Role of secondary structure in the asymmetric acylation reaction catalyzed by peptides based on chiral C alpha-tetrasubstituted alpha-amino acids

J Org Chem. 2004 May 28;69(11):3849-56. doi: 10.1021/jo040107v.

Abstract

In a recent series of papers, Miller and co-workers were able to show that His(pi-Me)-based, terminally protected peptides are potent catalysts of the asymmetric acyl transfer reaction, useful for the kinetic resolution of alcohols. In a structure-supporting solvent, one of the most active compounds, an Aib-containing tetrapeptide, is folded in a doubly intramolecularly H-bonded beta-hairpin motif incorporating a type-II' beta-turn conformation. In this work, we have expanded the study of the Miller tetrapeptide by examining a set of analogues and shorter sequences (dipeptide amides), characterized by chiral C(alpha)-tetrasubstituted alpha-amino acids of diverging bulkiness and optical configuration. Peptide synthesis in solution, conformational analysis by FT-IR absorption and (1)H NMR techniques, and screening of catalytic activity as well have been performed. Our results confirm the close relationship between the beta-hairpin 3D-structure and the catalytic activity of the peptides. A tetrapeptide analogue slightly more selective than the Miller compound has been found. However, the terminally protected, industrially more appealing, dipeptide amides are poorly effective.

MeSH terms

  • Acylation
  • Amino Acids / chemistry*
  • Catalysis
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Protein Conformation
  • Protein Structure, Secondary*
  • Solutions / chemistry
  • Spectroscopy, Fourier Transform Infrared
  • Stereoisomerism

Substances

  • Amino Acids
  • Peptides
  • Solutions