Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir

• DOI: 10.1021/acs.joc.3c01274
• Publication Date: 2023-08-22T21:50:49Z
• Authors: H. Daniel Preschel; Ruben T. Otte; Ying Zhuo; Rebecca E. Ruscoe; Ashleigh J. Burke; Rachel Kellerhals; Brendan Horst; Sven Hennig; Elwin Janssen; Anthony P. Green; Nicholas J. Turner; Eelco Ruijter
• Keywords: Pandemic; Protease inhibitor (pharmacology); 2019-20 coronavirus outbreak; Desymmetrization

In the wake of Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical combat future outbreaks SARS-CoV-2 or related viruses. The orally available main protease inhibitor nirmatrelvir proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis featuring highly enantioselective biocatalytic desymmetrization (>99% ee) and diastereoselective multicomponent reaction (>25:1 dr) as key steps. Our route avoids use transition metals peptide coupling reagents, resulting overall efficient atom-economic process.