Enabling the Synthesis of the 4'-Thioremdesivir Core

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.