FR2877335A1 - USE OF AN AROMATIC CARBOXYLIC ACID IN AN ASYMMETRIC CATALYSIS REACTION - Google Patents

Abstract

The present invention relates to the use of an aromatic carboxylic acid in an asymmetric catalysis reaction involving, as catalysts, chiral compounds derived from a diamine or from an amino alcohol, monosulfonylated and carbonylated, carrying a pyrrolidinyl group. The invention relates more particularly to reactions of aldolization or asymmetric ketolization.

Description

2877335 1

  USE OF AN AROMATIC CARBOXYLIC ACID IN A

  ASYMMETRIC CATALYSIS REACTION USING

  CHIRAL COMPOUNDS DERIVED FROM A DIAMINE OR AN AMINOALCOOL, MONOSULFONYL AND CARBONYL CARRIERS OF A PYRROLIDINYL GROUP.

  The present invention relates to the use of an aromatic carboxylic acid in an asymmetric catalysis reaction involving as catalysts, chiral compounds derived from a diamine or a amino alcohol, monosulphonylated and carbonylated, carrying a pyrrolidinyl group.

  The invention more particularly relates to aldolization reactions or asymmetric ketolization.

  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 the R-position 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

  syn / erythro E Enantiomers are obtained in a racemic mixture if no asymmetric induction is performed.

  In the patent application FR No. 04 00551 filed in the name of Rhodia Chimie, there is described a new chiral reagent capable of controlling the stereochemistry of the OH group formed.

  The said chiral compounds correspond to the following formula (I): RZ

H

HN

SO

R F (I)

  in said formula: - A symbolizes a skeleton of general formula (FI) or (F2): CD (x) R 'O (Y) 2 (F1) (F2) in formulas (FI) and (F2): - R and R "independently of one another are a hydrocarbon group having 1 to 20 carbon atoms which may be a linear or branched saturated or unsaturated acyclic aliphatic group; a saturated, unsaturated or aromatic carbocyclic or heterocyclic group; monocyclic or polycyclic, a chain of the aforementioned groups - or alternatively, 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 or aromatic, monocyclic or polycyclic, - Art 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 identify respectively l 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, which may or may not comprise at least one halogen atom, preferably a fluorine atom, - RZ represents a or any substituent on the pyrrolidinyl group, - G is a chiral group, - W is an oxygen atom or a RyN group in which Ry is 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 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.

  Another subject of the invention of the application FR No. 04 00551 lies in the use of the chiral compound as defined above in the field of asymmetric organic catalysis and more particularly aldolization or ketolization, asymmetric intermolecular or intramolecular .

  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 described in FR No. 04 00551, an β-aldol is formed with control of the stereochemistry of the OH group formed by the reaction of an aldehyde or a ketone with another enolabelable aldehyde. presence of a chiral compound according to the invention.

  A p-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.

  Application FR 04 00551 also contemplates the formation of a ketoaminoketone 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 US Pat. invention.

  Continuing our research, the Applicant has found that it was possible to improve the yield and enantioselectivity of an asymmetric reaction, in particular an asymmetric aldolization or ketolization reaction by combining the chiral compound derived from a monosulfonylated and carbonylated diamine or aminoalcohol carrying a pyrrolidinyl group with a strong aromatic carboxylic acid.

  By aromatic carboxylic acid is meant a carbocyclic aromatic compound of which a hydrogen atom directly attached to the aromatic ring is replaced by a carboxylic group or the carboxylic group is carried by a side chain.

  In the following description of the present invention, the term "aromatic" is understood to mean the conventional notion of aromaticity as defined in the literature, in particular by Jerry MARCH, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, 1992, pp. 40 and following.

  The term "strong aromatic carboxylic acid" means a carbocyclic aromatic compound having a pka lower than the pka of benzoic acid, namely a pka of 4.2 measured in water at 25 ° C. The pka advantageously varies between 2 and 4. lower limit is not critical and can be exceeded.

  The aromatic carboxylic acid may be represented by the following formula: ## STR2 ## in which: B represents the residue of an aromatic carbocycle having from 6 to 14 carbon atoms; valency bond, an alkyl or alkenyl chain having 1 to 3 carbon atoms, - Rg, identical or different, symbolize the substituents on the aromatic ring and represent at least one electron-withdrawing group, 30 - q represents the number of substituents.

  Of the acids of formula (X), those which are preferred have the formula wherein B is a benzene or naphthalenic ring. B is more preferably a benzene ring.

  As regards S, it is more particularly a valency bond, a methylene, ethylene, propylene or an ethynylene group. S is preferably a valid link. (X)

  The aromatic carboxylic acid of formula (X) comprises an aromatic ring which may carry one or more substituents.

  The number of substituents present on the ring depends on the carbon condensation of the ring and the presence or absence of unsaturations on the ring.

  The maximum number of substituents likely to be borne by a ring is easily determined by those skilled in the art.

