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

ConspectusCu-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 CuI and O2 did not lead to the formation of dinuclear Cu2O2 (as it was previously suggested) but produced CuII and H2O2, which generated mononuclear CuII-hydroperoxide oxidants. Based on our mechanistic analysis, we redesigned the reaction conditions to utilize CuII 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.