KR101165891B1 - Method of preparing ß-sustituted chiral g-lactol,g-lactone and 3-substituted chiral tetrahydrofurane and chiral g-lactol, g-lactone and chiral tetrahydrofurane prepared by thereof - Google Patents

Abstract

The present invention relates to a method for preparing optically active gamma-lactol, gamma-lactone and beta-substituted optically active tetrahydrofuran, and the light-producing gamma-lactol, gamma-lactone and A method for preparing an optically active gamma-lactol in which the beta-position is substituted is tetrahydrofuran. In the presence of a chiral amine catalyst in a gamma-hydroxy alpha, beta-unsaturated aldehyde, a benzene substituted with indole, pyrrole or amine group A 1,4-addition catalysis step is included.
Since the process is simpler than the conventional method, the beta-substituted optically active gamma-lactone and tertiary-substituted optically active tetrahydrofuran can be obtained in high yield easily used as intermediates for the synthesis of many materials. . In addition, since the organic compound itself is used as a catalyst without using a heavy metal catalyst, the process is easy and a separate heavy metal catalyst removal process is not required.

Description

Method for preparing optically active gamma-lactol, gamma-lactone and beta-substituted optically active tetrahydrofuran, and the optically active gamma-lactol, gamma-lactone and tetrahydrofuran {Method of preparing β-sustituted chiral γ-lactol, γ-lactone and 3-substituted chiral tetrahydrofurane and chiral γ-lactol, γ-lactone and chiral tetrahydrofurane prepared by conjugate}

The present invention provides a method for preparing optically active gamma-lactol, gamma-lactone and beta-substituted optically active tetrahydrofuran, and the optically active gamma-lactol, gamma-lactone and The present invention relates to tetrahydrofuran, and specifically, does not use a heavy metal catalyst, and thus, the process is simple, and the optically active gamma-lactol, gamma-lactone, and 3-position-substituted optical activity having a high enantioselectivity are substituted. The present invention relates to a process for obtaining tetrahydrofuran in high yield and to an optically active gamma-lactol, gamma-lactone and tetrahydrofuran produced thereby.

Optically active gamma-lactones are useful chiral intermediates used in the preparation of chiral compounds for various applications. Enantioselectively pure gamma-lactone is distributed in several natural products that exhibit pharmacological activity and plays an important role in synthesizing these natural products. It is used as agrochemicals, pharmaceutical intermediates, polymer solvents and polymerization catalysts, and is useful as a precursor for the synthesis of gamma-lactams and gamma-amino alcohols.

Due to the importance of gamma-lactones, efforts are being made to synthesize more easily and effectively. The production method of the optically active gamma-lactone developed to date can be divided into three types. First, there is a method for separating racemic gamma-lactone compounds using enzymes (see (a) Forzato, C .; Gandolfi, R .; Molinari, F .; Nitti, P .; Pitacco, G .; Valentin , E. Tetrahedron : Asymmetry 2001 , 12 , 1039. (b) Brenna, E .; Negri, DC; Fuganti, C .; Serra, S. Tetrahedron : Asymmetry 2001 , 12 , 1871.). However, this method is less efficient because only up to 50% of the desired gamma-lactone compound can be obtained. The second is a method of synthesizing optically active gamma-lactones using chiral auxiliaries (see: (a) Koch, SSC; Chamberlin, AR J. Org . Chem . 1993 , 58 , 2725. (b) de L. Vanderiei, JM; Coelho, F .; Almeida, WP Synth . Commun . 1998 , 28 , 3047.) In this method, suitable chiral materials should be used as auxiliary to obtain optically active gamma-lactone compounds. Such chiral braces are said to be recoverable and reusable, but they are very costly because they are rarely reused in practice. The third method is currently the most studied method of synthesizing gamma-lactone using a metal catalyst having a chiral environment. The third method has the characteristic of making an optically active gamma-lactone having high enantioselectivity using a small amount of catalyst, but using heavy metals such as rhodium (Rh) and cobalt (Co) as catalysts. Although these heavy metals show a high catalytic effect, they are expensive and have the disadvantage of removing residual heavy metals when developing medicines using synthesized compounds.

Optically active tetrahydrofuran substituted at position 3 is also distributed in various important natural products exhibiting pharmacological activity, and plays an important role in synthesizing such natural products. However, enantioselective synthesis of optically active tetrahydrofuran substituted at position 3 is not easy due to structural factors. Currently, only a method using a metal catalyst having a chiral environment is known as a method for synthesizing an optically active tetrahydrofuran substituted at the 3 position (Ref. Loy, RN; Jacobsen, EN J. Am. Chem . Soc 2009 , 131 , 2786). In this method, various substituents cannot be introduced, but are limited to the case where a methyl alcohol group is introduced.

