Short Total Synthesis of (±)-Sceptrin

Journal of the American Chemical Society

Volumn 126, Issue 12, 2004, Pages 3726-3727

  Baran, Phil S ^a   Zografos, Alexandros L ^a   O'Malley, Daniel P ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINOIMIDAZOLE; CYCLOALKANE; HYMENIDIN; IMIDAZOLE DERIVATIVE; NATURAL PRODUCT; OXAQUADRICYCLANE; SCEPTRIN; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL STRUCTURE; CHEMOREACTIVITY; CRYSTAL STRUCTURE; HALOGENATION; REACTION ANALYSIS; STEREOCHEMISTRY; SYNTHESIS;

ANIMALS; CARBOHYDRATE CONFORMATION; CRYSTALLOGRAPHY, X-RAY; MOLECULAR STRUCTURE; PORIFERA; PYRROLES; STEREOISOMERISM;

EID: 1642393701     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja049648s     Document Type: Article

References (17)

1. Walker, R. P.; Faulkner, D. J.; Van Engen, D.; Clardy, J. J. Am. Chem. Soc. 1981, 103, 6772-6773. For a review of pyrrole-imidazole alkaloids, see: Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783.
2. Walker, R. P.; Faulkner, D. J.; Van Engen, D.; Clardy, J. J. Am. Chem. Soc. 1981, 103, 6772-6773. For a review of pyrrole-imidazole alkaloids, see: Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783.
3. Antiviral and antibacterial: ref 1 and Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991, 56, 2965-2975. Antihistiminic: Cafieri, F.; Camuccio, R.; Fattorusso, E.; Taglialatela-Scafati, O.; Vallefuoco, T. Biorg. Med. Chem. Lett. 1997, 7, 2283-2288. Antimuscarinic: Rosa, R.; Silva, W.; de Motta, E.; Rodriguez, A. D.; Morales, J. J.; Orfiz, M. Experientia 1992, 48, 885-887. Sceptrin is the first and most potent nonpeptidic inhibitor of somatostatin and vasoactive intestinal peptide receptors: Vassas, A.; Bourdy, G.; Paillard, J. J.; Lavayre, J.; Pais, M.; Quirion, J. C.; Debitus, C. Planta Med. 1996, 62, 28-30. For additional reports of bioactivity, see ref 1.
4. Antiviral and antibacterial: ref 1 and Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991, 56, 2965-2975. Antihistiminic: Cafieri, F.; Camuccio, R.; Fattorusso, E.; Taglialatela-Scafati, O.; Vallefuoco, T. Biorg. Med. Chem. Lett. 1997, 7, 2283-2288. Antimuscarinic: Rosa, R.; Silva, W.; de Motta, E.; Rodriguez, A. D.; Morales, J. J.; Orfiz, M. Experientia 1992, 48, 885-887. Sceptrin is the first and most potent nonpeptidic inhibitor of somatostatin and vasoactive intestinal peptide receptors: Vassas, A.; Bourdy, G.; Paillard, J. J.; Lavayre, J.; Pais, M.; Quirion, J. C.; Debitus, C. Planta Med. 1996, 62, 28-30. For additional reports of bioactivity, see ref 1.
5. Antiviral and antibacterial: ref 1 and Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991, 56, 2965-2975. Antihistiminic: Cafieri, F.; Camuccio, R.; Fattorusso, E.; Taglialatela-Scafati, O.; Vallefuoco, T. Biorg. Med. Chem. Lett. 1997, 7, 2283-2288. Antimuscarinic: Rosa, R.; Silva, W.; de Motta, E.; Rodriguez, A. D.; Morales, J. J.; Orfiz, M. Experientia 1992, 48, 885-887. Sceptrin is the first and most potent nonpeptidic inhibitor of somatostatin and vasoactive intestinal peptide receptors: Vassas, A.; Bourdy, G.; Paillard, J. J.; Lavayre, J.; Pais, M.; Quirion, J. C.; Debitus, C. Planta Med. 1996, 62, 28-30. For additional reports of bioactivity, see ref 1.
6. Antiviral and antibacterial: ref 1 and Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991, 56, 2965-2975. Antihistiminic: Cafieri, F.; Camuccio, R.; Fattorusso, E.; Taglialatela-Scafati, O.; Vallefuoco, T. Biorg. Med. Chem. Lett. 1997, 7, 2283-2288. Antimuscarinic: Rosa, R.; Silva, W.; de Motta, E.; Rodriguez, A. D.; Morales, J. J.; Orfiz, M. Experientia 1992, 48, 885-887. Sceptrin is the first and most potent nonpeptidic inhibitor of somatostatin and vasoactive intestinal peptide receptors: Vassas, A.; Bourdy, G.; Paillard, J. J.; Lavayre, J.; Pais, M.; Quirion, J. C.; Debitus, C. Planta Med. 1996, 62, 28-30. For additional reports of bioactivity, see ref 1.
7. The shortest synthesis to date of 2 proceeds in six steps (ca. 12% overall yield), see: Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998, 63, 1248-1253.
8. Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243.
9. Attempted dimerization of 2 (synthesized by a route similar to ref 3) has failed in our hands, in line with the observations reported in ref 1. Approaches beginning with urocanic acid led to the cyclobutane framework (see: D'Auria, M.; Racioppi, R. Photochem. Photobiol. 1998, 112, 145-148), but further functionalization of such intermediates failed despite extensive efforts. Details of this effort and numerous other informative failed routes will be given in a full account of this work.
10. Laing, J.; McCulloch, A. W.; Smith, D. G.; McInnes, A. G. Can. J. Chem. 1971, 49, 574-582.
11. Nelsen, S. F.; Calabrese, J. C. J. Am. Chem. Soc. 1973, 95, 8385. This procedure requires tedious PTLC purification followed by several recrystallizations to separate 4 from numerous byproducts.
12. Prepared in quantitative yield by Diels-Alder cycloaddition of 2,5-dimethylfuran and dimethyl acetylenedicarboxylate followed by photoirradiation: Prinzbach, H.; Vogel, P.; Auge, W. Chimia 1967, 21, 469. See Supporting Information for detailed procedures.
13. Corey, E. J.; Nicolaou, K. C.; Machida, Y.; Balanson, R. D. Synthesis 1975, 590-591.
14. Kitamura, C.; Yamashita, Y, J. Chem. Soc., Perkin Trans. 1 1997, 1443-1447.
15. Han, Y.; Hu, H. Synthesis 1990, 122-124.
16. Lancini, G. C.; Lazzari, E.; Arioli, V.; Bellani, P. J. Med. Chem. 1969, 12, 775-780.
17. All compounds in the synthesis pathway are quite stable at 23 °C except for 1 and 3. See Supporting Information for details.