Synthesis of stable C-linked ferrocenyl amino acids and their use in solution-phase peptide synthesis

Incorporation of ferrocenyl group to peptides is an efficient method to alter their hydrophobicity. Ferrocenyl group can also act as an electrochemical probe when incorporated onto functional peptides. Most often, ferrocene is incorporated onto peptides post‐synthesis via amide, ester or triazole linkages. Stable amino acids containing ferrocene as a C‐linked side chain are potentially useful building units for the synthesis of ferrocene‐containing peptides. We report here an efficient route to synthesize ferrocene‐containing amino acids that are stable and can be used in peptide synthesis. Coupling of 2‐ferrocenyl‐1,3‐dithiane and iodides derived from aspartic acid or glutamic acid using n‐butyllithium leads to the incorporation of a ferrocenyl unit to the δ‐position or ε‐position of an α‐amino acid. The reduction or hydrolysis of the dithiane group yields an alkyl or an oxo derivative. The usability of the synthesized amino acids is demonstrated by incorporating one of the amino acids in both C‐terminus and N‐terminus of tripeptides in solution phase. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. An efficient route to the synthesis of amino acids containing a ferrocenyl unit as C‐linked side chains is reported. The method uses 2‐ferrocenyl‐1,3‐dithiane as a starting compound that is coupled with iodides derived from aspartic acid and glutamic acid in the presence of n‐butyllithium to acquire the desired compounds. The stability of the synthesized ferrocenyl amino acids is demonstrated by using them in solution‐phase peptide synthesis.