Total Synthesis of Isodaphlongamine H by Iridium‐Catalyzed Reductive [3 + 2] Cycloaddition of <i>N‐</i> Hydroxylactam

Abstract The total synthesis of isodaphlongamine H based on a lactam strategy, which enables quick access to complex cyclic amines, is described. The strategy begins with alkylation of a chiral lactam and subsequent N ‐oxidation via an imino ether to afford the N ‐hydroxylactam. For the key transformation to functionalize the amide carbonyl, an iridium‐catalyzed reductive [3 + 2] cycloaddition of the N ‐hydroxylactam provides a tricyclic isoxazolidine in a one‐pot process. After the coupling reaction with an allylic silane fragment, the total synthesis is accomplished through intramolecular Hosomi–Sakurai allylation to construct a pentacyclic core. The deoxygenated pentacyclic intermediate shows higher cytotoxicity against HeLa and U937 cell lines than isodaphlongamine H, and might become a lead compound for further biological study.