Tocopherols mechanism

Tocopherol Mechanically Pressed Soybean Oil Solvent-extracted Soybean Oil Solvent-extracted Wheat Germ Oil... 

Vitamin E actually consists of a family of compounds, the most active of which is a-tocopherol. The mechanism of the vitamin s action is not completely certain, but it seems likely that it might undergo hydrogen atom transfer reactions with free radicals to give a stable radical (see also Chapter 17, Problem 7). 

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha (a), beta ((3), gamma (y) and delta (8), and four tocotrienols (also a, (3, y, and 8). a-Tocopherol is present in nature in only one form, RRR a-tocopherol. The chemical synthesis of a-tocopherol results in eight different forms (SRR, SSR, SRS, SSS, RSR, RRS, RSS, RRR), only one of which is RRR a-tocopherol. These forms differ in that they can be right (R) or left (S) at three different places in the a-tocopherol molecule. RRR a-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore the form of vitamin E found in the largest quantities in the blood and tissue. A protein synthesized in the liver (a-TTP alpha-tocopherol transfer protein) preferentially selects the natural form of vitamin E (RRR a-tocopherol) for distribution to the tissues. However, the mechanisms for the regulation of vitamin E in tissues are not known... 

In 1922, Evans and Bishop named the animal nutritional factor essential of reproduction Vitamin E . In the 1960s, vitamin E was associated with antioxidant function. Twenty-five years later, vitamin E has been found to possess functions that are independent of its antioxidant and free radical scavenging ability. a-Tocopherol specific molecular mechanisms were discovered which are still under investigation. 

In the water-like solvent tert-butyl alcohol, a-tocopherol was found to prevent lipid oxidation, showing a distinct lag-phase for oxygen consumption. This was in contrast to quercetin or epicatechin, which were only weak retarders of lipid oxidation without any clear antioxidative effect. Quercetin or epicatechin, when combined with a-tocopherol, increased the lag-phase for oxygen consumption as seen for a-tocopherol alone. The stoichiometric factor for a-tocopherol, a-TOH, as chain-breaking antioxidant has the value n = 2 according to the well-established mechanism ... 

FIGURE 6.6 Hypothetical radical mechanism for the formation of 5a-a-tocopheryl henzoate (11) hy reaction of a-tocopherol (1) with dibenzoyl peroxide. 

Basically, three reactions were evoked to support the occurrence of 5a-C-centered radicals 10 in tocopherol chemistry. The first one is the formation of 5a-substituted derivatives (8) in the reaction of a-tocopherol (1) with radicals and radical initiators. The most prominent example here is the reaction of 1 with dibenzoyl peroxide leading to 5a-a-tocopheryl benzoate (11) in fair yields,12 so that a typical radical recombination mechanism was postulated (Fig. 6.6). Similarly, low yields of 5a-alkoxy-a-tocopherols were obtained by oxidation of a-tocopherol with tert-butyl hydroperoxide or other peroxides in inert solvents containing various alcohols,23 24 although the involvement of 5 a-C-centered radicals in the formation mechanism was not evoked for explanation in these cases. 

The formation of 5a-a-tocopheryl benzoate (11) upon reaction of a-tocopherol (1) with dibenzoyl peroxide, which has usually been taken as solid proof of the involvement of 5a-C-centered radicals in tocopherol chemistry (see Fig. 6.6), was shown to proceed according to a nonradical, heterolytic mechanism involving o-QM 3 (Fig. 6.9). 

The last reaction commonly evoked to support the involvement of radical species 10 in tocopherol chemistry is the disproportionation of two molecules into the phenol a-tocopherol and the ort/zo-quinone methide 3 (Fig. 6.8), the latter immediately dimerizing into spiro dimer 9. This dimerization is actually a hetero-Diels-Alder process with inverse electron demand. It is largely favored, which is also reflected by the fact that spiro dimer 9 is an almost ubiquitous product and byproduct in vitamin E chemistry.28,29 The disproportionation mechanism was proposed to account for the fact that in reactions of tocopheroxyl radical 2 generated without chemical coreactants, that is, by irradiation, the spiro dimer 9 was the only major product found. 

The questions whether 5a-C-centered radicals exist in oxidation chemistry of a-tocopherol and whether mechanisms proposed in early days of vitamin E research are correct might appear academic at a first glance, but as soon as one recalls the immense medical, physiological, and economic importance of a-tocopherol and its... 

The oxidation of a-tocopherol (1) to dimers29,50 and trimers15,51 has been reported already in the early days of vitamin E chemistry, including standard procedures for near-quantitative preparation of these compounds. The formation generally proceeds via orf/zo-quinone methide 3 as the key intermediate. The dimerization of 3 into spiro dimer 9 is one of the most frequently occurring reactions in tocopherol chemistry, being almost ubiquitous as side reaction as soon as the o-QM 3 occurs as reaction intermediate. Early accounts proposed numerous incorrect structures,52 which found entry into review articles and thus survived in the literature until today.22 Also several different proposals as to the formation mechanisms of these compounds existed. Only recently, a consistent model of their formation pathways and interconversions as well as a complete NMR assignment of the different diastereomers was achieved.28... 

The spiro dimer of a-tocopherol (9, see also Fig. 6.4) is formed as mixture of two diastereomers by dimerization of the o-QM 3 in a hetero-Diels-Alder reaction with inverse electron demand. Both isomers are linked by a fluxion process (Fig. 6.22), which was proven by NMR spectroscopy.53 The detailed mechanism of the interconversion, which is catalyzed by acids, was proposed to be either stepwise or concerted.53-55... 

Treatment of methano-dimer 28 with elemental bromine revealed a remarkable reactivity at low temperatures it proceeded quantitatively to the furano-spiro dimer 29, by analogy with the ethano-dimer 12 giving spiro dimer 9 upon oxidation. With increasing temperatures, the reaction mechanism changed, however, now affording a mixture of 5-bromo-y-tocopherol (30) and spiro dimer 9 (Fig. 6.24). Thus, the methano-dimer 28 fragmented into an a-tocopherol part, in the form of o-QM 3 that dimerized into 9, and a /-tocopherol part, which was present as the 5-bromo derivative 30 after the reaction. Thus, the overall reaction can be regarded as oxidative dealkylation. 

Treatment of a-tocopherol (1) with elemental bromine provided quantitative yields of 5a-bromo-a-tocopherol (46). The reaction was assumed to proceed according to a radical mechanism, but later a nonradical oxidation-addition mechanism was proven (Fig. 6.33). Bromine oxidized a-tocopherol (1) to the intermediate ortho-qainone methide (3), which in turn added the HBr produced in the oxidation step.60 If the HBr was removed by flushing with nitrogen, the spiro dimer (9) became the main product, and if it was purged by HC1 gas, mainly 5a-chloro-a-tocopherol was produced. 

FIGURE 6.33 Synthesis of 5a-bromo-a-tocopherol (46) from a-tocopherol (1) according to an oxidation-addition mechanism involving the o-QM intermediate 3. 

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