Benzoylation of Tetrols: A Comparison of Regioselectivity Patterns for O- and S-Glycosides of d-Galactose.

Jack Porter, Jacob Roberts, Gavin J Miller

The Journal of organic chemistry 2024 Oct 04

filter terms:

Efficient protecting group strategies are important for glycan synthesis and represent a unique synthetic challenge in differentiating sugar ring hydroxyl groups. Direct methods to enable regioselective protecting group installation are thus desirable. Herein, we explore a one-step regioselective benzoylation to deliver 2,3,6-protected d-galactose building blocks from tetrols across a variety of α- and β-, O- and S-glycoside substrates. We focus on benzoyl chloride as the esterifying reagent and a reaction temperature of -40 °C to screen the regioselectivity outcome for twenty-two different glycosides, based on isolated yields. Using this methodology, we demonstrate the capability for α-linked aryl and alkyl glycosides (O- and S- d-galactosides, d-galactosamines, and l-fucose), delivering consistent isolated yields (>65%) for 2,3,6-benzoylated products. We extend to explore β-linked systems, where the observed regioselectivity is not paralleled. We posit that both steric and electronic factors from the anomeric substituent contribute to modulating the reactivity competition between 2-OH and 4-OH, enabling the formation of regioisomeric mixtures. However, a certain balance of these factors within the aglycon can deliver 2,3,6-regioselectivity, notably for β-O-Et and β-O-CH2CF3 glycosides. The methodology contributes toward understanding the peculiarities of regioselective carbohydrate-protecting group installation, exploring the importance of the anomeric substituent upon ring hydroxyl group reactivity.

Citation

Jack Porter, Jacob Roberts, Gavin J Miller. Benzoylation of Tetrols: A Comparison of Regioselectivity Patterns for O- and S-Glycosides of d-Galactose. The Journal of organic chemistry. 2024 Oct 04;89(19):14090-14097