CN111875474B - Preparation method of (R, E) -4-phenylbutyl-3-ene-2-alcohol derivative - Google Patents

Preparation method of (R, E) -4-phenylbutyl-3-ene-2-alcohol derivative Download PDF

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CN111875474B
CN111875474B CN202010751264.6A CN202010751264A CN111875474B CN 111875474 B CN111875474 B CN 111875474B CN 202010751264 A CN202010751264 A CN 202010751264A CN 111875474 B CN111875474 B CN 111875474B
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phenylbutyl
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钟为慧
陈佳琛
凌飞
肖霄
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a preparation method of (R, E) -4-phenylbutyl-3-ene-2-ol derivatives. Specifically, the (E) -4-phenyl-3-alkene-2-ketone derivative is subjected to asymmetric hydrogenation by adopting a catalyst consisting of a PNN ligand of a chiral ferrocene skeleton and manganese pentacarbonyl bromide, and the (R, E) -4-phenylbutyl-3-alkene-2-alcohol derivative is generated with high yield and high enantioselectivity. Compared with the traditional splitting method, the method has the following beneficial effects: mild reaction conditions, simple and convenient operation, good stereoselectivity, high yield, short production period, less three wastes and easy industrialization, and has great implementation value and social and economic benefits.

Description

Preparation method of (R, E) -4-phenylbutyl-3-ene-2-alcohol derivative
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a (R, E) -4-phenylbutyl-3-ene-2-ol derivative.
Background
Over the past decades, considerable progress has been made in asymmetric hydrogenation, the asymmetric hydrogenation of prochiral ketones being one of the most important processes for preparing chiral alcohols. Chiral enols, as important pharmaceutical intermediates, are widely used in the synthesis of various natural products, pharmaceuticals, agrochemicals, and bioactive compounds. For example, allyl alcohol is a key pharmacophore of the side chain of statins and is also a key intermediate of cannabidiol (cannabidiol), and therefore, it is important to develop an effective asymmetric synthesis method for the compounds. Generally, asymmetric synthesis methods of chiral enols can be divided into three major classes: (ii) biocatalytic asymmetric reduction, (iii) chemocatalytic asymmetric reduction. Among them, chemical catalysis is most attractive from the viewpoint of practical use and economical utilization. Several methods have been successfully developed for chiral oxazaborolidine catalyzed hydroboration, chiral ruthenium/diphosphine/diamine catalyzed asymmetric hydrogenation or chiral iridium/chiral phosphine ligand catalyzed asymmetric hydrogenation. However, the synthesis method is still limited overall, and in most cases, the substrate has limitations, and the central metal is a precious metal which is scarce in reserves and toxic and harmful to human bodies. The manganese element is one of 18 trace elements for human life and health, and the residual quantity of the manganese in the human body can be 250ppm. Therefore, it is desired to develop an asymmetric synthesis method having high enantioselectivity using manganese as a central metal.
As early as 2002, professor Noyori, a scientist of japan, has reported that for asymmetric catalytic hydrogenation of 3-nonen-2-one, designing a class of chiral ruthenium/diphosphine/diamine catalyzed asymmetric hydrogenation to obtain the corresponding chiral alcohol in 99% ee,95% yield, which is promising for the originally difficult topic, but the substrates are limited to substrates with aliphatic groups at both ends (j.am.chem.soc., 2002,124, 6508-6509.). Subsequently in 2008, ohkuma teaches group modification of its ligands for asymmetric catalytic hydrogenation reduction of chalcone-based substrates limited to aromatic group substrates at both ends, yielding the corresponding chiral alcohols in maximum 99% yield and 98% ee (angelw.chem.int.ed., 2008,120, 7457-7460), resulting in a more active chiral ruthenium/diphosphine/diamine catalytic system. In 2018, professor James reported a method of asymmetric boration reduction of α, β -unsaturated ketones, obtaining cannabidiol drug intermediates (org. Lett.,2018,20, 381-384.) in 78% ee,94% yield.
Although the limitations of the substrate appear to have been addressed, there are several important problems that have not yet been addressed: 1) Asymmetric hydrogenation of polysubstituted substrates or condensed ring substrates such as quinoline rings, benzothiophene rings and the like on benzene rings is not reported in the connection of double bond sides; 2) The catalyst conversion number (TON) is too low to meet the requirements of industrial production; 3) The catalytic system is limited to the combination of noble metals such as ruthenium or iridium and chiral ligands; 4) The highly stereoselective preparation of key intermediates of cannabidiol using asymmetric catalytic hydrogenation remains challenging. Therefore, the development of a rich variety of chiral ligands and catalytic systems thereof is urgently needed to solve these problems.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of (R, E) -4-phenylbutyl-3-ene-2-alcohol derivatives, which has the advantages of high purity, high enantioselectivity and the like and can meet the requirement of industrial production.
