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: 10315179
• 负责人: Quinton James Bruch
• 金额: $ 6.56万
• 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/10315179
• 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; c new; 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.

项目总结/摘要 过渡金属催化的交叉偶联反应为构建新的C-X键提供了无数的途径 具有高的区域选择性、立体选择性和化学选择性。这导致了交叉耦合在 活性药物成分（API）的合成，最常用的是Pd基催化剂。但即使 必须从API中清除痕量的Pd以满足FDA标准，这通常需要额外的纯化步骤 这会对总产量产生负面影响并增加成本。因此，发展无过渡金属 用于交叉偶联的催化剂将是有益的，因为需要较不严格的纯化， 新的互补反应区域。该提案描述了一种新的方法， 催化亲核试剂-亲电试剂和亲电试剂-亲电试剂交叉偶联的非三角膦 C-C键结构的反应。在亲核-亲电偶联中，磷催化剂将是 通过PIII/PV氧化还原循环为Kumada和Negishi交叉偶联而开发。使用磷中心， 催化将颠覆传统的反应趋势，芳基卤氧化加成有利于活化的C- F和C-Cl键超过C-Br和C-I键。最初的努力将集中在了解逐步 在研究催化作用之前，反应性和决定每一种转化的基本热力学。在 一个互补的推力，非三角形氧膦基自由基阴离子的一个电子反应性将与 双电子氧化加成和还原消除以驱动芳基卤化物的还原交叉偶联。的 在该方法中的两个亲电活化步骤预期对芳基卤表现出相反的反应性顺序 键，允许化学选择性决定C-C键的形成。这最终将严重削弱 形成不希望的同偶联副产物，这对于过渡金属催化的 系统.这些磷催化转化的发展不仅将展示替代性 的方法，传统的过渡金属为基础的工艺在合成原料药，但也将强调 未发现的互补反应性领域，这将增强药物可获得的化学多样性 发现努力。 这项建议与研究金培训计划保持一致，确保主要群体的新技能得到发展。 催化和有机反应设计将发生。麻省理工学院的Radosevich实验室是一个理想的环境 这些技能的发展和由于他们在磷氧化还原催化方面的开创性工作而提出的工作。 此外，Radosevich教授致力于将博士后研究人员培养成成功的 独立调查员保证实现专业发展目标。而且 麻省理工学院现有的资源将确保获得必要的设备，培训和支持，以取得成功。