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3-(1-Piperidinyl)alanine formation during the preparation ofC-terminal cysteine peptides with the Fmoc/t-Bu strategy

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Summary

Several side reactions have been detected for cysteine-containing peptides. During the synthesis ofC-terminal cysteine peptides, a base-catalyzed elimination of the sulfhydryl-protected side-chain to afford the dehydroalanine derivative followed by a nucleophilic addition to the alkene was observed. MALDI-TOF analysis was a useful analytical technique to determine this phenomenon.

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Abbreviations

Acm:

acetamidomethyl

Boc:

tert-butyloxycarbonyl

t-Bu:

tert-butyl

DBU:

1,8-diazabicyclo[5.4.0]undec-7-ene

DIEA:

N,N-diisopropylethylamine

DMF:

N,N-dimethylformamide

Fmoc:

9-fluorenylmethyloxycarbonyl

HATU:

N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphateN-oxide

HBTU:

N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphateN-oxide

HOAt:

1-hydroxy-7-azabenzotriazole

HOBt:

1-hydroxybenzotriazole

HPLC:

high-performance liquid chromatography

MALDI-TOF:

matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

PAC:

4-hydroxymethylphenoxyacetic acid handle

PAL:

5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy-phenoxy)valeric acid handle

PEG-PS:

polyethylene glycol-polystyrene graft supports

PS:

polystyrene

Reagent R:

TFA/thioanisole/1,2-ethanedithiol/anisole (90:5:3:2)

S-t-Bu:

S-tert-butyl mercapto

TFA:

trifluoroacetic acid

Trt:

triphenylmethyl. Amino acid symbols denote thel-configuration, unless indicated otherwise

References

  1. Fields, G.B., Tian, Z. and Barany, G., In Grant, G.A. (Ed.) Synthetic Peptides, A Users Guide, W.H. Freeman, New York, NY, 1993, pp. 77–183.

    Google Scholar 

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

    Google Scholar 

  3. Dolling, R., Beyermann, M., Haenel, J., Kernchen, F., Krause, E., Franke, P., Brudel, M. and Bienert, M., J. Chem. Soc. Chem. Commun., (1994) 853, and references cited therein.

  4. Kates, S.A. and Albericio, F., Lett. Pept. Sci., 1 (1994) 213.

    Google Scholar 

  5. Bayer, E., Gil-Av, E., König, W.A., Nakapartksin, S., Oró, J. and Parr, W., J. Am. Chem. Soc., 92 (1970) 1738.

    Google Scholar 

  6. Engelhard, M. and Merrifield, R.B., J. Am. Chem. Soc., 100 (1978) 3559.

    Google Scholar 

  7. Giralt, E., Andreu, D., Miró, P. and Pedroso, E., Tetrahedron, 39 (1983) 3185.

    Google Scholar 

  8. Fields, C.G. and Fields, G.B., Tetrahedron Lett., 34 (1993) 6661.

    Google Scholar 

  9. Riniker, B. and Hartmann, A., In Rivier, J.E. and Marshall, G.R. (Eds.) Peptides: Chemistry, Structure and Biology (Proceedings of the 11th American Peptide Symposium), ESCOM, Leiden, The Netherlands, 1990, pp. 950–952.

    Google Scholar 

  10. Kates, S.A., Solé, N.A., Albericio, F. and Barany, G., In Basava, C. and Anantharamaiah, G.M. (Eds.) Peptides: Design, Synthesis and Biological Activity, Birkhäuser, Boston, MA, 1994, pp. 39–58.

    Google Scholar 

  11. Andreu, D., Albericio, F., Solé, N.A., Munson, M.C., Ferrer, M. and Barany, G., In Pennington, M.W. and Dunn, B.M. (Eds.) Peptide Synthesis and Purification Protocols, Vol. 35, Humana, Clifton, NJ, 1994, pp. 91–169.

    Google Scholar 

  12. McCurdy, S.N., Pept. Res., 2 (1989) 147.

    Google Scholar 

  13. Veber, D.F., Milkowski, J.D., Varga, S.L., Denkewalter, R.G. and Hirschmann, R., J. Am. Chem. Soc., 94 (1972) 5456.

    Google Scholar 

  14. Albericio, F., Grandas, A., Porta, A., Pedroso, E. and Giralt, E., Synthesis, (1987) 271.

  15. Weber, U. and Hartter, P., Physiol. Chem., 351 (1970) 1384.

    Google Scholar 

  16. Atherton, E., Clive, D.L.J. and Sheppard, R.C., J. Am. Chem. Soc., 97 (1975) 6584.

    Google Scholar 

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

    Google Scholar 

  18. Fujiwara, Y., Akaji, K. and Kiso, Y., In Okada, Y. (Ed.) Peptide Chemistry 1993 (Proceedings of the Japan Symposium on Peptide Chemistry), Protein Research Foundation, Osaka, Japan, 1994, pp. 29–32.