  In the present text, the term "several", generally, less than 4 substituents on an aromatic ring.

  q is preferably 1 or 2.

  The nature of the substituent or substituents symbolized by Rg can be very varied. Advantageously, it is desirable for Rg to represent at least one electron-withdrawing group.

  By electro-attractor group are meant groups as defined by H. C. BROWN in Jerry MARCH - Advanced Organic Chemistry, 4th Edition, John Wiley and Sons, 1992, Chapter 9, pp. 273 - 292.

  As examples of electron-withdrawing groups that may be present in the aromatic carboxylic acid, there may be mentioned, inter alia: a group of formula: COOR12 -CO-R13 -NO2

- CN

  -CO-NH-R12 - N + (R12) 3 - SO3R13 - SO2R13 - SO R13 -S-CF3

- Z -CF3

  - Cp F2p + 1 in said formulas, 35. the groups R12, which are identical or different, represent a hydrogen atom, a (C1-C12) alkyl group, (C2-C15) alkenyl or (C3-C8) cycloalkyl group; ), (C6-C18) aryl, (C7-C12) aralkyl; R13 has the meaning given for R12 and also represents alkyl, cycloalkyl, aryl substituted with one or more fluorine atoms; Z symbolizes a fluorine, chlorine or bromine atom, preferably a fluorine or chlorine atom; p represents a number ranging from 1 to 10.

  According to a preferred aspect of the present invention, the carboxylic aromatic acids used preferably correspond to the formula (X) in which Rg represents a group chosen from the groups of formula -CN, -SO2R13, -COOR12, perfluoroalkyl, -F, -NO2 where R12 and R13 represent an alkyl group and R13 also represents a perhalogenated alkyl group, preferably perfluorinated.

  Preferred examples of aromatic carboxylic acids include the following acids: - 2-nitrobenzoic acid - 3-nitrobenzoic acid - 4-nitrobenzoic acid - 2-bromobenzoic acid - 3-bromobenzoic acid - 4-bromobenzoic acid - 2-acid -fluorobenzoic acid 3-fluorobenzoic acid - 4-fluorobenzoic acid - 2-nitrocinnamic acid - 3,5-dinitrobenzoic acid - 5-hydroxy-4-nitrobenzoic acid - 2-nitro-5-aminobenzoic acid - 3-methylsulfonylbenzoic acid - 4- acid Methylsulfonylbenzoic acid Among the above-mentioned acids, 2-nitrobenzoic acid is preferred.

  According to the process of the invention, an aromatic carboxylic acid and a chiral catalyst as defined below are combined in an asymmetric catalysis reaction, preferably in an asymmetric aldolization or ketolization reaction, which reaction can be intermolecular or intramolecular.

  The process of the invention is applicable 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 0 + H (A) (B) (C)

O N H 1 + H

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): R 00 H C = O

I I

  R2 (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 an acyclic aliphatic group saturated or unsaturated, linear or branched; 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 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 the 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 valence bond or by one of the atoms or groups such as oxy, carbonyl, carboxy, sulfonyl, 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 groups R1, R2 and R3 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.

  As examples of carbonyl compounds used in the process of the invention, mention may be made inter alia of: saturated aliphatic aldehydes acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde, saturated aliphatic ketones acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, 2-pentanone, 3-pentanone, 2-carboxymethyl-3-pentanone-2-hexanone, 3-hexanone, 5-methyl-2-hexanone, 2-heptanone, 20-3-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 one ring - acetophenone 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) can therefore be a monocyclic or polycyclic compound.

  When it is a monocyclic compound, the number of carbon atoms 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 having 1 or 2 ring unsaturations, preferably 1 to 2 double bonds which are most often in the aa 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.

  The polycyclic, preferably bicyclic, carbocyclic compound may comprise two saturated carbocycles, 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 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 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 1 to 5, preferably 1 or 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 cycle is usually 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.

  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, dihydrocarvone, 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 1,2-Cyclopentanedione, 3,4-dimethyl-1,2-cyclopentanedione, 1,2-cyclohexanedione, 1,3-cyclohexanedione, 1,4-cyclohexanedione, 1,2-cycloheptanedione, a compound unsaturated monocyclic ketone 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-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-cyclohexadecenone.

  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 a or two carbonyl groups such as: camphor, norcamphor, 3-bromocamphor, 2,3-bornanedione, 1-decalone, 2-decalone, N- (ethoxycarbonyl) nortropinone, a saturated / unsaturated bicyclic 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.

  We have given above lists of aldehydes, alicyclic or cyclic ketones in no way limiting starting substrates may be implemented in the method of the invention.

