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

Area of Science:

• Chemical Biology
• Organic Chemistry
• Drug Discovery

Background:

• DNA-encoded libraries (DELs) are crucial for hit identification, enabling screening of billions of compounds.
• Current DEL diversification methods often require partially aqueous conditions, limiting reaction scope.
• Surfactant-DNA (Surf-DNA) complexes were previously introduced to enable anhydrous DEL reactions.

Purpose of the Study:

• To expand the utility of Surf-DNA complexes for novel chemical transformations.
• To demonstrate the application of Surf-DNA in amino radical transfer (ART) coupling for C(sp2)-C(sp3) bond formation.
• To optimize and simplify the Surf-DNA workflow for large-scale DEL production.

Main Methods:

• Utilized surfactant-DNA (Surf-DNA) complexes to facilitate reactions under anhydrous conditions.
• Applied amino radical transfer (ART) coupling to forge C(sp2)-C(sp3) bonds on DNA-bound molecules.
• Developed an optimized and simplified Surf-DNA workflow.

Main Results:

• Successfully expanded Surf-DNA applications to include ART coupling for challenging C(sp2)-C(sp3) bond formation.
• Demonstrated high functional group tolerance and broad substrate scope for the ART coupling reaction.
• Reported an optimized and simplified Surf-DNA workflow suitable for large-scale DEL synthesis.

Conclusions:

• Surf-DNA complexes effectively facilitate anhydrous chemical reactions, including ART coupling, for DEL diversification.
• The expanded methodology allows for the construction of complex molecules with C(sp2)-C(sp3) linkages within DELs.
• The optimized workflow streamlines DEL production, enhancing its utility in hit-finding campaigns.