Citation: Jing Zhang, Lichao Ning, Yong Qiu, Minghui Ji, Shiyu Wang, Yuji Wang, Fei Wang, Xiaoming Feng, Shunxi Dong. Enantioselective intramolecular C–H alkylation of pyridine derivatives with alkene by rare-earth catalysts: Facile synthesis of chiral tetrahydro-1,5-naphthyridines[J]. Chinese Chemical Letters, ;2026, 37(5): 111442. doi: 10.1016/j.cclet.2025.111442 shu

Enantioselective intramolecular C–H alkylation of pyridine derivatives with alkene by rare-earth catalysts: Facile synthesis of chiral tetrahydro-1,5-naphthyridines

Jing Zhang ^a ,
Lichao Ning ^a ,
Yong Qiu ^a ,
Minghui Ji ^b ,
Shiyu Wang ^a ,
Yuji Wang ^a ,
Fei Wang ^b ,
Xiaoming Feng ^a ,
Shunxi Dong ^{a, *,}

a.
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
b.
Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610047, China

dongs@scu.edu.cn

Received Date: 6 March 2025
Revised Date: 2 June 2025
Accepted Date: 10 June 2025
Available Online: 11 June 2025

Figures(6)

Chiral 1,2,3,4-tetrahydro-1,5-naphthyridines are frequently encountered in many bioactive compounds. However, the methods for their asymmetric synthesis are quite limited. Herein, we developed a straightforward and efficient route to enantioenriched tetrahydro-1,5-naphthyridines from pyridine derivatives tethered with alkene moieties (34 examples, up to 99% yield, 93% ee). The reaction proceeded via Csp²–H activation pathway initiated by site-selective deprotonation with the assistance of La[N(SiMe₃)₂]₃/PyBox, followed by alkene insertion into the resulting La-aryl bond. The potential utility of the current method in organic synthesis was highlighted by scale-up synthesis of chiral product and its further transformations. Moreover, some of the products show a pronounced inhibitory effect on A549 cell activity. In addition, experimental studies and DFT calculations were carried out to elucidate the origin of enantiocontrol.
- Asymmetric catalysis,
- Rare-earth,
- C–H activation,
- Pyridine,
- Alkylation,
- Tetrahydro-1,5-naphthyridine
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