  Of all the carbonyl compounds corresponding to formula (VII) or (VIII), those which are preferred are those of formula (VII) or (VIII) in which R 1, R 2 and R 3 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):

N H 'R4 (lXa)

  in said formula (IXa): - R4 has the meaning given above for R, - R7 represents: 5. a hydrogen atom, a hydroxyl group, a group OR8 a hydrocarbon group R8, a group of formula - NH - C - NH2

N R1t

  with R8, R9, R19, and R1 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 R8

N N

  Wherein R 4 H 4 R 4 (IXa 1) (IXa 2) R 9 NH 2 1 N / NR C N 10 N N 1 H R 4 HR 4 R 11 (1 x a 3) (IXa 4) in said formulas (IXa 1) to (lXa 4): R 9. a group of formula N 'R 10 - the groups R 4, R 8 to R 11 represent: a linear or branched alkyl group having from 1 to 12 carbon atoms, a cycloalkyl group having 5 to 12 carbon atoms, an aryl group having 6 to 12 carbon atoms, 5. an aralkyl group having 7 to 12 carbon atoms, an aryl group having 6 to 12 carbon atoms substituents such as an alkyl or alkoxy group 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, 10. an aryl group having 6 to 12 carbon atoms, a saturated or unsaturated heterocyclic group, an alkanoyl group having 1 to 12 carbon atoms, an arylcarbonyl group having 6 to 12 atoms of carbon, an arylalkanoyl group having from 6 to 12 carbon atoms, - R4 and R8, R4 and R10, R4 and R1 can form a carbocyclic or heterocyclic ring, substituted or unsubstituted, monocyclic or polycyclic, having 5 to 6 atoms in each cycle.

  In the formulas (XIa) to (IXa4), the groups R4, R8 to R11, which are identical or different, preferably represent: a linear or branched alkyl group having from 1 to 4 carbon atoms, a cyclopentyl or cyclohexyl group, a phenyl group a benzyl or phenylethyl group, a phenyl group bearing substituents such as an alkyl or alkoxy group having 1 to 4 carbon atoms, an amino group, (CIC4) alkylamino or di- ( C1-C4) alkylamino, a nitro group, a halogen atom, a (C1-C4) alkoxycarbonyl group, a naphthyl group, a saturated or unsaturated oxygen or nitrogen heterocyclic group with 5 or 6 atoms, an acetyl group, a group benzoyl, an arylalkanoyl group having from 6 to 12 carbon atoms. The compounds corresponding to formula (IXa1) are of the oxime type. Examples that may be cited include acetophenone oxime:

OH N CH3

  Compounds of formula (IXa2) are imines. As more specific examples, mention may be made of: 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-methoxyphenyl) ethane N-benzyl-1-imino-1- (2-methoxyphenyl) ethane 10. 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 (lXa3), 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-benzoylhydrozono) ethane, 1-p-methoxyphenyl-1- (2-benzoylhydrozono) ethane, 1-p-ethoxyphenyl-1- (2-benzoylhydrozono) ethane, 1 p-Nitrophenyl-1- (2-benzoylhydrozono) ethane, 1-p-bromophenyl-1- (2-benzoylhydrozono) ethane, 1-p-carboethoxyphenyl-1- (2-benzoylhydrozono) ethane, 1,2-d iphenyl-1- (2-benzoylhydrozono) ethane, 1,2-diphenyl-1- (2-benzoylhydrozono) ethane, 3-methyl-2- (2-pdimethylaminobenzoylhydrazono) butane, 1-phenyl-1- (2- p-Methoxylbenzoylhydrazono) ethane, 1-phenyl-1- (2-p-dimethylaminobenzoylhydrazono) ethane, ethyl-2- (2-benzoylhydrazono) propionate methyl-2- (2-benzoylhydrazono) butyrate methyl-2- (2-benzoylhydrazono) vatérate methyl-2-phenyl-2- (2-benzoylhydrazono) acetate The invention also includes semi-carbazones of formula (lXa4).

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

H

HNN, NH CH3O

CHO CH3O CH3O

  According to the invention, the selected reagents are used in the presence of the chiral compound of formula (I) combined with a strong aromatic carboxylic acid.

  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 amount of chiral compound of formula (I) expressed relative to the defect carbonyl reagent ranges from 0.01 to 0.3, preferably from 0.1 to 0.2.

  The amount of aromatic carboxylic acid is advantageously chosen so that the molar ratio between the chiral compound of formula (A) and the aromatic carboxylic acid varies between 0.8 and 1.2. The ratio is advantageously chosen close to stoichiometry, that is to say around 1. The reaction is advantageously 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; aliphatic or aromatic nitriles such as acetonitrile, propionitrile, butanenitrile, isobutanenitrile, benzonitrile, benzyl cyanide; ethers such as dioxane; tetramethylene sulfone (sulfolane), 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) pyrimidinone (DMPU); the aliphatic halides, preferably dichloromethane.

  Better stereoselectivity is achieved by using dimethylsulfoxide.

  A better conversion rate of the reactants is obtained by using acetonitrile, 1,4-dioxane and dichloromethane.

