FR2865204A1 - New chiral esters and amides of pyrrolidine-2-carboxylic acid, useful as catalysts for asymmetric aldolization and ketolization reactions - Google Patents

Abstract

Chiral esters and amides (I) of pyrrolidine-2-carboxylic acid are new. Chiral esters and amides of pyrrolidine-2-carboxylic acid, having formula (I), are new. A : groups F1 or F2; R' and R'' : 1-20C hydrocarbyl, i.e. acyclic, linear or branched, saturated or unsaturated aliphatic, carbo- or hetero-cyclic, mono- or poly-cyclic, saturated, unsaturated or aromatic, or a chain of such groups, or R' and R'' are linked to form a 4-20 atom carbo- or hetero-cyclic group, saturated, unsaturated or aromatic, mono- or poly-cyclic; Ar1 and Ar2two aromatic, carbo- or hetero-cyclic, rings optionally substituted, fused and/or containing one or more heteroatoms; x and y : bonds between A and heteroatoms; Rf1-20C hydrocarbyl, optionally containing at least one halo, preferably fluoro; Rzone or more substituents on pyrrolidinyl; G : a chiral group; W : O or RyN; Ry1-20C hydrocarbyl as for R', or a chain of such groups; n : number of ring substituents; m : 0-3, preferably 0 or 1; the wavy line : chiral bond; the broken line : chiral or non-chiral bond. An independent claim is also included for a method for preparing (I) by reacting an N-protected pyrrolidine-2-carboxylic acid (or alkyl ester) with the appropriate alcohol or amine. [Image] [Image].

Description

NOVEL CHIRAL COMPOUNDS DERIVED FROM A DIAMINE OR A

  AMINOALCOOL, MONOSULFONYL AND CARBONYL CARRIERS OF A PYRROLIDINYL GROUP, THEIR PREPARATION AND THEIR APPLICATIONS IN ASYMMETRIC CATALYSIS.

  The present invention relates to novel chiral compounds derived from a diamine or a amino alcohol, monosulfonylated and carbonyl, bearing a pyrrolidinyl group, their preparation and their applications in asymmetric catalysis.

  The invention relates more particularly to the use of said compounds as useful organic catalysts in particular for the asymmetric aldolization reaction.

  The production of pure optically active compounds is a problem that arises in many technical fields such as, for example, pharmacy, agrochemicals, the food industry (food additives, flavorings) and also in the perfume industry.

  This problem is expected to become increasingly important as more and more, it is found that in a given application only one of the stereomers has the desired property.

  In particular, optically pure products are required in the synthesis of compounds for therapeutic purposes.

  Thus, many active ingredients include a hydroxyl or amino group carried by a carbon atom in position (i) with respect to a carbonyl group, having a well-defined stereochemistry.

  For example, the cross-aldolization reaction between an aldehyde (or ketone) and an aldehyde leads to the formation of one or two chiral centers and thus two pairs of enantiomers can be obtained:

OH O OH O

OH O

OH O

  syn / erythro anti / threo - The enantiomers are obtained in racemic mixture if no asymmetric induction is carried out.

  The object of the present invention is to provide a chiral reagent capable of controlling the stereochemistry of the OH group formed.

New chiral compounds.

  More specifically, the invention aims, as new products, chiral compounds corresponding to the following formula (I):

RZ C = O N

  Wherein said symbol represents a skeleton of general formula (F 1) or (F 2): (x) R '(x) (Y) R "2 (Y) (## STR2 ## F1) (F2) in formulas (F1) and (F2): - R 'and R "represent, independently of one another, a hydrocarbon group having 1 to 20 carbon atoms which may be an acyclic aliphatic group saturated or unsaturated, linear or branched, a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the abovementioned groups; or alternatively, R 'and R "may be bonded together with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated or aromatic, monocyclic or polycyclic, - Ar and Ar2 represent, independently of one another, two aromatic, carbocyclic or heterocyclic rings, substituted or no, condensed or not and bearing, where appropriate, one or more heteroatoms, x and y respectively mark the two bonds established between the skeleton symbolized by A and the heteroatoms, Rf represents a hydrocarbon group having from 1 to 20 carbon atoms comprising or not at least one halogen atom, preferably a fluorine atom; - RZ represents any one or more substituents on the pyrrolidinyl group, - G represents a chiral group, - W represents an oxygen atom or a RyN group in which Ry represents a hydrocarbon group having from 1 to 20 carbon atoms which can be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic group; a sequence of the aforementioned groups, - n represents the number of substituents on the ring, - m is an equal number from 0 to 3, preferably equal to 0 or 1. ^ "symbolizes a chiral bond, symbolizes a chiral bond or not .

  The new chiral compounds according to the invention have the characteristic of having two centers of chirality.

  A first feature is the presence on the pyrrolidine ring of an asymmetric carbon atom located in position a of the imino group.

  A second characteristic is the existence of a second chiral center on the carbon atoms which carry the heteroatom O, N or N, N, or because of the presence of a chiral group G * present on an achiral ring, for example benzene.

  Examples of G groups are, for example, menthyl, proline, methylbenzylamino, bornyl, isobornyl.

  In the compounds corresponding to formula (I), the pyrrolidine ring may carry one or more substituents RZ insofar as they do not interfere with the process of the invention.

  The maximum number of substituents which can be carried by one ring is readily determined by those skilled in the art.

  In the present text, "several", generally, less than 3 substituents on the cycle.

  Examples of substituents are given below but this list is not limiting in nature. Mention may be made in particular of: linear or branched alkyl groups having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms, linear or branched, mono-, poly- or perhalogenated alkyl groups preferably having 1 to 6 carbon atoms and 1 to 13 halogen atoms and even more preferably 1 to 4 carbon atoms and 1 to 9 halogen atoms, Rb O- or thioether Rb-S- ether groups in which Rb represents a linear or branched alkyl group having from 1 to 6 carbon atoms and even more preferably from 1 to 4 carbon atoms or the phenyl group, - the acyloxy or aroyloxy Rb-CO-O- groups in which the Rb group has the meaning given above, the acyl or aroyl groups Rb-CO- in which the group Rb has the meaning given above, the ester groups -O-CO-Rb or -COORb in which Rb has the meaning given above, amino groups -N- (Rc) (Rd) in which R 1, Rd, which are identical or different, represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, the amido groups Rd-CO-NH- or (RC) (Rd) -N-CO- in which Re, Rd, have the meaning given above, a hydroxyl group, a nitro group, a halogen atom, preferably a fluorine atom.

  Among the above-mentioned RZ groups, the invention more particularly targets the following: a linear or branched alkyl group preferably having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms, an alkoxy Re O group or Rb-S-thioether in which Rb represents a linear or branched alkyl group having from 1 to 6 carbon atoms, a CF 3 group, a hydroxyl group, a halogen atom, preferably a fluorine atom.

  In the compounds corresponding to formula (I), Rf preferably represents a hydrocarbon group having 1 to 20 carbon atoms and more particularly: a C 1 to C 10 alkyl group, preferably a C 1 to C 4 alkyl group, and more preferably a methyl or ethyl group, - a C 1 -C 10, preferably C 1 -C 4, mono-, poly- or halogenated alkyl group having 1 to 21 halogen atoms, preferably a CF 3 group a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclohexyl group, an optionally mono-, poly- or perhalogenated cycloalkyl group having from 3 to 8 carbon atoms, a phenyl group, a mono-, poly- or perhalogenated phenyl group; a phenyl group substituted by at least one C1-C10, preferably C1-C4, optionally mono-, poly- or per- halogenated alkyl group or a nitro group; or nitrile; an optionally mono-, poly- or perhalogenated aryl group having 6 to 12 carbon atoms; More preferably, Rf represents a CF3, C4F9 group or a phenyl group substituted by one or more halogen atoms, preferably from fluorine, or with one or more mono-, poly- or perfluorinated C1-C2 alkyl groups.

  The preferred SO2-Rf sulfonyl groups are: tosyls (p-toluenesulfonyl) SO2 C6H4-CH3-brosyls (p-bromobenzenesulfonyl) -SO2-C6H4-Br-nosyls (p-nitrobenzenesulfonyl) -SO2-C6H4-NO2 - mesyls (methanesulfonyl) -SO2-CH3-triflyls (trifluoromethanesulfonyl) -SO2-CF3-nonaflyles (nonafluorobutanesulfonyl) -SO2-C4F9 -substyles (2,2,2-trifluoroethanesulfonyl) -SO2-CH2-CF3 Rf is no longer preferentially a trifluoromethyl group.

  As for the Ry group carried by the nitrogen atom, its nature is not critical.

  By way of examples, Ry may have the following meanings: a hydrogen atom, a C 1 to C 12 alkyl group, a C 2 to C 12 alkenyl or alkynyl group, a cycloalkyl group of preferably at C3 to O12; aryl or arylalkyl, preferably C6 to C12.

