JPH053863B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes using propargylcyclopentanes. More specifically ^{, 6,7} -disubstituted- ₂ -hydroxy-3-methylenebicyclo [3.3. 0] Regarding the production method of octanes.

<Conventional technology> Carbacyclin is a prostaglandin (sometimes abbreviated as PG), which is a physiologically active substance in the body.
I ₂ (PGI ₂ ) is a prostaglandin I 2 analog in which the oxygen atom at the 6,9-1 position is substituted with a methylene group, and is a natural prostaglandin _{I 2 that} has an enol ether partial structure in the molecule. Comparatively, it is chemically stable, making it a useful compound as a pharmaceutical agent such as an antithrombotic agent. In recent years, isocarbacyclin, a type of double-bond isomer of carbacyclin, i.e., 9(O)-methano-Δ ^6(9a) -prostaglandin I class ₁ , has been shown to have the strongest platelet aggregation potential among its congeners. It was discovered that it exhibits an inhibitory effect, and its application as a pharmaceutical was expected [Ikegami et al., Tetrahedron Letters]
Letters), 33 , 3493 and 3497 (1983)].

Previously, the present inventors discovered such 9(O)-methanol-
6,7-Disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes useful as key synthetic intermediates of Δ ^6(9a) -prostaglandin I ₁ (isocarbacyclines) and their production method A patent application was filed. The outline is as follows.

According to this method, allyl alcohol (C) (6,7-
The yield is 50% and half of (A) is lost. This makes allyl alcohol (C) more efficient.
It is desired to develop a method for synthesizing (6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes).

<Problems to be Solved by the Invention> The purpose of the present invention is to solve 9(O)-methano- ^Δ6(9a) -prostaglandin I class ₁ (isocarbacyclines)
is a useful key intermediate for 6,7-disubstituted-2-
An object of the present invention is to provide an efficient method for producing hydroxy-3-methylenebicyclo[3.3.0]octanes.

We have found that 9(O)-methano-Δ ^6(9a) -prostaglandin I ₁ is a useful synthetic key intermediate (isocarbacyclines). 6,7-disubstituted-2
-Hydroxy-3-methylenebicyclo[3.3.0]
As a result of intensive research to find an efficient method for producing octanes, we found that by using specific propargylcyclopentanones and cyclizing them with a reducing agent, we were able to produce the desired 6,7-disubstituted-2-hydroxy The present invention was achieved by discovering that -3-methylenebicyclo[3.3.0]octanes can be efficiently obtained.

<Means for solving the problem> In the present invention, the following formula [] [In the formula, R ¹¹ and R ²¹ are the same or different and represent a tri(C ₁ to C ₇ ) hydrocarbon silyl group, and R ³
represents a hydrogen atom, R ⁴ is a straight or branched chain
It represents a _C3 - _C8 alkyl group, and n represents 0. ] A compound represented by the formula and its enantiomers or propargylcyclopentanes, which are mixtures thereof in arbitrary proportions, are subjected to a cyclization reaction using a reducing agent using a metal species, and are also subjected to a deprotection reaction if necessary. , the following formula [] [In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom or a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, and R ³ , R ⁴ and n are the same as defined above. ] A method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes, which is a compound represented by the following and its enantiomer or a mixture thereof in any proportion, is provided.

In addition, in the present invention, the following formula [] is used as a raw material for the above production method. Provided are compounds represented by the formula [wherein R ¹ , R ² , R ³ , R ⁴ and n are the same as defined above] and their enantiomers, or cyclopentanes which are mixtures thereof in arbitrary proportions.

In the above formula [], R ¹¹ and R ²¹ are the same or different and represent a tri(C ₁ -C ₇ ) hydrocarbon silyl group, and other examples include a group that forms an acetal bond with the oxygen atom of a hydroxyl group.

