NITROGEN CONTAINING NATURAL PRODUCTS

含氮天然产品

• 批准号: 2734398
• 负责人: STEPHEN MARTIN
• 金额: $ 22.16万
• 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/2734398
• 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：这项研究计划的总体目标是开发新的 生物碱类天然产物及其他合成的策略和策略 具有生物活性的含氮化合物。在此上下文中， 已经确定了一些具体目标，这些目标可能是 分为方法论研究和生物学的全合成 活性生物碱及相关化合物。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Diels-Alder反应 构建生物碱中的杂环结构亚基；(2) 探讨合环复分解作为一种形成不饱和化合物的方法 (3)扩大氮杂环化合物的合成范围和用途 涉及分子间和分子内的文氏曼尼希反应 亚胺盐与亲核配对，特别是含氧配对的反应 呋喃；和(4)探索1，2-金属重排作为一种新的入口 不饱和氮化合物。在全合成领域，PI是 要：(1)应用分子内杂化Diels-Alder反应 用仿生化学方法合成复杂的吲哚生物碱 马钱子、艾吉马林和包括甘氨酸受体在内的萨帕金家族 拮抗剂马钱子宁、湿地卡品、多神经氨酸、奎伯丁和 麻醉剂阿卡米丁；(2)完成收敛不对称合成 使用一种策略，该策略具有一种 乙烯基酰亚胺的分子内(4+2)环加成及闭环反应 化合反应；以及(3)开发生物碱的一般方法 含丁内酯和哌啶亚基开发新型葡萄糖类 作为关键结构的Mannich加法并展示了更广泛的效果 将这一策略应用于百部生物碱的简明合成 包括杀虫镇咳药克罗明和相关的 生物碱司他莫胺，神经活性麦角生物碱甲基蛇床子门， 钠通道激活剂粉刺毒素251D与血管紧张素转换 酶抑制剂A58365A。其目的是准备合理的数量 目标化合物和选定的中间体提交给C.P. 斯塔克斯公司、礼来公司、默克公司和雅培生物实验室 评估。