New Methods for the Synthesis of Alkaloids

生物碱合成新方法

基本信息

批准号：
7413400
负责人：
Jeffrey Aube
金额：
$ 25.86万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-05-01 至 2010-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Many drugs and other biologically active molecules contain basic nitrogen groups that, in their physiological protonated state - and often constrained into intricate ring systems - contribute to the binding of the agent to its protein target. The major theme of this proposal is to develop new synthetic methods that utilize alkyl azides for the synthesis of cyclic nitrogen containing compounds, and to use those methods for the synthesis of biologically relevant compounds. Work in previous grant periods has resulted in the discovery and examination of three broadly useful reactions (the inter- and intramolecular Schmidt reactions of alkyl azides, and the insertion reaction of hydroxyalkyl azides) and has also demonstrated the utility of the reactions in complex molecule synthesis. We have obtained preliminary data that demonstrates how the Schmidt reaction can be linked with other powerful reactions, such as the Diels-Alder cycloaddition, the aldol condensation, and conjugate addition reactions, to provide one-step syntheses of complex lactams from very simple starting materials. We propose to develop these processes, concentrating on matters of scope, efficiency, and stereoselectivity. These new reactions will also be used to synthesize a variety of alkaloids in biological classes that range from NMDA antagonists to cytotoxic agents. The specific targets proposed include the antitussive agent neostenine, several members of the cylindricine family of natural products, the frog-derived indolizidine 223A, and pinnaic acid.

描述（由申请人提供）：许多药物和其他具有生物活性的分子包含基本的氮基团，这些氮基在其生理质子化状态下 - 通常被限制为复杂的环系统 - 有助于该剂与其蛋白质靶标的结合。该提案的主要主题是开发新的合成方法，该方法利用烷基叠氮化物来合成含有化合物的环状氮，并使用这些方法来合成生物学相关化合物。以前的赠款期间的工作导致了三种广泛有用的反应（烷基分子间和分子内的施密特反应，烷基烷基的分子间施密特反应，以及羟基烷基叠氮化物的插入反应），并也证明了复杂分子合成中反应的效用。我们获得了初步数据，这些数据表明了如何将Schmidt反应与其他强大的反应（例如Diels-Alder Cycloadition，Aldol凝结和共轭添加反应）联系起来，以提供非常简单的起始材料的复杂Lactams的一步合成。我们建议开发这些过程，专注于范围，效率和立体选择性问题。这些新反应还将用于合成从NMDA拮抗剂到细胞毒性剂的生物学类别中的各种生物碱。提出的具体靶标包括抗毒剂新苯胺，天然产物的圆柱核心家族的几个成员，青蛙衍生的吲哚苷223a和pinnaic Acid。