JP2709807B2 - Process for producing 3-chloro-4-silyloxy-2-cyclopenten-1-ones - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention
The present invention relates to a novel method for producing silyloxy-2-cyclopenten-1-ones. More specifically, 3-chloro-4- compound which can be a useful compound in producing pnaglandins having an excellent anticancer action and antiviral action.
The present invention relates to a method for producing silyloxy-2-cyclopenten-1-ones. [0002] In recent years, Telesto risi (Telesto risi), which has settled on the bottom of a boat collected on Oahu.
ei), a prostaglandin-related substance, pnaglandin, was isolated [Monthly Pharmaceutical Affairs, vol. 24, p. 41 (19)
86); Shoyer et al. Am. Chem. So
c. , 107, 2976 (1985)]. The three-dimensional structure has recently been found to be represented by the following formula. [0003] [Noyori et al. Am. Chem. So
c. , 108, 5021 (1986); Yamada et al. A
m. Chem. Soc. , 108, 5019 (198
6)]. It is known that punagrangins have an anticancer action as a physiological action [Fukushima et al., The 43rd Annual Meeting of the Cancer Society of Japan, p. 905 (1984); Advanced Improstaglandin Thromboxane and Leukotriene Research, Vol. 415, (1985),
Published by Reyban Press (New York)]. With regard to the synthesis of pulaglandins, the route shown in <Scheme 1> is known as a typical example [Noyori et al., J. Am. A
m. Chem. Soc. , 108, 5021 (198
6)]. According to the report, punaglandin (5) is obtained by sequentially adding an ω side chain and an α side chain to (4R) -3-chloro-4-tert-butyldimethylsilyloxy-2-cyclopenten-1-one (1). It is obtained by bonding. Further, the chirality at the 12-position of punaglandin (5) is derived from the chirality at the 4-position of compound (1). Therefore, the optically active 3- in the synthesis of punaglandin (5)
Chloro-4-tert-butyldimethylsilyloxy-
2-Cyclopenten-1-one can be said to be a very important synthetic intermediate of pulagrangins. [0005] The present inventors have paid attention to this point, and are keen on the synthesis of optically active 3-chloro-4-silyloxy-2-cyclopenten-1-ones and 4-silyloxy-2-cyclopenten-1-one. As a result of repeated studies, the present invention has been achieved. Heretofore, as a method for synthesizing optically active 3-chloro-4-silyloxy-2-cyclopenten-1-one, tetrahedron letters, Vol. 17, pp. 1539-1
The method described on page 542 (1979) is known. <
Scheme 2> That is, 3,5,5-trichloro-1,4-dihydroxycyclopent-1-carboxylic acid (7) obtained from trichlorophenol (6) is converted into a salt with (−)-brucine, and By fractional recrystallization (1
(S, 4S) -Trichloro-1,4-dihydroxycyclopent-1-carboxylic acid is obtained. Thus, (4R) -3-chloro-4-silyloxy-2-cyclopenten-1-ones were obtained in three steps. However, this method has a low yield from compound (6) to compound (7),
A complicated operation of fractional recrystallization using an expensive reagent called brucine is required. Compounds (10) and (1)
1) is extremely unstable. From the above, it has been very difficult to obtain a large amount of optically active 3-chloro-4-silyloxy-2-cyclopenten-1-one, which is an important synthetic intermediate for pulagrangins. DISCLOSURE OF THE INVENTION The present inventors have produced an optically active 3-chloro-4-silyloxy-2-cyclopenten-1-one which is a useful synthetic intermediate for pulagrangins at low cost. As a result of intensive studies on a method that can be manufactured in a specific manner, the present invention has been achieved. In the present invention, cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol represented by the formula [I] is represented by the following formula: (In the formula, R ¹ represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and stereoisomers derived therefrom exist. In the present invention, (1S, 4)
R), (1R, 4S), or a mixture of both in any proportion. ) By oxidation of the formula [II
I], embedded image (Wherein, R ¹ represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and a stereoisomer derived therefrom exists. 4S, or a mixture of both in any proportion.)
