NO148322B - CATALYST FOR ASYMMETRIC HYDROGENERATION - Google Patents

Description

The present invention relates to a catalyst of that kind

which is stated in claim l's preamble.

'j

When an olefin, which in its saturated form is optically active, is hydrogenated, the usual end product is optically inactive mainly because an equivalent amount of both enantiomers

fer (racemic mixture) is formed. To obtain the desired enantiomorph, the mixture must be separated into its optical components

ter. This method is labor-intensive and expensive, and resul-

often results in the destruction of the undesired enantiomorph. On

because of these difficulties, increased attention has been devoted to asymmetric syntheses, whereby essentially one of the enantiomorphs is obtained.

It has now been found that excellent yields of a desired enantiomorph of α-amino acids can be obtained from the olefinic compounds which are 3-substituted-α-aeylamido-acrylic acids and/or their salts by hydrogenation of the olefinic bond in the presence of a new optically active coordinated metal complex as hydrogenation catalyst. Such a reaction is illustrated using the following equation:

The 3-substituent can be exemplified by such groups as hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,

aralkyl, amino, benzylamino, dibenzylamino, nitro, carboxy-

syl and carboxyl ester, etc.

Examples of α-amino acids, whose enantiomorphs can be rapidly prepared with the catalyst according to the present invention

see, is alanine, p-chlorophenylalanine, tryptophan, phenylalanine, 3-(3,4-dihydroxyphenyl)-alanine, 5-hydroxytryptophan, lysine,

histidine, tyrosine, leucine, glutamic acid and valine.

Further examples of compounds which can be hydrogenated with the present catalyst are shown in NO' pat. No. 142.075.

The optically active hydrogenation catalysts according to the invention are soluble, coordinated otmplexes, which contain a metal in combination with at least one optically active phosphine ligand. These catalysts are soluble in the reaction mass, and are therefore referred to as "homogeneous" catalysts.

The phosphine ligand can e.g. be of the formula AR^R^R^, where A

5 6 V

means phosphorus and R , R and R are independently selected from the group consisting of hydrogen; alkyl or alkoxy, having at least one carbon atom and a maximum of 12 carbon atoms; substituted alkyl whereby, by said substitution, groups consisting of amino, carbonyl, aryl, nitro and alkoxy are selected, whereby said alkoxy has a maximum of 4 carbon atoms; aryl; aryloxy; phenyl; substituted phenyl, whereby in said substitution one selects groups consisting of alkoxy and alkyl, hydroxy, aryloxy, amino and nitro, and that in said substitution less than 3 substituents occur; cycloalkyl of at least 3 carbon atoms; substituted cycloalkyl; pyrryl; thienyl; furyl; pyridyl; piperidyl; and 3-cholesteryl. At least one of the ligands is optically active and contains an o-anisyl group.

The optical activity of the catalyst according to the present invention is due to the phosphine ligand. This optical activity is due to an optically active group being bound to the phosphorus atom.

The catalyst is characterized by what is stated in the characterizing part of claim 1.

In the above coordinated metal complex formulas, only one ligand (L) need be optically active.

The optical activity of the ligand is due to an optically active group that is bound to the phosphorus atom, and there only needs to be one such group, and the other two groups can be the same or inactive. In this case, only one of the groups R 5 , R 6 or R 7 needs to be optically active, whereby the remaining two groups can be the same or inactive.

Catalysts comprise coordinated metal complexes with the formulas below. In the formulas, a star indicates asymmetry and thus optical activity. The asterisk indicates an asymmetric atom or a dissymmetric group. As an example, R shows that phosphorus is asymmetric. When no star is found, this indicates that there is no optical activity.

4

5 6 7

where A, R , R and R have previously indicated meanings, and X is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and iodine.

It appears from the catalysts listed above that the dissymmetrical group can be R<5>, R<6> or R<7> and is not limited to just one group. In addition, there may be a combination of parts that are bonded to the metal.

