Synthesis and conformational studies of a Leu-enkephalin amide analogue containing a ferrocene substructure

Solution phase synthesis of a constrained Leu(5)-enkephalin amide analogue is reported, in which the cyclic ferrocenyl containing subunit was introduced as a mimetic of the tetrapeptide Tyr-Gly-Gly-Phe unit. Temperature dependence of the chemical shift of the amide protons of indicated a hydrogen bond between the same amino acid residues as observed for the natural Leu-enkepalin in the single-bend conformation. The rotational barrier (ΔGc‡=16.8 kcal/mol) of the C-terminal amide group, which was determined by DNMR spectroscopy, and NOESY experiments indicated that the two termini were more distant as compared to the single-bend conformation of natural Leu-enkephalin amide.