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

ConspectusCu-dependent metalloenzymes catalyze a wide array of oxidative transformations using O 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 O, these Cu-dependent metalloenzymes utilize HO as an oxidant. In 2015, our research lab reported that the catalytic hydroxylation of strong C-H bonds (e.g., cyclohexane) using Cu and HO 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 sp C-H hydroxylation reactions developed by Schönecker and co-workers. Our findings suggested that the reaction between Cu and O did not lead to the formation of dinuclear CuO (as it was previously suggested) but produced Cu and HO, which generated mononuclear Cu-hydroperoxide oxidants. Based on our mechanistic analysis, we redesigned the reaction conditions to utilize Cu and HO, 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, HO, and bidentate directing groups to include the γ-hydroxylation of sp C-H bonds and β-hydroxylation of sp 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/O 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.