  The cyclic groups may optionally carry one or more substituents and, as examples, reference may be made to the list given for R. However, it should be noted that there is no interest in the Ry group being complicated.

  Thus, Ry is more particularly an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl.

  According to a first variant of the invention, the preferred compounds of general formula (I) correspond to the general formula (Ib) in which A represents a group of formula (F2): ## STR2 ##

NOT

Ili RyN.

  Embedded image in which: Rf, Ry, RZ, (x), (y) are as defined above and Ar and Ar2 together represent an aromatic group which may be a carbocycle having from 6 to 12 atoms of carbon or a heterocycle having 5 to 12 atoms, - at least one of the bonds (x) and (y) symbolized by ---- is a chiral bond.

  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, these are nitrogen atoms N-protected.

  By way of illustration of the monocyclic heteroaromatic derivatives which are suitable for the present invention, there may be mentioned the pyridine, pyrimidine, pyridazine and pyrazine 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 representative of the compounds corresponding to the general formula (Ib), there may be mentioned more particularly those in which Ar 1 and Ar 2 together are either a diphenyl-2,2'-diyl group or a dinaphthyl-2,2'-group. diyl.

  In the case where Ar and Ar 2 together are a diphenyl-2,2'diyl group, the two phenyl rings are substituted so as to block the configuration of the corresponding structure with substituents such as an alkyl, alkoxy or alkylthio group in Cl. C6, preferably C1 to C4: said groups are preferably in position 3 and 3 '.

  The compounds of general formula (I) in which A represents a skeleton of formula (F) are in fact particularly interesting.

  More preferentially, these compounds correspond to the general formula (Ia):

RZ

NOT

  In which - Rf, Ry, RZ are as defined above in general formula (I), - R 'and R "independently represent one of the compounds of formula (I); other a carbocyclic or heterocyclic group, saturated, unsaturated or aromatic, monocyclic or polycyclic, - or R 'and R "may be linked so as to form with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic, - at least one of the bonds (x) and (y) symbolized by ---- is a chiral bond.

  In the general formula (Ia), 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 independently of each other represent an acyclic aliphatic group, saturated or unsaturated, linear or branched.

  More specifically, R 'and R "preferably represent a linear or branched saturated acyclic aliphatic group preferably having from 1 to 12 carbon atoms, and even more preferably from 1 to 4 carbon atoms.

  The invention does not exclude the presence of unsaturation on the hydrocarbon chain such as one or more double bonds which can be conjugated or not.

  The hydrocarbon chain may be optionally interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group to the extent that it does not react and there may be mentioned in particular a group such as in particular -CO-.

  The hydrocarbon chain may optionally carry one or more substituents (for example, halogen, ester) insofar as they do not interfere.

  The acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent. By ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.

  The acyclic aliphatic group may be linked to the ring by a valency bond, a heteroatom or a functional group such as oxy, carbonyl, carboxyl, sulphonyl, etc.

  As examples of cyclic substituents, it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 ring carbon atoms or benzenes, these cyclic substituents being themselves optionally carrying any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention. In particular, alkyl or alkoxy groups having 1 to 4 carbon atoms may be mentioned.

  Among the aliphatic groups carrying a cyclic substituent, cycloalkylalkyl groups, for example cyclohexylalkyl or arylkyl groups having 7 to 12 carbon atoms, in particular benzyl or phenylethyl, are more particularly targeted.

  In the general formula (Ia), the groups R 'and R "may also represent, independently of each other, a saturated carbocyclic group or group comprising 1 or 2 unsaturations in the ring, generally having from 3 to 8 carbon atoms, preferably 6 carbon atoms in the ring, said ring being substitutable As preferred examples of this type of group are cyclohexyl groups optionally substituted with linear or branched alkyl groups having from 1 to 4 carbon atoms.

  The groups R 'and R "may represent, independently of each other, an aromatic hydrocarbon group, and in particular a benzene group having the general formula (F3): in which: n' represents a number from 0 to 5, - Q represents a group selected from: a linear or branched alkyl group having 1 to 6 carbon atoms; 15 a linear or branched alkoxy group having 1 to 6 carbon atoms; a linear or branched alkylthio group having 1 to 6 carbon atoms, a group -NO2, a group -CN, a halogen atom, 20. a group CF3.

  R 'and R "may also independently of one another represent a polycyclic aromatic hydrocarbon group with rings capable of forming between them ortho-condensed, ortho- and peri-condensed systems, more particularly a naphthyl group; can be substituted.

  R 'and R "may also independently of one another represent a saturated, unsaturated or aromatic heterocyclic group, in particular having 5 or 6 atoms in the ring, one or two of which are heteroatoms such as nitrogen atoms (unsubstituted by a hydrogen atom), sulfur and oxygen, the carbon atoms of this heterocycle may also be substituted.

  R 'and R "may also represent a polycyclic heterocyclic group defined as either a group consisting of at least two aromatic or non-aromatic heterocycles containing at least one heteroatom in each ring and forming between them ortho- or ortho- and peri- condensed, or is a (F3) group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocyclic ring forming ortho or ortho- or peri-condensed systems between them, the carbon atoms of said rings possibly being substituted .

  As examples of heterocyclic groups R 'and R ", furyl, thienyl, isoxazolyl, furazannyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyranyl and quinolyl, naphthyridinyl and benzopyranyl groups may be mentioned, for example: benzofuranyl.

  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.

  R 'and R "may also be linked to represent carbocyclic or heterocyclic, mono- or poly-cyclic, saturated, unsaturated or aromatic, preferably bicyclic, groups 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.

  By way of illustration of this type of structure, mention may be made in particular of the following cyclic groups: ## STR2 ## Compounds of general formula (Ia) in which: R 'and R "are both phenyl, - R' are of particular interest; and R "are linked together so as to form with the carbon atoms which carry them a cyclohexyl group.

  As mentioned above, the compounds of general formula (I) are all the more interesting that they are in an optically active form.

  For this purpose, the two carbons of the general formula (I) involved respectively at the level of the bonds symbolized by (x) and (y) may constitute one or two centers of chirality.

  The preferred reagents according to the invention correspond to the following formula (Ic):

RZ

  in said formula, Rf represents an alkyl group having 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted with an alkyl group having 1 to 10 carbon atoms, 1 to 5 fluorine atoms or a group trifluoromethyl, - RZ represents an alkyl group having from 1 to 10 carbon atoms, - Ra represents a hydrogen atom or an alkyl or alkoxy group having from 1 to 10 carbon atoms, a trifluoromethyl group, a nitro group, - Ry represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

  Another preferred class of reagents are those which have the formula RZ Rf in said formula, - Rf represents an alkyl group having 1 to 10 carbon atoms, a phenyl group, an alkyl-substituted phenyl group having 1 to 10 carbon atoms, 1 to 5 fluorine atoms or a trifluoromethyl group, - RZ represents an alkyl group having 1 to 10 carbon atoms, - Ra represents a hydrogen atom or an alkyl or alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, a nitro group, - Ry represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

  Representative examples of illustrative compounds of the invention include: - (2R) -pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2S) -Pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-ethyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1S, 2S) - ( 1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1S, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2R) -pyrrolidine acid -2-Carboxylic acid, (1R, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1S, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonyl) amine n-ethyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1R, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, ( 1S, 2R) - (1,2-Diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2R) -pyr rolidine-2-carboxylic acid, (1R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2 2-diphenyltrifluoromethanesulfonylamino-cyclohexyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1S, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-acid carboxylic acid, (1S, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1R, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylamino) cyclohexyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1S, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1R, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1S, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, Preparation chiral compounds.

  According to the process of the invention, the chiral compounds of formula (I), preferably (la) to (Id), are obtained by reacting: - the amino acid in protected form which is L- or D- proline or derivative which may be represented by the formula: RZ in said formula, - P represents a protective group, - Re represents a hydrogen atom or an alkyl group preferably containing from 1 to 4 carbon atoms, RZa the meaning given above.

  and a diamine compound or amino alcohol carrying a sulfonyl group corresponding to the following formula: HW (G *) m HN 'SO 2 R f (IV) in the formula, A, W, Rf, G and m have the meaning given previously.

  In the formula (IV), WH is advantageously an OH or NH 2 group.

  The invention contemplates the use of proline in ester form, for example, alkyl ester having from 1 to 4 carbon atoms but from an economic point of view, the acid form is preferred. It is possible that the R 8 group is a hydrocarbon group of any other nature and the invention does not exclude it.

  However, from an economic point of view, this is of little interest.

  It should be noted that it is desirable to block the hydrogen atom of the imino group of the pyrrolidine ring with the aid of a protecting group. The protective groups commonly used for its purposes are used and may be mentioned in particular acyl groups (acetyl, benzoyl), BOC (butyloxycarbonyl), cbZ (carbobenzoxy), FMOC (trifluoromethyloxycarbonyl) or MSOC (methanesulfenyl-2 ethoxycarbonyl) ).

