Method for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2- hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one

Abstract

Process for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy- ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (I)) or a tautomer thereof which comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3-methyl-5- phenyl-pyrimidin-4-one (compound (II)) with a silane compound in the presence of a chiral copper compound.

Description

[0001] Method for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2- hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one

[0002] The present invention relates to a method for preparing 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy- ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I) as depicted below or a tautomer thereof or enantiomerically enriched forms thereof.

[0003] Technical background

[0004] 2-[2-(2-Chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (I) (or its tautomer) has been found to be a valuable intermediate in the preparation of 2,3- dihydrothiazolo[3,2-a]pyrimidinium compounds, and more specifically of 3-(2-chlorothiazol-5-yl)- 8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and enantiomerically enriched forms thereof if 2-[2-(2-chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one is used in an enantiomerically enriched form. Said pyriminidium compounds have insecticidal properties and are known, for example, from WO 2018 / 177970 or WO 2014 / 167084.

[0005] The methods thus far known for the preparation of these pyriminidium compounds are cumbersome and not yet satisfactory.

[0006] In WO 2018 / 177970, WO 2018 / 197541 and WO 2018 / 202654, non-racemic 2,3-dihydrothiazolo[3,2-a]pyrimidinium compounds are prepared by reaction of a non-racemic 4- heteroaryl-substituted thiazolidin-2-imine with a 2-substituted malonic acid derivative. In WO 2018 / 177970 and WO 2018 / 197541, the non-racemic 4-heteroaryl-substituted thiazolidin-2- imine is in turn prepared by catalytic asymmetric hydrogenation of a 1-heteroaryl-substituted ethanimine carrying in 2-position a leaving group. The resulting amine is then reacted with an isothiocyanate to the thiazolidin-2-imine. The reaction sequence is described in WO 2018 / 197541 as follows:

[0007]

[0008] RAis a sulfanyl or sulfinyl, phosphoroxy, alkoxy or benzyl group; Het is optionally substituted pyridin-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, R1is a (cyclo)aliphatic group and R2is 5- or 6-membered carbo- or heterocyclic ring.

[0009] In WO 2018 / 177970 the amine VII is obtained via another reaction path from the corresponding sulfinylimine.

[0010] WO 2018 / 177970 and WO 2018 / 202654 describe a further access to the non-racemic 4- heteroaryl-substituted thiazolidin-2-imine. This is here prepared starting from a heteroarylmethyl ketone, where the methyl group carries a leaving group, conversion of this leaving group into an alkylcarbonyloxy group, hydrolysis of the latter to a hydroxyl group, reaction of the resulting heteroarylhydroxymethyl ketone with a sulfamoyl halide to a 4-heteroaryl-5H-oxathiazole 2,2- dioxide, submission of the latter to a catalytic asymmetric hydrogenation to yield a non-racemic 4-heteroaryloxathiazolidine 2,2-dioxide and reaction thereof with an isothiocyanate to the thiazolidin-2-imine. The reaction sequence is described in WO 2018 / 202654 as follows: Het is optionally substituted pyridi n-3-yl, thiazol-5-yl or pyrimidin-5-yl, W and LG are leaving groups, M2is Li, Na, K, Al, Ba, Cs, Ca or Mg, RACis alkylcarbonyl, X1is halogen, R1is a (cyclo)aliphatic group and R2is 5- or 6-membered carbo- or heterocyclic ring.

[0011] WO 2022 / 200594 and WO 2022 / 157316 disclose processes for the reduction of compound II using formiates or hydrogen.

[0012] These methods are however not very economic. Some reagents are expensive, recycling of some of the reagents which are not or not entireyl consumed is difficult, the overall yield is not satisfactory and too many reaction steps are involved.

[0013] Summary of the invention

[0014] The present invention is directed to new processes for the preparation of 2-[2-(2-chlorothiazol-5- yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one and especially a process for the preparation of an enantiomerically enriched form thereof which yields the S or R enantiomer with high selectivity.

[0015] The problem is solved by a method for preparing an enantiomerically enriched form of 2-[2-(2- chlorothiazol-5-yl)-2-hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one of the formula (I): where the asterisk * shows the stereogenic center; or a tautomer thereof; which method comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl-6-hydroxy-3- methyl-5-phenyl-pyrimidin-4-one of the formula (II) or a tautomer thereof with a silane in the presence of a chiral copper catalyst; to obtain an enantiomerically enriched form of the pyrimidinone of the formula (I) or of a tautomer thereof.

[0016] The compound according to formula (I) and its tautomers are herein referred to as “compound

[0017] (I)” or “compound I’’ or “PAL”.

[0018] The compound according to formula (II) and its tautomers are herein referred to as “compound

[0019] (II)” or “compound II” or “PKET”.

[0020] Detailed description of the invention

[0021] Definitions

[0022] “Enantiomerically enriched form” of compound (I) or the compound (I) “in enantiomerically enriched form” and similar terms denote a non-racemic compound (I) in which either the S enantiomer or the R enantiomer predominates or is even present as only stereoisomer. The compound (I) has one stereogenic center which is at the aliphatic carbon atom carrying the OH group and marked with an asterisk.

[0023] The organic moieties mentioned below are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

[0024] The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

[0025] The term "alkyl" as used herein and in the alkyl moieties of alkoxy refers to saturated straight-chain (linear) or branched hydrocarbon radicals having 1 to 3 ("Ci-C3-alkyl "), 1 to 4 ("Ci-C4-alkyl "), 1 to 6 ("Ci-C6-alkyl”), 3 to 4 ("C3-C4-alkyl ") or 3 to 6 ("C3- Ce-alkyl”) carbon atoms. Ci-C3-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 3 carbon atoms. Examples are methyl, ethyl, n-propyl or isopropyl. Ci-C4-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Ci-C6-Alkyl denotes a saturated linear or branched aliphatic radical with 1 to 6 carbon atoms. Examples are, in addition to those mentioned for Ci-C4-alkyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dime- thylpropyl, 1 -ethyl propyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethyl- butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1 ,2-tri- methylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl. C3-C4-AI- kyl denotes a saturated linear or branched aliphatic radical with 3 or 4 carbon atoms. Examples are n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Ca-Ce-Alkyl denotes a saturated linear or branched aliphatic radical with 3 to 6 carbon atoms. Examples are, in addition to those mentioned for C3-C4-alkyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dime- thylpropyl, 1 -ethyl propyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethyl- butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1 ,2-tri- methylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0026] The term " Ci-C4-haloalkyl" as used herein, which can also be expressed as "alkyl” which is partially or fully halogenated", refers to straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above. Examples are chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoro- ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2- dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl. Ci-Cs-haloalkyl is additionally, for example, 1 -fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1 , 1-difluoropropyl, 2,2-difluoropropyl, 1 ,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1 , 1 , 1 -trifluoroprop- 2-yl, 3-chloropropyl, 4-chlorobutyl and the like.

[0027] The term "Ci-C4-alkoxy" refers to a Ci-C4-alkyl group, as defined above, attached via an oxygen atom to the remainder of the molecule. Examples are methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, 1 -methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1 ,1-dimethylethoxy (tert-butoxy).

[0028] If not specified otherwise, amino is NH2.

[0029] Ci-C4-Alkylamino is a group -NHR, where R is a Ci-C4-alkyl group, as defined above.

[0030] Di-(Ci-C4-alkyl)-amino is a group -NRR’, where R and R’, independently of each other, are a Ci-C4-alkyl group, as defined above.

