Lysine

Reactivity (psychology)

Leaving group

Reagent

Peptide

Catalysis

Nucleophile

Imidazole

Alternative medicine

Medicine

Biochemistry

Histidine

Organic chemistry

Enzyme

Alkylation

Electrophilic substitution

Chemistry

Amino acid

Pathology

Combinatorial chemistry

Cysteine

Electrophile

Stereochemistry

Journal of the American Chemical Society

Histidine (His) carries a unique heteroaromatic imidazole side chain and plays irreplaceable functional roles in peptides and proteins. Existing strategies for site-selective histidine modification predominantly rely on the N-substitution reactions of the moderately nucleophilic imidazole group, which inherently suffers from the interferences from lysine and cysteine residues. Chemoselective modification of histidine remains one of the most difficult challenges in peptide chemistry. Herein, we report peptide modification via radical-mediated chemoselective C–H alkylation of histidine using C4-alkyl-1,4-dihydropyridine (DHP) reagents under visible-light-promoted conditions. The method exploits the electrophilic reactivity of the imidazole ring via a Minisci-type reaction pathway. This method exhibits an exceptionally broad scope for both peptides and DHP alkylation reagents. Its utility has been demonstrated in a series of important peptide drugs, complex natural products, and a small protein. Distinct from N-...

Histidine-Specific Peptide Modification via Visible-Light-Promoted C–H Alkylation