Nitrogen Containing Natural Products

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。

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.