As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tri(C ₁ -C ₄ )alkylsilyl group such as t-butyldimethyl group, diphenyl(C ₁ -C 4 )alkylsilyl group such as t-butyldiphenylsilyl group, ₄ ) Preferable examples include an alkylsilyl group, a di(C ₁ -C ₄ )alkylphenyl group such as a dimethylphenyl group, and a tribenzylsilyl group. Tori (C ₁
~ _C4 ) Alkylsilyl, diphenyl ( _C1 ~ _C4 )
Alkylsilyl and phenyldi(C ₁ -C ₄ )alkylsilyl groups are preferred, and t-butyldimethylsilyl and trimethylsilyl groups are particularly preferred.

Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl group, 1
-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 6,6-dimethyl-3
-oxa-2-oxobicyclo[3.1.0]hex-4-yl group may be mentioned. 2-tetrahydropyranyl group, 2-tetrahydrofuranyl,
1-ethoxyethyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, 6,6-
Particularly preferred is dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl. Among them, 2-tetrahydropyranyl group is particularly preferred.

It is to be understood that these silyl groups and groups forming acetal bonds are hydroxyl protecting groups. These protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to form free hydroxyl groups useful as pharmaceuticals. Therefore, a hydroxyl protecting group having such properties can be used in place of a silyl group or a group forming an acetal bond.

In the above formula [], R ³ represents a hydrogen atom, but other examples include a methyl group or a vinyl group. In the above case [ ], R ⁴ represents a straight-chain or branched C ₃ -C ₈ alkyl group, but other examples include a straight-chain or branched C ₃ -C ₈ alkyl group containing an oxygen atom; a substituted or unsubstituted phenyl group; a substituted or unsubstituted phenoxy group; a substituted or unsubstituted _C3 - _C10 cycloalkyl group; or a _C1 - _C6 alkoxy group; Examples include a linear or branched _{C1-C5 alkyl group substituted with an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C3-C10 cycloalkyl group .} Straight-chain or branched _C3 - _C8 alkyl groups include propylo group, butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2- Methylpentyl group, 2-methylhexyl group, 2,2
-dimethylhexyl group and the like. Preferred are a butyl group, a benzyl group, a hexyl group, a heptyl group, a 2-hexyl group, a 2-methyl-2-hexyl group, a 2-methylbutyl group, and a 2-methylpentyl group. Examples of those containing an oxygen atom include a 2-methoxyethyl group and a 2-ethoxyethyl group.

Examples of straight-chain or branched _C3 - _C8 alkenyl groups that contain an oxygen atom include, for example, 1-butylvinyl, 2-propylaryl, 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4 -hexenyl, 1,4-dimethyl-3-pentenyl, 5-hebutenyl, 1-methyl-5-hexenyl, 6-methyl-5-heptenyl, 2,6
-dimethyl-5-heptenyl and the like are preferred.

Examples of the straight chain or branched C ₃ -C ₈ alkyl group which may contain an oxygen atom include 2-butyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3 -Pentynyl is preferred.

Substituted phenyl group, substituted phenoxy group, or
Examples of substituents for the _C3 to _C10 substituted cycloalkyl group include halogen atoms, protected hydroxyl groups (e.g. silyloxy groups, _C1 to _C6 alkoxy groups, etc.), _C1 to _C4 alkyl groups, etc. . C ₃ ～
Examples of the C ₁₀ cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group, and a cyclodecyl group. Cyclopentyl group and cyclohexyl group are preferred.

C ₁ to C ₆ alkoxy group, optionally substituted phenyl group, optionally substituted phenoxy group, or optionally substituted phenoxy group, or optionally substituted C ₃ to C ₁₀ cycloalkyl group Straight chain or branched chain C ₁ substituted with
In the _-C5 alkyl group, examples of the _C1 - _C6 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an itepropyloxy group, a butoxy group, a t-butoxy group, and a hexyloxy group. As the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted C ₃ to C ₁₀ cycloalkyl group, the substituents and the C ₃ to _{C 10} cycloalkyl group include the above-mentioned examples. The same thing can be mentioned. Examples of straight chain or branched _C1 - _C5 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group, etc. be able to. Among these, cyclohexyl,
phenyl, phenoxy, cyclopentyl metal,
Preferred examples include cyclohexylmethyl group. Note that the substituent may be bonded to any position thereof.

