A Convergent and Bio-Inspired Total Synthesis of Phorbol

佛波醇的收敛和仿生全合成

• 批准号: 7274991
• 负责人: Arthur John Catino
• 金额: $ 4.48万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274991
• 关键词: 3-hydroxybutanal; Anabolism; Binding; Biological; Biological Factors; Biomedical Research; Breathing; Carbon; Complex; Development; Disease; Diterpenes; Esters; Euphorbiaceae; Exhibits; Family; HIV; Light; Molecular Conformation; Nature; Object Attachment; Organic Chemistry; Phorbol; Phorbols; Physiological; Plants; Play; Preparation; Property; Protein Kinase C; Public Health; Range; Reaction; Reporting; Research; Research Proposals; Role; Route; Scientist; Side; Signal Transduction; System; Techniques; Tumor Promoters; analog; base; carcinogenesis; chelation; heuristics; response; tumor

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. **

描述（由申请人提供）：佛波醇的全合成是有机化学中一个艰巨的挑战。佛波醇是一种从大戟科植物中分离出来的四环惕各烷二萜，具有一个5-7-6-3稠合环系统，并带有一系列的立体中心。已知佛波醇和含有亲脂性酯侧链的衍生物是有效的肿瘤促进剂，并且还发现其诱导包括HIV表达在内的其它生物反应。佛波醇最显著的生理特性是其能够结合蛋白激酶C（PKC）的调节结构域，该蛋白激酶C在细胞信号转导中起核心作用。然而，由于其结构的复杂性，只有两个总的合成已被报道。非常需要一种实用且有效的途径来获得天然和非天然佛波醇衍生物。此外，尽管佛波醇与其他大环二萜（例如，瑞香烷和巨大戟烷），但统一的合成策略尚未出现。基于大自然的启发，提出了佛波醇的收敛全合成方法。自1977年以来，人们已经知道，Nature使用两个跨环碳-碳键形成反应从大环前体构建佛波醇。类似地，在本文中，官能化大环将提供用于螯合控制的跨环烯丙基化反应和构象控制的跨环羟醛缩合反应的模板。这种策略不仅将作为一种可行的手段来获取佛波醇，但将揭示这些复杂目标的生物合成。本研究提案的长期目标是有效制备和利用具有生物活性的佛波醇衍生物和其他大环二萜，以改善公众健康。** 开发用于创建自然界中发现的复杂分子的策略和技术至关重要。佛波醇和相关化合物已被证明对疾病的治疗表现出一系列的生物学反应。本研究为该类化合物的合成提供了一条有效可行的途径。**