CA1086771A - Asymmetric catalysis - Google Patents
Asymmetric catalysisInfo
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- CA1086771A CA1086771A CA259,754A CA259754A CA1086771A CA 1086771 A CA1086771 A CA 1086771A CA 259754 A CA259754 A CA 259754A CA 1086771 A CA1086771 A CA 1086771A
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- Prior art keywords
- substituted
- carbon atoms
- bis
- unsubstituted
- rhodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/303—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Abstract of the Disclosure Catalytic asymmetric hydrogenation of the Z geometric isomer of a compound of the formulae and
Description
`
~6~1 ASYMMETRIC CAT~L~SIS
This invention relates to new catalytic asymmetric hydrogenation processes. More specifically, this invention is directed to a hydrogenation process which provides outstanding levels of optical purity.
Homogeneous catalysis, i.e., those catalyzed reactions that are conducted where both reactants and catalysts are soluble in the reaction mass, have been found to be particularly useful in processes wherein an asymmetric result is obtained. For instance, it has been found that when an olefin, which is capable of forming a racemic mixture is hydrogenated in the presence of a homogeneous, optically active catalyst, one or the other of the possible optical enantiomorphs is obtained in a major amount with the other optical enantiomorph being obtained in minor amounts. ~urthermore, it has been found that certain such ole-finic substrates, for instance, precursors of ~ -amino acids containing ~-acylamido substituents, are particularly amenable to hydrogenation with homogeneous, optically active catalysts.
~- Such catalytic asymmetric hydrogenation processes have resulted in the production of large amounts of the desired optical enantlomorph. It has more recently been found that certain homogeneous, optically active catalysts containing optically active bis phosphine ligands provide outstanding levels of optical purity, i.e., reaching 80% and higher with such ~C-amino `
acid precursors. Other olefinic substrates which would provide such outstanding levels of optical purity, upon hydrogenation, are partloularly desirable.
It is an ob~ect of the present invention to provide such olefinic~substrates.
lt is a further object to provide novel catalytic asymmetric hydrogenation processes which produce large amounts of the desired optical enantiomorph.
, .. ~ , .. ,. . :. . ~ , . - .
~86~
These and other obJects, aspects and advantages of this invention will become apparent from a consideration of the - accompanying specification and claims.
Summary of the Invention : In accordance with the above obJects, the present in-vention provides catalytic asymmetric hydrogenation of the Z
geometric isomer of a compound of the formulae C = C.~
R'~ ~C~O :
: R
and R3 o :
o~ G C ~COOR
R~ ~ Rl . .-wherein~R, R1 and R2 each independently~represent hydrogen, substituted or unsubstituted alkyl having from 1 to 5 carbon :~.
: atoms or substituted or unsubstituted aryl, and R3 represents substituted or unsubstituted alkyl having from 1 to 5 carbon atoms or substituted or unsubstituted aryl, in the presence of :
a homogeneous, coordination complex catalyst comprising rhodium, iridium or ruthenium in combination with an optically active bis phosphine ligand. This process provides outstanding levels of optical purlty of desired optical enantiomorphs.
Description of the Preferred Embodiments The hydrogenation reaction is illustrated by the following equation: :
: R~ ~ `o~ ~o +H Rl * ~COOR2
~6~1 ASYMMETRIC CAT~L~SIS
This invention relates to new catalytic asymmetric hydrogenation processes. More specifically, this invention is directed to a hydrogenation process which provides outstanding levels of optical purity.
Homogeneous catalysis, i.e., those catalyzed reactions that are conducted where both reactants and catalysts are soluble in the reaction mass, have been found to be particularly useful in processes wherein an asymmetric result is obtained. For instance, it has been found that when an olefin, which is capable of forming a racemic mixture is hydrogenated in the presence of a homogeneous, optically active catalyst, one or the other of the possible optical enantiomorphs is obtained in a major amount with the other optical enantiomorph being obtained in minor amounts. ~urthermore, it has been found that certain such ole-finic substrates, for instance, precursors of ~ -amino acids containing ~-acylamido substituents, are particularly amenable to hydrogenation with homogeneous, optically active catalysts.
~- Such catalytic asymmetric hydrogenation processes have resulted in the production of large amounts of the desired optical enantlomorph. It has more recently been found that certain homogeneous, optically active catalysts containing optically active bis phosphine ligands provide outstanding levels of optical purity, i.e., reaching 80% and higher with such ~C-amino `
acid precursors. Other olefinic substrates which would provide such outstanding levels of optical purity, upon hydrogenation, are partloularly desirable.
It is an ob~ect of the present invention to provide such olefinic~substrates.
lt is a further object to provide novel catalytic asymmetric hydrogenation processes which produce large amounts of the desired optical enantiomorph.
, .. ~ , .. ,. . :. . ~ , . - .
~86~
These and other obJects, aspects and advantages of this invention will become apparent from a consideration of the - accompanying specification and claims.
Summary of the Invention : In accordance with the above obJects, the present in-vention provides catalytic asymmetric hydrogenation of the Z
geometric isomer of a compound of the formulae C = C.~
R'~ ~C~O :
: R
and R3 o :
o~ G C ~COOR
R~ ~ Rl . .-wherein~R, R1 and R2 each independently~represent hydrogen, substituted or unsubstituted alkyl having from 1 to 5 carbon :~.
: atoms or substituted or unsubstituted aryl, and R3 represents substituted or unsubstituted alkyl having from 1 to 5 carbon atoms or substituted or unsubstituted aryl, in the presence of :
a homogeneous, coordination complex catalyst comprising rhodium, iridium or ruthenium in combination with an optically active bis phosphine ligand. This process provides outstanding levels of optical purlty of desired optical enantiomorphs.
Description of the Preferred Embodiments The hydrogenation reaction is illustrated by the following equation: :
: R~ ~ `o~ ~o +H Rl * ~COOR2
2 ~ or
3 ~ optically 3 0 `` : G~ active R~ ~ :::
R~ ~Rl ~CH-CH 1 ~ ,.
-3- ~ :
16)~i36~
shows one or both carbon atoms are asymmetric wherein R, R1, R2 and R3 have the same meaning as described above.
It has been found that the geometric stereochemistry of the olefinic substrate being hydrogenated effects the results obtained. In general, it is necessary to utilize the Z geometric isomer to reali~e the outstanding levels of optical purity with the olefinic substrates of this invention. The E and Z geometric isomer nomenclature is described in detail in The Journal of Organic Chemistry, Vol. 35, No. 9, September 1970, pp 2849-2867.
