Optically Active Carotenoids

Optically active (6 i )-P,7-carotene [ent- 69)], prepared from racemic Y-ionone partly resolved via its menthydrazone, had Cotton effect opposite to that of natural p,y-carotene (69), which therefore has the 6 5-configuration (84). 

Recently total syntheses of the enolized P-diketones trikentriorhodin (39) and the 9-cis isomer of mytiloxanthin (38) with known stereochemistry at all chiral centres have been reported in brief (57). The route utilized the same intermediate methyl ketone used earlier in the total synthesis of capsorubin (66), although it was prepared from (-t- )-camphor by a different approach involving diastereoselective introduction of the chiral centre by hydroboration of an alkene intermediate. Synthetic (38) had chromatographic, IR, NMR and MS properties consistent with published data (5) the CD maxima appear to correspond to those of natural trikentriorhodin subsequently reported (59). However, the Cotton effect is very weak (59, 57). Comparative CD data for synthetic 9-cis (38) and the 9-cis isomer of natural mytiloxanthin were not given. 

Total syntheses of (35,3 5)-astaxanthin (28), (35 ,3 i )-astaxanthin [cn -(28)J and (35,3 5 )-astaxanthin have been accomplished (69,116,131). Also recently synthesized in the Roche laboratories were optically pure (3R,3 R)-zeaxanthin (26) (132), (35,3 5)-zeaxanthin [ent-(26)] and (3R,3 S)-zeaxanthin (50) (131), all-trans (35,3 S)-7,8-didehydroastaxanthin (80) and 3X -trans (35,3 S)-7,8,7, 8 -tetradehydroastaxanthin (34) (23d) as well as both actinioerythrin enantiomers [(70) and e t-(70)] (138). This important achievement has been discussed by Mayer (131). Furthermore, optically pure dW-trans (3R,3 R)-alloxanthin (31) has been obtained by total synthesis (153a). Recently (55,6R)-5,6-epoxy-5,6-dihydro-p,P-caro-tene (71) and (57 ,67 )-5,6-dihydro-P,P-carotene-5,6-diol (29) have been synthesized from azafrin (6) (71). The diol has not yet been encountered in nature, and correlations between the synthetic epoxide and naturally occurring mono- and diepoxides of p,P-carotene (162) remain to be carried out. This is also the case for the corresponding (55,6i )-5,6- 

A route to the key synthon (47 ,67 )-4-hydroxy-2,2,6-trimethylcyclo-hexanone had previously been developed by Leuenberger et al. 124) starting from the readily available isophorone. The chiral centre was introduced by enantioselective reduction with bakers yeast, and regio-selective reduction of one keto group was achieved by chemical reduction with nickel catalyst or by triisobutylaluminium under conditions where the desired trans diastereomer was the major product. 

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Sliwka HR. 1997. Selenium carotenoids 3. First synthesis of optically active carotenoid phosphates. Acta Chemica Scandinavica 51(3) 345-347. 

Sliwka HR and Liaaen-Jensen S. 1993a. Synthetic sulfur carotenoids 2. Optically-active carotenoid thiols. Tetrahedron-Asymmetry 4(3) 361-368. 

Lactone. Various fungi, including Bakers yeast and Geotrichum candi-dum, have been shown to produce optically active lactones, useful chiral synthon, via the stereoselective reduction of suitable unsaturated precursors (42). Figure 15 shows the production scheme for a chiral, substituted diketone, a synthon for optically active carotenoids. 

The acetylenic diol 1 has been used for the preparation of the phosphonium salts 9 (route 7 —and 10 (route 7 7772 70) which have been applied to the synthesis of p,p-carotene (3) [6]. The phosphonium salts 9 and 70 also proved their utility in the syntheses of 7,8-didehydroastaxanthin (402) and 7,8,7 ,8 -tetradehydroastaxanthin (400) [7] and of optically active carotenoids with 3,5,6-trihydroxy-5,6-dihydro-p-end groups [8]. Despite these interesting examples it is noteworthy that, in general, the diphosphonates are much better reagents for double olefination than the corresponding diphosphonium salts [9]. 

By use of the enantiomeric (( )S)- and ((+)-R)-a-ionones ((S)- and (R)-79), the naturally occurring (6 / )-P,e-carotene (7) and its enantiomer have been synthesized. This constituted the first synthesis of an optically active carotenoid [46]. The enantiomers of a-ionone (79) were obtained by resolution of the racemate via the menthylhydrazones [47]. Recently an improved route to the enantiomerically pure a-ionones ((S)- and (R)-79) on a preparative scale has been developed [48]. The procedure, which is based on the separation of diastereoisomers, is described in the Worked Example 7. 

Total syntheses of carotenoids until 1970 were expertly reviewed by Mayer and Isler (133) and up-dated in 1975 by Weedon (176). A complete account of total syntheses of optically active carotenoids is given elsewhere by Mayer (131). 

