JPS6212796B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel sesquiterpene derivative and a method for producing the same. The compounds of the present invention have the general formula (However, in the formula, R represents a lower alkylsilanoxy group.) It is a sesquiterpene derivative represented by the following compound. The compound of the present invention is a novel compound that has not been described in any literature and has the physical properties described in the Examples below. The compound of the present invention is an important intermediate in the total synthesis of the known substance warburganal, and the final synthetic substance, warburganal, is a natural product derived from the East African plant Warburgia. It was isolated as an extract component, its structural formula has been determined, and its physiological activity is known as a useful substance that acts as a powerful antifeedant against army warm [Chem.Comm ., p.1013
(1976)]. The compound of the present invention is useful as an important intermediate in the next step in the total synthesis of barbarganal. In the above step, the starting material 7-oxoisodrimenin is a compound of isodrimenine, which has already been isolated as a natural product [J.Chem.Soc., p.4685 (1960)].
[See HH Appel,
etal; JCS, 4685 (1960)], and the raw material isodorimenine has already been completely synthesized by the present inventor as a sesquiterpene derivative derived from l-abietic acid, and is easily available [Special See Application No. 52-38628 (Japanese Unexamined Patent Publication No. 53-124256)]. Furthermore, the present inventors have also succeeded in synthesizing isodorimenine from easily available β-lonone in an extremely short process (Japanese Patent Application No. 110359/1982). To explain the above process, the starting material 7-oxoisodorimenine is first induced into a ketal form, and then a ketone form, diacetate form, epoxy form, triol form, silyl form, carbonate form, alcohol form, aldehyde form, and ketal form. , the aforementioned barburganal can be synthesized by converting it into a diol form and an aldehyde form, respectively. To explain this step by step, first, the starting material 7-oxoisodorimenine (2) is treated with a dialcohol and an organic acid and refluxed to form a ketal.
(3) is obtained in high yield. The obtained ketal body (3) can be reacted with a reducing reagent in an organic solvent to lead to the ketone body (4) in high yield. By reacting the obtained ketone body (4) with an acetylating agent in a solvent, diacetate body 5 can be obtained in high yield. Epoxy compound (6) can be obtained in high yield by treating the obtained diacetate compound (5) with a peroxide in the presence of an aqueous alkali solution. The obtained epoxy body (6) is reacted with hydrazine hydrate to introduce a double bond and form a triol body.
(7) is obtained. The obtained triol compound (7) can be reacted with imidazole and trialkylsilyl chloride to obtain a silyl compound (8), which is a compound of the present invention in which the hydroxyl group of the aryl group is protected. The obtained silyl compound (8) is refluxed with phosgene or carbonylimidazole to obtain a carbonate compound (9) in which glycol is protected with carbonate in a high yield. The obtained carbonate (9) is treated with an organic acid to convert the silyl back into alcohol, and the alcohol (10) is quantitatively obtained. When the obtained alcohol compound (10) is reacted with an oxidizing agent, the aldehyde compound (11) is obtained in high yield. The obtained aldehyde (11) is further treated with a dialcohol and an organic acid to protect it with an acetal, thereby obtaining an alkali-stable ketal (12). By treating the obtained ketal (12) with an alkali, the diol (13) can be obtained in high yield. The obtained diol (13) is reacted with an oxidizing agent under basic or neutral conditions to obtain an aldehyde (14). When the aldehyde compound (14) thus obtained is reacted with an organic acid, the above-mentioned barburganal (15) is obtained. Barbaganal (15) synthesized in this way completely matches the physical properties of the natural product Barbaganal. The compound of the present invention can be produced by the following method. That is, the ketal compound (3) can be obtained in high yield by treating the 7-oxoisodorimenine (2) with a dialcohol and an organic acid and refluxing it. In this case, organic acids such as p-toluenesulfonic acid and camphorsulfonic acid are used, aromatic hydrocarbons such as benzene and toluene are used as solvents, and ethylene glycol, 1.3 -Propanediol etc. can be used, and it is particularly preferable to use p-toluenesulfonic acid or ethylene glycol in a benzene solution. The reaction temperature and reaction time at this time are not particularly limited, but are preferably 80 to 150°C and 4 to 12 hours, respectively. The obtained ketal body (3) can be reacted with a reducing reagent in an organic solvent to lead to the ketone body (4) in high yield. In the above reaction, lithium aluminum hydride is suitably used as the reducing reagent, and ethers such as ether, dioxane, and tetrahydrofuran are used as the solvent. In particular, when lithium aluminum hydride is used in anhydrous ether, suitable. The reaction temperature and reaction time are not particularly limited, and room temperature and 2 to 12 hours are suitable, respectively. By reacting the obtained ketone body (4) with an acetylating agent in a solvent, diacetate body (5) can be obtained in high yield. As the acetylating agent in this case, acetic anhydride-pyridine, acetyl chloride-pyridine, etc. can be used, but especially excellent results are obtained in the case of acetic anhydride-pyridine. In the above reaction, the reaction temperature and reaction time are not particularly limited, and particularly suitable results are obtained at room temperature for 4 to 12 hours. Epoxy compound (6) can be obtained in high yield by treating the obtained diacetate compound (5) with a peroxide in the presence of an aqueous alkali solution. The alkali used in this case is an aqueous solution of sodium hydroxide, potassium hydroxide, etc., the peroxide used is hydrogen peroxide, t-butyl hydroperoxide, etc., and the solvent is alcohol,
