l h, cooled and concentrated to leave an oil which was purified by chroma-tograpny over silica gel (2; g) eluting wi~h lnc~e~sing propor-tions of ether in benzene. The pertinent ~ractions were concentrated to give the cis and trans-isome s of the title compound.
_q,~ _ . ) 126~

cis isomer: ~ (ppm, CDC13): 8.5-7.5 (4H, aromatics), ~.67 (lH, d, J = 5, H-5), 5.31 (2~, ~B quartet, C~2-benzyl), 4.50 (2H, AB quartet, CH2N3), 4.33 (2H, d, AcOC~2), 4.26 ~lH, dt, H-6), 2.0 (3~, s, CH3).

trans isomer: o (ppm, CDC13): 8.5-7.~ (4H, a'omatics), 5.62 (lH, d, J = 2, ~-5), 5.33 (2H, A3 quartet, CH2-benzyl), 4.40 (lH, dt, ~-6), 4.50 (2~, A~ quartet, CH2l~3), 4.27 (2~, d, AcOCH2), 2.0 (3H, s, CH3).

h) trans 6-Acetoxvmeth~vl-2-aminometnyleen2m-3-carboxvlic Acid Hydrogenation of the above trans isomer by the procedure described in Example 28 gave the title com?ound.
vc=O 1775, 1740, 1616 cm 1 ~max 304 (~ = 3192).

i) cis 6-Acetoxvmethyl-2-aminomethvl?enem-3-carboxvlic Acid Hvdrogenation of the corresponding cis iscmer as described in Exam?le 28 gave ~he title compound as an unstable hygroscopic semi-solid.

- q/~

~2~i81~3 Example ~
The following compounds may be prepared according to t;~e general procedure of ~xample ~ .

~ /~x N ~
CO2 z Acylating Aaent Y X
CH3COCl -C~i20Ac -CH3 H
C~ 5 CH2 -C2H5 H

COCl -CH20AC ~ H
COCl -CH20Ac ~ H

~ OCl -CH20Ac ~ ~ H

N3(CH2)2 CH20 (CH2)2 2 H
N3(CH2)3COCl CH2 -(CH2)3~'2 N3(CH2)4COcl C 2 -(CH2)4N~2 H

02N(C 2)3 C 2 -(CH2)3N~OH H
cH3cocl -(CH2)20AC -c~3 H

COCl -(CH2)20Ac ~
3 2 -(CH2)20AC C 2 2 H
N3(CH2)2 -(CH2)20-~C -(CH2)2~iH2 H
~3( 2)3 -(CH2)20AC -(C1~2)3~H2 .3 -CH-OAc -CH3 H

~3 C 2 -CH-OAc -C!~2~1H2 11 _q,;l _ l~ti~

Exam~le 17 cis a~d trans 6-(l'-Hydroxy-1'-ethyl~-2-methyl~enem-3-carboxylic Acid Sodium Salts OH
(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 diisopropyl-amine (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, 12ti~318~

freshly distilled acetylaldehyde (0.5 ml) was added and stirring was continued for lo 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 O.lN hydrochloric acid (18 ml) and extracted with ethyl acetate ~3 x 20 ml). Concentration of ~he dried ethyl acetate phases left an oil (49 mg). The oil was dissolved in methylisobutyl ketone and treated with an excess of sodium methylhexanoate in the same solvent.
Addition of ether precipitated the title compounds as a white amorphous solid (25 mg). ~ (ppm, D2O): 5.6-5.83 (lH, m, H-5, cis and trans), 2.27 (3H, s, CH3 ), 1.22 and 0.90 (3H, 2d, CH3).

Example 18 cis 6-(l'-Hydroxy-l'-ethvl)-2-methylpenem-3-carbox~lic Acid, Sodium Salt (isomer "D") 2-Methylpenem-3-carboxylic acid (100 mg) was treated with LDCA and acetaldehyde as described in 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 con-verted to a sodium salt with sodium methyl hexanoate as described in Example 17. This yielded 29 mg of a white solid which was identified as cis-6-(l'-hydroxy-l'-ethyl)-2-methyl penem-3-carboxylic acid, sodium salt, contaminated with a little sodium 5-methyl-1,3-thiazole-4-carboxylate. ~ (ppm, DMSO-d6): 5.5 (lH, d, J = 4.1, H-5), 2.22 (3H, s, CH3), 1.02 (3H, d, J = 5.5, CH3).

Exam~le 19 cis and t~ans 6-(2'-Hydroxy-2'-~ro~yll-2-ethyl~enem-3-car~oxylic 5Acids. Potassium Salts (Y = (CH3)2 C-; X = -C2H5) OH

Substitution in the general procedure of Example 3 for the 2-methylpenem-3-carboxylic acid u6ed therein of an equimolar amount of 2-ethylpenem-3-carboxylic acid gave a mixture of potassium salts. ~ (ppm, DMSOd6 ): 5.60 and 5.56 (lH, 2d, J = 4 and J = 2, H-5), 3.92 and 3.60 (lH, 2d, J = 4 and J = 2, H -6), 2.88 and 2.86 (2H, 2q, CH2-CH3), 1.47, 1.41, 1.36 and 1.32 (6H, 4s, CH3), 1.2 and 1.4 (3H, 2t, CH2CH3)- ~ max 257 (~ = 3705) and 302 ( E = 3815).

20Example 20 cis and trans 6-1'-Hydroxy-l'-ethyl)-2-methoxymethylpenem-3-carboxYlic Acid. Sodium Salts To a solution of 2-methoxymethylpenem-3-carboxylic acid (see Preparation 6; 116 mg, 0.55 mmoles) in THF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) at O and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78. After stirring 2 min at -78 fre6hly distilled acetaldehyde (0.5 ml) was added and stirring was continued for 10 min. The reaction mixture was guenched with a saturated ammonium chloride solutlon (10 ml) and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (0.lN, 18 ml) and extracted with ethyl acetate (3 x 20 ml).
Concentration of the dried ethyl acetate phases left an oil (53 mg) which l;~ti~3183 was eonverted to a mixture of the ~odium salts of the title eompound6 as described in Example 17. White amorphous hydro-scopic powder (21 mg). ~ (ppm, D2O): 5.7-5.85 (lH, m, H-5, cis and trans) 3.38 (3H, 28, OCH3 1.22 and 0.92 (3H, 2d, CH3). vC=O 1770, 1600 cm~1.

Example 21 cis and trans 6-AcetYl-2-methYlpenem-3-_arbQxYlic Acid Sodium Salts (Y = -C-CH3; X = -CH3) To a solution of 2-methylpenem-3-carboxylic acid (100 mg, 0.54 mmoles) in THF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) at O and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78. After stirring for 2 min at -78, sthyl acetate (1 ml) was added and stirring wa6 continued for 10 min. The reaction mixture was quenched with a saturated ammonium ehloride solution (10 ml) and wa6hed with ethyl aeetate. The aqueous layer wa6 earefully aeidified at O with 0.lN hydroehlorie aeid and extraeted rapidly with ethyl aeetate (3 x 20 ml). Concentration of the dried extraets left an oil (36 mg) whieh was converted to the title compounds as desoribed in Example 17. ~ (ppm, D2O): 5.90-6.10 (lH, 2d, J = 4, J = 2, H-5), 3.8 (lH, m, H-6 eis and trans), 2.34 and 2.27 (3H, 2s, CH3), 2.12 and 2.0 (3H, 28, CH3).

Example 2 2 The following compounds may be prepared according to the general procedures of Examples 3-5 and 17-21.

o~N ~ X
co2z x y z -CH-nBu Na -C-0 Na -CH3 -CH20H Na -CHCF3 Na -C-CH3 Na -C-CH3 Na -C6H5 jOH
-CH-CH Na -C(CH3)2 K

-C-CH3 Na 12~8~

Y Z

OH
-CH-CH Na o - C ( C H 3 ) 2 ~ K

-CU20CH3 -g-CH3 Na -CH20CH3 -1C-0 Na -CHCH3 Na - C - ( C H 3 ) 2 K

~i~7 ~

~ 81~3 Example 23 The following compounds may be prepared according to the general procedure of Example 3.

S
L N

X Y
OH
-H -CHCH3 Na _ 99 _ ~; ~ 12681~33 x Y Z
OH
-H - CH -IZI K
0~1 -}~ -CH-C 6H 4 OCEI 3 2~a OH
-Ei -CH-n-C Ei7 Na OH
-H -CH-CF Na -EI CH20 ~a o _~ -C-CH 3 Na o -H -C-0 ~a OH
-CHCH 3 Na OH
-C~-~ EC
o -C-CH Na OH
-CH-CEi3 Na OH
CH2~ -CH-CH Na 0~
CH20~ -CH-~5 ;i OH
C 2~ l (CH3) 2 _ lo~

~ l~t~81~13 3 Example ~
2-(4'-Phthalimido-l'-butvl)~enem-3-carboxvlic Acid o CO ~ ~3 TEA~ H 5 ~N ` ~`~`9d To a solution of triethylamine nyd~osul_ide, previously prepared by bu~bling H2S gas through a methylene chloride ~200 ml) solution of triethyl2mine ~8.8 ml, 63.7 mmoies), was added dropwise a methylene chloride (75 ml) solution of t (Gæbriel 3er. 41, 2010) (10.65 ~, 40.2 m~.oles), at 0C ove-a 30 min period. The mixt~lre was stirred a_ 0C for l; min and 2 h at room temperature. The Ors2nic sol~tion w2s ciluted wi_h methylene chloride (125 ~1) and washed with 1~ YC1 (2 x lS ml), water (2 x 15 ml) and brine. It was dried ove; .~1.sSO4 2nd the solvent was flashed down to sive 10.5 S (100~) of 2 as a white solid. m.p.: 93-94C n.m.r. (CDC13) ~ 7.; - 8 (4H, m), 4.47 (lH, broad s), 3.5 - 3.9 (2H, m), 2.5 - 2.9 (2Y., m), 1.4 - 1.9 (4R, m). Anal. calc'd for C13H13NO3S: C, 59.29; ~, 4.97; N, 5.32;
S, 1217. ~ound: C, 58.92; H, 4.91, N, 5.42; S, 12.3'.

--/0/ ~

~X~j81~

F~Pc ~s~

~1aHC03 ` J~
/- ~ l A suspension of 2 (3.04 g, 11.6 mmoles) in a solution of IM sodium bicarbonate (11.6 ml) was stirred at room temperature under nitrogen for 15 min. To it was added 3 (l.S g, 11.6 mmoles) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and extracted with methylene chloride.
The organic phase was dried and evaporated in vacuo to give 3.82 g of solid 4; m.p.: 95 - 96C; i.r. (CHC13) 1775, 1710 cm~1. n.m.r. ~ 7.8 (4H, d, J = 2Hz) 7.05 (]-H, broad s), 5.25 (lH, dd, Jcis = 5Hz, Jtrans = 3Hz), 3.5 - 3.0 (2H, m) , 1.5 - 2.0 (4H, m) Anal. calc'd for: C16H16N24S 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.

`;X~

C~2~~

C2CH2 ~ No2 A benzene solution (30 ml) of 4 (3.0 g, 9.04 mmoles) and p-nitrobenzyl glyoxalate (2.22 g, 9.8 mmoles) was refluxed under a Dean-Stark condenser filled with 3A ~ole-c~lar sieves for 21 h. Evaporation of tne solvent a forded 5.4 g of 5 as an oil (100%). i.r. (neat) 3200 - 3600, 1770, 1710, 1525 cm n.m.r. tC~C13) 0 8.21 (2H, d J = 9:iz), 7.7S (4H, d J = 2Hz), 7.52 (2H, d, J = 9Hz, 5.52 (lH, broad s), 5.32 (3H, 2s), 4.55 (1~, broad s), 3.5 - 3.7 (2H, m), 3.45 (lH, dd J = l5Hz, J is = SHz) 3.02 (lH, dd, Jgem trans = 3Hz), 2.4 - 2.9 (2H, m), 1.4 - 2.0 (4H, m) ~ SOC12 ~

C 2 2 ~ ~2 CO Ck: ~ 2 Azetidinone glyoxalate 5 (4.9 g, 9.05 r~..oles) was treated at 0C with thionyl chloride (15 ml) at O~C

Cor 0.5 h and at room t~mDerat~l-e for 1 ~ he excoss o thionyl chloride was codistilled with ben-ene in vacuo to --/ o 3--l;~fi~

afford 6 as a yellow syrup (5.0 g, 100~6) n.m.r. (CDCL3) 0 8.2 (2H, d, J = 9Hz), 7.72 (4H, broad s), 7.60 (2H, d, J = 9Hz), 6.1 ( lH , broad s), 5.50 - 5.85 ~ lH , m), 5.32 t2H, 2s), 3.4 - 4.0 (2H, m), 3.1 - 3.3 (lH, m), 2.8 -3.05 (lH, m), 2.50 - 2.85 (2H, m), 1.5 - 1.9 ( H, m).

Co2Crl2~NO2 C02CH2~o2 A solu~ion of 6 (21.6 g, 38.8 mmoles) in tetrah~rdrofuran (85 ml, distilled ove_ I~H) was t-eated with triphenyl phosphine (10.2 g, 38.8 mmoles) and 2.6-lutidine (5.0 ml, 42.9 mmoles) for 18 h at 40C. The mixture was diluted wit~ benzene-etner 1:1 (30 ml), washed with wate-, lN HCl, saturated NaHCO3, brine znd dried over MgS04. rv2poration of the solvent afforded a dar~ brown oil.
It was passed through a silica gel (700 g) column (benzene-ether) to give 16.0 g (53~) of 7 as a thiclc oil. ~M~ (CDC13) 8.2 (2H, d, J = 9Hz), 7.8 (8H, d, J = 2Hz), 7.52 (16H, broad s), 5.2 (lH, broad s) 4.78 (lH, 2s), 4.30 - 4.52 (1~, m), 3.5 - 3.8 (2H, ~n), 2.8 - 3.5 (2H, m), 2.1 - 2.9 (4H, m), l.S - 1.9 (4H, m) --I O ~ ~

S r, _ ~ ~ F~

A solution of phosphorane l (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 1 n.m.r. (CDC13) ~ 8.22 (2H, d, J = 9Hz), 7.82 (4H, d, J = 2Hz), 7.65 (2H, d, J = 9Hz), 5.69 (lH, dd, Jci8 ~
4Hz, Jtran6 2Hz), 5.35 (2H, 2s), 5.12 (lH, dd, Jgem = 16Hz, Jci8 = 4Hz), 3.50 (lH, dd, Jgem = 16Hz~ Jtrans = 2Hz)~
3.1 - 3.8 (2H, m), 2.5 - 3.0 (2H, m), 1.4 - 2.0 (4H, m).
O O
~3 ~oF~~~~~

C2cH ~2 C02H

A two phase mixture made of ester 8 (196 mg, 0.
39 mmole) in ether (2 ml) , tetrahydrofuran (4 ml) and sodium, bicarbonate (32 mg, 0.39 mmoles) in water (2 ml) was hydrogenated on 30% Palladium on Diatomaceous earth (190 mg) in a Parr shaker at 40 p.s.i. H2. After 4.5 h it was filtered over "CELITE"* pad and the pad was washed with water and tetrahydrofuran. The filtrats and washings were combined and the organic phase was *Trade Mark .~

~ ~ ~2~i8~

separated. The aqueous solution was washed with ether, aci-dified with lN hydrochloric acid ~3 x 0.4 ml) and extracted tafter each acid portion added) with ethyl acetate (4 x 2 ml~.
The organic extracts were washed with brine, dried over MgS04 and the solvent was removed by evaporation to afford the acid 9, 67 mg (47~), as a yellow solid. i.r.("NUJoL")~ 1775, 170;, 16gO cm 1.
n.m.r. tDMsO) ~ 7.92 (4H, s), 5-71 (lH~ dd~ Jcis ~ 4~Z~ Jtrans 3 2Hz), 3.90 (lH, dd, Jgem = 16 Hz, Jcis = 4Hz), 3.47 (lH~ dd~

J = 16 Hz, J = 2Hz), 3.3 - 4.3 t3H, m), 2.7 - 3.05 2~, m), gem trans 1.5 - 2.0 (4H, m)~

*Trade Mbrk --/o6--~m~

Sodium 2-tAoetonylmethyl ox~me)-~enem-3-carboxylate o~N ~ 2 ~Cc 3 3 CO 2Na o~b `C 'CH F~ H 2--C - C H

C02PNB co2PNs Retal 1 (2.0 g, 4.54 mmoles) was treated at 0 with 95% TFA (20 cc) for 15 min. The mixture was diluted with brine and extracted with methylene chloride (4 x 30 cc).
The methylene chloride extracts were washed with, water-brine (3 times) and brine, and dried over MgSO4 (1.44 g, 80%).
~ (ppm, CDC13) 8.27 (2H, d, J = 9, Hm aromatic), 8.60 (2H, d, J = 9, Ho aromatic), 5.70 - 5.25 (m, CH2- PNs, H-C-O, OC~ f~
H-4, _C=C~ ).

4.75 (lH, bs, OH), 3.76 (center of ABq, CH2-CO), 3.47 (part of a dd~ J3_4 Ci8 = 5, H-3), 3.05 (2H, 2dd, Jgem = 15, J3 4 tran6 = 3, H-3), 2.30, 2.28 (1.67H, 2s, CH3), 1.98 (1.33 H, 8, CH3) v c=o (CHCl3) 1780, 1755, v NO2 1525.

o IN~_OCH3 Il ~SCOCH2-C-CH
35F~CUCH2CCH3 F~ I~fH

CO PNES ` co2P~a ti~

A methylene chloride (50 cc) solution of ketone 2 (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, O. 51 cc, 1 eq.~ wa6 then 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 MGS04 (1.52 g, 98%).
~ (ppm, CDC13) 8.12 t2H, d, J=8, Hm aromatic), 8.40 (2H, d, J = 8 Ho aromatic), 5.50-5.05 (4H, m, CH2- PNB, H-4, H-C-O), 3.80-3.60 (m, OCH3, part of H-3 cis, part of OH), 3.55-270 (m, part of H-3 Ci8, H-3 trans, CH2CO, part of OH), 1.97, 1.90, 1.88 (3H, 3s, CH3) VC=O (CHC13) 1770, 1750, 1690.

N OCH3 N__~OCH3 2-C-CH3 ~ SCOCH2 C 3 ~ pyridine ~ N ~ Cl Co2PNB C02PNB

A cold (-15C) THF (20 cc, distilled over LAH) solution of azetidinone 3 (1.52 g, 3.57 mmoles) was treated dropwise with pyridine (325 mg, 0.332 cc, 4.10 mmoles, 1.15 eg) 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 -lS. The solid was filtered off and washed with benzene. The resulting 601ution was evaporated down.
The residue was taken upon benzene and treated with charcoal (1.2 g, 76%) ~ (ppm, CDC13) 8.23 (2H, d, Hm aromatic), 7.80 (2H, d, Ho aromatic), 6. 12, 6.08 (lH, 2s, H-C-Cl) , 5.75 - 5.55 (lH, m, H-4), 5.40, 5. 30 (2H, 2s, CH2- PNB) , 3.95 - 3.80 t3H, 3B, OCH3) 3. 80 - 2.95 (4H, m, 2H-3, CH2-CO), 2.00 - 1.85 (3H, 4s, CH3) vc=O (CHC13) 1790, 1765 (shoulder), 1700, v N02 1530.

N--OC~3 N ~ OCH3 SCOCH -C-CH ~ SCOCH2-C-CH3 FN~f C 1 0 PN~

A THF (20 cc, distilled over LAH) golution of chloroazetidinone 4 (1.2 g, 2.70 mmoles) was treated with triphenyl phosphine (1.06 g, 4.05 mmole6 1.5 eq) and 2,6-lutidine (318 mg, 0.346 cc, 2.97 mmoles, 1.1 eq). The mixture was stirred for 4 days at room temperature under nitrogen atmosphere. It was diluted with ethyl acetate, washed with 2% aqueous HC1, H20, 2% aqueous NaHC03, water and brine. The solution was then dried over MgS04 and the solvent was evaporated. Crude 5 was purified on 6ilica gel (10 times by weight) column (ethyl acetate, 770 mg, 45%).
Vc=O (CHCl3) 1755, 1695, v 1630 - 1610, v NO 1525.

SCOCH -C-CH ~ CH2-C-CH3 I

'i~., I

~2~i8~
. ,.~

Phosphorane 5 (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 C17H17N3O6S: C~ 52-17;
Found: C, 51.15; H, 4.18; N, 10.33.
(ppm, CDC13) 7.70 (2H, d, Hm aromatic), 7.12 (2H, d, Ho aromatic), 5.00 (2H, 8, CH2PNB), 4.85 (lH, m, H-5), 3.75 - 2.70 (7H, m, CH30, CH2, H-6), 1.77, 1.72, 1.65 (3H, 8, CH3)-~ c=o (CHCl3) 1787, 1742, 1705, NO2 1530.

U.V. (EtOH) AmaX 318 (F = 8420), 262 ( E = 12,539) .

F;f~ ~ 3 H2 ~----~CH -C-CH

CO2PNB C2Na A mixture of ester 6 (151 mg, 0.386 mmole) in THF (20 cc), ether (40 cc) and NaHCO3 (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% ~d on "CELITE"* (200 mg) as catalyst. The catalyst was filtered off and washed with water and ether. The resulting aqueous mixture was washed with ether (3 x 60 cc) and lyophilized (32 mg, 30%).
~ (ppm, DMSO) 5.50 (m, H-5), 3.75 (s, OCH3), 0.77 (s, CH3).
Vc=O ("NUJOL MULL")* 1770, 1600, 1400.
U.V. (H2O) Amax 300 (= 2,800) , 255 ( ~= 2,400).
*Trade Mark ,~
,.

~2~8i~

~:x amP le ~
The following 2-penem compounds may be prepared by acylation of l-(p-nitrobenzyloxycarbonylmethyltriphenyl-?hosphoranyl)-4-(silver mercaptidyl)-2-azetidinone with the appropriate acylating agent followed by cyclization and debloc~ing steps. The general reaction scheme is shown below:

O O
SAg 1. RC-O-C-O-iBu ~ SCOR

N ~ p~3 2. RCOCl ~

Co2pNB C02PNB

H2/30~ Pd/diatomaceous R earth O ~

l~ S
¦ ~ R
N ~

for variation 1: use RC02~ + iBuCOC1 for variation 2: use HCl + PC15 + RCO2H

. ~,~ ~,.

12~8183 Acvlatin~ Aqent Method Product ~H-(c~l2)4 C2H 1 2-(4-Aminobutyl)penem-3-car~oxylic acid CH
0CH2OCONH-CX-CO2}1 1 2-(1-Aminoethyl)penem-3-(both D and ~) carboxylic acid 0c~2ocoNH-cH-co2H 1 2-(1-.~minopropyl)~enem-3-(both D and L) carboxylic acid cEI_cx3 1 2-(1-Amino-2-methyl?ropyl)-0cH2ocoNH-c~-co2H
(both D and L) p~nem-3-carboxylic acid 0CH2OCONH-CH-CO2H 1 2-(1-Aminobenzyl)penem-3-(both D and L) carboxylic acid ICH2~ 1 2-(1-Amino-2-~henylethyl)-(both D and L) penem-3-carboxylic acid CH OCX ~-NO2-~
1 2 2 - 1 2-(1-Amino-2-hydroxyethyl)-0CH2ocoNH-cx-co2H
(both D and L) penem-3-carboxylic acid CH2Co2cH2~-~o2-p ~CH2OCONH-CH-C02H 1 2-(1-Amino-2-carboxyethyl)-(both D and L) penem-3-carboxylic acid CH CONH
1 2 2 1 2-(1-~mino-2-carbamoylethyl)-penem-3-carboxylic acid (both D and L) 0CH2OCONX-CH-CO2~ 1 2-(1-Amino-3-methylthio?ropyl)-(both D and L) penem-3-carboxylic acid (CH2)4NHCO2CH2~
0CH20CONH-CH-C02H 1 2-(1,5-Diaminopentyl)?enem-(both D and L) 3-carboxylic acid CH3 1 2-~(~"lethylamino)methvll?er.em-3-car;~oxylic acic ICH3 1 2-~2-(~ethvlamino)ethyll-0CH2OCONCH2CH2CO2~ .
penem-3-carboxylic acia _~

12ti818~

Acylatinq Agent Method Product 0C~20CoNCH2CH2cli2co2~ 1 2- E3~ ethylamino)propyl]-penem-3-carboxylic acld Cll 0CH20CONCH2cH2c~2cH2co2~ 1 2-[4-(methylamino)butyl]-penem-3-carboxylic acid Cl2 s 1 2-[(Ethylamino)methyl]penem-3-carboxylic acid ~2HS
0C~120CONCH2CH2Co2~ 1 2-[2-(Ethylamino)ethyl]penem-3-carboxylic acid NcH2cH2c~i2co2H 1 2-[3-(ethylamino)propyl3-penem-3-carDoxylic acid NcH2cH2cH2cH2co2H 1 2-[4-(Ethylamino)bu~yl]-penem-3-carboxylic acid 0CH20CONCH2Co2H 1 2-[(Phenylamino)methyl]-penem- 3 -carboxylic ac,d 0CH20CONcH2C~2Co2H 1 2-[2-(Phenylamino)e,hyl]-penem-3-car~oxylic acid 0cH2ocoNcH2cH2cH2co2~ 1 2-[3-(Phenylamino)?royyl~-penem-3-carboxylic acid NcH2cH2cH2cH2co2H 1 2-[4-(Phenylamino)~utyl]-penem-3-carboxvlic acid CH3coNHc~I2co2H 1 2-[(~cetylamino)~ethyl]-penem-3-car~oxylic acid CH3CONHC 2 2 2 1 2-[2-(~cetylamino)et:~yl]-penem-3-carboxylic acic CH3coNHcH2cH2cH2co2H 1 2-[3-(~cetvlamino)?ropyl]-penem-3-carboxvllc aClG
- ll 3 ~oo 12~i81~;~

Acvlatinq Aqent Method Product CH3CONHCH2CH2C~2CH2C02H 1 2-[4-(Acetylamino)butyl]-penem-3-carboxylic acid C6H5CONHCH2C02H 1 2-[(Benzoylamino)methyl]-penem-3-ca-boxylic acid C6H5CONHCH2CH2C02H 1 2-[2-(Benzoylamino3ethyl]-penem-3-carboxylic acid C6H5C5NHCH2CH2CH2C2H 1 2-[3-(Benzoylamino)propylj penem-3-carboxylic acid C6H5CONHCH2CH2CH2CH2C02 1 2-[4-3enzoylamino)butyl]-penem-3-carboxylic acid 0cH2ocoNHcH2coNHcH2co2H 1 2-[(Glycinamido)methyl]-penem-3-carboxylic acid 0CH20CONHCH2CONHCH2CH2C02H 1 2-[2-(Glycinamido)ethyl]-penem-3-carboxylic acid 0CH20CONHC~2CONHCH2CH2CH2C02H 1 2-[3-(Glycinamido)propyl]-penem-3-carboxylic acid 0 2ocoNHcH2coNHcH2cH2cH2- 1 2-[4-(Glycinamido)butyl]-CH2C02H penem-3-carboxylic acid H2NCONHCH2C02H 1 2-(Ureidomethyl)?enem-3-carboxylic acid H2NCONHCH2CH2C02H 1 2-(2-Ureidoethyl)penem-3-carboxylic acid H2NCNHCH2CH2CH2C2H 1 2-(3-Ureidop.opyl)pene~-3-carboxylic acid H2NCONHCH2CH2C~2CH2C02H 1 2-(4-Ureidobutyl)penem-3-carboxylic acid ~2~i8183 .

Acvlatina A~ent Method Product CH3~CONHCH2C02H 1 2-[(Methylcarbamoylamino)-me~hyl]penem-3-carboxylic acid CH3NHcoN~cH2cH2co2H 1 2-~2-(Methylcar~amoylamino)-methyl]penem-3-carboxylic acid CH NHCONHCH CH CH2C02H 1 2-[3-(Methylcarbamoylamino)-3 2 2 . propyl~penem-3-carboxylic acid CH3NHcoNHcH2cH2cH2c~2co2~ 1 2-[4-(~lethylcarbamoylamino)-butyl]penem-3-carboxylic acid 0NHCONHCH2CO~H 1 2-t(Phenylcarbamoylamino)-m~thyl]penem-3-carboxylic acid 0NHcoNHcfi2cH2co2H 1 2-[2-Phenylcarbamoylamino)-ethyl]penem-3-carboxylic acid 0NHcoNHcH2cH2c~2co2H 1 2-~3-(Phenylcarbamoylamino)-propyl~penem-3-carboxylic acid 0NHcoNHcH2cH2c.~2cH2co2H 1 2-[4-(Phenylcarbamoylamino)-butyl]penem-3-carboxylic acid Cx3coNHcoNHcH2co2H 1 2-[(Acetylcarbamoylamino)-methyl]~enem-3-carboxylic acid CH3co~;~coNHcH2c~2co2H 1 2-~2-(Acetylcar~amoylami~o)-ethyl]penem-3-car~oxylic acid CH CONHCONHCH CH2CH2C02H 1 2-[3-(Acetylca-bamoylamino)-3 2 propyl]penem-3-carboxylic acid CH3coNHcoN~cH2c~2c~2c~i2co2H 1 2-[~-Acetylca~bamoylamino)-butyl]penem-3-car~oxylic acid 0CONHCONHCH2C02H 1 2-~(Benzoylcarbamoylamino)-methyl~penem-3-carboxylic acid ~2 ~8~

AcYlatinq Aqent Method Product 0CONHCONHCH2CH2C02H 1 2-[Z-(Benzoylcarbamoylamino~-ethyl]penem-3-carboxylic acid 0CONHCONHCH2CH2C~2CO2H 1 2-[3-(Benzoylcarbamoylamino)-propyl]penem-3-carboxylic acid 0coNHcoNHcH2cH2cH2cH2co2H 1 2-[4-(Benzoylcarbamoylamino)-butyl]-penem-3-carboxylic acid CH30CONHCONHCH2C02H 1 2-[(Carbomethoxycarbamoyl-amino)methyl]penem-3-carboxylic acid CH30CONHCONHCH2CH2C02H 1 2-[2-(Carbomethoxvcarbamoyl-amino)ethyl]penem-3-carboxylic acid CH30CONHCONHCH2CH2CH2C02H 1 2-[3-(Carbomethoxycarbamoyl-amino)propyl]penem-3-carboxylic acid CH3ocoNHcoNHcH2cH2cH2cH2co2~ 1 2-[4-~Carbomethoxycarbamoyl-amino)butyl]penem-3-carboxylic acid (CH3)35i(CH2)2ocoNHcoNHcH2co2H 1 2-[(2-trimethylsilylethyloxy-carbonylcarbamoylamino)-methyl]penem-3-carboxylic acid 3 3 ( 2)20-ONHcoNHcH2 1 2-[2- (2-trimethyisilylethyl-CH2C02H oxycarbonylcarbamoylamino)-ethyl]penem-3-carboxylic acid ( 3)3si(c~2)2ocoNHcoNHcH2- ~ 2-[3-(2-trimethylsilyletnyl-2C 2C02H oxycarbonylcarbamoylamino)-propyl]penem-3-carboxylic acià

_~

Acylatinq Acent ~ethod Product (cH3)3si(cH2)2ocoNHcoNHcx2- 1 2-[4-(2-Trimethylsilylethyl-C~2CH~CH2C02~ oxycarbonylcarDamoylamino)-butyl]penem-3-carboxylic acid CH3s2cNHcH2co2H 1 2-[(Methylthiotniocarbonvl-amino)met~yl]penem-3-carboxylic acid CH3s2c~JHcH2cH2co2H 1 2-[2~ ethylthiothiocarbon amino)ethyl]penem-3-carboxylic acid CH352C~ 2 2 2 2 1 2-[3-(Methylt~iothioCa~bOnVl-amino)?ropyl]?enem-3-carboxylic acid CH3s2cNHcH2c~2cH2cH2co2 1 2-[4-(.~ethylthiothioca.`onyl-amino)butyl]penem-3-carboxylic acid CH3so2NHcH2co2H 1 2-[(Methanesulfonylamino)-methyl]penem-3-carboxylic acid CH3so2NHcH2cH2co2H 1 2-[2-(Methanesulfonylamino)-etnyl]penem-3-carboxvlic acid CH3502NHC 2 2 2 2 1 2-[3-(Met~anesulfonylamino)-propyl~penem-3-carboxylic acid CH3so2~HcH2cH2cH2cH2co2H 1 2-~ ethanesulfor.vlamino)-butyl]penem-3-carboxvlic acid 02NY.CH2Co2H 1 2-[(Benzenesulfonylamino)-methyl]penem-3-carboxvlic acld 12~

Acylatinq Aaent Method Product H2cH2co2~ 1 2-~2-(~7-~ethylthiocarbamoyl-amino)ethyl]penem-3-carboxylic acid H3cNHcNHcH2c 2 2 2 1 2-[3-(N-~ethylthiocarbamoyl-amino)propyl]penem-3-carboxylic acid H3c~Hc~HcH2cH2cH2cH2co2H 1 2-[4-(N-Methylthiocarbamoyl-amino)butyl]penem-3-carboxylic acid 0N}LC~HCH2CO2H 1 2-[(~-Phenylthiocarbamoyl-amino)methyl]penem-3-carboxylic acid 0NHC~HCH2CH2C02H 1 2-~2-('N-Phenylt~iocarbamoyl-amino)et~yl]?enem-3-carboxylic acid s 0N~c~cH2cH2c~i2co2H 1 2-[3-(N-Phenylthiocarbamoyl-amino)?ropvl]?enem-3-carboxvlic acid 2c~2c~2cH2co2H 1 2-[4-(N-Pnenyl~niocarbamoyl-amino)butyl]penem-3-carboxylic acid , 11 NHCH2CO2H 1 2- [ (GUanV1aminO)metAY1]-HO ~ ~ penem-3-carboxylic acid ~2C~2C2~ 1 2-~2-(Guanylamino)ethyl]-o~ ?enem-3-carboxylic acid N 1l N~CX2C z 2 2 1 2-[3-(Guanylamino)?roovl~-N penem-3-carboxvlic acid ~O ~

Acyiatin~ A~ent Method Product Il ~HcH2cH2cH2cH2co2H 1 2-[4-(Guanylamino)butyl]-loi~ penem-3-car~oxylic acid `J ~ 1 2-[(.~cetimidoylamino)met;nyl]-J~ ~-CH2CO2H penem-3-car~oxylic acid -CH2CH2C02H 1 2-[2-(Acetimidoylamino)etAyl]-pene~-3-carboxylic acid C~2CH2 2 2 1 2-[3-(Acetimidoylamino)~ropyl¦-penem-3-carboxylic acld -CH2CH2CH2cH2c02~ 1 2-[4-(Acetimidoyl2mino)_utvl]-penem-3-carboxylic acla N ~ O
C~2C 2 1 2-[(Formimidoylamino)methyl]-penem-3-carboxylic acid ,- -C~2c~2c02 1 2-[2-(Formimidoylamino)etnyl]-penem-3-carboxylic acid -CH2CH2CH2c02 1 2-[3-(Formimidoylamino)?rs?yl)-~enem-3-carboxylic acid -CH2CH2C~i2cH2c02 1 2-[4-(Formimidovlamino)butyl]-penem-3-carboxylic acid o2NCH2c 2 1 2-[(Hydroxyamino)~.ethyl]-?enem-3-car~oxylic acid 02NcH2cH2co2~ 1 2-[2-(Hydroxyamino)et;~yl]-?enem-3-ca~::oxyllc aci~

02Nc~2cH2cH2cH2co2 1 2-[4-(Hydroxvamino)`_utyl~-penem-3-carboxylic ac~d " 1'~68183 Acylatina Aaent ~ethod Product olc~3 (CH3)3Si(CH2)20CON-CH2C02H * 1 2-[(~1ethoxyamino)methyl]-penem-3-carboxylic acid OCH
(cH3)3si(cH2)2ocoN-cH2cH2co2~ * 1 2-[2-(1~ethoxyamino)ethyl]-penem-3-carboxylic acid OCH
3)3si(cH2)2ocoNcH2cH2cH2co2H * 1 2-[3-(.~ethoxyamino)propyl]-?enem-3-carboxylic acid 3)3si(cH2)2o.coNcH2cH2cH2cH2co2H * 1 2-[4-(methoxyamino)butyl]-penem-3-carboxylic acid 3~35i(c~2)2ocoNcH2co2H * 2 2-[(Hydrazino)methyl]?enem-3-carboxylic acid ( 3)35i(CH2)20CONC~2CH2C02~ 2 2-[2-(Hydra2ino)ethyl~?enem-3-carboxylic acid NH
(cH3)3si(cH2)2ocoNcH2cH2c~2co2H * 2 2-[3-(Hydrazi~o)?ropyl]penem-3-carboxvlic acid NH
(ca3)3si(cH2)2ocoNcH2cH2cH2cH2co2H * 2 2-[4-(Hydrazino)butyl]?enem-3-car~oxylic acid N(CH3)2 (CX3)3Si(C~2)20cONcH2co2H * 2 2-[(2,2-Dimet~vlhvdrazino)-met;~yl]penem-3-carboxylic acid N(CH3)2 ( ~3)3si(c~2)2oco~cH2cH2co2H * 2 2-[2-(2,2-Dimetnylhydrazino)-ethyl]?enem-3-carboxylic acid N(CH3)2 (cH3)3si(cH2)2ocoNcH2cH2cH2co2H * 2 2-[3-(2,2-Dimethylhydrazino)-propyl~2enem-3-carboxvlic acid N(C~3)2 (cH2)2ocoNcH2cH2cH2c~2co2H * 2 2-[4-(2,2-Di.. et~ylAycrazino)-butyl]?enem-3-car20.Yylic acid * use trimethvlsilvlethyl instead of ~NB in azetidinone intermediate and deblock with F .

_l ~o---3~.

12~i81~

Acylatinq A~ent Method Product CH3CONHNHCH2C02H * 2 2-~(2-Acetylhydrazino)methyl]-penem-3-carboxylic acid C~3coN~NHc~2cH2co2~ * 2 2-~2-(2-Acetylhydrazino)-ethyl~penem-3-carboxylic acid CH3CONHNHCH2c 2 2 2 ~ 2 2-~3-(2-Acetylhydrazino)-propyl]penem-3-carboxylic acid C~3coNHNHcH2cH2cH2cH2co2H * 2 2-[4-(2-Acetylhydrazino)-butyl]penem-3-carboxylic acid (CH3)2~C~2c02 2 2-~(Dimethylamino)methyl]-penem-3-carboxylic acid CH3)2~cH2cH2co2H 2 2-[2-(Dimethylamino)ethyl]-penem-3-car~oxylic acid (CH3)2NC~2c 2 2 2 2 2-~3-(Dimethylamino)propyll-penem-3-carboxvlic acid (cH3)2NcH2cH2cH2cH2co2H 2 2-[4-(Dimethylamino)butyl]-penem-3-carboxy}ic acid CH3coNcH2co2H 1 2-~(N-Me'~ylacetamido)methyl¦-?enem-3-carboxylic acid fH3 CH3CONcH2 2 2 1 2-~2-(N-Methylacetamido)etnyll-penem-3-carboxylic acid CH3coNcH2cH2cH2co2H 1 2-[3-(n-Methylacetamido)propvl]-penem-3-carboxylic acid CH3CONc~2cH2 2 2 2 1 2-[4-(N-Met~ylacetamico)butyll-penem-3-car~oxylic acid ~1~1~

i8~

Acylating Aaent Method Product N-CH CO ~ 1 2-[(Phthallmido)methyl]penem-3-carboxylic acid 1 2-[2-(Phtnalimido)ethyl~-2 2 2 penem-3-carboxylic acid 1 2-[3-(Phthalimido)propyl]--cH2c~2cH2co2 penem-3-carboxylic acid 1 2-[4-(Phthalimido)butyl]-' ~ -CH2CH2CH2cH2c 2 penem-3-car~oxylic acid 0cH2oco~HcH2c~2ocH2co2H 1 2-[(2-Aminoethoxy)methyll-penem-3-carboxylic acid 0cH2ocoNHc~2cx2scH2co2H 1 2-[(2-Amlnoethylthio)methyll-penem-3-carboxylic acld 0CH2OCONHCH2CH2NCH2Co2H 1 2-[(2-Aminoethylamino)methyll-penem-3-carboxylic acid C~
0cH2ocoNHcH2cx2Nc-A2co2H 2 2-[N-(2-Aminoethyl)-N-methylaminolmethyl?enem-3-car~oxylis acid 0CH2OCONH ~ CH2co2H 1 2-(p-Aminobenzyl)pe~.em-3-carboxylic acid CH2C02H--~
0CH2OCONH ~ \ 1 2-(o-.~minobenzyl)oenem-3-carboxylic acid 0CH2OCONH ~ co2~ 1 2-(p-Amino?nenyl)penem-3-carboxylic acid 0CH2OCONH ~ 1 2-(m-Aminopheryl)per.em~-3-carboxylic a id ~ ;3 Acvlating Aqent~ethod Product C02H ~
0CH20CONH ~ 1 2-(o-Aminopnenyl)penem-3-carboxylic acid 0CH20CONHCH2 ~ co2~ 1 2-[p-(Aminomethyl)phenyl]-penem-3-carboxylic acid ,_~C02H
0cH2ocoNHc~2 ~ ~ 1 2-[m-(~minomethyl)phenyl]-penem-3-car~oxylic acid co2H ~
~CH20CONHCH2 ~ 1 2-[o-(Aminomethyl)?henyl]-penem-3-carboxylic acid _1~3_ ~lu-12~81~;~

~1 Example ~
The 2-penem products listed below as tAe triethylamine salts are treated with (CH3)3N S03 in CH2C12 solution at 0.
Addition of sodium 2-ethylhexanoate in l-butanol to the re-action solution results in precipitation of the indicated products as disodium salts.

