The oxidation of tetrasubstituted alkenes by cytochrome P450

Hexamethyl(Dewar benzene) (HMDB) was selected to probe the intermediacy of an alkene radical cation during cytochrome P450 (P450) catalyzed epoxidation. P450 catalyzed the allylic oxidation of HMDB exclusively; no rearranged products (indicative of a radical cation intermediate) nor epoxide was detected. In addition, P450 exclusively catalyzed the allylic oxidation of 1,2-dimethylcyclohexene (DMCH) and 1,2,4,5-tetramethyl-1,4- cyclohexadiene. The double bonds of HMDB and DMCH were readily epoxidized by (tetraphenylporphyrinato)iron-(III) chloride with minor production of allylic alcohols. The rates of alkene epoxidation by model systems tend to increase with increasing alkene substitution, but it is apparent that P450 has additional mechanistic options or constraints that depress the rate of epoxidation with increasing alkene substitution. The failure of P450 to epoxidize tetrasubstituted alkenes illustrates a failure of P450 model systems to truly mimic the chemistry of the P450 iron-oxo species.