JPS6156163A - Preparation of (5e)-prostaglandin e2 - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic raw material of PGE1 or PGF2alpha, in high yield, in short steps, by reacting a 2-allyloxycarbonylcyclopentanone derivative with a transition metal compex having low atomic valence. CONSTITUTION:The objective compound of formula II can be prepared by reacting the novel 2-alloyloxycarbonylcyclopentanone derivative, i.e. the compound of formula II [R<1> is H, 1-10C alkyl, phenyl, 3-10C cycloalkyl, etc.; R<2> and R<3> are H, tri(1-7C hydrocarbon)-silyl, or a group forming acetal bond with O of OH; R<4> is H, methyl or vinyl; R<5> is (O-containing) 3-8C alkyl, penyl, etc.; X is cis-vinylene or trans-vinylene; n is 0 or 1], its mirror-image isomer, or their arbitrary mixture with a transition metal complex having low atomic vlence [e.g. tetrakis(triphenyl-phosphine)palladium(0)].

Description

[Detailed description of the invention] Technical field The present invention relates to (5E)-prostaglandin E.

Concerning new manufacturing methods. More specifically, an erulate intermediate produced by conjugate addition reaction of an organocopper compound to 4-substituted-2-fuclopentenones, which are α,β-unsaturated ketones, is reacted with a carbonate derivative. α,β-substituted alkenyl group at β position of unsaturated ketone, α
New 2 with a substituted allyloxycarbonyl group introduced at the position
This invention relates to a new technique for producing the desired (5E)-prostaglandin E by producing an allyloxycarbonylcyclopentanone derivative and then reacting this with a low-valent transition metal complex. .

BACKGROUND OF THE INVENTION Natural prostaglandins (hereinafter sometimes abbreviated as PC) are known as local hormones (autacoids) with high biological and pharmacological activity. Therefore, research to develop new types of drugs by cleverly utilizing these physiological characteristics of PG is important.
This has been carried out not only for natural PGs but also for various derivatives.

Among natural PGs, PGE and PCF are compounds that have been known for a long time, and PGE2. PGP,
α has already been commercialized as a labor stimulant by utilizing its uterine smooth muscle contracting action, and has been used as a peripheral circulation treatment drug by utilizing its physiological effects such as PGE, platelet aggregation inhibiting action, and blood pressure lowering action. There is. These useful natural PGs
Among the classes, PGE2 class PGE, class or PCF,
It is an important compound as a raw material for the synthesis of α-class compounds, and is also an important target compound in synthetic chemistry.

Many methods have been developed and reported for the production of these PCFs and PCFs (J, B
, Blndra et al.
Synthesis, Academic Press
(1977) and Maetaka et al., Prostaglandins and related physiologically active substances, Kodansha University Press, P, 62-
P, 176 (1981)), among which the most innovative representative examples are (1) the method of biosynthesis of arachidonic acid or dihomo-γ-lylunic acid (B, Sa-muelaso
n et al + Angew, Chem, Int, Ed, Engl
.

4, 410 (1965)) (Method via Corey lactone, an important intermediate (E, J, Corey et al. J, Am,
Chem.

See Soe, Dan, 397 (1970)) (punishment
A method via 2-substituted-2-cyclobentenone, which is an important intermediate (C, J, Sin et al.

J, Am, Chem, Soe, 97.865
(1975)) Ov) 5.6-dehyde 0PG
E, or a method for selectively reducing PGF2a (E, S
, Ferdinandl et al., Can, J.

Chem-, 49, 1070 (197])) (C,
H.

Lin et al., Progtaglandin,
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 this is extremely low, making it difficult to increase purification from by-products. It is. 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, and therefore , the overall yield is very low.

In recent years, in order to overcome these difficulties, a three-component coupling process method using a conjugate addition reaction to a 2-cyclobentenone system followed by a trapping process of erulate has been devised as a direct synthesis method for the 13G skeleton (G , 5tork et al.
, A+n, Chem, Soc,.

Dane, 6260 (1975), K.G.
Untch et al., J. Org.

Chem, 44.3755).

However, these attempts require a multi-step process in which elerate is captured using low-molecular-weight compounds such as formaldehyde and trimethylsilyl chloride, and the jllPG skeleton is synthesized by chemical synthesis via the resulting important intermediate. However, the overall yield is also low.

The present inventor paid attention to this point, and developed Glotaglandin E, Glotaglandin E,
We are conducting intensive research to find an advantageous chemical synthesis method for Class F, which has the following advantages: (1) Use of easily obtained starting materials, (O) Short reaction steps, (■) High overall yield, etc. As a result, the hydroxyl group at the 7-position was selectively removed from 7-hydroxyprostaglandin E, which was obtained in high yield by one-step reaction from protected 4-hydroxy-2-cyclobentenone, and if desired, PGE by functional group transformation.

We found that PGFs can be obtained and have previously reported this separately. (Noyori et al., Tetrahedron Lett
ers.

23, 4057 (1982) and Tetrahed
ron Letters.

23, 5563 (1982)).

Furthermore, efforts have been made for quite some time to construct a PG skeleton by directly capturing the above-mentioned erulate with alkyl halides; The manufacturing method has not yet been established. ((11G, H, Po5ner et al.

Tetrahedron Letter8+ 2591
(1974) and J.

Am, Chem, Soe,, 97.107 (1
(2) Kuninaka et al.

JP-A-50-96542 and 5O-101337 (1
975) ; (31J-W, Patterson
et al., J, Org, Chern-+39, 2506 (
1,974); (4) G, 5tork et al., J, A
m.

Chem, 8oc-+ 97+ 6260 (197
5) : (5) J, A, Noguez et al! 5yn
6+
39 (1976); (61R, Dauls et al.
J, Org, Chem, 44.3755 (197
9); (7) A, J, Dlxon et al. + J, C
I+am, Soc,, Parkin T! 14
07Furthermore, although (5E)-prostaglandin E2 produced by the method of the present invention has attracted attention for its unique physiological activity, an efficient production method has been developed, which has led to the development of pharmaceutical products. This is a group of compounds for which the intended research has been relatively delayed. In other words, each of the above degrees
The f synthesis method is an advantageous method for producing (5z)-prostaglandin E2 having a natural three-dimensional structure, and has been reported to date (5E)-prostaglandin E,
The production of Plexaura homomal
A method for producing (5E)-prostaglandin E2 by induction method from (5E)-prostaglandin A derived from la) or photoisomerization of (52)-prostaglandin E (J, E, Pike et al. J, Arn, C.
hem, Soe, 94+2124 (1972)
1222 (1977)), the former method allows only the natural skeleton to be obtained, and the latter method has a low yield and cannot be said to be an efficient manufacturing method for the development of pharmaceuticals.

