A unified platform for nucleoside analog synthesis

Nucleoside analogs (NAs) are essential as antiviral and anticancer therapies. Despite decades of focused medicinal chemistry efforts, their related chemical space remains underexplored, mainly owing to their lengthy, single-molecule–oriented syntheses that lack the flexibility required to generate NA libraries. Here we report a flexible, robust, and efficient platform for the high-throughput synthesis of NAs using a photoredox coupling strategy. This approach produces both carbon- and nitrogen-linked NAs and unifies the synthesis of several disparate NA classes, including 4′-thio, 4′-imino, and ProTides, all from a simple, scalable intermediate. Using this platform, we demonstrate the production of a diverse NA library and identify several hit compounds with anti–HIV-1 activity. We expect that this newly developed approach to NAs will inspire and support drug discovery efforts in this area.