Enantioselective Synthesis of Chiral Azepines: A Cascade Strategy Featuring 1‐Aza‐Cope Rearrangement

The 1‐aza‐Cope rearrangement serves as a valuable method for constructing nitrogen‐containing compounds; however, its asymmetric variants remain largely underexplored due to unfavorable thermodynamics and reaction reversibility. To overcome these challenges, we developed a relay catalysis system comprising tetrapeptide bis‐quaternary phosphonium salts (PBPSs) in combination with a gold(I) catalyst. This strategy incorporates a ring‐opening process during the rearrangement to preserve stereocenters and facilitate product formation. Using this approach, we synthesized a variety of chiral azepines in excellent yields (up to 96%) and with high stereoselectivities (up to 98% ee and>20:1 dr). Mechanistic investigations clarified the origin of chirality and offered insights into the reaction pathway. This work presents a new strategy for constructing medium‐sized chiral nitrogen heterocycles and highlights the broader potential of relay catalysis integrating transition metals with bioinspired peptide–phosphonium salts (PPSs).