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

项目总结/摘要 有效药剂的发现需要方便地获得广泛的不同分子， 架构和药物化学家可用的化学工具既允许又限制了这种冒险。超过 在过去的半个世纪中，过渡金属催化的交叉偶联已经发展成为有机合成的一种强有力的策略。 合成.然而，d区元件的使用呈现出特定的缺点，包括可接受的低性能。 医药产品中的金属含量和对极性医药产品的非生产性配位的敏感性- 相关职能部门。因此，最近对开发交叉偶联催化剂的兴趣激增 含有P区天然丰富的主族元素。机械理解 主族催化剂的反应活性远远落后于过渡金属催化剂， 仍然有限。一种特别有前途的主基催化方法是利用P（III）→ P（V）氧化还原反应 电对如同人们将使用过渡金属催化剂的类似氧化还原电对。开发改进的 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个 催化剂开发的不同方法：用多元回归分析关联磷杂环丁烷结构 具有所需的氧化还原性能，并计算建模，以指导合理设计的一类新的硼， 和前线轨道能隙减小的含硅磷杂环丁烷。详细研究这些 催化剂将为磷基催化剂促进碳- 杂原子键的形成，使得能够发展直接药用化合物的烯丙基胺化反应， 本案无关 这项研究提案支持并符合奖学金的目标，要求在学习中学习新的技能。 无机合成，机械研究和计算建模，补充了以前的培训， 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， 这些国家在发展 磷催化反应Radosevich教授个人致力于支持博士后 研究人员在他们的发展成为独立的调查，确保专业培训目标将 实现。最后，麻省理工学院作为世界上最富有成效的研究机构之一， 以及进行所提议的研究所需的设备。

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.