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.

Altohyrtins包括一类新发现的有效细胞毒性类 海洋来源的大环内酯类。独立隔离和结构上 相同的，海绵蛋白表现出非凡的活动 多种肿瘤类型。这些天然的收敛合成组合 产品是我们的长期目标。 这些化合物在结构上是独一无二的 单位，基于1,7-Dioxaspiro [5.5] Undecane Ring System，哪个形成 他们的分子框架的骨干。这两个螺旋体 具有附着在C（2）碳的甲基苯二苯甲烷基。这 这些单个螺旋环系统的合成设计将是 我们的短期目标的重点。 这项研究的第一个目标是开发通往 具有C（2）乙酸附属物的基本螺旋体结构，用于 分子内的2-氧甲酮环打开策略形成了 基础。 由羰基辅助环裂解产生的氧化离子 2-氧甲酮环将被第二次羰基在内部捕获 组形成螺旋氧化离子。 反应将与 在该离子中添加基于硅烷的试剂。 以前的 研究人员的工作表明，dione前体的螺旋体前体 可以通过氧化性裂解环戊烯环获得形成， 并原地做出反应。 第二个目标将是对关键的透彻理解 立体控制在此反应中的各个方面。 取代基的影响 关于钥匙螺旋 - 氧化型离子的反应性构象 根据反应产品的立体化学的判断，中级将 可以确定。