Vitamin A, 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). 

The isophytol side chain can be synthesized from pseudoionone (Fig. 5) using chemistry similar to that used in the vitamin A synthesis (9). Hydrogenation of pseudoionone (20) yields hexahydropseudoionone (21) which can be reacted with a metal acetyUde to give the acetylenic alcohol (22). Rearrangement of the adduct of (22) with isopropenyknethyl ether yields, initially, the aHenic ketone (23) which is further transformed to the C g-ketone (24). After reduction of (24), the saturated ketone (25) is treated with a second mole of metal acetyUde. The acetylenic alcohol (26) formed is then partially hydrogenated to give isophytol (14). 

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. " ... 

Uses. Because of its strong lemon odor, citral is very important for aroma compositions such as citrus flavors. In perfumery it can be used only in neutral media due to its tendency to undergo discoloration, oxidation, and polymerization. It is used as a starting material in the synthesis of ionones and methylionones, particularly /3-ionone, which is an intermediate in vitamin A synthesis. 

Ionone is converted into intermediates for vitamin A synthesis. The hydrogenation of ionones and methylionones is of some importance. Dihydro or tetrahydro derivatives or ionols can be obtained depending on reaction conditions. 

Terpenes important for both fragrances and flavours can be prepared from citral, such as citronellol, linalool, nerolidol, geraniol, farnesol and bisabolol. Citral is also an important starting material for the synthesis of vitamins A and E, carotenoids and other flavour and fragrance compounds like ionones. Most of the /3-ionone synthesised is probably used for vitamin A synthesis. 

A vitamin A synthesis is based on such a method [422], and the process is industrially applied by Rhone Poulenc [424],... 

Sebrell Harris228 has provided a comprehensive review of the starting materials for Vitamin A synthesis,... 

Citranaxanthene 543 is found in citrus fruits and is used as a food dye like P-carotene. The same phosphonium salt synthon 505 as used for the vitamin A synthesis is monoolefinated with the polyene dialdehyde 539. The Wittig reaction of the resulting 540 with phosphorane 541 followed by aldol condensation of the obtained 542 with acetone gives citranaxanthene 54 3 255,263) (Scheme 92). In the preparation of the polyenedial 539 l,4-dibromo-2-butene 544 is reacted with trimethyl... 

The Wittig Reaction in the BASF Vitamin A Synthesis 2.1 Building Block Principle... 

With these reactions, a vitamin A synthesis based on acetylene was developed in the 50s, but this synthesis gained no industrial significance since the individual synthesis steps were not economically practicable. It was not possible to realise the concept aimed at, namely to link a C15 unit with a C5 building block, in the last stage. For this purpose, a reaction was required in which C—C linkage takes place with the formation of an olefmic double bond. The other double bonds are also possible linking points for the synthesis of the vitamin A molecule (2) ... 

The industrial development of the vitamin A synthesis from the C15 and C5 building blocks was characterized by the special features of the Wittig reaction and the sensitivity of the starting materials as well as of the end products to chemical and thermal effects. 

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). 

In their industrial production, the Wittig reaction is again a preferred process step for linking selected building blocks which are identical to those for the vitamin A synthesis or are logically derived from these. The advantages of the building block principle become particularly clear in the carotenoid syntheses 88,9 c,35). 

Carotene is also prepared industrially by a Wittig reaction. A dialdehyde is reacted with two equivalents of the same ylide used in the vitamin A synthesis, as shown in the following equation ... 

The preparation of 3,7-dimethyl-2-fra/ij-4-rranj-6-franj-octatrienoic acid (Scheme 62) is a good example of the introduction of a sulfonyl group from sodium sulfinate, of the coupling reaction of a sulfonyl carbanion and allylic bromide and finally of the elimination of the sulfonyl group in basic medium giving the aW-trans compound. The same method was used for vitamin A synthesis (Scheme 63). 

A modification of vitamin A synthesis was reported recently,using addition of allylic sulfone carbanion to aldehyde followed by a basic double elimination of the resulting -alkoxy sulfone with excellent stereocontrol (Scheme 64). 

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. 

Yet an important application is the analogous isomerization of 1,4-diacetoxy-2-butene (13) to the 1,3-isomer 14 (cis/trans mixture) with a Pt CU catalyst - a key step of the BASF vitamin A synthesis (eq. (15)). The lower-boiling product is enriched to a yield of 95 % and is further hydroformylated to form the vitamin A side chain [25] (see Chapter 1). 

Vitamin A synthesis. The addition of acetylene to methyl vinyl ketone is a key step in Isler s technical synthesis of vitamin A. The resulting carbinol (2) under... 

Use Perfumes, flavoring agent, intermediate for other fragrances, vitamin A synthesis. 

Use Monomerfor vinylresins, component of ionomer resins, intermediate in steroid and vitamin A synthesis, alkylating agent. 

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