Hydroxylation by Cytochrome P-450 and Metalloporphyrin Models. Evidence for Allylic Rearrangement

The allylic hydroxylation of 3,3,6,6-tetradeuteriocyclohexene, methylenecyclohexane, and β-pinene has been examined with phenobarbital-induced liver microsomal cytochrome P-450 (P-450_LM2) and with iron porphyrin and chromium porphyrin model systems. Aerobic and peroxide dependent enzymic regimes were investigated with purified P-450_LM2 and with microsomal suspensions. Epoixidation and allylic hydroxylation were the primary reactions with all substrates. With 3,3,6,6-tetradeuteriocyclohexene, the major hydroxylation product (60–80%) was the result of hydroxylation at the deuterated allylic site. In all cases, a significant amount (20–40%) of hydroxylation occurred with allylic rearrangement. The iron porphyrin/iodosylbenzene model system also showed preferential hydroxylation of the deuterated allylic site (70%) with significant allylic rearrangement (30%). By contrast, the chromium porphyrin/iodosylbenzene model system showed complete scrambling of the allylic system. Extensive rearrangement accompanied the hydroxylation of methylenecyclohexane and β-pinene by both the enzymic and metalloporphyrin systems whereas the selenium dioxide oxidation of these substrates gave selective allylic hydroxylation without rearrangement. A mechanism is suggested for allylic hydroxylation by cytochrome P-450 and by the metalloporphyrin model systems involving initial hydrogen atom abstraction from the allylic site and geminate, cage recombination of the incipient, allylic free radical.