Using Numerical Analysis Tools to Design and Study Chiral Catalysts

项目总结： 高效地产生手性、非外消旋化合物的能力是医学化学的核心 以及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，还需要更多的才能更彻底地进入化学空间。新技术的发展 反应通常需要大量的经验性筛选，才能在这两个方面达到理想的结果 反应产率和立体异构体纯度。因此，通过合作努力，我们的目标是 优化催化剂的综合方法。我们将解决基本问题，即如何 人们可以“设计”一种不对称催化剂。我们提出的计划探索了催化剂和底物结构 相互作用以产生特定的结果。仔细的、经典的机械学研究揭示了 反应的机械化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 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至关重要的。的统一功能 这个项目的目标是一个框架，用于理解这些力量在它们最终以高效和高度 选择性催化。阐述了金属有机化合物可采用的催化剂设计策略， 有机和生物群落是我们的目标。在这方面，该提案的三个目标评估了三个 不对称催化的多种模式。第一个目标是手性阴离子催化，其中非 导致不对称催化的共价相互作用在历史上很难定义，因为 询问底物/催化剂接触的复杂性。我们将利用新开发的技术 Sigman小组通过Toste/Sigman和Miller/Sigman实验室之前的合作研究提供帮助 允许发现数学关系，将底物和催化剂结构与物理结构联系起来 有机测量。这种方法论不仅可以进行有效的预测，从而设计出更好的 执行催化剂，但也提供了一种当代的，数据密集型的机制研究方法。在 第二个目的，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(有时带有两个手性元素)以开发一系列新的烯烃去功能化 在Toste和Sigman实验室内已经启动的反应。在最终目标中，我们提出问题 用于修饰或说明在小范围内底物和催化剂都具有较大动态特性的系统。 在米勒实验室研究的多肽催化过程。这些努力将考验建模的局限性 技术以及潜在地影响定向进化和酶催化剂设计的广泛领域。

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.