The present invention relates to a process for the stereoselective preparation of a compound of the general formula S,S-I or R,R-I,

S,S-I R,R-I having an enantiomeric and diastereomeric purity of at least 90% and to a process for the preparation of (3S,3'S)-astaxanthin or (3R,3'R)-astaxanthin, where the compounds of the general formula S,S-I or R,R-I are employed.

BACKGROUND OF THE INVENTION Due to its two chiral centers in the positions 3 and 3' astaxanthin (3,3'-dihydroxy-3,3'- carotene-4,4'-dione) may be present in the form of the (3S,3'S)-, (3R,3'R)-, (3S,3'R)-, (3R,3'S)-diastereomers or a mixture of these stereoisomers. The (3S,3'R)- and

(3R,3'S)-diastereomers are identical and constitute a meso form (see: Carotenoids Handbook, 2004 (eds.: G. Britton, S. Liaaen-Jensen, H. Pfander), main list nos. 404, 405 and 406).

The resulting three diastereomeric forms of astaxanthin are found in various natural sources. The chemical total synthesis, however, leads to a 1 :2:1 mixture of (3S,3'S)-, meso- and (3R,3'R)-astaxanthin, when starting from a racemic precursor (see e.g. E. Widmer et al., Helvetica Chimica Acta 1981 , 64, 2436).

The (3S,3'S)-diastereomer of astaxanthin (also called herein (3S,3'S)-astaxanthin) is of particular significance. It is biosynthesized in enantio- and diastereomerically enriched form by green algae (Haematococcus pluvialis) which are possibly the richest natural source for this diastereomer (see: M. Grung et al., J. Applied Phycology 1992, 4, 165; B. Renstram et al., Phytochemistry 1981 , 20, 2561 ). (3S,3'S)-Astaxanthin from green algae is used as a food supplement with positive effects on human health (see: G. Hussein et al., J. Nat. Prod. 2006, 69, 443). It has also been reported to be suitable as a potent antioxidant for blocking the disadvantageous prooxidant activity of rofecoxib (Vioxx) (see: R.P. Mason, J. Cardiovasc. Pharmacol. 2006, 47 Suppl. 1 , 7). However, considering the low concentration of (3S,3'S)-astaxanthin in green algae (see: J.-P. Yuan, J. Agric. Food Chem. 1998, 46, 3371 ), the availability of this active ingredient is very limited. In addition, (3S,3'S)-astaxanthin is present in the algae as a mixture of mono- and di-fatty acid esters and free astaxanthin, which causes a considerable level of complexity for the isolation and purification (see e.g. M. Grung et al., J. Applied Phycology 1992, 4, 165; B. Renstram et al., Phytochemistry 1981 , 20, 2561 ). In order to be able to provide (3S,3'S)-astaxanthin in larger quantities and high purity, chemical synthesis is therefore the technology of choice. The synthetic preparation of astaxanthin is extensively described in the literature, e.g. in the monograph G. Britton, S. Liaanen-Jensen, H. Pfander (editors), Carotenoids, Vol. 2, Birkhauser Verlag, Basel, 1996, in particular p. 1 1 , pp. 267 ff. and pp. 281 ff. and literature cited there, in various textbooks, such as B. Schafer, Natural Products in the Chemical Industry, Springer, Heidelberg, 2014, 626 ff. and literature cited there, in H. Ernst, Pure and Applied Chemistry, 2002, 74, 2213, and also in the patent literature, e.g. EP 1 197483 or EP 1285912.

The known synthetic routes towards astaxanthin usually start from racemic

3,4-dihydroxy-2,6,6-trimethylcyclohex-2-enone of the formula II, as shown in scheme 1 below. As a rule, this precursor of the formula I is initially protected via conversion to either the ketal or the acetal of the formula A. In a multi-step procedure the compound of the formula A is typically transformed into the C15-phosphonium salt or its phenylsulfonyl analogue of the formula B. The procedure includes the steps of introducing in position 1 (which is position 6 in apocarotenoid numbering) an ethinyl moiety carrying a substituted butenyl group via a Grignard reaction, elimination of water, partial reduction of the triple bond to a double bond and introduction of the phosphonium moiety or the phenylsulfonyl group. The compound of formula B is finally coupled via a Wittig reaction or a Julia olefination with the C10-dialdehyde of the formula C, as depicted in step b) below, to afford the all-trans derivative of astaxanthin, which however is a mixture of the three diastereomeric forms.

Scheme 1 :

It is apparent from the foregoing, that the C9 diol 3,4-dihydroxy-2,6,6-trimethyl- cyclohex-2-en-1 -one II, which can be present in the form of its (4S)- or (4R)-enantiomer of the formula S-ll or R-ll, respectively, is a valuable intermediate used in the industrial production of carotenoids, such as astaxanthin.

S-ll R-ll

In these production processes, the compound II is typically employed as a racemic mixture of the (4S)- and (4R)-enantiomer and in protected form, e.g. in form of their acetonites (compound A, where R ¹ and R ² are methyl). These processes are well described in the art.

E. Widmer et al., Helvetica Chimica Acta 1981 , 64, 2436, for example disclose a process for the synthesis of racemic astaxanthin by employing racemic 3,4-dihydroxy- 2,6,6-trimethyl-cyclohex-2-en-1 -one (S/R-ll) in the form of its acetonite.

EP 0633258 B1 discloses a process for the production of racemic astaxanthin, comprising the reaction of racemic 3,4-dihydroxy-2,6,6-trimethyl-cyclohex-2-en-1 -one (S/R-ll) with acetone, 2,2-dimethoxypropane or ethylvinylether. The thus protected C9 diols are then further converted to racemic astaxanthin. As mentioned above, the synthetic astaxanthin obtained from these processes typically consists of a 1 :2:1 mixture of (3S,3'S)-, meso- and (3R,3'R)-astaxanthin. Since for certain applications only individual isomers are desired, efforts have been made to prepare the C9 diols S-ll and R-ll in enantiomeric pure form, allowing the

enantioselective production of (3S,3'S)- and (3R,3'R)-astaxanthin.

