Mechanistically Guided Cross-Electrophile Coupling Approaches to Useful Csp2-Csp2 and Csp2- Csp3 Bonds

机械引导的交叉电耦合方法获得有用的 Csp2-Csp2 和 Csp2-Csp3 键

• 批准号: 10404552
• 负责人: Daniel John Weix
• 金额: $ 32.69万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404552
• 关键词: Address; Alcohols; Amines; Area; Biological; Carbon; Carboxylic Acids; Chemicals; Chemistry; Chlorides; Collection; Coupled; Coupling; Development; Drug Industry; Electrochemistry; Future; Goals; Grant; Industrialization; Industry; Ketones; Kinetics; Lead; Ligands; Light; Methods; Mission; Modernization; Nickel; Outcome; Palladium; Pharmaceutical Chemistry; Pharmaceutical Preparations; Postdoctoral Fellow; Process; Property; Public Health; Publishing; Reaction; Research; Route; Spectrum Analysis; Time; United States National Institutes of Health; Work; catalyst; chemical synthesis; computerized tools; design; dimer; drug candidate; functional group; graduate student; improved; innovation; method development; new therapeutic target; novel strategies; oxidation; programs; side effect; tool

Project Summary/Abstract Rapid advancements in biological and computational tools to find new therapeutic targets have outstripped available synthetic tools to synthesize drug candidates. Many proposed molecules are not tested because of the synthetic and time constraints of medicinal chemistry, where lead cores must be rapidly diversified in a modular fashion using robust, well-established methods, such as palladium-catalyzed cross-coupling and Grignard reactions. The major hurdles are the limited accessibility of carbon nucleophiles and the limited tolerance of most methods for the broad range of functional groups and reactivity present in drug candidates. We propose to develop collections of cross-electrophile coupling reactions that address these challenges and are adapted to modern parallel synthesis. Cross-electrophile coupling leverages the increased diversity of carbon electrophiles compared to nucleophiles (100 to 1000 times more commercially available derivatives); but achieving selectivity for cross-coupled product over dimeric products can be challenging and the factors that govern successful coupling remain unclear. This program's long-term goals are the development of methods for the selective cross-coupling of every major class of electrophile and the discovery of the fundamental properties that control selectivity and reactivity. In the proposed grant, a team of graduate students and postdocs will build upon the advances of the previous grant period to develop fourteen new cross-electrophile coupling reactions, explore new ways to utilize the largest substrate pools (organic chlorides, alcohols, amines, and carboxylic acids), and shed light on the reactive nickel intermediates that govern these processes. Our guiding hypothesis is that these challenges can be addressed by a combination of mechanistic studies, mechanism-guided design of new electrophiles, and an optimization approach that focuses on a collection of substrates rather than a single substrate pair. The specific aims of this proposal are to: (1) improve Csp2–Csp3 cross-electrophile coupling by the development of methods to engage new electrophiles, new combinations of old electrophiles, and by tailoring our optimization to the needs of medicinal chemistry; (2) address challenging Csp2–Csp2 cross-couplings by developing new, universal routes to challenging di(hetero)aryl ketones and bi(hetero)aryls; (3) shed light on the principles that govern nickel- catalyzed reactions by using electrochemical methods to study otherwise inaccessible reaction intermediates. The approach is innovative because cross-electrophile coupling is less studied than other cross-coupling methods and the proposed mechanistic studies will shed light on these little-understood processes. The proposed research is significant because the chemistry is increasingly important to industrial and academic chemical synthesis and the development of nickel chemistry has outpaced our understanding.

项目摘要/摘要 寻找新的治疗靶点的生物和计算工具的快速进步已经超过了 可用于合成候选药物的合成工具。许多被提议的分子没有被测试，因为 药物化学的合成和时间限制，其中铅芯必须在 使用可靠、成熟的方法的模块化方式，如钯催化的交叉偶联和 格利纳德反应。主要障碍是碳亲核试剂的可获得性有限，以及 大多数方法对候选药物中存在的广泛官能团和反应性具有耐受性。 我们建议开发交叉亲电偶联反应的集合，以应对这些挑战和 适用于现代并行合成。交叉亲电偶联利用了增加的多样性 碳亲电性与亲核性相比(商业上可获得的衍生物高出100到1000倍)； 但实现交叉偶联产物比二聚体产品更具选择性可能是具有挑战性的，而且这些因素 管理成功结合的因素仍然不清楚。这项计划的长期目标是发展 每一类电泳体的选择性交叉偶联的方法和发现 控制选择性和反应性的基本属性。在拟议的拨款中，一支毕业生团队 学生和博士后将在前一个资助期的基础上开发14个新的 交叉亲电偶联反应，探索利用最大底物池(有机)的新方法 氯化物、醇、胺和羧酸)，并揭示了活性镍中间体 管理这些流程。我们的指导性假设是，这些挑战可以通过以下组合来解决 机理研究，新亲电体的机理指导设计，以及一种优化方法 聚焦于基片的集合，而不是单个基片对。这项建议的具体目的是： (1)通过开发新的接合方法来提高Csp2-Csp3的交叉电泳偶联度 亲电性，旧亲电性的新组合，并通过量身定制我们的优化以满足 药物化学；(2)通过开发新的、通用的途径解决具有挑战性的Csp2-Csp2交叉偶联 挑战二(杂)芳基酮和双(杂)芳基；(3)阐明了支配镍- 通过使用电化学方法来研究原本难以获得的反应中间体来催化反应。 该方法具有创新性，因为与其他交叉偶联相比，对交叉亲电偶联的研究较少 方法和拟议的机制研究将阐明这些鲜为人知的过程。这个 提出的研究具有重要意义，因为化学对工业和学术越来越重要 化学合成和镍化学的发展已经超出了我们的理解。