JPS647063B2 - - Google Patents

Description

[Detailed description of the invention]

<Technical Field> The present invention relates to a novel method for producing 2,3-disubstituted-4-substituted cyclopentanones. More specifically, an enolate intermediate produced by conjugate addition reaction of an organocopper compound to 4-substituted-2-cyclopentynones, which are α,β-unsaturated ketones, is directly added to β,γ in the presence of an alkyl tin. - 2,3-disubstituted-4-substituted cyclopentane into which two types of substituents are introduced adjacent to the α and β positions of the original α,β-unsaturated ketone by reacting with an unsaturated compound This paper concerns a new method for producing non-alcoholic compounds. <Prior Art> Natural prostaglandins (hereinafter abbreviated as PG) are known as local hormones (autacoids) with high biological and pharmacological activity. We aim to develop new drugs by skillfully utilizing these physiological characteristics of PG.
Research is being conducted not only on the derivatives but also on various derivatives. A natural compound that is a typical compound of PGE and PGFs.
PGE ₂ , PGF ₂ 〓 has uterine smooth muscle contraction action,
It is offered as the most useful drug to promote labor. On the other hand, natural PGE ₁ is one of the type 1 prostaglandins, and is a compound with unique biological activities such as platelet aggregation inhibiting action and blood pressure lowering action.
It is a useful natural product that has recently been used as a therapeutic agent for peripheral circulation in medical production. Conventionally, many methods have been known in the area of PGE and PGF.
Bindra et al., Prostaglandin Synthesis;
Academic Press (JBBindra et al.
Prostaglandin Synthesis, Academic Press)
(1977)), representative methods include: (i) biosynthetic methods from arachidonic acid or dihomo-γ-linolenic acid (B. Samuelsson et al., Angewante Chemi International Edition in English); (Angev.Chem.Int.Ed.Engl.) 4 , 410 (1965)
(ii) Method via Corey lactone, which is a key intermediate (E.J.Corey et al., Journal of the American Chemical Society (E.J.Corey et al., J.Amer.Chem.Soc.)
397 (1970)) (iii) Method via 2-substituted-2-cyclopentenone, which is an important intermediate (CJSih et al., Journal of the American Chemical Society (CJSih et al., J.Amer.
Chem. Soc.) 97, 865 (1975)) (iv) Method for selectively reducing 5,6-dehydro PGE ₂ or PGFα (ES Ferdinandei et al., Canadian Journal of
Chemistry (ES Ferdinandi et al., Can.J.
Chem.), 49, 1070 (1971))
et al., Prostaglandin), 11, 377 (1976)). However, in these methods, it is difficult to obtain polyunsaturated fatty acids as raw materials using biosynthetic methods, and furthermore, the yield from these fatty acids is very low, and it is difficult to purify them from by-products. . The method of obtaining the starting material by chemical synthesis requires many steps to obtain the starting material, and on the other hand, even if the starting material is easily obtained, the production of prostaglandin from such a starting material still requires many steps. Therefore, there are drawbacks such as a very low overall yield. In recent years, in order to overcome these difficulties, a three-component coupling process method using a conjugate addition reaction to a 2-cyclopentenone system followed by an enolate trapping process has been devised as a direct synthesis method for the PG skeleton ((G.・G.Stock et al., Journal of the American Chemical Society (G.Stock et al.
J.Amer.Chem.Soc.), 97, 6260 (1975) KGUntch et al., Journal of the Organ Chemistry (KGUntch et al., J.Org.
(See Chem.) 44, 3755) However, these attempts have used low-molecular-weight compounds such as formaldehyde and trimethylsilyl chloride to capture enolates, and have achieved PG skeleton synthesis through chemical synthesis via the resulting key intermediates. It has the disadvantage that it requires multiple steps, and the overall yield is low. The present inventor has focused on these points and has found advantageous chemical synthesis methods for prostaglandins E and F, namely (i) using easily obtained starting materials, (ii) short reaction steps, and (iii) total yield. As a result of intensive research to find a synthetic method with advantages such as high yield, we found that from 7-hydroxyprostaglandin E, which can be obtained in high yield by one step reaction from protected 4-hydroxy-2-cyclopentenone. , by selectively removing the 7-position hydroxy group and optionally converting the functional group.
We found that PGE and PGFs can be obtained and have previously reported this separately. <Purpose of the Invention> The present inventors focused on the above-mentioned three-component coupled process method, and further developed a PG method that has a shorter reaction step and is more efficient.
As a result of intensive research on the construction of skeletons, 4-
The 2,3-disubstituted enolate intermediate produced by the conjugate addition reaction of an organocopper compound to substituted-2-cyclopentenones is directly alkylated with a β,γ-unsaturated compound in the presence of an alkyltin compound. The present invention was achieved by successfully producing -4-substituted cyclopentanones. Conventionally, there have been many attempts to construct a PG skeleton by alkylating enolates produced by conjugate addition reaction of organocopper compounds to α,β-unsaturated enones (especially 2-cyclopentenones) with halides. It has been done. Examples and explanations of reports related to this method include: (1) Tanaka et al., JP-A-50-96542 (July 31, 1975;
(filed on December 25, 1973) and Japanese Unexamined Patent Publication No. 1973-101337
(August 11, 1975; filed on January 21, 1974) G.E.T. Bosner et al., Tetrahedron Letters (GHPosner et al., Tetrahedron Letters)
2591 (1974), and G.H. Posner et al., Journal of the American Chemical Society (GHPosner et al., J.
