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
1. [1]
  (a) Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis, World Health Organization, Geneva, 2017 (WHO/EMP/IAU/ 2017.12). License: CCBY-NC-SA 3.0 IGO.
  (b) Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Nat. Rev. Drug Discovery 2007, 6, 29.
2. [2]
  (a) Kupferschmidt, K. Science 2016, 352, 758.
  (b) Liu, Y.; Li, R.; Xiao, X.; Wang, Z. Crit. Rev. Microbiol. 2019, 45, 301.
3. [3]
  World Health Organization WHO Annual Report on Global Priority List of Antibiotic-Resistant Bacteria, 2017.
4. [4]
  (a) Hamada, M.; Takeuchi, T.; Kondo, S.; Ikeda, Y.; Naganawa. H. J. Antibiot. 1970, 23, 170.
  (b) Kondo, S.; Shibahara, S.; Takahashi, S.; Maeda, K.; Umezawa, H. J Am Chem Soc. 1971, 93, 6305.
5. [5]
  (a) Uehara, Y.; Hori, M.; Umezawa, H. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 1974, 374, 82.
  (b) Uehara, Y.; Hori, M.; Umezawa, H. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 1976, 447, 406.
  (c) Uehara, Y.; Hori, M.; Umezawa, H. Biochim. Biophys. Acta, Nucleic Acids Protein Synth. 1976, 442, 251.
  (d) Mizuno, S.; Nitta, K.; Umezawa, H. J. Antibiot. 1970, 23, 589.
  (e) Mizuno, S.; Nitta, K.; Umezawa, H. J. Antibiot. 1970, 23, 581.
6. [6]
  (a) Arakawa, M.; Shiozuka, M.; Nakayama Y.; Hara, T.; Hamada, M.; Kondo, A.; Ikeda, D.; Takahashi, Y.; Sawa, R.; Nonomura, Y.; Sheykholeslami, K.; Kondo, K.; Kaga, K.; Suzuki-Miyagoe, Y.; Takeda, S.; Matsuda, R. J. Biochem. 2003, 134, 751.
  (b) Allamand, V.; Bidou, L.; Arakawa, M.; Floquet, C.; Shiozuka, M.; Paturneau-Jouas, M.; Gartioux, C.; Butler-Browne, G. S.; Mouly, V.; Rousset, J.-P.; Matsuda, R.; Ikeda, D.; Guicheney, P. J. Gene Med. 2008, 10, 217.
  (c) Taguchi, A.; Nishiguchi, S.; Shiozuka, M.; Nomoto, T.; Ina, M.; Nojima, S.; Matsuda, R.; Nonomura, Y.; Kiso, Y.; Yamazaki, Y.; Yakushiji, F.; Hayashi, Y. ACS Med. Chem. Lett. 2012, 3, 118.
  (d) Taguchi, A.; Hamada, K.; Hayashi, Y. J. Antibiot. 2018, 71, 205.
7. [7]
  Select asymmetric synthesis literature:
  (a) Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M. J. Am. Chem. Soc. 1972, 94, 4353.
  (b) Masters, J. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 4547.
  (c) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1996, 7, 1919.
  (d) Olivier, N. B.; Altman, R. B.; Noeske, J.; Basarab, G. S.; Code, E.; Ferguson, A. D.; Gao, N.; Huang, J.; Juette, M. F.; Livchak, S.; Miller, M. D.; Prince, D. B.; Cate, J. H. D.; Buurman, E. T.; Blanchard, S. C. Proc. Natl. Acad. Sci. 2014, 111, 16274.
  (e) For a recent summary about the total synthesis of negamycin, see: Zhu, L.; Hong, R. Tetrahedron Lett. 2018, 59, 2112.
8. [8]
  (a) Kondo, S.; Iinuma, K.; Yoshida, K.; Yokose, K.; Ikeda, Y.; Shimazaki, M.; Umezawa, H. J. Antibiot. 1976, 29, 208.
  (b) Uehara, Y.; Hori, M.; Kondo, S.; Hamada, M.; Umezawa, H. J. Antibiot. 1976, 29, 937.
  (c) Raju, B.; Mortell, K.; Anandan, S.; O'Dowd, H.; Gao, H.; Gomez, M.; Hackbarth, C.; Wu, C.; Wang, W.; Yuan, Z.; White, R.; Trias, J.; Patel, D. V. Bioorg. Med. Chem. Lett. 2003, 13, 2413.
  (d) Raju, B.; Anandan, S.; Gu, S.; Herradura, P.; O'Dowd, H.; Kim, B.; Gomez, M.; Hackbarth, C.; Wu, C.; Wang, W.; Yuan, Z.; White, R.; Trias, J.; Patel, D. V. Bioorg. Med. Chem. Lett. 2004, 14, 3103.
