title: 14-step synthesis of (+)-ingenol from (+)-3-carene.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Jørgensen
authors.forename: Steven J
authors.initials: SJ
authors.lastname: McKerrall
authors.forename: Christian A
authors.initials: CA
authors.lastname: Kuttruff
authors.forename: Felix
authors.initials: F
authors.lastname: Ungeheuer
authors.forename: Jakob
authors.initials: J
authors.lastname: Felding
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000081008:Bicyclic Monoterpenes; D002384:Catalysis; D004224:Diterpenes / Q000138:chemical synthesis*; D028481:Euphorbia / Q000737:chemistry; D039821:Monoterpenes / Q000737:chemistry*; D010088:Oxidoreductases / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D000081008:Bicyclic Monoterpenes; D004224:Diterpenes; D039821:Monoterpenes; D010088:Oxidoreductases; C030218:3-carene; C008125:ingenol