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

Published Online August 1 2013
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Science DOI: 10.1126/science.1241606

• Report

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

1. Lars Jørgensen¹,*,
2. Steven J. McKerrall¹,*,
3. Christian A. Kuttruff¹,
4. Felix Ungeheuer¹,
5. Jakob Felding²,
6. Phil S. Baran¹,†

+ Author Affiliations

1. ¹Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2. ²External Discovery, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark.

1. ↵†Corresponding author. E-mail: pbaran@scripps.edu

1. ↵* These authors contributed equally to this work.

• 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 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.