Total Syntheses of (()-Crinine, (()-Crinamine, and (()-6a-epi-Crinamine via the Regioselective Synthesis and Diels-Alder Reaction of 3-Aryl-5-bromo-2-pyrone Nguyen Thanh Tam, Jayhyok Chang, Eun-Ju Jung, and Cheon-Gyu Cho* Department of Chemistry, Hanyang UniVersity, Seoul, Korea 133-791 ccho@hanyang.ac.kr ReceiVed April 19, 2008 We have devised a new unified synthetic protocol to (()-crinine, (()-crinamine, and (()-6a-epi-crinamine from the Diels-Alder cycloadduct of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone with TBS vinyl ether. The requisite 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone was prepared from the C3-selective Stille coupling reaction of 3,5-dibromo-2-pyrone. Also noted is that the vinyl bromide can be used as a handle for further derivatization. Introduction Belonging to the Amaryllidaceae natural product family, the crinine-type alkaloids 1-3 1 (Figure 1) elicit continued interest in the synthetic community 2 due in part to their intriguing physiological activities, as exemplified by the recent study unveiling the highly selective apoptosis induction properties of crinamine 2 and haemanthamine 3 against tumor cells at as low as micromolar concentration. 3 Crinine alkaloids are closely related to other major Amaryl- lidaceae family natural products, lycorane- and galanthamine- type alkaloids, in the sense of biogenesis, being derived from the same precursor norbelladine. 4 As a part of our ongoing research program on 3,5-dibromo-2-pyrone 4 and its derivatives as novel enophile synthons, 5 we have explored their potential applicability to the target-oriented synthesis with the maximum use of the resultant densely functionalized cycloadducts. Scheme 1 shows our previous efforts in this context, total syntheses of (()-trans-dihydronarciclasine 5b and (()-joubertinamine. 5c The (1) For a review on crinine type alkaloids, see: (a) Mori, M. Chem. Pharm. Bull. 2005, 53, 457. (b) Jin, Z.; Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19, 454. (c) Hoshino, O. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1998; Vol. 51, p 323. (d) Martin, S. F. In The Alkaloids; Brossi. A., Ed.; Academic Press: New York, 1987; Vol. 30, p 251. (2) For a synthesis of crinine and related alkaloids, see: (a) Bohno, M.; Sugie, K.; Imase, H.; Yusof, Y. B.; Oishi, T.; Chida, N. Tetrahedron 2007, 63, 6977. (b) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8, 4755. (c) Zhang, F.-M.; Tu, Y.-Q.; Liu, J.-D.; Fan, X.-H.; Shi, L.; Hu, X.-D.; Wang, S.- H.; Zhang, Y.-Q. Tetrahedron 2006, 62, 9446. (d) Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043. (e) Nishimata, T.; Sato, Y.; Mori, M. J. Org. Chem. 2004, 69, 1837. (f) Bohno, M.; Imase, H.; Chida, N. Chem. Commun. 2004, 1086. (g) Banwell, M. G.; Harvey, J. E.; Jolliffe, K. A. J. Chem. Soc., Perkin Trans 1 2001, 17, 2002. (h) Baldwin, S. W.; Debenham, J. S. Org. Lett. 2000, 2, 99. (i) Watson, D. J.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 1519. (j) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc. 1998, 120, 3664. (k) Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607. (l) Pearson, W. H.; Lovering, F. E. J. Am. Chem. Soc. 1995, 117, 12336. (m) Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53, 3184. (n) Martin, S. F.; Campbell, C. L. Tetrahedron Lett. 1987, 28, 503. (o) Overman, L. E.; Sugai, S. HelV. Chim. Acta 1985, 68, 745. (p) Overman, L. E.; Mendelson, L. T.; Jacobsen, E. J. J. Am. Chem. Soc. 1983, 105, 6629. (q) Sanchez, I. H.; Lopez, F. J.; Soria, J. J.; Larraza, M. I.; Flores, H. J. J. Am. Chem. Soc. 1983, 105, 7640. (r) Danishefsky, S.; Morris, J.; Mullen, G.; Gammill, R. J. Am. Chem. Soc. 1982, 104, 7591. (s) Overman, L. E.; Mendelson, L. T. J. Am. Chem. Soc. 1981, 103, 5579. (t) Sanchez, I. H.; Mendoza, M. T. Tetrahedron Lett. 1980, 21, 3651. (u) Isobe, K.; Taga, J.; Tsuda, Y. Tetrahedron Lett. 1976, 2331. (v) Brossi, A.; Teitel, S. J. Org. Chem. 1970, 35, 3559. (w) Whitlock, H. W., Jr.; Smith, G. L. J. Am. Chem. Soc. 1967, 89, 3600. (x) Muxfeldt, H.; Schneider, R. S.; Mooberry, J. B. J. Am. Chem. Soc. 1966, 88, 3670. (3) McNulty, J.; Nair, J. J.; Codina, C.; Bastida, J.; Pandey, S.; Gerasimoff, J.; Griffin, C. Phytochemistry 2007, 68, 1068. (4) Jeffs, P. W.; Campbell, H. F.; Farrier, D. S.; Ganguli, G.; Martin, N. H.; Molina, G. Phytochemistry. 1974, 13, 933. 10.1021/jo8008353 CCC: $40.75  2008 American Chemical Society 6258 J. Org. Chem. 2008, 73, 6258–6264 Published on Web 07/16/2008