Process for obtaining 3′-epilutein

Details Process for obtaining 3′-epilutein Process for obtaining 3′-epilutein

2000-10-10

2002-07-16

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

Reexamination Certificate

active

06420614

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention refers to a process for obtaining epilutein and, more specifically to a process for obtaining 3′-epilutein from lutein-containing extracts, and to a process for the production of optically active zeaxanthin from said 3′-epilutein.
2. Description of the Related Art
More than 50 years have elapsed since Karrer & Jucker published an article in
Helv. Chim. Acta
30, 266 (1949) with respect to the first isomerization of an epsilon-endgroup in a carotenoid molecule into one with a beta-endgroup with the aid of a strong alkali. This includes an extension of the length of the polyene-chain from originally 10 to 11 conjugated double bonds, as illustrated in
FIG. 1
of the enclosed drawings.
However, only a few of the scientific laboratories in the world realized the importance of this invention, and so, the reaction generally fell into oblivion, and was regarded merely as a curiosity. In recent times the situation has changed drastically, mainly because of the following reasons:
1. The recognition of the general importance of the carotenoids as colorants for animal tissues either by ingestion from natural sources or from food additives [J. C. Bauernfeind, G. B. Brubacher, H. M. Kläui, W. L. Marusich, “
Use of Carotenoids
”, in “
Carotenoids
”(Ed. O. Isler, H. Gutmann, U. Solms), Birkhäuser, Basel, 1971, Pag. 743,ff; J. C. Bauernfeind (ed), “
Carotenoids as Colorants and Vitamin A Precursors
”, Academic Press, N.Y. 1981; K. Schiedt, “
Absorption and Metabolism in Birds, Fish and Crustaceans
”, in “
Carotenoids
”, Ed. G. Britton, S. Liaaen-Jensen, H. Pfander, Vol. 3:
Biosynthesis and Metabolism
” Birkhäuser, Basel, 1998, pag. 285, ff].
2. Significant progress in the experimental and practical handling of the epsilon-beta-arrangement (U.S. Pat. No. 5,523,494 issued Jun. 4, 1996 to Torres-Cardona et al., see also chronological survey of relevant references in this reference).
The situation today shows a fairly good and industrially useful conversion of lutein (I) (see
FIG. 1
) into a stereoisomer of zeaxanthin which itself proves to be a better colorant than lutein (I), e.g. for broilers and shrimps. This is very important because lutein is found in abundant quantities in yellow flowers and in all green leaves.
However, a main disadvantage of this rearrangement exists in the stereochemical situation: lutein from plant sources always has the (3R,3′R.6′R)-chirality [R. Buchecker, C. H. Eugster,
Chimia
, 25, 192 (1971)] as shown in formula I at FIG.
1
. Therefore, zeaxanthin prepared from lutein necessarily has the (3R,3′S)-chirality as depicted in II (see
FIG. 2
) and, consequently, is the meso-form [R. Buchecker, P. Hamm, C. H. Eugster,
Chimia
, 26, 134 (1972); A. G. Andrewes, G. Borch, S. Liaaen-Jensen,
Acta Chem. Scand
. B28,139 (1974)]. A trifling quantity of (3R,3′R)-zeaxanthin found in zeaxanthin prepared from lutein is derived from optically active zeaxanthin which naturally accompanies lutein in Tagetes, [U.S. Pat. No. 5,780,693 issued Jul. 14, 1998 to Bernhard K. et al.] and is not a product of an epimerization.
The main disadvantage of meso-zeaxanthin is caused by its lower potency in pigmenting of egg yolk, as shown by the following references: K. Schiedt, “
Absorption and Metabolism in Birds, Fish and Crustaceans
”, in
Carotenoids
”, (Ed. G. Britton, S. Liaaen-Jensen, H. Pfander), Vol. 3
: Biosynthesis and Metabolism
”, Birkhäuser, Basel, 1998, pag. 285 ff., and H. Hencken,
Poultry Science
, 71, 711-717, (1992):
(3R, 3′R)-zeaxanthin (III)
100% 
(3RS, 3′SR)-zeaxanthin (racemic)
92%
(3S, 3′S)-zeaxanthin (enantiomer)
86%
(3R, 3′S)-zeaxanthin (meso, II)
37%
On the other hand, Garnett et al, U.S. Pat. No. 5,747,544 issued May 5, 1998, discloses the convenience of obtaining (3R-3′R) stereoisomers of zeaxanthin, for treating or preventing retinal degeneration in humans, by administering a drug formulation containing said (3R-3′R) stereoisomers of zeaxanthin in a carrier substance.
From these results, there followed the necessity of developing a procedure to obtain optically-active III from lutein (I).
The conversion of meso-zeaxanthin into III (see FIG.
3
), or the racemate or the (3S,3′S)-zeaxanthin, to applicants knowledge, has no precedent, and no such publication has been found in the literature. It would require a selective protection of one of the two OH-groups, e.g. by acetylation followed by an enzymic hydrolysis. This, hopefully, could lead to 25% of the desired product at best.
Otherwise, instead of enzymic reaction, an inversion of the stereochemistry at the unprotected OH-group could be envisaged, e.g. by an Mitsunobu-reaction. However, the necessary reagents are costly and further, the yields in this reaction are usually low; see hereafter.
Accordingly, Applicants could not see the purpose of expending time and effort in the experimental testing of such a reaction.
Another remarkable way is described by Sanroma et al. (U.S. Pat. No. 5,998,678 issued Dec. 7, 1999 to Sanroma et al.) which mentions the oxidation of meso-zeaxanthin (II) into the dioxocompound IV (see
FIG. 4
) followed by a hydride reduction into the mixture of II and racemic zeaxanthin. Applicants do not see recommendable this multi-step sequence, mainly because they do not see a more efficient way to carry it out, as discussed below.
In further reflecting on these problems with racemic zeaxanthin, applicants focused on 3′-epilutein (V, see
FIG. 5
) as a possibly excellent starting material for the preparation of optically active (3R,3′R)-zeaxanthin (III), provided it also permitted one to carry on the epsilon-beta-rearrangement with alkali.
Overview of the Occurrence of 3′-epilutein in Nature and of the Preparation of 3′-epilutein
A search in libraries and in data banks proved that the occurrence of 3′-epilutein in plants is extremely rare.
Until the present time, it has only been detected in the following: flowers of
Caltha palustris
[A. G. Dabbagh, K. Egger, Zeitschr.
Pflanzenphysiol
. 72, 177 (1974)], anthers of roses and peonies [E. Marki-Fischer, C. H. Eugster,
Helv. Chim. Acta
37, 1205 (1990)], and flowers of Tagetes [F. Khachik, A. Steck, H. Pfander;
J. Agric. Food Chem
. 47,455 (1999)].
It occurs partly in esterified form. Common by-products are carotenes and carotenoles. From this, it follows that plants do not offer a reasonable source for the preparative isolation of 3′-epilutein.
In animal tissues and liquors 3′-epilutein is more widespread, but unfortunately, always in very low concentration; see the overview provided in T. Matsuno, T. Maoka, M. Katsuyama, T. Hirono, Y. Ikuno, M. Shimizu, T. Komori,
Comp. Biochem. Physiol
. B85, 77 (1986). Recent findings with respect to 3′-epilutein concern:—human plasma [F. Khachik, G. R. Beecher, M. B. Goli, W. R. Lusby, J. C. Smith jr.,
Anal. Chem
. 64, 2111 (1992)],—the skin of trouts [M. C. Vecchi, G. Englert, H. Mayer,
Helv. Chim. Acta
, 65, 1950 (1982)];—human breast milk [F. Khachik, C. J. Spangler, J. C. Smith jr., L. M. Canfield, A. Steck, H. Pfander,
Anal. Chem
. 69, 1873 (1997)].
The small quantities found made any preparative isolation prohibitively costly.
Synthesis of several epiluteins starting from lower synthons are described in H. Mayer “
Carotenoid Chemistry
&
Biochemistry
” Ed. G. Britton, T. W. Goodwin, Pergamon Press, London 1982, pag. 55, ff for various epimers, but not for 3′-epilutein itself.
A conversion of lutein into 3′-epilutein via 3′-O-didehydrolutein (oxolutein, VI) followed by a hydride reduction was described for the first time in R. Buchecker, C. H. Eugster, A. Weber,
Helv. Chim. Acta
61, 1962 (1978). It leads to a mixture of I:V with a ratio of 1:2 (I:V). The separation of both stereoisomers is easily performed by HPLC. Pure V was isolated by column-chromatography and fully characterize

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