Total Synthesis of Viniferifuran, Resveratrol‐Piceatannol Hybrid, Anigopreissin A and Analogues – Investigation of Demethylation Strategies

Abstract

Resveratrol‐based natural products constitute a valuable source of unique compounds with diverse biological activities. In this report we investigate demethylation strategies to minimize formation of cyclized and dimerized products during the synthesis of viniferifuran and analogues. We found that boron trichloride/tetra‐n‐butylammonium iodide (BCl3/TBAI) is typically more effective than boron tribromide (BBr3). Based on these findings we carried out the first syntheses of dehydro‐δ‐viniferin, resveratrol‐piceatannol hybrid and anigopreissin A. In addition, we have developed a short and efficient route to viniferifuran that was obtained in 13% yield over six steps.

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

“…With this promising result, we went forward to confirm the feasibility of cleaving cPrMe ethers with other reagents that are typically used for the methyl ether cleavage such as BBr 3 and BCl 3 . To our delight, both BBr 3 and BCl 3 /TBAI were successful to yield anigopreissin A 18 in 38 % and 34 % respectively compared to the methyl ether protecting group in which BBr 3 failed to give the desired polyphenol . In terms of yield, the cPrMe group is superior to the methyl ether, which resulted only in 23 % yield using BCl 3 /TBAI …”

“…To date, three synthetic strategies for preparation of anigopreissin A have been published . The earlier two synthesis were reported with the constraint that only permethylated anigopreissin A was obtained .…”

“…Despite several attempts to deprotect the methyl ether groups using for example, BBr 3 , BBr 3 ⋅SMe 2 and L‐Selectride, the authors observed either decomposition or partial deprotection . The third and successful total synthesis of this natural product was published by our group in 2016 in which the permethylated anigopreissin A was deprotected in 23 % yield using BCl 3 /TBAI . Based on these results we moved on and explored the cPrMe group as an alternative phenolic protecting group.…”

“…Encouraged by these results, we turned our attention towards the synthesis of resveratrol–piceatannol hybrid using cPrMe protection. Although resveratrol–piceatannol hybrid was successfully prepared using methyl ether protecting group, the final deprotection step resulted in low yield (13 %) when using BCl 3 /TBAI . The synthetic strategy for resveratrol–piceatannol hybrid utilizing cPrMe protection is outlined in Scheme .…”

“…To date, three synthetics trategies for preparation of anigo-preissinA have been published. [11,19] The earlier two synthesis were reportedw ith the constraint that only permethylated anigopreissin Aw as obtained. [19] Despite several attempts to deprotect the methyl ether groups using for example, BBr 3 , BBr 3 ·SMe 2 and L-Selectride,the authors observed either decompositiono rp artial deprotection.…”