Synthesis of thiourea-tethered C-glycosyl amino acids via isothiocyanate–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(alpha)-Fmoc-beta-amino-l-alanine). Three pairs of compounds with alpha- and beta-galacto, alpha- and beta-gluco, and alpha- and beta-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(alpha)-Fmoc-beta-amino-l-alanine and the N(alpha)-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.