JPH04279576A - Production of optically active 4-pentanolide derivative - Google Patents

Abstract

PURPOSE:To readily obtain the title compound useful as a synthetic intermediate for medicines by reacting an enantiomer mixture of pentanolide derivative with an acylating agent in the presence of an asymmetric hydrogenase. CONSTITUTION:First, an enantiomer mixture of pentanolide derivative shown by formula I (R is alkyl) is allowed to react with an acylating agent shown by the formula R<1>COOR<2> (R<1> is alkyl; R<2> is H or alkyl) in the presence of an asymmetric hydrogenase (e.g. lipase derived from Candida cylindracea) preferably at 25-50 deg.C to stereoselectively convert hydroxy group at the 3-position of one optically active substance into an acyloxy group. Then, a formed optically active 3-hydroxy-4-pentanolide derivative is separated and collected. The enantiomer mixture of the raw material, for example, is obtained by subjecting a propanal compound shown by formula II to the ring closure reaction in the presence of zinc and a di-lower alkylaluminum chloride.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to a method for producing optically active 4-pentanolide derivatives.

[Conventional technology]

Optically active 4-pentanolide derivatives, especially (2R,3R,4S)-2-alkyl-3-hydroxy-4-pentanolide, are hydrolysis products of antimycin A, and are useful as synthetic intermediates for pharmaceuticals and Streptomyces virginia (Streptomyces virginia)
The compound is useful as a compound having an activity of inducing the production of virginiamycin, an antibiotic for S. ces virginiae.

Conventionally, as a method for producing optically active 4-pentanolide derivatives, a method of synthesizing optically active 2-butyl-3-hydroxy-4-pentanolide using an optically active sugar derivative as a starting material (J. Antibiot., Vol. 2
5, 373 (1972) or Bull. Chem
．． Soc. Jpn. , Volume 48, 1254 (1975)
) and methyl trans-2-n-butylpent-3
-Trans-hydroxylation of enoate produces racemic 2-
Method for synthesizing butyl-3-hydroxy-4-pentanolide (Agr. Biol. Chem., Vol. 37, 9
15 (1973)), the 2- and 3-positions obtained by reducing 2-butyl-4-methyl-3-oxo-4-pentenoic acid benzyl ester with zinc borohydride are
-Butyl-3-hydroxy-4-pentenoic acid benzyl ester and racemic 2-butyl-3-hydroxy-
Method for synthesizing 4-pentanolide (Tetrahed
oron Lett. , Volume 24, 2657 (198
3)), (2R,3S)- by Claisen rearrangement of (R)-(E)-1-methyl-2-heptenyl glycolate
2-hydroxy-3-(1-propenyl)heptanoic acid is obtained, and optically active 2-butyl-3-hydroxy is obtained via (2S,3R,4S)-4-(1-propenyl)octane-2,3-diol. A method for synthesizing -4-pentanolide (Tetrahedoron Lett., Vol. 25, 5155 (1984)), 3,4-epoxy-5-methyldihydro-2 (obtained by epoxidation of optically active β-angelica lactone) Method for synthesizing optically active 2-butyl-3-hydroxy-4-pentanolide using 3H)-furanone as a reaction intermediate (Tetrahedoron Lett., Vol. 26, 2815 (1985), Tetrahedoron,
Many methods are known, such as Vol. 43, 2191 (1987)).

[Problem to be solved by the invention]

However, these production methods have drawbacks such as long synthetic routes and complicated operations, and low stereoselectivity, and cannot be said to be industrially advantageous.

[Means to solve the problem]

[0005] As a result of intensive research, the present inventors have found that
It has been found that a 4-pentanolide derivative [I] having a trans configuration at the 3rd and 4th positions can be easily resolved using an asymmetric hydrolase.

