Computational Models for Reactivity and Selectivity in Transition Metal-Catalyzed Olefin Functionalization

过渡金属催化的烯烃反应是最有效的合成方法之一。 用于生物医学研究的功能化有机化合物。最近的实验进展使 用于烯烃加氢和去功能化的有前景的催化方法，它添加了一个氢和一个官能团 碳-碳双键上的基团或两个不同的官能团--原子和步骤经济 时尚。这些方法可以作为生物活性有机化合物合成的重要新平台 因为它们可以用来构建结构多样化的靶分子，使用的范围很广 配对搭档。然而，有效控制区域和立体选择性仍然是一个重大挑战 在与易得的、未活化的烯烃反应中。当前最先进的方法依赖于 筛选辅助配体、添加剂和导向基团的实验试错法。合理的催化剂设计 仍然具有挑战性，因为对这些多步骤的机制缺乏理论上的了解 催化过程和催化剂-底物相互作用的复杂性。 这项提议的总体目标是开发和应用计算工具来应对这些挑战 过渡金属催化的烯烃功能化研究进展。我们将表演高水平的 用于揭示反应机理和开发普遍适用的反应性模型的计算研究 和选择性。这些理论模型旨在提供对影响的定量和直接预测。 配体和导向基团。因此，它们可以有效地应用于各种实验系统 指导未来新型催化反应的发展。在我独立职业生涯的头三年里，我的 该小组发表了24篇手稿，重点介绍了烯烃的三种一般实验策略 官能化：(1)催化剂控制的未活化烯烃的加氢功能化；(2)氢化和氢化 利用直接基团对烯烃进行双官能化；以及(3)自由基与烯烃的反应。在 在接下来的五年里，我们计划将我们的计算研究扩展到更广泛的反应范围。我们将进一步 优化和验证我们的理论模型，以实现更可靠的反应性和选择性预测。我们 我还打算与实验小组建立更多的合作，以简化理论见解的使用 来指导实验发现。 拟议的研究方案具有重大意义和创新性，因为它旨在应对普遍的挑战。 并提供对一系列催化反应的预测，而不是简单地解释现有的 具体的实验系统。我们的研究在与许多著名的实验合作方面是非常独特的 组。这些卓有成效的合作使我们不仅在许多具体的理解上取得了进步 烯烃官能化反应的例子，也是区域和区域发展的一般规则 在这些过程中的立体选择性。

Transition metal-catalyzed reactions of alkenes are among the most powerful approaches to synthesize functionalized organic compounds for biomedical research. Recent experimental advancements have enabled promising catalytic methods for hydro- and difunctionalization of alkenes, which add a hydrogen and a functional group or two different functional groups across a carbon-carbon double bond in an atom- and step-economical fashion. These approaches can serve as an important new platform for the synthesis of biologically active organic molecules because they can be utilized to construct structurally diverse target molecules using a broad scope of coupling partners. However, it remains a significant challenge to effectively control regio- and stereoselectivity in the reactions with readily available, unactivated alkenes. The current state-of-the-art approach relies on experimental trial-and-error to screen ancillary ligands, additives, and directing groups. Rational catalyst design remains challenging, due to the lack of theoretical understanding about the mechanisms of these multistep catalytic processes and the complex nature of the catalyst-substrate interactions. The overall goal of this proposal is to develop and apply computational tools to address these challenges in the development of transition-metal-catalyzed functionalizations of alkenes. We will perform high-level computational studies to reveal the reaction mechanisms and develop generally applicable models for reactivity and selectivity. These theoretical models aim to provide quantitative and straightforward prediction of the effects of ligands and directing groups. Therefore, they can be effectively applied to various experimental systems to guide future development of new catalytic reactions. During the first three years of my independent career, my group has published 24 manuscripts that focused on three general experimental strategies for alkene functionalization: (1) catalyst-controlled hydrofunctionalization of unactivated alkenes; (2) hydro- and difunctionalization of alkenes utilizing directing groups; and (3) radical-mediated reactions with alkenes. In the next five years, we plan to expand our computational studies to a broader scope of reactions. We will further optimize and validate our theoretical models to enable more robust prediction of reactivity and selectivity. We also intend to establish more collaborations with experimental groups to streamline the use of theoretical insights to guide experimental discovery. The proposed research program is significant and innovative because it aims to address general challenges and provide predictions to a broad range of catalytic reactions, rather than to simply explain existing results for specific experimental systems. Our research is highly unique in collaborating with many prominent experimental groups. These fruitful collaborations allowed us to progress in not only the understanding of many specific examples of alkene functionalization reactions, but also the development of general rules of regio- and stereoselectivity in these processes.