The 3-chloro-4-silyloxy-2-cyclopenten-1-one represented by the formula can be efficiently produced. In the compounds [I] and [III], R ¹ represents a silyl group which is a protecting group for a hydroxyl group, and specific examples thereof include trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl and (phenyldimethylmethyl). ) Dimethylsilyl, (triphenylmethyl) dimethylsilyl, tert-butyldiphenylsilyl, methyldiisopropylsilyl, methylditert-butylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triisopropylsilyl, triphenylsilyl and the like. Of these, tert-
Butyldimethylsilyl is particularly preferred. The oxidation reaction from compound [I] to [III] is carried out by using pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) and adding molecular sieves in methylene chloride or dimethylformamide if necessary. Can be done. P
CC or PDC is used in an amount of 1 to 7 moles, preferably 2 to 4 moles, per mole of the cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol represented by the formula [I]. It is. Whether to use PCC or PDC is appropriately selected depending on the stability of the silyl protecting group. When DMF is used, the amount of solvent used is PD
It is preferably 3 to 10 times the volume of C. When methylene chloride is used, the volume is preferably 10 to 15 times the volume of PCC. When methylene chloride is used as the solvent, it is preferable to add molecular sieves 4A.
An equivalent to twice the amount of CC is preferred. The reaction temperature is preferably from 0 to 10 ° C. both when using PCC and when using PDC. The reaction time varies depending on the type of the silyl ether of the formula [I], but is usually in the range of 1 to 20 hours, preferably 1 to 5 hours. After completion of the reaction, an organic solvent for extraction, for example,
The reaction solution is diluted with diethyl ether, washed with water, dried and concentrated to dryness. The product obtained by drying is purified and separated by column chromatography or the like. Thus, the above formula [II
3-Chloro-4-silyloxy-2-cyclopenten-1-one, which is a useful compound in the synthesis of pulagrangins represented by I], can be obtained efficiently. In the present invention, from optically active (1S, 4R) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol, optically active (4R) -3-chloro-4-silyloxy-2-ol is obtained. Cyclopenten-1-ones are obtained. From (1R, 4S) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol, optically active (4S) -3-chloro-4-silyloxy-2 is obtained.
-Cyclopenten-1-ones are obtained. Natural pulagrangins are derived from (4R) -3-chloro-4-silyloxy-2-cyclopenten-1-one <Scheme 1
> Can be synthesized by the method described in
(4S) -3-Chloro-4-silyloxy-2-cyclopenten-1-ones are also important compounds. In the present invention, the compound of the formula [I] is a 3-acetoxy-5-silyloxy-1-chlorocyclopentene represented by the formula [II]: Wherein R ¹ is as defined above.
Can be asymmetrically hydrolyzed using a hydrolase. That is, cis-3-chloro-4-silyloxy-2-cyclopenten-1-ols can be obtained as either one of the cis isomers or as a mixture of both cis isomers in any ratio. it can. The trans-3-acetoxy-5-silyloxy-1-chloro-cyclopentene remains without hydrolysis. Examples of the hydrolase include animal esterases such as liver esterase, pancreatic esterase, and acetylcholinesterase, and plant esterases.Furthermore, microorganisms belonging to the following genera, lichens, and microorganisms such as algae can be obtained. Hydrolytic enzymes. Rhodotorula, Trichod
erma, Candida, Hansenula, Ps
Eudomonas, Bacillus, Nocard
ia, Achromobacter, Chromoba
cterium, Flavobacterium, Rh
izopus, Mucor, Aspergillus,
Alkaligenes, Toulopsis, Co
rynebacterium, Endomyces, S
accaromyces, Arthrobacterte
r, Helminthosporium, Brevib
acterium, Escherichia, Citr
obactor, Absidia, Micrococc
us, Pediococcus, Klebsiell
a, Geotrichum, Lactobacillu
s, Cryptococcus, Pichia, Aur
eobasidium, Actinomucor, En
terobacter, Microbacteriu
m, Penicillium, Schizophyll
um. The form of use of the hydrolase used may be a purified enzyme, a crude enzyme, an enzyme-containing substance, a culture solution of a microorganism, a culture, a cell, a culture broth, or a product obtained by treating them, if necessary. It can be used in various forms. Further, it can be immobilized on a resin and used as an immobilized enzyme. The asymmetric hydrolysis reaction is carried out by reacting 3-acetoxy-5-silyloxy-1-chloro-cyclopentene represented by the formula [II] with the above-mentioned hydrolase, preferably pig liver esterase, pig pancreatic lipase, Pseudomo.
