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

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

|February 18, 2003

Summary

Minimizing aspartimide formation during peptide synthesis is crucial. Researchers found that using 3-methylpent-3-yl protection for the Asp side chain and Hmb backbone protection for Gly significantly suppressed aspartimide by-products.

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Area of Science:

Organic Chemistry
Peptide Chemistry
Biochemistry

Background:

The aspartimide side reaction is a common challenge in peptide synthesis, leading to unwanted by-products.
Protecting group strategies are essential for controlling side reactions in solid-phase peptide synthesis.

Purpose of the Study:

To investigate the aspartimide problem in detail by evaluating various Asp beta-carboxy protecting groups and Fmoc cleavage protocols.
To identify optimal protecting group combinations for minimizing aspartimide formation during peptide synthesis.

Main Methods:

Synthesis of a model hexapeptide (H-VKDGYI-OH) using different Fmoc-Asp-OH derivatives and backbone protection strategies.
Evaluation of three new Fmoc-Asp-OH derivatives: beta-(4-pyridyl-diphenylmethyl) ester, beta-(9-phenyl-fluoren-9-yl) ester, and an orthoester derivative.

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Quantification of aspartimide and related by-product formation using reversed-phase high-performance liquid chromatography (RP-HPLC).

Main Results:

The use of 3-methylpent-3-yl protection for the Asp side chain demonstrated significant improvements in reducing aspartimide formation.
Complete suppression of aspartimide formation was achieved by combining t-butyl (OtBu) side chain protection with Hmb backbone protection for the preceding Gly residue.
New Fmoc-Asp-OH derivatives were synthesized and tested, contributing to the understanding of their impact on aspartimide formation.

Conclusions:

Specific protecting group strategies, particularly the combination of OtBu and Hmb, can effectively suppress aspartimide formation in peptide synthesis.
The choice of Asp side chain and backbone protecting groups is critical for achieving high purity in synthesized peptides.
This study provides valuable insights for optimizing peptide synthesis protocols to avoid aspartimide-related impurities.