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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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).
The authors declare no competing financial interests.
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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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