JPS61115044A - Preparation of 2,3-disubstituted-4-substituted cyclopentanone - Google Patents

Abstract

PURPOSE:To obtain efficiently the titled compound through a short process, by subjecting 4-substituted-2-cyclopentenones to conjugate addition reaction with an organo copper compound, followed by directly alkylating the resultant enolated intermediate with a BETA, gamma-unsaturated conpound in the presence of alkyltins. CONSTITUTION:4-Substituted-2-cyclopentenones expressed by formula I(R<2> represents trihydrocarbonsilyl group or group forming an acetal bonding together with O atom OH), its enantiomer or mixture thereof in any ratio is subjected to conjugate addition reactuion with an organocopper compound obtained from both an organolithium com pound expressed by formula II (RB is alkyl, etc.) and a copper compound expressed by formula II (Q represents halogen atom, cyano, etc.) preferably in the presence of an organic phosphorus, followed by being reacted with a BETA, gamma-unsaturated compound expressed by formula V (RA is alkyl; X is halogen, etc.; Z is ethynylene, etc.) in the presence of alkyltins expressed by formula IV (R represents cycloalkyl, etc.; Y represents halogen atom, etc.) to obtain the compound expressed by formula VI, its enantiomer or mixture thereof in any ratio. USE:A raw material for PGEs and PGFs.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field PGEt, PGF, and α have a uterine smooth muscle aphrodisiac action and are used as the most useful labor promoting agents. On the other hand, natural PGE1 is one of the l-type prostaglandins, and is a compound that has unique biological activities such as inhibiting platelet aggregation and lowering blood pressure, and has recently been used as a peripheral circulation treatment drug in medical practice. It is a useful natural product.

Many methods have been known in the field of PGE and PGF, including (J, B.

Bindra et al. + Prostaglandin 5y
nthe+sia+Academic Press (
(1977)), among which representative methods include: (1) A method of biosynthetically obtaining it from arachidonic acid or dihomo-r-lylunic acid (B).

Samuelsson et al. + Angev, Chem.
Int, Ed, Engl.

41410 (1965), (1) Method via the 111' intermediate Corey lactone (E, J, Corey et al. J, Amer.
, Chem.

Soc, 92,397 (1j70))
A method via the important intermediate 2-ffii-2-cyclobentenone (C, J, Sih et al.

J, Amer, Chem, Soc, +97 +865
(1975)) Rei 5,6-dehydro PGE, or PGF,
Selective Kj unidimensional method for α (E, S, Ferdina
ndi et al.

Can, J. Chsm, w49, 1070 (1971)
Reference) (C, H, Lin et al. + Proatagl
andine 1 1 * 3 7 7 (197
(see 6)).

However, in these methods, it is difficult to obtain polyunsaturated fatty acids as raw materials using biosynthetic methods, and the yield from these fatty acids is extremely low, making it difficult to produce purified salts from the derived 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 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-cyclobentenone compound followed by a trapping process of erulate has been devised as a direct synthesis method for the PG skeleton (G, 5tock et al + J, A
mer, Cham, See, +97 +626
0 (1975), K.G., Untch et al., J.O.
rg.

(See Chem-44+ 3755).
(However, these attempts require a multi-step process in which erulate is captured using formaldehyde and trimethylsilyl chloride, which are low-molecular-weight compounds, and PG skeleton synthesis is achieved by chemical synthesis via the resulting important intermediate.) 2 The present inventor focused on these points and developed frostaglandin E,
Advantageous chemical synthesis methods for Group F: (1) Using readily available starting materials. (1) Reaction process is short, 0il)
The result of intensive research to find a synthetic method with advantages such as high overall yield.

From 7-hydroxyprostaglandin E, which is obtained in a higher yield than the protected 4-hydroxy-2-schiff-pentynon, the hydroxyl group at the 7-position is selectively removed, and if desired, a functional group is added. Convert K to PGE
.

We found that PGFs can be obtained and have previously reported this separately.

:Object of the Invention> The present inventors paid attention to the above-mentioned three-component coupling process method, and as a result of intensive research into the construction of a more efficient PC skeleton, we found that The 2,3-
The present invention was achieved by successfully producing disubstituted-4-substituted cyclopentanones.

Conventionally, attempts have been made to construct a PG skeleton by fullkylation with halide IIK of erulates produced by conjugate addition reaction of α,β-unsaturated dinones (especially 2-cyclobentenones) I/C organocopper compounds. has been done many times.

Let me exemplify and explain reports related to this method.

(1) Japan and China! ! # Kaisho 50-96542 (197
5°7.31; sunrise on December 28, 1973 m) and 1
IIi Kaisho 5O-101337 (1975, 8, 11;
1974, IA filed on 21st) G,)i, Po5ner
and others.

Tetrahedrori Latters, 25
91 (1974) and G, H, Poaner et al. + J-Am, Chem.
Soc, *97 +107 (1974); All of these reports were made after adding an organocopper compound to 2-cyclobentenone.

There are only examples of model systems for prostaglandin systems that are fully-killed with halides, so it may be possible to
There are no examples regarding -substituted-2-cyclobentenones.

(21J, W, Pattaraon+ Jr and J,
H, Fr1ed t J, Org.

Chem, 39t2506 (1974); In this report, this methodology was implemented with 2-cyclobentenone and 11-deoxypurusufuglandin E was successfully synthesized, but 4-substituted-2-cyclobentenone Descriptions and examples using the class have not been reported.

131 G, 5tork and M, Iaobe + J
, Am, Chem, Soc, +97 +62
60 (1975); In this report, the erulate obtained by adding an organic copper compound to 4-substituted-2-cyclopentanones was successfully captured with monomeric formaldehyde, but the alkylation reaction has a negative conclusion.

