Prostaglandins. 3. Synthetic Approaches to 11-Deoxyprostaglandins

Article abstract of DOI:10.1021/jo00133a029

A straightforward synthesis is described of dl-trans-2-<6-(methoxycarbonyl)hex-2(Z)-enyl>-3-formylcyclopentanone (5), a versatile intermediate for the sythesis of 11-deoxyprostaglandins and their analogues.Base-catalyzed cyclization of 1,2,4-tris(methoxycarbonyl)butane under kinetically controlled conditions led to (70percent) trans-2,3-bis(methoxycarbonyl)cyclopentanone (3).Treatment of 3 with hot benzyl alcohol gave (80percent) trans-2-(benzyloxycarbonyl)-3-(methoxycarbonyl)cyclopentanone (25), which was purified as its copper chelate.Alkylation of 25 with 6-cyanohex-2-ynol mesylate (20) with NaH/dimethoxyethane afforded 82percent 2-(6-cyanohex-2-ynyl)-2-(benzyloxycarbonyl)-3-(methoxycarbonyl)cyclopentanone (26).Catalytic reduction of 26 in ethanol/pyridine, using a Pd/BaSO4 catalyst followed by warming, gave (91.5percent) a 9:1 mixture of trans-2-(6-cyanohex-2(Z)-enyl)-3-(methoxycarbonyl)cyclopentanone (27) and its 2,3-dihydro derivative 29.Chromatography of the corresponding carboxylic acids gave the pure acid 30 (69percent from 26).Reduction (NaBH4) of the acid chloride (31) of acid 30 led to a mixture of diols 32.Saponification of the nitrile group of 32 afforded the C-1 epimeric mixture of the diol acids 33, which on CH2N2 esterification (69percent from 31) and Collins oxidation afforded (92percent) the desired 5.A second route to 5 also was explored.Cyclization (t-BuOK/t-BuOH) of 4-<2-(methoxycarbonyl)ethyl>tetrahydrofuran-2-one (12) led to cis-hexahydro-1H-cyclopentafuran-1,6-dione (4), which when alkylated (t-BuOK/t-BuOH) with 20 gave (90percent) the C-6a alkylation product 35.Alkaline saponification of 35 led to trans-2-(6-cyanohex-2-ynyl)-3-(hydroxymethyl)cyclopentanone (36) in only modest yield (15percent).A four-step sequence of catalytic reduction, nitrile hydrolysis, acid esterification, and oxidation then gave 5, in 44percent overall yield from 36.