IE902395A1 - Novel process and polymer - Google Patents

Abstract

The invention relates to chiral polymers and their use in asymmetric synthesis operations for deracemization and optical inversion, said polymers being characterized by the fact that they include a chiral pattern, a functionalization pattern, and an optional cross-linking pattern. Application: chiral organic synthesis.

Description

F R 0 M R tJ S. TRANSLATIONS dUi 'So 1 . 1 3' The present invention relates to chiral polymers permitting the asymmetric synthesis of amino acids on a support, and to new processes for the synthesis of enantiomerically pure amino acids.

There are a few examples of asymmetric syntheses supported on a polymer in the prior art. Their principle remains the same as in solution, requiring the presence of a chiral auxiliary in the proximity of the prochiral centre. Employing polystyrene supports in all cases, these examples concern the asymmetric syntheses of hydroxyacids (Kawana and Emoto, Bull. Chem. Soc.Japan, 1974, 47,, 160), of arylaliphatic esters (Me Manus et al., J. Org. Chem., 1981, 46, 3097) and of 2-methylcyclohexanone (Leznoff et al., Canad. J. Chem., 1982, 60, 1836; Frechet et al., Reactive Polymers, 1983, 1., 227).

However, with the exception of the work of Leznoff et al. (loc.cit.), the enantiomeric excesses remain average (5662%). Lastly, Leznoff et al. (Canad. J. Chem., 1982, 60, 2984) have effected the asymmetric protonation of the lithioenamine of racemic 2-methylcyclohexanone anchored on the chiral branch of a polystyrene.

Another strategy consists in employing a chiral polyacrylic support producing a supramolecular asymmetric induction (Calmes, Daunis, Jacquier, Nkusi, Verducci and Viallefont, Tetrahedron Letters, 1986, 27 . 4303).

However, when this strategy is applied to the synthesis of amino acids the operation must be performed at very low temperature (- 78°C).

In these conditions, in the synthesis of amino FROM R W S .

TRANSLATIONS < Μ Ο N ) 0 7.0 2 . acids, the enantiomeric excesses have not exceeded 63% in alkylations of enolates carried out at -78eC.

This is why one of the objectives of the present invention is to provide a class of polymers which can be employed for deracemizing or for changing from one enantiomer to the other.

This is why one of the objectives of the present invention is to provide a process for synthesis or deracemization employing the above polymers.

The subject of the present invention is a polymer capable especially of being obtained by chiral radical copolymerization of a monomer or of an oligomer or of a prepolymer, of a functionalizing agent and preferably of a crosslinking agent, characterized in that it comprises: - a chiral unit a functionalizing unit an optional crosslinking unit.

The chiral unit represents, expressed on a molar basis, a high percentage which varies according to the chemical characteristics of the chiral unit. When the chiral unit does not have sites capable of forming intramolecular hydrogen bonds with another chiral unit, it is desirable that the chiral unit should represent at least 2/3 advantageously 70% of all the units, preferably 3/4. When the chiral unit has sites capable of forming hydrogen bonds between two chiral units, the percentage may be significantly lower. It is preferable, however, that at least 1/2 preferably 2/3 of the units should be chiral ones . - 3 10 Although it is possible to envisage units obtained by polycondensation such as, for example, an amide unit as in polyamides, or an ester unit as in polyesters, the most suitable chiral unit is a unit which can be obtained polymerization of chiral monomers containing an unsaturation.

The chiral monomers may be obtained by grafting a group bearing unsaturation onto chiral groups; by way of teaching, for example, there may be mentioned: - The monomers obtained by amidation or esterification of acrylic acids, optionally substituted, by means of optically active molecules in which advantageously the asymmetric carbon is fairly unhindered, as in the case where the active carbon forms part of a ring.

The attachment of the chiral derivatives to the acrylic radical may be effected by means of an amide functional group (for example with the amino acids or their derivatives such as, for example, the amides and the esters) or of an ester functional group. It can also be effected by any technique known to the specialist, for example it is possible to graft vinyl groups onto the aromatic nuclei of the chiral derivatives which contain these, such as, for example, the phenylalanine derivatives of tryptophan, and derivatives of adrenaline and equivalents .

The chiral monomer can also be obtained by systems with reciprocal attachments, such as, for example, the manufacture of enol esters from optically active acids such as the amino acids or of enol ether FROM R lil S . TRANSLATIONS ►-•τώ-τ < Μ Ο N > 0 7 . 0 2 . . . . . - - ° - 4 from an alcohol containing an active group.

