Novel quinine fragment-containing chiral polydentate ligand as well as preparation method and application thereof

Abstract

The invention relates to a novel quinine fragment-containing chiral polydentate ligand and a preparation method and application thereof, based on the ligand provided by the invention, a pyridine oxazoline unit is coordinated with a transition metal, a chiral environment is provided by chiral oxazole and a chiral quinine fragment, and weak hydrogen bond interaction with a substrate is generated, so that the chiral polydentate ligand is obtained. Therefore, the reaction selectivity is better controlled, and the problem of poor enantioselectivity in the transition metal catalytic reaction in the prior art is solved.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a novel chiral multidentate ligand containing a quinine fragment, a preparation method and an application thereof. Background Art

[0002] Nitrogen-containing chiral ligands are a tool for creating chiral molecules, and their importance in the field of chiral synthesis is self-evident. Every innovation in the field of asymmetric catalysis is almost inseparable from the emergence of important ligands / catalysts. At present, the ligands commonly used in transition metal catalysis mainly include chiral bisphosphine-type ligands, BINOL-type ligands, bisoxazoline-type ligands, and so on. As an important type of chiral ligand, oxazoline ligands have shown control over the enantioselectivity of reactions in Lewis acid-catalyzed and transition metal-catalyzed reactions. However, with the rapid development of the field of organic chemistry, this type of traditional ligand has been difficult to meet the requirements of modern reactions for enantioselectivity. Therefore, it is of great significance to develop new ligands to assist in the catalytic asymmetric synthesis of chiral molecules.

[0003] Summary of the invention

[0004] The technical problem solved by the present invention is to provide a novel chiral multidentate ligand containing quinine fragments and a preparation method and application thereof, so as to solve the problem of poor enantioselectivity in transition metal catalytic reactions in the prior art.

[0005] The specific solutions provided by the present invention are as follows:

[0006] The present invention provides a novel chiral multidentate ligand containing a quinine fragment, the structure of which is shown in Formula L:

[0007]

[0008] Wherein, R is selected from one of isopropyl and benzyl.

[0009] The ligand of the present invention coordinates with the transition metal through the pyridine oxazoline unit, provides a chiral environment through the chiral oxazole and chiral quinine fragments, and generates a weak hydrogen bond interaction with the substrate, thereby better controlling the reaction selectivity.

[0010] The present invention also provides a method for preparing a novel chiral multidentate ligand containing a quinine fragment, comprising the following steps:

[0011] In an inert gas atmosphere, NaH is washed with n-hexane, and after washing, the n-hexane is removed, an anhydrous organic solvent and quinine are added to NaH, and the reaction is stirred for 0.5 to 2 hours, and then the pyridine oxazoline shown in formula S is added, and the reaction is stirred at 60 to 70° C. for 4 to 6 hours to react to generate a novel chiral multidentate ligand containing quinine fragments shown in formula L, wherein the organic solvent is tetrahydrofuran or dimethyl sulfoxide;

[0012]

[0013] Wherein, R is selected from one of isopropyl and benzyl.

[0014] According to the preparation method of the novel chiral multidentate ligand of the present invention, pyridine oxazoline S and quinine are used as raw materials, washed NaH is used as a base, and a chiral multidentate ligand L containing pyridine oxazoline S and quinine fragments is obtained by reaction in tetrahydrofuran solvent under anaerobic conditions, and almost no diastereomers are generated.

[0015] On the basis of the above scheme, the present invention can also be improved as follows:

[0016] Furthermore, the washing of NaH with n-hexane comprises: adding n-hexane to NaH, heating to 40-60° C., stirring for 0.5-2 min, then removing the n-hexane, and repeating the washing operation several times.

[0017] Furthermore, the process of removing n-hexane includes: standing still after the stirring is completed, and after the NaH solid is completely precipitated, sucking out the n-hexane with a straw, switching the double-row tube, and then draining the n-hexane with a pump.

