New Strategies for Stereoselective Radical Biocatalysis

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. 

Dr. Yang received his Ph.D. degree in Organic Chemistry in 2016 under the guidance of Prof. Steve Buchwald at MIT. In the Buchwald lab, he developed CuH-catalyzed methods for the asymmetric hydrofunctionalization of simple olefins. As an NIH Postdoctoral Fellow working with Prof. Frances Arnold at Caltech, Dr. Yang studied biocatalysis and protein engineering and developed biocatalytic asymmetric C–H amination. Dr. Yang started his independent career in the Department of Chemistry and Biochemistry at the University of California Santa Barbara in 2020. By integrating synthetic chemistry, biocatalysis, protein engineering and computational tools, the Yang group is reprograming nature’s biosynthetic machineries to address challenging problems in synthesis, catalysis and biomolecular engineering. The Yang group recently coined and implemented two new strategies to advance novel stereoselective biocatalytic reactions, including metalloredox radical biocatalysis and pyridoxal radical biocatalysis. Dr. Yang is a recipient of the Regent’s Junior Faculty Fellowship Award (2021), Faculty Career Development Award (2022), National Science Foundation (NSF) CAREER Award (2022), National Institutes of Health (NIH) Maximizing Investigators' Research Award (2022), Thieme Chemistry Journals Award (2023), Army Research Office (ARO) Young Investigator Award (2023), Packard Fellowship (2023), Sloan Research Fellowship (2024), Amgen Young Investigator Award (2024) and Department of Energy (DOE) Early Career Award (2024).