Although ether and the like can be used, it is particularly preferred to use hydrogen peroxide in methanol solvent in the presence of sodium hydroxide. The reaction temperature and reaction time are not particularly limited, but
A temperature around 0° C. and a time of 1 to 4 hours is suitable. The obtained epoxy body (6) is reacted with hydrazine hydrate to introduce a double bond and form a triol body.
We get (7). As the hydrazine, 100% hydrazine hydrate is suitable, and a solvent is not particularly required, and the reaction proceeds advantageously even in the absence of a solvent. The reaction temperature and reaction time are not particularly limited, but
Around 120°C (room temperature is also possible) and 10 to 30 minutes are suitable.The compound of the present invention, silyl compound, in which the obtained triol compound (7) is reacted with imidazole and trialkylsilyl chloride to protect the hydroxyl group of the aryl group. (8) can be obtained. In this reaction, dimethyl t-butylsilyl chloride gives suitable results as the trialkylsilyl chloride. The solvent is DMF (dimethylformamide),
Organic solvents such as DMSO (dimethyl sulfoxide) and acetate can be used as appropriate, especially
DMF is preferred. The reaction temperature and reaction time are not particularly limited, but
In particular, -10° to 0°C and 10 to 60 minutes are preferred. Further, the obtained silyl compound (8) is refluxed with phosgene or carbonylimidazole to obtain a carbonate compound (9) in which the carbonate is protected with glycol in a high yield. In this reaction, phosgene can be used, but since it is a dangerous gaseous substance, N.
N'-carbonylimidazole is preferably used. As the solvent, organic solvents such as benzene and chloroform are used. In addition, the reaction temperature and reaction time are not particularly limited, but especially around 90°C and 30°C.
~60 minutes is preferred. The obtained carbonate (9) is treated with an organic acid to convert the silyl back into alcohol, and the alcohol (10) is quantitatively obtained. As the organic acid used in this reaction, camphor
Organic acids such as sulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and acetic acid are used, and alcohols, ethers, etc. can be used as the solvent, and it is particularly preferable to use camphor sulfonic acid in methanol. It is. The reaction temperature and reaction time at this time are not particularly limited, but particularly good results are obtained at room temperature for 3 to 5 hours. When the obtained alcohol compound (10) is reacted with an oxidizing agent, the aldehyde compound (11) is obtained in high yield. Jones' reagent (chromic anhydride in dilute sulfuric acid) is preferably used as the oxidizing agent in this oxidation reaction, and acetone is particularly effectively used as the solvent, and the reaction temperature and reaction time are not particularly limited. , the reaction proceeds at -10° to 0°C and in a short time of about 5 to 30 minutes. The obtained aldehyde (11) is further treated with a dialcohol and an organic acid to protect it with an acetal, thereby obtaining an alkali-stable ketal (12). In this case, organic acids such as p-toluenesulfonic acid and camphorsulfonic acid are used, aromatic hydrocarbons such as benzene and toluene are used as solvents, and as dialcohols, ethylene glycol, 1,3-propanediol etc. can be used, especially in benzene solution, p-
Preferably, toluenesulfonic acid and 1,3-propanediol are used. Although the reaction temperature and reaction time at this time are not particularly limited, the reaction is well performed in a short time of about 80 to 150°C and about 10 to 30 minutes, respectively. By treating the obtained ketal (12) with an alkali, the diol (13) can be obtained in high yield. As the alkali in this case, an aqueous solution such as sodium hydroxide or potassium hydroxide can be used, and as the solvent, ethers such as ether, dioxane, and tetrahydrofuran can be used, but in particular, it is preferable to use sodium hydroxide in the dioxane solution. suitable. The reaction temperature and reaction time are not particularly limited, but
1 to 3 hours at room temperature is suitable. EXAMPLES Below, the method for producing the compound of the present invention will be specifically explained with reference to Examples. Reference example 1 (±)-Isodorimenine (1) 318 mg in acetic acid solution 30 ml
Add 400 mg of chromic acid to the mixture and stir at 50°C for 4 hours. After the reaction, water is added and extracted with ether, and the ether layer is washed with water, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over sodium sulfate. The solvent is then evaporated to give 301 mg of an oil. This was subjected to silica gel column chromatography (Lobar column; hexane:acetic ether =
3:1) and 7-oxoisodorimenine (2)
Get 239mg. This is further recrystallized from n-hexane-ether to obtain colorless prism crystals. (Material properties) Melting point: 107-109℃ Elemental analysis value: (calculated value) C, 72.55 H, 8.12 (actual value) C, 72.41 H, 8.12 Infrared absorption spectrum (CCl ₄ ) (IR): ν _nax
1770, 1680cm ^-1 Nuclear Magnetic Resonance Spectrum ( _CDCl3 ) (NMR): 0.93
(Me) 0.97(Me) 1.28(Me) 4.81(S;-〓-O- _C H2 ) Example 1 7-oxoisodorimenine obtained in Reference Example 1
(2) Add 2 ml of ethylene glycol and 30 mg of p-toluenesulfonic acid to 20 ml of a 254 mg benzene solution and reflux overnight in a Dean-Stark apparatus. After the reaction, the benzene layer is washed with 10% sodium carbonate water and saturated saline, and then dried over magnesium sulfate. After distilling off the solvent, it was subjected to silica gel column chromatography (Lobar column; hexane:acetic acid ether = 3:1) to obtain 281 mg of the ketal form (3).
get. When this is further recrystallized from n-hexane-ether, colorless prism crystals are obtained. (Physical properties) Melting point: 88.5-89.5℃ Elemental analysis values: (calculated value) C, 69.84 H, 8.27 (actual value) C, 69.82 H, 8.27 IR (CCl ₄ ): ν _nax 1760cm ^-1 NMR (CDCl ₃ ): 0.88( _Me ) 0.92(Me) 1.16(Me) ca 3.8 _~ 4.2(m, -OC H2CH2O- ) 4.68(S;

