Theoretical studies of oxygen atom transfer from flavin to electron-rich substrates

The flavoenzyme cyclohexanone monooxygenase (CHMO) can catalyze the oxidation of both electron-poor-e.g. ketones-and electron-rich-e.g. organic sulfides and amines-substrates. Massey and coworkers have experimentally demonstrated that the oxidizing intermediate in the Baeyer-Villiger oxidation of ketones is the flavin C4a-peroxide. To shed light on the CHMO oxidation mechanism of electron-rich substrates, the oxidation of trimethyl amine, iodide ion, and dimethyl sulfide by the model compound lumiflavin has been studied by computational methods. Three different oxidizing intermediates of lumiflavin have been considered: C4a-hydroperoxide, C4a-peroxide and C4a-hydroperoxide complexed with one water molecule. Inspection of the energetics of the TS formed by the three intermediates with each of the three electron-rich substrates showed that the lowest activation energy was obtained with the complexes formed with C4a-hydroperoxide-water. On the other hand, the reactivity for the substrates was iodide ion > dimethyl sulfide > trimethyl amine.