  Reference can be made to the work of Theodora W. Greene et al, Protective Groups in Organic Synthesis, (2nd edition) John Wiley & Sons, Inc. for leading the protection of the imino group as well as its deprotection.

  Thus, the process for preparing the chiral compounds of the invention comprises: a step of protecting the imino group of L- or D-proline or derivative; a step of coupling said amino acid or derivative with a diamine or a aminoalcohol having the formula (IV).

  a step of deprotection of the imino group.

  The coupling between the N-protected D- or L-proline and the diamine or aminoalcohol takes place under the conventional conditions of a peptide coupling.

  Thus, reference can be made to the literature and in particular to the work of M. BODANSZKY, Principles of Peptide Synthesis Springer Verlag, 1984, p. 9 to 44.

  The reaction is carried out in the presence of conventional coupling agents whose selection falls within the skill of the skilled person.

  As examples of coupling agents, there may be mentioned in particular: carbodiimides such as, for example, N, N'-dicyclohexylcarbodiimide, cyanamides, for example N, N-dibenzylcyanamide, keteneimines, isoxazolium such as, for example, N-ethyl-5-phenylisoxazolium-3-sulphonate, nitrogen heterocycles such as, for example, imidazolides, pyrazolides and 1,2,4-triazolides and more particularly N, N'-carbonyldiimidazole and N, N'-carbonyl-di-1,2,4-triazole, - alkoxylated acetylene and preferably ethoxyacetylene, - reagents such as ethyl chloroformate or isobutyl which forms an anhydrous mixed with the carboxyl function of the amino acid; nitrogenous heterocycles having a hydroxyl group on the nitrogen ring such as, for example, N-hydroxyphthalimide, N-hydroxysuccinimide and 1-hydroxybenzotriazole.

  Among the various coupling agents mentioned above, reagents such as ethyl chloroformate or isobutyl are preferred.

  The coupling reaction is generally carried out by contacting the amino acid and the diamine or the amino alcohol in the presence of a coupling agent in an organic solvent. As examples of solvents, mention may in particular be made of methylene chloride and tetrahydrofuran.

  In a next step, the deprotection of the imino group is carried out in a conventional manner.

  For example, in the case of a CbZ protecting group, a hydrogenation is carried out in the presence of a palladium salt, preferably palladium hydroxide (II).

  There is thus obtained a compound of formula (I).

  According to the process of the invention, the diamino compound or sulphonylated aminoalcohol of formula (IV) can be obtained by reacting a compound providing the SO 2 -Rf electron-attracting group and a diamine or an aminoalcohol of formula (V): HW. (G *) m H2N in said formula, W, A, G and m have the meaning given above.

  More specifically, the compound providing the sulfonyl group may be represented by the formula (VI):

O

  in said formula (VI): Rf has the meaning given above, Z represents: a halogen atom, preferably a chlorine or bromine atom, a -O-SO2-RfE group in which Rf ', which is identical to or different from Rf, has the meaning given for Rf.

  The preferred compounds have the formula (VI) wherein Z is chlorine or bromine.

  More particular examples of compounds of formula (VI) include: mesyl chloride, benzenesulfonyl chloride, tosyl chloride, trifluoromethanesulfonyl chloride, pentafluorobenzenesulfonyl chloride, p-chloride -trifluorométhylbenzènesulfonyle.

  A compound of formula (IV) is obtained.

  As more specific examples of compounds of formula (IV), there may be mentioned in particular: - (1S, 2S) -1-amino-2- (trifluoromethanesulfonamido) cyclohexane, - (1R, 2R) -1-amino-2- ( trifluoromethanesulfonamido) cyclohexane, - (1S, 2S) -1-amino-2- (pentafluorobenzene sulfonamido) cyclohexane, - (1R, 2R) -1-amino-2- (pentafluorobenzene sulfonamido) cyclohexane, - (1S, 2S) - 1-amino-2- (trifluoromethanesulfonamido) -1,2-diphenylethane, - (1R, 2R) -1-amino-2- (trifluoromethanesulfonamido) -1,2-diphenylethane, - (1S, 2S) -1-amino- 2- (trifluoromethanesulfonamido) -N-methylcyclohexane, - (1R, 2R) -1-amino-2- (trifluoromethanesulfonamido) -N-methylcyclohexane, - (1S, 2S) -1-amino-2- (methanesulfonamido) cyclohexane, - (1 R, 2R) -1-amino-2- (methanesulfonamido) cyclohexane, - (1S, 2S) -1-amino-2- (benzenesulfonamido) cyclohexane.

  - (IR, 2R) -1-amino-2- (benzenesulfonamido) cyclohexane.

  Configurations (1R, 2R) are preferred.

  The reaction between the diamine compound of formula (V) and the compound of formula (VI) takes place in the presence optionally of a base.

  It can therefore be used in the process of the invention, a base which can be a mineral or organic base whose role is to trap the acid formed during the reaction.

  Any type of base can be used.

  A base is used in which the pKa of the conjugated acid is greater than or equal to the pKa of the product obtained (IV).

  It should be noted that if the pKa of the product obtained is low (less than approximately 6), it is not necessary to use a base.

  PKa is defined as the ionic dissociation constant of the acid / base pair, when water is used as the solvent.

  For the choice of a base having a pKa as defined by the invention, reference may be made, inter alia, to the HANDBOOK OF CHEMISTRY AND PHYSICS, 66th edition, p. D-161 and D-162.

  Strong bases such as alkali metal hydroxides, preferably sodium or potassium hydroxide, or alkali metal salts, especially carbonates, bicarbonates, phosphates, hydrogen phosphates, sulphates, acetates and trifluoroacetates of metals, may be used. alkali.

  The concentration of the basic starting solution is not critical. The alkali metal hydroxide solution used has a concentration generally of between 10 and 50% by weight.

  A preferred variant of the invention consists in adding a base, preferably a tertiary amine, in order to trap the liberated hydracid.

  As preferred examples of tertiary amines, there may be mentioned, inter alia, triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine, pyridine, N, N-diethylcyclohexylamine. 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, Nn-butylpiperidine, 1,2-dimethylpiperidine, N-methylpyrrolidine, 1,2-dimethylpyrrolidine.

  Also suitable as bases are aromatic amines such as, for example, pyridine.

  The reaction of the compounds (V) and (VI) is conducted in the presence of a base, preferably in an organic solvent.

  Any type of polar or apolar organic solvent or a mixture of organic solvents is used.

  It is also possible to use an organic solvent which is inert under the reaction conditions. Thus, one can use aliphatic or cycloaliphatic hydrocarbons, halogenated or not, such as, for example, hexane, cyclohexane, dichloromethane, dichloroethane or aromatic, halogenated or not, such as benzene, toluene, xylenes, chlorobenzenes. ; esters such as methyl benzoate, methyl terephthalate, methyl adipate, dibutyl phthalate; esters or ethers of polyols such as tetraethylene glycol diacetate; linear or cyclic aliphatic ethers such as isopropyl ether, tetrahydrofuran or dioxane; aliphatic or aromatic nitriles such as acetonitrile, propionitrile, butanenitrile, isobutanenitrile, benzonitrile, benzyl cyanide.

  As for the different reagents and substrates, they are used in the amounts specified hereinafter.

  The concentration of the compound of formula (V) used in the solvent can vary within very wide limits. Generally, the concentration of the compound of formula (V) varies between 0.1 and 5 mol / l, preferably between 1.0 and 2.0 mol / l of solvent.

  The amount of base used, expressed as the ratio of the number of moles of base to the number of moles of compound of formula (VI) can vary within wide limits. Thus, the base / compound molar ratio of formula (VI) preferably ranges from 1.0 to 2.0.

  The amount of compound of formula (VI) employed expressed as the ratio between the number of moles of compound of formula (VI) and the number of moles of compound of formula (V) advantageously varies between 0.5 and 1, 0.

  The temperature at which the reaction of the compounds (V) and (VI) is carried out is between -15 ° C. and 50 ° C., preferably between 0 ° C. and room temperature (most often between 15 ° C. and 25 ° C.).

  According to a practical embodiment of the invention, it is possible to mix all the reagents in any order.

  A preferred embodiment of the invention consists in adding the compound of formula (VI) in a reaction medium comprising the base and the amine compound, optionally an organic solvent.

  At the end of the reaction, the compound of formula (IV) is recovered in a conventional manner. It is possible, for example, to add water, separate the organic phase and then dry it, in particular using sodium sulphate.

  This is removed by filtration and the organic phase is evaporated.

  It can also be separated by silica gel column chromatography. The compound obtained is used to prepare the chiral catalyst.

Asymmetrical organic catalysis.

  The subject of the present invention is also the use of a chiral compound as defined above in the field of asymmetric organic catalysis and more particularly intermolecular or intramolecular asymmetric or ketolization or cetolization.