Purpose of the Invention The present inventors focused on the method for constructing a PG skeleton using the three-component coupling process method, and as a result of conducting intensive research to establish a more efficient PG skeleton synthesis method with a shorter reaction step, An erulate intermediate produced by subjecting an optically active 4-substituted-2-cyclobentenone to a conjugate addition reaction with an organocopper compound is reacted with a carbonate derivative having a component corresponding to the α side chain of PGE to form a single carrier. , 2-allyloxycarbonylcyclopentanones, and then reacted with a low-valent transition metal complex to produce the desired (5E)-prostaglandin E2 class through a decarboxylation-recoupling reaction. The present invention was achieved by successfully synthesizing this.

Conventionally, the decarboxylation-allylation reaction using α-allyloxycarbonyl ketone as a starting material and a zero-valent palladium catalyst has already been reported one after another by Minuki et al. and Tsuji et al. ,Chem,Soc,,
1.02.6381 (1980) and Tsuji et al., T
etrahedron Lettres + 21 +
3199 (1980)). However, these reports only report on experimental examples using relatively simple systems such as cyclohexanone and cyclopentanone, and PG
System 1, in which relatively steric hindrance is expected for allylation at the 2-position, such as 3,4-disubstituted-2-allyloxycarbonylcyclopentanones required for synthesis (no application examples have been reported) .

On the other hand, the present inventors previously reported the present decarboxylation-allylation reaction with 3,4-disubstituted-2-allyloxycarbonylcyclopentanones (Nichi et al., JP-A-59-44336
). The outline of the reaction is shown in the following reaction formula.

That is, only the simplest 3,4-disubstituted-2-(unsubstituted) allyloxy7carbonylcyclobentano 7 is known, and as described later, 3+4 as in the method of the present invention is known.
-9-substituted-2-(41-substituted)allyloxycarbonylcyclopentanones are still unknown in the literature. Moreover, in the decarboxylation-allylation reaction in the 1 system such as the method of the present invention, the double bond #1 was completely rearranged during the reaction not only from the E isomer but also from the 2 isomer ( An efficient method for producing (5E)-prostaglandin E, which has the characteristics of obtaining 5E)-prostaglandin E, and no allyl rearrangement products, has been completed. , we have arrived at the present invention. The main points of the above reaction are shown in the following reaction formula.

Structure and Effects of the Invention The present invention provides a compound represented by the following formula (1) % (where n represents O or ]) and its enantiomer, or a mixture thereof in any proportion. - A compound represented by the following formula (n), its enantiomer, or a mixture thereof in any proportion, characterized by reacting an allyloxycarbonylcyclopentanone derivative with a low-valent transition metal complex (5E) - A novel method for producing Glostaglandin E, etc. is provided.

The 2-allyloxycarbonylcyclopentanone derivative represented by the above formula (1) used as a raw material in the present invention is a new compound, and is obtained by a method separately proposed by the present inventors (Tanaka et al., JP-A-59-44336). ') as well as melting et al.

Tetrahedron Lettera+ 4087
(1976) and Roo, 8alomon et al.
J, Org, Chem-+ 40+ 1488 (19
It is manufactured according to the method described in 75).

That is, 4-substituted-2-cyclobentenones represented by the following formula (m), their enantiomers, or mixtures thereof in arbitrary proportions are represented by the following formula [■], which represents a group forming an L acetal bond. . ” and the following formula [v]CuQ
......The copper compound represented by [v] is subjected to a conjugate addition reaction with an organocopper compound obtained from the compound, and then reacted with a carbonate ester derivative represented by the following formula %, and optionally protected. By subjecting the hydroxyl group and/or carboxylic acid to a deprotection reaction, a 2-allyloxycarbonylcyclopentanone derivative, which is a compound represented by the following formula [■], its enantiomer, or a mixture thereof in any ratio, is produced. This is the way to do it. In addition,
In this patent specification, when expressing a compound represented by a formula, its enantiomer, or a mixture thereof in any proportion, it is expressed as a compound represented by the formula.

In the present invention, 4-substituted-2-cyclobentenones, which are the raw materials for producing the 2-allyloxycarbonylcyclopentanone derivative represented by the above formula (I), are represented by the above formula Cm). In the above formula (IT), R21
)IJ(C'.

~C,) represents a group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group.

) ') (C1-C1) hydrocarbon silyl group,
For example, trimethylsilyl, triethylsilyl, triisopropylsilyl, tri(C2-C4)alkylsilyl such as t-butyldimethylsilyl, diphenyl(C1-C4) such as t-butyldiphenylsilyl,
, )alkylsilyl group, tribenzylsilyl group, etc. are preferred, and among them, t-butyldimethylsilyl group is 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-Pro26-・Biru group, (2-methoxyethoxy)methyl group.

Penzyloquinemethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group.

or 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl group, and 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.

4-substituted-2-cy1 represented by the above formula (m)
Specific examples of clobentenones include all those in which R21 is substituted.

What should be noted here is that the compound of formula (m) above has an asymmetric carbon, and therefore optical isomers exist. From the standpoint of synthesizing prostaglandins, the absolute configuration at position 4 is preferably R, but even if it is the d/isomer (mixture of R and S), the stereoisomers will be separated at an appropriate stage in the subsequent process. Since it is possible, it is sufficient to achieve the purpose.

In the present invention, first, the above-mentioned 4-substituted 1-2-cyclobentenones are conjugated with an organocopper compound obtained from an organolithium compound represented by the formula (TV') and a copper compound represented by the formula (V). It is carried out by reacting.

The organolithium compound of formula (TV) can be obtained, for example, by reacting the corresponding iodide with t-butyllithium by a method known per se. formula(
In IV), Rml represents a group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group (C1-C,), and the same groups as 121 above are preferably mentioned.

In formula (IV), R'ij is a hydrogen atom or a methyl group.

Or it represents a vinyl group.

In formula (mV), R5 is a linear or branched C1-C8 alkyl group containing an oxygen atom; a substituted or unsubstituted phenyl group, phenoxy group, or C1-C8 alkyl group;
CIO cycloalkyl group; or C5-C, alkoxy group, optionally substituted phenyl group, phenoxy group,
or 03-C1fl represents a linear or branched C2-C, alkyl group substituted with a cycloalkyl group.

Straight chain or branched chain C3-C which may contain oxygen,
Examples of the alkyl group include 2-methoxyethyl group, 2-ethoxyethyl group, and propyl group.

Butyl group, pentyl group, hexyl group, heptyl group, 2-
Examples include hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, 2-methylhexyl group, 2,2-dimethylhexyl group, but butyl group, pentyl group, hexyl group pheptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2
-Methylbutyl group and 2-methylpentyl group are preferred.

