Synergistic Catalysis between a Dipeptide Phosphonium Salt and a Metal‐Based Lewis Acid for Asymmetric Synthesis ofN‐Bridged [3.2.1] Ring Systems

Abstract We present an unprecedented synergic catalytic route for the asymmetric construction of fluorinated N ‐bridged [3.2.1] cyclic members of tropane family via a bifunctional phosphonium salt/silver co‐catalyzed cyclization process. A broad variety of substrates bearing an assortment of functional groups are compatible with this method, providing targeted compounds bearing seven‐membered ring and four contiguous stereocenters in high yields with excellent stereoselectivities. The gram‐scale preparations, facile elaborations and preliminary biological activities of the products demonstrate the application potential. Moreover, both experimental and computational mechanistic studies revealed that the cyclization proceeded via a “sandwich” reaction model with multiple weak‐bond cooperative activations. Insights gained from our studies are expected to advance general efforts towards the catalytic synthesis of challenging chiral heterocyclic molecules.