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Exploring solid-phase approaches for the preparation of new β-lactams from amino acids

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Abstract

Two solid-phase approaches, involving the base-assisted intramolecularalkylation of N-chloroacetyl-Phe derivatives anchored to appropriatesolid supports, were investigated for the preparation of novel β-lactams. When a BAL-type strategy was used, the resin-bound azetidinones were easily formed, as established by MAS-NMR, but final compounds could not be removed from the resin, unless a suitable two linkers system was used. In the second approach, in which the Phe residue is anchored to a Wang-type resin through the carboxylate group, the corresponding 1,4,4-trisubstituted 2-azetidinone was obtained in moderate to good yield and high purity.

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References

  1. McKittrick, B. A., Ma, K., Huie, K., Yumibe, N., Davis Jr., H., Clader, J. W., Czarniecki, M. and McPhail, A. T., Synthesis of C3 heteroatom substituted azetidinones that display potent cholesterol absortion inhibitory activity, J. Med. Chem., 41 (1998) 752–759.

    Article  CAS  Google Scholar 

  2. Yoakim, C., Ogilvie, W. W., Cameron, D. R., Chabot, C., Guse, I., Hache, B., Naud, J., O'Meara, J. A., Plante, R. and Deziel, R., β-Lactam derivatives as inhibitors of human cytomegalovirus protease, J. Med. Chem., 41 (1998) 2882–2891.

    Article  CAS  Google Scholar 

  3. Adlintong, R. M., Baldwing, J. E., Becker, G. W.,; Chen, B., Cooper, S. L., Hermann, R. B., Howe, T. J., McCoull, W., McNulty, A. M., Neubauer, B. L. and Pritchard, G. J., Design, synthesis, and proposed activity site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen, J. Med. Chem. 44 (2001) 1491–1508.

    Article  CAS  Google Scholar 

  4. Slusarchyk, W. A., Bolton, S. A., Hartl, K. S., Huang, M.-H., Jacobs, G., Meng, W., Ogletree, M. L., Pi, Z., Schumacher, W. A., Seiler, S. M., Sutton, M. L., Zahler, R., Zhao, G. and Bisacchi, G. S., Synthesis of potent and highly selective inhibitors of human tryptase, Bioorg. Med. Chem. Lett., 12 (2002) 3235–3238.

    Article  CAS  Google Scholar 

  5. Qabar, M. N., Meara, J. P., Ferguson, M. D., Lum, C., Kim, H.-O. and Kahn, M., Synthesis of 3-alkoxyazetidin-2-ones: Dipeptide mimics, Tetrahedron Lett., 39 (1998) 5895–5898.

    Article  CAS  Google Scholar 

  6. Linder, M. R. and Podlech, J., Synthesis of peptidomimetics containing a β-lactam moiety using peptide diazoketones and imines in a Staudinger reaction, Org. Lett., 1 (1999) 869–872.

    Article  CAS  Google Scholar 

  7. Palomo, C., Aizpurua, J. M., Galarza, R., Benito, A., Khamrai, U. K., Eikeseth, U. and Linden, A., On the question of the diastereoselective alkylation of 4-unsubstituted 3-amino-β-lactams. A concise synthesis of α-branched α-amino β-lactams and their coupling with α-amino acid esters, Tetrahedron, 56 (2000) 5563–5570.

    Article  CAS  Google Scholar 

  8. Alcaide, B., Almendros, P., Alonso, J. M. and Aly, M. F., Rapid and stereocontrolled synthesis of racemic and optically pure highly functionalized pyrrolidine system via rearrangement of 1,3-dipolar cycloadducts derived from 2-azetidinone-tethered azomethine ylides, J. Org. Chem., 66 (2001) 1351–1358.

    Article  CAS  Google Scholar 

  9. Ruhland, B., Bhandari, A., Gordon, E. M. and Gallop, M. A., Solid-supported combinatorial synthesis of structurally diverse β-lactams, J. Am. Chem. Soc., 118 (1996) 253–254.