The process for preparing the (R, E) -4-phenylbutyl-3-en-2-ol derivative with high purity and high enantioselectivity comprises the following steps:
the preparation process of the (R, E) -4-phenylbutyl-3-ene-2-ol derivative is characterized by comprising the following steps of:
1) Under the argon atmosphere at the temperature of 0-60 ℃, manganese pentacarbonyl bromide and chiral ligand L * Sequentially adding the mixture into a solvent A, and reacting for 0.5 to 6 hours to prepare a catalyst [ M]/L * ；
2) Sequentially adding a catalyst [ M ] obtained in the step 1) of (E) -4-phenylbutyl-3-alkene-2-ketone-derivative shown in the formula (1) into a reaction kettle under the argon atmosphere]/L * After replacing hydrogen with a solvent B and alkali, carrying out asymmetric hydrogenation reaction at 10-60 ℃ and 1.0-6.0 MPa for 2-24 hours, filtering the reaction liquid by diatomite, and carrying out reduced pressure concentration to recover the solvent B to obtain the (R, E) -4-phenylbutyl-3-ene-2-ol derivative shown in the formula (2);
the preparation process route is represented by the following reaction formula:
Figure BDA0002610075900000031
in the formulas (1) and (2): ar is aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl; wherein the substituent in the substituted aryl or the substituted heterocyclic aryl is halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl or heterocyclic aryl.
The chiral ligand L * As shown in the general formula (I):
Figure BDA0002610075900000032
in the general formula (I): r 1 Is aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl or C1-C6 alkyl, R 2 Is hydrogen, C1-C6 alkyl, aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl; the imidazole group is substituted imidazole or substituted benzimidazole; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl.
The preferred 6 chiral ligands L * The structure is as follows:
Figure BDA0002610075900000041
the solvent A for preparing the catalyst and the solvent B for asymmetric hydrogenation are respectively selected from one or more of dichloromethane, tetrahydrofuran, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol, and the solvents A and B can be the same.
The molar ratio of the catalyst to the (R, E) -4-phenylbutyl-3-en-2-ol derivative is 1.
Further, the temperature of the asymmetric hydrogenation reaction is 40-60 ℃.
Further, the pressure of the hydrogen gas in the asymmetric hydrogenation reaction is 2.0-3.0 Mpa.
The base used in the asymmetric hydrogenation reaction is selected from one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium methoxide, sodium hydroxide and potassium hydroxide.
By adopting the technology, compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel catalytic system [ M ] composed of chiral ferrocene PNN ligand and manganese pentacarbonyl bromide]/L * The method is used for catalyzing asymmetric hydrogenation of (E) -4-phenylbutyl-3-ene-2-ketone derivatives to generate (R, E) -4-phenylbutyl-3-ene-2-alcohol derivatives with high stereoselectivity, the dosage of the catalyst is small and can be reduced to less than ten thousandth, and the method has the characteristics of mild reaction conditions, easily obtained raw materials, simple experimental operation, high catalytic efficiency, capability of obtaining target products with better yield and ee value and the like, and can be used for preparing key cannabidiol drug intermediates.
Detailed Description
The present invention will be described with reference to examples, but the present invention is not limited to these examples.
Example 1: reference (Synlett, 2020,31, 285-289) literature preparation of ligand L1
Figure BDA0002610075900000051
After adding compound 1 (0.41g, 1mmol) and 2 (0.45g, 2mmol) to a reaction flask and displacing nitrogen, 5mL of methanol, naBH 4 (1 mmol) and reacted at 40 ℃ for 0.5 hour. Concentrating, and performing column chromatography to obtain yellow ligand L1 (0.40g, 65%). [ alpha ] to] D 20 ＝+115.0(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.53-7.49(m,2H),7.46-7.43(m,4H),7.35-7.33(m,3H),7.22-7.19(m,2H),7.15-7.11(m,2H),7.07-7.03(m,2H),7.01-6.97(m,1H),6.86(s,1H),4.45(s,1H),4.27(s,1H),4.02-3.98(m,1H),3.96(s,5H),3.79(s,1H),3.59-3.46(m,2H),2.36(s,3H),2.28(s,3H),1.45-1.43(d,J＝6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ152.3,141.2,140.0,139.9,137.9,137.8,136.2,135.3,135.1,134.8,132.6,132.4,131.7,130.9,129.6,129.1,128.3,128.2,128.13,128.1,127.9,126.9,119.7,110.3,98.4,98.2,75.0,71.1,69.7,69.3,69.2,60.5,51.4,51.4,43.5,21.3,21.1,20.5,20.4,14.3. 31 P NMR(162MHz,CDCl 3 )δ-24.27.HRMS(ESI)calcd for C 40 H 39 FeN 3 P[M+H] + :648.2226,found:648.2219.
