JP2542843B2 - Novel norbornane derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[Industrial application field] The present invention relates to a novel epijasmonoid.
The present invention relates to a norbornane derivative as an intermediate and a method for producing the same. [Background of the Invention] Jasmonoids (jasmonoi) widely existing in the plant kingdom
In recent years, their importance has been discussed with the potential of phytohormones by exhibiting remarkable and diverse plant growth regulating actions such as growth inhibition or aging (see "Plant Growth Substances 1985," Springer −Verli
g Berlin Heidelberg, 1986, pp. 139-147). In fact, 2,3-trans-disubstituted cyclopentanone derivatives have been synthesized using methyl lasmonate, which has been believed to be the main fragrance of jasmine essential oil, as a lead compound to produce a new fragrance or plant growth regulator. Attempts to discover are widely made. However, it has recently been found that the essential aroma of jasmine essential oil is not methyl jasmonate, but its epimer, methyl epijasmonate (J. Agric. Food Chem., 33, 425 (1985)). or,
Its reduced form, methyl cucurate
bate) showed stronger growth inhibitory activity than conventional trans-side chain jasmonoids (“Plant
Growth Substances 1973 "Hirokawa Publishing Co., 197
4, pp. 86-92). Furthermore, as the biosynthetic pathway of natural jasmonoids is elucidated, it is becoming clear that compounds having cis in the side chain (hereinafter referred to as epijasmonoids) are important in vivo (Plant Pysical., 75,458 (198
Four)). Under these circumstances, when searching for a new flavor or plant growth regulator, a new 2,3-cis-disubstituted cyclopentanone derivative was synthesized using methyl epijasmonate as a lead compound, and its activity was searched for. It is very meaningful to do. For that purpose, it is important to develop a novel epijasmonoid synthetic intermediate for obtaining various 2,3-cis-disubstituted cyclopentanone derivatives. However, for the trans-form, although many synthetic methods have already been developed in the area of jasmonoids and prostanoids, the thermodynamically unstable 2,3-cis-disubstituted cycloalkyl is used. At present, there are very few reports on the synthesis of pentanone derivatives. Methods for synthesizing methyl epijasmonate include the method of Torii et al. (J. Org. Chem., 40, 462 (1975)) and the method of Mori et al. (30th. TEAC Abstracts, 101 (1985)). However, the former method is excellent as a stereoselective method, but synthesizing an indanone derivative, which is a starting material, from inexpensive cyclopentanone requires several steps. Makes it difficult to obtain raw materials with good purity. In addition, it has a drawback that the process involves a reaction that is difficult to control. On the other hand, the latter method requires multiple steps and, in addition, does not allow stereocontrol of the side chains at all. [Problems to be Solved by the Invention] The present inventors have studied a method for synthesizing a 2,3-cis-disubstituted cyclopentanone derivative having excellent stereoselectivity and economical efficiency in order to overcome such a problem. As a result, they have invented a novel norbornane derivative, an extremely useful intermediate capable of introducing not only natural type but also various different substituents into the side chain of the epijasmonoid skeleton. It is. That is, an object of the present invention is to provide a norbornane derivative as a novel epijasmonoid intermediate which can lead to an epijasmonoid derivative useful as a flavor or a plant growth regulator, and a method for producing the same. [Means for Solving the Problems] The novel norbornane derivative of the present invention has the following formula [I]
Is represented by Wherein R ¹ represents a 2,2-dihalovinyl group, a carboxymethyl group or a lower alkoxycarbonylmethyl group, R ² represents a hydrogen atom, R ³ represents a hydroxyl group, or R ² and R ³ are Represents an oxygen atom. The norbornane derivative represented by the above formula [I] of the present invention includes any of the optically active isomers of the d-form and the l-form, or a mixture thereof at any ratio. Preferred specific examples of the norbornane derivative of the formula [I] of the present invention include the following. 7S ^* -(2,2-dichlorovinyl) bicyclo [2.2.1] heptane-2R ^* -ol, 7S ^* -(2,2-dibromovinyl)
Bicyclo [2.2.1] heptane-2R ^* -ol, 7S ^* -(2,2
-Dichlorovinyl) bicyclo [2.2,1] heptane-2-
On, 7S ^* -(2,2-dibromovinyl) dicyclo [2.2.
