EP1185488A1

EP1185488A1 - Sulphonylamides and carboxamides and their use in asymmetrical catalysis

Info

Publication number: EP1185488A1
Application number: EP00951592A
Authority: EP
Inventors: Alain Wagner; Charles Mioskowski; Barbara Mohar; Jean-Roger Desmurs; Frédéric LE GUYADER; Thierry Schlama
Original assignee: Rhodia Chimie SAS
Current assignee: Rhodia Chimie SAS
Priority date: 1999-06-15
Filing date: 2000-06-15
Publication date: 2002-03-13
Also published as: JP2003502296A; CA2374553A1; WO2000076942A1; AU6448200A; IL146952A0

Abstract

The invention concerns mainly novel diamine derivatives or the like of general formula (I) particularly useful, in their optically active form, as ligand of metal complexes. The invention also concerns the complexes, the method for preparing them and their use in asymmetrical synthesis, and particularly for enantioselective hydrogenation of ketone derivatives.

Description

SULFONYLAMIDES AND CARBOXAMIDES AND THEIR APPLICATION IN ASYMMETRIC CATALYSIS

The main object of the present invention is new compounds 5 of diamine, mono- or polyfluorinated, sulfonylated or carbonylated type, their preparation process and their application in asymmetric catalysis.

The claimed compounds are particularly advantageous in their optically active form as ligands of organometallic complexes. The corresponding metal complexes are in particular advantageous as catalysts for carrying out the asymmetric synthesis.

As an illustration of these asymmetric organic synthesis reactions, mention may be made in particular of asymmetric catalytic hydrogenation and more particularly that of ketone derivatives to their corresponding chiral secondary alcohols.

The optically active secondary alcohol derivatives are reagents which are particularly sought after in many fields, in particular pharmaceutical, agrochemical or perfumery. 0 Of course, during the synthesis of this type of products, there is generally a simultaneous production of an inactive enantiomer from which it is necessary to isolate the desired enantiomer.

It is therefore important to minimize the formation of this uninteresting enantiomer. To this end, reductions in ketone derivatives are conventionally carried out in the presence of asymmetric synthesis catalysts. Generally, these are transition metal complexes carrying chiral ligands. This is how certain organometallic complexes of chirally modified Rh (l), lr (l) and Ru (ll) types make it possible to reduce aromatic ketones with a very high substrate / catalyst ratio. However, the enantioselectivity obtained with this type of catalyst remains moderate.

More recently, a new type of Ru (ll)-based chiral catalyst has been developed which enables an enantioselective reduction of aromatic ketones to be carried out at room temperature. (R Noyori et al., J. Am. Chem. Soc. 1995, 117, 7562, 7563)

This catalyst is derived from the metal complex RuCI ₂ (-7 ⁶ mesitylene) ₂ . This is used in a form chelated by a diphenylethylenediamine derivative of formula A

in which Ra represents a radical chosen from C ₆ H ₅ CO-, pCH ₃ OC ₆ H ₄ S0 ₂ -, C ₆ H ₅ SO ₂ - and CF ₃ S0 ₂ -. In fact, among the sulfonated radicals tested, it is the radical CF ₃ S0 ₂ - which is considered to be the least interesting ligand in terms of enantioselective yield.

The object of the present invention is precisely to propose new diamine derivatives or the like capable of constituting effective chiral ligands for asymmetric synthesis and in particular for asymmetric hydrogenation of ketone functions.

It has now been found and this is what constitutes a first object of the invention of new products, namely diamine derivatives or the like corresponding to the following general formula:

in which

- B represents (i) -CO-, or (ϋ) -S0 ₂ -, - Rf represents

(i) a halogen atom, preferably fluorine,

(ii) a preferably C 1 to C ₁₂ and more preferably C ₂ to C ₆ alkyl radical, preferably a C ₃ to C ₁₂ cycloalkyl, and more preferably C ₆ , mono-, poly- or per- halogenated, the haloalkyl chain of which is optionally interrupted by one or more oxygen or sulfur atoms,

(iii) an aryl radical, preferably at C ₆ to C ₁₂ , substituted by at least one halogenated alkyl radical as defined in (ii), and preferably two perhalogenated alkyl radicals at C, to C ₃ , (iv) a aryl, mono-, poly- or per-halogenated radical preferably in

C ₆ to C ₁₂ and more preferably C ₆ , or

(v) a radical chosen from R _A -CF ₂ -, R _A -CF ₂ -CF ₂ -, R _A -CF ₂ -CF (CF ₃ ) -, CF ₃ -C (R _A ) F- and (CF ₃ ) R _A - with R _A representing a hydrogen atom or having any of the meanings given below for R _B and R _c ,

- Y represents an OH, SH, NH ₂ , NHR _B or NR _B R _{C group} , with R _B and R _c different from a hydrogen atom and representing independently of one another a radical chosen from:

(i) an alkyl chain, preferably from C to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or carboxyl groups,

(ii) an alkenyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more atom (s) d halogen or carboxyl group (s); (iii) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted by one or more halogen atom (s) or alkyl or alkenyl group (s);

(iv) an arylalkyl group, preferably from C ₇ to -I5, optionally substituted by one or more halogen atom (s);

(v) an arylalkenyl group, preferably at C ₈ to C ₁₅ , optionally substituted by one or more halogen atom (s) - A symbolizes a skeleton of general formula la or Ib.

in which

- R 'and R "independently of one another represent a hydrocarbon radical having from 1 to 20 carbon atoms which can be an acyclic saturated or unsaturated, linear or branched aliphatic radical; a saturated, unsaturated, aromatic cycloaliphatic radical, monocyclic or polycyclic incorporating or not incorporating one or more heteroatoms provided that when B represents a group S0 ₂ , na for zero, Rf represents a group CF ₃ , Y represents a group NH ₂ then R 'and R "do not simultaneously represent a unsubstituted phenyl ring; said cycloaliphatic radical optionally carrying a saturated or unsaturated, linear or branched aliphatic radical with the alkyl chain which can be interrupted by one or more oxygen atoms and / or carbonyl function and where appropriate preferably substituted at the end of chain by an aromatic or non-aromatic cyclic radical; said radicals possibly being substituted by one or more halogen atoms, preferably fluorine and / or one or more alkyl radicals at C, at C ₆ , preferably at C ₁ to C ₄ or else the two substituents R 'and R "are linked together so as to constitute a cycloaliphatic radical as defined above,

- X represents a methylene group optionally substituted,

- n is an integer varying from zero to 3, and

- Ar, and Ar ₂ symbolize, independently of one another, two substituted or unsubstituted aromatic rings, condensed or not and optionally carrying one or more heteroatoms, preferably C ₆ to C ₁₂ and which can form ortho systems or ortho and peri-condensed between them,

- x and y respectively identify the two bonds established between the skeleton symbolized by A and the amino groups and Y and its derivatives.

Within the meaning of the present invention, the term “derivatives” is intended to cover in particular the organic or mineral salts of the compounds of formula I as well as their racemic mixtures and their optically active isomers.

Unexpectedly and in contradiction with the results published with the trifluoromethanesulfonyl derivative of formula A, mentioned above, the inventors have demonstrated that the presence of a strongly electron-withdrawing group at the level of one or of the amino functions makes it possible significantly improve asymmetric ketone reductions when catalyzed by the corresponding metal complexes. The kinetics of the reaction is significantly increased and the expected enantiomer is recovered with a higher conversion rate for an equivalent enantiomeric yield.

This is how the electron-withdrawing group proves to be particularly effective when it comprises in its structure at least one halogen atom and more preferably a fluorine atom. According to the invention, the electron-withdrawing group appearing on the nitrogen atom of the amine function of the general formula I is represented by a group BRf in which Rf represents (i) a halogen atom, preferably fluorine, (ii) a C ₁ to C ₁₀ preferably C ₂ to C ₆ alkyl or a C ₃ to C ₁₀ preferably C _{6 to} cycloalkyl radical, mono-, poly- or perhalogenated,

(iii) a phenyl radical substituted by at least one C ₄ -C ₄ alkyl radical mono-, poly- or perhalogen, and preferably two C ₃ -C ₃ perhalogenated alkyl radicals, or

(iv) a C ₆ mono-, poly- or perhalogenated aryl radical.