It is also possible to employ compounds containing asymmetric carbons and a polymerizable double bond after optional optical resolution.

It is preferable that in the chiral monomer which generates the chiral unit the double bond should be close to the asymmetric carbon, more specifically it is preferable that the number of atoms between the double bond and the chiral centre should be at most equal to 5, prefer10 ably to 3 and, best, to 2.

Furthermore, the chiral unit advantageously contains at least one functional group bearing hydrogen capable of forming hydrogen bonds with another chiral unit of the same kind.

Among the functional groups there may be mentioned acidic functional groups, alcohol functional groups including phenols, amide functional groups and amine functional groups.

Among the chiral units usually employed there may be mentioned, by way of examples, acrylamides optionally substituted under the acryl group, formed from the following amines: - prolinol and optionally its derivatives in the form of esters or of ethers of the alcohol func25 tional group, - 1-amino-l-phenylethanes, especially N-methyl-1amino-l-phenylethane, FROM RUS. TRANSLATIONS ( Μ Ο Ν > Θ 7 . 0 2 .

U OJ PAGE 2 - N-alkyl-l-amino-2-alkoxypropane in which the alkyl or alkoxy groups may denote linear or branched alkyls, preferably a methyl or a hydrogen, - 1-pyrrolidin-2-yl-methylpyrrolidine, - l-amino-l-alkyl-2-hydroxyethane and its derivatives of mono- or dimethylation on the nitrogen and on the alcohol. The derivative which is disubstituted on the nitrogen being, of course, excluded since it is not capable of forming an amide bond with the acroyl group (however, it could be employed if an acrylic ester is employed as chiral monomer).

As a general rule, it is preferable that the chiral monomer generating the chiral unit should be of low molecular weight, that is to say advantageously at most equal to 200, preferably at most equal to approximately 150.

The functionalizing unit may be any unit bearing protective functional groups such as are defined in works which are well known to the specialist, such as the work by Theodora W. Greene Protective Groups in Organic Synthesis published by John Wiley and Sons, 1981, and that by J.F.W. McOmie, Protective Groups in Organic Chemistry published by Plenum Press, London and New York, 1973.

The protective groups can be converted into monomers giving functionalizing groups in the same way.

FROM R 1J S . TRANSLATIONS . 1 5 RASE - 6 mutatis mutandis, as in the case of the monomers and of the chiral units. Thus, it is possible to employ as monomer generating the functionalizing units anilide groups converted into acrylanilides bearing the said protective groups such as defined above. Among the protective groups which give the best results there may be mentioned aminobenzaldehyde derivatives, which are particularly useful during the synthesis or the deracemization of the (primary) amino derivatives such as the amino acids.

There may be mentioned the acryloylated (including methacryloylated) derivatives the derivatives produced by the amidation with acrylic acids of the following derivatives : CH3-NH-C(R1) (Rj)-CHO with Rx or R2 aryl or aralkyl.

It is also possible to imagine that the functionalizing units are units produced by the polymerization of chiral units of the above type, but on which the envisaged protective functional group will have been grafted.

It is very greatly preferable that the polymer according to the present invention should also contain crosslinking units. These crosslinking units are produced by monomers F R Ο Μ R I.J S . ΙΕ 902395 TRANSLATIONS PAGE 4 - 7 bearing generally 2 unsaturations. These monomers are well known to the specialist in the field of polymers. In particular, it is possible to employ the diesters or diamides of acrylic acids which are obtained by the action of acroylizing reagents on the dialcohols or diamides.

The various monomers are chosen according to techniques which are well known to the specialist so as to be compatible with a view to a harmonious polymerization.

The polymerization is not the only criterion, it is also advisable that the monomers should not interact with each other from a chemical point of view. The molar percentage of the crosslinking agent is advantageously between 0 and 20% of the chiral unit, preferably from 5 to 15, the functionalizing unit constituting the remainder of this functionalized chiral polymer.

Chiral monomer sequences may be inserted into a nonchiral polymer.

The various monomers are chosen so that the mass ratios, which are compatible with the molar ratios given above, should be advantageously between 50 and 65% in the case of the chiral unit, between 5 and 15% by weight in the case of the crosslinking unit, and between 40 to 25% in the case of the functionalizing unit.

The synthesis of the polymers according to the present invention is performed according to techniques which are well known to the specialist. Those which form the subject of Examples 1 to 3 can be taken as an example. - 8 The chiral polymers according to the present invention make possible the asymmetric synthesis, the deracemization and the optical inversion. The optical isomer obtained depends on the choice of the R or S form of the chiral monomer.

