De Novo Synthesis of Multisubstituted Pyrrolidines Based on a Programmed Radical [2 + 2 + 1] Annulation Strategy Using Sulfide-Based Electron Donor–Acceptor Catalysis

The pyrrolidine scaffold is a privileged motif widely embedded in natural products and pharmaceuticals, but its efficient, convergent synthesis remains a formidable challenge. Herein, we report a programmed radical cascade strategy that enables the highly selective [2 + 2 + 1]-type annulation of amine-tethered <i>N</i>-hydroxyphthalimide (NHPI) esters with two electronically distinct alkenes, affording multisubstituted pyrrolidines with complete regio- and chemoselectivities. This transformation is driven by the direct photoexcitation of a sulfide-NHPI ester electron donor-acceptor (EDA) complex, which timeously generates a <i>N</i>-centered radical (NCR) via photoinduced electron transfer, thus, eliminating the requirement for persistent catalysts or stoichiometric reductants. The resulting NCR undergoes a programmed sequence of intermolecular addition, sulfonium formation, and terminal cyclization to yield a pyrrolidine framework in a single step. This operationally simple protocol features a broad substrate scope, high functional-group tolerance, and scalability. Ultraviolet-visible (UV-vis) spectroscopy, fluorescence quenching, and control experiments support the intermediacy of the EDA complex and its photoactivation as the driving force. This study establishes a novel conceptual framework for programming radical cascades and translating synthetic algorithms into precise molecular architectures.