Metal-Catalyzed Nucleophilic Substitution Reactions of Alkyl Electrophiles

金属催化烷基亲电试剂的亲核取代反应

• 批准号: 10406704
• 负责人: GREGORY C FU
• 金额: $ 66.09万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406704
• 关键词: Address; Area; Biochemistry; Bioinorganic Chemistry; Biology; Biomedical Research; Carbohydrates; Carbon; Catalysis; Chemicals; Communities; Complex; Copper; Coupling; DNA; Development; Discipline; Family; Goals; Handedness; Investigation; Life; Metals; Methods; Nickel; Nitrogen; Organic Chemistry; Organic Synthesis; Oxygen; Pathway interactions; Peptides; Pharmaceutical Chemistry; Process; RNA; Reaction; Research; Time; Transition Elements; Vertebral column; enantiomer; insight; interest; nucleophilic substitution; programs; success

PROJECT SUMMARY / ABSTRACT The discovery of powerful new methods for the synthesis of organic compounds can be enabling for biomedical research, e.g., by providing more ready access to known families of target molecules or access for the first time to new classes of molecules. Catalytic and enantioselective methods for carbon–carbon, carbon– nitrogen, and carbon–oxygen formation are of particular interest, due to issues including sustainability, the potentially divergent bioactivity of the two enantiomers of a compound, and the predominance of such bonds in the backbone of organic molecules, respectively. The substitution reaction of an alkyl electrophile by a nucleophile is a particularly straightforward approach to the assembly of organic molecules. Classical pathways for substitution, such as the SN1 and the SN2 reactions, are limited in scope with respect to both the electrophile and the nucleophile. Furthermore, these pathways almost never provide access to highly enantioenriched products from readily available racemic starting materials. Through the use of transition-metal catalysis, wherein the electrophile is converted into an organic radical, it is possible to begin to address both of the key challenges in nucleophilic substitution reactions of alkyl electrophiles–broader scope and control of enantioselectivity. For example, chiral nickel and copper complexes can catalyze the enantioconvergent coupling of a number of racemic secondary and tertiary alkyl electrophiles with a variety of nucleophiles. To date, only a small fraction of the conceivable permutations of electrophilic and nucleophilic partners for metal-catalyzed substitution reactions of alkyl electrophiles have been explored, and still fewer such processes have been rendered enantioselective. The goal of this research program is to address the many unsolved challenges in this area. Efforts will focus on the development of mild and versatile methods to couple families of electrophiles and nucleophiles that have not previously been shown to be suitable reaction partners in aliphatic substitution reactions, including highly hindered substrates, while controlling stereoselectivity at the same time (at up to two stereocenters), including with racemic electrophiles and nucleophiles that lack directing groups. Success in this endeavor will substantially facilitate the synthesis of enantioenriched molecules. Mechanistic studies will be pursued in order to provide insight into the pathways by which the new metal- catalyzed substitution reactions proceed. The mechanistic investigations will facilitate reaction development, as well as enhance the community’s understanding of fundamental chemical reactivity.

项目摘要 /摘要 发现有机化合物合成的强大新方法可以实现 生物医学研究，例如，通过为靶标分子的已知家庭提供更多的访问或访问权限的访问 首次进入新的分子。碳 - 碳，碳 - 的催化和对映选择性方法 由于可持续性，包括可持续性， 化合物的两个对映异构体的潜在发散生物活性，并且这种键的优势 在有机分子的骨架中。 通过核雾化的烷基电力的替代反应是一个特别简单的 有机分子组装的方法。替代的古典途径，例如SN1和 SN2反应在相对于电力和核腓杆菌的范围受到限制。此外， 这些途径几乎永远无法从随时可用的外星人中提供高度映射的产品 起始材料。 通过使用过渡金属催化，其中电油被转化为有机自由基， 有可能开始解决核心替代反应的两个关键挑战 亲电器 - 范围的范围和对映选择性的控制。例如，手性镍和铜 复合物可以催化许多外星二级和第三级烷基的对映体耦合 带有各种核粉状的电力。 迄今 已经探索了饮酒的金属催化的替代反应，此类过程仍然很少 已被赋予对映选择性。该研究计划的目的是解决许多未解决的问题 这一领域的挑战。努力将重点介绍为夫妻家庭的轻度和通用方法的发展 以前尚未证明是在 脂肪族替代反应，包括高度阻碍的底物，同时控制着立体选择性 同一时间（最多两个立体中心），包括缺乏的外星电力和亲核器 导演组。这项努力的成功将基本上支持对映体的合成 分子。 将进行机械研究，以便深入了解新金属的途径 催化的替代反应进行。机械研究将促进反应发展， 以及增强社区对基本化学反应性的理解。