JPH05279281A - Production of intermediate for synthesis of @(3754/24)+)-grandisol - Google Patents

Abstract

PURPOSE:To readily produce the subject intermediate for synthesis of (+)-grandisol in a high yield by introducing a substituent group into 4 position of levoglucosenone and further modifying the side chain of the resultant alkylated four-membered ring. CONSTITUTION:A compound of the formula is reacted with an aromatic thiol, etc., in the presence of a base and an organothio group is introduced into 4 position thereof to obtain a compound of formula II (R1 is an alkyl or an aryl). A chlorination agent is reacted therewith so as to form a double bond between 3 and 4 positions and the organothio group is then substituted with methyl. Further, conjugate addition of a vinyl group is stereoselectively carried out at 4 position to obtain a compound of formula III. Carbonyl of the compound of formula III is reduced and, after protecting OH at 2 position, the double bond is hydroborated to give a compound of formula IV (R<2> is an OH-protecting group). After converting OH into an eliminable group and eliminating the OH-protecting group, OH is oxidized and treated with a base to obtain a compound of formula V. The resultant compound of formula V is subjected to Bayer-villiger reaction so as to give compound of formula VI and, after protection of OH, the resultant compound is methylated to provide a compound of formula VII (R<3> is an OH-protecting group). Removal of OH and deprotection of OH are carried out, thus producing the objective compound of formula VIII.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an intermediate compound for the synthesis of (+)-grandisol.

[0002]

2. Description of the Related Art Weevil Weevil (Anthonomus Grandis Boheman), which is a kind of weevils, is a cotton pest widely distributed in North America and causes great damage to cotton. The pesticides used for exterminating such pests need to take the environmental impact into consideration, and pheromones are often used. Pheromones act very specifically, and their effects generally appear in very small amounts. However, if it is to be obtained, it is necessary to chemically synthesize it because it exists in a very small amount in nature.

By the way, the sex pheromone produced by male weevils is a mixture of several kinds of compounds, and the most important component among them is (+)-grandisol, which has the following formula [ 18] is a compound having a structure represented by Therefore, for the purpose of using (+)-grandisol as a pesticide, many synthetic methods have been reported so far as a racemate and an optically active substance.

[Chemical 18]

As a synthesis example of an optically active substance, a method using optical resolution in combination (K. Mori, E. Nagano, Liebigs Ann. Chem.
1991, 341.) and a chiral ligand (K. Narasaka, H. Kusama, Y. Hayashi, Bull. Chem, S.
oc. Jpn., 64, 1471 (1991)).
In the former method, an optically active substance is obtained by optically resolving an intermediate derived from a cyclobutane derivative obtained by the reaction of an olefin and dichloroketene in several steps,
He is leading to Grandisol in a few more steps. In the latter, [2 + 2] cycloaddition using a chiral titanium reagent is a key step, and the target compound is obtained through multiple steps.

[0005]

However, in the former synthetic route, 50% of the raw material is wasted because the optically active substance is obtained by performing optical resolution. In the latter case, a special asymmetric ligand is used, the asymmetric yield is not as high as 88% ee, and recrystallization must be repeated to obtain an optically pure compound. There has been a demand for various synthetic methods.

[0006]

The inventors of the present invention have conducted extensive studies to achieve the above object. As a result, levoglucosenone is used as a starting material to form a four-membered ring by intramolecular alkylation, We succeeded in obtaining a known grandisol synthetic intermediate (JB Jones, MA Finch, I.
J. Jakovac, Can. J. Chem., 60, 2007 (1982)).

That is, the process for producing the (+)-grandisol synthetic intermediate of the present invention is carried out by adding an organic thiol to the 4-position of levoglucosenone represented by the formula [1] to obtain the formula [2].
A step (a) for obtaining a compound represented by the formula: wherein R ¹ represents an alkyl or aryl group;

[Chemical 19]

[Chemical 20] The compound represented by the above formula [2] forms a double bond at the 3rd and 4th positions to form the formula [3] (wherein R ¹ is alkyl,
Or (representing an aryl group) to obtain a compound (b),

[Chemical 21] A step (c) of substituting an organic thio group of the compound represented by the above formula [3] with a methyl group to obtain a compound represented by the formula [4],

[Chemical formula 22] A step (d) of stereoselectively conjugately adding a vinyl group to the 4-position of the compound represented by the above formula [4] to obtain a compound represented by the formula [5],

[Chemical formula 23] A step (e) of reducing the carbonyl group of the compound represented by the above formula [5] to obtain the compound represented by the formula [6],

