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. 2023 Sep 1;88(17):12565-12571.
doi: 10.1021/acs.joc.3c01274. Epub 2023 Aug 22.

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

H Daniel Preschel  1 , Ruben T Otte  1 , Ying Zhuo  2 , Rebecca E Ruscoe  2 , Ashleigh J Burke  2 , Rachel Kellerhals  1 , Brendan Horst  1 , Sven Hennig  1 , Elwin Janssen  1 , Anthony P Green  2 , Nicholas J Turner  2 , Eelco Ruijter  1
Affiliations

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

H Daniel Preschel et al. J Org Chem. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Retrosynthesis of Nirmatrelvir and Biocatalytic Synthesis of Imine 3
Scheme 2
Scheme 2. Synthesis of Isocyanide 4a
Scheme 3
Scheme 3. Synthesis of Nirmatrelvir
Scheme 4
Scheme 4. Streamlined Route to Nirmatrelvir
See this image and copyright information in PMC

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