JPH03176448A - Optically active 2-methylenepentane derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:An optically active compound shown by formula I (R<1> is H or readily eliminate protecting group selected from alkenyl, aralkyl, alkyloxymethyl, 1-alkyloxyethyl, hetero atom-containing cyclic alkyl and silyl; R<3> is readily eliminate protecting group selected from alkyl and aralkyl which may contain halogen-substituted group and two R<3> may be bonded to form cyclic acetal; X is halogen or R<4>SO3; R<4> is alkyl or aryl and * shows asymmetric carbon atom). USE:An intermediate for producing prostaglandins by an extremely shorter process than a well-known method. PREPARATION:A compound shown by formula II (X<1> is halogen) is made to react with an optically active compound shown by formula III in the presence of a base to give an optically active compound shown by formula I (R<1>=H) and a protecting group is introduced to OH thereof to give an optically active compound shown by formula I wherein R<1> excludes H.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to an optically active 2-methylenepentane derivative that is a raw material for producing prostaglandins and a method for producing the same.

(Prior art and problems to be solved) Conventionally, the mainstream method for producing prostaglandins has been to start from Corey lactone or 4-hydroxycyclobentenone, but in order to obtain the optically active form of this raw material, It is necessary to undergo steps such as optical resolution and asymmetric ice thawing using microorganisms, which causes problems such as a decrease in yield.

(Means for Solving the Problems) The present inventors have conducted intensive studies on a method for producing a prostaglandin intermediate in place of 4-hydroxycyclobentenone, and as a result, we have found that halogen or alkyl at the 1-position carbon Optically active 2,3-epoxypropane substituted with a sulfonyloxy group or an arylsulfonyloxy group (Vl
The present invention has discovered a method for synthesizing an optically active cyclobentenone derivative represented by the general formula (Xl) shown below, which is known as a prostaglandin intermediate, using a method using as a raw material. The present invention provides an optically active compound as an intermediate obtained by a reaction and a method for producing the same.

The present invention provides an optically active 2-
Methylenepentane derivative (in the above general formula (V), R1 is a hydrogen atom, an alkenyl group, an aralkyl group, an alkyloxymethyl group, 1
- an easily removable protecting group selected from an alkyloxyethyl group, a cyclic alkyl group having a heteroatom, and a silyl group; R3 is selected from an alkyl group and an aralkyl group which may have a halogen substituent; It is a protecting group that can be easily removed, and the two R3s may be different from each other, or the two R3s may be bonded to form a cyclic acetal. X is a halogen atom or R'303 group, R4
represents an alkyl group or an aryl group, and the symbol * represents an asymmetric carbon atom, respectively'''g) and the method for producing the same.

In the present invention, specific examples of R1 other than a hydrogen atom in formula (V) include allyl as an alkenyl group, benzyl, p-methoxybenzyl, diphenylmethyl, and trityl as an aralkyl group, and methoxymethyl and benzyl as an alkyloxymethyl group. Oxymethyl, t-butoxymethyl, 2,2.2-trichloroethoxymethyl, 2
-methoxyethoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-isopropoxyethyl as a 1-alkyloxyethyl group, tetrahydropyranyl as a cyclic alkyl group having a hetero atom,
Examples of the tetrahydrofuranyl and silyl groups include trimethylsilyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methyldi-t-butylsilyl, triphenylsilyl, phenyldimethylsilyl, and triphenylmethyldimethylsilyl. Specific examples of R3 include methyl, ethyl, 2,
2. An alkyl group such as 2-trichloroethyl, an aralkyl group such as benzyl, and an example in which two R3s are bonded are R
Examples include cyclic acetals represented by 3-0-C-OR3. Specific examples of X include halogen atoms such as chlorine, bromine, and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy and trifluoromethanesulfonyloxy, and benzenesulfonyloxy.

Examples include arylsulfonyloxy groups such as p-toluenesulfonyloxy, m-trifluoromethylbenzenesulfonyloxy, and m-chlorobenzenesulfonyloxy.

The compound represented by the general formula (V) of the present invention can be synthesized by the method shown in Reaction Route 1 below. The obtained compound of formula (V) has an optically active 2-
The methylene cyclopentanone derivative (I>) is combined and subsequently led to an optically active cyclobentenone derivative (XI), which is an intermediate of prostaglandin, according to reaction route 2 described below.

