NITROGEN CONTAINING NATURAL PRODUCTS

含氮天然产品

• 批准号: 6018490
• 负责人: STEPHEN MARTIN
• 金额: $ 22.66万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-01-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6018490
• 关键词: Diels Alder reaction; alkaloids; biological products; chemical addition; cyclization; diene; drug design /synthesis /production; furans; heterocyclic compounds; nitrogen compounds; stereochemistry

DESCRIPTION: The overall goal of this program of research is to develop new tactics and strategies to synthesize alkaloid natural products and other biologically-active nitrogen containing compounds. Within this context a number of specific objectives have been established, and these may be divided into methodological studies and the total syntheses of biologically active alkaloids and related compounds. On the methodological front, the principal goals are to: (1) examine cycloaddition reactions, especially Diels-Alder reactions involving heterodienes or vinylogous imides, to construct heterocyclic structural subunits found in alkaloids; (2) investigate ring-closing metathesis as a method for forming unsaturated nitrogen heterocycles; (3) expand the scope and synthetic utility of vinylogous Mannich reactions that involve inter- and intramolecular reactions of iminium salts with nucleophilic partners, especially oxygenated furans; and (4) explore 1,2-metallate rearrangements as a novel entry to unsaturated nitrogen compounds. In the arena of total synthesis, the PI is to: (1) apply intramolecular hetero Diels-Alder reactions in tandem with biomimetic chemistry to synthesize complex indole alkaloids of the Strychnos, Ajmaline, and Sarpagine families including the glycine receptor antagonist strychnine, condylocarpine, polyneuridine, quebrachidine and the anesthetic agent akuammidine; (2) complete a convergent asymmetric synthesis of the anticancer agent manzamine A using a strategy that features an intramolecular (4+2) cycloaddition of a vinylogous imide and ring-closing metathesis reactions; and (3) develop a general approach to alkaloids containing butyrolactone and piperidine subunits exploiting novel vinylogous Mannich additions as key constructions and demonstrate the broader efficacy of this strategy by applying it to concise syntheses of Stemona alkaloids including the insecticidal and antitussive agent croomine and the related alkaloid stemoamide, the neuroactive Ergot alkaloid methyl lysergate, the sodium channel activator pumiliotoxin 251 D, and the angiotensin converting enzyme inhibitor A58365A. It is intended to prepare reasonable quantities of the targeted compounds and selected intermediates for submission to C. P. Starks, Inc., Eli Lilly, Merck and Abbott Laboratories for biological evaluation.

描述：该研究计划的总体目标是开发新的 生物碱类天然产物及其它生物活性物质的合成策略 生物活性含氮化合物。 在这方面， 已经确定了一些具体目标，这些目标可能是 分为方法学研究和生物学的总合成 活性生物碱和相关化合物。 在方法论方面， 主要目标是：（1）研究环加成反应，特别是 涉及杂二烯或乙烯基亚胺的狄尔斯-阿尔德反应， 构建生物碱中的杂环结构亚基;（2） 研究闭环复分解作为形成不饱和 氮杂环化合物;（3）拓展了氮杂环化合物的应用范围和合成用途 涉及分子间和分子内的乙烯基曼尼希反应 亚胺鎓盐与亲核配体的反应，特别是氧化的 呋喃;和（4）探索1，2-金属重排作为一种新的进入， 不饱和氮化合物 在全合成的竞技场中，PI是 （1）将分子内杂原子Diels-Alder反应与 仿生化学合成复杂的吲哚生物碱 马钱子属、Ajelae和Sarpagine家族，包括甘氨酸受体 拮抗剂士的宁、髁果芸香碱、多聚神经苷、槲皮苷和 麻醉剂阿库阿米定;（2）完成收敛不对称合成 的抗癌剂manzamine A使用的策略，其特点是， 乙烯基双酰亚胺分子内（4+2）环加成和闭环 复分解反应;（3）开发生物碱的一般方法 含有丁内酯和哌啶亚基的新乙烯基化合物的开发 Mannich补充作为关键建设，并证明了更广泛的功效 通过将其应用于百部生物碱的简明合成， 包括杀虫和止咳剂克罗明和相关的 生物碱stemoamide，神经活性麦角生物碱甲基麦角酸酯， 钠通道激活剂pumiliotoxin 251 D和血管紧张素转换酶 酶抑制剂A58365 A。 其目的是准备合理数量的 目标化合物和选定的中间体提交给C. P. 斯塔克斯公司，Eli Lilly、Merck和Abbott实验室， 评价