1-, AND 1,1-DISUBSTITUTED-6-SUBSTITUTED-2-CARBAMIMIDOYL-1-CARBADETHIAPEN-2-EM-3-CARBOXYLIC ACIDS, A PROCESS FOR PREPARING AND AN ANTIBIOTIC COMPOSITION CONTAINING THE SAME

Abstract: Disclosed are 1-, and 1,1-disubstituted-6-substituted-2-­ carbamimidoyl-1-carbadethiapen-2-em-3-carboxylic acids having the structure: wherein R⁹ and R¹⁰ are, inter alia, hydrogen R⁹ and R¹⁰ are not both hydrogen) alkyl, cycloalkyl, aryl, and aralkyl; R⁹ and R¹⁰ may be joined; R⁶ and R⁷ are, inter alia, independently selected from the group consisting of hydrogen, alkyl, al­ kenyl, aryl, aralkyl; A is a direct, single bond connecting the indicated S and C atoms, or A is a cyclic or acylic connecting group selected, inter alia, from alkyl, cycloalkyl, aryl, het­ eroaryl, heteroalkyl; R¹ and R², which define the carbami­ midoyl function, are, inter alia, independently selected from hydrogen, alkyl, aryl; additionally, said carbamimidoyl is characterized by cyclic structures achieved by the joinder of the two nitrogen atoms via their substituents and by their joinder to connecting group A; additionally, "carbami­ midiums" are disclosed by quarternization of on of the nitrogen atoms of said carbamimidoyl. Such compounds as well as their pharmaceutically acceptable salt, ester and amide derivates are useful as antibiotics. Also disclosed are processes for the preparation of such compounds and phar­ maceutical compositions comprising such compounds.

Description: TITLE OF THE INVENTION 1-, AND 1,1-DISUBSTITUTED-6-SUBSTITUTED-2-CARBAM IMIDOYL- 1 -CARBADETHIAPEN-2-EM-3-CARBOXYLIC ACIDS, A PROCESS FOR PREPARING AND AN ANTIBIOTIC COMPOSITION CONTAINING THE SAME BACKGROUND OF THE INVENTION This invention relates to 1-, and 1,1disubstituted -6-substituted-2-carbamimidoyl-1- carbadethiapen-2-em-3-carboxylic acids (I) and the pharmaceutically acceptable salt, ester and amide derivatives thereof which are useful as antibiotics: EMI1.1 wherein: R9 and R10 are independently selected from the group consisting of: hydrogen (R9 or RIO are not both hydrogen); substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1.10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; wherein the heteroatom or atoms are selected from 0, N and S; wherein the substituent or substituents on R9 and R10 are independently selected from chloro, fluoro, bromo, hydroxy, alkylthio having 1-6 carbon atoms and alkoxyl having 1-6 carbon atoms; additionally R9 and R10 may be joined to form, together with the carbon atom to which they are attached, a cyclicalkyl having 3-6 carbon atoms. R6 and R7 are independently selected from the group consisting of: hydrogen; substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heteroalkyl, heterocyclyl and heterocyclylalkyl; wherein the heteroatom or atoms are selected from 0, N and S; wherein the substituent or substituents on R6 and R7 are independently selected from chloro, fluoro, bromo, hydroxy, alkylthio having 1-6 carbon atoms and alkoxyl having 1-6 carbon atoms; additionally R6 and R7 may be joined to form, together with the carbon atom to which they are attached, a cyclicalkyl having 3-6 carbon atoms. R8 is generically defined to be a "carbamimidoyl", which may be defined by the following structures: EMI3.1 wherein A, the cyclic or acylic connecting group, and R1 and R2 are defined below. The definition of 8 R8 also embraces cyclic structures, which may be generically represented, for example, thusly: EMI3.2 wherein the dotted lines indicate that the nitrogen atoms of the so called carbamimidoyl function may participate in the formation of the cyclic structures indicated above. Representative specific embodiments for R8 (as well as R6, R7, R9 and R10) follow, but, in the generic sense, the components: R1, R2 and A which comprise R8 are defined, thusly: A, the cyclic or acyclic connector, is selected from the group consisting of alkyl, alkenyl, and alkynyl having 1-10 carbon atoms which may be interrupted by a hetero atom selected from 0, S or N, or by a ring such as phenyl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl wherein such cyclic interruptions comprise 3-6 ring atoms selected from C, O, S and N; cycloalkyl, cycloalkenyl having 3-6 carbon atoms; heterocyclyl; heteroaryl; and phenyl; A also represents a direct, single bond connecting the indicated S and C atoms. R1 and R2 are independently selected from hydrogen and the previously defined values for the group A, such as: alkyl, aryl, cycloalkyl, heteroalkyl, alkylaryl, alkylarylalkyl, and heterocyclyl and heteroaryl. It should be noted that the final products of this invention (I) can exist in either neutral or zwitterionic (internal salt) forms. In the zwitterionic form, the basic function is protonated and positively charged and the carboxyl group is deprotonated and negatively charged. The zwitterionic form is the predominant species under most conditions and is in equilibrium with a minor amount of the uncharged, neutral species. The equilibrium process is conveniently visualized as an internal acid-base neutralization. The neutral and zwitterionic forms are shown below. EMI5.1 Neutral form Zwitterionic or Internal form Internal salt form wherein B is the carbamimidoyl group. Further, the final products of this invention I wherein R8 contains a positively charged quaternary nitrogen function such as the "carbamimidinium" can exist as zwitterionic (internal salt) forms or as external salt forms. The preferred form of this product group is the zwitteriinic or internal salt form. These forms are shown below: EMI5.2 Zwitterionic (internal salt) form EMI6.1 External salt form wherein Q represents the quarterized nitrogen group, and wherein X is a pharmaceutically acceptable anion such as those listed in U.S. Patent 4,194,047, issued 3/18/80, which is incorporated herein by reference. This invention also relates to the carboxyl derivatives of I which are antibiotics and which may be represented by the following generic structure (I): EMI6.2 wherein X' is oxygen, sulphur or NR' (R' = H or lower alkyl having 1-6 carbon atoms); and R3 is, hydrogen, or, inter alia is representatively selected to provide the pharmaceutically acceptable salt, ester, anhydride (R31 is acyl), and amide moieties known in bicyclic ss-lactam antibiotic art; R3 may also be a readily removable blocking group. The definition of R3' is given in greater detail below. This invention also relates to processes for the preparation of such compounds I; pharmaceutical compositions comprising such compounds; and to methods of treatment comprisinq administering such compounds and compositions when an antibiotic effect is indicated. There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues. Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inaminate systems. These antibiotics are active against a broad range of pathogens wich representatively include both Gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and Gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their nontoxic, pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention (I, above) are conveniently prepared by the following scheme: DIAGRAM I EMI8.1 EMI9.1 In words relative to the above reaction scheme, Diagram I, the step la to 2a to establish leaving group Xa is accomplished by acylating the bicyclic keto ester la with an acylating agent RXa such as p-toluenesulfonic acid anhydride, p-nitrophenylsulfonic acid anhydride, 2,4,6-triisopropylphenylsulfonic acid anhydride, methanesulfonic acid anhydride, trifluoromethane sulfonic acid anhydride, diphenyl chlorophosphate, toluenesulfonyl chloride, p-bromophenylsulfonyl chloride, or the like; wherein Xa is the corresponding leaving group such as toluene sulfonyloxy, p-nitrophenylsulfonyloxy, benzenesulfonyloxy, diphenylphosphoryl, and other leaving groups which are established by conventional procedures and are well known in the art. Typically, the above acylation to establish leaving group is conducted in a solvent such as methylene chloride, acetonitrile or dimethylformamide, in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like at a temperature of from -20 to 400 for from 0.1 to 5 hours. The leaving group Xa of intermediate 2a can also be halogen. The halogen leaving group is established by treating la with a halogenating agent such as 03PC12' O3PBr2, (OO)3PBr2, oxalyl chloride or the like in a solvent such as CH2C12, CH3CN, THF, or the like in the presence of a base such as diisopropylethylamine, triethylamine, or 4-dimethylaminopyridine or the like. = phenyl.] The reaction 2a to 22 is accomplished by treating 2a in a solvent such as dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, or the like, in the presence of an approximately equivalent to excess of the mercaptan reagent HSR8, wherein R8 is defined above, in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine, or the like at a temperature of from -40 to 250C for from 30 sec. to 1 hour. The final deblocking step 22 to I is accomplished by conventional procedures such as solvolysis or hydrogenation. The conditions of deblocking 22 to I are thus: typically 22 in a solvent such as tetrahydrofuran-water, tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water, or the like containing pH 7 morpholinopropanesulfonic acid-sodium hydroxide buffer, pH 7 phosphate buffer, dipotassium hydrogen phosphate, sodium bicarbonate, or the like, is treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a catalyst such as platinum oxide, palladium on charcoal, or palladium hydroxide on charcoal, or the like, at a temperature of from 0 to 50 C for from 0.25 to 4 hours to provide I. Photolysis, when R5 is a group such as o-nitrobenzyl, for example, may also be used for deblocking. Relative to Diagram I, the bicyclic keto ester la may be obtained by the following scheme, Diagram II. DIAGRAM II EMI11.1 The addition 3 to 4 is accomplished by treating 3 with l,l'-carbonyldiimidazole, or the like, in a solvent such as tetrahydrofuran (THF), dimethoxyethane, acetonitrile or the like, at a temperature of from 0 to 700C, followed by the addition of 1.1 to 3.0 equivalent of (R O2CCH2CO2)2Mg, at a temperature of from 0 to 700C for from 1 to 48 hours. The group R5 is a pharmaceutically acceptable ester moiety or a redily removable carboxyl protecting groups such as p-nitrobenzyl, benzyl, or the like. The diazo species 5 is prepared from 4 by treating 4 in a solvent such as CH3CN, CH2Cl2, THF, or the like with an azide such as p-carboxy benzenesulfonylazide-, p-toluenesulfonylazide, methanesulfonylazide, or the like in the presence of a base such as triethylamine, pyridine, diethylamine or the like for from 1 to 50 hours at 0-500C. Cyclization (5 to la) is accomplished by -treating 5 in a solvent such as benzene, toluene, THF, cyclohexane, ethylacetate or the like at a temperature of from 25 to 1100C for from 1-5 hours in the presence of a catalyst such as bis (acetylacetonato)Cu(II)[Cu(acac)2], CuSO4, Cu powder, Rh2(OAc)4 or Pd(OAc)2. Alternatively, the cyclization may be accomplished by irradiating 6 through a pyrex filter (a wave length greater than 300nm) in a solvent such as benzene, CC14, diethylether, or the like, at a temperature of from 0-250C for from 0.5 to 2 hours. ["OAc" = acetate.] Relative to Diagram II, the following scheme, Diagram III, crosses at intermediate 3 (R9 substituted): DIAGRAM III EMI13.1 DIAGRAM III EMI14.1 In words relative to the above diagram, the 4-(1,2-substituted-vinyl)azetidine-2-one, 4', is prepared by reacting an RÚ-oxybutadiene, 1', with chlorosulfonylisocyanate 2'. The reaction is conducted without solvent or may be run in solvent such as diethyl ether, ethyl acetate, chloroform, methylene chloride, or the like, at a temperature of from -780C to 250C for from a few minutes to 1 hour to provide 3'. The radical R1 is an easily removable acyl blocking group such as alkanoyl or aralkanoyl which bears no functional group or groups which might interfere with the desired course of reaction (1 + 2 to 3 to 4), and R9 is as defined in I. Intermediate species 3' is converted to the sulfinamide by reduction which is then hydrolyzed to 4' at pH 6-8. Typically the reaction solution comprising 3' is contacted (5-30 minutes) with an aqueous solution (at 0-250C) of a reducing agent such as sodium sulfite, thiophenol, or the like, at pH 6-8 to provide 4'. The reaction 4' to 5' is a reduction, and is preferably achieved by hydrogenation in a solvent such as ethyl acetate, ether, dioxane, tetrahydrofuran (THF), ethanol or the like at 0 to 250C for from 5 minutes to 2 hours under 1 to 10 atmospheres of hydrogen in the presence of a hydrogenation catalyst such as a platinum metal or oxide thereof such as 10% Pd/C or the like. The deblocking reaction 5' to 6' is usually desirable when R1 is acyl to permit the later alkylation, 7' to 8'. The preferred deblocking procedure is by alcoholysis wherein the solvent is a lower alkanol such as methanol, ethanol or the like in the presence of the corresponding alkali metal alkoxide, such as sodium methoxide. Typically, the reaction is conducted for from 5 minutes to I hour at a temperature of from -10 to 25 C . Blocking groups R and Rê are established (6' to 7') to provide a suitably protected species for alkylation (7' to 8' to 9'). There is no criticality in the choice of blocking groups, provided only that they do not interfere with the intended alkylation. R may be hydrogen, a triorganosilyl group such as trimethylsilyl or the like, or a cyclic ether such as 2-tetrahydropyranyl. R2 may also be cyclic ether such as 2-tetrahydropyranyl; alternatively R3 and R2 may be joined together to form protected species such as 7a: EMI16.1 For example, species such as 7a are conveniently prepared by treating 6' with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate, toluene sulphonic acid, or the like in a solvent such as methylene chloride, ether, chloroform, dioxane or the like at a temperature of from -100C to 350C for from a few minutes to 1 hour. Species 7' can be mono- or dialkylated at ring position 6'. Alkylation of 7' provides 8'. Typically, 7' is treated with a strong base such as lithium diisopropyl amide, sodium hydride, phenyl lithium or butyl lithium and the like in a solvent such as tetrahydrofuran (THF), ether, dimethoxyethane and the like at a temperature of from -800C to OOC., whereupon the alkylating agent of choice, R6X, is added (R6 is as described above and X is chloro, iodo or bromo; alternatively the alkylating agent may be R6-tosylate, R6-mesylate or an aldehyde or ketone such as acetone and the like) to provide monoalkylated species 8'. When desired, dialkylated species 9' may be obtained from 8' by repeating the alkylating procedure, 7' to 8'. The de-blocking reaction 9' to 10' is typically conducted by acid hydrolysis such as aqueous acetic acid at a temperature of from 250C to 750C for from 5 minutes to 3 hours. The acid 3 is prepared by treating 10' with an oxidizing agent such as Jones reagent in acetone or the like at a temperature of from 0-250C for from 5 minutes to 1 hour. The disubstituted azetidinone carboxylic acid 3 may be prepared from 3-substituted 1,4-butadiene (Diagram IV3. DIAGRAM IV EMI18.1 In words relative to Diagram IV, the substituted azetidinone 2" is prepared by reacting a 3-substituted 1,4-pentadiene 1" with chlorosulfonylisocyanate at 250C to 600C in a pressure bottle for 3-12 days. The resulting mixture is hydrolyzed with aqueous sodium sulfite solution between pH 6.5-7.5 at OOC to 250C for from 5 min. to 60 min. Azetidinone 2" is transformed (2" to 3") to establish the protecting group RO which may be a triorganosilyl group, such as t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsily, isopropyldi methylsilyl, for example, or may be 3,4-dimethoxybenzyl, for example. Silyl protection is preferred, and typically RO is established by treating 2" in a solvent such as dimethylformamide, acetonitrile, hexamethylphosphoramide, tetrahydrofuran or the like with a silylating agent such as t-butyldimethylchlorosilane, t-butyldiphenylchlorosilane, triphenylchlorosilane, or the like at a temperature of from -200 to 250C for from 0.5 to 24 hours in the presence of a base such as triethylamine, diisopropylethylamine. Alkylation of 3n provides 4". Typically, 3" is treated with a strong base such as lithium diisopropylamide, sodium hydride, phenyl lithium, butyl lithium, or the like in a solvent such as tetrahydrofuran, ether, dimethoxyethane or the like at a temperature of from -800C to OOC, whereupon the alkylating agent of choice, R6X/R7X is introduced (R6/R7 are described above and X is chloro, iodo or broad; alternatively the alkylating agent may be R6-tosylate, R6-mesylate, an aldehyde, or a ketone such as acetone, or the like) to provide monoalkylated species 4". When desired, dialkylated species 5 may be obtained from 4" by repeating the alkylating procedure, 4" to 5". The oxidation 5" to 6" is accomplished by treating 5" in a solvent such as methylenechloride, methanol, or the like, with ozone, at a temperture of from -1000 to OOC for from 0.1 to 4 hours, followed by treating the crude product with an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, or the like, at a temperature of from OOC to 1000C for from 1 to 100 hours. Deprotection of 6" by acid hydrolysis in 6.0 N HC1 in MeOH at temperature of from 0 to 250C for from 10 min. to 3 hours gives 3. With respect to starting reagent 1", its preparation is generally described in J. Amer. Chem. Soc., 74, 661 (1952) by E. B. Reid and T. E. Gompf, J. Org. Chem., 23, 1063 (1958) by R. Ciola and K. L. Burwell, Jr., and Belgium Patent 632,193 (1963) by R. Polster and E. Scharf. The Diagram V summarizes the preparation of 1". DIAGRAM V EMI21.1 In words relative to Diagram V, the diester 12 is prepared by treating the diacid 11 with thionyl chloride at reflux for two hours followed by reacting with ethanol at 800C for 4 hours. Reduction of the diester 12 with lithium aluminum hydride in ether at reflux for 4 hours followed by hydrolysis with 10% NaOH gives diol 13 which on further reaction with thionyl chloride gives dichloride 14. Reaction of the dichloride 14 with base such as 2-methylequinoline, DBU, or sodium hydroxide in polyethylene glycol gives the expected 3-substituted 1,4-pentadiene 1". ALKYLATING AND ACYLATING REAGENTS FOR ESTABLISHING R6 AND R7 The establishment of R6 and R7 by alkylation has been shown. There is a second scheme for establishing R6 and R7. It involves direct acylation followed by reduction. These schemes are conveniently compared and consolidated, below (Diagram Va) and, there following, is a representative list of suitable alkylating and acylating reagents for establishing R6 and R7. DIAGRAM Va EMI22.1 wherein Ra comprises the following five classes: 1) -CR9R10 COOR; R is a protecting group such as methyl, ethyl, p-nitrobenzyl, benzyl, triorganosilyl, or the like; R9 and R10 are as previously defined (R9 and R10 H); 2) -CR9R10CH=CH2; R9 and R10 are as previously defined; 3) -CR9R10CH2OR ; R9 and R10 are as previously defined; R is triorganosily, such as trimethylsilyl, t-butyldimethyl silyl, or the like; 4) -CH2C(SR)3; R is alkyl, aryl, or aralkyl;*whereip the alkyl has 1-6 carbon atoms, and the aryl is phenyl; 5) CH2C(SR)2 SiR3; wherein R is as defined above for Ic,4. The intermediates Ic(2-5) above, are disclosed in EPO Patent Application Serial Number 81,108,420.1 which is fullv incorporated herein by reference. Conversion of Ic, classes 1-5 to 3 are achieved by the following reactions: 1) Ic, Class 1. The starting material is first treated with 1.0 to 1.5 eq. of 6.0 N HC1 in methanol at room temperature for from 10 minutes to 2 hours to remove the triorganosilyl protecting group R followed by treating the mixture with 2.0 to 3.0 eq. of 2.5 N NaOH at room temperature for 30 minutes to 8 hours then acidified with HC1 to give 3. 2) Ic, Class 2. This conversion is previously described in Diagram IV, 5" to 6" to 3. 3) Ic, Class 3 to 3: The triorganosilyl protecting group is removed by acid hydrolysis with 6.0 N HC1 in methanol at room temperature for 10 minutes to 2 hours. The free hydroxyl group of Ic is oxidized by Jone's reagent in acetone at room temperature for 10 minutes to 1 hour to yield 3. 4) Ic, Class 4. This conversion is achieved by treating the starting material with a Lewis acid, such as mercuric chloride, silver tetrafluoroborate, or the like, in a solvent such as methanol at 0 to 600C for from 1 to 30 minutes. After the mixture is quenched with sodium bicarbonate, the methyl ester of 3 is obtained. Hydrolysis of the ester with 2.5 N NaOH in methanol at room temperature for 30 minutes to 8 hours, followed by acidification with HC1 gives 3. 