Mechanistic Studies of Malonic Acid-Mediated In Situ Acylation

Koushik Chandra, Johnny N. Naoum, Tapta Kanchan Roy, Chaim Gilon, R. Benny Gerber, Assaf Friedler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

We have previously introduced an easy to perform, costeffective and highly efficient acetylation technique for solid phase synthesis (SPPS). Malonic acid is used as a precursor and the reaction proceeds via a reactive ketene that acetylates the target amine. Here we present a detailed mechanistic study of the malonic acid-mediated acylation. The influence of reaction conditions, peptide sequence and reagents was systematically studied. Our results show that the methodology can be successfully applied to different types of peptides and nonpeptidic molecules irrespective of their structure, sequence, or conformation. Using alkyl, phenyl, and benzyl malonic acid, we synthesized various acyl peptides with almost quantitative yields. The ketenes obtained from the different malonic acid derived precursors were characterized by in situ1H-NMR. The reaction proceeded in short reaction times and resulted in excellent yields when using uronium-based coupling agents, DIPEA as a base, DMF/ DMSO/NMP as solvents, Rink amide/Wang/Merrifield resins, temperature of 20°C, pH 8–12 and 5 min preactivation at inert atmosphere. The reaction was unaffected by Lewis acids, transition metal ions, surfactants, or salt. DFT studies support the kinetically favorable concerted mechanism for CO2 and ketene formation that leads to the thermodynamically stable acylated products. We conclude that the malonic acid-mediated acylation is a general method applicable to various target molecules.

Original languageAmerican English
Pages (from-to)495-505
Number of pages11
JournalBiopolymers
Volume104
Issue number5
DOIs
StatePublished - Sep 2015

Bibliographical note

Publisher Copyright:
© 2015 Wiley Periodicals, Inc.

Keywords

  • SPPS
  • acylation
  • ketene
  • malonic acid
  • mechanism
  • peptides

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