Parallel arrangement of peptides appended to a rigid, bimetallic, constrained ring system

Abstract

Cyclic tungsten bis-alkyne complexes derived from a 1,1′-ferrocenyldialkyne (1 and 2) adopt a rigid conformation where the two alkynes are in a syn orientation and are likely positioned about 3.5 Å apart. Since intramolecular hydrogen bonding in protein secondary structures positions the donors and acceptors 3.3 Å apart, it is proposed that linking two peptides to the two alkynes in one of these complexes might be a way to generate a model system for generating peptide β-sheets. To explore this question, a series of peptide derivatives of 1 were prepared. Attachment of peptides to the bimetallic ring system was achieved by reaction of peptide derivatives of 4-iodobenzoic acid or 4-iodoaniline with 1 via a Sonogashira coupling. Subsequent reaction of these dialkynes with W(CO)3(dmtc)2 (dmtc = dimethylditiocarbamate) afforded the desired cyclic tungsten bis-alkyne complexes as a 1:1 mixture of diastereomers. The two diastereomers were not separable using typical chromatographic methods (TLC, HPLC and flash chromatography); however, their presence and relative amounts could be detected and measured in the 1H NMR spectra. The conformations of these peptide derivatives of 1 were examined using NMR and DFT methods. It was found that appending the peptides to the two alkynes did not alter the rigid conformation of the ferrocene-tungsten bis-alkyne ring system found in 1; the ring system remained rigid and retained the intramolecular hydrogen bond across the bimetallic ring system. Whether the amide and urethane NH protons in these complexes are involved in intramolecular hydrogen bonds was explored using a DMSO titration experiment and computational methods. Data from the DMSO titrations showed that there was only one robust intramolecular hydrogen bond, the hydrogen bond across the bimetallic ring; the other amide and urethane NH protons were accessible to the solvent. The DFT calculations showed the peptides attached to the bimetallic ring system can adopt a number of different orientations having similar energies, and that some of these conformations include cross-strand hydrogen bonds. The data indicate that appending peptides to the bimetallic ring system via the two alkynes produces molecules where the two peptides are held in a parallel arrangement.