Example 2: preparation of ligand L2
Figure BDA0002610075900000061
The reaction flask was charged with compound 1 (0.41g, 1mmol) and compound 2 (0.43g, 2mmol), and after replacement of nitrogen, 5mL of ethanol, naBH 4 (1 mmol) and reacted at 60 ℃ for 6 hours. Concentrating, and performing column chromatography to obtain yellow ligand L2 (0.43g, 70%). [ alpha ] of] D 20 ＝+109.0(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.58-7.54(m,2H),7.43(s,1H),7.37-7.35(m,3H),7.29-7.25(m,3H),7.15-7.11(m,2H),7.06-7.02(m,1H),4.51(s,1H),4.47-4.40(m,1H),4.32(s,1H),4.18-4.09(m,1H),3.98(s,5H),3.87(s,1H),3.64-3.53(m,2H),2.35(s,3H),2.33(s,3H),1.48-1.47(d,J＝6.4Hz,3H),1.42-1.37(m,6H),1.27-1.23(m,1H). 13 C NMR(100MHz,CDCl 3 )δ151.8,141.9,140.0,139.9,137.7,137.6,135.1,134.9,132.8,132.6,132.2,130.4,129.9,129.1,128.4,128.3,128.2,128.1,119.9,112.0,98.2,97.9,75.2,75.1,71.2,69.7,69.4,69.2,60.4,51.9,51.8,47.4,44.6,21.3,21.2,20.7,20.2,14.3. 31 P NMR(162MHz,CDCl 3 )δ-25.122.HRMS(ESI)calcd for C 37 H 41 FeN 3 P[M+H] + :614.2382,found:614.2336.
Example 3: preparation of ligand L3
Figure BDA0002610075900000062
The reaction flask was charged with compound 1 (0.41g, 1mmol) and 2 (0.38g, 2mmol), the nitrogen gas was replaced, and then 5mL of methanol, naBH 4 (1 mmol) and reaction at 50 deg.CShould be 3 hours. Concentrating, and performing column chromatography to obtain yellow ligand L3 (0.42g, 72%). [ alpha ] of] D 20 ＝+120.0(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.62-7.57(m,2H),7.47(s,1H),7.42-7.41(s,3H),7.28-7.24(t,J＝7.2Hz,2H),7.19-7.16(m,2H),7.12-7.11(m,1H),6.97(s,1H),4.56(s,1H),4.37-4.36(m,1H),4.23-4.16(m,1H),4.01(s,5H),3.92(s,1H),3.80-3.68(m,2H),3.29(s,3H),2.41-2.39(d,J＝4.8Hz,6H),1.60-1.58(d,J＝6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ151.9,140.6,140.16,140.1,137.4,137.3,134.9,134.8,134.4,132.3,132.1,130.8,130.0,128.9,128.0,127.9,127.8,127.7,119.2,109.0,97.8,97.6,77.2,76.8,76.5,71.0,69.4,69.1,68.9,60.2,51.2,43.6,29.1,20.3,20.0,19.9. 31 P NMR(162MHz,CDCl 3 )δ-24.75.HRMS(ESI)calcd for C 35 H 36 FeN 3 P[M+H] + :586.2069；Found:586.1976.
