JP5801137B2 - Oxovanadium catalyst, production method thereof, and production method of optically active ester - Google Patents

Description

  The present invention relates to an oxovanadium catalyst used for 1,3-rearrangement and racemization of allyl alcohol, a method for producing the catalyst, and a method for producing an optically active ester.

  Optically active allyl esters are extremely useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, fragrances and the like, and are widely used. Therefore, development of an environmentally friendly, simple, safe and inexpensive synthesis method is required.

The present inventor has used a known oxovanadium compound O = V (OSiPh ₃ ) ₃ and a commercially available hydrolase lipase in combination to quantitatively produce optically pure allyl ester from racemic allyl alcohol in a high yield. The method to obtain was developed (nonpatent literature 1).

  In this method, three different reactions of 1,3-rearrangement reaction and racemization reaction of allyl alcohol with oxovanadium compound and optical resolution reaction with lipase proceed simultaneously in one container. Therefore, it is a synthesis method that does not require isolation and purification of reaction intermediates, can reduce waste, and can save energy while proceeding near room temperature.

Angew. Chem. Int. Ed., 2006, 45, 2592-2595

However, this conventional method has substrate limitations and has room for further improvement. That is, allyl alcohol having a specific molecular structure so as to be racemized by 1,3-rearrangement, for example, in the formula (I-1) or (I-2) described below, R ¹ and R ² are the same It was necessary to select a substrate having a pseudo-symmetric ring structure.

  On the other hand, if the activity of the oxovanadium compound that catalyzes racemization is increased in order to cope with this problem, a new problem arises in that it reacts with the lipase present in the same container to deactivate each other.

  The present invention has been made in view of the circumstances as described above, and can proceed with a wide range of hydroxyl 1,3-rearrangement reaction and racemization of allyl alcohol at high speed, and optical activity such as optically active allyl ester. It is an object of the present invention to provide a novel catalyst capable of satisfying both the activity improvement of the catalyst and the coexistence with lipase in the synthesis of the ester, a method for producing the catalyst, and a method for producing the optically active ester.

  The oxovanadium catalyst of the present invention is an oxovanadium catalyst for rearrangement reaction and / or racemization reaction using alcohol as a substrate, and the oxovanadium moiety V = O is bonded to and fixed inside mesoporous silica (MPS). It is characterized by being.

  The method for producing an oxovanadium catalyst according to the present invention is a method for producing the above-mentioned oxovanadium catalyst, and includes a step of reacting an oxovanadium compound and mesoporous silica (MPS) in an organic solvent.

  The method for producing an optically active ester of the present invention comprises the following formula (I-1) or (I-2) in an organic solvent in the presence of the oxovanadium catalyst and lipase.

(Wherein R ¹ , R ² , and R ³ represent a hydrogen atom, a halogen atom, or an organic group, and R ¹ and R ³ may combine to form a ring) Or cyclic racemic allyl alcohol and the following formula (II)

(Wherein R ⁴ represents an organic group, and R ⁵ , R ⁶ , and R ⁷ represent a hydrogen atom, a halogen atom, or an organic group) and a vinyl ester represented by the following formula (III)

(Wherein R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above).

  The method for producing an optically active ester of the present invention comprises the following formula (I-3) in an organic solvent in the presence of the oxovanadium catalyst and lipase.

(Wherein R ^{8 to} R ¹⁴ represent a hydrogen atom, a halogen atom, or an organic group) and an alcohol represented by the following formula (II)

(Wherein R ⁴ represents an organic group, and R ⁵ , R ⁶ , and R ⁷ represent a hydrogen atom, a halogen atom, or an organic group) and a vinyl ester represented by the following formula (IV):

(Wherein, R ⁴ and R ^{8 to} R ¹⁴ have the same meanings as described above).

