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

机械引导交叉电耦合方法的多样性补充有用的 Csp2-Csp2 和 Csp2-Csp3 键

• 批准号: 10621607
• 负责人: Daniel John Weix
• 金额: $ 5.38万
• 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/10621607
• 关键词: Address; Alcohols; Amines; Award; Biological; Carbon; Carboxylic Acids; Chemicals; Chemistry; Chlorides; Collection; Coupled; Coupling; Development; Future; Goals; Grant; Industrialization; Ketones; Lead; Light; Methods; Mission; Modernization; Nickel; Palladium; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Postdoctoral Fellow; Process; Property; Public Health; Reaction; Request for Proposals; Research; Route; System; Time; United States National Institutes of Health; chemical synthesis; computerized tools; design; dimer; drug candidate; functional group; graduate student; improved; innovation; method development; new therapeutic target; 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 生物学和计算工具的快速进步以找到新的治疗靶标 可用的合成工具来合成候选药物。许多提出的分子未进行测试，因为 药物化学的合成和时间限制，其中铅核必须在A中迅速多样化 使用健壮，建立良好方法的模块化方式，例如钯催化的交叉耦合和 Grignard反应。主要的障碍是碳核粉状量有限的可及性和有限的 大多数方法对广泛的官能团和候选药物中的反应性的耐受性。 我们建议开发跨电动耦合反应的收集，以应对这些挑战和 适合现代平行合成。交叉噬菌体耦合利用了增加的多样性 与核phobiles相比，碳电到的碳（市售衍生品提高了100至1000倍）； 但是，可能会挑战与二聚体产品相对于二聚体产品的选择性的选择性和因素 控制成功的耦合尚不清楚。该计划的长期目标是发展 每个主要类的电力类别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特性。在拟议的赠款中，一个毕业生团队 学生和博士后将建立在上一个赠款期的进步基础上，以开发14个新的新 跨电动耦合反应，探索使用最大底物池的新方法（有机池 氯化物，醇，胺和羧酸），并在反应性镍中间散发灯光 管理这些过程。我们的指导假设是，这些挑战可以通过结合 机械研究，机理引导的新电力器设计以及一种优化方法 专注于底物的集合，而不是单个底物对。该提案的具体目的是： （1）通过开发新的方法来改善CSP2 – CSP3跨电动耦合 亲电器，旧电力的新组合，并通过根据需求来调整我们的优化 药化学； （2）通过开发新的通用路线来应对挑战CSP2 – CSP2交叉耦合 挑战DI（杂种）芳基酮和BI（杂种）芳基； （3）阐明控制镍的原理 通过使用电化学方法研究其他无法访问的反应中间体的催化反应。 该方法具有创新性，因为交叉噬菌体耦合比其他交叉耦合少。 方法和提议的机械研究将阐明这些小小的理解过程。 拟议的研究很重要，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过了我们的理解。