A highly efficient total synthesis of (+)-himbacine

Journal of the American Chemical Society

Volumn 118, Issue 40, 1996, Pages 9812-9813

  Chackalamannil, Samuel ^a   Davies, Robert J ^a   Asberom, Theodros ^a   Doller, Darío ^a   Leone, Daria ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HIMBACINE;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS;

EID: 0029860641     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja962542f     Document Type: Article

References (42)

1. (a) Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1961, 14, 106.
2. (b) Brown, R. F. C.; Drummond, R.; Fogerty, A. C.; Hughes, G. K.; Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1956, 9, 283.
3. (c) Ritchie, E.; Taylor, W. C. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1967; Vol. 9, p 529.
4. For X-ray crystallographic studies on himbacine, see: Fridrichsons, J.; Mathieson, A. M. Acta Crystallogr. 1962, 15, 119.
5. (a) Malaska, M. J.; Fauq, A. H.; Kozikowski, A. P.; Aagaard, P. J.; McKinney, M. Bioorg. Med. Chem. Lett. 1995, 5, 61 and references cited therein.
6. (b) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M. Bioorg. Med. Chem. Lett. 1992, 2, 797.
7. (c) Darroch, S. A.; Taylor, W. C.; Choo, L. K.; Mitchelson, F. Eur. J. Pharmacol. 1990, 182, 131.
8. (a) Miller, J. H.; Aagaard, P. J.; Gibson, V. A.; McKinney, M. J. Pharmacol. Exp. Ther. 1992, 203, 663.
9. (b) Dodds, H. N. Drugs Future 1995, 20, 157.
10. 2 receptor with a Ki value of 4.6 nM and with 20-fold selectivity against MI receptor (ref 3b).
11. For the total synthesis of himbacine, see: (a) Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995, 117, 9369
12. . For studies directed toward the total synthesis of himbacine, see: (b) Baldwin, J. E.; Chesworth, R.; Parker, J. S.; Russell, A. T. Tetrahedron Lett. 1995, 36, 9551.
13. (c) Baecke, G. D.; De Clercq, P. Tetrahedron Lett. 1995, 36, 7515.
14. For reviews on intramolecular Diels-Alder reactions, see: (a) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 513.
15. (b) Ciganek, E. In Organic Reactions; Dauben, W. G., Ed.; John Wiley & Sons, Inc.: New York, 1984; Vol. 32, p 1.
16. (c) Craig, D. Chem. Soc. Rev. 1987, 16, 87.
17. (d) Weinreb, S. W. Acc. Chem Res. 1985, 18, 16.
18. For a discussion of the substituent effect on intramolecular Diels-Alder reactions of enoates, see: Jung, M. E. Synlett 1990, 4, 186.
19. 1.3 strain induced facial selectivity of intermolecular Diels-Alder reactions, see: Adam, W.; Glaser, J.; Peters, K.; Prein, M. J. Am. Chem. Soc. 1995, 117, 9190 and references cited therein.
20. 1,3 strain induced stereoselectivity, see: Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
21. It has been reported that reduction of himbacine to dihydrohimbacine required catalytic hydrogenation over platinum oxide in glacial acetic acid for 16 h (ref 1a).
22. The resolution of 2-methylpiperidine was carried out according to the procedure given by Marckwald. Marckwald, W. Ber. 1896, 29, 43.
23. Also, see: (a) Craig, J. C.; Roy, S. K. Tetrahedron 1965, 21, 401.
24. (b) Munchof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084.
25. (c) Tallent, W. H.; Stromberg, V. L.; Horning, E. C. J. Am. Chem. Soc. 1955, 77, 6361.
26. The optical purity of (S)-2-methylpiperidtne was measured using O-acetylmandelic acid as a chiral solvating agent. Integration of the methyl doublet indicated 99% optical purity after four recrystallizations. See: Parker, D.; Taylor, R. J. Tetrahedron 1987, 43, 5451.
27. The workup procedure involved addition of excess of ammonium hydroxide. This step convened the unreacted reagent, which coeluted with the product, to more polar tert-butylurethane.
28. Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
29. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
30. The technical grade chromous chloride (95%) available from Aldrich was used. Chromous chloride of high purity (99.9%), purchased from Strem Chemicals, gave inferior yields.
31. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
32. (b) Alami, M.; Linstrumele, G. Tetrahedron Lett. 1991, 6109.
33. For reviews on Sonogashira reaction, see: (d) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int. 1995, 27 (2), 127.
34. (e) Sonogashira, K. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 521.
35. (S)-3-Butyn-2-ol was purchased from Chiroscience Ltd, Cambridge Science Park, Milton Rd, Cambridge, CB4 4WE, England. It is also available from DSM Fine Chemicals, 217 Rte 46 W., Saddle Brook, NJ 07663-6253.
36. The crude product, which was used for the next step without further purification, was contaminated with a small amount (5-10%) of saturated alcohol generated from the over-reduction of dienol 9. This side product underwent esterification at the next step to generate the corresponding ester which coeluted with the desired product 11. However, the presence of this side product did not affect the subsequent intramolecular Diels-Alder reaction.
37. Tanikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis 1983, 134.
38. Prolonged reaction time resulted in substantial amount of N-deprotection of 12. The corresponding free amine could be readily converted to 13 by treatment of the crude reaction mixture with Boc anhydride in the presence of 20% aqueous sodium hydroxide. Thermolytic deprotection of tert-butoxycarbonyl protecting group on indoles and pyrroles has been reported: Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141.
39. Large excess (8-12 wt equivs) of Raney nickel was necessary. Commercially available (Aldrich) Raney nickel was washed four times with water and four times with methanol prior to use.
40. 3).
41. 1b].
42. 1b].