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Optimized Coupling Protocols for the Incorporation of Cys Derivatives during Fmoc-SPPS

  • Guenther Loidl
  • Fritz Dick
  • Monika Mergler
  • Ralph O. Schoenleber
Part of the Advances in Experimental Medicine and Biology book series (volume 611)

Introduction

Incorporation of cysteine during Fmoc-SPPS can result in significant racemization depending on the coupling conditions [1, 2, 3, 4]. During the preparation of cysteine containing peptides as APIs, we identified the necessity to investigate coupling conditions for Fmoc-Cys(Trt)-OH and Fmoc-Cys(Acm)-OH based on previous results of other groups [2, 3, 4] in more detail.

Using the model peptide Z-Ala-Cys(PG)-Pro-OH, we studied the influence of coupling reagent, solvent, activation time, and temperature during preactivation and coupling on the racemization of Cys. SPPS was performed on H-Pro-2-chlorotrityl resin with 3 equiv. of amino acid derivative / coupling reagent / base or additive. Peptides were cleaved from the resin with 1% TFA in DCM. After evaporation, the residue was analyzed on HPLC (C18; gradient of ACN in 0.1% TFA). The content of the LDL-isomer was determined using the relative peak areas A from HPLC as: A(LDL-isomer) / [A(LDL-isomer) + A(LLL-isomer)].

Coupling...

Keywords

Acid Derivative Polar Solvent Clear Increase Relative Peak Weak Base 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

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    Kaiser, T., Nicholson, G. J., Kohlbau, H. J. and Voelter, W. Tetrahedron Lett. 37, 1187 (1996).CrossRefGoogle Scholar
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  4. 4.
    Angell, Y. M., Alsina, J., Albericio, F. and Barany, J. J. Peptide Res. 60, 292 (2002).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Guenther Loidl
    • 1
  • Fritz Dick
    • 1
  • Monika Mergler
    • 1
  • Ralph O. Schoenleber
    • 1
  1. 1.Bachem AGSwitzerland

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