Scalable Synthesis of Fmoc-Protected GalNAc-Threonine Amino Acid and T_N Antigen via Nickel Catalysis

Abstract

The highly α-selective and scalable synthesis of the Fmoc-protected GalNAc-threonine amino acid and TN antigen in gram scale (0.5-1 g) is described. The challenging 1,2-cis-2-amino glycosidic bond is addressed through a coupling of threonine residues with C(2)-N-ortho-(trifluoromethyl)benzylidenamino trihaloacetimidate donors mediated by Ni(4-F-PhCN)4(OTf)2. The desired 1,2-cis-2-amino glycoside was obtained in 66% yield (3.77 g) with α-only selectivity and subsequently transformed into the Fmoc-protected GalNAc-threonine and TN antigen. This operationally simple procedure no longer requires utilization of the commonly used C(2)-azido donors and overcomes many of the limitations associated with the synthesis of 1,2-cis linkage.