Development of New Catalytic Asymmetric Routes towards a Cost-Driving Building Block of Nirmatrelvir

Nirmatrelvir is an inhibitor of SARS-CoV-2 main protease and is the active ingredient in PaxlovidTM. Nirmatrelvir presents a significant synthetic challenge, in no small part due to a cost-driving lactam containing fragment with two stereogenic centers. Our goal was to help decrease the cost of nirmatrelvir, by developing a scalable low-cost synthesis of this fragment, avoiding use of cryogenic conditions reported in the initial route. Herein we disclose three catalytic asymmetric routes to-wards this fragment, via i) chiral Lewis acid (copper) catalysis, ii) chiral Brønsted base organocatalysis and iii) chiral bifunctional hydrogen-bond-donor organocatalysis.