WO2002040493A1 - Asymmetric metal complexes based on a transition metal useful for enantioselective reduction of ketone derivatives by hydride transfer - Google Patents

Abstract

The invention concerns asymmetric metal complexes based on a transition metal and comprising as ligand of said metal at least an optically active form of a compound of general formula (I). The invention also concerns the preparation and the use of said complexes in asymmetric organic synthesis and in particular for enantioselective reduction of ketone derivatives by hydride transfer.

Description

 ASYMMETRICAL METAL COMPLEXES BASED ON A METAL

TRANSITIONS USEFUL FOR THE ENANTIOSELECTIVE REDUCTION OF DERIVATIVES

KETONICS BY HYDRIDE TRANSFER

The main object of the present invention is optically active metal complexes having at least one asymmetric ligand of the pheno.a.kylarnine type, their preparation process and their application in asymmetric catalysis.

Asymmetric metal complexes based on rhodium, ruthenium or iridium are today widely used in asymmetric synthesis. As an illustration of these asymmetric organic synthesis reactions, mention may be made in particular of asymmetric reduction by hydride transfer and more particularly that of ketone derivatives to their corresponding chiral secondary alcohols.

Of course, during the synthesis of this type of products, there is generally a simultaneous production of an unwanted enantiomer which it is necessary to separate from the desired enantiomer. It is generally through the choice of the asymmetric catalyst and more particularly of the nature of the ligand carrying the center of asymmetry that it proves possible to effectively favor the majority synthesis of one of the two enantiomers. Generally, these are organometallic complexes of the Rh (l), lr (l) and Ru (ll) types chirally modified so as to lead to the reduction of aromatic ketones - with a very high substrate / catalyst ratio. In particular, with these types of complexes, diamine-type chiral ligands are advantageous.

The object of the present invention is precisely to propose new metal complexes chelated by an asymmetric ligand of phenolalkylamine type which are effective for asymmetric synthesis and in particular for the asymmetric reduction by hydride transfer of ketone functions. It has now been found and this is what constitutes a first object of the invention of new asymmetric metal complexes based on a transition metal and comprising as ligand of said metal at least one optically active form of a compound of general formula (I):

in which - R represents: (i) a hydrogen atom, (ii) an alkyl chain, preferably C, to C ₁₂ , optionally interrupted by one or more oxygen or sulfur atom (s), and optionally substituted by one or more halogen atom (s), a phenyl or benzyl group,

(iii) an alkenyl chain, preferably C ₂ to C _10> optionally interrupted by one or more oxygen or sulfur atom (s), and optionally substituted by one or more halogen atom (s),

(iv) a group SO ₁ or COR ₁ in which R. represents a group chosen from:

(α) a preferably C 1 -C ₁₂ alkyl or preferably C ₃ -C ₁₂ cycloalkyl group,

(β) an aryl group, preferably from C ₆ to C ₁₂ , the optionally substituted with at least one alkyl group as defined in (α), (χ) a C ₇ to C ₁₅ arylalkyl group such as benzyl, (λ) a group Rf in which Rf represents - (i) a C 1 -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl radical poly- or perhalogenated, and preferably perfluorinated

(ii) a phenyl radical substituted by a poly- or perhalogenated, and preferably perfluorinated, C ₄ -C ₄ alkyl radical or (iii) a C ₆ mono-, poly- or perhalogenated aryl radical, and preferably perfluorinated with l group of groups, α, β and χ which may be substituted by at least one halogen atom, an ether function, a tertiary amine and / or a thioether function. - R ₂ represents a hydrocarbon group having from 1 to 12 carbon atoms, which can be an acyclic saturated or unsaturated, linear or branched aliphatic group, a saturated, unsaturated, aromatic, monocyclic or polycyclic cycloaliphatic group incorporating or not one or more heteroatoms , or a sequence of one or more previous groups, with

said group being optionally carrying a saturated or unsaturated, linear or branched aliphatic group, and / or

the chain of said group possibly being interrupted by one or more oxygen atoms and / or substituted by an electron-withdrawing group,

- A symbolizes an aromatic, monocyclic or polycyclic cycle incorporating or not incorporating one or more heteroatoms.

As is apparent from the examples which follow, the metal complexes in accordance with the present invention prove to be particularly advantageous in terms of reactivity. They make it possible to carry out hydride transfer reactions with higher kinetics and in particular multiplied by a factor of 2 compared to the complexes mentioned above, that is to say chelated by ligands of diamine type.

In the following description of the present invention, the term “aromatic” is understood to mean the classic concept of aromaticity such as. defined in the literature, including arch J. "Advanced Organic Chemistry", ^4th ed., John Wiley & Sons, 1992, pp 40 ff.

