Thionium Ion Initiated Medium-Sized Ring Formation: The Total Synthesis of Asteriscunolide D

The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed, enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a gamma-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.