In the above formula [], n represents 0, but may be 1 as another example.

In the above formula [], R ¹ and R ² are the same or different and represent a hydrogen atom or a tri(C ₁ -C ₇ ) hydrocarbon silyl group, but other examples include a group that forms an acetal bond with the oxygen atom of a hydroxyl group. You can also give Here, the group that forms an acetal bond with the tri(C ₁ - _{C 7} ) hydrocarbon silyl group and the oxygen atom of the hydroxyl group is the above formula []
The same thing can be said for .

Examples of the metal species of the reducing agent used in the cyclization reaction using propargylcyclopentanes represented by the above formula [] include alkali metals such as lithium sodium and potassium, but sodium and lithium are particularly preferred. Further, examples of the metal species of the reducing agent include alkaline earth metals such as calcium and magnesium.
The amount of the alkali metal or alkaline earth metal to be used is 1.0 to 20.0 times, preferably 1.2 to 10.0 times, per mole of the propargylcyclopentane represented by formula [].

Such an alkali metal or alkaline earth metal reducing agent is used in the cyclization reaction as an anion radical solution. Liquid ammonia or naphthalene, 1-(N,
N-dimethylamino)-naphthalene or 4,
Ether solvents such as diethyl ether, tetrahydrofuran, and dimethoxyethane containing 4'-di-t-butylbiphenyl in an amount equal to or more than the alkali metal or alkaline earth metal are preferred;
Among these, tetrahydrofuran containing naphthalene or 4,4'-di-t-butylbiphenyl is most preferred. The amount used is sufficient as long as the reaction proceeds smoothly, and usually 1 to 100 times the volume, preferably 2 to 20 times the volume of the raw material compound is used.

Reaction temperature is -100℃~100℃, preferably -78℃
A temperature range of about -50°C, particularly preferably -78°C to 0°C is employed. Although the reaction time varies depending on the reaction temperature, the reaction is usually completed within several hours at -78°C to 0°C.

Zinc is also preferably used as a metal species used as a reducing agent. Such a cyclization reaction using zinc is usually carried out in the presence of trimethylchlorosilane and a base. The amount of zinc to be used is 1 to 50 times, preferably 10 to 30 times, per mole of the propargylcyclopentane represented by formula []. Furthermore, zinc activated with hydrochloric acid, copper, silver, mercury, etc. is used. Further, trimethylchlorosilane is used in an amount of 1 to 20 times, preferably 5 to 10 times, the amount of the compound represented by formula []. Moreover, 2,6-lutidine is preferably used as the base. The base is used in an amount of 1 to 10 times, preferably 1 to 5 times, the amount of the compound represented by formula [].

As the solvent for this cyclization reaction, ether solvents such as diethyl ether, tetrahydrofuran, and dimethoxyethane are preferred, and tetrahydrofuran is most preferred. The amount used should be sufficient for the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the raw material compound, preferably 2 to 100 times the volume of the raw material compound.
20 times the volume is used.

The reaction temperature is 1℃~100℃, preferably 20℃~80℃
A temperature range of about °C is adopted. The reaction time varies depending on the reaction temperature, but is usually 30 minutes at 20°C to 80°C.
The reaction is complete within 24 hours.

The product thus obtained can be taken out from the reaction system as a crude organism by quenching and extraction using saturated ammonium chloride water. The crude product can be purified, if desired, by purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization, or the like.

The product thus obtained by the cyclization reaction using zinc has the following formula [] It is a compound represented by the formula [wherein R ¹¹ , R ²¹ , R ³ , R ⁴ and n are the same as defined above], its enantiomer, or a mixture thereof in any proportion.

The 6,7-disubstituted-3- thus produced
As a method for hydrolyzing trimethylsilyl ether at the 2-position of methylene-2-trimethylsilyloxybicyclo[3.3.0]octanes to form a 2-hydroxy compound, a conventional trimethylsilyl ether cleaving reagent such as tetrabutylammonium fluoride (solvent tetrahydrofuran), p-toluenesulfonic acid (solvent methanol), potassium carbonate (solvent methanol), citric acid (solvent methanol),
It can be carried out using p-toluenesulfonic acid-pyridine (solvent methanol) or the like. That is, it can be converted into the desired compound by performing a reaction similar to the deprotection reaction described below.

