Efficient Synthesis of Bicyclic Peptide BI-32169 Utilizing a Novel Aryl Boronate Ester Protecting Group
Received date: 2017-10-30
Online published: 2017-11-22
Supported by
Project supported by the Natural Science Fund of Shandong Province and the National Natural Science Foundation of China (Nos. ZR2016HL57, 81700167).
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-OtBu 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.
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
[1] (a) Xu, Y.; Wang, L.; He, J.; Bi, Y.; Li, M.; Wang, T.; Wang, L.; Jiang, Y.; Dai, M.; Lu, J.; Xu, M.; Li, Y.; Hu, N.; Li, J.; Mi, S.; Chen, C.; Li, G.; Mu, Y.; Zhao, J.; Kong, L.; Chen, J.; Lai, S.; Wang, W.; Zhao, W.; Ning, G. JAMA 2013, 310, 948.
(b) Li, H.; Long, Y.-Q. Chin. J. Org. Chem. 2016, 36, 736. (李鹤, 龙亚秋, 有机化学, 2016, 36, 736.)
[2] (a) Shi, Y.-H.; Zhou, C.-M.; Zhang, P.-L.; Liu, J.-P.; Zhao, G.-L.; Wang, R.-L. Chin. J. Org. Chem. 2016, 36, 604. (史永恒, 周春梅, 张盼龙, 刘继平, 赵桂龙, 王玉丽, 有机化学, 2016, 36, 604.)
(b) Lu, P.; Liu, X.; Tang, Y.-T.; Xu, Y.-X.; Zhong, W.-L.; Sun, T.; Zhou, H.-G. Acta Chim. Sinica 2016, 74, 155. (卢骋, 刘祥, 唐延婷, 徐永学, 仲威龙, 孙涛, 周红刚, 化学学报, 2016, 74, 155.)
[3] Bringer, J.; Mirouze, J.; Marchal, G. Diabetes 1981, 30, 851.
[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] (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] Knappe, T. A.; Linne, U.; Xie, X. FEBS Lett. 2010, 584, 785.
[7] (a) Chen, Y.-X.; Liu, C.; Li, N.; Wu, Y.; Zhao, Q.-J.; Hu, H.-G.; Li, X.; Zou, Y. Chem. Biodivers 10.1002/cbdv. 201700414.
(b) Tang, S.; Zheng, J.-S.; Yang, K.; Liu, L. Acta Chim. Sinica 2012, 70, 1471. (唐姗, 郑基深, 杨可, 刘磊, 化学学报, 2012, 70, 1471.)
[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] (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] (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.; König, 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] (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] (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) Gonçalves, M.; Estieu-Gionnet, K.; Laïn, G.; Bayle, M. Tetrahedron 2005, 61, 7789.
[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.
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