R, Rl, R2 and R3 can be exempli~ied by alkyl groups such as methyl, ethyl~ propyl, etc. and by aryl groups such as phenyl, 4-chlorophenyl, 3,4-dihydroxyphenyl, 4-methylphenyl, etc.
Those skilled in the art will recognize that such substituents can be selected from a large number of groups and that this is limited only by the optical enantiomorph that is the desired end-product. Furthermore, it may occur that such substituent . ,~ , groups are themselves precursors of substituents that are desired substituents. For instance, if the desired substituent was hydroxyl the unsaturated precursor might contain the substituent "
-O-C-CH3 which would provide the hydroxyl by simple hydrolysis after the catalytic asymmetric hydrogenation.
The optical enantiomorphs resulting fro~ the process of this invention are particularly desirable in that optical activity is a characteristic of compounds which are biologically active, i.e. normally only one or the other optical enantiomorphs is useful in living organisms. For instance, those optical enantiomorphs resulting from this process which have an dC-hydroxy (resulting from simple hydrolysis) substituent on a carboxylic acid are recognized as replacements for ~ -amino acids.
R~ ~Rl ~CH-CH 1 ~ ,.
-3- ~ :
16)~i36~
shows one or both carbon atoms are asymmetric wherein R, R1, R2 and R3 have the same meaning as described above.
It has been found that the geometric stereochemistry of the olefinic substrate being hydrogenated effects the results obtained. In general, it is necessary to utilize the Z geometric isomer to reali~e the outstanding levels of optical purity with the olefinic substrates of this invention. The E and Z geometric isomer nomenclature is described in detail in The Journal of Organic Chemistry, Vol. 35, No. 9, September 1970, pp 2849-2867.
R, Rl, R2 and R3 can be exempli~ied by alkyl groups such as methyl, ethyl~ propyl, etc. and by aryl groups such as phenyl, 4-chlorophenyl, 3,4-dihydroxyphenyl, 4-methylphenyl, etc.
Those skilled in the art will recognize that such substituents can be selected from a large number of groups and that this is limited only by the optical enantiomorph that is the desired end-product. Furthermore, it may occur that such substituent . ,~ , groups are themselves precursors of substituents that are desired substituents. For instance, if the desired substituent was hydroxyl the unsaturated precursor might contain the substituent "
-O-C-CH3 which would provide the hydroxyl by simple hydrolysis after the catalytic asymmetric hydrogenation.
The optical enantiomorphs resulting fro~ the process of this invention are particularly desirable in that optical activity is a characteristic of compounds which are biologically active, i.e. normally only one or the other optical enantiomorphs is useful in living organisms. For instance, those optical enantiomorphs resulting from this process which have an dC-hydroxy (resulting from simple hydrolysis) substituent on a carboxylic acid are recognized as replacements for ~ -amino acids.
-4-.~ :
~)86'771 The compounds represented by the following structural formula provide excellent results with the process of this in-vention and there~ore represent compounds particularly amenable to the hydrogenation process of this invention Rl ~ COOR2 ~C = C~
R 0 ~ ~O
C~R3 wherein R, Rl, R2 and R3 have the same meaning as described above.
Particularly preferred embodiments of this invention are the catalytic asymmetric hydrogenation of (Z)-ethyl 2-(acetyloxy)-3-phenyl-2-propenoate~ (Z)-methyl 2-(acetyloxy)-2-propenoate and (~)-ethyl 2-(acetyloxy)-2-propenoate.
The L enantiomorphs of phenyllactic acid and lactic acid can be readily obtained by such procedures.
Such hydrogenation reactions are usually conducted in a solvent, such as benzene, ethanol, 2-propanol, toluene, cyclo- ~-hexane, and mixtures of these solvents. Almost any aromatic or saturated alkane or cycloalkane solvent, which is inactive to the hydrogenation conditions of this reaction, can be used. The preferred solvents are alcohols particularly methanol, ethanol and 2-propanol, for instance, those alcohols corresponding to the ester group in the olefinic substrate being hydrogenated are particularly desirable.
The homogeneous, optically active catalysts useful in this invention are soluble coordination complexes comprising a metal which is rhodium, iridium or ruthenium in combination with at least one optically active bis phosphine ligand, preferably at least about 0.5 moles of bis phosphine ligand per mole of metal.
These catalysts are soluble in the reaction mass and are there-fore referred to as "homogeneous" catalysts.
These catalysks contain optically active bis phosphine ~0 compounds of general formulae I and II below. These bis phosphine
~)86'771 The compounds represented by the following structural formula provide excellent results with the process of this in-vention and there~ore represent compounds particularly amenable to the hydrogenation process of this invention Rl ~ COOR2 ~C = C~
R 0 ~ ~O
C~R3 wherein R, Rl, R2 and R3 have the same meaning as described above.
Particularly preferred embodiments of this invention are the catalytic asymmetric hydrogenation of (Z)-ethyl 2-(acetyloxy)-3-phenyl-2-propenoate~ (Z)-methyl 2-(acetyloxy)-2-propenoate and (~)-ethyl 2-(acetyloxy)-2-propenoate.
The L enantiomorphs of phenyllactic acid and lactic acid can be readily obtained by such procedures.
Such hydrogenation reactions are usually conducted in a solvent, such as benzene, ethanol, 2-propanol, toluene, cyclo- ~-hexane, and mixtures of these solvents. Almost any aromatic or saturated alkane or cycloalkane solvent, which is inactive to the hydrogenation conditions of this reaction, can be used. The preferred solvents are alcohols particularly methanol, ethanol and 2-propanol, for instance, those alcohols corresponding to the ester group in the olefinic substrate being hydrogenated are particularly desirable.
The homogeneous, optically active catalysts useful in this invention are soluble coordination complexes comprising a metal which is rhodium, iridium or ruthenium in combination with at least one optically active bis phosphine ligand, preferably at least about 0.5 moles of bis phosphine ligand per mole of metal.
These catalysts are soluble in the reaction mass and are there-fore referred to as "homogeneous" catalysts.
These catalysks contain optically active bis phosphine ~0 compounds of general formulae I and II below. These bis phosphine
-5-4 3 Ll253 ~()86 compounds are characterized by the structural formula B B
wherein A and B each independently represent substituted and unsubstituted alkyl of from 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl having from 4 to 7 carbon atoms, substituted and unsubstituted aryl; provided that such substi-. tuents provide no significant inter~erence with the steric re-quirements around the phosphorus atom and A and B are different. ~.
