JPH0977708A - Method for producing optically active alcohol - Google Patents

Abstract

(57) [Summary] (Modified) SOLUTION: An optically active compound of the following compound (1) is reacted with an organic carboxylic acid (2) or a reactive derivative thereof to alkylate the obtained compound (3). React the agent (4),
A process for producing an optically active alcohol (6), which reduces the obtained compound (5). (R ¹ is hydrogen or an alkyl group, R ² is hydrogen, an aromatic group which may have a substituent or an aliphatic group which may have a substituent, and R ³ has a substituent. Shows a good aliphatic group, Y
Represents a halogen or a substituted sulfonic acid residue) [Effect] A wide range of optically active alcohols can be produced in a high yield by a simple operation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active alcohol, and more particularly to a method for producing an optically active alcohol which is industrially advantageous by using an asymmetric auxiliary group.

[0002]

2. Description of the Related Art Of the methods for synthesizing optically active compounds represented by optically active alcohols, the method via an asymmetric alkylation reaction using an asymmetric auxiliary group is the most reliable method and is therefore widely used. ing. Currently used chiral auxiliary groups include chiral oxazolidinone developed by Evans et al. And camphorsultam developed by Oppolzer et al. Both asymmetric auxiliary groups show high selectivity in asymmetric alkylation, and their utility is widely recognized.

[0003]

However, these conventional chiral auxiliary groups are limited to (1) an alkylating agent which is a compound having relatively high reactivity, and it does not react with an alkyl halide having a branch at the β-position. No, (2) two or more steps are required to remove an auxiliary group to obtain an optically active alcohol,
(3) The synthesis of an acyl compound has a drawback that a strong base such as sodium hydride or butyllithium is required.

Therefore, the objects of the present invention are the above (1) and (2).
Another object of the present invention is to provide a method for producing an optically active alcohol using a chiral auxiliary compound which does not have the disadvantages of (3) and has high optical selectivity.

[0005]

Therefore, the present inventors have synthesized various N-unsubstituted isoxazolidines, and studied a method for producing an optically active alcohol utilizing the asymmetric alkylation reaction. By using an optically active benzopyranoisoxazolidine compound represented by the following formula (1) as an asymmetric auxiliary group, (1) the compound has a branch at the β-position which has not reacted with a conventional asymmetric auxiliary group. Alkyl triflate also reacts smoothly. (2) The product can be converted into an optically active alcohol in one step. (3) Acylation can be easily performed with acid chloride and amine. (4) Further selection The inventors have found that all of the drawbacks of conventionally used asymmetric auxiliary groups can be solved, and that the present invention has been completed.

The present invention is represented by the following reaction formula.

[0007]

[Chemical 7]

[In the formula, R ¹ represents a hydrogen atom or an alkyl group, and R ² represents a hydrogen atom, an aromatic group which may have a substituent or an aliphatic group which may have a substituent. Show, R
³ represents an aliphatic group which may have a substituent, and Y represents a halogen atom or a substituted sulfonic acid residue]

That is, the present invention is obtained by reacting an optically active benzopyranoisoxazolidine represented by the general formula (1) with an organic carboxylic acid represented by the formula (2) or a reactive derivative thereof. A compound represented by the formula (3) is reacted with an alkylating agent represented by the formula (4), and then the obtained compound represented by the formula (5) is reduced. The present invention provides a method for producing an optically active alcohol represented by the formula (1).

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active substance of the benzopyranoisoxazolidines (1) (hereinafter sometimes referred to as compound (1)) used in the present invention is an asymmetric auxiliary compound (asymmetric auxiliary group). It acts as. In formula (1), since the carbon atoms at the 3rd and 4th positions of the benzopyran ring are asymmetric carbon atoms, there are a plurality of optical isomers. To use this compound (1) as an asymmetric auxiliary group, 3rd and 4th
The configuration of the position is preferably cis. Further, the cis isomer further has (+) or (−) isomers, and in the present invention, it is preferable to use either one of the optically active isomers. As the alkyl group represented by R ¹ in the formula (1), an alkyl group having 1 to 24 carbon atoms is preferable, an alkyl group having 1 to 6 carbon atoms is more preferable, and a methyl group is particularly preferable.

