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

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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.