JPWO2008140074A1 - Method for producing optically active carboxylic acid ester - Google Patents

Abstract

To provide a method for directly producing an optically active carboxylic acid ester from a racemic secondary alcohol and a carboxylic acid, and to provide a method for optical resolution of a racemic secondary alcohol by the same means as described above. (-)-Tetramisol, (+)-tetramisole, (-)-benzotetramisol, (+)-benzotetramisol, etc. are used as asymmetric esterification catalysts in the presence of benzoic anhydride or its derivatives. The enantiomer of any one of the racemic secondary alcohols and a carboxylic acid are subjected to a dehydration condensation reaction to produce an optically active carboxylic acid ester, and the other unreacted enantiomer is optically resolved.

Description

  The present invention relates to a method for producing an optically active carboxylic acid ester from a racemic secondary alcohol and a carboxylic acid, a method for optically resolving a racemic secondary alcohol, and an optically active lactone from a racemic hydroxycarboxylic acid having a secondary hydroxyl group. It relates to a method of manufacturing.

  Optically active carboxylic acid esters and secondary alcohols are used in various fields as pharmaceuticals, intermediates for physiologically active substances, intermediates for natural product synthesis, and the like.

  As a method for producing an optically active carboxylic acid ester, by reacting a racemic secondary alcohol with an acid chloride or an acid anhydride using an asymmetric acylation catalyst, a corresponding ester from the racemic secondary alcohol is obtained. A method of manufacturing is known. Patent Document 1 describes a method in which one enantiomer of a racemic secondary alcohol is selectively acylated and optically resolved using a specific asymmetric acylation catalyst.

  In Non-Patent Document 1, an optically active ester is produced from a racemic secondary benzylic alcohol in the presence of an acid anhydride using tetramisol or benzotetramisole as a catalyst, and the other enantiomer of the secondary alcohol Is described. Non-Patent Document 2 describes a method for optically resolving racemic propargyl alcohol in the presence of an acid anhydride using benzotetramisole as a catalyst.

However, these methods have a problem of poor substrate generality because the structures of acid chlorides and acid anhydrides used as acylating agents are extremely limited. Although this problem can be solved if an ester can be produced directly from an alcohol and a carboxylic acid, there has been no known method for producing an optically active carboxylic acid ester directly from an alcohol and a carboxylic acid. .
JP 2006-15255 A Org. Lett. , (2006) Vol. 8, no. 7, p. 1351-1354 Org. Lett. , (2006) Vol. 8, no. 21, p. 4859-4861

  An object of the present invention is to provide a method for directly producing an optically active carboxylic acid ester from a racemic secondary alcohol and a carboxylic acid.

  Another object of the present invention is to provide a method for optical resolution of racemic secondary alcohols by the same means as described above.

  Another object of the present invention is to provide a method for directly producing an optically active lactone from a racemic hydroxycarboxylic acid having a secondary hydroxyl group.

  The present inventors have previously developed an efficient dehydration condensation method for a carboxylic acid and an alcohol using a substituted benzoic anhydride as a dehydration condensation agent. According to this reaction, when 2-methyl-6-nitrobenzoic anhydride is used as a condensing agent in the presence of 4-dimethylaminopyridine (DMAP) as a base catalyst, carboxylic acid and alcohol are used as substrates. Corresponding esters can be produced.

  On the other hand, Non-Patent Documents 1 and 2 reported that tetramisole, which is a commercial product, and benzotetramisole, which is a derivative thereof, are effective catalysts for the kinetic optical resolution of secondary alcohols. Therefore, as a result of earnest and research on the possibility of applying tetramisol or the like instead of DMAP which is a base catalyst to the above substituted benzoic anhydride method, the present invention has been completed.

  That is, the present invention provides the following.

上記の式中、Ｘは、下記化学式（５）で表される置換基のいずれかである。

（式中、Ｒは保護基である。）(1) As asymmetric esterification catalyst, a compound represented by the following general formula (1), (2), (3) or (4) is used, and in the presence of benzoic anhydride or a derivative thereof, racemic 2 A method of producing an optically active carboxylic acid ester by dehydrating and condensing any enantiomer of a secondary alcohol and a carboxylic acid.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.)

  Of the compounds represented by (1) and (2) above, the compound in which X is Ph is tetramisole, and among the compounds represented by (3) and (4) above, X is Ph. One is benzotetramisole.

  (2) The method for producing the optically active carboxylic acid ester according to (1), wherein at least one carbon atom adjacent to the asymmetric carbon atom of the racemic secondary alcohol is bonded to another atom by a multiple bond. .

  (3) Of the carbon atoms adjacent to the asymmetric carbon atom of the racemic secondary alcohol, one atom is an atom bonded to another atom by a triple bond, and another atom is a double bond. The method for producing the optically active carboxylic acid ester according to (1), wherein the cobalt complex is bonded to the triple bond, which is an atom bonded to another atom.

  (4) The method for producing an optically active carboxylic acid ester according to (1), wherein the benzoic anhydride derivative is a phenyl ring in which an electron donating group is substituted.

上記の式中、Ｘは、下記化学式（５）で表される置換基のいずれかである。

（式中、Ｒは保護基である。）(5) Racemic secondary in the presence of benzoic anhydride or a derivative thereof using a compound represented by the general formula (1), (2), (3) or (4) as an asymmetric esterification catalyst A method for optical resolution of racemic secondary alcohols, wherein a racemic secondary alcohol is optically resolved by selectively reacting either enantiomer of alcohol with a carboxylic acid.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.)

上記の式中、Ｘは、下記化学式（５）で表される置換基のいずれかである。

（式中、Ｒは保護基である。）(6) As the asymmetric esterification catalyst, a secondary hydroxyl group is used in the presence of benzoic anhydride or a derivative thereof using a compound represented by the general formula (1), (2), (3) or (4) A process for producing an optically active lactone by selectively reacting the secondary hydroxyl group of one of the enantiomers of a racemic hydroxycarboxylic acid having a carboxylic acid group present in the molecule.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.)

  According to the present invention, an optically active carboxylic acid ester can be produced directly from a racemic secondary alcohol and a carboxylic acid.

  In addition, according to the present invention, racemic secondary alcohol can be easily optically resolved by the same means as the above method.

  Furthermore, according to the present invention, an optically active carboxylic acid ester can be produced directly from a racemic hydroxycarboxylic acid having a secondary hydroxyl group.

BEST MODE FOR CARRYING OUT THE INVENTION

<First embodiment>
Hereinafter, the first embodiment of the present invention will be described in detail.

上記の式中、Ｘは、下記化学式（５）で表される置換基のいずれかである。

（式中、Ｒは保護基である。）In the first embodiment of the present invention, when an optically active ester is produced from a racemic secondary alcohol and a carboxylic acid, a general ester (1), (2), (3) or ( 4) and using a benzoic anhydride or a derivative thereof as a dehydrating condensing agent.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.)

  Of the compounds represented by the above (1) and (2), the compound in which X is Ph is tetramisol, and among the compounds represented by (3) and (4) above, X is Ph. One is benzotetramisole.

  The protecting group R is a protecting group used for normal chemical synthesis, and examples thereof include an alkyl group. These compounds can be obtained as commercial products or synthesized from amino acids having these substituents as side chains.

  In order to obtain high enantioselectivity (ee) and high relative reaction rate ratio (s), the compound represented by formula (3) or (4) is preferable.