Purified or Crude Enzyme from Aspergillus, Aspergillus
Purification or crude enzyme of the origin can be carried out usually in a buffer solution or a mixture of an organic solvent and a buffer solution, if necessary, by adding a surfactant and stirring vigorously. Further, optically active (1S, 4R) -cis-
3-chloro-4-silyloxy-2-cyclopentene-
When 1-ols are obtained, it is particularly preferable to use pig pancreatic esterase. When (1R, 4S) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol is obtained, pig liver is used. It is particularly preferred to use esterases. When a mixture of an organic solvent and a buffer is used, the organic solvent used is usually a water-soluble solvent, for example, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, acetonitrile and propionitrile. And the like can be used. As the buffer, a commonly used buffer such as sodium phosphate, potassium phosphate, and sodium citrate can be used. The reaction temperature is preferably −10 ° C. to + 30 ° C., and the reaction time is preferably 2 to 50 hours, but is not limited thereto. After completion of the reaction, the hydrolysis reaction solution is filtered, if necessary, extracted with an organic solvent such as methyl isobutyl ketone, ethyl acetate, diethyl ether, dichloromethane, and the like, and the organic layer is purified by concentrated column chromatography. Desired cis-3-chloro-4-silyloxy-
2-cyclopenten-1-ols can be obtained. In addition, cis-3-chloro-4-silyloxy-2-
The optical purity of the cyclopenten-1-ols was determined from the 400 MHz NMR spectrum of the corresponding α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) ester. Furthermore, the fact that trans-3-chloro-4-silyloxy-2-cyclopenten-1-ols were not mixed in the asymmetric hydrolyzate was also confirmed by MTPA.
The ester was confirmed by high performance liquid chromatography. The 3-acetoxy-5-silyloxy-1-chlorocyclopentene represented by the formula [II] can be synthesized by the method represented by <Scheme 3>. That is, a known method (JP-A-57-62236)
4-hydroxy-2-cyclopentene-
After acetylation of 1-one (12), addition of chlorine and HC
1 is eliminated to give 4-acetoxy-2-chloro-2-cyclopenten-1-one (14). Subsequently, reduction is performed with sodium borohydride in methanol in the presence of cerium trichloride to obtain 2-chloro-4-acetoxy-2-cyclopenten-1-ol. It can be obtained by converting the alcohol moiety to a silyl ether with a trialkylchlorosilane in the presence of a suitable base. Compounds (13), (14), (15) and Formula [I
I] 3-acetoxy-5-silyloxy-
1-chlorocyclopentenes are all stable compounds and can be obtained in good yield. Embedded image 3-acetoxy- represented by the formula [II]
5-silyloxy-1-chlorocyclopentenes have two asymmetric carbons at the 3- and 5-positions, and (3S, 5
R) and the cis form of (3R, 5S), and (3S, 5S)
And (3R, 5R) trans forms. <Scheme 3>
The 3-acetoxy-5-silyloxy-1-chlorocyclopentenes represented by the formula [II] obtained by the method described above are mixtures of these four stereoisomers. Hereinafter, the present invention will be described in detail with reference to examples. Reference Example 1 4-acetoxy-2-chloro-2-cyclopentene-1
-One 4-hydroxy-2-cyclopenten-1-one 30.
