On-DNA Deoxygenative C(sp ² )–C(sp ³ ) Coupling Facilitated by Surfactant–DNA (Surf-DNA) Workflow

The expansion of chemical diversity in DNA-encoded libraries (DELs) is essential for broadening their potential in drug discovery. Herein, we introduce the extended utility of the Surfactant-DNA (Surf-DNA) workflow that enables on-DNA deoxygenative Csp²-Csp³ cross-coupling of on-DNA halides with activated alcohols via metallaphotoredox catalysis under anhydrous conditions. The developed reaction demonstrates broad substrate scope for both coupling partners, high conversion rates, and proficiency in preserving DNA integrity and allows for the efficient incorporation of alcohol-derived scaffolds, which are an underutilized and widely available class of building blocks.