[Chemical formula 24] A step (f) of protecting the ^2- hydroxyl group of the compound represented by the above formula [6] to obtain a compound represented by the formula [7] (in the formula, R ² represents a protective group for the hydroxyl group),

[Chemical 25] Step (g) of hydroborating the double bond of the compound represented by the above formula [7] to obtain the compound represented by the formula [8]
When,

[Chemical formula 26] By converting the hydroxyl group of the compound represented by the above formula [8] into a leaving group, the formula

[9] a step (h) of obtaining a compound represented by the formula (wherein X represents a leaving group),

[Chemical 27] The above formula

Deprotecting the hydroxyl group of the compound represented by [9] to obtain a compound represented by formula [10] (in the formula, X represents a leaving group);

[Chemical 28] A step (j) of oxidizing the hydroxyl group of the compound represented by the above formula [10] to obtain a compound represented by the formula [11] (in the formula, X represents a leaving group);

[Chemical 29] A step (k) of treating the compound represented by the above formula [11] with a base to obtain a compound represented by the formula [12],

[Chemical 30] A step (1) of performing a Bayer-Villiger reaction on the compound represented by the above formula [12] to obtain a compound represented by the formula [13];

[Chemical 31] A step (m) of protecting the hydroxyl group of the compound represented by the above formula [13] to obtain a compound represented by the formula [14] (in the formula, R ³ represents a hydroxyl protecting group);

[Chemical 32] Methylating the compound represented by the above formula [14] to obtain a compound represented by the formula [15] (in the formula, R ³ represents a hydroxyl-protecting group);

[Chemical 33] Removing the hydroxyl group of the compound represented by the above formula [15] to obtain a compound represented by the formula [16] (in the formula, R ³ represents a protective group for the hydroxyl group) (o),

[Chemical 34] Deprotecting the hydroxyl group of the compound represented by the above formula [16] to obtain an intermediate compound for synthesizing grandisol represented by the formula [17] (p),

[Chemical 35] Is included.

The method for producing the (+)-Grandisol synthetic intermediate of the present invention will be specifically described below by following each step. First, in step (a), the levoglucosenone represented by the above formula [1] is reacted with an aliphatic or aromatic thiol in the presence of a base to introduce an organic thio group at the 4-position.
A substituent such as a methyl group may be present on the aromatic ring of the aromatic thiol and is not particularly limited. As the base, tertiary amines such as triethylamine and pyridine, sodium hydroxide, sodium hydride and the like can be preferably used. The solvent used at this time may be a commonly used organic solvent such as benzene, ether, methylene chloride, and is not particularly limited.

In the subsequent step (b), the 4-position of the compound represented by the above formula [2] obtained in the step (a) is chlorinated and eliminated as hydrogen chloride (β-elimination) to give the 3-position. And a double bond extending to the 4-position is formed, but this chlorination reaction and β-elimination proceed all at once. As the chlorinating agent, N-chlorosuccinimide, cyanuryl chloride or the like can be used and is not particularly limited. The solvent used here may be a commonly used hydrocarbon-based organic solvent such as benzene or carbon tetrachloride, or a halogen-based organic solvent, and is not particularly limited.

In step (c), the compound represented by the above formula [3] is reacted with lithium dimethylcuprate at a low temperature using tetrahydrofuran as a solvent. Various organometallic reagents can be used to introduce a methyl group, and the amount used is 1 to 3 equivalents. The reaction temperature is -100 to-
The reaction time at 30 ° C. is preferably 0.1 to 10 hours. As the solvent used at this time, a commonly used organic solvent such as tetrahydrofuran, diethyl ether, benzene or the like can be used and is not particularly limited.

In the step (d), a vinyl group is conjugated and added to the compound represented by the above formula [4] to obtain the above formula [5].
The compound [4] can be obtained by reacting the compound [4] with, for example, vinylmagnesium bromide, copper iodide and hexamethylphosphoric triamide. The vinyl metal reagent used here is not limited to the Grignard reagent, but various organic metals YCH = CH ₂ (Y is Li, N
a, Ce, etc.) can also be used. As an additive, 0 to 10 equivalents of a complex of various copper salts, for example, copper iodide, copper cyanide, copper bromide and the like and methyl sulfide, amines such as hexamethylphosphoric triamide and triethylenediamine, chlorotrimethylsilane, etc. Can be used in an amount of 0 to 10 equivalents. The reaction temperature is −100 to 0 ° C., and the reaction time is 0.5 to 10 hours.