2 g (0.308 mol) was dissolved in 1500 ml of THF, and 47.2 g (0.462 mol) of acetic anhydride and 50.5 g (0.616 mol) of sodium acetate were added.
Stir for 5 hours. 300 ml of cold water was added to the reaction solution, and extracted three times with 200 ml of ethyl acetate. The extract was washed with 100% 10% saline solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 37.9 g of 4-acetoxy-2-cyclopenten-1-one. This was dissolved in 540 ml of ether, and chlorine was blown in at room temperature. It took 90 minutes to complete the reaction. After blowing excess nitrogen to remove excess chlorine, triethylamine 100m
1 was slowly added dropwise at 5 to 15 ° C. 10% in the reaction solution
-500 ml of an aqueous ammonium chloride solution was added, and the mixture was separated. The aqueous layer was extracted twice with 300 ml of ether. The extract was combined with 10% -salt 300 ml, 2N-hydrochloric acid 500 ml,
It was washed with 300 ml of 10% saline solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 47.0 g of crude crystals of the desired product. Recrystallization from ether-hexane gave 27.0 g of colorless crystals. Yield 50%, melting point 55 ° C. NMR (CDCl ₃ ) δH = (60 MHz): 2.08
(3H, s), 2.36 (1H, dd, J = 2.0 a
nd 18.0 Hz), 2.93 (1H, dd, J =
6.4 and 18.0 Hz), 5.75 (1H,
m), 7.50 (1H, d, J = 3.0 Hz). IR (film) v (neat): 1740 (s), 1
610 (m), 1400 (m), 1378 (m), 13
46 (m), 1290 (m), 1240 (s), 117
0 (m), 1036 (m), 976 (m), 957
(M) cm- ¹ . Reference Example 2 3-acetoxy-5-tert-butyldimethylsilyloxy-1-chlorocyclopentene 4-acetoxy-2-chloro-2-cyclopentene-1
27.0 g (0.155 mol) of methanol
Dissolved in 50 ml. 63.7 g of cerous chloride
(0.171 mol), and 6.4 g (0.169 mol) of sodium borohydride was divided into several portions to give 22 to 2
Added at 5 ° C. After stirring at 20 to 23 ° C for 20 minutes, 150 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. 400 ml of 0.5 N hydrochloric acid was added to the concentrated residue, and the mixture was extracted three times with 300 ml of ether. The extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 22.4 g of 4-acetoxy-2-chloro-2-cyclopenten-1-ol. This is DMF2
Dissolved in 20 ml, tert-butyldimethylchlorosilane 24.0 g (0.159 mol), imidazole 1
3.0 g (0.191 mol) was added, and the mixture was stirred at room temperature for 5 hours. Add 1100 ml of water, and add 4
Extracted times. The extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 47 g of a pale yellow oil. Purification by silica gel column chromatography gave 32.3 g of the desired compound as a colorless oil.
(Yield: 71%) n ²⁴ _D = 1.4604. NMR (CDC
l ₃ ) δH = (60 MHz): 0.11 (6H, s),
0.91 (9H, s), 2.01 and 2.03
(3H, s), 4.50 and 4.82 (1H,
m), 5.17 to 5.77 (1H, m), 5.87 (1
H, m). IR (film) ν (neat): 1750 (s), 1
634 (m), 1480 (m), 1470 (m), 14
50 (m), 1370 (m), 1242 (s), 113
5 (m), 1082 (m), 1030 (m), 950
(M), 861 (m), 839 (m), 779 (m) c
m- ¹ . Reference Example 3 4-tert-butyldimethylsilyloxy-3-chloro-2-cyclopenten-1-ol 3-acetoxy-5-tert-butyldimethylsilyloxy-1-chlorocyclopentene 30.0 g (0.1
03 mol) was dissolved in 600 ml of methanol. pH
= 7, 1800 ml of phosphate buffer, pig pancreatic lipase 1
5.0 g was added, and the mixture was stirred at 15 ° C. for 12 hours. The hydrolyzate was extracted three times with 1000 ml of ether and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 29.0 g of a colorless oil. Purified and separated by silica gel column chromatography, the raw material acetate and cis (1R, 4
21.2 g of a mixture with the raw material acetate of S) was recovered.