5) Ic, Class 5. The starting material is first converted to silyl lactone intermediate by reacting with mercuric oxide/mercuric chloride in a solvent such as methanol at reflux for 0.5 - 3 hours. The silyl ketone so obtained is then treated with an oxidizing agent, such as m-prebenzoic acid, peracetic acid, hydrogen peroxide or the like in a solvent such as methylene chloride, chloroform, carbon tetrachloride or the like, at reflux for 0.5 to 24 hours to afford 3. In words relative to Diagram Va, starting material Ia can be mono-, or dialkylated at ring position 3. Alkylation of Ia provides Ic. Typically, Ia is treated with a strong base such as lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, potassium hydride, lithium hexamethyldisilazane, phenyllithium or the like in a solvent such as tetrahydrofuran (THF)1 hexamethylphosphoramide, ether, dimethoxyethane, and the like at a temperature of from -800C to 0iC whereupon the alkylating agent of choice, R6X is added (X is chloro, iodo or bromo); alternatively the alkylating agent may be R6-tosylate, R6-mesylate or an aldehyde or ketone such as acetaldehyde to provide monoalkylated species Ib. When desired, dialkylated species Ic may be obtained from Ib by repeating the alkylating procedures IaIb. The eventual 6-substituents (nomenclature relative to final, bicyclic structure) can also be established by direct acylation using an acylating agent such as N-acyl imidazole or the like. Such Nacyl imidazole acylating reagents are listed below. Also given below is a detailed description of this second approach for establishing, R6 and R7. The following list is representative of useful alkylating agents for establishing R6 and R7, according to the above scheme Ia wIb ApIc (this will be referred to as Scheme I, to be distinguished from Scheme II, below, which involves acylation): Alkylating Agents CH3CHO #CH2CHO # = phenyl #CH2CH2CHO CH2O CH3I #CH2Br CH3COCH3 EMI26.1 CH3OCH2CHO CH3CH2I (CH3)2CHI N3CH2CHO CH3)2NCH2CHO RO2CCh2Br R = CH3, benzyl, p-nitrobenzyl CF3CF2CHO RO2CCH2CHO R = CH3, benzyl, p-nitrobenzyl CH3CH(CH3)CHO, CH3(CH3)CHCH2CHO, CH3CH2CHO, EMI28.1 CF3CHO, EMI28.2 EMI28.3 R = protecting group EMI29.1 R is removable carboxyl protecting group, such as benzyl. As mentioned above, the 6-substituents may also be established by acylation. Utilization of such acylating agents may be demonstrated in the following manner with regard to a preferred starting material Ib or Ic: EMI30.1 wherein R7, Ra and R are as defined above. R6 is defined relative to the definition of R6 and in that sense is the balance of the previously identified group R6. In other words, for purposes of this definition R6 (OH)- = R6. An especially preferred material Ib is when R7 is hydrogen and R6' is methyl. Basically, such l'-hydroxy R6' species Ib are prepared according to the following scheme: SCHEME II EMI30.2 The alkylation Ia#Ib, Scheme IT, is accomplished as previously described, by treating Ia in a solvent such as tetrahydrofuran, dimethoxyethane, diethylether, hexamethylphosphoramide, at a temperature of from -100 to -200C with a strong base such as lithium diisopropylamide, lithium hexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperidide, potassium hydride or the like followed by the addition of an equivalent to 10 fold excess of an aldehyde. This reaction gives a mixture of isomers from which the desired trans-R form Ib can be conveniently separated by chromatography or crystallization. Intermediate Ia may proceed directly to Ib as indicated above, or it may take the circuitous path via Ia'. The direct acylation, to Ia' is accomplished by treating Ia with two or more equivalents of a base such as lithium diisopropylamide, lithium hexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperidide, in a solvent such as tetrahydrofuran, diethylether, or dimethoxyethane, for example, at a temperature of from -100 to -200C with an acylating agent such as N-acyl imidazole or the like. Addition of the Ia plus base mixture to the acylating agent is preferred. Representative acylating agents for this scheme Ia#Ia'# Ib are listed below. EMI31.1 R=CH3, ClCH2, CH3CH2, N3CH2, CH3OCH2, EMI31.2 EMI31.3 R=CF3, CF2H, CH2=CH, EMI31.4 EMI31.5 Further with respect to Scheme II, the reduction, Ia'Ib is accomplished by contacting the ketone with a reducing agent such as potassium tri(sec-butyl)borohydride, lithium tri(sec-butyl)borohydride, sodium borohydride, sodium tris(methoxyethoxy)aluminum hydride, lithium aluminum hydride or the like in a solvent such as diethylether, tetrahydrofuran, toluene, i-propanol or the like at a temperature of from -78 to 250C. The reaction can conveniently be conducted in the presence of an added complexing salt such as potassium iodide, magnesium bromide or the like. In a similar manner, unresolvedIb (cis and trans) may be oxidized toIa' for reduction toIb as indicated above: EMI32.1 The oxidation is accomplished with an oxidizing agent such as dipyridine chromium (vet) oxide, trifluoroacetic anhydride-dimethylsulfoxide-triethylamine, pyridinium dichromate, acetic anhydride-dimethylsulfoxide in a solvent such as methylene chloride, acetonitrile, or the like at a temperature of from -i8 to 250C for from 5 minutes to 5 hours. The foregoing schemes describe the synthesis of racemic l,l-disubstituted-6-substituted-2carbamimidoyl-l-carbadethiapen-2-em-3-carboxylic acids I. To achieve a given chiral synthesis of I, the racemic azetidindone carboxylic acid 3 is resolved according to conventional optical resolution techniques, such as fractional crystallization of optically active ammonium salts, esters or chromatographic separation of such esters. Alternatively, the chiral azetidinone intermediates 3-6 (Diagram II) may also be conveniently prepared via alkylation of the corresponding unsctbstituted chiral azetidinone. The preparation of chiral precursor 24 is known; see: EPO Serial Number 80102338.3 (filed April 30, 1980); EPO Patent Application Serial Number 81,102,270.6- "Process for The Preparation of 1-Carbapenems; and Intermediates via silylsubstituted Dithioacetals"; and Serial Number 81,102,269.8 "Process for The Preparation of l-Cabapenems, and Intermediates via Trithioorthoacetates"; which are incorporated herein by reference. Diagram VI summerizes these reactions: DIAGRAM VI EMI33.1 In words relative to Diagram VII, the azetidinone carboxylate 24 (R=CH33 is treated with 2-2.5 eq. of a base such as lithium diisopropylamide or the like in a solvent such as THF, ether or the like at a temperature of from -780C to -200C for from 10 minutes to 30 minutes to form a dianion intermediate. The dianion so obtained is then treated with 2 to 100 eq. of a reagent (R9X, R10 X, X is a leaving group) calculated to establish R9/R10 (such reagents include halides, sulfonates and sulfates, for example: R9-halides, such as iodomethane, iodoethane, R9-sulfonates, or R9-sulfates such as dimethylsulfate, or the like) at -780-250C for from 0.5 minutes to 3 hours; the reaction is then quenched with 1.0N hydrochloric acid to give chiral species 25. By repeating the preceding procedure using 25 as starting material, the desired disubstituted azetidinone 26 is obtained. Hydolysis of 25 or 26 in the presence of 1.0 eq. of NaOH, followed by acidic work up gives chiral l-substituted and l,l-disubstituted 3. HSR8 REAGENTS Relative to the foregoing description of the invention, suitable carbamimidoyl and carbamimidinium mercaptans HSR8 which are utilized in the trans 8 formation 2a to 22 are listed below. Wherein R8 is: EMI35.1 and wherein R1 and R2 are as initially defined under R8; the two nitrogen atoms demonstrated in the above structure may participate in cyclic structures which are indicated by the dotted lines; A is a connecting group between the sulfur atom and carbamimidoyl function. It should be noted that while not all canonical forms of R8 are reproduced herein, the foregoing list is representative and constitutes together with the associated text a definition of the "carbamimidoyl" group of the present invention. R1 and R2 are independently selected from the group consisting of hydrogen; substituted and unsubstituted: straight and branched alkyl having from 1 to 6 carbon atoms; cycloalkyl having 3 to 6 carbon atoms; cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 6 carbon atoms; alkylcycloalkyl wherein alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms; aryl such as phenyl; arylalkyl such as benzyl; heterocyclyl (saturated and unsaturated) comprising mono- and bicyclic structures having from 5 to 10 ring atoms, wherein one or more of the heteroatoms is selected from oxygen, nitrogen, or sulfur, such as thiophene, imidazole, tetrazolyl, furyl, pyridine; heterocyclyalkyl groups which comprise the immediately preceding heterocyclyl moieties and the alkyl moiety comprises from 1 to 6 carbon atoms. The substituent or substituents relative to the above-named radicals comprising R1 and R2 are selected from the group consisting of amino, hydroxy, cyano, carboxyl, nitro, chloro, bromo, fluoro, alkoxy, and alkylthio having from 1 to 6 carbon atoms, mercapto, perhaloalkyl having 1 to 3 carbon atoms, guanidino, amidino, sulfamoyl. Particularly preferred groups under the definition of RÚ/Rê are: hydrogen, substituted and unsubstituted: straight and branched loweralkyl having from 1 to 6 carbon atoms; cycloalkyl having from 3 to 6 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 6 carbon atoms; aryl such as phenyl, arylalkyl such as benzyl; the substituents on the above-named radicals are selected from fluoro, hydroxy, mercapto, alkoxy and alkylthio having from 1 to 3 carbon atoms. In defining the bivalent, cyclic or acyclic connector group "A", it is to be noted that the recited radicals of definition are to be read both left to right and right to left. Thus, the prefered connecting groups "A" are selected from: substituted and unsubstituted: loweralkyl having from 1-6 carbon atoms; cycloalkyl having from 3-10 atoms; cycloalkvl having from 3-10 carbon atoms; cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 10 carbon atoms; alkylcycloalkyl wherein the alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms; loweralkenyl having from 2-10 carbon atoms, cycloalkenyl having from 3 to 10 carbon atoms, cycloalkenylalkyl wherein the cycloalkenyl moiety comprises 3 to 10 carbon atoms; and the alkyl moiety comprises 1 to 6 carbon atoms; alkynyl having from 2 to 10 carbon atoms; aryl such as phenyl and naphthyl; arylalkyl and alkylaryl such as benzyl, phenethyl and the like; heteroalkyl, alkylheteroalkyl, arylheteroalkyl and alkylheteroaryl wherein the hetero atoms are selected from the group of sulfur, oxygen and nitrogen, the alkyl moiety has 1 to 6 carbon atoms, and the aryl moiety is phenyl; heterocyclyl (saturated and unsaturated) comprising mono- and bicyclic structures having 5 to 10 ring atoms wherein one or more of the hetero atoms is selected from oxygen, nitrogen, or sulphur such as thiophene, imidazole, pyridine, tetrazolyl, furyl and the like; heterocyclyalkyl wherein heterocyclyl moiety comprises from 3 to 10 atoms and the alkyl moiety comprises from I to 6 atoms; the substituent (or substituents) relative to the above-named radicals are selected from the group consisting of amino, hydroxyl, cyano, carboxyl, nitro, chloro, bromo, fluoro, alkoxy having from 1 to 6 carbon atoms, mercapto, perhaloloweralkyl such as trifluoromethyl and alkylthio having from 1-6 carbon atoms. A particularly preferred class of connecting groups "A" are selected from: substituted and unsubstituted: straight and branched loweralkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms; phenyl; heterocyclyl such as thiophene, imidazole, pyridine, tetrazole and urbane; alkylheteroalkyl wherein alkyl moiety comprises 1 to 3 carbon atoms and the hetero atoms are sulfur, oxygen and nitrogen; the substituents relative to the above-named radicals are: amino, hydroxyl, chloro, bromo, fluoro, cyano, carboxyl alkoxy having from 1 to 3 carbon atoms, mercapto, trifluoromethyl, and alkylthio having from I to 3 carbon atoms. Representative examples of such preferred -SR8 groups (represented as HSR8) are: EXAMPLES EMI38.1 EMI39.1 EMI40.1 EMI41.1 n r 2-5, R2 r H, CH3 R1 r H, CH3 EMI41.2 EMI41.3 n = 2 -5, RÚ, Rê = H, CH3 EMI41.4 EMI42.1 EMI43.1 EMI44.1 EMI45.1 EMI46.1 EMI47.1 EMI48.1 EMI49.1 EMI50.1 EMI51.1 R1 = H, CH3 Rê = H, CH3 R1 = H, CH3 Rê = H, CH3 EMI52.1 R1 = CH3 Rê = CH3, NH2, OR R = H, CH3 RÚ = H, CH3 RÚ = H, CH3 Rê = H, CH3 n = 1 or 2 R = H, CH3 EMI53.1 EMI53.2 R =CH2CH3, CH3 EMI53.3 As noted above, the compounds of the present invention may also generally be represented by the following structural formula: : EMI54.1 wherein X' is oxygen, sulfur or NR' (R' is hydrogen or loweralkyl having from 1 to 6 carbon atoms); and R3, is hydrogen, or, inter alia, is representatively selected to provide the pharmaceutically acceptable salt, ester, anhydride (R is acyl), and amide moieties known in the 3' bicyclic ss-lactam antibiotic art; R may also be a readily removable blocking group. Identification of the Radical -CoX'R3 In the generic representation of the compounds of the present invention (I, above), the radical represented by -CoX'R3 is, inter alia, -COOH (X' is oxygen and R3 is hydrogen) and all radicals known to be effective as pharmaceutically acceptable ester, anhydride (R3 is acyl) and amide radicals in the bicyclic ss-lactam antibiotic art, such as the cephalosporins and penicillins and nuclear analogues thereof. Suitable, but representative, blocking esters R3' (X = 0) include those selected from the following list which is representative: (i) R3' = CHaRbRc wherein at least one of Ra, Rb, and Rc is an alectrondonor, e. g., p-methoxyphenyl. The remaining Ra, Rb and groups may be hydrogen or organic substituting groups. Suitable ester groups of this type include ±-methoxybenzyloxycarbonyl. (ii) R3 = CRaRbRC wherein at least a b C one of R , R and R is an electron-attracting group, e.g., p-nitrophenyl, trichloromethyl, and o-nitrophenyl. Suitable esters of this type include E-nitrobenzyloxycarbonyl, and 2,2,2-trichloroethoxycarbonyl. (iii) R3' = CRaRbRC wherein at least two of Ra, Rb and RC are hydrocarbon such as alkyl, e.g., methyl or ethyl, or aryl, e.g., phenyl and the remaining Ra, Rb and RC group, if there is one, is hydrogen. Suitable esters of this type include t-butyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonvl. Silyl esters. This category of blocking groups, may conveniently be prepared from a halosilane of the formula: R4SiX' 3 wherein X' is a halogen such as chloro or bromo and R4 is alkyl, having 1-6 carbon atoms, phenyl, or phenylalkyl. Pharmaceutically acceptable carboxyl derivatives of the present invention are those derived by reacting I with alcohols, acylating reagents and the like. For example, esters and amides of interest are the above-listed starting materials and final products having the -CoX'R3 group at the 3-position; wherein X' is oxygen, sulfur or NR' (R' is H or R31), and R3' is alkyl havinq 1-6 carbon atoms, straight or branched, such as methyl, ethyl, t-butyl, and the like; carbonylmethyl, including phenacyl; aminoalkyl including 2-methylaminoethyl, 2-diethylaminoethyl; alkanoyloxyalkyl wherein the alkanoyloxy portion is straight or branched and has 1-6 carbon atoms and the alkylportion has 1-6 carbon atoms, such as pivaloyloxymethyl; haloalkyl wherein halo is chloro, and the alkyl portion is straight or branched havinq 1-6 carbon atoms, e.g., 2,2,2-trichloroethyl; alkenyl having 1-4 carbon atoms such, as 2-propenyl, 3-butenyl, and 4-butenyl; aralkyl and lower alkoxyland nitro- substituted aralkyl such as benzyl, benzhydryl, o-nitrobenzyl, p-methoxybenzyl, and p-nitrobenzyl; phthalidyl; benzyloxyalkyl having 8-10 carbon atoms such as benzyloxymethyl, and (4-nitro) benzyloxymethyl. In addition to the esters (and thio esters) listed above, amides are also embraced by the present R' invention, i.e. wherein X' is the -N- group. Representatives of such amides are those wherein R' is selected from the group consisting of hydrogen and alkyl such as methyl and ethyl. The most preferred -CoX'R3 radicals of the present invention are those wherein (relative to Structure I above), X' is oxygen and R3 is hydrogen; loweralkyl having 1-4 carbon atoms; lower alkenyl such as 3-methylbutenyl, 4-butenyl and the like; benzyl and substituted benzyl such as p-nitrobenzyl; pivaloyloxymethyl, 3-phthalidyl; and phenacyl PREFERRED VALUES FOR R9 and R10 In the generic structure (I): EMI57.1 The following are preferred for R and R10: CH3, CH2CH3 CH(CH3)2 CH2C6H5 CH2F CHF2 CF3 CH2-Br EMI57.2 PREFERRED VALUES FOR R6 and R7 In the generic structure (I): EMI58.1 The preferred values for R6 and R7 independently are selected from: EMI58.2 EMI58.3 EMI58.4 An especially preferred substitution at position 6 finds R7=H, and R6 selected from EMI59.1 Preferred embodiments of the present invention employ the l-hydroxyethyl substituent at ring position 6. The foregoing description is repeated below to demonstrate these embodiments. All symbolism is as previously defined. These embodiments are both mono- and disubstituted as ring position 1. DTAGRAM I EMI59.2 EMI60.1 In words relative to the above reaction scheme, Diagram I, the step la to 2a to establish leaving group "a is accomplished by acylating the bicyclic keto ester la with an acylating agent RXa such as p-toluenesulfonic acid anhydride, p-nitrophenylsulfonic acid anhydride, 2,4,6-triisopropylphenylsulfonic acid anhydride, methanesulfonic acid anhydride, trifluoromethane sulfonic acid anhydride, diphenyl chlorophosphate, toluenesulfonyl chloride, p-bromophenylsulfonyl chloride, or the like; wherein xa is the corresponding leaving group such as toluene sulfonyloxy, p-nitrophenylsulfonyloxy, benzenesulfonyloxy, diphenylphosphoryl, and other leaving groups which are established-by conventional procedures and are well known in the art. Typically, the above acylation to establish leaving group is conducted in a solvent such as methylene chloride, acetonitrile or dimethylformamide, in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like at a temperature of from -20 to 400 for from 0.1 to 5 hours. The leaving group Xa of intermediate 2a can also be halogen. The halogen leaving group is established by treating la with a halogenating agent such as > 3PCl2w 3PBr2 (O)3PBr2, oxalyl chloride or the like in a solvent such as CH2C12, CH3CN, THF, or the like in the presence of a base such as diisopropylethylamine, triethylamine, or 4-dimethylaminopyridine or the like. [/ = phenyl.] The reaction 2a to 22 is accomplished by treating 2a in a solvent such as dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, or the like, in the presence of an approximately equivalent to excess of the mercaptan reagent HSR8, wherein R8 is defined above, in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine, or the like at a temperature of from -40 to 250C for from 30 sec. to 1 hour. The final deblocking step 22 to I is accomplished by conventional procedures such as solvolysis or hydrogenation. The conditions of deblocking 22 to I are thus: typically 22 in a solvent such as tetrahydrofuran-water, tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water, or the like containing pH 7 morpholinopropanesutfonic acid-sodium hydroxide buffer, pH 7 phosphate buffer, dipotassium hydrogen phosphate, sodium bicarbonate, or the like, is treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a catalyst such as platinum oxide, palladium on charcoal, or palladium hydroxide on charcoal, or the like at a temperature of from 0 to 50 C from 0.25 to 4 hours to provide I. Photolysis, when R5 is a group such as o-nitrobenzyl, for example, may also be used for deblocking. Relative to Diagram I, the bicyclic keto ester la may be obtained by the following scheme, Diagram II. DIAGRAM II EMI62.1 The addition 3 to 4 is accomplished by treating 3 with l,l'-carbonyldiimidazole, or the like, in a solvent such as tetrahydrofuran (THF), dimethoxyethane, acetonitrile or the like, at a temperature of from 0 to 700C, followed by the addition of 1.1 to 3.0 equivalent of (R O2CCH2CO2)2Mg, at a temperature of from 0 to 700C for from 1 to 48 hours. The addition 3 to 4 can also be achieved by using unprotected starting material 3 (RO'=RO=H, or partially protected 3: RO=H, R '=triorganosilyl). The group R5 is a pharmaceutically acceptable ester moiety or a redily removable carboxyl protecting groups such as p-nitrobenzyl, benzyl, or the like. The term "triorganosilyl" embraces those conventionally employed; wherein the organo moiety is independently selected from alkyl having 1-6 carbon atoms, phenyl, and phenylalkyl. Removal of protecting groups RO' and RO (4 to 5) (when RO and RO' are triorganosilyl such as t-butyldimethylsilyl) is accomplished by acidic aqueous hydrolysis of 4 in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, or the like, in the presence of an acid such as hydrochloric, sulfuric, acetic or the like at a temperature of from 0 to 1000C for from 0.5 to 18 hours. The diazo species 6 is prepared from 5 by treating 5 in a solvent such as CH3CN, CH2C12, THF, or the like with an azide such as p-carboxybenzenesulfonylazide, p-toluenesulfonylazide, methanesulfonylazide, or the like in the presence of a base such as triethylamine, pyridine, diethylamine or the like for from 1 to 50 hours at 0-500C. Cyclization (6 to la) is accomplished by treating 6 in a solvent such as benzene, toluene, THF, cyclohexane, ethylacetate or the like at a temperature of from 25 to 110 for from 1-5 hours in the presence of a catalyst such as bis (acetylacetonato)Cu(II)[Cu(acac)2], CuSO4, Cu powder, Rh2(OAc)4 or Pd(OAc)2. Alternatively, the cyclization may be accomplished by irradiating 6 through a pyrex filter (a wave length greater than 300nm) in a solvent such as benzene, CC14, diethylether, or the like, at a temperature of from 0-250C for from 0.5 to 2 hours. ("OAc" = acetate.] Relative to Diagram II, the following scheme, Diagram III, crosses at intermediate 3. DIAGRAM III EMI64.1 EMI65.1 In words relative to Diagram III for the preparation of 3, 4,4-disubstituted 1,3-oxazine 1' (wherein R9 and R10 are as defined in I; Ra and Rb are independently selected from the group of loweralkyl having 1-6 carbon atoms such as methyl, ethyl, and the like, or Ra and Rb are joined to form a spirocycloalkyl, such as spirocyclohexyl, and the like) is treated with diketene in a solvent such as ethanol, methanol or the like at a temperature of from -100C to 500C for from 1 hr to 6 hrs to give adduct 2'. The ss-ketoamide 2' is diazotized with a diazotizing agent such as p-toluenesulfonylazide, methanesulfonylazide, p-carboxylbenzenesulfonylazide, or the like in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran or the like in the presence of a base such as triethylamine, pyridine, diethylamine, or the like for from 10 min, to 4 hours at 0 - 500C to give diazo species 3'. The cyclization (3' to 4') is accomplished by treating 3' in a solvent such as benzene, toluene, THF, cyclohexane, ethylacetate or the like at a temperature of from 25 to 1100C,, for 10 min to 5 hours in the presence of a catalyst such as copper (II) sulfate, copper powder, rhodium acetate, palladium acetate, or the like. Alternatively, the cyclization may be accomplished by irradiating 3' through a pyrex filter (a wave length greater than 300 nm) in a solvent such as benzene, CCl4, diethylether, or the like at a temperature of from 0-250C for from 0.5 to 2 hours. Treatment of ketone 4' with a reducing agent such as sodium borohydride, lithium borohydride, K-selectride, or the like in a solvent such as THF, ethylether, or the like at a temperature of from 0 to 250C for from 0.5 to 5 hours affords alcohol 5'. The free hydroxy group of 5' is protected with an acid stable blocking group R' such as p-nitrobenzyloxycarbonyl, o-nitrobenzoxycarbonyl, or the like by treating 5' with 1 to 2 equivalents of chloroformate such as p-nitrobenzylchloroformate in a solvent such as DMF, THF, methylene chloride, or the like in the presence of a base such as p-dimethylaminopyridine, pryidine, triethylamine, or the like at a temperature of from -20 to 600C for from 0.5 to 6 hours. The conversion 6' to 7' is obtained by oxidation. The most preferred oxidation reaction is achieved by suspending 6' in a solvent such as acetone, benzene, hexane, or the like at a temperature of from OOC to 500C and treating with an oxidizing agent such as Jones reagent. Alternatively, compound 7' may be prepared from 6' by reaction with 50% trifluoroacetic acid/water at 0 to 500C for from 10 min to 1 hr. to give the intermediate alcohol which is then oxidized with Jones reagent to 8'. The partially protected 7' (R' = CO2PNB) can also be used as the starting material for the chain extension reaction (3 to 4, Diagram II). However, because of restricted solubility of 7' in organic solvent, it is preferable to use a soluble intermediate such as N,O-bis-organosilyl protected species 3 (RO'=RO=triorganosilyl) or O-silyl protected 3 (R0=H, R=triorganosilyl). The exchange of protecting group of 7' is accomplished by hydrolysis of 7' in an alkaline media such as aqueous -NaOH, KOH or the like to provide carboxylic acid salt 8' followed by esterification of 8' with p-nitrobenzylbromide in DMF at room temperature for 1-8 hrs to give 9' (R" is p-nitrobenzyl). Treatment of 9' with triorganosilyl chloride