WO2006048546A1

WO2006048546A1 - Use of an aromatic carboxylic acid in an asymmetric catalysis reaction

Info

Publication number: WO2006048546A1
Application number: PCT/FR2005/002717
Authority: WO
Inventors: Istvan Marko; Michaël DE PAOLIS; Gérard Mignani
Original assignee: Shasun Pharma Solutions Limited; Universite Catholique De Louvain
Priority date: 2004-11-03
Filing date: 2005-10-28
Publication date: 2006-05-11
Also published as: FR2877335A1

Abstract

The invention relates to the use of an aromatic carboxylic acid in an asymmetric catalysis reaction. More particularly, the use of an aromatic carboxylic acid in an asymmetric catalysis reaction with, as catalysts, chiral monosulphonylated and carbonylated derivatives of a diamine or an aminoalcohol, with a pyrrolidinyl group. The invention particularly relates to asymmetric aldolisation and ketolisation reactions.

Description

USE OF AN AROMATIC CARBOXYLIC ACID IN AN ASYMMETRIC CATALYSIS REACTION.

The present invention relates to the use of an aromatic carboxylic acid in an asymmetric catalysis reaction.

More specifically, the invention relates to the use of an aromatic carboxylic acid in an asymmetric catalytic reaction involving as catalysts, chiral compounds derived from a diamine or a amino alcohol, monosulfonylated and carbonylated, carriers of 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 we find 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 β-position relative 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:

The enantiomers are obtained in a racemic mixture if no asymmetric induction is performed. In the patent application FR No. 04 00551 or WO 2005/080299 filed in the name of Rhodia Chimie, a new chiral reagent has been described capable of controlling the stereochemistry of the OH group formed.

Said ante compounds (I):

in said formula:

- A symbolizes a skeleton of general formula (Fi) or (F ₂ ):

in formulas (Fi) 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, linear acyclic aliphatic group; or branched, a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a chain of the aforementioned groups; or alternatively, 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 1 and Ar _{2 represent} , 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 locate the two links established between the skeleton symbolized by A and the heteroatoms, R _f 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,

- R ₂ represents one or more substituents on the pyrrolidinyl group,

G represents a chiral group,

- W represents an oxygen atom or a group R _y N wherein R _y represents 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 aforementioned groups,

n represents the number of substituents on the cycle,

m is an equal number ranging from 0 to 3, preferably equal to 0 or 1.

- - → ^h symbolizes a chiral bond, - - symbolizes a chiral bond or not.

Another object of the invention of the application FR No. 04 00551 or WO 2005/080299 resides 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 in the α position of the carbonyl group . A bond is created between the carbon atom of the carbonyl group and the carbon atom in the α position of the carbonyl group.

Thus, in accordance with the process of the invention described in FR No. 04 00551 or WO 2005/080299, a β-aldol is formed with control of the stereochemistry of the OH group formed by reaction of an aldehyde or a ketone, with another ^~ enaldehyde aldehyde, in the presence of a chiral compound according to the invention.

A β-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. ^"~" Patent application FR No. 04 00551 or WO 2005/080299 also contemplates the formation of a β-aminoketone with control of the stereochemistry of the amino group formed by reaction of an enolizable aldehyde or an enolizable ketone with an imine in the presence of a chiral compound according to the invention. Continuing our research, the Applicant has found that it is possible to improve the yield and enantioselectivity of an asymmetric reaction, in particular of 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 discussion of the present invention, the term "aromatic", the classical 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. By "strong aromatic carboxylic acid" is meant a carbocyclic aromatic compound having a pk _a less than pk _a benzoic acid, namely a pk _a of 4.2 measured in water at 25 ° C.

The pk _a advantageously varies between 2 and 4. The lower limit is not critical and can be exceeded. The aromatic carboxylic acid may be represented by the following formula:

in said formula:

B represents the remainder of an aromatic carbocycle having from 6 to 14 carbon atoms,

S symbolizes a valency bond, an alkyl or alkenyl chain having from 1 to 3 carbon atoms,

- R _9, identical or ^~ ^{^"different,"} symbolize the substituents on the aromatic ring and represent at least one electron withdrawing group, - 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. 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 R ₉ can be very varied. Advantageously, it is desirable for R _{9 to} represent at least one electron-withdrawing group.

The term "electron withdrawing group" group as defined by HC BROWN in the work by 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, mention may be made inter alia of: a group of formula:

-COORi ₂ -CO-R ₁₃ -NO ₂ -CN -CO-NH-R ₁₂

-SO ₃ R ₁₃ -SO ₂ R ₁₃ -SO R ₁₃ -S-CF ₃

-Z

-CF ₃

-Cp F _2p + 1

. in said formulas,. the groups R ₁₂ , which are identical or different, represent a hydrogen atom, a (C ₁ -C ₁₂ ) alkyl group, (C ₂ -C ₁ S) alkenyl, (C ₃ -C ₈ ) cycloalkyl, aryl (C ₆ -C ₁₈ ), (C ₇ -C ₁₂ ) aralkyl; . R ₁ has the meaning given for R ₁ and also represents an alkyl, cycloalkyl or aryl group substituted by 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 R ₉ represents a group chosen from groups of formula -CN, -SO ₂ R 13, -COOR 1 ₂ , perfluoroalkyl, F, -NO ₂ where R12 and R13 represent an alkyl group and R ₁₃ also being an alkyl perhalogenated, 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-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-methylsulfonylbenzoic acid Of 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:

(A) (B) (C)

(A) (D) (E)

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 precisely, the compounds (A) and (B) carbonyl may be represented by the formulas (VII) or (VIII):

R-C = O H - C = O i i

R, R,

(VII) or (VIII) in said formulas (VII) and (VIII):

R ₁ and R ₂ , 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 R ₂ or R ₃ in position α with respect to the carbonyl group carries at least one atom, hydrogen,

R ₃ has the meaning given for R ₂ ,

- R ₁ and R ₂ can be bonded together to form a cycle leading to a cyclic ketone. In formulas (VII) and (VIII), R ₁ , R ₂ and R ₃ 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 single or conjugated double bonds.

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 insofar as they do not react under the reaction conditions and may be mentioned in particular a nitrile group, a nitro group or a trifluoromethyl group or a (Ph) _{2 group} . PO- or a group (PhO) ₂ -PO- or equivalent.

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 groups R ₁ , R ₂ and R ₃ may also represent a cyclic hydrocarbon group, saturated or unsaturated, preferably having 5 or 6 carbon atoms in the cycle ; 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,

methylisopropylketone,

- methyl isobutyl ketone,

- 2-pentanone,

3-pentanone, 2-carboxymethyl-3-pentanone

2-hexanone,

3-hexanone,

5-methyl 2-hexanone,

2-heptanone, 3-heptanone,

- 4-heptanone,

- 2-octanone,

- 3-octanone,

- diisobutylketone, - 5-methyl-2-octanone

- 2-nonanone,

2,6,8-trimethyl-4-nonanone

- ketones carrying a functional group

1,3-dihydroxy-2-propanone, diacetone alcohol,

- triacétonedialcool,

4-methoxy-4-methyl-2-pentanone,

- (diphenylphosphinoyl) acetaldehyde, 2- (diphenylphosphinoyl) propanal, - unsaturated aliphatic ketones

mesityl oxide,

3-butene 2-one,

4-methyl-4-pentene-2-one, - ketones carrying a cycle

- acetophenone

In formula (VII), R ₁ and R ₂ may be linked to form a ring comprising at least one carbonyl group. Thus, the compound of formula (VII) can be:

a monocyclic, carbocyclic, saturated or unsaturated ketone compound,

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 may be replaced by a heteroatom,

a polycyclic ketone compound comprising at least two carbocycles, one of which 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 comprising 1 or 2 unsaturations in the ring, preferably 1 to 2 double bonds which are most often in the α position of the carbonyl group.

The saturated or unsaturated carbocycle may carry substituents. The number of substituents on each ring can vary widely from 1 to 5. It is generally 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 the presence of a carbonyl group on one or ^"" the two cycles. 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 cycle is usually 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 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 or 2. The polycyclic carbocyclic compound may comprise at least one aromatic carbocycle, preferably a benzene ring and a carbocycle having preferably from 4 to 7 carbon atoms. carbon and comprising one or two carbonyl groups.

The polycyclic compound is preferably a bicyclic compound comprising a benzene ring and a 5- or 6-carbon bonded carbocycle 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 can 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, ^~ ^ dihYd7ocârvone,

cycloheptanone

cyclooctanone

cycloheptadecanone,

a saturated monocyclic ketone compound comprising two carbonyl groups such that:

- 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,

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-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 that:

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 / 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) -naphthalenedione.

a bicyclic ketone compound. unsaturated 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-pentamethyl-4 (5H) -indanone, 4- 0X0-4,5,6,7-tetrahydroindole.

a ketone 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. ^"Pirrnftous carbonyl compounds ^~ of formula (VII) or (VIII), those which are preferred are those of formula (VII) or (VIII) wherein R _1, R ₂ and R ₃ represent a hydrogen atom or an aliphatic group having 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 is compounds of formula (IX) in which Z represents a nitrogen atom or a functional group comprising a nitrogen atom and which are represented by formula (IXa): NOT

H ^A R4

(IXa) in said formula (IXa):

R ₄ has the meaning given above for R ₁

R7 represents: a hydrogen atom,

. a hydroxyl group, a group ORs. a hydrocarbon group Ra,

. a group of formula - N ^R io

. a group of formula - NH - C - NH ₂

II

NOT

with R ₈ , R ₉ , R ₁₀ , and R ₁₁ 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 may be derived from diketone compounds, the functional groups being in position α, β, γ or δ.

The compounds preferably used in the process of the invention more particularly correspond to the following formulas:

° R ₈ R ₈

N N

H R, H A. R,

in said formulas (IXa ₁ ) to (IXa ₄ ): the groups R ₄ and R ₈ ER _{1 1} represent:

. a linear or branched alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 5 to 12 carbon atoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms,

. an aryl group having 6 to 12 carbon atoms carrying substituents such as an alkyl or alkoxy group having 1 to 4 carbon atoms, amino, (C- _| -C ₄₎ alkylamino or DKC-iC ^ alkylamino , a nitro group, a halogen atom, a (C ₁ -C ₄ ) alkoxycarbonyl group, an aryl group having from 6 to 12 carbon atoms,

. a saturated or unsaturated heterocyclic group, an alkanoyl group having 1 to 12 carbon atoms, an arylcarbonyl group having from 6 to 12 carbon atoms, an arylalkanoyl group having from 6 to 12 carbon atoms, - R ₄ and R ₈ , R ₄ and R ₁₀ , R ₄ and R ₁₁ 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 (IX- _j ) to (IXa ₄ ), the groups R ₄ , R ₈ to R ₁₁ , which may be 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 from 1 to 4 carbon atoms, an amino group, (C ₁ -

C ₄₎ alkylamino or di- (C- | -C ₄₎ alkylamino, nitro, a halogen atom, a (C- _| -C ₄₎ alkoxycarbonyl,. a naphthyl group,. a saturated or unsaturated oxygen or nitrogen heterocyclic group with 5 or 6 atoms,

. an acetyl group, a benzoyl group,

. an arylalkanoyl group having from 6 to 12 carbon atoms,

The compounds corresponding to formula (IXa ₁ ) are of the oxime type. As examples, acetophenone can be used:

