Vitamin Acetate synthesis

Rearrangement of dehydrolinalool (4) using vanadate catalysts produces citral (5), an intermediate for Vitamin A synthesis as well as an important flavor and fragrance material (37). Isomerization of the dehydrolinalyl acetate (6) in the presence of copper salts in acetic acid followed by saponification of the acetate also gives citral (38,39). Further improvement in the catalyst system has greatly improved the yield to 85—90% (40,41). 

Conditions have been optimized for catalytic hydrogenation of the acetylene group of the vitamin A synthesis intermediate (110). Several chemical reactions of geometrical isomers of the product (111) and its acetate and of (110) have been described. " ... 

Formylcrotyl alcohol is employed in the form of its acetate (8 b) (C5 acetate) in the industrial vitamin A synthesis. Two routes have essentially proved suitable for its preparation. One uses methylglyoxalacetal (21) as the starting material and thus again realises the C3 + C2 principle, whilst the other uses the C4 building block butenediol diacetate (28). 

Numerous monographs [4] and reviews [5] on the famous Wittig reaction have been written since its discovery in 1953. The BASF vitamin-A synthesis depends in the final step on a Wittig coupling between vinyl-)ff-ionol (C15) and y-formyl-crotyl acetate (C5). This application was developed by Pommer et al. [6] of BASF in the 1960s. 

Sometimes reaction rates can be enhanced by using multifunctional reactors, i.e., reactors in which more than one function (or operation) can be performed. Examples of reactors with such multifunctional capability, or combo reactors, are distillation column reactors in which one of the products of a reversible reaction is continuously removed by distillation thus driving the reaction forward extractive reaction biphasing membrane reactors in which separation is accomplished by using a reactor with membrane walls and simulated moving-bed (SMB) reactors in which reaction is combined with adsorption. Typical industrial applications of multifunctional reactors are esterification of acetic acid to methyl acetate in a distillation column reactor, synthesis of methyl-fer-butyl ether (MTBE) in a similar reactor, vitamin K synthesis in a membrane reactor, oxidative coupling of methane to produce ethane and ethylene in a similar reactor, and esterification of acetic acid to ethyl acetate in an SMB reactor. These specialized reactors are increasingly used in industry, mainly because of the obvious reduction in the number of equipment. These reactors are considered by Eair in Chapter 12. 

In Chapter 27 we analysed the synthesis of bicyclic lactone (6). In his vitamine B12 synthesis Eschenmoser needed to lengthen the acetic acid side chain of (6) into the propionic side chain of (7). This he accomplished by the Arndt-Eistert procedure. 

The first industrial synthesis of ) -carotene by Hoffmann-La Roche followed the Ci9 + C2 + Ci9 principle. With the Ci4-aldehyde from the Vitamin A synthesis as the starting point, the sequence of acetal formation, Lewis acid-catalysed insertion of an enol ether, hydrolysis and elimination of ethanol, produces initially a Cjg-aldehyde. Repetition of this sequence with ethyl 1-propenyl ether gives the Cjg-aldehyde. 

In the 1980s, the Japanese firm Kuraray developed a stereoselective Vitamin A synthesis, which follows the Cm + Cm concept. The synthetic building blocks are cyclogeranyl phenyl sulfone and a Cm-aldehyde, which is obtainable by allylic oxidation of geranyl acetate with t-butyl hydroperoxide. [81] The alcohol function is protected as the THP-ether, and the sulfmic acid and hydroxytetrahydro-pyran are eliminated with potassium fbutoxide in petroleum ether. By means of this double elimination, the reduction step is avoided. 

When pseudoionone is treated with BF3 in acetic acid, ring closure takes place and a- and j8-ionone are produced. This is the next step in the vitamin A synthesis. 

The general biochemistry of vitamin E has been extensively reviewed (Azzi and Stocker, 2000 Brigelius Flohe and Traber, 1999 Stone and Papas, 1997). This review will primarily focus on the biochemical and health aspects of vitamin E in food. It is important, however, to contrast the chemical forms of vitamin E found in plants with that found in mammals and in dietary supplements. Vitamin E is often equated with a-tocopherol, which is the primary lipid-soluble antioxidant in human plasma, and the most potent form in protecting the fetuses of pregnant female rats from death and resorption. We will explore the hypothesis that vitamin E supplements containing a chemical distribution of tocopherols and tocotrienols similar to that found in plant oils may be superior to supplements containing only a-tocopherol or a-tocopheryl acetate. Finally, this review will summarize the very recent application of nutritional genomics to vitamin E synthesis in plants. 