In order to solve the above problems, an object of the present invention is not to use a heavy metal catalyst, the process is simple, and the beta-substituted optically active gamma-lactol, gamma-lactone, and 3-position-substituted optical having high enantioselectivity The present invention provides a method for producing an active tetrahydrofuran in high yield and an optically active gamma-lactol, gamma-lactone, and tetrahydrofuran.

The present invention to achieve the above object,

A catalytic reaction step of reacting benzene substituted with an indole, pyrrole or amine group with gamma-hydroxy alpha, beta-unsaturated aldehyde (γ-hydroxyα, β-unsaturated aldehyde) in the presence of a chiral amine catalyst. Provided is a method for preparing optically active gamma-lactol with a beta position substituted.

The indole may be represented by the following Chemical Formula 1:

[Formula 1]

(In Chemical Formula 1,

R ₁ Is a substituted or unsubstituted alkyl, aryl or allyl group having 1 to 14 carbon atoms,

R ₂ Is hydrogen, an alkyl group having 1 to 14 carbon atoms, an alkoxy group or a halogen group.)

The pyrrole may be represented by the following Chemical Formula 2:

[Formula 2]

(In Chemical Formula 2,

R ₃ Is a substituted or unsubstituted alkyl, allyl or aryl group having 1 to 14 carbon atoms)

Benzene substituted with the amine group may be represented by the following Formula 3:

(3)

(In Chemical Formula 3,

R ₄ Is dialkylamine having 1 to 10 carbon atoms,

R ₅ Is hydrogen or an alkyl alkoxy group having 1 to 10 carbon atoms.)

The gamma-hydroxy alpha, beta-unsaturated aldehyde may be represented by the following formula (4):

[Formula 4]

The chiral amine catalyst may be a compound represented by Formula 5 or 6 or a mixture thereof:

[Chemical Formula 5]

[Formula 6]

The catalytic reaction may be carried out in an organic solvent for 2 to 50 hours at -40 to -10 ℃.

The organic solvent may be a single or a mixture thereof selected from the group consisting of methylene chloride, benzene, diethyl ether, acetone, acetonitrile, toluene, tetrahydrofuran, methanol and isopropanol.

In the catalytic reaction, benzene substituted with indole, pyrrole or amine group and gamma-hydroxy alpha, beta unsaturated aldehyde may be reacted in a molar ratio of 1: 1 to 1: 3.

The chiral amine catalyst may be added in an amount of 5 to 20 mol% with respect to benzene substituted with indole, pyrrole or amine group.

The present invention to achieve another object of the present invention,

It provides a method for producing a beta-substituted optically active gamma-lactone comprising an oxidation step of oxidizing gamma-lactol prepared by the above method.

The oxidation reaction can be carried out by pyridinium chlorochromate.

The pyridinium chlorochromate may be added to the oxidation reaction in an amount of 1 to 5 equivalents to the gamma-lactol.

The present invention to achieve another object of the present invention,

Provided is a method for preparing an optically active tetrahydrofuran substituted at the 3rd position including a reduction step of reducing gamma-lactol prepared by the above method.

The reduction reaction can be carried out by trifluoroboron ether and triethylsilane.

The trifluoroboron ether and triethylsilane may be added to the reduction reaction in an amount of 1 to 2 equivalents based on gamma-lactol.

In order to achieve another object of the present invention,

It provides an optically active gamma-lactone prepared by the method for producing an optically active gamma-lactone substituted with the beta position.

In order to achieve another object of the present invention

Provided is an optically active tetrahydrofuran prepared by the method for producing an optically active tetrahydrofuran substituted with the 3-position.

According to the production method of the present invention, an optically active gamma-lactone having a beta position and an optically active tetrahydrofuran having a 3 position substitution can be obtained by a simpler method than before. In addition, by the production method of the present invention, optically active gamma-lactone substituted with beta position with high enantioselectivity and tetrahydrofuran with optically substituted position 3 can be obtained.

The production method of the present invention is efficient because the yields of the optically active gamma-lactone substituted at the beta position and the tetrahydrofuran of the optically substituted position 3 are high.

Since the production method of the present invention does not use an expensive heavy metal catalyst, cost is reduced and there is no need to remove the metal catalyst remaining after synthesis.

Hereinafter, the present invention will be described in detail so that those skilled in the art can easily practice.

First, a method for producing optically active gamma-lactol substituted with a beta position will be described.