+41 J, A, Noguez Tori, A, Mald
onado+SyntheticCOITlmun
ielLtlOnl t 6 + 39 (1976)
3 In this report, a lithium salt of cyanohydrin with a protected portion corresponding to the omega chain of prostaglandin was conjugately added to 2-cyclobentenone, and then captured with propargyl halides and converted into an 11-deoxyprostaglandin enzyme derivative. 4-substituted-2- of organocopper compounds just by guiding
There is no mention of cyclobentenones.

(51R, Davfg, G, [JntcL J-
Org, Chem-, 44*375s (1979); In this report, aripa-no1lide of erulate produced by conjugate addition of an organocopper compound corresponding to ωmK of prostaglandin to 4-km-2-cyclobentenones. It is discussed that various studies have been carried out, pointing to direct alkylation by 0, but all have ended in failure.

161 A.J. Dixon and R.J., Tay.
lor+ J, Chem, Soc, +Parkinl+
1407 (1981); In this report, we attempted the allylation of erulate produced from 2-cyclobentenone and an organocopper compound, which had been thought to be difficult to proceed, and obtained an intermediate for the synthesis of 11-deoxyprostaglandin. However, no attempt has been made regarding 4-substituted-2-cyclobentenones.

(7) Hyakude et al. + Tetrahedron Let
ters + 25 + 223 (1984) and 2
5.2487 (1984); In these reports, trimethylsilyllithium or methyllithiotrimethylsilyl77? -) was successfully added with 2-cyclopentenone diconjugate, tributyltin chloride was added, and then the erulate was successfully fully kylated with a propargylboumite threaded conductor. There are no application examples for -2-cyclobentenones.

The above is the historical background of prostaglandin skeleton synthesis by fullkylation of conjugate addition erulate of organocopper compounds.The synthesis of 11-deoxyprostaglandin visiting conductor from 2-cyclobentenone has been reported, There is no example in which a natural prostaglandin skeleton with stronger physiological activity has been successfully obtained from 4-substituted-2-cyclobentenones using this methodology.

The inventors of the present invention are fully aware of this point, and as a result of intensive research to overcome this difficulty, they have arrived at the present invention.

<Structure and Effects of the Invention> In the present invention, 4-substituted-2-cyclobentenones represented by the following formula (I) OR" or their enantiomers, or mixtures thereof in arbitrary proportions are substituted by the following formula [...] RBLi・・・・・・・・・
...... Organolithium compound represented by (n) and the following formula (III) Cu -Q ...
・・・・・・・・・・・・・・・(m) In formula 1, Q is a halogen atom! A military addition reaction is carried out with an organocopper compound obtained from a pot compound represented by the following formula (EV) Z-R・・・・・・・・・・・・・・・
・2,3- which is a compound represented by the following formula (Vl) 0R" and its enantiomer, or a mixture thereof in any proportion, characterized by reacting a β, r-unsaturated compound represented by (V) A method of making disubstituted-4-substituted cyclopentanones is provided.

The 4-substituted-2-cyclobentenones used as raw materials in the present invention are represented by the above formula (1). In the formula CI), RR is )! j (C1-C,) represents a group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group.

)! 7(C, ~C,) hydrocarbon silyl group, for example trimethylsilyl y)! + Tri(C,~C,)alkylsilyl such as ethylsilyl triisopcubylsilyl, t-butyldimethylsilyl group, diphenyl(C1-C4)furkylsilyl or tribenzylsilyl group such as t-butyldiphenylsilyl group, etc. can be mentioned as preferred. Among these, t-butyldimethylsilyl group is particularly preferred.

Groups that form an acetal bond with the 028 atom of the hydroxyl group include, for example, methoxymethyl, 1-ethoxyethyl, 2-methoxy-2F1=vil+2-ethoxy-2-
Propyl.

(2-methoxyethoxy)methyl 9benzyloxymethyl, 2-tetrahydropyranyl.

2-tetrahydrofuranyl or 6,6-cymethyl-3-
Oxa-2-oxobicyclo(3,1,0)hex-4
-yl group may be mentioned.

Among these, 2-tetrahydropyranyl.

2-tetrahydrofuranyl, l-ethoxyethyl, 2-
methoxy-2-propyl), (2-methoxyethoxy)
Methyl or 6,6-dimethyl-3-oxa-2-oxobicyclo(3,1,0)hex-4-yl group is preferred for fPK.

Typical examples of such compounds include the above)! J(C,
~C,) the above formula CI protected with a group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group
), 4-droxy-2-cyclobentenones, and enantiomers of &Ero, or mixtures thereof in arbitrary proportions can be cited as preferable as they are.

In the present invention, first, the above-mentioned 4-substituted-2-cyclobentenones are subjected 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 (m). It is implemented by forcing people to do something.

RB in the organolithium compound of formula (■) represents a substituted or unsubstituted C1-C1° alkyl group or alkenyl group. Examples of substituents in the substituted C2-C,6 alkyl group or alkenyl group include methyl group and ethyl group! Lower alkyl groups such as propyl group and butyl group; C1 to cyclohexyl group, etc.
C, cycloalkyl group; vinyl group: phenyl group: lower alkoxy group such as methoxy group, ethoxy group; or as a specific example of R2 in the above formula CI)! J(C,
~C,) A hydrocarbon silyl group or a hydroxyl group protected with a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group.

Among the C2-CIO furkyl groups or alkenyl groups which may be substituted with such substituents, the C1-C1° furkyl group is 1, for example, an ethyl group.

Propyl group, butyl group, t-isobutyl group, 5ec-butyl group, t-butylna, pentyl group, hexyl group, heptyl group! Octyl group, nonyl group.

Examples include a decyl group, and the C1 to CIO alkyl group is 1, for example, a vinyl group.

1-propenyl group, 1-7'tenyl group, 1-pentenyl group 91-hexenyl group, 1-hebutenyl group, 1-octenyl group, 1-nonyl group.

