Recent Advances in Bioinspired Cu-Directed C-H Hydroxylation Reactions

Cu-dependent metalloenzymes catalyze a wide array of oxidative transformations using O₂ as an oxidant under mild conditions. These include the hydroxylation of challenging organic substrates (e.g., oxidation of methane to methanol in particulate methane monooxygenase) and the regio- and enantioselective hydroxylation of complex molecules (e.g., benzylic hydroxylation of dopamine to noradrenaline in dopamine-β-monooxygenase). Lytic polysaccharide monooxygenase enzymes (LPMOs) promote the C-H hydroxylation and subsequent cleavage of the polysaccharide chains found in natural materials such as cellulose or chitin. Recent reports on the reactivity of LPMOs suggest that, instead of O₂, these Cu-dependent metalloenzymes utilize H₂O₂ as an oxidant. In 2015, our research lab reported that the catalytic hydroxylation of strong C-H bonds (e.g., cyclohexane) using Cu and H₂O₂ proceeded via formation of nonselective Fenton-like oxidants (hydroxyl and hydroperoxyl radicals). To achieve regioselectivity, LPMOs bind the organic substrate before exposing the Cu center to the oxidant, a reaction that leads to the formation of a highly organized ternary complex prior to substrate hydroxylation (i.e., metal-substrate-oxidant adduct). Based on this concept, our research lab has pioneered the use of Cu, directing groups, and green oxidants to promote the site-selective hydroxylation of ketones and aldehydes. In our first report on this topic, we carried out an extensive mechanistic analysis on the Cu-directed sp³ C-H hydroxylation reactions developed by Schönecker and co-workers. Our findings suggested that the reaction between Cu^I and O₂ did not lead to the formation of dinuclear Cu₂O₂ (as it was previously suggested) but produced Cu^II and H₂O₂, which generated mononuclear Cu^II-hydroperoxide oxidants. Based on our mechanistic analysis, we redesigned the reaction conditions to utilize Cu^II and H₂O₂, which improved the yield, cost, and practicability of the Schönecker oxidations. Since then, our research lab has broadened the scope of substrates that can be oxidized using Cu, H₂O₂, and bidentate directing groups to include the γ-hydroxylation of sp² C-H bonds and β-hydroxylation of sp³ C-H bonds. Our latest reports have focused on the regioselective hydroxylation of substituted unsymmetrical benzophenones (which occurred via the formation of an electrophilic CuOOH species) and, for the first time, enantioselective C-H hydroxylation reactions via the formation of Cu/O₂ species. Our work highlights the importance of a mechanistic understanding to improve oxidation processes as well as underlines the use of metal-directed transformations to study the mechanisms by which metalloenzymes functionalize organic molecules.