1] Heptan-2-one, 7S ^* -(carboxymethyl) bicyclo [2.2.1] heptan-2-one, 7S ^* -(methoxycarbonylmethyl) bicyclo [2.2.1] heptane-2-
On, 7S ^* -(ethoxycarbonylmethyl) bicyclo [2.2.1] heptan-2-one, and the like. The norbornane derivative of the present invention can be synthesized, for example, as follows. First, the following formula (II) The norbornylene represented by the following formula [III] CX ₃ CHO [III] [wherein X represents a chloro atom or a bromo atom in the presence of a Lewis acid. Reacting with trihaloacetaldehyde represented by
The following formula (IV) [Wherein, X is the same as above. ] And then treated with zinc dust-acetic acid to give the following formula [I-1] [Wherein, X is the same as above. To obtain a hydroxynorbornane derivative represented by the following formula: Then, if desired, the present compound is reacted with an oxidizing agent to give the following formula [I-2] [Wherein, X is the same as above. To obtain a norbornanone derivative represented by the following formula: Then, if desired, the present compound is treated with sulfuric acid, and if desired, the present reaction solution is subjected to the following formula [V] R ¹ OH [V] wherein R ¹ represents a lower alkyl group. ] With a lower alcohol represented by the following formula [I-
3] [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. ] The norbornanone derivative represented by these is obtained. Hereinafter, the method for producing the norbornane derivative of the present invention will be described in detail. Norbornylene represented by the above formula [II] as a starting material is commercially available at a low price and can be purchased in large quantities (Aldrich). In order to produce norbornane derivatives, the method of H. Fritz et al. (Helv. Chim. Acta. 58, 1
345 (1975)) and trihaloacetaldehyde [II] in an organic solvent in the presence of a Lewis acid.
I] to give an oxybrexane derivative [IV]. The used amount of trihaloacetaldehyde [III] is 1-1.1 times mol, particularly preferably strictly equimolar, with respect to norbornylene [II]. As the organic solvent used at this time, those which do not react with the Lewis acid, particularly preferable ones include methylene chloride, dichloroethane, chloroform and the like. The used amount may be 8 to 12 times the volume of norbornylene [II]. Fritz et al. Used carbon disulfide as a solvent for this type of reaction, but the inventors performed additional tests and found that the yield was low, and it was thought that carbon disulfide and norbornylene [II] had reacted. Organisms were produced in large quantities, and it was very difficult to separate the desired oxybrexane derivative [IV]. The Lewis acids used include aluminum chloride, titanium tetrachloride, zinc chloride, zinc bromide, tin tetrachloride, BF ₃ ,
Etherates and the like can be mentioned, and particularly preferred are aluminum chloride and titanium tetrachloride. The amount used is 2-10% based on norbonylene [II]
A molar range is appropriate. This reaction is carried out under a nitrogen atmosphere, and the reaction temperature is suitably from -10 ° C to room temperature, particularly preferably from 5 ° C to 15 ° C. The reaction time is usually in the range of 4-6 hours. The reaction mixture thus obtained is post-treated in a conventional manner, and the solvent is distilled off. Furthermore, in order to remove mixed acidic components, etc., norbornylene [II] was added under nitrogen atmosphere.
The mixture is heated under reflux for 1 hour together with 0.5 to 1.2 moles of triethylamine with respect to norbonylene [II] in -10 volumes of acetone or ether. After cooling the reaction mixture, the precipitate was separated by filtration, the solvent was distilled off, and then extracted by a conventional method, washed with water, dried and treated with activated carbon.
