Total Synthesis of Marine Polyether Natural Products

聚合型多环醚天然产物由海洋甲藻产生，但也存在于以它们为食的有机体和食物链较高的动物中。虽然这些天然产物(如短杆菌毒素和雪卡毒素)中的许多都是强效的神经毒素，但有些是潜在的开发新药的先导化合物。稠合聚醚是一些结构最复杂的天然产物，已被分离和表征。它们的大小、它们拥有的立体中心的数量以及多个中等大小的环的存在意味着它们构成了全合成领域的终极挑战。在过去的二十年里，少数研究小组已经成功地合成了一些较大的海洋聚醚，但已经完成的少量总合成通常具有50-100步的最长线性序列，总步数为数百步。显然，有必要开发更短的合成路线，以更有效地提供这些天然产物，并允许它们及其类似物接受全面的生物学评估。研究项目的目标是发明一种新颖、通用和高效的海洋聚醚快速合成方法，该方法利用聚醚天然产物结构中嵌入的显性和潜在性对称性。合成聚醚的新方法将涉及中心对称的反稠合双环醚的对映选择性去对称化。中心对称体系在目标定向合成中的应用很少，其不对称去对称化也没有得到广泛的研究。在以前的聚醚合成中，构建含有单一环醚的全功能化构建块通常需要15个以上的步骤。该方法将使稠合聚醚的合成效率更高，因为从简单的原料出发，只需六到七步就可以制备非手性双环醚构筑块。

Fused polycyclic ether natural products are produced by marine dinoflagellates but are also found in organisms that feed on them and in animals higher up the food chain. Although many of these natural products (e.g. the brevetoxins and ciguatoxins) are potent neurotoxins, some are potential lead compounds for the development of new drugs. Fused polyethers are some of the most structurally complex natural products to have been isolated and characterised. Their size, the number of stereogenic centres they possess and the presence of multiple medium-sized rings means that they constitute the ultimate challenge in the field of total synthesis. Over the past two decades, a small number of research groups has been successful in synthesizing some of the larger marine polyethers, but the small number of total syntheses that have been completed usually have longest linear sequences of 50-100 steps with overall step counts of several hundred. Clearly, there is a need to develop much shorter synthetic routes that will deliver these natural products more efficiently and allow them and their analogues to be subjected to full biological evaluation.The objective of the research project is the invention of a novel, general and highly efficient method for the rapid synthesis of marine polyethers that exploits both the apparent and latent symmetry embedded in the structures of the polyether natural products. The new approach to polyether synthesis will involve the enantioselective desymmetrisation of centrosymmetric trans-fused bicyclic ethers. Centrosymmetric systems have been used very rarely in target-directed synthesis and their asymmetric desymmetrisation has not been explored extensively. In previous polyether syntheses, construction of fully functionalized building blocks that contain a single cyclic ether has usually required more than 15 steps. The proposed method will enable fused polyethers to be synthesised more efficiently because achiral bicyclic ether building blocks will be prepared from simple starting materials in just six or seven steps.