Abstract
(25R)-26-Hydroxycholesterol (I) was synthesized in six steps from (22Z,25R)-cholesta-5,22-diene-3 beta,26-diol (II) in 31% overall yield. The 26-tert-butyldiphenylsilyl ether of II was converted via its 3 beta-tosylate to (22Z,25R)-6 beta-methoxy-26-(tert- butyldiphenylsilyloxy)-3 alpha,5-cyclo-5 alpha-cholest-22-ene (V). Removal of the 26-silyl group of V gave (22Z,25R)-6 beta-methoxy-3 alpha,5-cyclo-5 alpha-cholest-22-en-26-ol, which was hydrogenated over platinum oxide and then hydrolyzed to I. Catalytic reduction in the presence of deuterium or tritium gas gave [2H]-I or [3H]-I, respectively. Analysis of the [2H]-I by mass spectrometry showed that all the deuterium was located in the sterol side chain, mainly as d2, d3, and d4 species. The 2H and 13C nuclear magnetic resonance (NMR) spectra of [2H]-I indicated that most of the deuterium was located at C-22 and C-23, with lesser amounts at C-24 and minor amounts at C-20, C-21, C-25, and C-27. NMR spectra of [2H]-I and its alpha-methoxy-alpha-(trifluoromethyl)phenylacetate diester showed no detectable 20S epimer and approximately 2% of the 25S epimer. The [3H]-I was prepared analogously to [2H]-I using carrier-free tritium and showed a specific activity of 16.9 Ci/mmol. All synthetic intermediates were characterized fully by 1H and 13C NMR, and representative 1H-1H coupling constants are given for the ring A protons of i-steroids.
Highlights
The 2 H and 1% nuclear mag- concentrations that have been shown to lower the levels of netic resonance (NMR) spectra of [2H]-I indicated that most of hydroxy-3-mehylglutaryl coenzyme A (HMG-CoA) reductase activity in cultured mammalian the deuterium was located at C-22 and
Direct-inlet mass spectra of underivatized sterols were recorded on a Shimadzu QP-1000 quadrupole spectrometer by electronimpact at 70 eV and are reported as d z
The product was characterized only by the mass spectrometry or mass spectrum (MS) for its bis-TMS ether derivative, which showed a major peak at d z 554 corresponding to the incorporation of eight atoms of deuterium
Summary
The 2 H and 1% nuclear mag- concentrations that have been shown to lower the levels of netic resonance (NMR) spectra of [2H]-I indicated that most of HMG-CoA reductase activity in cultured mammalian the deuterium was located at C-22 and A number of oxygenated sterols have been shown to be highly active as inhibitors of sterol biosynthesis and in the regulation of the levels of 3-hydroxy-3-mehylglutaryl coenzyme A (HMG-CoA) reductase activity in cultured mammalian cells [1, 2]. (25R)-26-Hydroxycholesterol (Ia) is especially potent in this regard [3, 4] and shows synergism with another oxysterol in the lowering of HMG-CoA reductase activity in Chinese hamster ovary cells [5]. Other (25R)-26-oxygenated sterols display high activity in the regulation of the levels of reductase activity
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