Benzopyranoisoxazolidines (1)
Can be produced, for example, according to the following reaction formula.

[0012]

Embedded image

[Wherein R ¹ is the same as above]

That is, benzaldehydes (7) have ω
-Hydroxyxime (8) is condensed in the presence of an organotin compound and then hydrolyzed to give benzopyranoisoxazolidines (1).

Organotin compounds used as catalysts in the condensation reaction of benzaldehydes (7) with ω-hydroxyoximes (8) include dialkyltin oxides such as dibutyltin oxide and dioctyltin oxide; dialkyltins such as dibutyltin diacetate. Examples thereof include dicarboxylic acid esters.

The reaction of the benzaldehydes (7) with the ω-hydroxyoxime (8) is carried out in the presence of a trace amount of the organic tin compound, preferably 1 to 5 mol% based on the raw material, and an inert solvent such as toluene or benzene. It is preferable to heat and reflux for several hours (3 to 6 hours depending on the amount of catalyst). The molar ratio of the raw material compound used is not particularly limited, but is preferably 1: 1.

The subsequent hydrolysis is preferably carried out under acidic conditions. Acids used include hydrochloric acid, nitric acid,
Mineral acids such as sulfuric acid are preferred.

The compound (1) thus obtained is usually a cis isomer but not an optically active isomer. Therefore, it is desirable to use this compound (1) after optical resolution.

The preferred means of optical resolution differs depending on whether the compound in which R ¹ is a hydrogen atom or in the case where R ¹ is an alkyl group is (±) -1,3a, in which R ¹ is a hydrogen atom.
In the case of 4,9b-tetrahydro-cis-3H- [1] benzopyrano [4,3-c] isoxazole,
The (+)-form and the (-)-form can be easily obtained by resolving the salt of (+)-camphorsulfonic acid by the alternating resolution method. Further, R ¹ is an alkyl group (±) -1,3
a, 4,9b-tetrahydro-3,3-dialkyl-cis-3H- [1] benzopyrano [4,3-c] isoxazole is reacted with L-dibenzoyltartaric anhydride,
The obtained product is optically resolved by fractional crystallization, and each enantiomer is hydrolyzed to obtain a (+) form and a (−) form.

The former method of alternating resolution using (+)-camphorsulfonic acid is (±) -1,3a, 4,9b-tetrahydro-cis-3H- [1] benzopyrano [4,3-].
c) Isoxazole is converted to (+)-camphor sulfonate and crystallized from acetone, whereby the (+)-form and the (-)-form are deposited alternately. That is, this division follows the precipitation of the (+)-form salt as the first crystal, and the precipitation of the (-)-form salt in the second crystal. Further crystallization was repeated, and the salts of (+)-form (-)-form were alternately deposited in pure form, and both enantiomers were obtained purely with a single resolving agent ((+)-camphorsulfonic acid). To be
It is an efficient method. The division yields up to the 6th crystal reached 79% in the (+) form and 68% in the (-) form.

On the other hand, the latter optical resolution method using L-dibenzoyltartaric acid is (±) -1,3a, 4,9b-tetrahydro-3,3-dialkyl-cis-3H- [1] benzopyrano [4,3]. When (c) isoxazole is reacted with L-dibenzoyltartaric acid anhydride and the obtained product (monoamide) is crystallized, a (+) amide is obtained. If the (+) amide is hydrolyzed by a conventional method, the (-) isomer is selectively obtained. On the other hand, the filtrate obtained by obtaining the (+) amide form is hydrolyzed by a conventional method and then recrystallized to obtain the (+) form. This optical resolution also gives both enantiomers in high yield with a single resolving agent.

