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

项目摘要/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 具有很高的区域、立体和化学选择性。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。然而，即使是 必须从原料药中清除痕量的钯，以满足FDA的标准，通常需要额外的纯化步骤 这对整体产量产生了负面影响，并增加了成本。因此，无过渡金属的发展 交叉偶联催化剂将是有益的，因为它要求不那么严格的提纯，而且还提供了 到互补性反应的新领域。这项提议描述了一种新的方法，它利用严格的平面 非三角膦催化亲核与亲电交叉偶联 C-C键结构的反应。在亲核-亲核偶联中，磷催化剂将是 通过PIII/PV氧化还原循环为熊田和Negishi交叉耦合开发。磷中心的使用 在芳基卤化物氧化加成反应中，催化将通过有利于C-活化来颠覆传统的反应性趋势 C-Br键和C-I键上的F和C-Cl键。最初的努力将集中于逐步了解限制 在研究催化作用之前，反应性和决定每一次转化的基本热力学。在……里面 作为补充推力，非三角膦自由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驱动芳基卤化物的还原交叉偶联。这个 这一过程中的两个亲电活化步骤预计会对芳基卤化物表现出相反的反应顺序 键，允许化学选择性来决定C-C键的形成。这最终将严重削弱 形成不受欢迎的同质偶联副产物，这对过渡金属催化可能是困难的 系统。这些磷催化转化的发展不仅将展示替代 在原料药合成中采用传统的过渡金属工艺的方法，但也将强调 将增强药物可获得的化学多样性的互补性反应的未知领域 探索的努力。 这一建议与奖学金培训计划保持一致，确保主要群体发展新技能。 将进行催化和有机反应设计。麻省理工学院的Radosevich实验室是 这些技能的发展和拟议的工作归功于他们在磷氧化还原催化方面的开创性工作。 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 独立调查人员保证实现专业发展目标。此外， 麻省理工学院可用的资源将确保获得必要的设备、培训和支持，以取得成功。

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.