6) The condensation of 2-methyl-2-cyclohexen-1-one (XXIV) with the previously described azetidinone (III) by means of lithium diisopropylamide in THF, followed by flash chromatography, gives the enantiomerically pure 3-methoxy-3-cyclohexenylazetidinone (XXV), which by reduction with H2 over Pd/C in ethyl acetate followed by chromatography yields the previously described azetidinone (VIII). The cyclization of (VIII) with allyloxyoxalyl chloride (XXVI) by means of K2CO3 in dichloromethane affords (4S,8S,9R,10S)-1-[1(R)-(tert-butyldimethylsilyloxy)ethyl-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (XXVII), which is treated with tetrabutylammonium fluoride in THF/acetic acid to eliminate the TBS group giving the 1-hydroxyethyl derivative (XXVIII). Finally, this compound is treated with triphenylphosphine and potassium 2-ethylhexanoate to afford the potassium salt (XIV), already described in Scheme 18359601a.

1) The reaction of 2-methoxycyclohexanone (I) with dialkyl carbonate by means of NaH/KH in THF gives 3-methoxy-2-oxocyclohexanecarboxylic acid allyl ester (II), which is condensed with (3R,4R)-4-acetoxy-3-[1(R)-tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of NaH in THF yielding the condensation product (IV) as a mixture of the alpha- and beta-stereoisomers at the methoxy group. The protection of the NH group of (IV) with tert-butyldimethylsilyl (TBS) trifluoromethanesulfonate affords the bis-TBS-protected compound (V), which is stereospecifically decarboxylated with palladium acetate, formic acid and triphenylphosphine to the protected azetidinone (VI) also as alpha- and beta-isomers. The selective desilylation of (VI) with tetrabutylammonium fluoride (TBAF) in acetic acid gives the O-protected azetidinone (VII) also as a mixture, which is epimerized by sequential treatments with lithium diisopropylamide (LDA), with ZnBr2 and finally with diethyl malonate to afford the alpha-(S)-epimer (VIII). The acylation of (VIII) with benzyloxalyl chloride and pyridine in dichloromethane gives the N-benzyloxazyl derivative (IX), which is cyclized by means of triethyl phosphite in refluxing xylene yielding (4S,8S,9R,10S)-10-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid benzyl ester (X). The desilylation of (X) with TBAF in THF/acetic acid affords (XI) with a 1-hydroxyethyl group, which is hydrogenated with H2 over Pd/C in dioxane in the presence of 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (XII) giving the addition salt (XIII). The treatment of (XIII) with potassium 2-ethylhexanoate yields the corresponding potassium salt (XIV) (1), which is finally esterified with 1-chloroethyl cyclohexyl carbonate (XV) by means of benzyltrimethylammonium chloride in DMF.

1) The reaction of 2-methoxycyclohexanone (I) with dialkyl carbonate by means of NaH/KH in THF gives 3-methoxy-2-oxocyclohexanecarboxylic acid allyl ester (II), which is condensed with (3R,4R)-4-acetoxy-3-[1(R)-tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of NaH in THF yielding the condensation product (IV) as a mixture of the alpha- and beta-stereoisomers at the methoxy group. The protection of the NH group of (IV) with tert-butyldimethylsilyl (TBS) trifluoromethanesulfonate affords the bis-TBS-protected compound (V), which is stereospecifically decarboxylated with palladium acetate, formic acid and triphenylphosphine to the protected azetidinone (VI) also as alpha- and beta-isomers. The selective desilylation of (VI) with tetrabutylammonium fluoride (TBAF) in acetic acid gives the O-protected azetidinone (VII) also as a mixture, which is epimerized by sequential treatments with lithium diisopropylamide (LDA), with ZnBr2 and finally with diethyl malonate to afford the alpha-(S)-epimer (VIII). The acylation of (VIII) with benzyloxalyl chloride and pyridine in dichloromethane gives the N-benzyloxazyl derivative (IX), which is cyclized by means of triethyl phosphite in refluxing xylene yielding (4S,8S,9R,10S)-10-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid benzyl ester (X). The desilylation of (X) with TBAF in THF/acetic acid affords (XI) with a 1-hydroxyethyl group, which is hydrogenated with H2 over Pd/C in dioxane in the presence of 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (XII) giving the addition salt (XIII). The treatment of (XIII) with potassium 2-ethylhexanoate yields the corresponding potassium salt (XIV) (1), which is finally esterified with 1-chloroethyl cyclohexyl carbonate (XV) by means of benzyltrimethylammonium chloride in DMF.