More preferably, Rf represents a radical CF ₃ , C _n F _{2n + 1} with n representing an integer equal to or greater than 2 such as for example C ₄ F ₉ or a phenyl radical substituted by one or more halogen atoms, preferably fluorine , or by one or more mono-, poly- or perfluorinated CC ₂ alkyl groups.

The compounds in which B represents SO ₂ are particularly interesting.

As a preferred example of groups Y, there may be mentioned more particularly the radicals NH ₂ and NHR _B , with R _B as defined above.

In the preceding general formulas which follow, the halogen atom (s) mentioned as a substituent are preferably represented by a fluorine atom. According to a first variant of the invention, the compounds of general formula I correspond to the general formula l'b

in which :

^R f. ( ^χ ). (y) ^and Y ^{are such ~ ue} defined above and A and Ar ₂ together represent an aromatic group.

In the following discussion of this invention, "aromatic" means the conventional notion of aromaticity as defined in the literature, including J. March "Advanced Organic Chemistry", 4 ^{th ed.,} John Wiley & Sounds, 1992, pp 40 and following. In the context of the present invention, the aromatic derivative can be monocyclic or polycyclic. In the case of a monocyclic derivative, it can 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.

By way of illustration of the monocyclic heteroaromatic derivatives which are suitable for the present invention, mention may in particular be made of the pyridine, pyrimidine, pyridosine and pyrase derivatives.

The carbon atoms of the aromatic derivative can also be substituted. Two 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.

By way of illustration of this type of compound, mention may in particular be made of derivatives of naphthalene, quinoline and isoquinoline. As a representative of the compounds corresponding to the general formula l'b, mention may more particularly be made of those in which Ar, and Ar ₂ appear together either a group deriving from 2,2-diphenyl-diyl, or a 2-dinaphthyl group, 2'-diyle.

In the case where Ar, and Ar ₂ together represent a diphenyl-2,2'-yl group, the two phenyl rings are substituted so as to block the configuration of the corresponding structure. The compounds of general formula I in which A symbolizes a skeleton of formula la prove in fact to be particularly interesting.

More preferably, these compounds correspond to the general formula a

in which

- Rf, X, n, (x), (y) and Y are as defined above in general formula I, and

- R 'and R "independently of one another represent a carbocyclic or heterocyclic radical, saturated, unsaturated, aromatic, monocyclic or polycyclic, provided that when n is zero, Rf represents a group CF ₃ , Y a group NH ₂ then R 'and R "do not simultaneously represent an unsubstituted phenyl ring or R' and R" can be linked so as to constitute, with the carbon atoms carrying them, a carbocyclic or heterocyclic radical having 4 to 20 atoms saturated , unsaturated, aromatic, monocyclic or polycyclic.

Preferably, Y represents an NH ₂ or NHR _B radical, with R _B as defined above. In the general formulas la and a, R 'and R ", identical or different, can take various meanings. Different examples are presented below, but they are in no way limiting.

Thus, R 'and R "can represent, independently of each other, an acyclic, saturated or unsaturated, linear or branched aliphatic radical. More precisely, R' and R" represent an aliphatic, acyclic, linear or branched radical having preferably from 1 to 12 carbon atoms, saturated or comprising one to several, generally 1 to 3, double bonds. The hydrocarbon chain may optionally be interrupted by a group, preferably a heteroatom, and more particularly, an oxygen or nitrogen atom or alternatively carrying substituents, for example, a halogen atom, in particular, chlorine or a group -CF ₃ . This acyclic, saturated or unsaturated, linear or branched aliphatic radical may optionally carry a cyclic substituent. By cycle is meant a carbocyclic or heterocyclic, saturated, unsaturated or aromatic cycle. As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 carbon atoms in the ring or benzenic, these cyclic substituents possibly being themselves carriers of one or more substituents.

As examples of such radicals, mention may in particular be made of the benzyl radical.

In the general formulas I and a, the radicals R 'and R "can also represent, independently of one another, a carbocyclic radical saturated or comprising 1 or 2 unsaturations in the ring, generally having 3 to 8 atoms carbon, preferably 6 carbon atoms in the ring, said ring possibly being substituted.

As preferred examples of this type of radicals, mention may be made of cyclohexyl radicals optionally substituted by linear or branched alkyl radicals having from 1 to 4 carbon atoms.

R 'and R "can also be linked to represent carbocyclic or heterocyclic, mono- or poly-cyclic, saturated, unsaturated or aromatic, preferably bicyclic, radicals which means that at least two rings have two carbon atoms in common. In the case of polycyclic compounds, the number of carbon atoms in each cycle preferably varies between 3 and 6, the total number of carbon atoms being preferably equal to 5.

As an illustration of this type of structure, mention may in particular be made of the following cyclic radicals:

Thus, the radicals R ′ and R ″ may represent, independently of one another according to a preferred mode, an aromatic hydrocarbon radical, and in particular benzene radical corresponding to the general formula l'c

in which :

- n 'represents an integer from 0 to 5 and

- Q a radical chosen from:

A linear or branched alkyl radical having from 1 to 4 carbon atoms, “a linear or branched alkoxy radical having from 1 to 4 carbon atoms,

• a benzoyl group,

• an -OH group,

• a group -NH ₂ , • a group -N0 ₂ ,

• a phenyl radical,

• a halogen atom,

• a CF ₃ group,

• an SR _D group, or “an OR _D group with R _D meeting the definition given above for R _B. R ′ and R ″ can also represent, independently of one another, a polycyclic aromatic hydrocarbon radical with the rings which can form between them ortho-condensed, ortho and pericondensed systems. Mention may more particularly be made of a naphthyl radical; said ring can be substituted.

R 'and R "can also represent, independently of each other, a heterocyclic radical, saturated, unsaturated or aromatic, comprising in particular 5 or 6 atoms in the ring including one or two heteroatoms such as nitrogen, sulfur atoms and oxygen; the carbon atoms of this heterocycle can also be substituted.

R 'and R "can also represent a heterocyclic polycyclic radical defined as being either a radical constituted by at least two aromatic heterocycles or not containing at least one heteroatom in each cycle and forming between them ortho- or ortho- and peri-condensed systems , or either a radical condensed by 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 per-condensed systems, the carbon atoms of the said rings possibly being substituted. Examples of heterocyclic type R ′ and R ″ groups include, among others, the furyl, pyrrolyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, piridazinyl, pyrimidinyl, pyrannyl radicals and the quinolyl radicals. , naphthyridinyl, benzopyrannyl, benzofurannyl, indolyl. The number of substituents present on each cycle depends on the carbon condensation of the cycle and on the presence or not of unsaturation on the cycle. The maximum number of substituents capable of being carried by a cycle is easily determined by a person skilled in the art.

As examples of the compounds of general formula a, there may be more particularly mentioned those in which n has the value 0.

Of particular interest are the compounds of general formula a in which: - R 'and R "both represent a phenyl group, provided that when Rf represents a group CF ₃ and Y represents a group NH ₂ then at least one of R' and R" is at least monosubstituted or - R ' and R "are linked together so as to constitute, with the carbon atoms which carry them, a cyclohexyl radical.

Mention may in particular be made, for example of this type of compound, of ammonium chloride of (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine, (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2- cyclohexanediamine, (S, 2S) -N-trifluoromethanephenylsulfonyl-1, 2- cyclohexanediamine, (1 S, 2S) -NN- (Nonafluorobutanesulfonyl) -1, 2 -diphenylethylenediamine, (1 S, 2S) -N - (Nonafluorobutanesulfonyl) -1, 2 cyclohexanediamine, le (1 S, 2S) -N- (pentafluorophenylsulfonyl) -1, 2 cyclohexanediamine, le (1S, 2S) -N- (pentafluorophénylsulfonyl) -1, 2-diphenylethylenediamine 1S, 2S) -N- (3,5-bis (trifluoromethane) phenylsulfonyl) 1, 2-cyclohexanediamine, le (1 S, 2S) -N- (3,5-bis

(trifluoromethane) phenylsulfonyl) 1, 2-diphenylethylenediamine.

