Late Metal-Catalyzed Carbon-Carbon Bond Forming Reaction of Enolate Nucleophiles

晚金属催化烯醇化亲核试剂的碳-碳键形成反应

基本信息

批准号：
7847437
负责人：
John F Hartwig
金额：
$ 34.77万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847437
关键词：
3-hydroxybutanal Achievement Address Aldehydes Alkali Metals Alkylation Amides Anions Biological Factors Boron Bromides Carbon Carbonates Carboxylic Acids Chemistry Chloride Ion Chlorides Clinical Communities Complement Complex Coupling Data Development Diterpenes Electronics Electrons Esters Ethers Grant Health Human Imides Iodides Iridium Ketones Kinetics Lactams Lactones Left Life Ligands Metals Methods NMR Spectroscopy Nitriles Organic Chemistry Palladium Paper Pharmacologic Substance Preparation Procedures Process Publishing Pyrroles Reaction Reagent Research Personnel Series Silicon Synthesis Chemistry Testing Time Transition Elements Work Zinc alkalinity aryl halide base c new carbonyl compound catalyst cyclic ketone deprotonation drug candidate enol enolate improved insight morpholine oxidation phosphoramidite programs racemization research study stem stereochemistry thioester

3-hydroxybutanal Achievement Address Aldehydes Alkali Metals Alkylation Amides Anions Biological Factors Boron Bromides Carbon Carbonates Carboxylic Acids Chemistry Chloride Ion Chlorides Clinical Communities Complement Complex Coupling Data Development Diterpenes Electronics Electrons Esters Ethers Grant Health Human Imides Iodides Iridium Ketones Kinetics Lactams Lactones Left Life Ligands Metals Methods NMR Spectroscopy Nitriles Organic Chemistry Palladium Paper Pharmacologic Substance Preparation Procedures Process Publishing Pyrroles Reaction Reagent Research Personnel Series Silicon Synthesis Chemistry Testing Time Transition Elements Work Zinc alkalinity aryl halide base c new carbonyl compound catalyst cyclic ketone deprotonation drug candidate enol enolate improved insight morpholine oxidation phosphoramidite programs racemization research study stem stereochemistry thioester

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项目摘要

DESCRIPTION (provided by applicant): My group discovered the direct a-arylation of ketones concurrently with two other groups and has contributed significantly in recent years to the development the a-arylation of many types of carbonyl compounds and nitriles into practical synthetic methods. The relevance of this chemistry to human health has been demonstrated by its use multiple times by process chemists in the past few years to produce clinical candidates on a multi-kilo scale and by its use countless times by medicinal chemists to produce compounds for SAR studies. Further, this chemistry has been used by the academic community to prepare biologically active natural products, and our papers on this topic have been cited hundreds of times. During the past grant period we developed general, coupling reactions of weakly basic zinc and silicon enolates and, sparked by a mechanistic insight, we recently developed highly enantioselective couplings of ketone enolates. These are rare, but important, examples of enantioselective processes that form quaternary stereocenters. We also extended our studies on metal-catalyzed substitutions of enolate nucleophiles during the past grant period to an iridium-catalyzed, enantioselective allylation of silyl enol ethers. The iridium- catalyzed reaction is unusual because it creates a new stereocenter at the allyl electrophile and does so with high enantioselectivity. Our mechanistic studies led us to develop the first reductive eliminations of arylpalladium enolate compounds and to use these compounds to reveal the origins of electronic effects on C-C bond forming reductive eliminations. We also showed that aryl chlorides, bromides and iodides can undergo oxidative addition to the same metal by three different mechanisms. We propose during the next grant period to develop new classes of enolate couplings, including the coupling of aldehydes, aldehyde and ketone surrogates, a,(3-unsaturated carbonyl compounds, and new classes of esters. Based on our recent highly enantioselective couplings of aryl triflates, we propose to develop enantioselective couplings of enolates to form quaternary stereogenic centers and to use weakly basic Zn and Si enolates to conduct enantioselective couplings to form tertiary stereocenters. The rate- limiting step of the catalytic processes is transmetalation of the enolate or oxidative addition of the haloarene to Pd(0). Because little is known about the mechanism of transmetalation and the mechanism of oxidative addition in the presence of halides remains ambiguous, we propose to study the mechanism of a series of transmetalations and to test a new mechanism proposed for oxidative addition in the presence of halides. Finally, we propose to expand the scope of the iridium-catalyzed allylations by conducting reactions with main group enolates and activators we developed for the palladium coupling. We also plan to study the allylation processes using new classes of ligands that are isoelectronic with those in the active catalyst.

描述（由申请人提供）：我的小组与另外两个小组同时发现了酮的直接A型，并且近年来对开发的开发做出了重大贡献，将许多类型的羰基化合物和硝化液嫁给实际合成方法。在过去的几年中，通过过程化学家多次证明了这种化学与人类健康与人类健康的相关性，以在多kilo量表上生产临床候选者，并且通过药物化学家无数次使用，以生产用于SAR研究的化合物。此外，学术界已经使用了这种化学反应来准备生物活跃的天然产品，我们关于该主题的论文被引用了数百次。在过去的赠款期间，我们开发了一般的，弱碱性锌和硅的耦合反应，并在机械洞察力的引发，最近我们开发了酮烯醇的高度对映选择性耦合。这些是罕见但很重要的，是形成第四纪立体中心的对映选择过程的例子。我们还扩大了关于蜂蜜粒子在过去的赠款期间的金属催化的核催化取代的研究，以呈虹膜催化的，甲硅烷基烯醇乙醇的映射。虹膜催化的反应是不寻常的，因为它会在烯丙基电力机上产生新的立体中心，并以高的对映选择性进行。我们的机械研究导致我们开发了对芳基丙酰胺化合物的首次还原性消除，并使用这些化合物揭示了电子对C-C键影响形成还原性消除的起源。我们还表明，芳基氯化物，溴化物和碘化物可以通过三种不同的机制在同一金属中添加氧化。我们在下一个赠款期间建议开发新的酸化耦合，包括醛，醛和酮代替代醛的耦合，A（3-不饱和的羰基化合物，以及新的酯类类别，基于我们最近的高度启发性促成供应的高度启发性的供应，我们可以根据我们的最新高度启发性辅助供应，以供应供应供应供应供应促进型的供应。立体源性中心并使用弱基本的Zn和Si启用对映选择性耦合，以形成催化过程的速率步骤。为了研究一系列跨金属的机制，并在存在卤化物的情况下测试提出的氧化添加的新机制，我们建议通过与主要的组耐载体和激活剂进行反应来扩大虹膜催化的烯丙基化的范围。我们还计划使用与活性催化剂中的同核的新配体一起研究烯丙基化过程。