    Article  CAS  Google Scholar 

  10. Ruhland, B., Bombrun, A. and Gallop, M. A., Solid-phase synthesis of 4-arylazetidin-2-ones via Suzuki and Heck cross-coupling reactions, J. Org. Chem., 62 (1997) 7820–7826.

    Article  CAS  Google Scholar 

  11. Molteni, V., Annunziata, R., Cinquini, M., Cozzi, F. and Benaglia, M., Soluble polymer-supported synthesis of imines and β-lactams, Tetrahedron Lett., 39 (1998) 1257–1260.

    Article  CAS  Google Scholar 

  12. Gordon, K. H., Bolger, M., Kahn, N. and Balasubramanian, S. A., Stereoselective synthesis of 1,3,4-substituted β-lactams from polymer-supported chiral oxazolidine aldehyde, Tetrahedron Lett., 41 (2000) 8621–8625.

    Article  CAS  Google Scholar 

  13. Gordon, K. H. and Balasubramanian, S., Exploring a bezyloxyaniline linker utilizing ceric ammonium nitrate (CAN) as a cleavage reagent: Solid-phase synthesis of N-unsubstituted β-lactams and secondary amides, Org. Lett., 3 (2001) 53–56.

    Article  CAS  Google Scholar 

  14. Dasgupta, S. K. and Banik, B. K., A new entry to N-unsubstituted β-lactams through a solid-phase approach, Tetrahedron Lett., 43 (2002) 9445–9447.

    Article  CAS  Google Scholar 

  15. Delpiccolo, C. M. L. and Mata, E. G., Stereoselective solidphase synthesis of 3,4-substituted azetidinones as key intermediates for mono-and multicyclic β-lactam antibiotics and enzyme inhibitors, Tetrahedron: Asymmetry, 13 (2002) 905–910.

    Article  CAS  Google Scholar 

  16. Schunk, S. and Enders, D., Solid-phase synthesis of β-lactams via the ester enolate-imine condensation route, Org. Lett., 2 (2000) 907–910.

    Article  CAS  Google Scholar 

  17. Annunziata, R., Benaglia, M., Cinquini, M. and Cozzi, F., Soluble-polymer-supported synthesis of β-lactams on a modi-fied poly(ethylene glycol), Chem. Eur. J., 6 (2000) 133–138.

    Article  CAS  Google Scholar 

  18. Schunk, S. and Enders, D. Solid-phase synthesis of monocyclic β-lactam derivatives, J. Org. Chem., 67 (2002) 8034–8042.

    Article  CAS  Google Scholar 

  19. Meloni, M. M. and Taddei, M., Solid-phase synthesis of β-lactams via the Miller hydroxamate approach, Org. Lett., 3 (2001) 337–340.

    Article  CAS  Google Scholar 

  20. Gerona-Navarro, G., Bonache, M. A., Herranz, R., García-López, M. T. and González-Muñiz, R., New constrained tryptophans by N α -C α -cyclization to an azetidine-2-one core, Synlett, (2000) 1249–1252.

  21. Gerona-Navarro, G., Bonache, M. A., Herranz, R., García-López, M. T. and González-Muñiz, R., Entry to new conformationally constrained amino acids. First synthesis of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinone derivatives via an intramolecular N α -C α -cyclization strategy, J. Org. Chem., 66 (2001) 3538–3547.

    Article  CAS  Google Scholar 

  22. Boojamra, C. G., Burow, K. M. and Ellman, J. A., An expedient and high-yielding method for the solid-phase synthesis of diverse 1,4-benzodiazepine-2,5-diones, J. Org. Chem., 60 (1995) 5742–5743.

