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Using l-methionine (Met) as the endogenous directing group, we developed Pd-catalyzed β-C(sp 3 )-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 N,S -bidentate directing group and exhibited an effect superior to other amino acid residues such as l-aspartic acid (Asp), l-asparagine (Asn), and S -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.

Peptide modification by C(sp 3 )-H functionalization of residues at the internal positions remains underdeveloped due to the inhibitory effect of backbone amides. In this study, using histidine (His) as an endogenous directing group, we developed a novel method for the β-C(sp 3 )-H functionalization of alanine (Ala) at diverse positions of peptides. Through this approach, a wide range of linear peptides were modified on the side-chain of Ala adjacent to His to afford the functionalized peptides in moderate to good yield and excellent position selectivity. Furthermore, conjugation of peptides with functional molecules such as glucuronide, oleanolic acid, dipeptide, and fluorophore derivatives was achieved.

Peptide modification by C(sp 3 )-H functionalization of internal residues remains a major challenge due to the inhibitory effect of peptide bonds. In this work, we developed a methionine-directed β-C(sp 3 )-H arylation method for internal alanine functionalization. By tuning the σ C-C bond rotation of internal Ala through head-to-tail cyclization, we overcame the inhibitory effect and functionalized a wide range of head-to-tail cyclic peptides with aryl iodides with excellent position selectivity.

Postassembly modification of peptides via C(sp 3 )-H functionalization on aliphatic side chains provides a straightforward approach to access functionalized peptides as therapeutics. However, C(sp 3 )-H functionalization of C-terminal residues remains underdeveloped due to the inhibition effect of secondary amides in the backbone. Herein, we report a ligand-enabled, bidentate auxiliary-assisted β-C(sp 3 )-H arylation method, which is well tolerant of secondary amides. A wide range of peptides (tri- to dodecapeptides) underwent position-specific modification of alanine at the C-terminus.

Postassembly modification of peptides via C(sp 3 )-H functionalization provides an efficient way to prepare functionalized peptides for biological study and pharmaceutical development. In this work, we developed a new method for γ-C(sp 3 )-H functionalization of aliphatic side chains of N-terminus-unprotected peptides. With the N-terminal residues as directing groups, a wide range of di-, tri-, tetra-, and pentapeptides underwent C-H arylation of the residues (Val, Ile, Tle) at the +2 position from the N-terminus.

Site-selective modification of chemically and biologically valuable α-amino acids and peptides is of great importance for biochemical study and pharmaceutical development. Few methods based on remote C(sp 3 )-H functionalization of aliphatic side-chains of peptides has been disclosed in recent years. In this report, we developed a novel approach for γ-C(sp 3 )-H and γ-/δ-C(sp 2 )-H arylation of α-amino acids with α-hydrogen by native amine-directed C-H functionalization and further realized the γ-C(sp 3 )-H arylation of N -terminally unprotected peptides.