DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

The syntheses of DNA-encoded libraries (DELs) thus far tend to underexploit the capabilities of synthetic organic chemistry, affording compounds of low stereochemical diversity and topographic complexity. Here, we describe the design, construction, and validation of a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish scaffolds that could be functionalized with known DNA-compatible reactions. We quantified the impact of synthetic decisions on small-molecule physicochemical properties and library diversity via Tanimoto multi-fusion similarity analysis, among other techniques. Test screens against horseradish peroxidase and carbonic anhydrase IX—analyzed by a rigorous statistical framework—confirmed the success of the synthesis and screening procedures. These results demonstrate that diverse collections of structurally complex DNA-barcoded compounds may be synthesized without the development of novel DNA-compatible chemistry.