Propargylcyclopentanes represented by formulas [] and [] and 6,7-disubstituted-2-
Hydroxy-3-methylenebicyclo[3.3.0]octanes at position 7 and 3' of position 6 (or
If the hydroxyl group is protected at the 4' position, it can be deprotected as necessary to form a free hydroxyl group.

When the protecting group of the hydroxyl group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, the removal of the protecting group of the hydroxyl group is carried out using a catalyst such as acetic acid, a pyridinium salt of p-toluenesmephonic acid, or a cation exchange resin, etc. This reaction is preferably carried out using water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, or the like as a reaction solvent.
The reaction usually takes place in the temperature range of -78°C to +30°C for 10 minutes to 3
It is held for about a day. In addition, the protecting group is tri(C ₁
~ _C7 ) In the case of hydrocarbon silyl groups, examples include acetic acid, tetrabutylammonium fluoride,
Cesium fluoride, hydrogen fluoride, pyridine-
It is carried out in the presence of hydrogen fluoride in a reaction solvent as described above at a similar temperature and for a similar time.

Furthermore, in the compounds represented by the above formulas [], [], [], the carbon atoms to which the cyclopentane ring and bicyclo[3.3.0]ectane ring themselves and the substituents bonded to these rings are asymmetric. Although stereoisomers exist depending on the environment, the present invention includes any stereoisomers, and mixtures of these stereoisomers in arbitrary proportions are also acceptable. Further, the compound represented by the formula refers to all of these stereoisomers and a mixture of these isomers in any ratio, but the most preferred is a compound having the stereostructure represented by the formula.

The propargylcyclopentane represented by the above formula [] used in this reaction is the following formula [] It can be obtained by oxidizing propargylcyclopentanes represented by the formula [wherein R ¹¹ , R ²¹ , R ³ , R ⁴ and n are the same as defined above]. Such oxidizing agents include manganese dioxide, chromic acid, N-halocarboxylic acid amide, oxygen, 2,3
-dichloro-5,6-dicyano-1,4-benzoquinone, dimethyl disulfoxide and the like, among which manganese dioxide, chromic acid (especially pyridinium chromate) and dimethyl sulfoxide are preferred. The amount of the oxidizing agent used is determined by the amount of cyclopentanes 1 represented by the formula []
0.8 to 20 times, preferably 1.0 to 10 times relative to the mole,
Particularly preferably, the oxidizing agent is used in an amount of 1.2 to 5 times the mole.

The reaction temperature varies greatly depending on the oxidizing agent used and is carried out in the temperature range of -78℃ to 120℃, and the reaction time also varies depending on the oxidizing agent and reaction temperature.The disappearance of raw materials is monitored using thin layer chromatography. is preferable.

The reaction is carried out in an organic medium, such as those exemplified in step 1, as well as N, N,
- Organic media such as dimethylformamide and acetone are also used as appropriate. The amount of organic medium used is 1 to 100 times the volume of the raw material, preferably 2 to 20 times the volume.

Post-treatment, separation, and purification can be performed in the same manner as described above.

