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
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