That is, according to the present invention, general formula [I]

The optically active form of the 4-pentanolide derivative represented by the formula (wherein, R represents an alkyl group) can be obtained by preparing the enantiomeric mixture of the 4-pentanolide derivative [I] in the presence of an asymmetric hydrolase. Formula [II]

[Formula 8] (wherein, R1 represents an alkyl group, R2 represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkenyl group) to form one optically active compound. The 3-position hydroxy group of is stereoselectively converted to an acyloxy group, or the general formula [III]

[Image Omitted] A mixture of enantiomers of a 3-acyloxy-4-pentanolide compound represented by the formula (wherein R and R1 represent an alkyl group) is treated with an asymmetric hydrolase to form the 3-position of one optically active compound. It can be obtained by stereoselectively converting an acyloxy group into a hydroxy group, and then separating and collecting the 3-position hydroxy form from the reaction solution.

Specific examples of the optically active 4-pentanolide derivatives [I] of the present invention include, for example, groups R having 1 to 1 carbon atoms;
8 alkyl groups (e.g. methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, isopentyl group) , isohexyl group, isoheptyl group, isooctyl group, etc.).

Further, as specific examples of the acylating agent [II] and the 3-acyloxy-4-pentanolide compound [III], the group R1 is an alkyl group having 1 to 20 carbon atoms (for example, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, n-hexyl group, n-heptyl group, pentadecanyl group, heptadecanyl group, etc.) or an alkenyl group having 10 to 20 carbon atoms (e.g. , heptadecaenyl group, heptadecadienyl group, etc.), and R2 is a hydrogen atom, and an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, n-butyl group) , n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group,
isopropyl group, isobutyl group, isopentyl group, isohexyl group, isoheptyl group or isooctyl group, trichloroethyl group, trifluoroethyl group), carbon number 2
-6 unsubstituted alkenyl groups (eg, isopropenyl group, etc.).

In the enantiomeric mixture of the 4-pentanolide derivative [I] and the 3-acyloxy-4-pentanolide compound [III] according to the present invention, there is no particular restriction on the mixing ratio of the enantiomers, and in addition to the racemate, any Mixed proportions can also be used.

[0010] The lipase that can be used in the present invention may be any lipase that has an asymmetric hydrolysis ability. For example, lipases that have such an ability include microorganisms belonging to the genus Candida and Pseudomonas, and porcine pancreas ( P
orcine pancreas), and the like. Specific examples of lipases derived from such microorganisms include, for example, Candida cylindracea (Candida cylindracea).
ida cylindracea), Candida lipolytica,
Pseudomonas fluorescens
nas fluorescens), Pseudomonas sp.
Examples include lipase derived from These microorganisms may be wild strains or mutant strains, or may be derived from these microorganisms by biotechnological techniques such as genetic recombination and cell fusion.

[0011] These lipases can be obtained by culturing the microorganisms that produce them, but they can be used in the form of bacterial cell culture as is, crude enzyme, or purified enzyme. It is also possible to use a combination of microorganisms and microorganisms. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterial cells immobilized on a resin or other matrix.

[0012] Some of these microbial or animal lipases are commercially available and can be easily obtained. Specific examples thereof include the following. Those derived from Candida cylindracea include Lipase OF (Meito Sangyo Co., Ltd.) and Lipase Type
II (manufactured by Sigma), Lipase AY-30 (manufactured by Amano Pharmaceutical)
, Candida lipolitica
lipase L-10 (
Amano Pharmaceutical), Pseudomonas fluorescens (P
Those derived from Pseudomonas fluorescens include Lipase P (manufactured by Amano Pharmaceutical), Pseudomonas sp.
) derived from Lipase P (manufactured by Nagase Seikagaku Kogyo), Lipase CES (manufactured by Amano Pharmaceutical), and porcine pancreas (manufactured by Amano Pharmaceutical).
An example of the lipase derived from P. porcine pancreas is Lipase (manufactured by Wako Pure Chemical Industries, Ltd.).

The reaction between the enantiomeric mixture of the 4-pentanolide derivative [I] and the acylating agent (II) can be carried out in a suitable solvent in the presence of an asymmetric hydrolase. The ratio with the acylating agent is usually 1:0.6 to 1:10 (molar ratio), particularly preferably 1:0.6 to 1:5 (molar ratio).As the reaction solvent, , water-immiscible organic solvents can be used, such as benzene, toluene, n-hexane, ethyl ether, isopropyl ether, carbon tetrachloride, methylene chloride, ethyl acetate, methyl acetate, etc. This reaction proceeds suitably at room temperature to elevated temperature, particularly at 25 to 50°C.