Example 4: preparation of ligand L4
Figure BDA0002610075900000071
After adding compound 1 (0.41g, 1mmol) and 2 (0.32g, 2mmol) to a reaction flask and replacing nitrogen, 5mL of methanol, naBH 4 (1 mmol) and reacted at 40 ℃ for 4 hours. Concentrating, and performing column chromatography to obtain yellow ligand L4 (0.42g, 75%). [ alpha ] of] D 20 ＝+125.0(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 ):δ7.76(s,1H),7.64(s,2H),7.46(s,3H),7.28(m,5H),7.19(t,J＝6.8Hz,2H),7.11(m,1H),4.61(s,1H),4.42(s,1H),4.31-4.28(m,1H),4.07(s,5H),3.97(s,1H),3.86(d,J＝14.0Hz,1H),3.78(d,J＝14.0Hz,1H)3.38(s,3H),1.66(d,J＝6.8Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ152.6,141.9,139.9,139.8,137.2,137.1,135.7,134.9,134.7,132.2,132.0,128.8,127.8,127.5,121.8,121.3,119.0,108.6,97.5,97.3,74.6,74.6,71.0,69.9,69.3,69.0,68.8,51.0,43.4,29.0,19.8. 31 P NMR(162MHz,CDCl 3 )δ-24.91.HRMS(ESI)calcd for C 33 H 32 FeN 3 P[M+H] + :558.1756,found:558.1668.
Example 5: preparation of ligand L5
Figure BDA0002610075900000081
The reaction flask was charged with compound 1 (0.41g, 1mmol) and 2 (0.40g, 2mmol), the nitrogen gas was replaced, and 5mL of toluene, naBH 4 (1 mmol) and reacted at 0 ℃ for 1 hour. Concentrating, and performing column chromatography to obtain yellow ligand L5 (0.28g, 47%). mp90-92.5 ℃. 1 H NMR(400MHz,CDCl 3 )δ7.56-7.52(m,2H),7.46(s,1H),7.36-7.35(m,3H),7.29-7.21(m,5H),7.01(s,1H),4.45(s,1H),4.28(s,1H),4.13-4.08(m,2H),3.95(s,5H),3.80(s,1H),3.65(s,3H),2.37-2.35(d,J＝7.2Hz,6H),1.21-1.19(d,J＝6.4Hz,3H),0.82-0.80(d,J＝6.8Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ156.7,140.8,140.4,140.3,137.3,137.2,135.2,135.1,135.0,132.7,132.5,131.0,130.3,129.1,128.4,128.4,128.2,128.1,128.0,119.5,109.2,99.0,98.8,74.8,74.7,71.3,71.2,69.7,69.6,69.3,69.2,69.1,52.5,51.7,51.6,30.2,20.6,20.4,20.3,19.9. 31 P NMR(162MHz,CDCl 3 )δ-25.07.HRMS(ESI)calcd for C 36 H 39 FeN 3 P[M+H] + :600.2226,found:600.2209.
Example 6: preparation of ligand L6
Figure BDA0002610075900000091
The reaction flask was charged with compound 1 (0.41g, 1mmol) and 2 (0.53g, 2mmol), the nitrogen gas was replaced, and then 5mL of methanol, naBH 4 (1 mmol) and reacted at 0 ℃ for 0.5 hour. Concentrating, and performing column chromatography to obtain yellow ligand L6 (0.46g, 70%). mp70.5-72.5 deg.C, [ alpha ]] D 20 ＝+121.0(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.52-7.50(m,3H),7.36-7.35(m,3H),7.21-7.07(m,8H),6.98-6.89(m,3H),4.55-4.54(m,1H),4.32-4.30(m,1H),3.93-3.92(m,6H),3.29(s,1H),3.11(s,2H),2.37-2.34(m,9H),1.40-1.36(m,3H). 13 C NMR(100MHz,CDCl 3 )δ153.8,137.8,135.5,135.4,135.3,132.5,132.3,132.1,131.2,130.4,130.3,129.2,128.3,128.2,128.1,128.0,127.7,127.5,127.4,127.3,119.8,117.3,109.3,99.2,98.9,69.7,69.4,60.5,58.9,50.4,49.9,30.0,29.9,21.2,20.6,20.3,14.3. 31 P NMR(162MHz,CDCl 3 )δ-24.27.HRMS(ESI)calcd for C 41 H 40 FeN 3 P[M+H] + :662.2382,found:662.2377.
