Total Synthesis of Ingenol

By: William Sommer, Aldrich ChemFiles 2009,9.6, 4.

Aldrich ChemFiles 2009,9.6, 4.

In 2004, Wood and coworkers reported the synthesis of ingenol.1 This natural product has fascinated synthetic chemists for the past 20 years due to its promising biological activity and structure, which features four distinctive ring systems. Wood and coworkers devised an ingenious approach involving a ring-opening/cross metathesis and a ring-closing metathesis step (Scheme 2). With only 2 mol % of the Grubbs catalyst (1st Generation), the norbornene derivative afforded the desired dienes in nearly quantitative yield. It is important to note that the polymerization of norbornene was suppressed by using high dilution conditions and excess ethylene gas. Further functionalization of the diene set the stage for the ring-closing metathesis step. The desired product was obtained in 76% yield in the presence of 25 mol % of the Grubbs-Hoveyda catalyst (2nd Generation).

Scheme 2

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  1. Nickel,A. et al. J. Am. Chem. Soc. 2004, 126, 16300.

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