The treatment of the 3-acyloxy-4-pentanolide compound [III] with an asymmetric hydrolase can be carried out in an aqueous solution. The concentration of the 3-acyloxy-4-pentanolide compound (III) in this reaction is usually 0.01 to 50% by weight, especially 0.08% by weight.
Preferably it is 5% by weight. In addition, when carrying out this treatment, the pH of the reaction solution should be adjusted to the optimum pH of the enzyme used.
For this pH adjustment, an appropriate buffer may be used, or a pH stat may be used to control the pH with an aqueous solution such as sodium hydroxide. This reaction proceeds suitably at room temperature to elevated temperature, especially at 25 to 50°C.

The optically active 4-pentanolide derivative [I] thus produced can be obtained by removing the enzyme from the above reaction solution by a conventional method such as centrifugation or filtration, and if necessary adding a suitable organic solvent to the reaction solution from which the enzyme has been removed. (for example, ethyl ether, ethyl acetate, etc.) to extract the product, and then separate it by a conventional method such as column chromatography or recrystallization.
Can be collected.

The enantiomeric mixture of the 4-pentanolide derivative [I], which is the raw material compound of the present invention, can be synthesized, for example, as follows.

That is, general formula [IV]

embedded image A propanal compound represented by the formula (wherein R has the same meaning as above) was prepared using zinc, tributyltin lithium [(
C4H9)3SnLi] or tributyl lead lithium [(C4H9)3PbLi] in the presence of a di-lower alkyl aluminum chloride (for example, diethylaluminum chloride, diisobutylaluminum chloride, etc.). This ring-closing reaction can be suitably carried out in a suitable solvent (eg, tetrahydrofuran, dimethoxyethane, ethyl ether, hexane, pentane, or a mixture thereof).

In the above reaction, when zinc is used, the amount used is 50 times the molar amount relative to the propanal compound [IV], tributyltin lithium [(C4H9)
3SnLi] or tributyl lead lithium [(C4H
9) When using 3PbLi], it is appropriate to use about twice the molar amount, and the appropriate amount of di-lower alkyl aluminum chloride to be used is about twice the molar amount relative to the propanal compound [IV]. . Furthermore, the zinc is preferably activated by treatment with a solution of silver acetate in acetic acid immediately before use. In this reaction, it is preferable to gradually add the propanal compound [IV] to a solvent in which zinc and diethylaluminium chloride are mixed in advance, or to increase the amount of solvent to obtain a high dilution. . This reaction is
The process is preferably carried out at -50 to 70°C, especially at 30 to 60°C under an inert gas atmosphere such as argon gas.

The above propanal compound [IV] can be produced, for example, by a series of reaction steps such as reduction of a ketone compound, esterification, and cleavage of an olefin with ozone, as shown in the following reaction formula.

embedded image (In the formula, R3 and R4 represent a hydrogen atom or an alkyl group.)

Among the raw material compounds, the 3-acyloxy-4-pentanolide compound [III] is a compound represented by the 4-pentanolide derivative [I] and R1COCl (wherein R1 has the same meaning as above). etc. in an appropriate solvent (eg, benzene, n-hexane, pyridine, etc.) at -10 to 30°C.

[0021]

[Example] Example 1 (1) In a test tube with an outer diameter of 30 mm, enzyme 1 shown in Table 1 was added.
．． (±)-(
2RS, 3RS, 4SR)-2-hexyl-3-hydroxy-4-pentanolide [(±)-(2R
80 mg of S,3RS,4SR) and 66 mg of 2,2,2-trichloroethyl octanoate were added, and the mixture was shaken (200 rpm) at 30°C for 48 hours. After filtering off the enzyme, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 20:1 to 5:1) to obtain (2R, 3R, 4S)-2-hexyl-3-hydroxy-4-pentanolide ((2R,3R,4
S) body) and (2S,3S,4R)-2-hexyl-3-octanoyloxy-4-pentanolide (first
In the table, (2S, 3S, 4R) esters) were obtained with the yield and optical purity shown in Table 1, respectively.

