Abstract
The tatanans are members of a novel class of complex sesquilignan natural products recently isolated from the rhizomes of Acorus tatarinowii Schott plants. Tatanans A, B and C have previously been reported to have potent glucokinase-activating properties that exceed the in vitro activity of known synthetic antidiabetic agents. Here, using a series of sequential [3,3]-sigmatropic rearrangements, we report the total synthesis of tatanan A in 13 steps and 13% overall yield. We also complete a concise enantioselective total synthesis of more complex, atropisomeric tatanans B and C via a distinct convergent strategy based on a palladium-catalysed diastereotopic aromatic group differentiation (12 steps, 4% and 8% overall yield, respectively). A plausible biosynthetic relationship between acyclic tatanan A and spirocyclic tatanans B and C is proposed and probed experimentally. With sufficient quantities of the natural products in hand, we undertake a detailed functional characterization of the biological activities of tatanans A–C. Contrary to previous reports, our assays utilizing pure recombinant human enzyme demonstrate that tatanans do not function as allosteric activators of glucokinase.
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Change history
04 April 2013
In the original version of this Article published online, the term Acorus tatarinowii was spelled incorrectly. This has now been corrected in all versions of the Article.
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Acknowledgements
The authors thank Hongjun Zhou for continued assistance with NMR spectroscopy. This work was supported by the US National Institutes of Health (NIGMS GM077379 to A.Z., NIDDK DK081358 to B.G.M.) and additional kind donations from Eli Lilly and Amgen.
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Q.X., A.B., J.J.J. and J.M.B. planned, conducted and analysed the experiments. A.Z. and B.G.M. designed and directed the project. A.Z. and B.G.M. wrote the manuscript. All authors contributed to discussions.
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Xiao, Q., Jackson, J., Basak, A. et al. Enantioselective synthesis of tatanans A–C and reinvestigation of their glucokinase-activating properties. Nature Chem 5, 410–416 (2013). https://doi.org/10.1038/nchem.1597
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DOI: https://doi.org/10.1038/nchem.1597
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