It appears that the above-mentioned formulas not only represent the coordinated metal complexes, which contain two or three ligands as in the formula RhXnL3, but that they also represent coordinated metal complexes in which the number of ligand-metal coordinated bonds is described by the number of L in the formula, and whereby these bonds are determined by the multidentate type ligands. Although it e.g. can only be two ligands in a particular coordination metal complex, the formula RhX^L^ will still stand for the complex; if one or two ligands are bidentate, i.e. they give two coordination bonds. In the same way, the formula RhXnL^ also represents those complexes in which there is only one ligand present, and if this ligand is tridentate it will give three coordination bonds.

The substituents on the phosphorus atoms include, for example, the following: methyl, ethyl, propyl, isopropyl, butyl and its isomers, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers , decyl and its isomers, undecyl and its isomers, dodecyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxyphenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 3-cholesteryl, benzyl, pyrryl, furyl, pyridyl, thienyl, piperidyl, menthyl, bornyl and pinyl.

A list of optically active phosphine that may be used includes, but is not limited to, methylethylphosphine, methylisopropylphosphine, ethylbutylphosphine, isopropylisobutylphosphine, methylphenylphosphine, ethylphenylphosphine, propylphenylphosphine, butylphenylphosphine, phenylbenzylphosphine, phenylpyrrolephosphine, ethylisopropylisobutylphosphine, methylphenyl-4 -methylphenylphosphine, ethylphenyl-4^methylphenylphosphine, methyliso-propylphenylphosphine, ethylphenyl-2,4,5-trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethylisopropylphosphine, o-methoxyphenylmethylphenylphosphine, o-methoxyphenylcyclohexylmethylphosphine .

The optically active phosphines contain at least one phenyl group which has a substituent in the ortho position, namely a methoxy group. Excellent results have been obtained with methyl-phenyl-o-anisylphosphine and methylcyclohexyl-o-anisylphosphine. The latter compound, prepared together with the optically active coordinated metal complex as hydrogenation catalysts are new compounds. It has been shown that the desired enantiomorphs of substituted and unsubstituted phenylalanines can be easily prepared with excellent yield by using such optically active ligands in the method according to the invention.

Although only one optically active group or ligand is necessary in the coordination ion metal^ complex catalyst, it is preferred for reasons of ease of preparation that all three ligands are the same in the above-described formula RhXnL^. It is also preferred that the asymmetry be attributed to the phosphorus atom.

Cationic coordination metal complexes, containing 2 equivalents of phosphine per mol rhodium and a chelating bis-olefin, can also be used as catalysts according to the present invention. E.g. by using the organic rhodium complexes, as described above, such cationic coordination rhodium complexes can be prepared by preparing a slurry of organic rhodium complex in an alcohol, such as e.g. ethanol, and adding 2 equivalents of the optically active phosphine so that an ionic solution is formed, after which a suitable anion is added, such as e.g. tetrafluoroborate, tetraphenylborate or some other anion which can cause precipitation or crystallization of a solid, cationic coordination metal complex, either directly from the solution or after treatment in a suitable solvent.

Examples of cationic coordination metal complexes are cyclooctadiene-1,5-bis(methylcyclohexyl-o-anisylphosphine)rhodium tetrafluoroborate, cyclooctadiene-1,5-bis(methyl-cyclohexyl-l-anisylphosphine)rhodium tetraphenylborate and bicyclo-2.2.l-hepta -2,5-diene-bis(methylcyclohexyl-o-anisylphosphine)-rhodium tetrafluoroborate.

It is assumed that the catalyst is actually present as a catalyst precursor, and that the catalyst is converted into an active form on contact with hydrogen. This conversion can of course be carried out during the actual hydrogenation of the olefin bond, or it can be carried out by exposing the catalyst (or precursor) to hydrogen prior to addition to the olefin material for hydrogenation.

Hydrogenation reactions are usually carried out in a solvent, such as e.g. benzene, ethanol, toluene, cyclohexane, and mixtures of these solvents. Almost any solvent of aromatic or saturated alkane or cycloalkane, and which is inactive to the hydrogenation conditions during the reaction, can be used.

As mentioned above, the catalyst is added to the solvent either as a compound per see or in the form of its components which then form the catalyst in situ. When the catalyst is added in the form of its components, it can be added before or simultaneously with the 3-substituted α-acylamido-acrylic acid. Components for producing the catalyst in situ are soluble metal compounds and optically active phosphine ligand.

