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

Nature Chemistry volume 5, pages 410416 (2013) | Download Citation

This article has been updated

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.

  • Compound C36H48O9

    Tatanan A

  • Compound C35H46O9

    Tatanan B

  • Compound C35H46O9

    Tatanan C

  • Compound C12H16O4

    1-(2,4,5-Trimethoxyphenyl)propan-1-one

  • Compound C10H12O4

    2,4,5-Trimethoxybenzaldehyde

  • Compound C22H26O7

    (E)-2-Methyl-1,3-bis(2,4,5-trimethoxyphenyl)prop-2-en-1-one

  • Compound C22H28O7

    (R,E)-2-Methyl-1,3-bis(2,4,5-trimethoxyphenyl)prop-2-en-1-ol

  • Compound C25H32O8

    (R,E)-2-Methyl-1,3-bis(2,4,5-trimethoxyphenyl)allyl propionate

  • Compound C25H32O8

    (2R,3S,E)-2,4-Dimethyl-3,5-bis(2,4,5-trimethoxyphenyl)pent-4-enoic acid

  • Compound C27H34O7

    (4R,5S,E)-4,6-Dimethyl-5,7-bis(2,4,5-trimethoxyphenyl)hept-6-en-2-yn-1-ol

  • Compound C35H44O9

    5,5'-((1E,3S,4S,5Z)-7-(3,4-Dimethoxyphenoxy)-2,4-dimethylhepta-1,5-diene-1,3-diyl)bis(1,2,4-trimethoxybenzene)

  • Compound C35H44O9

    2-((3R,4S,5S,E)-4,6-Dimethyl-5,7-bis(2,4,5-trimethoxyphenyl)hepta-1,6-dien-3-yl)-4,5-dimethoxyphenol

  • Compound C8H16OS

    (R,E)-1-(tert-Butylsulfinyl)but-2-ene

  • Compound C25H40O6S

    (2R,3S,4R,E)-tert-Butyl 6-((R)-tert-butylsulfinyl)-2,4-dimethyl-3-(2,4,5-trimethoxyphenyl)hex-5-enoate

  • Compound C25H40O7S

    (2R,3S,4R,E)-tert-Butyl 6-(tert-butylsulfonyl)-2,4-dimethyl-3-(2,4,5-trimethoxyphenyl)hex-5-enoate

  • Compound C21H32O5

    (2R,3S,4S)-tert-Butyl 2,4-dimethyl-3-(2,4,5-trimethoxyphenyl)hex-5-enoate

  • Compound C17H29BrO3Si

    (4-Bromo-2,5-dimethoxyphenoxy)triisopropylsilane

  • Compound C51H82O10Si2

    (2R,3S,4S)-1,1-Bis(2,5-dimethoxy-4-((triisopropylsilyl)oxy)phenyl)-2,4-dimethyl-3-(2,3,5-trimethoxyphenyl)hex-5-en-1-ol

  • Compound C51H82O9Si2

    ((((2R,3S,4S)-2,4-Dimethyl-3-(2,3,5-trimethoxyphenyl)hex-5-ene-1,1-diyl)bis(2,5-dimethoxy-4,1-phenylene))bis(oxy))bis(triisopropylsilane)

  • Compound C53H84O11Si2

    (4S,5S,6R,E)-Methyl 7,7-bis(2,5-dimethoxy-4-((triisopropylsilyl)oxy)phenyl)-4,6-dimethyl-5-(2,3,5-trimethoxyphenyl)hept-2-enoate

  • Compound C36H46O12

    (4S,5S,6R,E)-7,7-Bis(4-hydroxy-2,5-dimethoxyphenyl)-4,6-dimethyl-5-(2,3,5-trimethoxyphenyl)hept-2-en-1-yl methyl carbonate

  • Compound C34H42O9

    (6S,7S,8R,9R,11S)-7-(4-Hydroxy-2,5-dimethoxyphenyl)-1,4-dimethoxy-8,10-dimethyl-9-(2,4,5-trimethoxyphenyl)-11-vinylspiro[5.5]undeca-1,4-dien-3-one

  • Compound C34H42O9

    (6S,7S,8R,9R,11S)-7-(4-Hydroxy-2,5-dimethoxyphenyl)-1,4-dimethoxy-8,10-dimethyl-9-(2,4,5-trimethoxyphenyl)-11-vinylspiro[5.5]undeca-1,4-dien-3-one

