WO2005014509A1

WO2005014509A1 - Process for the preparation of enantiomerically enriched esters and alcohols

Info

Publication number: WO2005014509A1
Application number: PCT/EP2004/007481
Authority: WO
Inventors: Gerardus Karel Maria Verzijl; Quirinus Bernardus Broxterman
Original assignee: Dsm Ip Assets B.V.
Priority date: 2003-07-15
Filing date: 2004-07-06
Publication date: 2005-02-17

Abstract

The invention relates to a process for the preparation of an enantiomerically enriched ester, in which a mixture of the enantiomers of the corresponding chiral secondary alcohol in the presence of a racemisation catalyst for the substrate is subjected to an enantioselective acylation with the aid of an acyl donor and a stereoselective acylation catalyst upon which the enantiomerically enriched ester and an acyl donor residue are formed, in the presence of a carbonyl compound and wherein the racemisation catalyst comprises at least one ligand and a metal M chosen from group IIIa, IIIb, IVb of the periodic system, preferably Al.

Description

PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED ESTERS AND ALCOHOLS

The invention relates to a process for the preparation of an enantiomerically enriched ester, in which a mixture of the enantiomers of the corresponding chiral secondary alcohol in the presence of a racemisation catalyst for the substrate is subjected to an enantioselective acylation with the aid of an acyl donor and a stereoselective acylation catalyst upon which the enantiomerically enriched ester and an acyl donor residue are formed. Such a process that is called a Dynamic Kinetic Resolution (DKR), is known for example from Backvall, J.Am.Chem.Soc.1999, 121 , 1645- 1650. In this process transition metal (Ru) based transfer hydrogenation catalysts are used as the racemisation catalyst. In Journal of Organometallic Chemistry 652 (2002) 105-111 , Backvall - who is a pre-eminent specialist in this field - describes the current insight that the so-called hydridic route (using catalysts based on transition metals like Ru, Ir and Rh) is the superior transfer hydrogenation mechanism, which is the mechanism that also operates in the transition metal based racemisation catalysis. This as opposed to the "classical" hydrogen transfer reactions which follow the so-called direct hydrogen transfer mechanism and use Meerwein, Ponndorf, Verley (MPV) catalysts based on for instance aluminium. A disadvantage of the hydridic method is that the racemisation catalyst, particularly the metal (e.g. Ru) in the catalyst is expensive. The invention now provides a process for the preparation of enantiomerically enriched esters in a DKR process wherein racemisation of the substrate is achieved via a direct hydrogen transfer mechanism wherein a catalyst based on a cheap metal, for instance Al, can be used. Surprisingly it appeared that the MPV catalyst has no or only low activity as a not stereoselective esterification catalyst under the reaction conditions. Moreover it has been found that catalytic amounts of this racemisation catalyst can be used. According to the invention this is achieved in a process wherein a direct hydrogen transfer mechanism based catalyst is present as the racemisation catalyst for the substrate, and wherein a carbonyl compound is present. It is expected that the racemisation proceeds via a direct hydrogen transfer mechanism, whereas in the transition metal catalyst based conversion described by Backvall et al. in Journal of Organometallic Chemistry 652 (2002) 105-111 the racemisation proceeds via the hydridic route. The direct hydrogen transfer mechanism essentially does not proceed through a metal hydride bond but rather via a cyclic mechanism as illustrated in Fig. 1 for a specific embodiment. The choice of the secondary alcohol is determined by the desired product. Also, mixtures of different secondary alcohols may be used. A secondary alcohol can, for instance, be represented by the following formula (1),

wherein * denotes a chiral centre, R¹ ≠ R² and R¹ and R² each independently represent an alkyl group with for instance 1-20 C-atoms, preferably 1-6 C-atoms, an alkenyl group with for instance 2-20 C-atoms, preferably 2-6 C-atoms, an alkynyl group with for instance 2-20 C-atoms preferably 2-6 C-atoms or an (hetero)aryl group optionally containing for instance one or more O, S or N atoms, with for instance 4-20 C-atoms, preferably 5-10 C-atoms; or wherein R¹ and R² together form an (un)saturated ring with for instance 3-20 C-atoms which ring may contain one or more hetero atoms, for instance O, S or N. The alkyl, alkenyl, and (hetero) aryl groups of R¹ and R² and the ring may include any substituents that are inert in the reaction system. Suitable substituents are, for example, alkyl groups, (hetero) aryl groups, alkoxy groups, alkenyl groups, (substituted) amine groups which are unreactive in the acylation reaction, halogens, nitrile, nitro, acyl, carboxyl, carbamoyl or sulphonate groups; the substituents may contain for instance 0-19 C-atoms, particularly 0-10 C-atoms. A particular class of secondary alcohols is the class of secondary alcohols with a double or triple bond at the β,γ-position ((2,3)-position) with respect to the (chiral) alcohol carbon (1 -position), for instance compounds with formula (1), wherein R¹ and/or R² represent an alkenyl or alkynyl group and wherein the alkenyl or alkynyl bond in R¹ and/or R² is located at the β,γ-position with respect to the (chiral) alcohol carbon. It is inferred from the literature that catalysts acting by the hydride mechanism deactivate by irreversible Michael- addition of the transition-metal-hydride complex to the double bond of (α,β)- unsaturated substrates (J. Am. Chem. Soc. 1997, 119, 8738-8739. A special feature of the MPV-catalyst is the ability of (α.β)-ketone reduction without significant deactivation of the MPV-catalyst. Therefore MPV-catalysts have addional advantage that negligible deactivation will occur during racemisation of (β,γ)-unsaturated secondary alcohols in the presence of (α,β)-unsaturated carboxy-com pounds (Michael-acceptors). The carbonyl compound is, for instance, an aldehyde or a ketone, preferably a ketone. The carbonyl compound may be represented by the formula R³-C(O)-R⁴, wherein R³ and R⁴ each independently for instance represent H, an alkylgroup with for instance 1-20 C-atoms, or an (hetero) arylgroup with for instance 3-25 C-atoms and for instance containing a 3-10, preferably a 5-8 membered aromatic ring with 0-4 hetero atoms, for example O, S or N or wherein R³ and R⁴ together form an (un)saturated ring with for instance 3-20 C-atoms which ring may contain one or more hetero atoms, for instance O, S or N; with the proviso that not both R³ and R⁴ are H. The alkyl and (hetero) aryl groups and the ring may include one or more substituents that are inert in the reaction system, for instance alkyl, alkenyl, alkynyl, alkoxy, amino, acyl, aryl, aralkyl, alkaryl, carboxamide, acylamino, or heteroaryl groups with, for instance, 1-20 C-atoms, or halogens, cyano or nitro groups. If the carbonyl compound is a ketone, it preferably corresponds to the substrate alcohol. The carbonyl compound may be added as such or prepared in situ. The result of the process according to the invention is an enantiomeric balance (e.b.) higher than 0. The enantiomeric balance is defined by the following formula wherein (R) and (S)-substrate and (R) and (S)-product are expressed in moles:

e.b. = (R)-substrate + (R)-product - (S)-substrate - (S)-product (R)-substrate + (S)-substrate + (R)-product + (S)-product ^{Λ υϋ /o}

The racemisation catalyst according to the invention is represented by the formula L_mMⁿ _pX_qS_r wherein: Each L independently represents a complex bound ligand being a ketone or an alcohol; during at least part of the reaction at least one of them being the substrate alcohol or the corresponding ketone. The integer m is > 0 and varies during the process; m = 0 corresponds, for instance, to the complex form in which there is a vacant complexation site (see Fig. 1). The integer m may have any value, for instance a value up to 100, or even higher,

Each M independently represents a metal of group lll^a , lll or IV^b of the periodic system in oxidation state n; Each X independently represents a covalently bound ligand; at least one X being an alkoxide;

Each S independently represents a neutral ligand that may be present in the catalyst and does not participate in the reaction mechanism; m is an integer > 0; n represents the oxidation state of the metal and is > 1 ; p represent the number of metal atoms in the catalyst and is > 1 ; q is equal to n x p; r is > 0.

L and X are easily exchangeable ligands that can be exchanged by other ligands. A ligand L can get converted into a ligand X and vice versa, as illustrated for an arbitrary example in Fig 1 (The square means a vacant complexation site where for instance an alcohol or ketone can complex). In Fig. 1 steps 1-4 represent an illustration of the preparation of an active species, which preparation can be performed separately or in situ using methods known per se. Steps 5-8 represent the formation of racemic alcohol (alcohol B in the example of Fig. 1) and steps 9- 11 represent the propagation step with alcohol exchange/liberation of alcohol B and capture of a new molecule (C in the example of Fig. 1 , which equals A). The overall effect of the two parts (steps 5-8, formation of racemic alcohols, on one side and steps 9-11 , propagation by exchange, on the other side) is a nett racemisation. Each metal M is independently chosen from group lll^a, group lll^b or group IV^bof the periodic system, and for instance represents B, Al, Ga, In, Tl, Sc, Y, Ti, Zr, Hf, a lanthanide, or an actinide. Preferably M represents Al. The integer n represents the oxidation state of the metal and is > 1 , for instance 1 ,2,3 Each X independently represents a covalently bound ligand of which at least one is an alkoxide. Suitable examples are halides, in particular Cl^" or Br^"; alkyl groups with e.g. 1-12 C-atoms, for example methyl, ethyl, n-propyl (^πPr) or i-butyl ('Bu) groups, alkoxy groups with e.g. 1-12 C-atoms, for example n- pentoxy, i-propoxy, t-butoxy groups preferably the alkoxy groups derived from a secondary alcohol; anions derived from amides, amino alcohols or amines; a CN^" group; anionic aromatic ligands, in particular cyclopentadienyl (Cp), pentamethyl cyclopentadienyl (Cp*) or indenyl. The integer q is equal to n x p and may have any value larger than or equal to 1 , for instance between 1 and 100. However, q may also represent higher values. Each S independently represents an easily exchangeable neutral ligand, for example a phosphine in particular PPh₃ or PCy₃, a nitrile or a coordinating solvent molecule, especially tetrahydrofuran (THF), acetonitrile, dimethylfomamide, an alcohol, an amine, in particular a tertiary amine, for example Et₃N. The integer r may represent any value larger than or equal to 0, up to 100 or even higher. The integer p represents the number of metal atoms in the catalyst and may range from 1 to any value. If p>1 the catalyst is in the form of a cluster. Such clusters may contain many metal atoms, for instance up to 100; in practice often 1-10. Clusters of aluminium alkoxide catalysts are for instance described in "Catalytic applications of aluminum isopropoxide in organic synthesis" by Jerome et al. Chattem Chemicals, Inc., Chattenooga, TN, USA. Chemical Industries (Dekker) (2003), 89 (Catalysis of Organic Reactions), 97-114, and references cited therein. The active species of the racemisation catalyst can be prepared according to methods known in the art for instance as described for MPV catalysts; for instance as described in (a) Yamamoto, H.; O ganometallics in Synthesis, A Manual, Second edition (Manfred Schlosser (Editor), 2002, 535-577 John & Wiley & Sons Ltd. and references cited herein (b) Eisch, J.J.; Comprehensive Organometallic Chemistry II, a reveiew of the literature 1982- 1994 (Wilkinson, G; Stone, G.GA; Abel, E.W. ed.), Vol. 1 , 1995, 431-502,

