Nickel-Catalyzed Enantioconvergent Cross-Couplings of Racemic Silyl Electrophiles

项目摘要 在过去的十年里，对映体选择性过渡金属取得了实质性的进展 烷基卤化物与多种有机亲核试剂催化交叉偶联生成新化合物 C-C债券。更重要的是，地球上丰富的金属已经被认识到是极好的 用于这些过程的催化剂与其贵金属对应的催化剂相比。与 目前的机械数据表明，镍、铜和铁等金属的使用 电子路径作为重要的过程提供了新的机会 不对称催化。例如，来自FU小组的最新研究提供了 令人信服的证据表明，在镍催化的交叉反应中形成了自由基中间体 烷基卤化物和有机金属配对之间的偶联。这反过来又允许一个 使用外消旋起始物质和手性催化剂的对映体收敛方法 构建以碳为中心的立体生成中心。这项提议是对这一概念的扩展。 发现和发展一种新型的对映体聚合型镍催化的交叉偶联反应 控制以硅为中心的立体形成中心的卤代硅烷和硼酸。第一 具体目标将包括两个方面。最初的焦点将是发现和 使用手性GC分析进行快速分析的这种方法的开发将是 以确定%转化率、%收益率和%ee。第二个方面将涉及 随着对已知的硅结合生物活性化合物的应用， 然后突出显示此方法。具体地说，第一次对映体选择性全合成 将实现新型肿瘤细胞生长抑制因子comretataatin A-4的硅类似物。 第二个具体目标将侧重于进行系统的机理研究 来阐明这种新的方法是否与以前的 对映体会聚系统或有独特的手术途径。中国的动力学研究 与电子顺磁共振、紫外可见光谱和质谱学相结合，将是 在这一努力中取得成功。

Project Summary The past decade has seen substantial progress in the enantioselective transition metal catalyzed cross couplings of alkyl halides with various organonucleophiles to form new C-C bonds. More importantly, earth abundant metals have been realized to be excellent catalysts for these processes compared to their precious metal counterparts. With the use of metals such as Ni, Cu and Fe, current mechanistic data has pointed to single electron pathways as important processes that provide new opportunities towards asymmetric catalysis. For example, recent studies from the Fu group have provided convincing evidence that radical intermediates are formed during Ni-catalyzed cross- couplings between alkyl halides and organometallic partners. This in turn has allowed an enantioconvergent approach using racemic starting materials and chiral catalysts to construct carbon-centered stereogenic centers. This proposal expands on this concept to discover and develop a novel enantioconvergent Ni-catalyzed cross-coupling between halosilanes and boronic acids to control silicon-centered stereogenic centers. The first specific aim will encompass two aspects. Initially the focus will be the discovery and development of this methodology using rapid assay using chiral GC analysis will be conducted to ascertain % conversion, % yield, and % ee. The second aspect will deal with applications towards known silicon incorporated biologically active compounds will then highlight this approach. Specifically, the first enantioselective total synthesis of a silicon analog of combretastatin A-4, a novel tumor cell growth inhibitor, will be achieved. The second specific aim will focus on systematic mechanistic studies will be performed to elucidate if this novel methodology is mechanistically related to previous enantioconvergent systems or has a unique operative pathway. Kinetic studies in combination with EPR, UV-vis and mass spectrometry will be invaluable tools for the success in this endeavor.