Inhibitors of sterol synthesis. An improved chemical synthesis of 26-oxygenated delta 8(14)-15-ketosterols having the 25R configuration.

(25R)-3 beta,26-Dihydroxy-5 alpha-cholest-8(14)-en-15-one (I) was synthesized in four steps from (25R)-3 beta,26-diacetoxycholesta-5,7-diene (III) in 30% overall yield. Isomerization of III with HCl in chloroform-dichloromethane at -60 degrees C gave (25R)-3 beta,26-diacetoxy-5 alpha-cholesta-7,14-diene together with the 5 alpha-delta 8,14 and 5 beta-delta 8,14 isomers in a 5:1:1 ratio. Epoxidation of the crude diene mixture with m-chloroperbenzoic acid, followed by hydrolysis in acetone containing concentrated HClO4 (0.1%) gave (25R)-3 beta,26-diacetoxy-5 alpha-cholest-8(14)-en-15-one (VIII), accompanied by numerous minor byproducts, including the 5 alpha,14 beta-delta 7, 5 alpha, 14 beta-delta 8 and 5 beta,14 beta-delta 8 isomers of VIII. All four 15-ketosterol esters were isolated by chromatography and fully characterized by mass spectrometry and 1H and 13C nuclear magnetic resonance. Treatment of VIII with potassium carbonate in degassed methanol gave I.