期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 136, 期 15, 页码 5799-5810出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja501881p
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资金
- LEO Pharma
- Carlsberg Foundation
- Danish Council for Independent Research (Technology and Production Sciences)
- Alexander von Humboldt Foundation
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.
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