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Total synthesis of marine natural products without using protecting groups

Nature volume 446, pages 404–408 (2007)Cite this article

Abstract

The field of organic synthesis has made phenomenal advances in the past fifty years, yet chemists still struggle to design synthetic routes that will enable them to obtain sufficient quantities of complex molecules for biological and medical studies. Total synthesis is therefore increasingly focused on preparing natural products in the most efficient manner possible. Here we describe the preparative-scale, enantioselective, total syntheses of members of the hapalindole, fischerindole, welwitindolinone and ambiguine families, each constructed without the need for protecting groups—the use of such groups adds considerably to the cost and complexity of syntheses. As a consequence, molecules that have previously required twenty or more steps to synthesize racemically in milligram amounts can now be obtained as single enantiomers in significant quantities in ten steps or less. Through the extension of the general principles demonstrated here, it should be possible to access other complex molecular architectures without using protecting groups.

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Figure 1: Approaches to chemical synthesis.
Figure 2
Figure 3: Protecting-group-free synthesis of ambiguine H (1) and hapalindole U (2).
Figure 4: Protecting-group-free total synthesis of fischerindole I (5) and welwitindolinone A (4).

References

  1. Nicolaou, K. C. & Sorensen, E. J. Classics in Total Synthesis (VCH, New York, 1996)

    Google Scholar 

  2. Nicolaou, K. C. & Snyder, S. A. Classics in Total Synthesis II (Wiley-VCH, Weinheim, 2003)

    Google Scholar 

  3. Wöhler, F. Ueber die Künstliche Bildung des Harnstoffe Poggendorfs. Ann. Phys. Chem. 12, 253–256 (1828)

    Article  ADS  Google Scholar 

  4. Service, R. F. Race for molecular summits. Science 285, 184–187 (1999)

    Article  CAS  Google Scholar 

  5. Seebach, D. Organic synthesis–where now? Angew. Chem. Int. Edn Engl. 29, 1320–1367 (1990)

    Article  Google Scholar 

  6. Kocienski, P. J. Protecting Groups 3rd edn (Thieme, New York, 2005)

    Book  Google Scholar 

  7. Green, T. W. & Wuts, P. G. Protective Groups in Organic Synthesis 3rd edn (Wiley, Hoboken, 1999)

    Book  Google Scholar 

  8. Hoffmann, R. W. Protecting group free synthesis. Synthesis 3531–3541 (2006)

    Article  Google Scholar 

  9. Sierra, M. A. & de la Torre, M. C. Dead Ends and Detours, Direct Ways to Successful Total Synthesis (Wiley-VCH, Weinheim, 2004)

    Google Scholar 

  10. Butler, M. S. The role of natural product chemistry in drug discovery. J. Nat. Prod. 67, 2141–2153 (2004)

    Article  CAS  Google Scholar 

  11. Wilson, R. M. & Danishefsky, S. J. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J. Org. Chem. 71, 8329–8351 (2006)

    Article  CAS  Google Scholar 

  12. Faber, K. Biotransformations in Organic Chemistry 3rd edn (Springer, New York, 1997)

    Book  Google Scholar 

  13. Stratmann, K. et al. Welwitindolinones, unusual alkaloids from the blue-green algae Hapalosiphon welwitschii and Westiella intricate. Relationship to fischerindoles and hapalindoles. J. Am. Chem. Soc. 116, 9935–9942 (1994)

    Article  MathSciNet  CAS  Google Scholar 

  14. Scholz, U. & Winterfeldt, E. Biomimetic synthesis of alkaloids. Nat. Prod. Rep. 17, 349–366 (2000)

    Article  CAS  Google Scholar 

  15. Eschenmoser, A. Vitamin B12: experiments concerning the origin of its molecular structure. Angew. Chem. Int. Edn Engl. 27, 5–39 (1988)

    Article  Google Scholar 

  16. Heathcock, C. H. The enchanting alkaloids of Yuzuriha. Angew. Chem. Int. Edn Engl. 31, 665–681 (1992)

    Article  Google Scholar 

  17. Moore, R. E., Cheuk, C. & Patterson, G. M. L. Hapalindoles: new alkaloids from the blue-green alga Hapalosiphon fontinalis. J. Am. Chem. Soc. 106, 6456–6457 (1984)

