Solvent effects on diketopiperazine formation from N-terminal peptide residues

Abstract

The kinetics of diketopiperazine formation from the peptide H-Ala-Pro-NH₂ with the unprotected amino group in the form of its trifluoroacetate salt have been investigated in a large number of solvents, including aprotic and hydroxylic solvents. The first-order rate constant is considerably affected by the solvent properties, its value spanning more than three orders of magnitude. Moreover, alkylammonium carboxylate salts are efficient catalysts of the reaction. The correlation with Kamlet–Taft solvent parameters shows that the reaction rate is retarded by solvents with a high capacity to stabilise solutes that are charged or dipolar, and that are hydrogen donors and/or acceptors. Solvents with high cohesive energy density values significantly increase the reaction rate. These results are discussed in terms of a proton switch in the rate determining step and of solvation stabilisation of the initial state of the peptide and of the transition state of the rate-limiting step.

References

1. B. J. Marsden, T. M.-D. Nguyen and P. W. Schiller, Int. J. Pept. Protein Res., 1993, 41, 313.
2. S. L. Steinberg and J. L. Bada, J. Org. Chem., 1983, 48, 2298.
3. U. Kertesher, M. Bienert, E. Krause, N. Sepetov and B. Mehlis, Int. J. Pept. Protein Res., 1993, 41, 207.
4. S. Capasso, F. Sica, L. Mazzarella, G. Balboni, R. Guerrini and S. Sanvadori, Int. J. Pept. Protein Res., 1995, 45, 567.
5. J. E. Battersby, W. S. Hancock, E. Canova-Davis, J. Oeswein and B. O'Connor, Int. J. Pept. Protein Res., 1994, 44, 215.
6. (a) K. Iénaga, K. Nakamura, M. Kurohashi, T. Nakanishi and T. Ichii, Phytochemistry, 1990, 29, 35; (b) J. Møss and H. J. Bundgaard, J. Pharm. Pharmacol., 1990, 42, 7; (c) T. Shiba, H. Uratani, I. Kubota and Y. Sumi, Biopolymers, 1990, 20, 7.
7. M. Bodanszky and J. Martinez, The Peptides, ed. E. Gross and J. Meienhofer, Academic Press, New York, 1983, vol. 5, ch. 3.
8. S. Capasso, A. Vergara and L. Mazzarella, J. Am. Chem. Soc., 1998, 120, 1990.
9. N. S. Isaac, Physical Organic Chemistry, Longman Scientific & Technical, 1992, ch. 2.
10. K. A. Connors, Chemical Kinetics: The Study of Reaction Rates in Solution, VCH Publishers, New York, 1990, ch. 8.
11. S. Capasso and L. Mazzarella, Peptides, 1998, 19, 1998.
12. M. Bodanszk, Principles of Peptide Synthesis, Springer-Verlag, Berlin, 1984.
13. (a) I. M. Kolthoff, Anal. Chem., 1974, 46, 1992; (b) C. Reichardt, Solvents and Solvent effects in Organic Chemistry, VCH, Weinheim, 1988; (c) M. H. Abraham, P. L. Grellier, J. M. Abboud, R. M. Doherty and R. W. Taft, Can. J. Chem., 1988, 66, 2673.
14. (a) E. S. Hand and W. P. Jencks, J. Am. Chem. Soc., 1975, 97, 6221; (b) R. W. Nagorski, T. Mizerski and J. P. Richard, J. Am. Chem. Soc., 1995, 117, 4718.
15. (a) M. J. Kamlet, J. L. Abboud and R. W. Taft, J. Am. Chem. Soc., 1977, 99, 6027; (b) ibid., 1972, 94, 8325; (c) M. J. Kamlet, J. L. Abboud, M. H. Abraham and R. W. Taft, J. Org. Chem., 1983, 48, 2877.
16. (a) W. P. Jencks, Acc. Chem. Res., 1976, 9, 425; (b) P. Camilleri, R. Ellul, A. J. Kirby and T. G. Mujahid, J. Chem. Soc., Perkin Trans. 2, 1979, 1617; (c) A. J. Kirby, T. G. Mujahid and P. Camilleri, J. Chem. Soc., Perkin Trans. 2, 1979, 1610; (d) J. P. Fox and W. P. Jencks, J. Am. Chem. Soc., 1974, 96, 1436.
17. (a) F. Hibbert, Adv. Phys. Org. Chem., 1986, 22, 113; (b) A. J. Kirby, Adv. Phys. Org. Chem., 1980, 17, 183.
18. B. H. Robinson, Proton-transfer Reactions, ed. E. Caldin and V. Gold, Chapman and Hall Ltd, London, 1975, ch. 5.
19. (a) C. Grathwohl and K. Wüthrich, Biopolymers, 1976, 15, 2025; (b) C. Grathwohl and K. Wüthrich, Biopolymers, 1976, 15, 2043.
20. (a) C. Grathwohl and K. Wüthrich, Biopolymers, 1981, 20, 2623; (b) K. B. Wiberg, P. R. Rabblen, D. J. Rush and T. A. Keith, J. Am. Chem. Soc., 1995, 117, 4261.