6-, 1- AND 2-SUBSTITUTED-1-CARBAPEN-2-EM-3-CARBOXYLIC ACIDS, PROCESSES FOR THE PREPARATION OF SUCH COMPOUNDS AND PHARMACEUTICAL COMPOSITION COMPRISING SUCH COMPOUNDS

Abstract: Disclosed are 6-, 1 - and 2-substituted-1­ -carbadethiapen-2-em-3 -carboxylic acids having the struc­ ture: wherein: R⁰ is H or -SR⁸; R¹, R⁶, R⁷ and R⁸ are, inter alia, independently selected from the group consisting of hyd­ rogen, alkyl, alkenyl, aryl and aralkyl. Such compounds as well as their pharmaceutically acceptable sale ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds and phar­ maceutical compositions comprising such compounds.

Description: 6-, 1- AND 2-SUBSTITUTED-1-CARBADETHIAPEN-2-EM-3- CARBOXYLIC ACIDS, PROCESSES FOR THE PREPARATION OF SUCH COMPOUNDS AND PHARMACEUTICAL COMPOSITION COM PRISING SUCH COMPOUNDS BACKGROUND OF THE INVENTION This invention relates to 6-, 1- and 2substituted-1-carbadethiapen-2-em-3-carboxylic acids and derivatives thereof which are useful as antibiotics and which may be represented by the following generic structural formula EMI1.1 wherein: R0 is H or -SR8; RÚ, R6, 6, R7 and 8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alenyl, 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; -yl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the linear chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituted relative to the above-named radicals are selected fr;: the group consisting of: amino, mono, di- and trialkylamino, hydroxyl, alkoxyl, mercmpto, alkylthio, arylthio such as phenylthio, sulfamoyl, amidi, guani1: nitro, chloro, bromo, fluoro, cyano anA carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms. This invention also relates to the carboxyl derivatives of I which are antibiotics and which may be represented by the following generic structure (I): EMI2.1 wherein X' is oxygen, sulphur or NR' (R' = H or lower alkyl having 1-6 carbon atoms); and R ' is, inter alia, representatively selected from the group consisting of hydrogen, conventional blocking groups such as trialkylsilyl, acyl and the pharmaceutically acceptable salt, ester and amide moieties known in the bicyclic ss-lactam antibiotic art; the definition of R3 is given in greater detail below. This z This invention also relates to processes for the preparation of such compounds (I); pharmaceutical compositions comprising such compounds; and to methods of treatment comprising 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 objection of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representaively include both gram positive bacteria such as S. aureua, 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 non-toxic 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 seheme: DIAGRAM I EMI4.1 EMI5.1 EMI6.1 In words relative to the above diagram, the 4- (1,2-substituted-vinyl) azetidine-2-one, ffi starting material is prepared by reacting an R1- and R-substitutedoxybutadiene, i 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 an alkanoyl or aralkanoyl which bears no functional group or groups which might interfere with the desired course of reaction (1 + 2#3#4). 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 is contacted (5-30 minutes) with an aqueous solution (at 0-25 C) of a reducing agent such as sodium sulfite, thiophenol, or the like at pH6-8 to provide j. The reaction 4#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 10t Pd/C or the like. The de-blocking reaction 5#6 is usually desirable when RÚ is acyl to permit the later alkylation, 7-8. The preferred de-blocking procedure is by alcoholysis wherein the solvent is a lower alkanol such as methanol, ethanol, or the like in the presence of the correspqnaing alkali metal alkoxide, such as sodium Typically, the reaction is conducted for from 5 minutes to 1 hour at a temperature of from -100 to 250C. Blocking groups R3 and R2 are established to provide a suitably protected species for alkylation (7#8#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 t-butyldimethylsilyl or the like; or a cyclic ether such as 2-tetrahydropyranyl; R2 may also be a cyclic ether such as 2-tetrahydropyranyl; alternatively, R3 and R2 may be joined together to form protected species such as 7a; EMI7.1 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¯35 C for from a few minutes to 1 hour. Species 7 can mono- or dialkylacetyl position Alkylation of 7 provides 5. Typicylly, 7 as treated with a strong base such as lithium diisopropylamide, sodium hydride, phenyl lithium or butyl lithium and the like in a solvent such as tatrahyd-ofuran (THF), ether, dimethoxyethane and t like at a temperature of from -800C to 0 C., whereupon the alkylation agent of choice, R5X, is added ( R 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 acetaldehyae and the like) to provide monoalkylated species 8. When desired dialkylated species 9 may be obtained from 8 by repeating the alkylatin procedure 7#8. The de-blocking reaction 9#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 aldehyde intermediate 11 is prepared by treating 10 with an oxidizing agent such as CrO3.2(pyridine) in CH3CN, 1:1 mixture of dimethylsulfoxide and acetic anhydride, cyclohexylcarbodiimide in DMSO, pyridium chlorochromate in CH2C12, or the like at a temperature of from 0-250C for from 5 minutes to 1 hour. The resulting species ss in a solvent such as acetonitrile, methylene chloride, chloroform or the like at a temperature of from -10 to 25 C is treated with an excess of the reagent HSR8in the presence of an acr3 catalyst such as boron trifluoride etherate, toluena sulphonic acid or the like to provide 12. Typically, the reaction requires from 1 to 60 minutes. The vinyl sulphide 14 is obtained via intermediate 13 by treating 12 with a halogen such as c brine or bromine (X = C1 or Br) in a solvent such as e t , methylene chloride, tetrahydrofuran, glyme or the like at a temperature of from -780 to 300C for from 1 to 30 minutes followed immediately by treating with an olefin such as cyclohexene, isobutylene, or the like in the presence of base such as. triethylamine, DBU, sodium hydride, or the like in a solvent such as DMF, glyme, THF, HMPA. The solution is held at -20 to 250C for from 1 to 8 hours to yield 14. The vinyl sulphide species 14 is reacted with a diester of oxomalonic acid (or its monohydrate) to provide 15. There is no criticality as to the identity of the ester moiety, R5, of the oxomalonic acid. R5 may be a conventional, easily removable blocking group or it may be a pharmaceutically acceptable ester moiety. Suitable ester radicals R5 are -nitrobenzyl, benzyl, o-nitrobenzyl, t-butyl, 2,2,2-trichloroethyl. The reaction 14#15 is typically conducted in a high boiling organic solvent such as benzene, toluene, cyclohexane, halo aromatic or the like at a temperature of from about 500C to reflux for from 0.5 to 6 hours. The halogenation reaction 15-iW16 is typically conducted in a solvent such as THF, glyme, ether, methylene chloride, chloroform or the like in the presence of a halogenating agent such as thionyl chloride, phosphorous pentachloride or the like in the presence of base such as pyridine at a temperature of from -20 to 250C for from 5 minutes to 3 hours. The selective reduction of 15--e17 via 16 is completed by treating with tributylphosphine, triphenylphosphine, or the like in aqueous DMF or similar aqueous systems involving dioxane, THF, glyme-DMSO, or acetone at a temperature of from about 0-500C for from 10 minutes to 5 hours. Species 17 is halogenated by the previous procedure (12 e 13), but omitting the addition of the cyclohexene or other olefin, to provide the dihalo species 18. Species 18 is treated with a base such as triethylamine, sodium hydride or potassium hydride in a solvent such as DMF, acetonitrile, methylene chloride, chloroform, glyme or the like at a temperature of from about -780 to 250C for i to 5 hours to provide 19. Species 19 is converted to 20 on treatment with a strong base such as 1,5-diazabicyclo[5#4#0]undec-5-ene(DBU), 1,5-diazabicyclo[3#4#0]non-5-ene(DBN), or the like in a solvent such as DMSO, acetone, chloroform, DMF, THF, glyme or the like or on treatment with AgF in pyridine at a temperature of from 0-400C for from 1/4 to 24 hours. The reaction 20#21 is conducted by treating 20 with an aromatic base such as pyridine, aqueous dimethylsulfoxide, s-collidine or lutidine, in the presence of a displacing agent such as lithium iodide, sodium chloride, lithium bromide, sodium bromide, or the like at a temperature of from about 80-1500C for from 15 minutes to 2 hours. An aqueous work up of the resulting reaction mixture provides 21. Isomerization of the double bond 22 is accomplished by treating 21 in a solvent such as DMF, DMSO, ethyl ether, THF, glyme, methylene chloride with a strong zase such as diisoprypylamine, DBU, DBN, or the like at a temperature of from 0 to about 250C for from a few minutes to 2 hours or until equilibrium has been established as determined by examination of sample aliquots by ultraviolet absorption or by thin layer chromatography. The final reaction 22¯+ I (hydrogenolysis of the blocking group is accomplished by treating 22 in a solvent such as dioxane, ethanol, THF or the like or an aqueous mixture thereof in the presence of a platinum metal catalyst such as Pd/C under a hydrogen pressure of from 1-4 atmospheres for from 0.5 to g hours at a temperature of from about 0-250C. In the foregoing description of the invention, suitable reagents HSR8 (11#12) are representatively illustrated by the following list:: HSCH2CH2CH2NHCO2PNB, PNBO2CNCH2CH2CH2SX, EMI11.1 HSC(CH3)2CH2NHCO2PNB, HS, HSCH2#, HSC(CH3) 3' HSC3, EMI11.2 and the like ( = phenyl; and PBN = p-nitrobenzyl), CH3SH, CH3CH2SH, CH3(CH2)2SH, (CH3)2CHSH, CH3(CH2)3SH, (CH3)2CH(CH2)2SH, CH2=CHCH2SH, CH=CCH2SH, EMI12.1 (CH2)3SH( = phenyl), (CH2) 2SH, HO(CH2) 2SH, H2N(CH2)2SH, H2N(CH2) 3SH, CH3 (CH2) 2NH (CH2) 2SH, EMI12.2 (CH3)2N(CH2)2SH, (CH3CH2)2N(CH2)2SH, HO2C(CH2)2SH, #CH2SH, EMI12.3 (n n = 0, 1 or 2; X= C1, Br, F, Cl, OCH3, CH3NH2, EMI12.4 EMI12.5 Similarly, suitable alkylating agents for establishing R6 and/or R7 ar ring position 6 (7#8#9) are: #CH2CHO, CH2CH2CHO, CH2Or CH3I, CH Br CH3 COCH3 Relative to the compounds of the present invention I: EMI13.1 the most preferred values for R1 include: ethyl, propyl, isopropyl, cyclopropyl, phenyl benzyl. The most preferred radicals for R6 and R7 are: R6 = H and R7 is selected from hydroxymethyl, l-hydroxyethyl, l-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyethyl; the most preferred values for R8 are: aminoethylthio, aminopropylthio, aminocyclopropylthio, aminoisopropylthio, amidinoisopropylthio @@@@@ @@ the present @@@ @@@ @@ctea from the group @@@@@@@@@@ @@@. isopropyl, cyclopropyl, phenyl, methyl, @@. 2-bromoethyl. The compounds of the present invention (I, above) wherein R0 is H are coveniently prepared by the following scheme: DIAGRAM II EMI14.1 EMI15.1 wherein RÓ, R7 and R1 are as defined; R and R' are readily removable blocking groups; R' may also be a pharmaceutically acceptable ester moiety. Typically, the blocking group R is an acyl such as a lower alkanoyl', aralkylcarbonyl or the like such as acetyl, bromo-t-butoxycarbonyl, benzyloxycarbonyl, formyl, trifluoroacetyl and the like or a trialkylsilyl such as a trimethylsilyl or t-butyl dimethylsilyl group; and typically the blocking group R' is substituted or unsubstituted alkyl, aralkyl, alkenyl, or the like such as benzyl, p-nitrobenzyl, o-nitrobenzyl, pivaloyloxymethyl, bromo-t-butyl and the like. In words relative to the above reaction diagram, a suitably substituted azetidinone (1) is reacted with a glyoxylate ester such as benzyl glyoxylate to form the corresponding 1-(benzyloxycarbonylhydroxymethyl)azetidinone (2). The reaction 1# 2 is conveniently carried out in a solvent such as benzene, toluene, xylene and the like at a temperature of from about 25 C to reflux for from 2 to 10 hours. There is no criticality as to the precise identity of the solvent, provided only that it adequately solubilizes the reactants and be inert or substantially inert to the desired course of reaction. Ihe halogenation reaction 2-- > 3 may be conducted by any of a variety of well-known halogenation means. Suitable reagents include: SOC12, POC13, oxalyl chloride and the like. A preferred means of chlorination involves treating 2 in a solvent such as tetrahydrofuran (THF), ether, CH2C12 and the like with thionyichloride in the presence of 1 to 1 equivalents (relative to the thionylchloride) of a base such as pyridine, triethylamine, quinoline and the like. Typicylly, the reaction is conducted at a temperature of from -30 to 25 C for from 0.5 to 1 hour. The resulting l-(benzyloxycarbonylchloromethyl)-azetidinone species, 3, is isolated, if desired, by conventional procedures for later reaction 3-- 4. The intermediate 4 is prepared from 3 by treating 3 in a solvent such as-dimethylformemide (DMF), dimethylsulfoxide (DMSO), THF, dimethoxyethane (DME) and the like with 1 to 1.5 equivalents of a phosphine such as triphenylphosphine, tributylphosphine, triethylphosphine, tris-(2-cyanoethyl)phosphine or the like. Typically the reaction is conducted under a nitrogen atmosphere at a temperature of from -200 to 250C., for for from 0.5 to 2 hours. The reaction 4# may be achieved by any of a variety of well-known deblocking procedures such as hydrolysis or hydrogenolysis. A particularly convenient means for the deblocking #5, when R=acyl, is by an alcoholysis procedure comprising treating jLin a lower alkanol such as methanol, ethanol, or the like in the presence of 0.1 to 1.4 equivalents of the corresponding alkali metal alkoxide such as sodium methoxide or the like; typically the reaction is conducted at a temperature of from 0 to 2; C., for from 