JP2006008589A - Method for producing optically active tertiary propargyl alcohol derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new production method for producing an optically active tertiary propargyl alcohol derivative by highly enantioselectively carrying out asymmetric addition reaction of a terminal alkyne with a ketone. <P>SOLUTION: The method for producing the optically active tertiary propargyl alcohol derivative comprises carrying out asymmetric addition reaction of the terminal alkyne with the ketone by using an organozinc compound and a salen ligand having a binaphthyl skeleton. A compound represented by formula (I) [wherein A is a divalent organic group; R<SP>1</SP>s are each independently hydrogen or a monovalent organic group] is preferably used as the salen ligand having the binaphthyl skeleton. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention is a method for producing an optically active tertiary propargyl alcohol derivative, more specifically, using a salen ligand having a binaphthyl skeleton as an asymmetric auxiliary agent and asymmetric addition reaction of a terminal alkyne to a ketone. To an optically active tertiary propargyl alcohol derivative.

The enantioselective alkynylation reaction of aldehydes and ketones is very useful as a method for synthesizing optically active propargyl alcohol derivatives. On the other hand, Carreira et al. Proceeded stoichiometrically with a highly enantioselective addition of alkynylzinc to aldehydes using N-methylephedrine, Zn (OTf) ₂ and NEt ₃ systems. To report. This addition reaction was later carried out catalytically at 60 ° C., but there was a problem that the effective substrate was limited to aliphatic aldehydes. In addition, Chan et al. And Pu et al. Independently demonstrated that the titanium-BINOL system has a high enantioselective reaction for addition of alkynylzinc to not only aliphatic aldehydes but also aromatic aldehydes. It is reported that it can be advanced catalytically.

  As described above, for aldehydes, the alkynylation reaction can proceed with high enantioselectivity and sufficient yield, but for ketones, some highly reactive ketones such as α-ketoesters The alkynylation reaction was not able to proceed with sufficient enantioselectivity and yield since the reactivity was low except for and the enantio-face was difficult to distinguish. Therefore, there is a demand for a method capable of allowing an alkynylation reaction to proceed with sufficient enantioselectivity and yield for various ketones.

In contrast, for example, Cozzi et al. Reported an addition reaction of alkynylzinc to a ketone using a Zn (salen) complex formed in the reaction system as a catalyst. There is a problem that the enantioselectivity is not sufficient (see Non-Patent Documents 1 and 2). In addition, Chan et al. Have reported that the combination of camphorsulfonamide and Cu (OTf) ₂ allows the alkynylzinc addition reaction to aromatic ketones to proceed in a highly enantioselective manner. When acetophenone was used, the enantiomeric excess was 88% ee, but with propiophenone it remained at 71% ee, and there was still room for improvement.

  On the other hand, the present inventors have clarified that a metal salen complex having a 2′-substituted binaphthyl unit exhibits a catalytic action in an asymmetric addition reaction to an aldehyde and proceeds the reaction with high enantioselectivity. (See Non-Patent Documents 3 and 4). Here, the orientation of the aldehyde bonded to the central metal is controlled by the salen ligand.

  In addition, Cozzi et al. Reported that a Zn (salen) complex having a t-butyl group at C3 and C3 ′ donates a Lewis acid site and a Lewis base site, and an addition reaction using the complex as a catalyst is carried out in the molecule. Propose to progress. That is, the ketone is coordinated to the zinc ion and activated, while the alkynyl zinc is bound to the oxygen atom of the phenoxide, and the alkynyl zinc attacks the ketone bonded to zinc in the molecule. Here, it is known that the Zn (salen) complex has a quadrangular pyramid-type coordination structure, and zinc ions are present at a position of 0.43 mm above the plane square. Therefore, it is considered that the cyclic transition state plays an important role in asymmetric induction in the ketone bonded to zinc and spaced from the ligand.

Cozzi P. G., Angew. Chem. Int. Ed., 2003, 42, 2895-2898. Cozzi P. G .; Papa A .; UmaniRonchi A., Tetrahedron Lett., 1996, 37, 4613-4616. Katsuki, T. Synlett, 2003, 281-297. Ito Y. N .; Katsuki, T. Bull. Chem. Soc. Jpn., 1999, 72, 603-619.

  Under such circumstances, the object of the present invention is to use various ketones as starting materials. An optically active tertiary propargyl alcohol is obtained by asymmetrically adding terminal alkynes to ketones with high enantioselectivity. It is to provide a novel production method for producing a derivative.

  As a result of diligent studies to achieve the above-mentioned object, the present inventors have used a salen ligand having a binaphthyl skeleton as an asymmetric auxiliary agent, whereby an asymmetric addition reaction of a terminal alkyne with a ketone is achieved. It has been found that tertiary propargyl alcohol derivatives can be produced with high enantioselectivity, and the present invention has been completed.

  That is, the method for producing an optically active tertiary propargyl alcohol derivative of the present invention is characterized in that a terminal alkyne is asymmetrically added to a ketone using an organozinc compound and a salen ligand having a binaphthyl skeleton. And

［式中、Ａは、二価の有機基であり；Ｒ¹は、それぞれ独立して水素又は一価の有機基である］で表される化合物が好ましい。ここで、上記式(I)中のＡとしては、炭素数４〜８のアルキレン基、炭素数５〜９のシクロアルキレン基、及び炭素数１４〜３０のアリールアルキレン基が好ましく、Ｒ¹としては、炭素数６〜１２のアリール基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基が好ましい。 In the production method of the present invention, the salen ligand having a binaphthyl skeleton is represented by the following formula (I):

[Wherein, A is a divalent organic group; each R ¹ is independently hydrogen or a monovalent organic group] is preferable. Here, the A in the above formula (I), the alkylene group of 4 to 8 carbon atoms, a cycloalkylene group having 5 to 9 carbon atoms, and preferably an aryl alkylene group of 14 to 30 carbon atoms, and R ¹ is , An aryl group having 6 to 12 carbon atoms, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms are preferable.

［式(II)及び式(III)において、Ｒ¹は、それぞれ独立して水素又は一価の有機基である。］ In a preferred example of the production method of the present invention, the salen ligand represented by the above formula (I) is represented by the following formula (II) or formula (III). In this case, the enantiomeric excess of the generated tertiary propargyl alcohol derivative can be further improved.

[In Formula (II) and Formula (III), each R ¹ is independently hydrogen or a monovalent organic group. ]

  In the production method of the present invention, the organozinc compound is preferably dialkylzinc.

In the production method of the present invention, the ketone includes the following formula (IV):
R ² —CO—R ³ (IV)
[Wherein R ² and R ³ are an alkyl group or substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group or substituted cycloalkyl group having 4 to 20 carbon atoms, an aryl group or substituted aryl having 6 to 15 carbon atoms, Or a aralkyl group having 7 to 15 carbon atoms or a substituted aralkyl group, which are different from each other].

In the production method of the present invention, as the terminal alkyne, the following formula (V):
R ⁴ —C≡CH (V)
[Wherein, R ⁴ represents an alkyl group or substituted alkyl group having 1 to 10 carbon atoms, an alkenyl group or substituted alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group or substituted cycloalkyl group having 3 to 15 carbon atoms, carbon An alkyne represented by the following formula: a cycloalkenyl group or substituted cycloalkenyl group having 4 to 15 carbon atoms, an aryl group or substituted aryl group having 6 to 15 carbon atoms, or an aralkyl group or substituted aralkyl group having 7 to 15 carbon atoms. .

［式中、Ｒ²、Ｒ³及びＲ⁴は、上記と同義である］で表されるアルコール等が挙げられる。 Examples of the optically active tertiary propargyl alcohol derivative obtained by the production method of the present invention include the following formula (VI):

[Wherein, R ² , R ³ and R ⁴ have the same meaning as described above].

In addition, the method for producing the optically active tertiary propargyl alcohol derivative of the present invention includes:
(i) adding the organozinc compound and the terminal alkyne to a solvent to produce alkynyl zinc;
(ii) adding a salen ligand having the binaphthyl skeleton to the resulting mixture to form a Zn (salen) complex;
(iii) It preferably comprises a step of adding the ketone to the obtained mixed solution to produce a propargyl alcohol derivative. Here, the Zn (salen) complex used as a catalyst is a complex having Zn as a central metal and a salen ligand having a binaphthyl skeleton as a ligand.

  According to the present invention, an optically active tertiary propargyl alcohol derivative is produced with high enantioselectivity by an asymmetric addition reaction of a terminal alkyne with a ketone using an organozinc compound and a salen ligand having a binaphthyl skeleton. can do.

