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Enantioselective synthesis of tatanans A–C and reinvestigation of their glucokinase-activating properties

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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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Figure 1: Tatanans A–C are structurally unusual novel sesquilignans isolated from the rhizomes of Acorus tatarinowii plants.
Figure 2: Description of the total synthesis of tatanan A using consecutive sigmatropic rearrangements as a key element of the synthesis design, setting the three adjacent stereogenic centres of the natural product.
Figure 3: Tatanans B and C can conceivably arise from cyclization of tatanan A during their biosynthesis.
Figure 4: Total synthesis of tatanans B and C by a palladium-catalysed cyclodearomatization.
Figure 5: In vitro enzymatic assays demonstrate that tatanans A–C do not activate human glucokinase.

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  • 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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Correspondence to Brian G. Miller or Armen Zakarian.

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The authors declare no competing financial interests.

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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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