Citation: Song Hui, Liu Chao, Wu Yijun, Hu Honggang, Yan Fang. Efficient Synthesis of Bicyclic Peptide BI-32169 Utilizing a Novel Aryl Boronate Ester Protecting Group[J]. Acta Chimica Sinica, ;2018, 76(2): 95-98. doi: 10.6023/A17100473 shu

Efficient Synthesis of Bicyclic Peptide BI-32169 Utilizing a Novel Aryl Boronate Ester Protecting Group

Song Hui ^a ,
Liu Chao ^b ,
Wu Yijun ^a ,
Hu Honggang ^b,, ,
Yan Fang ^a,,

a.
Department of Pharmacy, College of Pharmacy, Weifang Medical University, Weifang 261053
b.
Department of Organic Chemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433

Corresponding author: Hu Honggang, hhu66@smmu.edu.com Yan Fang, Yanfang303@163.com
Received Date: 30 October 2017
Available Online: 22 February 2017
Fund Project: the Natural Science Fund of Shandong Province and the National Natural Science Foundation of China ZR2016HL57the Natural Science Fund of Shandong Province and the National Natural Science Foundation of China 81700167Project supported by the Natural Science Fund of Shandong Province and the National Natural Science Foundation of China (Nos. ZR2016HL57, 81700167)

Figures(7)

