Amidines are an under-explored isostere of the amide bond that are emerging as a promising candidate for peptide bond surrogates because they more closely approximate the properties of the native amide bond. Amidines have been reported in natural as well as artificially synthesized peptide backbones and have shown to possess potent antibiotic properties. Amidines modulate hydrogen bonding interactions and stabilize helical structure of peptides much like amides, reinforcing their significance as an ideal amide bond isostere. Despite the significance of amidines, their incorporation into linear peptides remains synthetically challenging. To date, the sole reported strategy for installing amidines on linear peptides—via the attack of an amine on an electrophilic thioimidate—suffers from slow kinetics, undesired side reactions and difficult to monitor solid-phase steps, thereby limiting its broad applicability. We have developed strategies for rapid and direct installation of amidines into linear peptides which is compatible with the standard Fmoc solid phase peptide synthesis conditions. This work aims to overcome the critical roadblock of laborious amidine installation on linear peptides and enable their facile incorporation into peptide backbones.
