JP2507519B2 - Diastereoselective preparation of 3-substituted-1-cyclopentenol derivatives - Google Patents

Description

TECHNICAL FIELD The present invention relates to a diastereoselective method for producing a 3-substituted-1-cyclopentenol derivative. More specifically, a 2-cyclopentenol derivative and a 3-substituted-cis-1 alkene iodide derivative are reacted in an organic medium in the presence of a palladium catalyst and a basic compound. The present invention relates to a novel diastereoselective process for producing 1-cyclopentenol derivatives and enantiomers thereof, and mixtures thereof in any proportion.

<Prior Art> Natural prostaglandins (hereinafter sometimes abbreviated as PG) are used as local hormones (autocoids) that exhibit various physiological activities such as uterine contraction, suppression of gastric acid secretion, and hypotension. It has been clarified that it is essential for maintenance. Therefore, studies to develop new types of drugs by skillfully utilizing these physiological characteristics of PGs have been conducted not only for natural PGs but also for various derivatives. How to prepare such PG derivative how to control the stereochemistry of several kinds of asymmetric carbons characteristically present in the PG skeleton (for example, carbons at 8-position, 11-position, 12-position, 15-position in the PG nomenclature) It is an issue. Heretofore, many manufacturing methods have been devised and reported to overcome such PG manufacturing problems. Among them, PG production in which 4-hydroxy-2-cyclopentenone derivative is used as a starting material and a PG skeleton is constructed while introducing side chains on the 5-membered ring one by one, using the conjugate addition reaction with an organic copper compound as a key step. The method has become a useful PG skeleton manufacturing method today because of its simplicity, versatility, and efficiency. That is, the configurations of the asymmetric carbons corresponding to the 11- and 15-positions are secured in advance at the stage of the starting material, and the 12- and 8-positions are specifically obtained by the reaction.
It is a PG skeleton construction method that controls the three-dimensional position (JWPatt
erson et al., Journal of Organic Chemistry (J.Org.Chem.), 39,2509 (1974); Noyori et al., Journal of American Chemical Society (J. Org.
Am. Chem. Soc.), 107, 3348 (1985) and the references described in this document).

<Purpose of the Invention> The present inventors have used a single asymmetric source as a clue, and by utilizing the asymmetric induction reaction emitted from the asymmetric source, while controlling the configuration of all the remaining PGs, a large amount of As a result of earnest research focusing on the development of a synthesizable PG skeleton, the reaction of a 2-cyclopentenol derivative with a 3-substituted-cis-1-alkene iodide derivative using a catalytic amount of a palladium catalyst By 3-substitution-cis-1-
Aiming at diastereoselective asymmetric induction due to the asymmetric carbon in the molecule of the alkene derivative 3
The present invention has been achieved by finding the fact that a -substituted-1-cyclopentenol derivative can be obtained.

<Structure and Effect of Invention> In the present invention, the following formula [I] 2-cyclopentenol derivative represented by the following formula [II] The iodide 3-substituted-cis-1-alkene derivative represented by the formula: II-II is reacted in the presence of a palladium catalyst and a basic compound in an organic medium.
I] There is provided a diastereoselective method for producing a 3-substituted-1-cyclopentenol derivative represented by: and an enantiomer thereof, and a mixture thereof in any proportion.

In the 2-cyclopentenol derivative represented by the above formula [I] used as a raw material in the present invention, R ¹ represents a hydrogen atom or a tri (C ₁ -C ₇ ) hydrocarbon cisyl group. Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include tri (C ₁ -C ₄ ) alkylsilyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, and t-butyldimethylsilyl group, and t-butyl. Preferred examples include diphenyl (C ₁ -C ₄ ) alkylsilyl group such as diphenylsilyl group, di (C ₁ -C ₄ ) alkylphenylsilyl group such as dimethylphenylsilyl group, and tribenzylsilyl group. it can. Bird (C ₁
˜C ₄ ) Alkylsilyl and phenyldi (C ₁ -C ₄ ) alkylsilyl groups are preferred, with t-butyldimethylsilyl group being particularly preferred.

In the above formula [I], Z is a hydrogen atom or OR ¹
Represents a group. In the OR ¹ group, R ¹ has the same meaning as defined above. A method for producing the 2-cyclopentenol derivative represented by the above formula [I] is known, and a derivative in which Z is a hydrogen atom is easily obtained by, for example, reduction of 2-cyclopentenone, and R ¹ is Those having a tri (C ₁ -C ₇ ) hydrocarbon silyl group can be easily obtained by subjecting the product obtained by the above reduction, 2-cyclopentenol, to a usual silylation reaction. Among those in which Z is an OR ¹ group, those in which R ¹ is a hydrogen atom are known methods using cyclopentadiene as a starting material (GOSchenck et al., Angew. Chem.
m.), 68,248 (1956) and WRA Adams et al., Tetrahedron Letters, 1971,263))
Can be easily obtained, and by silylation by a known method, each R ¹ can be led to a tri (C ₁ -C ₇ ) hydrocarbon-silylated derivative. What is important here is that the starting material used in the present invention must be a meso-form 2-cyclopentenol derivative in which both OR ¹ groups have a cis configuration.

