Selective N-Arylation of p-Aminophenylalanine in Unprotected Peptides with Organometallic Palladium Reagents

The selective N-arylation of p-aminophenylalanine in polypeptides with pre-formed palladium oxidative addition complexes is described. The depressed pKa of the aniline NH2 group enables chemoselective C-N bond formation on peptides containing multiple other aliphatic amino groups at lysines or the N-terminus via Curtin-Hammett control under mild conditions. Using palladium complexes derived from electron-poor aryl halides, p-aminophenylalanine is fully arylated in aqueous buffer in as little as one hour at micromolar concentrations. A complementary protocol using the non-nucleophilic, organic base 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), expands the substrate scope to tolerate electronrich functional groups provides up to 97% conversion. These procedures enable the chemoselective conjugation of functionally diverse small molecule pharmaceuticals to p-aminophenylalanine containing derivatives of cell-penetrating peptides.

Automated summary

This study discusses the selective N-arylation of p-aminophenylalanine in polypeptides using pre-formed palladium oxidative addition complexes, enabling chemoselective C-N bond formation on peptides containing multiple other amino groups. By utilizing palladium complexes derived from electron-poor aryl halides, p-aminophenylalanine can be fully arylated at micromolar concentrations in aqueous buffer in a short amount of time. A complementary protocol using the non-nucleophilic, organic base 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) expands the substrate scope and provides high conversion rates of up to 97%.