  This reaction involves two functional groups carried by two different molecules or by the same molecule. One of the molecules has a carbonyl group and acts as electrophilic by its CO bond, the other nucleophilic by its enol form due to the presence of at least one hydrogen atom at the α-position of the carbonyl group . A bond is created between the carbon atom of the carbonyl group and the carbon atom at the α-position of the carbonyl group.

  Thus, in accordance with the process of the invention, a 13-aldol is formed with control of the stereochemistry of the OH group formed by reacting an aldehyde or a ketone with another enolable aldehyde in the presence of a chiral compound. according to the invention.

  A 13-ketol is formed with control of the stereochemistry of the OH group formed by reacting an aldehyde (or a ketone) with an enolatable ketone in the presence of a chiral compound according to the invention.

  The invention also contemplates the formation of an R-aminoketone with control of the stereochemistry of the amino group formed by reaction of an enolatable aldehyde or an enolizable ketone with an imine, in the presence of a chiral compound according to the invention .

  The method of the invention which consists in using the compound of formula (I) as a chiral inducer applies to any molecule comprising an aldehyde or ketone function on which another aldehyde, a ketone or an imine is reacted.

  Thus, the process of the invention relates to the following reaction schemes involving the following functional groups: O + H

O OH

(A) (B) (C)

NOT

O NH (A)

  According to the process of the invention, two molecules of aldehyde or two molecules of ketone [compounds (A) and (B)] or a molecule of aldehyde or ketone [compound (A)] with an imine are reacted. [compound (D)].

  More specifically, the compounds (A) and (B) carbonyl may be represented by the formulas (VII) or (VIII): R1 C = OHC = O R2 (VII) or R3 (VIII) in the said formulas (VII) and (VIII ): R 1 and R 2, which are identical or different, represent: a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a linear or branched, saturated or unsaturated aliphatic group carrying a cyclic substituent; at least one carbon atom present in the group R2 or R3 in position a with respect to the carbonyl group carries at least one hydrogen atom; R3 has the meaning given for R2, - R. and R2 may be bonded together to form a cyclic ketone ring.

  In formulas (VII) and (VIII), R1, R2 and R3 may have different meanings. Different examples are given below but they are in no way limiting.

  The carbonyl compound involved in the process of the invention more particularly corresponds to formula (VII) or (VIII) in which R 1, R 2 and R 3 represent an acyclic aliphatic group, saturated or unsaturated, linear or branched.

  More specifically, R 1, R 2 and R 3 represent a linear or branched acyclic aliphatic group preferably having from 1 to 12 carbon atoms, saturated or comprising one to more unsaturations on the chain, generally 1 to 3 unsaturations which may be double bonds. simple or conjugate.

  The hydrocarbon chain may be optionally interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group to the extent that it does not react and there may be mentioned in particular a group such as in particular -CO-.

  The hydrocarbon-based chain may optionally carry one or more substituents insofar as they do not react under the reaction conditions and mention may in particular be made of a nitrile group, a nitro group or a trifluoromethyl group or a (Ph) 2 PO 4 group. or a group (PhO) 2-PO- or the like.

  The acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent. By ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.

  The acyclic aliphatic group may be linked to the ring by a valency bond or by one of the atoms or groups such as oxy, carbonyl, carboxy, sulphonyl, etc.

  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 themselves being optionally carrying any substituent.

  In the general formulas (VII) and (VIII) of the acyclic carbonyl compounds, one of the radicals R 1, R 2 and R 3 may also represent a saturated or unsaturated cyclic hydrocarbon group preferably having 5 or 6 carbon atoms in the ring; a heterocyclic group, saturated or unsaturated, in particular containing 5 or 6 atoms in the ring, including 1 or 2 heteroatoms such as nitrogen, sulfur and oxygen atoms; an aromatic hydrocarbon group, monocyclic or polycyclic condensed or not.

  Examples of carbonyl compounds used in the process of the invention include: saturated aliphatic aldehydes acetaldehyde propionaldehyde butyraldehyde benzaldehyde saturated aliphatic ketones acetone methyl ethyl ketone methylisopropyl ketone methyl isobutyl ketone, 2-pentanone, 3-pentanone, 2-carboxymethyl-3-pentanone-2-hexanone, 3-hexanone, 25-5-methyl-2-hexanone, 2-heptanone, 3-heptanone, 4- heptanone, - 2-octanone, - 3-octanone, - diisobutyl ketone, - 5-methyl-2-octanone - 2-nonanone, - 2,6,8-trimethyl-4-nonanone - ketones having a functional group - 1,3 dihydroxy-2-propanone, diacetone alcohol, triacetal diol, 4-methoxy-4-methyl-2-pentanone, (diphenyl-phosophinoyl) acetaldehyde, 2- (diphenyl-phosophinoyl) propanal, unsaturated aliphatic ketones - mesityl oxide, 3- butene 2-one, 4-methyl-4-pentene 2-one, - ketones carrying a ring - acetophenol In formula (VII), R1 and R2 may be linked to form a ring comprising at least one carbonyl group. Thus, the compound of formula (VII) can be: - a monocyclic ketone compound, carbocyclic, saturated or unsaturated, - a polycyclic ketone compound comprising at least two carbocycles, saturated and / or unsaturated, - a polycyclic ketone compound comprising at least two saturated and / or unsaturated rings: one or more of the carbon atoms to be replaced by a heteroatom; - a polycyclic ketone compound comprising at least two carbocycles of which one of them is aromatic.

  The cyclic ketone of formula (VII) may be monocyclic or polycyclic.

  When it is a monocyclic compound, carbon in the ring can vary widely from 3 to 20 carbon atoms but is preferably 5 or 6 carbon atoms.

  The carbocycle may be saturated or comprising 1 or 2 unsaturations in the ring, preferably 1 to 2 double bonds which are most often at the α-position of the carbonyl group.

  The saturated or unsaturated carbocycle may carry substituents. The number of substituents on each cycle can vary widely from 1 to 5. It is usually 1 or 2.

  The carbonyl group is preferably carried by a saturated or unsaturated carbocycle having 5 or 6 carbon atoms. The compound may also be polycyclic, preferably bicyclic, which means that at least two rings have two carbon atoms in common.

  In the case of polycyclic compounds, the carbon condensation of each cycle is lower, generally from 3 to 8, but is preferably 5 or 6 carbon atoms.

  Thus, the polycyclic carbocyclic compound, preferably bicyclic, may comprise two saturated carbocyclic rings, each preferably having from 4 to 8 carbon atoms. There may be a carbonyl group on one or both rings. It is also possible that there are two carbonyl groups on the same ring. The carbonyl group is preferably carried by one or two saturated carbocyclic rings having 5 or 6 carbon atoms.

  In these polycyclic compounds, one or more carbon atoms, preferably two, may be replaced by a heteroatom, preferably a nitrogen or oxygen atom.

  The ring (s) of this polycyclic compound may carry substituents. The number of substituents on each ring is generally 1. The bicyclic carbocyclic compound may comprise two carbocycles, each preferably having from 4 to 7 carbon atoms, one saturated, the other unsaturated, generally with a single double bond. The carbonyl group can.

  to intervene both in the saturated and unsaturated cycle or both. The carbonyl group is preferably carried by a saturated or unsaturated carbocycle having 5 or 6 carbon atoms.

  The ring (s) of this polycyclic compound may carry substituents. The number of substituents on each ring is generally from 1 to 3, preferably 1 or 2.

  The polycyclic, preferably bicyclic carbocyclic compound may comprise two unsaturated carbocycles, each preferably having 5 or 6 carbon atoms. There may be a carbonyl group on one of the two rings.

  In these polycyclic compounds, one or more carbon atoms, preferably two, may be replaced by a heteroatom, preferably a nitrogen or oxygen atom.

  The ring (s) of this polycyclic compound may carry substituents. The number of substituents on each ring is generally from 1 to 5, preferably 1 to 2.

  The polycyclic carbocyclic compound may comprise at least one aromatic carbocycle, preferably a benzene ring and a carbocycle preferably having from 4 to 7 carbon atoms and comprising one or two carbonyl groups.

  The polycyclic compound is preferably a bicyclic compound comprising a benzene ring and a carbocycle of 5 or 6 carbon atoms comprising one or two carbonyl groups.

  The two rings of this bicyclic compound may carry substituents.

  The number of substituents on each ring is generally 1 or 2. As mentioned above, there may be on one or more rings one or more substituents as long as they do not interfere with the reaction according to the process of the invention. invention.

  As examples of substituents, there may be mentioned a linear or branched alkyl or alkoxy group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, a benzylidene group optionally carrying a halogen atom.

