JPH0977714A - Method for producing optically active ketones - 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),
Then, the obtained compound (5) was added to the Grignard reagent (6).
A process for producing an optically active ketone (7) which reacts with (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. A preferable aliphatic group, Y represents a halogen or a substituted sulfonic acid residue, X represents a halogen, and R ⁴ represents an aliphatic group which may have a substituent or an aromatic group which may have a substituent. (Effects) [Effect] A wide range of optically active ketones 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 ketone, and more particularly to a method for producing an industrially advantageous optically active ketone which utilizes an asymmetric auxiliary group.

[0002]

2. Description of the Related Art Of the methods for synthesizing optically active compounds represented by optically active ketones, the method via an asymmetric alkylation reaction using an asymmetric auxiliary group is the most reliable method and is therefore widely used. Has been done. 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 optically active ketones,
(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 ketone, which does not have the drawbacks of (3) and has a high optical selectivity, and which utilizes a chiral auxiliary compound.

[0005]

Therefore, the present inventors have been synthesizing various N-unsubstituted isoxazolidines and have been investigating a method for producing optically active ketones utilizing the asymmetric alkylation reaction. By using an optically active substance of benzopyranoisoxazolidines represented by the following formula (1) as an asymmetric auxiliary group, (1) branching at the β-position which has not reacted with a conventional asymmetric auxiliary group is achieved. The alkyl triflate that it has also reacts smoothly, (2) the product can be converted into optically active ketones in one step, (3) acylation can be easily performed with an acid chloride and an amine, (4) Furthermore, they have found that the selectivity is similar to that of the conventional chiral auxiliary group, and that all the drawbacks of the conventionally used asymmetric auxiliary groups can be solved, and the present invention has been completed.

The present invention is represented by the following reaction formula.

[0007]

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[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, R ⁴ represents an aliphatic group which may have a substituent or an aromatic group which may have a substituent, and X represents Indicates a halogen atom,
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. The compound represented by the formula (3) is reacted with the alkylating agent represented by the formula (4), and the obtained compound represented by the formula (5) is then Grignard reagent represented by the formula (6). (7) characterized by reacting
The present invention provides a method for producing an optically active ketone represented by:

[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]

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[Wherein R ¹ is the same as above]

That is, the benzaldehydes (8) have ω
-Hydroxyxime (9) 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 (8) with ω-hydroxyoxime (9) 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 (8) with the ω-hydroxyoxime (9) is carried out in the presence of a trace amount of the organotin 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. When the crystallization is further repeated, the salts of the (+)-form and the (-)-form are alternately precipitated in a pure form, and both enantiomers are pure with a single resolving agent ((+)-camphorsulfonic acid). It is an efficient method that can be obtained. Split yield up to 6 crystals is (+)
The body reaches 79% and the (-) body reaches 68%.

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 (-).

As the aliphatic group which may have a substituent and the aromatic group which may have a substituent, which is represented by R ⁴ in the Grignard reagent (6), those shown as R ² above can be used. Can be mentioned. The reaction between the compound (5) and the Grignard reagent (6) can be carried out according to a usual Grignard reaction, and for example, the compound (5) and the Grignard reagent may be reacted in an inert solvent such as tetrahydrofuran.

[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]

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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 (-1) compound 1-1 crystals.
5 g were obtained. 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 (nujol) 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 The (-)-N-propionyl-1-2 (6 obtained in Example 1 was used.
2 mg, 0.27 mmol), benzyl bromide (0.038 ml,
To a THF solution (1 ml) of 0.32 mmol), a toluene solution of potassium bistrimethylsilylamide (KHMDS) (0.5 M, 0.58 ml, 0.29 mmol) was added dropwise at -78 ° C. After reacting for 1 hour, add ammonium chloride solution,
After extraction 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-benzylpropionyl) -1-2 (94%).

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 (-)-N-propionyl-1-2 (1 obtained in Example 1
26 mg, 0.54 mmol) in ether solution (4 ml) -7
Toluene solution of KHMDS at 8 ℃ (0.5M, 1.1m
1, 0.55 mmol) was added via cannula. Furthermore, hexamethylphosphoryl triamide (HMPA) (0.2
8 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 give the compound (-)-N- (1
-Cyclohexylmethylpropionyl) -1-2 (93
%) Was obtained.

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 (-)-N-propionyl-1-1 (4) obtained in Example 1
92 mg, 2.11 mmol) in THF solution (6 ml) -78
KHMDS in toluene at 0.5 ° C (0.5M, 5.1ml,
2.55 mmol) was added dropwise. Furthermore, HMPA (1.1m
l, 2.55 mmol), pentyl iodide (0.55 ml,
4.21 mmol) was added subsequently. 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. Compound (-)-N after purification by chromatography
-(1-Pentylpropionyl) -1-1 was obtained. (4
55 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 TH of the compound (-)-N- (1-benzylpropionyl) -1-2 (160 mg, 0.50 mmol) obtained in Example 2
To the F solution (2 ml) at 0 ° C. was added a solution of methylmagnesium bromide in ether (3M, 0.66 ml, 1.98 mmol). After further warming to room temperature and stirring for 3 hours, aqueous ammonium chloride solution was added, extracted with ether, and purified by chromatography to obtain (S)-(+)-3-benzyl-2-butanone (70 mg, 80%). ,> 98% ee).

[Α] _D −42 (c = 2.09, ethanol).

Example 11 Using the compound obtained in Example 3 and in the same manner as in Example 10, (S)-(+)-3-benzyl-2-butanone (8
6%,> 98% ee).

Example 12 (S)-(+)-3-n-pentyl-2-butanone (70%,> 96% ee) was prepared in the same manner as in Example 10 except that the compound obtained in Example 9 was used. Got

Example 13 Using the compounds obtained in Examples 4 to 8, the corresponding (S)-(+)-ketone compound was obtained in the same manner as in Example 10.

[0066]

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

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[Procedure amendment]

[Submission date] September 14, 1995

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0031

[Correction method] Change

[Correction contents]

[0031]

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─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 49/213 C07C 49/213 49/76 9049-4H 49/76 A // C07D 498/04 101 C07D 498/04 101 C07M 7:00

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), the compound represented by the formula (6): R ⁴ -MgX (6) (In the formula, X represents a halogen atom and R ⁴ represents an aliphatic group which may have a substituent or an aromatic group which may have a substituent), and a Grignard reagent represented by the formula (7) 7] (In the formula, R ² , R ³ and R ⁴ are the same as the above), and a method for producing an optically active ketone.