JP4573159B2 - Bis (alkynyl) carbinols, process for producing optically active alcohols, optically active tertiary alcohols, and optically active amino alcohols - Google Patents

Description

The present invention relates to bis (alkynyl) carbinols.
The present invention also relates to a method for producing optically active alcohols by enantioselective hydroalumination of achiral bis (alkynyl) carbinols.
The present invention also relates to a method for producing optically active alcohols by catalytic enantioselective hydroalumination of achiral bis (alkynyl) carbinols.
The present invention also relates to optically active tertiary alcohols.
The present invention also relates to an optically active amino alcohol serving as an asymmetric catalyst used for catalytic enantioselective hydroalumination.

  Conventionally, a wide variety of methods for producing optically active alcohols have been reported. However, most of them are secondary alcohol production methods (enantioselective addition of carbon nucleophiles to aldehydes, asymmetric reduction of ketones), and it is generally difficult to obtain optically active tertiary alcohols with high optical purity. The problem that occurred.

In order to solve this problem, optical resolution by an enzymatic method (for example, see Non-patent Document 1) and diastereoselective synthesis method (for example, see Non-Patent Document 2) have been reported. Using these methods, optically active tertiary alcohols have been successfully obtained with high optical purity.
Same-Ting Chen and Jim-Min Fang J. Org. Chem. 1997, 62, 4349-4357 a) Ohmori, K .; Suzuki, T .; Taya, K, Tanabe, D .; Ohta, T .; Suzuki, K .; Org. Lett. 2001, 3, 1057-1060. b) Suzuki, T .; Ohmori, K .; Suzuki, K .; Org. Lett. 2001, 3, 1741-1744. c) Ohmori, K .; Hachisu, Y .; Suzuki, T .; : Suzuki, K .; Tetrahedron Lett, 2002, 43, 1031-1034.

Problems to be solved by the invention

  However, the above-described conventional synthesis method has a problem that it is difficult to obtain an optically active tertiary alcohol having an arbitrary structure because it depends greatly on the substrate structure in terms of the nature of the reaction.

  This invention is made | formed in view of such a subject, and it aims at providing the manufacturing method of optically active tertiary alcohol with higher generality.

  Still another object of the present invention is to provide an asymmetric catalyst having higher reaction activity.

  Still another object of the present invention is to provide an asymmetric catalyst that exhibits higher enantioselectivity.

Means for solving the problem

  The process for producing optically active alcohols of the present invention is to synthesize tertiary alcohols having alkenyl groups and alkynyl groups that can be converted into various functional groups as optically active substances.

（式中Ｒはアルキル基、アリール基、Ｘはシリル基、アリール基、アルキル基又はプロトンから選ばれる。）で示されるアルコールであり、又は一般式

（式中Ｒはアルキル基、アリール基、シリル基、２−アルコキシエチル基から選ばれ、Ｘはシリル基、アリール基、アルキル基又はプロトンから選ばれる。）で示されるアルコールである。In the invention of the present invention, in the invention of bis (alkynyl) carbinol, the general formula

(Wherein R is an alkyl group, an aryl group, X is selected from a silyl group, an aryl group, an alkyl group, or a proton), or a general formula

(Wherein R is selected from an alkyl group, an aryl group, a silyl group, and a 2-alkoxyethyl group, and X is selected from a silyl group, an aryl group, an alkyl group, or a proton).

（式中Ｒはアルキル基、アルケニル基、アルキニル基、アリール基、Ｘはシリル基、アリール基、アルキル基又はプロトンから選ばれる。）で示されるアルコールであり、又は一般式

（式中Ｒはアルキル基、アリール基、シリル基、２−アルコキシエチル基から選ばれ、Ｘはシリル基、アリール基、アルキル基又はプロトンから選ばれる。）で示されるアルコールである。Further, in the invention of alkenylalkynyl carbinol, the general formula

(Wherein R is an alkyl group, alkenyl group, alkynyl group, aryl group, X is selected from a silyl group, an aryl group, an alkyl group, or a proton), or a general formula

(Wherein R is selected from an alkyl group, an aryl group, a silyl group, and a 2-alkoxyethyl group, and X is selected from a silyl group, an aryl group, an alkyl group, or a proton).

