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Total synthesis of (–)-tubingensin B enabled by the strategic use of an aryne cyclization

Nature Chemistry volume 9, pages 944–949 (2017)Cite this article

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Abstract

Tubingensin B is an indole diterpenoid that bears a daunting chemical structure featuring a disubstituted carbazole unit, five stereogenic centres—three of which are quaternary—and a decorated [3.2.2]-bridged bicycle. We describe our synthetic design toward a concise and enantiospecific total synthesis of tubingensin B, which hinges on the strategic use of a transient aryne intermediate. Although initial studies led to unexpected reaction outcomes, we ultimately implemented a sequence of carbazolyne cyclization followed by Rh-catalysed fragmentation to install the seven-membered ring and vicinal quaternary stereocentres of the natural product. Coupled with a late-stage radical cyclization to construct the [3.2.2]-bridged bicycle, these efforts have enabled the total synthesis of tubingensin B. The design and evolution of our succinct total synthesis underscores the utility of long-avoided aryne intermediates for the introduction of structural motifs that have conventionally been viewed as challenging.

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Figure 1: The structures of tubingensins B and A.
Figure 2: Retrosynthetic analysis of tubingensin B.
Figure 3: Synthesis of coupling fragment 7 and assembly of tetrasubstituted alkene 13.
Figure 4: The key aryne cyclization forges the C20–C11 linkage.
Figure 5: Radical cyclization and first generation total synthesis of tubingensin B.
Figure 6: Concise total synthesis of tubingensin B.

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Acknowledgements

The authors are grateful to the NIH-NIGMS (R01 GM090007 to N.K.G.), the Dreyfus Foundation, the UCLA Gold Shield Alumnae, the National Science Foundation Graduate Research Fellowship Program (DGE-1144087 to M.A.C.) and the University of California, Los Angeles for financial support. We thank Y. Tang (University of California, Los Angeles) for an authentic sample of tubingensin B. These studies were also supported by shared instrumentation grants from the NSF (no. CHE-1048804) and the National Center for Research Resources (no. S10RR025631).

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  1. Michael A. Corsello and Junyong Kim: These authors contributed equally to this work.

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  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, 90095, California, USA

    Michael A. Corsello, Junyong Kim & Neil K. Garg

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  1. Michael A. Corsello
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Contributions

M.A.C. and J.K. designed and performed experiments and analysed experimental data. N.K.G. directed the investigations and prepared the manuscript with contributions from all authors; all authors contributed to discussions.

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Correspondence to Neil K. Garg.

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Corsello, M., Kim, J. & Garg, N. Total synthesis of (–)-tubingensin B enabled by the strategic use of an aryne cyclization. Nature Chem 9, 944–949 (2017). https://doi.org/10.1038/nchem.2801

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