  According to the present invention, the hydroxyl 1,3-rearrangement reaction and racemization of a wide range of allyl alcohol can proceed at high speed, and the activity of the catalyst can be improved in the synthesis of optically active esters such as optically active allyl esters and benzyl esters. It is possible to satisfy both coexistence with lipase.

4 is a graph showing evaluation results of racemization activity of optically active allyl alcohol in Example 3.

  The present invention is described in detail below.

  The oxovanadium catalyst of the present invention is an oxovanadium catalyst for rearrangement reaction and / or racemization reaction using alcohol as a substrate, and the oxovanadium moiety V = O is bonded to and fixed inside mesoporous silica (MPS). Has been.

  This oxo vanadium catalyst can be synthesized, for example, by reacting an oxo vanadium compound with mesoporous silica (MPS) in an organic solvent.

  Although it does not specifically limit as an oxo vanadium compound, For example, the following 3-5 valent oxo vanadium compound can be used.

As the trivalent oxovanadium compound, for example, an oxovanadium compound represented by the following formula (IV) can be used.
O = VL (IV)
(In the formula, L represents a substituent.)
As the tetravalent oxovanadium compound, for example, an oxovanadium compound represented by the following formula (V) can be used.
O = VL ₂ (V)
(In the formula, L represents a substituent. The two Ls may be the same or different, and two Ls may be bonded to form a ring.)
As the pentavalent oxovanadium compound, for example, an oxovanadium compound represented by the following formula (VI) can be used.
O = VL ₃ (VI)
(In the formula, L represents a substituent. Three Ls may be the same or different, and two or three Ls may be bonded to form a ring.)
In formula (IV) ~ (VI), examples of the substituent L, such can include _{^{-OR 8, -NR 9 2, -SR}} 10. Here, R ⁸ , R ⁹ and R ¹⁰ represent a C ₁ -C ₄₀ organic group.

  Examples of the organic group include a saturated aliphatic hydrocarbon group, an unsaturated aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and other hydrocarbon groups, an aromatic heterocyclic group, and a heteroatom-containing group. , Silyl groups, and those having a substituent introduced thereto.

  Saturated aliphatic hydrocarbon groups include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl Group, iso-pentyl group, sec-pentyl group, neo-pentyl group, tert-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group and other alkyl groups Etc.

  Examples of the unsaturated aliphatic hydrocarbon group include alkenyl groups such as vinyl groups and allyl groups, and alkynyl groups such as ethynyl groups.

  Examples of the alicyclic hydrocarbon group include cycloalkyl groups such as a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a norbornyl group, and a cycloalkenyl group such as a cyclohexenyl group.

  Examples of the aromatic hydrocarbon group include aryl groups such as phenyl group and naphthyl group, and arylalkyl groups such as benzyl group and phenethyl group.

  Examples of the aromatic heterocyclic group include monocyclic or polycyclic heterocyclic groups such as a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, a pyridyl group, a pyridazyl group, and a pyrimidyl group. Etc.

  Examples of the hetero atom-containing group include hetero atom-containing groups such as an ether bond-containing group, a thioether bond-containing group, a carbonyl group-containing group, an ester bond-containing group, and an amide bond-containing group.

  Examples of the silyl group include a silyl group having a hydrocarbon group or a heteroatom-containing hydrocarbon group. Examples of the hydrocarbon group include alkyl groups such as methyl group, ethyl group, isopropyl group, n-propyl group, n-butyl group, and t-butyl group, phenyl group, tolyl group, isopropylphenyl group, and t-butylphenyl group. Groups, aryl ring-containing groups such as methoxyphenyl group, dimethylaminophenyl group and trimethylsilylphenyl group, and silyl groups such as trimethylsilyl group, triphenylsilyl group and dimethylphenylsilyl group.

Examples of the substituent introduced into the above organic group include a halogen atom, a hydroxyl group, an amino group, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₆ alkoxy group, a C _2- C ₆ alkoxycarbonyl group, C ₆ -C ₁₀ aryloxy group, C ₂ -C ₈ dialkylamino group, C ₂ -C ₈ acyl group and the like can be mentioned.

