Retinols, synthesis

In a novel preparation of cm-isomers of retinoids, " thermal rearrangement of the vinylallene (87) gave an equimolar mixture of (IIZ)-, (11Z,13Z)-, and (9Z,llZ,13Z)-retinol. Synthesis of the vinylallene (87) is described. Another synthesis of (1IZ)-, (13Z)-, and (1 lZ,13Z)-retinal used organosilane protecting groups syn- and ant/-oximes of these retinol isomers were prepared. 

The economically most important processes today are those of Hoffmann-La Roche and BASF. At Hoffmann-La Roche, Isler et aL developed the first industrial retinol synthesis, which was based on a reaction sequence they had used in 1947 to synthesize crystalline retinol (1) (Isler et aL, 1947) The last C—C bonding step was the Grignard reaction between the C14 aldehyde (6) and the Cg acetylene compound (7) to give carbinol (8), which was then converted to retinyl acetate (9). 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

RBP is synthesized in the hepatocytes, where it picks up one molecule of retinol in the endoplasmic reticulum. Both its synthesis and its secretion from the hepatocytes to the plasma are regulated by retinol. In plasma, the... 

A. Synthesis of Tritium-labelled Retinol and Retinoic Acid... 

This reaction was also used in a synthesis of 13-cis-retinoic acid.2 Thus reduction of 3 under the same conditions gives the triethylsilyl ether (4) of 13-cis-retinol, with retention of the geometry of the terminal double bond. This product can be converted to 13-cis-retinoic acid by deprotection and oxidation (60% yield). 

The presence of a certain number of amino acids is significant for the restitution of the immune system s cells, interferon synthesis process and other factors realization of the immune defense system. The decrease of full-form protein consumption is one of the causes of secondary immune-deficiency states. The significance of ascorbic acid presence for the immune system is supported by the fact that its concentration in the neutrophil granulocytes is 150 times higher than in the blood serum. The significance of retinol s and carotenoids role is supported in the cases of cell differentiation, where DNA synthesis increase, and proliferation decrease thus stabilizing the organism when under infection. 

Since its discovery in 1909, the elucidation of its structure by Karrer in 1931 [5] and its first total synthesis [6], vitamin A has represented a challenging target molecule for chemists [7], The first industrial synthesis of retinol was performed at Hoffmann-La Roche (H-L R) [8], followed by other approaches of the Baadische Anilin- Soda Fabrik (BASF AG) [9], and Rhone-Poulenc (R-P) (today Aventis) [10]... 

Two patents by Takahashi et al. reported the synthesis of vitamin A via a Cio dihalogeno derivative [34,35]. In one procedure the halogenodiene was prepared by bromination of 3,7-dimethyl-2,5,7-octatrien-1-yl acetate. Addition of the latter and /BuOK in DMF to the Cio sulfone provided the retinol sulfone (34%). Again, double elimination (MeOK), gave vitamin A acetate, Fig. (13). 

A highly stereoselective synthesis of retinol via a Cm + C6 route was depicted by De Lera et al. [52]. A Suzuki reaction of a C14 alkenyliodide with a Cg alkenylboronic acid afforded retinol in 83% yield, with retention of the geometries of the coupling partners. The alkenyliodide was obtained by a zirconium-mediated methylalumination and a subsequent Al/I exchange by slow addition of ICN. Coupling with the C6 boronic acid (12 hrs to reach completion), afforded retinol in 83% yield [53], Fig. (21). 

In a comparable approach, Valla et al. [73] described the synthesis of 9-methylene analogues of retinol, retinal, retinonitrile and retinoic acid, using the p-methylenealdehyde derived from P-ionone. Homer-Emmons condensation with ethyl 4-(diethoxyphosphoryl)-3-methylbut-2-enoate carbanion afforded the ester in 55% yield, as a mixture of 13E/13Z isomers (50/50). This ethyl 9-methylene-retinoate was saponified with ethanolic NaOH to give the corresponding 9-methylene-retinoic acid in 55% yield (13 /13Z 50/50). The retinol analogue was obtained by DIBAL-H reduction of the ethyl ester (75%, 132T/13Z isomers 65/35). 

Altered vitamin A homeostasis, primarily manifested as decreased hepatic storage of vitamin A, is another established effect of PBBs in animals. Vitamin A is essential for normal growth and cell differentiation, particularly differentiation of epithelial cells, and some PBB-induced epithelial lesions resemble those produced by vitamin A deficiency. Because it is the primary storage site for vitamin A, the liver has a major role in retinol metabolism. Esterification of dietary vitamin A, hydrolysis of stored vitamin A, mobilization and release into the blood of vitamin A bound to retinol-binding protein, and much of the synthesis of retinol-binding protein occurs in the liver. 

Dietary vitamin A is stored in the liver and secreted into the bloodstream when needed. The circulating retinol is taken up by target cells and oxidized in part to retinoic acid, which induces the synthesis of proteins through the direct control of gene expression. This type of action—gene activation—establishes vitamin A (in the form of its metabolite, retinoic acid) as a hormone, similar to the steroid hormones and the thyroid hormone. 

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