Among such bis phosphine compounds~ those having two :~
dissimilar aryl groups on each phosphorus atom are also pre-ferred, particularly those wherein one such aryl group has an alkoxy substituent at the.ortho position. :
More preferred bis phosphine compounds useful in the ... present invention are t.he optically active bis phosphines ~ characterized by the structural formula `'., X - P - CH2CH2 - P - X
II ;
wherein X represents substituted and unsubstituted phenyl, Y represents substituted and unsubs~tituted 2-alkoxyphenyl ; .
wherein the alkoxy has from 1 to 6 carbon atoms; pro-vlded that such substituents provide no significant interference with the steric requirements around the phosphorus atom and X and Y are different.
The catalysts prepared utilizing those optically active bis phosphine compounds of more specific formula III, below, are more particularly preferred in the catalytic asymmetric hydro-genation react.ions of khis invention.
Still more particularly preferred optically active ' ~ bis phosphine compounds useful in the present invention are characterized by the structural formula N N III
-. ~ -6-.. . . . .
, 13-42531~
;77~
wherein M represen~s R"'O~_ N represents ~` , R' and R" each independently represent hydrogen, halogen~
alkyl having from l to 6 carbon atoms and alkoxy having from l to 6 carbon atoms, and :
. Rl'i represents normal alkyl having from l to 6 carbon atoms;
provided that M and N are different.
A particularly preferred optically active bis phosphine compound useful in the present invention is 1,2-bis(o-anisyl-phenylphosphino) ethane.
.~ : .
~; Other exemplary optically active bis phosphine com- .
: " . .
pounds useful in this invention are~
1,2-bis(o-anisyl-4-methylphenylphosphino) ethane 1,2-bis(o-anisyl-4-chlorophenylphosphino) ethane ` 1,2-bis(o-anisyl-3-chlorophenylphosphino) ethane ;~ ~ 1,2-bis(o-anisyl-4-bromophenylphosphino) ethane ,;
1,2-bis~(2-methoxy-5-chlorophenyl)-phenylphosphino] ethane 1,2-bisC(2-methoxy-5-bromophenyl)-phenylphosphino] ethane :: .
1,2-bis(2-ethoxyphenylphenylphosphino) ethane .:
1,2-bisCo-anisyl-(_-phenylphenyl)phosphino] ethane 1,2-blsC(2-methoxy-4-methylphenyl)-phenylphosphino] ethane 1~2~bis(2-ethoxyphenyl-4-chlorophenylphosphino) ethane 1,2-bis(o-anisyl-2-methylphenylphosphino) ethane 1,2-bis(o-anisyl-4-ethylphenylphosphino) ethane 1,2-bis(o-anisDl-3-ethylphenylphosphino) ethane 1,2-bis(o-anisyl-3-phenylphenylphosphino) ethane .
For these bis phosphine compounds to be useful in :
~, .
wherein A and B each independently represent substituted and unsubstituted alkyl of from 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl having from 4 to 7 carbon atoms, substituted and unsubstituted aryl; provided that such substi-. tuents provide no significant inter~erence with the steric re-quirements around the phosphorus atom and A and B are different. ~.
Among such bis phosphine compounds~ those having two :~
dissimilar aryl groups on each phosphorus atom are also pre-ferred, particularly those wherein one such aryl group has an alkoxy substituent at the.ortho position. :
More preferred bis phosphine compounds useful in the ... present invention are t.he optically active bis phosphines ~ characterized by the structural formula `'., X - P - CH2CH2 - P - X
II ;
wherein X represents substituted and unsubstituted phenyl, Y represents substituted and unsubs~tituted 2-alkoxyphenyl ; .
wherein the alkoxy has from 1 to 6 carbon atoms; pro-vlded that such substituents provide no significant interference with the steric requirements around the phosphorus atom and X and Y are different.
The catalysts prepared utilizing those optically active bis phosphine compounds of more specific formula III, below, are more particularly preferred in the catalytic asymmetric hydro-genation react.ions of khis invention.
Still more particularly preferred optically active ' ~ bis phosphine compounds useful in the present invention are characterized by the structural formula N N III
-. ~ -6-.. . . . .
, 13-42531~
;77~
wherein M represen~s R"'O~_ N represents ~` , R' and R" each independently represent hydrogen, halogen~
alkyl having from l to 6 carbon atoms and alkoxy having from l to 6 carbon atoms, and :
. Rl'i represents normal alkyl having from l to 6 carbon atoms;
provided that M and N are different.
A particularly preferred optically active bis phosphine compound useful in the present invention is 1,2-bis(o-anisyl-phenylphosphino) ethane.
.~ : .
~; Other exemplary optically active bis phosphine com- .
: " . .
pounds useful in this invention are~
1,2-bis(o-anisyl-4-methylphenylphosphino) ethane 1,2-bis(o-anisyl-4-chlorophenylphosphino) ethane ` 1,2-bis(o-anisyl-3-chlorophenylphosphino) ethane ;~ ~ 1,2-bis(o-anisyl-4-bromophenylphosphino) ethane ,;
1,2-bis~(2-methoxy-5-chlorophenyl)-phenylphosphino] ethane 1,2-bisC(2-methoxy-5-bromophenyl)-phenylphosphino] ethane :: .
1,2-bis(2-ethoxyphenylphenylphosphino) ethane .:
1,2-bisCo-anisyl-(_-phenylphenyl)phosphino] ethane 1,2-blsC(2-methoxy-4-methylphenyl)-phenylphosphino] ethane 1~2~bis(2-ethoxyphenyl-4-chlorophenylphosphino) ethane 1,2-bis(o-anisyl-2-methylphenylphosphino) ethane 1,2-bis(o-anisyl-4-ethylphenylphosphino) ethane 1,2-bis(o-anisDl-3-ethylphenylphosphino) ethane 1,2-bis(o-anisyl-3-phenylphenylphosphino) ethane .
For these bis phosphine compounds to be useful in :
~, .
6~7~
asymmetric hydrogenation reactions they must be utilized as the optically active enantiomorph and not in the meso ~orm.
Optical activity of the coordinated complex catalysts useful in this invention resides in the bis phosphine ligand.