R. Zell et al., Helvetica Chimica Acta 1981 , 64, 2447, for example describes several methods for the production of enantiomeric pure S-ll and R-ll, either by using a multi- step synthesis starting from chiral 4-hydroxy-2,6,6-trimethyl-cyclohex-2-en-1 -one or by optical resolution through the crystallization of diastereoisomeric salts of R/S-ll, or by using fermentative transformation. However, these processes are typically elaborative and suffer from low yields.

Another approach involves microbial optical resolutions of racemic 3-acetoxy-4-oxo- β-ionone - see E. Becher et al., Helvetica Chimica Acta 1981 , 64, 2419.

So far, there have been only scarce attempts to prepare the S-enantiomer of the compound of formula I as a chiral synthetic precursor for (3S,3'S)-astaxanthin which would allow a stereoselective preparation of (3S,3'S)-astaxanthin from scratch.

WO 2008/1 16714 A1 discloses a process for the enantioselective production of the C9 diols S-ll and R-ll comprising the enantioselective reduction of derivatives of

3,5,5-trimethyl-cyclohex-2-en-1 ,4-dione using a hydride donor in the presence of a chiral transition metal catalyst. The enantiomers S-ll and R-ll are obtained in high enantiomeric purity. Further disclosed is a process for the production of optically pure (3S,3'S)-astaxanthin, where the thus available enantiomeric pure diol S-ll is employed.

In order to obtain the desired (3S,3'S)- or (3R,3'R)-astaxanthin in sufficiently high optical purity, it is highly desirable to provide either the compound II or a suitable derivative thereof with high enantiomeric excess. However, the processes for the preparation of the enantiomeric pure C9 diols S-ll and R-ll as described in the prior art are often elaborative.

SUMMARY OF THE INVENTION

The object of the present invention is to provide an efficient process for the

enantioselective production of a derivative of the C9 diols S-ll or R-ll which can be used in the synthesis of stereoisomeric pure (3S,3'S)- or (3R,3'R)-astaxanthin. In particular, the process should allow using enantiomerically enriched C9 diols S-ll or R- II, which have only moderate optical purity. It was surprisingly found that the C9 acetals of the general formula S,S-I or R,R-I can be obtained with high stereospecificity by a process comprising the reaction of

S-ll or R-ll, having an enantiomeric excess of at least 80% ee, with a prochiral acetal of the formula III or with the prochiral enolether of the formula IV, respectively, in the presence of an acid and an anhydrous aprotic solvent.

S.S-I R,R-I III IV

In formulae S,S-I and R,R-I, respectively, and likewise in formula III, the radical R ¹ is selected from the group consisting of Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, phenyl and benzyl, where phenyl and benzyl are unsubstituted or carry one or two radicals R ^1a , selected from the group consisting of halogen, Ci-C3-alkyl and Ci-C3-alkoxy.

In formulae S,S-I and R,R-I, respectively, the asterisk indicates a center of chirality. In formulae III and IV, the radical R ² is Ci-C4-alkyl. In formula IV, the radicals R ³ are independently of each other selected from hydrogen, Ci-C3-alkyl, C2-C3-alkenyl, C2-C3-alkinyl and phenyl, where phenyl is unsubstituted or carries one or two radicals R ^1a , selected from halogen, Ci-C3-alkyl and Ci-C3-alkoxy, provided that in case one radical R ³ is phenyl, the other radical R ³ is hydrogen and in case the radicals R ³ in formulae IV are independently of each other selected from hydrogen, Ci-C3-alkyl, C2-C3-alkenyl and C2-C3-alkinyl, the maximum number of C-atoms of both radicals R ³ is 3.

Accordingly, a first aspect of the present invention relates to a process for the preparation of a compound of the general formulae S,S-I or R,R-I having an

enantiomeric and diastereomeric purity of at least 90%, in particular at least 95%, comprising the reaction of a compound of the formula S-ll or R-ll having an

enantiomeric excess of at least 80% ee with an acetal of the general formula III or an enolether of the general formulae IV, respectively, in the presence of an acid and an anhydrous aprotic solvent. The process of the present invention provides the C9 acetals of the formulae S,S-I and R,R-I, respectively in high yields and in high enantiomeric and diastereomeric purity with regard to the S,S-diastereomer of the formula S,S-I and to the R,R-diastereomer of the formula R,R-I, respectively, of at least 90%, in particular at least 95%.

Surprisingly, no racemization of the stereo center at C-4 in the compound S-ll and R-ll was observed, despite the acidic reaction conditions and the fact that the compounds may easily undergo isomerization via the pathway depicted in scheme 2.

Scheme 2:

Rather, the stereo center at position 4 of the compounds of the formulae S-ll and R-ll, respectively, provide for a strong chiral induction with regard to the second stereo center in formulae S,S-I and R,R-I located at the carbon atom bearing R ¹ . Furthermore, any formation of unwanted stereoisomers that might occur can be removed by common purification methods, in particular by preferential crystallization.

The compounds of the formulae S.S-I and R.R-i are particularly useful as starting materials in the production of (3S,3'S)-astaxanthin and (3R,3'R)-astaxanthin, respectively. Therefore, a further aspect of the present invention relates to a process for the preparation of (3S,3'S)-astaxanthin, which comprises providing a compound of the general formula S,S-I by the process as defined above and hereinafter, or for the preparation of (3R,3'R)-astaxanthin, which comprises providing a compound of the general formula R,R-I by the process as defined above and hereinafter.