Examples include 1-decyl group, and either (t)- or --stereoisomers may be used. Such substituted or unsubstituted C!
-C7゜Among the alkyl groups or alkenyl groups, the following formula [D'] Li/ is particularly preferable.
An example is an organolithium compound represented by the formula [■']. This is because it matches with the formula [■'], and Rs in the formula [■'] is the formula CI
) has the same definition as W in ), and the same groups as exemplified for Hg are preferred.

On the other hand, Q in the copper compound of formula (DI) represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, a cyano group, a phenylthio group, or an l-pentynyl group.

K to obtain an organocopper compound from the organolithium compound of formula (ff) and the copper compound of formula (III) is 1, for example, in Documents G, H
, Po5ner + Organic Reactio
n+ vol, 19+1 (1972); Noyori et al. + T
etrahedron Letters+21t124
7 (1980), 23.4057 (1982).

2315563 (1982) + 2411187 (198
3) 12494103 (1983), 25.1383 (
1984) and Isr, J. Chem, 24111
8 (1984) etc. are cited as references.

In the method of the present invention, a trivalent organophosphorus compound such as trialkylphosphine (fFIJt
C, triethylphosphine.

tributylphosphine, etc.), trialkyl phosphites (e.g., trimethylphosphite, triethylphosphite, triisopropylphosphite, 9-tri-n-
However, this conjugate addition reaction proceeds smoothly if a compound such as (butyl phosphite, etc.), hexamethylphosphorus triamide, or triphenyl phosphine is used, but *K) liptyl phosphine or hexamethyl phosphorus triamide is preferably used.

The method of the present invention uses 4-substituted-2- represented by the above formula CI).
It is carried out by reacting cyclobentenones with the above-mentioned organocopper compounds in the presence of a trivalent organophosphorus compound and an aprotic inert organic medium.

Although the 4-substituted-2-cyclobentenones and the wrinkled organic steel compound react in equimolar terms stoichiometrically, 1.
0.5 per mole of substituted-2-cyclobentenones
~2.0 times, preferably 0.8 to 1.5 times,! # is preferably carried out using 1.0 to 1.3 times the mole of the organic copper compound.

The reaction temperature was -100°C to 20°C, I! Preferably, a summer temperature range of about 8° C. to 0° C. is adopted. The reaction time varies depending on the reaction temperature.

It is usually sufficient to react at -78°C to -20°C for 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 media include, for example,
Saturated hydrocarbons such as pentane, hexane, heptane tube cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, tetrahydro7
Ether solvents such as Ran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; other hexamethylphosphoric tri7mide (HMP), N,
Examples include so-called aprotic polar solvents such as N-dimethylformamide (DMF), N,N-dimethyl 7cetamide (DMAC), dimethylsulfoxide sulfolane, and N-methylpyrrolidone, and mixtures of two or more solvents include It is also possible to use it as a solvent. Further, as the aprotic inert organic medium, 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 1t4-substituted-2-cyclobentenones into the reaction system in which the organocopper compound was produced. The amount of organic medium used is sufficient as long as it allows the reaction to proceed smoothly, and 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 organophosphorus compound can also be present during the above-described preparation of the organocopper compound.

The reaction can also be carried out by adding 4-substituted-2-cyclobentenones to the system.

In the method of the present invention, the 3-position f of the 4-substituted-2-cyclobentenones is present in the reaction system due to the previous operations.
It is assumed that RB, which is the organic group moiety of the lK&f organic steel compound, is added to form a so-called conjugated addition erlate in which an anion is generated at the 2-position.In the method of the present invention, for this conjugated addition erlate, In the presence of the alkyltin compound represented by the above formula (IV), the β-unsaturated compound represented by the above formula (V) is reacted. -Disubstitution-
4-substituted cyclopentanones are produced.

R8 in formula (IV) represents the same or different C, -C1 cycloalkyl group or phenyl group, one of which may be a halogen atom. Y represents a halogen atom or a triflate group.

Specific examples of the alkyl tin represented by the formula (IV) used here are as follows.

Tri(C,
~C,) cyclo7-rukyltin halide; triphenyltin chloride: dicyclohexyltin dichloride 9 dicyclopentyltin dichloride; di(C, ~Cq
) cycloalkyltin cybarides; diphenyltin cybarides such as diphenyltin dichloride and diphenyltin bromide; or triphenyltin triflate and tricyclohexyltin triflate. Triphenyltin chloride 9-tricyclohexyl chloride is particularly preferred.

In the monounsaturated compound represented by the formula (V), RA represents a substituted or unsubstituted C1-q alkyl group, X represents a halogen atom or a tosyl group, 2 represents an ethynylene group, a trans-vinylene group, or cis-vinylene group.

As substituted CI to C, substituents in alkyl groups,
For example, lower alkyl groups such as methyl group, ethyl group, propyl group, butyl group; C8-C? Cycloalkyl group; vinyl group,
Flukenyl groups such as allyl groups; aromatic groups such as phenyl groups; lower alkyl groups such as methoxy and ethoxy groups;
TriCCI""' Cy) A hydrocarbon silyl group or a water group protected with a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group: a lower 7-syloxy group such as an acetoxy group or a propionyloxy group; an oxo group; as well as methoxycarbonyl and ethoxycarbonyl groups.

Preferred substituents include lower alkyl dicarbonyl groups such as t-butoxycarbonyl group, which do not hinder the progress of the intended fullkylation. Examples of the lower alkyl group of CI-C include a methyl group, an ethyl group, and a propyl group.

Isopropyl group, butyl group, isobutyl group.

-butyl group, t-butyl group, pentyl group.

Straight chain or branched chains such as hexyl groups can be mentioned.