  (e) McKinney, D. C.; Basarab, G. S.; Cocozaki, A. I.; Foulk, M. A.; Miller, M. D.; Ruvinsky, A. M.; Scott, C. W.; Thakur, K.; Zhao, L.; Buurman, E. T.; Narayan, S. ACS Med. Chem. Lett. 2015, 6, 930.
  (f) Schmidt, U.; Stäbler, F.; Lieberknecht, A. Synthesis 1992, 482.
9. [9]
  Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M. J. Am. Chem. Soc. 1972, 94, 4353. doi: 10.1021/ja00767a059
10. [10]
  Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278. doi: 10.1021/jo982059i
11. [11]
  Ma, H. M.; Yang, L. L.; Ni, Y.; Zhang, J.; Li, C. X.; Zheng, G. W.; Yang, H. Y.; Xu, J. H. Adv. Synth. Catal. 2012, 354, 1765.
12. [12]
  (a) Reetz, M. T.; Li, X. G. J. Am. Chem. Soc. 2006, 128, 1044.
  (b) Ohkuma, T.; Tsutsumi, K.; Utsumi, N.; Arai, N.; Noyori, R.; Murata, K. Org. Lett. 2007, 9: 255.
13. [13]
14. [14]
  Müller, M. Angew. Chem., Int. Ed. 2005, 44, 362. doi: 10.1002/anie.200460852
15. [15]
  Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278. doi: 10.1021/jo982059i
16. [16]
  (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819.
  (b) Siegel C.; Thornton, E. R. J. Am. Chem. Soc. 1989, 111, 5722.
  (c) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
17. [17]
  Makino, K.; Jiang, H.; Suzuki, T.; Hamada, H. Tetrahedron: Asymmetry 2006, 17, 1644. doi: 10.1016/j.tetasy.2006.06.004
1. [1]
  Yingchun ZHANG , Yiwei SHI , Ruijie YANG , Xin WANG , Zhiguo SONG , Min WANG . Dual ligands manganese complexes based on benzene sulfonic acid and 2, 2′-bipyridine: Structure and catalytic properties and mechanism in Mannich reaction. Chinese Journal of Inorganic Chemistry, 2024, 40(8): 1501-1510. doi: 10.11862/CJIC.20240078
2. [2]
  Ziheng Zhuang , Xiao Xu , Kin Shing Chan . Superdrugs for Superbugs. University Chemistry, 2024, 39(9): 128-133. doi: 10.3866/PKU.DXHX202309040
3. [3]
  Feiya Cao , Qixin Wang , Pu Li , Zhirong Xing , Ziyu Song , Heng Zhang , Zhibin Zhou , Wenfang Feng . Magnesium-Ion Conducting Electrolyte Based on Grignard Reaction: Synthesis and Properties. University Chemistry, 2024, 39(3): 359-368. doi: 10.3866/PKU.DXHX202308094
4. [4]
  Meihui Cai , Yi Huang , Xingxing Ma , Qiuling Song . Exploring the Mysteries of the Petasis-Boronic Acid-Mannich Reaction. University Chemistry, 2025, 40(11): 184-190. doi: 10.12461/PKU.DXHX202412054
5. [5]
  Shuixing Dai , Jilei Jiang , Yuxiao Wang , Jinqi Hu , Minghua Huang . Application of Knoevenagel Reaction in Organic Chemistry Teaching. University Chemistry, 2025, 40(5): 334-341. doi: 10.12461/PKU.DXHX202405208
6. [6]
  Huijuan Liao , Yulin Xiao , Dong Xue , Mingyu Yang , Jianyang Dong . Synthesis of 1-Benzyl Isoquinoline via the Minisci Reaction. University Chemistry, 2025, 40(7): 294-299. doi: 10.12461/PKU.DXHX202409092
7. [7]
  Xiao Ma , Junjie Wang , Xin Chen , Jingcheng Li , Lihong Zhao , Xueping Sun , Shaojuan Cheng , Fang Wang . Exploring Innovative Approaches to Chemistry Instructional Organization Driven by Artificial Intelligence. University Chemistry, 2025, 40(9): 99-106. doi: 10.12461/PKU.DXHX202410085
8. [8]
  Jianqiang Zheng , Yongbin Huang , Wencan Ming , Yingju Liu . Intelligent Reaction Optimization: Synthesis of Acetylsalicylic Acid Driven by Deep Learning and Optimization Algorithms. University Chemistry, 2025, 40(9): 87-98. doi: 10.12461/PKU.DXHX202411062
