12/10-Helix in Mixed beta-Peptides Alternating Bicyclic and Acyclic beta-Amino Acids:
Probing the Relationship between Bicyclic Side Chain and Helix Stability
12/10-Helices constitute suitable templates that can be used to design original structures.
Nevertheless, they often suffer from a weak stability in polar solvents because they
exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work,
stable and functionalizable 12/10-helices were developed by alternating a highly constrained
beta(2, 3, 3)-trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic
acid ((S)-ABOC) and an acyclic substituted beta-homologated proteinogenic amino acid
(l-beta(3)-hAA). Based on NMR spectroscopic analysis, it was shown that such mixed
beta-peptides display well-defined right-handed 12/10-helices in polar, apolar, and
chaotropic solvents; that are, CD3OH, CDCl3, and [D-6]DMSO, respectively. The stability
of the hydrogen bonds forming the C-10 and C-12 pseudocycles as well as the benefit
provided by the use of the constrained bicyclic ABOC versus typical acyclic beta-amino
acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange
experiments and DFT calculations in various solvents. These studies showed that the
beta(3)-hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific
stabilization of the C-10 pseudocycles involving the bridgehead NH of the ABOC bicyclic
scaffold.