Indole-fused tetraazacyclooctadecanes: double-helical macrocycles

Transannular hydrogen bonding stabilizes a left-handed double helical conformation in the tryptophan-derived tetraazacyclooctadecane 1 both in solution and the solid state, whereas the analogous tryptamine-derived macrocycle 2 shows less tendency towards intramolecular hydrogen bonding and does not exist as a helix in the crystal. Azamacrocycles 1 and 2 are synthesized by a novel method and their secondary structure analysed by NMR spectroscopy, circular dichroism and X-ray diffraction. Molecular modelling does not account for the conformational differences between 1 and 2.