Pergamon Press, Oxford. The activation may be performed separately or in situ. The racemisation catalyst may be as well in the form of a heterogeneous catalyst as in the form of a homogeneous catalyst. Acyl donors that can be used in the process of the present invention are the well known acyl donors as for instance described in Enzyme Catalysis in Organic Synthesis. A comprehensive Handbook, Second, Completely Revised and Enlarged Edition. (Editors: K. Drauz and H. Waldmann), Vol II, 2002, 472, 544, Wiley-VHS, and references cited herein and by U.T. Bornscheuer and R.J. Kazlauskas in the handbook Hydrolases in Organic Synthesis - Regio- and Stereoselective Biotransformations, 1999, Wiley-VCH, chapter 4.2.3., for instance carboxylic acid esters, amides or anhydrides. Examples of suitable acyl donors are esters of CrC₂₀ carboxylic acids, preferably isopropyl acetate, isopropenyl acetate, isobutyl acetate, vinyl acetate, ethyl acetate, isopropyl laureate, isopropenyl laureate or other esters of carboxylic acids and C-ι-C₇ alcohols. Most preferably not activated carboxylic acid esters are used, in particular esters of saturated alcohols, preferably secondary alcohols, for instance isopropanol. The esters preferably are derived from a carboxylic acid with 3-20 C- atoms, particularly a carboxylic acid with 4-20 C-atoms, preferably from butyric acid. A particularly preferred ester to be used as acylating agent is isopropyl butyric acid ester. If the acyl donor residue obtained in the conversion of the secondary alcohol with the acyl donor, is irreversibly removed from the phase in which the enantioselective conversion takes place, preferably an acyldonor is chosen such that the acyldonor itself is (relatively) not volatile under the reaction conditions while its acyl donor residue is volatile, and oxidation of the substrate is prevented as much as possible under the reaction conditions. Examples of such acyldonors are carboxylic acid esters of an alcohol with 1-4 C-atoms and a carboxylic acid with 3-20 C-atoms, particularly a carboxylic acid with 4-20 C- atoms, for instance isopropyl butyric acid ester. Preferably the acyl donor residue is removed from the reaction mixture, more preferably it is removed on a continuous basis, for example by preferentially transferring the acyl donor residue to another phase relative to the acyl donor and the other reaction components. This can be achieved by physical and by chemical methods, or by a combination thereof. Examples of physical methods by which the acyl donor residue can irreversibly be removed from the phase in which the stereoselective acylation reaction occurs, are selective crystallisation, extraction, complexing to an insoluble complex, absorption or adsorption; or by such a choice of the acyl donor that the acyl donor residue is sufficiently volatile relative to the reaction mixture, or is converted in situ into another compound that is sufficiently volatile relative to the reaction mixture to remove the acyl donor residue irreversibly e.g. by distillation from the reaction mixture, does not interfere with the catalytic racemisation reaction and is not a substrate for the enantioselective acylation catalyst; an example of the latter is the application of isopropyl acetate as acyl donor resulting in volatile isopropyl alcohol as acyl donor residue. In order to remove the acyl donor residue use can be made of a reduced pressure, depending on the boiling point of the reaction mixture. The pressure (at a given temperature) is preferably chosen in such a way that the mixture refluxes or is close to refluxing. In addition it is known to one skilled in the art that the boiling point of a mixture can be lowered by making an azeotropic composition of the mixture. Examples of chemical methods of removal are covalent bonding or chemical or enzymatic derivatization. The concentration at which the reaction is carried out is not particularly critical. The reaction can be carried out without a solvent. For practical reasons, for instance when solid or higly viscous reactants or reaction products are involved , a solvent may be used. The reaction can suitably be carried out at higher concentrations, for example at a substrate concentration higher than 0.5 M, in particular higher than 1M. The enantioselective conversion of the secondary alcohol in the ester can be carried out with the known R- or S-selective asymmetric acylation catalysts, for example as described by Christine E Garrett et al., J.Am.Chem. Soc. 120,(1998) 7479-7483 and references cited therein, and Gregory C. Fu in Chemical innovation/January 2000,3-5. Preferably the enantioselective conversion of the secondary alcohol in the ester is carried out enzymatically. Suitable enzymes that can be used in the method according to the invention are for example the known enzymes with hydrolytic activity and a high enantioselectivity in such reactions that are also active in an organic environment, for example enzymes with lipase or esterase activity or, when an amide is used as acyl donor, enzymes with amidase activity and esterase or lipase activity, for example originating from Pseudomonas, in particular Pseudomonas fluorescens, Pseudomonas fragi; Burkholderia, for example Burkholderia cepacia; Chromobacterium, in particular Chromobacte um viscosum; Bacillus, in particular Bacillus thermocatenulatus, Bacillus licheniformis; Alcaligenes, in particular Alcaligenes faecalis; Aspergillus, in particular Aspergillus niger, Candida, in particular Candida antarctica, Candida rugosa, Candida lipolytica, Candida cylindracea; Geotrichum, in particular Geotrichum candidum; Humicola, in particular Humicola lanuginosa; Penicillium, in particular Penicillium cyclopium, Penicillium roquefortii, Penicillium camembertii; Rhizomucor, in particular Rhizomucor javanicus, Rhizomucor miehei; Mucor, in particular Mucor javanicus; Rhizopus, in particular Rhizopus oryzae, Rhizopus arrhizus, Rhizopus delemar, Rhizopus niveus, Rhizopus japonicus, Rhizopus javanicus; Porcine pancreas lipase, Wheat germ lipase, Bovine pancreas lipase, Pig liver esterase. Preferably an enzyme originating from Pseudomonas cepacia, Pseudomonas sp., Burkholderia cepacia, Porcine pancreas, Rhizomucor miehei, Humicola lanuginosa, Candida rugose or Candida antarctica or subtilisin is used. If an R-selective enzyme is used, for example from Candida antarctica, the R-ester is obtained as product. Obviously, in case the S-ester is the desired product, acylation will be performed with an S-selective enzyme. Such enzymes can be obtained via generally known technologies. Many enzymes are produced on a technical scale and are commercially available. The enzyme preparation as used in the present invention is not limited by purity etc. and can be both a crude enzyme solution and a purified enzyme, but it can also consist of (permeabilised and/or immobilised) cells that have the desired activity, or of a homogenate of cells with such an activity. The enzyme can also be used in an immobilised form or in a chemically modified form. The invention is in no way limited by the form in which the enzyme is used for the present invention. Within the framework of the invention it is of course also possible to use an enzyme originating from a genetically modified microorganism. The quantities of racemisation catalyst to be used are not particularly critical. As a rule the racemisation catalyst is used in an amount of less than 50, preferably less than 20, more preferably less than 15 mol%, calculated relative to the substrate. The optimum quantities of both catalysts are linked to each other; the quantity of acylation catalyst is preferably adapted so that the overall reaction continues to proceed efficiently, that is to say, that the racemisation reaction does not proceed much slower than the acylation reaction and thus the e.e. of the remaining substrate does not become too high. The optimum balance between racemisation catalyst and acylation catalyst for a given reaction/catalyst system can simply be established by experimental means. The secondary alcohol that is used as substrate (substrate alcohol) can if desired be formed on beforehand from the corresponding ketone in a separate step (that principally does not need to be stereoselective at all) with the aid of a reducing ancillary reagent, the reduction preferably being catalysed by the racemisation catalyst, and a cheap and preferably volatile alcohol being used as reducing ancillary reagent (non stereoselective transfer hydrogenation). The substrate alcohol can optionally be formed in situ from the corresponding ketone with the aid of a reducing ancillary reagent. This gives the freedom of choice to employ substrate ketone or substrate alcohol or mixtures of both as substrate. The choice will depend on the availability and the simplicity of the synthesis. If the alcohol is formed in situ from the ketone, a hydrogen donor is also added as ancillary reagent. As ancillary reagent preferably a secondary alcohol is added to the reaction mixture that promotes the conversion of the ketone to the substrate alcohol and is not converted by the acylation catalyst. The ancillary reagent is preferably chosen in such a way that it is not also removed from the reaction mixture by the same irreversible removal method by which the acyl donor residue is removed, that this ancillary reagent is not acylated by the acylation catalyst, and has sufficient reduction potential, relative to the substrate ketone, for the creation of a redox equilibrium. Reducing agents other than alcohols can of course also be used as ancillary reagents. One skilled in the art can simply determine by experimental means which compounds are suitable for use as ancillary reagents in his reaction system. The product ester obtained may subsequently be isolated from the mother liquor using common practice isolation techniques, depending on the nature of the ester, for instance by extraction, distillation, chromatography or crystallization. If the product is isolated by crystallization further enantiomeric enrichment may be obtained. If desired, the mother liquor (which may contain the alcohol, ester and/or ketone involved in the reaction) may be recycled to the non stereoselective reduction, for instance (transfer)hydrogenation, or to the conversion of the mixture of the enantiomers of the alcohol to the enantiomerically enriched ester. Normally, before recycling the solids will be removed from the mother liquor and, according to common practice, a purge will be built in in order to prevent built up of impurities. If desired, the ester in the mother liquor will first be saponified. This is especially desirable if saponification of the ester under the reaction conditions of the non stereoselective reduction by means of (transfer) hydrogenation respectively the conversion of the mixture of the enantiomers of the alcohol to the enantiomerically enriched ester, is rather slow. With the process according to the invention an enantiomerically enriched ester can be obtained with enantiomeric excess (e.e.) larger than 80%, preferably larger than 90%, more preferably larger than 95%, most preferably larger than 98%, in particular larger than 99%, optionally after (re)crystallization. The enantiomerically enriched ester obtained can subsequently be used as such. If the alcohol is the desired product, the enantiomerically enriched ester is subsequently converted by a known procedure into the corresponding enantiomerically enriched alcohol. This can for example be effected by means of a conversion catalysed by an acid, base or enzyme. When an enantioselective enzyme is used the enantiomeric excess of the product alcohol can be increased. When the enantioselective esterification according to the invention has been carried out with the aid of an enzyme, the same enzyme can very suitably be used for the conversion of the enantiomerically enriched ester into the enantiomerically enriched alcohol. When the ultimate goal is the preparation of the alcohol, the acyl donor can be freely chosen in such a way that the physical or chemical properties of the acyl donor and the acyl donor residue are optimal for the irreversible removal of the acyl donor residue and the treatment of the reaction mixture. With the process according to the invention enantiomerically enriched alcohols with an enantiomeric excess (e.e.) larger than 95%, preferably larger than 98%, more preferably larger than 99% can be obtained, optionally after recrystallization and/or hydrolysis with the aid of an enantioselective enzyme. The alcohols thus obtained form commonly used building blocks in the preparation of for example liquid crystals, agrochemicals, food additives, fragrance material and pharmaceuticals, for example of secondary aliphatic alcohols or aryl alcohols, for example of 1-aryl-ethanols, -propanols, -butanols or - pentanols. In the literature applications are known of for example

