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

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）：我的小组与其他两个小组同时发现了酮的直接α-芳基化，并且近年来对将多种类型的羰基化合物和腈的α-芳基化开发成实用的合成方法做出了重大贡献。这种化学物质与人类健康的相关性已被证明，在过去的几年中，过程化学家多次使用它来生产公斤级的临床候选药物，并且药物化学家无数次使用它来生产用于 SAR 研究的化合物。此外，这种化学方法已被学术界用来制备具有生物活性的天然产物，我们关于该主题的论文已被引用数百次。在过去的资助期间，我们开发了弱碱性锌和硅烯醇化物的一般偶联反应，并且在机理洞察的激发下，我们最近开发了酮烯醇化物的高度对映选择性偶联。这些是形成四元立构中心的对映选择性过程的罕见但重要的例子。在过去的资助期内，我们还将对烯醇亲核试剂的金属催化取代的研究扩展到了铱催化的硅基烯醇醚的对映选择性烯丙基化。铱催化的反应很不寻常，因为它在烯丙基亲电子试剂处产生了新的立体中心，并且具有高对映选择性。我们的机理研究引导我们开发出第一个芳基钯烯醇化合物的还原消除，并使用这些化合物揭示电子效应对形成还原消除的 C-C 键的起源。我们还表明，芳基氯化物、芳基溴化物和芳基碘化物可以通过三种不同的机制对同一金属进行氧化加成。我们建议在下一个资助期内开发新类别的烯醇化偶联，包括醛、醛和酮替代物、a,(3-不饱和羰基化合物和新类别的酯的偶联。基于我们最近的芳基的高度对映选择性偶联三氟甲磺酸酯，我们建议开发烯醇化物的对映选择性偶联以形成四元立体中心，并使用弱碱性 Zn 和 Si 烯醇化物进行对映选择性偶联形成三级立构中心，催化过程的限速步骤是烯醇化物的金属转移或卤代芳烃与 Pd(0) 的氧化加成，因为人们对金属转移的机制和氧化加成的机制知之甚少。卤化物的存在仍然不明确，我们建议研究一系列金属转移的机制，并测试在卤化物存在下氧化加成的新机制。最后，我们建议扩展。通过与我们为钯偶联开发的主族烯醇化物和活化剂进行反应来扩大铱催化烯丙基化的范围。我们还计划使用与活性催化剂中的等电子的新型配体来研究烯丙基化过程。