Total Synthesis of the Resveratrol Oligomers (±)‐Ampelopsin B and (±)‐ϵ‐Viniferin

Abstract

The total synthesis of the resveratrol dimers (±)‐ampelopsin B and (±)‐ϵ‐viniferin is reported. Highlights of the approach include the use of cyclopropylmethyl groups to protect aromatic alcohols. This group allows an acid promoted three‐step, one‐pot deprotection–epimerization–cyclization of an advanced intermediate to give (±)‐ampelopsin B. An important advantage with our strategy is the possibility of synthesizing analogs to these natural products to further study the chemistry and biology of resveratrol oligomers.

Exploring resveratrol dimers as virulence blocking agents – Attenuation of type III secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa

“…Several studies indicate that natural sources also have the potential to provide T3SS inhibitors for further exploration. Screening of marine invertebrate extracts led to the identification of the glycolipid caminoside A as an inhibitor of T3SS in (8), dehydro-δ-viniferin (10), anigopreissin A (11) and resveratrol-piceatannol hybrid (12). Wild-type P. aeruginosa PAK(pCS500) with GFP under the control of the exoS promoter was treated with different concentration of compounds under T3SSinducing contitions.…”

“…However, synthetic efforts toward (-)-hopeaphenol and derivatives have been challenging 9,10 due to the complex core structure composed of multiple fused rings and the presence of a number of stereocenters. As a first step, we therefore turned our attention to simplified hopeaphenol-related structures and synthesized (dihydro)benzofuran resveratrol dimers, additional stilbenoid natural products and analogues including viniferifuran, ampelopsin A and B, resveratrol-piceatannol hybrid and anigopreissin A 11,12 . Moreover, while (-)-hopeaphenol and related compounds compromise the Lipinski rules of 5 13 and are at the border of "hard to optimize" structures beyond the rule of 5 14 , the simplified structures of resveratrol dimers and analogues could be more amendable for further exploration.…”

Cyclopropylmethyl Protection of Phenols: Total Synthesis of the Resveratrol Dimers Anigopreissin A and Resveratrol–Piceatannol Hybrid

“…Our interest in these scaffolds originates from our finding of the resveratrol tetramer, (−)‐hopeaphenol—a complex plant stilbenoid isolated from the Papua Guinean tree species Anisoptera thurifera and Anisoptera polyandra —as an irreversible inhibitor of the type III secretion in gram‐negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa . Based on this finding, we initiated studies to expand our knowledge on the chemistry and biology of these scaffolds and recently published total syntheses of benzofuran based natural products (±)‐ampelopsin B and (±)‐ϵ‐viniferin . Subsequently, we reported the total synthesis of other benzofuran based natural products viz .…”

“…In this work, we explored the use of cyclopropylmethyl (cPrMe) ether inspired by a report from Nagata et al., in which the cPrMe ethers were selectively cleaved under acidic conditions and yet stable to a wide range of reaction conditions . Our group has applied the cPrMe protection during the total synthesis of the resveratrol oligomer (±)‐ampelopsin B that allowed an ultimate three‐step one‐pot deprotection, epimerization and cyclization to form the target compound . Given the lability of the cPrMe ethers to acids and the feasibility to cleave it off under variety of conditions, and in continuation of our efforts on the polyphenol natural products, we herein described the successful use of cPrMe as a protecting group in the total synthesis of anigopreissin A and resveratrol–piceatannol hybrid.…”

“…Subsequently, pinacol boronate 8 was prepared via Pd‐catalyzed coupling of arylbromide 6 and diboronyl reagent to give boronic ester 7 , which was protected with cPrMe groups to afford the key intermediate 8 . The phosphonate ester 10 was synthesized using our previously reported route from cPrMe‐protected 4‐hydroxybenzaldehyde 2 , which was transformed to the corresponding benzyl chloride 9 upon reduction with NaBH 4 and treatment with thionyl chloride. The resultant benzyl chloride 9 was reacted with triethylphosphite to yield the required phosphonate ester 10 .…”