2) The condensation of the previously referenced azetidinone (III) with 1-(trimethylsilyloxy)cyclohexene (XVI) by means of trimethylsilyloxy trifluoromethanesulfonate in acetonitrile gives the corresponding addition product (XVII), which by reaction first with p-toluenesulfonyl hydrazide in acetic acid and then with lithium diisopropylamide in THF yields the cyclohexenyl derivative (XVIII). The regioselective epoxidation of (XVIII) with magnesium monoperoxyphthalate (MgMPP) in dichloromethane affords the epoxide (XIX), which is submitted to ring opening with methanol/p-toluenesulfonic acid and oxidation with sulfur trioxide and pyridine to give the methoxycyclohexylazetidinone (VIII) already described in Scheme 18359601a. 3) The condensation of the previously referenced azetidinone (III) with (2-cyclohexenyl)bis(trans-2-methylcyclohexyl)borane (XX) at room temperature in hexane/THF yields the cyclohexenyl-azetidinone derivative (XVIII) already described. 4) The enzymatic resolution of trans-2-methoxycyclohexanol (XX) with Pseudomonas fluorescens lipase or with Candida antarctica lipase in dry THF containing vinyl acetate and triethylamine gives the (S,S)-isomer (XXI), which is oxidized with oxalyl chloride in dichloromethane, or with CrO3/H2SO4, or with NaOCl or with N-bromoacetamide in acetone yielding 2(S)-methoxycyclohexanone (XXII). Finally, this compound is condensed with the previously referenced azetidinone (III) by means of SnCl4 in dichloromethane to afford the methoxycyclohexylazetidinone (VIII) already described. 5) The reaction of the previously described 2(S)-methoxycyclohexanone (XXII) with trimethylsilyl trifluoromethanesulfonate and triethylamine in THF gives the corresponding trimethylsilyl ether (XXIII), which is then condensed with the previously referenced azetidinone (III) by means of the SnCl4.S(Me)2 complex in dichloromethane yielding the previously described methoxycyclohexylazetidinone (VIII).

1) The reaction of 2-methoxycyclohexanone (I) with dialkyl carbonate by means of NaH/KH in THF gives 3-methoxy-2-oxocyclohexanecarboxylic acid allyl ester (II), which is condensed with (3R,4R)-4-acetoxy-3-[1(R)-tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of NaH in THF yielding the condensation product (IV) as a mixture of the alpha- and beta-stereoisomers at the methoxy group. The protection of the NH group of (IV) with tert-butyldimethylsilyl (TBS) trifluoromethanesulfonate affords the bis-TBS-protected compound (V), which is stereospecifically decarboxylated with palladium acetate, formic acid and triphenylphosphine to the protected azetidinone (VI) also as alpha- and beta-isomers. The selective desilylation of (VI) with tetrabutylammonium fluoride (TBAF) in acetic acid gives the O-protected azetidinone (VII) also as a mixture, which is epimerized by sequential treatments with lithium diisopropylamide (LDA), with ZnBr2 and finally with diethyl malonate to afford the alpha-(S)-epimer (VIII). The acylation of (VIII) with benzyloxalyl chloride and pyridine in dichloromethane gives the N-benzyloxazyl derivative (IX), which is cyclized by means of triethyl phosphite in refluxing xylene yielding (4S,8S,9R,10S)-10-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid benzyl ester (X). The desilylation of (X) with TBAF in THF/acetic acid affords (XI) with a 1-hydroxyethyl group, which is hydrogenated with H2 over Pd/C in dioxane in the presence of 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (XII) giving the addition salt (XIII). The treatment of (XIII) with potassium 2-ethylhexanoate yields the corresponding potassium salt (XIV) (1), which is finally esterified with 1-chloroethyl cyclohexyl carbonate (XV) by means of benzyltrimethylammonium chloride in DMF.

