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Detection and minimization of H-phosphonate side reaction during phosphopeptide synthesis by a post-assembly global phosphorylation strategy

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Summary

In the course of solid-phase synthesis of phosphopeptides by a post-assembly global phosphorylation strategy, the corresponding H-phosphonate peptides form as byproducts. We describe model studies to investigate this side reaction as a function of reaction conditions, and use this information to develop conditions that minimize the problem, i.e., use of dibenzyl N,N-di-isopropyl phosphoramidite for phosphitylation, followed immediately by oxidation with anhydrous tert-butyl hydroperoxide in dry tetrahydrofuran under argon, and final acidolytic cleavage.

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References

  1. Ottinger, E.A., Solé, N.A., Tian, Z., Bernlohr, D.A. and Barany, G., In Schneider, C.H. and Eberle, A.N. (Eds.) Peptides 1992 (Proceedings of the 22nd European Peptide Symposium), ESCOM, Leiden, The Netherlands, 1993, pp. 334–335.

    Google Scholar 

  2. Ottinger, E.A., Xu, Q. and Barany, G., In Epton, R. (Ed.) Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Chemical Libraries 1996: Biomedical & Biological Applications, Mayflower Scientific Ltd., Kingswinford, U.K., 1996, pp. 495–498.

    Google Scholar 

  3. Ottinger, E.A., Shekels, L.L., Bernlohr, D.A. and Barany, G., Biochemistry, 32 (1993) 4354.

    Google Scholar 

  4. Koch, C.A., Moran, M., Sadowski, I. and Pawson, T., Mol. Cell. Biol., 9 (1989) 4131.

    Google Scholar 

  5. Pawson, T. and Gish, G.D., Cell, 71 (1992) 359.

    Google Scholar 

  6. Cantley, L.C. and Songyang, Z., J. Cell Sci. (Suppl.), 18 (1994) 121.

    Google Scholar 

  7. Bannwarth, W. and Trzeciak, A., Helv. Chim. Acta, 70 (1987) 175.

    Google Scholar 

  8. Andrews, D.M., Kitchin, J. and Seale, P.W., Int. J. Pept. Protein Res., 38 (1991) 469.

    Google Scholar 

  9. Perich, J.W., Nguyen, D.L. and Reynolds, E.C., Tetrahedron Lett., 32 (1991) 4033.

    Google Scholar 

  10. Pennington, M.W., In Pennington, M.W. and Dunn, B.M. (Eds.) Methods in Molecular Biology, Vol. 35: Peptide Synthesis Protocols, Humana Press, Totowa, NJ, U.S.A., 1994, pp. 195–200.

    Google Scholar 

  11. De Bont, H.B.A., Van Boom, J.H. and Liskamp, R.M.J., Tetrahedron Lett., 31 (1990) 2497.

    Google Scholar 

  12. Kitas, E.A., Knorr, R., Trzeciak, A. and Bannwarth, W., Helv. Chim. Acta, 74 (1991) 1314.

    Google Scholar 

  13. Poteur, L. and Trifilieff, E., Lett. Pept. Sci., 2 (1995) 271.

    Google Scholar 

  14. Hoffmann, R., Wachs, W.O., Berger, R.G., Waidelich, D., Bayer, E., Wager-Redeker, W. and Zeppezauer, M., Int. J. Pept. Protein Res., 45 (1995) 26.

    Google Scholar 

  15. Fields, G.B., Tian, Z. and Barany, G., In Grant, G.A. (Ed.) Synthetic Peptide: A Users Guide, Freeman, New York, NY, U.S.A., 1992, pp. 259–345.

    Google Scholar 

  16. 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 

  17. Ottinger, E.A., Hui, T.Y., Man, Z., Barany, G. and Bernlohr, D.A., Int. J. Pept. Protein Res., 46 (1995) 346.

    Google Scholar 

  18. Xu, Q., Zheng, J., Cowburn, D. and Barany, G., Lett. Pept. Sci., 3 (1996) 31.

    Google Scholar 

  19. Barany, G., Solé, N.A., Van Abel, R.J., Albericio, F. and Selsted, M.E., In Epton, R. (Ed.) Innovations and Perspectives in Solid Phase Synthesis and Related Technologies 1992: Peptides, Polypeptides and Oligonucleotides, Intercept, Andover, U.K., 1992, pp. 29–38.

    Google Scholar 

  20. King, D.S., Fields, C.G. and Fields, G.B., Int. J. Pept. Protein Res., 36 (1990) 255.

    Google Scholar 

  21. Giralt, E., Rizo, J. and Pedroso, E., Tetrahedron, 40 (1984) 4141.

    Google Scholar 

  22. Johnson, C. and Zhang, B.R., Tetrahedron Lett., 36 (1995) 9253.

    Google Scholar 

  23. Xu, Q., Musier-Forsyth, K., Hammer, R.P. and Barany, G., Nucleic Acids Res., 24 (1996) 1602.

    Google Scholar 

  24. Mark, V. and Van Wazer, J.R., J. Org. Chem., 29, (1964) 1006.

    Google Scholar 

  25. Arbuzov, A.E., J. Russ. Phys. Chem. Soc., 38 (1906) 291.

    Google Scholar 

  26. Aksnes, G. and Arknes, D., Acta Chem. Scand., 18 (1964) 1623.

    Google Scholar 

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Author notes

  1. Qinghong Xu

    Present address: The Rockefeller University, 1230 York Avenue, 10021, New York, NY, U.S.A.

  2. Elizabeth A. Ottinger

    Present address: Joslin Diabetes Center, One Joslin Place, 02215, Boston, MA, U.S.A.

  3. Nuria A. Solé

    Present address: Quality Controlled Biochemicals, Inc., 3 Avenue D, 01748, Hopkinton, MA, U.S.A.

Authors and Affiliations

  1. Department of Chemistry, University of Minnesota, 207 Pleasant Street S.E., 55455, Minneapolis, MN, U.S.A.

    Qinghong Xu, Elizabeth A. Ottinger, Nuria A. Solé & George Barany

Authors
  1. Qinghong Xu
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  2. Elizabeth A. Ottinger
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  3. Nuria A. Solé
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  4. George Barany
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Additional information

This work was taken in part from the Ph.D. Theses of E.A. Ottinger (1994) and Q. Xu (1996), University of Minnesota, Minneapolis, MN, U.S.A. Preliminary presentations of portions of this work were made at the Twenty-Second European Peptide Symposium, Interlaken, Switzerland, September 13–19, 1992, see Ref. 1, at the 14th American Peptide Symposium, Columbus, OH, U.S.A., June 18–23, 1995, and at the Fourth International Symposium on Solid Phase Synthesis & Combinatorial Chemical Libraries, Edinburgh, Scotland, U.K., September 12–16, 1995, see Ref. 2. The title side reaction was first discussed for tyrosine (see Refs 1 and 3), but all of the mechanism studies discussed herein are for serine and threonine.

Amino acid symbols denote the l-configuration, and abbreviations for amino acids and peptides follow rules of the IUPAC-IUB Commission of Biochemical Nomenclature [J. Biol. Chem., 247 (1972) 977].

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Xu, Q., Ottinger, E.A., Solé, N.A. et al. Detection and minimization of H-phosphonate side reaction during phosphopeptide synthesis by a post-assembly global phosphorylation strategy. Lett Pept Sci 3, 333–342 (1997). https://doi.org/10.1007/BF00127964

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  • DOI: https://doi.org/10.1007/BF00127964

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