In step (e), the carbonyl group of the compound represented by the above formula [5] is reduced to obtain the compound represented by the above formula [6]. As the reducing agent at this time, sodium borohydride, lithium aluminum hydride,
A hydride transfer reagent generally used for reduction of a carbonyl group such as L-selectride and a catalytic reduction reagent can be used, and there is no particular limitation. As the solvent, a commonly used organic solvent such as tetrahydrofuran, diethyl ether, benzene can be used and is not particularly limited.

In step (f), a protecting group R ² is introduced into the hydroxyl group of the compound represented by the above formula [6]. Protecting group R ²
Any group can be used as long as it is usually used for protecting a hydroxyl group, and for example, tetrahydrofuranyl, methoxymethyl, benzyl, and tert-butyldimethylsilyl can be preferably used. Further, the solvent used when introducing R ² may be a commonly used organic solvent and is not particularly limited.

In the step (g), the reaction of converting the vinyl group of the compound represented by the above formula [7] into a hydroxyethyl group can utilize, for example, a hydroboration reaction. That is, a hydroboration reagent such as diborane, borane methyl sulfide complex and 9-borabicyclo [3,3,1] nonane is preferably used, and the amount used is 1 to 10 equivalents. The reaction temperature is −78 to 80 ° C., preferably room temperature, and the reaction time is 0.5 to 30 hours. The solvent used at this time may be a commonly used organic solvent such as tetrahydrofuran, diethyl ether, benzene, etc., and is not particularly limited.

In step (h), the hydroxyl group of the compound represented by the above formula [8] is converted into a leaving group X 1. The leaving group referred to herein may be any leaving group such as a mesyl group, a tosyl group, a halogen, an acyl group or the like which is usually used as a leaving group. For example, in order to convert it into a mesyl group or a tosyl group, 1 to 5 equivalents of an organic sulfonyl chloride or an organic sulfonic acid anhydride, a tertiary amine liquid compound such as pyridine or triethylamine as a solvent, or a base such as dimethylaminopyridine is used. A general organic solvent containing a polar compound can be used. The reaction temperature is 0 to 40 ° C., and the reaction time is 0.5 to 30 hours.

In step (i), the above formula

The hydroxyl-protecting group R ² of the compound represented by [9] is removed. As the deprotection conditions, general conditions corresponding to the used protecting groups can be used and are not particularly limited. For example, when the protecting group R ² is a tert-butyldimethylsilyl group, a fluorine reagent such as tetrabutylammonium fluoride or hydrogen fluoride-pyridine complex or an acidic compound such as hydrochloric acid or acetic acid can be used.

In the step (j), in order to obtain the compound represented by the above formula [11] by oxidizing the hydroxyl group of the compound represented by the above formula [10], any ordinary oxidation reaction can be used. It can be used and is not particularly limited. Examples of the oxidizing reagent used in such an oxidation reaction include chromium trioxide, potassium permanganate,
Examples thereof include dimethyl sulfoxide / oxalyl chloride.

In the step (k), as a reagent for treating the compound represented by the above formula [11] with a base to form a four-membered ring in the molecule, sodium hydride, lithium diisopropylamide, potassium hesamethyl Any strongly basic substance such as disilazane may be used, and the amount of the base used is preferably 1 to 10 equivalents. The solvent used in the reaction may be a general organic solvent, for example, dimethyl sulfoxide, hexamethylphosphoric triamide,
Tetramethylethylenediamine and the like are preferably used. The reaction temperature is -100 to 100 ° C, and the reaction time is 0.5.
It is about 30 hours.

In step (l), as an oxidizing agent for carrying out the Bayer-Villiger reaction on the compound represented by the above formula [12], organic peroxides such as trifluoroperacetic acid and hydrogen peroxide solution are suitable. Used for. The amount of the oxidizing agent used is 1 to 10 equivalents. The solvent used in the reaction may be a general organic solvent, and for example, methylene chloride, acetic acid and the like are preferably used. The reaction temperature is −40 to 50 ° C., and the reaction time is 0.5 to 48 hours. After the reaction, if the product is a mixture of alcohol and formate,
If necessary, the alcohol solvent alone can be obtained by changing the reaction solvent to an organic solvent such as methanol, dioxane, or tetrahydrofuran, or treating with an acidic compound such as hydrochloric acid or acetic acid instead of water.

In step (m), a protecting group R ³ is introduced into the hydroxyl group of the compound represented by the above formula [13]. Protecting group
As R ³ , any group may be used as long as it is usually used for protecting a hydroxyl group, and for example, groups such as tetrahydropyranyl, methoxymethyl, benzyl and tert-butyldimethylsilyl can be preferably used. Also,
The solvent used when introducing R ³ can also be a commonly used organic solvent and is not particularly limited. For example, when a tert-butyldimethylsilyl group is used, 1 to 5 equivalents of tert-butyldimethylsilyl chloride, corresponding triflate, acid anhydride, etc. should be used and reacted in a commonly used organic solvent such as dimethylformamide or pyridine. You can Reaction temperature is -30 to 80
C, reaction time is 0.1 to 40 hours.

