Pratik R. Chheda, Dominic S. Finis, Nicholas Simmons, Zhicai Shi

Org. Lett. 2025

https://doi.org/10.1021/acs.orglett.5c03424

Abstract

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.

Summary

This study presents a novel method for expanding the chemical diversity in DNA-encoded libraries (DELs) through on-DNA deoxygenative C(sp2)−C(sp3) cross-coupling. The Surfactant−DNA (Surf-DNA) workflow enables this coupling under anhydrous conditions, leveraging metallaphotoredox catalysis. The method shows high conversion rates and broad substrate scope, including primary, secondary, and multifunctional alcohols, as well as various (hetero)aryl halides. The study demonstrates the preservation of DNA integrity and the potential for incorporating a wide range of alcohol-derived scaffolds, significantly broadening the chemical space accessible in DEL synthesis.

Highlights

- Introduction of a Surfactant−DNA (Surf-DNA) workflow for on-DNA deoxygenative C(sp2)−C(sp3) cross-coupling.

- Utilization of metallaphotoredox catalysis under anhydrous conditions.

- Demonstration of broad substrate scope and high conversion rates for both coupling partners.

- Preservation of DNA integrity and compatibility with elongated DNA substrates.

- Efficient incorporation of alcohol-derived scaffolds, expanding the chemical diversity in DELs.

Conclusion

The study successfully developed a robust protocol for on-DNA deoxygenative coupling via the Surf-DNA workflow. This method enables high efficiency, expansive substrate scope, functional group tolerance, and preservation of DNA integrity. By unlocking the potential of a widely available and historically underutilized class of alcohol building blocks, this approach allows for the construction of challenging C(sp2)−C(sp3) bonds and the generation of more structurally and functionally diverse libraries. This significantly broadens the chemical space accessible in DEL synthesis, enhancing their potential in drug discovery.