Selective Methylene Oxidation in α,β-Unsaturated Carbonyl Natural Products

α,β-Unsaturated carbonyl functionality- those with connected carbon-carbon and carbon-oxygen double bonds- are commonly found in bioactive compounds. Late-stage functionalization of these compounds could involve oxidation of methylene (2°) C—H bonds while leaving the C—C double bonds that are important for biological activity intact^1–3. Catalytic systems have been developed for selective oxidation of methylenes in the presence aromatics⁴ and N-heterocycles⁵, however olefins remain an unsolved problem. Here we show that replacing the carboxylic acid with a H-bond donor solvent in sterically hindered manganese PDP catalysts changes the active oxidant to one that accelerates electron rich methylene oxidation and significantly slows epoxidation of electron deficient olefins (k_C-H[O]/k_epox = 38.5). Chemoselective methylene oxidation is demonstrated in forty-five molecules housing α,β-unsaturated carbonyl functionality where all previous methods afforded allylic oxidation or epoxidation. Mechanistic studies support that the new oxidant proceeds via a more charged pathway that disfavors electron deficient bonds, demonstrating that highly reactive metal oxidants can be tuned to achieve chemoselectivity. These discoveries enable the first late-stage oxidations in complex natural products and derivatives housing these pharmacophoric substructures to furnish novel analogues and known metabolites.