（式中Ｒ^１はアルキル基、アリール基、Ｒ^２はアルキル基、アリール基、Ｒ^３はプロトン、アルキル基、アリール基、Ｒ^４はプロトン、アルキル基、アリール基、Ｒ^５はアルキル基、アリール基）で示されるアミノアルコールである。In the invention of the asymmetric catalyst, the general formula

(Wherein R ¹ is an alkyl group, aryl group, R ² is an alkyl group, aryl group, R ³ is a proton, alkyl group, aryl group, R ⁴ is a proton, alkyl group, aryl group, R ⁵ is an alkyl group, aryl Group).

  On the other hand, in the invention of the method of the present invention, the method for producing bis (alkynyl) carbinol is characterized in that two equivalents of alkynyl lithium are added to the ester at 0 ° C. in a THF solvent. This is a method for producing carbinol.

  The alkenyl alkynyl carbinol is produced by using lithium hydride in the presence of an equal amount of an asymmetric ligand (the above optically active amino alcohol) in THF solvent at room temperature with respect to the above bis (alkynyl) carbinol. This is a method for producing alkenylalkynylcarbinol, characterized by reacting aluminum.

Further, the present invention is a method for producing an alkenylalkynylcarbinol characterized by reacting a lithium aluminum hydride-THF complex in the presence of a catalytic amount of an asymmetric catalyst (the above-mentioned optically active amino alcohol) in a toluene solvent at room temperature.

  The method for producing an asymmetric catalyst (the above-mentioned optically active amino alcohol) is a method for producing an asymmetric catalyst (the above-mentioned optically active amino alcohol) characterized by using a Mannich reaction and a Grignard reaction.

In the present ^{invention, R,} R 1 ^{to R} 5, X is assumed to be selected from the group of the above functional groups, ^R before the reaction, R 1 ^{to R} 5, X is R after the reaction, ^{R 1} represent the same functional group as to R ^5, X. For example, when a tri (isopropyl) silyl group is selected as X before the reaction, X after the reaction represents a tri (isopropyl) silyl group.

  The present invention provides (1) synthesis of bis (alkynyl) carbinol and (2) development of enantioselective hydroalumination reaction of bis (alkynyl) carbinol. (3) It consists of three things, such as the development of a new asymmetric catalyst for carrying out the reaction of (2).

  (1) In the stage of “synthesis of bis (alkynyl) carbinol”, derivatization to bis (alkynyl) carbinol is performed in one step from the ester.

(2) In the stage of “development of enantioselective hydroalumination reaction of bis (alkynyl) carbinol”, an achiral bis (alkynyl) carbinol is led to an optically active alcohol. Specifically, an achiral bis (alkynyl) carbinol is enantioselectively reduced only in one of two alkynyl groups by reacting lithium aluminum hydride in THF at room temperature in the presence of an optically active amino alcohol. Then, the corresponding alkenylalkynyl carbinol is synthesized as an optically active substance. This reaction proceeds with high yield and high stereoselectivity.

Also, alkenylalkynylcarbinol is synthesized as an optically active substance from achiral bis (alkynyl) carbinol using a lithium aluminum hydride-THF complex and a catalytic amount of an optically active amino alcohol in toluene at room temperature.

(3) In the “development of a novel asymmetric catalyst”, an optically active amino alcohol having higher reaction activity and enantioselectivity is synthesized.

  It should be noted that the present invention is not limited to the above-described embodiment, and various other configurations can be adopted without departing from the gist of the present invention.

を作用させることにより、以下に示すビス（アルキニル）カルビノール

を得ることができる。Each of (1) to (3) will be described in more detail. (1) Regarding “synthesis of bis (alkynyl) carbinol”, the following method is used. The terminal alkyne XCCH was allowed to react with n-butyllithium in THF (tetrahydrofuran) at 0 ° C. to generate XCCLi in the reaction system.

Bis (alkynyl) carbinol shown below by acting

Can be obtained.

を光学活性体として合成することができる。Next, (2) “Development of enantioselective hydroalumination reaction of bis (alkynyl) carbinol” will be described. Alkenyl alkynyl carbinol can be synthesized as an optically active substance by asymmetric reduction of bis (alkynyl) carbinol synthesized by the method described above. That is, two equivalents of the above-mentioned bis (alkynyl) carbinol were reacted with an aluminum hydride reagent LiAlH ₃ L ^* (L ^* is an optically active amino alcohol) modified with an optically active amino alcohol in THF (tetrahydrofuran) at room temperature. An alkenylalkynylcarbinol shown below by enantioselectively reducing one of two alkynyl groups

Can be synthesized as an optically active substance.