Am.Chem.Soc.) 97, 107 (1974): In all of these reports, 2-cyclopentenone was conjugated with an organocopper compound and then alkylated with halides. There are only examples using model systems, and there are no examples regarding 4-substituted-2-cyclopentenones. (2) JW Patterson, JUNIA and JH Fleet, Journal of the Organ Chemistry (JW
Patterson, Jr. and JHFried, J.Org.Chem.),
39, 2506 (1974): In this report, the methodology was implemented with 2-cyclopentenone and 11-deoxyprostaglandin.
Although E ₁ was successfully synthesized, 4-substituted-2-
Descriptions and examples using cyclopentenones have not been reported. (3) G. Stork and M. Isope, Journal of the American Chemical Society (S. Stork and M. Isope, J. Am. Chem.
Soc.), 97, 6260 (1975): In this report, the enolate obtained by conjugate addition of an organocopper compound to 4-substituted-2-cyclopentanones was successfully captured with monomeric formaldehyde. However, alkylation reactions yielded negative conclusions. (4) JANoguez and LA Maldonado, Synthetic Communication
Communication), 6, 39 (1976); In this report, a lithium salt of cyanohydrin protected at the portion corresponding to the omega chain of prostaglandin was conjugately added to 2-cyclopentenone, and then captured with propargyl halides. It only introduces 11-deoxyprostaglandin derivatives, but does not describe anything about 4-substituted-2-cyclopentenones as organocopper compounds. (5) Earl Davis and KGUntch, Journal of the Organ Chemistry (R.Davis and KGUntch, J.Org.
Chem.), 44, 3755 (1979): In this report, the allyl halides of enolates produced by conjugate addition of organocopper compounds corresponding to the omega chain of prostaglandins to 4-substituted-2-cyclopentenones were proposed. It is discussed that various attempts have been made to achieve direct alkylation, but all have ended in failure. (6) A.G. Dickson and R.G.K. Theiler, Journal of the Chemical Society Perkin (A.J.
Dixon and RJKTaylor, J.Chem.Soc.
Parkin) I, 1407 (1981): In this report, we attempted the allylation of enolates produced from 2-cyclopentenone and organocopper compounds, which had been thought to be difficult to proceed, and
Although we succeeded in obtaining intermediates for the synthesis of deoxyprostaglandins, we also found that 4-substituted-2-
No attempts have been made with cyclopentenones. (7) Nishiyama et al., Tetrahedron Letters, 25, 223 (1984) and 25, 2487 (1984); In these reports, trimethylsilyllithium or methyllithiotrimethylsilyl acetate was conjugated to 2-cyclopentenone. After that, tributyltin chloride was added, and then the enolate was successfully alkylated with a propargyl bromide derivative, but there are no examples of its application to organocopper compounds or to 4-substituted-2-cyclopentenones. The above is the historical background of prostaglandin skeleton synthesis by alkylation of conjugated addition enolates of organocopper compounds.
Although the synthesis of -deoxy prostaglandin derivatives has been reported, there is no example in which a more physiologically active natural prostaglandin skeleton was successfully obtained from 4-substituted-2-cyclopentenones using this methodology. There are none. The present inventors were fully aware of this point, and as a result of intensive research to overcome this difficulty, they arrived at the present invention. <Structure and effects of the invention> In the present invention, the following formula [] [In the formula, R ² represents a tri(C ₁ -C ₇ ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] 4-substituted-2-cyclopentenones or their enantiomers or mixtures thereof in arbitrary proportions represented by the following formula [] R _B -Li ... [] [In the formula, R _B is substituted or unsubstituted] represents a _C2 - _C10 alkyl group or alkenyl group. ] An organic lithium compound represented by the following formula [] Cu-Q ... [] [wherein Q represents a halogen atom, a cyano group, a phenylthio group, or a 1-pentynyl group. [] [In the formula, R _{3 is} the same or different C ₃ - C ₇ cycloalkyl group] Alternatively, it represents a phenyl group, of which one R ₃ may be a halogen atom. Y represents a halogen atom or a triflate group. ] In _{the presence of} an alkyl tin represented by _the following formula [ _] It represents a halogen atom or a tosyl group, and Z represents an ethynylene group, a trans-vinylene group, or a cis-vinylene group. ] The following formula [] is characterized by reacting a β, γ-unsaturated compound represented by [In the formula, R ² represents a hydrogen atom, a tri(C ₁ -C ₇ ) hydrocarbon silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R _A represents a substituted or unsubstituted C ₁ -C ₆ represents an alkyl group,
R _B represents a substituted or unsubstituted C ₂ - C ₁₀ alkyl group or alkenyl group, Z is an ethynylene group,
Represents a trans-vinylene group or a cis-vinylene group. ] A 2,3-disubstituted compound represented by the formula and its enantiomer or a mixture thereof in any proportion
A method of making 4-substituted cyclopentanones is provided. The 4-substituted-2-cyclopentenones used as raw materials in the present invention are represented by the above formula []. In the above formula [], R ² represents a tri(C ₁ -C ₇ ) hydrocarbon silyl group or 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, tri(C ₁ -C ₄ )alkylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t
Preferred examples include diphenyl( _C1 - _C4 )alkylsilyl or tribenzylsilyl groups such as -butyldiphenylsilyl group. Among these, t-butyldimethylsilyl group is particularly preferred. Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl, 1-
Ethoxyethyl, 2-methoxy-2-propyl,
2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo[3,1, 0]hex-4-yl group. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-
ethoxyethyl, 2-methoxy-2-propyl),
(2-methoxyethoxy)methyl or 6,6-dimethyl-3-oxa-2-oxobicyclo[3,
1,0]hex-4-yl group is particularly preferred. Typical examples of such compounds include 4-hydroxy- represented by the above formula [] protected by the tri(C ₁ -C ₇ ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of the hydroxyl group.
