Pd-Catalyzed Olefin Functionalization Reactions for Organic Synthesis

描述（由申请人提供）：氧化反应是合成生物相关化合物中官能团操纵和杂原子引入的必要条件。新发现和显著改进的氧化过程可以直接影响目标合成的效率和方法。因此，发展选择性的、实用的氧化反应是学术界和工业界化学家面临的一个持续的挑战。一个关键的考虑因素是选择化学计量氧化剂，其中需要解决通用性，费用和环境影响。解决这一问题的一个有吸引力的方法是使用金属催化氧化耦合到一个实用的终端氧化剂，如分子氧或过氧化氢。因此，氧化催化和本项目的中心目标是发现和开发与实际氧化剂兼容的高活性、强效催化剂。具有氧化稳定配体的钯（II）盐之所以被选为催化剂，主要是因为它们能够有效地利用分子氧作为末端氧化剂。配体的使用允许高反应选择性，包括对映体选择性，以及设计具有高周转率的明确定义的pd配合物。重要的是，钯催化反应通过交叉偶联反应的发展彻底改变了合成，形成了大量的C-C， C-N， C-S和C-O键。因此，本研究的一个基本目标是将钯催化的氧化反应与交叉偶联过程结合起来。目前的建议是通过氧化化学方法开发新的pd催化烯烃功能化反应。具体来说，我们将(1)研究和发展我们最近发现的含有苯酚的苯乙烯的pd催化的有氧二氧基化反应，包括扩展到亲核试剂的串联分子内加成/Diels-Alder过程；(2)研究最近发现的配体调制的直接氧偶联瓦克氧化的范围和机制，并开发生成对映异构富集底物和产物的烯烃的动力学分辨率和动态动力学分辨率。(3)开发烯烃功能化反应，其中利用有机金属试剂的pd催化交叉偶联反应与有氧醇氧化配对。本文提出的研究将使用方法发现和发展，通过使用物理有机化学技术阐明机械细节来促进。提出的研究目标是开发新的金属催化烯烃氧化化学，采用简单的底物和实用的末端氧化剂（O2和简单过氧化物），以立体控制的方式创建不同的键结构。所提出的方法的进步将通过提供有效的途径获得生物活性核心结构的新型衍生物，直接影响生物医学任务。

DESCRIPTION (provided by applicant): Oxidation reactions are essential for both functional group manipulation and heteroatom introduction in the synthesis of biologically relevant compounds. Newly discovered and significantly improved oxidative processes can have a direct impact on the efficiency of and approaches to the execution of targeted synthesis. Therefore, the development of selective, practical oxidation reactions is a continuing challenge facing chemists in both academia and industry. A key consideration is selection of the stoichiometric oxidant where versatility, expense, and environmental impact need to be addressed. An attractive approach to this issue is the use of metal-catalyzed oxidations coupled to a practical terminal oxidant such as molecular oxygen or hydrogen peroxide. Therefore, a central goal of oxidation catalysis, and of this program, is the discovery and development of highly active, robust catalysts compatible with practical oxidants. Palladium(II) salts with oxidatively stable ligands have been selected as catalysts primarily due to their ability to effectively use molecular oxygen as a terminal oxidant. The use of ligands allows for high reaction selectivity, including enantioselectivity, and for the design of well-defined Pd-complexes capable of high turnover numbers. Importantly, Pd-catalyzed reactions have revolutionized synthesis through the development of cross-coupling reactions, forming a vast array of C-C, C-N, C-S, and C-O bonds. Therefore, a fundamental goal of the proposed research is to integrate Pd-catalyzed oxidation reactions with cross-coupling processes. The current proposal is directed toward the development of new Pd-catalyzed olefin functionalization reactions via oxidation chemistry. Specifically, we will (1) study and develop our recently discovered Pd-catalyzed aerobic dialkoxylation reactions of styrenes containing a phenol, including expansion to tandem intramolecular addition of nucleophiles/Diels-Alder processes, (2) investigate the scope and mechanism of a recently discovered ligand-modulated direct oxygen coupled Wacker oxidation and develop kinetic resolution and dynamic kinetic resolution of olefins yielding enantiomerically enriched substrates and products, and (3) develop olefin functionalization reactions wherein Pd-catalyzed cross-coupling reactions utilizing organometallic reagents are paired with aerobic alcohol oxidation. The proposed research described herein will be approached using method discovery and development, facilitated by elucidation of mechanistic details using physical organic chemistry techniques. The goal of the proposed research is to develop new metal catalyzed olefin oxidation chemistry employing simple substrates and practical terminal oxidants (O2 and simple peroxides) to create diverse bond constructions in a stereocontrolled manner. Advances in the proposed methodology will directly impact the biomedical mission by providing efficient access to novel derivatives of biologically active core structures.