APPROACH TO THE SPIROKETAL RINGS OF THE ALTOHYRTINS

阿尔托蛋白螺酮环的研究

• 批准号: 2114702
• 负责人: KEITH Thomas MEAD
• 金额: $ 10.36万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2114702
• 关键词: antineoplastic antibiotics; biological products; carbopolycyclic compound; chemical addition; chemical structure function; drug design /synthesis /production; ketal; macrolide antibiotics; silanes; stereochemistry

The altohyrtins comprise a newly-discovered class of potent cytotoxic macrolides of marine origin. The independently-isolated, and structurally identical, spongistatins have shown exceptional activity towards a variety of tumor types. Convergent synthetic assemblage of these natural products is our long term goal. Structurally unique, these compounds possess two separate spiroketal units, based on the 1,7-dioxaspiro[5.5]undecane ring system, which form the backbone of their molecular framework. Both of these spiroketals possess a methylenecarbonyl group attached to the C(2)-carbon. The synthetic design of these individual spiroketal ring systems will be the focus of our short term goals. The first objective of this research will be to develop a route to the basic spiroketal structure possessing a C(2) acetic acid appendage, for which an intramolecular 2-oxetanone ring opening strategy forms the basis. An oxocarbenium ion, generated by carbonyl-assisted ring cleavage of a 2-oxetanone ring, is to be trapped internally by a second carbonyl group to form a spiro-oxocarbenium ion. Reaction would terminate with nucleophilic addition of a silane-based reagent to this ion. Previous work by the investigator suggests that the dione precursor for spiroketal formation could be obtained by oxidative cleavage of a cyclopentene ring, and reacted in situ. The second objective will be to gain a thorough understanding of key aspects of stereocontrol in this reaction. The influence of substituents on the reactive conformation of the key spiro-oxocarbenium ion intermediate, as judged by the stereochemistry of reaction products, will be determined.

阿托甲状腺素 (altohyrtins) 是一类新发现的强效细胞毒性物质 海洋来源的大环内酯类。独立隔离的、结构上的 相同的海绵抑素已表现出非凡的活性 多种肿瘤类型。这些天然物质的聚合合成组合 产品是我们的长期目标。 这些化合物结构独特，具有两个独立的螺缩酮 单元，基于 1,7-二氧杂螺[5.5]十一烷环系统，形成 它们的分子框架的主干。这两种螺缩酮 具有连接至C(2)-碳的亚甲基羰基。这 这些单独的螺酮环系统的合成设计将是 我们短期目标的重点。 这项研究的首要目标是开发一条通往 具有 C(2) 乙酸附属物的基本螺缩酮结构，用于 其中分子内2-氧杂环丁酮开环策略形成 基础。 氧碳鎓离子，由羰基辅助环裂解产生 2-氧杂环丁酮环的内部被第二个羰基捕获 基团形成螺氧碳鎓离子。 反应将终止于 硅烷基试剂与该离子发生亲核加成。 以前的 研究人员的工作表明，螺缩酮的二酮前体 可以通过环戊烯环的氧化裂解来形成， 并在原地做出了反应。 第二个目标是全面了解关键内容 该反应中的立体控制方面。 取代基的影响 关键螺氧碳鎓离子的反应构象 根据反应产物的立体化学判断，中间体将 被确定。