2-cyclopentenones, their enantiomers, or mixtures thereof in arbitrary proportions can be cited as preferred. In the present invention, first, the above-mentioned 4-substituted-2-
This is carried out by subjecting cyclopentenones to a conjugate addition reaction with an organocopper compound obtained from an organolithium compound represented by the formula [] and a copper compound represented by the formula []. R _B in the organolithium compound of formula [] represents a substituted or unsubstituted C ₂ -C ₁₀ alkyl group or alkenyl group. Substituents in the substituted _C2 - _C10 alkyl group or alkenyl group include:
For example, lower alkyl groups such as methyl group, ethyl group, propyl group, butyl group; cyclopentyl group,
_C3 to _C7 cycloalkyl groups such as cyclohexyl groups; vinyl groups; lower alkoxy groups such as phenyl, methoxy, and ethoxy groups; or tri _{( C1} ~
C ₇ ) Hydrocarbon silyl groups or hydroxyl groups protected with groups that form an acetal bond with the oxygen atom of the hydroxyl group. Among the _C2 - _C10 alkyl groups or alkenyl groups which may be substituted with such substituents, examples of the _C2 - _C10 alkyl groups include ethyl group, propyl group, butyl group, isobutyl group, sec- butyl group,
Examples include t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc., and examples of the C ₂ to _{C 10} alkyl group include:
For example, vinyl group, 1-propenyl group, 1-butenyl group, 1-pentenyl group, 1-hexenyl group,
Examples include 1-heptenyl group, 1-octenyl group, 1-nonyl group, 1-decyl group, and (E) form, (Z) form.
Any stereoisomer may be used. Among these substituted or unsubstituted C ₂ -C ₁₀ alkyl groups or alkenyl groups, the following formula ['] is particularly preferable: In the formula, R ³ represents a tri(C ₁ -C ₇ ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] Examples include organic lithium compounds represented by the following.
The reason why the organolithium compound represented by formula [′] is particularly preferable is that it matches a part of the skeleton of natural prostaglandin, and R ³ in formula [′] is It has the same definition as R ² , and the same groups as exemplified for R ² are preferred. On the other hand, Q in the copper compound of formula [] represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, a cyano group, a phenylthio group, or a 1-pentynyl group. To obtain an organocopper compound from an organolithium compound of formula [] and a copper compound of formula [], for example, the literature GHPosner.Organic Reaction,
Vol.19, 1 (1972); Noyori et al., Tetrahedron Letters, 21, 1247
(1980), 23, 4057 (1982), 23, 5563 (1982), 24,
1187 (1983), 24, 4103 (1983), 25, 1383 (1984)
and Israel Journal of the Chemistry (Isr.J.Chem.), 24, 118 (1984). In the method of the present invention, a trivalent organic phosphorus compound such as a trialkylphosphine (e.g., triethylphosphine, tributylphosphine, etc.), a trialkylphosphite (e.g., trimethylphosphite, triethylphosphite, etc.) is used together with the organocopper compound. triisopropyl phosphite,
This conjugate addition reaction proceeds smoothly when using tri-n-butyl phosphite, hexamethylphosphorustriamide, triphenylphosphine, etc., but tributylphosphine and hexamethylphosphorustriamide are particularly preferably used. It will be done. The method of the present invention involves reacting a 4-substituted-2-cyclopentenone represented by the above formula [] with the above-mentioned organocopper compound in the presence of a trivalent organophosphorus compound and an aprotic inert organic medium. This will be implemented by 4-Substituted-2-cyclopentenones and the organocopper compound react in equimolar terms stoichiometrically, but usually 4-substituted-2-cyclopentenones 1
Based on moles, 0.5 to 2.0 times, preferably 0.8 to 1.5
The amount of the organic copper compound is preferably 1.0 to 1.3 times the amount by mole. The reaction temperature is -100°C to 20°C, particularly preferably -
A temperature range of about 78°C to 0°C is adopted. The reaction time varies depending on the reaction temperature, but is usually between -78°C and -20°C.
It is sufficient to react at a temperature of about 1 hour. The reaction is carried out in the presence of an organic medium. An inert aprotic organic medium is used that is liquid at the reaction temperature and does not react with the reaction reagents. Such aprotic inert organic medium includes:
For example, saturated hydrocarbons such as pentane, hexane, heptane, cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, tetrahydrofuran, dioxane,
Ether solvents such as dimethoxyethane and diethylene glycol dimethyl ether; other hexamethylphosphoric triamide (HMP), N,
Examples include so-called aprotic polar solvents such as N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), dimethyl sulfoxide, sulfolane, and N-methylpyrrolidone.