In the formula (2) showing the organic carboxylic acid used in the acylation reaction, the aromatic group which may have a substituent represented by R ² is not particularly limited, but for example, an aliphatic group, A nitro group, a cyano group, an amino group, a halogen atom, a phenyl group which may be substituted with an alkoxy group,
Examples thereof include a naphthyl group and various heterocyclic groups. Also, R
^The aliphatic group which may have a substituent represented by ² , is not particularly limited, for example, an aromatic group, a nitro group,
Examples thereof include a cyano group, an amino group, a halogen atom, an alkoxy group, and an aliphatic group (alkyl, alkenyl, etc.) which may be substituted with various heterocyclic groups.

Examples of the reactive derivative of the organic carboxylic acid (2) used in the acylation reaction include reactive derivatives of ordinary carboxylic acids such as acid halides and acid anhydrides, and acid halides are particularly preferable.

The reaction between the optically active compound of the compound (1) and the organic carboxylic acid (2) can be carried out under the same conditions as in ordinary acylation. Preferably, it is carried out by reacting compound (1) with organic acid halide (2) in the presence of a base such as triethylamine in an inert solvent such as methylene chloride.

As the aliphatic group which may have a substituent represented by R ³ in the alkylating agent (4), the above R
The same groups as those shown in ² are mentioned.

The reaction of the compound (3) with the alkylating agent (4) is carried out by first reacting the compound (3) with a metal amide or the like to enolate the compound (3) and then the alkylating agent (4).
Is preferably applied.

Since this alkylation reaction proceeds stereoselectively, the configuration of R ³ CH (R ⁴ )-in the obtained compound (5) is either (+) or (-). For example, when the compound (4) is (−), R ³ CH (R
⁴ ) -is (+). Further, when the compound (4) is (+), R ³ CH (R ⁴ )-of the obtained compound (5) is (-).

The reduction reaction of the obtained compound (5) is carried out by reacting a reducing agent such as lithium borohydride, lithium aluminum hydride and sodium (2-methoxyethoxy) aluminum hydride.

[0029]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 2- (3-Methyl-2-butenyloxy) benzaldehyde (190 g, 1 mol), 5-hydroxypentanal oxime (120 g, 1.03 mol) and dibutyltin oxide (5 g, 2 mol%) in toluene solution 5 (1L)
Heated to reflux for an hour. After the crystals precipitated by cooling are separated by filtration,
The solvent was evaporated, the crystals and the residue were combined and stirred in ethanol (1.2 L) and 2M hydrochloric acid (600 ml) at room temperature for 16 hours. The reaction was concentrated and then extracted with diethyl ether (2 x 200 ml). The aqueous layer was made alkaline with aqueous ammonia, extracted with methylene chloride, and crystallized to give 20
4 g (90%) of 1,3a, 4,9b-tetrahydro-
3,3-Dimethyl-cis-3H- [1] benzopyrano [4,3-c] isoxazole ((±) compound 1-
1) was obtained.

[0031]

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Melting point: 120-121 ° C. ¹ H-NMR; 7.37 (m, 1H), 7.22 (m, 1H), 6.95 (m, 2H), 4.50
(d, J = 6.6Hz, 1H), 4.20 (dd, J = 4.8,5.1Hz, 1H), 3.82 (dd, J =
10.8, 13.2Hz, 1H), 2.55 (m, 1H), 1.44 (s, 3H), 1.30 (s, 3
H). ¹³ C-NMR; 155.1, 131.0, 129.2, 121.4, 119.2, 117.1,
84.8, 63.5, 57.7, 48.1, 28.6, 21.3. MS m / z; 205, 173, 137, 120, 91. Elemental analysis (as C ₁₂ H ₁₅ NO ₂ ); Theoretical value: C, 70.22; H, 7.37; N, 6.82. Analytical value: C, 70.09; H, 7.33; N, 6.79.

Reference Example 2 1,3a, 4,9b-Tetrahydro-cis-3H was prepared in the same manner as in Reference Example 1 except that 2-allyloxybenzaldehyde was used instead of 2- (3-methyl-2-butenyloxy) benzaldehyde. -[1] benzopyrano [4,3
-C] Isoxazole ((±) compound 1-2) was obtained.