  In the present invention, benzoic anhydride and derivatives thereof act as a dehydrating condensation agent. The phenyl ring in benzoic anhydride may have a substituent. In obtaining a high enantioselectivity (ee) and a high relative reaction rate ratio (s), an unsubstituted benzoic anhydride and a phenyl ring are electron-donating groups such as alkyl groups, alkoxy groups, amino groups, hydroxyl groups. Preferred is benzoic anhydride substituted with or the like. Among them, a benzoic acid anhydride in which the phenyl ring is substituted with a mono-, di- or tri-alkyl group having 1 to 3 carbon atoms and an alkoxy group is preferable, and benzoic acid anhydride substituted with a mono- or di-methyl group and a methoxy group. More preferred.

Any secondary alcohol can be used. However, when the secondary alcohol is represented by (R ¹ ) (R ² ) CHOH, R ¹ and R ² are different substituents. Examples of R ¹ and R ² include an alkyl group, a cycloalkyl group, an arylalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group. These groups may have a substituent. The molecule may contain a double bond or a triple bond. Among them, one of the carbon atoms adjacent to the asymmetric carbon atom of the secondary alcohol is represented by the chemical formulas (6), (7), and (7a). As shown in the figure, it is preferable to be bonded to another atom by a multiple bond such as a double bond or a triple bond. Examples of such secondary alcohols are shown below.

  The secondary alcohol is an atom in which one of the carbon atoms adjacent to the asymmetric carbon atom of the racemic secondary alcohol is bonded to another atom by a triple bond, and another atom is A secondary alcohol which is an atom bonded to another atom by a double bond can also be used. Examples of such secondary alcohols include compounds represented by chemical formula (7b).

  When the secondary alcohol having a double bond and a triple bond in one molecule is used, the triple bond is preferably protected by binding a cobalt complex to the triple bond (for example, the compound ( 7c)). In the present invention, the multiple bond of the carbon atom adjacent to the asymmetric carbon atom contributes to the stereoselectivity of the ester formation reaction, but both the double bond and triple bond in the same molecule contribute to the stereoselectivity. As a result, the stereoselectivity in the whole molecule tends to be lost. On the other hand, when the triple bond is protected, only the remaining double bond contributes to the stereoselectivity. This is because the stereoselectivity is improved.

  Examples of the cobalt complex used for protecting the triple bond include a cobalt complex having carbon monoxide as a ligand and a cobalt complex having triphenylphosphine as a ligand. These cobalt complexes may be prepared by a conventionally known preparation method.

Arbitrary things can also be used for the carboxylic acid used for esterification reaction with a racemic secondary alcohol. For example, in the carboxylic acid represented by R ³ COOH, examples of R ³ include carboxylic acids having an alkyl group, a cycloalkyl group, an arylalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, and the like. These groups may have a substituent, and a double bond or a triple bond may be contained in the molecule. Specifically, as R ³ , C ₂ H ₅ , CH ₃ CH (CH ₂ ) ₂ , Ph (CH ₂ ) ₂ , Ph (CH ₂ ) ₃ , CH ₂ CH (CH ₂ ) ₂ , CH ₃ OCH ₂ And the above carboxylic acid having c-C ₆ H ₁₁ or the like.

  According to the present invention, one enantiomer of a racemic secondary alcohol selectively reacts with a carboxylic acid in the presence of an asymmetric esterification catalyst and a dehydrating condensing agent to produce an optically active ester. The secondary alcohol is optically resolved as a secondary alcohol having optical activity.

  The reaction of the present invention is carried out by introducing an asymmetric esterification catalyst, a dehydrating condensing agent, a racemic alcohol and a carboxylic acid into a solvent. The charging method into the solvent is arbitrary, and these may be added sequentially or simultaneously. The solvent is not limited, but dichloromethane and chlorobenzene are preferable. The reaction temperature is preferably 0 ° C. to 50 ° C., and the reaction time is preferably 1 hour to 12 hours.

  Although not limited, usually 0.5 equivalent to 0.75 equivalent of carboxylic acid and 1 mol% to 10 mol% of the catalyst are used per 1 equivalent of the secondary alcohol. The dehydrating condensation agent is used in an amount of 1.0 to 1.2 equivalents relative to the carboxylic acid. Further, as a reaction accelerator, diisopropylethylamine can be used in an amount of 2.0 equivalents to 2.4 equivalents with respect to the carboxylic acid.

  After stopping the reaction with saturated aqueous sodium hydrogen carbonate, the organic layer is separated, the aqueous layer is extracted with diethyl ether, mixed with the organic layer, and dried over anhydrous sodium sulfate. The solution is filtered, concentrated under reduced pressure, and fractionated using silica gel thin-layer chromatography to obtain the corresponding optically active ester and unreacted optically active alcohol.

<Second Embodiment>
Hereinafter, the second embodiment of the present invention will be described. In the following description, the same symbols are attached to the same words and phrases as in the first embodiment, and the same configurations as those in the first embodiment are described. Description is omitted.

上記の式中、Ｘは、下記化学式（５）で表される置換基のいずれかである。

（式中、Ｒは保護基である。）The second embodiment of the present invention uses a compound represented by the general formula (1), (2), (3) or (4) as an asymmetric esterification catalyst, and the presence of benzoic anhydride or a derivative thereof. An optically active lactone is produced by selectively reacting the secondary hydroxyl group of any enantiomer of a racemic hydroxycarboxylic acid having a secondary hydroxyl group with a carboxylic acid group present in the molecule. It has a special feature.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.)

  Any hydroxycarboxylic acid having a secondary hydroxyl group may be used as long as it is an asymmetric hydroxycarboxylic acid having an asymmetric center at the carbon atom to which the secondary hydroxyl group is bonded. It is preferable that at least one of the carbon atoms adjacent to the asymmetric carbon atom to which the alcohol is bonded has a multiple bond such as a double bond or a triple bond. Examples of such hydroxycarboxylic acid include a compound represented by the chemical formula (7d), specifically, 12-hydroxy-12-phenyldodecanoic acid, 15-hydroxy-15-phenylpentadecanoic acid. 16-hydroxy-16-phenylhexadecanoic acid.

（式中、ｎは正の整数である。）

(In the formula, n is a positive integer.)

  Hereinafter, the present invention will be described with reference to examples.

[Example 1 Effect of Substituent of Benzoic Anhydride (1)]
Using (−)-tetramisol as an asymmetric esterification catalyst, the effects of benzoic anhydride and its derivatives were investigated.

  In 0.2 mol of dichloromethane, 0.75 equivalent of 3-phenylpropionic acid, 0.90 equivalent of benzoic anhydride and derivatives thereof shown in Table 1 with respect to 1 equivalent of 1-phenyl-1-propanol, (- ) -Tetramisole 5 mol% and 1.8 equivalents of diisopropylethylamine were added and reacted at room temperature for 12 hours according to the reaction formula (8). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The produced optically active ester and unreacted optically active alcohol were separated by silica gel thin layer chromatography to obtain respective compounds.

Enantioselectivity (ee) was determined by HPLC analysis with a chiral column.
The s value was calculated as follows by the method of Kagan et al. (Top. Stereochem., 1988, vol 18, p249-330).
s = [ln (1-C) (1-ee of recovered alcohol)] / [ln (1-C) (1 + ee of recovered alcohol)].
Conversion C (%) = [ee of recovered alcohol] / [(ee of recovered alcohol) + (ee of produced ester)]

The obtained results are shown in Table 1.

  From this table, (S) -1-phenylpropyl 3-phenylpropanoate was obtained with high enantioselectivity, and optically active (R) -1-phenyl-1-propanol was optically resolved with high enantioselectivity. I understand that.

