Metal-Catalyzed Reactions for Organic Synthesis

有机合成的金属催化反应

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10350651
• 关键词: Address; Area; Carbon; Carboxylic Acids; Chemicals; Complex; Coupling; Data; Development; Fluorine; Foundations; Goals; Hydrogen Bonding; Metals; Methods; Modernization; Organic Chemistry; Organic Synthesis; Organometallic Chemistry; Pharmaceutical Chemistry; Reaction; Site; Structure; Transition Elements; Work; base; catalyst; chemical reaction; design; drug candidate; functional group; interest; invention; method development; next generation; novel strategies; programs

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.

项目摘要 总的来说，本计划将开发多种新型金属催化合成方法用于构建 以及后期生物相关分子的多样化。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。一是注重发展转型 其提供了进入新化学空间的途径和/或简化了现有结构的合成。第二、 所提出的努力是由详细的机理分析和有机金属化学指导的。 第一个项目延续了桑福德集团在开发碳排放新方法方面的长期努力， 氢键功能化。这一领域的传统方法侧重于发现高度选择性的 反应，其中催化剂、底物和反应条件被定制以将单个特定的C-H 结合成一个新的官能团。虽然这种方法是成功的，但由于过分注重 相对简单的底物，仅含有一个“反应性”C-H位点。拟议的努力将有助于 通过靶向反应来改变这种模式，在该反应中，单一的起始材料被转化为多个C-H 功能化产品。这将提供获得新结构的机会，这些结构在医学上具有高度的兴趣。 化学.此外，它还将提供大量有关反应性因素的机械数据 和选择性，将用于推动下一代催化剂的设计和新的反应发现。 第二个项目的目标是开发新的金属催化交叉偶联反应。特别是，交叉- 偶联是有机合成中最广泛使用的转化之一。拟议的努力提出了一个 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体作为偶联配偶体;（2）消除对 添加碱;（3）发明形成新型键的反应，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 通过共同的机械基础以集成的方式。 第三个项目利用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出现的挑战。SF5- 取代的（杂）芳族环作为整合到药物中的实体越来越重要 候选人然而，尽管这一官能团的重要性日益增加，但用于获得 芳基-SF 5衍生物仍然极其有限。本提案概述了关于综合和 金属-SF 5络合物的反应性（目前前所未有的物种）。这些研究将用于 以推动芳基-SF 5催化偶联反应的发展。