8 -Apo-P-caroten

For the synthesis of the naturally occurring (6 R)-p,G-carotene (127), (R)-a-ionone [(R)-78] was reacted with vinylmagnesium chloride (80) to give the Cis-alcohol 128 which was converted into the phosphonium salt 129. The subsequent Wittig reaction with 12 -apo-p-caroten-12 -al (130) and NaOMe as base gave 127 in 45% yield referred to (R)-78 (Scheme 29). 

The commercial apo-p-carotenoids ethyl 8 -apo-p-caroten-8 -oate (286) and 8 -apo-p-caroten-8 -al (287) may be prepared from the Cig-aldehyde 53, used in the synthesis of p,p-carotene (2). By reaction of 53 with the Cg-acetal 288 the C25-aldehyde 15,15 -didehydro-12 -apo-p-caroten-12 -al (289) is obtained [115], This compound can be transformed into the Cso-aldehyde 287 by consecutive enol ether condensations first with vinyl ethyl ether (17), to give the C2/-aldehyde 290, and then with prop-1-enyl ether (18), followed by partial hydrogenation and isomerization [116] Scheme 59... 

In another approach to the technical synthesis of the apocarotenoids 286, 287 and 292 [118] the C25-aldehyde 12 -apo-p-caroten-12 -al (293) is the key intermediate. Several ways to synthesize this compound have been developed, applying the Wittig reaction to couple the building blocks. By the reaction of the Cas-aldehyde 293 with the protected Cs-phosphonium salt 294 the Cao-aldehyde is obtained [119,120], and this can be transformed by a base-catalysed aldol condensation with acetone (295) to give the Css-ketone citranaxanthin (292) [121]. Alternatively the C2s-aldehyde 293 can be reacted in a Horner-Emmons reaction with the Cs-phosphonate 296 to give 292 [122] Scheme 61). 

NaOCH3, large excess of the keto compound, CH2CI2, 0°C (2 h) 12 -apo-P-caroten-2-al (507)... 

Many unsymmetrical carotenoids have also been synthesized by forming the double bond between C(ll)/C(12) and that between C(ir)/C(12 ) by successive Wittig reactions of two different phosphonium salts with the Cio-dialdehyde 84. The lower reactivity, in comparison to 34, of the 12-apo-p-caroten-I2-al (507) formed in the first step towards a second Wittig reaction leads to high selectivity of mono-condensation product, if 34 is used in excess in the first Wittig reaction. This has been exploited, for example in the synthesis of fucoxanthin (369) [83] (Scheme 17). 

In the commercial preparation of the apo-(3-carotenoids /, 482, 466, the C25-aldehyde 12 -Apo-P-caroten-12 -al (507) is a central intermediate and can be synthesized by Wittig olefina-tion in three ways as shown in Scheme 19. 

As has been shown in previous Chapters the Wittig and the Horner-Emmons reactions are of utmost importance for the coupling of carotenoid end groups with the polyene chain. In the following example, the synthesis of the naturally occurring C25-apocarotenal 507 (12 -apo-P-caroten-12 -al, (3-apo-12 -carotenal) and also ethyl 8 -apo-P-caroten-8 -oate (1) (P-apo-8-carotenoic acid ethyl ester), which is produced industrially by means of these reactions, is described. 

The importance of the enol ether condensation for the synthesis of polyenes and carotenoids is evident from the variety of reactions shown in Tables 1 (examples 13 to 15 and 19 and Table 2 examples 12 and 21). This reaction has also found use in large-scale production, for example in the technical synthesis of p,p-carotene (3) and 8 -apo-p-caroten-8 -al (482) (see Chapter 3 Part VII). 

The oxidation of P-carotene with potassium permanganate was described in a dichloromethane/ water reaction mixture (Rodriguez and Rodriguez-Amaya 2007). After 12 h, 20% of the carotenoid was still present. The products of the reaction were identified as apocarotenals (apo-8 - to apo-15-carotenal = retinal), semi-P-carotenone, monoepoxides, and hydroxy-p-carotene-5,8-epoxide. 

Figure 10.12 Chemical structures for annatto, p-carotene and p-apo-8 -carotenal.

The Reaction Specificity of Carotene Dioxygenase Whereasthe principal site of carotene dioxygenase attack is the 15,15 -central bond of p-carotene, there is evidence that asymmetric cleavage also occurs, leading to formation of 8 -, 10 -, and 12 -apo-carotenals, as shown in Figure 2.4. These apo-carotenals are metabolized by oxidation to apo-carotenoic acids, which are substrates for /3-oxidation to retinoic acid and a number of other metabolites. 

Fig. 3. Commercially important carotenoids P-carotene (10), canthaxanthin [514-78-3] (11), astaxanthin [472-61-7] (12), p-apo-8 -carotenal [1107-26-2] (13), p-apo-8 -carotenoic acid ethyl ester [1109-11-1] (14), and citranaxanthin [3604-90-8] (15).

Synthesis. The syntheses of 5,15-bis(4-acetamidophenyl)-10,20-bis(4-methylphenyl)porphyrin (28) and 7 -apo-7 -(4-carboxyphenyl)-p-carotene (14) have been reported previously 12, 32). 

Recent work in the area has concentrated on the reactions of carotenoids with peroxyl radicals, generated mainly by the thermal decomposition of azo-initiators that lead to a variety of products. " Most of these products seem to be apocarotenals or apocarotenons of various chain lengths produced by cleavage of a double bond in the polyene chain, such as P-apo-12 -carotenal, P-apo-14 -carotenal, P-apo-lO-carotenal, and P-apo-13-carolenone. Kennedy and Liebler " reported that 5,6-epoxy-p,p-carotene and 15,15 -epoxy-P,P-carotene and several unidentified polar products were formed by the peroxyl radical oxidation of P-carotene by the peroxyl radicals. 

The Wittig reaction is now one of the key processes in polyene chemistry. It has become indispensable for the synthesis of sensitive carotenoids. It was used on an industrial scale for the first time in the BASF processes for vitamin A and p,p-carotene (3) [8-11]. Since then, production processes that use the Wittig reaction as a key step have also been developed for other carotenoids such as 8 -apo-carotenoids, canthaxanthin (380) and astaxanthin (403) [11,12]. 

The alkylation/elimination methodology is also applicable to synthesis of carotenoids. The basic strategies for the apo-8 -p-carotenoids [ 12] and for p,p-carotene (3) [ 13] are depicted in Schemes 10 and 11. Vitamin A acetate (10) was reacted with sodium /7-phenoxybenzene-sulphinate to give the sulphone 31. The reaction of 31 with the bromo compounds 32 and 33, respectively gave the apocarotenoic acid ester 34 and the corresponding aldehyde 482. 

In second alternative excentric cleavage step of asymmetric cleavage, P-carotene (2) was converted to P-apo-lO -carotenal (23) and P-ionone (24) by P,P-carotene 9 ,10 -dioxygenase. These P-apo-carotenalscould be subsequently oxidized to the P-apo-carotenoic acids such as P-apo-10 -carotenoic acid (27) and P-apo-12 -carotenoic acid (28). Finally, these P-apo-carotenoic acids were further shortened to retinoic acid (20) (Figure 5). 

Third, their rat oral administrations of P-apo-12 -carotenal (28) and retinoic acid (20) receptor (RAR) a antagonist Ro 41-5253 (31) (Figure 6) could significantly increase the activity of the intestional P,P-carotene 15,15 -monooxygenase up to 4-55% and +94%, respectively. 

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