As mentioned above, the compounds of general formula I are particularly advantageous when they are in an optically active form.

To this end, the two carbons of the general formula I involved respectively at the level of the connections symbolized by (x) and (y) constitute two centers of chirality which are preferably of the same configuration.

Another subject of the invention lies in the process for the preparation of the compounds of general formula I.

More specifically, the second subject of the present invention is a process for the preparation of a compound of general formula I in which a compound of general formula II is reacted

with A and Y being as defined above with a compound of general formula III

Rf-B-X '(III)

with Rf and B being as defined above and X 'representing a halogen atom, preferably chlorine or fluorine or also in the case where B represents S0 ₂ an OS0 ₂ Rf group and in that one recovers said compound of general formula I.

In fact, the operating conditions adopted for carrying out the synthesis of the compounds of general formula I according to the claimed process are generally dictated by the chemical nature of the starting compounds. The implementation of this type of reaction in fact falls within the competence of a person skilled in the art.

The reaction can be carried out in a usual organic solvent and preferably in dichloromethane or 1,2-dichloroethane. 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 process can be carried out batchwise or continuously.

A practical embodiment consists in loading the derivative of formula II into the solvent and then slowly adding to it the sulfonylating agent of formula III. The reaction is carried out for a sufficient time to obtain the transformation of the product of formula 11 into formula I. The final compound is isolated by conventional techniques of reaction medium.

It is possible to carry out the reaction discussed above in the presence of a base. The amount of this base is adjusted so as to trap the halogenated acid released. Generally, it is in excess of up to 3 times the stoichiometric amount.

As mentioned above, the compounds of general formula I, a and l'b are very particularly advantageous in their optically active form.

Thus, the present invention also relates to the use of a compound of general formulas I, a and b, in an optically active form for the preparation of ligands of catalytic metal complexes useful for carrying out asymmetric syntheses in organic chemistry.

The compounds of formulas I, a and l'b, in an optically active form, thus prove to be very particularly useful for the preparation of ligands of catalytic metal complexes useful for carrying out an asymmetric enantioselective hydrogenation of ketone derivatives. It has also been shown that these same compounds of general formulas I, a and b, in an optically active form, could be used to prepare ligands of catalytic metal complexes useful for carrying out an enantioselective oxidation of hydroxyl functions.

Consequently, the present invention also relates to a metal complex based on a transition metal and comprising as ligand of said metal at least one optically active form of a compound of general formulas I, a and l b, as defined above. As examples of transition metals capable of forming complexes in accordance with the present invention, mention may be made in particular of metals such as rhodium, ruthenium, rhenium, iridium, cobalt, nickel, platinum, palladium.

Among the aforementioned metals, rhodium, ruthenium and iridium are preferred.

As examples of metal complexes in accordance with the present invention, mention may more particularly be made of those corresponding to general formula IV

H

in which :

- A, B, Rf and Y are as defined above in formula I,

- the carbons carrying the bonds (x) and (y) have the same absolute configuration,

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

- Z represents an anionic ligand coordinating and

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

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 IV 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 ligand or a cyclopentadienyl or cyclooctatriene ligand substituted where appropriate by one or more C ₄ to C ₄ alkyl groups.

Preferably, this complex corresponds to the general formula IVa

in which :

- R 'and R "independently of one another represent a C, C _{20 to} saturated, unsaturated, aromatic, monocyclic or polycyclic carbocyclic or heterocyclic radical as defined above, provided that when Rf represents a group CF ₃ , Y an NH ₂ group then R 'and R "do not simultaneously represent an unsubstituted phenyl ring or R' and R" are linked together so as to constitute, with the carbon atoms carrying them, a carbocyclic or heterocyclic radical of 4 with 20 atoms saturated, unsaturated, aromatic, monocyclic or polycyclic, and

- Rf represents

(i) a halogen atom, preferably fluorine, (ii) alkyl C, -C ₁₀ cycloalkyl or C ₃ -C _10, poly- or per-halogenated, (iii) phenyl substituted by at least one C radical at

C ₄ polyhalogenated,

(iv) a mono-, poly- or perhalogen phenyl radical and

- Y, L and Z are as defined above.

According to a preferred mode, Y represents an NH ₂ or NHR _B radical, with R _B as defined above.

As more specific examples, mention may be made of the complexes corresponding to the general formula IVb.

with L, Z and M as defined above.

Of particular interest are the compounds of formula IVb in which - L represents an aromatic chosen from benzene, para-methylisopropylbenzene or hexamethylbenzene,

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

- M a ruthenium atom.

Of particular interest are the complexes according to the present invention having, as ligand, a compound chosen from (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine, (1 S.2S) - N-trifluoromethanephenylsulfonyl- 1, 2-cyclohexanediamine, le (1S, 2S) -N- N- (Nonafluorobutanesulfonyl) -1, 2-diphenylethylenediamine, le (1 S, 2S) -N- (Nonafluorobutanesulfonyl) -1, 2 cyclohexanediamine, le (1S, 2S) -N- (pentafluorophenylsulfonyl) -1,2 cyclohexanediamine, le (1 S, 2S) -N- (pentafluorophenylsulfonyl) -1,2-diphenylethylenediamine, le (1 S, 2S) -N- (3,5-bis (trifluoromethane) phenylsulfonyl) 1,2-cyclohexanediamine, le (1 S, 2S) -N- (3,5-bis (trifluoromethane) phenylsulfonyl) 1,2-diphenylethylenediamine.

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 transition metal compound retained in an appropriate organic solvent. The complexes comprising, as ligand, the above-mentioned compound of formula I 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 diethyl ether, 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.

The present invention also relates to the use of a metal complex as defined above for carrying out asymmetric organic synthesis and more particularly the asymmetric reduction of ketone derivatives.

It also relates to the use of a metal complex as defined above for carrying out the enantioselective catalytic oxidation of a chiral secondary alcohol in the form of a racemic mixture. The ketone derivatives capable of being hydrogenated by a metal complex in accordance with the invention preferably correspond to the general formula V *

in which - R and R ₂ represent independently of each other:

(i) an alkyl chain, preferably from C to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or carboxyl groups, (ii) an alkenyl or alkynyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atom (s) or carboxyl group (s);

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

(iv) an arylalkyl group, preferably from C ₇ to C ₁₅ , optionally substituted by one or more halogen atom (s);

(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 ₂ of an asymmetry center located in position α of the carbonyl function.

By way of representative of the substituents R ₂ having a center of asymmetry, one can particularly mention the radicals R _{2 in} which the carbon atom carrying the center of asymmetry is substituted by a mono- or di-substituted amine function and by a function ester.

Advantageously, the use of a complex according to the invention to reduce a racemic mixture of ketone derivatives of this type, that is to say having in α of the ketone function a center of asymmetry, makes it possible to obtain the corresponding hydroxyl derivative by controlling the stereochemistry of two asymmetry centers. We are witnessing a kinetic dynamic resolution of the whole molecule.

The process of the invention applies very particularly to the preparation of an optically active hydroxyl compound of general formula VI

OH

in which :

- R. and R ₂ represent independently of each other:

(i) an alkyl chain, preferably from C to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or groups carboxyl,

(ii) an alkenyl or alkynyl chain, preferably C ₂ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more atom (s) ) halogen or carboxyl group (s); (iii) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted by one or more halogen atom (s) or alkyl or alkenyl group (s);

(iv) an arylalkyl group, preferably from C ₇ to C ₁₅ , optionally substituted by one or more halogen atom (s); (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

_**

as defined above in the presence of a metal complex, the transition metal of which has as 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 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 therefore using as a catalyst a metal complex according to the invention, that is to say liganded by an optically active derivative of general formula I.

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.

As is apparent from the examples below, it is possible to significantly accelerate the kinetics of the reaction by increasing the temperature of the reaction medium without prejudicing the enantiomeric yield. Consequently, 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 or a formic acid / tertiary amine mixture. 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 complex based on the compound of general formula I and the transition metal is used at a rate 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 insofar as it is stable under the operating conditions. Use is preferably made of a polar organic solvent such as dichloromethane.