  The cyclic ketones corresponding to formula (VII) preferably used in the process of the invention are chosen from: a saturated monocyclic ketone compound comprising a single carbonyl group, such as: cyclobutanone, cyclopentanone, 2-methylcyclopentanone, 3-methylcyclopentanone, 2-methyl-2-carboxymethylcyclopentanone-2,2-dimethylcyclopentanone, 2- (2-octenyl) -cyclopentanone, 2- (3,7-dimethyl-2,6-octadienyl) cyclopentanone, 2-cyclopentylidenecyclopentanone 2-Benzylidenecyclopentanone, 2 - [(p-chloro) benzylidene] cyclopentanone, 2-methyl-2-carboxymethyl-5 - [(p-chloro) benzylidene] cyclopentanone-2,4-dimethylcyclopentanone, 2,5-dimethylcyclopentanone, 3 4-dimethylcyclopentanone, 2,2,4-trimethylcyclopentanone, 5-methyl-2- (1-methylethylidene) -cyclohexanone, cyclohexanone, 3-methylcyclohexanone, 4-n-pentylcyclohexanone, 2-benzylidenecyclohexanone, 2- (N N, -dimethylamino) cyclohexanone, 3,5-dimethylcyclohexanone, dihy drocarvone, - cycloheptanone, cyclooctanone, - cycloheptadecanone, - a saturated monocyclic ketone compound comprising two carbonyl groups such as: - 1,3-cyclopentanedione - 2-allyl-2-methyl-1,3-cyclopentanedione, - 3,3-dimethyl -1,2cyclopentanedione, 3,4-dimethyl-1,2-cyclopentanedione, 1,2-cyclohexanedione, 1,3-cyclohexanedione, 1,4-cyclohexanedione, 1,2-cycloheptanedione, an unsaturated monocyclic ketone compound comprising a single carbonyl group, such as: - 2-cyclopentenone, 3-methyl-2-cyclopentenone, - 4,4-dimethyl-2-cyclopentenone, 2-pentyl-2-cyclopentenone, - 3-ethoxy-2-cyclopentenone, 2 3-hydroxy-3-ethyl-2-cyclopentenone, 2-hydroxy-3,4-dimethyl-2-cyclopentenone, 2-ethoxy-2-cyclohexenone, 3-bromo-2-cyclohexenone, carvone, 8-hydroxycarvotanacetone, 2-methyl-5- (1-methylethenyl) -2-cyclohexenone, 3,5,5-trimethyl-2-cyclohexenone, - methyl ester of abscisic acid, 2-hydroxy-3-methyl-6- (1- methylethyl) -2-cyclohexenone, 5-cycl ohexadécènone.

  an unsaturated monocyclic ketone compound comprising two carbonyl groups such as: - 2-cyclopentene-1,4-dione, 4-hydroxy-5-methyl-4-cyclopentene-1,3-dione, - a saturated bicyclic ketone compound comprising one or two carbonyl groups such as: camphor, norcamphor, 3-bromocamphor, 2,3-bornanedione, 1-decalone, 2-decalone, N- (ethoxycarbonyl) nortropinone, a saturated bicyclic / unsaturated ketone compound comprising one or two carbonyl groups such as: - bicyclo [3.2.0] hept-2-en-6-one, 1- (methoxymethyl) -bicyclo [2.2.0] hept-5-en-2-one, 3,4 , 8,8a-tetrahydro-8a-methyl-1,6 (2H, 7H) -naphtalènedione.

  an unsaturated bicyclic ketone compound comprising a carbonyl group, such as: 6,7-dihydro-cyclopenta-1,3-dioxin-5 (4H) -one 6,7-dihydro-1,1,2,3,3 4-pentamethyl-5 (5H) -indanone, 4-oxo-4,5,6,7-tetrahydroindole.

  a bicyclic ketone compound, one of which is aromatic, comprising one or two carbonyl groups, such as: 2-indanone, 2-methyl-1-indanone, 4-methyl-1-indanone, 4-methoxy- 1-indanone, 6-methoxy-1-indanone, 4-hydroxy-1-indanone, 5-bromo-1-indanone, 1,3-indanedione, 1-tetralone, 2-tetralone, 4-methyl -1-tetralone, 5,7-dimethyl-1-tetralone, 5-methoxy-1-tetralone, 6,7-dimethoxy-1-tetralone, 5-hydroxy-1-tetralone, levobunolol.

  Alicyclics, alicyclic or cyclic aldehydes, ketones or alicyclic ketones are in no way limiting to starting materials which may be used in the process of the invention.

  Of all the carbonyl compounds having the formula (VIl) or (VIII), those which are preferred are those of formula (VII) or (VIII) in which R1, R2 and R3 represent a hydrogen atom or an aliphatic group having from 1 to 12 carbon atoms, preferably a linear or branched alkyl group having 1 to 12 carbon atoms, preferably 1 to 4.

  Another class of substrates to which the process of the invention applies are the compounds of formula (IX) in which Z represents a nitrogen atom or a functional group comprising a nitrogen atom and which are represented by the formula ( IXa): R7 NH R4 (IXa) in said formula (IXa): - R4 has the meaning given above for R, - R7 represents: a hydrogen atom, a hydroxyl group, a group OR8 15. a hydrocarbon radical R8, a group of formula N R10 / R9 a group of formula - NH - C - NH2 N R1 with R8, R9, R10, and R11 which represent a hydrogen atom or a hydrocarbon group having from 1 to 30 carbon atoms.

  It should be noted that the invention also includes substrates which comprise several functional groups defined above and which can be derived from diketone compounds, the functional groups being in the α, β, γ or S position. The compounds used preferentially in the process of the invention more particularly correspond to the following formulas: OR8 R $

N N He He

HR4 HR4 (IXa1) (1Xa2) R9 NH2

N C N 10

NOT

NOT

  Embedded image in said formulas (IXa1) to (lXa4): - the radicals R4, R8 to R11 represent: a linear or branched alkyl radical having from 1 to 12 carbon atoms, a cycloalkyl radical having 5 to 12 carbon atoms, an aryl radical having 6 to 12 carbon atoms, an aralkyl radical having 7 to 12 carbon atoms, an aryl radical having 6 to 12 carbon atoms carrying substituents such as an alkyl or alkoxy radical having 1 to 4 carbon atoms, an amino, (C 1 -C 4) alkylamino or di (C 1 -C 4) alkylamino group, a nitro group, a halogen atom, a group ( C1-C4) alkoxycarbonyl, an aryl radical having 6 to 12 carbon atoms, a saturated or unsaturated heterocyclic radical, 15. an alkanoyl radical having 1 to 12 carbon atoms, an arylcarbonyl radical having 6 to 12 carbon atoms , an arylalkanoyl radical having from 6 to 12 carbon atoms, -R4 and R8, R4 and R10, R4 and R11 may form a carbocyclic or heterocyclic ring, substituted or unsubstituted, monocyclic or polycyclic, having from 5 to 6 atoms in each cycle.

  In the formulas (lXa1) to (lXa4), the radicals R4, R8 to R11, which may be identical or different, preferably represent: a linear or branched alkyl radical having from 1 to 4 carbon atoms, a cyclopentyl or cyclohexyl radical, and a radical phenyl is a benzyl or phenylethyl radical, a phenyl radical bearing substituents such as an alkyl or alkoxy radical having 1 to 4 carbon atoms, an amino, (C 1 -C 4) alkylamino or di (C 1 -C 4) alkylamino group, a nitro group, a halogen atom, a (C 1 -C 4) alkoxycarbonyl group, a naphthyl radical, a saturated or unsaturated oxygen or nitrogen heterocyclic radical with 5 or 6 atoms, an acetyl radical, a benzoyl radical, and a radical. arylalkanoyl having 6 to 12 carbon atoms, the compounds corresponding to the formula (IXai) are oxime type. Examples that may be mentioned include acetophenone oxime: ## STR2 ## Compounds of formula (1Xa 2) are imines. As more specific examples, there may be mentioned: as N-alkylketoimine-N-isobutyl-2-iminopropane N-isobutyl-1-methoxy-2-iminopropane as N-arylalkylketoimine N-benzyl-1-imino-1-phenyl ethane - N-benzyl-1-imino-1- (4-methoxypenyl) ethane - N-benzyl-1-imino-1 - (2-methoxyphenyl) ethane as N-arylketoimine - N-phenyl-2-iminopentane N - (2,6-Dimethylphenyl) -2-iminopentane N- (2,4,6-trimethylphenyl) -2-iminopentane-N-phenyl-1-imino-1-phenylethane-N-phenyl-1-methoxy-2- iminopropane N- (2,6-dimethylphenyl) -1-methoxy-2-iminopropane N- (2-methyl-6-ethylphenyl) -1-methoxy-2-iminopropane With regard to the compounds of formula (1Xa3), these are compounds of hydrazone type, optionally N-acylated or N-benzoylated, and there may be mentioned more particularly: 1-cyclohexyl-1- (2-benzoylhydrazono) ethane, 1-phenyl-1- (2-benzoylhydrazono) ) ethane, 1-p-methoxyphenyl-1- (2-benzoylhydrazono) ethane, 1-p-ethoxyphenyl-1- (2-benzoylhydraz) ono) ethane, 1-p-nitrophenyl-1- (2-benzoylhydrozono) ethane, 1-p-bromophenyl-1- (2-benzoylhydrozono) ethane, 1-p-carboethoxyphenyl-1- (2-benzoylhydrozono) ethane 1,2,6-diphenyl-1- (2-benzoylhydrozono) ethane, 1,2-d-phenyl-1- (2-benzoylhydrozono) ethane, 3-methyl-2- (2-p-dimethylaminobenzoylhydrazono) butane, 1-phenyl-1- (2-p-methoxylbenzoylhydrazono) ethane, 1-phenyl-1- (2-p-dimethylaminobenzoylhydrozono) ethane, ethyl-2- (2-benzoylhydrazono) propionate-methyl-2- (2-benzoylhydrazono) butyrate methyl-2- (2-benzoylhydrazono) valerate methyl-2-phenyl-2- (2-benzoylhydrozono) acetate The invention also includes the semi-carbazones of formula (1Xa4).

