1, 4-diaryl-2-fluoro-2-butenes and a method for their preparation are described in US 5,998,673. Said compounds are useful as insecticidal and acaricidal agents and for protecting plants from damage caused by insect and acarid attack and infestation. Although US 5,998,673 discloses and claims optical isomers of said 1, 4-diaryl-2-fluoro-2-butenes, it does not provide a practicable method for their preparation.

It is therefore an object of the present invention to provide a process for the preparation of chiral 1,4- diaryl-2-fluoro-2-butenes.

It is also an object of the present invention to provide intermediates useful in said process.

These and other objects are surprisingly achieved by the process as set forth below.

Accordingly the invention provides a process for the preparation of a chiral compound of formula I wherein Ar is aryl or a 5-or 6-membered heteroaromatic ring, each of which may be unsubstituted or substituted with 1,2 or 3 radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, Cl-C4haloalkoxy and hydroxy, preferably phenyl, which may be unsubstituted or substituted with 1,2 or 3 radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, Cl-C4alkoxy, Cl-C4haloalkoxy and hydroxy, 1-or 2-naphthyl, which may be unsubstituted or substituted with 1,2 or 3 radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, c1-C4alkoxy and Cl-C4haloalkoxy, or a 5-or 6-membered heteroaromatic ring, which may be unsubstituted or substituted with 1,2 or 3 radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy, R is Cl-C4alkyl, Cl-C4haloalkyl, C3-C6cycloalkyl or C3-C6halocycloalkyl ; Arl is aryl or a 5-or 6-membered heteroaromatic ring, each of which may be unsubstituted or substituted with 1 to 6 radicals selected from phenyl, phenoxy, benzyl benzoyl, halogen, Cl-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy, it being possible for phenyl, phenoxy, benzyl and benzoyl to be substituted or unsubstituted with 1 to 5 radicals selected from C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy, preferably, phenoxyphenyl optionally substituted with one to six radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy groups, phenyl optionally substituted with one to five radicals selected from halogen, C,-c,, alkyl, c1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy groups, biphenyl optionally substituted with one to five radicals selected from halogen, Cl-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy groups, phenoxypyridyl optionally substituted with one to five radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy groups, benzylpyridyl optionally substituted with one to five radicals selected from halogen, Cl-C4alkyl, Cl-CQhaloalkyl, Cl-C4alkoxy and C1-C4haloalkoxy groups, benzylphenyl optionally substituted with one to five radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy groups, benzoylphenyl optionally substituted with one to five radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy groups, 1-or 2-naphthyl optionally substituted with one to three radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-Cahaloalkoxy groups, or a 5-or 6-membered heteroaromatic ring optionally substituted with one to three radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy groups, which process comprises the following steps: a) treating a racemic ester of formula II wherein Ar and R are defined as hereinabove and R4 is Cl-CQalkyl with an esterase to form à first mixture of either R-acid IIIa and S-ester IIIb or of S-acid IIIc and R-ester IIId b) separating said acid IIIa or IIIc from said ester IIIb or IIId ; c) reducing said acid IIIa or IIIc or said ester IIIb or IIId to obtain a chiral alcohol IV having the R-or S-configuration d) transforming the chiral alcohol IV by conventional means into an ester VIII e) fluorinating said ester to afford a fluoro-ester of formula IX f) reacting said fluoro ester with an aldehyde ArICH2CHO, wherein Arl is defined as hereinabove, in a solvent in the presence of a base to afford a second mixture of 4 chiral diastereomeric hydroxy-esters of formula X; g) optionally separating said second mixture X into a third mixture Xa and a forth mixture Xb, each mixture having two chiral diastereomers; h) treating said hydroxy-ester mixtures X, Xa or Xb with an acylating agent R2COX1, wherein R2 is C1-C4alkyl and X1 is Cl, Br or R2COO, to afford a fifth mixture of 4 chiral diastereomeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or a seventh mixture of 2 chiral diastereomeric acyloxy esters XIb i) optionally separating said sixth or seventh mixture into essentially pure chiral diastereomeric acyloxy esters; j) hydrolyzing said pure chiral acyloxy esters or mixtures of esters of formula XI to afford a hydroxy- acid of formula XII, and k) heating said hydroxy-acid XII with an arylsulfonyl halide Ar3SO2X2, wherein Ar3 is phenyl, which is optionally substituted with C1-C4alkyl or halogen, preferably phenyl, p-chlorophenyl or p-methylphenyl and X2 is chloro or bromo to afford the desired chiral compound of formula I.

The invention also provides a method for the preparation of both the E-and Z-Isomers of the compounds of formula I. The wavy lines in structural formula I represent either the E isomeric or the Z isomeric configuration about the carbon-carbon double bond.

The invention further provides chiral intermediate compounds useful in the process of this invention.

The organic molecule moieties mentioned in the definition of the substituents are collective terms for individual enumerations of the individual group members. All hydrocarbon chains,. i. e. all alkyl, haloalkyl, alkoxy, and haloalkoxy groups can in each case be straight-chain or branched, where the prefix Cn-Cm in each case indicates the possible number of carbon atoms in the group. Halogenated substituents preferably carry one, two, three, four or five identical or different halogen atoms. The term halogen represents in each case fluorine, chlorine, bromine or iodine.

Examples of other meanings are: -Cl-C4alkyl : CH3, C2Hs, n-propyl, CH (CH3)2, n-butyl, CH (CH3)-C2H,, CH2-CH (CH3) Z and C (CH3) 3 ; - C1-C4alkoxy : OCH3, OC2H5, n-propyloxy, OCH (CH3) 2, n- butyloxy, OCH (CH3)-C2H5, OCH2-CH(CH3)2 and OC(CH3)3 ; -Cl-C4haloalkyl : a Cl-C4-alkyl radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i. e. for example fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl dichloromethyl, trichloromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-. bromoethyl, 2-iodoethyl, 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, pentafluoroethyl, 2-fluoropropyl, 3- fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2- bromopropyl, 3-brómopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, l-fluoromethyl-2-fluoroethyl, 1- chloromethyl-2-chloroethyl, 1-bromomethyl-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl and nonafluorobutyl; -Cl-C4haloalkoxy : a Cl-C4alkoxy radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i. e. for example fluoromethoxy, difluoromethoxy, trifluoro- methoxy, chloromethoxy dichloromethoxy, trichloro- methoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2- difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2, 2,2- trichloroethoxy, pentafluoroethoxy, 2-fluoropropyloxy, 3-fluoropropyloxy, 2, 2-difluoropropyloxy, 2,3-difluoro- propyloxy, 2-chloropropyloxy, 3-chloropropyloxy, 2,3- dichloropropyloxy, 2-bromopropyloxy, 3-bromopropyloxy, 3,3,3-trifluoropropyloxy, 3,3,3-trichloropropyloxy, 2,2,3,3,3-pentafluoropropyloxy, heptafluoropropyloxy, 1-fluoromethyloxy-2-fluoroethyloxy, 1-chloromethyloxy- 2-chloroethyloxy, 1-bromomethyloxy-2-bromoethyloxy, 4- fluorobutyloxy, 4-chlorobutyloxy, 4-bromobutyloxy and nonafluorobutyloxy ; -C3-C6cycloalkyl : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; -C3-C6halocycloalkyl : a C3-C6cycloalkyl radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i. e. for example, 1-fluorocyclopropyl, 1-chlorocyclopropyl ; -Aryl : phenyl-or 1-or 2-naphthyl, it being possible for phenyl to be condensed to a 5-or 6- membered aromatic heterocycle as mentioned below, thus forming e. g. indolyl, benzothienyl, quinolyl, isoquinolyl, quinoxalyl, quinazolyl, etc.

