JPH0535137B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to a method for producing optically active 4-hydroxy-2-cyclopentenone and related compounds.
More specifically, the present invention involves contacting 4-hydroxy-2-cyclopentenone with an optically active rhodium complex to selectively isomerize one optical isomer to form 1,3-cyclopentanedione;
At the same time, optical activity of R or S coordination was induced 4
-Regarding a new method for producing hydroxy-2-cyclopentenone. According to this production method, optically active 4-hydroxy-2-cyclopentenones, which are intermediates for the production of various pharmaceuticals such as prostaglandins with various pharmacological effects and maytansine with anticancer effects, can be produced in high yield. Furthermore, this production method is extremely significant from the viewpoint of stereochemistry. <Prior art> Conventionally, optically active 4-hydroxy-2-cyclopentenones such as (R)-4-hydroxy-2-cyclopentenone and (S)-4-hydroxy-2-cyclopentenone have been produced. For example, the following manufacturing method is known. That is, (1) diacetoxycyclopent-1-ene obtained from cyclopentadiene is hydrolyzed with an enzyme to obtain 3(R)-acetoxy-5(R)-hydroxycyclopent-1-ene; is oxidized with manganese dioxide to obtain 4(R)-acetoxycyclopent-2-en-1-one, which is optionally deprotected with a hydrolase (tetrahedron, 32 , 1713−1718
(1977), Tetrahedron, 32 , 1893 (1977), Tetrahedron, Letters, 27 , 1255 (1986),
26, 407 (1985), 5875 (1984), The Journal American Chemical Society,
106, 3695 (1984)) (2) Using D or L-tartaric acid as a starting compound,
D or L-1,4-
A method for producing (R) or (S)-4-hydroxy-2-cyclopentenone by reacting diiodo-2,3-isopropylidene dioxybutane with a lithio compound and then hydrolyzing it (tetra Hedron Letters, 10 , 759–762 (1976)
(3) As a starting material, 4(R)-
Method for producing acetoxy-2-cyclopentenone (Tetrahedron Letters, ( 29 ), 2553~
2556 (1978)), (4) 2,4,6-trichlorophenol is reacted with chlorine to form 3,5,5-trichloro-
1,4-dihydroxycyclopent-2-ene-1-carboxylic acid was obtained, which was optically resolved with brucine, and then subjected to four steps to obtain (R)-4.
-t-butyldimethylsiloxycyclopent-
Method for producing 2-enone (tetrahedron)
Letters, 1539-42 (1979) (17)), (5) Asymmetric reduction of 1-cyclopentene-3,5-dione with a compound obtained from a chiral binaphthol compound, an alcohol, and lithium aluminum hydride ( 4-hydroxy-2 of R) or (S)
- A method for obtaining cyclopentenone (see Noyori et al., JP-A-123932), (6) combining dl-4-hydroxy-2-cyclopentenone with an optical resolving agent to separate the product into two diastereomers. After separation, the resolving agent is deprotected by reaction to obtain an optically active compound, and the hydroxyl group is protected as necessary to produce the product (Hari et al., JP-A-159777 and Noyori et al., tetrahedron.
Letters, 23, 4057 (1982)), (7) dl-4-hydroxy-2-cyclopentenone as a half ester of ortho-phthalic acid,
This is converted into a salt with an optically active amine, one isomer is separated by recrystallization, the optically active form is obtained by deprotection, and the hydroxyl group is protected as necessary. 57-14560), (8) A method for obtaining D-glucose by chemical conversion using it as a starting material (Torii et al., The Journal of Organ Chemistry, 51, 254
(1986)) (9) 3 of cyclopent-3-en-1-ol,
Isomerization and oxidation of 4-epoxide to allyl alcohol using an asymmetric base catalyst (Asami et al., Tetrahedron Letters, 26, 5803)
(1985)) are known. In these methods, the optical yield of the 4-hydroxy-2-cyclopentenones obtained by methods (1) and (2) is not fully satisfactory, and the total yield is also low. Although methods (3) and (4) have high optical yields, method (3) uses a compound called terrain, which is difficult to obtain, as a starting material; In the method described above, optical resolution is performed during the manufacturing process, and
The total yield of either method (3) or (4) is not fully satisfactory. Method (5) is raw material 1
The disadvantage is that -cyclopentene-3,5-dione is used as a starting material which is expensive and relatively difficult to obtain. Furthermore, in the optical resolution methods (6) and (7), only 50% of one optically active substance can be used theoretically, and the total yield is not sufficient. Although the induction of (8) from D-glucose has a good optical yield, it has the disadvantage of requiring a long number of steps to reach the target product. In method (9), the starting materials are not easily available and the optical yield is unsatisfactory at 90% ee. In addition, as a conventional method for producing cyclopentane-1,3-dione, Dieckmann (β-ketoadipate ethyl ester)
Condensation reaction method (Earl Richter, Helvetica Chimica Acta, 32 , 1123 (1949) and J.E.T. Brose et al., Journal of
American Chemical Society, 75 , 1731
(1953)) or the cyclization reaction of levulinic acid ethyl ester (see J. Slaga et al., Synthesis, 282 (1977)). However, these methods are not necessarily satisfactory for industrial production in terms of yield and operational complexity. In addition, a method of obtaining 4-cyclopentenediol using cyclopentadiene is known (L.N.O.N et al., Journal.
