WO1996020285A1 - Kinetic resolution process - Google Patents

Kinetic resolution process Download PDF

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Publication number
WO1996020285A1
WO1996020285A1 PCT/GB1995/002981 GB9502981W WO9620285A1 WO 1996020285 A1 WO1996020285 A1 WO 1996020285A1 GB 9502981 W GB9502981 W GB 9502981W WO 9620285 A1 WO9620285 A1 WO 9620285A1
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WO
WIPO (PCT)
Prior art keywords
enantiomeric forms
enantiomerically pure
enzyme
compound
reaction
Prior art date
Application number
PCT/GB1995/002981
Other languages
French (fr)
Inventor
Jonathan Michael Jeremy Williams
Original Assignee
Loughborough University Innovations Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Loughborough University Innovations Limited filed Critical Loughborough University Innovations Limited
Priority to AU42690/96A priority Critical patent/AU4269096A/en
Publication of WO1996020285A1 publication Critical patent/WO1996020285A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction

Definitions

  • This invention concerns the de-racemisation of mixtures of enantiomers.
  • enantiomers Certain chemical compounds, such as those possessing chiral carbon atoms, exist as distinct optical isomers known as enantiomers. When, as is generally the case, these enantiomers are present in equimolar concentrations the mixture is said to be racemic.
  • enantiomers can react with an optically active reagent at drastically different rates. This property is especially important in biological processes, since enzymes occur in optically active forms.
  • enantiomers can have very different physiological properties; for example, (-) adrenalin is more active in contracting blood capillaries than (+) adrenalin, and (-) nicotine is more poisonous than (+) nicotine.
  • enantiomers can have very different physiological properties; for example, (-) adrenalin is more active in contracting blood capillaries than (+) adrenalin, and (-) nicotine is more poisonous than (+) nicotine.
  • the present invention provides a means of converting a mixture of enantiomers into a pure enantiomeric form. This process is termed de-racemerisation although it is understood that the process is not restricted to purely equimolar racemic mixtures, but rather can apply to mixtures of enantiomers present in any ratio thereof.
  • a method of producing a substantially enantiomerically pure compound from a precursor compound which is present in at least two enantiomeric forms wherein a transition metal catalyst is used to maintain an equilibrium between the enantiomeric forms, and an enzyme is used to effect a chemical reaction which converts one of the enantiomeric forms into an enantiomerically pure compound at a rate which is substantially greater than the rate of reaction of the other enantiomeric forms with said enzyme.
  • the method may produce the substantially enantiomerically pure compound in quantitative or near quantitative yield.
  • the precursor compound may be present as a racemic mixture.
  • the enzyme may be a lipase enzyme, and the transition metal catalyst may be PdCl 2 (MeCN) 2 .
  • the precursor compound may be an ester and the product may be an enantiomerically pure alcohol.
  • the precursor compound may be 2-phenyl-2-cyclohexenyl acetate and the enantiomerically pure compound may be 2-phenyl-2 cyclohexenol.
  • Figure 1 is a schematic illustration of prior art and present syntheses
  • the present invention comprises a method of producing a substantially enantiomerically pure compound from a precursor compound which is present in at least two enantiomeric forms, wherein a transition metal catalyst is used to maintain an equilibrium between the enantiomeric forms and an enzyme is used to effect a chemical reaction which converts one of the enantiomeric forms into an enantiomerically pure compound at a rate which is substantially greater than the rate of reaction of the other enantiomeric forms.
  • Figure 1(a) shows the prior art enzyme based method of producing a single enantiomer B from a precursor compound which exists in two enantiomeric forms A and A 1 .
  • FIG. 1(b) shows the principle of the present invention, wherein the transition metal catalyst (TMC) maintains an equilibrium between enantiomers A and A 1 .
  • TMC transition metal catalyst
  • the yield of B 1 depends only on the efficiency of the reaction A > B. Quantitative or near quantitative production of a single enantiomer from a mixture of precursor enantiomers is perfectly feasible, depending, of course, on the precise nature of the reaction selected. Typically, the precursor compound is present as a racemic mixture.
  • Figure 2 shows the reaction scheme for the conversion of a racemic mixture of 2-phenyl-2-cyclohexenyl acetate (1,1 ') into 2-phenyl-2-cyclohexenol.
  • the Pd Cl 2 (MeCN) 2 catalyst maintains an equilibrium between S-2-phenyl-2-cyclohexenyl acetate (1) and R-2-phenyl-2-cycolohexenyl acetate (T), whilst the lipase enzyme only catalyses the conversion of 1' into S-2-phenyl-2-cyclo hexenol(2).
  • the experimental procedure is described in more detail below.

Abstract

There is disclosed a method of producing a substantially enantiometrically pure compound from a precursor compound which is present in at least two enantiomeric forms wherein a transition metal catalyst is used to maintain an equilibrium between the enantiomeric forms and an enzyme is used to effect a chemical reaction which converts one of the enantiomeric forms into an enantiomerically pure compound at a rate which is substantially greater than the rate of reaction of the other enantiomeric forms.

