Nickel-Catalyzed Enantioconvergent Cross-Couplings of Racemic Silyl Electrophiles

镍催化外消旋甲硅烷基亲电子试剂的对映异构交叉偶联

• 批准号: 9927488
• 负责人: Robynne Kiley Neff
• 金额: $ 6.53万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927488
• 关键词: Biological; Biological Assay; Boronic Acids; Carbon; Catalysis; Cells; Chemicals; Combretastatin A-4; Competence; Coupling; Data; Development; Electron Spin Resonance Spectroscopy; Electrons; Goals; Growth Inhibitors; Kinetics; Ligands; Mass Spectrum Analysis; Mediating; Metals; Methodology; Methods; Nickel; Pathway interactions; Permeability; Pharmaceutical Preparations; Planet Earth; Process; Reaction; Research; Roentgen Rays; Scheme; Silanes; Silicon; Structure; System; Toxic effect; Transition Elements; alkyl group; analog; base; c new; catalyst; experience; neoplastic cell; novel; pi bond; success; tool

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.

项目摘要 在过去的十年里，过渡金属的对映选择性研究取得了很大的进展 卤代烷与各种有机亲核试剂的催化交叉偶联， 碳碳键更重要的是，地球丰富的金属已被认识到是优秀的 与它们的贵金属对应物相比，与 使用金属，如镍，铜和铁，目前的机械数据指出，单一的 电子途径作为重要的过程，提供了新的机会， 不对称催化例如，傅氏集团最近的研究提供了 令人信服的证据表明，自由基中间体形成过程中镍催化的交叉， 烷基卤化物和有机金属配合物之间的偶联。这反过来又使一个 使用外消旋原料和手性催化剂的对映会聚方法， 构建以碳为中心的立体异构中心。本提案扩展了这一概念 发现并开发了一种新的对映收敛Ni催化的交叉偶联， 卤代硅烷和硼酸以控制以硅为中心的立体异构中心。第一 具体目标将包括两个方面。最初的重点将是发现和 将开发使用手性GC分析的快速测定方法， 进行，以确定%转化率，%产率和% ee。第二个方面将处理 对于已知的硅结合的生物活性化合物的应用， 然后强调这种方法。具体地，第一个对映选择性全合成的化合物 将获得新型肿瘤细胞生长抑制剂考布他汀A-4硅类似物。 第二个具体目标将集中在系统的机制研究将进行 为了阐明这种新的方法是否与以前的方法在机制上相关， 对映会聚系统或具有独特的操作途径。动力学研究 结合EPR，UV-vis和质谱将是非常宝贵的工具， 在这一奋进中取得成功。