[0018] Experiments show that the sodium hydride cleaning process is crucial for generating the chiral ligands of the present invention. By using n-hexane as a cleaning agent, washing the oil on the surface of the sodium hydride under heating and stirring, and fully removing the n-hexane, the chiral ligands L1, L2 and L3 of the present invention can be obtained, avoiding the generation of diastereomers of the target product L (i.e., chiral racemization at oxygen α position 1), and obtaining a higher yield.

[0019] Furthermore, the ratio of the amounts of NaH, quinine and the pyridine oxazoline represented by the formula S is (2-4):1:(1-2).

[0020] Furthermore, the reaction was carried out in a Schlenk flask, and the Schlenk flask was evacuated to remove water before the reaction.

[0021] Furthermore, after the reaction is completed, distilled water is slowly added to the system until no bubbles appear, and then extracted with DCM for 2 to 4 times, the organic phases are combined, and the organic phase is extracted once with saturated brine, and an appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution for drying, and the filtrate is mixed with silica gel and spin-dried, and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (15 to 25):1 is first used as the first eluent to separate the pyridine oxazoline S, and then a mixed solvent of dichloromethane and methanol in a volume ratio of (15 to 20):1 is used as the second eluent to separate the novel chiral multidentate ligand L containing a quinine fragment.

[0022] Furthermore, the pyridine oxazoline represented by formula S is prepared from amino alcohol and cyanopyridine as raw materials.

[0023] Thus, a new class of multidentate ligands can be obtained by two simple steps starting from commercially available quinine, cyanopyridine and amino alcohols.

[0024] The application of the novel chiral multidentate ligand containing quinine fragment as a catalyst ligand in the metal-catalyzed synthesis of chiral allenes has high yield and enantioselectivity.

[0025] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 For the chiral multidentate ligand L1 1 H NMR image and partial enlargement (upper right corner).

[0027] Figure 2 For the chiral multidentate ligand L1 13 C NMR spectrum.

[0028] Figure 3 For the chiral multidentate ligand L2 1 H NMR image and partial enlargement (upper right corner).

[0029] Figure 4 For the chiral multidentate ligand L2 13 C NMR spectrum.

[0030] Figure 5 For the chiral multidentate ligand L3 1 H NMR image and partial enlargement (upper right corner).

[0031] Figure 6 For the chiral multidentate ligand L3 13 C NMR spectrum.

[0032] Figure 7 For chiral allene 3a1 H NMR spectra.

[0033] Figure 8 For chiral allene 3a 13 C NMR spectrum.

[0034] Fig. 9 This is the chiral HPLC spectrum of the chiral allene 3a racemate.

[0035] Fig.10 This is the chiral HPLC spectrum of the chiral allene 3a prepared in Example 5. DETAILED DESCRIPTION

[0036] Embodiments of the present invention are described in detail below. The embodiments described below are exemplary and intended to be used to explain the present invention, but should not be construed as limiting the present invention.

[0037] The novel chiral multidentate ligand containing quinine fragment according to the present invention has a structure as shown in Formula L:

[0038]

[0039] Wherein, R is selected from one of isopropyl and benzyl.

[0040] The ligand of the present invention coordinates with the transition metal through the pyridine oxazoline unit, provides a chiral environment through the chiral oxazole and chiral quinine fragments, and generates a weak hydrogen bond interaction with the substrate, thereby better controlling the reaction selectivity.

[0041] Specifically, the structure L is selected from one of the following structures:

[0042]

[0043] L1:(4R)-4-benzyl-2-(6-((1R)-(6-methoxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methoxy)pyridin-2-yl)-4,5-dihydrooxazole;

[0044] L2:(4R)-4-isopropyl-2-(6-((1R)-(6-methoxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methoxy)pyridin-2-yl)-4,5-dihydrooxazole;

[0045] L3:(4S)-4-benzyl-2-(6-((1R)-(6-methoxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methoxy)pyridin-2-yl)-4,5-dihydrooxazole;

[0046] The preparation method of the novel chiral multidentate ligand containing quinine fragments according to the present invention comprises the following steps:

[0047] In an inert gas atmosphere, NaH is washed with n-hexane, and after washing, the n-hexane is removed, an anhydrous organic solvent and quinine are added to NaH, and the reaction is stirred for 0.5 to 2 hours, and then the pyridine oxazoline shown in formula S is added, and the reaction is stirred at 60 to 70° C. for 4 to 6 hours to react to generate a novel chiral multidentate ligand containing quinine fragments shown in formula L, wherein the organic solvent is tetrahydrofuran or dimethyl sulfoxide;

[0048]

[0049] Wherein, R is selected from one of isopropyl and benzyl.

