FR2795070A1 - Sulfonylamides and carboxamides ligands and their transition metal complexes useful for the asymmetric syntheses of chiral secondary alcohols from ketones - Google Patents

Abstract

Sulfonylamide and carboxamide derivatives (I) are new. Sulfonylamide and carboxamide derivatives of formula (I) are new. B' = -CO-, or -SO2-; Rf = halo, alkyl or cycloalkyl that is mono-, poly- or per-halogenated and may be interrupted by one or more O or S, aryl substituted by halogenated alkyl, mono-, poly- or perhaloaryl, RaCF2-, RaCF2-CF2-, RaCF2CF(CF3)-, CF2-C(Ra)F-, or (CF3)Ra-; Ra = H or Rb; Y' = OH, SH, NH2, NHRb, or NRbRc; Rb, Rc = alkyl or alkenyl (optionally interrupted by one or more O, S, or CO and optionally substituted by one or more halo or carboxyl), aryl (optionally substituted by one or more halo, alkyl or alkenyl), aralkyl or aralkenyl (both optionally substituted by halo); A = a group of formulae (i) or (ii); R', R'' = 1-20C hydrocarbon which may be acyclic, cycloaliphatic (saturated, unsaturated, aromatic mono or polycyclic), and may incorporate one or more hetero atoms and may be substituted by aliphatic groups in which the alkyl chain may be interrupted by O, CO, and may be substituted by an aromatic or non-aromatic ring, and these groups may further be halogenated (with the proviso that when B is SO2n is zero, Rf is CF3, and Y is NH2, then R' and R'' are not both unsubstituted phenyl), or R' and R'' together may form a cycloaliphatic group as defined above; X = methylene optionally substituted; n = 0-3; Ar1, Ar2 = aromatic rings (optionally substituted and optionally condensed, and optionally ortho-ortho or ortho-peri condensed between themselves; x and y = two double bonds between the skeleton A and the groups amino and Y. Independent claims are also included for: (1) the preparation of (I); (2) transition metal complexes of formula (IV); (3) the preparation of secondary alcohols of formula RbCH(OH)Rc by asymmetric reduction of ketones of formula RbC(O)Rc using the transition metal complexes (IV). M = Rh, Ru, Re, Ir, Co, Ni, Pt, or Pd; Z = an anionic ligand ; L = an unsaturated aliphatic ligand having at least one double bond or a carbocyclic or heterocyclic ligand having at least one double bond, that may be charged. The bonds x and y being in the same absolute configuration.

Description

<Desc / Clms Page number 1>

 The main subject of the present invention is new compounds of the diamine, mono- or polyfluorinated, sulphonylated or carbonyl type, their method of preparation and their application in asymmetric catalysis.

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

 By way of illustration of these reactions of asymmetric organic syntheses, mention may be made especially of asymmetric catalytic hydrogenation and more particularly of ketone derivatives in their corresponding chiral secondary alcohols.

 The optically active secondary alcohol derivatives are reagents particularly sought after in many fields, in particular pharmaceutical, agrochemical or perfume.

 Of course, during the synthesis of this type of product, there is generally a simultaneous production of an inactive enantiomer which it is necessary to isolate the desired enantiomer.

 It is therefore important to minimize the formation of this enantiomer without interest. For this purpose, the ketone derivative reductions are conventionally conducted in the presence of asymmetric synthesis catalysts. Generally, these are transition metal complexes carrying chiral ligands. Thus, certain organometallic complexes of the Rh (1), ir (1) and Ru (II) chirally modified types make it possible to drive the reduction of 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 (II) -based chiral catalysts has been developed to reduce

<Desc / Clms Page number 2>

enantioselective aromatic ketones at room temperature. (R Noyori et al., J. Am Chem Soc., 1995, 117, 7562, 7563)
This catalyst is derived from the metal complex RuCl 2 (# 6 mesitylene) 2.

dans laquelle Ra représente un radical choisi parmi C6H5CO-, pCH3OC6H4SO2-, C6H5S02- et CF3S02 . En fait, parmi les radicaux sulfonés testés, c'est le radical CF3SO2- qui est considéré comme le ligand le moins intéressant en terme de rendement énantiosélectif. This is used in a chelated form with a diphenylethylenediamine derivative of formula A

wherein Ra represents a radical selected from C6H5CO-, pCH3OC6H4SO2-, C6H5SO2- and CF3SO2. In fact, among the sulphonated radicals tested, it is the radical CF3SO2- which is considered to be the least interesting ligand in terms of enantioselective yield.

 The object of the present invention is precisely to propose novel diamino derivatives or analogues capable of constituting chiral ligands effective for asymmetric synthesis and in particular for the asymmetric hydrogenation of ketonic functions.

dans laquelle - B représente (i) -CO-, ou (ii) -SO2-, It has now been found and this is a first object of the invention of new products, namely diamino-alkyl derivatives or analogues having the following general formula:

in which - B represents (i) -CO-, or (ii) -SO2-,

<Desc / Clms Page number 3>

 Rf represents (i) a halogen atom, preferably fluorine, (ii) an alkyl radical preferably of C1 to C10 or cycloalkyl preferably of C3 to C10, mono-, poly- or perhalogenated whose chain haloalkyl is optionally interrupted by one or more oxygen or sulfur atom (s), (iii) an aryl radical, preferably C6 to C12, substituted by a halogenated alkyl radical as defined in (ii), (iv) an aryl radical, mono-, poly- or perhalogenous, preferably C6 to C12, or (v) a radical chosen from RA-CF2, RA-CF2-CF2-, RA-CF2-CF (CF3) -, CF3 -C (RA) F- and (CF3) RA- with RA representing a hydrogen atom or having any of the meanings given below for RB and Rc, -Y represents a group OH, SH, NH2, NHRB or NRBRCc, with RB and Rc different from a hydrogen atom and representing, independently of one another, a radical chosen from: (i) an alkyl chain, preferably a C 1 to C 10 alkyl chain, optionally in terminated 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 a C 2 -C 10 alkenyl chain, optionally interrupted by one or more atom (s) or sulfur or carbonyl function (s) and optionally substituted with one or more halogen atom (s) or carboxyl group (s); (iii) an aryl group, preferably C6 to C12, optionally substituted with one or more halogen atoms or alkyl or alkenyl group (s); (iv) an arylalkyl group, preferably C7 to C15, optionally substituted with one or more halogen atom (s); (v) an arylalkenyl group, preferably C8 to C15, optionally substituted by one or more halogen atom (s);

<Desc / Clms Page number 4>

dans lesquelles - R' et R" représentent indépendamment l'un de l'autre un radical hydrocarboné ayant de 1 à 20 atomes de carbone qui peut être un radical aliphatique acyclique saturé ou insaturé, linéaire ou ramifié ; un radical cycloaliphatique saturé, insaturé, aromatique, monocyclique ou polycyclique sous réserve que lorsque B représente un groupement SO2, n a pour valeur zéro, Rf représente un groupement CF3, Y représente un groupement NH2 alors R' et R" ne représentent pas simultanément un noyau phényle non substitué ; ledit radical cycloaliphatique étant le cas échéant porteur d'un radical aliphatique saturé ou insaturé, linéaire ou ramifié avec la chaîne alkyle pouvant être interrompue par un ou plusieurs atomes d'oxygène et/ou fonction carbonyle et le cas échéant substituée de préférence en fin de chaîne par un radical cyclique aromatique ou non ; lesdits radicaux pouvant le cas échéant être substitués par un ou plusieurs atomes d'halogène, de préférence le fluor et/ou un ou plusieurs radicaux alkyles en C1 à Ce de préférence en C1 à C4 ou encore les deux substituants R' et R" sont liés entre eux de manière à constituer un radical cycloaliphatique tel que défini ci-dessus, - X représente un groupement méthylène le cas échéant substitué, - n est un entier variant de zéro à 3, et - Ar, et Ar2 symbolisent, indépendamment l'un de l'autre deux cycles aromatiques substitués ou non, condensés ou non et portant le cas - symbolized a skeleton of general formula la or Ib.

in which - R 'and R "represent, independently of one another, a hydrocarbon radical having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic radical; a saturated, unsaturated cycloaliphatic radical; aromatic, monocyclic or polycyclic provided that when B is SO2, n is zero, Rf is CF3, Y is NH2, and R 'and R "do not simultaneously represent an unsubstituted phenyl ring; said cycloaliphatic radical being optionally carrying a saturated or unsaturated aliphatic radical, linear or branched with the alkyl chain which may be interrupted by one or more oxygen atoms and / or carbonyl function and, if appropriate, preferably substituted at the end of chain by an aromatic cyclic radical or not; said radicals may optionally be substituted by one or more halogen atoms, preferably fluorine and / or one or more C1 to C6 alkyl radicals, preferably C1 to C4, or the two substituents R 'and R "are linked together so as to form a cycloaliphatic radical as defined above, - X represents a methylene group optionally substituted, - n is an integer ranging from zero to 3, and - Ar, and Ar2 symbolize, independently the one of the other two aromatic cycles substituted or not, condensed or not and bearing the case

<Desc / Clms Page number 5>

 optionally one or more heteroatoms, preferably C6 to C12 and capable of forming ortho or ortho and peri-condensed systems between them, - x and y respectively locate the two bonds established between the skeleton symbolized by A and the amino groups and Y and its derivatives.

 For the purposes of the present invention, the term "derivatives" is intended to cover, in particular, the organic or inorganic salts of the compounds of formula # 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 electroattractive group at one of the amine functions makes it possible to improve significantly asymmetric reductions of ketones when catalysed by the corresponding metal complexes.

 The kinetics of the reaction are significantly increased and the expected enantiomer is recovered with a higher conversion rate for equivalent enantiomeric yield.

 Thus, the electron-withdrawing group is 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 1, is represented by a group BRf in which Rf represents (i) a halogen atom, preferably fluorine, (ii) a C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl radical or perhalogen, (iii) a phenyl radical substituted by a poly (C 1 -C 4) alkyl radical or perhalogen, or (iv) ) a mono-, poly- or perhalogenated C 6 aryl radical.

<Desc / Clms Page number 6>

 More preferably, Rf represents a phenyl radical substituted with a CF3 group in the para position or a CF3 radical.

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

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

dans laquelle : Rf, (x), (y) et Y sont tels que définis précédemment et Ar1 et Ar2 figurent ensemble un groupement aromatique. According to a first variant of the invention, the compounds of general formula # correspond to the general formula b

wherein: Rf, (x), (y) and Y are as previously defined and Ar1 and Ar2 together represent an aromatic moiety.

 In the following description of the present invention, aromatic is understood to mean the classical notion of aromaticity as defined in the literature, in particular by J. March Advanced Organic Chemistry, 4th ed., John Wiley & Sons, 1992, pp 40 and following. In the context of the present invention, the aromatic derivative may be monocyclic or polycyclic.

 In the case of a monocyclic derivative, it may comprise at its ring level one or more heteroatoms chosen from nitrogen, phosphorus, sulfur and oxygen atoms. According to a preferred mode, they are nitrogen atoms.

<Desc / Clms Page number 7>

 By way of illustration of the monocyclic heteroaromatic derivatives which are suitable for the present invention, there may be mentioned the pyridine, pyrimidine, pyridosine and pyrasinic derivatives.

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

 As an illustration of this type of compounds, there may be mentioned derivatives of naphthalene, quinoline and isoquinoline.

 As a representative of the compounds corresponding to the general formula b, there may be mentioned more particularly those in which Ar1 and Ar2 together are a group derived from diphenyl-2,2'-diyl, or a group dinaphthyl-2,2 ' -diyle.

 In the case where Ar 1 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 # in which A symbolizes a skeleton of formula la are in fact particularly interesting.

dans laquelle More preferentially, these compounds correspond to the general formula

in which

<Desc / Clms Page number 8>

 - Rf, X, n, (x), (y) and Y are as defined above in general formula), and - R 'and R "represent a saturated, unsaturated, aromatic, monocyclic or polycyclic cycloaliphatic radical, under provided that when n is zero, Rf is CF3, Y is NH2, then R 'and R "do not simultaneously represent unsubstituted phenyl or R' and R" may be bonded together to form carbon which carry them a cycloaliphatic radical.

 In the general formulas 1a and 1a, R 'and R ", which may be identical or different, may have various meanings, various examples are presented below but they are in no way limiting.

 Thus, R 'and R "may represent an acyclic aliphatic radical, saturated or unsaturated, linear or branched.

 More precisely, R 'and R "represent an aliphatic, acyclic, linear or branched radical preferably having from 1 to 12 carbon atoms, saturated or comprising one to several, generally 1 to 3, double bonds.

 The hydrocarbon-based chain may optionally be interrupted by a group, preferably a heteroatom, and more particularly an oxygen or nitrogen atom or a carrier of substituents, for example a halogen atom, in particular chlorine, or a -CF3 group.

 It is also possible that in the compound of formula I or the formula, R 'and R "represent a saturated or unsaturated, linear or branched acyclic aliphatic radical which may optionally carry a cyclic substituent. carbocyclic or heterocyclic, saturated, unsaturated or aromatic.

 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 benzenes, these cyclic substituents possibly being themselves carrying one or more substituents.

<Desc / Clms Page number 9>

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

 In the general formulas # and a, the radicals R 'and R "may also represent a carbocyclic radical saturated or containing 1 or 2 unsaturations in the ring, generally having 3 to 8 carbon atoms, preferably 6 carbon atoms. carbon in the cycle, said cycle being substitutable.

 Preferred examples of radicals R 'R "include cyclohexyl radicals optionally substituted by linear or branched alkyl radicals having from 1 to 4 carbon atoms.

 R 'and R "may also be saturated or unsaturated, preferably bicyclic, polycyclic carbocyclic radicals, which means that at least two rings have two carbon atoms in common, and in the case of polycyclic compounds, the number of carbon in each cycle preferably ranges from 3 to 6, the total number of carbon atoms being preferably 5.

dans laquelle : - n' représente un entier de 0 à 5 et - Q un radical choisi parmi : # un radical alkyle linéaire ou ramifié, ayant de 1 à 4 atomes de carbone, # un radical alkoxy linéaire ou ramifié, ayant de 1 à 4 atomes de carbone, Thus, the radicals R 'and R "may represent, according to a preferred mode, an aromatic hydrocarbon radical, and in particular a benzene radical corresponding to the general formula

in which: n 'represents an integer of 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,

<Desc / Clms Page number 10>

 benzoyl group, OH group, NH 2 group, NO 2 group, phenyl group, halogen atom, CF 3 group, SRo group, or ORD group with Ro as defined above for RB.

 R 'and R "may also represent a polycyclic aromatic hydrocarbon radical with the rings capable of forming between them ortho-condensed, ortho- and peri-condensed systems, more particularly a naphthyl radical, said ring being able to be substituted.

 R 'and R "may also represent a saturated, unsaturated or aromatic heterocyclic radical containing in particular 5 or 6 atoms in the ring, one or two of which are heteroatoms such as nitrogen, sulfur and oxygen atoms; carbon of this heterocycle may also be substituted.

 R 'and R "may also represent a polycyclic heterocyclic radical defined as being either a radical consisting of at least two aromatic or non-aromatic heterocycles containing at least one heteroatom in each ring and forming ortho or ortho- and peri-condensed orthogonal systems between them, 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 peri-condensed systems, the carbon atoms of said rings possibly being substituted.

 By way of examples of heterocyclic groups R 'and R ", mention may be made, inter alia, of furyl, pyrrolyl, thienyl, isoxazolyl, furazanyl, isothiazolyl, imidazolyl and pyrazolyl radicals.

<Desc / Clms Page number 11>

 pyridyl, piridazinyl, pyrimidinyl, pyranyl and the quinolyl, naphthyridinyl, benzopyranyl, benzofuranyl, indolyl radicals.

 The number of substituents present on each ring depends on the carbon condensation of the ring and the presence or absence of unsaturation on the ring. The maximum number of substituents which can be carried on a ring is readily determined by those skilled in the art.

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

 Of particular interest are the compounds of general formula Ia wherein: - R 'and R "both represent a phenyl group, provided that when Rf is CF3 and Y is NH2 then at least one of R 'and R "are at least monosubstituted or - R' and R" are linked together so as to form with the carbon atoms which carry them a cyclohexyl radical.

 As a representative of this type of compound, there may be mentioned ammonium chloride of (1S, 2S) -N-trifluoromethanesulfonyl-1,2cyclohexanediamine, (1S, 2S) -N-trifluoromethanesulfonyl-1,2cyclohexanediamine and the (1S, 2S) -N-trifluoromethane-phenylsulfonyl-1,2-cyclohexanediamine.

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

 For this purpose, the two carbons of the general formula # involved respectively at the level of the bonds symbolized by (x) and (y) constitute two centers of chirality which are preferably of the same configuration.

 Another object of the invention resides in the process for preparing the compounds of general formula I.

<Desc / Clms Page number 12>

avec A et Y étant tels que définis ci-dessus avec un composé de formule générale III
Rf-B-X' (III) avec Rf et B étant tel que définis ci-dessus et X' représentant un atome d'halogène, de préférence le chlore ou le fluor ou encore dans le cas où B représente SO2 un groupement OSO2Rf et en ce que l'on récupère ledit composé de formule générale I. More specifically, the subject of the present invention is a process for preparing a compound of general formula 1 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-BX '(III) with Rf and B being as defined above and X' representing a halogen atom, preferably chlorine or fluorine or in the case where B represents SO2 a group OSO2Rf and in this case that said compound of general formula I is recovered.

 In fact, the operating conditions used to synthesize the compounds of general formula # according to the claimed process are generally dictated by the chemical nature of the starting compounds. The implementation of this type of reaction is in fact within the skill of those skilled in the art.

 The reaction may 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 the ambient temperature.

 Generally the reaction is conducted at atmospheric pressure.

It is also preferred to conduct 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.

<Desc / Clms Page number 13>

 A practical embodiment is to charge the derivative of formula II in the solvent and then slowly add the sulfonylating agent of formula III.

 The reaction is carried out for a period of time sufficient to obtain the conversion of the product of formula II into formula I. The final compound is isolated by conventional reaction medium techniques.

 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 released halogenated acid. Generally, it is in excess of up to 3 times the stoichiometric amount.

 As mentioned above, the compounds of general formula I, a and b are particularly interesting 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 catalytic metal complex ligands useful for carrying out asymmetric syntheses. in organic chemistry.

 The compounds of formulas I, a and b, in optically active form thus prove to be particularly useful for the preparation of catalytic metal complex ligands useful for carrying out an enantioselective asymmetric hydrogenation of ketone derivatives.

 It has also been shown that these same compounds of general formulas I, a and b, in optically active form could be used to prepare catalytic metal complex ligands useful for enantioselective oxidation of hydroxyl functions.

 Accordingly, 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.

<Desc / Clms Page number 14>

 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, rhenium, iridium, cobalt, nickel, platinum and palladium.

 Of the above metals, rhodium, ruthenium and iridium are preferred.

dans laquelle : - A, B, Rf et Y sont tels que définis précédemment en formule I, - les carbones portant les liaisons (x) et (y) possèdent la même configuration absolue, - M est un métal de transition choisi parmi le rhodium, le ruthénium, le rhénium, l'iridium, le cobalt, le nickel, le platine et le paladium, - Z représente un ligand anionique coordinant et - L représente un ligand hydrocarboné cyclique de préférence en C5 à C6 comprenant au moins deux doubles liaisons, chargé ou non. As examples of metal complexes according to the present invention, mention may be made more particularly of those corresponding to the general formula IV

in which: - A, B, Rf and Y are as defined above in formula I, - the carbons bearing 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 palladium, - Z represents a coordinating anionic ligand and - L represents a cyclic hydrocarbon ligand preferably of C5 to C6 comprising at least two double bonds , charged or not.

 As the valency at the metal atom is likely to vary, the nature and 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,

<Desc / Clms Page number 15>

 Z represents a halogen atom, preferably chlorine or bromine, L represents an aromatic ligand or pentaalkylcyclopentadienyl ligand.

dans laquelle : - R' et R" représentent un radical cycloaliphatique saturé, insaturé, aromatique, monocyclique ou polycyclique tel que défini précédemment, sous réserve que lorsque Rf représente un groupement CF3, Y un groupement NH2 alors R' et R" ne représentent pas simultanément un noyau phényle non substitué ou R' et R" sont liés entre eux de manière à constituer avec les atomes de carbone qui les portent un radical cycloaliphatique, et - Rf représente (i) un atome d'halogène, de préférence le fluor, (ii) un radical alkyle en C1 à C10 ou cycloalkyle en C3 à C10, polyou per-halogéné, (iii) un radical phényle substitué par un radical en C1 à C4 polyhalogéné, (iv) un radical aryle mono-, poly- ou perhalogéné en C6 et - Y, L et Z sont tels que définis ci-dessus. Preferably, this complex corresponds to the general formula IVa

in which: R 'and R "represent a saturated, unsaturated, aromatic, monocyclic or polycyclic cycloaliphatic radical as defined above, provided that when Rf represents a group CF3, Y a group NH2, then R' and R" do not represent simultaneously an unsubstituted phenyl ring or R 'and R "are linked together so as to form with the carbon atoms which carry them a cycloaliphatic radical, and - Rf represents (i) a halogen atom, preferably fluorine, (ii) a C 1 to C 10 alkyl or C 3 to C 10 cycloalkyl radical, poly (perhalogenated), (iii) a phenyl radical substituted by a polyhalogen C 1 to C 4 radical, (iv) a mono-, poly- or perhalogen at C6 and - Y, L and Z are as defined above.

As more specific examples, there may be mentioned the complexes corresponding to the general formula IVb.

<Desc / Clms Page number 16>

 with L, Z and M as defined above.

 Of particular interest are compounds of formula IVb wherein - L represents an aromatic selected from benzene, paramethylisopropylbenzene or hexamethylbenzene, - a chlorine atom or a bromine atom, and - M a ruthenium atom.

 The present invention also provides a process for preparing said complexes comprising reacting an optically active form of a compound of general formula 1 as defined above with the selected transition metal compound in a suitable organic solvent.

 Complexes comprising as a ligand the compound of formula # above and the transition metal can be prepared according to the known methods described in the literature.

 For the preparation of ruthenium complexes, reference can be made in particular to the publication of J. -P. Broom [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 conducted at a temperature between room temperature (15 to 25 C) and the reflux temperature of the reaction solvent.

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

<Desc / Clms Page number 17>

 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 to achieve 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.

dans laquelle - R, et R2 représentent indépendamment l'un de l'autre : (i) une chaîne alkyle, de préférence en C1 à C,O, éventuellement interrompue par un ou plusieurs atome (s) d'oxygène ou de soufre ou fonction(s) carbonyle et éventuellement substituée par un ou plusieurs atomes d'halogène ou groupes carboxyle, (ii) une chaîne alcényle ou alcynyle, de préférence en C2 à C10, éventuellement interrompue par un ou plusieurs atome (s) d'oxygène ou de soufre ou fonction(s) carbonyle et éventuellement substituée par un ou plusieurs atome (s) d'halogène ou groupe(s) carboxyle ; (iii) un groupe aryle, de préférence en Ce à C12, éventuellement substitué par un ou plusieurs atome (s) d'halogène ou groupe(s) alkyle ou alcényle ; The ketone derivatives which can be hydrogenated with a metal complex according to the invention preferably correspond to the general formula V

in which - R 1 and R 2 represent, independently of each other: (i) an alkyl chain, preferably a C 1 to C 4 O chain, optionally interrupted by one or more oxygen or sulfur atom (s) or function (s) carbonyl 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 atom (s) or sulfur or carbonyl function (s) and optionally substituted with one or more halogen atom (s) or carboxyl group (s); (iii) an aryl group, preferably a C6-C12 group, optionally substituted by one or more halogen atoms or alkyl or alkenyl group (s);

<Desc / Clms Page number 18>

 (iv) an arylalkyl group, preferably C7 to C15, optionally substituted with one or more halogen atom (s); (v) an arylalkenyl group, preferably C8 to C15, optionally substituted by one or more halogen atom (s); and - * indicates the possible presence in R2 of an asymmetric center located in position a of the carbonyl function.

 As a representative of the substituents R2 having a center of asymmetry, there may be mentioned particularly radicals R2, the carbon atom bearing the center of asymmetry is substituted by a mono- or disubstituted amine function and by an ester function.

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

dans laquelle : - R, et R2 représentent indépendamment l'un de l'autre : (i) une chaîne alkyle, de préférence en C1 à C10, éventuellement interrompue par un ou plusieurs atome (s) d'oxygène ou de soufre ou fonction(s) carbonyle et éventuellement substituée par un ou plusieurs atomes d'halogène ou groupes carboxyle, (ii) une chaîne alcényle ou alcynyle, de préférence en C2 à C10, éventuellement interrompue par un ou plusieurs atome (s) d'oxygène ou The process of the invention is particularly applicable to the preparation of an optically active hydroxyl compound of general formula VI

in which: R 1 and R 2 represent, independently of each other: (i) an alkyl chain, preferably a C 1 to C 10 chain, optionally interrupted by one or more oxygen or sulfur atom (s) or function (s) carbonyl and optionally substituted by one or more halogen atoms or carboxyl groups, (ii) an alkenyl or alkynyl chain, preferably a C2 to C10 chain, optionally interrupted by one or more oxygen atom (s) or

<Desc / Clms Page number 19>

tel que défini ci-dessus 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 1 telle que définie précédemment. sulfur or carbonyl function (s) and optionally substituted with one or more halogen atom (s) or carboxyl group (s); (iii) an aryl group, preferably C6 to C12, optionally substituted with one or more halogen atoms or alkyl or alkenyl group (s); (iv) an arylalkyl group, preferably C7 to C15, optionally substituted with one or more halogen atom (s); (v) an arylalkenyl group, preferably C8 to C15, optionally substituted by one or more halogen atom (s), and - * indicates the presence of a center of chirality at the carbon, 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 whose transition metal has as ligand at least one optically active form of a compound of general formula 1 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 method 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 thus using as catalyst a metal complex according to the invention, that is to say, liganded by an optically active derivative of general formula I.

<Desc / Clms Page number 20>

 The reduction of the ketone derivative is generally carried out at a temperature of 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 impairing the enantiomeric yield.

Accordingly, those skilled in the art are able to set the proper temperature range to achieve the best compromise between reaction rate and enantiomeric efficiency. Generally, this temperature is between 20 C and 50 C.

 The hydrogen donor is conventionally represented by a lower secondary alcohol or a mixture of formic acid and tertiary amine. Generally, this hydrogen donor is used as a solvent. As a representative of the lower secondary alcohols, there may be mentioned 2- or 3-butanol and isopropanol.

 The complex based on the compound of general formula # 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 n has no significant impact 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 the operating conditions. It is preferable to use 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.

 A basic compound may optionally be added during the reaction. This basic compound may be an alkaline base such as sodium or potassium hydroxide or 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.

<Desc / Clms Page number 21>

 As mentioned above, 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 hydrogenation reactions of ketonic functions in secondary alcohols.

 The examples which appear below are presented as non-limiting illustrations of the present invention.

EXAMPLE 1
Trifluoromethanesulfonylation of diaminocyclohexane

 In a three-necked flask of 100 ml, equipped with an addition funnel, a temperature probe and a magnetic stir bar with agitation by a magnetic stirrer.

 Charge: - 4.82 g of (1S, 2S) -1,2-cyclohexanediamine, - 7,11 g of trifluoromethanesulfonyl chloride, and - 40 ml of dichloromethane.

 The first step is to charge the diamine and dichloromethane and then establish an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 C with the aid of an ice bath. The sulfonylating agent is slowly charged (30 min) by means of an addition funnel. The reaction mixture is allowed to rise to room 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 corresponding to ammonium chloride (1S, 2S) -N-trifluoromethanesulfonyl-1,2cyclohexanediamine is recovered, which corresponds to a yield of 74%.

 In a 100 ml Erlenmeyer flask, 3.99 g of the solid and 15 ml of distilled water are charged. The pH of this aqueous phase is adjusted to between 7 and 8 by addition of a 2M aqueous solution of sodium hydroxide. We leave 16

<Desc / Clms Page number 22>

 hours at room temperature. The crystallized product is filtered. It is dried under vacuum. 1.78 g of (1S, 2S) -N-trifluoromethanesulfonyl-1,2-cyclohexanediamine are recovered in a yield of 51%.

EXAMPLE 2 Trifluoromethanephenylsulfonylation of diaminocyclohexane

 In a 10 ml flask are charged: 50 mg of (1S, 2S) -1,2-cyclohexanediamine, 89 mg of 4-trifluoromethanephenylsulfonyl chloride, 4.5 ml of dichloromethane.

 The first step is to charge the diamine and dichloromethane and then establish an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 C with the aid of an ice bath. 4-Trifluoromethane-phenylsulfonyl chloride is added slowly using a syringe. The reaction mixture is stirred at room temperature for 5 hours. It is diluted with 5 ml of dichloromethane and the solution is then washed with a saturated aqueous solution of NaHCO 3 (8 ml) and then dried over Na 2 SO 4. After evaporation of the solvent, 102 mg of a white powder corresponding to (1S, 2S) -N- (4-trifluoromethanephenylsulfonyl) -1,2-cyclohexanediamine are recovered, which corresponds to a yield of 88%.

EXAMPLE 3
Trifluoromethanesulfonylation of 1,2-diphenylethylenediamine

 In a 100 ml three-neck flask equipped with an addition funnel, a temperature probe and a stir bar with agitation by a magnetic stirrer, the following are charged: 4.97 g of (1S, 2S) -1,2-diphenylethylenediamine, 3.94 g of trifluoromethanesulfonyl chloride, and 30 ml of dichloromethane.

<Desc / Clms Page number 23>

 The first step is to charge the diamine and dichloromethane and then establish an atmosphere of inert gases (nitrogen). The reaction mixture is cooled to a temperature of 3 C with the aid of an ice bath. The sulfonylating agent is slowly charged (30 min) by means of an addition funnel. The reaction mixture is allowed to rise to ambient temperature (22 ° C.) with stirring for two hours and the white precipitate formed filtered off. 20 ml of dichloromethane are added and the organic phase is then washed with a 2M aqueous solution of HCl and with water saturated with NaCl. The organic phase is concentrated and then the white solid formed is filtered off. The white solid is dried under vacuum.

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

EXAMPLE 4
Reduction of acetophenone.

 A mixture composed of: isopropanol / KOH - [RuCl 2 (p-cymene)] 2 - (1S, 2S) -N-trifluoromethanesulfonyl-1,2-cyclohexanediamine is used as the reducing medium.

 In a 250 ml flask equipped with a condenser, a stir bar with stirring by means of a magnetic stirrer, 10 mmol of acetophenone -5.10 -2 mmol of [RuCl 2 (p-cymene)] are charged. 0.1 mmol of (1S, 2S) -N-trifluoromethanesulfonyl-1,2cyclohexanediamine - 0.25 mmol of KOH and - 100 ml of isopropanol.

 The ruthenium complex, the ligand and 20 ml of isopropanol are first charged and then an argon atmosphere is established. The reaction medium is heated at a temperature of 80 ° C. for 30 minutes. We charge

<Desc / Clms Page number 24>

 then 80 ml of isopropanol, potash and acetophenone. The reaction mixture is left stirring for 72 hours at 22 ° C. The product formed, namely 1-phenylethanol and the enantiomeric excess is determined 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 is: azeotropic mixture of formic acid and triethylamine [RuCl 2 (p-cymene)] 2 as the metal complex and (1S, 2S) -N-trifluoromethanesulfonyl-1,2-cyclohexanediamine or (1S, 2S) -N-trifluoromethanesulfonyl-1,2-diphenylethylenediamine as a chiral ligand.

 In a 25 ml flask equipped with a stir bar with agitation by a magnetic stirrer, the following are loaded: - 10 mmol of acetophenone - 0.05 mmol of [RuCl2 (p-cymene)] 2 - 0.1 mmol of ligand - 2 ml of formic acid - 3 ml of triethylamine.

 The ruthenium complex, the ligand and 10 ml of isopropanol are charged first. An argon atmosphere is established and the reaction medium is heated at a temperature of 80 ° C. for 30 minutes. The solvent is evaporated under reduced pressure and a red solid is obtained.

 In another 25 ml flask, cooled by an ice bath and provided with a magnetic stir bar with stirring by a magnetic stirrer, 3 ml of triethylamine, 2 ml of formic acid and 10 mmol are charged.

<Desc / Clms Page number 25>

 acetophenone. 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 duration of the reaction is mentioned in the table below.

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

The results obtained are recorded in Table 1 below:
This table also accounts for the reduction of acetophenone in the presence of a ligand not according to the present invention, (1S, 2S) -N-tosyl-1,2-cyclohexanediamine.

Exemple ligand durée Rendement e.e. Table 1

Example ligand duration Yield ee

H NHSO 2 CHF 4 NHSO 2 CF 3 72 h 85% 91% H NH 2 Ph H NHSO 2 CF 3 45 h 99% 93% Ph H NH 2 Control NHSO 4 - JY - CHy 38 h Control of NHSO 2 - (O - NH 2
It is noted that only the ligands bearing fluorine atoms on the carbon at the sulfonyl group are effective.

<Desc / Clms Page number 26>

EXAMPLES 7 AND 8
Reduction of acetophenone.

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

The results are recorded in the following table:
Table 2

<Tb>
<tb> Example <SEP> Temperature <SEP> Time <SEP> Yield <SEP> ee
<Tb>

7 <SEP> 5 C <SEP> 15 <SEP> days <SEP> 27% <SEP> 92 <SEP>% <SEP>
<tb> 8 <SEP> 50 C <SEP> 5 <SEP> h <SEP> 99% <SEP> 88%
<Tb>

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

EXAMPLE 9
Reduction of acetophenone.

 The same reducing medium as in Example 5 is used, 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, keeping everything else equal.

<Desc / Clms Page number 27>

 99% of the 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 of the catalyst / substrate ratio does not have a significant impact on the enantioselectivity of the reduction.

EXAMPLES 10 AND 11
Reduction of acetophenone.

 The same reducing medium as in Example 5 is used, the procedure of which is reproduced but the nature of the metal complex is modified. The retained complex is liganded with (1S, 2S) N-trifluoromethanesulfonyl-1,2-cyclohexanediamine.

Table 3

<Tb>
<tb> Ref <SEP> Complex <SEP> Time <SEP> Yield <SEP> ee
<Tb>

Ex. <SEP> metallic
<tb> 10 <SEP> [Cp * IrCl2] 2 <SEP> 96 <SEP> h <SEP> 52 <SEP> 90
<tb> 11 <SEP> [Cp * RhCl2] 2 <SEP> 72 <SEP> h <SEP> 86 <SEP> 89
<tb> 5 <SEP> [RuCl2 (p-cymene)] <SEP> 72 <SEP> h <SEP> 85 <SEP> 91
<Tb>
The results are comparable in terms of enantioselectivity.

<Desc / Clms Page number 28>

EXAMPLES 12 AND 13
Reduction of 3 ', 4'-dimethoxyacetophenone.

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

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

Ref Ligand Rendement e.e. ex. The results obtained are shown in Table 4 below:
Table 4

Ref Ligand Yield ee ex.

H 12 NHSO 2 CF 3 93% 75%: NH 2 NH 3 CO 2, 87% Ph! NHS02CF3 87% Ph q NH2

<Desc / Clms Page number 29>

 EXAMPLE 14 Preparation of p-keto-α-amino acid derivatives 1α, 1b.

The p-ketone-α-amino acid derivatives used are as follows:

Preparation of methyl (3,4-dimethoxyphenyl) -2- (benzoyloxycarbonyl) methylamino-3-oxopropanoate (1a)

 To LHMDS lithium hexamethyldisilazane cooled to -78 ° C (1.06 M in THF, 2 equivalents) was added a solution of Cbz-Sar-Ome (1 equivalent, 0.5 g / ml in THF), 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 a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic phase is dried with sodium chloride solution followed by MgSO 4 .H 2 O. By concentration an amber colored syrup is obtained in a quantitative yield.

 1 H-NMR (300 MHz, CDCl3): # 2. 84-2.86 (m, 3H, Nme), 3.62-3.91 (m, 9H, CO2Me, 2xOMe), 5. 13-5.14 (m, 2H, CHPh) , 6. 12 and 6. 40 (2s, 0. 8H, CH keto), 6. 58-7.62 (m, 8H, CH 2 Ph).

 Preparation of methyl (3,4-dimethoxyphenyl) -2- (benzoyloxycarbonyl) methylamino-3-oxopropanoate (1b).

<Desc / Clms Page number 30>

 Ketone amino acid 1b is prepared from 3,4-dimethoxybenzoic acid chloride according to the protocol described for derivative 1a. The concentrated residue is then purified by chromatography (eluent: hexane / EtOAc 3: 1, then 2: 1) and crystallized (hexane / EtOAc) to give a yield of 60% derivative 1b.

 1 H NMR (300 MHz, CDCl 3): 3.62 and 3. 74 (2 br, 3H, CO2Me), 3. 94 and 3. 98 (2s, 6H, 2xOMe), 5. (s, 2H, CH 2 Ph), 5. 97 and 6. 00 (d, 1.9H, CH keto, J = 7.9 Hz), 6. and 22 (d, 0.9H, NH, J = 7.9 Hz), 6. 94 -7.83 (m, 8H, C6H3CH2Ph).

EXAMPLE 15
Asymmetric hydrogen transfer hydrogenation of ssketo-α-amino acid derivatives using chiral Ru (ll) complexes.

 The general protocol implemented is as follows: [RuCl 2 (p-cym)] 2 and chiral diamine (1.5 equivalents relative to Ruthenium atom) are stirred in iso-propanol (1 ml, dry) at 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) were 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 sodium chloride solution (15 ml), dried over MgSO 4 and concentrated in order 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:

<Desc / Clms Page number 31>

th reo-(3 ,4-d iméthoxyphényl )-2 -[ (benzoyloxyca rbonyl)méthylamino]- 3-hydroxypropanoate de méthyle (threo-2a).

methyl reo- (3,4-dimethoxyphenyl) -2 - [(benzoyloxycarbonyl) methylamino] -3-hydroxypropanoate (threo-2a).

 1 H NMR (300 MHz, CDCl 3): # 2. 92 and 3. 08 (2 br s, 3H, Nme), 3.69-3.91 (m, 9H, CO2Me, 2xOMe), 4.71-5.39 ( m, 4H, CHN, CH 2 Ph, CHOH), 6.83-6.93 (m, 3H, C 6 H 3), 7. 15-7.35 (m, 5H, CH 2 Ph). methyl erythro- (3,4-dimetoxyphenyl) -2 - [(benzoyloxycarbonyl) methylamino] - 3-hydroxypropanoate (erythro-2a).

 1 H NMR (300 MHz, CDCl 3): # 2. 58 and 2. 60 (2 br s, 3H, NMe), 3.65 and 3. 74 (2s, 3H, CO2Me), 3.80 and 3. 87 (2s, 6H, 2xOMe), 4. 08-4.17 (m, 1H, CHN), 4.71 (brs, 1H, OH), 5. 04-5.26 (m, 3H, CH 2 Ph, CHOH), 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 HC02NH4 (0.13 g, 4 eq) in methanol overnight. The mixture was then filtered through Celite, concentrated, and extracted with dichloromethane (10 mL) in the presence of saturated sodium chloride solution (5 mL) and saturated aqueous NaHCO3 (2 mL). The organic phase is dried (Na2SO4) and concentrated to yield about 95% of 2a, b. Before the determination of the enantiomeric excess by HPLC on a Chiralpack AD column, the sample is purified on PLC plate (CH 2 Cl 2 / EtOH 40: 1).

 The products thus obtained are characterized by NMR.

 Methyl threo- (3,4-dimethoxyphenyl) -N-methylserine (threo-2a) ester.

 1 H NMR (300 MHz, CDCl 3): # 2.41 (s, 3H, Nme), 3. (d, 1H, CHN, J = 7.9Hz), 3.56 (s, 3.56 (s); , 3H, CO2Me), 3.87 and 3.89 (2s, 6H, 2xOMe), 4.53 (d, 1H, CHOH: J = 7.9Hz), 6. 82-6.92 (3H, m, C6H3).

<Desc / Clms Page number 32>

 Methyl erythro- (3,4-dimethoxyphenyl) -N-methylserine ester (erythro-2a).

 1 H NMR (300 MHz, CDCl 3): # 2. 42 (s, 3H, Nme), 3. 53 (d, 1H, CHN, J = 5.7Hz), 3.69 (s, 3H, CO 2 Me ), 3.87 and 3.88 (2s, 6H, 2xOMe), 4.93 (d, 1H, CHOH: J = 5.7Hz), 6. 76-6.84 (3H, m, C6H3).

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

<Desc / Clms Page number 33>

Conditions produits essai substrat diamine chirale S/C Temps, conv., threo %eeC h %a e hrob 1 la 0::",..0- 40 96 25 97/3 72 2 la NHS02 40 95 65 95/5 94 -CF, la pns-)- 40 62 75 95/5 82 >"'* 'NH NHSp2- .. ffllZ 95/5 Ph NH2 4 la ,NHSOZCF3 40 72 >95 95/5 98 -""NHzHa d 5 la .,,NfiS02CF3 40 72 100 88/12 86 NH2HCI 6 la Ph ,,NHSOZCF3 40 35 100 95/5 99 Ph NHz 7 lb "NHSOZCF3 40 42 100 94/4 NH2HCI 8 lb Ph NHS02CF3 40 15 100 92/8 Ph)NH2 Table 5

Chiral diamine substrate test conditions S / C Time, conv., Threo% eeH hrob 1 0 ", 0- 40 96 25 97/3 72 2 NHS02 40 95 65 95/5 94 - ## STR1 ## wherein: ## STR2 ## wherein: ## STR2 ## ## STR2 ## ## STR1 ##

<Desc / Clms Page number 34>

 Estimated by 1H-NMR analysis Determined by 1H-NMR analysis at 300 MHz of deprotected compound 3 Determined by HPLC analysis using a Chiralpack AD column [RuCl2 (benzene)] was 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:

In a 25 ml monocolon, the ruthenium complex (31 mg, 0.05 mmol), the ligand (2 eq) in solution in 10 ml of isopropanol are introduced. The reaction medium is brought to 80 ° C. under an argon atmosphere for 3 hours. It is concentrated to dryness on a rotary evaporator and then the racemic alcohol 3a-3b (1. 2 g, 10 mmol, 200 eq.) And the solvent (5 ml) are introduced. The mixture is then degassed by bubbling argon for 1/2 hour and then the powdered potash (14 mg, 0.25 mmol, 5 eq.) Is added. The medium is stirred under an argon atmosphere at 30 ° C.

<Desc / Clms Page number 35>

 The reaction is monitored by GC: column CYCLODEX B 236M 25m × 0.25m; initial temperature of the column 100 C; final temperature of the column 150 C; rate 2 C / min. ; temperature of the injector 150 C; detector temperature 240 C; volume injected 2 l; Retention time of cyclopentanone = 2.25 min, cyclopentanol = 2.6 min.n of acetophenone 5 = 6.6min., Of 4 = 9. 2min., 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 corresponds to 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 as a percentage surface area.

 By resuming 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 as a percentage surface area.

- The second ligand corresponds to the following formula:

<Desc / Clms Page number 36>

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 as surface 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 as a percentage surface area.

Claims (32)

 in which - B represents (i) -CO-, or (ii) -SO2-, - Rf represents (i) a halogen atom, preferably fluorine, (ii) an alkyl radical preferably of C1 to C10 or C 3 -C 10 cycloalkyl, preferably mono-, poly- or perhalogenated, the haloalkyl chain of which is optionally interrupted by one or more oxygen or sulfur atom (s), (iii) an aryl radical, preferably C 6 C12, substituted with a halogenated alkyl radical as defined in (ii), (iv) an aryl radical, mono-, poly- or perhalogenated preferably C6 to C12, or (v) a radical selected from RA- CF2, RA-CF2-CF2-, RA-CF2-CF (CF3) -, CF3-C (RA) F- and (CF3) RA- with RA representing a hydrogen atom or having any of the given meanings below for RB and RC, Y represents an OH, SH, NH 2, NHRB or NRBRC group, with RB and Rc different from a hydrogen atom and representing, independently of one another, a radical chosen from: (i) a chain has alkyl, preferably C1 to C10, optionally interrupted by one or more oxygen or sulfur atom (s) or

 1. Compound of general formula # <Desc / Clms Page number 38>  in which - R 'and R "independently of one another represent a hydrocarbon radical having 1 to 20 carbon atoms which may be a linear or branched saturated or unsaturated acyclic aliphatic radical; saturated, unsaturated, aromatic cycloaliphatic unradical , monocyclic or polycyclic provided that when B is SO2, n is zero, Rf is CF3, Y is NH2, and R 'and R "do not simultaneously represent an unsubstituted phenyl ring; said cycloaliphatic radical being optionally carrying a saturated or unsaturated aliphatic radical, linear or

 function (s) carbonyl and optionally substituted with one or more halogen atoms or carboxyl groups, (ii) an alkenyl chain, preferably C2 to C10, 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 C6 to C12, optionally substituted with one or more halogen atoms or alkyl or alkenyl group (s); (iv) an arylalkyl group, preferably C7 to C15, optionally substituted with one or more halogen atom (s); (v) an arylalkenyl group, preferably Ca to C15, optionally substituted by one or more halogen atom (s); - symbolized a skeleton of general formula la or Ib. <Desc / Clms Page number 39>  branched with the alkyl chain which may be interrupted by one or more oxygen atoms and / or carbonyl function and, if appropriate, preferably substituted at the end of the chain by an aromatic or non-aromatic cyclic radical; said radicals may optionally be substituted by one or more halogen atoms, preferably fluorine and / or one or more C1 to C6 alkyl radicals, preferably C 1 to C 4, or the two substituents R 'and R " are linked to each other so as to form a cycloaliphatic radical as defined above, X represents a methylene group which may be substituted, n is an integer ranging from zero to 3, and - Ar and Ar2 represent, independently one of the other two substituted or unsubstituted aromatic rings, condensed or not and optionally carrying one or more heteroatoms, preferably C6 to C12 and which can form ortho or ortho and peri-condensed systems between them, - x and there respectively locate the two links established between the skeleton symbolized by A and the amino groups and Y and its derivatives.  2. Compound according to claim 1, characterized in that B represents a group -SO2-.  3. Compound according to claim 1 or 2, characterized in that Y represents an NH 2 or NHRB group with RB 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 C1 to C10 alkyl radical or a C3 to C10 cycloalkyl polyou perhalogenated, <Desc / Clms Page number 40>  (iii) a phenyl radical substituted by a poly (C 1 -C 4) alkyl radical or a perfluorinated alkyl radical, 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 phenyl radical substituted by a CF3 group in the para position or a CF3 radical.  6. Compound according to one of the preceding claims, characterized in that it meets the general formula b

 wherein: Rf, (x), (y) and Y are as defined in one of claims 1 to 5 and Ar1 and Ar2 together are a group derived from diphenyl-2, 2'diyl or a group dinaphthyl-2 , 2'-diyl.  7. Compound according to one of claims 1 to 5, characterized in that it meets the general formula has

<Desc / Clms Page number 41>  in which - Rf, X, n, (x), (y) and Y are as defined in claims 1 to 4, and - R 'and R "represent a saturated, unsaturated, aromatic, monocyclic or polycyclic cycloaliphatic radical, under provided that when n is zero, Rf is CF3, Y is NH2, then R 'and R "do not simultaneously represent unsubstituted phenyl or R' and R" may be bonded together to form carbon which carry them a cycloaliphatic radical.  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 bonded together so as to form 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 selected from - ammonium chloride (1S, 2S) -N-trifluoromethanesulfonyl-1,2cyclohexanediamine, - (1S, 2S ) -N-trifluoromethanesulfonyl-1,2-cyclohexanediamine, and - (1S, 2S) -N-trifluoromethanephenylsulfonyl-1,2-cyclohexanediamine.  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, respectively involved at the level of the bonds symbolized by (x) and (y) constitute two centers of chirality of the same configuration. <Desc / Clms Page number 42>  13. Process for the preparation of a compound of general formula # 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-BX '(III) with Rf and B being as defined in claims 1 to 5 and X' representing a halogen atom, preferably chlorine or fluorine or a group OS02Rf and in that said compound of general formula I.  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 molar ratio II / III less than or equal to 1.  16. Use of a compound of general formula # as defined in any one of claims 1 to 12 and in optically active form for the preparation of catalytic metal complex ligands useful for performing asymmetric syntheses in organic chemistry. <Desc / Clms Page number 43>  17. Use of a compound of general formula I as defined in one of claims 1 to 12 and in optically active form for the preparation of catalytic metal complex ligands useful for performing an enantioselective asymmetric hydrogenation of ketone derivatives.  18. Use of a compound of general formula I as defined in one of claims 1 to 12 in optically active form for the preparation of catalytic metal complex ligands useful for performing 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 the general formula IV

 in which: - A, B, Rf and Y are as defined in one of claims 1 to 12, - the carbons bearing the bonds (x) and (y) have the same absolute configuration, - M is a metal of transition chosen from rhodium, ruthenium, rhenium, iridium, cobalt, nickel, platinum and palladium, <Desc / Clms Page number 44>  Z represents a coordinating anionic ligand, and L represents a cyclic hydrocarbon ligand, preferably of C5 to C6, comprising at least two double bonds, with or without charge.  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 an aromatic ligand or pentaalkylcyclopentadienyl.  22. Complex according to claim 19 or 21, characterized in that it corresponds to the general formula IVa

 in which: - R 'and R "represent a saturated, unsaturated, aromatic, monocyclic or polycyclic cycloaliphatic radical, with the proviso that when Rf represents a group CF3, Y a group NH2, then R' and R" do not simultaneously represent a phenyl ring; unsubstituted or R 'and R "are linked together so as to form with the carbon atoms which carry them a cycloaliphatic radical, -Rf represents (i) a halogen atom, preferably fluorine, (ii) a radical C1 to C10 alkyl or C3 to C10 cycloalkyl, polyhalohalogenated, (iii) a phenyl radical substituted by a polyhalogenated C1 to C4 radical, (iv) a mono-, poly- or perhalogenated C6 aryl radical, and <Desc / Clms Page number 45>  Y, L and Z are as defined in claims 19 to 21.  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. A complex according to claim 22 or 23, characterized in that - L represents an aromatic chosen from benzene, paramethylisopropylbenzene or hexamethylbenzene, - a chlorine atom or a bromine atom, and - M a ruthenium atom .  25. A process for the preparation of a complex according to one of claims 19 to 24, 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.  26. Use of a metal complex as defined in one of claims 19 to 24 to carry out the asymmetric reduction of a ketone derivative. <Desc / Clms Page number 46>  27. Use according to claim 26, characterized in that the compound bearing the ketonic function corresponds to the general formula V.

 in which - R1 and R2 represent, independently of each other: (i) an alkyl chain, preferably a C1 to C10 chain, optionally interrupted by one or more oxygen or sulfur atom (s) or function (s) ) carbonyl and optionally substituted by one or more halogen atoms or carboxyl groups, (ii) an alkenyl or alkynyl chain preferably C2 to C10, optionally interrupted by one or more atom (s) or sulfur or function (s) carbonyl and optionally substituted by one or more halogen atom (s) or carboxyl group (s); (iii) an aryl group, preferably C6 to C12, optionally substituted with one or more halogen atoms or alkyl or alkenyl group (s); (iv) an arylalkyl group, preferably C7 to C15, optionally substituted with one or more halogen atom (s); (v) an arylalkenyl group, preferably C8 to C15, optionally substituted by one or more halogen atom (s); - * indicates the possible presence R2 of an asymmetric center located in position a of the carbonyl function.  28. Process for preparing an optically active secondary alcohol of general formula VI <Desc / Clms Page number 47>  as defined in claim 27, in the presence of a metal complex whose transition metal has as ligand at least one form

 in which: R 1 and R 2 represent, independently of each other: (i) an alkyl chain, preferably C 1 to C 10, optionally interrupted by one or more oxygen or sulfur atom (s) or function (s) carbonyl 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 atom (s) or sulfur or carbonyl function (s) and optionally substituted with one or more halogen atom (s) or carboxyl group (s); (iii) an aryl group, preferably C6 to C12 'optionally substituted with one or more halogen atom (s) or alkyl or alkenyl group (s); (iv) an arylalkyl group, preferably C7 to C15, optionally substituted with one or more halogen atom (s); (v) an arylalkenyl group, preferably C8 to C15, optionally substituted by one or more halogen atom (s), and - * indicates the presence of a center of chirality at the carbon, characterized in that it implements the asymmetric reduction of a compound of general formula V

<Desc / Clms Page number 48>  optically active agent of a compound of general formula 1 as defined in claims 1 to 12.  29. The method of claim 28, characterized in that the metal complex is as defined in claims 20 to 24.  30. The method of claim 28 or 29, characterized in that the complex is used in a proportion of 1 / 10,000 to 1/1 relative to the carbonyl compound of general formula V.  31. Method according to one of claims 28 to 30, characterized in that the reaction is carried out in the presence of a hydrogen donor.  32. Use of a metal complex as defined in one of claims 19 to 24 for carrying out the enantioselective catalytic oxidation of a chiral secondary alcohol in the form of a racemic mixture.