JP2627507B2 - Cis-3-chloro-4-silyloxy-2-cyclopenten-1-ols and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (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, 4R), (1R , 4S),
Or a mixture of both in an arbitrary ratio. The present invention relates to novel cis-3-chloro-4-silyloxy-2-cyclopenten-1-ols represented by the formula:

More specifically, a novel cis-3-compound represented by the formula [I], which can be a useful compound in producing punaglagrins having excellent anticancer and antiviral activities.
Chloro-4-silyloxy-2-cyclopentene-1-
About oars and their manufacturing method.

In recent years, punaglandin, a green prostaglandin substance, has been isolated from Telesto riisei collected on a boat bottom collected on Oahu.

[Monthly Pharmaceutical Affairs, Vol. 24, p. 41 (1986); Shoyer et al., The
Journal of American Chemical Society, Vol. 107, p. 2976 (1985)]. Its tertiary structure has recently been found to be represented by the following formula.

[See Noyori et al., The Journal of American Chemical Society 108, 5021 (1986); Yamada et al., The Journal of American Chemical Society 108, 5019 (1986)] It is known to have a carcinostatic action as a physiological action. [Fukushima Masanori et al., The 43rd Annual Meeting of the Cancer Society of Japan, p. 905 (1984); Advanced in Prostaglandin Thromboxane and Loit Corien Research, Vol. 15, p. 415 (1985), published by Leban Press (New York)] Regarding the synthesis of the compounds, the route shown in <Scheme 1> is known as a typical example.
[Noyori et al., The Journal of American Chemical Society, 108, 5021 (1986)] According to which, punaglandin ( 5 ) is an optically active (4R) -3-chloro-4-tert-butylmethylsilyloxy-2. -Cyclopenten-1-one ( 1 ), which is obtained by sequentially linking an ω side chain and an α side chain.

In addition, 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-chloro-4 in the synthesis of punaglandin ( 5 )
-Tert-Butyldimethylsilyloxy-2-cyclopenten-1-one can be said to be a very important synthetic intermediate of pulagrangins.

The present inventors have paid attention to such a point, and have considered optically active 3-chloro-4-silyloxy-2-cyclopenten-1-ones and 4-silyloxy-2-cyclopenten-1-ones.
As a result of intensive studies on the synthesis of ON, the present invention has been achieved.

Conventionally, optically active 3-chloro-4-silyloxy-2
As a method for synthesizing -cyclopenten-1-one, the method described in Tetrahedron Letters, Vol. 17, pp. 1539-1542 (1979) is known. <Scheme 2> That is, it is obtained from trichlorophenol ( 6 ).
3,5,5-trichloro-1,4-dihydroxycyclopent-
Converting 1-carboxylic acid ( 7 ) into a salt with (-)-brucine;
By fractional recrystallization of this salt, (1S, 4S) -trichloro-
This gives 1,4-dihydroxy-cyclopent-1-carboxylic acid. From this, (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 ), and requires a complicated operation of fractional recrystallization using an expensive reagent called brucine.

Compounds ( 10 ) and ( 11 ) are extremely unstable. As described 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 of pulagrangins.

The present inventors have proposed an optically active 3-chloro-4-silyloxy-2-, which is a useful synthetic intermediate for pulagrangins.
As a result of intensive studies on a method capable of industrially producing cyclopenten-1-one at low cost, the present inventors have reached the present invention.

That is, the formula, (Wherein, R ¹ represents a silyl group which is a protecting group for a hydroxyl group.) 3-acetoxy-5-silyloxy-1-
Asymmetric hydrolysis of chlorocyclopentenes using an enzyme, (In the formula, 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, (1S, 4R) or (1R, 4
S) or a mixture of both in any proportion. Cis-3-chloro-, a novel compound represented by the formula:
It can be 4-silyloxy-2-cyclopenten-1-ols.

This is then converted to a formula by oxidizing the alcohol moiety to a ketone using an oxidizing agent, such as pyridinium chlorochromate, or pyridinium dichromate. (In the formula, 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, it is 4R, 4S, or a mixture of both at an arbitrary ratio. This is a method for producing 3-chloro-4-silyloxy-2-cyclopenten-1-one represented by the following formula:

In the present invention, 3-acetoxy-5-silyloxy-1-chloro-cyclopentenes represented by the formula [II] can be synthesized by a method represented by <Scheme 3>.