Example 7 preparation of (E) -4-phenylbutyl-3-en-2-ol 2A
Figure BDA0002610075900000101
(1) Ligand L1 (7.1mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.01mmol), DCM (2 mL) was added under argon and stirred at 0 ℃ for 3h to obtain a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1A (10 mmol), the catalyst solution prepared in step (1) (0.1 mmol), isopropanol (20 mL) and potassium carbonate (0.5 mmol) were added in this order to a reaction vessel, and after replacement of hydrogen, at 60 ℃ and 6MPaH 2 Asymmetric hydrogenation is carried out for 10 hours, reaction liquid is filtered by diatomite, filtrate is decompressed and concentrated to recover solvent, and (R, E) -4-phenylbutyl-3-alkene-2-alcohol 2A shown in formula (2) is prepared, the yield is 99%, and the ee value of the product is 75%. 1 H NMR(400MHz,CDCl 3 )δ7.36-7.34(m,2H),7.30-7.27(m,2H),7.23-7.19(m,1H),6.55-6.51(d,J＝16.0Hz,1H),6.26-6.20(dd,J 1 ＝4.0Hz,J 2 ＝15.6Hz,1H),4.48-4.42(m,1H),2.25-2.22(m,1H),1.35-1.33(d,J＝6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ136.8,133.7,129.3,128.6,128.5,127.6,126.5,68.8,23.4.[α] 20 D ＝+7.6(c＝1.0,CHCl 3 )；The ee was determined by HPLC on Chiralpak OD-H column,hexane:isopropanol＝90:10；flow rate＝0.8mL/min；UV detection at254nm；t R (R)＝14.06min(major),t R (S)＝21.08min(minor).
Example 8 preparation of (E) -4-phenylbutyl-3-en-2-ol 2A
Figure BDA0002610075900000111
(1) The ligand L2 (6.7mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.01mmol), THF (2 mL) was added under an argon atmosphere and stirred at 25 ℃ for 6h to make a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1A, the catalyst solution (0.01 mmol) prepared in step (1), ethanol (20 mL) and sodium tert-butoxide (0.5 mmol) are added in turn to a reaction kettle, and after hydrogen is replaced, the reaction kettle is heated to 40 ℃ and 3MPaH 2 Then, asymmetric hydrogenation reaction is carried out for 3 hours, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, and the (R, E) -4-phenylbutyl-3-alkene-2-alcohol 2A shown in the formula (2) is prepared, the yield is 99 percent, and the ee value of the product is 64 percent.
EXAMPLE 9 preparation of (E) -4-phenylbutyl-3-en-2-ol 2A
Figure BDA0002610075900000112
(1) Ligand L3 (6.4mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) was added under an argon atmosphere and stirred at 60 ℃ for 0.5h to obtain a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1A (10 mmol), the catalyst solution prepared in step (1) (0.001 mmol), methanol (20 mL) and potassium tert-butoxide (0.5 mmol) were added in this order to replace hydrogen, and then the mixture was heated at 40 ℃ and at 3MPaH 2 Asymmetric hydrogenation is carried out for 6 hours, reaction liquid is filtered by diatomite, filtrate is decompressed and concentrated to recover solvent, and (R, E) -4-phenylbutyl-3-alkene-2-alcohol 2A shown in formula (2) is prepared, the yield is 99%, and the ee value of the product is 76%.
EXAMPLE 10 preparation of (E) -4-phenylbutyl-3-en-2-ol 2A
Figure BDA0002610075900000121
(1) Adding into a reaction flaskLigand L4 (6.1mg, 0.011mmol), mn (CO) 5 Br (2.7mg, 0.001mmol), toluene (2 mL) was added under an argon atmosphere and stirred at 40 ℃ for 2h to prepare a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1A (10 mmol), the catalyst solution prepared in step (1) (0.0001 mmol), tetrahydrofuran (20 mL) and sodium methoxide (0.5 mmol) were added in this order to a reaction vessel, hydrogen was replaced, and then the mixture was heated at 40 ℃ and 1MPaH 2 Asymmetric hydrogenation is carried out for 2 hours, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, and the (R, E) -4-phenylbutyl-3-alkene-2-alcohol 2A shown in the formula (2) is prepared, the yield is 99 percent, and the ee value of the product is 68 percent.
Example 11 preparation of (E) -4-phenylbutyl-3-en-2-ol 2A
Figure BDA0002610075900000122
(1) Ligand L5 (6.6 mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) was added under an argon atmosphere and stirred at 30 ℃ for 3h to prepare a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1A (10 mmol), the catalyst solution prepared in step (1) (0.0005 mmol), toluene (20 mL) and sodium tert-butoxide (0.5 mmol) were added in this order to a reaction vessel, hydrogen was replaced, and then the reaction vessel was heated to 30 ℃ and 3MPa H 2 Then carrying out asymmetric hydrogenation reaction for 12 hours, filtering the reaction liquid by diatomite, decompressing and concentrating the filtrate to recover the solvent, and obtaining the (R, E) -4-phenylbutyl-3-ene-2-alcohol 2A shown in the formula (2), wherein the yield is 99 percent, and the ee value of the product is 63 percent.
