The first total synthesis of sespenine, a rare indole sesquiterpenoid from a mangrove endophyte, has been accomplished. A bioinspired aza-Prins/Friedel-Crafts/retro Friedel-Crafts cascade reaction assembles the bridged tetrahydroquinoline core. Further investigations on the aza-Prins cyclization imply that the C3 configuration of the hydroxyindolenine intermediate is crucial to the biosynthesis of sespenine and its congener xiamycin A.