    Article  CAS  Google Scholar 

  18. Moore, R. E. et al. Hapalindoles, antibacterial and antimycotic alkaloids from the cyanophyte Hapalosiphon fontinalis. J. Org. Chem. 52, 1036–1043 (1987)

    Article  CAS  Google Scholar 

  19. Smitka, T. A. et al. Ambiguine isonitriles, fungicidal hapalindole-type alkaloids from three genera of blue-green algae belonging to the Stigonemataceae. J. Org. Chem. 57, 857–861 (1992)

    Article  CAS  Google Scholar 

  20. Raveh, A. & Carmeli, S. Antimicrobial ambiguines from the cyanobacterium Fischerella sp. collected in Israel. J. Nat. Prod. doi: 10.1021/np060495r (in the press); published online 13 January 2007.

  21. Muratake, H., Kumagami, H. & Natsume, M. Synthetic studies of marine alkaloids hapalindoles. Part 3. Total synthesis of (±)-hapalindoles H and U. Tetrahedron 46, 6351–6360 (1990)

    Article  CAS  Google Scholar 

  22. Mehta, G. & Acharyulu, P. V. R. Terpenes to terpenes. Stereo- and enantio-selective synthesis of (+)-α-elemene and a short route to a versatile diquinane chiron. J. Chem. Soc. Chem. Commun. 2759–2760 (1994)

  23. Baran, P. S. & Richter, J. M. Direct coupling of indoles with carbonyl compounds: short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families. J. Am. Chem. Soc. 126, 7450–7451 (2004)

    Article  CAS  Google Scholar 

  24. Baran, P. S., Richter, J. M. & Lin, D. W. Direct coupling of pyrroles with carbonyl compounds: short enantioselective synthesis of (S)-ketorolac. Angew. Chem. Int. Edn Engl. 44, 609–612 (2005)

    Article  CAS  Google Scholar 

  25. Nicolaou, K. C., Bulger, P. G. & Sarlah, D. Palladium-catalyzed cross-coupling reactions in total synthesis. Angew. Chem. Int. Edn Engl. 44, 4442–4489 (2005)

    Article  CAS  Google Scholar 

  26. Larock, R. C. & Babu, S. Synthesis of nitrogen heterocycles via palladium-catalyzed intramolecular cyclization. Tetrahedr. Lett. 28, 5291–5294 (1987)

    Article  CAS  Google Scholar 

  27. Burns, B. et al. Palladium catalysed tandem cyclisation-anion capture processes. Part 1: Background and hydride ion capture by alkyl- and π-allyl-palladium species. Tetrahedr. Lett. 29, 4329–4332 (1988)

    Article  CAS  Google Scholar 

  28. Herrmann, W. A. et al. Palladacycles as structurally defined catalysts for the Heck olefination of chloro- and bromoarenes. Angew. Chem. Int. Edn Engl. 34, 1844–1848 (1995)

    Article  CAS  Google Scholar 

  29. Schkeryantz, J. M., Woo, J. C. G., Siliphaivanth, P., Depew, K. M. & Danishefsky, S. J. Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: Novel constructions of 2,3-disubstituted indoles. J. Am. Chem. Soc. 121, 11964–11975 (1999)

    Article  CAS  Google Scholar 

  30. Turro, N. J. Modern Molecular Photochemistry Ch. 13 (University Science Books, Sausalito, 1991)

    Google Scholar 

  31. Hudlicky, T. Design constraints in practical syntheses of complex molecules: current status, case studies with carbohydrates and alkaloids, and future perspectives. Chem. Rev. 96, 3–30 (1996)

    Article  CAS  Google Scholar 

  32. Baran, P. S. & Richter, J. M. Enantioselective total synthesis of welwitindolinone A and fischerindoles I and G. J. Am. Chem. Soc. 127, 15394–15396 (2005)

    Article  CAS  Google Scholar 

  33. Oikawa, Y. & Yonemitsu, O. Selective oxidation of the side chain at C–3 of indoles. J. Org. Chem. 42, 1213–1216 (1977)

    Article  CAS  Google Scholar 

  34. Shellhamer, D. F. et al. Reaction of xenon difluoride with indene in aqueous 1,2-dimethoxyethane and tetrahydrofuran. J. Chem. Soc. Perkin Trans. II, 401–403 (1991)

