De Novo Synthesis of a Highly Strained and Twisted Imide‐Bridged Bicyclic Scaffold

ABSTRACT Embedding functional motifs into bridged scaffolds is a powerful strategy for molecular recognition and drug design, yet imide‐bridged medium‐ring systems have remained synthetically inaccessible. Here, we report an expedient de novo synthesis of imidebridged bicyclo[4.3.1]decane scaffolds, featuring a highly strained anti ‐Bredt olefin and a twisted seven‐membered imide ring, with excellent diastereoselectivity (>20:1 dr). The one‐pot, palladium‐catalyzed sequential reaction of isocyanides with allenyl butenoates proceeds with complete atom economy and high bond‐forming efficiency. Mechanistic studies reveal that efficient leaving‐group recapture and a highly reactive inverse‐electron‐demand type II intramolecular Diels–Alder (IMDA) reaction are both critical to this transformation. Notably, these unprecedented products display promising antiproliferative activity against a panel of cancer cell lines, highlighting their potential for antitumor drug discovery.