12/10‐Helix in Mixed β‐Peptides Alternating Bicyclic and Acyclic β‐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 β 2, 3, 3 ‐trisubstituted bicyclic amino acid ( S )‐1‐aminobicyclo[2.2.2]octane‐2‐carboxylic acid (( S )‐ABOC) and an acyclic substituted β‐homologated proteinogenic amino acid ( l ‐β 3 ‐hAA). Based on NMR spectroscopic analysis, it was shown that such mixed β‐peptides display well‐defined right‐handed 12/10‐helices in polar, apolar, and chaotropic solvents; that are, CD 3 OH, CDCl 3 , 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 β‐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 β 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.