Metal-Catalyzed Reactions for Organic Synthesis

有机合成的金属催化反应

• 批准号: 10681940
• 负责人: MELANIE S. SANFORD
• 金额: $ 3.63万
• 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/10681940
• 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 总体而言，该程序将开发出各种新的金属催化合成方法 和生物学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，但由两个中央主题统一。首先，它重点是发展转型 这可以访问新的化学空间和/或简化现有结构的合成。第二， 拟议的工作以详细的机械分析和有机化学为指导。 一个第一个项目继续进行桑福德集团在开发新方法的碳 - 氢键功能化。该领域的传统方法重点是发现高度选择性 对催化剂，底物和反应条件进行量身定制以转换单个特定C – H的反应 结合成一个新的功能组。尽管成功，但这种方法受到不成比例的关注 相关的简单基板，仅包含一个“反应性” C – H位点。拟议的努力将有助于 通过靶向反应，将单个起始材料转换为多个C – H来转移此范式 功能化产品。这将提供对医疗备受兴趣的新结构的访问 化学。此外，它将提供有关负责反应性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。 第二个项目将针对新的金属催化交叉耦合反应的发展。值得注意的是， 耦合是有机合成中最广泛使用的转换之一。拟议的努力提出了 统一的方法针对与现代交叉耦合方法相关的三个核心挑战：（1）使用 绝对的羧酸衍生的电力作为耦合伴侣； （2）消除要求 添加了基础； （3）形成新型键的反应的发明，重点是引入氟 包含在医学化学中具有很高价值的官能团。这三个目标将完成 通过共同的机械基础以整合的方式进行。 第三个项目利用了桑福德集团在机械化学方面的专业知识，机械分析， 和催化反应的发展，以识别和应对有机合成中新兴的挑战。 SF5- 作为整合到药物的实体，取代（杂种）芳香环正在越来越重要 候选人。但是，尽管该功能群的重要性越来越重要，但合成方法用于访问 芳基-SF5衍生物仍然极为有限。该提议概述了综合和 金属– SF5复合物的反应性（目前是前所未有的物种）。然后将使用这些研究 驱动催化芳基-SF5偶联反应的发展。