Department of Chemistry Seminar - New Strategies for Stereoselective Radical Biocatalysis

Speaker: Dr. Yang YANG

Institution: Department of Chemistry and Biochemistry, University of California Santa Barbara

Hosted By: Professor Jianwei SUN

Abstract 

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 (pseudo)halogen transfer mechanism (XAT, X = F, Cl, Br, I, N3, SCN and OCN), a range of radical C–C, C–F and other C–X 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. Cooperative 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 stereoselective and protecting-group-free access to numerous 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. The ability to perform diversity-oriented synthesis combinatorially through previously elusive biocatalytic C–C bond formation marks a synthetically valuable advance, paving the way for broader adaptation and application of biocatalysis in medicinal chemistry. Furthermore, we demonstrate that the exploitation of biocatalyst-photocatalyst synergy affords a new paradigm to design and develop a range of stereoselective intermolecular radical reactions using new mechanisms.