6.4 g of the desired cis (1S, 4R) compound was obtained as a colorless oil. [0034] Yield 25.0%. [Α] ²⁵ _D = −31.7 ° (C = 0.75, MeO
H) Optical purity = 95% ee or more. n ²⁵ _D = 1.4711. NMR (CDCl ₃ ) δH = (100 MHz): 0.1
3 (3H, s), 0.15 (3H, s), 0.93 (9
H, s), 1.61 (1H, t, J = 4.3 Hz),
1.74 (1H, t, J = 4.3 Hz), 2.80 (1
H, dt, J = 7.0 and 14.2 Hz), 4.
48 (1H, dd, J = 4.3 and 7.0 Hz),
5.94 (1H, d, J = 2.6 Hz). IR (film) ν (neat): 3370 (s), 1
630 (m), 1478 (m), 1467 (m), 13
65 (m), 1259 (s), 1172 (m), 113
2 (s), 1086 (s), 1030 (s), 1004
(M), 941 (m), 861 (s), 840 (s),
800 (m), 780 (m) cm ^-1 . Example 1 4-tert-butyldimethylsilyloxy-3-chloro-2-cyclopenten-1-one (1S, 4R) -cis-3-chloro-4 obtained in Reference Example 3.
-Tert-butyldimethylsilyloxy-2-cyclopenten-1-ol 5.10 g (20.5 mmol)
Was dissolved in 100 ml of DMF. After cooling to 5 ° C., 27.0 g (71.8 mmol) of pyridinium dichromate were added. Stirred at 5 ° C for 3 hours. 600 ml of water in the reaction solution
And extracted three times with 100 ml of hexane. The extract was washed with 10% saline and dried over magnesium sulfate.
After filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow oil. Purification and separation by silica gel column chromatography gave 4.61 g of the desired compound as a colorless oil (yield 91%). [Α] ²⁵ _D = + 16.2 ゜ (C = 1.
1, n-hexane) ⁿ ₂₄ D = 1.4734. [Θ] ²⁴ ₃₃₃ = -694
0. NMR (CDCl ₃ ) δH = (60 MHz): 0.16
(3H, s), 0.18 (3H, s), 0.93 (9
H, s), 2.37 (1H, dd, J = 2.2 and
17.6 Hz), 2.83 (1H, dd, J = 5.8)
and 17.6Hz), 4.78 (1H, default)
med, dd, J = 2.2 and 5.8 Hz),
6.19 (1H, d, J = 1.4 Hz). IR (film) v (neat): 1730 (s), 1
597 (m), 1474 (ω), 1360 (ω), 12
60 (s), 1230 (ω), 1180 (ω), 116
0 (ω), 1110 (s), 1060 (ω), 993
(Ω), 940 (m), 868 (m), 839 (s),
780 (m) cm ^-1 .

Claims (1)

(57) [Claims] Formula [I], embedded image (In the formula, R ¹ represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and stereoisomers derived therefrom exist. In the present invention, it is (1S, 4R) , (1R, 4S), or a mixture of both in any proportions.) Wherein cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol is oxidized. [III], embedded image (Wherein, R ¹ represents a silyl group which is a protecting group for a hydroxyl group, * represents an asymmetric center, and a stereoisomer derived therefrom exists. In the present invention, 4R or 4S,
Or a mixture of both in an arbitrary ratio. A method for producing 3-chloro-4-silyloxy-2-cyclopenten-1-one represented by the formula: