In this work, we show that it is possible to perform directed evolution guided by computational results (performed in our group) to reprogram nonheme iron enzymes to catalyze an abiological C(sp3)‒H azidation reaction through iron-catalyzed radical relay. This biocatalytic transformation uses amidyl radicals as hydrogen atom abstractors and Fe(III)‒N3 intermediates as radical trapping agents. We established a high-throughput screening platform based on click chemistry for rapid evolution of the catalytic performance of identified enzymes. The final optimized variants deliver a range of azidation products with up to 10,600 total turnovers and 93% enantiomeric excess. Given the prevalence of radical relay reactions in organic synthesis and the diversity of nonheme iron enzymes, we envision that this discovery will stimulate future development of metalloenzyme catalysts for synthetically useful transformations unexplored by natural evolution.
This work was carried out by J. Rui, Q. Zhao, A. J. Huls, Z. Chen, V. Reshetnikov and Prof. X. Huang from the Department of Chemistry of the Johns Hopkins University, J. C. Paris and Prof. Y. Guo from the Department of Chemistry of Carnegie University and J. Soler and Dr. M. Garcia-Borràs from the DiMoCat group of the Institute of Computational Chemistry and Catalysis of the University of Girona.
We are very proud of the work by Marc Garcia-Borràs and Jordi Soler! Congratulations!!!
Jinyan Rui, Qun Zhao, Anthony J. Huls, Jordi Soler, Jared C. Paris, Zhenhong Chen, Viktor Reshetnikov, Yunfang Yang, Yisong Guo*, Marc Garcia-Borràs* and Xiongyi Huang*. Directed evolution of nonheme iron enzymes to access abiological radical-relay C(sp3)-H azidation. Science, 2022, 376, 6595. DOI: 10.1126/science.abj2830.