CARBAPENAM COMPOUND AND PROCESSES FOR THE PREPARATION THEREOF

Abstract: This invention relates to a new carbapenam compound and salt thereof. More particularly, it relates to a new carbape­ nam compound and salt thereof, which are useful intermedi­ ates for preparing carbapenam antibiotics, and to processes for the preparation thereof.

Description: CARBAPENAM COMPOUND AND PROCESSES FOR TXE PREPARATION THEREOF This invention relates to a new carbapenam compound and salt thereof. more particularly, it relates to a new carbapenam compound and salt thereof, which are useful intermediates for preparing carbapenem antibiotics, and to processes for the preparation thereof. Accordingly, one object of this invention is to provide a new carbapenam compound and salt thereof, which are useful intermediates for preparing carbapenem antibiotics having a strong antimicrobial activity against pathogenic microorganisms and 6-lactamase inhibitory activity. Anothor:object of this invention is to provide processes for the preparation of the carbapenam compound and salt thereof. The object carbapenam compound can be represented by the following formula EMI2.1 or a salt thereof in which R1 is l-hydroxy-l-methylethyl or l-protected hydroxy-l-methylethyl and R2 is carboxy or a protected carboxy. In the object compounds and the starting compounds in Processes 1 to 3 and methods A to B mentioned below, it is to be understood that there may be one or more stereoisomeric pair(s) such as optical and/or geometrical isomers due to asymmetric carbon atom(s) and double bond(s) in those molecules, and these isomers are also included within the scope of the present invention. With regard to the object compounds (I), it is to be noted that the 3,7-dioxo-l-azabicyclo[3.2.O]heptane ring system of the following formula (I) is well known to lie in tautomeric relation with the 3-hydroxy-7-oxo l-azabicyclo[3.2.Ohept-2-ene ring system of the following formula (I'), and accordingly, it is to be understood that both of these ring systems are substantially the same. EMI2.2 in which R1 and R2 are each as defined above. Suitable salts of the object compounds (I) are conventional basic and may include an inorganic basis salt, for example, a metal salt such as an alkali metal salt (e.g. Wodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), and an ammonium salt etc.; an organic basic salt, for example, an organic amine salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino)methane salt, etc.) etc. and the like. According to the present invention, the object compounds (I) and salts thereof can be prepared by the processes as illustrated by the following reaction schemes. EMI3.1 EMI4.1 or a salt thereof in which * and R2 are each as defined above. The starting compound (IIa) and other useful intemediate compounds for preparing carbapenem compound (e.g. carpetimycin, thienamycin, etc.) can be prepared, for example, by the following methods. Method A EMI4.2 EMI5.1 EMI6.1 EMI7.1 in which R1 15 lower alkyl or hydroxy(lower)alkyl, Rb1 is lower alkyl, hydroxy(lower)alkyl or a protected hydroxy(lower)alkyl, R3 is carboxy or a protected carboxy, and R4 and R5 are each lower alkyl. Further, the object compounds (I) or a salt thereof cansbe led to the carbapenem antibiotics and salts thereof, for example, by the process as illustrated by the following reaction schemes. Processes for preparing carbapenam antibiotics EMI8.1 in which R1 and R2 are each as defined above, R6 is acyl, R7 is acylamino(lower)alkyl or acylamino(lower) alkenyl, and Ra7 is amino(lower)alkyl, acylamino(lower)alkyl or acylamino (lower) alkenyl. In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in details as follows. The term "lower" is intended to mean 1 to 6 carbon atoms, unless otherwise indicated. Suitable "protected hydroxy moiety" in the terms "l-protected hydroxy-l-methylethyl" and "protected hydroxy(lower)alkyl" may include a hydroxy group substituted by a conventional hydroxy-protective group, which is commonly used in ss-lactam compounds such as thienamycin or carpetimycin derivatives or its analogue, for example, acyl such as mono(or di or tri)phenyl(lower)alkoxycarbonyl optionally substituted by nitro (e.g. benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.), ar(lower) - alkyl such as mono(or di- or tri)phenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.), trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, isopropyl-dimethylsilyl, tert-butyl timethylsilyl, diisopropyl-methylsilyl, etc.), triarylsilyl (e.g. triphenylsilyl, etc.) or triar(lower)alkylsilyl (e.g. tribenzylsilyl, etc.), and the like. Suitable "protected carboxy group" may include an esterified carboxy group which is commonly used in S-lactam compounds such as penicillin and cephalosporin compounds at their 3rd and 4th positions thereof. Suitable "ester moiety" in "esterified carboxy group" may include lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, tertpentyl ester, hexyl ester, etc.), lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.), lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.), lower alkoxy(lower)alkyl ester (e.g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, l-methoxy- ethyl ester, l-ethoxyethyl ester, etc.), lower alkylthio(lower)alkyl ester (e.g. methylthiomethyl ester, ethyithiomethyl ester, ethylthioethyl ester isopropylthiomethyl ester, etc.), amino- and carboxysubstituted-lower alkyl ester (e.g. 2-amino-2-carboxyethyl ester, 3-amino-3-carboxypropyl ester, etc.), protected amino- and protected carboxy-substituted-lower alkyl ester such as lower alkoxycarbonylamino- and mono (or di or tri)phenyl(lower)alkoxycarbonyl-substituted- lower alkyl ester (e.g. 2-tert-butoxycarbonylamino-2 benzhydryloxycarbonylethyl ester, 3-tert-butoxyzarbonyl- amino-3-benzhydryloxycarbonylpropyl ester, etc.), mono (or di or tri)haloClower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkanoyloxy (lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, isobutyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-ropionyloxyethyl ester, l-acetoxypropyl ester, etc.), lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester, etc.), ar(lower)alkyl ester which may have one or more substituent(s) such as monocor di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydryl ester, trityl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.), aryl ester which may have one or more suitable substituents (e.g. phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc.), heterocyclic ester (e.g. phthalidyl ester, etc.), trisubstituted silyl ester (e.g. trimethylsilyl ester, triethylsilyl ester, tert-butyl-dimethylsilyl ester, isopropyldimethylsilyl ester, phenyl-dimethylsilyl ester, etc.), and the like. More preferred example of the protected carboxy group thus defined may be mono(or di or tri)phenyl(lower)alkoxycarbonyl which may have nitro, and the most preferred one may be 4-nitrobenzyloxycarbonyl. Suitable "lower alkyl" and "lower alkyl moiety" in the terms "hydroxy(lower)alkyl", "protected hydroxy(lower)alkyl", "amino (lower) alkyl" and "acylamino(lower)alkyl" may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, and the like, in which the preferred one may include C1-C3alkyl. Suitable "lower alkenyl moiety" in the term "acylamino(lower)alkenyl" may include vinyl, propenyl and the like. Suitable "acyl moiety" in the terms "acylamino (lower)alkyl" and "acylamino(lower)alkenyl" may include lower alkanoyl (e.g. formyl, acetyl, etc.), phenyl (lower)alkoxyzarbonyl which may have nitro (e.g. benzyloxyzarbonyl, 4-nitrobenzyloxycarbonyl, etc.), and the like. Suitable "acyl" may include a residue of an organic sulfonic or phosphoric acid such as diaryloxyphosphoryl (e.g. diphenoxyphosphoryl etc.). Suitable salts of the compounds (V) to (IX) and (XV) to (XVIII) may include the same as those for the object compound (I). Suitable salts of the compounds (II), (IIa), (IIIj and (IV) are conventional basic or acidic salts and aY include an inorganic basic salt, for example, a meta salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium slat, etc.), and an ammonium salt etc.; an organic basic salt, for example, an organic amine salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino)methane salt, etc.] etc.; an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like. Suitable salt of the compound (XIV) may include the same acid addition salt as those for the compounds (it), (aha), (III) and (IV). The processes for preparing the object compounds (I) of the present invention are explained in details in the following. Process 1 The compound (III) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with malonic acid or its derivative or a salt thereof. Suitable salt of the malonic acid or its derivative may include the same salt with a base as that for the compound (I). Suitable derivative of the malonic acid may include mono- or di-ester such as exemplified in the explanation of "protected carboxy group". The reaction can be carried out in a conventional solvent such as dioxane, tetrahydrofuran, N,Ndimethylformamide or any other organic solvents which do not adversely influence the reaction, or a mixture thereof, in the presence of a condensing agent such as carbodiimide compounds (e.g. N,N'-diethylcarbodiimide, N,N-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N' -morpholinoethylcarbodiimide, N-cyclohexyl-N' - (4-diethylaminocyclohexyl) - carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,); N,N'-carbonylbis-(2-methylimidazole); keteneimine compounds (e.g. pentamethyleneketene-Ncyclohexylimine, diphenylketene-N-cyclohexylimine,); ethoxyacetylene; l-alkoxy-l-chloroethylene; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl chloride; a combination of triphenylphosphine with carbon tetrachloride or diazenedicarboxylate; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; l-(p-chlorobenzenesulfonyloxy)-6- chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.;¯or the like. The reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming. Process 2 The compound (tV) or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with acid azide. Suitable acid azide may include arenesulfonyl azide which may have substituent (e.g. benzenesulfonyl azide, p-toluenesulfonyl azide, p-carboxybenzenesulfon-l azide, etc.), lower alkenesulfonyl azide (e.g. methanesulfonyl azide, ethanesulfonyl azide, etc.), and the like. The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, methylene chloride, acetonitrile, N,N-dimethylformamide or any other organic solvents which do not adversely influence the reaction, or a mixture thereof, in the presence of an inorganic or organic base such as an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), tri(lower)alkylamine (e.g. trimethylamine, triethylamine, N,N-diisopropyl-Nethylamine, etc.), pyridine compounds (e.g. pyridine, picoline, lutidine, N,N-di(lower)alkylaminopyridine such as N,N-dimethylaminopyridine, etc.), quinoline, N-lower alkylmorphorine (e.g. N-methylmorphorine, etc.), N,N-di(lower)alkylbenzylamine (e.g. N,N-dimethylbenzylamine, etc.), and the like. The reaction temperature is not critical, and the reaction is usually carried out under from cooling to=warming. Process 3 The compound (I) or a salt thereof can be prepared by subjecting the compound (IV) or a salt thereof to cyclization. The reagent used in this cyclization reaction may include metal (e.g. cupper, etc.), metallic acetate (e.g. lead acetate, palladium acetate, rhodium acetate, cupric acetate, etc.), metallic sulfate (e.g. cupric sulfate, etc.), and the like. The reaction is usually carried out in a conventional solvent such as benzene, toluene, tetrahydrofuran, dioxane, acetonitrile or any other organic solvents which do not adversely influence the reaction, or a mixture thereof. The reaction temperature is not critical, and the reaction is usually carried out from at ambient temperature to heating. Methods A to B for preparing the new starting compound (II) used in Process 1 are explained in details in the following. Method A-l : (V) g (VI) The compound (VI) or a salt thereof can be prepared by reacting the compound (V) or a salt thereof with a metal amide and then reacting the resultant compound with a lower alkylating agent or a hydroxy(lower)alkylating agent such as an oxo(lower)alkane or a lower alkyl halide. The metal amide to be used in this reaction may include an alkali metal amide (e.g. lithium isopropyl cyclohexylamide, etc.) and the like. The oxo(lower)alkane to be used in this reaction may include acetone, acetaldehyde and the like. The lower alkyl halide to be used in this reaction may include metal iodide, ethyl iodide and the like. This reaction is usually carried out in a conventional solvent which does not adversely influence the reactiow such as tetrahydrofuran, dimethoxyethane, ether and the like. The reaction temperature of this reaction is not critical and the reaction is preferably carried out from under cooling to at ambient temperature. Method A-2 : (VII) (VIII) Method B-l : (X) ° (XI) The compounds (VIII) or a salt thereof and (XI) can be prepared by reacting the corresponding compounds (VII) or a salt thereof and (XI) with an organo lithium compound, respectively and then reacting the resultant compound with a lower alkylating agent or a hydroxy Clower)alkylating agent such as an oxo(lower)alkane or mono(or di) lower alkyl sulfate. The organo lithium compound may include alkyl lithium (e.g. n-butyl lithium, etc.), aryl lithium, aralkyl lithium and the like. The oxo(lower)alkane to be used in this reaction may include acetone, acetaldehyde and the like. Mono(or di) lower alkyl sulfate may include mono(or di)methyl sulfate, mono(or di)ethyl sulfate and the like. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as tetrahydrofuran, dimethoxyethane, ether and the like. The reaction temperature of this reaction is not critical and the reaction is preferably carried out from under cooling to at ambient temperature. Method A-3 : (VIII) ' CVI) Method B-2 : CXI) CXII) The compounds (VI) or a salt thereof and CXI I) can be prepared by subjecting the corresponding compounds (VIII) or a salt thereof and (XI) to removal reaction of the isocyano group, respectively. This removal reaction can be carried out in the presence of a reducing agent such as di(or tri)alkyltin hydride (e.g. tri(n-butyl)tin hydride, etc.), triaryltin hydrid (e.g. triphenyltin hydride, etc.) and the like. Tbe reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, lower alkanol (e.g. methanol, ethanol, propanol, etc.), tetrahydrofuran, N,N-dimethylformamide, benzene, toluene, etc., or a mixture thereof. The reaction temperature of this reaction is not critical and the reaction is preferably carried out from under cooling to under warming. Method A-4 : (VI) b (IX) Method B-3 : (XII) B (XIII) The compounds (IX) or a salt thereof and (XIII) can be prepared by subjecting the corresponding compounds (VI) or. a salt thereof and (XII) to introducing reaction of the hydroxy-protective group, respectively. The introducing agent of the hydroxy-protective group used in this reaction may include an acylating agent [e.g. an organic carboxylic, carbonic and sulfonic acid or a reactive derivative thereof (e.g. acid halide, an acid anhydride, an activated amide, an activated ester, etc.)], and the like. Suitable examples of the introducing agent may include phenyltlower)alkyl haloformate which may have nitro (e.g. 4-nitrobenzyl chloroforrnate, etc.) and the like; This introduction reaction is preferably carried out in the presence of an organic or inorganic base such as alkyl lithium (e.g. n-butyl lithium, etc.). The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as dioxane, benzene, tetrahydrofuran, N,N-dimethylformamide, pyridine, hexamethylphosphoramido, etc. or a mixture thereof. THis raction temeprature is not critical and the reaction is usually carried out from under cooling to at ambient temperature. Method B-4 : (XIII) b (XIV) The compound (XIV) or a salt thereof can be prepared by hydrolysing the compound (XIII). This hydrolysis is usually carried out in the presence of an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, acetic acid and the like. This hydrolysis can be carried out in a conventional solvent which does not adversely influence the reaction such as water or the like. This reaction temperature is not critical and the reaction is usually carried out from under cooling to under heating. Method A-S : (IX) g (II) Method B-5 : (XIV) g (II) The compound (IIa) or a salt thereof can be prepared by oxidizing the corresponding compound (IX) or a salt thereof or (XIV) or a salt thereof. This oxidation is usually carried out in the presence of an oxidizing agent such as ozone in combination with a per acid (e.g. m-chloroperbenzoic acid, etc.), alkali metal permanganate (e.g. potassium permanganate, etc.), alkali metal permanganate in combination with alkali metal periodate (e.g. sodium periodate, etc.), a mixture of chromium trioxide and sulfuric acid, a base salt of dichromic acid (e.g. pyridinium dichromate , etc.) or the like. This reaction is usually carried out in the presence of a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, tetrahydrofuran, dioxane, acetone, dichloromethane, N,N-dimethylformamide, a mixture thereof or the like. The suitable reaction solvent is selected according to a kind of the oxidizing agent to be used. This reaction temperature is not critical and the reaction is usually carried out from under cooling to under heating. The process for preparing the carbapenem antibiotics from the object compound (I) or a salt thereof are explained in detail in the following. Processes for preparing the carbapenem antibiotics The compound (V) or a salt thereof can be prepared by reacting the compound (I) or a salt thereof with