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.
Siddiqui
A U
AU
Department of Biochemistry, Rice University, Houston, Texas 77251-1892.
Wilson
W K
WK
Schroepfer
G J
GJ
D002784:Cholesterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013237:Stereoisomerism; D013261:Sterols / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification
D013261:Sterols; C055090:cholest-8(14)-ene-3,26-diol-15-one; D002784:Cholesterol