(S) -1-phenylpropyl 3-phenylpropanoate (1a)
HPLC (CHIRALCEL AS-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 10.5 min (4.9%), t _R = 11.1 min (95.1) %);
IR (neat): 3031, 1741, 1604, 1496, 752, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.27-7.14 (m, 7H, Ph), 7.13-7.07 (m, 3H, Ph), 5.59 (t, J = 7.0 Hz, 1H, 1-H), 2.87 (t, J = 8.0 Hz, 2H, 2′-H), 2.61 (ddd, J = 16.0, 9.0, 9.0 Hz, 1H, 3 '-H), 2.57 (ddd, J = 16.0, 9.6, 9.0 Hz, 1H, 3'-H), 1.86-1.66 (m, 2H, 2-H), 0.76 (t, J = 7.5 Hz, 3H, 3-H);
¹³ C NMR (CDCl ₃ ): δ 172.2, 140.48, 140.46, 128.4, 128.3, 128.2, 127.7, 126.5, 126.2, 77.4, 36. 1,30.9, 29.3, 9.8;
_{HR MS: calcd for C 18 H} 20 O 2 Na (M + Na +) 291.1356, found 291.1344.

(R) -1-Phenyl-1-propanol (2)
HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 25.9 min (86.6%), t _R = 29.6 min (13.4) %);
¹ H NMR (CDCl ₃ ): δ 7.12-6.96 (m, 5H, Ph), 4.31 (dt, J = 3.0, 6.6 Hz, 1H, 1-H), 1.79 ( d, J = 3.0 Hz, 1H, OH), 1.64-1.38 (m, 2H, 2-H), 0.65 (t, J = 7.5 Hz, 3H, 3-H);
¹³ C NMR (CDCl ₃ ): δ 144.5, 128.3, 127.4, 125.9, 75.9, 31.8, 10.1.

[Example 2 Effect of Substituent of Benzoic Anhydride (2)]
Using (+)-benzotetramisole as the asymmetric esterification catalyst, the benzoic anhydride and derivatives thereof represented by the general formula (9) are used, and the reaction is performed according to the reaction formula (10) in the same manner as in Example 1. I let you.

（１０）

(10)

The results are shown in Table 2.

  From Table 2, it can be seen that (+)-benzotetramisole has a high enantioselectivity and a higher reaction rate than (-)-tetramisole.

[Example 3 Effect of secondary alcohol and carboxylic acid]
Using (+)-benzotetramisole as an asymmetric esterification catalyst, various racemic secondary alcohols and carboxylic acids were reacted under the same conditions as in Example 1 according to the reaction formula (11).

The results are shown in Table 3.

(S) -1-phenyl-1-propanol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 26.6 min (2.1%) , T _R = 30.6 min (97.9%);
¹ H NMR (CDCl ₃ ): δ 7.12-6.96 (m, 5H, Ph), 4.31 (dt, J = 3.0, 6.6 Hz, 1H, 1-H), 1.79 ( d, J = 3.0 Hz, 1H, OH), 1.64-1.38 (m, 2H, 2-H), 0.65 (t, J = 7.5 Hz, 3H, 3-H);
¹³ C NMR (CDCl ₃ ): δ 144.5, 128.3, 127.4, 125.9, 75.9, 31.8, 10.1.

(S) -2-Methyl-1-phenyl-1-propanol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 25.7 min (95 .5%), t _R = 30.0 min (4.5%);
IR (neat): 3398, 3029, 1604, 1492, 760, 701 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.31-7.15 (m, 5H, Ph), 4.27 (dd, J = 6.6, 3.0 Hz, 1H, 1-H), 1.95- 1.79 (m, 2H, 2-H, OH),

(S) -2,2-dimethyl-1-phenyl-1-propanol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 20.3 min (79.1%), t _R = 29.6 min (20.9%);
¹ H NMR (CDCl ₃ ): d 7.26-7.13 (m, 5H, Ph), 4.30 (d, J = 2.7 Hz, 1H, 1-H), 1.78 (br s, 1H, OH), 0.83 (s, 9H, t-Bu);
¹³ C NMR (CDCl ₃ ): d142.1, 127.6, 127.5, 127.2, 82.4, 35.6, 25.9.

(R) -1-phenylpropyl propanoate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 17.4 min (94.7%), t _R = 22.0 min (5.3%);
IR (neat): 3034, 1734, 1604, 1495, 756, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.30-7.16 (m, 5H, Ph), 5.60 (dd, J = 7.5, 6.6 Hz, 1H, 1-H), 2.34- 2.22 (m, 2H, 2′-H), 1.93-1.65 (m, 2H, 2-H), 1.06 (t, J = 7.5 Hz, 3H, 3′-H) , 0.81 (t, J = 7.5 Hz, 3H, 3-H);
¹³ C NMR (CDCl ₃ ): δ 173.8, 140.7, 128.3, 127.7, 126.5, 77.1, 29.4, 27.8, 9.9, 9.1;
_{HRMS: calcd for C 12 H 16} O 2 Na (M + Na +) 215.1043, found 215.1049.

(R) -1-phenylpropyl 3-phenylpropanoate HPLC (CHIRALCEL AD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 14.5 min (95. 1%), t _R = 20.3 min (4.9%);
IR (neat): 3031, 1741, 1604, 1496, 752, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.27-7.14 (m, 7H, Ph), 7.13-7.07 (m, 3H, Ph), 5.59 (t, J = 7.0 Hz, 1H, 1-H), 2.87 (t, J = 8.0 Hz, 2H, 2′-H), 2.61 (ddd, J = 16.0, 9.0, 9.0 Hz, 1H, 3 '-H), 2.57 (ddd, J = 16.0, 9.6, 9.0 Hz, 1H, 3'-H), 1.86-1.66 (m, 2H, 2-H), 0.76 (t, J = 7.5 Hz, 3H, 3-H);
¹³ C NMR (CDCl ₃ ): δ 172.2, 140.48, 140.46, 128.4, 128.3, 128.2, 127.7, 126.5, 126.2, 77.4, 36. 1,30.9, 29.3, 9.8;
_{HR MS: calcd for C 18 H} 20 O 2 Na (M + Na +) 291.1356, found 291.1344.

(R) -1-phenylpropyl 4-phenylbutanoate HPLC (CHIRALCEL AD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 12.4 min (94. 9%), t _R = 16.5 min (5.1%);
IR (neat): 3030, 1734, 1603, 1496, 749, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): d 7.23-6.99 (m, 10H, Ph), 5.60 (t, J = 7.0 Hz, 1H, 1-H), 2.53 (t, J = 7.5 Hz, 2H, 2′-H), 2.29 (dt, J = 16.2, 7.5 Hz, 1H, 4′-H), 2.24 (dt, J = 16.2, 6. 6 Hz, 1H, 4′-H), 1.93-1.65 (m, 4H, 2-H, 3′-H), 0.80 (t, J = 7.5 Hz, 3H, 3-H) ;
¹³ C NMR (CDCl ₃ ): d172.7, 141.4, 140.6, 128.4, 128.3, 128.3, 127.7, 126.5, 125.9, 77.2, 35. 0, 33.8, 29.3, 26.5, 9.9;
_{HR MS: calcd for C 19 H} 22 O 2 Na (M + Na +) 305.1512, found 305.1507.

(R) -1-phenylpropyl 4-methylpentanoate HPLC (CHIRALCEL AD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 10.0 min (91. 4%), t _R = 12.0 min (8.6%);
IR (neat): 3033, 1742, 1604, 1495, 757, 700 cm ⁻¹ ; ¹ H NMR (CDCl ₃ ): d 7.31-7.13 (m, 5H, Ph), 5.59 (t, J = 7.5 Hz, 1H, 1-H), 2.33-2.17 (m, 2H, 2'-H), 1.93-1.63 (m, 2H, 2-H), 1.52 -1.36 (m, 3H, 3'-H, 4'-H), 0.88-0.73 (m, 9H, 3-H, Me, Me);
¹³ C NMR (CDCl ₃ ): d 173.3, 140.7, 128.3, 127.7, 126.5, 77.0, 33.7, 32.6, 29.3, 27.6, 22 19, 22.15, 9.9;
_{HR MS: calcd for C 15 H} 22 O 2 Na (M + Na +) 257.1512, found 257.1509.