In the continuation of the description, asymmetric synthesis and optical inversion reactions on amino acids will be employed as an example of what it is possible to implement by virtue of the monomer according to the present invention. In fact, the syntheses described below are well known to the specialist and have been described and exemplified many times in the scientific literature, the invention consisting in effecting the reactions of synthesis of inversion or of racemization on the polymer according to the present invention, and this makes it possible to obtain pure optically active compounds and makes it possible to deracemize or to invert according to techniques which usually make it possible to racemize.

A further subject of the present invention is a process of asymmetric synthesis, on a support, of amino acids from a prochiral derivative of general formula : H2N-CH(CH2)nCOOR2 (I) in which n is equal to 0 or 1.

R1 denotes a hydrogen atom or an alkyl or aralkyl group, and R2 denotes a linear or branched Ci-Ci alkyl group or an F R 0 Π R U S .

TRANSLATIONS wr&a OBiiLUl -J PAGE' 2 aryl group, which derivative is reversibly anchored for example by forming a Schiff base onto a chiral polymer functionalized with an aldehyde or an equivalent group, charac5 terized in that : - in a first stage, the derivative bonded to the chiral polymer is deprotonated with a strong base in a preferably aprotic, preferably polar solvent such as, for example, tetrahydrofuran; - in a second stage, either the alkylation or the protonation of the deprotonated derivative bonded to the chiral polymer is carried out so as to create or recreate an asymmetric carbon on the said derivative, and, - in a third stage, the Schiff base is hydrolysed to obtain an amino acid of general formula: i1 H2N-C-(CH2)n-COOH (II) r3 where Rt and n are such as defined above, and R3 denotes an alkyl or aralkyl group, R! and R3 being necessarily different.

As a strong base, there may be mentioned amides such as lithium diisopropylamide or lithium tetramethyl25 piperidide, the lithium salt of hexamethyldisilazane, the anions derived from the alkanes, such as butyllithium and the alcoholates such as potassium tert-butylate. This list is not exhaustive.

According to a preferred emobodirnent of the FROM R Π . ΙΕ 902395 τ MOM ·>6ν τ© 2 . 382031' ί* -ιοί process in accordance with the present invention, the I, protonation of the deprotonated derivative bonded to the chiral polymer is carried out by adding water, an alcohol or an inorganic or organic acid.

According to a preferred embodiment of the process in accordance with the present invention, the alkylation of the deprotonated derivative bonded to the chiral polymer is carried out using a halide of general formula R3X where X denotes Cl, Br or I, and R3 is such as defined above. R3 may also be a functionalized group of the type 2-(CHs)nin which n 1 to 4 Z = I, CN, CO2R4 (R4 = alkyl), ORS (R5 - CH3 tosyl, tetra15 hydropyranyl), Y-NH (Y = benzyloxycarbonyl, t-butyloxycarbonyl), R4S, ch2-ch0 The deprotonated derivative bonded to the chiral 20 polymer can also react: - in aldolization and ketolization reactions with R®CHO(R5 = alkyl, aryl or aralkyl) and with aliphatic or arylaliphatic ketones, - in 1,4- addition reactions, with acrylic esters, acrylonitrile or acrolein.

According to a particularly advantageous FROM R W Ξ. TRANSLATION (MON )07.02.

PAGE 4 - 11 arrangement of this preferred embodiment of the process according to the present invention, the deprotonated derivative bonded to the chiral polymer is reacted with the halide R3X, for lh to 4h.

To obtain, using the process according to the present invention, either of the two enantiomers of an amino acid, with an enantiomeric excess greater than 95%, the chiral polymer containing one of the two R or S isomers of N-acryloylprolinol is chosen, depending on the desired enantiomer.

In addition, by virtue of the use of a new support polymer in which the chiral link is N-acryloylprolinol, it is possible to equilibrate the intermediate enolates without it being necessary to operate at low temperature.

As a result of this, in contrast to the processes described in the prior art which can be performed only at very low temperatures of the order of -7 0 to -80°C, the process according to the present invention can be per20 formed wholly at room temperature and, surprisingly, it is even possible to improve its result by a stage of heating to a moderate temperature of the order of 60 to 70"G· According to a preferred embodiment of the process in accordance with the present invention the asymmetric synthesis of amino acids on a support is carried out at a temperature higher than 0eC.

