JPS6187638A - Preparation of 2,3-disubstituted-4-substituted cyclopentanone - Google Patents

Abstract

PURPOSE:To produce the titled compound from an easily available raw material, in short step, in high yield, by carrying out the conjugated addition reaction of a 4-substituted-2-cyclopentenone with an organic copper compound, and reacting the reaction product with a beta,gamma-unsaturated compound in the presence of an alkyltin compound. CONSTITUTION:The compound of formula I (R<2> is tri-hydrocarbon-silyl, or a group forming an acetal bond with the O of OH) is made to react with an organic copper compound prepared by the reaction of an organic lithium compound of formula RB-Li (RB is alkyl or alkenyl) with a copper compound of formula Cu-Q (Q is halogen, CN, phenylthio, etc.), in the presence of a trivalent organic phosphorus compound and an aprotic inert organic medium at -78-0 deg.C, and the resultant intermediate product is made to react with the compound of formula III (RA is alkyl; X is halogen or tosyl; Z is ethynylene or vinylene) in the presence of a compound of formula II (R is alkyl; Y is halogen or triflate) at -78--20 deg.C.

Description

[Detailed description of the invention]

Technical field> The present invention relates to 2,3-disubstituted-4-1i! Concerning a new method for producing cyclobentanone. More specifically, an erulate intermediate produced by conjugate addition reaction of an organocopper compound to 4-substituted 2-cyclobentenones, which are α,β-unsaturated ketones, is directly added to β, When reacted with a γ-unsaturated compound, a 2,3-disubstituted-4 with two types of substituents introduced adjacent to the α and β positions of the 9-aryl α, β-unsaturated keto/ The present invention relates to a method for producing -rft-substituted cyclopentanone. <Prior Art> Natural glostaglandins (hereinafter abbreviated as PG) are known as local hormones (autacoids) with high biological and pharmacological activity. Research is being conducted not only on natural PGs but also on various derivatives, with the aim of developing new pharmaceuticals by skillfully utilizing these physiological characteristics of PC. PGE, natural PGE which is a typical compound of PGFs,
. PGF2a has a uterine smooth muscle contraction effect and is most usefully provided as a drug as an anti-contraction agent. On the other hand, natural PGE is one of type 1 Glossa Grange y,
It is a compound that has unique biological activities such as inhibiting platelet aggregation and lowering blood pressure, and is a useful natural product that has recently been used as a peripheral circulation treatment drug in the medical field. Many methods have been known for cleaving these PGEs and PGFs (J. B. Bindra et al. Prostaglandin 5ynthesis,
(see Academic Pre3m (1977)),
Among these, the representative methods are (1) Arakito °
A method of obtaining biosynthesis from phosphoric acid or dihomo-r-lylunic acid (B, Smuelsson et al., Anger
, Churn, Int, Ed, Engl-4
+ 410 (1965)
-Chem, 5oe-+92, 397 (1970)
(Reference) (Ill) Method via 2-substituted-2-cyclobentenone, which is an important intermediate (C, J, Sih et al., J
. Amer, Ch@m, Soe,, 9L 865
(1975)) Iv) 5.6-dehydroP
Method for selectively reducing G, PGF, α (E, S
, F@rdinandi et al., Can, J. Chem, 49.1070 (1971).
C. H. Lin et al.
11.377 (1976)). 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 separate them from by-products. The method of obtaining the starting material by chemical synthesis requires many steps to obtain the starting material, and on the other hand, even if the starting material is easily obtained, the production of prostaglandin from such a starting material still requires many steps, and therefore , the overall yield is very low. In recent years, in order to overcome these difficulties, K of PG skeleton has been developed.
As a 'rM synthesis method, 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 (GIStock et al.
J, Arner, Chem, Soe, +9L
6260 (1975), K. G. Untch et al. J. OrH. Chern, 44.3755). However, these attempts require a multistep process in which eruleto is captured using low-molecular-weight compounds such as formaldehyde and trimethylsilyl chloride, and the resulting important intermediates are used to synthesize the PC skeleton through chemical synthesis. However, the overall yield is also low. The present inventor paid attention to this point, and the prostagrange: /E
Advantageous chemical synthesis methods for IFs include (1) using easily obtained starting materials, (11) short reaction steps, (
ill) As a result of intensive research to find a synthetic method with advantages such as high overall yield, the 4-hydroxy-
From 7-hydroxyprostaglandin E obtained in high yield by one step reaction from 2-cyclobentenone, 7
It has been found that PGE and PGFs can be obtained by selectively removing the human axy group at the position and converting the functional group as desired, and has previously reported this separately. <Purpose of the Invention> The present inventors focused on the three-component coupling process method and conducted intensive research on constructing a more efficient PG skeleton with shorter reaction steps. 2゜3-disubstituted-4-substituted by directly alkylating the erulate intermediate produced by conjugate addition reaction of ta 84 compound to bentenones with β, γ-unsaturated compound in the presence of alkyl tin. /Clopentanones were successfully produced, and the present invention was achieved. Conventionally, P has been obtained by alkylation with halides of erulates produced by conjugate addition reaction of organocopper compounds to α,β-unsaturated enones (especially 2-cyclobentenones).