[0034]

Embedded image

Melting point; 88 to 90 ° C. ¹ H-NMR (CDCl ₃ ) δ; 7.45 (d, J = 6.5 Hz, 1 H), 7.20 (m, 1 H),
7.00 (m, 2H), 5.00 (br, 1H), 4.20-4.50 (m, 3H), 3.75 (m, 2
H), 3.10 (m, 1H). ¹³ C-NMR (CDCl ₃ ) δ; 155.5, 131.3, 129.4, 121.6, 118.
5, 117.3, 72.8, 65.2, 57.3, 40.7.

Reference Example 3 The (±) compound 1-1 (66 g, 0.
32 mol) and L-dibenzoyl tartaric anhydride (110
g, 0.32 mol) in toluene (300 ml) at room temperature
Stir for hours. Ether (500 ml) was added to the reaction solution at 0 ° C., and the mixture was stirred for 1 hour. The crystals formed were collected by filtration and washed with ether to give 80 g of the (+) amide compound 1-1.
(91%) was obtained.

[0037] ^{_{[α] D 25: +125.1 (}} c = 2.45, CHCl 3) mp; 150 to 152 ° C. IR (Nujol) ν:.. 3490, 1715cm -1 1 H-NMR (CDCl 3) δ; 8.0 -8.1 (m, 4H), 7.35-7.62 (m, 7H),
7.02 (br, 1H), 6.94 (t, J = 7Hz, 1H), 6.74 (d, J = 7Hz, 1H), 6.
30 (t, J = 7Hz, 1H), 6.22 (d, J = 2.9Hz, 1H), 5.99 (d, J = 2.9Hz,
1H), 5.44 (d, J = 7.8Hz, 1H), 4.25 (dd, J = 5.0,11.0Hz, 1H),
3.74 (t, J = 11.0Hz, 1H), 2.72 (ddd, J = 5.1,7.8,10.9Hz, 1H),
1.54 (s, 3H), 1.45 (s, 3H). ¹³ C-NMR (CDCl ₃ ) δ; 167.0, 165.2, 164.8, 153.9, 133.
1, 130.7, 129.7, 129.6, 128.0, 127.9, 121.2, 120.4,
116.0, 98.2, 86.0, 71.3, 70.1,63.8, 53.6, 45.9, 2
5.3, 19.2.MS m / z; 528 (MH ₂ O), 396, 274, 205, 173, 137, 131, 1
05.HRMS calcd for C ₃₀ H ₂₈ NO ₉ (MH ⁺ ): 546.1764, found 54
6.1771; elemental analysis (as C ₃₀ H ₂₇ NO _9); theory:. C, 66.05; H, 4.99; N, 2.57 Found: C, 66.10; H, 4.79 ; N, 2.57.

The obtained (+) amide compound (80 g, 0.1
Water (500 ml) ethanol (300 ml) and sodium hydroxide (30 g, 0.75 mol) were added to 5 mol) and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain 27 g (90%) of crystals of (-) compound 1-1. Further, methylene chloride was extracted from the mother liquor to obtain 2.5 g of (-) compound 1-1 crystals. The crystals were combined and recrystallized from methylene chloride and hexane to obtain (-) compound 1-1 with a yield of 98%.

[3aR 9bS]-(-)-Compound 1-1: Melting point; 85-86 ° C. [Α] _D ²⁵ -11.1 (c = 1.14, CHCl ₃ ). HRMS calcd for C ₁₂ H ₁₅ NO ₂ : 205.1103 found 205.1099
Elemental analysis (as C ₁₂ H ₁₅ NO ₂ ); Theoretical value: C, 70.22; H, 7.37; N, 6.82. Found value: C, 69.92; H, 7.31; N, 6.80.