Incidentally, in the above NR ⁹ _2, the two R ⁹ may be the same or different, or may form a divalent organic group of C ₆ -C ₄₀ and they are bonded.

  In addition, a normal Bronsted acid conjugate base can be used as the substituent L. For example, fluoride ion, chloride ion, bromide ion, iodide ion, sulfate ion, nitrate ion, carbonate ion, perchlorate ion, tetrafluoroborate ion, hexafluorophosphate ion, methanesulfonate ion, trifluoromethanesulfone Acid ions, toluenesulfonate ions, acetate ions, trifluoroacetate ions, propionate ions, benzoate ions, hydroxide ions, oxide ions, methoxide ions, ethoxide ions, and the like.

In the formulas (V) and (VI), two or more L may be bonded to form one multidentate substituent. Examples of the multidentate substituent include a saturated alkylenedioxy group represented by —O (CH ₂ ) _n O— (where n is an integer of 2 to 10) (specifically, —OCH ₂ CH ₂ O- _{(ethylenedioxy), - OCH 2 CH 2 CH} 2 O- ( _{propylenedioxy), - OCH 2 CH 2 CH} 2 CH 2 O- ( butylenedioxy), and the like). Examples of the saturated alkylene group include unsaturated alkylenedioxy groups having one or more carbon-carbon double bonds or triple bonds. Alternatively, any carbon in the above saturated alkylene dioxy group or unsaturated alkylene dioxy group is replaced with the above-described alicyclic hydrocarbon, aromatic hydrocarbon, aromatic heterocycle, heteroatom-containing hydrocarbon ring, or the like. Things. In addition, one in which one or two of the two terminal oxygens of the saturated alkylenedioxy group and the unsaturated alkylenedioxy group are replaced with nitrogen or sulfur is also included. Furthermore, the case where the above-mentioned various organic groups are substituted on the above-mentioned multidentate substituents may also be mentioned.

  In the present invention, the mesoporous silica is a substance having uniform and regular pores (mesopores: pore diameter 2 to 50 nm, mainly 2 to 10 nm) made of silicon dioxide (silica). .

As an example, a powdery material having a pore diameter of 2.6 to 3.5 nm, a specific surface area of 0.82 to 1.15 m ² / g, and a pore volume of 1.2 to 1.6 cm ³ / g can be used.

  Mesoporous silica can be synthesized, for example, by a sol-gel method using a surfactant as a template. When the surfactant is dissolved in the aqueous solution at a concentration equal to or higher than the critical micelle concentration, micelle particles having a certain size and structure are formed according to the type of the surfactant. When left standing for a while, the micelle particles take a packed structure and become a colloidal crystal. When tetraethoxysilane or the like serving as a silica source is added to the solution and a small amount of acid or base is added as a catalyst, the sol-gel reaction proceeds in the gaps between the colloidal particles to form a silica gel skeleton. Finally, when fired at a high temperature, the surfactant used as a mold is decomposed and removed to obtain pure mesoporous silica.

  By changing the type of the surfactant, the size and shape of the pores and the filling structure can be controlled. As typical examples, the MCM series using a small molecular cationic surfactant and the SBA series using a block copolymer are known.

  The mesoporous silica as described above is considered to be able to exclude an enzyme having a molecular weight of tens of thousands of daltons to prevent contact with a high molecular lipase and to incorporate only allyl alcohol which is a substrate having a molecular weight of about 1000 or less.

  And when immobilizing an oxo vanadium compound on mesoporous silica, it can mix and mix in an organic solvent, such as benzene, heating suitably. Here, the immobilization is considered that one or two substituents of the oxovanadium compound are bonded to each other by being replaced with hydroxyl groups on the surface of the mesoporous silica.