The concentration of the substrate in the solvent advantageously varies between 0.01 and 3 moles per liter. Optionally, during the reaction, a basic compound can be added. 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.

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 the reactions for the hydrogenation of ketone functions into secondary alcohols.

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

EXAMPLE 1 Trifluoromethanesulfonylation of diaminocyclohexane.

In a 100 ml three-necked flask, fitted with an addition funnel, a temperature probe and a magnetic bar with stirring by a magnetic stirrer. We charge:

- 4.82 g of (1 S, 2S) -1, 2-cyclohexanediamine,

7.11 g of trifluoromethanesulfonyl chloride, and - 40 ml of dichloromethane.

We start by loading the diamine and dichloromethane then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C using an ice bath. The sulfonylating agent is slowly charged (duration of 30 min) using an addition funnel. The reaction mixture is allowed to return to ambient temperature (22 ° C) with stirring for two hours and then the precipitate formed filtered. It is rinsed with diethyl ether. The product is dried under vacuum. 9.24 g of a white solid are recovered, corresponding to ammonium chloride of (1S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine, which corresponds to a yield of 74%.

3.99 g of the solid and 15 ml of distilled water are loaded into a 100 ml Erlenmeyer flask. The pH of this aqueous phase is adjusted to between 7 and 8 by adding a 2M aqueous sodium hydroxide solution. It is left for 16 hours at room temperature. The crystallized product is filtered. It is dried under vacuum. 1.78 g of (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine are recovered with a yield of 51%.

EXAMPLE 2

Trifluoromethanephenylsulfonylation of diaminocyclohexane.

In a 10 ml flask we load:

- 50 mg of (1 S, 2S) -1, 2-cyclohexanediamine, - 89 mg of 4-trifluoromethanephenylsulfonyl chloride,

- 4.5 ml of dichloromethane.

We start by loading the diamine and dichloromethane then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C using an ice bath. The 4-trifluoromethanephenylsulfonyl chloride is added slowly using a syringe. The reaction mixture is stirred at room temperature for 5 hours. Diluted with 5 ml of dichloromethane then the solution is washed with a saturated aqueous solution of NaHC0 ₃ (8ml) and then dried over Na ₂ S0 ₄ . After evaporation of the solvent, 102 mg of a white powder are recovered, corresponding to (1 S, 2S) -N- (4-trifluoromethanephenylsulfonyl) -1, 2-cyciohexanediamine, which corresponds to a yield of 88%.

EXAMPLE 3

Trifluoromethanesuifonylation of 1,2-diphenylethylenediamine.

In a 100 ml three-necked flask, fitted with an addition funnel, a temperature probe and a magnetic bar with stirring by a magnetic stirrer:

- 4.97 g of (1S, 2S) -1, 2-diphenylethylenediamine,

- 3.94 g of trifluoromethanesulfonyl chloride, and - 30 ml of dichloromethane.

We start by loading the diamine and dichloromethane then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C using an ice bath. The sulfonylating agent is slowly charged (duration of 30 min) using an addition funnel. The reaction mixture is allowed to return to room temperature (22 ° C) with stirring for two hours and the white precipitate formed filtered. 20 ml of dichloromethane are added, then the organic phase is washed with a 2M aqueous HCl solution and with water saturated with NaCl. The organic phase is concentrated and then the white solid formed is filtered. The white solid is dried under vacuum.

1.8 g of (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-diphenylethylenediamine are recovered.

EXAMPLE 4 Reduction of acetophenone.

As a reducing medium, a mixture composed of: - isopropanol / KOH

- [RuCI ₂ (p-cymene)] ₂

- (1S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine. In a 250 ml flask, equipped with a condenser, a magnetic bar with stirring by a magnetic stirrer, are charged: - 10 mmol of acetophenone

- 5.10 ^"2 mmol of [RuCI ₂ (p-cymene)] ₂

0.1 mmol of (1S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine - 0.25 mmol of KOH and

- 100 ml of isopropanol.

We start by loading the ruthenium complex, the ligand and 20 ml of isopropanol then establishing an atmosphere of argon. The reaction medium is heated to a temperature of 80 ° C for 30 min. 80 ml of isopropanol, potassium hydroxide and acetophenone are then loaded. The reaction mixture is left under stirring for 72 hours at 22 ° C. The product formed, namely 1-phenylethanol and the enantiomeric excess, are assayed by gas chromatography.

68% of 1-phenylethanol is obtained with an enantiomeric excess of 82% in favor of the S isomer.

EXAMPLES 5 AND 6 Reduction of acetophenone.

The reducing medium used:

- an azeotropic mixture of formic acid and triethylamine

- [RuCI ₂ (p-cymene)] ₂ as a metal complex and

- (1S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine or (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-diphenylethylenediamine as chiral ligand.

In a 25 ml flask, fitted with a magnetic bar with stirring by a magnetic stirrer, we load: - 10 mmol of acetophenone

- 0.05 mmol of [RuCI ₂ (p-cymene)] ₂

- 0.1 mmol of ligand

- 2 ml of formic acid - 3 ml of triethylamine.

We start by charging the ruthenium complex, the ligand and

10 ml of isopropanol. An argon atmosphere is established and then the reaction medium is heated to a temperature of 80 ° C for 30 min. The solvent is evaporated off under reduced pressure and a red solid is obtained.

In another 25 ml flask, cooled by an ice bath and fitted with a magnetic bar with stirring by a magnetic stirrer, 3 ml of triethylamine, 2 ml of formic acid and 10 mmol of acetophenone are loaded. The reaction mixture is purged with argon and then this solution is transferred to the flask containing the catalyst.

The reaction mixture is left at room temperature (22 ° C) with stirring. The reaction time is listed in the table below.

The product formed, namely (1S) -1-phenylethanol, is assayed by gas chromatography.

The results obtained are recorded in Table 1 below:

This table also reports on the reduction of acetophenone in the presence of a ligand not in accordance with the present invention, (1 S, 2S) -N-tosyl-1, 2-cyclohexanediamine. Table 1

It is noted that only the ligands carrying fluorine atoms on the carbon at α of the sulfonyl group are effective.

EXAMPLES 7 AND 8 Reduction of acetophenone.

The same reducing medium is used as in Example 5, the procedure of which is reproduced by modifying the temperature.

The results are recorded in the following table Table 2

It is possible to increase the reaction rate by heating the reaction medium without prejudicing the enantiomeric yield.

EXAMPLE 9

Reduction of acetophenone.

The same reducing medium is used as in Example 5, the procedure of which is reproduced by modifying the substrate / catalyst ratio.

The reduction is therefore carried out on 1 mmol of acetophenone instead of 10 mmol in Example 5 while keeping everything else equal. 99% of 1-phenylethanol is obtained after 21 hours at 22 ° C. with an enantiomeric excess of 92% in favor of the S isomer.

It appears that the increase in the catalyst / substrate ratio has no significant effect on the enantioselectivity of the reduction.

EXAMPLES 10 AND 11 Reduction of acetophenone.

The same reducing medium is used as in Example 5, the procedure of which is reproduced, but by modifying the nature of the complex. metallic. The selected complex is ligated with (1 S, 2S) N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine.

Table 3

The results are comparable in terms of enantioselectivity.

EXAMPLES 12 AND 13

Reduction of 3 ', 4'-dimethoxyacetophenone.

The same reducing medium is used as in Example 5, the procedure of which is reproduced using either the ligand prepared in Example 1 or the ligand prepared in Example 3.

The duration is listed in the table below. The product formed, namely (R) -3 ', 4'-dimethoxy-1-phenylethanol, is assayed by high performance liquid chromatography.

The results obtained are recorded in Table 4 below: Table 4

EXAMPLE 14

Preparation of the β-keto-α-amino acid samples 1a, 1b.

The β-ketone-α-amino acid derivatives used are the following

1a, b a: R = Me b: R = H

Preparation of (3,4) -dimethoxyphenyl) -2-

(methyl benzoyloxycarbonyl) methylamino-3-oxopropanoate (1a).