The method for preparing an optically active gamma-lactol substituted with the beta position of the present invention includes a catalytic reaction step. By the above method, the optically active gamma-lactol substituted with the beta position with high enantioselectivity can be synthesized in a high yield without using a heavy metal catalyst.

Scheme 1 below outlines the catalysis step:

[Reaction Scheme 1]

Referring to Scheme 1, the catalysis step may be performed in the presence of a chiral amine catalyst in gamma-hydroxy alpha, beta-unsaturated aldehyde (gamma-hydroxy alpha, beta-unsaturated aldehyde) of benzene substituted with indole, pyrrole or amine group. , 4-addition reaction.

The indole may be represented by the following Chemical Formula 1:

[Formula 1]

In Formula 1, R ₁ may be selected from a substituted or unsubstituted alkyl group, allyl group, or aryl group having 1 to 14 carbon atoms, and preferably, the alkyl group may be a methyl group. R ₂ may be selected from hydrogen, an alkyl group having 1 to 14 carbon atoms, an alkoxy group or a halogen group, and preferably, the alkyl group may be a methyl group.

The pyrrole may be represented by the following Chemical Formula 2:

[Formula 2]

In Formula 2, R ₃ may be selected from a substituted or unsubstituted alkyl group, allyl group, and aryl group having 1 to 14 carbon atoms, and the alkyl group is preferably a methyl group.

Benzene substituted with the amine group may be represented by the following Formula 3:

(3)

In Formula 3, R ₄ Is dialkylamine having 1 to 10 carbon atoms, R ₅ Is hydrogen or alkylalkoxy having 1 to 10 carbon atoms.

The gamma-hydroxy alpha, beta-unsaturated aldehyde may be represented by the following formula (4):

[Formula 4]

In the 1,4-addition reaction, benzene substituted with indole, pyrrole or amine group and gamma-hydroxy alpha, beta unsaturated aldehyde may be reacted in a molar ratio of 1: 1 to 1: 3. When reacting at a ratio lower than 1: 1, the yield is low because 1,4-addition reaction of benzene substituted with indole, pyrrole, or amine group does not occur properly. Can not do it.

The chiral amine catalyst may be a compound represented by Formula 5 or 6 or a mixture thereof:

[Chemical Formula 5]

[Formula 6]

The chiral amine catalyst may be added in an amount of 5 to 20 mol% with respect to benzene substituted with indole, pyrrole or an amine group. If it is added less than 5 mol%, the catalytic reaction does not occur properly, so the yield of the reaction is low, and when it is added more than 20 mol%, the increase in the yield of the reaction is inefficient, which is not efficient.

The catalysis is carried out in an organic solvent at -40 to -10 ° C. When the reaction temperature is lower than -40 ℃, the reaction rate is slow, and the reaction time is long. When the reaction temperature is higher than -10 ℃, the reaction is terminated prematurely, and the reaction yield may be decreased. The organic solvent may be a single or a mixture thereof selected from the group consisting of methylene chloride, benzene, diethyl ether, acetone, acetonitrile, toluene, tetrahydrofuran, methanol and isopropanol. Preferably, a 9: 1 volume ratio mixture of methylene chloride and isopropanol may be used. The concentration of the organic solvent may be 0.1 to 1.0 M, preferably 0.3 M. If it exceeds 1.0 M, the dissolution of the reactants does not occur properly. If it exceeds 0.1 M, the reaction rate may be slowed.

The catalysis may be performed for 2 to 50 hours. Preferably it may proceed for 24 to 48 hours. If it is performed in less than 2 hours, the yield of gamma-lactol is lowered, and if it exceeds 50 hours, only the reaction time may be long without improving the yield.

An acid may be added to the catalysis. The addition of acid increases the enantioselectivity so that acid can be added as needed by those skilled in the art. The acid may be used without limitation as is known in the art, specifically, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, carbonic acid, acetic acid, trifluoroacetic acid, benzoic acid, and the like, and preferably trifluoroacetic acid may be used. The concentration of the acid uses the same concentration as the amount of catalyst used.

Hereinafter, a method for preparing an optically active gamma-lactone having a beta position substituted will be described.

The beta-substituted optically active gamma-lactone of the present invention comprises an oxidation step.

Scheme 2 briefly illustrates the oxidation reaction:

Scheme 2

Referring to Scheme 2, the oxidation step is to prepare a gamma-lactone of the beta-substituted optical activity by oxidizing the gamma-lactol of the beta-substituted optical activity prepared above. Not only can gamma-lactone be easily obtained from gamma-lactol by the oxidation reaction, but also high yield of optically active gamma-lactone substituted with beta position with high enantioselectivity.