In step (n), a compound represented by the above formula [14] can be obtained from the compound represented by the above formula [14] by reacting with an organometallic reagent such as methyllithium or methylmagnesium bromide. It can be used, and the amount used is 2 to 10 equivalents. The solvent used at this time may be a commonly used organic solvent such as tetrahydrofuran, diethyl ether, benzene, etc., and is not particularly limited. The reaction temperature is -78 to 80 ° C, and the reaction time is 0.1 to 10 hours.

In the step (o), in order to remove the secondary hydroxyl group of the compound represented by the above formula [15] to form a methylene group, the compound [15] is generally used such as sodium hydride and butyl lithium. After treatment with a base, carbon disulfide and methyl iodide or thiocarbodiimidazole are allowed to act on this to give a thiocarbamate, which is reduced with an organotin hydride to give compound [16]. it can. Alternatively, in addition to the above-mentioned method, the compound [15] can be converted into a phosphoric acid ester or the like and reduced by using lithium or the like in liquid ammonia.

In step (p), in order to remove the protecting group R ³ of the compound represented by the above formula [16], a method usually used for deprotecting each protecting group can be used. It is not particularly limited. For example, R ³
When a tert-butyldimethylsilyl group is used as the compound, a fluorine reagent such as tetrabutylammonium fluoride or hydrogen fluoride-pyridine complex, or an acidic compound such as hydrochloric acid or acetic acid can be used.

The product thus obtained has the above formula [17]
Is an intermediate compound for synthesis of (+)-Grandisol known from literature by comparing instrumental data such as optical rotation, ¹ H- and ¹³ C-NMR spectra. Can be confirmed.

The intermediate compound represented by the above formula [17] can be prepared, for example, from the above-mentioned literature (JB Jones, MA Finch, I.
J. Jakovac, Can. J. Chem., 60, 2007 (1982)), heat treatment in acetic anhydride to form an acetic acid ester, followed by reduction with lithium aluminum hydride (+) A 2: 1 mixture of grandisol and its isopropylidene-type isomer is obtained. Then, this mixture can be further purified by a gas chromatograph to easily recover (+)-grandisol represented by the above formula [18].

[0026]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples. In this example, thiophenol is used as an organic thiol, tert-butyldimethylsilyl group is used as a hydroxyl protecting group, and tosyl group is used as a leaving group. The following shows the case where each is used.

Step (a) 22.0 g (0.2 mol) of thiophenol and 20.2 g (0.2 mo
l) was added, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentration under reduced pressure was subjected to column chromatography using 150 g of silica gel, and 44.6 g of the compound represented by the formula [2] (yield 95% was obtained from the 20% ethyl acetate / hexane (v / v) outflow portion). %)
Was obtained as a colorless oil.

The properties of the compound represented by the above formula [2] are shown below. [Α] _D ²⁶ : −177.1 ° (c 0.76 CHCl ₃ ) IR (neat): 3060, 2976, 2908, 1734, 1584, 1483,
1439, 1412, 1307,1272, 1214, 1112, 1091, 1025, 99
6, 959, 911, 876, 752,692.

Step (b) N-chlorosuccinimide was added to a solution of 44.6 g (0.189 mol) of the compound of the formula [2] in carbon tetrachloride (500 ml) under ice cooling.
27.76 g (0.20 mol) was added, and the mixture was stirred at the same temperature for 2.5 hours. The reaction solution was filtered, and the filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography using 500 g of silica gel, and 20 to 30% ethyl acetate / hexane (v / v) was extracted from the compound represented by the formula [3]. 42.0 g (95% yield) was obtained as a yellow oil.

The properties of the compound represented by the above formula [3] are shown below. [Α] _D ²³ : −395.3 ° (c 0.63 CHCl ₃ ) IR (neat): 3060, 2974, 2900, 1684, 1566, 1479,
1441, 1294, 1108,992, 969, 932, 901, 864, 750, 69
0.