The aromatic cycle represented by A can thus comprise, at the level of its cycle, one or more heteroatoms chosen from nitrogen, phosphorus, sulfur and oxygen atoms. According to a preferred mode, they are nitrogen atoms.

Likewise, the carbon atoms of the aromatic derivative can also be substituted. Of them . vicinal substituents present on the aromatic ring can also form, together with the carbon atoms which carry them, a hydrocarbon ring, preferably aromatic and comprising, where appropriate, at least one heteroatom. The aromatic derivative is then a polycyclic derivative.

Thus, in the general formula (I), A can represent:

- A monocyclic, aromatic, in particular benzene carbocyclic ring, optionally itself carrying one or more substituents. As examples of such rings, mention may in particular be made of the phenyl group;

- an aromatic polycyclic carbocyclic group with the rings being able to form between them ortho-condensed, ortho- and peri-condensed systems, said ring being able to be substituted. As an example, there may be mentioned more particularly a naphthyl group;

- a monocyclic heterocyclic group, aromatic, comprising in particular 5 or 6 atoms in the cycle including one or two heteroatoms such as nitrogen, sulfur and oxygen atoms; the carbon atoms of this heterocycle can also be substituted;

- a group consisting of at least two aromatic heterocycles containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri-condensed systems; and

a condensed group comprising at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems with one of the two rings being aromatic and the carbon atoms of said rings possibly being substituted.

As an example of this type of heterocyclic aromatic, there may be mentioned, inter alia, the furyl, pyrrolyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinile, pyrimidinyl, pyrannyl and quinolyl, naphthyridinyl derivatives. , benzopyrannyl, benzofurannyl and indolyl.

Of course, the number of substituents present on the aromatic ring represented by A, depends on the carbon condensation and on the number of unsaturation of the ring. The maximum number of substituents capable of being carried by a cycle is easily determined by a person skilled in the art.

As regards the substituents present at the level of the compound of general formula (I), they are of course chosen so as not to interact during the applications of the complexes claimed, in particular during the reduction by hydride transfer.

In the particular case of group R ₂ , the substituents can be of the electron donor or electron withdrawing type.

As the electron donor group, mention may be made of C ₆ -C ₆ alkyl groups; CC ₆ alkoxy, phenyl optionally substituted by an alkyl or alkoxy group as defined above.

For the purposes of the present invention, the term “electron-withdrawing group” is understood to mean a group as defined by HC BROWN in the work of Jerry March "Advanced Organic Chemistry", 3 ^rd edition, chapter, 9, pages 243 and 244.

Mention may in particular be made, as representative of the electroattracfeùrs groups:

- a halogen atom,

- a group SO ₂ R., with R., as defined above, and - a group CN or N0 ₂ . In the preceding general formulas and in those which follow, the halogen atom (s) mentioned as a substituent are preferably represented by a fluorine atom.

According to a preferred variant of the invention, R ₂ is: - a C ₆ to C ₆ preferably C ₄ to C ₄ alkyl group;

- a phenyl or naphthyl group, optionally substituted with at least one C ₁ to C ₄ alkoxy; or

- a benzyl group.

The metal complexes according to the invention prove to be very particularly advantageous in which the compound of general formula (I) corresponds to the general formula (II):

in which :

- R ₂ and R are as defined above, - R _A , R _B , R _c and R _D independently of one another represent a hydrogen atom or a group chosen from:

A linear or branched alkyl group having from 1 to 4 carbon atoms,

• ^an alkoxy or thioether group, linear or branched, having from 1 to 4 carbon atoms,

• an ester or amide group,

• a phenoxy group,

• a NO ₂ group,

A phenyl group, “a phenylalkyl group,

• a halogen atom, and / or R _A and R _B on the one hand and / or R _c and R _D on the other hand can be linked to represent a carbocyclic or heterocyclic, mono- or polycyclic, saturated, unsaturated or aromatic group so as to form a compound of formula II bi- or polycyclic, which means that at least two rings have two carbon atoms in common.

Preferably R ₂ represents:

- a C ₆ to C ₆ preferably C ₄ to C ₄ alkyl group;

- a phenyl or naphthyl group, optionally substituted with at least one C ₁ to C ₄ alkoxy; or - a benzyl group.

More preferably, R _A and R _B simultaneously represent a hydrogen atom or are linked together so as to constitute, with the phenyl ring, a naphthyl group.

The compounds of general formula (la) in which:

- R _A and R _B on the one hand and R _c and R _D on the other hand are not linked to each other and constitute, with the carbon atoms which carry them, a benzene ring substituted or not, or

- R _A and R _B on the one hand or R _c and R _D on the other hand are linked together so as to constitute with the carbon atoms which carry them a benzene ring which, condensed with the original ring, leads the formation of a naphthalene ring which may or may not be substituted.