  Cyclic ketoimines with endo or exocyclic bond may also be mentioned as starting substrates and more particularly:

H

HNNNH

  CH3O CH3O N-CH2-COOCH3 SE CH3O CH3O

_CHO

  According to the invention, the selected reagents are used in the presence of the chiral compound of the invention.

  The molar ratio between the number of moles of the compound (A) and the number of moles of the compound (B) or (D) can vary widely between 1 and 100, and more preferably between 20 and 50.

  The reaction is conveniently carried out in an organic solvent. It may be any organic solvent, aprotic, polar or apolar.

  As preferred examples of solvents, mention may be made of aprotic, polar organic solvents and, more particularly, linear or cyclic carboxamides such as N, N-dimethylacetamide (DMAC), N, N-diethylacetamide and dimethylformamide (DMF). ), diethylformamide or 1-methyl-2-pyrrolidinone (NMP); dimethylsulfoxide (DMSO); hexamethylphosphoramide (HMPA), hexamethylphosphotriamide (HMPT); tetramethylurea; nitro compounds such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane or their mixtures, nitrobenzene; alpha or aromatic nitriles such as acetonitrile, propionitrile, butanenitrile, isobutanenitrile, benzonitrile, benzyl cyanide, tetramethylene sulfone (sulfolane), 1,3,5-dimethyl-3,4,5,6-tetrahydro- 2- (1, H) -pyrimidinone (DMPU).

  Better stereoselectivity is obtained by using dimethylformamide and even more particularly dimethylsulfoxide.

  Thus, a mixture of an aprotic solvent and of dimethylsulfoxide is advantageously chosen: the aprotic solvent may be one of the reactants, namely the ketone.

  A mixture of aprotic solvents, preferably ketone (A) and DMSO, is preferably chosen in proportions varying between (vlv) 0-100-50% / 100-0% but preferably 50-95% aprotic solvent. preferably ketone (A) and 5-50% DMSO.

  The reaction is carried out at a temperature between -78 ° C. and 50 ° C., preferably between 15 ° C. and 25 ° C.

  Generally, the reaction is conducted at atmospheric pressure but lower or higher pressures may also be suitable.

  It is not necessary to conduct the reaction under anhydrous conditions because the medium can withstand up to 5% by weight of water.

  From a practical point of view, the order of introduction of the reagents is indifferent. After contacting the reagents, the reaction mixture is brought to the desired temperature.

  At the end of the reaction, the desired product is obtained.

  The latter is recovered according to standard separation techniques, for example by extraction with the aid of a suitable organic solvent, for example ethyl acetate.

  It can also be recovered by crystallization, distillation or any other means, for example column chromatography.

  According to another embodiment of the invention, it is possible that the (3-aldol or p-ketol obtained in turn reacts with the aldehyde or ketone which is enolisable, namely the carbonyl compound which carries an atom The reaction can be carried out with or without separation of the intermediate product obtained.

EXAMPLES

  The following are examples of the preparation of the new chiral compounds of the invention as well as examples of aldolization reaction.

  In the examples, the transformation ratio (TT) corresponds to the ratio between the number of transformed substrates and the number of moles of substrate involved.

  The yield (RR) corresponds to the ratio between the number of moles of product formed and the number of moles of substrate engaged.

  The enantiomeric excess ee is the ratio of excess (R) excess (S) to excess (R) + excess (S).

Example 1

  In this example, the catalyst which will be used in Example 3 is prepared after deprotection carried out according to the procedure of Example 2.

  Condensation of L-proline protected with a CbZ group and (1S, 2S) 1, 2- (trifluoromethanesulfonamido) -2 (amino) -1,2-diphenylethane is carried out. In a 100 mL single-necked flask, 0.77 g (2.9 mmol, 1 eq) of commercial CbZ-L-proline in 15 ml of anhydrous THF of 0.3 g (2.9 mmol, 1 eq. .) triethylamine.

  The reaction mixture is brought to 0 ° C. and 0.32 g (2.9 mmol, 1.0 eq) of ethylchloroformate are added dropwise.

  The mixture is left stirring for 30 minutes and then 1.0 g (2.9 mmol, 1.0 eq.) Of a compound prepared according to Example 3 of WO 00/76942 (PCT / FR / 01662) are added to the reaction mixture. 5 mL of anhydrous THF and corresponding to the following formula: The temperature of the reaction mixture is then allowed to rise to 25 ° C. over 14 h and then refluxed for 3 h.

  After cooling, the solid is filtered in suspension, washed with 15 ml of ethyl acetate and then concentrated under reduced pressure.

  The residue obtained is then chromatographed on silica gel (heptane / ethyl acetate 1: 1) and 1.2 g (which corresponds to a yield of 75%) of a compound in the form of a solid are obtained. The following assays are as follows: H NMR (300 MHz, CDCl3): δ (ppm) 1.64-1.95 (m, 3H); 2.29-2.46 (m, 1H); 3.29-3.38 (m, 2H); 4.39-4.47 (m, 2H); 4.68 (t, 1H, J = 8.82 Hz); 4.98 (d, 1H, J = 12.81 Hz); 5.08-5.17 (m, 3H); 6.95-7.23 (m, 10H).

Example 2

  In this example, the deprotection of the nitrogen atom of the compound obtained according to Example 1 is carried out.

  In a steel reactor, 400 mg (0.7 mmol, 1 eq) of the compound of Example 1 are placed in 10 ml of anhydrous methanol.

  40 mg of Pd (OH) 2 are then added all at once.

  The reactor is placed under a hydrogen atmosphere (5 bar, 40 ° C.) for 4 hours. The solution is then filtered on celite and the volatiles are concentrated under reduced pressure.

  307 mg (which corresponds to a yield of: 92%) of a compound in the form of a pale pink solid which corresponds to the following formula are obtained: The analyzes are the following: H NMR (300 MHz CDCl3): δ (ppm) 1.52-1.60 (m, 2H); 1.77 (m, 1H); 2. 06 (m, 1H); 2.76-2.93 (m, 2H); 3.84 (m, 1H); 4.66 (d, 1H, J = 10.3 Hz); 5.18 (t, 1H, J = 11.0 Hz); 6.99-7.20 (m, 10H).

Example 3

  In this example, the compound prepared in Example 2 is used as a chiral catalyst for an aldolization reaction: 0.045 mmol of catalyst prepared according to Example 2 and 0.15 mmol are introduced into a 5 ml flask. of 4-nitrobenzaldehyde.

  With magnetic stirring, 1.5 ml of the chosen solvent mixture are added. It is then left with magnetic stirring at 25 ° C.

  Samples are taken to perform a follow-up in high performance liquid chromotography.

  After 24 hours, 5 ml of a saturated aqueous ammonium chloride solution are added.

  The organic phase is extracted with 3 x 5 mL of ethyl acetate and then dried over sodium sulfate, evaporated under reduced pressure.

The residue obtained is chromatographed on silica gel (Heptane / AcOEt 20 7/3) and the enantiomeric purity of the aldol is then measured by chiral HPLC. The results obtained are recorded in Table (I):

Table (I)

  Solvent composition TT (%) ee (%) (R) DMSO (%) Acetone (%) 0 100 100 40 80 100 80 65 100 85 50 20 88 35 10 90 20 10 92 These results clearly show the interest of use DMSO as a reaction cosolvent, compared to the reaction carried out in acetone alone. It is also relevant to use a solvent ratio that makes it possible to compromise the degree of conversion with the enantiomeric excess of the aldol formed.

  The best results with 35% DMSO have a TT of 100% and a decrease of 85%.

2865204 35

Example 4

  Example 3 is repeated but at a different temperature.

