Divergent Synthetic Strategy for the 2- and 4-Position Diversification of Pyrrolo[2,3-d]pyrimidines for DNA-Encoded Libraries

Abstract We report a divergent synthetic strategy for scaffold-level diversification of DNA-encoded pyrrolo[2,3-d]pyrimidines. Selective diversification at the 2- and 4-positions of the pyrrolo[2,3-d]pyrimidine scaffold enables the generation of six structurally distinct series. The resulting DNA-encoded derivatives were synthesized in high purity while maintaining sufficient DNA integrity for reliable amplification and decoding. By enabling the incorporation of a wide variety of structurally diverse building blocks into a privileged scaffold, this strategy substantially expands the chemical space accessible to DNA-encoded libraries and provides a practical platform for the construction of structurally diverse DNA-encoded libraries for ligand discovery.