Among such propargyl halides, the following formula [V'
] XCHs-Z (CHt)s C0OR' ・
The β-unsaturated compound represented by -."."...(V') is the most preferred because the prostaglandin skeleton can be constructed as it is by the method of the present invention.

Formula (v')<*iteR'haC,~C,67/l,-? /
1, JE I & substituted or unsubstituted phenyl group represents substituted or unsubstituted phenyl CC, -C1) alkyl group.

Examples of the C1-C1° alkyl group include methyl group, ethyl group, and propyl group! Isopropyl group, butyl group,
Inbutyl group, S mini-butyl group, t-butyl group, pentyl group, hexyl group.

Examples include linear or branched ones such as heptyl group, octyl group, and nonyl group.

Substituents for substituted or unsubstituted phenyl groups include 1, for example, halogen atom, protected hydroxy group + C1
~C,7 cyoxy group, C1~C, furkyl group optionally substituted with a halogen atom, C1~C4 alkoxy group optionally substituted with a halogen atom, nitrile group, or (C,~C,)alkoxy A carbonyl group is preferable. As the halogen atom, fluorine, chlorine or bromine, etc., and fluorine or chlorine are preferable. Examples of the C2-C acyloxy group include 7-cetoxy group, propionyloxy group, t-butyryloxy group, inbutyryloxy group, 9-valeryloxy group, invaleryloxy group, and caproyloxy group! Examples include an enantyloxy group and a benzoyloxy group.

Examples of the C8-C, furkyl group which may be substituted with a halogen atom include a methyl group and an ethyl group.

Preferred examples include propyl group, inpropyl group, butyljet, lylolomethyl group, dichloromethyl group, and trifluoromethyl group. Preferred examples of the CI to C4 alkoxy group which may be substituted with a nitrogen atom include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a dichloromethoxy group, a dichloromethoxy group, and a trifluoromethoxy group. It can be given as follows.

Examples of the (C, ~Co) alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group,
Examples include t-butoxylponyl group and hexyloxycarbonyl group.

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

Substituted or unsubstituted C, -C6° cycloalkyl groups include saturated or unsaturated C1-C1°, preferably C1-C6, particularly preferably substituted with the same substituents as mentioned above or unsubstituted. is C6 group 1 such as cyclopropyl group, cyclopentyl group! cyclohexyl group,
Cyclohexenyl group! Examples include a cycloheptyl group, a cyclooctyl group, and a cyfdidecyl group.

Examples of the ma or unsubstituted phenyl CC1-C-alkyl group include a benzyl group, an α-7enethyl group, and a β-7enethyl group in which the monophenyl group is substituted with the same substituent as mentioned above or unsubstituted. .

Further, in the β, r-unsaturated compound represented by formula (V) l (V'), X is a halogen atom or a tosyl group. Such halogen atoms include chlorine atom, bromine atom,
An example is an iodine atom, but an iodine atom is most preferable in consideration of the reactivity of the β,r-unsorated compound.

In the formula, 2 represents an ethynylene group, a trans-vinylene group, or a cis-vinylene group.

Any of them is preferably used, but in consideration of the skeleton of natural prostaglandins, a cis-vinylene group is most preferred, followed by an ethynylene group which can be derived from a cis-vinylene group 1C.

In the method of the present invention, the reaction between the conjugate addition elerate and the /br-unsaturated compound produced in the system is performed using K First, an alkyltin compound is added, and then the β-monounsaturated compound represented by the formula (V) (including formula 111 [V′]), which may be diluted with the aprotic organic medium, is added. Implemented by KotoK.

It is assumed that realyl tins react with the erulate produced by conjugate addition in a stoichiometrically equivalent manner to newly produce tin erulate. 2-cyclobentenone IQ1
0.8 to 1.5 times the mole, particularly preferably 1
．． It is carried out using 0 to 1.2 moles.

The reaction temperature is 00°C to 0°C, preferably 8°C to -
A temperature range of about 20'C is adopted, and one reaction time of one hour or less is sufficient.

In the method of the present invention, a j,r-unsaturated compound represented by formula [V] (including formula [V']) is then added to complete the purpose. The β-unsaturated compound reacts with the erulate produced by conjugate addition in stoichiometric amounts.

Usually, 0.8 to 5.0 times the mole of the 4-substituted-2-cyclobentenone used initially, [C preferably 10 to
A 2.0 molar volume is used.

The reaction temperature is 00°C to θ°C, preferably 8°C to -
A temperature range of about 20°C is adopted. The reaction time varies greatly depending on the type of β, r-unsaturated compound used and the reaction temperature. Usually, the reaction time is about 1 hour to 50 minutes at -78°C to -30°C.
The reaction is terminated by allowing the reaction to proceed over time, but it is efficient to track and determine the end point of one reaction using thin layer chromatography.

In the method of the present invention, the alkylation reaction with an I, r-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, separation by conventional means (post-treatment, extraction, washing, chromatography, distillation, or a combination of these),
Refined.

In this way, 2,3-disubstituted-4-substituted cyclopentanones represented by the above formula (Vl) are obtained. An illustration of a specific example of such a compound is the formula [E].

Formula [11] (including (If')), and Formula (V)
Preferred examples include any combination of the groups exemplified in (including (V')). Among them, organolithium compounds represented by the formula [■'] and β represented by the formula [V']
The following formula [■
'] Among the 2,3-disubstituted-4-substituted cyclopentanones represented by 0R1' δW, the derivative in which 2 is a cis-vinylene group is p-staglandin E, which is a useful compound for 4IK because it is the skeleton itself. , derivatives in which 2 is an ethylene group are also 5,6-dihydroprostaglandin E! Because it has a derivative skeleton, it is a very useful compound, and the present invention is important in that it also provides a method for producing such a compound. i.e. book 5
, 6-zohydrobrostaglandin E, and prostaglansif (PG) &? using derivatives as starting materials. El +
F1a1 p, a, DI+ DI and! , the process of guiding each of them is as follows.