Starting Material Product ~ ~ ~CH2)nNH~ ~ ~ ( 2)n 3 O O
C02N(C2H5)3 C2~a Exp. A n = 1 A. n = 1 Ex2. B n = 2 B. n = 2 rxp. C n = 3 C. n = 3 Exp. D n = 4 D. n = 4 2~
Examole ~' The 'ollowing 2-penem products may be prepared from the indicated starting materials by the procedure ~N ~ (CH2~nN(CH3)2 _ I 3 ~N ~ (CH2)2~(CH3)3 o CO2 C02PN}~

~X~

l~t~

H2~Pd ~ ~ (CEl2)n~(C~3)3 N
CO 2~

Starting Material Product (CH2)n~(C~3)2 ~ /\r (C~2)n'~(C~3)3 Exp. An = 1 A. n = 1 Exp. Bn = 2 B. n = 2 Exp. Cn = 3 C. n = 3 ~xp. Dn = 4 D. n = 4 ?9 _xamp le The following 2-?enem products may be prepared from the indicated starting materials by the procedu-Q
SAg SCO(C~2) Cl + Cl ~C~12) nCOCl N ~ p~3 ~

CO 2?~D
Co2pNB

~1~5~
~--(CH ) Cl ----------~~ ~ 2 o ¦ de~locXing ~debloc~ing ~ ~ ~C~2)n ~ ~N

Starting ~laterial Product ,~ ~ (C~2) nCl ~ ~ (C~2) n~N~) A n = 1 Exp. ~ n = 1 B n = 2 Ex?. B n = 2 Exp. C n = 3 C. n = 3 D n = 4 Exp. D n = 4 ~0 Example ~r The rollowing 2-penem products may be ?repared from the indicated starting materials by the procedure ~i8~

o o Il ~ ~PR ~ SC (CH2) m n' N OEi ~N ~ H \1' O N
H2NB SC (CH2)m N OH
O ~

~1 3 ~ SC- (CH2) ~-C-R , 1. 03P
socl2 >
> ,~ N ~ ~Cl 2 .
o r ~( CH 2 ) m~C- R - >

co2L~
OH
~( CH 2 ) m N ~

Z = ~ (C~2) 25i (C~3~ 3 m = 0-2 B = O ( C. 2 ~ 3 3 R = H, C~3 ~ ~ ' `~ 12~81~

Startin~ ~aterial Product S ~C- ( CH 2 ) m~C - R S N

~( C~ 2 ) m~C~ R

Exp. A R z H, m - 0 A. R = H, m = 0 r~xp. B R = H, m = l B. R = H, m = 1 EXp. C R = H, m = 2 C. R = H, m = 2 Ex?. D R = CH3, m = O D . R = CH 3, m = 0 Ex?. E R = CX3, m = l E. ~ = CH3, m = l Ex?. F R CH3, F. ~ c~3, Substitution in the above procedure of H2~0CH3 f t e H NO(C'~ )2Si(CU3)3 used therein resul_s i of the followi~g ~roducts.

OC~13 ( CE12 ) m O ~
c02H

Exp. A m = O, R = H
Ex?. B m = 1, R = H
Exp. C m = 2, R = H
EX? ~ m = O, R = C~13 Exp . E m = 1, R = C~l 3 Ex? . F m = 2, R = CH3 ~;, 1~i8~83 Susstitution in the above procedure of (CH3)35i-(CH2)2cNHNH2 for the Y2~o(cH2)2si(cH3)3used ther~in ~e-sults in for~ation of the following products, NN}12 ~(CH2) m~C~R
~N ~

Exp. A m = O, R = H
Exp. B m = 1, ~ = H
Exp. C m = 2, R = ~
Exp. D m = O, R = CH3 Exp. E m = 1, R = CH3 Exp. F m = 2, R = CH3 Substitution in the above procecure of (CH3)2NNH2 o~ the H2,`~0(CH2)~5i(CH3)3 use~ therein resuits in 'ormation of the followina ?rcducts:

~ ~N(CH3)2 LN ~(CH2 ) m-C-R
CO 2~

Ex?. A m = O, R = ~

Exp. B m - 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3 Exp. E m = 1, R = CH3 Exp. F m = 2 ~ = CH 3 _I.29 -1~i8183 Substitution in the above procedure of (CX3)35i(C~2)2OCO`.~-NH~ -or the H2NO(CH2)25i(CH3)3 used therein results in formation of the followins ?roducts:

~ S\ NNH0 ,~N ~(CX2)m-C-R

Ex~. A m = 9, R = H
Exp. B m = 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3 Exp. E m = 1, R = CX3 Exp. F m = 2, R = CH3.

-~3 i8183 Exam~le 31 o ~ ~ ~( ~ )2 ~ ~ P~3 2 2 Co2pNB C02PNa I I~ I T

A solution of L (1.1 g, 1.6 mmole) and II (0.16 ml, 1.6 mmole) in methylene chloride (30 mll was cooled in an ice bath and treated dropwise with lM solution of pyridine in methylene chloride (1.7 ml, 1.7 mmole~. ~he resulting reaction mixture was 6tirred 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 lN HCl (5 ml), water (5 ml), lM
NaHC03 (5 ml) and brine, and then dried (MgS04) and evaporated in vacuo to give IIL 900 mg (87%) as an amorphous solid. It was used in the next step without further purification. IR (CHC13) 1755, 1690 cm~1 NMR (CDC13) ~ 8.22 (2H, d, J=9 Hz), 7.55 (15H, m), 6.72 (2H, d, J=9 Hz), 5.7 (lH, m), 5.0 (2H, 28), 3.55 (2H, 28), 2.8 (4H, m).
*Trade Mark i81~33 ~H2Cl ~ P --~

C02PNa ~ s ~ ~(O ~<)2 III IV ~ ~ p~
1 0 C02PNa A mixture of IIL (1.3 g, 2 mmoles) and LY (0.65 ml, 3 mmoles) was heated at 80C for 4 h. The reaction mixture was diluted with methylene chloride (10 ml) and washed with water (2 x 5 ml). Organic layer was dried (MgS04) and evaporated in vacuo to give y, 1.4 g (90%), aæ
an amorphous solid. lt was used in the next 8 tep without further purification. IR (CHC13) 1755, 1690 cm 1 NMR
(CDC13) ~ 8.25 (2H, d, J=9 Hz), 7.55 (15 H, m), 6.8 (2H, d, J=9 Hz), 5.7 (lH, m), 5.1 (2H, 28), 4.72 (2H, dq J=12 Hz, J=6 Hz), 2.6 (4H,m), 1.4 (6H, 6), 1. 28 (6H, 8).

~ ~ )2 P~3 co2PNB ~ 8 ~o~ ~ 2 v C2~N3 VI
A ~olution of y (1.6 g, 2.06 mmoles) in toluene (60 ml) wa6 heated under reflux for 5 h.
The solvent was evaporated in vacuo and the residual oil was chromatographed on silica gel column 1~)8183 (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.: 83-40C from ether.
IR (CHC13 ) 1790, 1710 cm 1 NMR: (CDC13) ~ 8.2 (2H, d, J=9 Hz) , 7.6 (2H, d, J=9 Hz) 7.5 (2H, s) 5.65 tlH, dd, Jtrans = 4 Hz, Jcis = 2 Hz), 5.22 t2H, 2s), 4.75 (2H, dq J=12 Hz, J=6 Hz) 3.85 t1H, dd, Jgem = 15 Hz, J trans = 4 Hz), 3-5 (lH~ dd~ Jgem = 15 HZ~ ~ci8 = 2 HZ), 2. 8-3.3 (2H, m), 1.4 (6H, 8), 1. 28 t6H, 5).

~f ~'-<~ 2 ~ ( ~ )2 VI VII

To a solution of vq (200 mg, 0.4 mmole) in tetrahydrofuran (8 ml) and ether (4 ml) was added sodium bicarbonate t34 mg, 0. 4 mmole) , water (4 ml) and 30% Pd/
"CELITE"* (200 mg) followed by hydrogenation 2h at 40 p.s.i.
The mixture was filtered and layers were separated. The aqueous phase, after washing with methylene chloride (2 x 5 ml) , was cooled with ice, acidified with lN HCl (1 ml), and extracted with chloroform (5 x 5 ml). Organic extracts were dried (MgS04) and evaporated in vacuo to give ~IIL 76 mg (52%) , as an oil. IR (CHC13) 1790, 1710 cm 1. NMR
(CDC13) ~ 9.5 (lH, w6) , 5-65 (lH, dd, Jtran6 = 4Hz~ Jcis =
2 Hz), 4. 72 (2H, dq J=12 Hz, J=6 Hz) 4.2- 5.1 (2H, m), 3.4-4.1 (2H, m), 2.7-3.4 (2H, m), 1.35 (6H, s), 1.25 (6H, 8).

*Trade Mark ~r~

,_ .

Example 32 0 ~ R(OC,H5)2 SAs ~ R
+ ClC(CH2)3P(oc2H;)2 R

C02PNB ___ "S ~ (CH2)3P(OC2H5~2 I
l 2 O4 _ N ~ p~3 C02P~3 To a cooled (ice bath) mixture of 1 (1.324 9, 2 mmoles) and 2 (0,54 g, 2.2 mmoles, crude) in CH2Cl2 (15 ml) was added dropwise 1 M solution pyridine /CH2Cl2 (2.2 ml, 2.2 mmoles). The mixture was stirred at r.t. for 1 h and filtered over "CELITE"*. The filtrate wa6 washed ~uccessively with 0.5N HC1, H2O, 0.5 M NaHCO3 and brine. It was dried (MgSO4) and filtered over "CELITE"* charcoal to give after evaporation to dryness 0.9 g of an oil. The oil was chromatographed on SiO2 (10% H2O) and eluted with ethylacetate to give 0.5 g of 3. (32.8%). NMR
~ (ppm, CDC13) 7.0-8.4 (m, l9H), 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).

*Trade Mark ~2 5 ~ ~OEt)2 ~P
cO2PN3 ~ (OEt)2 3 (0.4 g, 0.52 mmole) in toluene (35 ml) was refluxed for 4 h and evaporated to dryness to give an oil which contained 3, 4 and 3P=O. 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 ~ (ppm, CDC13), 8.3 (2H, d), 7.67 (2.H, 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~l (~-lactam) 1710 cm~l (ester).

~\P (OEt) 2 ~ N _~
02PN3 F~S~~R (O_t) 2 4 o ~

A mixture of 4 (O. 1 g, O. 207 mmole) , 30% Pd/
"CELITE"* (0.1 g) and NaHC03 (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 lNHCl. It was extracted with CH2Cl2 and dried (MgS04). The CH2Cl2 solution was evaporated to give 48 mg of 5 (66. 5%) .
o IR spectrum ~ 1790 (~-lactam) ~ 1700 (-C-OH).

*Trade Mark ~`1 ,~

s~P (Ol~e) 2 N ~

o~ + (MeO)3~ 1~ p~ P~(O;~le) CO2PNB 2 3 l02PNE3 A mixture of l (1.07 g, 1.66 mmole) and 2 (0.42 g, 3 mmoles) in CH2Cl2 (3 ml) was heated at 80 for 5 h. The crude oil was chromatographed on SiO2 (3% H2O) and eluted with ether, ether-ethylacetate (1:1) and ethyl acetate: 5% EtOH to give 1.0 g of 3 (82%). The oil crystallized on 6tanding, M.P. (ether) 138-40.
NMR ~ (ppm, CDC13) 8.2 (2H, d) 7.0-8.0 (17H, m), 4.6-5.5(3H, m), 3. 8 (3H, 8), 3.6 (3H, s), 1.5-3.5 (6H, m).

~ ~ " ~ ~ ~ ~(C~e)2 Co2?~B 2 3 (0.5 g, 0.69 mmole) in toluene (30 ml) was refluxed for 4 h. It wa8 evaporated to dryness, chromatographed on SiO2 (3% H2O) and eluted with Et2O:
EtOAc (1:1) followed by EtOAc: 10% EtOH to give 0.18 g of 4 (58%). NMR ~ (ppm, CDC13, 8.25 (2H, d), 7.6 (2H, d), 5.65 (H, q), 5.3 (2H, d), 3.8 (3H, s) 3.6 (3H, 8), 2.7-3.6 (2H, m), 1.5-2.5 (4H, m).

~2~

s ~ 30~ ~d~"~E~ITE"*~
N ~ NaHCO3 1 0 CO2P:\13 ,o, F~ ~ P ( OMe ) ., C2Na S

A mixture of 4 (50 mg, 0.112 mmole), NaHCO3 (9.125 mg) 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 (RBr) 1770 cm~1 (B-lactam), 1610 cm~1 (-COO~).

*Trademark ~', i ,` - `

1~i8~

Example 34 (l'R.5R,6R) and (l'S SS,6S) 6-(1'-Hydroxy-l'-ethyl)-2-methylpenem-3-carboxylic Acid (isomer D) (illustrates most preferred process of introducinq 6-substituent in mid-synthesis OH

~ ~ c93 Co2Na~ K

A. Preparation of 4-Tritylthio-2-azetidinone Intermediates 1. 1-(Trimethylsilyl)-4-tritylthio-2-azetidinone ,sc~3 sc~3 1~ . } 1~N' 0~ ~ Si~Me)3 A solution of 4-tritylthio-2-azetidinone (345 mg, 1 mmole), 1, 3, 3, 3, -hexamethyldisilazane (80 mg, 0. 5 mmole) and chlorotrimethylsilane (55 mg, 0.5 mmole) in dichloromethane (20 ml) was heated under reflux for 18 h. Concentration of the reaction mixture left virtually pure title compound.
~ (ppm, CDC13): 7.32 (15H, m, aromatics), 4.22 (lH, dd, H-4), 2.67 (lH, dd, J = 4.1, J = 16, H-3), 2.22 (lH, dd, J = 2.2, J =
16, H-3), 0.3 (9H, s, CH3).

2. 1-(t-Butyldimethylsilyl~ ylthi~-2-aze~i~in~ne o ~ "~ ~ C~3 C (CH3) 3 Triethylamine (1.62 ml, 11.6 mmoles) was added dropwi B e in 5 min to a cooled (O) and stirred solution of 4-tritylthio-2-azetidinone (3.5 g, 10.1 mmoles) and chloro-t-butyldimethylsilane (1.68 g, 12.7 mmoles) in DMF (35 ml). The reaction mixture was stirred at room temperature for 18 h, diluted with water (250 ml) and ether (200 ml). The organic phase was washed with water (3 x 50 ml), dried and concentrated to leave an oil (4.33 g). Crystallization from pentane gave a total of 4.1 g(89%) of the title compound as a white solid, m.p. 113-4. ~
(ppm, CDC13 ): 7.45 (15H, m, aromatics), 4.2 (lH, dd, H-4), 2.63 (lH, dd, J = 4, J = 16, H-3), 2.13 (lH, dd, J = 2, J = 16, H-3), 1.0 (9H, s, t-Bu), 0.35 (6H, 6, Me).
Vc=O 1735 cm 1 Anal. calc'd for C28H33, NOSSi-: C, 73.15; H, 7.24;
N, 3.05; S, 6.97%. Found: C, 73.27; H, 7.32; N, 2.97; S 6.94%.

81~

3. 1-Methoxymethyl-4-tritylthio-2-azetidinone ~ SC~3 ~ SC~3 0 ~ N~ o CH20C.'13 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 (200mg of commercial 50%, 4.1 mmoles, washed with pentane) in THF (10 ml) maintained at -15. Methanol (12 drops) was added and the mixture was stirred at -15 for 0.5 h.
Methoxymethyl bromide (0.58 g, 4.6 mmoles) was added and the mixture was stirred for 2h, diluted with ether, washed with water and brine, dried and concentrated to leave an oil (1.72 g).
Crystallization from pentane gave a white solid (1.41 g) m.p.
72-76 ~ (ppm, CDC13 ): 7.3 (15H, m, aromatics), 4.4 (3H, m, NCH2O
and H-4), 3.22 (3H, s, CH3 ), 2.76 (2H, m, H-3).

4. 1-(Methoxyethoxvmethyl) -4-tritylthio-2-azetidinone sc~3 Sc~3 ~ _ ~ H ~ N ~_,o~ ~

To a suspension of tetrabutylammonium bromide (322 mg, 1 mmole) and potassium hydroxide (~5%, 70 mg, 1.1 mmole) in dichloromethane ~10 ml) cooled to 5 was added with vigorous stirring 4-tritylthio-2-azetidinone (345 mg, 1 mmole) and methoxyethoxymethyl chloride (187 mg, 1.5 mmole). The mixture was stirred at room temperature for 2 h, the 1~;8~3 .

solvent was evaporated and the residue partitioned between water and ethyl acetate. The dried organic phase was concentrated to leave a viscous oil (415 mg). Purification by column chromatography on silica gel eluting with ether (5~)-dichloromethane gave the title compound (206 mg, 48%) as an oil. ~ (ppm, CDC13): 7.30 (15H, m, aromatics), 4.57 (2H, AB
quartet, N-CH20), 4.46 (lH, dd, H-4), 3.50 t4H, s, OCH2CH20), 3.30 (3H, s, CH3), 2.75 (2H, m, H-3).

5. l-(2'-Tetrahvdropyranyl)-4-tritylthio-2-azetidinone ~ SC~3 ~ C~3 O ~ H N~

n-Butyl lithium (1.6M, 1.6 ml, 2.56 mmoles) was added dropwise to a solution of 4-tritylthio-2-azetidinone (863 mg, 2.5 mmoles) in THF maintained at -78. After stirring for 15 min, 2-chlorotetrahydropyran (560 mg, 4.7 mmoles) was added and the reaction mixture was allowed to come to room temperature in 1.5 h. The reaction solution was diluted with ethylacetate, washed with brine, dried and concentrated to leave an oil (635 mg).
Column chromatography on silica gel eluting with dichloromethane-ether gave a mixture of the isomeric title compounds contaminated with a little starting material. ~ (ppm, CDCl3 ): 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).

12681~

B. Pre~aration of 3-(1'-Hydxoxy-1'-ethyl) -l-methoxymethyl-4-t~i~y~Q-~- azetidinones pH
SC~p 3 ~ SC~3 ~N ~ ` O ~~

a~ (l'S.3S 4R and 1'R.3R.4S)isomer (isomer Cl A solution of lithium diisopropyl amide was prepared lS in THF (S ml) at -78C from n-butyl lithium (1.6M, 1.0 ml, 1.6 mmol) and diiæopropylamine (0.25 ml, 1.84 mmol). After 30 min a solution of 1-methoxymethyl-4-tritylthio-2-azetidinone (491 mg, 1.42 mmol) in THF (6 ml) was added dropwise and the solution was stirred for lS min. Acetaldehyde (3.0 ml) was added dropwise, followed, after 20 min, by water (30 ml). The mixture was acidified to pH 3 with 2% HCl and extracted with ethyl acetate (5 x 20 ml). The combined organic phases were washed with brine, dried and concentrated to leave an oil which crystallized upon trituration with ether: 440 mg, 80%, mp 188.5-9C; 1 Hmr (CDC13) ~:7.3- (lSH, m, aromatics), 4.37 (2H, ABg, N-CH20), 4.32 (lH, d, Jz2, H-4), 3.17 (3H, 8, OCH3), 3.32-2.70 (2H, m, H-3 and H-5), and 1.12 ppm (3H, d, J=7, CH3); Anal- calcd for C26H27N03S 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 601ution of lithium diisopropyl amide (0.482 mmol) is prepared at -78C in dry ether (3 ml) from butyl lithium 0.191 ml of 2.52 M solution in hexane, 0.482 mmol) and diisopropyl amine ""`i ~2~`81~3 , (0.067 ml, 0.482 mmol). After ~0 min, a solution of (4R and 4S) 1-methoxymethyl-4-tritylthio-2-azetidinone (0.171 g, 0.439 mmol) in a mixture of dry ether (lml) and dry THF (1 ml) was added dropwi6e and the resulting clear 801ution was stirred at -78C for 15 min. A 601ution of tetrabutyl ammonium fluoride (0.96 ml of a 0.5M 601ution in THF, 0.48 mmol) was then added. A precipitate was formed with the generation of a slight pink colour. After 5 min at -78C, the reaction mixture was guenched with freshly distilled acetaldehyde (0.2 ml, excess), and the stirring continued for 15 more min. The work-up was done by adding to a saturated solution of ammonium chloride and extracting with ethyl acetate (2 x 25 ml). The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under vacuum gave an oil (0.228 g) which was chromatographed on 10 g of silica gel A mixture of benzene and ethyl acetate (6:4)gave 0.106 g (62% recovery) of substrate and a mixture of the two isomer alcohol~ which were separated by chromatography on thic~ layer plates (same solvent-system). The alcohol with the hi~h Rf (0.033 g, 17 %) was identical to the above i60mer (i60mer C): mp 188.5-189C (Ether-dichloromethane); The alcohol with low Rf (0.030 g, 16%) (isomer B), was obtained as an oil which crystallized with difficulty from hexanes: mp 94-95C.
ir (CH2C12) Vmax : 3600 (OH), 1760 cm 1 (C=O); 1Hmr (CDC13) ~:6.9-7.5 (15H, m, aromatics), 4.2 (2H, center of ABq, J=11.5, CH2- 0-CH3), 4.28 (lH, d, J=2.0, 4-H), 3.65 (lH, center of a broad sextet, H-l'), 3.3 (lH, dd, J3,4 trang= 2-5~ J3,1 = 5-5~ H3)~ 3-15 (3H, 8, 0-CH3), 1.55 (lH, broad s, OH-l'), 1.05 (3H, d, J=6.5, H-2'); Anal. calcd for C26H27N03S: C 72.02, H 6.28, N 3.23, S
7.39; found: C 71.77, H 6.36, N 3.15, S 7.43%.

~2~818~

C. Pre~aration of trans 3-Acet l-l-methoxvmethyl-4-tritvlthio-2-azetidinone Y _ .

EtOA ~ CH3 ~

Lithium diisopropylamide was prepared under a nitrogen atmosphere at -78C in the usual manner from diisopropylamine (0.34 ml, 2.4 mmol) and n-butyl lithium (1.1 ml of a 2.2M solution in hexane, 2.4 mmol) in THF (3 ml). A solution of l-methoxymethyl-4-tritylthio-2-azetidinone (0.78 g, 2 mmol) in THF (3 ml) was added dropwise and, after stirring at -78C for 20 min, ethylacetate (0.53 g, 6 mmol) was added in one portion and stirrins continued for 0.75 h at -78C. The reaction mixture was diluted with ether and washed with an ammonium chloride solution, water and brine, aried and concentrated to give an oil (0.7 g). Purification was achieved by chromatography over silica gel (20 5) eluting with inc-easing amounts of ether in benzene. The pertinent fractions we_e concen-trated to give the title material as a colorless oil (0.32 g, 37~);
IHmr (CDC13) ~:7.7-6.8 (lSH, aromatics), 4.85 (lH, d, J=2, H-4), 4.5 (2H, s, N-CH2-O), 3.9 (lH, d, J=2, H-3), 3.22 (3H, s, CH3) and 2.0 ppm (3H, s, CH3); ir ~ : 1770, 1710 cm _ J ~

1~`81~

D. re~aration of trans 3-Acetyl-1-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone t-Bu LDA ~ ~ ~t-2u 3 2 ~(CH3)2 Diisopropyl lithium amide was prepared in the u5ual manner from diisopropylamine (0.18 ml, 1.24 mmol) and n-butyl-lithium (0.78 ml of a 1 6M solution in hexane, 1.24 mmol) in THF
(8 ml). A solution of l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (0.46 g, 1 mmol) in THF (8 ml) was added dropwise at -78C. After a 5 min stirring period~ethyl acetate (1 ml) was added in one portion and the mixture was stirred 3 h at -78C.
The mixture was acidified with cold hydrochloric acid (O.SN) to pH 6 and extracted with ethyl aCetate (2 X 20 ~1). The com.bined organic phases were dried and concentrated to give an oil (O. 5 g) which crystallized from pentane: 200 mg total, 40%; mp 122-4C;

ir V : 1750, 1710 cm ; lHmr (CDCl ) ~: 8-7.1 (15H, m, aromatics), max 3 4.83 (lH, d, J=2,Y.-4), 3.38 (lH, d, J=2, H=3), 1.80 (3H, s, CH3), 0.92 (9H, s, Bu and 0.3 ppm (6H, s, CH3).

E. ~ro~aration of trans-l-(t-Butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone SC~3 H ~ c~3 ~ 0~ ~
0~~-- ~ Si(CH3)2 S (CH3)2 t-Bu To a cooled (-78C) solution of diisopropylamine (0.34 ml, 2.4 mmol) in tetrahydrofuran (5 ml) was added dropwise, under N2, a =

,81~

solution oE 1.5 M n-BuLi (1.6 ml, 2.4 mmol). After stirring Cor 30 min, a solution of 1-(t-butyldimethylsilyi)-4-tritylthio-2-azeti-dinone (1.0 g, 2.18 mmol) in tetrahydrofuran (5 ml) was added dropwise and stirring was maintained for 30 min. Ethyl formate (0.8 ml, 9.9 mmol) was added and the cooled solution was stirred for 10 min. The reaction mixture was washed successively with cold lN hydrochloric acid (5 ml), lM sodium bicarbonate (6 ml), water (10 ml) and brine. The organic layer was dried (MgSO4), evaporated and crystalliæed from pentane to give 810 mg (76~) of formate as a white solid mp 132-3C; ir (CHC13) v : 1760, 1715 cm ; IHmr (CDCl3) ~: 9.0 (lH, d, J=1.25 Hz), 7.30 max (l;H, m), 4.7 (lH, d, J=1.5Hz) and 3.5 ppm (lH, ~, J=1.5 Hz).
NOTE: a) diisopropyl amine was distilled over CaH and stored on XOH
b) tetrahydrofuran was distilled over L.A.H. and stored on molecular sieves 3A
c) ethyl formate was stirred at room temperature wit~ K2CO3, then distilled over P2O5 d) n-BuLi was titrated with lN hycrochloric acid r. Pre~aration o~
l-(t-Butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinones. (4 isomers).

OH

Si/ Cl ~ N /tPu (~e)2 \(Me)2 n-Butyllithium (1.6M, 3.4 ml, 5.44 mmol) was added in 5 min to a solution of diisopropylamine (0.847 ml, 6.23 mmol) in THF (30 ml) maintained at -78C. After 0.5 h a solution of l-(t-butyldimethylsilyl)4-tritylthio-2-azetidinone (2.0 g, 4.4 mmol) in THF (20 ml) was added; after 15 min acetaldehyde (10 ml) was l~ti~

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 ~hases were washed with brine, dried and concentrated to leave an oil which was found to consist of a mixture of four isomers by tlc (labelled isomers A,~3,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 mother-liquors. The four pure compounds were obtained by preparative chro-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 T~F and the re~c~ion ~uenched after 1 min at -78C, the relative proportions of A,B,C, and 3 were:
12.9, 30.5, 38.2 and 18.4%. In ether, when the reaction was allowed to come to 20C in 2 h before quenching, the proportions were: 13.4, 24.6, 44, and 18%. When one molar equivalent of anhydrous maanesium bromide was added to the reaction mixture, the proportions changed to:
19.2, 19.7, 30.1 and 31%.
Isomer A: This isomer possesses a cis-stereochemistry at C3-C4. It is a racemic mixture composed of the (l'S, 3R, 4R) and the (l'R, 35, 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 Cl " C3 and C4. Com~ounds 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 Cl, and as "isomer C" for the inversion, at C3 mp 152-3C;
IHmr tCDC13) ~: 8.0-6.8 (15H, m, aromatics), 4.30 (lH, d, J=5.5, H-4), 3.78 (lH, m, H-l'), 3.10 (lH, dd, J=5.5, J=10, H-3), 1.22 (3H, d, J=6.5, CH3), 0.95 ~9H, s, Bu), 0.27 (6H, 2s, CH3). _n 1. calcd for:
C 30H37~O2Si: C 71.52, H 7.40, ~ 2.78, S 6.36~. found: C 71.28, H 7.41, N 2.48, S 6.19~.
-1~7 -~2~
- ~

Isomer B: This isomer posseses a trans-stereochemistry at C3-C4. It is a racemic mixture composed of the (l'R,35,4R) and the (1'5,3R,45) enantiomers. Compounds with the same configuration at Cl" C3 and C4 are referred to as "Isomer B"; ir (CHC13) V a : 1745 cm (C=O); mp 158-9C; lHmr (CDC13) ~: 7.60-7.10 (15H, m, aromatics), 4.02 (lH, d, J=0.8 H-4), 3.32 (lH, dd, J=3.0, J=0.8, H-3), 3.55-3.15 (lH, m, H-l'), 0.88 (12H, CH3, and t-Bu), 0.16 (6H, s, CH3);

Isomer C: This isomer possesses a trans-stereochemistry at C -C .

It is a racemate formed of the (l'S,35,4R) and the (l'R,3R,45) enantiomers. Compounds with the same configuration at Cl" C3 and C4 are referred to as "Isomer C". mp 134-6Ci IHmr (CDC13) ~: 7.60-7.10 (15H, m, aromatics), 4.32 (lH, d, J=1.8, H-4), 3.02 (lH, dd, J=2.7, J=1.8, H-3), 3.0-2.5 (lH, dq, J=2.7, J=6, H-l'), 1.02 (3H, d, J=6, CH3), 0.95 (9H, s, t-8u), 0.27 (6H, s, CH3); ir (CHC13) v : 1735 cm 1 (C=O).

Isomer D: This isomer possesses a cis-stereoc~emistry at C3-C4.
It is a racemate composed of the (l'R,3R,4R) and the (l'S,3S,4S) enantiomers. Compounds with the same configuration at Cl~, C3 and C4 are referred to as "Isomer D". mp 171-2C; Hmr (CDC13) : 7.80-6.90 (15H, m, aromatics), 4.70 (lH, d, J=4.5, H-4), 3.02 (lH, dd, J=4.5, J=0.;, H-3), 2.39 (lH, dq, J=0.5, J=6.i, H-l'), 1.0 (3H, c, J=6.5, CH3), 0.97 (9H, s, t-Bu), 0.32 (6H, s, CH3). Anal. calcd for C30H37NO2SSi: C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71-27, H 7.43, N 2.51, S 6.31~.

-/'f~
~ 1 ~_ 8~

OH

b) ~ SC~3 4 ~ ~ SC~3 ~Si~ ' ~Si/ u \Me2 \Me2 2 trans isomers A solution of trans 3-acetyl-1-(t-butyldimethyl-silyl)-4-tri_yl hio-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, 10 mmol) in ~HF (120 ml). The ice bath was removed anc the mixture was stirred at room temperature for 4 h. It was poured into ice-cold hydrochloric acid (lN, pH 6), stirred for 15 mir, and extracted with ether (3X). ~he co~bir.ed ether ext-ac~s -~e-e aried 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 119-121C; &4%.

c) ~ ~3 H, ~ SC~3 oL ~si (CH3)2 ~ S\i(C~3)2 t-3u Isomer 3 A suspension of cuprous iodide (4.78 g, 15 mmol) in e_her (50 ml) was cooled to 0C and treated under N2, wit;~ a 1.9 M
solution of methyl lithium (26 ml, 50 mmol). The brown solution was stirred at 0C for 10 min and then cooled 'o -oCC ar.c ~reazed droowise with the trans l-l(.-butyl dimethvlsilyl)-3-for~yl-4-t:itylthio-2-a-etidinone (2.43 g, 5.0 mmol) in a mixture of tetra-hydrofuran (10 ml)/ether (40 ml). Stirring was continued for 3 h.
The solution was warmed up to -40C and t~eated carefully with a lM

solution of ammonium chloride. The mixture was filtered over "CELITE"*
_~q _ *Trade Mark '~g~

`81~;~

and the organic phase was washed with a LM solution of ammonium chloride (3 x 5 ml) and then brine ana dried over sodiu~ sul~ate. ~lltration and evaporation gave alcohol, isomer B, which crystallized rom warm pentane to yield 1.6 g (65%), mp 160-1C; ir (CHC13) v : 1730 cm ;.
Hmr (CDC13) ~: 7.32 (15H, m),.4.05 (lH, s), 3.4 (lH, d, J=3HZ, 3.25-3.55 (lH, m), 1.6 (lH, s), 0.9 (12H, s) and 0.1 ppm (6H, s).
NOTE: a) tetrahydrofuran and ether were distilled over L.A.H.
b) methyl lithiu~ was titrated with lN hydrochloric acid c) copper (I) iodide was purified by continuous extraction with anhydrous tetrahydrofuran in a Soxhlet extractor for 18 h, then dried under vacuum in a dessicator (P205) for 18 h.

Q OH
d) ~ sc~3 CH ~ sc~3 O ~S i (~ ~ S i ~tBu ~tBu Methylmagnesium iodide (0.1 ml, 0.1 mmol) was added dropwise to a cooled (0C) and stirred solution of trans l-(t-butyl-dimethylsilyl)-3-formyl-4-tritylthio-2-a7etidinone (25 ms, 0.05 mmol) in THF (2 ml). The solution was stirred 1.5 h at 0C, ?oured onto an ammonium chloride solution, acidified with a hydrochloric acid solution (lN) and extracted with ether. Drying and concentration of the organic extracts left an oil consistins of starting material and a small amount of a mixture of the two trans title compouncs with isomer B ?redominating.

15~---,, U--~ti~

F. Pre~aration Of (l'S,35,4R and l'R,3R,4S) l-(t-~utyldimethylsilyl)-3-(1'-trimethyl-silyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (isomer C) OH 0Si--~3 ~ ~ sc~3 ~ ~si~ o ~s i~

A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldime-thylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in G~

~HF (6 ~1) ~as s~i-red at room temperature l~n~ 1 disa?~earance of .he starting material (15 min). Purification of the reaCtion mixture by column chromatography (silica gel, CH2C12) gave the desired compound as a white solid (128 mg, 74~) mp 144-46C. l~mr (C~C13) ~:
7.10-7.60 (15H, m, aromatics), 4.30 (lH, d, J=1.5, H-4), 2.25-2.89 (2H, m, H-3, H-l'), 0.82-1.07 (12H, m, t-Bu, H-2'), 0.2~ (6H, s, CH3), -0.10 (9H~ s, -O-Si(CH3)3i ir (CHC13) ~max 1736 cm (C=O) .

G. re~aration Of (l'S,3R,4R and l'R,35,4S) l'(t-8utyldimethylsilyl)-3-(1'-methoxymethoxv ether-l'-ethyl)-4-tritylthio-2-azetidinone (iso_e- A).

pCH OCH3 C~3 ~ (Me)2 Si(Me)2 ~ t-Bu t-Bu n-Butyllithium (ca 12.5 ml of 1.6M solution in hexane, 20 mmoli just enough to obtain a permanent pinX coloration) was added dropwise to a solution of (1'5,3R,4R and l'R,3S,4S) l-(t-3utyl-dimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer A) (10.1 g, 20 mmol) in T~F (100 ml) maintained at -78.
~l5l~
~ _ 1 12~

After a lS mi~ stirring period a solution of bromomet:~oxymethyl ether (2 ml, 24 mmol) in THF (30 ml) was added dropwise. ~e ~ixture w~s stirred 1 h at -78 and 2 h at room temperature and poured into an ammonium chloride solution (200 ml). Extraction with ethyl acetate (3 X 200 ml~, washing with ~rine, drying with sodium sulfate and concentration save the crude title compound which was purified by chromatography on silica gel eluting with increasing amounts of ether in benzene (10.4 g 95%). ~Hmr (C~C13) ~: 7.1-7.5 (lSH, m, aromatics), 4.47 (lH, d, H-4), 4.23 t2H, ~3q, J=7, 0-C'~2-0), 3.1-3.4 (2H, m, H-3 et H-l'), 3.23 (3H, s, O-CH3), 1.37 (3H, d, J=6.5, CH3), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH3).

'~. P-e~-a'ion Cf (1'5,35,4R and l'R,3R,45) 1-(t-~utyldimethylsilyl)-3-(1'-formyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer C) pH O,CHO
~3 ~ ~ c~3 ~ ~ S i;~ ~S i~

A solution or (1'5,35,4R and l'R,3R,45) l-('-butyldime~hyl-silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer c) (S0 mg, 0.1 mmol), p-bromobenzenesulfonylchloride (100 mg, 0.4 Dmol) and dimeL~ylam.nopyridine (24 mg, 0.2 mmol) in DMF (3 ml) was stirred at room temperature until disappearance of s'artins material (O.S h).

Then the reaction mixture was diluted with water and extractec. with ether. The organic extracts were washed with brine, d~iec. (M55O4) and evaporated. The title compound was ourified by column chromato-graphy. IHmr (CDC13) ~: 7.80 (lH, s, CHO), 7.20-7.6~ (lSH, m, aromati_s), 3.90-4.36 (lH, m, H-l'), 4.07 tlH, d, J=2, H-4), 3.22 (lH, broad s, H-3), 1.18 (3H, d, J=6.5, H-2'), 1.0 (~H, s, t-3u), 0.31 (6H, s, di-CH3).

_,, ~i81~

I Pre~aration of (l'R,3S,4R and l'S,3R,45) l'(t-ButyldimethylsilYl)-3-1'-acetoxy-l~-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OH OAc J ~ STr Ac O J"~ ~ Tr ~ ~ Si ~ Pyridine Si ~

A solution of (l'R,3S,4S and l'S 3R 45) l-(t-butyldi-methylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (13.8S 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%). IHmr (CDC13 ~:
7.64-7.03 (15H, m, H aromatic), 4.60 (lH, m, J=6, H-l'), 3.92 (lH, d, J=2, H-4), 3.S5 (lH, dd, J=2, J=F, H-3), 1.79 (3H, s, CH3CO), 0.98 (3H, d, J=6,CH3), 0.88 (9H, s, t-butyl), 0.12 (6H, s, CH3); ir (CHC13) Vm x 1775, 1740 cm (C=O) J. ?re~ara~ion of l-(t-ButyldimethylsilYl)-3-(1'-ParanitrObenzyldioxvca-hon~
ethyl)-4-tritylthio-2-azetidinone. (4 isomers) ~H OCO ?NB
C~3 ~ SC~3 O ~Si ~ ~ Si~ 2 \tBu \tBu "Isomer C" n-3utyllithium (8.8 ml of 1.6 M solution in hexane, 14 mmol; just enough to obtain a pe-manent pink coloration) ~as -l~3~
_ _ ~

added dropwise to a solution of "Isomer C" o~ l-(t-butyldime-thylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (6.55 g, 13 mmol) in THF (70 ml) maintained at -78C. After a 15 min stirring period a solution of paranitrobenzyl chloro-formate (3.2 g, 14.8 mmol) in THF (30 ml) was added dropwise.
~he ~xture was stirred 1 h at -78C and poured into an ammoniuttt 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 ~ure title compound was obtained by chromatography on silica gel (220 g) eluting with increasing ~-tmounts of ether in benzene. 93%,mp 118-9C (ether); IHmr (CDC13) ~: 8.3S-7 (19H, m, aromatics), 5.12 (2H, s, benzyl), 4.08 (lH, d, J=1.8, H-4), 4-3.5 (lH, d~, J=6.5, J=2, H-l'), 3.10 (lH, dd, J=2, J=1.8, H-3), 1.2 (3H, d, J=6.5, CH3), 1.0 (qH, s, Bu) and 0.30 ppm (6H, 2s, CH3); ir (CHC13) vm x 1745 cm (C=0); Anal. calcd for C38H42N2065iS: C 66.83, H 6.20, N 4.10, S 4.69; found: C 66.90, H 6.26, ~ 4.11, 5 4.59.

"Isomer B" The "Isomer B" of l-(t-butyldimet.;tylsilyl)-3-(1'-hydroxy-l'-ethyl(-4-tritylthio-2-azetidinone, treated as described above gave pure "Isomer B" of l-(t-butyldimethylsilyl)-3-(1'-para-nitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone as a foam, 95%. IHmr (CDC13) ~: 8.32-6.90 (lgH, m, aromatics), ~.1 (2H, s, benzyl), 4.65-4.20 (lH, m, H-l'), 3.97 (lH, d, J=1.5, H-4), 3.58 (lH, dd, J=1.5, J=5.8, H-3), 1.1 (3H, d, CH3), 0.7 (9H, s; Bu and 0.2 ppm (6H, s, CH3); ir (film) v : 1755, 1740 cm C=0.

"Isomer A" The "Isomer A" of l-(t-butyldimethylsilyl-3-(1'-hycroxy-l'-ethyl)-4-tritylthio-2-azetidinone, treated as described above gave pure "Isomer A" of l-(t-butyldimethvlsilyl-3-(1'-paranitro-benzyldioxycar~onyl-l'-ethyl)-4-tritylthio-2-azetidinone as an oil.
95% Hmr (CDC13) ~: 8.3-6.7 (19H,m, aromatics), 4.95 (2H, ~Bq, benzvl), - I S"~

~`B~3 4.53 (lH, p, J=7.5, J=7.5, H~ , 4.31 (lH, d, J=6, H-4), 3.32 (lH, dd, J=6, J=7.5, H-3), 1.44 (3H, d, J=6.5), 0.95 (9H, s, tBu) and 0.2 ppm (6H, 2s, CH3).

"Isomer D" Likewise "Isomer D" of l-(t-butyldimethylsilyl-3-(1'-nydroxy-l'-ethyl)-4-tritylthio-2-azetidinone, save pure "Isomer D"
of l-(t-butyldimethylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-tritylthio-2-azetidinone, g0~. IHmr (CDC13) ~: 8.3-6.7 (19H, m, aromatics), 5.20 (2H, ABq, benzyl), 4.72 (lH, d, J=5, H-4), 3.50 (lH, dq, J=6.5, J=0.5, H-l'), 2.85 (lH, dd, J=0.5, J=5, H-3), 1.03 (3H, d, J=6.5, CH3), 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH3);
mp 130-2C. Anal. calcd for C 66.83, H 6.20, N 4.10, S ~.70; ~ou..d:
C 66.56, H 6.28, N 3.96, S 4.89.

X. re~aration of (l'S,35,4R and l'R,3R,4S) l-(t-~utyldimethvlsilyl)-3-(1'-methane-sulfonyloxy-~-ethyl)-4-tritylthio-2-azetidinone (Isomer C) OH OMs C~3 ~ SC~3 S\i(CH3)2 ~t-3u A solution of ~ ,35,4R~anc l'R,3R,4S)-l-(t-butyldimethyl-silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (2.0 g, 4 mmol) in dichloromethane (80 ml) was treated at 5C, with methanesulfonyl chloride (0.99 g, 8.6 mmol) and triethylamine (0.87 g, 8.6 mmol). After stirring at that te~?erature for 1 h under N2, .he solution was washed with brine, dried (MgSO4) and eva?orated to dryness. After crystallization from ether-pet-ether, 1.9 g (81.93) of mesylate was obtained. mp 120-22C; Hmr (CDC13) ~: 7.13-7.61 - I 5~ -~2ti81~

(lSH, m, aromatics), 4.50 (lH, d, J=2, H-4), 3.62 (lH, dq, J=6.5, 2, H-l'), 2.96 (lH, 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-(CH3)2); ir v (CHC13): 1746 (C=O), 1343 and 1180 cm (SO2).

L . Pre~arat ion OI
(l'R,35,4R and l'S,3R,45) 1-(t-Butyldimethylsilyl)-3-(1'-methane-sulfonyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer 8) OH ~sO
SC~3 ~ SC~3 ~ S i+ S i ~

A solution of (l'R,35,4~ and l'S,3R,45) l-(t-butyldimethyl-silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) (5.03 g, 10 mmol), methanesulfonylchloride (2.52 g, 22.0 mmol) and triethylamine (2.23 g, 22.0 mmol) in CH2C12 (200 ml) was stir_ed at 5C for 1 h. Then the solution was washed with brine, dried (MgSO4) and evaporated to leave a residue which crystallized as a white solid when triturated in ether (5.40 g, 93~) mp 127-31C.
lHmr (CDC13) ~: 7.20-7.63 (15H, m, aromatics), 4.51 (lH, dq, J=5.0-6.2, H-l'), 4.10 (lH, d, J=2.0, H-4), 3.60 (lH, dd, J=5.0-2.0, H-3), 2.03 (3H, 5, -CH3), 1.01 (3H, d, J=6.2, H-2'), 0.90 (9H, s, t-Bu), 0.12 (6H, s, -CH3); ir (CHC13) Vmax: 1745 cm (C=O).