As examples of transition metals capable of forming complexes in accordance with the present invention, mention may in particular be made of metals such as rhodium, ruthenium, iridium, cobalt, nickel, platinum and palladium.

Among the aforementioned metals, very particularly suitable are rhodium, ruthenium and iridium. Ruthenium is more particularly preferred. As stated previously, the compounds of general formula

(I) are presented in an optically active form. Advantageously, the use of a complex according to the invention makes it possible to reduce a pro-chiral ketone or a racemic mixture of ketone derivatives having at α of the ketone function a center of asymmetry. In the latter case, the corresponding hydroxylated derivative can be obtained by controlling the stereochemistry of two centers of asymmetry. We are seeing a kinetic dynamic resolution of the whole molecule:

Preferably, the metal complexes in accordance with the present invention correspond to the general formula (III):

in which :

- A, R and R ₂ are as defined above in formula (I),

M is a transition metal chosen from rhodium, ruthenium, iridium, cobalt, nickel, platinum and palladium,

- Z is an anionic ligand coordinating and

- L is an unsaturated aliphatic neutral ligand comprising at least one double bond and preferably a carbocyclic or heterocyclic ligand preferably of 5 to 8 atoms and comprising at least one double bond, charged or not.

In the case of formula (III), the oxygen atom is probably directly linked by a covalent bond to the metal M. In this hypothesis, the hydrogen atom shown in parentheses does not exist. However, the invention is in no way limited to this mode of mechanism. It also extends to the complexes of formula (III) in which this bond between oxygen and the metal is of a dative nature. In this second hypothesis, the oxygen is then present in the form of a hydroxyl group.

The valence at the level of the metal atom being liable to vary, the nature and the number of ligands L and Z are then adjusted accordingly by those skilled in the art.

Of particular interest are the. compounds of formula (III) in which

- M represents ruthenium, rhodium or iridium,

Z represents a halogen atom, preferably chlorine or bromine,

- L represents a C ₆ to C ₁₂ aromatic compound or a ligand of the cyclopentadiene or cyclooctadiene type substituted where appropriate by one or more C ₄ to C ₄ alkyl groups.

As more specific examples, mention may be made of the complexes corresponding to the general formula (IV):

with L, Z, M, R _A and R _B as defined in formulas (II) and (III), with preferably R _A and R _B representing either a hydrogen atom or being linked so as to constitute with the ring phenyl a naphthyl ring.

Of particular interest are the complexes of formulas (III) or (IV) in which:

L represents an aromatic compound chosen from benzene, para-methylisopropylbenzene or hexamethylbenzene,

- Z is a chlorine atom or a bromine atom, and

- M a ruthenium atom. According to a preferred variant of the invention, the claimed complex has, as ligand, an optically active form of a compound chosen from: 1U

- (-) - 1- (2-hydroxyphenyl) -ethylamine,

- (+) - 1- (α-aminobenzyl) -2-naphthol and their respective enantiomers.

The present invention also provides a process for the preparation of said complexes comprising reacting an optically active form of a compound of general formula (I), as defined above with the suitable transition metal in a suitable organic solvent. The complexes comprising, as ligand, the compound of formula

(I) above and the transition metal can be prepared according to the known methods described in the literature.

For the preparation of ruthenium complexes, reference may be made in particular to the publication by J.-P. Genêt [Acros Organics Acta, 1, Nr. 1, pp. 1-8 (1994)] and for the other complexes in the article by Schrock R. and Osborn J.A. [Journal of the American Chemical Society, 93, pp. 2397 (1971)].

The reaction is generally carried out at a temperature between room temperature (15 to 25 ° C) and the reflux temperature of the reaction solvent.

As examples of organic solvents, there may be mentioned, inter alia, aliphatic hydrocarbons, halogenated or not and more particularly hexane, heptane, isooctane, decane, benzene, toluene, methylene chloride, chloroform ; solvents of ether or ketone type and in particular diethylether, tetrahydrofuran, acetone, methyl ethyl ketone; alcohol type solvents, preferably methanol, ethanol or isopropanol.

The metal complexes according to the invention, recovered according to conventional techniques (filtration or crystallization) are used in asymmetric hydrogenation reactions of substrates specified below. As regards the preparation of the compounds of general formula (I), it generally derives from the functionalization of the cycle represented by A.

The operating conditions used to carry out the synthesis of these compounds are generally dictated by the chemical nature of the starting compounds. The implementation of this type of reaction is in fact within the competence of a person skilled in the art.