Many attempts have been made to construct Gf ratings. Examples and explanations of reports related to this method include: (1) Tanaka et al., JP-A-5O-96542 (1975
, 7゜31; filed on December 28, 1973) and Japanese Unexamined Patent Publication No. 101337 (1975, August 11; 1)
974.January 21st sun) G, T(, Po5ne
r C:), Tetrahedron Lcttar
s, 2591 <! 974) r trigram and G, H, P
o5ner et al. J,Am,Chem,Soc,,97. 107 (1
974); All of these reports involve conjugate addition of an organocopper compound to 2-cyclobentenone, followed by alkylation with no-lides, and there are only examples of model systems for prostaglandin systems; Moreover, 4-substitution-
There are no examples for 2-cyclobentenones. (21 J, W, I'ntterson, Jr and J, H, Fr1ed+ J, Org. Che'm, 39.2506 (1974); in this report, the methodology was implemented with 2-7 Arborvitae/Tenon,
Although 11-deoxyprostaglandin E has been successfully synthesized, descriptions and examples using 4-substituted 12-cyclobentenones have not been reported. (31G, 5tork and M, Zsobe+ J,
Am, Chem, Soc, +97+6260 (
1975) ; In this report, whether it was possible to successfully capture erulate obtained by conjugate addition of organocopper compounds to 4-substituted-2-fuclopentanones with monomeric formaldehyde, or whether the algylation reaction was negative. has come to a conclusion. +41 J, A-Noguey, Tori, A, Ma
ldonado * 5yntheticCornrn
unications+ 6+ 39 (1976)
In this report, a lithium salt of cyanohydrin protected at a portion corresponding to the ω chain of prostaglandin was conjugately added to 2-cyclobentenone, and then captured with propargyl halides, followed by It-deoxybros tag 2-indi7. 4-substituted-2- of organocopper compounds by simply leading to derivatives
7. Nothing has been described in the phylum clopentenones. (51R-Dnvis, G, Untch+ J,
Orb;,, Chem-+ 44+3755 (1
! 179); In this report, direct argylation by one route of allyl halides produced by conjugate addition of a 4'' compound corresponding to the ω chain of glosstaglandin to 4-substituted-2-cyclopente 77 was proposed. It is argued that various studies have been carried out with the aim of 11 changes, but all have ended in failure. (GIA, J., Dixon and R.J., T.
aylor r J-Chem, Soc. Parkln (, 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 achieved an intermediate stage in the synthesis of 11-deoxyglostaglandin. Although I succeeded in obtaining the body, I still have 4-substitution-
No attempt has been made to modify 2-cyclobentenones. (7) Hyakude et al. + Tetrahedron I, ett
ers + 25 + 223 (1984) and 25
．． 2487 (1984); In these reports, after conjugate addition of trimethylsilyllithium or methyllithiotrimethylsilyl acetate to 2-cyclobentenone, triptyltin chloride was added, and then erulate was successfully alkylated with a propargyl bromide derivative. However, there are no examples of its application to organic can compounds or to 4-substituted-2-cyclobentenones. The above is the historical history of prostaglandin skeleton synthesis by conjugate addition of organocopper compounds to alkylation of erulate ((), and the synthesis of da-isomer () which induces 11-deoquine brostaglandin from 2-7 cucumbentenone (. ↓ () 1 has been reported, but it is more physiologically active.
There are no examples of success in extracting 1″f from cyclobentenones. As much as possible, I researched 7E1
I, too, have come up with this invention. (L't rl'j of the invention: F, - and action child) A
In the following formula, 4-R4hJ-2-cyclobentenone or its 1f isomer or a mixture thereof in any proportion is represented by the following formula CAT) RB Li ・・・・
...Organolithium compound represented by (H) and the following formula (Iil) Cu-Q...
......(A copper compound represented by Ill'1) is subjected to a conjugate addition reaction with an organic Fl compound obtained from
・River...In the presence of the alkyltin compound represented by [■], the following formula [v)
(By reacting with the “mistakeable β, γ-un” taunting compound)
Hardening of 2,3-disubstituted-4-substituted cyclopentanones, which are compounds represented by the following formula ffl'J, where the cylinder is vyt, and their enantiomers, or mixtures thereof in arbitrary proportions. Law number? : Served. The 4-substituted-2-cyclobentenones used as raw materials in the present invention are represented by the above formula [I]. In the formula Cr), R2ti) (c, ~C?) represents a group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group. As the tri(C, ~C,) hydrocarbon silyl group, ffl
For example, trimethylsilyl, triethylsilyl, triisopropylsilyl, tri(C,-C4)alkylsilyl such as t-butyldimethylnoryl, diphenyl(C,-C,)alkylsilyl or tribenzylnoryl such as t-butyldiphenylsilyl. Preferred examples include groups. Among these, t-butyldimethylmonlyl group is particularly preferred. An example of a group that forms an acetal bond with the oxygen atom of a hydroxyl group is methoxymethyl. 1-Ethoxyethyl, 2-methoxy-2-probyl. 2
-Ethoxy-2-propyl, (2-methV-ethquine)
Methyl, benzyloxymethyl, 2-Σ°trahydrobinyl, 2-tetrahydrofuranyl, or 6.6-dimeryl-3-oxer 2-oxymethyl, 2-Σ°trahydrobinyl, 2-Σ°,
1.01 can be changed to ζ. Among these, 2--ptrahydropyranyl, 2-
Tetrahydrofurani/l, + 1-ethoquinoethyl, 2-methoxy-2-propyl, (2-methoxyethoxy)methyl or 6,6-dime-1-3-oxa-2-
Particularly preferred is the oxobicyclo(3,i,O)hex-4-yl group. Typical examples of such compounds include the above-mentioned IJ (C,
~C7) The above formula CI reformulated with a group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group
4-Hydroxy-2-cyclobentenones represented by ), mirror forms thereof, or mixtures thereof in arbitrary proportions can be cited as preferable as they are. In Kiwaguchi 1, first, the above-mentioned 4-g1t-substituted-2-cyclobentenone is mixed with an organic phosphorus compound obtained from an organic lithium compound represented by formula (II) and a copper compound represented by formula (m). It is carried out by carrying out a conjugate addition reaction with a compound. RB in the lithium compound of formula [■] represents a substituted or unsubstituted C1-C7 alkyl group or alkenyl group. Examples of substituted C7-C1 alkyl groups and substituents on alkenyl 8 include lower alkyl groups such as methyl, ethyl, propyl, and butyl; C8 such as cyclopentyl and cyclohexyl groups;
~C7 cycloalkyl group; vinyl group; phenyl group; methoxy group. A lower alkoxy group such as an ethoxy group; or the above formula (
Specific examples of R1 in I) include) IJ (C. to C,) hydrocarbon silyl groups or hydroxyl groups protected with groups that form an acetal bond with the oxygen atom of the hydroxyl group. Among C1-C2° alkyl groups or alkenyl groups which may be substituted with such substituents, examples of C7-CIO alkyl groups include ethyl group, propyl group, butyl group, °isobutyl group, and 5ee-butyl group. , t-butyl group, hentyl group, hexyl group, 'heptyl group, octyl group, nonyl group, decyl group, etc.
Examples of the 1-C1° alkyl group include vinyl group,
1-propenyl, 2. t, 1-butenyl group, 1-bebutenyl group. Examples include 1-hexenyl group, 1-hebutenyl group, 1-octyl group, 1-nonyl group, 1-decyl group, etc.
