Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles

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用于碳-碳形成的催化和对映选择性方法 由于包括可持续性、两者的潜在不同生物活性等问题， 化合物的对映异构体，以及有机化合物主链中碳-碳键的优势 分子。 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 最近已经确定，通过经由过渡金属催化的取代反应， 途径，其中有机基团作为关键中间体，有可能开始解决这两个问题， 关键挑战-更广泛的范围和对映体选择性的控制。例如，手性镍络合物可以 催化多种外消旋仲烷基亲电试剂与一系列亲核试剂的偶联， 良好的对映选择性。 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取代反应，并且已经研究了更少的这样的方法。 使其具有对映选择性。本提案的目的是解决这一尚未解决的挑战。工作将集中 发展温和和通用的方法来偶联亲电试剂和亲核试剂家族， 以前没有显示在脂族取代反应中是合适的反应伙伴， 同时控制立体选择性（至多两个立构中心）。这一奋进的成功将 基本上促进了对映体富集的分子的合成， 生物医学研究的范围。 将进行机制研究，以便深入了解新金属- 进行催化的对映收敛取代反应。机械研究将有助于 反应的发展，以及提高社会的基本化学反应的理解。

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 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 carbon–carbon bonds in the backbone of organic molecules. 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 product from readily available racemic starting materials. It has recently been established that, by achieving substitution reactions via a transition-metal-catalyzed pathway wherein an organic radical serves as a key intermediate, it is possible to begin to address both of the key challenges–broader scope and control of enantioselectivity. For example, chiral nickel complexes can catalyze the coupling of a variety of racemic secondary alkyl electrophiles with an array of nucleophiles with good enantioselectivity. To date, only a small fraction of the conceivable permutations of electrophilic and nucleophilic partners for substitution reactions of alkyl electrophiles have been explored, and still fewer such processes have been rendered enantioselective. The goal of this proposal is to address this unsolved challenge. 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, while controlling stereoselectivity at the same time (at up to two stereocenters). Success in this endeavor will substantially facilitate the synthesis of enantioenriched molecules that have application across a broad spectrum of biomedical research. Mechanistic studies will be pursued in order to provide insight into the pathways by which the new metal- catalyzed enantioconvergent substitution reactions proceed. The mechanistic investigations will facilitate reaction development, as well as enhance the community’s understanding of fundamental chemical reactivity.