Substituted phenyl group, phenoxy group, or C1-CIO
Substituents for the cycloalkyl group include, for example, a halogen atom, a protected hydroxyl group (such as a silyloxy group, a C4
-C6 alkoxy group, etc.), C5-C4 alkyl group, etc.

Examples of the cycloalkyl group of C1 to CIO include cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclohexenyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, etc.
Cyclopentyl group and cyclohexyl group are preferred.

01-C, alkoxy group, optionally substituted phenyl group, phenoxy M, 4L<ViC3-C2゜ straight or branched chain C1-C substituted with cycloalkyl group
, alkyl groups, examples of C1-C6 alkoxy groups include methoxy, ethoxy, propyloxy, isopropyloxy, butquin, t-butoxy, and hexyloxy groups.

A substituent of an optionally substituted phenyl group, phenoxy group, or C3~Qo cycloalkyl group and a C3~
As the CIO cycloalkyl group, the same ones as mentioned above can be mentioned.

Examples of straight chain or branched C7-C, alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 1lee-butyl group, t-butyl group, pentyl group, etc. be able to. Preferred examples of R5 include a cyclopentylmethyl group and a cyclohexylmethyl group. Note that the substituent may be bonded to any position thereof.

In formula (IV), "represents 0 or 1".

On the other hand, Q in the copper compound of formula (V) is a chlorine atom, a bromine atom, an iodine atom, a cyano group,
A phenylthio group or a 1-pentynyl group.

In order to obtain an organocopper compound from the organolithium compound of formula (■) and the copper compound of formula [v], for example, documents G, H, Po
5ner, Organic Reaction, v
ol, 19゜1 (1972); Tetrahd
oron LetL+ 2L 1247 (1980)
;Noyori + Tetrahedron Letters
, 2] +1247 (1980), Dan4057 (
1982), 2, 5563 (1982), Dan, 11
87 (1983), 24.4103 (1983).

and 25.1383 (1984) are referred to as references.

In the method of the present invention, a trivalent organophosphorus compound such as a trialkylphosphine (eg, triethylphosphine) is used together with an organocopper compound.

tributylphosphine, etc.), trialkyl phosphites (e.g., trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tri-n-
This conjugate addition reaction proceeds smoothly when phosphite (such as butyl phosphite), hexamethylphosporastriamide, or triphenylphosphine is used, but tributylphosphine and hexamethylphosphorustriamide are particularly preferably used.

The method of the present invention uses 4-substituted-2 represented by the above formula ClID.
- 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 4-substituted-2-cyclobentenones and the organocopper compound react equimolarly in terms of chemical theory, usually
0.5 per mole of substituted-2-cyclobentenones
The amount of the organic copper compound is 2.0 times, preferably 0.8 to 1.5 times, particularly preferably 1.0 to 1.3 times by mole.

The reaction temperature is -100°C to 20°C, particularly preferably -78°C.
A temperature range of about °C to 0 °C is adopted. Although 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 33 that is liquid at the reaction temperature and does not react with the reaction reagent is used.

Such aprotic inert organic media include, for example,
Pentane, hexane, heptane.

Saturated hydrocarbons such as cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, -)methoxyethane.

Examples include unaether solvents such as diethylene glycol dimethyl ether, and so-called aprotic polar solvents such as hexamethylphosphoric triamide (HMP), dimethyl sulfoxide, and sulfolane, and can also be used as a mixed solvent of two or more solvents. It is possible. 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 the 4-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, usually 1 to 100 times the volume of the raw materials, preferably Fi2
~20 times the volume is used.

The trivalent organophosphorus compound may be present during the above-mentioned preparation of the organocopper compound, and the 4-substituted-
The reaction can also be carried out by adding 2-cyclobentenones.

In the method of the present invention, a substituted alkenyl group, which is the organic group moiety of the organocopper compound, is added to the 3-position of the 4-substituted-2-cyclopenteno 7 in the reaction system through the operations performed so far, and It is assumed that a so-called conjugate addition elerate is formed in which an anion is generated.

In the present invention, the above formula (V
By reacting the carbonate ester derivative represented by l), the desired 2-allyloxycarbonylcyclopentanone represented by the above formula (1) is produced.

In the carbonate ester derivative represented by formula [■], 2 represents a chlorine atom, a bromine atom, a phenylthio group, or a 1-imidazole group, and a chlorine atom and an I-imidazole group are preferred.

In formula (Vl), X represents a cis-vinylene group or a trans-vinylene group, and regardless of which group is used, the final product can be obtained as a trans-vinylene group.

In formula (VT), R11 is a C1-C1° alkyl group.

It represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted C1-C3° cycloalkyl group, or a substituted or unsubstituted phenyl(C1-C,)alkyl group.

Examples of C7 to C111 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ee-butyl group, t-butyl group, pentyl group, hekynyl group, hepetyl group, and octyl group. ,
Linear or branched groups such as nonyl and decyl groups can be used.

Substituents for substituted or unsubstituted phenyl groups include, for example, halogen atoms, protected hydroxy groups I C1-
C, acyloxy group, nitrile group, nitro group, or (C
+-Ca)alkoxycarbonyl group and the like are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. C7-C, acroxy group, for example, acetoxy group, propionyloxy group,
butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, caproyloxy 7 group,
Examples include enantyloxy group and benzoyloxy group. Examples of the (C+-Ca)alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, and a hexyloxycarbonyl group.

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

Substituted or unsubstituted C1-C111 cycloalkyl groups include saturated or unsaturated C1-C10, preferably C3-C6, particularly preferably C0, substituted with the same substituents as mentioned above or unsubstituted. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, and the like.

As the substituted or unsubstituted phenyl (C1-C,)alkyl group, the phenyl group is substituted with the same substituent as mentioned above, or an unsubstituted benzyl group, α-phenethyl group, β-phenethyl group is used. can give.

Among these, R11 is preferably a C1 to C1O alkyl group, a phenyl group, an IC1 to C10 cycloalkyl group, or a phenyl (O1 to C,) alkyl group.

In the method of the present invention, the reaction between the conjugate addition elerate produced in the reaction system and the carbonate derivative represented by formula (VT) results in the diconjugate addition of the organocopper compound to 4-substituted-2 to cyclobentenones. It is carried out by adding the carbonate ester derivative represented by the above formula [■] into the reaction system in the presence or absence of the above-mentioned aprotic organic medium (particularly preferably hexamethylphosphoric triamide). .

