SIOC English
有机化学
高级检索

有机化学 >

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

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

研究简报

抗革兰氏阴性菌耐格霉素的形式合成

  • 张世举 ,
  • 李晓彤 ,
  • 王燕 ,
  • 郑宇璁 ,
  • 韩世清 ,
  • 郁惠蕾 ,
  • 黄莎华
展开
  • 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

  网络出版日期: 2019-10-25

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.

收起

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

摘要

耐格霉素是具有抗革兰氏阴性菌活性的天然产物.以廉价易得的3-羰基-4-氯丁酸乙酯为原料，以八步29%的总收率实现了耐格霉素的形式合成.该工作改进了文献的合成路线，利用生物催化不对称还原高立体选择性引入C-5位的手性羟基，并将危险的叠氮引入反应放在合成后期，降低合成路线的操作风险.分子中C-3位的仲碳胺基手性中心通过Ellamn试剂介导的不对称Mannich反应构建.该路线易于放大，有望为构建耐格霉素类似物分子库以及高通量药物筛选奠定基础.

关键词： 耐格霉素; Mannich反应; 革兰氏阴性菌; 形式合成

本文引用格式

张世举 , 李晓彤 , 王燕 , 郑宇璁 , 韩世清 , 郁惠蕾 , 黄莎华 . 抗革兰氏阴性菌耐格霉素的形式合成[J]. 有机化学, 2020 , 40(2) : 521 -527 . DOI: 10.6023/cjoc201908025

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

参考文献

[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
文章导航

/

〈 〉