Expanding the chemical space of DNA-encoded libraries with radical reactivity

DNA-Encoded Library (DEL) technology serves as a cornerstone of modern drug discovery, providing a cost-effective platform for the rapid interrogation of therapeutic candidates. However, the prerequisite for DNA-compatible synthetic reactions under aqueous conditions has historically constrained DEL chemical diversity to planar, C(sp2)-rich architectures, resulting from a reliance on traditional two-electron polar transformations. This short review evaluates recent advances in radical-mediated transformations as a powerful means to increase the chemical space of DELs. By facilitating access to three-dimensional sp3-rich scaffolds, these radical methodologies have the potential to significantly broaden the structural diversity of modern DELs.