JPH06184051A - Optically active substituted cyclopropylalkanoic acid derivative and intermediate for its production - Google Patents

Abstract

PURPOSE:To provide an optically active substituted cyclopropylalkanoic acid derivative having a strong DNA polymerase alpha-inhibiting action and useful as an important key intermediate for synthesizing PHYLPA and its derivative expected as new type anti-tumor agent. CONSTITUTION:The compound of formula I (R<1> is H, lower alkyl ; (m) is 2-10; (n) is 3-11), e.g. (9R,10S)-9,10-methano-7,11-hexadecadienoic acid methyl ester. The compound is produced by reducing the carboxyl group of 3- methoxycarbonyl-2,3-methanopropionic acid of formula III into a hydroxymethyl group, reducing the carbonyl group of the produced compound of formula IV, subjecting the produced compound of formula V to a Wittig reaction, oxidizing the hydroxyl group of the produced compound of formula IIa, subjecting the produced compound of formula IIb to a Wittig reaction, and subsequently reducing the carbon-carbon double bond of the produced compound of formula IIc. The compounds of formulas IIa-IIc all are new compounds.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention provides a glycerophospholipid PHYLPA containing a methanoalkanoyl group represented by the following formula, which has a strong DNA polymerase α inhibitory activity and is expected to be used as an antitumor agent, and its derivative. Regarding manufacturing intermediates.

[Chemical 3]

[0002]

2. Description of the Related Art There is a strong demand from society for the development of excellent anticancer agents, and many anticancer agents have been developed and put into practical use. However, it is the current situation that the development of more effective anti-cancer agents is desired, and anti-tumor active compounds having novel skeletons and structures different from known ones are currently in practical use. There is a great possibility that an anticancer drug having more excellent characteristics will be developed. PHYLPA (K. Murakami-Murofush) which is a glycerophospholipid
i et al., J. Biol. Chem., 267, 21512 (1992).) has a characteristic structure that it contains a substituted cyclopropylalkanoyl group, and it has been developed as an entirely new type of antitumor compound. Be expected. On the other hand, introduction of a cyclopropane ring into a known skeleton has been conducted in many drug development studies so far as one of means for fixing a conformation to a specific one. However, a technique for efficiently introducing a cyclopropane ring into a carbon chain in an optically active form has heretofore been hardly established.

[0003]

The object of the present invention is to develop a novel method for producing PHYLPA and its derivatives, which are expected as a new type of antitumor agent.

[0004]

As a result of intensive studies, the present inventors have found that the optically active form of the substituted cyclopropylalkanoic acid derivative of the present invention is an important key intermediate for the synthesis of PHYLPA and its derivatives, The present invention has been completed.

That is, the present invention has the following general formula

[0006]

[Chemical 4]

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, and m and n may be the same or different,
m is an integer of 2 or more and 10 or less, and n is an integer of 3 or more and 10 or less), and the optically active isomer of the substituted cyclopropylalkanoic acid derivative represented by the following general formula

[0008]

[Chemical 5]

(In the formula, X is an optionally protected hydroxymethyl group or formyl group, or a general formula --CH
Represents a group represented by ═CHR ³ , wherein R ² is a C _{3 to} C ₁₁ linear alkyl group or an alkenyl group, or a C _{3 to} C ₁₀ linear alkyl group having a lower alkoxycarbonyl group at the terminal. Alternatively, it represents an alkenyl group, R ³
When R ² is a C ₃ -C ₁₁ linear alkyl group or alkenyl group, it represents a C ₁ -C ₈ linear alkyl group or alkenyl group having a lower alkoxycarbonyl group at the terminal, and R ² Represents a C ₃ -C ₁₀ linear alkyl group or alkenyl group having a lower alkoxycarbonyl group at the terminal, it represents a C ₁ -C ₉ linear alkyl group or alkenyl group). The present invention provides an optically active form of a cyclopropane derivative.

In the compound represented by the general formula [II], when X is a protected hydroxymethyl group, the protecting group for the hydroxyl group is benzyl group, p-methoxybenzyl group or 2,4-dimethoxybenzyl group. Group, p
-Chlorobenzyl group, m-bromobenzyl group, p-nitrobenzyl group, benzhydryl group, di-p-anisylmethyl group, arylmethyl group such as trityl group; trimethylsilyl group, triethylsilyl group, tripropylsilyl group, t-butyl Silyl group such as dimethylsilyl group; methyl group, ethyl group, allyl group, methoxyethyl group, 2-methoxyethoxymethyl group, benzyloxymethyl group, methylthiomethyl group, 2,2,2-trichloroethoxymethyl group, 2- (Trimethylsilyl) ethoxymethyl group, tetrahydropyranyl group, 1-ethoxyethyl group and other alkyl groups; formyl group, acetyl group, trifluoroacetyl group, pivaloyl group, benzoyl group, p-methoxybenzoyl group, p-chlorobenzoyl group , Methoxycarbonyl group, ethoxycarl Group, benzyloxycarbonyl group, and the like can be exemplified acyl group such as t- butoxycarbonyl group.

When X is a protected formyl group, examples of X include dimethoxyethyl group, diethoxymethyl group, ethylenedioxymethyl group and trimethylenedioxymethyl group.

The above compounds of the present invention include both cis and trans forms, and the optically active forms include all antipodes.

The optically active isomer of the substituted cyclopropylalkanoic acid derivative represented by the above general formula [I] can be produced by the following synthetic steps.

[0014]

[Chemical 6]

[Chemical 7]

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, and m and n may be the same or different,
m represents an integer of 2 or more and 10 or less, and n represents an integer of 3 or more and 10 or less. R ² represents a C ₃ -C ₁₁ linear alkyl group or alkenyl group, or a C ₃ -C ₁₀ linear alkyl group or alkenyl group having a lower alkoxycarbonyl group at the terminal. When R ² is a C ₃ -C ₁₁ linear alkyl group or alkenyl group, R ³ represents a C ₁ -C ₈ linear alkyl group or alkenyl group having a lower alkoxycarbonyl group at the terminal, When R ² represents a C _{3 to} C ₁₀ linear alkyl group or alkenyl group having a lower alkoxycarbonyl group at the terminal, C ₁ to
Represents a C ₉ linear alkyl group or alkenyl group)

[First Step] In this step, the carboxyl group of 3-methoxycarbonyl-2,3-methanopropionic acid is reduced to give 4-hydroxy- of the formula [V].
It produces methyl 2,3-methanobutyrate.

The optically active cis form can be obtained by the method described in the literature (P. Mohr et al., Helv. Chim. Acta, 66, 2501 (198
3).) Represented by the formula [III] (2)
By reducing the carboxyl group of (S, 3R) -3-methoxycarbonyl-2,3-methanopropionic acid, (2R, 3S) -4-hydroxy- represented by the formula [V].
Methyl 2,3-methanobutyrate can be obtained.

The reduction of the carboxyl group to the hydroxymethyl group is carried out by a method of reducing the compound of the formula [III] with a borane compound such as borane methyl sulfide complex, borane triethylamine complex and borane tetrahydrofuran complex. Furthermore, the reduction using the borane compound is more preferably carried out in the presence of trimethyl borate. The reduction of the carboxylic acid is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but ethers such as ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane are preferred. A solvent is used.

[Second Step] In this step, the methoxycarbonyl group of methyl (2R, 3S) -4-hydroxy-2,3-methanobutyrate represented by the formula [IV] is reduced to give the formula [V]. (2S, 3R) -4-hydroxy-
It is intended to produce 2,3-methanobutyraldehyde.

In the cis form, the hydroxycarboxylic acid ester represented by the formula [IV] is first converted into a protonic acid such as p-toluenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid, or aluminum chloride, After treatment with a Lewis acid such as zinc chloride, tin chloride or boron trifluoride ether complex to obtain a corresponding γ-lactone compound, lithium aluminum hydride, lithium tri-t-butoxyaluminum hydride, diisobutylaluminum hydride, The reduction is preferably performed using a reducing agent such as aluminum hydride. The reduction reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, preferably ether,
An ether solvent such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or a hydrocarbon solvent such as toluene or hexane is used. Reaction is -78 ° C
From 50 ℃ to proceed smoothly. In this case, a hemiacetal represented by the formula [VI], which is an equivalent product of the hydroxyaldehyde represented by the formula [V], is usually obtained as a product. Alternatively, it is represented by the formula [IV] (2
R, 3S) -4-Hydroxy-2,3-methanobutyric acid methyl group represented by the formula [V] is reduced by reducing the methoxycarbonyl group of (2S, 3R) -4-hydroxy-
2,3-methanobutyraldehyde can be obtained.

In the case of the trans form, the ester of the formula [IV] in which the hydroxyl group may be protected by a suitable protecting group is subjected to the same reduction reaction as described above to obtain the formula of the trans form. A hydroxyaldehyde represented by [V] can be obtained.

[Third step] In this step, a Wittig type reaction is carried out on the formyl group of (2S, 3R) -4-hydroxy-2,3-methanobutyraldehyde represented by the formula [V] or the formula [VI]. To extend the carbon chain to produce a disubstituted cyclopropane derivative having a hydroxymethyl group represented by the formula [IIa], which is a compound of the present invention.

The Wittig reaction is carried out by triphenylethylphosphonium bromide, triphenylpropylphosphonium bromide, triphenylbutylphosphonium bromide, triphenylpentylphosphonium bromide, triphenylhexylphosphonium bromide, triphenylheptylphosphonium bromide, odor. Triphenyloctylphosphonium bromide, triphenylnonylphosphonium bromide, triphenyl bromide
(2-carboxy) ethylphosphonium, triphenyl- (3-carboxy) propylphosphonium bromide, triphenyl- (4-carboxy) butylphosphonium bromide, triphenyl- (5-carboxy) pentylphosphonium bromide, tribromide Phenyl- (6-carboxy) hexylphosphonium, triphenyl- (7-carboxy) heptylphosphonium bromide, triphenyl- (8
-Carboxy) octylphosphonium, triphenyl- (9-carboxy) nonylphosphonium bromide, and the like.

The reaction is carried out in the presence of a base, and examples of the base used include sodium hydride, potassium hydride, sodium amide, methylsulfinylmethyl sodium, lithium diisopropylamide, lithium cyclohexyl isopropylamide, lithium hexamethyldisilazide. , Potassium hexamethyldisilazide, potassium t
-Butoxide is used. Any solvent can be used as long as it does not participate in the reaction, but ether, tetrahydrofuran, dioxane, ether solvents such as 1,2-dimethoxyethane, polar solvents such as dimethylsulfoxide, or toluene are preferable. ,
A hydrocarbon solvent such as hexane is used. The reaction is-
It proceeds smoothly at 78 ° C to 50 ° C.

[Step 4] In this step, a carbene is inserted into the carbon-carbon double bond of the allyl alcohol represented by the formula [VII] to form a hydroxymethyl group represented by the formula [IIa] which is a compound of the present invention. The present invention relates to another method for producing an optically active disubstituted cyclopropane derivative having

The cyclopropanation reaction is carried out by the method described in the literature [H. Takahashi et. Al., Tetrahedron Letters, 33, 2
575 (1992).], Allyl alcohol represented by the formula [VII], diethyl zinc, diiodomethane, a catalytic amount of optically active (1R, 2R) -1,2-bis (substituted sulfonylamino) cyclohexane or (1S , 2
S) -1,2-bis (substituted sulfonylamino) cyclohexane can be carried out enantioselectively to obtain a disubstituted cyclopropane derivative having a hydroxymethyl group represented by the formula [IIa]. You can As the solvent used, any solvent can be used as long as it does not participate in the reaction, but preferably, a halogenated hydrocarbon such as dichloromethane or chloroform, a hydrocarbon such as benzene, toluene or hexane, an ether,
An ether solvent such as tetrahydrofuran, dioxane, or 1,2-dimethoxyethane is used.

In this step, when a trans isomer is used as the allyl alcohol represented by the formula [VII] as a raw material, a disubstituted cyclopropane derivative having a hydroxymethyl group represented by the trans isomer [IIa] is obtained. When the cis isomer is used as the optically active substance, the corresponding optically active cis cyclopropane derivative can be obtained.

[Fifth Step] In this step, the hydroxyl group of the disubstituted cyclopropane derivative having a hydroxymethyl group represented by the formula [IIa] is oxidized to formyl group represented by the formula [IIb] which is a compound of the present invention. To produce a substituted cyclopropane derivative having

For the oxidation of alcohol to aldehyde,
Chromium-based oxidizing agents such as chromium trioxide and pyridinium chlorochromate, and organic-based oxidizing agents such as dimethyldisulfide-dicyclohexylcarbodiimide, dimethyldisulfide-acetic anhydride, dimethyldisulfide-trifluoroacetic anhydride, dimethyldisulfide-phosphorus pentoxide, etc. Is used. As the solvent to be used, any solvent can be used as long as it does not participate in the reaction, but halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, pyridine and the like are preferably used. The reaction proceeds smoothly at 0 ° C to 40 ° C.

[Sixth Step] In this step, the carbon chain is extended by a Wittig type reaction with the formyl group of the disubstituted cyclopropane derivative having a formyl group represented by the formula [IIb] to give a compound of the present invention. It is intended to produce a disubstituted cyclopropane derivative having an alkenyl group represented by the formula [IIc].

When R ² is a C ₃ -C ₁₁ linear alkyl or alkenyl group, the Wittig reaction is triphenyl- (1-carboxy) methylphosphonium bromide, triphenyl- (2-carboxy) ethyl bromide. Phosphonium, triphenyl- (3-carboxy) propylphosphonium bromide, triphenyl- (4-carboxy) butylphosphonium bromide, triphenyl- (5-carboxy) pentylphosphonium bromide, triphenyl- (6-
Using a substituted alkylphosphonium salt having a carboxyl group or a lower alkoxycarbonyl group at the terminal such as (carboxy) hexylphosphonium, triphenyl- (7-carboxy) heptylphosphonium bromide, triphenyl- (8-carboxy) octylphosphonium bromide, etc. Done. When R ² is a C ₃ -C ₁₀ linear alkyl group or alkenyl group having a carboxyl group or a lower alkoxycarbonyl group at the terminal, the Wittig reaction is triphenylmethylphosphonium bromide, triphenylethylphosphonium bromide, Triphenylpropylphosphonium bromide, triphenylbutylphosphonium bromide, triphenylpentylphosphonium bromide, triphenylhexylphosphonium bromide, triphenylheptylphosphonium bromide, triphenyloctylphosphonium bromide, triphenylnonylphosphonium bromide, etc. It is performed using a phosphonium salt. This step proceeds smoothly under the reaction conditions exactly the same as those in the third step.

[Seventh Step] In this step, the carbon-carbon double bond of the disubstituted cyclopropane derivative having an alkenyl group represented by the formula [IIc] is reduced to give a compound of the formula [I] of the present invention. To produce the represented substituted cyclopropylalkanoic acid derivative.

The hydrogenation reaction is carried out by a method of reacting hydrogen in the presence of a palladium-based or platinum-based heterogeneous catalyst, a diimide reduction method, or the like. More preferably,
The hydrogenated product can be obtained by the diimide reduction method in which potassium azodicarboxylate and acetic acid are generated in the reaction system without any reductive cleavage of the cyclopropane ring. The reduction reaction is carried out in a solvent, and as the solvent used, any one can be used as long as it does not participate in the reaction, but preferably, an alcohol solvent such as methanol, ethanol, propanol or isopropanol, acetic acid,
Lower carboxylic acid such as propionic acid, or ether,
An ether solvent such as tetrahydrofuran, dioxane, or 1,2-dimethoxyethane is used. 40 reactions
Smoothly progresses from ℃ to 70 ℃.

The compound of the present invention obtained in the above third to fifth steps can be converted into a derivative in which the hydroxymethyl group or formyl group is protected by a known method.

Hereinafter, the present invention will be described in detail with reference to Examples and Examples, but it goes without saying that the present invention is not limited to these.

[0036]

【Example】

 Reference example 1

[Chemical 8]

Reference [P. Mohr et al., Helv. Chim. Act
a, 66, 2501 (1983).] (2S,
3R) -3-Methoxycarbonyl-2,3-methanopropionic acid [mp. 88-89 ° C, [α] ²⁰ _D -10.9 ° (c 1.23, EtOH)] (5.63 g, 39.1 mm)
ol) was dissolved in tetrahydrofuran (100 mL), and trimethyl borate (13.2 mL, 117
mmol) was added. The reaction solution was cooled to −20 ° C., and borane methyl sulfide complex (4.0 mL, 10M hexane solution) was added dropwise. After stirring at room temperature for 24 hours, methanol (20 mL) was added, and the mixture was concentrated under reduced pressure. The crude product was purified using silica gel column chromatography (ethyl acetate / hexane) and methyl (2R, 3S) -4-hydroxy-2,3-methanobutyrate (5.06 g, 39.0).
mmol, yield 99%) was obtained.

IR (neat) 3405, 2953, 1727, 1440, 1388,
1283, 1175 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.1
1-1.18 (2H, m, cyclopropane-CH ₂ ),
1.62 (1H, m, C (3) H ₂ ), 1.79 (1H,
ddd, J = 5.8, 8.3, and 8.3 Hz, C
(3) H ₂ ), 2.00 (1H, br t, J = 5.0H
z, OH), 3.71 (3H, s, CO ₂ CH ₃ ), 3.7
7 (1H, ddd, J = 5.0, 7.5, and 11.
5 Hz, C (4) H ₂ ), 3.96 (1H, ddd, J =
5.0, 5.0, and 11.5 Hz, C (4) H ₂ ). EI-MS m / z = 129 (M-H ^<+> ), 99 (M-OMe ^<+> ).

Reference Example 2

[Chemical 9]

(2R, 3S) -4-hydroxy-2,3
-Methyl methanobutyrate (3.32 g, 25.6 mmol) was heated to reflux with p-toluenesulfonic acid monohydrate (370 mg, 1.9 mmol) in benzene (20 mL) for 30 minutes. After adding triethylamine (1 mL), the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and (1
R, 5S) -3-Oxabicyclo [3.1.0] hexan-2-one (2.26 g, 23.0 mmol, yield 90)
%).

[Α] ²⁰ _D + 67.1 ° (c 1.29,
CHCl ₃ ). IR (neat) 1769, 1478, 1450, 1373, 1035,
993, 974 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.8
9 (1H, ddd, J = 3.5, 4.8, and 4.8
Hz, C (6) H ₂ ), 1.28 (1H, ddd, J =
4.8, 7.5, and 9.0 Hz, C (6) H ₂ ),
2.08 (1H, m, C (5) H ₂ ), 2.27 (1H,
m, C (1) H ₂ ), 4.23 (1H, d, J = 9.2H
z, C (4)) H ₂ ), 4.33 (1H, dd, J = 4.
8 and 9.2 Hz, C (4) H ₂ ). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 12.
1, 17.2, 17.4, 69.3, 176.4 ppm. EI-MS m / z = 98 (M ⁺ ).

(1R, 5S) -3-obtained by the above reaction
Oxabicyclo [3.1.0] hexan-2-one (2.26 g, 23.0 mmol) in dichloromethane (75 mL) at -78 ° C under diisobutylaluminum hydride (0.95 M hexane solution, 25.4 mL, 24.
1 mmol) was added dropwise. After stirring at −78 ° C. for 1 hour, the reaction was stopped with methanol, a few drops of saturated saline was added, and the temperature was returned to room temperature. The precipitate was filtered off, the filtrate was concentrated under reduced pressure, and (1R, 5S) -2-hydroxy-3-oxabicyclo [3.1.0] hexane ((2R, 3S) -4-
Equivalent to hydroxy-2,3-methanobutyraldehyde)
The crude product of was obtained. This product was used in the next Wittig reaction without purification.

IR (neat) 3385, 2934, 2881, 1438, 1370,
1334, 1261, 1210, 1078, 1026,
980 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.2
5 (1H, ddd, J = 4.8, 4.8, and 4.8
Hz, C (6) H ₂ ), 0.61 (1H, ddd, J =
4.8, 8.0, and 8.0 Hz, C (6) H ₂ ),
1.65-1.70 (2H, m, C (1) H and C
(5) H), 2.60 (1H, br, OH), 3.80
(1H, d, J = 8.0 Hz, C (4) H ₂ ), 4.30
(1H, dd, J = 1.0 and 8.0Hz, C
(4) H ₂ ), 5.28 (1H, d, J = 3.5Hz, C
(2) H).

Example 1

[Chemical 10]

Sodium hydride (2.76 g, 69 mm)
ol) to dimethylsulfoxide (30 mL) and added
The mixture was stirred at 0 ° C for 1 hour. This was added to a dimethylsulfoxide solution (50 mL) of pentyltriphenylphosphonium bromide (28.5 g, 69 mmol) at room temperature and stirred for 5 minutes to prepare triphenylpentylidenephosphorane. To this red solution, the method of Reference Example 2 (1R, 5S)
Synthesized from -3-oxabicyclo [3.1.0] hexan-2-one (2.26 g, 23.0 mmol) (1
A solution of (R, 5S) -2-hydroxy-3-oxabicyclo [3.1.0] hexane in dimethyl sulfoxide (5 mL) was added at room temperature, and the mixture was stirred for 1 hour. The reaction was stopped with acetic acid (2.6 mL, 46 mmol) at 0 ° C., the reaction mixture was poured into saturated saline (100 mL), and extracted twice with ether. The ether layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to give (2S, 3S) -2,3-methano-4-nonene-1.
-Ol (2.10 g, 13.6 mmol, 60% yield)
Got

IR (neat) 3385, 2926, 1647, 1457, 1038c
m ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.3
9 (1H, ddd, J = 5.0, 5.0, and 5.0
Hz, cyclopropane _{-CH 2), 0.91 (3H,} t,
J = 7.0 Hz, C (9) H ₃ ), 1.01 (1H, dd
d, J = 5.0, 8.2, and 8.2 Hz, cyclopropane-CH ₂ ), 1.3-1.5 (5H, m, C (2)
H, C (7) H ₂ , and C (8) H ₂ ), 1.73
(1H, m, C (3) H), 2.15-2.22 (2H,
m, C (6) H ₂ ), 3.47 (1H, dd, J = 9.0)
And 11.8 Hz, C (1) H ₂ ), 3.78 (1
H, dd, J = 6.5 and 11.8 Hz, C (1)
H ₂ ), 5.11 (1H, ddd, J = 1.0, 9.8, and 10.8 Hz, C (4) H), 5.50 (1H, d
dt, J = 1.0, 10.8, and 7.5 Hz, C
(5) H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 12.
3, 13.8, 13.9, 20.8, 22.4, 27.3,
31.8, 63.8, 127.8, 132.2 ppm. EI-MS m / z = 154 (M +), 123 (M-HOCH 2 +).

Example 2

[Chemical 11]

Sodium hydride (904.6 mg, 22.
0 mmol) was added to dimethyl sulfoxide (10 mL), and the mixture was stirred at 60 ° C. for 1 hr. This was mixed with (6-carboxyhexyl) triphenylphosphonium bromide (5.33).
g, 11.0 mmol) in dimethylsulfoxide solution (10 mL) at room temperature and stirred for 5 minutes. To this was added (1R, 5S) -2-hydroxy-3-oxabicyclo [3.1.0] hexane (98) prepared according to Example 1.
A dimethyl sulfoxide solution (5 mL) of 5.2 mg, 9.84 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped with acetic acid (0.14 mL, 2.3 mmol) at 0 ° C.,
The reaction mixture was poured into saturated saline (50 mL) and extracted twice with ether. The ether layers were combined and extracted twice with a 1N aqueous sodium hydroxide solution, and then the aqueous alkaline solution was diluted to 0.
It was made acidic with concentrated hydrochloric acid at ℃. 2 with ether from acidic aqueous solution
The extract was extracted twice, the ether layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was dissolved in ether, and a separately prepared ether solution of diazomethane was added until nitrogen gas was not generated.
The crude product obtained by concentrating the ether layer under reduced pressure was subjected to silica gel column chromatography (ethyl acetate / hexane).
At (9S, 10S) -11-hydroxy-
Methyl 9,10-methano-7-undecenoate (1.08
g, 4.80 mmol, yield 49%) was obtained.

IR (neat) 3448, 2932, 1738, 1655, 1460,
1164, 1038 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.3
8 (1H, ddd, J = 5.0, 5.0, and 5.0
Hz, cyclopropane _{-CH 2), 1.02 (1H,} dd
d, J = 5.0,8.2, and 8.2 Hz, cyclopropane _{-CH 2), 1.2-1.8 (8H,} m, C (3)
_{H 2, C (4) H} 2, C (5) H 2, C (9) H 2, and _{C (10) H 2),} 2.18 (2H, m, C (6)
H ₂ ), 2.32 (2H, t, J = 7.5Hz, C (2)
H ₂ ), 3.47 (1H, dd, J = 9.0 and 11.
5Hz, C (11) H ₂ ), 3.67 (3H, s, CO ₂
CH ₃ ), 3.78 (1H, dd, J = 6.5 and
_{11.5Hz, C (11) H 2} ), 5.12 (1H, dd
d, J = 1.0, 9.0, and 10.5 Hz, C
(8) H), 5.48 (1H, ddt, J = 0.5, 1
0.5, and 7.5 Hz, C (7) H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 12.
3, 13.9, 20.8, 24.8, 27.4, 28.7,
29.2, 34.0, 51.5, 63.7, 128.1, 1
31.7, 174.3 ppm. EI-MS m / z = 208 (M-H 2 O +).

Example 3

[Chemical 12]

Methods described in the literature [H. Takahashi et. Al.,
Tetrahedron Letters, 33, 2575 (1992).]
(1R, 2R) -1,2-bis (p-nitrobenzenesulfonylamino) cyclohexane (29.1 mg, 0.0
6 mmol) in a dichloromethane solution (10 mL) under an argon atmosphere at room temperature for trans-2-undecene-1-
All (85.2 mg, 0.50 mmol) was added. −
Diethyl zinc (0.98 M hexane solution, 1.
02 mL, 1.0 mmol) and then diiodomethane (401.8 mg, 1.5 mmol) were added dropwise, and the mixture was stirred at the same temperature for 2.5 hours. 1N sodium hydroxide aqueous solution (5
The reaction was quenched with (mL) and extracted 3 times with ether. The organic layers were combined, washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane), and (2R, 3R) -2,3-methanoundecane-1-ol (79.6 mg, 0.432 mmol, yield 86). %).

[Α] ²⁰ _D -12.9 ° (c 0.50,
CHCl ₃ ). IR (neat) 3316, 2922, 2852, 1467 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.3
1 (1H, ddd, J = 4.8, 4.8, and 8.2
Hz, cyclopropane _{-CH 2), 0.36 (1H,} dd
d, J = 4.8,4.8, and 8.2 Hz, cyclopropane _{-CH 2), 0.60 (1H,} m, C (2) H),
0.84 (1H, m, C (3) H), 0.89 (3H,
t, J = 6.7 Hz, C (11) H ₃ ), 1.2-1.4
(15H, m, C (4) H ₂ , C (5) H ₂ , C (6) H
₂ , C (7) H ₂ , C (8) H ₂ , C (9) H ₂ , C (1
0) H _2, and OH), 3.4-3.5 (2H, m ,
C (1) H ₂ ).

Example 4

[Chemical 13] Pyridinium chlorochromate (2.80g, 13.0mm
ol), molecular sieves 3A (1.0 g), and sodium acetate (320 mg, 3.89 mmol) in a dichloromethane suspension (80 mL) (2S, 3S) -2,3.
-Methanononen-1-ol (820 mg, 5.32 m
Dichloromethane solution (10 mL) was added at room temperature, and the mixture was further stirred at room temperature for 1 hr. Ether (80 mL) was added to the reaction solution, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / hexane), (2S, 3S) -2,3-
Methano-4-nonenal (770 mg, 5.06 mmo
1, yield 95%) was obtained.

IR (neat) 2957, 2928, 2858, 1707, 1465,
1366, 1172, 1054 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 0.9
0 (3H, t, J = 7.0Hz, C (9) H 3), 1.2
8-1.49 (6H, m, cyclopropane-CH ₂ , C
(7) H ₂ and C (8) H ₂ ), 2.04-2.21
(3H, m, C (3) H and C (6) H ₂ ), 2.
30 (1H, m, C (2) H), 5.31 (1H, dd
d, J = 1.5, 9.0, and 11.0 Hz, C
(4) H), 5.53 (1H, ddt, J = 1.0, 1
0.8 and 7.0 Hz, C (5) H), 9.27
(1H, d, J = 5.5 Hz, CHO). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 13.
9, 15.4, 21.6, 22.3, 27.3, 30.2,
31.5, 125.2, 133.8, 201.0 ppm. EI-MS m / z = 152 (M ⁺ ).

Example 5

[Chemical 14]

(9S, 10S) -11 as in the fourth embodiment
Methyl -hydroxy-9,10-methano-7-undecenoate (465.0 mg, 2.05 mmol), pyridinium chlorochromate (886.2 mg, 4.11 mmo)
l), molecular sieves 3A (300 mg), sodium acetate (100.9 mg, 1.23 mmol),
Methyl (9S, 10S) -10-formyl-9,10-methano-7-undecenoate (344.0 mg, 1.41 m)
mol, yield 70%).

IR (neat) 2933, 2857, 1734, 1654, 1438,
1174 cm ^-1 . ¹ H-NMR (400 MHz, C ₆ D ₆ ): δ = 0.77
(1H, ddd, J = 4.8, 4.8, and 8.0H
z, cyclopropane _{-CH 2), 1.03 (1H,} dd
d, J = 4.8,5.0, and 6.5 Hz, cyclopropane _{-CH 2), 1.08-1.95 (10H,} m, C
(3) H ₂ , C (4) H ₂ , C (5) H ₂ , C (6) H ₂ ,
C (9) H, and C (10) H), 2.13 (2
H, t, J = 7.3 Hz, C (2) H ₂ ), 3.40 (3
H, s, CO ₂ CH ₃ ), 5.23 (1H, ddd, J =
1.5, 9.0, and 10.5 Hz, C (8) H),
5.36 (1H, ddt, J = 0.5, 10.5, and 7.0Hz, C (7) H), 9.11 (1H, d, J =
5.0 Hz, CHO)). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 15.
4, 21.6, 24.8, 27.4, 28.7, 28.9,
30.2, 34.0, 51.5, 125.7, 133.4,
174.2, 200.9 ppm. EI-MS m / z = 224 (M ⁺ ).

Example 6

[Chemical 15]

In the same manner as in Example 2, (6-carboxyhexyl) triphenylphosphonium bromide (3.50
g, 7.43 mmol), sodium hydride (594 m
g, 14.9 mmol), dimethyl sulfoxide (17
mL) was prepared from phosphonium ylide. To this (2
S, 3S) -2,3-methano-4-nonenal (54
A solution of 0.0 mg (3.55 mmol) in dimethyl sulfoxide (5 mL) was added, and the mixture was further stirred at room temperature for 1 hr.
Acetic acid (0.47 mL, 7.8 mmol) was added to stop the reaction, saturated brine (15 mL) was added, and the mixture was extracted 3 times with ether. The ether layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to obtain a crude carboxylic acid. The crude carboxylic acid was dissolved in ether, and a separately prepared ether solution of diazomethane was added until nitrogen gas was not generated. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) and methyl (9R, 10S) -9,10-methano-7,11-hexadecadienoate (850.
0 mg, 3.05 mmol, yield 86%) was obtained.

IR (neat) 2927, 2856, 1740, 1458, 1261,
1169 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): 0.45
(1H, ddd, J = 4.5, 4.5, and 4.5H
z, cyclopropane _{-CH 2), 0.90 (3H,} t, J
= 7.0 Hz, C (16) H ₃ ), 1.18 (1H, dd
d, J = 4.5,8.2, and 8.2 Hz, cyclopropane _{-CH 2), 1.30-1.68 (10H,} m, C
(3) H ₂ , C (4) H ₂ , C (5) H ₂ , C (14)
_{H 2, C (15) H} 2), 1.77-1.85 (2H, m,
C (9) H and C (10) H), 2.14 (4
H, m, C (6) H ₂ and C (13) H ₂ ), 2.
31 (2H, t, J = 7.5 Hz, C (2) H ₂ ), 3.
67 (3H, s, CO ₂ CH ₃ ), 5.05 (2H, m,
C (8) H and C (11) H), 5.43 (2
H, m, C (7) H and C (12) H)). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 14.
1, 16.0, 17.1, 22.5, 25.0, 27.4,
27.5, 29.0, 29.5, 32.1, 34.2, 51.
6, 129.1, 129.5, 130.6, 131.0, 1
74.4 ppm. EI-MS m / z = 278 (M ⁺ ).

Example 7

[Chemical 16]

Pentyltriphenylphosphonium bromide (1.75 g, 4.23 mmo) was prepared in the same manner as in Example 1.
l), sodium hydride (170.0 mg, 4.23 mm)
ol) and dimethyl sulfoxide (8 mL) to prepare a solution of triphenylpentylidenephosphorane in dimethyl sulfoxide. This contained methyl (9S, 10S) -10-formyl-9,10-methano-7-decenoate (340.
0 mg, 1.41 mmol) of dimethyl sulfoxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid (0.16 mL) was added at 0 ° C. to stop the reaction, and the mixture was poured into saturated saline (50 mL). After extraction with ether twice, the ether layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane), (9S, 10R).
Methyl -9,10-methano-7,11-hexadecadienoate (290.4 mg, 1.04 mmol, 74% yield)
Got The IR and ¹ H-NMR spectra were completely in agreement with those of the (9R, 10S) -form obtained in Example 6.

Example 8

[Chemical 17]

(9R, 10S) -9,10-methano-
Methyl 7,11-hexadecadienoate (475.5m
g, 1.70 mmol) and potassium azodicarboxylate
(16.6 g, 85.4 mmol) in methanol (5
Acetic acid (17.7 mL, 298 mmol) was added dropwise to 0 mL) over 1 hour while gently refluxing. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted 3 times with ether. The ether layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane), and methyl (9S, 10R) -9,10-methanohexadecanoate (460.0 mg, 1.63 mmol, yield) Rate 96
%).

[Α] ²⁰ _D + 0.19 ° (c 8.0, C
HCl _3). IR (neat) 2926, 2854, 1743, 1461, 1169c
m ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = −0.
33 (1H, ddd, J = 4.0, 4.0, and 4.
0 Hz, cyclopropane _{-CH 2), 0.56 (1H,} d
dd, J = 4.0,7.5, and 7.5 Hz, cyclopropane _{-CH 2), 0.64 (2H,} m, C (9) H
And C (10) H), 0.89 (3H, t, J = 7.
_{0Hz, C (16) H 3} ), 1.09-1.62 (22
H, m, C (3) H ₂ , C (4) H ₂ , C (5) H ₂ , C
(6) H ₂ , C (7) H ₂ , C (8) H ₂ , C (11)
H ₂ , C (12) H ₂ , C (13) H ₂ , C (14) H ₂ ,
C (15) H ₂ ), 2.30 (2H, t, J = 7.5H
z, C (2) H ₂ ), 3.67 (3H, s, CO ₂ C
H ₃ ). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 11.1.
1, 14.27, 14.32, 15.9, 16.0, 22.
9, 25.2, 28.86, 28.92, 29.4, 29.
5, 29.6, 30.3, 30.4, 32.1, 34.3,
51.6, 174.4 ppm. EI-MS m / z = 282 (M +), 251 (M-OCH 3 +). Elemental analysis: (C ₁₈ H ₃₄ O ₂ ) calculated value C = 76.5%, H = 12.1%. Analytical value C = 76.3%, H = 12.3%.

Example 9

[Chemical 18]

As in Example 8, (9S, 10R)-
Methyl 9,10-methano-7,11-hexadecadienoate (290.0 mg, 1.04 mmol) and potassium azodicarboxylate (5.0 g, 25.7 mmol), acetic acid (46 mL, 77.2 mmol) (9R , 10S)
Methyl -9,10-methanohexadecanoate (280.0
mg, 0.99 mmol, yield 95%). IR, ¹
H-NMR spectrum was obtained in Example 8 (9S, 1
0R) -perfectly consistent with that of the body.

[Α] ²⁰ _D −0.1 ° (c 5.4, CH
Cl ₃ ).

Example 10

[Chemical 19]

Methyl (9S, 10R) -9,10-methanohexadecanoate (390.0 mg, 1.38 mmol)
Was dissolved in tetrahydrofuran (10 mL), 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was heated at 80 ° C. for 4 minutes.
Stir for hours. After cooling to 0 ° C, the mixture was neutralized with concentrated hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was subjected to silica gel column chromatography (ethyl acetate /
(9S, 10R) -9,10-methanohexadecanoic acid (370.4 mg, 1.38 mmo)
1, yield 100%) was obtained.

IR (neat) 3400, 1914, 1710, 1461 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ = −0.
33 (1H, ddd, J = 4.0, 4.0, and 4.
0 Hz, cyclopropane _{-CH 2), 0.56 (1H,} d
dd, J = 4.0,7.5, and 7.5 Hz, cyclopropane _{-CH 2), 0.64 (2H,} m, C (9) H
And C (10) H), 0.89 (3H, t, J = 7.
_{0Hz, C (16) H 3} ), 1.09-1.62 (22
H, m, C (3) H ₂ , C (4) H ₂ , C (5) H ₂ , C
(6) H ₂ , C (7) H ₂ , C (8) H ₂ , C (11)
H ₂ , C (12) H ₂ , C (13) H ₂ , C (14) H ₂ ,
C (15) H ₂ ), 2.34 (2H, t, J = 7.5H
z, C (2) H ₂ ). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ = 10.
9, 14.1, 15.8x2, 22.7, 24.7, 28.
7, 29.1, 29.29, 29.35, 29.4, 30.
1, 30.2, 32.0, 34.1, 180.2 ppm. EI-MS m / z = 268 (M ⁺ ).

Reference Example 3

[Chemical 20]

1-O-benzyl-2,3-O-isopropylidene-sn-glycerol (158.0 mg, 0.7
1 mmol) in tetrahydrofuran (1 mL)
Liquid ammonia (5 mL) and lithium (62.4 mg,
To the blue solution of the Birch reducing agent prepared from (9.0 mmol) was added at -33 ° C, and the mixture was stirred at the same temperature for 1 hour. Ammonium chloride (443.0 mg, 8.28 mmol) was added in portions and the ammonia was evaporated. Saturated saline (10 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were washed together with saturated saline and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give crude 2,3-O
-Isopropylidene-sn-glycerol was obtained. This product was dissolved in dichloromethane (5 mL) without being generated, and this solution was synthesized in Example 10 (9S,
10R) -9,10-methanohexadecanoic acid (61.2
mg, 0.23 mmol) in dichloromethane (1 m
L), dicyclohexylcarbodiimide (49.5m
g, 0.24 mmol), dimethylaminopyridine (5.
5 mg, 0.05 mmol) was added. After stirring at room temperature for 12 hours, the reaction solution was filtered through Celite, and the residue was washed with dichloromethane. The methylene chloride layers were combined, washed with 2% hydrochloric acid, aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and 1-O-[(9S, 10R)-
9,10-methanohexadecanoyl] -2,3-O-isopropylidene-sn-glycerol (67.3 mg,
0.18 mmol, yield 77%) was obtained.

[Α] ²⁰ _D + 2.38 ° (c 1.21, CHCl ₃ ). ¹ H-NMR (400 MHz, CDCl ₃ ): δ = −0.
34 (1H, ddd, J = 4.0, 4.0, and 4.
0 Hz, cyclopropane _{-CH 2), 0.56 (1H,} d
dd, J = 4.0,7.5, and 8.9 Hz, cyclopropane _{-CH 2), 0.64 (2H,} m, cyclopropane -CHx2), 0.89 (3H, t , J = 7. 0Hz,
_{C (16 ') H 3)} , 1.10-1.80 (28H, m,
C (3 ′) H ₂ , C (4 ′) H ₂ , C (5 ′) H ₂ , C
(6 ′) H ₂ , C (7 ′) H ₂ , C (8 ′) H ₂ , C (1
1 ') H ₂ , C (12') H ₂ , C (13 ') H ₂ , C
(14 ′) H ₂ , C (15 ′) H ₂ , isopropylidene-
CH ₃ x2), 2.34 (2H, t, J = 7.5Hz, C
(2 ′) H ₂ ), 3.74 (1H, dd, J = 6.2 and 8.5 Hz, C (3) H ₂ ), 4.07 (1H, d
d, J = 6.2 and 8.5 Hz, C (3) H ₂ ),
4.10 (1H, dd, J = 5.8 and 11.5H
z, C (1) H ₂ ), 4.16 (1H, dd, J = 4.8)
And 11.5 Hz, C (1) H ₂ ), 4.31 (1
H, dddd, J = 4.8, 5.8, 6.2, and 6.
2 Hz, C (2) H).

1-O-[(9S, 10R) -9,10-
Methanohexadecanoyl] -2,3-O-isopropylidene-sn-glycerol (65.0 mg, 0.17 mm
ol) and pyridinium p-toluenesulfonate (1
0.0 mg, 0.04 mmol) in methanol (10 m
It was dissolved in L) and heated under reflux for 1.5 hours. After cooling to room temperature, the reaction solution was added to water and extracted 3 times with ether. The ether layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Crude 1-O-[(9
S, 10R) -9,10-Methanohexadecanoyl]-
Sn-glycerol was used in the next reaction without isolation and purification.

Triazole (70.5 mg, 1.02 mm
ol) in tetrahydrofuran (1 mL),
Phosphorus oxychloride (30 μL, 0.34 mmol) at ℃,
Triethylamine (0.5 mL, 3.6 mmol) was added, and the mixture was further stirred for 5 minutes. To the tetrahydrofuran solution of phosphoryl tristriazolide thus prepared, the above-mentioned 1-O-[(9S, 10R) -9,10-methanohexadecanoyl] -sn-glycerol tetrahydrofuran (2 mL) was added, Stir for 20 minutes at room temperature,
Cyclic phosphorylation was performed. The reaction solution is 2% hydrochloric acid (30 mL)
And extracted with ether. The ether layer was dried over anhydrous sodium sulfate. Separately, sodium hydride (60%
Mineral oil (8 mg, 0.2 mmol) was washed with pentane to remove the mineral oil, and the suspension in ether (5 mL) was added to the above glycerol ether solution and extracted with distilled water. The ether layer was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate / hexane) to obtain unreacted 1-O-[(9S, 10R) -9,10-methanohexadecanoyl] -2,3-O. -Isopropylidene-sn-
Glycerol (46.9 mg, 0.12 mmol) was recovered. The extracted aqueous solution was freeze-dried, and the obtained white powder was further subjected to preparative thin layer chromatography (chloroform:
Purified with methanol: water = 60: 20: 3), PHYL
PA, that is, 1-O-[(9S, 10R) -9,1
0-methanohexadecanoyl] -sn-glycerol 2,3-phosphate sodium salt (19.8 mg,
0.046 mmol, yield 27%, yield 97% in consideration of raw material recovery).

IR (neat) 2926, 2854, 1731, 1602, 1400,
1235, 1210, 1120 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ / CD ₃ OD =
3/1): δ = -0.33 (1H, ddd, J = 4.0,
4.0, and 4.0 Hz, cyclopropane-C
_{H 2), 0.57 (1H,} ddd, J = 4.0,7.5, and 8.5 Hz, cyclopropane -CH _2), 0.64
(2H, m, C (9 ') H and C (10')
H), 0.89 (3H, t, J = 7.0Hz, C (1
_{6 ') H 3), 1.10-1.80} (22H, m, C
(3 ′) H ₂ , C (4 ′) H ₂ , C (5 ′) H ₂ , C
(6 ′) H ₂ , C (7 ′) H ₂ , C (8 ′) H ₂ , C (1
1 ') H ₂ , C (12') H ₂ , C (13 ') H ₂ , C
_{(14 ') H 2, C} (15') H 2), 2.36 (2H,
t, J = 7.5 Hz, C (2 ′) H ₂ ), 3.97 (1
H, ddd, J = 7.0, 9.0, and 9.0 Hz,
C (1) H ₂ ), 4.20 (1H, dd, J = 5.0 and 12.0 Hz, C (3) H ₂ ), 4.25 (1H,
dd, J = 6.0 and 12.0 Hz, C (3)
H ₂ ), 4.28 (1H, ddd, J = 6.2, 9.0,
And 12.8 Hz, C (1) H ₂ ), 4.59 (1
H, dddddd, J = 5.0, 6.0, 6.0, 6.2,
And 7.0 Hz, C (2) H). ¹³ C-NMR (100 MHz, CDCl ₃ / CD ₃ OD =
3/1): δ = 11.1, 14.2, 15.98, 16.
0, 22.9, 25.1, 28.9, 29.0, 29.4,
29.6, 29.7, 30.4, 32.2, 34.2, 64.
5, 66.1, 73.5, 174.3 ppm. FAB-MS m / z = 449 (M + Na ⁺ ), 427 (M + H ⁺ ).

Claims (2)

[Claims] 1. The following general formula: (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, m and n may be the same or different, m represents an integer of 2 or more and 10 or less, and n represents an integer of 3 or more and 10 or less)
An optically active form of a substituted cyclopropylalkanoic acid derivative represented by: 2. The following general formula: (In the formula, X represents an optionally protected hydroxymethyl group or a formyl group, or a group represented by the general formula —CH═CHR ³ , and R ² represents a C _{3 to} C ₁₁ linear alkyl group or represents a linear alkyl group or alkenyl group of C ₃ -C ₁₀ having an alkenyl group or terminal in a lower alkoxycarbonyl group,, R ³ is, R ² is C ₃
~ In the case of a C ₁₁ linear alkyl group or alkenyl group, C ₁ ~ having a lower alkoxycarbonyl group at the terminal
When R ² represents a C ₈ linear alkyl group or alkenyl group, and R ² represents a C ₃ -C ₁₀ linear alkyl group or alkenyl group having a lower alkoxycarbonyl group at the terminal, C ₁ -C ₉ An optically active form of a disubstituted cyclopropane derivative represented by (representing a linear alkyl group or an alkenyl group).