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

催化碳-碳键形成反应机理及合理发展

基本信息

批准号：
8457135
负责人：
John F Hartwig
金额：
$ 36.08万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-06-01 至 2015-04-30
项目状态：
已结题

项目摘要

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 Our goals for the next grant period are based on published and unpublished findings on 1) new classes of coupling reactions of enolates we discovered that are becoming commonly practiced, 2) new classes of complexes we discovered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

描述（由申请人提供）：形成碳-碳键的交叉偶联是改善人类健康的分子合成中最常用的一些反应。它们占制药行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 项目的长期目标是创造新的过渡金属催化偶联反应，在具有药物活性的分子中形成碳-碳键类型。我们力求做到这一点，同时对这些反应的机制进行定量和精确的理解，为进一步的反应发现创建一个平台，并创建一个框架，在其中合理地将这些类别的反应应用于合成问题。为了实现这些目标，我们将寻求用我们之前发现的催化剂来揭示新的转化，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，并获得有关这些催化过程的各个步骤的精确信息，以在不同的反应之间建立联系。催化中间体的结构和性质以及整个反应的速率和选择性。我们下一个资助期的目标基于已发表和未发表的发现：1）我们发现的新型烯醇化物偶联反应，这些反应正在变得普遍应用；2）我们发现的介导芳基、乙烯基和芳香族化合物偶联的新型络合物。烯醇化物、氰化物、三氟甲基阴离子和主族有机金属试剂在许多情况下控制绝对立体化学的烯丙基亲电子试剂，以及3）我们最近发现的新机制信息重新评估先前提出的这些和其他常用偶联和 C-H 键官能化反应中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，目前尚未进行高产率、广泛的偶联，2) 铜催化的芳基卤化物与烯醇化物的反应以及三氟甲基阴离子源补充钯催化化学（并降低催化剂成本），3）钯催化偶联反应，例如如芳基卤化物的氰化和羰基化偶联，这对于药物活性化合物的合成很重要，但目前开发不佳或不可靠，4）由我们的机理研究衍生的无配体钯系统催化的芳基卤化物与芳烃的偶联，以及5）烯醇化物或硬亲核试剂的对映选择性或立体保留钯和铱催化反应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子试剂上。能够使用常见试剂的这些反应从单一的、易于获得的合成或商业中间体直接合成关键中间体和药效团，使候选药物包含由本提案的化学形成的碳-碳键类型。