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Base-induced side reactions in Fmoc-solid phase peptide synthesis:Minimization by use of piperazine as Nα-deprotectionreagent

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Abstract

Base-induced aspartimide (cyclic imide) and subsequentbase adduct formation in the Fmoc-solid phasesynthesis of sensitive sequences are serious sidereactions that are difficult to both anticipate andcontrol. The effect of extended treatment ofpiperazine as Nα-Fmoc deprotection reagenton two sensitive peptide sequences was examined. Forcomparison, other bases were also investigated,including piperidine, 1-hydroxypiperidine,tetrabutylammonium fluoride, and1,8-diazabicyclo[5.4.0]undec-7-ene. The results showedthat all bases induced varying degrees of bothaspartimide and, in some cases, base adduct formation,although piperazine caused the least side reaction.Use of N-(2-hydroxy-4-methoxybenzyl) peptidebackbone amide protection was confirmed to confercomplete protection against side reaction. In theabsence of such protection, for all bases, the use of1-hydroxybenzotriazole as additive had some, but notcomplete, beneficial effect in further reducing sidereaction. Best results were obtained with piperazinecontaining 0.1M 1-hydroxybenzotriazole indicating thatthis reagent merits serious consideration forNα-deprotection in the Fmoc-solid phasesynthesis of base-sensitive sequences. A furtheradvantage of this reagent is that it causes littleracemisation of resin-bound C-terminal cysteine, anoccasionally serious base-mediated problem in Fmoc-solidphase assembly.

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References

  1. Bodanszky, M., Principles of Peptide Synthesis, Springer-Verlag, Berlin, 1984.

    Google Scholar 

  2. Lauer, J.L., Fields, C.G. and Fields, G.B., Lett. Pept. Sci., 1 (1994) 197.

    Google Scholar 

  3. Dölling, M., Beyermann, M., Haenel, J., Kernchen, F., Krause, E., Franke, P., Brudel, M. and Bienert, M., In Epton, R. (Ed.) Innovation and Perspectives in Solid Phase Synthesis, Proceedings of the 3rd Solid Phase Synthesis Symposium, Mayflower Worldwide, Birmingham, 1994, pp. 489–492.

    Google Scholar 

  4. Dölling, M., Beyermann, M., Haenel, J., Kernchen, F., Krause, E., Franke, P., Brudel, M. and Bienert, M., J. Chem. Soc., Chem. Commun., (1994) 853.

  5. Ede, N.J., Chen, W., McCluskey, J., Jackson, D.C. and Purcell, A.W., Biomed. Pept. Protein Nucl. Acids, 1 (1995) 231.

    Google Scholar 

  6. Martinez, J. and Bodanszky, M., Int. J. Pept. Protein Res., 12 (1978) 277.

    Google Scholar 

  7. Dölling, R., Beyermann, M., Haenel, J., Kernchen, F., Krause, E., Franke, P., Brudel, M. and Bienert, M., In Maia, H.L.S. (Ed.) Peptides 1994, Proceedings of the 23rd European Peptide Symposium, ESCOM, Leiden, 1995, pp. 244–245.

    Google Scholar 

  8. Karlstrom, A. and Unden, A., Tetrahedron Letts., 37 (1996) 4243.

    Google Scholar 

  9. Quibell, M., Owen, D., Packman, L.C. and Johnson, T., J. Chem. Soc., Chem. Commun., (1994) 2343.

  10. Urge, L. and Otvos Jr., L., Lett. Pept. Sci., 1 (1994) 207.

    Google Scholar 

  11. Offer, J., Quibell, M. and Johnson, T., J. Chem. Soc., Perkin Trans. 1, (1996) 175.

    Google Scholar 

  12. Dawson, N.F., Macris, M., Tan, Y.-Y., Summers, R.J., Tregear, G.W. and Wade, J.D., J. Pept. Res., 53 (1999) 542.

    Google Scholar 

  13. Wade, J.D., Dawson, N.F., Macris, M., Mathieu, M., Lin, F., Tan, Y.-Y., Summers, R.J. and Tregear, G.W., In Hu, X., Wang, R. and Tam, J.P. (Eds.), Peptides — Biology and Chemistry, Proceedings of the 1998 Chinese Peptide Symposium, Kluwer, Dordrecht, 2000, pp. 81–84.

    Google Scholar 

  14. Wade, J.D., Bedford, J., Sheppard, R.C. and Tregear, G.W., Pept. Res., 4 (1991) 194.

    Google Scholar 

  15. Kochhar, S. and Christen, P., Anal. Biochem., 178 (1989) 17.

    Google Scholar 

  16. Atherton, E., Hardy, P.D., Harris, D.E. and Matthews, B.H., In Giralt, E. and Andreu, D. (Eds.), Peptides 1990, Proceedings of the 21st European Peptide Symposium, ESCOM, Leiden, 1991, pp. 243–244.

    Google Scholar 

  17. Lukszo, J., Patterson, D., Albericio, F. and Kates, S.A., Lett. Pept. Sci., 3 (1996) 157.

    Google Scholar 

  18. Pedroso, E., Grandas, A., de las Heras, X., Eritja, R. and Giralt, E., Tetrahedron Lett., 27 (1986) 743.

    Google Scholar 

  19. Atherton, E. and Sheppard, R.C., In Udenfriend, S. and Meienhofer, J. (Eds.) The Peptides. Analysis, Synthesis, Biology, Vol. 9, Academic Press, New York, NY, 1987, pp. 1–38.

    Google Scholar 

  20. Carpino, L.A., Acc. Chem. Res., 20 (1987) 401.

    Google Scholar 

  21. Fields, G.B. and Noble, R.L., Int. J. Pept. Protein Res., 35 (1990) 161.

    Google Scholar 

  22. Ueki, M. and Amemiya, M., Tetrahedron Lett., 28 (1987) 6617.

    Google Scholar 

  23. Kates, S.A., Solé, N.A., Beyermann, M., Barany, G. and Albericio, F., Pept. Res., 9 (1996) 106.

    Google Scholar 

  24. Pegoraro, S., Vigano, S., Rovero, P., Revoltella, R., Bicciato, S., Bagno, A., Dettin, M. and Di Bello, C., In Maia, H.L.S. (Ed.) Peptides 1994, Proceedings of the 23rd European Peptide Symposium, ESCOM, Leiden, 1995, pp. 254–255.

    Google Scholar 

  25. Nicolás, E., Pedroso, E. and Giralt, E., Tetrahedron Lett., 30 (1989) 497.

    Google Scholar 

  26. Fujiwara, Y., Akaji, K. and Kiso, Y., Chem. Pharm. Bull., 42 (1994) 724.

    Google Scholar 

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Authors and Affiliations

  1. Howard Florey Institute, University of Melbourne, Parkville, VIC 3052, Australia

    John D. Wade

  2. Howard Florey Institute, University of Melbourne, Parkville, VIC 3052, Australia

    Marc N. Mathieu, Mary Macris & Geoffrey W. Tregear

Authors
  1. John D. Wade
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  2. Marc N. Mathieu
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  3. Mary Macris
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  4. Geoffrey W. Tregear
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Correspondence to John D. Wade.

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Wade, J.D., Mathieu, M.N., Macris, M. et al. Base-induced side reactions in Fmoc-solid phase peptide synthesis:Minimization by use of piperazine as Nα-deprotectionreagent. Letters in Peptide Science 7, 107–112 (2000). https://doi.org/10.1023/A:1008966207751

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