9. [9]
  Yansong Xiao , Yi Huang , Xingxing Ma , Qiuling Song . The Matteson Reaction in Organic Synthesis: From Fundamentals to Frontiers. University Chemistry, 2025, 40(10): 114-120. doi: 10.12461/PKU.DXHX202411023
10. [10]
  Ming Chen , Zhenbo Mo . Research Progress on the Synthesis, Structure, and Chemical Reactivity of Borylenes. University Chemistry, 2026, 41(4): 250-263. doi: 10.12461/PKU.DXHX202502123
11. [11]
  Yi Huang , Yansong Xiao , Xingxing Ma , Qiuling Song . Zweifel olefination: an innovative approach to highly efficient stereoselective alkene synthesis. University Chemistry, 2026, 41(7): 119-125. doi: 10.12461/PKU.DXHX202506046
12. [12]
  Xinting XIONG , Zhiqiang XIONG , Panlei XIAO , Xuliang NIE , Xiuying SONG , Xiuguang YI . Synthesis, crystal structures, Hirshfeld surface analysis, and antifungal activity of two complexes Na(Ⅰ)/Cd(Ⅱ) assembled by 5-bromo-2-hydroxybenzoic acid ligands. Chinese Journal of Inorganic Chemistry, 2024, 40(9): 1661-1670. doi: 10.11862/CJIC.20240145
13. [13]
  Yajun Hou , Jinxin Liu , Tao Chen , Yi Zhang , Lei Zhou . Sonogashira coupling reaction in ionic liquids: a detailed exploration of experiment 4.4D in the “101 Plan” synthetic chemistry curriculum. University Chemistry, 2026, 41(6): 136-144. doi: 10.12461/PKU.DXHX202510101
14. [14]
  Qihao Tang , Xiaohua Xin , Yunxia Wang , Han Wang . Mechanochemically Promoted Photochemical Reactions in Organic Synthesis. University Chemistry, 2026, 41(6): 321-327. doi: 10.12461/PKU.DXHX202503131
15. [15]
  Peiling Li , Qing Feng , Hongling Yuan , Qin Wang . Live Interview Recording about the Penicillin Family. University Chemistry, 2024, 39(9): 122-127. doi: 10.3866/PKU.DXHX202311022
16. [16]
  Tianlong Zhang , Rongling Zhang , Hongsheng Tang , Yan Li , Hua Li . Online Monitoring and Mechanistic Analysis of 3,5-diamino-1,2,4-triazole (DAT) Synthesis via Raman Spectroscopy: A Recommendation for a Comprehensive Instrumental Analysis Experiment. University Chemistry, 2024, 39(6): 303-311. doi: 10.3866/PKU.DXHX202312006
17. [17]
  Renxiao Liang , Zhe Zhong , Zhangling Jin , Lijuan Shi , Yixia Jia . A Palladium/Chiral Phosphoric Acid Relay Catalysis for the One-Pot Three-Step Synthesis of Chiral Tetrahydroquinoline. University Chemistry, 2024, 39(5): 209-217. doi: 10.3866/PKU.DXHX202311024
18. [18]
  Lili Jiang , Shaoyu Zheng , Xuejiao Liu , Xiaomin Xie . Copper-Catalyzed Oxidative Coupling Reactions for the Synthesis of Aryl Sulfones: A Fundamental and Exploratory Experiment for Undergraduate Teaching. University Chemistry, 2025, 40(7): 267-276. doi: 10.12461/PKU.DXHX202408004
19. [19]
  Yan Kong , Wei Wei , Lekai Xu , Chen Chen . Electrochemical Synthesis of Organonitrogen Compounds from N-integrated CO₂ Reduction Reaction. Acta Physico-Chimica Sinica, 2024, 40(8): 2307049-0. doi: 10.3866/PKU.WHXB202307049
20. [20]
  Kangjuan Cheng , Chunxiao Liu , Youpeng Wang , Qiu Jiang , Tingting Zheng , Xu Li , Chuan Xia . Design of noble metal catalysts and reactors for the electrosynthesis of hydrogen peroxide. Acta Physico-Chimica Sinica, 2025, 41(10): 100112-0. doi: 10.1016/j.actphy.2025.100112

Get Citation

PDF

XML

Metrics

PDF Downloads(25)
Abstract views(3614)
HTML views(494)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142