DETAILED DESCRIPTION

The terms "enantiomeric purity" or "optical purity", as used herein, refer to a measure of the enantiomeric excess of a chiral substance (typically abbreviated as ee). The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R— S| ^* 100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R+S=1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([a]obs/[a]max) ^* 100, where [a]obs is the optical rotation of the mixture of enantiomers and [a]max is the optical rotation of the pure enantiomer. The terms "diastereomeric purity", "diastereomeric excess" or "de", as used herein, is defined by analogy to enantiomeric purity, enantiomeric excess or ee. The enantiomeric or diastereomeric excess can be determined by using a variety of analytical techniques, including for example NMR spectroscopy, chromatographic methods using chiral stationary phases or optical polarimetry.

The terms "enantiopure", "enantiomeric pure", "diastereomeric pure", "stereo isomeric pure" or "optically pure", as used herein, are intended to denote stereoisomeric compounds essentially composed of one stereoisomer. The term "essentially composed of one stereoisomer" means that these stereoisomeric compounds have an ee and/or de of at least 95%, in particular at least 98%.

For the purposes of the present invention, the term "Ci-C4-alkyl" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Preferably, Ci-C4-alkyl is selected from methyl, ethyl, n-propyl and isopropyl, in particular Ci-C4-alkyl is methyl or ethyl.

The term "Ci-Ca-alkyl" refers to methyl, ethyl, n-propyl or isopropyl. Preferably, C1-C3- alkyl is selected from methyl and ethyl, in particular methyl. The term "C2-C4-alkenyl" refers to unbranched radicals of 2 to 4 carbon atoms containing 1 or 2 double bonds or to branched radicals of 3 to 4 carbon atoms containing one double bond. Examples of C2-Ci-alkenyl are ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-methyl-1 -propenyl, 2-methyl-2-propenyl and the like. Preferably, C2-C4-alkenyl is selected from ethenyl, 2-propenyl, 1 -butenyl, 2-butenyl, 3-butenyl and 2-methyl-1 -propenyl, in particular from ethenyl and 2-propenyl.

The term "C2-C3-alkenyl" refers to ethenyl, 1 -propenyl and 2-propenyl. Preferably,

C2-C.3-alkenyl is selected from ethenyl and 2-propenyl, in particular is ethenyl. The term "C2-C4-alkinyl" refers, for example, to ethinyl, 1 -propinyl, 2-propinyl, 1 -butinyl, 2-butinyl, and 1 -methyl-2-propinyl. Preferably, C2-C4-alkinyl is selected from ethinyl, 1 - propinyl, 1 -butinyl and 2-butinyl, in particular from ethinyl and 1 -propinyl.

The term "C2-C3-alkinyl" refers to ethinyl, 1 -propinyl and 2-propinyl. Preferably, C2-C3- alkinyl is selected from ethinyl and 1 -propinyl, in particular is ethinyl.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine. Preferably, halogen is fluorine or chlorine, in particular chlorine. The term "Ci-C4-alkoxy" refers, for example, to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy. Preferably, Ci-C4-alkoxy is selected from methoxy, ethoxy and isopropoxy, more preferably from methoxy and ethoxy, in particular is methoxy.

The term "Ci-C3-alkoxy" refers to methoxy, ethoxy, n-propoxy and isopropoxy.

Preferably, Ci-C3-alkoxy is selected from methoxy and ethoxy, in particular is methoxy.

Preferably, the radical R ¹ in formulae S,S-I, R,R-I and III is selected from Ci-C4-alkyl, phenyl and benzyl, where phenyl and benzyl are unsubstituted or carry one or two radicals R ^1a , selected from halogen, Ci-C3-alkyl and Ci-C3-alkoxy.

More preferably, the radical R ¹ in formulae S,S-I, R,R-I and III is selected from C1-C4- alkyl, phenyl and benzyl, where phenyl and benzyl are unsubstituted or carry one or two radicals R ^1a , selected from chlorine, methyl and methoxy.

In particular, the radical R ¹ in formulae S,S-I, R,R-I and III is selected from Ci-C4-alkyl and phenyl. Preferably, the radical R ² in formulae III and IV is selected from methyl, ethyl, n-propyl and isopropyl, in particular from methyl and ethyl.

It is apparent that the moiety R ³ R ³ C= in formula IV corresponds to the radical R ¹ minus one hydrogen atom. Consequently, the total number of carbon atoms in both radicals R ³ corresponds to the number of carbon atoms of the radical R ¹ minus one carbon atom. Preferably, the radicals R ³ in formula IV are independently of each other selected from hydrogen, Ci-C3-alkyl and phenyl, where phenyl is unsubstituted or carries one or two radicals R ^1a , selected from halogen, Ci-C3-alkyl and Ci-C3-alkoxy, provided that in case one radical R ³ in formulae IV is phenyl, the other radical R ³ is hydrogen and in case the radicals R ³ in formulae IV are independently of each other selected from hydrogen and Ci-C3-alkyl the maximum number of C-atoms of both radicals R ³ is 3.

More preferably, the radicals R ³ in formula IV are independently of each other selected from hydrogen, Ci-C3-alkyl and phenyl, where phenyl is unsubstituted or carries one or two radicals R ^1a , selected from chlorine, methyl and methoxy, provided that in case one radical R ³ in formula IV is phenyl, the other radical R ³ is hydrogen and in case the radicals R ³ in formula IV are independently of each other selected from hydrogen and Ci-C3-alkyl the maximum number of C-atoms of both radicals R ³ is 3. In particular, the radicals R ³ in formula IV are independently of each other selected from hydrogen and Ci-C3-alkyl, in particular from hydrogen, methyl and ethyl, provided that the maximum number of C-atoms of both radicals R ³ is 3. The preferred embodiments of radicals R ¹ , R ² and R ³ mentioned above may be combined arbitrarily with one another.

