Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland.
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, 464-8602, Japan.
Nat Commun. 2020 Feb 20;11(1):982. doi: 10.1038/s41467-020-14755-6.
Although peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. Aspartimide formation leads to low yields in addition to costly purification or even inaccessible peptide sequences. Here, we report an alternative approach to address this longstanding challenge of peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable C-C bond. These functional groups-formally zwitterionic species-are exceptionally stable to all common manipulations and impart improved solubility during synthesis. Deprotection is readily and rapidly achieved under aqueous conditions with electrophilic halogenating agents via a highly selective C-C bond cleavage reaction. This protecting group is employed for the synthesis of a range of peptides and proteins including teduglutide, ubiquitin, and the low-density lipoprotein class A. This protecting group strategy has the potential to overcome one of the most difficult aspects of modern peptide chemistry.
尽管肽化学已经取得了很大的进展，但在肽合成过程中天门冬酰亚胺的频繁形成仍然是一个巨大的挑战。天门冬酰亚胺的形成不仅导致产率低，而且还需要昂贵的纯化甚至无法获得的肽序列。在这里，我们报告了一种通过利用氰硫酰基来通过稳定的 C-C 键掩蔽羧酸的替代方法来解决肽合成中的这个长期存在的挑战。这些官能团-形式上的两性离子物种-对所有常见的操作都非常稳定，并在合成过程中赋予更好的溶解度。通过高度选择性的 C-C 键断裂反应，在水相中使用亲电卤化剂可以很容易且快速地实现去保护。该保护基被用于合成一系列肽和蛋白质，包括特立格鲁肽、泛素和低密度脂蛋白 A 类。这种保护基策略有可能克服现代肽化学中最困难的方面之一。