  The present invention is described in detail below. The method for producing an optically active tertiary propargyl alcohol derivative of the present invention is characterized in that a terminal alkyne is asymmetrically added to a ketone using an organozinc compound and a salen ligand having a binaphthyl skeleton. . In the present invention, alkynyl zinc is produced from the organozinc compound and the terminal alkyne, and the alkynyl zinc attacks the ketone. Here, the salen ligand having a binaphthyl skeleton acting as an asymmetric auxiliary agent has a binaphthyl skeleton because C3 and C3 ′ adjacent to the oxygen atom of phenoxide have a bulky naphthyl group or a 2-substituted naphthyl group. Coordination of alkynyl zinc to the oxygen atom of the salen ligand is the same as the arrangement of alkynyl zinc to the oxygen atom of the salen ligand having t-butyl groups at C3 and C3 ′ used by Cozzi et al. Unlike the method of positioning, Zn (salen) complex formed from an organozinc compound and a salen ligand having a binaphthyl skeleton makes it possible to identify the enantio-face of the ketone in which the binaphthyl skeleton is bonded to zinc. The enantioselectivity of the asymmetric addition reaction of benzene to ketone.

  When a salen ligand having a 2-substituted naphthyl group is used for C3 and C3 ′, in the Zn (salen) complex formed from the salen ligand and an organic zinc compound, the 2-substituent is zinc. Since the discriminating ability of the enantio face of the ketone bonded to zinc located in the vicinity of the ion is improved, the enantioselectivity of the asymmetric addition reaction of the terminal alkyne to the ketone can be further improved.

  The salen ligand having a binaphthyl skeleton used in the production method of the present invention is preferably a compound represented by the above formula (I). In the formula (I), A is a divalent organic group. Examples of the divalent organic group include alkylene groups having 4 to 8 carbon atoms, cycloalkylene groups having 5 to 9 carbon atoms, and 14 to 30 carbon atoms. Specific examples of the alkylene group include 2,4-pentylene group and 2,3-butylene group, and examples of the cycloalkylene group include 1,2-cyclohexylene. Group, a 1,2-cyclopentylene group, and the like, and examples of the arylalkylene group include a 1,2-diphenylethylene group, a 1,2-di (3,5-dimethylphenyl) ethylene group, and the like. Among these, A is preferably a 1,2-cyclohexylene group from the viewpoint of the enantiomeric excess of the product.

In formula (I), each R ¹ is independently hydrogen or a monovalent organic group, and examples of the monovalent organic group include an aryl group having 6 to 12 carbon atoms and an alkyl group having 1 to 4 carbon atoms. Examples thereof include an alkyl group and an alkoxy group having 1 to 4 carbon atoms. Specific examples of the aryl group include a phenyl group, a 3,5-dimethylphenyl group, a 4-methylphenyl group, and a 4-biphenylyl group. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, and a t-butyl group. Examples of the group include a methoxy group and an ethoxy group. Among these, as R ¹ , a monovalent organic group is preferable from the viewpoint of the enantiomeric excess of the product, and a phenyl group, a methoxy group, and a 4-biphenylyl group are particularly preferable.

  In the production method of the present invention, the chirality of the diamine unit of the Zn (salen) complex produced from the organozinc compound and the salen ligand having a binaphthyl skeleton and the chirality of the vinylal unit greatly affect the asymmetric induction. Effect. Here, from the viewpoint of the enantiomeric excess of the product, in the formula (I), when the configuration of the vinylal unit is (R), the configuration of the diamine unit is (S, S) rather than (R, R). In the case where the steric configuration of the vinylal unit is (S), the steric configuration of the diamine unit is preferably (R, R) rather than (S, S). Therefore, as the salen ligand represented by the above formula (I), when A is a 1,2-cyclohexylene group, a compound represented by the above formula (II) or the formula (III) is particularly preferable.

  The amount of the salen ligand having the binaphthyl skeleton is preferably in the range of 5 to 15 mol% with respect to the molar amount of the ketone described below. When the amount of the salen ligand having a binaphthyl skeleton is less than 5 mol%, the enantioselectivity is decreased, and even when the amount exceeds 15 mol%, the enantioselectivity and the yield are not improved. There is no special merit.

  The organozinc compound used in the production method of the present invention has a function of acting on a terminal alkyne described later to generate alkynyl zinc, and a function of acting on a salen ligand having the binaphthyl skeleton to produce a Zn (salen) complex. And have. Here, as the organic zinc compound, dialkyl zinc is preferable, and the alkyl group in the dialkyl zinc preferably has 1 to 5 carbon atoms. Specific examples of the dialkyl zinc include dimethyl zinc and diethyl zinc. In addition, alkyl alkynyl zinc etc. are mentioned as alkynyl zinc produced | generated from dialkyl zinc and terminal alkyne.