The reaction can be carried out in a usual organic solvent and preferably in ethanol. The temperature is generally between 0 ° C and the reflux of the solvent and is preferably close to or equal to room temperature.

Generally the reaction is carried out at atmospheric pressure.

It is also preferred to carry out the reaction under an atmosphere composed of inert gases such as nitrogen or rare gases, for example argon. From a practical point of view, the method can be implemented batchwise or continuously.

For example, the compounds in which A represents a phenyl nucleus can be obtained by the transformation of a compound of the following formula:

en son oxime de formule

in its formula oxime

using NH ₂ - O— R _A with:

- R _A representing a lower alkyl group or a benzyl group, and

- R ₂ being as defined in general formula (I). The oxime derivative thus obtained can be reduced by catalytic hydrogenation or using reducing agents such as boron hydrides, preferably BH ₃ . Following this reduction, the expected compound is obtained in the form of a racemic. The isolation of the two optical isomers can be carried out in a conventional manner. One can in particular refer to the method described in US Pat. No. 5,120,853 which proposes to carry out the resolution of the two chiral isomers using mandelic acid.

As regards more particularly the compounds of general formula (I) in which A represents a naphthyl ring and R ₂ a phenyl group, they can be obtained via the formation of their imine intermediate according to the following protocol:

This synthetic route is more particularly described in the publication Tetrahedron Asymmetry 98, n ° 3667-3675. The imine thus obtained is then hydrolyzed in an acid medium.

The present invention also relates to the use of a metal complex as defined above to carry out asymmetric organic syntheses and more particularly enantioselective reductions of ketone derivatives by hydride transfer. The ketone derivatives capable of being hydrogenated by a metal complex in accordance with the invention preferably correspond to the general formula (V):

dans laquelle

in which

- R ₃ and R ₄ represent independently of each other: (i) an alkyl chain, preferably C, to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) and optionally substituted by one or more halogen atom (s) or hydroxylated, amine or carboxyl group (s),

(ii) an alkenyl or alkynyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) and optionally substituted by one or more halogen atom (s) or group (s) hydroxylated, amine or carboxyl;

(iii) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted by one or more halogen atom (s) or hydroxyl group, amine, alkyl, alkoxy or alkenyl, optionally substituted by a or more halogen atom (s);

(iv) an arylalkyl group, preferably from C ₇ to C ₁₅ , optionally substituted by one or more halogen atom (s) or hydroxylated or amine group (s), on the aromatic ring; (v) an arylalkenyl group, preferably from C ₈ to C ₁₅ , optionally substituted by one or more halogen atom (s); and

- * indicates the possible presence in R ₄ of an asymmetry center located in position α of the carbonyl function.

Among the amines proposed as substituents, secondary and tertiary amines are more particularly preferred. As a representative of the substituents R ₄ having a center of asymmetry, one can particularly mention the groups R ₄ whose carbon atom carrying the center of asymmetry is substituted by a mono- or di-substituted amine function and by a function ester. By way of illustration of the ketones of formula (V) capable of being transformed by the invention, mention may in particular be made of the following compounds:

- methylphenylketone,

- isopropylphenylketone, - cyclopropylphenylketone,

- allylphenylketone,

- p-methylphenylmethylketone,

- benzylphenylketone,

- o-bromoacetophenone, - α- bromoacetone,

- α-dibromoacetone,

- α-chloroacetone,

- -dichloroacetone,

- -trichloroacetone, - 1-chloro-3,3-dichloroacetone,

- 1-fluoro-2-oxobutane,

- 1-chloro-3-methyl-2-butanone,

- α-chloroacetophenone,

- 1-chloro-3-phenylacetone, - α-methylaminoacetone,

- α-dimethylaminoacetone,

- 1-butylamino-2-oxopropane,

- 1-dibutylamino-2-oxopropane.

- 1-methylamino-2-oxobutane, - 1-dimethylamino-2-oxobutane,

- 1-dimethylamino-3-methyl-2-oxobutane, - 1-dimethylamino-2-oxopentane,

- -hydroxyacetone,

- 1-hydroxy-3-methyl-2-butanone,

- 1-hydroxy-2-oxobutane, - 1-hydroxy-2-oxopentane,

- 1-hydroxy-2-oxohexane,

- 1-hydroxy-2-oxo-3-methylbutane,

- α-hydroxyacetophenone,

- l-hydroxy-3-phenylacetone, - α-methoxyacetone,

- α-methoxyacetophenone,

- α-butoxyacetophenone, - α-chloro-p-methoxyacetophenone,

- α-naphthenone, - 1-ethoxy-2-oxobutane,

- 1 -butoxy-2-oxobutane.