If necessary, it can be purified by means such as distillation under reduced pressure or column chromatography to obtain the oxybrexane derivative [IV] represented by the formula [IV]. Next, the oxybrexane derivative [IV] is treated with zinc dust-acetic acid to perform a reductive ring cleavage reaction, and the above-mentioned formula [I-
The hydroxynorbornane derivative represented by 1) can be obtained. In this case, the reaction is performed in the presence or absence of an organic solvent. The amount of zinc powder used is 5 to 10 times the molar amount of the oxybrexane derivative [IV], and the amount of acetic acid is 1.5 to 2 times the molar amount of the zinc powder, and especially 8 to 8 times when no other organic solvent is used. 12 times the capacity may be used. Examples of the organic solvent used at this time include ethyl ether, tetrahydrofuran, dioxane, benzene, and toluene. Particularly preferable ones include ethyl ether and tetrahydrofuran. The used amount may be 8 to 15 times the volume of the oxybrexane derivative [IV]. In this reaction, usually, a mixture of zinc powder, acetic acid and an organic solvent is stirred at room temperature for 20 to 30 hours to prevent side reactions due to oxides and the like mixed in commercially available zinc powder, and then added to oxybrexane. Derivative [IV] is added. In order to omit this operation, zinc powder pretreated with dilute hydrochloric acid may be used. This reaction is carried out under a nitrogen atmosphere, and the reaction temperature is suitably from -10 ° C to room temperature, particularly preferably from 5 to 15 ° C. The reaction time is usually in the range of 4-8 hours. The reaction product thus obtained can be subjected to ordinary post-treatment, and if necessary, purified by means such as recrystallization or column chromatography to obtain the hydroxynorbornane derivative represented by the above formula [I-1]. I can do it. Next, the hydroxynorbornane derivative is reacted with various oxidizing agents to obtain a norbornanone derivative represented by [I-2]. Pyridinium chlorochromate (PC
C), pyridinium dichromate (PDC), chromium oxide
Sulfuric acid, chromium oxide-pyridine, sodium dichromate-
Sulfuric acid, potassium permanganate, manganese dioxide, DMSO-
Examples include DCC, DMSO-acetic anhydride, DMSO-5 phosphorus oxide, DMSO-sulfur trisulfide-pyridine, and DMS-NCS. PCC or PDC is preferably used depending on the reaction yield and the ease of operation. In the case of PCC or PDC, the amount used is 1.5 to 2.5 times the molar amount of the hydroxynorbornane derivative [I-1], the reaction time is 1-3 hours, and the reaction temperature is in the range of 0 ° C. to room temperature. This reaction is carried out under a nitrogen atmosphere, and after the reaction, PCC or P
1Å1.5 times the weight of DC powdered 3 重量 or 4 DC
When a molecular sieve of the type is coexisted, the post-treatment is facilitated and the yield is improved. The reaction is usually carried out with a hydroxynorbornane derivative [I-
1), by vigorously stirring a mixture of molecular sieve and PCC or PDC, adding an organic solvent thereto, and further vigorously stirring. As the organic solvent, methylene chloride or dichloroethane is preferably used, and its use amount is suitably in the range of 15 to 20 times the volume of the hydroxynorbornane derivative [I-1]. To the reaction mixture thus obtained was added 2-3 volumes of ethyl ether based on methylene chloride, and the precipitate was separated by filtration. After evaporating the solvent, the residue was dissolved in ether, if necessary, and the insolubles were filtered off again. After treatment with activated carbon, if necessary, purification is carried out by means such as recrystallization or column chromatography to obtain the norbornanone derivative represented by the above formula [I-2]. Next, the norbornanone derivative [I-2] is hydrolyzed by treating with sulfuric acid, and, if desired, is esterified by adding a lower alcohol [V] to the reaction mixture, and is represented by the above formula [I-3]. A norbornanone derivative can be obtained. At this time, sulfuric acid having a concentration of 70-100% is used, and 95% sulfuric acid is suitable for smoothing the reaction and increasing the yield. The used amount is 8 to 12 times the volume of the norbornanone derivative [I-2]. The reaction temperature is from 0 ° C to room temperature, and 25-30 to make the reaction proceed smoothly
It is good to carry out at ° C. The reaction is usually terminated by disappearance of the starting material norbornanone derivative [I-2] by thin layer chromatography, but requires 1-2 days. Carboxylic acid [I-
3] Post-processing is performed here to obtain (R ¹ = H). To obtain the ester [I-3] (R ¹ = lower alkyl group), 95% sulfuric acid and an equivalent volume of a lower alcohol [V] are added to the above reaction mixture, and the reaction is further performed at room temperature for 5 to 10 hours. . The reaction mixture thus obtained is subjected to ordinary post-treatment, and if necessary, purified by a technique such as recrystallization or column chromatography to obtain the norbornanone derivative represented by the above formula [I-3]. In addition, 2,2-
The conversion reaction of a dichlorovinyl group and a 2,2-dibromovinyl group into a carboxymethyl group or its ester group by hydrolysis is a new reaction first discovered by the present inventors. An example of a 2,2-difluorovinyl group as a similar reaction has been reported by N. Ishikawa et al. (Chem. Let
t., 1980, 651), which allows for the enrichment of various carbonyl compounds (see scheme below). However, in the case of an aliphatic compound, sulfuric acid has not been successful, and after treatment with mercuric acetate-trifluoroacetic acid, the produced organic mercury compound is reduced, thereby achieving the purpose. [Wherein R ¹ and R ² represent a hydrogen atom, an alkyl group or an aryl group, and R ³ represents a hydrogen atom or an alkyl group, X
Represents a fluorine atom, a chloro atom or a bromo atom. The results of the present inventors show that the chloro or bromo derivative is easily and efficiently hydrolyzed by sulfuric acid, and that the 2,2-dichlorovinyl group and the 2,2-dibromovinyl group This finding is of great significance in synthetic chemistry because it can be synthesized more easily than a 2,2-difluorovinyl group. [Effects of the Invention] The thus obtained norbornane derivative represented by the above formula [I] is a very useful intermediate which can lead to epijasmonoids useful as a fragrance or a plant growth regulator. That is, as shown in the following scheme, the compound represented by the formula (I) is a very useful compound which is led to an epijasmonoid derivative through a synthetic route including cleavage of a C ₁ -C ₂ bond, for example, [I-3] undergoes ring cleavage by treatment with peracid to give a natural epijasmonoid, methyl epijasmonate or cucurbic acid (cucurbic acid).
