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

Preschel, H. Daniel; Otte, Ruben T.; Zhuo, Ying; Ruscoe, Rebecca E.; Burke, Ashleigh J.; Kellerhals, Rachel; Horst, Brendan; Hennig, Sven; Janssen, Elwin; Green, Anthony P.; Turner, Nicholas J.; Ruijter, Eelco

Abstract

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

Citation

Preschel, H. D., Otte, R. T., Zhuo, Y., Ruscoe, R. E., Burke, A. J., Kellerhals, R., Horst, B., Hennig, S., Janssen, E., Green, A. P., Turner, N. J., & Ruijter, E. (2023). Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir. Journal of Organic Chemistry, 88(17), 12565-12571. https://doi.org/10.1021/acs.joc.3c01274

• Journal Article Type: Article
• Acceptance Date: Jun 9, 2023
• Online Publication Date: Aug 22, 2023
• Publication Date: Sep 1, 2023
• Deposit Date: Jan 30, 2025
• Journal: The Journal of Organic Chemistry
• Print ISSN: 0022-3263
• Electronic ISSN: 1520-6904
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 88
• Issue: 17
• Pages: 12565-12571
• DOI: https://doi.org/10.1021/acs.joc.3c01274
• Keywords: Inorganic carbon compounds; Mixtures Organic compounds; Peptides and proteins; Solutions
• Public URL: https://keele-repository.worktribe.com/output/1053128