Retinyl acetate synthesis

The conversion of frans-retinyl acetate into retinoic acid in hamster organ culture,262 and of cis- and trans-rzimoxc acid into the 5,6-epoxy- and 4-oxo-derivatives and their glucuronides has been demonstrated.263 264 Strains of Aspergillus niger metabolize ionones and related compounds to oxygenated derivatives, some of which may be useful intermediates for carotenoid synthesis. The asymmetric oxidation of p-ionone to (25, 6/ ,7/ )-2,7-epoxydihydro-a-ionone (218) has been demonstrated.265 (i )-4-Hydroxy-p-ionone (219 X = OH)... 

In 1999, Orsat et al. [107, 108] discussed the lipase-catalyzed synthesis of ( )-retinyl acetate (185), an intermediate used in the synthesis of retinol (vitamin A) (186) (Scheme 6.48). Pumping a solution of the alcohol 187, in vinyl acetate (147) (10% w/v), through a packed bed containing 5.0 g of biocatalyst 188, the authors were... 

Scheme 6.48 Synthetic strategy forthe synthesis of ( )-retinyl acetate (185), an intermediate in the synthesis of retinol (vitamin A) (186).

Retinoids. Several routes have been described for the preparation of retinal and its derivatives. Two papers ° on the use of trimethylsilyl and triphenylsilyl protecting groups describe the preparation of the Ce intermediate -3-methyl-pent-2-en-4-yn-l-ol triphenylsilyl ether (100), and the four- or five-step synthesis of IIZ-retinal from this and the C14 aldehyde (101). A method for base-catalysed trans elimination of PhSOaH from the sulphone (102) affords retinyl acetate (103) in 86% yield. 

Immediately internal to this, the visceral yolk sac endoderm is rich in transcripts of cellular retinol binding protein (CRBP I) (6). The mechanism of transfer involves receptor-mediated uptake of retinol from maternal RBP-retinol by the visceral yolk sac endoderm, where it binds to CRBP I and interacts with the enzymes mediating RA synthesis (7). The assumption that retinol is retained specifically in CRBP I-expressing embryonic tissues has been verified by using 14C-labeled retinyl acetate (delivered intravenously to the pregnant dam) as a source of retinol (8). 

The original work on which subsequent study and synthesis of retinoids are based was carried out by Karrer and Morf (1933) and Heilbron et al, (1932, 1948). In 1931 Karrer et aL were able to determine the structure of retinol (1) using a highly purified vitamin A extract that they had obtained from shark liver oil (von Euler and Karrer, 1931). Using such retinol preparations, the first oily retinol esters [for example retinyl acetate (9)] were prepared (Karrer et al., 1931 Heilbron et al., 1932). 

In 1935 Hamano and Kawakami (1935) characterized retinol (1) as the P-naphthoate and anthraquinone P-carboxylate. Later Baxter and Robeson (1940) were able for the first time to obtain crystalline retinyl palmitate (113) and crystalline retinol (1) from liver oils. Crystalline retinyl acetate (9) and crystalline retinyl succinate were obtained at a later date (Baxter and Robeson, 1942). These very pure compounds made possible the accurate determination of a number of physical data. In 1946 Hanze et al. (1948) synthesized pure retinyl methyl ether (571) from crystalline retinol (1), and the total synthesis of this ether was reported at the same time by Milas et al. (1948). At this time also, syntheses of retinoids were carried out by Isler and associates and led to the first industrial synthesis of retinol derivatives (Isler et al., 1947 Isler, 1950 Heilbron and Weedon, 1958 Isler, 1979). 

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 course of almost 50 years of synthetic retinoid chemistry up to the present time, a large number of processes for the synthesis of retinol (1) and its esters, such as retinyl acetate (9) and retinyl palmitate (113), have been developed. The most important large-scale industrial processes today are based on the work of Isler et al. at Hoffmann-La Roche, and of Pommer et al. at BASF. These two processes probably satisfy a large part of the world demand for retinol (1) (vitamin A), most of which is used for the production of animal feeds. 

A short time after Wittig and Geissler had discovered the olefination of ben-zophenone with methylene triphenylphosphorane, Pommer et al. synthesized retinoic acid (3) and, soon thereafter, retinyl acetate (9), using this new C—C bond-forming synthetic procedure (Pommer, 1960, 1977 Pommer and Thieme, 1983). Thus, they laid the foundations of the BASF industrial synthesis of retinyl acetate (Reif and Grassner, 1973). 

For the synthesis of retinaldehyde (2), a large number of oxidation processes have been worked out that permit (2) to be prepared in a very simple manner from commercially available retinyl acetate (9). Thus, when manganese(lV) oxide precipitated in alkaline medium was used and the reaction was carried out in petroleum ether, retinol (1) was converted to retinaldehyde (2), without unde-... 

