Unsymmetrical 1,n′-disubstituted ferrocenoyl peptides: convenient one pot synthesis and solution structures by CD and NMR spectroscopy

Abstract

We present a systematic study on unsymmetrical amino acid derivatives of 1,1′-ferrocene dicarboxylic acid. A convenient and general one pot synthetic procedure is presented in which the unsymmetrical amino acid derivatives are readily separated by column chromatography. The following ferrocene derivatives Fe[C₅H₄-CO-Aaa₁-OMe][C₅H₄-CO-Aaa₂-OMe] with different amino acids were prepared and their solution structures studied by NMR and CD spectrosocopy (Aaa₁ = Aaa₂ = Phe, 1; Aaa₁ = Aaa₂ = DPhe, 1a; Aaa₁ = Aaa₂ = Ala, 2; Aaa₁ = Phe, Aaa₂ = Ala, 3; Aaa₁ = DPhe, Aaa₂ = Ala, 4; Aaa₁ = Aaa₂ = Pro, 5; Aaa₁ = Aaa₂ = Gly, 6; all amino acids are pure L enantiomers except where stated otherwise). NMR spectroscopy in CDCl₃ confirms intramolecular hydrogen bonds for the disubstituted derivatives 1–4 and 6. CD spectra were recorded for all derivatives in CH₂Cl₂. They clearly show a P helical isomer of the ferrocene moiety for the L amino acid derivatives 1–3 and M helicity for the DPhe derivative 1a. The racemic derivative 6 shows only intermolecular interactions, while the Pro derivative 5, which is devoid of amide protons, most likely exists in an “open conformation”. Most importantly, the unsymmetrical mixed D,L derivative 4 has only a weak CD signal in the ferrocene region which is interpreted as an equilibrium between the P and M helical isomers with a slight excess of the latter.