It is also possible to use a mixed solvent of two or more types of solvents. Further, as the aprotic inert organic solvent, the inert medium used for producing the organocopper compound can also be used as it is. That is, in this case, the reaction may be carried out by adding the 4-substituted-2-cyclopentenones into the reaction system in which the organocopper compound was produced. The amount of organic solvent used is sufficient as long as it allows the reaction to proceed smoothly, and the amount used is usually 1 to 100 times the volume of the raw materials, preferably 2 to 20 times the volume of the raw materials. The trivalent organic phosphorus compound can be present during the above-described preparation of the organic copper compound, and the reaction can also be carried out by adding 4-substituted-2-cyclopentenones to the system. In the method of the present invention, R _B , which is the organic group moiety of the organocopper compound, is added to the 3-position of the 4-substituted-2-cyclopentenone in the reaction system due to the previous operations, It is assumed that a so-called conjugated addition enolate is formed in which an anion is generated at the 2-position. In the method of the present invention, this conjugated addition enolate is reacted with a β,γ-unsaturated compound represented by the above formula [] in the presence of an alkyl tin represented by the above formula [], thereby achieving the desired 2,3-disubstituted-4-substituted cyclopentanones represented by formula [] are produced. R ₃ in formula [] represents the same or different C ₃ to C ₇ cycloalkyl group or phenyl group,
One of these R ₃ may be a halogen atom. Y
represents a halogen atom or a triflate group. Specific examples of alkyl tins represented by the above formula [] used here include tri(C ₃ -C ₇ ) Cycloalkyltin halide; triphenyltin chloride; di( _C3 - _C7 )cycloalkyltin halide such as dicyclohexyltin dichloride and dicyclopentyltin dichloride; diphenyltin dichloride such as diphenyltin dichloride and diphenyltin bromide; Halides; or triphenyltin triflate, tricyclohexyltin triflate, etc. Particularly preferred are triphenyltin chloride and tricyclohexyl chloride. In the β,γ-unsaturated compound represented by the above formula [], R _A represents a substituted or unsubstituted C ₁ to C ₆ alkyl group, X represents a halogen atom or a tosyl group, and Z represents an ethynylene group, a trans- Represents a vinylene group or a cis-vinylene group. Examples of substituents in the substituted _C1 - _C6 alkyl group include lower alkyl groups such as methyl, ethyl, propyl, and butyl; _C3 - _C7 cycloalkyl groups such as cyclopentyl and cyclohexyl; ; Alkenyl groups such as vinyl groups and allyl groups; aromatic groups such as phenyl groups; methoxy groups;
Lower alkoxy groups such as ethoxy groups; tri(C ₁
~ _C7 ) Hydrocarbon silyl group or hydroxyl group protected with a group that forms an acetal bond with the oxygen atom of the hydroxyl group; lower acyloxy groups such as acetoxy group and propionyloxy group; oxo group; and methoxycarbonyl group, ethoxycarbonyl group, A lower alkoxycarbonyl group such as a t-butoxycarbonyl group is preferred as a substituent that does not hinder the progress of the desired alkylation.
Examples of _C1 to _C6 lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group,
Examples include linear or branched ones such as t-butyl group, pentyl group, and hexyl group. _{Among such} ^propargyl halides ^, _the following _{formula [} '] phenyl group, substituted or unsubstituted
It represents a _C3 - _C10 cycloalkyl group or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, and X and Z are as defined above. ] The β,γ-unsaturated compound represented by the following is cited as the most preferred because the prostaglandin skeleton can be constructed as it is by the method of the present invention. In formula [′], R ¹ is a C ₁ to C ₁₀ alkyl group,
It represents a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl (C ₁ -C ₂ ) alkyl group. Examples of _C1 to _C10 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group,
Butyl group, isobutyl group, sec-butyl group, t-
Examples include linear or branched groups such as a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Substituents for substituted or unsubstituted phenyl groups include, for example, halogen atoms, protected hydroxy groups, _C2 - _C7 acyloxy groups, _C1 - _C4 alkyl groups optionally substituted with halogen atoms, halogen A _C1 - _C4 alkoxy group, a nitrile group, or a ( _C1 - _C6 ) alkoxycarbonyl group which may be substituted with an atom is preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the _C2 - _C4 acyloxy group include acetoxy group, propionyloxy group, butyloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group,
A caproyloxy group, an enantyloxy group, or a benzoyloxy group can be mentioned. C ₁ to _{C 4} optionally substituted with halogen atoms
Preferred examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, chloromethyl group, dichloromethyl group, and trifluoromethyl group.
Preferred examples of the C ₁ -C ₄ alkoxy group which may be substituted with a halogen atom include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a chloromethoxy group, a dichloromethoxy group, and a trifluoromethoxy group. I can give it to you. Examples of the ( _C1 - _C6 ) alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, and a hexyloxycarbonyl group. The substituted phenyl group has 1 to 1 substituents as described above.
You can have three, preferably one. Substituted or unsubstituted _C3 - _C10 cycloalkyl groups include saturated or unsaturated _C3 substituted or unsubstituted with the same substituents as mentioned above;
_-C10 , preferably _C5 - _C6 , particularly preferably _C6 groups, such as cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclohexenyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, etc. can. The substituted or unsubstituted phenyl (C ₁ -C ₂ ) alkyl group is one in which the phenyl group is substituted with the same substituent as mentioned above, or an unsubstituted benzyl group, α-phenethyl group, β-phenethyl group. can give. Further, in the β, γ-unsaturated compounds represented by formulas [] and [′], X is a halogen atom or a tosyl group. Such halogen atoms include chlorine atom, bromine atom, and iodine atom, but β, γ
- Considering the reactivity of unsaturated compounds, an iodine atom is most preferred. Further, in the formula, Z represents an ethynylene group, a trans-vinylene group, or a cis-vinylene group, and any of them is preferably used, but considering the skeleton of natural prostaglandins, a cis-vinylene group is most preferable, followed by a cis-vinylene group. An ethynylene group derivatized into a group is preferred. In the method of the present invention, the reaction between the conjugated addition enolate produced in the system and the β,γ-unsaturated compound is carried out within the reaction system in which the organocopper compound is conjugatedly added to the 4-substituted-2-cyclopentenone. The alkyltin compound is first added to the above formula [], which may be diluted with the above aprotic organic medium.
