New Methods for Nitrogen Heterocycle Synthesis

氮杂环合成新方法

• 批准号: 7135231
• 负责人: Sherry R Chemler
• 金额: $ 26.92万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135231
• 关键词: alkenes; amination; chemical registry /resource; chemical synthesis; combinatorial chemistry; copper; diamines; drug discovery /isolation; heavy metals; indoles; isoquinolines; ligands; method development; microwave radiation; nitrogenous heterocyclic compound; oligopeptides; pyrrolidines; small molecule

DESCRIPTION (provided by applicant): Nitrogen heterocycles are found in a large proportion of biologically active molecules. Chemical methods that enable the concise, selective and efficient de novo synthesis of nitrogen heterocycles empower the scientific community to gain access to known biologically active small molecules as well as provide an opportunity to create as yet unknown compounds with potential biological activity, which may be discovered through medicinal chemistry studies. The discovery, development and application of two new nitrogen heterocycle forming reactions, the intramolecular carboamination and diamination of olefins, are presented in this proposal. These reactions are enabled by novel copper(ll) chemistry discovered in our labs. Copper is an especially attractive transition metal to use in reaction processes due to its low cost and relatively low toxicity. Modern organic chemistry methods such as asymmetric synthesis and transition metal ligand design as well as technologies such as microwave reaction promotion are used to facilitate these studies. The full mechanistic understanding and synthetic application of these methods may inspire the development of other new methods and the design of small molecule libraries for biological studies. The optically enriched nitrogen heterocycles accessible through these transformations, hexahydro-1 H-benz[f]indoles, isoquinolines, pyrrolidines, vicinal diamines and potentially aporphines and azepines demonstrate a broad range of biological activity such as 1) dopamine antagonists, important in mood regulation conditions such as anxiety and depression, 2) anticancer activity and 3) protease inhibitory activity, important in the treatment of AIDS, Alzheimer's disease, hypertension and Malaria. In particular, the intramolecular diamination reaction provides a concise and unique access to compounds that may be useful as peptide isosteres. The study and development of novel methods for the concise synthesis of optically active small molecule nitrogen heterocycles is presented. Nitrogen heterocycles are found in a large proportion of biologically active molecules. The optically enriched nitrogen heterocycles accessible through these transformations demonstrate a broad range of biological activity such as 1) dopamine antagonists, important in mood regulation conditions such as anxiety and depression, 2) anticancer activity and 3) protease inhibitory activity, important in the treatment of AIDS, Alzheimer's disease, hypertension and Malaria.

描述（由申请人提供）：在很大一部分生物学活性分子中发现氮杂环。能够使氮杂环从头合成的简洁，选择性和有效的从头合成能够使科学界有能力获取已知的生物活性小分子，并提供了创造具有潜在生物学活性的未知化合物的机会，可以通过药物化学研究发现。该提案介绍了两种新的氮杂环形成反应的发现，开发和应用，分子内碳水化合物和裂解烯烃的发现。这些反应是通过在我们的实验室中发现的新型铜（LL）化学反应来实现的。铜是一种特别有吸引力的过渡金属，由于其低成本和毒性相对较低，因此在反应过程中使用。现代有机化学方法，例如不对称合成和过渡金属配体设计以及微波反应促进等技术，用于促进这些研究。这些方法的全部机械理解和合成应用可能会激发其他新方法的发展以及用于生物学研究的小分子库的设计。通过这些转变可进入光学丰富的氮杂环，六氢-1 H-苯子[F]吲哚，等喹啉，吡咯烷，吡咯烷，替代二氨基，替代性二氨基，潜在的azeporphines和azepornes和azepine and Azepines and Azepines concements and Moite antimenty and诸如MOISE拮抗剂，例如MOISE拮抗剂，例如MOISE ORGATISS，例如MOISE抑制条件。抑制活性，对治疗艾滋病，阿尔茨海默氏病，高血压和疟疾很重要。特别是，分子内胰岛素反应可简洁明了，独特的访问可能是肽ISOSTESTER的化合物。提出了新的方法的研究和开发，以简化光学活性小分子氮杂环的合成。氮杂环在很大一部分的生物活性分子中发现。通过这些转化可以使用光学丰富的氮杂环，表现出广泛的生物学活性，例如1）多巴胺拮抗剂，在诸如焦虑和抑郁之类的情绪调节状况中很重要，2）抗癌活性和3）蛋白酶抑制活性，对艾滋病的治疗，阿尔茨海默氏病的治疗，阿尔茨海默氏病，高血压，高血压和疟疾。