  Thus, a mixture of one of these aprotic solvents is advantageously chosen with an aprotic solvent which may be one of the reactants, namely the ketone.

  The reaction is carried out at a temperature of between -5 ° C. and 50 ° C., preferably between 15 ° C. and 25 ° C.

  It should be noted that the presence of the aromatic carboxylic acid makes it possible, at ambient temperature, to obtain a good yield and a high enantiomeric excess.

  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 since the medium can withstand up to 5% by weight of water.

  According to one embodiment of the invention, all the reagents can be mixed and then bring the reaction mixture to the desired temperature.

  According to a preferred embodiment of the invention, the chiral compound and the aromatic carboxylic acid are generally reacted at ambient temperature, most often between 15 ° C. and 25 ° C.

  Then, the reagent (s) carbonyl (s), aldehyde or ketone.

  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 α-aldol or the (3-ketol obtained in turn reacts with the aldehyde or ketone which is enolisable, namely the carbonyl compound which carries a a hydrogen atom on the carbon atom at the α-position of the carbonyl group The reaction may be carried out with or without separation of the intermediate product obtained.

  Thus, according to the process of the invention, it has been found that the yield and enantioselectivity of an asymmetric reaction are improved when a strong aromatic carboxylic acid is used.

Chiral compounds.

  The chiral compounds involved in the process of 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, by

benzene example.

  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 likely to be borne by a ring is easily 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, - the 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 group Rb has the meaning given above, - the acyl or aroyl groups Rb-CO- in which the Rb group 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 Rc, Rd, which are identical or different, represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, the amido groups Rc-CO-NH or (Rc) (Rd) -N-CO- in which in which Etc, 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 group Rb- O- or thioether Rb-S- in which Rb represents a linear or branched alkyl group having 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 from 1 to 20 carbon atoms and more particularly: a C1 -C10 alkyl group, preferably a C1 to C4 alkyl group, and more preferentially a group methyl or ethyl; - a C1-C10 alkyl group, preferably C1-C4, mono-, poly- or per- halogen having 1 to 21 halogen atoms, preferably a CF3 group, - a cycloalkyl group having from 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 phenyl mono- group, poly- or perhalogenated phenyl group substituted by at least one (1-4C) alkyl, preferably mono-, poly- or perhalogenated, or a nitro or nitrile group; an optionally mono-, poly- or perhalogenated aryl group having from 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 sulfonyl -SO 2 -Rf 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 - nonaflyls (nonafluorobutanesulfonyl) -SO2-C4F9 - tresyls (2,2,2-trifluoroethanesulfonyl) -SO2-CH2-CF3 Rf is more preferably 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, preferably a cycloalkyl group; at C3 to C12; 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 described in FR No. 04/00551, the preferred compounds of general formula (I) have the general formula (Ib) in which A represents a group of formula (F2): C = 0 i RN

H Y

(x) y.

  wherein: - Rf, Ry, RZ, (x), (y) are as defined above and Art and Are together an aromatic group which may be a carbocycle having from 6 to 12 carbon atoms 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 N-protected nitrogen atoms.

  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), mention may be made more particularly of those in which Art and Ar 2 are together either a diphenyl-2,2'-diyl group or a dinaphthyl-2,2'-diyl group. .

  In the case where Ar) and Ar2 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 C1-alkylthio group. C6, preferably C1 to C4: said groups are preferably in position 3 and 3 '.

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

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

RZ 1 H Rf

  in which - Rf, Ry, RZ are as defined above in general formula (I), - R 'and R "represent independently of each other a carbocyclic or heterocyclic, saturated, unsaturated or aromatic, monocyclic group 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 1 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 described in FR No. 04/00551 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 one another, an aromatic hydrocarbon group, and in particular a benzene group having the general formula (F3): (F3) in which: n' represents a number from 0 to 5, - Q represents a group chosen from: a linear or branched alkyl group having 1 to 6 carbon atoms, 10. a linear or branched alkoxy group having from 1 to 6 carbon atoms, a linear or branched alkylthio group with 1 to 6 carbon atoms, -NO 2, -CN, halogen, and CF 3.

  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 group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocyclic ring forming between them ortho- and peri-condensed ortho or systems, the carbon atoms of said rings possibly being substituted.

  As examples. heterocyclic groups R 'and R "include, inter alia, furyl, thienyl, isoxazolyl, furazanyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyranyl and quinolyl, naphthyridinyl, benzopyranyl, 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.

  As an illustration of this type of structure, mention may in particular be made of the following cyclic groups: ## STR2 ## Compounds of general formula (la) in which: R 'and R "are both phenyl, - R' 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): Rf in said formula, Rf represents an alkyl group having from 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.

  Another preferred class of reagents are those that meet the formula 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.