It may be a single stereoisomer or (2) a stereoisomer. Particularly preferred among such substituted or unsubstituted C8-C8 alkyl or alkenyl groups are organolithium compounds represented by the following formula [■OR''. The reason why % of the compound is preferred is that it matches part of the backbone of natural prostaglan 2, and 13 in formula C
The same definition as R2 in I) f) and the same groups as exemplified for R2 are preferred. On the other hand, Q in the copper compound of formula (III) represents a second salt atom, a bromine atom, an iodine atom, etc., a cyano group, a phenylthio group, or a 1-.=butenyl group. In order to obtain an organocopper compound from an organolithium compound of formula (TI) and a copper compound of formula (1'0), for example, reference G+H
, Po5n@r, Organic Reaction
, vol, IL 1 (1972)? [Yoraga +
Tetrahedron Letters + 21
+1247 (1980), 23.4057 (1982
), 23.5563 (1982), 24.1187
(1983), 24.4103 (1983). 25, 1383 (1984) and Iar, J. Ch.
References include Em., 24, 118 (1984). In the method of the present invention, trivalent organic phosphorus compounds such as trialkylphosphites (e.g., triethylphosphine, triethylphosphine, etc.), trialkylphosphites (e.g., trimethylphosphite, triethylphosphite, trivalent inpropyl phosphite, tri-n-butyl phosphite, etc.). This conjugate addition reaction proceeds smoothly when hexamethylphosphorustriamide or triphenylphosphine is used, but tributylphosphine and hexamethylphosphorustriamide are particularly preferably used. The great invention method is represented by the above formula (1) 4-setting ↑)-2
- Reacting cyclobentenones with the above-mentioned organocopper compounds in the presence of a trivalent mIJ compound and an aprotic inert organic medium. 4-Substituted-2-cyclopenteno 7 and the limb organic silk compound react in equimolar terms stoichiometrically, but usually 4-substituted-2-cyclopenteno
0.5 per mole of substituted-2-cyclobentenones
-2.0 times, preferably 0.8 to 1.5 times, particularly preferably 1.0 to 1.3 mo/L- times of the n-containing copper compound. The reaction temperature is -100°C to 20°C1. For special KIE, a temperature range of about 8°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 substance is used that is liquid at the reaction temperature and does not react with the reaction reagent. Such aprotic inert organic media include e.g.
Saturated hydrocarbons such as pentane, hexane, heptane, cyclohexane, p/zen. Aromatic hydrocarbon beds such as toluene and xylene, ethereal solvents such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether, and others such as hexamethylphosphoric triamide (IMP), N,N-dimethylformamide (
DMF), N,N-dimethylacetamide (DλtAc
), dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, and other so-called aprotic polar solvents, which can also be used as a mixture of two or more solvents. 'As active organic medium,
The nine inert L-forms used to produce organocopper compounds are
You can also use that f. That is, in this case, the 4-f'L-substituted-2-
The reaction may be carried out by adding cyclobentenones. The amount of organic medium used should be sufficient to allow the reaction to proceed smoothly, and the volume used is usually 1 to 100 times, preferably 2 to 20 times, the volume of the raw materials. The trivalent ffi +77 compound can be present during the above-described preparation of the organocopper compound, and the reaction can also be carried out by adding 4-fFj-2-cyclobentenones to the system. can. In the method of the great invention, RB, which is the organic group moiety of the organocopper compound, is added to the positive 3-position of the 4-substituted-2-cyclobentenone in the reaction system by the operations so far, and
It is assumed that a so-called conjugate addition elerate is formed in which an anion is generated at the position. In the method of the invention, this conjugate addition erulate is reacted with a β,γ-unsaturated compound represented by the above formula [v] in the presence of an alkyltin compound represented by the above formula (IVI) to achieve the objective. 2,3-disubstituted-4 represented by the above formula [VI]
-@converted cyclopentano/1 is produced. Specific examples of the alkyltin represented by the formula (IV) used here include trimethyltin chloride, trimethyltin bromide, triethyltin bromide, tripropyltin chloride, and triptyltin chloride. Tri(C1-C4)alkyltin chloride such as tributyltin bromide, tri(C7-C,)alkyltin bromide 6, dimethyltin dichloride. Examples include dialkyltin civalides such as diethyltin dichloride and dibutyltin dichloride, and tributyltin triflate, with triptyltin chloride being particularly preferred. For the β,γ-unsaturated compound represented by the above formula (V), RA represents a substituted or unsubstituted C1-C6 alkyl group, and X represents a halogen atom or a tosyl groupffUwaL
, Z Vi impersonates an ethynylene group, a trans-vinylene group, or a cis-vinylene group. Examples of the substituent in the C1-C6 alkyl group at position j include lower alkyl groups such as methyl group, ethyl group, probildi1L, and butyl group; cyclope/Z'+! +
/R a C8-C acycloargyl group such as hexyl group;
Alkenyl groups such as vinyl and allyl groups; aromatic groups such as phenyl groups; lower alkoxy groups such as methoxy and ethoxy groups; acetals with tri(C, ~C,) hydrocarbon silyl groups or hydroxyl groups Hydroxyl group centered on foil forming bond; lower acyloxy group such as acetoxy group, propionyloxy group; oxo group; and methoxycarbonyl group - ethoxy7carponyl group;
A lower alkoxycarbonyl group such as a t-butoxycarbonyl group is preferred as a substituent that does not hinder the progress of the desired alkylation. Examples of C5 to C0 lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, IIe
Straight chain or branched ones such as c-butyl group, t-butyl group, pentyl group, and hexyl group can be mentioned. Among such glopargyl I rides, the following formula [v
'] XCT(, -Z -(CH,), C0OR'
・ - ・ ・ ・ ・ ・ ・ ・ (β, γ -unsaturated compounds represented by V are the most preferable because the grostaglandin skeleton is $ IL: IL: IL: In V'3, R1 is C3-C1゜argyl or 'it unsubstituted phenyl group. For example, methyl #, ethyl group, probil di↓, isopropyl group, butyl horse, inbutyl group, see-butyl group, -
Butyl group, pentyl group. Hexyl group, heptyl group, octyl group. Examples include linear and branched groups such as nonyl and decyl groups. Examples of the substituent for the substituted or unsubstituted phenyl group include /.rogen atom, protected hydroquine A,
C, ~C, acyl group, C, ~C, alkyl group which may be substituted with a rogen atom. Preferred are C, -C4 alkoxy 74 which may be substituted with a halogen atom, a nitrile group, and a (C, -C,)alfky/carbonyl group. No.1'. Ho. Salt salt or bromine etc., especially t: 5 net C1 store 7 is preferable 02~C, acyl xib 1;
Finally, frll, acetokin μ;, propio,
- Nilocene, 〒ku, 1,000 sulfur oxy/ring;, isobutyryloxy group, valeryloxy convex, invaleryloxy group, caproyloxy group. Examples include enantyloxy group and benzoyloxy group. Preferred examples of the C, -C4 alkyl group which may be substituted with a halogen atom include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, crocomethyl group, dichloromethyl group, trifluoromethyl group, etc. be able to. Examples of the C, -C, alkoxy group which may be substituted with a halogen atom include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. Chloromethoxy group. Preferred examples include dichloromethoxy7 group and trifluoromethoxy group. As the (C1-C,)alkoxycarbonyl group,
Examples include methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, and hexyloxycarbonyl group. The substituted phenyl group can have 1 to 3, preferably 1, substituent groups as described above. 1i'j47 or unsubstituted C3-CIG cycloalkyl convex, saturated or unsaturated C, -C,, substituted with the same substituents as above or unsubstituted;
, preferably C3 to C111, particularly preferably C0 moss,
Examples include cycloprovir di(, cyclopentyl + 7-chlorohegycyl), cyclohegysenyl group/chloroheptyl group, cyclooctyl group, cyclodextyl group, etc. Substituted or unsubstituted phenyl (C+ ~ C,) alkyl 2 In each case, the phenyl group is in the same position F1 as above.
