Chemical Glycosylations in Water and Aqueous Media

For most organic chemists, glycosylation is associated with strictly anhydrous conditions. However, carbohydrate chemists may have noticed several high-impact papers on glycosylation in water or aqueous media over the past decade, highlighting its emergence as a promising area. In fact, glycosylation in water or aqueous media dates back to the earliest days of chemical glycosylation. Here we discuss the various types of glycosylation performed in the presence of water, including O-, N-, S-, C-, and Se-glycosylations. For each type, we examine the different approaches developed since the pioneering work of Koenigs and Knorr, who reported the first O-glycosylation in an aqueous medium. The reaction types span a wide range, from common substitution and addition reactions, radical-mediated processes, and anomeric O-, N-, or S-alkylations to metal-catalyzed reactions. Although glycosylations in water are more common than often assumed, the field remains underdeveloped. Protecting groups are still required in many cases; yet, dedicated strategies are lacking, and most protocols rely on glycosyl acceptors that are more nucleophilic than water or on chemistries where water is a poor competitor (e.g., radical processes). This review provides an overview of the field as of early 2025, and we hope it will inspire further development of chemical glycosylation in water.