[0031] Imino is a group containing a C=N double bond. The C=N bond can also be part of a heterocycle.

[0032] In chiral ligands which comprise just one phosphino group and additionally at least one of a phosphine oxide group, an amino group or an imino group, the amino and imino groups are nitrogen-containing groups in which the nitrogen atom can coordinate to a central metal in a complex. In this context, unlike defined above, the amino group is not limited to NH2, but is a group -NRR’, where R and R’, independently of each other, are hydrogen or an organic radical. Moreover, the amino or imino group can also be part of a heterocyclic ring, as is for example the case in ligand L.5 (depicted below). A phosphino group in this context is a group -PRR’, where R and R’, independently of each other, are hydrogen or an organic radical; and a phosphine oxide group is a group -P(=O)RR’, where R and R’, independently of each other, are hydrogen or an organic radical.

[0033] The 5- or 6-membered heteroaromatic ring having 1 , 2 or 3 heteroatoms selected from O, N and S are ring members may be attached to the remainder of the molecule via a carbon ring member or via a nitrogen ring member. As a matter of course, the heteroaromatic ring contains at least two carbon ring atoms. The heteroaromatic ring contains 1, 2 or 3 nitrogen atoms as ring members, or contains 1 oxygen atom and optionally one or two nitrogen atoms as ring members, or contains one sulfur atom and optionally one or two nitrogen atoms as ring members. Examples are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-1- pyrazolyl, 3",-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1 -imidazolyl , 2-imidazolyl, 4-imidazolyl, 5- imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1 ,3,4-triazol-1-yl, 1 ,3,4-triazol- 2-yl, 1 ,3,4-triazol-3-yl, 1 ,2,3-triazol-1-yl, 1 ,2,3-triazol-2-yl, 1 ,2,3-triazol-4-yl , 1 ,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,3,4-oxadiazol-2-yl, 1 ,2,5-thiadiazol-3-yl, 1,2,3- thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3- pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2- yl, 1 ,2,4-triazin-3-yl, 1 ,2,4-triazin-5-yl, and the like.

[0034] If R3and R4, together with the nitrogen atom to which they are bonded, form a 5- or 6- membered saturated heterocyclic ring (see below definition), the NR3R4group is 1 -pyrrolidinyl or 1-piperidinyl.

[0035] Group VIII metal catalysts refer to catalysts having a metal from group VIII of the periodic system of elements as central metal. Group VIII relates to the IUPAC group definition valid before 1985 and corresponds to groups 8, 9 and 10 of the current IUPAC group designation.

[0036] Compound (I) can be present as a tautomer thereof or as a mixture of different tautomeric forms. An example for a tautomeric form of the compound of the formula (I) as depicted above is the following formula:

[0037] Mixtures of different tautomeric forms are for example mixtures of this tautomer and the tautomer depicted above as formula (I).

[0038] Also compound II can be present as a tautomer thereof or as a mixture of different tautomeric forms. An example for a tautomeric form of the compound of the formula 1 as depicted above is the following formula:

[0039] Mixtures of different tautomeric forms are for example mixtures of this tautomer and the tautomer depicted above as formula (II).

[0040] For the sake of simplicity, reference is made herein only to compounds (I) and (II) are mentioned. Nevertheless, all embodiments also relate to their tautomers and mixtures of different tautomeric forms thereof.

[0041] The reaction sequence of the method of the invention can be depicted as follows:

[0042] According to the inventive process, the keto group in alpha position to the thiazolyl ring is reduced to give an alcohol group. This is done by through the use of a reducing agent. Typically, said reducing agent used in inventive processes is a silane.

[0043] Preferred reducing agents are phenyl silane, diphenyl silane or diethyl silane.

[0044] Typically, such reducing agents are used in an excess relative to compound (II). Typically, when the silane is a monosilane, silanes are used in an amount of 1.0 to 20.0 mol per mol of compound (II), preferably 1.1 to 10 mol or 1.5 to 8 mol per mol of compound (II).

[0045] Processes of the invention are carried out in the presence of a chiral metal compound, typically a copper compound.

[0046] Typically, such copper compound is present in the inventive processes in substoichiometric amounts, based on the molar amount of Cu ions and of compound (II). Thus, such copper compounds are typically present in catalytic amounts and such copper compounds act as a catalyst for the reduction reaction. Said copper compound is herein also referred to as the “copper catalyst”.

[0047] Preferably, the chiral copper catalyst, calculated on the basis of the copper content, is used in an amount of 0.01 to 10 mol%, more preferably from 0.05 to 5 mol-%, even more preferably from 0.1 to 5 mol-%, and in particular from 1 to 5 mol-%, relative to 1 mol of compound (II) According to the invention, the reduction reaction is carried in the presence of a chiral copper compound that can also be referred to as a copper complex. The term “copper compound” as used herein includes copper complexes. Typically, such chiral copper compound comprises one or more chiral ligands L coordinated to copper.

[0048] In one embodiment, said copper compound, in addition to the chiral ligands L as defined below, contains one or more further ligands, such further ligands may be coordinated to the copper center, or may be present as counterions.

[0049] In one embodiment, such further ligands are selected from halides (e.g. Cl, Br or I; among which Cl is preferred), sulfonate (e.g. triflate, mesylate, tosylate or nonaflate; among which tri- flate is preferred), carboxylate (e.g. acetate, trifluoroacetate, benzoate).

[0050] Such chiral copper compound is typically prepared from an achiral copper precursor (also referred to as the “copper source” or the “catalyst precursor”).

[0051] Said copper precursor is typically an achiral salt of copper. Typically, said copper precursor is a salt of copper in an oxidation state of +1, +11. It is also possible that such copper precursor has a calculated oxidation state between +1 and +11. It is also possible to use mixtures of more that one copper salts as the copper precursor.

[0052] In one embodiment, said copper precursor is a salt of Cu(l).

[0053] In one embodiment, salt copper precursor is a salt of Cu(ll).

[0054] In one embodiment, said copper precursor is selected from Cu(OAc)2, CuCI, CuBr, CuF, Cui, Cu(acac)2, CuSC , Cu(NOs)2, CuOTf or mixtures thereof.

[0055] (OAc means acetate, acac means acetylacetonate, OTf means triflate).

[0056] In one embodiment, such chiral copper compound is preformed prior to its use in processes of the invention and is added to the reaction mixture as such.

[0057] In one embodiment, said chiral copper compound is prepared in situ from a copper precursor and one or more chiral ligands L.

[0058] Preformed catalysts are typically prepared by mixing the catalyst precursor with the chiral ligand L (herein also referred to as the “chiral ligand” or “ligand L”). The reaction is generally carried out in a solvent. The catalyst precursor and the chiral ligand L are generally mixed in a molar ratio of from 2:1 to 1 :2, preferably 1.5:1 to 1 :1.5, in particular 1.3:1 to 1 :1.3 and specifically 1:1 to 1 :1.3, where the molar ratio is based on the amount of transition metal (in mol) in the catalyst precursor. The formed catalyst can either be isolated before being used in the reaction or the obtained reaction mixture can be used without isolation of the complex.

