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

doi:10.6023/A17100473

Acta Chimica Sinica ›› 2018, Vol. 76 ›› Issue (2): 95-98.DOI: 10.6023/A17100473 Previous Articles Next Articles

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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

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).

1. Efficient Synthesis of Bicyclic Peptide BI-32169 Utilizing a Novel Aryl Boronate Ester Protecting Group.PDF(315KB)

Abstract

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

Cite this article

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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