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

项目摘要 胺及其衍生物是普遍存在的物质，因为它们存在于绝大多数 药物分子、农用化学品、功能材料以及许多由生物产生的化合物 生物体(即天然产品)。值得注意的是，平均而言，在200个最好的 销售小分子药物，在这些药物中，80%至少含有一个N-杂环片段。它也是 估计45%的候选药物含有手性胺部分。毫不奇怪，有机化学家投资 为作为关键化学物质的胺的合成设计更好的策略的大量努力 用于制备生物活性化合物的积木，尤指在药物化学中。这些 简单原料化学品的早期功能化和后期功能化的策略都可以使用。 复杂分子的阶段性功能化。这些方法结合在一起，使探索新的 用于生物学研究的化学空间。因此，新的和强大的综合战略和方法，为 快速和直接地将氮引入到诸如烷烃等容易获得和廉价的前体中， 烯烃、芳烃、杂芳烃预计将对有机合成产生深远影响， 开设药物化学、生物化学、化学生物学等专业。特别是，引入了 在温和的条件下，无保护和/或官能化的氮原子将导致更多的工艺 比目前使用的多步骤路线更高效和更环保，最终将导致更快的发展 新药。 在拟议的项目过程中，我们将重点开发新的直接(即非催化) 烯烃去功能化方法。特别是，我们正在评估N-酰基-N-卤代-O-的天然反应性。 磺酰基和N-酰基-N-卤代-O-烷基/硅基羟胺与原料烯烃反应得到结构多样化 和多官能团的羟胺衍生物(即烯烃的卤代氨羟化)。这个 生成的化合物可用作结构复杂且用途广泛的亲电胺化试剂 与多种底物形成碳-氮键。例如，非催化以及金属催化的内部和 将探索分子间过程，利用化学计量和催化两方面的优势。 生成的亲电胺化试剂(即，分子内的复杂构筑转化 和/或分子间脂肪族和芳香族C-H胺化反应、烯烃氮化以及1，3-偶极 环加成)。因此，由结构简单的手性仲胺和叔胺直接合成手性仲胺和叔胺 前身将会实现。拟议的区域和立体选择性胺化工艺将是彻底的 进行调查，以揭示和了解它们的机械基础。重点将放在 开发可利用丰富而廉价的起始原料并将其转化为 在操作简单和温和的反应条件下，结构复杂/附加值高的产品。

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.