Retinoic acid esters

Boronate esters have been used for the preparation of polyunsaturated systems such as retinoic acid esters. 

Wittig olefination was discovered in 1953 during studies on the reactions of pentaphenyl-phosphorane, and was described in the following year as a widely suitable method for olefin synthesis [33]. As early as 1956 a patent application appeared [34], in which the synthesis of retinoic acid esters from p-ionylideneacetaldehyde and (3-alkoxycarbonyl-2-methyl)allyl-triphenylphosphonium bromide was claimed, evidence of the fact that the inventors had rapidly realized the economic potential and industrial practicability of this novel reaction [35,36]. 

Already in 1956, the first patent was published, in which the retinoic acid ester synthesis by a Wittig reaction was claimed. [52-54] Special about Wittig s discovery was, that this unanticipated reaction enabled for the first time the generation of carbon-carbon double bonds under very mild conditions. Moreover, the method was widely applicable. Wittig recognised both of these advantages very quickly. Nevertheless, it was not simple to answer the question, whether this new synthesis method could prove utility on an industrial scale. 

Chien and Amin (1980) condensed the tritiated aldehyde (Ib) with ethyl sene-cioate (XXIII) in the presence of potassium amide in ether and obtained a mixture of isomeric retinoic acid esters. After hydrolysis, the pure M-trans-retinoic-11- H acid could be isolated by crystallization. 

Labeling with tritium in position 15 could easily be accomplished by reduction of retinaldehyde with sodium borotritide (Mayer and Isler, 1971) or of retinoic acid esters with lithium aluminum tritide, and, again, oxidation of the tritiated retinol (Kaegi et aL, 1982c) to retinaldehyde-15- H. Because of the favorable isotope effect, most of the isotope should stay attached to the aldehyde group. However, Futterman et aL (1979) found that all-frany-retinaldehyde-15- H is inadequate as a tracer for 11-c/y-retinaldehyde formation in a biological system. 

Gander RJ, Gurney JA (1978) A -trans retinoic acid esters and amides. U.S. patent 4,108,880, August 22, 1978. ChemAbstrSS 89892... 

Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretlnide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with g-aminophe-nol to give ester 54 (13). 

There have been many reports on the use of this method for the syntheses of vitamin A, methyl retinoic acid methyl ester, related derivatives, and polyenes300-310. 

In intestinal cells, carotenoids can be incorporated into CMs as intact molecules or metabolized into mainly retinol (or vitamin A), but also in retinoic acid and apoc-arotenals (see below for carotenoid cleavage reactions). These polar metabolites are directly secreted into the blood stream via the portal vein (Figure 3.2.2). Within intestinal cells, retinol can be also esterified into retinyl esters. 

Base-induced elimination of sulphinate from homoallylic sulphones , from y-ketosulphones , and from 1,2-bissulphones has been used in synthetic sequences ranging from the preparation of retinoic acid and of its methyl ester , to a novel pentannulation sequence that leads to a range of cross-conjugated dienes , as exemplified by equation (69). The overall yield for the two steps was 63%. 

Baillet, A., Corbeau, L., Rafidson, R, and Ferrier, D., Separation of isomeric compounds by reversed-phase high-performance liquid chromatography using Ag+ complexation. Application to cis-trans fatty acid methyl esters and retinoic acid photoisomers, /. Chromatogr., 634, 251, 1993. 

Histochemical studies of bone marrow samples show that peroxidase-containing granules are detectable in promyelocytes. The human promyelo-cytic leukaemia cell line HL-60 grows easily in culture, and the cells resemble promyelocytes both structurally and functionally. Furthermore, they can be induced to differentiate in vitro upon addition of various agents, such as retinoic acid and phorbol esters, and these differentiated cells resemble more mature forms of neutrophils. HL-60 cells possess almost the same amount of myeloperoxidase (4.4 fig per 106 cells) as mature neutrophils, and the enzyme purified from these cells has the same subunit structure. The cells thus actively synthesise the enzyme only until they are induced to differentiate. This cell line has been extensively used to study the molecular events controlling the expression of enzymes such as myeloperoxidase, and also to investigate the molecular controls that lead to a cessation of their expression. 

