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.

项目摘要/摘要 潜在药物的发现需要权宜地进入广泛的潜水员分子 建筑和医学化学家可用的化学工具既可以启用并限制这项合资企业。超过 过去半个世纪，过渡金属催化的交叉耦合已发展为有机的有力策略 合成。但是，D-Block元素的使用呈现出特定的缺点，包括可接受的低 药品中的金属含量以及对极地药物的非生产性协调的敏感性 相关官能团。这是最近对开发交叉偶联催化剂的兴趣激增 包含P块的自然丰富的主要组元素。机械理解 主要组催化剂的反应性落后于过渡金属催化剂和合成应用的反应性 保持有限。主要组催化的一种特别有希望的方法是使用P（iii）⇌P（V）氧化还原 夫妇将采用过渡金属催化剂的类似氧化还原夫妇。发展进步 用于磷氧化还原循环化学化学的双智能催化剂，对 影响催化剂性能的因素。为此，拟议的研究将采用两个 催化剂开发的不同方法：多元回归分析以相关的磷酸结构 具有所需的氧化还原特性和计算建模，以指导新型硼一类的合理设计 以及含硅的磷酸磷酸盐，具有减少的前沿轨道能隙。这些的详细研究 催化剂将为基于磷的催化剂促进碳的能力提供宝贵的见解。 杂原子债券形成，使立即医学的垂直事故反应发展 关联。 这项研究建议通过要求在 无机合成，机理研究和计算建模，以补充先前的培训 合成有机方法开发。 Radosevich实验室提供了一个理想的研究环境 适合在这些领域促进培训，这是他们开发的开创性努力 磷催化的反应。拉多塞维奇教授对支持博士后的个人承诺 研究人员将其发展为独立研究人员，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生产的研究机构之一，提供资源 以及提出的研究所需的设备。