acid) with easy and complete stereocontrol. Furthermore, the modification of side chains in appropriate steps, such as alkylation or functional group conversion, enables the creation of various synthetic epijasmonoids. [In the above general formula, R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom or an alkyl group, and R ⁵ represents a hydrogen atom, an alkyl group or an acyl group. Further, the production method is extremely economical in that it can be carried out in large quantities and in high yield from inexpensive raw materials using ordinary reagents without any difficult reaction steps. Therefore,
The industrial significance of the present invention is immense. Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto. The compounds [I-1] (X = Cl) and [I-2] (X
= Cl), [I-3] (R = H) and [I-3] (R = M
e) are new compounds. Example 1 Aluminum chloride powdered into dry methylene chloride 1
10 g (75 mmol) was added and the mixture was stirred to form a suspension. A solution of 100 g (1.06 mol) of norbornylene [II] and 157 g (1.06 mol) of chloral [III] (X = Cl) in 200 ml of dry methylene chloride was added thereto. The solution was added dropwise at -20-0 ° C in about 1 hour. After stirring at room temperature for 4 hours, 1.5 l of 2N hydrochloric acid was poured under ice cooling, and the mixture was stirred at room temperature for 30 minutes and extracted with methylene chloride. After the organic layer was dried over magnesium sulfate, the solvent was distilled off. The obtained residue was dissolved in 600 ml of acetone, and triethylamine 1
10 g (1.09 mol) was added under ice cooling. After heating under reflux for 1 hour, the reaction mixture was cooled, and the generated insolubles were separated by filtration.
After concentrating the filtrate, the residue was dissolved in 500 ml of ethyl ether, the insolubles were filtered off again, water 1 was poured into the filtrate, and the mixture was extracted with ethyl ether. After hot treatment with activated carbon, the solvent was distilled off, and 228 g (88.8%) of almost pure oxybrexane derivative [IV]
I got Next, a suspension of 165 g (2.52 mol) of zinc dust, 250 g (4.17 mol) of acetic acid, and 750 ml of dry ethyl ether was stirred at room temperature for 20 hours. To this, 350 m of dry ethyl ether of 72.45 g (0.30 mol) of the crude oxybrexane derivative [IV] was added.
The solution was added dropwise over about 1 hour under ice cooling. After stirring at room temperature for 4 hours, insolubles were separated by filtration, the solvent and acetic acid were distilled off under reduced pressure, and the residue was extracted with ethyl ether. The organic layer with saturated aqueous sodium hydrogen carbonate solution was washed successively with saturated aqueous sodium chloride solution, the solvent was distilled off and dried over magnesium sulfate, substantially pure 7S ^* -
(2,2-dichlorovinyl) bicyclo [2.2.1] heptane-
62.8 g (101%) of 2R ^* -ol [I-1] was obtained. Recrystallization of part of this product from hexane gives colorless needles.

[Physical properties of [I-1] (X = Cl)] mp 77.5-78.5 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm; 0.93-1.97 (6H), 1.59 (1H, s), 2.04-2.37 (2H ),
2.50 (1H, d / m, J = 9.0Hz), 3.84 (1Hm), 6.45 (1H, d, J
= 9.0Hz). Example 2 The above crude hydroxynorbornane derivative [I-1] (X
= Cl) A mixture of 27.4 g (132 mmol), 68.8 g (320 mmol) of PCC and 80 g of powdered 3 molecular sieve was stirred vigorously under ice-cooling, and dried methylene chloride (400 m) was added thereto.
