Neighbor-Directed Histidine N (s)–Alkylation: A Route to Imidazolium-Containing Phosphopeptide Macrocycles-Biopolymers

Our recently discovered, selective, on-resin route to N(s)-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In this, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. Interestingly, these cationic moieties subsequently serve to charge-mask the phosphoamino acid group that directed their formation. Neighbor-directed histidine N(s)-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts.