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The aspartimide problem in Fmoc-based SPPS. Part II.

M Mergler1, F Dick, B Sax

  • 1BACHEM AG, Hauptstr. 144, CH-4416 Bubendorf, Switzerland.

Journal of Peptide Science : an Official Publication of the European Peptide Society
|September 4, 2003
PubMed
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Base-catalyzed aspartimide formation during Fmoc solid-phase peptide synthesis (SPPS) depends on amino acid sequence. Milder Fmoc cleavage methods or specific aspartic acid protection can reduce aspartimide by-product formation.

Area of Science:

  • Organic Chemistry
  • Biochemistry
  • Analytical Chemistry

Background:

  • Fmoc-based solid-phase peptide synthesis (SPPS) is a widely used method for peptide production.
  • Aspartimide formation is a common side reaction during SPPS, leading to impurities.
  • Understanding sequence-dependent side reactions is crucial for optimizing peptide synthesis.

Purpose of the Study:

  • To systematically investigate the sequence dependence of base-catalyzed aspartimide formation in Fmoc-SPPS.
  • To identify specific amino acid sequences that promote aspartimide by-product formation.
  • To evaluate strategies for mitigating aspartimide formation.

Main Methods:

  • Utilized peptide models (H-Val-Lys-Asp-Xaa-Tyr-Ile-OH) to study aspartimide formation.

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  • Employed reversed-phase high-performance liquid chromatography (RP-HPLC) to quantify aspartimide and by-products.
  • Tested different protecting groups for aspartic acid and various Fmoc cleavage conditions.

    • Main Results:

    • Significant aspartimide formation was observed with specific amino acid residues at the Xaa position, including Asp(OtBu), Arg(Pbf), Asn(Mtt), Cys(Acm), and unprotected Thr.
    • Incorporation of Asp(OMpe) effectively reduced aspartimide formation.
    • Milder Fmoc cleavage cocktails, such as hexamethyleneimine/N-methylpyrrolidine/HOBt/NMP/DMSO, also diminished by-product levels.

    Conclusions:

    • Aspartimide formation in Fmoc-SPPS is highly sequence-dependent.
    • Strategic selection of protecting groups (e.g., Asp(OMpe)) and optimization of cleavage conditions are key to minimizing aspartimide by-products.
    • These findings are critical for improving the purity and yield of synthetic peptides.