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DOI: 10.1039/A805478I (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 1, 1998, 3331-3340

Linear and cyclic β3-oligopeptides with functionalised side-chains (-CH2OBn, -CO2Bn, -CH2CH2CO2Bn) derived from serine and from aspartic and glutamic acid

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Jennifer L. Matthews, Karl Gademann, Bernhard Jaun and Dieter Seebach

Abstract

The natural β-amino acid derivative Boc-Asp(β-OH)-OBn, as well as Boc-β-HGlu(OBn)-OH and Boc-β-HSer(OBn)-OH (prepared from appropriately protected glutamic acid and serine, respectively, by Arndt–Eistert homologation), were employed as building blocks for the synthesis of linear (11–20) and cyclic (21–23) β-oligopeptides consisting of two to six β-amino acids [using trichloroethyl (TCE) ester groups for C-terminal protection and pentafluorophenyl-ester activation for macrocyclisation]. While the linear derivatives are soluble enough for reactions and structural investigations in solution, the cyclo-β-tri- and -hexapeptides are not (according to FT-IR measurements they form networks of hydrogen bonds, perhaps consisting of so-called nanotubes). The CD spectra of the Boc–OTCE-protected (19) and of the unprotected (20) β-hexapeptides [β-Asp(OBn)-β-HGlu(OBn)-β-HSer(OBn)]2 differ drastically, and only the unprotected form shows the familiar pattern of a negative Cotton effect between 210 and 220 nm (indicative of a 314 helix). An NMR analysis in methanol of the β-hexapeptide 20 with free termini reveals the presence of a single, central, left-handed helix turn (14-membered hydrogen-bonded ring). The results are discussed and compared with those obtained previously for analogous β-peptides carrying non-functionalised side chains.