    Google Scholar 

  19. Han, Y., Albericio, F. and Barany, G., J. Org. Chem., (1996), in press.

  20. Kaiser, T., Nicholson, G.J., Kohlbau, H.J. and Voelter, W., Tetrahedron Lett., 37 (1996) 1187.

    Google Scholar 

  21. Eritja, R., Ziehler-Martin, J.P.P., Walker, P.A., Lee, T.D., Legesse, K., Albericio, F. and Kaplan, B.E., Tetrahedron, 43 (1987) 2675.

    Google Scholar 

  22. Rietman, B.H., Peters, R.F.R. and Tesser, G.I., Recl. Trav. Chim. Pays-Bas, 114 (1995) 1.

    Google Scholar 

  23. Bodanszky, M. and Bodanszky, A., J. Chem. Soc. Chem. Commun., (1967) 591.

  24. Kovacs, J., Mayers, G.L., Johnson, R.H. and Ghatak, U.R., J. Chem. Soc. Chem. Commun., (1968) 1066.

  25. Albericio, F., Kneib-Cordonier, N., Biancalana, S., Gera, L., Masada, R.I., Hudson, D. and Barany, G., J. Org. Chem., 55 (1990) 3730.

    Google Scholar 

  26. Carpino, L.A., J. Am. Chem. Soc., 115 (1993) 4397.

    Google Scholar 

  27. Carpino, L.A., El-Faham, A., Minor, C. and Albericio, F., J. Chem. Soc. Chem. Commun., (1994) 201.

  28. Carpino, L.A., El-Faham, A. and Albericio, F., Tetrahedron Lett., 35 (1994) 2279.

    Google Scholar 

  29. Angell, Y., Thomas, T.L., Flentke, G.R. and Rich, D.H., J. Am. Chem. Soc., 117 (1996) 7279.

    Google Scholar 

  30. Bernatowicz, M.S., Kearney, T., Neves, R.S. and Köster, K., Tetrahedron Lett., 30 (1989) 4341.

    Google Scholar 

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

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

    Google Scholar 

  33. Koppel, I., Koppel, J., Lito, I., Pihl, V., Grehn, L. and Ragnarsson, U., J. Chem. Res., (1993) S446 and M2008.

  34. Wade, J.D., Bedford, J., Sheppard, R.C. and Tregear, G.W., Pept. Res., 4 (1996) 194.

    Google Scholar 

  35. Kates, S.A., Solé, N.A., Beyermann, M., Barany, G. and Albericio, F., Pept. Res., (1996), in press.

  36. Zalipsky, S., Chang, J.L., Albericio, F. and Barany, G., React. Polym., 22 (1994) 243.

    Google Scholar 

  37. Albericio, F., Bacardit, J., Barany, G., Coull, J.M., Egholm, M., Giralt, E., Griffin, G.W., Kates, S.A., Nicolás, E. and Solé, N.A., In Maia, H.L.S. (Ed.) Peptides 1994 (Proceedings of the 23rd European Peptide Symposium), ESCOM, Leiden, The Netherlands, 1995, pp. 271–272.

    Google Scholar 

  38. Barany, G., Albericio, F., Solé, N.A., Griffin, G.W., Kates, S.A. and Hudson, D., In Schneider, C.H. and Eberle, A.N. (Eds.) Peptides 1992 (Proceedings of the 22nd European Peptide Symposium), ESCOM, Leiden, The Netherlands, 1993, pp. 267–268.

    Google Scholar 

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Authors and Affiliations

  1. Peptide Synthesis and Analysis Laboratory, NIH-NIAID/LMS, 20852, Rockville, MD, U.S.A.

    Jan Lukszo

  2. PerSeptive Biosystems Inc., 500 Old Connecticut Path, 01701, Framingham, MA, U.S.A.

    Dale Patterson & Steven A. Kates

  3. Department of Organic Chemistry, University of Barcelona, E-08028, Barcelona, Spain

    Fernando Albericio

Authors
  1. Jan Lukszo
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  2. Dale Patterson
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  3. Fernando Albericio
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  4. Steven A. Kates
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Lukszo, J., Patterson, D., Albericio, F. et al. 3-(1-Piperidinyl)alanine formation during the preparation ofC-terminal cysteine peptides with the Fmoc/t-Bu strategy. Lett Pept Sci 3, 157–166 (1996). https://doi.org/10.1007/BF00132978

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  • DOI: https://doi.org/10.1007/BF00132978

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