Enzymatic multicomponent C–C bond forming reactions for diversity-oriented synthesis remain rare. Using cooperative photobiocatalysis, we developed a stereoselective three-component radical-mediated C–C coupling unknown in both organic chemistry and biochemistry. Directed evolution of repurposed pyridoxal decarboxylases enabled full fragment variability in this three-component coupling, giving rise to six classes of valuable products, many of which were inaccessible by other methods, even in a racemic fashion. This enzymatic platform integrates a range of asymmetric catalysis principles, including remote stereocenter construction, stereodivergent catalysis, kinetic resolution and parallel kinetic resolution, achieving excellent diastereo- and enantiocontrol over radical intermediates. The broad substrate scope and complementary specificities of evolved enzyme variants enabled combinatorial library synthesis, affording structurally and stereochemically diverse scaffolds for medicinal chemistry.
Zhang et al. (Thu,) studied this question.