Synthesis of chiral and achiral analogues of ambroxol via palladium-catalysed reactions

Abstract

Chiral cis- and trans-4-aminocyclohex-2-enols and achiral 4-aminocyclohexanols, which all are analogues of ambroxol, are prepared via stereoselective allylic substitution of cyclohex-2-ene-1,4-diol derivatives or 1-acetoxy-4-chlorocyclohex-2-ene. The chiral target molecules are obtained in enantiomerically pure form by employing a previously described enantiodivergent synthesis of cis- and trans-4-aminocyclohex-2-enols. It has been found that bis(amine) nucleophiles 7a and 7b react only at the benzylic amino group under the conditions employed.

References

1. (a) H. Koch, Drugs Today, 1979, 15, 523; (b) G. Caramia, R. Gagliardini, E. Ruffini, P. Osimani and A. Nobilini, J. Int. Med. Res., 1995, 23, 284; (c) W. Kuckelt, R. Dauberschmidt, J. Scharfenberg, K. Winsel, B. Lachmann, H. Frenzke, U. Hieronymi, H. Mrochen and M. Meyer, Respiration, 1980, 39, 264.
2. M. Bianchi, A. Mantovani, A. Erroi, C. A. Dinarello and P. Ghezzi, Agents Actions, 1990, 31, 275 and references cited therein.
3. In cooperation with: T. Eriksson, C. M. Andersson, H. Bergstrand, K. Karabelas and P. Sjö, at the Department of Medicinal Chemistry, Astra Draco AB, PO Box 34, S-221 00 Lund, Sweden.
4. (a) K. Ramesh, M. S. Wolfe, Y. Lee, D. Vander Velde and R. T. Borchardt, J. Org. Chem., 1992, 57, 5861; (b) N. Dyatkina, B. Costisella, F. Theil and M. von Janta-Lipinski, Tetrahedron Lett., 1994, 35, 1961; (c) N. B. Dyatkina, F. Theil and M. von Janta-Lipinski, Tetrahedron, 1995, 51, 761.
5. (a) S. Knapp, A. B. J. Naughton and T. G. Murali Dhar, Tetrahedron Lett., 1992, 33, 1025; (b) T. Hudlicky and H. F. Olivo, Tetrahedron Lett., 1991, 32, 6077.
6. R. G. P. Gatti, A. L. E. Larsson and J. E. Bäckvall, J. Chem. Soc., Perkin Trans. 1, 1997, 577.
7. For related work on enantioselective synthesis of 4-amino-cyclohex-2-enols see: B. M. Trost and S. R. Pulley, J. Am. Chem. Soc., 1995, 117, 10 143; B. M. Trost, Pure Appl. Chem., 1996, 68, 779.
8. J. E. Bäckvall, R. Gatti and H. E. Schink, Synthesis, 1993, 343.
9. R. J. Kazlauskas, A. N. E. Weissfloch, A. T. Rappaport and L. A. Cuccia, J. Org. Chem., 1991, 56, 2656.
10. J. E. Bäckvall, S. E. Byström and S. E. Nordberg, J. Org. Chem., 1984, 49, 4619.
11. (a) J. E. Bäckvall, J. E. Nyström and S. E. Nordberg, J. Am. Chem. Soc., 1985, 107, 3676; (b) J. Vågberg and J. E. Bäckvall, Org. Synth., 1990, 69, 38.
12. (a) J. E. Bäckvall, in Advances in Metal-Organic Chemistry, ed. L. S. Liebeskind, JAI press, Greenwich, CT, 1989, vol. 1, pp. 135–175; (b) J. E. Bäckvall, Palladium-Catalyzed 1,4-Additions to Conjugated Dienes, a review in ‘Metal-catalyzed Cross Coupling Reactions’, ed. P. Stang and F. Diederich, VCH, Weinham, in the press; (c) P. G. Andersson and J. E. Bäckvall, in Advances in Natural Product Synthesis, ed. W. Pearson, JAI Press, 1996; (d) H. E. Schink, H. Pettersson and J. E. Bäckvall, J. Org. Chem., 1991, 56, 2769; (e) D. Tanner, M. Sellén and J. E. Bäckvall, J. Org. Chem., 1989, 54, 3374.
13. T. Ukai, H. Kawazura, Y. Ishii, J. J. Bonnet and J. A. Ibers, Organomet. Chem., 1974, 65, 253.