New Methods for Nitrogen Heterocycle Synthesis

氮杂环存在于大部分生物活性分子中。化学方法 能够使氮杂环的简洁、选择性和有效的从头合成成为可能， 科学界获得已知的生物活性小分子，以及提供一个 创造具有潜在生物活性的未知化合物的机会，可能会被发现 通过药物化学研究。两种新氮肥的发现、开发和应用 杂环形成反应，烯烃的分子内碳胺化和二胺化，在 这个提议。这些反应是由我们实验室发现的新型铜（II）化学物质实现的。铜是 特别有吸引力的过渡金属，由于其低成本和相对低的 毒性现代有机化学方法如不对称合成和过渡金属配体设计 以及诸如微波反应促进的技术被用于促进这些研究。充分 对这些方法的机理性理解和综合应用，可能会启发其他方法的发展。 新的方法和小分子库的设计用于生物学研究。光学富集 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、邻位二胺和潜在的阿朴啡和氮杂卓证明了广泛的 生物活性，如1）多巴胺拮抗剂，在情绪调节条件如焦虑中很重要 和抑郁症，2）抗癌活性和3）蛋白酶抑制活性，在治疗AIDS中很重要， 老年痴呆症、高血压和疟疾。特别地，分子内二胺化反应 提供了对可用作肽电子等排体的化合物的简明和独特的途径。 光学活性小分子简洁合成新方法的研究与发展 氮杂环化合物。氮杂环化合物存在于大部分生物活性物质中， 活性分子通过这些转化可获得的光学富集的氮杂环 显示出广泛的生物活性，例如1）多巴胺拮抗剂，在情绪中很重要 调节条件如焦虑和抑郁，2）抗癌活性和3）蛋白酶抑制 活性，在治疗艾滋病、阿尔茨海默氏病、高血压和疟疾中很重要。

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.