In the following formula, R2 is a 1-alkyloxyethyl group,
an easily removable protecting group selected from a cyclic alkyl group and a silyl group having a heteroatom, x1 is a halogen atom,
The * symbol represents an asymmetric carbon atom.

Reaction route 1 (v-1) (IV) (III-3) (III-2> (1-1) (II) (I) To explain the above reaction, an acetal derivative of 2-halogenoacrylaldehyde, which is known per se. (VT) Tetrahydrofuran, diethyl ether.

Ethers such as ethylene glycol diethyl ether,
Alternatively, a vinyl anion produced by using a hydrocarbon such as hexane as a solvent and reacting with an equivalent or more of a strong base such as methyllithium, n-butyllithium, 5ec-butyllithium, or t-butyllithium is expressed by the formula (VI). When the optically active epoxy compound is reacted in the presence of a Lewis acid such as trifluoroboron etherate, a 4-hydroxy-2-methylenepentane derivative represented by the formula (V-2>, which is a compound of the present invention) is obtained. The reaction is preferably carried out at a low temperature of -30 to -100°C.This reaction proceeds without a catalyst, but the addition of a Lewis acid as described above accelerates the reaction.Next, the formula obtained in the above reaction is A protecting group is introduced into the hydroxyl group of the (V-2> compound to convert it into a compound of formula (V-1>).

The introduction of the protecting group R1 is carried out by a known method.

For example, in the case of an alkenyl group, an aralkyl group, an alkyloxymethyl group, and a silyl group, each corresponding RI Y
(Y represents a halogen atom such as chlorine, bromine, iodine, etc.) equivalent molar or more and a base, such as triethylamine, ethyldiinpropylamine.

The reaction can be carried out in the presence of at least an equimolar amount of a base such as pyridine, 4-dimethylaminopyridine, or imidazole, or an inorganic base such as sodium hydride or sodium amide. When R1 is a 1-alkyloxyethyl group or a cyclic alkyl group having a hetero atom, introduction is performed using at least an equivalent amount of the corresponding vinyl ether, an acid catalyst,
For example, hydrogen chloride, p-toluenesulfonic acid, lysine
The reaction may be carried out using p-toluenesulfonate and an acidic ion exchange resin (such as Amberly Storo 15).

When the acetal moiety of the above-obtained compound of the present invention (V-1> is hydrolyzed in the presence of a weak Lewis acid, 2
-methylenepentanal derivative (1v) is obtained. This reaction can be achieved by reacting with a weak Lewis acid catalyst such as copper sulfate, zinc bromide, or silica gel in a water-containing solvent, such as a mixed solvent of water and ethanol.

Next, the carbonyl group of the compound of formula (IV) is converted into a compound of formula (m-2) by cyanohydrination.

Cyanohydrination can be accomplished using hydrogen cyanide in a conventional manner. A simple method for cyanohydrination is to react with trimethylsilyl cyanide in the presence of a 18-crown ether-6 catalyst to obtain trimethylsilylated cyanohydrin formula (I [I-3>), which is then hydrolyzed. It can also lead to a compound of formula (I[l-2).Also, this trimethylsilylated compound of formula (III
-3> compound can also be directly derived into formula (II).

The optically active 1-cyano-1-pentanol obtained above (
III-2) is converted into a compound of formula (III-1) by introducing a protecting group R2 into the hydroxyl group of this compound.

As the protecting group, the above-mentioned 1-alkyloxyethyl group,
It can be appropriately selected from cyclic alkyl groups and silyl groups having a heteroatom. In this case, R2 may be the same as or different from R1. The protecting group R2 can be introduced using the same conditions as when converting a compound of formula (V-2> to a compound of formula (V-1)).

The compound of formula (III-1) is converted into a cyclized compound of formula (n) by reacting it with a strong base. Examples of strong bases include lithium hydride, sodium hydride, potassium hydride, lithium amide, and sodium amide. , potassium amide, lithium diisopropylamide, sodium hexamethyldisilazane, lithium hexamethyldisilazane, potassium hexamethyldisilazane, etc. are used, and the reaction temperature and solvent are appropriately selected depending on the type of strong base.For example, lithium diisopropyl In the case of amides, it is preferably carried out in diethyl ether or tetrahydrofuran at +60 to -100°C, and in the case of using sodium hexamethyldisilazane, in tetrahydrofuran.

