Synthesis of epibatidine homologues: Homoepibatidine and bis-homoepibatidine

Tetrahedron Letters

Volumn 37, Issue 22, 1996, Pages 3911-3914

  Malpass, John R ^a   Hemmings, David A ^a   Wallis, Anna L ^a  

^a UNIVERSITY OF LEICESTER   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALKENE DERIVATIVE; ANALGESIC AGENT; BISHOMOEPIBATIDINE; EPIBATIDINE; HOMOEPIBATIDINE; PYRIDINE DERIVATIVE; TROPANE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG CONFORMATION; DRUG SYNTHESIS; FROG;

EID: 0029975474     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)00687-9     Document Type: Article

References (31)

1. Spande, T.F.; Garraffo, H.M.; Edwards, M.W.; Yeh, H.J.C.; Pannell, L.; Daly, J.W. J.Amer. Chem.Soc., 1992, 114, 3475.
2. a. Early syntheses include: Broka, C.A.; Tetrahedron Letters, 1993, 34, 3251; Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J. J.Chem.Soc.Chem.Commun., 1993, 1216; Corey, E.J.; Huang, D.F.; Shen, T.Y. Tetrahedron Letters, 1993, 34, 4477; Loh, T.E.; AchyuthaRao, S.; Daley, D.C.; Sarshar, S. J.Org.Chem., 1993, 58, 5600 and reference 2b. Other syntheses published since 1993 are listed in a very recent paper: Xu, R.; Chu, G.; Bai, D. Tetrahedron Letters, 1996, 37, 1463.
3. a. Early syntheses include: Broka, C.A.; Tetrahedron Letters, 1993, 34, 3251; Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J. J.Chem.Soc.Chem.Commun., 1993, 1216; Corey, E.J.; Huang, D.F.; Shen, T.Y. Tetrahedron Letters, 1993, 34, 4477; Loh, T.E.; AchyuthaRao, S.; Daley, D.C.; Sarshar, S. J.Org.Chem., 1993, 58, 5600 and reference 2b. Other syntheses published since 1993 are listed in a very recent paper: Xu, R.; Chu, G.; Bai, D. Tetrahedron Letters, 1996, 37, 1463.
4. a. Early syntheses include: Broka, C.A.; Tetrahedron Letters, 1993, 34, 3251; Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J. J.Chem.Soc.Chem.Commun., 1993, 1216; Corey, E.J.; Huang, D.F.; Shen, T.Y. Tetrahedron Letters, 1993, 34, 4477; Loh, T.E.; AchyuthaRao, S.; Daley, D.C.; Sarshar, S. J.Org.Chem., 1993, 58, 5600 and reference 2b. Other syntheses published since 1993 are listed in a very recent paper: Xu, R.; Chu, G.; Bai, D. Tetrahedron Letters, 1996, 37, 1463.
5. a. Early syntheses include: Broka, C.A.; Tetrahedron Letters, 1993, 34, 3251; Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J. J.Chem.Soc.Chem.Commun., 1993, 1216; Corey, E.J.; Huang, D.F.; Shen, T.Y. Tetrahedron Letters, 1993, 34, 4477; Loh, T.E.; AchyuthaRao, S.; Daley, D.C.; Sarshar, S. J.Org.Chem., 1993, 58, 5600 and reference 2b. Other syntheses published since 1993 are listed in a very recent paper: Xu, R.; Chu, G.; Bai, D. Tetrahedron Letters, 1996, 37, 1463.
6. a. Early syntheses include: Broka, C.A.; Tetrahedron Letters, 1993, 34, 3251; Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J. J.Chem.Soc.Chem.Commun., 1993, 1216; Corey, E.J.; Huang, D.F.; Shen, T.Y. Tetrahedron Letters, 1993, 34, 4477; Loh, T.E.; AchyuthaRao, S.; Daley, D.C.; Sarshar, S. J.Org.Chem., 1993, 58, 5600 and reference 2b. Other syntheses published since 1993 are listed in a very recent paper: Xu, R.; Chu, G.; Bai, D. Tetrahedron Letters, 1996, 37, 1463.
7. b. Clayton S.C.; Regan, A.C. Tetrahedron Letters, 1993, 34, 7493.
8. Lehn, J.M. Fortschr.Chem.Forsch., 1970, 15, 311; Lambert, J.B. 'Topics in Stereochemistry', Allinger, N.L. and Eliel, L. Eds.; Wiley-Interscience: New York, 1971, Vol.6; Jennings, W.B.; Worley, S.D. J.Chem.Soc.Perkin Trans. 2, 1980, 1512 and references cited in these papers.
9. Lehn, J.M. Fortschr.Chem.Forsch., 1970, 15, 311; Lambert, J.B. 'Topics in Stereochemistry', Allinger, N.L. and Eliel, L. Eds.; Wiley-Interscience: New York, 1971, Vol.6; Jennings, W.B.; Worley, S.D. J.Chem.Soc.Perkin Trans. 2, 1980, 1512 and references cited in these papers.
10. Lehn, J.M. Fortschr.Chem.Forsch., 1970, 15, 311; Lambert, J.B. 'Topics in Stereochemistry', Allinger, N.L. and Eliel, L. Eds.; Wiley-Interscience: New York, 1971, Vol.6; Jennings, W.B.; Worley, S.D. J.Chem.Soc.Perkin Trans. 2, 1980, 1512 and references cited in these papers.
