JP2003510180A - Catalysts for asymmetric transfer hydrogenation - Google Patents

Abstract

  (57) [Summary] The present invention relates to catalysts for asymmetric transfer hydrogenation based on transition metal compounds and nitrogen-containing optically chiral ligands. The present invention also relates to various methods for producing compounds having high optical chirality using the catalyst of the present invention. In the catalyst of the present invention, the transition metal is iridium, ruthenium, rhodium or cobalt, and the chiral ligand includes sulfur in the form of thioether or sulfoxide, and the sulfur is bonded via two or more carbon atoms. Bound to nitrogen. Surprisingly, it has been found that with the catalyst according to the invention, it is possible to obtain high conversions with good enantiomeric excess of compounds with a high optical chirality. In addition, catalysts using iridium as the metal are also very stable in formic acid, so that formic acid can be used as a hydrogen donor, which makes the reaction irreversible, thereby allowing higher substrate concentrations to be used. Has been found to be possible to complete.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to catalysts for asymmetric transfer hydrogenation based on transition metal compounds and nitrogen-containing optically chiral ligands. The present invention also relates to various methods for producing a compound having a high optical chiral property using the catalyst of the present invention.

[0002]

[Prior art]

Asymmetric transfer hydrogenation is a method for the production of compounds with high optical chirality,
The presence of transition metal catalysts containing optically chiral ligands has been shown to be prochiral.
Ensure that the double bond of a chiral compound is asymmetrically reduced by hydrogen transfer with a hydrogen donating organic compound. This is taken to mean at least one excess of the enantiomer of the compound produced in the reaction product. This excess is referred to hereinafter as "enantiomeric excess" or ee (as determined by capillary GLC analysis on a chiral cycloSil-B column). The general advantage of such asymmetric transfer hydrogenations over reduction with, for example, molecular hydrogen is that the reaction can occur under relatively mild conditions with respect to temperature and pressure, while yield Is relatively high and the content of by-products is low, so that the manufacturing cost can be reduced. In fact, this asymmetric transfer hydrogenation is often used for the production of optically chiral alcohols from prochiral ketones. Such catalysts are known from EP 0-916-637. In this known catalyst, the nitrogen-containing optically chiral ligand is a diamine, an aminoalcohol or an aminophosphine compound, and the transition metal is selected from Group VIII of the periodic system, preferably ruthenium.

[0003]

[Problems to be Solved by the Invention]

A disadvantage of the known catalysts from EP 0-916-637, especially those containing amino-alcohol ligands, is that they are in fact sufficiently stable only when alcohols are used as hydrogen donors. This is due to the reversibility of the transfer hydrogenation reaction, and also due to the chemical similarity of the hydrogen donor alcohol and the optically chiral alcohol formed, to the ketones whose enantiomeric purity is often too low. It causes unique problems in reduction. An acceptable enantiomeric excess is not achieved unless a large excess of hydrogen donating alcohol is added. This results in relatively low space-time yields with a given size of the production equipment, and a large excess must be separated and purified for reuse, It is inconvenient because it adversely affects the economic situation. A further disadvantage is that known catalysts, especially those containing diamine and aminophosphine ligands, often have too low an activity and are not sufficiently enantioselective, so that the optical chirality obtained with them is obtained. Enriched compounds are those that have too low an enantiomeric excess (ee). The object of the present invention is therefore to provide a catalyst for asymmetric transfer hydrogenations which does not have the disadvantages mentioned above.

[0004]

[Means for Solving the Problems]

According to the invention, the object is, according to the invention, that the transition metal is iridium, ruthenium, rhodium or cobalt and the optically chiral ligand comprises sulfur in the form of a thioether or sulfoxide, the sulfur being more than one carbon atom. It is achieved in that it is bound to the nitrogen via.

It has been surprisingly found that very good results can be obtained with the catalysts of the invention. Hereafter, this is to be understood as meaning a fast and high conversion of compounds with a particularly high optical chirality into a good enantiomeric excess (ee). Preferably, the transition metal in the catalyst is iridium. With this, very good results are obtained. The iridium catalysts of the invention have been found to give very good enantiomeric excess and conversion and are also very stable. Surprisingly, it was also found to be stable in formic acid, so that formic acid can also be used as a hydrogen donor. Transfer hydrogenation with this species is irreversible, as the formic acid is converted to carbon dioxide gas upon reduction. In general, the use of hydrogen donors that undergo irreversible transfer hydrogenations (eg formic acid, partially unsaturated heterocycles and partially unsaturated hydrocarbons) is most advantageous. This allows the reaction to proceed to completion, thereby allowing the use of much higher substrate concentrations than when the alcohol is a hydrogen donor. Furthermore, the irreversible nature of the reaction prevents racemization of the product. A further advantage in the specific case of formic acid / trialkylamines over alcohols as hydrogen donors is that the reaction can take place in air rather than under argon.

