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

通过计算建模和多维分析开发新型双亲磷催化剂

• 批准号: 10536911
• 负责人: Marissa Nicole Lavagnino
• 金额: $ 6.68万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2025-08-16
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536911
• 关键词: Affect; Amination; Architecture; Area; Boron; Bromides; Carbon; Catalysis; Chemicals; Chemistry; Complement; Complex; Computer Models; Couples; Coupling; Data; Development; Disadvantaged; Elements; Ensure; Environment; Equipment; Exhibits; Fellowship; Generations; Glean; Goals; Institution; Investigation; Libraries; Linear Regressions; Metals; Methodology; Methods; Modification; Molecular; Organic Synthesis; Oxidation-Reduction; Performance; Periodicity; Pharmaceutical Chemistry; Pharmacologic Substance; Phosphorus; Positioning Attribute; Predisposition; Process; Property; Reaction; Regression Analysis; Research; Research Personnel; Research Proposals; Resources; Silicon; Structure; Structure-Activity Relationship; Study models; Technology; Testing; Training; Transition Elements; base; catalyst; design; drug discovery; frontier; functional group; improved; insight; interest; method development; novel; rational design; scaffold; skills; small molecule; tool

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.

项目概要/摘要 有效药剂的发现需要方便地获得各种不同的分子 建筑和药物化学家可用的化学工具既促进又限制了这一冒险。 在过去的半个世纪中，过渡金属催化的交叉偶联已发展成为有机合成的强大策略。 然而，d区元素的使用存在特定的缺点，包括可接受性低。 药品中的金属含量以及极性药物对非生产性配位的敏感性 因此，最近人们对开发交叉偶联催化剂的兴趣激增。 包含天然丰富的 p 区主族元素的机理理解。 主族催化剂的反应活性远远落后于过渡金属催化剂及其合成应用 一种特别有前景的主基团催化方法是利用 P(III)⇌P(V) 氧化还原。 一对作为一个整体将使用类似的过渡金属催化剂的氧化还原对来开发改进的催化剂。 用于磷氧化还原循环化学的双亲催化剂，对磷氧化还原循环化学有更完整的机理理解 为此，有必要研究影响催化剂性能的因素。 催化剂开发的独特方法：关联磷杂环丁烷结构的多元回归分析 具有所需的氧化还原性质和计算模型来指导一类新型硼的合理设计 以及具有减小的前沿轨道能隙的含硅磷烷。对这些的详细研究。 催化剂将为磷基催化剂促进碳的能力提供有价值的见解 杂原子键的形成，使直接药用的烯丙基胺化反应得以发展 关联。 该研究提案通过要求学习新技能来支持并符合奖学金目标 无机合成、机理研究和计算建模，补充了之前的培训 拉多塞维奇实验室提供了独特的理想研究环境。 适合促进这些领域的培训，他们在开发 拉多塞维奇教授个人对支持博士后的承诺。 研究人员在发展成为独立研究者的过程中确保专业培训目标 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，提供了资源。 以及进行拟议研究所需的设备。