an acylating agent. The present reaction can be carried out in a conventional acylation manner. Suitable acylating agents may be organic sulfonic or phosphoric acid or its reactive derivative such as acid halide, acid anhydride, and the like, for example, diarylphosphoryl halide (e.g. diphenylphosphoryl chloride, ditolylphosphoryl chloride, etc.), and the like. The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, hexamethylphosphoramide, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethglsulfoxide, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction, or a mixture thereof. When tht-acylating agent is used in a free acid form or its salt form in this reaction, the reaction is preferably carried out in the presence of a conventional condensing agent as exemplified in the explanation of the process 1. The reaction may also be carried out in the presence oflcan inorganic or organic base as exemplified in the explanation of the process 2. The reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming. The compound (XV) or a salt thereof can be isolated in a conventional manner, but can also be used as the starting compound of the Second Step without any isolation. The compound (XVI) or a salt thereof can be prepared by reacting the compound CXV) or a salt thereof with a thiol compound of the formula : R7SH CR7 is the same as defined above) or a salt thereof. Suitable salt of the thiol compound may include the same salt with a base as that for the compound (I). The reaction is usually carried out in a conventional solvent such as those given in the explanation of the First Step. The reaction may also be carried out in the presence of an inorganic or organic base such as those given in the explanation of the First Step. The reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming. The compound (XVI I) or a salt thereof can be prepared by subjecting the compound (XVI) or a salt thereof to removal reaction of the protective group(s). The present reaction is carried out in a conventional method such as hydrolysis, reduction, and the like. Hydrolysis is preferably carried out in the presence of a base or an acid in a conventional manner. The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming. The reduction method applicable for this removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), and the like. The reaction is usually carried out in a conventional solvent such as water, alkanol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid or any other organic solvents which do not adversely influence the reaction, or a mixture thereof around a neutral condition. The reaction temperature is not critical, and the reaction is usually carried out under from cooling to warming. The removal methods can be selected according to the kind of the protective groups to be removed. The compound (XVIII) or a salt thereof can be prepared by oxidizing the compound (XVI) or a salt thereof. T-he present oxidation reaction can be carried out in a similar manner to that in Method A-5, accordingly the reaction condition of present oxidation can be referred to that in Method A-5. The following test data show an antimicrobial activ o the representative compound of the carbapenem compounds (XVI) and (XVII). Test Method. One loopful of an overnight culture of each test strain in Trypticase-soy broth (108 viable cells per ml.) was streaked on heart infusion agar (HI-agar) containing graded concentrations of antibiotics, and the minimal inhibitory concentration (MIC) was expressed in terms of g/ml after incubations at 37 C for 20 hours. Test Compound Potassium (5R,6R)-3-(2-aminoethylthio)-6-(1hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate. Test Result EMI22.1 <tb> Test <SEP> organisms <SEP> MIC( g/ml) <tb> <SEP> Staphylococcus <SEP> aureus <SEP> 6 <SEP> 1.56 <tb> Pseudomonas <SEP> aeruginosa <SEP> 12.50 <tb> NCTC-10490 <tb> The following Preparations and samples are given :or the purpose of illustrating the present invention. Preparation 1 EMI23.1 r ixture of methyl Z-[(3S, 4R)-4-chloro-3- phthalimido-Z-oxoazetidin-yl]-3-methyl-2-butenoate (3.55 g) and allyltrimethylsilane (2.26 ml) in methylene chloride (25 ml) was cooled to -780C, and silver tetrafluoroborate (2.29 g) was added. The mixture was stirred for 2 hours during which time the temperature was gradally raised to OOC, and the stirring was continued for another 3.5 hours. Saturated aqueous sodium chloride (10 ml) was added to the reaction mixture and the pH value of the aqueous layer was adjusted to pH 7 by adding saturated aqueous sodium bicarbonate. After stirring for 20 minutes at 0 C, the precipitate was filtered off through a pad of Celite and the filtrate was scparated into the organic layer and the aqueous layer. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to leave an oil (4.0 g), which was chromatographed on silica gel (50 g) eluting with a mixture of benzene and acetone (10:1) to give methyl Z-[(3R, 4R)-4-allyl-3-phthalimido-2- oxoazetidin-1-yl]-3-methyl-2-butenoate (2.74 g) as an oil. I.R. (CH2C12) 1770 (shoulder), 1760, 1720 cm'l N.M.R. (CDC13) d: Z.ll (s, 3H), Z.26 (s, 3H), 2.4-2.6 (m, ZH), 4.40 (m, lH), 5.0-5.3 (m,3H), 5.70 (m,lR) Preparation 2 EMI24.1 To a solution of methyl 2-[(3R, 4R)-4-allyl-3- phthalimido-2-oxoatetidin-1-yl]-3-methyl-2-butenoate (2,64 g) in a mixture of methylene chloride (20 ml) and methanol (10 ml) was added N, N-dimethyl-1,5- propanediamine (1.98 ml) and the mixture was left n. 2 refrigerator for 3 days and at room temperature or 24 hours. The reaction mixture was evaporated and the residue. was dissolved in ethyl acetate (30 ml) washed with water, dried over magnesium sulfate anc evaporated to give an oil, which was chromatographed on silica gel eluting with a mixture of methylene chloride and acetone (6-5 : 1) to give methyl '-[(4R)- 3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (873 mg) as an oil. I R (CH2CL2) : 1755, 1720 cm 1 Preparation 3 EMI25.1 To a solution of methyl 2-[(3R, 4R)-4-allyl-3- phthalimido-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (6,78 g) in a mixture of methylene chloride (46 ml) and methanol (23 ml) was added N, N-dimethyl-1,3propanediamine (6.25 ml) at 0 C and the mixture was left at room temperature for 5 days. The reaction mixture was evaporated and the residue was chromatographed on silica gel eluting with a mixture of methylene chloride and ethyl acetate (10 : 1-5) to give methyl 2-[(3R, 4R)-3-amino-4-allyl-2-oxoazetidin1-yl]-3-methylbut-2-enoate (3.70 g) as an oil. I R (CH2Cl2): 1755, 1720 cm-Ú NMR (CD3COCD3) 6. 1.92 (3H, s), 1.15 (3H, s), 2.45 (broad t, 2H, J = 6, 5Hz), 3.73 (3H, s), 4.13 (d and t, 1H, J = 6.5 Hz, 2.5 Hz), 4.58 (1H, d, J = 2.5 Hz), 4.9 = 5.2 (2H, m), 5.5 -6.0 (1H, m). (continued to the next page) Preparation 4 EMI26.1 To a solution of methyl 2-[(3R, 4R)-3-amino-4-allyl- 2-oxoazetidin-1-yl]-3-methylbut-2-enoate (500 mg) in dichloromethane (5 ml) was added acetic formic anhydride (.0.34 ml) at 00. After stirring at the same temperature for one hour, the mixture was diluted with ethyl acetate C3S ml) and washed with a dilute aqueous sodium bicarbonate. The aqueous layer was saturated with sodium chloride and extracted with dichloromethane. The extracts were combined, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (2.i g) eluting wit- 10-30% acetone in dichloromethane afforded methyl 2-[(3R, 4R)-3-formamido-4-allyl-2-oxoazetidin-1-yl]-3methylbut-2-enoate (485 mg.) IR (CH2Cl). 3400, 1760, 1720 (sh), 1695 cm-Ú NMR (CDCl3) 6: 1.97 (s, 3H), 2.21 (s, 3H), 2.47 (t, J = 7Hz, 2H), 3.76 (s, 3H), 3.95 (dt, J = 3, 7Hz, 1H), 4.77 (dd, J = 3, 7Hz, 1H), 4.9-5.5 (m, 2H), 5.5-6.0 (m, 1H), 7.15 (brd, j = 7Hz, 1H), 8.19 (s, 1H) Mass Spectrum: m/e 266 (M ) Preparation 5 EMI27.1 2.6-Lutidine (3.82 ml) and phosphorus oxychloride (1.37 ml) were added to a solution of methyl 2-[(3R, 4R)- 3-formamido-2-oxo-4-allylazetidin-1-yl]-3-methylbut 2-enoate (970 mg) in dichloromethane (10 ml) at OOC, and the mixture was stirred for three hours at 0 C. Then, the reaction mixture was poured into a mixture of ethyl acetate (100 ml) and brine (50 ml). The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The oily residue was chromategraphed on silica gel ClS g) eluting with a mixture of hexane and ethyl acetate (10:1-3:1) to give methyl 2-[(3R, 4R)-3-isocyano-2 oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (766 mg) as an oil. I.R. (CH2Cl): 2145, 1775, 1720 cm-Ú N.M.R. (CDCl3) d. 1.96 (s, 3H), 2.24 8s, 3H) 2.3-2.6 (m, 2H), 3.80 (s, 3H), 4.20 (dt, 1H, J = 2.5, 6.5 Hz), 4.98 (d, 1h, J = 2.5 Hz), 5.0-5.3 (m, 2H), 5.5-6.0 (m, 1H) Mass Spectrum: m/e 248 (M ) Preparation 6 EMI28.1 2,2'-Azabis (2-methylpropionitrile) (98 mg) and tributyltin hydride (0.95 ml) were added to a solution of methyl 2-[(3R, 4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (740 mg) in benzene 815 ml) and the mixture was refluxed for 20 minutes. The reaction mixture was chromatographed on silica gel (15 d eluting with a mixture of hexane and ethyl acetate (5:1 - 3:1) to give methyl 2-[(4R)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2enoate (660 mg). IR (CH2Cl): 1750, 1720 cm-Ú NMR (CDCl3) #: 1,97 (s, 3H), 2.20 (s, 3H), 2.3-2.5 (m, 2H), 2.65 (dd, 1H, J = 3, 16 Hz), 3.11 8dd, 1H, J = 5, 16 Hz), 3.77 (s, 3H), 3.7-4.2 (m, 1H), 4.8-5.3 (m, 2H), 5.4-6.1 (m, 1H) Preparation 7 EMI29.1 A 0,9M solution of diethylaluminum chloride in hexane (24.4 ml) was added to a suspension of activated zinc powder 4.0 g) in etrahydrofuran (60 ml). After ten minutes the mixture was cooled to -20 C, A solution of methyl 2-[(3S, 4R)-3-bromo-4-methylthio-2-oxoazetidin1-yl]-3-methylbut-2-onoate (6.16 g) and acetone (1.84 m1) in tetrahydrofuran (4S ml) was added dropwise during 33 minutes at .2000 under a nitrogen atmosphere. The resulting mixture was stirred at -15 to -10 C for 1.5 hours and at coo for 30 minutes. The reaction was quenched by addition of pyridine (3 ml). After ten minutes 2N hydrochloric acid (40 ml) and ethyl acetate (100 ml) were added. The mixture was filtered through diatomaceous earth and the filtrate was diluted with N hydrochloric acid (4C ml) and ethyl acetate (100 ml). ±ne mixture was shaken and the organic layer was sepzrated, The aqueous layer was extracted with ethyl acetate (50 ml). The combined extracts were washed three times with brine, dried over magnesium sulfate, and evaporated to give an oil (6.0 g), The residue was chromatographed on silica gel (150 g, eluting with 2 to 25% acetone in dichloromethane) to give 3.79 g (66.0%) of methyl 2-[(3S, 4R)-3-(1-hydroxy-1-methylethyl)-4methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate and 1.36 g of impure material. rechromatography of the impure fraction on silica gel (100 g, eluting with 2 to 25% acetone in dichloromethane) afforded an additional 0.93 g (16.2%) of the desired product: 1F (CH2CH, 3550, 1745, and 1715 cm-Ú; NMR(CDCl3) #: 1.34 (s, 3H), 1.41 (s, 3H), 2.00 (s, 3H), 2.15 (s, 3H), 2.21 (s, 3H), 2.56 (s, 1H), 3,14 (d, J = 3Hz, 1H), 3.75 (s, 3H), and i.01 Cd, J=3H:, 1H), Preparation 8 EMI30.1 A 1.55 N solution of n-butyl lithium in hexane (0.44 ml) was added dropwise to a solution of methyl 2-[(3S, 4R)- 3-(1-hydroxy-1-methylethyl)-4-methylthio-2-oxoazetidin1-yl]-3-methylbut-2-enoate (164 mg) in tetrahydrofuran C2 ml) at -78 C under a nitrogen atmosphere. After five minutes a solution of 4-nitroben=yl chloroformate (147 mg) in tetrahydrofuran (1.5 ml) was added. The mixture was allowed to warm to 00C during 1.5 hours and stirred at the same temperature for 30 mites, After being left at ambient temperature for 30 minutes, the reaction was quenched by addition of acetic acid (three drops). The mixture was evaporated, and the residue was taken up into ethyl acetate (20 ml) and washed in turn with a dilute aqueous solution of sodium bicarbonate and brine. Drying over magnesium sulfate and removal of the solvent left an oil which was chromatographed on silica gel (6.5 g; eluting with 5 to 2% ethyl acetate in dichloromethane for the desired product followed by 20% acetone in dichloromethane for the starting material) to give 179 mg of the desired product contaminated with some impurities and 5 mg [32.7% recovery) of the starting material. further purification of the impure product on silica gel plates (20 cm x 20cm x 2 am, two pieces; twe developments with 2/1 hexane-ethyl acetate) afforded 138 mg (51.8%; ie 83.4% based on consumed starting material) of methyl 5-methyl-2-[(3S, 4R)-3- [1-methyl-1-(4-nitrobenzyloxycarbonyloxy) ethyl]-4methylthio-2-oxoazetidin-1-yl] but-2-enoate; IR(CH2Cl2) 1750, 1720, 1520 and 1350 cm-Ú; NMR (CHCl3) #: 1.64 (s, 3H), 1.71 (s, 3H), 2.01 (s, H), 2.09 (5, 3H), 2.23 (s, 3H), 3.70 (1H, hidden), 3.75 (s, 3H), 5.07 (d, J = 3Hz, 1H), 5.20 (s, 2H), 7,57 (d, J = 9Hz, 2H) and 8.18 (d, J=9Hz, 2H), Preparation 9 EMI31.1 A solution of chlorine (70 mg) in carbon tetrachloride (1.75 ml) was added to a solution of methyl 3-methyl2-[(3S, 4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-methylthio-2-oxoazetidin-1-yl] but-2-enoate (380 mg) in dichloromethane (4 ml) at .78 C. The mixture was allowed to warm to OOC during 40 minutes anc evaporated. The residue was dissolved in ca arbon tetrachloride (5 ml) and evaporated. This procedure Was repeated once and the residue was chromatographed on silica gel (8 g, eluting with 10 to 30% ethyl acetate in hexane) to give a 4.1 mixture of methyl 2-[(3S, 4R)-4-chloro-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methyllb: 2-enoate [(3S, 4R)-isomer] and its (3S, 4S)-isomer: IR (CH2Cl2): 1770, 1745, 1720, 1520 and 1350 cm-Ú NMR (CDCl3) o: 1.67 Cs, 2.4H), 1.74 (s, 2.4Hj, 1.79 (s, 0.6H), 1.82 (s, 0.6H), 2.02 (s, 2.4H), 2.08 (s, 0.6H), 2.30 (s, 3H), 3.74 (s, 2.4H), 3.75 (s, 0.6H) 3.93 (d, J = 2Hz, 0.8H), 4.02 (d, J-4Hz, 0.6H), 5.21 (s, 2H), 5.91 Cd, J = 2Hz, 0.8H), 5.95 (d, partially hidden, 0.ZH), 7.53 (d, J=9Hz, 2H), and 8.22 (d, J = 9 Hz, 2H). reparation 10 EMI32.1 Methyl 3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-methylthio-2-oxoazetidin1-yl]but-2-enoate (ss25 mg) was chlorinated in the same manner described above. Chromatography of the product on silica gel (10 g; eluting with 10 to 30% ethyl acetate in hexane) afforded 294 mg (70.9%) of methyl 2-[(3S,4R)-4-chloro-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methylbut-2 enoate [(3S,4R)-isomer] and 80 mg of the (35,45)-isomer contaminated some impurities. Crystallization of the impure (35,45)-isomer from ether gave 35 mg of the pure (3S,4R)-isomer. Spectral Data the (3S,4R)-isomer : IR (CH2Cl) : 1775, 1740, 1720, 1520 and 1350 cm-1; NMR (CDCl3)6: 1.66 (s, 3K), 1.71 (s, 3H), 2.02 Cs, 3H), 2.30 (s, 3H), 3.74 (s, 3H), 3.93 (d, J=2Hz, 1H), 5.20 (s, 3H), 5.91 (d, J=2Hz, 1H), 7.52 (d, J=8Hz, 2H), and 8.20 (d, J=8Hz, 2H). the (3S, 4R)-isomer : IR (CH2Cl2) : 1775, 1740, 1725, 1520, and 1350 cm-1; NMR (CDCl3) 6: 1.78 (s, 3H) 1.81 (s, 3H), 2.07 (s, 3H), 2.29 (s, 3H), 3.74 (s, 3H), 4.00 (d, J=5Hz, 1H), 5.18 (s, 2H), 5.93 (d, J=5Hz, 1H), 7.46 (d, J=9Hz, 2H), and 8.16 (d, J=9Hz, 2H). Preparation 11 EMI33.1 J=6, 8Hz), 3.75 (s, 3H), 4.04 (dt, 1H, J=6, 7Hz), 4.95.2 (m, 2H), 5.4-5.9 (m, 2H); and methyl 3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4allylazetidin-1-yl]but-3-enoate (28 mg); IR (CH2Cl2) : 1740 cm 1 NMR (CDCl3) # : 1.27 and 1.29 (a pair of d, 3H, J=8Hz 1.83 (broad s, 3H), 2.1-2.9 (m, 2H), 2.85 (dq, 1H, J=2, 8Hz), 3.2-3.4 (m, 1H), 3.74 and 3.76 (a pair of s, 3H), 4.8-5.2 (m, 5K), 5.5-6.0 (m, 1H); and a mixture of methyl 3-methyl-2-[(3R,4R)-3-methy 2-oxo-4-allylazetidin-1-yl]but-2-enoate and methyl 3-methyl-2-t(3S,4R)-3-methyl-2-oxo-4-allylasetidin-l- yl]but-3-enoate (36 mg) IR (CH2Cl2) : 1740 cm 1 Preparation 12 EMI35.1 1.55M Butyl lithium-hexane solution (1.66 ml) was added to a solution of N-isopropylcyclohexylamine (0.29 ml) in tetrahydrofuran (3 ml) at -700C, and the mixture was stirred for 20 minutes at -70 C and allowed to warm up to 0 C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4- allylazetidin-1-yl]but-2-enoate (100 mg) in tetrahydrofuran (3 ml) at -700C, and the mixture was stirred for 1 hour at -700C and allowed to warm up to -30 C during 30 minutes. IN Hydrochloric acid (3.6 ml) was added to the reaction mixture at -700C, and the mixture was diluted with ethyl acetate (30 ml). The solution was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (5:1 2:1) to give methyl 3-methyl-2-[(35,4R)-3-methyl-2- oxo-4-allylazetidin-1-yl]but-2-enoate (20 mg); IR (CH2Cl2) : 1740, 1715 cm-1; NMR (CDCl3) ô : 1.23 (d, 3K, J=8Hz), 1.95 Cs, H), 2.19 (s, 3H), 1.36 (t, 2H, J=7Hz), 3.36 (do, 1H, Preparation 13 EMI36.1 1.55M Butyl lithium-hexane solution (2.97 ml) was added to a solution of N-isopropylcyclohexylamine (0.76 ml) in tetrahydrofuran (6 ml) at -,0 C and the mixture was stirred for 20 minutes at -70 C. This mixture was added to a solution of methyl - methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2 enoate (210 mg) in tetrahydrofuran (6 ml) during minutes at -700C, and the mixture was stirred for 1 hour at -70oC and for 30 minutes at -30 C. Ethyl iodide (0.37 ml) was then added to the reactior. mixture at -70 C and the mixture was stirred for I hour at the same temperature and for 30 minutes at -30 C. 1N Hydrochloric acid t10 ml) was added to the reaction mixture at -700C and the mixture was diluted with ethyl acetate t120 ml). The solution was washed with water, brine, aqueous sodium -bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. Triethylamine (G,16 -±'j was added to a solution of the residue in dichloro- methyl (2 ml) at 0 C, and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.1N hydrochloric acid, brine, aqueous sodium bicarbonate and brine driec over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed cn si silica gel (5 ±) eluting with a mixture of hexane and ethyl acetate (10:1 - z:1) to give 169 mg of a 2.3 : 1 mixture