This is carried out by adding a β,γ-unsaturated compound represented by the formula (including the above formula [′]). It is assumed that the alkyl tin reacts in stoichiometrically equimolar amounts with the enolate produced by conjugate addition, and a new tin enolate is produced, but usually, the initially used 4-substituted-2-cyclo The amount is preferably 0.8 to 1.5 times, particularly preferably 1.0 to 1.2 times, per mole of pentenone. Reaction temperature is -100℃~0℃, preferably -78℃
A temperature range of about -20°C is used, and a reaction time of one hour or less is sufficient. In the method of the present invention, a β,γ-unsaturated compound represented by formula [] (including formula [′]) is then added to accomplish the object. The β,γ-unsaturated compound reacts with the enolate produced by conjugate addition in a stoichiometrically equimolar amount, usually 0.8 molar relative to the initially used 4-substituted-2-cyclopentenone. It is carried out using an amount of ~5.0 molar times, particularly preferably 10 to 2.0 molar times. Reaction temperature is -100℃~0℃, preferably -78℃
A temperature range of about -20°C is adopted. The reaction time varies greatly depending on the type of β, γ-unsaturated compound used and the reaction temperature, and the reaction is usually completed at -78°C to -30°C for about 1 hour to 50 hours. It is efficient to track and determine the end point using thin layer chromatography. In the process of the present invention, the alkylation reaction with a .beta., .gamma.-unsaturated compound is preferably carried out in the presence of the aforementioned aprotic polar solvent, especially hexamethylphosphoric triamide, which often gives good results. After the reaction, the usual means (post-treatment, extraction, washing, chromatography, distillation,
Alternatively, it can be separated and purified by a combination of these. Thus, 2,3- represented by the above formula []
Disubstituted-4-substituted cyclopentanones are obtained. Illustrative examples of specific examples of such compounds include formula [], formula [] (including [']), and formula [] ([']
Preferred examples include any combination of the groups exemplified above. Among them, the following formula ['] obtained by combining the organolithium compound represented by the formula ['] and the β, γ-unsaturated compound represented by the formula ['] [In the formula, R ¹ , R ² , R ³ and Z are the same as defined above] Among the 2,3-disubstituted-4-substituted cyclopentanones, Z is a derivative of a cis-vinylene group. is a particularly useful compound because it is a prostaglandin E ₂ skeleton itself, and a derivative in which Z is an ethylene group is also a particularly useful compound because it is a 5,6-dehydroprostaglandin E ₂ derivative skeleton, and the present invention The invention is significant in that it also provides a method for making such compounds. i.e. books 5 and 6
Prostaglandin (PG) E ₂ , E ₁ , using -dehydroprostaglandin E ₂ derivative as a starting material
The process of inducing each of F ₂ α, F ₁ α, D ₂ , D ₁ and I ₂ is illustrated as follows.

[Table] Reference Examples 1 to 5 specifically show some of the above induction reactions. Other conversion reactions have already been reported by some of the inventors. Furthermore, one feature of the method of the present invention is that all the reactions used proceed stereospecifically, and for this reason, starting materials having the configuration represented by the above formula [] ) is obtained, and from the enantiomer of the formula [], the enantiomer of the formula [] (including [']) is obtained, and it is a mixture in any proportion. From [], a mixture [] (including [']) that reflects the proportions will be obtained.
Furthermore, since the organolithium compound of formula ['] contains an asymmetric carbon, it has two types of optical isomers, and it includes any of the optically active forms or a mixture thereof in any proportion. Among these, the compound having the steric configuration represented by the above formula ['] has the same steric configuration as natural prostaglandins, making it a particularly useful stereoisomer. Another feature of the method of the present invention is that when two optically active starting materials (formula [] and formula []) are used as the dl form or a mixture of optical purity in arbitrary proportions, the synthesis route proceeds stereospecifically. intermediates and final products are diastereoisomers, and if one of the raw materials is optically active, each stereoisomer can be isolated as a pure product by separation at an appropriate step. It is in. EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto. Example 1 ( E )-1-iodo-3- t -butyldimethylsiloxy-1-octene (368.57)
593.1mg (1.61×10 ^-3 mol) t -butyllithium (1.87M)
1.72ml (3.22×10 ^-3 mol) Cuprous iodide (190.45)
306.6mg (1.61×10 ^-3 mol) Tri- n -butylphosphine (202.32, 0.812)
1.04ml (4.19×10 ^-3 mol) 4- t -butyldimethylsiloxy-2-cyclopentenone (212.36) 325.6mg (1.53×10 ^-3 mol) Ph ₃ SnCl (370.34, 95%)
627.6mg (1.61×10 ^-3 mol) ICH ₂ C≡C(CH ₂ ) ₃ COOCH ₃ (266.07)
814.2 mg (3.06×10 ^-3 mol) HMPA (179.20, 1.03) 2.80 ml (1.61×10 ^-2 mol) ( E )-1- in a 150 ml reaction tube purged with argon.