Mayer, H. Synthesis of optically active carotenoids and related compounds. Pure and Applied Chem. 51, 535 (1979). 

Foss BJ, Sliwka HR, Partali V, Kopsel C, Mayer B, Martin HD, Zsila F, Bikadi Z, and Simonyi M. 2005b. Optically active oligomer units in aggregates of a highly unsaturated, optically inactive carotenoid phospholipid. Chemistry-A European Journal 11(14) 4103—4108. 

Numerous other syntheses of carotenoids making use of the Wittig reaction have yielded p,y-carotene, optically active y,y-carotene 281), (+)-a-carotene 282), and some... 

According to the list of natural carotenoids by O. Straub 38), more than half of the over 400 natural carotenoids described are chiral. The asymmetric optically active terpene phosphonium salts which have recently become known, and which can be employed for the synthesis of chiral carotenoids, are contained in a review article by H. Mayer 47). 

Leuenberger, H. G., Boguth, W., Widmer, E., and Zell, R. 1976. Synthesis of optically active natural carotenoids and structurally related compounds. I. Synthesis of chiral key compound (4A 6A)-4-hydioxy-2,2,6-trimethylcyclohexanone. Helvetica Chimica... 

Stereochemistry.—Carotenoids. The absolute configuration of astaxanthin [3,3 -dihydroxy-/3,/3-carotene-4,4 -dione (33)] has been determined21 as (3S,3 S) by c.d. correlation of the tetrol (34) obtained by LiAlH4 reduction of astaxanthin diester (from lobster) with (37 ,3. R)-zeaxanthin (7). The astaxanthin thus cannot exist in vivo as a bis-dianion, e.g. (35), bound to protein, since chirality could not be introduced by solvent extraction. Actinioerythrin [3,3 -dihydroxy-2,2 -dinor-/3,/3-carotene-4,4 -dione 3,3 -diacylate (36)] is also optically active, with the two end-groups having the same (undetermined) chirality. The (3S,3 S) chirality has also been demonstrated for astaxanthin from the spider mite Schizonobia sycophanta.22... 

The synthesis of optically active carotenoidshas been extended to include the preparation of important possible carotenoid metabolites such as (4-)-abscisic acid (126), (-)-xanthoxin (127), (-)-loliolide (128), (-)-actinidiolide (130), and (-)-dihydroactinidiolide (129), all from one starting compound... 

Two key chiral building blocks used in the total synthesis of a-tocopherol were prepared via microbial reduction of unsaturated carbonyl compounds with baker s yeast and with Geotrichum candidum Similarly, a key intermediate in the total synthesis of optically active natural carotenoids was prepared by microbial reduction of oxoisophorone with baker s yeast. An alternative approach to the synthesis of a-tocopherol employs a chiral building block that was obtained by baker s yeast reduction of 2-methyl-5-phenylpentadienal. ... 

Unsymmetrical compounds can also be prepared via mixed Kolbe electrolyses of different carboxylates (heterocoupling). The disadvantagous but unavoidable formation of symmetrical dimers can be suppressed to the formation of essentially one by-product if the cheapter carboxylic acid is used in a 5- to 10-fold excess. Hydrogenated carotenoids, saturated and unsaturated fatty acids, optically active )-hydroxycarboxylic acids, and intermediates for the preparation of muscone and humulene have been obtained in this way [177b]. 

The aim of the present chapter is to discuss in some detail the mechanisms giving rise to optical activity in these molecules and to examine the main rules formulated for correlating structure and CD, critically analysing their use and limitations with suitable examples. Further information can be found in the original literature and in two recent review articles, by Gawronski and Walborsky and by Buchecker and Noack, covering the diene and polyene (limited to carotenoids) fields, respectively. 

A technical synthesis of (4i ,6/ )-4-hydroxy-2,2,6-trimethylcyclohexanone (85) starting from the readily available oxo-isophorone (86) has been described. (85) is an ideal precursor for the synthesis of optically active hydroxylated carotenoids (e.g. zeaxanthin). Chirality was introduced at C-6 (C-3, carotene numbering) by a stereoselective reduction of the double bond by baker s yeast." ... 

Mayer, H., and Rlittimann, A.. Synthesis of optically active, natural carotenoids and structurally related compounds. Part 4. Synthesis of (3E,37f,6 /f)-lutein, Helv. Chim. Acta, 63, 1451, 1980. 

Gerspacher. M., and Pfander. H.. C45 And Cjp-carotenoids. Synthesis of an optically active cyclic Cjq-building block and of decaprenoxanthine [(2E,6/f,2 /f,6 /f)-2,2 -frZ5(4-hydroxy-3-methylbut-2-enyl)-e.e-carotene], Helv. Chim. Acta, 72, 151, 1989. 

Zeaxanthin, which occurs in com and many other plants, is an Important carotenoid. Its synthesis in optically active form can be achieved on the basis of the three approaches depicted. 

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