Aerobic Oxidative Functionalization of Alkenes: Methods and Mechanisms

描述(申请人提供)：氧、氮、硫和其他杂原子对药物和其他具有生物活性的有机分子的生物功能至关重要。在这种背景下，氧化反应是有机化学中最重要的转化之一，因为它们增加了碳基分子的化学复杂性，并将杂原子取代基结合到碳基分子中。在这个项目中，我们将开发能够使用O2作为化学计量比氧化剂的钯催化的烯烃选择氧化方法。分子内氧化胺化反应将用于氮杂环的非对映和对映选择性合成，以及伯胺与烯丙基胺或烯丙醇的模块偶联，从而生成多种邻二胺和氨基醇产品。最近在这项工作中发现的高活性催化剂将被用于开发区域和立体选择性的烯烃分子间氧化胺化方法。这些分子内和分子间反应成功的关键是发现和开发支持高催化剂稳定性、活性和选择性的新型钯配体。实验和密度泛函计算方法将被用来表征这些反应的机理，并为设计更有效的催化剂提供基础。大多数这些氧化胺化反应都是通过烯烃的氨基配位反应进行的；然而，我们最近发现了一种新的催化剂体系，能够选择性地氧化烯丙基C-H键。这些反应的用途将通过改进催化剂体系的基于机理的设计和开发烯丙基C-H氧化的新的合成应用来扩大。最后，我们将把我们的见解应用到有氧氧化催化中，以开发一种有效的方法来实现芳基和乙烯基硼酸衍生物与电子无偏置烯烃的区域选择性有氧氧化偶联。总体而言，催化反应将导致高效和原子经济的方法，在药物相关的积木和复杂的有机分子中形成新的C-N，C-O和C-C键。 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): Oxygen, nitrogen, sulfur and other heteroatoms are critical to the biological function of pharmaceuticals and other biologically active organic molecules. In this context, oxidation reactions are among the most important transformations in organic chemistry because they increase the chemical complexity of and incorporate heteroatom substituents into carbon-based molecules. In this project, we will develop Pd-catalyzed methods for selective oxidation of alkenes that are capable of using O2 as the stoichiometric oxidant. Intramolecular oxidative amination reactions will be developed for diastero- and enantioselective synthesis of nitrogen heterocycles and for the modular coupling of primary amines with allylic amines or allylic alcohols enroute to versatile vicinial diamine and aminoalcohol products. Highly active catalysts recently discovered in the course of this work will be used to pursue the development of regio- and stereoselective methods for intermolecular oxidative amination of alkenes. The key to the success of these intra- and intermolecular reactions is the discovery and development of novel ligands for Pd that support high catalyst stability, activity and selectivity. Experimental and DFT computational methods will be used to characterize the mechanism of these reactions and provide a foundation for the design of more effective catalysts. Most of these oxidative amination reactions are expected to proceed via a mechanism involving aminopalladation of the alkene; however, we have recently discovered a novel catalyst system that enables selective oxidation of allylic C-H bonds. The utility of these reactions will be expanded through the mechanism-based design of improved catalyst systems and the development of new synthetic applications of allylic C-H oxidation. Finally, we will apply our insights into aerobic oxidation catalysis to develop an efficient method for regioselective aerobic oxidative coupling of aryl- and vinyl-boronic acid derivatives with electronically unbiased alkenes. Overall, the catalytic reactions will lead to highly efficient and atom- economical methods for the formation of new C-N, C-O and C-C bonds in pharmaceutically relevant building blocks and complex organic molecules. 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.