Further, the above-mentioned bis (alkynyl) carbinol is reacted with a lithium aluminum hydride-THF complex in toluene at room temperature, and then a catalytic amount of an optically active amino alcohol is added to the reaction system to show the alkenylalkynyl shown above. Carbinol can be obtained as an optically active substance.

  It should be noted that the present invention is not limited to the above-described embodiment, and various other configurations can be adopted without departing from the gist of the present invention.

に対し、酢酸中、パラホルムアルデヒド、ジアルキルアミン、触媒量の濃塩酸を混合した後還流することにより以下に示すアミノケトン

に誘導した後にエーテル−トルエン溶媒中０℃下Ｇｒｉｇｎａｒｄ反応剤Ｒ^２ＭｇＣｌ又はＲ^２ＭｇＢｒ又はＲ^２ＭｇＩを作用させることにより以下に示すアミノアルコール

を単一のジアステレオマーとして得ることができる。その後キラルＨＰＬＣにより両エナンチオマーを分取することにより光学活性アミノアルコールを得ることができる。Next, (3) “Development of a novel asymmetric catalyst” will be described. Ketones shown below

On the other hand, the following aminoketone is mixed by refluxing after mixing paraformaldehyde, dialkylamine and catalytic amount of concentrated hydrochloric acid in acetic acid.

Amino alcohol shown below by reacting Grignard reagent R ² MgCl or R ² MgBr or R ² MgI in ether-toluene solvent at 0 ° C.

Can be obtained as a single diastereomer. Thereafter, both enantiomers are separated by chiral HPLC, whereby an optically active amino alcohol can be obtained.

は高い反応活性を示し、前述のトルエン中における触媒反応の反応時間を大幅に短縮することができる。Amino alcohol obtained by this method

Shows a high reaction activity, and the reaction time of the catalytic reaction in toluene can be greatly shortened.

は高いエナンチオ選択性を発現し、前述の反応における生成物の光学純度を向上させることができる。Also, amino alcohol obtained by this method

Expresses high enantioselectivity and can improve the optical purity of the product in the aforementioned reaction.

  It should be noted that the present invention is not limited to the above-described embodiment, and various other configurations can be adopted without departing from the gist of the present invention.

  Next, the (first) embodiment according to the present invention will be described in detail. However, it goes without saying that the present invention is not limited to these examples.

(Test 1) Synthesis of bis (alkynyl) carbinol 1a (R = 3-phenylpropyl, X = triisopropylsilyl)
Alcohol 1a was prepared from the corresponding ester in one step. That is, 6.55 ml (10.42 mmol) of a hexane solution of 1.59M n-butyllithium acts on 2.45 ml (10.91 mmol) of (triisopropylsilyl) acetylene in THF at 0 ° C. in an argon atmosphere. After stirring at that temperature for 15 minutes, a THF solution of 884.2 mg (4.96 mol) of methyl 4-phenylbutanoate was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour, and then the reaction was stopped with a saturated aqueous ammonium chloride solution. To do. The reaction solution is extracted with hexane and dried over anhydrous sodium sulfate. After removing the solvent, the residue is purified by silica gel column chromatography to obtain 2.49 g of alcohol 1a (yield 98%). According to this operation, by performing the reaction at an equimolar ratio, alcohol 1b1,5- (triisopropylsilyl) -3-benzyl-pent-1,4-diin-3-ol was obtained from methyl phenylacetate in a yield of 46%. 99% yield of alcohol 1c 1,5- (triisopropylsilyl) -3-methyl-pent-1,4-diin-3-ol from ethyl acetate, alcohol 1d 1,5- (triisopropyl from methyl benzyloxyacetate Silyl) -3-benzyloxymethyl-pent-1,4-diin-3-ol in 65% yield, from methyl pivalate to 1e 1,5- (triisopropylsilyl) -3-tert-butyl-pent 1, 4-Diin-3-ol was synthesized with a yield of 100%.

○ Property data 1a: R ¹ = 3-phenylpropyl, X = triisopropylsilyl 1,5-bistriisopropylsilyl-3- (3-phenylpropyl) -1,4-diin-3-ol
_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.30-7.15 (m, 5H), 2.70 (t, J = 7.2Hz2H), 2.44 (s, 1H), 2.13-1. 95 (m, 4H), 1.11-0.95 (m, 42H)
¹³ C NMR (75 MHz, CDCl ₃ ) δ 142.41, 128.67, 128.58, 125.99, 107.80, 84.56, 64.16, 43.08, 35.36, 26.04, 18 .41, 10.95.
IR (neat, cm ⁻¹ ) 3458, 2944, 2866, 2168, 1463, 1073, 996, 883, 698, 678.