Developed as novel protecting groups for solid-phase peptide synthesis, aryl boronate ester based amino acid building blocks exhibit many advantages over Alloc/Allyl groups and other traditional protecting groups due to their environmental-friendly deprotection conditions and high deprotection efficiency. These protecting groups have been found to exhibit all of the chemical properties compatible to the standard Fmoc(9-Fluorenylmethyloxycarbonyl) solid-phase peptide synthesis and to be orthogonal to other protection groups, such as ^tBu (tert-butyl), pbf (2, 2, 4, 6, 7-penta-methyldihydroben zofuran-5-sulfonyl), Trt (trityl) and Boc (t-Butyloxy carbonyl). In this paper, the aryl bronate ester protected Asp was employed to synthesize a lactam-bridged bicyclic peptide, BI-32169 ([Gly-Leu-Pro-Trp-Gly-Cys-Pro-Ser-Asp]-Ile-Pro-Gly-Trp-Asn-Thr-Pro-Trp-Ala-Cys), which is a human glucagon receptor peptide inhibitor, via on-resin cyclization and solution phase oxidative folding. First of all, the Fmoc-Asp(pDobb)-OH (pDobb, dihydroxyborylbenzyl pinacol ester) was successfully synthesized via esterification between Fmoc-Asp-O^tBu and 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) followed by deprotection of ^tBu with trifluoroacetic acid. Subsequently, the fully protected linear peptide was obtained by incorporating Fmoc-Asp(pDobb)-OH into peptide backbone through standard SPPS using HCTU/DIPEA as the coupling reagent and base. The following release of pDobb group on Asp side chain and deprotection of the N-terminal Fmoc group on solid support provided the linear peptide containing a free Asp residue and an N-terminal amino group. The critical cyclization step was accomplished on resin using PyAOP/HOAt/NMM, followed by resin cleavage and global deprotection with TFA/Phenol/Water/TIPS to give the monocyclic peptide. Finally, the intramolecular disulfide bond was formed through oxidative folding in an aqueous environment with 10% DMSO to provide the final bicyclic target, BI-32169, with a total yield about 27%. In summary, the human glucagon receptor peptide inhibitor BI-32169 was successfully synthesized utilizing an aryl boronate ester based amino acid building block via an on-resin cyclization and solution phase oxidative folding strategy. This convenient and efficient synthetic route could provide a way for chemical total synthesis of BI-32169 and other analogues.
- aryl boronate ester,
- solid phase peptide synthesis,
- bicyclic peptide,
- BI-32169
1. [1]
2. [2]
3. [3]
  Bringer, J.; Mirouze, J.; Marchal, G. Diabetes 1981, 30, 851. doi: 10.2337/diab.30.10.851
4. [4]
  (a) Ahn, J. ; Medeiros, M. ; Trivedi, D. ; Hruby, V. J. J. Med. Chem. 2001, 44, 1372. (b) Kodra, J. T. ; Jorgensen, A. S. ; Andersen, B. ; Behrens, C. ; Brand, C. L. ; Christensen, I. T. ; Guldbrandt, M. ; Jeppesen, C. B. ; Knudsen, L. B. ; Madsen, P. ; Nishimura, E. ; Sams, C. ; Sidelmann, U. G. ; Pedersen, R. A. ; Lynn, F. C. ; Lau, J. J. Med. Chem. 2008, 51, 5387.
5. [5]
  (a) Potterat, O. ; Wagner, K. ; Gemmecker, G. J. Nat. Prod. 2004, 67, 1528. (b) Mazur, S. ; Jayalekshmy, P. J. Am. Chem. Soc. 2002, 101, 677.
6. [6]
  Knappe, T. A.; Linne, U.; Xie, X. FEBS Lett. 2010, 584, 785. doi: 10.1016/j.febslet.2009.12.046
7. [7]
8. [8]
  (a) Lagarias, J. G. ; Houghter, R. A. ; Rapoport, H. J. Am. Chem. Soc. 1978, 100, 8202. (b) Iacquier, R. ; Lazaro, R. ; Raniriseheno, H. J. Pept. Prot. Res. 1987, 30, 22. (c) Mazur, S. ; Jayalekshmy, P. J. Am. Chem. Soc. 2002, 101, 677.
9. [9]
