JPH03220158A - Preparation of optically active carbacycline derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel method for producing an optically active ruhacytalline derivative represented by formula [VA-3].

OH011CH.

(In the formula, R2 means a lower alkyl group.) The optically active carbacycline derivative produced by this method has an excellent antiulcer effect, platelet aggregation inhibiting effect, or vasodilatory effect. It is extremely useful as an anti-ulcer agent, a therapeutic agent for arteriosclerosis, a therapeutic agent for angina pectoris, and a prophylactic and therapeutic agent for ischemic diseases of the brain or heart.

[Conventional technology]

Conventional methods for producing optically active carbacyclines include (i) a method for producing from optically active Corey lactone [A] CA Angew, Chem, Int, Ed, Engl.
20.1046 (1981): Tetrahedron
Letter, 24.3527 (1983)] (1
1) Method for producing from optically active key intermediates (:BF [C] etc.) [J, Org, Chem, 44.2880 (1979
); Chem, Pharm, Bull, 33.26
88 (1985)] (iii) Method of production by asymmetric synthesis (J, Chem, Soc, Chem,
Commuu, 267 (1987)).

R (In the formula, R represents a hydrogen atom, benzoyl group, p-nitrobenzoyl group, or p-phenylbenzoyl group, and R/ means a hydrogen atom, t-butyldimethylsilyl group, benzyl group, or trityl group.) Furthermore, the following four methods are known as methods for stereoselectively reducing the allyl alcohol moiety present in the ω button of prostaglandins from the corresponding α,β-unsaturated ketone.

(a) E. J. Corey et al. J. Am. Ch.
em, Soc,,94. 8616 (1972) (b)
H, Yamamoto et al., J, Org, Chem, and 1363 (1979) (C) R, Noyori et al.
J,A+++,[:hem,Soc,,101.584
3 (1979) (d) E. J. Corey et al. J. Am.
[1: hem, Soc,, 109. 7925 (198
7) [Problems to be solved by the invention] However, (i) all use expensive optically active foury lactone as a starting material, and have the disadvantages of requiring a large number of steps and not having a high total yield. It is hard to say that this is an industrially useful manufacturing method. (11) also requires a relatively multi-step process, the total yield is not high, and it cannot necessarily be said that it is an industrially useful production method. Furthermore, (iii) also has many problems as an industrial production method.

In addition, although the methods known as stereoselective reduction reactions of α, β-unsaturated ketones show relatively high selectivity, they all use expensive asymmetric ligands or require expensive reducing agents. In this respect, there are problems in using it as an industrial manufacturing method.

Furthermore, prostaglandins generally have poor crystallinity, and it is extremely difficult to isolate even a small amount of the desired optically active substance with high purity from a mixture containing various diastereomers. It is necessary to use sophisticated separation means, such as high performance liquid chromatography. However, separation using high-performance liquid chromatography is not necessarily an effective method for purifying large amounts of samples.
There are various problems with industrial manufacturing methods.

[Means to Solve the Problem 2] The present inventor investigated a short process method for producing optically active carbacitalin [V] using an inexpensively available aldehyde derivative as a starting material, and completed the present invention. reached.

The present invention is directed to racemic aldehyde derivatives represented by the general formula [] (wherein, R3 means a lower alkyl group). ) by reacting an optically active Wittig reagent represented by formula [■A] and CI[IB
] (In the formula, R' means a hydroxyl group protected by an organic silyl group, and R2 has the same meaning as above.) After preparing a diastereomer mixture of each enone compound, cerium (I[ ) in the presence of a salt, reducing with a borohydride compound to obtain the general formula [IVA-3] [IVA-Rco [rVB
-R] and [rVB-3]1OHCH.

(In the formula, R' and R2 have the same meanings as above.) A mixture of diastereomers of each allyl alcohol derivative represented by the formula is prepared and subjected to an asymmetric epoxidation reaction to form diastereomers [■Δ-R]. [rV B −R,]
This invention relates to a method for producing an optically active carbacycline derivative [VA-S], which comprises selectively epoxidizing the derivative, followed by removing a hydroxyl protecting group and then separating and purifying it.

The method of the present invention will be explained in more detail.

