1′-Cyano Intermediate Enables Rapid and Stereoretentive Access to 1′-Modified Remdesivir Nucleosides

Tej Poudel; Subhankar Panda; Moyosore Orimoloye; Pooja V Hegde; Courtney C. Aldrich

doi:10.1021/acs.joc.2c01897

1′-Cyano Intermediate Enables Rapid and Stereoretentive Access to 1′-Modified Remdesivir Nucleosides

Tej Poudel, Subhankar Panda, Moyosore Orimoloye, Pooja V Hegde, Courtney C. Aldrich

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

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Abstract

While biochemical, structural, and computational studies have shown the importance of remdesivir's C1′-substituent in its perturbation of SARS-CoV-2 RdRp action, we recognized the paucity of methods to stereoselectively install substituents at this position as an obstacle to rigorous explorations of SAR and mechanism. We report the utilization of an anomerically pure 1′-cyano intermediate as an entry point to a chemically diverse set of substitutions, allowing for 1′diversification while obviating the need for the tedious separation of anomeric mixtures.

Original language	English (US)
Pages (from-to)	14452-14462
Number of pages	11
Journal	Journal of Organic Chemistry
Volume	87
Issue number	21
DOIs	https://doi.org/10.1021/acs.joc.2c01897
State	Published - Nov 4 2022

Bibliographical note

Funding Information:
This research was supported by a grant from the NIH (AI136445) to C.C.A. The authors would like to thank Dr. Victor G. Young, Jr., from the Department of Chemistry, University of Minnesota, for X-ray crystallographic analysis.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

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Research Support, N.I.H., Extramural

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abstract = "While biochemical, structural, and computational studies have shown the importance of remdesivir's C1′-substituent in its perturbation of SARS-CoV-2 RdRp action, we recognized the paucity of methods to stereoselectively install substituents at this position as an obstacle to rigorous explorations of SAR and mechanism. We report the utilization of an anomerically pure 1′-cyano intermediate as an entry point to a chemically diverse set of substitutions, allowing for 1′diversification while obviating the need for the tedious separation of anomeric mixtures.",

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AU - Hegde, Pooja V

AU - Aldrich, Courtney C.

N1 - Funding Information: This research was supported by a grant from the NIH (AI136445) to C.C.A. The authors would like to thank Dr. Victor G. Young, Jr., from the Department of Chemistry, University of Minnesota, for X-ray crystallographic analysis. Publisher Copyright: © 2022 American Chemical Society. All rights reserved.

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AB - While biochemical, structural, and computational studies have shown the importance of remdesivir's C1′-substituent in its perturbation of SARS-CoV-2 RdRp action, we recognized the paucity of methods to stereoselectively install substituents at this position as an obstacle to rigorous explorations of SAR and mechanism. We report the utilization of an anomerically pure 1′-cyano intermediate as an entry point to a chemically diverse set of substitutions, allowing for 1′diversification while obviating the need for the tedious separation of anomeric mixtures.

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1′-Cyano Intermediate Enables Rapid and Stereoretentive Access to 1′-Modified Remdesivir Nucleosides

Abstract

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