Provitamin D derivatives

The first vitamin D was isolated from the irradiation of the yeast sterol ergosterol (Figure 2). This vitamin D was thought to be identical to that produced in the skin of animals and humans. However, studies revealed that when vitamin D produced from yeast was fed to chickens, they were unable to utilize it and developed rickets. When chickens were fed natural vitamin D from fish liver oil, rickets was prevented. This led to the conclusion that vitamin D originating from yeast was different from that in fish liver oil and animal and human skin. In 1937, this mystery was solved when the structure of provitamin D from pig skin was determined. A structural analysis revealed that provitamin D derived from ergosterol differed from that derived from pig skin. The provitamin D (ergosterol provitamin D2) that came from yeast had a double bond between carbons 22 and 23 and a methyl group on carbon 24. 

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. 

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. 

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 derivatives of the provitamins have been synthesized in efforts to prepare the metabolites 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... 

A-10 Provitamin D is a simple derivative of cholesterol, which occurs when a hydrogen is removed from the number 7 carbon, which then forms a double bond with the number 8 carbon, in the second, or B ring of the cholesterol molecule. 

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]. 

A third approach [scheme (16)] involves deconjugation of a 1,4-dien-3-one to the 1,5-diene followed by selective hydroboration of the 1,2-olefin. This scheme gives both the la-hydroxy and 2a-hydroxy cholesterol derivatives. Application of this method to l,4,6-cholestatrien-3-one leads directly to the la-hydroxy provitamin D skeleton ... 

Cases exist, such as the natural or commercial preparation of provitamin D from provitamin D (Sect. 1) or the ring opening of cycIohexa-2,4-dienones to their dieneketene seco-isomers (Sect. 2), in which the photoreaction has the advantage. There are other instances such as the preparation of reactive or//(o-quinodimethane derivatives as intermediates in steroid synthesis ) (Sect. 3), in which either pliotoenoKzation or thermal seco-isomeriza-tions of appropriate benzocyclobutene derivatives may be used equally weU. 

It would seem that ergosterol, provitamin D2 (la), would serve as an ideal precursor for side chain oxygenated vitamin D derivatives because of its ready availability from yeast and its preexisting 5,7-diene system. However, the reactivity of the diene moiety in its free or protected form (vide infra) has complicated the selective manipulation of the side chain. Eyley and Williams have studied the reactions of the aldehyde (43) obtained in modest yield by selective ozonization of... 

Animal and plant tissues contain several provitamin D s (see Fig. 5-3). They all are composed of a steroid ring substituted by a hydroxyl on carbon 3, a methyl on carbons 18 and 19, and a side chain on carbon 17. All provitamin D s have the same steroid derivative 3(j8)-hydroxy-zl-5,7-steroid. Ergosterol was the first provitamin the structure of which was elucidated. It carries an extended side chain on carbon 17 as indicated by the formula, and the configuration of the side chain of ergosterol has been established by studies with the aid of X-ray crystallography. All other provitamins have a different side chain. There is no vitamin Di because the compound originally referred to as vitamin was found to be vitamin D2. 

A survey of recent literature shows the decreasing importance of TLC as an analytical technique in the vitamin D field. For the separation of photoisomers of irradiated provitamins D, TLC has been almost completely superseded by HPLC. Likewise, TLC has lost its impact as a purification step in the complex sample pretreatment schemes previously used to separate vitamin D from interfering sterols and fat-soluble vitamins present in oils, foods, and multivitamin preparations. The technique still has some potential for monitoring the purity of radiolabeled vitamin D derivatives. 

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. 

Vitamin A (retinol), present in carnivorous diets, and the provitamin (P-carotene), found in plants, form retinaldehyde, utilized in vision, and retinoic acid, which acts in the control of gene expression. Vitamin D is a steroid prohormone yielding the active hormone derivative calcitriol, which regulates calcium and phosphate metaboUsm. Vitamin D deficiency leads to rickets and osteomalacia. 

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