(a) First, a racemic aldehyde derivative represented by -Funazura [I] is reacted with an optically active Wittig reagent represented by general formula [n] to protect the hydroxyl group, thereby protecting the general formula [IIIA], [II[ A diastereomer mixture represented by [B] can be produced. - Ship warehouse [I]
The racemic aldehyde derivative represented by
It can be easily produced by the method described in Japanese Patent No. 156640. In addition, the optically active Wittig reagent indicated by the ship [IT] is a known compound, for example,
It can be easily produced by the method described in Japanese Patent No. 2-265279. - The reaction between Funako [N and the compound represented by the general formula [11] is carried out by the method described in JP-A-60-156640.

The protection of the hydroxyl group is carried out by a method well known to those skilled in the art, and the protecting group used is an organic silyl group, such as a trialkylsilyl group or a dialkylphenylsilyl group. Examples of the trialkylsilyl group include a trimethylsilyl group and a t-butyldimethylsilyl group. An example of the dialkylphenylsilyl group is a dimethylphenylsilyl group. Among these, t-
Butyldimethylsilyl group is used.

) Then, the diastereomer mixture represented by CIIIA], [I[[B], J, -L, Luch
Methods such as e EJ, ^m, Chem, Sac, ,
100.2226 (1978); J, Org.
Chem44, 2194 (1979)], in the presence of cerium (DI) salt, it was reduced with an inexpensive and safe boron hydride compound to produce EVVA-S, [rVA-R], [I
A diastereomeric mixture represented by [VB-R] and [IVB-3] can be obtained. The composition ratio of this mixture is [rvA-3]:[rvB-R]・
[TVAR]: [rVB-3]! ==9:9:
The ratio will be 1:1.

That is, according to the present method: - Shipyard [IA], 2 mB:
The 15-keto group in the compound shown in is reduced to the desired 15α-hydroxy group at a high rate, and the undesired 15β
The production of -hydroxy groups can be suppressed to approximately 1/10 of the production of 15α-hydroxy groups. This effect is thought to be produced by protecting the hydroxyl group with an organic silyl group, and when the reduction reaction is carried out without protecting the hydroxyl group, 15α-hydroxy groups and 15β-hydroxy groups are produced at approximately the same rate. Japanese Patent Publication No. 1-501390 discloses that a carbacycline intermediate product similar to the compound described in the present application (the hydroxyl group is protected) is subjected to the same reduction reaction as above to suppress the by-production of 15β-hydroxy group. b. Boron hydride compounds include sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, tetramethylammonium borohydride, and tetramethylammonium triacetoxyborohydride. Although sodium borohydride is also used, sodium borohydride is preferably used. Sodium borohydride is a compound [I[
IA], [I[0.5 to 1 for the mixture of [B]
Although 0 times the mole is used, it is sufficient to use 1 to 2 times the mole.

The cerium (m) salt is preferably cerium (I) chloride, which is industrially available at low cost, and is used in anhydrous or hydrated form. used.

As the reaction solvent, alcoholic solvents are generally used, but ethanol is preferred from the viewpoint of isomer ratio, and
Those water-containing solvents can also be used.

The reaction temperature is between -80 and 30°C, and is selected depending on the combination of reaction solvent and reducing agent used. For example, in the system of cerium chloride (III) - sodium borohydride - ethanol, the temperature is preferably -50 to -30°C, in terms of the isomer ratio, in the system of cerium chloride (III) - sodium borohydride - methanol. -80
~-60°C is preferred.

The reaction time is from a few minutes to 50 hours, depending on the choice of reaction temperature. After the completion of the reaction, by treating the reaction mixture with acid, the
A diastereomeric mixture represented by -R co, CIV B -S co can be obtained.

Although it is possible to separate a small amount of each diastereomer from the obtained diastereomer mixture using high performance liquid chromatography, it is extremely difficult to separate a large amount of the diastereomer. Therefore, in order to facilitate separation, the following measures are taken.

(C) Diastereomer mixture (both diastereomers are secondary allyl alcohols, and the configuration of the 15-position hydroxyl group is [rVA-3]; 15S,
[rVB-R; 15-R, [IVA-R]
;15-R1[rVB-R] ;15-3)
In contrast, the asymmetric ephokylation reaction of B, 5harpress et al. [j.

8m, Che+n, Soc,, 109.5765 (19
87) Apply ko. That is, epoxidation is carried out using t-butylhydroveroquinde in the presence of D-(-)-tartrate and tetraisopropoxytitanium. According to this method, one of the four diastereomers
Compounds with 5-R configuration [rVA-RE [rVB
-R] was selectively epoxidized, [TVB-5]
and the desired [IVA-5] is not epoxidized at all.

