SIOC English
有机化学
高级检索

有机化学 >

2024 , Vol. 44 >Issue 9: 2876 - 2888

DOI: https://doi.org/10.6023/cjoc202403015

研究论文

可溶性疏水性标签辅助的高效连续流液相多肽合成

  • 彭伟 ,
  • 程蓉 ,
  • 刘豪 ,
  • 刘冬梅 ,
  • 苏贤斌
展开
  • a 南京工业大学化工学院 南京 210000
    b 青岛科技大学化工学院 山东青岛 266000

收稿日期: 2024-03-12

  修回日期: 2024-04-08

  网络出版日期: 2024-05-11

收起

Highly Efficient Continuous Flow Liquid-Phase Peptide Synthesis Using a Soluble Hydrophobic Tag

  • Wei Peng ,
  • Rong Cheng ,
  • Hao Liu ,
  • Dongmei Liu ,
  • Xianbin Su
Expand
  • a College of Chemical Engineering, Nanjing Tech University, Nanjing 210000
    b College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong 266000
*E-mail:

Received date: 2024-03-12

  Revised date: 2024-04-08

  Online published: 2024-05-11

Fold

摘要

开发绿色、高效的合成工艺是实现治疗性多肽商业化生产的迫切要求. 报道了在微反应器中一种新型疏水性硅基载体双(4-((叔丁基二甲基硅基)氧基)苯基)甲胺(SPPM)辅助进行连续流动液相多肽合成(LPPS)的方法, 该方案由酰胺化模块(微通道反应器, 偶联时间9.0 s)、脱保护模块(填充床反应器, 脱保护时间31.4 s)和萃取洗涤模块(微通道混合器, 洗涤18.0 s)组成. 采用绿色溶剂(用乙酸乙酯代替被限制使用的N,N-二甲基甲酰胺)和N-苄氧羰基氨基酸(用氢解脱保护代替易制毒管制化学品哌啶脱保护), 合成了高纯度的(粗品收率>90%)五肽-3. 这种精确控制反应时间和温度的连续流方法, 从绿色和可持续的角度出发, 为大规模多肽合成开辟了新的前景.

关键词： 连续流动; 微反应器; 可溶性载体; 液相多肽合成

本文引用格式

彭伟 , 程蓉 , 刘豪 , 刘冬梅 , 苏贤斌 . 可溶性疏水性标签辅助的高效连续流液相多肽合成[J]. 有机化学, 2024 , 44(9) : 2876 -2888 . DOI: 10.6023/cjoc202403015

Abstract

The development of a green and efficient synthetic process is an urgent requirement for the commercial production of therapeutic peptides. In a microreactor, a novel hydrophobic silicon-based carrier bis(4-((tert-butyldimethylsilyl)oxy)- phenyl)methylamine (SPPM) assisted continuous flow liquid phase polypeptide synthesis (LPPS) method was reported. The protocol consists of an amidation module (microchannel reactor, coupling time 9.0 s), a deprotection module (packed bed reactor, deprotection time 31.4 s) and an extraction and washing module (microchannel mixer, washing 18.0 s). High-purity (crude yield >90%) pentapeptide-3 was synthesized by using green solvent (ethyl acetate instead of restricted N,N-dimethyl- formamide) and N-benzyloxycarbonyl-amino acid (hydrogenolysis instead of piperidine deprotection). This continuous flow method with precise control of short reaction time and temperature opens up new prospects for large-scale peptide synthesis from a green and sustainable perspective.