Eighty nine! OR"OR"? H 6w et al., Reference Examples 1 to 5 specifically show some of the above spinning reactions. Other conversion reactions have already been reported by some of the inventors.

Furthermore, one feature of the process of the invention is that all the reactions used proceed stereotypically, so that the formula C
From the starting material having the configuration represented by I), a compound having the configuration represented by the formula (VI) (including (VI')) can be obtained, and from the enantiomer of the formula CI), the compound having the configuration represented by the formula (VI') can be obtained. The enantiomer of Vl) (containing (Vl')) is obtained, and from the warm mixture CI) of any proportion, a mixture of (Vl) (containing (Vl')) reflecting that proportion is obtained. You will get it. Furthermore, since the organolithium compound of formula [■'] contains an asymmetric carbon, there are 281 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, and therefore is a particularly useful stereoisomer.

Another feature of the method of the present invention is that when a mixture of octads or an arbitrary proportion of optical purity is used as two optically active starting materials (formula (I) and formula [■]), the synthesis route can be stereospecifically The intermediates and the final product become a diastereomixture, and if one of the raw materials is optically active, each stereoisomer can be separated as a pure product by separation at an appropriate step. It lies in what you can do.

The present invention will be explained in more detail below using refreshing examples, but the present invention is not limited thereto.

Example 1 (day) -1-iodo-3-1-butyldimethylsiloxy-1-octene (368,57) 593.1 ml (
1,61X 1 G-3mo/)1-butyllithium (
1,87M) 1.72m (3,22X10-” mol) Cupric iodine (190,45) 306.6111i1 (1,61X 10-3 mol
) trinybutylphosphine (202,32sO,
812) 1.04U (4,19xlO-3
mo/)4-1-butyldimethylsiloxy-2-cyclobentenone (212,36) 325.6N9 (1,53X 10-”moJ)Ph
3SnCA' (370,34J 9596)627.
6JIF (1,61X 10-3mo7)ICH,C
=-C(CH*), C00CH, (2ct 6.07
)814.219 (3,06X 10-3 mol)
HMPA (179,20,1,03) 2.8011t (1,61X 10-2moAI) Argon-substituted 15 (14 reaction tubes K (E) -1-iodo-3-t-butylsiloxy-1-octene and Take the dry ether of 6a, cool it to -95°C and stir it. Add t-butyllithium to it using a syringe,
The mixture was stirred at -95 to -78°C for 3 hours. Separately, a 30i1 eggplant-shaped flask was prepared, cupric iodide was taken, and the inside of the flask was heated and dried under reduced pressure, and then replaced with argon.

Dry THF 6- 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°C and added to the previously prepared vinyllithium solution using a stainless steel tube under argon pressure, and the container was rinsed with 6M dry THF. After stirring at -78℃ for 10 minutes, Enon's T-HF#!
The liquid (12N) was added dropwise in 1 hour to KIIJ's TH
Rinse the container with F' and stir for 10 minutes.
ACl, 5jlj) was added, and after stirring for 30 minutes, P
h, 5n(J) solution in THF (2'j17) was added.

After raising the temperature to -30°C, a HMPA solution of 1-iodo-6-carpomethoxy-2-hexyne was added.

The mixture was stirred at -30°C for 4 hours and 30 minutes. Subsequently, after being left at -27°C for 13 hours, a saturated ammonium chloride aqueous solution (
2011j) and shaken vigorously. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with ether (201j
X2). 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 (Me
rck 7734 509.1 :6 (1-ethyl acetate:hexane+ctoom→1:20=ethyl acetate:hexane, 2
00th succession).

2; 542.1 (59,7516) IR (liquid film)
; 1746 t1246.827 t767aR-"Example 2, L e(E) -1-iodo-3-1-butyldimethylsiloxy-1-octene (368,37) 593.1 ~ (1,
61X 10-3 mo/ )t-butyllithium (1,
87M) 1.72m (3,22X 10-3 mol) Cupric iodide (190,45) 306.6N9 (L, SI X 10-3 moJ)
Tri-n-butylphosphine (202,32.

0.812) 1.04m (4,19X10-
3mo/) 4-t-butyldimethylsiloxy-2-cyclobentenone (212,36) 325.6I9 (1,53X 10-3mad) Ph
s 5nCI (370-34+ 9556) 627
．． 6j9 (1,61X l O-3me/ ) (Z)
-1-! -do-6-carbomethoxy-2-hexene (2
68,09) 1.231g (459X10-3mo/)HMPA
2.80 iu (1,61X10-3 mo/) (E)- in a 150 Mj reaction tube purged with argon.

Take the dry ether of 1-iodo-3-t-butyldimethylsiloxy-1-octene and 6-.

Cool to -95°C, stir (. Add 1-butyllithium using a syringe, and cool to -95 to -78°C for 30 minutes
Stir for hours. Separately, a No. 301114 eggplant-shaped flask was prepared, cupric iodide was taken, and the inside of the flask was heated and dried under reduced pressure, and then replaced with argon. Dry THF6- and tributylphosphine were added to this and stirred at room temperature (25°C) to form a homogeneous solution. This was cooled to -78℃, and then K1112
The solution was added to the vinyllithium solution using a stainless steel tube under argon pressure, and the container was further rinsed with 6 jlJ of dry THF. After stirring at -78°C for 10 minutes, Efun's THF solution (12-) was added dropwise over 1 hour. Furthermore, the container was washed with 1C111j of THF', and the mixture was added and stirred for 10 minutes. Add HMPA (1,5th passage), 30
After stirring for a minute, THF (Ph, 5nCJ) (21L
t) was added.