According to another preferred embodiment of the process according to the present invention the derivative FRO M R IJ S. TRANSLATIONS (MON) 0 7. 02.

PAGE S - 12 bonded onto the polymer is heated to the reflux temperature of tetrahydrofuran (67eC), at the end of the first stage, for a period of 15 min to 4 h.

In addition to the above arrangements, the 5 invention also comprises other arrangements which will emerge from the description which is to follow.

The present invention will be understood better with the aid of the remaining description below, which refers to examples of preparation of the chiral support polymer and to examples of use of the process for asymmetric synthesis of amino acids according to the present invention.

It should be clearly understood, however, that these examples are given solely by way of illustration of the subject of the invention, which they should not be considered to limit in any manner.

The enantiomeric excess values (ee) are determined either by measuring the rotatory powers, or preferably by using the Marfey reagent (Carlsberg Res. Comm., 1984, 49., 591) which permits the separation of the diastereoisomers by inverse phase HPLC with an excellent accuracy.

FROM RUS. TRANSLATIONS JO OOl - 13 i 4 PREPARATION OE A CHIRAL SUPPORT POLYMER Example 1 .1 g (0.065 moles) of (R) or (S) Nacryloylprolinol, 1.3 g of bis-acryloyl-Ν,Ν'-dimethyl5 ethylenediamine and 3.6 g (0.019 moles) of N-acryloyl-Nmethyl-p-aminobenzaldehyde are added into 30 ml of tetrahydrofuran, followed by 1.5 g of a2oisobutyronitrile. The mixture is heated for 1 h under reflux, is cooled to room temperature and is filtered. The solid is washed success10 ively with EtOH + 10% of ether and with CHZC12 + 10% of ether. The residue is suspended in 50 ml of ether and the lumps are broken up with a spatula. The solid is filtered off and dried under vacuum over P3O5 at room temperature. The material is screened between 0.08 g and 0.2 mm. Yield 90-95%.

The loading, measured by oximation, is 1.1 meq CHO per gram.

Example 2 The same quantities of the three monomers 20 employed in Example 1 are dissolved in a 1 j 1 mixture of alcohol and water. After degassing with a sonic probe, a stream of nitrogen is bubbled through for 15 min. A solution of 0.3 g of ammonium persulphate in 1 ml of water is then added, followed after homogenization by 0.3 ml of tetramethylethylenediamine. The mixture is homogenized and, after a few minutes, the temperature rises from 4 to 7°C. The mixture is left for 1 h, is filtered and is washed with acetone and with alcohol. The resin is suspended in ether and the operation is TRANSLATIONS ( Μ Ο Ν ) Θ 7 . Θ 2 rmorvzi-1 L.H .^-7 ' P'i£L<«SΙΕ 902395 - 14 continued as in Example 1. Yield 90-95% after screening. Loading identical with that in Example 1.

Example 3 In liquid paraffin (400 ml) and SPAN 85 5 Fluka (0.3 ml) are introduced into a 2-1 cylindrical reactor fitted with a stirrer and a nitrogen inlet. A strong stream of nitrogen is bubbled through for 30 minutes before the introduction of (R) or (S) N-acryloylprolinol (0.12 moles), of bisacryloyl-Ν,Ν'-dimethyl10 ethylenediamine (0.013 moles) and of N-acryloyl-N-methylp-aminobenzaldehyde (0.035 moles) diluted in water (110 ml) and ethanol or dimethylformamide (110 ml). The mixture is stirred under a slow stream of nitrogen and the stirring rate is adjusted until the droplets in suspension reach a diameter close to 0.1 mm. A solution of 0.5 g of ammonium persulphate in 1 ml of water is then added, followed by 0.36 ml of tetramethylethylenediamine. After a short induction period the temperature rises to about 30°C. After 30 mins the mixture is diluted with petroleum ether. The polymer beads are collected on a Buchner covered with a nylon cloth (100 m) , and are washed copiously successively with petroleum ether, acetone, aqueous acetone (1 : 1), water, ethanol and ether, and are finally dried under vacuum over P203 at room temperature. 90-95% yield of resin beads (diameter 0.1 and 0.2 mm). Loading identical with that in Example 1.

FROM RWS. TRANSLATIONS II ASYMMETRIC SYNTHESIS Example 4 s g copolymer from (S)-prolinol and 2. in 150 ml of toluene and < Μ Ο Ν , . .---- --.--Α-7| —.·~—.fl ιι.ι ι. ι, ! t - 15 OF AMINO ACIDS obtained in Examples 1, 2 or 3 9 g of racemic t-butyl alaninate a few drops of boron trifluoride etherate are heated under reflux while removing the water formed by means of a Dean and Stark separator. When the reaction is finished, the material is allowed to return to room temperature and the resin is filtered off and 10 washed with dichloromethane and with ether and is dried under vacuum over P£05 at room temperature.