  The oxovanadium catalyst thus obtained has a vanadium metal content of preferably 0.05 mmol / g or more, more preferably 0.1 mmol / g or more.

  Then, in the presence of the oxovanadium catalyst and lipase, the chain or cyclic racemic allyl alcohol represented by the above formula (I-1) or (I-2) in the organic solvent, and the above formula (II) The optically active allyl ester represented by the above formula (III) can be synthesized by reacting with the vinyl ester represented by formula (III).

In the formula (I-1) or (I-2), R ¹ , R ² , and R ³ are a hydrogen atom, a halogen atom, or preferably an organic group of C ₁ -C ₄₀ , more preferably C ₁ -C ₂₀ Indicates a group. Examples of the organic group include those described above. R ¹ and R ³ may be bonded to form a ring. In this case, for example, R ¹ and R ³ as a whole preferably form a divalent group of C ₃ -C ₄₀ , more preferably C ₃ -C ₂₀ .

In the formula (II), R ⁴ represents an organic group, and R ⁵ , R ⁶ and R ⁷ are a hydrogen atom, a halogen atom, or preferably a C ₁ -C ₄₀ , more preferably a C ₁ -C ₂₀ organic group. Indicates. Examples of the organic group include those described above.

  The reaction is preferably performed in the presence of an organic solvent. As the organic solvent, polar solvents such as acetonitrile and acetone, various ethers, low polar solvents such as toluene, hexane, and heptane, halogen-containing solvents such as chloroform and dichloromethane, and the like can be used depending on the type of substrate and the like. The reaction temperature, time, molar ratio, and the like can be appropriately set in consideration of conventional techniques such as Non-Patent Document 1.

  The synthesis reaction of this optically active allyl ester proceeds by the following mechanism. That is, 1,3-rearrangement and racemization of allyl alcohol proceed with an oxovanadium catalyst, and at the same time, lipase selectively catalyzes esterification of R-form allyl alcohol to produce an allyl ester.

  Further, in the presence of this oxovanadium catalyst and lipase, by reacting the alcohol represented by the above formula (I-3) with the vinyl ester represented by the above formula (II) in an organic solvent, The optically active benzyl ester represented by the above formula (IV) can be synthesized.

In formula (I-3), R ^{8 to} R ¹⁴ each independently represent a hydrogen atom, a halogen atom, or preferably an organic group of C ₁ -C ₄₀ , more preferably C ₁ -C ₂₀ . Examples of the organic group include those described above.

  The reaction is preferably performed in the presence of an organic solvent. As the organic solvent, polar solvents such as acetonitrile and acetone, various ethers, low polar solvents such as toluene, hexane, and heptane, halogen-containing solvents such as chloroform and dichloromethane, and the like can be used depending on the type of substrate and the like. The reaction temperature, time, molar ratio, and the like can be appropriately set in consideration of conventional techniques such as Non-Patent Document 1.

  By using the oxo vanadium catalyst of the present invention in which oxo vanadium is immobilized on mesoporous silica, the activity is higher than that of the conventional oxo vanadium catalyst, and both the yield and optical purity of the product in dynamic optical resolution are improved. . This is presumably because mesoporous silica prevented physical contact with the polymer lipase, and the coexistence of both catalysts was improved in one reaction vessel. Furthermore, since the oxovanadium catalyst of the present invention can be recovered and reused after the reaction, it has a great cost advantage.

