Development of a concise synthesis of (+)-ingenol.
The complex diterpenoid (+)-ingenol possesses a uniquely challenging scaffold and constitutes the core of a recently approved anti-cancer drug. This full account details the development of a short synthesis of 1 that takes place in two separate phases (cyclase and oxidase) as loosely modeled after terpene biosynthesis. Initial model studies establishing the viability of a Pauson-Khand approach to building up the carbon framework are recounted. Extensive studies that led to the development of a 7-step cyclase phase to transform (+)-3-carene into a suitable tigliane-type core are also presented. A variety of competitive pinacol rearrangements and cyclization reactions were overcome to develop a 7-step oxidase phase producing (+)-ingenol. The pivotal pinacol rearrangement is further examined through DFT calculations, and implications for the biosynthesis of (+)-ingenol are discussed.
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Steven J
SJ
McKerrall
Lars
L
Jørgensen
Christian A
CA
Kuttruff
Felix
F
Ungeheuer
Phil S
PS
Baran
D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D008956:Models, Chemical
D004224:Diterpenes; C008125:ingenol