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: 8473435
• 负责人: Matthew Beaver
• 金额: $ 1.51万
• 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 2012-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473435
• 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）：海洋梯子多醚天然产物表现出有效的抗肿瘤和抗真菌活性；但是，事实证明，这些复杂目标与自然来源的分离很困难。当前合成海洋梯子聚乙烯的方法涉及每个融合环系统的迭代结构，从而实现冗长而效率低下的方法。为了为研究人员提供有关药物研究的重要材料，需要采用更直接的方法。因此，该研究项目的长期目标是通过采用区域选择性环氧级别的级联反应来开发有效的聚醚合成方法。 Jamison组的最新研究表明，区域选择性环氧开采（6-ENDO）仅限于附加到反应伙伴（即羟基和环氧树脂）的四氢吡喃导向组的系统。其他模板组对这些级联事件的影响尚不清楚，因此排除了这种方法在结构多样性天然产物合成中的直接应用。该应用的目的是扩大在环保级联反应中耐受模板多样性的范围，并通过结合形成模板的形成并随后将环氧化物的级联反应纳入单个合成步骤，从而开发串联过程以加快这些目标的合成。第一个特定目的集中于具有不同模板环大小的模型系统的合成和随后的环氧开放式级联。这项研究提供了模板环的大小与环氧化物开放事件的区域选择性之间的相关性，目的是开发预测模型。第二个特定目的的重点是开发串联过程，该过程结合了模板形成和随后的环氧化物开放量为单个合成步骤。这使得可以从容易获得的起始材料中快速进入海洋梯子多醚天然产品的核心。最后，第三个特定目的提供了对该方法范围的见解，因为它应用于甘比尔酸A的F-J环片段A。这些特定的目的旨在提高海洋梯子多聚体合成的效率，这是发现新药物的必要步骤。 公共卫生相关性：海洋梯子多醚天然产品与有害的红潮发生事件有关，并负责大规模的鱼类死亡以及随后在全球的人类中毒。尽管这类化合物的负面影响显而易见，但它们的药用特性尚不清楚。无法分离大量材料会抑制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提供医学研究材料的必要步骤。