Stereoselective 1,2-cis glycosylation via intramolecular aglycone delivery: Opportunities and challenges

The stereoselective synthesis of 1,2-cis glycosidic linkages remains a vital challenge in carbohydrate chemistry owing to the lack of reliable anomeric directing effects. Intramolecular aglycon delivery (IAD) has emerged as an effective strategy to address this problem by employing temporary tethers that guide the glycosyl acceptor toward the anomeric center with high stereocontrol. As the methodology evolved, IAD has been advanced through the introduction of diverse acetal and ketal linkages, including dimethyl, dimethylsilyl, benzylidene, and iodoalkylidene tethers, enabling the efficient synthesis of challenging linkages such as β-mannopyranosides, β-L-rhamnosides, and α-glucosides. Further progress has been facilitated by the development of common alcohol protecting-group as tether, particularly p-methoxybenzyl (PMB) and 2-naphthylmethyl (NAP) groups, which have improved both the versatility and operational simplicity of IAD. A key advantage of this methodology lies in its ability to deliver exclusive 1,2-cis selectivity without generating anomeric mixtures, while also being amenable to iterative assembly of complex glycans. This chapter outlines the development, scope, and mechanistic insight of IAD, highlighting its limitations as well as its potential applications in the stereoselective synthesis of bioactive O-glycosides and structurally complex glycans.