α,β-Unsaturated carbonyl groups—which feature conjugated C=C and C=O bonds—are common 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 intact1–3. Although catalytic systems have been developed for selective oxidation of methylenes in the presence of aromatics4 and N-heterocycles5, olefins remain a long-standing challenge. Here we show that replacing the carboxylic acid with a hydrogen bond donor solvent in sterically hindered manganese PDP ([N,N′-bis(2-pyridylmethyl)]-2,2′-bipyrrolidine) catalysts changes the active oxidant to one that accelerates electron-rich methylene oxidation and significantly slows epoxidation of electron-deficient olefins (kC–H[O]/kepox = 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 operates via a more charged pathway that disfavours electron-deficient bonds, demonstrating that highly reactive metal oxidants can be tuned to achieve chemoselectivity. These findings enable the first late-stage oxidations in complex natural products and derivatives containing these pharmacophoric substructures, providing access to both new analogues and known metabolites.
