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

提出的研究涉及复杂的海洋天然产物甘比亚酸A的合成从简单的，商业上可用的起始材料。甘比亚酸（a - d）是从一种简单的海藻中分离出来的，这种海藻是在南太平洋甘比亚群岛海岸收集的。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。从同一藻类中分离的结构相关的天然产物具有高度的神经毒性（即它们阻止神经正常运作），但冈比利酸不具有这种活性，并且可以阻断类似结构的神经毒性海洋天然产物的毒性。甘比亚酸A具有非常复杂的分子结构，包括10个醚（含氧）环（其中9个融合在一起）和27个嵌在分子框架中的手性中心（即手性决定分子三维结构的碳原子）。该项目的目的是利用新的化学反应和策略以高效的方式合成甘比亚酸A，以构建环并将分子的复杂片段连接在一起。拟议中的研究极具挑战性，因为很少有大小和复杂程度相当的分子被合成，而构建这些分子的方法非常复杂，效率相对较低。该项目特别具有挑战性，因为一些环由于其大小而难以构建，并且必须明确设置所有27个手性中心的配置。我们合成的重要特点将是通过在两个方向上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），并将这些片段有效地结合以形成完整的分子。在复杂的天然产物合成中，双向链或环状结构的例子是非常罕见的，使用这种策略来组装如此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合成技术和工具，以有效的方式构建复杂的生物活性天然产物。冈比亚酸A的成功合成也将使天然产物的生物活性得到进一步的探索，并将使海洋聚醚分子结构与生物活性之间的关系得到更清晰的阐明。我们在项目中开发的合成策略、战术和反应将普遍适用于各种其他复杂的天然产物目标。

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.