Examples of D-(-)-tartrate include D=(-)-dimethyl tartrate, D-(-)-dimethyl tartrate, D-(-
) Diisopropyl tartrate, D-(-)-di-t-tartrate
Butyl or the like is used, but D-(-)-diethyl tartrate or D-(-)-diisopropyl tartrate is preferably used.

As the reaction solvent, methylene chloride, 1,2-dichloroethane, toluene, isooctane, etc. are used, and isooctane or methylene chloride is preferably used.

D-(-)-tartrate and tetraisopropoxytitanium may be used in catalytic amounts (approximately 10% mole) in the reaction in the presence of molecular sieves, but D-(-
)-tartrate ester is used in approximately 10% excess relative to tetraisopropoxytitanium.

t-1+ hydroperoxide has the general formula [IVA-R″
At least a stoichiometric amount must be used for J[IVB-R]. The reaction temperature is not particularly limited, but in order to avoid side reactions, it is preferably between -40°C and around room temperature, and more preferably carried out under a stream of an inert gas such as argon or nitrogen. The reaction time varies depending on the amounts of D-(-)-tartrate, tetraisopropoxytitanium and t-butyl hydroperoxide, and the reaction temperature, but is usually 30 minutes to 50 hours.

After the reaction is complete, a solution of citric acid monohydrate dissolved in acetone is added to the reaction mixture, and the precipitated crystals are filtered out. The mother liquor is washed with sodium sulfite water, sodium thiosulfate water, etc., and the organic solvent is washed. By drying the layer and distilling off the solvent, the compound represented by the general formula [IVA-3] [IVB-5] and the general formula [rVA-R] [IVB-R
A reaction mixture of an epoxy compound of the compound represented by is obtained. D-(-)tartrate can be easily recovered by silica gel chromatography at this stage, and can also be recovered in good yield by column chromatography after subsequent deprotection.

Next, the hydroxyl protecting group is removed by a method well known to those skilled in the art.
A mixture of compounds represented by [VB-8] is obtained.

leaf Mouth HC1 (.

(In the formula, R2 has the same meaning as above.)-9 Formula [V
The epoxy bodies represented by A-R] and [VB-R] and the compounds represented by the general formulas [VA-3] and [VB-3l can be usually separated without using advanced separation means such as high-performance liquid chromatography. It can be easily separated and purified in large quantities using oven column chromatography. Furthermore - Funagura [V
A-5] and [VB-3] can be separated and purified by ordinary oven column chromatography as described above, and the desired optically active carbacycline [VA
-3] can be obtained.

As stated above, the present inventors have established a method for producing photochemically active carbacyclines that can be produced industrially for the first time by combining highly stereoselective reduction reactions of α,β-unsaturated ketones and asymmetric epoxidation reactions. I was able to do so.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference example 1 8-(2-methoxycarbonylmethoxyethyl)-3,
Synthesis of 4-epoxy-bicyclo[4,3,0]nonane 8-(2-methoxycarbonylmethoxyethyl)-bicyclo[4,3,0 cononer 3-ene 25° 1g, sodium tungstate dihydrate 825mg 5-phosphorus acid 625
mg, cetyltrimethylammonium bromide 450
mg, 28.8 g of 30% hydrogen peroxide solution and 25-mg of water were added to 240 mE of 1,2-dichloroethane, and the mixture was heated under reflux for 4 hours.
Allowed time to react. The reaction solution was cooled to room temperature, separated into 1
．． The 2-dichloroethane layer was washed with an aqueous sodium thiosulfate solution, then with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 26.7 g of an oil. This product was subjected to silica gel chromatography using ethyl acetate-n-hexane system to obtain 23.0 g of the target compound.

N M R (CDC1,) δppm :3.10 (s, IH) 3.1 1 (s, LH) 3.51 (t, 2H.

J = 6.6 Hz) 3.76 (s, 3H) 4.07 (s, 2H) Reference example 2 4-(2-methoxycarbonylmethoxyethyl)-1,
Synthesis of 2-di-formylmethylcyclopentane 8-(2-methoxycarbonylmethoxyethyl)-3,4-epoxy-bincro[4,3,0] obtained in Reference Example 1
Nonane 23. Og was dissolved in 18 d of dichloromethane and added to an aqueous solution of 20.7 g of metaperiodic acid dissolved in 100 ml of water under water cooling. The mixture was stirred in a nitrogen stream for 1 hour while cooling with water and then at room temperature for 4 hours to separate the layers. Extracted with dichloromethane 25, washed the dichloromethane layer with aqueous sodium thiosulfate, then washed with water, dried over magnesium sulfate, and distilled off the solvent under reduced pressure to obtain 27.8 g of oil. Chromatography was performed using ethyl acetate-n-hexane system to obtain 20.3 g of the target compound.

