Metal-Catalyzed Reactions for Organic Synthesis

有机合成的金属催化反应

基本信息

批准号：
10350651
负责人：
MELANIE S. SANFORD
金额：
$ 37.74万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

项目摘要

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.

项目概要总体而言，该计划将开发多种新的金属催化合成方法用于构建以及生物相关分子的后期多样化。拟议的工作涵盖许多不同的内容。化学反应的类型，但由两个中心主题统一，首先，它侧重于发展转变。提供新的化学空间和/或简化现有结构的合成。拟议的努力以详细的机理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碳新方法方面的长期努力—— 该领域的传统方法侧重于发现高度选择性的氢键功能化。反应，其中催化剂、底物和反应条件经过定制以转化单个特定的 C–H 虽然成功，但这种方法受到过分关注的限制。相对简单的底物仅包含一个“反应性”C-H 位点，所提出的努力将有助于这一点。通过将单一起始材料转化为多个 C-H 的靶向反应来改变这种范式这将为医学界高度关注的新结构提供机会。此外，它将提供有关反应性因素的大量机械数据。和选择性，将用于推动下一代催化剂设计和新反应发现。第二个项目将致力于开发新的金属催化交叉偶联反应。偶联是有机合成中最广泛使用的转化之一。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）使用丰富的羧酸衍生的亲电子试剂作为偶联配偶体；(2)消除了对添加碱；以及（3）形成新型键的反应的发明，重点是引入氟- 含有在药物化学中具有高价值的官能团这三个目标都将实现。通过通用的机械基础以集成的方式。第三个项目利用了桑福德集团在有机金属化学、机械分析、和催化反应开发，以确定和解决有机合成中的新挑战。取代的（杂）芳环作为整合到药物中的实体越来越受到重视然而，尽管该功能组的重要性日益增加，但用于访问的合成方法仍然存在。该提案概述了芳基-SF5 衍生物的合成和基础研究。然后将使用金属-SF5 络合物（目前前所未有的物种）的反应性。推动催化芳基-SF5偶联反应的发展。