One can also envisage substrates of the aldehyde / ketone type, that is to say having a second carbonyl group in position α, β, χ or δ relative to the first carbonyl group. Examples of such diketonic compounds are:

- 3,4-dioxohexane,

- 4,5-dioxooctane,

- 1-phenyl-1, 2-dioxopropane,

- 1-phenyl-2,3-dioxobutane, - 1, 2-cyclopentanedione,

- 1, 2-cyclohexanedione,

- acetylacetone,

- 3,5-heptanedione,

- 1-phenyl-1, 3-butanedione, - 1-phenyl-1, 3-pentanedione,

- 1-phenyl-1, 3-hexanedione, - 1-phenyl-1, 3-heptanedione,

- 1, 3-di (trifluoromethyl) -1, 3-propanedione,

- 3-chloro-2,4-pentanedione

- 1,5-dichloro-2,4-pentanedione, - 1,5-dihydroxy-2,4-pentanedione, - 1,5-dibenzyloxy-2,4-pentanedione, - 1,5-diamino-2,4- pentanedione, - 1,5-di (methylamino) 2,4-pentanedione, - 1,5-di (dimethylamino) -2,4-pentanedione, - 3,5-dioxo-methyl hexanoate.

- 3-carbomethoxy-2,4-pentanedione, - 3-carboethoxy-2,4-pentanedione,

- 1, 3-cyclopentanedione,

- 1, 3-cyclohexanedione, - 1, 3-cycloheptanedione.

As other examples of ketones, mention may be made, among others, of cyclic, saturated or unsaturated, monocyclic or polycyclic ketone compounds, keto acids, or ketones of steroid type. The substrates chosen must of course not have additional functions capable of interfering in the reaction according to the invention.

The process of the invention applies very particularly to the preparation of an optically active hydroxylated compound of general formula (VI):

dans laquelle :

in which :

- R ₃ and R ₄ represent independently of each other (i) an alkyl chain, preferably C ₁₀ to C _10> optionally interrupted by one or more oxygen or sulfur atom (s) and optionally substituted by one or more halogen atom (s) or group (s) ) hydroxylated, amine or carboxyl, (ii) an alkenyl or alkynyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) and optionally substituted by one or more atom (s) s) halogen or hydroxylated group (s), amine or carboxyl;

(iii) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted by one or more halogen atom (s) or hydroxyl group, amine, alkyl, alkoxy or alkenyl, optionally substituted by a or more halogen atom (s);

(iv) an arylalkyl group, preferably from C ₇ to C ₁₅ , optionally substituted by one or more halogen atom (s) or hydroxylated or amine group (s), on the aromatic ring;

(v) an arylalkenyl group, preferably from C ₈ to C ₁₅ , optionally substituted by one or more halogen atom (s); and

- * signals it _. presence of a chirality center at the carbon level, characterized in that it implements the asymmetric reduction of a compound of general formula (V):

avec R₃ et R₄ tels que définis ci-dessus et * indiquant la présence éventuelle dans R₄ d'un centre d'asymétrie situé en position α de la fonction carbonyle en présence d'un complexe métallique dont le métal de transition possède à titre de ligand au moins une forme optiquement active d'un composé de formule générale (I) telle que définie précédemment. De préférence, le complexe répond à l'une des formules (III) ou (IV) précisées ci-dessus.

with R ₃ and R ₄ as defined above and * indicating the possible presence in R ₄ of an asymmetry center located in position α of the carbonyl function in the presence of a metal complex whose transition metal has at titer of ligand at least one optically active form of a compound of general formula (I) as defined above. Preferably, the complex corresponds to one of the formulas (III) or (IV) specified above.

According to a preferred variant of the invention, the complex is generated in situ in the reaction medium of the catalytic reduction according to the process mentioned above. It is only after the complex has been prepared that the ketone derivative of formula (V) to be treated is added to said medium.

The selective asymmetric reduction of said substrate of formula (V) is carried out using therefore as a catalyst a metal complex according to the invention, that is to say liganded by an optically active derivative of general formula (I) or (11) or such as defined in formula (111) or (IV).

The reduction of the ketone derivative is generally carried out at a temperature between 5 ° C and 100 ° C in the presence of a hydrogen donor.

Those skilled in the art are able to set the appropriate temperature range to obtain the best compromise between the reaction rate and the enantiomeric yield. Generally, this temperature is between 20 ° C and 50 ° C.

The hydrogen donor is conventionally represented by a lower secondary alcohol. Generally, this hydrogen donor is used as a solvent. As representative of the lower secondary alcohols, mention may be made of 2- or 3- butanol and isopropanol.