The carbonate ester derivative reacts with the erulate produced by the conjugate addition reaction in a stoichiometrically equimolar amount, but usually 0.5 molar amount relative to the initially used 4-41-substituted-2-cyclobentenone. ~5.0 mole times, preferably 0.7-2
．． It is carried out using 0 times the molar amount, particularly preferably 0.8 to 1.2 times the molar amount.

The reaction temperature is -100°C to 0°C, preferably -8°C to -
A temperature range of about 20°C is adopted. The reaction time varies greatly depending on the type of carbonate ester derivative used and the reaction temperature, and the reaction is usually completed at -78°C to -30°C for about 1 hour to 50 hours, but the end point of the reaction is determined by thin layer chromatography. It is efficient to track and determine using graphics.

The alkylation reaction using the carbonate ester derivative in the method of the present invention is preferably carried out in the presence of the aforementioned aprotic polar solvents, especially hexamethylphosphoric triamide, and good results are often obtained. After the reaction, it is separated and purified by conventional means (post-treatment, extraction, washing, chromatography, distillation, or a suitable combination thereof).

In this way, a protected 2-allyloxycarbonylcyclopentanone derivative represented by the following formula (1/-) is obtained, which is protected by a method known per se (protected hydroxyl group and/or carboxylic acid By carrying out the deprotection reaction, a 2-allyloxycarbonylcyclopentanone derivative represented by the above formula [■], which is the desired new compound group, can be obtained.

As judged from the above explanation, the reaction of the present invention proceeds in a position-specific manner, and the 3-substituted 4-substituted-2-cyclobentenones
A substituted alkenyl group is introduced at the 2-position, and a substituted allyloxycarbonyl group is introduced at the 2-position.
The substituent at position, the newly introduced substituent at position 3, and the substituent newly introduced at position 3,
The newly introduced substituents at the position and the 2-position are introduced while maintaining a trans relationship with each other. Therefore, the above formula (
From the 4-substituted-2-cyclobentenones having the steric structure represented by m), a 2-allyloxycarbonylcyclopentanone derivative having the steric structure represented by the above formula CI) is obtained as a product; The enantiomer of the formula (m) will yield the enantiomer of the formula [■], and the stereoisomer mixture will yield a product reflecting the initial mixing ratio.

One more thing to note is that although asymmetric carbon exists in the organolithium compound represented by formula (mV), the method of the present invention includes any stereoisomer, and a mixture of stereoisomers in any proportion can be used without any problem. I can do it. Moreover, even if a stereoisomeric mixture is used in any proportion, if the other raw material, 4-substituted-2-cyclobentenone, is optically pure, the final product separated at an appropriate stage will be optically pure. This is one of the major features of the method of the present invention.

In this way, novel 2-allyloxycarbonylcyclopentanones represented by the above formula C1,), their enantiomers, or mixtures thereof in arbitrary proportions are obtained. Typical examples of derivatives having the above-mentioned properties are shown below.

(Of) (2R,3R,4R) -2-1Zl-6-
Carboxy-2-hexenyloxycarbonyl) -3-((Sl-(Bl-3-hydroxy-
1-octenyl)-4-hydroxycyclopentanone (O2) (2R,3R,4R)-2-((El-6-lylboxy2-hexenyloxycarbonyl)-3-(+8)-(t))-3 -Human(1xy-1-octenyl)-4-hydroxycyclopentanone (O3)(2R,3R,4R)-2-((2))-6-
Carpoxo 2-hexenyloxycarbonyl) -3-((St-(t))-3-hydroquine-3-methyl-1-octenyl) -4-hydroxyclopentanone (O4) (2R, 3R, 4R) -2-((El-6-carpoxy-2-hexenyloxycarbonyl) -3-((S)-(t))-3-hydroxy-3-methyl-1-octenyl) -4-hydroxycyclopentanone 1 (O5) (2R, 3R, 4R) 2
((Zl 6-carboxy-2-hexenyloxycarbonyl) -3-((R1-(t))-3-hydroxy-3-methyl-1-octenyl) -4-hydroxyclopentanone (O6) ( 2R, 3R, 4R)-2-((g))-6-
carpoquine-2-hexenyloxenyl-7carbonyl) -3-((R1-FW)-3-human0loquine-3-methyl-1-octenyl) -4-hydroxycyclopentanone (O7) (2R,3R,4R)-2 -((Zl6-carboxy-2-hexenyloxycarbonyl)-3-((t))-3-human waxy 3-vinyl-]-octenyl)-4-hydroxycyclopentanone(O8) (2R, 3R, 4R) -2-((E)-6-carpogin-2-hexenyloxycarbonyl)-3-((El-3-hydroquine-3-vinyl-1-octenyl)-4-hydroxycyclopentanone (O9) ( 2R, 3R, 4R)-2-(fZl-6-
carboxy-2-hexenyloxene(carbonyl)-3-((S)-(t))-3-hydroxy-
3-Cyclopentyl-1-propenyl)-4-hydroxycyclopentanone (10)(2R,3R,4R)-2-((t))-6-
Carboxy-2-hexenyloxycarponyl)-3-((81-(t))-3-hydroxy-3-cyclopentyl-1-propenyl)-4-hydroxycyclopentanone (11)(2R,3R,4R )-2-((2))-6-
Carboxy-2-hexenyloxycarbonyl) -3-((81-(El -3-hydroxy-3-cyclohexyl-1-propenyl)-4-hydroxycyclopentanone (12) (2R,3R,4R)- 2-((E)-6-carboxy-2-hexenyloxycarbonyl)-3-((Sl-(t))-3-hydroxy-3-cyclohexyl-1-propenyl)-4-hydroxycyclopentanone (13) (2R,3R,4R)-2-((Zl-6-carboxy-2-hexenyloxycarbonyl)-3-((38,58)-(ex-3-hydroxy-5-methyl- 1-nonenyl)-4-hydroxycyclopentanone (14) (2R,3R,4R) -2-((El-6
-carboxy-2-hexenyloxycarbonyl)-3-((3S,5S)-(El-3-hydroquine-5-methyl-1-nonenyl)-4-hydroxycyclopentanone (15) (2R,3R ,4R)-2-((Zl-6-carboxy-2-hexenyloxycarbonyl)-3-((3S,5R)-(El-3-hydroxy-5-methyl-1-nonenyl)-4-hydroxy Cyclopentanone (16) (2R,3R,4R)-2-((EI-6-carboxy-2-hexenyloxycarbonyl)-3-((3S+5R)-(E)-3-hydroxy-5- Methyl-1-nonenyl)-4-hydroxycyclopentanone (17)(2R,3R,4R)-2-((2))-6-
carboxy-2-hexenyloxycarbonyl) -3-((sl-CFJl -3-hydroxy-4-cyclohexyl-1-butenyl)-4-hydroxycyclopentanone (18) (2R,3R,4R)-2-NZ >-6-carboxy-2-hexenyloxycarbonyl)-3-((S)-(El-3-hydroxy-5-cyclopentyl-1-pentenyl)-4-hydroxycyclopentanone (19) (2R, 3R, 4R)-2-((Zl-6-carboxy-2-hexenyloxycarbonyl)-3-((81-(El-3- and droxy-4,4-dimethyl-1-octenyl)-4-hydroxy cyclopentanone (20) (2R,3R,4R)-2-NZ)-6-carpoxy-2-hexenyloxycarbonyl)-3-((81-(El-3-hydroxy-4-phenoxy-1-butenyl) )-4-Hydroxycyclopentanone (21) (2B, 3R, 4R)-2-NZ)-6-carboxy-2-hexenyloxycarponyl)-3-((Sl-(El-3-hydroxy-
4-(m-chlorophenoxy)-1-butenyl)-4-hydroxycyclopentanone (22)(2R,3R,4R)-2-1Z)-6-carpoxy2-hexenyloxycarbonyl)-3-( (81-(t))-3-Hydroxy-5,9-dimethyl-1,8-decadi4-4-hydroxycyclopentanone (23) (2R,3R,4R)-2-(( ZI-6-
carpoquin-2-hexenyloxycarbonyl) -3-(+8)-(El -3-hydroxy-4-methyl-1-octenyl) -4-hydroxycyclopentanone (24) (2R,3R,4R)-2 -((2))-6-
carpoquin-2-hexenyloxycarbonyl)-3-((El-4-hydroxy-4-methyl-1-octenyl)-4-hydroxycyclopentanone (25)(2R,3R14R)'-2-((Zl -6-
Carboxy-2-hexenyloxycarbonyl)-3-((t))-4-hydroxy-4-methyl-1-octenyl)-4-hydroxycyclopentanone (26)(2R,3R,4R)-2 -((g))-6-
Carboxy-2-hexenyloxycarbonyl)-3-((t))-4-hydroxy-4-methyl-1-octenyl)-4-hydroxycyclopentanone (27) (2R,3R,4R)-2 -NZ)-6-carpoxy2-hexenyloxycarbonyl)-3-(+E'l -4-hydroxy-4-vinyl-1-octenyl)-4-hydroxycyclopentanone (28) (2R, 3R, 4R: )-2-1El-localoxy2-hexenyloxycarbonyl)-3-((El-4-hydroxy-4-vinyl-1-octenyl)-4-hydroxycyclopentanone (29)(O1) to (29 ) methyl esters (30
) (O1) to (29) ethyl esters (31) (O
1) to (29) t-butyl esters (32) (O1) to (29) decyl esters (33)
) (O1) to (29) phenyl esters (34) (
Cyclohexyl esters (35) of O1) to (29), benzyl esters (35) of (O1) to (29)
6) Phenethyl esters (37) of (O1) to (29)
(O1) to (36) bis(t-butyldimethylsilyl) ethers (38) (O1) to (36) bis(2-tetrahydropyranyl) ethers (39) (O1) to (36) 4-t-Butyldimethylsilyl-3' (or 4')-) dimethylsilyl ethers (40) (O1) to (36) 2-Tetrahydropyranyl) ethers (41) (Ol) to (36) 4-(2-tetrahydropyranyl)-3' (or 4')-butyldimethylsilyl ethers (42) (Ol) Examples include, but are not limited to, the mirror bodies of (41).