[0059] If the catalyst is formed in situ, catalyst precursor and chiral ligand L come into contact with each other in the presence of at least one of the reactants, e.g. of starting compound (II) and / or silane. In this case, too, the catalyst precursor and the chiral ligand L are generally used in a molar ratio of from 2:1 to 1 :2, preferably from 1.5:1 to 1 :1.5, in particular from 1.3:1 to 1:1.3 and specifically from 1:1 to 1 :1.3, where the molar ratio is based on the molar amount of copper in the catalyst precursor. In one embodiment, the catalyst is preformed. In a particular embodiment, catalyst precursor and the chiral ligand are reacted with each other, and the obtained reaction mixture is used, i.e. it is brought into contact with compound (II), without isolation of the preformed catalyst. In another particular embodiment, catalyst precursor and the chiral ligand L are reacted with each other, and the obtained complex is isolated and if desired purified before being used in the reduction method of the present invention. Isolation can be carried out by usual means, such as simply removing the solvent, optionally after aqueous workup, or extracting the reaction mixture and then removing the solvent. Further purification can for example be carried out by (recrystallization.

[0060] Specifically, the catalyst is obtainable by reacting one of the aforementioned chiral ligands L with Cu(OAc)2, CuCI, CuBr, CuF, Cui, Cu(acac)2, CuSO4, Cu(NO3)2, CuOTf or mixtures thereof in a molar ratio of from 2:1 to 1 :2, preferably from 1.5:1 to 1 :1.5, in particular from 1.3:1 to 1 :1.3 and specifically from 1 :1 to 1 :1.3, where the molar ratio is based on the amount of transition metal (in mol) in the catalyst precursor.

[0061] In one embodiment said chiral ligand L contains phosphorous atoms. In one embodiment, said chiral ligand contains phosphine groups.

[0062] In one embodiment, said chiral ligand is a bisphosphine.

[0063] In one embodiment, said chiral ligand is a bisphosphine and contains a biphenyl or binaphtyl moiety and said two phosphine groups bound to different aromatic moieties of said biphenyl, bispyridyl or binaphthyl moiety.

[0064] In one embodiment, the chiral transition metal catalyst contains one bidentate bisphosphine ligand.

[0065] In one embodiment, said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formulae L1 to L.18

[0066]

[0067] L.14.1 L.14.2 where in L.1 :

[0068] R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Ci-Ce-alkyl, Cs-Cs-cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; in L.2:

[0069] R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Ci-Ce-alkyl, Cs-Cs-cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl; in L.3:

[0070] R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; and

[0071] R3and R4are methyl; in L.4:

[0072] R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Ci-Ce-alkyl, Cs-Cs-cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; in L.5:

[0073] R1is phenyl or naphthyl, where phenyl and naphthyl may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; and

[0074] R2is Ci-C4-alkyl; in L.6:

[0075] R1is selected from the group consisting of Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy;

[0076] R2is phenyl; and

[0077] R3and R4, independently of each other, are Ci-C4-alkyl; in L.7:

[0078] R1is phenyl; in L.8:

[0079] R1and R2are phenyl; in L.9:

[0080] R1is Cs-Ce-cycloalkyl;

[0081] R2is phenyl; and

[0082] R3and R4, independently of each other, are Ci-C4-alkyl; in L.10:

[0083] R1and R2are phenyl; and

[0084] R3and R4, independently of each other, are Ci-C4-alkyl; in L.1 1 : each R1is independently selected from the group consisting of Ci-Ce-alkyl, phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkoxy, tri- fluoromethyl, amino, Ci-C4-alkylamino and di-(Ci-C4-alkyl)-amino; and a 5- or 6-membered heteroaromatic ring having 1 , 2 or 3 heteroatoms selected from O, N and S are ring members;

[0085] R2aand R2dare hydrogen; and

[0086] R2band R2care Ci-C4-alkoxy; or

[0087] R2aand R2bform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or -O-CH2-CH2-O-; and

[0088] R2° and R2dform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or -O-CH2-CH2-O-; or

[0089] R2aand R2dare hydrogen; and R2band R2cform together a bridging group -O-(CH2)n-O- with n = 1 to 5, preferably 2 to 4, preferably 3;or

[0090] R2a and R2d are identical and halogen, especially Cl; and R2b and R2c are identical and Ci- C4-alkoxy, especially methoxy; or

[0091] R2aand R2bform together a bridging group -O-CF2-O-; and simultaneously R2° and R2dform together a bridging group -O-CF2-O-; in L.12: each R1is independently phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy, in L.13: each R1ais independently CrCe-alkyl; each R1bis independently Ci-Ce-alkyl; where R1aand R1bbound on the same P atom are not identical; in L.14.1 and L.14.2:

[0092] R1is phenyl; in L.15: each R1is independently phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; each R5is independently H or methyl; and n is 0, 1 or 2; in L.16:

[0093] R1and R2as well as R3and R4form a bridging group -CH2-(CH2)n-CH2, with n being a number from 0 to 2, preferably 0 or 1 , more preferably 0;

[0094] R5, R6, R7and R8are alkyl, preferably methyl. in L.17:

[0095] R1is an aryl rest, preferably a phenyl rest that is optionally substituted, more preferably R1 is phenyl or xylyl, especially preferably, R1is phenyl;

[0096] R2is alkyl or alkoxy, preferably C1-C4 alkyl or C1-C4 alkoxy, more preferably methyl or methoxy, even more preferably methoxy. in L18:

[0097] R1an R2are different; preferably R1and R2are different alkyl groups; in one embodiment R1is tert.-butyl and R2is methyl

[0098] In one embodiment, said chiral ligand has the structure L.1 where: the two radicals R1are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; and the two radicals R2are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl;

[0099] In one embodiment, said chiral ligand has the structure L.2 where:

[0100] R1is selected from the group consisting of CrCe-alkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl; and the two radicals R2are identical and selected from the group consisting of Ci-C3-alkyl, C3-C6- cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl;

[0101] In one embodiment, said chiral ligand has the structure L.3 where: the two radicals R1are identical and selected from the group consisting of Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4- alkyl and Ci-C4-alkoxy; the two radicals R2are identical and selected from the group consisting of Cs-Cs-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4- alkyl and Ci-C4-alkoxy; and

[0102] R3and R4are methyl;

[0103] In one embodiment, said chiral ligand has the structure L.4 where: the two radicals R1are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; the two radicals R2are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl;

[0104] In one embodiment, said chiral ligand has the structure L.5 where: the two radicals R1are identical and selected from the group consisting of phenyl or naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; and

[0105] R2is Ci-C4-alkyl;

[0106] In one embodiment, said chiral ligand has the structure L.6 where: the two radicals R1are identical and selected from the group consisting of Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4- alkyl and Ci-C4-alkoxy;

[0107] R2is phenyl; and

[0108] R3and R4are identical and are Ci-C4-alkyl;

[0109] In one embodiment, said chiral ligand has the structure L.7 where:

[0110] R1is phenyl;

[0111] In one embodiment, said chiral ligand has the structure L.8 where:

[0112] R1and R2are phenyl;

[0113] In one embodiment, said chiral ligand has the structure L.9 where: the two radicals R1are identical and are Cs-Ce-cycloalkyl;

[0114] R2is phenyl; and

[0115] R3and R4are identical and are Ci-C4-alkyl; In one embodiment, said chiral ligand has the structure L.10 where:

[0116] R1and R2are phenyl; and

[0117] R3and R4are identical and are Ci-C4-alkyl;

