Regioselective reactions for programmable resveratrol oligomer synthesis

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Abstract

Although much attention has been devoted to resveratrol, a unique polyphenol produced by plants and credited as potentially being responsible for the ‘French paradox’—the observation that French people have a relatively low incidence of coronary heart disease, even though their diet is high in saturated fats—the oligomers of resveratrol have been largely ignored despite their high biological activity. Challenges in achieving their isolation in sufficient quantity from natural sources, coupled with an inability to prepare them easily synthetically, are seen as the main obstacles. Here we report a programmable, controlled and potentially scalable synthesis of the resveratrol family via a three-stage design. The synthetic approach requires strategy- and reagent-guided chemical functionalizations to differentiate two distinct cores possessing multiple sites with the same or similar reactivity, ultimately leading to five higher-order natural products. This work demonstrates that challenging, positionally selective functionalizations of complex materials are possible where biosynthetic studies have indicated otherwise, it provides materials and tools with which to unlock the full biochemical potential of this family of natural products, and it affords an intellectual framework within which other oligomeric families could potentially be accessed.

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Figure 1: The diversity of selected terpene and polyphenolic oligostilbene natural products: products of privileged starting materials.
Figure 2: Nature’s putative biogenesis of the resveratrol family and our specific plan for achieving their controlled assembly.
Figure 3: Use of substrate-guided halogenations to synthesize two resveratrol trimers and tetramers (16 and 17) and an unnatural analogue (30) from protected pallidol (22) and 25.
Figure 4: Use of reagent-guided halogenations to synthesize three resveratrol trimers and tetramers(18, 19 and 38) from protected ampelopsin F (31).

References

  1. 1

    Fischbach, M. A. & Clardy, J. One pathway, many products. Nature Chem. Biol. 3, 353–355 (2007)

  2. 2

    Christianson, D. W. Structural biology and chemistry of the terpenoid cyclases. Chem. Rev. 106, 3412–3442 (2006)

  3. 3

    Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009)

  4. 4

    Sotheeswaran, S. & Pasupathy, V. Distribution of resveratrol oligomers in plants. Phytochemistry 32, 1083–1092 (1993)

  5. 5

    Quideau, S., Deffieux, D., Douat-Casassus, C. & Pouységu, L. Plant polyphenols: chemical properties, biological activities, and synthesis. Angew. Chem. Int. Edn 50, 586–621 (2011)

  6. 6

    Snyder, S. A., ElSohly, A. M. & Kontes, F. Synthetic approaches to oligomeric natural products. Nat. Prod. Rep. 28, 897–924 (2011)

  7. 7

    Takaya, Y., Yan, K.-X., Terashima, K., Ito, J. & Niwa, M. Chemical determination of the absolute structures of resveratrol dimers, ampelopsins A, B, D and F. Tetrahedron 58, 7259–7265 (2002)

  8. 8

    Takaya, Y., Yan, K.-X., Terashima, K., He, Y.-H. & Niwa, M. Biogenetic reactions on stilbene tetramers from Vitaceaeous plants. Tetrahedron 58, 9265–9271 (2002)

  9. 9

    Wang, S., Ma, D. & Hu, C. Three new compounds from the aerial parts of Caragana sinica . Helv. Chim. Acta 88, 2315–2321 (2005)

  10. 10

    Tanaka, T. et al. Six new heterocyclic stilbene oligomers from stem bark of Shore hemsleyana . Heterocycles 55, 729–740 (2001)

  11. 11

    Wang, S. & Ma, D. &. Hu, C. Two new oligostilbenes from Caragana sinica . J. Asian Nat. Prod. Res. 6, 241–248 (2004)

  12. 12

    Oshima, Y., Ueno, Y., Hisamichi, K. & Takeshita, M. Ampelopsins F and G, novel bridged plant oligostilbenes from Ampelopsis brevipedunculata var. hancei roots (Vitaceae). Tetrahedron 49, 5801–5804 (1993)

  13. 13

    Tanaka, T., Ito, T., Nakaya, K., Iinuma, M. & Riswan, S. Oligostilbenoids in stem bark in Vatica rassak . Phytochemistry 54, 63–69 (2000)

  14. 14

    Jang, M. et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218–220 (1997)

  15. 15

    Milne, J. C. et al. Small molecules activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007)

  16. 16

    Tsukamoto, T. et al. Vaticanol C, a resveratrol tetramer, activates PPARα and PPARβ/γ in vitro and in vivo. Nutr. Metabol. 7,. 10.1186/1743–7075–7-46 (2010)

  17. 17

    Ito, T. et al. Antitumor effect of resveratrol oligomers against human cancer cell lines and the molecular mechanism of apoptosis induced by vaticanol C. Carcinogenesis 24, 1489–1497 (2003)

  18. 18

    Abe, N. et al. Resveratrol oligomers from Vatica albiramis . J. Nat. Prod. 73, 1499–1506 (2010)

  19. 19

    Atun, S., Aznam, N., Arianingrum, R., Takaya, Y. & Niwa, M. Resveratrol derivatives from stem bark of Hopea and their biological activity test. J. Physiol. Sci. 19, 7–21 (2008)

  20. 20

    Yamada, M. et al. Stilbenoids of Kobresia nepalensis (Cyperaceae) exhibiting DNA topoisomerase II inhibition. Phytochemistry 67, 307–313 (2006)

  21. 21

    Langcake, P. & Pryce, R. J. Oxidative dimerisation of 4-hydroxystilbenes in vitro: production of a grapevine phytoalexin mimic. J. Chem. Soc. Chem. Commun. 208–210 (1977)

  22. 22

    Sako, M., Hosokawa, H., Ito, T. & Iinuma, M. Regioselective oxidative coupling of 4-hydroxystilbenes: synthesis of resveratrol and ε-viniferin (E)-dehydrodimers. J. Org. Chem. 69, 2598–2600 (2004)

  23. 23

    Li, W., Li, H. & Hou, Z. Total synthesis of (±)-quadrangularin A. Angew. Chem. Int. Edn 45, 7609–7611 (2006)

  24. 24

    Li, W., Li, H., Luo, Y., Yang, Y. & Wang, N. Biosynthesis of resveratrol dimers by regioselective oxidative coupling reaction. Synlett 1247–1250 (2010)

  25. 25

    Velu, S. S. et al. Regio- and stereoselective biomimetic synthesis of oligostilbenoid dimers from resveratrol analogues: influence of the solvent, oxidant, and substitution. Chem. Eur. J. 14, 11376–11384 (2008)

  26. 26

    Takaya, Y. et al. Biomimetic transformation of resveratrol. Tetrahedron 61, 10285–10290 (2005)

  27. 27

    He, Y.-H., Takaya, Y., Terashima, K. & Niwa, M. Determination of absolute structure of (+)-davidiol A. Heterocycles 68, 93–100 (2006)

  28. 28

    Kim, I. & Choi, J. A versatile approach to oligostilbenoid natural products—synthesis of permethylated analogues of viniferifuran, malibatol A, and shoreaphenol. Org. Biomol. Chem. 7, 2788–2795 (2009)

  29. 29

    Kraus, G. A. & Gupta, V. A new synthetic strategy for the synthesis of bioactive stilbene dimers. A direct synthesis of amurensin H. Tetrahedr. Lett. 50, 7180–7183 (2009)

  30. 30

    Jeffrey, J. L. & Sarpong, R. Concise synthesis of paucifloral F using a Larock annulation. Org. Lett. 11, 5450–5453 (2009)

  31. 31

    Nicolaou, K. C., Kang, Q., Wu, T. R., Lim, C. S. & Chen, D. Y.-K. Total synthesis and biological evaluation of the resveratrol-derived polyphenol natural products hopeanol and hopeahainol A. J. Am. Chem. Soc. 132, 7540–7548 (2010)

  32. 32

    Snyder, S. A., Zografos, A. L. & Lin, Y. Total synthesis of resveratrol-based natural products: a chemoselective approach. Angew. Chem. Int. Edn 46, 8186–8191 (2007)

  33. 33

    Snyder, S. A., Breazzano, S. P., Ross, A. G., Lin, Y. & Zografos, A. Total synthesis of diverse carbogenic complexity within the resveratrol class from a common building block. J. Am. Chem. Soc. 131, 1753–1765 (2009)