Take iodo-3- t -butylsiloxy-1-octene and 6 ml of dry ether, cool to -95°C and stir. t -Butyllithium was added thereto using a syringe, and the mixture was stirred at -95 to -78°C for 3 hours. Separately, a 30 ml eggplant-shaped flask was prepared, cuprous iodide was removed, the inside of the flask was heated and dried under reduced pressure, and then replaced with argon. 6 ml of dry THF and tributylphosphine were added to this, and the mixture was stirred at room temperature (23°C) to form a homogeneous solution. This was cooled to -78 DEG C., and the previously prepared vinyllithium solution was added all at once to the Hestin rest tube under argon pressure, and the container was further rinsed with 6 ml of dry THF. 10 at −78℃
After stirring for a minute, a THF solution (12 ml) of enone was added dropwise over 1 hour. The container was further rinsed with 1 ml of THF and stirred for 10 minutes. After adding HMPA (1.5 ml) and stirring for 30 minutes, a THF solution of Ph ₃ SnCl (2 ml) was added. After heating to -30℃, 1-iodo-6-carbomethoxy-2-hexyne
HMPA solution was added and stirred at -30°C for 4 hours and 30 minutes. Subsequently, after being allowed to stand at -27°C for 13 hours, a saturated ammonium chloride aqueous solution (20 ml) was added, and the mixture was shaken vigorously. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with ether (20 ml x 2). The ether layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure and subjected to silica gel column chromatography (Merck 7734, 50 g, 1:60 = ethyl acetate: hexane, 600 ml → 1:20 = ethyl acetate: hexane, 200 ml). 2 ; 542.1 mg (59.7%) IR (liquid film); 1746, 1246, 827, 767 cm ^-1 Example 2 ( E )-1-iodo-3- t -butyldimethylsiloxy-1-octene (368.37)
593.1mg (1.61×10 ^-3 mol) t -butyllithium (1.87M)
1.72ml (3.22×10 ^-3 mol) Cuprous iodide (190.45)
306.6mg (1.61×10 ^-3 mol) Tri- n -butylphosphine (202.32, 0.812)
1.04ml (4.19×10 ^-3 mol) 4- t -butyldimethylsiloxy-2-cyclopentenone (212.36) 325.6mg (1.53×10 ^-3 mol) Ph ₃ SnCl (370.34, 95%)
627.6mg (1.61×10 ^-3 mol) ( Z )-1-iodo-6-carbomethoxy-2-
Hexene (268.09) 1.231g (459×10 ^-3 mol) HMPA 2.80ml (1.61×10 ^-3 mol) ( E )-1- in a 150ml reaction tube purged with argon
iodo-3- t -butyldimethylsiloxy-1-
Take octene and 6 ml of dry ether, cool to -95°C and stir. To this, t-butyllithium was added using a syringe, and the mixture was stirred at -95 to -78°C for 3 hours. Separately, a 30 ml eggplant-shaped flask was prepared, cuprous iodide was removed, the inside of the flask was heated and dried under reduced pressure, and then replaced with argon. Add this to 6ml of dry THF
and tributylphosphine were added and stirred at room temperature (25°C) to form a homogeneous solution. This was cooled to -78°C and added to the vinyllithium solution prepared earlier in a stainless steel tube under argon pressure, and the container was further rinsed with 6 ml of dry THF.
THF solution of enone (12ml) after stirring for 10 minutes at -78℃
was added dropwise over 1 hour. The container was further rinsed with 1 ml of THF, added, and stirred for 10 minutes.
After adding HMPA (1.5 ml) and stirring for 30 minutes,
Ph ₃ SnCl in THF (2 ml) was added. After heating to -30℃, ( Z )-1-iodo-6-carbomethoxy-2
A solution of -hexene in HMPA was added and stirred at -30°C for 3 hours. Subsequently, after standing at -27℃ for 97.9 hours, saturated ammonium chloride aqueous solution (20ml) was added.
Shake vigorously. After separating the organic layer and the aqueous layer, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure and subjected to chromatography (Merck 7734 5 g, 1:5 = ethyl acetate:hexane) to remove highly polar substances (Bu ₃ P,
After removing Ph ₃ SnCl), the mixture was subjected to silica gel column chromatography (Merck 7734 50 g, 1:60 ethyl acetate:hexane, 780 ml → 1:20 ethyl acetate: hexane, 600 ml). 3~; 647 mg (71%) IR (liquid film); 1743, 1243, 1000, 964, 927, 828, 768 cm ^-1 Reference example 1 Acetylene compound 4 ~ (48.2 mg, 0.081 mmol) and synthetic quinoline (25 mg) were mixed with benzene (2.5 ml)
cyclohexane (2.5 ml), followed by 5
After adding %Pd-BaSO ₄ (25 mg), under hydrogen atmosphere.
After stirring at 25℃ for 3 hours, synthetic quinoline (50mg) and 5% Pd-BaSO ₄ (50mg) were added, and the mixture was stirred at 40℃.
Stirred for 4.5 hours. After the catalyst was filtered off, the mixture was washed with ethyl acetate, and the mixture was concentrated under reduced pressure. Silica gel column chromatography (8g,
After concentrating the collected fractions under reduced pressure, the residue was further left under vacuum pump vacuum (<4 mmHg) for 7 hours to produce PGE ₂ methyl ester 11,15-bis-t-butyl. Dimethylsilyl ether 5 (41.8 mg, 87%) was obtained. TLC; Rf 0.58 (ethyl acetate-hexane = 1:5) IR (liquid film); 1743, 1243, 1000, 964, 927, 828, 768 cm ^{-1 1} HNMR (CDCl ₃ ) δ; 0.03 and 0.06 (s, respectively) 12, SiCH ₃ ×4),
0.8−1.0 (m, 21, C−CH ₃ ×7), 1.2−1.5
(m, 8, CH ₂ × 4), 1.6−2.9 (m, 12,
CH ₂ CO×2, CH ₂ C=×2, CH×2, and
CH ₂ , 3.67 (s, 3, OCH ₃ ), 4.06 (m, 2,
CHO Si×2), 5.37 (m, 1, vinyl), 5.54
(m, 1, vinyl) [α] ²¹ _D ; -52.7゜ ( C 1.28, CH ₃ OH) This compound completely corresponded to the protected disilyl form of 11,15 derived from (-)- _PGE2 . . Reference example 2 Silyl derivative 5~ (40 mg, 0.067 mmol) was dissolved in anhydrous acetonitrile (8 ml), HF-pyridine (0.1 ml) was added at 0°C, stirred for 30 minutes at 24°C, and then dissolved again.