Example 11 preparation of (E) -4-phenylbutyl-3-en-2-ol 2A
Figure BDA0002610075900000131
(1) Ligand L6 (7.3mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), adding toluene (2 mL) under argon atmosphere, stirring at 40 deg.C for 5h to obtainA catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1A (10 mmol), the catalyst solution prepared in step (1) (0.0002 mmol), isopropanol (20 mL) and lithium tert-butoxide (0.5 mmol) were added in this order to a reaction vessel, the hydrogen was replaced, and the reaction vessel was heated to 50 ℃ and 4MPa H 2 Then, asymmetric hydrogenation reaction is carried out for 16 hours, the reaction liquid is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, and the (R, E) -4-phenylbutyl-3-alkene-2-alcohol 2A shown in the formula (2) is prepared, the yield is 99 percent, and the ee value of the product is 67 percent.
Example 12: preparation of (R, E) -4- (naphthalen-2-yl) butyl-3-en-2-ol 2B
Figure BDA0002610075900000132
(1) Ligand L3 (6.4mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) was added under an argon atmosphere and stirred at 60 ℃ for 0.5h to obtain a catalyst solution.
(2) Under an argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1B (1.96g, 10mmol), the catalyst solution (0.001 mmol) prepared in step (1), isopropanol (20 mL), and potassium carbonate (69.0 mg, 0.5mmol) were added in this order to a reaction vessel, hydrogen gas was replaced, and the reaction vessel was cooled to 40 ℃ and 3MPa H 2 Asymmetric hydrogenation reaction is carried out for 16 hours. After the reaction is finished and hydrogen is released, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, the conversion rate of the filtrate is 99 percent by GC analysis, and the ee value of the reaction product 2B is 85 percent by HPLC analysis. 1 H NMR(400MHz,CDCl 3 )δ7.78-7.75(m,3H),7.70(s,1H),7.58-7.56(m,1H),7.46-7.40(m,2H),6.73-6.69(d,J＝16.0Hz,1H),6.40-6.34(dd,J 1 ＝4.0Hz,J 2 ＝16.0Hz,1H),4.56-4.49(m,1H),1.79-1.76(m,1H),1.41-1.39(d,J＝6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 134.0,133.1,131.2,130.5,129.6,128.3,128.0,127.7,126.4,126.1,123.7,73.8,69.1,23.6. The enantiomeric excess was determined using an HPLC Chiralpak OJ-H chiral column, n-hexane: isopropanol = 99; flow rate =0.8mL/min; UV detection at 254nm; t is t R (S)＝55.43min(minor),t R (R)＝74.88min(major)。
Example 13: preparation of (R, E) -4- (benzofuran-2-yl) butyl-3-en-2-ol 2C
Figure BDA0002610075900000141
(1) Ligand L3 (6.4mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) under argon and stirring at 60 ℃ for 0.5h to make a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1C (1.86g, 10mmol), the catalyst solution (0.001 mmol) prepared in step (1), isopropanol (20 mL), and potassium carbonate (69.0mg, 0.5mmol) were sequentially added to a reaction kettle, hydrogen gas was replaced, and then the mixture was heated at 40 ℃ and 3MPa H 2 Asymmetric hydrogenation reaction is carried out for 16 hours. After the reaction is finished and hydrogen is released, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, the conversion rate of the filtrate is 99 percent by GC analysis, and the ee value of the reaction product 2C is 84 percent by HPLC analysis. 1 H NMR(400MHz,CDCl 3 )δ7.56-7.54(d,J＝16.0Hz,1H),7.49-7.47(d,J＝8.0Hz,1H),7.32-7.30(m,1H),7.26-7.22(m,1H),6.61-6.57(m,3H),4.61-4.55(m,1H),1.82(s,1H),1.45-1.44(d,J＝4.0Hz,3H). 13 C NMR(100MHz,CDCl 3 ) δ 154.8,154.3,135.7,129.0,124.6,122.9,120.9,117.7,111.0,104.8,68.4,23.5 the enantiomeric excess was determined using an HPLC Chiralpak OD-H chiral chromatography column, n-hexane: isopropanol = 90; flow rate =0.8mL/min; UV detection at 254nm; t is t R (S)＝8.62min(minor),t R (R)＝10.06min(major)。
