Formal Synthesis of Gram-Negative Antibiotic Negamycin

doi:10.6023/cjoc201908025

Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (2): 521-527.DOI: 10.6023/cjoc201908025 Previous Articles Next Articles

抗革兰氏阴性菌耐格霉素的形式合成

张世举^a, 李晓彤^b, 王燕^c, 郑宇璁^d, 韩世清^b, 郁惠蕾^d, 黄莎华^a,c

a 上海应用技术大学化学与环境工程学院上海 201418;
b 南京工业大学生物与制药工程学院南京 211816;
c 中国科学院上海有机化学研究所分子合成卓越中心天然产物有机合成化学重点实验室上海 200032;
d 华东理工大学生物反应器工程国家重点实验室上海生物制造技术协同创新中心上海 200237

收稿日期:2019-08-16 修回日期:2019-10-10 发布日期:2019-10-25
通讯作者: 王燕, 韩世清, 黄莎华 E-mail:wangyan@sippe.ac.cn;hanshiqing@njtech.edu.cn;shahua@sit.edu.cn
基金资助:
国家自然科学基金（No.21402121）和上海市杨帆计划（No.16YF1414400）资助项目.

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

Received:2019-08-16 Revised:2019-10-10 Published:2019-10-25
Supported by:
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).

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Abstract

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.

Key words: negamycin, Mannich reaction, gram-negative pathogens, formal synthesis

Cite this article

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.

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抗革兰氏阴性菌耐格霉素的形式合成

Formal Synthesis of Gram-Negative Antibiotic Negamycin

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