0.5 to 2 hours or is by an acid hydrolysis by treating 4 (R triorganosilyl) with HC1 in THF, DMF, or the like at 250C for 1 to 15 minutes. The ring closure reaction 5#7 proceeds via the oxo intermediate 6 and is achieved by treating 5 with an equivalent of an oxidizing system such as 1:1 mixture of dimethylsulfoxide (DMSO) and acetic anhydride (Ac2O); other oxidizing systems include cyclohexylcarbodiimide in DMSO, CrO3.2(pyridine) in CH2C12, and pyridinum chlorochromate in CH2C12 for example. Typically, the closure step 57 is conducted at a temperature of from about 0 to 100 C for from 0.25 to 24 hours in the oxidative system (DMSO/Ac2O) described above or by heating from 100-160 C (after isolation of the oxo compound 6) in a solvent such as benzene, toluene, dioxane, xylene, or DMF. The carboxyl deblocking step l-8 may be achieved by a number of well-known procedures such as hydrolysis, hydrogenation, or photolysis of a suitable R' group. Suitable hydrogenation catalysts for deblocking include the platinum metals and their oxides such as palladium on carbon and the like; suitable solvents for the hydrogenation include methanol, dioxane/H20, ethanol/H20 and the like in the presence of hydrogen at a es@@@e of @@@@m 1 to 50 atmospheres; the drogenation is typically conducted for from 5 min. to hours at a temperature of about 25 C in the optional presence of a mild base such as sodium bicarbonate or the like The carboxyl deblocking can also be achieved by photolysis of 7 in dioxane/H20, methanol/H2O or ethanol/H2O under u.v. radiation ( 2 - 350 mn) for 1 to 4 hr. at 250C. The glyoxylate esters la used to react with 1 can be prepared by oxidation of the corresponding tartaric acid esters with oxidants such as periodic acid or lead tetracetate in a solvent such as THF, benzene, or methylene chloride at 20 to 250 for 1/2 to 4 hours. The tartarate esters are prepared from dilithio tartarate or disodio tartarate by reaction with R'X wherein X is chloro, bromo or iodo and R3 is as defined above in a solvent such as DMF or DMSO at 25e to 700C. for from 4 to 48 hrs. As noted above, R' may be a pharmaceutically acceptable aster moiety. Such pharmaceutically acceptable esters and amides, however, may also be prepared from the free acid of I according to the procedure of co-pending U.S. Patent Application Serial Number 861,314 filed December 16, 1977, which is directed to the pharmaceutically acceptable ester and amides of thienamycin and their preparation. Accordingly, for its disclosure relative to such pharmaceutically acceptable forms and their means of preparation, the above-cited application is incorporated herein by reference. The following diagram summarizes the synthesis of substituted azetidinone material, 1. EMI19.1 In words relative to the above via for th preparation of 1, the 4-(l-methy-2-aeetoxyvinyl)azetidia 2-one (3') is prepared by reacting chlorosuiphonyl isocyanate and an acyloxybutadiene fl') suc as l-acetoxy2-methylbutadiene' in a solvent such as anhydrous diethyl ether at a temperature of from about -300C to 0 C under a nitrogen atmosphere. The reaction intermediate j is converted to 3' by hydrolysis. The reduction of 3' to provide the 4- (l-methyl-2-acetoxyethyl) -2-azetidinone (4') is conducted by any convenient means such as hydrogenation in the presence of a catalyst such as platinum, palladium or oxides thereof under a hydrogen pressure of from 1 to 20 atmospheres in a solvent such as ethanol, ethylacetate, or the like at a temperature of from 0 to 250C. for from 5 minutes to 1 hour. The 4-(2-hydroxyl-methyl-ethyl)-2-azetidinone species 5' is obtained from 4' by hydrolysis. The 8-oxo-2,2-dimethyl-5-methyl-3-oxa 1-azabicyclo[4#2#0]octane species 5 is obtained on treatment of 5' with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate in a solvent such as methylene chloride at a temperature of from 0 to 400C. for from 1 to 40 minutes. Alternatively, 5' can be treated with boron trifluoride etherate and trimethylorthoformate to give 8-oxo-2-methoxy-5-methyl-3 oxa-l-azabicyclo[4.2-0]octane which can be mono- or dialkylated following the procedures for 6'#7' or 8'. Alkylation of 6' provides 7'. Typically, $ is treated with a strong base such as lithium diisopropylamide, 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 80&commat;C to 0 C., whereupon the alkylating agent of choice, R1X is added (R1 is as described above and X is chloro or bromo; alternatively the alkylating agent may be R1tosylate, RÚ-mesylate or an aldehyde or ketone such as acetaldehyde and the like) to provide mono- alkylated species 7'. When desired dialkylated species 8' may be obtained from 7' by repeating the alkylating procedure, 6'#7'. Species 9' is obtained from 7' or 8' by acid hydrolysis. The desired blocked-species 1 is obtained by treating 9 with an silylating agent such as t-butyldimethylchlorosilane, trimethylchlorosilane and the like in a solvent such as DMF, CH2Cl2, THF or the like in the presence of a base such as imidazole or the like at 0 C to 250C for from 0.5 hr to 6 hr or with an acylating agent such as acetyl chloride, formic acetic anhydride, trifluoroacetic anhydride and the like in a solvent such as CH2C12, CHCl3, THF and the like at a temperature of from -20 to about 250C. for from 0.5 to about 4 hours. The starting material 1 may be isolated for later reaction in accordance with the procedures of the present invention for t preparation of the compounds of the present invention. It should be noted that in the establishment of R (-v9'l), he ring nitrogen may be protected by an easily removable blocking group. R": EMI21.1 wherein R" is acyl or triorganosilyl such as trimethylsilyl, t-butyldimethylsilyl, trifluoroacetyl, formyl, or the like. Removal of R" is accomplished by hydrolysis to provide 1 according to well-known procedures. Starting material 1 may alternatively be prepared by the following scheme: EMI22.1 wherein all symbolism is as previously, defined. Reaction 5'#5a' is accomplished by treating 2' with 2,3-dihydropyran in a solvent such as p-dioxane benzene, and the like in the presence of p-toluenesulfonic acid, perchioric acid, or the like at a temperature off from 0 to about 300C. The intermediate 5a' may be isolated for later alkylation to obtain 7a and 8a' by procedures analogous to previously described reactions 6'#7'#8'. Intermediate species 9' is obtrained from 7a' or 8a-' by mild acid hydrolysis. Finally, it should be noted that intermediate species 9a' may" conveniently be prepared for later reaction in the above scheme by internal acylation according to the following reaction: EMI23.1 O 1 9 wherein R is lower alkyl, acyl, or the like. Typically, the above reaction is conducted in a solvent such as tetrahydrofuran, ether, dLmethoxyethane, or the like in the presence of 1 to 2 equivalents of a strong base such as lithium diisopropylamide, sodium hydride, potassium hydride ot the like at a temperature of from -78 to 25'C., for from 0.5 to 24 hours. It will be recognized that the compounds of the present invention, structure I, above, exhibit stereoi-somerism. The nature of which depend upon the identity of ring substituents R6, R7 and R1. The total synthesis of I is capable of stereo-selectivity. Preferably-the paths leading the ultimate diastereoners of I diverge-at intermediate level 6', 7' or 8' (see above reaction diagram). Fractional crystallization or practically any chromatographic technique is suitable for resolving the diastereoisomers at the preferred intermediate level. Completion of the synthesis after such resolution provides, if desired, the diastereoisomers of I in substantially pure form. A representative example of such resolution is presented below in the Examples section. Preparation of the Substituted Acyloxy-butadiene, 1' EMI24.1 The substituted 1,3-butadiene reagent 1' is prepared according to known procedures, which may be EMI25.1 wherein R1 and R are as defined above. The &alpha;,ss-unsaturated aldehyde intermediates ± is prepared on condensation of A and t in the presence of a base such as NaOH, or the like at a temperature of from 0 to 1000C for from 10 min. to 2 hours. Condensation of C with the isopropenyl ester D in the presence of cupric acetate (1 to 10 mole percent relative to 2 and a strong acid such as p-toluene sulfonic acid, perchloric acid, sulfuric acid or the like (1 to 10 mole percent relative to C) provides . Typically the reaction is.conducted at 90 to 120 C fo from 1 to 8 hours. Repesentative examples illuetrating this preparation of 1' are given below. In tne generic dascri'ti.on of ;-he present invention (I, above; when R0=H), the substituents R6, R7 and RÚ are preferably selected from the group consisting of hydrogen; substituted and unsubstituted: straight and branched loweralkyl having from 1 te 10 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 10 carbon atoms; alkylcycloalkyl wherein the alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms; aryl such as phenyl and naphthyl; aralkyl such as benzyl, phenethyl and the like; heterocyclyl (saturated and unsaturated) comprising mono d bicyclic structures having from 5 to 10 ring atoms wherein one or more of the hetero atoms is selected from oxygen, nitrogen or sulphur, such as thiophene, imidazolyl, tetrazolyl, furyl and the like; heterocyclylalkyl which comprises the immediately preceding heterocyclyl moieties and the alkyl.moiety comprises from 1 to 10 carbon atoms; the substituent (or substituents) relative to the above-named radicals is selected from the group consisting of amino, hydroxyl, cyano, carboxyl, nitro, chloro, bromo, fluoro, lower alkoxy having from 1 to 6 carbon atoms, mercapto, perhaloloweralkyl such astrifluoromethyl, loweralkylthio, guanidino, amidino, sulfamoyl, and N-substituted: sulfamoyl, amidino and guanidino wherein the N-substituent is loweralkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms. A particularly preferred class of compounds are those wherein Rê is hydrogen, R is selected from the group consisting of substituted and unsubstituted: loweralkyl having from 1 to 6 carbon atoms, cyclopropyl, benzyl and phenyl; and R1 is an a-substituted alkyl wherein the a-substituent is hydroxyl, amino or mercapto and wherein the alkyl moiety is straight or branched and comprises 1 to 6 carbon atoms; the substituents relative to the above-named preferred radicals are selected from the group consisting of hydroxyl, bromo, fluoro, chloro, amino, amidino, guanidino, phenyl, mercapto, carboxyl, trifluoromethyl, loweralkylthio and loweralkoxyl wherein the alkyl moiety of the loweralkylthio and loweralkoxyl comprises 1 to 6 carbon atoms. The preferred esters used as protecting groups are those where R' is benzyl, p-nitrobenzyl, o-nitrobenzyl, t-butyl, bromo-t-butyl, t-butyl-dimethylsilyl, trimethylsilyl, trichloroethyl; or R' represents pharmaceutically acceptable ester moieties such as pivaloyloxymethyl, allyl, methallyl, (2-methylthio)-ethyl, 3-meOhyl-2- butenyl, p-t-butylbenzyl, 5-indanyl, 3-phthalidyl. The compounds made available by the present invention are valuable antibiotics active against various gram-positive and gram-negative bacteria and, accordingly, find utility in human and veterinary medicine. Such sensitive bacteria representatively include: Staphylococcus aureus, Escherichia coli, Klebsiella pneumuaniae, Serratia, Salmonella typhosa, Pseudomonas and Bacterium proteus. The resulting compounds may further be utilized as additives to animal feed, for preserving foodstuffs, and as disinfectants. 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 and 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. These antibiotics may be used alone or in combination as an active ingredient in an one of a variety of pharmaceutical preparations. These antibiotics and their corresponding salts may be employed in capsule form or as tablets, powders or liquid-solutions or as suspensions or elixirs. They may be administered orally, intravenously or intramuscularly. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica; disintegrants, for example, potato starch or 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 suspension, solution, emulsions, or syrups; or may be presented as a dry product, for reconstitution with water or other suitable vehicles before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible oils, for example almond oil, fractionated coconut oil, oily esters, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl hydroxybenzoates or sorbic acid. Compositions for injection may be presented in unit dose form in ampules, or in multidose container. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water1 before use. The compositions may also z e prepard in suitable forms for absorption through the mucous membranes of the nose and throat or bronchial tissues and may conveniently take the ;orm of powder or liquid sprays or inhalants, lozenges, throat paints, etc. For medication of the eyes or ears, the preparations may be presented as individual capsules, in liquid or semi-solid form, or may be used as drops etc. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, or lotions. Also, in addition to a carrier, the instant compositions may include other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricators, suspending agents, viscosity agents or flavoring agents and the like. In addition, there may also be included in the compositions other active ingredients to provide a broader spectrum of antibiotic activity. For veterinary medicine the composition may, for example, be formulated as an intramammary preparation in either long or quick-release bases. The dosage to be administered depends to a large extent upon the general health and weight of the subject being treated, and the route and frequency of administration -- the parenteral route being preferred for generalized infections and the oral route for intestinal infections. In general, a daily oral dosage consists of from about 2 to about 600 mg. of active ingredient per kg. of body weight of the subject in one or more applications per day. in the range of from about 15 to 150 mg. of active ingredient per Ar, of body weight. The instant compositions may be administered in several unit dosage forms as, for example, in solid or liquid orally ingestible dosage form. The compositions per unit dosage, whether liquid or solid may contain from 0.1% to 99% of active material, , the preferred range being from about 10-60%. The composition will generally contain from about 1 rng. to about 1500 mg. of the active ingredient; however, in general, it is preferably 'o employ a dosage amount in the ranqe of from about 100 mg. to 1000 mg. In parenteral administration the unit dosage is usually the pure compound in a slightly acidified sterile water solution or in the form of a soluble powder intended for solution. specially preferred pharmaceutically acceptable salts and esters involving the carboxyl group of compounds of the present invention (I) are disclosed and claimed in co-pendinq U.S. Patent Application Serial Number 861,314 (filed 12-16-77) which application is directed, inter alia, to pharmaceutically acceptable salts and esters of the carboxyl group of thienamycin. It is precisely these salts and esters which are preferred in the present invention and they are prepared in a manner analogous to that disclosed in U.S. Patent Application Serial slumber 861,314, which is incorporated herein by reference. Thus, especially preferred salts include sodium, potassium, ammonium, and the like; and especially preferred esters include pivaloxymethyl, p-t-butylbenzyl, 5-indanyl, 3-phthalidyl, 3-methyl-2-butenyl, and the like. One should note that when, in the total synthesis outlined above, R2 is a pharmaceutically acceptable ester moiety, there is no need for the final deblocking step if it is desired to have the final product I in the form of a pharmaceutically acceptable ester. Especially preferred embodiments @ the present invention are those, as defined above, excel that any unsubstituted amino group borne on radical R8 of Structure I is derivatized according to the teachings of Belgium Patent 848,545 (issued 5-20-77); the resulting amino group being represented thusly (partial structure): EMI32.1 wherein X and Y are defined by the publication; species wherein X is H or lower alkyl and Y is tE2 are especially preferred. The following examples, illustrate but do not limit the product, process,. compositional or method of treatment aspects of the present invention. All reaction temperatures are in C. EXAMPLE 1 EMI33.1 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 (R3- 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 addled dropwise 1 eq. of 1N NaON 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 crude product. The desired product ( is obtained by fractional distillation through a Widmer column. Isopropenyl acetate (2 eq), cupric acetate (0.002 eq) p-toluenesulfonic acid (0.008 eq.) and the a,-unsaturated aldehyde5D(1 eq.) are placed in a three-necked round-bottom flask equipped with a thermometer, a nitrogen inlet tube and a Widmer column which is attached with a distillation head. The mixture is heated at 93-11O0C until quantitative acetone is collected. The mixture is then allowed to cool to r.t. and filtered from solids. The dark brown filtrate is mixed with triethanolamine in water at OOC. The two layer mixture is distilled quickly under reduced pressure. The organic layer of the distillate is separated. The aqueous layers extracted with 200 ml ether. The combined organic layer is washed with 10% K2C03, dried over Na2SO4, and evaporated in vacuo. The residue so obtained is mixed with 2.0 g N-phenyl-ss-naphthamine and distilled under reduced pressure to give the desired 2-substitued 1-acetoxy-1,3-butadiene (1'). Following the procedure of Example 1, the following R3 substituted species are obtained. (Table I). EMI34.1 TABLE TABLE I ¯ ¯ ¯¯¯¯¯¯¯¯¯¯¯¯ EMI34.2 <tb> <SEP> n3 <SEP> R <tb> 1. <SEP> CH3 <SEP> CH33 <tb> 2. <SEP> CH <SEP> 3CH2 <SEP> CH38 <tb> 3. <SEP> CH3CH2CH2 <SEP> CH3 <tb> 4. <SEP> CH3 <SEP> CH38 <tb> <SEP> 3\ <tb> <SEP> CH <tb> <SEP> 3 <tb> S <SEP> ' <SEP> 9 <tb> <SEP> 2 <SEP> - <SEP> 'P <SEP> CH3C <tb> 6. <SEP> Ph <SEP> (Ph=phenyl) <SEP> ;. <SEP> t <SEP> CH <tb> 3 <tb> <SEP> and <tb> 7. <SEP> PhCH2 <SEP> . <SEP> CH3 <tb> EXAMPLE 2 Preparation of 6-(1-hydroxyethyl)-1-methyl-2-(2-amino-1 methylethylthion)carbadethiapen-2em-3-carboxylic acid Step A EMI35.1 Preparation c-l' EMI35.2 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. (250C) 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 C). 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-B-naphthamine and distilled under reduced pressure to give 2(97 g), b.p. 81-91 (66mm). Step 3 Preparation of 2' and 3' EMI36.1 @ Chlorosulfonylisocyanate (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-equalized 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-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 lOg 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 hydrolysis 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. 77-78,5 ; m.s. l69(+); IR 1760 cm ( ss-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 C Preparation of 4': EMI37.1 4-(1-methyl-2-acetoxyvinyl)azetidine2-one (3') (6.5 g) is hydrogenated on a Parr shaker at r.t. under 40 psi hydrogen in the presence of 10% Pc/C (0.6 g) in 200 ml athylacetate 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 chromatograph (HPLC) (silical gel column, 30% ethylacetate/CH2C12 solvent system) affords a white crystalline product $ (6.04g) after evaporation of solvent. The product shows following physical characteristics: ms 171 (M+); IR(Neat) 1754 cm 1 NMR (60 MHz, CDCl3): 0.96 (d), 1.01 (d), 2.06 (d, OAc), 2.75-3.80- (m), 3.99 (d)and 6.80 (broad) ppm. STEP D Preparation of 5' EMI38.1 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 gla@al acetic acid (65 mg). Removal of methonol "¯ vacuo gives crude 4-(1-methyl-2-hydroxyethyl)-2- azetidinone (5') as an oil. The product is purified chromatography on silica gel eluting with ethyl acetate a to give 0.78g of 5': IR (neat) : 1740 cm NMR (CDCl3): 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 colorless solids in the refrigerator. STEP E Preparation of EMI39.1 A solution of 4-(1-methyl-2-hydroxyethyl)- 2-azetidinone (0.5 g) and 2,2-dimethoxypropane (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 S ml saturated NaHC03. The organic layer is separated, dried over Na2SO4 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 6'8 is accomplished by high pressure liquid chromatograph (HPLC) (silica gel) eluting with 40% ethylacetate/hexanes. After evaporation of the solvents affords 150 mg of 6'ss as an oil and 200 mg of 6'&alpha; as a white solid. NMR (300 MHz,CDCl3) of 6'&alpha;: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 Ft Preparation of 7'&alpha; EMI40.1 At -780C, diisopropylamine (2.2 g) in 20 ml of anhydrous tetrahydrofuran is treated with n-butyllithium (1.6N in n-hexane, 14 ml) for 5 min. To the solution is added 8-oxo-5a, 2,2-trimethyl-1-3-oxa azabicyclo(4.2.O3octane (6'&alpha;) (3.4 g) and the mixture is stirred for 10 min. The resulting lithium 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 (25 C). The mixture is extracted with ethylacetate (2 x 100 rnl). 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'&alpha; is purified and separated by HPLC (silica gel) eluting with 50% ethylacetate/methylene chloride to give 3.5 g of trans-7'&alpha; and 0.5 g of cis-7'&alpha;. Both isomers.are crystalline solids. STEP Fb Preparation of 7'ss EMI41.1 Following the procedure of Step Fa, 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 Fc Preparation of 7"ss EMI42.1 Under anhydrous conditions at 0 C a solution of R enriched trans-7'ss (2.90 g) in 60 ml methylene chloride is treated 4-dimethylaminopyridine (3.32 g) 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 Hcl, 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 dissolved in 20 ml ether and chilled at -5 C give the o-nitrobenzyl alcohol (0.5 g) which is separated by filtration. The isomeric mixture trans-7"ss is purified and separated by HPLC (silica gel) eluting with 40% ethylacetate/cyclohexane to give 1.2 g of S-trans-7"B and 1.0 g of R-trans-7"ss. The' spectra data of.R-trans-7 : 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": NMR (300 MHZ, CDC13): 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 Fd Preparation of EMI43.1 Following the procedure of Step Fc; except replacing the starting material trans-7'8 ss with trans-7'a isomer, the products R-trans-7"a and S-trans-7"&alpha; are obtained. STEP Ga Preparation of R-trans-91: EMI44.1 ss-Cxo-3-oxa-5ss-2,2-trimathyl-7&alpha;- (lR-o-nitrobenzylcarbonyldioxyethyl)-l-azabicyclo [4.2.0]octane (R-trans-7 ) (2.1 g) is dissolved in 4 ml trifluoroacetic acid and 4 ml water at room temperature and the mixture is stirred for 10 minutes. The resulting homogeneous solution is slowly poured into a vigorously stirred saturated solution of potassium bicarbonate (30 ml) in a 200-ml beaker. The mixture is extracted with methylene chloride (200 ml). The organic layer is separated, dried over Na2SO4 and allowed to evaporate in vacuo to give crude product 25 which is purified by a silica gel column eluting with 40% ethylacetate/cycylhexane to afford product R-trans-9'ss as an oil. NMR (300 MHz, CDC13): 0.98 (d), 1.28 (d), 2.85 (m), 3.20 (q), 3.62 (m), 5.12 (m), 5.57 (q), 6.40 (s), 7.53 (t), 7.66 (m) and 8.14 (d). STEPS H-K Steps H, I, J and K complement Steps E, Fa-d, and G for the preparation of 3-(l-p(and o)nitrobenzylcarbonyldioxyethyl)-4-(1-methyl-2 hydroxyethyl)azetidinone EMI45.1 STEP H Preparation of 1-(2-Tetrahydropyranyl)-4-[1-methyl-2(2tetrahydropyranyl)oxethyl]-2-azetidinone EMI46.1 Under nitrogen and at 250C, a solution of 4 (1-methyl-2-hydroxyethyl)-2-azetidione (62 mg), in 0.5 ml of anhydrous p-dioxane is treated with 2,3-dihydropyran (.98 ml) and p-toluenesulfonic acid monohydrate (19 mg). The resulting solution is stirred for a period of 60 minutes and then partitioned between 10 ml of ,5M pH 7 phosphate buffer and 10 ml of ethyl acetate. The aqueous phase is extracted a second time with ethyl acetate. The combined ethyl acetate solutions are washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give 216 mg of crude product. Purification by preparative thick-layer chromatography developing with ethyl acetate,gives 80 mg of 1- (2-tetrahydropyranyl) -4- (l-methyl-2- (2-tetrahydrop- yranyl)-oxyethyl]-2-azetidinone as an oil. STEP I Preparation of Cis and Trans-l-(2-tetrahydropyranyl)-3- (1-hydroxyethyl)-4-[1-methyl-2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone EMI47.1 Following the procedure described for the preparation of 8-oxo-2 , 2,5-trimethyl-7a andg-(l-hydroxyethyl)-3-oxa-l- azabicyclo[4.2.0]octane from 8-oxo-2,2,5-trimethyl-3-oxa1-azabicyclo[4.2.0]octane and using 1-( 2-tetrahydropyranyl) - 4-[1-methyl-2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone one obtains a diastereomeric mixture of both cis and trans -1-(2-tetrahydropyranyl)-3-(1-hydroxyethyl)-4-[1-methyl- 2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone. STEP J Preparation of Cis and Trans-l-(2-tetrahydropyranyl)-3- (1-p-nitrobenzylcarbonyldioxyethyl)-4-[1-methyl-2 (2-tetrahydropyranyl)oxyethyl)-2-azetidinone EMI48.1 Following the procedure described for the preparation of 8-oXo-2,2,5-trimethyl-7a-(1-p-nitrobenzylcarbonyldioxyethyl)- 3-oxa-1-azabicyclo[4.2.0]octane from 8-oxo-2,2,5-trimethyl 7&alpha;-(1-hydroxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane and using trans-l-(2-tetrahydropyranyl)-3-(1-hydroxyethyl)- 4-[1-methyl-2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone there is obtained trans-l-(2-tetrahydropyranyl)-3-(1-p- nitrobenzylcarbonyldioxyethyl)-4-[1-methyl-2-(2tetrahydropyranyl)oxyethyl]-2-azetidinone. The cis diastereoisomers axe obtained in an analogous manner. STEP K Preparation of Cis and trans-3-(1-p-nitrobezylcarbonyldioxyethyl)-4-(1-methyl-2-hydroxyethyl)-2-azetidinone EMI49.1 A solution of trans-1-(2-tetrahydropyranyl)-3-(1-p- nitrobenzylcarbonyldioxyethyl)-4[1-methyl-2-(2 tetrahydropyranyl) oxyethyl] -2-azetidinone in methanol at 250C is treated with .1 molar equivalent of toluene- sulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1M pH 7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give trans-3-(lp-nitrobenzylcarbonyldioxyethyl)-4-(1-methyl-2 hydroxyethyl) -2-azetidinone. The cis diastereoisomers are obtained in an analogous manner. STEP L Preparation of I2 EMI50.1 To 6.75 ml anhydrous pyridine (83.9 mmole) in 350 ml anhydrous acetonitrile is added 4.05 g anhydrous powedered chromium trioxide (mw = 100; 40.5 mmole) After stirring at room temperature (25"C) for 30 minutes, 9.6g dried Supercell is added and stirring is continued for 5 additional minutes. -A solution of 3.21 g trans-3-(l p-nitrobenzylcarbonyldioxyethyl) -4- (l-methyl-2-hydroxy- ethyl)-2-azetidinone in 30 ml anhydrous acetonitrile is added all at once. The reaction mixture is stirred under anhydrous conditions at room temperature (25 C) for one hour. Addition of 9.6g NaHSO3 is followed by 5 minutes of stirring after which the reaction mixture is filtered through a mixed packed bed of 40g silica gel and 40 g anhydrous magnesium sulfate. The bed is washed repeatedly with acetonitrile (total volume of filtrate 600 ml). tie filtran- . concetrated under a N2 stream to 130 ml total volume. To this solution containing crude aldehyde at 0 C under N2 is added 9.64g