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

Nirmatrelvir is an inhibitor of the SARS-CoV-2 main protease and is the active ingredient in Paxlovid. 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 the use of cryogenic conditions reported in the initial route. Herein, we disclose three catalytic asymmetric routes toward this fragment, via (i) chiral Lewis acid (copper) catalysis, (ii) chiral Bro̷nsted base organocatalysis, and (iii) chiral bifunctional hydrogen-bond-donor organocatalysis.