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

项目概要/摘要 寻找新治疗靶点的生物学和计算工具的快速发展已经超过了 现有的合成工具来合成候选药物。许多提出的分子没有测试，因为 药物化学的合成和时间限制，其中铅芯必须迅速多样化， 模块化的方式，使用强大的，完善的方法，如钯催化的交叉偶联， 格氏反应。主要障碍是碳亲核试剂的可及性有限， 大多数方法对候选药物中存在的广泛官能团和反应性的耐受性。 我们建议开发交叉亲电偶联反应的集合，以解决这些挑战， 适应现代并行合成。交叉亲电体偶联利用了增加的亲电体的多样性。 与亲核试剂相比的碳亲电试剂（100至1000倍的市售衍生物）; 但是实现交叉偶联产物相对于二聚产物的选择性可能是具有挑战性的， 控制成功偶联的因素仍不清楚。该计划的长期目标是发展 方法的选择性交叉偶联的每一个主要类别的亲电试剂和发现的 控制选择性和反应性的基本性质。在拟议的赠款中，一个研究生团队 学生和博士后将建立在前一个赠款期的进步，开发十四个新的 交叉亲电偶联反应，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， 管理这些过程。我们的指导假设是，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 聚焦于基板的集合而不是单个基板对。这项建议的具体目标是： (1)通过开发新的方法来改善Csp 2-Csp 3交叉亲电偶联， 亲电体，旧亲电体的新组合，并通过调整我们的优化，以满足 药物化学;（2）通过开发新的通用途径解决具有挑战性的Csp 2-Csp 2交叉偶联 挑战二（杂）芳基酮和二（杂）芳基;（3）阐明了镍- 通过使用电化学方法研究催化反应，否则难以获得的反应中间体。 该方法是创新的，因为交叉亲电耦合比其他交叉耦合研究得更少 方法和拟议的机制研究将阐明这些鲜为人知的过程。的 拟议的研究是重要的，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。

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.