l-(p-nitrobenzyloxycarbonylamino)-2-propanethiol as prepared below (Step M). To the stirred reaction mixture is mixture is aided 8.0 ml boron trifluoride etherate (63.4 mmole). After 1.5 hours at 0 C the reaction mixture is poured into a stirred ice-cold mixture of 69 g K2HPO4 - 500 ml H2O and 700 ml ethyl acetate (EA). The layers are separated, and the aqueous one is saturated with NaCl and re-extracted with additional EA. The combined organic layers are washed twice with brine, dried over anhydrous MgSO4 and filtered. The filtrate is concentrated under a N2 stream and then pumped on high vacuum to give crude 12. The material is chromatographed on 450 g silica gel (column height = 48 cm; diameter = 5.5 cm) packed and applied in CHCl3 and eluted with increasing percentages of MeOH in CHCl3 (0-4% MeOH/CHC13). Those fractions containing the desired product are combined, concentrated under a N2 stream; and pumped on high vacuum to give 12. STEP M Prepration of 1-(p-Nitrobenzyloxycarbonylamino)-2propanethiol EMI52.1 To 600 ml diethyl ether (Et2O) - 75 ml H2O in an ice bath with stirring is added 3.2g l-amino-2-propanethiol hydrochloride (2G.lmmole). A solution of 7.14 g NaHCO3 (35 mmole) in 75 ml H2O is added. The ice bath is removed, and at room temperature a solution of 6.75g p-nitrobenzylchloroformate (31.3 mmole) in 270 ml Et2O is added dropwise over a period of one hour. After 10 additional minutes. the layers are separated. The ether layer is extracted with 150 ml 0.25 HC1, and then with 200 ml brine. Each aqueous layer is then backwashed successively with 100 ml Et2O. The combined ET2O layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream. The crystalline residue is slurried in a small amount of ether, filtered, and the pale yellow crystals are dried under high vacuum to give 4.7 g product. STEP N Prepration of 14 EMI53.1 To 14.2 ml pentane (dried over qA we Dole cular sieves) is added 0.5 ml Br2. To 5g of 12 in 58 ml tetrahydrofuran (THF) (freshly dried from lithium aluminum hydride (LAH) and 65 ml Et2O (dried over 3A 1/16 Linde molecular sieves) at 0 C under N2 with stirring is added dropwise 10 ml of the above 0.66M B2 solution. After 10 minutes at 0 C, 0.67 ml cyclohexene is added. After 5 minutes at 0 C., 1.7 ml triethylamine is added immediately 'followed by 40 ml ice-cold dimethylformamide (DMF) (distilled from anhydrous CaSO4 at 40 mm and stored over 4A Linde molecular sieves). The ice bath is removed, and stirring is continued for 2 1/4 hours at room temperature. The reaction mixture is poured into a stirred ice-cold mixture of 12.6 ml lMKH2P04 160 ml H20 500 ml (EA). After separation of the layers, the aqueous one is saturated with sodium chloride and re-extracted with EA. The combined organic layers are extracted once with brine, dried over anhydrous MgSO4, filtered and concentrated under a N2 stream followed by pumping under high vacuum to provide crude 14. The material is chromatographed on 250 g silica gel (height = 45 cm; diameter = 4.5 cm) packed and applied in CHCl3 and eluted with increasing percentages of MeOH in CHCl3 (0-3% MeOH/CHCl3). Those fractions containig clean product are combined, concetrated under a N2 strem, and pumped on high vacuum to give STEP O Preparation of 5 EMI55.1 To a stirred solution of 2.48 g di(p-nitrobenzyl)ketomalonate (Step P ) in 400 ml hot anhydrous toluene is added a solution of 2.52 g of 14 in 20 ml THF (distilled from LAH) and 40 ml anhydrous toluene. After some of the solvent is boiled off, additional anhydrous toluene is added, and the azeodrying process is repeated three times. The solution is then refluxed under N2 for 30 minutes. Additional tolune is then allowed to boil off yet the volume is not allowed to diminish so much that precipitation occurs. Total heating time is approximately 2 1/2 hours. The clear yellow reaction mixture is removed from the oil bath and placed under a stream of N2. After concentration to a oil, the residue is dissolved in CH2C12, dried over anhydrous MgS04, filtered, and concentrated under a N2 stream to give crude 15. The material is chromatographed on 250 g silica gel packed and applied in CHCl3 (height = 43 cm; diameter - 4.5 cm). Elution with 500 ml 0.5% MeOH/CHC13 is followed by continued elution with 1% MeOH/CHC13 for the remainder of the chromatography. After the emergence of excess reagent, those fractions containing pure are combined, concentrated under a N2 stream and then on high vacuum to give 15. STEP P Preparation of di-p-Nitrobenzyl Ketomalonat EMI56.1 A mixture of 100 g p-nitrobenzyl bromide (0.46 mole), 28.6 g malonic acid (0.275 mole) and 750 ml ethanol (EtOH) is stirred and warmed on the steam bath until solution is achieved. A solution of 33g KOR in 200 ml of water is added carefully with swirling. An additional 200 ml of water is added, and the two-phase system is refluxed for 1.8 hours. The lighter color homogeneous solution is cooled in ice for 1 hour and the crude product isolated by filtration, washed twice with a minimum of cold EtOH, and dried by pulling dry N2 through the cake; 33.7 g of solid is obtained. If, curing the refluxing stage the reaction mixture is slowly concentrated to ca. half volume by allowing ref fluxing solvent to distill off; the crude proudct yield rises to 77g. The material is recrystallized from methanol to give pure di-p-nitrobenzyl malonate. A mixture of 23.4 of di-p-nitrobenzyl malonate lOg SeO2, and 30-40 ml of xylene is stirred in a flask immersed in an oil bath The bath temperature is raised over 1 hour to 130-1350. A gradual darkening of the reaction mixture is noted, and after a total of 4 hours at 130-1350, most of the insoluble residue is black Se . The mixture is cooled, MqS04 is added to remove the water, and Celite is added to aid in filtration. The mixture is filtered through Celite and the cake washed with xylene and a small portion of EtOAc. Final volume: 60 ml. A 100 g column of Baker silica gel iS prepared in benzene and 10 ml of filtrateapplied, tht eluted with increasing amount of EtOAc in benzene, 503 ml fractions being collected. After one 2% ethyl acetate (EtOAc)/H, and two 10% EtOAc/H fractions, the third 1^% and first 20% EtOAc/H provide the bulk of the product (l.6g from 10 ml filtrate) and judged by tlc (208 EtOAc/CHC13; silica gel GF). Recrystallization from benzene, (lg in ca. 50 ml concentrated to 1/3 volume and "spiked" with 1 ml of H2O saturated benzene): provides di-p-nitrobenzyl ketomalonate. STEP 0 Preparation of 17: EMI58.1 A solution of 1.468g of 15 in CH2C12 is dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream, and dried further under high vacuum just prior to the following reaction To a solution of 15 in 24 ml THF (freshly distilled from LAH) at -200C is added 0.206 ml anhydrous pyridine. With stirring under N2, 294 mg of freshly distilled thionyl chloride in 5 ml THF is added dropwise. The reaction mixture is stirred for 10 minutes at -200C., then 1/2 hour at 0 C and finally 1 hour at 250C. The pyridine hydrochloride is filtered under N2 and washed with 20 ml THF. The filtrate is concentrated under N2 stream followed by,pumping on high vacuum. To this freshly prepared chloro compound is added with stirring a freshly shaken suspension of 678 mg tributylphosphine in 36.5 ml 9:1 DMF - H20 followed by 294 mg K2HPO4. The reaction mixture is stirred at 250C., for 35 minutes. After dilution with 120 ml EA and 60 ml brine, the layers are separated, and the aqueous one is extracted two times with EA. The combined organic layers are washed one time with brine, dried over anhydrous MgSO4, filtered and concentrated under a N2 stream followed by pumping on high vacuum to give crude The material is chromatographed on 100 g silica gel (height = 28.5 cm; d= 4 cm) packed and applied in CHCl3 and eluted with 0.5% MeOH in CHCl3. Those fractions containing clean product are combined, concetrated under a N2 stra@ then on high vacuum to give 17. (EA s ethyl acetate. STEP R Preparation of 19: EMI59.1 To 8.5 ml pentane (dried over 4A Linde molecuar sieves) is added 0.2 ml Br2. To 0.706 g of 17 in 18 ml THF (freshly distilled from LAH) and 5.7 ml Et20 (dried over 3A 1/16" Linde molecular sieves) at 0 C under N2 with stirring is added dropwise 1.8 ml of the above 0.45M Br2 solution (0.81 mmole) to give dibromide 18. After 15 minutes at 0 C., 0.42 ml triethylamine is added immediately followed by 10.5 ml ice-cold DMF (distilled from CaSO4 at 40 mm and stored over 4A Linde molecular sieves). The ice-bath is removed, and stirring at room temperature is continued for 2 hours. The reaction mixture is poured into a stirred, ice-cold mixture of 2.1 ml 1M KH2PO4 70 ml H20 - 100 ml EA. The layers are separated, and the aqueous one is saturated with NaCl and re-extracted with EA. The combined organic layers are washed once with brine, dried over anhydrous MgSO4, and filtered. The filtrate is concentrated under a N2 stream and then pumped on high vacuum to give crude 19. The material is chromatographed on 60 g silica gel (diameter = 2.8 cm) packed and applied in CHCl3 and is eluted with 100 ml - 2% EA/CHCl3; 100 ml - 4% EA/CHC13 and then 5% EA/CHC13 for the remainder of the chromatography. The fractions containiag pure 19 are combined, concentrated under a N2 stream, and pumped on high vacuum to give 19. STEP S Preparation of EMI61.1 To Zi mg anhydrous silver fluoride is added a solution of 146 mg of 19 in 3.5 ml anhydrous pyridine. The stoppered reaction mixture is stirred at room temperature in the dark for one hour and then poured into 20 ml cold water - 30 ml EA. After separation of the layers, the aqueous one is extracted two times with EA and one time with CHC13. Each organic layer is extracted one time with H2O and one time with brine. The combined organic layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream followed by pumping on high vacuum to give crude 20. 'V Preparative thin layer chromatography (eluant = 408 acetone/hexane; repeated extraction of desired u.v. band with a large volume of CHC13) yields slightly contaminated 20. Re-chromatographing on silica using EA in CHCl3 as an eluting system gives pure STEP T Preparation of 21: EMI63.1 A solution of 77 mg of 20 in 0.9 ml S-collidine (distilled from powdered KOH) is added to 13.4 mg anhydrous LiI (dried for few hours at 1000C over P205 under vacuum). With stirring under N2, the reaction mixture is heated in an oil bath at 120 C. After a total of 30 minutes, the reaction mixture is cooled to 250C., diluted with CH2C12, and transferred to a round bottom flask for concentration under a N2 stream and then on high vacuum. Partitioning the residue between EA-H2O and 1 ml 1M KH2PO4 is followed by extraction of the aqueous layer two additional times with EA and one time with CHC13. Each organic layer is then backwashed with brine. The combined organic layers are dried over anhydrous MgS04 filtered, concentrated under a N2 stream and then on high vacuum to give crude 21. Preparative thin layer chromatography on silica gel yields 21. STEP U Preparation of EMI64.1 To 49 mg of 21 in 0.7 ml DMSO (distilled from CaH2 at 8 mm and stored over 4A Linde molecular sieves) is added 100p1 diisopropylamine (distilled from NaH under N2 and stored over 4A Linde molecular sieves). The stoppered reaction mixture is stirred for a few minutes and tehn allowed to stand for 2 hours. The amine and most of the DMSO are then concentrated off under high vacuum with no external heating. The residue is passed quickly through a column of silica gel (packed, applied and eluted with EA) to remove residual DMSO. After concentration under a N2 stream of all fractions having u.v. absorbance, the material is chromatographed on a thin layer silica gel plate (eluant = 50% EA/CHC13; repeated extraction of desired u.v. bands with a large volume of chloroform) to give 22. STEP V Preparation of I: EMI65.1 To 5.2 mg 22 is added 0.60 ml dioxane, 0.05 ml ethanol, 0.35 ml deionized water and 0.01 ml of l.OM K2HP04. To the resultant clear solution is added 5 mg of 10% Pd/C. The suspension is flushed with N2, then 5-6 times alternately with 50 psi H2 atmosphere for 30-40 minutes. After centrifugation, the Pd/C is washed and centrifuged 2-3X with 0.5 ml portions of deionized water. The combined centrifugates are extracted 5x1 - 2 ml ether. Residual ether is removed under vacuum 'and the aqueous solution is chromatographed on an XAD-2 column (20 x 140 mm) which is eluted with water to give the desired product I. EXAMPLE 3 Preparation of Bis-(p-Nitrobenyloxycarbonylamino-2propyl)disulfide EMI66.1 Under nitrogen at -200C, bromide (1.21 ml, .022 mmole) is added to a solution of p-nitrobenzyloxycarbonylamino2-propanethiol (11.28g), in 100 ml of anhydrous tetrahydrofuran. The cooling bath is removed, and the cold solution is stirred for 15 minutes. The solution is then diluted with 400 ml ethyl acetate and washed with 200 ml 1M pH 7 phosphate buffer, 200 ml 1M dibasic potassium phosphate, water (2 x 200 ml, 100 ml) and 200 ml brine. It is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo giving a yellow solid residue. This material is chromatographed on silica gel eluting with 5% ethyl acetate/chloroform to give crystalline product. EXAMPLE 4 Following the procedure of Example 2, Steps A - Ga, the following substituted azetidinones 10 are obtained when an equivalent amount of the appropriately substituted butadiene reagent is substituted for the l-acetoxyl-2-methyl-l,3-butadiene of Example 2, Step A. The following chart gives the final azetidinone product, the necessary reagents and any pertinent rsmarks. EMI67.1 EMI67.2 <tb> <SEP> 10 <tb> Com- <SEP> 1 <SEP> Butadiene <SEP> used <SEP> in <tb> pound <SEP> R <SEP> R <SEP> Example <SEP> 2, <SEP> Step <SEP> A <tb> 1.) <SEP> COOCH2 <SEP> < <SEP> NO2 <SEP> CH3CH2- <SEP> 