Orthoesters formation leading to mismatched Helferich glycosylations at O-3 of N-trichloroacetylated glucosamine residues

•α-L-fucosylation with an armed donor proceeded at N-trichloroacetylated glucosamine residue.•Helferich glycosylation with disarmed donors proceeded at the N-acetylated residue.•Transient unstable orthoester formation may explain apparently mismatched glycosylations.•Conversion of trichloroacetamido to acetamido allowed Helferich galactosylation.•AgOTf catalyzed β-D-galactosylation proceeded kinetically at N-trichloroacetylated residue. [Display omitted] Using trisaccharide diol acceptors displaying two glucosamine residues free at O-3, we observed that α-l-fucosylation with α armed donor proceeded smoothly at the most accessible N-trichloroacetyl nonreducing end glucosamine residue. In contrast, glycosylations with peracetylated glycosyl bromide donors activated under Helferich conditions seemed to proceed preferentially or exclusively at the more sterically hindered N-acetylated reducing end unit. Thus, we concluded that disarmed donors were mismatched at O-3 of the N-trichloroacetylated glucosamine residue regardless of α or β configuration of the glycosidic bond formed and d or l configuration of the donor. Interestingly orthoester formation occurred in some cases at this position while they were not observed at the reducing end unit. Conversion of the nonreducing end trichloroacetamido to an acetamido allowed the Helferich catalyzed galactosylation to occur at both positions and revealed the impact of the N-trichloroacetamido on the mismatched glycosylations. Changing the activation conditions from the mild Lewis acid Hg(CN)2 to the stronger acid AgOTf revealed that in fact β-d-galactosylation at the less hindered N-trichloroacetylated residue was kinetically favored over that at the reducing end residue. Isolation of equal amounts of orthoester at this position suggested that it was formed first but that the strong AgOTf Lewis acid was able to promote rearrangement to the β-d-galactosidic bond. These results shed additional light on the apparent mismatch of disarmed glycosyl donors with hydroxyl groups deemed more accessible. Depending on electronic factors imposed by the acceptor and activation conditions, transient unstable orthoester formation may explain in some cases why these donors appear mismatched with the most accessible hydroxyl groups which are otherwise glycosylated by armed donors.