Pratik R. Chheda; Nicholas Simmons; Zhicai Shi
Org. Lett., 2024, 26(20), 4365-4370
https://doi.org/10.1021/acs.orglett.4c01398

Abstract

DNA-encoded libraries (DELs) are a key technology for identifying small-molecule hits in both the pharmaceutical industry and academia, but their chemical diversity is largely limited to water-compatible reactions to aid in the solubility and integrity of encoding DNA tags. To broaden the DEL chemical space, we present a workflow utilizing DNA–cationic surfactant complexation that enables dissolution and reactions on-DNA in anhydrous organic solvents. We demonstrate its utility by developing DEL-compatible photoredox decarboxylative C(sp2)–C(sp3) coupling under water-free conditions. The workflow is optimized for the 96-well format necessary for large-scale DEL productions, and it enables screening and optimization of DEL-compatible reactions in organic solvents.