-5-or 6 membered aromatic heterocycles in general comprise 1,2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyridazine, 1, 3,5-triazine, thiophene, furane, oxazol, isoxazole, thiophene, thiazole, isothiazole, 1, 3,5-thiadiazole, and 1,3,5 triazole.

In a more preferred embodiment of the present invention there is provided a method for the preparation of chiral compounds of formula I wherein Ar, R and Arl independently from one other, but preferably in combination with one another, have the meanings given below: Ar : phenyl which is unsubstituted or substituted with 1,2 or 3 radicals, preferably with one radical, selected from halogen, Cl-C4alkyl, Cl-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy, in particular halogen.

In a particularly preferred embodiment of the invention, Ar is p-chlorophenyl.

Arl : phenoxyphenyl, especially 3-phenoxyphenyl which is substituted as mentioned above, and preferably by 1,2 or 3 halogen atoms. In a particularly preferred embodiement of the present invention, at least on halogen atom is located on the phenyl ring of the phenoxyphenyl radical. In a specific embodiement of the invention, Ar. is 4-fluoro-3-phenoxyphenyl.

R: Cl-C4alkyl, especially isopropyl, or preferably C3-C6cycloalkyl, especially cyclopropyl.

In accordance with the process of this invention racemic ester II is enzymatically hydrolyzed with an esterase to afford either a first mixture of acid IIIa having the R-configuration, and unhydrolyzed ester IIIb, having the S-configuration, or a mixture of acid IIIc having the S-configuration, and unhydrolyzed ester IIIb, having the R-configuration. These mixtures are then seperated to afford the enantiomeric pure compounds (enantiomeric excess preferably at least 90: 10), Said acid IIIa (or IIIc) or said ester IIIb (or IIId) is reduced to obtain a chiral alcohol IV having the R-or S-configuration. Alcohol IV is then transformed into the ester VIII, preferably by reacting the alcohol IV with an sulfonyl halide RaSO2X to afford a sulfonate of formula V; treating said sulfonate with a cyanide-delivering agent to afford a nitrile of formula VI; said nitrile being hydrolyzed to yield an acid of formula VII ; said acid being esterified with an alcohol ROH to yield an ester of formula VIII; said ester is fluorinated to afford a fluoro-ester of formula IX; said fluoro-ester is reacted with an. aldehyde ArICH2CHO in a solvent in the presence of a base to afford a second mixture of 4 chiral diasteromeric hydroxy-esters of formula X; optionally said second mixture can be separated into a third mixture Xa and a fourth mixture Xb, each mixture having two chiral diastereomers; said hydroxy-ester mixture X, Xa, or Xb is treated with an acylating agent R2COX, to afford a fifth mixture of 4 chiral diasteromeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or seventh mixture of chiral diasteromeric acyloxy esters XIb; optionally, said sixth or seventh mixture can be separated into essentially pure chiral diastereomeric acyloxy esters; said pure chiral acyloxy esters or mixtures of esters of formula XI are hydrolyzed to a hydroxy acid of formula XII; and finally, said hydroxy acids are heated with an arylsulfonyl halide Ar3SOzXz to afford the desired chiral compound of formula I. The preferred process is depicted in Flow Diagram I wherein R4 is depicted as methyl.

Flow Diagram I R 1. Esterase R H R H Reduction + Ar C02 CH32. Separation Ar COZY Ar C°2CH3 II IIIa IIIb R RaSO2X R Cyanide R Hydrolysis OH Ra CN Ar * Ar * 2 Ar * IV V VI R Esterification R Fluorination COZH C02R1 Ar * Ar > VII VIII R OH ArICHCHO R COX ly 2 Solvent Ar--, Ar F Base F CO2Ri F Base COR IX X R COR2 R OH Arl Hydrolysis Ar. Ar * Ar * F CO2R1 F CO2H XI XII R H Ar Ar * F I Non-polar solvents suitable for use in the process of the invention are essentially water-free solvents such as aromatic hydrocarbons (e. g. toluene, benzene, xylene, naphthalene or the like, preferably toluene), halogenated aromatic hydrocarbones (e. g. chlorobenzene, dichlorobenzene or the like), aliphatic hydrocarbons (e. g. hexane, heptane), halogenated hydrocarbon (e. g. chloroform, methylene chloride, dichlorethane, or the like, or any of the conventional, preferably water miscible, organic non-polar solvents.

Preferred non-polar solvents suitable for use in the process of the invention are hydrocarbons and aromatic hydrocarbons such as hexane, heptane, toluene, ethylbenzene or the like.

Polar aprotic solvents suitable for use in the inventive process are dimethylformamide, dimethyl- sulfoxide, tetrahydrofuran, diethyl ether, or the like.

Preferred polar aprotic solvents suitable for use in the process of the invention are dimethylformamide and dimethylsulfoxide.

In general, the term"aqueous solution"is to be understood as a solution in water or in a mixture of water and an organic solvent, which is miscible with water, such as tetrahydrofurane or Cl-C4alcanols, e. g. methanol.

Steps a and b): In actual practice, racemic ester II in water is treated with an esterase enzyme, preferably horse. liver esterase. The reaction is preferably performed at pH 7.1-8.0. The pH is preferably maintained during hydrolysis by addition of a base in water, preferably a dilute solution of an inorganic base such as sodium hydroxide or potassium hydroxide. Thus, a first mixture of. either R-acid IIIa and S-ester IIIb or S-acid IIIc and R-ester IIId is obtained.

Said acid can be separated from said ester by standard extraction techniques, preferably with aqueous sodium bicarbonate followed by acidification with mineral acid, preferably dilute hydrochloric acid and reextraction. Preferably the separation is achived by chromatographic techniques, preferably on silica gel.

Step c): Reduction of the acids IIIa or IIIc and of the esters IIIb or IIId can be achieved by conventional methods known to a skilled person to afford chiral alcohol IV having the R-or the S-configuration.

Preferably said acid IIIa or IIIc is reduced with diborane or borane-ether complex. Preferably said ester IIIb or IIId is reduced with alkylaluminum hydrides such as diisobutylaluminum hydride.. However other reducing agents such as lithium aluminum hydride, lithium tri-Cl-C4-alkoxyaluminum hydride, catalytic hydrogenation (see for example J. March, Advanced Organic Chemistry, 4th ed. 9 1206 ff.,. J. Wiley and Sons 1992, and literature cited therein).

Step d) : The transformation of alcohol IV into the ester VIII can be achieved by conventional means known to a skilled person. For example, alcohol IV can be transformed into ist corresponding halide IVa, wherein Hal is halogen, in particular its bromide by treatment of the alcohol IV with a halogenating agent such as sulfonylchloride, sulfonylbromide, PC13, PBr3 or BBr3. The thus obtained halide IVa is then transformed into the acid VII by using an appropriate Cl-synthon, for example by treating the halide IVa with a cyanide-delivering agent to obtain the nitrile VI and hydrolizing said nitrile VI or by transferring the halide IVa into an organometallic compound, e. g. a Grignard reagent followed by the addition of CO2 to obtain the acid VII after work-up which is then esterified to obtain said ester VIII.