such as t-butyldimethylchlorosilane, trimethylchlorosilane, or the like in the presence of a strong base such as triethylamine, diisopropylethylamine or the like in a solvent such as DMF, methylene chloride, at -20 to 500C for 0.5 to 8 hrs affords N,O-bisprotected species 10' (RO'=RO=triorganosilyl) selective O-silylation of 11' to give 12' (R =triorganosilyl, RO=H) is accomplished by using a weak base such as imidazole to replace the strong base in the proceeding silylation reaction. [Typically, the "organo" moiety in the reagent triorganosilyl is independently selected from alkyl, akyl, or aralkyl; wherein the alkyl has 1-6 carbon atoms and the aryl is phenyl.] Hydrogenolysis of 10' (RO'=RO are triorganosilyl, such as t-butyldimethylalkyl) in the presence of a nobel metal catalyst such as 10t Pd/C, PtO2, or the like in a solvent such as ethylacetate, benzene, or the like at room temperature for from 30 min. to 3 hrs affords N,O-diprotected free acid 3. With respect to starting material 1' (Diagram III), its preparation is summarized in Diagram IV. DIAGRAM IV EMI69.1 In words relative to Diagram IV, the substituted 1,3-oxazine 1' (wherein R9, Rl0, Ra and Rb are as defined in Diagram III) is prepared by treating 3,3-disubstituted 1,5-pentanediol 11' with 0.5 to 1.0 equivalents of p-toluenesulfonylchloride in a solvent such as DMF, THF, methylene chloride, pyridine, or the like in the presence of base such as triethylamine, pyridine or the like at a temperature of from 0 to 500C for from 0.5 to 5 hours. The mono-tosyl alcohol 12' is treated with I to 5 equivalents of sodium azide in a reaction medium such as polyethylene glycol (m.w. 200 to 600) at a temperature of from 90 to 1400C and the product, azido alcohol 13', is obtained by continuing collection of the distillate from the reacting mixture in 1 to 8 hrs. Reduction of the azido alcohol to the corresponding amino alcohol (13' to 14') is accomplished by hydrogenation of (13' under 1 to 50 atm. of hydrogen in a solvent such as cyclohexane, methanol, ethylacetate, or the like in the presence of a catalyst such as 10% palladium on charcoal, palladium oxide, platinum or the like at a temperature of from 0 to 50 C for from 2 to 20 hours. Condensation of 14' with a ketone such as cyclohexanone, cyclopentanone, acetone, or the like in a solvent such as cyclohexane, benzene, toluene, or the like with azeotropic removal of water by an apparatus such as Dean-Stark trap at reflux for 0.5 to 6 hours affords the desired substituted 1,3-oxazine 1'. The ketone in condensation with 14' may generically be represented as EMI71.1 wherein Ra and Rb are as previously defined and the dotted line indicates that Ra and Rb may be joined. Alternatively, the azetidinone carboxylic acid 3 may be prepared from 3-substituted 1,4-butadiene (Diagram V). DIAGRAM V EMI71.2 In words relative to Diagram V, the substituted azetidinone 2" is prepared by reacting a 3-substituted 1,4-pentadiene 1" with chlorosulfonylisocyanate at 250C to 600C in a pressure bottle for 3-12 days. The resulting mixture is hydrolyzed with aqueous sodium sulfite solution between pH 6.5-7.5 at OOC to 250C for from 5 min. to 60 min. Azetidinone 2" is transformed (2" to 3") to establish the protecting group R which may be a triorganosilyl group, such as t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsily, isopropyldimethylsilyl, for example, or may be 3,4-dimethoxybenzyl, for example. Silyl protection is preferred, and typically RO is established by treating 2" in a solvent such as dimethylformamide, acetonitrile, hexamethylphosphoramide, tetrahydrofuran or the like with a silylating agent such as t-butyldimethyl chlorosìlane, t-butyldiphenylchlorosilane, triphenylchlorosilane, or the like at a temperature of from -200 to 250C for from 0.5 to 24 hours in the presence of a base such as triethylamine, diisopropylethylamine. Alkylation of 3" provides Q". Typically, 3" is treated with a strong base such as lithium diisopropylamide, sodium hydride, phenyl lithium, butyl lithium, or the like in a solvent such as tetrahydrofuran, ether, dimethoxyethane or the like at a temperature of from -800C to OOC, whereupon the alkylating agent of choice, acetaldehyde is introduced. The free hydroxyl group of 4" is protected by a triorganosilyl group such as t-butyldimethylsilyl by treating 4" with t-butyldimethylchlorosilane and p-dimethylaminopyridine in a solvent such as DMF, acetonitrile, CH2C12 or the like at -20 to 600C for from 0.5 to 8 hours. The oxidation 5" to 3 is accomplished by treating 5" in a solvent such as methylenechloride, methanol, or the like, with ozone, at a temperture of from -1000 to OOC for from 0.1 to 4 hours, followed by treating the crude product with an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, or the like, at a temperature of from OOC to 1000C for from 1 to 100 hours. R ' and RO are readily removable protecting groups such as triorganosilyl. With respect to starting reagent 1", its preparation is generally described in J. Amer. Chem. Soc., 74, 661 (1952) by E. B. Reid and T. E. Gompf, J. Org. Chem., 23, 1063 (1958) by R. Ciola and K. L. Burwell, Jr., and Belgium Patent 632,193 (1963) by R. Polster and E. Scharf. The following scheme summarizes the preparation of 1". DIAGRAM VI EMI74.1 In words relative to Diagram VI, the diester 12 is prepared by treating the diacid 11 with thionyl chloride at reflux for two hours followed by reacting with ethanol at 800C for 4 hours. Reduction of the diester 12 with lithium aluminum hydride in ether at reflux for 4 hours followed by hydrolysis with 10% NaOH gives diol 13 which on further reaction with thionyl chloride gives dichloride 14. Reaction of the dichloride 14 with base such as 2-methylquinoline, DBU or sodium hydroxide in polyethylene glycol gives the expected 3-substituted 1,4-pentadiene 1". The foregoing Diagrams (I-VI) describe the synthesis of racemic l,l-disubstituted-6-[1 hydroxyethyl] -2-carbamimidoyl-l-carbadethiapen-2-em-3- carboxylic acids I. The preferred configuration of final products I is represented by the following drawing: EMI75.1 The corresponding configuration at the level of intermediate 3 is represented by the following drawing: EMI76.1 With respect to the chiral synthesis of I, the racemic azetidindone carboxylic acid 3 (RO' and RO are H or.protecting groups, Diagrams II) is resolved according to conventional optical resolution techniques, such as fractional cystallization of optically active ammonium salts, esters, or chromatographic separation of such esters. Alternatively, the chiral azetidinone intermediates 3-6 (Diagram II) may also be conveniently prepared via alkylation of the corresponding unsubstituted chiral azetidinone 27, 31 and 35. (Diagram VII, below) Chiral precursors 24, 28 and 32 are known. Diagram VIII summerizes these reactions: Diagram VIII EMI77.1 EMI77.2 EMI78.1 EMI78.2 In words relative to Diagram VIII, the free hydroxy function of the azetidinone carboxylate 24 (R=CH3) is selectively protected by treating 24 with 1-2 eq of a triorganosilylating agent such as t-butyldimethylchlorosilane in a solvent such as DMF, CH2Cl2, or the like, in the presence of 2-5 eq. of imidazole at room temperature for 1 to 8 hrs. to give 25 (R=CH3, RO'=t-Butyldimethylsilyl, for example). Treatment of 25 at -780C under a nitrogen atmosphere with 2-2.5 eq. of a base such as lithium diisopropylamide or the like in a solvent such as THF, ether or the like for from 10 min. to 30 min. yields dianion intermediate. The dianion so obtained is then treated with 2 to 100 eq. of a reagent (R9X, R10X, X is a leaving group) calculated to establish R9/R10 (such reagents include halides, sulfonates, and sulfates, for example: R9-halides, such as iodomethane, iodoethane, R9 sulfonates, or R9-sulfates such as dimethylsulfate, or the like) at -780-250C for from 0.5 min. to 3 hrs; the reaction is then quenched with 1.ON hydrochloric acid to give chiral species 26. By repeating the preceding procedure using 26 as starting material, the desired disubstituted azetidinone 27 is obtained; hydrolysis of 27 in the presence of 1 eq of NaOH, followed by acidic work up gives chiral species 3. Similarly prepared are 31 and 35 from 28 and 32, respectively, by the procedure described above. However, it should be noted that the transformation 33 to 34 (or 34 to 35) nominally requires an additional equivalent of base. The compounds of the present invention (I) are valuable antibiotics active against various Gram-positive and Gram-negative bacteria and accordingly find utility in human and veterinary medicine. Representative pathogens which are sensitive to antibiotics I include: Straphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Bacillus subtilis, Salmonella typhosa Psuedomonas and Bacterium proteus. The antibacterials of the invention are not limited to utility as medicaments; they may be used in all manner of industry, for example: additives to animal feed, preservation of food, disinfectants, and in other industrial systems where control of bacterial growth is desired. For example, they may be employed in aqueous compositions in concentrations ranging from 0.1 to 100 parts of antibiotic per million parts of solution in order to destroy or inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example in waterbased paints and in the white water of paper mills to inhibit the growth of harmful bacteria. The products of this invention may be used in any of a variety of pharmaceutical preparations. They may be employed in capsule, powder form, in liquid solution, or in suspension. They may be administered by a variety of means; those of prinicipal interest include: orally, topically or parenterally by injection (intravenously or intramuscularly). Such tablets and capsules, designed for oral administration, may be in unit dosage form, and may contain conventional excipients, such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, sugar, cornstarch, calcium phosphate, sorbitol, or glycerine; lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica; disintegrants, for example, potato starch, acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of aqueous or oily suspensions, or solutions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, or carboxymethyl cellulose. Suppositories will contain conventional suppository bases, such as cocoa butter or other glycerides. Compositions for injection, the preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents. Alternatively, the active ingredient may be in powder form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water. The compositions may also be prepared in suitable forms for absorption through the mucous membranes of the nose and throat or bronchial tissues and may conveniently take the form of liquid sprays or inhalants, lozenges, or throat paints. For medication of the eyes or ears, the preparation may be presented in liquid or semi-solid form. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders. The dosage to be administered depends to a large extent upon the condition and size of the subject being treated as well as the. route and frequency of administration -- the parenteral route by injection being preferred for generalized infections. Such matters, however, are left to the routine discretion of the therapist accordinq to principles of treatment well known in the antibiotic art. In general, a daily dosage consists of from about 5 to about 600 mg of active ingredient per kg. of body weight of the subject in one or more treatments per day. A preferred daily dosage for adult humans lies in the range of from about 10 to 240 mg. of active ingredient per kg. of body weight. Another factor influencing the precise dosaqe regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the chosen species of this invention (I). The compositions for human delivery per unit dosage, whether liquid or solid, may contain from 0.1% to 99% of active material, the preferred ranqe being from about 10-608. The composition will generally contain from about 15 mg. to about 1500 mq. of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage is usually the pure compound I in sterile water solution or in the form of a soluble powder intended for solution. For zwitterionic species described under Structure I, the pH of such solutions typically will correspond to the zwitterionic point; however, consideration of individual properties of solubility and stability may require such aqueous solutions to have a pH other than that of the zwitterionic point, for example in the range of 5.5 to 8.2. In the foregoing word description of the above, schematic reaction diagram for the total synthesis of the defined carbapenem antibiotics, it is to be understood that there is considerable latitude in selection of precise reaction parameters. Suggestion of this latitude and its breadth is generally indicated by the enumeration of equivalent solvent systems, temperature ranges, protecting groups, and range of identities of involved reagents. Further, it is to be understood that the presentation of the synthetic scheme as comprising distinct steps in a given sequence is more in the nature of a descriptive convenience than as a necessary requirement; for one will recognize that the mechanically dissected scheme represents a unified scheme of synthesis and that certain steps, in actual practice, are capable of being merged, conducted simultaneously, or effected in a reverse sequence without materially altering the progress of synthesis. The following examples recite a precise scheme of total synthesis. It is to be understood that the purpose of this recitation is to further illustrate the total synthesis and not to impose any limitation. Temperature is in OC. EXAMPLE SECTION - PART I EXAMPLE I Preparation of 3 (Method I) EMI84.1 Step A EMI84.2 Into a 1000-ml three-necked flask equipped with a machanical stirrer is charged with 300 ml pyridine and 2,2-dimethyl-1,3-propane-diol (75 g). The flask is kept in an ice-bath. p-Toluenesulfonyl chloride (137.3 g) in pyridine (487 ml) is dropped into the flask through a dropping funnel. The mixture is stirred at OOC overnight, then hydrolyzed with 100 ml water and crushed ice and acidified with conc. HC1. The mixture is extracted with 1.0 L ether. The organic layer is separated, dried over MgSO4 then evaporated in vacuo to give product 2 (174 g). Step B: EMI85.1 The tosylate (37 g), sodium azide (27.9 g) and polyethyleneglycol (mw 400, 100 ml) are placed in a 500-ml round bottomed flask attached with a distillation head. The mixture is heated at 135OC under vacuum (2-10 mm Hg) for 3.0 hours. The product is collected as colorless oil (17.2 g), 60 MHz NMR (CDC13):0.95(s), 2.70 (broad singlet), 3.21 (s), and 3.38 (s); IR (Neat): 2100 Cm-1 (N3). Step C: EMI85.2 The azido propanol (37.8 g) in 120 ml cyclohexane is hydrogenated under 40 psi of hydrogen in the presence of 2.0 g of 10% Pd/C for 3 hours. The mixture is filtered from catalyst then evaporated in vacuo to give 35.7 g of product 4, 60 MHz NMR (CDC13):0.85 (s), 2.62 (s), 2.70(s), 3.40 (s). Step D: EMI86.1 The amino alcohol 4 (75 g) and cyclohexanone (90 ml) in cyclohexane (400 ml) are heated at reflux. The water resulting from condensation is continuously removed by a Dean-Stark trap. After 4.5 hours, the mixture is evaporated in vacuo then distilled to give 94 g of product 5, 60 MHz NMR (CDC13):0.90 (s), 1.50-2.10 (m), 2.62 (s) and 3.40 (s), Step E: EMI87.1 The starting material 5 (17.0 q) in ethanol (128 ml) is mixed with diketene (8.01 ml) and then stirred at 250C for 4 hours. The mixtue is evaporated in vacuo and the crude product is purified by silical gel column (4.4 x 30 cm) eluting with 35% EtOAc/cyclohexane to give product 6 (8.3 g). MS: m/e 267 (M+), 252 (M+-15), 224 (M+-44): 60 MHz NMR (CDC13): 81.00 (s), 2.24 (s), 3.03 (s), 3.36 (s), 3.41 (m). Step F: EMI87.2 The ss-ketoamide 6 (8.3 g) in acetonitrile (62 ml) is treated with EtOH (4.8 ml) and polymer-SO N3 (14 g) at 250 C for 12 hours. The mixture is filtered from polymer, and the filtrate is evaporated in vacuo to give product 7 (6.4 g), IR (CHC13): 2128 (N2), 1644 Cm 1; 60 MHz NMR (CDCl3): 1.02 (s), 1.40-2.20 (m), 1.34 (s), 3.17 (s), 3.24 (s). Step G: EMI88.1 The diazo compound 7 (94 g) is dissolved in 940 ml 50% EtOAc/cyclohexane and heated at reflux in the presence of 270 mg of rhodium acetate for 6.0 hour. The mixture is washed with water, and brine. The organic layer is separated, dried over MgSO4, then concentrated and chromotographed by a silica gel column (3.2 x 8") eluting with 50% EtOAc/cyclohexane to give product 8 (94 g), MS: 265 (M+), 222 (M+-43); 60 MHz NMR (CDCl3): 0.90 (s), 1.07 (s), 1.50-2.20 (m), 2.35 (s), 3.40-4.60 (m). Step H: EMI89.1 The ketone 8 (3.39 g) in 35 ml absolute ethanol is treated with sodium borohydride (0.49 g) at 0 C for 50 minutes, then mixed with 1 ml water and stirred at 250C for 30 minutes. The mixture is titrated with saturated ammonium chloride until the organic layer is clear. The mixture is filtered from ppts. then evaporated in vacuo. The crude product is redissolved in EtOAc and washed with water, and brine. The organic layer is separated, dried over MgSO4, concentrated, and chromatographed by a silica gel column eluting with 50% EtOAc/cyclohexane to give product 9 (1.40 g), MS: m/e 267 (M+), 224 (M+-43) , 180 (M+-87); 300 MHz NMR (CDCl3) 80.86 (s), 0.88 (s), 0.70 (s), 1.08 (s), 1.15 (d), 1.17 (d), 1.30-2.90 (m), 2.95 (m), 3.11 (d), 3.29 (d), 3.35 (d), 3.57 (d,d), 4.05 (m), 4.15 (m). Step I: EMI90.1 The alcohol 9 (16.1 g) is dissolved in 309 ml CH2C12. The solution is cooled to -200C by an methanol-dry-ice bath. To the solution is added 4-N,N-dimethylaminopyridine (10.3 g) and p-nitrobenzylchloroformate (19.5 g). The mixture is stirred without cooling bath for 4 hours, then hydrolyzed with 200 ml 0.1 N HC1, washed with water and brine. The organic layer is separated, dired over Na2SO4 then chromatrographed by a silica gel column (3.2 x 12") eluting with 30% EtOAc/cyclohexane to 22.0 g of product 10 MS m/e 446 (M+), 418 (M+-28). 300 MHz NMR (CDC13): 0.82 (s), 0.84 (s), 1.06 (s), 1.42 (d), 1.45 (d), 1.50-2.00 (m), 3.50-3.65 (m), 5.12 (quintets), 5.28 (d), 5.33 (d), 7.60 (m), 8.30 (m). Step J EMI91.1 The bicyclic azetidinone 7' (6.0 g) in 60 ml acetone is treated with 4N Jones reagent (9.4 ml) at OOC for 30 min. The reaction is quenched with 1 ml isopropanol at OOC for 10 min, then mixed with 250 ml ethylacetate and washed with water and brine until blue color disappeared in the organic layer. The organic layer is separated, dried over MgSO4, and evaporated in vacuo to give crude product which is purified by a silica gel column (4.4 x 10 cm) eluting with ethylacetate to give 3.1 g of 8' as crystalline solid. Step K EMI91.2 The azetidinone carboxylic acid 8' (3.0 g) is suspended in 50 ml water. The mixture is stirred and treated with 2.5N NaOH and maintained at pH 12.0 at room temperature for 30 min. The resulting solution is neutralized with 2.5N HC1 to pH 7.5. After the mixture is extracted with EtOAc, the aqueous layer is concentrated and lypholized to give white solid product 9'. Step L EMI92.1 The azetidinone carboxylic acid sodium salt 9' (2.2 g) and p-nitrobenzylbromide (2.94 g) are stirred at room temperature in DMF (29.3 ml) for 5 hrs. The mixture is diluted with EtOAc and washed with water and brine. The organic layer is separated, dried over MgSO4 and evaporated to give crude product which is purified by TLC plates eluting with 50% EtOAc/cyclohexane to give product 10'. Step M EMI92.2 The ester 10' (1.33 g) is stirred with t-butyldimethylchlorosilane (2.49 g), triethylamine (4.61 ml) in DMF (16 ml) at room temperature overnight. The mixture is filtered from ppts and evaporated in vacuo to give crude product 11' which is redissolved in ethylacetate and washed with water, brine, dried over Na2SO4, concentrated to 0.5 ml then purified by TLC eluting with 30% EtOAc/cyclohexane to give product 11'. Step N EMI93.1 The bis-silyl azetidinone ester 11' (1.60 g) in 30 ml EtOAc is hydrogenated under 50 psi hydrogen in the presence of 0.32 g 10% Pd/C for 30 min. The mixture is filtered from catalyst. The catalyst is washed with MeOH. The methanol and ethylacetate solutions are combined and evaporated in vacuo to give white solids. The crude product is re-dissolved in ethylacetate and washed with 0.lN HCl. The organic layer is separated, dried over Na2SO4 and evaporated to give white solid product 3. EXAMPLE 2 Preparation of 3 (Method II) EMI94.1 Step A: Preparation of 3,3-Dimethyl-1,4-pentadiene EMI94.2 Procedure a ss,ss-Dimethylglutaric acid (1.0 mole) is refluxed for 2 hours with thionyl chloride (68% excess). After removal of excess thionyl chloride, absolute ethanol (109% excess) is added slowly. The mixture is refluxed for 3 hours then distilled to collect the product, diethyl 6,ss-dimethylglutarate (98% yield). To a suspension of lithium aluminum hydride (24 g) in ether (860 ml) is added dropwise with rapid stirring a solution of diethyl ss,ss-dimethylgultarate (124 g in 250 ml ether). The mixture is refluxed for 6 hours, then cooled to room temperature. Water (25 ml) is added slowly. The mixture is then titrated with 10% NaOH until a clear organic layer is obtained. The organic layer is separated, di red over anhydrous sodium sulfate then evaporated in vacuo to give the resulting diol as an oil (90% yield). The 3,3-dimethyl-1.5-pentanediol (0.5 mole) is treated with thionyl chloride (1.05 mole) at reflux for 3 hours. After removal of excess thionyl chloride in vacuo, the 3,3-dimethyl-1,5-dichloropentane is obtained (90% yield). 3,3-Dimethyl-1.5-dichloropentane (41 g) is added dropwise at 1700C to a mixture of 48 g of sodium hydroxide and 40 g of polyethylene glycol tetramer and the mixture is distilled to give 3,3-dimethyl-1,4-pentadiene (66%). Step B: EMI96.1 In a sealed tube, 3,3-dimethyl-1,4- pentadiene (9.6 g) and chlorosulfonyl isocyanate (14.2 g) are allowed to stand at room temperature for 6 days. The resulting mixture is diluted with methylene chloride and added slowly to a stirred aqueous solution which contains 20 g of Na2S03 and 50 g of K2HPO4 at 0-50C for 30 minutes. The organic layer is separated and dried over Mg2SO4. After evaporation, the crude product is chromatographed on silica gel GF eluting with EtOAc to give 2'. Step C: EMI96.2 t-Butyldimethylchlorosilane (7.51 g) is added in one portion to an ice-cold, stirred solution of 4- (l-methyl-prop-2-ene) -azetidin-2-one (6.54 g) and triethylamine (12 ml) in anhydrous dimethylformamide (100 ml). The reaction mixture is stirred at a temperature ranging from 0 to 50C for 1 hour and then allowed to warm to room temperature. Most of the solvent is removed under vacuum to give a residue which is partitioned between diethyl ether (250 ml) and water. The ethereal phase is washed with 2.5N hydrochloric acid (50 ml), water (3 X 50 ml), and brine, dried with magnesium sulfate, filtered and evaporated under vacuum to provide a crude product which is purified by chromatography on silica gel (20% ether in petroleum ether) to yield 3'. EMI97.1 n-Butyllithium in hexane (26.25 mmol) is added slowly by syringe to a solution of diisopropylamine (26.55 mmol) in anhydrous tetrahydrofuran (100 ml) at -780C. The resulting solution is stirred for 15 min. prior to the addition of a solution of 3' (25.0 mmol) in anhydrous tetrahydrofuran (25 ml). After stirring for 15 min. at -780C acetaldehyde (75 mmol) is added by syringe and the resulting solution is stirred at -780C for 5 min. Saturated aqueous ammonium chloride solution (15 ml) is added by syringe and the reaction mixture is allowed to warm to room temperature, then diluted with ether (250 ml) and washed 2.5N hydrochloric acid solution (2 x 50 ml), water (100 ml) and brine and dried over magnesium sulfate. Solvents are removed in vacuo and the residue is chromatographed on silica gel (1:1, ether: petroleum ether) to give the expected product 4'. Step E: EMI98.1 At OOC, the alcohol 4' (5.00 g) is dissolved in DrtF (50 ml) and treated wtih t-butyl-dimethylchlorosilane (7.51 g) and triethylamine (12 ml). The mixture is allowed to warm to room temperature with constant stirring for 2 hours, then filtered from solids, evaporated in vacuo to give oil residue which is re-dissolved in ethylacetate and washed with 0.1 N HC1, water, and brine. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give crude product 5'. HPLC purification of product (20% ethylacetate/cyclohexane) affords 5'. steP F: EMI99.1 A solution of 5' (3.0 mmol) in dry methylene chloride (30 ml) is cooled to -780C (dry-ice acetone) and a stream of ozone is bubbled through until the reaction mixture becomes blue. The ozone flow is then stopped and the reaction is purged by bubbling through nitrogen until the blue color disappears. Solid m-chloroperbenzoic acid (3.0 mmol) is added and the cold bath is removed. When the reaction mixture reaches room temperature, the flask is fitted with a reflux condenser and the mixture is heated at reflux for three days. Removal of solvents in vacuo gives crude product which is chromatographed on silica gel (2% glacial acetic acid in methylene chloride) to 3'. EXAMPLE 3 Preparation of la: EMI100.1 Step A: EMI100.2 The N,O-bis-silyl azetidinone carboxylic acid 1' (500 mg) suspended in acetonitrile (14.8 ml) is treated with l,l'-carbonyldiimidazole (229.6 mg) and stirred at room temperature for 30 min. The mixture is then treated with p-nitrobenzylmalonate magnesium salt (1.18 g) and heated at 600C for 3 hrs. The mixture is diluted with CH2C12 and washed with water, brine, and dried over Na2SO4. TLC purification (75% EtOAc/cyclohexane) of the crude product provides 0.50 g of product 2'. Step B: EMI101.1 The bis-silyl S-keto ester 2' (667 mg) in methanol (16 ml) is stirred with 2 ml 6N HC1 at room temperature for 2 hrs. The mixture is diluted with ethylacetate, washed with 0.1M sodium phosphate buffer, brine, dried over Na2S04 then evaporated in vacuo to give 0.6 g of crude product which is purified by TLC eluting with 100% ethylacetate to give product 3'. Step C: EMI101.2 The ss-keto ester 3' (270 mg) in 3.2 ml acetonitrile p-toluene-sulfonylazide (1.11 g, 3.33 meq/g), triethylamine (0.31 ml) are placed in a 25 ml round-bottomed flask. The mixture is stirred under nitrogen atmosphere at room temperature for 1 hr. The mixture is diluted with ethylacetate and washed with water, brine, and dried over MgSO4. The crude product is purified by TLC eluting with 50% EtOAc/cyclohexane to give 4'. Step D: EMI102.1 The diazo B-keto ester 4' (38.6 mg) in toluene (1 ml) is heated at 800C in the presence of rhodium acetate (1.7 mg) for 10 min. The mixture is diluted with ethylacetate (10 ml) and washed with water and brine. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give bicyclic keto ester la. EXAMPLE 4 Chiral Synthesis Step A: EMI103.1 At OOC, under N2, the chiral starting material 1 (0.94 g), methylene chloride (8.2 ml), triphenylphosphine (3.34 g) and formic acid (1.15 g, 97%) are placed in a 50-ml three-necked flask. To the solution is slowly added di-isopropyl azodicarboxylate (2.58 g). The mixture is then stirred at room temperature overnight; thin layer chromatograph (tLC) shows that all the starting material is consumed. The mixture is cooled to 0 C and treated with methanol (11.48 ml), water (4.9 ml) and concentrated hydrochloric acid (1.7 ml) for 2 hr, then extracted with methylene chloride. The organic layer is separated, dried over MgSO4 and evaporated to give product 2. Step B: EMI104.1 The free hydroxyl azetidinone 2 (374 mg) in DMF is treated with imidazole (688 mg) and t-butyldimethylchlorosilane (603 mg) at room temperature for 7 hrs. The mixture is evaporated in vacuo and the residue is re-dissolved in ethyl acetate and washed with 1 N HC1, water and brine. The organic layer is separated, dried over MgSO4, and evaporated in vacuo to give 3. Step C: EMI104.2 Under N2, at -780C, diisopropylamine (1.68 ml) in 12.5 THF is treated with n-butyllithium (12.5 ml, 1.6 M in hexane) for 10 min. To the solution is added THF solution of 3 (1.51 g in 5 ml THF) and the mixture is stirred for 20 min, then is treated with iodomethane (1.87 ml). After stirring 40 min at -780C, the mixture is allowed to warm to OOC then hydrolyzed with 0.1 N HCl. The mixture is extracted with ethyl acetate. The organic layer is washed with water, brine then dried over MgSO4 and evaporated in vacuo to give 2.1 g of mixture of 4. EMI105.1 Under N2, at -780C, diisopropylamine (0.84 ml) in 6.3 ml THF is treated with n-BuLi (6.3 ml, 1.6 M in hexane) for 10 min. To the solution is added THF solution of 3 (0.75 g in 5 ml THF) and the mixture is stirred for 20 min, then is treated with iodomethane (0.99 ml). After stirring 40 min at -780C, the mixture is allowed to warm to OOC then hydrolyzed with 0.1 N HC1. The mixture is extracted with ethyl acetate. The organic layer is washed with water, brine then dried over MgSO4 and evaporated in vacuo to give 5. Step E: EMI105.2 The methyl ester 5 (1.0 g) is treated with NaOH solution (2.5 N, 1.4 ml) in methanol (5 ml) at room temperature for 5 hr. The mixture is acidified with 1N HCl to pH 1.0 then extracted with ethyl acetate. The organic layer is separated and dried over MgSO4 and evaporated to give product 6. Step F: EMI106.1 The carboxylic acid (300 mg) suspension in acetonitrile is treated with l,l'-carbonyldiimidazole (194.6 mug) at room temperature for 30 min. The mixture becomes homogeneous within 5 min. To the solution is added magnesium p-nitrobenzylmalorate (1.00 g), then the mixture is heated at 650C for 3 hr. The final reaction mixture is evaporated in vacuo to give oily residue which is re-dissolved in 10 ml ethyl acetate and washed with water and brine. The organic layer is separated, dried over MgSO4 then evaporated in vacuo to give product 7. Step G: EMI106.2 The starting material 7 (400 mg) is dissolved in 4 ml methanol and treated with 6N HC1 (0.41 ml) at room temperature for 80 min. The mixture is diluted with ethyl acetate and washed with 0.1 N pH 7.0 phosphate buffer and brine. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give crude product 7 as solids which is triturated in petroleum ether then filtered to give 8. Step H: EMI107.1 The B-keto ester 8 (269 mg) dissolved in 3.2 ml acetonitrile is gently stirred with Amberlite XE-301-SO2N3 (1.5 g, 3.33 meq of N3/g) and triethylamine (0.46 ml) at room temperature for 1.5 hr. The mixture is filtered from polymer beads and the filtrate is evaporated in vacuo to give product 9. Step G: EMI107.2 The diazo compound 9 (145 mg) is dissolved in 4.1 ml toluene and 2.5 ml ethyl acetate. The mixture is heated at 80-850C in the presence of rhodium acetate (2.9 mg) for 15 min. The solution is allowed to cool to room temperature then diluted with 10 ml ethyl acetate and washed thoroughly with water, and brine. The organic layer is separated, dried over MgSO4 then evaporated in vacuo to give product 10. EXAMPLE 5 EMI108.1 The bicyclic keto ester la (33.3 mg) in acetonitrile (0.47 ml) at OOC under N2 atmosphere is treated with diphenyl chlorphosphate (20.97 a1) at 0 C and stirred for 30 min. To the mixture is added DMSO (0.20 ml) solution of N,N-dimethylmercaptoacetamidine hydrochloride (18.68 mg) and diisopropylethylamine (24.3 p1) and stirred for 1 min. at OOC. The mixture is then mixed with 10 ml ether and centrifuged to separate the oil product which is subsequently re-dissolved in 3.72 ml THF and 2.80 ml 0.1 M 1H 7.0 sodium phosphate buffer. The solution is hydrogenated under 50 psi hydrogen in the presence of 50.0 mg of 10% Pd/C at room temperature for 30 min. Additional 50 mg of 10% Pd/C is added and the mixture is further hydrogenated for 30 minutes then filtered from catalysts. The filtrate is extracted with ether, concentrated to 4 ml then chromatographed by a Dowex-50X4 (Na cycle) column (2.2 x 6 cm) which is eluted with DI water to give product I. Lypholization of the aqueous solution gives product I. EXAMPLE 6 EMI109.1 Bz = benzyl The starting material 1 (2;10) is treated with t-butyldimethylchlorosilane (1.29 g) and imidazole (1.46 g) in DMF (8.6 ml) at room temperature for 3 hours. The mixture is evaporated in vacuo and the residue is redissolved in ethyl acetate and washed with water and brine. The organic layer is separated, dried over Na2SO4, and evaporated in vacuo to give product 2. EXAMPLE 7 EMI110.1 At -780C, under N2, diisopropylamine (168.2 l) is treated with n-butyllithium (1.6 M, 1.13 ml) in THF (0.84 ml) for 10 min. To the solution is added 1 (280 mg in 0.2 ml THF). The solution becomes deep-red upon the addition of 1. After the mixture is stirred for 20 min., iodomethane (0.7 ml) is added and stirred for an additional 40 min. at -780C, then the mixture is allowed to warm to room temperature. The mixture is hydrolyzed with saturated NH4C1, and diluted with ethyl acetate. The organic layer is separated, dried over Na2SO4, and evaporated in vacuo to give product 2. EXAMPLE 8 Following the foregoing text and examples, the following species I are obtained when the corresponding bicyclic keto ester is treated with HSR8. EMI111.1 EMI111.2 <tb> <SEP> R8 <SEP> R9 <SEP> R10 <tb> <SEP> NH <tb> <SEP> 1) <SEP> Q <SEP> 2-t-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> <SEP> 2) <SEP> CH2-8-NHCi3 <SEP> -E-NHCK <SEP> CH3 <SEP> CH3 <tb> <SEP> 2 <tb> <SEP> 3) <SEP> M2N(CH3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> N <SEP> QI3 <tb> <SEP> 4) <SEP> CH2-!-NHCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> N <SEP> - <SEP> C2H5 <tb> 5) <SEP> CH2 <SEP> 1 <SEP> -NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> 6) <SEP> CH2-t <SEP> -NCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> 25 <tb> <SEP> NH <tb> <SEP> 7) <SEP> CH2-t <SEP> - <SEP> N(C2R5)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> 5'2 <tb> <SEP> 8) <SEP> CH2-8-µC-(CH3)3 <SEP> CH3 <SEP> CH3 <tb> EMI112.1 <tb> <SEP> R8 <SEP> R9 <SEP> R10 <tb> <SEP> R8 <SEP> R9 <SEP> R10 <tb> <SEP> NH <tb> <SEP> 9) <SEP> CH-C-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> NH <tb> 10) <SEP> CH-C-NHCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> 3 <tb> <SEP> NCH3 <tb> <SEP> 11) <SEP> CR <SEP> a <SEP> - <SEP> N(CH3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> 2 <tb> <SEP> NH <tb> <SEP> n <tb> <SEP> 12) <SEP> CH-C- <SEP> N(CH3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> NH <tb> <SEP> 13) <SEP> CR-C-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> 14) <SEP> C-C-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH2 <tb> <SEP> WH <tb> <SEP> 15) <SEP> CH-C <SEP> -NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CHsCH2 <tb> EMI113.1 <tb> <SEP> R8 <SEP> R9 <SEP> R10 <tb> <SEP> rJ <tb> 16) <SEP> CR2-CR2-C-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> 17) <SEP> CH2-CH-C-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> OCH3 <tb> 18) <SEP> CH2-CH-C <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> 2, <SEP> \NH2 <tb> <SEP> OH <tb> <SEP> NH <tb> 19) <SEP> CH2-C-C-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> N-OCH3 <tb> <SEP> NH <tb> 2Q) <SEP> CH2-CH,-C-NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> <SEP> NH <tb> <SEP> 21) <SEP> N <tb> <SEP> 2-C-N(aj3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CO2H <tb> <SEP> 22) <SEP> CH,- <SEP> C <SEP> = <SEP> NH <SEP> CH3 <SEP> CH3 <tb> <SEP> S <SEP> NH <tb> <SEP> 2 <tb> <SEP> CH3 <tb> <SEP> NH <tb> <SEP> 23) <SEP> WH2-C <SEP> -NHP <SEP> CR3 <SEP> CR3 <tb> EMI114.1 <tb> <SEP> R <SEP> R9 <SEP> R10 <tb> <SEP> NRZ <tb> <SEP> 24) <SEP> (CR2) <SEP> C <SEP> CR3 <SEP> CR3 <tb> <SEP> n <SEP> \NHR1 <tb> <SEP> n <SEP> = <SEP> 2-5, <SEP> R <SEP> - <SEP> H, <SEP> CR3 <tb> <SEP> R1 <SEP> a <SEP> H, <SEP> CH3 <tb> <SEP> CH3 <SEP> NH <SEP> C <SEP> CH3 <SEP> CH3 <tb> <SEP> CR2C, <SEP> <tb> <SEP> CH3 <SEP> NX2 <tb> <SEP> CH <tb> <SEP> 26) <SEP> NR2 <SEP> CR3 <SEP> ,2 <tb> <SEP> Ln <SEP> NR'R' <tb> n <SEP> - <SEP> 2 <SEP> -5, <SEP> R1, <SEP> R2 <SEP> a <SEP> H, <SEP> CH3 <tb> 27) <SEP> CR3 <tb> 27) <SEP> (CH2)2-s-CH2-c-N(CH3)2 <SEP> CH3 <tb> 28) <tb> 28) <SEP> (CH2)2-O-CX2CH2-C-NH2 <SEP> CH3 <SEP> CH3 <tb> 29) <SEP> & <SEP> NH <SEP> CH3 <SEP> CH3 <tb> <SEP> CR3 <SEP> 2 <tb> <SEP> C,H3 <SEP> gH <SEP> CH3 <SEP> CH3 <tb> 30) <SEP> C <SEP> - <SEP> CH2- <SEP> C <tb> <SEP> CH3 <SEP> 9 <SEP> 2 <tb> EMI115.1 <tb> <SEP> R8 <SEP> 9 <SEP> R10 <tb> <SEP> CM3 <SEP> µ <tb> 31) <SEP> CH-CH2-S-86(CH3)2 <SEP> CH3 <SEP> CH3 <tb> 32) <SEP> CHH)2 <SEP> ° <SEP> CH3 <SEP> CR3 <SEP> CH3 <tb> <SEP> NH <tb> 33) <SEP> CH2CH2-C, <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> 34) <SEP> ' <SEP> CH2C$IN <SEP> CH3 <SEP> CH3 <tb> <SEP> L <tb> 35) <SEP> ZH2-C/t <SEP> 2 <SEP> CH3 <SEP> CH3 <tb> <SEP> I <tb> <SEP> CH3 <tb> <SEP> NH <tb> 36) <SEP> CR2CH2C\' <SEP> CH3 <SEP> CH3 <tb> <SEP> HNC(CH3)3 <tb> C,H3 <tb> <SEP> 3 <tb> <SEP> 9 <SEP> NCH3 <tb> <SEP> NH <tb> 38) <SEP> M, <SEP> CH3 <SEP> CH <tb> CH2C <tb> <SEP> NH-CH <SEP> (CH3) <SEP> 2 <tb> <SEP> NH <tb> CH2 <SEP> C <SEP> CH3 <SEP> CH3 <tb> <SEP> b <tb> EMI116.1 <tb> <SEP> R <SEP> R9 <SEP> R10 <tb> <SEP> NH <SEP> CH <SEP> CH3 <tb> 40) <SEP> oH2-C <SEP> 3 <tb> <SEP> N <tb> <SEP> NH <tb> ll <SEP> CH3 <SEP> CH3 <tb> 42) <tb> <SEP> Cs <SEP> CH3 <SEP> CH3 <tb> <SEP> NCCH3)2 <tb> <SEP> NH <tb> CH2 <SEP> C <SEP> CH3 <SEP> CH3 <tb> <SEP> Et <tb> 44) <SEP> CHi-C <SEP> CH3 <SEP> CH3 <tb> <SEP> CH2-C <tb> <SEP> CH3 <tb> <SEP> NH <tb> 45) <SEP> CH2-C <SEP> CH3 <SEP> CH3 <tb> <SEP> NH-CH2 <tb> <SEP> NH <tb> 46) <SEP> " <SEP> CR3 <SEP> CR3 <tb> <SEP> CR2-C, <SEP> C83 <tb> <SEP> NH-CH2 <SEP> n <tb> EMI117.1 <tb> <SEP> R8 <SEP> R9 <SEP> R10 <tb> <SEP> R8 <SEP> R <SEP> -- <SEP> R10 <tb> <SEP> NH <tb> <SEP> 47j <SEP> CH2-C <SEP> CH3 <SEP> CH3 <tb> <SEP> 2, <tb> <SEP> NH-CH2 <SEP> ¯ <tb> <SEP> 5 <tb> <SEP> 48) <SEP> NH <SEP> CH3 <SEP> CR3 <tb> <SEP> CR2-C, <tb> <SEP> NH-CH2 <SEP> < ) <tb> <SEP> 10 <tb> <SEP> NH <tb> <SEP> 49) <SEP> CH2- <SEP> C <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <SEP> -NH <SEP> <tb> <SEP> 15 <tb> <SEP> 50) <SEP> CR3 <SEP> CH3 <tb> <SEP> 2 <tb> <SEP> CH3 <tb> <SEP> 20 <SEP> NH <SEP> CR3 <SEP> CR3 <tb> <SEP> 51) <SEP> CHZ <SEP> CH3 <SEP> CH, <tb> <SEP> NH <tb> 25 <SEP> NH <SEP> CH3 <SEP> CH3 <tb> <SEP> 52) <SEP> CR2-C, <tb> <SEP> NH-N(CH3)2 <tb> <SEP> NH <tb> 30 <SEP> 2 <SEP> | <tb> <SEP> NHOCR3 <tb> <SEP> NH <tb> <SEP> CR3 <SEP> CR3 <tb> <SEP> 54) <SEP> CR2-C <tb> <SEP> I <tb> <SEP> oNs <tb> <SEP> CH3 <SEP> OCH3 <tb> EMI118.1 <tb> <SEP> R8 <SEP> R <SEP> R10 <tb> <SEP> NH <tb> 55) <SEP> CH2-C <SEP> CH3 <SEP> CH3 <tb> <SEP> CR3 <SEP> NH2 <tb> 56) <SEP> 2CR3 <SEP> CR3 <SEP> CR3 <tb> <SEP> CH <SEP> - <SEP> C <tb> <SEP> NH2 <tb> 57) <SEP> C,R2 <SEP> CR3NH,, <SEP> CR3 <SEP> CR3 <tb> 57) <SEP> CH <SEP> C <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CH3) <SEP> 2 <tb> 58) <SEP> PH-CH2-C <SEP> CH3 <SEP> CH3 <tb> <SEP> CH-CH2-C, <tb> <SEP> NH <tb> <SEP> 2 <tb> 59) <SEP> C,R3 <SEP> NH <SEP> CH3 <SEP> CH3 <tb> <SEP> CH3 <SEP> CH <tb> <SEP> N(CH3)2 <tb> <SEP> NCH3 <tb> 6Q) <SEP> C <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> <SEP> N(c)2 <tb> <SEP> CflZ-C <SEP> (CR3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> EMI119.1 <tb> <SEP> R8 <SEP> R8 <SEP> R9 <SEP> R10 <tb> <SEP> NH <SEP> CR <tb> 62) <SEP> CH2NCH2C <SEP> -N(CH3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> NCR3 <tb> 63) <SEP> CH2N-CH2CH2C <SEP> NCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> NH <SEP> N(CH3)2 <tb> 64) <SEP> CH2C-CH2CH <SEP> - <SEP> N(CH3t2 <SEP> CH3 <SEP> CH3 <tb> 65) <SEP> (32 <SEP> CR3 <SEP> CR3 <tb> <SEP> N(CR3).2 <tb> 66) <SEP> -H2 <SEP> 9 <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CR3) <SEP> 2 <tb> <SEP> H <tb> 67) <SEP> CH2 <SEP> t <SEP> CH3 <SEP> CH3 <tb> 68) <SEP> 9 <SEP> CH3 <SEP> CH3 <tb> <SEP> N <tb> 69) <SEP> t <SEP> CH3 <SEP> CH3 <tb> EMI120.1 <tb> <SEP> R8 <SEP> R9 <SEP> 10 <tb> <SEP> 70) <SEP> < <SEP> CH3 <SEP> CH3 <tb> <SEP> -(CR3) <SEP> 2 <tb> <SEP> 71) <SEP> < <SEP> (CR3) <SEP> 2 <SEP> CH3 <SEP> CR3 <tb> <SEP> 721 <SEP> Q <SEP> N(CH3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> 73) <tb> <SEP> N(CR3)2 <SEP> CR3 <SEP> CR3 <tb> <SEP> 74) <tb> <SEP> 74) <SEP> a <SEP> NH <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CR3) <SEP> 2 <tb> 75) <SEP> CH2 <SEP> ThN(CR3) <SEP> CH3 <SEP> CH3 <tb> <SEP> N <tb> 76) <SEP> c <SEP> C <SEP> - <SEP> NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> 77) <SEP> 9 <SEP> -NHCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> 78) <SEP> . <SEP> v <SEP> C <SEP> - <SEP> -N(CH3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH2 <SEP> gp <SEP> CH3 <SEP> CH3 <tb> <SEP> CH3 <tb> 80) <SEP> < 3 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH2C02H <tb> EMI121.1 <tb> <SEP> R <SEP> R <SEP> R10 <tb> 89) <SEP> H <SEP> M(CH3) <SEP> 2 <SEP> CH3 <SEP> CH3 <tb> <SEP> (3)2 <tb> <SEP> NH <tb> <SEP> 9Q) <SEP> 9 <SEP> SC'J2C¯ <SEP> N(CH3) <SEP> 2 <SEP> CH3 <SEP> CH3 <tb> <SEP> 91) <SEP> CR2- <SEP> NCR3 <SEP> CR3 <SEP> CR3 <tb> <SEP> fiN <SEP> (-CH3)2 <tb> <SEP> N <tb> <SEP> 92) <SEP> CH2-C <SEP> CH3 <SEP> CH3 <tb> <SEP> 5 <tb> 93) <SEP> CR2NCff <SEP> 2 <SEP> CR3 <SEP> CH3 <SEP> CH3 <tb> <SEP> NCCH3) <SEP> 2 <tb> 94) <SEP> 2 <SEP> R1 <SEP> a <SEP> H, <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> RIR <SEP> R <SEP> s <SEP> H, <SEP> CH3 <tb> 95) <SEP> 9 <SEP> R <SEP> ¯ <SEP> H, <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> 2 <SEP> 3 <tb> <SEP> NR1R2 <SEP> R <SEP> a <SEP> H, <SEP> CH3 <tb> EMI122.1 <tb> <SEP> R8 <SEP> R <SEP> R10 <tb> <SEP> NCH, <tb> <SEP> NCH3 <tb> <SEP> 81) <SEP> zNCR3 <SEP> CH3 <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> CR3 <SEP> CH2 <SEP> CH <SEP> CR3 <tb> 82) <SEP> CR2CR2CN(CH3)2 <tb> 83) <SEP> ( > <SEP> CH2C <SEP> CH3 <SEP> CH3 <tb> <SEP> CR2C\ <tb> <SEP> N(CH3)2 <tb> 84) <SEP> t > <SEP> CHCH <SEP> CH3 <SEP> CH3 <tb> <SEP> CHZC' <tb> <SEP> 2 <tb> <SEP> CR2C\*NR <SEP> CR3 <SEP> CR3 <tb> 85) <SEP> N(CR3)2 <tb> 86) <SEP> tCN <SEP> 2 <SEP> CR3 <SEP> CR3 <tb> <SEP> k <SEP> \NH2 <tb> <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CR3 <tb> 87) <SEP> N(CE3) <SEP> 2 <tb> Ne <tb> 88) <SEP> N(CH3)2 <SEP> CH3 <SEP> CH3 <tb> EMI123.1 <tb> <SEP> R8 <SEP> R9 <SEP> R10 <tb> <SEP> CO2H <tb> <SEP> 96) <SEP> CR3 <SEP> CR3 <tb> <SEP> 2 <tb> <SEP> N-CN <tb> <SEP> 97) <SEP> K, <SEP> )I <SEP> CR3 <SEP> CR3 <tb> <SEP> CH2 <SEP> -C <tb> <SEP> 21 <tb> <SEP> N(CH3)2 <tb> <SEP> 98) <SEP> N-S02NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH2-F <tb> <SEP> CR2[ <tb> <SEP> N(CH3)2 <tb> <SEP> R1 <SEP> R2 <SEP> NH <tb> <SEP> '. <SEP> I <tb> <SEP> 99) <SEP> CH <SEP> - <SEP> CH- <SEP> C <SEP> -NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> R1 <SEP> . <SEP> CR3 <tb> <SEP> R2 <SEP> - <SEP> CH3, <SEP> NR2, <SEP> OR <tb> <SEP> 3 <tb> <SEP> R3 <SEP> r <SEP> H, <SEP> CH3 <tb> <SEP> NR1 <tb> 100) <SEP> NR1 <SEP> CR3 <SEP> CR3 <tb> <SEP> CH2 <SEP> C <tb> <SEP> CR3- <SEP> N <SEP> -CH2CH2N(CH3)2 <tb> <SEP> 1 <tb> <SEP> R1 <SEP> . <SEP> H, <SEP> CH3 <tb> 101) <SEP> NRl <SEP> CH3 <SEP> CH3 <tb> <SEP> CH2-C <tb> <SEP> R2-N-(CR2)nCO2H <tb> <SEP> R1 <SEP> CIf3 <tb> <SEP> 2 <SEP> H, <SEP> CR3 <tb> <SEP> R <SEP> - <SEP> H, <SEP> CH3 <tb> <SEP> n <SEP> - <SEP> 1 <SEP> or <SEP> 2 <tb> EMI124.1 <tb> <SEP> R <SEP> R <SEP> R10 <tb> <SEP> 102) <SEP> CH3 <SEP> VCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> VCR3 <tb> <SEP> R <SEP> a <SEP> H, <SEP> H <SEP> CH3 <tb> <SEP> RNCH3 <tb> <SEP> 103) <SEP> NCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> CH2-C <tb> <SEP> NHCH2CH3 <tb> <SEP> 104) <SEP> CR <SEP> NCR3 <SEP> CH3 <SEP> CH3 <tb> <SEP> Ij <tb> <SEP> NHCH <SEP> (CH3)2 <tb> <SEP> 105) <SEP> NcH3 <SEP> CH <SEP> CH3 <tb> <SEP> CR2C, <tb> <SEP> N(CH2CH3)2 <tb> <SEP> NH <tb> 106) <SEP> CH2-t <SEP> CH3 <SEP> CH3 <tb> <SEP> CR3 <SEP> -N-CR2 <SEP> CR3 <tb> <SEP> NR <SEP> Rr <SEP> CI,CEI3, <SEP> CH3 <tb> 107) <SEP> CR <SEP> NR <SEP> R <SEP> aCR2CH3, <SEP> CR3 <SEP> CR3 <SEP> CR3 <tb> <SEP> 2 <SEP> 1 <tb> <SEP> CH3-N-cH2cH2oH <tb> 108) <SEP> > 4 <SEP> CH3 <SEP> CH3 <tb> 109) <tb> <SEP> · <SEP> CH3 <SEP> CH3 <tb> EMI125.1 <tb> <SEP> R8 <SEP> R9 <SEP> R1O <tb> 110) <SEP> < <SEP> CH3 <SEP> CH3 <tb> 111) <SEP> Th· <SEP> CH3 <SEP> CH3 <tb> <SEP> J <tb> 112) <SEP> NH <SEP> CH3 <SEP> CH3 <tb> <SEP> (CH3)2 <tb> <SEP> 9 <tb> 113) <SEP> i <SEP> Y) <SEP> CH3 <SEP> CH3 <tb> <SEP> .3 <tb> Compounds 114-227 correspond to the above 9. compounds 1-113 except R is ethyl. Compounds 228-341 correspond to above compounds 1-113 except R9 is phenyl. Compounds 342-455 correspond to the above 9. compounds 1-113 except R is CH2F. Compounds 456-569 correspond to the above 9 compounds 1-113 except R is cyclopropyl. Compounds 570-683 correspond to the above compounds 1-113 except R9 is trifluoromethyl. Compounds 684-797 correspond to the above compounds 1-113 except that both R9 and R10 are ethyl. Compounds 798-911 correspond to the above compounds 1-113 except that R9 and R10 are joined to form -CH2CH2CH2- EXAMPLE SECTION - PART II EXAMPLE 1 Preparation of 3 (Method I) EMI127.1 Step A: CH3CHO + R3CH2CHo NaOH EMI127.2 EMI127.3 The a,ss-unsaturated aldehydes (C) are prepared by modified procedures reported by M. B. Green and W. J. Hickinbottom in J. Chem. Soc. 3262 (1957); and W. J. Bailey and R. Barclay Jr., J. Org. Chem., 21, 328 (1956). Acetaldehyde (1 eq.) and propionaldehyde (R -CH3) (1 eq.) are placed in a three-necked round-bottom flask which is equipped with a mechanical stirrer, a dry-ice condenser, and a pressure equalized dropping-funnel. To the solution is added dropwise 1 eq. of 1N NaOH through the dropping funnel with constant stirring. After completion of the mixing, the mixture is stirred for 10 min, then poured into a beaker containing crushed ice. Extraction of the mixture with ether gives the crude product. The desired product (C) is obtained by fractional distillation through a Widmer column. Step B: Preparation of 1' EMI128.1 Isopropenyl acetate (182 g), cupric acetate (0.40 g), 2-methyl-2-butenal (84 g) and p-toluenesulfonic acid (1.52 g) are placed in a 1.0-1 three-necked flask equipped with a thermometer, a nitrogen inlet tube and a 10-in. Widmer column which is attached with a distillation head. The mixture is heated at 93-1100C until 73 ml of acetone is