~ ~ 56 -12~i818~

M. Pre~aration of (1'5,3S,4R and l'R,3R,4S) 3~ p-~3romobenzenesulfonyloxy-1'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) OH 2~
SC~3 ~ SC~3 ~ , S i~

A solution of (1'5,35,4R and l'R,3R,4S) l-(t-butyldime~hyl-silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (2.5 g, 5 mmol) in dry THF (100 ml) was cooled to -78C and treated with 2.52M butyllithium/hexane (2.38 ml, 6 mmol). After 3-4 min p-bromobenzenesulfonylchloride (1.53 g, 6 mmol) dissolved in THF
was added dropwise. The solution was stirred at -78C for 3 h and then allowed to Come to room temperature. Then the solvent was evaporated and the desired product purified by column chromatography (silica gel, CH2C12) (3.36 g, 94.6~) mp 142-44C; IHmr (CDC13) 0:
7.68 (4H, s, benzenefulsonyl), 7.28-7.60 (15H, m, aromatics), 4.59 (lH, d, J=1.8, H-4), 3.68 (lH, dq, J=6.2, H-l'), 2.99 (lH, dd, J=1.8, 2.0, H-3), 1.18 (3H, d, J=6.2, H-2'), 1.08 (9H, s, t-~u), 0.40 and 0.38 (6H, 25, -CH3); ir (CHC13) Vmax: 1749 cm (C=O).

81~

N. ?re~aration of (1'5,3R,4R and l'R,35,4S) 3~ ethoxymethyl-1'-ethyl)-4-tritylthio-2-azetidinone (isomer A).

~3 ~ 5i~ 2 N ~H
t-3U

A cold (0C) H~PA-H2O (116 ml-13 ml) solution of Isomer A of l-(t-butyldimethylsilyl)-3-(1'-methoxymethyl-1'-ethyl)-4-tritylthio-2-azetidinone (11 g, 20 mmol) was treated with sodium azide (2.7 g, 42 mmol). The cold bath was removed and the mixture was stirred for 30 min. It was then poured into cold water (1.3 ~) and dried. The title compound recrystallized from ethyl acetate-hexanes (7.2 g, 83~) as a white solid mp 173-174C. IHmr (CDC13) ~: 7.10-7.
(15H, m, aromatics), 4.85 (2H, A}3a, J=7.4, O-CH2-O), 4.53 (lH, d, J=5.2, H-4), 4.42 (lH, s, N-H), 4.15 (lH, m, H-l'), 3.5 (lH, m, H-3), 3.47 (3H, s, O-CH ), l.S (3H, d, J=6, CH ). ir (~3r) V : 3400-3500 3 3 max (N-H) and 1760 cm (C=O).

0. ?~e~2ration Of (l'S,35,4R and l'R,3R,45) 3-(l'.~ethox~methyloxy-1'-ethvl)-4-tritvlthio-2-azetidinone (Isomer C) Tr J ~Si + ~ NH

A cold (dry ice-acetone bath) solution of (1'5,3S,4R
and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (5.03 g, 10 mmol) in THF (50 ml, distilled over LAH) was treated dropwise with a 1.6M solution of n-butyl _l S ~_ `` 1;~818~

lithium in hexane tl3.0 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 dro~wise. The mixture was stirred at -78C
for 30 min and for a 3 h period at 0C. It was poured in an ice cold ammonium chloride solution and extracted with ether. The ether extracts were combined, washed with water, dried (MgS04) and concentrated to give crude (l'S,3S,4R and l'R,3R,45) 1-(t-butyldimethylsilyl)-3-(1'-methoxy-methyloxy-l'-ethyl)-4-tritylthio-2-azetidinone t5.83 g, 100%) which was deprotected as described below:
A cold (ice bath) solution of the above derivative (5.83 g, 10 mmol) in HMPA-H20 (90 ml-10 ml) was treated with sodium azide (1.365 g, 21 mmol). The cooling bath was removed and the mixture was stirred at room temperature for a 2 h period. It was ~hen poured slowly into ice cold water (900 ml) and stirred for 30 min. The precipi-tate was collected by filtration and redissolved in methylene chloride.
The solution was washed with water and brine and dried (MgS04) to give the title compound (3.0 g, 69.3%), mp 172-2.5 (ethyl acetate-h.exane); ir (CHC13) v : 340CI (N-H) and 1760 cm (C=O) IHmr (CDC13) ~: 7.67-7.12 (lSH, m, H aromatics), 4.63 (2H, center of .~Bq, J=6, 0-CH2-0), 4.49 (lH, s, N-H), 4.40 (lH, d, J=3, H-4~, 4.25-3.80 (lH, m, H-1'), 3.35-3.15 and 3.26 (4H, s + m, CH3 and H-3) and 1.30 ppm (3H, d, J=6, CH3) .l~q lXti81~
, -P. Pre~aration of (l'R,3S,4R and l'S,3R,4S) 3~ Formyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OSO ~Br OCHO
C~~ SC~3 ~ ~Si/~ ~ H

A solution of (1'5,3S,4R and l'R,3R,4S) 3-(1'-p-oromo-benzenesulfonyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) in DMF (3 ml) was heated at ;0C for 48 h and then at 100C for 4 h. The reaction mixture was then diluted with H2O and extracted with ether. The ethereal extracts were washed with brine, dried (MgSO4) and evaporated. The title compound was obtained as white crystals after purification by column chro-matography (silica gel, 5~ CH3CN-CH2C12) (2 mg, 4.8~) mp 131-32C
IHmr (C3C13) ~: 8.07 (lH, s, CHO), 7.24-7.56 (lSH, m, aromatics), 5.23 (lH, dq, J=6.4, 7, H-l'), 4.38 (lH, dm J=2.4, H-4), 4.25 (lH, s, NH), 3.20 (lH, dd, J=7, 2.4, H-3), 1.43 (3H, d, J=6.4, H-2'); ir (CHCl ) v : 3400 (NH), 1765 (C=O), 1725 c~ (C=O).
3 max Q. Pre~aration of azetidinone (isomer B) OAc OAc J ~ STr J' ~ STr HMPT O NH
tBDMS
Pure derivative ~l'R,35,4R and l'S,3R,4S) l-(t-butyl-dimethylsilyl)-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).

/ C~O~

~ i8~

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 tlc) 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 CH2C12, washed with water ttwice) and brine and dried over MgSO4. Solvent evaporation left a foam which crystallized out from ether-petroleum ether (4.90 g, 96.5~, mp 143-44.5C).

ir (CH2C12)V : 3395 (N-H), 1772, 1738 cm (C=O). lHmr (CDC13) : 7.9-6.8 (lSH, m, H aromatic), 5.12 (lH, center of dq, J=6.5, 7.5, H-l'), 4.33 (lH, d, J=2.8, H-4), 4.20 (lH, bs, N-H), 3.17 (lH, ddd, J3-1' 7 5~ J3_4=2.8, J3_NH=l, H-3), 2.1 (3H, s, CH3CO), 1.35 (3H, d, J-6.5, CH3).

R. re~ara'ion of 3-(l'-Hydroxy-l'-ethyl)-4-tritylthio-2-a7etidinone. Mixture of four isomers) OH OAc ~3 ~A ~ ~ py ~

i-Cl ~ c~3 D~ -N(Et)3 ~ si~

A solution of lithium diisopropyl amidel(0.74 mmol) was prepared at -78C in dry tetrahydrofuran (5 ml) from diisopropyl amine (0.103 ml, 0.74 mmol) and 3uLi (0.29 ml of a 2.52 L~ in hexane).
After 30 min at -78C, a solution of the (R and S) 1-t_imethylsilyl-4-tritylthio-2-azetidinone (0.292 g, 6.99 mmol) in dry tet~ahydrofurane (2 ml) was added dropwise. After 5 min, excess of f_eshly distilled acetaldehyde (0.2 ml) was added all at once. After 20 min at -78C, tlc indicated complete disappearance of starting materials and the reaction -/6l ~2~

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 NH4Cl, brine and drying on anhydrous magnesium sulfate gave, after evaporation of the solvent, a yellow oil. Filtration of this oil on silica gel (10 g, elution C6H6:EtOAc, 6:4) gave a mixture of alcohols(0.215 g, ,30%~. This mixture (IHmr) cannot be separated either by hplc or by tlc.
a: Acetylation Acetylation of an aliquot of the mixture (0.06; 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~i b) 17.4 c) 30.1%i d) 17.9%. Compound a) was identical to the isomer B by di-ect comparison (hplc).4 b~ t tvldimetyl 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 dimethvlformamide (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%i d = 4.6%
(the identity of each one has not been established)4 NOTE:
IButyl lithium and lithium hexamethyl disilazane were inef~ective 20rder of increasing ?olarity 3Acetylation of the product derived from l-t-butyldimethylsilyl-4-tritylthio-2-azetidinone gave the following ratio:
d = 29.5%; c = 24.1~; b = 33 ~; a = 12.6~
4Reaction of a mixture of alcohols derived from (2 and S) l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone gave tie .ollowing proportions: a = 5.2i; b = 41.3~; c = 48~; d = 4.6 -l6 ;L-~ lX~i81~

S. Pre~aration of (l'R,35,4R and l'S,3R,4S) 3~ 3enzoxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer 8) MsO OCO~
SC~3 O N ~ H N ~ H

A solution of (l'S,3S,4~ and l'R,3R,45) 3-(1'-methanesulfo-nyloxy-l ' -ethyl)-4-tritylthio-2-azetidinone (Isomer C) (035 mg, 2 mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H2O-DMF (10 ml) was heated at 90C for 7.5 h. Then the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated.
The residue, purified by column chromatography (silica gel, ;% CH3 CN-CH2C12) gave the title compound as a white solid (108 mg, 23.2%) mp 158C~ IHmr (CDC13) ~: 7.03-8.25 (20H, m, aromatics), 5.32 (lH, dq, J=6.1, 9, H-l'), 4.40 (lH, d, J=2.5, H-4), 4.30 (lH, s, N-H), 3.40 (lH, dd, J=9, 2.5, H-3), 1.50 (3H, d, J=6.1, H-2');ir (CHC13) V : 3400 (N-H), 1765 tC-O), 1715 cm (C=O).
max T . ?re~ara~ ion of 3-(1'-Paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (4 isomers).

OCO P~8 ~3 Si H
\tBu "Isomer C"

a) A solution of "Isomer C" of l-(t-butyldimethyl-silyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-t-ityl-thio-2-azetidinone (~.3 g) in a mixture of TFA (5 ml), water ~/~ 3`

(5 ml), dichloromethane (20 ml) and methanol (30 ml) was stirred for 2 days at room temperature. The solution was diluted witn water and Ihe aqueous ?hase extracted with dichloro~.ethar.e. The combined organic phases -~ere washed -~ith ~odiu.~ bicarbonate ~nd water, dried and concentrated to leave an oil. Crystallization from ether gave the pure title compound (902 mg), mp 78-80C;
'~mr (CDC13) : 8.25-6.75 (19H, m, aromatics), 5.21 (2H, s, benzyl), 5.05 (lH, m, H-l'), 4.40 (lH, s, N-H), 4.27 (lH, d, J=2.8, H-4~, 3.37 (lH, dd, J=5.3, 2.8, H-3) and 1.37 ppm (3H, d, J=6.5, CH3);
ir (CHC13) ~ a : 3390 (N-H), 1765 and 1745 tshoulder) (C=O, and 1525 cm (NO2).

b) A cold (0C) HMPT-H2O (90 ml - 19 ml) solution of "Isomer C" of l-(t-butyldimethylsilyl)- -(l'-pàranitrobenzyldioxy-carboxyl-l'-ethyl)-4-tritylthio-2-azetidinone (9.11 g, 13.3 mmol) was treated with sodium azide (1.82 g, 27.9 mmol). The cold bath was removed and the mixture was stirred for 30 min. It was then poured into water (1 ~) and extracted with ether (5 x 200 ml).
The ether fractions were combined and washed with water (5 x 200 ml), brine and dried over MgSO4. Alternatively since the title comDound precipitated out on water dilution, it w2S filtered of r and recrystallized from ether; 7.22 g, 89~, mp 78-80C.

"Isomer 8"
"Isomer B" of 3-(1'-Daranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the "Isomer C"; 92%; mp 155.5-6C (ether); IHmr (CDC13) ~: 8.25-6.80 (19H, m, aromatics), 5.20 (2H, s, benzvl), 4.95 (lH, m, H-l'), 4.35 (lH, d, J=2.9, H-4), 4.17 (lH, s, N-H), 3.20 (lH, dd, J=10.8, J=2.9, H-3) and 1.40 ppm (3H, d, J=7.5, CH3);

ir (CHCl ) v : 3480, 3390 (N-H), 1772, 1750 (C=O), and 1525 cm 3 max (NO2). Anal. calcd for C32H28N2O6S: C 67.59, H 4.96, N 4.93, S 5.64; found: C 67.48, H 4.98, N 4.92, S 5.67.

81~5 "Isomer A"
"Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the "Isomer C"; mp 205-6C. IHmr (CDC13) ô: 8.2-6.7 (19H, m, aromatics), 5.22 (2H, ABq, benzyl), 5.57-4.85 (lH, m, H-l'), 4.65 (lH, N-H), 4.50 (lH, d, J=6.5, H-4), 3.65 (lH, dd, J=6.5, 12, JN H=l~ H-3) and 1.52 ppm (3H, d, J=7.5).
"Isomer D"
"Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for "Isomer C"; lHmr (CDC13) ~: 8.15-6.70 (19H, m, aromatics), 5.23 (2H, ~c, benzyl), 5.20 (lH, m, H-l'?, 4.75 (lH, NH), 4.52 (lH, d, J=5.5, H-4), 3.42 (lH, J=5.5, 3, H-3 and 1.5 ppm (3H, d, J=6.5, CH3). (J value for H-3 taken after D2O- exchange).
U. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(1'-methanesulfonyloxy-1l-ethyl)-4-tritylthio-2-azetidinone (isomer B) MsO MsO
3 _ ~ ~ C~3 ~Si ~ ~ N ~
\

A solution of (l'R,35,4R and l'S,3R,.S) l-(t-butyldimethyl-silyl)-3-(1'-methanesulfonyloxy-1'-ethyl)-4-trithylthio- -azetidinone.
(Isomer 3) (4.95 g, 8.5 mmol) and sodium azide (i.ll g, 17.0 mmol) in 10~ H20-HMPA (50 ml) was stirred at room temperat~re for 30 min.
Then the solution was diluted with water (250 ml) and extracted with ether. The organic extracts were washed with brine, dried (MgSO4) and evaporated. Crystallization of the residue (ether-?et-ether) gave the title compound (3.33 g, 83.8~). mo 130-31C. lHmr (CDC13) ~: 7.20-7.62 (15H, m, aromatics), 4.9, (lR, c~, J=6.4, 6.1, H-l'), 4.56 (lH, d, J=2.8, H-4), 4.22 (lH, m, N-H), 3.27 (lH, dd, J=6.1, 2.8, H-3), 3~0 (3H, s, -CH3), 1.63 (3H, d, J=6.4, H-2');

r (nujol) V : 3195 (n-H), 1768 cm (C=O).
max ~ 6 ~-_ ~ .

~Z~8183 V. Pre~aration of (l'a,3S,4R and l'R,3R,4S)3-tl'-~ethanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone. (Is mer C) SC~3 ~ ~ C~3 ~i(CH3)2 N ~ H
t-Bu A solution of (l'S,3S,4R and l'R,3R,45)1-~t-butyldimethy!-silyl)-3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer C) (2.85 g; 4.9 mmol) in 10~ aqueous HMæA (25 ml) was treated with sodium azide (0.65 g, 10 mmol) and stirred at 25C for 0.5 h. By diluting the solution with water (250 ml), the reaction product was forced to cr~stallize out. The crude mesylate was redissolved in dichloromethane, washed with brine, dried (MgSO4) and evaporated.
Trituration in ether gave the title compound as white crystals mp 155-60C;
1.80 g; 78.6%; lHmr (CDC13) ~: 7.43 (15H, m, aromatic), 5.02 (lH, dq, J=6.9, 4.9, H-l'), 4.55 (lH, s, N-H), 4.95 (lH, d, J=3, H-4), 3.33 (lH, dd, J=4.9, 3, H-3), 1.51 (3H, d, J=6.9, H-2'); ir V : 3395 (N-H), 1768 cm (C=O);
max Anal. calcd for C2~H25NO4S. C 64.22, H 5.39, N 3.00; found: C 63.93, H 5-39 N 3.24~.

W. ?re~aration Of (l'S,3S,4R and l'R,3R,4S) 3-(1'-p-~romobenzenesulfonvloxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) 2~ 2-SC~3 ~ c~3 \ 0 N ~

A solution of tl'S,3S,4R and l'R,3R,4S) 3-(1'-p-bromoben-zenesulfoxyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) (1.42 g, 2 mmol) and sodium benzoate (0.865 g, ~2~i~3183 6 mmol) in 10~ H20-HM~A t40 ml) was stirred at room temperature for 1 h. Then the solution was diluted With H2O (100 ml) and extracted with ether. The ether extracts were washed with brine, dried (MgSO4) and evaporated. The crude crystalline title compound was triturated in a small volume of ether and collected by filtration (0.92 g, 77%) mp 125-26C. IHmr (C~C13) ~: 7.80 (4H, s, benzenesul-onyl), 7.30-7.6~ (lSH, m, aromatics), 5.13 (1~, dq, J=6.5, 4.0, H-l'), 4.50 (lH, d, J=2.9, H-4), 4.40 (lH, s, N-H), 3.40 (lH, dd, J=4.0, 2.9, H-3), 1.50 (3H, d, J=6.5, H-2');ir (CHC13) V : 3400 cm (N-H), 1770 cm (C=O) .

:~. Pre~aration Of (l'R,35,4R and 1'5,3R,45) 3-(1'-aydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer 3) OSO ~Br OH
~3 ~ c~3 O ~ S i~

To a warm solution of (1'5,35,4R and l'R,3R,45) 3-(1'-p-bromobenzenesulfonyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-trityl-thio-2-azetidinone (Isomer C) in HMPA (S ml) was added dropwise 1_ml of H2O. The reaction mixture was ~ept at 90C ~or 20 h, then diluted with ether and washed 4 times with brine. The or5anic solution was dr ed (M5SO4), evaporated and the crude title compound purified by column chromato5raphy (silica gel, 15% CH3CN-CH2C12).

A white solid was obtained (122 m5~ 44.5~) mp la7-189C wnic:~ was found to be identical to a sa~le o~ the ~itl- co~ound ?reparod by another method.

12~ 3 Y. Pre~aration o~
3~ Ydroxv-l'-ethvl~-4-tritvlthio-2-azetidinone pH OIH
SC~3 ~ SC~3 o ~ N ~5 ~ N ~

Both isomers, (l'S,3S,4R and l'R,3R,45) 3-(1'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) and (l'R,3S,4R and l'S,3R,45) 3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) were prepared by the same method. For exa~le, a solution of (1'5,3S,4R and l'R,3R,4S) l-(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% H2O - DMF (40 ml) was stirred at room temperature for 18 h. Then the reaction mixture was diluted with H2O and extracted with e2her. The organic extracts were washed with brine, dried (MgSO4) and evaporated. ~he crude title compound was crystallized from cold ether (0.47 g, 61%) mp 134-35C. IHmr (CDC13) ~: 7.12-7.56 (15H, m, aromatics), 4.48 (lH, s, N-H), 4.28 (lH, d, J=2.8, H-4), 2.94 (lH, dq, J=6.5, 6.2, H-l'), 3.06 (lH, dd, J=6.2, 2.8, H-3), 2.18 (lH~ s, -OH), 1.30 (3H, d, J=6.5, H-2');ir (CHC13) v : 3400 (n-H), 1760 c~ (C=O).

Similarly (l'R,3S,4R and 1'5,3R,45) 1-(t-butyldimet~ylsilyl)-3-(l'-nydroxy-l'-etnyl)-4-tritylthio-2-azetidinone (Isomer B) mp 190-92C. IHmr (CDC13) ~: 7.10-7.55 (lSH, m, aromatics), 4.45 (lH, d, J=2.5, H-4), 4.28 (lH, s, NH), 4.10 (lH, dq, J=6.4, 5.3, H-l'), 3.08 (lH, dd, J=5.3, 2.5, H-3), 1.50 (lH, s, -OH), 1.30 (3H, d, J=6.4, H-2');ir (CHC13) ~ : 3400 (N-H), 1760 cm (C=O ) 18~

Z. Pre~aration Of (l'S,3R,4R and l'R,35,45)_3~ ethoxymethyl-1'-ethyl)-1-(~aranitro-benzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones (Isomer A) OCH2OC~3 OCH2OCH3 5C~3 ~ ~ OH

A mixture of Isomer A of 3-(1'-methoxymethyl-1'-ethyl)-4-tritylthio-2-azetidinone (7.5 g, 17.3 mmol), paranitrobenzyl glyoxylate hydrate (4.7 g, 20.8 mmol) and toluene (300 ml) was heated under re_lux for 1 h in a Dean and Stark apparatus filled with 3A molecular sieves.
The solution was cooled in ice and triethylamine (0.24 ml, 1.7 mmol) was added dropwise. The mixture was stirred for 1 h, washed with diluted hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound as a foam (10.5 g, 94%). lHmr (CDC13) ~: 8.25-6.84 (19H, m, aromatics), 5.24 (2H, s, benzyls), 4.67-4.83 (3H, m, O-CH2 and H-4), 4.34-4.55 (lH, m, H-Z"), 4.02 (lH, m, H-l'), 3.54 (lH, m, H-3), 3.40 (3H, s, O-CH3), 1.38 (3H, d. J=6.5, CH3); ir (~Br) v : 3360 (OH), 1770 (C=O of 3-lactam), 1735 (C=O of ester) and 1605 cm max (aromatics).

.~A. ?re~a-ation of (l'S,3S,4R and l'R,3R,4S) 3-(1'~ etho.~vmethoxv.l'-ethyl)-1-(pa~ar.i~ro-benzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) O ~ ~ ~ OH
O PNB
A solution of hydrated ~aranitrobenzyl slyoxylate (1 73 g, 7.11 mmol) was refluxed in toluene (90 ml) using a Dean Sta-~ condenser filled with 3A molecular sieves for a 2 h period. To the boiling solution was added (1'5.35,4R and l'R,3R,45) 3-(1'-~ethoxvmet~yloxv-1'--l6~-_ C ,' ~ 12~8183 ethyl)-4-tritylthio-2-azetidinone (3.0 g, 6.93 mmol) and the mixture was refluxed for 2 h more. The mixture was cooled to room temperature, triethyl amine (70 mg, 97 ~l, 0.69 mmol) was added and it was stirred for 2 h. The reaction mixture was diluted with ether, washed with 1% aqueous HC1, water,1% aqueous NaHC03 water and brine, driea (MgSo4 and concentrated to give the title compound (4.60 g, 100%); ir (CHC13) vmax: 3530-3100 (0-H), 1765, 1750 (C=0) and 1525 cm 1 (N02); 1Hmr (CDC13) ~: 8.22, 8.18 (2H, 2d, J=8, Hm aromatics), 7.67-7.0 (17H, m, H-aromatics), 5.3 (2H, bs, CH2-PNB), 5.30-5.02 (m, H-2~), 4.89-4.52 (m, H-l~ and 0-H), 4.63, 4.59 (lH, 2d, J=2, H-4), 4.33, 4.30 (2H, 2 center of 2 ABq, J=7, J=7, 0-CH2-0), 4.1-3.67 (lH, m, H-l'), 3.2 (lH, H-3), 3.1, 3.6 (3H, 2s, CH3-0), ar.d 1.15 ppm (3H, d, J=6.5, CH3).

B~. Pre~ara~ion of l1'R,3S.4R a~d lS.3R.4S) 3-(l'Acetoxy-1'-ethyl)-1--2"-hyd~gxy - ~ acetate) 4 - tritylthio-2-azetidi~gne pAc J",~STr ~HO J ,~STr _Isomer ~"
A 601ution of hydrated p-nitrobenzlyl glyoxylate (triturated with ether) (1.82 (g, 30 mol) wa6 refluxed in benzene o through a Dean Stark condenser filled with 3A molecular sieves for 2 h . To that was added azetidinone (1'R,3S,4R and 1'S,3R,4S) 3-(l'-acetoxy-1'-4-tritylthio- 2-azetidinone (10-88 g, 25.2 mmol) and the mixture was refluxed for 1 h more. The solution was cooled at room temperature and triethyl amine (0.35 ml, 2.5 mmol was added. It was then stirred for 2 h; the reaction progression being followed by tlc. *Solvent evaporation afforded a white , . .

12681~3~

fo2m in quantitative yield (l00~., mixture of epimers) ~l.ernatively the soluti^n can be acid and base ~:zshed. ir (CH3Cl2) v a : 3520 (OH), 1775, 1795 cm (C=O); l~r (C~Cl3) ~: 8.2, P.18 (2H, 2d, J=~, ~o aromatic), 7.8C-6.0 (l~H, m, "-a.omatic), 5.28, 5.17 (2H, 24, CH2-PNB, 4.89 (0.67~, d, J=7.2, CHO), ,.80 ~center OI m, H-l'), 4 3~ (0 33 1~, 2d, J=8.8, CH~), 4.22 (D.3311, d, J4 3=2.5, H-~j, 4.09 (0.671~, d, J4 3=
2 l ~1-4) 3.65 (D.67H, dd, J3-l' 5-8~ 3_4 dd, J3 l~=5 5 J3 4=2.5, H-3), 3.33 (0.33H, d, J=8.8, OH), 3.23 (0.67H, d, J=7.5, OH), 1.38, l.86 (3H, 2s, CH3CD), l.l0, 1.06 (3H, 2d, J=5.8, 6.3, C1~3) CC. Pre~aration of 3~ aranitrobenzyldioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate)4-tritylthio-2-azetidinone (4 isomers).

~3 ~ SC~3 H ~

"Isomer C"
A mixture of "Isomer C" or 3-(l'-paranit-obenzyl-dioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (l.70 g, 0.3 mmol), paranitrobenzyl glyoxylate hydrate (815 mg, 3.6 mmol) and toluene (50 ml) was heated under reflux 7 days in a Dean and Stark apparatus filled with 3~ molecular sieves. The cooled solution was washed with dilute hvdrochloric acid, sodium bicar-bonate and brine, dried and concentrated to give the title compound (2.l g) as an epimeric mixture at carbon-2". Purirication was effected by chromatography over silica gel. Alternatively the title compound could be prepared by using a catalytic amount of triethyl _/q ~ _ ~2~81~33 amine. Less polar epimer at 2": lHmr (CDC13) ~: 8.25-6.80 (23H, m, aron,atics), S.30 and 3.12 (4H, 2s, benzyls), 4.65 (lH, d, J=9, H-2"), 4.45 (lH, d, J=2.5, H-4), 4.45-4.10 (lH, m, H-l'), 3.50 (lH, d, J=9, 2"-OH), 3.28 (lH, dd, J=2.5, J=2.5, H-3) and 1.23 ppm (3H, d, J=6.5, CH3); ir (CHC13) Vmax: 3530 to 3200 (D-H), 1765, 1750 (C=O) and 1525 cm (N02). More polar isomer at C-2": Hmr (CDC13) ~: 8.25-6.85 (23H, m, aromatics), 5.25 and 5.08 (4H, 2s, benzyls), 5.05 (lH, d, J=7, H-2"), 4.35 (lH, d, J=2.5, H-4), 4.40-4.05 (lH, m, H-l'), 3.42 (lH, J=7, 2"-OH), 3.33 (lH, dd, J=2.5, 2.5, H-3), 1.23 (3H, d, J=6.5, CH3); ir (CHC13) V : 3520 to 3200 (O-H), 1755 (C=O) and 1525 cm (NO ).
max 2 "Isomer B"
A mixture of hydrated paranitrobenzylglyoxylate (1.74 g, 7.66 mmol) and (1'~,3S,4R and 1'5,3R,45) 3-(1'-paranit_obenzyldioxy-carbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (3.63 g, 6.38 mmol) was refluxed in toluene (70 ml) on a Dean Stark conaenser filled with 3A molecular sieves for 3h. The solution was cooled down to room temperature and triethyl amine (64.5 mg, 89 ml, 0.639 mmol) was added. It was then stirred for 4 h, diluted with ether and washed with 2~ aqueous HCl, water, 2~ aqueous NaHCO3, water and brine. It was dried and concentrated to give oure title compound (5.02 g, 100%).
Separation of the 2 epimers was effected on preparative silica gel plate. Less oolar e?imer at 2": ir (CHC13) V : 3500 (O-H), 1772, 1750 (C=O) 1525 cm (N02); IHmr (CDC13) ~:8.30-8.0 and 7.65-6.80, (23H, m, aromatics), 5.27 and 5.13 (4H, 2s, benzyls), 4.71 (lH, m, J=6.5, 6.5, H-l'), 4.28 (lH, d, J=2.2, H-4), 4.23 (lH, d, J=8.7, H-2"), 3.50 (lH, dd, J=2.2, 6.5, H-3), 3.28 (lH, d, J=8.7, O-H) and 1.18 opm (3H, d, J=6.;, CH3). More ?olar epimer: ir (CHC13) ~ 3480 (O-H) 1772, 1750 (C=O) and 1525 cm (NO2); Hmr (C~C13) ~: 8.35-6.90 (23H, m, aromatics), 5.15 (4H, benzyls), 4.72 (lH, d, J=7.5, H-2"0),4.90-12~i~318~

4.50 (lH, m, ~=6.5, 6.5, H-l'), 4.10 (lH, d, J=2, H-4), 3.68 (lH, dd, J=2, 6.5, H-3), 3.28 ~lH, d, J=6.5, O-H) and 1.15 ppm (3H, d, J=6.5, "Isomer A"
The "Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of "$somer A" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones.
lHmr (CDC13) ~: 8.3-6.7 (23H, m, aromatics), 5.17 (2H, benzyls), 5.0 (lH, m, H-l'), 4.9 and 4.8 (lH, 2d, J=6, H-4, two epimers), 4.32 and 3.96 (lH, 2s, H-2", two epimers), 3.68 (lH, dd, J=6, 6, H-3( and 1.47 ppm (3H, 2d, J=6.5, CH3, two epimers).

"Isomer D"
The "Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone likewise save a mixture of "Isomer D" or 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones.
lHmr (CDC13) ~: 8.30-6.60 (23H, m, aromatics), ;.20 (4H, m, benzyls), 4.83 (1~, 2d, J=5, H=4), 5.50-4.30 (2H, m, H-l' and H-2"), 3.48 (lH, m, H-3), 3.15 (lH, m, O-H), 1.37 and 1.30 ppm (3H, 2d, CH3).

~D. ?re~arat-on of (1'5,35,4R and l'R,3R,45)3-(1'-~1ethanesulfonylox~i-1'-ethvl~-1-(parani-t_obenzyl 2"-hydroxy-2"-acetatel~-tritylthio-2-azetidinor.e (isome- C) (eDimers at C2"l.

-OMs OMs SC~3 ~ ~C?3 C ~ ~ ~ ~ N ~ OH

A solution of paranitrobenzylglyoxylate hvdrate (3.~2 g;42.~ mmol) in benzene (350 ml) was refluxed ror 2 h, removing he water azeotropically in a Dean-Stark trap. To that solution was adàed the - / ~3-~ 12~i8~3 (1'S,3S,4R and l~R,3R,4S)3- (l~-methanesulfonyloxy-l~-ethyl) -4-tritylthio-2-azetidinone (16.62 g, 35.5 mmol) and the reflux maintained for an additional 0.5 h. Then the reaction mixture was cooled to room temperature, treated with triethylamine (0.5 ml;
3.5 mmol) and stirred for 3 h in order to complete the reaction.
Evaporation of the solvent left a white foam which was used as such in the next step. 1Hmr (CDC13) ~: 8.12 (2H, d, J=9, Hm aromatic), 7.28 (17H, part of d,Ho aromatic, trityl), 5.28 (2H, s, -CH2-PNB), 4.88 (O.S H, 6, H-l"), 4.62 (1.5H, m, H-2" and H-4), 4.00 (2H, m, H-l', -OH), 3.15 (lH, m, H-3), 2.73 (3H, s, mesylate and 1.30 ppm (3H, d, J=6 Hz, H-2');ir max:3520 (O-H), 1775 (C=O) and 1765 cm~1 (C=O).

EE. Pre~aration of (1'S.3R.4~ and l'R.3S.4S) 3-rl-Methoxymethvl-l'-ethyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (Isomer A) OC~120C~3 OCH20CH3 20 ~ SC~3 ~_~SC~3 J--I OH "L~ ~Cl 2 ~B C02~NB

Pyridine (1.1 ml, 14.2 mmol) was added dropwise to a solution of Isomer A of 3-(1'-methoxymethyl-1'-ethyl) -l-(paranitrobenzyl-2"-hydroxy-2"-acetate) -4-tritylthio-2-azetidinone (7 g, 10.9 mmol) in THF (350 ml) cooled to -15C. Immediately after thionyl chloride (1.0 ml, 14.0 mmol) was added dropwise and the mixture was stirred at -150 for 0.5 h. The precipitate was removed by filtration and washed with benzene. The combined filtrates were concentrated , the residue dissolved in fresh benzene and the solution treated with activated charcoal, filtered and concentrated to leave to title compound as an oil (6.5 g, 90%), 1 Hmr (CDC13) ~: 6.65-8.35 (19H, m, aromatics), 5.24 (2H, c, benzyl), 3.43 (3H, s, OCH3) and 1.42 ppm (3H, d, J=6, CH3).

i2~`8~&~
, .~

FF. Pre~aration of (l'S,3S,4R and l'R,3R,4S) 3-(1'- ethoxymethyloxY-l'-ethyl)-1-(paranltro-benzyl 2"-chloro-2'`-acetate)-4-tritylthio-2-azetidinone (Isomer C) J STr 2 ~ ~ STr ~ ~ ~ OH ~ ~ Cl A cold (ice-MeOH bath) THF (60 ml, distilled over L~H) solution of (1'5,3S,4R and l'R,3R,4S) 3-(1'-methox~methyloxy-1'-ethyl)-l-paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (4.25 g, 6.62 mmol) was treated dropwise with ovridine (0.696 ml, 8.61 mmol) and thionyl chloride (0.;30 ml, 8.61 mmol). The mixture was stirred for 30 min at -15C. The precipitate was collected by fil-tration 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 Ce~ite pad and subsequent benzene evaporation afrorded the title com~ound (4.86 g, 100~); ir (CHC13) Vmax: 1770 (C=O) and 1525 cm (NO2); Hmr (CDC13) ~: 8.15, 8.12 (2H, 2d, H-aromatics), 7.70-7.00 (17H, m, H-aromatics), 5.62, 5.02 (lH, 2s, H-2"), 5.27 (2H, s, CH2-PN~), 4.7 (lH, d, H-4), 4.7-3.7 (m, O-CH2-O, H-l'), 3.s-2.a (m, H-3), 3.12, 3.08 (3H, 2s, O-CH3), and 1.30-0.96 ppm (3H, m, CH3).

-t ~1 '5 --" lZ681~;~

GG. Pre~aration of (l'R, 3S,4R and 1'5.3R,4S) 3-(1'-Acetoxy-l'-ethvl)-l-(paranitrobenz~l 2"-chloro-2"acetate)-4-tritylthio-2-azetidinone Ac pAc O ~ SOCl o ~N

"Isomer B"
A THF (distilled over LAH) solution of (l'R,35,4R and l'â, 3R,4S) 3-(1'-acetoxy-1'-ethyl)-1-(paranitrobenzyl-2"-hvdroxy-2"-acetate)-4-tritylthio-2-azetidinone (from 10.88 9 of N-H) was treated at -15C
(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). '"he 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. ~he suspension was filtered through a celite pad and solvent evaporation left a foam; ir (CH2C12) Vmax: 1780, 1740 cm 1 (C=O) I'~mr (CDC13 o:
8.17, 8.21 (2H, 2d, J=8, Ho aromatic) 7.76-6.88 (17H, m, H-~romatic), 5.31, 5~16, 5.12, 4.73 (3H, 4s, CH2-PNB, CHCl), 5.12-4.S5 tlH, m, H-l'), 4.35-4.25 (lH, m, H-4), 3.80-3.45 (lH, m, H-3) 1.90 (3H, s, CH3CO), 1.12 1.07 (3H, J=6.5, CH3).

-l7~ -~H. 3~ Paranitrobenzyldioxycarbonyl-l'-ethyl)-l-(paranitroben2yl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinones (mixture of e~imers at C2").

OCO PNB OCO PNB
SC~3 ~ ~ sc~3 o~ N~ c 1 CO 2PN~3 o 2~'NB

"Iso_er C"
Pyridine (58 mg, 0.73 mmol) was added dropwise to a solution of "Isomer C" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate)-3-tritylthio-2-azetidinones (470 mg, 0.6 ~mol; mixture o~ epimers at C-2") in THF (15 ml) cooled to -15"C. Immediately after thionyl chloride (86.5 mg, 0.73 mmol) was added dropwise and the mixture was stirred at -15C for 0.5 h.
The precipitate was removed by 'iltration and washed with benzene.
The combined filt_ates were concentrated, the residue dissolved in fresh benzene and the solution treated ~it-a acti~ated cha-cGal, ~i:te-ed and concentrated to leave the title compound as an oil. 530 mg; 100~.
IHmr (CDC13) ~: 8.7-6.8 (23H, m, aromatic), 5.53 (lH, s, H-2"), 5.30 and 5.17 (4H, 2s, benzyls), 4.52 (lH, d, J=2, H-4), 4.20-3.70 (lH, m, H-1'), 3.31 (lH, dd, H-3), 1.27 and 1.21 ppm (3H, 2d, J=6.5); ir (CHC13) : 1780, 1750 ~C=O) and 1525 cm tNO ).
max 2 "Isomer B"
"Isomer B" of 3-(1-paranitrobenzyldioxycarbonyl-1'-ethyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate)-~ritylthio-2-azetidinones (mixture of C-2" epimers) was prepared as described abo~e or ~he "Isomer C" in quantitative yield. IHmr (CDC13) ~: 8.25-6.90 (23H, m, aromatics), 5.40-5.0 (4H, m, benzyls), 5.40-4.45 (lH, m, H-1'), 4.82 and 4.57 (lH, 2s, H-2"), 4.36 and 4.31 (lH, 2d, J=2.5, H-4), 3.63 ~lH, m, J=2.5, J=6.5, H-3), 1.25 and 1.18 ?pm (3H, 2d, J=6.5, CH3)i ir (CHC13) : 1?80, 1750 (C=O), and 1525 cm (~2)' ~ ., "Isomer A"
"Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-l'-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinones (~mixture of C-2" epimers). IHmr (CDC13) ~: 8.30-6.80 (23H, m, aromatics), 5.45-4.80 (lH, m, H-l'), 5.18 and 5.21 (4H, 2s, benzyls), 4.87 (lH, 2d, H-4), 4.22 and 3.87 (lH, 2s, H-2"), 4.05-3.40 (lH, m, H-3), 1.57 and 1.50 ppm (3H, 2d, CH3).

"Isomer D"
"Isomer D" of 3-(1"-paranitrobenzyldioxycarbonyl-1'-ethyl-l'-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinones (mixture of C-2" epimers). IHmr (CDC13) ~: 8.30-6.70 (23H, m, aromatics), 5.32-5.10 (4H, m, benzyls), 5.48 and 5.30 (lH, 2s, H-2"), 4.~2 (lH, d, J=5, H-4), 5.30-5.20 (lH, m, H-l'), 3.15 (lH, m, H-3), 1.40 and 1.30 ppm (3H, 2d, J=6.5, CH3); ir CHC13) ~ : 1780, 1750 (C=O) and 152S cm (N02) II. -e~aration Of (1'5,35,4R and l'R,3R,45)3-(1'-~ethanesulfonyloxy-1'-ethyl~-1-(t~aranitro-benzyl 2"-chloro-2"-acetate(-4-tritylthio-2-azetidinone (isomer C) (epimers at C2").

OMs OMs SC~3 ~ SC~3 NOH ~ N ~ 1 C02PN8 ~02PN8 To a cold solution (5C) of (l'S,3S,4R and l'R,3R,7S)3-(l'-methar~sulfonyloxy-l'-ethyl)-l-(paranitroben7yl 2"-hydroxy-2'`-acetate~-4-tritylthio-2-azetidinone (24.0 g, 35.; mmol) in dry tetrahydrofuran (350 ml) was added pyridine (3.65 g, 46.2 mmol) and thionyl chloride (5.5 g, ~6.2 mmol) dropwise. After stirring for 45 min, ether (100 ml) was added to precipi~ate the hydrochloride salt which was filte_ed of~.

~ -O

12~

The filtrate was evaporated and the residue redissolved in ben2ene (200 ml) and treated with charcoal. Evaporation of the solvent left a nearly whlte foam which was used as such in the next step. IHmr (CDC13) ~:
8.18 (2H, d, J=9, Hm aromatiC), 7.72 (17H, m, part of d.Ho aromatic, trityl), 5.57 and 5.12 (lH, s, H-2"), 5.28 (2~, s, -CH2PNB), 4.73 (lH, 2d, H-4), 3.21 (lH, 2dq, H-3), 2.78 (3H, 2s, mesylate and 1.21 ppm (3H, 2d, H-6H2; H-2'); ir Vmax 1779 cm (C=O) aJ. ~re~aration Of (1'5,3R,4R and l'R,3S,4S) 3-(ll-~ethoxv~ethox~ ethyl)-l ~
benzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritvlthio-2-azetidinone (Isomer ~) OCH20cH3 OCH20CH3 SC~3 ~ C~

O ~ ~ Cl N ~ ~

A miXture of Isomer A of 3-(1'-methoxyme~hoxv-1'-ethyl)-1-(paranitrobenzyl-2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (6.6 g, 10 mmol), triphenylphosphine (3.3 g, 12.; mmol), 2,6-luti-dine (1.3 ml, 11 mmol) and dioxane (140 ml) was heated under reflux for 2 days. The solution was diluted with ether, washed wi'h dilute acid (5~ HCl), water, dilute sodium bicarbonate solution and brine, dried and concentrated. The residue was purified bv chromatography on silica gel eluting with 10~ ether in benzene. Concent~ation of the pertinent fractions left the title compound as a foam (1.4 9, 13.73) ir (K3r) V : 1750 (C=O) and 1660-1650 cm (C=C, aromatics).

-.3~
-/1q-12~

K~. ?re~aration of (1'5,35,4R and l'R,3R,4S) 3-(1'-Methoxymethyloxy-1'-ethyl)-1-(paranitro-benzyl 2"-triphenylphosDhoranylidene-2"-acetate)-4-tritvlthio-2-azetidinone (Isomer C).

OCH2OCH3 J STr J~ ~ P ~

O PNB
~O22NB 2 A dioxane (100 ml, distilled over LAH) solution of (l'S, 3S,4R and l'R,3R,4S) 3-(1'-meLhoxymethyloxy-1'-et}lyl)-1-(paranitrobenzyl-2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (4.86 g, 6.62 mmol), triphenylphosphine (2.60 g, 9.93 mmol) and 2,6-lutidine (770 mg, 0.837 ml, 7.20 mmol) was heated under reflux for 4 h and kept in a hot bath (100C) for 16 h. The mixture was diluted with ether, washed with 1~ aqueous HCl, water, 10~ aqueous NaHCO3, water and brine and dried (MgSO4). The solution was concentrated and the residue filtered throush a silica gel (65 g) column (5%, 10~ and 20~ ether-benzene) to give the title compound (2.8 g, 48%). ir (CHC13) vmax: 1795 (C=O), 1620 and 1605 (?hos?horane) and 1515 cm (NO2).