  34. 34

    Sculimbrene, B. R., Morgan, A. J. & Miller, S. J. Enantiodivergence in small-molecule catalysis of asymmetric phosphorylation: concise total syntheses of the enantiomeric D-myo-inositol-1-phosphate and D-myo-inositol-3-phosphate. J. Am. Chem. Soc. 124, 11653–11656 (2002)

  35. 35

    Lewis, C. A. & Miller, S. J. Site-selective derivatization and remodeling of erythromycin A by using peptide-based chiral catalysts. Angew. Chem. Int. Edn 45, 5616–5619 (2006)

  36. 36

    Bertolini, F. & Pineschi, M. Recent progress in the synthesis of 2,3-dihydrofurans. Org. Prep. Proced. Intl 41, 385–418 (2009)

  37. 37

    Corey, E. J. & Chaykovsky, M. Dimethyloxosulfonium methylide and dimethylsulfonium methylide. Formation and application to organic synthesis. J. Am. Chem. Soc. 87, 1353–1364 (1965)

  38. 38

    Bach, N. J. et al. Bicyclic and tricyclic ergoline partial structures. Rigid 3-(2-aminoethyl)pyrroles and 3- and 4-(2-aminoethyl)pyrazoles as dopamine agonists. J. Med. Chem. 23, 481–491 (1980)

  39. 39

    Baker, R. Cooke, N. G., Humphrey, G. R, Wright, S. H. B. & Hirshfield, J. Stereoselective synthesis of the dihydrobenzo[b]furan segments of the ephedradine alkaloids. Chem. Commun. 1102–1004 (1987)

  40. 40

    Kurosawa, W., Kobayashi, H., Kan, T. & Fukuyama, T. Total synthesis of (−)-ephedradine A: an efficient construction of optically active dihydrobenzofuran-ring via C–H insertion reaction. Tetrahedron 60, 9615–9628 (2004)

  41. 41

    Snyder, S. A., Treitler, D. S. & Brucks, A. P. Simple reagents for direct halonium-induced polyene cyclization. J. Am. Chem. Soc. 132, 14303–14314 (2010)

  42. 42

    Gustafson, J., Lim, D. & Miller, S. J. Dynamic kinetic resolution of biaryl atropisomers via peptide-catalyzed asymmetric bromination. Science 328, 1251–1255 (2010)

  43. 43

    Corey, E. J. & Cheng, X. M. The Logic of Chemical Synthesis (Wiley, 1995)

  44. 44

    Boger, D. L. & Brotherton, C. E. Total synthesis of azafluoranthene alkaloids: rufescine and imeluteine. J. Org. Chem. 49, 4050–4055 (1984)

  45. 45

    Burke, M. D. & Schreiber, S. L. A planning strategy for diversity-oriented synthesis. Angew. Chem. Int. Edn 43, 46–58 (2004)

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Acknowledgements

We thank G. Sukenick of The Memorial Sloan Kettering Cancer Research Institute and J. Decatur of Columbia University for NMR assistance, Y. Itagaki for mass spectrometric assistance, C. Stathakis for preliminary attempts to form dihydrofuran units on the pallidol core, A. ElSohly for theoretical calculations and discussions, and K. Shaw and J. Boyce for preparing some starting materials. Financial support was provided by Columbia University, the National Institutes of Health (R01-GM84994), Bristol-Myers Squibb, Eli Lilly, the Research Corporation for Science Advancement (Cottrell Scholar Award to S.A.S.), and the Austrian Science Fund (FWF, Schrödinger postdoctoral fellowship J2986-N19 to A.G.).

Author information

S.A.S. conceived and directed the research, as well as composed the manuscript. A.G. developed the dihydrofuran synthesis approach and completed compounds 16, 17, 30, and 38. M.I.C. completed compound 19 as well as the majority of the route towards compound 18 including the BDSB-based functionalization. Both A.G. and M.I.C. worked to complete 18, and provided commentary and feedback on the manuscript.

Correspondence to Scott A. Snyder.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Figures 1-16 with legends, Supplementary Notes and Data (see contents list for full details), Supplementary Tables 1-5 and additional references. (PDF 3270 kb)

Supplementary Information

This file contains the NMR spectra for all intermediates and final products. (PDF 12809 kb)

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Snyder, S., Gollner, A. & Chiriac, M. Regioselective reactions for programmable resveratrol oligomer synthesis. Nature 474, 461–466 (2011) doi:10.1038/nature10197

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