The reaction can be carried out in dioxane, benzene or toluene at a temperature ranging from room temperature to 110°C. The amount of strong base is determined by the formula (I
[I-1> Used in an amount of 1 to 10 times the equivalent, preferably 1 to 5 times the equivalent of the compound.

The compound of the above formula (I For example, hydrochloric acid.

Acids such as p-toluenesulfonic acid and acetic acid, acidic ion exchange resins, or trifluoroboron etherate,
It can be carried out in a water-containing solvent at a temperature of 0 to 100°C using a Lewis acid such as zinc bromide or aluminum chloride or a weakly acidic substance such as pyridine/p-toluenesulfonate. When R2 is a silyl group, it is also possible to deprotect with a quaternary ammonium fluoride salt such as tetra-n-butylammonium fluoride. In the case of an aralkyl group, hydrogenolysis using palladium is also an effective means.

Decyanohydrogenation uses sodium hydroxide, potassium hydroxide,
inorganic bases such as sodium bicarbonate, potassium carbonate,
Ammonia, triethylamine.

This can be achieved by reacting with a table equivalent of an organic base such as pyridine or 4-dimethylaminopyridine.

In the above reaction formula, specific examples of R2 include the same groups as the 1-alkyloxyethyl group, cyclic alkyl group having a hetero atom, and silyl group listed for R1, and Xl is chlorine.

Examples include bromine and iodine.

The optically active 2-methylenecyclopentanone derivative represented by the general formula (I) obtained above can be obtained as a prostaglandin intermediate by the method shown in the following reaction route 2. can lead to active cyclobentenone derivatives. In the following formula, R5
represents a straight-chain or branched alkyl group, alkenyl group, alkynyl group, or alkyl-substituted phenyl group which may contain oxygen, sulfur or silicon, including alkoxy, alkyloxydialkoxy, cyclic or non-cyclic acetal means a group having 5 to 22 carbon atoms, which may include a group, a silyl group, or an alkylthio group. M is an organozinc compound such as (CH3)2ZnLi or an organocopper compound such as Cu(CN)Li, Cu(ON)
MgBr.

Cu (CN) Mq (J, Cu (CN) MQI.

(CuLi)v2. (2-thienyl)Cu(C
N) L 12. CLJ (PBLJ3) n (n
= 2-3.3u means a butyl group), etc. R6Z
R6 of YI represents a methyl, phenyl, p-tolyl, p-chlorophenyl, or 2-pyridyl group, Z represents selenium or sulfur, and Yl represents a halogen atom such as chlorine, bromine, or iodine, or ZR6.

Reaction route 2 (I> 2) R6ZYl (IX) (X) (XI) A 2-methylenecyclopentanone derivative represented by formula (I) is reacted with a separately prepared organometallic compound represented by formula (■). After introducing the α chain, the resulting erulate is substituted with an organic selenium compound or an organic sulfur compound represented by the general formula (IX) to obtain a compound of formula (X), which is then treated with an oxidizing agent such as hydrogen peroxide or an organic peracid. oxidize using and then 0
The elimination reaction can be carried out at a temperature of ~150°C to obtain the cyclobentenone derivative (XI).

Organometallic compound R represented by formula (■) used above
5M is prepared as follows. Organocopper compound is R5X1
(XI is a halogen atom such as chlorine, bromine, or iodine)
methyllithium, 5ec-butyllithium, t-
After lithiation with an organic lithium compound such as butyllithium, metallic lithium, etc., or a Grignard reagent with metallic magnesium, cupric cyanide, cupric iodide, or separately prepared (2-thienyl)Cu (CN) is used. Li
It can be made by processing. Further, the organozinc compound can be obtained by separately reacting a tetramethylethylenediamine complex of zinc chloride with 2 equivalents of methyllithium to obtain dimethylzinc, and adding thereto the reaction solution obtained by lithiation of R5Xi. The preparation of R5M is carried out in an inert solvent, e.g.
The reaction can be carried out in a hydrocarbon such as hexane or toluene, an ether such as diethyl ether, tetrahydrofuran or dioxane, or a mixed solvent thereof at a temperature of 0 to -100°C.

As a specific example of R5 above, -CH=CH(CH2)30H (OC2Hs>2.

0 mouth 3 10th = C day (0 mouth 2) 400HO0205゜-C mouth = C mouth (0 mouth 2) aO3i (C605) 2t-C409゜-<0 mouth 2) sO3i (0 day 3〉3゜- (0 mouth 2) 30 low-CHC mouth (00 mouth 3) 2゜-(C
H2) 25CH2CH(OC2Hs) etc.

The optically active cyclobentenone derivative represented by the general formula (XI) obtained above is an acetal of R5.

When a silyl or alkyloxyalkyl group is deprotected in the above-mentioned direction of separation, it can be converted to an aldehyde or alcohol. C prostaglandin derivatives can be synthesized from the compound of formula (XI) by known means.

(Example) Example 1 Synthesis of formula (V-2) compound> To a solution of 9.35 CI (44.9 mmof) of 2-bromo-3,3-jethoxypropene in 80 ml of anhydrous tetrahydrofuran cooled to -78°C, While stirring under an argon atmosphere, n-butyllithium was added dropwise over 20 minutes, followed by further stirring at -78°C for 40 minutes to prepare a vinyllithium solution.

On the other hand, an anhydrous tetrahydrofuran 70-solution of optically active (S)-epichlorohydrin (chemical purity 98.5% or more, optical purity 99% or more>3.46 (J (37.4 mmol)) cooled to -78°C 5.31 g of trifluoroboron etherate with stirring under argon atmosphere.
(37.4 mmol) was added dropwise and further stirred for 10 minutes.

The previously obtained vinyllithium solution was added dropwise to the above epichlorohydrin solution at -78°C over 35 minutes, and the mixture was further stirred for 20 minutes. This reaction mixture was poured into a pre-cooled saturated ammonium chloride aqueous solution with vigorous stirring, the aqueous layer was extracted six times with ether, the ether extract was washed twice with a saturated ammonium chloride aqueous solution and twice with saturated brine, and then After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an optically active 4-hydroxy-2-methylenepentane derivative (V-2-a) 6.97 (1 (yield 84%)) represented by the following chemical formula. Ta.

NMR (CDα3> δ: 1.23 (6H, t, J= 7.OH
2, CH3) 2.34-2.52 (2N, m,
CH2) 3.25-4.17 (9H, m, CH20
, Ct12Cfl, CI.

0H) 4.70 (IN, S, OCI+-0)
5.14-5.50 (2N, m, =Ch) Same as above except that optically active (S)-epi70 mohydrin was used instead of optically active (S)-epichlorohydrin in the above synthesis. Optical activity 4 shown by the above chemical formula
-Hydroxy-2-methylenepentane derivative (V-2-
b) was obtained.

NMR (CDα3> δ: 1.23 (6H, t, J= 7.OH
z, CH3) 2.34-2.55 (2tl, m
, C)12)3.29~3.80 (8t-1,r
n, C1-120, Cl-128r, Ctl)3.
80~4.14 (1M, m, 0H) 4.71
゛(if-1,s, 0CH-0)5.14~5
．． 32 (2H, m, =CH2) Formula (V-1> Synthesis of compound> Optically active 4-hydroxy-2-methylenepentane derivative (V-2-a) obtained above 6.96 g of N, N-
Imidazole 6.43 (] (994.5 mmol) was added dropwise to a dimethylformamide 10 d solution under stirring at 0°C, and then t-butyldiphenylsilyl chloride 14
, ()7(+ (51,3m mof>) was added dropwise and stirred on a water bath for a day and night, then neutralized with 3N hydrochloric acid, the aqueous layer was extracted three times with ether, and the extract was extracted twice with saturated sodium bicarbonate solution. , and then washed three times with saturated saline and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure to obtain an optically active 2-methylenepentane derivative (V- 1-a19.96 (J was obtained.

X=C1(V-1-a) > instead of the optical activity (
An optically active (V-1-b) compound represented by the above chemical formula was obtained in the same manner except that the compounds v-2 to b) were used.

