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

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

doi:10.1021/acs.joc.3c01274

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

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

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	12565-12571
Number of pages	7
Journal	The Journal of organic chemistry
Volume	88
Issue number	17
Early online date	22 Aug 2023
DOIs	https://doi.org/10.1021/acs.joc.3c01274
Publication status	Published - 1 Sept 2023

Bibliographical note

Funding Information:
This work was supported by the Bill & Melinda Gates Foundation.

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

Funding

We thank Koen Hoek, Lars Feddema, Alexander Warnaar, and Dr. Matteo Faltracco (all VUA) for practical support, Dr. Christophe Vande Velde (University of Antwerp) for helpful advice in solving the crystal structure, and Prof. Romano Orru (Maastricht University) for useful discussions. Silpa Sundaram (Bill & Melinda Gates Foundation) and BMGF consultants John Dillon and Trevor Laird are warmly acknowledged for valuable suggestions. This work was supported by the Bill & Melinda Gates Foundation. This work was supported by the Bill & Melinda Gates Foundation.

Funders
Bill and Melinda Gates Foundation
Universiteit Antwerpen

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title = "Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir",

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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AU - Preschel, H Daniel

AU - Otte, Ruben T

AU - Zhuo, Ying

AU - Ruscoe, Rebecca E

AU - Burke, Ashleigh J

AU - Kellerhals, Rachel

AU - Horst, Brendan

AU - Hennig, Sven

AU - Janssen, Elwin

AU - Green, Anthony P

AU - Turner, Nicholas J

AU - Ruijter, Eelco

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

Abstract

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