Regioselective reactions for programmable resveratrol oligomer synthesis

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.

Figure 1. The diversity of selected terpene and polyphenolic oligostilbene natural products: products of privileged starting materials

Me = methyl, Ph = phenyl, Ac = acetate, Bz = benzoate.

Figure 2. The challenge of the resveratrol family in context: Nature’s putative biogenesis and a specific plan for achieving their controlled assembly

Critical for the controlled synthesis of dimeric natural products in the class proved to be a unique starting material (21) well removed from resveratrol itself. From these cores, regioselective functionalizations and a dihydrofuran formation protocol with divergent stereocontrol were then needed. These final challenges are the subject of this work.

Figure 3. A: Development of a strategy-level approach for selective brominations of the symmetric pallidol core followed by diastereocontrolled dihydrofuran formation to synthesize 16, 17, and 30. B: Critical details of the final dihydrofuran formation cascade

Reagents and conditions: a) NBS, THF, −78 °C; b) Br₂, CH₂Cl₂, −78→25 ° C; c) n-BuLi, THF, −78 °C; d) NBS, THF, −78→2 5 ° C; e) n-BuLi, 3,5-dimethoxybenzaldehyde, THF, −78→25 °C; f) Dess-Martin periodinane, NaHCO₃, CH₂Cl₂, 25 °C, g) BBr₃, CH₂Cl₂, 70 °C; h) BnBr, n-Bu₄NI, K₂CO₃, acetone, 70 °C; i) n-BuLi, Me₃SI, THF, 0 °C; j) ZnI₂, benzene, 25 °C; k) 4-benzyloxyphenylmagnesium bromide, THF, 25 °C; l) H₂, 30% Pd/C, EtOAc/MeOH (1:1), 25 °C, then Amberlite IR-12-OH, 25 °C; m) KHMDS, −78 °C. NBS = N-bromosuccinimide, THF = tetrahydrofuran, n-BuLi = n-butyllithium, Bn = benzyl, KHDMS = potassium (bis)hexamethyldisilazide.

Figure 4. Use of substrate- and reagent-guided halogenations to synthesize three resveratrol trimers and tetramers (18, 19, and 38) from protected ampelopsin F (31)

Reagents and conditions: a) NBS, CH₂Cl₂, −78→25 °C; b) NBS, CH₂Cl₂, −78→25 °C; c) BDSB, CH₂Cl₂, −78 °C; d) BDSB, CH₂Cl₂, −78 °C. AcOH = acetic acid, NBSac = N-bromosaccharin, TBCO = tetrabromocyclohexadienone, NBA = N-bromoacetamide, TCCA = trichloroisocyanuric acid, BDSB = bromodiethylsulfide bromopentachloroantimonate.