  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-trifluoromethanesulfonylaminoethyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1S, 2S) - ( 1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylaminoethyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylaminoethyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylamino-ethyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylamino-ethyl) amide, (2S) - acid pyrrolidine-2-carboxylic acid, (1S, methanesulfonylaminoethyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylaminocyclohexyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylamino - cyclohexy 1) Amido, (2R) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylaminocyclohexyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylamino-cyclohexyl) amide, - (2R) - acid pyrrolidine-2-carboxylic acid, (1R, methanesulfonylaminocyclohexyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1R, methanesulfonylaminocyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1S, methanesulfonylamino-cyclohexyl) amide, 25) - (1,2-diphenyl-2-trifluoro-2S) - (1,2-diphenyl-2-one) trifluoro-2R) - (1,2diphényl-2trifluoro-2S) - (1,2diphényl-2trifluoro-2R) - (1,2diphényl-2trifluoro-2R) - (1,2-diphenyl 2-trifluoro-2R) - (1,2-diphenyl-2-trifluoro-2S) (1,2-diphenyl-2-trifluoro-2S) - (1,2-diphenyl-2-trifluoro-2S) - (1 2-diphenyl-2-trifluoro-2R) - (1,2-diphenyl-2-trifluoro-2S) - (1,2-diphenyl-2-trifluoro-2R) - (1,2-diphenyl-2-trifluorone) Preparation of compounds chiral.

  The chiral compounds of formula (I), preferably (la) to (Id), can be obtained by reacting: the amino acid in protected form which is L- or D-proline or derivative which is can represent by the formula: Rz

P

  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, - RZ has the meaning given above.

  and a diamino compound or amino alcohol carrying a sulphonyl group corresponding to the following formula: ## STR3 ## in which formula A, W, Rf, G and m have the meaning given above.

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

  The invention described in FR No. 04/00551 contemplates the use of proline in the form of an ester, for example an 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 group Re 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 (acetyl, benzoyl), BOC (butyloxycarbonyl), Cbz (carbobenzoxy), Fmoc (9fluorenylmethoxycarbonyl) or MSOC (2-methanesulfenylethoxycarbonyl) groups. ).

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

  Thus, the process for preparing the chiral compounds of formula (I) comprises: a step of protecting the imino group of L- or D-proline or a derivative, a step of coupling said amino acid or derivative with a diamine or an 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 may 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, nitrogenous 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 preferentially ethoxyacetylene, - reagents such as ethyl chloroformate or isobutyl which forms a mixed anhydride with the function carboxyl of the amino acid; nitrogenous heterocycles having a hydroxyl group on the nitrogen ring such as, for example, N-hydroxyphthalimide, N-hydroxysuccinimide and 1-hydoxybenzotriazole.

  Among the various coupling agents mentioned above, the 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 described in FR No. 04/00551, the diamino or sulphonylated aminoalcoholic compound of formula (IV) can be obtained by reacting a compound supplying the SO 2 -Rf electron-withdrawing group and a diamine or an aminoalcohol of formula ( V): HW ,, (G *) m H2N (V) 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

  ZS - Re n 0 (VI) in said formula (VI): - Rf has the meaning given above, - Z represents: 20. a halogen atom, preferably a chlorine or bromine atom, a -O 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.

  As more particular examples of compounds of formula (VI), mention may be made in particular of: mesyl chloride, benzenesulfonyl chloride, tosyl chloride, trifluoromethanesulfonyl chloride, pentafluorobenzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl.

  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, - (IR, 2R) -1-amino-2- ( trifluoromethanesulfonamido) cyclohexane, - (1S, 2S) -1-amino-2- (pentafluorobenzene sulphonamido) cyclohexane, - (1R, 2R) -1-amino-2- (pentafluorobenzene sulphonamido) 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, - (1R, 2R) -1-amino-2- (methanesulfonamido) cyclohexane, - (1S, 2S) -1-amino-2- (benzenesulfonamido) cyclohexane.

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

  Configurations (IR, 2R) are preferred.

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

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

  It is possible to add a base, preferably a tertiary amine in order to trap the hydracid released.

  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 carried out 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 below.

  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) used 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.).

  From a practical point of view, all the reagents can be mixed in any order.

  Another mode of preparation 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 compound. 15

EXAMPLES

  Examples of embodiments of the invention are given below, but beforehand, the process for preparing the chiral compound which is then used in the process of the invention is specified.

  In the examples, the conversion ratio (TT) corresponds to the ratio between the number of moles of substrate transformed 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 the CbZ-protected L-proline and (1S, 2S) 1- (trifluoromethanesulfonamido) -2 (amino) -1,2-diphenylethane was carried out in a 100 ml monocolumn flask. magnetic stirring, 0.73 g (2.9 mmol, 1 eq) of commercial CbZ-L-proline in 15 mL of anhydrous THF of formula: 0.3 g (2.9 mmol, 1 eq.) are then added of 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: ## STR2 ## The temperature of the reaction mixture is then allowed to rise to 25.degree. 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. white which corresponds to the following formula: N i

Z N

  The analyzes are as follows: 1 H NMR (300 MHz, CDCl 3): 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); 6.95-723 (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 is 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:

N-H HN "

O_SO F3C

  The analyzes are as follows: 1 H NMR (300 MHz, CDCl 3): 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

  The catalyst prepared according to the preceding examples (2 mg, 0.1 eq.) And paranitrobenzaldehyde (7 mg, 0.0464 mmol) is introduced into a reactor under a nitrogen atmosphere before injecting 400 μl of acetonitrile.