The oxidation reaction can be carried out using a variety of oxidizing agents, the oxidizing agent may be preferably used pyridinium chlorochromate (PCC). The pyridinium chlorochromate may be added at 1 to 5 M, preferably at 2 M. If the amount is less than 1 M, oxidation does not occur properly, and thus the yield of the reaction is lowered.

Next, the manufacturing method of the optically active tetrahydrofuran by which position 3 was substituted is demonstrated.

Method for producing an optically active tetrahydrofuran substituted in position 3 of the present invention includes a reduction reaction step. By the above method, tetrahydrofuran in which position 3 is easily substituted from gamma-lactol can be obtained as well as optically active tetrahydrofuran in position 3 having high enantioselectivity in high yield.

In the reducing step, the beta-substituted optically active gamma-lactol is reduced to prepare tetrahydrofuran having the 3-substituted optical activity.

Scheme 3 below briefly illustrates the reduction reaction.

Scheme 3

Referring to Scheme 3, gamma-lactol is easily converted to optically active tetrahydrofuran substituted at position 3 by a reduction reaction.

The reduction reaction may be performed using various reducing agents, and as the reducing agent, trifluoroboron ether and triethylsilane may be preferably used. The trifluoroboron ether and triethylsilane may be added to the reduction reaction in an amount of 1 to 2 equivalents based on the gamma-lactol. When the trifluoroboron ether and triethylsilane is included in less than 1 equivalent, the yield of tetrahydrofuran may be lowered, and when included in excess of 2 equivalents, the increase in yield is insignificant and inefficient.

By the following examples will be described in more detail the present invention. However, the following examples are only for illustrating the present invention and do not limit the scope of the present invention.

< Example  1> indole beta substitution gamma- Lactol  synthesis

1-1. (4- (1- methyl -1H-indol-3-yl) Tetrahydrofuran 2-ol)

       121 mg (1.0 mmol) of N-methylindole and 25 mg (0.10 mmol) of the catalyst of Chemical Formula 6 were placed in a flask, and 1.8 ml of methylene chloride and 0.2 ml of isopropanol were added dropwise. The reaction flask was placed in a low temperature reactor at −40 ° C. and 0.1 mL (0.10 mmol) of 1 N triplefuoroacetic acid was added. After stirring for 10 minutes, 170 mg (2.00 mmmol) of 4-hydroxy-2-butenal was injected. The reaction solution was continuously stirred until N-methylindole was completely reacted, and the reaction was carried out at -40 ° C for 24 hours. The completion of the reaction was confirmed by thin-layer chromatography (TLC). The reaction product was then purified by forced-flow chromatography using ICN 60 silica gel 63 (32-64 mesh) with 40% ethyl acetate / hexanes to give a colorless title compound (215 mg, 99). % Yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.66 (d, J = 8.1 Hz, 0.4H), 7.60 (d, J = 7.8 Hz, 0.4H), 7.07-7.27 (m, 4H), 6.95 (s, 0.4 H), 6.85 (s, 0.6H), 5.72 (d, J = 4.8 Hz, 1H), 4.50 (t, J = 7.8 Hz, 0.6H), 4.25 (t, J = 7.8 Hz, 0.4H), 3.88 -4.12 (m, 2H), 3.71 (s, 3H), 2.10-2.77 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 137.6, 137.5, 127.5, 127.3, 125.9, 125.5, 122.1, 121.7, 119.5, 119.4, 119.2, 119.1, 115.1, 114.2, 109.7, 109.6, 99. 6, 99.2, 73.4, 72.4, 40.9, 40.8, 36.3, 34.3, 32.9

1-2. Synthesis of (4- (1-allyl-1H-indol-3-yl) tetrahydrofuran-2-ol)

      Gamma-lactol was synthesized in the same manner as in Example 1-1, except that 39 mg (0.25 mmol) of N-allylyindole was used. The reaction product was purified by silica gel chromatography on 40% ethyl acetate / hexanes to give a colorless gamma-lactol (58 mg, 95% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.64 (d, J = 8.1 Hz, 0.4H), 7.58 (d, J = 7.8 Hz, 0.4H), 7.11-7.29 (m, 4H), 6.93 (s, 0.4 H), 6.85 (s, 0.6H), 5.70 (d, J = 4.8 Hz, 1H), 5.05-5.24 (m, 2H), 4.72 (d, J = 5.4 Hz, 2H), 4.52 (t, J = 7.8 Hz, 0.6H), 4.26 (t, J = 7.8 Hz, 0.4H), 3.88-4.12 (m, 2H), 2.10-2.77 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 137.7, 137.6, 135.2, 127.2, 127.1, 125.8, 125.5, 122.0, 121.7, 119.6, 119.4, 119.1, 119.0, 117.2, 115.0, 114.7, 109.7, 109.5, 99. 3, 99.0, 73.2, 72.4, 51.3, 48.7, 48.5, 35.9, 34.2, 32.7

