Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Chembiochem. 2018 May 18;19(10):1031-1035. doi: 10.1002/cbic.201800121. Epub 2018 Apr 26.
Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between β-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 α-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles.
肽大环广泛应用于高亲和力配体的开发，包括订书钉α-螺旋。1,3-二炔基键的线性刚性在 i,i+4 氨基酸侧链的β-碳原子之间提供了最佳距离（7 Å），因此表明其在稳定α-螺旋结构方面的有用性。在这里，我们报告了一种在树脂上通过铜氯化物、必需的 bpy-二醇配体和二异丙基乙胺在室温下进行两个炔基末端侧链之间的分子内 Glaser 反应的策略，该反应的效率通过使用非天然氨基酸炔丙基丝氨酸合成（i,i+4）-、（i,i+5）-、（i,i+6）-和（i,i+7）-订书钉 BCL-9α-螺旋肽来举例说明。总的来说，这种程序简单的方法依赖于廉价且广泛可用的试剂来生成低分子量的 23、26、29 和 32 元肽大环。
