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 rare2–5. 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 reactions7,8. 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 enzyme10,11 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.
