Nitrogen Containing Natural Products

含氮天然产物

• 批准号: 6856468
• 负责人: STEPHEN MARTIN
• 金额: $ 24.11万
• 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 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856468
• 关键词: Diels Alder reaction; alkaloids; biological products; chemical addition; cyclization; diene; drug design /synthesis /production; furans; heterocyclic compounds; imines; immunosuppressive; indoles; ketones; nitrogen compounds; nitrogenous heterocyclic compound; phospholipase inhibitor; stereochemistry; vascular cell adhesion molecule

DESCRIPTION: (provided by applicant) The objective of this research program is to develop new tactics and strategies to synthesize alkaloid natural products and other biologically-active nitrogen containing compounds. Within this context, there are a number of specific objectives that fall into the two main categories of methodological studies and total synthesis. On the methodological front, the specific goals are to: (1) Explore and develop a novel cascade of reactions involving tandem cyclizations of imines and iminium ions that allows for the rapid, convergent and stereoselective synthesis of fused nitrogen heterocycles; (2) Develop a synthetic method for the homologation of carboxylic acids into alpha, beta-unsaturated ketones; and (3) Develop an efficient, stereoselective procedure for the synthesis of cis-2,5-pyrrolidines having unsaturated substituents. In the arena of total synthesis, the specific goals are to: (1) Apply biogenetically-inspired transformations to the syntheses of the indole alkaloids condylocarpine and akuammidine, an anesthetic agent; (2) Apply ring-closing metathesis as a key step in the concise syntheses of the potent nicotinic acetylcholine receptor agonists anatoxin-a and pinnamine and the anticancer alkaloid peduncularine; (3) Apply a novel, intramolecular variant of the vinylogous Mannich reaction as a key construction in a short synthesis of the potent immunosuppressive agent FR9O1483; (4) Apply cascade imine/iminium ion cyclizations to the concise syntheses of the complex spirocyclic alkaloids halichlorine, a selective inhibitor of the induced vascular cell adhesion molecule-1, and pinnaic acid, a specific inhibitor of cytosolic phospholipase A2 and (5) Submit selected intermediates to Eli Lilly, Merck Research Laboratories, Pfizer, Inc., and Abbott Laboratories for biological evaluation.

描述：（由申请人提供）本研究项目的目的是 开发生物碱类天然产物合成的新策略 和其它生物活性含氮化合物。在这 在这方面，有一些具体的目标，分为两个主要的 方法研究和全面综合的类别。就方法 具体目标是：（1）探索和开发一种新颖的级联 涉及亚胺和亚胺鎓离子的串联环化的反应， 用于稠合氮的快速、收敛和立体选择性合成， （2）发展了羧酸同系化的合成方法 酸转化为α，β-不饱和酮;和（3）开发一种有效的， 用于合成顺式-2，5-吡咯烷的立体选择性方法 不饱和取代基。在全面综合的竞技场中， （1）将生物遗传学启发的转化应用于合成 吲哚类生物碱髁果芸香碱和阿枯脒，麻醉剂;（2） 应用闭环复分解作为简明合成的关键步骤， 有效的烟碱乙酰胆碱受体激动剂类毒素-A和pinnamine， 抗癌生物碱长柄草碱;（3）应用一种新的分子内 作为一个关键的结构在一个短的乙烯基曼尼希反应的变体 高效免疫抑制剂FR 9 O 1483的合成;（4）应用级联反应 亚胺/亚胺鎓离子环化反应合成了配合物 螺环生物碱盐氯，诱导的选择性抑制剂 血管细胞粘附分子-1和羽叶酸，一种特异性的 胞质磷脂酶A2和（5）将选定的中间体提交给Eli Lilly， 默克研究实验室，辉瑞公司，和雅培实验室， 生物学评价