This optical activity results from having two different groups, in addition to the ethane bridge, on the phosphorus atom.
Illustrative coordination metal complexes can be represented by the ~ormula MeTL wherein Me is a transition metal selected ~rom the group consisting of rhodium, iridium and ruthen-ium; T is selected ~rom the group consisting of hydrogen, fluorine,bromine, chlorine and iodine; L is the optically active bis phosphine ligand as previously de~ined.
It has been found that outstanding levels of optical purity of the desired optical enantiomorphs can be achieved not only with the above-described catalysts represented by the formula MeTL, which are coordination complexes o~ a metal selected ~rom the group consisting of rhodium, iridium and ru-thenium, but can also be achieved when the hydrogenation is carried out in the presence of an in situ complex catalyst that comprises a solution of a transition metal selected from the group consisting of rhodium, iridium and ruthenium and at least about 0.5 moles of the optically active bis phosphine ligand per mole of metal. For instance, such catalysts can be prepared by dissolving a soluble compound of the appropriate metal in a suitable solvent together with an optically active bis phosphine compound as the ligand wherein the ratio of ligand to metal is at least 0.5 moles of ligand per mole of metal, preferably one mole of ligand per mole of metal. It has been found that the catalyst is formed in situ by adding a soluble metal compound to the reaction mass together with the addition of the proper amount of the optically active bis phosphine ligand to the reaction mass either before or during hydrogenation.
~,:
113-~1253.~
~llDI!~67~ -The preferred metal ror use in this process is rhodium.
Soluble rhodium compounds that can be utilized include rhodium trichloride hydrate, rhodium tribromide hydrate, rhodium sul~ate, organic rhodium complexes with ethylene, propylene, etc., and bis olefins such as 1,5-cyclooctadiene and 1,5-hexadiene, bicyclo-2.2.1-hepta-2,5-diene and other dienes which can ~orm bidentate ligands, or an active ~orm o~ metallic rhodium that is readily solubilized.
It has been found that a preferred embodiment of this invention is the hydrogenation process where the optically active bls phosphine ligand is present in a ratio of about 0.5 to about -` 2.0, preferablg, 1.0, moles of bis phosphine ligand per mole of metal. In practice, it is preferred to have the optically active catalyst in a solid form for purposes of handling and storage.
It has been ~ound that outstanding results can be obtained with solid, cationic coordination metal complexes.
Catlonic coordination metal complexes containing one mole of the optlcally active bis phosphine ligand per mole of :
metal and a chelating bis olefin represent a pre~erred form of the oatalysts useful in the present invention. For instance, using organic rhodium complexes, as described above, one can prepare such cationic coordination rhodium complexes by slurrying the organic rhodium complex in an alcohol, such as ethanol, adding one mole per mole of rhodium of the optically active bis phos-phine compound 8G that an ionic solution is formed, followed by the addition of a suitable anion, such as, for instance, tetra-fluoroborate, tetraphenylborate or any other anion that will result in the preclpltation or crystallization of a solid, cationic coordination metal complex either directly from the solvent or upon treatment in an appropriate solvent.
~ Exemplary cationic coordination metal complexes are cyclooctadiene-1,5-[1,2-bis(o-anisylphenylphosphina) ethane]
':'' - .
_g_ .. , : - : . . - -6~7~
rhodium tetrafluoroborate, cyclooctadiene-1,5-[1,2-bls(o-anisyl-phenylphosphino) ethane] rhodium tetraphenyl borate and bicyclo-2.2.1-hepta-2,5-diene-[1,2-bis(o-anisylphenylphosphino) ethane]
rhodium tetrafluoroborate.
Wikhout prejudice to the present invention it is thought that the catalyst is present actually as a catalyst pre-cursor and that upon contact with hydrogen the catalyst is con-verted to an active form. This conversion can, of course, be carried out during the actual hydrogenation or can be accomplished by subjecting the catalyst (or precursor) to hydrogen prior to addition to the reaction mass to be hydrogenated.
As previously noted, the catalyst can be added to the solvent either as a compound per se or as its components wh~ch then form the catalyst in situ. When the catalyst is added as its components it may be added prior to or after the addition of the olefinic substrate. Components for the preparation of the catalyst in situ are the soluble metal compound and the optically active bis phosphine compound. The catalyst can be added in any effective catalytic amount and generally in the ~0 range of about 0.001% to about 5% by weight of contained metal based on the olefinic substrate to be hydrogenated.
Within the practical limits, means should be provided so as to avoid contacting the catalyst or reaction mass with oxidlzing materials. In particular, care should be taken so as to avoid contact with oxygen. It is preferred to carry out the hydrogenation reaction preparation and actual reaction in gases (other than H2) that are inert to both reactants and catalysts such as, for instance, nitrogen or argon.
After addition of the reactants and catalyst to the solvent, hydrogen is added to the mixture until about 0.5 to about 5 times the mole quantity of the olefinic substrate present has been added. The pressure of the system will ., : . , . . : . . ., - :
113-L1253~
:
~l~)86~77~
necessarily vary since it wlll be dependent upon the type of reactant, type of catalyst, size of hydrogenation apparatus, amount of reactants and catalyst and amount of solvent.
Lower pressures, including atmospheric and sub-atmospheric pressure can be used as well as higher pressure.
Reaction temperatures may be in the range of about -20C. to about 110C. Higher temperatures may be used but are normally not required and may lead to an increase of side reac-tions.
Upon completion of the reaction which, is determined by conventional means, the product ~s recovered by conventional means.
Many natura].ly occurring products and medicaments exist in an optically active form. In these cases only the L or D
form is usually effective. Synthetic preparation of these com-pounds in the past has required an additional step of separating the products into its enantiomorphs. This process is expensive and time consuming. The process of the present invention permits the direct formation of desired optical enantiomorphs with out-standing optical purity thus eliminating much of the time consum-ing and expensive separation of such optical enantiomorphs.Furthermore, the process provides a higher yield of the desired optical enantiomorph while concurrently decreasing the yield of the unwanted optical enantiomorph.
The hydrogenation process of this invention is particu-; larly deslrable because of its ability to not only provide an : ;
unusually high optical purity of the desired optical enantiomorph but also because of its ability to afford a rapid rate of hydro~
genation at low catalyst concentrations.
The following examples will serve to illustrate certain specific embodiments within the scope of this invention and arenot to be construed as limiting the scope thereof. In the examples, the percent optical purity is determined by the follow-.