:, I; or unsubstituted base/dino l-;q, α-phenethyl group, β-phenethyl,
I am struck by force. ``i?-Mr. 11'V), (V')?J is β
, γ−non! (sum fl+ r>'i'7 IC↓, ・X is a halogen atom or 1.1". Such a halogen atom is +X cumulative atom T'l+c atom,
Examples include iodine atoms, β, γ-def: 4. '(II
Considering the reactivity of the compound, if the iodine atom is 75 tons,
Delicious. Further, 2 in the formula represents an ethynylene group, a trans-vinylene group, or a cis-vinylene group, and any of them is preferably used, but considering the skeleton of natural prostaglandins, a cis-vinylene group is preferable in terms of quantity, and a cis-vinylene group is preferable in terms of quantity. An ethynylene group that can be converted into a vinylene group is preferred. In the method of the present invention, the reaction between the conjugate addition elerate generated in the system and the β, γ-f3-koji compound is a conjugate addition of the organocopper compound to the 4-1-substituted-2-cyclobentenones. β represented by the above formula [V] (including the above formula [7]), which may be diluted with the aprotic organic medium by first adding an alkyltin compound into the reaction system prepared above. This is carried out by adding r-unsaturated compounds. It is assumed that the alkyltin reacts with the erlate formed by conjugate addition at a stoichiometric K'd equimolar amount to newly generate the stannerate, but usually, the initially used 4-substituted 2- 0.8 to 1.5 times mole per mole of cyclobentenone, particularly preferably Vi
, using 1.0 to 1.2 mole times. The reaction temperature is -100°C to 0°C, preferably -8°C to -
A temperature range of 20″c T=degrees was adopted, and during the reaction I′I
rl within 1-L for 1 hour is sufficient. In the method of the invention, a β,γ-unsaturated compound of formula [V] (including formula [V']) is then added to complete the objective. The β,γ-unsaturated compound reacts with the erulate produced by co-addition in a stoichiometrically small molar amount, but usually the initial concentration of 24 V'
c('A-2-7ria0.8-5 for bentenones
．． It is carried out using Q mo/L times, particularly preferably 10 to 2.0 times a. L4 temperature r' (: -100℃-0℃, preferable t L <
i, t The temperature range of approximately -78"C to -20°C is adopted. The reaction time 171 varies greatly depending on the f/1 class of the β, γ-futsuwa compound used and the reaction temperature, and usually, -78℃~-
The reaction is at least completed at 30° C. for about IPv to 50 hours, but it is efficient to follow and determine the end point of the reaction by layer chromatography or the like. In the method of the present invention, the alkylation reaction with β,γ-unsaturated compounds is preferably carried out in the presence of the aprotic polar solvents mentioned in 1*, especially hexamethylphosphoric triamide, which often gives good results. . After the reaction, molecules: '3.
It is made of one sheath. Thus, 2,3-disubstituted-4-substituted cyclopentanones represented by the above formula [-]] are obtained. Specific examples of such compounds include formula [191 formula [■]] (C
I')), and formula (V) (also including (V'))
exemplified by

[7] Any combination of the above groups is preferred. Among them, the following formula [■'] obtained by combining an organolithium compound represented by the formula (n) and a β, γ-unsaturated compound represented by the formula [7] OR"6g"TE=,'-upperwasafl-ru2+3-2V'(f'
s -4-Rj% Shipo Among hentanones, 2
It is a particularly useful compound because it is the 212.1 body of 7 supinylene group 1''F7''a staglandy E, the skeleton itself, and the derivative where 2 is ethynylene is also 5,6-zohydroprostagfundin E23 It is a particularly useful compound for forming a conductor skeleton, and the present invention is important in that it also provides a method for producing such a compound. That is, prostaglandin (PG'') E using wood 5,6-zohydroprostaglandin E, 'rJg conductor as a starting material.
