A Straightforward Route to Potent Phenolic Chain‐Breaking Antioxidants by Acid‐Promoted Transposition of 1,4‐Benzo[b]oxathiines to Dihydrobenzo[b]thiophenes

Abstract

The transformation of simple phenols with limited antioxidant activity into potent chain-breaking antioxidants was achieved by a three-step protocol, consisting of the conversion of phenols into 1,4-benzo[b]oxathiines followed by an unprecedented acid-promoted transposition to o-hydroxydihydrobenzo[b]thiophenes, or dihydrobenzo[de]thiochromenes, starting from phenols or naphthols, respectively. These derivatives, bearing a benzo-fused heterocycle with a sulfide sulfur ortho to the phenolic OH, have a rate constant of reaction with alkylperoxyl radicals (kinh ) comparable to that of α-tocopherol. A solid rationale for the transposition mechanism as well as for the structure-antioxidant activity relationship is presented.

Protective Role of Natural and Semi-Synthetic Tocopherols on TNFα-Induced ROS Production and ICAM-1 and Cl-2 Expression in HT29 Intestinal Epithelial Cells

“…However, δ-Toc, due to the lack of two methyl groups on the aromatic ring, is roughly one order of magnitude less active than α-Toc as a chain breaking antioxidant with a k inh = 4.4 × 10 5 mol −1 s −1 difference that is not observed in the measures reported in this manuscript. In the last two decades we have studied the effect of sulfur introduction on the activity of natural phenolic antioxidants [48][49][50][51][52][53][54][55][56][57][58][59][60]. In particular, the synthesis of (δ-Toc) 2 S and (δ-Toc) 2 S 2 , and related tocopherol sulfides and disulfides [34], has allowed us to measure their chain breaking antioxidant activity.…”

Chain Breaking Antioxidant Activity of Heavy (S, Se, Te) Chalcogens Substituted Polyphenols

“…We could rationalise this result having developed a new procedure for the preparation of 7-hydroxydihydrobenzo[ b ]thiophenes based on an acid promoted transposition of benzoxathiines. Thus, these latter heterocycles, are, at the same time, an interesting skeleton for antioxidant polyphenols and starting material for new phenolic derivatives [67]. When carried out on structurally properly designed starting materials, the 2,3-dihydrobenzo[1,4]oxathiine → hydroxydihydrobenzo[ b ]thiophene transposition allows the preparation of potent chain breaking antioxidants like 30–32, taking advantage of the ortho -endocyclic sulfur effects discussed before, namely (i) the ED effect on ArO• stabilization by the para -alkoxy and ortho -sulfide groups; (ii) the weak ArOH stabilization by negligible intra-HB [67] (Figure 9).…”

“…Indeed, X-ray analysis of derivative 30 indicates that the dihedral angle among the aromatic and the heterocyclic ring is very similar to that measured in benzoxathiines like 23 or 24, supporting, at least in the solid-state, the above justification. However, it must be underlined that the transformation reported in Figure 9 used for the synthesis of compounds 30–32, represents the one-step conversion of a non-phenolic derivative with no antioxidant activity into a potent phenolic chain breaking antioxidant [67].…”

Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds

“…When the ChR substituent is in ortho -position to the phenolic OH, the perpendicular conformation of the ChR group is further stabilized by the H-bond interaction of the filled p-orbital of the Ch atom with the OH group (see Scheme 2 b) [ 26 ]. Interestingly, if the ortho -ChR group is forced in a planar conformation by inclusion in a 5 or 6-membered cycle, the H-bond is not formed because of the wrong orientation of the filled p-orbital ( Scheme 2 c,d) [ 27 ].…”

“…In the case of para substituted ChR phenols, this effect is less evident because the preference for the perpendicular conformation is less important than in ortho -ChR phenols [ 26 ]. Of course, if the ortho -ChR substituent is forced to be planar by inclusion into a ring, the interaction of the filled p orbital is possible, leading to good stabilization of the radical and fast reaction with X• ( Scheme 2 c) [ 27 ]. A specific effect is observed when the ortho -ChR group is included into an aromatic cycle, such as in 7-OH benzothiophene ( Scheme 2 d).…”