Prostaglandins. 2. Synthesis of Prostaglandin F_2α in Optically Active Form from Chiral Precursors

A synthetic route to optically active prostaglandins is described which uses chiral starting materials. Acylation of the bis(magnesiobromide) salt of methyl hemimalonate with (S)-(−)-2-acetoxysuccinyl chloride led to the unstable dimethyl (S)-4-acetoxy-3,6-dioxosuberate (1b). Treatment of the latter with basic magnesium carbonate then afforded a 4:1 mixture of methyl (S)-(−)-2-[2-(methoxycarbonyl)-3-oxo-5-acetoxycyclopent-1-enyl]acetate (2b) and its 4-acetoxy isomer (2d), from which the former was easily isolated by recrystallization. Catalytic reduction of 2b over a palladium-on-barium sulfate catalyst gave [2-(methoxycarbonyl)-3-oxo-5-acetoxycyclopentyl] acetate (9). Further reduction of the latter compound with sodium borohydride under conditions of carefully controlled pH afforded the corresponding 3α′-hydroxy derivative 10 as an oil. Basic hydrolysis of 10 with KOH/methanol followed by acidification yielded the bicyclic lactonic acid 12, or its methyl ester (11) if an anhydrous base was used. Proof of structure of these compounds and of the optical integrity of the route was achieved by chemical correlation with a commercially available optically active sample of the related 6-hydroxy compound 14. In continuing the main synthetic scheme, 12 was converted to 14 by acetylation of the 7-hydroxy group which in turn was transformed into the alcohol 14 by means of sodium borohydride reduction of its acid chloride. Oxidation of 14 with chromium trioxide-pyridine complex followed by treatment of the resulting crude aldehyde 23 with methanolic hydrogen gave the corresponding acetal 24b. Conversion of 24b to its 7-O-THP derivative 25 was followed by reduction of the lactone group to the hemiacetal 26. Introduction of the α side chain was accomplished by condensation of the latter with the sodium salt 28 of the ylide derived from (4-carboxybutyl)triphenylphosphonium bromide (27). Methylation (diazomethane) and acetylation of the resulting hydroxy acid 29 gave the corresponding 5′-O-acetyl methyl ester 30 which underwent diacetalation on mild acid treatment to give the aldehyde 31. Condensation of crude 31 with the sodium salt of dimethyl (2-oxoheptyl)phosphonate afforded methyl (+)-9α-acetoxy-11α-hydroxy-15-oxoprosta-5(Z), 13(E)-dienoate (32). The conversion of 32 to (+)-PGF_2α (33) followed conventional lines. A total chiral synthesis of (+)-prostaglandin F_αα (33) was achieved by the condensation of the 11-O-THP derivative 43 of 31 with the ylide derived from [(S)-2-hydroxyheptyl]triphenylphosphonium iodide (prepared in six steps from d-mannitol), followed by mild acid and then basic hydrolysis. However, the overall yield of 33 from 31 using this method of introducing the β side chain is low.