Example 14: preparation of (R, E) -4- (2-chloro-6, 7-dimethylquinolin-3-yl) butyl-3-en-2-ol 2D
Figure BDA0002610075900000151
(1) Ligand L3 (6.4 mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) under argon and under argonStirring for 0.5h at 60 ℃ to prepare a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1D (2.59g, 10mmol), the catalyst solution (0.001 mmol) prepared in step (1), isopropanol (20 mL), and potassium carbonate (69.0mg, 0.5mmol) were sequentially added to a reaction kettle, and after hydrogen gas was replaced, the reaction kettle was purged at 40 ℃ and 3MPa H 2 Asymmetric hydrogenation reaction is carried out for 16 hours. After the reaction is finished and hydrogen is released, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, the conversion rate of the filtrate is 99 percent by GC analysis, and the ee value of the reaction product 2D is 86 percent by HPLC analysis. 1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.52-7.50(d,J＝8.0Hz,1H),7.33-7.31(d,J＝8.0Hz,1H),6.99-6.96(d,J＝16.0Hz,1H),6.36-6.31(dd,J 1 ＝6.0Hz,J 2 ＝16.0Hz,1H)),4.59-4.56(m,1H),2.67(s,3H),2.47(s,3H),1.85-1.75(m,1H),1.44-1.42(d,J＝6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 ) δ 148.9,146.2,138.4,137.7,134.6,133.8,130.1,128.2,125.9,124.9,124.5,68.8,23.4,20.8,13.4 the enantiomeric excess was determined using an HPLC Chiralpak OD-H chiral chromatography column, n-hexane: isopropanol = 90; flow rate =0.8mL/min; UV detection at 254nm; t is t R (R)＝8.34min(major),t R (S)＝8.71min(minor)。
Example 15: preparation of (R, E) -4- (quinolin-3-yl) butyl-3-en-2-ol 2E
Figure BDA0002610075900000161
(1) Ligand L3 (6.4 mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) was added under an argon atmosphere and stirred at 60 ℃ for 0.5h to obtain a catalyst solution.
(2) Under an argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1E (1.97g, 10mmol), the catalyst solution (0.001 mmol) prepared in step (1), isopropanol (20 mL), and potassium carbonate (69.0mg, 0.5mmol) were sequentially added to a reaction kettle, and after hydrogen gas was replaced, the reaction kettle was heated at 40 ℃ and 3MPa H 2 Asymmetric hydrogenation reaction is carried out for 16 hours. After the reaction is finished and hydrogen is released, the reaction liquid is filtered by diatomite,the filtrate was concentrated under reduced pressure to recover the solvent, and the filtrate was analyzed by GC to find that the conversion was 99%, and the reaction product 2E was analyzed by HPLC to find that the ee value was 81%. 1 H NMR(400MHz,CDCl 3 )δ8.06-8.04(d,J＝8.0Hz,1H),7.98-7.96(d,J＝8.0Hz,1H),7.71-7.63(m,2H),7.46-7.43(m,2H),6.93-6.89(d,J＝16.0Hz,1H),6.83-6.78(dd,J 1 ＝5.2Hz,J 2 ＝16.0Hz,1H),4.65-4.58(m,1H),3.84(s,1H),1.43-1.41(d,J＝6.4Hz,3H). 13 C NMR(100MHz,CDCl 3 ) δ 155.8,147.7,140.9,136.4,129.7,129.2,128.8,127.4,127.2,126.2,118.9,68.0,23.2 the enantiomeric excess was determined using an HPLC Chiralpak OD-H chiral chromatography column, n-hexane: isopropanol = 90; flow rate =0.8mL/min; UV detection at 254nm; t is t R (R)＝11.7min(major),t R (S)＝17.3min(minor)。
Example 16: preparation of (R, E) -4- (2, 6-dimethoxy-4-pentylphenyl) but-3-en-2-ol 2F
Figure BDA0002610075900000171
(1) Ligand L3 (6.4 mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) was added under an argon atmosphere and stirred at 60 ℃ for 0.5h to obtain a catalyst solution.
