Photoredox-Mediated Deoxygenative Alkylation of DNA-Tagged Alkenes with Activated Alcohols

DNA-encoded library (DEL) screens have become a key technology to find small molecule binders to biological targets for drug discovery applications. The development of new DNA-compatible chemistries to expand the accessible DEL chemical space is imperative to enhance screen success across broad target classes and modalities. Additionally, reactions that use commonly available building blocks as well as those that enable the fsp(3) of library members to be increased would have high impact for accessing diverse drug-like structures. Herein, we report a DNA-compatible Giese-type addition of nonstabilized C-centered radicals generated by the deoxygenation of preactivated alcohols into on-DNA olefins. Although alcohols have been historically underused as a building block class within DEL synthesis, their activation to a xanthate enables Csp(3)-Csp(3) coupling to furnish sp(3)-rich products. This reaction is compatible with multiple classes of functional groups, does not damage the DNA tag, and is suitable for use in DEL productions.