The concentration of the substrate in the hydrogen donor solvent advantageously varies between 0.01 and 3 moles per liter and preferably between 0.05 and 1 mole per liter. The complex based on the compound of general formula (I) and the transition metal is used in an amount of 1/10000 to 1/1 moles relative to the carbonyl compound of general formula (V). It appears that the increase in the catalyst / substrate ratio has no significant effect on the enantioselectivity of the reduction. The reaction is preferably carried out in an organic co-solvent. Any solvent is used as long as it is stable under operating conditions. Use is preferably made of a polar organic solvent such as dichloromethane.

Generally, the reaction is carried out in the presence of a basic compound. This basic compound can be an alkaline base such as sodium or potassium hydroxide or else a primary, secondary or tertiary amine, and more particularly pyridine, pyperidine, triethylamine, and preferably triethylamine. It activates the catalyst by generating the corresponding metal hydride.

The amount of base is dependent on the amount of metal. It generally varies on the order of 1 to 10 expressed in moles relative to the number of metal atoms present in the complex.

As mentioned previously, the use of the compounds of general formula (I) as ligands makes it possible to significantly improve the enantiomeric excess and the kinetics in certain asymmetric reactions, in particular in reactions for reducing ketone functions into secondary alcohols by hydride transfer.

The examples which appear below are presented by way of illustration and without limitation of the present invention.

EXAMPLE 1:

Acetophenone reduction

1) in the presence of a ruthenium complex carrying as ligand (-) - 1 - (2-hydroxyphenyl) -ethylamine. The reduction is carried out according to the following summary scheme:

S / Ru / ligand / KOH = 200 / l / l / 4

In a 150 ml monocol, 31 mg of the ruthenium complex (0.05 mmol), 14 mg of (-) - 1- (2-hydroxyphenyl) -ethylamine (ee = 94% determined by HPLC) and 10 ml of isopropanol are loaded. The reaction medium is heated at 80 ° C for 30 min. under an argon atmosphere. After adding 90 ml of isopropanol and 1, 2 ml of acetophenone and degassing of the reaction medium with argon for 15 minutes, 20 mg of KOH are added. The reaction mixture is stirred at room temperature and the progress of the reaction is followed by gas chromatography (column CYCLODEX B 236M 25mX0.25μm; initial column temperature 100 ° C; final column temperature 150 ° C; heating rate 2 ° C / min.; Injector temperature 150 C; detector temperature 240 ° C; injected volume 2 μl). After two hours, the conversion rate is 60%.

2) in the presence of a ruthenium complex ligated by (S) - (+) - 1- (α-aminobenzyl) -2-naphthol (Betti base).

(S) - (+) - 1- (α-aminobenzyl) -2-naphthol is previously prepared according to the procedure described in Tetrahedron: Asymmetry 9, (1998), 3667-3675.

The reduction is carried out according to a synthesis scheme analogous to that of Example 1.

The procedure is as in Example 1 but starting with 31 mg of the ruthenium complex (0.05 mmol), 25 mg of (S) - (+) - 1- (α- aminobenzyl) -2-naphthol (Betti base) (ee = 89% determined by HPLC) of 1.2 ml of acetophenone and 20 mg of potassium hydroxide. After two hours, the conversion rate is 95% and the phenylethanol is formed with an ee of 67%.

By way of comparison, these tests were reproduced with a diamine, the monotosylated diphenylethylene diamine PhCH (NH ₂ ) CHPh NH-S0 ₂ - pToluene.

Table 1 below gives an account of the different kinetics observed. It is noted that only the complexes chelated by ligands in accordance with the invention lead to particularly rapid reduction kinetics.

Table 1

Ligand Duration TT (%)

Betti-Base ex 2 2 h 95

Aminophenol ex 1 2 h 60

Diamine 2 h 41

EXAMPLE 2:

Variation in the number of ligand equivalent compared to metal.

In this test, the reduction of acetophenone is repeated under the conditions set out in example 2 but by varying from 1 to 10 the number of equivalent in (S) - (+) - 1- (α-aminobenzyl) -2 -naphthyl with respect to the ruthenium atom. The concentration of ruthenium complex is 0.1 mol / l and the enantiomeric transformation rates and excess are measured by gas chromatography. The results obtained are presented in Table 2:

Table 2

No. of ligand equivalent in relation to TT Duration (%) ee (%) to metal

Trial 1 1 lh 90 67

Test 2 2 lh 85 68

Test 3 5 lh 21 70

Trial 4 10 lh 41 62

It is noted that an excess of ligand is not necessary in terms of transformation rate and enantiomeric yield.

EXAMPLE 3:

Reduction of different carbonyl substrates.

Each reduction is carried out by reproducing the operating conditions presented in example 1.

The substrates tested are shown below and Table 3 reports the results obtained.