of methyl 3-methyl-2-[(3R,4R)-3-ethyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate [(3R,4R)-isomer] and its (3S,4R) -isomer: IR (CH2Cl2) : 1740, 1720 cm-1 NMR (CDCl3) #: 1.04 and 1.12 (a pair of t, 3H, J=8Hz), 1.6-2.0 (m, 2H), 1.96 (s, 3H), 2.20 (s, 3H), 2.22,61 (m, 2H), 2,80 and 3.14 (a pair of dq, 1H, J=2,i, 7Hz and J=6, 7.5H (2.3:1), 3,70 and 4.04 Ca pair of dt, 1H, J=2.5, 7Hz and J=6, 7Hz), 3.76 (s, 3H), 4.9-5.3 (m, 2H), 5.5-6.0 (m, 1H) Preparation 14 EMI37.1 Methyl 3-methyl-2-[(3R,4R)-3-ethyl-2-oxo-4allylazetidin-1-yl]but-2-enoate [(3R,4R)-isomer] and its (oS,4R)-isomer were prepared r. z similar manner to that of preparation 13. For the (3R,4R)-isomer: IR (CH2Cl2) : 1740, 1710 cm 1 NMR (CDCl3) #: 1.32 (d, 3H, J=7.5Hz), 1.93 (s, 1H), 1.19 (s, 1H), 2.36 (q, 2H, J=8Zh), 2.84 (dq, 1H, J=2.5, 7.5Hz), 3.56 (dt, 1H, J=2.5, 8Hz), 3.72 (s, 3H), 4.9-6.3 (m, 2H), 5.5-6.0 (m, 1H). For the (3S,4R)-isomer : IR (CH2C12) : 1740, 1715 cm-1 NMR (CDCl3) # : 1.23 (d, 3H, J=8Hz), 1.95 (s, 3H), 2.19 (s, 3H), 1.36 (t, 2H, J=7Hz), 3.36 (dq, 1H, J=6, 8Hz), 3.75 Cs, 3H), 4.04 Cdt, 1H, J=6, 7Hz), 4.9-5.2 (m, 2K), 5.4-5.9 (m, 2H) EMI38.1 1.55M Butyl lithium-hexane solution (2.82 ml) was added to a solution of N-isopropylcyclohexylamire (0.72 ml) in tetrahydrofouran (6 ml) at -70 C, and the mixture was stirred for 20 minutes at -70 C. This mixture was added to a solution of methyl 3methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2enoate (247 mg) in tetrahydrofuran (6 mlj at -70 C and the mixture was stirred for 1 hour at -70 C, and for 50 minutes at -30 C, Acetone (0.12 ml) was added to the reaction mixture at -700C, and the mixture was stirred for 1 hour at -70 C and for 30 minutes at -30 C - -13 C SN Hydrochloric acid was added to the reaction mixture at -70 C and the mixture was diluted with ethyl acetate (200 ml). The solution was washed with water, brine, aqueous sodium bicarbonate and brine1 dried over magnesium sulfate, and evaporated in vacuo. Triethylamine (0.15 ml) was added to a solution of the residue i dichloromethane (3 ml) at 0 C and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (2C ml) and the solution was washed with 0.1N hydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (10:1 - 2:1) to give methyl 3-methyl-2-[(3S, 4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazeitidin1-yl]but-2-enoate (100 mg); IR (CH2Cl2) : 1740, 1715 cm-1 NMR (CDCl3) # : 1.31 (s, 3H), 1.38 (s, 3H), 1.96 (s, 3H), 2.18 (s, 3H), 2.2-2.5 (m, 3H), 2.90 (d, 1H, J=3Hz), 3.76 (s, 3H), 3.81 (dt, J=3, 7Hz), 4.9-5.2 (m, 2H), 5.5-6.0 (m, 1H) and methyl 3-methyl-2-[(3R,4R)-3-(1-hydroxy-1methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (50 mg). NMR (CDCl3) # : 1.39 (s, 3H), 1,52 (s, 3H), 1.99 (s, 3H), 2.19 (s, 3H), 2.21 (broad s, 1H), 2.74 (t, 2H, J=7Hz), 3.30 (d, 1H, J=6Hz), 3.74 (s, 3H), 4.12 (dt, 1H, J=6, 7Hz), 4.9-5.2 (m, 2H), 5.5-5.9 (m, 1H) EMI40.1 Methyl 3-methyl-2-[(3S,4R)-3-[(1RS)-1-hydroxyethyl -2-oxo-4-allylazetidin-1-yl]but-2-enoate [(3S,4R)-isomer] and methyl 3-methyl-2-[(3R,4R)-3- [(1RS)-1-hydroxyethyl -2-oxo-4-allylazetidin-1-yl]but2-enoate [(3R,4R)-isomer] were prepared in a similar manner to that of Preparation 15. For the (3S,4R)-isomer: IR (CH2C12) : 1740, 1720 cm-1 NMR (CDCl3) # : 1.32 (d, 3H, J=7Hz), 1.96 (s, 3H), 2.20 (s, 3H), 2.3-2.5 (m, 2H), 2.6 (broad s, 1H), 2.90 (dd, 1H, J=7, 2.5Hz), 3.76 (s, 3H), 3.82 (dt, 1H, J=2.5, 6Hz), 4.0-4.3 (m, 1H), 5.0-5.2 (m, 2H), 5.5-6.0 (m, 1H) For the (3R,4R)-isomer : IR (CH2C12) : 1740, 1720 cm NMR (CDCl3) # : 1.22 (d, 3H, J=5.5Hz), 2.00 (s, 3H), 2.20 (s, 3H), 2.2-2.8 (m, 3H), 3.24 (dq, 1H, J=4.5, 5.5Hz), 3.75 (s, 3H), 3.9-4.3 (m, 2H), 4.9-5.2 (m, 2H), 5.5-6.0 (m, 1H) EMI41.1 and its other isomers 1.55 Butyl lithium-hexane solution (5.63 ml) was added to a solution of N-isopropylcyclohexylamine (1.44 ml) In tetrahydrofuran (10 ml) at -70 C, ae solution was stirred for 20 minutes at -70 C and allowed to warm up to -20 during 5 minutes. This mixture was added to a solution of methyl 3 - methyl-2-[(4R)-2-oxo-4-ally-azetidin-1-yl]but-2enoate (650 mg) in tetrahydrofuran (10 ml) during 15 minutes at -700C, and the mixture was stirred for 1 hour at -70 C and for 30 minutes at -30 C. A solution of acetaldehyde (187 mg) in tetrahydrofuran (4.4 ml) was added to the reaction mixture at -70 C. ine mixture was stirred for 1 hour at -70 70 C and or 30 minutes at -30 C. 1N Hydrochloric acid (20 ml) was added to the reaction mixture at -70 C and the mixture was diluted with ethyl acetate (250 ml), The solution was washed with brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (30 g eluting with a mixture of benzene and acetone 10:1 - 3:1) to give methyl 3-methyl-2-{(3S,4R)-3-[(1RS)-1 hydroxymethyl]-2-oxo-4-allylazetidin-1-yl]but-2 enoate (278 mg) [(3S,4R)-isomer] and is other isomers (257 mg). For the (3S,4R)-isomer: IR (CH2Cl2) : 1740, 1720 cm-1 NMR (CDCl3) # : 1.32 (d, 3H, J=7Hz), 1.96 (s, 3H), 2.20 (s, 3K), 2.3-2.5 (m, 2H), 2.6 (broad s,lH), 2.90 (dd, 1H, J=7, 2.5Hz), 3.76 (s, 3H), 3.82 (dt, 1H, J=2.5, 6Hz), 4.0-4.3 (m, 1H), 5.0-5.2 (m, 2H), 5.5-6.0 (m, 1H) Preparation 18 EMI42.1 -4-Dimethylaminopyridine (79 mg) and 4 nitrobenzyl chloroformate (90 mg) were added to a solution of a 1:3 mixture of methyl 3-methyl-2 [(3S,4R)-3-[(1RS)-1-hydroxyethyl]-2-oxo-allylazetidin 1-yl]but-2-enoate (86 mg) in dichloromethane (4 ml) at 0 C and the mixture was stirred for three hours at 0 C. The reaction mixture was diluted with ethyl acetate (50 ml), and washed in turn with 0.1N hydrochloric acid (20 ml), brine, aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (2 g) eluting with hexane and ethyl acetate (5:1-2:1) to give a 1:3 mixture of methyl 3-methyl-2-(3S , 4R)- 3-[(1RS)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]2-oxo-4-allylazetidin-1-yl]but-2-enoate (122 mg) as an oil. IR (CH2Cl2) : 1746, 1715, 1520 cm-1 NMR (CDCl3) #: 1.48 (d, 3H, J=7Hz), 1.96 (s, 3H), 1,20 Cs, 3H), 2.2-2.6 (m, 2H), 3.03 and 3.18 (dd, J=7.5, 2.5Hz and dd, J=5, 2.5Hz, 1H (1:3)), 3.75 Cs, 3K), 3.8-4.0 (m, 1H), 5.0-5.3 Cm, 2H), i.27 (s, 2H), 5.5-5.9 (m, 1H), 7.89 (A2B2, 4H, J=8.5Hz) Preparation 19 EMI43.1 A 1:3 mixture of methyl 3-methyl-2-[(3S,4R)-3- [(1RS)-1-hydroxyethyl]-2-oxo-4-allylazetidin-1-yl]but 2-enoate (55 mg) was dissolved in tetrahydrofuran (2 ml) and triphenylphosphine (135 mg) and formic acid (19.4 l) were added to the mixture. This mixture was cooled to 0 C and a solution of dimethyl azodicarboxylate (81 l) in tetrahydrofuran (1 ml) was added. After stirring at the same temperature overnight, the mixture was diluted with ethyl acetate (30 ml), washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed an silica ge (5 g) eluting with hexane and ethyl acetate (10:1 2:1) to give 25 mg of methyl 3-methyl-2- -3- [(1R)-1-formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2 -enoate. IR (CH2Cl2) : 1745, 1720 cm 1 NMR (CDCl3) #: 1.42 (d, 3H, J=6Hz), 1.96 (s, 3H), 2.20 (s, 3H), 2.38 (q, 2H), J=6Hz), 3.00 (dd, 1H, J=7.5, 2.SHz), 3.76 (s, 3H), 3.7-4.0 Cm, 1H), 4.9-5.2 (m, 2H), 5.3-5.9 (m, 2H), 8.00 (s, 1H) Preparation 20 EMI44.1 Methyl 3-methyl-2-(3S,4R)-3-[(3R)-1 formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2 enoate (23 mg) was dissolved In methanol (1 ml) and cooled to 0 C, To this solution was added a solution of sodium methoxide in methanol (0.49M, 0.16 ml) and the mixture was stirred for 1 hour at the same temperature. An additional 0.08 ml of the sodium methoxide solution was added and the mixture was stirred for 30 minutes at the same temperature. Acetic acid (2 drops) was then added and the mixture was evaporated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by preparative thin layer To a solution of methyl 2-[(3S,4R)-3-[(1S)-1-(tert- butyldimethylsilyloxy)ethyl]-4-methylthio-2-oxoazetidin1-yl]-3-methylbut-2-enoate (60 mg) in dichloromethane (2 ml) was added a solution of chlorine (24 mg) in carton tetrachloride (0.2 ml) at -50 C. The solution was allowed to warm to -100C during 30 minutes and cooled to -50 C. An additional solution of chlorine (12 mg) in carbon tetrachloride (0.1 ml) was added. The solution was allowed to warm to -5 C and evaporated. The residue was chromatographed on silica gel (1.5 g, eluting with 8-10t ethyl acetate in hexane) to give 21.0 mg (36.1%) of methyl 2-[(3S,4R)-3-[(1S)-1-(tert- butyldimethylsilyloxy)ethyl]-4-chloro-2-oxoazetidin1-yl]-3-methylbut-2-enoate. NMR (CDC13) Ï : 0.12 (s, 6H), 0.93 (s, 9H), 1.34 (d, J=6.5Hz, 3H), 2.01 (s, 3H), 2.29 (s, 3H), 3.56 (dd, J=1.5, 5Hz, 1H), 3.77 (s, 3H) 4.30 (dq, J=5, 6.5Hz, 1H), 5.80 (d, J=1.5Hz, 1H). chromatography (silica gel) developing with methylene chloride and ethyl acetate (2:1) to give methyl 3-methyl-2-[(3S,4R)-3-[(1R)-1-hydroxyethyl] 2-oxo-4-allylazetidin-1-yl]but-2-enoate (20 mg). IR (CH2Cl2) : 5550, 1740, 1710 cm-1 NMR (CDCl3) #: 1.32 (d, 3H, J=7Hz), 1.96 (s, 3H), 2.20 (s, 3H), 2.3-2.6 (m, 2H), 2.90 (dd, 1H, J=7, 2.5 Hz), 3.76 (s, 3H), 4.00 (dt, 1H, J=2.5, 6.5Hz), 4.1-4.4 (m, 1H), 5.0-5.3 (m, 2H), 5.5-6.0 (m, 1H). Preparation 21 EMI46.1 Methyl 3-methyl-2-[(3S,4R)-3-[(1R)-1-(4nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazatidin-1-yl]but-2-enoate was prepared in a similar manner to that of Preparation 18. IR (CH2Cl2) : 1745, 1715, 1520 cm-1 NMR (CDCl3) # : 1.45 (d, 3H, J=6Hz), 1.94 (s, 3H), 2.19 (s, 3H), 2.37 (q, 2H, J=6Hz), 3.01 (dd, 1H, J?7.5, 2.5Hz), 3.76 (s, 3H), 3.92 (dt, 1H, J=2.3 6Hz), 4.9-5.3 (m, 3H), 5.4-5.8 (m, 1H), 7.83 (A2B2, 4H, J=9Hz) EMI47.1 Silver tetrafluoroborate (205 mg) was added to a stirred solution of 4-nitroben=yl 3-(trlmethyl silylmethyl)but-3-enoate (422 mg) and a 4:1 mixture of methyl 2-[(3S,4R)-4-chloro-3-[1-methyl-1-(4nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]3-methylbut-2-enoate and its (3S,4S)-isome- (;0; mg) in dlchloromethane (3 ml) at -780C under a nitrogen atmosphere. The mixture was gradually allowed to warm to 0 C during 40 minutes and kept at the same tem erature for one hour. ine resulting mixture was diluted wit dichloromethane (1 ml) and stirred at 0 C or 30 minutes and at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (10 ml) and a saturated aqueous solution of sodium chloride (4 ml) was added. The mixture was brought to ph ; with a saturated aqueous solution of sodium bicarbonate and filtered through diatomceous earth. The filtrate was diluted with ethyl acetate (30 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on sIlica gel (12 g, eluting with 1 to 5% acetone In dichloromethane) to give 120 mg of the desired product contaminated with some impurities, Furthe- purirication on a TLC plate (20 cm x 20cm x 2mm, 1:1 hexane-ethyl acetate) afforded 100 mg (22.3%) of methyl 3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4 nitrobenzyloxycarbonyloxy)ethyl]-4-[2-(4 nitrobenzyloxycarbonyl-methyl)allyl]-2-oxoazetidin 1-yl]but-2-enoate : IR (CH2Cl2) : 1740, 1720(sh), 1520, and 1350 cm-1; NMR (CDCl3), #: 1.65 (s, 3H), 1.69 (s, 3H), 1.98 (s, 3H), 2.19 (s, 3H), 2.48 (brd, J=7Hz, 2H), 3.13 (s, 2H), 3.44 (d, J=2.5Hz, 1H), 3.76 (s, 3H), 4.24 (dt, J=2.5 and 7Hz, 1H), 5.01 (m, 2), 5.19 (s, 2H), 5.22 (s, 2H), 7.52 (d, J=9Hz, 2H), 7.56 (d, J=9Hz), 2H), and 8.22 (d, J=9Hz, 4H). Preparation 23 EMI48.1 In a manner similar to that of Preparation 22; 258 mg of methyl 2-[(3S,4R)-4-chloro-3-[1-methyl-1-(4- nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]3-methylbut-2-enoate affored 70.0 mg (18.9%) of methyl 3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4 nitrobenzyloxycarbonyloxy)ethyl]-4-[2-(4 nitrobenzyloxycarbonylmethyl)allyl]-2-oxoazetidine 1-yl]-but-2-enoate. Preparation 24 EMI49.1 A stream of ozone was bubbled into a solution of methyl 3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4nitrobenzyloxycarbonyloxy)ethyl]-4-[2-(4nitrobenzyloxycarbonylmethyl)allyl]-2-oxoazetidin1-yl]but-2-enoate (163 mg) in ethyl acetate (10 ml) at -?8 C until a permanent blue color developed. After three minutes the excess ozone was removed by bubbling nitrogen. The solution was warmed and poured Into a mixture of ethyl acetate (10 ml) and dilute aqueous solution of sodium bisulfite (900 mg). The mixture was shaken and the organic layer was separated. The solution was washed with brine, dried over magnesium sulfate and evaporated to leave 158 mg of an amorphous solid. This residue was dissolved in dichloromethane (2.5 ml) and cooled to 0 C. Dimethyl sulfide (0.? ml) and methanol (7.5 ml) were added. The solution was stirred at 0 C for 8 hours and left at ambient temperature for i5 hours under a nitrogen atmosphere, The mixture was then heated to 55 C for 26 hours and evaporated. The residue was chromatographed on a TLC plate (20cm x 20cm x 2mm, 10% acetone in dichloromethane) to give 7S mg (58.3%) of 4-nitrobenzyl 4-[(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxazetidin-2-yl]-3 oxobutanoate : IR (CH2Cl2) : 3370, 1760, 1741, 1710, 1520, and 1345 cm-1; NMR (CDCl3) #: 1.57 (s, 3H), 1762 (s, 3H), 2.4-3.2 (m, small signals), 2.9 (n, 1.5H), 3.34 (d, J=3Hz, 1H), 3.56 (s, 2H), 3.96 (m, 1H) 5.15 (s, 2H), 5.24 (s, 2H), 6.42 (brs, 1H), 7.50 (d, J=9Hz, 4H), and 8.16 (d, J=9Hz, 4H). (The product may exist as a equilibrium mixture of the keto- and enol-form.) Preparation 25 EMI50.1 To a solution of (3R,4R)-4-(2-oxoethyl)-3- phthalimidazetidin-2-one (52 mg) in a mixture of methanol (3 ml) and dichloromethane (1 ml) was added a solution of sodium borohydride (8 mg) in methanol (2 ml) at 0 C during one hour. The reaction was quenched by addition of acetic acid (two drops). After cvaporation in vacuo, the residue was chromato- graphed on silica gel (1,6 g; eluting with 3 to 5% methanol in dichlormethane) to give 32 mg of crude crystals. Crystallization from a mixture or methanol and ether afforded 27 mg (51.5%) of (3R,4R)-4-(2hydroxyethyl)-3phthalimidoazetidin-2-one. IR (Nujol) : 3350(br), 3250, 1750, and 1705 cm-1; NMR (DMSO-d6) #: 1.79 (q, J=6Hz, 2H), 3.46 (m, 2H), 3.97 (dt, J=2.5 and 6Hz, 1H), 4.47 (brs, 1H), 4.89 (d, J=2.5Hz, 1H), 7.86 (s, 4H), and 8.42 (brs, 1H). Preparation 26 EMI51.1 Boron trifluoride etherate (5 ;1) was added to a suspension of (3R,4R)-4-(2-hydroxyethyl)-3- phthalimidoazetidin-2-one (126 mg) and 2,2-dimethoxypropane (74 ;1) in dichloromethane (3 ml) at ambient temperature. The mixture was stirred for two hours. Additional dimethoxypropane (50 ;1) was added and the mixture was stirred for an additional 1.5 hours. The resulting solution was poured into a saturated aqueous solution of sodium chloride and sodium bicarbonate and extracted twice with dichloromethane. inc combined extracts were dried over magnesium sulfate and evaporated to give a crystalline solid. Chromatography or. silica gel (4 g; eluting with h 39 acetone in dichlormethane) and washing the crystals with ether afforded 100 mg of (6R,7R)2,2-dimethyl-7-phthalamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one : IR (CH2Cl2) : 1770 aqnd 1720 cm-1; NMR (CDCl3) #: 1.56 (s, 3H), 1.81 (s, 3H), 1.7-2.0 (m, 2H), 3.7-4.1 (m, 3H), 5.01 (d, J=2Hz, 1H), and 7.5-7.9 (m, 4H). Preparation 27 EMI52.1 N,N-Dimethylaminopropylamine (91 l) was added to a solution of (6R,7R)-2,2-dimethyl-7-phthalimido- 1-aza-3-oxabicyclo[4.2.0]octan-8-one (80 mg) in a mixture of methanol (1.4 ml) and dichlormethane (0.7 ml) t 0 C under a nitrogen atmosphere. The solution was stirred at the same temperature or two hours and left at ambient temperature for 24 hours. The mixture was evaporated and the residue was chromatographed on silica gel (1.5 g; eluting with 3 to 5% methanol in dichloromethane) to give 27 mg (59.5%) of (6R,7R)-7-amino-2,2-dimethyl-1-aza-3oxabicyclo[4.2.0]octan-8-one : IR (CH2Cl2) : 31003600 (broad) and 1735 cm-1; NMR (CDCl3) #: 1.41 (s, 3H), 1.72 (s, 3H), 1.5-2.1 (m, 4H), 3.34 (ddd, J=2, 5 and 10 Hz, 1H), and 3.7-3.9 (m, 3H) EMI52.2 To a solution of methyl 2-[(3R,4R)-3-isocyano- 2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (106.9 mg) in tetrahydrofuran (2.1 ml) was added dropwise z solution of n-butyl lithium (0.375 ml of 1.38M solution in hexane) at -78 C. After stirring for 15 minutes at -78 C, the reaction mixture was added wit a solution of acetone (0.0385 ml) in tetrahydrofuran (C.3465 ml) at -780C. After stirring for 25 minutes at -78 C, the reaction mixture was added with acetic acid (0.0493 ml) at -78 C, diluted with ethyl acetate (30 ml), and washed with chilled brine (10 ml), aqueous sodium bicarbonate (10 ml), brine (10 ml) , and saturated aqueous sodium chloride (10 ml). After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo, The residual oil was chromatographed on silica gel (1.2 g) eluting with a mixture of ethyl acetate and hexane (1:5 - 1:3) to give methyl 2-[(3R,4R)-3-(1- hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin1-yl]-3-methylbut-2-enoate (96.i mg) as an oil. IR (CH2Cl2) : 2115, 1770, 1720 cm-1 NMR (CDCl3) #: 1.40 (s, 3H), 1.53 (s, 3H), 1.97 (s, 3H), 2.23 (s, 3H), 2.39 (s, 1H), 2.53 (t, 2H, J=7Hz), 3.76 (s, 3H), 4.24 (t, 1H, J=7Hz), 5.0-5.3 (m, 2H), 5.5-5.9 (m, 1H) Preparation 29 EMI53.1 Tributyltin hydride (0.707 ml) was added to a mixture of methyl 2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)- 3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbutenoate (630 mg) and azobisisobutyronitrile (34 mg,' 1.. benzene (6 ml) at room temperature, and the mixture was refluxes for 15 minutes. The reaction mixture was cooled and chromatographed on silica gel (20 g) eluting with a mixture o hexane and ethyl acetate (3:1 - 1:1) to give a 3:1 mixture (559 mg) of methyl 2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4allylazetidin-1-yl]-3-methylbut-2-enoate and its (3R,4R)-isomer. IR (CH2Cl2) : 1740, 1715 cm-1 NMR (CDCl3) #: 1.31 (s, 3H x 3/4), 1.38 (s, 3H), 1.52 (s, 3H x 1/4), 1.96 (s, 3H x 3/4), 1.99 (s, 3H x 1/4), 2.18 (s, 3H), 2.1-2.8 (m, 2H), 2.90 (d, 1H x 3/4, J=3Hz), 3.30 (d, 1H x 1/4, J=6Hz), 3.74 (s, 3H x 1/4), 3.76 (s, 3H x 3/4), 3.8-4.2 (m, 1H), 4.9-5.2 (m, 2H), 5.5-5.9 (m, 1H) Preparation 30 EMI54.1 Potassium carbonate (113 mg; was added to a solution of methyl 2-[(3R,4R)-3-isocyano-2-oxo-4- allylazetidin-1-yl]-3-methylbut-2-enoate (203 mg) in acetone (2 ml) at 0 C, and the mixture was stirred for 20 hours at ambient temperature. Potassium carbonate (210 mg) and acetone (1.5 ml) were added to the reaction mixture at ambient tempera- ture, and the mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with dichlormethane (3 ml) and filtered. The filtrate was evaporated in vacuo, and the residue was chromato- graphed on silica gel (2 ±) eluting with a mixture of hexane and ethyl acetate (3:1) to give methyl 2-[(3P,4R)- 3-allyl-5,5-dimethyl-1-oxo-2,8-diaza-6-oxaspiro[3,4]oct5-en-2-yl]-3-methylbut-2-enoate (120 mg). IR (CHsCl2) : 1755, 1715, 1610 cm-1 NMR (CDCl3) #: 1.40 (s, 3H), 1.64 (s, 3H), 2.01 (s, 3H), 2.23 (s, 3H), 2.3-2.6 (m, 2H), 3.77 (s, 3H), 4.11 (t, 1H, J=7Hz), 4.9-5.2 (m, 2H), 5.4-5.8 (m, 1H), 6.94 (s, 1H). Preparation 31 EMI55.1 A solution of 1,8-diatabycyclo[3,4,0]undec-@- ene (17 l) in methylene chloride (0.1 ml) was added to a solution of methyl 2-[(3R,4R)-3-(1-hydroxy-1methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl] i-methylbui-2-enoate (17 mg) in methylene chloride (1 ml) and acetone (1 ml) at 0;C, and the mixture was stirred or 20 hours at ambient temperature. Acetic acid (2 drops) was added to the reaction mixture at OOC, and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (20 ml), an the solution was washed with iO% aqueous phosphor a brine, phosphate buffer (pH 6.9), aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 2-[(3R,4R)-3- allyl-5,5-dimethyl-1-oxo-2,8-diaza-6-oxaspiro[3,4]oct7-en-2-yl]-3-methylbut-2-enoate (19 mg) as cake crystals. Preparation 32 EMI56.1 A solution of n-butyl lithium (0.42 ml of 1. SM solution in hexane) was added to a solution of methyl 2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4allylazetidin-1-yl]-3-methylbut-2-enoate (150 mg) in tetrahydrofuran (3 ml) during 3 minutes at -70 C and the mixture was stirred for 5 minutes at -70 C, A solution of p-nitrobenzyl chloroformate (161 mg) in tetrahydrofuran (1. 