SIOC 中文
CJOG
Adv search

Chinese Journal of Organic Chemistry >

2020 , Vol. 40 >Issue 2: 521 - 527

DOI: https://doi.org/10.6023/cjoc201908025

Formal Synthesis of Gram-Negative Antibiotic Negamycin

  • Zhang Shiju ,
  • Li Xiaotong ,
  • Wang Yan ,
  • Zheng Yucong ,
  • Han Shiqing ,
  • Yu Huilei ,
  • Huang Shahua
Expand
  • 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 date: 2019-08-16

  Revised date: 2019-10-10

  Online 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).

Fold

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 . DOI: 10.6023/cjoc201908025

References

[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] (a) Kupferschmidt, K. Science 2016, 352, 758.
(b) Liu, Y.; Li, R.; Xiao, X.; Wang, Z. Crit. Rev. Microbiol. 2019, 45, 301.
[3] World Health Organization WHO Annual Report on Global Priority List of Antibiotic-Resistant Bacteria, 2017.
[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] (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] (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.; Shi-ozuka, 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] 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] (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] Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M. J. Am. Chem. Soc. 1972, 94, 4353.
[10] Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
[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] (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] (a) Xu, J.; Lin, X. I. Chin. J. Org. Chem. 2007, 27, 1473(in Chinese). (许建明, 林贤福, 有机化学, 2007, 27, 1473.)
(b) Liao, X.; Jiang, Y.; Lai, S.; Liu, Y.; Wang, S.; Xiong, X. Chin. J. Org. Chem. 2019, 39, 668(in Chinese). (廖旭, 蒋岩, 赖石林, 刘源岗, 王士斌, 熊兴泉, 有机化学, 2019, 39, 668.)
[14] Müller, M. Angew. Chem., Int. Ed. 2005, 44, 362.
[15] Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
[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] Makino, K.; Jiang, H.; Suzuki, T.; Hamada, H. Tetrahedron:Asymmetry 2006, 17, 1644.
Options
Outlines

/

〈 〉