The optically active 2-methylenepentanal derivative (IV
Y, optically active 1-cyano-2-methylenepentane derivative (■), optically active 2-methylenecyclopentanone derivative (I) via optically active 2-methylenecyclopentane cyanohydrin derivative (n), From this, an optically active cyclopentanone derivative (XI) known as a prostaglandin intermediate was found.

Bottom of formula (IV) compound> The optically active 2-methylenepentane derivative (Vl-a)
19.8γq in 80% methanol aqueous solution 120r111
10.09 g of Wt copper acid was added thereto, and the mixture was heated and stirred for 1 hour. The reaction mixture was filtered through Celite, 300 ml of benzene was added to the filtrate, methanol and water were distilled off azeotropically, the residual liquid was extracted with ether, and the ether extract was washed with saturated aqueous sodium bicarbonate. After the aqueous layer was extracted six times with ether, the extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an optically active 2-methylenepentanal derivative (IV -a)
18.66g was obtained.

NMR (CDα3) δ: 1.07 (9H.

2.49-2.71 (2H.

3.34 (2H.

3.94-4.26 (IH.

5.99 (IN.

6.24 (1H.

X=C1(IV-a) X=Br(IV-b) CH3) C)12) J=5. OH2, CH2) CH) =CH) =CH) γ, 29-7.91 (IOH, m, Cs Is
>9.94 (1)1. S, CHD
>JR (neat) 1685, 1480.1100. 700 cm −1 In the above combination, optically active 2-methylenepentane derivative (
Optical activity (V-1) where X=Br instead of V-1-a)
An optically active (1v-b) compound represented by the above chemical formula was obtained in the same manner except that the compound -b) was used.

NMR (CDCj23) δ: 1.07 (9N, S, CH3)2.
43~2.83 (2N, m, CH2) 3.21
(2H, d, J= 5.0H2, CH2)
3.86-4.23 (IH, ITI, C1) 5.9
9 (IN, br s, =C11)6.26
(1)1. br s, =Cl1)7.29
~7.91 (IOH, m, C611s >9.9
4 (IH,s, CHO)IR(neat) 1685, 1580.1100. yoocm-'base of formula (III-2) compound> The optically active 2-methylenepentanal derivative (IV
-a > To 18.66a, under an argon atmosphere, a catalytic amount of potassium cyanide complex of 18-crown ether was added, and while stirring, 3.65 g of trimethylsilyl cyanide (36.8 m
mof> was added dropwise. The reaction mixture was further stirred on a water bath for 1 hour, then diluted with 100 ml of tetrahydrofuran, 30-mL of 1N hydrochloric acid was added, and the mixture was stirred for 20 minutes. The aqueous layer was extracted six times with ether, and the extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A crude product of pentane derivative (III-2-8) was obtained. This was treated with n-hexane:ether=8:1 using silica gel column chromatography to produce purified products 6 and 1.
4(] was obtained. The yield from formula (V-2-a) was 47.4
%Met. In addition, at this time, the raw material (IV-a) compound 2
．． 80! Collected J.

X=α(III-2-a) X=Br(III-2-b) NMR(CD(j!3) δ:1.0-1.17 (9M, d, CH3>2
．． 51~2.86 (2H, m, CH2)3, OO~
3゜57 (3H, m, CH2, CH) 3.91~4
．． 23 (IH, m, CH) 4.71-4.96 (I
H, m, 0H) 5.21-5.63 (2H, m,
=CH2)7.25~7.91 (1H, m, CI>
In the above synthesis, instead of the optically active 2-methylenepentanal derivative (IV-a), the optically active (
An optically active (Il-2-b) compound represented by the above chemical formula was obtained in the same manner except that the compound IV-b) was used.

