Are Bronsted Acids the True Promoter of Metal-Triflate-Catalyzed Glycosylations? A Mechanistic Probe into 1,2-cis-Aminoglycoside Formation by Nickel Triflate

Metal triflates have been utilized to catalytically facilitate numerous glycosylation reactions under mild conditions. In some methods, the metal triflate system provides stereocontrol during the glycosylation, rather than the nature of protecting groups on the substrate. Despite these advances, the true activating nature of metal triflates remains unclear. Our findings indicated that the in situ generation of trace amounts of triflic acid from metal triflates can be the active catalyst species in the glycosylation. This fact has been mentioned previously in metal-triflate-catalyzed glycosylation reactions; however, a thorough study on the subject and its implications on stereoselectivity has yet to be performed. Experimental evidence from control reactions and F-19 NMR spectroscopy have been obtained to confirm and quantify the triflic acid released from nickel triflate, for which it is of paramount importance in achieving a stereoselective 1,2-cis-2-amino glycosidic bond formation via a transient anomeric triflate. A putative intermediate resembling that of a glycosyl triflate has been detected using variable temperature NMR (H-1 and C-13) experiments. These observations, together with density functional theory calculations and a kinetic study, corroborate a mechanism involving triflicacid-catalyzed stereoselective glycosylation with N-substituted trifluoromethylbenzylideneamino-protected electrophiles. Specifically, triflic acid facilitates formation of a glycosyl triflate intermediate which then undergoes isomerization from the stable a-anomer to the more reactive beta-anomer. Subsequent S(N)2-like displacement of the reactive anomer by a nucleophile is highly favorable for the production of 1,2-cis-2-aminoglycosides. Although there is a previously reported work regarding glycosyl triflates, none of these reports have been confirmed to come from the counterion of the metal center. Our work provides supporting evidence for the induction of a glycosyl triflate through the role of triflic acid in metal-triflate-catalyzed glycosylation reactions.