LL. (l'R,3S,4R and 1'5,3R,4S) 3-(l~-Acetoxy-ll-ethyl)-l-(paranit-oben 2"-triphenylphosphoranylidene-2"-acetate)-4-tritvlthio-2-azeditinone (Isomer B) OAc OAc J ~ STr ~3P J ~ STr O ~ 2,6-lutidine ~ N~69~3 CO2~NB CO,?~8 A cioxane ~100 ml, freshly distilled over L~Y.) solution of crude (l'R,35,4R and 1'5,3R,45) 3-(1'-acetoxy-1'-ethyl)-1-(?aranitro-~ / ~0 -12~

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 18 h. The solvent was evaporated and the residue was redissolved in methylene chloride. The resulting solution was successively washed with diluted HCl, H20, diluted aqueous NaHC03,H20 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 tCH2C12) v : 1750 (C=O) and 1620, 1610 cm (phosphorane).

~M. 3-(1'-Para-itrobenzvldioxvcarbonyl-1'-ethyl)-1-(~aranitrobenzyl-2"-triphenylphosphoranvlidene-2'`-acetate)-4-tritvlthio-2-azetidinone.

SC~3 N ~ Cl ~
02P~3 C02~Na ISOMER B
A mixture of (l'R,35,4R and l`S,3R,4S) 3-(1'-paranit-o-benzyl-dioxycarbonyl-l'-ethyl)-l-(paranit-obenzyl-2"-chloro-2"-acetate) -4-tritylthioazetidinone (isomer B) (4.96 g, 6.22 mmol, mix;ure of epimers at C-2"), triphenyl phosphine (2.47 g, 9.42 mmol) and 2,6-lutidine (740 mg, 0.80 ml, 6.91 mmol) was refluxed in dioxane ('reshly distilled over LAH) for 30 h. The solution was dilut-d with ethe_ and ethyl acetate, washed wi~h 5~ acueous HCl, wate-, 10~ a~ueous NaHCO3, water and brine and dried (MgSO4). Solvent evaporation afCorded a 12~i8~

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 la9-190 (ether);
ir (CHC13) v : 1750 (C=O), 1620, 1605 (phosphorane) and 1522 cm ( 2) ISOMER C
Isomer C of 3~ paranitrobenzyldioxycarbonyl-1'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone was prepared as described above ~or isomer 3. ir (CHC13) v : 1750 (C=0), 1610, 1620 (phos~horane) and 1520 cm (NO ); lHmr max ~ 2 (CDC13) ô: 8.6=6.7 (H, aromatics), 5.22 and 4.95 (benzyls), 4.70 (~.-4), 2.6 (H-3), 1.19 and 1.07 ppm (C~3).

ISOMER D

A mixture of Isomer D of 3-(1'-p-nitrobenzyldioxycarbonyl-l'-ethyl)-l-(p-nitrobenzyl 2"-cnhloro-2"-acetate)-4-tritylthio-2-azet -dinone (4.598 g, 4.45 mmol; purity 77~, mixture o_ epime-s at C-2"), t-iphenylphosphine (1.425 g, 5.44 mmol; ~ldrich) anc 2,6-lutidine (0.63 ml, 580 mg, 5.40 mmol; ~nachemia) in dioxane (65 ml; cistille~
from L~H) was heated at gentle reflux under N2 for 41 h, ~onitorins the reaction by tlc (benzene:e~her=3~ he da-`~ reac~`cn ~ -e was cooled, diluted with ~-t5Ac and washed successively witi 0.1 ~HCl, water, 2~ NaHC03 and then brine. Drying (Na25O~) and evaooration of tne solvents gave 4.18 g of a dark coloured oil which was ?uri ied by column chromatography (SiO2, 88 g; eluent 13-25% a~e~ i~
yielding 1.108 g (1.08 mmole, yield 24.3~) or the title com?ound as a yellowish foam: IHmr (CDC13) ~: 1.08 (d, J=6Hz, l'-CH3): ir (neat) v : 1745 cm 1 (s, C=O).
max -~0 12681~3 . ~

NN. P-e~aration o.
(1'5,3S,4R and llR~3R~4s)3~ Methanesulfonvloxv-ll-ethyl)~ ananitr benzyl 2"-triphenylphosphor2nylidene-2"-acetate)-4-t-itylthio-2-azetidi-none (isomer C) OMs - OMs SC~3 ~ sc~3 A solution of (l'S,35,4R and l'R,3R,45)3-(1'-methanesul-~onyloxy-l'-ethyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (24.7 g, 35.5 mmol), triphenylphosphine (11.2 g, 42.7 mmol) and 2.6-lutidine (4.2 9, 39.1 mmol) in dry dioxane (350 ml) was re l~lxe~
under nitrogen for 19 h. The solvent was evaporated 2nd the cruce ?rscucz redissolved in ethyl acetate and washed successively with dilute :~Cl, NaHCO3 and brine. Purification was completed bv chromatography on a silica gel column (8.S x 12 cm). Elution with 10~ ethe~-dichlorometna-.e (1.5 ~ and then ether (1.5 Q) gave the purified phosphorane; 12.36 g (40~).
Hmr (CDC13) O: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir v : 1/49 and 1620 cm 1 (C=O) 00. ?re~P-~tior. o~
(l'R,3S,4R and l'S,3R,4S) 3-(1'-HvdroxY-l'-ethvl)-l-(Darani~robenzvl-2"-triDhenvlDhosDhoranYlidene-2"-acetate) 4-tritvlth o-2-azetidinone (Isomer B).

OAc OH
1 ~ ~ STr NaOH ~ J ~T-O ~ 3 O ~ 3 C02PNB C02PNt3 A solution of phosphorane (l'R,35,4.~ and l'S,3R,45) 3-(l'-acetoxy-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranyl-idene-2"-acetate)-4-tritylth`o-2-azetidinone (4.43 9, 5.00 mmol) ~2~i8~8;~

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 tlc*. The mixture was diluted with ether-ethyl acetate and washed with HCl, H2O, aqueous NaHCO3, H20 and brine. Solvent evaporation arforded a residue which was crystallized fro~ benzene-ether (3.7 g, 87.7%) mp 169.5-170.5~C.
ir (CH2C12) vmax: 1745 (C=O) and 1620 cm 1 (phosphorane ~Heating the mixture increased the reaction rate.

?7. Pre~aration o~
(1'5,3R,4R and l'R,3S,4S) Silver 3-(1'-methoxymethyl-1'-ethyl)-1-(?ara-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (Isomer A) OCH20C~i3 OCH20CH3 ~ ~3 ~N ~ p~

2P~B
Silver 3-(l'-methoxymethyl-l'-ethvl)-1-(Dar2nit-obenzyl -2"-t~iphenylphosphoranylidene-2"-acetate)-3-tritylthio-2-azetidinone (isomer A), was prepared as described elsewhere for ~he isomer C of the paranitrobenzyldioxy carbonyl derivative. Yield 50~. ir (neat : 1745 cm 1 (C=O).
max 12~

aQ. Pre~aration of 1'5,3S,4R and l'R,3R,45) Silver 2-(1'-methoxymethyloxv-1'-ethyl)-1-(paranitrobenzyl 2"-tri?henyl?hosphoranyliden~-2"-acetate)-2-azetidinone-4-thiolate (Isomer C).

J ~ STr AgN0 J"' Ag 0 ~ ~ P~3 ~o ~ N ~ P~3 2 C02PN~

(l'S,35,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-ethyl)-1-(para-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (887 mg, 1.0 mmol) was 'irst dissolved in hot ( 10C) methanol (30 ml), treated with pyridine (103 mg, 0 105 ml, 1.3 mmol) and, after coo'_nb, ~as ~roated ~i'h 5 0 15 ~! ~e~h~nol solution of silver nitrate (8.7 ml, 1.3 mmol). The mixture was stirred for 1 h at 23C, cooled (ice bath) and stirred for 20 min. The sait was filtered and washed successively with cold methanol and ether (3 times, 671 mg, 87%). ir (CHC13) vmax: 1745 (C=0), 1605 (phos?horane) and 1520 cm (N02).

~P~. ?re?æ~ation of Silver 3-(1'-oarani~robenzvldioxYcarbonYl-l'-ethYl)-l-(oararit-obenzyl 2"-trishenylohosphoranylidene-2"-~cetate)-2-azetid none-4-thiolate.

SC~3 ~ S~s o ~ ~3 0 ~ ~3 "Isomer 3"
(l'R,3S,4R and l'S,3R,4S) 3-(1'-?aranitrobenzylcarbonvl-dioxy-l'-ethyl)-l-(paranit~obenzvl-2"-triphenylphos?ho-anvlidene-2"-acetate)-4-trithio-2-azetidinone (1.02 g, 1 mmol)-~as f~~s~ dissol-;ed n ~ ~ _ _ J ~

~2~81~3 CH2C12 (3 ml) and diluted with hot ~55C) MeOH (20 ml). The hot ~olution was treated fir6t with pyridine (120 ml, 117 mg, 1.48 mmol) and a hot (55C) 0.15M methanolic ~olution of silver nitrate (8 ml, 1.2 mmol). The mixture was stirred at room temperature for 15 min, then at 0C 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 (-15C) methanol and three times with ether. (917 mg, 100%), ir ("NUJOL MULL")* vmax: 1745 (C=O), 1600 (phosphorane) and 1517 cm 1 (N02).
"Isomer C"

Silver 3-(l'-Paranitrobenzyldioxycarbonyl-l'-ethyl) -1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-triphenylphosphora-nylidene-2"-acetate)-2-azetidinone-4-thiolate, "Isomer C", was prepared as described above for the "Isomer s"; ir("NUJO~")* vmax:
1745 (C=O) and 1600 cm 1 (phosphorane).

"Isomer D"

A solution of I60mer D of 3-(l'-p-nitrobenzylcarbonyl-dioxy-l'-ethyl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (145 mg, 0.142 mmol) was prepared by first dissolving it in CH2Cl2 t5 ml), removing the CH2Cl2 at 55- 60 and adding hot MeOH (4 ml). To the above solution was added a hot solution of AgN03 in MeOH (0.15 M, 1.14 ml, 0.17 mmol, 1.2 eq), followed by pyridine (14 ~l, 0.17 mmol, 1.2 eg). The 6ilver mercaptide started to precipitate immediately.
The mixture was stirred 2 h at room temperature and 1 h at 0. The mercantide was collected by filtration and waæhed with ice-cold MeOH and ether, yielding 99 mg (O. 11 mmol, 78%) of the title compound as a brownish solid: ir ("NUJOL") Vmax: 175~ cm 1 (s, c =o ) -*Trade Mark ~2~

SS. Pre~ara'ion of (l'R,3S,4R and l'S,3R,4S) Silver 3~ hydrcxy-1'-ethvi)-1-)?aranitro-benzyl-2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate_(Isomer B) OH OH
J ~ STr AsNO3 ~ ~ SAg N ~ P~3 C5H5N ~ P~3 A solution* of (l'R,3S,4R and l'S,3R,45) 3-(1'-hydroxy-l'-ethyl)-l-(paranitropenzyl-2"-triphenylphos?horanylidene-2"-acetate)-4-t_itylthio-2-azetidinone (lg, 1.19 mmol) in MeOH (10 ml), was treated with pyridine (124 yl, 121.3 mg, 1.53 mmol) and at 10C
with a 0.lSM solution of silver nitrate in MeOH (lS ml, 2.25 mmol -or until no more precipitation of the silver mercaptide occ~rred). The mixture was stirred ror 1 h and concentrated on the _otary eva?orator (no bath) to a??roximatively 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 ("NWJOL MULL")*

v : 3500-3400 (O-H), 1752 (C=O) 1595 (phos?horane) and 1525 c~ (NO2) max *The cr~stalline material was i-st dissolved in CH2C12.

TT. Pre~arzticn o~
(l'R,3R,4R and l'S,3S,4S) 4-Acetylthio-3-(1'-o-nitro~enzvldioxvcar_cr.yl-l'-ethyl)~ p-nitrobenzyl 2"-t_i~henvl?hos?horanvlidene-2"-acetate)-2-azetidinone (Isomer D) 2 OC02~N3 CH2C12~ ~ ~ 3 CO P~

To a stirred solution o' silver 3-(1'-~arani__ohenz--l 2"-tri?henyl?hosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate --I ~7-~--*Trade Mark ,r~ .

~2~

(isomer D) (85 m~, 0.095 mmol) in CH2C12 (S ml) containing pyridine (30 ~1,~ 0.37 mmol; Fisher) was added at 0-5C CH3COCl (20 ~1, 0.28 mmol) and the mixture was stirred at 0-5C for 30 min. The precipitate ~r.ic:~
formed was filtered and washed with CH2C12. The filtrate and washinss were combinea, washed successively with brine, diluted HCl, saturated NaHCO3 and then brine, dried (Na2SO4) and evaporated yielding 75 mg (0.091 mmol, crude yield 95%) of the title compound as a syrup: IHmr (CDC13) ~: 2.33 (s, -S0COCH3); ir (neat) vmax: 1750 (~-lactam, ester), 1695 (thioester), 1520 and 1350 cm (-NO2).

u~. Pre~ar~tion o~
(l'R,SR,6R and l'S,55,6S) cis D-Nitrobenzvl 2-methyl-6-(ll-o-nit-oben dioxycarbonylmethyl-penem-3-carboxylate (Isomer D) 2 ~ 2 SAc toluene CO PNB

A solution of the above acetylthioazetidinone (74 mg, 0.09 mmol) in toluene (30 ml) was heated at re lux under N2 atmos?here for 7 h. After evaporation of the solvent, the residue was purified by hplc (sio2i eluent, benzene:etne~=3~ v`e:G-n~ 2~ ~ (o.G'~Il ~.o , yield 49%) of the penem ester as a syrup. (Note: this oil could be crystallized from THF-et;~er o- CH2C'2-?~he : .~~ (C~r~3) ~ 'o (3H, d, J=6.5 Hz, l'-CH3), 2.38 (3H, s, 2-CH3), 4.07 (lH, dd, J5 6=4Hz, J6 1=9Hz, 6-H), 5.05-5.30-5.34-S.S9 (2H, AB type, 3-CO2CH2-Ar), 5.30 (2H, s, 1'-OCO2-C~2-Ar), 5.1-5.6 (lH, m, l'-H), 5.68 (lH, d, J- 6= .Hz, S-H), 7.49-7.64-8.18-8.33 (4H, A2'B2', l'-aromatic Hs), 7.53-7.68-3.'3-8.83 (4H, A2'B2', 3-aromatic Hs)i ir (neat) Vmax: 1780 (2-lactam)~
1750 (-OCO2-), 1710 (ester), 1520 and 1350 cm (-NO2).

_~

~2~i81~

W . P,e~aration of (l'R,5R,6R and 1'5,55,65) Potassium and sodium 6~ hydroxyethyl)-2-~ethylpenem-3-carboxvlate (isomer D).
OH
OC02PN~
SH /Pd-~"~F~ITE"* ~ ~ H3 o ~ THF_ethar_X20 o ~ 0 ~ ~a~

A solution of the above penem ester (24 mg, 0.044 mmol) in TY~ (5 ml) was ~ixed with elhe~(l0 ml), H2O (5 ml?, ?hos?hate bur-er (1.00 ml, 0.05 molar pH 7.00: Fisher) and 30% Pd-"OELIT~(50 mg, Enaelhard).
This mixture was hydrogenated at 35 psi for 21.5 h at room temDe-at~re.

After removal of the catalyst ~over"cELITE") the aaueous layer w~s se?arated, washed -~ith etner and lyophilized yielding 12 m6 of the title mixture o~ sodium and potPssium sal s as a white powder: lHmr (D2O) o: 1.23 ~3H, d, J=6Hz, l'-C~3), 2.27 (3~., s, 2-CH3), 3.85 (lH, dd, J5 6=4HZ~ J6 1=9Hz, 6-H), 4.3 ~lH, m, '-H) and 5.65 ppm (lH, d, J5 6=4Hz, 5-H); ir("NUJOL") vmax: 1755 ( -lactam) and 1570 cm (-CO2~ ; uv (H20)~ : 297 (E 2300, calcd as K-salt), 258 (E 1900, calcd as K-salt). This ~aterial was identical to a samole of title compound orepared bv an aldol concensation of acetal-dehyde with the dianion of 2-methvlpenem-3-carboxylic acid.( Hmr, ir,~

*Trade Mbrk / n 12~i81~

Exam~le ~g~
(l'S,5R,6S and l'R~5S~6R) 6-1;-H~oroxy-l'-eth~l)-2-methyl~ene~-3-c~rboxylic Ac-d (isomer C) OH

~H3 Method A:

OCO 2PNB 2 f 2 OH
SAc ~ ~5 ~ ~ ~ S

o~ P~3 d~--N ~P~3 O~ I ~:H3~?

Method 3:

OCO PNB OCO ~PNB 2 2 3 ~+ J~5~+ J;~ A~

SAc ~r~5Ac _ J qo -l~ti~

~ETHOD A

1) (l'S,35,4R and l'R,3R,45) 4-Acetylthio-3-(ll-oaranitrobenzyldioxv-carbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-tri?henylphosphoranvlidene-2"-acetate)-2-azetidinone (isomer C).

J '" CH3COCl J -f Ac (~ P O

A cold (ice-MeOH bath) solution of 1' â, 3S,4R and l'R,3R,4S) silver 3-(1'-paranitrobenzyl-dioxycarbonyl-1'-ethyl)-1-(paranitro~enzyl 2"-triphenylphcsphoranylidene-2"-acetate)-2-azetidinone-4-thiolate ~isomer C) (1.14 g, 1.30 mmol) in CH2C12 (60 ml) was treated with pyridine (0.6 ml, 0.74 mmol) and dropwise with acetyl chloride (236 ms, 0.213 ml, 3.00 mmol). The reaction mixture was stirred for 1 h at -15C. The precipitate was filtered and washed with ether. The f ltrate was washed with 2% aqueous HCl, water, 2% aqueous NaHC03, water and brine and dried (MgSO4). The _esidue upon solvent evaporation was triturated in ether (895 mg, 83.7~, m? 184-5C dec); ir (CHC13) v : 1755, 1695 (C=O), 1620 and 1605 cm 1 (?hos~horane). ~nal. calc max for C42H36N3OllSSi: C 61.38, H 4.42, N 5.11, S 3.90; found: C 61.25, H 4.49, N 4.a8, S 4.26.

_l 9l--8;~

2) (1'5,5~,6S and l'R,55,6~) ?aranitrobenzvl 2-methvl-6-(1'-3aranitro-benzyldioxycarbonyl-l'-ethyl)-?enem-3-carboxylate (isomer C) ~3 ~ ~ CH3 A solution of (l'S,35,4R and l'R,3R,4S) 4-acetylthio-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone (isomer C) (855 mg, 1.04 mmol) in toluene (60 m}) was heated unde~ reflux for 4.5 h. The residue upon concentration of the solution was passed through a silica gel (10 g) column (1% ether in benzene) to give the pure title compound (393 mg, 69.6~), mp 157-158C (CHC13-ether);
ir (CHC13) V : 1785, 1745, 1710 (C=O) and 1525 cm (NO2); IHmr (CDC13) ~: 8.30-7.2 (8H, m, H-aromatics) 5.46 (lH, d, J=1.8, H-S), 5.40-;.0 (SH, m, Z CH2-PNB and H-l'), 3.95 (lH, dd, J=1.8, J=5.4, H-6), 2.35 (3H, s, CH3) and 1.43 ppm (3H, d, J=5.4, CH3); Anal. calcd for C24H21N3OloS: C 53.04, H 3.89, N 7.73; ~ound C 52.76, H 3.86, N 7.69.

3) (l'S,5R,6S and l'R,55,6~) 6-(1'-'iydroxy-1'-ethyl)-2-methvl ?enem-3-carboxvlic acid (isomer C) 2 qH
CH 2 ~ ~ ~ CH

A mixture made of (l'S,5R,6S and l'R,55,6R) parani-trobenzyl 2-methyl-6-(1'-paranitrobenzyldioxvcarbonyl-1'-ethyl)-penem-3-carboxylate (206 m5, 0.379 m~ol), T~-ether-H20 (30 ml, 40 ~1, 20 ml), a O.OS M pH 7 ~uffer solution (7.64 ml, 0.382 mmol) and 30~
Pd on"CELITE"(500 mg) was hydrogenated at 42 psi H2 on a Parr shaker _,q ~-.-~
*qrade Mark -`` lZ~81~33 for 16 h. The catalyst was filtered and washed with water. The aqueous phase was washed with ether (3 times), acidified Dortionwise with cold 1~ aqueous ~Cl 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). EvaDoration of the solvent and trituration of the residue with ether gave the title compound (57 mg, 65.6%), ir (K3r) v : 3580-3300 (O-H), 1755 and 1660 cm (C=O); uv (EtOH) ~ 311 (~ 6538), 262 (c 3672); IHmr (DMSO-d6) ~: ;.57 (lH, d, J=1.7, H-5), 4.02 tlH, m, H-1'), 3.75 (lH, dd, J=1.7, J=3.5, H-6), 2.23 (3H, s, CH3) and 1.23 ~Dm (3H, d, CH3) ~ETHOD B

1) Silver (l'S,3S,4R and l'R,3R,45) 1-(t-~utvldimethylsilyl)-3-(1'-oara-nitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone-4-thiolate (isomer C) C2 B ~ 2 ~tBu ~t~u Isomer C of l'-(t-bu.vldimethylsil~,~')-3-(1'-Daranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-~ze-tidinone (1 g, 143 mmol) was dissolved by stirring in hot ~40C) methanol (12 ml). ~ solution of silver nit~ate (0.59 g) in methanol (12 ml) was added followed by Dyridine (0.13 ml). The mixture was stirred vigorously 1 h at room temDerature and 2 n at 0. The solid silver mercaDtide was collected py ilt_aticr.
and washed with ether, 352 mg (46~). ir v : 1/35 cm (C=O).

-l13~
--~

~2ti~

2) (l'S,3S,4~ and l'R,3R,45) 4-Acetylthio-l-(t-butvldimethylsilvl-3-(l'-oaranitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone (isomer C) OC02PNB OC02P~B
SAg ~ S~c 0~ ~S i . ~S i t3u ~ tBu To a solution of isomer C of silver l-(t-butyldi-methylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-2-azeti-dinone-4-thiolate (880 ms) in dichloromethane t40 ml) stirred at 0C was added pvridine (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 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). IHmr (CDC13) ~: 8.2 and 7.48 (4H, 2d, aromatics), 5.40 (lH, d, J=2.2, H-4), 5.2 (2H, s, benzyl), 5.3-4.9 (lH, m, H-l'), 3.42 (lH, dd, J=2, H-3), 2.32 (3H, s, CH3), 1.40 (3H, d, J=6.5, CH3), 0.95 (9H, s, t-Bu) and 0.2 ~m (6H, CH3).

3) (1'5,3S,4R and l'R,3R,45) 4-.'.cetylthio-3-(1'-~a_anitrobenzyldioxY-carbonyl-1'-e hyl)-2-azetidinone. (isomer C) C02 1OC02~'NB
SAc ~ S~c N ~ ~ 2 tBu Tsomer C -' the above S-acetyl N-t-~utyl-met.~yl-silyl-~zetidincne derivative (1.4 g) was dissolved in a mixture of ~A (0.5 ml), water (0.5 ml), methanol (3 ml) and dichloromethane (2 ml) and stirred at room tem~erature for 48 h.
~he solution was diluted ~i~h water (100 ml) and extracted witn dichloromethane (4 x 20 ml). ~he combined organic ext~ac~s were /qy `818:~

washed with sodium bicarbonate (2~) and brine, dried and concen-trated 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. IHmr (CDC13) ~: 8.15 and 7.45 (4H, 2d, aromatics), 6.18 (lH, N-H), 5.19 (2H, s, benzyl), 5.05 (2H, m, H-4 and H-l'), 3.35 (lH, dd, J=2.5, 4.5, H-3), 2.34 (3H, s, CH3) and 1.42 ?pm (3H, d~ J=6-5~ CH3); ir Vmax 1780~ 1750~ 1695 cm (C=0).

4) (l'S,35,4R and l'R,3~,4S~ 4-Acetylthio-3-(1'-paranitrobenzyldioxycar-bonyl-l'-ethyl)-l-(paranitrobenzyl 2"-hydroxv-2"-acetate)-2-azetidinones (e~imers at C-2"). (isomer C) SAc y SAc O ~ ~ H N ~ H
O2~B
A mixture of isomer C of 4-acetylthio-3-(1'-?aranitro-benzyldioxycarbonyl-l'-ethyl)-2-azetidinone (750 mg), paranitrobenzyl-glyoxylate hydrate (525 mg) and benzene (50 ml) was heated under reflux for 3 days over a Dean and Star~ apparatus filled with 3~
molecular sieves. A second portion of glyoxylate (52 mc) was added and refl~x was continued for 2 more days. The mixtu_e was diluted with ether, washed with hydrochloric acid (2~), water, sodium bicarbonate (2~) and water, d_ied and concentrated to leave an oily residue (975 mc). Chromatography on silica gel, eluting with benzene-ether (85=15) gave the ?ure title com?ouncs. ~Hmr (CDC13) ~: 8.25-o.75 (8H, m, aromatics), 5.30 and 5.12 (4H, 2s, benzyls), 5.05-4.70 (lH, H-2"), 4.45-4.35 (lH, 7d, .-.-4), 4.50-4.10 (lH, m, H-l'), 3.30 (lH, m, H-2 and 1.25 ppm (3H, 2d, CH3).

5) (1' S.3S.4R and l'_R.~R.4S) 4-acetylthio-3-(1' -paranit~obenzyldioxv-carbonyl-l' -ethvl)-l-tParanitrobenzvl 2"-tri~henylphosphoranYlidene-2"-acetate)2-azQtidinone tisomer C) OCO~PNB 2 j)co2PNa ~ SOC12 ~ 3 ~ ~ S~c 10c~L N CH ~ N ~Cl ~N ~, i) ~2PNB , ~:02PN~3 C02PNB

Isomer C of 4-acetylthio-3-(1' -paranitrobenzyl-dioxycarbonyl-l' -ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate) -2-azetidinone (577 mg, 1 mmol) was dissolved in anhydrous THF
(10 ml) and Pyridine (95 mg, 1. 2 mmol) was added to the solution.
20 The solution was cooled to 0 and thionyl chloride (143 mg, 1. 2 mmol) was added slowly. ~he 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 25 chloro compound. It was dissolved in THF (20 ml), triphenylphosphine (314 mg, 1. 2 mmol) and 2, 6-lutidine (129 mg, 1. 2 mmol) were added and the solution was stirred at 45C for 4 days. The solids were removed by filtration, washed with benzene and the combined filtrates were concentrated to leave an oil 30 whose spectral characteristic6 and tlc 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 the title compound according to the method of steps 2 and 3 of 35 Example 35 (Method A).

Ex~le ~
(l'R,5R~6S and l'S,5S,6R) 6-(1'-Hydroxy-l'-ethyl)-2-methylpenem-3-carboxylic Acid (isomer B) OH

METHOD A

SAg l SAc 1 ___~S 1 ~ S~
0~ ~3 O ~ P~3 0~ _N ~C 3 ~ I _~ CH
N ~ 02PNB C02PNB C02PNB 02H

METHOD B

OH OH OH OH
SAg l)TMS/TEA ~ SAc ~ ~CH 3 ~ 5 ~CH 3 ~p~3 2) AcCl ~ N~ P~ 2 ~ C02H

METHOD A

1) (l'R,35,4R and 1'5,3R,45) 4-Acethylthio-3-(l'-paranitroben7yl-dioxy-carbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone, (isomer B) J ~ SAg AcCl J - ~ SAc ~ 5 5 ~ N ~ p~3 A solution of (l'R,35,4R and 1'5,3R,4S) silver 3-(1'-paranitrobenzyldio~lcarbonyl-l'-ethyl) l'-paranitrobenzyl 2"-triphenyl-phosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (isomer B) (917 mg, 1.03 mmol) in CH2C12 t20 ml) was treated at -15C (ice-MeOH
bath) with pyridine (242 ~1, 247 mg, 3.13 mmol) and dropwise with acetyl chloride (142 ~1, 157 mg, 2.0 mmol). The mixture was stirred _ /9~--12~

for 15 min at -15C and the solid was filtered and washed witn ether.
The organic solution was washed with 2~ aqueous HCl, water, 2~ aqueous NaHC03, water and brine and dried over MgSO4. The residue upon solvent evaporation crystallized from ether (710 mg, 80~, mp 183-185C; ir (CHC13) vmax: 17S5, 1695 (C=0), 1620, 1605 (phosphorane) and 1625 cm 1 (N02);

2) (l'R,SR,6S and 1'5,5R,6R) Paranitrobenzyl 2-methvl-5-(1'-paranitro-benzyl~ ~xycarbonyl-l'-ethyl)-enem-3-carboxvlate. (isomer B) C2P~3 ~ 2 ~N ~ 2~3 ~ ~

A solution of (l'R,3S,4R and l'S,3R,45) 4-acetylthio-3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-l~paranitrobenzyl 2"-triphe-nylphosphoranylidene-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 com~ound (0.5~ ether-benzene to 2~ ether-benzene) was obtained as a white solid; 329 mg, 77~, mp 134-135C, (CH2C12-ether); ir (CHC13) V : 1785, 1745, 1705 (C=O) and 1525 cm (~2) IHmr (C~C13) ~:
8.20 (2H, d, Ho aromatic), 7.60 (2H, d, Hm aromatic), 5.55 (lH, d, J=1.5, H-s), 5.5-4.75 (5H, m, 2CH2-PNB, H-l'), 3.86 (lH, dd, J=7.8, J=1.5, ~-6), 2.38 (3H, s, C-H3) and 1.50 ppm (3H, d, J=6.3, CH3); Anal. calcd for C24H21N30105: C 53.04, H 3.89, N 7.73, S 5.90; found: C ;3.05, H 3.98, N 7.63, S 6.02.

-/q~ -~--1'~ 318~

3 ) ~1 ' R, 5R, 65 and l'S,55, 6R) 6~ Xydroxy-l'-ethvl)-2-met~vl ~enem -3-carboxylic acid (isomer B) 2 ~ ~ CH3 2 ~O2H

A mixture of (l'R,SR,6S and l'S,5~,6~) paranitrobenzyl Z-methyl-6-(ll-paranitrobenzyldioxycar~onyl-ll-ethyl)-penem-3-carb late (_somer.B) (6; mg, 0.12 mmol), 0.05 M pH 7 buffer ,olution (1.06 eq), H20-THF-ether (10 ml, 10 ml, 25 ml) was shaken on a ?ar-hydrogenator using 30~ Pd on"CELITE" (200 mg) -or 16 h at 50 psi H2.
The catalyst was filtered and wa5hed with 5mall volumes of water. The aqueous layer was washed with ether (3 times), acidified 70rtionwise with 1% cold acUeoUs HCl, ext-acted with ethyl aCetate bet~een each addition of HCl, and saturated with ~rine and extracted throuchly wit~ ethyl aCetate. The ethyl aCetate extraCts were combined, washec.
with ~rine (5 times) and dried (MsSO4). Solvent evaporation a ordec a solid residue whiCh was triturated with methylene chloride (19.4 mS, 71~). ir("NUJOL"~ 3500 (O-H), 1785, 1672 cm (C=O)i uv (_tOH) : 260 (c 3450), 309 (~ 6400); IHmr ~DMSO d6) ~: 5 54 (lH, d, max J=l.;, H-5), 3.88 (lH, m, H-l'), 4.2-3.5 (2H, ~s, O-H), 3.65 (lH, dd, J=6.5, J=1.5, H-6), 2.28 (3H, s, CH3) and 1.15 p~m (3H, d, J=6, CH3).

*Trade Mark _ / 9 q -'.~

~2~`8~33 METHOD B

l) (l'R,3S.4R and 1'S.3R.4S) 4-Acetvlthio-3-(l'-trimethvlsilvloxv-l'-ethyl)~ aranitrobenzyl 2"-triphenvlphos~horanylidene-2"-aQetate) -2-azetidinone (isomer B) ~H OTMS
J-.. ~iAg TMSCl ACCl J'~SAC
10o ~ 3 TEA - C5H5N ~

A su6pension of (l'R,3S,4R and l'S,3R,4S) silver 3-(l'hydroxy-l'-ethyl)-l(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (505 mg, 0.715 mmol) in THF (25 ml) was cooled to -15C (ice-MeOH bath), treated dropwi 6 e with triethyl amine (289 mg, 398 ~l, 2.86 mmol), trimethyl chlorocilane (310 mg, 362 ~l, 2.85 mmol) and finally with imidazole (SO mg, 0.734 mmol), 6tirred for 3 h at -15'C and at room temperature for 16 h. (ir of an aliquot showed ab~ence of hydroxyl group,). The mixture was cooled to -15'C, diluted with CH2Cl2 (20 ml), treated with pyridine (226 mg, 231 ~l, 2.86 mmol) and acetylchloride (168 mg, 152 ~l, 2.14 mmol), 6tirred for 0.5 h, diluted with ether, washed with dilute aqueous HC1, water 5% aqueous NaHCO 3 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) Vmax : 1750, 1790 (C~O), 1620 (phosphorane) and 1518 cm 1 (N02).

12~ 83 2) (l'R,3S,4R and l'S,3R,4S) 4-Acetylthio-3-(1'-hvdroxv-1'-ethvl)-1-(paranitrobenzyl 2"-triphenylphos~horanvlidene-2"-acetate)-2-azeti-dinone (isomer B) OTMS OH
J SAc H3 ~ ~ SAc o~L ~ 0~ N~P~3 A solution of (l'R,3S,4R and l'S,3R,4S) 4-acetylthio-3-l'-trimethylsilyloxy-l'-ethyl)-l(parani~robenzyl 2"-triphenylphospho-ranylidene-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 NaHCO3, water and brine and dried (MgSO4). Solvent evaporation afforded the title compound (334 mg, 100~); ir (CY.C13) v : 175;, 1690 (C=O), 1620, 1605 (phosphorane and 1520 c~ (N02)-max 3) (l'R,SR,6S and l'S,SS,6R) Paranitrobenzyl 2-methvl-6-(1'-hvdroxv-1'-ethyl)-~enem-3-carboxylate (isomer B) OH OH

~N ~ P~3 O ~
C02PN~3 C02P~B

A solution of (l'R,3S,4R and l'S,3R,45) 4-acetvlthio-3-(1'-hydroxy-1'-ethyl)-l~paranitrobenzyl 2"-triphenylphos~horanyl-idene-2"-acetate)-2-azetidinone (410 mg, 0.638 .~mol) in toluene (40 ml) was refluxed for a 7 h period. Toluene was ?artially evaporated. ~he residue was passed throush a silica ael (1 to 12 ratio) ~olumn (3~, 4% and 5% ether in benzene) to give the title compound (151 mg, 65%) as a white solid mp 161-161.5C;
ir (C~C13) v : 3600, 3500-3400 (OH), 1780, 1608 (c=C) and 1525 c~
(NO2); IHmr (C~C13) ~: 8.20 (2H, d, J=7, Ho aromatic), 7.60 (2H, d aromatic), 5.57 (lH, d, J=2, H-S), 5.29 (2H, center o. ABq, J=15, CH2-PNB), 4.2 (lH, dq, J=7, J=6, H-l'), 3.67 (lH, dd, J=7, J=2, Y.-6), 126~183 2.33 (3H, s, CH3) and 1.33 ppm t3H, d, J=6, CH3); Anal.
calcd for C16H16N26S: C 52.74, H 4.43, N 7.69, S 8.80;
found: C 52.67, H 4.41, N 7.71, ~ 8.96.
4) (1'R 5R.6S and l~S.5S 6R) 6~ Hydroxy-1~-ethyl)-2-methYl ~enem -3-carboxvlic acid (i~omer B) OH
OH

o ,~N ~ _ 2 ~ CH 3 C02PNB CO;~H
A mixture of (1~, 5R, 6S and l'S,5S,6R) paranitrobenzyl 6-(1'-hydroxy-l'-ethyl) -2-methylpenem-3-carboxylate (89 mg, 0.244 mmol), THF-H2O-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) wa~ shaken on a Parr hydrogenator for 3.5 h at 45 psi H2. A work-up identical to the one previously described gave title compound (32 mg, 57%).
Example 37 (1'S 5R.6R and 1'R.5S.6S) 6-(1'-Hvdroxy-1'-ethyl) -2-methylpenem-3-carboxylic Acid (isomer A) pH
~H3 cO2H
1) (1'S.3R.4R and 1'R.3S.4S) 4-Acetylthio-3-(l'-methoxymethoxy-l'-ethyl)-l(~aranitrobenzyl 2~'-triphenylphosphoranylidene -2"-acetate)-2-azetidinone ~LLQ~Q~ al ~Ag ~ SAc o~L N~ 3 ~d--N ~ 3 *TradeMark ~2~i8183 Isomer A of 4-acetylthio-3-(1'-methoxymethoxy-1'-ethyl) -l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate~-2-azeti-dinone was prepared as described elsewhere for isomer C of the paranitro-benzyl dioxycarbonyl derivative, yield 85%. ir (neat) v : 1750 and 1690 cm 1 (C=O).

2) (1'5,3~,4S and 1'~,35,4S) 4-Acetylthio-3~ -hydroxy-l~-ethyl)-l-(para nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone, (isomer A) ~ca 2CH3 OH
Ac ~ Ac O ~ 3 O ~ ~3 Isomer A of 4-acetyl~hio-3-(ll~el-hoxvmethoxy-ll-ethyl) l-(paranitrobenz~1-2"-triphenylphosphoranylidene-2"-acetate)-2-azetidi-none (500 mg, 0.68 mmol) was added to a cooled solution (0C) of '~ri-fluoroacetic acid (50 ml) and water (10 ml) and stirred .or 15 min in ice and 3 h at -oom temperature. ~he reaction mixture was concen-trated, dichloromethane was added and the solution was washec with sodium bicarbonate, water, and brine, dried and concentratec to 3ive the title compound (450 mg, 96%); ir (neat) ma : 3400 (OH), 1745 and 1690 cm 1 (C=Oj.

_~ 3~-~2681~

3) (1~S.5R.6R and l~R.5S 6S) Paranitrobenzvl 6-(1'-hydroxy -1'-ethyl)-2-~ethvl ~enem-3-caxboxvlate (isomer A
OH OH
~I~SAC

O PNi3 Prepared as described for isomer C of the paranitro~enzyl dioxycarbonyl derivative, ~ield 45%, 1Hmr (CDC13) ~- 7-9 (4H, ABq, aromatics), 5.68 (lH, d, J=4.0, H-5), 5.33 t2H, ABq, benzyl), 4.3 (lH, m, H-l'), 3.8 (lH, dd, J=4.0, H-6), 2.41 (3H, s, CH3), 2.31 (lH, s, OH), and 1.42 ppm (3H, d, J=6, CH3 ); ir (CHC13) Vmax: 3100--3600 (OH), 1780 and 1710 cm 1(C=o).
4) (1'S.5R.6R and 1'R.5S 6S) 6-(1'-Hydroxy-1'-ethvl) -2-methvl penem-3-carboxylic acid (isomer A) OH OH

A mixture of isomer A of paranitrobenzyl 6-(1'-hydroxy- 1'-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 #SO-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 extraated with ethyl acetate (5 x 10 ml). The combined organic extracted were washed with brine, dried and concentrated. The foamy solid was *TradeMark 12~8183 triturated in ether to give a white 601id t2 mg, 44%). ir ("NUJOL")* vmax: 3500 (OH), 1765 and 1665 cm 1 (C=O) ; uv (EtOH) Vmax: 301 (~ 5922), 260 (~ 4280).
Exam~le 38 (l'R.5R.6S and l'S.5S.6R)2-Aminomethvl-6- (l'-hydroxv-l'-ethvl) -penem-3-carboxylic Acid (isomer B) 1 0 o~N

(l'R.3S.4R and l'S.3R.4S) 4-azidoacetvlthio-3-rl'-hydroxv-1'-ethyl)-1-(Daranitrobenzvl 2"-tri~henvl~hos~horanylidene-2"-acetate~-2-azetidinone (isomer B) OH
OH SAg TMSCl 2 3 ~3 ~ 2 3 o~N~P~3 T_~ . d~ ~P¢'3 C02PN}3 C 2 A ¢old (ice-MeOH bath) suspension of (1'R,3S,4R and 1'S,3R,4S) silver 3-(1'-hydroxy-1'-ethyl)-1- (paranitrobenzyl 2'~-triphenyl phosphoranylidene -2"-acetate) -2-azetidinone-4-thiolate (970 mg, 1.37 mmol, from 1 g of the corre6ponding trityl) in THF (40 ml) was treated dropwise with trimethylchlorosilane (0.69S ml, 595 mg, 5.48 mmol), triethyl amine (0.765 ml, 555 mg, 5.49 mmol) and imidazole (50 mg, 0.734 mmol). The mixture was stirred under N2 for 17 h, then cooled to -15C (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 tlc). The solid was filtered and washed with ether. The filtrate was diluted with more ether, washed with 1% aqueous HCl, water, 1% agueous NaHC03 , water and brine and dried (MgS04). The residue *Trade Mark `'~

-' 12~81~

upon solvent evaporation was taken up in moist CH2Cl2 (50 ml) and treated with TFA ( 3 drops, cleavage of TMS-ether being followed by tlc). The methylene chloride solution was then washed with 1%
aqueous NaHCO3, water and brine and dried (MgS04). The residue was passed through a silica gel (B times its weight) column (benzeneether 1:1, ether and ethylacetate-ether 1:1) to give the title compound (565 mg, 69.8%); ir (film) vmaX : 3500-3200 (0-H), 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'-hydroxy-1'-ethyl~-~enem-3-carboxylate (isomer B~

OH ~
J ~ SCc~2~3 ~o luene J"'~H 2~ 3 A solution of (l'R,3S,4R and l'S,3R,4S) 4-azido-acetylthio-3-(1'-hydroxy-l'-ethyl)-l-(paranitrobenzyl 2~-triphenyl-phosphoranylidene-2~'-acetate)-2-azetidinone (500 mg, 0.731 mmol) in toluene 100 ml was refluxed under N2 for 30 min.
The solution was concentrated under vacuum and the residue was passed through a silica gel (5 g) column (3.5-4% ether-benzene) and yielded the title compound (193 mg, 65.1~) as a yellowish solid 1Hmr (CDCl3) ~ 8.13 (2H, d, Ho aromatic), 7.52 (2H, d, Hm aromatic), 5.59 (lH, d, J=1.8, H-5), 5.27 (2H, center of ABq, J=13.5, CH2-PNB), 4.50 (2H, center of ABq, J=16, CH2-N3), 4.15 (lH, m, H-1'), 3.73 (lH, dd, J=6.3, J=1.8, H-6), 1.92 (lH, d, J=4, O-H) and 1.33 ppm (3H, d, J=6.3 CH3); ir (CHCl3) vmax :
2110 (N3), 1785, 1705 (C=O) and 1520 cm 1 (NO2).

