Inhibitors of sterol synthesis. Synthesis and spectral properties of 3 β-hydroxy-25,26,26,26,27,27,27-heptafluoro-5 α-cholestan-15-one

• Published in: Chemistry and physics of lipids 1997-04, Vol.86 (2), p.95-119
• Main Authors: Siddiqui, Abdul U, Swaminathan, Shankar, Su, Xiangdong, Wilson, William K, Schroepfer, George J
• Format: Article
• Language: English
• Subjects: 15-ketosterols; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Cholestenones - chemical synthesis; Cholestenones - chemistry; Cholestenones - pharmacology; Cholesterol - biosynthesis; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Liquid-ammonia reduction; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; NMR; Sterols - chemical synthesis; Sterols - chemistry; Sterols - pharmacology
• ISSN: 0009-3084; 1873-2941
• DOI: 10.1016/S0009-3084(97)02656-X

3 β-Hydroxy-25,26,26,26,27,27,27-heptafluoro-5 α-cholestan-15-one ( 4) has been prepared as part of a program to synthesize 15-ketosterols that are not readily metabolized to cholesterol or side-chain oxygenated species. Saponification of 3 β-acetoxy-5 α-chola-8(14),23-dien-15-one ( 5) followed by lithium-ammonia reduction with a bromobenzene quench gave 3 β-hydroxy-5 α-chol-23-en-15-one ( 6). Addition of (CF 3) 2CFI to 6 in the presence of triethylborane gave an iodide preparation, which was reduced to 4 with tributyltin hydride (71% overall yield of 4 from 5). The 23-iodide preparations consisted of 6:1 mixtures of (23 R)-3 β-hydroxy-23-iodo-25,26,26,26,27,27,27-heptafluoro-5 α-cholestan-15-one ( 9a) and its C-23 epimer 9b with variable amounts of 4. Compound 4 was also prepared by lithium-ammonia reduction of the Δ 8(14) analogs of 4 and iodides 9a and 9b. The presence of small amounts of 6 in the latter product suggested a side reaction involving cleavage of the C24–C25 bond with loss of a (CF 3) 2CF· radical. Also prepared were 25,26,26,26,27,27,27-heptafluoro-5 α-cholestane-3 β,15 α-diol, its 15 β epimer, the 7 α-methyl analog of 4, 3 β-hydroxy-7 α-methyl-5 α-cholestan-15-one ( 16), and (25 R)-3 β,26-dihydroxy-5 α-cholestan-15-one. Full 1H and 13C-NMR data of high precision with complete signal assignments are given for all new compounds. Definitive 1H-NMR stereochemical assignments of the C-24 protons were established for most sterols with a C 8H 17 side chain based on analysis of the downfield H-24 resonance in a 750-MHz spectrum of 16. Detailed electron-impact mass spectral data are presented together with a summary of major fragmentation patterns for 15-hydroxy- and 15-ketosteroids with and without a Δ 8(14) bond.