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 是一种有效的 有毒天然产物，因其季节性而对人类健康造成危害 为人类养殖的贻贝（贻贝）受到污染 消耗。最近从爱尔兰贻贝中分离出这种独特的毒素（2 mg/20 kg 贻贝组织），并导致多种急性中毒 人类。 azaspiracid 的结构仅被部分指定 光谱研究的基础，但实际结构可能是以下四种之一 可能的异构体。阿扎螺酸的功率为 842 MW。含 40 个碳的 omega-氨基酸 骨架被前所未有的两个稠合多环阵列打断 结构域通过 2,6-二取代吡喃基半缩酮连接并终止于 螺缩醛胺。小鼠的致死剂量确定为 0.2 mg/kg（腹腔注射）。 注射）。尽管其作用机制还有待探索， azaspiracid 不会抑制蛋白丝氨酸/苏氨酸磷酸酶 2A 受到其他腹泻性贝类毒素的影响。复杂但未定义 氮杂螺酸的结构及其对脊椎动物的潜在毒性 合成、结构和生物学研究的独特机会。这 该提案的主要目标是开发和应用新型合成材料 氮杂螺酸组分快速聚合组装的策略 多环结构域，并利用这些合成产物来分配 天然产物的完整结构并提供替代来源 全合成用于进一步的生物学评价和环境监测。 氮杂螺酸已逆合成分为两个主要领域 代表天然产物的碳1-20和21-40。 C1-C20部分 氮杂螺酸含有 8 个立体中心，由 四氢呋喃稠合 6-5-6 三氧螺四环系统（环 A-B-C-D） 通过单个无环甲醇碳 (C20) 连接到半缩酮， 吡喃基E环。螺稠合 A-B-C 环系是类似的代表 其他几种具有生物活性的天然产物中的结构基序。它 将以一种新颖的聚合方法组装，其中涉及亲核 A-B环前体与C-D环内酯的偶联，然后是酸 触发转缩酮化以关闭 B 环并完成 三氧螺缩酮系统。氮杂螺酸的 C21-C40 结构域由 分离的半缩酮 E 环和独特的螺缩醛融合 2,9-二氧杂双环(3.3.1)壬烷环系统（环F-G-H-I）并包含12 立体中心。 F-I 系统提供了开发新颖的、 仿生多环化级联序列将提供独特的合成 访问这个多循环数组将有助于分配 立体化学和开发天然产物的全合成。