Retinol , acetate: synthesis

Total synthesis is applied for carotenoids on a lO t scale per year. One usually starts with the cheapest carbonyl components (formaldehyde, acetone) and carbanions (acetylide, acetoacetate, cyanide, Wittig ylides) available. A typical industrial synthesis of retinol acetate (vitamin A) is outlined in Scheme 5.3,1. 

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). 

Retinoids. A new procedure has been described for the synthesis of vitamin A [retinol (95)] and related compounds via ir-allyl Pd complexes. Thus prenyl acetate (96) with PdCl2 gave the complex (97), the structure of which was... 

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).

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. 

P-Ketobutyraldehyde acetal (140) has also been reported as the C4 component in a synthesis of retinol (1) that was based on the (Cj5 + C4 + Cj) method (Robeson and Lindsay, 1954). Aldol condensation of the C15 aldehyde (4) with (140) gave the Cjg acetal (144) (Shchavlinskii et al., 1982). The remaining... 

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-... 

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). 

Acyl esters of retinol may be prepared conveniently by reacting retinol with the appropriate fatty-acid chlonde (26) or fatty acid anhydride (27). Retinol (1-10 mg, as appropriate) is dissolved in 1 or 2 mL triethylamine. Fatty-acid chloride or fatty acid anhydride (approx 0.5 mL or 0 5 g) is added, and the reaction mixture is allowed to stand m the dark at room temperature. For synthesis of the acetate or propionate esters, the reaction is rapid and exothermic, and should be cooled on ice initially. Progress of the reaction is monitored by TLC (the esters are fluorescent, as is the retinol-starting matenal, the esters migrate more rapidly on silica-gel TLC). Complete synthesis of short-chain esters such as acetate is rapid (usually within 30 min) synthesis of long-chain esters such as palmitate and stearate is quite slow (often not complete after standing overnight). The product may be purified by HPLC or by TLC, as descnbed earlier. 

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