A solution of lithium diisopropylamide (50 moles) in 90 ml of tetrahydrofuran is added at room temperature to a stirred suspension of the Schiff base thus obtained, in 200ml of anhydrous tetrahydrofuran. The mixture is heated under reflux for 2 h, is cooled again to 20°C, 40 ml of water is added and the mixture is left for 2 h. The resin is then filtered off and washed copiously successively with tetrahydrofuran, dichloromethane and 20 anhydrous ether.

A suspension of the above resin in 200 ml of 1.5 N hydrochloric acid is stirred for 4 h at room temperature.

It is filtered off, washed with 200 ml of water and the filtrates are combined and are concentrated to dryness under vacuum.

The amino acid hydrochloride residue is stirred for 1 h with 10 ml of hexamethyldisilazane. The insoluble material is filtered off, 20 ml of methanol are added to the filtrate; after 10 min the solvent is evaporated off F R Ο M R U S .

TRANSLATIONS < MON )07.02. ur: - 16 and the (R)-alanine residue is dried under vacuum. Yield 95- 97%; enantiomeric excess (determined by polarimetry) 96- 98%.

The resin recovered can be recycled after drying. 5 Example 5 The same operation as in Example 4 is performed with a polymer prepared from (R)-prolinol. (S)-Alanine is obtained in the same chemical yield and with the same enantioselectivity, Example 6 The same operating procedure as in Example 4 is performed but the whole deprotonation and reprotonation reaction is carried out at -78DC. (R)-Alanine is obtained with an ee = 61%.

Example 7 The same operation as in Example 4 is performed, but starting with (RS)-t-butyl valinate. (R)-Valine is obtained in a 95-97% yield and with an ee - 98-99%. Example 8 Same operation as in Example 4, but the supported Schiff base is prepared from t-butyl glycinate. After formation of the enolate by the action of lithium diisopropylamide in tetrahydrofuran at 20°, the mixture is heated under reflux for 2 h, is cooled again to 20°, 15 moles of methyl iodide in 10 ml of tetrahydrofuran are added dropwise and the mixture is left for 2 h.

After treatment as shown in Example 4, (S)alanine is isolated in a 95-97% yield and with an ee 98-99%.

F R Ο M R A N D A L L W ϋ 0 L C 0 Τ Τ < Μ Ο Ν ) 0 7 . 0 2 . ,. - - 1 - 1 11 ',... . 1 έ ΙΕ 902395 - 17 Example 9 Same operating procedure as in Example 8, using a copolymer prepared from (R)-prolinol. In these conditions (R)-alanine is isolated in the same yield and with the same enantioselectivity as in Example 8.

Example 10 Same operating procedure as in Example 8, but avoiding heating the enolate to reflux. (S)-Alanine is obtained with an ee = 82%.

In each of the processes illustrated by the examples above, about ten recyclings of the polymer were carried out without loss in yield or in enantioselectivity.

As follows from the above, the invention is not limited in any way to those of its embodiments of implementation and of application which have just been described more explicitly; on the contrary, it embraces all the alternative forms which can occur to a specialist in this field, without departing from the scope or from the extent of the present invention.

Example 11 The same operation as in Examples 4 and 7 is performed starting with (RS)-t-butyl phenylalaninate. (R)-Phenylalanine is obtained in a 95-97% yield and with an ee > 99%.

Example 12 The same operation as in Example 8 is performed, but with methyl iodide replaced with isopropyl iodide.

FROM RANDALL W 0 0 L Ο Ο Τ T (MON )07.02. -- 4103^8/44^ _ 1 - RAGE 3 - 18 After treatment as shown, (S)-valine is isolated in a 95-97% yield and with an ee > 99%.

Example 13 The same operation as in Example 8 is performed, but with methyl iodide replaced with benzyl bromide. (S)Phenylalinine is isolated in a 95-97% yield and with an ee > 99%.

Example 14 The same operation as in Example 4 is performed, but starting with (S)-t-butyl alaninate. (R)-Alanine is obtained in a quantitative yield and with an ee > 99%. Example 15 The same operation as in Example 4 is performed, but with the N-acryloylated derivative of (R)- -methyl15 benzylamine employed as linking agent. When 5 equivalents of L.D.A. are employed, (R)-alanine is isolated in a 95% yield and with an ee = 86%. The ee falls to 37% when 1 equivalent of LDA is employed.