[0050] According to the preparation method of the novel chiral multidentate ligand according to the embodiment of the present invention, pyridine oxazoline S and quinine are used as raw materials, and washed NaH is used as a base to react in tetrahydrofuran solvent under anaerobic conditions to obtain a chiral multidentate ligand L containing pyridine oxazoline S and quinine fragments, with almost no generation of diastereomers.

[0051] According to the preparation method of the novel chiral multidentate ligand containing quinine fragments according to the embodiment of the present invention, the washing of NaH with n-hexane comprises: adding n-hexane to NaH, heating to 40-60° C., stirring for 0.5-2 min, then removing the n-hexane, and repeating the washing operation several times.

[0052] According to the preparation method of the novel chiral multidentate ligand containing quinine fragments according to the embodiment of the present invention, the process of removing n-hexane includes: standing after stirring, and after the NaH solid is completely precipitated, sucking out the n-hexane with a straw, switching the double-row tube, and then draining the n-hexane with a pump. Experiments show that the sodium hydride cleaning process is crucial for the generation of the chiral ligands in the present invention. Using n-hexane as a cleaning agent, washing the oil on the surface of sodium hydride under heating and stirring, and fully removing the n-hexane, the chiral ligands L1, L2 and L3 in the present invention can be obtained, avoiding the production of diastereomers of the target product L (i.e., chiral racemization of oxygen α position 1), and a higher yield can be obtained.

[0053] According to the method for preparing the novel chiral multidentate ligand containing quinine fragments according to the embodiment of the present invention, the washing times are 3 to 4 times.

[0054] In the method for preparing a novel chiral multidentate ligand containing quinine fragments according to an embodiment of the present invention, the molar ratio of the NaH, quinine and the pyridine oxazoline represented by the formula S is (2-4):1:(1-2).

[0055] According to the method for preparing the novel chiral multidentate ligand containing quinine fragments according to the embodiment of the present invention, the reaction is carried out in a Schlenk flask, and the Schlenk flask is evacuated to remove water before the reaction.

[0056] Preferably, the pumping is performed three or more times to remove moisture.

[0057] The preparation method of the novel chiral multidentate ligand containing quinine fragment based on the embodiment of the present invention is as follows: after the reaction is completed, distilled water is slowly added to the system until no bubbles appear, then extracted with DCM 2 to 4 times, the organic phases are combined, the organic phase is extracted once with saturated brine, an appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution for drying, suction filtration, the filtrate is mixed with silica gel and spin-dried, firstly a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (15 to 25):1 is used as the first eluent to separate pyridine oxazoline S, and then a mixed solvent of dichloromethane and methanol in a volume ratio of (15 to 20:1 is used as the second eluent to separate the novel chiral multidentate ligand L containing quinine fragment.

[0058] According to the preparation method of the novel chiral multidentate ligand containing quinine fragments in the embodiment of the present invention, the pyridine oxazoline shown in formula S is prepared from amino alcohol and cyanopyridine as raw materials. Thus, the chiral multidentate ligand of the present invention can be obtained by two simple steps from commercially available quinine, cyanopyridine and amino alcohol.

[0059] Preferably, under the protection of argon, add dry anhydrous zinc chloride, chlorobenzene, 6-bromo-2-cyanopyridine, and L-phenylalaninol, stir and reflux at 130-140° C., after the reaction is completed, cool to room temperature, the solution after the reaction is dried by a rotary evaporator, dissolved in ethyl acetate, washed three times with distilled water, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, an appropriate amount of anhydrous sodium sulfate is added thereto, dried, filtered, an appropriate amount of silica gel is added to the filtrate, and dried, and purified by petroleum ether and ethyl acetate column chromatography to obtain the pyridine oxazoline shown in formula S.

