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 γ-hydroxy propiolate as a handle for butenolide
formation via Ru-catalyzed alkene–alkyne coupling.