A Tocopherol-quinone

Lipid radicals and other radicals may be removed by a number of endogenous compounds as well as GSH. One is vitamin E, (which includes a-tocopherol) a lipophilic substance. It can react with and neutralize lipid radicals and hydroperoxides, in the process becoming a free radical itself. This a-tocopheryl radical is relatively stable and can then be converted back into the a-tocopherol by vitamin C (ascorbate) or react with more radicals and become a-tocopherol quinone ... 

Antagonists of vitamin K substances include dicoumarol, sulfonamides, antibiotics, a-tocopherol quinone, dihydroxysteanc acid glycide, salicylates, iodinin, warfarin. Synergists include ascorbic acid, somatotropinn (growth hormone), and vitamins A and E. 

In human subjects, however, 8 weeks of vitamin E supplementation (800 IU/day) to the diet produced a lowered plasma PGI2 level, as measured by 6-keto-PGF1(X, compared with that in non-supplemented controls [129]. Addition of vitamin E to human platelets in concentrations which resemble normal plasma levels produced a moderately potent but consistent reduction in cyclo-oxygenase activity, with a dose-dependent response up to 1 mM. a-Tocopherol quinone was equally effective in this test [ 130]. 

Lipid radicals and other radicals may be removed by a number of endogenous compounds as well as glutathione. One is vitamin E (a-tocopherol), which reacts with lipid hydroperoxide radicals to yield the hydroperoxide and a-tocopherol quinone ... 

Studies of the metabolism of vitamin E were triggered by the observations of Alaupovic and coworkers [126, 127]. When " [Cj-D-a-tocopherol-5-methyl was administered to rats or pigs and attempts were made to detect metabolic derivatives, two compounds were separated by chromatography. One of the compounds is " [C]-D-a-tocopherol quinone the other is either a dimer or a trimer of a-tocopherol. The dimer and trimer are terminal oxidation products of a-tocopherol and are excreted in the bile. a-Tocopherol quinone can be converted to a-hydroquinone. a-Tocopherol hydroquinone may be esterified in liver and eliminated in the feces after concentration in the bile and excretion in the intestine, or it may be oxidized in the kidney to a-tocopheronic acid, which may be converted into an a-tocopheronolactone conjugate, which is excreted in the urine. In conclusion, vitamin E is excreted as such in the urine or the bile after conversion to a dimer or a trimer, in the form of a conjugated hydroxy-quinone or tocopheronic acid (see Fig. 4-43). 

Among the metabolites identified, a-tocopherol quinone seems to be the active compound. That compound is known to participate in photosynthetic electron transport in chloroplasts, but there is no evidence that it functions on an active vitamin E. In fact, no available evidence indicates that a metabolite of the vitamin constitutes the active form. 

Interest in the role of vitamin E in disease prevention has encouraged the search for reliable indices of vitamin E status. Most studies in human subjects make use of static biomarkers of status, usually a-tocopherol concentrations in plasma, serum, erythrocytes, lymphocytes, platelets, lipoproteins, adipose tissues, buccal mucosal cells, and LDL, and the a-tocopherol 7-toco-pherol ratio in serum or plasma. Other markers of vitamin E status include susceptibility of erythrocyte or plasma LDL to oxidation, breath hydrocarbon exhalation, and the concentration of a-tocopherol quinone in cerebrospinal fluid. There is no consensus as to the threshold concentration of plasma or sermn a-tocopherol at which a person can be defined as having inadequate tocopherol status, but values of <11.6, 11.6-16.2, and >16.2 pmol are normally regarded as indicating a deficient, low, and acceptable vitamin E status, respectively. It is recommended that... 

The recommended daily allowance for vitamin E ranges from 10 international units (1 lU = 1 mg all-rac-prevent vitamin E deficiency in humans. High levels enhance immune responses in both animals and humans. Requirements for animals vary from 3 USP units /kg diet for hamsters to 70 lU /kg diet for cats (13). The complete metaboHsm of vitamin E in animals or humans is not known. The primary excreted breakdown products of a-tocopherol in the body are gluconurides of tocopheronic acid (27) (Eig. 6). These are derived from the primary metaboUte a-tocopheryl quinone (9) (see Eig. 2) (44,45). 

Encouraged by the short synthesis of K vitamins, the chromium-mediated benzannulation was extended to the synthesis of vitamin E 68 [59]. The problem of imperfect regioselectivity of alkyne incorporation - which did not hamper the approach to vitamin K due to the final oxidation to the quinone - was tackled by demethylation of both regioisomeric hydroquinone monomethyl ethers 67 to give the unprotected hydroquinone. Subsequent ring closure yielded a-tocopherol (vitamin E) 68 (Scheme 39). 

The third primary intermediate in the oxidation chemistry of a-tocopherol, and the central species in this chapter, is the orr/zo-quinone methide 3. In contrast to the other two primary intermediates 2 and 4, it can be formed by quite different ways (Fig. 6.4), which already might be taken as an indication of the importance of this intermediate in vitamin E chemistry. o-QM 3 is formed, as mentioned above, from chromanoxylium cation 4 by proton loss at C-5a, or by a further single-electron oxidation step from radical 2 with concomitant proton loss from C-5a. Its most prominent and most frequently employed formation way is the direct generation from a-tocopherol by two-electron oxidation in inert media. Although in aqueous or protic media, initial... 

FIGURE 6.4 Reactions and products of the primary oxidation intermediates of a-tocopherol (1), the tocopheroxyl radical 2, ortho-quinone methide 3, and chromanoxylium cation 4. 

The initiator-derived radical products generate a-tocopheroxyl radicals (2) from a-tocopherol (1). The radicals 2 are further oxidized to ort/io-quinone methide 3 in a formal H-atom abstraction, thereby converting benzoyloxy radicals to benzoic acid and phenyl radicals to benzene. The generated o-QM 3 adds benzoic acid in a [ 1,4] -addition process, whereas it cannot add benzene in such a fashion. This pathway accounts for the observed occurrence of benzoate 11 and simultaneous absence of a 5 a-phenyl derivative and readily explains the observed products without having to involve the hypothetical C-centered radical 10. 

FIGURE 6.9 Confirmed heterolytic formation pathway for 5a-a-tocopheryl benzoate (11) without involvement of 5a-C-centered radicals and its proof by trapping of ortho-quinone methide 3 with ethyl vinyl ether to pyranochroman 13. Shown are the major products of the reaction of a-tocopherol (1) with dihenzoyl peroxide. 

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. 

FIGURE 6.17 Oxidation of a-tocopherol (1) conventionally leads to its spiro dimer (9) via ortho-quinone methide 3 (path A). The zwitterionic o-QM precursor 3a is stabilized by NMMO in complex 17, which upon rapid heating produces small amounts of new dioxocine dimer 18 (path B). Acid treatment of 18 causes quantitative conversion into spiro dimer 9, via o-QM 3 (path C). 

It was shown that complexes 19 of the zwitterionic precursors of ortho-quinone methides and a bis(sulfonium ylide) derived from 2,5-di hydroxyl 1,4 benzoquinone46 were even more stable than those with amine N-oxides. The bis(sulfonium ylide) complexes were formed in a strict 2 1 ratio (o-QM/ylide) and were unaltered at —78 °C for 10 h and stable at room temperature under inert conditions for as long as 15—30 min (Fig. 6.18).47 The o-QM precursor was produced from a-tocopherol (1), its truncated model compound (la), or a respective ortho-methylphenol in general by Ag20 oxidation in a solution containing 0.50-0.55 equivalents of bis(sulfonium ylide) at —78 °C. Although the species interacting with the ylide was actually the zwitterionic oxidation intermediate 3a and not the o-QM itself, the term stabilized o-QM was introduced for the complexes, since these reacted similar to the o-QMs themselves but in a well defined way without dimerization reactions. 

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... 

FIGURE 6.46 Oxidation chemistry of 5-(4-methylphenyl)- y-tocopherol (76), establishing a reaction system phenylogous to a-tocopherol (1), with quinone methide 77 and benzyl bromide 78 being the conjugatively stabilized, phenylogous counterparts of o-QM 3 and 5a-bromo-a-tocopherol (46), respectively. 

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