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

Abstract

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, and 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.

Dinuclear Metal‐ProPhenol Catalysts: Development and Synthetic Applications

“…Zn‐ProPhenol‐catalyzed alkynylation using methyl propiolate 68 was utilized in the total synthesis of asteriscunolide D 71 (Scheme ) . The key intermediate 69 was obtained in 84 % ee and was converted to the corresponding butenolide 70 via a ruthenium‐catalyzed alkene–alkyne coupling with allyl alcohol.…”

Transition-Metal-Catalyzed Synthesis of Aspergillide B: An Alkyne Addition Strategy

“…Methyl propiolate, a more acidic alkyne, has been shown to give significantly higher yields in additions to enolizable aldehydes under the standard conditions. 15 …”

Zweikernige Metall‐ProPhenol‐Katalysatoren: Entwicklung und Anwendungen in der Synthese

“…Die Zn‐ProPhenol‐katalysierte Alkinylierung mittels Methylpropiolat 68 wurde bei der Totalsynthese von Asteriscunolid D 71 eingesetzt (Schema ) . Das Schlüsselintermediat 69 wurde mit 84 % ee erhalten und durch eine Ruthenium‐katalysierte Alken‐Alkin‐Kupplung mit Allylalkohol in das entsprechende Butenolid 70 überführt.…”