(2) Put the above (1) into a test tube with an outer diameter of 30 mm.
Macilvaine (
30 ml of McIlvaine buffer (pH 6.5) and 25 mg of (2S,3S,4R)-2-hexyl-3-octanoyloxy-4-pentanolide obtained in (1) above were added, and at 30°C, Shake for 36 hours (200
r. p. m. )do. After extracting the reaction solution with ethyl ether, it was washed with saturated brine, dried over magnesium sulfate,
The solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent: n-hexane:ethyl acetate = 10:1~
(2S, 3S, 4R) by purification at 5:1)
-2-hexyl-3-hydroxy-4-pentanolide (indicated as (2S,3S,4R) form in Table 1) was obtained in the yield and optical purity shown in Table 1. In addition, 2-hexyl-
An optically active preparation of 3-hydroxy-4-pentanolide can be obtained by hydrolyzing antimycin A (
2R,3R,4S)-isomer was obtained. Optical purity is (R)-
It was derived from (+)-2-methoxy-2-(trifluoromethyl)phenylacetate and determined by high performance liquid chromatography (HPLC).

[0023]

[Table 1]

Example 2 To 200 ml of anhydrous benzene in which 2.0 g of lipase (manufactured by Wako Pure Chemical Industries) was suspended,
160 mg of R)-2-hexyl-3-hydroxy-4-pentanolide and 500 mg of 2,2,2-trichloroethyl octanoate are added and stirred at 30°C for 3 days. After filtering off the enzyme from the reaction solution, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate = 20:1 to 5:1), and then n-hexane-ethyl acetate = 20:1 to 5:1). By recrystallization from ether, (2R,3R,4S)-2-hexyl-3
-Hydroxy-4-pentanolide (64 mg) was obtained. Yield: 40% Optical purity >99%ee (HPLC) m. p. 57-58.5°C [α]D21-11.85° (c=0.986, methanol)

Example 3 1.5 g of Lipase P (manufactured by Nagase Seikagaku Kogyo) was added to 15 ml of anhydrous benzene (±)-(2RS, 3RS, 4
SR)-2-hexyl-3-hydroxy-4-pentanolide (80 mg) and 220 mg of octanoic acid 2,2,2-trichloroethyl ester were added, stirred at 50°C for 7 hours, and then the enzyme was filtered off. After distilling off the solvent, add again a suspension of Lipase P (1.0 g) in anhydrous benzene (15 ml).
Stir at 50° C. for 7 hours. After filtering off the enzyme, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: n-hexane: ethyl acetate = 20:1 ~
(2R, 3R, 4S) by purification at 5:1)
32 mg of -2-hexyl-3-hydroxy-4-pentanolide was obtained. Yield 40%

Example 4 (1) (±)-(2RS,3RS,4SR)-2-hexyl-3-hydroxy-4-pentanolide 73 mg (
0.37 mmol) and 60 μl of triethylamine, 4-
5 mg of N,N-dimethylaminopyridine are dissolved in anhydrous benzene. Under ice cooling, 65 mg (0.40 mmol) of octanoyl chloride is added dropwise to the solution, and the mixture is stirred at room temperature for 3 hours. Pour the reaction mixture into cold water and extract with ethyl acetate. After washing and drying the extract, silica gel column chromatography (solvent: n-hexane: ethyl acetate = 10
:1), (±)-(2RS,3
97 mg of RS,4SR)-2-hexyl-3-octanoyloxy-4-pentanolide are obtained. Yield 81%

[
1H-NMR (CDCl3) δ: 0.86 (
6H, t, J = 5.8Hz), 1.44 (3H, d, J
=6.4Hz), 1.15-2.0 (20H, m), 2
．． 31 (2H, t, J = 7.6Hz), 2.66 (1H
, m), 4.33 (1H, dq, J=6.4Hz, J=
4.6Hz), 4.90 (1H, dd, J=5.6Hz
, J=4.6Hz) IRliquidνmax (cm-1): 2930, 2
860, 1790, 1750, 1475EI-MS
(m/e): 326 (M+)

