Total Synthesis of Ingenol

Abstract

A total synthesis of the biologically important diterpene ingenol has been completed. Ring-closing olefin metathesis was used to construct the strained "inside-outside" tetracyclic skeleton, and a series of diastereoselective reactions were employed to complete the synthesis. Another naturally occurring ingenane, 20-deoxyingenol, has also been prepared.

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…269 Ingenol has long served as a holy grail for total synthesis due to its complex oxygenation pattern and the unique “ in,out” stereochemistry observed at the bridgehead positions of the bicyclo[4.4.1]undecane motif. 270 While many groups have studied its synthesis, 271 only Winkler (2002), 272 Kuwajima (2003), 273 Kigoshi (2004), 274 Wood (2004), 275 and Baran (2013) 276 have published total or formal synthetic routes to ingenol, the latter two of which utilized the chiral pool of terpenes and will be discussed herein.…”

Synthesis of Natural Products Containing Medium‐Size Carbocycles by Ring‐Closing Alkene Metathesis

“…RCM-based strategies for the construction of the B ring of ingenol were reported by Wood [72] and Kigoshi [73]. In Wood's total synthesis, compound 289 (synthesized from 3-carene) underwent Diels-Alder cycloaddition with cyclopentadiene to afford 290 (Scheme 1.53 Kigoshi's formal synthesis (Scheme 1.54) relies on the efficient spirocyclization reaction of ketone 296 also prepared from 3-carene.…”

Metathesereaktionen in der Totalsynthese

“…[41] Wood und Mitarbeiter vertrauten vor kurzem in ihrer Totalsynthese von Ingenol (16, Schema 5) in einer komplexen Situation auf eine Olefin-Metathese. [42] Ingenol (16), die Stammverbindung einer großen Klasse von Ingenan-Diterpenen, hat Synthesechemiker über 20 Jahre lang fasziniert. [43] Der Reiz dieses bemerkenswerten Naturstoffs beruht teilweise auf seiner vielversprechenden biologischen Aktivität, [44] aber auch auf seiner hoch oxidierten polycyclischen Molekülstruktur, deren auffälligstes Merkmal die gespannte "Inside-outside"(trans)-Konfiguration der Brückenkopfato-me im bicyclischen BC-Ringsystem ist.…”