Provitamin irradiation

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... 

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. 

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). 

The photoequilibrium between 1,3-cyclohexadienes and 1,3,5-hexatrienes 3t5,3i6) s key step jn synthesis of vitamin D, as shown in the formation of vitamin D3 (R = C8H17) via a [l,7]sigmatropic H-shift from previtamin D which is obtained by irradiating provitamin D (3.9) 317). 

Vitamin D is the collective term for a group of compounds formed by the action of ultraviolet irradiation on sterols. Cholecalciferol (vitamin D3) and calciferol (vitamin D2) are formed by irradiation of the provitamins 7-dehydrocholesterol and ergosterol, respectively. The conversion to vitamin D3 occurs in the skin. The liver is the principal storage site for vitamin D, and it is here that the vitamin is hydroxylated to form 25-hydroxyvitamin D. Additional hydroxylation to form 1,25-dihydroxyvita-min D occurs in the kidney in response to the need for calcium and phosphate. A discussion of the role of vitamin D in calcium homeostasis is provided in Chapter 66. 

Vitamin D is represented by cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), which are structurally similar secosteroids derived from the UV irradiation of provitamin D sterols. In vertebrates, vitamin D3 is produced in vivo by the action of sunlight on 7-dehydrocholesterol in the skin. Vitamin D2 is produced in plants, fungi, and yeasts by the irradiation of ergosterol. On irradiation, the provitamins are converted to previtamin D, which undergoes thermal transformation to vitamin D. 

FIGURE 66.1 Vitamins D3 and D2 are produced by ultraviolet irradiation of animal skin and plants, respectively. The precursor of vitamin D3 in skin is 7-dehydrocholesterol, or provitamin D. In humans, the storage, transport, metabolism, and potency of vitamins D2 and D3 are identical, and the net biologic activity of vitamin D in vivo results from the combined effects of the hydroxylated derivatives of vitamins D2 and D3. 

The precursors of vitamins D2 and D3 are ergosterol and 7-dehydrocholesterol, respectively. These precursors or provitamins can be converted into the respective D vitamins by irradiation with ultraviolet light. In addition to the two major provitamins, there are several other sterols that can acquire vitamin D activity when irradiated. The provitamins can be converted to vitamin D in the human skin by exposure to sunlight. Because very few foods are good sources of vitamin D, humans have a greater likelihood of vitamin D deficiency than of any other vitamin deficiency. Enrichment of some foods with vitamin D has significantly helped to eradicate rickets, which is a vitamin D deficiency disease. Margarine and milk are the foods commonly used as carrier for added vitamin D. 

By contrast, the retro electrocyclization by photochemical irradiation is well known. For example, the photochemical transformation (6e conrotato ring opening) of provitamin D (5) to previtamin D (3) and then thermal isomerization (1,7-H shift) of the latter is a well-established sequence leading to vitamin D (4). It is a sequence involved in vitamin D biosynthesis and in the laboratory synthesis of vitamin D. Moreover, the process is used commercially. 

The observation that the uv spectrum of provitamin D changed with uv irradiation and also produced antirachitic activity led to the conclusion that vitamin D was derived from the provitamin. Wiudaus found the vitamin D2 formula C2gH O 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 irradiation. 

Vitamin D Analogues - A patent covering the photochemical conversion of the diene (112) into the triene (113) within what is called a microreactor has been published. The microreactor system is a zeolite with the appropriate size of the cavity to provide stereochemical control of the reaction. The use of the 2,7-dimethyl-3,6-diazacyclohepta-1,6-diene tetrafluoroborate/biphenyl filter solution has allowed the double wavelength irradiation (290-300 nm and X. > 330 nm) of procalcitriol as a route to la,25-dihydroxycholecalciferol. A study of the control that can be exercised upon the reaction by changes in temperature was carried out. The results of a study of the influence of intensity on the picosecond laser irradiation of provitamin D have been published. Other research has been aimed at the examination of the photochemical behaviour of previtamin 03. ... 

Vitamin D Analogues - A complex mixture of products is formed on irradiation of a new 19-phenylsulfonyl provitamin D analogue. 

Chemistry. There are two forms of vitamin D, and both are considered biologically equivalent. Irradiation of the major plant sterol, ergosterol, produces ergocalciferol, also known as vitamin Dg (Fig. 8.11).Because they are photochemical reactions and in contrast to enzyme-catalyzed biochemical reactions, the formation of cholecalciferol is not clean. Exposure of human skin to sunlight of295-300 nm converts 7-dehydrocholesterol to provitamin D,. The isomerization to cholecalciferol (vitamin Dg) is heat catalyzed. Continuous exposure to ultraviolet radiation from the sun results in the reversible formation of lumisterol... 

Cholesterol can be converted to vitamin D photochemically from 7-dehydrocholes-terol (provitamin D) (Special Topic 6.4) and this procedure is still used in industry.616 Vitamin D can also be made by irradiating yeasts rich in ergosterol. In addition, vitamin A (retinol) (see Special Topic 6.1) is synthesized by E Z photoisomerization (Section 6.1.1), sensitized by chlorophyll or other chromophores (Section 6.8) of its 11 -cis isomer, which is produced industrially by conventional synthetic steps.1310... 

The active forms of vitamin D analogues (1-14) were synthesized by the coupling of the steroid moiety [20] with the corresponding phenyl sulfone derivatives [21] to constitute the side chain part followed by the UV irradiation of the provitamins and the subsequent thermal isomerization of the previtamin D derivatives [22], These active forms of vitamin D analogues were also prepared through the cyclovitamin D derivatives [23]. 

Further products have been identified from the irradiation of 7-dehydro-cholesterol [(130), provitamin D3]. In ether or alcohol the main component of the photolysate was assigned structure (131) which results from the photochemical cyclization of the trans-Z-cis-conformation of the triene (132) formed by ringopening of the cholesterol.92 From reaction in ethanol two alcohol-addition products (133) and (134) have been identified. Two other products of the toxisterol type have been assigned structures (135), the difference between them... 

Ergosterol is the provitamin of vitamin D2, which differs from 7-dehy-drocholesterol and vitamin D3, respectively, only by having a double bond between C22 and C23 and a methyl group at C24. Vitamin D2 is the constituent in many commercial vitamin preparations and in irradiated milk and bread. The antirachitic potencies of D2 and D3 in humans are equal, but both must be converted to 25-(OH)-cholecalciferol and eventually to the active form calcitriol (1,25-(0H)2D3) for biologic activity. 

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