NMR(CDC1,)δppm: 3.50 (
t, 2HJ = 6.4 Hz) 3.75 (s, 3H) 4.06 (s, 2H) 9.7 4 (-CHO.

2H,) Reference Example 3 3-(2-methoxycarbonylmethoxyethyl)-6-
Synthesis of formyl-hydroxy-picyclo[3,3,0]octane 4-(2-methoxycarbonylmethoxyethyl)-12-di-formylethylcyclopentane obtained in Reference Example 2 8
．． 0g was dissolved in dichloromethane 53- under nitrogen atmosphere,
41 mg of piperidine and 16 mg of acetic acid were added under water cooling and reacted for 1 hour in a nitrogen stream.

Add 100% of a saturated ammonium sulfate aqueous solution to this,
The liquid was separated. The dichloromethane layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7.6 g of an oil. This product was subjected to silica gel chromatography using ethyl acetate-n-hexane system to obtain 5.4 g of the target compound.

NMR (CDCI) δ ppm: 3.5
63.76 4.09 9.77 (t, 2H.

6,6Hz) (s, 3H) (s, 2H) (-CHO.

IH) H Example ■ 3-(2-methoxycarbonylmethoxyethyl)-
Synthesis of 6-[:3-oxo-5(S)-methyl-1(E)-nonenyl]-7-hydroxybicyclo[3,3,O]octane Similarly to Reference Example 3, 4-(2-methoxy 20 g of (carbonylmethoxyethyl)-1,2-di-formylmethylcyclopentane was dissolved in 130 ml of dichloromethane under a nitrogen atmosphere.
100 mg of piperidine and 40 mg of acetic acid were added under water cooling, and the mixture was stirred for 1 hour.

3.0 g of 60% sodium hydride was suspended in 700 rJ of tetrahydrofuran, and (4S)-4- was suspended at room temperature.
Dimethyl methyl-2-oxooctylphosphonate20.
5g was dissolved in 32g of tetrahydrofuran and added, and the mixture was stirred for 1 hour. The above dichloromethane solution was added to this at room temperature and reacted for 2 hours. Brine and toluene were added to the mixture for extraction, the toluene layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 54.6 g of an oily substance. This product was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate as an eluent to obtain 19.1 g of the target compound as an oil.

NMR(CDCI)) δppm: 0.88 (m, 6H)
3. 54 (t, 2H.

J = 6.7 H2) 3.76 (s, 3H) 4.09 (s, 2H) 6.20 (d, IH.

J=16Hz) 6.74 (q, If-() According to HPLC analysis, (Is, 3R, 5S.

6R,7R)-3-(2-methoxycarbonylmethoxyethyl)-6-C3-oxo-5(S)methyl-1(E
)-nonenyl]-7-hydroxybicyclo[3,3,
O'l octane and (IR, 3S, 5R, 6S, 7S) -
3-(2-methoxycarbonylmethoxyethyl)-6-
The ratio with C3-oxo-5(S)-methyl-1(E)-nonenyl]-7-hydroxybicyclo(3,3,0]octane was 55.3 to 44.7.

■ 3-(2-methoxycarbonylmethoxyethyl)-
Synthesis of 6-[3-oxo-5(S)-methyl-1(E)-nonenyl)-7-t-butyldimethylsilyloxy-bicyclo[3,3,0]octane 3- obtained by method ① (2-methoxycarbonylmethoxyethyl)-6-[3-oxo-5(S)methyl-1(E
)-nonenyl]-7-hydroxybicyclo[3,3,
0] 15.8 g of octane and 76-g of dimethylformamide
to which 4.18 g of imidazole and 7.2 g of t-butyldimethylchlorosilane were added at room temperature, and the solution was dissolved in
Time reacted. The reaction solution was poured into 300 g of water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 22.5 g of an oily substance. This product was subjected to silica gel chromatography using ethyl acetate-n-hexane to obtain 18.8 g of the target compound.

