Synthesis of resveratrol tetramers via a stereoconvergent radical equilibrium

Abstract

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.

Fig. 1. Synthetic design

Merging de novo and biomimetic strategies allows for selective, scalable, and efficient preparation of resveratrol oligomers by the use of persistent radical and bis(p-quinone methide) intermediates (Bn, benzyl).

Fig. 2. Diastereoconvergent cyclization of 4a

(TFA, trifluoroacetic acid).

Fig. 3. Characterization of homolytic dissociation equilibrium of representative bis(p-quinone methide) 4a

(a) Experimental (black) and fitted (red) EPR spectrum of 1a● recorded at 295 K. (b) Experimental (black) and calculated (red) hyperfine coupling constants for 1a●. (c) Spin density distribution in 1a● predicted by DFT (B3LYP/TZVP). (d) Temperature dependence of equilibrium constants determined by EPR (black) and UV-Vis (red) spectroscopy and corresponding calculated thermochemical parameters. The error bars represent standard deviations for three or more combined measurements. (e) Temperature dependence of absorbance corresponding to 1a● (inset: full spectrum of 4a at 323 K). (f) Second-order decay of absorbance at 414 nm following nanosecond–pulsed irradiation of 4a at 308 nm under an atmosphere of either nitrogen (black) or oxygen (red).

Fig. 4. 13-step total synthesis of resveratrol tetramers

(A) Preparation of ε-viniferin derivatives, reagents and conditions are as follows: ⁱPr₂NH, n-BuLi, THF, then 11a/b, then 10, −78 °C to RT, then 0 °C, TBAF, 0.5 h, 85% for 6a, 80% for 6b. (B) Synthesis of nepalensinol B and vateriaphenol C, reagents and conditions are as follows: (a) THF, 0 °C, then KHMDS, then FeCp₂PF₆, 97% for 5a, 63% (14% recovered SM) for 5b; (b) For 5a, BF₃·OEt₂, CH₂Cl₂, −60 °C to −30 °C, (44% 12a + 9% 13/14a). For 5b, BF₃·OEt₂, CH₂Cl₂, −78 °C, (59% 12b + 15% 13/14b); (c) 1. Pd/C (30 wt%), MeOH/EtOAc (1:1 v/v), H₂ (1 atm), filter, concentrate, then 2. TFA (0.05 M) in CH₂Cl₂/MeNO₂ (1:1 v/v), 75% for 7, 60% for 8/15. THF = tetrahydrofuran, TBAF = tetra-n-butylammonium fluoride, KHMDS = potassium hexamethyldisilazide, dr = diastereomeric ratio, SM = starting material, RSM = recovered starting material.