Claims (11)

1. Polymer characterized in that it comprises: - a chiral unit - a functionalizing unit - an optional crosslinking unit

2. Polymer according to Claim 1, characterized in that it can be obtained by radical chiral copolymerization of a monomer or of an oligomer or of a prepolymer, of a functionalizing agent, and preferably of a crosslinking agent.

3. Polymer according to either of Claims 1 and 2, characterized in that the said chiral unit represents, expressed on a molar basis, a percentage at least equal to 1/2, preferably 2/3, advantageously to 70%, more advantageously to 3/4.

4. Process according to one of Claims 1 to 3 taken separately, characterized in that it can be obtained by radical copolymerization of a chiral monomer, of a crosslinking agent and of a functionalizing agent, characterized in that: - the chiral monomer consists of N-acryloylprolinol, either in the R form or in the S form; PAGE 4 - 20 1 , ί - the crosslinking agent consists of bieacryloyl-N, N'-dimethylethylenediamine or of bisacryloylpiperazine; - the functionalizing agent consists of para-Nacryloyl-N-methylaminobenzaldehyde, and in which one or more of the acryloyl groups is optionally replaced, either in the chiral link or in the functionalizing agent or in the crosslinking agent, by a methacryloyl group.

5. Process of asymmetric synthesis, characterized in that it consists in grafting onto a polymeric support consisting at least of a sequence of a polymer comprising: - a chiral unit - a functionalizing unit - an optional crosslinking unit.

6. Process according to Claim 5 for asymmetric synthesis of amino acids characterized in that it consists from a prochiral derivative of general formula: H 2 N-CH(CH 2 ) n COOR 2 (I) in which n is equal to 0 or 1. R x denotes a hydrogen atom or an alkyl or aralkyl group, and 1*2 denotes a linear or branched Cx-Cj alkyl group or an aryl group, which derivative is reversibly anchored by L M ft Ml·IAt L L wOOLCOTT (MON >07.02. PfiGE 6 2753007445 • * . . . ' ; ' - 2i - ; ι , · ; t forming a Schiff base onto the chiral polymer and In that» - in a first stage, the derivative bonded to the chiral polymer is deprotonated at room temperature with a strong base in an aprotic solvent, preferably tetrahydrofuran; - in a second stage, either the alkylation or the protonation of the deprotonated derivative bonded to the chiral polymer is carried out so as to create an asymmetric carbon on the said derivative, and, - in a third stage the Schiff base is hydrolysed to obtain an amino acid of general formula» r* H 2 N-C-(CH 2 ) n -COOH (II) Ra where R t and n are such as defined above, and R s denotes an alkyl or aralkyl group, R x and R, being necessarily different.

7. Process for the asymmetric synthesis, on a support, of amino acids, according to either of Claims 5 and 6, characterized in that the protonation of the deprotonated derivative bonded to the chiral polymer is carried out by adding water, an alcohol or an inorganic or organic acid.

8. Process for the asymmetric synthesis, on a support, of amino acids, according to Claim 7, characterized in that the alkylation of the deprotonated derivative bonded to the chiral polymer is carried out using a FROM RANCALL UOOLCOTT 07.02. . PAGE 7 0753887445 “ j ' - 22 ί : halide of general formula R, X, where χ denotes Cl, Br or I, and R 3 denotes an alkyl or aralkyl group.

9. Process for the asymmetric synthesis, on a support, of amino acids according to Claim 6, characterized in that the asymmetric synthesis of amino acids on a support is carried out at a temperature higher than 0*C, preferably at the reflux temperature of tetrahydrofuran, at the end of the first stage, for a period of 15 min to 4 h.

10. Configuration inversion process characterized in that it consists in grafting an optically active compound onto a resin comprising at least by means of sequence a polymer comprising» - a chiral unit - a functionalizing unit - an optional crosslinking unit; and in subjecting the compound thus formed to a known reagent for racemizing or for inverting a configuration.

11. 11. 11.II. Deracemization process characterized in that it consists in grafting an at least partially racemic compound onto a resin comprising at least by means of sequence a polymer comprising» - a chiral unit - a functionalizing unit - an optional crosslinking unit; FROM RP-NCSLL UOOLCOTT 0753887445 ” RAGE Θ - 23 and in eubjecting the compound thus formed to a known reagent for racemizing.