1-(4-methoxyphenyl)-2-propenyl-1-ol in J. Heterocycl. Chem (1977), 14 (5), 717- 23; 1-(4-methoxyphenyl)-1-propanol in the preparation of liquid crystals and pharmaceuticals (JP-A-01000068); 1-(4-fluorophenyl)-1-ethanol in the preparation of antiarrhytmic agents (d-Sotalol; Org. Process Res. Dec. (1997), 1 (2), 176-178); 1-(2-chlorophenyl)-1-butanol in EP-A-314003; 1-(2,6-difluorophenyl)-1-ethanol in the preparation of antiepileptics (EP-A-248414); 1-(3,5-difluorophenyl)-1-pentanol in the preparation of liquid crystals (WO-A-8902425); 1-(3,4-difluorophenyl)-1- propanol in the preparation of means for the treatment of prostatic hyperplasia and prostatitis (WO-A-9948530); 1-(2-trifluoromethyl-phenyl)-1-ethanol in the preparation of a tocolytic oxytocine receptor antagonist (US-A-5726172); 1-(3-trifluoromethyl-phenyl)-1-ethanol in the preparation of a fungicide (JP-A- 10245889); 1-(3,5-bis(trifluoromethyl)-phenyl)-1-ethanol in the preparation of tachykinin receptor antagonist (US-A-5750549); 1-(2-fluor-5-nitro-phenyl)-1- ethanol in the preparation of a herbicide (DE-A-4237920);

