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

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

Funders	Funder number
Bill and Melinda Gates Foundation
Universiteit Antwerpen

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10.1021/acs.joc.3c01274

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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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note = "Funding Information: This work was supported by the Bill & Melinda Gates Foundation. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

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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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