9 <SEP> OAc <tb> <SEP> C25 <tb> <SEP> 2.) <SEP> COUCH2 <SEP> < <SEP> No2 <SEP> CH3CH2CH2 <SEP> 3H7 <tb> <SEP> C3H7 <tb> 3.) <SEP> COOCH2 <SEP> 9 <SEP> NO2 <SEP> 3 <SEP> \ <SEP> cr%c <tb> <SEP> CH3 <tb> <SEP> 4') <SEP> COOCH2 <SEP> < <SEP> NO2 <SEP> > <tb> <SEP> 5.) <SEP> COOCH2 <SEP> z <SEP> No2 <SEP> Ph- <SEP> OAc <tb> <SEP> Ph <tb> <SEP> zoc,., <SEP> (0 <SEP> PhCH2 <SEP> < <SEP> ?hCH2 <tb> <SEP> CH2Ph <tb> EXAMPLE 5 Following the procedure of Example 2, Steps L - V, the following species of the present invention are obtained when the azetidinones 10 of Example 4 are substituted in equivalent amounts, respectively for the azetidinone of Example 2, Step A. The products of this Example are presented in tabular fashion below: EMI68.1 EMI68.2 <tb> Compound <SEP> R1 <tb> 1.) <SEP> CH3CH2 <tb> 2.) <SEP> CH3CH2CH2 <tb> <SEP> CH <tb> 3.) <SEP> CH3N <tb> <SEP> CH <tb> <SEP> CH3 <tb> 4.) <tb> 5.) <SEP> the <tb> 6.) <tb> EXAMPLE 6 Preparation of 8-oxo-2,2,5,7-tetramethyl-3-oxa- l-azabicyclo[4,2.0]octane EMI69.1 THF, (20 ml) is placed under N2 treated with 1.54 ml diisopropylamine and cooled to -780C. A solution of n-butyl lithium 1.97M in hexane 5.6 ml is added dropwise over 5 min. The reaction mixture is stirred at -780C for 10 min and then treated with 8-oxo-2,2,5-trimethyl 3-oxa-l-azabicyclo[4.2.cijoctane (1.55 g) in 15 ml THF added dropwise over 5 min. After another 10 min hexamethylphosphoramide 1.97 ml is added. The mixture is stirred another 10 min, then treated with 2 ml of methyl iodide. The reaction mixture is stirred at -78 for 15 min and allowed to warm to 250C and stirred for 15 min. The reaction mixture is diluted with EtOAc, washed once with pH 7 phosphate buffer and dried and evaporated. The residue is chromatographed on silica gel using 25% EtOAc/C6H6 as eluant to give 8-oxo-2 ,2,5 ,7-tetramethyl-3-oxa-l-azabicyclo [4.2.0] octane. EXAMPLE a Preparation of 8-oxo-2,2,5,7-tetramethyl-7-(hydroxy- methyl) -3-oxa-l-azabicyclo (4 2 0] octane EMI70.1 To a solution of 1.1 equivalents of freshly prepared lithium diisopropylamide in anhydrous tetrahydrofuran under a nitrogen atmosphere at -78 is added a solution of 8-oxo-2,2,5,7-tetramethyl-3-oxa-1-azabicycla- [4.2.O]octane in anhydrous tetrahydrofuran which has been cooled to -780C. After two minutes, the resulting lihtium enolate is treated with excess formaldehyde, introduced as a gas just above the surface of the stirred solution. The solution is stirred for 30 minutes at -780,and then poured into water. The aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The combined ethyl acetate solutions are dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give the crude product. Purification by chromatography on silica gel using ethyl acetate/benzene gives 8-oxo-2,2,5,7tetramethyl-7-(hydroxymethyl)-3-oxa-1-azabicyclo[4.2.0]octane. EXAMPLE 8 Preparation of 8-Oxo-2,2,5,7-tetramethyl-7-(p nitrobenzylcarbonyldioxymethyl) -3-oxa-l-azabicyclo- [4.2-0]octane EMI71.1 Under anhydrous conditions at OOC. a solution of 8-oXo-2,2,5,7-tetramethyl-7-(hydroxymethyl)-3-oxa-1- azabicyclo[4.2.0]octane (60 mg) in 0.6 ml ether is treated with powdered potassium hydroxide (19 mg). After a period of 15 minutes, pnitrobenzyl chloroformate (65 mg) is added to the reaction mixture. Stirring is continued at 250C for an additional 15 hours. The mixture is partitioned between 1M pH 7 phosphate buffer and more ether. The ehter phase is washed with water and brine, dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives 67 mg of a colorless oil. Purification by preparative thick-layer chromatography on silica gel-developing with 1:9 ethyl acetate/benzene gives ss-oxo-2,2,5,7- tetramethyl-7-(p-nitrobenzylcarbonyldioxymethyl)-3 oxa-l-azabicyclo[4 2.0]octane as a mixture of diastereomers. EXAMPLE 9 Preparation of 3-methyl-3-(p-nitrobenzylcarbonyldioxymethyl)-4-(1-methyl-2-hydroxyethyl)-2-azetidinone EMI72.1 8-Oxo-3-oxa-2-2-5-7-tetramethyl-7-(1-p-nitrobenzyl carbonyldioxymethyl)-l-azabicyclo[4.2.0]octane (I'. 0 g) is dissolved in 8 ml trifluoroacetic acid and 8 ml water and heated at 250C for 15 min. The reaction mixture is neutralized with KHC03, and then extracted with EtOAc. The organic layer is separated, dried over MgSO4 and evaporated in vacuo. The residue is taken up in benzene and evaporated to give 3-methyl-3 (p-nitrobenzylcarbonyldioxymethyl)-4-(1-methyl-2hydroxyethyl)-2-azetidinone as a mixture of diastereoisomers. EXAMPLES 10-13 Examples 10, 11, 12, and 13 complement Examples 6, 7 8 and 9 for the preparation of 3-methyl-3-(p-nitrobenzyl- carbonyldioxymethyl)-4-(1-methyl-2-hydroxyethyl)-2- azetidinone EMI73.1 EXAMPLE 10 Preparation of 1-(2-Tetrahydropyranyl)-3-methyl-4-[-methyl2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone EMI73.2 Under nitrogen and at 250C, a solution of 3-methyl 4- (l-methyl-2-hydroxyethyl) -2-azetidinone (62 mg) in 0.5ml of anhydrous p-dioxane is treated with 2,3dihydropyran (.98 ml) and p-toluenesulfonic acid monohydrate (19 mg). The resulting solution is stirred for a period of 60 minutes and then partitioned between 10 ml of 0.5MpH 7 phosphate buffer and 10 ml of ethyl acetate. The aqueous phase is extracted a second time with ethyl acetate. The combined ethyl acetate solutions are washed with brine, dried- over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give 216 mg of crude product. Purification by preparative thick-layer chromatography developing with ethyl acetate gives 80 ml of 1-(2 tetrahydropyranyl)-3-methyl-4-[1-methyl-2-(2-tetrahydro- pyranyl)-oxyetilyl]-2-azetidinone as an oil. EXAMPLE 11 Preparation of l-(2-tetrahydropyranyl)-3-methyl-3 (l-hydroxymethyl)-4-[1-methyl-2-(2-tetrahydropyranyl)- oxyethyl}-2-azetidinone EMI74.1 Following the procedure described for the preparation of 8-oxo-2,2,5,7-tetramethyl-7-(hydroxymethyl)-3-oxa-1azabicyclo [4 2 0]octane from 8-oxo-2,2,5,7-tetramethyl3-oxa-1-azabicyclo[4.2.0]octane (Example 6, above) and using 3-methyl-1-(2-tetrahydropyranyl)-4-[1-methyl-2-(2tetrahydropyranyl)-oxyethyl]-2-azetidinone one obtains a diastereomeric mixture of l-(2-tetrahydropyranyl)-3methyl-3-(hydroxymethyl)-4[1-methyl-2-(2-tetrahydropyranyl) oxyetyl]-2-azetidinone. EXAMPLE 12 Preparation of 3-Methyl-1-(2-tetrahydropyranyl)-3 (1-p-nitrobenzylcarbonyldioxymethyl)-4-[1-methyl-2 (2-tetrahydropyranyl) oxyethyl] -2-azetidinone EMI75.1 Following the procedure described for the preparation of 8-oxo-2,2,5,7-tetramethyl-7-(1-p-nitrobenzylcarbonyldioxymethyl)-3-oxa-1-azabicyclo[4.2.0]octane from 8 oXo-2,2,5,7-tetramethyl-(1-hydroxymethyl)-3-oxa-1- azabicyclo[4.2.0]octane and using 3-methyl-1-(2tetrahydropyranyl)-3-(hydroxymethyl)-4-[1-methyl-2(2 tetrahydropyranyl)oxyethyl]-2-azetidinon there is obtained 3-methyl-l-(2-tetrahydropyranyl)-3-(p- nitrobenzylcarbonyldioxymethyl)-4-[1-methyl-2-(2tetrahydropyranyl)oxyethyl]-2-azetidinone. EXAMPLE 13 Preparation of 3-Methyl-3-(p-nitrobenzylcarbonyl dioxymethyl)-4-(1-methyl-2-hydroxyethyl)-2-azetidinone EMI76.1 A solution of 3-methyl-l-(2-tetrahydropyranyl)-3 (p-nitrobenzylcarbonyldioxymethyl)-4-[1-methyl-2-(2- ! tetrahydropyranyl) oxyethyl] -2-azetidinone in methanol at 25eC is treated with .1 molar equivalent of - toluenesulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1M pH 7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give 3-methyl-3-(p-nitrobenzylcarbonyldioxymethyl)-4 (l-methyl-2-hydroxyethyl) -2-azetidinone. EXAMPLE 14 Preparation of 1 ,6-dimethyl-2-(2-aminoethylthio) -6- (hydroxymethyl) -l-carbadethiapen-2-em-3- carboxylic acid Step A: Preparation of 12' EMI77.1 To 6.75 ml anhydrous pyridine in 350 ml anhydrous acetonitrile is added 4.05 g anhydrous powdered chromium trioxide. After stirring at room temperature (250C) for 30 minutes, 9.6 g dried Supercell is added and stirring is continued for 5 additional minutes. A solution fo 3.21 g 3-methyl-3-(p-nitrobenzylcarbonyldioxymethyl)-4-(1-methyl-2-hydroxyethyl)-2-azetidinone in 30 ml anhydrous acetonitrile is added all at once. The reaction mixture is stirred under anhydrous conditions at room temperature (250C) for one hour. Addition of 9.6 g NaHSO3 is followed by 5 minutes of stirring after which the reaction mixture is filtered through a mixed packed bed of 40 g silica gel and 40 g anhydrous magnesium sulfate. The bed is washed repeatedly with acetontrile (total volume of filtrate 600 ml). The filtrate is concentrated under a N2 stream to 130 ml total volume. To this solution containing crude aldehyde at 0 C under N2 is added 9.64g - nitrobenzyloxycarbonylaminoethanethiol as prepared below (Example 14, Step B). To the stirred reaction mixture is added 8.0 ml boron trifluoride etherate. After 1.5 hours at OOC., the reaction mixture is poured into a stirred ice-cold mixture of 69 g K2HPO4 - 500 ml H20 and 700 ml ethyl acetate (EA). The layers are separated, and the aqueous one is saturated with NaCl and re-extracted with additional EA. The combined organic layers arewashed twice with brine, dried over anhydrous MgSO4 and filtered. The filtrate is concentrated under a N2 stream and then pumped on high vacuum to give crude 12'. The The material is chromatographed on 450 g silica gel (column hieght = 48 cm; diameter = 5.5 cm) packed and applied in CHCl3 and eluted with increasing percentages of MeOH in CHCl3 (0-4% MeOH/CHC13). Those fractions containing the desired product are combined, concentrated under a N2 stream; and pumped on high vacuum to give 12'. STEP B Preparation of p-nitrobenzyloxycarbonylaminoethathiol EMI79.1 To 600 ml diethyl ether (Et2O) - 75 ml H2O in an ice bath with stirring is added 3,2 g cysteamine hydrochloride (mw=114; 28.1 mmole). A solution of 7.14g NaHCO3 (mw=34, 35 mmole) in 75 ml H2o is added. The ice bath is removed and at room -temperature a solution of 6.75 g p-nitrobenzylch oformate (mw = 216; 31.3 mmole) in 270 ml Et2 is added dropwise over a period of one hour. AFter 10 additional minutes, the layers are separated. The ether layer is extracted with 150 ml 0.25 NHC1, and then with 200 ml brine. Each aqueous layer is then backwashed successively with 100 ml ET2O. The combined Et2O layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 strea. The crystalline residue is slurried in small amount of ether, filtered, and the pale yellow crystals are dried under high vacuum to give 4.7 g p-nitrobenzyloxycarbonylaminoethanethiol (65% yield). NMR (CDCl3) 8.18 (d, J=8Hz, aromatic protons ortho to nitro), 7.47 (d, J=8Hz, aromatic protons meta to nitro), 5.27 (-NH-), 5.20 (s, -CH2- #-pNO2), 3.40 (m, -CH2-NH-), 2.67 (m, -CH2-SH), 1.35 (t, J= 8.5Hz, -SH) in ppm downfield from TMS. IR(CHCl3 solution) carbonyl- 1725 cm 1 molecular ion-256, (M-47) at 209, (M-136) at 120 +CH2#pNO2 at 136. STEP C Preparation of 14' EMI80.1 To 14.2 ml pentane (dried over 4A Linde molecular sieves) is added 0.5 ml Br2. To 5g of 12' in 58 ml tetrahydrofuran (ThF) (freshly distilled from lithium aluminum hydride) (LAH) and 65 ml Et20 (dried over 3A 1/16" Linde molecular sieves) at OOC under N2 with stirring is added dropwise 10 ml of the above 0.66M Br2 solution. After 10 minutes at OOC, 0.67 ml cyclohexene is added. After 5 minutes at 0 C., 1.7 ml triethylamine is added immediately followed by 40 ml ice-cold dimethylformamide (DMF) (distilled from anhydrous CaSO4 at 40 mm and stored over 4A Linde molecular sieves). The ice bath is removed, and stirring is continued for 2 1/4 hours at room temperature. The reaction mixture is poured into a stirred ice-cold mixture of 12.6 ml 1M KH2P04 160 ml H20 - 500 ml (EA). After separation of the layers, the aqueous one is saturated with sodium chloride and re-extracted with EA. The combined organic layers are extracted once with brine, dried over anhydrous MgSO4, filtered and concentrated under N2 stream followed by pumping under high vacuum to provide crude 14'. The material is chromatographed on 250 g siica gel (height = 45 cm; diameter = 4.5 cm) packed and applied in CHCl3 and eluted with increasing percentages of MeOH in CHCl3 (0-3% MeOH/CHC13). Those fractions containing clean product are combined, concentrated under a N2 stream, and pumped on high vacuum to give 14'. STEP D EMI82.1 To a stirred solution of 2.48 g di(p nitrobenzyl)ketomalonave in 400 ml hot anhydrous toluene is added a solution of 2.52 g of 14' in 20 ml THF (distilled from LAH) and 40 ml anhydrous toluene. After some of the solvent is boiled off, additional anhydrous toluene is added, and the azeodrying process is repeated three times. The solution is then refluxed under N2 for 30 minutes. Additional toluene is then allowed to boil off yet the volume is not allowed to diminish so much that precipitation occurs. Total heating time is approximately 2 1/2 hours. The clear yellow reaction mixture is removed from the oil bath and placed under a stream of N which instantaneously causes clouding. After concentration to a yellow oil, the residue is dissolved in CH2C12, dried of anhydrous MgSO4, filtered, and concentrated under a N2 stream to give crude The material is chromatographed on 250 g silica gel packed and applied in CHCl3 (height = 43 cm; diameter= 4.5 cm). Elution with 500 ml 0.5% MeOH/CHC13 is followed by continued elution with 1% MeOH/CHC13 for the remainder of the chromatography. After the emergence of excess reagent, those fractions containing pure combined, concentrated under a N2 stream and then on '-' vacuum to give STEP E Preparation of : 7' EMI83.1 To 8.5 ml pentane (dried over 4A Linde molecular sieves) is added 0.2 ml Br2. To 0.706g of in 18 ml THF (freshly distilled from LAH) and 5.7 ml Et2O (dried over 3A 1/16" Linde molecular sieves) at 0 C under N2 with stirring is added dropwise 1.8 ml of the above 0.45M Br2 solution. After 15 minutes at 0 C., 0.42 ml triethylamine is added immediately followed by 10.5 ml ice-cold DMF (distilled from CaSO4 at 40 mm and