[0118] In one embodiment, said chiral ligand has the structure L.11 where: each R1is independently selected from the group consisting of Ci-Cs-alkyl, phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C -alkyl, C1-C4- alkoxy, trifluoromethyl, amino, Ci-C4-alkylamino and di-(Ci-C4-alkyl)-amino; and a 5- or e- membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from O, N and S are ring members;

[0119] R2aand R2dare hydrogen; and

[0120] R2band R2care Ci-C4-alkoxy; or

[0121] R2aand R2bform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or-O-CHz-CHz-O-; and

[0122] R2cand R2dform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or -O-CH2-CH2-O-; or

[0123] R2aand R2dare hydrogen; and R2band R2° form together a bridging group -O-(CH2)n-O- with n = 1 to 5, preferably 2 to 4, preferably 3;or

[0124] R2aand R2dare identical and halogen, especially Cl; and R2b and R2c are identical and C1-C4- alkoxy, especially methoxy; or

[0125] R2aand R2bform together a bridging group -O-CF2-O-; and simultaneously R2cand R2dform together a bridging group -O-CF2-O-;

[0126] In one embodiment, said chiral ligand has the structure L.11 where: the four radicals R1are identical and selected from the group consisting of Ci-Ce-alkyl, phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkoxy, amino, Ci-C -alkylamino and di-(Ci-C4-alkyl)-amino; and a 5- or 6-mem- bered heteroaromatic ring having 1 , 2 or 3 heteroatoms selected from O, N and S are ring members;

[0127] R2aand R2dare hydrogen; and

[0128] R2band R2care identical and are Ci-C4-alkoxy; or

[0129] R2aand R2bform together a bridging group -CH=CH-CH=CH-; and simultaneously R2cand R2dform together a bridging group -CH=CH-CH=CH-; or

[0130] R2aand R2bform together a bridging group -O-CH2-O-; and simultaneously R2° and R2dform together a bridging group -O-CH2-O-;

[0131] In one embodiment, said chiral ligand has the structure L.12 where: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy,

[0132] In one embodiment, said chiral ligand has the structure L.13 where: the two radicals R1aare identical and are Ci-Ce-alkyl; the two radicals R1bare identical and are Ci-C6-alkyl; where R1aand R1bbound on the same P atom are not identical;

[0133] In one embodiment, said chiral ligand has the structure L.14.1 or L.14., where:

[0134] R1is phenyl;

[0135] In one embodiment, said chiral ligand has the structure L.15 where: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C^alkoxy; each R5is independently H or methyl; and n is 0, 1 or 2.

[0136] In one embodiment, said chiral ligand has the structure L.16 where:

[0137] R1and R2as well as R3and R4form a bridging group -CH2-(CH2)n-CH2, with n being a number from 0 to 2, preferably 0 or 1 , more preferably 0;

[0138] R5, R6, R7and R8are alkyl, preferably methyl.

[0139] In one embodiment, said chiral ligand has the structure L.17 where:

[0140] R1is an aryl rest, preferably a phenyl rest that is optionally substituted, more preferably R1 is phenyl or xylyl, especially preferably, R1is phenyl;

[0141] R2is alkyl or alkoxy, preferably C1-C4 alkyl or C1-C4 alkoxy, more preferably methyl or methoxy, even more preferably methoxy.

[0142] In one embodiment, said chiral ligand has the structure L.18 where:

[0143] R1an R2are different; preferably R1and R2are different alkyl groups; in one embodiment R1is tert-butyl and R2is methyl

[0144] In one embodiment, said chiral ligand has the structure L.1 where: the two radicals R1are identical and selected from the group consisting of Ca-Cs-alkyl, cyclohexyl, phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; and naphthyl; and the two radicals R2are identical and selected from the group consisting of Ca-Cs-alkyl, cyclohexyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl;

[0145] In one embodiment, said chiral ligand has the structure L.2 where:

[0146] R1is selected from the group consisting of Cs-Ce-alkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl; and the two radicals R2are identical and selected from the group consisting of C3-C5-alkyl, cyclohexyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl;

[0147] In one embodiment, said chiral ligand has the structure L.3 where: the two radicals R1are identical and selected from the group consisting of C3-C6-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of C1-C4- alkyl and Ci-C4-alkoxy; the two radicals R2are identical and selected from the group consisting of Cs-Cs-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of C1-C4- alkyl and Ci-C4-alkoxy; and

[0148] R3and R4are methyl;

[0149] In one embodiment, said chiral ligand has the structure L.4 where: the two radicals R1are identical and selected from the group consisting of Cs-Cs-alkyl, cyclohexyl and phenyl; the two radicals R2are identical and selected from the group consisting of Cs-Cs-alkyl, cyclohexyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl;

[0150] In one embodiment, said chiral ligand has the structure L.5 where: the two radicals R1are identical and are naphthyl; and

[0151] R2is C3-C4-alkyl;

[0152] In one embodiment, said chiral ligand has the structure L.6 where: the two radicals R1are identical and selected from the group consisting of cyclohexyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-al- kyl and Ci-C4-alkoxy;

[0153] R2is phenyl; and

[0154] R3and R4are methyl;

[0155] In one embodiment, said chiral ligand has the structure L.7 where:

[0156] R1is phenyl;

[0157] In one embodiment, said chiral ligand has the structure L.8 where:

[0158] R1and R2are phenyl;

[0159] In one embodiment, said chiral ligand has the structure L.9 where: the two radicals R1are identical and are cyclohexyl;

[0160] R2is phenyl; and

[0161] R3and R4are methyl;

[0162] In one embodiment, said chiral ligand has the structure L.10 where:

[0163] R1and R2are phenyl; and

[0164] R3and R4are methyl;

[0165] In one embodiment, said chiral ligand has the structure L.11 where: the four radicals R1are identical and selected from the group consisting of C3-C6-alkyl, phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of C3-C4-alkyl, Ci-C4-alkoxy and di-(Ci-C4-alkyl)-amino; and furyl;

[0166] R2aand R2dare hydrogen; and

[0167] R2band R2care identical and are Ci-C4-alkoxy; or

[0168] R2aand R2bform together a bridging group -CH=CH-CH=CH-; and simultaneously R2cand R2dform together a bridging group -CH=CH-CH=CH-; or

[0169] R2aand R2bform together a bridging group -O-CH2-O-; and simultaneously R2cand R2dform together a bridging group -O-CH2-O-;

[0170] In one embodiment, said chiral ligand has the structure L.12 where: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy,

[0171] In one embodiment, said chiral ligand has the structure L.13 where: the two radicals R1aare identical and are Cs-Cs-alkyl; the two radicals R1bare identical and are Ci-Ce-alkyl; where R1aand R1bbound on the same P atom are not identical;

[0172] In one embodiment, said chiral ligand has the structure L.14.1 or 14.2 where: R1is phenyl;

[0173] In one embodiment, said chiral ligand has the structure L.15 where: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; each R5is independently H or methyl; and n is 0, 1 or 2.

[0174] In one embodiment, the chiral ligands are selected from the group consisting of the ligands of formulae L.1.1 to L.15.2:

[0175]

[0176] 

[0177]

[0178] L.9.1

[0179]

[0180] 15 L.13.1 L.13.2

[0181] L.15.1 L.15.2 L.17 where R1, R2, R3, R4, R5and n are as defined as above.