collected. After cooling to r.t. (220C) the mixture is filtered from solids. The dark brown filtrate is cooled in an ice-bath and mixed with 3.4g triethanolamine in 200 ml water. The two layer mixture is distilled quickly at 53 mm (b.p. 54 ). The organic layer of the distillate is separated. The aqueous layer is extracted with 200 ml ether. The organic layers are combined and washed with 10% K2CO3, dried over Na2SO4, and evaporated in vacuo. The residue so obtained is mixed with 2.0g N-phenyl-ss-naphthamine and distilled under reduced pressure to give 1'(97 g), b.p. 81-910 (66mm). Following the procedure of Example 1, the following R9 substituted species are obtained. (Table I). TABLE I EMI129.1 <tb> <SEP> R9 <SEP> R <tb> <SEP> 1. <SEP> CH3 <SEP> CH38 <tb> 2. <SEP> CH3CH2 <SEP> CH38 <tb> 3. <SEP> CH3CH2CH2 <SEP> CR3 <tb> 4 <SEP> CH <SEP> CH38- <SEP> CR3 <tb> <SEP> CR <tb> <SEP> 3 <tb> 5. <SEP> CH3C <tb> 6. <SEP> Ph <SEP> (Ph phenyl) <SEP> CR3 <tb> 7. <SEP> PhCH2 <SEP> CH3C9 STEP C Preparation of 2' and 3' EMI129.2 Chlorosulfonylisocyante (CSI) (6.5 ml) is placed in a three-necked, 100-ml flask equipped with a thermometer, a magnetic stirring bar a nitrogen inlet tube and a 25-ml pressure-equalizing dropping funnel. The CSI is chilled to -500C and mixed with 12.5 ml ether through the dropping funnel. The etheral solution of CSI is allowed to warm up to -250C, to the solution is added dropwise l-acetoxyl2-methyl-1,3-butadiene (1') (5.9 ml in 12.5 ml ether) in 30 min. The mixture is then stirred for 20 min at -20 + 30C. The white precipitate formed initially is redissolved at the end of the reaction. In a 500-ml round bottom flask, a solution of 10g sodium sulfite and 25g potassium hydrogen phosphate in 100 ml water is prepared and is cooled in an ice bath. Ether (100 ml) and crushed ice (lOOg) are added and the mixture is vigorously stirred in an ice bath. At the end of 20 minutes reaction time, the reaction mixture which contains 2' is transferred into the dropping funnel and added dropwise to the hydolysis mixture in 5 minutes. The hydrolysis is allowed to continue for an additional 30 minutes at 30C. The organic layer is separated and the aqueous is extracted with 50 ml ether. The organic layers are combined, dried over Na2SO4 and evaporated to give crystalline product 31 (2.3g), m.p. 77-78,5 ; m.s. 169(M+); IR 1760 cm 1 (B-lactam); NMR (300 MHz, CDC13): 1.70 (d), 2.16(s), 2.84 (qq), 3.18 (qq), 4.20 (m), 5.82 (broad, and 6.26 (s) ppm. Step D: Preparation of 4': EMI131.1 4- (l-methyl-2-acetoxyvinyl) azetidine-2-one (3') (6.5 g) is hydrogenated on a Parr shaker at r.t. under 40 psi hydrogen in the presence of 10% Pd/C (0.6 g) in 200 ml ethylacetate for 2 hr. The mixture is filtered from the catalyst and the filtrate is evaporated in vacuo to give the crude product. Purification of the crude product by high pressure liquid chromatography (HPLC, silical gel column, 30% ethylacetate/CH2C12 solvent system) affords white crystalline product 4' (6.04g) after evaporation of solvent. The product shows following physical characteristics: ms 171 (M+); IR(Neat) 1754 cm1; NMR (60 MHz, CDC13): 9.96 (d), 1.01 (d), 2.06 (d, OAc), 2.75-3.80 (m), 3.99 (d) and 6.80 (broad) ppm. Step E: Preparation of 5' EMI131.2 Under N2 at 00, a solution of 4- (l-methyl-2-acetoxyethyl) -2-azetidinone 4' (1.2 g) in 10 ml methanol is treated with sodium methoxide (57 mg). After stirring for 1 hr, the solution is neutralized with glacial acetic acid (65 mg). Removal of methanol in vacuo gives crude 4- (1-methyl- 2-hydroxyethyl)-2-azetidinone 5' as an oil. The product is purified and chromatography on silica gel eluting with ethyl acetate to give 0.78 of 5': IR (neat): 1740 cm 1; NMR (CDC13): 0.77 (d), 0.96 (d), 1.90 (m), 2.60-3.30 (m), 3.60 (m), 4.19 (s), and 7.23 (s). The product crystallizes as a colorless solid in the refrigerator. Step F: Preparation of 6' EMI132.1 A solution of 4-(1-methyl-2-hydroxyethyl)-2azetidinone (0.5 g) and 2,2-diemthoxypropane (0.48 g) in 10 ml anhydrous methylene chloride is treated with boron trifluoride (55 mg) at room temperature for 90 min. The mixture is washed with 5 ml saturated NaRCO3. The organic layer is separated, dried over Na2S04 and allowed to evaporate in vacuo to give crude isomeric mixture of 6' (0.48 g) as an oil. Separation of isomers 6'a and 6'ss is accomplished by high pressure liquid chromatography (HPLC, silica gel) eluting with 40% ethylacetate/ hexanes. After evaporation of the solvents affords 250 mg of 6'ss as an oil and 200 mg of 6'a as a white solid. NMR (300 MHz, CDC13) of 6'a: 0.81 (d), 1.31 (s), 1.68 (s), 1.62 (m), 2.52 (q), 3.05 (m), 3.42 (t), and 3.66 ppm (q), NMR (300 MHz, CDC13) of 6'ss: 1.10(d), 1.38 (s), 1.67 (s), 1.90 (m), 2.80 (q), 2.86 (q), 3.62 (q), 3.78 (m) and 3.98 (q) ppm. Step G: Preparation of 7'a EMI133.1 At -78 C, diisopropylamine (2.2 g) in 20 ml of anhydrous tetrahydrofuran is treated with n-butyl-lithium (1.6M in n-hexane, 14 ml) for 5 min. To the solution is added 8-oxo-5a, 2,2-trimethyl-lazabicyclo[4.2.0]octane (6'a) (3.4 g) and the mixture is stirred for 10 min. The resulting lithiuim enolate is treated with acetaldehyde (1.68 ml). The mixture is stirred for 1 min. then is quenched with 24 ml saturated ammonium chloride at -780C, then allowed to warm to room temperature (250C). The mixture is extracted with ethylacetate (2 x 100 ml). The organic layer is separated, dried over Na2SO4 and allowed to evaporate in vacuo to give 4.5 g of the crude product 7'a. The crude isomeric mixture of 7'a is purified and separated by HPLC (silica gel) eluting with 50% ethylacetate/methylene chloride to give 3.5 of trans-7'&alpha; and 0.5 g of cis-7'a. Both isomers are crystalline solids. Step G': Preparation of 7'ss EMI134.1 Following the procedure of Step G, except replacing the starting material 6'a with 6'ss isomer, the products, trans-7'ss (4.0 g) and cis-7'ss (0.1 g), are obtained. Step H: Preparation of 7"ss EMI134.2 Under anhydrous conditions at 0 C a solution of R enriched trans-7'S (2.90 g) in 60 ml methylene chloride is treated with 4-dimethylaminopyridine (3.32 q) and o-nitrobenzylchloroformate (5.88 g). The mixture is allowed to warm to room temperature and stirred for 1 hr. The resulting mixture is washed with 0.1N HC1, water, brine and water. The organic layer is separated, dried over Na2SO4 and allowed to evaporate in vacuo to give crude products. The crude products are dissolved in 20 ml ether and chilled at -50C gives the o-nitrobenzyl alcohol (0.5 g) which is separated by filtration. The isomeric mixture comprising trans-7"ss is purified and separated by HPLC (silica gel) eluting with 40% ethylacetate/cyclohexane to give 1.2 g of S-trans 7I3 and 1.0 g of R-trans-7"ss. The spectra data of R-trans-7"ss: NMR (300 MHz, CDC13): 1.12 (d), 1.40 (s), 1.46 (d), 1.73 (s), 1.95 (m), 3.20 (q), 3.60 (q), 3.74 (q), 3.95 (q), 5.07 (m), 5.58 (q), 7.56 (t), 7.70 (m) and 8.19 (d) ppm. The spectra data of S-trans-7"ss: NMR (300 MHZ, CDCl3): 1.10 (d), 1.40 (s), 1.43 (d), 1.72 (s), 1.94 (m), 3.34 (q), 3.61 (q), 3.67 (q), 3.96 (q), 5.13 (m), 5.64 (d), 7.53 (m), 7.68 (m), and 8.17 (d) ppm. Step H: Preparation of 7"a EMI136.1 Following the procedure of Step H; except replacing the starting material trans-7'ss with trans-7'a isomer, and using p-nitrobenoxychloroformate as carbonating agent, the products R-trans-71a and S-trans-7"&alpha; are obtained. The following chart summarizes the foregoing separation. EMI137.1 (R = p-nitrobenzyloxycarbonyl) Step I: EMI138.1 The bicyclic azetidinone 7' (6.0 g) in 60 ml acetone is treated with 4N Jones reagent (9.4 ml) at OOC for 30 min. The reaction is quenched with 1 ml isopropanol at 0 C for 10 min, then mixed with 250 ml ethylacetate and washed with water and brine until blue color disappeared in the organic layer. The organic layer is separated, dried over MgSO4, and evaporated in vacuo to give crude product which is purified by a silica gel column (4.4 x 10 cm) eluting with ethylacetate to give 3.1 g of 8' as a crystalline solid. Step J: EMI138.2 The azetidinone carboxylic acid 8' (3.0 g) is suspended in 50 ml water. The mixture is stirred and treated with 2.5N NaOH and maintained at pH 12.0 at room temperature for 30 min. The resulting homogenous solution is neutralized with 2.5N HC1 to pH 7.5. After the mixture is extracted with EtOAc, the aqueous layer is concentrated and lyophilized to give 9' a white a solid; 60 MHz NMR (CDCL3): 1.15(d, 3H, J=6.0Hz), 1.23(d, 3H, J=6.0Hz), 2.45(m, lH), 3.02 (q, 1H, J=2.0 and 5.8Hz), 3.68(q, 1H, J=2.0 and 8.0Hz), 4.12(m, 1H). Step K: EMI139.1 The azetidinone carboxylic acid sodium salt 9' (2.2 g) and p-nitrobenzylbromide (2.94 g) are stirred at room temperature in DMF (29.3 ml) for 5 hrs. The mixture is diluted with EtOAc and washed with water and brine. The organic layer is separated, dried over MgSO4 and evaporated to give crude product which is purified by TLC plates eluting with 50% EtOAc/cyclohexane to give 1.34- g of white solid product TO', 60 MHz NMR (CDC13): 1.28(d, 3H, Jw7.0Hz), 1,23(d, 3H, J=7.0Hz), 2.80(m), 3.00(q, 1H, J=2.0 and 6.0Hz), 3.84(q, 1H, J=2.0 and 7.0Hz), 4.14(m, 1H), 5.28(s, 2H), 6.73(broad singlet), 7.53(d, 2H), and 8.23(d, 2H). Step L: EMI140.1 The ester 10' (1.33 g) is stirred with t-butyldimethylchlorosilane (2.49 g), triethylamine (4.61 ml) in DMF (16 ml) at room temperature overnight. The mixture is filtered from solids and evaporated in vacuo to give crude product 11' which is redissolved in ethylacetate and washed with water, brine, dried over Na2SO4, concentrated to 0.5 ml then purified by TLC eluting with 30% ETOAc/cyclohexane to give 1.65 g of-product 11', 60 MHz NMR (DCCl3): 0.06(s, 3H), 0.10 (s, 3H), 0.12(s, 3H), 0.16(5, 3H), 0.90(s, 9H), 0.96(s, 9H), 1.06(d, 3H, J=7.8Hz), l.lO(d, 3H, J=6.0Hz), 3.00(m, 1H), 3.28(q, 1H, J=2.2 and 7.8Hz), 3.71(q, 1H, J=2.2 and 4.0Hz), 4.06(m, 1H), 5.22(s, 2H), 7.53(d, 2H) and 8.22(d, 2H). Step M: EMI140.2 The bis-silyl azetidinone ester 11' (1.60 g) in 30 ml EtOAc is hydrogenated under 50 psi hydrogen in the presence of 0.32 g 10% Pd/C for 30 min. The mixture is filtered from catalyst. The catalyst is washed with MeOH. The methanol and ethylacetate solutions are combined and evaporated in vacuo to give white solids. The crude product is re-dissolved in ethylacetate and washed with 0.1N HCl. The organic layer is separated, dried over Na2S04 and evaporated to give white solid product 3 (1.30 g), 60MHz NMR (CDCl3): 0.03(s, 3H), 0.05(s, 3H), 0.10(s, 3R), 0.15(s, 3H), 0.91(s, 9H), 0.99(s, 9H), 1.20(d, 3H, J=7.2Hz), 1.22(d, 3H, J=6.2Hz), 2.94(m, 1H), 3.31(q, 1H, J=2.4 and 7.6Hz), 3.75(q, 1H, J=2.4 and 4.0Hz), 4.09(m, 1H) and 10.72(s, 1H). EXAMPLE 2 Preparation of 3 (Method II) EMI141.1 Step A: Preparation of 3-Methyl-1,4-Pentadiene 1' EMI141.2 Procedure a S-Methylglutaric acid (1.0 mole, obtained from Aldrich Chemical Company), is refluxed for 2 hours with thionyl chloride (68% excess). After removal of excess thionyl chloride, absolute ethanol (109% excess) is added slowly. The mixture is refluxed for 3 hours then distilled to collect the product, diethyl B-Methylglutarate. To a suspension of lithium alumium hydride (24 g) in ether (860 ml) is added dropwise with rapid stirring a solution of diethyl ss-methylglutarate (124 g in 250 ml ether). The mixture is refluxed for 6 hours, then cooled to room temperature. Water (25 ml) is added slowly. The mixture is then titrated with 10% NaOH until a clear organic layer is obtained. The organic layer is separated, dried over anhydrous sodium sulfate then evaporated in vacuo to give diol 1'. The 3-methyl-1.5-pentanediol (0.5 mole) is treated with thionyl chloride (1.05 mole) at reflux for 3 hours. After removal of excess thionyl chloride in vacuo, the 3-methyl-1,5-dichloropentane is obtained. 3-methyl-l.5-dichloropenane (41 g) is added dropwise at 1700C to a mixture of 48 g of sodium hydroxide and 40 g of polyethylene glycol tetramer and the mixture is distilled to give 3-methyl-l,4- pentadiene. Procedure b At -400C, 1,3-dichlorobutane (50 g) is mixed with alumium chloride (5 g). The ethylene is bubbled through the solution for 4 hours. The mixture is allowed to warm to room temperature, then hydrolyzed with water and extracted with ethyl acetate to give 3-methyl-1,5-dichloropentane. A mixture of 0.5 mole of 3-methyl-1,5dichloropentane, 2-methylquinoline (2 moles), and sodium iodide (0.1 mole) is refluxed in a flask equipped with a Vigreaux column at the top of which is a condenser and take-off. The diolefin 1' is collected during 8 hours reaction. The product is dried over anhydrous sodium sulfate. Step B: EMI143.1 In a sealed tube, 3-methyl-1,4-pentadiene (9.6 g) and chlorosulfonyl isocyanate (14.2 g) are allowed to stand at room temperature for 6 days. The resulting mixture is diluted with methylene chloride and added slowly to a stirred aqueous solution which contains 20 g of Na2SO3 and 50 g of K2HP04 at 0-50C for 30 minutes. The organic layer is separated and dried over Mg2S04. After evaporation, the crude product is chromatographed on silica gel GF eluting with EtOAc to give 2'. Step C: EMI144.1 t-Butyldimethylchlorosilane (7.5 g) is added in one portion to an ice-cold, stirred solution of 4-(1- methyl-prop-2-ene)-azetidin-2-one (6.54 g) and triethylamine (12 ml) in anhydrous dimethylformamide (100 ml). The reaction mixture is stirred at a temperature ranging from 0 to 50C for 1 hour and then allowed to warm to room temperature. Most of the solvent is removed under vacuum to give a residue which is partitioned between diethyl ether (250 ml) and water. The ethereal phase is washed with 2.5N hydrochloric acid (50 ml), water (3 x 50 ml), and brine, dried with magnesium sulfate, filtered and evaporated under vacuum to provide a crude product which is purified by chromatography on silica gel (20% ether in petroleum ether) to yield 3'. Step D: EMI144.2 n-Butyllithium in hexane (26.25 mmol) is added slowly by a syringe to the solution of diisopropylamine (26.25 mmol) in anhydrous tetrahydrofuran (100 ml) at -78 C. The resulting solution is stirred for 15 min. prior to the addition of a solution of 3' (25.0 mmol) in anhydrous tetrahydrofuran (25 ml). After stirring for 15 min. at -780C, acetaldehyde (75 mmol) is added by syringe and the resulting solution is stirred at -780C for 5 min. Saturated aqueous ammonium chloride solution (15 ml) is added by syringe and the reaction mixture is allowed to warm to room temperature, then diluted with ether (250 ml) and washed 2.5N hydrochloric acid solution (2 x 50 ml), water (100 ml) and brine and dried over magnesium sulfate. Solvents are removed in vacuo and the residue is chromatographed on silica gel (1:1, ether: petroleum ether) to give the expected product 4'. Steps: EMI145.1 At OOC, the alcohol 4' (5.00 g) is dissolved in DMF (50 ml) and treated with t-butyl-dimethylchlorosilane (7.51 g) and triethylamine (12 ml). The mixture is allowed to warm to room temperature with constant stirring for 2 hours, then filtered from solids, evaporated in vacuo to give oil residue which is -re-dissolved in ethylacetate and washed with 0.1 N HC1, water, and brine. The organic layer is separated, dried over MgS04 and evaporated in vacuo to give crude product 5'. HPLC purification of product (20% ethylacetate/cyclohexane) affords 5'. Step F: EMI146.1 A solution of 5' (3.0 mmol) in dry methylene chloride (30 ml) is cooled to -780C (dry ice-acetone) and a stream of ozone is bubbled through until the reaction mixture becomes blue. The ozone flow is then stopped and the reaction is purged by bubbling through nitrogen until the blue color disappears. Solid m-chloroperbenzoic acid (3.0 mmol) is added and the cold bath is removed. When the reaction mixture reaches room temperature, the flask is fitted with a reflux condenser and the mixture is heated at reflux for three days. Removal of solvents in vacuo gives crude product which is chromotographed on silica gel (2% glacial acetic acid in methylene chloride) to 3'. EXAMPLE 3 Preparation of la: EMI147.1 Step A: EMI147.2 PNB X p-nitrobenzyl The N,O-bis-silyl azetidinone carboxylic acid 1' (500 mg) suspended in acetonitrile (14.8 ml) is treated with l,l'-carbonyldiimidazole (229.6 mg) and stirred at room temperature for 30 min. The mixture is then treated with p-nitrobenzylmalonate magnesium salt (1.18 q) and heated at 600C for 3 hrs. The mixture is diluted with CH2C12 and washed with water, brine, and dried over Na2S04. TLC purification (75% EtOAc/cyclohexane) of the crude product provides 0.50 g of product 2', 60MHz NMR (CDCl3): 0.05(s), 0.15(s), 0.28(s), 0.90(s), 0.97(s), 1.11 (d, 3H, J=7.0HZ), 1.19(d, 3H, J=6.0HZ), 2.80-3.30(m), 3.50(S, 2H), 3.50-4.20(m), 5.18(s, 2H), 7.37(d) and 8.06(d). Step B: EMI148.1 The bis-silyl ss-keto ester 2' (667 mg) in methanol (16 ml) is stirred with 2 ml 6N HC1 at room temperature for 2 hrs. The mixture is diluted with ethylacetate, washed with 0.1M sodium phosphate buffer, brine, dried over Na2SO4 then evaporated to give 0.6 g of crude product which is purified by TLC eluting with 100% ethylacetate to give product 3' (277 mg), IR (neat): 1754 cm-1; 60MHz NMr (CDCl3): 1.21(d), 2.68-3.20(m), 3.20-4.10(m), 3.70(s), 5.27(s), 6.80(broad, NH), 7.43(d) and 8.13(d). Step C: EMI148.2 The 6-keto ester 3' (270 mg) in 3.2 ml acetonitrile p-toluene-sulfonylazide (1.11 g, 3.33 meq/g), triethylamine (0.31 ml) are placed in a 25 ml round-bottomed flask. The mixture is stirred under nitrogen atmosphere at room temperature for 1 hr., then diluted with ethylacetate and washed with water, brine, and dried over MgS04. The crude product is purified by TLC eluting with 50% EtOAc/ cyclohexane to give 221.6 mg of 4'. IR (CHC13): 2140 (C=N2), 1740 and 1650 cm 1. Step D: EMI149.1 The diazo ss-keto ester 4' (38.6 mg) in toluene (1 ml) is heated at 800C in the presence of rhodium acetate (1.7 mg) for 10 min. The mixture is diluted with ethylacetate (10 ml) and washed with water and brine. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give bicyclic keto ester la (30.6 mg). EXAMPLE 4 EMI150.1 The bicyclic keto ester la (33.3 mg) in acetonitrile (0.47 ml) at OOC under N2 atmosphere is treated with diphenyl chlorophosphate (20.97 p1) and diisopropylethylamine (19.22 ijl) at OOC and stirred for 30 min. To the mixture is added DMSO (0.20 ml) solution of N,N-dimethylmercaptoacetamidine hydrochloride (18.68 mg) and diisopropylethylamine (24.3 1) and stirred for 1 min. at OOC. The mixture is then mixed with 10 ml ether and centrifuged to separate the oil product which is subsequently re-dissolved in 3.72 ml TRF and 2.80 ml 0.1 M 1H 7.0 sodium phosphate buffer. The solution is hydrogenated under 50 psi hydrogen in the presence of 50.0 mg of 10% Pd/C at room temperature for 30 min. Additional 50 mg of 108 Pd/C is added and the mixture is further hydrogenated for 30 minutes then filtered from catalysts. The filtrate is extracted with ether, concentrated to 4 ml then chromatographed by a Dowex-50X4 (Na+Cycle) column (2.2 x 6 cm) which is eluted with DI water to give product I. Lyophilization of the aqueous solution gives product I as white powder (6.20 mg), Uv H20 max 293 nm (g =8,796); 300 MHz NMR (D20): 1.20 (d, 3H, J=8.0 Hz), 1.29 (d, 3H, J=6.0Hz), 3.19 (s, 3H), 3.35 (5, 3H), 3.54 (q, 1H, J=2.2 and 6.0 Hz), 4.26 (m). EXAMPLE S Preparation of 9 EMI151.1 Step A: EMI151.2 At OOC, under N2, the chiral starting material 1 (0.94 g), methylene chloride (8.2 ml), triphenylphosphine (3.34 g) and formic acid (1.15 g, 97% are placed in a 50-ml three-necked flask. To the solution is slowly added di-isopropyl azodicarboxylate (2.58 g). The mixture is stirred at room temperature overnight; TLC shows all the starting material consumed. The mixture is cooled to OOC and treated with methanol (11.4 ml), water (4.9 ml) and concentrated hydrochloric acid (1.7 ml) for 2 hours, then extracted with methylene chloride. The organic layer is separated, dried over MgSO4 and evaporated to give product 2. Step B: EMI152.1 The free hydroxyl azetidinone 2 (374 mg) in DMF is treated with imidazole (688 mg) and t-butyldimethylchlorosilane (603 mg) at room temperature for 7 hours. The mixture is evaporated in vacuo and the residue is re-dissolved in ethyl acetate and washed with 1N HC1, water and brine. The organic layer is separated, dried over MgS04 and evaporated in vacuo to give 3. Step C: EMI152.2 Under N2, at -78 C, diisopropylamine (1.68 ml) in 12.5 ml THF is treated with n-butyllithium (12.5 ml, 1.6 M in hexane) for 10 min. To the solution is added starting material 3 (1.51 g in 5 ml THF) and the mixture is stirred for 20 min., then is treated with iodomethane (1.87). After stirring 40 min. at -78 C, the mixture is allowed to warm to 0 then hydrolyzed with 0.1 N HC1. The mixture is extracted with ethyl acetate. The organic layer is washed with water, brine then dried over MgSO4 and evaporated in vacuo to give 2.1 g of isomeric mixture of 4 which is chromatographically by HPLC separated to give pure a-methyl 4. 60 MHz Nmr (CDC13): 0.10 (s, 6H), 0.90 (s, 9H), 1.25 (d, 6H), 2.60 (m), 3.71 (s, 3H), 4.18 (quintet, 1H), and 6.21 (broad singlet). Step D: EMI153.1 The methyl ester 4 (1.0 g) is treated with NaOH solution (2.5 N, 1.4 ml) in methanol (5 ml) water (1 ml) at room temperature for 5 hours. The mixture is acidified with 1 N HC1 to pH 1.0 then extracted with ethyl acetate. The organic layer is separated and dried over MgS04 and evaporated to give 0.70 g of 5 as white crystalline solids. Step E: EMI154.1 The carboxylic acid (300 mg) suspension in acetonitrile is treated with l,l'-carbonyldiimidazole (194.6 mg) at room temperature for 30 min. The mixture becomes homogeneous within 5 min. To the solution is added magnesium p-nitrobenzylmalonate (1.00 g), then the mixture is heated at 650C for 3 hours. The final reaction mixture is evaporated in vacuo to give an oily residue which is re-dissolved in 10 ml ethyl acetate and washed with water and brine. The organic layer is separated, dried over MgS04 then evaporated in vacuo to gipe 0.76 g of crude product which is purified by silica gel TLC plates eluting with 50% EtoAc/cyclohexane to give 0.41 g of product 6, 60MHz NMR (CDCl3): 0.10 (s, 6H) 0.90 (s, 9H) 1.26 (d, 6H), 2.76 (m), 3.64 (s, 2H), 4.12 (quintet, 1H), 5.27 (s, 2H), 6.40 (broad singlet, 1H), 7.43 (d, 2H) and 8.12 (d, 2H). Step F: EMI155.1 The starting material 6 (400 mg) is dissolved in 4 ml methanol and treated with 6 N HC1 (0.41 ml) at room temperature for 80 minutes, The mixture is diluted with ethyl acetate and washed with 0.1 N pH 7.0 phosphate buffer and brine. The organic layer is separated, dried over MgS04 and evaporated in vacuo to give crude product 7 as solids which is triturated in pet. ether then filtered to give 269 mg of 7, 60 MHz NMR (CDC13): 1.11 (d), 1.34 (d), 1.96 (m), 2.80-4.20 (m), 3.60 (s), 5.24 (s), 7.43 (d) and 8.17 (d). SteP G: EMI155.2 The B-keto ester 7 (269 mg) dissolved in 3.2 ml acetonitrile is gently stirred with Amberlite XE-301-SO2N3 (1.5 g, 3.33 meq of N3/g) and triethylamine (0.46 ml) at room temperature for 1.5 hours. The mixture is filtered from polymer beads and the filtrate is evaporated in vacuo to give oily residue which is purified by TLC (silica gel) eluting with ethyl acetate to give diazo keto ester 8 as crystalline solids (147.1 mg), IR (film): 2150 cm 1 (N2); 60 MHz NMR (CDC13): 1.14 (d), 1.23 (d), 2.80-4.20 (m), 5.26 (s), 6.44 (broad singlet), 7.38 (d) and 8.08 (d). Step H: EMI156.1 The diazo compound 8 (145 mg) is dissolved in 4.1 ml toluene and 2.5 ml ethyl acetate. The mixture is heated at 80-850C in the presence of rhodium acetate (2.9 mg) for 15 minutes. The solution is allowed to cool to room temperature then diluted with 10 ml ethyl acetate and washed thoroughly with water, and brine. The organic layer is separated, dried over MgSO4 then evaporated in vacuo to give product 9 (113.3 mg) as solids. 