1-(3-chloro-4,5-dimethoxy-phenyl)-1-ethanol in inhibitors of plasmogen activator inhibitor- 1 (WO-A-9736864); 1-methyl-3-(4-acetylphenyl)-1-propanol and 1-methyl-2-(4-acetylphenyl)-1 -ethanol in the preparation of liquid crystals (EP-A-360622/JP-A-03236347); 4-(1-hydroxyethyl)-benzonitrile in the preparation of nicotine amides as PDE4 D isoenzyme inhibitors (WO-A-9845268);

1-naphthalene-1 -ethanol in the separation of enantiomers via HPLC with chiral stationary phase on the basis of polysaccharides (WO-A-9627615); 1-naphthalene-1-propanol as an example of a product in the asymmetrically catalysed dialkyl zinc addition to aldehydes (Chem. Lett. (1983), (6), 841-2); 1-(1 ,3-benzodioxol-5-yl)-1-butanol in the preparation of a proteinase 3 inhibitor in the treatment of leukemia (US-A-8508056). The invention also relates to the preparation of an enantiomerically enriched alcohol from the enantiomerically enriched ester obtained. The invention will be elucidated on the basis of the examples, without however being limited by them. In all examples the enantioselective transesterification is catalysed by Novozym® 435 (Candida antartica). For the chiral alcohols tested the lipase is selective for the R-alcohol. The chiral esters were thus obtained with R-selectivity.

Examples are illustrated by following model reaction:

DKR-conditions

Analysis:

The enantiomeric excess of 1 and 2 as well as the quantification of 1 , 2 and 3 were performed by capillary chiral GC: Sample: ~20 μL of clear reaction mixture was diluted in CH₂CI₂ (1 mL) and injected on WCOT Fused Silica 25 m x 0.25 mm coating CP Chirasil- dex CB DF=0.25 column. Program: isothermal at 120°C R_t: acetophenone: 2.6 min, (R)-l-phenylethanol (1a): 4.8 min,

(S)-l-phenylethanol (1b): 5.1 min, (S)-l-phenylethyl butyrate (2a): 7.2 min and (R)-l-phenylethyl butyrate (2b): 7.5 min.

Example I A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (915 mg, 7.5 mmol), acetophenone (3) (900 mg, 7.5 mmol), isopropyl butyrate (1.95 g, 15 mmol) and o-xylene (20 mL). To the well-stirred reaction mixture was added Novozym^® 435 (150 mg). The reaction mixture was heated to 70°C and pressure was slowly decreased to 65-70 mbar in order to get distillation conditions. Smooth distillation of isopropanol generated by enzymatic transesterification, accompanied by distillation of small amounts of isopropyl butyrate and o-xylene was performed for 2 hours. The reaction mixture was degassed by 5 cycles of vacuum and purge of dry nitrogen. Then, solid aluminum isopropoxide (204.3 mg, 1 mmol) was added to the reaction mixture. Dynamic kinetic resolution was continued for 4 hours under similar distillative conditions giving 2 in 96 % yield and 98 % e.e.. The reaction mixture still presents starting material (1) in 22 % yield and 1 % e.e.. Calculated yields of 1 and 2 are based on the amount of starting material (1) introduced at the beginning of the reaction. The combined yields of: 1) recovered 1 and 2) product 2, is higher as the expected theoretical yield due to catalytic hydride transfer of 3 with residual isopropanol (acyl donor residue from enzymatic transesterification) as hydrogen source. Example II A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with acetophenone (3) (288 mg, 2.4 mmol), o-xylene (20 mL) and aluminum isopropoxide (163.4 mg, 0.8 mmol). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. The reaction mixture was heated to 70°C and pressure was slowly decreased to 65-70 mbar in order to get distillation conditions. Reaction was conducted for 1 hour without notible reduction of 3. The experiment was continued by the addition of (RS)-l-phenylethanol (1) (976 mg, 8 mmol), isopropyl butyrate (2.08 g, 16 mmol) and Novozym^® 435 (150 mg). The reaction mixture was degassed once more by dry nitrogen purge. The DKR was preceded at 70°C by contineous distillation of isopropanol and small amounts of isopropyl butyrate and o-xylene at 70 mbar. The enantiomeric convertion was carried out for 18 hours. Then, solvent and excess acyl donor were slowly distilled by lowering the pressure smoothly to 10 mbar giving a residue which contains 2 in 86 % yield and 97 % e.e.. Furthermore, 1 and 3 were recovered in 4 % (e.e.1 = 4 %) and 10 % yield respectively. Calculated yields are based on the amount of starting material (1) and the corresponding ketone 3 introduced at the beginning of the reaction.

DKR using AI('OPr)g as racemisation catalyst and various acyldonors.

