Stereoselective Radical Processes for C-H Alkylation and Amination

C-H 烷基化和胺化的立体选择性自由基过程

• 批准号: 10357917
• 负责人: X. Peter ZHANG
• 金额: $ 39.13万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357917
• 关键词: Address; Alkylation; Amides; Amination; Arts; Azides; Benign; Biological; Biology; Carbon; Catalysis; Cobalt; Complex; Development; Electrons; Exhibits; Goals; Grant; Hydrogen Bonding; Isomerism; Lead; Ligands; Medicine; Metals; Methodology; Methods; Natural Products; Nature; Optics; Organic Synthesis; Pharmacologic Substance; Porphyrins; Process; Reaction; Reagent; Research; Research Project Grants; Source; Structure; System; Temperature; Transition Elements; base; carbene; catalyst; chemical reaction; chiral molecule; cost effective; cyclic compound; design; diazo compound; nitrene; small molecule; tool

Modified Project Summary/Abstract Section 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.

修改后的项目摘要/摘要部分 手性分子在生物学和医学中至关重要。合成方法的发展允许选择性地将普遍存在的 C-H 键转化为光学活性化合物，同时安装各种功能，有望改变有机合成的艺术和实践，并应带来许多新的应用。在不同的方法中，通过金属催化的卡宾/氮烯插入进行的不对称C-H烷基化/胺化是C-H键对映选择性官能化最有吸引力的方法之一。这种类型的催化卡宾/氮烯转移过程为通过立体选择性 C-C/C-N 键形成来功能化有机化合物中的 C-H 键提供了一种直接且通用的方法。它是设计和合成生物学和药学上重要的手性有机分子的有用工具。虽然通过使用某些类型的重氮化合物作为卡宾源和ArI=NT作为氮宾源，现有的催化系统在C-H烷基化和胺化方面取得了相当大的进展，但该领域仍然存在重要的挑战，需要确定更有效的卡宾和氮宾源，同时开发用于C-H烷基化和胺化的全新金属催化剂。 该研究项目以金属自由基催化（MRC）概念为指导，旨在开发用于立体选择性C-H烷基化和胺化反应的新型催化系统。作为稳定的金属自由基，卟啉的钴(II)络合物[Co(Por)]已被证明可以作为一类独特的催化剂，通过逐步自由基机制进行C-H烷基化和胺化。在带有酰胺官能团的卟啉配体的支持下，基于Co(II)的MRC已被证明在激活不同类别的重氮试剂和有机叠氮化物以进行自由基烷基化和不同类型的C-H键的胺化方面特别有效，从而导致C-C和C-N键的形成，并有效控制反应性和选择性。在本提案中，我们将重点关注利用手性酰胺卟啉[Co(II)(Por*)]的钴(II)配合物作为手性金属自由基催化剂来推进对映选择性C-H烷基化和胺化反应，以立体选择性合成光学活性有机分子，包括生物学上重要的碳环和N-杂环。 我们希望这些研究最终能够开发出基于 Co(II) 的立体选择性 C-H 烷基化和胺化反应的新型催化系统，该系统可普遍应用于生物学上重要的天然产物和药学上有趣的化合物的实际合成。