Approaches to stereoselective 1,1'-glycosylation

Nonreducing disaccharides are prevalent in non-mammalian glycans and glycolipids, serving as pivotal structural components in mycobacterial glycans, microbial oligosaccharide and nucleoside antibiotics, as well as biologically active mimetics of bacterial pathogen-associated molecular patterns (PAMPs). As integral components of PAMPs, 1,1'-linked disaccharide-containing biomolecules play important roles in host-pathogen interactions, cellular signaling, and pathogenesis. Accessing complex biomolecules containing nonreducing disaccharides is often hindered by difficulties in isolating them from natural sources, which can result in impure or degraded products, particularly when sensitive functional groups are involved. Consequently, approaches to 1,1'-glycosylation for the synthesis of nonreducing disaccharides with defined anomeric configurations are essential for the development of 1,1'-disaccharide-containing biomolecules used in vaccine research, as well as for therapeutic and diagnostic applications. The assembly of nonreducing 1,1'-linked disaccharides presents greater challenges than conventional chemical glycosylation due to the need for simultaneous control of stereochemistry at two anomeric centers. The structural complexity of natural biomolecules entailing 1,1'-disaccharides, which feature asymmetrically distributed functional groups across their two pyranose rings, emphasizes the importance of robust, stereoselective synthetic strategies capable of producing fully orthogonally protected 1,1'-linked sugars suitable for selective chemical modification. This review highlights recent advances in 1,1'-glycosylation and provides an overview of selected glycosylation strategies, including those aimed at forming α,β-, β,β-, and α,α-1,1'-glycosidic linkages. Particular emphasis is placed on the challenges of achieving stereoselectivity with lactol glycosyl acceptors, which commonly exist as mixtures of anomers and are therefore problematic to use in chemical glycosylation reactions.