  The amount of the organozinc compound used is preferably in the range of 3 to 5 equivalents (eq) with respect to the ketone described below. If the amount of the organozinc compound used is less than 3 equivalents (eq) relative to the ketone, the yield will decrease, and if it exceeds 5 equivalents (eq), there will be no special merit.

The ketone used in the production method of the present invention is not particularly limited as long as it is a prochiral ketone. For example, a ketone represented by the above formula (IV) can be preferably used. In the formula (IV), R ² and R ³ are different from each other, and are an alkyl group or substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group or substituted cycloalkyl group having 4 to 20 carbon atoms, or 6 to 15 carbon atoms. An aryl group or a substituted aryl group, or an aralkyl group or a substituted aralkyl group having 7 to 15 carbon atoms. Specifically, examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, n -Butyl group, i-butyl group, s-butyl group, t-butyl group and the like. Examples of the cycloalkyl group include cyclohexyl group and cyclopentyl group. Examples of the aryl group include phenyl group, p -Methoxyphenyl group and the like, and examples of the aralkyl group include phenethyl group, benzyl group and the like, and these alkyl groups, cycloalkyl groups, aryl groups and aryl groups. Hydrogen in alkyl group may be substituted with a halogen or nitro group such as Cl and Br.

The terminal alkyne used in the production method of the present invention is not particularly limited as long as hydrogen is bonded to at least one of the triple-bonded carbons. For example, the terminal alkyne represented by the above formula (V) is used. It can be used suitably. In formula (V), R ⁴ represents an alkyl group having 1 to 10 carbon atoms or a substituted alkyl group, an alkenyl group having 2 to 10 carbon atoms or a substituted alkenyl group, a cycloalkyl group having 3 to 15 carbon atoms, or a substituted cycloalkyl group. A C4-C15 cycloalkenyl group or substituted cycloalkenyl group, a C6-C15 aryl group or substituted aryl group, or a C7-C15 aralkyl group or substituted aralkyl group, Examples of the alkyl group include an n-pentyl group. Examples of the alkenyl group include a hexenyl group. Examples of the cycloalkyl group include a cyclopentyl group and a cyclohexyl group. Examples of the cycloalkenyl group include 1-cyclohexenyl group and the like, and as the aryl group, phenyl group, tolyl group and the like can be mentioned, Examples of the aralkyl group include a benzyl group, and the hydrogen in the alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, aryl group and aralkyl group includes an alkoxy group such as a methoxy group, a halogen such as F, and the like. May be substituted.

  The amount of the terminal alkyne used is preferably in the range of 3 to 5 equivalents (eq) based on the ketone. If the amount of terminal alkyne used is less than 3 equivalents (eq) relative to the ketone, the yield decreases, and use exceeding 5 equivalents (eq) is uneconomical.

The optically active tertiary propargyl alcohol derivative obtained by the production method of the present invention is produced using the above ketone and terminal alkyne as raw materials, and various propargyl alcohol derivatives can be obtained by appropriately selecting the raw materials. Here, when the ketone represented by the above formula (IV) and the terminal alkyne represented by the above formula (V) are used as starting materials, a propargyl alcohol derivative represented by the above formula (VI) is obtained, where R ² , R ³ and R ⁴ in the formula (VI) are as defined above. Moreover, both enantiomers of optically active tertiary propargyl alcohol derivatives can be obtained by appropriately selecting the configuration of the salen ligand having a binaphthyl skeleton to be used.

  More specifically, the production method of the present invention is obtained in the first step by adding the organozinc compound and the terminal alkyne to a solvent to produce alkynyl zinc, and in the second step, obtained in the first step. Into the mixed solution, a salen ligand having the binaphthyl skeleton is added to form a Zn (salen) complex, and in the third step, the ketone is added to the mixed solution obtained in the second step to generate a propargyl alcohol derivative. It is preferable to do so. Reduce the number of steps in the production process by generating a Zn (salen) complex in the reaction system and using it as a catalyst for the asymmetric addition reaction of a terminal alkyne to a ketone without isolating the Zn (salen) complex can do.

The production method of the present invention is generally carried out in an organic solvent. Examples of the organic solvent include halogenated hydrocarbons such as dichloromethane (CH ₂ Cl ₂ ) and aromatic hydrocarbons such as toluene. Among these, from the viewpoint of improving the enantiomeric excess of the product, a mixed solution of dichloromethane and toluene is preferable. The amount of the solvent used is preferably in the range of 1 to 5 mL per 1 mmol of the ketone.