(R) -2-methyl-1-phenylpropyl propanoate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/50, flow rate = 1.0 mL / min); t _R = 7.3 min (95.0 %), T _R = 9.1 min (5.0%);
IR (neat): 3033, 1739, 1605, 1495, 739, 701 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.39-7.13 (m, 5H, Ph), 5.40 (d, J = 7.5 Hz, 1H, 1-H), 2.37-2.18 ( m, 2H, 2′-H) 2.09-1.93 (m, 1H, 2-H), 1.06 (t, J = 7.5 Hz, 1H, 3′-H), 0.89 ( d, J = 6.6 Hz, 3H, Me) 0.72 (d, J = 6.6 Hz, 3H, Me);
¹³ C NMR (CDCl ₃ ): δ 173.6, 139.8, 128.1, 127.6, 126.9, 80.6, 33.5, 27.8, 18.7, 18.4, 9. 1;
_{HR MS: calcd for C 13 H} 18 O 2 Na (M + Na +) 229.1199, found 229.12000.

(R) -2-methyl-1-phenylpropyl 3-phenylpropanoate HPLC (CHIRALCEL AD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 12 .4 min (96.0%), t _R = 18.3 min (4.0%);
IR (neat): 3030, 1734, 1604, 1496, 751, 699 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): d 7.28-7.02 (m, 10H, Ph), 5.41 (d, J = 7.5 Hz, 1H, 1-H), 2.88 (t, J = 7.5 Hz, 2H, 2'-H), 2.65-2.53 (m, 2H, 3'-H), 2.07-1.83 (m, 1H, 2-H), 0.85 (D, J = 7.0 Hz, 3H, Me), 0.70 (d, J = 7.0 Hz, 3H, Me);
¹³ C NMR (CDCl ₃ ): d172.1, 140.4, 139.6, 128.4, 128.2, 128.1, 127.6, 127.0, 126.2, 81.0, 36. 0, 33.4, 30.9, 18.6, 18.4;
_{HR MS: calcd for C 19 H} 22 O 2 Na (M + Na +) 305.1512, found 305.1520.

(R) -2,2-dimethyl-1-phenylpropyl propanoate HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/1000, flow rate = 0.5 mL / min); t _R = 11.1 min (96 .4%), t _R = 13.2 min (3.6%);
IR (neat): 3033, 1740, 1495, 738, 702 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): d 7.37-7.23 (m, 5H, Ph), 5.51 (s, 1H, 1-H), 2.56-2.30 (m, 2H, 2 '-H), 1.17 (t, J = 7.5 Hz, 3H, 3'-H), 0.94 (s, 9H, t-Bu);
¹³ C NMR (CDCl ₃ ): d 173.4, 138.6, 127.7, 127.5, 127.4, 82.5, 35.0, 27.9, 26.0, 9.2;
_{HR MS: calcd for C 14 H} 20 O 2 Na (M + Na +) 234.1356, found 234.1354.

(R) -2,2-dimethyl-1-phenylpropyl 3-phenylpropanoate HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 11.9 min (97.9%), t _R = 12.9 min (2.1%);
IR (neat): 3030, 1737, 1604, 1496, 740, 702 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.40-7.17 (m, 10H, Ph), 5.53 (s, 1H, 1-H), 3.00 (t, J = 7.5 Hz, 2H, 2'-H), 2.79-2.68 (m, 2H, 3'-H), 0.93 (s, 9H, t-Bu);
¹³ C NMR (CDCl ₃ ): δ 172.0, 14.04, 138.4, 128.5, 128.2, 127.7, 127.6, 127.4, 126.2, 82.9, 36. 0, 35.0, 30.9, 26.0;
_{HR MS: calcd for C 20 H} 24 O 2 Na (M + Na +) 319.1669, found 319.1660.

[Example 4 Effect of reaction solvent]
Using (+)-benzotetramisol as an asymmetric esterification catalyst, the solvent was changed, and the reaction was carried out under the same conditions as in Example 1 according to the reaction formula (12).

The results are shown in Table 4.

Example 5 Effect of Substituent on Carboxylic Acid on Ester Formation Reaction
Using (+)-benzotetramisole as the asymmetric esterification catalyst, the reaction was carried out under the same conditions as in Example 1 according to the reaction formula (13). As for the carboxylic acid is reacted with secondary alcohol, in the reaction formula (13), a functional group represented by R ^1, were changed as shown in Table 5.

The results are shown in Table 5.

(R) -1-phenylpropyl cyclohexanecarboxylate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 11.2 min (88.0%) , T _R = 13.6 min (12.0%);
IR (neat): 3033, 1742, 1452, 757, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.29-7.12 (m, 5H, Ph), 5.59 (t, J = 7.5 Hz, 1H, 1-H), 2.32-2.17 ( m, 1H, 2'-H), 1.92-1.05 (m, 12H, 2-H, 3'-H, 4'-H, 5'-H), 0.81 (t, J = 7.5Hz, 3H, 3-H);
¹³ C NMR (CDCl ₃ ): δ 175.3, 140.9, 128.3, 127.6, 126.3, 76.6, 43.3, 29.5, 29.0, 28.9, 25. 7, 25.43, 25.40, 9.9;
_{HR MS: calcd for C 16 H} 22 O 2 Na (M + Na +) 269.1512, found 269.1509.

Example 6 Effect of Substituent on Secondary Alcohol on Ester Formation Reaction
Using (+)-benzotetramisole as the asymmetric esterification catalyst, the reaction was carried out in the same manner as in Example 1 according to the reaction formula (14). The substituents on the benzene ring of the secondary alcohol shown in the reaction formula (14) were changed as shown in Table 6.

The results are shown in Table 6.

(S) -1-phenylethanol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 30.5 min (9.8%), t _R = 37.8 min (90.2%);
¹ H NMR (CDCl ₃ ): δ 7.41-7.31 (m, 3H, Ph), 7.28 (tt, J = 6.7, 1.9 Hz, 2H, Ph), 4.94-4. 85 (m, 1H, 1-H), 1.86-1.74 (brs, 1H, OH), 1.51 (dd, J = 6.4, 0.9 Hz, 3H, 2-H).

(S) -1- (4-fluorophenyl) ethanol HPLC (CHIRALPAK AS-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 33.4 min (16.3 %), T _R = 37.6 min (83.7%);
¹ H NMR (CDCl ₃ ): δ 7.20-7.13 (m, 2H, Ph), 6.92-6.85 (m, 2H, Ph), 4.68 (q, J = 6.5 Hz, 1H, 1-H), 3.18 (brs, 1H, OH), 1.31 (d, J = 6.5 Hz, 3H, 2-H).

(S) -1- (4-Nitrophenyl) ethanol HPLC (CHIRALPAK AS-H, i-PrOH / hexane = 1/9, flow rate = 1.0 mL / min): t _R = 23.2 min (11.5 %), T _R = 29.2 min (88.5%);
¹ H NMR (CDCl ₃ ): δ 8.15 (d, J = 8.7 Hz, 2H, Ph), 7.51 (d, J = 8.7 Hz, 2H, Ph), 5.05-4.94 ( m, 1H, 1-H), 2.34-2.15 (m, 1H, OH), 1.49 (d, J = 6.3 Hz, 3H, 2-H).

