Sustainable Manufacturing of trans-4-Trifluoromethyl-l-proline via Stereochemical Editing: A Combined In Silico and Experimental Approach

Ibuzatrelvir (1) is a second-generation, orally bioavailable, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor clinical candidate. Herein, we report the implementation of an in silico and high-throughput experimentation strategy leading to the identification of a rapid, efficient, and sustainable route to trans-4-trifluoromethyl-l-proline (2), a key building block for ibuzatrelvir. This novel synthetic route features a key stereochemical editing step to enable an efficient and scalable protocol that operates under mild conditions with high stereoselectivity, providing effective access to more than 235 kg of trans-4-trifluoromethyl-l-proline 2 in a five-step synthetic sequence from readily available starting materials.