Nitrogen Containing Natural Products

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 螺环生物碱卤氯，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

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.