2) The condensation of the previously referenced azetidinone (III) with 1-(trimethylsilyloxy)cyclohexene (XVI) by means of trimethylsilyloxy trifluoromethanesulfonate in acetonitrile gives the corresponding addition product (XVII), which by reaction first with p-toluenesulfonyl hydrazide in acetic acid and then with lithium diisopropylamide in THF yields the cyclohexenyl derivative (XVIII). The regioselective epoxidation of (XVIII) with magnesium monoperoxyphthalate (MgMPP) in dichloromethane affords the epoxide (XIX), which is submitted to ring opening with methanol/p-toluenesulfonic acid and oxidation with sulfur trioxide and pyridine to give the methoxycyclohexylazetidinone (VIII) already described in Scheme 18359601a. 3) The condensation of the previously referenced azetidinone (III) with (2-cyclohexenyl)bis(trans-2-methylcyclohexyl)borane (XX) at room temperature in hexane/THF yields the cyclohexenyl-azetidinone derivative (XVIII) already described. 4) The enzymatic resolution of trans-2-methoxycyclohexanol (XX) with Pseudomonas fluorescens lipase or with Candida antarctica lipase in dry THF containing vinyl acetate and triethylamine gives the (S,S)-isomer (XXI), which is oxidized with oxalyl chloride in dichloromethane, or with CrO3/H2SO4, or with NaOCl or with N-bromoacetamide in acetone yielding 2(S)-methoxycyclohexanone (XXII). Finally, this compound is condensed with the previously referenced azetidinone (III) by means of SnCl4 in dichloromethane to afford the methoxycyclohexylazetidinone (VIII) already described. 5) The reaction of the previously described 2(S)-methoxycyclohexanone (XXII) with trimethylsilyl trifluoromethanesulfonate and triethylamine in THF gives the corresponding trimethylsilyl ether (XXIII), which is then condensed with the previously referenced azetidinone (III) by means of the SnCl4.S(Me)2 complex in dichloromethane yielding the previously described methoxycyclohexylazetidinone (VIII).

2) The condensation of the previously referenced azetidinone (III) with 1-(trimethylsilyloxy)cyclohexene (XVI) by means of trimethylsilyloxy trifluoromethanesulfonate in acetonitrile gives the corresponding addition product (XVII), which by reaction first with p-toluenesulfonyl hydrazide in acetic acid and then with lithium diisopropylamide in THF yields the cyclohexenyl derivative (XVIII). The regioselective epoxidation of (XVIII) with magnesium monoperoxyphthalate (MgMPP) in dichloromethane affords the epoxide (XIX), which is submitted to ring opening with methanol/p-toluenesulfonic acid and oxidation with sulfur trioxide and pyridine to give the methoxycyclohexylazetidinone (VIII) already described in Scheme 18359601a. 3) The condensation of the previously referenced azetidinone (III) with (2-cyclohexenyl)bis(trans-2-methylcyclohexyl)borane (XX) at room temperature in hexane/THF yields the cyclohexenyl-azetidinone derivative (XVIII) already described. 4) The enzymatic resolution of trans-2-methoxycyclohexanol (XX) with Pseudomonas fluorescens lipase or with Candida antarctica lipase in dry THF containing vinyl acetate and triethylamine gives the (S,S)-isomer (XXI), which is oxidized with oxalyl chloride in dichloromethane, or with CrO3/H2SO4, or with NaOCl or with N-bromoacetamide in acetone yielding 2(S)-methoxycyclohexanone (XXII). Finally, this compound is condensed with the previously referenced azetidinone (III) by means of SnCl4 in dichloromethane to afford the methoxycyclohexylazetidinone (VIII) already described. 5) The reaction of the previously described 2(S)-methoxycyclohexanone (XXII) with trimethylsilyl trifluoromethanesulfonate and triethylamine in THF gives the corresponding trimethylsilyl ether (XXIII), which is then condensed with the previously referenced azetidinone (III) by means of the SnCl4.S(Me)2 complex in dichloromethane yielding the previously described methoxycyclohexylazetidinone (VIII).