12~81~33 (l'R,5R,65 and 1'5,55,6R) 2-aminomethyl-6-(1'-hvdroxy-1'-ethyl)-Denem-3-carobxylic acid (isomer B) OH
2PN3 H7 ~ NH2 A solution of (l'R,5R,65 and 1'5,55,6R) paranitro-benzyl 2-azidomethyl-6-(1'-hydroxy-1'-ethyl)-Denem-3-car~oxylate (25 mg, 0.062 mmol) in TH~-ether-water (6 ml, 6 ml, 15 ml) was shaken on a Parr hydrogenator for 2.5 h at 40 psi H2 us ng 10~ Pd on carbon (100 mg). The catalyst was filtered and washed wi~.h small volumes of water. The aaueous layer was washed with e'her (3 times) and lyophilized to give t~e title compound (11 mg, 73~).
lHmr (D20) ~: 5.75 (lH, d, J=2, H-5), 4.30 (lH, center of m, J=6.;, H-l'), 4.02 (lH, dd, J=6.5, J=2, H-6) and 1.37 ppm (3H, d, J=6.5, CH3); ir (nujol mull) vmax: 3550-2450 (O-H, N-H), 1765 (C=0) and 1600 cm (CO2~ ; uv (H20), ~ : 309 (~ 3650), 255 (~ 2815).

.~o~ ~

~2~ 83 . ~

Exam~le 39 ll'R.5R~6S and l'~S.5$.6R)-2-(4-Amino~utyl)-6-tl'-hydroxy-ethyl)--penem-3-carboxylic Acid (isomer B) OH

rN ~ ( Z ) 4 2 COOH

(l'R.3S.5R and l'S.3R.4S) 4-(~-azidobutanoylthio)-3-(1'-hydroxyethyl)-1-(paranitrobenzyl ~"-tri~henylpho6phoranylidene -2"-acetate)-2azetidinone 20 ~ THSCl N3 (CH2) 4COCl H ~H -C (C~2) 4N3 3 C5H5N H20 ~ ~C=PPh3 COOPN3 OOPNa ~ solution of (1'R,3S,4R and l'S,3R,4S) silver 3-(1'-hydroxyethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene 2"-acetate)-2-azetidinone -4-thiolate (3.03 g, 4.28 mmol) in dry THF (55 ml) kept under a nitrogen atmosphere was cooled to -25C and successively treated 30 with triethylamine (2.39 ml, 17.12 mmol) trimethylchlorosilane t2.18 ml, 17.12 mmol) and imida301e (0.10 g, 1.47 mmol). The reaction mixture was stirred at -25C for 0.25 h, the cooling bath was 12~81~

removed, and the ~tirring wa6 continued for 16 h. The reaction mixture was cooled to 0C and diluted with CH~C12 (55 ml); it was then treated successively with pyridine (0.73 ml, 9.0 mmol) and with a solution of 4-aminobutanoyl chloride (1.36 ~, 8.56 mmol) in CH2C12(10 ml). The reaction mixture was stirred at 0C for 1 h and filtered through a "CELITE"* pad. The pad was washed with CH2C12 (25 ml); the filtrate and wa6hing6 were combined and diluted with EtOAc (300 ml) . The organic solution was washed with lN HCl solution, H2O, 6aturated NaHCO3 601ution and H2O, dried over anhydrous MgSO4 and concentrated on a rotary evaporator to an orange syrup (3.83 g). The syrup was dissolved in CH2C12 (75 ml) and water (4 ml) and TFA (0.2 ml) were added;
the reaction mixture was stirred at 23C for 1.5 h, washed with NaHCO3 and H2O, dried over anhydrou6 Na2SO4 and concentrated to an orange 6yrup (3.4 g). Purification of the syrup wa6 achieved by a column chromatography (sili¢a gel G 60, 80 g; eluent: EtOAc in CH2C12 10% ~ 75%). Evaporation of the appropriate fractions gave an oil; 2.14 g, 67.7%. Anal. calcd for C37H36N5O7SP: 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.
(1'R.5R.6S and 1'S.5S 6R) paranitrobenzyl 2-(~-azidobutvl)-6 -(l'-hydroxyethvl)-~enem-3-carboxylate OH R OH
J"" ,_~ SC (CH 2 ) 4N 3 ~ J ",~5 O L N ~ Toluene o ~ N ~ 2 4 3 cl=PPh3 ~OOP
COOPNB

A solution of (1'R,3S,4R and l'S,3R,4S) 4-t -azido-butanoylthio)-3-(1'-hydroxy-1'-ethyl)-1-(paranitrobenzyl-2"-tri-phenylpho6phoranylidene-2"-acetate)-2-azetidinone (2.04 g, 2.81 mmol) in a toluene-CH2C12 mixture (30:1, 310 ml) was refluxed for 9 h under a *Trade Mark r ~2~j81~3 -nitrogen atmosphere (The CH2C12 was removed at the beginning of reflux). The reaction mixture wa6 cooled to 23C 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). ~he appropriate fractions were combined and concentrated to a 6yrup which was cry6tallized from an ether-pet.ether mlxture, 0.443 g, mp 85C, 35.2%. Anal. calcd for C1gH21N5O6S: 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. ~he fractions corresponding to unreacted 6tarting material were cyclized as described above to give an additional quantity (0.276 mg, 21.9%) of title compound. Vmax : 2100 (N3), 1770 (C=O, B-lactam,) and 1705cm~
(C=O, PNB ester); ~v(H2O 23C) ~max 268 (E 13757)~ 316 (~ 69826). lHmr (CDC13):~ 1-36 (d~JH-2"-H-1"= 6-3 Hz~ 3H~
methyl), 1.52-1.77 (m, 4H, H-2', H-3'), 2.57-3.00 (m, 2H, H-4'), 3.00-3.42 (m, 2H, H-l'), 3-72 (dd, JH-6-H-5 = 1-6 Hz~
JH_6_H_lll=6.4 Hz, H-6), 4.02-4.42 (m, lH, H-l"), 5.32 (ABq, J
a-b= 13.6 Hz, 2H, CH2 of PNB ester), 5.60 (d, JH_5_H_6 = 1.6 Hz, 1H~H 5), 7-61 (d~ JHm_HO =8-8 Hz, 2H, Hm of PNB ester) and 8.21 ppm (d~ JHo-Hm= 8-8 Hz, 2H, Ho of PNB ester).

(1'R.5R.6S and l'S.5S.6R) 2-(4-aminobutyl~-6 -(l'-hydroxyethyl)-penem-3-carboxvlic acid OH
OH
,~ ~ (CH ) N109 Pd/C ~ ,~--(CH2) 4NH2 o M~ 2 4 3DME: Et20, H20 0 --~OOH
OOPNB

To a solution of (1'R, 5R, 6S and l'S,5S,6R) paranitro-benzyl 2-( -azidobutyl)-6-(l~-hydroxyethyl) -penem-3-carboxylate (0.54 g, 1.21 mmol) in dimethexyethane (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 23C for 3 h. The reaction .~ .

~2~
.

mixture was filtered over a "CE~ITE"*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 (XBr) vmax: 1760 (C=0, B-lactam) and 1565 cm 1 (C-0, carboxylate); 1Hmr (D2O) ~: 1.32 (d, JcH3-H-l''=6.4 Hz, 3H, CH3), 1.45-1.85 (m, 4H, H-l',H-3'), 2.50-3.20 (m, 4H, H-l', H-4'), 3.84 (dd~ JH-6-H-l~= 6-1 Hz, J H-6-H-s =1.4 Hz, 1-H, H-6), 4.00-4.45 (m, lH, H-l"- and 5.62 ppm (d, J H-S-H-6 =1.4 Hz, lH, H-5); ~v (H20) max : 260 ( 4240), 302 (E 5480).
Example 40 ~l"R.5R.6S and l'S.5S.6R~-2-(trans-3'-Amino-l'-cvclobutyl)-6-(l"-hydroxv.-l"
ethyl)penem-3-carboxylic Acid (isomer B) OH
J ~ ~ 2 COOH
(l"R.3S,4R and l"S.3R.4S) 4-(trans-3'-azidocyclobutanoylthio)-3-(1"-hydroxy-l"-ethyl)-l-(~aranitrobenzyl 2"'-triphenylDhosphoranylidene-2"' -acetate)-2-azetidi~one OH r~
J~ SAg Cl~--C> N3 H
3 C5~5 H2 ~ ~ f pp~
cooPNs COOPN3 A 601ution of (l'R,3S,4R and l'S,3R,4S) 6ilver 3-(l~-hydroxyethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene -2"acetate)-2-azetidinone -4-thiolate (1.01 g, 1.43 mmol) in dry THF (25 ml), kept under a nitrogen atmo6phere, wa6 cooled to -40C and 6ucce6sively treated with triethylamine (0.80 ml, 5.74 mmol) trimethylchloro6ilane (0.726 ml, 5.72 mmol) and imidazole (0.10 g, 1.47 mmol). The reaction mixture was warmed to -15C, 6tirred for 3 h, the cooling bath wa6 removed and the 6tirring was continued for 18 h.
The reaction mixture was cooled to -15C and diluted with CH2C12 (25 ml); it was *~radeMark j~f~

``~ 1;~6~

then treated with pyr~dine (0.15 ml, 1.85 mmol) and trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The cooling bath wa~ removed and the solution was stirred for 1 h and treated wilh pyridine (0.15 ml, 1.85 mmol) and trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The reaction mixture was stirred at 23C for 1 h and filtered through a "CELITE"*pad. The filtrate wa6 diluted with EtoAc (100 ml) and washed with lN HC1, H20, 6aturated NaHC03 601ution and H20, dried over anhydrous MgS04 and concentrated on a rotary evaporator to an orange 6yrup (1.47 g). To a solution of the syrup in CH2C12 (50 ml) was added H20 (2 ml) and TFA (0.2 ml).
The reaction mixture was stirred at 23C for 2 h, washed with ~aturated ~aHC03 601ution and H20, dried over anhydrou6 Na2S04 and concentrated to an orange 6yrup (1.1 g). Purification of the syrup wa6 achieved by column chromatography (silica gel 60, 20 g;
eluent EtOAc-ether 35% ~ 70%) . Evaporation of the appropriate fractions gave the title compound a6 an oil; 0.77 g, 74.4% ir (neat1 vmax: 3440 (OH), 2100 (N3), 1755 (C=O B-lactam), 1735 (C=O), 1680 (C=O) and 1625 cm~1 (aromatics).
11" R. 5R 6S and l"S SS.6R) paranitrobenzvl 2-(trans-3'-azidocyclobutvl~-6-(1"-hYdroxv-l"-ethvl)penem-3-carboxvlate 3 ~ N 3 COOPNB
COOPNB

A solution of (l"R, 3S,4R and 1"S,3R,4S) 4-(tran~-3'-azidocyclobutanoylthio)-3-(1~-hydroxy-1~-ethyl)-1-(paran-itrobenzyl-2"'-triphenylphosphoranylidene-2"' -acetate)-2-azetidinone (2.27 g, 3.14 mmol) in CHC13 (40 ml) was diluted with toluene (300 ml) and refluxed under a nitrogen atmo6phere for 6 h. The first 60 ml of solution (CHC13 ~ toluene) were removed with a Dean-Stark trapp. The reaction mixture was cooled to 23C and the eolvent wa6 evaporated *Trade Mark '.~;

~Z~183 under a reduced pressure leaving an orange syrup which was purified by a silica gel column (silica gel 60, 35 g, eluent, ether-benzene, 0 6%). Evaporation of the appropriate fractions gave the title compound, 0.38 g, Mp 134-5C, 27.3%. Anal calcd for C1gH1gN5O6S: 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) vmax : 2110 (N3), 1765 C=O B-lactam), 1690 (C=O P~B ester), 1510 (NO2 ) and 1355 cm~
(NO2); 1Hmr (CDCl3) ~: 1-36 (d, JCH3-H-1=6 3 Hz~ 3H~ CH3 )~
2.0-2.75 (m, 4H, H-2', H-4'), 3-67 (dd, JH-6-H-5"1-5 Hz~
JH_6_H_l"= 6.5 Hz, lH, H-6), 3.8-4.55 (m, 3H, H-l', H-3' and , .30 (ABq, Ja-b =13.6 Hz, 2H, CH2-Ph-NO2~, 5.60 (d JH S H 6=1-5 Hz, lH, H-5), 7-59 (d, JHo-Hm=8 3 Hz~ 2H~
PNB) and 8.20 (d,JHm_Ho=8.8 Hz, 2H, H-O of PNB). uv (CHCl3, 23C) ~max : 266 ( E 13050) and 322 ppm ( E 10008). The unreacted pho~phorane was recovered mixed with Ph3P-O and cyclized as described before to give an additional quantity of title compound: 0.145 g, 10.4% for a total yield of 37.7%.
(l"R.5R.6S and l"S 5S.6R~-2-(tran6-3'-amino-l'-çyclobutyl(-6-(l~-hydroxyethyl)penem-3-carboxylic acid .N 10~ Pd/C ~""NH2 ~ DME, et~e~, H20 ~ ~
OOPNB COOH

To a 601ution of (l"R,5R,6S and l"S,5S,6R) paranitrobenzyl 2-(trans-3'-azidoayclobutyl)-6- (l"-hydroxyethyl)-penem-3-carboxylate (0. 33 g, O. 74 mmol) in dimethoxyethane (40 ml) added ether (40 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 wa6hings were combined and diluted with ether. The aqueous phase was 8eparated, washed with ether and lyophylized, 0.20 g, 95%, uv (H2O, 23C) Amax: 258 t 2725) and 306 ( 3613).
The crude material was triturated ~268i~33 with water and the white solid was filtered and dried over P205 under high vacuum for 5 h, 84 mg, 4096; lHmr (D20) ~:
1-34 (d~ JH-2l~-H-ln=6~3 Hz, 3H, H-2"-, 2.3-2.7 (m, 4H, H-2~, H-4~), 3.90 (dd, J H_6_H_5=1-5 Hz, J H-6-H-l" =6-1 Hz, lH, H-6) and 5.68 (d, JH_5_H_6=1.5 Hz, lH, H-5); uv (H20, 23C) ~max : 258 (~ 4738) and 306 ( 6318). The filtrate was purified by hplc, 58 mg; uv (H20, 23C) ~max:
257 ( 3580) and 306 (F 5033).

,~

12~'8183 ,Yl Example ~r .-ollowing the general procedure of Exa~ple ~ , the following 2,6-disubstituted penem compounds may be prepared using the indicated electrophiles.

Elect-ophile Product ~N

co2;

C~3I C~3-CH 3CY 2S 2--e3 CH 3 CH 3CH 2 -C~;C~2C~20502 ~ C~3 CH3CH2 2 C~2-C~-C~2-3r CH2=
HC-CCH
HC_C-C~2Br 2 D ~ D~

~:

~~15 _~

~2~i81~33 .

~lectro~hile R =

52 ~ c 3 0CH23r 0CH2-Cd3 3r CB, 0CH2CH2CH20S02~CH3 0~\

0C~I=C8C'H2Br 0C_CCH23r 0C-CCH -3r '3r CH3CH-C'd CB3CCB2Cl CH30CH2-CH35Ci2Cl CY.3SC~d2- ~) ~ Cl ~ ~
Cd3ocH2cH2cl C~3CCH2C-A2-CB3SC 2 2 C~.35C;12C-d2-ACY.O ~CC'A2-O O
may be oxidized to ~roduce CH35CH2- and C~35C:~2-O O
~ay be oxiAized to ~roduce CY35CA2CY'2- a~d CY35O2CH2C~2-o OH srotec~ed ~ia -C-O?NB

12~81~

~lect_o~hile R =
-GH
CH3C-H2CHO C''3C~2C''-GH
~ CH CH-CH -~SCH2CH2- ~9 5'~
r~~a C' CH-C.'' - ~ @~

~ ~ OH

0OC.~2Cl . ~OCH~-0cH2ocy2cl 0CH2OC.'2-0OCH2C.'.2C1 ~ 2 2 0C.' 2oCH2CH2C1 0cH2Gc~.2cH2 0sc~L~2cl 05C~2- 5 0cH2scH2cl 0CH25CH2- ~) 0scH2c:~2cl 0SC''~2C~'2- ~) 0C' SC.'. C32C1 0C'~25C~2c 2 OH
0~ ~ I ~
?

SH protected -C-O-~B
~ay ~e oxidized to produce '.iO35C.':2C'.'2-may ~e oxidized to _roduce CH3CH-CY2-so3~may be oxici7ed to ?rod~ce 0~CH2 -nd 0S02C.'.2-may be oxidized .o ?roduce 0CH25C.''2- ar.d 0C.'.25O2C:i2-O mav _e oxidized to produce 0SCH2CH - and 0S02CH2C'.i2-0 may ~e oxicized to produce 0C'.i25CH2C.'2- and 0CH25O2CH2C~l2~

_~

12~81~

~lectro~hile R =

~~S 0~
S~ .

0C}~2CX 0~ OH
0CX=CH-CHO 0 ~'\\~ (~) C 3 2 2 3 Ca3CH2C-~I~cl ~-~

S S
C~I 3C-SC 2H _ ~I\

Jl~Cl 0 \~\`Cl O O
~// ~R
P O
0 ~ 0~~
0C02CX3 0 ~\

(g) s~ay ~e oxidi2ed to ?rocuce 0 503E~

Electro~hile - o ~ '~
s 02C~3 \~\Cl ~/~

~5 ~Cl ~, /~
,~, 0C~i=CL'CO CH 0 CH

0C_C-CHO 0C_C-CH-o 0c--c-c02c~H3 0C--C-C-o}~

o Il C' S~\
~8~ ~J

3r -~ 19-~t~81~

lec_ros~hile ~ =

~3.~ 3r ~

3_ ~\
~ ~3r f ~^

r ~ N

Br ~ \y \>~3r ~\y`

~W~ Br [~,~/~ Br O
C2H50C -Cl C 2H 50C

C 2EI. 50CCrI 2Br C 2H. _OC ~\

~C -CP. 2C 1 ~C ~\

-~o 12~j818;~

E 1 es~tro~h i L
FCH2CH2C02CH3 F ~~

02~l-cH2cl HO~H
S~ 5~ O~
OCH 2 C 1 ~ i (PNB-O) 2P H203 NH
CH3CHO /~ (~) 9 ~) OH O,MS ~3 Q v~a 0 51 0,~ 0~
/ ~
l, ~H2 ~IHC02 ~N ~ 3 ~8 ~H2 ~HCH3 ~-CO2?~Tr3 Also, ~ CT~3 1~

or 12~i81~:~ f NH 2 N ( CH3 ) 2 ~ ( C~3 ) 2 O ~ ~C02~

or ~H 3 or NHCONHR

r co H
~ = El, C~3, or C:~3co-NH2 NHC02C2E~; NHC2C2~-~' ~ C~C02~

_~

Also, ~ST~ /~

o S i_~ 2 or OCONHC}~ OCONhC.'. 3 ;Tr ~ p; co~

or L~ ~
OH O~S CH3--S--S H
;Tr '`r~ S~C~3 ~/ 3 C02~;
--.~

-- 12`~i8183 Electrophile ?IRR' R, R~ = H, CH3 IZ)C~ 2CHO (I) ~T'-- R, R~ = El, C~3 RR ' ~

CH3CC:1 - 2 'l ~
~--~2~

Exam~le 42 (1'S 5R.6S and 1'R.5S.6R) B-TrimethYlsi1ylethyl-6(1'-acetox~-1' -ethyl)-2-methvl~enem-3-c~k~xylate (Isomer C) OAc ~ ~
~ e ~ CO 2 ~ ~

10 3~hydroxv-l'-ethyl)-l-L~-trimethvlsilYlethYl-2'l-triphen ~h~s~horanylidene-2~-acetate)-4-tritvlthio-2-azetidinone ~ STr 1) LDA ~ Me ~Tr 2 2) C~3CHO ~ SiMe3 20~o a solution of diisopropylamine (185 mg, 1.84 mmol) in tetrahydrofuran (5 ml) at -78 C was added n-butyl lithium (1.3 ml, 2.0 mmol) with stirring. After 5 min, a solution of 1-(B-trimethylsilylethyl 2'- triphenylphosphoranylidene -2'-acetate)--4-tritylthio-2-azetidinone (1.27 g, 1.67 mmol) in tetrahydrofuran (15 ml) was added dropwi~e over 20 min with stirring. After 2 min, freshly distilled acetaldehyde (1 ml) was added and the solution was stirred for 5 min. Hydrochloric acid (12.6 ml of 0.3M) was added and the mixture was 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 6aturated sodium chloride (20 ml each), dried and the solvent was evaporated in vacuo to give crude product, 1.37 g. The product was ab60rbed from methylene chloride onto 7 g of siliaa gel and placed (dry) on a 28 g silica gel column. The column was eluted with ether (100 ml) and then with ether/ethyl acetate 1:1 (50 ml). ~he first 20 ml of column fractions were discarded. The rest were combined and the solvent was ~2681~;~

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) znd ~her. with eth~l acetate (~00 ~1). L~Jer ~r~ cr.s were combined (major low Rf spot on tlc) 2nd the solvent was ev~?or~ted in vacuo to give partially purified title compound, ~40 mg (33%);
ir V : 3400 (OH) and 1750 cm (~-lactam and ester); IHmr ~CHC13) ~:
too poorly resolved to make peak assignments other than aromatics and trimethylsilyl.

Silver 3~ hydroxy-1'-ethyl)-1-(~-trimethvlsilylethyl 2"-tri?her.yl-Dhosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate.

OH OH
Me ~ S~r AgNo3/pyridine ~ Me ~ Ag iMe3 C2 Si.Me3 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.;0 mmol) in ether (10 ml).
The mixture was stirred visorously for 1 h. The preciDitate was collected by filtration and washed with water and ether to give the title mercaptide 267 mg (80~). ir V : 3400 (OH) ar.d 1750 c~
(~-lactam and ester).

--L~

12~i~31&~3 4-AcetYlthio-3-(1~-acetoxy-1~-ethYl)-l-~B-trimethYlsil~let-hvl 2"-tri-~henvlphosDhoranvlidene-2"-acetate)-2-azetidinone OH OAc Me~Ag AcCl/pyridine Me ~ SAc PPb3 2 5 ~ ~5e 3 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 t267 mg, 0.40 mmol) and pyridine (70 mg, 0.88 mmol) in methylene chloride (5 ml) at 0C. The mixture was stirred at 0C for 1.5 h and then at 23C for 15 min. The precipitate was filtered off and the solution was washed with O.l 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 vmax:
3450 (OH), 1750 (~-lactam and ester) and 1690 cm~l (thioester); lHmr (CDC13) 6: 7.5-8.2 (m, 15H, Ph), 5.85 (br, lH, H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH2, H-3), 2.0-2.6 (3 singlets; 6H, OAc, SAc), 0.9-1.7 (m, 5H, CH3, CH2Si) and 0.20 ppm (s, 9H, SiMe3).
(l'S.5R.6S and l'R.SS.6R) B-trimethylsilylethyl 6-(1'-acetoxv-1'-ethYl) 2-methvlpenem-3-carboxylate ~isomer C~.
OAc OAc I ~ H
Me~O ~ 3 Me/~~SiMe3 A solution of the above phosphorane (150 mg, 0.23 mmol) in toluene (15 ml) was heated under reflux for 2 h. The solution 12~i8~

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 ~olumn (dry) and eluted with ether. The first 5 ml fraction (single high Rf spot on tlc), on evaporation of the solvent, gave the title compound, 65 mg (76%) as a waxy solid. ir vmax: 1790 (~-lactam), 1740 (ester) and 1700 cm~l (OAc); lHmr (CDC13) ~: (d, J=2Hz, lH, H-5), 5.4 (m, lH, H-l'), 4.3 (m, 2H, OCH2), 3.90 (q, J=2Hz, 4Hz, lH, H-7), 2.37 (s, 3H,2 - CH3), 2.11 (s, 3H, OAc), 1.42 (d, J=6.5, HZ, 10 3H, 2'-CH3), 1.1 (m, 2H,CH2Si) and 0.05 ppm (s, 9H, SiMe3).
The product was found to be a single isomer.
Exam~le 43 (l'R.5R.6S and l'S.5S.6R) 6-1'-Amino-l'-ethyl~-2-methvlpenem-3-carboxvlic Acid ~H2 ~CH 3 Procedure A
(l'R.3S.4R and 3R 4S)3-(1 '-azido-l'-ethvl~ ~aranitrobenzyl 2"-triphonvlphosphoranvlidene-2"-acetate)-4-tritylthio -2-azetidinone (isomer B~
~ sc0~ ~Cp3 N~ ~3 N~3 C02PNB C02PNE~
A solution of (l'S,3S,4R and l'R,3R,4S)3-(1-methane-sulfonyloxy-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (isomer C) (12. 36 g, 13.4 mmol) in 10~ H20-HMPA (135 ml) was heated at 85C for 7 h in the presence of sodium azide (1.75 g 27.0 DOl). The solution was then poured into 12~i81~33 _, cold water (1 Q ) and the reaction product which crystallized out was collected by filtration. Redissolution in dichloromethane, washing with brine and drying (MgS04) 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 Vmax (CHC13): 2100 (N3), 1740 and 1610 cm~l (C=o).

(l'R.3S.4R and l'S.3R.4S)4-acetylthio-3-(1'-azido-1'-ethvl) -l-rDaranitrobenzYl 2"-tri~henylphosphoranylidene -2"-acetate) -2-azetidinone ~isomer B) 3 ~ S ~ 2H5 ~ SCOCH 3 ~ N ~P~3 N~P~ 3 15C02PNB Co22N~ co2PNs A cooled solution (5C) of (l'R,3S,4R and l'S,3R,4S)3-(l'-azido-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidine-2"-acetate)-4-tritylthio-2-azetidinone (8.9 g, 10.25 mmol) in dichloromethane (30 ml) was treated with a solution of mercuric acetate (2.12 g, 6.66 mmol) in methanol (30 ml). After stirring at 5C for 0.5 h and room temperature for 1.5 h, the solvent was evaporated and the crude mercuric salt redissolved in dichloromethane and washed with dilute NaHC03 and brine.
After drying (MgS04) the solution was cooled to 5C and treated directly with pyridine (1.66 g, 21 mmol) and dropwise with acetyl chloride (1.65 g, 21 mmol). The reaction mixture was stirred at 5C for 1 h. The precipitated mercuric chloride was filtered off and the filtrate washed successively with dilute HCl, NaHC03 and brine. Then the organic solution was saturated at 5C 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) 126~318;~
. . . ~

and 15% acetonitrile-dichloromethane: 5.1 g (74.6%); 1Hmr (CDC13) ~: 3.70 (lH, m, H-l'), 2.98 (lH, m, H-3), 2.33 and 2.20 (3H, 2s, acetyl), 1.28 (3H, d, J=6.2 Ha, H-2'); ir ~max (CHC13): 2115 (N3) 1758, 1693 and 1620 cm 1 (C=O) 5 (l'R.5R 6S and 1'$.5S.6R) ~aranitrobenzvl 6-(l'azido-1'-ethyl) -2-mathyl~enem-3-aarboxvlate (isomer B) ~p~3 ~ CH3 A solution of (l'R,5R,6S and l'S,5S,6R)4-acetylthio-2-(1'-azido-l'-ethyl)-l-paranitrobenzyl 2~-triphenylphosphoranylidene-2~-acetate)-2-azetidinone (5.lg, 13.1 mmol) in toluene (100 ml) was refluxed for 2 h under nitrogen. The #olvent was evaporated and the reaction mixture purified by chromatography on a silica gel column (7 x 5 cm). The azido penem was eluted with dichloromethane (further elution with 10% ether-dichloromethane allowed to recover 1.82 g of unreacted phosphorane):1.21 g (40.6%) mp 132-34C; 1Hmr (CDC13) 6: 8.21 (2H, d, Hm aromatic), 7.60 (2H, d, Ho aromatic), 5.51 (lH, d, J=1.6 Hz, H-5), 5.33 (2H, ABq, H-benzyl), 3.92 (lH, dq, J=8, 6.4 Hz, H-l'), 3.67 (lH, dd, J=1.6, 8 Hz, H-6), 2.37 (3H, 8, CH3), 1.46 (3H, d, J=6.4 Hz, H-2'); ir ~max (CDC13): 2123 (N3), 1788 and 1712 cm~1 (C=O).

12~

~l'R.5R.6S and l'S,5S.6R)6-tl'amino-1'-ethYl)-2-methyl penem-3-carboxylic acid risomer B) ~Nf--~ 3 ~ CH 3 A solution of (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 6-(l'azido-1'-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 1 h in the presence of 10% Pd-C
(440 mg). The catalyst was filtered off, the filtrate extracted with ether and the aqueous phase lyophilized. The crude amino acid (100 mg) was purified by hplc: 19.5 mg lHmr (D20) ~: 5.69 (lH, d, J=O.9 Hz, H-5), 3.94 (2H, m, H-6, H-l'), 2.28 (3H, 6, CH3), 1.50 (3H, d, J=6.4 Ha, H-2'); ir v max ("NUJOL")*: 1767, 1576 cm~l (C=O); uv (H20) Amax 300 m~ ( 532~).

Procedure (l'R.3S.4S and l'S.3R.4S) 3-(1'-azido-1'-ethyl~-4-tritylthio-2azetidinone (Isomer B) ~ i ~ sC~3 t-au A solution of (l'S,3S,4R and l'R,3R,4S) l-(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 10% H20:HMPA (15 ml) was heated under N2 at 75-80C for 3 h. Then the reaction mixture was diluted with ethyl acetate and washed several times with brine. The organic phase was dried (MgS04 ) and evaporated to leave an oil which crystallized spontaneously.

~Trade Mark ,~

. ,..... ~ -l~i8183 Trituration in ether and iltration gave 9Sl mg (76.5~) of the azido compound as a white solid mp 185-90C, dec. I~R (CDC13) 0:
7.23-7.78 (lSH, m, aromatics1, 4.43 (lH, d, J=3, H-4), 4.37 (lH, s, N-H), 3.89 (lH, dq, J=7, 6.5, H-l'), 3.16 (lH, dd, J=7, 3, H-3), l.S0 (3H, d, J-6.5, H-2'); ir V (CHC13): 3410 (n-H), 2123 (N3) and 1765 cm (C-O).

(l'R,35,4~ and 1'5,3R,4S) 3-(1'-amino-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B).
.

SC~3 ~ sc~3 N ~ H N ~ H

A suspension of (l'R,35,4R and l'S,3R,4S) 3~ azico-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) (1.0 g, 2.41 mmol) and ?latinum oxide (100 mg) in ethyl acetate (100 ml) was nvdroge-nated for 1 h at a pressure of 50 psi. Since the react-on was incom?lete, 200 mg of platinum oxide was added and the mixture hydrogenated tor one additional hour. Finally, 200 mg of ?latinum oxide was aga-n acded and the reaction continued _or 2.5 h. Total catalvst: S00 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 128-30C. IHmr (CDC13) 0: 7.13-7.63 (lSH, m, aromatics), 4.40 (lH, d, J=2.5, H-4), 4.30 (lH, broad, H-l), 3.30 (7H, cq, J=S.l, 6.3, H-l'), 3.03 (lH, dd, J=S.l, 2.5, H-3), 1.20 (3H, d, J=6.3, H-2') ar.d 1.0-1.80 ppm (2H, broad, NH2).

_~3 (l'R,35,4R and l'S,3R,4S) 3-(1'-D-nitrobenzyloxycarbonylamino-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) NH2 HNCO2P~3 C~3 ~ c~3 0 ~ N ~ 0 ~

A solution of (l'R,35,4R and l'S,3R,4S) 3-tl'-amino-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) (1.00 g, 2.;7 mmol) in dichloromethane (100 ml) was cooled to 5C and treated with p-nitro-benzylchloroformate (0.61 g, 2.83 mmol) and ?yridine (0.22 g, 2.83 mmol). After stirring at 5C ~or 45 min and at room temperature for 2.25 h, the reaction mixture was washed with dilute HC1, brine, dried (MgSO4) and finally evaporated to dryness. The cr~de car~amate was crystallized from ether: 1.03 g (70.5%). mp 147-50C. IHmr (CDC13) 0:
7.10-8.33 (19H, m, aromatics), 5.23 (2H, s, benzyl), 5.08 (lH, N-H), 4.40 (lH, s, N-H), 4.29 (lH, d, J=2.2, H-4), 4.10 (lH, ~a, J=8, 6, H-l'), 3.18 (lH, dd, J=2.2, 8, H-3) and 1.~3 ppm (3H, d, J=5, H-2'); i- V
(CHC13): 3395 (N-H), 1765 and 1724 cm (C=0).

(l'R,SR,65 and l'S,SS,6~) p-nitrobenzyl 2-methyl 6-(1'-p-nit~obenzvl-oxycarbonylamino-l'-ethyl) ~enem-3-ca boxylate (Isome~ 3) H ~ ~ N ~ 3 The title product was prepared ~rom ~l'R,SR,65 and l'S,SS,6R) 3-(1'-p-nitrobenzyloxycarbonylamino-1'-ethyl)-4-tritylt.hio-2-azetidinone (isomer B) by the standard procedure; mp 13~-113C. IH~lr (CDC13) o: 7.50-8.40 (8H, m, aromatics), ;.;8 (lH, d, J=1.20, H-S), _L33-_~

~2~i818~3 5.35 (2H, ABq, benzyl ester), 5.20 (2H, B, benzyl carbamate), 4.90 (lH, broad N-H), 4.20 (lH, dq, J=6, 8, H-11), 3.80 (lH, dd, J=1.2, 8.0, H-6), 2.40 (3H, s, (CH3 ), 1.40 (3H, d, J=6, CH3 );
ir vmax : 3435 (n-H), 1777 and 1717 cm 1 (C=0).
The p-nitrobenzyl ester may be subjected to catalytic hydrogenation as by the procedure of example 43 (Procedure A) to provide the corresponding carboxylic acid.

Exam~le 44 6-Dimethylaminomethyl-2-methyl~enem-3-carboxylic Acid C~3 ~ o2CH3 1-(t-butyldimethyl6ilyl)-3-dimethylaminomethyl-4-tritvlthio-2-azetidinone (cis and trans).

~ C~3 Me2NHc ~ ~ SC~3 ~ ~ i~Me2 3 \t-BIl To a solution of dimethylamine (18.5 ml of a 2N 601ution in methanol, 36.9 mmoles) in methanol (80 ml) was added a 601ution of hydrochloric acid in methanol (2.5 ml) of a 5N 601ution in methanol) followed by trans 1-(t-butyl-dimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (3.0 g, 6.16 mmoles) and by sodium cyanoborohydride (0.27 g, 4.31 mmoles). The mixture was stirred at room temperature for 3.5 h, poured onto ice-hydrochloric acid (pH=2) and made basic with sodium ~ .

~2ti8~8~.~
. ~

hydroxide (lN NaOH, pH =9) The mixture wa~ extracted with ether and the ether phrase was washed with brine, dried and evaporated to give the title compound as a crude oil (3.0g).

cis and trans 3-dimethYlaminomethyl-4-tritylthio-~=~zetidinone M~ ~ sc~3 NaN3 ~ ~ sc~3 Me o Sl ~T Me ~ ~H

\t-Bu A solution of the above crude compound (3.0 g, 6 mmoles) in hexamethylphosphorous triamide (HMPT, 16 ml) containing water (10%) was cooled (50) and treated with sodium azide (0.78 g, 12 mmol). The mixture was 6tirred 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 (lN) and the acidic extracts washed well with ether to remove the HMPT. The acidic phase was made basic (lN, 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.
129-131C (Pentane); ~ (ppm, CDC13 ): 6.8-7.8 (15H, m, aromatics), 4.5 (lH, N-H), 4.28 (lH, d, J=2.5, H-4), 3.35 (lH, m, H-3), 2.75-2.1 (2H, m, H-l'), 2.3 (6H, 8, CH3 ).
Cis isomer: 0.5 g, m.p. 132-3 C (ether-pentane); ~ (ppm, CDC13):
7.7-6.7 (15H, m, aromatics), 4.72 (lH, N-H), 4.5 (lH, d, J=5.3, H-4), 3.5 (lH, n:, H-3), 2.85-2.35 (2H, m, H-l'), 2.31 (6H, s, CH3 ). The cis to trans ratio can be varied by changes in conditions.
* Trade Mark ~.~

~2~

cis and trans 6-dimethvlaminomethYl-2-methYlpenem-3-carboxvlic acid The title compound was prepared from cis and trans 3-dimethylaminomethyl-4-tritylthio-2-azetidinone by the procedure of Example 58.
(ppm, CDC13): 5.5 (lH, d, J=1.3), 3.7 (lH, dt, J=1.3, J=8), 2.8 (2H, d, J=8), 2.35 (6H, s), 2.3 (3H, s).

~2~i81~3 .

Example 45 2-Amininoacetoxvmethyl-penem-3-carboxvlic-Acid (via mercaptide intermediate ~C~H 20CCH 2NH 2 C02~

4-AzidoacetoxYacetvlthio-l-(ParanitrobenzYl 2~-trihenyl~hos~horanylidene-2~-acetate)-2-azetidinone S~OH 2 3 , o~
~F~P~3 C6H5N N~P/!)3 A cold (ice-MeOH bath) solution of 4-hydroxyacetylthio -l-(paranitrobenzyl 2'-triphenylphosphoranylidene -2'-acetate) -2-azetidinone (586 mg, 0.954 mmol) in methylene chloride (15 ml) was treated successively with azido acetyl chloride 240 mg, 2.01 mmol) and dropwise with i81~

pyridine (226 mg, 231 ml, 3.0 mmol) in methylene chloride ~10 ml);
At the end of the addition tlc showed disappearance or starting material The mixture was diluted with ether, washed succ~ssively with dilute HCl, water, dilute aqueous sodium bicarbonate, water and brine. }t was dried over sodium sulfate. Purification of the residue was performed on a silica gel tlO g) column, eluting with 20% ether in benzene, ether, and 30~ ethyl acetate in ether. Concentration of the ?ertinent fraction gave the title compound as a foam; 533 mg, 80.1%i ir v (CHC13): 1763, 1702 (C=O), 1625 (C=P~3), 1522 (N02) and 2110 cm ~N3).

~ranitrobenz~l 2-azidoacetox~rmethvl?enem-3-carboxvlate S ~ ~ 3 ~ ~ ~ ~3 A solution of phosphorane (S33 mg, 0.,64 mmol) was heated under rerlux in toluene (90 ml) for O.S h using a catalyti_ amount of hydroquinone. The solvent was concentrated on the evaporator and the concentrated solution was passed throug~ 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 -ound to ~e ms_~ie at room tæmperature. _t was kept at -78C until needed. !:~mr (CDC13) 0:
8.21 (2H, d, Hm aromatic), 7.57 (2H, d, Ho aromatic), 5.68 (lH, cd, 5-6 cis ' S-6 trans 2~ H ;), 5.43 (2H~ center of ~Bq, ~=16, CH2-PNB), 5.39 (2H, CH20), 3.93 (2H, s, CH2-N3), 3-72 (?art Of dd~ J6 S i =4~ H-6)~
gem 17~ J6-; tranS=2, H-6); ir v (CHCl ): 1795 17S5, 1710 (C=O), 1525 (N02), 2110 cm (~3), ~ &~

~2~
`~

2-Aminoacetoxymethyl~enem-3-carbox~.~lic acid 3 ~ ~ ~ ~ N~2 A mixture of above ester (219 mg, 0.522 ~mol) in THF
(16 ml)-ether (30 ml) and water (16 ml) was shaken on a Pa-r hydro-genator 'o~ 2.25 h at 50 psi of H2 using 10~ Pd/C (240 mg) as catalyst.
The ~atalyst was Cil ered off and washed with water and ether. The aqueous ?hase was wasr.ed with etner (3 x 30 ml) an~ lJo?hil zed. The crude powder was ?uLri iec on a reversed phase h?l- col~mn and save the t_tle compound ~8 mg, 6.7~) as a whi~e pow~er. H.~r (D2O) ~: 5.72 5-5 cis ' 5-6 trans 2~ H-5), 5.37 (2~, center or ABc, J=13.5, CH2-O), 3.96 (2H, s, CH2-~H2), 3.87 (lH, dd, J =16.5, J6 5 .3.5, ~-6) and 3.49 ~mr (lH, d~, Jcem=16 5~ J6-~ trans 2~ H 6); ir Vmax ("NUJOL"): 1775, 1755 and 1600 cm (C=O); uv (H20) ,~ 306 (~4900), 256 (~3000).

_ ~q_ *Trade Mbrk ~`

1~i8~8~

~-x~ e~3~r Silver l-(~-Tri~et~.-r'si'r'ethyl-2'-t~i~hen~ ~no~.ore?.,r ._ene-~'-acefate~-2-~zetidinone-h-thio'ate ~ SAg o~N~ P~3 C~
Q2CH2CH25i~ CH3 di-B-trimethvlsilylethvl f-marate Cl ~ 3 ~ ~ ~CH3J35i ~ i~CH3)3 To a cold (-10C) ether (20 ml) solution o4 2-_rime_hyl-sil~l ethanol ~4.73 g, 0.04 mmol) lH. Gerlach Helv. Chim. Acta 50, 3039 (19~7)~ and pyridine (5.66 ml, 0.07,~mol), under ni.rosen, was added dro~wise (15 min) f-~maryl chloride (3.78 ml, 0.035 mol) dissolvec in ether (10 ml). The black mixture was stirred five minutes at -lO~C and ten at room temperature. Charcoal was acded and ~he reaction mixture filtered on a"CELlTE'~?ac. The filtrate was washed with sodlum bicarbonate 1~ - brine (1:1, 150 ml). The aaueous phase was back extracted with ether (30 ml). The etner solutions were combined, washi~ed with brine, dried over sodium sulfate, 4iltered and concentrated under reduced ~ressure to give -L ~~
*Trade Mbrk a brown solid. This compound was purified on a silica gel pad (30 5, 4 X 5 cm) With benzene (300 ml) as eluent to give an oil (4.85~ g, 77~) which solidified on standing: mp 33-34C. Anal. calcd for C14H28O45i2: C 53.12, H 8.91i found: C 53.35, H 8.91. IHmr (CDC13) ~:
6.78 (2H, s, C=CH), 4.26 (4H, m, CH2-O), 1.03 (4H, m, CH2-Si) and 3)3 i); ir (CHC13) Vmax: 1710 (C=O of ester) 1643 (C=C), 1267, 1258, 862 and 840 cm 1 (Si-C).