After raising the temperature to -30°C, a HMPA solution of (Z)-1-iodo-6-carpomethoxy-2-hexene was added, and the temperature was raised to -30°C.
The mixture was stirred for 3 hours. Continued [After being left at -27°C for 97.9 hours, saturated ammonium chloride water bath solution (201Lt)
was added and shaken vigorously. After separating the organic layer and the aqueous layer, the organic layer was washed with saturated brine and dried over anhydrous sodium chloride. Concentrate under reduced pressure by passing through e, short quamado (
Merck 7734 59, 1:5=ethyl acetate:hexane) and high polarity 11jt (Bu, P+ Ph
, 5n(J), and then silica gel column chromatography (Merck ??34 509, 1
: 60 = Ethyl acetate: hexane, 7g Qiu → 1 :
20 = ethyl acetate: hexane + e o o ”) K was provided.

3:647j9 (719) IR (liquid film); 1743+1243+1000,964,927°82
8*768cxr-” Reference Example 1 Acetylene Compound 4 (48,2■, 0.081rw
nol) and synthetic quinoline (25~) in benzene (
2,5jlj) K dissolved in cyclohexane (2,5jlj)
IIj), followed by 596Pd Ba5O* (25
After adding "P) t' and stirring for 3 hours at 25°C under hydrogen atmosphere, synthetic quinoline (50W9) and 5% P
d-Ba5O.

(50 da) was added and stirred at 40°C for 4.5 hours.

After treating the catalyst with P, it was washed with ethyl acetate, and the mixture was concentrated under reduced pressure.

It was subjected to silica gel column chromatography (81° ether-hexane = 1:10), and both collected fractions were subjected to paper pressure am, and then the 6-scan was subjected to vacuum pump reduction (<4W...
fl) IIC After standing for 7 hours, PGEt methyl ester 11T15-bis-t-butyldimethylsilyl ether 5 (41,8111P, 87516) was obtained.

TLC; Rf O, 58 (ethyl acetate-hexane = 1:5) IR (liquid film); 1743t1243. +000t964,927°82
0.03 and 0.06 (respectively Ill 1215
iCH, x4)+0.8-1.0 (In+ 21 t
C-CH5X7) +1.2-1.5 (m+ L
CH,X4)+1,6-2,9(nl+12
w CHtCOX2? C=X2 to C.

CHX2 and CMl).

3.67 (a * 3 vOc) is )t 4.
06 (m*2 *CHOS lX2)+5.37(m
elt vinyl) + 5.54 (mtl*vinyl) (('
)"6 n -52,7° (C1,28, CHIOH)
This compound is derived from (c)-PGE, tt, ts
It completely matched with the protected disilyl form of .

Reference example 2 Silyl compound 5 (4019+ 0.067rwnol)
was dissolved in anhydrous 7cetonitrile (8-) and HF-
After adding pyridine (0,1117) and stirring at 24°C for 30 minutes, add HF-pyridine (Q, 41j) to the mixture.
Stir for hours. After pouring into a saturated Na1 (COs aqueous solution (20 times)), it was extracted with ethyl acetate three times (3QljX3).The mixture was dried over Na and SO4, and then concentrated under reduced pressure.Toluene was added to remove pyridine in the residue. It was further concentrated under reduced pressure using a vacuum pump (<4 txjJ9).
I'm After standing for a while, silica gel column chromatography (2I1. Ethyl acetate-hexane (1:
1)→(1:O) Gradient)→-PGE
, methyl ester 6 (24,111P198N) was obtained.

TLC; 0°29 (Ethyl acetate-cyclohexane-THF 6:3:1) IRC liquid film); 368G-3080-1744t970cIN-''H
NMR (CDCAI, ) δ; 0.90 (ttl, J=6.5HzlC).

1.1-2.9(m+20tcH1COx2.CB, x
5. CHtC=x2゜CHx2L 3.08(br+
1+OH)*3.66(!!s3.OcH,).

4.06 (m + 3 + CHOx2 and OH).

5.34 (m+L vinyl) + 5.70 (m+1+vinyl)l Hatake CNMR (CDCl, ) δ; 14
．． 0.22.6.24.7.25.1.26.6.31
．． 7゜33.5137.3.46.1 Book 51.5.53
゜? , +4.5°72.0.73.0.126.6.
130.8+ 131.5゜136.8.174.0+
214.1 (α) p p 71.7° (CI, 0
43 + CHsOH) Reference Example 3 Poor 7 Rain methylaluminum hydride (1 equivalent) previously produced by KAMl / Toluene solution (0,192
MgoIns 2.24 m, 0.43 mmo/
) at -78℃ and ketone body 4 (25,5j910.
A toluene solution (1-) of 043 mmoi) was added.

After stirring at -78°C for 2 hours, the mixture was heated and stirred at -25 to -20°C for 3 hours. Saturated sodium hydrogen tartrate aqueous solution (
IOM) and shaken vigorously.

3 times with ethyl acetate (20+10+10114) at room temperature
After extraction and combined drying over Na, 804, vacuum lIm
did.

Silica gel column chromatography (5I.

Ethyl acetate-hexane=5:1) to obtain alcohol 7 (23,519,192%, low polar component).

TLC; RfO, 29 (ethyl acetate-hexane = 1:5) IRC liquid film); 364G-3080, 1745, 1247, 1020°970.930.830.770cm-''HNMR (
CD(J,)δ; 0.02 and O,OS <a + 12 + respectively
S iC 几×4).

0.7-1.0 (No. 121.C-CH, X7).

2.1-3-5(m+20 tc&cO+ CH,xL
CHsC=x2.

CHX2) 93.69 (dll, J=8.3Hz,
OH).

3.67 (s, 3.QC) fdt 4.00 and 4.24 (br, 3 tcHOx3
).

5.40 (mw2+vinyl) (α) B e + 0.37° (C0,715+C
H) Reference example 4 7cetiL/7 compound? (28,7#, 0.048
mmol) was dissolved in benzene (114)K, cyclohexane (1μ) and Lindlar catalyst (28,711F)
After adding 12% of
Stir for hours. The catalyst was filtered, washed with ethyl acetate, and the mixture was concentrated under reduced pressure.

