Authors:
Lars Jørgensen, Steven J. McKerrall, Christian A. Kuttruff, Felix Ungeheuer, Jakob Felding, & Phil S. Baran
Summary:
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 employing a two-phase design. This synthesis will allow for the creation of fully synthetic analogs of bioactive ingenanes to address pharmacological limitations and also 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.
Source:
Science; (08/01/13)