  (a) Goncalves, V. ; Gautier, B. ; Garbay, C. ; Vidal, M. ; Inguimbert, N. J. Pept. Sci. 2008, 14, 767. (b) Huang, Y. -C. ; Li, Y. -M. ; Chen, Y. ; Pan, M. ; Li, Y. -T. ; Yu, L. ; Guo, Q. -X. ; Liu, L. Angew. Chem., Int. Ed. 2013, 52, 4858. (c) De, V. M. ; Sinnaeve, D. ; Van, B. J. ; Coenye, T. ; Martins, J. C. ; Madder, A. Chemistry 2014, 20, 7766. (d) Hill, T. A. ; Shepherd, N. E. ; Diness, F. ; Fairlie, D. P. Angew. Chem., Int. Ed. 2014, 53, 13020. (e) Pan, M. ; Gao, S. ; Zheng, Y. ; Tan, X. -D. ; Lan. H. ; Tan, X. -L. ; Sun, D. -M. ; Lu, L. -N. ; Wang, T. ; Zheng, Q. -Y. ; Huang, Y. -C. ; Wang, J. -W. ; Liu, L. J. Am. Chem. Soc. 2016, 138, 7429. (f) Tang, S. ; Liang, L. -J. ; Si, Y. -Y. ; Gao, S. ; Wang, J. -X. ; Liang, J. ; Mei, Z. -Q. ; Zheng, J. -S. ; Liu, L. Angew. Chem., Int. Ed. 2017, 56, 13333.
10. [10]
  (a) Wiley, R. A. ; Rich, D. H. Med. Res. Rev. 1993, 13, 327. (b) Fairlie, D. P. ; Abenante, G. ; March, D. R. Curr. Med. Chem. 1995, 2, 654. (c) Bursavich, M. G. ; Rich, D. H. J. Med. Chem. 2002, 45, 541. (d) Grauer, A. ; K nig, B. Eur. J. Org. Chem. 2009, 30, 5099. (e) Hill, T. A. ; Shepherd, N. E. ; Diness, F. ; Fairlie, D. P. Angew. Chem., Int. Ed. 2014, 53, 13020. (f) Pelay-Gimeno, M. ; Glas, A. ; Koch, O. ; Grossmann, T. N. Angew. Chem., Int. Ed. 2015, 54, 8896.
11. [11]
  (a) Liu, C. ; Zou, Y. ; Song, H. ; Jiang, Y. -Y. ; Hu, H. -G. Eur. J. Org. Chem. 2017, 39, 5916. (b) Li, J. -B. ; Li, Y. -Y. ; He, Q. -Q. ; Li, Y. -M. ; Li, H. -T. ; Liu, L. Org. Biomol. Chem. 2014, 12, 5435.
12. [12]
  (a) Lear, S. ; Munshi, T. ; Hudson, A. S. ; Hatton, C. ; Clardy, J. ; Mosely, J. A. ; Bull, T. J. ; Sit, C. S. ; Cobb, S. L. Org. Biomol. Chem. 2016, 14, 4534. (b) Gon alves, M. ; Estieu-Gionnet, K. ; La n, G. ; Bayle, M. Tetrahedron 2005, 61, 7789.
13. [13]
  (a) Guo, Y. ; Liu, C. ; Song, H. ; Wang, F. -L. ; Zou, Y. ; Wu, Q. -Y. ; Hu, H. -G. RSC Adv. 2017, 7, 2110. (b) Cui, H. -K. ; Guo, Y. ; He, Y. ; Wang, F. -L. ; Chang, H. -N. ; Wang, Y. -J. ; Wu, F. -M. ; Tian, C. -L. ; Liu, L. Angew. Chem., Int. Ed. 2013, 52, 9558. (c) Guo, Y. ; Sun, D. -M. ; Wang, F. -L. ; He, Y. ; Liu, L. ; Tian, C. -L. Angew. Chem., Int. Ed. 2015, 54, 14276.
1. [1]
  Yinuo Wang , Siran Wang , Yilong Zhao , Dazhen Xu . Selective Synthesis of Diarylmethyl Anilines and Triarylmethanes via Multicomponent Reactions: Introduce a Comprehensive Experiment of Organic Chemistry. University Chemistry, 2024, 39(8): 324-330. doi: 10.3866/PKU.DXHX202401063
2. [2]
  Rui Gao , Ying Zhou , Yifan Hu , Siyuan Chen , Shouhong Xu , Qianfu Luo , Wenqing Zhang . Design, Synthesis and Performance Experiment of Novel Photoswitchable Hybrid Tetraarylethenes. University Chemistry, 2024, 39(5): 125-133. doi: 10.3866/PKU.DXHX202310050
3. [3]
  Yongpo Zhang , Xinfeng Li , Yafei Song , Mengyao Sun , Congcong Yin , Chunyan Gao , Jinzhong Zhao . Synthesis of Chlorine-Bridged Binuclear Cu(I) Complexes Based on Conjugation-Driven Cu(II) Oxidized Secondary Amines. University Chemistry, 2024, 39(5): 44-51. doi: 10.3866/PKU.DXHX202309092
4. [4]
  Qiangqiang SUN , Pengcheng ZHAO , Ruoyu WU , Baoyue CAO . Multistage microporous bifunctional catalyst constructed by P-doped nickel-based sulfide ultra-thin nanosheets for energy-efficient hydrogen production from water electrolysis. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1151-1161. doi: 10.11862/CJIC.20230454
5. [5]
  Danqing Wu , Jiajun Liu , Tianyu Li , Dazhen Xu , Zhiwei Miao . Research Progress on the Simultaneous Construction of C—O and C—X Bonds via 1,2-Difunctionalization of Olefins through Radical Pathways. University Chemistry, 2024, 39(11): 146-157. doi: 10.12461/PKU.DXHX202403087
6. [6]
  Guang Huang , Lei Li , Dingyi Zhang , Xingze Wang , Yugai Huang , Wenhui Liang , Zhifen Guo , Wenmei Jiao . Cobalt’s Valor, Nickel’s Foe: A Comprehensive Chemical Experiment Utilizing a Cobalt-based Imidazolate Framework for Nickel Ion Removal. University Chemistry, 2024, 39(8): 174-183. doi: 10.3866/PKU.DXHX202311051
7. [7]
  Ling Liu , Haibin Wang , Genrong Qiang . Curriculum Ideological and Political Design for the Comprehensive Preparation Experiment of Ethyl Benzoate Synthesized from Benzyl Alcohol. University Chemistry, 2024, 39(2): 94-98. doi: 10.3866/PKU.DXHX202304080
