Cycloaddition Reactions as a Tool for Expanding Chemical Space of DNA-Encoded Libraries
Abstract
DNA-encoded libraries (DELs) have emerged as a powerful platform for high-throughput hit identification in drug discovery, yet the repertoire of DNA-compatible reactions for library construction remains limited. Cycloaddition reactions offer a particularly attractive solution, enabling the simultaneous construction of complex ring systems and generation of stereochemical diversity in a single transformation, while providing efficient access to sp 3 -rich, three-dimensional scaffolds that are underrepresented in conventional DEL libraries. This review systematically surveys on-DNA cycloaddition reactions reported to date, organizing them into four mechanistic classes: [2+1], [2+2], [3+2], and [4+2] cycloadditions. For each class, we discuss reaction design and condition optimization, substrate scope, mechanistic basis, and DNA compatibility, alongside representative scaffolds accessible through each strategy. Collectively, these transformations have enabled the efficient on-DNA construction of cyclopropanes, cyclobutanes, isoxazolidines, triazoles, dihydropyrans, pyridazines, and isoquinolones under mild conditions compatible with DEL workflows. The mechanistic and practical insights compiled herein are intended to serve as a ready reference for researchers developing next-generation DEL cycloaddition strategies. Future advances are expected to arise from the adaptation of emerging mild-condition cycloadditions, the incorporation of pharmacologically privileged cyclic scaffolds, and the broader use of complexity-generating reactions that deliver spiro- and fused-ring architectures, thereby expanding chemical space coverage in DEL-based drug discovery.