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14-Step Synthesis of (+)-Ingenol from (+)-3-Carene

Science  23 Aug 2013:
Vol. 341, Issue 6148, pp. 878-882
DOI: 10.1126/science.1241606

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Ingenol Ingenuity

The diterpenoid i ngenol is the core structure of a topical drug recently commercialized to treat actinic keratosis, a precancerous skin condition. Sourcing the compound from the Euphorbia plants that produce it is relatively inefficient, so Jørgensen et al. (p. 878, published online 1 August) devised a chemical synthesis starting from the comparatively simple and inexpensive monoterpene chiral (+)-3-carene. The synthetic sequence involves 14 steps—less than half as long as prior chemical routes to the target—and relies on a two-stage approach, inspired by the posited biosynthetic pathway, in which preliminary assembly of the fused ring framework precedes hydroxylation of the periphery.

Abstract

Ingenol is a diterpenoid with unique architecture and has derivatives possessing important anticancer activity, including the recently Food and Drug Administration–approved Picato, a first-in-class drug for the treatment of the precancerous skin condition actinic keratosis. Currently, that compound is sourced inefficiently from Euphorbia peplus. Here, we detail an efficient, highly stereocontrolled synthesis of (+)-ingenol proceeding in only 14 steps from inexpensive (+)-3-carene and using a two-phase design. This synthesis will allow for the creation of fully synthetic analogs of bioactive ingenanes to address pharmacological limitations and provides a strategic blueprint for chemical production. These results validate two-phase terpene total synthesis as not only an academic curiosity but also a viable alternative to isolation or bioengineering for the efficient preparation of polyoxygenated terpenoids at the limits of chemical complexity.

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