Synthesis of thiourea-tethered C-glycosyl amino acids viaisothiocyanate–amine coupling

Abstract

A new class of C-glycosyl amino acids displaying a thiourea segment as a linker has been designed and synthesized by addition of peracetylated glycosylmethyl isothiocyanates to an amine-functionalized amino acid (N_α-Fmoc-β-amino-L-alanine). Three pairs of compounds with α- and β-galacto, α- and β-gluco, and α- and β-manno configuration have been prepared with yields ranging between 70 and 75%. The orthogonal set of protective groups (O-acetyl in the carbohydrate moiety and N-Fmoc in the amino acid residue) makes these compounds suitable substrates for the co-translational modification of natural peptides. The couplings of model hydroxy-free and perbenzylated glycosylmethyl isothiocyanates with the above N_α-Fmoc-β-amino-L-alanine and the N_α-Boc-protected analogue have been carried out as well, thus broadening the scope of the coupling reaction. Nevertheless, there are limitations of this isothiocyanate–amine coupling in complex systems, and these are briefly discussed.