To LHMDS lithium hexamethyldisilazane cooled to -78 ° C (1.06 M in THF, 2 equivalents) is added a solution of Cbz-Sar-Ome (1 equivalent, 0.5 g / ml in THF), in THF. After stirring for 1 hour, a solution of 3,4-dimethoxybenzoic acid chloride (1 eq., 0.5 g / ml THF) is added via a cannula. The reaction medium is stirred for 30 min, poured into an aqueous solution saturated with NH ₄ Cl and extracted with EtOAc. The organic phase is dried with a sodium chloride solution followed by MgSO ₄ .H ₂ 0. By concentration, an amber colored syrup is obtained in a quantitative yield.

RMN- ¹ H (300 MHz, CDCI ₃ ): δ 2.84-2.86 (m, 3H, Nme), 3.62-3.91 (m, 9H, C0 ₂ Me, 2xOMe), 5.13-5.14 (m, 2H, Ç_H ₂ Ph ), 6.12 and 6.40 (2s, 0.8H, CH keto), 6.58-7.62 (m, 8H, CH ₂ Ph).

Preparation of (3,4) -dimethoxyphenyl) -2-

(methyl benzoyloxycarbonyl) methylamino-3-oxopropanoate (1b). The ketonic amino acid 1 b is prepared from the chloride of 3,4-dimethoxybenzoic acid according to the protocol described for the derivative 1 a. The concentrated residue is then purified by chromatography (eluent: hexane / EtOAc 3: 1, then 2: 1) and crystallized (hexane / EtOAc) to yield a yield of 60% of derivative 1b. RMN- ¹ H (300 MHz, CDCI ₃ ): δ 3.62 and 3.74 (2 br s, 3H, C0 ₂ Me), 3.94 and 3.98 (2s, 6H, 2xOMe), 5.15 (s, 2H, Ç_H ₂ Ph), 5.97 and 6.00 (d, 1.9H, CH keto; J = 7.9Hz), 6.20 and 6.22 (d, 0.9H, NH; J = 7.9Hz), 6.94-7.83 (m, 8H, C ₆ H ₃ CH ₂ Ph ).

EXAMPLE 15

Asymmetric hydrogenations by hydrogen transfer of β-keto-α-amino acid derivatives using chiral Ru (ll) complexes.

The general protocol used is as follows: [RuCI ₂ (p-cym)] ₂ and the chiral diamine (1, 5 equivalent with respect to the Ruthenium atom) are stirred in / so-propanol (1 ml, dry ) to 80- 85 ° C for 3 hours under argon. After cooling to room temperature, the ketonic amino acid (1 mmol) in dichloromethane (1 ml distilled over CaH ₂ ) and a mixture of formic acid-triethylamine (5: 2, 1 ml) are added consecutively. Stirring is maintained at 50 ° C at the time indicated in Table 5. The reaction medium is then extracted with ethyl acetate (15 ml) in the presence of a saturated solution of sodium bicarbonate (15 ml). The organic phase is then washed with a sodium chloride solution (15 ml), dried over MgSO ₄ and concentrated so as to yield the hydroxy derivative of the expected amino acid.

The threo-2a and erythro-2a derivatives obtained at the end of the catalytic hydrogenation are characterized by NMR:

- threo- (3,4-dimethoxyphenyl) -2 - [(benzoyloxycarbonyl) methylamino] -

Methyl 3-hydroxypropanoate (threo-2a).

RMN- ¹ H (300 MHz, CDCI ₃ ): δ 2.92 and 3.08 (2 br s, 3H, Nme), 3.69- 3.91 (m, 9H, C0 ₂ Me, 2xOMe), 4.71-5.39 (m, 4H, CHN , ÇH ₂ Ph, ÇHOH), 6.83-6.93 (m, 3H, C ₆ H ₃ ), 7.15-7.35 (m, 5H, CH ₂ Ph).

erythro- (3,4-dimetoxyphenyl) -2 - [(benzoyloxycarbonyl) methylamino] - methyl 3-hydroxypropanoate (erythro-2a).

RMN- ¹ H (300 MHz, CDCI ₃ ): δ 2.58 and 2.60 (2 br s, 3H, NMe), 3.65 and 3.74 (2s, 3H, C0 ₂ Me), 3.80 and 3.87 (2s, 6H, 2xOMe), 4.08-4.17 (m, 1 H, CHN), 4.71 (br s, 1 H, OH), 5.04-5.26 (m. 3H, ÇH ₂ Ph, ÇHOH), 6.72-6.92 (m, 3H, C ₆ H ₃ ), 7.24-7.39 (m, 5H, CH ₂ Ph).

The compounds 2a, b (0.5 mmol) are then deprotected according to the following protocol: They are stirred with 10% Pd-C (15 mg) and HCO ₂ NH ₄ (0.13 g, 4 eq.) In the methanol overnight. The mixture is then filtered through Celite, concentrated, and extracted with dichloromethane (10 ml) in the presence of a saturated solution of sodium chloride (5 ml) and a saturated aqueous solution of NaHCO ₃ (2 ml). The organic phase is dried (Na ₂ S0 ₄ ) and concentrated to yield approximately 95% of 2a, b. Before determining the enantiomeric excess by HPLC on a Chiralpack AD column, the sample is purified on a PLC plate (CH ₂ CI ₂ / EtOH 40: 1). The products thus obtained are characterized by NMR.

The methyl threo- (3,4-dimethoxyphenyl) - / V-methylserine ester (threo-2a).

RMN- ¹ H (300 MHz, CDCI ₃ ): δ 2.41 (s, 3H, Nme), 3.20 (d, 1 H., CHN; J = 7.9Hz), 3.56 (s, 3.56 (s, 3H, C0 ₂ Me), 3.87 and 3.89 (2s, 6H, 2xOMe), 4.53 (d, 1 H, ÇHOH: J = 7.9Hz), 6.82-6.92 (3H, m, C ₆ H ₃ ).

The erythro - (3,4-dimethoxyphenyl) - / V-methyl methylserine ester

(erythro-2a).

RMN- ¹ H (300 MHz, CDCI ₃ ): δ 2.42 (s, 3H, Nme), 3.53 (d, 1 H., CHN; J = 5.7Hz), 3.69 (s, 3H, C0 ₂ Me), 3.87 and 3.88 (2s, 6H, 2xOMe), 4.93 (d, 1H, ÇHOH: J = 5.7Hz), 6.76-6.84 (3H, m, C ₆ H ₃ ).

Table 5 below reports the operating conditions in terms of time and substrate / catalyst ratio used for each chiral ligand tested and the yields of hydroxyl derivatives obtained as well as enantiomers. Table 5

³ Estimated by ¹ H-NMR analysis ^b Determined by ¹ H-NMR analysis at 300 MHz of deprotected compound 3 ^d Determined by HPLC analysis using a Chiralpack AD column ^of [RuCI ₂ (benzene)] is used.

It is noted that the enantioselectivity is lower when the chiral ligands are not in accordance with the invention (tests 1 and 3).

In addition, it is necessary to significantly extend the reaction over time for these two tests in order to obtain a significant enantiomeric yield.

EXAMPLE 16

Catalytic oxidation using ruthenium complexes according to the invention.

The oxidation is carried out according to the following reaction scheme:

Solvent

3a 3b

In a 25 ml monocol, the ruthenium complex (31 mg, O.Oδmmol) and the ligand (2 eq.) Dissolved in 10 ml of isopropanol are introduced. The reaction medium is brought to 80 ° C. under an argon atmosphere for ³ λ of an hour. The mixture is concentrated to dryness on a rotary evaporator and then the racemic alcohol 3a-3b (1.2g, 10 mmol, 200 eq.) And the solvent (5 ml) are introduced. The mixture is then degassed by bubbling argon for Î hour then, the potassium hydroxide powder is added (14mg, 0.25mmol, 5 eq.). The medium is stirred under an argon atmosphere at 30 ° C. The reaction is monitored by CPG: CYCLODEX B 236M column 25mx0.25μm; initial column temperature 100 ° C; final column temperature 150 ° C; rate 2 ° C / min. ; injector temperature 150 ° C; detector temperature 240 ° C; injected volume 2μl; Cyclopentanone retention time = 2.25 min., Cyclopentanol = 2.6 min. N of acetophenone 5 = 6.6 min., 4 = 9.2 min., 3 = 9.8 min.

