Total synthesis of a natural antioxidant and structure-activity relationships of related compounds

A total synthesis of benzodioxole derivative 1 was achieved via a palladium(0)-catalyzed cross-coupling reaction in a 68% overall yield (4 steps). A novel series of benzodioxoles bearing a variety of aromatic and heterocyclic rings was also prepared and the antioxidative activity evaluated using in vitro model systems. Structure-activity studies revealed that i) intramolecular hydrogen-bonding in the phenol moiety reduced activity, ii) introduction of disubstituents at the ortho location relative to the phenol increased activity, and iii) the methylene-dioxy function contributed to stabilization of the phenoxy radical. Among of these compounds, 5,7-di-(4-methoxyphenyl)-4-methoxy-6-hydroxy-1,3-benzodioxole (7p) was the most favorable agent and more potent than n-propyl gallate.