使用新型芳基硼酸酯保护基高效合成双环肽BI-32169
收稿日期: 2017-10-30
网络出版日期: 2017-11-22
基金资助
项目受山东省自然科学基金、国家自然科学基金（Nos.ZR2016HL57，81700167）资助.
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).
宋慧 , 刘超 , 吴仪君 , 胡宏岗 , 阎芳 . 使用新型芳基硼酸酯保护基高效合成双环肽BI-32169[J]. 化学学报, 2018 , 76(2) : 95 -98 . DOI: 10.6023/A17100473
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.
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