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


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   

  1. 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;;
  • 基金资助:

Formal Synthesis of Gram-Negative Antibiotic Negamycin

Zhang Shijua, Li Xiaotongb, Wang Yanc, Zheng Yucongd, Han Shiqingb, Yu Huileid, Huang Shahuaa,c   

  1. 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).

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