Synergistic Peptide–Phosphonium/Lewis Acid Catalysis Enables Direct Asymmetric Synthesis of Indole-Derived N -Bridged [4.2.1] Ring Systems

The direct catalytic asymmetric construction of pseudo-natural chiral frameworks—particularly exemplified by azabicyclo[4.2.1]nonane architectures—represents a long-standing and formidable challenge in synthetic organic chemistry. Despite many advances in methodology, an efficient and general enantioselective route to such structurally intricate N-bridged scaffolds remains elusive. Herein, we address this unmet need by introducing a synergistic dual catalytic system that merges a chiral peptide–phosphonium salt with an achiral Lewis acid metal catalyst. This cooperative strategy enables a dipolar cycloaddition (formal [6 + 2]) between readily accessible starting materials, thereby allowing modular and stereocontrolled access to a diverse range of [4.2.1] azabicyclic systems. The process proceeds under mild conditions and exhibits broad functional group tolerance, delivering products bearing four contiguous 3°/4° stereocenters in high yields with satisfactory diastereo- and enantioselectivity. Key to this transformation is the development of a dual activation mode governed by multipoint weak interactions within an ion-pair/Lewis acid catalytic assembly. Gram-scale reactions and downstream derivatizations further underscore the practicality and potential of this methodology for the streamlined synthesis of complex pseudo-natural architectures.