The halogenation and epoxidation of some 3-substituted cholest-5-enes

Abstract

The mechanisms of halogenation and epoxidation of simple olefins and the known results of halogenation, epoxidation, and other electrophilic addition reactions involving 5, 6-unsaturated steroids are reviewed. The isomerization and autoxidation of cholest-5-en-3-one also are reviewed. The results of a detailed investigation of the mechanisms of halogenation and epoxidation of unsubstituted, 3α-substituted, 3β-substituted, and 3-keto-cholest-5-ene are described, and are discussed in terms of transition-state structures, and electronic, steric, and conformational effects. Epoxidation of these substrates using m-chloroperbenzoic acid is stereoselective. It is proposed that the oxidation involves a highly asymmetrical transition state and is sterically controlled. In the presence of pyridine, 5, 6-epoxycholestan-3-ones rearrange to 6-hydroxycholest-4-en-3-ones with retention of configuration at the 6-carbon. The mechanism is discussed. Halide-catalysed halogenation of cholest-5-enes proceeds with predominantly α-attack by the electrophile. It is proposed that the stereochemistry of attack is controlled mainly by steric effects upon the pre-equilibrium complexation of the halogen and olefin. Non-catalysed and pyridine-catalysed halogenation of 3-tetrahedral cholest-5-enes via halonium ions is highly stereoselective; but similar halogenation of the 3-ketone is almost non-stereoselective. These features are explained in terms of substantially bridged transition states and, where appropriate, pre-equilibria, It is proposed that addition to the 3-tetrahedral cholest-5-enes is sterically controlled. Similar steric effects must influence the halogenation of the ketone; but it is proposed that β-attack is accelerated through the accessibility of a boat conformation of the A-ring. The fates of the halonium intermediates are deduced and discussed. Those derived from 3-tetrahedral cholestenes give adducts; those derived from the 3-ketone are in part trapped by nucleophiles to give adducts and in part deprotonated to give 6-halocholest-4-en-3-ones. Halogenation of the ketone also gives some 6β-halocholest-4-en-3-one by a fully concerted SE2' mechanism. 5-Bromocholestan-3-ones readily undergo 1, 2-dehydrobromination by a free-radical chain mechanism.