1-3. (4- (1-benzyl-1H-indol-3-yl) Tetrahydrofuran 2-ol)

      Gamma-lactol was synthesized in the same manner as in Example 1-1, except that 52 mg (0.25 mmol) of N-benzylindole was used. The reaction product was purified by silica gel chromatography on 40% ethyl acetate / hexanes to give a colorless gamma-lactol (73 mg, 95% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.06-7.66 (m, 9H), 6.94 (s, 0.4H), 6.86 (s, 0.6H), 5.74 (d, J = 4.8 Hz, 1H), 5.28, ( s, 2H), 3.88-4.55 (m, 3H), 2.10-2.77 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 137.7, 137.6, 131.8, 128.7, 127.9, 127.4, 127.3, 125.8, 125.5, 124.6, 122.0, 121.6, 119.6, 119.4, 119.2, 119.0, 115.0, 114.3, 109.8, 109.7, 98. 8, 98.7, 73.4, 72.4, 50.2, 50.1, 36.3, 34.3, 32.9

1-4. (4- (1-benzyl-5- Methoxy -1H-indol-3-yl) Tetrahydrofuran 2-ol)

      Gamma-lactol was synthesized in the same manner as in Example 1-1, except that 60 mg (0.25 mmol) of N-benzyl-5-methoxy-indole was reacted at -30 ° C. The reaction product was purified by silica gel chromatography on 40% ethyl acetate / hexanes to give a colorless gamma-lactol (78 mg, 97% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.05-7.70 (m, 8H), 6.88 (s, 0.4H), 6.76 (s, 0.6H), 5.84 (d, J = 4.5 Hz, 1H), 5.28, ( s, 2H), 3.94 (s, 3H), 3.84-4.57 (m, 3H), 2.08-2.75 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 154.3, 154.1, 138.1, 137.9, 131.6, 128.6, 127.3, 125.7, 125.4, 124.3, 119.8, 119.5, 119.0, 118.8, 115.2, 114.7, 109.6, 109.4, 98.8, 98.7, 73.4, 72.4, 59.3, 50.3, 50.2, 36.4, 34.3, 32.8

1-5. (4- (1-benzyl-5- Benzyloxy -1H-indol-3-yl) Tetrahydrofuran 2-ol)

      Gamma-lactol was synthesized in the same manner as in Example 1-1, except that 78 mg (0.25 mmol) of N-benzyl-5-benzyloxy-indole was reacted at -20 ° C. The reaction product was purified by silica gel chromatography on 40% ethyl acetate / hexanes to give a colorless gamma-lactol (99 mg, 99% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.07-7.72 (m, 13H), 6.85 (s, 0.4H), 6.77 (s, 0.6H), 5.88 (d, J = 4.8 Hz, 1H), 5.55, ( s, 2H), 5.28, (s, 2H), 3.88-4.59 (m, 3H), 2.11-2.78 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 154.3, 154.1,142.5, 138.0, 137.8, 131.5, 128.9, 127.0, 125.6, 125.4, 124.5, 119.8, 119.6, 119.0, 118.8, 115.0, 114.7, 109.7, 109.5, 98.9, 98.7, 79.3, 73.4, 72.7, 50.4, 50.2, 36.7, 34.5, 32.6

1-6. (4- (1-benzyl-5- Bromo -1H-indol-3-yl) Tetrahydrofuran 2-ol)

      Gamma-lactol was synthesized in the same manner as in Example 1-1, except that 72 mg (0.25 mmol) of N-benzyl-5-bromo-indole was reacted at -20 ° C. The reaction product was purified by silica gel chromatography on 30% ethyl acetate / hexanes to give a colorless gamma-lactol (47 mg, 51% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.10-7.67 (m, 8H), 6.90 (s, 0.4H), 6.85 (s, 0.6H), 5.77 (d, J = 4.5 Hz, 1H), 5.65, ( s, 2H), 3.90-4.57 (m, 3H), 2.08-2.70 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 138.9, 138.7, 131.5, 128.5, 127.7, 127.4, 127.3, 125.8, 125.5, 124.5, 122.1, 121.8, 119.7, 119.6, 119.1, 118.9, 115.0, 114.8, 109.7, 109.6, 98.7, 98.6, 73.7, 72.8, 50.3, 50.1, 36.5, 34.2, 32.7

< Example  2> pyrrole beta-substituted gamma- Lactol  synthesis

2-1. Synthesis of (4- (1-allyl-1H-pyrrol-3-yl) tetrahydrofuran-2-ol)

