使用新型芳基硼酸酯保护基高效合成双环肽BI-32169

doi:10.6023/A17100473

化学学报 ›› 2018, Vol. 76 ›› Issue (2): 95-98.DOI: 10.6023/A17100473 上一篇下一篇

研究通讯

使用新型芳基硼酸酯保护基高效合成双环肽BI-32169

宋慧^a, 刘超^b, 吴仪君^a, 胡宏岗^b, 阎芳^a

a 潍坊医学院药学院潍坊 261053;
b 第二军医大学药学院有机化学教研室上海 200433

投稿日期:2017-10-30 发布日期:2017-11-22
通讯作者: 胡宏岗, 阎芳 E-mail:hhu66@smmu.edu.com;Yanfang303@163.com
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

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

Received:2017-10-30 Published:2017-11-22
Contact: 10.6023/A17100473 E-mail:hhu66@smmu.edu.com;Yanfang303@163.com
Supported by:
Project supported by the Natural Science Fund of Shandong Province and the National Natural Science Foundation of China (Nos. ZR2016HL57, 81700167).

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摘要/Abstract

芳基硼酸酯作为一种新型的多肽固相合成保护基，相比较烯丙基等传统保护基具有脱除条件简便、高效以及脱保护试剂绿色环保等优势.采用标准9-芴甲氧羰基（Fmoc）固相合成策略，通过固相环合方法，以芳基硼酸酯作为Asp侧链保护基成功首次合成具有独特双环结构的人胰高血糖素受体多肽类抑制剂BI-32169.该方法合成效率高，操作简便，能够为其他类似环肽的化学全合成提供参考.

关键词: 芳基硼酸酯, 多肽固相合成, 双环肽, BI-32169

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.

Key words: aryl boronate ester, solid phase peptide synthesis, bicyclic peptide, BI-32169

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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.

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.

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使用新型芳基硼酸酯保护基高效合成双环肽BI-32169

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

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