Bis- and Trisamides Derived From 1′-Aminoferrocene-1-carboxylic Acid and α-Amino Acids: Synthesis and Conformational Analysis

Abstract

Ferrocene derivatives with one or two achiral and chiral arms based on α-amino acids (Gly, l-Ala, l-Val) attached to the cyclopentadienyl rings were prepared by solution-phase peptide synthesis from N-acetyl- and N-Boc-protected 1′-aminoferrocene-1-carboxylic acids (Boc = tert-butoxycarbonyl). The conformational preference in the solid state of selected examples was elucidated by X-ray crystallography. The chiroptical properties of chiral bis- and trisamides were investigated by circular dichroism (CD) spectroscopy in solution. The conformational preference was studied by NMR and IR spectroscopy, as well as by molecular modeling (DFT). For the bisamides, a conformational library is observed in solution. Increasing the steric bulk of the amino acid side chain disfavors several energetically accessible conformers of bisamides and specific conformers can be selected by changing the environment (type of solvent; solid/solution). For the trisamides, a single conformer is highly stabilized by two intramolecular hydrogen bonds irrespective of the size of the protecting group, the size of the amino acid side chain and the medium.

Conjugates of 1'-Aminoferrocene-1-carboxylic Acid and Proline: Synthesis, Conformational Analysis and Biological Evaluation

“…Ac-Fca-Pro-OMe ( 1 ) and Boc-Fca-Pro-OMe ( 2 ) were prepared by coupling of N -protected Fca [25] with C -protected proline following the well-established procedure [16,17,18,19,20,21]. Therefore, HCl·Pro-OMe was treated with an excess of NEt 3 to give the free base which was coupled in situ with Y-Fca-OH (Y = Ac, Boc), previously activated by using the standard HOBt/EDC protocol.…”

“…e ., the incorporation of the conformational constraints (non-peptide moieties) in order to reduce conformational flexibility, the amide bond replacement, the conjugation of peptides with small molecules and the backbone cyclization. 1,1'-Disubstituted ferrocene templates [ferrocene-1,1'-dicarboxylic acid (Fcd), ferrocene-1,1'-diamine (Fcda) and 1'-aminoferrocene-1-carboxylic acid (Fca)] were recognized as useful and efficient bioorganometallic constraints designed to induce chirally organized structures upon conjugation with natural amino acids {Fn-[CO-(AA) m -OMe] 2 ( I ) [6,7,8,9,10,11,12,13]}, {Fn-[NH-(AA) m -OMe] 2 ( II ) [14,15]}, {Y-Fca-(AA) m -OMe ( III ) [16,17,18,19,20,21]} and {Y-(AA) n - Fca-OMe ( IV ) [22]} [Fn = ferrocenylene; AA = amino acid; Y = di- tert- butyldicarbonate (Boc), acetamide (Ac); m = 1, 2; n = 1]. Namely, the introduction of the chiral peptide chains into the ferrocene scaffold enables their communication through intramolecular hydrogen bonds required for 3D structure formation and function of biological systems.…”

“…Our group demonstrated that the attachment of alanine-containing sequences at N - or C - terminus of Fca [25] lead to peptidomimetics III [16,17,18,19,20,21] and IV [22] able to adopt key structural features of protein secondary structure. Certainly, the number and position of hydrogen bond donating sites as well as protecting groups on the N- and C-termini strongly influenced their conformational preferences.…”

The Outer-Coordination Sphere: Incorporating Amino Acids and Peptides as Ligands for Homogeneous Catalysts to Mimic Enzyme Function

“…Many different metals have been used. Fe has been very prevalent in this area because of the stability of ferrocene (161,(164)(165)(166)(167)(168)(169)(170)(171)(172), but Ru (27,173) and Co (174,175) have also been studied (Fig. 44) Most of this work has been focused on structural characterization and has yielded very interesting insights.…”

N-acylbenzotriazole mediated microwave assisted synthesis of protected and novel unprotected ferrocenoylamidoamino acids

“…Ferrocene amino acids [3,4,5,6,7,8,9,10,11,12] and peptides [13,14,15,16,17] have been widely prepared and used in different applications such as binding or caging structures for metal ions [18]. In previous preparation procedures, ferrocenoyl halides (i.e.…”