Total Synthesis of Aconicarmisulfonine A, a Sulfonated Diterpene Alkaloid

Diterpene alkaloids have fascinated the synthetic community for well over half a century and have long documented use in the treatment of pain and other ailments. Recently Shi and Zhang isolated a new class of sulfonated diterpene alkaloids from the roots of Aconitum carmichaelii. These zwitterionic alkaloids possess several unprecedented new ring systems and displayed potent analgesic properties in preliminary pain model studies in mice. Herein we describe synthetic entry into this subclass of C(20) diterpene alkaloids via a total synthesis of the most potent analgesic member aconicarmisulfonine A, which features an unusual sulfonated bicyclo[3.3.1]nonane core. Key synthetic maneuvers include a Ir-catalyzed caprolactam synthesis, a stereoselective Mannich cyclization, and a highly diastereoselective Mukaiyama-Michael cascade. A late-stage thiol to sulfonate oxidation completed the synthesis.