Late-Stage Kinetic Hydrolysis to Prepare an Advanced Intermediate for Ibuzatrelvir

Abstract Ibuzatrelvir is a second-generation, orally administered protease inhibitor of the SARS-CoV-2 MPro virus that is currently being evaluated for the treatment of Covid-19. The molecule contains a substituted trans-trifluoromethylproline fragment that, although it had been the focus of previous synthetic efforts, was still identified as a target for improvement. Herein, we describe a route featuring the late-stage introduction of a stereocenter via a mechanistically distinct diastereoselective kinetic hydrolysis. This bold strategy has resulted in significant efficiency, environmental, and process dividends, underscoring the impact of a continuous-improvement approach to chemical development.