Mechanism and Rational Development of Catalytic Carbon-Carbon Bond-Forming Reacti

描述(由申请人提供)：形成碳-碳键的交叉偶联反应是合成改善人类健康的分子最常用的反应之一。它们构成了制药业过程化学家实践的所有碳-碳键形成反应的近四分之一。我们这个NIH计划的长期目标是创造新的过渡金属催化的偶联反应，在具有药用活性的分子中形成碳-碳键类型。我们试图做到这一点，同时获得对这些反应机理的定量和准确的了解，以创建一个进一步发现反应的平台，并创建一个框架，在其中合理地应用这些反应类别来解决合成问题。为了实现这些目标，我们将寻求发现我们以前发现的催化剂的新转化，揭示将臭名昭著的反复无常的反应转化为可靠方法的新催化剂，并获得关于这些催化过程的各个步骤的准确信息，以建立催化中间体的结构和性质与整个反应的速度和选择性之间的联系。我们在下一个授权期的目标是基于已发表和未发表的发现：1)我们发现的正在变得普遍的烯醇酸盐的新类型的偶联反应，2)我们发现的新类型的化合物，我们发现在许多情况下介导芳基、乙烯基和烯丙基电子与烯醇酸酯、氰化物、三氟甲基阴离子和主族有机金属试剂的偶联，并在许多情况下控制绝对立体化学，以及3)我们最近发现的新的机理信息，要求重新评估以前提出的中间体在这些反应中的身份和反应活性，以及其他常用的偶联和C-H键官能化反应。为了实现这些短期目标，我们将开发1)钯催化的芳基卤化物与烯醇酸盐的反应，这些反应目前没有进行高产率和大范围的偶联；2)铜催化的芳基卤化物与烯醇酸盐的反应以及补充钯催化的化学(并降低催化剂成本)的三氟甲基阴离子的来源；3)钯催化的偶联反应，如芳基卤化物的氰化反应和羰基化偶联反应，这些反应对合成具有药物活性的化合物很重要，但目前开发得不够成熟或不可靠，4)芳基卤化物与芳烃的偶联反应是由我们的机理研究得出的无配体钯系统催化的。和5)对映体选择性或立体保留的钯和铱催化的烯醇酸盐或硬核亲核剂的反应，这些反应形成含有立体生成的季碳的产物。所有这些反应都发生在常见的亲核试剂和无处不在的芳基或卤化乙烯类亲电试剂上。正是利用普通试剂的这些反应从单一的、容易获得的合成或商业中间体直接合成关键中间体和药效团的能力，导致候选药物包含由本提案的化学形成的碳-碳键的类型。 与公众健康相关：该项目产生的许多催化剂和反应极大地改进了制备药物中间体的方法，我们的催化剂的新反应、新应用，以及拟议的研究将产生的对这些系统的机理理解，对这些和其他生物活性材料的合成同样重要。因此，拟议研究的成功发展将大大增加改善人类健康的化合物的可及性。

DESCRIPTION (provided by applicant): Cross-couplings to form carbon-carbon bonds are some of the most utilized reactions for the synthesis of molecules that improve human health. They constitute nearly a quarter of all carbon-carbon bond-forming reactions practiced by process chemists in the pharmaceutical industry. Our long-term objective for this NIH program is to create new transition metal-catalyzed coupling reactions that form the types of carbon-carbon bonds in molecules with medicinal activity. We seek to do so while gaining a quantitative and precise understanding of the mechanisms of these reactions to create a platform for further reaction discovery and to create a framework within which to rationally apply these classes of reactions to synthetic problems. To meet these objectives, we will seek to uncover new transformations with catalysts we discovered previously, to reveal new catalysts that turn notoriously capricious reactions into reliable methods, and to gain precise information about the individual steps of these catalytic processes to build a connection between the structure and properties of the catalytic intermediates and the rates and selectivities of the overall reaction. Our goals for the next grant period are based on published and unpublished findings on 1) new classes of coupling reactions of enolates we discovered that are becoming commonly practiced, 2) new classes of complexes we discovered that mediate the coupling of aryl, vinyl, and allyl electrophiles with enolates, cyanide, trifluoromethyl anions, and main group organometallic reagents with control of absolute stereochemistry in many cases, and 3) new mechanistic information we recently discovered that mandates a reassessment the identity and reactivity of previously proposed intermediates in these and additional commonly practiced coupling and C-H bond functionalization reactions. To achieve these short-term goals we will develop 1) palladium-catalyzed reactions of aryl halides with enolates that currently do not undergo coupling in high yields with broad scope, 2) copper-catalyzed reactions of aryl halides with enolates and sources of trifluoromethyl anions that complement palladium-catalyzed chemistry (and that reduce catalyst cost), 3) palladium-catalyzed coupling reactions, such as the cyanation of aryl halides and carbonylative couplings, that are important for the synthesis of medicinally active compounds but are currently poorly developed or unreliable, 4) coupling of aryl halides with arenes catalyzed by ligandless palladium systems derived from our mechanistic studies, and 5) enantioselective or stereoretentive palladium- and iridium-catalyzed reactions of enolates or hard nucleophiles that form products containing stereogenic quaternary carbons. All of these reactions occur with common nucleophiles and ubiquitous aryl or vinyl halide electrophiles. It is the ability to use these reactions of common reagents for the direct synthesis of key intermediates and pharmacophores from a single, readily available synthetic or commercial intermediate that causes drug candidates to contain the types of carbon-carbon bonds formed by the chemistry of this proposal. PUBLIC HEALTH RELEVANCE: Many of the catalysts and reactions that have resulted from this project dramatically improve methods to prepare pharmaceutical intermediates, and new reactions, new applications of our catalysts, and a mechanistic understanding of these systems that will result from the proposed research promise to be equally important for the synthesis of these and other biologically active materials. Thus, successful development of the proposed research will significantly increase the accessibility of compounds that improve human health.