[Formula]) Example 2 To 100 ml of an anhydrous ether solution containing 3.3 g of the ketal compound (3) obtained in Example 1, 2 g of lithium aluminum hydride was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. After the reaction, water and 10% HCl are added and extracted with ether. The ether layer is washed with saturated brine and dried over magnesium sulfate. When the solvent is distilled off, the ketone body (4) 2.960
g is obtained. (Physical properties) Mass spectrometry (high resolution mass spectrum):
m/e: 234 (M ⁺ −H ₂ O) IR (CCl ₄ ): ν _nax 3400, 1665 cm ^-1 NMR (CDCl ₃ ): 0.88 (Me) 0.92 (Me) 1.15 (Me) Example 3 10 ml of acetic anhydride is added to 10 ml of a pyridine solution containing 2.960 g of the ketone body (4) obtained in Example 2, and the mixture is left at room temperature for 4 hours. After the reaction, water was added under cooling and ether extraction was performed, and the ether layer was diluted with 10% HCl and 10%
After washing with Na ₂ CO ₃ and saturated saline, drying with magnesium sulfate. After distilling off the solvent, the residue was subjected to silica gel chromatography (hexane:ether=1:1) to obtain 2.550 g of diacetate (5). When this is further recrystallized from n-hexane-ether, colorless needle crystals are obtained. (Physical properties) Melting point: 87-88℃ Elemental analysis value: (calculated value) C, 67.83 H, 8.39 (actual value) C, 67.89 H, 8.36 IR (CCl ₄ ): ν _nax 1745, 1680 cm ^-1 NMR ( CDCl ₃ ): 0.91 (Me) 0.94 (Me) 1.18 (Me) 2.00 (OAc) 2.05 (OAc) Example 4 1.060 g of diacetate compound (5) obtained in Example 3
5 ml of 30% hydrogen peroxide and then 2.5 ml of 10% sodium hydroxide were added to 30 ml of methanol solution of 30% and stirred at 0°C for 1 hour. After the reaction, the solvent is distilled off and extracted with ether. The ether layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain 835 mg of crystals of epoxy compound (6). When this is further recrystallized from ether-hexane, colorless needle crystals are obtained. (Physical properties) Melting point: 117-118℃ Elemental analysis value: Calculated value C: 67.13 H: 9.02 Actual value C: 67.11 H: 9.08 IR (CHCl ₃ ): ν _nax 3590, 3460, 1695 cm ^-1 NMR (CDCl ₃ ): δ 0.84 (Me) 0.86 (Me) 1.13 (Me) Example 5 100% to 835 mg of epoxy body (6) obtained in Example 4
Add 12 ml of NH ₂ NH ₂ .H ₂ O and heat at 120°C for 15 minutes. After the reaction, the mixture is extracted with ether, and the ether layer is washed with saturated brine and dried over magnesium sulfate. After evaporation of the solvent, 720 mg of the triol compound (7) is obtained. After subjecting a portion to preparative thin layer chromatography (silica gel: ethyl acetate), recrystallization from ether yields colorless prism crystals. (Physical properties) Melting point: 137-138℃ Mass: m/e: 223 (M ⁺ -CH ₂ OH) IR (CHCl ₃ ): ν _nax 3470 cm ^-1 NMR (CDCl ₃ ): 0.80 (Me) 0.90 (Me ) 0.92 (Me) 5.86 (broad, 7-H) Example 6 Add 85 mg of imidazole to 2 ml of dimethylformamide solution containing 106 mg of the triol compound (7) obtained in Example 5.
Then, 1 ml of a solution of 63 mg of dimethyl t-butylsilyl chloride in dimethylformamide was added, and the mixture was stirred for 20 minutes under ice cooling. After the reaction, the mixture is extracted with ether, and the ether layer is washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent, it was subjected to preparative thin layer chromatography (silica gel; hexane:ether = 1:1) to obtain 84 mg of silyl compound (8).
get. (Physical properties) Mass: m/e: 337 (M ⁺ -CH ₂ OH) IR (CHCl ₃ ): ν _nax 3420 cm ^-1 NMR (CDCl ₃ ): 5.81 (broad; 7-H) Reference example 2 342 mg of N.N'-carbonyldiimidazole was added to 15 ml of a benzene solution containing 194 mg of the silyl compound (8) obtained in Example 6, and the mixture was refluxed for 30 minutes. Next, after adding ether and washing with saturated saline, drying over magnesium sulfate and distilling off the solvent, the carbonate form was obtained.
(9) 224 mg is obtained. When recrystallized from n-hexane, fine colorless needle crystals are obtained. (Physical properties) Melting point: 59-60℃ Elemental analysis value: (calculated value) C, 66.96 H, 9.71 (actual value) C, 67.26 H, 9.73 IR (CHCl ₃ ): ν _nax 1785 cm ^-1 NMR (CDCl ₃ ): 4.17 (S; −C〓 ₂ −OSi) 4.32 (d, J=9,

