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Modulating the structure of phenylalanine‐incorporated ascidiacyclamide through fluorination
Author(s) -
Asano Akiko,
Yamada Takeshi,
Doi Mitsunobu
Publication year - 2014
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2668
Subject(s) - chemistry , stereochemistry , phenylalanine , ring (chemistry) , benzene , residue (chemistry) , fluorine , peptide , alkyl , aromaticity , crystallography , molecule , organic chemistry , amino acid , biochemistry
We designed four fluorinated Phe‐incorporated ascidiacyclamide ([Phe]ASC) analogs, (cyclo(−Xxx1‐oxazoline2‐ d ‐Val3‐thiazole4‐Ile5‐oxazoline6‐ d ‐Val7‐thiazole8‐)), [(4‐F)Phe]ASC (Xxx1: 4‐fluorophenylalanine), [(3,5‐F 2 )Phe]ASC (Xxx1: 3,5‐difluorophenylalanine), [(3,4,5‐F 3 )Phe]ASC (Xxx1: 3,4,5‐trifluorophenylalanine) and [(F 5 )Phe]ASC (Xxx1: pentafluorophenylalanine), to modulate the π ‐electron density of the aromatic ring of the Phe residue. X‐ray diffraction analysis, 1 H NMR and CD spectra all suggested that the interactions between the benzene ring of the Xxx1 residue and the alkyl groups of oxazoline2 contribute to the stability of the folded structure of these analogs. Substituting fluorines for the hydrogens progressively weakened those interactions through reducing the π ‐electron density, thereby mediating transformation from the folded to square structure. As a result, [(F 5 )Phe]ASC preferred the square form more than the other analogs did. Also contributing to the preference for the square form may be the hindrance of the rotation around the C α –C β bond by the two ortho‐fluoro substituents of [(F 5 )Phe]ASC. These findings demonstrate that the structure of ASC can be modulated by using fluorine as an electron‐withdrawing group. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.