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

描述(申请人提供)：海洋梯形聚醚天然产物显示出强大的抗肿瘤和抗真菌活性；然而，从天然来源中分离这些复杂的靶标已被证明是困难的。目前合成海洋梯形聚醚的方法是迭代构建每个稠环体系，导致方法冗长且效率低下。需要更直接的方法来为研究人员提供医学研究的重要材料。因此，本研究项目的长期目标是开发一种高效的仿生合成聚醚的方法，采用区域选择性的环氧化物开级联反应。Jamison小组最近的研究表明，区域选择性环氧化物开环(6-endo)仅限于在反应伙伴(即羟基和环氧化物)上附加四氢吡喃导向基团的体系。其他模板基团对这些级联事件的影响还没有得到很好的了解，因此无法直接应用这一方法来合成结构多样的天然产物。本申请的目的是扩大在环氧化物级联中容许模板多样性的范围，并开发串联工艺，通过将模板的形成和随后的环氧化物级联结合到单一合成步骤中来加速这些目标的合成。第一个具体目标是合成具有不同模板环大小的模型体系以及随后的环氧化物开级联。这项研究提供了模板环大小和环氧化物开环事件的区域选择性之间的关联，目的是开发一个预测模型。第二个具体目标的重点是开发一种串联工艺，它将模板形成和随后的环氧化物开环结合到一个单一的合成步骤中。这使得能够从容易获得的起始材料中快速获得海洋梯形聚醚天然产品的核心。最后，第三个具体目的是深入了解这一方法的范围，因为它适用于冈比亚酸A的F-J环片段。这些具体目的有助于提高海洋梯形聚醚合成的效率，这是发现新药剂的必要步骤。 公共卫生相关性：海洋阶梯聚醚天然产品与有害的赤潮事件有关，并导致全球范围内大量鱼类死亡和随后的人类中毒。虽然这类化合物的负面影响是显而易见的，但人们对它们的药用特性还没有很好的了解。无法分离大量的物质阻碍了海洋毒素作为治疗剂的研究，因此这些天然产物的化学合成是为医学研究提供材料的必要步骤。

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.