t The method of the present invention is achieved by reacting the thus obtained 2-allyloxycarbonylcyclopentanone represented by the formula CI), which is a raw material for the method of the present invention, with a low-valent transition metal complex.

Examples of low-valent transition metals include zero-valent palladium, zero-valent nickel, zero-valent platinum, and monovalent rhodium, with zero-valent palladium being particularly preferred. These low-valent transition metals are preferably used in the form of a complex coordinated with a suitable ligand. The most preferred ligand for such a complex is triphenylphosphine, and a specific example of a triphenylphosphine complex is tetrakis(triphenylphosphine)palladium (O1).

Tetrakis(triphenylphosphine)nickel (11
, tetrakis (triphenylphosphine 7) platinum (O),
or tris(triphenylphosphine)rhodium+I
) chloride, and tetrakis(triphenylphosphine)palladium (O) is particularly preferred.

Since such a transition metal complex acts catalytically on the decarboxylation reaction of 2-allyloxycarbonylcyclopentanones, it is necessary to An amount of mol % to 30 mol %, usually 3 to 10 mol %, preferably 5 mol %, exhibits a sufficient function as a catalyst.

It is generally known that in this type of reaction, the progress of the reaction and the products vary slightly depending on the solvent used, but in the method of the present invention, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran are used.

Benzene, t-butanol, etc. can be suitably used, and N,N-dimethylformamide is particularly preferably used. The amount of solvent used is 1 to 10% based on the volume of reactant.
The amount used is 0 times the volume, preferably 5 to 30 times the volume.

The reaction temperature is 0°C to 100°C, preferably 20°C to 60°C.
The reaction time varies depending on the reaction temperature, so the reaction is monitored using thin layer chromatography, etc., but it is usually carried out at 20°C to 60°C for 10 minutes to 5 hours = 5
3- The gap is sufficient.

After the reaction, isolation operations such as extraction, washing, and chromatographic separation are carried out by conventional methods to obtain the compound represented by the above formula (IT) (
5E)-Prostaglandin E2s or stereoisomers thereof are obtained.

It is known that the decarboxylation allylation reaction of the method of the present invention proceeds stereospecifically while maintaining positional specificity. Therefore, the configuration of the 2-position of the starting material 2-allyloxycarbonylcyclopentanone remains unchanged in the product (5E)-prostaglandin E.

As a result, the configuration at the 2-position is uniquely determined. In other words, 3
The initial 4-substituted-2-cyclobentenones are converted into 3
A substituted alkenyl group, which is the organic group part of the organosteel lithium compound, was introduced at the 4th position while maintaining a trans steric relationship with the substituent at the 4th position, and then a substituted allyl group was introduced at the 2nd position, and from now on the 3rd position This is due to the fact that it is introduced while maintaining a trans steric relationship with the substituted alkenyl group. Furthermore, a characteristic result of the method of the present invention is that a double bond (double bond at the 5th and 6th positions in the prostaglandin nomenclature) derived from the carbonate derivative represented by the formula (VT) is produced in the process of decarboxylation and allylation. has the E form, i.e., 5.6-) lance conformation (5E
)-prostaglandin E, etc. are produced.