1b: R ¹ = benzyl, X = triisopropylsilyl 1,5- (triisopropylsilyl) -3-benzyl-pent-1-in-4-en-3-ol
_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.43-7.25 (m, 5H), 3.22 (s, 2H), 2.47 (s, 1H), 1.22-1.00 (m, 42H)
¹³ C NMR (75 MHz, CDCl ₃ ) δ 134.92, 131.02, 127.81, 127.11, 107.01, 85.71, 64.40, 49.51, 18, 72, 11.32.
IR (neat, cm ⁻¹ ) 3452, 2944, 2866, 2172, 1463, 1074, 996, 883, 700, 678.

1c: R ¹ = methyl, X = triisopropylsilyl 1,5- (triisopropylsilyl) -3-methyl-pent-1-in-4-en-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.48 (s, 1H), 1.78 (s, 3H), 1.09-1.05 (m, 42H)
¹³ C NMR (75 MHz, CDCl ₃ ) δ 108.51, 83.29, 60.48, 32.01, 18.73, 11.29.
IR (neat, cm ⁻¹ ) 3337, 2944, 2866, 2173, 1463, 1179, 1069, 883, 815, 675.

1d: R ¹ = benzyloxymethyl, X = triisopropylsilyl 1,5- (triisopropylsilyl) -3-benzyloxymethyl-pent-1-in-4-en-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.38-7.27 (m, 5H), 4.75 (s, 2H), 3.75 (s, 2H), 3.08 (s, 1H) 15-1.02 (m, 42H)
¹³ C NMR (75 MHz, CDCl ₃ ) δ 137.94, 128.46, 127.78, 127.59, 105.26, 85.42, 64.16, 73.93, 63.64, 18.64, 11 .20.
IR (neat, cm ⁻¹ ) 3551, 3446, 2944, 2171, 1678, 1463, 1253, 1306, 997, 697. .

1e: R ¹ = t-butyl, X = triisopropylsilyl 1,5- (triisopropylsilyl) -3-t-butyl-pent-1-in-4-en-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.31 (s, 1H), 1.17 (s, 9H), 1.12-1.16 (m, 42),
¹³ C NMR (75 MHz, CDCl ₃ ) δ 106.98, 84.94, 71.44, 39.87, 24.99, 18.78, 11.41
^{IR (neat, cm -1) 3614,3464,2943,2164,1463,1364,1115,1070,883,667} .

(Test 2) Enantioselective hydroalumination of bis (alkynyl) carbinol Synthesis of optically active alcohol 2a (R ¹ = 3-phenylpropyl, X = triisopropylsilyl) Hydrogenated against THF (10 mL) under argon atmosphere Lithium aluminum in THF (1.14 M) (0.078 mL) was added dropwise, and amino alcohol 3a (R ¹ = benzyl, R ² = phenyl, R ³ = H, R ⁴ = methyl, R ⁵ = methyl) 25.3 mg ( 0.089 mmol) is mixed, and after 30 minutes, a solution of alcohol 1a (R ¹ = 3-phenylpropyl, X = triisopropylsilyl) 41.5 mg (0.081 mmol) in THF is added. After 50 minutes, the reaction is quenched with solid sodium sulfate decahydrate, hexane (10 mL) and anhydrous sodium sulfate are added and stirred vigorously. Stirring was stopped and the organic layer was confirmed to be transparent. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-ether 15: 1) and optically active alcohol 2a (R = 3-phenylpropyl, X = triisopropylsilyl) was obtained (40.3 mg, yield 97%, optical purity 59% ee). According to this operation, the reaction was carried out at an equimolar ratio to synthesize alcohol 2d (R = benzyloxymethyl, X = triisopropylsilyl) from alcohol 1d in a yield of 85% and 24% ee.

