A novel chiral polydentate ligand containing a quinine fragment, its preparation method and use

Abstract

The present application relates to a kind of novel chiral polydentate ligand containing quinine fragment and its preparation method and application, based on the ligand of the present application, by pyridine oxazoline unit and transition metal are coordinated, by chiral oxazoles and chiral quinine fragment provide chiral environment and by with substrate weak hydrogen bond interaction, to better control the selectivity of reaction, to solve the problem of poor enantioselectivity in the transition metal catalyzed reaction in the prior art.

Description

Technical Field

[0001] The present 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, etc. As an important class of chiral ligands, 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 a quinine fragment 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] Under an inert gas atmosphere, NaH is washed with n-hexane. After washing, the n-hexane is removed, and an anhydrous organic solvent and quinine are added to the NaH, and the reaction is stirred for 0.5 to 2 hours. Then, a pyridine oxazoline represented by formula S is added, and the reaction is stirred at 60 to 70° C. for 4 to 6 hours to react to produce a novel chiral multidentate ligand containing a quinine fragment represented by 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, 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 diastereomers 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 minutes, 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 pipette, switching the double-row tube, and then draining the n-hexane with a pump.

[0018] Experiments have shown that the sodium hydride cleaning process is crucial for the production of the chiral ligands of the present invention. Using n-hexane as a cleaning agent, the oil on the surface of the sodium hydride is cleaned under heating and stirring, and the n-hexane is fully removed to obtain the chiral ligands L1, L2, and L3 of the present invention, avoiding the production of diastereomers of the target product L (i.e., chiral racemization at the oxygen α position 1) and achieving a higher yield.

[0019] Furthermore, the molar ratio of the 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 the system is extracted with DCM 2 to 4 times. The organic phases are combined, and 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, and the solution is filtered with suction. The filtrate is mixed with silica gel and spin-dried. 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 through 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 set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 For the chiral multidentate ligand L1 1 H NMR spectrum and local magnification (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 spectrum and local magnification (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 spectrum and local magnification (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 spectrum.

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

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

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

[0036] The 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 understood as limiting the present invention.

[0037] The novel chiral multidentate ligand containing quinine fragments 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] Under an inert gas atmosphere, NaH is washed with n-hexane. After washing, the n-hexane is removed, and an anhydrous organic solvent and quinine are added to the NaH, and the reaction is stirred for 0.5 to 2 hours. Then, a pyridine oxazoline represented by formula S is added, and the reaction is stirred at 60 to 70° C. for 4 to 6 hours to react to produce a novel chiral multidentate ligand containing a quinine fragment represented by 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 diastereomer formation.

[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 minutes, then removing the n-hexane, and repeating the washing operation several times.

[0052] The method for preparing a novel chiral multidentate ligand containing a quinine fragment according to an embodiment of the present invention comprises the following steps: after stirring, the mixture is allowed to stand for a period of time, and after the NaH solid has completely precipitated, the n-hexane is aspirated with a pipette, the double-row pipe is switched, and then the n-hexane is pumped out. Experiments have shown that the sodium hydride cleaning process is crucial for generating the chiral ligands of the present invention. Using n-hexane as a cleaning agent, the oil on the surface of the sodium hydride is cleaned under heating and stirring, and the n-hexane is fully removed. The chiral ligands L1, L2, and L3 of the present invention can be obtained, avoiding the production of diastereomers of the target product L (i.e., chiral racemization at the oxygen alpha position 1) and achieving a higher yield.

[0053] According to the preparation method of 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] The preparation method of the new chiral polydentate ligand containing quinine fragment according to the embodiment of the present application, the mass ratio of the NaH, quinine and the pyridine oxazoline shown in the formula S is (2-4):1:(1-2).

[0055] The preparation method of the new chiral polydentate ligand containing quinine fragment according to the embodiment of the present application, the reaction is carried out in a Schlenk bottle, and the Schlenk bottle is evacuated before the reaction to remove moisture.

[0056] Preferably, the number of evacuations is three or more to remove moisture.

[0057] The preparation method of the new chiral polydentate ligand containing quinine fragment according to the embodiment of the present application, after the reaction is completed, distilled water is slowly added to the system until no bubbles appear, and then extracted with DCM for 2-4 times, the organic phase is combined and extracted with saturated brine once, and then dried by adding an appropriate amount of anhydrous sodium sulfate to the obtained organic solution, suction filtered, and the filtrate is mixed with silica gel and rotary evaporated, and then the pyridine oxazoline S is separated out by using a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of (15-25):1 as a first eluent, and then the new chiral polydentate ligand L containing quinine fragment is separated out by using a mixed solvent of dichloromethane and methanol with a volume ratio of (15-20):1 as a second eluent.

