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：
8651922
负责人：
John F Hartwig
金额：
$ 36.58万
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 2016-12-31
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 Our goals for the next grant period are based on published and unpublished findings on 1) new classes of coupling reactions of enolates we discovered that are becoming commonly practiced, 2) new classes of complexes we discovered that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）：形成碳键的交叉耦合是综合改善人类健康的分子的一些反应。它们构成了制药行业过程化学家实行的所有碳碳键形成反应的近四分之一。我们对该NIH计划的长期目标是创建新的过渡金属催化的耦合反应，从而形成具有药用活性的分子中碳碳键的类型。我们寻求这样做，同时获得对这些反应机制的定量和精确理解，以创建一个平台，以进一步反应发现并创建一个框架，以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，我们将寻求使用以前发现的催化剂来发现新的转变，以揭示新的催化剂，这些催化剂将反复无常的反应变成可靠的方法，并获得有关这些催化过程的各个步骤的精确信息，以在催化中间体的结构和特性之间建立连接，并选择了整体反应的速率和选择性。 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在许多情况下，以及3）我们最近发现的新机械信息，要求重新评估这些先前提出的中间体在这些和其他常用耦合以及C-H键函数化反应中的身份和反应性。 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)钯催化的耦合反应，例如芳基卤化物和羰基耦合的氰化反应，对于合成药物活性化合物至关重要，但目前发育不良或不可靠，4）4）偶联的芳基卤化物与芳基甲基甲酯与我们的无孔系统衍生的芳基体系衍生的机制和5），以及5）钯和虹膜催化的烯醇或硬核诱导的反应，形成含有立体源性碳的产物。所有这些反应都与普通的亲核试剂和普遍存在的芳基或乙烯基卤化物电力物发生。从单个，易于获得的合成或商业中间体中直接合成关键中间体和药物归因于关键中间体和药物归因的能力，这会导致候选药物的类型由该提案的化学形成。