, l El * F'! fflFIcEtD,
, D, and I, respectively, are illustrated as follows. 11GD. oat" 6□1 11GJ). Reference Examples 1 to 5 specifically show some of the above induction reactions. Other conversion reactions have already been reported by some of the inventors. One feature of the method of the invention is that all the reactions used proceed stereospecifically, so that the formula C
From the starting material having the configuration represented by I), a compound having the configuration represented by the formula (Vl) (including (1:VI')) can be obtained, and from the characteristic body of the formula [I], The enantiomer of the formula (Vl) ((containing Vl) is obtained, and it is a mixture in an arbitrary ratio. From (1), a mixture reflecting that ratio is obtained (Ml) ((containing S'1) ) is obtained.Furthermore, since the organolithium compound of the formula contains an asymmetric carbon, there are two types of optical isomers. Among these, the compound having the stereochemistry represented by the above formula [■] is a particularly useful stereoisomer because it has the same stereoconfiguration as natural prostaglandins. Another feature of the method of the present invention is that when two optically active starting materials (formula (1) and formula [■]) are used as the d/isomer or a mixture of optical purity in any proportion, the steric It progresses through the synthetic route specifically, and the intermediates and final products become a diastereomixture, and if one of the raw materials is optically active, it must be separated at an appropriate step (1) to separate each stereoisomer. The reason is that it can be isolated as a pure product.The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto. Cuprous iodide (9
9, IQ, 0.52 mmoJ) was weighed out, the inside of the tube was dried under reduced pressure, and then replaced with argon again. Dry tetrahydrofuran (2g) and tributylphosphine (0.337m, 1.35mmo/) were added thereto and stirred at 20°C to form a homogeneous solution. After cooling this solution to -78°C, n-butyllithium (1,60
M, 0.325 itj, 0.52 mmo/) was added thereto, and the mixture was stirred at -'18°C for 10 minutes. Then (R1-4-t-butyldimethylsiloxy-2-
Cyclopentenoy (100119,0,471mmo
J) in tetrahydrofuran (2+s/) at -78°C.
It was added dropwise over a period of 10 minutes. Furthermore, the container was washed with Q, 5ynl of tetrahydrofuran, and this washing liquid was added dropwise in the same manner, followed by stirring at -78°C for 10 minutes. Then, hexamethylphosphoric triamide (1mt) was added to
Stirring was continued for 40 minutes at 8°C. Then tributyl tin o2ide (0.14 ml, 0.520 mmol)
After adding, the temperature was raised to -40'G K, and l-iodo-2-
A solution of octyne (184 rp, 0.78 mmoJ) in tetrahydrofury (ls+/) was mixed and stirred for 2 hours. After adding ether (5 ml) to the reaction solution, saturated ammonium chloride aqueous solution (511j), saturated potassium thiocyanate aqueous solution ('5 aJ), and saturated brine (
The separated organic layer was dried over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (Merck 7734.6% water content, 20 g; hexane: ethyl acetate = 30: l'), and (2R93R,
4R) -3-Butyl-4-t-butyldimethylsiloxy-2-(2-octenyl)cyclopentano 7 (88
, 1q, 0.233 mmd, 49%). TLC; Rf 0.39 (hexane: ethyl acetate = 10:1) IR (liquid film): 1750j 1460.1247, 1098, 834°771 signal-1°N M R (CDCj,) δ; 0.05 and 0 .09 (respectively at 6+ 5i
CH, x2). 0.89 (@ * 15 e 5iC(CH3)3
*CHs X 2 ) +1.1-1.7 (m,
I L CH, x6). 1.8~2.4 (m, 5, CH2CmiCX2.CH
X I L2.4~2.8 (m, 3.CH2C0x2.
CI■CO). 4. Oj (dd, 1 + J-13-0 and 6.4
f■y, , Cl1O8i). 13CNMR(CDCl3)δ;-4,9,-4
, 5, 13, 9 (for 2 pieces), 18.6. 19.1
゜22.1. 22.9. 25.7 (4i[-1
minutes), 28.7. 29.0°3 1.0. 3
1.7. 4 7.7. 48.6. 52.5. 7
3.3°77.0. 81.9. 215.4゜λ(S
(75eV; m, /a); 3 7 8 (M ten, 3 2 1 (M-1
--C411,). Fruit 11 Example 2 OS+'5 O8+x Argon I
Quaternary iodide] (19
8rnQ, 1.04 mmol) was weighed out, and the inside of the tube was placed under reduced pressure with argon. 673trtl, 2.7
Or+tmo/')ri was added and stirred at 19°C to obtain a homogeneous solution. After cooling this solution to -78°C, n-
Butyl lithium (1,60M, 0.64717/,
1.04 mmo/ ) was added and stirred at -78'C for 10 minutes. Next I't' (R1-4~t-butyldimethylsiloquine-
2-cyclobentenone (20C117,0,942mm
o/) of tetrahydrofuran (15 ml) Q solution”
: It was dropped over 0.8 hours using a syringe drive at -78°C. Furthermore, after washing the container with 2 ml of tetrahydrofuran and dropping this washing liquid in the same way, -78
The mixture was stirred at ℃ for 10 minutes. Thereafter, hexamethylphosphoric triamide (2d) was added and stirring was continued at -78°C for 40 minutes. Next, triptyltin chloride (0.28 ml. 1.04 mrr+o/) was added, the temperature was raised to -30°C, and 1-bromo-2-octyl chloride (197 m9. 1.0
A solution of 4 mmoJ) in tetrahydrofuran (2 ml) was added and stirred for 17.5 hours. Ether (1
After adding 0 m/) of saturated ammonium chloride aqueous solution (1
0m/), saturated potassium thiocyanate aqueous solution (10rn/), saturated potassium thiocyanate aqueous solution (10rn
l), wash the face with saturated saline (10 ml), and remove the separated organic layer with anhydrous sulfuric acid). It was dry. Roca! The 'H1 product obtained by pressure concentration was subjected to column chromatography (Merck 7734.6).
% water content, 40 g; hexane:ethyl acetate - 30:1) to give a product consistent with that obtained in Example 1 (
2R93R,4R)-3-butyl-4-t-butyldimethylsiloxy 2-(2-octynyl)cyclopentanone (58,8m9.0.155 mmol, 16%)
folded. ',! ! : Koji Example 3 A Example 3 (-T
f%, t-butyllithium (1,77M* 1.09 rnlr 1.9
2 mmo/) was added dropwise and stirred at -95 to -78°C for 3 hours. Separately, cupric iodide (183 m9.o, 961 mmoj!) was weighed into a 30 m eggplant-shaped flask, and after drying the inside of the tube under reduced pressure, the flask was replaced with hyalgon. In it, tetrahydrofuran (411/) tri)butylphosphine (0.62 ml, 2.50 mmol)
) was added and stirred at 21°C to obtain a homogeneous solution. This homogeneous solution was added to the alkenyllithium solution prepared previously using a stainless steel tube under argon pressure,
Furthermore, the container was washed with tetrahydrofuran (4 ml), and this solution was added dropwise in the same manner, followed by stirring at -78°C for 5 minutes. Then (R1-4-t-butyldimethylsiloxy-2-cyclobentenone (200M?, 0.942
A solution of 15 mmol) in tetrahydrofuran (15+s/) was added dropwise over 1 hour using a syringe drive at -78°C. Furthermore, the container was washed with 2-t of tetrahydrofuran, and this washing liquid was also added dropwise in the same manner, followed by stirring at -78°C for 1 hour. Then, add hexamethylphosphoric triamide (<2 ml) and stir at -78°C for 40 minutes.
