New Methods for Nitrogen Heterocycle Synthesis

氮杂环在很大比例的生物活性分子中被发现。化学方法 使简明、选择性和高效的氮杂环从头合成成为可能 科学界获得已知的生物活性小分子，并提供 创造具有潜在生物活性的未知化合物的机会，这些化合物可能被发现 通过药物化学研究。两种新型氮肥的发现、开发和应用 杂环形成反应，分子内的碳胺化和烯烃的二胺化，在 这项提议。这些反应是由我们实验室发现的新的铜(II)化学实现的。铜是 由于其低成本和相对较低的价格，在反应过程中使用的过渡金属特别有吸引力 毒性。不对称合成和过渡金属配体设计等现代有机化学方法 以及微波反应促进等技术被用于促进这些研究。完整的 对这些方法的机械理解和综合应用可能会对其他方法的发展起到启发作用 用于生物学研究的小分子文库的新方法和设计。光学富集型 可通过这些转化获得的氮杂环，六氢-1H-苯并[f]吲哚，异喹啉， 吡咯烷、邻二胺和潜在的阿朴吗啡和氮杂环丙烷展示了广泛的 生物活性，如1)多巴胺拮抗剂，在情绪调节条件下(如焦虑)很重要 和抑郁，2)抗癌活性和3)在艾滋病治疗中重要的蛋白酶抑制活性， 阿尔茨海默病、高血压和疟疾。尤其是分子内的二缩化反应 提供了一种简明而独特的途径，可以获得可能用作多肽异构体的化合物。 光学活性小分子简洁合成新方法的研究与开发 介绍了氮杂环化合物。氮杂环在很大比例的生物中被发现 活性分子。通过这些转化可获得光学富集型氮杂环 显示出广泛的生物活性，例如1)多巴胺拮抗剂，对情绪很重要 调节条件，如焦虑和抑郁，2)抗癌活性和3)蛋白酶抑制 活动，在治疗艾滋病、阿尔茨海默病、高血压和疟疾方面很重要。

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 isosters. 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.