Key words： continuous flow; microreactor; soluble carrier; liquid phase peptide synthesis

参考文献

[1]
(a) Lau, J. L.; Dunn, M. K. Bioorg. Med. Chem. Lett. 2018, 26, 2700.
[1]
(b) Tanemura, Y.; Mochizuki, Y.; Kumachi, S. Biology 2015, 4, 161.
[1]
(c) Lin, K. J. V.; Emrick, J. J.; Kelly, M. J. S.; Herzig, V. Cell 2019, 178, 1362.
[1]
(d) Drucker, D. J. Nat. Rev. Drug Discovery 2020, 19, 277.
[2]
(a) Thomas, K.; Markus, M. Methods Mol. Bol. 2022, 2384, 175.
[2]
(b) Ceccato, M. L.; Chenu, J.; Mery, J.; Follet, M.; Calas, B. Tetrahedron Lett. 1990, 31, 6189.
[2]
(c) Nicolas, E.; Clemente, J.; Ferrer, T. Tetrahedron 1997, 53, 3179.
[3]
(a) Vincent, d. V.; Charlotte, R. J. Am. Chem. Soc. 1953, 75, 4879.
[3]
(b) Fan, J. H.; Bian, Y. N.; Su, X. B. Chem. J. Chin. Univ. 2018, 39, 2679 (in Chinese).
[3]
(范佳辉, 卞亚楠, 苏贤斌, 高等学校化学学报, 2018, 39, 2679.)
[3]
(c) Lawrenson, S. B.; Arav, R.; North, M. Green Chem. 2017, 19, 1685.
[4]
Rasmussen, J. H. Bioorg. Med. Chem. 2018, 26, 2914.
[5]
Jadhav, S.; Seufert, W.; Lechner, C. Chimia 2021, 75, 476.
[6]
Eggen, I. F.; Bakelaar, F. T.; Petersen, A. J. Pept. Sci. 2005, 11, 633.
[7]
Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
[8]
Yin, H.; Chen, X. T. Acta Chim. Sinica 2022, 80, 444 (in Chinese).
[8]
(尹昊, 陈西同, 化学学报, 2022, 80, 444.)
[9]
Zhuang, H.; Hao, H.; Qiu, Y. Chin. J. Chem. 2023, 41, 2010.
[10]
Li, T.; Zhang, Y. Peng, P. Chin. J. Chem. 2022, 40, 1571.
[11]
Al Musaimi, O.; de la Torre, B. G.; Albericio, F. Green Chem. 2020, 22, 996.
[12]
Bonnamour, J.; Metro, T. X.; Martinez, J.; Lamaty, F. Green Chem. 2013, 15, 1116.
[13]
(a) Egelund, P. H. G.; Jadhav, S. ACS Sustainable Chem. Eng. 2021, 9, 14202.
[13]
(b) Martin, V.; Jadhav, S.; Egelund, P. H. G. Green Chem. 2021, 23, 3295.
[13]
(c) Xu, B. F.; Yang, S.; Zhu, J. M.; Ma, Y. D.; Zhao, G.; Guo, Y.; Xu, L. Chem. Res. Chin. Univ. 2014, 30, 103.
[14]
Shemyakin, M. M.; Ovchinnikov, Y. A. Tetrahedron Lett. 1965, 6, 2323.
[15]
Pillai, V. N. R.; Mutter, M.; Bayer, E. J. Org. Chem. 1980, 45, 5364.
[16]
(a) Bayer, E.; Mutter, M. Nature 1972, 237, 512.
[16]
(b) Bayer, E.; Mutter, M.; Uhmann, R.; Polster, J.; Mauser, H. J. Am. Chem. Soc. 1974, 96, 7333.
[16]
(c) Musaimi, O.; Albericio, F. Green Chem. 2020, 22, 996.
[16]
(d) Mutter, M.; Hagenmaier, H.; Bayer, E. Angew. Chem. Int. Ed. 1971, 10, 811.
[16]
(e) Mutter, M.; Bayer, E. Angew. Chem. Int. Ed. 1974, 13, 88.
