Asymmetric Synthesis of Benzofused <i>N</i>-Bridged [3.2.1] Skeletons via Bifunctional Phosphonium Salt-Catalyzed Annulation

We have disclosed a highly efficient asymmetric formal [3 + 2] cycloaddition reaction catalyzed by a tunable bifunctional phosphonium salt catalyst. With this protocol, a library of structurally and functionally diverse enantioenriched polycyclic and fused <i>N</i>-bridged [3.2.1] skeletons bearing four vicinal 4°/3° stereocenters were constructed in a highly stereoselective fashion with excellent yields. The practicality and utility of this process were demonstrated by a scaled-up synthesis. The complex spatial structure as well as the absolute configuration of such <i>N</i>-bridged [3.2.1] ring was assigned based on the X-ray crystal structural analysis. Preliminary mechanistic studies elucidated that the H-bonding and ion-pair interactions of bifunctional phosphonium salt catalyst are critical for chiral control. The insights gained from our studies are expected to advance general efforts toward the asymmetric synthesis of biology-oriented <i>N</i>-bridged heterocyclic skeletons and pseudonatural products in synthetic chemistry.