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14-step synthesis of (+)-ingenol from (+)-3-carene.

Science (New York, N.Y.) (2013-08-03)
Lars Jørgensen, Steven J McKerrall, Christian A Kuttruff, Felix Ungeheuer, Jakob Felding, Phil S Baran
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
(1S)-(+)-3-Carene, 99%
Supelco
(+)-3-Carene, analytical standard
Sigma-Aldrich
3-Carene, 90%
Sigma-Aldrich
3-Carene, ≥90%