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

Ferrocene‐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, 1 H and 13 C 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 NH AA2 with 1‐FcCO, 1′‐FcCO and/or N AA1 (Fc = ferrocenyl). The same experiments revealed that NH AA1 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 –1 cm –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 .