Water (500 ml), ethanol (300 ml) and sodium hydroxide (40 g, 1 mol) were added to the filtrate from which crystals of the (+) amide compound were obtained, and the mixture was hydrolyzed at room temperature for 3 hours to give the (+) compound. Crystals of 1-1 36g (84% ee)
I got This was recrystallized from ether (±) compound 1
-1 was obtained as 6 g, and the residue was recrystallized from methylene chloride and hexane to obtain 28 g (85%) of (+) compound 1-1.

[3aS 9bR]-(+)-Compound 1-1: Melting point; 85-86 ° C. [α] _D ²⁵ +11.1 (c = 1.33, CHCl ₃ ). HRMS calcd for C ₁₂ H ₁₅ NO ₂ : 205.1103 found 205.1099
Elemental analysis (as C ₁₂ H ₁₅ NO ₂ ); Theoretical value: C, 70.22; H, 7.37; N, 6.82. Actual value: C, 70.47; H, 7.22; N, 6.87.

Reference Example 4 To the (±) compound 1-2 (132 g) obtained in Reference Example 2, (+)-camphorsulfonic acid (186 g) and 1.3 L of hot acetone were added and dissolved. This was stored in a refrigerator to obtain (+)-camphorsulfonate of (±) compound 1-2 as crystals. The obtained (+)-camphor sulfonate of (±) compound 1-2 (68 g) was dissolved in boiling acetone (680 ml) and gradually cooled to room temperature.
17.5 g ([α] _D ²⁵ +60.8) of (+) as the first crystal
A salt was obtained. The mother liquor and the washings were combined and concentrated to about 400 ml, and allowed to stand at room temperature for 16 hours to obtain 13.3 g ([α] _D ²⁵ -11.6) of (-) salt as a second crystal. Repeated similar crystallization, 5.4g as 3rd crystal
The (+) salt of ([α] _D ²⁵ +59.8) was used as the fourth crystal.
The (-) salt of 0 ([α] _D ²⁵ -11.4) was 3.6 g as the fifth crystal (+) salt of ([α] _D ²⁵ +60.3) and 3.7 g as the sixth crystal ([[ The (−) salt of α] _D ²⁵ −11.6) was obtained. Each of the (+) salt and the (-) salt thus obtained was added with 1 M sodium hydroxide and then extracted with methylene chloride to give a (+) compound 1-2 or a (-) compound 1-2, respectively. Obtained.

[3aS 9bR]-(+)-Compound 1-2: Melting point 95-96 ° C. [α] _D ²⁵ +62.4 (c = 1.11, CHCl ₃ ); IR (nudule) ν: 3180 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ; 7.45 (d, J = 6.5Hz, 1H), 7.20 (m, 1H),
7.00 (m, 2H), 5.00 (br, 1H), 4.20-4.50 (m, 3H), 3.75 (m, 2
H), 3.10 (m, 1H). ¹³ C-NMR (CDCl ₃ ) δ; 155.5, 131.3, 129.4, 121.6, 118.
5, 117.3, 72.8, 65.2, 57.3, 40.7.MS m / z; 177 (M ⁺ , 27), 145 (100), 131 (38), 115 (17), 91
(16), 77 (14), 65 (13), 51 (13), 39 (21) .HRMS calcd for C ₁₀ H ₁₁ NO ₂ : 177.0790, found 177.078
7; Elemental analysis (C ₁₀ H ₁₁ as NO _2); theory:. C, 67.78; H, 6.26; N, 7.90 Found: C, 67.70; H, 6.26 ; N, 7.87.

[3aR 9bS]-(-)-Compound 1-2: [α] _D ²⁵ -62.4 (c = 1.11, CHCl ₃ ). Melting point; 95-96 ° C. HRMS calcd for C ₁₀ H ₁₁ NO ₂ : 177.0790, found 177.079
1; Elemental analysis (C ₁₀ H ₁₁ as NO _2); theory:. C, 67.78; H, 6.26; N, 7.90 Found: C, 67.69; H, 6.27 ; N, 7.88.

