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

• 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
• 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

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.

项目概要： 有效生产手性、非外消旋化合物的能力是医学化学的核心 和药物合成的过程化学方面。虽然有大量有用的反应 现在已经存在，还需要更多的东西来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选才能在两方面达到理想的结果 反应产率和立体异构体纯度。因此，我们的目标是通过共同努力， 简化催化剂优化的综合方法。我们将解决一个基本问题：如何 人们可以“设计”一种不对称催化剂。我们提出的计划探讨了催化剂和基质结构如何 相互作用以产生特定的结果。仔细、经典的机制研究揭示了基本原理 反应的机械步骤将与现代物理有机参数化/建模相结合 西格曼集团开发的技术。这些策略的结合将指导催化剂设计和 探索反应范围。不对称催化领域已经认识到， 弱的非共价相互作用在许多对映选择性反应中至关重要。的统一特征 该项目的目标是建立一个框架来理解这些力量，因为它们最终会产生高效和高度的影响。 选择性催化。阐明有机金属可采用的催化剂设计策略， 有机和生物社区是我们的目标。在此背景下，该提案的三个目标评估了三个 多种不对称催化模式。第一个目标是关注手性阴离子催化，其中非 负责不对称催化的共价相互作用历来难以定义，因为 询问底物/催化剂接触的复杂性。我们将利用在该领域开发的新技术 西格曼小组协助托斯特/西格曼和米勒/西格曼实验室之前的合作研究 允许发现数学关系，将底物和催化剂结构与物理联系起来 有机测量。这种方法不仅可以进行有效的预测，从而可以设计出更好的 发挥催化剂的作用，而且还提供了一种现代的、数据密集型的机制研究方法。在 第二个目标，我们通过结合手性评估有机金属反应来增加复杂性 阴离子催化（有时具有两个手性元素）以开发新的烯烃二官能化组合 Toste 和 Sigman 实验室均已发起反应。在最终目标中，我们提出问题 涉及在小规模背景下具有更大动态方面的底物和催化剂的系统 米勒实验室研究的肽催化过程。这些努力将测试建模的极限 技术以及潜在影响定向进化和酶催化剂设计的广泛领域。