(S) -1- (4-cyanophenyl) ethanol HPLC (CHIRALPAK AS-H, i-PrOH / hexane = 1/9, flow rate = 1.0 mL / min): t _R = 29.2 min (14.7) %), T _R = 42.9 min (85.3%);
¹ H NMR (CDCl ₃ ): δ 7.55-7.48 (m, 2H, Ph), 7.42-7.36 (m, 2H, Ph), 4.85 (q, J = 6.6 Hz, 1H, 1-H), 2.71-2.56 (m, 1H, OH), 1.39 (d, J = 6.3 Hz, 3H, 2-H).

(S) -1- (4-Tolyl) ethanol HPLC (CHIRALPAK AS-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 27.6 min (10.1% ), T _R = 31.0 min (89.9%);
¹ H NMR (CDCl ₃ ): δ 7.34 (d, J = 8.1 Hz, 2H, Ph), 7.25 (d, J = 8.1 Hz, 2H, Ph), 4.91 (dq, J = 6.3, 3.2 Hz, 1H, 1-H), 2.62-2.53 (m, 1H, OH), 2.46 (s, 3H, Me), 1.56 (d, J = 6) .3Hz, 3H, 2-H).

(S) -1- (4-methoxyphenyl) ethanol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 48.6 min (38.3 %), T _R = 58.6 min (61.7%);
¹ H NMR (CDCl ₃ ): δ 7.18-7.10 (m, 2H, Ph), 6.78-6.69 (m, 2H, Ph), 4.66 (qd, J = 6.3) 2.4 Hz, 1H, 1-H), 3.65 (s, 3H, OMe), 2.63 (brs, 1H, OH), 1.32 (d, J = 6.3 Hz, 3H, 2-H) ).

(S) -1- (2-Tolyl) ethanol HPLC (CHIRALPAK IA, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 23.4 min (9.6%), t _R = 25.9 min (90.4%);
¹ H NMR (CDCl ₃ ): δ 7.45 (dd, J = 7.8, 1.5 Hz, 1H, Ph), 7.22-7.06 (m, 3H, Ph), 5.03 (q, J = 6.0 Hz, 1H, 1-H), 2.38-2.34 (brs, 1H, OH), 2.29 (s, 3H, Me), 1.39 (d, J = 7. 0 Hz, 3H, 2-H).

(R) -1-phenylethyl 3-phenylpropanoate HPLC (CHIRALPAK AS-H, i-PrOH / hexane = 1/50, flow rate = 0.3 mL / min): t _R = 18.3 min (94. 6%), t _R = 20.0 min (5.4%);
¹ H NMR (CDCl ₃ ): δ 7.28-7.05 (m, 10H, Ph), 5.80 (q, J = 6.6 Hz, 1H, 1-H), 2.86 (t, J = 7.5 Hz, 2H, 2′-H), 2.67-2.48 (m, 2H, 3′-H), 1.41 (d, J = 6.6 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 172.1, 141.6, 140.4, 128.4, 127.8, 126.2, 126.0, 72.3, 36.1, 30.9, 22. 1.

(R) -1- (4-fluorophenyl) ethyl 3-phenylpropanoate HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 13 .4 min (7.5%), t _R = 16.0 min (92.5%);
IR (neat): 3029, 1733, 1605, 1513, 835, 750, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.25-7.05 (m, 7H, Ph), 6.97-6.83 (m, 2H, Ph), 5.78 (q, J = 7.0 Hz, 1H, 1-H), 2.86 (t, J = 7.5 Hz, 2H, 2′-H), 2.64-2.51 (m, 2H, 3′-H), 1.40 (d , J = 7.0 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 172.1, 162.3 (d, J = 246.0 Hz), 140.3, 137.4, 128.5, 128.3, 127.9 (d, J = 8 .3 Hz), 126.2, 115.3 (d, J = 21.7 Hz), 71.7, 36.1, 30.9, 22.1;
_{HR MS: calcd for C 17 H} 17 FO 2 Na (M + Na +) 295.1105, found 295.1093.

(R) -1- (4-nitrophenyl) ethyl 3-phenylpropanoate HPLC (CHIRALPAK AD-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min): t _R = 16 .9 min (91.5%), t _R = 36.1 min (8.5%);
IR (neat): 3029, 1734, 1605, 1522, 1348, 855, 752, 699 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 8.10-8.02 (m, 2H, Ph), 7.33-7.25 (m, 2H, Ph), 7.22-7.05 (m, 5H, Ph), 5.81 (q, J = 6.6 Hz, 1H, 1-H), 2.87 (t, J = 7.5 Hz, 2H, 2′-H), 2.71-2.53 ( m, 2H, 3'-H), 1.42 (d, J = 6.6 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 171.9, 148.9, 147.3, 140.0, 128.4, 128.2, 126.6, 126.3, 123.7, 71.2, 35. 8, 30.8, 22.1;
_{HR MS: calcd for C 17 H} 17 NO 4 Na (M + Na +) 322.1050, found 322.1054.

(R) -1- (4-cyanophenyl) ethyl 3-phenylpropanoate HPLC (CHIRALPAK AD-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min): t _R = 16 .9 min (91.4%), t _R = 25.6 min (8.6%);
IR (neat): 3029, 2229, 1736, 1609, 1497, 838, 753, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.54-7.46 (m, 2H, Ph), 7.28-7.04 (m, 7H, Ph), 5.77 (q, J = 6.6 Hz, 1H, 1-H), 2.87 (t, J = 7.5 Hz, 2H, 2-H), 2.69-2.52 (m, 2H, 3′-H), 1.40 (d, J = 6.6 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 171.8, 146.8, 140.0, 132.3, 128.4, 128.2, 126.4, 126.2, 118.5, 111.4, 71. 4, 35.8, 30.7, 22.0;
_{HR MS: calcd for C 18 H} 17 NO 2 Na (M + Na +) 302.1151, found 302.1165.

(R) -1- (4-Tolyl) ethyl 3-phenylpropanoate HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 11. 3 min (5.4%), t _R = 12.6 min (94.6%);
IR (neat): 3028, 1738, 1604, 1517, 817, 750, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.20-7.02 (m, 9H, Ph), 5.77 (q, J = 6.7 Hz, 1H, 1-H), 2.85 (t, J = 7.6 Hz, 2H, 2′-H), 2.60-2.49 (m, 2H, 3′-H), 2.25 (s, 3H, Me), 1.40 (dd, J = 6) .7, 1.5 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 172.1, 140.5, 138.6, 137.5, 129.1, 128.4, 128.3, 126.1, 126.0, 72.2, 36. 1,30.9, 22.0, 21.1;
HR MS: calcd for C ₁₈ H ₂₀ O ₂ Na (M + Na ⁺ ) 291.1356, found 291.1364.

(R) -1- (4-methoxyphenyl) ethyl 3-phenylpropanoate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/4, flow rate = 0.5 mL / min): t _R = 27 .3 min (4.0%), t _R = 31.6 min (96.0%);
IR (neat): 3029, 1730, 1612, 1516, 831, 751, 700 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.22-7.04 (m, 7H, Ph), 6.82-6.73 (m, 2H, Ph), 5.77 (q, J = 6.6 Hz, 1H, 1-H), 3.71 (s, 3H, OMe), 2.85 (t, J = 7.7 Hz, 2H, 2′-H), 2.63-2.45 (m, 2H, 3'-H), 1.40 (d, J = 6.6 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 172.1, 159.2, 140.4, 133.6, 128.4, 128.3, 127.5, 126.1, 113.7, 72.0, 55. 2, 36.1, 30.9, 21.9;
_{HR MS: calcd for C 18 H} 20 O 3 Na (M + Na +) 307.1305, found 307.1317.