of the Chemical Society, 4035
(1952): G.M. Colaciu et al., Organic Synthesis, 42 , 50 (1962): G.H.
Rasmutsen et al., Organic Synthesis;
VolV, 234 (1973): Journal of the Organ Chemistry, 37 , 2905 (1972) and references cited therein). However, these methods also have drawbacks in terms of yield and process complexity. In addition, an advantageous process for the preparation of 1,3-cyclopentanedione using norbornene has recently been proposed (see Rick et al., Chemisier Berichte, 111 , 2461).
(1978)). This method has significantly improved productivity compared to conventional manufacturing methods. However, the process involves several steps and is not necessarily satisfactory in terms of operation. Additionally, a method has been proposed to obtain 2,3-epoxycyclopentanone by isomerizing it (Japanese Patent Application Laid-open No. 1983-1979-
069537, The Journal American Chemical Society, 102 , 2095 (1980)]. Although this method is short-step, the yield is unsatisfactory. <Object of the invention> As described above, conventional methods for producing optically active 4-hydroxy-2-cyclopentenone and 1,3-cyclopentanedione cannot necessarily be said to be industrially superior. . Therefore, the present inventors have developed an industrially advantageous optically active 4-hydroxy-4-hydroxy compound that has a high optical yield and a high total yield, using easily available compounds.
We conducted extensive research to find a method for producing 2-cyclopentenone and 1,3-cyclopentanedione.
That is, the knowledge that the conventionally known allylcol gives an asymmetric carbonyl compound through a 1,3-hydrogen transfer reaction using an asymmetric catalyst (Gazeta Chimia Italiana, 106 , 1131 (1976),
pure and applied chemistry,
57, 1845 (1985)), optically active 4-hydroxy-2-cyclopene was produced by kinetic resolution by contacting 4-hydroxy-2-cyclopentenone with an asymmetric rhodium catalyst. The present invention was achieved by discovering that tenone and 1,3-cyclopentanedione can be obtained efficiently. <Structure of the invention> That is, the present invention has the following formula [] [In the formula, the ~ ~ ~ line represents an arbitrary ratio of α and β-bonds. ] The following formula [] is characterized by contacting 4-hydroxy-2-cyclopentenone represented by with an optically active rhodium complex. [In the formula, * represents an asymmetric carbon atom in which optical activity is induced. ] This is a method for producing optically active 4-hydroxy-2-cyclopentenone and 1,3-cyclopentanedione represented by the following. In the production method of the present invention, 4-hydroxy-2-cyclopentenone represented by the above formula [] is used as a starting material. ~ ~ ~ The line represents an arbitrary ratio of hydroxyl group bonds to α or β bonds, and the ratio is 1/1, that is, the dl form can be easily obtained by a conventionally known method (Noyori et al., JP-A No. Showa 54-
154735, Tanaka et al., JP-A-56-086128). Further, starting materials containing an excess of one of the optical isomers, that is, those having an α/β ratio of 1 or more or 1 or less, can also be used as raw materials for this production method. By treating such 4-hydroxy-2-cyclopentenone with an optically active rhodium complex, kinetic resolution is performed, and the products are optically active 4-hydroxy-2-cyclopentenone and 1,
3-Cyclopentanedione is obtained at the same time. The optically active rhodium complex used here has the following formula [] <Rh(binap)Ln> - binaphthyl;
L represents a ligand, X represents perchlorate or tetrafluoroborate, and n represents an integer of 1 or 2. ] The ligand for L includes cyclooctadiene, norbornadiene, methanol, acetone, etc., and cyclooctadiene and methanol are particularly preferred. Such complexes are described in known literature (e.g. Japanese Publication No.
