Enabling the Synthesis of the 4'-Thioremdesivir Core.

Authors

Liuqing Wei, Mahesh Kasthuri, Christina Na, Scott Bagley, Aanya Bhalla, James Bradow, Li Chengwei, Zahira Tber, Zhe Chen, Chulho Choi, Kevin DeBoyace, Christopher Cameron, Richard Loach, Martin R M Koos, Lauren Prentis, Alandra Quinn, Andre Shavnya, Ormacinda White, Franck Amblard, Gary M Chinigo, Raymond F Schinazi

Published in

Chemistry (Weinheim an der Bergstrasse, Germany). Pages e71678. Sep 10, 2026. Epub Sep 10, 2026.

Abstract

Nucleosides and nucleoside analogs represent a long established and highly important class of pharmaceutical agents, with numerous U.S. Food and Drug Administration (FDA)-approved examples spanning antiviral, anticancer, and immunological indications. Among these, 4'-thionucleosides-wherein the endocyclic ribose oxygen is replaced by sulfur-have emerged as particularly attractive bioisosteric analogs, frequently exhibiting enhanced pharmacokinetic and pharmacodynamic properties. Despite decades of investigation into 4'-thionucleosides, the literature overwhelmingly focuses on anomeric N-linked derivatives, while reports describing C-linked 4'-thionucleosides remain remarkably scarce. In this study, we report the first successful synthesis of the parent 4'-thionucleoside core of remdesivir. In contrast to the well-established β-selective deoxycyanation observed in the ribose series, substitution of oxygen with sulfur results in a pronounced reversal of anomeric selectivity, favoring the undesired α-isomer. This intrinsic bias was overcome through the discovery and exploitation of an unprecedented bridged oxythioketal intermediate, enabling access to the β-configured product. The relative and absolute stereochemistry was confirmed by single-crystal x-ray diffraction, correcting a recent misassignment in the literature. Computational and NMR reaction monitoring studies provide mechanistic insight into thioribose reactivity and establish a framework for controlling anomeric stereochemistry in C-linked 4'-thionucleoside synthesis. These results establish a foundation for future C-linked 4'-thionucleoside antiviral development.

PMID:
42720396
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.