(R) -1- (2-Tolyl) ethyl 3-phenylpropanoate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 26. 7 min (4.4%), t _R = 32.8 min (95.6%);
IR (neat): 3028, 1733, 1604, 1494, 761, 699 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.26-7.21 (m, 1H, Ph), 7.20-7.14 (m, 2H, Ph), 7.12-7.01 (m, 6H, Ph), 5.99 (q, J = 6.7 Hz, 1H, 1-H), 2.62-2.50 (m, 2H, 3′-H), 2.26 (s, 3H, 3- H), 1.38 (d, J = 6.4 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 172.0, 140.4, 140.0, 134.7, 130.3, 128.4, 128.2, 127.5, 126.21, 126.16, 125. 2, 69.3, 36.0, 30.9, 21.3, 19.0;
_{HR MS: calcd for C 18 H} 20 O 2 Na (M + Na +) 291.1356, found 291.1362.

[Example 7: Effect on ester formation reaction when aromatic ring of secondary alcohol is changed]
In 0.2 mol of dichloromethane, 1 equivalent of 1- (2-naphthyl) -1-ethanol, 0.5 equivalent of 3-phenylpropionic acid, benzoic anhydride (Bz ₂ O) or paramethoxybenzoic anhydride (PMBA) 0.60 equivalent, (+)-benzotetramisol 5 mol%, and diisopropylethylamine 1.2 equivalent were added, and it was made to react at room temperature for 12 hours according to Reaction formula (15). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The produced optically active ester and unreacted optically active alcohol were obtained by silica gel thin layer chromatography.

Moreover, 1- (2-naphthyl) -1-ethanol which is a secondary alcohol was changed to 1- (1-naphthyl) -1-ethanol, and the same reaction was performed. The results are shown in Table 7.

(S) -1- (2-naphthyl) ethanol HPLC (CHIRALCEL OB-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min): t _R = 17.1 min (90.3% ), T _R = 19.3 min (9.7%);
¹ H NMR (CDCl ₃ ): δ 7.79-7.69 (m, 4H, Ph), 7.46-7.33 (m, 3H, Ph), 4.98 (q, J = 6.4 Hz, 1H, 1-H), 2.00 (brs, 1H, OH), 1.50 (d, J = 6.4 Hz, 3H, 2-H).

(S) -1- (1-naphthyl) ethanol HPLC (CHIRALCEL OB-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min): t _R = 18.1 min (94.3% ), T _R = 21.8 min (5.7%);
¹ H NMR (CDCl ₃ ): δ 8.08-8.00 (m, 1H, Ph), 7.84-7.75 (m, 1H, Ph), 7.70 (d, J = 8.3 Hz, 1H, Ph), 7.60 (d, J = 7.2 Hz, 1H, Ph), 7.50-7.36 (m, 3H, Ph), 5.60 (q, J = 6.4 Hz, 1H) , 1-H), 1.88 (brs, 1H, OH), 1.60 (d, J = 6.4 Hz, 3H, 2-H).

(R) -1- (2-Naphtyl) ethyl 3-phenylpropanoate HPLC (CHIRALPAK AD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 17. 0 min (96.3%), t _R = 26.3 min (3.7%);
IR (neat): 3027, 1732, 1603, 1497, 818, 748, 699 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 7.80-7.65 (m, 4H, Ph), 7.45-7.32 (m, 3H, Ph), 7.22-7.05 (m, 5H, Ph), 5.97 (q, J = 6.6 Hz, 1H, 1-H), 2.88 (t, J = 7.7 Hz, 2H, 2′-H), 2.69-2.52 ( m, 2H, 3'-H), 1.51 (d, J = 6.6 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 172.2, 140.4, 138.9, 133.1, 133.0, 128.4, 128.31, 128.28, 128.0, 127.6, 126. 21, 126.19, 126.0, 125.0, 124.1, 72.5, 36.1, 30.9, 22.1;
_{HR MS: calcd for C 21 H} 20 O 2 Na (M + Na +) 327.1356, found 327.1368.

(R) -1- (1-naphthyl) ethyl 3-phenylpropanoate HPLC (CHIRALPAK AD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 16. 0 min (95.7%), t _R = 21.2 min (4.3%);
IR (neat): 3027, 1732, 1598, 1496, 800, 778, 699 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ): δ 8.01-7.93 (m, 1H, Ph), 7.82-7.68 (m, 2H, Ph), 7.51-7.30 (m, 4H, Ph), 7.24-7.05 (m, 5H, Ph), 6.57 (q, J = 6.6 Hz, 1H, 1-H), 2.90 (t, J = 7.8 Hz, 2H) , 2'-H), 2.71-2.54 (m, 2H, 3'-H), 1.59 (d, J = 6.6 Hz, 3H, 2-H);
¹³ C NMR (CDCl ₃ ): δ 172.2, 140.4, 137.3, 133.8, 130.2, 128.9, 128.43, 128.39, 128.28, 126.3, 126. 2, 125.3, 123.2, 123.1, 69.5, 36.1, 30.9, 21.6;
_{HR MS: calcd for C 21 H} 20 O 2 Na (M + Na +) 327.1356, found 327.1365.

[Example 8: Ester formation reaction using secondary alcohol having triple bond (1)]
Using (+)-benzotetramisol as an asymmetric esterification catalyst, the reaction was carried out in the same manner as in Example 1 according to the reaction formula (16). As the acid anhydride, benzoic anhydride (Bz ₂ O) or 4-methylbenzoic anhydride (TolBA) was used.

The results are shown in Table 8.

(S) -4-phenyl-3-butyn-2-ol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 14.7 min (12 .6%), t _R = 17.0 min (87.4%);
¹ H NMR (CDCl ₃ ): δ 7.24-6.97 (m, 5H, Ph), 4.50 (q, J = 6.6 Hz, 1H, 1-H), 1.82 (br s, 1H , OH), 1.30 (d, J = 6.6 Hz, 3H, 2-H).

(R) -2- (4-Phenylbut-3-yn) yl 3-phenylpropanoate HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min): t _R = 19.4 min (89.2%), t _R = 22.4 min (10.8%);
¹ H NMR (CDCl ₃ ): δ 7.40-7.06 (m, 10H, Ph), 5.62 (q, J = 6.6 Hz, 1H, 1-H), 2.91 (t, J = 7.5 Hz, 2H, 2'-H), 2.70-2.51 (m, 2H, 3'-H), 1.47 (d, J = 6.6 Hz, 3H, 2-H).

Example 9 Ester Formation Reaction Using Secondary Alcohol with Triple Bond (2)
Using (+)-benzotetramisol as the asymmetric esterification catalyst and 1-phenyl-2-heptyn-1-ol as the secondary alcohol, the reaction is carried out in the same manner as in Example 1 according to the reaction formula (17). I let you. The addition amount of (+)-benzotetramisole was 5 mol%, and the addition amount of diisopropylethylamine was 1.35 equivalents.

  Moreover, the ester production | generation reaction was similarly performed about the compound which protected the triple bond of the secondary alcohol with the carbonyl cobalt complex according to the following procedures.

(Cobalt complexation of alkynyl alcohol)
To 16 mL of diethyl ether solution of 295.8 mg (1.571 mmol) of 1-phenyl-2-heptyn-1-ol, 590.9 mg (1.728 mmol) of octacarbonyl dicobalt was added at room temperature. The reaction mixture was stirred for 1 hour at room temperature and then concentrated under reduced pressure. The resulting mixture was separated using silica gel thin layer chromatography to obtain the corresponding cobalt complexed alcohol (678.0 mg, 91%). Obtained.