[0060] The application of the novel chiral multidentate ligand containing quinine fragment as a catalyst ligand in the metal-catalyzed synthesis of chiral allenes has high yield and enantioselectivity.

[0061] Example 1

[0062] Synthesis route of chiral multidentate ligand L1:

[0063]

[0064] (1) Preparation of pyridine oxazoline S1: A reflux reaction apparatus was built using a 100 mL three-necked flask, a spherical condenser and other instruments, and the water was removed by pumping at least three times. Under the protection of argon, dry anhydrous zinc chloride (0.408 g, 3 mmol), 60 mL of chlorobenzene, 6-bromo-2-cyanopyridine (3.66 g, 20 mmol), and L-phenylalaninol (4.54 g, 30 mmol) were added to the reaction apparatus, and the mixture was stirred and refluxed at 135°C for 48 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was dried by rotary evaporation. The residue was dissolved in ethyl acetate and washed three times with distilled water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and dried by adding an appropriate amount of anhydrous sodium sulfate. The mixture was filtered, and an appropriate amount of silica gel was added to the filtrate for drying, and a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 was used as an eluent for column chromatography purification to obtain a white product S1 (2.61 g, 41% yield).

[0065] (2) Pump and fill a 20 mL Schlenk bottle at least three times to remove moisture. Add NaH mineral oil dispersion (60%) (0.36 g, 9 mmol) under the protection of argon, then drop 1 mL of n-hexane, heat to 50°C, continue stirring for 1 min, stop stirring, wait until the solid in the bottle is completely precipitated, suck out the n-hexane with a pipette, switch the double-row tube, use a pump to drain the n-hexane, and repeat the cleaning operation 3 times. Then turn on the stirring, add dry tetrahydrofuran (7.8 mL) to the system with a syringe, add quinine (1.0 g, 3 mmol), and stir the reaction for 1 hour. Under the protection of argon, add S1 (1.43 g, 4.5 mmol) to the system, and continue stirring at 66°C for 5 hours.

[0066] (3) After the reaction is completed, the system is cooled to room temperature and distilled water is slowly added to the system until no bubbles appear. The system is extracted three times with DCM, and the organic phases are combined. The organic phase is extracted once with saturated brine, and an appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution for drying. The filtrate is filtered by suction, and the filtrate is mixed with silica gel and spin-dried. The pyridine oxazoline S is separated using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 as the first eluent, and then a mixed solvent of dichloromethane and methanol in a volume ratio of 20:1 is used as the second eluent for elution to obtain a white solid product L1 (1.45 g, 84% yield).

[0067] Structural characterization data of L1:

[0068] 1H NMR (400MHz, CDCl3) δ = 8.69 (d, J = 4.5Hz, 1H), 7.97 (d, J = 9.2Hz, 1H), 7.71 (d, J = 2.7Hz, 1H), 7.62 (t, J = 7.8 Hz,1H),7.57–7.48(m,2H),7.34(dd,J=9.2,2.6Hz,1H),7.25–7.15(m,5H),6.92(d,J=8.2Hz,1H),5.88–5. 79(m,1H),5.09–4.92(m,2H),4.59–4.51(m,1H),4.23(t,J=9.0Hz,1H),4.09(t,J=8.1Hz,1H),4.03(s,3H) ,3.40(dd,J=11.6,4.1Hz,1H),3.35–3.02(m,3H),2.69(dd,J=13.7,8.8Hz,4H),2.31(s,1H),1.88(s,4H).

[0069] 13 C NMR (101MHz, CDCl3) δ = 162.8, 162.0, 157.8, 147.3, 144.9, 144.5, 144.0, 141.7, 139.4, 137.5, 131.4, 129.2, 128.4, 127. 3,126.5,121.9,118.9,117.9,114.4,113.6,101.9,74.3,71.9,67.6,60.0,56.7,55.9,42.7,41.3,39.7,27.6,23.5.[α] D 25 =21.53 (c = 0.75 in CHCl3).