Accordingly, the present invention relates in particular to a process, as defined above, where

R ¹ in formulae S,S-I , R,R-I and I II is selected from Ci-C4-alkyl, phenyl or benzyl, where phenyl and benzyl are unsubstituted or carry one or two radicals R ^1a , selected from chlorine, methyl and methoxy,

R ² in formulae I I I and IV is methyl or ethyl and

R ³ in formula IV are independently of each other selected from hydrogen, Ci-C3-alkyl and phenyl, where phenyl is unsubstituted or carries one or two radicals R ^1a , selected from chlorine, methyl and methoxy, provided that in case one radical R ³ in formulae IV is phenyl, the other radical R ³ is hydrogen and in case the radicals R ³ in formulae IV are independently of each other selected from hydrogen and Ci-C3-alkyl, the maximum number of C-atoms of both radicals R ³ is 3.

Especially, the present invention relates to a process, as defined above, where

R ¹ in formulae S,S-I , R,R-1 and II I is selected from Ci-C4-alkyl and phenyl,

R ² in formulae I I I and IV is selected from methyl and ethyl and

R ³ in formula IV are independently of each other selected from hydrogen, methyl and ethyl, provided that in formula IV the maximum number of C-atoms of both radicals R ³ is 3.

The acetals that are applied in the process of the present invention are preferably selected from compounds of the general formula I I I, wherein R ¹ is Ci-C4-alkyl, phenyl or benzyl, where phenyl and benzyl are unsubstituted or carry one or two radicals R ^1a , selected from chlorine, methyl and methoxy, and R ² is selected from methyl or ethyl.

More preferably, the acetals that are applied in the process of the present invention are selected from compounds of the general formula I I I, wherein R ¹ is Ci-C4-alkyl or phenyl and R ² is selected from methyl or ethyl.

Particularly preferred compounds of the general formula I I I are 1 , 1 -dimethoxyethane, 1 , 1 -dimethoxypropane, 1 , 1 -dimethoxybutane, 1 , 1 -dimethoxy-2-methyl-propane, 1 , 1 -diethoxyethane, 1 , 1 -diethoxypropane, 1 , 1 -diethoxybutane, 1 , 1 -diethoxy-2-methyl- propane, dimethoxymethylbenzene and diethoxymethylbenzene. The enolethers that are applied in the process of the present invention are preferably selected from compounds of the general formula IV, wherein R ² is methyl or ethyl and R ³ are independently of each other selected from hydrogen, Ci-C3-alkyl and phenyl, where phenyl is unsubstituted or carries one or two radicals R ^1a , selected from chlorine, methyl and methoxy, with the proviso that in case one radical R ³ in formula IV is phenyl, the other radical R ³ is hydrogen and in case the radicals R ³ in formula IV are independently of each other selected from hydrogen and Ci-C3-alkyl the maximum number of C-atoms of both radicals R ³ is 3.

More preferably, the enolethers that are applied in the process of the present invention are selected from compounds of the general formula IV, wherein R ² is methyl or ethyl and one of the radicals R ³ is hydrogen and the other radical R ³ is selected from hydrogen, Ci-C3-alkyl and phenyl.

Particularly preferred compounds of the general formula IV are vinyloxymethane, vinyloxyethane, 1 -methoxyprop-1 -ene, 1 -ethoxyprop-1 -ene, 1 -methoxybut-1 -ene and 1 -ethoxybut-1 -ene. The compounds of the general formulae III and IV can either be purchased or they can be prepared by synthetic processes that are well known to the skilled person.

According to the present invention, the reaction of the diol S-ll or R-ll with an acetal of the general formula III or an enolether of the general formula IV, respectively, is performed in the presence of an acid.

Generally, the acid used in the process of the present invention is selected from

mineral acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid or nitric acid,

- alkylsulfonic acids, such as methanesulfonic acid, ethanesulfonic acid or

camphersulphonic acid,

haloalkylsulfonic acids, such as trifluoromethanesulfonic acid,

arylsulfonic acids, such as benzenesulfonic acid or para-toluenesulfonic acid, and Ci-C7-carboxylic acids, such as formic acid and acetic acid,

- halogenated carboxylic acids, such as trichloroacetic acid or trifluoroacetic acid.

Preferably, the acid used in the process of the present invention is selected from alkylsulfonic acids, haloalkylsulfonic acids, arylsulfonic acids and halogenated carboxylic acids. More preferably, the acid used in the process of the present invention is selected from methanesulfonic acid and para-toluenesulfonic acid.

In particular, the acid used in the process of the present invention is para- toluenesulfonic acid.

Typically, the amount of acid used in the process of the present invention is in the range of from 0.1 to 5 mol-%, preferably in the range of from 0.2 to 3 mol-%, in particular in the range of from 0.5 to 1 mol-%, based on 1 mol of the compounds S-ll or R-ll.

The reaction of the diols S-ll or R-ll with the acetals III or enolethers IV, respectively, can in principle be carried out in solution, in the form of a suspension or in the form of an emulsion. Preferably, the reaction of the diols S-ll or R-ll with the acetals III or enolethers IV, respectively, is performed in solution.

According to the present invention, the reaction of the diol S-ll or R-ll with the acetals III or enolethers IV, respectively, is carried out in the presence of an anhydrous aprotic solvent. In this context, the term "anhydrous" refers to solvents that contain at most 0.1 weight-%, preferably at most 0.05 weight-%, in particular at most 0.01 weight-% of water. The term "aprotic", as used herein, refers to solvents that are not able to donate or accept protons.

The aprotic solvent used in the process of the present invention is preferably selected from

Cs-Cs-alkanes, such as pentane, hexane, heptane, petrol ether or ligroin,

C5-C8-cycloalkanes, such as cyclopentane, cyclohexane or cycloheptane, chlorinated Ci-C2-alkanes, such as dichloromethane, trichloromethane or 1 ,2-dichloroethane,

- benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl, C1-C4- alkoxy and chlorine, such as benzene, toluene, ethylbenzene, xylene, methoxybenzene or chlorobenzene,

Ci-C4-dialkyl ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether,

- cyclic ethers, such as tetrahydrofuran or 1 ,4-dioxane,

and mixtures thereof.