Step (c) Methyllithium was added to a suspension of copper iodide (146 mg, 0.77 mmol) in tetrahydrofuran (2 ml) at 0 ° C. under an argon atmosphere.
1.02 ml (1.54 mmol) of 1.5 M ether solution was slowly added dropwise. After stirring for 15 minutes at the same temperature, the mixture was cooled to -78 ° C. 180 mg (0.7) of the compound represented by the formula [3] was added to this solution.
7 mmol of tetrahydrofuran solution (1 ml) was added, and 10
Stir for minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, the precipitate was filtered off, the organic layer was separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain 67 mg of a compound represented by the formula [4] (yield: 20-40% ethyl acetate / hexane (v / v)). 62%) as a pale yellow oil.

The properties of the compound represented by the above formula [4] are shown below. [Α] _D ²⁶ : −467 ° (c 1.95 CHCl ₃ ) IR (neat): 2978, 2902, 1690, 1630, 1437, 1381,
1315, 1296, 1257, 1108, 990, 963, 899, 870, 833, 77
4, 735.

Step (d) Under an argon atmosphere, a suspension of copper iodide (381 mg, 2.0 mmol) in tetrahydrofuran (3 ml) was added to a solution of vinylmagnesium bromide (4.3 ml, 4.0 mmol) in 0.93M tetrahydrofuran at -30 to -20 ° C. Was slowly added dropwise. After stirring for 15 minutes at the same temperature, the mixture was cooled to -78 ° C. To this solution was added a tetrahydrofuran solution (1 ml) containing 140 mg (1.0 mmol) of the compound represented by the formula [4], and the mixture was stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, the precipitate was filtered off, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography to obtain 103 mg of the compound represented by the formula [5] from the 15% ethyl acetate / hexane (v / v) outflow portion (yield 61% ) Was obtained as a colorless oil.

The properties of the compound represented by the above formula [5] are shown below. [Α] _D ²⁴ : −314.9 ° (c 0.43 CHCl ₃ ) IR (neat): 3088, 3974, 2936, 2912, 1742, 1642,
1120, 1015, 977,911, 874, 851.

Step (e) 84 mg of a compound represented by the formula [5] under an argon atmosphere
In a tetrahydrofuran solution (1 ml) of (0.5 mmol), -7
A solution of 1 ml (1.0 mmol) of L-selectride in 1M tetrahydrofuran was added dropwise at 8 ° C. The reaction solution was stirred for 1.5 hours, water was added thereto, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography, and 20% ethyl acetate / hexane (v / v)
84 mg of the compound represented by the formula [6] (yield 99
%). Recrystallization from ether / hexane gave colorless needle crystals.

The properties of the compound represented by the above formula [6] are shown below. Melting point: 161 to 161.5 ° C [α] _D ²⁶ : −38.8 ° (c 0.425 CHCl ₃ ) IR (KBr): 3414 (br), 2966, 1638, 1390, 1325, 11
56, 1120, 1029, 928, 913, 864.

Step (f) 87 mg of a compound represented by the formula [6] under an argon atmosphere
To a dimethylformamide solution (2 ml) containing (0.51 mmol), imidazole (139 mg, 2.05 mmol) and tert-butyldimethylsilyl chloride (154 mg, 1.02 mmol) were added at room temperature, and the mixture was stirred overnight. Water was added to the reaction solution, which was extracted with ether, washed with saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain 10% ethyl acetate / hexane (v
/ v) 140 mg of the compound represented by the formula [7] from the outflow part
(Yield 96%) was obtained as a colorless oil.

The properties of the compound represented by the above formula [7] are shown below. [Α] _D ²⁶ : −54.5 ° (c 0.945 CHCl ₃ ) IR (neat): 2960, 2896, 2862, 1638, 1257, 1122,
1085, 1064.

Step (g) 298 mg of the compound represented by the formula [7] under an argon atmosphere.
To a tetrahydrofuran solution (5 ml) of (1.05 mmol) was added 2.1 ml (1.05 mmol) of 0.5M tetrahydrofuran solution of 9-borabicyclo [3,3,1] nonane at room temperature, and the mixture was stirred for 1 hour, and then 3.1 ml of 9 ml was added. -Borabicyclo [3,3
[3,1] Nonane solution was added and stirred for 1 hour. Water, 3M aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide solution (2 ml each) were sequentially added to the reaction solution, and the mixture was stirred at 40 to 45 ° C for 1 hr. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain 316 mg of the compound represented by the formula [8] from the 20% ethyl acetate / hexane (v / v) outflow portion (yield 100% ) Was obtained as a colorless oil.

The properties of the compound represented by the above formula [8] are shown below. [Α] _D ²⁵ : −30.0 ° (c 0.585 CHCl ₃ ) IR (neat): 3405 (br), 2958, 2932, 2896, 2862, 14
73, 1462, 1386,1363, 1257, 1170, 1127, 1089, 1064,
1035, 944, 926,878, 857, 777.

Step (h) A compound 5.315 represented by the formula [8] under an argon atmosphere.
To a pyridine solution (60 ml) of g (17.6 mmol), 3.69 g (19 mmol) of tosyl chloride and dimethylaminopyridine (catalytic amount) were added at room temperature, and the mixture was stirred overnight. Water was added to the reaction solution, which was extracted with ether, washed with saturated saline and then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give 20%.
Ethyl acetate / hexane (v / v) Formula from the outflow part

In addition to obtaining 7.427 g (yield 93%) of the compound represented by [9], 248 mg of unreacted raw material was recovered.

The above formula

The properties of the compound represented by [9] are shown below. [Α] _D ²⁰ : −23.0 ° (c 0.225 CHCl ₃ ) IR (neat): 2932, 2860, 1601, 1464, 1363, 1257,
1178, 1125, 1058,944, 878, 814, 777, 662, 555.

Step (i) In a plastic reaction vessel, the formula

To an ether solution (4 ml) of 187 mg (0.41 mmol) of the compound represented by [9], 1 ml of hydrogen fluoride-pyridine complex was added under ice cooling, and the mixture was allowed to stand at room temperature for 2 hours.
After stirring for an additional time, hydrogen fluoride-pyridine complex 0.2
ml was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with ether, saturated aqueous sodium hydrogencarbonate solution was carefully added, extracted with ethyl acetate, washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography, and 138 mg of the compound represented by the formula [10] (yield 96% was obtained from the 50% ethyl acetate / hexane (v / v) outflow portion. ) Was obtained as colorless needle crystals.

The properties of the compound represented by the above formula [10] are shown below. Melting point: 104.5 to 105.5 ° C. [α] _D ²² : −27.3 ° (c 0.40 CHCl ₃ ) IR (KBr): 3482 (br), 2950, 1332, 1189, 1176, 11
23, 1040, 1021, 926.

Step (j) A compound of the formula [10] 782 under an argon atmosphere.
To a solution of methylene chloride (25 ml) in mg (2.3 mmol), 2.3 g of powdered molecular sieves 4A activated at room temperature and 1.29 g (3.4 mmol) of pyridinium dichromate were added and stirred for 2.5 hours. The reaction solution was diluted with ether, filtered through Celite, and thoroughly washed with ether. The combined washings were evaporated under reduced pressure to remove the solvent, and the resulting residue was subjected to silica gel column chromatography. Ether: methylene chloride: hexane = 1: 1: 3 (v / v)
718 mg (yield 92%) of the compound represented by 1] was obtained. The product recrystallized with an ethyl acetate-hexane system was a colorless plate crystal.

The properties of the compound represented by the above formula [11] are shown below. Melting point: 70.5 to 71 ° C. [α] _D ²³ : −132.6 ° (c 0.675 CHCl ₃ ) IR (KBr): 2972, 2918, 1736, 1599, 1359, 1174,
1108, 909, 888, 772,665, 555.

Step (k) 5 mg of dimethyl sulfoxide was added to 85 mg of sodium hydride (50% in mineral oil, 1.76 mmol) washed with hexane under an argon atmosphere, and the mixture was stirred at 50 to 60 ° C. for 1 hour. After returning the reaction solution to room temperature, the compound of the formula [11] 500 mg
A solution of (1.47 mmol) in dimethyl sulfoxide (1 ml) was added, and the mixture was stirred for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline, and then dried over sodium sulfate. Further, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain 198 mg of a compound represented by the formula [12] (yield 80 %).

The properties of the compound represented by the above formula [12] are shown below. [Α] _D ²⁴ : −193 ° (c 0.35 CHCl ₃ ) IR (neat): 2962, 1734, 1458, 1383, 1290, 1234,
1114, 1038, 1013,967, 899, 835.

Step (l) At room temperature under an argon atmosphere, a solution of the compound of the formula [12] 42 mg (0.25 mmol) in acetic acid (1 ml) was added with 40% at room temperature.
0.2 ml of peracetic acid was added and stirred for 4 hours. A few drops of dimethyl sulfide were added to decompose excess peracetic acid, and the mixture was further stirred for 30 minutes. The solvent was distilled off under reduced pressure, 2 ml of methanol and 1 drop of hydrochloric acid were added to the residue, and the mixture was stirred overnight at room temperature. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography, 60% ethyl acetate / hexane
(v / v) 50 mg of a mixture of the compound represented by the formula [13] and dimethyl sulfone was obtained from the outflow portion. This can be used for the next reaction without further isolation and purification.