60 MHz NMR (CDC13): 1.24 (d), 1.37 (d), 2.71 (m), 3.22 (q), 3.71 (q), 4.22 (quintet), 4.88 (s), 5.28 (s), 7.47 (d), and 8.16 (d). EXAMPLE 6 EMI157.1 The starting material 1 (2.10) is treated with t-butyldimethylchlorosilane (1.29 g) and imidazole (1.46 g) in DMF (8.6 ml) at room temperature for 3 hours. The mixture is evaporated in vacuo and the residue is redissolved in ethyl acetate and washed with water and brine. The organic layer is separated, dried over Na2SO4, and evaporated in vacuo to give 574 mg product 2: IR 2155 (N2), 1754 cm 1 (ss-lactam); 60 MHz NMR (CDC13): 0.08(s), O.90(s), 1.12(d), 2.60-3.20(m), 3.80-4.20(m), 5.40(s), 6.26(broad singlet), 7.53(d) and 8.21(d). EXAMPLE 7 EMI158.1 At -780C, under N2, diisopropylamine (168.2 1) is treated with n-BuLi (1.6 M, 1.13 ml) in THF (0.84 ml) for 10 min. To the solution is added 1 (280 mg in 0.2 ml THF). The solution became deep-red color upon the addition of 1. After the mixture is stirred for 20 min., iodomethane (0.7 ml) added and stirred for additional 40 min. at -78 C. The solution is allowed to warm to room temperature then hydolyzed with saturated NH4C1, extracted with ethyl acetate. The organic layer is separated, dried over Na2SO4, and evaporated in vacuo, to give Product 2: IR 2125 (N2), 1754 cm 1 (ss-lactam); 60 MHz NMR (CDCl3): 0.03(s), 0.86(s), 1.15(d), 1.26(d), 2.40-3.00(m), 3.90-4.20(m), 4.90(s), 7.50(d), 8.21(d). EXAMPLE 8 EMI159.1 The chiral starting material 1 (9.35 g) dissolved in 100 ml DMF is treated with 5-butyldimethylchlorosilane (15.10 g) and imidazole (17.20 g) at room temperature for 4 hours. The mixture is evaporated in vacuo and the residue is redissolved in ethyl acetate and washed with 1.0 N HC1, water and brine. The organic layer is separated in vacuo to give 15.8 g of 2. 60 MH NMR (CDCl3): 0.04(s), 0.89(s), 1.27(d), 2.61(d), 2.82(m), 3.68(s), 3.90-4.20(m), 6.33(s). EXAMPLE 9 EMI159.2 (R= t-butyl(dimethyl)silyl) Under nitrogen, at -780C, diisopropylamine (i.68 ml) in THF (12.5 ml) is treated with n-butyllithium (1.6 M, 12.5 ml) and stirred for 10 min. To the solution is added 1 (1.51 g in 5 ml THF) and stirred for 20 min. The resulting orange solution is treated with iodomethane (1.87 ml) and stirred at -780C for 40 min. then gradually warmed to OOC. The mixture is hydrolized with 2 ml saturated NH4C1, diluted with ethyl acetate. The organic layer is separated, dried over Na2SO4 and evaporated in vacuo to give product 2, 60 MHz NMR: 0.05(5),, 0.92(s), 1.30(d), 1.31(d), 2.60-3.10(m), 3.69(s), 3.90-4.30(m), 6.72(broad singlet). EXAMPLE 10 Following the foregoing text and examples, the following species I are obtained when the corresponding bicyclic keto ester is treated with HSR8 . TABLE I EMI160.1 EMI161.1 <tb> <SEP> R8 <SEP> R9 <tb> <SEP> N- <SEP> C2H5 <SEP> CH3 <tb> L. <SEP> CH <SEP> C <SEP> NH <tb> <SEP> NH <tb> CR2- <SEP> NCH3 <tb> C2H5 <tb> <SEP> 25 <tb> 3. <SEP> CH2-t <SEP> - <SEP> CR3 <tb> <SEP> NH <tb> 4. <SEP> CH2-t-µC-(CH3)3 <SEP> CH3 <tb> <SEP> NH <tb> <SEP> II <SEP> CR3 <tb> 5. <SEP> CH-C-NH2 <tb> <SEP> CH3 <tb> <SEP> NH <tb> <SEP> 6. <SEP> CH-r- <SEP> NH <SEP> CR3 <tb> <SEP> NHQI <tb> <SEP> CH3 <tb> <SEP> NCH3 <tb> <SEP> 7. <SEP> CH2t <SEP> - <SEP> N(CH3)2 <SEP> CR3 <tb> <SEP> NH <tb> <SEP> 8. <SEP> CH-C- <SEP> N(CH3)2 <tb> <SEP> CH3 <tb> <SEP> NH <tb> <SEP> CR <tb> <SEP> 9. <SEP> CH-C-NH2 <tb> <SEP> 8 <tb> <SEP> NH, <SEP> CR3 <tb> 10. <SEP> C-C-2lH2 <tb> <SEP> CH2 <tb> <SEP> 11. <SEP> &num;H <SEP> CR3 <tb> <SEP> CR-C-NH2 <tb> <SEP> I <tb> <SEP> l <tb> <SEP> CR-CR2 <tb> EMI162.1 <tb> <SEP> R8 <SEP> R9 <tb> 12. <SEP> CH2 <SEP> CH2 <SEP> C <SEP> NH2 <SEP> CH3 <tb> <SEP> cL <SEP> c <tb> 13. <SEP> CH2-C,H-C <SEP> NR <tb> <SEP> CR2-CR,-C-NH2 <SEP> CR3 <tb> <SEP> OCH3 <tb> <SEP> EH2 <SEP> CH3 <tb> 14. <SEP> CH2C,H <SEP> C¯NH2 <tb> <SEP> OH <tb> <SEP> NH <tb> <SEP> CH <tb> 15. <SEP> CR2-C,,-C-NH2 <tb> <SEP> N-OCR3 <tb> NH <tb> <SEP> CR2-CR-C-NH2 <tb> <SEP> 2 <tb> <SEP> NH <tb> 17. <SEP> 2-C"--N <SEP> (CH3)2 <SEP> CH3 <tb> <SEP> CO2H <tb> <SEP> CH <tb> <SEP> 1E. <SEP> CR- <SEP> C <SEP> = <SEP> NH <SEP> CR3 <tb> <SEP> 2 <tb> <SEP> S <SEP> NH2 <tb> <SEP> CH3 <tb> <SEP> NH <SEP> CH3 <tb> <SEP> NH <SEP> CH2 <tb> <SEP> CR2-C <SEP> -NH <tb> EMI163.1 <tb> <SEP> R9 <tb> <SEP> R8 <tb> 20. <SEP> (CR2)nC/NR2 <SEP> 2-S, <SEP> R2 <SEP> - <SEP> H, <SEP> CN3 <SEP> CH3 <tb> <SEP> R1 <SEP> R <SEP> - <SEP> H, <SEP> CH3 <tb> 21. <SEP> CR,3 <SEP> NH <SEP> CH3 <tb> <SEP> CH <SEP> C <SEP> <tb> <SEP> 22 <tb> <SEP> CR3 <tb> 22. <SEP> NR2 <SEP> n <SEP> - <SEP> 2 <SEP> -5, <SEP> R1, <SEP> R2 <SEP> r <SEP> HI <SEP> CH, <tb> 22. <SEP> (CH,)nT( <SEP> r <SEP> n <SEP> r <SEP> 2 <SEP> -5, <SEP> R <SEP> , <tb> NR'R' <tb> <SEP> (CR2)2-S-CR2-C-W(CH3) <SEP> CH3 <tb> 24. <SEP> JH <SEP> CR3 <tb> 24- <SEP> (CH2)2-O-CS2CH2 <SEP> C <SEP> 2 <SEP> CH3 <tb> <SEP> CR3 <SEP> NH <SEP> CR3 <tb> 25. <tb> <SEP> 033 <SEP> H2 <tb> <SEP> CR3 <SEP> CR <tb> <SEP> 26. <SEP> CH3 <SEP> CH3 <SEP> 3 <tb> <SEP> 26. <tb> <SEP> I <SEP> w <SEP> 2 <tb> EMI164.1 <tb> <SEP> R8 <SEP> R9 <tb> <SEP> CH3 <SEP> H <tb> 27. <SEP> H-CH2-S-sss(CH3)2 <SEP> CH3 <tb> <SEP> H <tb> <SEP> N <tb> <SEP> 28. <SEP> CH <SEP> CH-C < (CH3)2 <tb> <SEP> NH <tb> <SEP> 1' <SEP> CR3 <tb> 29. <SEP> Q <SEP> 2CH2-C <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> <SEP> N <tb> 30. <SEP> Cg2-C/ <SEP> Ii <SEP> CH3 <tb> <SEP> CH2-C <SEP> NH <tb> <SEP> 31. <SEP> CH2¯Ct <SEP> CH3 <tb> <SEP> CHZ-C\1 <tb> <SEP> CH3 <tb> <SEP> NH <tb> <SEP> 32. <SEP> 2CR2C\' <SEP> CH3 <tb> <SEP> HNC(CR3)3 <tb> <SEP> CH3 <tb> <SEP> 33. <SEP> NCR3 <SEP> CR3 <tb> <SEP> 9 <SEP> NCH3 <tb> EMI165.1 <tb> <SEP> R8 <SEP> R9 <tb> <SEP> NH <tb> <SEP> 34. <SEP> CH2-C <SEP> CR3 <tb> <SEP> CR2-C, <tb> <SEP> NH-CH(CH3)2 <tb> <SEP> NH <tb> <SEP> 35. <SEP> CH <SEP> CH3 <tb> <SEP> CHZIC <SEP> 3 <tb> <SEP> 36. <SEP> NH <SEP> CH3 <tb> <SEP> CH2-C, <tb> <SEP> 2 <tb> <SEP> NH <tb> <SEP> 37. <SEP> || <SEP> CH3 <tb> <SEP> CH2 <SEP> o <tb> 38. <SEP> N <SEP> Hz <SEP> CH3 <tb> <SEP> (CH3)2 <tb> EMI166.1 <tb> <SEP> R8 <SEP> R9 <tb> 39. <SEP> NH <SEP> CH3 <tb> <SEP> CH2-C, <tb> <SEP> NH <tb> <SEP> NH <tb> 40. <SEP> N <SEP> CH3 <tb> 40. <SEP> CH2-C <SEP> CH3 <tb> <SEP> Is' <tb> <SEP> CH3 <tb> <SEP> NH <tb> 41. <SEP> CH <SEP> 2-F <SEP> CH3 <tb> <SEP> NH-CR2 <tb> <SEP> NH <tb> 42. <SEP> 01 <SEP> I-F <SEP> CH3 <tb> <SEP> NH-CH, <SEP> -kL/ <tb> <SEP> L <tb> 43. <SEP> tH2-C <SEP> 3 <tb> <SEP> NH-CH2 < N <tb> <SEP> NH <tb> 44. <SEP> CH <tb> <SEP> CR2-C, <SEP> CH3 <tb> <SEP> 3 <tb> <SEP> NH <tb> N <tb> 45. <SEP> CR2- <SEP> C <tb> <SEP> - <SEP> CH3 <tb> <SEP> CH3 <tb> EMI167.1 <tb> <SEP> R8 <SEP> R9 <tb> CH2 <SEP> /\ <SEP> B <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> NH <tb> 47. <SEP> NH <SEP> CH3 <tb> <SEP> CR2C, <tb> <SEP> NH <tb> 48. <SEP> NH <SEP> CH3 <tb> <SEP> M,-C <tb> <SEP> NH-N(CH3)2 <tb> NH <tb> <SEP> CHZIC <SEP> CH3 <tb> <SEP> I <tb> <SEP> NHOCH3 <tb> <SEP> NH <tb> CH2 <SEP> CR2-C" <SEP> CR3 <tb> <SEP> I <tb> <SEP> CH3 <SEP> OCH3 <tb> <SEP> NH <tb> 51. <SEP> CH2-c <SEP> Cz3 <tb> <SEP> CHZIC <SEP> CH3 <tb> <SEP> CR3 <SEP> NH2 <tb> EMI168.1 <tb> <SEP> R8 <SEP> R9 <tb> 5-2. <SEP> CH2CH3wH <SEP> CH3 <tb> <SEP> CH <SEP> - <SEP> C <tb> <SEP> NH <tb> <SEP> 2 <tb> 53. <SEP> CH2CH3NS <SEP> CH3 <tb> <SEP> 33 <SEP> - <SEP> C <tb> <SEP> N(CH3)2 <tb> <SEP> CH3 <SEP> NH <tb> 54. <SEP> CH-CH2-C, <SEP> 3 <tb> <SEP> NH <tb> <SEP> 2 <tb> CH3 <SEP> ;33-CHl-F <SEP> CR3 <tb> 55. <SEP> CH-CH2-C <SEP> 3 <tb> <SEP> N(CH3)2 <tb> <SEP> 56. <SEP> NCH3 <SEP> CH3 <tb> <SEP> C <tb> <SEP> N(CH3)2 <tb> <SEP> N <SEP> (CH3)2 <SEP> CR3 <tb> <SEP> Cf3-C <SEP> X <tb> <SEP> CH2C <tb> <SEP> N(CH3)2 <tb> EMI169.1 <tb> <SEP> R8 <SEP> R9 <tb> <SEP> NH <tb> a <SEP> CR2N1CR2 <SEP> -N(CR3)2 <SEP> CR3 <tb> 58- <SEP> CH2vCH2C <SEP> -N(CH3)2 <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> NCR3 <tb> II <SEP> 1 <SEP> EJCH <SEP> CR <tb> CH.N-Cf,CH,C <SEP> NCH3 <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> 60. <SEP> NH <SEP> N(CR3)2 <SEP> CH3 <tb> <SEP> CH2C-CH2-CH <SEP> - <SEP> N(CH3L2 <tb> <SEP> 61. <SEP> 2 <SEP> CR3 <tb> <SEP> N(CR3)2 <tb> <SEP> L <tb> <SEP> 62. <SEP> CH2 <SEP> < <SEP> CH3 <tb> <SEP> N(QI3)2 <tb> <SEP> H <tb> <SEP> CH2 <SEP> Hz <SEP> CH3 <tb> <SEP> 64. <SEP> n <SEP> CH3 <tb> <SEP> 65. <SEP> A <SEP> CH3 <tb> EMI170.1 <tb> <SEP> R8 <SEP> R <tb> 66. <SEP> G <SEP> II <SEP> CH3 <tb> <SEP> cH3)2 <tb> 67. <SEP> < <SEP> N(CH3)2 <SEP> CH3 <tb> 68. <SEP> N <SEP> (CH3)2 <SEP> CH3 <tb> <SEP> 3 <tb> 69. <SEP> a¯ <SEP> N(CH3)2 <SEP> CH3 <tb> 70. <SEP> ffi <SEP> NH <SEP> CH3 <tb> <SEP> N(CEF?) <SEP> 2 <tb> 71. <SEP> CR2 <SEP> % <SEP> NtCH3)2 <SEP> CH3 <tb> <SEP> SY. <tb> 72. <SEP> C" <SEP> -NH2 <SEP> CH3 <tb> <SEP> NH <tb> 73. <SEP> 9 <SEP> NHCH3 <SEP> CH3 <tb> <SEP> NH <tb> 74. <SEP> C" <SEP> -N(CH3)2 <SEP> CH3 <tb> <SEP> N <tb> 75. <SEP> CH2 <SEP> < p <SEP> CH3 <tb> <SEP> CH3 <tb> 76. <SEP> 4;7. <SEP> CH3 <tb> <SEP> CIZ-lJ <SEP> CH <tb> <SEP> CH2C02H <tb> EMI171.1 <tb> <SEP> R8 <SEP> 9 <tb> 77. <SEP> C <SEP> CR3 <tb> <SEP> N(CH3)2 <tb> 78. <SEP> CR2 <SEP> CR2CN(CR3) <SEP> 2 <SEP> CR3 <tb> <SEP> CH3 <tb> 79. <SEP> 2 <SEP> NH <SEP> cur3 <tb> <SEP> CR2C' <tb> <SEP> 'N(CR <tb> <SEP> 32 <tb> 80. <SEP> CR,C&num;1 <SEP> CH3 <tb> <SEP> 2 <tb> <SEP> N)I <tb> 81. <SEP> 4 <SEP> CH2Cv <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> <SEP> NH <SEP> <tb> 82. <SEP> G <SEP> -- <SEP> CH3 <tb> <SEP> C\Ny.2 <tb> <SEP> \Nf2 <tb> 83. <SEP> CR3 <SEP> CR3 <SEP> N(CH322 <SEP> CH3 <tb> <SEP> ¸ <tb> <SEP> NCH3 <tb> 84. <SEP> m;;NCH3) <SEP> CH3 <tb> EMI172.1 <tb> <SEP> R8 <SEP> R9 <tb> <SEP> NH <tb> 85. <SEP> F <SEP> no <SEP> CH3 <tb> <SEP> N(CR3) <SEP> 2 <tb> <SEP> NH <tb> 86. <SEP> F <SEP> N <SEP> N(.CH3)2 <SEP> CH3 <tb> <SEP> < 0SCi!,C <tb> Y <SEP> J <SEP> CH <tb> <SEP> CR2-? <tb> <SEP> k(CH3)2 <tb> <SEP> NCH3 <tb> 88. <SEP> CH, <SEP> C <SEP> C93 <tb> NCH2 <SEP> CR3 <SEP> CR3 <tb> <SEP> CH2 <SEP> g <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> EMI173.1 <tb> <SEP> R8 <SEP> R9 <tb> 90. <SEP> R2 <SEP> R1 <SEP> w <SEP> H, <SEP> CH3 <SEP> CH3 <tb> <SEP> RIR <SEP> R <SEP> = <SEP> H, <SEP> CH3 <tb> 91. <SEP> rN <SEP> R1 <SEP> <SEP> H, <SEP> CH3 <SEP> CH3 <tb> <SEP> Y <SEP> R <SEP> = <SEP> H, <SEP> CH3 <tb> <SEP> R2 <SEP> r <SEP> H, <SEP> CH3 <tb> <SEP> NR <SEP> R <tb> <SEP> CO <SEP> H <tb> 92. <SEP> 4 <SEP> NH <SEP> CH3 <tb> <SEP> NH2 <tb> <SEP> N-CN <tb> <SEP> 93. <SEP> 11 <SEP> CH3 <tb> <SEP> CH2-f <tb> <SEP> N(CH3)2 <tb> <SEP> N-S02NH2 <tb> <SEP> 94 <SEP> CH2- <SEP> F <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> EMI174.1 <tb> <SEP> R8 <SEP> R9 <tb> <SEP> R1 <SEP> R2 <SEP> NH <SEP> R1 <SEP> . <SEP> CH3 <tb> - <SEP> ' <SEP> ff <SEP> 2 <SEP> 1 <SEP> CH,r <SEP> NR <SEP> OR <SEP> CR3 <tb> <SEP> CH <SEP> - <SEP> CH- <SEP> C <SEP> -NH2 <SEP> R <SEP> = <SEP> CH3, <SEP> NR2, <SEP> QR <tb> <SEP> R3 <SEP> e <SEP> H, <SEP> CH3 <tb> <SEP> NOR <tb> <SEP> 96. <SEP> CH2-C <SEP> R1 <SEP> = <SEP> H, <SEP> CH3 <SEP> CH3 <tb> <SEP> CR3- <SEP> N <SEP> -CH2CH2N(CH3)2 <tb> 97. <SEP> NR1 <SEP> R1 <SEP> = <SEP> H, <SEP> CH3 <tb> <SEP> CH2-cl <SEP> R2 <SEP> = <SEP> H, <SEP> CH3 <SEP> CH3 <tb> <SEP> 22 <SEP> 1 <tb> <SEP> R <SEP> - <SEP> (CHZ)nCO,H <SEP> n <SEP> - <SEP> 1 <SEP> or <SEP> 2 <tb> <SEP> 98. <SEP> CH3 <SEP> VCR3 <SEP> CR <tb> <SEP> CR- <SEP> C <SEP> R <SEP> = <SEP> H, <SEP> CR3 <SEP> 3 <tb> <SEP> RNCH3 <tb> <SEP> 99. <SEP> NCR3 <SEP> CH3 <tb> <SEP> CH2 <SEP> -C, <tb> <SEP> NHCH2CH3 <tb> 100. <SEP> NCH3 <SEP> CH <tb> <SEP> CH2-C <SEP> 3 <tb> <SEP> NHCH(CH3)2 <tb> 101. <SEP> NCH3 <tb> <SEP> I, <SEP> CR <tb> <SEP> CH2-C <SEP> 3 <tb> <SEP> N(CH2CH3)2 <tb> <SEP> NH <tb> 102. <SEP> CE2-C <SEP> cH3 <tb> <SEP> CH3-ss-CH2CH3 <tb> <SEP> 103. <SEP> NR <SEP> CH3 <tb> <SEP> CR <SEP> - <SEP> R <SEP> - <SEP> CH2CH3 <SEP> CR3 <tb> <SEP> Rr <SEP> CH,CH, <SEP> r <SEP> CH3 <tb> <SEP> CH3-N-CH2cH2oH <tb> EMI175.1 <tb> <SEP> R8 <SEP> R9 <tb> <SEP> R8 <SEP> R <tb> 104. <SEP> ¯ <SEP> CH3 <tb> 105. <SEP> CH3 <tb> 106. <SEP> CH3 <tb> <SEP> 11 <tb> 107. <SEP> r < <SEP> CH3 <tb> <SEP> J <tb> 108. <SEP> X <SEP> NH <SEP> CH3 <tb> <SEP> N(CH3)2 <tb> 109. <SEP> Ç <SEP> CH3 <tb> <SEP> CH3 <tb> <SEP> NH <tb> 110; <SEP> CH2 <SEP> -NH2 <SEP> CH3 <tb> <SEP> NH <tb> 111. <SEP> CH2-C-NHCH3 <SEP> CH3 <tb> 112. <SEP> CH2-C-N(CH3)2 <SEP> CH3 <tb> <SEP> CR2-CR3 <tb> 113. <SEP> CE3 <tb> Compounds 114 - 227 correspond to the above compounds 1-113 except R9 is ethyl; see Example 1, Step A wherein R9 is ethyl. Compounds 228-341 correspond to above compounds 1-113 except R9tiS phenyl; see Example 1, Step A wherein R9 is phenyl. Compounds 342-455 correspond to the above compounds 1-113 except R is CH2F; see Example 1, Step A wherein R9 is CH2F. Compounds 456-569 correspond to the above compounds 1-113 except R is cyclopropyl; see 9 Example 1, Step A wherein R9 is cyclopropyl. Compounds 570-683 correspond to the above compounds 1-113 except R9 is trifluoromethyl; see Example 1, Step A wherein R9is trifluoromethyl. EXAMPLE SECTION - PART III EXAMPLE 1 Preparation of 3 (Method I) EMI177.1 Step A: CH3CH0 + R CH2CH0 NaOH EMI177.2 EMI177.3 The a,ss-unsaturated aldehydes (C) are prepared by modified procedures reported by M. B. Green and W. J. Hickinbottom in J. Chem. Soc. 3262 (1957); and W. J. Bailey and R. Barclay Jr., J. Org. Chem., 21, 328 (1956). Acetaldehyde (1 eq.) and propionaldehyde (R =CH3) (1 eq.) are placed in a three-necked round-bottom flask which is equipped with a mechanical stirrer, a dry-ice condenser, and a pressure equalized dropping-funnel. To the solution is added dropwise 1 eq. of 1N NaOH through the dropping funnel with constant stirring. After completion of the mixing, the mixture is stirred for 10 min, then poured into a beaker containing crushed ice. Extraction of the mixture with ether qives the crude product. The desired product (C) is obtained by fractional distillation through a Widmer column. Step B: Preparation of 1' EMI178.1 Isopropenyl acetate (182 g), cuPric acetate (0.40 g), 2-methyl-2-butenal (84 g) and p-toluenesulfonic acid (1.52 g) are placed in a 1.0-1 three-necked flask equipped with a thermometer, a nitrogen inlet tube and a 10-in. Widmer column which is attached with a distillation head. The mixture is heated at 93-1100C until 73 ml of acetone is collected. After cooling to r.t. (220C) the mixture is filtered from solids. The dark brown filtrate is cooled in an ice-bath and mixed with 3.4g triethanolamine in 200 ml water. The two layer mixture is distilled quickly at 53 mm (b.p. 540). The organic layer of the distillate is separated. The aqueous layer is extracted with 200 ml ether. The organic layers are combined and washed with 10* K2CO3, dried over Na2SO4, and evaporated in vacuo. The residue so obtained is mixed with 2.0q N-phenyl-ss-naphthamine and distilled under reduced pressure to give 1'(97 g), b.p. 81-91 (66mm). Following the procedure of Example 1, the following R9 substituted species are obtained. (Table I). EMI179.1 TABLE I EMI179.2 <tb> <SEP> ¯ <SEP> R <SEP> R <tb> <SEP> 1. <SEP> CH3 <SEP> cE38 <tb> 2. <SEP> CH3CH2 <SEP> CH38 <tb> 3. <SEP> CH3CH2CH2 <SEP> CX38 <tb> 4. <SEP> CR3NCR <SEP> CR3g <tb> <SEP> \ <SEP> CH <SEP> CH38 <tb> <SEP> 3 <tb> > <SEP> CH3C <tb> 6. <SEP> Ph <SEP> (Phrphenyl) <SEP> CH3CO <tb> 7. <SEP> PhCR2 <SEP> CR <SEP> <tb> 8. <SEP> CH2Br <SEP> 3 <tb> STEP <SEP> C <SEP> CR3 <SEP> Preparation of 2' and 3' EMI179.3 Chlorosulfonylisocyante (CSI) (6.5 ml) is placed in a three-necked, 100-ml flask equipped with a thermometer, a magnetic stirring bar a nitrogen inlet tube and a 25-ml pressure-equalizing dropping funnel. The CSI is chilled to -500C and mixed with 12.5 ml ether through the dropping funnel. The etheral solution of CSI is allowed to warm up to -250C, to the solution is added dropwise l-acetoxyl 2-methyl-l,3-butadiene (1') (5.9 ml in 12.5 ml ether) in 30 min The mixture is then stirred for 20 min at -20 + 30C. The white precipitate formed initially is redissolved at the end of the reaction. In a 500-ml round bottom flask, a solution of 10g sodium sulfite and 25g potassium hydrogen phosphate in 100 ml water is prepared and is cooled in an ice bath. Ether (100 ml) and crushed ice (lOOg) are added and the mixture is vigorously stirred in an ice bath. At the end of 20 minutes reaction time, the reaction mixture which contains 2' is transferred into the dropping funnel and added dropwise to the hydolysis mixture in 5 minutes. The hydrolysis is allowed to continue for an additional 30 minutes at 30C. The organic layer is separated and the aqueous is extracted with 50 ml ether. The organic layers are combined, dried over Na2SO4 and evaporated to give crystalline product 3' (2.3g), m.p. 77-78,50; m.s. 169(M+); IR 1760 cool (B-lactam); NMR (300 MHz, CDCl3): 1.70 (d), 2.16(s), 2.84 (qq), 3.18 (qq), 4.20 (m), 5.82 (broad, and 6.26 (s) ppm. Step D: Preparation of 4': EMI181.1 4-(1-methyl-2-acetoxyvinyl)azetidine-2-one (3') (6.5 g) is hydrogenated on a Parr shaker at r.t. under 40 psi hydrogen in the presence of 10% Pd/C (0.6 ql in 200 ml ethylacetate for 2 hr. The mixture is filtered from the catalyst and the filtrate is evaporated in vacuo to give the crude product. Purification of the crude product by high pressure liquid chromatography (HPLC, silical gel column, 30% ethylacetate/CH2C12 solvent system) affords white crystalline product 4' (6.04g) after evaporation of solvent. The product shows following physical characteristics: ms 171 (M ); IR(Neat) 1754 cm 1; NMR (60 MHz, CDCl3): 9.96 (d), 1.01 (d), 2.06 (d, OAc), 2.75-3.80 (m), 3.99 (d) and 6.80 (broad) ppm. Step E: Preparation of 5' EMI181.2 Under N2 at 00, a solution of 4-(1-methyl-2-acetoxyethyl)-2-azetidinone 4' (1.2 g) in 10 ml methanol is treated with sodium methoxide (57 mg). After stirring for 1 hr, the solution is neutralized with glacial acetic acid (65 mg). Removal of methanol in vacuo gives crude 4- (1-methyl- 2-hydroxyethyl)-2-azetidinone 5' as an oil. The product is purified and chromatography on silica gel eluting with ethyl acetate to give 0.78 of 5': IR (neat): 1740 cm 1 NMR (CDC13): 0.77 (d), 0.96 (d), 1.90 (m), 2.60-3.30 (m), 3.60 (m), 4.19 (s), and 7.23 (s). The product crystallizes as a colorless solid in the refrigerator. SteP F: Preparation of 6' EMI182.1 A solution of 4- (l-methyl-2-hydroxyethyl) -2- azetidinone (0.5 g) and 2,2-diemthoxypropane (0.48 g) in 10 ml anhydrous methylene chloride is treated with boron trifluoride (55 mg) at room temperature for 90 min. The mixture is washed with 5 ml saturated NaHCO3. The organic layer is separated, dried over Na2SO4 and allowed to evaporate in vacuo to qive crude isomeric mixture of 6' (0.48 a) as an oil. Separation of isomers 6'a and 6'ss is accomplished by high pressure liquid chromatography (HPLC, silica gel) eluting with 40% ethylacetate/ ?iexanes. After evaporation of the solvents affords 250 mg of 6'ss as an oil and 200 mg of 6' as a white solid. NMR (300 MHz, CDC13) of 6'a: 0.81 (d), 1.31 (s), 1.68 (s), 1;62 (m), 2.52 (q), 3.05 (m), 3.42 (t), and 3.66 ppm (q), NMR (300 MHz, CDC13) of 6'ss: 1.10(d), 1.38 (s), 1.67 (s), 1.90 (m), 2.80 (q), 2.86 (q), 3.62 (q), 3.78 (m) and 3.98 (q) ppm. Step G: Preparation of 7' EMI183.1 A solution of diisopropylamine (10.5 mmol) in anhydrous THF (40 ml) is cooled to -780C and stirred under N2 atmosphere while n-butylithium in hexane (10.5 mmol) is added slowly by syringe. After 15 minutes, a solution of 6' (10.0 mmol) in anhydrous THF (12 ml) is added slowly. The mixture is stirred at -780C for 20 minutes then treated with acetaldehyde (30.0 mmol) for 10 minutes. The mixture is quenched with saturated ammonium chloride solution and allowed to warm to room temperature. The reaction mixture is diluted with ethylacetate and washed with water and brine. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo to give crude product 7', which is purified by a silica gel column chromatography. Step H: Preparation of 7' EMI184.1 At -780C, diisopropylamine (2.2 g) in 20 ml of anhydrous tetrahydrofuran is treated with n-butyl-lithium (1.6M in n-hexane, 14 ml) for 5 min. To the solution is added 8-oxo-2,2,5,7-tetra-methyl-l azabicyclo[4.2.0]octane (6') (3.4 g) and the mixture is stirred for 10 min. The resulting lithiuim enolate is treated with acetaldehyde (1.68 ml). The mixture is stirred for 1 min. then is quenched with 24 ml saturated ammonium chloride at -780C, then allowed to warm to room temperature (25eC). The mixture is extracted with ethylacetate (2 x 100 ml). Step I: Preparation of 8' EMI185.1 Under anhydrous conditions at OOC a solution of 1' (2.90 g) in 60 ml methylene chloride is treated with 4-dimethylaminopyridine (3.32 q) and p-nitrobenzylchloroformate (5.88 g). The mixture is allowed to warm to room temperature and stirred for 1 hr. The resulting mixture is washed with 0.1N HC1, water, brine and water. The organic layer is separated, dried over Na2SO4 and allowed to evaporate in vacuo to give crude products. The crude product, is purified by HPLC (silica gel) eluting with 40% ethylacetate/cyclohexane to give 8'. Step J: EMI186.1 The bicyclic azetidinone 8' (6.0 g) in 60 ml acetone is treated with 4N Jones reagent (9.4 ml) at OOC for 30 min. The reaction is quenched with 1 ml isopropanol at OOC for 10 min, then mixed with 250 ml ethylacetate and washed with water and brine until blue color disappeared in the organic layer. The organic layer is separated, dried over MgSO4, and evaporated in vacuo to give crude product which is purified by a silica gel column (4.4 x 10 cm) eluting with ethylacetate to give 3.1 g of 9' as a crystalline solid. Step K: EMI187.1 The azetidinone carboxylic acid 9' (3.0 q) is suspended in 50 ml water. The mixture is stirred and treated with 2.5N NaOH and maintained at pH 12.0 at room temperature for 30 min. The resultinq homogenous solution is neutralized with 2.5N HC1 to pH 7.5. After the mixture is extracted with EtOAc, the aqueous layer is concentrated and lyophilized to give product 10'. Step L: EMI188.1 The azetidinone carboxylic acid sodium salt 10' (2.2 g) and p-nitrobenzylbromide (2.94 g) are stirred' at room temperature in DMF (29.3 ml) for 5 hrs. The mixture is diluted with EtOAc and washed with water and brine. The organic layer is separated, dried over MgSO4 and evaporated to give crude product which is purified by TLC plates eluting with 50% EtOAc/cyclohexane to give product 11'. Step M: EMI189.1 The ester 11' (1.33 g) is stirred with t-butyldimethylchlorosilane (2.49 g), imidatole (2.2 g) in DMF (16 ml) at room temperature overnight. The mixture is filtered from solids and evaporated in vacuo to give crude product 12' which is redissolved in ethylacetate and washed with water, brine, dried over Na2SO4, concentrated to 0.5 ml then purified by TLC eluting with 30% ETOAc/cyclohexane to give product 11'. Step N: EMI190.1 The azetidinone ester 12' (1.60 g) in 30 ml EtOAc is hydrogenated under 50 psi hydrogen in the presence of 0.32 g 10% Pd/C for 30 min. The mixture is filtered from catalyst. The catalyst is washed with MeOH. The methanol and ethylacetate solutions are combined and evaporated in vacuo to give white solids. The crude product is re-dissolved in ethylacetate and washed with 0.1N HCl. The organic layer is separated, dried over Na2SO4 and evaporated to give white solid product 3. EXAMPLE 2 Preparation of chiral intermediate 3: EMI191.1 Step A: EMI191.2 A solution of diisopropylamine (10.5 mmol) in anhydrous THF (40 ml) is cooled to -780C and stirred under nitrogen atmosphere while n-butyllithium in hexane (10.5 mmol) is added slowly by syringe and stirred for 10 minutes. To the solution is added 1' (10.0 mmol) in 12 ml THF. The resulting solution is stirred at -780C for 20 minutes, then treated with excess MeT (50 mmol). The mixture is allowed to warm to room temperature then quenched with saturated ammonium chloride. The mixture is extracted with ehtyl acetate two give product 2' which is purified by a silica gel column chromatography. Step B: EMI192.1 At -780C, under nitrogen atmosphere, to a lithium diisopropylamide solution (10.5 mmol in 40 ml THF) is added starting material 2' (10 mmol). The mixture is stirred at -780C for 10 minutes, then mixed with acetaldehyde (30 mmol). After 10 minutes reaction at -780C, the mixture is quenched by the addition of saturated aqueous ammonium chloride solution, and allowed to warm to room temperature. The reaction mixture is extracted with ethyl acetate and washed with 2.5 N HC1, water and brine. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo to give product 3'. Step C: EMI193.1 The starting material 3' (2.3 mmol) is 5% aqueous methanol (12 ml) is mixed with mercinic oxide (3.5 mmol) and mercinic chloride (5.1 mmol). The mixture is heated at reflux for 45 minutes then cooled and filtered from solids. The filtrate is concentrated to 5 ml, then diluted with ethyl acetate and washed with saturated ammonium chloride, water and brine. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo to give crude silyl ketone intermediate which is purified by a silca gel column chromatography. The silyl ketone intermediate (1.0 mmol) in chloroform is treated with m-chloroperbenzoic acid (1.0 mmol) at reflux for 4 hours, then cooled, concentrated in vacuo, and the residue chromatographed on silica gel column to give 4'. Step D: EMI194.1 The starting material 4 (1.0 mmol) in CHUCK (10 ml) is treated with l,l'-carbonyldilmidazole (1.1 mmol) at room temperature for 30 minutes, then mixed with 1 ml of meOH. After I hour reaction time, the mixture is evaporated in vacuo and the residue is redissolved in 5 ml meOH. To the methanol solution is added 0.2 ml of 6 N HC1 and the mixture stirred at r.t. for 1 hour then evaporated in vacuo. The residue is extracted with ethyl acetate to give product 5'. Step E: EMI195.1 The starting material 5' (5 mmol) in DMF (25 ml) is treated with t-butyldimethyl-chlorosilane (10 mmol) and imidazole (20 mmol) at r.t. for 5 hours. The mixture is evaporated in vacuo to give an oily residue which is re-dissolved in ethyl acetate and washed with 0.1 N HC1, water and brine. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo to give crude product 6' which is purified by a silica gel column chromatography. Step F: EMI196.1 At -780C, under nitrogen atmosphere, the starting material 6' (1 mmol) in 5 ml TRF is treated with lithium diisopropylamide (2.0 mmol) for 20 minutes. To the solution is added iodomethane (20 mmol). The mixture is allowed to warm to room temperature then is hydrolized with saturated ammonium chloride (1 ml) and diluted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate and chromatographed on silica gel column to give product 7'. Step G: EMI197.1 The methyl ester 8' (10 mmol) in 20 ml methanol is treated with 0.25 N NaOH (10 mmol) at room temperature for 5 hours. The mixture is extracted with ether (50 ml), acidified with 1 N HC1 and then extracted with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate and evaporated in vacuo to give product 9'. EXAMPLE 3 Preparation of la: EMI198.1 Step A: EMI198.2 PNB = p-nitrobenzyl The azetidinone carboxylic acid 1' (500 mg) suspended in acetonitrile (14.8 ml) is treated with l,l'-carbonyldiimidazole (229.6 mg) and stirred at room temperature for 30 min. The mixture is then treated with p-nitrobenzylmalonate magnesium salt (1.18 q) and heated at 600C for 3 hrs. The mixture is diluted with CH2Cl2 and washed with water, brine, and dried over Na2SO4. TLC purification (75% EtOAc/cyclohexane) of the crude product provides 0.50 g of product 2'. Step B: EMI199.1 The B-keto ester 2' (667 mg) in methanol (16 ml) is stirred with 2 ml 6N HC1 at room temperature for 2 hrs. the mixture is diluted with ethylacetate, washed with 0.1M sodium phosphate buffer, brine, dried over Na2SO4 then evaporated to give 0.6 9 of crude product which is purified by TLC eluting with 100% ethylacetate to give product 3'. Step C: EMI199.2 The B-keto ester 3' (270 mg) in 3.2 ml acetonitrile p-toluene-sulfonylazide (1.11 g, 3.33 meq/g), triethylamine (0.31 ml) are placed in a 25 ml round-bottomed flask. The mixture is stirred under nitrogen atmosphere at room temperature for 1 hr., then diluted with ethylacetate and washed with water, brine, and dried over MgSO4. The crude product is purified by TLC eluting with 50% EtoAc/cylcohexane to give 4'. Step D: EMI200.1 The diazo ss-keto ester 4' (38.6 mg) in toluene (1 ml) is heated at 800C in the presence of rhodium acetate (1.7 mg) for 10 min. The mixture is diluted with ethylacetate (10 ml) and washed with water and brine. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give bicyclic keto ester la. EXAMPLE 4 EMI201.1 The bicyclic keto ester la (33.3 mg) in acetonitrile (0.47 ml) at OOC under N2 atmosphere is treated with diphenyl chlorophosphate (20.97 > 1) and diisopropylethylamine (19.22 ul) at 0 C and stirred for 30 min. To the mixture is added DMSO (0.20 ml) solution of N,N-dimethylmercaptoacetamidine hydrochloride (18.68 mg) and diisopropylethylamine (24.3 p1) and stirred for 1 min. at OOC. The mixture is then mixed with 10 ml ether and centrifuged to separate the oil product which is subsequently re-dissolved in 3.72 ml THF and 2.80 ml 0.1 M 1H 7.0 sodium phosphate buffer. The solution is hydrogenated under 50 psi hydrogen in the presence of 50.0 mg of 10% Pd/C at room temperature for 30 min. Additional 50 mg of 10% Pd/C is added and the mixture is further hydrogenated for 30 minutes then filtered from catalysts. The filtrate is extracted with ether, concentrated to 4 ml then chromatographed by a Dowex-50X4 (Na+Cycle) column (2.2 x 6 cm) which is eluted with DI water to give product I. EXAMPLE 5 Preparation of chiral intermediates 3. EMI202.1 Step A: EMI202.2 The starting material 1' (5 mmol) is treated with lithium diisopropylamide (5.1 mmol) in THF (20 ml) at -780C for 10 minutes. To the solution is added ethyl iodide (1 ml). The mixture is stirred for 30 minutes at -780C then allowed to warm to room temperature. After quenching with saturated ammonium chloride, the mixture is extracted with ethyl acetate which is then dried over magnesium sulfate and purified by silica gel chromatography to give 2'. Step B: EMI203.1 The starting material 2' (1.0 mmol) in 20 ml methanol is treated with mercinic chloride (3.0 mmol) at OOC for 3 minutes, then quenched with sodium bicarbonate (8.0 mmol). The mixture is filtered from solids and the filtrate is evaporated in vacuo and chromatographed on a silica gel column to give 3'. Step C: EMI203.2 The starting material 3' (2.0 mmol) in 5 ml methanol is treated with 6.0 N HC1 (0.2 ml) at room temperature for 30 minutes, then evaporated in vacuo and chromatographed by a silica gel column to give 4'. Step D: EMI204.1 The methyl ester 4' (1.0 mmol) is treated with lithium diisopropylamide (2.1 mmol) in THF (5 ml) at -780C for 10 minutes, then mixed with exces iodomethane (1.0 ml). The mixture is allowed to warm to room temperature, hydrolyzed with saturated ammonium chloride, then extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate, and evaporated in vacuo to give 5'. Step E: EMI204.2 Repeating reaction of step D, using 5' as starting material, the desired product 6' is obtained. Step F: EMI205.1 The methyl ester 6' (1 mmol) in 2 ml methanol is treated with 0.25 N NaOH (1 mmol) at room temperature for 5 hours. The mixture is extracted with ether, acidified with 1 N HC1 and extracted with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate and evaporated in vacuo to give product 7'. EXAMPLE 6 Preparation of la: EMI206.1 Step A: EMI206.2 The silyl azetidinone carboxylic acid 1' (500 mg) suspended in acetonitrile (14.8 ml) is treated with 1,11-carbonyldiimidazole (229.6 mg) and stirred at room temperature for 30 min. The mixture is then treated with p-nitrobenzylmalonate magnesium salt (1.18 g) and heated at 60 C for 3 hrs. The mixture is diluted with CH2C12 and washed with water, brine, and dried over Na2SO4. TLC purification (75% EtOAc/cyclohexane) of the crude product provides product 2'. Step B: EMI207.1 The G-keto ester 2' (270 mg) in 3.2 ml acetonitrile p-toluene-sulfonylazide (1.11 g, 3.33 meq/g), triethylamine (0.31 ml) are placed in a 25 ml round-bottomed flask. The mixture is stirred under nitrogen atmosphere at room temperature for 1 hr. The mixture is diluted with ethylacetate and washed with water, brine, and dried over MgSO4. The crude product is purified by TLC eluting with 50% EtOAc/cyclohexane to give 3'. Step D: EMI208.1 The diazo X-keto ester 3' (38.6 mg) in toluene (1 ml) is heated at 800C in the presence of rhodium acetate (1.7 mg) for 10 min. The mixture is diluted with ethylacetate (10 ml) and washed with water and brine. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give bicyclic keto ester la. EXAMPLE 7 EMI209.1 The bicyclic keto ester la (33.3 mg) in acetonitrile (0.47 ml) at OOC under N2 atmosphere is treated with diphenyl chlorphosphate (20.97 u1) at OOC and stirred for 30 min. To the mixture is added DMSO (0.20 ml) solution of N-methylmercaptoacetamidine hydrochloride (18.68 mg) and diisopropylethylamine (24.3 u1) and stirred for 1 min. at OOC. The mixture is then mixed with 10 ml ether and centrifuged to separate the oil product which is subsequently re-dissolved in 3.72 ml THF and 2.80 ml 0.1 M 1H 7.0 sodium phosphate buffer. The solution is hydrogenated under 50 psi hydrogen in the presence of 50.0 mg of 10% Pd/C at room temperature for 30 min. Additional 50 mg of 10% Pd/C is added and the mixture is further hydrogenated for 30 minutes then filtered from catalysts. The filtrate is extracted with ether, concentrated to 4 ml then chromatographed by a Dowex-50X4 (Na+cycle) column (2.2 x 6 cm) which is eluted with DI water to give product I. Lypholization of the aqueous solution gives product I. EXAMPLE 8 Following the procedure of Example 2, Steps A to G, and Example 5, Steps A to F, the following substituted azetidinone carboxylic acids are obtained when an equivalent amount of the indicated alkylating agents are substituted for the alkylating agents of Example 2, Steps A and F, and Example 5, Steps A, D and E. EMI210.1 EMI210.2 <tb> Compound <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> 1 <SEP> H <SEP> CH2 H <SEP> CH3 <SEP> H <tb> <SEP> 2 <SEP> H <SEP> CH2CF3 <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> <SEP> 3 <SEP> H <SEP> CH2CH-CH2F <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> <SEP> 4 <SEP> HHCF3 <SEP> CH3 <SEP> H <tb> EMI211.1 <tb> Compound <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> R <tb> <SEP> OH <tb> <SEP> 5 <SEP> H <SEP> CHCH20 <SEP> CH3 <SEP> H <tb> <SEP> NH <tb> <SEP> 6 <SEP> H <SEP> ECE23 <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> <SEP> 7 <SEP> H <SEP> CH2CHCH3 <SEP> CH3 <SEP> H <tb> <SEP> 8 <SEP> H <SEP> CH2CH20H <SEP> CH3 <SEP> H <tb> <SEP> 0 <tb> <SEP> 9 <SEP> H <SEP> C(CH3)2 <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> 10 <SEP> H <SEP> C(CH3)2 <SEP> CH3 <SEP> H <tb> 11 <SEP> H <SEP> CH2 <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> 12 <SEP> H <SEP> CHCH(CH3)2 <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> 13 <SEP> H <SEP> C1H <SEP> < <SEP> CH3 <SEP> H <tb> <SEP> SH <tb> 14 <SEP> H <SEP> CE-CE3 <SEP> CH3 <SEP> H <tb> EMI212.1 <tb> Compound <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> OH <tb> 15 <SEP> H <SEP> CH-CH <SEP> Hz <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> 16 <SEP> H <SEP> CHCH2C1 <SEP> CH3 <SEP> H <tb> <SEP> 0 <tb> 17 <SEP> H <SEP> COMe <SEP> CH3 <SEP> H <tb> <SEP> 0 <tb> <SEP> 11 <tb> 18 <SEP> H <SEP> CNE2 <SEP> CH3 <SEP> H <tb> <SEP> 0 <tb> <SEP> U <tb> 19 <SEP> H <SEP> CNHCE3 <SEP> CH3 <SEP> H <tb> 20 <SEP> H <SEP> CH2CH2NH2 <SEP> CH3 <SEP> H <tb> <SEP> 21 <SEP> H <SEP> 4 <SEP> CH3 <SEP> H <tb> 22 <SEP> H <SEP> CE2OH <SEP> CH3 <SEP> CH3 <tb> 23 <SEP> H <SEP> 2CF3 <SEP> CH3 <SEP> CH3 <tb> <SEP> OH <tb> 24 <SEP> H <SEP> CE3 <SEP> CE3 <tb> <SEP> cHzcaCH3 <SEP> CHJ <SEP> CH3 <tb> <SEP> NH2 <tb> 25 <SEP> H <SEP> CECE3 <SEP> CH3 <SEP> CH3 <tb> EMI213.1 <tb> <SEP> 6 <SEP> 7 <SEP> 9 <SEP> 10 <tb> Compound <SEP> R <SEP> R <SEP> R9 <SEP> R <tb> <SEP> OH <tb> <SEP> 26 <SEP> H <SEP> C(CH3)2 <SEP> CH3 <SEP> CH3 <tb> <SEP> 27 <SEP> H <SEP> CH2CH2OH <SEP> CH3 <SEP> CH3 <tb> <SEP> OH <tb> <SEP> 28 <SEP> H <SEP> bd <SEP> CH3 <SEP> CH3 <tb> <SEP> OH <tb> <SEP> 29 <SEP> H <SEP> CHCH2F <SEP> CH3 <SEP> CH3 <tb> <SEP> SH <tb> <SEP> 30 <SEP> HHCH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> 0 <tb> <SEP> 31 <SEP> H <SEP> 1H2 <SEP> CH3 <SEP> CH3 <tb> <SEP> 0 <tb> <SEP> II <tb> <SEP> 32 <SEP> H <SEP> COCH2NH2 <SEP> CH3 <SEP> CH3 <tb> <SEP> OH <tb> <SEP> 33 <SEP> H <SEP> CECH3 <SEP> C2H5 <SEP> H <tb> <SEP> OH <tb> <SEP> 34 <SEP> H <SEP> CECH3 <SEP> C2H5 <SEP> C2H5 <tb> <SEP> OH <tb> <SEP> 35 <SEP> H <SEP> CECE3 <SEP> CE7 <SEP> H <tb> EMI214.1 <tb> <SEP> 6 <SEP> 7 <SEP> 9 <SEP> 10 <tb> Compound <SEP> R <SEP> R <SEP> R <SEP> R <tb> <SEP> OH <tb> <SEP> 36 <SEP> H <SEP> CHCB3 <tb> <SEP> OH <tb> <SEP> 37 <SEP> H <SEP> CECE3 <SEP> H <tb> <SEP> OH <tb> <SEP> 38 <SEP> CH3 <SEP> CHCH3 <SEP> CH2CH <SEP> H <tb> <SEP> 39 <SEP> H <SEP> CH2 H <SEP> CF3 <SEP> H <tb> <SEP> 40 <SEP> H <SEP> CE2OH <SEP> CH2 <SEP> 8 <SEP> H <tb> <SEP> 2 <tb> <SEP> 41 <SEP> H <SEP> CE2CE2OH <SEP> < <SEP> CH3 <tb> <SEP> 42 <SEP> CH3 <SEP> CE2OH <SEP> CH3 <SEP> CH3 <tb> <SEP> 43 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> 44 <SEP> CE3 <SEP> 0CE3 <SEP> CH3 <SEP> H <tb> <SEP> 45 <SEP> CH3 <SEP> Cl <SEP> CH3 <SEP> CE3 <tb> <SEP> OH <tb> <SEP> 46 <SEP> H <SEP> CECH3 <SEP> C2F5 <SEP> H <tb> EMI215.1 <tb> Compound <SEP> R6 <SEP> R7 <SEP> 9 <SEP> R10 <tb> <SEP> R <tb> <SEP> 47 <SEP> CR3 <SEP> CH2OH <SEP> CH3 <SEP> C <SEP> 2H5 <tb> <SEP> 48 <SEP> < <SEP> H <SEP> CH3 <SEP> 2+ <tb> Compound <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> OHCU, <tb> <SEP> 49 <SEP> H <SEP> CHCH3 <tb> <SEP> OH3 <tb> <SEP> 3 <tb> <SEP> 50 <SEP> H <SEP> CECH3 <SEP> 3 <tb> <SEP> OH <tb> <SEP> I <SEP> C <SEP> 8) <tb> <SEP> 51 <SEP> H <SEP> CHCH3 <tb> <SEP> OH. <tb> <SEP> 52 <SEP> H <SEP> RCH3 <SEP> CH2= <tb> EMI216.1 <SEP> R6¯+¯R7 <SEP> R9 <SEP> R10 <tb> Compound <SEP> R <SEP> + <SEP> 37 <SEP> ¯¯¯¯¯¯¯¯¯¯¯¯¯¯ <tb> <SEP> 53 <SEP> CH2= <SEP> CH3 <SEP> H <tb> <SEP> 54 <SEP> HOOCH= <SEP> CH3 <SEP> CH3 <tb> <SEP> 55 <SEP> C <SEP> R <SEP> CH3 <SEP> H <tb> <SEP> 56 <SEP> POCU3 <SEP> C2H5 <SEP> CH3 <tb> <SEP> C3 <tb> Compound <SEP> R6 <SEP> + <SEP> R <SEP> R9 <SEP> + <SEP> R10 <tb> <SEP> 57 <SEP> CH2= <SEP> CA3 <tb> <SEP> 3 <tb> <SEP> 58 <SEP> HOCH <tb> <SEP> 59 <SEP> Hz <SEP> t3 <SEP> CH <SEP> ¯ <tb> <SEP> u <SEP> 3 <tb> <SEP> 6 <SEP> - <SEP> C > 3 <tb> <SEP> 60 <SEP> HOCE2CE EXAMPLE 9 Following the procedure of Example 3, Steps A to D and Example 4, the following species of present invention are obtained when azetidinones A of Example 8, are substituted in equivalent amounts, respectively, for the azetidinone of Example 3, SteP EMI217.1 EMI217.2 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R <SEP> R10 <tb> <SEP> NH <tb> <SEP> 1 <SEP> CH2-C-NH2 <SEP> CR3 <SEP> CR3 <SEP> CR3 <SEP> H <tb> <SEP> NH <SEP> OH <tb> <SEP> 2 <SEP> CR2-C-NRCH3 <SEP> (CH3)2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> <SEP> I.' <tb> <SEP> 3 <SEP> CH2-C-N(CH3)2 <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> NCH <tb> <SEP> It <tb> <SEP> 4 <SEP> CH2-C-NHCH3 <SEP> OHCH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> e <tb> <SEP> CR2 <SEP> CR3)2 <SEP> 3 <SEP> 2 <SEP> 3 <tb> <SEP> S <SEP> -C-N(CR3)2 <SEP> 3 <SEP> CR <SEP> H <SEP> CH3 <SEP> H <tb> EMI218.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R <SEP> 10 <tb> <SEP> N11-C2E5 <tb> <SEP> 6 <SEP> CH2-C-NH2 <SEP> FCH2CH2 <SEP> E <SEP> C2E5 <SEP> H <tb> <SEP> NH <SEP> CE3 <tb> 7 <SEP> CH2-C-N <SEP> CE3CE2 <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> C2E5 <tb> <SEP> NH <tb> <SEP> 8 <SEP> CH2-C-N(C2H5)2 <SEP> HOCH2CH2 <SEP> CH3 <SEP> < <SEP> H <tb> <SEP> NH <tb> 9 <SEP> CH2-C-NHC(CH3)3 <SEP> HOCH2CH2 <SEP> CH3 <SEP> H <tb> <SEP> NH <SEP> NH2 <tb> <SEP> II <SEP> I <tb> 10 <SEP> FH-C-NH <SEP> CH3CH <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> CH3 <tb> <SEP> NR <SEP> O <tb> 11 <SEP> CH-C-NHCH3 <SEP> H2NC <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 3 <SEP> 2 <tb> <SEP> CH3 <tb> <SEP> NCH <SEP> O <tb> <SEP> I <SEP> U <tb> <SEP> 12 <SEP> CH2-C-N(CH3)2 <SEP> H2NC <SEP> H <SEP> CH3 <SEP> CH3 <tb> 13 <SEP> NH <SEP> OH <tb> <SEP> II <tb> <SEP> CH-C-N-(CH3)2 <SEP> HzCH <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> I <SEP> N-(CH3)2 <SEP> CH <tb> <SEP> CH3 <tb> EMI219.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R <SEP> R10 <tb> <SEP> NH <SEP> SH <tb> 14 <SEP> CH--NR <SEP> CH3CH <SEP> CH3 <SEP> 2 <SEP> 5 <SEP> CR3 <tb> <SEP> 2 <tb> <SEP> NH <tb> 15 <SEP> C-C-NH <SEP> HOOCH2 <SEP> CH3 <SEP> C <SEP> H <SEP> H <tb> <SEP> CH2 <tb> <SEP> NH <tb> 16 <SEP> CH <SEP> CH <SEP> -U¯NH <SEP> H <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> NH <tb> <SEP> II <tb> 17 <SEP> CH2-CH-C-NH2 <SEP> CH2O <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> 3 <tb> <SEP> NH <tb> 18 <SEP> CR <SEP> -CR-NE <SEP> CR <SEP> CR <SEP> CR <SEP> CR <SEP> CR <SEP> H <tb> <SEP> 2 <SEP> CH,CH,CH, <SEP> 2 <SEP> 3 <SEP> 2 <SEP> 2 <SEP> 3 <SEP> 3 <tb> <SEP> OH <tb> <SEP> NH <SEP> CR3 <tb> <SEP> II <tb> 19 <SEP> CH2-C-C-NH2 <SEP> CH <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> II <tb> <SEP> N-OCR3 <SEP> CH3 <tb> <SEP> NH <tb> <SEP> 1I <tb> 20 <SEP> CH2-CR1-C-NR2 <SEP> CO <SEP> 2Me <SEP> H <SEP> CH3 <SEP> C3g7 <tb> <SEP> N(CH3)2 <tb> EMI220.1 <tb> <SEP> 6 <SEP> 7 <SEP> 10 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R <SEP> ¯¯¯¯¯¯ <SEP> R <SEP> R10 <tb> <SEP> NH <tb> <SEP> II <tb> <SEP> 21 <SEP> CH2-CH-C-NH2 <SEP> CF <SEP> CH3 <SEP> CH2OH <SEP> R <tb> <SEP> 21 <SEP> 2 <SEP> 3 <SEP> 3 <SEP> 2 <tb> <SEP> N(CH3)3 <tb> <SEP> NH <SEP> OH <tb> <SEP> II <tb> <SEP> 22 <SEP> CH2-C-N(CH3)2 <SEP> CH3CH <SEP> OMe <SEP> CH3 <SEP> H <tb> <SEP> 2 <tb> <SEP> NH <tb> <SEP> II <tb> <SEP> 23 <SEP> FHC-NH <SEP> HOCK2 <SEP> 3 <SEP> CE3 <SEP> C <SEP> H <tb> <SEP> SCH3 <tb> <SEP> NH <SEP> OH <tb> <SEP> 9 <SEP> CHZ'5-NE8' <SEP> C3 <tb> <SEP> 24 <SEP> CH <SEP> 11 <SEP> g <SEP> CH3CH <SEP> H <SEP> R <SEP> + <SEP> R10 <tb> <SEP> N-OCB, <SEP> OH <tb> <SEP> 3 <SEP> J <SEP> OH <tb> <SEP> 25 <SEP> CH2-C-NH2 <SEP> CH3CH <SEP> H <SEP> R <SEP> + <SEP> R10: <SEP> 7 <SEP> c <tb> <SEP> NH <SEP> OH <tb> <SEP> U <SEP> 9 <SEP> t <SEP> 10 <tb> <SEP> 26 <SEP> CR2CH2-c-NE-CR3 <SEP> ski <SEP> CHCHCE3CE <SEP> H <SEP> R <SEP> + <SEP> R <SEP> : <SEP> CH2= <tb> <SEP> NH <tb> <SEP> 27 <SEP> CHZ-C-e-N82 <SEP> CR <SEP> OR <SEP> CH3 <SEP> R9 <SEP> + <SEP> 10 <SEP> ROCK2 <tb> <SEP> 2 <SEP> 2 <tb> <SEP> (CH3)2 <tb> <SEP> NE <SEP> OR <tb> <SEP> 28 <SEP> CR <SEP> -CR--NH <SEP> CR <SEP> 9 <SEP> 10 <tb> <SEP> 2 <SEP> CH <SEP> 2 <SEP> CH31OCHH <SEP> H <SEP> P <SEP> + <SEP> P <SEP> : <tb> <SEP> OCH3 <tb> EMI221.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R <SEP> R10 <tb> <SEP> NCH <tb> 29 <SEP> CH2CH29-NH2 <SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> 30 <SEP> CH2CH2-S-CH2C-N(CH3)2 <SEP> R6 <SEP> + <SEP> R7: <SEP> CH3 <SEP> H <tb> <SEP> 30 <SEP> C)IZCBZ-S <SEP> -CII,C-N <SEP> (CH3) <SEP> 2 <tb> <SEP> NH <tb> <SEP> if <SEP> 6 <SEP> 7 <tb> 31 <SEP> CH2CH2-O-CH2CH2-C-NH2 <SEP> R <SEP> + <SEP> R <SEP> : <SEP> CH3 <SEP> CH3 <tb> <SEP> c <SEP> rLr <SEP> <tb> <SEP> CH3 <SEP> NCH3 <tb> 32 <SEP> CHCH2-S-C-N(CH3)2 <SEP> R6 <SEP> + <SEP> R7: <SEP> CH3 <SEP> C <SEP> H <tb> <SEP> 2 <tb> <SEP> I <SEP> y'U3 <tb> <SEP> NCH <tb> <SEP> Ii <SEP> 6 <SEP> 7 <tb> 33 <SEP> CH-CH-C-N(CH3)2 <SEP> 2 <SEP> 2 <SEP> R <SEP> : <SEP> CHZI <SEP> CZHS <SEP> " <tb> <SEP> NH <tb> <SEP> II <tb> 34 <SEP> CH2CH2-C-N(CH3)2 <SEP> R <SEP> + <SEP> R <SEP> : <SEP> HOCH2CH <SEP> CH3 <SEP> H <tb> 35 <SEP> CH2-C <SEP> 3 <SEP> R6 <SEP> + <SEP> R7: <SEP> R9 <SEP> 10, <tb> <SEP> N <SEP> HOCH2CH <SEP> C3 <tb> <SEP> H <SEP> /\ <SEP> cU <SEP> 3 <tb> <SEP> 36 <SEP> CH2-C\ <SEP> R6 <SEP> + <SEP> R7: <SEP> R9 <SEP> + <SEP> 10 <SEP> CH <tb> <SEP> I\rtU3 <SEP> R <SEP> CH2" <tb> <SEP> OEl. <tb> EMI222.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R9 <SEP> 10 <tb> <SEP> NH <SEP> NH <tb> 37 <SEP> CH2CH2-C-NC(CH3)3 <SEP> CH3CH <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> <SEP> N <SEP> SH <tb> 38 <SEP> CEI3h <SEP> H <SEP> C2E5 <SEP> H <tb> <SEP> 39 <SEP> -C( <SEP> C3 <SEP> OH <tb> <SEP> Nc3 <SEP> t4C*3 <SEP> C83CB <SEP> CH <SEP> < <SEP> H <tb> <SEP> OH <tb> <SEP> INCH3 <SEP> I <tb> 40 <SEP> CH2-C-N(CH3)2 <SEP> (cE3)2c <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> NH <SEP> OR <tb> 41 <SEP> CH2-C-CH(CH3)2 <SEP> CR3CH2H <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> NB <tb> 42 <SEP> CH2-C <SEP> -N <SEP> H2NCH2CH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> NH <SEP> OH <tb> 2 <SEP> > <SEP> CH <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> NH <SEP> OH <tb> 44 <SEP> CE2- <SEP> -N <SEP> CH2CH <SEP> H <SEP> 3 <SEP> 3 <tb> EMI223.