11. a. N-Alkyl derivatives: see Davies, J.W.; Durrant, M.L.; Walker, M.P.; Belkacemi, D.; Malpass, J.R. Tetrahedron, 1992, 48, 861, and references therein.
12. b. N-Chloro derivatives: see Durrant, M.L.; Malpass, J.R. Tetrahedron, 1995, 51, 7063; Davies, J.W.; Durrant, M.L.; Walker, M.P.; Malpass, J.R. Tetrahedron, 1992, 48, 4379 and references to the work of others therein (e.g. footnote 4e in the first reference under 4b).
13. b. N-Chloro derivatives: see Durrant, M.L.; Malpass, J.R. Tetrahedron, 1995, 51, 7063; Davies, J.W.; Durrant, M.L.; Walker, M.P.; Malpass, J.R. Tetrahedron, 1992, 48, 4379 and references to the work of others therein (e.g. footnote 4e in the first reference under 4b).
14. c. X-ray crystallographic studies: Davies, J.W.; Malpass, J.R.; Fawcett, J.; Prouse, L.J.S.; Lindsay, R.; Russell, D.R. J.Chem.Soc.Chem.Commun., 1986, 1135.
15. 15N NMR studies in azanorbornanes, tropanes and homotropanes: Belkacemi, D.; Davies, J.W.; Malpass, J.R.; Naylor, A.; Smith, CR. Tetrahedron, 1992, 48, 10161.
16. 3 solution showed a relatively sharp signal at -70 ppm, tentatively assigned to the pyridyl nitrogen, together with broad (> 40 ppm) signals in the -70 ppm and -300 ppm region which only appeared at temperatures above 310K. On addition of trifluoracetic acid at 233K, only the signal at ca. -70 ppm was visible; however, a broad signal at ca. -300 ppm developed at 298K. [All spectra measured at 21.688 MHz; chemical shifts relative to external nitromethane = 0.] Further studies are in progress. We thank Dr. G. Griffith for measurement of N NMR spectra.
17. b. We are very grateful to Dr. Andrew Regan (University of Manchester) for the loan of a sample of epibatidine and for advice on conditions for Pd-catalysed coupling reactions.
18. a. Tropanes and 6,7-dehydro-derivatives: Naylor, A.; Howarth, N.; Malpass, J.R. Tetrahedron, 1993, 49, 451.
19. b. 1-Hydroxy-derivatives: Justice, D.E.; Malpass, J.R. J.Chem.Soc.Perkin Trans. 1, 1994, 2559.
20. a. Homotropanes, 7,8-dehydrohomotropanes, and 1-alkyl derivatives: Smith, C.R.; Justice, D.E.; Malpass, J.R.; Tetrahedron, 1993, 49, 11037.
21. b. 1-Hydroxyhomotropanes, nor-, and 7,8-dehydroderivatives: Smith, C.R.; Justice, D.E.; Malpass, J.R.; Tetrahedron, 1994, 50, 11039.
22. 15N NMR studies on epibatidine were presented at the Hong Kong International Symposium on Heterocyclic Chemistry in August 1995. [Abstract OP 17, p. 41]
23. a. Yields in this work are not yet optimised. b. In the reductive coupling reaction in the homotropane system, a small amount of a minor isomer was isolated from one reaction (performed at higher temperature) and shows the characteristics expected of the endo-stereoisomer of (3b). Very minor products in the tropane series have still to be investigated.
24. See, for example, Woolley, J.G. Rood's Chemistry of Carbon Compounds, Supplement to Second Edition, Vol. IV, Part B. 1985, Chapter 11.
25. a. Bremner, J.B.; Smith, R.J.; Tarrant, G.J. Tetrahedron Letters, 1996, 37, 97. We thank Professor Bremner for a preprint of this paper and for helpful discussions.
26. b. Conditions and yields for these reactions are still being improved; the deoxygenation of (7) proceeded more slowly than that of (9).
27. c. Some opening of the epoxide occurred from time to time when this reaction was performed in ethanol. This could be avoided by the use of t-butanol as solvent.
28. Justice, D.E.; Malpass, J.R. Tetrahedron Letters, 1995, 36, 4689.
29. Justice, D.E.; Malpass, J.R. Tetrahedron Letters, 1995, 36, 4685.
30. 13C & HH COSY NMR spectra were in accord with the proposed structures.
31. N.B. Following acceptance of our manuscript, we received a copy of a very recent paper which describes the synthesis of homoepibatidine in 8 steps from 6β-hydroxytropinone; the compound is reported to show potent analgesic activity in hot-plate assays: Xu, R.; Bai, D.; Chu, G.; Tao, J.; Zhu, X. Bioorg.Med.Chem.Lett. 1996, 6, 279.