NMR (CDC13) δ: 1.0-1.32 (9H, II, CH3)2.
55-3.67 5M, m, CH2, CH)3.
90-4.21 1H, m, CI) 4.84
1M, s, 0tl) 5.18-5.67 2H,
m, =CH2)7.28~7.85 10H,m,
Synthesis of Ca Hs ) Formula (II-1) Compound> The optically active 1-cyano-2-methylenepentane derivative (III-2-a) 6.14! II (14.8m
A catalytic amount of p-toluenesulfonic acid was added to a solution of 90 mol of anhydrous benzene under an argon atmosphere, and 1.18 g (16.3 mol) of ethyl vinyl ether was added under stirring on a water bath.
mol> was added dropwise. After stirring for an additional 40 minutes, the aqueous layer was neutralized with pre-cooled saturated sodium bicarbonate solution, extracted four times with ether, the extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was distilled off to obtain 6.68 g of an optically active 1-cyano-2-methylenepentane derivative (III-1-a>) represented by the following chemical formula.

NMR (CDα3) δ: 0.93-1.43 (15H, m, CH3)2
．． 35~2.74 (2H, m, CH2) 3.23~
3.77 (4H, m, CH2) 3.89-4.11
(IH, m, CH) 4.34-5.03 (2N,
m, CH) 5.19 (IH, br s,
=CH)5.43~5.63(IN, m, =C
H) 7.29-7.91 (IOH, m, Co
11s > In the above synthesis, optically active 1-cyano-2
- Optical activity (I[l
-1-b) Compound was obtained.

NMR (CDCf13> δ: 0.93-1.43 (15H, m, CH3)2
．． 37~2.74 (2H, m, CH2) 3.09~
3.77 (4H, m, CH2, CM) 3.89-4
．． 23(1)1. m, C) l) 4.60-5.1
4 (2H, III, CI) 5.14-5.71 (
2H,m, =CH2)7.31~7.91 (1ON
, m, Ca Is ) IR (neat) 1700 (c=c), 1110.1050. 940
．． 830°γ40. 700cm-1 Synthesis of formula (Ilr) compound> Benzene solution of sodium hexamethyldisilazane (2
Add 0.66 N > 10.3 rri1 to 50 ml of anhydrous tetrahydrofuran under an argon atmosphere, and while stirring, add 1.23 g of the above optically active 1-cyano-2-methylenepentane derivative (III-1-a) to 20 ml of anhydrous tetrahydrofuran. The solution was added dropwise at 50° C. over 70 minutes.

The above reaction solution was poured into a pre-cooled saturated aqueous ammonium chloride solution with vigorous stirring, and then extracted with a needle five times, and the extract was washed successively with 1N hydrochloric acid and brine. This was purified by silica gel column chromatography (n-hexane:ether = 20:1) to obtain optically active 2-methylenecyclopentane cyanohydrin derivative (II) 756mo (from formula (■ to 2-a) compound) shown by the following chemical formula. A yield of 61.6%) was obtained.

NMR (CDα3) δ: 0.93-1.57 (1511°2.06-2.
71 (4H.

3.23-3.86 (1M.

4.14~4.60 (1) 1° 4.69-5.11 (IN.

5.11-5.37 (IH.

m, CH3) m, CH2) m, CFl) III, Cl)! II, CH) II, CH) 5.37-5.66 (1N, rtr, CH)7
．． 31-7.90 (1ON, m, C6H5) In the above synthesis, optically active (III-1- When compound b) was used, the optically active (n) compound was obtained in the same yield as above.

Synthesis of Formula (I) Compound> Optically active 2-methylenecyclopentane cyanohydrin derivative (II) obtained above 756mQ (1,68
A catalytic amount of pyridine p-toluenesulfonate was added to a solution of 30 mmol) of anhydrous methanol under an argon atmosphere, and the mixture was refluxed for 1.2 hours. After distilling off the solvent under reduced pressure, 25 m of anhydrous tetrahydrofuran and 10 rrd of saturated sodium bicarbonate solution were added to the residue.
t was added at room temperature and stirred for 1.5 hours. Ether was added to the reaction mixture for extraction, and the extract was washed with brine. The aqueous layer was further extracted with ether five times, these extracts were combined, washed successively with 1N hydrochloric acid and brine, dried, the solvent was distilled off under reduced pressure, and then silica gel column chromatography (n-hexane:ether-40 :1) to obtain an optically active 2-methylenecyclopentanone derivative (I> 307.5 mg (yield 52.2%) represented by the following chemical formula)
I got it.

f) IR(neat) 1730, 1645.1100. 730cm-110
NMR (CDC13) δ: 1.04 (9H,S, CH3) 2.4
2 (2M, d, J= 5.0H2,C
H2) 2.72 (2H, quint, 2.
4Hz, CH2) 4.47 (10,quin
t, 5.01 (z, CH) 5.29 (iH, d
t, J=2.4Hz, 1.5flz.

