NL1009346C2 - Catalyst for preparing optically active compounds asymmetric transfer hydrogenation comprises transition metal compound and optically active amino acid amide, peptide or protein ligand - Google Patents

Abstract

Catalyst for asymmetric transfer hydrogenation comprises a transition metal compound and an optically active amino acid amide, peptide or protein ligand. Independent claims are also included for the following: (1) production of an optically active compound from the corresponding prochiral compound by asymmetric transfer hydrogenation in the of the catalyst and a hydrogen donor; (2) production of an optically active compound by reduction of a prochiral ketone, imine, oxime or hydrazone in the presence of the catalyst and a hydrogen donor; (3) production of an optically active compound from an alcohol, in which the alcohol group is bonded to a chiral center, by catalytic oxidation with a ketone in the presence of the catalyst; (4) production of an optically active compound by reducing a ketone, imine, oxime or hydrazone containing a chiral center elsewhere in the molecule in the presence of the catalyst.

Description

- 1 - PN 9548

ASYMMETRICAL TRANSFER HYDROGENATION

The invention relates to a catalyst for asymmetric transfer hydrogenation on the basis of a transition metal compound and an optically active N-containing ligand.

Such catalysts are known from WO-A-9720789, in which asymmetric transfer hydrogenations are described in the presence of transition metal complexes and asymmetric ligands, the asymmetric ligands being optically active N-containing compounds, in particular optically active diamines, amino alcohols and amino phosphines.

A drawback of the known catalysts is that the components used, in particular the ligands, are difficult to access and expensive. In particular, a cleavage procedure must be developed separately for each ligand to obtain the ligand in optically active form.

The invention now provides asymmetric transfer hydrogenation catalysts employing ligands which are readily accessible in optically active form.

This is achieved according to the invention by using optically active amino acid amides, peptides or proteins as optically active ligands.

Amino acid amides are readily available in optically active form where the same process, for example the amidase process as described in Specialty Chemicals, 1997, Hl, 186-193, is applicable to a large group of compounds. This is particularly of particular advantage since the optimum ligand must be re-searched for each substrate, the easy accessibility of a large number of optically active ligands being crucial.

The transition metal compound catalyst and the optically active ligand 5 can be used in the form of separate components one of which is the transition metal compound and another is the optically active ligand, or as a complex containing the transition metal compound and the optically active ligand.

A preferred catalyst precursor is a catalyst precursor of the general formula

MnXpSqLr 15 where: n is 1,2,3,4 ...., - p, q and r, each independently representing 0,1,2,3,4 ..., - M is a transition metal, for example a metal of 20 groups 8, 9 or 10 of the periodic table according to the new IUPAC version as shown in the table printed in the cover of the Handbook of Chemistry and Physics, 70th Edition, CRC press, 1989-1990, in particular iron, cobalt, nickel, ruthenium, rhodium, iridium, osmium, palladium or platinum. In the transfer hydrogenation, ruthenium, iridium or rhodium is preferably used. * X is an anion such as, for example, hydride, halide, carboxylate, alkoxy, hydroxy or tertrafluoroborate; 30 s is a so-called spectator ligand, a neutral ligand that is difficult to exchange, for example an aromatic compound or an olefin, in particular 1009346-3-a diene. Examples of aromatic compounds are: benzene, toluene, xylene, cumene, cymene, naphthalene, anisole, chlorobenzene, indene, dihydroindene, tetrahydronaphthalene, bile acid, benzoic acid and phenylglycine. It is also possible that the aromatic is linked to the optically active ligand via a bond. Examples of dienes are norbornadienes, 1,5-cyclooctadienes and 1,5-hexadiene.

L is a neutral ligand which is relatively easy to exchange with other ligands and is, for example, a nitrile or a coordinating solvent, in particular acetonitrile, dimethyl sulfoxide (DMSO), methanol, water, tetrahydrofuran, dimethylformamide, pyridine and N-methylpyrrolidinone .

