DNA-Compatible Synthesis of Pyrrolidine-Fused Scaffolds via a One-Pot Three-Component Cycloaddition Strategy

Pyrrolidines are privileged scaffolds commonly found in natural products, endowed with distinctive biological activities and significant pharmaceutical relevance. Herein, we describe a robust, DNA-compatible strategy for the efficient synthesis of pyrrolidine-fused scaffolds via a three-component cycloaddition of azomethine ylides. The resulting scaffolds, bearing reactive N-termini, can be further diversified using a range of reagents, thereby enhancing the chemical diversity of drug-like pyrrolidine-fused DNA-encoded library (DEL). Critically, the practical utility of this methodology was demonstrated through its application to on-DNA synthesis of bioactive compounds and the construction of prototype DELs.