Selective Methylene Oxidation in ,-Unsaturated Carbonyl Natural Products - Nature

"Catalytic systems have been developed for selective oxidation of methylenes in the presence aromatics 4 and N-heterocycles 5, 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 ( 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 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."

α,β-Unsaturated carbonyls contain connected carbon–carbon and carbon–oxygen double bonds and are common in bioactive compounds. Late-stage functionalization can target methylene (2°) C–H bonds while preserving C–C double bonds important for activity. Existing catalysts selectively oxidize methylenes near aromatics and N-heterocycles, but olefins remained challenging. Replacing carboxylic acid with an H-bond donor solvent in sterically hindered manganese PDP catalysts alters the active oxidant to favor electron-rich methylene oxidation and markedly reduce epoxidation of electron-deficient olefins. Chemoselective methylene oxidation was achieved in forty-five substrates with α,β-unsaturated carbonyls. Mechanistic data indicate a more charged oxidant pathway that disfavors electron-poor bonds, enabling tunable chemoselectivity and late-stage oxidations of complex natural products to access novel analogues and metabolites.

Read at Nature