Compounds of formula (IXa2) are imines. As more specific examples, mention may be made of: as N-alkylketoimine

- N-isobutyl-2-iminopropane

5-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 15-N-phenyl-1-methoxy-2-iminopropane

N- (2,6-dimethylphenyl) -1-methoxy-2-iminopropane

N- (2-methyl-6-ethylphenyl) -1-methoxy-2-iminopropane

As regards the compounds of formula (IXaβ), they are compounds of the hydrazone type, optionally N-acylated or N-benzoylated, and there may be mentioned more particularly:

1-cyclohexyl-1- (2-benzoylhydrozono) ethane,

1-phenyl-1- (2-benzoylhydrazono) ethane,

1-p-methoxyphenyl-1- (2-benzoylhydrozono) ethane,

1-p-ethoxyphenyl-1- (2-benzoylhydrozono) ethane, 25-1-p-nitrophenyl-1- (2-benzoylhydrozono) ethane,

1-p-bromophenyl-1- (2-benzoylhydrozono) ethane,

- 1 -p-carboéthoxyphényl-1 - (2-benzoylhydrazono) ethane, - 1, 2-diphenyl-1- (2-benzoylhydrazono) ethane, - 1, 2-diphenyl-1- (2-benzoylhydrazono) ethane, ^"30 ^^ τiéthyl-2- (2-p-diméthylaminobenzoylhydrazono) 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 35-methyl-2- (2-benzoylhydrazono) valerate

- methyl-2-phenyl-2- (2-benzoylhydrazono) acetate

The invention also includes the semi-carbazones of formula (IXa ₄ ). Cyclic ketoimines with endo or exocyclic bond may also be mentioned as starting substrates and more particularly:

A preferred application of the process of the invention is to react an α, β-unsaturated aldehyde with a ketone or a β-ketoester such as, for example, an alkyl acetoacetate, thus making it possible to manufacture "statin" chains.

Thus, an example of a reaction is given. A compound (Ai) of formula (IX) and a compound (B-i) of formula (X) can be reacted:

in said formulas:

- R _m and R _n , identical or different, represent a hydrogen atom or an alkyl group having 1 to 6 atoms or an aryl group having 6 to 12 carbon atoms, preferably an optionally substituted phenyl group, an aralkyl group; having 7 to 12 carbon atoms, preferably a benzyl group,

- R _p has the meaning given for R _m or R _n .

- R _q has the meaning given for R _m or R _n or a group -CO-ORt, Rt having the meaning given for R _m or R _n .

X represents a halogen atom or an electron-withdrawing group, preferably a trichloromethyl, trifluoromethyl or a group

. . SPh ₁ SOPh ₁ SO ₂ Ph.

By halogen atom is meant a fluorine, chlorine, bromine or iodine atom, preferably a chlorine or bromine atom.

X also represents an electro-attracting group by inductive and / or mesomeric effect. Preferred compounds (Ai) include those of formula (IX) wherein Rm represents a hydrogen atom; R _n represents a phenyl group optionally substituted in particular by alkyl or alkoxy groups having

1 to 4 carbon atoms or a nitro group and X represents a bromine or chlorine atom.

As regards the preferred compounds (Bi), mention may be made of alkyl acetoacetates having 1 to 4 carbon atoms, preferably tert-butyl.

According to the invention, the selected reagents are used in the presence of the chiral compound of formula (I) associated 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 corresponding to the formula (I) expressed with respect to the defective carbonyl reagent varies between 0.01 and 0.5, preferably between 0.2 and 0.4.

The amount of aromatic carboxylic acid is advantageously chosen such that the molar ratio between the chiral compound of formula (I) and the aromatic carboxylic acid varies between 0.8 and 3. The ratio is advantageously chosen close to the stoichiometry c that is, around 2.

The reaction is conducted in the absence of a solvent, one of the excess reagents being able to serve as a solvent. It is also possible to use an organic solvent. It is preferably an aprotic polar organic solvent. As preferred examples of solvents, mention may be made of aprotic, polar organic solvents and mention may be made more particularly of linear or cyclic carboxamides, such as Λ, Λ-dimethylacetamide (DMAC), Λ /, Λ-diethylacetamide, dimethylformamide (DMF), diethylformamide or 1-methyl-2-pyrrolidinone (NMP); dimethylsulfoxide (DMSO) π'hexaméthyfphôsphôramide ^"(HMPA), hexamethylphosphotriamide (HMPT); tetramethylurea; nitro compounds such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane or mixtures thereof, nitrobenzene; aliphatic or aromatic nitriles such as acetonitrile, propionitrile, butanenitrile, isobutanenitrile, benzonitrile, benzyl cyanide; ethers such as the ^"dioxane; tetramethylene sulfone (sulfolane), 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (DMPU); the aliphatic halides, preferably dichloromethane. The amount of organic solvent used is generally such that the concentration of carbonyl reagent in default varies between 0.05 and 5 moles / liter.

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 β-aidol or the β-ketol obtained in turn reacts with the aldehyde or ketone which is enolisable, namely the carbonyl compound which carries a carbon atom. hydrogen on the carbon atom in the α position of the carbonyl group. The reaction can 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 characteristic is the presence on the pyrrolidine ring of an asymmetric carbon atom located in the α position of the imino group. A second characteristic is the existence of a second chiral center either on the carbon atoms which carry the heteroatom O, N or N ₁ N, or because of the presence of a chiral group G * present on an achiral cycle, for example benzene.

Examples of G groups include, for example, menthyl, proline, methylbenzylamino, bomyl, isobomyl.

It should be noted that in formula (I), the bonds symbolized by - are preferably chiral bonds.

In the compounds corresponding to formula (I), the pyrrolidine ring may carry one or more substituents R ₂ insofar as they do not interfere with the process of the invention. The groups R ₂ may be identical or different.