Example A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (1.22 g, 10 mmol), acetophenone (3) (360 mg, 3 mmol), acyl donor (20 mmol) and toluene (20 mL). To the well-stirred reaction mixture was added Novozym^® 435 (see table). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Then, solid aluminum isopropoxide (204.3 mg, 1 mmol) was introduced into the reaction mixture. After degassing by dry nitrogen, AI(0'Pr)₃ was dissolved at 70°C. The reaction was continued at 70°C for 2 hours under contineous distillation of the acyl donor residue at pressures give in table below. Exp. Acyl donor E P 1 (R)-products Ester (mg) (mbar) (%) (%) (%) E.e. (%) 1 Isopropenyl 75 260 9 57 82 37 acetate 2 Isopropyl 75 260 45 66 61 46 acetate 3 150 260 32 74 72 62 4 Isopropyl 150 260 69 59 35 96 butyrate 5 150 200 39 72 64 97 6 75 200 51 69 53 95 7 Vinyl 75 200 29 49 55 78 butyrate

Example IV To a 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (915 mg, 7.5 mmol), acetophenone (900 mg, 7.5 mmol), isopropyl butyrate (1.95 g, 15 mmol) and o-xylene (20 mL). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added Novozym^® 435 (150 mg) and solid aluminum isopropoxide (245.1 mg, 1.2 mmol). The reaction mixture was heated to 70°C and pressure was slowly decreased to 90 mbar in first hour to 65 mbar in second hour. Smooth distillation of isopropanol generated by enzymatic transesterification, accompanied by distillation of small amounts of isopropyl butyrate and o-xylene was performed for 2 hours giving (R)-l-phenylethyl butyrate (2) in 89 % yield and 98 % e.e.. The reaction mixture still presents starting material (1) in 15 % yield and 21 % e.e.. The combined yields of 1 and 2 are higher then the expected theoretical yield. This can be attributed to reduction of 3 to 1 by catalytic hydride transfer as described in example I. Example V

Illustration ketone effect

A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (976 mg, 8 mmol), isopropyl butyrate (2.08 g, 16 mmol), toluene (20 mL) and Novozym^® 435 (150 mg). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added solid aluminum isopropoxide (163.4 mg, 0.8 mmol). The reaction mixture was heated to 70°C and pressure in the reaction vessel was slowly decreased to approximately 200 mbar in order to get distillation conditions. The isopropanol generated by enzymatic transesterification, together with small amounts of isopropyl butyrate and toluene, were slowly distilled under given conditions. The reaction was performed without ketone for 2 hours (step 1). Next step was initiated by the addition of benzophenone (291.5 mg, 1.6 mmol). The reaction was continued for 1 hour under ditillation conditions at 200 mbar (step 2). The observations are listed in table 1.

Table 1

Example VI A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (976 mg, 8 mmol), isopropyl butyrate (2.08 g, 16 mmol), benzophenone (728.9, 4 mmol), o-xylene (20 mL) and solid aluminum isopropoxide (163.4 mg, 0.8 mmol). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added Novozym^® 435 (150 mg). The reaction mixture was heated to 70°C and pressure in the reaction vessel was slowly decreased to 70 mbar in order to get distillation conditions. The isopropanol generated by enzymatic transesterification, together with small amounts of isopropyl butyrate and o-xylene, were slowly distilled under given conditions. The dynamic kinetic resolution was continued during 1 night (Table 2).

Table 2

Example VII

Illustration in situ catalyst preparation

Method A A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (976 mg, 8 mmol) and toluene (20 mL). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the reaction mixture, a 2 M solution of trimethyialuminum in toluene (0.4 ml, (0.8 mmol) was added. After stirring the reaction mixture for 5 minutes at room temperature, the temperature was increased to 70°C. Trimethyialuminum was allowed to react with 1 for 15 minutes. Experiment was continued by subsequent addition of isopropyl butyrate (2.08 g, 16 mmol), benzophenone (728.9, 4 mmol) and Novozym^® 435 (150 mg). To create destination conditions, the pressure was slowly decreased to 190 mbar within 1 hour. The isopropanol generated by enzymatic transesterification, together with traces of isopropyl butyrate and toluene, were slowly distilled. The dynamic kinetic resolution was continued for 5 hours (Table 4). Method B A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with toluene (20 mL) and isopropanol (192 mg, 3.2 mmol). The reaction mixture was degassed by 5 cycles of vacuum and pre-dried nitrogen purge. To the reaction mixture, a 2 M solution of trimethyialuminum in toluene (0.4 ml, (0.8 mmol) was added. Trimethyialuminum was allowed to react with isopropanol at 70°C for 15 minutes. Experiment was continued by subsequent addition of isopropyl butyrate (2.08 g, 16 mmol), (RS)-1 -phenylethanol (1) (976 mg, 8 mmol) benzophenone (728.9, 4 mmol) and Novozym^® 435 (150 mg). To create destination conditions, the pressure was slowly decreased to 190 mbar over a period of 1 hour. The isopropanol generated by enzymatic transesterification, together with small amounts of isopropyl butyrate and toluene, were slowly distilled under given conditions. The dynamic kinetic resolution was continued for 6 hours (Table 4).

Table 4

Racemisation catalyst prepared from 1 ,1 '-bi-2-naphthol and AI(CH₃)₃ Example VIII

A stock solution of 1 ,1 '-bi-2-naphthol in toluene was prepared under a dry atmosphere of nitrogen:

Into a 20-mL vial equipped with a magnetic stirrer was added 1 ,1'-bi-2-naphthol (286.3, 1 mmol) and toluene (10 ml). The vial was sealed, degassed and the ligand dissolved at 70°C. To avoid precipitation of the ligand at lower temperature, the stock solution was maintained at 70°C. Degassed toluene (9.5 mL) and a 2 M toluene solution of AI(CH₃)₃ (0.5 ml, 1 mmol) were placed in a dry three-neck round bottom flask of 100 mL equipped with thermometer, distillation unit and magnetic stirring bar under an atmosphere of dry nitrogen. To the AI(CH₃)₃-solution was added dropwise at room temperature (r.t.), the previously prepared warm stock solution of 1 ,1'-bi-2-naphthol. The reaction mixture was allowed to stir for 15 minutes at r.t.. (RS)-1 -phenylethanol (1) (1.22 g, 10 mmol) was slowly added and the mixture was stirred for 30 minutes at 70°C. Isopropyl butyrate (2.6 g, 20 mmol), acetophenone (3) (360 mg), 3 mmol) and Novozym^® 435 (150 mg) were subsequently added to the catalyst solution. The acyl donor residue (isopropanol), was distilled at a continuous base at 70°C and 190 mbar for 22 h giving 2b in 94 % yield and 98 % e.e.. Yield calculation of 2b is based on the total amount of 1 and 3 introduced at the beginning of the experiment.

