Reed T. Larson, Ben W. H. Turnbull, Patrick J. Moon, Dan Lehnherr, Jonathan M. E. Hughes, Stasik Popov, Gilmar Brito, Teresa Andreani, Suhong Kim, James H. Herbort, Renee J. Sifri, Shorouk O. Badir, Chibueze I. Onyeagusi, Nicholas R. Deprez, Douglas A. L. Otte, Donald R. Gauthier, Nadine Kuhl, Yining Ji, Andrew J. Neel, Ryan D. Cohen, Jeffrey S. Derrick, Cecilia Bottecchia, Clara Hartmanshenn, David A. Vargas, Guilherme Dal Poggetto, Alex M. Confer, Xue Zheng, Yangzhong Qin, Ajit Vikram, Justin A. Newman, Zeinab Sakhaei, Riki J. Drout, Chen Lü, Zhenhua Wu, S. M. M. de Castro, Sarah María Regueira Betancourt, Gurpreet Longia, Brittany Kassim, Yingju Xu, Jamie M. McCabe Dunn, Nastaran Salehi Marzijarani
An enantioselective seven-step synthesis of MK-7845, an investigational protease inhibitor for the treatment of COVID-19 is described. Key features of the synthesis include the preparation of a chiral isonitrile intermediate utilizing an asymmetric ruthenium-catalyzed reductive amination reaction to set the key amine stereocenter; a highly enantioselective, biocatalytic oxidation reaction with a monoamine oxidase enzyme to furnish a bicyclic imine; and, finally, the union of these fragments via a diastereoselective three-component Joullié-Ugi coupling reaction en route to MK-7845.