  • Compound C34H42O9

    (6R,7R,8R,9S,10R,11S)-7-(4-Hydroxy-2,5-dimethoxyphenyl)-1,4-dimethoxy-8,10-dimethyl-9-(2,4,5-trimethoxyphenyl)-11-vinylspiro[5.5]undeca-1,4-dien-3-one

  • Compound C35H46O9

    (6R,7S,8S,9S,10R,11R)-7-Ethyl-1,4-dimethoxy-8,10-dimethyl-9,11-bis(2,4,5-trimethoxyphenyl)spiro[5.5]undeca-1,4-dien-3-one

  • Compound C25H34O7

    (2R,3S,E)-2,4-Dimethyl-3,5-bis(2,4,5-trimethoxyphenyl)pent-4-en-1-ol

  • Compound C25H32O7

    (2R,3S,E)-2,4-Dimethyl-3,5-bis(2,4,5-trimethoxyphenyl)pent-4-enal

  • Compound C26H32Br2O6

    5,5'-((3S,4R,E)-6,6-Dibromo-2,4-dimethylhexa-1,5-diene-1,3-diyl)bis(1,2,4-trimethoxybenzene)

  • Compound C27H36O7

    (2Z,4S,5S,6E)-4,6-Dimethyl-5,7-bis(2,4,5-trimethoxyphenyl)hepta-2,6-dien-1-ol

  • Compound C36H46O9

    5,5'-((3S,4S,5R,E)-2,4-Dimethyl-5-(2,4,5-trimethoxyphenyl)hepta-1,6-diene-1,3-diyl)bis(1,2,4-trimethoxybenzene)

  • Compound C36H46O9

    5,5'-((3S,4S,5S,E)-2,4-Dimethyl-5-(2,4,5-trimethoxyphenyl)hepta-1,6-diene-1,3-diyl)bis(1,2,4-trimethoxybenzene)

  • Compound C8H16S

    (E)-But-2-en-1-yl tert-butyl sulfide

  • Compound C16H19Cl2NO3S

    (1S,2S,4R)-3,3-Dichloro-1,7,7-trimethyl-2'-(phenylsulfonyl)spiro[bicyclo[2.2.1]heptane-2,3'-[1,2]oxaziridine]

  • Compound C16H22O5

    (E)-tert-Butyl 3-(2,4,5-trimethoxyphenyl)acrylate

  • Compound C52H84O10Si2

    (4S,5S,6R,E)-7,7-Bis(2,5-dimethoxy-4-((triisopropylsilyl)oxy)phenyl)-4,6-dimethyl-5-(2,4,5-trimethoxyphenyl)hept-2-en-1-ol

  • Compound C54H86O12Si2

    (4S,5S,6R,E)-7,7-Bis(2,5-dimethoxy-4-((triisopropylsilyl)oxy)phenyl)-4,6-dimethyl-5-(2,4,5-trimethoxyphenyl)hept-2-en-1-yl methyl carbonate

  • Compound C35H44O9

    (6S,7R,8R,9S,10R,11R)-1,4-Dimethoxy-8,10-dimethyl-7,9-bis(2,4,5-trimethoxyphenyl)-11-vinylspiro[5.5]undeca-1,4-dien-3-one

  • Compound C35H44O9

    (6S,7R,8R,9S,10R,11R)-1,4-Dimethoxy-8,10-dimethyl-7,9-bis(2,4,5-trimethoxyphenyl)-11-vinylspiro[5.5]undeca-1,4-dien-3-one

  • Compound C35H44O9

    (6R,7R,8R,9S,10R,11S)-1,4-Dimethoxy-8,10-dimethyl-7,9-bis(2,4,5-trimethoxyphenyl)-11-vinylspiro[5.5]undeca-1,4-dien-3-one

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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.

Author information

Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA

    • Qing Xiao
    • , Jeffrey J. Jackson
    • , Ashok Basak
    •  & Armen Zakarian
  2. Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, USA

    • Joseph M. Bowler
    •  & Brian G. Miller

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Brian G. Miller or Armen Zakarian.

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DOI

https://doi.org/10.1038/nchem.1597