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

Science. 2013 Aug 23;341(6148):878-82. doi: 10.1126/science.1241606. Epub 2013 Aug 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Bicyclic Monoterpenes
  • Catalysis
  • Diterpenes / chemical synthesis*
  • Euphorbia / chemistry
  • Monoterpenes / chemistry*
  • Oxidoreductases / chemistry
  • Stereoisomerism

Substances

  • Antineoplastic Agents
  • Bicyclic Monoterpenes
  • Diterpenes
  • Monoterpenes
  • Oxidoreductases
  • 3-carene
  • ingenol