【formula】) 4.75 (d, J=9,

[Formula]) 6.05 (broad, 7-H) Reference example 3 15 mg of camphor sulfonic acid was added to 6 ml of a methanol solution containing 63 mg of the carbonate compound (9) obtained in Reference Example 2, and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off, the mixture was extracted with ether and methylene chloride, and the ether-methylene chloride solution was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over magnesium sulfate. After distilling off the solvent, the residue was crystallized from n-hexane-ether to obtain 45 mg of alcohol compound (10). Recrystallization from n-hexane-benzene gives colorless needle-like crystals. (Physical properties) Melting point: 146-149℃ Elemental analysis values: (calculated value) C, 68.54 H, 8.63 (actual value) C, 68.98 H, 8.80 IR (CHCl ₃ ): ν _nax 3600, 3400, ^{1785 cm -1} NMR (CDCl ₃ ): 0.82 (Me) 0.90 (Me) 0.92 (Me) 4.19 (S; 2H, CH ₂ −OH) 4.36 (d, J=9,

【formula】) 4.71 (d, J=9,

[Formula]) 6.15 (dd, J=5, 2; vinyl H) Reference example 4 To 6 ml of an acetone solution containing 69 mg of the alcohol compound (10) obtained in Reference Example 3, 6 drops of Jones' reagent were added while stirring on ice, and the mixture was stirred for 5 minutes. After the reaction, isopropanol was added and the solvent was distilled off, water was added, ether-methylene chloride extraction was carried out, and the ether-methylene chloride solution was diluted with saturated brine,
After washing with saturated sodium bicarbonate and saturated saline,
Dry with magnesium sulfate. When the solvent is distilled off,
69 mg of aldehyde compound (11) is obtained. benzene-n-
Recrystallization from hexane gives colorless needle-shaped crystals. (Physical properties) Melting point: 133-135℃ Elemental analysis values: (calculated value) C, 69.04 H, 7.97 (actual value) C, 68.97 H, 8.13 IR (CHCl ₃ ): ν _nax 1790, 1695 cm ^-1 NMR ( CDCl ₃ ): δ 0.83 (Me) 0.94 (Me) 0.96 (Me) 4.34 (d, J=9,

