Bioinspired Radical Stetter Reaction: Radical Umpolung Enabled by Ion-Pair Photocatalysis

A bioinspired, intermolecular radical Stetter reaction of alpha-keto acids and aldehydes is disclosed that is contingent on a formal "radical umpolung" concept. Enabled by secondary amine activation, electrostatic recognition ensures that the alpha-ketocarboxylic acids, which function as latent acyl radicals, are proximal to the in situ generated iminium salts. This photoactive contact ion pair is an electron donor-acceptor (EDA) complex, and undergoes facile single electron transfer (SET) and rapid decarboxylation prior to radical-radical recombination. Importantly, decarbonylation is mitigated by this strategy. The initial computational validation on which the process is predicated matches closely with experiment. Synergising organo- and photocatalysis activation principles finally expands the mechanistic and synthetic scope of the classic Stetter reaction to include alpha,beta-unsaturated aldehydes as acceptors.