A new chemical synthesis of 5alpha-cholest-8(14)-en-3beta,5alpha-diol

Reduction of 3beta-benzoyloxy-14alpha,15alpha-epoxy-5alpha-cholest-7-ene with lithium in ethylenediamine gave 5alpha-cholest-8(14)-en-3beta, 5alpha-diol in high yield. This procedure offers an alternate synthesis through the reductive rearrangement of an alpha,beta-unsaturated steroidal epoxide.     

Sterol synthesis: studies of the metabolism of 14 alpha-methyl-5 alpha-cholest-7-en-3 beta-ol

[3 alpha-3H]14 alpha-Methyl-5 alpha-cholest-7-en-3 beta-ol has been prepared by chemical synthesis. The metabolism of this compound has been studied in the 10,000 g supernatant fraction of liver homogenates of female rats. Efficient conversion to cholesterol was observed. Other labeled compounds recovered after incubation of [3 alpha-3H]14 alpha-methyl-5 alpha-cholest-7-en-3 beta-ol with the enzyme preparations include the unreacted substrate, 5 alpha-cholesta-7,14-dien-3 beta-ol, 5 alpha-cholesta-8,14-dien-3 beta-ol, cholesta-5,7-dien-3 beta-ol, 5 alpha-cholest-8(14)-en-3 beta-ol, 5 alpha-cholest-8-en-3 beta-ol, and 5 alpha-cholest-7-en-3 beta-ol. In addition, significant amounts of incubated radioactivity were recovered in steryl esters. The steroidal components of these esters were found to contain labeled 14 alpha-methyl-5 alpha-cholest-7-en-3 beta-ol, 5 alpha-cholesta-8,14-dien-3 beta-ol, 5 alpha-cholesta-7,14-dien-3 beta-ol, 5 alpha-cholest-8-en-3 beta-ol, 5 alpha-cholest-7-en-3 beta-ol, and cholesterol.     

Crystal structure of 3 beta-benzoyloxy-6 alpha-chloro-5 alpha-cholest-7-ene, a key intermediate in the chemical synthesis of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one

The X-ray crystal structure of 3 beta-benzoyloxy-6 alpha-chloro-5 alpha-cholest-7-ene (IV) was determined by the heavy atom method and refined to R = 0.063 (space group P21, a = 11.364, b = 11.089, c = 12.232, beta = 99.43 degrees, Z = 2). IV was previously shown to be an important intermediate in the acid-catalyzed isomerization of 7-dehydrocholesteryl benzoate. The present work unequivocally establishes the location of the double bond and the configuration of the chlorine of IV, information which is essential to the correct formulation of the mechanism of this reaction.     

A facile synthesis of (1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-en-1-ol

A facile and short synthesis of (1S,5R,6S)-5-azido-6-benzyloxycyclohex-2-en-1-ol (1) has been achieved in high yield starting from 4,5-epoxycyclohex-1-ene by using a catalytic asymmetric allylic oxidation reaction.     

Inhibition of sterol synthesis in L cells by 14alpha-ethyl-5alpha-cholest-7-en-15alpha-ol-3-one at nanomolar concentrations

14α-Ethyl-5α-cholest-7-en-15α-ol-3-one was prepared in 85% yield by selective oxidation of the 3β-hydroxyl function of 14α-ethyl-5α-cholest-7-en-3β,15α-diol by cholesterol oxidase. 14α-Ethyl-5α-cholest-7-en-15α-ol-3-one caused a 50% inhibition of the incorporation of [1-¹⁴C]-acetate into digitonin-precipitable sterols at a concentration of 6 × 10^?9M in L cells and a 50% reduction in level of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase activity in the same cells at a concentration of 4 × 10^?8 M.     

Synthesis of iodine-131 labeled 6 beta-iodomethyl-19-norsitost-5(10)-en-3 beta-ol and 19-iodositost-5-en-3 beta-ol for adrenal imaging.

6 BETA-Iodomethyl-19-norsitost-5(10)-en-3 beta-ol (V) was synthesized by homoallylic rearrangement of 19-iodositost-5-en-3 beta-ol (IV), which was obtained by the hydrolysis of 19-iodositost-5-en-3 beta-ol acetate (III) derived from the displacement of sitost-5-ene-3 beta, 19-diol 3-acetate 19-p-toluenesulfonate (I) with sodium iodide in isopropanol. The radioiodinated IV and V were prepared by isotope exchange with sodium iodide-I-131.     

Synthesis of 3 beta-hydroxy-5 alpha-cholest-8-en-7-one and 3 beta-hydroxy-5 alpha-cholest-8-en-11-one: evaluation as potential hypocholesterolemic agents

An efficient procedure for the chemical synthesis of 3 beta-hydroxy-5 alpha-cholest-8-en-7-one and 3 beta-hydroxy-5 alpha-cholest-8-en-11-one is described. These ketosterols have been shown to have possible significant hypocholesterolemic effects when fed to normal rats at a level of 0.15% in a laboratory chow diet. The diets containing the steroids caused significant decreases in food consumption which were associated with decreases in the rate of gain in body weight.     

