Highly Convergent Total Synthesis of Gambieric Acid A Using Iterative and Two-Directional Ring-Closing Metathesis Reactions

利用迭代和双向闭环复分解反应高度收敛全合成冈比亚酸 A

• 批准号: EP/F031505/1
• 负责人: J Stephen Clark
• 金额: $ 119.03万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF031505%2F1
• 关键词: Highly; Convergent; Total; Synthesis; Gambieric

The proposed research concerns the synthesis of the complex marine natural product gambieric acid A from simple, commercially available starting materials. The gambieric acids (A-D) were isolated in minute amounts from a simple marine alga which was collected off the coast of the Gambier Islands in the South Pacific. These natural products possess very powerful activity against certain types of disease-causing fungi. Structurally related natural products isolated from the same alga are highly neurotoxic (i.e. they prevent nerves from functioning properly), but the gambieric acids do not possess this activity and can block the toxicity of neurotoxic marine natural products of similar structure. Gambieric acid A has a very complex molecular structure comprising 10 ether (oxygen-containing) rings - nine of which are fused together - and 27 chiral centres (i.e. carbon atoms where the handedness defines the three-dimensional structure of the molecule) embedded in the molecular framework. The aim of the project is to synthesise gambieric acid A in a highly efficient manner using new chemical reactions and strategies to construct the rings and join complex fragments of the molecule together. The proposed research is extraordinarily challenging because few molecules of comparable size and complexity have been synthesised and very elaborate and relatively inefficient routes have been used to construct those that have. The proposed project is particularly challenging because some of the rings are difficult to construct, due to their size, and the configurations of all 27 chiral centres must be set unambiguously.The important features of our synthesis will be the highly efficient and rapid synthesis of molecular fragments by simultaneous construction of rings in two directions (so-called two-directional or bi-directional synthesis) and the efficient union of these pieces to form the intact molecule. Examples of two-directional chain or ring construction are very rare in complex natural product synthesis, and the use of this strategy to assemble such a complex target is unprecedented. The research project will allow us to test whether two-directional ring construction is a viable strategy and will allow us develop the synthetic techniques and tools required to construct complex biologically active natural products in an efficient manner. The successful synthesis of gambieric acid A will also permit the biological activity of the natural product to be explored further and will allow the relationship between the molecular structure and the biological activity of marine polyethers to be elucidated more clearly. The synthetic strategies, tactics and reactions that we develop during the project will be generally applicable to a wide variety of other complex natural product targets.

拟议的研究涉及复杂的海洋天然产物冈比亚酸A的合成从简单的，市售的起始材料。从南太平洋甘比尔群岛沿岸采集的一种简单海洋生物中分离出微量的甘比尔酸（A-D）。这些天然产物对某些类型的致病真菌具有非常强大的活性。从同一种海洋生物中分离出的结构相关的天然产物具有高度神经毒性（即它们阻止神经正常运作），但冈比亚酸不具有这种活性，并且可以阻断具有类似结构的神经毒性海洋天然产物的毒性。冈比亚酸A具有非常复杂的分子结构，包括10个醚（含氧）环（其中9个稠合在一起）和27个嵌入分子框架中的手性中心（即手性定义分子三维结构的碳原子）。该项目的目的是使用新的化学反应和策略以高效的方式合成冈比亚酸A，以构建环并将分子的复杂片段连接在一起。拟议的研究是非常具有挑战性的，因为很少有类似大小和复杂性的分子被合成，并且非常复杂和相对低效的路线被用于构建那些具有类似结构的分子。拟议的项目特别具有挑战性，因为一些环由于其尺寸而难以建造，我们合成的重要特点是通过两个方向同时构建环来高效快速地合成分子片段（所谓的双向或双向合成）和这些片段的有效结合以形成完整分子。双向链或环结构的例子在复杂的天然产物合成中是非常罕见的，使用这种策略来组装这样一个复杂的目标是前所未有的。该研究项目将使我们能够测试双向环构建是否是一种可行的策略，并将使我们能够开发以有效方式构建复杂生物活性天然产品所需的合成技术和工具。冈比亚酸A的成功合成还将允许进一步探索天然产物的生物活性，并将允许更清楚地阐明海洋聚醚的分子结构和生物活性之间的关系。我们在项目期间开发的合成策略，战术和反应将普遍适用于各种其他复杂的天然产物目标。

项目成果

Synthesis of Cyclopropyl-Substituted Furans by Brønsted Acid Promoted Cascade Reactions

布伦斯台德酸促进级联反应合成环丙基取代呋喃

• DOI: 10.1002/ange.201500625
• 发表时间: 2015
• 期刊: Angewandte Chemie
• 作者: Clark J

Recent Progress in the Total Synthesis of Gambieric Acid A, a Marine Polyether with Potent Anti-Fungal Activity

具有强效抗真菌活性的海洋聚醚冈比亚酸A全合成最新进展

• 发表时间: 2009
• 作者: Stephen Clark

Organocatalytic synthesis of highly substituted furfuryl alcohols and amines.

• DOI: 10.1002/anie.201207300
• 发表时间: 2012-11
• 期刊: Angewandte Chemie
• 作者: J. Clark;Alistair Boyer;A. Aimon;Paloma Engel García;D. Lindsay;Andrew D. F. Symington;Yves Danoy