Leveraging Hydrazide as Protection for Carboxylic Acid: Suppression of Aspartimide Formation during Fmoc Solid-Phase Peptide Synthesis

Org Lett. 2024 May 31;26(21):4497-4501. doi: 10.1021/acs.orglett.4c01317. Epub 2024 May 20.

Abstract

Despite numerous optimizations in peptide synthesis, the formation of aspartimide remains a significant side reaction that needs to be addressed. Herein, we introduce an approach that utilizes hydrazide as a carboxylic-acid-protecting group to reduce the formation of aspartimide. The aspartic acid hydrazide effectively suppressed the formation of aspartimide, even under microwave conditions, and was readily converted to native aspartic acid using CuSO4 in an aqueous medium.

MeSH terms

  • Aspartic Acid* / analogs & derivatives
  • Aspartic Acid* / chemistry
  • Carboxylic Acids* / chemistry
  • Hydrazines / chemistry
  • Microwaves
  • Molecular Structure
  • Peptides* / chemical synthesis
  • Peptides* / chemistry
  • Peptides* / pharmacology
  • Solid-Phase Synthesis Techniques*

Substances

  • Carboxylic Acids
  • Peptides
  • Aspartic Acid
  • aspartimide
  • Hydrazines