Among the (5E)-prostaglandin E represented by the formula (IT) thus obtained, the derivative in which R1 and R1 are hydrogen atoms is itself physiologically active, and the natural prostaglandin Etm is 52 They are a group of compounds that are useful as pharmaceuticals, as they are expected to exhibit unique physiological activities compared to their three-dimensional structures.

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

Example 1 (81-(El-3-t-butyldimethylsilyloxy-1-iodo-octene (2,024g + 5.5m
1.9 M t-
Butyllithium in pentane solution (5.79 ml).

11-Ommol) was added at -78°C and stirred for 2 hours. Add 1-pentynyl copper (7181R9゜5) to this solution.
．． 5 mmol) and hexamethylphosphorus triamide (1-79 g, 11.0 mmoA!)
y+/) solution was added and stirred at -78°C for 1 hour. Then (R)-4-t-butyldimethylsilyloxy-2-
Cyclobentenone (1,06g, 5.0 mmo
Add an ether (10 m/) solution of J) to this reaction solution.
It was added at 8°C and stirring was continued at -40°C for 2 hours.

Furthermore, IZ)-6-medoxycarbonyl-2-hex
1senylchloroforme) (2,43Fl, 1
Add a solution of 1.0 mmo/) in ether (10 liters),
The mixture was stirred at -40°C for 1 hour. 4.0M acetate buffer was added and extracted with hexane, and the resulting organic layer was washed successively with an aqueous ammonium chloride solution and 1 brine, dried over anhydrous magnesium sulfate, and concentrated after washing to obtain a crude product. . This product was separated by silica gel column chromatography (hexane:ethyl acetate≠10:1), and (2R, 3R,
4R)-2-((Zl-6-medoxycarbonyl-2
-hexenyloxycarbonyl) -3-((81-(
))-3-t-Butyldimethylsilyloxy-1-octenyl)-4-t-butyldimethylsilyloxycyclopentanone (2,36El, 3.7 mrno
1, 174%).

'HNMR (CDCJs, δ (ppm)); 0.0
3 and 0.06 (12H), 0.87 (21H).

1.1-1.5 (8H, m), 1.6-2.6 (8
H, m).

3.0-3.2 (2H, m), 3.60 (3H
,s)-3, Fl-4,2(2H,m), 4.6
0 (2H, d, J=5Hz).

5.3-5.6 (4H, m).

IR (liquid film + Cr1L-'); 2870, 1?65. 1740. 1645. 1
245°1120.965,845,835. '175
゜(a)”D 27.8°(CO, 58, Meo
H) FD-MS; 639 (M+1), 581 (M-
57).

E IMS (20eV; n+/e 1%
); 581 (M-57, 14), 481 (6), 423
(62).

323(21), 265(39), 195(29).

141 (Zoo), 75 (80).

“CNMR (CDCIl, a) Knee 4.8.
-4.3. 14.0. 18.0. 18.2. 2
2.6. 24.6°25.0. 25.9, 26.9
．． 31.8.33.6. 38.4, 47.4゜51
．． 5, 51.7, 60.5, 61.2, 72.6. 1
24.2°126.7. 134.1. 136.9.
167.7. 173.8゜206.5゜Example 2 The conjugate addition reaction was carried out under almost the same conditions as in Example 1 (scale 7.0 mmoj), and the obtained erulate solution K
1-((Zl-6-medoxycarbonyl-2-hexenyloxycarbonyl)imidazole (2,094
A solution of 11,8,3 mrnol, ) 1.18 eq) and hexamethylphosphoric triamide (IQm/) in tetrahydrofuran (20 m/) was added and stirred at -40°C for 3 hours. After post-treatment and column separation in the same manner as in Example 1, (2R,3R,4R)-2-(+Z)-6-medoxycarbonyl-3-hexenyloxycarbonyl)-
3-(+8l-(El-3-t-butyldimethylsilyloxy-1-octenyl)-4-t-butyldimethylsilyloxycyclopentanone (1,83112,87
mmol+41%) was obtained. Various spectral data of this product were consistent with those of Example 1.

Example 3 ( 2 R, 3R, 4R) obtained in Example Process and 2
-2-((Zl -6-medoxycarbonyl-2-tol
xenyloxycarbonyl)-3-((sl-
(El3-t-butyldimethylsilyloxy-1-octenyl)-4-t-butyldimethylsilyl oxine cyclobentanone (1-43fi, 2.24 mmol
) was dissolved in 10 ml of N,N-dimethylformamide, and after purging with argon, tetrakis(triphenylphosphine)palladium (O1 (130~).

0.112 mmoA'+·5 ma1%) was added thereto, and the mixture was heated and stirred at 50° C. for 30 minutes. Water was added and extracted with hexane, and the resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated on a Roca column to obtain a 1.36 F crude product. This book describes silica gel column chromatography (hexane: acid 11x-f-ru 19:
3) Addition of K gave (5E)-31°15-bis(t-butyldimethylsilyl) prostaglandin E, methyl ester (850q, L43mrno1.64%).

'HNMR (CDCA'3.δ (ppm)): 0.
03 and 0.06 (12H), 0.8~1.0 (2
1H).

1.1-1.5 (8H, m), 1-5-2.8 (12H
2m).

3.53 (31(,s), 3.7~4.2 (2
H,m).

5-1~5.3 (2H, m), 5.3~5.5 (
2IT, m).

JR (liquid film, cIn-1); 1745, 1250. 1095. 1005. 9
65. 9210835.775°(al”p 42°(CO,81,MeOH)FD-
MS; 537 (M-57).

El-MS (20eV; m/a, %); 5
79 (M-15, 3), 538 (100), 537 (9
9).

512 (23), 463 (17), 405 (50).

379(41), 337(58), 277(78).

245(49), 215(43), 161(37).

73(98).

"CNMR (CD(J,, δ); -4,6,-4,2,14,1,l 8.1. 18.
3. 22.1024.6. 25.1. 25.9.
30.4, 31.9. 33.4°38.6,47.
7,51.4.52.1.53.9.72.8゜73.
4. 127.4. 128.6. 132.2. 1
36.5°174.0. 215.4゜Example 4 (5K)-11,15-pyro-1-s(t-butyldimethylsilyl) prostaglandin E obtained in Example 3
2 methyl ester (510 μ, 0.86 mmoJ) was dissolved in 10-acetonitrile, and pyridine (O, 51
17), hydrofluoric acid-pyridine (1.0 m/) was added, and the mixture was stirred at room temperature for 3 hours. The aqueous solution obtained by adding a saturated aqueous sodium hydrogen carbonate solution was extracted with ethyl acetate, and the separated organic layer was washed with a saturated aqueous potassium hydrogen sulfate solution and brine, dried (MgSO,), and concentrated to 300 μm. A crude product was obtained. This product was subjected to silica gel column chromatography (hexane:ethyl acetate/L, g=1:2)
After separation, 5E)-prostaglandin E2 methyl ester (184 μm, 0.50 mmoC 58%) was obtained.

