Site‐ and Stereoselective Glycomodification of Biomolecules through Carbohydrate‐Promoted Pictet–Spengler Reaction

• Published in: Angewandte Chemie Vol. 136; no. 16
• Main Authors: Liu, Bo, Zou, Xiangman, Zhang, Yue, Yang, Yang, Xu, Hao, Tang, Feng, Yu, Huixin, Xia, Fei, Liu, Zhi, Zhao, Jianwei, Shi, Wei, Huang, Wei
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 15.04.2024
• Subjects: Aldehydes; Biocompatibility; Biological activity; Biomolecules; Carbohydrates; Glycan; Glycoconjugates; Glycopeptides; Glycoproteins; Hydrogen bonds; Peptides; Polysaccharides; Stereoselectivity; Substrates; Tryptamine; Tryptamines; Tryptophan
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202401394

Carbohydrates play pivotal roles in an array of essential biological processes and are consequently involved in many diseases. To meet the needs of glycobiology research, chemical enzymatic and non‐enzymatic methods have been developed to generate glycoconjugates with well‐defined structures. Herein, harnessing the unique properties of C6‐oxidized glycans, we report a straightforward and robust strategy for site‐ and stereoselective glycomodification of biomolecules with N‐terminal tryptophan residues by a carbohydrate‐promoted Pictet–Spengler reaction, which is not adapted to typical aldehyde substrates under biocompatible conditions. This method reliably delivers highly homogeneous glycoconjugates with stable linkages and thus has great potential for functional modulation of peptides and proteins in glycobiology research. Moreover, this reaction can be performed at the glycosites of glycopeptides, glycoproteins and living‐cell surfaces in a site‐specific manner. Control experiments indicated that the protected α‐O atom of aldehyde donors and free N−H bond of the tryptamine motif are crucial for this reaction. Mechanistic investigations demonstrated that the reaction exhibited a first‐order dependence on both tryptophan and glycan, and deprotonation/rearomatization of the pentahydro‐β‐carbolinium ion intermediate might be the rate‐determining step. A glycomodification strategy targeting N‐terminal tryptophan of biomolecules was developed using C6‐oxidized glycans through a carbohydrate‐promoted Pictet–Spengler reaction, providing homogeneous glycoconjugates with stable linkages. This method features high efficiency, mild conditions, robustness, biocompatibility, and applicability to a wide range of substrates, including glycans, peptides, proteins, and living‐cell surfaces.