[0006]   The optically chiral ligand in the catalyst of the present invention has the formula:

[Chemical 1] [Wherein each R _{1 to} R ₇ can in principle be any substituent, R ₁ cannot be hydrogen and n is 0 or 1 (thioether or sulfoxide)
, R ₆ and R ₇ are hydrogen (secondary or primary amines) and there must be at least one chiral center in the molecule] Have. Further, R _{1 to} R ₇ are, for example, hydrogen (excluding R ₁ ), alkyl, aryl, aralkyl, alkenyl or alkynyl group (1
~ 20 carbon angels) or one or more heteroatoms, eg O
, N, P or S, or a group containing a functional group. Each of the substituents R _{1 to} R ₇ can form a ring together with other substituents. Sulfur and / or nitrogen can themselves also form part of a ring.

In general, sulfur can be attached to nitrogen through more than one carbon atom.
X can be empty, thus the sulfur containing group and amine are vicinal,
It may also contain one or more carbon or heteroatoms in the ring or otherwise.
An example is a methionine-derived ligand with 3 carbon atoms between nitrogen and sulfur. If heteroatoms are present between the sulfur and nitrogen groups, these are preferably
Separated from sulfur and nitrogen by more than one carbon atom. Preferably, in the catalyst of the present invention, sulfur is bound to nitrogen via two carbon atoms. It has been found that such catalysts have a higher activity.

The nitrogen in the optically chiral ligand is preferably an amine group. To obtain good activity and enantioselectivity, the amine groups are at most once (secondary amine) substituted or preferably unsubstituted, which means that R ₆ or R ₇ is hydrogen. And more preferably R ₆ and R ₇ are both hydrogen.

In the catalyst of the present invention, sulfur is thioether or sulfoxide (n is 0).
Or it has the form of 1). Sulfur is substituted with groups containing at least one carbon. Preferably sulfur is substituted with a substituted or unsubstituted alkyl, (hetero) aryl or (hetero) aralkyl group. Heteroatoms can be present in the aromatic ring. Examples of suitable sulfur substituents are isopropyl, cyclohexyl, phenyl, benzyl, 2-phenethyl, naphthyl, thiophene and furan. This increases reactivity and ee.

For good enantioselective transfer hydrogenation, the ligand in the catalyst of the present invention must be highly chiral. This is taken to mean that one of the enantiomers of the ligand is present in the catalyst in excess. Preferably the enantiomeric excess is above 90%, more preferably above 95% and most preferably above 99%.

The chiral centers in the optically chiral active ligand in the catalysts of the invention can in principle be located in different places, but are preferably near or in the vicinity of nitrogen-containing groups or thioether groups. is there. In one embodiment, the chiral center is located at the carbon to which the nitrogen containing group is attached. Such optically chiral ligands can be easily derived from optically chiral cysteines (Table 1, Ligand 1). It is a widely available and thus inexpensive amino acid. Preferably, the carboxylic acid groups are reduced to alcohol groups (Table 1, ligand 2). This embodiment has higher activity. However, preferably,
Of the two or more carbon atoms linking sulfur to nitrogen, at least the carbon bonded to sulfur is chiral. This has the advantage that a higher ee is obtained.

A particularly high ee is achieved if the optically chiral ligand in the catalyst of the invention has two or more chiral centers. In a preferred embodiment of this catalyst, the optically chiral ligand is a sulfoxide and one of the two or more chiral centers is sulfur of the sulfoxide (Table 1, Ligand 3). It can be prepared in a simple manner by the oxidation of cheap starting materials, for example peroxides, eg cysteine or alcohols derived therefrom (Table 1, Ligand 2), and thus the ligands are very cheap Ligands are particularly attractive. In another preferred embodiment of the catalyst in which the ligand has more than one chiral center, the optically chiral ligand is a thioether in which both the thioether and the carbon atom to which the amino group is attached are chiral ( For example, Table 1, ligands 4, 5 and 6). These catalysts have a high activity and give a very high enantioselectivity.

