Conformational preferences and synthesis of isomers Z and E of oxazole‐dehydrophenylalanine

Dehydrophenylalanine, ΔPhe, is the most commonly studied α,β‐dehydroamino acid. In nature, further modifications of the α,β‐dehydroamino acids were found, for example, replacement of the C‐terminal amide group by oxazole ring. The conformational properties of oxazole‐dehydrophenylalanine residue (ΔPhe‐Ozl), both isomers Z and E , were investigated. To determine all possible conformations, theoretical calculations were performed using Ac‐(Z/E)‐ΔPhe‐Ozl(4‐Me) model compounds at M06‐2X/6‐31++G(d,p) level of theory. Ac‐(Z/E)‐ΔPhe‐Ozl‐4‐COOEt compounds were synthesized and the conformational preferences of each isomer, Z and E, were investigated using FTIR and NMR‐NOE in solutions of increasing polarity (CHCl 3 , DMSO‐d6). The solid‐state low‐temperature structures of Ac‐(Z)‐ΔPhe‐Ozl‐4‐COOEt and its intermediate analog Ac‐(Z)‐ΔPhe‐Ozn(4‐OH)‐4‐COOEt were also determined. In a weakly polar environment, the ΔPhe‐Ozl residue has a tendency to adopt the conformation β2 with the calculated φ and ψ angles of −127° and 0° for the isomer Z and −170° and 26° for the isomer E. The increase of environment polarity favors the helical conformation α and the beta‐turn like conformation β, but the conformation β2 seems to be still accessible. The (E)‐ΔPhe‐Ozl residue can be obtained from the isomer Z in photoisomerization reaction. However, hydroxyl‐oxazoline‐dehydrophenylalanine ΔPhe‐Ozn(4‐OH) decomposes in such conditions. Alternatively, (E)‐ΔPhe‐NH 2 can be applied as a substrate in the Hantzsch reaction. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 283–294, 2016.