By TLC: eluent petroleum ether / ethyl acetate 95/5; UV developer; Rf acetophenone = 0.44; Rf phenyl ethanol = 0.28.

1) Test with a chiral ligand:

The first ligand has the following formula

This test is carried out in acetone. The reaction medium is orange and becomes brown during the reaction. After 6 hours at 30 ° C., 50% of 4 and an enantiomeric excess of 64% in favor of alcohol 3b are obtained in area percentage.

By repeating this test in cyclopentanone, a red reaction mixture is obtained which becomes brown during the reaction. After 6 hours at 30 ° C., 44% of 4 and an enantiomeric excess of 52% in favor of alcohol 3b are obtained in area percentage.

The second ligand has the following formula:

A first test carried out in acetone leads to a pink reaction medium. After 5 hours at 30 ° C., 53% of 4 and an enantiomeric excess of 85% in favor of alcohol 3b are obtained in area percentage.

The same test carried out in cylopentanone leads to a red reaction medium. After 5 hours at 30 ° C., 41% of 4 and an enantiomeric excess of 85% in favor of alcohol 3b are obtained in area percentage.

EXAMPLE 17 (1 S, 2S) -N- (Nonafluorobutanesulfonyl) -1, 2-diphenylethylenediamine

To a solution of (1 S, 2S) -1, 2-diphenylethylenediamine (100 mg, 0.47 mmol) and 4-dimethylaminopyridine (57 mg, 0.47 mmol) in acetonitrile (5 ml), nonafluorobutanesulfonyl fluoride

(100 μl, 0.56 mmol). After stirring overnight, a new part of nonafluorobutanesulfonyl fluoride is added (100 μln 0.56 mmol).

The mixture is added one day, concentrated and extracted between water (10 ml) and ethyl acetate (20 ml). The organic phase is dried (Na ₂ S0 ₄ ) and concentrated so as to obtain a mixture of the starting product and the final product. Purification by chromatography

(EtOAc / MeOH 40.1) followed by treatment with ether to obtain a compound in crystalline form (115 mg, 49%). ¹ H NMR (300 MHz, CDCI ₃ ): 4.41 (d, 1 H, CHNH ₂ ; J = 3.0 Hz), 4.76

(d, 1 H, CHNH; J = 3.0 Hz), 7.38 (m, 10H, 2 x Ph).

EXAMPLE 18

Asymmetric hydrogenation by means of a ruthenium complex comprising, as ligand, the compound of Example 17. [RuCI ₂ (p-cymene)] ₂ (12.5 μmol) and (1S, 2S) -N-

(nonafluorobutanesulfonyl) -1,2-diphenylethylenediamine (30 μmol, 1.2 eq. per ruthenium atom) are stirred in isopropanol (1 ml) at 80 ° C for 2 hours. Methyl oxopropanoate 2- [(benzyloxycarbonyl) methylamino] -3- (3,4-dimethoxyphenyl) (0.40 g, 1 mmol) in dichloromethane (1 ml) and HC0 ₂ H-Et ₃ N (5.2, 1 ml) are then successively added at room temperature. Stirring is maintained at 45 ° C for 27 hours so as to obtain 10% conversion. The reaction mixture is then extracted between ethyl acetate and a saturated NaHCO _{3 solution} , the organic phase is washed with a sodium chloride solution, dried (MgSO ₄ ) and concentrated. ¹ H NMR (300 MHz, CDCI ₃ ): threo / erythro = 95.5.

EXAMPLE 19 (1 S, 2S) -N- [3,5-Bis (trifluoromethane) phenylsulfonyl] -1, 2-cyclohexanediamine.

In a 50 ml three-necked flask, fitted with an addition funnel, a temperature probe and a magnetic bar with stirring by a magnetic stirrer:

We charge:

-0.50 g of (1S, 2S) -1, 2-cyclohexanediamine,

-1.37 g of 3,5-bis (trifluoromethane) phenylsulfonyie chloride, and

-20 ml of dichloromethane. We start by charging the sulfonyl chloride and dichloromethane then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C using an ice bath. The diamine dissolved in dichloromethane (10 ml) is slowly charged (duration 10 min) using an addition funnel. The reaction mixture is allowed to return to ambient temperature (22 ° C) with stirring for two hours. The reaction medium is diluted with 30 ml of dichloromethane then washed with 10 ml of HCl (2M). The aqueous phase is adjusted to a pH between 7 and 8 by adding a 2M aqueous sodium hydroxide solution and then is extracted with 2 x 25 ml of dichloromethane. The organic phase is dried over Na ₂ S0 ₄ and then evaporated under vacuum. 330 mg of a white solid corresponding to (1 S, 2S) -Λ / - [3,5-bis (trifluoromethyl) benzenesulfonyl] -1, 2-cyclohexanediamine are recovered.

EXAMPLE 20 (1 S, 2S) -N- [3,5-Bis (trifluoromethane) benzenesulfonyl] 1,2-diphenylethylenediamine.

-2 g of (1 S, 2S) -1, 2-diphenylethylenediamine, -2.94 g of 3,5-bis (trifluoromethyl) benzenesulfonyl chloride, and -25 ml of dichloromethane. We start by loading the diamine and dichloromethane (20 ml) then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C using an ice bath. The sulfonyl chloride dissolved in dichloromethane (5 ml) is slowly charged (duration 10 min) using an addition funnel. The reaction mixture is allowed to return to ambient temperature (22 ° C) with stirring for two hours then the solid formed is filtered. The solid is dissolved in dichloromethane (50 ml) then this organic phase is washed with distilled water (10 ml). The organic phase is dried over Na ₂ S0 ₄ and then evaporated under vacuum. 2.2 g of a white solid is recovered, corresponding to (1S, 2S) -Λ / - [3,5- bis (trifluoromethyl) benzenesulfonyl] -1, 2-diphenylethylene diamine. EXAMPLE 21

(1 S, 2S) -N- (pentafluorobenzenesuifonyl) 1, 2-cyclohexanediamine.

In a 50 ml three-necked flask, fitted with a temperature probe and a magnetic bar with stirring by a magnetic stirrer:

We charge:

-0.50 g of (1 S, 2S) -1, 2-cyclohexanediamine,

-650 μl of pentafluorobenzenesulfonyl chloride, and -10 ml of dichloromethane.

We start by loading the diamine and dichloromethane then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C using an ice bath. The sulfonyl chloride is slowly charged (duration 5 min) using a syringe. The reaction mixture is allowed to return to ambient temperature (22 ° C) with stirring for two hours. The reaction medium is diluted with 30 ml of dichloromethane and then washed with 10 ml of HCl (2M). The aqueous phase is then adjusted to a pH between 7 and 8 by adding a 2M aqueous sodium hydroxide solution and then is extracted with 2 x 25 ml of dichloromethane. The organic phase is dried over Na ₂ S0 ₄ and then evaporated under vacuum. 250 mg of a white solid are recovered, corresponding to (1 S, 2S) -Λ / -pentafluorobenzenesulfonyl-1, 2-cyclohexanediamine.

EXAMPLE 22

(1S, 2S) -N- (pentafluorobenzenesulfonyl) 1, 2-diphenylethylenediamine.

We charge: -2.15 g of (1 S, 2S) -1, 2-diphenylethylenediamine,

-500 μl of pentafluorobenzenesulfonyl chloride, and

-25 ml of dichloromethane.

We start by loading the diamine and dichloromethane (20 ml) then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C using an ice bath. The sulfonyl chloride dissolved in dichloromethane (5 ml) is slowly charged (duration 30 min) using an addition funnel. The reaction mixture is allowed to return to ambient temperature (22 ° C) with stirring for two hours then the solid formed is filtered. The organic phase is washed successively with 5 ml of HCl

(2M) and 5 ml of a saturated aqueous NaCl solution, dried over Na ₂ S0 ₄ and then evaporated in vacuo. 1.01 g of a white solid is recovered, corresponding to the ammonium chloride of (1 S, 2S) -Λ / - pentafluorobenzene sulfonyl-1, 2-diphenylethylene diamine.

EXAMPLE 23

(1 S, 2S) -N- (nonafluorobutanesulfonyl) 1, 2-cyclohexanediamine.

In a 50 ml three-necked flask, fitted with an addition funnel, a temperature probe and a magnetic bar with stirring by a magnetic stirrer: Load: -1.0 g of (1 S, 2S) -1 , 2-cyclohexanediamine,

-3.5 ml of nonafluorobutanesulfonyl fluoride, -6.9 ml of diisopropylethylamine, and -15 ml of dichloromethane.

We start by loading the diamine and dichloromethane (20 ml) then establishing an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 ° C. using a ice cream. The base is then charged slowly (duration 10 min) the sulfonyl fluoride. The reaction mixture is allowed to return to ambient temperature (22 ° C) with stirring for six hours. The reaction medium is diluted with diethyl ether (50 ml) then washed successively with 3 × 10 ml of HCl (2M) and 5 ml of an aqueous solution saturated with NaCl. The organic phase is then dried over Na ₂ S0 ₄ and then evaporated in vacuo. The residue obtained is crystallized from diethyl ether and 0.70 g of a white solid is recovered, corresponding to ammonium chloride of (1S, 2S) -Λ / - nonafluorobutanesulfonyl-1, 2-cyclohexane diamine.

EXAMPLE 24

Reduction of acetophenone.

The reducing medium used: - an azeotropic mixture of formic acid and triethylamine

- [RuCI ₂ (p-cymene)] ₂ as a metal complex and (1S, 2S) -N- (3,5-bis (trifluoromethane) benzenesulfonyl) 1,2 cyclohexane diamine: ligand 1, le (1 S, 2S) -N- (3,5-bis- (trifluoromethane) benzenesulfonyl) 1,2-diphenylethylene diamine: ligand 2,

- (1 S, 2S) -N- (pentafluorobenzenesulfonyl 1, 2 cyclohexane diamine: ligand 3,

- (1 S, 2S) -N- (pentafluorobenzenesulfonyl)) 1, 2-diphenylethylene diamine: ligand 4, and - (1 S, 2S) -N- (nonafluorobutanesulfonyl) 1, 2 cyclohexane diamine: ligand 5. as chiral ligands.

- 0.05 mmol of [RuCI ₂ (p-cymene)] ₂

- 0.1 mmol of the ligand considered - 2 ml of formic acid

- 3 ml of triethylamine.

We start by loading the ruthenium complex, the ligand and 10 ml of isopropanol. An argon atmosphere is established and then the reaction medium is heated to a temperature of 80 ° C for 30 min. The solvent is evaporated off under reduced pressure and a red solid is obtained.

The results obtained are reported in Table 6 below:

Table 6

It is noted that all of the ligands tested leads to a satisfactory ee. EXAMPLE 25

Reduction of 3 ', 4'-dimethoxyacetophenone.

The same reducing medium is used as in Example 24, the procedure of which is reproduced using either ligand 1 or ligand 2.

The results obtained are recorded in Table 7 below:

Table 7

EXAMPLE 26

Reduction of ethyl benzoylacetate.

The same reducing medium is used as in Example 24, the procedure of which is reproduced using the ligand prepared in Example 1, namely (1S, 2S) -N- (trifluoromethanesulfonyl) -1, 2 cyclohexanediamine, or the ligand 2 of example 24.

The duration is listed in the table below.

The results obtained are recorded in Table 8 below: Table 8

Claims

1. Compound of general formula

in which - B represents

(i) -CO-, or (ϋ) -S0 ₂ -,

- Rf represents

(i) a halogen atom, preferably fluorine, (ii) a preferably C 1 -C ₁₂ alkyl or preferably C ₃ -C ₁₂ cycloalkyl radical, mono-, poly- or per-halogenated, the haloalkyl chain is optionally interrupted by one or more oxygen or sulfur atom (s),

(iii) an aryl radical, preferably C ₆ to C ₁₂ , substituted by at least one halogenated alkyl radical as defined in (ii),

(iv) an aryl, mono-, poly- or per-halogenated preferably C ₆ -C ₁₂ radical, or

(v) a radical chosen from R _A -CF ₂ , -R _A -CF ₂ -CF ₂ -, R _A -CF ₂ -CF (CF ₃ ) -, CF ₃ -C (R _A ) F- and (CF ₃ ) R _A - with R _A representing a hydrogen atom or having any of the meanings given below for R _B and R _c ,

- Y represents an OH, SH, NH ₂ , NHR _B or NR _B R _{C group} , with R _B and R _c different from a hydrogen atom and independently representing one of the other a radical chosen from: ( i) an alkyl chain, preferably C ₁₀ to C ₁₀ , optionally interrupted by one or more oxygen or sulfur atom (s) or carbonyl function (s) and optionally substituted by one or more halogen atoms or carboxyl groups,

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

(iii) an aryl group, preferably C ₆ to C ₁₂ , optionally substituted by one or more halogen atom (s) or alkyl or alkenyl group (s); (iv) an arylalkyl group, preferably from C ₇ to C ₁₅ , optionally substituted by one or more halogen atom (s);

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

- A symbolizes a skeleton of general formula la or lb.

in which

- R 'and R "independently of one another represent a hydrocarbon radical having from 1 to 20 carbon atoms which can be an acyclic saturated or unsaturated, linear or branched aliphatic radical; a saturated, unsaturated, aromatic cycloaliphatic radical, monocyclic or polycyclic, incorporating or not incorporating one or more heteroatoms provided that when B represents a group S0 ₂ , na for zero, Rf represents a group CF ₃ , Y represents a group NH ₂ then R 'and R "do not simultaneously represent an unsubstituted phenyl ring; said cycloaliphatic radical optionally carrying a saturated or unsaturated, linear or branched aliphatic radical with the alkyl chain which can be interrupted by one or more oxygen atoms and / or carbonyl function and optionally substituted preferably at the end of the chain by a cyclic aromatic radical or not; said radicals possibly being substituted by one or more halogen atoms, preferably fluorine and / or one or more C ₆ to C ₆ preferably C ₄ to C ₄ alkyl radicals or alternatively the two substituents R ′ and R "are linked together so as to constitute a cycloaliphatic radical as defined above, - X represents a methylene group optionally substituted,

- n is an integer varying from zero to 3, and

- A and Ar ₂ symbolize, independently of one another, two substituted or unsubstituted aromatic rings, condensed or not and optionally carrying one or more heteroatoms, preferably C ₆ to C ₁₂ and which can form ortho or ortho and peri-condensed between them,

2. Compound according to claim 1, characterized in that B represents a group -S0 ₂ -.

3. Compound according to claim 1 or 2, characterized in that Y represents an NH ₂ or NHR _{B group} with R _B as defined in claim 1.

4. Compound according to one of claims 1 to 3, characterized in that Rf represents (i) a halogen atom, preferably fluorine,

(ii) a C 1 -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl mono- poly- or per-halogenated radical, (iii) a phenyl radical substituted by at least one C ₄ to C ₄ alkyl radical monopoly- or perhalogen, or

(iv) a C ₆ mono-, poly- or perhalogenated aryl radical.

5. Compound according to one of claims 1 to 4, characterized in that Rf represents a radical CF ₃ , C ₄ F ₉ , or a phenyl radical substituted by one or more halogen atoms, preferably fluorine, or by a or several alkyl groups in CC ₂ mono-, poly- or perfluorinated.

6. Compound according to one of the preceding claims, characterized in that it corresponds to the general formula l'b

in which :

Rf, (x), (y) and Y are as defined in one of claims 1 to 5 and A ^ and Ar ₂ together represent a group derived from 2-diphenyl, 2'-diyl or a 2-dinaphthyl group , 2'-diyle.

