A Convergent and Bio-Inspired Total Synthesis of Phorbol

佛波醇的收敛和仿生全合成

• 批准号: 7383899
• 负责人: Arthur John Catino
• 金额: $ 4.68万
• 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/7383899
• 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）：Phorbol的总合成代表了有机化学中的巨大挑战。佛波尔从欣快的植物家族中分离出来，是一种四环素的tigliane二萜，具有融合的5-7-6-3环系统，上面装饰有一系列立体源性中心。已知植物和含有亲脂酯侧链的佛比尔和衍生物是有效的肿瘤促进剂，并且也发现诱导其他生物学反应，包括HIV表达。佛波尔最著名的生理特性是它结合蛋白激酶C（PKC）调节结构域的能力，蛋白激酶C（PKC）在细胞信号转导中起着核心作用。然而，由于其结构上的复杂性，仅报道了两个总合成。一条实用和高效的途径非常需要访问天然和不自然的佛波尔衍生物。此外，尽管佛波尔与其他大环二萜的相似性（例如，达弗纳尼和ingenanes），但统一的合成策略尚未到来。基于自然的灵感，提出了佛波尔的融合总合成。自1977年以来，人们就已经知道，自然界使用两种跨碳碳键形成反应从大环前体构建佛罗宝贝。同样，在这里，官能化的大环将提供螯合控制的透明烯丙基化反应和构象控制的透明藻反应的模板。该策略不仅将是访问佛罗宝石的可行手段，而且还将阐明这些复杂靶标的生物合成。这项研究建议的长期目标是对生物活性植物衍生物和其他大环二萜的有效制备和利用，以改善公共卫生。 **发展自然界中发现的复杂分子的策略和技术在根本上很重要。佛波和相关化合物已显示出对疾病治疗的一系列生物学反应。这项研究为这些化合物提供了有效而实用的途径。 **