Trimethylsil~le_hvl 51yoxvlate hycrate i ~ 1) O3 C2 ~ i(CH;)3 A solution of ci-~-tr.methylsilylethyl ~ m2rate (37 g, 0.117 mmol) in methylene chloride (1.1 ~) was ozonized at -78C until a blue color pe_sisted. The exCess ozone was pur5ed with nitrogen and dimethyl sulfide (2.57 ml, 0.351 mol) was accded.
The solution was allowed to gradually warm to 23C. The reaction miXture was diluted with carbon tet-achloride to 2 lite~s and washed with 1~ aoueous solution of sodium carbonate (500 ml). The o_5anic phase was dried over socdium sulfate, filtered on"CELITE" and evapo--ated (~ 25C) to drvness to give 43.9 5 of t~e title com~ound (97%);

r (neat) V : 3450 (-OH), 1740 (este-, 1255, 360 and 84C c~ ~âi-C).
max l-(~-trime'hylsilyle hvl 2'-hvdroxy-2'-ace-ate)-4-t-itylthio-2-aze._dinone ~ C2 ~ 3 ~ ~ ~ âi(CH3)3 Trime'hylsilylethyl 51yoxy.ate hydrate (4.000 5, 11.6 mmol) and the 4-t~itylthio-2-azetidinone (4.8 5, 24.96 mmol) were refluxed in benzene (25 ml) throu5h a Dean Stark condense-, under nit-ogen for 24 h. The solvent was evaporated under a vacuum. The product was chromatographed on a silica 5el column (450 g, 8.5 x 14.5 cm) and eluted with ethyl acetate: methylene -2y/-*Trade Nark chloride (1:19) until the title compound started to come out (- l.S ~) and then with eth~lacetate: methylene chloride (1:9, 2 ~). The fractions containing the title compound were com~ines and evaporated to dryness to give 5.415 g (89%) of the title compound. 1Hmr (CDC13) ~: 7.80 to 6.70 (15H, m, trityl), 5.23 and 4.90 (lH, 2s, H-C-O), 4.50 to 4.10 (3H, m, H-3 and O-CH2), 2.60 (2H, m, H-2), 0.95 (2H, m, C~2-Si and 0.1 ppm (9H, s, Si-CH3) ir (CHC13) v : 3520 (-OH), 176; (C=O of ~-lactam), 1740 (C=O of ester), 1595 (C-H, aromatic), 1257, 860 and 840 cm (C-Si) l-(~-trimethylsilylethvl 2'-chloro-2'-acetate)-4-t-i~vlthio-2-a-e~idi-.one STr pyridine ~ S.r C2 Si(CH3)3 C~2 Si(CH3) A solution of thionyl chloride (0.74 ml, 10.37 mmol) in dry THF (9 ml) was added dropwise with sti--ing to a solution of '-(R-trimethylsilylet~yl 2'-hydroxy-2'-acetate)-4-tritylthio-2-azeticinone (..9 g, 9.37 ~mol), Fyridine (0.84 ml, 10.38 mmol) anc dry TH~ (40 ml) at -15C unser a nitrogen atmos?here. The mixturQ
was stirred at -15C .or 2 h. mhe ?recipitate was rsmoved by filtration on a"-FTTTE"~ad and washed with benzene (;0 ml). The filtrate W25 evaporated in vacuo at 30C. The -esidue was dissolves in benzene (100 ml), treated with charcoal and -ilt--_d th-cugh a Celite pad. Evaporation of the solvent gave a ~esidue which was puri~ied through a silica gel pad (100 g, 4.7 x 11 cm): hexane-benzene (1:1, 400 ml), ether-benzene (1:19, 1 ~). Evaporation of the ~ertinent '-actions gave 4.64 g of tne title compound (923).

H~r (C~C13) ~: 7.30 (lSH, m, aromatic H), ;.77 and ;.43 (lH, 2s, CH-Cl), 4.7 to 4.2 (3H, m, H-4 and CH2-O), 2.8; 'o 2.50 (2H, m, H-3), 1.1; (2H, m, CH2-Si) and 0.06 ppm (9H, s, Si-CH3); ir (neat) v : 1760 (C=O), 860 and 840 cm (C-Si).
max *Trade Mark --2'12. -!~3 i ~ i2~818~

~ -trimeth lsil lethvl-2'-triDhenvl~hos~horanylidene-2'-acetate)-4-Y Y
tritylthio-2-azetidinone Tr 2,6-lutldine ~N~

2 Si(CH3)3 2 Si(CH3)3 A dioxane (20 ml) solution of the above chloroazeti-dinone (4.12 g, 7.568) was treated with triphenylphosphir.e (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 TXF. The .iltrate was eva?orated to ~ryness. The residue was purified on a silica 5el column (200 5, 4 x 31 cm) using ethvlacetate-hexane (3:7, 1 ~; 7:3, 1 ~) lo give the title phospnorane (4.836 g, 83%). ir (film) `~ : 1755 (C=0), 1615 (phosphorane), 850 and 830 cm (si-c). Anal. calcd for C47H46NO3PSSi: C 73.89, H 6.07, N 1.81; found: C 72.18, H o.08, N 1.83 Silver 1-(3-trimethylsilylet~yl 2'-t-i?henyl?hos?r.oranylidene-2'-acetate)-2-azetidinone-4-thiolate STr S~5 + AgNO3 + (nBu)3N + C 3CC2-~ ~ e~/- C ~ ~ ?~3 2 Si(~H3)3 ~ Si(CH3) 3 1-(5-trimethylsilylethyl 2'-tri?henyl ?hos?horanylidene-2'-azeta~e) -2-azetidinone (7.64 5, 10 mmol) was dissolved in etker (oO ml).
An aqueous solution of silver nitrate (O.SM, 80 ml, 40 mmol) was added followed ~y a rapid addi'ion ( 1 min) o a solutian Or tributylamine (3 ml, 12.58 mmol) and t-ifluoroacetic acid (0.15. ml, ~~3 ~

3~ 3 0.2 mmol) in ether (20 ml). The mixture was mechanically 8tirred for 19 min. The precipitate was filtered, rinsed with ether (200 ml), triturated in water ~70 ml), filtered again and rinsed with ether (100 ml). The light brown solid was dried under vacuum (water aspirator 10 min and pump 65 min) to give the title compound (6.52 g). IR (CHC13 ) v max :1862 (C=0),1630 (phosphorane), 860 and 840 cm~1 (Si-C).

- 243a -12~i8i~;~
-Example 47 6-Formamidomethvl-2-methvl~enem-3-carboxvlic acid, sodium and potassium salts --~o ~la~3 and hÇ~) trans l-lt-butyldimethYlsilyl~
-3-methanesulfonylox,ymethyl-4-tritYlthio -2-azetidinone ~S;~(C~13)2 ~-31 t-3u A solution of trans-l-(t-butyldimethylsilyl)-3-hydroxy-methyl-4-tritylthio-2-azetidinone (8.0 g, 16.36 mmol) in dichloromethane (50 ml) was treated at 5C with methanesulfonyl chloride (1.4 ml, 18 mmol) in dichloromethane (10 ml) and triethylamine (2.5 ml, 18 mmol).
Stirring was maintained for 1 h under N2. Then the solution was washed ~2~ial~3 successively with cold lN hydrochloric acid, lM sodi~m bicarbonate and brine, dried (MgS04) and evaporated in vacuo. The residue ~mixtu-e of hydroxy and mesylate cpd) was treated a second time as be~ore, to give the mesylate (90 g, 97%) as an amor?hous solid. It was used as such in the next step without further purification. The analytical sample was recrystallized from methylene chloride mp 167-168C; ir (neat) Vm : 1755 cm ; lHmr (CDC13) ~: 7.3 (15H, m), 4.4 (lH, d, J=2H2), 3.9 (lH, dd, J=8Hz, 4HZ), 3.2 (2H, bs), 2.8 (3H, s), 0.95 (9H, s) and 0.3 ?pm (6H, s).

trans 3-methanesulfonyloxYmethv1-4-tritylthio-2-azetidinone 2r.d t-~ns-.
3-azidomethvl)-4-tritylthio-2-azetidinone H H H H H H

Ms~""'~ C~3 ~ ~ $3 ~" ~ sc~3 S\i(CH3)2 H O H

t-BU

A solution of trans -l-(t-butyldimethylsilyl)-3-methane-sulfonylmethyl-4-tritylthio-2-azetidinone (21.0 g, 37.0 mmol) in H~A
(90 ml) was cooled in an ice bath and treated with sodium azide (2.7 g, 41.2 mmol) in H20 tlO ml). The reaction mixture was stirred at room tem~erature 'or 1 h, diluted with ethyl acetate, washed wit.. H20 (5 x 100 ml), dried (MgS04) and evaporated in ~tacuo. The trans-i-methanesulfonyloxvmethyl-4-tritylthio-2-azetidinone was diluted with HMPA (90 ml), treated at room tem?erature with sodium azice (2.7 g, 41.2 mmol) in H20 (10 ml), heated at 60C 'or 2 h and tri~urated with cold water. The crude azide was diluted with benzene-e~her (5:1) and washed with water (5 x 20 ml). Evaporation of the soitent followed by crystallization 'rom ether gave 18.0 g (77~) o~ azide as a white solid. The analytical sample was recrystallized rom C'H2C12/

ether mp 174-5C; .~nal. calcd ~or C H N~OS: C 68.97, H 5.03, N 13.99;

5~

~2ti8183 found C 68.78, H S.00, N 14.16; ir (nujol) v : 2100, 1765 cm : IHmr (CDC13) ~: 7.35 (lSH, m), 4.75 (lH, bs), 4.4 (lH, d J=2Hz), and 3.1-3.7 ppm (3H, m).

trans-3-aminomethyl-4-tritylthio-2-azetidinone N H SC~ H H

H NH
To a solution of trans 3-azidomethyl-4-tritylthio-2-azetidinone (10.0 g, 47.; mmol) in dry methanol (500 ml) was added ammonium chloride (19.0 g) and zinc powder (1.0 g) and the suspension was stirred at room temperature for 5 h. The reaction mixture was filtered and evaporated. The residue was partitioned between 1 hydrochloric acid and benzene. The aqueous layer was basified with lM sodium bicarbonate and extracted with methylene chloride.
The extracts were washed with brine, dried (MsSO4) and evaporated in vacuo. The crude amine crystallized from ether, 14.05 g (793);
mp 139-9C; Anal. calcd for C23H22N20Cl l/4 CH2C12: C 70.56, H 5.73, N 7.08; Found: C 70.68, H 5.94, N 7.27; ir (CHC13) v : 3400 and 1760 cm ; lHmr (CDC13) ~: 7.35 (lSH, m), S.lS (lH, m), 4.3 (lH, bs), 2.7-3.5 (3H, m) and 1.3 ppm (2H, m).

~~ ~6 ~

l~ti~

trans 3-Dhthalimidomethyl-4-tritylthio-2-azetidinone H2N ~ 3 ) ~ N H

A solution of trans 3-aminomethyl-4-tri.ylthio-2-azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimiae (8.3 g, 37.9 mmol) in benzena (200 ml) was heated under refl~lx 'or lS h. The solvent was evaporated in vacuo and the residue crystallized from ether to give 17.4 g (93%) of the title compound;
mp 172-3C; Anal. calcd for C31H24N2035: C 73.78, H 4.79, N 5.55, 'ound: C 73.92, H 4.87, N 5.49, ir (CHC13) V ax 1770 and 171~ cm IHmr (CDC13) ~: 7.8 (4H, m), 7.3 (lSH, m), 4.45 (lH, d, J=2Hz), 3.3-4.1 (3H, m) and 3.3-4.6 ppm (lH, m).

trans 3-phthalimidomethyl-1-tparanitrobenzyl 2'-hydrox,v-2'-acetate)-4-tritylthio-2-azetidinone " ~ C~3 ~ ~ . ~ ~ 3 2?NB

A mixture of trans-3-phthalimidomethyl-4-tritylthio-2-azetidinone (17.4 g, 34.52 mmol), paranitrobenzylglyoxylate hydrate (9.4 g, 41.4 mmol) and triethylamine (4.8 ml, 34.S mmol) in ~etr~-hydrofuran (250 ml) was stirred at room temperature for 20 h. The -eaction mix'ure was evaporated in vacuo and the residue was tr-atad with charcoal in benzene. Evaporation of the solvent vielced the crude hydroxyglyoxylate (2S g, quantitative) as an amor?hous solid.

~ ~7-~ti81~3 It was used in the next step without further ?urification. ir (CHC13) v : 1770 and 1715 cm ; IHmr (CDC13) ~: 8.1 (2~, d, J=9Hz), 7.;5 max ~3H, d, J=9Ha), 7.3 (19H, m), 5.0-5 ' (2H, bs), 4.3-5.0 (2H, m) and 2.8-3.8 ppm (4H, m).

trans-3-Dhthalimidomethyl-l-(paranitrobenzyl-2'-chloro-2'-acetate)-4-trit~lthio-2-azetidinone O O

O ~ ~ OH O O ~ ~ Cl CO2PN~ 2 To a cooled (ice bath, O~C) solution of -trans-3-?hthai-imidomethyl-l-(?aranitrobenzyl-2'-hydroxy-2'-acetate)-4-tritylthio-2-azetidinone (25 g, 35 mmol) in tel~ahydrofuran !l;o ml) was added dropwise a 1~ solution of thionyl chloride in tetrahvdrofuran (46 ml, 46 mmol) followed by a L~ solution of pyridine in tetrahydrofuran (46 ml, 46 mmol). The reaction mixture was stirred at room tem?e-rature for 20 min, diluted with ?et-ether (50 ml) anc 'iltered ove-a ~ITE~charcoal bed. The solvent was evaporated in vacuo to sive the chloro azetidinone (26 g, quantitative) as an amor?hous solid.
I~ was used in '.he next step wi_hout -urther ?uri-ication. i- (C-.IC.3 ~ma : 1775 and 1720 c~ . l~mr (CDC13) ~: 8.12 (2~, d, J=9H-), 7.60 (2H, d, J=9Hz), 7.3 (19H, m), 5.25 (2H, m), 4.7-5.4 (lH, m), '.55 (lH, bs) and 3.3-4.0 ppm (3H, m).

*Trade Mark -L~ ~~

` ' 12~,8~83 trans-3-phthal~midomethyl-1-(paranitrobenzyl-2'-triDhenylphos?hora-nylidene-2'-acetate)-4-tritylthio-2-azetidinone H H H d A mixture of trans-3-phthalimidomethyl-1-(paranitro-benzyl-2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone (26 g, 35.; mmol), triphenylphosphine (10.25 g, 39.1 mmol) and 2.6 lutidine (4.6 ml, 39.1 mmol) in dioxane (200 ml) was heated at 100C for 20 h.
The reaction mixture was filtered over"~F~,ITE'~and eva?orated. The residue was chromatographed on a silica gel column (350 g) el~ting with benzene to benzene/ether (1:1) to yield the phos?horane 21 g, 62~) as a white solid. ir (C~C13) vmax: 1750 and 1710 cm ~Hmr (CDC13) ~: 7.4 (38H, m), 4.8-5.4 (3H, m), 4.6 (2H, m) and 3.7 p?m (lH bs).

trans-3-?hthalamidomethyl-1-(paranitrobenzyl-2'-tri?henvl?hos?hora-nvlidene-2'-acetate)-4-tritylthio-2-azet-dinone H H ~ H ~ ~ 3 CO~PNB C02PNB

A cooled (ice bath) suspension of trans-3-phthalimi~o-methyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-ace~ate)-4-tritylthio-2-azeticinone (18.02 9, 18.83 mmol) in tet-ahydrofuran (30 ml), water (30 ml) and acetone (30 ml) was treatec dropwise with sodium sulfide (4.97 ~, 20.7 mmol) in acetone/water 1:1 (30 ~1) and heated to reflux for 8 h. The -eaction mixture was cilutec with water, acidified with lN hydr~chloric acid and extracted with dichlo-- 2~-*Trade Mbrk _5~}*~

~.1 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 urification. ir (neat) v : 3150-3600, 1750 and 1700 cm i IHmr max (CDC13) ~: 7.4 (38H, m) and 3.3-5.5 ppm (8H, m).

trans-3-phthalisoimidomethyl-1-(oaranitrobenzyl-2'-triphenylphos-phoranylidene-2'-acetate)-4-tritylthio-2-azetidinone ~3 ~ ~ ~ SC~-3-02:i O N ~ -~3 ~ ~ ~3 .. solution of t-ans-3-phthalimidomethyl-1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (17,1 g, 17,54 mmol) in dichloromethane (125 ml) was treated dropwise at room temperature with N,N'-dicyclohexylcarbodiimide (3.62 g, 17,54 mmol) in dichloromethane (30 ml). ~he solution was filtered over"CELITE" and evaporated to give the ti~le compound (18.23 g, quantitative) as an oil. It was used in the next step without fu-ther puri~ication. ir (neat) V : 2110, 1755 and 1710 cm ; Hmr (CDC13) ~:
7.5 (38H, m), 4.6-5.3 ~4H, m) and 3.9 ppm ~2H, ~s).

*Trade Mbrk 8~

trans-3-aminomethyl-1-(paranitrobenzyl-2'-trip enylphos horanylidene-2'-acetate)-4-tritylthio-2-azetidinone ~= H H 5 Ip H2N~ 3 N ~ P~3 N ~ ~3 02PNB C02PN}3 A solution of trans-3-phthalisoimidomethyl)-1-(parani-trobenzyl-2'-triphenylphosphoranylidene-2'-acetate~-4-tritylthio-2-azetidinone (5.9 g, 6.16 mmol) in tetrahydrofuran (40 ml), cooled to -20C, was treated dropwise under N2 with hydrazine (0.2 ml, 6.16 mmol) and stirring was maintained for 30 min. The reaction mixture was acidified with lN hydrochloric acid and washed with ether; the aqueous phase was basified with lM sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine, dried (MgS04) 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%) of the amino phosphorane as an amor?hous solid.
ir (CHC13) Vmax: 1730, 1710 cm ; I~mr (CDC13) ~: 6.5-8.1 (34H, m), 3.8-5.3 (6H, m) and 0.9-1.9 Dpm (2H, m).

trans 3-formamidomethyl-1-(paranitrobenz~1-2'-triphenvl~hos?hora-nylidene-2'-acetate)-4-tritylthio-2-azetidinone H2N ~ ~ ~3 R ~ SC~3 ~ N ~ ~3 To a cooled (ice bath) solution of trans 3-(aminomethyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (5.0 g, 6.04 mmol) in dichlorome~hane (50 ml) was added dropwise under N2 a solution of acetic formic anhvdride (600 mg, 6.8 mmol) in dichloromethane (5 ml) followed by -2~/---~5S~--a solution of triethylamine (l ml, 7 mmol) in dichloromethane (2 ml).
Stirring was continued for 30 min. The solution was washed successively with lN hydrochloric acid, water, lM 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 the formamide as an amorphous solid. ir (CHC13) vmax: 1740, 1685 and 1620 cm : l~r (C~C13) s: 6.6-8.2 (35H, m), and 2.5-5.3 ppm (7H, m).

trans silver 3-formamidomethyl-1-(paranitrobenzyl-2'-triohenyl~hos-phoranylidene-2'-acetate)-2-azetidinone-4-thiolate H~N ~ ~ 3 HCRN ~ ~ g N ~ P~3 N ~ p~3 C2~NB 2 A solution of trans 3-formamidomethyl-l-(paranitro-benzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio- -azetidinone (550 mg, 0.64 mmol) in dichlorome~_hane (10 ml) was evaporated to dryness and diluted with hot methanol (20 ml). The solution was stirred at 60C and treated with a pre-heated (60C) solution of 0.15 ~ silver nitrate in methanol (5.7 ml, 0.86 mmol) followed by a solution of 1.5 ~ 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 mc ~65~) of the silver salt as a beige solid. It was used in the nexl step without further p`urification.

1~68183 trans 4-acetylthio-3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone 0 ~ ~ P~3 o ~ 3 To a cooled (ice bath) solution of trans silver 3-formamidomethyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone-4-thiolate (800 mg, 1.11 mmol) in dichloromethane (10 mlj was added dropwise under N2 a solution of lM acetylchloride in dichloromethane (1.33 ml, 1.33 mmol) followed by a solution of L~ pyridine in dichloromethane (1.33 ml, 1.33 mmol). ~he solution was stirred in a cold bath 'or 1 h, 2n.d '~2S ~hen ~ilte~ed o~e~ "CELITE". The filtrate was washed successively with lN hydrochloric acid, water, 1.~ soc um bicarbonate and brine and the organic layer was dried (MgSO4) and evaoorated.
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~) o~ the title comoound: ir (CHC13~ vmax: 1755, 1685 and 1620 cm Hmr (CDC13) ~: 8.18 (2H, d, Js9Hz), 7.0-8.0 (20H, m), 6.75 (2H, d, J=9 Hz), 6.3 (lH, m), S.S (lH, m), 5.2 (2H, bs), 4.9 (lH, bs), 3.6 (lH, m), 3.0 (lH, m) and 2.2 oom (3H, two s).

*Trade Mark ~ ~3~
~ .

~2~8183 Daranitrobenzyl 6-for~amidomethyl-2-methylpenem-3-carboxylate p~3 HeN ~ ~ 2 A solution of trans 4-acetylthio-3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-2-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 (C~C13) vmax: 1780 and 1690 c~ ; lHmr (CDC13) ~: 8.2 (2H, d, J=9~.z), 8.2 (lH, s), 7.6 (2H, d, Js9Hz), 6.9 (lH, m), 5.55 (lH, s), 5.35 (2H, 2s), 3.3-4.1 (3H, m) and 2.33 ppm (3H, s).
6-formamidomethyl-2-methylDenem-3-carboxylic acid sodium and potassium salts ~ a and A mixture of paranitrobenzyl 5-formidomethyl-2-methvl-penem-3-carboxylate (80 mg, 0.21 mmol), palladium on"CELITE'~(30%, 100 mg), tetrahydrofuran (10 ml), ether (25 ml) and 0.05 M bu''er 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"C$LlT~"and washed wiLh water.
The filtrate and washings were combined and the Dhases sepa-ated.
The aqueous phase was washed with ether (3 x 15 ml) and lyophyli-ed.

*Trade Mbrk ~~5~~

12~i~318~
- .

The crude solid was purified by hplc to give 18 mg of a mixture of the ~odium and potassium ~alt6.
(H2O) max: 299 ( 4933), 259 (F 4094) ; ir ("NUJOL")*
max: 3100-3650 and 1755 cm 1; lHmr (D2O)~ : 8.15 (lH, 8), 5.53 (lH, d, J=1.4Hz), 4.0 (lH, m), 3.74 (2H, d, ~=5Hz), 3.25-4.25 (lH, m) and 2.27 ppm (3H, 8).
Ex~mple 48 (1'S.5R.6S. and l'R 5S 6R) 6-(1'-Hydroxv-1'-pro~vl)-2-methvl~enem-3-carboxvlic acid. sodium 6alt ri60mer C) ~ ~ ~ 3 co2~a tran6 1-t-Butvldimethyl6ilyl-3-propionyl-4-tritylthio -2-azetldinone~
o ~ 5 + LDA + CH3cH2c-ocH3 ~ ~lMe + -t 2 pROCEDURE:
n-BuLi (37.50 ml, 1. 6M/hexane, 60 =mmol) was added dropwi6e under N2 to a cooled (dry ice-acetone bath) and stirred 601ution of dii60propylamine (8.50 ml, 60 mmol) in dry THF (200 ml). The mixture was 6tirred in the cold and 1-t-butyldimethyl-silyl-4-tritylthio-2-azetidinone (22.9 g, 50 mmol) in dry THF
30 (100 ml) wa6 added. After 15 min, methyl propionate (40 ml, exce66) wa~ added and the reaction mixture wa6 kept at -78 for 4 h. Then the cooling bath wa6 removed and the internal temperature wac allowed to come to OC (-40 min). It wa6 poured over ice-HCl (pH - 6) and extracted with ether. The layers were separated and the aqueou6 layer was extracted with ether. The combined ether 601ution was wa6hed with water and brine and dried *Trade Mark ~ ' , .

(Na2S04). It was evaporated in vacuo to give an oil in quantitative yield. This oontained a mixture of starting material and title compound. It was u~ed a6 such and o purified in the next step. ir (Neat) vmax : 1710 (-C-), 1750 cm~l (B-lactam).

l-t-Butvldimethvl6ilyl-3-(l'-hydroxY-l'-pro~yll-4-tritvlthio-2-azetidinone~

~Sr ~STr PROCEDURE:
A solution of 1-t-butyldimethylsilyl-3-propionyl-4-tritylthio-2-azetidinone (26 g, 50 mmol) and 60dium borohydride (7.6 g, 200 mmol) in THF (400 ml) was stirred at, room temperature for 18 h. It was poured onto ice-HCl (lN) (pH 6) and extracted with ether. The acidic pha6e wa6 extracted 6everal time6 with ether and the combined ether 601ution was wa6hed with brine, drled (Na2S04) and evaporated to give an amorphou6 6elid, 25.0 g. Thi6 crude product was chromatographed on SiO2 (ACT. 1, 400 g) and eluted fir6t with CH2C12 to give 10.8 g of 1-t-butyldimethylsilyl-4-tritylthio-2-azetidinone. Elution with 1~ 20% ether in CH2C12 gave 10.3 g of the title compound a6 a mixture of two isomeric trans alcohols. This was separated by hplc (Water As60ciates, System 500*), and using 10% EtoAc in ; CH2C12 as eluent. Isomer C, white solid, 3.8 g; mp (pet. ether) 134-36C. 1Hmr (CDC13)~ : 7.1-7.8 (lSH, m, STr), 4.35 (H, d), 3.1 tH, dd), 2.5 (H, m), 0.7-1.7 (5H, m), 0.97 (9H, 6) and 0.25 ppm (6H, 6). Anal. calcd for C31H39N02SSl: C 71.91, H 7.59, N 2.71;
found: C 71.51, H 7.60, N 2.96. lsomer B, white 601id, 5.4 g; mp (pentane-pet. ether) 97-99C. 1Hmr (CDC13) ~ : 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, 6) and 0.1 ppm (6H, 8).
*Trade Mark 1~68~

97-99C. lHmr (CDC13 ) ~: 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m~, 0.7-1.7 (5,H, 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%.

rl'S 3S 4R and l'R 3R,4S~
l-t-~utvldimethylsilvl-3-(l~-~aranitrobenzvldigxycarbonvl-l'-pro~yl)-4-tritylthio-2-azetidinone ~isomer C).

OH ~o2p~3 J""'n~S~r + c C02PNB ~ ;~STr ~ N~ si~e2 ~ SiMe2 PROCEDURE:
To a cooled (dry ice-acetone bath) solution of (l'S,3S, 4R and l'R,3R,4S) 1-t-butyldimethylsilyl-3-(l'-hydroxy-l'-propyl)-4-tritylthio-2-azetidinone (isomer C) (3.1 g, 6 mmol) in dry THF (20 ml) was added dropwise under N2 a solution of 1.6M
n-BuLi/hexane (4.88 ml, 7.8 mmol) stirred at -78C for 25 min Paranitrobenzyl chloroformate (1.56 g, 7.2 mmol) in dry THF (10 ml) was then added dropwise and the resulting mixture was stirred at -78C for 4 h. It was diluted with ether and washed with NH4Cl solution brine. The organic phase was dried (Na2SO4 ) and evaporated to dryness to give 4.2 g of title compound (Quantative yield). 1Hmr (CDC13) ~:
8.2 (2H, d), 7.0-7.7 (17H, m), 5.13 (2H, s), 4.05 (H, d), 3.75 (H, dt), 3.25 (dd), 0.55-1.8 (5H, m), Q.9 (9H, s) and 0.25 ppm (6H, d).

~2~

(l'S.3S.4R and l'R 3R.4S~ 3~
paranitrobenzyldioxycarbonyl-l'-propyl) -4-tritylthio-2-azetidinone (isomer C) ~,J~ ~ ~ STr ~J.. ,_~ STr + HMPT + NaN3 ~ l l S~e2 (10~ H20) ~ ~H

PROCEDURE:
To a cooled (ice bath) solution of (l'S,3S,4R and l'R,3R,4S) l-t-butyldimethylsilyl-3-(1'-paranitrobenzyldioxy-carbonyl-l'propyl)-4-tritylthio -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 temperature for 1 h.
It was diluted with water (100 ml) and extracted with benzene: pet. ether (1:1) (4 x 15 ml). The organic phase was washed several times with water (6 x 30 ml) and brine. It was dried (Na2SO4 ) 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 84-86C; lHmr (CDC13) ~: 8.2 (2H, d), 7-7.7 (17H, n), 5.2 (2H, s), 4.95 (H, dt), 4.4 (NH), 4.25 (H, d), 3.4 (H, dd), 1.7 (2H, m) and 0.95 ppm (3H, t).

12~i818~

(l'S,3S,4R and l'R,3~,4S) 3-~1'-paranitrobenzvldioxYcarbonyl~
propyl)-l-(paranitrobenzyl 2"-hyd-oxy-2"-hydroxv-2"-acetate)-4-tritvlthio-2-azetidinone tisomer C).

~CO PNB

J ~ STr THF ~", ~ STr N ~ PNB glyoxalate TE~ ~

PROCEDURE:
To a solution of (1'5,3S,4R and l'R,3R,4S) 3-(1'-paranitro-benzyldioxycar~onyl-l'-propyl)-4-tritylthio-2-azetidinone (isomer C) (3.2 g, 5.5 mmol) and paranitrobenzyl glyoxylate hydrate (1.362 g, 6 mmol) in dry THF (50 ml) was added a catalytic amount of TEA
(4 drops) and Na2SO4 (to absorb H20 formed). The resulting mixture was stirred at room temperature for 6 h. It was filtered and evaporated to dryness to give 4.35 9 of an amorphous solid ~uar.-titati~e ~ield). 1Hmr (CDC13) ~: 8.25 (4H, dd), 7-7.9 (19H, m), 5.28 (2H, s), 5.1 (2H, s), 4.8 (H, d), 4.4 (H, dd), 4.1 (H, dt), 3.4 (H, m), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t).

(l'S,3S,4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxYcarbonyl-l'-2roDyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate(-4-~_itylthio-2-a7etidinone (isomer C) STr J .~ J STr Py/THF
- N ~ OH SOC12/THF D o~N ~C
O P~B
2 C32P~3 PROCEDURE:

To a cooled (ice salt bath) solution of the aDove slyoxylate (4.35 g, 5.5 mmol) in dry THF (30 ml) was added L~ py/T~F (7 ml, 7 mmol) followed by dropwise addition of L~ SOC12/THF (7 ml, 7 mmol). ~e .e--2~9_ --sulting mixture ~as sti-red at the ~bove-indicated te~perature ror 1 h.
It was diluted with benzene (30 ml), stirred in the cold (ice water bath) for 30 m n and filtered over~cELITE~-charcoal~ The filtrate was evaporated to dryness to give 3.8 g of an amorphous solid (85.3~ mr (CDC13) ~: 8.15 (4H, d), 6.75-7.7 ~19H, m), 5.65 (H, s), 5.2 t2H, s), S.l (2H, s), 4.5 tH, m), 3.85 (H, m), 3.4 (H, m), 1.25-2.0 (2H, m) and 0.9 ppm (3H, t).

(1'5,35,4R and l'R,3R,45) 3-(1'-Daranitrobenzyldioxvcarbonyl-l'-propyl)-l-(paranitrobenzyl 2"-tri~henylphosshoranylidene-2"-acetate) -4-tritylthio-2-azetidinone (isomer C) ' J ~ ~3p ~ ., ~ ST-o ~ N y Cl lutidineO ~ ~ ~ P~3 PROCEDU~E:
To a solution of the above chloro compound (3.7 g, 4.568 mmol) in dioxane (35 ml) was added ~3P (1.197 g, S mmol) and lutidine (0.54 g, 5 mmol). The mixture was heated in an oil bath at 100 C for 3 days. It was cooled, diluted with ether and washed successively with lN HCl, LM NaHCO3 and brine.
It was dried (Na25O4) and filtered over Celite-charcoal. T~e filt-ate ~as evaporated to dryness to give 3.6 g of an oil.
This was chromatographed on SiO2 (120 g) and eluted with benzene, benzene-ether to give 1.4S g of title compound as an amorphous solid (31~); ir (neat) vmax: 17S0 cm (broad).

*Trade Mark -LC~-~; -. . ~, tl~S.3S 4R and llR 3R 4S~4-acetylthio-3-~l'~aranitrobenzvldioxycarbonyl-l'-propyl)-l-(paranitrobenzyl 2"-triphenyl~hosphoranvlidene ~ -acetate~-2-azetidinone ~isomer C) 2 B ~CO2pNs 2 5~r AgN03~J,. ~ SAg C~3~Cl `J ~SAc C~N~F~3 Py/MeOH J-- ~ o~N ~P~3 PROCEDURE:
To a hot solution (60C) of the above phosphorane (1 4 g, 1.35 mmol) in MeOH (40 ml) was added with stirring a hot solution of AgNO3 (0.3 g, 1.76 mmol) in MeOH (10 ml) followed by pyridine (0.107 g, 0.11 ml, 1.76 mmol). The silver mercaptide began to precipitate immediately. The mixture was stirred at room temperature for 15 min and at OC for 2 h. It was filtered, and the solid washed well with cold MeOH and ether, 1.2 g (quantitative yield); mp 113-115C (d); ir("NUJOL")*. vmax : 1740-1760 cm~l ~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 (0.118 g, 0.107 ml, 1.5 mmol) in CH2C12 (2 ml) followed by pyridine (0.119 g, 0.122 ml, 1.5 mmol) in CH2C12 (2 ml). The mixture was stirred at 0C for 30 min. It was filtered over "CELITE"* to remove silver salt and the filtrate was washed successively with HCl (0.5N), H2O, NaHCO3 (0.5 M) and brine.
The CH2C12 solution was dried (MgSO4) and evaporated to dryness to give 0.94 g of title compound as an amorphous solid. (83.4%) ir (neat) vmax: 1750 cm~l (broad).

*Trade Mark 81~3 . ~ .

(l'S,5~,6S and l'R,SS,6R) paranitrobenzyl 6-(1'-paranitrobenzyldioxy-carbonyl-l'-propyl)-2-methylpenem-3-carboxylate (isomer C) CO2P B O~CO2PN~

~3 ~ ~ CH3 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 dis~illed off. Thç 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 SiO2 tACT 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) 160-162C; IHmr (CDC13) ~: 7.3-8.4 (8H, m, aromatic), 5.4 ~H,d), 5.3 ~4H, benzyls, m), 5.0 (H, dt), 4.0 (H, dd), 2.35 (6H, s), 0.8 (2H, dq) and 1.0 ppm (3H, t).

(l'S,SR,6S and l'R,SS,6R) 6-(1'-hydroxy-1'-prooyl)-2-methylpenem-3-carboxylic acid (isomer C), sodium salt.

... ~ S ~ H /Pd-"rF~ITE" ~O ~ ~ ~ CH3 ~ ~ phosphate O N ~
PROCEDURE: \CH3 buffer - +
A mixture of the above ester (48 mg, 0.086 mmol) and 30~ Pd-Celite (100 mg) in THF (10 ml), Et2O (20 ml), H2O (10 ml) and phosphate buffer (pH7, 2 ml) was hydrogenated at an initial pressure of 50 psi for 23 h. It was _iltered over "CELITS'~and the layers separated. The organic layer was washed with H2O (2 x 5 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 (~-lactam), and 1600 -1650 cm (broad, -CO2 ); uv ~ a : 258 (~ 1105) and 305 (~ 1244).

l~i8183 Exampl e 4 9 (1'R 5R 6S and l'S 5S 6R) 6-~l'-HYdroxv~ ro~vl)-2-methvl~enem -3-carboxvlic acid. sodium and Dotassium salts (isomer B) ~ cs3 (1'R 3S 4R and l~S.3R 4S) 1-t'-ButYldimethylsilyl-3-(1'-formYloxv -1'-propyl)-4-tritylthio2-azetidinone (isomer ~l.
OH HCO2H, Et3N OCHO Tr ~J. ~ STr DMAP, AC20 'J n~5 ~SiMe2 C~2Cl2 . SiMe2 4-Dimethylaminopyridine (DMAP) was prepared according to a) H.C. Brown et al. Org. Synth. Collect. Vol. 5, 977 (1973) and b) Helmet Vorbruggen et al. Angew. Chem. Int. Ed., 17, 569, (1978).
PROCEDURE:
To a cooled (0C) solution of (l'R,3S,4R and l'S,3R,4S) 20 1-t-butyldimethylsilyl-3(1'-hydroxy-1'-propyl)-4-trityl-thio-2-azetidinone (isomer B) (3.612 g, 7 mmol) in CH2Cl2 (50 ml) was added Et3N ( 4.48 ml, 35 mmol). HC02H (0.63 ml, 16.8 mmol) and DMAP (0.854 g, 7 mmol) followed by dropwise addition of acetic anhydride (7.14 g, 7 mmol). The yellow solution was 6tirred at -40C and milky mixture. It wa6 poured onto ice-lN
HCl (pH 6) and the layers were 6eparated. The CH2C12 solution was washed with lM NaHC03 and brine. It was dried (Na2S04 ) 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 125-27C; ir (neat) vmax: 1720 (H-C) and 1750 cm 1 (B-lactam); 1Hmr (CDC13) ~: 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, 35 m), 0.95 (9H, 8), 0.8 (3H, t) and 0.1 ppm (6H, s); Anal. calcd for C32H39N03SSi:C 70.42; H 7.20; N 2.57; found: C 70.20; H
7.33, N 2.73.

(l'R,3S,4R and l'S,3R,45) 3-(1'-formyloxy-1'-propyl)-4-tritylthio-2-azetidinone (isomer B) OCHO OCHO
J ~ STr ~ . ~ Tr ~ ~ SiMe2 + NaN3 10% H2O O ~ ~ H

PROCEDURE:
To a cooled tice bath) solution of (3.7 g, 6.77 mmol) in HMPT (40 ml) containing 10% H20 was added NaN3 (0.91 g, 14 mmol).
The mixture was stirred at room temperature or 1.5 h. It was ~oured onto ice water (200 ml) 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 (Na2504) and evaporated to dryness to give 2.92 g of a thic colorless oil. (~ua~.-~ tati~e ~ield). lH~nr (CDC13) ~: 8.1 (H, H-C-,S), 7.1-7.7 (lSH, m, -STr), 5.23 (H, m, J=7), 4.38 (H, d, J=2.5), 4.3 (H, -~H), 3.35 (H, dd, J=2.5, J=7), 1.75 (2H, m) and 1.0 ppm (3H, t).

(l'R,35,4R and l'S,3R,45) 3-(1'-formyloxy-1'-ethvl)-1-(Paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidlnone (isomer ;3) J CHO STr OC~O STr PNB GLYOXYLATE ~
H Et3N/THF O ~ OH

PROCEDURE:
A mixture of 3-~1'-formyloxY-1'-propyl)-4-tritylthio-2-azetidinone (isomer B), (2.9 g, 6.77 mmol), PN3 gi~-xyla~e (1.59 g, 7 mmol), Et3N (S drops) and Na2S04 (anhydrous, 5.0 g) in T~F (50 ml) was stirred at room temperature for 18 h. It was filtered and evaporated to dryness to give an amor?hous solid in au2rt_t2zi~-yield (4.33 g); ~Hmr (CDC13) ~: 8.2 (2H, d), 7.1-7.8 (18H, m), 5.2 -2G~-~--i8183 (2H, d), 4.9 (H, m), 4.65 and 4.3 [H, 4.65 (1/2 H,s) 4.3 (1/2 H, s)], 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-1'-propyl)-1-(~aranitrobenzyl 2"-chloro-2"-acetate)-4-tritvlthio-2-azetidinone l isomer B) OC~O OC~O
J,F~SSr SOC12/THF ~J ;~cr ST~

CO2PN~ cO2~NB

PROCEDURE:
To a cooled (ice salt bath) solution of the above glyoxylate (4.3 g, 6.77 mmol) and lM Py/THF (8 ml, 8 mmol) in dry THF (30 ml) was added dropwise lM SOC12 /py (8 ml, 8 mmol). The resulting solid mixture was stirred at the above temperature for 1 h. It was diluted with benzene (30 ml) and stirring was continued for 20 min. It was filtered over "CELITE"*- charcoal and the filtrate was evaporated to dryness to give 4.1 g of an amorphous solid (92%). ir (neat) O O
max : 1720 (H-C-), 1750 (-C-OPNB) and 1780 cm~l (~-lactam); lHmr (CDC12 ~: 8.25 (2H, d), 7.8 (H, s, H-~-), 7-7.75 (17H, m), 5.25 (2H, d), 5.0 (H, m), 4.6 -(H, s), 4.4 (H, d), 3.7 (N, m), 1.6 (2H, m) and 0.9 ppm (3H, t).

*Trade Mark ~2i~

~l'R,35,4R and l'S,3R,4S) 3-(l'-formyloxY-l~-~ro~yl)-l-(paranitroben 2"-tri?henylphosphoranylidene-2"-acetate)-4-tritvlthio-2-azetidinone (isomer ~) OCHO OCHO
STr 03P dioxane ~ ~ ~ STr lutidine o ~ ~ P~3 PROCEDURE:
_ A mixture of t~e above chloro compound (4.0 g, 6.01 mmol) ~3P (1.834 g, 7 mmol) and lutidine (0.749 g, 7 mmol) in dioxane (40 ml) was heated at 100C (oil bath) for 2 days. It was cooled, diluted with ether and washed successively with cold solution of lN HCl, lM NaHCO3 and brine. The organic solution was dried (Na2SO4) and filtered over "OELITE"-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) v : 1720 (H-C-O-), and 1750-1760 cm (-C02PNB and R-lactam).

(l'R,35,4R and l'S,3R,45) 4-acetylthio-3-(1'-~ormyloxy-1'-propyl)-1-(paranitrobenzyl 2"-triphenylphos~horanylidene-2"-acetate)-2-azetidinone (isomer B).

~OCHO O,CHO OCHO

O ~ ~ 3 ~ ~
; 2 CO2PNB CO2PN3 PROCrDURE:
A warm solution (60C) of 0.15 M ~sNO3-C~3CE (8.7 ~1, 1.3 mmol) was added to a mixture of the above phosphorane (0.88 g, 1 mmol) and pvridine (0.103 g, 1.3 mmol) in MeOH (S ml) warmed -L~ ~
*Trade Mark -~S1~-~2~i818~

to 60C. The mixture was stirred at room temperature for 15 min and at OOC 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 CH2Cl2 (10 ml) was added dropwise CH3COC1 (0.079 g, 1 mmol) in CH2Cl2 (S ml). After stirring at 0C for 1 h, it was filtered. The filtrate was washed well with a cold solution of 0.SM HC1, 0.SM NaHCO3 and brine. It was dried (Na2SO4) and evaporated to dryness to give 0.43 g of an oil. (63%); ir (neat) max:
1700-1760 cm 1 (broad -C and B-lactam).
(1'R.3S 4R and l'S.3R 4S) and acetylthio-3-(l'-hydroxy -l'-pro~vl-l-(~aranitrobenzyl 2~'-tri~henyl~hos~horanylide -2"-acetate~-2-azetidinone (isomer B) OCHO IOH
J~ n~ HCl/MeOH ~ ~ SAc 0,~ N~ P~ 3 N ~P~ 3 ~ROCEDURE:
The above formate (1.0 g, 1.45 mmol) in THF (10 ml) was treated at room temperature with HC1/MeOH (10 ml, prepared from 2 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 lM NaHCO3, extracted with EtOAc solution, washed with brine and dried tNa2SO4 ). It was evaporated to give 0.9 g of crude title compound. This wa~ chromatographed on SiO2 and eluted with ether and ether: EtOAc (1:1) to give 0.6 g of pure title compound as an amorphous solid (62.5%); 1Hmr (CDC13)~ :
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), l.S (2H, m) and 0.9 ppm (3H, t).

