Metal-Catalyzed Reactions for Organic Synthesis

项目总结 总体而言，该计划将开发各种新的金属催化合成方法用于建筑 以及生物相关分子的后期多样化。拟议的工作包括许多不同的 化学反应的类型，但由两个中心主题统一。首先，它专注于开发转型 提供进入新的化学空间和/或简化现有结构的合成。第二, 所提出的努力以详细的机械分析和有机金属化学为指导。 第一个项目延续了桑福德集团在开发新的碳排放方法方面的长期努力- 氢键官能化。这一领域的传统方法侧重于发现具有高度选择性的 反应，其中催化剂、底物和反应条件被调整以转化单一的、特定的C-H 结成一个新的功能团体。尽管取得了成功，但这种方法受到过度关注于 相对简单的底物，只含有一个“活性”C-H位。拟议的努力将有助于 通过靶向反应改变这种模式，在这种反应中，单一的起始材料被转化为多个C-H 功能化产品。这将提供进入对药物高度感兴趣的新结构的途径 化学反应。此外，它还将提供有关导致反应性的因素的大量机械数据。 以及将用于推动下一代催化剂设计和新反应发现的选择性。 第二个项目的目标是开发新的金属催化的交叉偶联反应。值得注意的是，交叉- 偶联反应是有机合成中应用最广泛的转化反应之一。拟议的努力提出了 针对与现代交叉耦合方法相关的三个核心挑战的统一方法：(1)使用 以丰富的羧酸衍生的亲电体作为偶联伙伴；(2)取消 增加的碱；以及(3)形成新型键的反应的发明，重点是引入氟- 含有在药物化学中有很高价值的官能团的。这三个目标都将实现 通过共同的机制基础以一种综合的方式。 第三个项目利用了桑福德集团在有机金属化学、机械分析、 和催化反应的发展，以确定和解决有机合成中的一个新挑战。SF5- 取代(杂环)芳环作为药物集成的实体正变得越来越重要 候选人。然而，尽管这个官能团的重要性与日俱增，但用于获得 芳基-SF5衍生物仍然极其有限。该提案概述了合成和合成的基础研究 金属-SF5络合物(目前史无前例的物种)的反应性。然后这些研究将被使用 推动芳基-SF5催化偶联反应的发展。

PROJECT SUMMARY Overall, this program will develop a variety of new metal-catalyzed synthetic methods for the construction and late-stage diversification of biologically relevant molecules. The proposed work encompasses many different types of chemical reactions but is unified by two central themes. First, it focuses on developing transformations that provide access to new chemical space and/or that streamline the synthesis of existing structures. Second, the proposed efforts are guided by detailed mechanistic analysis and organometallic chemistry. A first project continues the Sanford group's long-standing efforts in developing new approaches to carbon– hydrogen bond functionalization. The traditional approach in this area focuses on the discovery of highly selective reactions, in which the catalyst, substrate, and reaction conditions are tailored to convert a single, specific C–H bond into a new functional group. While successful, this approach is limited by a disproportionate focus on relatively simple substrates that contain only one “reactive” C–H site. The proposed efforts will contribute to shifting this paradigm by targeting reactions in which a single starting material is converted into multiple C–H functionalization products. This will provide access to new structures that are of high interest in medicinal chemistry. Additionally, it will provide a wealth of mechanistic data about the factors responsible for reactivity and selectivity that will be used to drive next-generation catalyst design and new reaction discovery. A second project will target the development of new metal-catalyzed cross coupling reactions. Notably, cross- coupling is among the most widely used transformations in organic synthesis. The proposed efforts present a unified approach to target three central challenges associated with modern cross-coupling methods: (1) the use of abundant carboxylic acid-derived electrophiles as coupling partners; (2) elimination of the requirement for added base; and (3) the invention of reactions that form new types of bonds, with a focus on introducing fluorine- containing functional groups that are of high value in medicinal chemistry. All three goals will be accomplished in an integrated fashion via a common mechanistic foundation. A third project leverages the Sanford group's expertise in organometallic chemistry, mechanistic analysis, and catalytic reaction development to identify and tackle an emerging challenge in organic synthesis. SF5- substituted (hetero)aromatic rings are gaining increasing prominence as entities for integration into drug candidates. However, despite the growing significance of this functional group, synthetic methods for accessing aryl–SF5 derivatives remain extremely limited. This proposal outlines fundamental studies of the synthesis and reactivity of metal–SF5 complexes (species that are currently unprecedented). These studies will then be used to drive the development of catalytic aryl–SF5 coupling reactions.