[0070] Example 2

[0071] Synthesis route of chiral multidentate ligand L2:

[0072]

[0073] (1) Preparation of pyridine oxazoline S2: A reflux reaction apparatus was built using a 100 mL three-necked flask, a spherical condenser and other instruments, and the water was removed by pumping at least three times. Under the protection of argon, dry zinc chloride (0.408 g, 3 mmol), 60 mL of chlorobenzene, 6-bromo-2-cyanopyridine (3.66 g, 20 mmol), and L-leucine alcohol (3.1 g, 30 mmol) were added to the reaction apparatus, and the mixture was stirred and refluxed at 135°C for 48 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was dried by rotary evaporation. The residue was dissolved in ethyl acetate and washed three times with distilled water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and dried by adding an appropriate amount of anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was mixed with silica gel and dried, and a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 was used as an eluent for column chromatography purification to obtain a white product S2 (2.12 g, 39% yield).

[0074] (2) Pump and fill a 20 mL Shrek bottle at least three times to remove moisture. Add NaH mineral oil dispersion (60%) (0.36 g, 9 mmol) under the protection of argon. Then drop 1 mL of n-hexane, heat to 50°C, continue stirring for 1 min, stop stirring, wait until the solid in the bottle is completely precipitated, suck out the n-hexane with a pipette, switch the double-row tube, use a pump to drain the n-hexane, and repeat the cleaning operation 3 times. Then turn on the stirring, add dry tetrahydrofuran (7.8 mL) to the system with a syringe, add quinine (1.0 g, 3 mmol), and stir the reaction for 1 hour. Under the protection of argon, add S2 (1.2 g, 4.5 mmol) to the system and continue stirring at 66°C for 5 hours.

[0075] (3) After the reaction is completed, the system is cooled to room temperature and distilled water is slowly added to the system until no bubbles appear. The system is extracted three times with DCM, and the organic phases are combined. The organic phase is extracted once with saturated brine, and an appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution for drying. The filtrate is filtered by suction, and the filtrate is mixed with silica gel and spin-dried. The pyridine oxazoline S is separated using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 as the first eluent, and then eluted using a mixed solvent of dichloromethane and methanol in a volume ratio of 20:1 as the second eluent to obtain a white solid product L2 (1.19 g, 77% yield).

[0076] Structural characterization data of L2:

[0077] 1H NMR (400MHz, CDCl3) δ = 8.69 (t, J = 3.3Hz, 1H), 7.98 (dd, J = 9.3, 2.6Hz, 1H), 7.70 (d, J = 2.7Hz, 1H), 7.61 (t, J = 7.4Hz, 1H), 7.53 (t,J=5.0Hz,2H),7.41–7.32(m,1H),7.27(d,J=5.3Hz,1H),6.92(dd,J=8.4,2.7Hz,1H),5.81(dt,J=17.7,8.8Hz,1H),5.07– 4.91(m,2H),4.32(q,J=7.9,6.2Hz,1H),4.14–3.99(m,5H),3.48–3.36(m,1H),3.24(s,1H),3.09(td,J=11.9,9.9,3.5Hz,1H ),2.74–2.58(m,2H),2.31(d,J=9.8Hz,1H),1.84(d,J=9.8Hz,5H),1.53(s,1H),0.99(t,J=5.0Hz,3H),0.89(t,J=5.0Hz,3H).

[0078] 13 C NMR(101MHz, CDCl3)δ=162.1,161.9,157.7,147.2,144.8,144.4,144.1,141.6,139.4,131.3,127.2,121.9,118 .9,117.7,114.4,113.4,101.7,74.4,72.5,70.4,59.8,56.7,55.9,42.6,39.7,32.7,27.6,23.3,18.8,18.2.[α] D 25 =15.60 (c = 0.75inCHCl3).

