Palladium-Catalyzed Oxidative Amination of Alkenes

钯催化烯烃的氧化胺化

• 批准号: 7876175
• 负责人: Shannon S Stahl
• 金额: $ 14.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876175
• 关键词: Address; Aerobic; Air; Alcohols; Alkaloids; Alkenes; Amides; Amination; Amino Sugars; Area; Attention; Carbamates; Catalysis; Chemicals; Chemistry; Claisen rearrangement; Classification; Complex; Coupling; Cyclization; Development; Exhibits; Gases; Goals; Hydrogen Peroxide; Imides; In Situ; Ireland; Isocyanates; Kinetics; Lead; Ligands; Methods; Molecular; Nitrogen; Organic Chemistry; Organic Synthesis; Outcome; Oxidants; Oxygen; Palladium; Pathway interactions; Pharmacologic Substance; Physical condensation; Play; Preparation; Production; Property; Pyrrolidines; Reaction; Reagent; Recording of previous events; Research; Rest; Role; Structure; System; Therapeutic Agents; Ursidae Family; Work; base; carbene; carboxylate; catalyst; density; design; functional group; inorganic phosphate; insight; oxidation; programs; public health relevance; pyrrolidine; uptake

DESCRIPTION (provided by applicant): Efficient methods for the incorporation of nitrogen functional groups into organic molecules are critical for the discovery, development and production of pharmaceuticals and related biologically active molecules. This proposal addresses the oxidative coupling of alkenes and nitrogen nucleophiles (amides, imides and carbamates), which represents a long-standing challenge in synthetic organic chemistry. Recent results in our lab have led to several important breakthroughs in this area. Efficient palladium-catalyzed methods have been developed for the intramolecular oxidative amination of alkenes with molecular oxygen (and, in some cases, ambient air) as the stoichiometric oxidant. Unlike early precedents of this chemistry, these reactions are compatible with the use of well-defined palladium catalysts coordinated by oxidatively stable ancillary ligands. The latter property creates the opportunity to pursue enantioselective catalytic methods. Separately, the first methods for intermolecular aerobic oxidative amination of alkenes were developed. This proposal outlines a comprehensive program to expand the scope and utility of aerobic oxidative amination reactions and to develop enantioselective methods for the synthesis of nitrogen-containing heterocycles. The first thorough mechanistic studies of this class of reactions will be undertaken in order to gain insights into the factors that promote efficient product formation and contribute to substrate- and catalyst-controlled stereoselectivity. The mechanistic work will utilize a number of complementary approaches, including gas-uptake kinetic methods, in-situ spectroscopic analysis of catalytic reactions, the use of suitably designed substrate probes and density functional theoretical calculations to illuminate fundamental features of the reaction pathway. Mechanistic insights provide the basis for our synthetic efforts to expand the scope of Pd-catalyzed aerobic oxidation reactions, including the development of new methods for oxidative difunctionalization of alkenes (aminooxygenation and aminoalkylation). Diversely functionalized and stereochemically defined substrates for these reactions will be accessed via the Ireland-Claisen rearrangement and via condensation of chiral allylic and homoallylic alcohols with isocyanates. Use of these substrates in the synthesis of target structures such as small pyrrolidine alkaloids and aminosugar derivatives will enable us to probe important issues related to the diastereoselectivity and functional group compatibility of these methods. New chiral palladium catalysts have been designed to pursue enantioselective catalysis. The goals in this area include the development of a completely new class of N-heterocyclic-carbene ligands based on a seven-membered heterocyclic framework that exhibits axial chirality. Insights from recent mechanistic studies suggest that chiral anionic ligands represent additional promising targets for the catalytic asymmetric synthesis of nitrogen heterocycles. PUBLIC HEALTH RELEVANCE: The development of efficient methods for the synthesis of organic molecules is critical for the discovery, development and commercial production of pharmaceuticals and therapeutic agents. The research outlined in this proposal will lead to new catalytic methods for the preparation of such biologically active molecules.

描述（由申请人提供）：将氮官能团掺入有机分子的有效方法对于药物和相关生物活性分子的发现、开发和生产至关重要。该提案解决了烯烃和氮亲核试剂（酰胺、酰亚胺和氨基甲酸酯）的氧化偶联问题，这是合成有机化学中长期存在的挑战。我们实验室的最新成果在这一领域取得了多项重要突破。已经开发出有效的钯催化方法，用于以分子氧（在某些情况下，环境空气）作为化学计量氧化剂对烯烃进行分子内氧化胺化。与这种化学的早期先例不同，这些反应与使用由氧化稳定的辅助配体协调的明确的钯催化剂兼容。后一种特性为追求对映选择性催化方法创造了机会。另外，还开发了第一种烯烃分子间有氧氧化胺化方法。该提案概述了一个综合计划，旨在扩大需氧氧化胺化反应的范围和实用性，并开发用于合成含氮杂环的对映选择性方法。将对此类反应进行首次彻底的机理研究，以便深入了解促进有效产物形成并有助于底物和催化剂控制的立体选择性的因素。机械工作将利用许多补充方法，包括气体吸收动力学方法、催化反应的原位光谱分析、使用适当设计的底物探针和密度泛函理论计算来阐明反应途径的基本特征。机理见解为我们扩大钯催化有氧氧化反应范围的合成努力提供了基础，包括开发烯烃氧化双官能化（氨基氧化和氨基烷基化）的新方法。这些反应的多种官能化和立体化学定义的底物将通过爱尔兰-克莱森重排以及手性烯丙醇和高烯丙醇与异氰酸酯的缩合获得。在合成目标结构（例如小吡咯烷生物碱和氨基糖衍生物）中使用这些底物将使我们能够探讨与这些方法的非对映选择性和官能团相容性相关的重要问题。新型手性钯催化剂旨在实现对映选择性催化。该领域的目标包括开发一类全新的 N-杂环卡宾配体，该配体基于具有轴向手性的七元杂环框架。最近的机理研究表明，手性阴离子配体代表了氮杂环催化不对称合成的其他有前景的靶标。 公共卫生相关性：开发有效的有机分子合成方法对于药物和治疗剂的发现、开发和商业生产至关重要。该提案中概述的研究将带来用于制备此类生物活性分子的新催化方法。