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

基本信息

批准号：
10797784
负责人：
Daniel John Weix
金额：
$ 17.64万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目概要/摘要寻找新治疗靶点的生物和计算工具的快速进步已经超越了由于可用的合成工具来合成候选药物，许多提议的分子并未经过测试。药物化学的合成和时间限制，其中铅芯必须快速多样化使用稳健、完善的方法的模块化方式，例如钯催化的交叉偶联和格氏反应的主要障碍是碳亲核试剂的可及性有限和有限。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子偶联反应的集合来应对这些挑战和适应现代并行合成。交叉亲电子偶联利用了增加的多样性。与亲核试剂相比，碳亲电子试剂（市售衍生物多 100 至 1000 倍）；但实现交叉偶联产物相对于二聚体产物的选择性可能具有挑战性，并且因素控制成功耦合的因素仍不清楚。该计划的长期目标是开发每种主要亲电子试剂的选择性交叉偶联方法以及发现在拟议的拨款中，一个研究生团队控制了选择性和反应性的基本特性。学生和博士后将在上一个资助期的进步的基础上开发十四个新的交叉亲电子偶联反应，探索利用最大底物池（有机氯化物、醇、胺和羧酸），并揭示了反应性镍中间体我们的假设是，这些挑战可以通过组合来解决。机理研究、新型亲电子试剂的机理引导设计以及优化方法该提案的具体目标是： (1) 通过开发新的方法来改善 Csp2–Csp3 交叉亲电子偶联亲电子试剂，旧亲电子试剂的新组合，并根据需要定制我们的优化药物化学；（2）通过开发新的通用途径解决具有挑战性的 Csp2-Csp2 交叉偶联挑战二（杂）芳基酮和二（杂）芳基；（3）阐明了镍的控制原则；通过使用电化学方法来研究否则无法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，交叉亲电子偶联的研究较少方法和拟议的机制研究将揭示这些鲜为人知的过程。拟议的研究意义重大，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。