Silica gel column chromatography (6I.

Ethyl acetate-hexane-benzene = 1:15:1
2), olefin body 8 (23.2 to +81%)
I got it.

TLC; Rf 0.32 (ethyl acetate-hexane = 1:5) IR (liquid film); 3610 3280+1745+1250+1000+
970.938.830.770ctt-1'HNMR
(CDC/,)a ; 0.03 and 0.05 (s+12+5ic1(
, x4) +0.8 1.0 (mt21*c-C几X7
)+1.2-2.4 (m+20.CH, CO+ CH
, x6+CHtC=x2°CHx2), 2.69(d+
LJ=9.511z+OR).

3.67(s, 3+Oc&), 4.05(br+3
tcHOx3).

5.40 (my2+vinyl) [α moat; + 12.3” (C1,037, CHsO
H) The IR and 'HNMR spectra of 5 are (g)
-PGE, completely coincided with those of the disilyl derivative derived from α.

Reference example 5 0H9B silyl body 8 (213 kgt O, 035 mmo/) was dissolved in acetic acid (]1), H, 0 (0,331 Lt)
, THF (0°l-) was 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,0.

The residue was subjected to silica gel column chromatography (3 g, ethyl acetate-hexane (1:1) → (1:0) gradient end), and (t)-PGF, α-methyl ester 9 (
IIIP, 85%).

TLC; RfQ, 2 (ethyl acetate-cyclohexane-THF=6:3
:IR (liquid film); 3640-3040.1738.1435.1160
.

1116.1042 +1020 +968.858c
m-1'HNMR (CD Cds) a pO, 89
(t,3.J=6.5Hz,C)i,).

1.2-2.4 (mt20 +CH, Cot CH,
x6, CB, C=x2.

CHX2) + 2.57 (br, 1+OH), 3.2
9(br+1tOH)+3.69(st3+0cHa)
+ 4.03 (brm, 3+CHOx3) +5.3
5.6 (m, 2+ vinyl) IsCNMR (CD Cds ) J; 14.0.2
2.6+ 24.8.25.2+ 25.6.26.6
゜31.8.33.5.37.3.43.0.50.5
．． 51.6°55.81 72.9,73.0.78.
0,129.1°129, L 132.6,135.
3,174.3 [α)”; +31.4° (C0,4
23B10H) Spectrum of the compound (IR, 'HN
M.R.

"CNMR, TLC) was derived from (g)-P G Ftα (g)-PGF, a methyl ester
completely matched.

Procedural amendment 8 (method) % formula %! , Indication of the case Patent application No. Sho 59-235307 λ Name of the invention 2. Process for manufacturing 3-disubstitution-4-substitution/R a penta/class 7 3. Person making the amendment Relationship to the case Patent issuer
(Representative: Sashibu Okamoto 5, date of amendment order: February 26, 1985, 6)
[(
J. B. Bindra et al. Prostaglandin
5 synthesis.

(See Academic Press (1977))
That's it [(Ju. Bee, Bindra et al., Broth Tag 2
Jinjin Synthesis, Academic Press (J, B,
Bindra et al., Prostaglandin 5
ynth-esia, Academic Press
) (1977))”.

21 Page 8, lines 15 to 17 [(B.

Samuelsson et al., Angev, Chem.
Int, Ed, Engl, 4°410 (1965)
)” [(Hee.

Samuel Sonra, Angebante Kemi Innotana/Yonal Eteinyo/Ino I/Grissonyu (Ange
v, Chem, Int, Ed, Engl,) 4.

410 (1965))".

31 Page 8, lines 18 to 20 [(E.

J, Coray et al., J, Amer, Chem, So.
c., 92, 397 (1970))” [
(Yi, Jie Hooley et al., Nyanar Off Sa
American Chemical Society (E, J.

Corey et al., J.Amer.Chem.Soc.
), 397 (1970))”.

(4) r(C,J
,Sih et al., J,Amer,Chem,Soc,.
97, 865 (1975))"

Journal of the American Chemical Society (C, J, Sih et al., J, Amer.

Chem, Soc, ), 97.865 (see 1975)”.

(5) Go to page 9, line 6 of the same page 9th line ni r < is
.

Ferdinandi et al., Can-J, Che
m,,Q,1070 (see 1971) (C,H,L
in et al., Prastaglandin, 11
.

377 (1976))” is replaced with “(E.

Nis 2 Fuerteinandei et al., Kanatia/Journal of Chemistry (E, S.

Ferdinand i et al., Can, J.C.
hem, ), 49.1070 (1971)) (C. H., Lin et al.

-joy, p Grandsif (C, H, LIn et al., Pr
oata grandin).

11°377 (1976))”.

(6) [(G.

5tack et al., J.Amer.Chem.Soc.
, 97, 6260 (1975), K.G.U.
ntch et al., J, Org, Chem, 4C3755
(See Gee, Stock et al., Journal
Off the American Chemical Society (G
, 5tack et al., J. Amer.

Chem, Soc, ), 97, 6260 (1975)
, Goo. G9 Kunte et al., Journal of Organic Chemistry (K, G, Untch et al., J.

Org, Chern, ), 4.4.3755)
I am corrected.

(7) On page 12, lines 7 to 10, [,G,
H.

Po5nar et al., Tatrahedron Let
ters, 2591 (1974), and G, H, P
o5ner et al., J. Am. Chem.

Soc, 97, 107 (1974): J.
Gee.

Ecchi, Bosner et al., Tetra Hedokun Letters (G,
H, Po5nsr et al., Tetrah@dron Let
ters).

2591 (1974), and G. H. Posner et al., Journal of the American Chemical Society (G. H. Posner et al.

