Optimization and Automation of Helical Aromatic Oligoamide Foldamer Solid-Phase Synthesis

Helically folded oligoamides of 8-amino-2-quinolinecarboxylic acid composed of up to 41 units were prepared using optimized manual solid-phase synthesis (SPS). The high yield and purity of the final products places these SPS protocols among the most efficient known to date. Furthermore, analytical methods allowing for the clear identification and purity assessment of the products were validated, including H-1 NMR, a seldom used method for such large molecules. Adaption of the SPS protocols, in particular using in situ acid chloride activation under Appel's conditions, made it possible to efficiently implement SPS on a commercial peptide synthesizer, leading to a dramatic reduction of the laboratory work required to produce long sequences. Automation constitutes a breakthrough for the development of helical aromatic oligoamide foldamers.