  Thus, since the oxovanadium catalyst of the present invention can coexist with various enzymes, it enables dynamic optical resolution of a wide range of substrates. In addition, there are great practical advantages in industrial processes such as flexibility of raw material synthesis, reduction of the total number of steps, and recovery and reuse of catalysts. That is, it is possible to synthesize an optically active allyl ester important as a synthetic intermediate for pharmaceuticals, agricultural chemicals, fragrances and the like from easily available raw materials in a short process and in a high yield, and is suitable for industrial process.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples at all.
<Example 1> Synthesis of mesoporous silica (MPS)
Dissolve 10.4 g (1.0 eq) of n-hexadecyl (trimethyl) ammonium bromide in 120 mL of pH 0.5 distilled water at room temperature and stir for 2 hours. Then add 15.4 mL (2.4 eq) of tetraethoxysilane dropwise at room temperature and stir for 5 hours. did. Then, 12 mL (6.2 eq) of 28% aqueous ammonia was added dropwise at room temperature. After stirring for 24 hours, the reaction solution was filtered, and the resulting solid was washed with ethanol (40 mL) and acetone (40 mL) and filtered. The obtained solid was dried at 50 ° C. for 16 hours, sintered at 500 ° C. for 4 hours, cooled to room temperature, and dried under reduced pressure to obtain 5.03 g of mesoporous silica (MPS).

As a result of analyzing the structure of MPS prepared several times using a BET specific surface area analyzer, the pore diameter was 2.6 to 3.5 nm, the specific surface area was 0.82 to 1.15 m ² / g, and the pore volume was 1.2 to 1.8 cm ³ / g. It was.
Example 2 Synthesis and Structural Analysis of Mesoporous Silica Immobilized Vanadium Catalyst (MPS-V) MPS 0.50 g and O = V (OSiPh ₃ ) ₃ (0.53 g, 0.60 mmol) obtained above in 40 mL of benzene And heated at reflux for 24 hours. The reaction was cooled to room temperature and concentrated. Thereafter, anhydrous methylene chloride (10 mL) and anhydrous hexane (5 mL) were added, and the mixture was centrifuged for 1 minute and centrifuged, and the supernatant was decanted. Anhydrous methylene chloride (5 mL) and anhydrous hexane (5 mL) were added to the precipitate, and the same ultrasonic irradiation and decantation operations were repeated 6 times. The resulting precipitate was dried under reduced pressure with a vacuum pump for 3 hours to obtain MPS-V (0.52 g) as white crystals. The supernatants were combined and concentrated, and further dried under reduced pressure with a vacuum pump to recover an unreacted vanadium compound (0.48 g). 50.8 mg of the recovered vanadium compound (0.48 g) was dissolved in MeOH (2 mL), and K ₂ CO ₃ (8.4 mg, 61 μmol) and H ₂ O (20 mg, 1.1 mmol) were added and stirred for 2 hours. . The reaction solution was concentrated under reduced pressure, and the white crystals obtained by further drying under reduced pressure for 1 hour were quantified for vanadium using a high frequency inductively coupled plasma emission spectrometer. As a result, it was found that 0.137 mmol of vanadium was immobilized and 0.463 mmol of vanadium was recovered without being immobilized. From this, the vanadium content of MPS-V was estimated to be 0.26 mmol / g. In addition, MPS-V elemental analysis revealed that it contained 8.81% carbon.

Summing up these results, in the obtained MPS-V, 1.5 OSiPh ₃ groups are bonded to vanadium on average, and one or two of O = V (OSiPh ₃ ) ₃ used are combined. It is thought that OSiPh ₃ replaced the hydroxyl group on the MPS surface.
<Example 3> Racemization catalytic activity test of MPS-V and comparison with known catalyst Using the immobilized vanadium catalyst MPS-V (B) obtained in Example 2, the racemization activity of optically active allyl alcohol was evaluated. The catalyst activity was compared with that of the conventional catalyst (A). According to the following scheme, vanadium catalyst (A or B) (10 mg each) and optically active allyl alcohol (R) -2a were dissolved in acetonitrile in separate reaction vessels and stirred at 35 ° C. The optical purity of (R) -2a was measured every hour.