       54 mg (0.50 mmol) of N-allylpyrrole and 13 mg (0.05 mmol) of the catalyst of Chemical Formula 6 were added to the flask, and 0.9 ml of methylene chloride and 0.1 ml of isopropanol were added dropwise. The reaction flask was placed in a low temperature reactor at −40 ° C. and 0.05 mL (0.05 mmol) of 1 N triplefuoroacetic acid was added. After stirring for 10 minutes, 66 mg (0.75 mmmol) of 4-hydroxy-2-butenal was injected. The reaction solution was continuously stirred until the N-arylpyrrole completely reacted, and the reaction was carried out at -40 ° C for 4 hours. The completion of the reaction was confirmed by thin-layer chromatography (TLC). The reaction product was then purified by force-flow chromatography using ICN 60 silica gel 63 (32-64 mesh) with 30% ethyl acetate / hexanes to give a colorless title compound (42 mg, 44). % Yield).

¹ H NMR (300 MHz, CDCl ₃ ) 6.21-6.42 (m, 3H), 5.64 (d, J = 4.8 Hz, 1H), 5.05-5.24 (m, 2H), 4.26-4.73 (m, 3H), 3.78 -4.10 (m, 2 H), 2.15-2.75 (m, 3 H); ¹³ C NMR (75 MHz, CDCl ₃ ) 132.5, 129.7, 129.5, 122.4, 122.2, 116.2, 115.1, 114.2, 109.8, 109.6, 73.4, 72.4, 58.1, 57.8, 36.4, 34.4, 32.8

2-2. (4- (1-benzyl-1H-pyrrol-3-yl) Tetrahydrofuran 2-ol)

      Gamma-lactol was synthesized in the same manner as in Example 2-1, except that 40 mg (0.25 mmol) of N-benzylindole was used. The reaction product was purified by silica gel chromatography on 30% ethyl acetate / hexanes to give a colorless gamma-lactol (25 mg, 42% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.11-7.38 (m, 5), 6.24-6.45 (m, 3H), 5.66-5.72 (m, 1H), 5.11 (s, 2H), 3.75-4.44 (m, 3H), 2.10-2.78 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 131.7, 129.7, 129.5, 128.7, 127.5, 124.4, 122.3, 122.0, 115.0, 114.5, 109.7, 109.5, 73.5, 72.7, 59.3, 59.1, 36.7, 34.0, 32.4

< Example  3> An amine group  Branch is gamma-substituted by benzene Lactol  synthesis

3-1. (4- (4-dimethylamino-2- Methoxyphenyl ) Tetrahydrofuran 2-ol)

       38 mg (0.25 mmol) of N, N-dimethyl-m-anisidine and 13 mg (0.05 mmol) of the catalyst of Chemical Formula 6 were added to the flask, and 0.5 ml of methylene chloride was added dropwise. The reaction flask was placed in a -10 low temperature reactor and 0.05 mL (0.05 mmol) of 1N triplefuoroacetic acid was added. After stirring for 10 minutes, 43 mg (0.38 mmmol) of 4-hydroxy-2-butenal was injected. The reaction solution was continuously stirred until N, N-dimethyl-m-anisidine was completely reacted, and the reaction was carried out at -10 ° C for 36 hours. The completion of the reaction was confirmed by thin-layer chromatography (TLC). The reaction product was then purified by forced-flow chromatography using ICN 60 silica gel 63 (32-64mesh) with 30% ethyl acetate / hexanes to give a colorless title compound (57 mg, 97 % Yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.03 (d, J = 7.8 Hz, 1H), 6.25-6.43 (m, 2H), 5.66 (d, J = 4.8 Hz, 1H), 3.83 (s, 3H), 3.74-4.12 (m, 3H), 2.94 (s, 6H), 2.11-2.74 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 157.3, 157.1, 150.9, 150.4, 127.5, 127.3, 121.7, 121.5, 115.3, 115.0, 96.9, 96.8, 73.5, 72.7, 55.4, 41.0, 36.3, 34.1, 32.6

3-2. (4- (4- Dibenzylamino -2- Methoxyphenyl ) Tetrahydrofuran 2-ol)

       Gamma-lactol was synthesized in the same manner as in Example 3-1, except that 76 mg (0.25 mmol) of N, N-dibenzyl-m-anisidine was used. The reaction product was purified by silica gel chromatography on 30% ethyl acetate / hexanes to give a colorless gamma-lactol (37 mg, 38% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.11-7.39 (m, 10H), 6.96 (d, J = 8.2 Hz, 1H), 6.23-6.44 (m, 2H), 5.68 (d, J = 4.5 Hz, 1H ), 4.63 (s, 4H), 3.72-4.13 (m, 3H), 3.62 (s, 3H), 2.14-2.75 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) 156.4, 156.2, 149.7, 149.6, 137.2, 127.0, 125.9, 125.5, 125.4, 125.1, 122.7, 122.5, 113.2, 113.0, 95.8, 95.7, 73.7, 72.9, 53.7, 53.2, 36.5, 34.7, 32.8

The gamma-lactone substituted with the beta position synthesized by Examples 1 to 2 is shown in Table 1 below.

