New catalytic methods for the rapid synthesis of N-unprotected chiral aziridines and amines

快速合成N-未保护的手性氮丙啶和胺的新催化方法

• 批准号: 10782916
• 负责人: Laszlo Kurti
• 金额: $ 9.83万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10782916
• 关键词: Agrochemicals; Alkanes; Alkenes; Amination; Amines; Award; Aziridines; Biochemistry; Biological; Biology; Chemicals; Chemistry; Communities; Complex; Development; Environment; Friends; Funding; Hydroxylamine; Investments; Medicine; Metals; Methods; Natural Products; Nitrogen; Organic Synthesis; Organism; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preparation; Process; Production; Reaction; Reagent; Research; Research Personnel; Route; biological preparation; cost; cycloaddition; drug candidate; halogenation; novel; rapid technique; response; small molecule; tertiary amine

Project Summary Amines and their derivatives are ubiquitous substances since they are present in the overwhelming majority of drug molecules, agrochemicals, functional materials as well as many compounds that are produced by living organisms (i.e., natural products). Notably, there are, on average, 2.8 nitrogen atoms in each of the 200 best- selling small molecule drugs and, of these drugs, 80% contain at least one N-heterocyclic fragment. It is also estimated that 45% of drug candidates contain a chiral amine moiety. Not surprisingly, organic chemists invest a considerable amount of effort devising better strategies for synthesis of amines that serve as key chemical building blocks for the preparation of biologically active compounds, especially in medicinal chemistry. These strategies may be used for both the early-stage functionalization of simple feedstock chemicals and the late- stage functionalization of complex molecules. Together these approaches enable the exploration of new chemical space for biological studies. Consequently, new and powerful synthetic strategies and methods for the rapid and direct introduction of nitrogen into readily available and inexpensive precursors such as alkanes, alkenes, arenes, heteroarenes are expected to have a far-reaching impact upon how organic synthesis, medicinal chemistry, biochemistry and chemical biology are practiced. In particular, the introduction of unprotected and/or functionalized nitrogen atoms under mild conditions will result in processes that are more efficient and “greener” than currently used multi-step routes and ultimately will lead to the faster development of new medicines. During the course of the proposed project we will focus on the development of novel direct (i.e., non-catalytic) olefin difunctionalization methods. In particular, we are evaluating the native reactivity of N-acyl-N-halo-O- sulfonyl as well as N-acyl-N-halo-O-alkyl/silyl hydroxylamines with feedstock olefins to obtain structurally diverse and multifunctional hydroxylamine derivatives in a single pot (i.e., halo-aminohydroxylation of alkenes). The resulting compounds can serve as structurally complex and versatile electrophilic aminating agents that readily form C-N bonds with a variety of substrates. For example, non-catalytic as well as metal-catalyzed intra- and intermolecular processes will be explored that take advantage of both stoichiometrically and catalytically generated electrophilic aminating agents (i.e., complexity-building transformations, such as in intramolecular and/or intermolecular aliphatic and aromatic C-H amination reactions, olefin aziridinations as well 1,3-dipolar cycloadditions). Thus, the direct synthesis of chiral secondary and tertiary amines from structurally simple precursors will be achieved. The proposed regio- and stereoselective amination processes will be thoroughly investigated to uncover and understand their mechanistic underpinnings. Emphasis will be given to the development of reactions that can utilize abundant and inexpensive starting materials and convert these to structurally complex/value added products under operationally simple and mild reaction conditions.

项目摘要 胺及其衍生物是无处不在的物质，因为它们存在于绝大多数 药物分子，农产品，功能材料以及许多通过生物产生的化合物 生物（即天然产物）。值得注意的是，平均有200个最佳的氮原子2.8 出售小分子药物，其中80％的药物至少包含一个N-杂环片段。也是 估计有45％的候选药物含有手性胺部分。毫不奇怪，有机化学家投资 为合成胺作为关键化学物质的胺的综合制定更好的策略的大量努力 制备生物活性化合物的构建基块，尤其是在医学化学中。这些 可以将策略用于简单原料化学物质的早期功能和晚期功能 复杂分子的阶段功能化。这些方法共同探索了新的 生物学研究的化学空间。因此，新的和强大的合成策略和方法 快速直接将氮引入到易于使用和廉价的前体中，例如烷烃， 预计烯烃，竞技场，杂种人对有机合成的影响有深远的影响， 实践药物化学，生物化学和化学生物学。特别是引入 在轻度条件下，未受保护和/或功能化的氮原子将导致更多的过程 高效且“绿色”比目前使用的多步路线，最终将导致更快的发展 新药物。 在拟议项目的过程中，我们将重点关注新型直接的发展（即非催化） 烯烯型烯烃五官能化方法。特别是，我们正在评估N-酰基-N-HALO-O-O-的天然反应性 磺酰基以及N-酰基-N-HALO-O-O-Akalyl/silyl羟胺与原料烯丙胺可获得结构上多样的 以及单个锅中的多功能羟胺衍生物（即烯烃的卤代羟基化）。 产生的化合物可以用作结构复杂且通用的亲电合作用剂 与各种底物形成C-N键。例如，非催化和金属催化的内部和金属催化 将探索分子间的过程，该过程在石化和催化 产生的亲电胺化剂（即复杂性建筑转换，例如分子内分子 和/或分子间脂肪族和芳香族C-H胺化反应，烯烃的氮杂化以及1,3-二极性 环加成）。这是从结构简单的手性次级和第三级胺的直接合成 将实现前体。拟议的区域和立体选择性胺化过程将彻底 调查以发现并了解其机械基础。重点将给予 开发可以利用丰富且廉价的起始材料并将其转换为的反应 在操作简单和轻度反应条件下结构复杂/增值产品。