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.
A conformational study of branimycin was performed using single-crystal X-ray crystallography to characterize the solid-state form, while a combination of NMR spectroscopy and molecular modeling was employed to gain information about the solution structure. Comparison of the crystal structure with its solution counterpart showed no significant differences in conformation, confirming the relative rigidity of the tricyclic system. However, these experiments revealed that the formerly proposed stereochemistry of branimycin at 17-C should be revised.
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