Example 1 (+) Compound 1-1 obtained in Reference Example 4 (1.65 g, 8.
04 mmol) and triethylamine (1.24 ml, 8.90)
methylene chloride solution (20 ml) was cooled to 0 ° C. and propionyl chloride (0.70 ml, 8.06 mmo) was added.
l) was added dropwise. After stirring for 1 hour at 0 ° C., ether (40 m
It was diluted with l) and washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. After purification by chromatography, it is crystallized to give compound (-)-N
-Propionyl-1-1 (1.93 g, 92%) was obtained.

[0046] _{mp; 73~74 ℃ [α] D -267} (c = 1.09, CHCl 3) IR ν:... 1665, 1580cm -1 1 H-NMR (CDCl 3); 7.84 (m, 1H), 7.17 (m, 1H), 6.97 (m, 1H),
5.42 (d, J = 7.5Hz, 1H), 4.27 (dd, J = 5.0,11.3Hz, 1H), 3.81
(dd, J = 10.8,10.8Hz, 1H), 2.40-2.70 (m, 3H), 1.40 (s, 3
H), 1.27 (s, 3H), 1.18 (t, J = 7.2Hz, 3H). ¹³ C-NMR (CDCl ₃ ) δ; 177.7, 132.1, 128.8, 122.0, 121.
9, 116.6, 84.3, 64.6, 53.6, 46.8, 26.6, 25.4, 19.7,
8.7. HRMS (EI) calcd for C ₁₅ H ₁₉ NO ₃ : 261.1365, found 261.1
342; Elemental analysis (C ₁₅ H ₁₉ as NO _3); theory:. C, 68.94; H, 7.32; N, 5.36 Analytical values: C, 69.08; H, 7.14 ; N, 5.26.

Similarly, (-) compound 1-1 (1.21 g,
5.91 mmol), triethylamine (0.99 ml, 7.
10 mmol), propionyl chloride (0.52 ml, 6.
00 mmol) to the compound (+)-N-propionyl-1-
1 (1.42 g, 92%) was obtained.

Melting point: 73-74 ° C. [α] _D +267 (c = 1.09, CHCl ₃ ).

Similarly, (+) compound 1-2 (1.08 g,
6.10 mmol), triethylamine (0.90 ml, 6.
46 mmol), propionyl chloride (0.53 ml, 6.
10 mmol) to the compound (-)-N-propionyl-1-
2 (1.42 g, 92%) was obtained.

Melting point: 76 to 77 ° C. [α] _D -293 (c = 1.40, CHCl ₃ ). IR (nujol) ν: 1660 cm ⁻¹ ; ¹ H-NMR (CDCl ₃ ) δ; 7.67 (m, 1 H ), 7.18 (m, 1H), 7.00 (m, 1
H), 6.86 (m, 1H), 5.44 (d, J = 8.1Hz, 1H), 4.30 (dd, J = 4.8,1
1.3Hz, 1H), 4.00 (m, 2H), 3.86 (dd, J = 9.0,11.3Hz, 1H), 3.
15 (m, 1H), 2.40-2.60 (m, 2H), 1.18 (t, J = 7.5Hz, 3H). ¹³ C-NMR (CDCl ₃ ) δ; 177.5, 154.9, 131.5, 128.9, 122.
1, 121.8, 116.9, 71.4, 65.3, 52.3, 40.4, 26.1, 8.6.HRMS (EI) calcd for C ₁₃ H ₁₅ NO ₃ : 233.1052, found 233.1
052; (as C ₁₃ H ₁₅ NO ₃₎ Elemental analysis; theory:. C, 66.94; H, 6.84; N, 6.00 Analytical values: C, 66.69; H, 6.44 ; N, 6.02.

Similarly, (-) compound 1-2 (0.97 g,
5.46 mmol), triethylamine (1.24 ml, 8.
90 mmol), propionyl chloride (0.48 ml, 5.
52 mmol) to the compound (+)-N-propionyl-1-
2 (1.21 g, 95%) was obtained.

Melting point: 76-77 ° C. [α] _D +294 (c = 1.06, CHCl ₃ ).