6 ml) was added ro the mixture during S minutes at -70 C and the mixture was stirred for 15 minutes at -70 C. The mixture was allowed to warm to O C during 30 minutes and stirred for 2 hours at OOC. Acetic acid (0.,037 ml) was added to the mixture at 0 C and the mixture was evaporated in vacuo The residue was dissolved i ethyl acetate (50 ml), and the was washed with water (10 ml), 10% phosphoric acid (10 ml), phosphate buffer (pH 7.0) (10 ml x 2), aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (5:1 - 1:1) to give methyl 3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2enoate (135 ng) as an oil. IR (CH2C12) : 1740, 1710, 1520, 1345 cm 1 NMR (CDCl3) d: 1.66 (s, 3H), 1.69 (s, JH), 1.97 Cs, 3H), 2.19 (s, 3H), 2.2-2.5 Cm, 2K), 3.40 Cd, 1K, J=2.5Hz), 3.71 (s, 3H), 4.03 (dt, 1H, J=6.5Hz), 4.9-5.2 (m, 2H), 5.19 (s, 2H), 5.5-5.9 (m, 1H), 7.90 (A2B2, 4H), J=9H:) EMI57.1 A solution of n-butyl lithium (0.46 ml of 1.38M solution in hexane) was added to 2 solution of methyl 2-[(3R,4R)-3-(1-hyxdroxy-1-methylethyl)-2-oxo-4allylazetidin-1-yl]-3-methylbut-2-enoate (150 mg) in tetrahydrofuran (3 ml) at -70 C and the mixture was stirred for 15 minutes at -70 C. A solution of p- nitrobenzyl chloroformate (161 mg) in tetrahydrofuran (3.2 ml) was added to the reaction mixture at acid the mixture was stirred for IC minutes at @@ C. The mixture was allowed to warm to 0 C during 30 minutes and stirred at 0 C for l. hours. Acetic acid (0.043 ml) was added to the mixture at 0 C an the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed with brine, aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) elutlng with a mixture of hexane and ethyl acetate (10:1 - 3:1) to give methyl 3-methyl-2-[(3R,4R)-3 [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyxl]-2oxo-4-allylazetidin-1-yl]but-2-enoate (123 mg) as an oil. IR (CH2C12) : 1745, 1720, 1;Z0, 1350 cm 1 NMR (CDCl3) #: 1.70 (s, 3H), 1.81 (s, 3H), 2.01 (s, 3H), 2.10 (s, 3H), 2.64 (t, 2H, J=7Hz), 3.59 (d, 1H, J=5Hz), 3.74 (s, 3H), 4.17 (dt, 1H, J=5,7Hz), 4.9-5.3 (m, 2H), 5.21 (s, 2H), 5.5-5.9 (m, 1H), 7.87 (A2B2, 4H, J=9Hz) EMI58.1 Ozone was bubbled into a solution of methyl 3methyl-2-[(3S,4R)-3-[1-methyl-1-(4 nitrobenzyloxycarbonyl)ethyl]-2-oxo-4-allylazetidin1-yl]but-2-enoate (50 mg) in ethyl acetate (3 ml) at -70 C until z blue color appeared. After stirring for 15 minutes at the sam temperature, the mixture was purged wit nitrogen. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with an aqueous solution of sodium bisulflte and sodium sulfite (2:1), and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methylene chloride (3 ml) and m-chloroperbenzoic acid (48 mg) was added to the solution at 0C. The mixture was stirred for 24 hours at ambient temperature. Additional m chloroperben:oic acid (48 mg) was added1 and the mixture was stirred for 24 hours at ambient temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol (3 ml) and the mixture was heated for 24 hours at 500C. The mixture was evaporated in vacuo and the residue was chromatographied or silica gel (4 g) eluting with a mixture of methylene chloride and methanol (20:1 - 5:1) to give [(2R,3S)-3-[1-methyl- nitrobenzyloxycarbonyl)ethyl]-4-oxoazetidin2-yl)acetic acid (43 mg) as an oil. IR (CH2Cl2) : 1740, 1520, 1350 cm 1 NMR (CDCl3) #: 1.60 (broad s, 6H), 2.3-2.8 (m, 2H), 3.36 Qbroad s, 1H), 3.7-4.0 (m, 1H), 5.16 (s, 2K), 7.1-7.3 (broad, 1H), 7.84 (A2B2, 4H, J=8Hz), 9.1-9.6 (broad, 1H) Preparation 35 EMI60.1 A solution of diazomethane in ether t1 ml) was added to a solution of [(2R,3S)-3-[1-methyl-1-(4- nitrobenzyloxycarbonyl)ethyl]4oxoazetidin-2-yl]acetic acid (29 mg) in a mixture of methylene chloride (1 ml) and methanol (1 ml) at 0 C and the mixture was stired for 15 minutes at 0 C. Acetic acid (1 drop) was added to the mixture at 0 0C and the mixture was evaporated in vacuo. The residue was chromatographed on silica gel (1 g) eluting with a mixture of methylene chloride and ethyl acetate (10:1) to give methyl [(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxazetidin-2-yl]acetate (31 mg). IR (CH2Cl2) : i760, 1740, 152C, 1350 cm NMR (CDCl3) #: 1.61(s, 3H), 1.65 (s, 3H), 2.4-1.6 (m, 2H, 3.36 (d, 1H, J=3Hz), 3.69 (s, 3H), 3.8-4.0 (m, 1H), 5.17 (s, 2H), 6.40 (s, 1H), 7.87 (A2B2, 4H, J=9Hz) Preparation 36 EMI61.1 Ozone was bubbled into a solution of methyl 2 [(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4allylazetidin-1-yl]-3-methylbut-2-enoate (159 mg) in ethyl acetate (5 ml) at -70 C until a blue color appeared. After stirring for 15 minutes at same temperature, the mixture was purged with nitrogen. The mixture was diluted with ethyl acetate (30 ml) and the solution was washed with an aqueous solution of sodium bisulfite and sodium sulfite (2:1). The aqueous layer was extracted with ethyl acetate tlG ml). The combined organic layers we washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was dissolved in methylene chloride t3 ml) and m-chloroperbenzoic acid (244 mg) was added at ambient temperature. The mixture was refluxed or 24 hours and evaporated in vacuo. The residue was dissolved in methanol (3 ml) and m-chloroperbenzoic acid (244 mg) was added. The mixture was heated at 50 C for 20 hours and evaporated in vacuo. The residue. was chromatographed on silica gel (3 g) eluting with a mixture of methylene chloride and methanol C9:l - 2:1) to give [(2R,3S)-3-(1-hydroxy-1- methylethyl)-4-oxoazetidin-2-yl]acetic acid (25 mg). IR (CH2Cl2) : 1750, 1730, 1710 cm-1 NMR (CDCl3) #: 1,28 (s, 3H), 1.32 (s, 3H), 2.5-1.1 (m, 2H), 2.90 (d, 1H, J=2.5Hz), 5.8-4.0 (m, 1H). Preparation 37 EMI62.1 A solution of diazomethane in ether (2 ml) was added to a solution of [(2R,3S)-3-(1-hydroxy-1- methylethyl)-4-oxoazetidin-2-yl]acetic acid (2; mg) in methanol C3 ml) at 0 C and the mixture was stirred for an hour at 0 C. Acetic acid (2 drops) was added to the mixture at 0 C and the mixture was evaporated in vacuo to give methyl [2R,3S)-3-(1- hydroxy-1-methylethyl]-4-oxoazetidin-2-yl]acetate (25 mg). IR (CH2Cl2) : 1760, 1733 cm-1 NMR (CD3OD) #: 1.28 (s, 3H), 1.34 (s, 3H), 2.6-2.8 (m, 2H), 2.89 (d, 1H, J=2.5Hz), 3.70 (s, 3H), 3.8 4.0 (m, 1H). - Preparation 38 EMI62.2 Ozone was bubbled into a solution of methyl 3-methyl-2-[(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylacetidin-1-yl]but2-enoate (120 mg) in ethyl acetate (5 ml) at -70 C until a blue color appeared. After stirring for 15 minutes at the same temperature, the mixture was purged wth nitrogen. The reaction mixture was diluted with ethyl acetate (30 ml) and the solution was washed wit an aqueous solution of sodium bisulfite and sodium sulfite (2:1), and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was dIssolved in methylene chloride (3 ml) and m-chloroperbenzoic acid (112 mg) was added at OOC. The mixture was stirred for 24 hours at ambient temperature, and evaporated in vacuo. The residue was dissolved in methanol (5 ml) and m-chloroperbenzoic acid (112 mg) was added. The mixture was heated at 50 C for 2 does and evaporated in vacuo, The residue was omatographed on silica gel (6 g) eluting with a mixture of methylene chloride and methanol (20:1 5:1) to give [(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoacetidin-2-yl]acetic acid (43 mg) as an oil. IR (CH2Cl2): 1755, 1520, 1350 cm-1 NMR (CDCl3) 6: 1.60 (s, 6H), 1.72 (s, 3H), 2.5-3.2 (m, 2H), 3.4-3.7 (m, 1H), 3.9-4.2 (m, 1H), 5,18 (s, 2H), 7.82 (A2B2, 4H, J=9Hz), 8.4-9.1 (broad, 1H). Preparation 39 EMI64.1 Ozone was bubbled into a solution of methyl 2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4 allylazetidin-l-yl]-3-methylbut-2-enoa=e (2iO mg) in ethyl acetate (5 ml) at -700C until a blue color appeared. After stirring for 15 minutes at -70 C. The mixture was purged with nitrogen. The mixture was diluted with ethyl acetate (30 ml) and the solution was washed with aqueous saturated sodium bisulfite. The aqueous layer was extracted with chloroform t10 ml). The combined organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methYlene chloride (3 ml) and m-chloroperbenzoic acid (368 mg) was added at ambient temperature. After stirring for 20 hours at ambient temperature, the mixture was evaporated in vacuo. The residue was dissolved in methanol (5 ml) and m-chloroperbenzoic acid (368 mg) was added. The mixture was heated at 50 C for 2 days, left for a day at room temperature, and evaporated in vacuo, The residue was chromatographed on silica gel (3 g) eluting with a mixture of methylene chloride and methanol (10:1 - 2:1) to glve (1R,6R)-2,2-dimethyl-4,8-dioxo-7-aza-3-oxabicyclo [4.2.0]octane (48 mg). m.p. 180-182 C. IR (CH2Cl2): 1775, 1740 cm-1 NMR (CD3OD) 6: 1.46 (s, 3H), 1.60 (s, 3H), 2.82 (dd, 1H, J=17Hz, 2Hz), 2.96 (dd, 1H, J=17Hz, 4Hz), 3.50 (d, 1H, J=5Hz), 4.18 (ddd, 1H, J=5Hz, 4Hz, 2Hz), 4.62 (s, 3H), Elemental Analysis: C 56.42%, H 6.26%, N 8.24% Caled for C8H11NO3: C 56.80%, H 6.55%, N 8.28% Preparation 40 EMI65.1 To a solution of methyl [(3R,4R)-3-amino-4- allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (7.0 g' in methylene chloride (110 ml) were added 2,6- lutidine (4.11 ml) and benzyl chloroformate (5.03 ml) at 0 C and the mixture was stirred for 30 minutes at 0 C. The reaction mixture was diluted with ethyl acetate (800 ml) and the solution was washed with diluted hydrochloric acid, brine, aqueous saturates sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (200 g) eluting with a mixture of methylene chloride and ethyl acetate (20:1 - 4:1) to give methyl [(3R,4R)- 3-benzyloxycarbonylamino-4-allyl-2-oxoacetidin-1-yl)3-methylbut-2-enoate (10.7 g) as an oil. IR (CH2Cl2): 3380, 1750, 1720 cm-1 NMR (CD3OD) 6: 1.95 (s, 3H), 2.17 (s, 3H), 1.44 (t, -2H, J=7Hz), 3.73 (s, 3H), 4.06 (dt, 1H, J=2.5, 7Hz), 4.44 (d, 1H, J=2.5Hz), 4.9-5.2 (m, 2H), 5. 0 (s, 2H), 5.5-6.0 (m, 1H), 7,34 (s, 5H) Preparation 41 EMI66.1 Ozone was bubbled into a solution of methyl [(3R,4R)-3-benzyloxycarbonylamino-4-allyl-2oxoazetidin-1-yl]-3-methybut-2-enoate (5 g) in methanol (100 ml) at -600C until a blue color was appeared. After stirring or 10 minutes at -60 C, the mixture was purged with nitrogen. Dimethyl sulfide (5 ml) was added to the mixture at -60 C and the mixture was allowed to warm to 0 C during 15 minutes, After stirring for an hour at 0 C, the mixture was left for 20 hours at ambient tem- perature. Dimethyl sulfide (2 ml), dimethyl orthoformate (5 ml), and p-toluenesulfonic acid monohydrate (150 mg) were added to the mixture and the mixture was heated at 50 C for 6 hours. Pyridine (0.076 ml) was added to the reaction mixture at ambient temperature and the mixture was evaporated in vacuo, The residue was dissolved in ethyl acetate and the solution was washed with water, dilute hydrochloric acid, brine, aqueous sodium bicarbonate, and brine, he orgar.ic layer was dried over magnesium. sulfate, and evaporated in vacuo. The residue was dissolved in methanol (10C ml), and the solution was heated at 50 C for 3 hours and left at ambient temperature or 2 days. The mixture was evaporated in vacuo and the residue was chromatographed on silica gel (100 g) eluting with a mixture of methylene chloride and acetone (10:1-2:1) to give (3R,4R)-3- benzyloxycarbonylamino-4-dimethoxyethyl)azetidin2-one (2.83 g) as an oil, IR (CH2Cl2) : 1770, 1720 cm-1 NMR (acetone-d6) #: 1.8-2.2 (m, 2H), 3.30 (s, 6H), 3.66 (dt, 1H, J=3, 7Hz), 4.42 (dd, 1H, J=3, 9Hz), 4.31 (t, 1H, J=5.5Hz), 5.12 (s, 2H), 7.0 (brs, 1H), 7.2 (m, 1H), 7.40 (s, 5H) Preparation 42 EMI67.1 To a solution of (3R,4R)-3-benzyloxycarbonylamino4-(2,2-dimethoxyethyl)azetidin-2-one (2.15 g) in acetic acid (3.2 ml) were added dimethylsulfide (2 ml) and water (8.8 ml) at ambient temperature and the mixture was heated at 50 C for 4,5 hours. The reaction mixture was evaporated In vacuc and the residue was dissolved In xylene (40 ml). The mixture was evaporated in vacuo and the residue was chromatographed on silica gel (10 g) eluting wit a mixture of methylene chloride and acetone (5:1 2:1) to give a cristalline solid. This crude rystals were washed with ether and dried over phosphorous pentoxide to give (3R,4R)-3- benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2one (863 mg). IR (CH2Cl2) : 1780, 1720 cm-1 NMR (acetone-d6)#: 2.7-3.1 (m, 2H) 3.8-4.0 (m, 1H), 4.43 (dd, 1H, J=2, 8Hz), 5.07 (s, 2H), 6.9-7.2 (broad, 1H), 7.30 (s, 5H), 9.69 (s, 1H) Preparation 43 EMI68.1 To a solution of (3R,4R)-3-benzyloxycarbonylamino- 4-(2-oxoethyl)azetidin-2-one (850 mg) in methanol (17 ml) was added sodium borohydride (123 mg) at 0 C and the mixture was stirred for 15 minutes at 0 C, Acetic acid (0.37 ml) was added to the mixture at After stirring for 15 minutes at 0 C, the mixture was evaporated in. vacuo, The residue was chromato- graphed on silica gel (17 g) eluting with a mixture of methylene chloride and methanol (20:1 - 10:1) t give a crystalline solid. d. This crude crystals wee washed with ether and dried over phosphorous pentoxide to give (3R,4R)-3-benzyloxycarbonylamino-4-(2hydroxyethyl)azetidin-2-one (748 mg), mp. 120-121 C. IR (CH2Cl2) : 1770, 1720 cm-1 NMR (acetone-d6) #: 1.7-2.11 (m, 2H), 2.82 (s, 1H 3.5-3.8 (m, 3H), 4.39 (dd, 1H, J=3, 8Hz), 5.05 (s, o.