Aryl esters of retinoids have also received some interest. The 4-(acet-amido)phenyl ester of (all- )-retinoic acid, for example, showed topical activity in various animal models but was ineffective for the local treatment of acne in patients [86]. This difference is probably due to the prodrug being readily hydrolyzed in mice skin homogenates but not in human skin preparations. 

Watson DG, Wainer BH, Lenox RH Phorbol ester- and retinoic acid-induced regulation of the PKC substrate MARCKS in immortalized hippocampal cells. J Neurochem 63 1666-1674, 1994... 

The past twenty years have witnessed considerable progress in the synthesis and use of other retinoid-like molecules related to vitamin A. The aromatic retinoid etretin (8.54) and its ester etretinate (8.55) had some effectiveness in the treatment of psoriasis, a disorder of skin. 13-cA-Retinoic acid (isotretinoin) produces sebaceous gland atrophy and could prove useful in the treatment of severe acne vulgaris. Although these compounds have toxic side effects and are not in regular use, they have opened up new therapeutic possibilities. Retinoic acid (tretinoin, 8.56) has been employed in the treatment of acne. 

Retinyl esters and the P-carotene are incorporated into chylomicrons and taken up mainly by hepatocytes. In the liver retinol may be stored in stellate cells as retinyl esters, oxidized to retinoic acid or liberated into cells bound to retinol-binding proteins (RBP). All E retinoic acid and its 9Z isomer have an affinity for nuclear receptors. They activate the transcription and bind as dimers to specific nucleotide sequences, present in promoters of target genes. 

These compounds were converted to the corresponding all E and 9Z-retinoic acids via P-ionylideneacetaldehydes. Thus, the reaction with the lithium salt of (Et0)2P(0)CH2C(Me)=CHC00Et in THF made possible the C20 ester-complex. The complex was removed by CuCh in EtOH (98%) and saponification of the ethyl retinoate, the retinoic acids could be obtained all E 89%, 13Z 8% and 9Z 59%, 9Z,13Z 12%, respectively). 

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). 

Retinol A. can be enzymically formed from retinoic acid. B. is transported from the intestine to the liver in chylomicrons. C. is the light-absorbing portion of rhodopsin. D. is phosphorylated and dephosphorylated during the visual cycle. E. mediates most of the actions of the retinoids. Correct answer = B. Retinyf esters are incorporated into chylomicrons. Retinoic acid cannot be reduced to retinol. Retinal, the aldehyde form of retinol, is the chromophore for rhodopsin. Retinal is photoisomerized during the visual cycle. Retinoic acid, not retinol, is the most important retinoid. 

VITAMIN A. This substance also has been referred to as retinol, axerophthol, biosterol, vitamin Ai, anti-xerophthalmic vitamin, and anti-infective vitamin. The physiological forms of the vitamin include Retinol (vitamin A ) and esters 3-dehydroretinol (vitamin A2) and esters 3-dehydroretinal (retinme-2) retinoic acid neovitamin A neo-b-vitamin Ai. The vitamin is required by numerous animal species. All vertebrates and some invertebrates convert plant dietary carotenoids in gut to vitamin Ai. which is absorbed. Most animal species store appreciable amounts... 

The major dietary sources for preformed vitamin A are vertebrate animal products that are rich in vitamin A esters (liver, kidney, oil, dairy products, and eggs). Liver and oil, particularly from fish, are the major dietary sources of preformed vitamin A. Levels in milk and eggs depend on dietary retinoid and carotenoid intake. Freshwater fish are a source of vitamin A2 (3,4-dehydroretinol), which shows reduced vitamin A activity. Levels of retinal in food are very low, whereas retinoic acid has not been found. 

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