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. We can mention in particular:

linear or branched alkyl groups having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms,

the linear or branched mono, poly or perhalogenated alkyl groups 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 carbon atoms; halogen atoms,

the ether groups R _b -O- or thioether R _b -S- in which R _b represents a linear or branched alkyl group having from 1 to 6 carbon atoms and even more preferentially from 1 to 4 carbon atoms or the phenyl group ,

the acyloxy or aroyloxy groups R _b -CO-O- in which the group R _b has the meaning given above, the acyl or aroyl groups R _b -CO- in which the Rb group has the meaning given above,

the ester groups -O-CO-R _b or -COOR _b in which R _b has the meaning given above,

Amino groups -N- (R ₀ ) (Rd) in which R ₀ , R _d , which may be identical or different, represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,

the amido groups R _C -CO-NH- or (R ₀ ) (R _d ) -N-CO- in which R ₀ , R _d , have the meaning given above,

A hydroxyl group,

a nitro group,

a halogen atom, preferably a fluorine atom.

Among the R ₂ groups mentioned above, 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 R _b -O- or thioether R _b -S- in which R _b represents a linear or branched alkyl group having from 1 to 6 carbon atoms

a group CF ₃ ,

A hydroxyl group,

a halogen atom, preferably a fluorine atom.

In the compounds corresponding to formula (I), R _f preferably represents a hydrocarbon group having 1 to 20 carbon atoms and more particularly:

A Ci-Ci ₀ , preferably Ci-C ₄ , alkyl group, and more preferentially a methyl or ethyl group,

a C ₁ to C ₁₀ , preferably C 1 to C ₄ , alkyl group, mono-, poly- or perhalogen having 1 to 21 halogen atoms, preferably a CF ₃ group,

^~ 30 ^~~ - a cycloalkyl group having 3 to 8 carbon atoms, preferably cyclohexyl,

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 with at least one C ₁ -C ₁₀ , preferably C ₁ -C ₄ , alkyl group, optionally mono-, poly- or perhalogen or a nitro or nitrile group; an optionally mono-, poly- or perhalogenated aryl group having from 6 to 12 carbon atoms,

More preferably, R _f represents a CF ₃ , C ₄ F ₉ group or a phenyl group substituted with one or more halogen atoms, preferably fluorine, or with one or more C ₁ -C ₂ alkyl groups, mono-, poly - or perfluorinated. Preferred sulfonyl groups -SO ₂ -R _f are:

tosyls (p-toluenesulfonyl) -SO ₂ -C ₅ H ₄ -CH 3

brosyls (p-bromobenzenesulfonyl) -SO ₂ -C ₆ H ₄ -Br

nosyles (p-nitrobenzenesulfonyl) -SO ₂ -CgH ₄ -NO ₂ - mesyls (methanesulfonyl) -SO ₂ -CHs

triflyl (trifluoromethanesulfonyl) -SO2-CF3

nonaflyls (nonafluorobutanesulfonyl) -SO ₂ -C ₄ F ₉

the tresyls (2,2,2-trifluoroethanesulfonyl) -SO ₂ -CH ₂ -CF ₃ Rf is more preferably a trifluoromethyl group. In terms of R _is carried by the nitrogen atom, its nature is not critical.

By way of examples, R _y can have the following meanings:

a hydrogen atom,

a C ₁ -C ₁₂ alkyl group, a C ₂ -C ₁₂ alkenyl or alkynyl group,

a cycloalkyl group, preferably C ₃ to C ₁₂ ,

an aryl or arylalkyl group, preferably of Ce to C ₁₂

The cyclic groups may optionally carry one or more substituents and, by way of example, reference may be made to the list given for R ₂ . However, it should be noted that there is no interest in the R group _will be difficult.

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. In a first variant of ^~ ^~ rιnvention ^"décïïte ^~ in FR No. 04 / 00,551 or

WO 2005/080299, the preferred compounds of general formula (I) have the general formula (Ib) in which A represents a group of formula (F ₂ ):

in which :

R _f , R y, R ₂ , (x), (y) are as defined above and An and Ar ₂ together represent an aromatic group which may be a carbocycle having 6 to 12 carbon atoms or a heterocycle having 5 to 12 carbon atoms; at 12 atoms,

at least one of the bonds (x) and (y) symbolized by - is a chiral bond.

In the following discussion of this invention, "aromatic" means the conventional notion of aromaticity as defined in the literature, including J. March "Advanced Organic Chemistry", 4 ^th ed., John Wiley & Sons , 1992, pp 40 et seq.

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.

Illustrative examples of monocyclic heteroaromatic derivatives suitable for the present ^~ iήvention, there may be mentioned pyridine derivatives, pyrimidine, pyridazine and pyrazine.

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

As an illustration of this type of compounds, there may be mentioned derivatives of naphthalene, quinoline and isoquinoline. As a representative of the compounds corresponding to the general formula (Ib), mention may be made more particularly of those in which Aη and Ar ₂ together appear either a diphenyl-2,2'-diyl group or a dinaphthyl-2,2'-group. diyl.

In the case where Ar ₁ 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 -C _6, preferably C l -C _4: said groups are preferably in position 3 and 3 '.

The compounds of general formula (I) in which A represents a skeleton of formula (F-1) are in fact particularly interesting.

More preferentially, these compounds correspond to the general formula

in which - R _f , Ry, R _z are as defined above in general formula (I),

- R 'and R "represent, independently of each other, 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 carry them a carbocyclic group or LHCyclic 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 hereinafter, 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 precisely, 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. 04/00551 or WO 2005/080299 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 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, sulfonyl, 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 bearing 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 contains 1 or 2 unsaturations in the ring, generally having 3 to ^8" carbon atoms preferably 6 carbon atoms in the ring; said cycle being substitutable. Preferred examples of such groups are cyclohexyl groups optionally substituted with linear or branched alkyl groups having 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 (F ₃ ):

in which :

n 'represents a number from 0 to 5,

Q represents a group chosen from:

. a linear or branched alkyl group having from 1 to 6 carbon atoms, a linear or branched alkoxy group having from 1 to 6 carbon atoms,

. a linear or branched alkylthio group having from 1 to 6 carbon atoms,

. a group -NO2,

. a -CN group,

. a halogen atom, a group 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-systems -condensates, or is a group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming ortho- or ortho- and peri-condensed systems therein, 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 in 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 easily determined by the skilled person.

R ¹ 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 ring preferably varies between 3 and 6. As an illustration of this type of structure, mention may be made in particular of the following cyclic groups:

Of particular interest are the compounds of general formula (Ia) in which: - R 'and R "both represent a phenyl group,

- 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, preferably two centers of chirality. The preferred reagents according to the invention correspond to the following formula (Ic): ^"

in said formula,

R _f represents an alkyl group having from 1 to 10 carbon atoms, a phenyl group, a phenyl group substituted by an alkyl group having from 1 to 10 carbon atoms, from 1 to 5 fluorine atoms or a trifluoromethyl group,

R ₂ represents an alkyl group having from 1 to 10 carbon atoms,

- R ₃ 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 from 1 to 4 carbon atoms.

Another class wavers to the formula

in said formula, R _f 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 trifluoromethyl group;

R ₂ represents an alkyl group having from 1 to 10 carbon atoms,

R _a represents a hydrogen atom or an alkyl or alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, a nitro group, - R _y 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, 2S-1H, 2-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide, - (2f) -pyrrolidine-2-carboxylic acid, (1R, 2S) 1- (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-trifluoromethanesulfonylaminoethyl) amide,

- (2R) -pyrrolidine-2-carboxylic acid, (1R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1R, 2R) (1, 2-Diphenyl-2-trifluoromethanesulfonylaminohexyl) amide, -fd-) -pyrrolidine-2-carboxylic acid, (1S, 2S) - (1,2-diphenyl-2-trifluoromethanesulfonylamino); cyclohexyl) amide, (2S) -pyrrolidine-2-carboxylic acid, (1S, 2S-1, 2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide,

(2 R) -pyrrolidine-2-carboxylic acid, (1R, 2S) -1,2-diphenyl-2-trifluoromethanesulphonylamino-cyclohexyl) acid,

- (2R) -pyrrolidine-2-carboxylic acid, (1S, 2R) - (λ, 2-dipropenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1R, 2SJ- 1,1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, -f2S) -pyrrolidine-2-carboxylic acid, (1S, 2R) - {1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide,

(1 ', 2S) -Pyrrolidine-2-carboxylic acid, (1S, 2S) -1,2-diphenyl-2-tosamino-cyclohexyl) amide. Preparation of chiral compounds

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 formu

in said formula,

- P represents a protective group, - R _e represents a hydrogen atom or an alkyl group preferably having from 1 to 4 carbon atoms,

- R ₂ has the meaning given above.

and a diamino compound or amino alcohol carrying a sulphonyl group corresponding to the following formula:

in said formula, A, W, R _f , 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 or WO 2005/080299, contemplates the use of praline 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 R _e 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 (9-fluorenylmethoxycarbonyl) or MSOC (methanesulfenyl) -2 ethoxycarbonyl). Reference can be made to the work of Theodora W. Greene et al, Protective Groups in Organic Synthesis, (2nd ^ed. ) 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-praline or derivative,

a step of coupling said amino acid or derivative with a diamine or an aminoalcohol corresponding to 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, one can refer 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 is within the competence of the skilled person.

As examples of coupling agents, mention may in particular be made of:

carbodiimides such as, for example, N, N'-dicyclohexylcarbodiimide,

cyanamides, for example N, N-dibenzylcyanamide, keteneimines,

the isoxazolium salts such as, for example, N-ethyl-5-phenylisoxazolium-3-sulphonate,

- nitrogen-containing heterocycles such as for example the imidazolides, pyrazolides, and 1, 2,4-triazoIides and more particularly N ₁ N'-carbonyldiimidazole and N, N'-carbonyl-di-1, 2,4-triazole ,

alkoxylated acetylene and preferably ethoxyacetylene,

the reagents, such as ethyl or isobutyl chloroformate, which form an anhydrous mixture 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, 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 (II) hydroxide.

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

According to the process described in FR No. 04/00551 or WO

2005/080299, the diamino compound or sulfonylated aminoalcohol of formula (IV) can be obtained by reacting a compound bringing the electro-attractor group

- SO ₂ - R _f and a diamine or an aminoalcohol of formula (V):

in said formula, W, A, G and m have the meaning given above.

More specifically, the compound providing the sulphonyl group can be represented by the formula (VI):

O

II

Z - S -R _f

II '

⁰ (Vl) in said formula (Vl):

R _f has the meaning given above,

Z represents: a halogen atom, preferably a chlorine or bromine atom,

. a group -O-SO ₂ -R _f in which R _f ', which is identical to or different from R _f , has the meaning given for R _f .

The preferred compounds have the formula (VI) wherein Z represents a chlorine or bromine atom. As more specific examples of compounds of formula (VI), there may be mentioned in particular:

mesyl chloride,

benzenesulphonyl chloride,

tosyl chloride, trifluoromethanesulfonyl chloride,

pentafluorobenzenesulfonyl chloride,

p-trifluoromethylbenzenesulfonyl chloride.