More preferably, the aprotic solvent used in the process of the present invention is selected from hexane, heptane, cyclohexane, dichloromethane, toluene, diisopropyl ether, methyl tert-butyl ether and mixtures thereof. Particularly preferable are aprotic solvents that are able to form an azeotropic mixture with methanol or ethanol. Accordingly, the aprotic solvent used in the process of the present invention is particularly preferably selected from dichloromethane, toluene and cyclohexane, and especially is dichloromethane.

The reaction according to the present invention can be performed at a temperature in the range of from -10°C to the boiling point of the particular aprotic solvent used. Typically, the reaction according to the present invention is performed at a temperature in the range of from 0°C to 1 10°C, preferably in the range of from 0°C to 80°C, in particular in the range of from 0°C to 50°C.

The reaction according to the present invention can generally take place at ambient pressure or at reduced or elevated pressure. Preferably, the reaction according to the present invention is carried out at a pressure in the range of from 0.1 to 10 bar.

The reaction according to the present invention can take place in the absence of or in the presence of an inert gas. The expression inert gas generally means a gas, which under the prevailing reaction conditions does not enter into any reactions with the starting materials, reagents, or solvents participating in the reaction, or with the resultant products. It is preferable that the reaction according to the present invention takes place in the presence of an inert gas. Typically, the reaction of the diol S-ll or R-ll with the acetals III or enolethers IV, respectively, is carried out by first placing the diol S-ll or R-ll in the form of a solution in the anhydrous aprotic solvent together with a catalytic amount of the acid into a suitable reaction vessel. Following this, the acetal of the general formula III or the enolether of the general formula IV, respectively, is added to the solution of the diol S-ll or R-ll and the acid. The acetal III or the enolether IV, respectively, can be added in one portion at the start of the reaction or in several portions, e.g. in 2 to 20 portions, or continuously over the course of the reaction, e.g. over a time period of from 5 minutes to several hours, to the solution of the diol S-ll or R-ll and the acid. Preferably, the acetal III or the enolether IV, respectively, is added to the solution of the diol S-ll or R-ll and the acid in 5 to 20 portions, or continuously over a time period of from 10 minutes to 3 hours.

Typically, the acetal of the general formula III or the enolether of the general formula IV, respectively, is applied in excess with respect to the diol S-ll or R-ll. The molar ratio of the diol S-ll or R-ll to the acetals III or the enolethers IV, respectively, used in the process of the present invention is generally in the range of from 1 :1 .2 to 1 :5, preferably in the range of from 1 :1 .5 to 1 :3, in particular in the range of from 1 :1 .8 to 1 :2.6.

According to the process of the present invention, the diol S-ll or R-ll is either reacted with an acetal of the general formula III or with an enolether of the general formula IV. Both variants of this transformation are performed essentially under the same reaction conditions and are, thus, equally suitable for the preparation of the compounds of the general formulae S,S-I or R,R-I. However, the enolethers IV are generally more reactive than the acetals III.

Therefore, a preferred embodiment of the present invention relates to the preparation of a compound of the general formula S,S-I or R,R-I, as defined above, where the diol S-ll or R-ll, having an enantiomeric excess of at least 80% ee, is reacted with an enolether of the general formula IV.

The reaction according to the present invention, can be designed to take place either continuously, semi-batchwise or batchwise. The batchwise reaction can be conducted in a reaction apparatus conventionally used for this purpose, e.g. a stirred reactor. The continuous reaction can for example be carried out in a tube reactor or in a cascade of at least three back-mixed reactors. The reactors can be operated nearly isothermally or nearly adiabatically. In the case of continuously operated reactors, the diol S-ll or R-ll, the acetal III or the enolether IV, respectively, the solvent as well as the acid are fed as liquid streams to the reactor. Preferably, the temperature, pressure and composition of the feed is chosen in such a way that the mixed feed stream at the reactor entrance is liquid (i.e. does not have a gaseous phase) and homogeneous (no separation into two liquid phases).

After completion of the reaction, the reaction mixture, comprising the desired C9 acetals S,S-I or R,R-I, is subjected to common work-up procedures, preferably extractive work-up. Typically, the reaction mixture is first neutralized by the addition of a mineral base, e.g. KHCO3, NaHC03 or NaOH, preferably in form of an aqueous solution. The water phase and the organic phase of the resulting biphasic mixture can then be separated using conventional methods. After removal of the volatiles from the separated organic phase, the acetals S,S-I or R,R-I are typically obtained in high purity.

The process of the present invention provides the C9 acetals S,S-I or R,R-I in high yields as well as in high optical purity. Typically, the C9 acetals S,S-I or R,R-I obtained by the process of the present invention have an enantiomeric and diastereomeric purity of at least 90%. The enantiomeric and diastereomeric purity of the acetals S,S-I and R,R-I obtained by the process of the present invention typically depends on the enantiomeric purity of the applied diols S-ll or R-ll, respectively. However, if required, the optical purity of the acetals S,S-I and R,R-I can be further improved by using common purification methods, such as for example chromatographic methods or crystallization methods. In particular, the optical purity of the acetals S,S-I and R,R-I can be further improved by crystallization.

