Citation: Zhang Shiju, Li Xiaotong, Wang Yan, Zheng Yucong, Han Shiqing, Yu Huilei, Huang Shahua. Formal Synthesis of Gram-Negative Antibiotic Negamycin[J]. Chinese Journal of Organic Chemistry, ;2020, 40(2): 521-527. doi: 10.6023/cjoc201908025 shu

Formal Synthesis of Gram-Negative Antibiotic Negamycin

Zhang Shiju ^a ,
Li Xiaotong ^b ,
Wang Yan ^c,, ,
Zheng Yucong ^d ,
Han Shiqing ^b,, ,
Yu Huilei ^d ,
Huang Shahua ^a,c,,

a.
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418
b.
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816
c.
Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
d.
State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation, Center for Biomanufacturing, East China University of Science and Technology, Shanghai 200237

Corresponding author: Wang Yan, wangyan@sippe.ac.cn Han Shiqing, hanshiqing@njtech.edu.cn Huang Shahua, shahua@sit.edu.cn
Received Date: 16 August 2019
Revised Date: 10 October 2019
Available Online: 25 February 2019
Fund Project: Project supported by the National Natural Science Foundation of China (No. 21402121) and the Shanghai Science and Technology Commission for the Shanghai Sailing Program (No. 16YF1414400)the Shanghai Science and Technology Commission for the Shanghai Sailing Program 16YF1414400the National Natural Science Foundation of China 21402121

Figures(4)

Negamycin is a potent gram-negative antibiotic. By using commercial available ethyl 4-chlorobutyrate as starting material, the formal synthesis of negamycin was achieved within 8 steps and 29% overall yield. This modified synthetic route features in-situ enzymatic promoted asmmetric reduction reaction to introduce chiral hydroxy group at C-5, a late-stage azidination at C-6 to avoid the introduction of explosive azide group in the early stage in previous syntheses. The C-3 aza-chiral center was constructed via Ellman reagent-based asymmetric Mannich reaction. This efficient route is scalable and suitable to establish a library of negamycin analogues for future high-throughput screening.
- negamycin,
- Mannich reaction,
- gram-negative pathogens,
- formal synthesis
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