The propargylcyclopentane represented by the above formula [] is the following formula [] [In the formula, R ¹¹ , R ²¹ , R ³ , R ⁴ and n are the same as defined above. R ⁵ represents a hydrogen atom or a trimethylsilyl group. ] The propargylcyclopentanes represented by the following can be obtained by a hydroboration reaction followed by an oxidation reaction, or further by selectively deprotecting R ⁵ when R ⁵ is a trimethylsilyl group. The hydroboration reaction can be carried out using conventional techniques. [Organic Reactions, Volume 13,
Chapter I, John, Wiley & Sons Ine. New York,
1963; New Experimental Chemistry Course, Synthesis and Reactions of Organic Compounds I, pp. 497-505, see Maruzen et al.] As a hydroboration test, diamylborane ((CH ₃ ) ₂
CHCH( _CH3 )BH), 9-borabicyclo [3.3.1]
Nonane (9-BBN), dicyclohexylborane,
Dialkylborane such as diisopinocamphenylborane and disubstituted borane such as catecholborane and dihaloborane can be used, but diamylborane and 9-borabicyclo[3.3.1]nonane (9-BBN) are preferably used. As the oxidizing agent used in the oxidation reaction following hydroboration, hydrogen peroxide-sodium hydroxide, methylamine oxide, air oxidation, etc. can be used, but hydrogen peroxide-sodium hydroxide is particularly preferred.
The amount of hydroboration reagent used is stoichiometrically equivalent to the cyclopentane represented by the formula [], and the reaction proceeds, but it is usually 0.5 to 5 times the mole of the starting material compound, preferably 0.8 to 2 times the mole amount is used. The reaction temperature is about -100°C to 50°C, preferably about -20°C to room temperature. The reaction time varies depending on the reaction temperature, but is usually about 10 minutes to 20 hours, preferably about 30 minutes to 5 hours. The reaction is usually carried out in the presence of an organic medium. The medium used is an inert aprotic organic medium that does not react with the reaction reagent, preferably an ether solvent such as tetrahydrofuran, diethyl ether, diglyme, or trigram, with tetrahydrofuran being particularly preferred. The alkylborane produced by the hydroboration reaction is usually not isolated, but is oxidized by adding an oxidizing agent directly to the reaction system to form the following formula ['] [In the formula, R ¹¹ , R ²¹ , R ³ , R ⁴ and n are the same as defined above. ] This leads to the alcohol form represented by . When hydrogen peroxide is used as an oxidizing agent, a base such as sodium hydroxide is used at the same time. Hydrogen peroxide can be used at any concentration, but concentrations around 30% are commonly used. The amount of hydrogen peroxide used is 0.5 to 0.5 of the hydroboration reagent used.
It is 50 times the molar amount, preferably 3 to 10 times the molar amount. Sodium hydroxide can be used as such or as an aqueous solution, but generally an aqueous solution with a concentration of 1 to 10 normal is used. The amount used is 0.5 to 50 times the mole of the hydroboration reagent, preferably 3
~10 times molar. The reaction concentration at this time is 0℃ ~
The temperature is 100°C, preferably 40°C to 70°C.
The reaction time is from 5 minutes to 5 hours, preferably
The duration is 20 minutes to 1 hour. When trimethylamine oxide is used as an oxidizing agent, it is usually used in an amount of 0.5 to 50 times, preferably 3 to 10 times, the amount of the hydroboration reagent.

The product thus obtained can be taken out from the reaction system as a crude product by quenching, extraction, etc. in accordance with a conventional method. The crude product can be subjected to column chromatography, thin layer chromatography, liquid chromatography,
It can be purified by purification means such as recrystallization.

The compound represented by the above formula [] can also be obtained by selectively deprotecting a compound represented by the above formula ['] in which R ⁵ is a trimethylsilyl group. This deprotection reaction of the acetylene terminal can be carried out by a conventional method [Silicon Reagents for Organic Synthesis].
Organic Synthesis），Reactivity and Structure
Concepts Organic Chemistry Volume 14, Chapter
9, Springer-Verlag, 1983] As deprotection reaction reagents, silver nitrate-ethanol-water, potassium cyanide-water, potassium hydroxide water, potassium fluoride-methanol, etc. are used.

The propargylcyclopentane represented by the above formula [] is the following formula [] [In the formula, R ¹¹ , R ²¹ , R ³ , R ⁴ and n are the same as defined before and after. ] A methylenating agent prepared from titanium tetrachloride-zinc-dibromomethane (see L. Lombardo et al., Tetrahedron Letters, Vol. 23, p. 4293, 1982),
It can be obtained by methylenation using a methylene agent prepared from titanium tetrachloride-zinc-diiodomethane (see Hajime Nozaki et al., Tetrahedron Letters, Vol. 26, p. 5581, 1985) or other methylenating agents. .

