Epoxide-Opening Cascade Approach to the Synthesis of Marine Ladder Polyethers

描述（由申请人提供）：海洋阶梯聚醚天然产物具有强大的抗肿瘤和抗真菌活性；然而，从自然来源中分离出这些复杂的目标已被证明是困难的。目前海洋阶梯聚醚的合成方法涉及到每个熔合环体系的迭代构建，导致方法冗长而低效。需要更直接的方法为研究人员提供重要的药物研究材料。因此，本研究项目的长期目标是通过采用区域选择性环氧化合物打开级联，开发一种高效的仿生聚醚合成方法。Jamison小组最近的研究表明，区域选择性环氧化物开口（6-末端）仅限于在反应伙伴（即羟基和环氧化物）上附加有四氢吡喃导向基团的体系。其他模板组对这些级联事件的影响尚不清楚，因此排除了将该方法直接应用于合成结构多样的天然产物。本申请的目的是扩大模板多样性在环氧化合物开孔级联中的耐受范围，并开发串联工艺，通过将模板的形成和随后的环氧化合物开孔级联结合到单个合成步骤中来加速这些靶标的合成。第一个具体目标集中在具有不同模板环尺寸的模型系统的合成和随后的环氧化合物打开级联。本研究提供了模板环尺寸与环氧化物打开事件的区域选择性之间的相关性，目的是建立一个预测模型。第二个具体目标的重点是开发串联工艺，将模板形成和随后的环氧化物打开结合到单个合成步骤中。这允许从易于获取的起始材料快速获得海洋阶梯聚醚天然产品的核心。最后，第三个特定目标提供了对该方法范围的深入了解，因为它适用于甘比酸a的F-J环片段。这些特定目标有助于提高海洋阶梯聚醚合成的效率，这是发现新药物的必要步骤。

DESCRIPTION (provided by applicant): Marine ladder polyether natural products exhibit potent antitumor and antifungal activity; however, the isolation of these complex targets from natural sources has proven difficult. Current methods for the synthesis of marine ladder polyethers involve the iterative construction of each fused ring system, resulting in lengthy and inefficient approaches. More direct methods are necessary to provide researchers with significant material for medicinal studies. Therefore, the long term goal of this research project is to develop an efficient biomimetic approach to polyether synthesis by employing regioselective epoxide-opening cascades. Recent studies by the Jamison group have indicated that regioselective epoxide-openings (6-endo) are limited to systems in which there is a tetrahydropyran-directing group appended to the reacting partners (i.e., hydroxyl group and epoxide). The influence of other templating groups on these cascade events is not well understood, thus precluding the direct application of this methodology towards the synthesis of structurally-diverse natural products. The objective of this application is to expand the scope to which template diversity is tolerated in epoxide-opening cascades, and to develop tandem processes to expedite the synthesis of these targets by incorporating the formation of a template and subsequent epoxide-opening cascade into a single synthetic step. The first specific aim focuses on the synthesis and subsequent epoxide-opening cascades of model systems with varying template ring size. This study provides a correlation between template ring size and the regioselectivity of epoxide-opening events, with the goal of developing a predictive model. The focus of the second specific aim is to develop a tandem process, which combines template formation and subsequent epoxide-opening into a single synthetic step. This allows for rapid access to the core of marine ladder polyether natural products from readily accessible starting materials. Lastly, the third specific aim provides insight into the scope of this methodology, as it is applied to the F-J ring fragment of gambieric acid A. These specific aims serve to increase the efficiency of marine ladder polyether synthesis, a necessary step for the discovery of new medicinal agents. PUBLIC HEALTH RELEVANCE: Marine ladder polyether natural products are associated with harmful red tide events, and are responsible for massive fish death and subsequent human poisoning worldwide. While the negative impacts of this class of compounds are obvious, their medicinal properties are not as well understood. The inability to isolate significant quantities of material inhibits the research of marine toxins as therapeutic agents, and thus the chemical synthesis of these natural products is a necessary step to provide material for medical research.