INHIBITORS OF STEROL SYNTHESIS - SYNTHESIS AND SPECTRAL PROPERTIES OFDERIVATIVES OF ,27,27-HEPTAFLUORO-5-ALPHA-CHOLEST-8(14)-EN-15-ONE FLUORINATED AT CARBON-7 OR CARBON-9 AND THEIR EFFECTS ON 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE-ACTIVITY IN CULTURED-MAMMALIAN-CELLS

As part of a program to prepare Delta(8(14))-15-ketosterols that canno t readily be metabolized to cholesterol or sidechain oxygenated specie s, we have prepared 3 beta-hydroxy-7 alpha-fluoro-5 alpha-cholest-8(14 )-en-15-one (VII) and the 9 alpha-hydroxy (IV), 9 alpha-fluoro (VI) an d 7 alpha-fluoro (VIII) derivatives of 3 beta-hydroxy-25,26,26,26,27,2 7,27-heptafluoro-5 alpha-cholest-8(14)-en-1 5-one (II). Sterol IV was prepared by oxidation of the Delta(8,14) dienol ethyl ether of the 3 b eta-acetate of II with m-chloroperbenzoic acid, followed by mild alkal ine hydrolysis of the 3 beta-acetate derivative of IV. Treatment of IV with hydrogen fluoride-pyridine gave VI. The 7 alpha-fluoro-15-ketost erols VII and VIII were synthesized by treating the 3 beta,15-bis-trim ethylsilyl Delta(7,14)-dienol ether derivative of the appropriate Delt a(8(14))-15-ketosterol with N-fluoropyridinium triflate, followed by h ydrolysis of residual trimethylsilyl ethers and purification by high-p erformance liquid chromatography. The combined results of H-1 and C-13 nuclear magnetic resonance (NMR) chemical shifts, H-1-H-1 coupling co nstants, H-1-F-19 long-range coupling constants and molecular modeling indicated that a 7 alpha-fluoro, 9 alpha-fluoro or 9 alpha-hydroxy su bstituent has negligible effect on the conformation of the 15-ketoster ols. H-1 and C-13-NMR data are also given for Delta(6,8(14))- and Delt a(8(14),9(11))-15-ketosterols, synthetic byproducts that could not be detected readily in samples of the fluoro-15-ketosterols by chromatogr aphic methods. Mass spectra of VI and of previously reported 9 alpha-f luoro and 9 alpha-hydroxy-Delta(8(14))-15-ketosterols showed abundant M-62 or M-60 ions that appear to correspond to loss of ketene and HF o r H2O. The 9 alpha-hydroxy-F-7-15-ketosterol IV, the 7 alpha-fluoro-15 -ketosterol VII and the 7 alpha-fluoro-F-7-15-ketosterol VIII were of equivalent potency to the parent 3 beta-hydroxy-5 alpha-cholest-8(14)- en-15-one (I) in lowering the levels of 3-hydroxy-3-methylglutaryl coe nzyme A reductase activity in CHO-K1 cells. The 9 alpha-fluoro-F-7-15- ketosterol VI showed high potency but appeared to be slightly less act ive than I.