The catalyst can be used in a catalytically effective amount, which is usually in the range from approx. 0.0001% to approx. 5% by weight metal content based on 3_substituted-α-acylamido-acrylic acid and/or the content of its salts.

As previously mentioned, it has been found that the asymmetric hydrogenation is enhanced in the presence of a base in the reaction mass. Although the asymmetric hydrogenation can be carried out in a reaction mass that is free of base, and even if it can be carried out under acidic conditions, the hydrogenation is enhanced by the addition of small amounts, which can amount to one equivalent basic material per moles of acrylic acid. It is surprising that a small amount of basic material added to even an acidic reaction mass will result in an enhanced asymmetric hydrogenation, and in fact it has been found that the formation of a small amount of salt of acrylic acid is sufficient to achieve these improved results.

Some bases that can be used are tertiary bases, such as e.g. triethylamine, NaOH, and almost any basic material that can form a salt with the carboxylic acids.

After adding the components to the solvent, hydrogen is added to the mixture, until approx. 1 to approx. 5 times the molar amount of 3-substituted-α-acylamido-acrylic acid, or in an amount ratio necessary to complete the hydrogenation to the desired point. The pressure of the reaction system will necessarily vary depending on the type of 3-substituted-α-acylamido-acrylic acid, catalyst type, the size of the hydrogenation apparatus, the ratio of the components and the amount of solvent and/or base. Lower pressures, including atmospheric or subatmospheric pressure, can be used as well as higher pressures.

The reaction temperatures can be in the range of approx. -20°C to approx. 110°C. Higher temperatures can be used, but are not normally necessary and can lead to an increase in side reactions.

After completion of the reaction, as determined by conventional methods, the solvent is removed and the products and catalyst are separated by conventional methods.

Desired enantiomorphs of the α-amino acids can be prepared by hydrogenation of the appropriate [3-substituted-α-acylamido-acrylic acid according to the present invention, after which the acyl group is removed from α-amino and other blocking groups by conventional methods, thereby obtaining the desired enantiomorphic compound.

It has been found that α-amino acids prepared from β-substituted-α-acylamido-acrylic acids and/or their salts can be readily prepared with a large predominance of the desired enantiomorphic compound. Thereby, the present catalyst becomes particularly valuable.

The following examples shall illustrate the invention. In the following, "parts" means parts by weight unless otherwise stated. In the examples, % optical purity is determined using the following equation, (the optical activities expressed as specific rotations are measured in the same solvent):

EXAMPLE 1

The optically active phosphines can be prepared according to the procedure of Mislow and Korpiun, J. Am. Chem. Soc. 89, 4784

(1967).

To a suitable container equipped with a stirring device, a temperature measuring instrument and a material coating device, 250 parts of phenyldichlorophosphine, 240 parts of pyridine and 495 parts of hexane were added. The solution was cooled

to approx. 5 - 10°C and a mixture consisting of 96 parts methanol and 27 parts hexane was added with stirring and over a period of approx. 1 - 1/2 hour. The hardened mixture was further stirred for 2 - 1/2 hours while heating to approx. 25°C. The reaction then took place in an inert nitrogen atmosphere.

Pyridine hydrochloride, which was formed during the reaction, was removed by filtration, and the filtrate was concentrated. The yellow residue was distilled collecting a colorless fraction boiling at 95.5-97°C/17 mm (82% yield dimethylphenylphosphonite). [Harwood and Grisley, J. Am. Chem. Soc, 82, 423 (1960)].

11 parts of dimethylphenylphosphonite, 2.5 parts of methyl iodide and 9 parts of toluene were added to a suitable container which was equipped with a stirring device, a temperature measuring instrument and material deposition devices. The resulting solution was heated slowly. The reaction is exothermic and the temperature increases from approx. 110°C, the reaction mixture is kept at a temperature of approx. 100-120°C and a further 185 parts of dimethylphenylphosphonite are added slowly. Additional quantities of methyl iodide, i.e. quantity increases of approx. 1 part, is added, if necessary, during the phosphate addition. Reak's ion mixture was kept at approx. 110°C for a further 1 hour followed by addition of the components. The reaction mixture was then distilled, and the fraction boiling at 148-149°C/17 mm was collected. (96% yield methylphenylmethylphosphinate.)