Step (m) Under an argon atmosphere, the mixture 50 obtained in the above step (l) is used.
mg (crude product) in dimethylformamide (1 ml)
To the above, at room temperature, imidazole 44 mg (0.64 mmol) and tert-butyldimethylsilyl chloride 72 mg (0.48 mmol) were added,
Stir for 1.5 hours. Water was added to the reaction solution, which was extracted with ether, washed with saturated saline and then dried over sodium sulfate. Further, the solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain 75 mg of the compound represented by the formula [14] from the 30% ethyl acetate / hexane (v / v) outflow portion (step (l ) And the step (m), a total yield of 87% was obtained. Further, this was recrystallized from hexane to obtain colorless needle crystals.

The properties of the compound represented by the above formula [14] are shown below. Melting point: 82-82.5 ° C [α] _D ²⁵ : -13.5 ° (c 1.43 CHCl ₃ ) IR (KBr): 3429 (br), 2956, 2932, 2862, 1754, 14
64, 1381, 1348, 1305, 1263, 1170, 1114, 1071, 1036,
1031, 961, 930, 839,777.

Here, the compound 2 represented by the formula [14]
A solution of 36mg (0.87mmol) in tetrahydrofuran (3ml)
At room temperature, 1.05 ml of tetrabutylammonium fluoride in 1M tetrahydrofuran solution was added and stirred for 30 minutes. Water was added to the reaction solution obtained by removing the protecting group introduced in the above step (m), extracted with ethyl acetate, washed with saturated saline and then dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography, 60% ethyl acetate / hexane
(v / v) 107 mg of the compound of the formula [13] (yield 78
%). When this was recrystallized from ether-hexane, colorless needle crystals were obtained.

The properties of the compound represented by the above formula [13] are shown below. Melting point: 48.5 to 49 ° C [α] _D ²⁵ : + 26.0 ° (c 0.43 CHCl ₃ ) IR (KBr): 3400 (br), 2952, 2878, 1758, 1441, 13
46, 1305, 1170, 1145, 1073, 1031.

Step (n) 9 mg of a compound represented by the formula [14] under an argon atmosphere
Methyllithium 0.15 ml (1.1 M ether solution) was added to a tetrahydrofuran solution (1 ml) of (33 mmol) under ice cooling, and the mixture was stirred for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography to obtain 10 mg of the compound represented by the formula [15] (yield 100% from the 30% ethyl acetate / hexane (v / v) outflow portion). ) Got. Further, this was recrystallized from ether-hexane to give colorless needle crystals.

The properties of the compound represented by the above formula [15] are shown below. Melting point: 66.5 to 67 ° C [α] _D ²⁵ : + 14.9 ° (c 1.10 CHCl ₃ ) IR (KBr): 3374 (br), 2970, 2864, 1475, 1381, 12
47, 1195, 1108, 1094, 1038, 1006, 942, 893, 837, 77
7, 665.

Step (o) In a tetrahydrofuran suspension (1 ml) of 17 mg of sodium hydride (50% in mineral oil, 0.35 mmol) washed with hexane under an argon atmosphere, the compound of the formula [15] was added at room temperature.
A tetrahydrofuran solution (1 ml) of 35 mg (0.115 mmol) and imidazole (one piece) was added and stirred for 20 minutes, 22 ml (0.35 mmol) of carbon disulfide was added all at once, and the mixture was further stirred for 30 minutes. After adding 22 ml (0.35 mmol) of methyl iodide to the reaction solution and stirring for 15 minutes, a few drops of acetic acid was added to terminate the reaction, and the solvent was distilled off under reduced pressure. The residue is benzene (0.5 ml)
Dilute with tributyltin hydride (47 ml, 0.17 mmol) and triethylborane (0.17 ml, 0.17 mmol) in 1M hexane and stir for 30 minutes. Stir for hours. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain 5% ethyl acetate / hexane (v
/ v) 11 mg of the compound represented by the formula [16] from the outflow portion
(Yield 33%) was obtained.

The properties of the compound represented by the above formula [16] are shown below. [Α] _D ²⁰ : + 12.6 ° (c 0.45 CHCl ₃ ) IR (neat): 3446 (br), 2958, 2862, 1464, 1377, 12
57, 1093, 1031, 1006, 940, 835, 775, 663.

Step (p) To a solution of 9 mg (32 mmol) of the compound of the formula [16] in tetrahydrofuran (0.5 ml) was added at room temperature 48 ml (48 mmol) of tetrabutylammonium fluoride in 1M tetrahydrofuran, and the mixture was stirred for 30 minutes. did. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain 4 mg of the compound represented by the formula [17] from the 60% ethyl acetate / hexane (v / v) outflow portion (yield 73% ) Got. Further, this was recrystallized from heptane to obtain colorless needle crystals of the intermediate compound of the present invention.

