Synergistic photobiocatalysis for enantioselective triple-radical sorting

Multicomponent reactions-those where three or more substrates combine into a product-have been highly useful in rapidly building chemical building blocks of increased complexity¹, but achieving this enzymatically has remained rare^2-5. This limitation primarily arises because an enzyme's active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates⁶. Recently, chemical catalytic radical sorting has emerged as an enabling strategy for a variety of useful reactions^7,8. However, making such processes enantioselective is highly challenging owing to the inherent difficulty in the stereochemical control of radicals⁹. Here we repurpose a thiamine-dependent enzyme^10,11 through directed evolution and combine it with photoredox catalysis to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials-aldehydes, α-bromo-carbonyls and alkenes-to give access to enantioenriched ketone products. Mechanistic investigations provide insights into how this dual photocatalyst-enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 24 out of 33 examples achieving ≥97% enantiomeric excess.