1,4-Diazepine-2,5-dione ring formation during solid phase synthesis of peptides containing aspartic acid β-benzyl ester

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Abstract

The Fmoc-based SPPS of H-Xaa-Asp(OBzl)-Yaa-Gly-NH2 sequences results in side reactions yielding not only aspartimide peptides and piperidide derivatives, but also 1,4-diazepine-2,5-dione-peptides. Evidence is presented to show that the 14-diazepine-2,5-dione derivative is formed from the aspartimide peptide. The rate of this ring transformation depends primarily on the tendency to aspartimide and piperidide formation, which is influenced by the nature of the amino acid following the aspartic acid β-benzyl ester (Xaa). However the bulkiness of the amino acid side chain preceeding the aspartic acid β-benzyl ester (Yaa) is also important. Under certain conditions the 1,4-diazepine-2,5-dione peptide derivative may even be formed dominantly, which is a highly undesirable side reaction in peptide synthesis, but which provides a new way for the synthesis of diazepine peptide derivatives with targeted biological or pharmacological activity.

Original languageEnglish
Pages (from-to)742-748
Number of pages7
JournalJournal of Peptide Science
Volume13
Issue number11
DOIs
Publication statusPublished - Nov 1 2007

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Keywords

  • 1,4-diazepine-2,5-dione-peptides
  • Aspartimide
  • Fmoc technique
  • SPPS

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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