Inhibitors of sterol synthesis. Chemical synthesis, structure, and biological activities of (25R)-3 beta,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one, a metabolite of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one

3 beta-Hydroxy-5 alpha-cholest-8(14)-en-15-one (I) is a potent inhibitor of sterol synthesis with significant hypocholesterolemic activity. (25R)-3 beta,26-Dihydroxy-5 alpha-cholest-8(14)-en-15-one (II) has been shown to be a major metabolite of I after incubation with rat liver mitochondria. Described herein is the chemical synthesis of II from diosgenin. As part of this synthesis, improved conditions are described for the conversion of diosgenin to (25R)-26-hydroxycholesterol. Benzoylation of the latter compound gave (25R)-cholest-5-ene-3 beta,26-diol 3 beta,26-dibenzoate which, upon allylic bromination followed by dehydrobromination, gave (25R)-cholesta-5,7-diene-3 beta,26-diol 3 beta,26-dibenzoate. Hydrogenation-isomerization of the delta 5.7-3 beta,26-dibenzoate to (25R)-5 alpha-cholest-8(14)-ene-3 beta,26-diol 3 beta,26-bis(cyclohexanecarboxylate) followed by controlled oxidation with CrO3-dimethylpyrazole gave (25R)-3 beta,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one 3 beta,26-bis(cyclohexanecarboxylate). Acid hydrolysis of the delta 8(14)-15-ketosteryl diester gave II. 13C NMR assignments are given for all synthetic intermediates and several major reaction byproducts. The structure of II was unequivocally established by X-ray crystal analysis. II was found to be highly active in the suppression of the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cultured mammalian cells and to inhibit oleoyl coenzyme A-dependent esterification of cholesterol in jejunal microsomes.     

Inhibitors of sterol synthesis. Chemical synthesis and spectral properties of 3 beta-hydroxy-5 alpha-cholesta-8(14),24-dien-15-one, 3 beta,25-dihydroxy-5 alpha-cholest-8(14)-en-15-one, and 3 beta,24-dihydroxy-5 alpha-cholest-8(14)-en-15-one and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells.

Side-chain functionalized delta 8(14)-15-ketosterols have been synthesized from 3 beta-acetoxy-24-hydroxy-5 alpha-chol-8(14)-en-15-one (VI) as part of a program to prepare potential metabolites and analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism. Oxidation of VI to the 24-aldehyde VII, followed by Wittig olefination with isopropyltriphenylphosphonium iodide gave 3 beta-acetoxy-5 alpha-cholesta-8(14),24-dien-15-one (VIII), which was hydrolyzed to the free sterol IX. Oxymercuration of VIII followed by hydrolysis of the 3 beta-acetate gave 3 beta,25-dihydroxy-5 alpha-cholest-8(14)-en-15-one (IV). Hydroboration-oxidation of VIII followed by hydrolysis of the 3 beta-acetate gave 3 beta,24-dihydroxy-5 alpha-cholest-8(14)-en-15-one (V) as a 5:4 mixture of the 24R and 24S epimers. 1H and 13C nuclear magnetic resonance (NMR) assignments and mass spectral fragmentation patterns, supported by high-resolution measurements, are presented for IV and its 3 beta-acetate, V, VII, VIII, and IX. Characterization of IV by NMR and of trimethylsilyl ethers of IV and V by gas chromatography-mass spectrometry was compatible with spectral data for samples of IV and V isolated previously after incubation of I with rat liver mitochondria in the presence of NADPH. Sterols IV, V, and IX were very potent in lowering of the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in Chinese hamster ovary cells; their potency was comparable to that of I.     

Inhibitors of sterol synthesis. Synthesis and spectral characterization of fatty acids esters of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one

Reported herein are the chemical syntheses of 29 fatty acid esters of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one. These compounds were characterized by the results of ultraviolet, 1H nuclear magnetic resonance, and mass spectral studies.     

Inhibitors of sterol synthesis. Characterization of beta,gamma-unsaturated analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells

Treatment of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (1), a potent regulator of cholesterol metabolism, with perchloric acid in methanol resulted in its partial isomerization to the beta,gamma-unsaturated 15-ketosterols, 3 beta-hydroxy-5 alpha,14 beta-cholest-8-en-15-one (2) and 3 beta-hydroxy-5 alpha,14 beta-cholest-7-en-15-one (3), which were easily separated from 1 by chromatography. Isomers 1, 2, and 3 could be distinguished by their chromatographic retention times as well as by their physical and spectral properties. Reduction of 2 with sodium borohydride gave 5 alpha,14 beta-cholest-8-ene-3 beta,15 beta-diol (4), for which the C-15 configuration was established from the lanthanide-induced shifts of its 3 beta-tert-butyldimethylsilyl ether. 1H and 13C NMR chemical shift differences between 2, 3, and 4 indicated the involvement of variable populations of conformers that differ in the flexible C-D ring system and in the side chain. Compounds 2, 3, and 4 lowered the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells.     

Two new 9,11-secosterols from the marine sponge Spongia officinalis. Synthesis of 9,11-seco-3 beta,6 alpha,11-trihydroxy-5 alpha-cholest-7-en-9-one.

Two new 9,11-secosterol, 9,11-seco-3 beta,6 alpha,11-trihydroxy-5 alpha-cholest-7-en-9-one (2) and 9,11-seco-3 beta,6 alpha,11-trihydroxy-24- methylene-5 alpha-cholest-7-en-9-one (3), have been isolated from the marine sponge Spongia officinalis and their structures elucidated by analysis of spectral data including 1H nuclear magnetic resonance correlation spectroscopy (COSY) experiments. Partial synthesis of 2 starting from 3 beta,6 alpha-dihydroxy-9-oxo-9,11-seco-5 alpha-cholest-7-en-11- al (1) confirmed the structure assignment.