Glycopeptide Synthesis Based on a TFA‐Labile Protection Strategy and One‐Pot Four‐Segment Ligation for the Synthesis of O‐Glycosylated Histone H2A

This paper describes the chemical synthesis of O‐glycosylated protein, histone H2A, using the trifluoroacetic acid (TFA)‐labile protection strategy for sugar alcohols in the preparation of the glycosylated peptide segment and the one‐pot four‐peptide‐segment native chemical ligation (NCL) using a peptide thioester and two orthogonal thioester equivalents. Using these key methods, the entire sequence of H2A carrying O‐(N‐acetylglucosamine) at Ser[40] was successfully obtained in a high overall yield. O‐glycosylated protein–histone H2A– was chemically synthesized by novel two methodologies: 1) the TFA‐labile protection strategy using MBn group for a facile glycopeptide synthesis; 2) the one‐pot four‐peptide‐segment ligation using the peptide thioester and two orthogonal thioester equivalents. These methods provided more efficient synthesis to obtain H2A having O‐GlcNAc at Ser.[40]