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12/10‐Helix in Mixed β‐Peptides Alternating Bicyclic and Acyclic β‐Amino Acids: Probing the Relationship between Bicyclic Side Chain and Helix Stability
Author(s) -
Simon Matthieu,
Milbeo Pierre,
Liu Hongtao,
André Christophe,
Wenger Emmanuel,
Martinez Jean,
Amblard Muriel,
Aubert Emmanuel,
Legrand Baptiste,
Calmès Monique
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201804404
Subject(s) - bicyclic molecule , hydrogen bond , chemistry , helix (gastropod) , stereochemistry , amino acid , side chain , octane , crystallography , molecule , organic chemistry , snail , biology , ecology , biochemistry , polymer
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.