(2) Under argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1F (2.76g, 10mmol), the catalyst solution (0.001 mmol) prepared in step (1), isopropanol (20 mL), and potassium carbonate (69.0mg, 0.5mmol) were sequentially added to a reaction kettle, and after hydrogen gas was replaced, the reaction kettle was heated at 40 ℃ and 3MPa H 2 Asymmetric hydrogenation reaction is carried out for 16 hours. After the reaction is finished and hydrogen is released, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, the conversion rate of the filtrate is 99 percent by GC analysis, and the ee value of the reaction product 2F is 85 percent by HPLC analysis. 1 H NMR(400MHz,CDCl 3 )δ6.85-6.81(d,J＝16.4Hz,1H),6.67-6.61(dd,J 1 ＝7.2Hz,J 2 ＝16.4Hz,1H),6.37(s,2H),4.47-4.40(m,1H),3.84(s,6H),2.58-2.54(m,2H),1.65-1.59(m,4H),1.37-1.33(m,6H),0.91-0.88(t,J＝6.8Hz,3H.). 13 C NMR(100MHz,CDCl 3 )δ158.50,143.87,136.67,120.34,104.30,71.03,55.80,36.77,31.69,31.18,23.58,22.70,14.19 the enantiomeric excess was determined using an HPLC Chiralpak AD-H chiral chromatography column, n-hexane: isopropanol = 85; flow rate =0.8mL/min; UV detection is at 220nm; t is t R (S)＝7.30min(minor),t R (R)＝8.29min(major)。
Examples 17 to 24: preparation of (R, E) -4-phenylbutyl-3-en-2-ol derivative 2G-2N
Figure BDA0002610075900000181
(1) Ligand L3 (6.4mg, 0.011mmol), mn (CO) was added to the reaction flask 5 Br (2.7mg, 0.001mmol), toluene (2 mL) was added under an argon atmosphere and stirred at 60 ℃ for 0.5h to obtain a catalyst solution.
(2) Under an argon atmosphere, (E) -4-phenylbutyl-3-en-2-one 1G-1N (10 mmol), the catalyst solution prepared in step (1) (0.001 mmol), isopropanol (20 mL), and potassium carbonate (69.0 mg,0.5 mmol) were added in this order to a reaction vessel, and after replacement of hydrogen gas, the reaction vessel was evacuated at 40 ℃ and 3MPa H 2 Asymmetric hydrogenation reaction is carried out for 16 hours. After the reaction finishes and releases hydrogen, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated to recover the solvent, and the filtrate is analyzed by GC to obtain the conversion rate and the enantioselectivity.
Figure BDA0002610075900000182
Figure BDA0002610075900000191
The above description is only an embodiment of the present invention, but the technical features of the present invention are not limited thereto, and any changes and modifications within the technical field of the present invention by those skilled in the art are included in the scope of the present invention.

Claims (5)

1. A method for producing a (R, E) -4-phenylbutyl-3-en-2-ol derivative, comprising the steps of:
1) Under the argon atmosphere, manganese pentacarbonyl bromide is reacted with a chiral ligand L * Sequentially adding the mixture into a solvent A, and reacting for 0.5 to 6 hours at the temperature of between 0 and 60 ℃ to prepare a catalyst [ M]/L * ；
2) Under argon atmosphere, sequentially adding (E) -4-phenylbutyl-3-alkene-2-ketone derivative shown in formula (1) and catalyst [ M ] prepared in step 1) into a reaction kettle]/L * After replacing hydrogen, solvent B and alkaline substance carry out asymmetric hydrogenation reaction for 2-24 hours at 10-60 ℃ and 1.0-6.0 MPa, the reaction liquid is filtered by diatomite, and the filtrate is decompressed and concentrated to recover the solvent B, thus obtaining the (R, E) -4-phenylbutyl-3-ene-2-alcohol derivative shown in the formula (2);
the reaction equation is as follows:
Figure FDA0003797216680000011
in formula (1) and formula (2): ar is aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl; wherein the substituent in the substituted aryl or the substituted heterocyclic aryl is halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl or heterocyclic aryl;
the chiral ligand L * The structure comprises the following structures:
Figure FDA0003797216680000021
2. the method for preparing (R, E) -4-phenylbutyl-3-en-2-ol derivative of claim 1, wherein solvent A and solvent B are independently selected from one or more of dichloromethane, tetrahydrofuran, toluene, methanol, ethanol, n-propanol, isopropanol, and tert-butanol.
3. Process for the preparation of (R, E) -4-phenylbutyl-3-en-2-ol derivatives according to claim 1Characterized by the catalyst [ M ] in step 2)]/L * The molar ratio to the substrate (E) -4-phenylbutyl-3-en-2-one derivative is 1.
4. The process for producing (R, E) -4-phenylbutyl-3-en-2-ol derivative according to claim 1, characterized in that the asymmetric hydrogenation in step 2) is carried out at a temperature of 40 ℃ to 60 ℃; the hydrogen pressure is 2.0-3.0 MPa; the reaction time is 10 to 16 hours.
5. The method for preparing a (R, E) -4-phenylbutyl-3-en-2-ol derivative as set forth in claim 1, wherein the basic substance in step 2) is one selected from the group consisting of potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium methoxide, sodium hydroxide, and potassium hydroxide.
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