[0182] In one embodiment, the rests in structures L.1 to L.18 have the following meanings: in L.1.1 , L.1.2, L.1.3 and L.1.4: the two radicals R1are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; and the two radicals R2are identical and selected from the group consisting of Ci-Ce-alkyl, C3-C6- cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; in L.2.1 , L.2.2, L.2.3, L.2.4, L.2.5, L.2.6, L.2.7 and L.2.8:

[0183] R1is selected from the group consisting of Ci-C6-alkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl; and the two radicals R2are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl; in L.3.1 , L.3.2, L.3.3 and L.3.4: the two radicals R1are identical and selected from the group consisting of Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; the two radicals R2are identical and selected from the group consisting of C3-C6-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; and R3and R4are methyl; in L.4.1, L.4.2, L.4.3 and L.4.4: the two radicals R1are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; the two radicals R2are identical and selected from the group consisting of Ci-Cs-alkyl, C3-C6- cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; in L.5.1 , L.5.2, L.5.3 and L.5.4: the two radicals R1are identical and selected from the group consisting of phenyl or naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; and R2is Ci-C4-alkyl; in L.6.1 , L.6.2, L.6.3, L.6.4, L.6.5, L.6.6, L.6.7 and L6.8: the two radicals R1are identical and selected from the group consisting of Cs-Cs-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy;

[0184] R2is phenyl; and

[0185] R3and R4are identical and are Ci-C4-alkyl; in L.7.1 , L.7.2, L.7.3 and L.7.4:

[0186] R1is phenyl; in L.8.1 , L.8.2, L.8.3 and L.8.4:

[0187] R1and R2are phenyl; in L.9.1 : the two radicals R1are identical and are C3-C6-cycloalkyl;

[0188] R2is phenyl; and

[0189] R3and R4are identical and are Ci-C4-alkyl; in L.10.1:

[0190] R1and R2are phenyl; and

[0191] R3and R4are identical and are Ci-C4-alkyl; in L.11.1 and L.11.2: each R1is independently selected from the group consisting of Ci-C6-alkyl, phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkoxy, trifluoromethyl, amino, Ci-C4-alkylamino and di-(Ci-C4-alkyl)-amino; and a 5- or 6-membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from O, N and S are ring members; R2aand R2dare hydrogen; and R2band R2care Ci-C4-alkoxy; or

[0192] R2aand R2bform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or -O-CH2-CH2-O-; and

[0193] R2cand R2dform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or -O-CH2-CH2-O-; or

[0194] R2aand R2dare hydrogen; and R2band R2° form together a bridging group -O-(CH2)n-O- with n = 1 to 5, preferably 2 to 4, preferably 3;or

[0195] R2a and R2d are identical and halogen, especially Cl; and R2b and R2c are identical and C1- C4-alkoxy, especially methoxy; or

[0196] R2aand R2bform together a bridging group -O-CF2-O-; and simultaneously R2cand R2dform together a bridging group -O-CF2-O-; in L.12.1 and L12.2: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy, in L.13.1 and L.13.2: the two radicals R1aare identical and are Ci-C6-alkyl; the two radicals R1bare identical and are Ci-Ce-alkyl; where R1aand R1bbound on the same P atom are not identical; in L.14.1 and L.14.2:

[0197] R1is phenyl; in L.15: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; each R5is independently H or methyl; and n is 0, 1 or 2; in L.17:

[0198] R1is an aryl rest, preferably a phenyl rest that is optionally substituted, more preferably R1 is phenyl or xylyl, especially preferably, R1 is phenyl;

[0199] R2is alkyl or alkoxy, preferably Ci-C4alkyl or Ci-C4alkoxy, more preferably methyl or methoxy, even more preferably methoxy.

[0200] In one embodiment, said chiral ligand has the structure L.1.1, L.1.2, L.1.3 or L.1.5 where: the two radicals R1are identical and selected from the group consisting of C3-C3-alkyl, cyclohexyl, phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci- C4-alkyl and Ci-C4-haloalkyl; and naphthyl; and the two radicals R2are identical and selected from the group consisting of C3-Cs-alkyl, cyclohexyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl;

[0201] In one embodiment, said chiral ligand has the structure L.2.1, L.2.2, L.2.3, L.2.4, L.2.5, L.2.6, L.2.7 and L.2.8, where:

[0202] R1is selected from the group consisting of C3-Ce-alkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl; and the two radicals R2are identical and selected from the group consisting of C3-Cs-alkyl, cyclohexyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl;

[0203] In one embodiment, said chiral ligand has the structure L.3.1, L.3.2, L.3.3 and L.3.4, where: the two radicals R1are identical and selected from the group consisting of Cs-Cs-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; the two radicals R2are identical and selected from the group consisting of Cs-Cs-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; and

[0204] R3and R4are methyl;

[0205] In one embodiment, said chiral ligand has the structure L.4.1, L.4.2, L.4.3 and L.4.4, where: the two radicals R1are identical and selected from the group consisting of Ca-Ce-alkyl, cyclohexyl and phenyl; the two radicals R2are identical and selected from the group consisting of C3-C3-alkyl, cyclohexyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl;

[0206] In one embodiment, said chiral ligand has the structure L.5.1, L.5.2, L.5.3 and L.5.4, where: the two radicals R1are identical and are naphthyl; and

[0207] R2is C3-C4-alkyl;

[0208] In one embodiment, said chiral ligand has the structure L.6.1, L.6.2, L.6.3, L.6.4, L.6.5, L.6.6, L.6.7 and L.6.8, where: the two radicals R1are identical and selected from the group consisting of cyclohexyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy;

[0209] R2is phenyl; and

[0210] R3and R4are methyl;

[0211] In one embodiment, said chiral ligand has the structure L.7.1, L.7.2, L.7.3 and L.7.4, where: R1is phenyl;

[0212] In one embodiment, said chiral ligand has the structure L.8.1, L.8.2, L.8.3 and L.8.4, where:

[0213] R1and R2are phenyl;

[0214] In one embodiment, said chiral ligand has the structure L.9.1, where: the two radicals R1are identical and are cyclohexyl;

[0215] R2is phenyl; and

[0216] R3and R4are methyl;

[0217] In one embodiment, said chiral ligand has the structure L.10.1 , where:

[0218] R1and R2are phenyl; and

[0219] R3and R4are methyl;

[0220] In one embodiment, said chiral ligand has the structure L.11.1 and L.11.2, where: the four radicals R1are identical and selected from the group consisting of Cs-Ce-alkyl, phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of C3-C4-alkyl, C1-C4- alkoxy and di-(Ci-C4-alkyl)-amino; and furyl;

[0221] R2aand R2dare hydrogen; and

[0222] R2band R2care identical and are Ci-C4-alkoxy; or

[0223] R2aand R2bform together a bridging group -CH=CH-CH=CH-; and simultaneously R2cand R2dform together a bridging group -CH=CH-CH=CH-; or

[0224] R2aand R2bform together a bridging group -O-CH2-O-; and simultaneously R2cand R2dform together a bridging group -O-CH2-O-;

[0225] In one embodiment, said chiral ligand has the structure L.12.1 and L.12.2, where: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy,

[0226] In one embodiment, said chiral ligand has the structure L.13.1 and L.13.2, where: the two radicals R1aare identical and are C3-C6-alkyl; the two radicals R1bare identical and are Ci-Ce-alkyl; where R1aand R1bbound on the same P atom are not identical;

[0227] In one embodiment, said chiral ligand has the structure L.14.1 and L.14.2, where: R1is phenyl;

[0228] In one embodiment, said chiral ligand has the structure L.15, where: the four radicals R1are identical and are phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; each R5is independently H or methyl; and n is 0, 1 or 2.

