Vitamin from phytol

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. 

The naphthoquinone nucleus of the above-mentioned compounds originates from chorismic acid and y-hydroxybutyryl-2 -thiamine pyrophosphate ( activated succinylsemialdehyde ) derived from oc-ketoglutarate (C 4). An important intermediate is 2-succinylbenzoic acid. Naphthohydroquinone-2-carboxylic acid is the first naphthalene derivative formed. Juglone is synthesized via a symmetrical intermediate, in contrast to the vitamins K, e.g., phylloquinone, and to lawsone. The side chain of phylloquinone derives from phytol (D 6.3). 

Vitamin Ki is best synthesized by condensation of a menadiol 1-ester with phytol or isophytol and subsequent saponification and oxidation. Vitamin Ki synthesized from phytol appears to be identical with the natural product vitamin Ki from synthetic isophytol differs slightly in having a racemic phytyl chain. The double bonds in /3,7-position of all vitamin K compounds have the same, most probably the irons, configuration. 

Vitamin Kp also known as vitamin Kk20)> phylloquinone or phytylmenaquinone, contains a hexahydrotetraprenyl chain (2-methyl-3-phytyl-l,4-naphthoquinone, 5-44). Phylloquinone occurs in foods of plant origin. The side chain derived from phytol has 20 carbon atoms (four isoprenoid units, of which three are reduced). The isomer with a cis-configuration in the side chain is not biologically active. The systematic name of vitamin Kj is (2 ,7 R,ll R)-2-methyl-3-(3, 7Ml, 15 -tetramethyUiexadecyl)naphtho-l,4-quinone. The second compound with the activity of vitamin K is vitamin K2 (5-45), also known as vitamin K2( ), menaquinone, menaquinone-n, MK-n or 2-methyl-3-multiprenyl-l,4-naphthoquinone (n = 0-13). The most common menaquinones contain 4-10 isoprene units, such as MK-7, additionally called pharnoquinone. Vitamin K2 is produced by many bacteria and actinomycetes. A multiprenyl side chain... 

Arnhold, T, Ehnazar, M.M.A., and Nau, H., Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all frara-retinoic acid, Toxicol. Sci., 66, 274, 2002. 

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. 

Other studies have shown biological actions from these kinds of structure and indicate interrelationships between the chemicals in terms of their potencies. Tomita [229] found that the substances, vitamin A, vitamin K, vitamin E, /1-carotene, ubiquinone (15), phytol and squalene (16), from green-yellow vegetables could suppress the growth of tumour cells and enhance T-cell cytotoxicity, but /1-carotene, which does have both ends of the chain substituted with a bulky / -ionone ring on each end-group did not. Hydrophobic chain... 

In methodology developed by Fieser, unprotected menadiol (5) was condensed with natural phytol using oxaHc acid as catalyst (25). Oxidation of the hydroquinone to the naphthoquinone yielded vitamin K. A similar approach has been reported (26). The commercial synthesis of vitamin is largely based on the above with some important improvements from Roche (27) and Merck (28). 

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. 

Vitamin K,(2-methyl-3-phytyl-l,4-naphthoquinone (84) has been unambiguously prepared from l-acetoxy-2-methyl-4-hydroxynaphthalene and phytol under mildly acidic conditions and the intermediate product hydrolysed and oxidised (ref.87). (Scheme 43)... 

Compounds in the vitamin K series are 2-methyl-l,4-napthoquinones, which are substituted with side chains at carbon 3. FhyUoquinone (Ki type) synthesized in plants and the menaquinones (K2 type) of bacterial origin are the two principal natural classes of vitamin K (Figure 30-6). The principal vitamin Ki (phyUoquinone) bears a saturated, phytol, 20-carbon side chain derived from 4 isoprenoid units this is the main K vitamin produced by plants and is tire major dietary form for humans. K2 shows greater vari-... 

Vitamin E obtained from natural products is, however, much costlier than the one synthesized from 2,3,6-trimethyl phenol, via 2,3,6-trimethyl hydroquinone and phytol. 

Reformatsky reactions have been used in the total synthesis of various important natural products such as phytol,225 naturally occurring polyenes,226 and vitamin A (from / -ionylideneacetaldehyde).227... 

Similar results were observed with other allylic alcohols. This rearrangement was used to obtain the optically active Ci4-carbon unit 3, which is an important intermediate in vitamin E synthesis, originally prepared from natural phytol. 

Phytol is a fatty alcohol with 20 carbon atoms (3, 7, 11, 15-tetramethyl-2-hexadecene-l-ol, C20H40O) from the group ofterpenes. Phytol is used in the synthesis of vitamins E and K]. In addition, it is a lipophilic component of chlorophyll. Because of a double bond cis- and trans-isomers exist. The trans-isomer is used as a fixener in the perfume industry. 

Ditarpenes terpenes derived from four isoprene units (C20H32). Phytol, an aliphatic D., is important as the ester component of chlorophyll and as a part of vitamins K and E. Other examples of naturally occurring D. are Stevioside (see), vitamin A, retinol (chromophore of visual purple), certain alkaloids (cassaine, aconitine), and hormones such as gibberellins, trisporic acids and antheridiogens. Many cyclic D. are acids (e.g. the resinic acid, abie-tic acid Fig.). 

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). 

The rotation of vitamin Ki thesdzed from natural phytol was found to be = —0.71 st 0.02°, the determination being performed on the un-dflutid oily compound using sodium li t. Vitamin Ki from isophytol shows no rotation as, so far, only racemic isophytol has been produced by total [ thesis. The compounds of the Ki series have no optical activity. 

Biological Activity of Vitamin Ki with a Racemic Side Chain and Vitamin Ki with Optically Active Side Chain (From Natural Phytol)... 

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. 

Vitamin K,(20) (VKl), or phylloquinone, is the generic name of 2-methyl-3-eicosa-2 -ene-l,4-naphthoquinone. The (2 -tram-) phytyl side chain in position 3 of the naphthoquinone nucleus contains 20 carbon atoms, structured in four isoprene units, the last three of them totally reduced (see Structure 1 in Fig. 1). If a synthetic VKl is analyzed, always a mixture of di/trans -isomers can be detected, deriving from synthetic phytol, which consists of a mixture of these isomers. VKl in pure form an orange oil and a fat-soluble vitamin is insoluble in water, slightly soluble in ethanol, and can be easily solved in ether, hexane. 

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... 

As described above, phytol (301) and isophytol (302) can be manufactured from gera-nylacetone in a sequence exactly analogous to those for the production of geraniol and linalool from methylheptenone. Geranylacetone, in turn, can be obtained from either myr-cene or linalool. Both phytol and isophytol are important as intermediates in the synthesis of vitamins E and K and isophytol is used as a diluent in higher price fragrances (82). 

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