Inhibitors of sterol synthesis. An improved chemical synthesis of 26-oxygenated Δ8(14)-15-ketosterols having the 25R configuration

Abstract

(25R)-3β,26-Dihydroxy-5α-cholest-8(14)-en-15-one (I) was synthesized in four steps from (25R)-3β,26-diacetoxycholesta-5,7-diene (III) in 30% overall yield. Isomerization of III with HCI in chloroform-dichloromethane at −60°C gave (25R)-3β,26-diacetoxy-5α-cholesta-7,14-diene together with the 5 α- Δ 8,14 and 5 β- Δ 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 HC10 4 (0.1%) gave (25R)-3β,26-diacetoxy-5α-cholest-8(14)-en-15-one (VIII), accompanied by numerous minor byproducts, including the 5 α,14 β- Δ 7, 5 α, 14 β- Δ 8 and 5 β,14 β- Δ 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.