Add l almost at once. After further stirring vigorously for 2.5 hours under ice-cooling, 800 ml of ethyl ether was added to the reaction solution, the insoluble matter was separated by filtration through celite, and the filtrate was concentrated. 300 ml of ethyl ether was added to the residue, and the insoluble matter was removed again by silica gel (C-300). And filtered. The solvent was distilled off after treating the filtrate with activated carbon while hot,
The residue was recrystallized from methanol to give colorless prisms, 7S
^* 19.2 g (71.0%) of-(2,2-dichlorovinyl) bicyclo [2.2.1] heptan-2-one [I-2] was obtained.

[I-2] (Physical properties of X = Cl) mp 37 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm; 1.36-2.98 (9H), 5.79 (1H, d, J = 8.6 Hz). Reference Example 1 Norbornenone derivative [I-2] (X = Cl) 21.6 g (1
(05 mmol) was added to 200 ml of 95% sulfuric acid at once with stirring under ice-cooling, and the mixture was stirred as it was. After about 15 minutes, when the crystals dissolve,
Stir at room temperature for 2 days, pour the reaction mixture into ice water 1,
Extracted with methylene chloride. After the extract is dried over sodium sulfate, the solvent is distilled off, and the residue is dissolved in ether and heated with activated carbon. After evaporating the solvent, 17.2 g (97.0%) of almost pure 7S ^* -(carboxymethyl) bicyclo [2.2.1] heptan-2-one [I-3] (R = H) was obtained. Recrystallization of a portion of the product from carbon tetrachloride gives colorless granular crystals.

[I-3] (R = H) physical properties: mp 35-37 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm; 1.34-2.66 (11H), 10.94 (1H, brs). ¹³ C-NMR (CDCl ₃ ) δ ppm; 23.5 (t), 27.7 (t) 32.2 (t), 37.6 (d), 4
0.2 (t), 45.0 (d), 53.3 (d), 176.2 (s), 217.8
(S). Reference Example 2 1.0 g of norbornanone derivative [I-2] (X = Cl) (4.
9 mmol) was added to 10 ml of 95% sulfuric acid at a time under ice-cooling and stirring.
Stir as it is. When the crystals are dissolved, the mixture is stirred at room temperature for 2 days, then, 10 ml of methanol is added under ice cooling, and the mixture is further stirred at room temperature for 5 hours. The reaction solution was poured into ice water (200 ml), extracted with ethyl ether, and the organic layer was washed with saturated sodium bicarbonate and brine in that order, and dried over sodium sulfate. After evaporating the solvent, silica gel column chromatography (hexane / hexane)
The product was purified by ethyl acetate = 10: 1) to give 7S ^* -as a colorless oil.
0.73 g (82.2%) of (methoxycarbonylmethyl) bicyclo [2.2.1] heptan-2-one [I-3] (R = Me)
I got

[I-3] (R = Me) physical properties ¹ H-NMR (CDCl ₃ ) δ ppm; 1.27-2.60 (11H), 3.68 (3H, s).

Claims (4)

(57) [Claims] 1. The following formula [I] [Wherein, R ¹ represents a 2,2-dihalovinyl group, R ² represents a hydrogen atom, R ³ represents a hydroxyl group, or R ² and R ³ together represent an oxygen atom. ] The norbornane derivative represented by these. 2. The norbornane derivative according to claim ¹ , wherein in the formula (I), R ¹ is a 2,2-dichlorovinyl group. 3. The following formula [II] The norbornylene represented by the following formula [III] CX ₃ CHO [III] [wherein X represents a chloro atom or a bromo atom in the presence of a Lewis acid. Reacting with trihaloacetaldehyde represented by
The following formula (IV) [Wherein, X is the same as above. And then treated with zinc dust-acetic acid, characterized by the following formula [I-
1] [Wherein, X is the same as above. ] The manufacturing method of the hydroxy norbornane derivative represented by these. 4. The following formula [II] The norbornylene represented by the following formula [III] CX ₃ CHO [III] [wherein X represents a chloro atom or a bromo atom in the presence of a Lewis acid. Reacting with trihaloacetaldehyde represented by
The following formula (IV) [Wherein, X is the same as above. ] And then treated with zinc dust-acetic acid to give the following formula [I-1] [Wherein, X is the same as above. Wherein a hydroxynorbornane derivative represented by the following formula [I-2] is reacted with an oxidizing agent. [Wherein, X is the same as above. ] A method for producing a norbornanone derivative represented by the formula: