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Total synthesis of marine natural products without using protecting groups

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).

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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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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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