INHIBITORS OF STEROL SYNTHESIS - SYNTHESIS AND SPECTRAL PROPERTIES OF3-BETA-HYDROXY-5-ALPHA-CHOLESTAN-15-ONE AND ITS 14-BETA-EPIMER AND THEIR EFFECTS ON 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE-ACTIVITY

3 beta-Hydroxy-5 alpha-cholestan-15-one (2a) and its 14 beta-epimer 2b were prepared from 3 beta-acetoxy-5 alpha-cholest-8(14)-ene (3). Hydr oboration of 3 at 45-50 degrees C gave a mixture of 5 alpha, 14 alpha- cholestane-3 beta, 15 alpha-diol and 5 alpha,14 beta-cholestane-3 beta ,15 beta-diol, which were separated on silica gel as their 3 beta-tert -butyldimethylsilyl ethers 5a and 5b. Oxidation of 5a with pyridinium chlorochromate, followed by desilylation with tetrabutylammonium fluor ide gave 2a. Analogous transformations of 5b gave 2b contaminated with 2a. Desilylation of 5b followed by oxidation with pyridinium chloroch romate resulted in a mixture composed mainly of 5 alpha,14 beta-choles tane-3,15-dione and 2b. Successive chromatographic separations on sili ca gel and reversed phase media gave 2b of high purity. Compound 2a wa s also prepared by lithium-ammonia reduction of 3 beta-hydroxy-5 alpha -cholest-8(14)-en-15-one (96% yield) and by selective reduction of 5 a lpha-cholestane-3,15-dione with lithium tri-tert-butoxyaluminum hydrid e (90% yield). Isomers 2a and 2b were readily epimerized under acidic or basic conditions or under conditions used for gas chromatographic a nalysis. The purities of 2a and 2b were measured from nuclear magnetic resonance (NMR) spectra; chromatographic methods gave less reliable e stimates of purity. NMR data also showed that ring C of the 14 beta st erols is predominantly in a chair conformation. The effects of 2a and 2b, on the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase h ave been studied in Chinese hamster ovary cells.