Inhibitors of sterol synthesis. Synthesis and spectral properties of 3 beta-hydroxy-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholestan-15-one.
3 beta-Hydroxy-25,26,26,26,27,27,27-heptafluoro-5 alpha-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 beta-acetoxy-5 alpha-chola-8(14),23-dien-15-one (5) followed by lithium-ammonia reduction with a bromobenzene quench gave 3 beta-hydroxy-5 alpha-chol-23-en-15-one (6). Addition of (CF3)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 (23R)-3 beta-hydroxy-23-iodo-25,26,26,26,27,27,27-heptafluoro-5 alpha-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 delta 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 (CF3)2CF radical. Also prepared were 25,26,26,26,27,27,27-heptafluoro-5 alpha-cholestane-3 beta, 15 alpha-diol, its 15 beta epimer, the 7 alpha-methyl analog of 4, 3 beta-hydroxy-7 alpha-methyl-5 alpha-cholestan-15-one (16), and (25R)-3 beta,26-dihydroxy-5 alpha-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 C8H17 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 delta 8(14) bond.
Siddiqui
A U
AU
Department of Biochemistry, Rice University, Houston, TX 77005, USA.
Swaminathan
S
S
Su
X
X
Wilson
W K
WK
Schroepfer
G J
GJ
D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002783:Cholestenones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D013261:Sterols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005466:Fluorocarbons
D000924:Anticholesteremic Agents; D002783:Cholestenones; D002784:Cholesterol; D004791:Enzyme Inhibitors; D013261:Sterols; C084394:3-hydroxy-25,26,26,26,27,27,27-heptafluoro-5-cholest-8(14)-en-15-one; D005466:Fluorocarbons