References

  1. D. Seebach and J. L. Matthews, Chem. Commun., 1997, 2015 RSC.
  2. D. H. Apella, L. A. Christianson, I. L. Karle, D. R. Powell and S. H. Gellman, J. Am. Chem. Soc., 1996, 118, 13071 CrossRef CAS.
  3. D. H. Apella, L. A. Christianson, D. A. Klein, D. R. Powell, S. Huang, J. J. Barchi and S. H. Gellman, Nature (London), 1997, 387, 381 CrossRef CAS.
  4. S. Hanessian, H. Yang and R. Schaum, J. Am. Chem. Soc., 1996, 118, 2507 CrossRef CAS; S. Hanessian, personal communication.
  5. D. Seebach, K. Gademann, J. V. Schreiber, J. L. Matthews, T. Hintermann, B. Jaun, L. Oberer, U. Hommel and H. Widmer, Helv. Chim. Acta, 1997, 80, 2033 CAS; D. Seebach, S. Abele, K. Gademann, G. Guichard, T. Hintermann, B. Jaun, J. L. Matthews, J. V. Schreiber, L. Oberer, U. Hommel and H. Widmer, Helv. Chim. Acta, 1998, 81, 932 CrossRef CAS.
  6. D. Seebach, M. Overhand, F. N. M. Kühnle, B. Martinoni, L. Oberer, U. Hommel and H. Widmer, Helv. Chim. Acta, 1996, 79, 913 CrossRef CAS; D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo, L. Oberer, U. Hommel, R. Amstutz and H. Widmer, Helv. Chim. Acta, 1996, 79, 2043 CrossRef CAS.
  7. J. L. Matthews, M. Overhand, F. N. M. Kühnle, P. E. Ciceri and D. Seebach, Liebigs Ann. Chem., 1997, 1371 Search PubMed.
  8. J. M. Fernández-Santín, J. Aymamí, A. Rodríguez-Galán, S. Muñoz-Guerra and J. A. Subirana, Nature (London), 1984, 311, 53 CAS.
  9. F. Chen, G. Lepore and M. Goodman, Macromolecules, 1974, 7, 779 CrossRef CAS.
  10. C. Alemán, J. J. Navas and S. Muñoz-Guerra, Biopolymers, 1997, 41, 721 CrossRef CAS.
  11. M. García-Alvarez, A. Martínez de Ilarduya, S. León, C. Alemán and S. Muñoz-Guerra, J. Phys. Chem. A, 1997, 101, 4215 CrossRef and references cited therein.
  12. M. Kajtar, M. Hollosi and Zs. Riedl, Acta Chim. Acad. Sci. Hung., 1976, 88, 301 CAS.
  13. D. Seebach, J. L. Matthews, A. Meden, T. Wessels, C. Baerlocher and L. B. McCusker, Helv. Chim. Acta, 1997, 80, 173 CrossRef CAS.
  14. T. D. Clark, L. K. Buehler and M. R. Ghadiri, J. Am. Chem. Soc, 1998, 120, 651 CrossRef CAS.
  15. T. Hintermann and D. Seebach, Chimia, 1997, 51, 244 CAS.
  16. M. B. Freeman, Y. H. Paik, G. Swift, R. Wilczynski, S. K. Wolk and K. M. Yocum, Biodegradability of Polycarboxylates: Structure-Activity Studies, in Hydrogels and Biodegradable Polymers for Bioapplications, ACS Symposium Series 627, ed. R. M. Ottenbrite, S. J. Huang and K. Park, American Chemical Society, New York, 1996, pp. 118–136 Search PubMed.
  17. T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 2nd edn., 1991 Search PubMed.
  18. J. L. Matthews, C. Braun, C. Guibourdenche, M. Overhand and D. Seebach, Preparation of Enantiopure β-Amino Acids from α-Amino Acids Using the Arndt-Eistert Homologation, in Enantioselective Synthesis of β-Amino Acids, ed. E. Juaristi, Wiley-VCH, New York, 1997, pp. 105–126 Search PubMed; J. Podlech and D. Seebach, Liebigs Ann., 1995, 1217 Search PubMed.
  19. T. Hoffmann and D. Seebach, Liebigs Ann., 1996, 1277 CAS.
  20. J. Bandekar, Biochim. Biophys. Acta, 1992, 1120, 123 CAS; W. K. Surewicz and H. H. Mantsch, Infrared Absorption Methods for Examining Protein Structure in Solution, in Spectroscopic Methods for Peptide and Protein Structure in Solution, ed. H. A. Havel, VCH, New York, Weinheim, Cambridge, 1996, p. 135 Search PubMed.
  21. The values of the observed IR bands are also very close to those displayed by the nanotubes of cyclic D, L-α-peptides. See X. Sun and G. P. Lorenzi, Helv. Chim. Acta, 1994, 77, 1520 Search PubMed; J. D. Hartgerink, J. R. Granja, R. A. Miligan and M. R. Ghadiri, J. Am. Chem. Soc., 1996, 118, 43 CrossRef CAS and refs. cited therein.
  22. Since the benzylic ester groups are remote from the chirality centres, they should not induce significant changes in the CD spectrum. The CD spectrum of poly-L-α-Glu(OBn) exhibits the typical pattern of an α-helix despite the benzylic ester groups. See R. W. Woody, Circular Dichroism of Peptides, in The Peptides: Conformation in Biology and Drug Design, ed. V. J. Hruby, Academic Press, Orlando, 1985, vol. 7, p. 15 Search PubMed.
  23. M. Karplus, J. Chem. Phys., 1959, 30, 11 CrossRef CAS; A. Pardi, M. Billeter and K. Wüthrich, J. Mol. Biol., 1984, 180, 741 CAS; A. de Marco, M. Llinas and K. Wüthrich, Biopolymers, 1978, 17, 617 CAS.
  24. W. Humphrey, A. Dalke and K. Schulten, J. Mol. Graphics, 1996, 14, 33 CrossRef.
  25. E. A. Merrit and M. E. P. Murphy, J. Appl. Crystallogr., 1994, 24, 246; D. J. Bacon and W. F. A. Anderson, J. Mol. Graphics, 1988, 6, 219 CrossRef.
  26. D. Seebach, A. K. Beck and A. Studer, in Modern Synthetic Methods 1995, ed. B. Ernst and C. Leumann, VHCA, Basel and VCH, Weinheim, 1995, vol. 7, pp. 1–178 Search PubMed.
  27. X. Daura, W. F. van Gunsteren, D. Rigo, B. Jaun and D. Seebach, Chem. Eur. J., 1997, 3, 1410 CAS; X. Daura, B. Jaun, D. Seebach, W. F. van Gunsteren and A. E. Mark, J. Mol. Biol., 1998, 280, 925 CrossRef CAS.
  28. K. Gademann, R. Perozzo, G. Folkers, L. Scapozza, B. Jaun and D. Seebach, unpublished results, ETH Zürich, 1998.
  29. D. N. J. White, C. Morrow, P. J. Cox, C. N. C. Drey and J. Lowbridge, J. Chem. Soc., Perkin Trans. 2, 1982, 239 RSC.
  30. A. L. Davis, E. D. Laue, J. Keeler, D. Moskau and J. Lohman, J. Magn. Reson., 1991, 94, 637 CAS.
  31. S. P. Rucker and A. J. Shaka, Mol. Phys., 1989, 68, 509 CAS.
  32. A. L. Davis, J. Keeler, E. D. Laue and D. Moskau, J. Magn. Reson., 1992, 98, 207 CAS.
  33. W. Willker, D. Leibfritz, U. Kerssebaum and W. Bermel, Magn. Reson. Chem., 1993, 31, 287.
  34. C. Griesinger and R. R. Ernst, J. Magn. Reson., 1987, 75, 261 CAS.
  35. F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang, T. Hendrickson and W. C. Still, J. Comput. Chem., 1990, 11, 440 CrossRef CAS.