A Cascade Reaction to Synthesize Ladder Polyethers with 1,3 Diaxial Methyl Groups

级联反应合成1,3双轴甲基梯形聚醚

• 批准号: 8645131
• 负责人: Matthew Herman Katcher
• 金额: $ 4.99万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645131
• 关键词: Acids; Alzheimer' s Disease; Anabolism; Antifungal Agents; Biological; Biological Factors; Biomimetics; Chemicals; Cyclic Ethers; Development; Disease; Epoxy Compounds; Fishes; Human; Knowledge; Marines; Mediating; Methods; Molecular; Neurodegenerative Disorders; New Zealand; Pattern; Poison; Poisoning; Prevalence; Process; Property; Reaction; Reporting; Route; Series; Source; Staging; Structure; Structure-Activity Relationship; System; Time; Toxic effect; Toxin; analog; anticancer activity; base; brevetoxin B; chemical reaction; gambieric acid A; gambierol; harmful algal blooms; killings; maitotoxin; methyl group; public health relevance; receptor; red tide; success

DESCRIPTION (provided by applicant): Although marine ladder polyethers are extremely toxic compounds, they are also known to have antifungal and anticancer properties. The biosynthesis of these compounds is proposed to occur via an epoxide-opening cascade reaction, and several biomimetic reactions have been developed to synthesize portions of these molecules. In general, a cascade reaction is a consecutive series of chemical reactions that proceed via reactive intermediates and create multiple new bonds in one sequential process. These reactions allow for the rapid creation of molecular complexity and provide a more efficient synthetic route than building a molecule in an iterative fashion. In particular, the cascade reaction described in this proposal will enable the synthesis of fused polyether ring systems with 1,3-diaxial methyl groups, a motif that is present in many ladder polyethers. Despite the prevalence of this motif in these compounds, no cascade reactions have been reported that create rings containing this substitution pattern. This proposal also describes the application of this cascade reaction to the synthesis of a portion of brevisulcenal F and several other marine ladder polyethers. Brevisulcenal F is a marine ladder polyether natural product that was identified as a component of a harmful algal bloom (HAB) off the coast of New Zealand in 1998. It is one of the largest and most toxic marine polyethers that has been isolated. Therefore, its synthesis would provide material to study its unique bioactivity and determine possible applications for treating disease. Importantly, gambierol, a related ladder polyether, has been used as a chemical probe to study receptors implicated in the molecular basis of Alzheimer's disease. In this proposal, a strategy for the synthesis of the B-D and F-I rings of brevisulcenal F is outlined in which several rings are created iteratively, and the cascade process is then applied to the synthesis of the remaining rings. A similar strategy is presented for portions of maitotoxin, gambierol, gambieric acid A, and brevetoxin B. It is expected that the success of this proposal will set the stage for the total synthesis of these molecules and provide material to study their mechanisms of action.

描述（由申请人提供）：虽然海洋梯形聚醚是剧毒化合物，但已知它们也具有抗真菌和抗癌特性。这些化合物的生物合成被认为是通过环氧化物开环级联反应发生的，并且已经开发了几种仿生反应来合成这些分子的一部分。一般来说，级联反应是一系列连续的化学反应，这些反应通过活性中间体进行，并在一个顺序过程中产生多个新键。这些反应允许快速产生分子复杂性，并提供比以迭代方式构建分子更有效的合成路线。特别地，在该提议中描述的级联反应将使得能够合成具有1，3-二轴甲基的稠合聚醚环系统，这是存在于许多梯形聚醚中的基序。尽管在这些化合物中普遍存在这种基序，但没有报道产生含有这种取代模式的环的级联反应。该建议还描述了应用该级联反应合成一部分短磺烯醛F和其他几种海洋梯形聚醚。Brevisulcenal F是一种海洋阶梯聚醚天然产物，1998年被确定为新西兰沿海有害藻华（HAB）的一种成分。它是已分离出的最大和毒性最大的海洋聚醚之一。因此，它的合成将为研究其独特的生物活性和确定其在治疗疾病方面的可能应用提供材料。重要的是，甘比尔醇（一种相关的梯状聚醚）已被用作化学探针来研究与阿尔茨海默病分子基础有关的受体。本文提出了短磺烯醛F的B-D环和F-I环的合成策略， 概述了几个环迭代创建，级联过程，然后应用于其余环的合成。对美托毒素、甘比洛尔、甘比酸A和短尾蛇毒素B的部分提出了类似的策略。预计该提案的成功将为这些分子的全合成奠定基础，并为研究其作用机制提供材料。