Under an argon atmosphere, 0.592 mL of a lithium aluminum hydride-THF complex in toluene (0.60 M) and amino alcohol 3a (R ¹ = benzyl, R ² ) with respect to a toluene solution (10 mL) of 102 mg (0.200 mmol) of alcohol 1a = Phenyl, R ³ = H, R ⁴ = methyl, R ⁵ = methyl) 5.7 mg (0.02 mmol) is added. After 2 hours, the reaction is quenched with solid sodium sulfate decahydrate, hexane (10 mL) and anhydrous sodium sulfate are added and stirred vigorously. Stirring was stopped and the organic layer was confirmed to be transparent. After filtration and evaporation of the solvent, 96 optical silica 2a was purified by silica gel column chromatography (eluent: hexane-ether 15: 1). 0.2 mg (yield 94%, optical purity 68% ee) was obtained. According to this operation, alcohol 1b to alcohol 2b were obtained in a yield of 96% and 65% ee, alcohol 1c to alcohol 2c in a yield of 98% and 42% ee, and alcohol 1e to alcohol 2e in a yield of 100% and 98% ee, respectively. Synthesized.

Under an argon atmosphere, a toluene solution of lithium aluminum hydride-THF complex (0. 0 mL) to a toluene solution (10 mL) of 65.6 mg (0.128 mmol) of alcohol 1a (R ¹ = 3-phenylpropyl, X = triisopropylsilyl). 60M) 0.257 mL and 4.0 mg (0.0128 mmol) of amino alcohol 3b (R ¹ = benzyl, R ² = phenyl, R ³ = H, R ⁴ = isopropyl, R ⁵ = methyl) are added. After 1 hour, the reaction is quenched with solid sodium sulfate decahydrate, hexane (10 mL) and anhydrous sodium sulfate are added and stirred vigorously. Stirring was stopped and the organic layer was confirmed to be transparent. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-ether 15: 1) and optically active alcohol 2a (R ^{As a result} , 64.0 mg (yield 97%, optical purity 66% ee) of ¹ = 3-phenylpropyl and X = triisopropylsilyl were obtained.

Under an argon atmosphere, a toluene solution of a lithium aluminum hydride-THF complex (0. 0 mL) against a toluene solution (10 mL) of 98.9 mg (0.194 mmol) of alcohol 1a (R ¹ = 3-phenylpropyl, X = triisopropylsilyl). 725M) 0.294 mL and 7.0 mg (0.0194 mmol) of amino alcohol 3c (R ¹ = 1-naphthylmethyl, R ² = phenyl, R ³ = H, R ⁴ = isopropyl, R ⁵ = methyl) are added. After 3 hours, the reaction is quenched with solid sodium sulfate decahydrate, hexane (10 mL) and anhydrous sodium sulfate are added and stirred vigorously. Stirring was stopped and the organic layer was confirmed to be transparent. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-ether 15: 1) and optically active alcohol 2a (R ^{As a result} , 97.3 mg (yield 98%, optical purity 73% ee) of 3-phenylpropyl and X = triisopropylsilyl was obtained, and alcohol 2e was synthesized from alcohol 1e in 100% yield and 98% ee according to this operation. did.

○ Physical property data 2a: R ¹ = 3-phenylpropyl, X = triisopropylsilyl 1,5-bistriisopropylsilyl-3- (3-phenylpropyl) -4-penten-1-in-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29-7.15 (m, 5H), 6.13 (d, J = 18.9 Hz, 1H), 6.04 (d, J = 18.9 Hz, 1H) ) 2.66 (m, 2H), 2.05 (s, 1H) 1.88-1.70 (m, 4H), 1.13-0.98 (m, 42H).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 149.96, 142.29, 128.48, 128.36, 125.78, 123.61, 108.69, 87.15, 73.88, 41.71, 35 80, 26.37, 18.67, 18.64, 11.12, 10.89.
IR ^{(neat, cm} -1). 3453, 2943, 2865, 2165, 1605, 1463, 1072, 994, 883, 676.

2b: R ¹ = benzyl, X = triisopropylsilyl 1,5-bistriisopropylsilyl-3-benzyl-4-penten-1-in-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.36-7.23 (m, 5H), 6.17 (d, J = 18.9 Hz, 1H), 6.08 (d, J = 18.9 Hz, 1H) ) 3.06 (d, J = 13.2 Hz1H), 3.00 (d, J = 13.2 Hz1H) 2.13 (s, 1H), 1.27-0.99 (m, 42H).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 149.08, 135.67, 130.87, 127, 88, 126.81, 123.90, 108.16, 88.26, 73.81, 48.65, 18 .77, 11.36, 11.05.
IR (neat, cm ⁻¹ ). 3447, 2943, 2865, 2167, 1606, 1463, 994, 883, 742, 676.