【formula】) 4.62 (d, J=9,

[Formula]) 7.21 (d, d, J=5, 2; 7-H) 9.40 (S; CHO) Reference example 5 Add 1.5 ml of 1,3-propanediol to 40 ml of a benzene solution containing 308 mg of the aldehyde compound (11) obtained in Reference Example 4.
ml and a small amount of p-toluenesulfonic acid and refluxed for 15 minutes in a Dean-Stark apparatus. After the reaction, add ether to make the ether layer 10
After washing with % sodium carbonate aqueous solution and saturated saline,
Dry with magnesium sulfate. After distilling off the solvent, crystallization from ether-hexane yields a ketal form.
(12) 360 mg is obtained. Recrystallization from ether-hexane gives colorless needle-shaped crystals. (Physical properties) Melting point: 167-168℃ Elemental analysis values: (calculated value) C, 67.83 H, 8.39 (actual value) C, 67.92 H, 8.42 IR (CHCl ₃ ): ν _nax 1780 cm ^-1 NMR (CDCl ₃ ): δ 0.80 (Me) 0.88 (Me) 0.91 (Me) 4.30 (d, J=9;

【formula】) 5.04 (S;

【formula】) 5.12 (d, J=9;

[Formula]) 6.31 (d, d, J=5, 2; 7-H) Reference example 6 Add 3 ml of 10% sodium hydroxide solution to 10 ml of dioxane solution containing 200 mg of the ketal compound (12) obtained in Reference Example 5.
Add 5 ml of water and stir at room temperature for 1 hour and 30 minutes.
After the reaction, the mixture is extracted with ether, and the ether layer is washed with saturated brine and then dried over magnesium sulfate. After distilling off the solvent, the residue was subjected to silica gel chromatography (hexane:ether=1:4) to obtain 181 mg of diol compound (13). Recrystallization from ether-hexane gives colorless columnar crystals. (Physical properties) Melting point: 99-100℃ Elemental analysis values: (calculated value) C, 69.64 H, 9.74 (actual value) C, 69.77 H, 9.75 IR (CHCl ₃ ): ν _nax 3500cm ^-1 NMR (CDCl ₃ ): 0.87 (Me) 0.91 (2XMe) 5.14 (S:

【formula】) 6.23 (broad, 7-H)

Claims (1)

[Claims] 1 Formula: (However, in the formula, R represents a lower alkylsilanoxy group.) A compound represented by the following. 2 formula: A general formula characterized by reacting a compound represented by with hydrazine hydrate and further reacting with imidazole and trialkylsilyl chloride: (However, in the formula, R represents a lower alkylsilanoxy group.) A method for producing a compound represented by the following. 3 formula: In the presence of an alkaline solution, the compound represented by
By treatment with peroxide formula: A general formula characterized by reacting a compound represented by with hydrazine hydrate and further reacting with imidazole and trialkylsilyl chloride: (However, in the formula, R represents a lower alkylsilanoxy group.) A method for producing a compound represented by the following. 4 formula: By reacting the compound represented by with an acetylating agent, the formula: By obtaining a compound represented by the formula and treating the compound with a peroxide in the presence of an alkaline solution, the formula: A general formula characterized by reacting a compound represented by with hydrazine hydrate and further reacting with imidazole and trialkylsilyl chloride: (However, in the formula, R represents a lower alkylsilanoxy group.) A method for producing a compound represented by the following. 5 Formula: The compound represented by is reacted with lithium aluminum hydride to form the formula: A compound represented by the formula: By treating the compound with peroxide in the presence of an alkaline solution, the formula: A general formula characterized by reacting a compound represented by with hydrazine hydrate and further reacting with imidazole and trialkylsilyl chloride: (However, in the formula, R represents a lower alkylsilanoxy group.) A method for producing a compound represented by the following. 6 formula: By reacting the compound represented by the formula with a dialcohol and an organic acid, the formula: A compound represented by is obtained, and the compound is reacted with lithium aluminum hydride to obtain the formula: A compound represented by the formula: By obtaining a compound represented by the formula and treating the compound with a peroxide in the presence of an alkaline solution, the formula: A general formula characterized by reacting a compound represented by with hydrazine hydrate and further reacting with imidazole and trialkylsilyl chloride: (However, in the formula, R represents a lower alkylsilanoxy group.) A method for producing a compound represented by the following.