Neighbor-directed Histidine N(τ)-Alkylation: A Route to Imidazolium-containing Phosphopeptide Macrocycles.

Our recently discovered, selective, on-resin route to N()-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()-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 663-673, 2015.