  The conditions and results are summarized in the following table: Table (II) Solvent composition Temperature Time TT (%) ee (%) (R) DMSO (%) Acetone (%) 65 25 C 12 h 100 85 65 0 C 24 h 100 93 65 -15 C 36 h 100 98

Example 5

  Example 4 is repeated at a temperature of 25 ° C but using the protected L-proline as described above and the diamine corresponding to the following formula: ## STR1 ## The results obtained are as follows: 32% -ee = 61%. (R)

Example 6

  Example 4 is repeated at a temperature of 25 ° C., but using the protected D-proline as described above and the diamine corresponding to the following formula:

HN F3C

  The results obtained are the following: - TT = 100% -ee = 80%. (S)

Examples 7 to 10

  In the examples which follow, a cross aldolisation reaction is carried out.

  In a first step, an aldol of the following formula is prepared: OH (A) in which Ra is defined in Table (III), by reacting the acetaldehyde with an aldehyde of the following formula: (B) In a second step, the final derivative of the following formula is prepared: ## STR2 ##

OH

  by reaction of the acetaldehyde with the aldol obtained (A).

1. Preparation of aldol (A).

  In a 10 ml flask under nitrogen, 0.09 mmol of catalyst prepared according to Example 1 and 0.3 mmol of purified MeCHO are introduced.

  With magnetic stirring, 3 ml of dimethylsulfoxide are added.

  This reaction mass is cooled to 0 ° C. and 0.3 mmol of RaCH 2 CHO maintained at a temperature of 0 ° C. is poured in 10 hours.

  It is then left under magnetic stirring at 0 C.

  Samples are taken in order to follow up in high performance liquid chromatography.

  After 24 hours of reaction at 0 ° C., 15 ml of a saturated aqueous NH4Cl solution are added.

  The organic phase is extracted with 3 × 15 mL of AcOEt, dried over Na 2 SO 4 and evaporated under reduced pressure.

H

O OH

  The residue obtained is chromatographed on silica gel (Heptane / AcOEt, 80/20) and the enantiomeric purity of the aldol is then measured by high performance liquid chromatography.

  The results are given in Table (III).

  2. Preparation of the final derivative (C).

  In a 10 ml flask under nitrogen, 0.09 mmol of catalyst prepared according to Example 1 and 0.10 mmol of purified MeCHO are introduced.

  With magnetic stirring, 3 ml of dimethylsulfoxide are added.

  This reaction mass is cooled to 0 ° C. and poured over 10 h, 0.10 mmol of aldol previously obtained, maintained at a temperature of 0 ° C. It is then left under magnetic stirring at 0 ° C. Samples are taken in order to achieve follow-up in high performance liquid chromatography.

  After 24 hours of reaction at 0 ° C., 20 ml of a saturated aqueous NH4Cl solution are added.

  The organic phase is extracted with 3 × 15 mL of AcOEt, dried over Na 2 SO 4 and evaporated under reduced pressure.

  The residue obtained is chromatographed on silica gel (Heptane / AcOEt, 80/20).

  The final derivative is obtained which is mainly in the cyclic form.

  The analyzes confirm the structure of this derivative.

Table (III)

  Ref. RaCH2CHO Aldol (A) Final derivative (C) ex. ee (Ph) CHO-CH2-CHO 95 93 8 Ph2P (O) -CH2-CHO 95 91 (ArO) 2 P (O) -CH2-CHO 92 91 Ar = 2-tert- butyl Ph

Claims (24)