Therefore, a preferred embodiment of the present invention relates to a process for the preparation of a compound of the general formula S,S-I or R,R-I, having a enantiomeric and diastereomeric purity of at least 90%, as defined above, where the raw product obtained after the reaction of the compound S-ll or R-ll with the acetal III or enolether IV, is purified by crystallization. The crystallization of the raw C9 acetals S,S-I and R,R-I can be performed by using common crystallization techniques, e.g. by using a temperature gradient, counter- diffusion or evaporation, optionally together with seeding. Preferably, the crystallization of the raw C9 acetals S,S-I and R,R-I is performed by using crystal seeding. Typically, the crystallization is carried out by first preparing an oversaturated solution of the acetal S,S-I or R,R-I to be purified. Following this, seed crystals, consisting of the desired acetal S,S-I or R,R-I in optically pure form, are added to this solution to foster the selective crystallization of the corresponding stereoisomer.

The thus obtained C9 acetals S,S-I and R,R-I have an enantiomeric and

diastereomeric purity of at least 95%, frequently of at least 96%, more frequently of at least 97%. Often, the other stereoisomers are not detectable within the detection limits of the chromatographic method used for analyzing the purity and composition of the acetals S,S-I and R,R-I. The detection limit of the used chromatographic analysis system is estimated to be about 0.1 weight-%.

As mentioned above, the C9 diols of the formulae S-ll and R-ll that can be applied in the process of the present invention do not necessarily need to have a high

enantiomeric purity, e.g. an enantiomeric purity of more than 95% ee. Rather, it may be sufficient to employ C9 diols of the formulae S-ll and R-ll having an enantiomeric purity in the range from 80 to 95% ee. The C9 diols of the general formulae S-ll and R-ll that are applied in the process of the present invention preferably have an enantiomeric purity of at least 85% ee, in particular of at least 90% ee.

The C9 diols of the general formulae S-ll and R-ll, having the enantiomeric purity given above, can be prepared using processes that are known in the art. Preferably, the enantiomeric pure diols S-ll and R-ll are prepared analogously to the process described in WO 2008/1 16714 A1 . In this connection reference is made to the disclosure of WO 2008/1 16714 A1 in its entirety.

Accordingly, a preferred embodiment of the present invention relates to a process as defined above, where the compounds of the general formulae S-l l or R-l l having an enantiomeric excess of at least 80% ee are prepared by the reaction of a compound of the general formula V

V wherein

M ⁺ is selected from alkali metal cations, the group (M ¹ i 2) ⁺ and the group (M ¹ X) ⁺ , where M ¹ is an alkaline earth metal cation and X is a singly charged anion, with a hydrogen donor in the presence of a chiral transition metal catalyst, which comprises a transition metal and one chiral ligand.

Preferably, the variable M ⁺ in the compound of the formula I I is selected from:

alkali metal cations, such as Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ or Cs ⁺ , preferably Na ⁺ or Ka ⁺ , in particular Na ⁺ ;

- a group (M ¹ i 2) ⁺ or a group (M ¹ X) ⁺ , wherein M ¹ is an alkaline earth metal cation such as Mg ²⁺ , Ca ²⁺ , Sr ²⁺ or Ba ²⁺ , in particular Mg ²⁺ , and X is a singly charged anion, such as for example halogen, acetate or dihydrogenphosphate.

The transition metal of the chiral transition metal catalyst is preferably ruthenium. I particular, the chiral transition metal catalyst comprises just one ruthenium atom.

Preferred chiral transition metal catalysts, such as in particular chiral ruthenium catalysts, can be obtained e.g. by reacting a suitable transition metal precursor compound, such as in particular a ruthenium compound, for example a ruthenium compound of the formula Ru-I

[RuY ₂ (n ⁶ -Ar)] ₂ , (Ru-I) with a suitable chiral ligand, where in formula Ru-I , the variable Y is halogen selected from fluorine, chlorine, bromine and iodine, and in particular is chlorine, and Ar is benzene or a substituted benzene derivative, especially a benzene derivative substituted by one or more Ci-C4-alkyl groups, such as in particular p-cymene. A particularly preferred ruthenium compound is of the formula Ru-I with Y being chlorine and Ar being p-cymene, i.e. 1 -methyl-4-(propan-2-yl)benzene.

In a preferred embodiment, the chiral transition metal catalyst used for preparing the compounds of the general formulae S-ll or R-ll comprises one chiral ligand, which is derived from optically active amines or optically active amino acids, and in particular derived from optically active amines. The optically active amine ligand preferably has an enantiomeric excess of at least 90% ee. Typically, the optically active amines or the optically active amino acids are converted into the chiral ligands by deprotonating an amino group of the optically active amine or amino acid during the reaction with the suitable transition metal compound, such as e.g. [RuY ₂ (n _, ⁶ -Ar)] ₂ .

Preferred optically active amines here are the optically active diastereomers of an amine having two chiral centers. It is apparent that a particular optically active diastereomer of such an amine will selectively produce one enantiomer of the compound of formula II, while its optical antipode will produce the other enantiomer of the compound of formula II. A skilled person can readily find out by routine, which antipode is required to selectively form the desired enantiomer S-ll or R-ll. The amine having two chiral centers is preferably selected from 1 ,2-diphenyl-2-amino-ethanol (H ₂ N-CHPh-CHPh-OH), 1 -phenyl-2-methyl-2-amino-ethanol (H ₂ N-CHMe-CHPh-OH), N-methyl-1 -phenyl-2-methyl-2-amino-ethanol (MeHN-CHMe-CHPh-OH) and

N-p-toluenesulfonyl-1 ,2-diphenyl-ethylenediamine (H2N-CHPh-CHPh-NHTs), and in particular is H ₂ N-CHPh-CHPh-NHTs. Thus, the chiral ligand of the chiral transition metal catalyst is preferably the monoanion of an amine, which is selected from H ₂ N-CHPh-CHPh-OH, H ₂ N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH and H ₂ N-CHPh-CHPh-NHTs, and in particular is

H ₂ N-CHPh-CHPh-NHTs. Accordingly, these preferred chiral ligands are formed when an optically active diastereomer, selected from the diamines of the group

H ₂ N-CHPh-CHPh-OH, H ₂ N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH and

