Synthesis of retinoic acid

Scheme 2.2-15. Synthesis of retinoic acid receptor agonists.

Alkylation of phenyl sulfones.1 A convergent synthesis in which two synthons become attached through a double bond depends on the a-alkylation of the anion of a phenyl sulfone followed by a / -elimination. The synthesis of retinoic acid (4) is typical of the process. Potassium r-butoxide is used as base the recommended solvent is THF/NMP = 50 10. 

The alkylation of sulfur-stabilized anions has been the subject of an excellent recent review633. Anions adjacent to a wide range of sulfur functionalities may be alkylated readily, the most common being sulfoxide and sulfone a-anions. In the synthesis of retinoic acid derivatives and vitamin A634-636, a-sulfonyl anions have been alkylated with an co-acetoxy-containing allyl halide in good yield (equation 96). 

The enzymes are widely distributed in microorganisms, plants, and animals. " Three Mo-MPT enzymes have been found in mammals (1) xanthine dehydrogenase see Dehydrogenase) has many, varied roles in purine catabolism, drug metabolism, and oxidative stress response, (2) aldehyde oxidase is important in drug metabolism and the synthesis of retinoic acid from retinal, and (3) sulfite oxidase plays a cmcial role in the detoxification of sulfite produced in the degradation of cysteine and methionine. Genetic Mo-MPT deficiency in... 

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]. 

Posch, K C., Ennght, W. E, and Napoli, J. L (1989) The synthesis of retinoic acid from retinol by cytosol from alcohol dehydrogenase negative deermice Arch Biochem Biophys. 274, 171-178. 

Hyaluronan hinders the onset of differentiation, as discussed earlier. Retinoic acid retards the differentiation of epidermal keratinocytes, as shown in skin organ cultures, a result of the ability of retinoic acid to stimulate HA deposition.263-265 Retinoic acid leads to the accumulation of HA in the superficial layers of the epidermis by stimulating HA synthesis specifically in keratinocytes. Some of this accumulation occurs as expanded intercellular HA, which may account for the weakened cohesion of keratinocytes observed both in vivo and in vitro. 

Tammi, R. and Tammi, M., Influence of retinoic acid on the ultrastructure and hyaluronic acid synthesis of adult human epidermis in whole skin organ culture, J. Cell. Physiol., 126, 389, 1986. 

Intracellular concentrations of retinoic acid are controlled not only by the rate of synthesis, hut also hy catabolism. At least in culture, prior exposure of cells to retinoic acid induces the enzymes of retinoic acid catahoUsm (Chytil, 1984 Napoli and Race, 1987). The major metabolite of retinoic acid is the glucuronide (Section 2.2.1.3). 

With hydroxylamine, al -trans, ll-c/5-, and 13-cw-retinal gave a mixture of the syn- and anti-oximes, whereas 11,13-di-cw-retinal gave only the syn-oxime/ The synthesis of the dansyl-lysyl-lysine-N-retinylidene Schiff base has been described/ The products of a colour reaction of retinoic acid (121) in 74% H2SO4 have been identified as (122) and (123)/ The oxidation and isomerization of retinoic acid by I2 and light have been used to prepare the a -trans- and 13-CI5-isomers of 4-oxoretinoic acid (124) which were separated by h.p.l.c/ The photoisomerization of the retinoid (125) has been studied. The many isomers produced were separated by h.p.l.c. and characterized by H and n.m.r. ... 

Introduction.—This Report covers the literature published up to approximately the end of September, 1981. Few new carotenoid structures have been reported. The main advances in carotenoid chemistry have been in the stereospecific synthesis of carotenoids with chiral end-groups. Current interest in the possible use of retinoids in cancer chemotherapy has prompted the preparation of a considerable number of retinoic acid analogues. There has been no major new development in the use of physical methods but h.p.l.c. becomes more and more the method of choice for carotenoid separation, purification, and assay, and the increasing number of papers on resonance Raman spectroscopy emphasizes the potential value of this technique in the carotenoid field. 

Wilson EL and Reich E (1978). Plasminogen activator in chick fibroblasts induction of synthesis by retinoic acid synergism with viral transformation and phorbol ester. Cell, 15, 385-392. 

McCaffery, P., Drager, U.C. 1994. Hot spots of retinoic acid synthesis in the developing spinal cord. Proc. Natl. Acad. Sci. USA 91, 7194-7197. 

Scheme (7). Synthesis of the ester of retinoic acid and active forms of vitamin D3. 

The Julia olefination found its first industrial application for the produdion of retinoic acid. [74, 75] The original design ofthe synthesis, however, concealed a difficulty The allyl anion, substituted on both sides with electron-accepting substituents, does not react regioselectively. 

Pautus S, Aboraia AS, Bassett CE, Brancale A, Coogan MP, Simons C (2009) Design and synthesis of substituted imidazole and triazole N-phenylbenzo[t/]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26. J Enzyme In-hib Med Chem 24 487 98... 

Additionally, the synthesis of fluorinated analogues of retinoic acid featured the conversion of 55 to 56 under standard conditions, as a key step in the work of Pawson and coworkers. 

F. A., A. Molotkov, D. M. Benbrook, and G. Duester. 2003. Retinoid Activation of Retinoic Acid Receptor but Not Retinoid X Receptor Is Sufficient to Rescue Lethal Defect in Retinoic Acid Synthesis. P Natl Acad Sci USA 100, no 12 7135-40. 

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