The methylenating agent prepared from titanium tetrachloride-zinc-diprommethine is diprommethane 1.
per g, titanium tetrachloride 0.5g~2g, zinc 0.8~
A mixture consisting of 2.5 g of
It represents the product that was stirred and left at ℃ for 5 hours to 3 days.

Also, the methylenating agent prepared from titanium tetrachloride-zinc-diiodomethane is 1g of diiodomethane.
For that, titanium tetrachloride 0.1-0.2g, zinc 0.3-0.6
g in tetrahydrofuran at 25°C.
This represents the result of stirring for 30 minutes.

The reaction between the cyclopentanones represented by the above formula [] and the methylenating agent is carried out in the presence of an organic medium. A medium is used. Preferred examples of such a medium include halogenated hydrocarbons such as dichloromethane, dichloroethane, and tetrachloroethane. The amount of organic medium used should be sufficient to allow the reaction to proceed smoothly, and is usually 1 to 200 times the volume of the raw materials.
Preferably, 5 to 50 times the volume is used. The reaction temperature is -20°C to 70°C, preferably 0°C to 50°C. The reaction time is 10 minutes to 24 hours. The product thus obtained is quenched with saturated aqueous sodium bicarbonate and can be extracted from the reaction system by extraction or the like. The crude product can be purified by purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization, etc., if desired.

The propargyl cyclopentanones represented by the above formula [ ] were prepared according to the method of Noyori et al. (Yoji Noyori et al., Journal of American Chemical
Society, Vol. 107, p. 3348, 1985) and can be obtained by performing a three-component ligation reaction as shown below.

[In the formula, R ¹¹ , R ²¹ , R ³ , R ⁴ , R ⁵ and n are the same as defined before and after. ] The 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes represented by the formula [] obtained by the novel cyclization reaction have the antithrombotic properties mentioned above. It is useful as an intermediate for isocarbacyclin, which is useful as a pharmaceutical agent such as 9(O)-methano-Δ ^6(9a) -prostaglandin I class ₁ . That is, 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes of the formula [] (wherein R ¹ and R ² represent R ¹¹ and R ²¹ as defined above, respectively) reacts with an organolithium compound regioselectively at the γ-position of its allyl alcohol to form the above-mentioned isocarbacycline,
That is, it is a useful key intermediate capable of constructing the 9(O)-methano-Δ ^6(9a) -prostaglandin I ₁ skeleton.

<Examples> Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Examples 1 to 4 show examples of the cyclization reaction from the following formula [a] to the following formula [a].

Example 1 15 mg of metallic lithium and 266 mg of naphthalene were added to 7 ml of tetrahydrofuran and stirred at room temperature for 2 hours to prepare a dark green anion radical solution. Cool this to -50°C, and add a solution of 50 mg of [a] in 3 ml of tetrahydrofuran. After 5 minutes, the mixture was quenched by adding a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over magnesium sulfate, and concentrated the solvent under reduced pressure to obtain 346 mg of a crude product. This was subjected to silica gel column chromatography eluting with a mixed solvent of hexane-ethyl acetate 9:1 to obtain 34 mg of [a]. Yield 67%.

This [a] is the following [aα] 14mg and [aβ]
Consisting of 20mg.

Spectral data NMR (δ ^CDCI3 _TMS ) [aα] [aβ] Common 0.8 to 1.0 (21H, m) 3.5 to 4.2 (4H, br) 4.91 (1H, brs), 5.01 (1H, brs), 5.43 (2H, m ) Rf value (silica gel thin layer chromatography, developing solvent n-hexane-ethyl acetate 4:1) [aα] 0.43, [aβ] 0.30 Example 2 15 mg of metallic lithium, 553 mg of 4,4'-di-t-butylbiphenyl, and tetrahydrofuran 5ml at 0℃
Stir for 18 hours to prepare a dark green anion radical solution. Cool this to -50℃ [a] 50.6
Add a solution of 1.0 mg in 3 ml of tetrahydrofuran. After 5 minutes, quench, post-process and purify in the same manner as in Example 1,
Obtained 30 mg of [a] (11 mg of [aα], 19 mg of [aβ]. Yield 59%.

