Bio-inspired Herringbone Foldamers: Strategy for Changing the Structure of Helices

Cyclic
oligomers of azole peptides were isolated from a multitude
of marine organisms and were used for a large number of molecular
machines. As shown previously, oligomers derived from achiral imidazole amino acids fold into canonical helices.
Here we show that a minor change, the introduction of a methyl group
in the δ position, results in a significant change in the secondary
structure of the corresponding oligomers. Instead of a canonical helix,
a noncanonical herringbone helix is formed. In the latter, the slope
along the helix changes its sign at least twice per turn. This strategy
allows a remarkable change of the secondary structure via a small
modification. By means of enantiomerically pure amino acids, we were
able to control, for the first time, both the helicity of the helix
and the form of the herringbone. The investigation of the underlying
herringbone basic element and its folding to a noncanonical helix
were conducted by NMR and CD spectroscopy, as well as by X-ray crystallography
and quantum chemical calculations.