7) The potassium salt (XIV), immediate precursor of sanfetrinem cilexetil can also be obtained as an enantiomeric mixture by the following sequence: The reduction of 2-oxocyclohexanecarboxylic acid ethyl ester (XXIX) with H2 over PtO2 in ethanol gives a mixture of the cis- and trans-2-hydroxycyclohexane (XXX), which is separated by distillation and treated with tert-butyldimethylsilyl chloride and imidazole in THF to yield cis-2-(tert-butyldimethylsilyloxy)cyclohexanecarboxylic acid ethyl ester (XXXI) as an enantiomeric mixture cis-(S,R)/cis-(R,S) (for the sake of clarity only one of the enantiomers is presented). The reduction of (XXXI) with diisobutylaluminum hydride (DIBAL) in ether affords the corresponding aldehyde (XXXII), which is treated with lithium trimethylsilylamide in THF to give the silylated imine (XXXIII). The cyclization of (XXXIII) with lithium tert-butyl acetate (XXXIV) in THF yields the silylated azetidinone (XXXV), which is deprotected by treatment with tetrabutylammonium fluoride (TBAF) in THF affording the hydroxyazetidinone (XXXVI). The reaction of (XXXVI) with 2,2-dimethoxypropane (XXXVII) and BF3 ethearate in dichloromethane gives the acetonide (XXXVIII), which is condensed with acetyltrimethylsilane (XXXIX) by means of lithium diisopropylamide (LDA) and potassium tert-butoxide (in order to introduce the 1-hydroxyethyl group) yielding the alkylated acetonide (XL). The trimethylsilyl protection of (XL) was removed and substituted with a more stable tert-butyldimethylsilyl (TBS) group affording (XLI), which is treated with pyridine chlorochromate (PCC) to give the previously reported 2-oxocyclohexylazetidinone (XVII) (Scheme 2), but as an enantiomeric mixture. The reaction sequence was continued (XVII) -> (XVIII) -> (XIX) -> (VIII) as in Scheme 2, and (VIII) -> (IX) -> (X) -> (XI) -> potassium salt (XIV) (all the compounds as enantiomeric mixtures). Note that if the starting compound is 2-oxocyclohexane-1(S)-carboxylic acid ethyl ester, instead of the racemic compound (XXIX), the potassium salt (XIV) can be obtained in enantiomerically pure form.

2) The condensation of the previously referenced azetidinone (III) with 1-(trimethylsilyloxy)cyclohexene (XVI) by means of trimethylsilyloxy trifluoromethanesulfonate in acetonitrile gives the corresponding addition product (XVII), which by reaction first with p-toluenesulfonyl hydrazide in acetic acid and then with lithium diisopropylamide in THF yields the cyclohexenyl derivative (XVIII). The regioselective epoxidation of (XVIII) with magnesium monoperoxyphthalate (MgMPP) in dichloromethane affords the epoxide (XIX), which is submitted to ring opening with methanol/p-toluenesulfonic acid and oxidation with sulfur trioxide and pyridine to give the methoxycyclohexylazetidinone (VIII) already described in Scheme 18359601a. 3) The condensation of the previously referenced azetidinone (III) with (2-cyclohexenyl)bis(trans-2-methylcyclohexyl)borane (XX) at room temperature in hexane/THF yields the cyclohexenyl-azetidinone derivative (XVIII) already described. 4) The enzymatic resolution of trans-2-methoxycyclohexanol (XX) with Pseudomonas fluorescens lipase or with Candida antarctica lipase in dry THF containing vinyl acetate and triethylamine gives the (S,S)-isomer (XXI), which is oxidized with oxalyl chloride in dichloromethane, or with CrO3/H2SO4, or with NaOCl or with N-bromoacetamide in acetone yielding 2(S)-methoxycyclohexanone (XXII). Finally, this compound is condensed with the previously referenced azetidinone (III) by means of SnCl4 in dichloromethane to afford the methoxycyclohexylazetidinone (VIII) already described. 5) The reaction of the previously described 2(S)-methoxycyclohexanone (XXII) with trimethylsilyl trifluoromethanesulfonate and triethylamine in THF gives the corresponding trimethylsilyl ether (XXIII), which is then condensed with the previously referenced azetidinone (III) by means of the SnCl4.S(Me)2 complex in dichloromethane yielding the previously described methoxycyclohexylazetidinone (VIII).

