Department of Medicinal Chemistry, Division of Medicinal Chemical Sciences, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Biopolymers. 2011;96(2):228-39. doi: 10.1002/bip.21410.
We have studied the "S-acyl isopeptide method" for the synthesis of peptides containing difficult sequences. The S-acyl isopeptide, which contains a beta-thioester instead of the native N-acyl bond at a Cys residue, can be converted into the target peptide via an S-to-N intramolecular acyl migration reaction. However, the synthesis of the S-acyl isopeptide structure by Fmoc-based SPPS is hampered by repetitive base treatments; decomposition of the thioester and the epimerization of the thioesterified residue are commonly observed. Here, we adopted allyloxycarbonyl (Aloc) protective group to avoid the problem. Catalytic amount of Pd in the presence of scavengers such as PhSiH3 and dimedone selectively removed the Aloc group with neither decomposition of the thioester structure nor epimerization at the thioesterified residue. A model pentapeptide and amylin(1-12) with difficult sequences were efficiently synthesized by the improved S-acyl isopeptides method. Finally, the isolated S-acyl isopeptides were quantitatively converted into the desired peptides via the S-to-N intramolecular acyl migration reaction. The S-acyl isopeptide method will be a usefuI method to prepare the difficult sequence-containing peptides with Cys residue.
我们研究了用于合成含有困难序列的肽的“S-酰基异肽法”。S-酰基异肽在半胱氨酸残基处含有β-硫酯而不是天然的 N-酰基键，可通过 S 到 N 分子内酰基迁移反应转化为目标肽。然而，基于 Fmoc 的 SPPS 合成 S-酰基异肽结构受到重复碱处理的阻碍；通常观察到硫酯的分解和硫酯化残基的差向异构化。在这里，我们采用了烯丙氧羰基 (Aloc) 保护基来避免这个问题。在 Pd 催化剂和清除剂如 PhSiH3 和二亚甲基酮的存在下，催化量的 Pd 选择性地去除 Aloc 基团，既不会分解硫酯结构，也不会使硫酯化残基差向异构化。通过改进的 S-酰基异肽法，有效地合成了具有困难序列的模型五肽和胰淀素（1-12）。最后，通过 S 到 N 分子内酰基迁移反应，将分离的 S-酰基异肽定量转化为所需的肽。S-酰基异肽法将成为一种有用的方法，用于制备含有半胱氨酸残基的困难序列肽。
