Annulative Editing of Peptide Side Chains: N-Pyridination of Lysine via Chichibabin Pyridine Synthesis in Hexafluoroisopropanol

Modifying the lysine side chain through N-heteroaryl annulation offers a unique opportunity to tailor or edit the structure and properties of the parent peptides. Here, we report two new applications of the Chichibabin pyridine synthesis for lysine-specific peptide modification under mild conditions, employing two distinct classes of aldehyde reagents. Reactions with 2-arylacetaldehydes afforded symmetrical 3,5-diarylpyridinium products via an abnormal Chichibabin pathway, whereas reactions with 2-hydroxyacetaldehyde yielded unsymmetrical 3-hydroxy-4-hydroxylmethylpyridiniums (HHMP) products through an unusual, redox-neutral process. The use of a hexafluoroisopropanol (HFIP) solvent was crucial for the reactivity and selectivity in both reactions. Notably, these Lys-specific N-pyridination strategies demonstrated a rare tolerance toward highly nucleophilic cysteine residues.