title: Nineteen-step total synthesis of (+)-phorbol.
abstract: Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical structure and the medicinal potential of phorbol esters. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes, germacrenes, taxanes and ingenanes have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C-C bond constructions and C-H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kawamura
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Chu
authors.affiliation: Front End Innovation, LEO Pharma A/S Industriparken 55, 2750 Ballerup, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Felding
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
mesh_terms: D000081008:Bicyclic Monoterpenes; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D060326:Chemistry Techniques, Synthetic; D004224:Diterpenes / Q000138:chemical synthesis; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D010703:Phorbol Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification; D010704:Phorbols / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000081008:Bicyclic Monoterpenes; D001688:Biological Products; D004224:Diterpenes; D039821:Monoterpenes; D010703:Phorbol Esters; D010704:Phorbols; C530110:ingenane; C030218:3-carene; D010100:Oxygen; C033085:phorbol