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 complexity⁴, but achieving this enzymatically has remained rare.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 due to the inherent difficulty in the stereochemical control of radicals⁹. Here, we repurpose a thiamine-dependent enzyme^10,11 through directed evolution, 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 photo-/enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking new enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 25 out of 33 examples achieving ≥97% enantiomeric excess.