Total Synthesis of Marine Polyether Natural Products

海洋聚醚天然产物的全合成

• 批准号: 2308487
• 金额: --
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2308487
• 关键词: Total; Synthesis; Marine; Polyether; Natural

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.

融合多环醚天然产物是由海洋鞭毛藻产生的，但也存在于以它们为食的生物和食物链较高的动物中。虽然许多天然产物（如短链毒素和雪卡毒素）是强效神经毒素，但有些是开发新药的潜在先导化合物。熔融聚醚是一些结构最复杂的天然产物已经分离和表征。它们的大小，它们所拥有的立体中心的数量以及多个中型环的存在意味着它们构成了全合成领域的终极挑战。在过去的二十年中，少数研究小组已经成功地合成了一些较大的海洋聚醚，但已经完成的少数总合成通常是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，并使它们及其类似物能够接受全面的生物学评估。该研究项目的目标是发明一种新的、通用的、高效的方法来快速合成海洋聚醚，利用聚醚天然产物结构中明显和潜在的对称性。聚醚合成的新方法将涉及中心对称跨熔双环醚的对映选择性不对称。中心对称体系在靶向合成中很少使用，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，包含单环醚的全功能化构建块的构建通常需要超过15个步骤。所提出的方法将使熔融聚醚的合成更有效，因为非手性双环醚构建块将从简单的起始材料中制备，只需六到七个步骤。