    Article  CAS  Google Scholar 

  23. Jensen, K. J., Alsina, J., Songster, M. F., Vagner, J., Albericio, F. and Barany, G., Backbone amide linker (BAL) strategy for solid-phase synthesis of C-terminal-modified linear and cyclic peptides, J. Am. Chem. Soc., 120 (1998) 5441–5452.

    Article  CAS  Google Scholar 

  24. Gerona-Navarro, G., Bonache, M. A., Reyero, N., García-López, M. T. and González-Muñiz, R., Amino acid-derived 4-alkyl-4-carboxy-2-azetidinones. New insights into β-lactam ring formation and N-deprotection, Heterocycles, 57 (2002) 501–513.

    Article  CAS  Google Scholar 

  25. O'Donnell, M. J., Delgado, F. and Pottorf, R. S., Enantioselective solid-phase synthesis of α-amino acid derivatives, Tetrahedron, 55 (1999) 6347–6362.

    Article  Google Scholar 

  26. The benzyl-like group of BAL resin became more resistant to the acidic hydrolysis in our β-lactams than in other lactams (diketopiperazines) or amides. The presence of the electron-withdrawing group CO2R in position 4 could be responsible, at least in part, of the reduced lability to the acid media. The carboxylate group could attenuate the basicity of the amide carbonyl oxygen preventing debenzylation reaction, as previously found for a series of maleimide derivatives: Watson, D.J., Dwody, E.D., Li, W.-S., Wang, J., Polniaszek, R., Electronic effects in the acid-promoted deprotection of N-2,4-dimethoxybenzyl maleimides, Tetrahedron Lett., 42 (2001) 1827–1830.

    Article  CAS  Google Scholar 

  27. Schwalbe, H. and Bielecki, A., Recent advances in high-resolution solid-state NMR spectroscopy, Angew. Chem. Int. Ed., 40 (2001) 2045–2050.

    Article  CAS  Google Scholar 

  28. Tam, J. P., Tjoeng, F. S. and Merrifield, R. B., Design and synthesis of multidetachable resin supports for solid-phase peptide synthesis, J. Am. Chem. Soc., 102 (1980) 6117–6127.

    Article  CAS  Google Scholar 

  29. Szardenings, A. K., Burtoth, T. S., Look, G. C. and Campbell, D. A. A., Reductive alkylation procedure applicable to both solution-and solid-phase syntheses of secondary amines, J. Org. Chem., 61 (1996) 6720–6722.

    Article  CAS  Google Scholar 

  30. Boeijen, A., Kruijtzer, J. A. W. and Liskamp, R. M. T., Combinatorial chemistry of hydantoins, Bioorg. Med. Chem. Lett., 8 (1998) 2375–2380.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Instituto de Química Médica, CSIC, Madrid, Spain

    Guillermo Gerona-Navarro & Ma Teresa García-López

  2. Department of Organic Chemistry, University of Barcelona, Barcelona, Spain

    Guillermo Gerona-Navarro, Miriam Royo & Fernando Albericio

  3. Combinatorial Chemistry Unity, University of Barcelona, Barcelona Science Park, Barcelona, Spain

    Miriam Royo

  4. Barcelona Biomedical Research Institute, University of Barcelona, Barcelona Science Park, Barcelona, Spain

    Fernando Albericio

  5. Instituto de Química Médica, CSIC, Madrid, Spain

    Rosario González-Muñiz

Authors
  1. Guillermo Gerona-Navarro
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  2. Miriam Royo
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  3. Ma Teresa García-López
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  4. Fernando Albericio
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  5. Rosario González-Muñiz
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Correspondence to Rosario González-Muñiz.

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Gerona-Navarro, G., Royo, M., García-López, M.T. et al. Exploring solid-phase approaches for the preparation of new β-lactams from amino acids. Mol Divers 6, 75–84 (2003). https://doi.org/10.1023/B:MODI.0000006837.36303.eb

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  • DOI: https://doi.org/10.1023/B:MODI.0000006837.36303.eb

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