J, Am, Chem, Soc, ), 97.107 (1
974): Corrected as J.

(8) Same number! On page 2, lines 17 to 18, it says “J.

W, patterson,, rr and J, H, Fr1ed.
,J,Org,Chem.

39,. 2506 (1974);
Double 21, Pattern/, Junior and Ju. Sex,
Fleet, Journal Off the Organic Chemistry (J, W.

Patterson, Jr. and J.H., Fr1sd., J.
Org, Ch@m,).

39.2506 (1974): Corrected as J.

(9) [G, 5t
ork and M, l5obe, J, Am, Chem, 3oc
,, 97.6260 (1975);
Stork and M, Isope, Journal of the American Chemical Society (S, 5tork and M.

l5ope, J, Am, Chem, Soc, ), 97.
6260 (1975): Corrected to J.

αα　Page 13, lines 12-13 [J.

A, Noguez Tori, A, Maldonado, 5y
nthetic Comm-unications, 6
．． 39 (1976): ``J, A, Noguez Tori, A
, Maldonado, SyntheticComm
6.39 (1976);
Correct it with J.

αυ [RoDav
i s Toni, G, Untch, J, Org, Chem
, 44, 3755 (1979);
R, Davis and Dayi, Unchi, Journal of Organic Chemistry (R, Dayi)
3,G,Unteh,J,Org,Chem,),
44.3755 (1979): Corrected as j.

α2 [A] on page 13, lines 11-12.

Dixon, J. and Taylor, J., Ch.
em, Soc, Parkin I, 1407 (1981
) ; There is J and [knee, nk-, taken-n and ryo-]
A, J, Dix
on and R, J, Taylor, J, Chem, So
C., Parkin) 1.1407 (1981): J
I am corrected.

a3 r on page 14, line 20 to line 1 of member 15
Tetrahedron Letters J Toru wo 1 Tetrahedron Letters
Letters) Correct as J.

+141 [G,
)L.

Po5ner, Organic Raaction, v
ol, 19.1 (1972); Noyori et al., Tetrah
@dron Letters, 21. J and Aruwo [JE, Ecchi, Bozner, Orca ° Nick Reaxia a
l (G, H, Po5ner, OrganicRea
ction), voL19, 1 (19? 2)
; Noyori et al., Tetrahesd
ronLetters), 21, J.

αS Same page 23, line 14: “IarJ, Chem,
, J. [Israel Journal Off.

The Chemistry (Isr, J, Chem, )J
Amend the above procedure in January 1985? 9th day

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^2 is a tri(C_1 to C_7) hydrocarbon silyl group or an oxygen atom of a hydroxyl group. Represents a group that forms an acetal bond. ] 4-substituted-2-cyclopentenones represented by the following formula [II] R_B-Li・・・・・・・・・・・・・・・・・・... [
II] [In the formula, R_B is substituted or unsubstituted C_2-C
_1_0 represents an alkyl group or an alkenyl group. ] and the following formula [III]Cu-
Q...................................................[III] [Wherein, Q represents a halogen atom, a cyano group, a phenylthio group, or a 1-pentynyl group. ] A conjugate addition reaction is carried out with the organic copper compound obtained from the copper compound represented by the following formula [IV] R_3SnY・・・・・・・・・・・・・・・
IV] [In the formula, R represents the same or different C_3 to C_7 cycloalkyl group or phenyl group, and one R 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 [V]
...[V] [In the 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-vinylene group, or a cis-vinylene group. represents a group. ] The following formula [VI] is characterized by reacting β, γ-unsaturated compounds represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
・・・・・・[VI] [In the formula, R^2 is a hydrogen atom, tri(
C_1 to C_7) represents a hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R_A represents a substituted or unsubstituted C_1 to C_6 alkyl group, and R_B represents a substituted or unsubstituted C_2 to C
_1_0 represents an alkyl group or an alkenyl group, and Z represents an ethynylene group, a trans-vinylene group, or a cis-vinylene group. A method for producing 2,3-disubstituted-4-substituted cyclopentanones, which are the compound represented by the following formula, its enantiomer, or a mixture thereof in arbitrary proportions. 2. The organic lithium compound represented by formula [II] is the following formula [II'] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
・・・・・・[II′] [In the formula, R^3 is tri (C_1~
C_7) Represents a group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or 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 [V] has the following formula [V'] XCH_2-Z-(CH_2)_3COOR'...
......[V'] In the formula, R^1 is C_1 to C_
1_0 alkyl group, substituted or unsubstituted phenyl group,
It represents a substituted or unsubstituted C_3-C_1_0 cycloalkyl group or a substituted or unsubstituted phenyl(C_1-C_2) 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. Claims 1 to 3 in which X is an iodine atom
The method for producing 2,3-disubstituted-4-substituted cyclopentanones according to any one of the above. 5. Production of 2,3-disubstituted-4-substituted cyclopentanones according to any one of claims 1 to 4, wherein the alkyltin is triphenyltin chloride or tricyclohexyltin chloride. Law. 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. β in the presence of hexamethylphosphoric triamide
, Claim 1 in which a γ-unsaturated compound is reacted.
2,3-disubstituted-4- according to any one of Items 1 to 6
Method for producing substituted cyclopentanones. 8. The 2,3-disubstituted-4-substituted cyclopentanones represented by formula [VI] are represented by the following formula [VI'] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...[VI'] [In the formula, R^1, R^2, R^3 and Z are the same as defined above. ] Any one of claims 1 to 7 which is a 2,3-disubstituted-4-substituted cyclopentanone represented by
A method for producing 2,3-disubstituted-4-substituted cyclopentanones as described in 2. 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. Claims 1 to 10 in which Z is an ethynylene group
A method for producing 2,3-disubstituted-4-substituted cyclopentanones according to any one of Item 8.