N M R (CDCl2) δppm Knee 0.01
(s, 3H) 0.00 (s, 3H) 3.54 (t 2H.

J==6.8Hz) 3.76 (s, 3H) 4.08 (s, 2H) 6.12 (d, LH.

J = 16.5 H' z ) 6.70 (Q, LH) ■ 3-(2-methoxycarbonylmethoxyethyl)-
6-[3-hydroxy-5(S)-methyl 1 (E)
-nonenyl]-7-t-butyldimethylsilyloxy-
Synthesis of bicyclo[3,3,0]octane 3-(2-methothendicarbonylmethoxyethyl)-6-[3-oxo-5(S)-methyl-1(E)-
18 g of nonenyl]-7-t-butyldimethylsilyloxy-bicyclo[3,3,O]octane and 18 g of ethanol.
Cerium chloride 7 permanent 16
．． After 9 g was added and dissolved, it was cooled to -60°C.

Add 1.72 g of sodium borohydride, -50 to -
After reacting at 40° C. for 19 hours, adding 3% aqueous hydrochloric acid and raising the temperature to room temperature, the reaction solution was poured into brine and extracted with ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution and a saline solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the target compound 1.
7.0g was obtained.

According to HPLC analysis, 3-(2-methoxycarbonylmethoxyethyl)-6-C3(S)-hydroxy-5(
S)-Methyl-1(E)-nonenyl]-7-t-butyldimethylsilyloxy-bicyclo[3,3,0]octane and 3-(2-methoxycarbonylmethoxyethyl')
-6-(:3(R)-hydroxy-5(S)-methyl-
1(E)-nonenyl]-? -t-butyldimethylsilyloxy-bicyclo[3,3,0]octane ratio is 9
:1 is 1.

NMR(CDC1,) δppm:0.02
(s, 6H) 3.53 (t, 2H.

J = 6.9 Hz) 3.75 (s, 3H) 4.08 (s, 2H) 5.50 (m, 2H) O5i〈→　0)I　C1l.

■ (Is, 3R, 5S, 6R, 7R)-3
-(2-methoxycarbonylmethoxyethyl)-6-[
3(S)-hydroxy-5(S)-methyl-1(E)-
nonenyl]-7-hydroxybicyclo[3,3,03
Synthesis of octane - 5.2 g of (-)-diisopropyl tartrate was dissolved in 50 g of dichloromethane, and 14 Molecular Seams were dissolved in 4.5 g of diisopropyl tartrate.
9 g was added, and the mixture was cooled to -25°C under a nitrogen atmosphere. Add titanium (rV) isopropoxide 6°9-, -20
After stirring at ℃ for about 1 hour, obtained in ① (Is, 3R, 5S
, 6R, 7R)-3(2-methoxycarbonylmethoxyethyl)-6-[3(S)-hydroxy-5(S)-methyl-1(E)-nonenyl:]-]7-t-butyldimethylrinril Okinbicyclo 3,3.0] Octane 9.
8 g was dissolved in 25-dichloromethane and added.

Furthermore, 3.5-m dichloromethane solution of t-butyl hydroperoxide adjusted to 3M was added, and the solution was heated to 48°C at 20°C.
Time reacted.

A solution of 10.6 g of citric acid monohydrate dissolved in 50% acetone was added dropwise to stop the reaction, the precipitated crystals were filtered, the filter liquid was washed with aqueous sodium sulfite and aqueous sodium bicarbonate, and then,
After washing with water, drying over magnesium sulfate, and concentrating the solvent under reduced pressure, 13.2 g of an oily substance was obtained. This was subjected to silica gel chromatography on ethyl acetate-n using a beef sanitation system, and (Is, 3R, 5S, 6R, 7R
)3-(2-methoxycarbonylmethoxyethyl)-6
-[3(S)-hydroxy-5(S)-methyl-1(
E)-nonenyl]-7-t-butyldimethylsilyloxy-bicyclo[3,3,0]octane and a small amount of (is,
3R15S, 6R, 7R)-3-(2-methoxycarbonylmethoxyethyl)-6-N, 2-epoxy-3(R
)-hydroxy-5(S)-methyl-nonyl)-7-t
-butyldimethylsilyloxy-bicyclo[3,30]
Octane, and (IR, 3S, 5R, 6S, 75)-
3-(2-methoxycarbonylmethoxyethyl)-6-
[1,2-epoxy-3(R)-hydroxy-5(S)
-Methyl-nonyl]? -t-butyldimethylsilyloxy-bicyclo[3,3,01 octane and a small amount of (IR,
3S.