--11-- . -`.' '.' ' '~ ' ' ''" ' '' '''. .
. .
L~3_ Ll 253~
~16'771 ing equation tit being understood that the optical activity, ex-pressed as specific rotation, is measured in the same solvent):
%Optical = Observed optical activity of the mixture x 100 Purity Optical activity o~ pure optical isomer.
Exam~le 1 Preparation of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate A solution containing 22 g. of ethyl phenylpyruvate, 65 g. of acetic anhydride and 20 mg. of _-toluenesulfonic acid monohydrate was refluxed for 2.5 hours. Excess acetic anhydride was stripped from the reaction mass and the product, crude 10 (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate, was distilled at about 1.6 mm. Hg. (b.p. 120-135C.). The recovered product crystallized on standing in refrigeration and was recovered by filtration and recrystallized from ethanol, recovered 12.1 g., m.p. 41-47C.; second recrystallization, 10.5 g., m.p. 47-49C.;
third recrystallization, 9.2 g., m.p. 47-49C.
Example 2 ~; Preparation of ethyl_2~(acetyloxy)-3-phenylpropanoate (A) 1.9903 g. of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate and 0.0175 g. of cyclooctadiene-1,5-[1,2-bis(o-20 anisylphenylphosphino) ethane~ rhodium tetrafluoroborate in 30 cc. of ethanol was shaken in a Hoke bomb at about 27 atm. and ;
.-50C. Hydrogen uptake was essentially complete in 2 hours. The resulting solution was stripped of ethanol on a rotary evaporator j and examined by NMR which confirmed the presence of the hydro-genation product~ ethyl-2-(acetyloxy)-3-phenylpropanoate, as an oil. The product was-recovered by vacuum distillation. 1.6 g.
o~ di.stillate, b.p. 80-83C. at 0.05 mm.Hg. were recovered. NMR ~;
`
assay shows the product to consist of 97.6% of the desired hydro-genation product and 2.4% of the starting olefin. Gas chromato-: ~ .
30 graphy confirmed this assay. The [~ ]20 = -6.91 (C = 6.o in CHC13). Optical purity was 79.4%, if ad~usted for assay would be 81.5%
~-' (B) 2.2721 g. of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate and 0.0202 g. cyclooctadiene 1,5-[1~2-bis(_-anisyl-phenylphosphino) ethane] rhodium tetrafluoroborate in 30 cc. of ethanol was subjected to 3 atm. H2 pressure at 51C. The resul-ting solution was stripped of ethanol on a rotary evaporator.
NMR shows 89% completion after 6 hours. The product~ ethyl-2-: (acetyloxy)-3-phenylpropanoate, was recovered by flash distilla-tion, b.p. 80-85C. at 0. 5 mm. Hg. NMR assay shows 87.o% of the desired product. The observed rotation of the product was 0.515~ -~o~]D = 8.27 (C=6.o in CHC13). Optical purity adjusted for assay was 95%.
Example 3 Preparation of (Z)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate A solution of 27.8 g. (0.145 mole) of ethyl-3-oxo-3-phenylpropanoate, 29.0 g. of 2-acetyloxy-1-propene, and 100 mg.
of _-toluenesulfonic acid monohydrate was heated to reflux for 17 hours. The reaction mass was poured into 50 ml. of a 5C.
saturated solution of NaHCO3 and the organic phase was extracted into ethyl ether. The ether solution was dried and the solvent was stripped off. Distillation of the residue at 0.1 mm. of Hg.
, yielded 8.3 g. of a yellow oil, b.p. 110-120C. ~he distillate ~-was shown by GLC, NMR and W analysis to be (Z)-ethyl-3-(acetyl-oxy)-3-phenyl-2-propenoate.
Example 4 Preparation of ethyl-3-(acetyloxy)-3-phenylpropanoate A solution of 2.5 g. of (Z)-ethyl-3-(acetyloxy) 3-phenyl-2-propenoate (2.65 g.) and 0.0373 g. of cyclooctadiene-1,5-[1,2-bis(o-anisylphenylphosphino) ethane] rhodium tetrafluoro-borate in 30 cc. of ethanol was hydrogenated at 27 atm. and 50C.
` 30 in a Hoke bomb. After 12 hours the produck was isolated by re-moving the ethanol on a rotary evaporator. NMR analysis indicated that the hydragenation product to olefin ratio was 89:11. In `
~: - , .
. ~ . -, ., ,~, 4 3_ L~ 2 5 3~
~ 36~7~
addition, some ethyl 3-phenylpropanoate was present, which arose from hydrogenolysis.
2.5 g. of crude product was subjected to distillation, a first fraction was collected, b.p. 75-87C. at 0.1 mm. of Hg., which was ethyl 3-phenylpropanoate. The remaining material that distilled at 95-110C. and 0.1 mm. of Hg. was an 86:14 (NMR) mixture o~ ethyl-3-(acetyloxy)-3-phenylpropanoate and (Z)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate.
[C]D = ~4 74 (neat, 1=1). With correction for NMR
assay, the optical purity is 90.5%.
Example 5 Preparation of (E)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate A solution of 5.2 g. of (Z)-ethyl-3-(acetyloxy)-3~
phenyl-2-propenoate in 60 ml. of CXC13 was irridiated with 3100 A
light for 72 hours. The solvent was removed on a rotary evapora-tor. Distillation of the residue at 0.03 mm. of Hg. yielded 1.3 g. of yellow oil, b.p. 92-98C. The distillate was shown by ~LC, NMR, and UV analysis to be (E)-ethyl-3-(acetyloxyj-3-phenyl-2-propenoate of 86% purity.
Example 6 Preparation of ethyl-3-(acetyloxy)-3-phenylpropanoate A salution of 1.1566 g. of the (E)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate prepared in Example 5 (86% purity) and 0.027 g. of cyclooctadiene-1,5-[1,2-bis(_-anisylphenylphosphino) ; ethane] rhodium tetrafluoroborate in 30 cc. of ethanol was hy-drogenated ~or 5 hours at 27 atm. and 50C. Ethanol was then ` stripped on a rotary evaporator and the product examined by NMR
analysis. The hydrogenation product to olefin ratio was 76:24.
This product mix was distilled at 95-120C. and 0.2 mm. of Hg.
