All rac-a-tocopherol

Vitamin E RRR- a-tocopherol all-rac- a-tocopherol HepG2 dose response No difference in EC50 or IC50 [17]... 

Unless otherwise noted, the vitamin E supplements discussed in this chapter contain either natural AAA-a-tocophcrol (also known as [Pg.329]

Commercially, tocopherol is available as a pure all-rac-a-tocopherol, mixed tocopherols having various contents of a-, p-, y-, or 8-tocopherols (diluted in vegetable oil) and synergistic mixtures containing tocopherols, ascorbyl palmitate or other antioxidants, and synergists such as lecithin, citric acid, and carriers. Extraction of tocopherols from natural sources and chemical synthesis of tocopherols are well described by Schuler (100). 

Property i7//-n7iva-Tocopherol RRR-a-T ocopherol all-rac-d-T ocopheryl Acetate RRR-a-Tocopheryl -Acetate... 

Although all four tocopherols have been synthesized as their all-rac forms, the commercially significant form of tocopherol is i7//-n7i a-tocopheryl acetate. The commercial processes ia use are based on the work reported by several groups ia 1938 (15—17). These processes utilize a Friedel-Crafts-type condensation of 2,3,5-trimethylhydroquinone with either phytol (16), a phytyl haUde (7,16,17), or phytadiene (7). The principal synthesis (Fig. 3) ia current commercial use iavolves condensation of 2,3,5-trimethylhydroquiQone (13) with synthetic isophytol (14) ia an iaert solvent, such as benzene or hexane, with an acid catalyst, such as ziac chloride, boron trifluoride, or orthoboric acid/oxaUc acid (7,8,18) to give the all-rac-acetate ester (15b) by reaction with acetic anhydride. Purification of tocopheryl acetate is readily accompHshed by high vacuum molecular distillation and rectification (<1 mm Hg) to achieve the required USP standard. 

The all-rac forms of P-, y-, and 5-tocopherols can be synthesized using the same condensation reaction as used for i7//-n7iC-a-tocopherol. To synthesize i7//-n7iC-P-tocopherol, 2,5-dimethylhydroquinone instead of trimethyUiydroquinone is condensed with isophytol. For all-rac- - and 5-tocopherol, 2,3-dimethylhydroqiiinone and methyUiydroquinone are used, respectively. 

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). 

Label claims for tocopherol levels in preparations can be based on milligrams or International Units. Only the RRR or all-rac-International Units ate also used in some reference books and compendia, eg. Food Chemicals Codex (40,53), which is of particular importance for specifications for food fortification. 

Due to bleeding risk, individuals on anticoagulant therapy or individuals who are vitamin K-deficient should not take vitamin E supplementation without close medical supervision. Absent of that, vitamin E is a well-tolerated relatively non-toxic nutrient. A tolerable upper intake level of 1,000 mg daily of a-tocopherol of any form (equivalent to 1,500 IU of RRR a-tocopherol or 1,100 IU of all-rac-a-tocopherol) would be, according to the Food and Nutrition Board of the Institute of Medicine, the highest dose unlikely to result in haemorrhage in almost all adults. 

The strong Bronstedt acid nature of some hexacoordinated phosphorus derivatives, [7",H ] (Et20)4 in particular, was recently used within the context of an industrial application [36]. The conjugated acid of tris(oxalato)phosphate anion 7 was found to effectively catalyze the ring-forming reaction of trimethyl-hydroquinone 63 with isophytol 64 to give (all rac)-a-tocopherol 65 (ethylene-carbonate/heptane 1 1,100 °C, 90%, Scheme 19). This process is particularly... 

It should be noted that pharmacological vitamin E is not a free natural RRR-a-tocopherol or synthetic All rac a-tocopherol but its acetate ester. a-Tocopheryl acetate has the phenolic hydroxyl group blocked and therefore, is not a genuine antioxidant, but this compound is very rapidly hydrolyzed in vivo into a-tocopherol. It is interesting that the biological activity of a-tocopheryl acetate is the same as that of a-tocopherol in humans but significantly lower in rats [30]. ( A man is not a rat Professor KU Ingold.)... 

This first example of a Bi(OTf)3-catalyzed Friedel-Crafts alkylation originated in the following procedures, including benzylations of 2,4-pentanediones or hydroarylation and hydroalkylation reactions. A related procedure was simultaneously developed by Bonrath et al. [39]. The authors utilized Bi(OTf)3 in the synthesis of (all-rac)-a-tocopherol (Vitamin E) [39], Besides rare earth metal triflates, such as Ga(OTf)3, Hf(OTf)3, Sc(OTf)3 and Gd(OTf)3, Bi(OTf)3 was shown to be the most efficient catalyst for the Friedel-Crafts-type reaction between trimethylhydroquinone acetate 10b and isophytols 11a, b. With only 0.02 mol% Bi(OTf)3 (substrate to catalyst ratio 5,000 1) the desired a-tocopherols 12a and 12b were isolated in excellent yields (Scheme 10). 

