Development of Novel Biphilic Phosphorus Catalysts via Computational Modeling and Multidimensional Analysis

项目摘要/摘要 发现有效的药物需要方便地接触到各种不同的分子。 建筑，以及药物化学家可用的化学工具，都支持和限制了这种冒险。完毕 在过去的半个世纪里，过渡金属催化的交叉偶联已经发展成为一种强有力的有机策略 综合。然而，d块元件的使用存在特定的缺点，包括可接受性低 药物中的金属含量和药物极性对非生产性配位的敏感性- 有关的功能组别。因此，最近人们对开发交叉偶联催化剂的兴趣激增 含有p-块的天然丰富的主族元素。从机械论的角度理解 主族催化剂的反应活性远远落后于过渡金属催化剂和合成应用 仍然是有限的。一种特别有希望的主基催化方法是利用P(III)⇌P(V)氧化还原 合二为一将使用类似的过渡金属催化剂的氧化还原对。开发改进后的产品 用于磷氧化还原循环化学的双亲催化剂，更完整的机理理解 影响催化剂性能的因素是必要的。为此，拟议的研究将采用两项 催化剂开发的不同方法：用多元回归分析关联磷烷结构 具有所需的氧化还原特性和计算模型，以指导一类新型硼的合理设计- 以及前线轨道能隙减小的含硅膦烷。对这些的详细研究 催化剂将为磷基催化剂促进碳转化的能力提供有价值的见解。 杂原子键的形成，使立即药物的烯丙胺化反应得以发展 关联性。 本研究计划通过要求学习新技能来支持并与奖学金目标保持一致 无机合成、机理研究和计算建模是对以前培训的补充 有机合成方法的发展。Radosevich实验室提供了一个理想的研究环境 适合于促进这些领域的培训，这从他们在开发 磷催化的反应。拉多塞维奇教授个人对博士后支持的承诺 研究人员在发展成为独立调查人员的过程中，确保了专业培训目标将 才能实现。最后，麻省理工学院作为世界上最具生产力的研究机构之一，提供了 并提出了开展研究所需的设备。

PROJECT SUMMARY/ABSTRACT The discovery of potent pharmaceutical agents requires expedient access to a wide range of diverse molecular architectures, and the chemical tools available to the medicinal chemist both enable and limit this venture. Over the past half century, transition metal-catalyzed cross-coupling has grown into a powerful strategy for organic synthesis. However, the use of the d-block elements presents specific disadvantages, including low acceptable metal content in pharmaceutical products and susceptibility to unproductive coordination by polar medicinally- relevant functional groups. Thus, there has been a recent surge in interest in developing cross-coupling catalysts containing the naturally abundant main group elements of the p-block. Mechanistic understanding of the reactivity of main group catalysts lags far behind that of transition metal catalysts, and synthetic applications remain limited. One particularly promising approach for main group catalysis is to utilize the P(III)⇌P(V) redox couple as one would employ the analogous redox couples of transition metal catalysts. To develop improved biphilic catalysts for phosphorus redox cycling chemistry, a more complete mechanistic understanding of the factors affecting catalyst performance is necessary. Towards this end, the proposed research will employ two distinct approaches to catalyst development: multivariate regression analysis to correlate phosphetane structure with desired redox properties, and computational modeling to guide the rational design of a novel class of boron- and silicon-containing phosphetanes with reduced frontier orbital energy gaps. The detailed study of these catalysts will provide valuable insights into the ability of phosphorus-based catalysts to facilitate carbon- heteroatom bond formation, enabling the development of an allylic amination reaction of immediate medicinal relevance. This research proposal supports and aligns with the fellowship goals by requiring new skills to be learned in inorganic synthesis, mechanistic study, and computational modeling that complement previous training in synthetic organic methods development. The Radosevich lab provides an ideal research environment uniquely suited to facilitate training in these areas, as evidenced by their pioneering efforts in the development of phosphorus-catalyzed reactions. Prof. Radosevich’s personal commitment to supporting postdoctoral researchers in their development into independent investigators ensures that the professional training goals will be achieved. Lastly, MIT, as one of the most productive research institutions in the world, provides the resources and equipment necessary to carry out the research proposed.