Pd-Catalyzed Olefin Functionalization Reactions for Organic Synthesis

描述(申请人提供)：氧化反应对于合成生物相关化合物中的官能团操纵和杂原子引入都是必不可少的。新发现的和显著改进的氧化过程可以直接影响靶向合成的效率和执行方法。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持续挑战。一个关键的考虑是选择化学计量比的氧化剂，在那里需要解决通用性、费用和环境影响问题。解决这一问题的一个有吸引力的方法是使用金属催化的氧化与实际的终端氧化剂，如分子氧或过氧化氢。因此，氧化催化的中心目标是发现和开发与实际氧化剂相容的高活性、坚固的催化剂。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终端氧化剂。配体的使用允许高的反应选择性，包括对映体选择性，并允许设计能够高周转数的定义良好的Pd-络合物。重要的是，钯催化的反应通过交叉偶联反应的发展使合成发生了革命性的变化，形成了大量的C-C、C-N、C-S和C-O键。因此，该研究的一个基本目标是将钯催化的氧化反应与交叉耦合过程相结合。目前的建议是通过氧化化学开发新的钯催化的烯烃官能化反应。具体地说，我们将(1)研究和开发我们最近发现的Pd催化的含苯酚的苯乙烯的有氧二烷氧基化反应，包括扩展到亲核分子内串联加成/Diels-Alder过程，(2)研究最近发现的配体调节的直接氧偶联Wacker氧化的范围和机理，并开发生成对映体富集烯的烯烃的动力学拆分和动态动力学拆分，以及(3)开发烯烃功能化反应，其中使用有机金属试剂的Pd催化的交叉偶联反应与好氧醇氧化配对。本文描述的拟议研究将使用方法发现和开发来进行，通过使用物理有机化学技术阐明机理细节来促进。这项研究的目标是开发新的金属催化的烯烃氧化化学，使用简单的底物和实用的终端氧化剂(O2和简单的过氧化氢)以立体控制的方式创建不同的键结构。拟议方法学的进展将直接影响生物医学使命，因为它提供了获得生物活性核心结构的新衍生物的有效途径。

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.