In a preferred embodiement, the alcohol IV is transformed into the ester VIII by a 4-step sequence (steps dl to d4) as given below, starting with derivatizing the alcohol into the corresponding sulfonyl compound V. step dl) : The derivatization of the alcohol IV can be performed according to conventional methods known to a skilled person.

Derivatizing agents suitable for use in the formation of V are arylsulfonyl halides such as p- toluene sulfonyl chloride, p-toluene sulfonyl bromide, p-toluene sulfonyl fluoride, benzenesulfonyl bromide, benzenesulfonyl chloride, benzenesulfonyl fluoride, p- chlorobenzenesulfonyl bromide, p-chlorobenzenesulfonyl chloride and p-chlorobenzenesulfonylfluoride and alkylsulfonyl halides such as methane sulfonyl chloride, preferably an arylsulfonyl chloride, in particular p-toluene sulfonyl chloride. Preferably, alcohol IV is reacted with at least one molar equivalent of the sulfonyl halide..

Preferably, the reaction is performed in the presence of a base. Suitable, bases are resin-bound tertiary organic bases such as polystyrene diisopropyl ethylamine and tertiary organic bases, e. g. trialkyl amines such as triethyl amine and diisopropyl ethyl amine and pyridene bases such as pyridine, preferably trialkylamines, especially triethlamine. Preferably, the reaction is performed in the presence of at least one molar equivalent of a base.

The reaction is preferably performed in an aprotic non-polar solvent, in particular a halogenated hydrocarbon, e. g. dichloromethane. The reaction may also be performed in a mixture of the alcohol IV and the sulfonylhalide and the base.

Reaction temperatures may vary from about 0°C to reflux, preferably from about. 25°C to about 50°C, more preferably about 25°C.

Step d2): Sulfonate V is reacted with a cyanide-delivering agent to yield said nitrile VI according to conventional methods.

Cyanide delivering agents suitable for the formation of nitrile VI comprise metal cyanides such as alkali earth metal cyanide and alkali metal cyanide such as potassium cyanide and sodium cyanide, and zinc cyanide. Alkali metal cyanide, in particular sodium cyanide, are preferred. Preferably the cyanide- delivering agent is used in molar excess, e. g. 1.5 to 10 moles per mole of sulfonate V.

The reaction is preferably performed in an aprotic polar solvent, in particular dimethylsulfoxide.

Reaction temperatures may vary from about 25°C to about 180°C, preferably from about 50°C to about 125°C, more preferably about 90°C.

Step d3): The hydrolysis of the nitrile VI can be performed according to conventional methods known to a skilled person.

Suitable agents for the hydrolysis of nitrile VI are aqueous acids such as sulfuric acid or hydrochloric acid in the presence of or in the absence of alcohol, preferably Cl-C4-alcanol such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol and t- butyl alcohol. Aqueous alkali or alkali earth bases such as potassium hydroxide, calcium hydroxide and sodium hydroxide, preferably sodium hydroxide might also be employed.

In a preferred embodiment of the invention the nitrile VI is reacted in dilute aqueous sodium hydroxide followed by acidification of the resulting salt with strong mineral acid, preferably concentrated hydrochloric acid, to yield acid VII.

Reaction temperatures may vary from about 25°C to about 100°C, preferably from about 50°C to about 100°C, more preferably about 100°C.

Step d4): The esterfication of the acid VII can be performed according to conventional methods known to a skilled person.

Preferably the esterification is achieved by acid. catalysis. Useful acid catalysts are strong acids, such as hydrochloric acid, sulfuric acid or arylsulfonic acids e. g. p-toluene sulfonic acid and resin bound sulfonic acids (strong acidic cation-exchange resins), e. g. polystyrene sulfonic acid. Usually the alcohol R1OH is used in molar exess.

Preferably the esterification is perforemed in the alcanol ROH as solvent. In particular R1OH is methanol.

Reaction temperatures suitable for the esterifi- cation of acid VII vary from about-10°C to about 40°C, preferably about-10°C to about 30°C.

Step e): The fluorination of the a-position in carbonyl compounds is known to a skilled person (see for example J. March, Advanced Organic Chemistry, 3rd ed. p. 529 and the literature cited therein). The fluorination of carbonyl compounds is usually achieved by treating the enolate of the carbonyl compound with a fluorine- delivering compound, usually with an electrophilic fluorinating agent, such as CF3-OF, XeF2, XeF6 on graphite, perchlorylfluoride, preferably N- fluoroimides, such as N-fluoro-bis-N- (alkylsulfonyl imide) (F-N (SO2-Alkyl) and more preferably N-fluoro- bis-N- (arylsulfon) imide (F-N (SO2-Aryl), such as N- fluorobenzensulfonimide.

Bases suitable for the generation of the enolate anion of ester VIII are alkali metal hexaalkylsilyl- amides such as lithium hexamethylsilylamide or sodium hexamethylsilylamide, alkali metal dialkyl amides such as sodium diisopropylamide, metal hydrides such as sodium hydride and potassium hydride, preferably lithium diisopropyl amide.

Preferably, the enolate of VIII is generated by treatment of VIII with a base in an aprotic solvent, preferably an ether such as tetrahydrofurane, followed by quenching the enolate with the flourinating agent to yield fluoro-ester IX.

Reaction temperatures vary from about-78°C to about 25°C, preferred starting temperature is about -78°C, with the ending temperature about 25°C.

Step f): According to the invention, fluoro-ester IX is reacted with an aldehyde ArlCH2CHO in the presence of a base in an aprotic solvent to afford a second mixture of 4 chiral diasteromeric hydroxy-esters of formula X.

Suitable bases for treating fluoroester IX are metal hydrides such as sodium hydride and potassium hydride, preferably alkali metal amides such as alkali metal hexaalkylsilylamide, e. g. sodium hexamethyl- silylamide or lithium hexamethysilylamide, more preferably alkali metal dialkylamides such as sodium diisopropylamide or lithium diisopropylamide, in particular lithium diisopropylamide.

Preferred aprotic solvents are ethers, in particular tetrahydrofurane.

Reaction temperatures vary from about-100°C to about 0°C, preferably from-80°C to-30°C.

Preferably, the enolate of IX is generated by treatment of IX with a base in an aprotic solvent, preferably an ether such as tetrahydrofurane, followed by the addition of the aldehyde ArlCH2CHO.

Thus, a mixture of 4 chiral diasteromeric hydroxy esters X is obtained. Starting from fluoro-ester IX having R-configuration yields a mixture of the RRR, RSS, RSR and the RRS isomers. Starting from fluoro- ester IX having S-configuration yields a mixture of SRR, SSS, SSR and SRS isomers.

The aldehydes ARCH 2CHO are known from the literature or can be prepared by conventional methods, as outlined in the examples.

Step_q) : Advantageously, the second mixture X may be separated into a third mixture Xa and a fourth mixture Xb, each mixture having two chiral diastereomers.

Separation is achieved by conventional means, preferably by chromatographic techniques, more preferably by chromatography on silica gel.