H ₂ N-CHPh-CHPh-NHTs, in particular a diastereomer of H ₂ N-CHPh-CHPh-NHTs, is reacted with a suitable transition metal compound, in particular a suitable ruthenium compound, such as especially the compound of the formula Ru-I. Particularly preferred optically active diastereomers in this context are selected from (1 S,2S)-N-p-toluenesulfonyl-1 ,2-diphenyl-ethylenediamine

((1 S,2S)-H ₂ N-CHPh-CHPh_NHTs) and (1 R,2R)-N-p-toluenesulfonyl-1 ,2-diphenyl- ethylenediamine ((1 R,2R)-H ₂ N-CHPh-CHPh-NHTs). Accordingly, in a preferred embodiment of the present invention the chiral transition metal catalyst is obtainable by reacting a suitable ruthenium compound, such as especially [RuY ₂ (n ⁶ -Ar)] ₂ , with one of the diastereomers of H ₂ N-CHPh-CHPh-OH, H ₂ N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH or H ₂ N-CHPh-CHPh-NHTs, and in particular with (1 S,2S)-H ₂ N-CHPh-CHPh-NHTs or (1 R,2R)-H ₂ N-CHPh-CHPh-NHTs.

When the preparation of the compound S-ll or R-ll is carried out with a deprotonated (1 S,2S)-H ₂ N-CHPh-CHPh-NHTs or a deprotonated (1 R,2R)-H ₂ N-CHPh-CHPh-NHTs as the chiral ligand of the chiral transition metal catalyst, in particular of a chiral ruthenium catalyst, the S-enantiomer and the R-enantiomer, respectively, of the compound of formula (I) can be obtained in high enantiomeric excess.

Preferably, the hydrogen donor used in the enantioselective reduction of a compound of the formula V is selected from organic compounds, comprising at least one secondary alcohol-group, such as isopropanol, 2-butanol, 2-pentanol, 2-hexanol or 3- hexanol. In particular, the hydrogen donor used in the enantioselective reduction is isopropanol.

The amount of chiral transition metal catalyst used in the enantioselective reduction is preferably 0.5 to 10 mmol, in particular 1 to 5 mmol, based on 1 mol of the compound of the formula V.

The enantioselective reduction is preferably carried out at a temperature of from 10°C to 85°C, in particular at a temperature of from 15°C to 75°C.

The enantioselective reduction is preferably performed in the presence of a solvent. Preferably, the solvent is selected from mixtures of a secondary alcohol, in particular isopropanol, with water. Particularly preferred are chiral transition metal catalysts, where the chiral ligand is obtained by a single deprotonation of optically active H ₂ N-CHPh-CHPh-OH,

H ₂ N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH or H ₂ N-CHPh-CHPh-NHTs, in particular by a single deprotonation of (1 S,2S)-N-p-toluenesulfonyl-1 ,2-diphenyl- ethylenediamine or (1 R,2R)-N-p-toluenesulfonyl-1 ,2-diphenyl-ethylenediamine.

Preferably, an aqueous solution of a mineral base, such as e.g. KOH, NaOH, is used for the single deprotonation of the optically active ligand.

After completion of the enantioselective reduction, a compound of the formula S-ll' or R-ll', which is a salt of the desired product S-ll or R-ll, respectively, is obtained,

S-ll' R-ll' wherein M ⁺ has one of the meanings as defined above.

Typically, the salt of the formula S-ll' or R-ll' is converted into the compound of the formula S-ll or R-ll, respectively, by an acidification step, for example as described in Helvetica Chimica Acta 1981 , 64, 2436. If the enantioselective reduction of a compound of the general formula V is performed using a deprotonated (1 S,2S)-H ₂ N-CHPh-CHPh-NHTs or a deprotonated

(1 R,2R)-H ₂ N-CHPh-CHPh-NHTs as chiral ligand of the chiral transition metal catalyst, in particular a chiral ruthenium catalyst, followed by an acidic work-up of the resulting reaction mixture, the S-enantiomer S-ll and the R-enantiomer R-ll, respectively, is obtained in high enantiomeric excess.

Accordingly, the compound of the formula S-ll having an enantiomeric excess of at least 80% ee is particularly preferably prepared by a process as defined above, where deprotonated (1 S,2S)-N-p-toluenesulfonyl-1 ,2-diphenyl-ethylenediamine is employed as chiral ligand.

Likewise, the compound of the formula R-ll having an enantiomeric excess of at least 80% ee is particularly preferably prepared by a process as defined above, where deprotonated (1 R,2R)-N-p-toluenesulfonyl-1 ,2-diphenyl-ethylenediamine is employed as chiral ligand.

The C9 acetals S,S-I and R,R-I obtainable by the process of the present invention are valuable intermediates that can be employed in the preparation of carotenoids, which are for example described in G. Britton, S.Liaanen-Jensen, H.Pfander, Carotenoids, Vol. 2, Birkenhauser Verlag, Basel, 1996, pp. 283 ff.. In particular, the C9 acetals S,S-I and R,R-I can advantageously be employed in the preparation of (3S,3'S)- or (3R,3'R)- astaxanthin.

Therefore, a further aspect of the present invention relates to a process for the preparation of (3S,3'S)-astaxanthin, which comprises providing a compound of the general formula S,S-I by a process as defined above, as well as to a process for the preparation of (3R,3'R)-astaxanthin, which comprises providing a compound of the general formula R,R-I by a process as defined above. Starting from either S,S-I or R,R-I , (3S,3S')-astaxanthin or (3R,3R')-astaxanthin can be prepared following the established non-stereoselective synthesis routes that are for example described in G. Britton, S.Liaanen-Jensen, H .Pfander, Carotenoids, Vol. 2, Birkenhauser Verlag, Basel, 1996, or in Helvetica Chimica Acta 1981 , 64, 2447, or in the patent literature, such as for example in EP 1 197483 or EP 1285912.