  Although the manufacturing method of this invention can be implemented at room temperature and it is not specifically limited, It is preferable to implement in 25-30 degreeC. If the reaction temperature is too high or too low, the enantiomeric excess of the product will decrease. Moreover, reaction time is not specifically limited, According to the said reaction temperature, it selects suitably.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples.

(Ligand synthesis example 1)
(1S, 2S) -1,2-cyclohexanediamine [Fujimoto Molecular Chemistry] (10.8 mg, 0.0947 mmol) was dissolved in ethanol (5 mL), and (R) -3-formyl-2-hydroxy-2 ′ was dissolved in this solution. -Phenyl-1,1′-binaphthyl [synthesized by the method described in H. Sasaki, R. Irie, T. Hamada, K. Suzuki, T. Katsuki, Tetrahedron, 1997, 50 (41), 11827] (85.3 mg, 0.189 mmol) and stirred at room temperature for 10 hours. The resulting yellow precipitate is filtered with a glass filter and washed with ethanol (5 mL). The precipitate collected by filtration is vacuum-dried at 60 ° C. for 5 hours to obtain a compound represented by the following formula (VII) (93 mg, yield 100%). The results of IR measurement (KBr method) of the obtained compound were 3051, 2926, 2856, 1630, 1506, 1442, 1385, 1346, 1288, 1258, 1145, 1096, 1026, 943, 820, 746, 702 cm ^−1. It is.

(Ligand synthesis example 2)
(1S, 2S) -1,2-cyclohexanediamine [Fujimoto Molecular Chemistry] (167 mg, 1.46 mmol) was dissolved in ethanol (30 mL), and (R) -3-formyl-2-hydroxy-2′- was dissolved in this solution. (4-biphenylyl) -1,1′-binaphthyl [H. Sasaki, R. Irie, T. Hamada, K. Suzuki, T. Katsuki, Tetrahedron, 1997, 50 (41), 11827 Synthesis] (1.07 g, 2.85 mmol) is added and stirred at room temperature for 10 hours. The resulting yellow precipitate is filtered off with a glass filter and washed with ethanol (20 mL). The precipitate collected by filtration is vacuum-dried at 60 ° C. for 5 hours to obtain a compound represented by the following formula (VIII) (1.18 g, yield 93%). The results of IR measurement (KBr method) of the obtained compound are 3053, 2928, 2858, 1630, 1441, 1344, 1258, 1120, 945, 816, 746, 696, 619 cm ⁻¹ .

(Ligand synthesis example 3)
(1S, 2S) -1,2-cyclohexanediamine [Fujimoto Molecular Chemistry] (40.2 mg, 0.352 mmol) was dissolved in ethanol (10 mL), and (R) -3-formyl-2-hydroxy-2 ′ was dissolved in this solution. -Methoxy-1,1'-binaphthyl [A. van Doorn, DJ Rushton, M. Bos, W. Verboom, DN Reinhoudt, Recl. Trav. Chim. Pays-Bas, 1992, 111, 415 Synthesis] (231 mg, 0.704 mmol) is added and refluxed for 10 hours. The resulting yellow precipitate is filtered through a glass filter and washed with ethanol (10 mL). The precipitate collected by filtration is vacuum-dried at 60 ° C. for 5 hours to obtain a compound represented by the following formula (IX) (148 mg, yield 57%). The results of IR measurement (KBr method) of the obtained compound were 3055, 2932, 2837, 1630, 1506, 1441, 1340, 1258, 1182, 1148, 1082, 1045, 1020, 945, 808, 748, 617 cm ^-1 It is.

(Ligand synthesis example 4)
(1R, 2R) -1,2-cyclohexanediamine [Fujimoto Molecular Chemistry] (171 mg, 1.5 mmol) was dissolved in ethanol (15 mL), and (aR) -3-formyl-2-hydroxy-2′- was dissolved in this solution. Phenyl-1,1′-binaphthyl [synthesized by the method described in H. Sasaki, R. Irie, T. Hamada, K. Suzuki, T. Katsuki, Tetrahedron, 1997, 50 (41), 11827] (1.10 g , 3.0 mmol) and heat at 60 ° C. for 10 hours. The reaction solution is cooled to room temperature, and the resulting yellow precipitate is filtered off with a glass filter and washed with ethanol (10 mL). The precipitate collected by filtration is vacuum-dried at 60 ° C. for 5 hours to obtain a compound represented by the following formula (X) (1.18 g, yield 95%). The results of IR measurement (KBr method) of the obtained compound are 3053, 2930, 2858, 1630, 1506, 1443, 1383, 1344, 1290, 1259, 1119, 943, 822, 750, 700, 619 cm ⁻¹ . .