2c: ^{R 1} = methyl, X = triisopropylsilyl 1,5-bis-triisopropylsilyl-3-methyl-4-penten-1-yn-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.18 (d, J = 18.9 Hz, 1H), 6.10 (d, J = 18.9 Hz, 1H) 2.07 (s, 1H), 1.57 (S, 3H), 1.14-1.00 (m, 42H).
¹³ C NMR (75 MHz, CDC1 ₃ ) δ 150.70, 121.99, 109, 67, 85.66, 30.25, 18.78, 18.76, 18.73, 11.32, 11.00.
IR (neat, cm ⁻¹ ). 3333, 2943, 2166, 1614, 1463, 1382, 1066, 994, 883, 659.

2d: R ¹ = benzyloxymethyl, X = triisopropylsilyl 1,5-bistriisopropylsilyl-3-benzyloxymethyl-4-penten-1-in-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35-7.26 (m, 5H), 6.24 (d, J = 18.9 Hz, 1H), 6.12 (d, J = 18.9 Hz, 1H) ), 4.70 (d, J = 12.3 Hz, 1H) 4.65 (d, J = 12.3 Hz, 1H), 3.61 (d, J = 9.3 Hz, 1H), 3.53 ( d, 9.3 Hz, 1H), 2.94 (s, 1H) 1.13-0.99 (m, 42H).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 146.37, 138.09, 128.45, 127.73, 127.57, 125.79, 107.27, 86.90, 73.70, 72.94, 18 70, 18.65, 11.23, 10.89.
IR (neat, cm ⁻¹ ) 3449, 2943, 2865, 1463, 1383, 1113, 995, 883, 697, 667.

2e: R ¹ = t-butyl, X = triisopropylsilyl 1,5-bistriisopropylsilyl-3-t-butyl-4-penten-1-in-3-ol
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.22 (d, J = 18.9 Hz, 1H), 6.11 (d, J = 18.9 Hz, 1H), 1.93 (s, 1H) 1.17 -1.01 (m, 51H),
¹³ C NMR (75 MHz, CDCl ₃ ) δ 47.51, 124.53, 108.64, 87.22, 79.46, 38.67, 25.44, 18.85, 18.81, 11.45, 11 12.
IR (neat, cm ⁻¹ ) 3454, 2942, 2866, 2166, 1616, 1463, 1383, 883, 697, 667.

(Test 3) Synthesis of optically active amino alcohol Synthesis of amino alcohol 3b (R ¹ = benzyl, R ² = phenyl, R ³ = H, R ⁴ = isopropyl, R ⁵ = methyl)
In acetic acid (5 ml), 1.91 g (11.76 mmol) of isovalerophenone, 458.7 mg (15.29 mmol) of paraformaldehyde, 1.25 g (15.29 mmol) of dimethylamine hydrochloride and a catalytic amount of concentrated hydrochloric acid were mixed. After refluxing for 2 days, the solvent is distilled off, and acid-base extraction is performed to obtain 2.04 g (79%) of aminoketone. Thereafter, benzylmagnesium chloride (5.55 mmol) was allowed to act on ether at 40 ° C. (1.85 mmol) in an ether atmosphere at 0 ° C. in an argon atmosphere. After stirring for 1 hour, the reaction was stopped with 1N NaOH _aq. To do. The reaction solution is extracted with ether, concentrated, 1N HCl _aq is added and stirred, and the precipitated white crystals are filtered off. When white crystals are dissolved in 1N NaOH _aq and extracted with ethylene chloride, 3b is obtained as a single diastereomer in 519.2 mg (yield 90%). According to this procedure, 1-naphthylmethylgenenium chloride is used instead of benzylmagnesium chloride, whereby amino alcohol 3c ((R ¹ = 1-naphthylmethyl, R ² = phenyl, R ³ = H, R ⁴ = isopropyl, R ⁵ = Methyl) is obtained with a yield of 98%.