53−13605, The Journal of American Chemical Society, 102 , 7932
(1980)). When the optically active rhodium complex prepared in this manner is brought into contact with the raw material, one of the optical isomers undergoes an isomerization reaction preferentially, producing 1,3-cyclopentanedione while 4 having induced optical activity. -hydroxy-2-cyclopentenone results. A medium can be used in the reaction, for example ethers such as tetrahydrofuran, ether, diosane, particularly preferably tetrahydrofuran, for example toluene,
Aromatic hydrocarbons such as xylene and benzene, particularly preferably toluene. The medium used is used in an amount of 1 part to 100 parts, preferably 10 parts to 50 parts, based on the raw material. The reaction is usually carried out at -20°C to 70°C, preferably -5°C.
Proceeds at ~30°C. The reaction progresses with proton-
It can be traced by means such as nmr or thin layer chromatography, and the reaction time can be set depending on the properties of the desired product. All products are highly soluble in water, so
It is preferable to directly separate and purify the reaction mixture by means such as flash column chromatography.
It is also extracted with an organic solvent by adding phosphate buffer (PH7.4). The aqueous layer is concentrated again under reduced pressure and then extracted with an organic solvent to further obtain a product. Ethyl acetate or methyl isobutyl ketone is preferably used as the extraction solvent. Also, one of the products, cyclopentane-1,3
-Diones may crystallize in the medium and can be easily separated by filtration. Thus, the optically active 4- represented by the above formula []
Hydroxy-2-cyclopentenone and 1,3
- Cyclopentanedione is obtained. Optically active 4-hydroxy-2-cyclopentenone may further have its hydroxyl group protected as required. In order to protect the hydroxyl group of such a compound, a known reaction can be employed. That is, the protecting group is, for example, an acetyl group, a propanoyl group, a chloroacetyl group, a benzoyl group, a p
In the case of an acyl group such as a -bromobenzoyl group, p-nitrobenzoyl group, or Motsuya's reagent, a protecting group can be easily introduced by reacting an acid halide or acid anhydride with pyridine. When the protecting group is a trialkylsilyl group such as a trimethylsilyl group or a dimethyl-t-butylsilyl group, the protecting group is introduced by reacting a trialkylsilyl halide, imidazole, and hexamethylphosphoric triamide. be able to. In addition, the protecting group is 2-tetrahydropyranyl group; 2-tetrahydrofuranyl group, α-ethoxyethyl group, α-ethoxy-α-
In the case of a methyl ethyl group, etc., a protective group can be introduced by contacting the corresponding vinyl ether compound dihydropyran, dihydrofuran, ethyl vinyl ether, ethyl isopropenyl ether in the presence of an acidic catalyst such as para-toluenesulfonic acid. . This product having a protected hydroxyl group may be treated by means such as recrystallization to further increase its optical purity. In particular, when the protecting group is a butyldimethylsilyl group, it can be recrystallized at low temperature using hydrogen oxides such as pentane or hexane to increase the optical purity. As described above, optically active 4-hydroxy-2-cyclopentenone, which can be used as a synthetic intermediate for various prostaglandins, has an optical yield higher than that of easily available 4-hydroxy-2-cyclopentenone. 1,3-cyclopentanedione can be obtained at the same time. This production method is able to utilize the skeletal structure of 4-hydroxy-2-cyclopentenone used as a raw material almost quantitatively, and can induce relatively high optical activity easily and under mild conditions. The number of steps is very short compared to the method of
It can be said that this is a new and advantageous method that can obtain the desired optically active substance. <Example> Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 5 mm tube that was previously dried and replaced with argon
Approximately 2 mg of Rh [(R)-binap] in the NMR tube
(CH ₃ OH) ₂ ] ⁺ ClO ₄ ^- was weighed out, and 0.5% of deuterated tetrahydrofuran (THF-d ₃ ), which had been distilled from sodium-potassium and stored in a sodium mitten, was added.
