Using Numerical Analysis Tools to Design and Study Chiral Catalysts

使用数值分析工具设计和研究手性催化剂

基本信息

批准号：
9402626
负责人：
Scott J Miller
金额：
$ 46.32万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9402626
关键词：
Address Adopted Alkenes Anions Biological Boronic Acids Catalysis Chemicals Chemistry Communities Complex Data Data Analyses Development Directed Molecular Evolution Elements Enzymes Fluorine Goals Kinetics Knowledge Lead Ligands Mathematics Measurement Medical Methodology Modeling Modernization Outcome Oxazolone Peptides Pharmacologic Substance Phenols Play Process Reaction Research Resolution Role Site Structure System Techniques Testing base catalyst design flexibility improved inorganic phosphate insight mathematical model metal complex new technology programs screening skills small molecule tool

Address Adopted Alkenes Anions Biological Boronic Acids Catalysis Chemicals Chemistry Communities Complex Data Data Analyses Development Directed Molecular Evolution Elements Enzymes Fluorine Goals Kinetics Knowledge Lead Ligands Mathematics Measurement Medical Methodology Modeling Modernization Outcome Oxazolone Peptides Pharmacologic Substance Phenols Play Process Reaction Research Resolution Role Site Structure System Techniques Testing base catalyst design flexibility improved inorganic phosphate insight mathematical model metal complex new technology programs screening skills small molecule tool

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项目摘要

Project Summary: The ability to produce chiral, non-racemic compounds efficiently is central to both the medical chemistry and process chemistry aspects of pharmaceutical synthesis. While a substantial number of useful reactions now exist, many more are needed to more thoroughly access chemical space. The development of new reactions often requires significant empirical screening to achieve a desirable outcome in terms of both reaction yield and stereoisomeric purity. Therefore we are targeting, through a collaborative effort, a comprehensive approach to streamline catalyst optimization. We will address the essential question of how one might “design” an asymmetric catalyst. Our proposed plan explores how catalyst and substrate structure interact to produce specific outcomes. Careful, classical mechanistic studies that reveal the fundamental mechanistic steps of reactions will be combined with modern physical organic parameterization/modeling techniques developed in the Sigman Group. The combination of these strategies will guide catalyst design and exploration of reaction scope. The field of asymmetric catalysis has come to recognize that the accumulation of weak, noncovalent interactions is critical in a myriad of enantioselective reactions. The unifying feature of the Aims of this project is a framework for understanding these forces as they culminate in efficient and highly selective catalysis. The elucidation of catalyst design strategies that can be adopted by the organometallic, organic and biological communities is our goal. In this context, the three Aims of the proposal evaluate three diverse modes of asymmetric catalysis. The first aim is focused on chiral anion catalysis where the non- covalent interactions responsible for asymmetric catalysis have been historically difficult to define due to the complexity of interrogating the substrate/catalyst contacts. We will exploit new technology developed in the Sigman group aided through previous collaborative studies between the Toste/Sigman and Miller/Sigman labs that allow mathematical relationships to be discovered, relating substrate and catalyst structure to physical organic measurements. This methodology not only allows for effective prediction, and thus the design of better performing catalysts, but also provides a contemporary, data-intensive approach to mechanistic study. In the second aim, we increase the complexity by evaluating organometallic reactions in combination with chiral anion catalysis (sometimes with two chiral elements) to develop a portfolio of new alkene difuntionalization reactions that have been initiated within both the Toste and Sigman labs. In the final aim, we ask questions pertaining to systems with greater dynamic aspects of both substrate and catalyst in the context of small peptide-catalyzed processes studied in the Miller lab. These efforts will test the limits of the modeling techniques as well as potentially impact the broad fields of directed evolution and enzyme catalyst design.

项目摘要：有效产生手性的非流行化合物的能力对于两种医学化学都是至关重要的和药物合成的过程化学方面。而大量有用的反应现在存在，还需要更多才能更彻底地进入化学空间。新的发展反应通常需要大量的经验筛查，以实现这两者的理想结果反应产量和立体异构体纯度。因此，我们通过协作的努力来瞄准简化催化剂优化的综合方法。我们将解决一个基本问题可能会“设计”不对称的催化剂。我们提出的计划探讨了催化剂和底物结构如何相互作用以产生特定的结果。谨慎，经典的机械研究揭示了基本的反应的机械步骤将与现代物理有机参数化/建模相结合 Sigman Group开发的技术。这些策略的结合将指导催化剂设计和反应范围的探索。不对称催化的领域已经认识到在无数的对映选择性反应中，弱，非共价相互作用至关重要。统一功能的功能该项目的目的是理解这些力量的框架，因为它们高效且高度高度选择性催化。阐明器官可采用的催化剂设计策略，有机和生物社区是我们的目标。在这种情况下，提案的三个目标评估了三个不同的不对称催化模式。第一个目的是专注于手性阴离子催化在历史上，由于历史上难以定义，负责不对称催化的共价相互作用。询问底物/催化剂触点的复杂性。我们将利用在 Sigman Group通过Toste/Sigman和Miller/Sigman Labs之间的以前的合作研究协助可以发现数学关系，将底物和催化剂结构与物理联系起来有机测量。这种方法不仅允许进行有效的预测，从而设计更好执行催化剂，但还提供了一种当代的，数据密集型的机械研究方法。在第二个目的，我们通过评估有机反应与手性相结合来增加复杂性阴离子催化（有时具有两个手性元素），以发展新的烷烃差异化投资组合在Toste和Sigman Labs中启动的反应。在最终目标中，我们提出问题与在小的背景下具有更大动态方面的系统有关的系统米勒实验室中的肽催化过程研究。这些努力将测试建模的限制技术以及有可能影响定向进化和酶催化剂设计的广泛领域。