[0229] In one embodiment, ligand L is (“(R)-C3-TunePhos”). In one embodiment, ligand L is (“(R)-DTBM-SEGPHOS”).

[0230] In one embodiment, ligand L is (“(R)-DM-SEGPHOS”).

[0231] In one embodiment, ligand L is (“(3S,3'S)-BABIBOP”). In one embodiment, ligand (“(2R,2;R,3R,3'R)-BIBOP”).

[0232] In one embodiment, ligand )-Furan-MeOBIPHEP”).

[0233] In one embodiment, ligand -(R)-Xylyl-P-Phos”).

[0234] In one embodiment, ligand L is („(R,R)-CHIRAPHOS”).

[0235] In one embodiment, ligand L is (“(S)-MeO-Phenylfuran”).

[0236] In one embodiment, ligand (2S,2'S,3S,3'S)-WingPhos.

[0237] In one embodiment, ligand L is (“(R)-CI-MeO-BIPHEP”)

[0238] In one embodiment, ligand L is (“(R.R)-iPr-DUPHOS”).

[0239] In one embodiment, ligand L is (“(R)-SYNPHOS”).

[0240] In one embodiment, ligand L is (“(R)-DIFLUORPHOS)”).

[0241] In one embodiment, ligand L is (“(S)-PHANEPHOS”).

[0242] In one embodiment, ligand L is (“(R,R,R)-(+)-Ph-SKP”).

[0243] In one embodiment, ligand L is (“(2S,S'S)-DI-Me-BABIBOP”).

[0244] In one embodiment, ligand L is (“(R,R)-Me-DUPHOS”).

[0245]

[0246] Typically, the chiral ligand is used in the inventive processes in an amount of 1.0 to 3.0 mol per mol of Cu, preferably 1.0 to 2.0 mol per mol of Cu or 1 .0 to 1.3 mol per mol of Cu.

[0247] The reaction time depends on various factors, such as the reaction temperature, the concentration of the reactants in the reaction mixture and the like. Typically, it is in the range of from about 0 to 48 h, preferably from 1 to 24 h, in particular from 1 to 18 h, specifically from 10 to 18 h. A reaction time of “0 h” in this context means that after complete addition of all components, the reaction can be sufficiently complete to continue with the isolation of the desired compound (I). This can for example be the case if the addition of the reactants has lasted rather long or if it is intended to recycle the non-reacted starting material.

[0248] The reaction is preferably carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar aprotic solvents, polar protic solvents, C1-C4-alkyl acetates, chlorinated alkanes, open-chained ethers, aromatic solvents and mixtures thereof. In principle many solvents are suitable for carrying out processes of the invention. Typically, said solvent dissolves the silane under the reaction conditions. The copper precursor is typically not well soluble in such solvent. Typically, such solvent is chosen such that preformed copper catalyst, compound-1, compound II silane and ligand are at least partially soluble in solvent under the reaction conditions. In one embodiment, such solvent is chosen such that preformed copper catalyst, compound-1, silane and ligand are completely dissolved in the solvent under the reaction conditions.

[0249] The reaction is preferably carried out in the presence of a solvent. The solvent is preferably selected from the group consisting of polar aprotic solvents or polar protic solvents. In one embodiment the solvent is selected from Ci-C4-alkyl acetates, chlorinated alkanes, open-chained ethers, aromatic solvents and mixtures thereof.

[0250] Polar aprotic solvents are polar solvents without a functional group from which a proton can dissociate. Examples for suitable polar aprotic solvents are amides, such as dimethylformamide (DMF), diethylformamide, dibutylformamide, and dimethylacetamide; cyclic ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane and 1 ,4-dioxane; sulfoxides, such as dimethylsulfoxide (DMSO); nitriles, such as acetonitrile; lactams, such as N-methylpyrrolidone (NMP), N-(n-butyl)-pyrrolidone or N-(tert-butyl)-pyrrolidone; sulfones, such as sulfolane; carbonic acid esters, such as dimethylcarbonate, ethylenecarbonate or propylene carbonate; lactones, such as y-butyrolactone or y-valerolactone; ureas, such as N,N,N’,N’-tetramethyl urea, N,N,N’,N’-tetrabutyl urea, dimethylpropylene urea (DMPU) or 1 ,3-dimethyl-2-imidazolinone (DMEU; DMI); and nitro compounds, such as nitromethane.

[0251] Polar protic solvents are solvents with a functional group from which a proton can easily dissociate. Examples of suitable polar protic solvents are Ci-C4-alkanols, fluorinated Ci-C4-alkanols, glycols and mixtures thereof. Ci-C4-Alkanols are for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol. Fluorinated Ci-C4-alkanols are for example 2-fluoroethanol, 3-fluoropropanol, 1-fluoropropan-2-ol, 4-fluorobutanol, 1 , 1 -difluoro- ethanol, 2,2-difluoroethanol, 2,2-difluoropropanol, 3,3-difluoropropanol, 1 ,1-difluoropropan-2-ol, 2,2,2-trifluoroethanol, 3,3,3-trifluoropropanol, 4,4,4-trifluorobutanol and the like. Examples for glycols are ethylene glycol, diethylene glycol and triethylene glycol.

[0252] Examples for suitable Ci-C4-alkyl acetates are methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate.

[0253] Examples for suitable chlorinated alkanes are dichloromethane, trichloromethane or dichloroethane.

[0254] Open-chained ethers are compounds of formula R-O-R’, where R and R’, independently of each other, are an aliphatic, cycloaliphatic or aromatic group. In contrast to cyclic ethers, R and R’ do not form together a bridging group; i.e. the ether oxygen atom is not a ring member of a cyclic ring system. Examples are di-(Ci-C4-alkyl)-ethers, such as diethyl ether, dipropylether, diisopropylether, dibutylether or methyl-tert-butyl ether; and anisole (methoxybenzene). Examples for suitable aromatic solvents are benzene, toluene, trifluorotoluene, the xylenes (i.e. 1,2-xylene, 1 ,3-xylene or 1 ,4-xylene), chlorobenzene, dichlorobenzene or anisole.

[0255] In one embodiment, said solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,3- dioxane, 1 ,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dime- thylacetamide (DMAC), C1-C4-alkanols, fluorinated C1-C4-alkanols, C1-C4-alkyl acetates, chlorinated C1-C2-alkanes, di-(C1-C4-alkyl)-ethers, benzene, toluene, trifluorotoluene, the xylenes, chlorobenzene, dichlorobenzene, anisole and mixtures of the aforementioned solvents.

[0256] In one embodiment, said solvent is selected from 2-methyltetrahydrofuran, 1,4-dioxane, DMSO, DMF, C1-C3-alkanols, 2,2,2-trifluoroethanol, ethyl acetate, chlorinated C1-C2-alkanes, di-(C1- C4-alkyl)-ethers, toluene, anisole, dimethoxy ethane, monochloro benzene, cyclopentyl methyl ether, N,N-dimethyl acetamide and mixtures of the aforementioned solvents.

[0257] In one embodiment, said solvent is selected from toluene, xylene, dioxane, 2-methyltetrahydro- furan, monochloro benzene, dimethoxy ethane, cyclopentyl methyl ether, N,N-dimethyl acetamide, or mixtures thereof.

[0258] Typically, the inventive processes are carried out at a temperature from -5 to 120°C.