  Ortho-nitrobenzoic acid (10 μl of a 8.6% solution in acetonitrile, 0.1 eq.) Is added followed by water (8 μl, 10 eq demineralized) and then acetone (50 μl). ).

  The system is sealed to best contain acetone and then stirred overnight.

  The mixture is concentrated under reduced pressure (about 20 mm Hg) and then analyzed by NMR.

  After purification by chromatography on silica gel (eluent: petroleum ether / ether 9/1 * 4/6), the aldolization product is obtained with a yield of -95% (9 mg).

  The enantiomeric excess (ee) is measured by high performance liquid chromatography on a normal phase chiral OD-H column with a hexane / methyl tert-butyl ether (60/40) eluent. It is 94%.

Examples 4-7

  The preceding example is repeated but using other aromatic carboxylic acids.

  The results obtained are recorded in Table (I).

Table (I)

  Ref. Example Nature of Acid Yield Carboxylic (%) Enantiomeric Excess (ee) 4 Acid 2- 95 92 Nitrocinnamic Acid 3,580 92 Dinitrobenzoic acid 6 5-Hydroxy-4-nitrobenzoic acid 7 7 2-nitro-5- 95 94 Aminobenzoic Acid By reproducing Example 3, without using a carboxylic acid but in the presence of just water, the following results are obtained: Yield = 95% - Excess enantiomeric ee = 70

Examples 8 to 12

  The operating procedure of Example 3 is repeated, but the aldehyde is varied.

  The results obtained are recorded in Table (II).

Table (II)

  Ref. Example Nature of the aldehyde Yield Excess (%) enantiomeric (ee) 8 2,6-dichlorobenzaldehyde 94 90 9 benzaldehyde 80 92 4-chlorobenzaldehyde 91 83 11 2-chlorobenzaldehyde 82 83 12 4-hydroxybenzaldehyde 25 74

Claims (29)

