Development of Nontrigonal Phosphorus Catalysts for Redox-Mediated Cross-Coupling Transformations

用于氧化还原介导的交叉偶联转化的非三方磷催化剂的开发

• 批准号: 10468667
• 负责人: Quinton James Bruch
• 金额: $ 6.72万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2024-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468667
• 关键词: Address; Adopted; Adoption; Anions; Area; Automobile Driving; Catalysis; Chemicals; Coupling; Development; Electron Transport; Electrons; Elements; Ensure; Environment; Exhibits; Fellowship; Geometry; Goals; Investigation; Kinetics; Mediating; Outcome; Oxidation-Reduction; Pathway interactions; Pharmacologic Substance; Phosphines; Phosphorus; Positioning Attribute; Process; Property; Reaction; Research Personnel; Resources; Structure-Activity Relationship; System; Technology; Thermodynamics; Training; Training Support; Transition Elements; Work; aryl halide; base; catalyst; cost; design; drug discovery; equipment training; improved; innovation; novel strategies; pharmacophore; phosphorus compounds; skill acquisition; skills; trend

PROJECT SUMMARY/ABSTRACT Transition metal-catalyzed cross-couplings afford innumerous pathways for the construct of new C–X bonds with high regio-, stereo-, and chemoselectivity. This has led to widespread adoption of cross-coupling in the synthesis of active pharmaceutical ingredients (APIs), most commonly using Pd-based catalysts. However, even traces of Pd must be purged from the API to meet FDA standards, often requiring additional purification steps that negatively impact overall yields and increases cost. Therefore, the development of transition metal-free catalysts for cross-coupling would be beneficial by requiring less stringent purification and also affording access to new areas of complementary reactivity. This proposal describes a new approach that utilizes rigidly planar nontrigonal phosphines to catalyze nucleophile-electrophile and electrophile-electrophile cross-coupling reactions for C–C bond construction. In nucleophile-electrophile couplings, phosphorus catalysts will be developed for Kumada and Negishi cross-couplings via a PIII/PV redox cycle. The use of a phosphorus center in catalysis will subvert traditional reactivity trends in aryl halide oxidative addition by favoring the activation of C– F and C–Cl bonds over C–Br and C–I bonds. Initial efforts will focus on understanding limitations in stepwise reactivity and the underlying thermodynamics that dictate each transformation before investigating catalysis. In a complementary thrust, the one electron reactivity of nontrigonal phosphinyl radical anions will be merged with two-electron oxidative addition and reductive elimination to drive reductive cross-coupling of aryl halides. The two electrophile activation steps in this process are expected to exhibit inverse orders of reactivity for aryl halide bonds, allowing for chemoselectivity to dictate C–C bond formation. This ultimately will severely diminish the formation of undesired homocoupling byproducts, something that can be difficult for transition metal-catalyzed systems. The development of these phosphorus-catalyzed transformations will not only demonstrate alternative approaches to traditionally transition metal-based processes in the synthesis of APIs, but will also highlight undiscovered areas of complementary reactivity that will enhance the chemical diversity accessible to drug discovery efforts. This proposal aligns with the fellowship training plan by ensuring the development of new skills in main group catalysis and organic reaction design will take place. The Radosevich lab at MIT is an ideal environment for the development of these skills and the proposed work due to their pioneering work in phosphorus redox catalysis. Additionally, Prof. Radosevich’s commitment to developing postdoctoral researchers into successful independent investigators guarantees that professional development goals will be met. Furthermore, the resources available at MIT will ensure access to the necessary equipment, training, and support to succeed.

项目摘要/摘要 过渡金属催化的交叉耦合提供了无数途径的新C – X键 具有高区域，立体和化学选择性。这导致采用宽度 活性药物成分（API）的合成，最常用于基于PD的催化剂。但是，甚至 必须从API清除PD痕迹以满足FDA标准，通常需要其他净化步骤 这会对总体产量产生负面影响，并增加成本。因此，不含过渡金属的发展 交叉耦合的催化剂将通过不太严格的纯化并提供访问来有益 到完整反应的新领域。该提案描述了一种使用严格平面的新方法 非三角磷催化亲核 - 电动噬菌体和亲电的电动交叉偶联 C – C键构建的反应。在核电子噬菌耦合中，磷催化剂将是 通过PIII/PV氧化还原循环为kumada和negishi交叉耦合开发。在 催化会通过有利于C –的激活来颠覆芳基卤化物氧化添加的传统反应性趋势。 C – BR和C – I键上的F和C – Cl键。最初的努力将集中于逐步理解限制 反应性和基础热力学在研究催化之前决定了每种转化。在 一个完全推力，非三角磷酸自由基阴离子的一种电子反应性将与 添加了两种电子氧化物和减少消除，以驱动芳基卤化物的交叉偶联减少。 在此过程中，有两个亲电的激活步骤有望表现出反应性的反应性芳基卤化物的反应性逆点 键，允许化学选择性决定C – C键的形成。最终将严重减少 形成不想要的同耦合副产品，这对于过渡金属催化可能很难 系统。这些磷催化的转化的发展不仅会证明替代方案 在API合成中，传统上基于金属的过程的方法，但也将突出显示 完全反应性的未发现的区域将增强药物可访问的化学多样性 发现工作。 该建议通过确保主要小组的新技能发展与奖学金培训计划保持一致 将进行催化和有机反应设计。麻省理工学院的Radosevich实验室是理想的环境 这些技能的发展以及由于其在磷氧化还原催化中的开创性工作而提出的工作。 此外，拉多瑟维奇教授致力于将博士后研究人员发展成成功 独立调查人员保证将实现专业发展目标。此外， 麻省理工学院可用的资源将确保访问必要的设备，培训和支持以取得成功。