I did 1. Then triptyltin chloride (0.26m
l, 0.961 mmol) at −15°C.
flF = 1-iodo-6-medoxycarponyl-2-hexy7 (276m9. 1.04mono/
) of tetrahydrofuran (2'l) 'I+ solution and stirred for 1 hour. After adding ether (20 mt) immediately after the reaction, a saturated aqueous ammonium chloride solution (30 mt >
r f, :; wa thiocyanine Q potassium water-soluble group (30 m
/ri, l'3 Japanese saline solution (30F+/) was washed sequentially, and the molecular q-depleted stratum trueum was dried on an anhydrous sodium-resistant 4.7! Shita. The crude product obtained by condensation under reduced pressure was subjected to gel column chromatography (Merck 7734, 6% water content, 40.9; hexane: 1i1:r, 1-f-le=
4 n: 1) K supply L-C minute 1''j L, 11
゜15-bis(t-butyldimethylnoryl)-5゜6-
Dihydroprostaglandin E2 methyl ester (
1n ”'+, 6rp+ 0-178 mmol, I
9%) to (11. TLC: Rf (1,50 (ethyl acetate-hequinane = 15) IR (liquid film); +746.1246.827.76'lσ-1'rr
NMRCCDCl, -CCI4=l:1)δ;0
．． 04 and Q, Q6 (respectively S, I 2+ 5iC
H3X2). 0.89 (' F T 18+ S+C(CH3
)5X 2) +0-92 (t, 1.J""6.5
T(z,CH3)+1.1-1.5(m+8.CH
2x4). 1-7 2.9 (m, 121CH2COX2.CHz
CEX2. CHX2° and CH2). 3.65 (s, 3.0CH3), 4.05 (
m, 2. CHO3iX2). 5.4 5.7 (m*2, vinyl)”CNM
R(CDC/,)δ; -4,7,-4,5 (for 2 pieces), ~4.2. 13.6
．． 14.0°16.9. l 8.0. 18.2
．． 22.6. 24.2. 25.0°25.8 (
3 pieces), 25.9 (3 pieces), 31.9°32.7.
38.6. 47.7. 51.4. 51.9.
52.9°72.7. 73.1. 77.3. 80
．． 8. 128.2°136.8. , 173.4.
213.4(α)'j: -13,9°(C1,5
9, CH, OII) Actual 1f1 Example 4 Into a reaction tube with 1"l of argon and 1150 m/g, (see. 3S)-3-t-butyldimethylsiloquine-1-iodo-1-octene (351!ri, 0 .961 mmo/
) in dry ether (5 ml) and cooled to -95°C.
1. +19 ml, 1.92 mmol CcW
5 down to goo Q5 - 31 days 1 at 78°C (mixed 4R/
ζ. Separately, add 12 L of iodide (I R3F? (1,9': i Irnmol) to a 30r/'tn eggplant 1-2 flask, and dry the inside of the tube under reduced pressure (z1 again in the argon apparatus 1). :
It was 1. In it, tetrahydrofuraf (4 ml) and tributylphosphine ((1,62 ml, 2.50
mmog) and stirred at 24° C. to obtain a homogeneous solution. This homogeneous solution is first f! 1. Add the prepared alkenyllithium f + j 'L stainless steel to the stainless steel under argon vn IE using a vacuum, wash the container with tetrahydrofuran (2 ml), and add this solution dropwise in the same way. , stirred for 5 minutes at -78°C. Then (R)
A solution of -4-t-butyldimethylsiloxy-2-cyclobentenone (20 (l12.0.942 mmol) in tetrahydrofuran (IQm/) was added dropwise at -78°C using a syringe drive over a period of 30f+.
The container was washed with 2 ml of tetrahydroflough, and this washing liquid was also added dropwise in the same manner, followed by stirring at -78'C for 10 minutes. Then, triptyltin chloride (0.26 ml)
, 0.961 mmol) was added and stirred at -78°C for 1 hour. Then 1-iodo-6-medoxycarbonyl-2-hequinine (276 nq. 1.04 mmol) was added to tetrahydrofuraf (2rn
l) After adding the solution and stirring for 20 minutes, add hexamethylphosphoric triamide (0.9 m/) and heat to -78°C.
Stirring was continued for 15 minutes. Next, the mixture was externally heated to -45°C and stirred for 30 minutes, and then hexamethylphosphoric triamide (0.9ml) was added and stirred for 1 hour and 30 minutes. After adding a saturated aqueous ammonium chloride solution (30 ml) to the reaction solution and shaking vigorously, 4G 71 and water was added for 1 minute.
3(j,, the organic layer was diluted with a saturated aqueous potassium thiocyanate solution (
30m/) and saturated saline (30r+t),
On anhydrous @acid sodium 1:・S: , 1. F. I did. Roca, I got it by doing the pressure M HN! u ′h f-
< iLl sirupu Jge! Rep J Lamb chromatography (Merck 7734. (5% water content, 40.9.1:4
0 ri "1', qethyl-bek11n)" to 1lli
FF L/, 11.15-viny((t-butyldimethylsilyl)-5,6-zohydroprosculandine E, methyl ester (173.9 m + 0.29
3 mmo431%) IC was obtained. Each f1 spectrum in this book is 5j1. Case 3 ((It was the same.) Dry ether of (E. (5-) After adding the solution and cooling it to -95°C, t-butyllithium (1,77M, '1.091
-95 by dropping Rt, 1.92 rnmoA')
Stirred at ~-78°C for 3 hours. Separately, in a 304 eggplant-shaped flask, add -'M iodide (183 m9゜0.961 mm
After drying the inside of the tube under reduced pressure, tetrahydrofuran <4R was added to the tube which was replaced with argon again.
