SYNTHESIS AND STRUCTURE OF THE MARINE TOXIN AZASPIRACID

海洋毒素氮杂螺酸的合成与结构

• 批准号: 6412424
• 负责人: Craig J. Forsyth
• 金额: $ 2.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6412424
• 关键词: Bivalvia; environmental contamination; environmental toxicology; marine toxins; protein biosynthesis; protein structure

DESCRIPTION: (Principal Investigator's Abstract) Azaspiracid is a potently toxic natural product that represents a human health hazard due to its seasonal contamination of mussels (Mytilus edulis) that have been cultivated for human consumption. This unique toxin was isolated recently from Irish mussels (2 mg/20 kg mussel tissue) and is responsible for the acute poisoning of several humans. The structure of azaspiracid has been only partially assigned on the basis of spectroscopic studies, but the actual structure may be one of four possible isomers. Azaspiracid is an 842 MW. omega-amino acid with a 40 carbon backbone that is punctuated by an unprecedented array of two fused polycyclic domains connected via a 2,6-disubstituted pyranyl hemiketal and terminating in a spiroaminal. The lethal dose in mice was determined to be 0.2 mg/kg (i.p. injection). Although the mechanism of action remains to be explored, azaspiracid does not inhibit the protein serine/threonine phosphatase 2A that is affected by other diarrhetic shellfish toxins. The complex yet undefined structure of azaspiracid, coupled with its potent vertebrate toxicity, presents unique opportunities for synthetic, structural, and biological study. The primary goals of this proposal are to develop and apply novel synthetic strategies for the rapid and convergent assembly of azaspiracid's component polycyclic domains, and to utilize these synthetic products to assign the complete structure of the natural product and provide an alternative source via total synthesis for further biological evaluation and environmental monitoring. Azaspiracid has been retrosynthetically divided into two major domains representing carbons 1-20 and 21-40 of the natural product. The C1-C20 portion of azaspiracid contains 8 stereogenic centers and is comprised of a tetrahydrofuran-fused 6-5-6 trioxaspirotetracyclic ring system (rings A-B-C-D) that is linked via a single acyclic carbinol carbon (C20) to a hemiketal, pyranyl E ring. The spiro-fused A-B-C ring system is representative of similar structural motifs in several other biologically active natural products. It will be assembled in a novel convergent approach that involves the nucleophilic coupling of an A-B ring precursor with a C-D ring lactone, followed by an acid triggered transketalization to close the B ring and complete the trioxaspiroketal system. The C21-C40 domain of azaspiracid consists of the isolated hemiketal E ring and the unique spiroaminal-fused 2,9-dioxabicyclo(3.3.1)nonane ring system (rings F-G-H-I) and contains 12 stereogenic centers. The F-I system presents an opportunity to develop a novel, biomimetic polycyclization cascade sequence that will provide unique synthetic access to this polycyclic array that will be instrumental for assigning the stereochemistry and developing a total synthesis of the natural product.

描述：（主要研究者的摘要）Azaspiracid是有效的 由于其季节性，代表人类健康危害的有毒天然产品 已为人类种植的贻贝（Mytilus Edulis）的污染 消耗。这种独特的毒素最近是从爱尔兰贻贝中分离出来的（2个 mg/20 kg贻贝组织），并负责几种急性中毒 人类。 Azaspiracid的结构仅部分分配了 光谱研究的基础，但实际结构可能是四个 可能的异构体。 Azaspiracid是842兆瓦。带有40碳的欧米茄 - 氨基酸 由两个融合多环子的空前阵列打断的骨干 通过2,6二取代的吡喃基结和终止的结构域 螺旋藻。确定小鼠的致死剂量为0.2 mg/kg（i.p. 注射）。尽管行动机理仍有待探索，但 氮杂酸不会抑制蛋白质丝氨酸/苏氨酸磷酸酶2a 受其他腹泻性贝类毒素的影响。综合大楼却不确定 偶氮尿素的结构，再加上其有效的脊椎动物毒性，礼物 合成，结构和生物学研究的独特机会。这 该建议的主要目标是开发和应用新颖的合成 快速和收敛的偶氮酸酯组成部分的策略 多环状域，并利用这些合成产品分配 天然产品的完整结构，并通过 用于进一步的生物学评估和环境监测的总合成。 azaspiracid已被缩回分为两个主要领域 代表天然产品的1-20和21-40碳。 C1-C20部分 偶氮二硫酸含有8个立体中心，由A组成 四氢呋喃融合的6-5-6三人螺旋环磁环系统（环A-b-c-d） 通过单个无环碳纤维碳（C20）连接到半球 吡喃基环。 Spiro融合的A-B-C环系统代表了类似的 其他几种生物活性天然产物中的结构基序。它 将以一种涉及亲核的新型收敛方法组装 A-B环前体与C-D环内酯的耦合，然后是酸 触发transketlization关闭B环并完成 三人螺旋体系统。 Azaspiracid的C21-C40域由 孤立的半蛋白环和独特的螺旋式融合 2,9-Dioxabicyclo（3.3.1）非反环系统（环F-G-H-I），包含12 立体中心。 F-I系统提供了开发小说的机会 仿生多环化级联序列将提供独特的合成 访问此多环切阵列将有助于分配 立体化学并开发自然产物的完全合成。