stored over 4A Linde molecular sieves). The ice-bath is removed, and stirring at room temperature is continued for 2 hours. The reaction mixture is poured into a stirred ice-cold mixture of 3.1 ml 1M KH2PO4 - 70 ml H20 - 100 ml EA. The layers are separated, and the aqueous one is saturated with NaCl and re-extracted with EA. The combined organic layers are washed once with brine, dried over anhydrous MgSO4, and filtered. The filtrate is concentrated under a N2 stream and then pumped on high vacuum to give crude The material is chromatographed on 60 g silica gel (diameter = 2.8 cm) packed and applied in CHCl3 and is eluted with 100 ml - 2% EA/CHC13; 100ml - 4% EA/CHC13 and then 5% EA/CHCl3 for the remainder of the chromatography. The fractions containing pure 19' are combiend, concentrated under a N2 stream, and pumped on high vacuum to give 19'. STEP F Preparation of 19' EMI85.1 To 8.5 ml pentane (dried over 4A Linde molecular sieves) is added 0.2 ml Br2. TO 0.706 of 17 in 18 ml THF (freshly distilled from LAH) and 5.7 ml Et2O (dried over 3A 1/16" Linde molecular sieves) at 0 C under N2 with stirring is added dropwise 1.8 ml of the above 0.45M Br2 solution. After 15 minutes at 0 C., 0.42 ml triethylamine is added immediately followed by 10.5 ml ice-cold DMF (distilled from CaSO4 at 40 mm and stored over 4A Linde molecular sieves). The ice-bath is removed, and stirring at room temperature is continued for 2 hours. The reaction mixture is poured into a stirred ice-cold mixture of 3.1 ml 1M KH2PO4 - 70 ml H20 - 100 ml EA. The layers are separated, and the aqueous one is saturated with NaCl and re-extracted with EA. The combined organic layers are washed once with brine, dried over anhydrous MgSO4, and filtered. The filtrate is concentrated under a N2 stream and then pumped on high vacuum to give crude 19' The material is chromatographed on 60 g silica gel (diameter = 2.8 cm) packed and applied in CHCl3 and is eluted with 100 ml - 2% EA/CHC13; 100 ml - 4% EA/CHC13 and then 5% EA/CHC13 for the remainder of the chromatography. The fractions containing pure 19' are combined, concentrated under a N2 stream, and pumped on high vacuum to give 19' STEP , Preparation of 20' EMI87.1 To 29 mg anhydrous silver fluoride is added a solution of 146 mg of 19' in 3.5 ml anhydrous pyridine. The stoppered reaction mixture is stirred at room temperature in the dark for one hour and then poured into 20 ml cold water - 30 ml EA. After separation of the layers, the aqueous one is extracted two times with EA and one time with CHC13. Each organic layer is extracted one time with H20 and one time with brine. The combined organic layers are dried over anhydrous MgSO4, filtered, and concentrated under a N2 stream following by pumping on high vacuum to give crude 19'. Preparative thin layer chromatograph (eluant = 40% acetone/hexane; repeated extraction of desired u.v. band with a large volume of HCC13) yields slightly contaminated /\,20 Re-chromatographing on silica gel using EA in CHCl3 as an eluing system gives 20'. STEP H Preparation of 21' EMI88.1 A solution of 77 mg of 20' in 0.9 ml S-collidine (distilled from powdered KOH) is added to 13.4 mg anhydrous Lil (dried for few hours at 1000C over P205 under vacuum). With stirring under N2, the reaction mixture is heated in an oil bath at 1200C. After a total of 30 minutes, the reaction mixture is cooled to 250C., diluted with CH2C12, and transferred to a round bottom flask for concentration under a N2 stream and then on high vacuum. Partitioning the residue between EA-H2O and 1 ml 1M KH2PO4 is followed by extraction of the aqueous layer two additional times with EA and one time with CHC13. Each organic layer is then backwashed with brine. The combined organic layers are dried over anhydrous NgSO4, filtered, concentrated under a N2 stream and then on high vacuum to give crude 21'. Preparative thin layer chromatography on silica gel (plate is eluted two times wtih 40% acetone/hexane; repeated extraction of the appropriate u.v. bands with large volume of CHC13) yields 21'. STEP I Preparation of 22' EMI89.1 To 49 mg of 21' in 0.7 ml DMSO (distilled from CaH2 at 8mm and stored over 4A Linde molecular sieves) is added 100W1 diisopropylamine (distilled from NaH under N2 and stored over 4A Linde molecular sieves).' The stoppered reaction mixture is stirred for a few minutes and then allowed to stand for 2 hours. The amine and most of the DMSO are then concentrated off under high vacuum with no external heating. The residue is passed quickly through a column of silica gel (packed, applied, and eluted with EA) to remove residual DMSO. After concentration under a N2 stream of all fractions having u.v. absorbance, the material is chromtographed on a thin layer silica gel plate (eluant = 50% EA/CHC13; repeated extraction of desired u.v. bands with a large volume of chloroform) to give 22'. STEP J Preparation of (I) EMI90.1 To 5.2 mg 22' is added 0.60 ml dioxane, 0.05 ml ethanol, 0.35 ml deionized water and 0.01 ml of 1.OM K2HP04. To the resultant clear solution is added 5 mg of 10% Pd/C. The suspension is flushed with N2, then 5-6 times alternately with 50 psi H2 and vacuum. Finally, it is shaken under a 50 psi H2- atmosphere for 30-40 min. After centrifugation, the Pd/C is washed and centrifuged 2-3X with 0.5 ml portions of deionized water. The combined centrifugates are extracted 5x1 - 2 ml ether. Residual ether is removed under vacuum and the aqueous solution applied to an XAD-2 column (20 ,x 140 mm). Fractions of 100 drops (6-7 ml) are collected, with continuous W monitoring, by elution with deionized water to give (I). EXAMPLE 15 Preparation of Bis (p-nitrobenzyloxycarbonylamino- ethyl)disulfilde EMI91.1 Under nitrogen at -20 C. bromine (1.21 ml, .022 mmole) is added to a solution of -n}-obenzyloxyzarbonylamino- ethanethiol (11.28 g, .044 mole) in 100 ml of anhydrous tetrahydrofuran. The cooling bath is removed, and the cold solution is stirred for 15 minutes. The solution is then diluted with 400 ml ethyl acetate and washed with 200 ml 1M pH 7 phosphate buffer, 200 ml 1M dibasic potassium phosphate, water (2 x 200 ml, 100 ml) and 200 ml brine. It is dried over' anhydrous magnesium sulfate and filtered. The filtrate is evaporation in vacuo giving a yellow solid residue. This material is chromatographed on silica gel eluting with 50% ethylacetate/chloroform to give 10.5 g of crystalline bis (p-nitrobenzyloxycarbonyl- aminoethyl) disulfide: IR (CH2Cv2) : 3.04NH 5.96 carbonyl 6.22, 6.61 nitro EMI91.2 <tb> NBR <SEP> (CDCl3) <SEP> : <SEP> 8.24 <tb> <SEP> d, <SEP> J=8.5Hz, <SEP> ArH <tb> <SEP> 7.54 <tb> 5.37, broad s, NH 5.26, s, ArCH2O 3.60 q, J=6Hz and 6Hz,NHCH2CH2 2-86, t, J=6Hz,NHCH2CH2S EXAMPLE 16 Preparation of 8-oxo--2,2,5,-trimethyl-7a and B- hydroxymethyl-3-oxa-1-azabicyclo[4.2.0]octane EMI92.1 The procedure of Example 7, substituting 8-oxo-2,2,5-trlmethyl-3-oxa-l-azabicyclo[4 2 0]octane for 8-oxo-2,2,5,7-tetramethyl-3-oxa-1-azabicyclo[4.2.0]octane is carried out. Upon purification by silica gel chromatography, the title compound is obtained. EXAMPLE 17 Preparation of l-methyl-2-(2-aminoethylthio)-6-hydroxymethyl l-carbadethiapen-2- em-3-carboxylic acid EMI92.2 Following the procedure described above for the preparation of 1,6-dimethyl-2-(2-aminoethylthio)-6-hydroxymethyll-carbadethiapen-2-em-3-carboxylic acid, except that in Example 8 an equivalent.amount of 8-oxo-?,2,5-trimethyl -7-hydroxymethyl-3-oxa-1-azabicyclo[4.2.0]octane rather than the 2,2,5,7-tetramethyl species is taken; the tile compound is obtained when the procedures ,f Examples 8, 9 and 14 are followed. EXAMPLE 18 Preparation of 8-oxo-2,2,5-trimethyl-7&alpha; and - (l-hydroxy-2-phenylethyl)-3-oxa-1-azabicyclo[4.2.0]- octane ¯¯¯ ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ EMI93.1 Following the procedure of Example 2, Step Fa except that instead of acetaldehyde, an equivalent amount of phenylacetaldehyde is used, upon purification by silica gel chromatography, the title compound is obtained. EXAMPLE 19 Preparation of 1-methyl-(2-aminoethylthio)-6-(1-hydroxy-2phenylethyl)-1-carbadethiapen-2-em-3-carboxylic acid EMI93.2 Following the procedure of Example 8 except that 8-oxo-2,2,5-trimethyl-7-(1-hydroxy-2-phenylethyl)3-oxa-1-azabicyclo[4.2.0]octane is substituted in equivalent amount for its analogous substrate, the title compound is obtained. Preparetion of 8-oxo-2,2,5-trimethyl-7&alpha;-benzyl-3-oxa- 1-azabicyclo[4.2.0]octane EMI94.1 Following the procedure of Example 6 and using benzyl bromide instead of methyl iodide there is obtained 8-oxo-2,2,5-trimethyl-7c-benzyl-3-oxa-l- azabicyclo[4.2.0]octane EXAMPLE 21 Preparation of 8-oxo-2,2,5-trimethyl-7a and -benzyl-7ss and &alpha;-1-hydroxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane EMI94.2 Using the procedure of Example 7 but substituting an equivalent amount of 8-oxxo-2,2,5-trimethyl-7&alpha; ;-benzyl-3- oxa-1-azabicyclo[4.2.0]octane (Example 20) for 8- o-2,2,5,- 7-tetramethyl-3.oxa-1-azabicyclo[4.2.0], and an equivalent amount of acetaldehyde for 'formaldehyde, there is obtained, upon purification by silica gel chromatography, the title compounds. EXAMPLE 22 Preparation of 8-oxo-2,2,5-trimethyl-7&alpha;(1- masyloxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane EMI95.1 Under nitrogen at 00 a solution of 8-oo-2,2,- 5-trimethyl-7, 1-hydroxyethyl-3-oxa-1-azabicyclo [4.2.0]octane (128 mg) and triethylamine (134 1) in 5 ml of sieve dried methylene chloride is treated with redistilled methane sulfonyl chloride (55 1). The resulting solution is stirred for 30 minutes. It is then washed with 10 ml each of cold water, 1 molar pH 3 phosphate buffer, 5% sodium bicarbonate, water and finally brine. The organic phase is dried over magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give the crude product. This material is chromatographed on preparative thick layer silica gel plates developed with acetone/hexane to give a separated diastereomeric mesylate. EXAMPLE 23 Preparation of 8-oxo-2,2,5-trimethyl-7a-(1-azidoethyl)- 3-oxa-1-azabicyclo[4.2.0]octane EMI96.1 A solution of lithium azide, prepared by stirring over night a mixture of 170 mg sodium azide and 100 mg lithium chloride in 3 ml of anhydrous dimethyl sulfoxide, followed by filtration, is added to 160 mg of 8-oxo 2,2,5-trimethyl-7a(1-mesyloxyethyl)-3-oxa-1-azabicyclo- [4.2.0]octane and stirred under nitrogen at 250C for eight hours. The mixture is then poured into 10 ml ice water and extracted with ethyl acetate, the combined extracts washed once with water, once with saturated sodium chloride solution, dried'(MgSO4) and evaporated under a nitrogen stream. The crude product is purified by preparative tlc to afford the title compound. EXAMPLE 4 Preparation of 8-oxo-2,2,5-trimethy1-7a-(1-p- nitrobenzyloxycarbonylaminoethyl)-3-oxa-1-azabicyclo [4.2.0]octane EMI97.1 A mixture of 107 mg of 8-oxo-2 2,5-trimethyl-7&alpha;-(1- azidoethyl)-3-oxa-1-azabicyclo[4.2.0]octane and 50 mg of 10% Pd/C in 2 ml of anhydrous dioxane is shaken under 3 atmospheres of hydrogen for 1.5 hours. The mixture is filtered and concentrated to 1 ml under a nitrogen stream, then treated with 1 ml of 1M K2HPO4 and 1 ml methylene chloride. The mixture is stirred vigorously in an ice bath under nitrogen while a solution of 120 mg of p-nitrobenzylchloroformate in 0.5 ml methylene chloride is added dropwise over one minute. The solution is stirred for another 15 minutes, then treated with 0.1 ml pyridine in 2 ml water and stirred vigorously for another 15 minutes. The organic phase is removed and the aqueous phase is extracted several more times with methylene chloride. The combined organic phases are washed twice witn water, once with saturated NaCl, dried (Mg504) and evaporated under reduced pressure. Purification by preparative tIc affords the title compound. EXAMPLE 25 Preparation of 8-oxo-2,2,5-trimethyl-7(1-onitrobenzylthioethyl)-3-oxa-1-azabicyclo[4.2.0]octane EMI98.1 When in Example 23 an equivalent solution of onitrobenzyl mercaptan in DMF is substituted for the lithium azide solution, the title compound is obtained. EXAMPLE 26 Preparation of 4-(1-methyl-2,2-bisbenzylthioethyl)-3mothyl-3(p-nitrobenzylcarbonyloxymethyl)-2-azetidinone EMI98.2 When in Example 14, Step A, an equivalen' amount of benzyl mercaptan is substituted for 2-(p-nitrobenzyloxy- carbonylamino)ethane thiol, the title compound is obtain EXAMPLE 27 Preparation of 3-methyl-4-[1-methyl-2,2-bis-(1',1'- dimethyl-p-nitrobenzoxycarbonylaminoethylthio]3-(p-nitrobenzylcarbonyldioxyme5thyl)-2-azetidinone EMI99.1 When in Example 14, Step A, an equivalent amount of 2-(p-nitrobenzyloxycarbonylamino)-1,1-dimethylethanethiol is substituted for 2-(p-nitrobenzyloxycarbonylamino) ethane thiol, the title compound is obtained. EXAMPLE 13 Preparation of 1,6-dimethyl-2-benzylthiohydroxymethyl-1-carbadethiapen-2-em-3-carboxylic acid EMI100.1 Following the procedure of Example 14, Steps A-K, except substituting for the indicated azetidinone the azetidinone of Example 26, the title compound is obtained. EXAMPLE 29 Preparation of 1,6-dimethyl-2-(2-amino-1,1-dimethylethylthio)-6-(1-hydroxymethyl)-1-carbadethiapen-2-em-3 carboxylic acid EMI100.2 Following the procedure of Example 14, step A-K, except substituting for the indicated azetidinone t azetidinone of Example 27, the title compound is obtain EXAMPLE 30 Following the procedure of the foregoing Examples and text, the following representative compounds of the present invention (Table I) are obtained EMI101.1 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> 1.) <SEP> -(CH2)3NH2 <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> HS(CH2)3NHCO2PNB, <tb> <SEP> Example <SEP> 17. <tb> <SEP> NH <tb> 2.) <SEP> -(CH2)3NHC <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> Compound <SEP> 1. <SEP> of <SEP> Example <tb> <SEP> H <SEP> 30 <SEP> in <SEP> reaction <SEP> with <SEP> methyl <tb> <SEP> formimidate <SEP> hydrochloride <tb> <SEP> in <SEP> water <SEP> at <SEP> pH <SEP> 8.5. <tb> EMI101.2 EMI101.3 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> 1.) <SEP> -(CH2)3NH2 <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> HS(CH2)3NHCO2PNB, <tb> <SEP> Example <SEP> 17. <tb> <SEP> NH <tb> 2.) <SEP> -(CH2)3NHC <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> Compound <SEP> 1. <SEP> of <SEP> Example <tb> <SEP> H <SEP> 30 <SEP> in <SEP> reaction <SEP> with <SEP> methyl <tb> <SEP> formimidate <SEP> hydrochloride <tb> <SEP> in <SEP> water <SEP> at <SEP> pH <SEP> 8.5. <tb> EMI102.1 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> <SEP> NH <tb> 3.) <SEP> -(CH2)3NHC <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> Compound <SEP> 1 <SEP> of <SEP> Example <tb> <SEP> CH3 <SEP> 30 <SEP> in <SEP> reaction <SEP> with <SEP> ethyl <tb> <SEP> acetimidate <SEP> hydrochloride <tb> <SEP> in <SEP> water <SEP> at <SEP> pH <SEP> 8.5 <tb> 4.) <tb> <SEP> #-CH2NH2 <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HS-#-CH2NHCO2PNB, <tb> <SEP> Example <SEP> 17 <tb> 5.) <SEP> NH <tb> <SEP> #-CH2NHC <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> As <SEP> in <SEP> 2., <SEP> above. <tb> <SEP> H <tb> 6.) <SEP> NH <tb> <SEP> #-CH2NHC <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> As <SEP> in <SEP> 3., <SEP> above. <tb> EMI103.1 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> <SEP> NH <SEP> CH2NHCO2PNB <tb> 7.) <SEP> # <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HS-# <SEP> Example <SEP> 17. <tb> 8.) <SEP> NH <tb> <SEP> -CH2NHC <tb> <SEP> # <SEP> H <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> As <SEP> in <SEP> 2., <SEP> above. <tb> 9.) <SEP> NH <tb> <SEP> -CH2NHC <tb> <SEP> # <SEP> H <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> As <SEP> in <SEP> 3., <SEP> above. <tb> 10.) <SEP> S <tb> <SEP> S <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HS <SEP> CH3 <tb> <SEP> CH3 <SEP> N <SEP> N <tb> <SEP> N <SEP> N <SEP> Example <SEP> 17 <tb> EMI104.1 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> 11.) <SEP> -CH-CH2-NH2 <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HSCH(CH3)CH2NHCO2PNB, <tb> <SEP> CH3 <SEP> Example <SEP> 17. <tb> 12.) <SEP> -CH <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HSCH3, <SEP> Example <SEP> 17. <tb> 13.) <SEP> # <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HS#, <SEP> Example <SEP> 17. <tb> 14.) <SEP> N <SEP> N <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From: <SEP> N <SEP> N <tb> <SEP> N <SEP> N <tb> <SEP> N <SEP> HS <SEP> N <tb> <SEP> CH3 <SEP> CH3 <tb> <SEP> Example <SEP> 17. <tb> EMI105.1 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> 15.) <SEP> NH2 <tb> <SEP> -CH2CHCH3 <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HSCH2CH(CH3)NHCO2 <tb> <SEP> PNB, <SEP> Example <SEP> 17. <tb> <SEP> NH2 <tb> 16.) <SEP> -CH2CHCH3 <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> HSCH2CH(CH3)NHCO2PNB <tb> <SEP> Example <SEP> 17. <tb> 17.) <SEP> # <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> From <SEP> SH <tb> <SEP> # <tb> <SEP> N <tb> <SEP> Example <SEP> 17. <tb> EMI106.1 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> 18.) <SEP> -SCH2CH2NH2 <SEP> H <SEP> CH2OH <SEP> CH3 <SEP> Example <SEP> 17. <tb> <SEP> NH2 <tb> 19.) <SEP> -ACH2CH2NH2 <SEP> H <SEP> CH3CH- <SEP> CH3 <SEP> From <SEP> azetidinone <SEP> of <tb> <SEP> Example <SEP> 24, <SEP> followed <SEP> the <tb> <SEP> procedure <SEP> of <SEP> Example <SEP> 17. <tb> <SEP> Cl <tb> 20.) <SEP> -SCH2CH2NH2 <SEP> H <SEP> CH3CH- <SEP> CH3 <SEP> From <SEP> azetidinone <SEP> of <tb> <SEP> Example <SEP> 22, <SEP> followed <SEP> the <tb> <SEP> procedure <SEP> of <SEP> Example <SEP> 23 <tb> <SEP> except <SEP> substituting <SEP> LICL <tb> <SEP> for <SEP> LIN3 <SEP> and <SEP> Example <SEP> 17. <tb> <SEP> OH <tb> 21.) <SEP> -SCH2CH2NH2 <SEP> CH3 <SEP> CH3CH- <SEP> CH3 <SEP> From <SEP> azetidinone <SEP> of <SEP> Example <tb> <SEP> 6 <SEP> followed <SEP> the <SEP> procedure <tb> <SEP> of <SEP> Example <SEP> 7 <SEP> except <tb> <SEP> substituting <SEP> acetaldehyde <tb> <SEP> for <SEP> formaldehyde <SEP> and <tb> <SEP> Example <SEP> 17. <tb> <SEP> NH2 <tb> 22.) <SEP> S# <SEP> CH3 <SEP> CH3CH- <SEP> CH3 <SEP> From <SEP> azetidinone <SEP> of <tb> <SEP> Example <SEP> 6, <SEP> followed <SEP> Example <SEP> 17 <tb> <SEP> except <SEP> substituting <SEP> thio <SEP> phenol <SEP> for <SEP> cysteamine. <tb> EMI107.1 Compound <SEP> R8 <SEP> R6 <SEP> R7 <SEP> R' <SEP> Remarks <tb> <SEP> OH <tb> 23.) <SEP> -SCH2CH2CH2NH2 <SEP> CH3 <SEP> CH3CH <SEP> CH3 <SEP> Same <SEP> as <SEP> compound <SEP> 21 <SEP> except <tb> <SEP> using <SEP> aminopropanethiol <tb> <SEP> instead <SEP> of <SEP> aminoethane <SEP> thiol <tb> <SEP> OH <tb> 24.) <SEP> -S# <SEP> CH3 <SEP> CH2CH <SEP> CH3 <SEP> Same <SEP> as <SEP> compound <SEP> 21, <SEP> except <tb> <SEP> using <SEP> thiophenol <SEP> instead <SEP> of <tb> <SEP> aminoethanethiol. <tb> 25.) <SEP> -SCH2CH2NH2 <SEP> H <SEP> CH2OH <SEP> C2H5 <SEP> Same <SEP> as <SEP> for <SEP> (18). <SEP> except <tb> <SEP> replacing <SEP> 1-acetoxyl-2-methyl <SEP> 1,3-butadiene <SEP> with <SEP> 1-acetoxyl <SEP> 2-ethyl-1,3-butadiene <SEP> in <tb> <SEP> Example <SEP> 2, <SEP> Step <SEP> A. <tb> <SEP> OH <tb> 26.) <SEP> -SCH2CH2NH2 <SEP> CH3 <SEP> CH3CH <SEP> CH3 <SEP> Same <SEP> as <SEP> for <SEP> (21), <tb> <SEP> CH <SEP> except <SEP> replacing <SEP> 1-acetoxyl <SEP> CH3 <SEP> -2-methyl-butadiene <SEP> with <tb> <SEP> 1-acetoxyl-2-isopropyl <SEP> butadiene. <tb> EXAMPLE 31 Following the foregoing procedure, the following species of the present invention are obtainec' by analogy. EMI108.1 EMI108.2 <tb> Compound <SEP> R <tb> 1.) <SEP> CH3CH2 <tb> 2.) <SEP> 3CH2cH2 <tb> 3.) <SEP> CH3 <tb> <SEP> OH <tb> <SEP> CH3 <tb> 4.) <tb> 5.) <SEP> 5 & BR< <tb> 6.) <SEP> wI02 <tb> 7.) <SEP> CH3 <tb> EXAMPLE 32 Preparation of 6- (l-hydroxyethyl) -l-methyl-l- carbadethiapen-2-em-3-carboxylic acid EMI109.1 Preparation of R-trans-l3: EMI110.1 The starting material R-trans-9'ss(1.58 g, 4.5 mmol) is treated with 5 equivalents of t-butyldimethylchlorosilane, 10 equivalents of imidazole in 5 ml anhydrous N,N-dimethylformamide (DMF) at room temperature for 3 hrs. The mixture is allowed to evaporate in vacuo to give crude product. Purification of the crude product by a silica gel eluting with 30% ethylacetate/cyclohexane gives 2.0 g of the product (R-trans-1ss), NMR (300 MHz, CDC13): 0.04 (s), 0.88 (s), 0.98 (d), 1.26 (d), 1.82 (m), 3.20 (q), 3*60 (m), 5.15 (m), 5.59 (q), 5.94(s), 7.54 (t), 7.68 (m) and 8.18 (d)ppm. (R is o-nitrobenzyloxycarbonyl.) EMI111.1 o-Nitrobenzyl-d-tartarate (1.8 g) is oxidized with periodic acid (0.97 g) in 18 ml of anhydrcus tetrahydrofuran at 250C for 30 min. The mixture is filtered from solids and the filtrate is allowed to evaporate in vacuo to give o-nitrobenzylglyoxylate which is then taken up in 100 ml benzene and transferred into a 250-ml round bottom flask. To the solution is added trans-3-[1(R)-o-nitrobenzyloxycarbonyl oxyethyl]-4-llss-methyl-2-t-butyldimethylsilyoxy)eth 2-azetidinone (R-trans-lss) (2.0 g). The mixture is heated at reflux and water removed with a Dean-Stark trap packed with CaH2 (1 g). for 6 hr. The mixture is cooled, filtered, evaporated and chromatographed on silica gel eluting with 30% ethylacetate/cyclohexane to give 2. EMI112.1 Trans-1-(o-nitrobenzyloxycarbonylhydroxymethyl) 3-[1(R) -o-nitrobenzyloxycarbonyloxyethyl ]-4-[(1a- methyl-2-t-butyldimethylsilyloxy)ethyl]-2-azetidinone (2) (3.92 g) in 20 ml anhydrous tetrahydrofuran at -20 C is treated with pyridine (0.42 ml) and thionyl chloride (0.37 ml). The mixture is allowed to warm to 25 C with stirring, then filtered from solids. After removal of solvent in vacuo, product 3 is obtained. The chloride 3 is redissolved in 25 ml anhydrous DMF and treated with triphenylphosphine (1.1 g) with stirring at 25 C for 1 hr. Solvent is removed in vacuo and the residue is dissolved in 100 ml methylene chloride and washed with 0.1N pH 7.2 phosphate buffer 30 ml, chromatographic purification on silica gel,eluting with 40% ethylacetate/ cyclohexane,givas product 4 (1.0 g), IR (CHC13): 1750 cm 1 (B-lactam), 1620 cm 1 (ylide ester). Preparation of EMI113.1 Trans-1-(nitrobenzyloxycarbonyltripenyl phosphoranylmethyl) -3- [1(R) -o-nitrobenzyloxycarbonyloxy- ethyl]-4-[1ss-methyl-2-t-butyldimethylsilyloxy)ethyl]-2- azetidinone (4) (1.0 g) is dissolved in 10 ml tetrahydrofuran and is treated with conc. HC1 (0.41 ml) at 25 C for 10 min. The mixture is diluted with 200 ml methylene chloride then washed with 0.1M Na2HP04 (50 ml) The organic layer is separated, dried over Na2S04 and evaporated in vacuo to give crude 5. Chromatographic pruification of the crude product eluting with 30% ethylacetate/cyclohexane gives 0.68 g of IR (CHC1): 1750 and 1610 cm 1. Preparation of 7 EMI114.1 trans-1-(o-nitrobenzyloxycarbonyltripenylphosphoranylmethyl)-3-[1(R)-o-nitrobenzyloxycarbonyloxy ethyl]-4-[(1ss-methyl-2-hydroxySethyl]-2-azetidinonetAL (70 mg) is treated with 1 ml DMSO and 1 ml acetic anhydr:. at r.t. overnight. After solvents evaporated in vacuo the residue is chromatographed on TLC plate (silica gel GF, 500 p) eluting with 50% ethylacetate/cyclohexane to give 12 mg of 7, IR (CKCl3): 1770 cm 1, and 1740 cm-1; NMR (300 MHZ, CDCl3): 1.15 (d), 2.80 3.30 (m) 3.53 (q) , 4.35 (q), 5.21 (quintet), 4.55 (d), 4.82 (d) , 4.55 (d) , 4.62 (d), 6.51 (d) 7.49 (q), , 7.55 7.83 (d) and 8.12 (m)ppm. Preparation of (I) EMI115.1 Trans-6-[l(R)-o-nitrobenzyloxycarbonyloxyethyl]- l-methyl-l-carbadethiapen-2-em-3-carboxylic acid onitrobenzyl ester (4 mg) in 4 ml H20 and 4 ml dioxane is photolysized in a quartz tube under 3500A in the presence of NaHC03 (5 mg) at 20 C for 2.5 hr. The mixture is extracted with-ether. The aqueous layer is neutralized with HC1 then concentrated to 1 ml. Chromatographic purification of the crude product by a XAD-2 resin (1.5 x 5 cm) eluting with water gives (I) (0.13 mg) as sodium salt. Electrophoresis shows single bioactive zone which moves 7.9 cm toward anode at 2KV, for 20 min in 0.05M pH 7.0 phosphate buffer. EXAMPLE 33 Following the foregoing text and Examples, the following species (I) are obtained by analogy. EMI116.1 EMI116.2 <tb> Com- <SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <tb> pound <SEP> R1 <SEP> R2 <SEP> R <SEP> R4 <tb> 1.) <SEP> HOCH2 <SEP> H <SEP> -OH3 <SEP> Na+ <tb> 2.) <SEP> CH3 <SEP> H <SEP> OH3 <SEP> Na+ <tb> 3.) <SEP> 9 <tb> <SEP> H <SEP> 9 <SEP> 94 <SEP> H <SEP> CH3 <SEP> H <tb> 4.) <SEP> CH3g <SEP> H <SEP> -OH3 <tb> 5.) <SEP> (CH3)2C(O'.)- <SEP> H <SEP> -OH3 <SEP> Na+ <tb> 6.) <SEP> CH3CH(N3)- <SEP> H <SEP> CH3 <SEP> Na+ <tb> 7.) <SEP> CH3CH(OH)- <SEP> CH3 <SEP> CH3 <SEP> Na+ <tb> 8.) <SEP> HOCH2- <SEP> OH3OH2 <SEP> CH3 <SEP> H <tb> 9.) <SEP> CH3g <SEP> CH3 <SEP> CH3 <SEP> Na+ <tb> 10.) <SEP> CH3CH(oH)- <SEP> H <SEP> CH3CHz <SEP> Na+ <tb> 11.) <SEP> CH3CH(OH)- <SEP> CH3 <SEP> OH3OH2 <SEP> H <tb> EMI117.1 <tb> pOOound <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <tb> pound <SEP> RI-RZ <SEP> R3 <SEP> R4 <tb> 12.) <SEP> HOCH2- <SEP> CH3 <SEP> Na+ <tb> 13.) <SEP> CH3CH <SEP> (OH) <SEP> CH2 <SEP> H <SEP> CH3 <SEP> (C2H5)4N <tb> 14.) <SEP> CH3CH(OCH2SCH3)¯ <SEP> H <SEP> H <SEP> CH3 <SEP> Na+ <tb> <SEP> r-n <SEP> OH <tb> 15.) <SEP> > <SEP> Ei- <SEP> H <SEP> CH3 <SEP> Na <SEP> + <tb> <SEP> fiE <tb> 16.) <SEP> W <SEP> H <SEP> CH3CH(CH3)- <SEP> Na+ <tb> 17.) <SEP> W <SEP> H <SEP> CH <SEP> Na+ <tb> 18.) <SEP> N <SEP> b <SEP> H <SEP> CH3 <SEP> Na+ <tb> 19.) <SEP> CH3CH <SEP> (SH)- <SEP> H <SEP> CH3 <tb> of Pharmaceutical Compositions One such unit dosage form is prepared by mixing 120 mg of 1-methyl-6-(1-hydroxyethyl)-2-(2- aminoethylthio)-1-carbadethiapen-2-em-3-carboxylic acid 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 1 mess lactose, other dosage forms can be put up in No. 3 gelatin capsules and should it be ncessary to mix more than 145 mg. of ingredients, together large capsules such as compressed tablets and pills can also be prepared. The following examples are illustrative of the preparation of pharmaceutical formulations: TABLET PER TABLET 1-methyl-6-(1-hydroxyethyl)-2 (2-aminoethylthio)-1-carbadethiapen2-em-3-carboxylic acid 125 mg. Dicalcium Phosphate 192 mg. Cornstarch, U.S P. 6 mg. Lactose, U.S.P. 190 mg. Magnesium Stearate Balance The active ingredient is blended with the dicalcium phosphte, 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 45 C and screened again through No. 16 screens. The balance of the cornstarch and the magnesium stearate is added and the mixture is compressed into tablets, approximately 0.5 inch in diameter each weighing 800 mg. PARENTERAL SOLUTION Ampoule: 1-methyl-6-(1-hydroxyethyl)-2-(2aminoethylthio)-1-carbadethiapen-2-em-3carboxylic acid 500 mg. Diluent: Sterile Water for Injection 5 cc OPTHALMIC SOLUTION 1-methyl-6-(1-hydroxyethyl)-2 (2-aminoethylthio)-1-carbadethiapen-2-em-3-carboxylic acid 100 mg. Hydroxypropylmethyl cellulose 5 mg. Sterile water to 1 ml. OTIC SOLUTION l-methyl-6- (l-hydroxyethyl) -2- (2-aminoethylthio)-1-carbadethia- pen-2-em-3-carboxylic acid 100 mg. Benzalkonium chloride 0.1 mg. Sterile water to 1 ml. TOPICAL OINTMENT l-methyl-6- (1-hydroxy ethyl) -2- (2-aminoethylthio)-1-carbadethia- pen-2-em-3-carboxylic acid 100 mg. Polyethylene Glycol 4000 U.S.P. 400 mg. Polyethylene Glycol 400 U.S.P. 1.0 gram. The active ingredient in the above formulations may be administered alone or in combination with other biologically active ingredients as, for example, with other antibacterial agents such as lincomycin, a penicillin, streptomycin, novobiocin, gentamicin, neomycin, colistin and kanamycin, or with other therapeutic agents such as probenecid.