t> and tributylphosphine (0.62 m1.2.5
0 mmoj) was added thereto and stirred at 29°C to form a homogeneous solution. This homogeneous solution was added to the previously prepared alkenyllithium solution under argon pressure using a stainless steel tube.The container was then washed with tetrahydrofuran (2*/), and this solution was added dropwise in the same manner. The mixture was stirred at ℃ for 5 minutes. Next, 1-4-butyldimethylsiloxy-2-7 clopentenone (200 ml, 0.9
A solution of 42 mmoJ) in tetrahydrofuran (10 ml) was added dropwise over 30 minutes using a syringe drive at -78°C. Furthermore, the container was washed with 2-h of tetrahydrofuran, and after this washing η (also under the same RICI@),
The mixture was stirred for 10 minutes. Triptyltin chloride (0.26r!I/+ 0.961 mmoJ) was added to the bale and stirred at -78°C for 30 minutes. Then, after adding hexamethylphosphoric triamide (IJml), (7
1-1-iodo-6-carpomethoxy-2-hexene (
A solution of 279 ny, 1.04 mmoJ) in tetrahydrofuran (2 ml) was added, the temperature was raised to -45°C, and the mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution (40 ml) was added to the reaction solution and the mixture was shaken vigorously. The organic layer and the sluice were separated, and the organic layer was washed successively with a saturated aqueous potassium thiocyanate solution (40 ml) and a saturated brine solution (40 ml). Dry over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was subjected to silica gel column chromatography (Merck 7734, 40.9, 1:20 acetic acid/hexane) to separate 11.15-
Bis(t-butyldimethylsilyl) prostaglandin E, methyl ester (142,5m9゜0.239m
mol 25%) was obtained. TLC: Rf 0.58 (ethyl acetate-hexane = 85) IR (liquid film); 1743, 1243. 1,000. 96.1.
927°828.768am'' HNMR (CDCJ,) δ; 0.03 and 0.06 (II 12t 5t respectively
ctt, X4). 0-8 1.0 (m=21.CCHaX7). 1.2-1.5 (m, 8.C) 12X4 L
l, 6-2.9 (m, 12.CHICOX2.C
H2C"'X2゜CHX2.and CHI) + 3.67 (a, 3,0CH3), 4.06 (m, 2.
Cl0SiX2). 5.37 (me L vinyl L 5.54 (
m, L viny/ ) [α) M: -52-7
° (C1,28, CI(,OH) Reference Example 1 Acezalene Compound 1 (48,2 g, 0.081 m
mol) and synthetic quinoline (25ry) were dissolved in benzene (2.5ml), and cyclohexaney (2.5ml) was dissolved in benzene (2.5ml).
l), followed by 5% Pd BaSO4 (25”?
) for 3 hours at 25°CIC under hydrogen atmosphere (
, 1 after stirring, synthetic quinoli 7 (50rr9)k and 5%
Pd-HaSo. (50'''9)] was added, stirred at 40°C for 4.5 hours, and 7CoI)-1!:J!JH was added to 71 j41 t,
Afterwards, the mixture was washed with vinegar/71 ml, and the mixture was concentrated under reduced pressure. The mixture was subjected to Nori gel column chromatography (8p, ether-hexane-1:10), the collected fractions were concentrated under reduced pressure, and the remaining residue was further concentrated under reduced pressure with a vacuum pump (<4-1g) for 7 hours. If left alone, P(', E2
Methyl ester 11.15-bis-t-butyldimethylsilyl ether 2 (41.8g, 87%) is ()
It was done. TLC; Rf 11.58 (ethyl acetate-quina y-1:5) IR (to liquid 1i); +743.1243,1000,964,927°82
−1′HNMR(CDC7,)δ of 8.768; 0.03 and 0.06 (respectively sr I L 5i
CH3X 4 ) rO,8-1,0(m, 21.
C-CH5X7). 1.2-'1.5 Cm, 8. CH,X4 L
l-6-2,9(m, 12.CH2C0X 2.CH2
C= X 21CHX 2 * and CH2) + 3.67 (II, 3.0CH3) + 4.0
6(m, 2.Cll08ix2). 5-37 (m, 1. vinyl) + 5-54 (
rn-1, vinyl) [α]B: -5z, 76<
C1,2s, CH3OH> This compound is (→-PGE,
It completely coincided with the protected disilyl form of 11.15, which was further identified. Reference Example 2 And silyl compound 2 (40q, 0.067 mmoj) was dissolved in hot water acetonitrile (8111/) K and then heated with H at 0°C.
After adding F-pyridine y <n, 1ne> and stirring at 21°C for 30 minutes, 1(F-pyridine (0.4 m/) was added and stirred for 3 hours. Saturated Na) fcO3 water m le (
201nl) and then diluted with ethyl acetate 3 times (3
0^! ×3) Extracted. The combined mixture was dried over Na2SO4 and concentrated under reduced pressure by 4 hours. Toluene was added to remove residual pyridine, and the mixture was further concentrated under reduced pressure. Vacuum pump under reduced pressure (<
After leaving it for a while in a silica gel column (2I, dithyl acetate-hexane (1
:1)→(1:O) Gradient)→-PG
E, methyl ester 3 (24,1 mS', 98%)
I got it. TLC; 0.29 (ethyl acetate-cyclohexane-TH
F=6:3:l) Summer R (n i1 self membrane); 3680-3080.1744.970 one 1'11
NMR (CD(Js); 0.90 (t+L J=6.5Hz, CH3
). 1.1-2.9 (m, 20. CH2C0X 2
．． C) tlX 5°CH, C field X2. CHX2). 3.08 (br, 1.OH), 3.66 (
s, 3.0CH3). 4-06 (m+ 3. CHOx 2 and OH). 55-3rL (*1+ vinyl), 5.70 (m, 1
．． Vinyl)” CNMR (CD(J,)δ; 14.0. 22.6. 24.7. 25.1. 2
6.6. 31.7°33.5. 37.3. 46.