(Ligand synthesis example 5)
(1S, 2S) -1,2-diphenylethylenediamine [Fujimoto Molecular Chemistry] (318 mg, 1.5 mmol) was dissolved in ethanol (15 mL), and (aR) -3-formyl-2-hydroxy-2′- was dissolved in this solution. Phenyl-1,1′-binaphthyl [synthesized by the method described in H. Sasaki, R. Irie, T. Hamada, K. Suzuki, T. Katsuki, Tetrahedron, 1997, 50 (41), 11827] (1.10 g , 3.0 mmol) and heat at 60 ° C. for 10 hours. The reaction solution is cooled to room temperature, and the resulting yellow precipitate is filtered off with a glass filter and washed with ethanol (10 mL). The precipitate collected by filtration is vacuum-dried at 60 ° C. for 5 hours to obtain a compound represented by the following formula (XI) (1.31 g, yield 94%). The results of IR measurement (KBr method) of the obtained compound were 3055, 3032, 1628, 1495, 1445, 1385, 1344, 1319, 1290, 1259, 1184, 1150, 1119, 1028, 943, 819, 756, 700 , 544cm ^-1 .

(Ligand synthesis example 6)
(2S, 4S) -pentanediol [Aldrich] (499 mg, 3.84 mmol), methanesulfonyl chloride (1.49 mL, 19.2 mmol) and triethylamine (3.75 mL, 26.9 mmol) were dissolved in dichloromethane (30 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 10 hours. Next, the mixed solution was extracted with dichloromethane, and then the solvent was removed under reduced pressure. The obtained compound and sodium azide (549 mg, 8.45 mmol) were dissolved in dimethylformamide (25 mL) under a nitrogen atmosphere, and the solution was stirred at 80 ° C. for 10 hours. Next, the mixed solution was extracted with ether, the solvent was removed under reduced pressure, and then the mixture was separated by silica gel chromatography using a mixed solution of hexane / ethyl acetate (9/1), and (2R, 4R) -pentanedi About 300 mg of azide is obtained.
(2R, 4R) -pentanediazide (300 mg, 2.0 mmol) and palladium / carbon (32 mg) were dissolved in ethanol (6.5 mL) under a hydrogen atmosphere, and the solution was stirred at room temperature for 10 hours. Next, the mixed solution is filtered through celite and washed with ethanol. (S) -3-formyl-2-hydroxy-2′-phenyl-1,1′-binaphthyl [H. Sasaki, R. Irie, T. Hamada, K. Suzuki, T. Katsuki, Tetrahedron , 1997, 50 (41), 11827] (1.29 g, 3.5 mmol) is added and stirred at room temperature for 10 hours. The resulting yellow precipitate is filtered off with a glass filter and washed with ethanol (8.5 mL). The precipitate collected by filtration is vacuum-dried at 60 ° C. for 5 hours to obtain a compound represented by the following formula (XII) (1.3 g, yield 93%). The results of IR measurement (KBr method) of the obtained compound are 3051, 2964, 2866, 1630, 1501, 1443, 1387, 1344, 1261, 1147, 1119, 1024, 941, 822, 754, 700 cm ⁻¹ . .

Example 1
Dimethylzinc (2.0 M toluene solution 150 μL, 0.3 mmol) and phenylacetylene (32.9 μL, 0.3 mmol) are dissolved in a mixed solution of dichloromethane / toluene (300 μL / 150 μL) under a nitrogen atmosphere, and the solution is stirred at room temperature for 1 hour. Stir. Further, the compound of formula (VII) (6.6 mg, 8.0 μmol) was added to the mixed solution, and the mixture was further stirred for 1 hour. Next, acetophenone (11.7 μL, 0.1 mmol) was added to the mixed solution, and the mixture was further stirred at room temperature for 2 days to perform an asymmetric addition reaction. Thereafter, 2 drops of water were added to the reaction mixture to stop the reaction, diluted with diethyl ether, and then passed through celite and sodium sulfate. Next, after removing the solvent under reduced pressure, the mixture was chromatographed on silica gel using a hexane / ethyl acetate (19/1) mixture to obtain the corresponding alcohol (16.5 mg, yield 74%). The enantiomeric excess of the resulting alcohol was analyzed by high performance liquid chromatography (HPLC) using a chiral stationary phase column (Daicel / Chiralcel OD-H) and a hexane / isopropanol (19/1) mixture. % Ee. Moreover, the sign of optical rotation in chloroform was (−).