'HNMR (CDCj3.δ(Ppm)): 0-85
(3I(,m), 1.0~2.9 (22H,m)
.

3.54 (3H, s), 3.65-4.20 (2H, m
).

5.05-5.30 (2H, m), 5-30-5.50
(2H+m).

IR (liquid film + (:ML'): 3410.17
40.1245, 1160.1075°1015.96
5,910,730° (a) Sweet-62° (C0,90, MeOH) FD-MS
; 367 (M+1), 349 (M-17)E I
MS (20eV; m/e*%); 3
48 (M-18, 10), 330 (20).

317(6), 299(8), 277(23).

245 (16), 208 (42), 190 (100).

164 (2B), 141 (33), 133 (27).

119(50), 109(21), 108(23).

107(22), 99(24).

13CNMR (CDC/, δ); 14.0.22
．． 6, 24.5, 25.2, 30.1, 31.1031
．． 8, 33.4, 37.4.46.3, 51.5.53
．． 2゜54.6, 72.1, 72.8. 127.2,
130.5, 132.5° 137.3, 174.1, 2
13.9° Examples 5 to 13 The following compounds were synthesized in the same manner as in Examples 1 and 2.

Example 5: (2R,3R,4R)-2-((g))
-6-Medoxycarbonyl-2-hexenylokynecarbonyl)-3-((81-(E)-3-t-butyldimethylsilyloxy-1-octenyl)-4-t-butyldimethylsilyloxycyclopentanone (68%).

Example 6; (2R,3R,4R)-2-NZI-6
-methoxycarbonyl-2-hegysenyloxycarbonyl) -3-((El -3-)dimethylsilyloxy-3-methyl-1-octenyl)-4-t-butyldimethylsilyloxycyclopentanone (64% ).

Example 7: (2R,3R,4R)-2-((Zl-
6-methoxycarbonyl-2-hexenyloxycarponyl) -3-((81-(B)-3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)-4-t-butyldimethylsilyloxy Cyclopentanone (73%).

Example 8: (2R,3R9JR)-2-NZI-6-
+methoxycarbonyl-2-hexenyloxycarbonyl)-3-((S) 1El-3-t-butyldimethylsilyloxy-3-cyclohexyl-1-propenyl)
-4-tert-butyldimethylsilyloxycyclopentanone (73%).

Example 9; (2R,3R,4R)-2-((Z)-
6-methoxycarbonyl-2-hexenyloxycarbonyl)-3-((3S,5S)-(t))-3-t
-butyldimethylsilyloxy-5-methyl-1-nonenyl)-4-t-butyldimethylsilyloxycyclopentanone (72%).

Example 1o; (2R,3R,4R)-2-((Zl
-6-Medoxycarbonyl-2-hexenyloxycarbonyl) -3-((3S,5R)-(t))-3-
t-Butyldimethylsilyloxy-5-methyl-1-nonenyl)-4-t-butyldimethylsilyloxycyclopentanone (71%).

Example 11; (2R,3R,4R)-2-((Zl
-6-Medoxycarbonyl-2-hexenyloxycarbonyl)-3-((S) -(E)-3-t-butyldimethylsilyloxy-4,4-dimethyl-1-octenyl)-4-t- Butyldimethylsilyloxycyclopentanone (61%).

Example 12; (2R,3R,4R)-2-((Z)-6
-Medoxycarbonyl-2-hexenyloxycarponyl)-3-((El-4-trimethylsilyloxy-4-methyl-1-octenyl)-4-t-butyldimethylsilyloxycyclopentanone (58%).

Example 13; (2R,3R,4R)-2-NZI-6
-Medoxycarbonyl-2-hexenyloxycarbonyl)-3-((El-4-)dimethylsilyloxy-4
-vinyl-1-octenyl)-4-t-butyldimethylsilyloxycyclopentanone (56%).

Characteristic spectral data of these compounds are listed in Table 1.

Examples 14-22 The following compound was synthesized by the same method as in Example 3.

Example 14; (5E)-11,15-bis(1-butyldimethylsilyl) PGE, methyl ester (80%
).

Example 15; (5E)-11-t-butyldimethylsilyl-15-trimethylsilyl-15-methyl-PGE,
Methyl ester (59%).

Example 16; (5F)-11,15-bis(1-butyldimethylsilyl) -16,17,18,19°20-
Pentanol-15-cyclopentyl-PG E2 methyl ester (63%).

Example +7; (5E)-11,15-bis(1-butyldimethylsilyl)-16,17,18,19°20-pentanol-15-cyclohexyl-PGE2 methyl ester (61%).

Example 18; (5E)-11,15-bis(1
-butyldimethylsilyl) -17(S), 20-dimethyl-1'GE, methyl ester (58%
).

Example 19; (5F)-11,15-bis(1-butyldimethylsilyl)-17(R1,20-dimethyl-PG
E2 methyl ester (59%).

Example 20: (5E)-11,15-bis(1-butyldimethylsilyl)-16,16-dimethyl-PGE, methyl ester (60%).

Example 21: (5E)-11-t-Butyldimethylsilyl-15-deoxy-16-toIJ methylsilyloxy-16-methyl-PGE, methyl ester (55%
).

Example 22; (5E)-11-t-butyldimethyl7ly-15-deoxy-16-drimethylsilyloxy-16-vinyl-PGE, methyl ester (49%)
.

Characteristic spectral data of these compounds are listed in Table 2.

Examples 23-30 The following compound was synthesized by the same method as in Example 4.

Example 23: (5E)-15-methyl-PGE2 methyl ester (65%).

Example 24: (5K > -16,17,18,1
9,20-pentanol-15-cyclopentyl-PCB
.

Methyl ester (82%).

Example 25; (5K) -16,17,18,1
9,20-pentanol-15-cyclohexyl-PG
E.

Methyl ester (79%).

Example 26; (5E)-178,20-dimethyl-PG E2 methyl ester (89%).

Example 27; (5E)-171,20-dimethyl-PG
E, methyl ester (87%).

Example 28; (5E)-16,16-dimethyl-PGE, methyl ester (79%).

Example 29; (5g) -15-deoxy-16-hydroxy-16-methyl-PGE, methyl ester (82%
).

Example 30; (5E)-15-deoxy-16-hydroxy-16-pinyl-PGE, methyl ester (74%
).

