Abstract
Most cytochrome P450 (P450) oxidations are considered to occur with the active oxidant being a perferryl oxygen (FeO(3+), Compound I). However, a ferric peroxide (FeO(2)(®), Compound 0) mechanism has been proposed, as well, particularly for aldehyde substrates. We investigated three of these systems, the oxidative deformylation of the model substrates citronellal, 2-phenylpropionaldehyde, and 2-methyl-2-phenylpropionaldehyde by rabbit P450 2B4, using (18)O labeling. The formic acid product contained one (18)O derived from (18)O(2), which is indicative of a dominant Compound 0 mechanism. The formic acid also contained only one (18)O derived from H(2)(18)O, which ruled out a Compound I mechanism. The possibility of a Baeyer-Villiger reaction was examined by using synthesized possible intermediates, but our data do not support its presence. Overall, these findings unambiguously demonstrate the role of the Compound 0 pathway in these aldehyde oxidative deformylation reactions.