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

描述（由申请人提供）：形成碳-碳键的交叉偶联是用于合成改善人类健康的分子的一些最常用的反应。它们构成了制药工业中工艺化学家实践的所有碳-碳键形成反应的近四分之一。我们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。我们试图这样做，同时获得定量和精确的了解这些反应的机制，为进一步的反应发现创造一个平台，并创建一个框架内，合理地应用这些类的反应合成问题。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变，揭示将众所周知的反复无常的反应转化为可靠方法的新催化剂，并获得有关这些催化过程的各个步骤的精确信息，以建立催化中间体的结构和性质与整个反应的速率和选择性之间的联系。我们下一个资助期的目标是基于以下方面的已发表和未发表的研究结果：1）我们发现的烯醇化物的新类型的偶联反应正变得越来越普遍，2）我们发现的新类型的络合物，其介导芳基，乙烯基和烯丙基亲电试剂与烯醇化物，氰化物，三氟甲基阴离子和主族有机金属试剂的偶联，在许多情况下控制绝对立体化学，和3）我们最近发现的新的机理信息，其要求重新评估先前提出的在这些和另外的通常实践的偶联和C-H键官能化反应中的中间体的身份和反应性。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化物的反应，这些反应目前没有以高产率进行广泛的偶联，2）铜催化的芳基卤化物与烯醇化物的反应和三氟甲基阴离子的来源，补充钯催化的化学（和降低催化剂成本），3）钯催化的偶联反应，如芳基卤化物的氰化和羰基化偶联，其对于合成药物活性化合物是重要的，但目前开发不足或不可靠，4）通过得自我们的机理研究的无配体钯体系催化芳基卤化物与芳烃的偶联，和5）烯醇化物或硬亲核试剂的对映选择性或立体保留性钯和铱催化的反应，其形成含有立体季碳的产物。所有这些反应都发生在常见的亲核试剂和普遍存在的芳基或乙烯基卤化物亲电试剂中。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，导致候选药物含有由该提议的化学形成的碳-碳键类型。

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 Our goals for the next grant period are based on published and unpublished findings on 1) new classes of coupling reactions of enolates we discovered that are becoming commonly practiced, 2) new classes of complexes we discovered that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.