Inhibitors of sterol synthesis. Synthesis and spectral properties of 3β-hydroxy-5α-cholestan-15-one and its 14β-epimer and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity

• Published in: Chemistry and physics of lipids Vol. 74; no. 1; pp. 1 - 15
• Main Authors: Siddiqui, Abdul U., Wilson, William K., Parish, Edward J., Gerst, Nicolas, Pinkerton, Frederick D., Schroepfer, George J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ireland Ltd 20.10.1994
• Subjects: 15-Ketosterols; Conformational analysis; Liquid-ammonia reduction; NMR; NMR; 15-Ketosterols; Liquid-ammonia reduction; Conformational analysis
• ISSN: 0009-3084; 1873-2941
• DOI: 10.1016/0009-3084(94)90106-6

3β-Hydroxy-5α-cholestan-15-one ( 2a) and its 14β-epimer 2b were prepared from 3β-acetoxy-5α-cholest-8(14)-ene ( 3). Hydroboration of 3 at 45–50°C gave a mixture of 5α, 14α-cholestane-3β, 15α-diol and 5α, 14β-cholestane-3β, 15β-diol, which were separated on silica gel as their 3β- tert-butyldimethylsilyl ethers 5a and 5b. Oxidation of 5a with pyridinium chlorochromate, followed by desilylation with tetrabutylammonium fluoride gave 2a. Analogous transformations of 5b gave 2b contaminated with 2a. Desilylation of 5b followed by oxidation with pyridinium chlorochromate resulted in a mixture composed mainly of 5α, 14β-cholestane-3, 15-dione and 2b. Successive chromatographic separations on silica gel and reversed phase media gave 2b of high purity. Compound 2a was also prepared by lithium-ammonia reduction of 3β-hydroxy-5α-cholest-8(14)-en-15-one (96% yield) and by selective reduction of 5α-cholestane-3, 15-dione with lithium tri- tert-butoxyaluminum hydride (90% yield). Isomers 2a and 2b were readily epimerized under acidic or basic conditions or under conditions used for gas chromatographic analysis. The purities of 2a and 2b were measured from nuclear magnetic resonance (NMR) spectra; chromatographic methods gave less reliable estimates of purity. NMR data also showed that ring C of the 14β sterols is predominantly in a chair conformation. The effects of 2a and 2b on the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase have been studied in Chinese hamster ovary cells.