  1 - Use of a Strong Aromatic Carboxylic Acid in an Asymmetric Catalyst Reaction Using as Catalysts Chiral Derivatives Derived from a Monosulfonylated and Carbonylated Diamine or Amino Alcohol, Which Carry a Pyrrolidinyl Group   2 - Use according to claim 1 characterized in that the asymmetric reaction is an asymmetric, intermolecular or intramolecular aldolization or ketolization reaction.   3 - Use according to one of claims 1 and 2 characterized in that the chiral compound corresponds to the following formula (I): RZ in said formula: - A symbolizes a skeleton of general formula (FI) or (F2): R11 (Y) (FI) (F2) in formulas (FI) and (F2): - R 'and R "represent, independently of one another, a hydrocarbon group having 1 to 20 carbon atoms which can be a linear or branched saturated or unsaturated acyclic aliphatic group, a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group, a chain of the abovementioned groups, or R 'and R "may be linked so as to form with the carbon atoms which carry them a carbocyclic or (I) heterocyclic group having from 4 to 20 atoms, saturated, unsaturated or aromatic, monocyclic or polycyclic, Art and Are symbolize, independently of one another, two aromatic, carbocyclic rings; or heterocyclic If substituted or unsubstituted, condensed or not, and optionally bearing one or more heteroatoms, x and y respectively identify the two bonds established between the backbone symbolized by A and the heteroatoms. Rf represents a hydrocarbon group having from 1 to 20 carbon atoms, whether or not comprising at least one halogen atom, preferably a fluorine atom, - RZ represents one or more substituents on the pyrrolidinyl group, - G represents a chiral group, - W represents an oxygen atom or RyN wherein Ry is a hydrocarbon group having 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 abovementioned groups, - n represents the number of substituents on the ring, - m is an equal number ranging from 0 to 3, preferably equal to 0 or 1, - symbolizes a chiral bond, --- symbolizes a chiral bond or not.   4 - Use according to claim 3 characterized in that the chiral compound has the following formula (I) wherein RZ represents: - a linear or branched alkyl group having 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms, 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 preferably from 1 to 4 carbon atoms and from 1 to 9 halogen atoms, an Rb-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 atoms carbon or 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, an ester group -O-CO-Rb or -COORb in which Rb has the meaning given above, - an amino group -N- (Rc) (Rd) in which Rc, Rd, identical or different, represent a hydrogen atom or an alkyl group having from 1 to 6 atoms of carbon, - an amido group Rc-CO-NH- or (Rc) (Rd) -N-CO- in which Rc, Rd, have the meaning given above, - a hydroxyl group, - a nitro group, - a halogen atom, preferably a fluorine atom.   - Use according to claim 4 characterized in that the chiral compound has the following 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, - a Rb-O- alkoxy or thioether Rb-S- group in which Rb represents a linear or branched alkyl group having from 1 to 6 carbon atoms, - a CF3 group, - a hydroxyl group, - a halogen atom, preferably a fluorine atom.   6 - Use according to one of claims 3 to 5 characterized in that the chiral compound has the following formula (I) wherein Rf represents: - a C1 to C10 alkyl group, preferably C1 to C4i and more preferably a methyl or ethyl group, - a Ci-C 10 alkyl group, preferably a C 1 -C 4 alkyl group, mono-, poly- or perhalogenated having from 1 to 21 halogen atoms, preferably a CF 3 group, 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, - a phenyl group, - a phenyl group mono-, poly- or perhalogenated phenyl group substituted by at least one C1-C10, preferably C1-C4, optionally mono-, poly- or perhalogenated alkyl group or a nitro or nitrile group; an optionally mono-, poly- or perhalogenated aryl group having from 6 to 12 carbon atoms.   7 - The use as claimed in claim 6, characterized in that the chiral compound corresponds to the following 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 one or more mono-, poly- or perfluorinated C1-C2 alkyl groups.   8 - Use according to one of claims 3 to 7 characterized in that the chiral compound has the following formula (I) wherein Ry represents: 1 5 - a hydrogen atom, - an alkyl group preferably C1 C12, - a preferably C2-C12 alkenyl or alkynyl group, - a C3-C12 cycloalkyl group, - a C6-C12 aryl or arylalkyl group.   9 - Use according to claim 8 characterized in that the chiral compound has the following formula (I) wherein Ry represents an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl isobutyl, sec-butyl, tertbutyl.   - Use according to one of claims 3 to 9 characterized in that the chiral compound corresponds to formula (I) and that it has on the pyrrolidine ring, an asymmetric carbon atom located in position a 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.   11 - Use according to claim 10 characterized in that the chiral G * group is a menthyl group, a proline group, methylbenzylamino, bornyl, isobornyl.   12 - Use according to one of claims 3 to 11 characterized in that the chiral compound corresponds to the general formula (lb): wherein Rf, Ry, RZ, (x), (y) are as defined previously and Art 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.   13 - Use according to claim 12 characterized in that the chiral compound corresponds to the formula (Ib) in which Art and Ar2 together are a diphenyl-2,2'-diyl group or a 2,2'-dinaphthyl group -diyle.   14 - Use according to one of claims 3 to 11 characterized in that the chiral compound corresponds to the general formula (la): RZ (v), - \ HN 'R "SO2 R, f (la) in which - Rf, Ry, RZ are as defined above in general formula (I), (Y HN ' IF Rf   - R 'and R "represent, independently of one another, a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group, - or R' and R" may be bonded so as to constitute with the carbon atoms which carries 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.   15 - Use according to one of claims 3 to 14 characterized in that the chiral compound corresponds to formula (I) or (la) wherein R 'and R ", identical or different, represent: - an acyclic aliphatic group saturated 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.   16 - Use according to one of claims 3 to 14 characterized in that the chiral compound corresponds to formula (I) or (la) wherein R 'and R "can be linked to represent carbocyclic or heterocyclic groups, mono or polycyclic, saturated, unsaturated or aromatic, preferably the following cyclic groups: Use according to one of Claims 3 to 14, characterized in that the chiral compound corresponds to formula (I) or (la) in which R 'and R ", which are identical or different, both represent a phenyl group or are linked together so as to form, with the carbon atoms which carry them, a cyclohexyl group.   