8. [8]
  Ping Song , Nan Zhang , Jie Wang , Rui Yan , Zhiqiang Wang , Yingxue Jin . Experimental Teaching Design on Synthesis and Antitumor Activity Study of Cu-Pyropheophorbide-a Methyl Ester. University Chemistry, 2024, 39(6): 278-286. doi: 10.3866/PKU.DXHX202310087
9. [9]
  Bingliang Li , Yuying Han , Dianyang Li , Dandan Liu , Wenbin Shang . One-Step Synthesis of Benorilate Guided by Green Chemistry Principles and in vivo Dynamic Evaluation. University Chemistry, 2024, 39(6): 342-349. doi: 10.3866/PKU.DXHX202311070
10. [10]
  Cheng Zheng , Shiying Zheng , Yanping Zhang , Shoutian Zheng , Qiaohua Wei . Synthesis, Copper Content Analysis, and Luminescent Performance Study of Binuclear Copper (I) Complexes with Isomeric Luminescence Shift: A Comprehensive Chemical Experiment Recommendation. University Chemistry, 2024, 39(7): 322-329. doi: 10.3866/PKU.DXHX202310131
11. [11]
  Yuhao SUN , Qingzhe DONG , Lei ZHAO , Xiaodan JIANG , Hailing GUO , Xianglong MENG , Yongmei GUO . Synthesis and antibacterial properties of silver-loaded sod-based zeolite. Chinese Journal of Inorganic Chemistry, 2024, 40(4): 761-770. doi: 10.11862/CJIC.20230169
12. [12]
  Lirui Shen , Kun Liu , Ying Yang , Dongwan Li , Wengui Chang . Synthesis and Application of Decanedioic Acid-N-Hydroxysuccinimide Ester: Exploration of Teaching Reform in Comprehensive Applied Chemistry Experiment. University Chemistry, 2024, 39(8): 212-220. doi: 10.3866/PKU.DXHX202312035
13. [13]
  Jinghua Wang , Yanxin Yu , Yanbiao Ren , Yesheng Wang . Integration of Science and Education: Investigation of Tributyl Citrate Synthesis under the Promotion of Hydrate Molten Salts for Research and Innovation Training. University Chemistry, 2024, 39(11): 232-240. doi: 10.3866/PKU.DXHX202402057
14. [14]
  Yang Xia , Kangyan Zhang , Heng Yang , Lijuan Shi , Qun Yi . 构建双通道路径增强iCOF/Bi₂O₃ S型异质结在纯水体系中光催化合成H₂O₂性能. Acta Physico-Chimica Sinica, 2024, 40(11): 2407012-. doi: 10.3866/PKU.WHXB202407012
15. [15]
  Jiapei Zou , Junyang Zhang , Xuming Wu , Cong Wei , Simin Fang , Yuxi Wang . A Comprehensive Experiment Based on Electrocatalytic Nitrate Reduction into Ammonia: Synthesis, Characterization, Performance Exploration, and Applicable Design of Copper-based Catalysts. University Chemistry, 2024, 39(6): 373-382. doi: 10.3866/PKU.DXHX202312081
16. [16]
  Xuzhen Wang , Xinkui Wang , Dongxu Tian , Wei Liu . Enhancing the Comprehensive Quality and Innovation Abilities of Graduate Students through a “Student-Centered, Dual Integration and Dual Drive” Teaching Model: A Case Study in the Course of Chemical Reaction Kinetics. University Chemistry, 2024, 39(6): 160-165. doi: 10.3866/PKU.DXHX202401074
17. [17]
  Lei Shu , Zhengqing Hao , Kai Yan , Hong Wang , Lihua Zhu , Fang Chen , Nan Wang . Development of a Double-Carbon Related Experiment: Preparation, Characterization and Carbon-Capture Ability of Eggshell-Derived CaO. University Chemistry, 2024, 39(4): 149-156. doi: 10.3866/PKU.DXHX202310134
18. [18]
  Jin Yan , Chengxia Tong , Yajie Li , Yue Gu , Xuejian Qu , Shigang Wei , Wanchun Zhu , Yupeng Guo . Construction of a “Dual Support, Triple Integration” Chemical Safety Practical Education System. University Chemistry, 2024, 39(7): 69-75. doi: 10.12461/PKU.DXHX202405008
19. [19]
  Linhan Tian , Changsheng Lu . Discussion on Sextuple Bonding in Diatomic Motifs of Chromium Family Elements. University Chemistry, 2024, 39(8): 395-402. doi: 10.3866/PKU.DXHX202401056
20. [20]
  Wei Gao , Jinyue Yang , Wenwei Zhang . Practice and Exploration of Promoting the “Double Reduction” Work with Popular Science Resources in Universities. University Chemistry, 2024, 39(9): 385-391. doi: 10.3866/PKU.DXHX202311008

Get Citation

PDF

XML

Metrics

PDF Downloads(10)
Abstract views(2126)
HTML views(555)

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