When the C14 aldehyde (363) was employed in Isler s industrial synthesis of retinyl acetate, the product obtained was the 9Z compound (366) (Oediger et al., 1966). 

Using the same synthesis sequence, the retinyl acetate derivatives (445) and (446) were obtained, as isomer mixtures, from the C,5 aldehyde (4) and appropriately fluorinated C5 phosphonates. By coupling (440) and (441) to a fluori-nated C5 phosphonate, retinoids containing two fluorine substituents in the olefinic side chain were also obtained. 

A very simple process can be used for the synthesis of the C20 hydrocarbon axerophthene (568) (Newton et aL, 1978). When retinol (1), retinyl methyl ether (571), or retinyl acetate (9) was reacted with triphenylphosphine and an acid, a C20 phosphonium salt [for e.g., the hydrogen sulfate (95) (Nurrenbach and Pommer, 1969 Surmatis etaL, 1969)], was obtained (Pommer, 1960 Schwieter et aL, 1966). Alkaline hydrolysis of this product gave axerophthene (568). 

Retinol-11,12- H2 of low specific activity has been prepared (Isler et al., 1960) based on the work of Isler et al. (1947) on the synthesis of retinyl acetate. The same sequence of reactions as shown in Fig. 8, with several improvements in technique because of the small scale, was applied by Perry et al. (1982) to the preparation of retinoic acid tritiated at very high specific activity. Pure, recrystallized diol (XXVI) was partially hydrogenated with tritium over Lindlar catalyst in the presence of quinoline and the dihydro compound (XXVII), acety-lated in such a way as to afford mainly the monoacetate (XXVIII). Exposure of the acetate at low temperature for a very short time to very dilute hydrogen bromide in methylene chloride gave, after chromatography, pure retinyl-11,12- H2 acetate (XXIXa). Simultaneous hydrolysis and oxidation of the retinyl acetate by silver oxide in aqueous methanolic sodium hydroxide then yielded all-fran -reti-noic-11,12- H2 acid (Vllh). The specific activities obtained ranged from 25 to 40 Ci/mmol. 

An adaptation of the synthesis of retinol, as developed by Isler et aL (1947), has been used for the preparation of retinyl acetate labeled with tritium in positions 11 and 12 and has been mentioned by Mayer and Isler (1971) and Bru-bacher et aL (1962). The preparation was discussed in Section Il,A,l,b,iii because retinyl acetate is an intermediate in the preparation of all-rmn -retin-oic-ll,12- H2 acid labeled at high specific activity (Perry et aL, 1982). 

A method for incorporation of a carbon-14 label in the ring geminal methyl groups of retinyl acetate has been described by Colwell et aL (1979). The synthesis, shown in Fig. 14, involves monomethylation of 2,6-dimethylcyclo-hexanone (LII) with methyl-iodide as catalyzed by potassium hydride. The trimethylcyclohexanone (LIU), labeled in one methyl group, was condensed with the 11-carbon acetylenic side chain (LIV) to give the acetylenic carbinol... 

Fig. 14. Synthesis of ring- C-methyl retinyl acetate (XXIXb).

Possibly in support of the first hypothesis. Rosso et al. (1981) have shown that retinoid-deficient rats accumulate an oligosaccharide-lipid of the composition Man5(GlcNAc)2PPDol (reaction 2, Fig. 1), and that this shortened intermediate is rapidly replaced by the normal intermediate GlCjManglGlcNAcljPPDol upon treatment of the rats with retinyl acetate (reactions 3 and 4, Fig. 1). One interpretation of these data is that MRP might function in the synthesis of the oligosaccharide-lipid intermediate or that either retinoids or MRP, specifically, affect the activity of the MDP-dependent mannosyltransferase. In further support of this mechanism, De Luca et al. (1982) have demonstrated an accumulation of... 

De Luca, L. and Yuspa, S. H. (1974). Altered glycoprotein synthesis in mouse epidermal cells treated with retinyl acetate in vitro. Exp. Cell Res., 86,106... 

Enzymically synthesized retinyl palmitate had a lower peroxide value (POV = 2.5 mEq/ kg under Na gas) than that obtained by the conventional organic synthesis (43 mEq/kg under Na) as is shown in Table 5. In the case of retinyl oleate synthesis from retinyl acetate and oleic acid, a similar difference was observed between enzymic and organic syntheses the POV of retinyl oleate was 9.0 mEq/kg for enzymic synthesis under Na, which was one-twentieth as much as that for organic synthesis (200 mEq/kg under Na). Therefore, the synthesis of biologically interesting substances, such as eicosapentaenoic acid esters [62], will become possible under quite mild conditions by the use of enzymes such as PEG-lipase. 

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