Nitrogen Containing Natural Products

含氮天然产物

• 批准号: 6623694
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623694
• 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：(申请人提供)本研究项目的目标是 开发合成生物碱天然产物的新策略和新策略 以及其他具有生物活性的含氮化合物。在这个范围内 背景下，有一些具体的目标属于两个主要的 方法论研究的类别和总的综合。论方法论 在前线，具体目标是：(1)探索和开发新的级联 涉及亚胺和亚胺离子的串联环化反应 用于快速、收敛和立体选择性地合成熔融氮 杂环化合物；(2)开发一种羧酸同系物的合成方法 酸转化为α，β-不饱和酮；以及(3)开发一种有效的， 顺式-2，5-吡咯烷的立体选择性合成 不饱和取代基。在全合成的舞台上，具体的目标 是：(1)将生物遗传转化应用于合成 吲哚类生物碱--蜈蚣碱和麻醉剂苦参碱；(2) 应用闭环复分解作为简明合成的关键步骤 有效的烟碱型乙酰胆碱受体激动剂Anatoxin-a和Pinnamine以及 抗癌生物碱马钱子碱；(3)应用一种新的分子内 作为一种关键结构的乙烯曼尼希反应的变体 强效免疫抑制剂FR9O1483的合成(4)级联应用 亚胺/亚胺离子环合反应简明合成该配合物 螺环生物碱卤代氯，一种选择性的诱导 血管细胞黏附分子-1和品甲酸，一种血管细胞黏附分子的特异性抑制物 胞浆磷脂酶A2和(5)将选定的中间体提交给礼来公司， 默克研究实验室、辉瑞公司和雅培实验室 生物评价。