Chiral ferrocene amines derived from amino acids and peptides: Synthesis, solution and X-ray crystal structures and electrochemical investigations

For the recognition of all but the simplest naturally occurring molecules, electrochemical sensors based on ferrocene will certainly require chiral ce nters. To advance the necessary chemistry, this work describes the synthesi s and ferrocene derivatives of enantiomerically pure amino acids, peptides, and other chiral amines. Ferrocene properties of aldehyde is condensed wit h amino acid esters to yield the corresponding Schiff bases 2, which are re duced by NaBH4 in methanol to the ferrocene methyl amino acids 3. An X-ray single-crystal analysis was carried out on the phenylalanine derivative 3a (monoclinic space group P2(1), a = 10.301(1) Angstrom, b = 9.647(1) Angstro m, c = 18.479(2) Angstrom, beta = 102.98(2)degrees. Z = 4). Further peptide chemistry at the C terminus proceeds smoothly as demonstrated by the synth esis of the ferrocene labeled dipeptide Fc-CH2-Phe-Gly-OCH3 5 (Fe = ferroce nyl ((eta -C5H4)Fe(eta -C5H5))). We also report the synthesis of the C,N-bi s-ferrocene labeled tripeptide Phe-Ala-Leu and its electrochemical characte rization. Starting from the enantiomerically pure ferrocene derivative 9, w hich was synthesized from ferrocene aldehyde and L-1-amino-ethylbenzene, tw o diastereomers 10 were obtained by peptide coupling with N-Boc protected D - and L-alanine. There. was, however, only very little diastereomeric induc tion if 0.5 equiv of a racemic: mixture of alanine were used. This suggests that amino acid activation rather than coupling is the rate-determining st ep. A combination of NOESY (nuclear Overhauser effect spectroscopy) spectra and molecular modeling furnished detailed insights into the solution struc tures of 3, 9, and 10 and was used to rationalize their different reactivit y.