Description

K I N E T I C R E S O L U T I O N P R O C E S S
This invention concerns the de-racemisation of mixtures of enantiomers.
Certain chemical compounds, such as those possessing chiral carbon atoms, exist as distinct optical isomers known as enantiomers. When, as is generally the case, these enantiomers are present in equimolar concentrations the mixture is said to be racemic. There is, however, enormous current interest in the field of organic synthesis in the production of pure enantiomeric forms of chiral compounds, since enantiomers can react with an optically active reagent at drastically different rates. This property is especially important in biological processes, since enzymes occur in optically active forms. Thus, enantiomers can have very different physiological properties; for example, (-) adrenalin is more active in contracting blood capillaries than (+) adrenalin, and (-) nicotine is more poisonous than (+) nicotine. Clearly, there are widespread applications for a process which can produce 'benevolent' compounds in their active optical forms and, conversely, produce potentially dangerous compounds in a harmless isomeric form.
The present invention provides a means of converting a mixture of enantiomers into a pure enantiomeric form. This process is termed de-racemerisation although it is understood that the process is not restricted to purely equimolar racemic mixtures, but rather can apply to mixtures of enantiomers present in any ratio thereof.
According to the present invention there is provided a method of producing a substantially enantiomerically pure compound from a precursor compound which is present in at least two enantiomeric forms, wherein a transition metal catalyst is used to maintain an equilibrium between the enantiomeric forms, and an enzyme is used to effect a chemical reaction which converts one of the enantiomeric forms into an enantiomerically pure compound at a rate which is substantially greater than the rate of reaction of the other enantiomeric forms with said enzyme.
The method may produce the substantially enantiomerically pure compound in quantitative or near quantitative yield.
The precursor compound may be present as a racemic mixture.
The enzyme may be a lipase enzyme, and the transition metal catalyst may be PdCl2(MeCN)2. The precursor compound may be an ester and the product may be an enantiomerically pure alcohol.
The precursor compound may be 2-phenyl-2-cyclohexenyl acetate and the enantiomerically pure compound may be 2-phenyl-2 cyclohexenol.
Methods of producing a substantially enantiomerically pure compound according to the invention will now be described with reference to the accompanying diagrams in which :-
Figure 1 is a schematic illustration of prior art and present syntheses;
and Figure 2 shows the synthesis of enantiomerically pure 2-phenyl-
2-cyclohexenol. The present invention comprises a method of producing a substantially enantiomerically pure compound from a precursor compound which is present in at least two enantiomeric forms, wherein a transition metal catalyst is used to maintain an equilibrium between the enantiomeric forms and an enzyme is used to effect a chemical reaction which converts one of the enantiomeric forms into an enantiomerically pure compound at a rate which is substantially greater than the rate of reaction of the other enantiomeric forms. The principle of the method is illustrated in Figure 1. Figure 1(a) shows the prior art enzyme based method of producing a single enantiomer B from a precursor compound which exists in two enantiomeric forms A and A1. If the enzyme is selective with respect to enantiomer A (i.e. kA»kAI where k represents a rate constant) then only enantiomer B is produced. Therefore, if the precursor compound is present as a racemic mixture, the maximum yield of the single enantiomer B is 50%. Figure 1(b) shows the principle of the present invention, wherein the transition metal catalyst (TMC) maintains an equilibrium between enantiomers A and A1. Again, if kA»kA, then only enantiomer B is produced by enzyme catalysed chemical reaction. However, as enantiomer A is depleted by said reaction the equilibrium is driven to the left as shown, producing more enantiomer A. Consequently, over the course of the reaction all of the precursor compound is made available for conversion into the single enantiomer B, irrespective of the initial proportions of reactive enantiomer A and unreactive enantiomer A'.
Therefore, with the present invention, the yield of B1 depends only on the efficiency of the reaction A > B. Quantitative or near quantitative production of a single enantiomer from a mixture of precursor enantiomers is perfectly feasible, depending, of course, on the precise nature of the reaction selected. Typically, the precursor compound is present as a racemic mixture.
Figure 2 shows the reaction scheme for the conversion of a racemic mixture of 2-phenyl-2-cyclohexenyl acetate (1,1 ') into 2-phenyl-2-cyclohexenol. The Pd Cl2(MeCN)2 catalyst maintains an equilibrium between S-2-phenyl-2-cyclohexenyl acetate (1) and R-2-phenyl-2-cycolohexenyl acetate (T), whilst the lipase enzyme only catalyses the conversion of 1' into S-2-phenyl-2-cyclo hexenol(2). The experimental procedure is described in more detail below.
The synthesis of the 2-phenyl-2-cyclohexenyl acetate starting material was performed according to the literature method (C R Johnson and 1 1 Sakaguchi, Synlett, 1992, 813). To a solution of 2-phenyl-2-cyclohexenyl acetate ( 5 mg 0.23 mmol) in ammonium acetate buffer (pH 7.0) (4 ml) at 40°C was added pseudomonas fluorescens lipase (30 mg, 4000 units mmol"1 of substrate). The pH was maintained between 7.5 - 8.0 using 1.0M sodium hydroxide solution. The reaction was monitored by GC analysis (BP-1 column, 150°C). At 50% conversion, PdCl2(MeCN)2 (3 mg) was added. The pH was adjusted to and maintained at pH 7.5-8.0 for the duration of the reaction. GC analysis revealed the completion of the reaction after 10 days, at which point diethyl ether (10 ml) was added and the organic layer separated. The aqueous layer was extracted with diethyl ether (2 x 10ml) and the combined organic layers were dried over MgS04 and concentrated in vacuo. The crude product was purified by flash chromatography (petroleum ether : ether 3: 1) to afford 2-phenyl-2-cyclohexenol (2) (81% yield), identified by 'H nmr. The enantiomeric excess was determined by hplc using a Chiralcel OD column (1% isopropyl alcohol/hexane). A similar result was obtained when the palladium catalyst was added at the beginning of the reaction.
•H nmr data for the product 2 (250 MHz): δ 7.8 - 7.2 (5H,m,Ph), 6.15 (lH,dd,J= 4.5,3.5 Hz, CH=), 4.70 (IH, br.S, CHO), 2.30 - 2.18 (2H,m,CH2C=), 1.96-1.64 (4H,m,CH2CH2).
It will be apreciated that it is not intended to limit the invention to the above example only, many variations, such as might readily occur to one skilled in the art, being possible, without departing from the scope thereof as defined by the appended claims.

Claims

1. A method of producing a substantially enantiomerically pure compound from a precursor compound which is present in at least two enantiomeric forms wherein a transition metal catalyst is used to maintain an equilibrium between the enantiomeric forms and an enzyme is used to effect a chemical reaction which converts one of the enantiomeric forms into an enantiomerically pure compound at a rate which is substantially greater than the rate of reaction of the other enantiomeric forms with said enzyme.
2. A method according to claim 1 in which the substantially enantiomerically pure compound is produced in quantitative or near quantitative yield.
3. A method according to claim 1 or claim 2 in which the precursor compound is present as a racemic mixture.
4. A method according to any one of the previous claims in which the enzyme is a lipase enzyme.
5. A method according to any one of the previous claims in which the transition metal catalyst is PdCl2(MeCN)2.
6. A method according to any one of the previous claims in which the precursor compound is an ester and the product is a substantially enantiomerically pure alcohol.
7. A method according to claim 6 in which the precursor compound is 2- phenyl-2-cyclohexenyl acetate and the substantially enantiomerically pure compound is 2-phenyl-2-cyclohexenol.
PCT/GB1995/002981 1994-12-24 1995-12-20 Kinetic resolution process WO1996020285A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU42690/96A AU4269096A (en) 1994-12-24 1995-12-20 Kinetic resolution process

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9426260.7 1994-12-24
GBGB9426260.7A GB9426260D0 (en) 1994-12-24 1994-12-24 De-racemisation

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0089886A1 (en) * 1982-03-23 1983-09-28 Centre National De La Recherche Scientifique (Cnrs) Process for the preparation of a free alpha-L-amino acid
JPS61254545A (en) * 1985-05-07 1986-11-12 Ube Ind Ltd Racemization of optically active phenylalaninamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0089886A1 (en) * 1982-03-23 1983-09-28 Centre National De La Recherche Scientifique (Cnrs) Process for the preparation of a free alpha-L-amino acid
JPS61254545A (en) * 1985-05-07 1986-11-12 Ube Ind Ltd Racemization of optically active phenylalaninamide

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CARL R. JOHNSON ET AL: "Enantioselective Transesterifications Using Immobilized, Recombinant Candida antarctica Lipase B: Resolution of 2-Iodo-2-cycloalken-1- -ols", SYNLETT, October 1992 (1992-10-01), pages 813 - 816 *
CHEMICAL ABSTRACTS, vol. 106, no. 21, 25 May 1987, Columbus, Ohio, US; abstract no. 176868k, page 779; *
MINORU INAGAKI ET AL: "Lipase-Catalyzed Kinetic Resolution with in Situ Racemization: One-Pot Synthesis of Optically Active Cyanohydrin Acetates from Aldehydes", J. AM. CHEM. SOC., vol. 113, 1991 *
SHUI-TEIN CHEN ET AL: "Resolution of Amino Acids in a Mixture of 2-Methyl-2-propanol/Water (19:) Catalyzed by Alcalase via in Situ Racemization of One Antipode Mediated by Pyridoxal 5-Phosphate", J. ORG. CHEM., vol. 59, 1994, XP002163217, DOI: doi:10.1021/jo00104a007 *

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AU4269096A (en) 1996-07-19

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