Large-scale and chromatography-free synthesis of an octameric quinoline-based aromatic amide helical foldamer

The synthesis of helical aromatic oligoamide foldamers derived from 8-amino-2-quinolinecarboxylic acid is described. The precursors are commercially available and products up to and including the octamer are obtained. The procedure covers the synthesis of the monomer, reduction of N-terminal nitro groups into amines, saponification of C-terminal methyl esters to form carboxylic acids, and coupling of amines and acids to form amides via acid chloride activation. Emphasis is given to how these reactions can be scaled up and how purification can be greatly simplified using recrystallization methods, thus providing considerable improvements over previously described procedures. As an illustration of the improvement, 8.4 g of an octamer can now reliably be prepared from a nitro-ester monomer in a matter of 8 (working) weeks without any chromatography.