8 10 Table 3 substrate Duration TT (%) ee (%)

Trial 5 7 lh 99 45

Test 6 8 lh 90 67

Trial 7 9 lh 81 63

Trial 8 10 lh 67 57

Claims

1. Asymmetric metal complexes based on a transition metal and comprising as ligand of said metal at least one optically active form of a compound of general formula (I):

in which: - R represents: (i) a hydrogen atom, (ii) an alkyl chain, preferably C, to C ₁₂ , optionally interrupted by one or more oxygen or sulfur atom (s), and optionally substituted by one or more halogen atom (s), a phenyl or benzyl group, (iii) an alkenyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s), and optionally substituted by one or more halogen atom (s), (iv) a group SO _z R ^ or COR ₁ in which R. represents a group chosen from: (α) an alkyl group, preferably C ₁ -C ₁₂ cycloalkyl or 5 preferably C ₃ -C _12, (β) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted with at least one alkyl group as defined in (α), (χ) a C ₇ to C ₁₅ arylalkyl group such as benzyl, (λ) a Rf group wherein Rf represents o (i) an alkyl radical in C, to C ₁₀ cycloalkyl or C ₃ -C _1Q poly- or perhalogenated, preferably perfluorinated (ii) a phenyl radical substituted by a poly- or perhalogenated, and preferably perfluorinated, C ₄ -C ₄ alkyl radical or (iii) a C ₆ mono-, poly- or perhalogenated aryl radical, and preferably perfluorinated with l 'all of the groups, α, β and χ which may be substituted by at least one halogen atom, an ether function, a tertiary amine or a thioether function; - R ₂ represents a hydrocarbon group having from 1 to 12 carbon atoms, which can be an acyclic saturated or unsaturated, linear or branched aliphatic group, a saturated, unsaturated, aromatic, monocyclic or polycyclic cycloaliphatic group incorporating or not one or more heteroatoms , or a sequence of one or more previous groups, with said group being optionally carrying a saturated or unsaturated, linear or branched aliphatic group, and / or the chain of said group possibly being interrupted by one or more oxygen atoms and / or substituted by an electron-withdrawing group, - A symbolizes an aromatic, monocyclic or polycyclic cycle incorporating or not incorporating one or more heteroatoms. 2. Complex according to claim 1, characterized in that A appears in general formula (I): - a monocyclic, aromatic carbocyclic ring, optionally itself carrying one or more substituents; - an aromatic polycyclic carbocyclic group with the rings being able to form between them ortho-condensed, ortho- and peri-condensed systems, said ring being able to be substituted; - a monocyclic heterocyclic group, aromatic, comprising in particular 5 or 6 atoms in the ring including one or two heteroatoms such as nitrogen, sulfur and oxygen atoms and with the carbon atoms of this heterocycle being able to be substituted; - a group consisting of at least two aromatic heterocycles containing at least one heteroatom in each cycle and forming between 5 them ortho- or ortho- and peri-condensed systems; and a condensed group comprising at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems with one of the two rings being aromatic and the carbon atoms of said groups io cycles which can possibly be substituted. 3. Complex according to claim 1 or 2, characterized in that the compound of general formula (I) corresponds to the general formula (II):

20 in which: - R ₂ and R are as defined in claim 1, - R _A , R _B , R _c and R _D independently of one another represent a hydrogen atom or a group chosen from: • a linear or branched alkyl group having from 1 to 4 atoms of 25 carbon, An alkoxy or thioether group, linear or branched, having from 1 to 4 carbon atoms, • an ester or amide group, • a phenoxy group, 30 “a group N0 ₂ , • a phenyl group, A phenylalkyl group, • a halogen atom, and / or R _A and R _B on the one hand and / or R _c and R _D on the other hand can be linked to represent a carbocyclic or heterocyclic, mono- or polycyclic, saturated, unsaturated or aromatic group so as to form a compound of bi- or polycyclic formula II. 4. Complex according to one of claims 1 to 3, characterized in that R ₂ is: 10 - a C ₁ to C ₆ , preferably C, to C ₄ alkyl group; - a phenyl or naphthyl group, optionally substituted with at least one C ₄ -C ₄ alkoxy; or - a benzyl group. 5. Complex according to claim 3 or 4, characterized in that: - R _A , R _B , R _c , R _D are not linked to each other and constitute, with the carbon atoms which carry them, a benzene ring, substituted or not, or - R _A and R _B on the one hand or R _c and R _D on the other hand are linked together so as to constitute with the carbon atoms which carry them a benzene ring which, condensed with the original ring, leads to the formation of a naphthalene cycle, substituted or not. 6. Complex according to one of claims 1 to 5, characterized in that the metal is chosen from rhodium, ruthenium, iridium, cobalt, nickel, platinum, palladium. 7. Complex according to one of claims 1 to 6, characterized in that it corresponds to the general formula (III):

