Provitamine

The reaction has been applied successfully to the synthesis of a precursor of provitamin D. 520, which has a homoannular conjugated diene in the B ring[340]. Treatment of the 7a-carbonate 518 with Pd cataJy.st at 40 C afforded the 5.7-diene 520 regioselcctively in good yield. No heteroannular diene 521... 

Provitamins Prov. stuartii 4GR Prov. stuartii Rahal Pro-Xan process Proxcel CRL Proxel CRL... 

Ref. 2. Vitamin A is reported as retinol [68-26-8] equivalents/L. RE = 1 /ig of all trans-i.etSio 6 )lg of all /ra j -(3-carotene, and 12 )lg of other provitamin A cartenoids, with older definitions giving 3.33 lU vitamin A from retinol and 10 lU vitamin A activity from -carotene. 

An important function of certain carotenoids is their provitamin A activity. Vitamin A may be considered as having the stmcture of half of the P-carotene molecule with a molecule of water added at the end position. In general, all carotenoids containing a single unsubstituted P carotene half have provitamin A activity, but only about half the activity of P carotene. Provitamin A compounds are converted to Vitamin A by an oxidative enzyme system present in the intestinal mucosa of animals and humans. This conversion apparendy does not occur in plants (see Vitamins, VITAMIN a). 

In this regard, tryptophan is considered a provitamin and is assigned a niacin equivalent of 1/60. The following fists the vitamin content of many common foodstuffs and in Table 3, values of vitamin B content are compared to niacin potential from tryptophan. 

Vitamin A constitutes the most significant sector of the commercial retinoid market and is used primarily in the feed area. In the pharmaceutical area, there are several important therapeutic dermatologic agents which stmcturaHy resemble vitamin A and they are depicted in Figure 2 (see Pharmaceuticals). The carotenoids as provitamin A compounds also represent an important commercial class of compounds with P-carotene [7235-40-7] (10) occupying the central role (Fig. 3) (9). 

Biological, spectroscopic, and chromatographic methods have been used to assay vitamin A and the carotenoids. Biological methods have traditionally been based on the growth response of vitamin A—deficient rats. The utiUty and shortcomings of this test have been reviewed (52,53). This test has found apphcabiUty for analogues of retinol (54,55). Carotenoids that function as provitamin A precursors can also be assayed by this test (56). 

Many carotenoids function in humans as vitamin A precursors however, not all carotenoids have provitamin A activity (Table 3). Of the biologically active carotenoids, -carotene has the greatest activity. Despite the fact that theoretically one molecule of -carotene is a biological source of two molecules of vitamin A, this relationship is not observed and 6 p.g -carotene is equivalent to 1 p. vitamin A. Although -carotene and vitamin A have complementary activities, they caimot totally replace each other. Because the conversion of -carotene to vitamin A is highly regulated, toxic quantities of vitamin A cannot accumulate and -carotene can be considered as a safe form of vitamin A (8). 

Animals cannot synthesize vitamin A-active compounds and necessary quantities are obtained by ingestion of vitamin A or by consumption of appropriate provitamin A compounds such as P-carotene. Carotenoids are manufactured exclusively by plants and photosynthetic bacteria. Until the discovery of vitamin A in the purple bacterium Halobacterium halobium in the 1970s, vitamin A was thought to be confined to only the animal kingdom (56). Table 4 Hsts RDA and U.S. RDA for vitamin A (67). 

D. Bhatia, ed., "Vitamius, Part III Vitamin A and Provitamin Carotenoids," iu the Emyc/opedia of Food Science and Techno/og, ]olm. Wiley Sons, Inc., New York, 1991. 

Vitamin (cholecalcifetol calciol), (5Z,7E)-(33)-9,10-seco-5,7,10(19) cholestatriene-3-ol (4), is the naturally occurring active material found ki all animals. It is produced ki the skin by the kradiation of stored 7-dehydrocholesterol (provitamin E) ), cholesta-5,7-diene-3B-ol (3). 

Common name CAS Registry Number Provitamin Trivial name lUPAC-IUB name... 

The vitamins D ate 9,10-secosteroids, that is, steroid molecules with an opened 9,10 bond of the B-ring. The relationship between the provitamin steroid (pethydto-l,2-cyclopentanophenanthrene ring system) and the 9,10-secosteroid nucleus is shown in stmctures (5) and (6), cholestane and 9,10-secocholestane (calcitane), respectively. 

The observation that the uv spectmm of provitamin D changed with uv inradiation and also produced antirachitic activity led to the conclusion that vitamin D was derived from the provitamin. Windaus found the vitamin D2 formula to be isomeric with the provitamins. 

Windaus and Boch (13) isolated and characterized 7-dehydrocholesterol in 1937 from pig skin. They further showed that vitamin D could be generated from the provitamin by uv inradiation. 

