Stereoselective Synthesis and Solvolytic Behavior of the Isomeric 7-Dehydrocholesterol 5,6-Oxides

Article abstract of DOI:10.1021/jo00211a009

Cholesterol oxide hydrolase is recently described mammalian enzyme which catalyzes the hydration of Δ⁵-sterol oxides to 5,6-glycols in the liver.As the isomeric 7-dehydrocholesterol 5,6-oxides represent useful mechanistic probes of the action of the enzyme, synthetic procedures were sought for the stereoselective preparation of these unstable epoxides.Direct epoxidation of 7-dehydrocholesterol with peracid in the presence of aqueous buffer stereoselectively provided the α-oxide 2b in good yield.Synthesis of the β-oxide 12 proved more difficult in that attemptedformation of an intermediate bromohydrin with appropriate stereochemistry proved unsatisfactory.The finding that 7α-bromocholesteryl benzoate undergoes selective β-epoxidation and that the desired Δ⁷-double bond could be formed by treatment with potassium tert-butoxide resulted in the successful synthesis of the β- oxide 12.Both epoxides undergo cis addition of benzoic acid in chloroform at the allylic carbon and trans addition of 2-mercaptoethanol in base at the same position.Hydrolytic reactions prove to be more complex.Aqueous acid hydrolysis of the α-oxide 2b produced triol 5a and dienediol 6, which can further dehydrate to the trienol 7.Under identical conditions the β-oxide 12 hydrolyzes to a single product.Both epoxides, particulary the β-oxide 12, proved to be effective inhibitors of cholesterol oxide hydrolase.