The optically chiral ligand in the catalyst of the present invention can also be very suitably prepared by converting an optically chiral aziridine compound with a thiol compound. This reaction proceeds via stereoselective ring opening, and thus optically chiral thioether compounds are obtained according to the following reaction scheme:

[Chemical 2]

This method is for producing aziridine in a simple manner by dehydration of optically chiral vicinal amino alcohol using, for example, triphenylphosphine and DIAD (di-isopropylazodicarboxylate). Has the further advantage that Optically chiral vicinal amino alcohols are often widely available and relatively inexpensive. Examples include ephedra-alkaloids such as ephedrine and norephedrine, and
Includes reduced amino acids. Therefore, preferably, in the catalyst of the present invention, the optically chiral ligand is derived from aziridine (which is itself derived from an optically chiral vicinal aminoalcohol) by reaction with a thiol compound. Be induced. Optically chiral ligands having a single chiral center at the carbon beside sulfur can be prepared, for example, by conversion of aziridine derived from reduced phenylglycine with thiol compounds. In a more preferred embodiment the two carbons of the aziridine ring are substituted so that the ligand has two chiral centers and the ligand in the catalyst is eg 2-amino-1-.
It is benzyl thioether-1,2-diphenylethane. This ligand has chiral centers at the carbon by sulfur and the carbon by nitrogen. The catalyst with this ligand has a very good activity, resulting in a very good enantioselectivity.

In the case of a catalyst in which the ligand has two or more chiral centers (diastereomers) and the ligand forms a mixture of diastereomers, at least one of the diastereomers is enantiomerically enriched. If so, asymmetric transfer hydrogenation can occur. However, preferably in that case too many single enantiomers of a single diastereomer are used to give the most possible ee.

Catalysts based on transition metal compounds and optically chiral ligands can be applied in the form of separate components, one of which is a transition metal compound, while the other one is an optical pair. It can be applied as a chiral ligand or as a complex containing a transition metal compound and an optically chiral ligand.

[0017]   For transition metal compounds, preferably the general formula:

Embedded image M _n X _p S _q L _r (where n is 1, 2, 3, 4, ...; P, q, and r are each independently 0, 1, 2, 3, 4, ... M is the transition metal ruthenium, iridium, rhodium or cobalt, most preferably iridium; X is an anion such as hydride, halide, carboxylate, alkoxy, hydroxy or tetrafluoroborate; S is a so-called spectator ligand, which is a neutral ligand that is difficult to exchange, such as an aromatic compound or an olefin, especially a diene. Examples of aromatic compounds are benzene, toluene, xylene, cumene, cymene, Naphthalene,
Anisole, chlorobenzene, indene, dihydroindene, tetrahydronaphthalene, cholic acid, benzoic acid and phenylglycine. Examples of dienes are norbornadiene, 1,5-cyclooctadiene and 1,5-hexadiene. L is a neutral ligand and can be exchanged relatively easily with other ligands, for example nitrile or a coordinating solvent, especially acetonitrile, dimethylsulfoxide (DMSO), methanol, water, tetrahydrofuran, dimethylformamide, A catalyst precursor of pyridine and N-methylpyrrolidinone) is used.

[0018]   Examples of suitable transition metal compounds are:

[Chemical 4] Is.

Most preferably, the transition metal compound is [Ir (COD) Cl] ₂ . Very good results have been obtained with this.

The invention also relates to the process for the preparation of the catalysts according to the invention described above, wherein the sulfur is bound to the nitrogen atom via two or more carbon atoms and contains sulfur in the form of a thioether or a sulfoxide. Includes the addition of nitrogen-containing optically chiral ligands to catalyst precursors (including transition metals), anions and spectator ligands (which are difficult to exchange). The catalyst can be prepared before it is used as an asymmetric transfer hydrogenation catalyst, or in situ, either immediately before or during use, optionally in the presence of a reagent to be catalytically converted. ).