The properties of the intermediate compound represented by the above formula [17] are shown below. Melting point: 61 to 62 ° C. [α] _D ²⁴ : + 17.2 ° (c 0.38 CHCl ₃ ) IR (KBr): 3374 (br), 2970, 2868, 1464, 1379, 13
65, 1303, 1232,1172, 1133, 1064, 940, 832. 1 H-NMR (CDCl 3): 1.04 (3H, s), 1.06 (3H, s), 1.1
7 (3H, s), 1.4 ~ 2.1 (9H, m), 3.60 (1H, ddd, J = 5.3, 8.
7, 10.3 Hz), 3.67 (1H, ddd, J = 6.7, 8.3, 10.3 Hz). ¹³ C-NMR (CDCl ₃ ): 17.90, 28.26, 28.92, 29.12,
30.53, 37.68, 41.73, 56.04,60.06,72.16.

[0060]

INDUSTRIAL APPLICABILITY As described above, if an easily obtainable intermediate, which can be easily synthesized according to the present invention, is used as a raw material, (+)-grandisol, which is difficult to obtain from the natural world, can be obtained. It became possible to synthesize easily and opened the way to supply the weevil pheromone in an amount sufficient for use as a pesticide.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI technical display location C07D 493/08 B 9164-4C (72) Inventor Hiroshi Kawakami 6-2 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Life Science Research Institute (72) Inventor Katsuya Matsumoto 2 6 Umegaoka, Midori-ku, Yokohama, Kanagawa Prefecture Japan Tobacco Inc. Life Science Institute (72) Inventor Hajime Matsushita 6 Umegaoka, Midori-ku, Yokohama, Kanagawa Prefecture Address 2 Japan Tobacco Inc. Life Science Institute

Claims (1)

[Claims] 1. A step of adding an organic thiol to the 4-position of levoglucosenone represented by the formula [1] to obtain a compound represented by the formula [2] (in the formula, R ¹ represents an alkyl or aryl group) ( a) and [Chemical 2] The compound represented by the above formula [2] forms a double bond extending to the 3rd and 4th positions to form the formula [3] (in the formula, R ¹ is alkyl,
Or (representing an aryl group) to obtain a compound (b), A step (c) in which an organic thio group of the compound represented by the above formula [3] is substituted with a methyl group to obtain a compound represented by the formula [4]; A step (d) of stereoselectively conjugate-adding a vinyl group to the 4-position of the compound represented by the above formula [4] to obtain a compound represented by the formula [5]; A step (e) of reducing the carbonyl group of the compound represented by the above formula [5] to obtain a compound represented by the formula [6]; A step (f) of protecting the compound at the 2-position of the compound represented by the above formula [6] to obtain a compound represented by the formula [7] (in the formula, R ² represents a protective group for the hydroxyl group); 7] Step (g) of hydroborating the double bond of the compound of the above formula [7] to obtain the compound of the formula [8]
And, Converting the hydroxyl group of the compound represented by the above formula [8] into a leaving group to obtain a compound represented by the formula [9] (in the formula, X represents a leaving group); ] Deprotecting the hydroxyl group of the compound represented by the above formula [9] to obtain a compound represented by the formula [10] (wherein X represents a leaving group); A step (j) of oxidizing the hydroxyl group of the compound represented by the above formula [10] to obtain a compound represented by the formula [11] (in the formula, X represents a leaving group); A step (k) of treating the compound represented by the above formula [11] with a base to obtain a compound represented by the formula [12]; A step (l) in which a compound represented by the above formula [12] is subjected to a Bayer-Villiger reaction to obtain a compound represented by the formula [13]; A step (m) of protecting the hydroxyl group of the compound represented by the above formula [13] to obtain a compound represented by the formula [14] (in the formula, R ³ represents a protective group for the hydroxyl group); A step (n) in which the compound represented by the above formula [14] is methylated to obtain a compound represented by the formula [15] (in the formula, R ³ represents a hydroxyl-protecting group); A step (o) of removing the hydroxyl group of the compound represented by the above formula [15] to obtain a compound represented by the formula [16] (in the formula, R ³ represents a protective group for the hydroxyl group); Deprotecting the hydroxyl group of the compound represented by the above formula [16] to obtain an intermediate compound for synthesizing grandisol represented by the formula [17] (p); The manufacturing method of the (+)-grandisol synthetic intermediate characterized by including.