Irradiated ergosterol was found not to be as antirachitic in the chick as in the rat, whereas the chick could be protected by direct kradiation. The provitamin in cholesterol was shown not to be ergosterol. Rygh (14) in 1935 found that 1 rat unit of cod Hver oil was 100 times more potent in chicks than 1 rat unit of vitamin D2. Brockmann (15) in 1936, prepared the pure crystalline 3,5-dinitrobenzoate derivative of vitamin D obtained from tuna Hver oil... 

Occurrence. The provitamins, precursors of the vitamin Ds, are distributed widely in nature, whereas the vitamins themselves are less prevalent. The amounts of provitamins D2 and D in various plants and animals are Hsted in Table 2. 

Table 2. Occurrence of the Provitamins D in Selected Plants and Animals, Parts per Thousand of Total Sterol...

Provitamin. The chemistry of the D vitamins is intimately involved with that of their precursors, the provitamins. The manufacture of the vitamins and their derivatives usually involves the synthesis of the provitamins, from which the vitamin is then generated by uv irradiation. The chemical and physical properties of the provitamins are discussed below, followed by the properties of the vitamins. 

P-Hydroxy steroids which contain the 5,7-diene system and can be activated with uv light to produce vitamin D compounds are called provitamins. The two most important provitamins are ergosterol (1) and 7-dehydrocholesterol (3). They are produced in plants and animals, respectively, and 7-dehydrocholesterol is produced synthetically on a commercial scale. Small amounts of hydroxylated detivatives of the provitamins have been synthesized in efforts to prepare the metaboHtes of vitamin D, but these products do not occur naturally. The provitamins do not possess physiological activities, with the exception that provitamin D is found in the skin of animals and acts as a precursor to vitamin D, and synthetic dihydroxalated... 

Provitamin Ergosterol is isolated exclusively from plant sources. The commercial product is ca 90—100% pure and often contains up to 5... 

Provitamin D. Provitamin is made from cholesterol, and its commercial production begias with the isolation of cholesterol from one of its natural sources. Cholesterol occurs ia many animals, and is generally extracted from wool grease obtained by washing wool after it is sheared from sheep. This grease is a mixture of fatty-acid esters, which contain ca 15 wt % cholesterol. The alcohol fraction is obtained after saponification, and the cholesterol is separated, usually by complexation with 2iac chloride, followed by decomplexation and crystallisation. Cholesterol can also be extracted from the spiaal cords and brains of animals, especially catde, and from fish oils. 

Commercially, the irradiation of the 5,7-diene provitamin to make vitamin D must be performed under conditions that optimize the production of the previtamin while avoiding the development of the unwated isomers. The optimization is achieved by controlling the extent of irradiation, as well as the wavelength of the light source. The best frequency for the irradiation to form previtamin is 295 nm (64—66). The unwanted conversion of previtamin to tachysterol is favored when 254 nm light is used. Sensitized irradiation, eg, with fluorenone, has been used to favor the reverse, triplet-state conversion of tachysterol to previtamin D (73,74). 

The irradiation of the provitamin has been achieved using the acetate and benzoate esters, although the free alcohol form of the provitamin is usually used (77). 

Physical Properties. The physical properties of the provitamins and vitamins D2 and are Hsted ia Table 6. The values are Hsted for the pure substances. The D vitamins are fat-soluble and, as such, are hydrophobic. 

The provitamins are also unstable to heat and light. They generally should be stored in a dark, cool, dry place. The provitamin is more stable if shipped with 10—15 wt % methanol rather than in a dry form. 

The development of rehable uv analysis permitted the dependable detection and assay of the provitamins and vitamins. Prior to this, the Lieberman-Bouchard chemical test was used, but the color reaction gave many false positives and was relatively inaccurate. 

Provitamin D. The molecular extinction coefficient of 7-dehydrocholesterol at 282 nm is 11,300 and is used as a measure of 7-dehydro isomer... 

Rosenheim reaction CHCI3 + lead tetraacetate in green fluorescence not given by esters of provitamin D can... 

PApo-8 -carotenal. The specifications of this colorant. (38) were discussed earlier. P-Apo-8 -carotenal has provitamin activity with 1 g of the colorant equal to 1,200,000 lU of vitamin A. Like all crystalline carotenoids, it slowly decomposes ia air through oxidatioa of its coajugated double boads and thus must be stored ia sealed coataiaers uader an atmosphere of iaert gas, preferably under refrigeration. Also like other carotenoids P-apo-8 -carotenal readily isomerizes to a mixture of its cis and trans stereoisomers when its solutions are heated to about 60°C or exposed to ultraviolet... 

Up to now, far more than 5000 retinoic acid analogs have been synthesized, out of which the following three generations have been established for therapy of various disorders First, the nonaromatic retinoids (3-carotene (provitamin A), alWraras-retinoic acid (RA) (tretinoin) and 13-cis-RA (isotretinoin), second, the monoaromatic retinoid derivatives trimethyl-methoxyphenyl analog of RA (etretinate) and9-(4-methoxy-2,3,6-trimethylphenyl)-... 

---