- Epimerization-free C-terminal peptide activation, elongation and cyclization
- Award date
- 13 May 2015
- Number of pages
- Document type
- PhD thesis
- Faculty of Science (FNWI)
- Van 't Hoff Institute for Molecular Sciences (HIMS)
C-terminal peptide activation and cyclization reactions are generally accompanied with epimerization (partial loss of C‐terminal stereointegrity). Therefore, the focus of this thesis was to develop epimerization-free methods for C-terminal peptide activation to enable C-terminal peptide elongation and ultimately peptide cyclization.
Chapter 1 briefly screens some parts of the history of peptide synthesis with a special attention to coupling reagents, peptide ligation methods and the origin of the epimerization.
Chapter 2 is dedicated to the synthesis of strained 7-membered homodiketopiperazine rings via C-terminal peptide thioesters in aqueous medium. However, efficient cyclization was only achieved in the reversed sequence containing β-alanine at the C-terminus.
Chapter 3 covers the epimerization-free synthesis of peptide aryl esters and further activation. The linear peptide acids were converted to the aryl esters by a Chan-Lam-Evans (CLE) type esterification reaction. The possibility of C-terminal epimerization is excluded because a Cu(OTf)2-mediated process allows formation of the peptide ester in a such manner that the carboxylic oxygen atom remains in the ester product, which is opposite to the standard coupling reagents. Access to the activated peptides was envisioned through installation of 4-(methylthio)phenyl ester followed by oxidation using OXONE or mCPBA.
Chapter 4 describes application of the 4-(methylsulfonyl)phenyl peptide esters in both C-terminal elongation (NCL and aminolysis) and cyclization reactions with a closer look at the stereointegrity. By careful balancing the reaction conditions, cyclo(-βAla-Phe-) and cyclo(-βAla-D-Phe-) were synthesized in enantiopure form. Finally, the synthesis of gramicidin S was demonstrated by a multistep sequence through C-terminal activation, fragment coupling and cyclization.
- Research conducted at: Universiteit van Amsterdam