Chiral Ferrocene Amines Derived from Amino Acids and Peptides:  Synthesis, Solution and X-ray Crystal Structures and Electrochemical Investigations

Abstract

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 P2(1), a = 10.301(1) A, b = 9.647(1) A, c = 18.479(2) A, beta = 102.98(2) degrees, 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 ((eta-C5H4)Fe(eta-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.

Preparation, Reactivity and Peptide Labelling Properties of (η6‐Arene)ruthenium(II) Complexes with Pendant Carboxylate Groups

“…A range of sandwich complexes have been prepared for this purpose in recent years including the ferrocenylmethyl [30,31] and [(η 5 -Cp*)M{η 6 - nϩ (R ϭ N-succinimide; M ϭ Ir, n ϭ 2; M ϭ Ru, n ϭ 1) fragments. [32,33] We, therefore, prepared both [(η 6 -C 6 Me 6 )Ru(η 6 -ppa)](OTf) 2 and [(η 6 -C 6 Me 6 )Ru(η 6 -pba)](OTf) 2 (10) as potential N-terminal labels for peptides.…”

The synthesis and structural characterization of novel N-meta-ferrocenyl benzoyl dipeptide esters

“…The stability of the ferrocenyl group and its derivatives, in addition to its spectroscopic, electrochemical properties and ease of use make it suitable for biological applications and conjugation with biologically important compounds. The synthesis and structural characterization of novel N-ferrocenoyl and N-ferrocenyl amino acid and peptide derivatives has been reported [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In addition ferrocene has been incorporated in drugs such as antibiotics, aspirin, anti-malarial drugs and anti-cancer drugs such as tamoxifen [22][23][24][25].…”

The synthesis and structural characterization of novel N-meta-ferrocenyl benzoyl amino acid esters

“…The incorporation of a ferrocene group onto proteins has shown the mediation of electron transfer between electrodes and the protein redox site [3,5]. The synthesis and structural characterization of novel N-ferrocenoyl and N-ferrocenyl amino acid and peptide derivatives has been reported [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. The aim of this research is to incorporate three key moieties in the synthesis of unusual biological materials, namely (i) an electroactive core, (ii) a conjugated linker that can act as a chromophore and (iii) an amino acid derivative that can interact with other molecules via hydrogen bonding.…”