(Asymmetric esterification of alkynyl alcohol-cobalt complex)
Cobalt complexed alcohol 44.8 mg (0.0945 mmol, 1.0 eq), benzoic anhydride 19.2 mg (0.0850 mmol, 0.90 eq) and 3-phenylpropionic acid 10.6 mg (0.0709 mmol, 0 eq) .75 equivalents) in dichloromethane (0.9 mL), 0.022 mL (0.128 mmol, 1.35 equivalents) of diisopropylethylamine and 2.4 mg (9.45 μmol, 10 mol%) of (+)-benzotetramisole. ) In each order at room temperature. The reaction mixture was stirred for 12 hours and then quenched with saturated aqueous sodium bicarbonate. After separating the organic layer, the water bath was extracted with dichloromethane three times. The organic layers were mixed and then dried over anhydrous sodium sulfate. The solution was filtered and then concentrated under reduced pressure, and the resulting mixture was fractionated using silica gel thin layer chromatography to obtain 20.9 mg of the corresponding optically active cobalt complexed ester (yield 37%, 97% ee). As a result, 15.1 mg of unreacted optically active cobalt complexed alcohol (yield 34%, 80% ee) was obtained. s = 181.

(Synthesis of optically active alkynyl ester by decomplexation)
75.6 mg (0.138 mmol) of cerium ammonium nitrate was added at 0 ° C. to 0.3 mL of a methanol solution of 20.9 mg (0.0345 mmol) of the cobalt complexed ester. The reaction mixture was stirred for 1 hour and then quenched with water. After separating the organic layer, the water bath was extracted three times with ethyl acetate. The organic layers were mixed and then dried over anhydrous sodium sulfate. The solution was filtered and then concentrated under reduced pressure, and the resulting mixture was fractionated using silica gel thin layer chromatography to obtain 9.1 mg (yield 83%, 97% ee) of an alkynyl ester.

(Synthesis of optically active alkynyl alcohol by decomplexation)
60.3 mg (0.127 mmol) of cerium ammonium nitrate was added at 0 ° C. to 0.3 mL of methanol solution of 15.1 mg (0.0318 mmol) of cobalt complexed alcohol. The reaction mixture was stirred for 1 hour and then quenched with water. After separating the organic layer, the water bath was extracted three times with ethyl acetate. The organic layers were mixed and then dried over anhydrous sodium sulfate. The solution was filtered and then concentrated under reduced pressure, and the resulting mixture was fractionated using silica gel thin layer chromatography to obtain 4.5 mg of alkynyl alcohol (yield 75%, 79% ee).

The above results are shown in Table 9.

  From Table 9, it can be seen that when both carbons adjacent to the asymmetric carbon of the secondary alcohol have multiple bonds, the stereoselectivity of the ester formation reaction is lowered. On the other hand, it can be seen that by protecting the triple bond, which is one of multiple bonds, with a cobalt complex, the stereoselectivity is restored and the reaction proceeds with a high enantioselectivity.

(R) -1-phenyl-2-heptin-1-ol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min); t _R = 12.6 min (10 .6%), t _R = 16.6 min (89.4%);
¹ H NMR (CDCl ₃ ): δ 7.55 (d, J = 7.2 Hz, 2H, Ph), 7.41-7.23 (m, 3H, Ph), 5.47-5.45 (m, 1H, 1-H), 2.28 (dt, J = 6.9, 2.1 Hz, 2H, 4-H), 2.07 (d, J = 6.0 Hz, 1H, OH), 1.58 -1.39 (m, 4H, 5-H, 6-H), 0.92 (t, J = 6.9 Hz, 3H, 7-H);
¹³ C NMR (CDCl ₃ ): δ 141.2, 128.5, 128.2, 126.6, 87.7, 79.8, 64.8, 30.6, 21.9, 18.5, ¹³ . 6).

(R) -1-phenyl-2-heptin-1-ol-cobalt complex HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 22. 5 min (10.1%), t _R = 27.3 min (89.9%);
¹ H NMR (CDCl ₃ ): δ 7.45-7.29 (m, 5H, Ph), 5.91 (d, J = 3.3 Hz, 1H, 1-H), 2.70 (dt, J = 9.0, 5.7 Hz, 2H, 4-H), 2.29 (d, J = 3.3 Hz, 1H, OH), 1.66-1.41 (m, 4H, 5-H, 6- H), 0.67 (t, J = 6.9 Hz, 3H, 7-H);
¹³ C NMR (CDCl ₃ ): δ 199.6, 143.8, 128.5, 128.1, 125.3, 101.7, 99.1, 74.2, 34.0, 33.2, 22. 7, 13.8.

(S) -1- (1-phenylhept-2-yne) yl 3-phenylpropanoate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/50, flow rate = 0.5 mL / min); t _R = 21.8 min (1.6%), t _R = 24.0 min (98.4%);
¹ H NMR (CDCl ₃ ): δ 7.49-7.15 (m, 10H, Ph), 6.47 (t, J = 2.1 Hz, 1H, 1-H), 2.96 (t, J = 7.8 Hz, 2H, 3′-H), 2.69 (dd, J = 7.8, 3.9 Hz, 2H, 2′-H), 2.27 (dt, J = 7.2, 2.. 1 Hz, 2H, 4′-H), 1.58-1.35 (m, 4H, 5-H, 6-H), 0.91 (t, J = 6.9 Hz, 3H, 7-H).

(S) -1- (1-Phenylhept-2-yne) yl 3-phenylpropanoate-cobalt complex HPLC (CHIRALPAK AD-H, i-PrOH / hexane = 1/300, flow rate = 0.5 mL / min); t _R = 15.2 min (98.7%), t _R = 22.8 min (1.3%);
¹ H NMR (CDCl ₃ ): δ 7.39-7.17 (m, 10H, Ph), 7.00 (s, 1H, 1-H), 3.00 (t, J = 7.6 Hz, 2H, 3'-H), 2.77 (t, J = 7.6 Hz, 1H, 2'-H), 2.73-2.57 (m, 2H, 4-H), 1.59-1.41. (M, 4H, 5-H, 6-H), 0.96 (t, J = 7.2 Hz, 3H, 7-H).

[Example 10 Effect of double bond other than benzene ring on ester formation reaction (1)]
Using (+)-benzotetramisol as an asymmetric esterification catalyst, the reaction was carried out in the same manner as in Example 1 according to the reaction formula (18).

  The yield was 39% for (S) -2- (3-phenylpropyloxy) propanoate, 46% for benzyl (R) -2-hydroxypropanoate, and the enantioselectivity was (S) -2- (3 -Phenylpropyloxy) propanoate was 77%, (R) -2-hydroxypropanoate was 47%, and s was 12.

Benzyl (R) -2-hydroxypropanoate HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/50, flow rate = 1.0 mL / min): t _R = 19.4 min (87.5%) , T _R = 21.9 min (12.5%);
¹ H NMR (CDCl ₃ ): δ 6.91-6.87 (m, 5H, Ph), 4.69 (s, 2H, 2′-H), 3.80 (qd, J = 7.2, 5 .3 Hz, 1H, 1-H), 2.28 (d, J = 5.3 Hz, 1H, OH), 0.92 (d, J = 7.2 Hz, 3H, 2-H).

Benzyl (S) -2- (3-phenylpropyloxy) propanoate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/1, flow rate = 0.5 mL / min): t _R = 24.4 min (11 .3%), t _R = 29.9 min (88.7%);
¹ H NMR (CDCl ₃ ): δ 7.58-7.31 (m, 10H, Ph), 5.39-5.25 (m, 3H), 3.12 (t, J = 7.8 Hz, 2H) 2.96-2.77 (m, 2H), 1.64 (d, J = 7.2 Hz, 3H).

[Example 11 Effect of double bond other than benzene ring on ester formation reaction (2)]
Example 1 according to the reaction formula (19) using (+)-benzotetramisol as an asymmetric esterification catalyst and using a compound represented by the following (A) or (B) as a secondary alcohol: It was made to react similarly.

The results are shown in Table 10.