The result is shown in FIG. Compared to the conventional catalyst O = V (OSiPh ₃ ) ₃ A, which took 8 hours for racemization, the immobilized oxovanadium catalyst MPS-V (B) racemized in 2.5 hours. Thus, the catalyst activity was greatly improved by immobilization on mesoporous silica (MPS).
Example 4 Lipase-catalyzed dynamic optical resolution using MPS-V (Part 1)
Using the immobilized oxovanadium catalyst (B) obtained in Example 1, lipase-catalyzed dynamic optical resolution of racemic allyl alcohol (±) -1a was examined according to the following scheme. Moreover, it compared with the dynamic optical resolution using the conventional catalyst (A).

  Racemic allyl alcohol (±) -1a 65 mg (0.44 mmol), immobilized lipase C. antarctica lipase, B (195 mg), vinyl acetate 81 μl (2.0 eq), MPS-V (B) (32 mg, vanadium 6.9 μmol, about 0.02 eq) was added to 5.5 mL of acetonitrile, and the mixture was stirred at 35 ° C. for 24 hours under a nitrogen atmosphere. The reaction solution was filtered through celite and concentrated under reduced pressure to obtain (R) -3a having a yield of 90% and an optical purity of 99% ee. The optical purity of (R) -3a was determined by HPLC analysis using a chiral column OD-H (Hexane, flow rate = 1.0 mL / min, 20 ° C., UV = 254 nm).

In contrast, the conventional catalyst O = V (OSiPh ₃ ) ₃ A was used at 0.20eq, (±) -1a (65 mg), immobilized lipase C. antarctica lipase, B (195 mg), vinyl acetate 81 μl ( 2.0 eq) for 3 days at 50 ° C. The yield of the obtained optically active allyl ester (R) -3a was 64%, and the optical purity was 93% ee. Thus, the suitability to optical resolution was greatly improved by immobilization on mesoporous silica (MPS).

<Example 5> Lipase-catalyzed dynamic optical resolution using MPS-V (part 2)

  Racemic allyl alcohol (±) -1b 68 mg (0.41 mmol), immobilized lipase C. antarctica lipase, B (200 mg), vinyl acetate 77 μl (2.0 eq), MPS-V (B) (35 mg, vanadium 7.6 μmol, about 0.02 eq) was added to 5 mL of acetonitrile, and the reaction was stirred at 35 ° C. for 24 hours under a nitrogen atmosphere. Post-treatment as described above was performed to obtain optically active allyl ester (R) -3b having a yield of 80% and an optical purity of 99% ee. The optical purity of (R) -3b was determined by HPLC analysis using a chiral column OD-H (Hexane, flow rate = 0.8 ml / min, 20 ° C., UV = 254 nm).

On the other hand, the reaction was similarly carried out at 50 ° C. for 3 days using 0.20 eq of the conventional catalyst O = V (OSiPh ₃ ) ₃ A. The yield of the obtained optically active allyl ester (R) -3b was 56%, and the optical purity was 94% ee. Thus, the suitability to optical resolution was greatly improved by immobilization on mesoporous silica (MPS).

Example 6 General procedure for synthesizing optically active ester by dynamic optical resolution of racemic alcohol (±) -1 using MPS-V (Table 3, entry 1)
Under argon, alcohol (±) -1c (40.0 mg, 0.26 mmol) in anhydrous CH ₃ CN (3.2 ml, 0.08 M) solution with lipase CAL-B (120 mg, 3 w / w), MPS-V (15.7 mg , 0.005 mmol) and vinyl acetate (48 μl, 0.52 mmol) were added at room temperature, sealed and stirred at 35 ° C. for 1 day. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexanes / EtOAc = 20: 1) to obtain (R) -3c (46 mg, 90% yield, optical purity 96% ee). The optical purity of (R) -3c was determined by subjecting an alcohol obtained by alkaline hydrolysis of this product to HPLC analysis using Daicel CHIRALCEL AD-3.