Step h): Said hydroxy ester mixture X, Xa or Xb is treated with an acylating agent R2COX1. Preferred acylating agents. are anhydrides (RCO) 20, more preferably acetic anhydride. The acylating agent is usually employed in at least equimolar amounts, preferably in molar excess.

The reaction is conventionally. performed in a non- polar solvent, preferably methylene chloride.

Preferably the reaction is performed in the presence of an acylation catalyst, e. g. an organic amine, preferably N, N-dimethylaminopyridine. The amount of catalyst may vary from 0,1 mol to 1 mol per mole of hydroxyester X.

Starting from the mixture X affords a fifth mixture of 4 chiral diastereomeric acyloxy esters XI while starting from the mixtures Xa or Xb affords a sixth mixture of 2 chiral diastereomeric aryloxy esters of formula XIa, or a seventh mixture of 2 chiral diasteromeric acyloxy esters of formula Xib, respectively.

Step i): Advantageously said sixth or seventh mixture is separated into essentially pure chiral diastereomeric acyloxy esters by conventional means, preferably by chromatographic techniques, more preferably with silica gel. However, the following step m) can also be performed on the mixtures.

Step Said pure chiral acyloxy esters or mixtures of esters of formula XI are hydrolyzed by conventional means with acid or base to yield the corresponding hydroxy acid XII.

The hydrolysis is preferably performed by reacting XI in a dilute aqueous solution of a metal hydroxide, more preferably in dilute aqueous sodium hydroxide followed by acidification with a strong mineral acid, such as sulfuric acid or hydochloric acid, preferably concentrated hydrochloric acid, to afford a hydroxy- acid of formula XII.

Reaction temperatures may vary from 25°C to reflux temperature of the reaction mixture.

Step k): The hydroxy acid XII obtained from step j) is reacted in the presence of an aryl-sulfonyl halide Ar3SO2X2, preferably an aryl-sulfonyl chloride, more preferably p-toluene sulfonyl chloride, to afford the desired chiral compound of formula 1. The sulfonyl- halide is usually employed in at least equimolar amount, preferably in molar excess and more preferably from 1.5 to 5 mole per mole of hydroxy acid.

Preferably the reaction is performed in the presence of an organic base. Suitable organic bases for the formation of I are pyridine and substituted pyridines, such as or y-picoline, ethylpyridines, a-or y-lutidine and preferably collidine (2,4,6- trimethylpyridine). Preferably the base is used in molar excess, based on the amount of XII. In particular the base is used as a solvent for the arylsulfonyl halide and the hydroxy acid XII.

Reaction temperatures vary from about 25°C to about 200°C, preferably from about 100°C to about 200°C, more preferably from about 170°C to about 180°C.

Starting with RSS or the RRR isomer of the hydroxy acid XII yields the R, E isomer of compound I, while starting from compound RRS or RSR yields the R, Z isomer. Starting with SSS or the SRR isomer of the hydroxy acid XII yields the R, E isomer of compound I, while-starting from compound RRS or RSR yields the R, Z isomer. The present invention also provides chiral compounds of formula XIII wherein Ar, Ar1 and R have the meanings given above.

Preferably Ar, R and Arl independently from one other, but preferably in combination with one another, have the meanings given below:.

Ar is phenyl, which may be unsubstituted or substituted with 1,2 or 3 radicals selected from halogen, Cl-C4alkyl, Cl-c4 haloalkyl, C1-C4alkoxy, Cl-C4haloalkoxy and hydroxy, 1-or 2-naphthyl, which may be unsubstituted or substituted with 1,2 or 3 radicals selected from halogen, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy and Cl-C4haloalkoxy, or a 5-or 6-membered heteroaromatic ring, which may be unsubstituted or substituted with 1,2 or 3 radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy, R is C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl or C3-C6halocycloalkyl; Ari is phenoxyphenyl optionally substituted with one to six radicals selected from halogen,.

C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy groups, phenyl optionally substituted with one to five radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy groups, biphenyl optionally substituted with one to five radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy groups, phenoxypyridyl optionally substituted with one to five radicals selected from halogen, Cl-C4alkyl, Cl-C4haloalkyl, Cl-CQalkoxy and C1-C4haloalkoxy groups, benzylpyridyl optionally substituted with one to five radicals selected from halogen, C,-c4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy groups, benzylphenyl optionally substituted with one to five radicals selected from halogen, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy and C1-C4haloalkoxygroups, benzoylphenyl optionally substituted with one to five radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, Cl-C4alkoxy and Cl-CQhaloalkoxy groups, 1-or 2-naphthyl optionally substituted with one to three radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy groups, or a 5-or 6-membered heteroaromatic ring optionally substituted with one to three radicals selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and Cl-C4haloalkoxy groups, and R, is H or Cl-C, alkyl ; and Z is H or COR2, wherein R2 is C1-C4 alkyl.

More preferred compounds of the formula XIII are those wherein Ar, R and Ar. independently from one other, but preferably in combination with one another, have the meanings given below: Ar is phenyl which is unsubstituted or substituted with 1,2 or 3 radicals, preferably with one radical, selected from halogen, Cl-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy, in particular halogen; Arl is phenoxyphenyl, in particular 3-phenoxyphenyl which is substituted as mentioned above, and preferably by 1,2 or 3 halogen atoms.

R is Ci-c. alkyl, in particular isopropyl, or more preferably C3-C6cycloalkyl, in particular cyclopropyl.

More preferred compounds XIII are those wherein Ar1 is phenyl optionally substituted with one to three halogen groups ; and R is C 3-c. cycloalkyl, in particular cyclopropyl.

In a particular preferred embodiment of the invention, Ar in formula XIII is p-chlorophenyl.

In a particular preferred embodiement of the present invention, Ar 1 is 3-phenoxyphenyl wherein at least on halogen atom is located on the phenyl ring of the 3-phenoxyphenyl radical. In a specific'embodiement of the invention, Arl is 4-fluoro-3-phenoxyphenyl.

Most preferred compounds are those selected from the group consisting of methyl (2S, 3S)-2 [ (R)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate; methyl (2R, 3R)-2- [ (R)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate; methyl (2S, 3R)-2- [ (R)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate; methyl (2R, 3'S)-2- [ (R)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate; methyl (2S, 3S)-2- [ (S)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate; methyl (2R, 3R)-2-[(S)-(4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro4-(4-fluoro-3-phenoxyphenyl)- butanoate; methyl (2S, 3R)-2- [ (S)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate ;. methyl (2R, 3S)-2- [ (S)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate; methyl (2S, 3S)-3- (acetyloxy)-2- [ (S)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoate ; methyl (2R, 3R)-3- (acetyloxy)-2- [ (S)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoate; methyl (2R, 3R)-3- (acetyloxy)-2- [ (S)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoate; methyl (2S, 3R)-3- (acetyloxy)-2- [ (S)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoate ; methyl (2S, 3S)-3- (acetyloxy)-2- [ (R)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoa-te ; methyl (2R, 3R)-3- (acetyloxy)-2- [ (R)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoate; methyl (2R, 3S)-3- (acetyloxy)-2- [ (R)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoate; methyl (2S, 3R)-3- (acetyloxy)-2- [ (R)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3- phenoxyphenyl) butanoate; (2S, 3S)-2-[(S)-(4-chlorophenyl) (cyclopropyl) methyl]-2- fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid; (2R, 3R)-2-[(S)-(4-chlorophenyl) (cyclopropyl) methyl]-2- fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid; (2R, 3S)-2- [ (S)- (4-chlorophenyl). (cyclopropyl) methyl]-2- fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid ; (2S, 3R)-2- [ (S)- (4-chlorophenyl) (cyclopropyl) methyl]-2- fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid; (2S, 3S)-2-[(R)-(4-chlorophenyl) (cyclopropyl) methyl]-2- fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid; (2R, 3R)-2-[(R)-(4-chlorophenyl) (cyclopropyl) methyl]-2- fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid ; (2R, 3S)-2- [ (R)- (4-chlorophenyl) (cyclopropyl) methyl-2- fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid, and (2S, 3R)-2-[(R)-(4-chlorophenyl) (cyclopropyl) methyl]-2- . fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxy- butanoic acid.