-7.3 (broad, 2K), 7.30 (s, 5H) Preparation 44 EMI69.1 A solution of (3R,4R)-3-benzyloxycarbonylamino4-(2,2-dimethoxyethyl)azetidin-2-one (0.60 g) in a mixture of tetrahydrofuran (10 ml) and 0.5N hydro- chloric acid (2 ml) was heated at 500C for 1 hour. The mixture was cooled to 00C and 1N aqueous sodium bicarbonate (1.2 ml) was added to the mixture at 0 C. After stirring for 3 minutes at 0 C, sodium borohydride (0.10 g) was added to the mixture at 0 C, After stirring for 15 minutes at 0 C, acetone (0.77 ml) and acetic acid (0,30 ml) were added to the mixture at O"C, The mixture was evaporated In vacuo and the residue was dissolved in methylene chloride (60 ml). The solution was dried over magnesium sulfate and evaporated in vacuo, The residue was dissolved in xylene C20 ml) and the solution was evaporated in vacuo. The residue was chromatographed on silica gel (12 g) eluting with a mixture of methylene chloride and methanol (20:1 - 10:1) to give (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (314 mg) as a crystalline sill. Preparation 45 EMI70.1 To a suspension of (3R,4R)-3-benzyloxy- carbonylamino-4-(2-hydroxyethyl)azetidin-2-one (735 mg) in methylene chloride (30 ml) ) were added 2,2-dimethoxypropane (0.513 ml) and boron trifluoride etherate (0.026 ml) at 0 C. The mixture was stirred or 10 minutes at 0 C and for 5 hours at ambient temperature. The reaction mixture was poured into mixture o methylene chloride (30 ml) and aqueous sodium bicarbonate and sodium chloride (1:1). The organic layer was separated and the aqueous layer was extracted with methylene chloride (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (16 g) eluting with a mixture of methylene chloride and acetone (10:1 - 5:1) to give (6R,7R)-3 benzyloxycarbonylamino-2,2-dimethl-1-aza-3-oxabicyclo [4.2.0]octan-8-one (/753 mg) as an oil. IR (CH2Cl2) : 1760, 1725 cm-1 NMR (acetone-d6) #: 1.36 (s, 3H), 1.61 (s, 3H), 1.4-2.1 (m, 2H), 3.5-3.9 (m, 3H), 4.38 (dd, 1H, J=2, 8Hz), 5.08 (s, 2H), 7.0 (broad, 1H), 7.33 (s, 5H) reparation 46 EMI71.1 A mixture of (6R,7R)-7-benzyloxycarbonylamino2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (748 mg) and 10% palladium charcoal (180 mg) in ethyl acetate (15 ml) was stirred under a hydrogen atmosphere for 1.i hours at ambient temperature. The mixture was filtered and the filtrate was eva- porated in vacuo to give (6R,7R)-7-amino-2,2- dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (382 mg) as a crystalline solid. IR (CH2Cl2) : 1740 cm-1 NMR (CDCl3) #: 1.42 (s, 3H), 1.72 (s, 3H), 1.5-2.1 (m, 2H), 1.86 (s, 2H), 3.34 (ddd, 1H, J=Z, 3, 10Hz) 3.6-3.9 (m, 3H). Preparation 47 EMI71.2 To a solution of (6R,7R)-7-amino-2,2,-dimethyl- 1-aza-3-bicyclo[4.2.0]octan-8-one (300 mg) were added pyridine ±0.25 ml) and freshly prepared acetic formic anhydride (0.38 ml) at 000. After stirring for 45 minutes at 0 C, the reaction mixture was evaporated in vacuo. The residue was dissolved in xylene and the solution was evaporated In vacuo. The residue was chromatographed on silica gel (6 6- eluting with a mixture of methylene chloride and methanol (25:1 - 10:1) to give (6R,7R)-2,2dimethyl-7-formamido-1-aza-3-oxabicyclo[4.2.0]octan8-one (378 mg) as an oil. IR (CH2Cl2) : 1755, 1685 cm-1 NMR (CDCl3) #: 1.43 (s, 3H), 1.72 (s, 3H), 1.8-2.1 (m, 2H), 3.56 (ddd, 1H, J=2, 5, 10Hz), 3.7-3.9 (m, 2H), 4.37 (dd, 1H, J=2, 8Hz), 7.33 (broad d, 1H, J=8Hz), 8.11 (s, 1H) Preparation 48 EMI72.1 To z solution of (6R,7R)-2,2-dimethyl-7- formamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one (345 mg) were added 2,6-lutidine (2.05 ml) and phosphorus oxychloride (0.52 ml) at 0 C. After stirring for 3 hours at OOC, the mixture was poured into a mixture of ethyl acetate (80 ml) and ice- water. The organic layer was separated, washed in turn with 10% phosphoric acid, water, brine, an aqueous mixture of sodium bicarbonate and sodium chloride (1:1), and brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with a mixture of petroleum ether and ether (1:1) and dried over phosphorus pentoxide to give (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3oxabicyclo[4.2.0]octan-8-one (205 mg). IR (CH2C12) : 2140, 17;0 cm 1 NMR (CDCi;) o: 1.45 (s, 3K), 1.72 (s, Y.), 1.4-2,i Cm, 2K), 3.7-3.9 (m, 3H), 4.30 Cd, 1H, J=2Hz). Preparation 49 EMI73.1 Ozone was passed into a solution of methyl 2-{(3S,4R)-3-[(1R)-1-(4-nitrobenzyloxycarbonyloxy) ethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2 enoate (100 mg) in methanol (3 ml) at -70 C until a blue color was appeared. In the course of the reaction, white crystals were precipitated from the reaction mixture, After stirring for 10 minutes at -700C,the mixture was purged ith nitrogen. Cold methylene chloride (2 ml) and dimethyl sulfide (0.6 ml) were added to the mixture at -70 C and the mixture was warm to 0 C during 1 hour, Then the mixture was left at 0 C for 3 hours and at ambient temperature for 12 hours. The mioiture was evaporated in in vacuo and the residue was dissolved ip. methanol Dimethyl sulfide (0.3 ml), trimethyl orthoformate (0.5 ml) and p-toluenesulfonic acid monohydrate (4.3 mg) were added to the solution and the mixture was heated for an hour at 58-55 C. Pyridine (2 drops was added to the mixture at ambient temperature anc the mixture was evaporated in vacuo, The residue was dissolved with ethyl acetate (30 ml) and the solution was washed in turn with water, brine containing 0.1N hydrochloric acid, brine, an aqueous saturated sodium bicarbonate cantaining sodium chloride, and brine, dried over magnesium sulfate, and evaporated in vacuo, The residue was dissolved in methanol (; ; ml) and the solution was left for 15 hours at ambient temperature. The mixture was evaporatec in vacuo and the residue was chromatographed on silica gel (2 g) eluting with a mixture of methylene chloride and acetone (20:1-5:1) to give (35, 4R)-4-(2,2- dimethoxyethyl)-3-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]azetidin-2-one (75 mg) as an oil. IR (CH2Cl2) : 1760, 1730, 1520, 1350 cm-1 NMR (CDCl3) #: 1.44 (d, 3H, J=7Hz), 1.94 (t, 2H, J=6Hz), 3.03 (dd, 1H, J=2, 5Hz), 3.32 (s, 6H), 3.70 (dt, 1H, J=2, 6Hz), 4.43 (t, 1H, J06Hz), 5.0-5.3 (m, 1H), 5.24 (s, 2H), 6.65 (s, 1H), 7,86 (A2B2, 4H, J=9Hz). Preparation 50 EMI75.1 A mixture of (6R,7R)-2,2-dimethyl-7-isocyano1-aza-3-oxabicyclo[4.2.0]octan-8-one (150 mg), tribulyltinhydride (O,Z63 ml), and azobisisobutyronitrile (14 mg) in benzene (4.5 ml) was refluxed for 15 minutes. The resulting solution was chromatographed on silica gel (4.5 g) eluting with a mixture of benzene and acetone (15:1-6:1) to give the crude product (140 mg) as an oil, which was purified by silica gel (S g) chromatography (eluate: a mixture of methylene chloride and ethyl acetate 30:-5:1) to give (6R)-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0] octan-8-one (98 mg) as an oil. IR (CH2Cl2) : 1740 cm-1 NMR (CDCl3) o: 1.42 (s, 3K), 1,77 (s, 3H), 1.4-2.1 (m, 2H), 2.56 (dd, 1H, J=2.5, 14.5Hz), 3.08 (dd, 1H, J=5, 14.5Hz), 3.5-3.7 (m, 1H), 3.87 (dd, 2H, J=2.5, 8Hz). Preparation 51 EMI76.1 To z solution of (6R,7R)-2,2-dimethyl-7- isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (200 mg) in tetrahydrofuran (4 ml) was added a solution of n-butyllithium in hexane (0.93 ml of 1.55M solution) at -70 C and the mixture was stirred at -70 C for 15 minutes A solution of acetaldehyde (73 mg) in tetrahydrofuran (0.8 ml) was added to the mixture at -700C and the mixture was stirred at -70 C for 30 minutes. Acetic acid (0.19 ml) was added to the mixture at -70 C and the mixture was poured into mixture or methyl acetate (100 ml) and aqueous sodium bicarbonate containing a small amount of sodium chloride. The aqueous layer was separated anc extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3 g) eluting with a mixture methylene chloride and ethyl acetate (20:1-5:1) to give a mixture of (6R,7R)-2,2dimethyl-7-[(1S)-1-hydroxyethyl]-7-isocyano-1-aza-3oxabicyclo[4.2.0]octan-8-one, its (1R,6R,7R) isomer, its (1R,6R,7S) isomer, and its (1S,6R,7R) isomer as a solid (230 mg). IR (CH2Cl2): 3600, 2140, 1770 cm-1 NMR (CDCl3) #: 1.3-1.6 (m, 3H), 1.44 /s, 3H), 1.76 (s, 3H), 1.6-2.2 (m, 3H), 2.8-3.1 (m, 1H), 3.7-4.1 (m, 2H), 4.0-4.4 (m, 1H). Preparation 52 EMI77.1 To a mixture of (6R,7R)-2,2-dimethyl-7-[(1S)-1- hydroxyethyl]-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one, its (1R,6R,7R) isomer, its (1R,6R,7S) isomer, and its (lS,6R,7S) isomer (210 mg) in benzene (10 ml) were added tributyltinhydride (0.297 ml) and azobisisobutyronitrile (15 mg) at ambient temperature anc the mixture was refluxed for 30 minutes. The resulting solution was chromatographed on silica gel (7.5 g) 'eluting With a mixture of methylene chloride and acetone (10:1-5:1) to give the crude product, which was purified by silica gel (10 g) chromatography (a mixture of hexane and ethyl acetate 5:1-1:5) to give a mixture of (6R,7R)-2,2-dimethyl-7-[(1S)-1hydroxyethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one, its (1R,6R,7R) isomer, its (lR,6R,7S) isomeT, and its (1S,6R,7R) isomer as an oil (15, mg). IR (CH2Cl2) : 3400, 1740 cm 1 NMR (CDCl3) #: 1.1-1.4 (m, 3H), 1.43 (2,3H), 1.76 (s, 3H), 1.6-2.2 (m, 3H), 2.2-3.0 (m, 1H), 3.0-3.2 (m, 1H), 3.6-4.0 (m, 2H), 4.0-4,4 (m, 1H) Preparation 53 EMI78.1 A solution of p-nitrobenzyl chloroformmate (251 mg) in methylene chloride C2.5 ml) was added to a mixture of (6R,7R)-2,2-dimethyl-7-[(1S)-1- hydroxyethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one, its (1R,6R,7R) isomer, its (lR,6R,7S) isomer, its (1S,6R,7S) isomer, and 4-(dimethylamino)pyridine C143 mg) in methylene chloride (3 ml) at 0 C. After stirring t 0 C for 30 minutes, the mixture was allowed to warm to ambient temperature during 45 minutes and stirred zt ambient temperature or 1.5 hours. A solution of p-nitrobenzyl chloroformate (100 mg) in methylene chloride (1 ml) and 4 (dimethylamino)pyridine (58 mg) were added to the mixture at 0 C and the mixture was stirred ambient temperature for 1.5 hours. 3-Dimethylaminopropylamine (0.158 ml) ) was added to the mixture at 0 C and the mixture was stirred at OOC for 15 minutes, The mixture was poured into a mixture of ethyl acetate (70 ml) and dilute hydrochloric acid. The organic layer was separated, washed wit brine, aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated in vacuo, The residue was chromatographed on silica gel (10 g, eluting with a mixture of methylene chloride and ethyl acetate (10:1-2:1) to give a 9:11:4: :1 mixture of (6R,7R)-2,2-dimethyl-7-[(1S)-1 (4-nitrobenzyloxycarbonyoxy)ethyl]-1-aza-3-oxabicyclo [4.2.0]octan-8-one, its (1R,6R,7R) isomer, its ClR,6R,7S) isomer, and its (1S,6R,7S) isomer as an oil (167 mg). The residue was chromatographed on silica gel (15 g) eluting with a mixture of cyclohexane and ethyl acetate (5:1#1:1) to give 70 mg of the (1S,6R,7R) isomer and 60 mg of the (1R,6R,7R)-isomer, and 10 mg of the (1R,6R,7S)-isomers. Deta for the (1S,6R,7R)-isomer: IR (CH2Cl2):1745, 1525, 1350 cm-1; NMR tCDC13) o: 1.2-2.0 Cm, 2K), 1.50 (d, 3H, J=6Hz), 1.74 (s, 3H), 3.42 (dd, 1H, J=5, 11Hz), 3.6-4.0 (m, 1H), 5.22 (dq, 1H, J=11, 6Hz), 5.30 (s, 2H), 7.94 (A2B2, 4H, J=9Hz). Deta for the (lR,6R,7R)-isomer: IR CCH2C12): 1745, 1525, 1350 cm-1; NMR (CDCl3) #: 1.3-2.0 (m, 2H), 1.4 (d, 3H, partially hidden), 1.44 (s, 3H), 1.75 (s, 3H), 3.39 (dd, 1H, J=5.5, 9Hz), 3.7-4.1 (m, 3H), 5.1-5.4 (m, 1H), 5.34 (s, 2H), 7.98 (A2B2, 4H, J=9Hz). Date for the (1R,6R,7S)-isomer: IR (CH2Cl2): 1745, 1525, 1350 cm-1; NMR (CDCl3) #: 1.3-2.0 (m, 2H), 1.42 (s, 3H), 1.47 (d, 3H, J=6Hz), 1.76 (s, 3H), 3.00 Cdd, 1H, J=2, 8Hz), 3.5-4.0 (m, 3H), 5.1 (m, 1K), 5.30 (s, 2H), 7.96 (A2B2, 4H, J=9Hz). EMI80.1 To a solution of (6R,7R)-2,2-dimethyl-7-isocyano- 1-aza-3-oxabicyclo[4.2.0]octan-8-one (500 mg) in tetrahydrofuran (15 ml) was added a solution of nbutyllithium in hexane (2.33 ml of 1.55M solution) t -70 C and the mixture was stirred at -70 C for 15 minutes. A solution of acetone (0.265 ml) in tetrahydrofuran (2.4 ml) was added to the reaction mixture at -700C and the mixture was stirred at -70 C for 25 minutes. Acetic acid (0.477 ml) was added the mixture at -70 C. After stirring at . 70 C for 20 minutes, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (80 ml) and the solution was washed with aqueous sodiwt: bicarbonate, The aqueous layer was separated and extracted with ethyl acetate (ZO ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated i In vacuo. The crysatalline residue was washed with isopropyl ether and filtered to give (6R,7R)-2,2-dimethyl-7- (1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3oxabicyclo[4.2.0]octan-8-one (460 mg). The mother liquor was chromatographed ce silica gel (5 g) eluting with a mixture of hexane and ethyl acetate (20:1-1:1) to give additional (6R,7R)-2,2- dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1aza-3-oxabicyclo[4.2.0]octan-8-one (65 mg) [(6R,7R)isomer] and its (6R,7S)-isomer (103 mg). For (6R, 7R) isomer: IR (CH2Cl2) : 212, 1765 cm NMR (CDCl3) #: 1.38 (s, 3H), 1.43 (s, 3H), 1.50 (s, 3H), 1.74 (s, 3H), 1.5-2.2 (m, 2H), 2.10 (s, 1H), 3.7-4.0 (m, 3H) For (6R,7S)-isomer IR (CH2Cl2) : 2125, 1765 cm 1 NMR (CDCl3) 6 : 1.40 (s, 3K), 1.48 Cs, 3H), 1.63 Cs, 3H), 1.74 (s, 3H), 1.5-1.9 Cm, 1H), 2.21 (s, 1H), 2.6-3.0 (m, 1H), 3.7-4.0 (m, 3H), Preparation 55 EMI81.1 To a mixture of (6R,7R)-2,2-dimethyl-7-(1- hydroxy-1-methylethyl)-7-isocyano-1-aza-3oxabicyclo[4.2.0]octan-8-one and its (6R,7S)-isomer (2.5 g) in benzene 75 w..l) were added tributyltin- hydride [3.07 ml) and azobisisobutyronitrile (170 mg) at ambient temperature and the mixture was refluxed for 30 minutes. The reaction mixture was chromatographed on silica gel (65 g) eluting with a mixture of methylene chloride and acetone (10:1 2:1) to give a crude product, which was purified by silica gel (75 g) chromatography (hexane and ethyl acetate) to give (6R, 7S)-2,2-dimethyl-7-(1-hydroxy- 1-methylethyl)-1-aza-3-oxabicyclo[4,2,0]-octan-8one (0.545 g) [(6R,7S)-isomer] and its (6R,7R)isomer (1.406 g). For (6R, 7S)-isomer : IR (CH2C12) : 1735 cm NMR (CDCl3)# : 1.29 (s, 3H), 1.36 (s, 3H), 1.42 (s, 3H), 1.74 (s, 3H), 1.5-2.0 (m, 2H), 1.96 (s, 1H), 2.81 (d, 1H, J=2Hz), 3.52 (dddd, 1H, J=2, 5.5, 11Hz), 3.83 (dd, 2H, J=3, 8.5Hz) For (6R, 7R) isomer IR (CH2Cl2): 1755 cm-1 NMR (CDCl3)# : 1.28 (s, 3H), 1.40 (s, 3H), 1.47 (s, 3H), 1.74 (s, 3H), 1.5-2.0 (m, 1H), 1.98 (s, 1H), 2.5-2.9 (m, 1H), 3.15 (d, 1H, J=5Hz), 3.6-3.9 (m, 3H) In the same manner described above, (6R, 7S)-2,2- dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1aza-3-oxybicyclo[4.2.0]octan-8-one (50 mg) afforded a 2:i mixture of (6R, 7S)-2,2-dimethyl-7-(1-hydroxy-1- methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one and its (6R, 7R)-isomer (40 mg). Preparation 56 EMI83.1 To a solution of methyl 2-[(3R,4R)-3-isocyano- 2-oxo-4-allylzetidin-1-yl]-3-methylbut-2-enoate (127.6 mg) in tetrahydrofuran (2.55 ml) was added dropwise a solution of n-butyl lithium (0.409 ml of 1.51 M solution in hexane) at -78 C over a period of 3 minutes. After stirring for iS minutes at -78 C, the reaction mixture was added dropwise with a solution of acetone (0.0459 ml) in tetra- hydrofuran (0.459 ml) at -780C over a period of minutes. After stirring for 25 minutes at -78 C, the reaction mixture was added dropwise with a solution of 4-nitrobenyl chloroformate (124.1 mg) in tetrahydrofuran (1.24 ml) at -78 C over a period of 3 minutes. The resulting solution was allowed to warm to 0 C over a period of 40 minutes and added with acetic acid (0.0412 ml) at 0 C. The solvent was distilled off in vacuc at 0 C and the residue was dissolved in ethyl acetate (30 ml) and washed with brine, aqueous sodium bicarbonate, brine and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (285.4 mg) was chromatographed on silica gel (5.7 g) eluting with a mixture of ethyl acetate and hexane 1:5-1:5) to give methyl 2-((3R, 4R)-3-iosocyano-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl)-3methylbut-2-enoate (211.2 mg) as an oil. IR (CK2C12) : 21,0, 1775, 1750, 1720, 1520, 1350 cm-1 NMR (CDCl3)# :1.74 (s, 3H), 1.85 (s, 3H), 1.97 (s, 3H), 2.22 (s, 3H), 2.53 (t, 2H, J=7Hz), 3.71 (s, 3H), 4.32 (t, 1H, J=7Hz), 5.0-5.5 (m, 4H), 5.5-5.9 (m, 1H), 7.84 (A2B2, 4H, J=9Hz). Preparation 57 EMI84.1 To a solution o methyl 2-[(3R, 4R)-3-isocyano- 2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (198.0 mg) in tetrahydrofuran (3.96 ml) was added dropwise a solution of n-butyl lithium (0.634 ml of 1.51 M solution in hexane) at -7 -78 C over a period of 5 minutes. After stirring or 15 minutes at -78 C, the reaction mixture was added with a solution of acetone (0.0713 ml) in tetrahydrofuran c0.642 ml) at -78 C over a period of 5 minutes. After stirring or 25 minutes at -78 C, the reaction mixture was added dropwise with z solution cf benzyl chloroformate (0.1274 ml) in tetrahydrofuran (1.15 ml) at -78 C over a period c 5 minutes. The resultin6 solution was allowed to warm to 0 C over a period of 40 minutes and added With acetic acid (0.0639 ml) at 0 C. The solvent was distilled off in vacuo at 0 C and the residue was dissolved in ethyl acetate (30 ml) and washed with brine, aqueous sodium bicarbonate, brine, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (381.2 mg) was chromatographed on silica gel (11 g) eluting with a mixture of ethyl acetate and hexane [1:10-1:5) to give methyl 2-[(3R,4R)-3 (l-benzyloxycarbonyloxy-l-methylethyl)-3-isocyano-2oxo-4-allylazetidin-1-yl)-3-methylbut-2-enoate (221.2 mg) as an oil. IR (CH2Cl2); 2130, 1770, 1745, 1720 cm-1 NMR (CDC13) # : 1.71 (s, 3H), 1.85 (s, 3H), 1.95 (s, 3K), 2.20 (s, 3H), 2.53 (t, 2K, J=7Hz), 3.63 (s, 3K), 4.35 (t, 1K, J=7Hz), 5.0-5.35 (m, 4H), 5.5-6.0 (m, 1H), 7.3-7.5 (m, 5H) Preparation 58 EMI85.1 A mixture of methyl 2-[(3R, 4R)-3-(1-benzyloxycarbonyloxy-1-methylethyl)-3-isocyano-2-oxo-4 allylazetidin-1-yl)-3-methylbut-2-enoate (42.7 mg) tri-n-butyltinhydride (0.0308 ml) and azobisisobutyro- nitrile (0.622 mg) in benzene (2.14 ml) was refluxed for 30 minutes. The resulting solution was chromatographed on silica gel (2.1 g) eluting with a mixture of ethyl acetate and hexane (1:10-1:2) to give a mixture of methyl 2-[(3R, 4R)-3-(1-benzyloxy- carbonyloxy-1-methylethyl)-2-oxo-4-allylazetidin-1yl]-3-methylbut-2-enoate and methyl 2-[(3S, 4R)-3 (1-benzyloxycarbonyloxy-1-methylethyl)-2-oxo-4allylazetidin-1-yl]-3-methylbut-2-enoate (39.8 mg; ratio = 1:2.3) as an oil. IR (CH2Cl2) : 1750, 1740, 1730 cm 1 NMR (CDCl3)# :1.59 (s, 2.1H), 1.61 (s, 0.9H), 1.65 (s, 2.1H), 1.67 (s, 0.9H), 1.75 (s, 0.9H), 1.91 (s, 2.1H), 1.96 (s, 0.9H), 2.18 (s, 2.1H), 2.31 (t, 1.4H, J=7Hz), 2.61 (t, 0.6H, J=7Hz), 3.42 (d, 0.7H, J=2Hz). 3.5-3.8 (m, 3.3H), 3.88-4.22 (m, 1H), 4.8-5.2 (m, 4H), 5.3-5.9 (m, 1H), 7.0-7.5 (m, 5H) Preparation 59 EMI86.1 To a solution cf methyl 2-{(3S, 4R)-3-[1-methyl- 1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl)-3-methylbut-2-enoate (72.9 mg) in acetone (2.03 m. .. added a :. M solution c- phosphate butter pH) 6.5, 1.35 ml) at ambient temperature. To ne resulting suspension was added dropwise a solution of sodium periodate (86.0 2c; in water (0.594 ml) at ambient temperature. After stirring for 10 minutes, the reaction mixture was added with sodium periodate (117.2 mg) and potassium permanganate (37.5 mg) and stirred at ambient temperature overnight. The resulting mixture was diluted with water-acetone (15 ml - 15 ml) and filtered with celite and the filter cake was washed with water-acetone (1:1). The combined filtrates were concentrated in vacuo at 0 C, acidified to pK 1 with 10% aqueous phosphoric acid, and extracted with chloroform. The organic layer was extracted with chilled 10% aqueous sodium bicarbonate (X3). The aqueous extracts were acidified with 3N hydrochloric acid and reextracted with chloroform (X3). The chloroform extracts were washed with saturated aqueous sodium chloride containing a small amount of 3N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated to give {(2R, 3S)-3-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}acetic acid (36.4 mg) as an amorphous solid. IR (CH2Cl2) : 1740, 1520, 1350 cm 1 EMI87.1 n-Butyllithium (1.51N in hexane, 0.99 ml) was added dropwise to a solution of methyl 2-[(3R, 4R)-3- isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut enoaze (308 mg) in tetrahydrofurane (6 ml) during a three-minutes period t -78 C under a nitrogen atmosphere. After 15 minutes at -78 C a solution of acetaldehyde in tetrahydrofuran (2M, 0.93 ml) was added dropwise. The mixture was stirred at -78 C for 30 minutes and quenched by addition of acetic acid (143 $). The solution was allowed to warm to OOC, poured into a mixture of a saturated aqueous solution of sodium bicarbonate and brine, and extracted with ethyl acetate (50 ml). The extract was washed with brine, dried over magnesium sulfate and evaporated to give an oil t274 mg). The residue was chromatographed on silica gel (5 g; eluting with 5-10% acetone in dichloromethane) to give 199 mg (54.9t) of four diastereomeric mixture of methyl 2-[(4R)-3-(I- hydroxyethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl 3-methylbut-2-enoate. IR [CH2Cl2) : 3450, 2140, 1770, 1725 cm 1 Preparation 61 EMI88.1 Tri(n-butyl)tin hydride (0.20 ml) and azobisisobutyronitrile (11.5 mg) were added to a solution of the four isomeric mixture of methyl 2-[3-(1- hydroxyethyl)-3-isocyano-2-oxo-4(R)allylazetidin-1 yl]-3-methylbut-2-enoate (195 mg) in anhydrous ben¯ene (4 ml) . The stirring mixture was heated to re=ux for 15 minutes. The reaction mixture was cooled to ambient temperature and chromatographed on silica gel (6g ; elutlng with a mixture of 5-20% acetone in dichloromethane to give 155 mg (87.3%) of the fourisomeric mixture of methyl 2-[(4R)-3-(1-hydroxyethyl)- 2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate as a crude oil. This crude oil (118 mg) was chromatographed on silica gel (10 g ; eluting with 4-20% acetone in benzene) to give 47 mg of methyl 2-[(3S, 4R)-3-((lR^a)-l-hydroxyethyl)-2-oxo-4-allyla¯e.iGin- l-yI]-3-methylbut-2-enoate and 54 mg of methyl 2-[( R,4R)-3-((lRS)-l-hydroxyethyl)-2-oxo-4-allyl- azetidin-1-yl)-3-methylbut-2-enoate. IR (CH2C12) for the mixture of four isomers, 3640, 550, 3100-3600, 1735, and 1715 cm-1 Preparation 62 EMI89.1 A solution o 4-nitrobenzyl chloroformate (64., mg) in dichloromethane (0.65 ml) was added to z solution of methyl 2-[(3S, 4R)-3-(1RS)-1-hydroxethyl)- 2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (54 mg) and dimethylaminopyridine ( 6.7 mg) in dichloromethane (2.55 ml) at 0 C under a nitrogen atmosphere. After three minutes the heterogeneous mixture was allowed to warm to ambient temperature (27 C). After two hours-stirring, additional 4-nitrobenzyl chloroformate (45 mg) and dimethylaminopyridine (25 mg) were added at 0 C. The mixture was stirred at ambient temperature for 15 hours and the resulting solution was evaporated. The residue was taken up into ethyl acetate (20 ml), washed in turn with dilute hydrochloric acid, water, a dilute aqueous solution of sodium bicarbonate, and brine dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (2.5 g ; eluting with 2% acetone in dichloromethane) to give 76 mg (84.5 t) of a 4:7 mixture of methyl 2-[(3S, 4R)-3-[(1RS)-1-(4- nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]-5-methylbut-2-enoate IR (CH2Cl2): 1750, 1720, 1525, and 2350 cm-1 NMR (CDCl3)#: 1.46 (d, J=7Hz, 1.2H), 1.48 (d, J=7Hz, 1.8H), 1.97 (s, 3H), 2.20 (s, 3H), 2.4 (m, 2H), 3.06 (dd, J=3, 8Hz, 0.4H), 3.19 (dd, J=3, 5Hz, 0.6H), 3.76 (s, 3H), 3.92 (m, 1H), 4.9-5.4 (m, 3H), 5.28 (s, 2H), 5.5-6.0 (m, 1H), 7.56 (d, J=9Hz, 0.8H), 2.58 (d, J=9Hz, 1.2H), and 8.23 (d, J=9Hz, 2H) Preparation 63 EMI91.1 In a mannar similar to the Preparation 62, except using five molar excess of reagents, 47.0 mg of methyl 2-[(3R, 4R)-3-((1RS)-1-hydroxyethyl)-2-oxo4-allylazetidin-1-yl]-3-methylbut-2-enoate afforded 64 mg (81.5%) of a 3:7 mixture of methyl 2-{(3R, 4R)- 3-[(1RS)-1-(4-nitrobenzyloxycarbonyloxy)ethyl)-2-oxo4-allylazetidin-1-yl)-3-methylbut-2-enoate and 7 mg (15%) of the starting material. This mixture (60 mg) was chromatographed on a silica gel plate (20 cm x 20 cm x 2 mm, three developments with a mixture of 6:4 hexane-ethyl acetate) to ive 39 mg of the 15 isomer and 20 mg of the 1R isomer. Deta for the 1S isomer IR (CH2Cl2): 1745, 1720, 1525, 1350 cm 1 NMR (CDCl3)#: 1.57 (d, J=6Hz, 3H), 1.94 (s, 3H), 2.20 (s, 3H), 2.40 (t, J=7Hz, 2H), 3.51 (dd, J=5.5 and 11Hz, 1H), 3.74 (S, 3H), 4.14 Cdt, J=5.5 and 7Hz), 4.9-5.3 (m, 3K), 5.27 (s, 2H), 5.4-5.9 (m, 1H), 7.57 (d, J=9H, 2H), and 8.25 (d, J09Hz, 2H) ppm. Deta for the 1R isomer: IR (CH2Cl2): 1745, 1720, 1525, 1330 cm-1 NMR (CDCl3)#: 1.53 (d, J=6Hz, 3Hz), 2.03 (s, 3H), 2.22 (s, 3H), 2.40 (t, J=7Hz, 2H), 3.39 (dd, J=4 and 6Hz, 1H), 3.76 (s, 3H), 4.13 (dt, J=6 and 7Hz, 1H), 4.7-5.3 (m, 3H), 5.30 (s, 2H), 5.4-5.9 (m, 1H), 7.56 (d, J=9Hz, 2H), and 8.25 (d, J=9Hz, 2H) ppm. Preparation 64 EMI92.1 To a solution of (6R, 7R)-2,2-dimethyl-7-(1- hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-one (600 mg) in tetrahydrofuran (24 ml) was added a solution of n-butyllithium (2.36 ml of 1.55 M solution in hexane) at -700C and the mixture was stirred at -70 C for 15 minutes. A solution of 4-nitroben=yl chloroformate t788 mg) in tetrahydrofuran (7 ml) was added to the mixture at -70 C. After stirring at -700C for 15 minutes, the reaction mixture was allowed to warm to 0 C during 50 minutes, stirred at 0 C for 30 minutes, and evaporated in vacuc. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with aqueous sodium bicarbonate. The aqueous layer was separates and extracted with ethyl acetate (20 ml). The combined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, and evaporated in vacuo The residue was chromatographed on silica gel (40 g) eluting with a mixture af hexane and ethyl acetate (10:1 to 1:1) to give a crystalline residue. The residue was washed with isopropyl ether and filtered to give (6R, 7R)-2,2-dimethyl-7-[1-methyl-1-(4nitrobenzyloxycarbonyloxy)ethyl]-1-aza-5-oxabicyclo [4.2.0]octan-8-one (520 mg). IR (CH2Cl2) : 1740, 1520, 1350 cm 1 NMR (CDCl3)#: 1.41 (s, 3H), 1.62 (s, 3H), 1.77 (s, 6H), 1.5-1.9 Cm, 1H), 2.2-2.5 Cm, 1H), 3.42 (d, 1H, J=5.SHz) 3.6-4.0 (m, 3H), 5.20 (s, 2H), 7.88 (A2B2, 4H, J=9Hz) Preparation 65 EMI93.1 A solution of (6R, 7R)-2,2-dimethyl-7-[1-methyl- 1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-aza-5 oxabicyclo[4.2.0]octan-8-one (200 mg) in a mixture of acetic acid (3.2 ml) and water (0.8 ml) was heated at 65 C for 1 hour. The mixture was cooled to room temperature and evaporated in vacuo. The crystalline residue was washed with ether to give (3R, 4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloyxcarbonyloxy)ethyl]azetidin-2-one (151 mg) IR (CH2Cl2): 3575, 3375, 1750, 1520, 1350 cm NMR (DMSO-d6)#: 1.57 (s, 3H), 1.64 (s, 3H), 1.88 (q, 2H, J=7Hz), 3.1-3.6 (m, 3H), 3.6-3.9 (m, 1H), 4.47 (t, 1H, J=5Hz), 5.24 (s, 2H), 7,90 (A2B2, 4H, J=9Hz), s.08 (s, 1H). Preparation 66 EMI94.1 To a solution of (3R,4R)-4-(2-hydroxyethyl)- 3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]azetidin-2-one (10 mg) in acetone (0.6 ml) was added ZN Jones reagent (50 l) at 0 C and the mixture was stirred at 0 C for 20 minutes. Isopropyl alcohol (100 l) was added to the mixture at 0 C and the mixture was evaporated in vacuo. The residue was dissolved in chloroform (10 ml) and the solution was washed with brine. The aqueous layer was separated and extracted with chloroform (5 ml). The conbined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (0.5 g) eluting with a mixture of methylene chloride and methanol (20:1 to 5:1) to give pure C(ZR,3R)-3-[l-methyl-1-(4- nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl} acetic acid (3 mg) and impure material (5 mg). IR (CH2Cl2) : 1735, 1520, 1350 cm 1 Preparation 67 EMI95.1 A solution of (3R, 4R)-4-(2-hydroxyethyl)-3-(1methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]azetidin-2-one (10 mg) in dichloromethane (1.5 ml) was added to a suspension of pyridinium chlorochromate (9.2 mg) in dichloromethane at 0 C. The stirring mixture was allowed to warm to ambient temperature and kept at the same temperature for 1.5 hours. The reaction mixture was poured into a mixture of dichloromethane (20 ml) and dilute hydrochloric acid. The organic layer was separated and washed in turn with brine, dilute aqueous solution of sodium bicarbonate containing sodium thlosulfate, and brine, The organic layer was dried over magnesium sulfate and evaporated to give a crystalline solid (12 mg). A silica gel chromatography (O .5 g) eluting wlth a mixture of dichloromethane and acetone (10:1 to 5:1) afforded (3R, 4R)-5-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one (9.7 mg) as a crystalline solid. IR (CH2Cl2): 3375, 1760, 1750 (shoulder) 1715, 1520, 1350 cm -l Preparation 68 EMI96.1 To a solution of (3R, 4R)-3-[1-methyl-1-(4-nitro- benzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)azetidin2-one (9 mg) in acetone (1 ml) was added 2N Jones reagent (60 l) at 0 C and the mixture was stirred at 0 C for 30 minutes. After addition of isopropyl alcohol (100 uL), the mixture was evaporated in vacuo. The residue was taken up in chloroform (20 ml) and washed with brine The aqueous layer was extracted with chloroform (5 ml) The combined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, and evaporated to give {(2R, 3R)-5-[1-methyl- 1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}acetic acid (7 mg). IR (CH2Cl2): 1735, 1520, 1350 cm-1 Preparation 69 EMI96.2 To a solution of (3R, 4R)-3-(benzyloxycarbonylamino)- 4-(2,2-dimethyloxyethyl)azetidin-2-one (1.014 g) in tetrahydrofuran (15 ml) were added portionwise 2 solution. of sodium cyanoborohyde (460 mg) in tetrahydrofuran (2.30 ml) and 2N hydrochloric acid (7.5 ml) at ambient temperature during a period of 90 minutes. The solution was adjusted to pH ¯ with saturated aqueous sodium hydrogen carbonate and concentrated in vacuo. The concentrate was acidified to pK 1 with 2N hydrochlorid acid, saturated with sodium chloride and extracted four times with chloroform. The combined extracts were cried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g, eluting with 3-10% methanol in dichloromethane) to give a crystalline solid, which was washed with ether and collected by filtration to give 553 mg of (3R,4R)-3 benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one. IR (CH2C12) : 1770, 1720 cm 1 Preparation 70 EMI97.1 Ozone was bubbled intro a solution of methyl 2-[(3R, 4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)azetidin-1-yl]-3-methylbut-2-enoate (119 mg) in ethyl acetate (6 ml) at -780C until a permanent blue color developed. The excess ozone was removed by a stream of nitrogen and dimethyl sulfide (0. ml) was added. The mixture was allowed to warm to 4 C, kept in a refrigerator (40C) for 7 hours and left at room temperature for 39 hours. The yellow solution was concentrated under reduced pressure and the residue was dissolved in methanol (4 ml). Aqueous potassium hydrogen carbonate (1.0M, 0.4ml) was added therein and the resulting mixture was stirred at roc temperature for 30 minutes. The solution was then cooled to 0 C and sodium borohydride (22 mg) was added to the solution. After 17 minutes stirring, acetic acid (0.15 ml) was added to the mixture and the mixture was evaporated in vacuo. The residue was dissolved in chloroform and washed with saturated aqueous sodium chloride containing sodium hydrogen carbonate. The aqueous layer was extracted twice with chloroform. The combined extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (2 g, eluting with 5-10E methanol in dichloromethane) to give 50 mg of (3R, 4R)-3-benzyloxycarbonylamino-4- (2-hydroxyethyl)azetidin-2-one. IR (CH2Cl2): 1770, 1720 cm-1 Preparation 71 EMI98.1 Ozone was bubbled Into a solution of methyl 2 [(3R, 4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl) azetidin-1-yl)-3-methylbut-2-enoate (382 mg) in methanol (8 ml) at -78 C until a permanent blue color developed. After five minutes st@@ 5 the exces ozone was removed by a stream of nitrogen. Dimethylsulfide (0.4 ml) was added and the solution was stirred at -78 C for @S minutes. Sodium borohydride (80 mg) was then added the solution an the reaction was continued or 40 minutes at the same temperature and quenched by addition of acetic aci (0.15 ml). The resulting mixture was stirred at -75 C for 30 minutes, allowed to warm to 0 C during 50 minutes and concentrated in vacuo. The residue was dissolved in a 10:1 mixture of ethyl acetate and chloroform (30 ml) and washed in turn with saturated aqueous sodium chloride (twice), 2 mixture of saturated aqueous sodium chloride and saturated aqueous sodium hydrogen carbonate, and saturated aqueous sodium chloride. The resultant mixture was dried over magnesium sulfate and concentrated under reduced pressure to give 352 mg of methyl 2-[(3$, 4R)-3-benzyloxycarbonylamino- 2-oxo-4-(2-oxoethyl)azetidin-l-yl]-2-hydroxyacetate. IR (CH2Cl2) : 3300-3700 (br), 3380, 1770, 1740 (sh) 1720 cm-1 NMR (CDCl3)#: 2.0 (1H. br), 2.97 (2H, brd, J=6Hz), 3.72 (3H, s), 4.16 (1H, dt, J=2.6Hz), 4.47 (1H, dd, J=2.7Hz), 6.06 (2H, s), 5.52 (1H, brs), 5.91 (1H, d, J=7Hz), 7.28 (5H, s), 9.65 (1H, s) The aldehyde (318 mg) obtained above was dissolved in methanol (5 ml) and the solution was cooled to 0 C. 1N Aqueous potassium hydrogen carbonate (0.5 ml) was added and the mixture was stirred at 0 C for S minutes and at ambient temperature for 30 minutes. Sodium borohydride (38 mg) was then added to the mixture at 0 C and the mixture was stirred zt the same temperature for 15 minutes and quenched b addition of acetic acid (G.15 ml). After concentration in vacuo, the residue was dissolved in chloroform and washed with brine con tairIng sodium hydrogen carbonate. The aqueous layer was extracted three times with chloroform. The combined extracts were dried over magnesium sulfate and evaporated in vacuo to give a crystalline solid, which was chromato- graphed on silica gel (6 g, eluting with 3-10% methanol in dichloromethane) to give 113 mg of (3R,4R)-3benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one. IR (CH2Cl2): 1770, 1720 cm-1 Preparation 72 EMI100.1 o^one was bubbled into a solution o5 methyl 2 [(3R, 4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-3enyl)azetidin-1-yl]-3-methylbut-2-enoate (255 mg) in ethyl acetate (6.5 ml) at -78 C until a permanent blue color developed. The excess cone was removed by a stream of nitrogen. The solution was allowed to warm to 0 C and washed with dilute aqueous sodium hydrogen sulfide and brine. The resultant mixture was dried over magnesium sulfate and concentrated under reduced pressure to give 25i mg of methyl 2-[(3R, 4R)-3- benzyloxycarbonylamino-2-oxo-C-(1,2,4 .rloxola-3-vl- methylazetidin-1-yl]-2-oxoacetate. IR (CH2Cl2) : 3390, 1810, 1745, 1720, 1705 cm 1 Preparation 73 EMI101.1 To a solution of methyl 2-[(R,4R)- - benzyloxycarbonylamino-2-oxo-4-(1,2,3,-trioxolan-3-yl)methylazetidin-1-yl]-2-oxoacetate (205 mg) in methanol (4 ml) was added 1N aqueous potassium hydrogen carbonate (0.5 ml) at ambient temperature. The mixture was stirred for 25 minutes and cooled to 0 C. Sodium borohydride (40 mg) and 1N aqueous potassium hydrogen carbonate were added to the mixture at 000. The reaction mixture was stirred at 0 C for 30 minutes and at ambient temperature for an additional 30 minutes, and quenched by addition of acetic acid (0.20 ml). The resulting mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with brine containing sodium hydrogen carbonate. The aqueous lay.er was extracted three times with chloroform. The combined extracts were dried over magnesium sulfate, evaporated in vacuo, and chromatographed on silica gel ( g, eluting with 10-30% acetone in dichloromethane) to give 66 mg of (3R,4R)-3- benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one. IR (CH2Cl2): 1770, 1720 cm-1 reparation 74 EMI102.1 A solution of osmium tetroxide (0.61 mg) in water (0.05 ml) was added to a solution of methyl 2-[(3R,4R)- 3-benzyloxycarbonylamino- 2-oxo-4- (prop- -enyl) azetidin- l-yl)-3-methylbut-2-enoate (58 mg) and sodium chlorate (50 mg) in a mixture of tetrahydrofuran (1 ml) anc water (1 ml) and the mixture was stirred for 17 hours at ambient temperature. . Sodium periodate (60 m.g) was then added and stirring was continued for 30 minutes. The resulting mixture was diluted with brine and extracted with ethyl acetate. The extract was washed successively with brine, brine containing sodium bicarbonate, and brine. The mixture was dried over magnesium sulfate and concentrated under reduced press to give an oil, which was chromatographed on silica gel (1.5 g, eluting with 2.5t methanol in dichloromethane) to give 49 mg of methyl 2-[(3R, 4R)-3-benzyloxycarbonylamino- 2-oxo-4-(2-oxoethyl)azetidin-1-yl]-3-methylbut-2-enoate. IR (CH2Cl2): 3420, 1765, 172S cm 1 Preparation 75 EMI103.1 A solution of osmium tetroxide (0.61 mg) 'in water (0.05 ml) was added to a mixture of methyl 2-[(3R,4R)- 3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)azetidin- 1-yl]-3-methylbut-2-enoate (106 mg) and sodium periodate (36.5 mg) in a mixture of tetrahydrofuran (1 ml) and water (1 ml). After 25 minutes stirring at ambient temperature, additional sodium periodate (101.2 mg) was added and the mixture was stIrred at ambient temperature for 4.5 hours. The resulting mixture was diluted with brine containing sodium bicarbonate and extracted twice with dichloromethane . The combined extracts were dried over magnesium sulfate and evaporated to give 110 mg of methyl 2-[(3R, 4R)-3-benzyloxycarbonylamino-2-oxo4-(2-oxoethyl)azetidin-1-yl]-3-methylbut-2-enoate as oil. IR (CH2Cl2): 3420, 1765, 1725 cm Preparation 76 EMI103.2 Sodium borohydride (10 mg) was added to a solution of methyl 2-[(3R, 4R)-3-benzyloxycarbonylamino-2-oxo2-(2-oxoethyl)azetidin-1-yl)-3-methylbut-2-enoate (49 mg) in methanol (1 ml) at 0 C. The mixture was stirred at the same temperature for 20 minutes and quenched with acetic acid (#0.05 ml). The resulting solution was evaporated in vacuo. The residue was dis- solved in dichloromethane and washed with brine contain- ing sodium bicarbonate. The extract was dried over magnesium sulfate, evaporated, and chromatographed on silica gel (1.5 g, eluting with 5-10% acetone in dichloromethane) to give 39 mg of methyl 2-[(3R, 4R)-3- benzyloxycarbonylamino-4- Ç2-hydroxyethyl) -2-oxoazetidin- 1-yl]-3-methylbut-2-enoate. IR (CH2Cl2) : 1765, 1720 (br) cm 1 NMR (CDCl3) : 1.7-2.2 (2H, m), 1.90 (3K, s), 2.17 (3H, s), 3.4-4.0 (4H, m), 3.71 (3H, s), 4.56 (1H, dd, J=2,7Hz), 5.11 (2K, s), 6.10 1H, m), 7.33 (5K, s) Preparation 77 EMI104.1 A stream of ozone was bubbled into a solution of methyl 2-[(3R, 4R)-3-benzyloxycarbonylamino-4-(2 hydroxyethyl) -2-oxoazetidin-l-yl) -3-methylbut-2-enoate (76 mg) in methanol (6 ml) at -78 C until the starting material disappeared The excess ozone was removed by a stream of nitrogen. Dimethyl sulfide (0.5 ml) was added and the results @@@ solution was allowed to warm to ambient temperature # =or five hours. The solution was cooled to 0 C, to which a solution of sodium methoxide in methanol (01.M, 0.25 ml) was added. mixture was stirred at 0 C for 30 minutes and quenched by addition of acetic acid (excess), The solution was evaporated in vacuo and the residue was chromatographed on silica gel (1.5 g, eluting with 2.5-10% methanol in dichloromethane) to give 46 mg of a crystalline solid, which was triturated in diethyl ether and filtered to give 40 mg of (3R, 4R)-3-benzyloxycarbonylamino- 4-(2-hydroxyethyl)azetidin-2-one. IR (CH2C17) : 1770, 1720 cm 1 Precaration 78 EMI105.1 A stream of ozone was bubbled into a solution of methyl 2-[(3R, 4R)-3-benzyloxycarbonylamino-2-oxo-4 (prop-2-enyl)azetidin-1-yl)-3-methylbut-2-enoate (85.6 g) in methanol (1.54 1) at -78 C until a permanent blue color developed. After 30 mimute the excess ozone was removed by purging nitrogen into the solution and dimethyl sulfide (85.6 ml) was then added. The solution was allowed to warm to 4 C, kept at the same temperature for 15 hours and left at ambient temperature for 24 hours, To the resulting solution were added methyl orthoformate (171.2 ml) and p-toluenesulfonic acid monohydrate (1.18 g). The solution was heated at 5000 for three hours, cooled to ambient temperature, neutralized with pyridine (0.71 ml) and concentrated in vacuo. The residue was dissolved in ethyl acetate (1.5 #) and washed with brine containing 1N hydrochloric acid, and brine. The aqueous layers were combined and extracted wit ethyl acetate. The combined organic layers were washed with brine, brine containing sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (1. 