Synthetic a-tocopherol

An enantioselective hydrogenation of this type is also of interest in the production of a-tocopherol (vitamin E). Totally synthetic a-tocopherol can be made in racemic form from 2,3,5-trimethylhydroquinone and racemic isophytol. The product made in this way is a mixture of all eight possible stereoisomers. 

Knowledge of the chemical structures of the major vitamins was acquired during the 30 years after 1920, and some were identified as known compounds. They were classified as fat-soluble and water-soluble vitamins. The only heterocyclic compounds in the former class are the tocopherols (vitamin E). They were discovered through their action in preventing sterility in rats, but they appear to play an important part in the metabolism of skeletal muscle. Vitamin E deficiency appears to occur rarely in man, but vitamin E therapy is tried in a number of clinical disorders. The tocopherols may be isolated from vegetable oils, and synthetic a-tocopherol (61) is made by condensing trimethylhydroquinone with phytol or phytyl halides (Scheme 2). For medicinal use they may be converted into their acetates or succinates. 

The U.S./Canadian tolerable upper level is set at 1,000 mg per day, based on reports of prolonged prothrombin time in people receiving anticoagulants and consuming 1,100 to 2,100 mg of vitamin E per day. It is noteworthy that although the report specifically excluded the 2S isomers of synthetic a-tocopherol from calculations of nutritional requirements, this tolerable upper level includes all forms of the vitamin, regardless of their tissue retention and biological activity (Institute of Medicine, 2000). 

While there is no universally accepted scientific terminology for representation there is general agreement on a certain working nomenclature (refs. 97,98). Thus a-tocopherol, the natural stereoisomer is as stated earlier (RRR)-a-tocopherol, the 2-epimer is 2-epi-a-tocopherol and a mixture of (RRR) and (SRR)-a-tocopherols is 2-ambo-a-tocopherol. Synthetic a-tocopherol prepared from synthetic phytol or isophytol is called all-rac-a-tocopherol, since it is theoretically a mixture of (RRR) and (SSS). The mixture of reduction products of 5,7,8-trimethyltocotrienol is called 4 -ambo-8 -ambo-a-tocopherol since as a natural product, although it has a 2R centre, the stereochemistry from hydrogen addition at the 4- and 8- positions is probably substantially RS. 

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

Supplementation of Finnish smokers with 50mg/d of synthetic a-tocopherol for 6 years was associated with a 34% decrease in prostate cancer incidence, and p-carotene (50mg on alternate days) supplementation of male physicians with low baseline seram p-carotene concentrations for 12 years was associated with a 32% decrease in prostate cancer incidence. These data may indicate that men with low intake or increased destruction of these compounds, e.g., through oxidative stress, represent subgroups that could benefit from supplementation. 

Commercially available vitamin E consists of either a mixture of namrally occurring tocopherols and tocotriraiols (from natural sources), RRR-a-tocopherol (formerly called d-a-tocopherol), synthetic a-tocopherol, consisting of the eight possible side-chain stereoisomers at eqnal amonnts (all roc-a-tocopherol, formerly called dl-a-tocopherol), or their esters (a-tocophrayl succinate, a-tocopheryl acetate, a-toco-... 

Tocopherylquinone, the synthetic a-tocopherol triene, various dimethyl- and trimethylbenzoquinones and -ubiquinones, as well as vitamin Ki and vitamin Kj (20) (geranylgeranyl), and samples of /3-, T-, and S-tocopherol were obtained through the courtesy of F. Hoffmann-La Roche and Co., Basle, Switzerland. Ubichromanol (20), hexahydro-ubiquinone (20), and the chroinanol and chromenol of the latter were kindly supplied by Merck Sharp and Dohmo, Rahway, New Jersey, a-, /S-, y-, and 8-tocopherol, a-tocopheryl acetate, and tocoquinone were obtained from Distillation Products Industries, Eastman Kodak Co., Rochester, New York. 

Three types of tocopherol are produced for sale (i) natural tocopherols isolated from soybean, sunflower or other vegetable oils which are mixtures of the a, p, Y and 5 compounds, (ii) natural mixtures which have been methylated to convert the P, y and 8 compounds to a tocopherol (the trimethyl compound) with higher vitamin E activity, and (iii) synthetic a-tocopherol made from trimethylhydroquinone and phytyl bromide. This is entirely the trimethyl compound but a mixture of eight stereoisomers. All three show antioxidant and vitamin E activity but only the last two can be sold as vitamin E. 

Synthetic a-tocopherol exhibits, unKke natural a-tocopherol, lower biological activity, because it consists of the C-2 enantiomers, (2J )-a-tocopherol and (2S)-a-tocopherol. In short, synthetic a-tocopherol is (2J S)-a-tocopherol (D,L-a-tocopherol or 2-ambo-a-tocopherol). Synthetic a-tocopherol can also be a racemic mixture of all possible stereoisomers and it then consists of (2RS)-, (A RS)-and (8 J S)-a-tocopherol (or 2-ambo-, A -ambo and 8 -ambo-a-tocopherol), which is called all-rac-a-tocopherol. 

Natural vitamin E is produced at a level of about 2000 tonnes/year from soybean deodorizer distillate. This is methylated to increase the proportion of a-tocopherol and is used mainly in human applications (largely pharmaceutical). It could be considered to be semi-synthetic a-tocopherol. The major producers are Henkel (USA), Archer Daniels Midland (USA), Eisai (Japan), andHoffmann-La Roche/Cargill (USA). 

In three other meta-analyses that combined the results of randomized controlled trials for prevention or treatment of cardiovascular disease [82-84], no significant effect of daily vitamin E dietary supplementation up to 800IU/day (727mg/day of synthetic a-tocopherol) on cardiovascular deaths was found up to 6.3 years (400IU/day). 

The chemical synthesis of a-tocopherol results in an equal mixture of eight different stereoisomers (RRR, RSR, RRS, RSS, SRR, SSR, SRS, SSS) or, more formally, 2,5,7,8-tetramethyl-2RS-(4 RS,8 RS,12 trimethyltridecyl)-6-chromanol. To indicate that synthetic a-tocopherol is a racemic mixture, it is called d //-rac-a-tocopherol, or on labels, factors used to convert international units (lU) to milligrams. For example, if a vitamin E supplement is labeled 400 lU and it is d/-a-tocopheryl acetate, then 400 times 0.45 equals 180mg2R-a-tocopherol, but if it is labeled d-a-tocopheryl acetate, then 400 times 0.67 equals 268 mg2R-a-tocopherol. 

Moore, Martin, and Rajogopal (94) first noticed that the vitamin A roiscives of the livem of rats which had been kept on a diet deficient in itarnin JC, but high in vitamin A (ca. 150 I.U. daily) were much lower than the reserves of. similar animals wliich had received the same allowance of itamin A togetlier with supplements of wheat-genn oil concentrate. In some experiments the differences were as much as tenfold. Moore (95) subsequently ob.servcd the same effect when synthetic a-tocopherol was... 

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