Surf–DNA-Enabled DNA-Encoded Library-Compatible Amino Radical Transfer C(sp²)–C(sp³) Coupling

DNA-encoded libraries (DELs) enable screening of billions of molecules in a single pool through affinity-based selection and have become an indispensable hit finding technology. Although DELs provide relatively easy access to billions of molecules, some methodologies to chemically diversify DELs remain adapted to partially aqueous conditions. To address this challenge, we recently demonstrated the use of surfactant-DNA (Surf-DNA) complexes as an effective approach to facilitate DEL-compatible reactions under anhydrous conditions. Herein, we report the expansion of Surf-DNA to affect an amino radical transfer (ART) coupling for forging challenging C(sp2)-C(sp3) bonds on DNA with high functional group tolerance over a broad range of substrates. We also report an optimized and simplified Surf-DNA workflow, enabling seamless transition into large-scale DEL productions.