Benzoylation of\nTetrols: A Comparison of Regioselectivity\nPatterns for <i>O-</i> and <i>S-</i>Glycosides\nof d‑Galactose

Efficient protecting group strategies are important for\nglycan\nsynthesis and represent a unique synthetic challenge in differentiating\nsugar ring hydroxyl groups. Direct methods to enable regioselective\nprotecting group installation are thus desirable. Herein, we explore\na one-step regioselective benzoylation to deliver 2,3,6-protected d-galactose building blocks from tetrols across a variety of\nα- and β-, <i>O</i>- and <i>S</i>-glycoside\nsubstrates. We focus on benzoyl chloride as the esterifying reagent\nand a reaction temperature of −40 °C to screen the regioselectivity\noutcome for twenty-two different glycosides, based on isolated yields.\nUsing this methodology, we demonstrate the capability for α-linked\naryl and alkyl glycosides (<i>O</i>- and <i>S</i>- d-galactosides, d-galactosamines, and l-fucose), delivering consistent isolated yields (>65%) for 2,3,6-benzoylated\nproducts. We extend to explore β-linked systems, where the observed\nregioselectivity is not paralleled. We posit that both steric and\nelectronic factors from the anomeric substituent contribute to modulating\nthe reactivity competition between 2-OH and 4-OH, enabling the formation\nof regioisomeric mixtures. However, a certain balance of these factors\nwithin the aglycon can deliver 2,3,6-regioselectivity, notably for <i>β-O</i>-Et and <i>β-O</i>-CH<sub>2</sub>CF<sub>3</sub> glycosides. The methodology contributes toward understanding\nthe peculiarities of regioselective carbohydrate-protecting group\ninstallation, exploring the importance of the anomeric substituent\nupon ring hydroxyl group reactivity.