Angew.Chem.Int.Ed.http://dx.doi.org/10.1002/anie.201409773(2015)

The apparent health benefits of polyphenolic compounds — such as resveratrol and its oligomers — have attracted a great deal of attention. Their biological activity has been attributed to their ability to act as radical traps — but systematic studies, particularly on the kinetics of these reactions, have not been performed. Now, Derek Pratt and Corey Stephenson from the Universities of Ottawa and Michigan, respectively, and their co-workers have described a scalable synthesis of two resveratrol dimers — (±)-pallidol and (±)-quadrangularin A — and used the products to evaluate their antioxidant activity.

Biomimetic syntheses of related oligomeric natural products have proved difficult to control. Thus Pratt, Stephenson and co-workers resorted to the use of a resveratrol starting material with two of its phenols protected as ethers and two of its aryl C–H groups — those meta to the remaining phenol — masked as tert-butyl groups. On treatment with a ferrocenium oxidant a remarkably chemoselective dimerization occurs, producing a mixture of three diastereomers. Two of these three products — the enantiomers (and not the meso product) — undergo two subsequent Lewis acid-catalysed cyclization reactions to produce the 5,5-fused ring system of (±)-pallidol. To gain access to (±)-quadrangularin A, dimerization was followed by a base-induced tautomerization, resulting in the loss of one stereocentre and the E-selective formation of a stilbene-type double bond. The synthesis was completed by Lewis acid-catalysed cyclization followed by removal of the ether and tert-butyl protecting groups.

With these compounds, and their tetrabutylated intermediates, in hand, studies on their radical trapping activities were undertaken. In organic solution — using the alkylated derivatives (for solubility reasons) as a proxy for the natural products — they were found to be no better than the common food additive BHT (butylated hydroxytoluene). When studied in a lipid bilayer the alkylated derivatives were found to be most active, followed by another well-known antioxidant (α-tocopherol) and the natural products themselves coming in third. All of this suggests that the radical-trapping ability of these natural products is not at the heart of their bioactivity.