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 合成有机化合物的强大新方法的发现可以使 生物医学研究，例如，通过提供更容易访问已知的靶分子家族或访问 第一次发现了新的分子类别。碳-碳、碳-碳-碳的催化和对映选择性方法 由于可持续性等问题，氮和碳-氧的形成特别令人感兴趣 化合物的两个对映体的潜在不同生物活性以及这种键的优势 分别在有机分子的主干中。 亲核剂取代亲烷基是一种特别简单的反应。 有机分子组装的方法。经典的替代途径，如SN1和 SN2反应，对于亲核性和亲核性都是有限的。此外， 这些途径几乎从不提供从现成的外消旋中获得高对映体富集物的途径。 起始材料。 通过使用过渡金属催化，其中亲水性被转化为有机自由基， 有可能开始解决烷基的亲核取代反应中的两个关键挑战。 亲电剂.对映体选择性的更广泛的范围和控制例如，手性镍和铜 配合物可以催化一些外消旋仲烷和叔烷的对映体聚合偶联。 与各种亲核试剂的亲电性。 到目前为止，只有一小部分可以想象到的亲电和亲核伙伴的排列 金属催化的烷基亲电取代反应已经被探索过，但这样的过程更少。 已经被赋予了对映体选择性。这个研究计划的目标是解决许多悬而未决的问题 这一领域的挑战。努力将重点放在开发温和而多样的家庭配对方法上 以前没有被证明是合适的反应伙伴的亲电性和亲核性 脂肪取代反应，包括高度受阻的底物，同时控制立体选择性 同时(最多在两个立体中心)，包括外消旋亲电体和亲核体 导演团。这一努力的成功将大大促进富对映体的合成。 分子。 将继续进行机械研究，以深入了解这种新金属- 催化的取代反应继续进行。机理研究将促进反应的发展， 以及加强社区对基本化学反应的了解。