[16]
(f) Bayer, E.; Mutter, M. Chem. Ber. 1974, 107, 1344.
[17]
Hitoshi, T.; Tomoyuki, O. Bull. Chem. Soc. Jpn. 2001, 74, 733.
[18]
Takahashi, D.; Yamamoto, T. Tetrahedron Lett. 2012, 53, 1936.
[19]
Takahashi, D. Org. Lett. 2012, 14, 4514.
[20]
(a) Li, H.; Chao, J.; Qin, C. G. J. Org. Chem. 2020, 85, 6271.
[20]
(b) Li, H.; Chao, J.; Qin, C. G. Org. Chem. Front. 2020, 7, 689.
[20]
(c) Li, H.; Chao, J.; Qin, C. G. Org. Lett. 2020, 22, 3323.
[21]
Lu, D.; Wang, S.; Yin, H. Synlett 2020, 31, 1163.
[22]
(a) Tetsu, T.; Hidekazu, O.; Shu, K. Nature 2015, 520, 329.
[22]
(b) Sheng, B. S.; Li, C.; Liu, Y. Y.; Wang, A. J.; Wang, Y.; Zhang, J.; Liu, W. X. Chem. J. Chin. Univ. 2019, 40, 1365.
[23]
Adamo, A.; Beingessner, R. L.; Behnam, M. Science 2016, 352, 61.
[24]
Szloszar, A. ChemistrySelect 2017, 2, 6036.
[25]
Audubert, C.; Gamboa, M. O. J.; Lebel, H. Angew. Chem. 2017, 129, 6391.
[26]
(a) Cheng, D.; Chen, F. E. Chem. Ind. Eng. Prog. 2019, 38, 556 (in Chinese).
[26]
(程荡, 陈芬儿, 化工进展, 2019, 38, 556.)
[26]
(b) Gordon, C. P. Org. Biomol. Chem. 2018, 16, 180.
[27]
Loubiere, K.; Oelgemoller, M.; Aillet, T.; Dechy-Cabaret, O.; Prat, L. Chem. Eng. Process. 2016, 104, 120.
[28]
Mizuno, K.; Nishiyama, Y.; Ogaki, T.; Terao, K.; Ikeda, H.; Kakiuchi, K. J. Photochem. Photobiol., C 2016, 29, 107.
[29]
Fuse, S.; Otake, Y.; Nakamura, H. Eur. J. Org. Chem. 2017, 6466.
[30]
Otake, Y.; Nakamura, H.; Fuse, S. Tetrahedron Lett. 2018, 59, 1691.
[31]
Politano, F.; Oksdath-Mansilla, G. Org. Process Res. Dev. 2018, 22, 1045.
[32]
Di Filippo, M.; Bracken, C.; Baumann, M. Molecules 2020, 25, 356.
[33]
Bacsa, B.; Kappe, C. O. Nat. Protoc. 2007, 2, 2222.
[34]
Szloszar, A.; Mandity, I. M. J. Flow Chem. 2018, 8, 21.
[35]
Hartrampf, N.; Saebi, A.; Poskus, M.; Gates, Z. P.; Pentelute, B. L. Science 2020, 368, 980.
[36]
Mandity, I. M.; Olasz, B.; Otvos, S. B.; Fulop, F. ChemSusChem 2014, 7, 3172.
[37]
Nishimura, S.; Higashi, N.; Koga, T. J. Polym. Sci., Part A: Polym. Chem. 2019, 10, 71.
[38]
Fuse, S.; Mifune, Y.; Takahashi, T. Angew. Chem. Int. Ed. 2014, 53, 851.
[39]
Otake, Y. Adachi, K. Fuse, S. React. Chem. Eng. 2023, 8, 863.
[40]
Li, S. J.; Yang, Y.; Cui, Y. Y.; Su, X. B. Chem. J. Chin. Univ. 2020, 41, 1559 (in Chinese).
[40]
(李士杰, 杨洋, 崔营营, 苏贤斌, 高等学校化学学报, 2020, 41, 1559.)
[41]
Sabatini, M. T.; Boulton, L. T.; Sneddon, H. F. Nat. Catal. 2019, 2, 10.
Options
文章导航

/

〈 〉