7. Compound according to one of claims 1 to 5, characterized in that it corresponds to the general formula a

in which

- Rf, X, n, (x), (y) and Y are as defined above in general formula I, and

- R 'and R "independently of one another represent a carbocyclic or heterocyclic radical, saturated, unsaturated, aromatic, monocyclic or polycyclic, provided that when n is zero, Rf represents a group CF ₃ , Y a group NH ₂ then R 'and R "do not simultaneously represent an unsubstituted phenyl ring or R' and R" can be linked so as to constitute, with the carbon atoms carrying them, a carbocyclic or heterocyclic radical having 1 to 20 atoms saturated, unsaturated, aromatic, monocyclic or polycyclic carbon.

8. Compound according to one of claims 1 to 5 or 7, characterized in that n has the value 0.

9. Compound according to one of claims 1 to 5 or 7 and 8, characterized in that R 'and R "are linked together so as to constitute with the carbon atoms which carry them a cyclohexyl radical.

10. Compound according to one of claims 1 to 5 and 7 to 9, characterized in that it is chosen from - ammonium chloride (1S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine,

- (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine,

- (1 S, 2S) -N-trifluoromethanephenylsulfonyl-1, 2-cyclohexanediamine,

- (1 S, 2S) -N-N- (Nonafluorobutanesulfonyl) -1, 2-diphenylethylenediamine, - (1 S, 2S) -N- (Nonafluorobutanesulfonyl) -1, 2 cyclohexanediamine,

- (1 S, 2S) -N- (pentafluorophenylsulfonyl) -1, 2 cyclohexanediamine,

- (1 S, 2S) -N- (pentafluorophenylsulfonyl) -1, 2-diphenylethylenediamine, (1 S, 2S) -N- (3,5-bis (trifluoromethane) phenylsulfonyl) 1,2-cyclohexanediamine, and (1 S, 2S) -N- (3,5-bis (trifluoromethane) phenylsulfonyl) 1, 2 - diphenylethylenediamine.

11. Compound according to one of the preceding claims, characterized in that it is in an optically active form.

12. Compound according to one of the preceding claims, characterized in that the two carbons of the general formula I, involved respectively at the level of the connections symbolized by (x) and (y) constitute two centers of chirality of the same configuration.

13. Process for the preparation of a compound of general formula I as described in one of claims 1 to 12, characterized in that a compound of general formula II is reacted

with A and Y being as defined in claims 1 to 12 with a compound of general formula III

Rf-B-X '(NI)

with Rf and B being as defined in claims 1 to 5 and X 'representing a halogen atom, preferably chlorine or fluorine or an OS0 ₂ Rf group and in that said compound of general formula I is recovered .

14. Preparation process according to claim 13, characterized in that the reaction is carried out in the presence of a base.

15. Preparation process according to claim 13 or 14, characterized in that the compound of general formula II is reacted with the compound of general formula III in a ll / III molar ratio less than or equal to 1.

16. Use of a compound of general formula I as defined in any one of claims 1 to 12 and in an optically active form for the preparation of ligands of catalytic metal complexes useful for carrying out asymmetric syntheses in organic chemistry.

17. Use of a compound of general formula I as defined in one of claims 1 to 12 and in an optically active form for the preparation of ligands of catalytic metal complexes useful for carrying out an asymmetric enantioselective hydrogenation of ketone derivatives.

18. Use of a compound of general formula I as defined in one of claims 1 to 12 in an optically active form, for the preparation of ligands of catalytic metal complexes useful for carrying out an enantioselective oxidation of hydroxyl functions.

19. A metal complex 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 as defined in one of claims 1 to 12.

20. Metal complex according to claim 19, characterized in that it corresponds to general formula IV

in which :

- A, B, Rf and Y are as defined in one of claims 1 to 12,

Z represents an coordinating anionic ligand, and

21. Complex according to claim 20, characterized in that

- M represents ruthenium, rhodium or iridium,

- Z represents a halogen atom, preferably chlorine or bromine, - L represents a C ₆ to C ₁₂ aromatic ligand or a cyclopentadienyl or cyclooctatriene unit substituted, where appropriate, by one or more C ₄ to C ₄ alkyl groups .

22. Complex according to claim 19 or 21, characterized in that it corresponds to the general formula IVa

in which :

- R 'and R "independently of one another represent a carbocyclic or heterocyclic radical at C., at C ₂₀ saturated, unsaturated, aromatic, monocyclic or polycyclic as defined above, provided that when Rf represents a group CF ₃ , Y an NH ₂ group then R 'and R "do not simultaneously represent an unsubstituted phenyl ring or R' and R" are linked together so as to constitute, with the carbon atoms carrying them, a carbocyclic or heterocyclic radical of 4 to 20 atoms saturated, unsaturated, aromatic, monocyclic or polycyclic, and

- Rf represents

(i) a halogen atom, preferably fluorine, (ii) alkyl C, -C ₁₀ cycloalkyl or C ₃ -C _10, poly- or per-halogenated,

(iii) a phenyl radical substituted by at least one polyhalogenated C ₄ -C ₄ radical,

(iv) a mono-, poly- or perhalogenated phenyl radical and - Y, L and Z are as defined above.

23. Complex according to one of claims 19 to 22, characterized in that it corresponds to the general formula IVb.

with L, Z and M as defined in claim 20 or 21.

24. Complex according to claim 22 or 23, characterized in that

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

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

- M a ruthenium atom.

25. Complex according to one of claims 19 to 24, characterized in that it has as ligand at least one compound chosen from (1 S, 2S) -N-trifluoromethanesulfonyl-1, 2-cyclohexanediamine, the ( 1 S, 2S) -N- trifluoromethanephenylsulfonyl-1, 2-cyclohexanediamine, le (1 S, 2S) -NN- (Nonafiuorobutanesulfonyl) -1, 2-diphenylethylenediamine, le (1S, 2S) -N-

(Nonafluorobutanesulfonyl) -1, 2 cyclohexanediamine, (1S, 2S) -N- (pentafluorophenylsulfonyl) -l, 2 cyclohexanediamine, (1S, 2S) -N- (pentafluorophenylsulfonyl) -l, 2-diphenylethylenediamine , 2S) -N- (3,5-bis (trifluoromethane) phenylsulfonyl) 1,2-cyclohexanediamine, le (1 S, 2S) -N- (3,5-bis (trifluoromethane) phenylsulfonyl) 1,2-diphenylethylenediamine.

26. Process for the preparation of a complex according to one of claims 19 to 25, characterized in that it consists in reacting a compound of general formula I as defined in claims 1 to 12 and in an optically active form with the transition metal compound retained in a suitable organic solvent.

27. Use of a metal complex as defined in one of claims 19 to 25 for carrying out the asymmetric reduction of a ketone derivative.

28. Use according to claim 27, characterized in that the compound carrying the ketone function corresponds to the general formula V.

_**

in which

- R., and R ₂ represent independently of each other:

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

(v) an arylalkenyl group, preferably from C ₈ to C1 ₅ , optionally substituted by one or more halogen atom (s);

- * indicates the possible presence R ₂ of an asymmetry center located in position α of the carbonyl function.

29. Process for the preparation of an optically active secondary alcohol of general formula VI

in which: - R., and R ₂ represent independently of each other:

(v) an arylalkenyl group, preferably C ₈ to C ₁₅ , optionally substituted by one or more halogen atom (s), and - ^* indicates the presence of a chirality center at the carbon level, characterized in that that it implements the asymmetric reduction of a compound of general formula V

as defined in claim 28, in the presence of a metal complex whose transition metal has as ligand at least one optically active form of a compound of general formula I as defined in claims 1 to 12.

30. The method of claim 29, characterized in that the metal complex is as defined in claims 20 to 25.

31. Method according to claim 29 or 30, 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.

32. Method according to one of claims 29 to 31, characterized in that the reaction is carried out in the presence of a hydrogen donor.

33. Use of a metal complex as defined in one of claims 19 to 25 for carrying out the enantioselective catalytic oxidation of a chiral secondary alcohol in the form of a racemic mixture.