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: 9213619
• 负责人: Scott J Miller
• 金额: $ 48万
• 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/9213619
• 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： 高效生产手性非外消旋化合物的能力对医药化学和生物化学都至关重要。 和药物合成的过程化学方面。虽然大量有用的反应 现在已经存在，需要更多的人来更彻底地进入化学空间。发展新 反应往往需要大量的经验筛选，以达到理想的结果， 反应产率和立体异构体纯度。因此，我们通过合作努力， 一种综合的流线型催化剂优化方法。我们将解决一个关键问题， 可以“设计”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 互动，产生具体的结果。仔细的，经典的机械研究揭示了 反应的机械步骤将与现代物理有机参数化/建模相结合 Sigman集团开发的技术。这些策略的结合将指导催化剂的设计， 反应范围的探索。不对称催化领域已经认识到， 弱的非共价相互作用在无数的对映选择性反应中是关键的。的统一特征， 这个项目的目的是一个框架，了解这些力量，因为他们最终在高效和高度 选择性催化阐明了有机金属催化剂可以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 不同的不对称催化模式。第一个目标是集中在手性阴离子催化，其中非- 不对称催化的共价相互作用历来难以定义， 询问底物/催化剂接触的复杂性。我们将开发新技术， Sigman小组通过Toste/Sigman和米勒/Sigman实验室之前的合作研究提供帮助 这允许发现数学关系，将基质和催化剂结构与物理性质相关联， 有机测量这种方法不仅允许有效的预测，从而设计更好的 催化剂，但也提供了一个当代的，数据密集型的方法，机械研究。在 第二个目标，我们增加了复杂性，通过评估有机金属反应结合手性 阴离子催化（有时具有两个手性元素），以开发一系列新的烯烃双官能化 Toste和Sigman实验室都已经启动了反应。在最后的目标，我们问问题， 与在小环境中具有基质和催化剂的更大动态方面的系统有关。 在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 技术以及潜在的影响定向进化和酶催化剂设计的广泛领域。