Total Synthesis of Aconicarmisulfonine A, a Sulfonated Diterpene Alkaloid

High Resolution Image Download MS PowerPoint Slide 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.