Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
J Am Chem Soc. 2014 Apr 16;136(15):5799-810. doi: 10.1021/ja501881p. Epub 2014 Apr 8.
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.
（+）-表儿茶素拥有一个独特的挑战性支架，是最近批准的抗癌药物的核心。本全面报道详细描述了一种简短的（+）-1 合成方法，该方法分两个独立阶段（环化酶和氧化酶）进行，大致模仿萜类生物合成。最初的模型研究证实了 Pauson-Khand 方法构建碳框架的可行性，这些研究也被记录下来。还介绍了广泛的研究，这些研究导致开发了 7 步环化酶阶段，将（+）-3-蒈烯转化为合适的丁香烷型核心。通过 DFT 计算进一步研究了关键的频哪醇重排，并讨论了其对（+）-表儿茶素生物合成的影响。
