On-DNA photochemical methods for expanding DNA-encoded library (DEL) chemical space

Abstract

DNA-encoded libraries (DELs) have become a mainstay of small-molecule discovery, enabling millions to billions of compounds to be screened in a single pooled affinity selection in which each small molecule is covalently linked to a unique DNA identifier. However, the chemistry available for their construction remains limited compared to conventional synthetic chemistry. On-DNA chemistry is constrained by the requirement for aqueous, dilute, and DNA-compatible conditions. Classical on-DNA reactions such as amide coupling, reductive amination, SNAr and transition-metal cross-coupling have enabled reliable library synthesis, but they tend to favour planar, sp2-rich products. Photochemistry and photocatalysis have recently emerged as a powerful strategy to broaden this toolbox. Excited-state activation opens reaction pathways that are difficult or impossible to reach through conventional ground-state chemistry and can facilitate novel transformations towards the construction of more complex and sp3-rich scaffolds. This review surveys the field of on-DNA photochemistry, looking at different activation modes including photoredox single-electron transfer (SET), hydrogen-atom transfer (HAT), metallaphotoredox dual catalysis, electron donor–acceptor (EDA) complexes, energy-transfer (EnT) catalysis, and direct photolysis. Collectively, these methods have translated a broad range of useful transformations to be amenable to on-DNA synthesis and unlocked access to many medicinally valuable motifs.