Example IX

A stock solution of catalyst was prepared from AI(CH₃)₃ and 1 ,1'- bi-2-naphtol in toluene under a dry atmosphere of nitrogen: A 50-mL Schlenk equipped with a magnetic stirring bar was charged with freshly degassed toluene (9.5 mL) and a 2 M toluene solution of AI(CH₃)₃ (0.5 ml, 1 mmol). To the AI(CH₃)₃-solution was added dropwise at r.t., a warm solution of ,1'-bi-2-naphtol (286.3, 1mmol) in toluene (10 mL). After stirring the complex solution for 15 minutes at r.t., (RS)-l-phenylethanol (1) (122 mg, 1 mmol) was then added to the Al-complex solution and the resulting mixture was stirred for 15 minutes at 70°C and cooled to r.t.. The catalyst solution was used as such in DKR. For DKR purpose, a 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (1.15 g, 9.4 mmol), acetophenone (3) (360 mg, 3 mmol), toluene (18 mL), isopropyl butyrate (2.6 g, 20 mmol) and Novozym^® 435 (150 mg). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Then the catalyst solution (1 mL) was added to the reaction mixture. The temperature was increased to 70°C and the acyl donor residue (isopropanol) was distilled during the course of the DKR by smooth decrease of the pressure to190 mbar. An additional amount of catalyst solution (1 ml) was added after 1 hour and 17 hours respectively (total catalyst amount is 3 mol %). The reaction was continued for 18 hours by contineous distillation of isopropanol giving 2b in 95 % yield and 99 % e.e.. Yield calculation of 2b is based on the total amount of 1 introduced at the beginning of the experiment.

Example X

Partial oxidation substrate by acetone and subsequent DKR

A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (1.59 g, 13 mmol), toluene (20 mL), isopropyl butyrate (3.38 g, 26 mmol), acetone (1 mL) and Novozym^® 435 (190 mg). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Then, solid aluminum isopropoxide (266 mg, 1.3 mmol) was added to the reaction mixture and dissolved at 70°C. The Oppenauer-oxidation was carried out at 70°C and atmospheric pressure for 1 hour, and then the pressure was decreased to 210 mbar smoothly in order to get distillation of the liberating isopropanol and the remaining acetone. The DKR was continued for 1 night at 70°C and 210 mbar giving 2b in 83 % yield and 95 % e.e..

Illustration of MPV-DKR with in situ formation of racemic alcohol

Example XI A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with acetophenone (3) (960 mg, 8 mmol), isopropyl butyrate (2.08 g, 16 mmol), benzhydrol (1.77 g, 9.6 mmol) and toluene (20 mL). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Solid aluminum isopropoxide (163.4 mg, 0.8 mmol) and Novozym^® 435 (150 mg) was added to the well-stirred reaction mixture. The mixture was degassed once more by 5 cycles of vacuum and dry nitrogen purges. The Meerwein-Ponndorf-Verley reduction/dynamic kinetic resolution (MPV-DKR) was started by heating the reaction mixture to 70°C and by smooth distillation of the generated isopropanol at approximately 190 mbar from the reaction mixture. Removal of isopropanol was accompanied by distillation of small amounts of isopropyl butyrate and toluene. The MPV/DKR was continued for 1 night (table 6). Table 6

MPV-DKR of alifatic ketone

7b

Example XII A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with cyclohexylmethyl ketone (6) (1.01 g, 8 mmol), benzhydrol (1.77 g, 9.6 mmol) isopropyl butyrate (2.08 g, 16 mmol), toluene (20 mL) and Novozym^® 435 (150 mg). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. Solid aluminum isopropoxide (245 mg, 1.2 mmol) was added to the well- stirred reaction mixture and dissolved at 70°C. The mixture was degassed once more by 5 cycles of vacuum and dry nitrogen purge. The MPV-reduction of 6 was initially performed at atmospheric pressure for 2 hours. Then, the Meerwein- Ponndorf-Verley reduction/dynamic kinetic resolution (MPV-DKR) was conducted by smooth distillation of the generated isopropanol at approximately 210 mbar. Removal of isopropanol was accompanied by distillation of small amounts of isopropyl butyrate and toluene. The MPV/DKR was continued for 24 hours giving 7b in 83 % yield and 99 % e.e.. Illustration of DKR at high concentration Example XIII A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (6.1 g, 50 mmol), acetophenone (3) (1.8 g, 15 mmol), isopropyl butyrate (13 g, 100 mmol) and toluene (50 mL). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added solid aluminum isopropoxide (1.02 g, 5 mmol) and Novozym^® 435 (930 mg) respectively. The mixture was degassed once more by 5 cycles of vacuum and dry nitrogen purges. The reaction was started by heating to 70°C and by slow adjustment of the pressure to approximately 190 mbar to get distillative removal of isopropanol. In first 3 hours of the reaction, a significant volume of isopropanol, together with small amounts of acetone, isopropyl butyrate and toluene was collected. The reaction was terminated after 23 hours by cooling to room temperature. Filtration of Novozym^® 435 and solid side products through a glass filter followed by evaporation under reduced pressure of residual isopropyl butyrate and toluene gave a glacial colorless liquid of product. The crude product was hydrolysed in a mixture of methanol (25 mL) and 5 N KOH (12 mL) for 30 minutes at room temperature. Methanol was evaporated at rotary vapor at 40°C to get a mixture of 1b and residual 2 and 3 in water. The obtained mixture was diluted with water (38 mL) and extracted by 3 portions of 50 ml CH₂CI₂. Residual alumina solids were disolved by extraction of the combined CH₂CI₂ layers with 1 portion of 50 ml 1 N HCI from. After separation of the acidic water layer, the organic phase was dried over anhydrous Na₂S0₄. Filtration and evaporation under reduced pressure gave a mixture of 1b and 3 (6.36 g). Analysis by ¹H NMR turned out that only 7.7 % (m/m) of 3 was left in the isolated product. According to ¹H NMR and GC analysis the product (1 b) was isolated in 96 % yield and 90 % e.e.. Calculations of the isolated yield were based on the amount of starting material

