A tandem in situ peptide cyclization through trifluoroacetic acid cleavage

Koushik Chandra, Tapta Kanchan Roy, Deborah E. Shalev, Abraham Loyter, Chaim Gilon, R. Benny Gerber, Assaf Friedler

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

We present a new approach for peptide cyclization during solid phase synthesis under highly acidic conditions. Our approach involves simultaneous in situ deprotection, cyclization and trifluoroacetic acid (TFA) cleavage of the peptide, which is achieved by forming an amide bond between a lysine side chain and a succinic acid linker at the peptide N-terminus. The reaction proceeds via a highly active succinimide intermediate, which was isolated and characterized. The structure of a model cyclic peptide was solved by NMR spectroscopy. Theoretical calculations support the proposed mechanism of cyclization. Our new methodology is applicable for the formation of macrocycles in solid-phase synthesis of peptides and organic molecules. A new approach for solid-phase peptide cyclization under highly acidic conditions involves tandem in situ deprotection, cyclization, and trifluoroacetic acid cleavage (see scheme). The cyclization occurs between a lysine side chain and a succinic acid derivative at the peptide N-terminus and proceeds via a highly active succinimide intermediate, which was isolated and characterized.

Original languageAmerican English
Pages (from-to)9450-9455
Number of pages6
JournalAngewandte Chemie - International Edition
Volume53
Issue number36
DOIs
StatePublished - 1 Sep 2014

Keywords

  • cyclic peptides
  • cyclization
  • peptide NMR spectroscopy
  • peptide synthesis
  • peptides

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