A Convergent and Bio-Inspired Total Synthesis of Phorbol

描述（申请人提供）：荧光体的全合成是有机化学中一项艰巨的挑战。phorbol是一种从大戟科植物中分离出来的四环tigliane二萜，具有一个融合的5-7-6-3环系统，上面装饰着一系列立体中心。含有亲脂酯侧链的佛波尔及其衍生物被认为是有效的肿瘤促进剂，也被发现可诱导包括HIV表达在内的其他生物反应。phorbol最显著的生理特性是它能够结合蛋白激酶C （PKC）的调控结构域，PKC在细胞信号转导中起着核心作用。然而，由于其结构复杂，仅报道了两种全合成。一个实用和有效的途径将是非常可取的，以获得天然和非天然的象素衍生物。此外，尽管佛博尔与其他大环二萜（例如，水仙烷和银烷）相似，但统一的合成策略尚未出现。从自然界的启发出发，提出了一种收敛全合成法。自1977年以来，人们就知道Nature通过两个跨环碳-碳键形成反应，从一个大环前体构建了phorbol。类似地，一个功能化的大环将为螯合控制的跨环烯丙基化反应和构象控制的跨环醛醇反应提供模板。这一策略不仅将作为一种可行的手段来获取phorbol，而且将阐明这些复杂靶点的生物合成。本研究计划的长期目标是有效制备和利用具有生物活性的佛波尔衍生物和其他大环二萜，以改善公众健康。**开发在自然界中发现的复杂分子的创造策略和技术是至关重要的。佛波和相关化合物已被证明在治疗疾病方面表现出一系列的生物学反应。本研究为这些化合物的合成提供了一条高效实用的途径。**

DESCRIPTION (provided by applicant): The total synthesis of phorbol represents a formidable challenge in organic chemistry. Isolated from the Euphorbiaceae plant family, phorbol is a tetracyclic tigliane diterpene that possesses a fused 5-7-6-3 ring system adorned with an array of stereogenic centers. Phorbol and derivatives containing lipophilic ester side chains are known to be potent tumor promoting agents and have also been found to induce other biological responses including HIV expression. The most notable physiological property of phorbol is its ability to bind the regulatory domain of protein kinase C (PKC) which plays a central role in cellular signal transduction. As a consequence of its structural complexity however, only two total syntheses have been reported. A practical and efficient route would be highly desirable to access both natural and unnatural phorbol derivatives. Moreover, despite the similarity of phorbol to other macrocyclic diterpenes (e.g., the daphnanes and ingenanes), a unifying synthetic strategy has not been forthcoming. Based on inspiration from Nature, a convergent total synthesis of phorbol is proposed. It has been known since 1977 that Nature constructs phorbol from a macrocyclic precursor using two transannular carbon-carbon bond forming reactions. Similarly herein, a functionalized macrocycle will provide the template for a chelation-controlled transannular allylation reaction and a conformation-controlled transannular aldol reaction. This strategy will not only serve as a viable means to access phorbol, but will shed light on the biosynthesis of these complex targets. The long-term objective of this research proposal is the efficient preparation and utilization of biologically active phorbol derivatives and other macrocyclic diterpenes for the improvement of public health. ** The development of strategies and techniques for the creation of complex molecules found in Nature is fundamentally important. Phorbol and related compounds have been shown to exhibit a range of biological responses toward the treatment of disease. This research provides an efficient and practical route to these compounds. **