Organic Chemistry Seminar

Radical reactions have enjoyed widespread applications in both small molecule and macromolecule synthesis. However, it remains challenging to control the stereochemistry of radical transformations and to discover novel modes of radical catalysis which are not known in either organic chemistry or biochemistry. Combining synthetic chemistry, enzymology and protein engineering, our group advanced two new biocatalytic strategies for stereoselective free radical processes. First, by capitalizing on the innate redox properties of first-row transition-metal cofactors, we repurposed and evolved natural metalloproteins to catalyze unnatural radical reactions in a stereocontrolled fashion. Through a metalloenzyme-catalyzed halogen atom transfer mechanism (XAT, X = F, Cl, Br and I), a range of radical C–C, C–Br, and C–F bond forming reactions proceeded with excellent total turnover numbers (up to 20,000) and outstanding stereocontrol. Second, by merging visible light photoredox catalysis and biocatalysis, we advanced a novel mode of pyridoxal radical biocatalysis which is new to both chemistry and biology. Synergistic photobiocatalysis allowed us to repurpose structurally and functionally diverse pyridoxal phosphate (PLP)-dependent enzymes as radical enzymes, leading to novel radical PLP enzymology. Pyridoxal radical biocatalysis provides convergent, stereoselective, and protecting-group-free access to a range of useful non-canonical amino acids, including those bearing a stereochemical triad and/or tetrasubstituted stereocenters which remained difficult to prepare by other chemical and biocatalytic means. Furthermore, we demonstrate that the exploitation of biocatalyst-photocatalyst synergy affords a new paradigm to design and develop stereoselective intermolecular radical reactions with synthetic utility.