Determination of vitamin E different matrices Determination of all-rac-a-tocopherol in virgin olive oil... 

The acetate ester of a-tocopherol, rather than the free alcohol, is used as a food supplement on account of its greater stability. Both 7 7 f -a-tocopheryl acetate and totally synthetic all-rac-a-tocopheryl acetate are commercially available, the former having a biological activity of 1.36 IU/mg and the latter 1.00 IU/mg (44). The / / / -a-tocopheryl acetate is obtained by extraction from vegetable oils. Since it is not isolated without some chemical processing, it cannot legally be called natural, but it can be described as derived from natural sources. 

In the analysis of foods that contain significant amounts of both naturally occurring toco-pherols and supplemental a-tocopheryl acetate, saponification, by hydrolyzing the esterified vitamin E, allows the total a-tocopherol content to be measured as a single peak by HPLC. It should be noted that if totally synthetic all-rac-a-tocopheryl acetate is the supplemental form used, its hydrolysis product, all-rac-a-tocopherol, is less biologically active than is naturally occurring RRR-a-tocopherol, making it impossible to calculate a potency value for the total vitamin E. This problem does not arise if the supplement used is / / / -a-tocopheryl acetate. 

AOAC official method 992.03. Vitamin E activity (all-rac-a-tocopherol) in milk-based infant formula. Liquid chromatographic method. In MP Bueno, ed. Official Methods of Analysis of AOAC International. 16th ed. Arlington, VA AOAC International, 1995, p. 50-4-50-5. 

A related transformation is the rearrangement-aromatization of ketoisophorone to trimethylhydroquinone diacetate, an intermediate in the industrial synthesis of (all-rac)-a-tocopherol. Of heterogeneous catalysts, Nafion-silica exhibited the best catalyst performance858 [Eq. (5.313)], but activities decreased with repeated use because of the leaching of Nafion resin. 

Since vitamin E is very sensitive to oxidation, stable esters have mainly been used for topical formulations and are considered to be safe.64 As had previously been shown for skin of hairless mice,65 but not for human skin,66 the bioconversion of vitamin E acetate by esterases to vitamin E with its known antioxidant effects has recently also been demonstrated in human skin.48 When supplemented orally a-tocopherol acetate or a-tocopherol succinate get readily hydrolyzed to a-tocopherol in the gut47 with the natural single stereoisomeric form (RRR-a-tocopherol) appearing to have about twice the systemic availability of the synthetic form (all-rac-a-tocopherol)67... 

All-rac-a-Tocopherol occurs as a yellow to amber, clear, viscous oil. It is a form of vitamin E. It oxidizes and darkens in air and on exposure to light. It is insoluble in water freely soluble in alcohol and miscible with acetone, with chloroform, with ether, with fats, and with vegetable oils. 

Labeling All label claims that are in terms of International Units (IU) should be based on the following 1 mg of all-rac-a-Tocopherol = 1.1 IU. 

Procedure Chromatograph 2 to 5 xL of the Assay Preparation, and record the chromatogram as described under Calibration. Measure the areas under the major peaks occurring at relative retention times of approximately 0.51 (a-tocopherol) and 1.00 (hexadecyl hexadecanoate), and record the values as ajj and ah respectively. Calculate the weight, in milligrams, of all-rac-a-Tocopherol in the sample by the formula... 

Assay, Acidity, and Optical (Specific) Rotation Determine as directed in the monograph for all-rac-a-Tocopherol. Lead Determine as directed in the Flame Atomic Absorption Spectrophotometric Method under Lead Limit Test, Appendix IIIB, using a 10-g sample. 

Gum Arabic Ammonia Solution All-rac-a-Tocopherol RRR-a -T ocopherol RRR-Tocopherols Concentrate, Mixed RRR-a-Tocopheryl Acetate All-rac-a-Tocopheryl Acetate RRR-a-Tocopheryl Acetate Concentrate RRR-a-Tocopheryl Acid Succinate... 

The U.S./Canadian Dietary Reference intakes report (Institute of Medicine, 2000) departed from tradition by considering only the contribution of the 2R isomers to vitamin E intake, and proposed an equivalence of 0.45 iu per mg for synthetic all-rac-a-tocopherol, although in consideration of upper tolerable levels of intake (Section 4.6.1), they considered the contribution of aU isomers equally However, although the 2S isomers have a shorter half-life than -tocopherol in the circulation, and hence a lower apparent biological availability, they are active in animal biological assays (Hoppe and Krennrich, 2000). 

---