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Regioselective reactions for programmable resveratrol oligomer synthesis

Nature volume 474, pages 461–466 (2011)Cite this article

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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).

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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.).

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Authors and Affiliations

  1. Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027, USA,

    Scott A. Snyder, Andreas Gollner & Maria I. Chiriac

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  1. Scott A. Snyder
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Contributions

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.

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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). https://doi.org/10.1038/nature10197

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