< Example  4> gamma-lactone substituted with beta position (4- (1- methyl -1H-indol-3-yl) Dihydrofuran 2-one)

1.0 ml of methylene chloride was added dropwise to 43 mg (0.20 mmol) of 4- (1-methyl-1H-indol-3-yl) tetrahydrofuran-2-ol synthesized in Example 1-1. Then pyrididium chloromate was added at room temperature. After 2 hours additional 1 equivalent of pyridinium chloride was added. After 24 hours, the resulting mixture was purified from 10% ethyl acetate / hexanes. Purification by silica gel chromatography gave the title compound as a colorless (28 mg, 65% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.53 (dd, J = 0.9, 7.8 Hz, 1H), 7.11-7.35 (m, 3H), 6.93 (s, 1H), 4.72 (t, J = 7.8 Hz, 1H ), 4.30 (t J = 7.5 Hz, 1 H), 3.98-4.10 (m, 1 H), 3.77 (s, 3 H), 2.71-3.00 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) 177.2, 137.6, 126.6, 125.6, 122.5, 119.7, 118.8, 113.2, 110.0, 73.9, 35.5, 33.4, 33.0

< Example  5> tetrahydrofuran substituted in position 3 (1- methyl -3- ( Tetrahydrofuran -3-yl) -1H- indole ) Synthesis of

To 33 mg (0.15 mmol) of 4- (1-methyl-1H-indol-3-yl) tetrahydrofuran-2-ol synthesized in Example 1-1, 0.8 ml of methylene chloride was added dropwise. 48 μl (0.30 mmol) of triethylsilane was added to the reaction solution, which was then placed in a low temperature reactor at −40 ° C., and 55 μl (0.45 mmol) of trifluoroboron ether was added thereto. After stirring at this temperature for 10 minutes, the temperature was raised to room temperature, followed by further stirring for 3 hours, followed by extraction with water and methylene chloride, and the extract was washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then in 10% ethyl acetate / hexanes. Purification by silica gel chromatography gave the title compound as a colorless (20 mg, 67% yield).

¹ H NMR (300 MHz, CDCl ₃ ) 7.66 (d, J = 6.0 Hz, 1H), 7.26-7.35 (m, 2H), 7.15 (dd, J = 0.9, 6.0 Hz, 1H), 6.92 (s, 1H ), 4.25 (t, J = 5.7 Hz, 1H), 4.10 (dt, J = 3.6, 6.0 Hz, 1H), 4.00 (q, J = 5.7 Hz, 1H), 3.86 (t, J = 5.7 Hz, 1H ), 3.78 (s, 3H), 3.71 (t, J = 5.7 Hz, 1H), 2.37-2.48 (m, 1H), 2.08-2.17 (m, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) 137.2, 127.2, 125.2, 121.8, 119.2, 118.8, 115.6, 109.4, 73.7, 68.2, 36.4, 33.4, 32.7

< Experimental Example  1> Example  Gamma of 1 to 3 Lactol  Confirmation of Mirror Image Selectivity

Gamma-lactol synthesized in Examples 1 to 3 was prepared by gamma-lactone through the method of Example 4, and then subjected to enantioselectivity using chiral HPLC. The column used a Chiralcel column as follows: OD-H (25 cm), OD guard (5 cm), AD (25 cm) and AD guard (5 cm). The results are shown in Table 2 below.

HPLC conditions of each Example are as follows.

Example 1-1 AD-H column, 10% isopropanol / hexanes, 1.0 mL / min flow, lambda = 220 nm; minor isomer t _r = 15.4 min, major isomer t _r = 17.3 min.

Example 1-2 AD-H column, 10% isopropanol / hexanes, 1.0 mL / min flow, lambda = 220 nm; minor isomer t _r = 12.6 min, major isomer t _r = 13.5 min.

Examples 1-3: AD-H column, 10% isopropanol / hexanes, 1.2 ml / min flow, lambda = 220 nm; minor isomer t _r = 18.9 min, major isomer t _r = 21.4 min.

Examples 1-4: AD-H column, 10% isopropanol / hexanes, 1.2 ml / min flow, lambda = 220 nm; minor isomer t _r = 25.3 min, major isomer t _r = 27.2 min.

Example 1-5 AD-H column, 10% isopropanol / hexanes, 1.2 mL / min flow, λ = 220 nm; minor isomer t _r = 40.2 min, major isomer t _r = 44.3 min.

Examples 1-6: AD-H column, 10% isopropanol / hexanes, 1.0 mL / min flow, lambda = 220 nm; minor isomer t _r = 23.1 min, major isomer t _r = 27.2 min.

Example 2-1: AD-H column, 2% isopropanol / hexanes, 1.0 mL / min flow, lambda = 220 nm; major isomer t _r = 44.4 min, minor isomer t _r = 49.7 min.

Example 2-2: OD-H column, 10% isopropanol / hexanes, 1.0 mL / min flow, lambda = 220 nm; minor isomer t _r = 63.8 min, major isomer t _r = 69.5 min.

Example 3-1; AD-H column, 10% isopropanol / hexane, 1.0 mL / min flow, λ = 220 nm; major isomer t _r = 11.6 min, minor isomer t _r = 13.3 min.

Example 3-2: AD-H column, 10% isopropanol / hexanes, 1.0 mL / min flow, lambda = 220 nm; minor isomer t _r = 20.8 min, major isomer t _r = 23.8 min.

As described above, according to the production method of the present invention, optically active gamma-lactone substituted with beta position with high enantioselectivity and tetrahydrofuran with substituted third position in optical yield can be obtained. In addition, the manufacturing method is simpler than the conventional method, and thus it is easier to obtain optically active gamma-lactone in which the beta position is substituted and tetrahydrofuran in the third position is substituted, and a metal catalyst is not used. No metal catalyst removal process is necessary.

Claims (15)

Beta-substituted optically active gamma comprising a catalysis step of adding 1,4-addition reaction of indole, pyrrole or amine-substituted benzene to gamma-hydroxy alpha, beta-unsaturated aldehyde in the presence of a chiral amine catalyst. In the manufacturing method of lactol,
The indole is represented by the following Formula 1,
[Formula 1]

(In Formula 1,
R ₁ is a methyl group, allyl group or benzyl group,
R ₂ is hydrogen, methoxy, benzyloxyl or bromo.)
The pyrrole is represented by the following formula (2),
(2)

(In Formula 2,
R ₃ is an allyl group or benzyl group)

Benzene substituted with the amine group is represented by the following formula (3),
(3)

(In Chemical Formula 3,
(R ₄ is dimethylamine or dibenzylamine,
R ₅ is a methoxy group.)
The gamma-hydroxy alpha, beta-unsaturated aldehyde is represented by the following formula (4),
[Chemical Formula 4]

The chiral amine catalyst is a compound represented by the following formula (6),
[Chemical Formula 6]

Method for producing a beta-substituted optically active gamma-lactol, characterized in that the beta-substituted optically active gamma-lactol is represented by the following formula 1-1 to 3-2:
[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

[Formula 1-4]

[Formula 1-5]

[Formula 1-6]

[Formula 2-1]

[Formula 2-2]

[Formula 3-1]

[Formula 3-2]

delete delete delete delete delete The method of claim 1,
Method for producing a beta-substituted optically active gamma-lactol, characterized in that the catalytic reaction is carried out in an organic solvent for 2 to 50 hours at -40 to -10 ℃. The method of claim 7, wherein
Wherein the organic solvent is methylene chloride, benzene, diethyl ether, acetone, acetonitrile, toluene, tetrahydrofuran, methanol and isopropanol alone or a mixture thereof. Method for preparing gamma-lactol. A method for preparing an optically active gamma-lactone having a beta position substituted by oxidizing the gamma-lactol prepared by the method of claim 1. 10. The method of claim 9,
Method of producing a beta-substituted optically active gamma-lactone, characterized in that the oxidation proceeds by pyridinium chlorochromate. A method for producing an optically active tetrahydrofuran substituted at position 3, comprising the step of reducing the gamma-lactol prepared by the method of claim 1. The method of claim 11,
Method for producing an optically active tetrahydrofuran substituted at the 3 position, characterized in that the reduction reaction is carried out by trifluoroboron ether and triethylsilane. A beta-substituted optically active gamma-lactol, which is prepared by the method of any one of claims 1, 7 and 8. A beta-substituted optically active gamma-lactone, which is prepared by the method of claim 9 or 10. An optically active tetrahydrofuran substituted at position 3, which is prepared by the method according to claim 11 or 12.