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: 10625376
• 负责人: GREGORY C FU
• 金额: $ 96.74万
• 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/10625376
• 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.

项目总结/摘要 有机化合物合成新方法的发现， 生物医学研究，例如，通过提供对已知靶分子家族的更容易的获取或对靶分子的获取， 第一次发现了新的分子类型碳-碳、碳- 氮和碳-氧形成是特别感兴趣的，由于包括可持续性， 化合物的两种对映异构体的潜在不同生物活性，以及此类键的优势 在有机分子的骨架上。 烷基亲电试剂被亲核试剂的取代反应是特别简单的。 有机分子组装的方法。经典的取代途径，如SN 1和 SN 2反应在亲电试剂和亲核试剂的范围方面受到限制。此外，委员会认为， 这些途径几乎从未提供从容易获得的外消旋体获得高度对映体富集的产物的途径 起始材料 通过使用过渡金属催化，其中亲电试剂被转化为有机基团， 有可能开始解决烷基亲核取代反应中的两个关键挑战， 亲电试剂-更广泛的范围和对映选择性的控制。例如，手性镍和铜 配合物可以催化许多外消旋仲烷基和叔烷基的对映会聚偶联， 亲电体与各种亲核体。 到目前为止，只有一小部分的亲电和亲核伙伴的可能排列， 已经探索了烷基亲电试剂的金属催化的取代反应，并且更少的这样的方法 已经被赋予了对映选择性。这项研究计划的目标是解决许多悬而未决的问题， 这方面的挑战。努力将集中在发展温和和多功能的方法，以夫妇的家庭 亲电试剂和亲核试剂，以前没有被证明是合适的反应伴侣， 脂肪族取代反应，包括高度受阻的底物，同时控制在 同时（在多达两个立构中心），包括与缺乏外消旋亲电试剂和亲核试剂 指导组。这一奋进的成功将大大促进对映体富集的化合物的合成。 分子。 将进行机制研究，以便深入了解新金属- 进行催化的取代反应。机理研究将促进反应的发展， 以及提高社会对基本化学反应性的理解。