Du Ya, Duan Shengzu, Huang Shuntao, Liu Tongqi, Zhang Hongbin, Walsh Patrick J, Yang Xiaodong
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products; School of Pharmacy, Yunnan University, Kunming 650500, P. R. China.
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, United States.
J Am Chem Soc. 2024 Nov 13;146(45):30947-30957. doi: 10.1021/jacs.4c09750. Epub 2024 Oct 30.
New methods for the enantioselective synthesis of N-alkylated indoles and their derivatives are of great interest because indoles are pivotal structural elements in biologically active molecules and natural products. They are also versatile intermediates in organic synthesis. Among well-established asymmetric hydroamination methods, the asymmetric hydroamination with indole-based substrates is a formidable challenge. This observation is likely due to the reduced nucleophilicity of the indole nitrogen. Herein, a unique nickel-catalyzed enantio- and branched-selective hydroamination of 2-azadienes with indoles and structurally related N-heterocycles is reported for the generation of enantioenriched ,-aminals. Salient features of this reaction include good yields, mild reaction conditions, high enantioselectivities, and broad substrate scope (60 examples, up to 96% yield and 99% ee). The significance of this approach with indoles and other N-heterocycles is demonstrated through structural modification of natural products and drug molecules and the preparation of enantioenriched N-alkylated indole core structures. Mechanistic studies reveal that olefin insertion into a Ni-H bond in the hydroamination is the enantio-determining step and oxidative addition of the N-H bond may be the turnover-limiting step.
N-烷基化吲哚及其衍生物的对映选择性合成新方法备受关注，因为吲哚是生物活性分子和天然产物中的关键结构单元。它们也是有机合成中用途广泛的中间体。在成熟的不对称氢胺化方法中，以吲哚为底物的不对称氢胺化是一项艰巨的挑战。这种现象可能是由于吲哚氮的亲核性降低所致。本文报道了一种独特的镍催化2-氮杂二烯与吲哚及结构相关的N-杂环的对映和支链选择性氢胺化反应，用于生成对映体富集的α-氨基化合物。该反应的显著特点包括产率高、反应条件温和、对映选择性高以及底物范围广（60个实例，产率高达96%，对映体过量值高达99%）。通过天然产物和药物分子的结构修饰以及对映体富集的N-烷基化吲哚核心结构的制备，证明了该方法用于吲哚和其他N-杂环的重要性。机理研究表明，氢胺化反应中烯烃插入Ni-H键是对映体决定步骤，而N-H键的氧化加成可能是周转限制步骤。
