Postassembly Modification of Peptides by Histidine-Directed β-C(sp<sup>3</sup>)–H Arylation of Alanine at the Internal Positions: Overcoming the Inhibitory Effect of Peptide Bonds

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.

Late-Stage Glycosylation of Peptides by Methionine-Directed β-C(sp³)–H Functionalization with 1-Iodoglycals

Ding,

Yao

2024

Late-Stage Modification of Peptides with Maleimides through Palladium-Catalyzed β-C(sp³)–H Alkylation

Lu,

Geng,

Wang

et al. 2024

Transition-metal-catalyzed C−H activation has proven to be a powerful tool for the late-stage modification of peptides. We herein report a method for site-selective alkylation of peptides with maleimides through Pd-catalyzed β-C(sp 3 )−H activation. In this protocol, the methionine residues within peptides serve as the directing groups, which circumvented the preinstallation and subsequent removal of the directing groups. This chemistry exhibited broad substrate scope and can be utilized for peptide ligation.

Triple C–H Activation/Annulation: In Situ Construction of Fluorescent Peptides

Zhang,

Wan,

Quan

et al. 2024

Herein, we report a Rh(III)-catalyzed triple C−H activation−annulation of Phe-based peptides with alkynes for the preparation of fluorescent peptides. The robustness of this protocol is reflected by a broad substrate scope, high atom-and stepeconomy, and excellent chemo-and site-selectivity. An in situ generated polycyclic aromatic hydrocarbon carbocation as a fluorophore exhibits good fluorescence properties (maximum emission wavelength up to 628 nm) and low cell cytotoxicity. The synthetic utility of this method is further demonstrated by versatile product applications in bioconjugation with the protein BSA and specifically targeting lysosomes and mitochondria of live mammalian cells.