64 l) and cooled to 4 C. A 4.9M methanolic sodium methoxide (0.151 ml) was then added and the resultant solution was stirred for 15 minutes, quenched with acetic acid (0.151 ml) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed in turn with brine containing sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was subjected to column chromato- graphy on silica gel (1 kg, eluting with 10 to 30% acetone in dichloromethane). The eluate was concentrated under reduced pressure to give a residue, which was crystallized from a 1:1 mixture of methyl ether and oiisopropyl ether to give 48.23 g of (3R,4R)-3- benzyloxycarbonylamino-4-(2,2-dimethoxyethyl)azetidin2-one. IR (CH2Cl2) : 1770, 1720 cm I Preparation 79 EMI107.1 A solution of (6R, 7RS)-2,2-dimethyl-7-(1-hydroxy- 1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (920 mg), triphenyltin hydride (1.694 g) and azobisisobutyronitrile (63.4 mg) in benzene (46 mi) was heated at 50 C for thirty minutes under a nitrogen atmosphere. The mixture was cooled to ambient temperature. The precipitates were filtered off and washed with benzene. The filtrate and washings were combined and chromatographed on silica gel (27.6 g, eluting with 10 to 25% acetone in dichloromethane) to give a crude product mixture, which was re-chromato- graphed on silica gel (46 g; 230-400 mesh, elutlng with a 6:1 to 1:2 mixture of hexane and ethyl acetate) to give 513 mg of (6R, 7R)-2,2-dimethyl-7-(1-hydroxy-1- methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-one after crystallization from diisopropyl ether and i?O mg of its 7S isomer as a crystalline solid. Preparaeion 80 EMI107.2 Ozone was bubbled into a solution of methyl 3-methyl-2-{(3R, 4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(prop-2-enyl)azetidin-1yl}but-2-enoate (100 mg) in a mixture of methanol C3 ml) and ethyl acetate r3 ml) at -70 C until a blue color appeared. After stirring for 20 minutes at -70 C, the excess ozone was removed by a stream of nitrogen at the same temperature and dimethyl sulfide t1 ml) was added to the mixture, which was allowed to warm to ambient temperature over a period of an hour and to stand at 20 C for 20 hours. After evaporation of the solvent, the residue was dissolved in methanol (5 ml). Trimethyl orthoformate (0.5 ml), dimethyl sulfide (0.3 ml) and p-toluenesulfonic acid monohydrate (4.1 mg) were added to the solution and the mixture was heated at 50 C for 50 minutes. After cooling, pyridine (3 drops) was added to the mixture. The resulting solution was evaporated in vacuo, dissolved in ethyl acetate (20 ml) and washed in turn with water, 0.1N hydrochloric acid, water, aqueous sodium bicarbonate and brine. The ethyl acetate layer was dried over magnesium sulfate and evaporated In vacuo; The reside was dissolved in methanol (5 ml) and the solution was heated at 50 C for 5 hours. After evaporation of the solvent, the residue was chromatographed on silica gel (2 g) eluting with a mixture of methylene chloride and ethyl acetate (20:1 to 1:2) to give (3R, 4R)-4-(2,2-dimethoxyethyl)-3- [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl)azetidin-2-one (75 mgj as an oil. IR (CH2Cl2) : 3400, 1760, 1520, 1350 cm 1 NMR (CDCl3) #: 1.70 (3H, s), 1.78 (3H, s), 2.9-2.5 (2H, m) 3.42 (6H, s), 3.67 (1H, d, =5Hz), 3.8-4.1 (1K, m), 4.55 (1H, t, J=5.5Hz), 8.51 (2H, s) 6.56 (1K, s), .68 (2H, d, J=9Kz), 8.38 (2H, d, J=9Hz). Preparation 81 EMI109.1 A solution of (3R, 4R)-4-(2,2-dimethoxyethyl)- 3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl] azetldin-2-one (64 mg) in 80% aqueous acetic acid (3.0 ml) was heated at 50-55 C for 4 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (20 ml) and the solution was washed with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (10 ml). The organic layers were combined, washed with water and brine, dried over magnesium sulfate zcd evaporates in vacuo to give (3R, 4R)-3-[1-methyl-1-(4- nitrobenzyloxycarbonyloxy)ethyl) -4- (2-oxoethyl) azetidin-2-one 55 mg) as a solid. IR (CH2Cl2) : 1735, 1520, 1350 cm -l Preparation 82 EMI110.1 A solution of (3R, 4R)-4-(2-hydroxyethyl)-3- [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl] azetidin-2-one (50 mg) in acetone (3 ml) was added to a solution of 2N Jones reagent (0.284 ml) in acetone í; ml) at ambient temperature over a period of 30 minutes and the mixture was stirred for 30 minutes. After addition of an excess of isopropyl alcohol to the mixture, the solvent was evaporated off. The residue was dissolved in chloroform and washed with water. The aqueous layer was extracted twice with chloroform. - The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in chloroform (5 mll and the solution was extracted with 0.lN aqueous solution of sodium bicarbonate (2 ml), 0.05N aqueous solution of sodium bicarbonate t2 ml) and water. The aqueous extracts were combined, acidIfied with 1N' hydrochloric acid and extracted three times with chloroform. The combined chloroform extracts were washed with brine, dried over magnesium sulfate and evaporated to give {(2R, 3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}acetic acid (56 mg) IR (CH2Cl2): 1735, 1520, 1350 cm-1 Preparation 83 EMI111.1 To a solution of methyl 2-{(3R, 4R]-3-[1-methyl-1-(4- nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(prop-2enyl)azetidin-1-yl}-3-methylbut-2-enoate (50 mg) in acetone (2.79 ml) were added water (0.93 ml) and a 0.7M solution of phosphate buffer (pH 6.8, 1.86 ml) at ambient temperature. Sodium periodate (139 mg) was added to the resulting suspension at ambient temperature and the mixture was stirred for 20 minutes. Potassium permanganate (26 mg) was then added and the resulting mixture was stirred for 26 hours at ambient temperature. The mixture was acidified with 2N hydrochloric acid (2 ml) and filtered using diatomaceous earth, and the filter-cake was washed with acetone and water. The filtrates were combined and concentrated 'under reduced pressure to a half volume. The concentrate was extracted three times with chloroform. The organic layers were combined, washed with brine and extracted with 5% aqueous sodium bicarbonate and water. The combined aqueous extracts were acidified with ZN hydrochloric acid and extracted three times with chloroform. The organic extracts were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo to give {(2R, 3R)-3-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}acetic acid (16 mg). IR (CH3@@ @@ 1730, @@@, 1350 cm-1 Preparation 84 EMI112.1 Pyridinium dichromate (3.74 g) was added to a solution of (3R, 4R)-4-(2-hydroxyethyl)-3-[1-methyl 1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo azetidine (1.00 g) in N,N-dimethylformamide (20 ml) at 0 C, and the stirring mixture was allowed to warm to ambient temperature After stirring at ambient temperature for 16 hours, the reaction mixture was poured into a mixture of ethyl acetate (150 ml), 10% aqueous sodium bisulfite (40 ml) and 3N hydrochloric acid (15 ml). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (100 ml x 2). The organic layers were com- bined, washed in turn with water and an aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was dissolved in chloroform (30 ml) and the resultant solution was extracted with 5% aqueous -sodium bicarbonate (20 ml), 2.5% aqueous sodium cica-- bonate (20 ml) and then water (15 ml x 2) The aqueous solutions were combined and acidified with 3N hydro chlorid acid, followed by re-extraction three times with chloroform (20 ml). The combined extracts were washed with an aqueous sodium chloride, dried over magnesium sulfate, and evaporated to give {(2R, 3R)-3- [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4oxo-azetidin-2-yl}acetic acid (810 mg). IR (CH2Cl2) : 1735, 1520, 1350 cm-1 Example I EMI114.1 To a solution of [(2R,3S)-3-[1-methyl-1-[4- nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl] acetic acid 56.4 mg) in tetrahydrofuran (1.13 ml) was added N,N-carbonyldiimidazole (27.5 mg) at ambient temperature. After stirring for 6 hours at ambient temperature, the magnesium salts of the mono-p-nitro benzyl ester of malonic acid (84.8 mg) was added and the resulting mixture was stirred overnight at ambient temperature. The solvent was distilled off and the residue was dissolved in ethyl acetate t30 ml) and filtered with a diatomacetous earth. The filtrate was washed with IN hydrochloric acid, water, phosphate butter solution (pH 6.8), and saturated aqueous sodium chloride After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil C78.8 mg) was chromatographed on silica gel (1.6 g) eluting with a mixture of methylene chloride and ethyl acetate (10:1 to 2:1) to give 4-nitrobenzyl 4-{(2R,3S)-3 [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4 axoazetidint-2-yl)-3-oxobutanoate (64.2 mg) as an amorphous solid. IR (CH2Cl2) : 3380, 1760, 1740, 1720, 1520, 1340 NMR (CDCl3) # : 1.60 (s, 3H), 1.66 (s, 3H), 2.86-3.12 Cm, 2H), 3.41 (d, 1H, J=2Hz), 3.65 Cs, 2K), 3.94-4.18 (m 1H), 5.25 Cs, 2H), 5.34 (s, 2K), 6.60 (broad s, 1H), 7.63 (d, 4H, 3-9Hz), 8.30 (d, 4H, J=9Hz) Example 2 EMI115.1 To a solution of 4-nitrobenzyl 4-{(2R,3S)-3- [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4oxoazetidine-2-yl}-3-oxobutanoate (58.3 mg) in acetomitrile (1.17 ml) was added a solution of p-toluenesulfonyl azide (25.3 mg) in acetonitrile (0.228 ml) at 0 C. After stirring for 5 minutes at OOC, a solution of triethylamine (53.7 e) in acetonitrile (0.483 ml) was added dropwise. The stirring mixture was allowed to warm to ambient temperature during 15 minutes and kept at the same temperature for 20 minutes. The solvent was distilled off and the residue (85.9 mg) was flash chromatogrphed on silica gel (1 g) eluting with a mixture of methylene chloride and ethyl acetate CSO:l to 3:1) to give 4-nitroben:yl 2-diazo-4 {(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxabutanoate (58.4 mg) as aZL amorphous solid IR (CH2Cl2) : 3380, 2140, 1760, 1740, 1715, 1645, 1520, 1345 cm-l NMR (CDCl3) # : 1.63 (s, 3H), 1.67 (s, 3H), 2.88-3.34 (m, 2H), 3.46 (d, 1H, J=2Hz), 3.90-4.20 (m, 1H), 5.26 (s, 2H), 5.45 Cs, 2H), 6.48 (broad s, 1H), 7.65 (d, 4H, J=9Hz), 8.30 (d, 2H, J=9Hz), 8.34 (d, 2H, J=9Hz) Example 3 EMI116.1 A mixture of 4-nitrobenzyl 2-diazo-4-{(2R,3S) 3- methyl-l- (4-nitrobenzyloxycarbanyloxy) ethyll -4- oxoazetidine-2-yl)-3-oxobutanoate (58.0 mg) and rhodium CII) acetate C0.1 mg) in benzene (3.4 ml) was refluxed for 30 minutes. After cooling to ambient temperature, the mixture was filtered with a diatomaceous earth and evaporated to give 4-nitrobenzyl (2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (47.8 mg) as an amorphous solid. IR (CH2Cl2) : 1760, 1735, 1730, 1515, 1345 cm NMR (CDCl3) # : 1.70 (s, 3H), 2.49 (AB part of ABX system centred at 2.49, 2H, JAB=18Hz, JAX=JBX=7Hz), 3.78 (d, 1H, J=2Hz), 4.21 Cdt, 1H, J=2, 7Hz), 4.79 (s, 1H), 5.21 (s, 2H), 5.30 (ABq, 1H, J=12Hz), 7.53 (d, 2H, J=9Hz), 8.22 (d, 2H, J=9Hz) Example 4 EMI116.2 To a solution of 4-nitrobenzyl (2R, 5R, 6S) -3,7 - dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (47.8 mg) and 4,- (N ,N-dimethylamino)pyridine (1.08 ms) in acetonitrile (2.39 ml) was added dropwise a solution of di-isopropylethylamine (18,5 ) in acetonitrile C166.5 l) followed by addition of a solution of diphenyl chlorophosphate (19.2 l) in acetonitrile (172.8 l) at OOC. After stirring for an hour at OOC, a solution of di-isopropylethylamine (61.5 l) in acetonitrile (553.5 uL) was added followed by addition of a solution of N-(2-mercaptoethyl)- acetamide (11.05 mg) in acetonitrile (99.45 l) at 15 C. The mixture was allowed to stand overnight at -150C. The resulting solution was diluted with ethyl acetate (34 ml) and washed with dilute aqueous sodium chloride and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (76.4 mg) was chromatographed on silica gel (1.5 g) eluting with a mixture of methylene chloride and acetone (20:1 to 2:1) to give 4-nitrobenzyl (5R, 6S)-3-(2-acetamido-ethylthio)-6 [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (54.0 mg) as an amorphous solid IR (CH2Cl2) : 3410, 1775, 1725, 1710, 1685, - 1520, 1350 cm NMR (CDCl3) # : 1.65 (s, 6H), 1.98 (s, 3H), 2.7-3.6 Cm, 6H), 3.77 (d, 1H, J-3Hz), 4.27 (dt, 1H, J=3, 8Hz), 5.18 (s, 2H), 5.33 (ABq centered at 5.33, 2H, J-l3Hz), 6.21 (broad s, 1H), 7.50 Cd, 2H,, J"9Hz), 7.58 (d, 2H, J=9Hz), 8.14 (d, 2H, J-9Hz), 8.16 (d, 2H, J=9Hz) Example 5 EMI118.1 A mixture of 5% palladium-charcoal (40.0 mg), water (0.96 ml) and dioxane (2.24 ml) was shaken for 30 minutes under hydrogen atmosphere (40 psi) at ambient temperature. The mixture was added to a solution of 4-nitrobenryl (5R, 6S)-3-(2-acetamido ethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate c40.0 mg) in a mixture of water (0.24 ml) and. dioxane (0.56 ml), and shaken for 2 hours under hydrogen atmosphere (40 psi) at ambient temperature. The resulting mixture was added with 1% aqueous sodium hydrogen carbonate (0.522 ml) at 0 C and filtered by using diatomaceous earth. The filtered cake was washed with water C3 x 5 ml) and the combined filtrates were concentrated, washed with ethyl acetate (3 x 20 ml) and evaporated in vacuo. The- residue was dissolved in water (25 ml) containing sodium chloride (0.7 g) and chromatographed on a non ionic adsorption resin HP-20 (trademark, made by Mitsubishi Chemical Industries) (1.0 x 20 cm) eluting with a mixture of water and acetone 100:0 to - 7:3, 200 ml). The fractions containing the product were combined and lyophilized to give sodium (5R, 6S)- 3-(2-acetamido-ethylthio)-6-(1-hydroxy-1-methylethyl)7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (6.9 mg) as a white solid. IR (CH2Cl2) : 3310, 1745, 1655, 1600, 1555, 1400 cm-1, UV (in H2O) : 301 nm. Example 6 EMI119.1 To a solution of 4-nitrobenzyl (ZR,SR,65)-3,7-dloxo- 6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1azabicyclo[3.2.0]heptane-2-carboxylate (148.5 mg) and 4-N,N-dimethylaminopyridine c3.35 mg) in acetonitrile (7.4 ml) was added dropwise a solution of di-isopropyl- ethylamine (57,3 l) in acetonitrile (0.516 ml). To the mixture was further added a solution of diphenyl chlorophosphate C59.6 l) in acetonitrile (0.536 ml) at 0 C. After stirring for an hour at OOC, a solution of diisopropylethylamine (190.9 l) in acetonitrile (1.72 ml) was added to the mixture To the mixture was further added a solution of N-(4-nitrobenzyloxycarbonyl)cysteamine (73.8 mg) in acetonitrile (0.664 ml) at -15 C. The mixture was allowed to stand overnight at -15 C. The resulting solution was diluted with ethyl acetate (15 ml) and washed in turn with water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated fn vacuo. The residue was chromatographed. on silica gel c3 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 5:1) to give 4nitrobenzyl(5R, 6S)-6-[1-methyl-1-(4-nitrobenzyloxy carbonyloxy) ethyl) -3- [2- (4-nitrobenzyloxycarbonylamino) - ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate (167.8 mg) as an amorphous solid. IR (CH2Cl2) : 3390, 1775, 1730, 1725,- 1610, 1520, 1350 cm-1 NMR (CDCl3) # : 1.62 (6H, s), 2.80-3.60 (6H, m), 3.78 (1H, d, J=3.0Hz), 4.29 (1H, dt, J=3,8Hz), 5.17 (2H, 5), 5.34 (4H, ABq, J=14Hz), 7.30-7.80 (6H, m), 8.05-8.30 (6H, m) Example 7 EMI120.1 To a solution of 4-nitrobenzyl (5R,6S)-3-(2- acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (17.6 mg) in methylene chloride (0.70 ml) was added dropwise a solution of m-chloroperbenzoic acid C6.50 mg) in methylene chloride (0.319 ml) over a period of S minutes at -200C. After stirring for 30 minutes at -20 C, the reaction mixture was diluted