Characteristic spectral data of these compounds are listed in Table 3.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼……[I] [In the formula, R^1 is a hydrogen atom, C_1 to C_1_0 alkyl group, substituted or unsubstituted represents a phenyl group, a substituted or unsubstituted C_3-C_1_0 cycloalkyl group, or a substituted or unsubstituted phenyl (C_1-C_2) alkyl group, R^2 and R^3 are the same or different, and a hydrogen atom, a 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^4 represents a hydrogen atom, methyl group, or vinyl group, and R^5 contains an oxygen atom. Straight chain or branched chain C_3-C_8 alkyl group; substituted or unsubstituted phenyl group, phenoxy group, or C_3-C_1_0 cycloalkyl group; or C_1-C_6 alkoxy group, optionally substituted phenyl group, phenoxy group, or C_3 to C_1_0
Represents a straight chain or branched chain C_1 to C_5 alkyl group substituted with a cycloalkyl group. Moreover, X represents a cis-vinylene group or a trans-vinylene group, and n is 0
Or represents 1. ] The following formula [II] is characterized by reacting a 2-allyloxycarbonylcyclopentanone derivative, which is a compound represented by the formula and its enantiomer or a mixture thereof in any proportion, with a low-atom transition metal complex. , chemical formulas, tables, etc.▼・・・・・・・・・
[II] [In the formula, R^1, R^2, R^3, R^4, R^5, and n are the same as defined above. ] A novel method for producing (5E)-prostaglandin E_2, which is a compound represented by the following and its enantiomer or a mixture thereof in any proportion. 2. The low-valent transition metal complex is tetrakis(triphenylphosphine)palladium(O), tetrakis(triphenylphosphine)nickel(O), tetrakis(triphenylphosphine)platinum(O), or tris(triphenylphosphine) The method for producing rhodium (I) chloride according to claim 1. 3. The production method according to claim 1, wherein the low-valent transition metal complex is tetrakis(triphenylphosphine)palladium (O). 4. The production method according to any one of claims 1 to 3, wherein the reaction with a low-valent transition metal complex is carried out in N,N-dimethylformamide. 5. The following formula [III] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ...... [III] [In the formula, R^2^1 is a tri(C_1-C_7) hydrocarbon silyl group or acetal together with the oxygen atom of the hydroxyl group. Represents a group that forms a bond. ] 4-Substituted-2-cyclopentenones, their enantiomers, or mixtures thereof in arbitrary proportions represented by the following formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼......[IV] In the formula, R^4, R^5, and n are the same as defined above, and R^3^1 is 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. represent. ] and the following formula [V]CuQ...[V] [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 [VI] ▲ There are mathematical formulas, chemical formulas, tables, etc. is a C_1 to C_1_0 alkyl group,
Represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted C_3-C_1_0 cycloalkyl group, or a substituted or unsubstituted phenyl (C_1-C_2) alkyl group, and Z is a chlorine atom, a bromine atom, a phenylthio group, or 1 - represents an imidazole group, and X is as defined above. ] By reacting with the carbonate ester derivative represented by and optionally subjecting to the deprotection reaction of the protected hydroxyl group and/or carboxylic acid, the following formula [I] ▲Mathematical formula, chemical formula, table, etc. are obtained▼... ...[I] [In the formula, R^1, R^2, R^3, R^4, R^5, X
, and n are the same as defined above. ] The following formula is characterized in that a 2-allyloxycarbonylcyclopentanone derivative, which is a compound represented by the formula and its enantiomer or a mixture thereof in any proportion, is produced and then reacted with a low-valent transition metal complex. [I
I]▲There are mathematical formulas, chemical formulas, tables, etc.▼......[II] [In the formula, R^1, R^2, R^3, R^4, R^5 and n are the same as defined above. . ] A method for producing (5E)-prostaglandin E_2, which is a compound represented by the following and its enantiomer, or a mixture thereof in any proportion. 6. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼......[I] [In the formula, R^1 is a hydrogen atom, C_1 to C_1_0 alkyl group, substituted or unsubstituted phenyl group, substituted or Represents an unsubstituted C_3-C_1_0 cycloalkyl group or a substituted or unsubstituted phenyl (C_1-C_2) alkyl group, R^2 and R^3 are the same or different, and a hydrogen atom, a tri(C_1-C_7) hydrocarbon Represents a silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R^4 represents a hydrogen atom, a methyl group, or a vinyl group, and R^5 represents a straight chain or branched chain that may contain an oxygen atom. Branched C_3-C_8 alkyl group; substituted or unsubstituted phenyl group, phenoxy group, or C_3-C_1_0 cycloalkyl group; or C_1-C_6 alkoxy group, optionally substituted phenyl group, phenoxy group, or C_3-C_1_0
Represents a straight chain or branched chain C_1 to C_5 alkyl group substituted with a cycloalkyl group. Moreover, X represents a cis-vinylene group or a trans-vinylene group, and n is 0
Or represents 1. ] A 2-allyloxycarbonylcyclopentanone derivative which is a compound represented by the above, its enantiomer, or a mixture thereof in any proportion. 7. The 2-allyloxycarbonylcyclopentanone derivative according to claim 6, wherein X is a cis-vinylene group. 8. The 2-allyloxycarbonylcyclopentanone derivative according to claim 6, wherein X is a trans-vinylene group. 9. The 2-allyloxycarbonylcyclopentanone derivative according to any one of claims 6 to 8, wherein n is 0. 10. The 2-allyloxycarbonylcyclopentanone derivative according to any one of claims 6 to 8, wherein n is 1. 11. Claims 6 to 10, wherein R^1 is a hydrogen atom, an alkyl group of C_1 to C_1_0, a phenyl group, a cycloalkyl group of C_3 to C_1_0, or a phenyl(C_1 to C_2) alkyl group 2-allyloxycarbonylcyclopentanone derivative according to any one of the items. 12. R^2 and R^3 are the same or different hydrogen atoms,
Tri(C_1-C_4)alkylsilyl group, diphenyl(C_1-C_4)alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2 −
Any one of claims 6 to 11 which is a methoxyethoxy)methyl group or a 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl group 2-allyloxycarbonylcyclopentanone derivative according to item 1. 13. Claims 6 to 13 in which R^4 is a hydrogen atom
2-allyloxycarbonylcyclopentanone derivative according to any one of Item 12. 14. Claims 6 to 14, wherein R^4 is a methyl group
2-allyloxycarbonylcyclopentanone derivative according to any one of Item 12. 15. Claims 6-- in which R^4 is a vinyl group
2-allyloxycarbonylcyclopentanone derivative according to any one of Item 12. 16, R^5 is a butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, cyclopentyl group, cyclohexyl group, phenyl The 2-allyloxycarbonylcyclopentanone derivative according to any one of claims 6 to 15, which is a phenoxy group, a cyclopentylmethyl group, or a cyclohexylmethyl group.