To other alcohol (±) -1c to 1f, (±) -2g, (±) -2h (40.0 or 50.0 mg) in anhydrous CH ₃ CN solution, add lipase CAL-B, MPS-V, and vinyl acetate (± ) -1c was added at the same molar ratio (lipase is by weight) and stirred at 35 ° C. for 1 day to carry out the same post-treatment and purification. The yield and optical purity of the optically active ester (R) -3c-3h are summarized in Table 3.
HPLC conditions
(R) -3c was analyzed with the corresponding alcohol: CHIRAL AD-3, hexanes / 2-propanol = 99: 1, 1.0 ml / min, 20 ° C, retention times 21.2 (S), 19.3 min (R)).
(R) -3d was analyzed with the corresponding alcohol: CHIRAL AD-3, hexanes / 2-propanol = 99: 1, 1.0 ml / min, 20 ° C, retention times 12.1 (S), 11.7 min (R)).
(R) -3e was analyzed with the corresponding alcohol: CHIRAL AD-3, hexanes / 2-propanol = 90:10, 1.0 ml / min, 20 ° C, retention times 10.1 (S), 11.2 min (R)).
(R) -3f: CHIRAL AD-3, hexanes, 1.0 ml / min, 20 ° C, retention times 53.9 (S), 62.9 min (R)).
(R) -3g: CHIRAL AD-3, hexanes / 2-propanol = 99: 1, 1.0 ml / min, 20 ° C, retention times 7.1 (S), 5.8 min (R)).

<Example 7> General synthesis of optically active ester (S) -5 by dynamic optical resolution of racemic chlorohydrin (±) -4 using MPS-V (Table 4, entry 1)
Under argon, alcohol (±) -4a (50.0 mg, 0.24 mmol) in anhydrous heptane (2.9 ml, 0.08 M) solution with lipase PS-D (150 mg, 3 w / w), MPS-V (14.2 mg, 0.005 mmol) and vinyl acetate (44 μl, 0.47 mmol) were added at room temperature and sealed, and the mixture was stirred at 35 ° C. for 1 day. After filtration through celite, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexanes / EtOAc = 5: 1) to give (S) -5a (57 mg, 95% yield, optical purity 97% ee). The optical purity of (S) -5a was determined by HPLC analysis using Daicel CHIRALCEL OJ-H.

Other alcohol (±) -3b to 3d (40.0 or 50.0 mg) in anhydrous heptane solution with lipase PS-D, MPS-V, and vinyl acetate in the same molar ratio as lipase (±) -3a (lipase is weight) And stirred at 35 ° C. for 1 day for the same workup and purification. The yield and optical purity of the optically active esters (S) -4b to 4d are summarized in Table 4.
HPLC conditions
(S) -5a: CHIRAL OJ-H, hexanes / 2-propanol = 80:20, 1.0 ml / min, 20 ° C, retention times 16.2 (S), 15.1 min (R)).
(S) -5b: CHIRAL OJ-H, hexanes / 2-propanol = 70:30, 1.0 ml / min, 20 ° C, retention times 20.3 (S), 18.8 min (R)).
(S) -5c: CHIRAL AD-3, hexanes / 2-propanol = 60:40, 1.0 ml / min, 20 ° C, retention times 14.1 (S), 22.5 min (R)).
(S) -5d: CHIRAL OJ-H, hexanes / 2-propanol = 92.5: 7.5, 1.0 ml / min, 20 ° C, retention times 10.7 (S), 12.9 min (R)).

<Example 8>
Repeated use of lipase and MPS-V Under argon, lipase CAL-B (150 mg, 3 w / w), MPS-V (20.4 mg, 0.007 mmol) in a mixture of alcohol (±) -1a (50.0 mg, 0.34 mmol) ) In anhydrous CH ₃ CN (4.0 ml, 0.08 M) and vinyl acetate (62 μl, 0.67 mmol) were added at room temperature and stirred at 35 ° C. for 1 day. After the reaction solution was centrifuged, the supernatant was separated by cannulation. Anhydrous CH ₃ CN (5.0 ml) was added to the reaction vessel, stirred for 5 minutes, centrifuged, and the supernatant was separated by cannulation. Two supernatants were combined and concentrated under reduced pressure, and the residue was purified by column chromatography (hexanes / EtOAc = 10: 1) to give (R) -3a (64 mg, 100%, 98% ee). The optical purity of (R) -3a was determined by HPLC analysis using Daicel CHIRALCEL OD-H [hexanes, 1.0 ml / min, 20 ° C., retention times 41.0 (S), 31.7 min (R)].

