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 centers. To advance the necessary chemistry, this work describes the synthesis and
properties of ferrocene derivatives of enantiomerically pure amino acids, peptides, and other chiral amines. Ferrocene
aldehyde is condensed with amino acid esters to yield the corresponding Schiff bases 2, which are reduced 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 P21, a = 10.301(1) Å, b = 9.647(1) Å, c = 18.479(2)
Å, β = 102.98(2)°, Z = 4). Further peptide chemistry at the C terminus proceeds smoothly as demonstrated by
the synthesis of the ferrocene labeled dipeptide Fc-CH2-Phe-Gly-OCH3 5 (Fc = ferrocenyl ((η-C5H4)Fe(η-C5H5))).
We also report the synthesis of the C,N-bis-ferrocene labeled tripeptide Phe-Ala-Leu and its electrochemical
characterization. Starting from the enantiomerically pure ferrocene derivative 9, which was synthesized from
ferrocene aldehyde and l-1-amino-ethylbenzene, two diastereomers 10 were obtained by peptide coupling with
N-Boc protected d- and l-alanine. There was, however, only very little diastereomeric induction 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 step. A combination of NOESY (nuclear Overhauser effect spectroscopy) spectra and molecular
modeling furnished detailed insights into the solution structures of 3, 9, and 10 and was used to rationalize their
different reactivity.