=CH) 6.03 (IN, dt, J=2.4H2,1,
5H2°=CH) 7.31-7.91 (IOH, m.

Hs ) B 13CNMR (CDCII3) δ: 19.06. 26.79. 40.02.
48.26. 68.51゜118.03.127.7
0.127.76, 129.82.129.86°13
3.50.133.73.135.64.143.22
．． 204.40 <Synthesis of formula (X) compound> Under an argon stream, a solution of 8 mg (0,831 mmol) of vinyl iodide derivative 247 represented by the following formula (XI [>) in n-hexane 7rr11 was cooled to -78°C. Then, while stirring, t-butyllithium was added dropwise using a syringe over a period of 5 minutes, followed by stirring at the same temperature for 90 minutes to obtain a vinyllithium compound represented by the following chemical formula.

Meanwhile, 230.8 mg of tetramethylethylenediamine complex of zinc chloride (0.9
14 mmol> was added, 7 volumes of anhydrous tetrahydrofuran was added, and the mixture was cooled to -20°C and stirred.
28 m mol> was added dropwise using a syringe over 3 minutes,
After stirring for an additional 10 minutes, the mixture was cooled to -80°C.

The vinyllithium compound solution was added dropwise to this solution using a bridge while stirring at -78°C for 5 minutes, and the mixture was further stirred at -60°C for 1 hour. This was added to the optically active 2-methylenecyclopentanone derivative (I) obtained above.
>223.5 mg (0.6376 mmol) of anhydrous tetrahydrofuran solution 7 was added dropwise over 40 minutes at -78°C with thorough stirring. Furthermore, this container is 2r
111 of anhydrous tetrahydrofuran, added to the reaction solution over 10 minutes with stirring, and further stirred at -78°C for 30 minutes.

To this reaction solution was added diphenyl diselenide 996, Omg (3
, 197 mmol) of anhydrous tetrahydrofuran was added using a syringe at −78° C. with vigorous stirring. After stirring at -50°C for 30 minutes, the above reaction solution was poured into a cooled saturated ammonium chloride aqueous solution with vigorous stirring, and after decomposition, the aqueous layer was extracted six times with ether, and the ether solutions were combined to form a saturated brine solution. After washing twice with water, it was dried with anhydrous magnesium sulfate. This was filtered, the solvent of the filtrate was distilled off, and the crude product was subjected to silica gel column chromatography (n-hexane:ether-5=1).
Optically active 2-phenylselenocyclopentanone derivative (X) 220.1m purified by
g (yield 50.9%) was obtained.

NMR (CDC13) δ: 1.04 (9H.

1.04-1.74 (12H.

1.82-2.86 (6N.

3.30-3.82 (4M.

4.34-4.78 (2H.

S, CH3) m, CH3, CH2) m, CH2Co, CH2C=C) m, CH20) m, 0CII) 5.15-5.50 (2N, m, =CH) 7.1
0-7.70 (15H, m, Cs us )IR
(neat> 1730, 1105. 740. 700 cm -1 <Synthesis of compound of formula (Xl)> 115.7 mg (0,170 mm
ol> in tetrahydrofuran, cooled to 0°C, and stirred with 30% hydrogen peroxide, 0.14d (156
, 1 mg.

1.80 mmol) was added to the solution. The reaction solution was gradually warmed to room temperature and further stirred at room temperature for 3 hours. The reaction solution was diluted with ether, and the ether layer was separated and washed with saturated brine. The aqueous layer was further extracted five times with ether, and the ether layers were combined and washed again with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residual oil was purified by silica gel chromatography (n-hexane:
Ether = 5 = 1), and further purified by high performance liquid chromatography (silica gel "31-160J, 7.6φX3
0cm, n-hexane:ethyl acetate = 1:4)
to obtain an optically active cyclobentenone derivative (XI-1>40.6n+g (yield 45
．． 9%> and 25.8 mq8 by-products of undetermined structure were obtained.