HF-pyridine (0.4 ml) was added and stirred for 3 hours. After pouring into saturated NaHCO ₃ aqueous solution (20 ml), the mixture was extracted with ethyl acetate three times (30 ml x 3). The mixture was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Toluene was added to remove the pyridine in the residue, and the mixture was further concentrated under reduced pressure. After leaving for a while under reduced pressure with a vacuum pump (<4 mmHg), silica gel column chromatography (2 g, ethyl acetate-hexane (1:
1) → (1:0) gradient) (-)
-PGE ₂ methyl ester 6 (24.1 mg, 98%) was obtained. TLC; 0.29 (ethyl acetate-cyclohexane-THF=
6:3:1) IR (liquid film); 3680-3080, 1744, 970cm ^{-1 1} HNMR (CDCl ₃ ) δ; 0.90 (t, 1, J = 6.5Hz, CH ₃ ), 1.1-2.9
(m, 20, CH ₂ CO × 2, CH ₂ × 5, CH ₂ ×
5, CH ₂ C = × 2, CH × 2), 3.08 (br, 1,
OH), 3.66 (s, 3, OCH ₃ ), 4.06 (m, 3,
CHO×2 and OH), 5.34 (m, 1, vinyl),
5.70 (m, 1, vinyl) ¹³ CNMR (CDCl ₃ ) δ; 14.0, 22.6, 24.7, 25.1, 26.6, 31.7, 33.5,
37.3, 46.1, 51.5, 53.7, 54.5, 72.0, 73.0,
126.6, 130.8, 131.5, 136.8, 174.0, 214.1 [α] ²² _D ; −71.7° ( C 1.043, CH ₃ OH) Reference example 3 Previously prepared diisobutylaluminum hydride (1 equivalent)/2,6-di-t-butyl-4
- To a toluene solution (0.192 Msoln, 2.24 ml, 0.43 mmol) of methylphenol (2 equivalents) was added a toluene solution (1 ml) of ketone body 4 (25.5 mg, 0.043 mmol) at -78°C. After stirring at -78℃ for 2 hours, the temperature was raised to -25 to -20℃.
The mixture was stirred for 3 hours. A saturated aqueous sodium hydrogen tartrate solution (10 ml) was added and the mixture was shaken vigorously. Extracted three times (20+10+10 ml) with ethyl acetate at room temperature, and the combined mixture was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Silica gel column chromatography (5g,
Ethyl acetate-hexane=5:1) to obtain alcohol 7 (23.5 mg, 92%, low polar component). TLC; Rf 0.29 (ethyl acetate-hexane = 1:5) IR (liquid film); 3640-3080, 1745, 1247, 1020, 970, 930,
830, 770 cm ^{-1 1} HNMR (CDCl ₃ ) δ; 0.02 and 0.05 (s, 12, SiCH ₃ ×4, respectively),
0.7−1.0 (m, 21, C−CH ₃ ×7), 2.1−3.5
(m, 20, CH ₂ CO, CH ₂ ×6, CH ₂ C≡×
2), CH×2), 3.69 (d, 1, J=8.3Hz,
OH), 3.67 (s, 3, OCH ₃ ), 4.00 and
4.24 (br, 3, CHO×3), 5.40 (m, 2, vinyl) [α] ²¹ _D ; +0.37° ( C 0.715, CH ₃ OH) Reference example 4 Acetylene compound 7 (28.7 mg, 0.048 mmol) was dissolved in benzene (1 ml) and cyclohexane (1 ml) was dissolved in cyclohexane (1 ml).
