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

过渡金属催化的烯烃反应是合成多环芳烃的最有效的方法之一 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 烯烃加氢和双官能化的有前途的催化方法，其添加氢和官能基， 基团或两个不同的官能团跨碳-碳双键在一个原子-和步骤-经济 时尚.这些方法可以作为一个重要的新平台，为生物活性的有机合成 分子，因为它们可用于使用广泛的免疫调节剂构建结构多样的靶分子。 伴侣然而，有效控制区域和立体选择性仍然是一个重大挑战 在与容易获得的未活化的烯烃的反应中。目前最先进的方法依赖于 实验试错法来筛选辅助配体、添加剂和导向基团。合理的催化剂设计 仍然具有挑战性，由于缺乏对这些多步骤机制的理论理解， 催化过程和催化剂-底物相互作用的复杂性质。 这项提案的总体目标是开发和应用计算工具，以解决这些挑战， 过渡金属催化烯烃官能化反应的发展。我们将执行高水平 计算研究，以揭示反应机制，并开发普遍适用的反应模型 和选择性。这些理论模型旨在提供定量和直接的预测效果 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， 指导未来新催化反应的发展。在我独立工作的头三年里， 该小组已经发表了24篇论文，重点是烯烃的三种一般实验策略 官能化：（1）未活化烯烃的催化剂控制的加氢官能化;（2）加氢和 利用导向基团的烯烃的双官能化;和（3）与烯烃的自由基介导的反应。在 未来五年，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，以实现更稳健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 拟议的研究计划是重要的和创新的，因为它旨在解决一般的挑战 并为广泛的催化反应提供预测，而不是简单地解释现有的结果， 具体的实验系统。我们的研究是非常独特的合作与许多著名的实验 组这些富有成效的合作使我们不仅在理解许多具体的 烯烃官能化反应的例子，而且区域和 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.