Application of the Hydrogen‐Bond‐Mediated Aglycone Delivery (HAD) Reaction to the Synthesis of α ‐ and β ‐Linked 2‐Azido‐2‐deoxyglucosides

ABSTRACT

Controlling stereoselectivity of glycosylation reactions remains one of the central challenges in synthetic carbohydrate chemistry. In this study, we explore the impact of O‐ picoloyl (Pico) protecting group positioning on the stereoselectivity of glycosylation with 2‐azido‐2‐deoxyglucosyl donors. Three glycosyl donors were designed and synthesized, each bearing the Pico group at a different position (C‐3, C‐4, or C‐6). The glycosyl donor performance was evaluated through H‐bond‐mediated aglycone delivery (HAD) glycosylation reaction with a series of primary and secondary glycosyl acceptors. All donors exhibited good to high yields across a range of substrates. However, the stereochemical outcome proved highly dependent on the position of the Pico group: 3‐Pico and 6‐Pico donors were β ‐gluco selective, whereas 4‐Pico donors produced predominantly α ‐linked products, albeit with moderate selectivity. The performance of the 6‐Pico derivative that produced glycosides with complete β ‐gluco selectivity in all applications, was the most impressive. We then showcased how the 6‐Pico donor could be applied to the synthesis of β ‐linked glycosaminoglycans up to a tetramer. Each glycosylation step proceeded with complete β ‐selectivity, which opens a viable perspective to synthesizing this type of glycan sequence with glycosyl donors lacking a participating group at C‐2.