Preparation and Conformation Analysis of N‐(Ferrocenoyl)dipeptide Esters and Their 1′‐Acetyl Derivatives

Abstract

AbstractFerrocene‐containing dipeptides X‐Fn‐CO‐AA‐AA‐OMe(3/4, X = H, AA = Gly/Ala; 5/6, X = Ac, AA = Gly/Ala, Fn = ferrocene‐1,1′‐diyl) were prepared in 51–67 % yields from the starting appropriate ferrocenecarboxylic acid and dipeptide ester by the HOBt/EDC protocol. Conformation analysis of these bioconjugates was performed by spectroscopic methods (IR, 1H and 13C NMR, CD) and by X‐ray crystal structure analysis, as well as by molecular modelling (DFT). Crystallographic analysis showed that self‐assembly processes prevailed in compound 5, and almost exclusively hydrogen‐bonded species were also detected in all the compounds studied in the solid state by IR spectroscopy (KBr). Spectroscopic studies of conjugates 3–6 undertaken in solution in nonpolar solvents demonstrated formation of intra‐ and interchain weak to medium hydrogen bonds spanning NHAA2 with 1‐FcCO, 1′‐FcCO and/or NAA1 (Fc = ferrocenyl). The same experiments revealed that NHAA1 is not involved in hydrogen bonds. The interchain hydrogen bond in conjugate 6 caused a (P)‐helical arrangement of the ferrocene moiety exhibiting a positive Cotton effect at 495 nm (246 deg M–1cm–1). All of the experimental findings were corroborated by DFT calculations, which furthermore showed conformation preferences in respect to the natural amino acid side chain of conjugates 3–6.