The design and the synthesis of a new family of hydroxy-4-thiaflavanes, in which the reactive phenolic OH is ortho to the sulfur atom of the benzofused oxathiin ring, allowed to prepare antioxidants that show rate constants for the reaction with peroxyl radicals (k(inh)), and bond dissociation energies (BDE), of the ArO-H group identical to those of α-tocopherol, the main component of vitamin E and the most effective lipophilic antioxidant known in nature. The peculiar conformation of the six-membered heterocyclic ring prevents the formation of an intramolecular hydrogen bond between the OH group and the S atom, while ensuring a good stabilization by electron donation of the phenoxyl radical formed after the reaction with peroxyl radicals. The preparation of these compounds was achieved through an inverse electron demand hetero Diels-Alder reaction of styrenes with o-thioquinones, in turn prepared from accurately designed 1,3-dihydroxy arenes. Properly arranging the substitution pattern on the aromatic ring, as in derivatives 9 and 11, allowed to reach values of k(inh) up to 4.0×10(6) M(-1) s(-1) and BDE((OH)) of 77.2 kcal mol(-1). This approach represents an innovative way to obtain highly active antioxidants without using strongly electron donating alkylamino groups which are associated with adverse toxicological profiles.
A simple and original inverse electron demand hetero‐Diels–Alder reaction has been successfully applied to the synthesis of (2‐ambo,4′R,8′R)‐α/β/γ/δ‐4‐thiatocopherol. Commercially available methyl hydroquinones and (2E,7R,11R)‐(+)‐phytol were exploited for the preparation of the ortho‐thioquinones, acting as electron‐poor dienes, and of the proper 1,3‐diene used as dienophile, respectively. The benzoxathiine cycloadducts, with the required tocopherol‐like skeleton, were obtained with complete control of regio and chemoselectivity. The antioxidant activity of 4‐thiatocopherols was measured and rationalized in comparison with that of the corresponding natural components of Vitamin E.
A new family of phenolic antioxidants… …in which the reactive phenolic group is ortho to the sulfur atom of a 4-thiaflavane moiety has been prepared. The rate constants for the reaction with peroxyl radicals measured for these compounds, as well as the bond dissociation energies of the ArOÀH bond, are very similar to those measured for a-tocopherol, the main component of vitamin E. In their Full Paper on page 12396 ff., S. Menichetti, R. Amorati et al. describe how the stereoelectronic features triggered by the sulfur atom have been exploited to design this new class of compounds.
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