in which : - A, R and R ₂ are as defined in claims 1 to 4, - M is a transition metal chosen from rhodium, ruthenium, iridium, cobalt, nickel, platinum and palladium, - Z is an anionic ligand coordinating and - L is an unsaturated aliphatic neutral ligand comprising at least one double bond. 8. Complex according to one of claims 1 to 7, characterized in that it corresponds to formula (IV):

with L, Z and M as defined in claim 7 and R _A and R _B in claim 3 or 5. 9. Complex according to claim 7 or 8, characterized in that: L represents an aromatic compound chosen from benzene, para-methylisopropylbenzene or hexamethylbenzene, Z is a chlorine atom or a bromine atom, and - M a ruthenium atom. 10. Complex according to one of claims 7 to 9, characterized in that R _A and R _B represent either a hydrogen atom or are linked so as to constitute with the phenyl ring a naphthyl ring. 11. Complex according to one of claims 1 to 10, characterized in that it has, as ligand, an optically active form of a compound chosen from: - (-) - 1- (2-hydroxyphenyl) -ethylamine, - (+) - 1- (α-amihbbenzyl) -2-naphthol and their respective enantiomers. 12. Process for the preparation of a complex according to one of claims 1 to 11, characterized in that it consists in reacting an optically active form of a compound of general formula (I) as defined in claims 1 to 5 with the transition metal compound retained in a suitable organic solvent. 13. Use of a metal complex as defined in one of claims 1 to 11 in asymmetric catalysis 14. Use of a metal complex as defined in one of claims 1 to 11 for the enantioselective reduction of a ketone derivative by hydride transfer. 15. Use according to claim 14, characterized in that the compound carrying the ketone function corresponds to the general formula (V):

. in which - R ₃ and R ₄ represent independently of each other: (i) an alkyl chain, preferably C ₁₀ to C ₁₀ , optionally interrupted. by one or more oxygen or sulfur atom (s) and optionally substituted by one or more halogen atom (s) or 5 hydroxylated, amine or carboxyl group (s), (ii) an alkenyl or alkynyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) and optionally substituted by one or more halogen atom (s) or group (s) hydroxylated, amine or carboxyl; 0 (iii) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted by one or more halogen atom (s) or hydroxyl group, amine, alkyl, alkoxy or alkenyl, optionally substituted by one or more halogen atom (s); (iv) an arylalkyl group, preferably from C ₇ to C ₁₅ , optionally substituted by one or more halogen atom (s) or hydroxylated or amine group (s), on the aromatic ring; (v) an arylalkenyl group, preferably from C ₈ to C ₁₅ , optionally substituted by one or more halogen atom (s); and - * indicates the possible presence in R ₄ of an asymmetry center o located in position α of the carbonyl function. 16. Process for the preparation of an optically active secondary alcohol of general formula (VI):

0 in which:. - R ₃ and R ₄ represent independently of each other (i) an alkyl chain, preferably C ₁₀ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) and optionally substituted by one or more halogen atom (s) or group (s) ) hydroxylated, amine or carboxyl, (ii) an alkenyl or alkynyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) and optionally substituted by one or more atom (s) s) halogen or. hydroxyl, amine or carboxyl group (s); (iii) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted by one or more halogen atom (s) or hydroxyl group, amine, alkyl, alkoxy or alkenyl, optionally substituted by a or more halogen atom (s); (iv) an arylalkyl group, preferably from C ₇ to C ₁₅ , optionally substituted by one or more halogen atom (s) or hydroxylated or amine group (s), on the aromatic ring; (v) an arylalkenyl group, preferably from C ₈ to C ₁₅ , optionally substituted by one or more halogen atom (s); and - * signals the presence of a chirality center at the carbon level, characterized in that it implements the asymmetric reduction of a compound of general formula (V):

with R ₃ and R ₄ as defined above and * indicating the presence in R ₄ of an asymmetry center in position α of the carbonyl function, in the presence of a metal complex as defined in claims 1 to 11 . 17. The method of claim 15 or 16, characterized in that the complex is used at a rate of 1 / 10,000 to 1/1 relative to the carbonyl compound of general formula (V). 18. The method of claim 16 or 17, characterized in that the reaction is carried out in the presence of a hydrogen donor. 19. The method of claim 18, characterized in that the hydrogen donor is a lower secondary alcohol used as a reaction solvent. 20. Method according to one of claims 16 to 19, characterized in that the reaction is carried out in the presence of a basic compound. 21. The method of claim 20, characterized in that the basic compound is present in an amount between 1 and 10 expressed in moles relative to the number of metal atoms present in the complex.