(Example 2)
In place of a mixed solvent of dichloromethane / toluene (300 μL / 150 μL), a toluene (450 μL) solvent was used, and phenylacetylene was added to acetophenone in the same manner as in Example 1. The results are shown in Table 1.

(Examples 3 to 7)
Instead of the compound of formula (VII), the compound of the above formula (VIII), formula (IX), formula (X), formula (XI) or formula (XII) was used as a ligand in the same manner as in Example 1. Thus, phenylacetylene was added to acetophenone. The results are shown in Table 1.

Reaction formulas corresponding to Examples 1 and 3 to 7 in Table 1 are shown below.

  From the comparison between Example 1 and Example 2, it can be seen that the enantiomeric excess is higher in the dichloromethane / toluene mixed solvent than in the toluene solvent. Moreover, from the results of Example 1, Example 3, and Example 4, it can be seen that the substituent at the 2-position of the binaphthyl skeleton can be changed to various substituents.

  Furthermore, from the comparison of Example 1 and Example 5, when the configuration of the main product depends on the configuration of the diamine unit and the configuration of the vinylal unit is (R), the configuration of the diamine unit is From the viewpoint of yield and enantiomeric excess, it can be seen that (S, S) is preferable to (R, R). In addition, this result indicates that when the configuration of the vinylalty unit is (S), the configuration of the diamine unit is preferably (R, R) rather than (S, S).

  Furthermore, from Example 1, Example 6 and Example 7, although the diamine unit of the salen ligand can be changed to various structures, 1,2-cyclohexanediamine is used to form the diamine unit. It can be seen that the most preferable.

(Examples 8 to 13)
The same procedure as in Example 1 was performed except that a ketone in which the phenyl group of acetophenone was substituted with the organic group shown in Table 2 was used instead of acetophenone. In Example 8, Example 11 and Example 13, a mixture of Daicel / Chiral Cell OD-H and hexane / isopropanol (49/1) was used for the measurement of the enantiomeric excess, and in Example 9, the enantiomer was used. In the measurement of excess, Daicel-Chiralcel OD-H and a hexane / isopropanol (99/1) mixture were used. In Example 12, the measurement of the enantiomeric excess was performed using Daicel-Chiralcel OD-H and hexane / isopropanol ( 97/3) A mixed solution was used. These results are shown in Table 2.

Reaction formulas corresponding to Examples 8 to 13 in Table 2 are shown below.

  From the results of Table 2, it can be seen that the method of the present invention can be applied to various ketones and can produce various optically active tertiary propargyl alcohol derivatives corresponding to the ketones. Further, although the orientation of the ketone bonded to zinc of the Zn (salen) complex is determined by steric repulsion between C3 and C3 ′ of the salen ligand having a binaphthyl skeleton and the carbonyl substituent of the ketone, Example 11 From the results, it can be seen that it is difficult to distinguish the difference based on steric repulsion between methyl carbon and methylene carbon.

(Examples 14 to 16)
The same procedure as in Example 1 was performed except that a ketone in which the methyl group of acetophenone was replaced with an organic group shown in Table 3 was used instead of acetophenone. In Example 14, a mixture of Daicel-Chiralcel OD-H and hexane / isopropanol (24/1) was used to measure the enantiomeric excess. In Example 15, Daicel In Example 16, a mixture of Chiralcel OD-H and hexane / isopropanol (19/1) was used. In Example 16, for measurement of enantiomeric excess, Daicel-Chiralpack AD-H and hexane / isopropanol (19/1) mixture were used. Using. These results are shown in Table 3.

Reaction formulas corresponding to Examples 14 to 16 in Table 3 are shown below.

  From the results in Table 3, it can be seen that the method of the present invention can be applied to various ketones, and various optically active tertiary propargyl alcohol derivatives corresponding to the ketones can be produced. In addition, in the report of Chan et al., It was said that the enantiomeric excess rate was lower when propiophenone was used than acetophenone. However, in the method of the present invention, the enantiomeric excess rate was conversely reduced. Rose. From these, it can be seen that the π-π interaction between the C3 and C3 ′ substituents of the salen ligand having a binaphthyl skeleton and the phenyl group of the ketone affects the enantioselectivity of the reaction.

