Sialyl Tn Unit with TFA‐Labile Protection Realizes Efficient Synthesis of Sialyl Glycoprotein

Amino acids bearing 4‐methylbenzyl (MBn) and 4‐methoxybenzyl (MPM)‐protected sialic acid were synthesized and used for the 9‐fluorenylmethoxycarbonyl (Fmoc) solid‐phase synthesis of a glycopeptide. The α‐sialyl linkage of the MBn‐protected unit was partially cleaved under the final deprotection by trifluoroacetic acid (TFA). In addition, the removal of several MBn groups were incomplete. On the other hand, the MPM‐protected unit gave the desired glycopeptide without decomposition of the α‐sialyl linkage. Using this unit, peptide thioesters of the tandem repeat unit of MUC1 mucin were synthesized by the N‐alkylcysteine (NAC) method and used for the one‐pot ligation by the thioester method. As a result, the three tandem repeats of MUC1 carrying sialyl Tn antigens were successfully synthesized. A novel protection strategy for an efficient synthesis of sialylpeptides was developed. Two acid‐labile protecting groups, MPM groups for Neu5Ac and MBn groups for GalNAc, realized the one‐pot final deprotection using a TFA cocktail, keeping α‐sialyl linkage intact. The fully deprotected sialyl glycopeptides were thioesterified by the N‐alkylcysteine method and ligated by the thioester method in one‐pot to obtain the MUC1 three‐tandem repeat domain carrying sialyl Tn antigens.