    Article  Google Scholar 

  35. Baran, P. S. & Shenvi, R. A. Total synthesis of (±)-chartelline C. J. Am. Chem. Soc. 128, 14028–14029 (2006)

    Article  CAS  Google Scholar 

  36. Reisman, S. E., Ready, J. M., Hasuoka, A., Smith, C. J. & Wood, J. L. Total synthesis of (±)-welwitindolinone A isonitrile. J. Am. Chem. Soc. 128, 1448–1449 (2006)

    Article  CAS  Google Scholar 

  37. Trost, B. M. The atom economy—a search for synthetic efficiency. Science 254, 1471–1477 (1991)

    Article  ADS  CAS  Google Scholar 

  38. Wender, P. A. & Miller, B. L. in Organic Synthesis: Theory and Applications (ed. Hudlicky, T.) Vol. 2 27–66 (JAI Press, Greenwich, Connecticut, 1993)

    Google Scholar 

  39. Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, New York, 1995)

    Google Scholar 

  40. Hendrickson, J. B. Systematic synthesis design. IV. Numerical codification of construction reactions. J. Am. Chem. Soc. 97, 5784–5800 (1975)

    Article  CAS  Google Scholar 

  41. Bertz, S. H. Convergence, molecular complexity, and synthetic analysis. J. Am. Chem. Soc. 104, 5801–5803 (1982)

    Article  CAS  Google Scholar 

  42. Evans, D. A. Synthesis Design and the Oxidation State Issue (Lecture at Scripps Research Institute, 12 February, 2004)

    Google Scholar 

  43. Nicolaou, K. C., Edmonds, D. J. & Bulger, P. G. Cascade reactions in total synthesis. Angew. Chem. Int. Edn Engl. 45, 7134–7186 (2006)

    Article  CAS  Google Scholar 

  44. Hoveyda, A. H., Evans, D. A. & Fu, G. C. Substrate-directable chemical reactions. Chem. Rev. 93, 1307–1370 (1993)

    Article  CAS  Google Scholar 

  45. WenderP. A.Frontiers in Organic Synthesis. Chem. Rev. 96 , (special issue)1–600 (1996)

  46. Vanderwal, C. D., Vosburg, D. A., Weiler, S. & Sorensen, E. J. An enantioselective synthesis of FR182877 provides a chemical rationalization of its structure and affords multigram quantities of its direct precursor. J. Am. Chem. Soc. 125, 5393–5407 (2003)

    Article  CAS  Google Scholar 

  47. Nicolaou, K. C. & Snyder, S. A. The essence of total synthesis. Proc. Natl Acad. Sci. USA 101, 11929–11936 (2004)

    Article  ADS  CAS  Google Scholar 

  48. Dörwald, F. Z. Side Reactions in Organic Synthesis (Wiley-VCH, Weinheim, 2005)

    Google Scholar 

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Acknowledgements

We are grateful to M. R. Ghadiri for discussions and comments on the manuscript, P. Mariano for his comments on the mechanism of photocleavage, and B. Whitefield for his technical contributions. We thank S. Carmeli for a sample of natural ambiguine H (1). We also thank D.-H. Huang and L. Pasternack for NMR spectroscopic assistance, and G. Siuzdak and R. Chadha for mass spectrometric and X-ray crystallographic assistance, respectively. We also thank Biotage for a generous donation of process vials used extensively throughout these studies. Financial support for this work was provided by The Scripps Research Institute, Amgen, AstraZeneca, the Beckman Foundation, Bristol-Myers Squibb, DuPont, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, the Searle Scholarship Fund, the Sloan Foundation, NSF (predoctoral fellowship to J.M.R.) and the NIH.

The X-ray crystallographic coordinates for the structures of compounds 1 (CCDC # 623052), 2 (CCDC # 623050), and 12 (CCDC # 623051) were deposited with the Cambridge Crystallographic Data Center. These data can be obtained free of charge at www.ccdc.cam.ac.uk/retrieving.html.

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  1. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA,

    Phil S. Baran, Thomas J. Maimone & Jeremy M. Richter

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  1. Phil S. Baran
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Correspondence to Phil S. Baran.

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Baran, P., Maimone, T. & Richter, J. Total synthesis of marine natural products without using protecting groups. Nature 446, 404–408 (2007). https://doi.org/10.1038/nature05569

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