Raymond D. Wilson

Stereochemistry of epoxidation of cholest-5-en-3-one and of the base-catalysed rearrangement of the derived epoxides

The epoxidation of cholest-5-en-3-one by m-chloroperbenzoic acid in deuteriochloroform and in benzene has been investigated by 1H n.m.r. spectroscopy. The product mixtures contain 3,4-secocholest-5-eno-3,4-lactone and the α-epoxide, both recognised by previous workers; the β-epoxide accompanies them, the α : β ratio being ca. 2 : 1 in both solvents. Both α- and β-epoxides undergo smooth rearrangement when treated with pyridine in deuteriochloroform, and give the expected 6-hydroxycholest-4-en-3-one. By this treatment the mixed products of epoxidation of 4β-deuteriocholest-5-en-3-one lose exclusively (within experimental error) the 4α-hydrogen atom. The epoxidation of some 3α- and 3β-substituted cholest-5-enes under the same conditions was also carried out to monitor our experimental procedures.

Autoxidation of cholest-5-en-3-one, and its accompanying isomerization, in acetic acid

Im Dunkeln lagert sich das Cholestenon (I) in Essigsaure zum Isomeren (II) um, das in Gegenwart von Sauerstoff und Cu(II)-Ionen von den Autoxidationsprodukten (III), ihren os-Isomeren und dem Dion (IV) begleitet wird.

The kinetics and mechanisms of additions to olefinic substances. Part 13. Reactions of 3-substituted cholest-5-enes with sources of electrophilic bromine

The kinetics of second-order bromination in acetic acid, and of third-order bromination in chlorobenzene, have been examined for a series of 3β-substituted cholest-5-enes; the results confirm that the rates of these reactions are subject to polar influences approximately of the magnitude expected for a substituent insulated by two saturated carbon atoms from the site of development of the carbocationic centre. The products of reactions of a number of these substrates with sources of electrophilic bromine and chlorine, in chlorobenzene, chloroform, and acetic acid as solvents, have been investigated by 1H n.m.r. spectroscopy. In most cases the main products are the expected 5α-halogeno-6β-substituted adducts. 5β,6α-Adducts are formed in minor amounts also in the bromination of 3β-trifluoroacetoxycholest-5-ene, and in the reactions of a number of 3β-substituted cholest-5-enes with bromine chloride in deuteriochloroform and in chlorobenzene. Some of the mechanistic implications of these findings are discussed.

The kinetics and mechanisms of additions to olefinic substances. Part 15. Chlorination of cholest-5-ene and its 3-substituted derivatives, including cholest-5-en-3-one; factors affecting the α : β ratio for electrophilic attack, and for product formation, in cholest-5-enes

Reactions of cholest-5-ene or its 3β-substituted derivatives with chlorine in chloroform or chlorobenzene give as kinetically controlled products the expected 5α,5β-dichloride, accompanied by the isomeric 5β,6α-dichloride as a minor component. The proportion of the latter decreases with the electron-withdrawing power of the 3β-substituent. Neither added pyridine nor added chloride ion affects the product proportions significantly. Cholest-5-en-3-one, on the other hand, when treated with chlorine in chlorobenzene containing 2-methyloxiran gives not only the expected 5α,6β-dichloride but also much 6α- and 6β-chlorocholest-4-en-3-one. Comparison with the results for 4β-deuteriocholest-5-ene shows that the formation of 6α-chlorocholest-4-en-3-one involves mainly displacement of the 4β-hydrogen atom, and that the formation of its 6β-isomer involves mainly but not exclusively displacement of the 4β-hydrogen atom. Similar products are obtained in deuteriochloroform containing pyridine; in acetic acid, substitution is accompanied by little addition and much unidentified material The results are compared with the corresponding results for bromination, epoxidation, and iodination. It is argued that halogenation of cholest-5-en-3-one differs from that of cholest-5-ene and its 3-monosubstituted derivatives in the ratio of attack on the α- and β-faces of the molecule for two main reasons: because of the availability of a concerted pathway for substitution involving the chair conformation of ring A of the enone, and because in non-concerted pathways for addition and substitution, ring A of the intermediate halogenonium ion derived from the enone can reach a boat conformation. Two types of AdE3 additions having different stereochemical preferences can also be recognised.

The kinetics and mechanisms of additions to olefinic substances. Part 14. Reactions of cholest-5-en-3-one with electrophilic brominating agents

Electrophilic brominations of cholest-5-en-3-one with molecular bromine and with bromine chloride have been studied in several solvents. The major products are 5α,6β-adducts and the 6-bromocholest-4-en-3-ones; in some circumstances a small proportion of 5β,6α-adduct was recognised. Results obtained by using bromine chloride establish that the diaxial adducts arise by electrophilic attack on both the α- and the β-face of the steroid. 6α-Bromocholest-4-en-3-one is formed by proton loss from the ionic α-bromonium intermediate; study of 4β-H/D isotope effects on the rates and products of bromination establish that 6β-bromocholest-4-en-3-one is obtained not only by this route, in which the 4α-proton is preferentially released, but also by way of a concerted, stereoselectively syn, SE2′ mechanism. In the presence of excess of halide ion, substitution is reduced in proportion through catalysis of an AdE3 mechanism involving electrophilic attack on the α-face of the molecule to give the diaxial adduct. The pathways available for substitution and addition in cholest-5-en-3-one are compared with those found for the 3β-substituted cholest-5-enes (accompanying paper).