Triple Nucleophilic Head-to-Tail Cascade Polycyclization of Diazodienals via Combination Catalysis: Direct Access to Cyclopentane Fused Aza-Polycycles with Six-Contiguous Stereocenters

Reported herein are the bench stable (2E,4E)-diazohexa-2,4-dienals (diazodienals) and their unprecedented polycyclization with aldimine and arylamines enabled by Rh­(II)/Brønsted acid relay catalysis. This scalable and atom-economical reaction provides direct access to the biologically important azatricyclo­[6.2.1.04,11]­undecane fused polycycles having six-contiguous stereocenters. Mechanistic studies revealed that polycyclization proceeds through an unusual triple-nucleophilic cascade initiated by aldimine attack on remote Rh-carbenoid, 6π-electrocyclization of aza-trienyl azomethine ylide, stereoselective aza-Michael addition via iminium activation, and inverse electron-demand intramolecular aza Diels–Alder reaction. The π–π secondary interactions play a crucial role in the preorganization of reactive intermediates for the pericyclic reactions and, hence, the overall efficiency of the polycyclization.