The 4,6-O-phenylboronic ester protection for 1,2-cis-α-selective glucosylation, previously reported by the Crich group, was revisited and the stereodirecting effect of the cyclic protecting group was unveiled. 4,6-O-Phenylboronic ester-protected glucosyl and 2-azido-2-deoxyglucosyl donors exhibited higher α-selectivity of the glucosylation than the corresponding benzylidene-protected donors. Broad substrate scope showcased the utility of the 4,6-O-phenylboronic ester-directed α-glucosylation.

Abstract

1,2-cis-α-Selective glucosylation is highly desirable for synthesis of naturally occurring, biologically important α-glucosides; however, its implementation remains challenging due to the absence of conventional neighboring group participation. In this study, we reinvestigated the α-glucosylation using 4,6-O-phenylboronic ester-protected thioglycoside donor, originally reported by Crich and coworkers in 2003. We report that methyl trifluoromethanesulfonate promoted glucosylation using glucosyl and 2-azido-2-deoxyglucosyl donors in CH₂Cl₂ under reflux conditions, achieving good to excellent α-selectivity (up to α/β = >20/1). Notably, the stereodirecting effect of 4,6-O-phenylboronic ester protection was greater than that of 4,6-benzylidene protection. Mechanistic insight into the origin of the α-selectivity in the glucosylation, obtained from substrate scope results and density function theory calculations, proposed an S_N1 pathway via the formation of an unprecedented borate-type oxocarbenium intermediate favoring α-selective nucleophilic attack. The phenyl boronic ester protecting group can be readily and quantitatively removed by phase-switching aqueous workup using 1.0 m solution of d-sorbitol and Na₂CO₃ after the glucosylation.