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

环氧化物开环级联法合成海洋梯状聚醚

• 批准号: 8208283
• 负责人: Matthew Beaver
• 金额: $ 4.84万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2012-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208283
• 关键词: Acids; Address; Algal Blooms; Anabolism; Antifungal Agents; Antifungal Antibiotics; Binding; Biological; Biological Factors; Biological Models; Biomimetics; Cessation of life; Complex; Cyclic Ethers; Cyclization; Development; Epoxy Compounds; Event; Excision; Exhibits; Fishes; Future; Goals; Human; In Situ; Knowledge; Marine Toxins; Marines; Medical Research; Methodology; Methods; Modeling; Outcome; Pathway interactions; Poisoning; Process; Property; Publishing; Reaction; Research; Research Personnel; Research Project Grants; Source; Structure; System; Therapeutic Agents; Toxic effect; Toxin; anticancer activity; brevetoxin; brevetoxin B; chemical synthesis; direct application; gambieric acid A; hydroxyl group; improved; insight; interest; novel; predictive modeling; public health relevance; red tide

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.

描述（由申请人提供）：Marine ladder聚醚天然产物显示出有效的抗肿瘤和抗真菌活性;然而，已证明难以从天然来源中分离这些复杂的靶标。目前用于合成海洋梯形聚醚的方法涉及每个稠环系统的迭代构建，导致冗长且低效的方法。更直接的方法是必要的，为研究人员提供重要的材料进行医学研究。因此，本研究计划的长期目标是开发一种有效的仿生方法，通过采用区域选择性环氧开放级联聚醚合成。Jamison小组最近的研究表明，区域选择性环氧化物开环（6-内）限于其中有四氢吡喃导向基团附加到反应配偶体上的体系（即，羟基和环氧化物）。其他模板组对这些级联事件的影响还没有得到很好的理解，从而排除了直接应用这种方法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开放级联中容许模板多样性的范围，并开发串联方法，以通过将模板的形成和随后的环氧化物开放级联并入单个合成步骤中来加速这些靶标的合成。第一个具体的目标集中在合成和随后的环氧化物开放级联模型系统与不同的模板环的大小。本研究提供了模板环的大小和环氧化物开放事件的区域选择性之间的相关性，与开发一个预测模型的目标。第二个具体目标的重点是开发一种串联工艺，该工艺将模板形成和随后的环氧化物开放结合到单个合成步骤中。这允许从容易获得的起始材料快速获得海洋阶梯聚醚天然产品的核心。最后，第三个具体目标提供了对该方法范围的深入了解，因为它适用于冈比亚酸A的F-J环片段。这些特定的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。 公共卫生关系：海洋阶梯聚醚天然产物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很明显，但它们的药用特性还没有得到很好的了解。由于无法分离出大量的物质，抑制了将海洋毒素作为治疗剂的研究，因此，这些天然产品的化学合成是为医学研究提供材料的必要步骤。