Solution phase peptide synthesis with ferrocenyl amino acid derivatives

Abstract

We report the successful stepwise synthesis of di- and tripeptides starting from ferrocenyl amino acids in solution. This methodology is extended to the synthesis of homo- and hetero-bimetallic peptides. Using the fluorenyl-methoxy-carbonyl (Fmoc) protecting group, the ferrocenyl methyl leucine derivative 2 is obtained quantitatively as a starting material. Coupling to PG-Ala-OH (PG=protecting group, tert-butoxy-carbonyl (Boc) or Fmoc) and Boc-Met-Phe-OH yields dipeptides 3a, b and the tripeptide 5 in very good yield. The Fmoc derivative 3b can be used for further deprotection/coupling cycles and serves as a precursor for the bis(ferrocenyl) tripeptide 7 after deprotection and coupling to Fc-CH 2-Phe-OH. Coupling of Fmoc deprotected 3b to benzoic acid chromium tricarbonyl yields the hetero-bimetallic dipeptide 8 in good yield. In addition to reversible electrochemistry of the ferrocenyl group, compound 8 shows characteristic IR bands around 2000 cm −1 which enable its sensitive detection. All new compounds are completely characterized. Their constitution is established by MS and characteristic NMR spectra. Two isomers are observed at room temperature because rotation about the tertiary amide bond is slow on the NMR time scale (Δ G ‡=70±1 kJ mol −1 by VT 1H-NMR). Cyclic and square wave voltammetry experiments on the bis(ferrocenyl) tripeptide 7 do not indicate an electronic interaction between the two ferrocenyl moieties. Molecular modelling and NMR investigations do not give any indication of a rigid structure in solution but suggest a through-space distance of about 10 Å between the metal centres.