[0259] In one embodiment, the inventive processes are carried out at a temperature of from 10 to 80°C.

[0260] In one embodiment, the inventive processes are carried out at a temperature of from 30 to 60°C.

[0261] The inventive process can typically be carried under acidic, neutral or basic conditions. However, strongly acidic , e.g. a pH below 5, or strongly basic conditions, e.g. pH above 8, are normally avoided.

[0262] The reaction is generally carried out by mixing the starting compound II, the chiral catalyst (either in preformed form or in form of a catalyst precursor and a chiral ligand), optionally the solvent, the silane and optionally any further additives at the desired reaction, or mixing the components, and bringing then the temperature to the desired range. The order of addition is normally not particularly critical.

[0263] For instance,

[0264] (i) the starting compound (II) is dissolved in a solvent, the catalyst (or catalyst precursor and ligand, if the catalyst is to be prepared in situ), optionally dissolved in a solvent, is added, and silane is added; or

[0265] (ii) the starting compound (II), optionally dissolved in a solvent, is added to the catalyst (or a mixture of catalyst precursor and ligand, if the catalyst is to be prepared in situ) dissolved in a solvent, and silane is added.

[0266] After completion of the reaction, the pyrimidinone of the formula (I) in enantiomerically enriched form can be isolated from the reaction mixture. When the inventive processes are carried out on a commercial scale, workup of compound (I) is not always necessary. Rather Compound (I) can be used in the next synthesis step without further purification.

[0267] If compound (I) is to be isolated and purified, isolation typically comprises adding water to the reaction mixture, isolating and optionally purifying the pyrimidinone of the formula (I) precipitated upon addition of water. Alternatively, isolation comprises setting the pH of the reaction mixture acidic; removing at least a part of the solvent, if any, to obtain a concentrate; adding water and a solvent which has low or no miscibility with water to the concentrate; extracting the pyrimidinone of the formula (I) into the solvent which has low or no miscibility with water; and isolating the pyrimidinone of the formula (I) from the extract. The solvent which has low or no miscibility with water is preferably selected from the group consisting of 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methylisopropyl ketone, and chlorobenzene.

[0268] In one embodiment, processes of the invention allow the preparation of enantiomerically enriched compound (I) with S configuration (compound (l-S) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0269] In one embodiment, processes of the invention allow the preparation of enantiomerically enriched compound (I) with R configuration (compound (l-R) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0270] The starting compound (II) is obtainable by reaction of N-methylthiourea with an alkyl 2-phe- nylmalonate to 6-hydroxy-3-methyl-5-phenyl-2-sulfanyl-pyrimidin-4-one or the corresponding thiolate and reaction thereof with 2-chloro-1-(2-chlorothiazol-5-yl)ethanone to the compound (II). These reactions are known.

[0271] N-methylthiourea and alkyl 2-phenylmalonates are commercially available. 2-Chloro-1-(2-chloro- thiazol-5-yl)ethanone can be prepared, for example, as described in WO 2018 / 197541 or WO 2018 / 202654 by reaction of 2-chlorothiazole with a Grignard reagent to the corresponding chloro-(2-chlorothiazol-5-yl) magnesium species and reaction thereof with 2-chloro-N-methoxy- N-metyl-acetamide. Alternatively, the compound 3 can be prepared from thiourea according the method described by T. Chalopin et al. in Org. Biomol. Chem., 2016, 14, 3913-3925.

[0272] The present method leads to the compound (I) in high yields and stereoselectivity.

[0273] The compound (I) can be converted in just one further step into 3-(2-chlorothiazol-5-yl)-8-me- thyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate, and especially into enantiomerically enriched forms thereof. For this purpose, the compound (I) is subjected to an internal cyclization by a nucleophilic attack of the unsubstituted nitrogen atom of the pyrimidine ring on the carbon atom carrying the aliphatic OH group. This reaction is described under separate cover, e.g. in PCT / EP2022 / 051368. While the compound (I) can be converted in just one step into 3-(2-chlorothiazol-5-yl)-8-methyl- 7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-olate and enantiomerically enriched forms thereof, it can also be first subjected to some modifications, such as etherification of the hydroxyl group on the pyrimidine ring, substitution of the Cl atom on the thiazole ring or introduction of substituents on the phenyl ring, so as to allow formation of 2,3-dihydrothiazolo[3,2- a]pyrimidinium compounds other than 3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5- olate.

[0274] The present invention inter alia offers the following advantages: Processes of the invention are easy and economical to carry out. Processes of the invention are environmentally friendly.

[0275] Processes of the invention yield compound (I) in high yields.

[0276] Processes of the invention yield compound (I) with high purity.

[0277] Processes of the invention allow the preparation of enantiomerically enriched compound (I) with an enantiomeric excess (EE) of at least 55 %ee, preferably at least 60 %ee, more preferably at least 70 %ee, even more preferably at least 80%ee, or at least 90 %ee or at least 95%ee.

[0278] The present invention is further illustrated in the following examples.

[0279] Examples

[0280] Abbreviations:

[0281] THF tetrahydrofuran

[0282] MCB monochloro benzene

[0283] 2-MeTHF 2-methyltetrahydrofuran

[0284] MeOH methanol

[0285] EtOAc ethyl acetate iPrOH isopropanol t time min minute(s) h hour(s) rc.t. reaction time r.t. room temperature rt retention time

[0286] Methods:

[0287] The compounds were characterized by coupled High Performance Liquid Chromatography.

[0288] Achiral HPLC for conversion and chemoselectivity:

[0289] Software: Agilent Series 1100

[0290] Column: Dr. Maisch Retrospher 100 C18, 4.6x75 mm, 3.0 pm

[0291] Eluent: -A: H2O with 0.1 vol% TFA

[0292] -B: MeCN with 0.1 vol % TFA

[0293] Detector: UV detector X = 220 nm, band width = 4 nm

[0294] Inject, vol.: 2 pL

[0295] Temperature: 30°C

[0296] Analysis time: 15 min

[0297] Chiral HPLC for %ee:

[0298] Software: Agilent Series 1260

[0299] Column: Chiralpak AD-RH 5 pm 150*4.6 mm from Daicel

[0300] Eluent: - A: H2O with 0.1 vol% H3PO4

[0301] - B: MeCN / 2- Propanol (1:1)

[0302] Detector: UV detector = 216 nm, band width = 4 nm

[0303] Inject, vol.: 3 pL

[0304] Temperature: 40°C

[0305] Analysis time: 22 min

[0306] Pressure: ca. 95 bar

[0307] Examples 1 to 7: Screening of ligands L

[0308] A suspension of compound (II) (50 mg, 1 eq., 0.13 mmol), chiral ligand L (0.0013 mmol, 0.01 eq, 1 mol%) and Cu(OAc)2'H2O (0.0013 mmol, 0.01 eq, 1 mol%) in toluene (1 mL) are stirred for 10 min, silane (1.2 eq., 0.152 mmol) was added in one portion at room temperature. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). The reaction mixtures were stirred overnight (18 h). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0309] Experiments 8 to 24: Screening of Silane Sources

[0310] A suspension of compound (II) (50 mg, 1 eq., 0.127 mmol), chiral ligand L (0.038 mmol, 0.3 eq, 30 mol%) and Cu(OAc)2-H2O (0.038 mmol, 0.3 eq, 30 mol%) in toluene (1 mL) are stirred for 10 min, silane (1.2 eq., 0.152 mmol) was added in one portion at room temperature. Reaction sampling was done by taking 20 pL and dissolving it in MeOH (1 mL). The reaction mixtures were stirred overnight (18 h). All reactions were monitored by HPLC (“PAL A %” denotes the yield of compound (I)).