1. 51.5. 53.7. 54.5°72.0,
73.0. 126.6. 130.8. 131.5
゜1 36.8. 174.0. 21 4.1 [C1
”, i ; −71,7° (C1,043, CH,
OI() Reference Example 3 First l! diisobutylaluminum hydride (1 equivalent) prepared by Li/2.6-di-t-butyl-4-
Methylphenol (2 equivalent ft) in toluene solution (0.1
92Msoln+ 2.24 ml+ 0.43 ro
Ketone body 1 (25,5m? +
0.043 mmol) toluene solution (I+I+/)
added. After stirring at -78°C for 2 hours, the temperature was raised to -25~=20°
The mixture was stirred at C for 3 hours. Add a saturated aqueous solution of sodium bitartrate (10 m/ml) and shake vigorously. Vinegar G in Muroba! ! 3 times with ethyl (20 + 10 +10
m1) and the combined extracts were dried over Na2SO4 and concentrated under reduced pressure. It was subjected to silica gel column chromatography (5 g, ethyl acetate-hexane-5:1), and alcohol 4 (23.5 m9. 92%, low polar component) was added once. TLC: Rf 0.29 (ethyl acetate-hexane concentration 1:5) IR (!;':!) ; 3 (i40-3080, 174511247.1020
゜970.93L 830,770Crn'' If
NMR(CDC13)δ; 0.02 and 0.05
(s, 12.5ICH5X 4 respectively). 0.7-1.0 (m, 21, C-Cl, x 7
). 2.1-3.5 (m, 20. CH2Co,
CI (2X 6. C) I2C-X 21CT (X2
). 3.69 (dl 11 J=8.3Hz, OH)
. 3-67 (g + 3 + OCH3) +4.
00 and 4.24 (br, 3.CHOX3). 5-40 (m, 2+ vinyl) [α]'j;
+ 0.37° (CO, 715, CM, OH) Reference example 4 Ahichile/Compound 4 (28,7TI'1. 0.04
8 mmol) was dissolved in benzene (1 ml), cyclohexane (1 ml) and Lindlar catalyst (28,7
m! ;l), then under hydrogen atmosphere 22-23.5
It was incubated at ℃ for 12 hours. The catalyst was filtered off, washed with ethyl acetate, and the mixture was subjected to vacuum flN. /Gel column chromatography (6g. Nl'it ethyl-hexane-benzene = 1:15:2
) and subjected to olefin decomposition 5 (23,2+y, 81%
) was obtained. TLC; Rf O, 32 (ethyl acetate-hexane=
1:5) IR (liquid film); 361 (1-3280, 1745, 1250, 1000
゜970.938,830.770 Confucian-1' HN M
' R (CDC/3) δ; 0.03 and 0.05 (3+ 12+ 5ICH3X 4 respectively) +0.8
-1.0 (m, 21, C-Cl, X7)+
1.2-2.4 (m, 20. C1(2CO,CH
2X L CH2C=X2°CII×2). 2.69 (rl, ], J = 9.5Hz, 0H)
13.67 (s, 3.0CI(3), 4.05 (b
r, 3. CHOX3). 5.40 (rn, 2. vinyl) [α electric; +1
2.3° (C1,037, C1(,OH) Note that 5 I
n and 'H NMR spectra are (10)-1'GE2α
The results were completely consistent with those of the disilyl derivative derived from the above. Reference Example 5 Syrylic acid 5 (21m9.0.035 mmol) was dissolved in vinegar (1ml), H,O (0.33ml)
), THF (0,1g) was added, and the mixture was heated at 55°C for 1.
Stirred for 5 hours. The mixture was transferred to a large container, toluene was added, and concentration under one pressure was repeated several times to remove acetic acid and H2O. The residue was subjected to silica gel column chromatography (3 g, ethyl acetate/lehexane C1:1)→(1:0 gradient) to obtain (+)-PGF2α methyl ester 6 (11 chromatography, 85%). ~ TLC: Rf O,2 (ethyl acetate-cyclohexane-TI (F=6:3:1) IR (liquid film); 3640-3040.1738.1435.1160°1116.1042.1020.968,858 -1
' )(N M R (CDC/,) δ; 0.89 (t
, 3. J=6.5Hz, CH3). 1.2-2.4 (m, 20.CII, Co, CH, X
6. CH2C=X2°CHX2). 2.57 (br, 1.OH), 3.29 (br
, l, OH). 3.69 (s + 3 lOCH3) + Co
3 (brm+3.CHOX3). 5.3-5.6 (m, 2. vinyl) 13cN
Phylum R (CDC/, ) δ; ] 4.0. 22.6. 24.8. 25.2.
25.6. 26. L3 1.8. 33.5. 3
7.3. 43.0. 50.5. 51.6°55.
8. 72.9. 73.0. 78.0. 129.
1°J 29.6. 1 32.6. 1 35.3
．． 1 74.3 [α) p: +31.4° (CO, 4
23, CHlOH) and the spectrum of the compound (IR,'
HN! 1 R1” CNMR. TLC) was derived from (+l − PGF, α (+l −
It completely matched with PGF and αmethyl aster. °~111. -7゛

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
・[I] [In the formula, R^2 represents a group that forms an acetal bond with the oxygen atom of a tri(C_1 to C_7) hydrocarbon silyl group or hydroxyl group. ] 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 to C_1
_0 represents an alkyl group or an alkenyl group. ] and the following formula [III] Cu-Q.
......[III] [In the formula, Q represents a halogen atom, a cyano group, a phenylthio group, or a 1-pentynyl group. [In the formula, R is the same or different C_1 to C_4] represents a lower alkyl group, of which 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] In the formula, X represents a halogen atom or a tosyl group, and Z represents an ethynylene group, a trans-vinylene group, or a cis-vinylene group. ] The following formula [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 represents a hydrogen atom, a tri(C_1 to C_7) hydrocarbon silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R_A is a substituted or unsubstituted C_1 to C_6
represents an alkyl group, R_B is substituted or unsubstituted C
_2 to C_1_0 represents an alkyl group or 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 represents 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. ] 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] is the following formula [V'] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
[V'] [In the formula, R^1 is a C_1 to C_1_0 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C_3 to C_1_0 cycloalkyl group, or a substituted or unsubstituted phenyl (C_1 to C_2) It represents an 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
2. A method for producing 2,3-disubstituted-4-substituted cyclopentanones according to any one of the above items. 5. 2 according to any one of claims 1 to 4, wherein the alkyltin is triptyltin chloride.
, 3-disubstituted-4-substituted cyclopentanones. 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.