(2) Outer diameter 3
Add 0.5 of lipase (Wako Pure Chemical Industries) to a 0mm test tube.
(±)-(2RS,3
RS,4SR)-2-hexyl-3-octanoyloxy-4-pentanolide 54 mg (0.17 mmol)
and shake at 30℃ for 4 days (200r.p.m.
．． )do. The reaction solution was extracted with ethyl ether, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate = 10:1), and then recrystallized from n-hexane-ethyl ether to obtain (2S,3S,4R)-2-hexyl. -3-
17 mg of hydroxy-4-pentanolide are obtained. Yield: 51% Optical purity: 45%ee (HPLC)

Reference Example (1) To an ethanol solution (500 ml) of 98.2 g (1.0 mol) of medityl oxide was added 10.5 g (0.28 mol) of sodium borohydride under ice cooling and stirring, and then Stir at room temperature for 3 hours. After condensing the reaction mixture, water (500 ml) was added to the residue, and ethyl ether (500 ml) was added to the residue.
x2), and after drying, the solvent was distilled off. By distilling the residue under reduced pressure, 4-hydroxy-2-methyl-2-
75.0 g of pentene is obtained. Yield: 75%

1H-NMR (CDCl3) δ: 1.20
(3H, d, J=6.4Hz), 1.67 (6H, s)
, 1.93 (1H, s, OH), 4.49 (1H, dq
, J=6.4Hz, J=8.8Hz), 5.16(1H
, d, J=8.8Hz) IRliquidνmax (cm-1): 3350, 2
975, 2925, 1680, 1455, 1385

0
(2) 4-hydroxy-2- obtained in (1) above
8.0 g (0.080 mol) of methyl-2-pentene, 45 ml of triethylamine, and 1.0 g of 4-N,N-dimethylaminopyridine were dissolved in anhydrous benzene (200 ml), and the temperature of the reaction mixture was adjusted to 10 ml while stirring. 19.5 g of 2-bromooctanoyl chloride (
0.081 mol) was added dropwise. After stirring for an additional 30 minutes at room temperature, the reaction mixture was poured into cold water (300 ml) and extracted with ethyl ether (300 ml x 3). 10% hydrochloric acid (30%
0 ml), saturated saline (300 ml), sodium bicarbonate aqueous solution (300 ml), saturated saline (300 ml)
After washing with l) and drying, the solvent is distilled off. The residue was purified by silica gel chromatography (solvent: n-hexane) to obtain 13.0 g of 4-(2-bromooctanoyloxy)-12-methyl-2-pentene. Yield: 54%

1H-NMR (CDCl3) δ: 0.89
(3H, d, J=5.0Hz), 1.28 (3H, d,
J=6.0Hz), 1.72 (6H, s), 1.05-
2.50 (10H, m), 4.12 (1H, t, J=7
．． 0Hz), 5.10 (1H, d, J=9.0Hz),
5.47 (1H, dq, J=6.0Hz, J=9.0H
z) IR liquid νmax (cm-1): 2970, 2
930, 2860, 1745, 1680, 1475, 1
460, 1385

(3) 4-(2-bromooctanoyloxy)-2-methyl-2-pentene obtained in the above (2) 1.
00 g (3.3 mmol) in methanol solution (50 ml
) under ice cooling (-5°C), and ozone gas was introduced (for 3 hours). After expelling ozone with nitrogen gas, cool on ice (-5°C).
), 2.43 ml (0.033 mol) of dimethyl sulfide were added, the reaction temperature was raised to room temperature over 2 hours, and the mixture was further stirred overnight. The solvent was distilled off, and the residue was subjected to silica gel chromatography (solvent: n-hexane: ethyl acetate = 1
0:1)) to obtain 0.76 g of 2-(2-bromooctanoyloxy)-1-propanal. Yield: 82%

1H-NMR (CDCl3) δ: 0.87
(6H, t, J=5.0Hz), 1.42 (3H, t,
J=7.2Hz), 1.06-2.36 (10H, m)
,4.24(1H,t,J:7.0Hz),5.08(
1H, q, J = 7.2Hz), 9.44 (1H, s) IR liquid νmax (cm-1): 3480, 2
970, 2940, 2870, 1750, 1470, 1
390

