Studies Towards the Synthesis of Azadirachtin: Enantioselective Entry into the Azadirachtin Framework through Cascade Reactions†
K. C. Nicolaou Prof. Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorA. J. Roecker
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorHolger Monenschein Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorPrasuna Guntupalli Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorMarkus Follmann Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorK. C. Nicolaou Prof. Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorA. J. Roecker
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorHolger Monenschein Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorPrasuna Guntupalli Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorMarkus Follmann Dr.
Department of Chemistry and, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Search for more papers by this authorWe thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR spectroscopic and mass spectroscopic assistance, respectively, and Dr. Raj Chadha for X-ray crystallographic analysis. This work was financially supported by the National Institutes of Health (USA), The Skaggs Institute for Chemical Biology, predoctoral fellowships from the Division of Organic Chemistry of the ACS sponsored by Novartis and the Division of Medicinal Chemistry of the ACS sponsored by Pfizer (both to A.J.R.), a Feodor Lynen postdoctoral fellowship from the Alexander von Humboldt Foundation (to H.M.), and a postdoctoral fellowship from Bayer AG (to M.F.).
Graphical Abstract
Das Gerüst steht: Die Grundstruktur von Azadirachtin (1) wurde enantioselektiv aufgebaut: Die Verbindungen 2 a–c wurden durch Kaskadenreaktionen erhalten, die auf intramolekularen Radikaladditionen und säurevermittelten Redoxreaktionen beruhen. Die Zielverbindung erscheint damit zum Greifen nah.
References
- 1For the isolation, see: J. H. Butterworth, E. D. Morgan, Chem. Commun. 1968, 23–24.
- 2For the structure determination, see:
- 2aJ. N. Bilton, H. B. Broughton, P. S. Jones, S. V. Ley, Z. Lidert, E. D. Morgan, H. S. Rszepa, R. N. Sheppard, A. M. Z. Slawin, D. J. Williams, Tetrahedron 1987, 43, 2805–2815;
- 2bW. Kraus, M. Bokel, A. Bruhn, R. Cramer, I. Klaiber, A. Klenk, G. Nagl, H. Pohnl, H. Sadlo, B. Vogler, Tetrahedron 1987, 43, 2817–2830;
- 2cC. J. Turner, M. S. Tempesta, R. B. Taylor, M. G. Zagorski, J. S. Termini, D. R. Schroeder, K. Nakanishi, Tetrahedron 1987, 43, 2789–2804; Synthetic studies:
- 2dS. V. Ley, C. E. Gutteridge, A. R. Pape, C. D. Spilling, C. Zumbrunn, Synlett 1999, 1295–1297;
- 2eA. A. Denholm, L. Jennens, S. V. Ley, Tetrahedron 1995, 51, 6591–6604;
- 2fS. V. Ley, A. A. Denholm, A. Wood, Nat. Prod. Rep. 1993, 10, 109–157;
- 2gH. Kolb, S. V. Ley, Tetrahedron Lett. 1991, 32, 6187–6190;
- 2hM. G. Brasca, H. B. Broughton, D. Craig, S. V. Ley, A. A. Somovilla, P. L. Toogood, Tetrahedron Lett. 1988, 29, 1853–1856;
- 2iY. Yamamoto, J. Ishihara, N. Kanoh, A. Murai, Synthesis 2000, 1878–1893;
- 2jH. Watanabe, T. Watanabe, K. Mori, T. Kitahara, Tetrahedron Lett. 1997, 38, 4429–4432;
- 2kY. Nishikimi, T. Iimori, M. Sodeoka, M. Shibasaki, J. Org. Chem. 1989, 54, 3354–3359;
- 2lK. J. Henry, Jr.,B. Fraser-Reid, J. Org. Chem. 1994, 59, 5128–5129;
- 2mH. Schlesiger, E. Winterfeld, Chirality 1997, 9, 454–458;
- 2nT. Durand-Reville, L. B. Gobbi, B. L. Gray, S. V. Ley, J. S. Scott, Org. Lett. 2002, 4, 3847–3850;
- 2oT. Fukuzaki, S. Kobayashi, T. Hibi, T. Ikuma, J. Ishihara, N. Kanoh, A. Murai, Org. Lett. 2002, 4, 2877–2880;
- 2pK. C. Nicolaou, A. J. Roecker, M. Follmann, R. Baati, Angew. Chem. 2002, 114, 2211–2214;
10.1002/1521-3757(20020617)114:12<2211::AID-ANGE2211>3.0.CO;2-W Google ScholarAngew. Chem. Int. Ed. 2002, 41, 2107–2110.10.1002/1521-3773(20020617)41:12<2107::AID-ANIE2107>3.0.CO;2-4 CAS PubMed Web of Science® Google Scholar
- 3K. C. Nicolaou, M. Follmann, A. J. Roecker, K. W. Hunt, Angew. Chem. 2002, 114, 2207–2210;
10.1002/1521-3757(20020617)114:12<2207::AID-ANGE2207>3.0.CO;2-Z Google ScholarAngew. Chem. Int. Ed. 2002, 41, 2103–2106.10.1002/1521-3773(20020617)41:12<2103::AID-ANIE2103>3.0.CO;2-S CAS PubMed Web of Science® Google Scholar
- 4R. Hanselmann, M. Benn, Synth. Commun. 1996, 26, 945–961.
- 5T. Nagamitsu, T. Sunazuka, R. Obata, H. Tomoda, H. Tanaka, Y. Harigaya, S. Omura, A. B. Smith III, J. Org. Chem. 1995, 60, 8126–8127.
- 6G. Sourkouni-Argirusi, A. Kirschning, Org. Lett. 2000, 2, 3781–3784.
- 7A. F. Barrero, S. Arseniyadis, J. F. Quilez del Moral, M. Mar Herrador, M. Valdivia, D. Jimenez, J. Org. Chem. 2002, 67, 3781–3784.
- 8G. Eichberger, G. Penn, K. Raber, H. Griengl, Tetrahedron Lett. 1986, 27, 2843–2844.
- 9P. G. Gassman, S. J. Burns, K. B. Pfister, J. Org. Chem. 1993, 58, 1449–1457.
- 10For a bromoketalization precedent, see: J. D. White, P. Theramongkol, C. Kuroda, J. R. Engegrecht, J. Org. Chem. 1988, 53, 5909–5921.
- 11For another substrate-directed 6-endo-trig over 5-exo-trig radical cyclization, see: C. Anies, L. Billot, J.-Y. Lallemand, A. Pancrazi, Tetrahedron Lett. 1995, 36, 7247–7250.
- 12For an example of a 1,5 hydrogen-transfer reaction, see: D. P. Curran, H. Yu, Synthesis 1992, 123–127.
- 13For further mechanistic characterization, the cyclization of the minor bromoketal was also performed with nBu3SnD. The product showed incorporation of deuterium by MALDI MS and by 1H NMR (presumably the deuterium was incorporated at C8; the signal for the proton at C8 is obscured by other protons in the same region).
- 14For another example of an intramolecular redox reaction through a 1,5 hydride shift, see: H. Berner, G. Schultz, H. Schneider, Tetrahedron 1980, 36, 1807–1811.
- 15P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem. 1981, 46, 3936–3938.
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