That is, a known method [Publication of Japanese Patent Publication No. Sho 57-6223
6], the 4-hydroxy-2-cyclopenten-1-one ( 12 ) is acetylated, and then, after addition of chlorine and HC
1 is eliminated to give 4-acetoxy-2-chloro-2-cyclopenten-1-one ( 14 ). Subsequently, reduction is carried out 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 3-acetoxy- represented by the formula [II]
All 5-silyloxy-1-chlorocyclopentenes are stable compounds and can be obtained in good yield.

In the 3-acetoxy-5-silyloxy-1-chlorocyclopentenes represented by the formula [II], R ¹ represents a silyl group which is a protecting group for a hydroxyl group.

Specific examples of R ¹ include trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, (phenyldimethylmethyl) dimethylsilyl, (triphenylmethyl) dimethylsilyl, tert-butyldiphenylsilyl, methyldiisopropylsilyl,
Examples include methylditert-butylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triisopropylsilyl, triphenylsilyl and the like. Of these, tert-butyldimethylsilyl is particularly preferred.

3-acetoxy-5-silyloxy-1-chlorocyclopentenes represented by the formula [II] have 3-position and 5-position
There are two asymmetric carbons at the position, and there are cis-forms of (3S, 5R) and (3R, 5S) and trans-forms of (3S, 5S) and (3R, 5R). Formula [II] obtained by the method of <Scheme 3>
3-acetoxy-5-silyloxy-1- represented by
Chlorocyclopentenes are a mixture of their four stereoisomers.

When 3-acetoxy-5-silyloxy-1-chlorocyclopentene represented by the formula [II] is subjected to asymmetric hydrolysis using a hydrolase described below, it becomes one of the cis-form optically active forms. Alternatively, cis-3-chloro-4-silyloxy-2-cyclopenten-1-ols can be obtained as a mixture of both cis-forms in any ratio.

Trans-3-acetoxy-5-silyloxy-1-
Chloro-cyclopentenes remain without hydrolysis.

As hydrolases, for example, liver esterase,
Examples include animal esterases such as pancreatic esterase and acetylcholinesterase, and plant esterases, and further include hydrolases obtained from microorganisms belonging to the following genera, lichens, and algae.

Rhodotorula, Trichoderma, Candida, Hansenula, Pseudomonas, Bacillus, Nocardia, Achromobacter, Chromobacterium, Flavobacterium, Rhizopus, Mucor, Aspergillus, Alkaligenes, Torulopsis, Corynebacterium, Endomyces, Saccharomyces, Arthrobacter, Cihr, bacterium, bacterium, bacterium, Escher, bacterium, Eminus , Klebsiella, Geotrichum, Lactobacillus, Cryptococcus, Pichia Aureobasidium, Actinomucor, Enterobacter, Microbacterium, Penicillium, Schizophyllum.

In the present invention, the use form of the hydrolase used is a purified enzyme, a crude enzyme, an enzyme-containing substance, a microorganism culture solution, a culture, a bacterial 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 or the like and used as an immobilized enzyme.

The asymmetric hydrolysis reaction is performed by purifying 3-acetoxy-5-silyloxy-1-chlorocyclopentene represented by the formula [II] and the above-mentioned hydrolase, preferably pig liver esterase, pig pancreatic lipase, or Pseudomonas-derived. , Crude enzyme, purified from Aspergillus or crude enzyme,
Usually, in a buffer solution or a mixture of an organic solvent and a buffer solution, if necessary, a surfactant is added, followed by vigorous stirring.

Also, optically active (1S, 4R) -cis-3-chloro-4
When obtaining -silyloxy-2-cyclopenten-1-ols, it is particularly preferable to use pig pancreatic esterase, and (1R, 4S) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ols In the case of obtaining, it is particularly preferable to use pig liver esterase.

The organic solvent used when using a mixture of an organic solvent and a buffer is usually a water-soluble solvent, for example, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, and nitriles such as acetonitrile and propionitrile. 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 as necessary,
Extraction with an organic solvent such as methyl isobutyl ketone, ethyl acetate, diethyl ether, dichloromethane, and the like, and purification of the organic layer by concentrated column chromatography yielded the desired cis-3-chloro-4-silyloxy-2-cyclopentene-1. -Alls can be obtained.