Example 2 Compound (-)-N-propionyl-1-obtained in Example 1
2 (62 mg, 0.27 mmol), benzyl bromide (0.03
8 ml, 0.32 mmol) in THF solution (1 ml) at -78 ° C.
With potassium bistrimethylsilylamide (KHMDS)
Solution of toluene (0.5M, 0.58ml, 0.29mmo
l) was added dropwise. After reacting for 1 hour, an ammonium chloride solution was added, the mixture was extracted with ether, the extract was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. After purification by chromatography, it was crystallized to give the compound (-)-N-
(1-Benzylpropionyl) -1-2 (94%) was obtained.

Melting point: 73 to 74 ° C. [α] _D −141 (c = 1.22, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ; 7.58 (m, 1H), 7.20 (m, 6H), 6.98 (m, 1
H), 6.86 (m, 1H), 5.47 (d, J = 8.1Hz, 1H), 4.30 (dd, J = 5.3,1
1.3Hz, 1H), 4.05 (m, 2H), 3.86 (dd, J = 7.5,11.3Hz, 1H), 3.
22 (m, 1H), 3.13 (m, 1H), 3.08 (dd, J = 5.3,13.5Hz, 1H), 2.6
8 (dd, J = 7.5,14Hz, 1H), 1.10 (d, J = 6.3Hz, 3H). ¹³ C-NMR (CDCl ₃ ) δ; 178.8, 154.9, 139.5, 131.5, 129.
2, 129.0, 128.2, 126.2, 122.1, 121.7, 116.9, 71.7,
65.2, 51.9, 40.4, 40.2, 15.7.HRMS calcd for C ₂₀ H ₂₁ NO ₃ : 323.1521, found 323.151
8; (as C ₂₀ H ₂₁ NO ₃₎ Elemental analysis; theory:. C, 74.28; H, 6.55; N, 4.33 Analytical values: C, 74.47; H, 6.41 ; N, 4.25.

Examples 3 to 7 The compounds shown in Table 1 were prepared in the same manner as in Example 2.

[0056]

[Table 1]

Example 8 Compound (-)-N-propionyl-1- obtained in Example 1
2 (126 mg, 0.54 mmol) in ether (4 ml)
Toluene solution of KHMDS (0.5M,
1.1 ml, 0.55 mmol) was added by cannula. In addition, hexamethylphosphoric triamide (HMP
A) (0.28 ml, 1.61 mmol), a solution of cyclohexylmethyltrifluoromethanesulfonate (1 mmol) in ether was added successively. After reacting for 1 hour, an ammonium chloride solution was added, the mixture was extracted with ether, the extract was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. After purification by chromatography, it was crystallized to obtain the compound (-)-N- (1-cyclohexylmethylpropionyl) -1-2 (93%).

Melting point; 98 to 99 ° C. [α] _D −161 (c = 1.38, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ; 7.64 (m, 1H), 7.17 (m, 1H), 7.00 (m, 1
H), 6.88 (m, 1H), 5.50 (d, J = 8.4Hz, 1H), 4.30 (dd, J = 5.0,1
1.2Hz, 1H), 4.00 (m, 2H), 3.88 (dd, J = 8.7,11.2Hz, 1H), 3.
15 (m, 2H), 1.65 (m, 7H), 1.10-1.35 (m, 4H), 1.10 (d, J = 6.9
Hz, 3H), 0.85 (m, 2H). ¹³ C-NMR (CDCl ₃ ) δ; 179.9, 155.2, 131.7, 129.1, 122.
3, 122.1, 117.1, 71.9, 65.5, 52.0, 42.2, 40.6, 35.
2, 33.7, 33.6, 33.2, 26.7, 26.2,26.1, 16.9.HRMS calcd for C ₂₀ H ₂₇ NO ₃ : 329.1991, found 329.199
4; Elemental analysis (as C ₂₀ H ₂₇ NO _3); theory:. C, 72.92; H, 8.26; N, 4.25 Analytical values: C, 72.77; H, 8.32 ; N, 4.15.

Example 9 Compound (-)-N-propionyl-1-obtained in Example 1
1 (492 mg, 2.11 mmol) in THF (6 ml) at -78 ° C in KHMDS in toluene (0.5 M, 5.
1 ml, 2.55 mmol) was added dropwise. Furthermore, hexamethylphosphoric triamide (HMPA) (1.1 ml,
2.55 mmol), pentyl iodide (0.55 ml, 4.2)
1 mmol) was added in succession. After reacting for 1 hour, an ammonium chloride solution was added, the mixture was extracted with ether, the extract was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. After purification by chromatography, it was crystallized to obtain the compound (-)-N- (1-pentylpropionyl) -1-1. (455 mg, 72%)

[Α] _D -165 (c = 1.60, CHCl ₃ ). ¹ H-NMR (CDCl ₃ ) δ; 7.81 (d, J = 7.8Hz, 1H), 7.15 (m, 1H),
6.97 (m, 1H), 6.87 (d, J = 8.5Hz, 1H), 5.45 (d, J = 7.8Hz, 1H),
4.27 (dd, J = 4.8,11.4Hz, 1H), 3.82 (dd, J = 10.8,10.8Hz, 1
H), 3.01 (m, 1H), 2.68 (m, 1H), 1.61 (m, 1H), 1.40 (m, 4H),
1.26 (brs, 9H), 1.13 (d, J = 6.7Hz, 3H), 0.82 (t, J = 7.0Hz,
3H). ¹³ C-NMR (CDCl ₃ ) δ; 180.2, 154.6, 132.0, 128.7, 122.
3, 122.0, 116.6,84.2, 64.6, 53.2, 46.9, 36.0, 35.
0, 31.7, 26.4, 25.7, 22.4, 19.7, 15.6, 13.9.HRMS calcd for C ₂₀ H ₂₉ NO ₃ : 331.2147, found 331.215
0; (as C ₂₀ H ₂₉ NO ₃₎ Elemental analysis; theory:. C, 72.47; H, 8.82; N, 4.23 Analytical values: C, 72.07; H, 8.72 ; N, 4.38.

Example 10 An ether solution of the compound (-)-N- (1-benzylpropionyl) -1-2 (48 mg, 0.15 mmol) obtained in Example 2 and ethanol (0.030 ml, 0.51 mmol). (3 ml) at 0 ° in LiBH ₄ in THF (2M,
0.24 ml, 0.48 mmol) was added. Further, the mixture was stirred at room temperature for 12 hours and 2M hydrochloric acid (2 ml) was added. The product obtained is purified by chromatography, (−)-2-
Benzyl-1-propanol (19 mg, 84%) was obtained.

[Α] _D −11.0 (c = 1.00, benzene).

Examples 11 to 18 Using the compounds of Table 1 and the compounds of Examples 8 and 9, the compounds shown in Table 2 were obtained in the same manner as in Example 10. Moreover, the optical activity of all the alcohols obtained in Examples 10 to 18 was> 98% ee.

[0064]

[Table 2]

[0065]

According to the method of the present invention, a wide range of optically active alcohols can be produced in a high yield with a simple operation.

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Claims (1)

[Claims] 1. A compound represented by the general formula (1): (Wherein R ¹ represents a hydrogen atom or an alkyl group), and an optically active benzopyranoisoxazolidine compound represented by the formula (2): R ² CH ₂ COOH (2) (wherein R ² represents a hydrogen atom, an aromatic group which may have a substituent or an aliphatic group which may have a substituent)
An organic carboxylic acid represented by the following formula or a reactive derivative thereof is reacted to obtain a compound of formula (3) (In the formula, R ¹ and R ² are the same as above), the compound represented by the formula (4): R ³ -Y (4) (In the formula, R ³ may have a substituent. Represents a good aliphatic group, and Y represents a halogen atom or a substituted sulfonic acid residue)
An alkylating agent represented by the formula: (Wherein R ¹ , R ² and R ³ are the same as above) are reduced, and the compound represented by the formula (6): (In the formula, R ² and R ³ are the same as the above).