Figure 3.5 Schematic representation of modular microreactor setup employed for the vitamin A acetate synthesis (1 pressure probe 2 micromixer 3 microheat exchanger 4 capillary reactor with electrical heating 5 thermal liquid inlet for heat exchanger).

Figure 3.6 Exemplary results of the study of the vitamin A acetate synthesis with an MMRS. (a) HPLC conversion and yield versus temperature 7i = T2. (b) HPLC conversion and...

X5lenol is an important starting material for insecticides, xylenol—formaldehyde resins, disinfectants, wood preservatives, and for synthesis of a-tocopherol (vitamin E) (258) and i7/-a-tocopherol acetate (USP 34-50/kg, October 1994). The Bayer insecticide Methiocarb is manufactured by reaction of 3,5-x5lenol with methylsulfenyl chloride to yield 4-methylmercapto-3,5-xylenol, followed by reaction with methyl isocyanate (257). Disinfectants and preservatives are produced by chlorination to 4-chloro- and 2,4-dich1oro-3,5-dimethylpheno1 (251). 

Hoffmaim-La Roche has produced -carotene since the 1950s and has rehed on core knowledge of vitamin A chemistry for the synthesis of this target. In this approach, a five-carbon homologation of vitamin A aldehyde (19) is accompHshed by successive acetalizations and enol ether condensations to prepare the aldehyde (46). Metal acetyUde coupling with two molecules of aldehyde (46) completes constmction of the C q carbon framework. Selective reduction of the internal triple bond of (47) is followed by dehydration and thermal isomerization to yield -carotene (21) (Fig. 10). 

Dye-Sensitized Photoisomerization. One technological appHcation of photoisomerization is in the synthesis of vitamin A. In a mixture of vitamin A acetate (all-trans stmcture) and the 11-cis isomer (23), sensitized photoisomerization of the 11-cis to the all-trans molecule occurs using zinc tetraphenylporphyrin, chlorophyU, hematoporphyrin, rose bengal, or erythrosin as sensitizers (73). Another photoisomerization is reported to be responsible for dye laser mode-locking (74). In this example, one metastable isomer of an oxadicarbocyanine dye was formed during flashlamp excitation, and it was the isomer that exhibited mode-locking characteristics. 

Schemes 15 and 16 summarize the syntheses of intermediates that represent rings A and D of vitamin Bi2 by the Eschenmoser group. Treatment of lactam/lactone 51, the precursor to B-ring intermediate 8 (whose synthesis has already been described, see Scheme 8), with potassium cyanide in methanol induces cleavage of the y-lac-tone ring and furnishes intermediate 76 after esterification of the newly formed acetic acid chain with diazomethane. Intermediate 76 is produced as a mixture of diastereomers, epimeric at the newly formed stereocenter, in a yield exceeding 95%. Selective conversion of the lactam carbonyl in 76 into the corresponding thiolactam...

Trost and coworkers have devised a stereocontrolled 1,3-diene synthesis employing a palladium-catalysed decarboxylative elimination procedure from allylic acetates carrying carboxylic acid functionality ji- to the acetate group (equation 18)48. This decarboxylative elimination strategy has been applied to the synthesis of an insect pheromone, codlemone48a and the ethyl ester of vitamin A carboxylic acid (Table 5)48b. 

In the case of the synthesis of 10,19,19,19-2H4-vitamin A, the most useful for biological studies, three deuterium atoms were incorporated into /i-ionone 30, in >98% by deuterium exchange with excess D2O in the presence of Na02H (and pyridine). The tri-deuteriated 30, utilized in Wittig-Horner reaction with dideuterio triethyl phosphonate, provided tetradeuteriated ethyl /J-ionilidene acetate 31 with more than 98% 2H4 (by NMR). No deuterium loss in the subsequent synthetic steps was observed as evidenced by MS and NMR analysis. 

Reductive elimination of an allylic diol group. A new synthesis of vitamin A involves reduction of the allylic diol 1, prepared in several steps from JJ-ionone, with a low valent titanium formed from TiCl3 and LiAlH, in the ratio 2 1. Thus, the allylic diol group of 1 [either (E) or (Z)] is reduced to an (E,E)-1,3-diene group to form the silyl ether (2) of vitamin A.1 When the primary hydroxyl group is protected as an acetate, the reduction gives a mixture of (E)- and (Z)-2. 

The Wittig process for the synthesis of vitamin A acetate is carried out on the industrial scale and produces a mixture of the all-trans and 11-cis isomers. Only the all-trans form is suitable for pharmaceutical or... 

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