Example 3 An anion radical solution is prepared by stirring 14 mg of sodium metal, 85 mg of naphthalene, and 2 ml of tetrahydrofuran at room temperature for 2.5 hours. After cooling this to -170°C, a solution of 51 mg of [a] in 1.2 ml of tetrahydrofuran was added. After stirring at -70℃ for 1 hour, quenching with saturated ammonium chloride water, post-treatment and purification in the same manner as in Example 1, [a] 25 mg ([aα] 7
mg, [aβ] 18 mg). Yield 42%.

Example 4 A flask containing 28 mg of metallic sodium was cooled to -70°C under a nitrogen gas atmosphere, and about 7 ml of liquid ammonia was added.
The solution was taken and concentrated while stirring. -45℃〔a〕
A solution of 51 mg in 3.5 ml of tetrahydrofuran was added thereto, and the mixture was stirred for 50 minutes. After that, 432 mg of sodium benzoate was added, and the mixture was stirred at room temperature for 20 minutes and ammonia was vaporized. After adding water and extracting twice with ether, the organic phase was extracted with saturated sodium bicarbonate solution, saturated ammonium chloride solution,
After washing with brine and drying over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 48 mg of a crude product.
By silica gel column chromatography, n
Elution was performed with a mixed solvent of -hexane-ethyl acetate 97.5:2.5 to obtain 10 mg of [a] ([aβ] only).
Yield 20%.

Examples 5 to 8 show examples of obtaining [a] through a cyclization reaction from the following formula [a] to the following formula [a].

Example 5 Zinc powder is stirred in 10% hydrochloric acid for 5 minutes. After removing the supernatant by decantation, wash with water (1 time), acetone (3 times), and ether (2 times), and then evaporate in vacuum for 2 times.
Activated by drying for an hour. Add 138 mg of this zinc powder to [a] 53 mg and add 68 mg of trimethylchlorosilane.
1 ml of tetrahydrofuran is added, and 32 mg of 2,6-lutidine is added, and the mixture is heated under reflux for 4 hours. Decantation separates solids and liquids,
10 ml of diethyl ether was added to the liquid side. The organic phase was washed with saturated aqueous potassium hydrogen sulfate, saturated aqueous sodium bicarbonate, and brine in this order, dried over magnesium sulfate, and then the solvent was removed under reduced pressure. The crude product containing [a] thus obtained was dissolved in 3 ml of methanol, a small amount of pyridine p-toluenesulfonate was added, and the mixture was stirred at room temperature for 10 minutes. Saturated sodium bicarbonate solution is added thereto, methanol is concentrated under reduced pressure, and then ether extraction is performed. The organic phase was washed with brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The crude product was eluted with silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate of 19:1 to obtain 11.8 mg of [a]. Yield: 23% Example 6 Zinc dust is stirred with 3% hydrochloric acid for 1 minute. Repeat this wash 4 times. After washing 5 times with distilled water, washing twice with 2% copper sulfate aqueous solution, then with distilled water (5 times),
Absolute ethanol (4 times), diethyl ether (5 times)
The mixture was washed in the order of 3 times), filtered through a glass filter under a stream of nitrogen gas, and activated by drying under reduced pressure for 4 hours.

To 53 mg of [a] were added a solution of 138 mg of this zinc powder and 68 mg of trimethylchlorosilane in 1 ml of tetrahydrofuran, and 32 mg of 2,6-lutidine, and the mixture was heated under reflux for 4 hours.

The same post-treatment, desilylation and purification as in Example 5 were carried out to obtain 16 mg of [a]. Yield 31%.

Example 7 350 mg of zinc powder was stirred with 10% hydrochloric acid for 4 minutes, and then the supernatant was removed by decantation. After washing with acetone and ether in that order, a 1.7 ml suspension of 12 mg of silver acetate in boiling acetic acid was added and stirred for 1 minute. After removing the supernatant with a syringe, it was washed with 1 ml of acetic acid, 2 ml of ether (3 times), 2 ml of methanol, 2 ml of ether (4 times), and 2 ml of tetrahydrofuran (4 times), followed by activation by drying in vacuum for 3 hours. .