Examples of suitable transition metal compounds are: [RuCl2 (--benzene)] 2, [RuC12 [η-cymene)] 2, [RuC12 (J7-mesitylene)] 2, [RuC12 (rj-hexamethylbenzene)] 2, [ RuCl2 (»7- 1,2,3,4-tetramethylbenzene)] 2, [RuCl2 (rj-1,3,5-20 triethylbenzene)] 2, [RuCl2 (rj-1,3,5-tripropylbenzene)] 2 , [RuCl2 {η-tetramethylthiophene)] 2, [RuCl2 (77-methoxybenzene)] 2, [RuBr2 (77-benzene)] 2 / [RuI2 (/ 7-benzene)] 2 / trans-RuCl2 (DMSO) 4, RuC12 (PPh3) 3, [Ir (COD) 2Cl] [Rh (C6H10C1] 2 (where C6H10 = hexa-1,5-di-ene), 2.5 CoCl2, [Rh (C0D) Cl] 2.

Suitable optically active ligands which can be used in the catalyst according to the invention are, for example, amino acid amides, peptides and proteins, in particular 30 α-amino acid amides of the general formula: 1009346 - 4 -

R2 O

r'-JX.n / r5

r3 '^ - n / l

14 R6

R

wherein: R 1 and R 2 are not equal to each other and each independently represents H, an alkyl, aryl, alkenyl or alkynyl group with 1-20 C atoms which groups may also contain one or more hetero atoms and / or functional groups 10, and may form a ring with R3, R4, R5 or R6; one of R3 and R4 represents hydrogen; and the other is an alkylaryl, alkenyl or alkynyl group having 1-20 C atoms which groups may also contain one or more hetero atoms and / or functional groups and may form a ring with R1, R2, R5, or R *; one of R5 and R5 represents hydrogen; and the other is an alkyl, aryl, alkenyl, alkynyl or acyl group with 1-20 C atoms which groups may also contain one or more hetero atoms and / or functional groups, or a sulfonyl group, or a phosphonyl group having 0 -20 C atoms, and can form a ring with R1, R2, R3 or R4.

The optically active amino acid amide may be part of a peptide, or a protein, wherein Rs or R6 is an amino acid, peptide or protein fragment.

1009346 - 5 -

Suitable examples of amino acid amides are the L and D enantiomers of amides prepared from the corresponding (natural) amino acids, for example: alaninamide, argininamide, asparaginamide, cysteinamide, cystinamide, glutaminamide, histidinamide, hydroxylysinamide, hydroxyprolinamide, prolinamide, isoleucinamide, leucinamide , methioninamide, phenylalaninamide, serinamide, threoninamide, tryptophanamide, tyrosinamide, 10-valine amide, phenylglycinamide, p-hydroxyphenylglycinamide, o-chlorophenylglycinamide, 2-methylphenylglycinamide, 2-allylphenylglycinamide, 2-methylvalinamide-2-ethylphenyl caprolactam; dipeptides, for example, aspartame and L, L-15 AlaPro; polypeptides, for example, polyleucine, polyisoleucine, polyhistidine; protein; for example serum albumin or lipases.

Suitable catalysts according to the invention are, for example, catalysts as described above, which are readily soluble in water or very polar solvents, for example catalysts in which: 1. The optically active ligand next to the amine and the amide contains a very polar group, for example derived from a carboxylic acid, a sulfonic acid, a phosphoric acid or salts thereof, for example sodium, potassium or calcium salts. The presence of an additional tetraalkylammonium group can also lead to water solubility. It is even possible that the ligand contains several of these groups. Examples of such water-soluble, optically active ligands 10U9346-6 - are aspartic acid alpha-amide sodium salt or 4-sodium sulfonato-phenylalaninamide; or wherein: 2. An optionally present aromatic group forming the "spectator ligand" contains a very polar group leading to water solubility. Examples of such very polar groups are basically the same very polar groups as described under 1.

