Recent development on stereoselective intramolecular O-glycosylation methodology

Abstract

Carbohydrates are increasingly recognized for their versatility as scaffolds in biological, pharmaceutical and biotechnological applications, due to their structural diversity, biocompatibility, hydrophilicity, low toxicity, bioavailability, and excellent ADME properties. The important role of carbohydrates in biological systems deepens, the demand for well-defined and anomerically pure carbohydrates in biomedical research has surged. Chemical synthesis remains the most viable method to meet this demand, despite the inherent challenges in glycosylation reactions. Carbohydrate oligomers, in particular, pose significant difficulties due to the need for complex protecting and leaving group modifications, functionalization, labour-intensive purification, and detailed characterization. A precise stereo and regio-control during glycosylation remains one of the major challenges in organic synthesis. To enhance the selectivity in glycosylation products, the concept of 'Intramolecular Glycosylation' was developed, offering a more advanced and efficient alternative route to conventional methods. Various intramolecular glycosylation methods can be classified primarily into three categories: Intramolecular Aglycone Delivery (IAD), Leaving Group-based Intramolecular Glycosylation, and the Molecular Clamp concept. This review article explores the fundamentals of these three methodologies, their significant advancements, and highlights their growing impact on the stereoselective synthesis of numerous bioactive O-glycosides, glycans with diverse functionalities, complex oligosaccharides, and various macrocycles with definite stereoselectivity.