To 53 mg of [a] were added a solution of 138 mg of this zinc powder and 68 mg of trimethylchlorosilane in 1 ml of tetrahydrofuran, and 32 mg of 2,6-lutidine, and the mixture was heated under reflux for 4 hours. Post-treatment similar to Example 5, desilylation,
After purification, 18 mg of [a] was obtained. Yield: 34% Example 8 4.12 g of zinc powder was stirred with 10% hydrochloric acid for 2 minutes, and the supernatant was removed. After washing with 5 ml of distilled water four times, a solution of 0.8 g of mercuric chloride was added to 5 ml of boiling water and stirred for 10 minutes. After removing the supernatant, add 5 ml of distilled water, 5 ml of ethanol (7 times), and 5 ml of ether.
(7 times). Activated zinc was prepared by vacuum drying for 3 hours.

To 53 mg of [a] were added a solution of 138 mg of this zinc powder and 68 mg of trimethylchlorosilane in 1 ml of tetrahydrofuran, and 32 mg of 2,6-lutidine, and the mixture was heated under reflux for 4 hours. The same post-treatment, desilylation and purification as in Example 5 were carried out to obtain 17 mg of [a]. Yield 32%.

Next, an example of the oxidation reaction from the following formula [a] to the following formula [a] is shown in Reference Example 1.

Reference Example 1 5.05 ml of pyridine was dissolved in 50 ml of methylene chloride, 3.12 g of chromium trioxide was added, and the mixture was stirred at room temperature for 20 minutes. Here [a] 1.30g of methylene chloride 3ml
The solution was added and stirred at room temperature for 15 minutes. ether
150 ml was added and filtered through Celite to remove solids. The organic phase was washed with saturated potassium hydrogen sulfate solution, saturated sodium bicarbonate solution, and brine (twice) in this order. After drying over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 1.32 g of crude product. When this was purified by silica gel column chromatography, 1.01 g of [a] was obtained in the n-hexane-ethyl acetate (19:1) eluate.
Yield 77%.

NMR spectrum data of [a] δ ^CDCI3 _TMS : ppm 0.88 (21H), 2.87 (1H, m), 3.7−4.3 (2H, m), 5.43 (2H, m), 9.97 (1H, d, J=3HZ)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹¹ and R ²¹ are the same or different and represent a tri(C ₁ to C ₇ ) hydrocarbon silyl group, R ³ represents a hydrogen atom, and R ⁴ represents a straight or branched C ₃
- represents a _C8 alkyl group, and n represents 0. ] A compound represented by the formula and its enantiomers or propargylcyclopentanes, which are mixtures thereof in arbitrary proportions, are subjected to a cyclization reaction using a reducing agent using a metal species, and are also subjected to a deprotection reaction if necessary. The following formula [] [In the formula, R ¹ and R ² are the same or different and represent a hydrogen atom or a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, and R ³ , R ⁴ and n are the same as defined above. ] A method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes, which are a compound represented by the above, its enantiomer, or a mixture thereof in any proportion. 2. The method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to claim 1, wherein the metal used as the reducing agent is an alkali metal. 3 Claim 2 in which the alkali metal used as the reducing agent is sodium or lithium
6,7-Disubstituted-2-hydroxy-3- as described in
Method for producing methylenebicyclo[3.3.0]octanes. 4. 6, 7 according to claim 1, wherein the metal species used as the reducing agent is an alkaline earth metal.
-Production method of disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes. 5. The method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo[3.3.0]octanes according to claim 4, wherein the alkaline earth metal used as the reducing agent is calcium or magnesium. . 6. 6,7-Disubstituted-2 according to claim 1, wherein the metal species used as the reducing agent is zinc.
-Hydroxy-3-methylenebicyclo[3.3.0]
Method for producing octanes.