Specific examples of the compound represented by the above formula [I] include R ¹
It will be obvious based on the definitions of Z and Z, and specific examples thereof.

The other starting material in the production method of the present invention is the iodo-3-substituted-cis-1-alkene derivative represented by the above formula [II]. Such a 3-substituted-cis-1-alkene iodide derivative can be easily produced by a known method (FS Alvarez et al., Journal of American Chemical Society (J. Am. Chem. Soc.), 94,7823.
(1972); AF Kluge et al., Ibid., 94, 7827 and 9256 (197).
2); JG Miller et al., Ibid., 96, 6774 (1974)).

In the above formula [II], R ² represents a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a 1-alkoxy substituted (C ₁ -C ₄ ) alkyl group, and R ³ represents a linear or branched chain (C ₁ To C ₁₀ ) alkyl group or a substituted or unsubstituted (C _{3 to} C ₈ ) cycloalkyl group.

The tri (C ₁ ~C ₇₎ hydrocarbon silyl group R ^2, groups exemplified as R ¹ in the formula [I] is used as it suitably, R ¹ and R ² are optionally substituted by one or more identical May be. The 1-alkoxy-substituted (C ₁ -C ₅₎ alkyl group R ^2, for example, methoxymethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl, 1-ethoxy-1-methylethyl, 1
Examples thereof include-(2-methoxyethoxy) methyl, benzyloxymethyl, 2-tetrahydropyranyl and 2-tetradrofuranyl groups. Among them, 1-ethoxyethyl, 1-methoxy-1-methylethyl, 2-tetrahydropyranyl group is preferable.

Methyl, ethyl, propyl, isopropyl, butyl as a linear or branched (C ₁ -C ₁₀ ) alkyl group of R ³ ,
Isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 1-methylpentyl, 1-methixyl, 1,1-dimethylpentyl, 2-methylpentyl, 2-methylhexyl, 5- Methylhexyl, 2,5
A dimethylhexyl group and the like. Of these, butyl, pentyl, hexyl, 1-methylpentyl and 2-methylhexyl groups are preferable, and the pentyl group is particularly preferable.

The unsubstituted (C ₃ ~C ₈₎ cycloalkyl group substituted or unsubstituted (C ₃ ~C ₈₎ cycloalkyl group R ^3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group Of these, cyclopentyl and cyclohexyl groups are preferred. Examples of the group which may be substituted on the (C ₃ -C ₈ ) cycloalkyl group include halogen atoms such as fluorine, chlorine and bromine atoms, and methyl, ethyl, propyl, isopropyl, butyl and t-butyl groups ( C _{1 to} C ₄ ) alkyl groups, halogenated alkyl groups such as trifluoromethyl groups, and the like, and these substituents are substituted at any position of the (C _{3 to} C ₈ ) cycloalkyl group with one or more substituents. You may have.

Specific examples of the compound represented by the above formula [II] are also the above R ²
Based on the definition of R ³ and R ³ , and specific examples thereof, it will be obvious.

In the production method of the present invention, 2- represented by the above formula [I]
It is achieved by reacting a cyclopentenol derivative with a 3-substituted-cis-1-alkene iodide derivative represented by the above formula [II] in an organic medium in the presence of a palladium catalyst and a basic compound.

The 2-cyclopentenol derivative is 3-substituted iodide-
It is stoichiometrically equimolar to the cis-1-alkene derivative, but is usually 0.8 to 10 mole times, preferably 1 to 5 mole times, relative to the iodo-3-substituted-cis-1-alkene derivative. Particularly preferably, it is carried out by using 1.2 to 3 times the molar amount.

The organic medium used is tetrahydrofuran, 1,2-
Ether-based media such as dimethoxyethane and dioxane, aromatic hydrocarbons such as benzene and torunene,
Alcohol media such as methanol, ethanol and butanol, nitriles such as acetonitrile, propionitrile and isobutyronitrile, or N, N-dimethylformaldehyde are used, and tetrahydrofuran and acetonitrile are particularly preferable. To be The amount of such an organic medium used may be an amount sufficient to allow the reaction to proceed smoothly, and is usually 1 to 100 times, preferably 2 to 30 times the volume of the reactant. The reaction is usually preferably carried out under an atmosphere of an inert gas such as nitrogen or argon.

The palladium catalyst used in the production method of the present invention may be divalent or zero-valent, and is usually used in the form of a salt or a complex, but it is particularly preferably used in the form of a Hoffphine complex. As a method for preparing such a phosphine complex, a method in which a phosphine complex of palladium is previously formed is used, and a palladium salt and a phosphine ligand are mixed in the reaction system to form a palladium complex in the reaction system. Although there is a method of making it possible, any method is preferably used. The true active species in the production method of the present invention are
It is presumed that a zero-valent palladium catalyst, which is well known in palladium chemistry, is proceeding the reaction.

Specific examples of the palladium phosphine complex and the phosphine-free palladium complex include tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium acetate, bis (acetylacetonato) palladium, and tris (dibenzylideneacetone). Palladium compounds such as dipalladium-chloroform complex and tris (tribenzylideneacetylacetone) tripalladium are preferred.

When preparing such a complex in the reaction system, organic acid palladium salts such as palladium acetate, palladium propionate, palladium butyrate, and palladium benzoate, and inorganic acid palladium salts such as palladium chloride, palladium sulfate, and palladium nitrate are coordinated with phosphine. It is achieved by contacting the child. Examples of such a ligand include triethylphosphine, tributylphosphine, tricyclohexylphosphine, 4-methyl-1-phospha-3,5,
Trialkylphosphines such as 8-trioxabicyclo [2.2.2] octane, triphenylphosphine,
Triaromatic hydrocarbon phosphines such as tri (o-tolyl) phosphine, triethylphosphite, triisopropylphosphite, triphenylphosphite, 4-ethyl-1-phospha-2,6,7-trioxabicyclo [2.2.2] Phosphites such as octane,
Examples of the ligand include phosphine bidentate ligands such as 1,2-diphenylphosphinoethane, 1,3-diphenylphosphinopropane, and 1,4-diphenylphosphinobutane. Phosphine, tri (o-
Trilyl) phosphine is particularly preferred.

In addition, in the method of the present invention, as described above, the reaction proceeds sufficiently even in the absence of such a phosphine ligand.

The amount of the palladium catalyst used was 0. 3 with respect to the iodo-3-substituted-cis-1-alkene derivative represented by the above formula [II].
It is carried out using an amount of 001 to 30 mol%, preferably 0.01 to 25 mol%, more preferably 0.01 to 20 mol%, usually 5 to 10 mol%, but the reaction scale became an industrial large scale. In this case, 1 mol% or less is sufficient. When a ligand is used, it is used in an amount of 0.1 to 50 mol times, preferably 1 to 10 mol times, and particularly preferably 2 to 5 mol times, relative to palladium.

The production method of the present invention is carried out in the presence of a basic compound. Since the basic compound is used to capture hydrogen iodide generated in the system during the production of the present invention, any basic compound having such properties can be used,
The amount to be used may be a sufficient amount to capture the generated hydrogen iodide. As such a basic compound, salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium acetate and organic bases such as tributylamine are used, but the presence of a basic compound having a stronger basicity than necessary is It is not preferable because it accelerates the decomposition of the product. The amount of the basic compound used is usually in the range of 1.0 to 2.0 times the molar amount of the iodo-3-substituted-cis-1-alkene derivative.

The reaction temperature varies depending on the type and amount of the palladium catalyst used and the type of organic medium, but a temperature range of room temperature to the boiling point of the organic medium used, preferably a temperature range of 50 ° C to 100 ° C is adopted. The reaction time also depends on the type and amount of palladium catalyst used, the type of organic medium, and the reaction temperature, and the end point of the reaction is determined by tracking by thin layer chromatography, etc. 1-2 at temperature
The reaction ends within a day.

After completion of the reaction, 3-substituted-represented by the above formula [III]
The 1-cyclopentenol derivative is prepared by a conventional post-treatment method, for example, addition of water which may contain an electrolyte such as sodium chloride or ammonium chloride, extraction with a solvent such as hexane, ether, ethyl acetate, washing, The 3-substituted-1-cyclopentenol derivative represented by the above-mentioned [III], which is the object of the production method of the present invention, is isolated by separating and purifying using a separation means such as drying, separation, concentration, distillation, and chromatography. Can be separated. In addition,
It should be particularly noted here that when R ¹ of the 2-cyclopentenol derivative represented by the above formula [I] used as a starting material in the method of the present invention is a hydrogen atom, it is represented by the above formula [III]. The 3-substituted-1-cyclopentenol derivative described above easily causes isomerization of keto-enol as referred to in organic chemistry, and has the following formula [III ′] It is obtained as a 3-substituted cyclopentanone derivative represented by. This can be reasonably explained as follows in view of the reaction mechanism used in the method of the present invention. That is, as shown in the scheme, first, the iodide 3-substituted-cis-
The 1-alkene derivative reacts with the palladium catalyst to produce the vinylpalladium intermediate [IV]. This active species [IV]
To the intermediate [V] by double-bonding the double bond of the 2-cyclopentenol derivative of the formula [I] into the intermediate [V], and when the palladium is desorbed from this intermediate [V], , A hydrogen atom bonded to the carbon to which the OR ¹ group is bonded is removed to form a 3-substituted-1-cyclopentenol derivative represented by the formula [III]. Further, when R ¹ is a hydrogen atom, the formula [III] is isomerized to the formula [III ′] to be the most stable form of the 3-substituted cyclopentanone derivative.

In the present invention, the reaction between the 2-cyclopentenol derivative represented by the formula [I] and the iodo-3-substituted-cis-1-alkene derivative represented by the formula [II] proceeds diastereoselectively. The mode of selection differs slightly depending on the difference in Z in formula [I]. When Z is a hydrogen atom, the 1-position of the 2-cyclopentenol derivative represented by the formula [I] is an asymmetric carbon. On the other hand, 3-iodide represented by the formula [II]
Since the substituted-cis-1-alkene derivative has an asymmetric carbon at the 3-position, diastereoselection occurs when two asymmetric molecules react on the 3-position carbon of the 2-cyclopentenol derivative of the formula [I]. Sex is expressed. As an example similar to this example, an iodide 3-substituted-cis-1- represented by the formula [II] is shown.
Although it has been observed in the conjugate addition reaction of an organocopper reagent derived from an alkene derivative with a 4-substituted-2-cyclopentenone derivative (AFKluge et al., Journal of American Chemical Society (J. Am. Chem. So.
c.), 94, 9256 (1972); JG Miller et al., ibid, 96, 6774 (1).
974); G. Stork et al., Ibid., 99, 1275 (1977)), in the reaction under the palladium catalyst of the present invention, the properties of palladium metal are utilized to the maximum extent, and the palladium bond is added to the double bond in a catalytic reaction. The present invention has been completed by devising a method of dehydrogenatively oxidizing palladium. When Z is an OR ¹ group, the 2-cyclopentenol derivative represented by the formula [I] has a meso-form 4-cyclopentenone-group in which both OR ¹ groups are arranged on the same side (cis). It is a 1,3-diol derivative, and in such a compound, the 4- and 5-positions, which are double bond carbons, are apparently equivalent. An iodide 3-substituted-cis-1-alkene derivative having the asymmetric 3-position represented by the formula [II] is selected from these two equivalent reaction points, and diastereoselectivity is exhibited.
Further, as in the case where Z is a hydrogen atom, the added palladium is dehydrogenatively released to give a product represented by the formula [III] or the formula [III ']. It should be noted that the product represented by the formula [III] or the formula [III ′] has a odor of 4
It was also found that the OR ¹ group existing at position 3 and the substituent newly introduced at position 3 react with each other while maintaining a trans steric relationship. Therefore, in the method of the present invention, the product of formula [II
I] or the compound represented by the formula [III ′] substantially depends on the optical purity of the asymmetric carbon at the 3-position of the 3-substituted-cis-1-alkene iodide derivative represented by the formula [II] as a raw material. To obtain a derivative having an absolute structure represented by the formula [III] or the formula [III '], and its enantiomer, racemate, and a mixture thereof at any ratio.

In the thus obtained derivative represented by the formula [III] or the formula [III ′], the newly introduced substituent at the 3-position has a known [2,3] sigmatropic rearrangement reaction (J. G Miller et al.
It can be easily converted into a functional group possessed by natural prostaglandins by the Journal of American Chemical Society (see J. Am, Chem. Soc.), 96, 6774 (1974). In addition, since the 2-position is the α-position of the carbonyl group, it has reactivity, and the product represented by the formula [III] or the formula [III ′] produced by the present invention is a plastaglandin due to this functionality. It is useful as an intermediate in synthesis.

As described above, the 2-cyclopentenol derivative represented by the formula [I] and the 3-substituted-cis-1-alkene iodide derivative represented by the formula [II] are reacted in the presence of a palladium catalyst as described in detail. At least 3 represented by the formula [III]
The method for producing a substituted-1-cyclopentenol derivative has the following features. That is, (1) an asymmetric discrimination reaction in which an easily obtainable compound is used as a starting material and all the steric groups of the prostaglandin skeleton can be controlled by one asymmetric source.

(2) Making full use of the properties of palladium, and in addition, the reaction proceeds catalytically.

(3) The reaction conditions are relatively mild and simple, and the yield is high, which facilitates large-scale synthesis.

(4) It has high diastereoselectivity and is easy to asymmetrically synthesize.

(5) The obtained product is a useful compound as an intermediate in the synthesis of prostaglandins.

And so on.

Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 2-Cyclopentenol (60 mg, 0.71 mmol) and 3-
To a solution of (1-ethoxyethoxy) -1-iodo-cis-1-octene (158 mg, 0.48 mmol) in acetonitrile (4 ml) was added palladium acetate (11 mg, 0.05 mmol), tri-o-.
Tolylphosphine (30 mg, 0.10 mmol) and potassium carbonate (104 mg, 0.75 mmol) were added, and under an argon atmosphere, 85
The mixture was heated under reflux at ˜90 ° C. for 7 hours and a half. The reaction mixture was poured into ice water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product. To confirm the diastereoselectivity of the reaction product, the crude product obtained was dissolved in a mixed solvent of water (2 ml) and acetone (2 ml), and pyridinium p-toluenesulfonic acid (25 mg, 0.1 mmol) was added. And stirred at room temperature for 1 day. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product. The crude product was subjected to silica gel column chromatography to give 3- (3-hydroxy-cis-1-octenyl) cyclopentanone (57 mg, 0.2
9mmol, 61%) as a diastereomixture (mixture of 1a and 1b)
Got as.

IR (liquid film): 3400 (OH), 2953, 2920, 2842, 1740 (C = O), 1648 (C = C), 908 cm ^-1 . ¹ H-NMR (60MHZ, CDCl ₃ ): δ 0.65 to 2.72 (m, 18H, CH ₃ , CH ₂ , OH), 2.72 to 3.70 (m, 1H, CH-C =), 4.16 to 4.64 (m, 1H , CH-O), 5.18 to 5.68 (m, 2H, CH = CH).

Rf: 0.19 (hexane: ethyl acetate = 2: 1).

The ratio of diastereomers of the reaction product was determined by acetylating the product and then ¹ H-NMR of the obtained acetylated product.
(500 MHz) was measured and it was determined that 1a: 1b = 75: 25.

Main product 1a; IR (liquid film): 3400 (OH), 2953,2920,2842 , 1720 (C = O), 1648 (C = C), 908cm -1 1 H-NMR (500MHZ, CDCl 3): δ 0.88 (t, _{J = 6.9Hz, 3, CH 3} ), 1.22-1.73 (m, 10, CH 2, OH), 1.93 (d, d, J = 10.8,18.3Hz, 1, CH-C = O), 2.14-2.23 (M, 2, CH-CH-C = O), 2.31-2.39 (m, 2, CH-C = O), 3.11-3.19 (m, 1, CH-C-C = O), 4.39-4.45 ( m, 1, CH-O), 5.39-5.46 (m, 2, CH = CH), ¹³ C NMR (125 MHz, CDCl ₃ ): δ 14.020 (q), 22.294 (t), 25.081 (t), 30.504 ( tf), 31.721 (t), 35.604 (d), 37.690 (t), 38.274 (t), 45.447 (t), 68.129 (d), 133.457 (d), 134.166 (d), 218.485 (s). By-product 1b; IR (liquid film): 3400 (OH), 2953, 2920, 2842, 1720 (C = O), 1648 (C = C), 908 cm ^{-1 1} H NMR (500MHZ, CDCl ₃ ): δ 0.89 (t, J _{= 6.9Hz, 3, CH 3)} , 1.24-1.73 (m, 10, CH 2, OH), 1.97 (d, d, J = 10.6,18.3H1,1, CH-C = O), 2.08-2.25 ( m, 2, CH-CH-C = O), 2.36 (d, d, J = 7.8,17.6Hz, 1, CH-C = O), 2.447 (d, d, J = 7.8,18.3Hz, 1, CH-C = O), 3.12-3.22 (m, 1, CH-C-C = O), 4.42-4.49 (m, 1, CH-O), 5.40-5.49 (m, 2, CH = CH), ¹³ C NMR (125 MHz, CDCl ₃ ): δ 14.007 (q), 22.597 (t), 25.087 (t), 30.458 (t), 31.740 (t), 35.565 (d), 37.700 (t), 38.256 (t). , 45.487 (t), 68.060 (d), 133.440 (d), 134.132 (d), 218.382 (s). 1a acetate; IR (liquid film): 2908,2839,1747 (C = O), 1713 (C = O), 1223,1016 cm ^{-1 1} H NMR (500MHz, CDCl ₃ ): δ 0.87 (t, J = 6.9Hz, 3) _{, CH 3), 1.22-1.33 (m} , 6, CH 2), 1.43-1.51 (m, 1, CH 2 -C-O), 1.58-1.70 (m, 2, CH-C-O, CH-C = O), 1.92 (d, d, J = 18.2,10.8Hz, 1CH-C = O), 2.032 (s, 3, CH 3 -C = O), 2.16-2.27 (m, 2, CH-CH- C = O), 2.31 (d, d, J = 17.6,8.4Hz, 1, CH-C = O), 2.34 (d, d, J = 18.2,7.6Hz, 1, CH-C = O), 3.22 -3.31 (m, 1, CH-C-C = O), 5.319 (d, d, J = 11.0, 9.0Hz, 1, C = CH-C-O), 5.455 (d, d, J = 11.0, 9.9Hz, 1, CH = C- C-O), 5.496 (d, t, J = 9.0,7.3Hz, 1, CH-O), 13 C NMR (125MHz, CDCl 3): δ 13.955 (q), 21.319 (q), 22.594 (t), 24.764 (q), 30.207 (t), 31.512 (t), 34.589 (t), 35,687 (d), 38.246 (t), 45.263 (t), 70.436 (d), 128.944 (d), 135.814 (d), 170.392 (s), 218.521 (S). 1b acetate; IR (liquid film): 2908,2839,1727 (C = O) , 1713 (C = O), 1237,1016cm -1 1 H NMR (500MHz, CDCl 3): δ 0.88 (t, J = 6.9Hz, 3 , CH ₃ ), 1.24-1.34 (m, 6, CH ₂ ), 1.47-1.53 (m, 1, CH-CO), 1.59-1.70 (m, 2, CH-CO, CH-C- C = O), 1.909 (d , d, J = 18.4,10.4Hz, 1, CH-C = O), 2.018 (s, 3, CH 3 -C = O), 2.03-2.13 (m, 1, CH -C-C = O), 2.16-2.55 (m, 1, CH-C = O), 2.33 (d, d, J = 18.7,8.3Hz, 1, CH-C = O), 2.47 (d, d) , J = 18.4,7.4Hz, 1, CH-C = O), 3.24-3.34 (m, 1, CH-C-C = O), 5.326 (d, d, J = 9.3,10.3Hz, 1, C = CH-CO), 5.459 (t, J = 10.3Hz, 1, CH = CCO), 5.508 (d, t, J = 9.3,6.8Hz, 1, CH-O). ¹³ C NMR (125 MHz, CDCl ₃ ): δ 13.964 (q), 21.284 (q), 22.508 (t), 24.804 (t), 30.323 (t), 31.546 (t), 34.654 (t), 35.670 (d). , 38.309 (t), 45.254 (t), 70.264 (d), 128.887 (d), 136.082 (d), 170.308 (S), 218.322 (s). Examples 2 to 4 In order to investigate the effect of the protecting group of the 3-substituted-cis-1-alkene iodide derivative on the diastereoselectivity,
The same experiment as in Example 1 was conducted using the following protecting groups for R ² of the 3-substituted-cis-1-alkene iodide derivative. The yield and diastereoselectivity are shown below.

The physical property data of the protected product obtained in the intermediate are shown below.

Physical property value The compound of Example 3; ¹ H NMR (60 MHz, CDCl ₃ ): δ 0.05 (s, 6, CH ₃ —Si) 0.88 (s, 9, (CH ₃ ) ₃ —C), 0.65 to 1.75 (m, 11, CH ₂ , CH ₃ ), 1.85-2.55 (m, 6, CH 2), 2.90-3.40 (m, 1, CH-C = C), 4.00-4.60 (m, 1, CH-O), 5.15-5.45 (m, 2, CH = CH). The compound of Example 4; ¹ H NMR (60 MHz, CDCl ₃ ): δ 0.60-2.45 (m, 23, CH ₂ , CH ₃ ), 2.75-3.45 (m, 1, CH-C = C), 3.47 (q, J = 7Hz, 2) _{, CH 2 -O), 4.05-4.60 (} m, 1, CH-O), 4.64 (q, J = 5Hz, 1, CH-O), 4.96-5.62 (m, 2, CH = CH), IR ( Liquid film): 2950,2920,2850,1742 (C = O), 1651 (C = C), 1460,1392,1128,1090, 920,736 cm ^-1 . 2a; X = OH, Y = H 2b; X = H, Y = OH t-butyldimethylsilyl ether of 2-cyclopentenol (139 mg, 0.70 mmol) and 3-t-butyldimethylsilyloxy-1-iodo- Cis-1-octene (185m
g, 0.50 mmol) in acetonitrile (2 ml), palladium acetate (12 mg, 0.05 mmol) and potassium carbonate (109 mg, 0.7
9 mmol) was added, and the mixture was heated under reflux at 90 ° C. for 16 hours under an argon atmosphere.

The reaction mixture was poured into ice water and extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was passed through a short silica gel column to give a crude product (242 mg) containing ethanol silyl ether (2a and 2b). Was obtained. ¹ H NMR (500 MHz, CDCl ₃ ): δ 0.029,0.049 (s, 6, CH ₃ —Si), 0.146 (s, 6, CH ₃ Si), 0.882 (s, 9, (CH ₃ ) ₃ C—Si ), 0.922 (s, 9, (CH 3) 3 C-Si), 0.82-0.94 (m, 3, CH 3), 1.21-1.57 (m, 8, CH 2), 1.78-2.39 (m, 4, CH ₂ ), 3.47-3.53 (m, 1, CH-C = C), 4.40-4.47 (m, 1, CH-O), 5.15-5.25 (m, 2, CH = CH), 6.16-6.20 (m , 1, CH = C). Example 6 In the same manner as in Example 5, 3-t-butyldimethylsilyloxy-1 iodo-cis-1-octene was replaced with 3-
(1-Methoxy-1-methylethoxy) -1-iodo-
Worked up with cis-1-actene, the alkenyl compounds (2a and 2b) were obtained as a diastereomeric mixture (2a: 2b = 92: 8).

Example 7 Meso 4-cyclopentene-1,3-diol (205m
g, 2.0 mmol) and 3-t-butyldimethylsilyloxy-
To a solution of 1-iodo-cis-1-octene (369 mg, 1.0 mmol) in acetonitrile (3 ml) was added palladium acetate (22.8 m
g, 0.10 mmol) and sodium carbonate (155 mg, 1.5 mmol) were added, and the mixture was heated under reflux at 90 ° C. for 25 hours under an argon atmosphere.
The reaction mixture was cooled to room temperature, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography to obtain the desired 3- (3-t-).
Butyldimethylsilyloxy-cis-1-octenyl)
-4-Hydroxycyclopentanone was obtained as a diastereomixture (284mg, 0.87mmol, 87%).

IR (liquid film): 3400 (OH), 2918, 2840, 1734 (C = O), 1643 (C = C), 1458, 1244, 1070, 831, 770,725 cm ^-1 . ¹ H-NMR (60 MHz, CDCl ₃ ): δ 0.08 (s, 6H, CH ₃ —Si), 0.65 to 3.23 (m, 26H, CH ₃ , CH ₂ , CH, OH), 3.87 to 4.60 (m, 2H , CH-O), 4.94 to 5.70 (m, 2H, CH = CH).

The ratio of diastereoisomers was determined to be 3a: 3b = 98: 2 by isolating each diastereoisomer by hydrolysis of the above product and then by silica gel column chromatography. Yield 9
Five%.

Main product; IR (film liquid): 3310 (OH), 2917,2840,1734 (C = O), 1640 (C = C), 1450,1396,1138,1050, 1008cm -1 1 H NMR (500MHz, CDCl 3): δ 0.88 (t, = 7Hz, 3, CH 3), 1.23-1.39 (m, 6, CH 2), 1.47-1.55 (m, 1, CH-C-O), 1.59-1.67 (m, 1, CH -CO), 1.78 (brs, 1, OH), 2.074 (ddd, J = 18.6,11.7,1.2Hz, 1, CH-C = O), 2.305 (ddd, J = 18.6,9.0,2.0Hz, 1, CH-C = O), 2.599 (ddd, J = 18.6,1.6Hz, 1, (CH-C = O), 2.722 (dd, J = 18.6,6.7Hz, 1, CH-C = O), 3.094 (dddd, J = 11.7,9.6,8.2,8.0Hz, 1, CH-C = C), 4.051 (ddd, J = 9.0,8.0,7.4Hz, 1, CH-O), 4.15 (brs, 1, OH), 4.375 (dt, J = 8.3,7.5Hz, 1, CH-O), 5.464 (dd, J = 11.8,9.6Hz, 1, CH = C), 5.674 (dd, J = 11.8,8.3Hz, 1, C = CH—C—O), ¹³ C NMR (126 MHz, CDCl ₃ ): δ 13.995 (q), 22.577 (t), 25.092 (t), 31.687 (t), 37.058 (t), 44.029 (d). ), 44.977 (t), 46.837 (t), 67.028 (d), 73.088 (d), 133.4 91 (d), 136.001 (d), 213.096 (s) .By-products: IR (liquid film): 3340 (OH), 2918,2842,1731 (C = O), 1640 (C = C), 1452,1395,1140,1044, 1008 cm ^{-1 1} H NMR (500MH1, CDCl ₃ ): δ 0.88 (t, J = 7Hz, 3, CH ₃ ), 1.23-1.64 (m, 9, CH ₂ , OH), 1.040 (dd, J = 18.6 <10.0Hz, 1, CH-C = O), 2.314 (Ddd, J = 18.1,8.3,1.8Hz, 1, CH-C = O), 2.626 (ddd, J = 18.6,8.0,1.9Hz, 1, CH-C = O), 2.665 (dd, J = 18.1) , 6.8Hz, 1, CH-C = O), 3.244 (dddd, J = 11.0,10.0,8.0,7.5Hz, 1, CH-C = C), 4.126 (ddd, J = 8.3,7.5,6.8Hz, 1, CH-O), 4.460 (dt, J = 8.0,8.2Hz, 1, CH-O), 5.343 (dd, J = 11.0,10.9Hz, 1, CH = C), 5.268 (dd, J = 10.9) , 8.0 Hz, 1, C = CH-C-O). 13 C NMR (126 MHz, CDCl ₃ ): δ 14.012 (q), 22.586 (t), 25.102 (t), 31.738 (t), 37.788 (t), 43.862 (d), 44.620 (t), 46.615 (t), 68.708 (d), 74.253 (d), 130.949 (d), 135.821 (d), 213.738 (s). Examples 8 and 9 In order to study the influence of the protecting group on the diastereoselectivity as in Examples 2 to 4, the same experimental procedure as in Example 7 was carried out. The yield (yield before hydrolysis) and diastereoselectivity (selectivity after hydrolysis) are shown below.