[0311] Experiments 25 to 33: Screening of catalyst loading, temperature, and solvents

[0312] A stock solution was made of Cu(OAc)2H2O (5 mg, 0.0012 mmol) and ligand (S)-BTFM-Garphos (30 mg, 0.0012 mmol) in Toluene (1 mL) under argon atmosphere. The suspension was heated to 40 °C for 15 min and then left to come to room temperature. The suspension had turned into a light blue solution. Every 50 pL equated to 1 mol% catalytic loading. Compound (II) (50 mg, 0.127 mmol) was suspended in solvent (see below table) follow by addition of PhSiH3(1.2 eq., 0.152 mmol) under argon atmosphere. To each reaction stock solution was added. The reactions were monitoredf'PAL A %” denotes the yield of compound (I)).

[0313] Experiments 34 to 39: Screening of solvents

[0314] Preparation of a catalyst solution: A stock solution was made of Cu(OAc)2 H2O (5 mg, 0.0012 mmol, 1 mol%) and ligand (S)-BTFM-Garphos (30 mg, 0.0012 mmol, 1 mol%) in Toluene (1 ml_) under argon atmosphere. The suspension was heated to 40 °C for 15 min and then left to come to room temperature. The suspension had turned into a light blue solution. Every 50 pL equated to 1 mol% catalytic loading.

[0315] Compound (II) (50 mg, 0.127 mmol) was suspended in mixture of solvent (0.2 mL, 4 vol, see Table) followed by the addition of 50 pL (1 mol%) of the catalyst solution. Then PhSiH3 (1.2 eq, 0.152 mmol) was added in one portion and the reaction was stirred under inert atmosphere at specified temperature for 4-18 h (“PAL A %” denotes the yield of compound (I)).

Claims

Claims1. Process for preparing an enantiomerically enriched form of 2-[2-(2-chlorothiazol-5-yl)-2- hydroxy-ethyl]sulfanyl-6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (I)) or a tautomer thereof which comprises reducing 2-[2-(2-chlorothiazol-5-yl)-2-oxo-ethyl]sulfanyl- 6-hydroxy-3-methyl-5-phenyl-pyrimidin-4-one (compound (II)) with a silane compound in the presence of a chiral copper compound.

2. Process according to claim 1 , where said copper compound is used in substoichiometric amount relative to compound (II).

3. Process according to any of claims 1 to 2 where said silane is selected from phenyl silane, diphenyl silane and diethyl silane.

4. Process according to any of claims 1 to 3, where the chiral copper catalyst is prepared from an achiral copper precursor and a chiral ligand.

5. Process according to any of claims 1 to 4, where said copper precursor is selected from salts of Cu(l) or Cu (II).

6. Process according to any of claims 1 to 5, where said copper precursor is selected from CU(OAC)2, CUCI, CuBr, CuF, Cui, Cu(acac)2, CuSO4, Cu(NO3)2, CuOTf or mixtures thereof.

7. Process according to any of claims 1 to 6, where said chiral ligand is a phosphorous containing ligand.

8. Process according to any of claims 1 to 7, where said chiral ligand contains phosphine groups.

9. Process according to any of claims 1 to 8, where said chiral ligand is a bisphosphine.

10. Process according to any of claims 1 to 9, where said chiral ligand is selected from the group consisting of the chiral forms of the ligands of formulae L.1 to L.18L.1 L.2 L.315 L.14.1 L.14.2where in L.1 :R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Ci-Cs-alkyl, Cs-Ce-cycloalkyl, phenyl and naphthyl, where phenyl and naphthyl may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; in L.2:R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Ci-Cs-alkyl, Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl; in L.3:R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Cs-Ce-cycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; and R3and R4are methyl; in L.4:R1and R2, independently of each other and independently of each occurrence, are selected from the group consisting of Ci-Cs-alkyl, Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and C1-C4- haloalkyl;in L.5:R1is phenyl or naphthyl, where phenyl and naphthyl may carry 1, 2 or 3 substituents selected from the group consisting of Ci-C alkyl and Ci-C haloalkyl; and R2is Ci-C4-alkyl; in L.6:R1is selected from the group consisting of Cs-Ce-cycloalkyl and phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy;R2is phenyl; andR3and R4, independently of each other, are Ci-C4-alkyl; in L.7:R1is phenyl; in L.8:R1and R2are phenyl; in L.9:R1is Cs-Ce-cycloalkyl;R2is phenyl; andR3and R4, independently of each other, are Ci-C4-alkyl; in L.10:R1and R2are phenyl; andR3and R4, independently of each other, are Ci-C4-alkyl; in L.11 : each R1is independently selected from the group consisting of Ci-Cs-alkyl, phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl, C1-C4- alkoxy, trifluoromethyl, amino, Ci-C4-alkylamino and di-(Ci-C4-alkyl)-amino; and a 5- or 6- membered heteroaromatic ring having 1, 2 or 3 heteroatoms selected from O, N and S are ring members;R2aand R2dare hydrogen; andR2band R2care Ci-C4-alkoxy; orR2aand R2bform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or -O-CH2- CH2-O-; andR2cand R2dform together a bridging group -CH=CH-CH=CH- or -O-CH2-O- or -O-CH2- CH2-O-; orR2aand R2dare hydrogen; and R2band R2° form together a bridging group -O-(CH2)n-O- with n = 1 to 5, preferably 2 to 4, preferably 3;orR2a and R2d are identical and halogen, especially Cl; and R2b and R2c are identical and Ci-C4-alkoxy, especially methoxy; orR2aand R2bform together a bridging group -O-CF2-O-; and simultaneously R2cand R2dform together a bridging group -O-CF2-O-; in L.12: each R1is independently phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy, in L.13: each R1ais independently Ci-Ce-alkyl; each R1bis independently Ci-Ce-alkyl; where R1aand R1bbound on the same P atom are not identical; in L.14.1 and L.14.2:R1is phenyl; in L.15: each R1is independently phenyl which may carry 1 , 2 or 3 substituents selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy; each R5is independently H or methyl; and n is 0, 1 or 2; in L.16:R1and R2as well as R3and R4form a bridging group -CH2-(CH2)n-CH2, with n being a number from 0 to 2, preferably 0 or 1, more preferably 0;R5, R6, R7and R8are alkyl, preferably methyl. in L.17:R1is an aryl rest, preferably a phenyl rest that is optionally substituted, more preferably R1 is phenyl or xylyl, especially preferably, R1 is phenyl;R2is alkyl or alkoxy, preferably C1-C4 alkyl or C1-C4 alkoxy, more preferably methyl or methoxy, even more preferably methoxy. in L18:R1 an R2 are different; preferably R1and R2are different alkyl groups; in one embodiment R1is tert-butyl and R2is methyl11. Process according to any of claims 1 to 10, where said chiral ligand contains a biphenyl or binaphtyl moiety and where two phosphine groups bound to different aromatic moieties of said biphenyl, bispyridyl or binaphthyl moiety.

12. Process according to any of claims 1 to 11 , where the chiral copper compound, calculated on the basis of the copper content, is used in an amount of from 0.1 to 5 mol-%, preferably from 1 to 5 mol-%, relative to 1 mol of compound II.

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