Polyamides containing
N-methylimidazole (Im) and
N-methylpyrrole (Py) amino acids are synthetic ligands that have an affinity and specificityfor DNA comparable to those of many naturally occurring DNA binding proteins. A machine-assisted Fmoc solid phase synthesis of polyamideshas been optimized to afford high stepwise coupling yields (>99%). Two monomer building blocks, Fmoc-Py acid and Fmoc-Im acid, wereprepared in multigram scale. Cleavage by aminolysis followed by HPLC purification affords up to 200 mg quantities of polyamide with puritiesand yields greater than or equal to those reported using Boc chemistry. A broader set of reaction conditions will increase the number andcomplexity of minor groove binding polyamides which may be prepared and help ensure compatibility with many commercially availablepeptide synthesizers.