合成路线1

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.

合成路线2

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.

合成路线3

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.

合成路线4

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.

合成路线5

Preparation of the 15-methylerythromycin A precursor (XI) is accomplished by a chemobiosynthetic approach, utilizing the diketide surrogate (IX). Synthesis of (IX) is carried out as follows. Acylation of (S)-4-benzyl-2-oxazolidinone (I) with propionyl chloride (II) affords the N-propionyl oxazolidinone (III). Diastereoselective aldol condensation of (III) with butyraldehyde (IV) employing dibutylboron triflate leads to adduct (V). Deacetylation of cysteamine hydrochloride (VI) with Ac2O provides (VII). Then, selective hydrolysis of the thioester function of (VII) under alkaline conditions provides thiol (VIII). Condensation of the acyl oxazolidinone (V) with thiol (VIII) in the presence of AlMe3 gives rise to the thioester substrate (IX) (1). Incubation of a recombinant Streptomyces coelicolor strain with the diketide surrogate (IX) leads to the production of 6-deoxy-15-methylerythronolide B (X). Subsequent bioconversion of the aglycone (X) in a Saccharopolyspora erythraea strain affords the desired 15-methylerythromycin A (XI).

合成路线6