In a further embodiment, the catalysts of the present invention may be readily soluble in water or highly polar solvents. The catalyst of the present invention can be rendered water-soluble by introducing into the ligand a water-soluble group such as a carboxylic acid salt, a sulfonic acid salt and a phosphoric acid salt. Another possibility is the introduction of trialkylammonium or tetraalkylammonium salts into the ligand. A third group of substituents that can be introduced into the ligand are neutral polar groups that may be present in the molecule in various ways, such as alcohols and sulfoxides. Another way to make the catalyst water-soluble is to use difunctional counterions for metals such as biscarboxylic acids, bisphosphates and bissulfonates. One of the two acid groups serves as a counterion for the metal, while the other acid group is present, for example as a salt of sodium, potassium or lithium, providing water solubility. It is also possible to introduce water-soluble groups into the spectator ligand. The advantage of water-soluble catalysts is that the transfer hydrogenation reaction is carried out in a two-phase system, such as a (more) polar aqueous phase and (less polar)
It can be carried out in an organic phase, for example water / organic solvent, the catalyst and the reducing agent being in the aqueous phase and the starting materials and products being in the organic phase. As a result, the catalyst can be separated from the product very easily. A mixture of triethylamine and formic acid can also be chosen as the more polar phase. An example is the reduction of a ketone in a two-phase system, the more polar phase comprising an azeotrope of triethylamine and formic acid,
The less polar phase comprises a ketone and an alcohol formed therefrom, optionally in the presence of a water immiscible solvent. At the end of the reaction, the products can be easily separated by phase separation and the more polar phase can be reused in the reduction of a new batch of ketone after addition of excess formic acid. Another example of a more polar phase is an ionic liquid. Examples of these are salts of imidazoles such as 1-hexyl-3
-Methyl-imidazolium salt or N-alkylpyridinium salt. These compounds are characterized by the fact that they are liquid at room temperature.

The present invention also relates to a process for preparing optically chiral compounds from the corresponding prochiral compounds by catalytic asymmetric transfer hydrogenation in the presence of hydrogen donors and the catalysts of the invention described above. This method can be suitably used, for example, in the preparation of optically chiral alcohols, hydrazines or amines starting from the corresponding prochiral ketone and hydrazone, oxime derivative or imine, respectively.

The catalysts of the invention also include a carbonyl compound (eg ketone or aldehyde) or a dynamic resolution of an imine, oxime or hydrazone, which already contains at least one chiral center elsewhere in the molecule and which exists in racemic form. Can be used to advantage. Most preferably, the reduction of the carbonyl compound, imine, oxime or hydrazone occurs in only one of the two enantiomeric forms. about
By stopping the reaction when 50% conversion is achieved, the ketone (aldehyde, imine, oxime, hydrazone) can be recovered in substantially one enantiomeric form and the other enantiomer then , Substantially converted to the corresponding alcohol, amine or hydrazine.

The catalysts of the invention can also be used to advantage for the dynamic resolution of racemic alcohols by oxidation in the presence of the catalysts of the invention. In this reaction it is highly preferred that only one of the enantiomers of the alcohol be oxidized, and thus about 50
After% conversion, a mixture of alcohol consisting essentially of a single enantiomer and the corresponding ketone formed from the other enantiomer was formed. Suitable oxidizing agents for this purpose are ketones or aldehydes such as acetone or chloral (hydrate).

The catalysts according to the invention can also be used advantageously for asymmetrical mesodiols by oxidation in the presence of the catalysts according to the invention. In this reaction, the mesodiol is oxidized to the hydroxyketone in a stereoselective manner such that the product hydroxyketone consists essentially of a single enantiomer.

The catalysts according to the invention are also in principle, after about 50% conversion, substantially formed from one of two absolute configurations at the enantiomerically enriched ketone (chiral center not attached to the OH group). ) And two diastereomers of the optically chiral alcohols (consisting essentially of the absolute configuration of the other at the chiral center not bound to the OH group) of the present invention are formed. It can be advantageously used to prepare ketones in enantiomeric excess from racemic alcohols containing additional chiral racemic centers which are not bound to OH groups by oxidation in the presence of a catalyst.

However, if the chiral center not attached to the OH group is enantiomerically enriched, then
Oxidation with the catalysts of the invention yields ketones that are highly chiral. However, the catalysts of the present invention, in principle, selectively oxidize one of the two diastereomers that are epiisomeric at the carbon attached to the OH group, and thus after about 50% conversion, optical chirality. Rich in ketones (formed essentially from one of two optically chiral epimers) and diastereomerically enriched alcohols (consisting essentially of the other optically chiral epimer) ) Can be used to form a mixture.

The present invention also relates to a method of preparing optically chiral compounds having two or more chiral non-racemic centers, wherein the chiral non-racemic ketone, imine, oxime or hydrazone is It is reduced in the presence of the inventive catalyst. In this method, the ketone (imine, oxime or hydrazone) is completely reduced to a compound having substantially only one relative configuration between the existing chiral non-racemic center and the new chiral non-racemic center. To be done.

