Science DOI: 10.1126/science.1241606
14-Step Synthesis of (+)-Ingenol from (+)-3-Carene
- Lars Jørgensen1,*,
- Steven J. McKerrall1,*,
- Christian A. Kuttruff1,
- Felix Ungeheuer1,
- Jakob Felding2,
- Phil S. Baran1,†
+ Author Affiliations
- 1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
- 2External Discovery, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark.
- ↵* These authors contributed equally to this work.
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.
- Received for publication 7 June 2013.
- Accepted for publication 18 July 2013.