Introduced by ml distillation. Degassed and dried (±)-4-hydroxy-2-cyclopentenone (25μ) was added to the previously prepared THF- _d3 catalyst solution (some insoluble ). 0℃ after two degassing operations
The temperature was raised to 1 and left for 13 days. During this time, it completely becomes a solution, changing from a yellow-orange color to a dark green solution. The reaction mixture was directly subjected to flash column chromatography (6 g of silica gel, ether-hexane 8:1.5 → ether → dichloromethane-methanol 9:1), and the catalyst and 8.5 mg of the target product 4-hydroxy-2-cyclopentenone ( A) and 17.9 mg of 1,
3-Cyclopentanedione (B) was separated. The separated 4-hydroxy-2-cyclopentenone is immediately dissolved in methylene chloride (0.5 ml), Motscher's reagent ((+)-MTPACl) (20 μ) and pyridine (50 μ) are added, and the mixture is left at room temperature for 1 to 5 hours. The reaction mixture was mixed with ether (total amount approx. 15%) under acidic conditions.
ml), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil. This mixture was subjected to flash chromatography (6 g of silica gel, ether-hexane 1:5 → 1:
Separation was performed in step 3) to obtain 24 mg of (+) MTPAC ester. Determined to be 87% ee by HPLC analysis. Examples 2-9 Kinetic resolution similar to Example 1 was carried out, and results were obtained under various conditions such as catalyst, solvent, temperature, time, etc., as shown in the table below. [Table] [Table] Reference Example 1 Synthesis of 4(R)-t-butyldimethylsiloxy-2-cyclopenten-1-one 4(R)-hydroxy-2-cyclopenten-1-
Dissolve 1.84 mg (1.88 mmol) of
t-Butyldimethylsilyl chloride at ℃369
mg (2.45 mmol) and stirred overnight. After the reaction, add ether and wash with water to obtain 320 mg of an oily substance. This was subjected to column chromatography and n-hexane-ethyl acetate (2:
Purification according to 1) yields 294 mg (74%) of 4(R)-t-butyldimethylsiloxy-2-cyclopenten-1-one. [α ²³ _D : +55.7° C: 0.42 MeOH Reference Example 2 Recrystallization-1 Obtained 4(R)-t-butyl- with optical purity of 87% ee
Dimethylsiloxy-2-cyclopentenone 2.360
g (crystal at room temperature) (R form = 2.207 g, S form = 0.153
Take g) in a 200ml eggplant flask and dissolve in 110ml of pentane. This is placed in a cooling bath of isopropyl alcohol under _N2 , and pieces of dry ice are added little by little into the cooling bath to cool it down gradually. White needle-like crystals form at approximately -45°C. The temperature was kept at about -50°C and the mixture was allowed to stand for 1 hour, then transferred to a 3G glass filter cooled to -50°C and instantly filtered under low temperature under reduced pressure. Dry the separated crystal part under reduced pressure to give 0.755g (32%)
Crystals of were obtained. In addition, the mother liquor was concentrated under reduced pressure and dried under reduced pressure to obtain 1.605 g (68%) of the mother liquor (crystallized at room temperature).
I got it. The optical purity and yield of these mps are shown in the table below. [Table] Recrystallization-2 1.605g of mother liquor in Recrystallization-1 was mixed with 70g of pentane.
ml, and perform low temperature recrystallization at -50℃ in the same manner as in Recrystallization-1 to obtain 1.042g (yield 44%) of crystals.
and 0.563 g (24%) of mother liquor-2 was obtained. Their optical purity and yield are shown in the table below. 【table】

Claims (1)

[Claims] 1. The following formula [] [In the formula, the ~ ~ ~ line represents an arbitrary ratio of α and β-bonds. ] The following formula [] is characterized by contacting 4-hydroxy-2-cyclopentenone represented by with an optically active rhodium complex. [In the formula, * represents an asymmetric carbon atom in which optical activity is induced. ] A method for producing optically active 4-hydroxy-2-cyclopentenone and 1,3-cyclopentanedione. 2 The optically active rhodium complex has the following formula [] <Rh(binap)Ln> can be,
L represents a ligand, X represents perchlorate or tetrafluoroborate, and n represents an integer of 1 or 2. ] A method for producing optically active 4-hydroxy-2-cyclopentenone and 1,3-cyclopentanedione according to claim 1, which are complexes represented by the following. 3. Optically active 4- according to claim 2, wherein the ligand is methanol or cyclooctadiene.
Hydroxy-2-cyclopentenone and 1,3-
Production method of cyclopentanedione.