[0029]   As the prochiral compound, for example, a compound represented by the general formula:

[Chemical 5] A prochiral ketone of [wherein R and R'are not the same and are each independently an alkyl, aryl, aralkyl, alkenyl or alkynyl group (having 1 to 20 carbon atoms)
Or together to form a ring with the carbonyl C-atom to which they are attached, R and R ′ can also contain one or more heteroatoms or functional groups. Suitable examples of prochiral ketones include acetophenone, 1-acetonaphthone, 2-acetonaphthone, 3-quinuclidinone, 2-methoxycyclohexanone, 1-phenyl-2-butanone, benzyl-isopropyl ketone, benzylacetone, cyclohexyl-methyl ketone, tert. -Butyl-methyl ketone, tert-butyl-phenyl ketone, isopropyl-phenyl ketone, ethyl- (n-propyl) ketone,
o-, m- or p-methoxyacetophenone, o-, m- or p- (fluoro-, chloro-
, Bromo- or iodo-) acetophenone, o-, m- or p-cyano-acetophenone, o-, m- or p-nitro-acetophenone, 2-acetylfluorene, acetylferrocene, 2-acetylthiophene, 3-acetylthiophene , 2-acetylpyrrole, 3-acetylpyrrole, 2-acetylfuran, 3-acetylfuran, 1-indanone, 2-hydroxy-1-indanone, 1-tetralone, p-methoxyphenyl-p'-cyanophenylbenzophenone, cyclo Propyl- (4-methoxyphenyl) ketone, 2-
Including acetylpyridine, 3-acetylpyridine, 4-acetylpyridine, acetylpyrazine]; General formula:

[Chemical 6] A prochiral imine of [wherein R, R ′ and R ″ are, for example, each independently, alkyl, aryl,
Represents an aralkyl, alkenyl or alkynyl group (having 1 to 20 carbon atoms) or together forms a ring with the atom to which they are attached, R
, R ′ and R ″ can also contain one or more heteroatoms and functional groups, and R ″ can also be the group to be eliminated. Suitable prochiral imines can be prepared from the above-mentioned ketones and alkylamines, aralkylamines or arylamines or amino acid derivatives such as amino acid amides, amino acid esters, peptides or polypeptides. A suitable alkylamine,
Examples of aralkylamines and arylamines are benzylamine, such as benzylamine or o-, m- or p-substituted benzylamine, α-alkylbenzylamine, naphthylamine, such as naphthylamine, 1-, 2-, 3-, 4- , 6-, 7-, 8-,
Or 9-substituted naphthylamine and 1- (1-naphthyl) alkylamine or 1- (2
-Naphthyl) alkylamine. Suitable imines are, for example, N- (2-ethyl-6-methylphenyl) -1-methoxy-acetoneimine, 5,6-difluoro-2-methyl-1,4-benzoxazine, 2-cyano-1-pyrroline. , 2-ethoxycarbonyl-1-pyrroline, 2-phenyl-1-pyrroline, 2-phenyl-3,4,5,6-tetrahydropyridine and 3,4-dihydro-6,7-dimethoxy-1-methyl-isoquinoline The general formula:

[Chemical 7] An oxime or hydrazone [wherein -X contains a hetero atom and represents NH, NR or O, for example, R is alkyl, aryl,
Represents an aralkyl, alkenyl or alkynyl group (having 1 to 20 carbon atoms). R ₁ and R ₂ each independently represent an alkyl, aryl, aralkyl, alkenyl or alkynyl group (having 1 to 20 carbon atoms), or with each other,
Alternatively, R ₃ and the atom to which they are attached form a ring, which groups may also contain one or more heteroatoms and / or functional groups. In the case of an oxime or oxime ether, R ₃ is H or an alkyl, aryl, aralkyl, alkenyl or alkynyl group (having 1 to 20 carbon atoms)
And these groups can also contain one or more heteroatoms and / or functional groups; in the case of hydrazine, it is H, alkyl, aryl, alkenyl, alkynyl, acyl, phosphonyl or sulfonyl groups ( Having 1 to 20 carbon atoms), these groups may also contain one or more heteroatoms and / or functional groups. ] Can be used.

The process according to the invention is carried out in the presence of one or more hydrogen donors, which in the context of the invention comprise hydrogen in any manner, for example thermally or catalytically. It is understood to mean a compound that can be delivered to a substrate. Examples of suitable hydrogen donors which can be used are aliphatic or aromatic alcohols, especially secondary alcohols having 1 to 10 C-atoms, such as 2-propanol and cyclohexanol, acids such as formic acid, H 2. ₃ PO ₂ , H ₃ PO ₃ and salts thereof, partially unsaturated hydrocarbons, partially unsaturated heterocyclic compounds, hydroquinones or reducing sugars. Preferably 2-
Propanol or formic acid is used. The molar ratio of substrate to hydrogen donor is preferably between 1: 1 and 1: 100.

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

The temperature at which the asymmetric transfer hydrogenation is carried out is generally a compromise between the reaction rate on the one hand and the degree of racemization on the other hand, and is preferably −20 to 100 ° C., in particular 0 to 60 ° C.
The asymmetric transfer hydrogenation can in principle be carried out in an oxygen-containing atmosphere, but preferably the asymmetric transfer hydrogenation is carried out in an inert atmosphere, for example under nitrogen.

As solvent, in principle, any solvent which is inert in the reaction mixture can be used. In a preferred embodiment, a solvent that also acts as a hydrogen donor, such as 2-
Propanol is used. If the asymmetric transfer hydrogenation is carried out in water and a two-phase system is formed, water-soluble catalysts are preferably used. Catalysts for asymmetric transfer hydrogenations include hydrogenation with hydrogen, if desired, or bases such as alkaline (alkaline earth) compounds, such as alkaline (alkaline earth) hydroxides, alkaline (alkaline earth) carboxyls. Acid salts or alkali (alkaline earth) alkoxides (1-20 C-
It can be activated by treatment with (having atoms), the alkali metal is, for example, Li, Na or K, and the alkaline earth metal is, for example, Mg or Ca. Suitable bases are, for example, sodium hydroxide, potassium hydroxide,
Potassium-t-butoxide and magnesium methoxide.

In the preparation of the catalyst, the molar ratio of metal to optically chiral ligand is preferably selected from 2: 1 to 1:10, preferably from 1: 1 to 1: 6.

As the hydrogen donor in the method of the present invention, a hydrogen donor that performs irreversible transfer hydrogenation is advantageously used. An example of such a hydrogen donor is formic acid or formate salt, preferably in combination with triethylamine. In this case, formic acid decomposes and carbon dioxide gas is formed in the transfer hydrogenation reaction, which is out of reaction equilibrium and the reaction goes to completion. With these hydrogen donors that undergo irreversible transfer hydrogenation, higher substrate concentrations can be selected compared to alcohols such as isopropanol.

Preferably, the concentration of prochiral compound is at least 0.2 mol, more preferably at least 0.5 mol, even more preferably at least 0.7 mol per liter of hydrogen donor. Under these conditions, the catalysts of the invention have been found to be stable, especially when iridium is used as the transition metal.

[0037]   The present invention will be described with reference to examples, but is not limited to the examples.

[0038]

【Example】

Examples I-XIX and Comparative Examples C1-C3 Various catalysts according to the invention were prepared and tested under different conditions for their enantioselectivity and conversion. Here, the ligand, hydrogen donor, catalyst precursor and prochiral compound were changed. In Comparative Examples C1 to C3, for the catalyst according to the invention with very good performance, the sulfur in the optically chiral ligand (ligand 6) was replaced by oxygen (ligand 7). In all experiments, a standard combination of conditions as defined below was always used. The changes in these standard conditions used are given in Table 2 below, together with the results.

The reaction with formic acid as a hydrogen donor proceeds as follows. A solution of [IrCl (COD)] ₂ (0.01 mmol, 6.7 mg) as catalyst precursor (where COD is cyclooctadiene), 0.05 mmol of ligand and 4 mmol of substrate as substrate. Acetophenone was heated under argon at 65 ° C. for 30 minutes. The argon feed was stopped and 3 ml of a 5/2 azeotrope of formic acid (as hydrogen donor) and triethylamine was added in air. The reaction proceeded at 60 ° C. in an open vessel for the indicated time.

The reaction with 2-propanol as a hydrogen donor proceeds as follows. [I
A solution of rCl (COD)] ₂ (0.01 mmol, 6.7 mg), 0.05 mmol of ligand and 5 ml of 2-propanol was heated for 30 minutes at 80 ° C. After cooling to room temperature, the mixture was diluted with 33.75 ml 2-propanol and 4 mmol acetophenone and t-BuOK (1.25 ml, 0.1 M in propan-2-ol, 0.125 mmol). Was done.
The reaction was carried out at room temperature under argon for the indicated times.

The enantiomeric excess of the 1-phenethyl alcohol formed was 25 mCyclosil-B (
Capillary GL using Carlo Erba GC 6000 Vega 2 with chiral column
Measured by C. The enantiomer excess ratio is (([R] − [S]) / ([R] + [S
])) * 100%, where [R] and [S] are the concentrations of the R and S enantiomers. The conversion, expressed as the percentage of acetophenone converted in 1 hour, was measured by GLC. Optical rotation is Perk
Measured using an in-Elmer 241 automatic polarimeter.

The ligands used are given in Table 1 where Bn is benzyl, iPr is isopropyl and Ph is phenyl and are described below. The results of the examples and comparative examples according to the present invention are shown in Table 2.

S-benzyl- (R) -Cysteinol Sulfoxide (3) Hydrogen peroxide (30% in water, 5 mmol, 0.51 ml) was added at -70 ° C.
In S-benzyl- (R) -cysteinol (1 g, 5 mmol) in methanol was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. It was evaporated to dryness resulting in a white solid (100%). The two diastereomers were separated by repeated crystallization from ethanol.

S-benzyl- (R) -cysteinol (S) -sulfoxide (3 (S, R)
)

S-benzyl- (R) -cysteinol (R) -sulfoxide (3 (R, R)
)

(1R, 2S) -2-Amino-1-phenyl-1-isopropylthio-propa
(4) A slight excess of isopropyl mercaptan was added to (2S, 3S)-in methanol.
Added to the solution of 3-methyl-2-phenylaziridine. The solution was stirred at 65 ° C. overnight. The solvent and excess isopropyl mercaptan were removed under reduced pressure. The product was obtained as a pale yellow oil after column chromatography (silica gel 60, eluent: dichloromethane / 5% methanol, R _f value: 0.40).

(1R, 2S) -2-Amino-1-phenyl-1-benzylthio-propane (
5) A slight excess of benzyl mercaptan was converted to (2S, 3S) -3- in methanol.
Methyl-2-phenylaziridine was added to the solution. The solution was stirred at 65 ° C. overnight. The solvent was removed under reduced pressure. The product was subjected to column chromatography (silica gel 60, eluent: dichloromethane / methanol: 9/1, R _f value: 0).
． After 38) it was obtained as a pale yellow oil.

(1R, 2S) -2-Amino-1,2-diphenyl-1-benzylthio-ethane
(6) A slight excess of benzyl mercaptan was added to (2S, 3S) -2,
Added to the solution of 3-diphenylaziridine. The reaction mixture was stirred under reflux of methanol for 3 days. The solvent was removed under reduced pressure. The product was subjected to column chromatography (silica gel 60, eluent: ethyl acetate / hexane: 1/1, R _f
After a value of 0.37) was obtained as a pale yellow oil.

(1R, 2S) -2-Amino-1-phenyl-1- (2′-phenylethylthio)
E) -Propane (8) A slight excess of 2-phenylethyl mercaptan was added to (2S, 3
S) -3-Methyl-2-phenylaziridine was added to the solution. The solution is 6
It was stirred at 5 ° C. for 3 days. The solvent was removed under reduced pressure. The product was subjected to column chromatography (silica gel 60, eluent: diethyl ether, R _f value: 0.19).
After) was obtained as a colorless oil.

(1R, 2S) -2-Amino-1-phenyl-1-cyclohexylthio-pro
Bread (9) Slight excess of cyclohexyl mercaptan in (2S, 3S) in methanol
Added to the solution of -3-methyl-2-phenylaziridine. The solution was refluxed overnight. The solvent was removed under reduced pressure. The product was obtained as a colorless oil after column chromatography (silica gel 60, eluent: diethyl ether, R _f value: 0.14).

(1S, 2R) -2-Amino-1,2-diphenyl-1- (2′-phenylene
Tylthio) -ethane (10) A slight excess of 2-phenylethyl mercaptan gives (2R, 3
R) -2,3-diphenylaziridine was added to the solution. The solution was refluxed for 6 days. The solvent was removed under reduced pressure. The product was analyzed by column chromatography (
Obtained as a pale yellow oil after silica gel 60, eluent: ethyl acetate / hexane: 1/1).

[0052]

[Table 1]

[0053]

[Table 2] Table 2 1) Formic acid / triethylamine used as hydrogen donor 2) 2-Propanol used as hydrogen donor 3) The substrate is 1-naphthyl-methylketone. 4) The substrate is phenyl-ethylketone. 5) The catalyst precursor is [Ru (p-Cy) Cl 2] 2. 6) The catalyst precursor is [Rh (COD) Cl] ₂ .

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) // C07B 61/00 300 C07B 61/00 300 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Kamel, Paulus, Clemens, Joseph Holland, 1412 N. Werner Ruden, Froedscap 24 (72) Inventor van Leeuwen, Petrus, Wil Helms, Nicolas, Maria Netherlands, 3628 Schiekockengen, Roeldonp 45 (72) Inventor De Vries, Hanes, Geraldas The Netherlands, 6228 Gizet Marstricht, Bornedar 33 (72) Inventor Shemakael, Hans, Egbert The Netherlands, 6166 Aegean, Norbertinenstraat 10 F Term (reference) 4G069 AA06 AA08 BA27A BA27B BC67A BC70A BC71A BC74B BE03B BE09B BE46B CB57 DA02 4H006 AA02 AC41 AC81 BA20 BA22 BA23 BA24 BA52 BE20 4H039 CA60 CB20

Claims (22)

[Claims] 1. A catalyst for asymmetric transfer hydrogenation based on an optically chiral ligand containing a transition metal compound and a nitrogen, wherein the transition metal is iridium, ruthenium, rhodium or cobalt. A catalyst characterized in that the chiral ligand comprises sulfur in the form of a thioether or a sulfoxide, the sulfur being bound to the nitrogen via two or more carbon atoms. 2. The catalyst according to claim 1, wherein the transition metal is iridium. 3. A catalyst according to claim 1 or 2 in which the sulfur is bound to the nitrogen via two carbon atoms. 4. The catalyst according to any one of claims 1 to 3, wherein among the two or more carbon atoms that bond sulfur to nitrogen, at least the carbon bonded to sulfur is chiral. 5. The catalyst according to claim 1, wherein the ligand having a high optical chirality has two or more chiral centers. 6. The catalyst according to claim 5, wherein the optically chiral ligand is a sulfoxide, and one of the two or more chiral centers is sulfur of the sulfoxide. 7. The catalyst according to claim 5, wherein the ligand having a high optical chirality is a thioether in which both the carbon atom to which the thioether and the carbon atom to which the amino group are attached are chiral. 8. The catalyst according to claim 5, wherein the ligand having a high optical chirality is in a single diastereomeric form. 9. The catalyst according to claim 1, wherein sulfur is substituted with a substituted or unsubstituted aryl or heteroaryl, aralkyl or heteroaralkyl or an alkyl group. 10. The catalyst according to any one of claims 1 to 9, wherein the ligand having a high optical chiral property is derived from cysteine having a high optical chiral property. 11. The optically chiral ligand is derived by the reaction of an optically chiral aziridine converted with a thiol compound.
The catalyst according to claim 1. 12. A process for the preparation of a catalyst according to claim 1, wherein the sulfur is bound to the nitrogen via two or more carbon atoms and the sulfur is in the form of a thioether or sulfoxide. Comprising adding a nitrogen-containing optically chiral ligand, comprising a transition metal, an anion, and a catalyst precursor containing a spectator ligand that is difficult to exchange, to a catalyst precursor. 13. A method for producing a compound having a high optical chirality from a corresponding prochiral compound by catalytic asymmetric transfer hydrogenation in the presence of a catalyst and a hydrogen donor, which is any one of claims 1 to 11. A method comprising using the catalyst according to claim 1. 14. The method according to claim 13, wherein a prochiral ketone, imine, oxime or hydrazone is used as the prochiral compound. 15. A method for the dynamic resolution of a chiral racemic ketone, aldehyde, imine, oxime or hydrazone, which comprises a chiral racemic ketone,
One enantiomer of an aldehyde, imine, oxime or hydrazone,
13. A method for stereoselectively reducing in the presence of the catalyst according to any one of 11 above. 16. A method for producing a compound having a high optical chirality having two or more chiral centers, which is a chiral non-racemic ketone, imine, oxime or hydrazone. A method for diastereomerically reducing in the presence of the catalyst according to item 1. 17. A process for the dynamic resolution of racemic alcohols by the selective oxidation of one of the enantiomers of the alcohol in the presence of a catalyst according to claim 1. 18. A method for producing a hydroxyketone in an enantiomeric excess by the oxidation of mesodiol in the presence of the catalyst according to any one of claims 1 to 11. 19. Oxidation in the presence of a catalyst according to claim 1 to the corresponding racemic alcohol containing an additional chiral center not directly linked to the OH group, in enantiomeric excess to the ketone. And / or a method for producing alcohol. 20. Isopropanol is used as hydrogen donor.
20. A method for producing a compound having a high optical chiral property according to any one of 3 to 19. 21. Formic acid or formate is used as hydrogen donor.
17. A method for producing a compound having a high optical chiral property according to any one of 3 to 16. 22. The method for producing a compound having high optical chirality according to claim 21, wherein the content of the prochiral compound is at least 0.2 mol per liter of the hydrogen donor.