The examples below are intended to provide a further explanation of the invention. EXAMPLES I) High performance liquid chromatography (HPLC) analysis: HPLC-system: Agilent Series 1 100

HPLC-Column: Zorbax Eclipse XDB-C18, 1 ,8 μηι, 50*4,6 mm from Agilent®

Eluent: Eluent A: Water with 0.1 vol.-% H ₃ P0 ₄

Eluent B: Acetonitril with 0.1 vol.-% H ₃ P0 ₄

Detektor: UV-Detektor λ=262 nm, BW=6 nm

I I) NMR analysis

The ¹ H- ¹ H-ZQF-NOESY experiments were performed at 360 MHz I I I) Production examples: Example 111.1

Preparation of (2S,7aS)-2,4,6,6-tetramethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one. To 108.7 g of a 40.6% solution of (4S)-3,4-dihydroxy-2,6,6-trimerhyl-cyclohex-2-en-1 - one in dichloromethane (259 mmol) 279 mg (1 .47 mmol) of para-toluenesulfonic acid monohydrate was added at 25°C. To this, 42.4 g (588 mmol) ethylvinylether was added dropwise over one hour. The resulting mixture was then stirred for 80 minutes at 40°C. After completion of the reaction, 30 ml of a 5% aqueous sodium hydroxide solution was added and the resulting biphasic mixture was stirred for 15 minutes at 20°C. The organic phase was separated, washed with 30 ml of water and the volatiles were removed under reduced pressure. The residue was dissolved in 30 ml of methanol at 45°C. Then, 20 ml of water was added and the solution was slowly cooled to 0°C. At 34°C, seed crystals were added. The resulting suspension was stirred for 1 hour at 0°C, filtered and washed with 40 ml of a cold mixture of methanol : water (1 :1 ) and 50 ml of cold water. The obtained solid was then dried in a vacuum drying cabinet at 30 mbar and 40°C. 39.7 g (2S,7aS)-2,4,6,6-tetramethyl-7,7a-dihydro-1 ,3-benzodioxol-5- one (95.4% purity, 74.4% yield) were obtained as a colorless, crystalline solid, which proved to be a uniform product both in HPLC and in NMR spectroscopy. Using ¹ H- ¹ H- ZQF-NOESY-NMR experiments and in the knowledge of the absolute configuration of the starting material the absolute configuration at the asymmetric center in position 2 was determined as (S).

Example 111.2

Preparation of (2S,7aS)-2-ethyl-4,6,6-trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one.

10g of a 25% solution of (4S)-3,4-dihydroxy-2,6,6-trimerhyl-cyclohex-2-en-1 -one in dichloromethane (15 mmol) together with 36.5 mg of para-toluenesulfonic acid monohydrate were placed at 25°C into a suitable reaction vessel. To this, 2.86 g (33 mmol, 2.2 equivalents) ethyl-1 -propenylether was added dropwise. The resulting mixture was then stirred for 1 hour under reflux. Following this, the reaction mixture was cooled to 20°C and washed with 10 ml of a 5% aqueous sodium hydrogen carbonate solution and with 10 ml of water. The organic phase was dried over Na2S0 ₄ and the volatiles were removed under reduced pressure. 2.83 g (2S,7aS)-2-ethyl-4,6,6 trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one were obtained, which proved to be a uniform product both in achiral and chiral HPLC.

Example 111.3

Preparation of (2S,7aS)-2-n-propyl-4,6,6-trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one 10g of a 25% solution of (4S)-3,4-dihydroxy-2,6,6-trimerhyl-cyclohex-2-en-1 -one in dichloromethane (15 mmol) together with 36.5 mg of para-toluenesulfonic acid monohydrate were placed at 25°C into a suitable reaction vessel. To this, 3.31 g (33 mmol, 2.2 equivalents) ethyl-1 -n-butenylether was added dropwise. The resulting mixture was then stirred for 1 hour under reflux. Following this, the reaction mixture was cooled to 20°C and washed with 10 ml of a 5% aqueous sodium hydrogen carbonate solution and with 10 ml of water. The organic phase was dried over Na2S0 ₄ and the volatiles were removed under reduced pressure. 2.48 g (2S,7aS)-2-n-propyl- 4,6,6-trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one were obtained, which proved to be a uniform product both in achiral and chiral HPLC. Example 111.4

Preparation of (2S,7aS)-2-iso-propyl-4,6,6-trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5- one. 10g of a 25% solution of (4S)-3,4-dihydroxy-2,6,6-trimerhyl-cyclohex-2-en-1 -one in dichloromethane (15 mmol) together with 36.5 mg of para-toluenesulfonic acid monohydrate were placed at 25°C into a suitable reaction vessel. To this, 5.1 g (33 mmol, 2.2 equivalents) isobutyraldehyde diethyl acetal was added dropwise. The resulting mixture was then stirred for 1 hour under reflux. Following this, the reaction mixture was cooled to 20°C and washed with 10 ml of a 5% aqueous sodium hydrogen carbonate solution and with 10 ml of water. The organic phase was dried over Na2S0 ₄ and the volatiles were removed under reduced pressure. 2.61 g (2S,7aS)-2-iso-propyl- 4,6,6-trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one were obtained, which proved to be a uniform product both in achiral and chiral HPLC.

Example 111.5

Preparation of (2S,7aS)-2-phenyl-4,6,6-trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one.

(4S)-3,4-dihydroxy-2,6,6-trimerhyl-cyclohex-2-en-1 -one was reacted with benzaldehyde dimethyl acetal analogous to examples III.2 to III.4. The thus obtained

(2S,7aS)-2-phenyl-4,6,6-trimethyl-7,7a-dihydro-1 ,3-benzodioxol-5-one proved to be a uniform product both in achiral and chiral HPLC.