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。在这些含氮的化合物中 超过三分之一的化合物、芳香族和杂芳胺(即苯胺)作为核心结构出现。 候选药物，而氮杂环丙烷，三元和同样高度紧张的氮类似物 环氧化物是合成结构复杂分子的重要合成中间体，因为它们具有多种用途。 在无数的区域和立体选择性转换中。毫不奇怪，有机化学家投入了相当多的资金 为合成胺设计更好的策略所做的努力，这些胺是 生物活性化合物的制备，尤指在药物化学中。这些策略还可以 用于复杂分子的后期官能化，使之能够探索新的化学空间 用于生物学研究。因此，新的和强大的综合策略和方法为快速和直接 将氮引入到容易获得和廉价的前体中，例如烷烃、烯烃、芳烃、 杂芳烃和羰基化合物预计将对有机 开设了合成、药物化学、生物化学、化学生物学等专业。特别是引言 在温和的条件下，一步完成无保护的氮和其他杂原子的合成 比目前使用的多步骤路线更高效、更环保，最终将导致更快的 开发新药。 在拟议的项目过程中，新的金属催化和有机催化胺化工艺将 将利用催化和化学计量比产生的亲电 胺化试剂。因此，手性和非手性伯胺和仲胺的直接合成法 芳香族和杂芳族化合物，酮和羧酸的α-氨基羰基化合物 来自酮胺、酮肟和酮敏酯的全取代胺和NH-的酸衍生物，以及 将从分离的/未活化的烯烃中获得N-烷基氮杂环丙烷。建议的催化胺化工艺 将被彻底调查，以揭示和了解它们的机械基础。重点将是 致力于反应的发展，这种反应可以利用丰富而廉价的原料并转化为 这些都是在操作简单和温和的反应条件下合成结构复杂/附加值的产品。

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. Among these nitrogen-containing compounds, aromatic and heteroaromatic amines (i.e., anilines) appear as core structures in more than one third of drug candidates while aziridines, the three-membered and equally highly-strained nitrogen analogues of epoxides, are important synthetic intermediates en route to structurally complex molecules due to their versatility in myriad regio- and stereoselective transformations. 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 can also be used for late-stage functionalization of complex molecules that enables 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 as well as carbonyl compounds 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 nitrogen and other heteroatoms in a single step and 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 novel metal-catalyzed and organocatalytic amination processes will be developed that will take advantage of both catalytically and stoichiometrically generated electrophilic aminating agents. Thus, the direct synthesis of chiral as well as achiral primary and secondary anilines from aromatic and heteroaromatic compounds, of alpha-aminated carbonyl compounds from ketones and carboxylic acid derivatives, of fully-substituted amines from ketimines, ketoximes and ketiminoesters and of NH- as well as N-alkylaziridines from isolated/unactivated olefins will be achieved. The proposed catalytic 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.