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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

基本信息

批准号：
10668364
负责人：
Quinton James Bruch
金额：
$ 1.07万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-02 至 2023-08-31
项目状态：
已结题

项目摘要

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。这导致了交叉耦合的广泛采用活性药物成分 (API) 的合成，最常用的是钯基催化剂。然而，即使必须从 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，开发无过渡金属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到新的互补反应领域。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 C-C 键构建反应。在亲核-亲电子偶联中，磷催化剂将通过 PIII/PV 氧化还原循环为 Kumada 和 Negishi 交叉耦合开发。磷中心的用途催化将通过有利于 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 键高于 C-Br 和 C-I 键。最初的努力将集中于逐步了解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。在互补的推力，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。这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需要的自偶联副产物，这对于过渡金属催化来说可能是困难的系统。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将进行催化和有机反应设计。麻省理工学院的拉多塞维奇实验室是一个理想的环境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。此外，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。