○ Physical property data 3b: (R ¹ = benzyl, R ² = phenyl, R ³ = H, R ⁴ = isopropyl, R ⁵ = methyl)
3- (Dimethylaminomethyl) -4-methyl-1,2-diphenylpentan-2-ol (300 MHz, CDCl ₃ ) δ 7.61-7.17 (m, 10H), 3.49 (d, J = 13 .8 Hz 1 H), 3.16 (d, J = 13.8 Hz, 1 H), 2.43 (dd, J = 12.6 Hz, J = 12.6 Hz, 1 H), 2.17-2.05 (m, 7H), 1.85 (dd, J = 12.9 Hz, J = 2.4 Hz, 1H), 1.76 (m, 1H), 0.86 (d, J = 9.9 Hz, 3H), 0. 05 (d, J = 9.9 Hz, 3H).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 146.05, 138.51, 131.50, 127.69, 127.56, 127.41, 126.50, 126.00, 80.37, 56.39, 45 43, 44.81, 44.70, 25.72, 23.49, 16.57.
IR (neat, cm ⁻¹ ) 3060, 2957, 2827, 1601, 1469, 1182, 1041, 1013, 771, 703.

3c: (R ¹ = 1-naphthylmethyl, R ² = phenyl, R ³ = H, R ⁴ = isopropyl, R ⁵ = methyl)
3- (Dimethylaminomethyl) -4-methyl-1-naphthyl-2-diphenylpentan-2-ol (300 MHz, CDCl ₃ ) δ 8.32 (d, J = 8.4 Hz 1H), 7.82 (d, J = 7.8 Hz 1H), 7.72-7.65 (m, 2H), 7.52-7.25 (m, 8H), 3.98 (d, J = 14.7 Hz 1H), 3.73 (d , J = 14.4 Hz 1H), 2, 51 (t, J = 12.3 Hz, 1H), 2.22 (sept, J = 6.6 Hz, 1H), 2.06 (s, 6H), 1.98. -1.86 (m, 2H), 0.87 (d, J = 6.6 Hz 1H), 0.04 (d, J = 6.6 Hz 1H).
¹³ C NMR (75 MHz, CDCl ₃ ) δ 146.17, 134.63, 133.95, 133.70, 129.04, 128.36, 127.67, 127.33, 126.61, 126.45, 125 46, 125.25, 124.98, 124.83, 80.68, 56.32, 45.27, 44.82, 41.26, 26.14, 23.63, 16.67.
^{IR (neat, cm -1) 3054,2956,2826,1596,1464,1181,1041,1006,780,703} .

The invention's effect

  According to the present invention, it is possible to synthesize tertiary alcohols having alkenyl groups and alkynyl groups that can be converted into various functional groups as optically active substances, which means that the present invention can be used for the development of pharmaceuticals, agricultural chemicals and various functional substances. It shows that it can contribute. Many optically active alcohols having physiological activity are known, and the present invention can be used as a synthesis method for these raw materials and intermediates.

In addition, the optically active alcohol itself of the present invention itself is expected to be used as a novel physiologically active substance, and research and development can be performed with an unprecedented approach.

  Further, with the optically active amino alcohol 3b developed in the present invention, a more efficient catalytic reaction can be performed, and the target optically active alcohol can be obtained with a higher yield and selectivity.

  Further, with the optically active amino alcohol 3c developed in the present invention, a more efficient catalytic reaction can be performed, and the target optically active alcohol can be obtained with higher optical purity.

Claims (4)

General formula in THF solvent

(Wherein R is an alkyl group or a silyl group, and X is a silyl group, an aryl group, an alkyl group or a proton), and the achiral bis (alkynyl) carbinol is modified with an optically active amino alcohol A hydroalumination reaction is carried out enantioselectively using an aluminum hydride reactant LiAlH ₃ L ^* (L ^* represents an optically active amino alcohol).

The manufacturing method of optically active tertiary alcohol represented by these. The optically active amino alcohol has the general formula

(Wherein R ¹ , R ² and R ⁵ are each an alkyl group or an aryl group, and R ³ and R ⁴ are each a proton, an alkyl group or an aryl group)
The method for producing an optically active tertiary alcohol according to claim 1, wherein General formula in toluene solvent

(Wherein, R is an alkyl group or a silyl group, X is a silyl group, an aryl group, an alkyl group or a proton in a) an achiral bis (alkynyl) carbinol represented by, LiAlH ₄ and a catalytic amount of optically active Hydroalumination reaction is carried out enantioselectively using amino alcohol,

The manufacturing method of optically active tertiary alcohol represented by these. The optically active amino alcohol has the general formula

(Wherein R ¹ , R ² and R ⁵ are each an alkyl group or an aryl group, and R ³ and R ⁴ are each a proton, an alkyl group or an aryl group)
The method for producing an optically active tertiary alcohol according to claim 3, wherein