Inhibitors of sterol synthesis. Tritium-labeled 26-hydroxycholesterol of high specific activity from a byproduct of the Clemmensen reduction of diosgenin.
(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.
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Department of Biochemistry, Rice University, Houston, TX 77251-1892.
Kisic
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Wilson
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Schroepfer
G J
GJ
D003903:Deuterium; D004144:Diosgenin / Q000737:chemistry*; D006888:Hydroxycholesterols / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D014316:Tritium
D006888:Hydroxycholesterols; D014316:Tritium; C007042:cholest-5-ene-3 beta,26-diol; D003903:Deuterium; D004144:Diosgenin