The present invention additionally provides chiral compounds of formula XIV wherein Q is -CO2H; -CO2CH3; -CH2OH; -CH2OSO2Ar2; -CH2CN; -CH2CO2H ; -CH2CO2R1; or -CHFCO2R1; Ar2 is phenyl, p-chlorophenyl, or p-tolyl; and Ri is Cl-C4alkyl.

Most preferred compounds are selected from the group consisting of (2R)-2- (4-chlorophenyl)-2-cyclopropylethyl 4- methylbenzenesulfonate; (2S)-2- (4-chlorophenyl)-2-cyclopropylethyl 4- methylbenzenesulfonate ; (3R)-3- (4-chlorophenyl)-3-cyclopropylpropanenitrile ; (3S)-3- (4-chlorophenyl)-3-cyclopropylpropanenitrile ; (3R)-3- (4-chlorophenyl)-3-cyclopropylpropanoic acid; (3S)-3- (4-chlorophenyl)-3-cyclopropylpropanoic acid; methyl (3R)-3- (4-chlorophenyl)-3-cyclopropylpropanoate ; methyl (3S)-3- (4-chlorophenyl)-3-cyclopropylpropanoate ; methyl (3R)-3- (4-chlorophenyl)-3-cyclopropyl-2- fluoropropanoate ; methyl (3S.)-3- (4-chlorophenyl)-3-cyclopropyl-2- fluoropropanoate ; In order to present a clear understanding of the invention, the following examples are set forth below.

These examples are merely illustrative, and are not to be understood as limiting the scope and underlying principles of the invention'in any way.

I. Preparation of the Aldehydes ArICH2CHO Preparation of (4-Fluoro-3-phenoxyphenyl) acetaldehyde: Step i): 4-Fluoro-3-phenoxybenzaldehyde After dissolving sodium metal (0.41 g, 17.8 g- atom) in ethanol (25 ml), nitropropane (1.65 g) and 4- (bromomethyl)-l-fluoro-2-phenoxybenzene (5.00 g) are added. and the mixture stirred for 3.5 h. The reaction was filtered and concentrated in vacuo. The residue is taken up in ether and'washed with water (10 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether: hexane (10: 90) to afford the title compound as a colorless liquid which is characterized by 1HNMR spectral analyses.

Step ìi) l-Fluoro-4-[(E)-2-methoxyethenyl]-2- phenoxybenzene To a stirred suspension of (methoxymethyl) tri- phenylphosphonium chloride (2.48 g) in ether (50 ml) at room temperature under nitrogen is added phenyllithium (4 ml of a 1.8 M solution in ether, 7.2 mmol) and the resulting mixture stirred for 20 minutes. 4-fluoro-3- phenoxybenzaldehyde (1.30 g, 6.0 mmol) is then added and the reaction is stirred for 4 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (20 ml) and diethyl ether (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether: hexane (5: 95) to afford the title compound as a colorless liquid (1.30 g, 89%) which is characterized by'HNMR, IR and mass spectral analysis.

Step iii): (4-Fluoro-3-phenoxyphenyl) acetaldehyde F Conc. HCl w w I/ - CH30 O THF OHC \ A mixture of l-fluoro-4-[(E)-2-methoxyethenyl]-2- phenoxybenzene (0.50 g), concentrated hydrochloric acid (2 ml) and tetrahydrofuran (10 ml) is stirred at room temperature for 1 hour. The reaction is diluted with water (100 ml), the organic layer is separated and dried over anhydrous sodium sulfate, and the solvent is removed in vacuo to give the title compound as a colorless liquid (0.43 g, 41%) which is characterized by 1HNMR, mass spectral analyses and used without further purification.

II. Preparation of chiral l, 4-diaryl-2-fluoro-2- butenes I EXAMPLE 1: (2R)-(4-chlorophenYl) (cYclopropvl) ethanoic acid and Methvl (2S)-(4-chlorophenYl) (cyclopropyl)- ethanoate (steps a + b) Y Horse A sH liver \COCH3 I C02H estérase Cul Cul H 1 C02 CH3 ci Cl Horse liver esterase (4. 6 g horse liver acetone powder, Sigma Chemical Co.) was suspended in water (200 ml) at room temperature and the pH is adjusted to 7.5 with 1.0 M sodium hydroxide. Methyl (2RS)- (4-chloro- phenyl) (cyclopropyl) ethanoate (7.0 g, 31.4 mol) was added and stirring was continued at room temperature with the addition of 1.0 M sodium hydroxide as needed to maintain the pH at 7.1-8.0. After 14 ml of base had been consumed, the pH was brought to 3 with 10% hydrochloric acid, ethyl acetate was added and the mixture was filtered through diatomaceous earth. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography afforded (2R)- (4- chlorophenyl) (cyclopropyl) ethanoic acid (2.5 g, 37.9%) and recovered ester (4.1 g). The ester was resubjected to the hydrolysis conditions with additional-horse liver esterase (1.0 g) for an extended period during which an additional 4.4 ml of 1. 0 M sodium hydroxide was consumed. Acidification, workup and purification as described above affords methyl (2S)- (4- chlorophenyl)- (cyclopropyl) ethanoate (3.1 g, 36.2%) The enantiomeric excess of (2R)- (4-chlorophenyl) (cyclo- propyl) ethanoic acid (as the methyl ester) and (2R)- (4- chlorophenyl)- (cyclopropyl) ethanoic acid are determined with the chiral NMR shift reagent Eu (hfc) 3 to be >96 : 4 and >98: 2 respectively.

EXAMPLE 2 : (2R)-2-(4-chloroPhenyl)-2-cycloproDvlethan (step c) Borane-tetrahydrofuran complex (58 ml of a 1.0 solution iS tetrahydrofuran, 58 mmol) was added dropwise over one hour to a stirred solution of (2R)- (4-chloro- phenyl) (cyclopropyl) ethanoic acid (7.25 g, 34.4 mmol) in tetrahydrofuran (200 ml) at 0°C under nitrogen The solution was allowed to warm to room temperature and stirred for an additional 4 h. The reaction mixture was cooled to 0°C and carefully quenched by the dropwise addition of water: THF (1: 1,50 ml). The mixture was diluted with ethyl acetate (250 ml) and washed with water (250 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ether: hexane (25: 75 to 40: 60) to afford the title compound as a colorless syrup (5.70 g, 84%) which was characterized by HNMR, 3CNMR and mass spectral analyses.