Cis-3-chloro-4-silyloxy- described in Examples
The optical purity of the 2-cyclopenten-1-ols was determined from the 400 MHz NMR spectrum of the corresponding α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) ester.

Also, trans-3-chloro-4-silyloxy-2
The absence of -cyclopenten-1-ol during the asymmetric hydrolysis was confirmed by high performance liquid chromatography, also as an MTPA ester.

Novel cis-3-chloro-4 represented by the formula [I]
-Silyloxy-2-cyclopenten-1-ol is subjected to an oxidation reaction, and is an extremely important intermediate in the synthesis of pulagrangins, 3-chloro-4-silyloxy-2-cyclopentene represented by the formula [III] -1-ones are obtained.

Optically active (4R) -3-chloro-4-silyloxy-2-cyclopenten-1-one is derived from optically active (1S, 4R) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol. Kind is obtained.

Further, from (1R, 4S) -cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol, it is possible to obtain optically active (4S) -3-chloro-4-silyloxy-2-cyclopenten-1-one. Kind is obtained.

The natural type punaglandins are (4R) -3-chloro-4-
From silyloxy-2-cyclopenten-1-ones <
Although it can be synthesized by the method shown in Scheme 1>, (4S) -3-chloro-4-silyloxy-2-
Cyclopenten-1-ones are also important compounds.

The oxidation reaction from compound [I] to [III] can be carried out using pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC) in methylene chloride or dimethylformamide, if necessary, with addition of molecular sieves. it can.

The amount of PCC or PDC used is 1 to 7 times, preferably 2 to 4 times the molar amount of the novel cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol represented by the formula [I]. Is a mole.

Whether to use PCC or PDC is appropriately selected depending on the stability of the silyl protecting group.

When using DMF, the amount of the solvent used is three times as large as that of PDC.
10 volumes are preferred.

When methylene chloride is used as the solvent, 1
A volume of 0 to 15 times is preferred.

When methylene chloride is used as the solvent, it is preferable to add molecular sieves 4A, and the amount used is
An equivalent to twice the amount of PCC is preferred.

The reaction temperature is preferably 0 to 10 ° C. in both cases where PCC and PDC are used. The reaction time is determined according to the above formula [I]
The reaction is usually carried out for 1 hour to 20 hours, preferably 1 to 5 hours, although it depends on the type of silyl ether used. After completion of the reaction, the reaction solution is diluted with an organic solvent for extraction, for example, 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, 3-chloro-4-silyloxy-2-cyclopenten-1-one represented by the above formula and [III], which is a useful compound in synthesizing pulagrangins, can be efficiently obtained.

 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 of acetic anhydride was dissolved.
(0.462 mol) and 50.5 g (0.616 mol) of sodium acetate were added, and the mixture was stirred at 35 ° C. for 15 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 10% -brine (100 ml) 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 10
0 ml was slowly added dropwise at 5-15 ° 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 washed with 300 ml of 10% saline, 500 ml of 2N hydrochloric acid and 300 ml of 10% saline, 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 ) δ _H = (60 MHz): 2.08 (3H, s), 2.36 (1H,
dd, J = 2.0and18.0Hz), 2.93 (1H, dd, J = 6.4and18.0H)
z), 5.75 (1H, m), 7.50 (1H, d, J = 3.0 Hz).

IR (film) ν (neat): 1740 (s), 1610 (m), 1400
(M), 1378 (m), 1346 (m), 1290 (m), 1240
(S), 1170 (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 -one was dissolved in 750 ml of methanol. Cerous chloride (63.7 g, 0.171 mol) was added, and sodium borohydride (6.4 g, 0.169 mol) was added in several portions at 22 to 25 ° C. After stirring for 20 minutes at 20-23 ° C,
150 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. 400 ml of 0.5N-hydrochloric acid was added to the concentrated residue, and 300 ml of ether was added.
Extracted three times. 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 was dissolved in DMF (220 ml), and tert-butyldimethylchlorosilane (24.0 g, 0.159 mol) imidazole
13.0 g (0.191 mol) was added, and the mixture was stirred at room temperature for 5 hours. water
1100 ml was added, and the mixture was extracted four times with 200 ml of ether.