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,

5 - (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,

- ₍₁ 2RJ 1R-1-amino-2- (trifluoromethanesulfonamido) -1, 2-diphenylethane,

- (1S, 2S) -I -amino-2- (trifluoromethanesulfonamido) -Λ / -méthylcyclohexane, 10 - (1R, _2R>) -1-amino-2- (trifluoromethanesulfonamido) -Λ / -méthylcyclohexane,

- (1S, 2S> 1-amino-2- (methanesulfonamido) cyclohexane,

- (1R, 2RJ-1-amino-2 - (methanesulfonamido) cyclohexane,

- (1S, 2S) -1-amino-2- (benzenesulfonamido) cyclohexane.

- (1R, 2R> 1-Amino-2- (benzenesulfonamido) cyclohexane The (1S, 2S) configurations 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 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 25 6), it is not necessary to implement 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, among others, the HANDBOOK OF CHEMISTRY AND PHYSICS, 3G ^~ ^"66 ^th 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 liberated hydracid.

Preferred examples of tertiary amines include, but are not limited to, 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, it is possible to use aliphatic or cycloaliphatic hydrocarbons, halogenated or not, such as, for example, hexane, cyclohexane, dichloromethane, dichloroethane or aromatic, halogenated or non-halogenated such as benzene, toluene, xylenes or 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 ef ^~ 5 mol / L, ^~ de ^~ prefehce 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 (VH) is preferably 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 reaction is carried out of compounds (V) and (Vl) is between -15 ° C and 5O ⁰ C ₁ preferably between 0 ⁰ C and room temperature (usually between 15 ⁰ C and 25 ⁰ 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.

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 corresponds to the ratio between the excess (R) - the excess (S) over the excess (R) + the 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- (trifluoromethanesulfonamido) -2 (amino) -1,2-diphenylethane is carried out,

In a 100 mL monocolumn flask, 0.73 g (2.9 mmol, 1 eq) of commercial CbZ-L-proline in 15 mL of anhydrous THF 3 of formula:

0.3 g (2.9 mmol, 1 eq) of triethylamine are then added.

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 mixture. 5 ml of anhydrous THF and having 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. white which corresponds to the following formula:

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); 6.95-7.23 (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:

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 para-nitrobenzaldehyde (7 mg, 0.0464 mmol) are introduced into a reactor under a nitrogen atmosphere before injecting 400 .mu.l of acetonitrile.

Was added ortho-nitrobenzoic acid (10 .mu.l of a 8.6% solution in acetonitrile, ^~ 0.1 ^~ eq.) - puis1'eau- (8 ^"μLτ10 demineralized eq.) And acetone (50 L ).

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 (HPLC) on a normal phase chiral OD-H column with a hexane / methyl tert-butyl ether (60/40) eluent and 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)

By reproducing Example 3, without using a carboxylic acid but in the presence of just water, the following results are obtained:

- Yield = 95%

- Energetic excess 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

Example 13

The operating procedure of Example 3 is repeated, but the Rf group of the catalyst is varied.

The Rf group in the catalyst is a -C ₆ H ₆ -CH ₃ tolyl group.

The mixture is stirred for 48 hours and then treated as before.

The aldolization product is then obtained with a yield of 92% and an enantioselectivity of 99%.

Example 14

The catalyst of Example 2 (0.15 eq), o-nitrobenzoic acid (0.30 eq) and alpha-chloro-cinnamaldehyde (19 mg, 0.114 mmol, 1 eq) are introduced into the reactor.

The tert-butyl acetoacetate is then added (200 μl) so as to solubilize all the reagents followed by the amount of water (10 eq.).

The reaction medium is stirred for 3 days.

The tert-butyl acetoacetate is then removed under high vacuum (2 - 8.10 ^-4 mbar) and the residue analyzed by NMR.

The majority compound obtained has the following chemical formula:

The conversion is 80%.

The residue is then purified on silica gel (eluent petroleum ether / Et ₂ θ 10: 1 to 7: 3 v / v) and the compound is obtained with a yield of 50%.

The enantioselectivity (ee) of the reaction is 92% determined by HPLC on a Daicel Chiralpack IB column, eluent hexane / tert-butyl methyl ether 75:25. The NMR characteristics of the product obtained are as follows:

¹ H NMR (300 MHz, CDCl ₃ ) 58.10 (d, 1H, J = 7.7 Hz), 7.63-7.32 (m, 4H), 6.90 (s, 1H) ₁ 4.84 (dd, 1H, J = 3.0, 8.7 Hz), 3.44 (s, 2H) ₁ 3.13 (dd, 1H, J = 3.0, 17.6 Hz), 3.00 (dd, 1H, J = 8.7, 17.5 Hz), 1.50 (s, 9H).

¹³ C NMR (62.5 MHz, CDCl ₃ ) δ 203.0, 166.2, 134.1, 129.4, 128.4, 125.3, 82.7, 72.0, 51.4, 47.9, 28.1

Example 15

Example 14 is repeated, but in reaction with tert-butyl acetoacetate, the following aldehyde:

The results obtained are as follows:

- yield = 55%

- ee = 93%

The enantiomeric excess is determined on a Daicel Chiralpack IB column, eluent hexane / tert-butyl methyl ether 50:50.

The NMR characteristics of the product obtained are as follows: ¹ H NMR (250 MHz) 8.09 (d, 1H, J = 8.1 Hz), 7.65-7.47 (m, 4H), 7.24 (s, 1H), 4.90 ( m, 1H), 3.46 (s, 2H), 3.15 (dd, 1H, J = 3.0 and 17.5Hz), 3.00 (dd, 1H, J = 8.7 and 17.5Hz), 1.50 (s, 9H).

¹³ C NMR (75 MHz) δ 203.0, 168.7, 133.6, 132.4, 132.1, 130.4, 129.25, 126.65, 125.0, 83.0, 72.7, 51.7, 48.5, 28.5.

Claims

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 aldolization or ketolization, asymmetric, intermolecular or intramolecular.