A new method of synthesis for the key intermediate (3S,4R)-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[3(R)-methoxy-2-ox o-1(R)-cyclohexyl]azetidin-2-one ([VIII] in original monograph) of sanfetrinem has been described: The oxidation of (1S,2S)-2-methoxycyclohexanol (I) with CrO3/H2SO4 in water gives 2(S)-methoxycyclohexanone (II), which is then condensed with the comercially available (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of SnCl4 and diisopropylethylamine or triisobutylamine in dichloromethane or chlorobenzene to afford intermediate (VIII) after crystallization of the isomeric mixture.

A new synthesis of sanfetrinem has been published: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

A new synthesis of sanfetrinem has been puplished: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

1) The reaction of 2-methoxycyclohexanone (I) with dialkyl carbonate by means of NaH/KH in THF gives 3-methoxy-2-oxocyclohexanecarboxylic acid allyl ester (II), which is condensed with (3R,4R)-4-acetoxy-3-[1(R)-tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of NaH in THF yielding the condensation product (IV) as a mixture of the alpha- and beta-stereoisomers at the methoxy group. The protection of the NH group of (IV) with tert-butyldimethylsilyl (TBS) trifluoromethanesulfonate affords the bis-TBS-protected compound (V), which is stereospecifically decarboxylated with palladium acetate, formic acid and triphenylphosphine to the protected azetidinone (VI) also as alpha- and beta-isomers. The selective desilylation of (VI) with tetrabutylammonium fluoride (TBAF) in acetic acid gives the O-protected azetidinone (VII) also as a mixture, which is epimerized by sequential treatments with lithium diisopropylamide (LDA), with ZnBr2 and finally with diethyl malonate to afford the alpha-(S)-epimer (VIII). The acylation of (VIII) with benzyloxalyl chloride and pyridine in dichloromethane gives the N-benzyloxazyl derivative (IX), which is cyclized by means of triethyl phosphite in refluxing xylene yielding (4S,8S,9R,10S)-10-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid benzyl ester (X). The desilylation of (X) with TBAF in THF/acetic acid affords (XI) with a 1-hydroxyethyl group, which is hydrogenated with H2 over Pd/C in dioxane in the presence of 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (XII) giving the addition salt (XIII). The treatment of (XIII) with potassium 2-ethylhexanoate yields the corresponding potassium salt (XIV) (1), which is finally esterified with 1-chloroethyl cyclohexyl carbonate (XV) by means of benzyltrimethylammonium chloride in DMF.

6) The condensation of 2-methyl-2-cyclohexen-1-one (XXIV) with the previously described azetidinone (III) by means of lithium diisopropylamide in THF, followed by flash chromatography, gives the enantiomerically pure 3-methoxy-3-cyclohexenylazetidinone (XXV), which by reduction with H2 over Pd/C in ethyl acetate followed by chromatography yields the previously described azetidinone (VIII). The cyclization of (VIII) with allyloxyoxalyl chloride (XXVI) by means of K2CO3 in dichloromethane affords (4S,8S,9R,10S)-1-[1(R)-(tert-butyldimethylsilyloxy)ethyl-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (XXVII), which is treated with tetrabutylammonium fluoride in THF/acetic acid to eliminate the TBS group giving the 1-hydroxyethyl derivative (XXVIII). Finally, this compound is treated with triphenylphosphine and potassium 2-ethylhexanoate to afford the potassium salt (XIV), already described in Scheme 18359601a.

A new synthesis of sanfetrinem has been published: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

A new synthesis of sanfetrinem has been puplished: The condensation of (3S,4R)-4-acetoxy-3-[1(R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (I) with 2-methoxy-2-cyclohexen-1-one (II) by means of lithium bis(trimethylsilyl)amide (LHMDA) in THF gives a mixture of diastereomers that are separated by flash chromatography yielding pure enantiomer (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in ethyl acetate affords another mixture of diastereomers that are also separated by flash chromatography giving pure enantiomer (IV). The cyclization of (IV) with allyl acrylate (V) by means of triethylamine yields (4S,8S,9R,10S)-10-[1(R)-hydroxyethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid allyl ester (VI), the silylated allyl ester of sanfetrinem. Finally, this compound is desilylated by treatment with tetrabutylammonium fluoride (TBAF)/acetic acid in THF, and saponified with potassium 2-ethylhexanoate (KEH).