(1)-

DKR of (RS)- -vinyl benzylalcohol. (RS)-α-vinyl benzylalcohol as representative substrate for (β,v)-unsaturated secondary alcohols

Example XIV A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with (RS)-α- vinylbenzylalcohol (4) (13.42 g, 10 mmol), benzophenone (546 mg, 3 mmol), toluene (10 mL), isopropyl butyrate (2.6 g, 20 mmol) and Novozym^® 435 (100 mg). The reaction mixture was degassed by 5 cycles of vacuum and dry nitrogen purge. To the well-stirred reaction mixture was added solid aluminum isopropoxide (204.25 mg, 1 mmol). The mixture was degassed once again by dry nitrogen. The reaction was started by heating the reaction mixture to 70°C and distillation of isopropanol at approximately 190 mbar. Distillation of isopropanol is accompanied by distillation of acetone, isopropyl butyrate. Distillation was continued for 24 hours giving 5b in 87 % yield and 96 % e.e..

Other MPV-catalysts Example XV

A stock reaction mixture of 1 was prepared seperately under a dry atmosphere of nitrogen:

A 100-mL Schlenk equipped with a magnetic stirring bar was charged with (RS)-1- phenylethanol (1) (6.10 g, 50 mmol), isopropyl butyrate (10.4 g, 80 mmol), acetophenone (3) (1.8 g, 15 mmol) and freshly degassed toluene (50 mL). The stock solution did contain approximately 0J9-mmol 1/g mixture. The well-stirred stock solution was degassed by dry nitrogen.

A 100 mL three-neck round bottom flask equipped with thermometer, distillation unit and magnetic stirring bar was charged with MPV-catalyst (0.5 mmol) under an atmosphere of dry nitrogen. The stock reaction mixture (12.4 g) and Novozym 435 (150 mg) was introduced to the catalyst containing reaction vessel and the total mixture was degassed by dry nitrogen. The DKR was performed at 70°C for 17 hours under contineous distillation of isopropanol at approximately 200 mbar giving 2b in yields given in table below. Distillation was accompanied by distillation of traces of toluene and isopropyl butyrate.

Claims

1. Process for the preparation of an enantiomerically enriched ester, in which a mixture of the enantiomers of the corresponding chiral secondary alcohol in the presence of a racemisation catalyst for the substrate is subjected to an enantioselective acylation with the aid of an acyl donor and a stereoselective acylation catalyst upon which the enantiomerically enriched ester and an acyl donor residue are formed, in the presence of a carbonyl compound and wherein the racemisation catalyst has the formula L_mMⁿ _pX_qS_r wherein: Each L independently represents a complex bound ligand being a ketone or an alcohol; Each M independently represents a metal of group III³ , III or IV^b of the periodic system in oxidation state n; Each X independently represents a covalently bound ligand; at least one X being an alkoxide; Each S independently represents a neutral ligand that may be present in the catalyst and does not participate in the reaction mechanism; m is an integer > 0; n represents the oxidation state of the metal and is > 1 ; p represent the number of metal atoms in the catalyst and is > 1 ; q is equal to n x p and is >1 ; r is > 0.

2. Process according to claim 1 wherein the chiral secondary alcohol is a secondary alcohol with a double or triple bond at the β,γ-position ((2,3)- position) with respect to the (chiral) alcohol carbon (1 -position),

3. Process according to claim 1 or 2 wherein M represents Al.

4. Process according to any one of claims 1 - 3, in which th enantioselective acylation is an enzymatic conversion.

5. Process according to any one of claims 1-4 wherein the mixture of the enantiomers of the chiral secondary alcohol is prepared in situ from the corresponing ketone.

6. Process according to claim 5, in which a mixture of the chiral secondary alcohol and the corresponding ketone is used as substrate.

7. Process according to claim 5 or 6, in which the chiral secondary alcohol is prepared from the corresponding ketone in the presence of a secondary alcohol as a hydrogen source.

8. Process according any one of claims 1-7, wherein the acyl donor residue obtained in the conversion of the secondary alcohol with the acyl donor, is irreversibly removed from the phase in which the enantioselective conversion takes place.

9. Process according to any one of claims 1-8, in which the acyl donor is chosen so that the acyl donor residue is converted in situ into another compound.

10. Process according to any one of claims 1-9, in which the acyl donor residue is removed via distillation under reduced pressure.

11. Process according to any one of claims 1 -10, in which the acyl donor is chosen from the group of carboxylic acid esters of a secondary alcohol .

12. Process according to claim 11 , in which the secondary alcohol is isopropanol.

13. Process according to any one of claims 1-12 wherein the acyl donor is derived from a carboxylic acid with 3-20 C-atoms.

14. Process according to claim 13 wherein the carboxylic acid is butyric acid.

15. Process according to any one of claims 1-14, wherein the enantiomerically enriched ester obtained is subsequently converted into the corresponding enantiomerically enriched alcohol.

16. Process according to claim 15, in which the conversion of the enantiomerically enriched ester into the enantiomerically enriched alcohol is carried out in the presence of an enantioselective enzyme.

17. Process according to any one of claims 1-16, in which the ester or alcohol obtained is subsequently converted into a liquid crystal, an agro chemical, a food additive, a fragrance material or a pharmaceutical.

18 Use of the esters or alcohols obtained with the process of any one of claims 1-16 in the preparation of liquid crystals, agro chemicals, food additives, fragrance materials or pharmaceuticals.