3 - Use according to one of claims 1 and 2 characterized in that the chiral compound corresponds to the following formula (I):

in said formula:

- A symbolizes a skeleton of general formula (FO or (F ₂ ):

in formulas (Fi) and (F ₂ ):

R 'and R "represent, independently of each other, 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 carbocyclic or heterocyclic group; unsaturated or aromatic, monocyclic or polycyclic, a chain of the aforementioned groups;

or R 'and R "may be linked so as to form, with the carbon atoms which carry them, a carbocyclic group or heterocyclic having from 4 to 20 atoms, saturated, unsaturated or aromatic, monocyclic or polycyclic,

- Ari and Ar ₂ symbolize, independently of each other two aromatic rings, carbocyclic or heterocyclic, substituted or unsubstituted, condensed or not and bearing optionally one or more heteroatoms,

x and y respectively locate the two links established between the skeleton symbolized by A and the heteroatoms,

R _f 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,

- R _z represents one or more substituents on the pyrrolidinyl group,

G represents a chiral group; W represents an oxygen atom or an R _y N group in which R _y represents a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or acyclic aliphatic group; 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 ranging from 0 to 3, preferably equal to 0 or 1,

- - ^ w 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 R _z represents:

a linear or branched alkyl group having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms,

a linear or branched mono-, poly- or perhalogenated 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 9 carbon atoms; halogen atoms,

an ether group R _b -O- or thioether R _b -S- in which R _b represents a linear or branched alkyl group having from 1 to 6 carbon atoms and even more preferentially from 1 to 4 carbon atoms or the phenyl group ,

an acyloxy or aroyloxy group R _b -CO-O- in which the group R _b has the meaning given above, an acyl or aroyl group R _b -CO- in which the group Rb has the meaning given above,

an ester group -O-CO-R _b or -COOR _b in which R _b has the meaning given above; an amino group -N- (R _c ) (R _d ) in which R ₀ , R _d , which are identical or different represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,

an amido group R _C -CO-NH- or (R _c ) (R _d ) -N-CO- in which R ₀ , Rd, have the meaning given above, a hydroxyl group,

a nitro group,

a halogen atom, preferably a fluorine atom.

5 - Use according to claim 4 characterized in that the chiral compound corresponds to the following formula (I) wherein R ₂ represents:

an alkoxy group R _b -O- or thioether R _b -S- in which R _b 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.

6 - Use according to one of claims 3 to 5 characterized in that the chiral compound has the following formula (I) wherein R _f represents:

a Ci to Cio alkyl group, preferably a Ci to C ₄ alkyl group, and more preferentially a methyl or ethyl group,

a C 1 to C ₁₀ , preferably C 1 to C ₄ , alkyl group, mono-, poly- or perhalogen having 1 to 21 halogen atoms, preferably a CF ₃ 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 mono-, poly- or perhalogenated phenyl group, a phenyl group substituted with at least one C 1 -C 10 alkyl, preferably C ₁ -C ₄ alkyl group, optionally mono-, poly- or perhalogen 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 R _f represents a CF ₃ , C ₄ Fg group or a phenyl group substituted with one or more halogen atoms of preferably fluorine, or with one or more mono-, poly- or perfluorinated C ₁ -C ₂ alkyl groups.

8 - Use according to one of claims 3 to 7 characterized in that the chiral compound has the following formula (I) wherein R _y represents: - a hydrogen atom,

- alkyl preferably Ci-Ci ₂

an alkenyl or alkynyl group, preferably of C ₂ to C ₁₂ ,

a cycloalkyl group, preferably C ₃ to C ₁₂ ,

an aryl or arylalkyl group, preferably of C ₆ to C ₁₂ .

9 - Use according to claim 8 characterized in that the chiral compound has the following formula (I) wherein R _y represents an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl.

10 - 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 α of the imino group and a second chiral center is on the carbon atoms which carry the O, N or ^~ N, N heteroatoms, or in the presence of a chiral G ^{* group} present on an achiral ring, preferably benzene.

11 - Use according to claim 10 characterized in that the chiral group G * is a menthyl group, a praline 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 (Ib):

in which :

- R _f , Ry, R _z , (x), (y) are as defined above and An and Ar ₂ together represent an aromatic group which may be a carbocycle having from 6 to 12 carbon atoms or a heterocycle having at 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) wherein An and Ar ₂ 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):

in which

R _f , Ry and R ₂ are as defined above in general formula (I), - R 'and R "represent, independently of each other, a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group,

- or R ¹ 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.

15 - Use according to one of claims 3 to 14 characterized in that the chiral compound corresponds to the formula (I) or (la) wherein R 'and R ", identical or different, represent:

a saturated or unsaturated, linear or branched acyclic aliphatic group having from 1 to 12 carbon atoms, preferably from 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 cycle being substitutable

an aromatic hydrocarbon group, preferably benzene, which may be 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 ^"is defined as a group consisting of at least two aromatic or nonaromatic heterocycles containing at least one heteroatom in each ring and forming between them ortho- or ortho- and peri-fused, or is a group consisting of at least one aromatic or non-aromatic hydrocarbon ring and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems, the carbon atoms of said rings possibly being substituted. 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:

17 - Use according to one of claims 3 to 14 characterized in that the chiral compound corresponds to the formula (I) or (la) wherein R 'and R ", 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.

