Vitamin Tocopherols, Phytol

An important representative of diterpenoid alcohols is phytol (2 ,3,7ff,llff,15)-3,7,ll,15-tetramethylhexadec-2-en-l-ol, a constituent of chlorophylls, tocopherols and K group vitamins. Free phytol arises during chlorophyll hydrolysis by chlorophyUase as an integral part of plant catabolism in fruit ripening and yellowing of leaves. Microbial decomposition of phytol creates some unusual branched fatty acids, such as pristanic and phytanic acids (see Section 3.2.3.3.2). Acyclic diterpenic alcohol is also retinol (vitamin Aj) (see Section 5.2.1). 

One of the simplest and most significant of the diterpenes is phytol, a reduced form of geranylgeraniol, which constitutes the lipophilic side-chain of the chlorophylls. Phytol also forms a part of vitamin E (tocopherols) and K molecules. Vitamin A is also a 20-carbon-containing compound, and can be regarded as a diterpene. However, vitamin A is formed from a cleavage of a tetraterpene. Among the medicinally important diterpenes, paclitaxel, isolated from Taxus brevifolia (family Taxaceae), is one of the most successful anticancer drugs of modern time. 

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 synthesis of Vitamin E, that is, a-tocopherol (5,7,8-trimethyltocol) in the past has been accomplished primarily by reacting trimethylhydroquinone (TMHQ) with isophytol (3,7,ll,15-tetramethylhexadec-l-en-3-ol) or phytol (3,7,ll,15-tetramethylhexadec-2-en-l-ol) in a condensation reaction. The reaction is well known and has been practiced for many years (Stalla-Bourdillon, Ind. Chim. Belg., 35, 13 (1970) "The Vitamins" Vol. 5, pages 168-223, Academic Press, New York, 1967). 

Vitamin E, a-tocopherol, an effective antioxidant, is obtained as a diastereoisomeric mixture in the 2,3 (S),7 (R),11 (R), form and the natural 2,3 (R),7 (R), 11 (R), form (83) by the reaction of phytyl bromide with trimethylhydroquinone in the presence of zinc chloride (ref.86), the phytol required being obtained from chlorophyll. 

Phytol, CAS no. [150-86-7] C20H40O, an alcohol obtained by the decomposition of chlorophyll is an odorless liquid, BP 202—204°C/10mm Hg and has been used in the synthesis of vitamin E. On reaction with trimethyl hydroquinone phytol is converted to a-tocopherol, etc. 

Fig-1 Structures of natural phytol, vitamin l[Pg.72]

The well-known series of natural tocopherols consists of methylated tocols derived from phytol. Recently Green ct al. (1959a, 1960) showed the existence of a second, closely related series of natural tocopherols containing an unsaturated (trimethyltrideca-3,7,ll-trienyl) side chain, as represented by e- and fi-tocopherol (Table II). Further chromanols, chromenols, and benzoquinones which may play a role together with or similar to that of vitamin E in the living cell are also listed in Table II. 

Vitamin E is in the NADH cytochrome c reductase system. When the system was extracted with isoectane, NADEl oxidation was blocked normal oxidation rates can be restored by adding a-tocopherol, but many other lipid substances are also active in that respect e.g., vitamin K, ubiquinone, phytol. Of course, such observations do not exclude the possibility that in vivo vitamin E is in fact the only substance capable of maintaining the integrity of the NADH cytochrome c reductase system. 

Phytol is an alcohol with which chlorophyll (Chapter 12) is esterified. After the phytol is isolated by hydrolysis, it is subsequently used in the manufacture of vitamin E (of which a variety of similar compounds are categorized). Interestingly, the particular vitamin E derivative commonly prepared (a-tocopherol) is obtained by heating phytol and 2,3,5-trimethylhydroquinone (a compound derived in the plant from shikimic acid, vide infra) in the presence of an acid catalyst (Scheme 11.70). 

Scheme 11.70. A common synthesis of a-tocopherol. The phytol and 2,3,5-trimethylhydroquinone are brought together in the presence of an acid catalyst to produce vitamin E.

A criterion for a substance to be a member of the respiratory chain is its ability to reactivate an enzymatic system from which this component has been removed. Such a system has been described by Nason and Lehman (1956), who used a rat skeletal muscle cytochrome c reductase inactivated by extraction with isooctane. In such a test vitamin E (Nason and Lehman, 1956) and vitamin K (Deul et ah, 1958) were found to be active. In an extensive study Weber et ah (1958a, b) showed, however, that this reactivation is not related to the redox system but to the isoprene-like side chain. Esterified tocopherol and the diacetates of the dihydro forms of vitamin Ki, Kj, and of ubiquinone(50) are as active as the free forms. Moreover, isolated side chains, such as phytol and squalene, showed exactly the same activity as the corresponding menadione derivatives, compared on a molar basis. The authors speculate that in this experiment a special function of the isoprene-like side chain, namely the binding of this vitamin to the fat material of the mitochondria, is demonstrated. 

The chromane ring is derived from the diterpenic alcohol phytol, with the systematic name (2 ,7 ,11 )-3,7,11,15-tetramethylhexadec-2-en-l-ol, but in addition to the hydroxyl groups in position C-6 it contains another methyl group at position C-2. The presence of these functional groups is essential for the biological activity of all vitamers. Four forms of vitamin E with a saturated terpenoid side chain derived from the tocol are called tocopherols (5-33) four forms with unsaturated... 

Valentin, H. E., Lincoln, K., Moshiri, F., Jensen, P. K., Qi, Q., Venkatesh, T. V, Karunanandaa, B., Baszis, S. R., Norris, S. R., Savidge, B., Gmys, K. J. Last, R. L. (2006). The Arabidopsis vitamin E pathway gene5-l mutant reveals a critical role for phytol kinase in seed tocopherol biosynthesis. Plant Cell, 18, 212-224. 

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