The unnatural organometallic amino acid 1'-aminoferrocene-1-carboxylic acid (Fca) induces a turn structure in a tetrapeptide with anti-parallel strands which is stabilized by two intra-molecular hydrogen bonds in the solid state and in solution.

We present a detailed structural study of peptide derivatives of 1'-aminoferrocene-1-carboxylic acid (ferrocene amino acid, Fca), one of the simplest organometallic amino acids. Fca was incorporated into di- to pentapeptides with D- and L-alanine residues attached to either the carboxy or amino group, or to both. Crystallographic and spectroscopic studies (circular dicroism (CD), IR, and NMR) of about two dozen compounds were used to gain a detailed insight into their structures in the solid state as well as in solution. Four derivatives were characterized by single-crystal X-ray analysis, namely Boc-Fca-Ala-OMe (16), Boc-Fca-D-Ala-OMe (17), Boc-Fca-beta-Ala-OMe (18), and Boc-Ala-Fca-Ala-Ala-OMe (21) (Boc=tert-butyloxycarbamyl). CD spectroscopy is an extremely useful tool to elucidate the helical chirality of the metallocene core. Unlike in all other known ferrocene peptides, the helical chirality of the ferrocene is governed solely by the chirality of the amino acid attached to the N terminus of Fca. Depending on the degree of substitution of both cyclopentadiene (Cp) rings, different hydrogen-bonding patterns are realized. (1)H NMR and IR spectroscopy, together with the results from X-ray crystallography, give detailed information regarding not only the hydrogen-bonding patterns of the compounds, but also the equilibria between different conformers in solution. Differences in chemical shifts of NH protons in dimethyl sulfoxide ([D(6)]DMSO) and CDCl(3), that is, the variation ratio (vr), is used for the first time as a measure of the hydrogen-bonding strength of individual COHN bonds in ferrocenoyl peptides. In dipeptides with one intramolecular hydrogen bond between the pendant chains, for example, in dipeptide 16, an equilibrium between hydrogen-bonded and open forms is observed, as testified by a vr value of around 0.5. Higher peptides, such as tetrapeptide 21, are able to form two intramolecular hydrogen bonds stabilizing one single conformation in CDCl(3) solution (vr approximately 0). Due to the low barrier of Cp-ring rotation, new and unnatural hydrogen-bonding patterns are emerging. The systematic work described herein lays a solid foundation for the rational design of metallocene peptides with unusual structures and properties.

The main conformer of symmetrical conjugates of ferrocene‐1,1′‐dicarboxylic acid with natural amino acids – Fn(CO–AA1–2–OMe)2 (type I, Fn = ferrocene‐1,1′‐diyl, AA = L‐α‐amino acid) – is supported by two hydrogen bonds between the peptide substituents. To compare intramolecular hydrogen bond patterns of type I conjugates with related asymmetrically substituted derivatives, type II (MeNHCO–Fn–CO–AA–OMe) and type III conjugates (MeNHCO–Fn–CO–AA–NHMe) were prepared in moderate‐to‐good yields in a few steps starting from 1′‐(methoxycarbonyl)ferrocene‐1‐carboxylic acid by using the HOBt/EDC method (AA = Gly, Ala, Val). 1H NMR spectroscopic variation ratio analysis suggests that an increase in the steric demand of the amino acid side chains favours conformations with hydrogen‐bonded FnCONHMe groups. CD spectroscopy of chiral derivatives reveals that (P)‐helical conformations predominate in solution. The experimental findings are in accordance with DFT calculations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Structurally different ferrocene peptides I-VI exhibit considerable conformational differences. This study has explored the structural properties of VII [Y-AA-Fca-OMe; Y = di-tert-butyl dicarbonate (Boc), acetyl (Ac); AA = L-Ala, D-Ala; Fca = 1Ј-aminoferrocene-1-carboxylic acid] with an exchanged sequence of constituent amino acids relative to VI (Y-Fca-AA-OMe; Y = Boc, Ac; AA = L-Ala, D-Ala). The ferrocene peptides VII were obtained by coupling C-protected Fca with Boc-L-Ala-OH and Boc-D-Ala-OH, respectively. The Boc protecting groups of the obtained conjugates Boc-AA-Fca-OMe (2a, AA = L-Ala; 2b, AA = D-Ala) were converted to sterically less demanding Ac groups to give Ac-AA-Fca-1820 Avance 300 MHz spectrometer in CDCl 3 solutions with Me 4 Si as the internal standard. Double resonance experiments (COSY, NOESY, and HMBC) were performed in order to assist in signal assignment. CD spectra were recorded using a Jasco-810 spectropolarimeter in CH 3 CN. Molar ellipticity coefficients, [θ], are in degrees, concentration, c, is given in molL -1 , and path length, l, is given in cm, to give units for [θ] of deg cm 2 dmol -1 . Computational Details:The starting geometries of 2a and 3a were generated by the MacroModel v9.8 [26] molecular modeling program using several different search methods and force fields. The conformers were fully optimized at the B3LYP/LanL2DZ level of theory. [23] The most stable were reoptimized in chloroform (using IEF-PCM to describe implicit solvent effects) with the B3LYP method and 6-311+G(d,p) basis set. [24] Iron was modeled using the ECP set LanL2DZ. Quantum mechanical calculations were performed with Gaussian 09, v.A.02. [27] Molecules were visualized using GaussView [28] and Chem 3D (CambridgeSoft, Cambridge, MA) programs. The topological analysis of the selected compounds was performed with the AIM2000 program. [29] Boc-AA-Fca-OMe (2a/2b): The syntheses of 2a and 2b were performed according to our recent paper: [9] the fully protected ferrocene amino acid Boc-Fca-OMe [5] (1) was N-deprotected by gaseous HCl in EtOAc to give the hydrochloride salt, which was treated with NEt 3 and coupled with Boc-AA-OH (AA = l-, d-Ala, previously activated by using EDC and HOBt). After standard workup and TLC-purification, Boc-l-Ala-Fca-OMe (2a) and Boc-d-Ala-Fca-OMe (2b) were obtained as orange resins.

The organometallic amino acid 1′‐aminoferrocene‐1‐carboxylic acid (Fca) was incorporated internally into a peptide sequence by solid‐phase methods combining natural Fmoc‐protected amino acids and Boc‐Fca‐OH to give the pentapeptide Boc‐Fca‐Ala‐Gly‐Val‐Leu‐NH2 (2) and the octapeptide Ac‐Val‐Gly‐Ala‐Fca‐Ala‐Gly‐Val‐Leu‐NH2 (3). Compound 3 was found to have a helically ordered structure by NMR and CD spectroscopy, which is stabilized by intramolecular hydrogen bonding in an antiparallel β‐sheet‐like arrangement. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)