[0079] Example 3

[0080] Synthesis route of chiral multidentate ligand L3:

[0081]

[0082] (1) Preparation of pyridine oxazoline S3: A 100 mL three-necked flask, a spherical condenser and other instruments were used to build a reflux reaction apparatus, and the reaction was evacuated at least three times to remove moisture. Under the protection of argon, dry zinc chloride (0.408 g, 3 mmol), 60 mL of chlorobenzene, 6-bromo-2-cyanopyridine (3.66 g, 20 mmol), and D-phenylalaninol (4.54 g, 30 mmol) were added to the reaction apparatus, and the mixture was stirred and refluxed at 135°C for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was dried by rotary evaporation. The residue was dissolved in ethyl acetate and washed three times with distilled water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and dried by adding an appropriate amount of anhydrous sodium sulfate. The filtrate was filtered, the filtrate was mixed with silica gel and dried, and the mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 was used as an eluent for column chromatography purification to obtain a white product S3 (2.52 g, 40% yield).

[0083] (2) Pump and fill a 20 mL Shrek bottle at least three times to remove moisture. Add a mineral oil dispersion of NaH (60%) (0.36 g, 9 mmol) under the protection of argon. Then drop 1 mL of n-hexane, heat to 50°C, continue stirring for 1 min, stop stirring, wait until the solid in the bottle is completely precipitated, suck out the n-hexane with a pipette, switch the double-row tube, use a pump to drain the n-hexane, and repeat the cleaning operation 3 times. Then turn on the stirring, add dry tetrahydrofuran (7.8 mL) to the system with a syringe, add quinine (1.0 g, 3 mmol), and stir the reaction for 1 hour. Under the protection of argon, add S3 (1.43 g, 4.5 mmol) to the system, and continue stirring at 66°C for 5 hours.

[0084] (3) After the reaction is completed, the system is cooled to room temperature and distilled water is slowly added to the system until no bubbles appear. The system is extracted three times with DCM, and the organic phases are combined. The organic phase is extracted once with saturated brine, and an appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution for drying. The filtrate is filtered, and the filtrate is mixed with silica gel and spin-dried. The pyridine oxazoline S is separated using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 as the first eluent, and then a mixed solvent of dichloromethane and methanol in a volume ratio of 20:1 is used as the second eluent for elution to obtain a white solid product L3 (1.52 g, 86% yield).

[0085] Structural characterization data of L3:

[0086] 1H NMR (400MHz, CDCl3) δ=8.70(d,J=4.5Hz,1H),7.99(d,J=9.2Hz,1H),7.69(d,J=2.7Hz,1H),7.64–7.54(m,2H),7.51(d,J=4.5H z,1H),7.36(dd,J=9.2,2.6Hz,1H),7.28(d,J=7.3Hz,2H),7.21(d,J=7.5Hz,3H),7.14(d,J=6.3Hz,1H),6.89(d,J=7.8Hz,1H), 5.89–5.81(m,1H),5.06–4.95(m,2H),4.57–4.49(m,1H),4.31(t,J=9.0Hz,1H),4.00(d,J=12.1Hz,4H),3.44(q,J=7.8Hz,1H) ,3.27(s,1H),3.18(dd,J=13.8,5.2Hz,1H),3.08(dd,J=13.8,10.1Hz,1H),2.75–2.62(m,3H),2.30(s,1H),1.99–1.73(m,4H).

[0087] 13 C NMR (101MHz, CDCl3) δ = 162.9, 162.1, 157.7, 147.4, 144.6, 144.2 141.7,139.4,137.8,131.4,129.1,128.5,127.5,126.5,121.8,119.0,117.9,114.4,1 13.4,102.0,74.2,72.1,67.9,60.1,56.7,55.7,53.4,42.7,41.6,39.8,27.6,23.9.[α] D 25 =33.80 (c = 0.75 in CHCl3).

[0088] Example 4

[0089] The same as Example 1, except that dimethyl sulfoxide (DMSO) was used instead of tetrahydrofuran (THF), to obtain a white solid product L1 (0.83 g, 48% yield).

