Bioinspired Radical Stetter Reaction: Radical Umpolung Enabled by Ion‐Pair Photocatalysis.

A bioinspired, intermolecular radical Stetter reaction of α‐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 α‐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 α,β‐unsaturated aldehydes as acceptors. A bioinspired radical Stetter reaction of α‐keto acids and aldehydes is contingent on a formal "radical umpolung". Electrostatic recognition ensures that the α‐keto carboxylates, which function as latent acyl radicals, are proximal to the iminium ions generated in situ. Synergising organo‐ and photocatalysis activation principles finally expand the mechanistic and synthetic scope of the classic Stetter reaction to include α,β‐unsaturated aldehyde acceptors. [ABSTRACT FROM AUTHOR]