12~i~318~

(llR~sR~6s and 1'5,55,6R) Daranitrobenzyl 6-~1'-hvdroxy-1'-orooyl)-2-methylpenem-3-carboxylate (isomer B).

O ~ 3 PROCEDURE:
The above phosphorane (0.2 g, 0.3 mmol) in toluene (45 ml) was heated to reflux and 5 ml of toluene was distilled off.
The resulting solution was refluxed for 6 h. It was cooled and evaporated to dryness to give 0.2 g af an oil. This was chroma-tographed on SiO2 and eluted with ether to give 0.1 g of title compound as a white solid. (87~); mp (pentane) 133-135C; IHmr (CDC13) ô: 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, CH3), 2.2 (H, OH), 1.7 (2H, m) and 1.05 ppm (3H, t).

(l'R,5R,6S and 1'5,5S,6R) 6-1'-hydroxy-1'-oroDvl)-2-methyl?enem-3-carbox-~lic ac id (isomer 3), ~z'xed K an~ na salts JOH ~ H

CO2PNB 2 (Na~) PROC_DURE:
A mixture of the above ester (0.07 g, 0.185 mmol), 30%
PdJ~CELITE"(150 mg) ancd buffer solution (pH 7, 4 ml) in THF (15 ml, Et2O (25 ml) and deionized water (15 ml was hydrogenated at an initial pressure of 48 psi for 4 h. It was filtered over Celite and the layers were separated. The aqueous layer was washed with ethylacetate and then lyophilized to give 91 mg of a solid;
~r (K3r) v x 1780 (~-lactam) and 1650 cm 1 (broad, -CO2 ); uv H O ~ : 255 (~ 983) and 300 (~ 1092).
2 max *Trade Mark ~~J~-l~t~8~

5~
Ex~m~le ~
(l'R,5~,6S and 1'5,55~6R) 6-(1'-Hydroxy-2'-~henylethyl)-2-m.et.~.yl~enem-3-carboxylic acid (isomer 3) H. ,PH
~ ;;~,~
~ N ~ 3 trans l-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio-2-azetidinGne ~Tr + LDA + QCH C0 Et ` ~ ST_ N - SiMe2 2 2 0 N ~ e2 l-t-Butyldimethylsilyl-4-tritylthio-2-azetidinone (18.32 g, 40 mmol) in dry THF (100 ml) was added dropwise under N2 to a cooled (-78C) LDA solution [prepared under N2, at -78C from dropwise addition of 1.6 ~ n-BuLi (101.25 ml, 162 mmol) to diisopropyl amine (22.95 ml, 162 mmol) in dry THF (1;0 ml) and stirred at -78C ~or 30 min~. The mixture was stirred at -78"C ~or 30 min and e hyl phenylacetate (15.66 g, 15.12 ml 15.12 ml, 93.6 mmol) in dry ~'E~ (50 ml) was added and the reaction mixture was stirred at -78C for 2 h. It was poured onto ice-lN HCl (pH 5-6) and extracted with ether several times. The ether solution was washed with brine and dried (Na2504). r I was evaporated to dryness to give 33.7 g of a c-ude soli~. This was dissolvecd in ether (10 ml) and triturated with pentane (200 ml).
The solid was filtered and washed several times with _entane to give 18.3 g or a white solid (79.63) mp 141-143. I,~m~r (C3C13 A
7.0 - 7.6 (20H, m), 4.a (H~ d), 3.7 (H, d), 3.53 (H, s), 3.43 (H, s) 1.5 (9H, s) and 0.3 ppm (6H, s).

_L~,q_ lX68183 l-(t-butyldimethylsilyl-3-(1'-hydroxy-2'-phenylethyl) -4-tritylthio-2-azetidinone ~2 trans diastereomers).
OH
~ ~ STr ~ ~ ~Tr o ~ 2 N -~iMe2 trans 1-(t-butyldimethylsilyl)-3-phenylacetyl -4-tritylthio2-azetidinone (28.8 g, 50 mmol) and NaBH4 (0.5 g, 0.25 mole) in THF (200 ml) were stirred at room temperature for 18 h. The mixture was poured onto ice-lN HCl and extracted with CH2C12. The CH2C12 solution w~s washed with brine and dried (Na2SO4 ). It was evaporated to give an amorphous solid (27.7 g). A portion of the solid (23.0 g) was chromatographed on SiO2 and eluted with hexane: ether to give off-white solid (14.4 g) which was found to be a mixture of (l'R,3S,4R and l'S,3R,4S) and (l'S,3S,4R and l'R,3R,4S) isomers in the ratio of 1:1 (60~). 1Hmr (CDC13) ~: 7-7.7 (20H, m), 4.37 (1/2H, d), 4.18 (1/2H, d), 3.3-3.8 (H, m), 3.45 (1/2H, dd), 3.1 (1/2H, dd), 2.7 (2H, m), 0.87 (9H, d) and 0.25 ppm (6H, s).

1-(t-butyldimethylsilYl~-3-(1'-formyloxy-2'-phenylethvl) -4-tritylthio-2-azetidinone o ON ~ H ~ HO STr O ~

0 ~ 2 ~ - ti.~e2 N- ~e2 isomer 3 isomer c To a cooled (-40C) solution of the above mixture of alcohols (14.4 g, 24.9 mmol) in CH2C12 (250 ml) was added Et3N (15.93 ml, 125 mmol), HCO2H (2.24 ml, 59.76 mmol) and DMAP (3.04 g, ~268183 24.9 mmol) . After stirring for 5 min acetic anhydride (2.
35 ml, 249 mmol) was added dropwise. The clear solution was stirred at -40C for 15 min whereby it turned into a white cloudy mixture. It was kept at -40C for another 45 min (total time 1 h). It was poured onto ice-lN HCl, and the layers separated. The CH2C12 solution was washed well with cold lN HCl,H20, lM NaHC03 and brine. It was dried (MgS04 ) 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 172-73C and "Isomer C" 6.0 g mp 188-89C. Total yield of pure compound 12.0 g (73.2%).
Isomer C: lHmr (CDC13) 6: 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 (9H7 8) and 0.2 ppm (6H, s). Isomer B: lHmr (CDC13) ~: 7.75 (H, B) ~ 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-(1'-formYloxv-2'-phenvlethvl)-4-tritvlthio-2-azetidinone (l'R.3S.4R ~nd l'S.3R.4S enantiomers~
,~OCHO

~N--SiMe2 o~N b I somcr 3 To a cooled (ice bath) solution of the above formate (5.9 g, 9.375 mmol) ~n HMPT containing 10~ water (50 ml) was 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 (Na2S04 ) and evaporated to give a solid residue. This was treated with *Trade Mark ~.~

~ 2~2a i ~

petroleum ether and filtered to give 4.4 g of a white solid (92~) mp 169-71C. Anal. calcd for C31H27N03S: C 75.43, H 5.51, N 2.84; found: C 7504, H S.64 N 2.78. 1Hmr(CDCl3)~ : 7.9 (H, 8), 7.1-7. 6 (20H, m), 5. 4 (H, m), 4. 6 (H, NH), 4. 2 (H, d), 3.3 (H, 5 dd), 3. 15 (H, 8) and 3.0 tH, 8).

3 - ( 1' -formvloxv-2'-phenvlethyl)-l-(paranitrobenzvl 2"-hvd~oxy-2" a~.~tate) 4-tritvlt~io-2-azetidinone ( 1' R.3S, 4R and 1' S, 3R. 4S enantiomers) C02~NB

A suspension of PNB glyoxylate (2.37 g, 10.16 mmol) in dry benzene (100 ml) was refluxed under a Dean Stark apparatus (packed with molecular sieve 3~) for 2 h. Then the above N-H compound (4.2 g, 8.537 mmol) was added and refluxing continued for 1 more h, It was cooled to room temperature Et3N
(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 quantltative yield as a mixture of two isomeric alcohols, 1Hmr (CDC13)6 : 8.0-8. 3 (2H, two doublets), 7.5 and 7.6 (H, two singlets), 7.0-7.4 (20H, m), S.25 (2H, d), 4.9 (H, OH), 4.25 and 4.35 (H, two doublets~, 3. 5-4.5 (H, m, broad), 3. 1- 3. 3 (H, m) and 2.9 ppm (2H, m).

, ~ .

~2~i81~
, 3-(1'-formyloxy-2'-phenylethyl)~ aranitxobenzY1 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (1'R.3S.4R and l'S.3R.4S
enantiomers) H OCHO H OC~10 ;Tr ~STr ~N ~fOH

To a cold (ice salt bath) ~olution of the above glyoxylate (6.0 g, 8.537 mmol) in dry THF (30 ml) was added a lM solution of pyridine in THF (10 ml, 10 mmol) followed by the dropwise addition of a lM solution of thionyl chloride in THF (10 ml, 10 mmol). After 1 h at the above temperature was diluted with benzene (30 ml) and stirring wac 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%): 1Hmr (CDC13) : 8.2 (2H, m), 7-7.7 (23H, m), 5.8 (H, s), 5.25 (2H, s), 4.35 tH, d), 3.5-4.0 (H, m), 3.3 (H, m) and 2.9 ppm (2H, d).
3-(1'-formyloxv-2'-phenYlethvl)-1-(Daranitrobenzyl 2"-tri~henvl~hos~horanvlidene-2"-acetate)-4-tritYlthio -2-azetidinone (1'R.3S.4R and lS.3R.4S enantiomers).

~ ~r~ST-N~Cl N

35 A mixture of the above chloro compound (6.0 g 8.333 mmol), ~3P
(2.489 g, 0.5 mmol) and lutidine (1.0165 g, 1.1 ml, 9.5 mmol) *Trade Mark 2~i81t~;~

in dioxane (50 ml) was heated at 110C (bath temp) for 18 h.
It was cooled and filtered over "CELITE". The ~iltrate -~as diluted with ethyl acetate and washed with cold lN HCl, H2O, lM
NaHCO3 and brine. It was dried (Na2SO4) and evaporated to give 8.0 g of a crude product. This was chromatographed on SiO2 and eluted with ether: hexane (1:1) and ether to give 4.0 g of the title compound. mp (needless from ether) 235-37C (d). (S1~);
ir (film) Vmax: 1720, 1750 cm 4-aGetvlthio-3-(1'-'ormyloxv-2'-Dhenylethyl)-1-(parani~-obenzyl 2"-t~i~henylphosphoranylidene-2"-acetate)-2-azetidinone (l'R,35,4R
and l'S,3R,45 enantiomers) OCHO ~ ~ ~ SAg ~8AC

O ~ 3 O N ~ 3 To a refluxing solution of the above ?hosphorane (3.6 5, 3.8 mmol) and pyridine (0.33 g, 4.2 mmol) in CH2C12 (30 ~1) and ~eOH
(30 ml) was added 2ropwise a 0.15M AgNO3/MeOH solution (28 ml, 4.2 mmol).
The mix.ure was stirred at room temperature for 2.15 h. It was concentrated to a small vol~me (_10 ml), cooled and filtered to cive the silver mercaptide as a yellow solid (2.3 g, 77~). This mer_aptide and pyridine (0.277 g, 3.5 mmol) in ice-cold (CH2C12 (20 ml) was treated dropwise with CH3COCl (0.27 g, 3.5 mmol) in CH2C12 (5 ml).
The mixture was stirred at room temperature for 3 h. Tt was 'iltered over Celite and the filtrate was washed with cold lN HCl, H2O, L~
NaHCO3 and brine. It was dried (MgSO4) and eva?orated to dr-fness to give 1.0 g of an amorphous solid (89.8~ Hmr (CDC13) ~: 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).

*Trade Mark ~ Z`7 ~2~i8~

4-acetylthio-3-(1'-hvdroxy-2'-~henylethyl)-1-(paranitrobenzvl 2"-triphenylphosphoranylidene 2"-acetate)-2-azetidinone (l'R,3S,4R
and l'S,3R,4S enantiomers).

OCNO SA ~ OH SA

N ~ P~3 ~ 3 CO PNB

A solution of the above phosphorane (1.8 g, 2 416 mmol) in THF (10 ml) was treated with lN 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 lM NaHC03 and extracted with CHC13. The CHC13 solution was dried (~gS04) and evaporated to give 1.65 g of an amorphous solid. This was chro-matographed on SiO2 and eluted with ether: ethyl acetate to give 1.30 g of the title compound (75~ Hmr (CDC13) ~: 8.2 (2H, d), 6.7-8.0 (22H, m), 4.0-6.0 (5H, m), 2.5-3.5 (3H, m) and 2.2 ppm (3H, SAc).

paranitrobenzyl 6-(1'-hydroxY-2'-phenylethyl)-2-methylpenem-3-carboxylate (l'R,5R,6S and l'S,5S,6R enantiomers) SAc ~N_ ~ 3 N ~ SAc 2 A solution of the above phosphorane (1.2 g, 1.67 ~mol) in toluene (80 ml) was heated to reflux (10 ml was distilled of~
to remove moisture and low boiling point _olvent present) ~or 6 h.
It was evaporated to cryness and the crude product was chromato-graphed on SiO2. The title compound was obtained by eluting the column with ether to give 0.65 g of amorphous solid (89~ Hmr -2 ?~-12`8183 (CDC13) ~: 8.2 ~2H, d), 7.6 (2H, d), 5.4 ~H, d), 5.2-5.4 (2H, d), 4.0~4.5 tH, m), 3.7-4.0 (H, dd), 3.0 (2H, d) and 2.3 ppm (3H, s).

6-(1'-hvdroxy-2'-Dhenylethyl)-2-methylpenem-3-carboxylic acid (l'R,SR,65 and l'S,55,6R enantiomers) CA 3 ~ ~N ~ 3 2 C~2H

A mixture of the paranitrobenzyl ester (0.33 9, 0.75 mmol), 0.05 M guffer solution (pH 7, 17.4 ml), THF (30 ml), Et20 (30 ml), distilled H20 (60 ml), and 30% Pd~cELITE~o.69 g) was hydrogenated at an initial pressure of 50 psi for 24 h. It was filtered over Celite and the organic laver washed with water.
The combined water layer was washed several times with EtOAc and it was lyophilized for 18 h to give the title compound as a yellow solid salt. This was treated with a small amount of water, acidified with cold 1~ HCl and extracted well with CHC13. m e CHC13 solution was dried (MgSO4) and evaporated to give a solid residue. This was treated with ether and filtered to give 30 mg of a white solid (13.2~), mp 165-167C; ir("NUJOL")v a : 3580 (OH, Sharp), 1660 and 1760 cm ; uv (MeOH) ~max 310 (~ 5490) and 254 (c 4880).

Mbrk -~iS-- 2?--12~i8~
. .

Exam~le 51 4'R 5R.6S and 4'S.5S.6R) 6-(2'.2'-Dimethyl-1'. 3'-dioxolan -4'-vl)-2 methvlpenem-3-carboxvliç ACid (isomer C) ~... , s o _~

A. PREPARATION OF

~ ~ STr ~ " ~ STr 0 Si~ and Si~

(4'R,3S,4R and 4'S,3R,4S) and (4'S,3S,4R and 4'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(2~,2'-dimethyl-1'-,3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone ("Isomer C" and "Isomer B") l~i81~

Ethvl 0-(2-methoxy-2-oropyl)glycolate ) POC13 ~ 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, 3S mg, 0.23 mr..ol) and the mixture was stirred at 0-5 for 15 min and at room temperature Cor 1.5 h. This was then auenchec. with pyridine (30 drops), stirred 45 min and the solvent evaporated. The residue diluted with pentane (150 ml) was dried over R2CO3. After filtration, the solvent was evaporated yieldin5 27.89 g (0.158 mol, 100%; 94.9% pure) of the title compound as a colourless oil:
Hmr (CC14) ~: 1.25 (3H, t, J=7Hz -CH2CH3), 1.28 (6H, s, Me2), 3.12 (3H, S, -OCA3), 3.88 (2H, s, -OCH2CO-), 4.10 (2H, q, J=7Hz, -CH2CH3);
ir (neat) V : 1760 and 1735 cm (ester).
1) J. Meinwald Q~ o~., Tet. Lett., 4327 (1978) 2) ~.S. Ne~man and M.C. Vander Zwan, J. Org. Chem.,38, 2910 (1973).

(3S,4R and 3R,45) 1-(t-Butyldimethvlsilyl)-3-(1'-keto-2'-(2"-methoxy-2"-iso~ropyloxy)-1'-ethyl)-4-tritylthio-2-azetidinone ~ STr 1) LDA/THF ~ X ~ "" ~

O ~ ~ Si/ 2) ~ Et 3 ~ ~Si/

To a stirred solution of diisopropylamine (18 5 ml, 0.134 mol) in THF (400 ml; rreshly distilled from L~H~ at -78C
was added n-butyllithium (1.6M in hexane, 90 ml, 0.144 mol) under _ 7~ ~

12~i~18~3 N2 atmosphere. After 30 ~in, a solution of l-(t-butyldimethylsilyl) 4-tritylthio-2-azetidinone (50.0 g, 0.109 mol~ in T~F (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 NH4Cl solution (200 ml) was added followed by brine (100 ml). The aqueous phase was extracted with Et2O (3 x 100 ml). The combined organic extracts were washed with brine, dried (Na2SO4) 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 sam?le was obtained by column chromatography (SiO2, eluent: 2~ Et2O in benzene);
Hmr (C~C13) ~: 0.30 (6H, s, Si-CH3), 0.95 (9H, s, t-Bu), 1.12 (3H, s, CH3), 1.15 (3H, s, CH3), 3.15 (3H, s, OCH3), 3.57 (lH, A of AB, J

17Hz), 3.77 (lH, d, J=1.6Hz, H-3), 3.97 (lH, B of AB, J =17Hz), 4.83 (lH, d, J=1.6Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs); ir (neat) ~ :
1750, 1725, 1710 cm (C=O); tlc, Rf 0.53 (benzene; Et20=4:1), Rf 0.61 (hexane: EtOAc = 2:1).

(35,4R and 3R,45) 1-(t-;3utyldimethylsilyl)-3-(1'-hydroxy-2'-methoxv-isopropyloxyethyl)-4-tritylthio-2-azetidinone (mixture of epimers at C-l') ~s i ~ S i>C

A solution of crude l-(t-butyldimethylsilyl)-3-(1'-~eto-2' (2"-methoxy-2"-isopropyloxy)-1'-ethyl)-4-trityl~hio-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 0C NaBH4 (4.88 g, 0.156 mol). The ~ixture was stirred at room temperat~re for 2 h and quenched bv slow addition of brine (280 ml). The mixture was extracted with Et2O (3 x lSO ml) and the extracts were washed with brine, dried (Na25O4) and evaporated to yield a yellow residue which was redissolved in CH2C12 (500 ml). This was dried (Na25O4) again and evaporated yielding 57.1 g (0.0966 mol, crude yield 93.8~) of the title compound as a crude yellow foam: Hmr (CDC14) ~: 0.17 (s, SiCH3), 0.80, 0.87 (2s, Si-tBu), 1.22, 1.25 (2s, CH3), 3.03 (s, OC~3), 4.32 (d, J=2Hz, H-4), 7.0-7.7 (m, aromatic Hs); ir (~eat) v 3460 (OH), 1745 (C=O), 1595 (aromatics): Rf 0.47 and 0.42 (hexanes: ~t0Ac=2:1).
This crude material was used in the next step without purification.

(4'R,3S,4R and 4'5,3R,4S) and (4'S,3S,4R and 4'R,3R,4S) l-(t-3utvldimethyl-silyl)-3-(2'.2'-dimethyl-1',3'-dioxolan-4'-yl)-4-tritvlthio-2-azetidinone.
(Isomer C and Isomer B) P T 2 ~ / ~C

A solution of (35,4R and 4R,4S) l-(t-butyldimethylsilyl)-3-(1'-hydroxy-2'-methoxyiso?ropyloxye~hyl)-4-tritylthio-2-azetidinone (mixture of diastereomers at C-l' (57.1 g, 0.0966 mol; cruce) in CH2C12 (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 (Na25O4) and evaporated yielding 49.64 g (0.0888 mol, c-ude vield 91.9~) of a mixture of the title compounds (Isomer B and Isomer C) as yellowish foam. This was ?uri'ied by H~Lc('~TERs500 SILICAGEL"*; elue~'~ hexane:
~t0Acs9:1) and by crystallization yielding 14.28 g (25.5 mmol, 26.4~) of the title compound (Isomer C) as white crystals; mp 146-7C (?entane);
Hmr (CC14) ~: 0.27 (6H, s, Si-CH3), 0.95 (9H, s, Si-tBu), l.lS (6H, s, 0~
*Trade Mark i~r -~ 12~i8~

di-.~e), 2.5-2.9 (lH, m, H-4'), 2.97 (lH, t, J=1.8 Hz, H-3), 3.25-3.9 (2H, m, H-S'), 4.27 llH, d, J=1.8Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs);
("NUJOL")VmaX: 1750 (C=O) and 1595 cm (aromatics); Rf 0.45 (hexanes:
~tOAc=4:1) and 14.50 g (25.9 mmol, yield 25.9%) of the title compound (Isomer B) as white crystals: mp 144-5C (Et20-pentane); IHmr (CC14) ~:
0.02 (6H, s, SiMe), 0.833 (9H, s, Si-tBu), 1.13, 1.18 (6H, 2s, ciMe), 2.5-2.8 (lH, m, H-4'), 3.3-4.1 (2H, m, H-S'), 3.48 (lH, dd, J3 4=l.SRZ, J3 4,-5.0Hz, H-3), 3.93 (lH, d, J4 3=l.SHz, H-4), 7.1-7.7 (lSH, m, aromatic Hs); ir(~JOL") v ax 1650 (C=O) and lS9S cm ~aromatics);
Rf 0.37 (hexanes: ~tOAc=4:1). Anal calcd for C33H41N035Si: C 70.80, H 7.38, N 2.50, 5 5.73; found: (Isomer C) C 70.23, H 7.30, H 7.3-;
N 2.41, S ;.53 and (Isomer B) C 70.52, H 7.31, N 2.40, S 5.05.

*Trade Mbrk _ Z~ ~
~--\
12~i8~83 B. Pre~a a on of the Penem Product (Isom (4'R,35,4R and 4'5,3R,45) 3-(2~,2'-Dimethyl-1`,3'-dioxolan-4'-y~) 4-tritylt~io-2-azetidinone (Isomer C) 7~ 7~' ~-,. ~ NaN3 ~ ~ sTr /i ~ HMP~-H2O N -H

To a stirred solution of (4'R,3S,4R and 4's,3R,45) l-tt-butyl-dimethylsilyl)-3-(2~2~-dimethyl-l~3~-dioxolan-4~-yl)-4-trit thio-2-azetidinone (Isomer C) )14.3 g, 25.6 mmol) in hexamethylphos-phoric triamide (230.4 ml) was added slowly ( in 20 min) at 0-5~C a solution of sodium azide (2.50 9, 38.4 mmol; 1.5 ea) in H2O (25-6 ml)-The mixture was stirred at room temperature for 2 h anc ?Ured into cold water (2.5 ~). The white precipitate formed was collected, washed with H2O and dried yielding 11.26 g (25.3 mmol, crude yield i l compound as a white soli obtained by crystallization from CH2Cl2-Et2O: m~ 192-3C (dec-); Hmr (CDC13)~:1.33, 1.3~ (6H, 2s, di-~e), 3.27 (lH, t, J=3Hz, H-3), 3-8-4-4 5') 4 40 (lH, d, Js3Hz, H ) *
7 1 7 7 ppm (lSH, m, aromati 3220 (NY.), 1760 (C=O) and 1950 cm (aromatics); R~^ 0.31 (hexanes:
EtOAc 5 3:2).

*Trade Mbrk ~ 2~P

~J

~2~`8183 (4'R,3S,4R and 4'8,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2") (Isomer C) STr ICHO ~ ~ Tr ~H Et3N/THF N ~ OH

A suspension of p-nitrobenzvl glyo~ylate hydrate (6.57 g, 28.95 mmol; 1.15 e~) in benzene (500 ml) was heated at reflux wi~h Dean-Sta-~ t_ap for 2 h. Evaporation of the solvent gave p-nitrobenzyl glyoxylate as an oil. A mixture of t.~is oil and (4'R,35,4R and 4'S,3R,45) 3-(2',2'-dimethyl-1'-3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer C) (11.2 g, 25.2 mmol) in THF (350 ml, distilled from LAH) was treated with triethylamine (289 ms, 2.86 mmol) at room temperature under N2 for 18 h (overnight).
After evaporation of the solvent, the residue diluted wit.~ CH2C12 (200 ml) was washed successively with brine containing lN HC1 (2.9 ml) sat. NaHCO3 and brine, dried (Na2SO4) and evaporated a~ter addition of Et2O (30 ml) to give 17.2 g (26.3 mmol, crude yield 100~; ?urity 95.8%) of the title compound as a white ~oam: Rf 0.40 and 0.i0 (benzene: Et20=3:2).
Each isomer was separated by hplc (SiO2, eluent, benzene: Et2O=3:2) and puriried by crystallization from CH2C12-Et20. Isomer I: Rc 0.40 (benzene:
Et20=3:2); mp 1;3-4C; IHmr (CDC13) ~: 1.20 (6H, s, di-~e), 3.1 (2H, m, H-3 and OH), 3.5-4.2 (3Y., m, H-4' and H-5'), 4.55 (lH, d, J=2Y.z, :i-4), 5.12 (lH, br, H-2"), 5.30 (2H, s, OCH2Ar) and 7.1-8.3 ppm (19H, m, ~2~8~8~

aromatic Hs~; ir (nujol) V : 3370 (OH), 1775 (~-lactam) and 1745 cm (ester); Anal. calcd for C36H34N208S: C 6S.04, H ;.23, N 4.28, found:
C 65.85, H 5.64, N 4.11. Isomer II: Rf 0.30 (benzene: Et20=3:2);
mp 164-5C; lHmr (CDC13) ~: 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 (lH, d, J=2Hz, H-4), 5.23 (lH, br, -2"), 5.27 (2H, s, -OCH2Ar), and 7.1-8.3 ppm (19H, m, aromatic Hs);
ir (nujol) V : 3340 (OH), 1765 (3-lactam) and 1740 cm (ester);

Anal. calcd for C36H34N20aS: C 66.04, H 5.23, N 4.23~ S 4-90~ found:

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

c ~ 'C,~R. a~) 3-~2~2~-Dimetiv~ 3~-dioxolan-4~-vl) (~-nit-obenzvl 2"-chloro-2"-acetate)-4-tritvlth o-2-azetidino~o (mixture of e~imers at C-2") (Isomer C) Tr SOC12-Pyr ~ ' ~ STr H THF C N ~ 1 O P~B

To a stirred solution of (3'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzvl 2"-hvdroxy-2"-acetate)-4-trityltiio-2-azetidinone (Isomer C) (17.13 5, 25.07 mmol;
mixture of epimers at C-2") in THF (250 ml) was added at -15C under N2 pyridine (2.84 ml, 35.1 mmol) and lien immediately a~terwards tiionyl chloride (2.20 ml, 30.1 mmol; Anachemia). The mixture was stirred 'or 20 min at -15 and then tie white ~recipitate was ~iltered off. After washing witi benzene, tie ~iltrates and washin5s were combined and concentrated. The residue dissolved in benzene (250 ml) was treated wit'n activated charcoal, filtered and evaporated, yieldins 17.94 g (26.65 mmol, crude yield lOO~i purity 94.1~) o the c_uce title compound as white foam: Rr 0.76 .(benzene: Et2C=3:2); IHmr (CDC13) ~:

~~

2~8~

1.2Q (6H, s, dii"e), 3.17 (1~, m, H-3), 3.4-3.9 (3~, m, H-4' and H-5'), 4.67, 4.72 (lH, 2d, J=2.5 Hz, H-4), 5.30 ~2~, s, OCH2Ar), 5.83 (s, H-2") and 7.1-8.3 ppm (19 H, m, aromatic Hs); ir (neat) vmax: 1770 cm (3-lactam and ester). This material was used in the next step without purification.

(4'R,3S,4R and 4'5,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (Isome- C) . STr 3 ~ ~'~ ; CT-~N ~ C1 diox. ~ P~3 CO 2PNB CO 2P~3 A mixture of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-c_methyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (~some_ C) (17.87 g, 25.0 mmol; ?urity 94.1% mixture of epimers at C-2"), triphenylphosphine (7.27 5, 27.5 mmol) and 2,6-lutidine (3.19 ml, 27.5 mmol) in dioxane (350 ml; distilled ~rom LAH) was heated at reflux under N2 for 40 h. Evaporation of the solvent in vac.o cave 29.5 of dark oil which was purified by column chromatosra?hy (SiO2 330 g; eluent 20-50~ Et2O in benzene), yi~lding 10.5 g of yellowish solid. This solid was rinsed with Et20 to sive 7.49 g (8.33 mmol, yield 33.3~) of tne title compound as slishtly yellow crystals: IHmr(C~Cl3) ~: 1.07 ts, di-Me) and 7.1-8.2 ppm (m, aror_-ic Hs); ir("NUJOL")vmax: 1760 cm (C=0). An analytical sample was obtained by crystallization 'rom CH2C12-Et2O:
mp 231-2C; Anal. calcd for C54H47N2O~PS: C 72.14, H 5.27, N 3.12, S 3.5,:
found: C 72.18, H 5.43, N 2.98, S 3.41; Rf 0.17 tbenzene: Et2O=l:l).

*Trade Mark ~ Z ~ 5 ~

~ ~2~,8i83 (4'R,35,4R and 4'5,3R,4S) Silver 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate tIsomer C) STr AgNOl-Pyr ~ SAg N ~ P~3 ~eOH p~

A solution of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranvlidene-2"-acetatel-4-tritylthio-2-azetidinone (Isomer C) (319 mg, 0.35~ ~ol) in CH2C12 (10 ml) was evaporated to vield an oily residue which was redissolved in hot methanol (8 ml; 60). To this solution was added at 60 a hot solution of AgNO3 in .~eOH (0.lSM, 4.0 ml, 0.60 mmol) and ~hen pyridine (29 ~1, 0.36 mmol). The mixture was sti--ed at room temperature for 5 h and at 0C for 1 h. The precipitate was collected and washed wi'~ ice-cold me'hanol and then cold Et20, ylelcing 25; mg (0.334 mmol, yield 94.1%) of the title compour.d as a brownish solid: ir("NUJOL")`Jmax: 1750 cm (s, C=O).

(4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Di~ethvl-1',3'-dioxolan-4'-vl)-l-(p-nitrobenzyl 2"-tri?henylphosphoranvlidene-2"-acetate)-4-acety'-thio-2-azetidinone (Isomer C) ~,J. ~ S~g CH3COCl/PYr ~ ~ SAc 2~3 CH2C12 O ~ P~3 2 2~NB
To a solution of (4'R,3S,4R and 4'5,3R,45) silver 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2'`-acetate-2-azetidinone-4-t~iolate (Isomer C) (254 mg, 0.333 mmol) in CH2C12 (lS ml) containing ~~ ~6 ~
*Trade Mark ~1 `2.
~1 pyridine (100 ~1, 1.24 mmol; 3.72 eq) was added at 0-5C acetyl chloride (71 ~1, 1.0 mmol; 3.0 eq). The mixture was stirred at 0-5C for 40 min. After filtration of the precipitate over "CF~ITE"
the filtrate was washed successively with brine containing 1~ HCl tl.25 ml), sat. NaHC03 and then brine, dried (Na2S04) and evaporated, yielding 200 mg of an oil which was crystallized from Et20 to give 15; mg (0.222 mmol, yield 66.7%) of the title comDound as white crystals: lHmr (CDC13) ~: l.Z3 (s, di-Me), 2.20, 2.33 (2s,-SAc) and 7 2-8 3 ppm (m, aromatic Hs): irt NUJOL )vmax este_) and 1690 cm (thioester). An analytical sample was obtained by c-ystallization from CH2C12-Et20: mp 177-8~C: Anal. calcd for C37H35~208PS: C 63.60, H 5.05, N 4.01, S 4.59; found: C 63.34, ~ 5.32, N 3.83, S 4.31; Rf 0.62 ~OAc)-(4'R,SR,65 and 4'5,4S,6R) ~-Nitrobenzyl 6-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-2-methvlpenem-3-carboxylate (Isomer C) . ~ toluene I ~

2 ~022~3 A sus?ension of (4'R,3S,4~ and 4'S,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-t~iphenylphos?ho-ranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (443 mg, 0.634 mmol) in toluene (70 ml) was heated at _eflux unde~ N2 for 6 h.
Evaporation of the solvent gave white solid whi_; was ?urified by column chromatography (SiO2 10 g; eluent 10% Et20 ir. _enzer.e) yielding 247 mg (0.587 mmol, yield 92.7~) of the title compou..d as white solid: lHmr (CDC13) ô: 1.42 (6H, s, di-~e), '.38 (3H, s, 2-CH3), 3.8-4.5 (4H, m, H-6, H-4' and H-5'), 5.02-5.25-5.33-5.57 (2H, ~3 ty?e, _ ~ ~7 -*Trade Mark ~X~-~, .' -OCH2Ar), 5.57 (lH, d, J=1.8 Hz, H-5) and 7.52-7.67-8.12-a.27 ppm (4H, A2~B2', aromatic Hs); ir~''NUJOL''~Vmax: 1760 (B-lactam) and 1700 cm (ester). An analytical sample was obtained by crystallization _rom CH2C12-Et2O: mp 161-8C; uv (EtOH) ~max 265 t~ 14,000) and 314 mu ( 10,000); ~nal. calcd for C1gH20N2O75: C 54.28, H 4.79, N 6.66, S 7.63;
found: C 54.15, H 4.78, N 6.54, 5 7.64; Rf 0.62 (benzene-Et20=1:1).

(4'R,5R,65 and 4'5,55,6R) 6-(2',2'-Dimethyl-1',3'-dioxolan-4'-vl) -2-methylpenem-3-carboxylic acid (Isomer C) CH3 ~ ~
CO 2PNB O 2'A

A solution of (4'R,SR,65 and 4'5,55,6R) p-nitrobenzyl 6-(2',2'-dimethyl-1',3'-dioxolan-4-yl)-2-methylpenem-3-carboxylate (Isomer C) (l9S mg, 0.464 mmol) in THF (20 m~) was mixed with Et20 (20 ml), H2O (20 ml), NaHCO3 (39 mg, 0.46 mmol) and 10% Pd-C (2~0 mg, Engelhard). This mixture was hydrosenated at 35 psi ~or 4 ~ at room temperature. ACter removal of the catalyst (over Celite), ~e acueous layer was washed with ~'~c (x2), satur~ted with NaCl, acidi_ied with lN HC1 (0.47 ml) and immediately extracted with _~Ac (20 ml x 3).
The extracts washed with brine were cried (Na25O4) and evaporated yieldins 94 mg of yellowish solid which was rinsed wit;~ pentane to give 89 mg (0.31 mmol, yield 67%) of the ti~le compound as yellowish solid: mp 132-3C; Ri 0.60 (Acetone: HOAc=5: 0.7); IHm_ (CDC13) ~:
1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-CA3), 3.9-4.6 (4A, m, H-6, H-4' and H-S') and 5.59 ppm (lH, d, J=1.7 Hz, H-;): ir (nujol) v 1760 (~-lactam) and 1660 cm (CO2H); uv (~tOH) ~max 309 ( 6300) and 263 mU ( 3800).
- ~ Y5~-*Trade Mark ,,E~`i i81~:~

Exa~le ~
(L's~5R~6s and 4'~5S,6R) 6-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-2-methyl~enem-3-carbox~lic Acid (Isomer B~

~"" S

(4'5,35,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer B) ~ ~ Tr aN ~ ~ Tr / ~

The title compound was prepared as described in _xa~p:e~5 for the "Isomer C" from (4'5,35,4R and 4'R,3R,4S) l-(t-butyl-dimethylsilyl)-3-(2',2'-dimethyl-1',3'-dioxolan-3'-yl)-4-trityl-tnio-2-azetidinone (Isomer B) (14 4 g, 25.8 mmol): yield 10.8 g, 24.3 mmol, 94.1~i mp 155C (CH2C12-Et2O); Rf 0.24 (nexanes:
EtOAc=2:1); Hmr (CDC13) : 1.37, 1.40 (6H, 2s, d--~.e), 3.23 (lH, dd, J3-4=2.5 Hz, J3 4,=5Hz, H-3), 3.7-4.5 (4H, ~, H-4',H-5',N-H), 4 50 (lH, d, J=2.5Hz, H-4) and 7.1-7 6 ppm (15H, m, aromatic Hs);
ir (nujol) 3170 (NH) and 1745 cm (C=O); Anal. calcd for C27H27No3s:
C 72.78, H 6 11, N 3 14, 5 7.20; found: C 72.16, H 6.11, N 3.14, S 7.17.

-2~q ~
~--(4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-vl)-l-(p-nitrobenzyl 2ll-hydroxy-2ll-acetate)-4-tritylthio-2-azetidinone (mixture of eDimers at C-2'') (Isomer B) STr Co2pNB O~s~aTr N ~H Et3N/THF ~ ~P

The title compound was prepared as described in _X ~?;e `03 for the "Isomer C" from (4'5,35,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer a) (lo. 8 5, 24.3 mmol): yield 15.8 5, 24.1 mmol, 99.3%)i yellowish .oami Rf 0.29 and 0.22 (benzene: Et2O+l:l); IHmr (CDC13) ~: 1.28, 1.34 (2s, di-Me), 3.4-4.4 (m, H-3, H-4',H-5', H-2",0H), 4.39, 4.;3 (2c, J=2Hz, H-4), 5.15, 5.25 (2s, OCH2Ar) and 7.1-8.3 pDm (m, aromatiC Hs)i ir (neat) Vmax: 3440 (br, OH), 1760 (C=O), 1520, 1350 cm (NO2).

(4'S,35,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-vl)-l-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2") (Isomer 3) ~ 7~
C(~ ~ STr soCl2-Dyr ~ ~STr TH~ y CO ~B

The title compound was prepared ~s described in Ex~ a 183 for the "Isomer C" Erom (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-c methyl-1',3'-1',3'-dioxolan-4'-yl)-1- (D-nitrobenzvl 2"-hydroxv-2"-acetate)-4-tritylthio-2-azetidinone (Isomer 3) (14.9 g, 22.8 ~noli mixture oE

~ 0~

`` 12~i8183 epimers at C-2"); ~ield 14.1 9, 20.9 ~mol, 91.9~; yellowish foam;
Rf 0.52 (ber.zene: Et20=3:2); ~Hmr (CDC13) ~: 1.30, 1.38 (6H, 2s, di-Me), 3.4-4.5 (4H, m, H-3, H-4',H-5'), 4.57 (lH, d, J=3Hz, H-4), 5.13 (s, H-2"), 5.27 (s, OCH2Ar) and 7.1-8.3 ppm (19H, m, aromatic Hs);
ir (neat) Vm X: 1780 cm (~-lactam, ester).

(4'5,3S,4R and 4'R,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-triphenylphosphoranilidene-2"-acetate)-4-trit~lthio-2-azetidlnone (Isomer 3) STr ~3 ~ ~ ~ Tr ~N ~ Cl diox. N ~ P~3 The title compound was prepared as desc ibed -n ~xP-~le 103 for the "Isomer C" from (4'5,35,4R and 3'R,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (Isomer B) (14.0 g, 20.8 mmol; mixture o~
epimers at C-2"): yield 4.64 g, 5.16 mmol, 24.8~; mp 190-95C (dec., CH2C12-Et20); IHmr (CDC13) ~: 1.12, 1.20, 1.27, 1.35 (4s, di-Me) and 1.0-8.1 ppm (m, aromatic Hs); ir (CH2C12) Vmax: 1750 cm (~-lactam ester); Anal. calcd for C54H47N207PS: 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; R 0.21 (benzene: Et20=1:1).

l~i818~3 (4'S.3S.4R and 4'R 3S.4R) Silver 3-(2'.2'-dimethYl-1'.3'-dioxolan -4'-vl)-l-(~-nitrobenzvl 2"-tri~henvl~hos~horanvlidene -2"-acetate)2-azetidinone-4-thiolate (Isomer B) --b ~STr AgNO~-pyr 7~;~A9 ~ MeOH o ~

The title compound was prepared as de6cribed in Example 51 for the "Isomer C" from (4'S,3S,4R and 4'R,3S,4R) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-triphenyl-pho6phoranylidene-2"-acetate) -4-tritylthio-2-azetidinone (Isomer B) (1.00 g, 1.12 mmol):
yield 580 mg, 0.760 mmol, 67.8%; mp 129-135C (dec); ir (nujol) Vmax: 1745 cm~1 (B-lactam, ester).

(4'S.3S 4R and 4'R 3R 4S) 3-(2' 2'-Dimethyl-1' 3'-dioxolan -4'-yll-1-(~-nitrobenzYl 2"-tri~henvl~hos~horanylidene-2 -acetate)-4-acetylthio-2-azetidinone (I~omer B) ;~;~SAg 3 ~ ~

~ Q PNB

The title compound was prepared as described in Example 51 for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S) silver 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone -4-thiolate (Isomer B) (2.46 g, 3.22 mmol): yield after purification by column chromatography (SiO2 ~ '8~8~

32 g, eluent 10~-50~ EtOAc in CH2C12=1~ Hmr (CDC13) ~: 1.23, 1.27, 1.30 (3s, di-Me), 2.22, 2.33 t25, SAc) and 7.3-8.3 ppm (m, aromatic Hs) r (neat) v 1755 (~-lactam, ester) and 1695 cm 1 (thioester).
max (4'5,SR,65 and 4'R,5S,6R) p-Nitrobenzvl 6-(2',2' dimethyl-1',3'-dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer B) ~N ~ ~ 3 ;~J ~r~

The title compound was prepared as described ir. ~ le 133 for the "Isomer C" from (4'S,35,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1', 3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) (200 mg, 0.286 mmol):
yield 64 mg, 0.15 mmol, 53~; mp 151-2C (CH2C12/Et20); R~ 0.67 (benzene Et20=1:1); IHmr (CDC13) ~: 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, ABc, -OCH2Ar), 5.47 (lH, d, J=1.5Hz, H-5) and 7.42-7.55-8.05-3.15 ppm (4H, A2'B2', aromatic Hs); ir (neat) v : 1785 cm (3-lactam) and 1713 cm (ester); uv (EtOH) ~max 266 (~ 13,300) and 314 m~ (~ 9,700); Anal. calcd ClgH20N207S: C 54.28, H 4.79, N 6.o6, S 7.63; found: C 54.00, H 4.75, N 6.68, S 7.61.