The water-soluble catalysts can be used very advantageously in a transfer hydrogenation process, in which the substrate and the product are in the organic phase, and the catalyst and the hydrogen donor in the aqueous or very polar phase. An example is the reduction of 15 ketones in a two-phase system, the polar phase consisting of an azeotropic mixture of triethylamine and formic acid, and the non-polar phase consisting of the ketone and the alcohol formed therefrom, whether or not in the presence of a water-immiscible solvent. At the end of the reaction, the product can be easily separated by phase separation and the non-polar phase can be reused after the addition of additional formic acid to reduce a new batch of ketone.

The invention also relates to the preparation of optically active compounds via asymmetric transfer hydrogenation of the corresponding prochiral compound in the presence of a catalyst according to the invention and a hydrogen donor.

For example, the process can be very suitably used in the preparation of optically active alcohols, hydrazines or amines starting from the corresponding prochiral ketones, respectively imines, hydrazones or oxime derivatives.

The catalysts of the invention can also be used advantageously for the kinetic resolution of carbonyl compounds - for example ketones or aldehydes - or imines or hydrazones that already contain at least one chiral center elsewhere in the molecule and are present in racemic form.

Here, reduction of the carbonyl compound or of the imine most preferably occurs in only one of the two enantiomeric forms. Due to the reaction at ca.

To stop 50%, the ketone (aldehyde, imine) can be recovered essentially in one enantiomeric form; The other enantiomer is then substantially converted to the corresponding alcohol (alcohol or amine).

The catalysts of the invention can also be advantageously used for a kinetic resolution of chiral alcohols, in which the alcohol group attached to a chiral center is oxidized with ketones, for example acetone, cyclohexanone or other (cheap) ketones. In this reaction, very preferably only one of the enantiomers of the alcohol is oxidized, so that after about 50% conversion, a mixture is formed of the alcohol consisting essentially of one enantiomer and the corresponding ketone formed from the other enantiomer.

The catalysts of the invention can also be used with good results for the diastereomeric reduction of ketones, imines, oximes 1009346-8 and hydrazones with a chiral center elsewhere in the molecule. Here, the ketone (imine, oxime, hydrazone) is completely reduced to a compound having essentially only one relative configuration between the pre-existing chiral center and the new chiral center.

Prochiral ketones of the general formula: 10 can be used, for example, as prochiral compounds

O

R ^ R 'wherein R and R' are not equal to each and independently represent an alkyl, aryl, alkenyl or alkynyl group having 1-20 C atoms or together with the C atom to which they are attached form a ring, wherein R and R 'may also contain one or more heteroatoms or functional groups, for example acetophenone, 1-acetone-afton, 2-acetone-afton, 3-20 quinuclidinone, 2-methoxycyclohexanone, 1-phenyl-2-butanone, benzyl isopropyl ketone, benzyl acetone, cyclohexylmethylketone, t.-butylmethylketone, t.-butylphenylketone, isopropylphenylketone, ethyl (2-methylethyl) ketone, o, m or p-methoxyacetophenone, o, m 25 or p- (fluorine, chlorine, bromine or iodine) acetophenone, o, m or p-cyanoacetophenone, o, m or p-nitroacetophenone, 2-acetylfluorene, acetylferrocene, 2-acetylthiophene, 3-acetylthiophene, 2-acetylpyrrole, 3-acetylpyrrole 2-acetylfurane, 3-acetylfuranone , 1009346 - 9 - 2-hydroxy-1-indanone, 1-tetralone, p-methoxyphenyl-p'-cyanophenyl benzophenone, cyclopropyl (4-methoxyphenyl) ketone, 2-a cetylpyridine, 3-acetylpyridine, 4-acetylpyridine, acetylpyrazine; 5 prochiral iraines with the general formula: / R "

N

ji wherein R, R 'and R "each independently represent, for example, an alkyl, aryl, alkenyl, or alkynyl group having 1-20 C atoms or forming a ring together with the atoms to which they are attached, wherein R , R 'and R "may also contain one or more heteroatoms and functional groups, and R" may additionally be a cleavable group, eg imines prepared from the above-described ketones and an alkyl or arylamine or an amino acid derivative, eg amino acid amide, an amino acid ester, a peptide or a polypeptide Examples of a suitable alkyl or arylamine are a benzylamine, for example benzylamine, or an o, m or p-substituted benzylamine, an a-alkylbenzylamine, a naphthylamine, for example naphthylamine, a 1,2,3,4,6,7,8 or 9-substituted naphthylamine and a 1-25 (1-naphthyl) alkylamine or a 1- (2-naphthyl) alkylamine Suitable imines are, for example, N- (2- ethyl 6-methylphenyl) -1-methoxy-acetonimine, 5,6-difluoro-2- 1009346 - 10-methyl-1,4-benzoxazine, 2-cyano-1-pyrroline, 2-ethyoxycarbonyl-1-pyrroline, 2-phenyl-1-pyrroline, 2-phenyl-3,4,5,6-tetrahydropyridine and 3 , 4-dihydro-6,7-dimethoxy-1-methyl-isoquinoline; 5 oximes or hydrazones of the general formula

N

R 1 R 2 wherein 15-X contains a heteroatom and represents, for example, NH, NR or O, wherein R represents an alkyl, aryl, alkenyl or alkynyl group having 1-20 C atoms.

R 1 and R 2 each independently represent an alkyl, aryl, alkenyl or alkynyl group having 1 to 20 C atoms, or with each other or with R 3 and the atoms to which they are attached forming a ring, which groups also form one or can contain multiple heteroatoms and / or functional groups.

- R 3 in the case of an oxime or oxime ether, H is an alkyl, aryl, alkenyl or alkynyl group with 1-20 C atoms, which groups may also contain one or more hetero atoms and / or functional groups; and in the case of a hydrazone H, an alkyl, aryl, alkenyl, alkynyl, acyl, phosphonyl or sulfonyl group having 0-20 C atoms, which groups are also one or more hetero atoms and / or functional groups.

35 1009346 - 11 -

The process according to the invention is carried out in the presence of one or more hydrogen donors, which in the context of this invention are meant to mean compounds which can transfer hydrogen in any way to the substrate, for example thermally or catalytically.

Suitable hydrogen donors which can be used are, for example, aliphatic or aromatic alcohols, in particular secondary alcohols with 1-10 C atoms, acids, for example formic acid, H3P02, H3P03, and salts thereof, unsaturated hydrocarbons and heterocyclic compounds, reducing agents sugars. Preferably 2-propanol or formic acid is used. The substrate to hydrogen donor molar ratio is preferably between 1: 1 and 1: 100.

In the asymmetric transfer hydrogenation, a molar ratio of metal present in the transition metal compound to substrate 20 between 1:10 and 1: 1,000,000, in particular between 1: 100 and 1: 100,000, is preferably used.

The temperature at which the asymmetric transfer hydrogenation is carried out is generally a compromise between the rate of the reaction on the one hand and the degree of racemization on the other, and is preferably between -20 and 100 ° C, in particular between 0 and 60 ° C.

The asymmetric transfer hydrogenation can in principle be carried out in an oxygen-containing atmosphere; preferably, however, the asymmetric transfer hydrogenation is carried out in an inert atmosphere, for example under nitrogen.

In principle, any solvent which is inert in the 1009346-12 reaction mixture can be used as solvent. Preferably, a solvent is used which also functions as a hydrogen donor, for example 2-propanol.

When the asymmetric transfer hydrogenation is carried out in water, resulting in a 2-phase system, a water-soluble catalyst is preferably used.

The catalyst for the asymmetric transfer hydrogenation can, if desired, be activated by hydrogenation with hydrogen or by treatment with a base, for example an (earth) alkali compound, for example an alkali hydroxide, an (earth) alkali carboxylate or an (earth) alkali metal oxide with 1-20 ° C. atoms, the alkali metal being, for example, 15 Li, Na or K and the alkaline earth metal, for example, Mg or Ca. Suitable bases are, for example, sodium, potassium hydroxide, potassium t-butoxide, and magnesium methoxide.

In the preparation of the catalyst, a molar ratio of metal to complexing (eg, amino, amido) groups and the optically active ligand is preferably between 2: 1 and 1:10, preferably between 1: 1 and 1: 6.

The invention will be further elucidated on the basis of the examples, without, however, being limited thereto.

Example I

0.015 mmol [RuCl 2 cymene] 2, 0.036 mmol D-Val-NH 2 'HCl and 0.1 mmol potassium butoxide j were placed in a 100 ml three-necked flask under 30 inert conditions. The whole was taken up in 20 g of isopropanol. The reaction mixture was stirred until 1009346-13 - all [RuCl 2 cymene] 2 had dissolved. Then 35 g of isopropanol and 2.33 ml of acetophenone were added to the reaction mixture. The reaction was carried out using chiral HPLC analyzed on the e.e. and conversion. Column: 5 Chiralcel OB. Eluent: hexane / isopropanol = 90:10. Flow: 0.5 ml / min. Detection: U.V. (254 nm) and a polarimeter. Acetophenone was enantioselectively reduced to S-phenethyl alcohol over 2 hours with an e.e. of 57%. Acetophenone was reduced enantioselectively to S-phenethyl alcohol with an e.e. in 20 hours with 93% conversion. of 59%.

example II

0.015 mmol [RuCl] benzene 2 and 0.1 mmol D-Val-NH 2 were placed in a 100 ml three-necked flask under 15 inert conditions. The whole was heated to 80 ° C in 20 g of isopropanol for 15 minutes. The reaction mixture was then cooled to room temperature. 35 g of isopropanol, 2.33 ml of acetophenone and 0.1 mmol of potassium cbutoxide were added successively. The reaction was carried out using chiral HPLC analyzed on the e.e. and conversion. Column: Chiralcel OB. Eluent: hexane / isopropanol = 90:10. Flow: 0.5 ml / min. Detection: U.V. (254 nm) and 25 a polarimeter. Acetophenone was enantioselectively reduced to S-phenethyl alcohol with an e.e. in 3.5 hours with 52% conversion. of 57%. Acetophenone was reduced enantioselectively to S-phenethyl alcohol with an e.e. in 82 hours with 82% conversion. of 54%. 30 1009346 - 14 -

Example in

In a 100 ml three-necked flask, 0.1 mmole D-Val-NH2'HCl and 0.1 mmole potassium tbutoxide were dissolved in 20 g isopropanol under inert conditions. After stirring for 1 hour, 0.015 mmol [RuCl 2 cymene] 2 was added to the opal solution. The solution was heated to 80 ° C for 15 minutes. The reaction mixture was then cooled to room temperature. Successively, 35 g of isopropanol, 2.33 ml of acetophenone and 0.1 mmol of potassium butoxide were added. The reaction was carried out using chiral HPLC analyzed on the e.e. and conversion. Column: Chiralcel OB. Eluent: hexane / isopropanol = 90:10. Flow: 0.5 ml / min.

Detection: U.V. (254 nm) and detection using a 15 polarimeter. Acetophenone was enantioselectively reduced to S-phenethyl alcohol with an e.e. in 20 hours with 88% conversion. of 58%.

Example IV

In a 10 ml Schlenk tube, 6.1 mg (0.01 mmol) [RuCl 2 cymene] 2 and 5.7 mg (0.05 mmol) L-prolinamide were weighed. 0.47 ml (4 mmol) of acetophenone was added to this. The mixture was stirred at 65 ° C under N2 for 25 minutes. The mixture was cooled to room temperature. 3 ml of a mixture of formic acid / triethylamine (7 mmol) was then added to the mixture. The mixture was stirred in air at 65 ° C. Acetophenone is reduced in 20 hours with 44% conversion enantioselectively to R-phenethyl alcohol with an e.e. of 51%.

1009346 - 15 -

Example V-XV

In an inert condition of 100 ml, 0.015 mmol of [RuCl 2 cymene J 2 and 0.1 mmol of an optically active amino acid amide as ligand 5 were dissolved in 20 g of isopropanol under inert conditions. The solution was heated to 80 ° C for 15 minutes. The reaction mixture was then cooled to room temperature. Successively, 35 g of isopropanol, 2.33 ml of acetophenone and 0.1 mmol of potassium cbutoxide were added. The reaction was carried out using chiral HPLC analyzed on the e.e. and the conversion. Column: Chiralcel OB. Eluent: hexane / isopropanol = 90:10. Flow: 0.5 ml / min. Detection: U.V. (254 nm) and detection using a polarimeter. The results are listed in Table 11.

1009346 - 16 - Table 1

Ligand time e.e conf conv image (h) (%) (S / R) 1 '(%) V 20 58 s 88

Nh2 VI '/ ^> ^ VvNH2 20 35 s 88

NlH2 ch3 o VII ^ 1 II 20 62 R 69 nh2 VIII i O 20 52 R 48 AA ../ nh2 IX NHz 2 51 S 53 X. mh2

Onf X 17 52 S 32 XI ^ [_ Ι2 20 61 S low X. mh2 J0 &

HO

1009346 i - 17 - XII / -v 17 77 R 20 O .. ../ 2

O.

XIII Q 20 32 S 32 00 ^ XIV Q 2 75 R 52 _Km2> 20 64

IN

XV 20 18 R 58 O NH, λΧ / nYy HO] | O 1 o / och 3 11 Configuration of the excess enantiomer of phenethyl alcohol.

1 0U9346

Claims (10)

1. Catalyst for asymmetric transfer hydrogenation on the basis of a transition metal compound and an optically active N-containing ligand, characterized in that the optically active ligand is an optically active amino acid amide, peptide or protein. Catalyst according to claim 1, characterized in that the optically active ligand is an α-amino acid amide. Catalyst according to claim 1 or 2, characterized in that the transition metal compound contains ruthenium, iridium or rhodium. Catalyst according to any one of claims 1-3, characterized in that the catalyst is water-soluble. 5. Process for the preparation of an optically active compound from the corresponding prochiral compound via catalytic asymmetric transfer hydrogenation in the presence of a catalyst and a hydrogen donor, characterized in that a catalyst according to any one of claims 1-4 is used. The method according to claim 5, wherein a prochiral compound is used as a prochiral ketone, imine, oxime or hydrazone. Process for the preparation of an optically active compound in which a prochiral ketone, 1009346 - 19 - imine, oxira or hydrazone is reduced in the presence of a catalyst and a hydrogen donor, characterized in that a catalyst according to any one of claims 1-4 5 is applied. 8. Process for the preparation of an optically active compound from an alcohol in which the alcohol group is bound to a chiral center, via catalytic oxidation with a ketone, characterized in that a catalyst is used as a catalyst according to any one of claims 1-4 . 9. A process for the preparation of an optically active compound in which a ketone, imine, oxime or hydrazone containing a chiral center elsewhere in the molecule is reduced in the presence of a catalyst, characterized in that a catalyst according to any one of the claims 1-4 is applied. 10. Catalyst, process for the preparation of this catalyst and use thereof as described and illustrated by the examples. 1009346 COOPERATION TREATY (PCT) REPORT ON NEWNESS RESEARCH OF INTERNATIONAL TYPE OF IDENTIFICATION OF THE NATIONAL APPLICATION Characteristic of the applicant or of the authorized representative 9548NL The Netherlands »application no. Submission date 1009346 June 9, 1998 Invoked Priority Date Applicant (Name) DSM of International type Granted by the International Investigation Initiative (ISA) to the request for an International Type Investigation No. SN 31355 EN I. CLASSIFICATION OF THE SUBJECT TRPI When using different classifications, specify all classification symbols) Complies with International Classification ((PCI Int Cl.6: 31/18, C 07 B 53/00, C 07 C 33/22, C 07 C 29/143 II AREAS OF TECHNIQUE EXAMINED _ Minimum documentation examined _Classification system__Classification symbols _ Int. Cl.6 B 01 J, C 07 B, C 07 C Onoerzocn® documentation other than the minimum documentation to the extent that you The documents in the areas examined are included. KL 1 I NO RESEARCH CAN BE DRAWN UP FOR CERTAIN CONCLUSIONS (comments on supplementary sheet) IV. | 1 LACK OF UNIT OF INVENTION (comments on supplement sheet) Form PCT / 1SA / 201 la) 07.1979