2) The condensation of the previously referenced azetidinone (III) with 1-(trimethylsilyloxy)cyclohexene (XVI) by means of trimethylsilyloxy trifluoromethanesulfonate in acetonitrile gives the corresponding addition product (XVII), which by reaction first with p-toluenesulfonyl hydrazide in acetic acid and then with lithium diisopropylamide in THF yields the cyclohexenyl derivative (XVIII). The regioselective epoxidation of (XVIII) with magnesium monoperoxyphthalate (MgMPP) in dichloromethane affords the epoxide (XIX), which is submitted to ring opening with methanol/p-toluenesulfonic acid and oxidation with sulfur trioxide and pyridine to give the methoxycyclohexylazetidinone (VIII) already described in Scheme 18359601a. 3) The condensation of the previously referenced azetidinone (III) with (2-cyclohexenyl)bis(trans-2-methylcyclohexyl)borane (XX) at room temperature in hexane/THF yields the cyclohexenyl-azetidinone derivative (XVIII) already described. 4) The enzymatic resolution of trans-2-methoxycyclohexanol (XX) with Pseudomonas fluorescens lipase or with Candida antarctica lipase in dry THF containing vinyl acetate and triethylamine gives the (S,S)-isomer (XXI), which is oxidized with oxalyl chloride in dichloromethane, or with CrO3/H2SO4, or with NaOCl or with N-bromoacetamide in acetone yielding 2(S)-methoxycyclohexanone (XXII). Finally, this compound is condensed with the previously referenced azetidinone (III) by means of SnCl4 in dichloromethane to afford the methoxycyclohexylazetidinone (VIII) already described. 5) The reaction of the previously described 2(S)-methoxycyclohexanone (XXII) with trimethylsilyl trifluoromethanesulfonate and triethylamine in THF gives the corresponding trimethylsilyl ether (XXIII), which is then condensed with the previously referenced azetidinone (III) by means of the SnCl4.S(Me)2 complex in dichloromethane yielding the previously described methoxycyclohexylazetidinone (VIII).

2) The condensation of the previously referenced azetidinone (III) with 1-(trimethylsilyloxy)cyclohexene (XVI) by means of trimethylsilyloxy trifluoromethanesulfonate in acetonitrile gives the corresponding addition product (XVII), which by reaction first with p-toluenesulfonyl hydrazide in acetic acid and then with lithium diisopropylamide in THF yields the cyclohexenyl derivative (XVIII). The regioselective epoxidation of (XVIII) with magnesium monoperoxyphthalate (MgMPP) in dichloromethane affords the epoxide (XIX), which is submitted to ring opening with methanol/p-toluenesulfonic acid and oxidation with sulfur trioxide and pyridine to give the methoxycyclohexylazetidinone (VIII) already described in Scheme 18359601a. 3) The condensation of the previously referenced azetidinone (III) with (2-cyclohexenyl)bis(trans-2-methylcyclohexyl)borane (XX) at room temperature in hexane/THF yields the cyclohexenyl-azetidinone derivative (XVIII) already described. 4) The enzymatic resolution of trans-2-methoxycyclohexanol (XX) with Pseudomonas fluorescens lipase or with Candida antarctica lipase in dry THF containing vinyl acetate and triethylamine gives the (S,S)-isomer (XXI), which is oxidized with oxalyl chloride in dichloromethane, or with CrO3/H2SO4, or with NaOCl or with N-bromoacetamide in acetone yielding 2(S)-methoxycyclohexanone (XXII). Finally, this compound is condensed with the previously referenced azetidinone (III) by means of SnCl4 in dichloromethane to afford the methoxycyclohexylazetidinone (VIII) already described. 5) The reaction of the previously described 2(S)-methoxycyclohexanone (XXII) with trimethylsilyl trifluoromethanesulfonate and triethylamine in THF gives the corresponding trimethylsilyl ether (XXIII), which is then condensed with the previously referenced azetidinone (III) by means of the SnCl4.S(Me)2 complex in dichloromethane yielding the previously described methoxycyclohexylazetidinone (VIII).