Synthesis of Psi[CH(R-F)NH]Gly-peptides

Serena Bigotti, Stefano V. Meille, Alessandro Volonterio, Matteo Zanda

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13 Citations (Scopus)

Abstract

We describe in full-detail the synthesis of new Psi[CH(R-F)NH]-peptidomimetics, having different fluoroalkyl groups RF, as peptide bond surrogates. A key step in the synthesis is a stereoselective aza-Michael addition of chiral alpha-amino acid esters to beta-fluoroalkyl-alpha-nitroethenes. The diastereoselection of the process was influenced by the electronegativity, rather than by the steric bulk, of the fluorinated residue R-F in the beta-position of the nitroalkene acceptors. Replacement of a single F atom of R-F by a hydrogen or methyl group brings about a dramatic drop of stereocontrol, whereas Br, Cl and CF3, albeit bulkier than F, provide inferior results in terms of stereocontrol. A mechanistic hypothesis is provided. (c) 2008 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)767-774
Number of pages8
JournalJournal of Fluorine Chemistry
Volume129
Issue number9
Early online date27 Jun 2008
DOIs
Publication statusPublished - Sep 2008

Keywords

  • Peptidomimetics
  • Fluorine
  • Electronegativity
  • Peptide bond surrogate
  • Fluoroalkyl
  • Aza-Michael
  • cathepsin-K
  • protease inhibitors
  • peptides
  • transport
  • design

Cite this

Bigotti, S., Meille, S. V., Volonterio, A., & Zanda, M. (2008). Synthesis of Psi[CH(R-F)NH]Gly-peptides. Journal of Fluorine Chemistry, 129(9), 767-774. https://doi.org/10.1016/j.jfluchem.2008.06.018