The physical property data of the protected product obtained in the middle are as follows.

Intermediate product of Example 8; IR (liquid film): 3400 (OH), 2950,2920,2852 , 1748 (C = O), 1641 (C = C), 1395, 1132,1102,1062,1038,741cm -1 1 H-NMR (60MHz , CDCl ₃ ): δ 0.65 to 1.78 (m, 18H, CH ₃ , CH ₂ , OH), 1.90 to 2.70 (m, 4H, CH ₂ -C = O), 2.70 to 3.85 (m, 3H, CH-C) _{=, CH 2 -O), 3.85~5.10} (m, 3H, CH-O), 5.10~5.65 (m, 2H, CH = CH).

Intermediate product of Example 9; IR (liquid film): 3340 (OH), 2980, 2960, 2840, 1740 (C = O), 1643 (C = C), 1375, 1203, 1142, 1055, 1012, 903, 728 cm ^-1 . ¹ H-NMR (60 MHz, CDCl ₃ ): δ 0.60 to 1.73 (m, 18H, CH ₃ , CH ₂ , OH), 1.80 to 3.10 (m, 5H, CH ₂ —O═O, CH—C =), _{3.17 (s, 3H, CH 3} O), 3.70~4.75 (m, 2H, CH-O), 5.10~5.60 (m, 1H, CH = C), 5.80~5.95 (m, 1H, CH = C).

Examples 10 to 15 Using the iodo-3-substituted-cis-1-alkene derivative used in Example 8, various experimental conditions were verified. The experimental conditions used and the yield of 3-alkenylation product are shown below. The amount of raw material and reactant used is diol (1.0 mmo
l), alkenyl iodide (0.5 mmol), base (0.75 mmol)
And pd (OAc) ₂ and P (o-tol) ₃ are expressed in mol ratio.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location // C07B 53/00 7419-4H C07B 53/00 C 61/00 300 61/00 300

Claims (6)

(57) [Claims] 1. The following formula [I]: 2-cyclopentenol derivative represented by the following formula [II] The iodide 3-substituted-cis-1-alkene derivative represented by the formula: II-II is reacted in the presence of a palladium catalyst and a basic compound in an organic medium.
I] A diastereoselective process for producing a 3-substituted-1-cyclopentenol derivative represented by the formula (1) and enantiomers thereof, and a mixture thereof at any ratio. 2. The method for producing a 3-substituted 1-cyclopentenol derivative according to claim ¹ , wherein R ¹ is a hydrogen atom. 3. The 3-substituted- according to claim ¹ , wherein Z is OR ^1.
Process for producing 1-cyclopentenol derivative. 4. The method for producing a 3-substituted-1-cyclopentenol derivative according to claim 1, wherein R ³ is a linear (C ₁ -C ₁₀ ) alkyl group. 5. The method for producing a 3-substituted-1-cyclopentenol derivative according to claim 1, wherein the palladium catalyst is palladium acetate. 6. The method for producing a 3-substituted-1-cyclopentenol derivative according to claim 1, wherein the basic compound is sodium carbonate or potassium carbonate.