5R,6S,7S)-3-(2-methoxycarbonylmethoxyethyl)-6-C3(S)-hydroxy-5(S
7.4 g of a mixture with )-methyl-1(E)-nonenyl]=7-t-butyldimethylsilyloxy-bicyclo[:3,3.0]octane were obtained.

A 1/1/3 solution of water/methanol/acetic acid was added to 7.4 g of the mixture, and the mixture was reacted at room temperature for 15 hours, then poured into brine and extracted with ethyl acetate.

The extract was washed with aqueous sodium bicarbonate, then with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 8.8 g of oil. 8.7g of this was added to ethyl acetate-n
- Chromatography using silica gel in a hexane system was performed to obtain 2.2 g of the target compound.

According to HPLC analysis, only the target compound was detected (
IR,3S,5R,6S,7S)-3-(2-methoxycarbonylmethoxyethyl)-6-[3(R)-hydroxy-5(S)-methyl-1(E)-nonenyl]-7-
HumanroxybicycloC3,3,01 octane was not detected.

NMR(CDCl2) δppm: 0.88
(m, 6H)3.53 (t, 2H.

J=7Hz) 3.77 (s, 3H) 4.09 (s, 2H) 5.48 (m, 2H)

Claims (3)

[Claims] (1) General formulas [IVA-S] [IVA-R] [IVB-R] and [IVB-S] ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ [IVA-S] ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ [IVA-R] ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ [IVB-R] ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ [IVB-S] (In the formula, R^1 is protected by an organic silyl group The hydroxyl group
R^2 means a lower alkyl group. ) by subjecting the diastereomer mixture of each allyl alcohol derivative represented by asymmetric epoxidation reaction to the diastereomer [
General formula [VA-S] characterized by selectively epoxidizing [IVA-R] and [IVB-R], and then separating and purifying after removing the protecting group of the hydroxyl group ▲Mathematical formula, chemical formula, table, etc. A method for producing an optically active carbacycline derivative represented by ▼[VA-S] (wherein R^2 has the same meaning as above). (2) General formulas [IIIA] and [IIIB] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IIIA] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IIIB] (In the formula, R^1 is an organic silyl group Protected hydroxyl group,
R^2 means a lower alkyl group. ) of the diastereomeric mixture of each enone compound represented by cerium (I
II) In the presence of a salt, the general formulas [IVA-S], [IVA-R], [IVB-R] and [IVB] are reduced with a borohydride compound.
-S] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IVA-S] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IVA-R] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IVB-R] ▲ Mathematical formulas , chemical formulas, tables, etc. ▼ [IVB-S] (In the formula, R^1 and R^2 have the same meanings as above.) As a diastereomer mixture of each allyl alcohol derivative, an asymmetric epoxy The general formula [VA-S] is characterized by selectively epoxidizing the diastereomers [IVA-R] and [IVB-R] by subjecting them to a chemical reaction, and then separating and purifying them after removing the protecting group for the hydroxyl group. ] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [VA-S] (In the formula, R^2 has the same meaning as above.) A method for producing an optically active carbacycline derivative. (3) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] (In the formula, R^2 means a lower alkyl group.) The racemic aldehyde derivative represented by the general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^3 means a lower alkyl group.) After reacting with an optically active Wittig reagent, the hydroxyl group is protected, and the general formula [ IIIA] and [IIIB
] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IIIA] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IIIB] (In the formula, R^1 means a hydroxyl group protected by an organic silyl group, and R^2 has the same meaning as above), and then reduced with a borohydride compound in the presence of a cerium (III) salt to obtain the general formula [IVA-S] [IVA -R] [IVB-R] and [IVB-S] ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ [I
VA-S] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IVA-R] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IVB-R] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IVB-S] ( In the formula, R^1 and R^2 have the same meanings as above.) A diastereomer mixture of each allyl alcohol derivative represented by the above formula is prepared, and the diastereomer [IVA-R] is subjected to an asymmetric epoxidation reaction. General formula [VA-S] characterized by selectively epoxidizing and [IVB-R] and then separating and purifying after removing the hydroxyl protecting group ▲There are mathematical formulas, chemical formulas, tables, etc.▼[VA- A method for producing an optically active carbacycline derivative represented by S] (wherein R^2 has the same meaning as above).