Synthesis and structure analysis of ferrocene-containing pseudopeptides

Area of Science:

• Organometallic Chemistry
• Medicinal Chemistry
• Supramolecular Chemistry

Background:

• Ferrocene, known for its redox properties and medicinal applications (cytotoxic, antianemic), is an attractive building block.
• Incorporating ferrocene into functional moieties can impart unique structural and electronic characteristics.
• Pseudopeptides offer versatile scaffolds for drug design and materials science.

Purpose of the Study:

• To synthesize and characterize two novel pseudopeptides functionalized with a ferrocene (Fc) moiety at the N-terminus.
• To investigate the structural and conformational properties of these ferrocene-containing pseudopeptides in solid-state and solution.
• To explore the influence of the Fc moiety on molecular interactions and conformation.

Main Methods:

• Synthesis and purification of ferrocene-containing pseudopeptides Fc-l-Phe-d-Oxd-OBn and Fc-(l-Phe-d-Oxd)2-OBn.
• Structural analysis using X-ray diffraction, FT-IR, and 1H NMR spectroscopy.
• Conformational analysis in solution using FT-IR, 1H NMR, and chiroptical spectroscopies (ECD, VCD).
• Quantum-mechanical calculations to rationalize spectroscopic data.

Main Results:

• Fc-l-Phe-d-Oxd-OBn crystals exhibit strong π-π interactions between ferrocenyl and phenyl rings, with no N-H•••O=C hydrogen bonds.
• Fc-(l-Phe-d-Oxd)2-OBn adopts a turn conformation stabilized by intramolecular N-H•••O=C hydrogen bonds in solution.
• Chiroptical spectroscopies indicate a lack of well-defined folding but reveal Fc-specific ECD signals, including one sensitive to temperature and Fc core helicity.
• Solid-state ECD spectra correlate with X-ray geometry and computational findings.

Conclusions:

• The ferrocene moiety significantly impacts the structural and conformational behavior of pseudopeptides.
• Distinct intermolecular and intramolecular interactions govern the solid-state and solution structures.
• Ferrocene-based pseudopeptides possess unique spectroscopic properties, particularly in ECD, related to their helicity and conformation.