Acid-promoted reaction of the stilbene antioxidant resveratrol with nitrite ions : mild phenolic oxidation at the 4′-hydroxystiryl sector triggering nitration, dimerization, and aldehyde-forming routes

In 0.1 M phosphate buffer, pH 3.0, and at 37 °C, resveratrol ((E)-3,4',5-trihydroxystilbene), an antioxidant and cancer chemopreventive phytoalexin, reacted smoothly at 25 mM or 1 mM concn. with excess nitrite ions (NO2-) to give a complex pattern of products, including two novel regioisomeric a-nitro and 3'-nitro derivs. along with some (E)-3,4',5-trihydroxy-2,3'-dinitrostilbene, four oxidative breakdown products, 4-hydroxybenzaldehyde, 4-hydroxy-3-nitrobenzaldehyde, 3,5-dihydroxyphenylnitromethane, and 3,5-dihydroxybenzaldehyde, two dimers, the resveratrol (E)-dehydrodimer and restrytisol B, and a partially cleaved dimer. The same products were formed in the absence of oxygen. 1H,15N HMBC and LC/MS anal. of the crude mixt. obtained by reaction of resveratrol with Na15NO2 suggested the presence of 3,4',5,b-tetrahydroxy-a-nitro-a,b-dihydrostilbene (I) as unstable intermediate which escaped isolation. Under similar conditions, the structurally related catecholic stilbene piceatannol ((E)-3,3',4,5'-tetrahydroxystilbene) gave, besides (E)-3,3',4,5'-tetrahydroxy-b-nitrostilbene, 3,4-dihydroxybenzaldehyde and small amts. of 3,5-dihydroxybenzaldehyde. Mechanistic expts. were consistent with the initial generation of the phenoxyl radical of resveratrol at 4'-OH, which may undergo free radical coupling with NO2 at the a- or 3'-position, to give eventually nitrated derivs. and/or oxidative double bond fission products, or self-coupling, to give dimers. The oxygen-independent, NO2- -mediated oxidative fission of the double bond under mild, physiol. relevant conditions is unprecedented in stilbene chem. and is proposed to involve breakdown of hydroxynitro(so) intermediates of the type I.