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> N <SEP> O <tb> 45 <SEP> CH <SEP> C <SEP> N(CH <SEP> ) <SEP> H2NC <SEP> CH3 <SEP> C2H5 <SEP> H <tb> <SEP> NH <SEP> OR <tb> 46 <SEP> CH <SEP> uC <SEP> N <SEP> O <SEP> CH3CH <SEP> OCH3 <SEP> C3E7 <SEP> CH3 <tb> <SEP> NH <SEP> OH <tb> 47 <SEP> CH <SEP> C <SEP> NHCH <SEP> 4 <SEP> CR3CR <SEP> SOCH3 <SEP> X <SEP> CH3 <tb> 48 <SEP> NH <tb> <SEP> CH2-C-NHCH2 <SEP> o <SEP> 2 <SEP> CFR2CR2 <SEP> H <SEP> H <tb> <SEP> OH <tb> 49 <SEP> CH <SEP> - <SEP> ( <SEP> <SEP> HOCH2CH2CH <SEP> H <SEP> CR <SEP> H <tb> <SEP> CUfphlCny\ <tb> <SEP> NH <SEP> OH <tb> 50 <SEP> CH2-t-NHOCH3 <SEP> ssCH2CH <SEP> H <SEP> CH3 <SEP> H <tb> 51 <SEP> CR2 <SEP> NH <SEP> OCR3 <SEP> 4 <SEP> H <SEP> CR3 <SEP> H <tb> <SEP> CH3 <tb> <SEP> C2H5 <SEP> NH <SEP> C3 <tb> 52 <SEP> CH2-C-NH2 <SEP> HO <SEP> H <SEP> CR3 <SEP> CH3 <tb> <SEP> C <SEP> 2B5 <SEP> NH <tb> 53 <SEP> CRCR2-NH2 <SEP> CR <SEP> CR <SEP> H <SEP> CH3 <SEP> H <tb> EMI224.1 <tb> <SEP> 6 <SEP> 7 <SEP> 9 <SEP> 10 <tb> Compound <SEP> R <SEP> R6 <SEP> R <SEP> R <SEP> R10 <tb> <SEP> CH3 <SEP> NH <tb> <SEP> 54 <SEP> CRCH2--N(cR3)2 <SEP> CR3CE2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> NCR <SEP> OH <tb> <SEP> j3 <tb> <SEP> 55 <SEP> -N(CE3)2 <SEP> (cE3)2c <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> N <SEP> (cur3) <tb> <SEP> 2 <tb> <SEP> 56 <SEP> CH2-C-N(CH3)2 <SEP> CH2 H <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> NH <tb> <SEP> 57 <SEP> CH2-N-CR2-N(CH3)2 <SEP> CH2F <SEP> CH3 <SEP> CH3 <SEP> H <tb> <SEP> CH3 <tb> <SEP> 58 <SEP> CB2 <SEP> "3 <SEP> CR3CH2 <SEP> 3 <SEP> 2 <SEP> C2 <SEP> H <SEP> H <tb> <SEP> 59 <SEP> CR2 <SEP> Hz? <SEP> CH3CR2 <SEP> H <SEP> < <SEP> H <tb> <SEP> 60 <tb> <SEP> CH,CH, <SEP> H <SEP> CE&num; <SEP> H <tb> <SEP> I <tb> <SEP> OH <tb> <SEP> 61 <SEP> ¸) <SEP> (CH3)2C <SEP> H <SEP> CH3 <SEP> H <tb> EMI225.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R <SEP> R10 <tb> <SEP> OH <tb> <SEP> II <tb> 62 <SEP> 4K <SEP> CCJ) <SEP> OCH2CH <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> SH <tb> 63 <SEP> (CH3)2 <SEP> (C <SEP> 434 <SEP> H <SEP> 3)2 <SEP> CH3 <SEP> H <tb> <SEP> 64 <SEP> tnr <SEP> 46cm3) <SEP> H <SEP> 2 <SEP> C25 <SEP> H <tb> <SEP> NH <tb> <SEP> flc <tb> 65 <SEP> II <SEP> (C^35 <SEP> \ <SEP> 2 <SEP> CH3 <SEP> CH3 <tb> <SEP> NH2 <tb> 66 <SEP> 2 <SEP> e <SEP> tv <SEP> (CR3)2C <SEP> H <SEP> 7 <SEP> H <tb> <SEP> NH <SEP> NH <tb> <SEP> 67 <SEP> G <SEP> 1-NH2 <SEP> (CH3)2C2 <SEP> H <SEP> H <tb> 68e-NHcff, <tb> <SEP> CR <SEP> CR <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> OR <tb> 69 <SEP> CR3CR2CR <SEP> H <SEP> CHCHH <SEP> CH3 <SEP> CH3 <tb> <SEP> r4d <tb> 70 <SEP> - <SEP> t <SEP> ROCR2CR2 <SEP> H <SEP> 2 <SEP> 3 <SEP> H <tb> EMI226.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> rJP <tb> <SEP> 71 <SEP> ¯ROo <SEP> CH2FCH2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> 72 <SEP> > < 5 <SEP> Hzc*C <SEP> 4( <SEP> 3); <SEP> CH3CHF <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> OR <tb> <SEP> 73 <SEP> ,0L <SEP> -CE2CE <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> N <SEP> F\ <SEP> OH <tb> <SEP> 74 <SEP> t3CU*c <SEP> - <SEP> Sf <SEP> CE <SEP> CH <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> <SEP> 75 <SEP> L <SEP> FCH2CHH <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> 0 <tb> <SEP> 76 <SEP> +G <SEP> H <SEP> 3) <SEP> NCR2C <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> <SEP> 77 <SEP> < < N <SEP> SC*3b* <SEP> CH3CH <SEP> CH3 <SEP> H <tb> <SEP> OH <tb> <SEP> 78 <SEP> CECR2H <SEP> CH, <SEP> o <SEP> 2 <SEP> 3 <SEP> CH3 <SEP> CH3 <tb> <SEP> 78N( <tb> <SEP> 79 <SEP> h)UL <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 80 <SEP> + <SEP> ( <SEP> ) <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> H <SEP> cA3 <tb> EMI227.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> 81 <SEP> C83CH2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> 82 <SEP> < ( <SEP> OR <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> (CR3) <SEP> 2CR <tb> 83 <SEP> < (7 <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> 84 <SEP> < (9 <SEP> ?H <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> (CR3) <SEP> 2C <tb> 85 <SEP> < g4 <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> C <tb> <SEP> 86 <SEP> or <SEP> 4 <SEP> OcH <SEP> H <SEP> CH3 <SEP> H <tb> tJ <SEP> (CH3)2 <tb> 87 <SEP> t40 <SEP> C <SEP> *3 <SEP> CH3CR2 <SEP> H <SEP> CH3 <SEP> H <tb> EMI228.1 <tb> Compound <SEP> R8 <SEP> - <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> 88 <SEP> A)*Cd3 <SEP> CH3CH3 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> NCtI <tb> 89 <SEP> 4 <SEP> g3) <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> /C <SEP> IJGB <tb> 90 <SEP> <SEP> SCR <SEP> ; <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 2 <tb> 91 <SEP> CE3CE2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 2 <tb> 92 <SEP> Hz <SEP> E <SEP> 1L <SEP> OH <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> (CH3)2C <tb> 93 <SEP> t <SEP> K <SEP> 1L <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> rrlCf <tb> <SEP> (Cffj) <SEP> 2 EMI229.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> 95 <SEP> ( <SEP> 5(C <SEP> J <SEP> , <SEP> CR3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> f <SEP> c <SEP> , <tb> <SEP> 96 <SEP> r3 <SEP> 4 <SEP> Cc <SEP> 435no <SEP> CR3CR2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> CU <tb> <SEP> 97 <SEP> < < <SEP> 9 <SEP> c341; <SEP> OR <SEP> H <SEP> CR3 <SEP> H <tb> <SEP> Plj <SEP> CI <SEP> (CH3) <tb> <SEP> 98 <SEP> OH <SEP> H <SEP> CR3 <SEP> CR3 <tb> <SEP> (cur3) <tb> <SEP> 99cctt3, <SEP> HOCH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 1 <tb> 100 <SEP> < f <SEP> N <SEP> (C <SEP> %) <SEP> CR2FCR2 <SEP> H <SEP> CH3 <SEP> H <tb> 101 <SEP> t <SEP> OH <SEP> H <SEP> (CH3)2} <SEP> CH3 <SEP> H <tb> <SEP> 3b <SEP> (CR3)2 <tb> EMI230.1 <tb> Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> 102 <SEP> (C <SEP> OR <SEP> H <SEP> CR3 <SEP> CE3 <tb> <SEP> (CE3) <SEP> CH3 <tb> 103 <SEP> ( <SEP> i <SEP> ?R <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> > <SEP> a <SEP> > <SEP> CH <tb> 104 <SEP> < r <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> 105 <SEP> t < <SEP> CR3 <SEP> OH <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 1 <tb> <SEP> (CE3) <SEP> 2C <tb> 106 <SEP> t < N <SEP> 4 <SEP> 43) <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> NU <tb> 107 <SEP> Ccwca,ce2 <SEP> CE <SEP> CR <SEP> U3) <SEP> CH3CH2 <SEP> H <SEP> CH3 <SEP> CH3 <tb> <SEP> 2 <SEP> 1 <tb> 108 <SEP> raj <SEP> ROCE2CE2 <SEP> H <SEP> 2 <SEP> CH3 <SEP> H <tb> EMI231.1 <tb> <SEP> ComPound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R9 <SEP> R10 <tb> <SEP> 109 <SEP> ROCR2CH2 <SEP> H <SEP> CH3 <SEP> H <SEP> C3 <SEP> CH3 <tb> 110 <SEP> < < <SEP> AJ <SEP> Hz 3) < Z <SEP> CH3CHF <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> 3 <tb> 111 <SEP> iCEF <SEP> tK)CE1CIIF <SEP> H <SEP> CH3 <SEP> H <tb> <SEP> sVU <tb> NOTE: Compounds such as No. 24, Example 9, above, wherein two radicals are joined are to be interpreted from the drawing as showing all but the point of common attachment. Thus, for example, EMI231.2 EXAMPLE 11 Preparation of Pharmaceutical Compositions One such unit dosage form is prepared by mixing 120 mg of compound A: EMI232.1 Compound A with 20 mg of lactose and 5 mg of magnesium stearate and placing the 145 mg mixture into a No. 3 gelatin capsule. Similarly, by employing more of the active ingredient and less lactose, other dosage forms can be put up in No. 3 gelatin capsules, and, should it be necessary to mix more than 145 mg of ingredients together, larger capsules such as compressed tablets and pills can be prepared. The following examples are illustrative of the preparation of pharmaceutical formulations: TABLET PER TABLET Compound A 125 mg. Cornstarch, U.S.P. 6 mug. Dicalcium Phosphate 192 mg. Lactose, U.S.P. 190 mg. Magnesium Stearate Balance/800 mg. The active ingredient is blended with dicalcium phosphate, lactose and about half of the cornstarch. The mixture is then granulated with 15% cornstarch paste (6 mg) and rough-screened. It is dried at 450C and screened again through No. 16 screens. The balance of the cornstarch and magnesium stearate is added and the mixture is compressed into tablets, approximately 0.5 inch in diameter each weighing 800 mg. PARENTERAL SOLUTION PER TABLET Ampoule: Compound A 500 mg. Diluent: Sterile Water for Injection 2 cc. OPHTHALMIC SOLUTION Compound A 100 mg. Hydropropylmethyl Cellulose 5 mg. Sterile Water to 1 ml. OTIC SOLUTION Compound A 100 mg. Benzalkonium chloride 0.1 mg. Sterile Water to 1 ml. TOPICAL OINTMENT Compound A 100 mg. Polyethylene Glycol 4000 U.S.P. 400 mg. Polyethylene Glycol 400 U.S.P. 1.0 gram

Claims: WHAT IS CLAIMED IS: 1. A compound having the structural formula: EMI234.1 and the pharmaceutically acceptable salt, ester and amide derivatives thereof; wherein: R6 and R7 and R9 and R10 are independently selected from the group consisting of substituted and unsubstituted: hydrogen (R9 and R10 are not both hydrogen), alkyl, alkenyl, and alkynyl having 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety; aryl, aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl, wherein the alkyl moiety has 1-6 carbon atoms and the heteroatoms are selected from 0, N and S; R6 and R , and R9 and R10 may be joined to form a cyclicalkyl having, together with the carbon atom to which they are attached, 3-6 carbon atoms; wherein the substituent or substituents on R6, R7,R9 and R10 are independently selected from chloro, fluoro, hydroxy, bromo, alkylthio having 1-6 carbon atoms, and alkoxyl having 1-6 carbon atoms; and R 8. is is a carbamimidoyl selected from the group consisting of: EMI235.1 wherein: A is a single, direct bond, or A, the cyclic or acyclic connector, is selected from the group consisting of alkyl, alkenyl, and alkynyl having 1-10 carbon atoms which may be interrupted by a hetero atom selected from 0, S or N, or by a ring such as phenyl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl wherein such cyclic interruptions comprise 3-6 ring atoms selected from C, O, S and N; cycloalkyl, cycloalkenyl having 3-6 carbon atoms; heterocyclyl; heteroaryl; and phenyl; R1 and R2 are independently selected from hydrogen and the previously defined, but monovalent, values for the group A; and wherein the dotted lines indicate provision for cyclic structures formed by the joinder of the indicated nitrogen atom and the connector group A and by the joinder of the indicated nitrogen atoms; when R6/R7 is hydrogen, then R7/R is not l-hydroxyethyl. 2. A compound acording to Claim 1 wherein R1 and R2 R1 and R2 are independently selected from: hydrogen, alkyl, aryl, cycloalkyl, alkylaryl, aralkyl, alkylarylalkyl, heterocyclyl, and heteroaryl. 3. A compound according to Claim 1 wherein: R1 and R2 are independently selected from the group consisting of hydrogen; substituted and unsubstituted: straight and branched loweralkyl having from 1 to 6 carbon atoms; cycloalkyl having 3 to 6 carbon atoms; cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 6 carbon atoms; alkylcycloalkyl wherein the alkyl moiety comprises I to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms; phenyl; phenylalkyl having 7-10 carbon atoms; heterocyclyl (saturated and unsaturated) comprising mono- and bicyclic structures having from 5 to 10 ring atoms, wherein one or more of the heteroatoms is selected from oxygen, nitrogen, or sulfur; heterocyclyalkyl wherein the alkyl moiety comprises from 1 to 6 carbon atoms, and the heterocyclyl is as defined above; the substitutent or substituents relative to the above-named radicals are selected from the group consisting of amino, hydroxy, cyano, carboxyl, nitro, chloro, bromo, fluoro, alkoxy and alkylthio having from 1 to 6 carbon atoms, mercapto, perhaloalkyl having 1 to 3 carbon atoms, guanidino, amidino, and sulfamoyl atoms; and alkylthio having from I to 3 carbon atoms. 4. A cçmpoundJaccording to Claim 1 wherein R1 and R2 are independently selected from: hydrogen; substituted and unsubstituted: straight and branched loweralkyl having from 1 to 6 carbon atoms; cycloalkyl having from 3 to 6 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 atoms and the alkyl moiety comprises 1 to 6 carbon atoms; phenyl, benzyl; wherein the substitutent or substitutents on the above-named radicals are selected from fluoro, hydroxy, mercapto, alkoxy having from 1 to 3 carbon atoms; and alkylthio having from 1 to 3 carbon atoms. 5. A compound according to Claim 1 wherein the connecting group A is selected from: a single, direct bond; substituted and unsubstituted: alkyl having from 1 to 6 carbon atoms; cycloalkyl having from 3 to 10 atoms; cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 10 carbon atoms; alkylcycloalkyl wherein the alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms; alkenyl having from 2 to 10 carbon atoms, cycloalkenyl having from 3 to 10 carbon atoms, cycloalkenylalkyl wherein the cycloalkenyl moiety comprises 3 to 10 carbon atoms and the alkyl moiety comprises 1 to 6 carbon atoms; alkynyl having from 2 to 10 carbon atoms; phenyl; naphthyl; arylalkyl and alkylaryl wherein the aryl is phenyl and the alkyl has 1 to 6 carbon atoms; heteroalkyl, alkylheteroalkyl, arylheteroalkyl and alkylheteroaryl wherein the heteroatom or atoms are selected from the group of sulfur, oxygen bond nitrogen, the alkyl moiety has 1 to 6 carbon atoms, and the aryl moiety is phenyl; heterocyclyl (saturated and unsaturated) comprising mono- and bicyclic structures having 5 to 10 ring atoms wherein one or more of the heteroatoms is selected from oxygen, nitrogen, or sulphur; heterocyclylalkyl wherein heterocyclyl moiety comprises from 3 to 10 atoms and the alkyl moiety comprises from 1 to 6 atoms; the substituent or substituents relative to the above-named radicals are selected from the group consisting of amino, hydroxyl, cyano, carboxyl, nitro, chloro, bromo, fluoro, alkoxy having from 1 to 6 carbon atoms, mercapto, perhaloalkyl and alkylthio having from 1 to 6 carbon atoms. 6. A compound according to Claim 1 wherein the connecting group A is selected from: a single, direct bond, substituted and unsubstituted: straight and branched loweralkyl having from 1 to 6 carbon atoms cycloalkyl having from 3 to 6 carbon atoms; phenyl; heterocyclyl selected from: thiophene, imidazole, pyridine, tetrazole and furane; alkylheteroalkyl wherein alkyl moiety comprises 1 to 3 carbon atoms and the heteroatom or atoms are sulfur, oxygen and nitrogen, the substituents relative to the above-named radicals are: amino, hydroxyl, chloro, bromo, fluoro, cyano, carboxyl, alkoxy having from 1 to 3 carbon atoms, mercapto, trifluoromethyl, and alkylthio having from 1 to 3 carbon atoms. 7. A compound according to Claim 1 wherein -SR8 is selected from the group consisting of: EMI239.1 EMI240.1 EMI241.1 EMI242.1 n = 2-5, Rê = H, CH3 RÚ = H, CH3 n = 2-5, RÚ, Rê = H, CH3 EMI242.2 EMI243.1 EMI244.1 EMI245.1 EMI246.1 EMI247.1 EMI248.1 EMI249.1 EMI250.1 EMI251.1 EMI252.1 RÚ = H, CH3 Rê - H, CH3 R1 = H, CH3 Rê = H, CH3 EMI253.1 RÚ = CH3 Rê = CH3, NR2, Or R = H, CH3 R1 = H, CH3 RÚ = H, CH3 Rê = H, CH3 n = 1 or 2 R a H, CH3 EMI254.1 R = CH2CH3, CH3 8. A compound according to Claims 1, 2, 3, 9 and @10 4, 5, 6 or 7 wherein R and R are independently selected from the group consisting of: substituted and unsubstituted alkyl having 1 to 6 carbon atoms, cycloalkyl, l,l-spiroalkyl having 3-6 carbon atoms, cycloalkylalkyl, phenyl, phenylalkyl wherein the substituent or substituents are selected from chloro, fluoro, bromo, hydroxy, alkylthio, and alkoxyl. 9. A compound according to Claim 8 wherein R9 and R10 are alkyl. 10. A compound according to Claim 9 wherein R9 and R10 are methyl. 11. A compound according to Claim 8 wherein R9 and R10 are independently selected from the group consisting of: CH3 CH2CH3 CH(CH3)2 CH2C6H5 CH2F CF3 CR2Br -CH=CH2 EMI255.1 CHF2 CH2Cl. CH2Oh CH2SMe CH2OMe EMI256.1 12. A compound according to Claim 1, wherein R7 is selected from H, OCH3 and CH3. 13. A compound according to Claiml2 wherein R6 is selected from the group consisting of: substituted and unsubstituted: alkyl, alkenyl and cycloalkylalkyl wherein the substituent or substituents are selected from hydroxyl, alkoxyl having from 1-6 carbon atoms, phenoxy, amino, and carboxy. 14. . A compound according to Claims 12 or 13 wherein R6 is selected from the group consisting of alkyl, cycloalkylalkyl, alkyl substituted by one or more hydroxyl groups, or cycloalkylalkyl substituted by one or more hydroxyl groups. 15. A compound according to Claims 12, 13 or 14 wherein R7 is hydrogen. 16. A compound according to Claims 1, 12, 13 14, or 15 wherein R6 is selected from: EMI257.1 = phenyl EMI257.2 #CH2 EMI257.3 CH2=CHCH2 (CH3)2C=CHCH2 EMI258.1 CH3 CH3CH2 (CH3)2CH EMI258.2 HO2CCH2 EMI258.3 HOCH2CH2 EMI259.1 HOCH2CH2CH2 EMI259.2 EMI260.1 EMI261.1 EMI262.1 17. A compound according to Claims 1,12,13, 14, 15 or 16 wherein R6 is: CH3CH2 EMI262.2 FCH2CH(OH) (CH3)2C(OH) EMI263.1 HOCH2 HO2CCH2 EMI263.2 18. A compound according to Claim 1 wherein: R7 is hydrogen, hydroxyl, alkoxy, alkylthio, :nercapto, chloro, fluoro, bromo, alkyl and substituted alkyl wherein the substituent or substituents are: alkoxyl or hydroxyl. 19.. A compound according to Claim. wherein R7 is hydrogen, hydroxyl, OCH3, CX3, hydroxyl- and polyhydroxyl-substituted alkyl. 20. A compound according to Claim 19 wherein' R7 is nydrogen, CH3 or OCH3. 21. A compound according to Claim20 wherein R6 is: hydrogen; substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl; wherein the substituent or substituents are selected from: hydroxyl, chloro, fluoro, bromo, carboxyl, oximino, alkoximino, ureido, amino, alkoxyl, or alkylthio. 22. A compound according to Claim 21 wherein the substituent or substituents on R6 are hydroxyl. 23. A compound according to Claim 1 wherein R7 is hydrogen, hydroxyl, alkoxyl, alkylthio, chloro, fluoro, bromo, alkyl and substituted alkyl wherein the substituent or substituents are: alkoxyl, or hydroxyl; and R6 is: hydrogen; substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl; wherein the substituent or substituents are selected from: hydroxyl, chloro, fluoro, bromo, oximino, alkoximino, ureido, amino, alkoxyl or alkylthio. 24 . A compound according to Claim 1 wherein R7 is.,hydrogen, hydroxyl, alkoxyl, alkylthio, 'nercapto, chloro,-fluoro, broad, alkyl and substituted alkyl wherein the substituent or substituents are: alkoxyl, or hydroxyl; and R6 is hydrogen; substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl; wherein the substituent or substituents are selected from: hydroxyl, chloro, fluoro, bromo, oximino, alkoximino, ureido, amino, alkoxyl or alkylthio. 25 A compound according to Claim 24 wherein R7 is hydrogen, CH3 or OCH3. 26 A compound according to Claim 25 wherein R6 is selected from: N, EMI265.1 wherein: y g O or 1; X - OH, NH2; SH; n - 0 or R - substituted or unsubstituted: alkyl, alkenyl or alkynyl having 1-6 carbon atoms wherein the substituent is R1; R1 = alkoxyl, carboxyl, CF3, OH, H, linear or branched alkyl bearing 1 or more hydroxyl groups, amino, aminoalkyl, Cl, F, Br, alkylthio, amidino, guanidino, oximino, phenyloxy, phenylthio, EMI266.1 27 . A compound according to Claim 25 wherein R6 is selected from: -H -CH2OH -CH(OH)CH3 -CH2CH2OH -CH(OH)CH(CH3)2 -CH(OH)CH2CH(CH3)2 -CH2CH2CH2OH -CH2CH2CH2CH2OH -CH(OH)CH2CH2OH EMI267.1 -CH(OH)CH2CH3 EMI267.2 EMI267.3 -CH(OH)CF3 EMI267.4 -CH(NH2)CH3 EMI267.5 -CH(OH)CH2Cl -CH(OH)CH2F 28. A process for preparing a compound of the structural formula: EMI268.1 and the pharmaceutically acceptable salt, ester and amide derivatives thereof; wherein: R6 and 7 and R9 and R10 are independently selected from the group consisting of substituted and unsubstituted: hydrogen (R9 and R10 are not both hydrogen), alkyl, alkenyl, and alkynyl having 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety; aryl, aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl, wherein the alkyl moiety has 1-6 carbon atoms and the heteroatoms are selected from 0, N and S; R6 and R7, and R9 and R10 may be joined to form a cyclicalkyl having, together with the carbon above to which they are attached, 3-6 carbon atoms; wherein the substituent or substituents on R6, R7, R9 and R1,0 are independently selected from chloro, fluoro, bromo, hydroxy, alkylthio having 1-6 carbon atoms, and alkoxyl having 1-6 carbon atoms; and R8 is a carbamimidoyl selected from the group consisting of: EMI269.1 EMI270.1 wherein: A is a single, direct bond, or A, the cyclic or acyclic connector, is selected from the group consisting of alkyl, alkenyl, and alkynyl having 1-10 carboy atomslwhich may be interrupted by a hetero atom selected from 0, S or N, or by a ring such as phenyl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl wherein such cyclic interruptions comprise 3-6 ring atoms selected from C, O, S and N; cycloalkyl, cycloalkenyl having 3-6 carbon atoms; heterocyclyl; heteroaryl; and phenyl; R1 and R2 are independently selected from hydrogen and the previously defined, but monovalent, values for the group A; and wherein the dotted lines indicate provision for cyclic structures formed by the joinder of the indicated nitrogen atom and the connector group A and by the joinder of the indicated nitrogen atoms; comprising the step of treating: EMI270.2 with HSR8; wherein Ka is a leaving group and R5 is a protecting group. 29. An antibiotic composition comprising a therapeutically effective amount of a compound according to Claim 1 and a pharmaceutically effective carrier therefor. 30. A compound according to Claim 1-28 wherein R is H and R7 is CH3CH(OH)-. 31. A compound according to Claim 30 wherein R10 is H. CLAIM FOR AUSTRIA A process for preparing a compound of the structural formula: EMI272.1 and the pharmaceutically acceptable salt, ester and amide derivatives thereof; wherein: R6 and R7, and R9 and R10 are independently selected from the group consisting of substituted and unsubstituted: hydrogen (R9 and R10 are not both hydrogen), alkyl, alkenyl, and alkynyl having 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety; aryl, aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl, wherein the alkyl moiety has 1-6 carbon atoms and the heteroatoms are selected from 0, N and S; R6 and R7, and R9 and R10 may be joined to form a cyclicalkyl having, together with the carbon above to which they are attached, 3-6 carbon atoms; wherein the substituent or substituents 10 on R6, R7, R9 and R are inQependently selected from chloro, fluoro, bromo, hydroxy, alkylthio having 1-6 carbon atoms, and alkoxyl having 1-6 carbon atoms;- and 8 R8 is a carbamimidoyl selected from the group consisting of: EMI273.1 EMI274.1 wherein: A is a single, direct bond, or A, the cyclic or acyclic connector, is selected from the group consisting of alkyl, alkenyl, and alkynyl having 1-10 carboa atomsswhich may be interrupted by a hetero atom selected from 0, S or N, or by a ring such as phenyl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl wherein such cyclic interruptions comprise 3-6 ring atoms selected from C, O, S and N; cycloalkyl, cycloalkenyl having 3-6 carbon atoms; heterocyclyl; heteroaryl; and phenyl; R1 and R2 are independently selected from hydrogen and the previously defined, but monovalent, values for the group A; and wherein the dotted lines indicate provision for cyclic structures formed by the joinder of the indicated nitrogen atom.and the connector group A and by the joinder of the indicated nitrogen atoms; comprising the step of treating: EMI274.2 with HSR8; wherein Xa is leaving group and R5 is a protecting group.

Inventors: CHRISTENSEN, BURTON G., LEANZA, WILLIAM J., RATCLIFFE, RONALD W., SHIH, DAVID H.
Applicants: MERCK & CO. INC.
Application year: 1982
Main classification: C07D487
IPC codes: C07F7, C07C45, C07D477, C07D409, C07D519, C07D265, C07C17, C07D498, C07D205