Gas chromatography assay of the distillate indicated the ethyl-3-(acetyloxy)-3-phenylpropanoate to (E)-ethyl-3-(acetyloxy)-3- -phenyl-2-propenoate to ethyl 3-phenylpropanoate ratio was 64:18:18.
.. . . . . . .
. . .: ~ ~ . : , . . . : , ,, - :. ~ .: : . . . -~lO8~ 7~
This mixture had a Cc~]20 = +0.515 (neat, 1=1) with correction - -for assay of the desired hydrogenation product the COr]D
+0.805 (neat>l=l). Optical purity is 15.4~.
While the invention has been described herein with regard to certain specific embodiments, it is not so limited. It is to be understood that variations and modifications thereof may be made by those skilled in the art without departing from the spirit and scope o~ the invention.
.~ .
.. .
.
. .: .
, , ~ . ~.
~'~
. . ..
';
: ~.
.
. -15- .
:. - ~ , -~. : : ~ . .. -.~ ~ - , . . .
asymmetric hydrogenation reactions they must be utilized as the optically active enantiomorph and not in the meso ~orm.
Optical activity of the coordinated complex catalysts useful in this invention resides in the bis phosphine ligand.
This optical activity results from having two different groups, in addition to the ethane bridge, on the phosphorus atom.
Illustrative coordination metal complexes can be represented by the ~ormula MeTL wherein Me is a transition metal selected ~rom the group consisting of rhodium, iridium and ruthen-ium; T is selected ~rom the group consisting of hydrogen, fluorine,bromine, chlorine and iodine; L is the optically active bis phosphine ligand as previously de~ined.
It has been found that outstanding levels of optical purity of the desired optical enantiomorphs can be achieved not only with the above-described catalysts represented by the formula MeTL, which are coordination complexes o~ a metal selected ~rom the group consisting of rhodium, iridium and ru-thenium, but can also be achieved when the hydrogenation is carried out in the presence of an in situ complex catalyst that comprises a solution of a transition metal selected from the group consisting of rhodium, iridium and ruthenium and at least about 0.5 moles of the optically active bis phosphine ligand per mole of metal. For instance, such catalysts can be prepared by dissolving a soluble compound of the appropriate metal in a suitable solvent together with an optically active bis phosphine compound as the ligand wherein the ratio of ligand to metal is at least 0.5 moles of ligand per mole of metal, preferably one mole of ligand per mole of metal. It has been found that the catalyst is formed in situ by adding a soluble metal compound to the reaction mass together with the addition of the proper amount of the optically active bis phosphine ligand to the reaction mass either before or during hydrogenation.
~,:
113-~1253.~
~llDI!~67~ -The preferred metal ror use in this process is rhodium.
Soluble rhodium compounds that can be utilized include rhodium trichloride hydrate, rhodium tribromide hydrate, rhodium sul~ate, organic rhodium complexes with ethylene, propylene, etc., and bis olefins such as 1,5-cyclooctadiene and 1,5-hexadiene, bicyclo-2.2.1-hepta-2,5-diene and other dienes which can ~orm bidentate ligands, or an active ~orm o~ metallic rhodium that is readily solubilized.
It has been found that a preferred embodiment of this invention is the hydrogenation process where the optically active bls phosphine ligand is present in a ratio of about 0.5 to about -` 2.0, preferablg, 1.0, moles of bis phosphine ligand per mole of metal. In practice, it is preferred to have the optically active catalyst in a solid form for purposes of handling and storage.
It has been ~ound that outstanding results can be obtained with solid, cationic coordination metal complexes.
Catlonic coordination metal complexes containing one mole of the optlcally active bis phosphine ligand per mole of :
metal and a chelating bis olefin represent a pre~erred form of the oatalysts useful in the present invention. For instance, using organic rhodium complexes, as described above, one can prepare such cationic coordination rhodium complexes by slurrying the organic rhodium complex in an alcohol, such as ethanol, adding one mole per mole of rhodium of the optically active bis phos-phine compound 8G that an ionic solution is formed, followed by the addition of a suitable anion, such as, for instance, tetra-fluoroborate, tetraphenylborate or any other anion that will result in the preclpltation or crystallization of a solid, cationic coordination metal complex either directly from the solvent or upon treatment in an appropriate solvent.
~ Exemplary cationic coordination metal complexes are cyclooctadiene-1,5-[1,2-bis(o-anisylphenylphosphina) ethane]
':'' - .
_g_ .. , : - : . . - -6~7~
rhodium tetrafluoroborate, cyclooctadiene-1,5-[1,2-bls(o-anisyl-phenylphosphino) ethane] rhodium tetraphenyl borate and bicyclo-2.2.1-hepta-2,5-diene-[1,2-bis(o-anisylphenylphosphino) ethane]
rhodium tetrafluoroborate.
Wikhout prejudice to the present invention it is thought that the catalyst is present actually as a catalyst pre-cursor and that upon contact with hydrogen the catalyst is con-verted to an active form. This conversion can, of course, be carried out during the actual hydrogenation or can be accomplished by subjecting the catalyst (or precursor) to hydrogen prior to addition to the reaction mass to be hydrogenated.
As previously noted, the catalyst can be added to the solvent either as a compound per se or as its components wh~ch then form the catalyst in situ. When the catalyst is added as its components it may be added prior to or after the addition of the olefinic substrate. Components for the preparation of the catalyst in situ are the soluble metal compound and the optically active bis phosphine compound. The catalyst can be added in any effective catalytic amount and generally in the ~0 range of about 0.001% to about 5% by weight of contained metal based on the olefinic substrate to be hydrogenated.
Within the practical limits, means should be provided so as to avoid contacting the catalyst or reaction mass with oxidlzing materials. In particular, care should be taken so as to avoid contact with oxygen. It is preferred to carry out the hydrogenation reaction preparation and actual reaction in gases (other than H2) that are inert to both reactants and catalysts such as, for instance, nitrogen or argon.
After addition of the reactants and catalyst to the solvent, hydrogen is added to the mixture until about 0.5 to about 5 times the mole quantity of the olefinic substrate present has been added. The pressure of the system will ., : . , . . : . . ., - :
113-L1253~
:
~l~)86~77~
necessarily vary since it wlll be dependent upon the type of reactant, type of catalyst, size of hydrogenation apparatus, amount of reactants and catalyst and amount of solvent.
Lower pressures, including atmospheric and sub-atmospheric pressure can be used as well as higher pressure.
