Hydrophobic Surfactant-DNA Complex (Surf-DNA) Enables DNA-Encoded-Library-Compatible Decarboxylative Arylation under Anhydrous Conditions.

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.

Oxoammonium Salt-Mediated On-DNA Alcohol Oxidation for DEL Synthesis.

On-DNA carboxylic acids are important synthetic intermediates in the synthesis of DNA-encoded library (DEL) structures. Herein, we report an oxoammonium salt-mediated, room temperature, solution-phase oxidation of DNA-linked primary alcohols into carboxylic acids. This method exhibits a wide substrate scope, encompassing aliphatic, benzylic, and heterobenzylic alcohols, and is compatible with DEL encoding strategies. This advancement facilitates a DEL strategy to utilize unprotected alcohols as inert, masked carboxylic acids and enables access to noncommercial bifunctional carboxyl intermediates to enhance the accessible chemical diversity within DELs.