Total Synthesis of (±)-Stemocurtisine via Catalytic Carbonylation.

We report herein the first total synthesis of (±)-stemocurtisine, a rare insecticidal Stemona alkaloid natural product possessing a cage-like polycyclic skeleton with five O/N-heterocycles including a characteristic pyrido[1,2-a]azepine ring system and a highly oxidized tetrasubstituted double bond. Our synthesis features a palladium-catalyzed cyclopropanol ring-opening carbonylative lactonization to build a fused bicyclic lactone as a platform to construct the rest of the ring systems and an unusual bis(iodozincio)methane-mediated cyclopropanation of an α,β-epoxyketone to prepare the key cyclopropanol substrate. Two complementary approaches were developed to build the pyrido[1,2-a]azepine ring system. The first one is based on conventional nitrogen alkylation chemistry using SN2 reactions. The second one features modern transition metal-catalyzed borrowing hydrogen chemistry to form two C-N bonds intramolecularly between a free amine and two primary alcohols under redox neutral conditions, which is more concise and atom-economical. Lastly, the tetrasubstituted double bond was installed using a Horner-Wadsworth-Emmons olefination protocol followed by oxidation state adjustment. Overall, these enabling transformations led to (±)-stemocurtisine in 15 or 17 steps from two known and readily available starting materials.