~ ~ 3 ~

~2~

(4'S,SR,6S and 4'R,5S,6R) 6-(2'~2~-Dimethyl~ 3~-dioxolan-4~-yl)-2-methylPenem-3-carboxylic acid (Isomer B) 3 ~H3 The title compound was prepared as descri~ed -n ExR~le 103 for the "Isomer C: from (4'5,5R,65 and 4'R,55,6R) p-nitrobenzyl 6-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-2-methylpenem-3-car~oxylate (Isomer 8) (79 mg, 0. 19 mmol): yield after recrystallization rom CH2C12-pentane 9 mg, 0.032 mmol, 17~; Rl 0.54 ~Acetone: HCAc=;:0.5);
lHmr (CDC13) ~: 1.35, 1.44 (6H, 2s, di-Me), 2.37 (3H, s, 2-CH3), 3.6-4.5 ~4H, m, H-6, H-4',H-5') and 5.56 ppm (lH, brs, H-5); ir (neat) '- :
1785 cm (3-lactam); uv (EtOH) ~m : 307 (~ 4300) and 262 m~ (~ 370C).

_x2m~1e ~
1 'R.iR,65 and l'S ,5S,6R) 6-(1 '-~rdrox~f-2~-me~hox~e~..ox~r-2'-ethy~)-2-e~ l)-2-methyl~e~em-3-c2rbc~,r''c 2c~ A ( -, so~er C) OH

0~'""~ 5 N ~ 3 (l'R,35,4R and 1'5,3R,45) 3-(1',2'-dihydroxyet~yl)-1-(?-nitrobenzyl 2"-tri?henylphosphoranylidene-2"-acetate)-4-acer,~lthio-2-aze~idinone (Isomer C) / QH

H ~ ~ 33 C32PNB C02P~B
A solution of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1',3'-c ioxol an-4'-yl)-1-(?-nitrobenzyl 2"-tri?henvl?'nos-_ 9y~

l~ti818~i phoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (472 mg, 0.676 mmol) in tri'luoroacetic acid (1.0 ml) and H20 (0.1 ml) was left at room temperatUre for 30 min. The mixture was a~ded dropwise to a cold solution of NaHC03 (2.5 g) in H20 (50 ml) and extracted with CH2C12 (20 ml x 3). The extracts washed with sat.
NaHC03 and then brine were dried (Na2S04) and avaporated yielding 458 mg (0.695 mmol, crude yield 100~; pUrity 97.3~) o~ the crude title compound as yellowish foam: IHmr (CDC13) ~: 2.20, 2.32 t25, SAc) and 7.2-8.3 ppm (m, aromatic Hs); ir (neat) V : 3420 (OH), 1745 (~-lactam, ester) and 1690 Cm (thioester); Rf 0.16 ~'~O~C).

(l'R,35,4R and l'S,3R,45) 3-(l'-Hydroxy-2'-methoxymethoxy-l'-ethYl)-l-(p-nitrobenzyl 2"-triphenylphos?horanylidene-2"-acetate)-4-acetyl-thio-2-azetidinone (Isomer C) OH
HO OH SAC BrCH20CH3-dimethylaniline ~ ~ ~ SAc p~3 CH2C12 N ~ ~

CO P~B
co7 2 To a solution of (l'R,3S,4R and l'S,3R,4S) 3-tl',2'-dihydroxyethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (291 mg, 0.430 mmol;
purity 97.3~) and bromomethylmet'nylether (55.2 ms, 0.442 mmol; 4 drops) in CH2C12 (8 ml) was added at 0C, N,N'-dimethylaniline (58.8 mg, 0.183 mmol;
5 drops) and the mixture was stirred at room temperature for 20 h. Addi-tional br~momethylmethylether (2 drops) and ~,N'-dimethylaniline (2 drops) were added and it was stirred for anothe_ 4 h. The mixture diluted with CH2C12 was washed successi-~ely with lN HCl, sat. NaHC03 and brine, dried (Na2S04) and evapora.ed. The crude residue was purified by '~pl~ (SiO2, eluent ~tCAC) collecting (31 mg, 0.186 mmol, yield 42.2~) of the title compound as an oil: Rs- 0.24 ~tOAC); iHmr (C~C13) ~: 2.20, 2.32 (2s, S~c), 3.30 (s, OCH3), 4.52 (s,-OCH20-) and 7.4-8.3 ppm (m, aromatic ~s); ir (neat) V : 3420 (OH), 1755 (br, B-lactam and ester) and 1690 c~
(thioester).

~Z68183 (l'R,SR,6S and l'S,SS,6R) p-Nitrobenzyl 6-(1'-hvdroxv-2'-methoxy-methoxy-2'-ethyl)-2-methylpenem-3-carboxylate OH
~,", ~ SAc ~ ~ ~f ~ S ~
toluene _~C02P~B

I A solution of (l'R,3S,4R and l'S,3R,45) 3-(1'-hydroxy-2'-methoxymethoxy-1'-ethyl)-1-(p-nitrobenzyl 2"-triohenylphosohora-nylidene-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 the solvent in vacuo gave oily residue which was ourified by hplc (SiO2, eluent EtOAc) to give 68 mg (0.16 mmol, yield 67%) of the title compound as an oil: Rf 0.61 OEtOAc), 0.15 (benzene: Et2O=l:l);
lHmr tCDC13) ~: 2.38 (3H, s, 2-CH3), 3.35 (lH, br, OH), 3.40 ~3H, s, OCH3), 3.6-3.8 (2H, m, H-2')~ 3.90 (lH, dd~ J6 S=2HZ~ J6 1-=4Hz' H-6)~ 4-13 (lH, m, H-l'), 4.67 t2H, s, -OCH20-), 5.03-5.27-5.38-5.62 (2H, ABq, OCH2Ar), 5.65 (lH, d, J=2Hz, H-5) and 7.55-7.70-8.15-8.30 pom (4H, A2'B2', aromatic Hs); ir (neat) v : 3450 (OH), 1785 (~-lactam), 1710 (ester) and 1520 cm (NO2); uv (EtOH) ~ : 266 (e 13000) and 313 mu (~ 9100); Anal. calcd ror C18H20N2O8S: C 50.94, H 4.75, N 6.60; found: C 51.13, ~ 4.77, ~ 6.36.

_2 9~ -(l'R,SR,65 and l'S,SS,6R) 6-(1'-Hydroxy-2'-methoxymethoxv-2'-et~yl)-2-methylpenem-3-carboxylic acid (Isomer C) OHOH

A solution of (l'R,5~,6S and 1'5,55,6~) p-ni~-obenzyl 6-~1'-hydroxy-2'-methoxymethoxy-2'-ethyl)-2-methvlpen~m-3-car~oxvlate (Isomer C) (Sl ms, 0.12 mmol) in TY.F (10 ml) was mixed with Et2O
(10 ml), H2O (10 ml), NaHCO3 (10 mg, 0.12 mmol) and 10% Pd-C (50 mg Engelhard). It was hydrogenated at room temperature at 32 25i 'or 3 h. After filtration of the catalyst over"CELIT$" the aaueous ;ayer separated was washed with Et2O (x 3) and saturated with NaCl.
The aaueous phase acidified at 0C with 0.1N HCl (1.2 ml) was immediately extracted with ~'~Ac (15ml x 3). The extracts were washec with brine, dried (Na25O4) and evaporated yielding 22 mg o~ yellowisn solid which was rinsed with a small amount of Et2O to give 20 ms (0.069 mmol, yield 58~) of the title compounc as slishtly yellow solid:
Pmr (DMSO-d6) ~: 2.28 (3H, s, 2-CH3), 3.27 (3H, s, OCH3), 3.49(2H, d, J=6.2HZ, 2'-H), 3.87 (lH, dd, J6_5=1.7Hz, J6-1' 3 3H~ 6 ), (2H, s, -OCH2O-) and S.SS ~pm (lH, d, J=1.7 Hz, 5-H); ir (X3r) ~ x 3410 (OH), 1~55 (~-lactam) and 165; cm 1 (CO2H); uv (EtOH) ~ :
308 (~ 6800) and 262 m~ (~ 4200), mp 137-8C (dec.).

*Trade Mbrk- 2~7-12~

Example 54 1'Sl5R.6S and l'R.5S.6R) 6-tl'-Hydroxv-2'-methoxymethoxy -2'-ethyl)-2-methylpenem-3-carboxylic acid (Isomer Bl ~0~ 0~. S
~;~CH3 1 O 02~

(1'S.3S.4R and 1'R.3R.4S) 3-(l' 2'-dihydroxyethyl) -l-(p-nitrobenzyl 2"-triphe~y~hosphoranYlidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) OH
~S,,~SAC l~F-H O HO~J~,~SAc N~P~3 2 ~ N ~P~3 02PNB C02P~B

The title compound wa6 prepared a6 de6cribed in Example 53 for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-l',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"acetate)-4-acetylthio -2-azetidinone (Isomer B) (1.03 g, 1.47 mmol): yield 970 mg, 1.47 mmol, 100%; yellowi6h foam: 1Hmr (CDC13) ~: 2.20, 2.32 (2s, -SAc) and 7.3-8.2 ppm (m, aromatic H6); ir (neat) v max: 3410 (OH), 1750 (B-lactam, e6ter) and 1690 cm~1 (thioester): Rf 0.16 (EtOAc).

,~

~2~,~18~

(l'S,3S,4R and l'R,3R,4S) 3-(1'-Hvdroxy-2'-methoxymethoxy~ ethvl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetyl-thio-2-azetidinone (Isomer B) OH OH
HO ~ ", SAc ~ O ~ ",___~SAc ~ BrCH20CH3/dimethylaniline l l O ~ N ~ P~3 CH2C12 ~ N ~ p~3 The title compound was prepared as described i~, EX2~p~
for the "Isomer C" from (1's,3S,4R and l'R,3R,45) 3-(1',2'-dihydroxy-ethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) (485 mg, 0.736 mmol): yield 205 mg, 0.292 mmol, 39.6~; oil; 1Hmr (CDC13) ~: 2.22, 2.33 (2s, SAc), 3.32 (s, OCH3), 4.57 (s,-OCH2O-) and 7.2-8.3 ppm (m, aromatic Hs ir (neat) V : 3420 (OH), 1755 (~-lactam, ester) and 1690 (thioester) ~f 0.32 (EtOAc)-(l'S,5R,6S and l'R,5S,6R) p-Nitrobenzyl 6-(1'-hydroxy-1'-methoxy-methoxy-2'-ethyl)-2-methylpenem-3-carboxylate OH ~H
O ~ . SAc ~O ~ ."
toluene-HQ ~ ~ ~ CH3 ~02PNP 02PNB
The title compound was prepared as described i~. rxs~?lc for the "Isomer C" from (l'S,3S,4R and l'R,3R,45) 3-(1'-hydroxy-2'-met~oxymethoxy-l'-ethyl)-l-(p-nitrobenzyl 2"-triphenylphosphor2nyl-idene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) (20C mg, 0.292 mmol) and hydroquinone (10 mg, 0.09 mmol): yield 38 mg, 0.090 mmol, 31~; 152-4C; Rf 0.23 (benzene: Et2O=l:l); IHmr (CDC13) ~:
2.37 (3H, s, 2-CH3), 3.40 (3H, s, OCH3), 3.4-3.9 (3H, m, H-6, H-2"), 4. 15 tlH, M, H-l' ), 4. 67 (2H, 6, -OCH2O-), 5. 10-5. 27-5. 39-5. 56 (2H, ABq, -OCH2Ar), 5. 67 (lH, d, J=1. 5 HZ, H-5) and 5. 55-5. 16-8. 15-8. 27 ppm (4H, A2'B2', aromatic H3); ir (CH2Cl2 mull) vmax : 3370 (OH), 1785 (B-lactam) and 1700 cm~l (e6ter);
uv (THF-EtOH=l:l) Amax: 265 ( 10400) and 314 m~ (~ 7800).

(l'S.5R.6S and 1'R.5S.6R) 6-(l'-Hydroxy-2'-methQxymethoxv-2'-ethyl)-2-methvlenem-3-carboxvlic acid (Isome~ B) OH OH
~o ~ ~ CH H2/~d-The title compound was prepared as described in Example 53 for the "Isomer C" from (l'S,5R,6S and l'R,5S,6R) p-nitrobenzyl 6-(1'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methylpenem -3-carboxylate (Isomer B) t36 mg, 0.085 mmol): yield 7.5 mg, 0.026 mmol, 30%; yellowish cry6tals; 1Hmr (CDC13) 8 : 2.36 (3H, 6, 2-CH3), 3.39 (3H, 8, OCH3), 3.6-3.9 (3H, m, H-6, H-2'), 4.15 (lH, m, H-l'), 4.66 (2H, 8, OCH20) and 5.67 ppm (lH, d, J 1-4 Hz~ H 5); ir (CH2C12) max: 1785 (B-lactam) and 1675 cm~1 (CO2H); uv (EtOH) Amax: 308 (E 2900) and 263 m~ (~ 2900) 1~i8~8~
, ~

Exam~le 55 .2-Benzimidovlaminomethvl~enem-3-carboxvlic Acid 2-DH- C-c~2~3 COOH
A. ~CH2~H2~02N~ ~ tCOC1)2 2 12 ~ ~H2~H2co (I) (II) To a 6uspen6ion of 0. 38 g (0. 0015 mole) of sodium 3-benzyl-1, 2,4-oxadiazol-5-one-4-acetate (I) 1 in 10 ml of methyl chloride, containing 2 drops of DMF, was added at room temperature 0. 13 ml (0. 0015 mole) of oxalyl chloride, causing the 15 mixture to effervesce. The reaction mixture was stirred at room temperature for 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.
20 1. K. Takacs and K. Harsanyi, B~r. 103, 2330 (1970).
B. (II) ~ 2C12 ~ C~ ~2~3 (III) (Iv) A 601ution of 1. 0 g 10. 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 4. The acid chloride (II) solution was added all at once to the solution of (III) and the reaction 30 mixture was stirred at 4 for 5 minutes, then at room temperature for 1. 5 hrs. A thick precipitate formed in the reaction mixture.
The mixture was filtered and the filtrate diluted with methylene chloride to a volume to 7090 ml. The organic phase wa6 then washed successively with 70 ml of 0.1~ hydrochloric acid, 80 ml 35 of 1% sodium bicarbonate and 80 ml of water. The methylene chloride phase was dried over magnesium sulfate. The solvent was removed at ,!

~2~i8~

reduced pressure and the residual oil chromatographed on Mallinckrodt "SILIC AR CC-7"*silica gel using chloroform a6 the eluant, siving 0.4 g (30.5%) of (IV) as an oil. The infrared and nuclear magnetic resonance spectra were con6i6tent for (IV).
tolucne ~ ~ CH2~) 02~NB
(~) 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 waæ removed at reduced pressure and the re~idue chromatographed on Mallinckrodt"SILICAR
CC-7"* silica gel, using 5% ethyl acetate in methylene chloride a6 eluant, affording O.lS g (66.6%) of V as an oil which solidified. The infrared and nuclear magnetic resonance spectra were consistent for V.
Anal. Calcd for C23 H 18N407S: C, 55-86; H, 3.67; N, 11.33.
Found: C, 56.17; H, 3.76; N, 11.23.

10~ Pd/C ~ ~ 2 A solution of 0.135 g (0.00027 mole~ of V in 40 ml of tetrahydrofuran and 40 ml of anhydrous diethyl ether was added to a slurry of 10% palladium on carbon catalyst in 40 ml of water under a nitrogen atmosphere. The resultant mixture wa6 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 pBi. The catalyst was removed by filtration, washing the filter pad well with water. Additional diethyl ether wa6 added to the filtrate and the phases were separated. The agueous phase was extracted 3x with diethyl ether.
The aqueous phase was then concentrated to dryness at reduced pressure. The residue was chromatographed, using the high pressure liquid chromatography technique, to afford 0.050 g (58%) of the title penem acid; decomp 156-173. The infrared and nuclear *Trade Mark ~2~`81~3~3 magnetic resonance spectra were consistent for the desired product.
Anal. Calcd for C15H15N303S~1.5H20: C, 52.31; H, 5.27; N, 12.20.
Found: C, 51-64; H, 4.95; N, 12.31.
Example 56 2-Phenylimidoylaminomethylpenem-3-carboxylic Acid ~ ~ CH -NH-C

COOH

Pollowing the procedure of Example 55 but using an equimolar amount of sodium 3-phenyl-1,2,4-oxadiazol-5--one-4-acetate as the starting material in place of the sodium 3-benzyl-1,2,4-oxadiazol-5-one-4-acetate used therein, there was produced the title product.
Biological Data Representative compounds of the present invention were sub~ected to in vitro antibiotic screening against a variety of microorganisms. Samples of the indicated compounds after solution in water and dilution with ~utrient Broth were found to exhibit the following Minimum Inhibitory Concentration (MIC) in mcg./ml. versus the indicated microorganisms as determined by overnight incubation at 37C. by the tube dilution method.

~2~

M.I.C. in mcq/ml Com~ound (ExamDle No.) Oraanism Streptococcus pneumoniae 125 Streptococcus pyogenes >125 Staphylococcus aureus 10 Staph aureus ~50% 8 Serum A9537 Staphylococcus aureus 32 Staphylococcus aureus ~15097 Streptococcu6 faecalis 125 Escherichia coli 8 Escherichia coli Rlebsiella pneumoniae 125 Klebsiella species 4 Proteus mirabilis 8 Proteus mirabili 6 63 30 Proteus morganii 63 Proteus rettgeri 32 Serratia marcescens Enterobacter cloacae 16 Enterobacter cloacae 16 Pseudomonas aeruginosa Pseudomonas aeruginosa >125 Hemophilus influenzae Haemophilu6 influenzae Bacteroides fragilis Bacteroides fragilis 12~i~318;~
,~

M.I.C. in mcg/ml ~ Compound tExam~le No.) 5Oraanism 2 3 Streptococcus pneumoniae Streptococcus pyogenes 2 4 10 Staphylococcus aureus 8 2 Stapn aureus l50% >63 >63 Serum A9 5 3 7 Staphylococcus aureu~ 4 4 Staphylococcus aureu6 8 32 Streptococcus faecalis 63 125 20 Escherichia coli 32 63 Escherichia coli 32 63 Klebsiella pneumoniae . 63 125 Rlebsiella species >125 >125 Proteus mirabilis 63 63 30 Proteus vulgaris 63 32 Proteus morganii 63 125 Providencia stuartii 32 63 Serratia marcescens 125 63 Enterobacter cloacae 125 125 40 Enterobacter cloacae >125 125 Pseudomonas aeruginosa >125 >125 P~eudomonas aeruginosa >125 >125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis .f.'~'~

~ 12~8183 M I . C. in mca/ml Compound (Exam~le No.) 5Organism 4 5 Streptococcus pneumoniae 1 .5 Streptococcus pyogenes 4 4 10 Staphylococcus aureus 8 4 Staph aureus +50% >63 >63 Serum A9537 Staphylococcus aureus 4 9 Staphylococcus aureus 125 63 Streptococcus faecalis 125 125 20Escherichia coli >126 63 Escherichia coli >125 125 Rlebsiella pneumoniae >125 63 Xlebsiella species >125 >125 Proteus mirabilis 63 63 30 Proteus vulgaris 63 32 Proteus morganii 125 125 Providencia stuartii 125 32 Serratia marcescens >125 63 Enterobacter cloacae >125 125 40 Enterobacter cloacae >125 125 P6eudomonas aeruginosa - >125 Pseudomonas aeruginosa - >125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis M.I C. in mcg/ml ComDound ~Example No.) Organism 11(5) 11(6) streptococcus pneumoniae Streptococcus pyogenes Staphylococcus aureus Staph aureus +50~ 63 Serum A9537 32 Staphylococcus aureus 32 125 Staphylococcus aureus 63 63 Streptococcus faecalis >63 125 Escherichia coli Escherichia coli A20341-1 >63 125 Klebsiella pneumoniae 63 125 Klebsiella species A20468 ~63 ~125 Proteus vulgaris 63 32 Proteus moraanii Serratia marcescenS 32 63 Enterobacter cloacae A9659 63. 63 Enterobacter cloacae 63 63 Pseudomonas aeruginosa 16 32 Pseudomonas aeruginosa A21213 32 >125 He~ophilus influenzae ~ae~ophilus influenzae ~21522 Bacteroides fragilis ~20931 Bacteroides fragilis ~20929 _3~~
~--12~i8183 `

M.I.C. in mcg/ml Compound ~Example No.) 5Organism 12 Streptococcu~ pneumoniae .016 Sreptococcus pyogenes .06 10 Staphylococcus aureus .13 Staph aureus +50% .4 Serum A9537 Staphylococcus aureus 8 Staphylococcus aureus 125 Streptococcus faecalis 63 20 E6cherichia coli .5 Escherichia coli 63 Rleb6iella pneumoniae 8 Klebsiella species >125 Proteus mirabilis Proteus vulgaris Proteus morganii Proteus rettgeri 2 8erratia marcescens Enterobacter cloacae 2 Enterobacter cloacae Pseudomonas aeruginosa Pseudomonas aeruginosa 125 Haemophilus influenzae 125 Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis M I.C. in mc~/ml ComPound (Exam~le No.) streptococcus pneumoniae32.25 .25 .016 Streptococcus pyogenes 8 2 .25 Staphylococcus aureus 8 4 .03 Staph aureus +50~ 32 63 63 Serum A9537 Staphylococcus aureus 16 4 16 Staphylococcus aureus 63 16 >125 Streptococcus faecalis >i25 125 16 Escheri chi a coli 63 4 63 AlSll9 Escherichia coli >125 16 >125 Xlebsiella pneumoniae 125 32 >125 Klebsiella species >125 125 >125 Proteu5 mirabilis 63 16 32 Proteus vulgaris 125 16 Proteus morganii 125 32 32 Proteus rettgeri 63 32 Serratia marcescens 63 32 16 Enterobacter cloacàe 125 32 >125 Enterobacter cloacae 125 63 l~S

Pseudomonas aeruginosa 125 125 >12;

Pseudomonas aeruginosa 125 125 >125 Hemophilus influenzae Haemophilus influenzae - - _ Bacteroides fragilis Bacteroides fragilis A20g29 _3 ~2tjt~1~33 M.I.C. in mc~ml Com~ound (Exam~le No.) Orqanism 32 I8 24 Pseudomonas aeruginosa - - -Pseudomonas aeruginosa Pseudomonas aeruginosa - - -Proteus species - -Proteus mirabilis - _ 16 Providencia stuartii - - 63 1268~8~
M.I.C. in mcg/ml Com~ound (Exam~le No.) 5Organism _25 Streptocoocus pneumoniae 2 Streptococcus pyogenes 16 10 Staphylococcus aureus 32 Staph aureus ~50% >63 Serum A9537 Staphylococcus aureus >125 Staphylococcus aureus >125 Streptococcus faecalis 125 20 Escherichia coli 63 Escherichia coli >125 Klebsiella pneumoniae >125 Rlebsiella specie6 >125 Protèus mirabilis 63 30 Proteus vulgaris - -Proteus morganii 125 Proteu6 rettgeri 125 Serratia marcescens >125 Enterobacter cloacae >125 40 Enterobacter cloacae >125 Pceudomonas aeruginosa 125 . A9843A
P6eudomonas aeruginosa 125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis !

i M. I . C . in mcq~ml Compound (Exam~le No.
Orqanism 25 Pseudomonas aeruginosa PseudoNonas aeruginosa Pseudomonas aeruginosa Proteus species Proteus mirabilis 63 Proteus mirabilis ~2~318~'3 M.I.C. in mca/ml Compound (Exam~le No.) 5Oraanism 31 Sreptococcus pneumoniae 63 Streptococcus pyogenes 125 10 Staphylococcus aureus 32 Staph aureus +50% 32 Serum A9537 Staphylococcus aureus >125 Staphylococcus aureus 63 Streptoco¢cus faecalis 63 20 Escherichia coli 63 Escherichia coli 32 Klebsiella pneumoniae >125 Klebsiella 6pecies 63 Proteus mirabilis 125 30 Proteus vulgaris >125 Proteus morganii 125 Proteus rettgeri 125 Serratia marcescens 125 Enterobacter cloacae 125 40 Enterobacter cloacae 32 P~eudomonas aeruginosa 125 P~eudomonas aeruginosa 125 Hemophilus influenzae Haemophilus influenzae Bacteroide6 fragili6 Bacteroides fragilis ~2~`818~
, M.I.C. in mcg/ml Compound (Example No.) 5Organism 33 34 Streptococcus pneumoniae .06 .25 Streptococcus pyogenes .13 2 10 Staphylococcus aureus 1 4 Staph aureus +50% 16 63 Serum A9537 Staphylococcus aureus 125 4 Staphylococcus aureus >125 16 Streptococcus faecalis 125 125 20 Escherichia coli 16 4 Escherichia coli >125 16 Klebsiella pneumoniae 125 32 Klebsiella species >125 125 Proteus mirabilis 8 16 30 Proteus vulgaris 63 16 Proteus morganii 32 32 Proteus rettgeri 16 32 Serratia marcescens 63 32 Enterobacter cloacae 125 32 40 Enterobacter cloacae 63 63 Pseudomonas aeruginosa 125 125 Pseudomonas aeruginosa 125 125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis ;~

- . .

12ti~

M.I.C. 'n mog/ml ComDound (Exam~le No.) 5 ~ Organism 35 36 40 Streptococcus pneumoniae 32 .2S .004 A9585 32 .25 .008 Streptococcu6 pyogenes125 1 .004 A9604 125 1 .004 10 Staphylococcus aureu~ - - .008 A9537 >125 2 .008 Staph aureus +50% - - .06 Serum A9537 >63 8 .06 Staphylococcus aureus - - .06 A9606 >125 4 .06 Staphylococcu6 aureu6 - - .06 A15097 >125 8 .25 Streptococcus faecalis>125 63 .5 A20688 >125 63 .5 20 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 Rlebsiella 6pecie6 >125 16 .5 A20468 >125 16 .5 Proteus mirabili6 >125 32 <.25 A9900 >125 16 .25 30 Proteus vulgaris >125 16 ~.25 A21559 >125 16 .25 Proteu6 morganii >125 32 A15153 >125 16 Proteus rettgeri >125 16 <.25 A21203 >125 16 .5 Serratia marce~cens >125 16 .5 A20019 >125 16 .5 Enterobacter cloacae>125 32 4 A9659 >125 - 2 40 Enterobacter cloacae>125 16 .5 A9656 >125 - .5 Pseudomonas aeruginosa>125 >125 16 A9843A >125 - 16 PB eudomonas aerugino6a>125>125 125 A21213 >125 - 63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis ~ r 2~i8~83 M I.C in mc /ml Compound ~Example No.) Or~anism 37 38 39 streptococcus pneumoniae A9585 .03 .03 .016 Streptococcus pyogenes .06 .5 .03 Staphylococcus aureus .06 staph aurA95375~ 4 .25 .13 Staphylococcus aureus 1 .25 .13 Staphylococcus aureus 2 5 .25 Streptococcus faecalis 2 32 4 Escher chia coli 2 8 2 Escherichia coli 8 8 2 Proteus mirabilis 2 2 4 Proteus vulgaris 2 2 Proteus morganii 2 4 Proteus rettgeri 2 2 4 Serratia marcescens 8 16 4 Enterobacter cloacae 8 32 4 Enterobacter cloacae32 1 16 Pseudomonas aeruginosa 63 2 16 Pse~domonas aeruginosa ~21213 He~ophilus influenzae Haemop~ilus influenzae Bacteroides fragilis ~20931 Bacteroidcs fragilis A20929 _ ~26~i~33 M. I . C. in mcq/ml ComPound (Example No.) 5Organism 43 Sreptococcus pneumoniae >63 Streptococcus pyogenes >63 10 Staphylococcus aureus >63 Staph aureus +50% >32 Serum A9537 Staphylococcus aureus >63 Staphylococcus aureus >63 Streptococcus faecalis >63 20 Escherichia coli >63 Escherichia coli >63 Klebsiella pneumoniae >63 Kleb6iella species >63 Proteus mirabilis >63 30 Proteus vulgaris >63 Proteus morganii >63 Proteus rettgeri >63 Serratia marcescens >63 Enterobacter cloacae >63 40 Enterobacter cloacae >63 Pseuaomonas aeruginosa >63 Pseudomonas aeruginosa >63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis j\~

1~i8183 .

M. I . C. in mca/ml Compound (Exam~le No. ) 5Orcanism 45 Streptococcus pneumoniae 2 Streptococcus pyogenes 16 10 Staphylococcus aureus 32 Staph aureus +50% ~32 Serum A9537 Staphylococcus aureus 2 Staphylococcus aureus 8 Streptococcus faecalis 63 20 Escherichia coli 2 Escherichia coli 32 Klebsiella pneumoniae 8 Kleb~iella species >63 Proteus mirabilis 4 30 Proteus vulgaris 16 Proteus morganii 8 Proteu~ rettgeri 8 I Serratia marcescens 8 Enterobacter cloacae 8 40 Enterobacter cloacae 8 Pseuaomonas aeruginosa 63 Pseudomonas aeruginosa >63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis M.I.~. in mcq/ml Com~ound (Exam~le No.
5Organi 8 m 47 Streptococcus pneumoniae .5 Streptococcus pyogene6 .5 10 Staphylococcus aureus 8 Staph aureu6 ~50% 32 Serum A9537 Staphylococcus aureus 16 Staphylococcus aureus 32 Streptococcus faecali 6 > 63 20 Escherichia coli 32 Escherichia coli 32 Klebsiella pneumoniae 63 Klebsiella species 63 Proteus mirabili6 32 30 Proteus vulgaris 32 Proteus morganli 63 Proteus rettgeri 32 Serratia marcescens 63 Enterobacter cloacae 63 40 Enterobacter cloacae 63 Pseuaomona6 aeruginosa >63 Pseudomona6 aeruginosa >63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis -`-` 1268~8~

M I . C. in mcq/ml Com~ound (Exarnple No . ) Orqanism 48 49 50 Streptococcus pneumoniae >125 1 32 A9 6 04 > 125 16 32 A95 37 > 125 32 125 Serum A95 37 > 63 > 63 > 63 A9 6 0 6 > 125 32 > 125 A15 09 7 > 125 > 125 > 125 Streptococcus faecalis >125 >125 >125 Escheri chi a coli> 125 > 125 > 125 A20 341- 1 > 125 > 125 > 125 Klebsiella pneumoniae>125 >125 >125 Klebsiella species>125 >125 >125 Proteus mirabilis >125 >125 >125 Proteus vulgaris >125 >125 >125 Proteus morganii >125 >125 >125 Proteus rettgeri >125 >125 >125 Serratia marcescens>125 >125 >125 Enterobacter cloacae >125 >125 >125 Enterobacter cloacae >125 >125 >125 Pseudomonas aeruginosa >125 >125 >125 ~9843A
Pse~domonas aeruginosa >125 >125 >125 ~21213 He~ophilus influenzae ~9833 Hae~nOphilus influenzae ~21522 Bacteroides fragilis Bacteroicles fragilis A209 29 - 32~-~--318~

M . I . C. in mcq/ml compound lExample No. ) Organism 51 52 53 54 Streptococcus pneumonlae Streptococcus pyogenes 63 32 4 32 A9537 > 63 63 > 8 63 Staph aureus +509~ >32 ~32>32 >32 A9606 > 63 63 63 > 63 Staphylococcus aureus >63 63 >63 >63 Streptococcus faecalis>63 63 >63 >63 Escherichia coli >63 >63 63 63 A20341 -1 > 63 ~ 6363 63 Xlebsiella pneumoniae >63 >63 63 >63 A2046 8 > 63 > 63> 63> 63 A99 00 63 > 63> 63 63 Proteus vulgaris > 63 > 63> 63> 63 A15153 > 63 > 63> 63> 63 A21203 > 63 63 32 63 A200 19 > 63 .> 63> 6363 A9659 > 63 > 6363 > 63 A 9656 > 63 > 6363 63 Pseudomonas aeruginosa 63 63 63 63 Pseudomonas aeruginosa 63 63 63 63 Hemophilus influen~ae )3aelT~ophilus inf luenzae ~21522 Elacteroides f rag ilis Bacteroi c~cs f raq i li s ~--~t~818;~

M .C. in mC~/ound (Example No~) ~ . 55 56 Streptococcus pneumonlae 25 Streptococcus pyogenes .25 Staphylococcus aureus 25 Staph aureus +50~
Serum A9537 16 Staphylococcus aureus >63 >125 Streptococcus faecalis >63 125 Escherichia coli 63 63 Escherichia coli ~63 >125 Klebsiella pneumoniae >63 125 ~lebsiella species >63 >125 Proteus ~rulgaris 63 125 Proteus morganii 63 63 Proteus rettgeri 63 63 Serratia marcescens 63 125 Enterobacter cloacae >63 125 Enterobacter cloacae 63 125 Pseudomonas aeruginosa 63 63 Pseudomonas aeruginosa 63 125 He~ophilus influenzae ~aemophilus influenzae ~21522 Bacteroides fragilis Bacteroides fraqilis ~20929 -32~-Representative compounds of the present invention were also tested in vivo in mice and their PD50 (dose of compound in mg/kg required to protect 50% of the treated mice against an otherwise lethal infection of a microorganism) values determined with respect to the test organisms shown below.

12~8183 .

S. aureus A9537 # of infecting organisms of S. aureus # of Treatment PD50 5 Compound a 9537 treatments route (ma/ka/treatment Compound of Ex.65 7.8 x 105 2 IM 0.12 Compound of Ex.36 6.6 x 105 2 IM 7.7 L2~i818~

S. aureus A9537 # of infecting organisms of S. aureus # of Treatment PD50 Compound a 9537 treatments route (ma/ka/treatment Compound lo of Ex.62 8.6 x 105 2 IM 1.0 Compound of Ex.56 8 x 105 2 IM >5 Compound of Ex.39 8 x 105 2 IM 0.04 li~ti81~

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 _ 20 30 45 60 90 120 Compound of Ex. 40 44.7 34.4 23.7 17.6 9.8 3.6 *Average of 6 mice

Claims (5)

1, A process for the preparation of a compound of the formula wherein Y is hydrogen, ethyl or hydroxyethyl; Q is phenyl or (lower)alkyl, R" is an easily removable ester group and X is:

(a) a radical of the formula (i) -ORa in which Ra is hydrogen;
(ii) -ORb in which Rb is hydrogen, hydroxy, optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl group being one or more of halo, hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower)-alkylamino, di(lower)alkylamino, (lower)-alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or more of hydroxy,(lower)-alkoxy, halo, (lower)alkyl, halo(lower)-alkyl, methanesulfonyl, oxo, (lower)alkyl-thio, amino, (lower)alkylamino, di(lower)-alkylamino, (lower)alkanoylamino, (lower)-alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or (iii) -OCOR 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)alkvl radical, substituents for the above-mentioned aliphatic, cycloaliphatic, phenyl or hetero-cyclic groups being (i) or in which R1 is hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzyl;
(ii) -ORd in which Rd 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 and heterocyclic groups being as defined under (a)(ii);
(iii) -O(CH2)nORr in which n is an integer from 1 to 6 and Rr is optionally sub-stituted (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 Rr' is amino, (lower)-alkylamino, di(lower)alkylamino or Rr, with the proviso that Rr' may not be unsubstituted (lower)alkyl;
(v) -OSO3H;
(vi) -O?(OH)2;
(vii) -OSO2Rr in which Rr is as defined under (b)(iii);

(viii) -O?(ORe)(ORr) in which Re is (lower)alkyl and Rr is as defined under (b)(iii);
(ix) -S(O)nRd in which n is 1 or 2 and Rd is as defined under (b)(ii) or is in the case where n=0 in which R4 is hydrogen or (lower)alkyl and R5 and R6 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, -NHNH2, -NR17NR18, -NHOR19, -S-R17, -0(CH2)n-A-Re or -NReRg in which R17, R18 and Re are (lower)alkyl R19 is hydrogen or (lower)alkyl, A is 0, S, NH or NCH3 and n and Rg are as defined under (b)(iii) and (b)(viii);
(xi) -PO(ORw)2 in which Rw is hydrogen or (lower)alkyl;

xii) -NHRh in which Rh is optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -SO3H, -OH, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, -NHCOCH3,-CS2CH3,-SO2CH3, -SO2NH2, , , , , in which R7 and R8 are each independently (lower)alkyl, phenyl or phenyl(lower)alkyl, in which R9 is (lower)alkyl, phenyl or phenyl(lower)-alkyl, or in which Ri is amino(lower)-alkyl, -NH2, (lower)alkylamino, di(lower)-alkylamino, , in which R10 is (lower)alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being defined under (a)(ii), , (lower)alkoxy, -OCH2 , -OCH2NO2 or -O(CH2)2Si(CH3)3;
(xiii) in which R11 is (lower)alkyl substituted by amino, (lower)alkylamino or di(lower)alkylamino;
(xiv) -NRjRk in which Rj is (lower)alkyl and Rk is (lower)alkyl, (lower)alkoxy, heterocyclic, amino, or in which Ri is as defined under (b)(xii) or, when taken together with the nitrogen, Rj and Rk represent , providing that when Rk is amino or -CH2CH2NH2, Rj is methyl and also providing that Rj and Rk may not both be (lower)alkyl;
(xv) -NRj'Rk' in which Rj' is (lower)alkoxy and Rk' is (lower)alkyl, heterocyclic, amino(lower)alkyl, (lower)alkylamino-(lower)alkyl, di(lower)alkylamino(lower)-alkyl or in which Ri is as defined under (b)(xii) or, when taken together with the nitrogen, Rj' and Rk' represent ?
(xvi) -NR1RmRn in which R1, Rm and Rn are each 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 de-fined under (a)(ii);
(xviii) -N=CRxRy in which Ry 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);
(xix) =N-Rp in which Rp is hydroxy, (lower)alkoxy, amino, di(lower)alkylamino or ; or (xx) in which n is an integer from 1 to 6 and R15 and R16 are each in-dependently hydrogen or (lower)alkyl;

said process comprising reacting an intermediate selected from the group consisting of a compound of the formula III

wherein Y is hydrogen, ethyl or hydroxyethyl, Q is phenyl or (lower)alkyl, R" is an easily removable ester 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; and a compound of the formula III(a) in which Y, Q and R" are as defined above, in an inert solvent, with an acylating agent for the moiety , wherein X is the desired penem 2-substituent.

2. A Process as in claim 1 wherein the actylating agent is the acid , or an acid halide or anhydride thereof.

3. A process according to claim 1 wherein Y is hydrogen or a-hydroxyethyl and X is a radical of the formula (a) in which n is an integer from 1 to 6;
(b) -(CH2)nNHOH in which n is an integer from 1 to 6;
(c) -(CH2)nPO(O-C1-C6 alkyl)2 in which n is an integer from 1 to 6;

(d) -(CH2)n alkyl in which n is an integer from 1 to 6;

(e) in which n is an integer from 1 to 6:

(f) in which n and m are each independently 1 or 2 and RA and RB
are each independently hydrogen or (lower)alkyl or (g) in which n is an integer from 1 to 6 and Rc is C1-C4 alkyl, phenyl or in which m is 1 or 2.

4. A compound of the formula wherein Y is hydrogen, ethyl or hydroxyethyl; Q is phenyl or (lower)alkyl, R" is an easily removable ester group and X is:

(a) a radical of the formula (i) -ORa in which Ra is hydrogen;
(ii) -ORb in which Rb is hydrogen, hydroxy, optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl group being one or more of halo, hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower)-alkylamino, di(lower)alkylamino, (lower)-alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or more of hydroxy,(lower)-alkoxy, halo, (lower)alkyl, halo(lower)-alkyl, methanesulfonyl, oxo, (lower)alkyl-thio, 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 hetero-cyclic groups being (i) or in which R1 is hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzyl;
(ii) -ORd in which Rd 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 and heterocyclic groups being as defined under (a)(ii);
(iii) -O(CH2)nORr in which n is an integer from 1 to 6 and Rr is optionally sub-stituted (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 Rr' is amino, (lower)-alkylamino, di(lower)alkylamino or Rr, with the proviso that Rr' may not be unsubstituted (lower)alkyl;
(v) -OSO3H;

(vi) (vii) -OSO2Rr in which Rr is as defined under (b)(iii);

(viii) (ORe) in which Re is (lower)alkyl and Rr is as defined under (b)(iii);
(ix) -S(O)nRd in which n is 1 or 2 and Rd is as defined under (b)(ii) or is in the case where n=0 in which R4 is hydrogen or (lower)alkyl and R5 and R6 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, -NHNH2, -NR17NR18, -NHOR19, -S-R17, -O(CH2)n -A-Re or -NR3Rg in which R17, R18 and Re are (lower)alkyl R19 is hydrogen or (lower)alkyl, A is O, S, NH or NCH3 and n and Rg are as defined under (b)(iii) and (b)(viii);
(xi) -PO(ORw)2 in which Rw is hydrogen or (lower)alkyl;

(xii) -NHRh in which Rh is optionally substituted phenyl, optionally substituted heterocyclic, -CH=NH, -SO3H, -OH, (lower)alkoxy, amino, (lower)alkylamino, di(lower)alkylamino, -NHCOCH3, -CS2CH3,-SO2CH3, , -SO2NH2, , , in which R7 and R8 are each independently (lower)alkyl, phenyl or phenyl(lower)alkyl, in which R9 is (lower)alkyl, phenyl or phenyl(lower)-alkyl, or in which Ri is amino(lower)-alkyl, -NH2, (lower)alkylamino, di(lower)-alkylamino, , in which R10 is (lower)alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being defined under (a)(ii), , (lower)alkoxy, , or -O(CH2)2Si(CH3)3;
(xiii) n which R11 is (lower)alkyl substituted by amino, (lower)alkylamino or di(lower)alkylamino;
(xiv) -NR Rk in which Rj is (lower)alkyl and Rk is (lower)alkyl, (lower)alkoxy, heterocyclic, amino, or in which Ri is as defined under (b)(xii) or, when taken together with the nitrogen, Rj and Rk represent , providing that when Rk is amino or -CH2CH2NH2, Rj is methyl and also providing that Rj and Rk may not both be (lower)alkyl;
(xv) -NRj'Rk' in which Rj' is (lower)alkoxy and Rk' is tlower)alkyl, heterocyclic, amino(lower)alkyl, (lower)alkylamino-(lower)alkyl, di(lower)alkylamino(lower)-alkyl or in which Ri is as defined under (b)(xii) or, when taken together with the nitrogen, Rj' and Rk' represent ;

?
(xvi) -NR1RmRn in which R1, Rm and Rn are each 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 de-fined under (a)(ii);
(xviii) -N=CRXRy in which Ry 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);
(xix) =N-Rp in which Rp is hydroxy, (lower)alkoxy, amino, di(lower)alkylamino or ; or (xx) in which n is an integer from 1 to 6 and R15 and R16 are each in-dependently hydrogen or (lower)alkyl.

5. A compound according to claim 4, wherein Y is hydrogen or .alpha.-hydroxyethyl and X is a radical of the formula (a) in which n is an integer from 1 to 6;
(b) -(CH2)nNHOH in which n is an integer from 1 to 6;

(c) -(CH2)nPO(O-C1-C6 alkyl)2 in which n is an integer from 1 to 6;

(d) alkyl in which n is an integer from 1 to 6;

(e) in which n is an integer from 1 to 6;

(f) in which n and m are each independently 1 or 2 and RA and RB
are each independently hydrogen or (lower)alkyl;
or (g) in which n is an integer from 1 to 6 and Rc is C1-C4 alkyl, phenyl or in which m is 1 or 2.