  1 - Chiral compounds corresponding to the following formula (I): RZ in said formula: - A symbolizes a skeleton of general formula (F 1) or (F 2): (x) R "2 (Y) (F 1) (F 2) ) in the formulas (F 1) and (F 2): R 'and R "represent, independently of one another, a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated acyclic aliphatic group, linear or branched; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a sequence of the aforementioned groups; or R 'and R "may be linked so as to constitute, with the carbon atoms which carry them, a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated or aromatic, monocyclic or polycyclic, Ar, and Are symbolize, independently of one another, two aromatic, carbocyclic or heterocyclic rings, substituted or unsubstituted, condensed or not and bearing optionally one or more heteroatoms, x and y respectively identify the two bonds established between the skeleton symbolized by A and heteroatoms, CO = (G *) m H (I)   Rf represents a hydrocarbon group having from 1 to 20 carbon atoms optionally comprising at least one halogen atom, preferably a fluorine atom; - RZ represents one or more substituents on the pyrrolidinyl group, - G represents a group chiral, - W represents an oxygen atom or a RyN group in which Ry represents a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic group; a sequence of the aforementioned groups, - n represents the number of substituents on the ring, - m is an equal number from 0 to 3, preferably equal to 0 or 1, - ^^ "symbolizes a chiral bond, symbolizes a chiral bond or not.   2 - Compounds according to claim 1, characterized in that they correspond to the formula (I) in which RZ represents: a linear or branched alkyl group having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms; carbon, - a mono-, poly- or perhalogenated, linear or branched alkyl group preferably having from 1 to 6 carbon atoms and from 1 to 13 halogen atoms and even more preferentially from 1 to 4 carbon atoms and from 1 to at 9 halogen atoms, - a Re O- or thioether Rb-S- ether group in which Rb represents a linear or branched alkyl group having from 1 to 6 carbon atoms and even more preferably from 1 to 4 carbon atoms or the phenyl group, - an acyloxy or aroyloxy group Rb-CO-O- in which the Rb group has the meaning given above, - an acyl or aroyl group Rb-CO- in which the Rb group has the meaning given above, - a ester group -O-CO-Rb or -OOORb in which Rb has the meaning given above, - an amino group -N- (Rc) (Rd) in which Rd, Rd, identical or different, represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, - a amido group Rc-CO-NH- or (RC) (Rd) -N-CO- in which Rd, Rd, have the meaning given above, a hydroxyl group, a nitro group, a halogen atom, preferably, a fluorine atom.   3 - Compounds according to claim 2 characterized in that they correspond to the formula (I) wherein RZ represents: a linear or branched alkyl group preferably having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms; - an alkoxy group Re O- or thioether Rb-S- in which Rb represents a linear or branched alkyl group having 1 to 6 carbon atoms, - a CF3 group, - a hydroxyl group, - a hydrogen atom. halogen, preferably a fluorine atom.   4 - Compounds according to one of claims 1 to 3 characterized in that they correspond to the formula (I) wherein Rf represents: - a C 1 to C 4 alkyl group, preferably C 1 to C 4 , and more preferably a methyl or ethyl group, - a C, C, p, preferably C 1 to C 4, alkyl group, mono-, poly- or perhalogen having from 1 to 21 halogen atoms, preferably a CF 3 group, a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclohexyl group, an optionally mono-, poly- or perhalogenated cycloalkyl group having 3 to 8 carbon atoms, phenyl group, a mono-, poly-perhalogenated phenyl group, a phenyl group substituted with at least one C 1 -C 4, preferably C 1 -C 4, alkyl group, optionally mono-, poly-perfluogenated or a nitro or nitrile group; an optionally mono-, poly- or perhalogenated aryl group having from 6 to 12 carbon atoms.   - Compounds according to claim 4 characterized in that they correspond to the formula (I) in which Rf represents a CF3, C4F9 group or a phenyl group substituted with one or more halogen atoms, preferably fluorine, or by a or more mono-, poly- or perfluorinated C1-C2 alkyl groups.   6 - Compounds according to one of claims 1 to 5 characterized in that they correspond to the formula (I) wherein Ry represents: - a hydrogen atom, - an alkyl group, preferably C 1 to C 12, a C 2 -C 12 alkenyl or alkynyl group, a C 3 -C 12 cycloalkyl group or a C 6 -C 12 aryl or arylalkyl group.   7 - Compounds according to claim 6 characterized in that they correspond to the formula (I) in which Ry an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl.   8 - Compounds according to one of claims 1 to 7 characterized in that they correspond to formula (I) and they have on the pyrrolidine ring, an asymmetric carbon atom located at the α position of the imino group and a second chiral center is on the carbon atoms which carry the heteroatom O, N or N, N, or because of the presence of a chiral group G * present on an achiral ring, preferably benzene.   9 - Compounds according to claim 8 characterized in that the chiral G * group is a menthyl group, a proline group, methylbenzylamino, bornyl, isobornyl.   - Compounds according to one of claims 1 to 9 characterized in that they correspond to the general formula (lb): RZ   in which: Rf, Ry, RZ, (x), (y) are as defined above and Ar, and Ar2 together represent an aromatic group which may be a carbocycle having from 6 to 12 carbon atoms or a heterocycle having from 5 to 12 atoms, - at least one of the bonds (x) and (y) symbolized by ---- is a chiral bond.   11 - Compounds according to claim 10 characterized in that they correspond to the formula (Ib) in which Ar, and Ar2 together appear to be a diphenyl-2,2'-diyl group or a 2,2'-dinaphthyl group diyl.   12 - Compounds according to one of claims 1 to 9 characterized in that they correspond to the general formula (la): RZ NOT H RyN R '(x)', R " HN SO2   Rf (la) in which - Rf, Ry, RZ are as defined above in general formula (I), - R 'and R "represent, independently of each other, a saturated or unsaturated carbocyclic or heterocyclic group; or aromatic, monocyclic or polycyclic, - or R 'and R "may be bonded so as to constitute with the carbon atoms which carry them a carbocyclic or heterocyclic group having from 4 to 20 atoms, saturated, unsaturated, monocyclic or polycyclic, - at least one of the bonds (x) and (y) symbolized by ---- is a chiral bond.   13 - Compounds according to one of claims 1 and 12 characterized in that they correspond to the formula (I) or (la) wherein R 'and R ", identical or different, represent: - a saturated aliphatic acyclic group or unsaturated, linear or branched having 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms.   a linear or branched, saturated or unsaturated, acyclic aliphatic group may optionally carry a cyclic substituent, preferably a bezen cycle, a saturated carbocyclic group or comprising 1 or 2 unsaturations in the ring, having from 3 to 8 carbon atoms; carbon, preferably 6 carbon atoms in the ring; said ring being substitutable - an aromatic hydrocarbon group, preferably benzene, optionally substituted, - a polycyclic aromatic hydrocarbon group with the rings being able to form between them ortho-condensed, ortho- and peri-condensed systems, preferably a naphthyl group.   a heterocyclic group, saturated, unsaturated or aromatic, comprising 5 or 6 atoms in the ring, one or two of which are heteroatoms, preferably the nitrogen atoms (not substituted by a hydrogen atom), of sulfur and of oxygen; the carbon atoms of this heterocycle may also be substituted.   a polycyclic heterocyclic group defined as being either a group consisting of at least two aromatic or non-aromatic heterocycles containing at least one heteroatom in each ring and forming between them ortho- or ortho- and peri-condensed systems, or a group consisting of 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 can optionally be substituted.   14 - Compounds according to one of claims 1 and 12 characterized in that they correspond to the formula (I) or (la) wherein R 'and R "can be linked to represent carbocyclic or heterocyclic groups, mono- or poly-cyclic, saturated, unsaturated or aromatic, preferably the following cyclic groups: - Compounds according to one of claims 1 and 12 characterized in that they correspond to the formula (I) or (la) wherein R and R ", which are identical or different, both represent a phenyl group or are bonded together so as to form with the carbon atoms which carry them a cyclohexyl group.   16 - Compounds according to one of claims 1 and 12 characterized by the fact that they correspond to the following formula (Ic): RZ Rf   in said formula, Rf represents an alkyl group having 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted with an alkyl group having 1 to 10 carbon atoms, 1 to 5 fluorine atoms or a group trifluoromethyl, - RZ represents an alkyl group having from 1 to 10 carbon atoms, - Ra represents a hydrogen atom or an alkyl or alkoxy group having from 1 to 10 carbon atoms, a trifluoromethyl group, a nitro group, - Ry represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.   17 - Compounds according to one of claims 1 and 12 characterized in that they correspond to the following formula (Id): RZ in said formula, - Rf represents an alkyl group having 1 to 10 carbon atoms, a group phenyl, an alkyl-substituted phenyl group having 1 to 10 carbon atoms, 1 to 5 fluorine atoms or a trifluoromethyl group, - RZ represents an alkyl group having 1 to 10 carbon atoms, - Ra represents a hydrogen atom or an alkyl or alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, a nitro group, - Ry represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.   18 - Compounds according to one of claims 1 to 17 characterized in that they correspond to the following formula: - (2R) -pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2-diphenyl- 2-trifluoro-methanesulfonylaminoethyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, (2R) - acid pyrrolidine-2-carboxylic acid, (1S, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1S, 2S) - (1,2-diphenyl) 2-trifluoromethanesulfonylaminoethyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1R, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, C = ON N, Ry N - (2R) -pyrrolidine acid -2-Carboxylic acid, (1S, methanesulfonylaminoethyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylaminoethyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylamino ethyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1R, methan Estronylaminocyclohexyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylamino-cyclohexyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylaminocyclohexyl) amide, - (2S) - acid pyrrolidine-2-carboxylic acid, (1S, methanesulfonylamino-cyclohexyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylaminocyclohexyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylamino cyclohexyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylamino-cyclohexyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylaminocyclohexyl) amide, 19 - Preparation process a chiral compound of formula (I), preferably (la) to (Id) described in one of claims 1 to 18, characterized in that it is obtained by reacting: - the amino acid in protected form which is L- or D-proline or derivative that can be represented by the formula: RZ   in said formula, - P represents a protective group, - Re represents a hydrogen atom or an alkyl group preferably having from 1 to 4 carbon atoms, - R, has the meaning given above.   2R) - (1,2-diphenyl-2-trifluoro-25) - (1,2-diphenyl-2-trifluoro-2R) - (1,2diphiényl-2-trifluoro-2R) - (1,2-diphenyl 2trifluoro-2R) - (1,2-diphenyl-2trifluoro-2S) - (1,2-diphenyl-2trifluoro-2S) - (1,2-diphenyl-2trifluoro-2S) (1.2 (2-diphenyl-2-trifluoro-2R) - (1,2-diphenyl-2-trifluoro-2S) - (1,2-diphenyl-2-trifluoro-2R) - (1,2-diphenyl-2-trifluoro-) and a diamino compound or amino alcohol carrying a sulfonyl group corresponding to the following formula: HW (G *) m R f (IV) in said formula, A, W, Rf, G and m have the meaning given above.   - Process according to claim 19 characterized in that in the formula (IV), WH is preferably an OH or NH2 group.   21 - Process according to claim 19, characterized in that proline is used in the form of an ester, preferably an alkyl ester having from 1 to 4 carbon atoms. claim 19, characterized in that the hydrogen atom of the imino group of the pyrrolidine ring is blocked with a protecting group, preferably an acyl (acetyl, benzoyl), BOC (butyloxycarbonyl) group; ), cbZ (carbobenzoxy), FMOC (trifluoromethyloxycarbonyl) or MSOC (2-methanesulfenyl ethoxycarbonyl).   23 - Process according to claim 19 characterized in that it comprises: - a step of protecting the imino group of L- or D-proline or derivative, - a step of coupling said amino acid or derivative with a diamine or a aminoalcohol having the formula (IV).   a step of deprotection of the imino group.   24 - Method according to one of claims 19 to 23 characterized in that the coupling is performed in the presence of a coupling agent selected from: carbodiimides; cyanamides; keteneimines; isoxazolium salts; imidazolides, pyrazolides and 1,2,4triazolides; alkoxylated acetylene; ethyl or isobutyl chloroformate; nitrogenous heterocycles having a hydroxyl group on the nitrogen ring - Process according to claim 24, characterized in that the coupling agent is chosen from: N, N'-dicyclohexylcarbodiimide; N, N-dibenzylcyanamide; N-ethyl-5-phenylisoxazolium-3-sulfonate; N, N'-2865204 carbonyldiimidazole and N, N'-carbonyl-di-1,2,4-triazole; ethoxyacetylene; ethyl or isobutyl chloroformate; N-hydroxyphthalimide, N-hydroxysuccinimide and 1-hydroxybenzotriazole.   26 - Process according to claim 24 characterized in that the coupling agent is ethyl chloroformate or isobutyl.   27 - Method according to one of claims 19 to 26 characterized in that the coupling reaction is carried out by bringing into contact the amino acid and the diamine or the aminoalcohol, in the presence of a coupling agent in a solvent organic, preferably methylene chloride and tetrahydrofuran.   28 - Use of a chiral compound described in one of claims 1 to 18 in the field of asymmetric organic catalysis.   29 - Use of a chiral compound described in one of claims 1 to 18 to achieve aldolization or ketolization, asymmetric, intermolecular or intramolecular.   30 - Use of a chiral compound described in one of claims 1 to 18 for carrying out the reaction of two molecules of aldehyde, two molecules of ketone, an aldehyde molecule and a ketone molecule or an aldehyde or a ketone with an imine.   31 - Use according to claim 30 characterized in that the aldol or the ketol obtained reacts again with an aldehyde or ketone enolisable. 32 - Use according to one of claims 29 to 31 characterized in that the carbonyl compounds correspond to one of the formulas: RCOHC = 0 1 II R2 R (VII) or R3 (VIII) in said formulas (VII) and (VIII): R1 and R2, which are identical or different, represent: a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a linear or branched, saturated or unsaturated aliphatic group carrying a cyclic substituent; at least one carbon atom present in the group R2 or R3 in position a with respect to the carbonyl group carries at least one hydrogen atom, - R3 has the meaning given for R2, - R1 and R2 can be linked together to form a cycle leading to a cyclic ketone.