NMR (CD(lff13) δ: 1.07 (9H, S, CH3) 1.0
7-1.79 (12H, m, CH2, CH31,8
γ~2.26 (2N, m, CH2) 2.34~
2.54 (211, m, CH2>2.70~2.9
4 (2H, m, CH2) 3.18~3.82 (4
M, m, CH2)4.66 (IH,q
, J=5.5Hz.

4.75-4.98 (IH, m, CI>5.44
(IH,m,=Cti)6.88~7.02(lt
l, m, =CH) 7.26-7.78 (100,
m, Cs Hs )> CH) IR(neat) 1715, 1105. 700 cm-1 Optically active cyclobentenone derivative obtained above (XI-1>31.9
m (1 (0,06 m mol) of anhydrous methanol 2d
A catalytic amount of p-toluenesulfonic acid was added to the solution under water cooling in an argon stream, and the mixture was stirred for 1 hour and 20 minutes under water cooling, and then further stirred at room temperature for 1 hour. This reaction solution was neutralized with pre-cooled saturated sodium bicarbonate solution, and the aqueous layer was extracted 5 times with dichloromethane.
The extracts were combined, washed twice with saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residual oil was subjected to silica gel column chromatography (n-
Hexane:ether = 1:1) to produce an optically active cyclobentenone derivative (Xl-
2>24.8m(It (yield 90.2%)) was obtained.

＼C6th.

(XI-2> [α tube = +31.85° (c = 0.496. Methanol) 1 day NMR (CDCI13) δ: 1. Or (9H, S, CH3) 1.15
~1.79 (5H, m, CH2, DH>1.87~
2.27 (2H, m, CH2)2.06
(2H, br q, J= 6.4Hz.

CH2) (2H, br d, J = 6.0Hz.

CH2) 3.62 (2H, t, J= 6.4NZ,
CH2) 4.75-4.96 (1) 1. m, C
M) 5.30-5.55 (2N, m, =CH)6
．． 93-6.98 (1H, m, =CH) 7.27-7
．． 75 (IOH, m, Ce Hs) blind'CN
MR (CDCU3) δ: 19.72. 23.24. 2B, 22.
27.47. 32.89°43.94. 46.00
．． 63.34. 70.54.125.38°128
．． 41.130.58.132.64.134.26.
136.26°146.51.157.23.177.
871R(neat) 2.87 3400, 1710.1110.1070. 780.
700Cm-1 (Effects of the Invention) The compound of the present invention is useful as a raw material for producing prostaglandins, and is more effective than conventional methods using coley lactone and 4-hydroxycyclobentenone, which are synthetic intermediates. It has the advantage of being able to omit a large number of complicated processes and can be achieved in an extremely short process time.

Claims (3)

[Claims] (1) An optically active 2-methylenepentane derivative represented by the following general formula (V). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) In the above general formula (V), R^1 is a hydrogen atom, an alkenyl group, an aralkyl group, an alkyloxymethyl group, 1
- an easily removable protecting group selected from an alkyloxyethyl group, a cyclic alkyl group having a heteroatom, and a silyl group; R^3 is selected from an alkyl group and an aralkyl group which may have a halogen substituent; The two R^3s may be different from each other, or the two R^3s may be combined to form a cyclic acetal. . X is a halogen atom or R^4SO_
3 groups, R^4 represents an alkyl group or an aryl group, and the symbol * represents an asymmetric carbon atom. (2) An optically active 2-methylenepentane derivative according to claim 1, wherein R^1 in the general formula (V) is a hydrogen atom. (3) General formula (VI) below ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (VI) (In general formula (VI), R^3 is an alkyl group or an aralkyl group that may have a halogen substituent. It is a selected easily removable protecting group, and the two R^3s may be different from each other, or the two R^3s may be combined to form a cyclic acetal. (X^1 each represents a halogen atom) A compound represented by the general formula (VII) ▲ in the presence of a base.
There are mathematical formulas, chemical formulas, tables, etc.▼(VII) (In general formula (VII), X is a halogen atom or R^
4SO_3 group, R^4 is an alkyl group or aryl group, *
The method for producing an optically active 2-methylpentane derivative according to claim 2, characterized in that the reaction is carried out with an optically active compound represented by (the symbol represents an asymmetric carbon atom).