A systematic evaluation of different hydrogen bonding patterns in unsymmetrical 1,n′-disubstituted ferrocenoyl peptides

The synthesis and spectroscopic characterization of 21 l,l′-disubstituted ferrocenoyl peptides of the general formula [Fe(C5H4-CO-Aal-OR) (C5H4-CO-Aa2-OR′)] is reported, with Aal and Aa2 being different amino acids. The one-pot synthesis from activated ferrocene-l,l′-dicarboxylic acid and two different amino acid esters gives the unsymmetrical ferrocenoyl peptides in yields between 27% and 42%, which can be easily separated from their symmetrical byproducts by column chromatography. All new compounds are comprehensively characterized by mass spectrometry (El and FAB, including high-resolution EI-MS), 1H and 13C NMR, and UV/Vis spectroscopy. CD spectroscopy in conjunction with 1H NMR is used to elucidate the solution structures. Using the achiral glycine (Gly) as Aal permits to determine qualitatively the structure-determining influence of the different amino acids Aa2. Helically chiral structures in ferrocene amino acids in this study are stabilized by hydrogen bonds. If one hydrogen bond partner is systematically moved away by the introduction of methylene groups, then indeed the strength of the hydrogen bond decreases as indicated by 1H NMR chemical shifts of the amide protons and the strength of characteristic CD bands. As proline (Pro) is the only naturally accuring secondary amino acid it cannot contribute any amide proton to intra-strand hydrogen bonding. DFT calculations on the compound [Fe(C5H4-CO-Gly-OMe)(C5H4-CO-Pro-OMe)] with one achiral and one secondary amino acid were therefore performed to quantify the more subtle influence of the relative orientations of the ferrocene carbonyl groups and the cis-/trans-conformation of both amide bonds. Not unexpectedly, the conformations with both amide bonds in cis orientation are highest in energy. Surprisingly, the calculations suggest the presence of a low-energy conformation with a non-classical hydrogen bond between the proline ester carbonyl oxygen and a glycine Hα atom. However, a second conformation with no apparent intra-strand contacts but optimal positioning of all relevant groups is similar in energy. Although two conformations were observed in solution for this compound, the experimental data did not permit to assign those two conformations.

The unsymmetrical organometallic peptides 1–12 are prepared in a one-pot procedure, starting from ferrocene diacid and two different amino acids. They are easily separated from the symmetrical byproducts and isolated in 27–42% yield. Their H-bonding dominated secondary structures are studied by 1H NMR, CD and DFT methods.Figure optionsDownload as PowerPoint slide