Total Synthesis of the Proposed Azaspiracid-1 Structure, Part 2: Coupling of the C1–C20, C21–C27, and C28–C40 Fragments and Completion of the Synthesis†
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 authorDavid Y.-K. Chen 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 authorYiwei Li
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 authorWenyuan Qian 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 authorTaotao Ling 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 authorStepan Vyskocil 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 authorTheocharis V. Koftis 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 authorMugesh Govindasamy 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 authorNoriaki Uesaka 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 authorDavid Y.-K. Chen 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 authorYiwei Li
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 authorWenyuan Qian 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 authorTaotao Ling 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 authorStepan Vyskocil 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 authorTheocharis V. Koftis 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 authorMugesh Govindasamy 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 authorNoriaki Uesaka 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 spectrometric assistance, respectively, and Dr. Raj Chadha for X-ray crystallographic analysis. Financial support for this work was provided by the National Institutes of Health (USA), The Skaggs Institute for Chemical Biology, predoctoral fellowships from Eli Lilly and The Skaggs Institute for Research (both to Y.L.), and a postdoctoral fellowship from The Skaggs Institute for Research (to W.Q.).
Graphical Abstract
Fata Morgana: Die Synthese von 1 und FGHI-epi-1 zeigte, dass diese Verbindungen nicht mit dem Naturstoff Azaspiracid-1 identisch sind. Somit konnten zwei aktuelle Strukturvorschläge für dieses wichtige marine Neurotoxin ausgeschlossen werden, die Frage nach seiner tatsächlichen Struktur bleibt jedoch weiterhin ungeklärt.
References
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- 6The 1H NMR (600 MHz, CDCl3) signal observed for 20-H (δ=3.62 ppm, J=9.6 Hz) after reduction of compound 4 with DIBAL-H was essentially identical in terms of both chemical shift and coupling constant to that observed after the reduction of compound 36 with DIBAL-H described in the preceding Communication.[1]
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- 10CCDC-210123 (10) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or [email protected]).
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- 12We thank Dr. Masayuki Satake for an authentic sample of azaspiracid-1 and for providing us with NMR spectra. Comparison of authentic azaspiracid-1 against 1 and FGHI-epi-1 by TLC (chloroform/methanol/H2O 20:3:1) showed that the authentic sample is more polar than either of the synthetic materials. In addition, the 1H NMR (600 MHz, 0.5 % CD3COOD in CD3OD) spectra of compounds 1 and FGHI-epi-1 were noticeably different from that of the natural azaspiracid-1,[2] particularly in the olefinic region; natural azaspiracid-1: δ=5.74 (4-H), 5.46 (5-H), 5.76 (8-H), 5.65 (9-H), 5.36 (44a-H), 5.18 ppm (44b-H); synthetic 1: δ=5.79 (4-H), 5.57 (5-H), 6.02 (8-H), 5.76 (9-H), 5.35 (44a-H), 5.31 ppm (44b-H); synthetic FGHI-epi-1: δ=5.79 (4-H), 5.57 (5-H), 6.02 (8-H), 5.76 (9-H), 5.38 (44a-H), 5.33 ppm (H-44b). The values for the synthetic materials correspond to those of the major product in each case. It was also observed that the chemical shifts for the “upper” domain olefinic protons (4-H, 5-H, 8-H, and 9-H) remain relatively constant, whereas those of the “lower” region of the molecule (44a-H and 44b-H) change considerably upon addition of CD3COOD.
- 13Note added in proof: Based on available information, we propose that the true azaspiracid-1 structure differs from that of FGHI-epi-1 by the position of the double bond in ring A (7,8 instead of 8,9). Ongoing studies aim to confirm this conjecture.
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