Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles

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-碳形成的催化和对映选择性方法 特别令人感兴趣的是，由于包括可持续性、两者潜在的不同生物活性等问题 化合物的对映体，以及有机骨架中碳-碳键的优势 分子。 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容易获得的外消旋中获得高对映体富集物的途径。 起始材料。 最近已经证实，通过过渡金属催化的取代反应 其中有机自由基作为关键中间体的途径，可以开始处理这两个 关键挑战--更广泛的范围和对映体选择性的控制。例如，手性镍配合物可以 催化多种外消旋仲烷基亲电体与一系列亲核试剂的偶联 良好的对映选择性。 到目前为止，只有一小部分可以想象到的亲电和亲核伙伴的排列 烷基亲电化合物的取代反应已经被探索过，而这样的过程更少。 具有对映选择性的。这项提议的目标是解决这一悬而未决的挑战。努力将集中在 关于开发温和而通用的方法来连接亲电体和亲核体家族， 以前没有被证明是脂肪族取代反应中合适的反应伙伴，而 同时控制立体选择性(最多两个立体中心)。这一努力的成功将 极大地促进了具有广泛应用的富对映体分子的合成 生物医学研究领域。 将继续进行机械研究，以深入了解这种新金属- 催化的对映体聚合取代反应继续进行。机械性的调查将有助于 反应发展，以及加强社区对基本化学反应性的了解。

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.