[Harwood and Grisley J. Am. Chem. Soc, 82, 423 (1960)].

To a suitable container equipped with a stirring device, a condensing device, a temperature measuring instrument and a material-dispensing device, 187 parts of methylphenyl-methylphosphinate and 1600 parts of carbon tetrachloride were added. To this mixture was added 229 parts of phosphorus pentachloride divided into three portions of 50 parts each and one portion of 79 parts. A temperature rise was observed during the addition of the first three portions. The mixture was stirred at approx. 60°C for two hours, and then carbon tetrachloride and phosphorus oxychloride were removed by distillation. The residue was distilled and the fraction boiling at 138-141°C/17 mm was collected (95% yield methylphenylphosphine chloride). [Method according to organic chemistry (Houben-Weyl) vol. XII/I, p. 243],

To a suitable vessel equipped with a stirring device, a condensing device, a temperature measuring instrument and a material deposition device, 78 parts of 1-menthol (Ua]^<5> = -50° in ethanol) and 72 parts of diethyl ether were added. 119 parts of triethylamine were added to the resulting solution, and the resulting mixture was cooled at approx. 0°C. To this mixture, 87 parts of methylphenylphosphine chloride were added with stirring over a time period of approx. 1 - 1/2 hour and at a temperature of approx. 0°C. The mixture was allowed to heat up to approx. 25°C and was then heated under reflux for approx. 10 - 1/2 hour.

To remove the triethylamine hydrochloride, the mixture was filtered and the filtrate concentrated. The concentrated filtrate gave a solid yield melting at 50-65°C, which is a mixture of diastereoisomers of 1-menthyl-methylphenylphosphinate (60% S and 40% R).

The above-prepared mixture of diastereoisomers of 1-menthylmethylphenylphosphinate was purified by crystallization several times in hexane followed by crystallization in diethyl ether and gave a solid melting at 78-82°C, which is in the S form of 1-Jthientylmethylphenylphosphinate ,

Under an inert nitrogen atmosphere, 18.3 parts of magnesium shavings, 13 parts of diethyl ether and an amount of iodine necessary for the initiation of the reaction were added to a suitable container equipped with a tube, device, temperature measuring instrument, material deposition device and condenser. A small amount of o-anisyl bromide was added to start the reaction, and then a mixture consisting of 138 parts of o-bromoanisole and 400 parts of diethyl ether was added so slowly that a suitable reflux of the reaction mixture could be maintained. After the mixture was all added, it was kept under reflux for a further 2 hours.

To this mixture was added a mixture consisting of 74 parts of either the R or S form of 1-menthyl-methyl-phenylphosphinate (the choice of the S or R form depends on the enantiomorph desired after the asymmetric hydrogenation) and 450 splits benzene. The diethyl ether was then removed and the resulting mixture heated for 64 hours at 78°C.

The reaction product of the magnesium complex was decomposed

in a solution of ammonium chloride, and the product extracted from the aqueous phase with benzene. After removal of benzene, the residual oil was distilled, whereby, after a pre-fraction consisting of menthol, a product with a boiling point of 180

- 190°C at 0.5 mm pressure. The crude methylphenyl-o-anisylphosphine oxide was obtained in 60% yield. By using the R form, a product was obtained with a specific rotation [a]^5= +27° (methanol). By using the S shape, a product with the opposite rotation was obtained.

Under an inert nitrogen atmosphere, 16 parts of trichlorosilane and 100 parts of benzene were added to a suitable container equipped with a stirring device, a temperature measuring instrument and a material coating device at approx. 5°C. A mixture of 12 parts triethylamine and 50 parts benzene was added to this mixture at 4 - 6°C. The resulting mixture was heated to 70°C and a mixture consisting of 7.5 parts of optically active methylphenyl-o-anisylphosphine oxide in 30 parts of benzene was added. The mixture was heated to 70°C for 1 hour and then cooled to 25°C.

The reaction product consisting of the silicone complex was decomposed by addition under a nitrogen atmosphere of 75 parts of 20% sodium hydroxide at 25°C under cooling. From the organic layer, the desired methylphenyl-o-anisylphosphine was obtained, which had a specific rotation [a]^ = +41° (methanol) when the above-mentioned produced phosphine oxide with a specific rotation [a]D 25 +27 o (methanol) was applied. With the opposite enantiomorphic phosphine oxide, a phosphine with opposite rotation was obtained.

EXAMPLE 2

Preparation of methylcyclohexyl-o-anisylphosphine

To a 1 liter autoclave were added 143 parts of (+)-methylphenyl-o-anisylphosphine oxide (prepared according to the above), 28 parts of 5% rhodium on carbon and 250 parts of methanol. The batch was heated to 75°C and stirred under 56 kg/cm<2> of hydrogen. After completion of hydrogen absorption, nmr analyzes showed that the reaction, which is illustrated by the above-mentioned equation, was 75% complete. A further 7.0 parts of catalyst were added, after which a pressure corresponding to 56 kg/cm 2 was applied and the batch allowed to go to 96% reaction.

The catalyst was filtered and methanol removed in vacuo. The crude oil was taken up in 200 parts of dibutyl ether and cooled to 0°C. The crystals, which were separated, were filtered and washed with hexane. 6 3 parts of methylcyclohexyl-o-anisyl phosphine oxide were obtained, which melts at 108-110°C and has a

20

specific rotation [a]D = +63 (methanol).

The above phosphine oxide can be reduced to methylcyclohexyl-o-anisylphosphine with a 95% yield by using HSiCl3 and triethylamine, and which was described earlier for methylphenyl-o-anisylphosphine. The resulting methylcyclohexyl-o-anisylphosphine is a solution with the specific ro-20

tation [ct]<Dw> = +98.5° (methanol).

EXAMPLE 3

Asymmetric hydrogenation of a-benzamido-4-hydroxy-3-cinnamic acid

To a hydrogenation apparatus equipped with a pressure gauge, temperature measuring instrument and heating device, 25 parts of <x-benzamido-4-hydroxy-3-methoxy-cinnamic acid and 186 parts of methanol and 64 parts of 5% sodium hydroxide were added. The batch was carefully purged to remove any trace of air and finally the pressure was regulated to 3.5 kg/cm with hydrogen at 25°C.

A catalyst solution was prepared by dissolving 0.0059 g of rhodium-1,5-hexadiene chloride ([Rh(1,5-hexadiene)Cl] 2 ) J. Am. Chem.Soc. 86, 217 (1964) in 2 ml of benzene under a nitrogen atmosphere. Then 0.0139 g of (+)-methylphenyl-o-anisylphosphine in 1.3 ml of benzene was added. Hydrogen was then allowed to flow through the mixture for 5 minutes. The resulting catalyst solution was then pressed into an autoclave using hydrogen pressure. The hydrogenation starts immediately and is completed after 3-4 hours at 25°C and 3.5 kg/cm<2>.

A sample of the solution obtained shows an optical purity of 56.4%, and this corresponds to a 78/22 L/D mixture of the sodium salt of N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine.

The N-benzoyl-substituted amino acid can be obtained in 95% yield by evaporating off the methanol and neutralizing the sodium salt with hydrochloric acid.

The obtained L-enantiomorph can be converted to L-DOPA by means of simple hydrolysis, which thereby removes the blocking groups, benzoyl and methyl in the 3-substitution position in phenyl.

EXAMPLE 4

25.0 g of α-benzamido-4-hydroxy-3-methoxy-cinnamic acid, 300 ml of methanol and 0.6 ml of 5% aqueous NaOH were added to a 1 liter autoclave. The batch was stirred at 25°C under 2.8 kg/cm<2 >pure hydrogen until it was ensured that there was no leakage. Subsequently, approx. 1 ml (0.01% Rh, 0.05% phosphine) of the following catalyst solution added by means of a membrane so that the pressure is not affected,

[the catalyst solution was prepared by dissolving under nitro-

gene atmosphere 0.0050 g [Rh (1,5-hexadiene)Cl]2 in 0.33 ml solution of methylphenyl-o-anisylphosphine with a specific rotation [a]D 25 = +42 o (methanol) in benzene, which contained 0.041 g/ml and diluting to 1 ml with methanol].

A stirring speed of 1400 rpm. is kept in the reaction mass, and hydrogen begins to absorb after a 2-5 minute induction period and the hydrogenation is finished in 2 hours.

Methanol is evaporated and the acid is dissolved in one mole of aqueous NaOH. The neutral catalyst is extracted with benzene and set aside for recovery. The free amino acid is then precipitated using concentrated HCl during crystallization. 24 g of N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine is obtained, which contains 73% L-enantiomorph and 27% D-enantiomorph. The L-enantiomorph can be converted to L-DOPA by hydrolysis as shown in example 4.

THE EXAMPLES 5 - IQ

Other optically active α-amino acids were prepared as described in Examples 3 and 4, together with the hydrogenated olefin compounds, the phosphine ligand using

des in the rhodium catalyst and the optical purity obtained are as follows:

EXAMPLE 11

An autoclave was charged with 25.0 g (0.085 mol) of α-acetamido-4-hydroxy-3-methoxycinnamic acid acetate, 300 ml of methanol and 0.36 ml of 50% NaOH. The autoclave was put under 2.5 kg/cm2 pressure with a 50/50 mixture of N2 and H2.

A catalyst solution was prepared by dissolving 0.0050 g (0.023 meq) of [Rh(1,5-hexadiene)Cl]2 in 0.5 ml of benzene and, under a nitrogen atmosphere, adding 0.051 meq. (+)-methylcyclohexyl-o-anisyl-phosphine (optical purity = about 90%) in 2.4 ml of benzene. Hydrogen was allowed to bubble through the solution for 10 minutes.

The catalyst solution was then added to the autoclave. The hydrogenation was carried out at 60°C and finished in 4 hours.

The product obtained by evaporation of the solvent was N^acetyl-3-(4-hydroxy-3-methoxyphenyl)"alanine acetate, which had a specific rotation [<x]D 25 = +38.2' (Na salt in water).Pure N-acetyl-3-(4-hydroxy--3-methoxyphenyl)-L-alanine acetate, as well as a sodium salt in water, had a specific

2 5 o

rotation [ct]D = + 54.0 .

Thus, the optical purity of the hydrogenation product was 70.7% or better than 85% of L-enantiomorph and 15% of D-enantiomorph.

By using a similar procedure and with (-)-methyl-cyclohexyl^o-anisylphosphine (optical purity = approx. 80%), a hydrogenation product containing mainly D-enantiomorph was obtained (optical purity of the reaction product mixture was 65%). Thus, by suitable choice of (+)- or (-)-phosphine, mainly one enantiomorph could be prepared.

EXAMPLE 12

A similar procedure as described in example 21 was applied to (-)-methylcyclohexyl-o-anisylphosphine, as optically active ligand and α-benzamido-4-hydroxy-3-methoxy-cinnamic acid as (3-substituted-α-acylamido -acrylic acid.

The hydrogenation product obtained was N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine which contained mainly D-enantlomorph (optical purity of the reaction product mixture = approx. 65%).

Claims (4)

1. Hydrogenation catalyst for asymmetric hydrogenation of 3-substituted α-acylamido-acrylic acids and/or salts thereof, characterized in that it consists of a rhodium coordination complex with at least one optically active phosphine ligand, which complex has the formula RhX n L3 -., where X betv- r H, Cl, F, Br or I, n is 1 or 3 and L-. means three phosphine ligands, of which at least one is optically active and contains an o-anisyl group, or the catalyst contains two equivalents of an optically active phosphine ired o-anisyl group per moles of rhodium, and a chelating biolefin. 2. Hydrogenation catalyst according to claim 1, characterized in that the optically active phosphine ligand contains a methyl group. 3. Hydrogenation catalyst according to claim 1, characterized in that the optically active phosphine ligand is methyl-phenyl-o-anisylphosphine. 4. Hydrogenation catalyst according to claim 1, characterized in that the optically active phosphine ligand is methyl-cyclohexyl-o-anisylphosphine.