18 - Use according to one of claims 3 to 11 characterized in that the chiral compound corresponds to the general formula (Ic):

in said formula,

R ₂ represents an alkyl group having from 1 to 10 carbon atoms,

R _a 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 from 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):

in said formula,

R ₂ represents an alkyl group having from 1 to 10 carbon atoms,

- R _a represents a hydrogen atom or an alkyl or alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, a. nitro group,

20 - 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-diphenyl-2-trifluoromethanesulfonylaminoethyl) amide,

(2S) -Pyrrolidine-2-carboxylic acid, (1R, 2R) - (λ, 2-diphenyl-2-trifluoromethanesulfonylaminoethyl) 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-2-carboxylic acid, (1R, 2S) - [1,2-diphenyl-2-trifluoromethanesulfonylaminoethyl] amide, (2H) -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-trifluoromethanesulfonylaminoethyl) amide,

(2R) -Pyrrolidine-2-carboxylic acid, (1 R, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide,

(2S) -Pyrrolidine-2-carboxylic acid, (1R, 2R) - (1, 2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide,

(2R) -Pyrrolidine-2-carboxylic acid, (1S, 2S) - (λ, 2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1S, 2S ) - (N, 2-Diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2 R) -pyrrolidine-2-carboxylic acid, (1R, 2S) - (λ, 2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2R) -pyrrolidine-2-carboxylic acid, (1S, 2R) - (λ, 2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide,

(2S) -Pyrrolidine-2-carboxylic acid, (1R ₁ 2S) - (λ, 2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide,

2S) -pyrrolidine-2-carboxylic acid, (1S, 2R) - (1,2-diphenyl-2-trifluoromethanesulfonylamino-cyclohexyl) amide, - (2S) -pyrrolidine-2-carboxylic acid, (1S, 2S) 1- (2-diphenyl-2-tosylamino-cyclohexyl) amide.

21 - Use according to one of claims 1 to 20 characterized by the fact that the strong aromatic carboxylic acid has a pk _a less than 4.2, preferably between 2 and 4.

22 - Use according to claim 21, characterized in that the aromatic carboxylic acid corresponds to the following formula:

in said formula:

B represents the remainder of an aromatic carbocycle having from 6 to 14 carbon atoms, S symbolizes a valency bond, an alkyl or alkenyl chain having from 1 to 3 carbon atoms,

- R _9, identical or different, symbolize the substituents on the aromatic ring and represent at least one electron-withdrawing group, - 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 valid 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 electro-attractor group is:

a group of formula:

-COORi ₂

-CO-R ₁₃ -NO ₂

CN

-CO-NH-R ₁₂

-N ⁺ (R ₁₂ ) S

-SOaR _1S ^" -SO ₂ ^{^} R ₁₃

-SO R ₁₃

-S-CF ₃

-Z

-CF ₃ -Cp F _2p + -i

. in said formulas, . the groups R ₁₂ , which are identical or different, represent a hydrogen atom, a (C ₁ -C ₁₂ ) alkyl group, (C ₂ -C ₁₅ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl or (C ₃ -C ₈ ) aryl groups; ₆ -C ₁₈ ), (C ₇ -C ₁₂ ) aralkyl;

. R- ₁₃ has the meaning given for R ₁₂ and also represents an alkyl, cycloalkyl or aryl group substituted by one or more fluorine atoms;

. 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) in which R ₉ represents a group chosen from groups of formula -CN, -SO ₂ R ₁ S, -COOR ₁₂ , perfluoroalkyl, -F, -NO ₂ where R ₁₂ and R _1S represent an alkyl group and R ₁₃ 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-nitrobenzoic acid

- 2-nitro-5-aminobenzoic acid

- 3-methylsulfonyIbenzoic 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. 30 - 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 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 meet one of the formulas: R-C = O H - C = O

II II ^R2 (VII) or ^Rs (VIII) in said formulas (VII) and (VIII):

R ₁ and R ₂ , identical or different, represent:

at least one carbon atom present in the group R ₂ or R ₃ in position α with respect to the carbonyl group carries at least one hydrogen atom,

R3 has the meaning given for R ₂ ,

" _. - _. R 1 and R ₂ may be bonded together to form a cycle leading to a cyclic ketone.

34 - Process for preparing 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 takes place ^" in the presence of a chiral compound of formula (I) and a strong aromatic carboxylic acid described in one of claims 3 to 29. 35 - Process according to claim 34 characterized in that the amount of chiral compound corresponding to the formula (I) expressed relative to carbonyl reagent fault ranges between 0.01 and 0.5, preferably between 0.2 and 0 4.

36 - Process according to one of claims 34 and 35 characterized in that the molar ratio between the chiral compound of formula (I) and the aromatic carboxylic acid varies between 0.8 and 3 and is preferably around 2.

37 - Method according to one of claims 34 to 36, characterized in that the reaction is conducted at a temperature between -5 ⁰ C and 50 ⁰ C, preferably between 15 ⁰ C and 25 ° C.

38 - Process according to one of claims 34 to 37 characterized in that the reaction is conducted in an organic solvent, preferably dimethylsulfoxide, acetonitrile, 1,4-dioxane and dichloromethane.

39 - Process according to one of claims 34 to 38, characterized in that a compound (A-O of formula (IX) and a compound (Bi) of formula

in said formulas:

- R _m and R _n , identical or different, represent a hydrogen atom or an alkyl group having 1 to 6 atoms or an aryl group having 6 to 12 carbon atoms, preferably an optionally substituted phenyl group, an aralkyl group; having 7 to 12 carbon atoms, preferably a benzyl group, -R _p has the meaning given for R _m or R _n

Rq has the meaning given for R _m or R _n or a group -CO-ORt, R _t having the meaning given for R _m or R _n . X represents a halogen atom or an electron-withdrawing group, preferably a trichloromethyl, trifluoromethyl or a SPh ₁ SOPh ₁ SO ₂ Ph group.

40 - Process according to claim 39, characterized in that the compound (Ai) corresponds to the formula (IX) in which R _m represents an atom hydrogen; R _n represents a phenyl group optionally substituted in particular with alkyl or alkoxy groups having 1 to 4 carbon atoms or a nitro group and X represents a bromine or chlorine atom and the compound (Bi) is an alkyl acetoacetate having from 1 to 4 carbon atoms, preferably tert-butyl.