EXAMPLE 3: (2S)-2- (4-chlorophenvl)-2-cyclopropvlethanol (step c) <.. , COzCH3 DIBAL/ . I CHZOH 11 Cl cul Diisobutyl aluminum hydride (86 ml of a 1.0 M solution in methylene chloride, 86.0 mmol) was added to a stirred solution of methyl (2S)- (4-chloro- phenyl) (cyclopropyl) ethanoate (7.72 g, 34.4 mmol) in methylene chloride (300 ml) at-78°C under nitrogen.

The reaction mixture was allowed to warm to room temperature and stirred for an additional hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride and then filtered. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ether: hexane (15: 85) to afford the title compound as a colorless liquid (5.45 g, 80%) which was characterized by HNMR, 13CNMR and mass spectral analyses.

EXAMPLE 4: (2R)-2- 4-Chlorophenyl)-2-cvclopropvlethvl 4-methylbenzenesulfonate (step dl) (2R)-2- (4-Chlorophenyl)-2-cyclopropylethanol (6.50 g, 33.0 mmol), tosyl chloride (7.86 g, 41.0 mmol) and 6.0 ml of triethylamine (6.0 ml) were dissolved in dichloromethane (150 ml) and allowed to stir for 3 days. The reaction mixture was washed successively with aqueous 1 N HC1 (100 ml), water (100 ml) and saturated brine solution (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ether: hexane (10: 90 to 25: 75) to afford the title compound as a colorless oil (11.1 g, 96%) which was characterized-by 1HNMR, 13CNMR and mass spectral analyses.

EXAMPLE 5: (2S)-2- (4-Chlorophenyl)-2-cvclopropvlethvl 4-methvlbenzenesulfonate (step dl) Using the procedure of Example 4, (2S)-2- (4- chlorophenyl)-2-cyclopropylethanol yields the title compound as a colorless liquid which is characterized by HNMR, IR and mass spectral analyses.

EXAMPLE 6: (3R)-3- (4-chlorophenvl)-3-cvclopropvl- propanenitrile (step d2) A mixture of (2R)-2- (4-chlorophenyl)-2-cyclopro- pylethyl 4-methylbenzenesulfonate (11.00 g, 31.3 mmol) and NaCN (4.62 g, 94.3 mmol) in dimethyl sulfoxide (100 ml) was heated at to 90°C for 3 hours. The dimethyl sulfoxide was removed in vacuo and the resulting mixture was partitioned between water (200 ml) and diethyl ether (200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ether: hexane (25: 75) to afford the title compound as a colorless oil (5.62 g, 87%) which was characterized by HNMR, IR and mass spectral analyses.

EXAMPLE 7: Preparation of (3S)-3- (4-chloro-Qhenyl)-3- cvcloprouvlpropanenitrile (step d2) Using the procedure of Example 6, (2S)-2- (4- chlorophenyl)-2-cyclopropylethyl 4-methylbenzene- sulfonate yields the title compound as a colorless liquid which is characterized by 1HNMR, IR and mass spectral analyses.

EXAMPLE 8: Preparation of (3R)-3- (4-Chlorophenvl)-3- cyclopropylpropanoic acid (step d3) , H , CH2 CN-1. 10%'Aq. NAOH 5 : ll CH 2COOH 2 Cl 2. Conc. HC1 Cl C1 (3R)-3- (4-Chlorophenyl)-3-cyclopropylpropane- nitrile (5.30 g, 25.8 mmol) was refluxed for 18 hours in a mixture of methanol (100 ml) and 10% by weight aqueous sodium hydroxide (100 ml). Methanol was removed in vacuo, the residual solution was cooled to 0°C and acidified to pH 4 with concentrated hydro-chloric acid.

The aqueous layer was extracted with ethyl acetate (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a colorless liquid (5.79 g, 100%) which was characterized by 1HNMR, IR and mass spectral analysis and used without further purification.

EXAMPLE 9 : (3S)-3- (4-chlorophenvl)-3-cvclopropyl- propanoic acid (step d3) 'H H CH CN 1. 10% Aq. NAOH C. H COOH a \ I CH3QH Cl, \ 2. Conc. HC1 Using the procedure of Example 8, (3S)-3- (4- chlorophenyl)-3-cyclopropylpropanenitrile yields the title compound as a colorless oil, which is characterized by HMMR, IR and mass spectral analyses.

EXAMPLE 10: Methvl (3R)-3-(4-chloroPhenvl)-3-cyclo- propylpropanoate (step d4) Hydrogen chloride gas was bubbled into a solution of of (3R)-3- (4-chlorophenyl)-3-cyclopropylpropanoic acid (5. 79 g, 25.85 mmol) in methanol (100 ml) at 0°C. for 30 seconds. The solution was allowed to warm to room temperature and stirred for 18 hours. The solution was concentrated in vacuo, diluted with chloroform (100 ml) and washed with 5% aqueous sodium bicarbonate (100 ml).

The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ether: hexane (10: 90) to yield the title compound as a colorless liquid (5.15 g, 84% from (3R)-3- (4-chlorophenyl)-3- cyclopropylpropanenitrile) which was characterized by 1HNMR, IR and mass spectral analyses.

EXAMPLE 11: Methvl (3S)-3-(4-chlorophenyl)-3-cyclo- propvlpropanoate (step d4) Using the procedure of Example 10, (3S)-3- (4- chlorophenyl)-3-cyclopropylpropanoic acid yields the title compound as a colorless liquid which is characterized by HNMR, IR and mass spectral analyses.

EXAMPLE 12: Preparation of Methyl (3R)-3- (4-chloro- phenvl)-3-cvclopropvl-2-fluoropropanoate (step e) To a stirred solution of lithium diisopropyl amide (30 mmol) in dry tetrahydrofuran (125 ml) under nitrogen at-78°C was added dropwise a solution of methyl (3R)-3- (4-chlo. rophenyl)-3-cyclopropylpropanoate (6.5 g, 27.2 mmol) in dry tetrahydrofuran (50 ml). The reaction mixture was allowed to warm to 0° over 5 minutes, re-cooled to-78°C, and N-fluorobenzene- sulfonimide (19.1 g, 60.6 mmol) was added. The reaction was allowed to warm to room temperature, stirred an additional 2 hours, and then partitioned between ether (200 ml) and saturated ammonium chloride (200 ml). The solids were filtered off and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ether: hexane (10: 90) to yield the title compound as a colorless liquid (6.40 g, 92%) which was characterized by 1HNMR, IR and mass spectral analyses.

EXAMPLE 13: Methvl (3S)-3- (4-chlorophenvl)-3-cvclo- propvl-2-fluoropropanoate (step e) Using the procedure of Example 12, methyl (3S)-3- (4-chlorophenyl)-3-cyclopropylpropanoate yields the title compound as an off-white semi-solid which is characterized by HNMR, IR and mass spectral analyses.

