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.

项目概要/摘要 过渡金属催化的交叉偶联为构建新的 C-X 键提供了无数途径 具有高区域选择性、立体选择性和化学选择性，这导致了交叉偶联在该领域的广泛采用。 然而，活性药物成分 (API) 的合成最常用的是钯基催化剂。 必须从 API 中清除微量钯才能满足 FDA 标准，通常需要额外的纯化步骤 这会对整体产量产生负面影响并增加成本，因此，开发不含过渡金属的材料。 用于交叉偶联的催化剂将是有益的，因为需要不太严格的纯化并且还提供访问 该提案描述了一种利用严格平面的新方法。 非三角膦催化亲核试剂-亲电试剂和亲电试剂-亲电试剂交叉偶联 在亲核-亲电子偶联反应中，磷催化剂将是 C-C 键构建的反应。 通过 PIII/PV 氧化还原循环为 Kumada 和 Negishi 交叉偶联开发 磷中心的使用。 催化将通过有利于 C– 的活化来颠覆芳基卤化物氧化加成的传统反应趋势 F 和 C-Cl 键优于 C-Br 和 C-I 键。最初的努力将集中于理解逐步的局限性。 在研究催化之前，反应性和决定每次转化的潜在热力学。 互补的推力，非三角膦基阴离子的单电子反应性将与 双电子氧化加成和还原消除来驱动芳基卤化物的还原交叉偶联。 该过程中的两个亲电试剂活化步骤预计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 C-C 键的形成。 形成不需要的自偶联副产物，这对于过渡金属催化来说是困难的 这些磷催化转化系统的发展不仅将展示替代方案。 API 合成中传统的基于过渡金属的工艺的方法，但也将强调 未被发现的互补反应领域将增强药物可利用的化学多样性 发现努力。 该提案通过确保主要群体新技能的发展与奖学金培训计划保持一致 麻省理工学院的拉多塞维奇实验室将进行催化和有机反应设计。 由于他们在磷氧化还原催化方面的开创性工作，这些技能的发展和拟议的工作。 此外，拉多塞维奇教授致力于将博士后研究人员培养成成功的人 独立调查员保证实现职业发展目标。 麻省理工学院的可用资源将确保获得成功所需的设备、培训和支持。