4) The reaction of phenyl thiobutyrate (XIX) with 9-borabicyclo[3.3.1]nonane (9-BBN) gives the enol ester (XX), which is condensed with the optically active imine (XXI) [prepared from 3-(trimethylsilyl)propynal (XXIII) and (S)-alpha-methylbenzylamine (XXII)] to afford the adduct (XXIV). The cyclization of (XXIV) by means of tert-butylmagnesium chloride in ether yields 3alpha-ethyl-1-(alpha-methylbenzyl)-4beta-[2-(trimethylsilyl)ethynyl]azetidin-2-one (XXV), which is deprotected with tetrabutylammonium fluoride giving the free acetylene derivative (XXVI). The partial reduction of (XXVI) with H2 over Pd-CaCO3-PbO yields the corresponding ethylene compound (XXVII), which is hydroxylated with disiamylborane (DSB) to give the 2-hydroxyethylazetidinone (XXVIII). The protection of (XXVIII) with tert-butyldimethylsilyl chloride yields the silylated compound (XXIX), which is treated with Na-NH3 to afford 3alpha-ethyl-4beta-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XXX). The protection of (XXX) with tert-butyldimethylsilyl chloride as before gives the fully silylated compound (XXXI), which is submitted to a controlled hydrolysis yielding 3alpha-ethyl-4beta-(2-hydroxyethyl)-1-(tert-butyldimethylsilyl)azetidin-2-one (XXXII). The oxidation of (XXXII) with CrO3 - pyridine gives the acetic acid derivative (XXXIII), which is deprotected to afford 2-(3alpha-ethyl-2-oxoazetidin-4beta-yl)acetic acid (XXXIV). The reaction of (XXXIV) with carbonyldiimidazole (XXXV) gives the corresponding imidazolide (XXXVI), which is condensed with magnesium 4-nitrobenzyl malonate (XXXVII) yielding 4-nitrobenzyl 4-(3alpha-ethyl-2-oxoazetidin-4beta-yl)-3-oxobutanoate (XXXVIII). The diazotation of (XXXVIII) with 4-azidobenzoic acid (XXXIX) gives the 2-diazo-3-oxobutanoate derivative (XL), which is finally cyclized to carbapen derivative (XII) in the presence of rhodium acetate. The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.

1) The cyclization of ethyl 3(S)-hydroxybutanoate (I) with N-anisylcinnamylideneamine (II) gives 1-(4-anisyl)-3alpha-[1(S)-hydroxyethyl]-4-(2-phenylvinyl)azetidin-2-one (III), which is esterified with thiocarbonyldiimidazole (IV) yielding the thioester (V). The reduction of (V) with NaBH4 in hot DMSO affords 1-(4-anisyl)-3alpha-ethyl-4-(2-phenylvinyl)azetidin-2-one (VI), which is oxidized with KMnO4 - NaClO4, giving the carboxylic acid (VII). The oxidative decarboxylation of (VII) with lead tetraacetate yields 4-acetoxy-1-(4-anisyl)-3alpha-ethylazetidin-2-one (VIII), which is submitted to dearylation with ammonium cerium (IV) nitrate to afford 4-acetoxy-3alpha-ethylazetidin-2-one (IX). The condensation of (IX) with 4-nitrobenzyl 2-diazo-3-(tert-butyldimethylsilyloxy)-3-butenoate (X) gives the diazo keto ester (XI), which is cyclized yielding 4-nitrobenzyl 6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (XII). The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.

2) The hydroxyethylazetidinone (III) is esterified with p-toluenesulfonyl chloride to the corresponding tosylate (XVI), which is reduced with NaBH4 to the ethylazetidinone (VI), which is oxidized with KMnO4 - NaClO4, giving the carboxylic acid (VII). The oxidative decarboxylation of (VII) with lead tetraacetate yields 4-acetoxy-1-(4-anisyl)-3alpha-ethylazetidin-2-one (VIII), which is submitted to dearylation with ammonium cerium (IV) nitrate to afford 4-acetoxy-3alpha-ethylazetidin-2-one (IX). The condensation of (IX) with 4-nitrobenzyl 2-diazo-3-(tert-butyldimethylsilyloxy)-3-butenoate (X) gives the diazo keto ester (XI), which is cyclized yielding 4-nitrobenzyl 6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (XII). The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.

3) The reduction of (III) to (VI) can also be performed by treatment of (III) with methanesulfonyl chloride giving mesylate (XVII), which is treated with NaI to yield iodo derivative (XVIII). This compound is reduced to (VI) with NaBH4, which is oxidized with KMnO4 - NaClO4, giving the carboxylic acid (VII). The oxidative decarboxylation of (VII) with lead tetraacetate yields 4-acetoxy-1-(4-anisyl)-3alpha-ethylazetidin-2-one (VIII), which is submitted to dearylation with ammonium cerium (IV) nitrate to afford 4-acetoxy-3alpha-ethylazetidin-2-one (IX). The condensation of (IX) with 4-nitrobenzyl 2-diazo-3-(tert-butyldimethylsilyloxy)-3-butenoate (X) gives the diazo keto ester (XI), which is cyclized yielding 4-nitrobenzyl 6-ethyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (XII). The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.

5) The esterification of olivanic acid MM-17880 (XLI) with 4-nitrobenzyl chloride (XLII) gives the corresponding ester (XLIII), which is ethoxylated with triethyloxonium tetrafluoroborate yielding the ethyl sulfate (XLIV). Elimination of sulfuric acid affords the ethylidene derivative (XLV), which is finally reduced to PS-5 4-nitrobenzyl ester (XV) by means of NaBH4.

A new and stereoselective synthesis of (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), a key intermediate in the synthesis of PS-5 has been developed: The oxidation of 3-benzyloxy-1-propanol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of NaH yielding a mixture of the (Z)- and (E)-isomers of 5-benzyloxy-2-ethyl-2-pentenoic acid ethyl ester (IV) and (V). The undesired (Z)-isomer (IV) is isomerized by treating the mixture with diphenyldisulfide in refluxing THF. The hydrolysis of (V) with LiOH in THF/methanol/water gives the expected free acid (VI), which is treated with SOCl2 in refluxing benzene to afford the acid chloride (VII). The condensation of (VII) with the chiral oxazolidinone (VIII) by means of butyllithium in THF gives the acylated compound (IX), which is treated with benzenethiol and butyllithium in THF to give the addition compound (X) that is purified by medium pressure column chromatography to eliminate the undesired diastereomer. The elimination of the oxazolidinone group of (X) by reaction with trimethylaluminum, benzylthiol and butyllithium in THF yields the thioester (XI), which is treated with silver trfluoroacetate and water to afford the corresponding free acid (XII). The reaction of (XII) with methoxyamine and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDPC) in water affords the methoxyamide (XIII), which is methylated by means of methyl iodide and silver perchlorate to give the sulfonium salt (XIV). The cyclization of (XIV) by means of K2CO3 yields the azetidinone (XV), which is debenzylated by means of calcium in liquid ammonia affording (3R-trans)-3-ethyl-4-(2-hydrxyethyl)azetidin-2-one (XVI). Finally, this compound is silylated with tert-butyldimethylsilyl (TBDMS) trifluoromethanesulfonate affording (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), the desired target key intermediate in the synthesis of PS-5.