Stereoselective Radical Processes for C-H Alkylation and Amination

项目总结/摘要 立体选择性C-H烷基化和胺化的催化自由基过程 手性分子在生物学和医学中具有核心重要性。合成橡胶的发展 允许将无所不在的C-H键选择性转化为光学活性的方法 化合物，同时安装各种功能，承诺改变艺术和实践的有机 合成，并应导致许多新的应用。在不同的方法中，不对称C-H 通过金属催化的卡宾/氮烯插入进行烷基化/胺化是最有吸引力的方法之一 C-H键的对映选择性官能化的方法。这种类型的催化卡宾/氮烯 转移过程为C-H键的功能化提供了一种直接和通用的方法， 通过立体选择性C-C/C-N键形成有机化合物。它是一个有用的工具， 生物学和药学上重要的手性有机分子的设计和合成。而 利用现有的催化体系，C-H烷基化和胺化反应已经取得了相当大的进展 通过使用某些类型的重氮化合物作为卡宾源和ArI=NTs作为氮宾源， 在该领域仍然存在重要的挑战，这些挑战证实了需要确定更有效的卡宾， 氮烯来源与C-H反应的新型金属催化剂的开发相结合 烷基化和胺化。 在金属自由基催化（MRC）概念的指导下，本研究项目旨在 立体选择性C-H烷基化和胺化反应的新催化体系的开发。 作为稳定的金属自由基，卟啉的钴（II）络合物[Co（Por）]已被证明具有如下功能： 通过逐步自由基机理的C-H烷基化和胺化的独特类别的催化剂。 由带有酰胺官能团的卟啉配体支撑，基于Co（II）的MRC已被证明 特别有效地活化不同种类的重氮试剂和有机叠氮化物， 不同类型的C-H键的烷基化和胺化，导致C-C和C-N键的形成， 反应性和选择性的有效控制。在本提案中，我们将重点关注钴（II）的利用。 手性氨基卟啉[Co（II）（Por*）]配合物作为手性金属自由基催化剂， 用于立体选择性合成光学活性的对映选择性C-H烷基化和胺化反应 有机分子，包括生物学上重要的碳环和N-杂环。 我们希望这些研究将最终导致开发基于Co（II）的新催化剂。 可普遍应用的用于立体选择性C-H烷基化和胺化反应的系统 对生物学上重要的天然产物和药学上感兴趣的实用合成 化合物.

PROJECT SUMMARY/ABSTRACT Catalytic Radical Processes for Stereoselective C–H Alkylation and Amination Chiral molecules are of central importance in biology and medicine. The development of synthetic methodologies that allow for selective conversion of omnipresent C–H bonds into optically active compounds while installing various functionalities promises to transform the art and practice of organic synthesis and should lead to many new applications. Among different approaches, asymmetric C–H alkylation/amination via metal-catalyzed carbene/nitrene insertion represents one of the most attractive methods for enantioselective functionalization of C–H bonds. This type of catalytic carbene/nitrene transfer process provides a direct and general approach for the functionalization of C–H bonds in organic compounds through stereoselective C–C/C–N bond formation. It serves as a useful tool for the design and synthesis of biologically and pharmaceutically important chiral organic molecules. While considerable progress has been made for C–H alkylation and amination by existing catalytic systems with the use of certain type of diazo compounds as carbene sources and ArI=NTs as nitrene sources, important challenges remain in the field that validate the need to identify more effective carbene and nitrene sources in conjunction with the development of fundamentally new metal catalysts for C–H alkylation and amination. Guided by the concept of metalloradical catalysis (MRC), this research project is directed toward the development of new catalytic systems for stereoselective C–H alkylation and amination reactions. As stable metalloradicals, cobalt(II) complexes of porphyrins [Co(Por)] have been shown to function as a unique class of catalysts for C–H alkylation and amination through stepwise radical mechanism. Supported by porphyrin ligands bearing amide functionalities, the Co(II)-based MRC has been shown to be particularly effective in activating different classes of diazo reagents and organic azides for radical alkylation and amination of diverse types of C–H bonds, leading to C–C and C–N bond formation with effective control of reactivity and selectivity. In this proposal, we will focus on the utilization of cobalt(II) complexes of chiral amidoporphyrins [Co(II)(Por*)] as chiral metalloradical catalysts to advance enantioselective C–H alkylation and amination reactions for stereoselective synthesis of optically active organic molecules, including biologically important carbocycles and N-heterocycles. We hope these studies will ultimately lead to the development of Co(II)-based new catalytic systems for stereoselective C–H alkylation and amination reactions that can be generally applied toward practical synthesis of biologically important natural products and pharmaceutically interesting compounds.