Astaxanthin synthesis

KAJIWARA S, KAKIZONO T, SAITO T, KONDO K, OHTANI T, NISHIO N, NAGAI S and MISAWA N (1995) Isolation and functional identification of a novel cDNA for astaxanthin biosynthesis from Haematococcus pluvialis, and astaxanthin synthesis in Escherichia coli . Plant Mol Biol, 29, 343-52. 

Zeaxanthin, lutein short-chain diesters and intermediates for canthaxanthin and astaxanthin synthesis... 

Harker M, Young AJ. 1995. Inhibition of astaxanthin synthesis in the gieen-alga floematococcus pluvialis. European Journal of Phycology 30 179-187. 

Arrhenius, Svante, 86,353 Arsenic, 573-574 Asparagine, 622t Aspartic acid, 622t Aspirin. See Acetylsalicylic acid Astaxanthin, 157 Asymmetric synthesis, 601 Atherosclerosis, 604... 

Frey DA, Kataisto EW, Ekmanis JL, O Malley S, and Lockwood SF. 2004. The efficient synthesis of disodium disuccinate astaxanthin (Cardax). Organic Process Research Development 8(5) 796-801. 

Jackson HL, Cardounel AJ, Zweier JL, and Lockwood SF. 2004. Synthesis, characterization, and direct aqueous superoxide anion scavenging of a highly water-dispersible astaxanthin-amino acid conjugate. Bioorganic Medicinal Chemistry Letters 14(15) 3985-3991. 

For racemic (3RS,3 RS)-astaxanthine (58), an industrially practicable synthesis was developed which uses oxo-isophorone (55) as the starting compound, and yields... 

Schoefs, B., Rmiki, N., Rachidi, J., and Lemoine, Y. 2001. The accumulation of astaxanthin in Haematococcus plmialis cultivated in light-light stress condition requires a cytochrome P450-dependent enzyme and an active synthesis of fatty acids. FEBS Lett. 500, 125-128. 

A maximum cellular content of carotenoids could be estimated since there was a quantitative relationship between total carotenoid content and average fluorescence intensity of a culture. A maximum yield of between 14,600 and 19,(XX) jig g was obtained. However, there was considerable heterogenity in autofluorescence among individual cells which suggests that the yield could be improved. Maximum synthesis could also be improved by directed transport, esterification of astaxanthin, or excretion as described below. 

Methylcholanthrene-induced (Meth-A) mouse tumor cells grown in an astaxanthin-supplemented medium had reduced cell numbers and lower DNA synthesis rates 1 to 2 days postincubation than control cultures. Similarly, astaxanthin inhibited murine... 

The pioneering synthetic work quickly led to the synthesis of carotenoids on an industrial scale. The industrial production of p,p-carotene (3) began in 1954, only four years after its first synthesis on a laboratory scale. This extremely rapid development was made possible by the enthusiasm and perseverance of Isler and his colleagues at Roche in Basel. Since then, commercial synthesis of carotenoids has continuously advanced and today the two major industrial producers Roche and BASF produce six different carotenoids, namely p,p-carotene (3), canthaxanthin (380), optically inactive astaxanthin (403) and the apocarotenoids 8 -apo-p-caroten-8 -al (482), 8-apo-p-caroten-8 -oic acid (486) ethyl ester, and citranaxanthin (466). The total annual sale is now in the region of US 300 million, and the commercially produced carotenoids are used mainly as food and feed additives. 

The middle part is always a conjugated polyene (symmetrical or unsymmetrical) and can be prepared by a number of established methods which are discussed in detail in Chapter 3 Part I. Some of these middle parts are readily available more common ones, e.g. the Cio-dialdehyde, are manufactured on a ton scale as industrial intermediates for the technical syntheses of (3,(3-carotene (3) and astaxanthin (406). For the synthesis of unsymmetrical carotenoids, the Cio-dialdehyde can be converted into a monoacetal derivative. The free aldehyde moiety is coupled with one end group, and the intermediate product is deprotected and then combined with the second end group. In these reactions, there are some positions which permit a coupling in high yield [C(9)-C(10) and C(11)-C(12)] and others [C(7)-C(8)] which, for cyclic carotenoids, give products in only low yield because of steric hindrance due to the adjacent methyl groups. The choice of the middle part and its synthesis has become a simple matter today. 

The C 10-dialdehyde is chosen as the middle part because its synthesis has already been evaluated extensively (see Chapter 3 Part I) and the compound is available on an industrial scale. The corresponding C 15-end groups have been synthesized in high yield from the C9-cyclic compound and the acetylenic C6-buiIding block. These procedures were developed in the early 1960s and became the basis of the present day industrial syntheses of such carotenoids as astaxanthin (403) (Scheme 2) and zeaxanthin (119) [1,2]. 

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 use of 1,2-epoxybutane in these reactions is superior in some respects to the use of alkali metal alcoholates as bases. Thus, for example, in the synthesis of the a-hydroxyketone (3i 5,3 / 5)-astaxanthin [(3RS,yRS)-403] from the Cis-phosphonium salt 3RS)-49 the yields achieved, after thermal isomerization and recrystallization, were 77% with NaOMe as proton acceptor and 83% in boiling 1,2-epoxybutane, based on the dialdehyde 34 used [69] (Scheme 12). 

The first synthesis of (35,3 5)-astaxanthin (406) starting from the C9-hydroxyketone 63 was reported by Roche [37], Later, the synthesis of 406 starting from p-ionone (1) [38] and the separation of the mixture of the three diastereoisomers via the corresponding diastereoisomeric di-(-)-camphanates have been described. 

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