EXAMPLE 14: Preparation of Methyl 2- [ (4-chlorophenyl)- (cvclopropvl)-methvl-2-fluoro-4- (4-fluoro-3-phenoxv- phenyl)-3-hvdroxv-butanoate f (SRR and (SRS or SSR) 1 and Methyl 2-f (4-chlorophenrvl (cvclopropvl) methvl-2-fluoro- 4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(SSS) and (SSR or SRS)] (steps f + cr) (SRR) and (SRS or SSR) (sss) and (SSR or SRS) A solution of methyl (3S)-3- (4-chlorophenyl)-3- cyclopropyl-2-fluoropropanoate (3.6 g, 11.9 mmol) in dry tetrahydrofuran was added dropwise to a stirred solution of lithium diisopropylamide in tetrahydrofuran (7.75 ml of 2M lithium diisopropylamide in tetrahydrofuran added to 50 ml of dry tetrahydrofuran) under nitrogen at-78°C, and the resulting mixture was stirred for 15 minutes keeping the temperature at -78°C. A solution of (4-fluoro-3-phenoxyphenyl)- acetaldehyde (3.23 g, 14.0 mmol) in dry tetrahydrofuran was then added dropwise and the resulting mixture was stirred for 2 hours at-78°C. The reaction was quenched at-78°C with saturated aqueous ammonium chloride (2 ml) and partitioned between ether (50 ml) and water. (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo.

The residue was chromatographed on silica gel eluting with ether: hexane (25: 75) to yield methyl 2- [ (4- chlorophenyl) (cyclopropyl) methyl-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl)-3-hydroxybutanoate [ (SRR) and (SRS or SSR)] (1.17 g) as a colorless oil, and Methyl 2- [ (4- chlorophenyl) (cyclopropyl) methyl-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl)-3-hydroxybutanoate [ (SSS) and (SSR or SRS)] (1.65 g) as a colorless oil, both of which are characterized by 1HNMR and"FNMR spectral analyses.

The overall yield based on recovered starting materials was 50%.

EXAMPLE 15: Methyl 2-r (4-chlorophenYl) (cyclopropyl)- methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxy butanoate f (RSS) and (RSR) or (RRS) 1 and Methyl 2-r (4- <BR> <BR> chlorophenvl) (cvclopropvl) methvl-2-fluoro-4- (4-fluoro- 3-phenoxvphenvl)-3-hvdroxybutanoate f (RRR) and (RSR or RRS) 1 (steps f + a) (RSS) and (RSR or RRS) (RRR) and (RSR or RRS) Using the procedure of Example 14, methyl (3R)-3- (4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate yields the title compounds which are characterized by HNMR and 19FNMR spectral analyses.

EXAMPLE 16: Methvl (2R, 3R)-3- (acetyloxy) 2-r (S)- (4- chlorophenyl) (cyclopropyl) methvll-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl) butanoate (SRR isomer) and methyl (2R, 3S or 2S, 3R)-3-(acetyloxy)2-[(S)-(4-chlorophenyl)- (cvclopropvl) methvll-2-fluoro-4- (4-fluoro-3-phenoxy- phenyl) butanoate (SRS or SSR isomer/Diastereomer A) (steps h + i) (SRR) Diastereomer A (SSR or SRS) A solution of methyl 2- [ (4-chlorophenyl) (cyclo- propyl) methyl-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)-3- hydroxybutanoate [ (SRR) and (SRS or SSR)] (1.17 g, 2.40 mmol), acetic anhydride (1.50 ml) and dimethylamino- pyridine (0.11 g) in methylene chloride was stirred for 2 hours at room temperature (30 ml). The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with ether: hexane (15: 85) to afford methyl (2S, 3S)-3- (acetyloxy)-2- [ (S)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3-phenoxy- phenyl) butanoate (0.20 g) and methyl (2R, 3S or 2S, 3R)-3- (acetyloxy) 2- [ (S)- (4-chlorophenyl) (cyclopropyl) methyl]- 2-fluoro-4- (4-fluoro-3-phenoxyphenyl) butanoate (SRS or SSR isomer/Diastereomer A) (0.80 g) as pure diastereomers in 79% overall yield and >98% ee as determined by 19FNMR spectral analysis.

EXAMPLE 17: Methyl (2S, 3S)-3- (acetvloxv)-2-r (S)- (4- <BR> <BR> chlorophenyl) (cvclopropyl) methvll-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl) butanoate (SSS isomer) and methyl ( (2R, 3S or 2S, 3R)-3-(acetyloxy)-2-[(S)-(4- <BR> <BR> chlorophenvl) (cvclopropvl) methvll-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl) butanoate (SRS or SSR isomer/Diastereomer B) (steps h + i) (SSS) Diastereomer B (SRS or SSR) Using the procedure of Example 16, methyl 2- [ (4- chlorophenyl) (cyclopropyl) methyl-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl)-3-hydroxybutanoate { (SSS) and (SRS or SSR)] affords the title compounds as pure diastereomers which were characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 18: Methyl (2S, 3S)-3-(acetyloxy)-2-C (R)-(4- chlorophenyl) (cyclopropyl) methyll-2-fluoro-4- (4-fluoro- 2-phenoxYphenYl) butanoate (RSS isomer) and Methyl (2S, 3R or 2R, 3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)- (cyclopropyl) methvll-2-fluoro-4- (4-fluoro-2- phenoxyphenyl)butanoate (RSR or RRS/Diastereomer C) (RSS) Diastereomer C (RRS) or (RSR) Using the procedure of Example 16, methyl 2- [ (4- chlorophenyl) (cyclopropyl) methyl-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl)-3-hydroxybutanoate [ (RSS) and (RSR or RRS)] yields the title compounds as pure diastereomers which are characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 19: Methyl (2R, 3R)-3-(acetyloxy)-2-[(R)-(4- chlorophenyl) (cyclopropyl) methvll-2-fluoro-4- (4-fluoro- 3-phenoxYphenyl) butanoate (R, R, R) and Methvl (2S, 3R or 2R,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)- (cyclopropyl) methvll-2-fluoro-4- (4-fluoro-3- phenoxyphenyl)butanoate (RSR or RRS/Diastereomer'D) (RRR) Diastereomer D (RSR or RRS) Using the procedure of Example 16, methyl 2- [ (4- chlorophenyl) (cyclopropyl) methyl-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl)-3-hydroxybutanoate [ (RRR) and (RSR or RRS)] yields the title compounds as pure diastereomers which are characterized by 1HNMR and 19FNMR spectral analysis. The structure of methyl (2S, 3S)-3- (acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl) methyl] -2-fluoro-4- (4-fluoro-3-phenoxyphenyl) butanoate is. also confirmed by x-ray crystal structure analysis.

EXAMPLE 20: Preparation of (2R, 3S or 2S, 3R)-2-P(S)-(4- chlorophenyl) (cyclopropyl) methyll-2-fluoro-4-(4-fluoro- 3-phenoxvphenyl)-3-hvdroxvbutanoic acid (SRS or SRR /Diastereomer E) (step-i) F zozo C1 F CO2CH3 t cl i Diastereomer B (SRS) or (SSR) 10% aq. NaOH CH30H THF v H H OH F COOH c 1 Diastereomer E (SRS) or (SSR) A mixture of methyl (2R, 3S or 2S, 3R)-3- (acetyloxy).-2- [ (S)- (4-chlorophenyl) (cyclopropyl)- <BR> <BR> <BR> methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl) butanoate (Diastereomer B) (0.80 g, 1.50 mmol), aqueous sodium hydroxide (25 ml), methanol (20 ml) and tetrahydrofuran (5 ml) was refluxed for 1 hour. The organic solvents were removed in vacuo, the mixture was diluted with ethyl acetate and acidified to pH 3 with concentrated hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title. compound as a colorless semi solid, which was characterized by 1HNMR and 19FNMR and used without further purification.

