Utilization of bench-stable and readily available nickel(II) triflate for access to 1,2-cis-2-aminoglycosides

The utilization of substoichiometric amounts of commercially available nickel(II) triflate as an activator in the reagent-controlled glycosylation reaction for the stereoselective construction of biologically relevant targets containing 1,2-cis-2-amino glycosidic linkages is reported. This straightforward and accessible methodology is mild, operationally simple and safe through catalytic activation by readily available Ni(OTf)₂ in comparison to systems employing our previously in-house prepared Ni(4-F-PhCN)₄(OTf)₂. We anticipate that the bench-stable and inexpensive Ni(OTf)₂, coupled with little to no extra laboratory training to set up the glycosylation reaction and no requirement of specialized equipment, should make this methodology be readily adopted by non-carbohydrate specialists. This report further highlights the efficacy of Ni(OTf)₂ to prepare several bioactive motifs, such as blood type A-type V and VI antigens, heparin sulfate disaccharide repeating unit, aminooxy glycosides, and α-GalNAc-Serine conjugate, which cannot be achieved in high yield and α-selectivity utilizing in-house prepared Ni(4-F-PhCN)₄(OTf)₂ catalyst. The newly-developed protocol eliminates the need for the synthesis of Ni(4-F-PhCN)₄(OTf)₂ and is scalable and reproducible. Furthermore, computational simulations in combination with ¹H NMR studies analyzed the effects of various solvents on the intramolecular hydrogen bonding network of tumor-associated mucin Fmoc-protected GalNAc-threonine amino acid antigen derivative, verifying discrepancies found that were previously unreported.