[0090] The synthesis route of chiral allene 3a is shown in the following reaction formula:

[0091]

[0092] Example 5

[0093] The application of ligand LI as a catalyst ligand in the copper-catalyzed chiral synthesis of allene 3a is as follows:

[0094] A 10 mL Schlenk reaction tube was evacuated three times under argon protection and placed in a glove box. Copper tetrafluoroborate tetraacetonitrile (3.15 mg, 0.01 mmol), chiral ligand L1 (6.73 mg, 0.012 mmol) and anhydrous tetrahydrofuran (0.5 mL) were added to the reaction tube in the glove box, and the mixture was stirred at room temperature for half an hour and then taken out.

[0095] Under argon conditions, propargyl ester substrate 1a (0.2mmol), fac-Ir(ppy)3 (2.0mg, 0.003mmol), and anhydrous N,N-dimethylformamide (1.5mL) were added to the reaction tube, and the reaction system was deoxygenated three times under liquid nitrogen low temperature conditions. Then trimethylsilyl cyanide (75μL, 0.6mmol) was added to the reaction system, and it was placed under 2 3W purple lamps and stirred for 24 hours. After adding silica gel to the reaction system, it was spin-dried and separated by column chromatography to obtain a colorless liquid product chiral allene 3a (column chromatography used silica gel column, petroleum ether and ethyl acetate mixed solvent as eluent, petroleum ether / ethyl acetate (v / v) = 100:1), with a yield of 67% and an ee value of 36%.

[0096] The structural characterization data of chiral allene 3a are as follows:

[0097] 1 H NMR (400MHz, CDCl3) δ=7.39–7.25(m,5H),6.59(t,J=2.9Hz,1H),2.36–2.31(m,2H),1.65–1.53(m,2H),1.48–1.34(m,2H),0.93(t,J=7.3Hz,3H).

[0098] 13 C NMR (100MHz, CDCl3) δ = 213.2, 130.7, 129.0, 128.7, 127.7, 114.9, 99.6, 86.2, 31.3, 29.6, 21.8, 13.6.HRMS (APCI) for C 14 H 15 N[M] + :calcd 197.1199,found 197.1196.IRν max / cm -1 (in CHCl3):2958;2924;2219;1944;1600;1495;1367;829;750;692.[α] D25 =-21.52 (c=0.51in CHCl3).Ee value was determined by HPLC analysis (Chiralpak AS-H column, hexane / i-PrOH, 97:3v / v, flow rate 0.5mL / min, λ=254nm, 25℃), tR(major)=13.312min, tR(minor)=15.457min.

[0099] Fig. 9 This is the chiral HPLC spectrum of the chiral allene 3a racemate (rac-3a). Fig.10 This is the chiral HPLC spectrum of the chiral allene 3a prepared in Example 5. The ligand of the present invention as a catalyst ligand enables copper-catalyzed synthesis of chiral allenes to have higher enantiomeric selectivity.

[0100]

[0101] Example 6

[0102] The application of L2 as a catalyst ligand in the copper-catalyzed chiral synthesis of allene 3a, the specific steps are the same as Example 5.

[0103] Example 7

[0104] The application of L3 as a catalyst ligand in the copper-catalyzed chiral synthesis of allene 3a, the specific steps are the same as Example 5.

[0105] Comparative Example 1

[0106] The commonly used ligand Bn-Pybox is used as a catalyst ligand in the copper-catalyzed chiral synthesis of allene 3a. The specific steps are the same as those in Example 5.

[0107]

[0108] Comparative Example 2

[0109] The same as Example 1, except that in step (2), no cleaning operation is performed on NaH, and no target product is generated after the reaction is completed.

[0110] Comparative Example 3

[0111] The same as Example 1, except that in step (2), toluene is used to replace tetrahydrofuran, and no target product is generated after the reaction is completed.

[0112] Comparative Example 4

[0113] The same as Example 1, except that tetrahydrofuran is replaced by n-hexane in step (2), and no target product is generated after the reaction is completed.

[0114] Comparative Example 5

[0115] The same as Example 1, except that tetrahydrofuran is replaced by ether in step (2), and no target product is generated after the reaction is completed.

