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

Article abstract of DOI:10.1016/0009-3084(94)90072-8

(25R)-3β,26-Dihydroxy-5α-cholest-8(14)-en-15-one (I) was synthesized in four steps from (25R)-3β,26-diacetoxy-cholesta-5,7-diene (III) in 30% overall yield. Isomerization of III with HCl in chloroform-dichloromethane at -60°C gave (25R)-3β,26-diacetoxy-5α-cholesta-7,14-diene together with the 5α-Δ^8,14 and 5α-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 HClO₄ (0.1%) gave (25R)-3β,26-diacetoxy-5α-cholest-8(14)-en-15-one (VIII), accompanied by numerous minor byproducts, including the 5α,14β-Δ⁷, 5α, 14β-Δ⁸ and 5β,14β-Δ⁸ 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.