(S) -1- (2-thienyl) ethanol HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min): t _R = 17.1 min (58.4% ), T _R = 20.4 min (41.6%);
¹ H NMR (CDCl ₃ ): δ 7.16 (dd, J = 4.7, 2.1 Hz, 1H, thienyl 5-H), 6.98-6.86 (m, 2H, thienyl 3, 4-H ), 5.13-4.99 (m, 1H, 1-H), 1.93 (brs, 1H, OH), 1.53 (d, J = 6.6 Hz, 3H, 2-H).

(S) -1- (2-furyl) ethanol HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/100, flow rate = 0.5 mL / min): t _R = 14.9 min (58.2% ), T _R = 17.2 min (41.8%);
¹ H NMR (CDCl ₃ ): δ 7.30 (dd, J = 2.4, 1.8 Hz, 1H, furyl 5-H), 6.25 (dd, J = 2.4, 1.8 Hz, 1H, furyl 4-H), 6.18-6.13 (m, 1H, furyl 3-H), 4.81 (dq, J = 10.5, 6.6 Hz, 1H, 1-H), 1.89. (Br s, 1H, OH), 1.47 (d, J = 6.6 Hz, 3H, 2-H).

(R) -1- (2-thienyl) ethyl 3-phenylpropanoate HPLC (CHIRALCEL OJ-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min): t _R = 20. 7 min (15.7%), t _R = 23.9 min (84.3%);
¹ H NMR (CDCl ₃ ): δ 7.24-7.06 (m, 6H, Ph, thienyl 5-H), 6.97-6.93 (m, 1H, thienyl 4-H), 6.88 ( dd, J = 5.0, 3.5 Hz, thienyl 3-H), 6.10 (q, J = 6.6 Hz, 1H, 1-H), 2.87 (t, J = 7.2 Hz, 2H) , 2′-H), 2.61-2.53 (m, 2H, 3′-H), 1.53 (d, J = 6.6 Hz, 3H, 2-H).

(R) -1- (2-furyl) ethyl 3-phenylpropanoate HPLC (CHIRALCEL OD-H, i-PrOH / hexane = 1/100, flow rate = 0.5 mL / min): t _R = 14. 5 min (23.5%), t _R = 16.3 min (76.5%);
¹ H NMR (CDCl ₃ ): δ 7.54-7.50 (m, 1H, furyl 5-H), 7.45-7.28 (m, 5H, Ph), 6.50-6.41 (m , J = 6.6 Hz, furyl 3,4-H), 6.10 (q, J = 6.6 Hz, 1H, 1-H), 3.08 (t, J = 7.8 Hz, 2H, 2 ′ -H), 2.82-2.72 (m, 2H, 3'-H), 1.74-1.66 (m, 3H, 2-H).

Example 12 Synthesis Reaction of Optically Active Lactone Using Hydroxycarboxylic Acid
To 4.3 mL of dichloromethane solution of 15.0 mg (0.0663 mmol) of benzoic anhydride and 1.1 mg (0.0044 mmol) of (+)-benzotetramisole, 27.0 μL (0.155 mmol) and 16 of diisopropylethylamine were added. -30.3 mg (0.0869 mmol) of phenylhexadecanoic acid was added in turn at room temperature. The reaction mixture was stirred for 12 hours at room temperature and then quenched with saturated aqueous ammonium chloride. After separating the organic layer, the aqueous layer was extracted three times with diethyl ether. The organic layers were mixed and then dried over anhydrous sodium sulfate. The solution was filtered and then concentrated under reduced pressure, and the resulting mixture was fractionated using silica gel thin layer chromatography to obtain 4.2 mg of the corresponding optically active lactone (yield 15%, 100% ee) as well as unreacted. 9.3 mg (yield 31%, 66% ee) of optically active hydroxycarboxylic acid was obtained.

  A similar test was performed by changing the amount of dichloromethane added and the type of acid anhydride to be added (paramethoxybenzoic anhydride (PMBA) or 3,4,5-trimethoxybenzoic anhydride (TMBA)).

The results are shown in Table 11.

  From Table 11, it was found that when an asymmetric ester formation reaction was performed using hydroxycarboxylic acid as a substrate, an optically active lactone was formed by condensing the hydroxyl group and carboxyl group of hydroxycarboxylic acid with stereoselectivity.

(S) -16-hydroxy-16-phenylhexadecanoic acid HPLC of the corresponding diol derived from the hydroxycarboxylic acid (CHIRALCEL OB-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / t) _R = 16.2 min (82.8%), t _R = 25.8 min (17.2%);
¹ H NMR (CDCl ₃ ): δ 7.35-7.15 (m, 5H, Ph), 4.59 (dd, J = 7.4, 6.0 Hz, 1H), 2.26 (t, J = 7.5 Hz, 2H), 1.80-1.06 (m, 26H).

(R) -16-phenylhexadecanolide HPLC of the corroding diol from the lactone (CHIRALCEL OB-H, i-PrOH / hexane = 1/9, flow rate = 0.5 mL / min); t _R = 16 .2 min (<0.1%), t _R = 25.8 min (>99.9%);
¹ H NMR (CDCl ₃ ): δ 7.41-7.13 (m, 5H, Ph), 5.78 (dd, J = 9.6, 3.6 Hz, 1H), 2.42-2.17 ( m, 2H), 1.97-1.02 (m, 26H);
¹³ C NMR (CDCl ₃ ): δ 173.3, 141.3, 128.4, 127.6, 126.2, 75.5, 36.8, 34.7, 28.3, 28.0, 27. 8, 27.7, 27.0, 27.0, 26.9, 26.8, 26.7, 25.1, 25.0;
_{HR MS: calcd for C 22 H} 34 O 2 Na (M + Na +) 353.2456, found 353.2584.

  According to the present invention, an optically active carboxylic acid ester can be produced directly from a racemic secondary alcohol and a carboxylic acid.

  The obtained optically active ester and the separated optically active secondary alcohol are used in various fields as pharmaceuticals, bioactive substance intermediates, natural product synthesis intermediates, and the like.

Claims (6)

As an asymmetric esterification catalyst, a compound represented by the following general formula (1), (2), (3) or (4) is used, and in the presence of benzoic anhydride or a derivative thereof, a racemic secondary alcohol A method of producing an optically active carboxylic acid ester by dehydrating condensation reaction of any one of enantiomers and carboxylic acid.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.)   The method for producing an optically active carboxylic acid ester according to claim 1, wherein one of the carbon atoms adjacent to the asymmetric carbon atom of the racemic secondary alcohol is bonded to another atom by a multiple bond.   Of the carbon atoms adjacent to the asymmetric carbon atom of the racemic secondary alcohol, one atom is an atom bonded to another atom by a triple bond, and another atom is another atom by a double bond. The method for producing an optically active carboxylic acid ester according to claim 1, wherein a cobalt complex is bonded to the triple bond.   The method for producing an optically active carboxylic acid ester according to claim 1, wherein the derivative of benzoic anhydride is a phenyl ring substituted with an electron donating group. As the asymmetric esterification catalyst, any of the racemic secondary alcohols is used in the presence of benzoic anhydride or a derivative thereof using the compound represented by the general formula (1), (2), (3) or (4). A method for optical resolution of racemic secondary alcohols, wherein a racemic secondary alcohol is optically resolved by selectively reacting one of the enantiomers with a carboxylic acid.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.) A racemic compound having a secondary hydroxyl group in the presence of benzoic anhydride or a derivative thereof using a compound represented by the general formula (1), (2), (3) or (4) as an asymmetric esterification catalyst A process for producing an optically active lactone by selectively reacting the secondary hydroxyl group of one of the enantiomers of a hydroxycarboxylic acid with a carboxylic acid group present in the molecule.

In the above formula, X is any of the substituents represented by the following chemical formula (5).

(In the formula, R is a protecting group.)