Enantioselective Synthesis of Aminals Via Nickel-Catalyzed Hydroamination of 2-Azadienes with Indoles and N-Heterocycles

被引:1
作者
Du, Ya [1 ,2 ,3 ]
Duan, Shengzu [1 ,2 ,3 ]
Huang, Shuntao [1 ,2 ,3 ]
Liu, Tongqi [1 ,2 ,3 ]
Zhang, Hongbin [1 ,2 ,3 ]
Walsh, Patrick J. [4 ]
Yang, Xiaodong [1 ,2 ,3 ]
机构
[1] Yunnan Univ, Minist Educ, Key Lab Med Chem Nat Resource, Kunming 650500, Peoples R China
[2] Yunnan Univ, Yunnan Key Lab Res & Dev Nat Prod, Kunming 650500, Peoples R China
[3] Yunnan Univ, Sch Pharm, Kunming 650500, Peoples R China
[4] Univ Penn, Dept Chem, Roy & Diana Vagelos Labs, Penn Merck Lab High Throughput Experimentat, Philadelphia, PA 19104 USA
基金
中国博士后科学基金; 美国国家科学基金会; 国家重点研发计划;
关键词
ASYMMETRIC-SYNTHESIS; DRUG LEADS; ALKYLATION; FUNCTIONALIZATION; ALLYLATION; ALDEHYDES;
D O I
10.1021/jacs.4c09750
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 N,N-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.
引用
收藏
页码:30947 / 30957
页数:11
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