with ethyl acetate (10 ml), washed in turn with chilled 108 aqueous s-odium hydrogen carbonate (O.5 ml) and saturated aqueous sodium chloride, filtered and concentrated under reduced pressure to give an oil (20.6 mg) - The. residual oil was chromatographed on silica gel (400 mg) eluting with a mixture of methylene chloride and acetone (10:1 to 2:1) to give 4-nitrobenzyl CSRr6S) 3 ±2-acetamidoethylsulfinyl) - 6 - El-methyl-I- (4 - nitrobenzyloxycarbonyloxy)thyl]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (15.9 mg) as an oil IR (CH2Cl) : 1780, 1740, 1705, 1670, 1605, 1530, 1350 NMR (CDCl3) # : 1.27 (3H, s), 1.66 (3H, s), 2.02 (2.1H,s), 2.18 (0.9K, s), 2.50-4.05 (7H, m), 4.10-4.70 (1H, m), 5.18 (2H, s), 5.37 (2H, ABq, J-l3Hz), 6.45 (1H, broad s), 7.30-7.80 (2H, m), 8.00-8.45 (2H, m) Example 8 EMI121.1 A mixture of platinum oxide (60.0 mg), water (4.2 ml) aqueous dipotassium hydrogen phosphate (1.0M, 0.385 ml) and ethanol (0.6 ml) was shaken for 30 minutes under t hydrogen atmosphere (50 psi) at ambient temperature. The mixture was added to a solution of 4-nitrobenzyl (5R,6S)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]3-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (60.0 mg) in dioxane (7.2' ml) and shaken for 30 minutes under a hydrogen atmosphere (50 psi) at ambient temperature. The reaction mixture was filtered with diatomaceous earth. The filter-cake was washed with water (20 ml) and the combined filtrates (32 ml) were lyophilized over a. period of 6 hours. The residue was. chromatographed on nonionic adsorption resin, Diaion HP-20-AG (trade mark, made by Mitsubishi Chemical Industries) (15 x x 260 mm) eluting with water (230 ml) and then a mixture of water and methanol (7:3, 140 ml)* The fractions showing W maxima at 298 nm were collected, concentrated and lyophilized to give potassium (5R, 6S)-3-(2-aminoethylthio)6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept2-ene-2-carboxylate (12.1 mg) as pale yellow powder. IR (Nujol) : 3350, 1750, 1575, 1380 W (H2O) : 298 nm (e - 7970). NMR (D2O) #: 1.34 (3H, s), 1.38 (3H, s), 3.00-3.38 (6H, m), 3.47 (1H, d, J-3Hz), 4-22 (1H, dt, J"3.8Hz) EMI122.1 N',N' -Carbonyldiimidazole (;40 mg) was added to a solution of [(2R,3R)-3-(1-methyl-1-(4-nitrobenzyloxycarbonyloxy] ethyl -oxoazetidin-Z-yl) acetic acid (1.06 g) in tetrahydrofuran (50 ml) at ambient temperature. After stirring for f hours at the same temperature, magnesium salt of mono-p-nitrobenzyl malonate (1.45 g) was added thereto, and the resultant mixture was -stirred overnight at ambient temperature. The solvent was distilled off in vacuo. The residue was dissolved in ethyl acetate ClOO ml) and filtered The filtrate was washed in turn with O.lN hydrochloric acid, water, saturated aqueous sodium chloride, aqueous sodium bicarbonate', water, saturated aqueous sodium chloride, 5% aqueous citric acid, water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was evaporated. The residue was chromatographed on silica gel (30 g) eluting witls a mixture of methylene chloride and ethyl acetate (50:1 to Z:l) to give formy substance, which was crystallized from a mixture of chloroform and diisopropyl ether, washed with diisopropyl ether and then dried in vacuo to give 4-nitrobenzyl 4-[(2R,3R)-3-{1-methyl-1 (4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl] 3-oxobuttnoate (1.31 g), mp 123-125 C (dec.). IR (CH2C12) : 3400, 1760, 1750, 1720, 1525, 1350cm-1 NMR (acetone-d6) # #: 1.64 (3H, s), 1.74 (3H, s), 3.35 (2H, d, J=6.5Hz), 3.65 (1H, d, J=6Hz), 3,74 (2H, s), 4.20 (1H, m), 5.28 (2M, s), 5.31 (2H, s), 7.18 (1H, s), 7.93 (3H, A2B2, J=8Hz) Example 10 EMI123.1 A solution of p-toluenesulfonyl azide (435 mg) in acetonitrile (3.9 ml) was added to a solution of 4nitrobenzxyl 4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyl oxycarbonyloxy) ethyl}-4-oxoazetidin-2-yl) -3-oxobutanoate (1.00 g) in acetonitrile (20 ml) at 0 C. After stirring at 0 C for 5 minutes, triethylamine (0.923 ml) was added dropwise thereto. After stirring at OOC for additional 20 minutes, the reaction mixture was evaporated. The residue was chromatographed on silica gel (20 g) eluting with a mixture of n-hexane and ethyl acetate (10:1 to 1:4) to give 4-nitrobenzyl 2diazo-4-[(2R, 3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (1.08 g). IR (CH2Cl2) : 3400, 2150, 1765, 1750, 1720, 1655, 1525, 1350 cm-1 NMR (CDC13) 6: 1.68 (3H, s), 1.79 3H, s), 3.4-3.7 (2H, m), 3.46 (ZN, d, J"4.5Hz), 4.0-4.3 (1H, m), 5.20 (2H, s), 5.35 (2H, s), 6.22 (1H, s), 7.80 (4H, A2B2, J=9Hz), 7.85 (4H, A2B2, J-9Hz) Example 11 EMI124.1 A mixture of 4-nitrobenzyl 2-diazo-4-[(2R,3R)-3- {1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4oxoazetidin-2-yl]-3-oxobutanoate (1.00 g) and rhodium (IT) acetate (5 mg) in benzene (50 ml) was refluxed for 25 minutes. After cooling to ambient temperature, the mixture was filtered through cellulose powder. The filtrate was evaporated to give 4-nitrobenzyl (2R, SR, 6R)-3,7- dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]1-azabicyclo[3.2.0]heptane-2-carboxylate (0.94 g) as an amorphous solid. IR (CH2Cl2) : 1770, 1750, 1525, 1350 cm-1 NMR (CDCl3) #: 1.64 (3H,s), 1.84 (3H, s), 2.74 (1H, dd, J=19Hz, 8Hz), 3.34 (1H, dd, J=19Hz, 8Hz), 3.77 (1K, d, J=6Hz), 4.34 (1H, dt, J=6Hz, 8Hz), 4.76 (1H, s), 5.18 (2H, s), - 5.32 (2K, ABq, J-16Hz), 7.88 (4H, A2B2, J-9Hz), 7.91 (4H,A2B2, J=9Hz) Example 12 EMI125.1 To a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7- dioxo--6- [l-methyl-l-(4-nitrobenzyloxycarbonyloxy) ethyl) - 1-azabicyclo[3.2.0]heptane-2-carboxylate (58 mg) and 4-(N,N-dimethylamino)pyridine (1.3 mg) in acetonitrile (3 ml) was added a solution of diisopropylethylamine (22.4 4) in ac.etonitr,ile (0.21 ml) at 0 C. To the mixture was added a solution of diphenyl chlorophosphate (23.3 l). in acetonitrile (0.21 ml) at OOC. After stirring at 0 C for 1.5 hours, the reaction mixture was cooled to -15 C. to which a solution of diisopropylethylamine (74.6 l) in acetonitrile (0.73 ml) was added. To the mixture was added a solution of N-(2mercaptoethyl)acetamide (13.4 mg) in acetonitrile (0.12 ml). After standing overnight at -15µC, the mixture was diluted with ethyl acetate (50 ml), washed in turn with water and saturated aqueous sodium chloride, and dried over ma'gmesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (2 g) eluting with a mixture of methylene chloride and acetone (20:1 to 2:1) to give 4-notrobenzyl (5R,6R)-3-(2- acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene2-carboxylate C56 mg) as an amorphous solid. IR (CH2Cl2) : 3400, 177'5,. 174-5, 1695, 1675, 1530, 1350 NMR (CDCl3) #: 1.68 (3H, s), 1.81 (3H, s), 1.096 (3H, s), 2.8-4.0 (6H, m), 3.76 (1H, d, J=6Hz), 4.2-4.6 (1H, m), 5.18 (2H, s), 5.38 (2H, ABq, J-15Hz), 6.30 (1H, broad t, J=6Hz), 7.88 (4H, A2B2, J-9Hz), 7.95 (4H, A2B2, J=9Hz) Example 13 EMI126.1 A mixture of 5% palladium on activated carbon (175 mg), dioxane (12.5 ml) and 1/30M sodium phosphate buffer (pH 7.0, 5.5 ml) was shaken for an hour under a hydrogen atmosphere (40 psi) at ambient temperature A solution of 4-nitrobenzyl (SR,6R)-3-(2-acetanidoethyl- thio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (175 mg) in a mixture of dioxane (12 ml) and 1/30M sodium phosphate buffer (pH7.0, 5 ml) was added to the mixture at 00c and the resulting. mixture was shaken under a hydrogen atmosphere (40 psi) for an hour, during which time the reaction temperature rose to ambient temperature. 1% Aqueous solution of sodium bicarbonate (Z.29 ml) was added therein at 0 C and the mixture was filtered through cellulose powder. The filter-cake was washed with water (3x20 ml). The combined filtrates were concentrated to a half volume, washed with ethyl acetate (3x50 ml),. and evaporated in vacuo. The residue was dissolved in water c220 ml) containing sodium chloride (6.6 g) and chromatographed on Diaion non-ionic adsorption resin, HP-20 AG (trade mark, made by Mitsubishi Chemical Industries) (150-300u, #2.2 x 36 cm) eluting with water- (360 ml) and a mixture of water and acetone (10:0 to 7:3, 600 ml). The fractions, whose W spectra showed #max 300 nm, were combined and lyophilized to give sodium (5R,6R)-3-(2-acetamidoethylthio)-6-(1-hydroxy-1methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate (46.5 mg) as white powder. IR (KBr) : 1750, 1650, 1590, 1550, 1400 cm-I NMR (D2O) 6: 1.29 (3H, s), 1.40 (3H, s), 1.97 (3H, s), 2.90 (ZH, t, J-8Hz), 3.04 (1H, dd, J"17Hz, 10Hz), 3.36 (ZH, t, J-8Hz), 3.67 (1H, d, J-6Hz), 3.76 (1K, dd, J-17Hz, 9Hz), 4.14 (1H, ddd, J=6Hz, 9Hz, 10Hz) Example 14 EMI127.1 To a solution of 4-nitrobenzyl (2R,5R,6R)-3,7- dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]1-azabicyclo[3.2.0]heptane-2-carboxylate (602 mg) and 4-(N,N-dimethylamino)pyridine (13.6 ml) in acetonitrile (30 ml) was added a. solution of diisopropylethylaminc (0.232 ml) in acetonitrile (2.08 ml) at 0 C. To the mixture was further added a solution of diphenyl chlorophosphate (0.242 ml) in acetonitrile (2.18 ml). After stirring at 0 C for an hour, the mixture was cooled- to -15 C'. To the mixture was added a solution of diisopropylethylamine (0.775 ml) in acetonitrile (6.97 ml) and N-(4-nitrobenzyloxycarbonyl)cysteamine (299 mg) were added. After standing overnight at -15 C, the mixture was evaporated in vacua. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed in turn with water and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (18 g) elut ing with a mixture of benzene and acetone (20:1 to 6:1) to give 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxy carbonylamino)ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept 2-ene-2-carboxylate (716 mg) as an amorphous solid. ZR (CH2Cl2) : 3430r 1780, 1745, 1730, 1710, 1605, 1520, 1345 cm-1 NMR (CDCl3) #: 1.64 (3H, s), 1.80 (3H, s) 2.7-3.5 (5H, m). 3.5-4.0 (1K, m), 3.70 (1H, d, J=5Hz), 4.3 (1H, m)F 5.09 (2H, s), 5.13 (2H, s), 5.32 (2H, ABq, J=13Hz), 7.78 (8H, A2B2, J=8Hz), 7.85 (4H, A2B2, J=8Hz) Example 15 EMI129.1 A mixture of platinum oxide (60.0 mg), water (4.2 ml), aqueous dipotassium hydrogen phosphate (1.OM, 0.385 ml) and ethanol (0.6 ml) was shaken for 30 minutes under a hydrogen atmosphere (50 psi) at ambient temperature. The mixture was added to a solution of 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2carboxylate (60.0 mg) in dioxane (7.2 ml) and shaken for 2 hours under a hydrogen atmosphere (50 psi) at ambient temperature,. The reaction mixture was filtered using diatomaceous earth and the filter-cake was washed with water (20 ml). The combined filtrates (32 ml) were lyophilized over a period of 4 hours. The. residue was chromatographed on non-ionic adsorption resin,. Diaion HP-2-AG (,trade mark, made by Mitsubishi Chemical Industries) (13 x 230 mm) eluting with water (120 ml) and then a mixture of water and isopropanol (19:1, 60 ml). The fractions showing W maxima at 296 um were collected, concentrated and lyophilized to give potassium (SR,.6R)3-(2-aminoethylthio)-6-(1-hydroxy-1-methylethyl)-7oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10.4 mg) as pale yellow powder. IR (Nujol) : 3350, 1750, ISSO, 1375 cm-I UV (H2O) : 296 nm (c = 6580). NMR (D2O) #: 1.31 (3H, s), 1.43 (3H, s), 2.70-3.38 (6H, m), 3.69 (1H, d, J=5Hz), 4.25 (1H, dt, J=5,8Hz). Example 16 EMI130.1 A solution of diisopropylethylamina (0.386 ml) in acetonitrile (0.34 ml) was added to a solution of 4nitrobenzyl (2R, 5R, 6R)-3, 7-dioxo-6-[1-methyl-1-(4nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo [3. 2. 0] heptane-2-carboxylate (100 mg) and 4-(N, N-dimethylamino)pyridine C2. 3 mg) in acetonitrile (5 ml) at O C. A solution of diphenyl chlorophosphate (.0.0402 ml) in acetonitrile (0.36 ml) was then added at O C. After strring at O C for 30 minutes, the mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed in turn with water and brine, dried over magnesium sulfate, and evaporated to give 4-nitrobenzyl CSR, 6R)-3-(diphenoxy- phosphoryloxy)-6-[1-methyl-1-(4-nitrobenzxyloxycarbonyl oxy)ethyl]-7-oxo-1-azabicyclo [3. 2. 0] hept-2-ene-2carboxylate (148 mg) * IR (CH2Cl2) = 1780, 1745, 1725, 1640, 1520, 1485, 1345 cm-1 NMR (CDCl3) = 1.61(s, 3H), 1.80 (s, 3H), 3.14(dd, 1H, J=9.16 Hz), 3.73(d, 1H, J=6 Hz) 3.5-4.0 (m, 1H), 4.0-4.3 (m, 1H), 5.00 (s, 2H), 5.18 (ABq, 2H, J=14 Hz), Example 17 EMI131.1 A solution of diisopropylethylamine (0.0579 ml) in acetonitrile ('0.5 ml) was added to a solution of 4-nitrobenzyl (2R, 5R, 6R) -3, 7-dioxo-6-El-methyl-L- (4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo [3. 2. 0] heptane-2-carboxylate( 150 mg) and 4-(N, Ndimethylamino) pyridine (3.38 mg) in acetonitrile (20 ml) at O 0C A solution of diphenylchlorophosphate (78 mg) in acetonitrile (0.54 ml) was added to the mixture, which' was stirred at 0 C for 15 minutes. Sodium iodide (415 mg) and silver (Z)-2-acetamidoethylenethiolate(93mg) were added at O C and the mixture was stirred at 0 C for 2.5 hours. After the precipitate was filtered off, the filtrate was evaporated in vacuo and the residue was dissolved. in ethylacetate (50 ml). The organic solution was washed in tu: with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (4 g) eluting with a mixture of benzene and acetone (20:1-8:1) to give 4-nitrobenzyl (5R, 6R)-3-[(Z)-2-azetamidovinyl-thio]-6 [1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo -1-azabicyclo [3. 2. 0] hept-2-ene-2-carboxylate (155 mg) as an oil. IR (CH2Cl2) : 1785, 1750, 1710, 1630, 1515, 1350 cm-1 NMR (CDCl3) #: 1.62 (s, 3H), 1.78 (s, 3H), 2.06 (s, 3H), 2.96 (dd, 1H, J=11, 18 Hz), 3.66 (dd, 1H, J=8, 18 Hz), 3.76 (d, 1H, J=5 Hz), 4.0-4.5(m, 1H), 5.14 (s, 2H), 5.28 (d, 1H, J=7 Hz), 5.37 (ABq 2H, J=13 Hz), 7.3-7.8(m, 6H), 8.22 d, 4H, J=8 Hz) Example 18 EMI132.1 A mixture of 4-nitrobenzyl (5R, 6R)-3-[(Z)-2acetamidovinylthio]-67-[1-methyl-1-(4-nitrobenzyloxy carbonyloxy)ethyl]-7-oxo-1-azabicyclo [3. 2. 0] hept-2ene-2-carboxylate (100 mg), platinum (IV) oxide monohydrate (50 mg), ethanol (I ml) and 0.1 X aqueous solution of dipotassium hydrogen phosphate (4.68 ml) in a mixture of water (5 ml) and dioxane t12 ml) was shaken under a hydrogen atmosphere (40 psi) at ambient temperature for an hour After the catalyst was filtered off, the filtrate was evaporated to the half volumn. The aqueous solution was washed three times with ether and evaporated The residue was dissolved in water (50 ml) and potassium chloride (2.5 g) was added The aqueous solution was chromatographed on a column of non-ionic adsorption resin Diaion HP-20 AG (trade mark, Mitsubishi Chemical Industries) eluting with water (200 ml) and 10 * aqueous isopropyl alcohol (200 ml). The fractions, whose UV spectra showed # max 308 nm, were combined and lyophilized to give potassium (5R, 6R)-3-[(Z)-2-acetamido-vinylthio]-6-(1 hydroxy-1-methylethyl) -7-oxo-1-azabicyclo [3. 2. 0 hept -2-ene-2-carboxylate ( 30 mg) as powder. LR (nujol) : 1750, 1670 1620, 1585 cm 1 UV (H2O): #max 234 nm (#=11460), 308 nm (11650)

Claims: We claim 1. A carbapenam compound of the formula EMI134.1 wherein R1 is l-hydroxy-l-methylethyl or l-protected hydroxy-l-methylethyl and R2 is carboxy or a protected carboxy and a salt thereof. 2. A compound according to claim 1, in which R1 is I-protected hydroxy-l-methylethyl and R2 is a protected carboxy. 3. A compound according to claim 2, in which R1 is l-[mono(or di or tri)phenyl(lower)alkoxy carbonyl]-l-methylethyl optionally substituted by nitro and R2 is mono(or di or tri)phenylClower)alkoxycarbonyl optionally substituted by nitro. 4. A compound according to claim 3, in which R1 is 1-(4-nitrobenzyloxycarbonyloxy)-1-methylethyl and R2 is 4-nitrobenzyloxycarbonyl. 5. A process for preparing a carbapenam compound of the formula EMI134.2 wherein R1 is l-hydroxy-l-methylethyl or l-protected hydroxy-1-methylethyl and R2 is carboxy or a protected carboxy or a salt thereof, which comprises subjecting a compound of the formula EMI135.1 wherein R1 and R2 are each as defined above or a salt thereof, to cyclization. 6. A compound of the formula EMI135.2 wherein Rb is lower alkyl, hydroxy(lower)alkyl or a protected hydroxy(lower)alkyl, and R3 is carboxy or a protected carboxy. 7. A compound according to claim 6, in which RbÚ is lower alkyl, hydroxy(lower) alkyl or mono (or di or tri) phenyl (lower) alkoxy carbonyloxy(lower)alkyl optionally substituted by nitro; R3 is carboxy or mono(or di or tri)phenyl(lower) alkoxy carbonyl. 8. A compound according to claim 7, in which Rb Rb is methyl, ethyl, l-hydroxyethyl, l-hydroxy-1-methylethyl, 1-(4-nitrobenzyloxycarbonyloxy)ethyl, 1-(4-nitrobenzyloxycarbonyloxy)-1-methylethyl or l-benzyloxycarbonyloxy-l-methylethyl, R3 is carboxy or 4-nitrobenzyloxycarbonyl or a salt thereof. 9. A process for preparing a compound of the formula EMI136.1 wherein RbÚ is lower alkyl, hydroxy(lower)alkyl or a protected hydrdoxy(lower)alkyl, and R3 is carboxy or a protected carboxy or a salt thereof, which comprises, (a) reacting a compound of the formula EMI136.2 wherein R3 is the same as defined above, or a salt thereof with a metal amide and then reacting the resultant compound with a lower alkylating agent or a hydroxy(lower)alkylating agent to give a compound of the formula EMI137.1 wherein R1 is lower alkyl or hydroxy(lower)alkyl and R3 is the same as defined above, or a salt thereof; or (b) subjecting a compound of the formula EMI137.2 wherein Ra and R3 are each as defined above, or a salt thereof, to removal reaction of the isocyano group, to give a compound of the formula EMI137.3 wherein Ra and R3 are each as defined above or a salt thereof; and then, if desired, subjecting the resulting compound to introducing reaction of the hydroxy-protective group.

Inventors: ARATANI, MATSUHIKO, HASHIMOTO, MASASHI, SAWADA, KOZO
Applicants: FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1982
Main classification: C07D487
IPC codes: C07D477, C07D205, C07D491, A61P31, C07D505, C07D498, A61K31, C07F9, C07F7