The extract was washed with brine and dried over magnesium sulfate. After filtering, 47 g of pale yellow oil was concentrated under reduced pressure.
Obtained. Purification by silica gel column chromatography gave 32.3 g of the desired compound as a colorless oil. (71% yield) n ²⁴ _D = 1.4604. NMR (CDCl ₃ ) δ _H (60 MHz): 0.11 (6H,
s), 0.91 (9H, s), 2.01and2.03 (3H, s), 4.50and4.82
(1H, m), 5.17 to 5.77 (1H, m), 5.87 (1H, m).

IR (film) ν (neat): 1750 (s), 1634 (m), 1480
(M), 1470 (m), 1450 (ω), 1370 (m), 1242
(S), 1135 (m), 1082 (m), 1030 (m), 950 (m),
861 (m), 839 (m), 779 (m) cm ^-1 .

Example 1 4-tert-butyldimethylsilyloxy-3-chloro-
-2-cyclopenten-1-ol 3-acetoxy-5-tert-butyldimethylsilyloxy-1-chlorocyclopentene 30.0 g (0.103 mol)
Was dissolved in 600 ml of methanol. 1800 ml of a phosphate buffer having a pH of 7 and 15.0 g of porcine pancreatic lipase were added, followed by stirring 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, trans raw material acetate and cis (3R, 4S)
21.2 g of a mixture of the raw material acetate was recovered. 6.4 g of the desired cis- (1S, 4R) compound was obtained as a colorless oil.

Yield 25.0%. [Α] ²⁵ _D = −31.7 ° (C = 0.75, MeOH) Optical purity = 95% ee or more. n ²⁵ _D = 1.4711.

NMR (CDCl ₃ ) δ _H (100 MHz); 0.13 (3H, s), 0.15 (3H,
s), 0.93 (9H, s), 1.61 (1H, t, J = 4.3Hz), 1.74 (1H, t,
J = 4.3Hz), 2.80 (1H, dt, J = 7.0and14.2Hz), 4.48 (1H,
dd, J = 4.3 and 7.0 Hz), 5.94 (1H, d, J = 2.6 Hz).

IR (film) v (neat); 3370 (s), 1630 (m), 1478
(M), 1467 (m), 1365 (m), 1259 (s), 1172
(M), 1132 (s), 1086 (s), 1030 (s), 1004
(M), 941 (m), 861 (s), 840 (s), 800 (m), 780
(M) cm ^-1 .

Production Example 2 4-tert-butyldimethylsilyloxy-3-chloro-
2-cyclopenten-1-one (1S, 4R) -cis-3-chloro-4-t obtained in Example 1
5.10 g (20.5 mmol) of ert-butyldimethylsilyloxy-2-cyclopenten-1-ol was dissolved in 100 ml of DMF. Cool to 5 ° C and add pyridinium dichromate 27.0
g (71.8 mmol) was added. Stirred at 5 ° C for 3 hours.
600 ml of water was added to 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 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 = -6940.

NMR (CDCl ₃ ) δ _H (60 MHz); 0.16 (3H, s), 0.18 (3H,
s), 0.93 (9H, s), 2.37 (1H, dd, J = 2.2and17.6Hz), 2.8
3 (1H, dd, J = 5.8and17.6Hz), 4.78 (1H, deformed, dd, J
= 2.2 and 5.8 Hz), 6.19 (1H, d, J = 1.4 Hz).

IR (film) v (neat); 1730 (s), 1597 (m), 1474
(Ω), 1360 (ω), 1260 (s), 1230 (ω), 1180
(Ω), 1160 (ω), 1110 (s), 1060 (ω), 993 (ω),
940 (m), 868 (m), 839 (s), 780 (m) cm ^-1 .

Claims (2)

(57) [Claims] 1. The formula: Cis-3-chloro-4-silyloxy-2 represented by the formula
-Cyclopenten-1-ols (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. 1S, 4R), (1R, 4S), or a mixture of both in any proportion.) 2. The formula: (Wherein, R ¹ represents a silyl group which is a protecting group for a hydroxyl group), wherein an ester represented by the following formula is hydrolyzed in the presence of an enzyme: (In the formula, 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, (1S, 4R) or (1R,
4S) or a mixture of both in any proportion. A method for producing cis-3-chloro-4-silyloxy-2-cyclopenten-1-ol represented by the formula: