Synthesis of resveratrol tetramers via a stereoconvergent radical equilibrium

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Science  09 Dec 2016:
Vol. 354, Issue 6317, pp. 1260-1265
DOI: 10.1126/science.aaj1597

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Catching a break in polyphenol synthesis

Chemical synthesis is usually rather different from playing with a modeling kit. If two large fragments of a molecule are not properly oriented, it is not typically possible to break them apart, rotate one, and then paste them back together. Yet that is precisely the trick that Keylor et al. used to synthesize two plant-derived polyphenols. Resveratrol forms a variety of dimers, trimers, and tetramers. When one central carbon-carbon bond links the fragments, it is weak enough to break spontaneously and reversibly at room temperature. The authors leveraged this equilibrium to generate an efficient route to two of the tetramers, nepalensinol B and vateriaphenol C.

Science, this issue p. 1260


Persistent free radicals have become indispensable in the synthesis of organic materials through living radical polymerization. However, examples of their use in the synthesis of small molecules are rare. Here, we report the application of persistent radical and quinone methide intermediates to the synthesis of the resveratrol tetramers nepalensinol B and vateriaphenol C. The spontaneous cleavage and reconstitution of exceptionally weak carbon-carbon bonds has enabled a stereoconvergent oxidative dimerization of racemic materials in a transformation that likely coincides with the biogenesis of these natural products. The efficient synthesis of higher-order oligomers of resveratrol will facilitate the biological studies necessary to elucidate their mechanism(s) of action.

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