Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan.
Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan.
J Org Chem. 2022 Sep 2;87(17):11362-11368. doi: 10.1021/acs.joc.2c00828. Epub 2022 Aug 15.
The development of protecting group-free synthesis has come to the forefront this century, as there is an increasing need to switch to greener synthetic methods. In peptide synthesis, a strategy of maximum protection offers the most efficient synthetic pathway, but minimal side chain protection is more favorable in terms of green chemistry. Here, we describe solid-phase peptide synthesis (SPPS) without hydroxy side chain protection based on an aqueous microwave (MW)-assisted method. First, we investigated the extent of -acylation of the hydroxy side chain of Ser, Thr, and Tyr occurring in our method, which uses 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. Under aqueous MW-assisted conditions, the coupling reaction proceeded efficiently without substantial -acylation. Next, we applied the aqueous synthetic protocol without hydroxy side chain protection to synthesis of a laminin-related peptide, H-Tyr-Ile-Gly-Ser-Arg-NH. HPLC analysis of the crude peptide revealed a single peak, suggesting the absence of side reactions including -acylation and racemization. We also succeeded in synthesizing a difficult peptide sequence, acyl carrier protein (65-74) peptide, by aqueous SPPS without hydroxy or carboxamide side chain protection. Based on the eighth criterion of the 12 principles of green chemistry, namely, "reduce derivatives", our approach without hydroxy side chain protection will provide a greener peptide synthesis.
本世纪保护基团免保护合成的发展已成为前沿领域，因为人们越来越需要转向更绿色的合成方法。在肽合成中，最大保护策略提供了最有效的合成途径，但就绿色化学而言，最小化侧链保护更为有利。在这里，我们描述了基于水相微波（MW）辅助方法的无羟基侧链保护的固相肽合成（SPPS）。首先，我们研究了在我们的方法中，使用 4-(4,6-二甲氧基-1,3,5-三嗪-2-基）-4-甲基吗啉鎓氯化物时，Ser、 Thr 和 Tyr 的羟基侧链发生的-酰化程度。在水相 MW 辅助条件下，偶联反应高效进行，没有发生大量的-酰化。接下来，我们将无羟基侧链保护的水相合成方案应用于层粘连蛋白相关肽 H-Tyr-Ile-Gly-Ser-Arg-NH 的合成。粗肽的 HPLC 分析显示出单一峰，表明没有包括-酰化和外消旋化在内的副反应。我们还成功地通过无羟基或羧酰胺侧链保护的水相 SPPS 合成了难以合成的肽序列，酰基辅酶 A 蛋白（65-74）肽。根据绿色化学的 12 条原则中的第 8 条，即“减少衍生化”，我们这种无羟基侧链保护的方法将提供更绿色的肽合成。
