Palladium-Catalyzed Oxidative Amination of Alkenes

描述(由申请人提供)：将含氮官能团结合到有机分子中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。这项建议解决了烯烃和氮亲核试剂(酰胺、亚胺和氨基甲酸酯)的氧化偶联问题，这是合成有机化学中的一个长期挑战。我们实验室的最新结果导致了这一领域的几项重要突破。发展了以分子氧(在某些情况下，环境空气)作为化学计量比氧化剂的烯烃分子内氧化胺化反应的有效的钯催化方法。与这种化学的早期先例不同，这些反应与使用定义明确的钯催化剂是相容的，这些催化剂由氧化稳定的辅助配体配位。后一种性质创造了寻求对映选择性催化方法的机会。另外，首次开发了烯烃分子间好氧氧化胺化反应的方法。这项建议概述了一个全面的计划，以扩大好氧氧化胺化反应的范围和用途，并开发合成含氮杂环的对映选择性方法。将对这类反应进行第一次彻底的机理研究，以深入了解促进有效产物形成和有助于底物和催化剂控制的立体选择性的因素。机理工作将利用一些补充的方法，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。机理方面的见解为我们的合成工作提供了基础，以扩大钯催化的有氧氧化反应的范围，包括开发烯烃氧化去功能化(氨氧化和氨基烷基化)的新方法。这些反应的不同官能化和立体化学定义的底物将通过爱尔兰-克莱森重排和手性烯丙醇和高烯丙醇与异氰酸酯的缩合来获得。使用这些底物来合成目标结构，如小分子吡咯烷生物碱和氨基糖衍生物，将使我们能够探索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。为了实现对映选择性催化，人们设计了新型手性钯催化剂。这一领域的目标包括开发一类全新的基于具有轴向手性的七元杂环骨架的N-杂环-卡宾配体。最近的机理研究表明，手性阴离子配体是催化不对称合成氮杂环的另一个有希望的目标。 与公共卫生相关：开发有效的有机分子合成方法对于药物和治疗剂的发现、开发和商业化生产至关重要。这项提案中概述的研究将导致制备此类生物活性分子的新催化方法。

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.