[0116] The yields and ee values ​​of chiral allene 3a synthesized in Examples 5-7 and Comparative Example 1 are shown in Table 1:

[0117] Table 1. Yield and ee value of chiral allene 3a

[0118] Ligand Yield (%) ee value Example 5 L1 67％ 36％ Example 6 L2 60％ 20％ Example 7 L3 62％ 38％ Comparative Example 1 Bn-Pybox 43％ 10％

[0119] As can be seen from Table 1, based on the method of the present invention, a chiral multidentate ligand containing a pyridine oxazoline unit and a quinine fragment can be prepared, and the chiral multidentate ligand has a high yield and a high enantioselectivity in the catalytic synthesis of chiral allene 3a. The pyridine oxazoline compounds in the prior art, such as the compound Bn-Pybox, mainly rely on steric hindrance to regulate stereoselectivity. Based on the chiral multidentate ligand of the present invention, while providing a chiral environment through chiral oxazole and chiral quinine fragments, the oxygen α position 1 and the nitrogen alpha position 2 on the quinine fragment have a certain acidity, which is easy to produce a weak hydrogen bond interaction with the intermediate product generated by the chiral allene, and better stabilize the chiral configuration, thereby obtaining a higher enantioselectivity.

[0120] Although the embodiments of the present invention have been described in detail above, those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims

1. A novel chiral multidentate ligand containing quinine fragment, characterized in that: The structure is shown in formula L: Wherein, R is selected from one of isopropyl and benzyl.

2. The novel chiral multidentate ligand containing quinine fragment according to claim 1, characterized in that: The steps include: In an inert gas atmosphere, NaH is washed with n-hexane, and after washing, the n-hexane is removed, an anhydrous organic solvent and quinine are added to NaH, and the reaction is stirred for 0.5 to 2 hours, and then the pyridine oxazoline shown in formula S is added, and the reaction is stirred at 60 to 70° C. for 4 to 6 hours to react to generate a novel chiral multidentate ligand containing quinine fragments shown in formula L, wherein the organic solvent is tetrahydrofuran or dimethyl sulfoxide; Wherein, R is selected from one of isopropyl and benzyl.

3. The novel chiral multidentate ligand containing quinine fragment according to claim 2, characterized in that: The washing of NaH with n-hexane comprises: adding n-hexane to NaH, heating to 40-60° C., stirring for 0.5-2 min, then removing the n-hexane, and repeating the washing operation several times.

4. The novel chiral multidentate ligand containing quinine fragment according to claim 3, characterized in that: The process of removing the n-hexane comprises: standing still after the stirring is completed, and after the NaH solid is completely precipitated, sucking out the n-hexane with a straw, switching the double-row tube, and then draining the n-hexane with a pump.

5. The novel chiral multidentate ligand containing quinine fragment according to claim 2, characterized in that: The organic solvent is tetrahydrofuran.

6. The novel chiral multidentate ligand containing quinine fragment according to claim 2, characterized in that: The molar ratio of the NaH, quinine and the pyridine oxazoline represented by the formula S is (2-4):1:(1-2).

7. The novel chiral multidentate ligand containing quinine fragment according to claim 2, characterized in that: The reaction was carried out in a Schlenk flask, which was evacuated to remove water before the reaction.

8. The novel chiral multidentate ligand containing quinine fragment according to claim 2, characterized in that: After the reaction is completed, distilled water is slowly added to the system until no bubbles appear, then extracted with DCM for 2 to 4 times, the organic phases are combined, and the organic phase is extracted once with saturated brine, and an appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution for drying, and the solution is filtered with suction, and the filtrate is mixed with silica gel and spin-dried, and the pyridine oxazoline S is first separated using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (15 to 25):1 as the first eluent, and then a mixed solvent of dichloromethane and methanol in a volume ratio of (15 to 20):1 is used as the second eluent to separate the novel chiral multidentate ligand L containing a quinine fragment.

9. The novel chiral multidentate ligand containing quinine fragment according to claim 2, characterized in that: The pyridine oxazoline shown in formula S is prepared from amino alcohol and cyanopyridine as raw materials.

10. Use of the novel chiral multidentate ligand containing quinine fragment as claimed in claim 1 as a catalyst ligand in metal-catalyzed synthesis of chiral allenes.

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