Late-Stage Glycosylation of Peptides by Methionine-Directed β-C(sp)-H Functionalization with 1-Iodoglycals.

Using l-methionine (Met) as the endogenous directing group, we developed Pd-catalyzed β-C(sp)-H glycosylation of peptides with 1-iodoglycals. A wide range of tri- to hexapeptides containing the Ala-Met motifs underwent Ala C-H glycosylation under the standard conditions to give the glycopeptides smoothly. 15 proteinogenic amino acids (with easily removable protecting groups) were well tolerated. Control experiments indicated that Met acted as a -bidentate directing group and exhibited an effect superior to other amino acid residues such as l-aspartic acid (Asp), l-asparagine (Asn), and -protected l-cysteine (Cys). In addition, further transformation by HFIP-promoted 1,4-elimination furnished another type of glycopeptide with the 1,3-diene motif, which provides a handle for further derivatization.