Claims: WHAT IS CLAINED IS 1. .A compound having the structure: EMI120.1 and the ph¯--mScautically acceptable salts thereof wherein R is H; pharmaceutically acceptable salt cation; or a pharmaceutically ceptable ester moiety; and R1, R6, R7 and R8 are independently selected from the group consisting of hydrogen, is not H), 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 moietiens; phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di-, and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms; ana wherein the alkyl moieties of the above-recited substitnt have 1-6 carbon atoms 2. compound according to Claim 1 wherein R1 is alkyl, or cycloalkyl. 3. A compound according to Claim 1 wherein R6 is H or methyl and R7 is alkyl, phenyl, aralkyl or hydrohylsubstituted alkyl,pheny or aralkyl. 4. A compound according to Claim 1 wherein: R6 is hydrogen or methyl and R8 is selected from the group consisting of: H, CH3, (CH2)2NH, C(CH3)2CH2NH2 EMI121.1 EMI121.2 CH2CH2CH2NH2 , CH2CH(CH3)CH2NH2 , EMI121.3 EMI122.1 EMI123.1 CH(CH3)CH2NH2 , EMI123.2 and R7 is selected from: EMI123.3 -CH3 -CH2CH3 EMI124.1 5. A process for preparing a compound according to Claim 1 comprising: cvclizina in the Presence of base to form: EMI124.2 dehydrohalogenating th resulting intermediate in the presence of base to form: EMI124.3 heating the resulting intermediate in the presence of a displacing agent to form: EMI124.4 isomerizing the position of the double bond of the resultinq intermediate to form: EMI125.1 wherein X is halo. 6. A process for preparing a compound according to Claim 1 comprising treating: EMI125.2 with a base capable of isomerizing the double bond to form: EMI125.3 7. A compound having the structure: EMI125.4 and its pharmaceutically acceptable salts and esters. 8. A compound according to 1am the structure: EMI126.1 and the pharmaceutically acceptable salts thereof wherein R is H; pharmaceutically acceptable salt cation; or a pharmaceutically acceptable.ester moiety; and R6, R7 and R8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; R1 is selected from the group consisting of methyl, ethyl1 propyl, isopropyl cyclopropyl, phenyl and benzyl. r 9. A compound having the structure: EMI127.1 and the pharmaceutically acceptable salts and esters thereof; wherein R1,, and z Rare independently selected from the group consisting; of hydrogen (R1 is not H) and substituted and unsubstituted: alkyl having 1-6 carbon atoms, phenyl, phenylalkyl wherein the alkyl moiety has 1-6 carbon atoms, cycloalkyl and cycloalkylalkyl havin3 to 6 ring carbon atoms and 1-6 carbon atoms in the alkyl moiety; wherein the substituient or substituents on R1, R6 and R7 are selected from chloro, bromo, fluoro, hydroxyl, amino, mono-, di-, and trialkylamino (each alkyl having 1-6 carbon atoms), alkoxyl having 1-6 carbon atoms, cyano and carboxyl 10. A compound according to Claim 9 wherein R is alkyl, cyclopropyl, benzyl or phenyl; R6 is hydrogen and R7 is alkyl or phenylalkyl substituted by hydroxyl or amino. 11. A compound according to Claim10 wherein R1 is methyl,, ethyl, isopropyl, t-butyl or phenyl and i is l-hydroxyethyl, methyl, or hydroxymethyl. 12. A process for preparing according to Claim 9 comprising treating a compound of the formula: EMI128.1 wherein R is a readily removable protecting group with a glyoxylate ester wherein the ester moiety is a pharmaceutically acceptable ester moiety or a readily removable blocking group, R', to provide a compound having the structure: EMI128.2 followed by halogenating to provide a compound having the structure: EMI128.3 wherein X is halogen followed by treating with triphenylphosphine and mild aqueous hydrolysis to Provide: EMI128.4 followed by cyclizing the above structure after treating with an oxidizing agent. ss. A process for preparing a compound according to Claim 9 comprising cyclizing: EMI129.1 wherein is phenyl, and R' is a pharmaceutically acceptable ester moiety or a readily removable blocking group. 14. A compound having the formula: EMI130.1 and its pharmaceutically acceptable salts and esters wherein R1 is selected from the group consisting of substituted and unsubstituted loweralkyl having from 1-6 carbon atoms, phenyl, phenylloweralkyl, cycloalkyl having from 3 to 6 carbon atoms, and cycloalkylalkyl having 4 to 7 carbon atoms in the chain and 3-6 carbon atoms in the ring; wherein said substituents on R1 are selected from the group consisting of halogen, hydroxyl, amino, and substituted amino, alkoxyl, azido, cyano, carboxyl. 15. A compound according to Clain 14 wherein R1 is methyl, phenyl, ethyl, cyclopropyl, propyl and isopropyl. 16. A process for preparing a compound according to Claim 14 comprising treating a compound of the formula: EMI130.2 wherein R is a readily removable protecting group with a glyoxylate ester wherein the ester moiety is a pharmaceutically acceptable ester moiety or a readily removable blocking group, R2, to provide a compound having the structure: EMI131.1 followed by halogenating to provide a compound having the structure: EMI131.2 wherein X is halogen followed by treating with triphenylphosphine and mild aqueous hydrolysis to provide: EMI131.3 followed by cyclizing the above structure after treating with an oxidizing agent. 17 A process for preparing a compound according to Claim 14 comprising cyclizing: EMI131.4 wherein is phenyl, and R" is a pharmaceutically acceptable ester moiety or a readily removable blocking group. 18. A compound having the formula: EMI132.1 and its pharmace ically acceptable salts and esters wherein R1 is selected from the group consisting of substituted and unsubstituted loweralkyl having from 1-6 carbon atoms, phenyl, phenylloweralkyl, cycloalkyl having from 3 to 6 carbon atoms, and cycloalkylalkyl having 4 to 7 carbon atoms in the chain and 3-6 carbon atoms in the ring; wherein said substituents on R1 are selected from the group consisting of halogen, hydroxyl, amino, alkoxyl-having 1-6 carbon atoms, azido, cyano, and carboxyl. 1q A compound according to Claim 18 wherein R1 is methyl, phenyl, benzyl, ethyl, cyclopropyl, propyl and isopropyl. 20. A compound according to Claim wherein R1 is methyl having the structure EMI132.2 21. A compound having the formula: EMI132.3 wherein R is H or CH3. 22 a process for preparing a compound according to Claim 1 having the structure: EMI133.1 and its pharmaceutically acceptable salts; comprising: cyclizing in the presence of base EMI133.2 to torm: EMI133.3 dehydrohalogenating the resulting intermediate in the presence of base to form: EMI133.4 heating the resulting intermediate in the presence of a displacing agent to form: EMI133.5 isomerizing the position of the double bond of the resulting intermediate to form: EMI133.6 debloking to form. EMI133.7 wherein R4 and R5 are blocking groups, and X is halo. 23. A process for preparing a compound accordi to Claim 18having the structure: EMI134.1 and its pharmaceutically acceptable salts; comprising: cyclizing in the presence of bese EMI134.2 to form: EMI134.3 dehydrohalogenating the resulting intermediate in the presence of base to form: EMI134.4 heating the resulting intermediate in tbe presence of a displacing agent to form: EMI134.5 isomerizing the position of the double bond of the resulting intermediate to form: EMI135.1 wherein R4 and Rs are blocking groups, and X is halo. 26 A process for preparing a compound according to Claim 18 having the structure: EMI135.2 comprising treating: EMI135.3 with a base.capable of isomerizing the double bond to form: EMI135.4 wherein R4 and R5 are blocking groups. 25. An antibiotic pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claims 1 to 4, 7 to 11 14, 15 or 18 to 21 and a pharmaceutically carrier therefor. Claims for @@@@ria 1. A process for preparing a compound having the structure: EMI136.1 and the pharmaceutically acceptable salts thereof wherein R is H; pharmaceutically acceptable salt cation; or a pharmaceutically accetable ester moiety; and RÚ,R6,R7 and R8 are independently selected from the group consisting of hydrogen, (R1 is not H), 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; phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di-, and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms comprising: cyclizing in the presence of base: EMI137.1 dehydrohalogenating the resulting intermediate in the presence of base to form: EMI137.2 heating the resulting intermediate in the presence of a displacing agent to form: EMI137.3 isomerizing the position of the double bond of the resulting intermediate to form: EMI137.4 wherein X is halo. 2. A process for preparing a compound according to Clain 1 comprising treating: EMI138.1 with a base capable of isomerizing the double bond to form: EMI138.2 3. A process for preparing a compound having the structure: EMI138.3 and the pharmaceutically acceptable salts and esters thereof; wherein R11 R2. and R3 are independently selected from the group consisting of hydrogen (R1 is not H) and substituted and unsubstituted: alkyl having 1-6 carbon atoms, phenyl, phenylalkyl wherein the alkyl moiety has 1-6 carbon atoms, cycloalkyl and cycloalkylalkyl having 3 to 6 ring carbon atoms and 1-6 carbon atoms in the alkyl moiety; wherein the substituent or substituents on R1, R2 and R3 are selected from chloro, bromo, fluoro, hydroxyl, amino, mono-, di-, and trialkylamino (each alkyl having 1-6 carbon atoms), alkoxyl having 1-6 carbon atoms, cyano and carboxyl comprising treating a compound of the formula: EMI139.1 wherein R is a readily removable protecting group. with a glyoxylate ester wherein the ester moiety is a pharmaceutically acceptable ester moiety or a readily removable blocking group, R', to provide a compound having the structure: EMI139.2 followed by halogenating to provide a compound having the structure: EMI139.3 wherein X is halogen followed by treating with triphenylphosphine and mild aqueous hydrolysis to provide: EMI139.4 followed by cyclizing the above structure after treating with an oxidizing agent. 3. A process for preparing a compound according to Claim 3 cc:nDrisir,g cyclizing: EMI140.1 wherein is phenyl, and R' is a pharmaceutically acceptable ester moiety or a readily removable blocking group. 5. A process for preparing a compound having the formula: EMI140.2 and its pharmaceutically acceptable salts and esters wherein R1 is selected from the group consisting of substituted and unsubstituted loweralkyl having from 1-6 carbon atoms, phenyl, phenylloweralkyl, cycloalkyl having from 3 to 6 carbon atoms, and cycloalkylalkyl having 4 to 7 carbon atoms in the chain and 3-6 carbon atoms in the ring; wherein said substituents on R1 are selected from the group consisting of halogen, hydroxyl, amino, and substituted amino, alkoxyl, azido, cyano, carboxyl comprising treating a compound of the formula: EMI140.3 wherein R is a readily removable protecting group with a glyoxylate ester wherein the ester moiety is a pharmaceutically accetable ester moiety or a readi removable blocking group, Rê , to provide a compound having the structure: EMI141.1 followed by halogenating to provide a compound having the structure: EMI141.2 wherein X is halogen followed by treating with triphenylphosphine and mild aqueous hydrolysis to provide: EMI141.3 followed by cyclizing the above structure after treating with an oxidizing agent. 6. A process for preparing a compound according to Claim 5 comprising cyclizing: EMI141.4 wherein # is phenyl, and Rê is a pharmaceutically acceptable ester moiety or a readily removable' blocking group. 7. A process for preparing a compound according to Claim 1 having the structure: EMI142.1 and its pharmaceutically acceptable salts; comprising: cyclizing in the presence of base EMI142.2 to form: EMI142.3 dehydrohalogenating the resulting intermediate in the presence of base to form: EMI142.4 heating the resulting intermediate in the presence of a displacing agent to form: EMI142.5 isomerizing the position of the double bond of the resulting intermediate to tOr:fl: EMI143.1 deblocking to form: EMI143.2 wherein R4 and R5 are blocking groups, and X is halo. 8. A process for preparing a compound having the formula: EMI143.3 and its pharmaceutically acceptable salts wherein R1 is selected from the group consisting of substituted and unsubstituted loweralkyl having-from 1-6 carbon atoms, phenyl, phenylloweralkyl, cycloalkyl having from 3 to 6 carbon atoms, and cycloalkylalkyl having 4 to 7 carbon atoms in the chain and 3-6 carbon atoms in the ring; wherein said substituents on R1 are selected from the group consisting of halogen, hydroxyl, amino, alkoxyl having 1-6 carbon atoms azido, cyano, and carboxyl comprising: cyclizing in the presence of base EMI143.4 to form: EMI143.5 dehydrohalogenating the resulting intermediate in the presence of base to form: EMI144.1 heating the resulting intermediate in the presence of 2 displacing agent to form: EMI144.2 isomerizing the position of the double bond of the resulting intermediate to form: EMI144.3 wherein R4 and R5 are blocking groups, and X is halo. 9. A process for preparing a compound.having the formula: EMI144.4 wherein R is selected from the group consisting of substituted and unsubstituted loweralkyl having from 1-6 carbon atop, phenyl, phenylloweralkyl, cycloalkyl having from 3 to 6 carbon atoms, and cycloalkylalkyl having 4 to 7 carbon atoms in the chain and 3-6 carbon atoms in the ring; wherein said substituents on R1 are selected from the group consisting of halogen, hydroxyl, amino, alkoxyl-baving 1-6 carbon atoms, azido, cyano, and carboxyl. comprising treating. EMI145.1 with a base capable of isomerizing the double bond to form: EMI145.2 wherein R4 and R5 are blocking groups.

Inventors: CHRISTENSEN, BURTON G., SHIH, DAVID H.
Applicants: MERCK & CO. INC.
Application year: 1979
Main classification: C07D487
IPC codes: C07C205, C07F9, C07D498, C07D205, C07D477, C07F7