18 - Use according to one of Claims 3 to 11, characterized in that the chiral compound corresponds to the general 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.   19 - Use according to one of claims 3 to 11 characterized in that the chiral compound corresponds to the general formula (Id): RZ H   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.   - Use according to one of claims 3 to 19 characterized in that the chiral compound has the following formula: - (2R) -pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2-d-phenyl) 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, 25) - (1,2-diphenyl) 2-trifluoromethanesulfonylaminoethyl) amide, (2R) -pyrrolidine-2-carboxylic acid, (1R, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, ( 1S, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl) 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-trifluoro) thanesulfonylamino-ethyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-acid carboxylic acid, (1R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1S, 25) - (1,2-d) -phenyl-2-trifluoromethanesulfonylamino -cyctohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1S, 25) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, ( 1R, 25) - (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-2trifluorométhanesulfonylamino-cyclohexyl) amide.   21 - Use according to one of claims 1 to 20 characterized in that the strong aromatic carboxylic acid has a pka less than 4.2, preferably between 2 and 4.   22 - Use according to claim 2: 1 characterized in that the aromatic carboxylic acid has the following formula: (Rg) q S --COOH (X) in said formula: - B represents the rest of an aromatic carbocycle having 6 to 14 carbon atoms, - S symbolizes a valence bond, an alkyl or alkenyl chain having 1 to 3 carbon atoms, - Rg, identical or different, symbolize the substituents on the aromatic ring and represent at least one group electro-attractor, - q represents the number of substituents.   23 - Use according to claim 22 characterized in that the aromatic carboxylic acid corresponds to the formula (X) wherein B represents a benzene or naphthalenic ring, preferably a benzene ring.   24 - Use according to one of claims 22 and 23 characterized in that the aromatic carboxylic acid corresponds to the formula (X) wherein S represents a valency bond, a methylene group, ethylene, propylene or an ethynylene group preferably a valential link.   - Use according to one of claims 22 to 24 characterized in that the aromatic carboxylic acid of formula (X) comprises an aromatic ring bearing at least one electron-withdrawing substituent.   26 - Use according to claim 25 characterized in that the electron-withdrawing group is: - a group of formula: - COOR12 -CO-R13 NO2 - CN   -CO-NH-R12 -N + (R12) 3 -S03R13 -SO2R13 -SO R13 -S-CF3 -z-CF3 -Cp F2p +1 in said formulas, 35. R12 groups, which are identical or different, represent an atom of hydrogen, (C1-C12) alkyl, (C2-C15) alkenyl, (C3-05) cycloalkyl, (C6-C15) aryl, (C7-C12) aralkyl; R13 has the meaning given for R12 and also represents alkyl, cycloalkyl, aryl substituted with one or more fluorine atoms; Z symbolizes a fluorine, chlorine or bromine atom, preferably a fluorine or chlorine atom; p represents a number ranging from 1 to 10.   27 - Use according to one of claims 22 to 26 characterized in that the aromatic carboxylic acid corresponds to the formula (X) wherein Rg represents a group selected from groups of formula -CN, -SO2R13, COOR12, perfluoroalkyl , -F, -NO2 where R12 and R13 represent an alkyl group and R13 also represents a perhalogenated alkyl group, preferably perfluorinated.   28 - Use according to one of claims 22 to 27 characterized in that the aromatic carboxylic acid is selected from the following acids: - 2-nitrobenzoic acid - 3-nitrobenzoic acid - 4-nitrobenzoic acid - 2-bromobenzoic acid - 3-bromobenzoic acid - 4-bromobenzoic acid - 2-fluorobenzoic acid - 3-fluorobenzoic acid 4-fluorobenzoic acid - 2-nitrocinnamic acid - 3,5-dinitrobenzoic acid - 5-hydroxy-4-nitro benzoic acid - 2-nitro acid 5-aminobenzoic acid - 3-methylsulfonylbenzoic acid - 4-methylsulfonylbenzoic acid 29 - Use according to one of claims 22 to 28, characterized in that the aromatic carboxylic acid is 2-nitrobenzoic acid.   - Use according to one of claims 1 to 29 characterized in that the molar ratio between the chiral compound of formula (I) and the aromatic carboxylic acid varies between 0.8 and 1.2, and is preferably at around 1.   31 - Use according to one of claims 1 to 30 characterized in that it is reacted with two molecules of aldehyde, two molecules of ketone, an aldehyde molecule and a molecule of ketone or an aldehyde or a ketone with an imine.   32 - Use according to claim 31 characterized in that the aldol or ketol obtained reacts again with an aldehyde or ketone enolisable.   33 - Use according to one of claims 31 and 32 characterized in that the carbonyl compounds correspond to one of the formulas: RCOHCO R2 (VII) or R3 (VIII) in said formulas (VII) and (VIII): - R1 and R2, which are identical or different, represent: a hydrocarbon group having 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 may be bonded together to form a cyclic ketone ring.   Process for the preparation of an aldol or a ketol by reaction of two molecules of aldehyde, two molecules of ketone, an aldehyde molecule and a ketone molecule characterized in that the reaction has in the presence of a chiral compound of formula (I) and a strong aromatic carboxylic acid described in any one of claims 21 to 29.   - Process according to claim 34, characterized in that the amount of chiral compound corresponding to the formula (I) expressed relative to the carbonyl reagent in default varies between 0.01 and 0.3, preferably between 0.1 and 0. 2.   36 - Process according to one of claims 34 and 35 characterized in that the molar ratio between the chiral compound of formula (A) and the aromatic carboxylic acid varies between 0.8 and 1.2 and is preferably at around 1.   37 - Method according to one of claims 34 to 36, characterized in that the reaction is conducted at a temperature between -5 C and 50 C, preferably between 15 C and 25 C.   38. Process according to one of claims 34 to 37, characterized in that the reaction is carried out in an organic solvent, preferably dimethylsulfoxide, acetonitrile, 1,4-dioxane and dichloromethane.