(Examples 17 to 20)
The same procedure as in Example 13 (using 3,3-dimethyl-2-butanone as the ketone) was used except that a terminal alkyne in which the phenyl group of phenylacetylene was substituted with the organic group shown in Table 4 was used instead of phenylacetylene. It was. In Example 17, a mixture of Daicel-Chiralcel OD-H and hexane / isopropanol (199/1) was used to measure the enantiomeric excess, and in Example 18, Daicel In Example 19, a mixture of Chiralcel OD-H and hexane / isopropanol (24/1) was used. In Example 19, a mixture of Daicel-Chiralcel OD-H and hexane / isopropanol (999/1) was used to measure the enantiomeric excess. In Example 20, after converting the product to the corresponding benzoate, the enantiomeric excess was measured using a mixed solution of Daicel-Chiralcel OD-H and hexane / isopropanol (1999/1). These results are shown in Table 4.

Reaction formulas corresponding to Examples 17 to 20 in Table 4 are shown below.

  From the results of Table 4, it can be seen that the method of the present invention can be applied to various terminal alkynes and can produce various optically active tertiary propargyl alcohol derivatives corresponding to the terminal alkynes. In addition, since the enantiomeric excess in Examples 17 to 20 is almost the same, the identification of the enantio-face of 3,3-dimethyl-2-butanone (pinacolone) is mainly governed by the salen ligand. I understand that.

  The production method of the present invention is very useful for the production of optically active tertiary propargyl alcohol derivatives by the thioselective alkynylation of ketones. Moreover, the optically active tertiary propargyl alcohol derivative obtained by the production method of the present invention can be used for the synthesis of medical and agrochemical products.

Claims (9)

  A method for producing an optically active tertiary propargyl alcohol derivative, which comprises subjecting a ketone to an asymmetric addition reaction of a terminal alkyne using an organozinc compound and a salen ligand having a binaphthyl skeleton. The method for producing an optically active tertiary propargyl alcohol derivative according to claim 1, wherein the salen ligand having a binaphthyl skeleton is represented by the following formula (I).

Wherein A is a divalent organic group; each R ¹ is independently hydrogen or a monovalent organic group. ] A in the above formula (I) is an alkylene group having 4 to 8 carbon atoms, a cycloalkylene group having 5 to 9 carbon atoms, or an arylalkylene group having 14 to 30 carbon atoms, and each R ¹ is independently The optically active tertiary propargyl alcohol derivative according to claim 2, which is an aryl group having 6 to 12 carbon atoms, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. Production method. 4. The production of an optically active tertiary propargyl alcohol derivative according to claim 3, wherein the salen ligand represented by the formula (I) is represented by the following formula (II) or formula (III): Method.

[In Formula (II) and Formula (III), each R ¹ is independently hydrogen or a monovalent organic group. ]   The method for producing an optically active tertiary propargyl alcohol derivative according to claim 1, wherein the organozinc compound is dialkylzinc. The method for producing an optically active tertiary propargyl alcohol derivative according to claim 1, wherein the ketone is represented by the following formula (IV).
R ² —CO—R ³ (IV)
[Wherein R ² and R ³ are an alkyl group or substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group or substituted cycloalkyl group having 4 to 20 carbon atoms, an aryl group or substituted aryl having 6 to 15 carbon atoms, Group, a C 7-15 aralkyl group or a substituted aralkyl group, which are different from each other. ] The method for producing an optically active tertiary propargyl alcohol derivative according to claim 1, wherein the terminal alkyne is represented by the following formula (V).
R ⁴ —C≡CH (V)
[Wherein, R ⁴ represents an alkyl group or substituted alkyl group having 1 to 10 carbon atoms, an alkenyl group or substituted alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group or substituted cycloalkyl group having 3 to 15 carbon atoms, carbon It is a C4-C15 cycloalkenyl group or substituted cycloalkenyl group, a C6-C15 aryl group or substituted aryl group, or a C7-C15 aralkyl group or substituted aralkyl group. ] The method for producing an optically active tertiary propargyl alcohol derivative according to claim 1, wherein the tertiary propargyl alcohol derivative is represented by the following formula (VI).

[Wherein R ² , R ³ and R ⁴ have the same meanings as described above. ] (i) adding the organozinc compound and the terminal alkyne to a solvent to produce alkynyl zinc;
(ii) adding a salen ligand having the binaphthyl skeleton to the resulting mixture to form a Zn (salen) complex;
(iii) The method for producing an optically active tertiary propargyl alcohol derivative according to claim 1, comprising the step of adding the ketone to the obtained mixed solution to form a propargyl alcohol derivative.