Reaction temperatures may be in the range of about -20C. to about 110C. Higher temperatures may be used but are normally not required and may lead to an increase of side reac-tions.
Upon completion of the reaction which, is determined by conventional means, the product ~s recovered by conventional means.
Many natura].ly occurring products and medicaments exist in an optically active form. In these cases only the L or D
form is usually effective. Synthetic preparation of these com-pounds in the past has required an additional step of separating the products into its enantiomorphs. This process is expensive and time consuming. The process of the present invention permits the direct formation of desired optical enantiomorphs with out-standing optical purity thus eliminating much of the time consum-ing and expensive separation of such optical enantiomorphs.Furthermore, the process provides a higher yield of the desired optical enantiomorph while concurrently decreasing the yield of the unwanted optical enantiomorph.
The hydrogenation process of this invention is particu-; larly deslrable because of its ability to not only provide an : ;
unusually high optical purity of the desired optical enantiomorph but also because of its ability to afford a rapid rate of hydro~
genation at low catalyst concentrations.
The following examples will serve to illustrate certain specific embodiments within the scope of this invention and arenot to be construed as limiting the scope thereof. In the examples, the percent optical purity is determined by the follow-.
--11-- . -`.' '.' ' '~ ' ' ''" ' '' '''. .
. .
L~3_ Ll 253~
~16'771 ing equation tit being understood that the optical activity, ex-pressed as specific rotation, is measured in the same solvent):
%Optical = Observed optical activity of the mixture x 100 Purity Optical activity o~ pure optical isomer.
Exam~le 1 Preparation of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate A solution containing 22 g. of ethyl phenylpyruvate, 65 g. of acetic anhydride and 20 mg. of _-toluenesulfonic acid monohydrate was refluxed for 2.5 hours. Excess acetic anhydride was stripped from the reaction mass and the product, crude 10 (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate, was distilled at about 1.6 mm. Hg. (b.p. 120-135C.). The recovered product crystallized on standing in refrigeration and was recovered by filtration and recrystallized from ethanol, recovered 12.1 g., m.p. 41-47C.; second recrystallization, 10.5 g., m.p. 47-49C.;
third recrystallization, 9.2 g., m.p. 47-49C.
Example 2 ~; Preparation of ethyl_2~(acetyloxy)-3-phenylpropanoate (A) 1.9903 g. of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate and 0.0175 g. of cyclooctadiene-1,5-[1,2-bis(o-20 anisylphenylphosphino) ethane~ rhodium tetrafluoroborate in 30 cc. of ethanol was shaken in a Hoke bomb at about 27 atm. and ;
.-50C. Hydrogen uptake was essentially complete in 2 hours. The resulting solution was stripped of ethanol on a rotary evaporator j and examined by NMR which confirmed the presence of the hydro-genation product~ ethyl-2-(acetyloxy)-3-phenylpropanoate, as an oil. The product was-recovered by vacuum distillation. 1.6 g.
o~ di.stillate, b.p. 80-83C. at 0.05 mm.Hg. were recovered. NMR ~;
`
assay shows the product to consist of 97.6% of the desired hydro-genation product and 2.4% of the starting olefin. Gas chromato-: ~ .
30 graphy confirmed this assay. The [~ ]20 = -6.91 (C = 6.o in CHC13). Optical purity was 79.4%, if ad~usted for assay would be 81.5%
~-' (B) 2.2721 g. of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate and 0.0202 g. cyclooctadiene 1,5-[1~2-bis(_-anisyl-phenylphosphino) ethane] rhodium tetrafluoroborate in 30 cc. of ethanol was subjected to 3 atm. H2 pressure at 51C. The resul-ting solution was stripped of ethanol on a rotary evaporator.
NMR shows 89% completion after 6 hours. The product~ ethyl-2-: (acetyloxy)-3-phenylpropanoate, was recovered by flash distilla-tion, b.p. 80-85C. at 0. 5 mm. Hg. NMR assay shows 87.o% of the desired product. The observed rotation of the product was 0.515~ -~o~]D = 8.27 (C=6.o in CHC13). Optical purity adjusted for assay was 95%.
Example 3 Preparation of (Z)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate A solution of 27.8 g. (0.145 mole) of ethyl-3-oxo-3-phenylpropanoate, 29.0 g. of 2-acetyloxy-1-propene, and 100 mg.
of _-toluenesulfonic acid monohydrate was heated to reflux for 17 hours. The reaction mass was poured into 50 ml. of a 5C.
saturated solution of NaHCO3 and the organic phase was extracted into ethyl ether. The ether solution was dried and the solvent was stripped off. Distillation of the residue at 0.1 mm. of Hg.
, yielded 8.3 g. of a yellow oil, b.p. 110-120C. ~he distillate ~-was shown by GLC, NMR and W analysis to be (Z)-ethyl-3-(acetyl-oxy)-3-phenyl-2-propenoate.
Example 4 Preparation of ethyl-3-(acetyloxy)-3-phenylpropanoate A solution of 2.5 g. of (Z)-ethyl-3-(acetyloxy) 3-phenyl-2-propenoate (2.65 g.) and 0.0373 g. of cyclooctadiene-1,5-[1,2-bis(o-anisylphenylphosphino) ethane] rhodium tetrafluoro-borate in 30 cc. of ethanol was hydrogenated at 27 atm. and 50C.
` 30 in a Hoke bomb. After 12 hours the produck was isolated by re-moving the ethanol on a rotary evaporator. NMR analysis indicated that the hydragenation product to olefin ratio was 89:11. In `
~: - , .
. ~ . -, ., ,~, 4 3_ L~ 2 5 3~
~ 36~7~
addition, some ethyl 3-phenylpropanoate was present, which arose from hydrogenolysis.
2.5 g. of crude product was subjected to distillation, a first fraction was collected, b.p. 75-87C. at 0.1 mm. of Hg., which was ethyl 3-phenylpropanoate. The remaining material that distilled at 95-110C. and 0.1 mm. of Hg. was an 86:14 (NMR) mixture o~ ethyl-3-(acetyloxy)-3-phenylpropanoate and (Z)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate.
[C]D = ~4 74 (neat, 1=1). With correction for NMR
assay, the optical purity is 90.5%.
Example 5 Preparation of (E)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate A solution of 5.2 g. of (Z)-ethyl-3-(acetyloxy)-3~
phenyl-2-propenoate in 60 ml. of CXC13 was irridiated with 3100 A
light for 72 hours. The solvent was removed on a rotary evapora-tor. Distillation of the residue at 0.03 mm. of Hg. yielded 1.3 g. of yellow oil, b.p. 92-98C. The distillate was shown by ~LC, NMR, and UV analysis to be (E)-ethyl-3-(acetyloxyj-3-phenyl-2-propenoate of 86% purity.
Example 6 Preparation of ethyl-3-(acetyloxy)-3-phenylpropanoate A salution of 1.1566 g. of the (E)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate prepared in Example 5 (86% purity) and 0.027 g. of cyclooctadiene-1,5-[1,2-bis(_-anisylphenylphosphino) ; ethane] rhodium tetrafluoroborate in 30 cc. of ethanol was hy-drogenated ~or 5 hours at 27 atm. and 50C. Ethanol was then ` stripped on a rotary evaporator and the product examined by NMR
analysis. The hydrogenation product to olefin ratio was 76:24.
This product mix was distilled at 95-120C. and 0.2 mm. of Hg.
Gas chromatography assay of the distillate indicated the ethyl-3-(acetyloxy)-3-phenylpropanoate to (E)-ethyl-3-(acetyloxy)-3- -phenyl-2-propenoate to ethyl 3-phenylpropanoate ratio was 64:18:18.
.. . . . . . .
. . .: ~ ~ . : , . . . : , ,, - :. ~ .: : . . . -~lO8~ 7~
This mixture had a Cc~]20 = +0.515 (neat, 1=1) with correction - -for assay of the desired hydrogenation product the COr]D
+0.805 (neat>l=l). Optical purity is 15.4~.
While the invention has been described herein with regard to certain specific embodiments, it is not so limited. It is to be understood that variations and modifications thereof may be made by those skilled in the art without departing from the spirit and scope o~ the invention.
.~ .
.. .
.
. .: .
, , ~ . ~.
~'~
. . ..
';
: ~.
.
. -15- .
:. - ~ , -~. : : ~ . .. -.~ ~ - , . . .
Claims (6)
1. An asymmetric hydrogenation process comprising hydrogenating the Z geometric isomer of a compound of the formulae and wherein R, R1 and R2 each independently represent hydrogen, sub-stituted or unsubstituted alkyl having from 1 to 5 carbon atoms or substituted or unsubstituted aryl, and R3 represents substi-tuted or unsubstituted alkyl having from 1 to 5 carbon atoms or substituted or unsubstituted aryl, in the presence of a catalytic amount of a homogeneous, coordination complex of rhodium, iridium or ruthenium in combination with an optically active bis phosphine ligand represented by the formula wherein A and B each independently represent substituted and un-substituted alkyl of from 1 to 12 carbon atoms, substituted and unsubstituted cycloalkyl having from 4 to 7 carbon atoms, sub-stituted and unsubstituted aryl; provided that such substituents provide no significant interference with the steric requirements around the phosphorus atom and A and B are different.
2. A hydrogenation process according to Claim 1 wherein the bis phosphine ligand is represented by the formula wherein X represents substituted and unsubstituted phenyl, Y represents substituted and unsubstituted 2-alkoxyphenyl wherein the alkoxy has from 1 to 6 carbon atoms; pro-vided that such substituents provide no significant interference with the steric requirements around the phosphorus atom and X and Y are different.
3. A hydrogenation process according to Claim 1 wherein the bis phosphine ligand is represented by the formula wherein M represents , N represents , R' and R" each independently represent hydrogen, halogen, alkyl having from 1 to 6 carbon atoms and alkoxy having from 1 to 6 carbon atoms, and R''' represents normal alkyl having from 1 to 6 carbon atoms;
provided that M and N are different.
provided that M and N are different.
4. A hydrogenation process according to Claim 1 wherein the bis phosphine ligand is 1,2-bis(o-anisylphenylphosphino) ethane.
5. A process according to Claim 1 wherein the metal utilized in the catalyst complex is rhodium.
6. A hydrogenation process according to Claim 1 wherein the compound being hydrogenated is (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60709075A | 1975-08-25 | 1975-08-25 | |
| US607,090 | 1975-08-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1086771A true CA1086771A (en) | 1980-09-30 |
Family
ID=24430767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA259,754A Expired CA1086771A (en) | 1975-08-25 | 1976-08-24 | Asymmetric catalysis |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5850207B2 (en) |
| AU (1) | AU499782B2 (en) |
| BE (1) | BE845454A (en) |
| BR (1) | BR7605568A (en) |
| CA (1) | CA1086771A (en) |
| CH (1) | CH624088A5 (en) |
| DE (1) | DE2638070A1 (en) |
| FR (1) | FR2322126A1 (en) |
| GB (1) | GB1501558A (en) |
| NL (1) | NL7609340A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9823716D0 (en) | 1998-10-29 | 1998-12-23 | Isis Innovation | Diphosphines |
-
1976
- 1976-08-23 NL NL7609340A patent/NL7609340A/en not_active Application Discontinuation
- 1976-08-24 BE BE170021A patent/BE845454A/en not_active IP Right Cessation
- 1976-08-24 CA CA259,754A patent/CA1086771A/en not_active Expired
- 1976-08-24 GB GB3512576A patent/GB1501558A/en not_active Expired
- 1976-08-24 JP JP10027876A patent/JPS5850207B2/en not_active Expired
- 1976-08-24 CH CH1070576A patent/CH624088A5/en not_active IP Right Cessation
- 1976-08-24 BR BR7605568A patent/BR7605568A/en unknown
- 1976-08-24 FR FR7625642A patent/FR2322126A1/en active Granted
- 1976-08-24 AU AU17094/76A patent/AU499782B2/en not_active Expired
- 1976-08-24 DE DE19762638070 patent/DE2638070A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| NL7609340A (en) | 1977-03-01 |
| FR2322126A1 (en) | 1977-03-25 |
| BR7605568A (en) | 1977-08-09 |
| JPS5227716A (en) | 1977-03-02 |
| JPS5850207B2 (en) | 1983-11-09 |
| DE2638070A1 (en) | 1977-03-10 |
| GB1501558A (en) | 1978-02-15 |
| CH624088A5 (en) | 1981-07-15 |
| BE845454A (en) | 1977-02-24 |
| FR2322126B1 (en) | 1980-05-16 |
| AU1709476A (en) | 1978-03-02 |
| AU499782B2 (en) | 1979-05-03 |
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