Development of a Concise Synthesis of (+)-Ingenol
Development of a Concise Synthesis of (+)-Ingenol
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DOI：
10.1021/ja501881p
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发表时间：
2014-04-16
影响因子：
15
通讯作者：
Baran, Phil S.
中科院分区：
文献类型：
--
作者：
McKerrall, Steven J.;Jorgensen, Lars;Baran, Phil S.
复杂的二萜类化合物（+）-巨大戟二萜醇具有独特的具有挑战性的支架，并构成了最近批准的抗癌药物的核心。这个完整的帐户详细介绍了一个简短的合成1，发生在两个独立的阶段（环化酶和氧化酶）的发展松散后，萜烯生物合成的模型。最初的模型研究建立一个Pauson-Khand的方法来建立碳框架的可行性进行了叙述。广泛的研究，导致发展的7步环化酶相转化（+）-3-？克服了各种竞争性的频哪醇重排和环化反应，开发了7步氧化酶相生产（+）-巨大戟二萜醇。通过DFT计算进一步研究了关键的频哪醇重排，并讨论了对（+）-巨大戟二萜醇生物合成的影响。
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.