ml) and Lindlar's catalyst (28.7 mg), and the mixture was stirred at 22 to 23.5°C for 12 hours under a hydrogen atmosphere. The catalyst was filtered off, washed with ethyl acetate, and the mixture was concentrated under reduced pressure. Silica gel column chromatography (6g,
Ethyl acetate-hexane-benzene = 1:15:2)
Olefin compound 8 (23.2 mg, 81%) was obtained. TLC; Rf 0.32 (ethyl acetate-hexane = 1:5) IR (liquid film); 3610-3280, 1745, 1250, 1000, 970, 938,
830, 770 cm ^{-1 1} HNMR (CDCl ₃ ) δ; 0.03 and 0.05 (s, 12, SiCH ₃ ×4, respectively),
0.8−1.0 (m, 21, C−CH ₃ ×7), 1.2−2.4
(m, 20, CH ₂ CO, CH ₂ ×6, CH ₂ C=×2,
CH×2), 2.69 (d, 1, J=9.5H ₂ , OH),
3.67 (s, 3, OCH ₃ ), 4.05 (br, 3, CHO
×3), 5.40 (m, 2, vinyl) [α] ²³ _D ; +12.3° (C1.037, CH ₃ OH) The IR and ¹ HNMR spectra of 5 are (+)
-Completely coincided with those of the disilyl derivative derived from PGE ₂ α. Reference example 5 Silyl compound 8 ~ (21 mg, 0.035 mmol) was mixed with acetic acid (1
ml), H ₂ O (0.33 ml) and THF (0.1 ml) were added, and the mixture was stirred at 55°C for 1.5 hours. The mixture was transferred to a large container, toluene was added, and concentration under reduced pressure was repeated several times to remove acetic acid and H ₂ O. The residue was subjected to silica gel column chromatography (3 g, ethyl acetate-hexane (1:1) → (1:0) gradient), and (+)-PGF ₂ α methyl ester 9 (11 mg,
85%). TLC; Rf 0.2 (ethyl acetate-cyclohexane-TEF=
6:3:1) IR (liquid film); 3640-3040, 1738, 1435, 1160, 1116,
1042, 1020, 968, 858 cm ^{-1 1} HNMR (CDCl ₃ ) δ; 0.89 (t, 3, J = 6.5 Hz, CH ₃ ), 1.2-2.4
(m, 20, CH ₂ CO, CH ₂ ×6, CH ₂ C=×2,
CH×2), 2.57 (br, 1, OH), 3.29 (br,
1, OH), 3.69 (s, 3, OCH ₃ ), 4.03
(brm, 3, CHO x 3), 5.3-5.6 (m, 2,
Vinyl) ¹³ CNMR (CDCl ₃ ) δ; 14.0, 22.6, 24.8, 25.2, 25.6, 26.6, 31.8,
33.5, 37.3, 43.0, 50.5, 51.6, 55.8, 72.9,
73.0, 78.0, 129.1, 129.6, 132.6, 135.3,
174.3 [α] ²⁰ _D ; +31.4° ( C 0.423, CH ₃ OH) Spectrum of the compound (IR, ¹ HNMR,
¹³ CNMR, TLC) was completely consistent with (+)-PGF ₂ α methyl ester derived from (+)-PGF 2 _α .

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ² represents a tri(C ₁ -C ₇ ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] 4-substituted-2-cyclopentenones or their enantiomers or mixtures thereof in arbitrary proportions represented by the following formula [] R _B -Li ... [] [In the formula, R _B is substituted or unsubstituted] represents a _C2 - _C10 alkyl group or alkenyl group. ] An organic lithium compound represented by the following formula [] Cu-Q ... [] [wherein Q represents a halogen atom, a cyano group, a phenylthio group, or a 1-pentynyl group. [] [In the formula, R is the same or different _C3 to _C7 cycloalkyl group _or It represents a phenyl group, of which one R may be a halogen atom. Y represents a halogen atom or a triflate group. ] In _{the presence of} a hydrocarbon tin represented by _the following formula [ _] X represents a halogen atom or a tosyl group, and Z represents an ethynylene group, a trans-vinylene group, or a cis-vinylene group. ] The following formula [] is characterized by reacting a β, γ-unsaturated compound represented by [In the formula, R ² represents a hydrogen atom, a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R _A represents a substituted or unsubstituted C ₁ to C 7 ₆ represents an alkyl group,
R _B represents a substituted or unsubstituted C ₂ - C ₁₀ alkyl group or alkenyl group, Z is an ethynylene group,
Represents a trans-vinylene group or a cis-vinylene group. ] A 2,3-disubstituted compound represented by the formula and its enantiomer or a mixture thereof in any proportion
Method for producing 4-substituted cyclopentanones. 2 The organic lithium compound represented by the formula [] is the following formula [′] [In the formula, R ³ represents a tri(C ₁ -C ₇ ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] A method for producing 2,3-disubstituted-4-substituted cyclopentanones according to claim 1, which is an organolithium compound represented by: 3 The β, _{γ -} unsaturated compound represented by _the formula [] is the ^following formula _{[ ′} ^] group, substituted or unsubstituted phenyl group, substituted or unsubstituted
It represents a _C3 - _C10 cycloalkyl group or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, and X and Z are as defined above. ] A method for producing 2,3-disubstituted-4-substituted cyclopentanones according to claim 1 or 2, which is a β,γ-unsaturated compound represented by: 4. The 2,3-disubstituted-4 according to any one of claims 1 to 3, wherein X is an iodine atom.
- A method for producing substituted cyclopentanones. 5. Any one of claims 1 to 4, wherein the hydrocarbon tin is triphenyltin chloride or tricyclohexyltin chloride.
A method for producing 2,3-disubstituted-4-substituted cyclopentanones as described in 2. 6. 2,3-disubstituted-4-substituted cyclopentanones according to any one of claims 1 to 5, wherein the conjugate addition reaction is carried out in the presence of a trivalent organic phosphorus compound. Manufacturing method. 7. The 2,3-disubstituted-4-substituted cyclo compound according to any one of claims 1 to 6, which is reacted with a β,γ-unsaturated compound in the presence of hexamethylphosphoric triamide. Method for producing pentanones. 8 2,3-disubstituted-4- represented by formula []
Substituted cyclopentanones have the following formula [′] [In the formula, R ¹ , R ² , R ³ and Z are the same as defined above. ] The 2,3-disubstituted-4-substituted cyclopenta according to any one of claims 1 to 7, which is a 2,3-disubstituted-4-substituted cyclopentanone represented by Method for producing non-alcoholic products. 9. The method for producing 2,3-disubstituted-4-substituted cyclopentanones according to any one of claims 1 to 8, wherein Z is a cis-vinylene group. 10. The method for producing 2,3-disubstituted-4-substituted cyclopentanones according to any one of claims 1 to 8, wherein Z is an ethynylene group.