The reaction vessel in which the lipase and MPS-V remained was dried under reduced pressure, and then purged with argon. Alcohol (±) -1a (50.0 mg, 0.34 mmol) in anhydrous CH ₃ CN (4.0 ml, 0.08 M) and vinyl acetate (62 μl, 0.67 mmol) were added at room temperature and stirred at 35 ° C. for 1 day. . The same post-treatment was performed to obtain a second (R) -3a (95% yield, optical purity 98% ee). Similarly, the reaction was repeated 5 times in total, and the yield and optical purity of (R) -3a are summarized in Table 5.

<Example 9>
Dynamic Resolution of Benzyl Alcohol Derivative (±) -6 Lipase CAL-B (150 mg) in anhydrous CH ₃ CN (4.1 ml, 0.08 M) solution of alcohol (±) -6 (50.0 mg, 0.33 mmol) under argon , 3 w / w), MPS-V (20 mg, 0.0066 mmol) and vinyl acetate (61 μl, 0.66 mmol) were added at room temperature and sealed, and the mixture was stirred at 35 ° C. for 1 day. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexanes / EtOAc = 10: 1) to obtain (R) -7 (60 mg, 94% yield, optical purity 96% ee). The optical purity of (R) -7 was determined by HPLC analysis using Daicel CHIRAL AD-3 (hexanes / 2-propanol = 90:10, 1.0 ml / min, 20 ℃, retention times 9.0 (S), 8.5 min (R)]. Determined.

In contrast, a conventional catalyst O = C (OSiPh ₃ ) ₃ A (0.10 eq) was similarly used for a reaction at 35 ° C. for 1 day. The yield of (R) -7 obtained was 54% and optical purity was 97% ee.

Claims (4)

An oxo vanadium catalyst for 1,3 rearrangement reaction of allyl alcohol or racemization reaction of alcohol , wherein the oxo vanadium moiety V = O is bonded and fixed inside mesoporous silica (MPS).   A method for producing an oxovanadium catalyst according to claim 1, comprising a step of reacting an oxovanadium compound and mesoporous silica (MPS) in an organic solvent. The following formula (I-1) or (I-2) in an organic solvent in the presence of the oxovanadium catalyst according to claim 1 and a lipase:

(Wherein R ¹ , R ² , and R ³ represent a hydrogen atom, a halogen atom, or an organic group, and R ¹ and R ³ may combine to form a ring) Or cyclic racemic allyl alcohol and the following formula (II)

(Wherein R ⁴ represents an organic group, and R ⁵ , R ⁶ , and R ⁷ represent a hydrogen atom, a halogen atom, or an organic group) and a vinyl ester represented by the following formula (III)

(Wherein R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above). The following formula (I-3) in an organic solvent in the presence of the oxovanadium catalyst according to claim 1 and a lipase:

(Wherein R ^{8 to} R ¹⁴ represent a hydrogen atom, a halogen atom, or an organic group) and an alcohol represented by the following formula (II)

(Wherein R ⁴ represents an organic group, and R ⁵ , R ⁶ , and R ⁷ represent a hydrogen atom, a halogen atom, or an organic group) and a vinyl ester represented by the following formula (IV):

(Wherein R ⁴ and R ^{8 to} R ¹⁴ have the same meanings as described above). A method for producing an optically active ester, comprising synthesizing an optically active benzyl ester represented by:

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