EXAMPLE 21 : (2S, 3R or 2R3S)-2-r (s)-(4-chlorophenyl- (cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3- phenoxvphenvl)-3-hvdroxvbutanoic acid (Diastereomer F) H H OCOCH 3 0 F, CO 2CH3 ci Diastereomer A (SSR) or (SRS) 10% aq. NaOH CH3OH THF H H OH F CO H F COZY ci Diastereomer F (SSR) or (SRS) Using the procedure of Example 20, methyl (2S, 3R or 2R, 3S)-3- (acetyloxy)-2- [ (S)- (4-chlorophenyl) (cyclo- propyl) methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate (Diastereomer. A) yields the title compound as a pure diastereomer which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 22: (2S, 3S)-2-[(S)-(4-chlorophenyl)(cyclo- propyl) methvll-2-fluoro-4- (4-fluoro-3-phenoxvphenvl)-3- hvdroxvbutanoic acid Using the procedure of Example 20, methyl (2S, 3S)- <BR> <BR> 3- (acetyloxy)-2- [ (S)- (4-chlorophenyl) (cyclopropyl,)-<BR> <BR> methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl) butanoate yields (2S, 3S)-2- [ (S)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)-3- hydroxybutanoic acid as a pure diastereomer which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 23: (2R, 3R)-2- [ (S)- (4-chlorophenvl) (cyclo- propyl) methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3- hydroxybutanoic acid Using the procedure of Example 20, methyl (2R, 3R)-3- (acetyloxy) 2- [ (S)- (4-chlorophenyl)- (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro-3-phenoxy- phenyl) butanoate yields the title compound as a pure diastereomer which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 24: (2R, 3R)-2-f (R)- (4- chlorophenyl) (cvclopropvl) methvll-2-fluoro-4- (4-fluoro- 3-phenoxvphenvl)-3-hydroxvbutanoic acid Using the procedure of Example 20, methyl (2R, 3R)- 3- (acetyloxy)-2- [ (R)- (4-chlorophenyl) (cyclopropyl)- methyl]-2-fluoro-4- fluoro-3-phenoxyphenyl) butanoate yields the title compound as a pure diastereomer which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 25: (2S, 3R or 2R, 3S)-2- [(R)-(4-chlorophenyl) (cyclopropyl) methvll-2-fluoro-4- (4-fluoro-3- phenoxvphenvl)-3-hvdroxvbutanoic acid F H OCOCH3 I // 0 F C02 CH3 Cl/ Diastereomer D (RSR or RRS) 10% aq. NaOH CH30H THF F CO H CH F H H OH -. H. F COZY Cl \/ Diastereomer G (RSR or RRS) Using the procedure of Example 20, methyl (2S, 3R or 2R, 3S)-3- (acetyloxy)-2- [ (R)- (4-chlorophenyl) (cyclo- propyl) methyl]-2-fluoro-4- (4-fluoro-3-phenoxyphenyl)- butanoate (Diastereomer D) yields the title compound as a pure diastereomer which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 26: Preparation of 4-[(2Z, 4S)-4-(4- <BR> <BR> chlorophenvl)-4-. cvclopropyl-3-fluoro-2-butenvll-1- fluoro-2-phenoxvbenzene (step k) H H OH I" F cozy cul/ Diastereomer E (SRS or SSR) TsCl Collidine 0 F . A \ 1 3 C1 I A solution of crude (2R, 3S or 2S, 3R)-2- [ (S)- (4- chlorophenyl) (cyclopropyl) methyl]-2-fluoro-4- (4-fluoro- 3-phenoxyphenyl)-3-hydroxybutanoic acid (Diastereomer E) (0.72 g, 1.5 mmol), tosyl chloride (0.58 g, 3.0 mmol) and collidine (20 ml) was heated at 170°C for 2 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ether: hexane (5: 95) to yield the title compound as a colorless liquid (0.43 g, 69% from diasteriomer B), +35. 8 (C=0.0438, CHCl3) which is characterized by HNMR and 19FNMR spectral analyses.

EXAMPLE 27: Preparation of 4-r (2Z, 4S)-4- (4- Chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1- fluoro-2-phenoxvbenzene F // /\""0 C1 F CO2E A C1/ Diastereomer F (SSR) or (SRS) TsCl Collidine A w H A I ) f Cl ci 1 Using the procedure of Example 26, (2S, 3R or 2R, 3S)-2- [ (S)- (4-chlorophenyl) (cyclopropyl) methyl-2- <BR> <BR> fluoro-4- (4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid (Diastereomer F) yields the title compound as a colorless liquid which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 28: 4-[(2E,4S)-4-(4-chlorophenyl)-4-cyclo- propyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene < H 4 OH F g H OH // ,, 0 1 F co2H Cul/ (SSS) \ TsCl Collidine A F < X zu \ I F \ ci Using the procedure of Example 26, (2S, 3S)-2- [ (S)- (4-chlorophenyl) (cyclopropyl) methyl]-2-fluoro-4- (4- fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid yields the title compound as a colorless liquid which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 29: 4-r (2E, 4S)-4-(4-chlorophenyl)-4-cyclo- <BR> <BR> propvl-3-fluoro-2-butenvll-1-fluoro-2-phenoxvbenzene < H F loH OH I F CO2H > I'I (SRR) !)) TsCl Collidine A F O 1-, jazz Using the procedure of Example 26, (2R, 3R)-2- [ (S)- (4-chlorophenyl) (cyclopropyl) methyl]-2-fluoro-4- (4- fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid yields the title compound as a colorless liquid which is characterized by HNMR and 19FNMR spectral analyses.

EXAMPLE 30: 4-[(2E,4R)-4-(4-Chlorophenyl)-4-cyclo- <BR> <BR> propvl-3-fluoro-2-butenvll-l-fluoro-2-phenoxvbenzene F g H OH // ,---o C1 F CO2H 4 C1/ (RRR) \ TsCl Collidine A F HO 'R' 5 9 X Cul Using the procedure of Example 26, (2R, 3R)-2- [ (R)- (4-chlorophenyl) (cyclopropyl) methyl]-2-fluoro-4- (4- fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid yields the title compound as a colorless liquid which is characterized by 1HNMR and 19FNMR spectral analyses.

EXAMPLE 31 : 4-[(2Z,4R)-4-(4-chlorophenyl)-4-cyclo- <BR> <BR> propvl-3-fluoro-2-butenvll-1-fluoro-2-phenoxvbenzene F IN H OH /\ v"O C1 F COOH < cri Diastereomer G (RSR or RRS) TsCl Collidine A F \ I I,.,. O /'/ Cul \ Using the procedure of Example 26, (2S, 3R or 2R, 3S)-2- [ (R)- (4-chlorophenyl) (cyclopropyl) methyl]-2- fluoro-4- (4-fluoro-3-phehoxyphenyl)-3-hydroxybutanoic acid (Diastereomer G) yields 4- [ (2Z, 4R)-4- (4- chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1- fluoro-2-phenoxybenzene as a colorless oil which is characterized by 1HNMR and 19FNMR spectral-analysis.