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

Abstract

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-substitution reactions, the unsubstituted nitrogen groups of the modified imidazole ring are conserved in the C–H alkylated products.

Proximity‐driven, Regioselective Chemical Modification of Peptides and Proteins

“…These efforts have been extensively reviewed [1–5] . More recently, several more of these methods have been reported that utilize novel functional groups to demonstrate impressive chemoselectivity to Cys, [6–9] Lys, [10–13] His, [14–16] Met, [17–19] Trp, [20] and Tyr [21] …”

Site‐Selective Trifluoromethylation Reactions of Oligopeptides

“…Conversely, by switching to MeCF 2 SO 2 Na, the corresponding difluoroethylation took place selectively at the His unit. Likewise, the reactivity pattern wherein aromatic His residue was selectively modified in the presence of Trp and Tyr residues was also observed when utilizing non‐fluorinated alkyl radical precursors . Although the mechanism of these trifluoromethylation reactions are not commented in the original publications, a plausible scenario would likely entail a Minisci‐type C−H functionalization step of the imidazole core with the ensuing electrophilic radical species …”

Photocatalytic methods for amino acid modification

“…20). 37 It is believed that homolytic cleavage of the C-C bond in a Hantzsch ester, dihydropyridine (DHP) alkylating reagent occurs under visible light irradiation. The alkyl radical formed can then attack a protonated histidine imidazole ring.…”