(4) Under an argon atmosphere, 7.02 g of zinc prepared by treating with an acetic acid solution of silver acetate and 4.30 mmol of diethylaluminium chloride were suspended in anhydrous tetrahydrofuran (10 ml), and suspended at 55° C. for 30 min.
Stir for a minute. Then, at the same temperature, 2- obtained in the above (3)
A solution of 600 mg (2.2 mmol) of (2-bromooctanoyloxy)-1-propanal in 80 ml of tetrahydrofuran was slowly added dropwise over 5 hours. Pyridine 2
．． The reaction was stopped by adding 5 ml of the solution, and insoluble matter was filtered off and washed with ethyl ether. The filtrate and washing liquid were collected and
ml of ethyl ether and 2N-hydrochloric acid (150 ml).
), washed with saturated brine, and dried over magnesium sulfate. After distilling off the solvent, silica gel column chromatography (
n-hexane:ethyl acetate=5:1), (±)-
250 mg of (2RS, 3RS, 4SR)-2-hexyl-3-hydroxy-4-pentanolide was obtained. yield:
59%

1H-NMR (CDCl3) δ: 0.88
(3H, t, J=6.9Hz), 1.45 (3H, d,
J=6.3Hz), 1.25-1.65 (9H, m),
1.86 (1H, m), 2.02 (1H, d, J=5.
4Hz), 2.55 (1H, ddd, J=5.7Hz,
J=7.7Hz, J=8.6Hz), 3.84(1H,
ddd, J=5.4Hz, J=6.3Hz, J=8.6
Hz), 4.20 (1H, quint, J=6.3Hz
) IRNujolνmax (cm-1): 3400, 17
30(lactone)IRChloroformνm
ax (cm-1): 1776 (lactone) EI-
MS (m/e): 201 (M+H)+m. p. 60.5
~65℃

【Effect of the invention】

The above-mentioned present invention provides (2R,3R,4S)-
Since 2-alkyl-3-hydroxy-4-pentanolide and its enantiomers can be easily produced using inexpensive raw materials and without complicated steps, it can be an industrially advantageous production method.

Claims (7)

[Claims] Claim 1: A mixture of enantiomers of a 4-pentanolide derivative represented by the general formula [I] [Formula 1] (wherein R represents an alkyl group) is prepared by the general formula [II] in the presence of an asymmetric hydrolase. [Formula 2] [In the formula, R1 represents an alkyl group, R2 represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkenyl group] to react with an acylating agent to obtain one optically active compound. A method for producing an optically active 4-pentanolide derivative [I], which comprises stereoselectively converting the hydroxyl group at the 3-position of the 4-pentanolide derivative into an acyloxy group, and then separating and collecting the hydroxyl group at the 3-position from the reaction solution. Claim 2: By treating the enantiomeric mixture of the compound represented by the general formula [III] [Chemical formula 3] (wherein R and R1 represent an alkyl group) with an asymmetric hydrolase in an aqueous solution, General formula [I] [Chemical formula 4] (formula (wherein, R represents an alkyl group.) A method for producing an optically active 4-pentanolide derivative. 3. The method according to claim 1, wherein the target optically active 4-pentanolide derivative [I] has a configuration of (2R, 3R, 4S). 4. The method according to claim 2, wherein the target optically active 4-pentanolide derivative [I] has a steric configuration of (2S, 3S, 4R). [Claim 5] The asymmetric hydrolase is derived from Candida (Ca.
ndida), Pseudomonas
The method according to claim 1, 2, 3 or 4, wherein the lipase is derived from a microorganism belonging to the genus As) or from porcine pancreas. [Claim 6] A compound represented by the general formula [IV] [Chemical formula 5] (wherein, R represents an alkyl group) is combined with zinc, tributyltin lithium [(C4H9)3SnL
i] or tributyl lead lithium [(C4H9)3P
General formula [I] characterized by intramolecular ring closure in the presence of [bLi] and di-lower alkyl aluminum chloride
A method for producing a 4-pentanolide derivative represented by the formula (wherein, R represents an alkyl group). [Claim 7] 2 of 4-pentanolide derivative [I]
The method according to claim 6, wherein the steric configuration at the 3rd and 3rd positions is trans, and the 3rd and 4th positions are trans.