[0058] The preparation method of the new chiral polydentate ligand containing quinine fragment according to the embodiment of the present application, the pyridine oxazoline shown in the formula S is prepared from amino alcohol and cyano pyridine. Thus, the chiral polydentate ligand in the present application can be obtained from commercially available quinine, cyano pyridine and amino alcohol through two simple operations.

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

[0060] The new chiral polydentate ligand containing quinine fragment as described above is used as a catalyst ligand in the application of metal-catalyzed synthesis of chiral diene reaction, and has high yield and enantioselectivity.

[0061] Embodiment 1

[0062] The synthesis route of the chiral polydentate ligand L1:

[0063]

[0064] (1) Preparation of pyridine oxazoline S1: A reflux reaction apparatus was constructed using a 100 mL three-necked flask, a spherical condenser, and other equipment. The reaction was evacuated at least three times to remove moisture. 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 stirred at 135°C for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature and dried using a rotary evaporator. 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 an appropriate amount of silica gel was added to the filtrate for drying. A mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 was used as the 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 flask 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 flask is completely precipitated, suck out the n-hexane with a pipette, switch to a double-row tube, and use a pump to drain the n-hexane. 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, the organic phases are combined, and the organic phase is extracted once with saturated brine. An appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution and dried. The filtrate is filtered, and the filtrate is mixed with silica gel and 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 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 constructed using a 100 mL three-necked flask, a spherical condenser, and other equipment. 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 L-leucinol (3.1 g, 30 mmol) were added to the reaction apparatus and stirred and refluxed at 135°C for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature and dried using a rotary evaporator. 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 then purified by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent 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 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, and continue stirring for 1 min. Stop stirring and wait until the solid in the bottle is completely precipitated. Use a pipette to suck out the n-hexane, switch to a double-row tube, and use a pump to drain the n-hexane. 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, the organic phases are combined, and the organic phase is extracted once with saturated brine. An appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution and dried. The filtrate is filtered, and the filtrate is mixed with silica gel and dried by spin drying. 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 equipment were used to build a reflux reaction apparatus, and the reaction mixture was pumped and filled 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 mixture was cooled to room temperature, and the reaction solution was dried using a rotary evaporator. 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 then purified by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent 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, and continue stirring for 1 min. Stop stirring and wait until the solid in the bottle is completely precipitated. Use a pipette to suck out the n-hexane, switch to a double-row tube, and use a pump to drain the n-hexane. 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, the organic phases are combined, and the organic phase is extracted once with saturated brine. An appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution and dried. The filtrate is filtered, and the filtrate is mixed with silica gel and dried by spin drying. 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 L3 (1.52 g, 86% yield).

[0085] Structural characterization data of L3:

[0086] 1H NMR (400 MHz, CDC13) δ = 8.70 (d, J = 4.5 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.7 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.51 (d, J = 4.5 Hz, 1H), 7.36 (dd, J = 9.2, 2.6 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.21 (d, J = 7.5 Hz, 3H), 7.14 (d, J = 6.3 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.89 - 5.81 (m, 1H), 5.06 - 4.95 (m, 2H), 4.57 - 4.49 (m, 1H), 4.31 (t, J = 9.0 Hz, 1H), 4.00 (d, J = 12.1 Hz, 4H), 3.44 (q, J = 7.8 Hz, 1H), 3.27 (s, 1H), 3.18 (dd, J = 13.8, 5.2 Hz, 1H), 3.08 (dd, J = 13.8, 10.1 Hz, 1H), 2.75 - 2.62 (m, 3H), 2.30 (s, 1H), 1.99 - 1.73 (m, 4H).

[0087] 13 C NMR (101 MHz, CDC13) 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, 113.4, 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 CHCI3).

[0088] Example 4

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

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

[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 (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 within the glove box. The mixture was stirred at room temperature for half an hour and then removed.

[0095] Under argon, propargyl ester substrate 1a (0.2 mmol), fac-Ir(ppy)3 (2.0 mg, 0.003 mmol), and anhydrous N,N-dimethylformamide (1.5 mL) were added to a reaction tube. The reaction system was then pumped and deoxygenated three times under low-temperature liquid nitrogen. Trimethylsilyl cyanide (75 μL, 0.6 mmol) was then added to the reaction system, and the mixture was stirred under two 3W violet lamps for 24 hours. Silica gel was added to the reaction system, dried by spin drying, and then separated by column chromatography (using silica gel with a mixed solvent of petroleum ether and ethyl acetate (v / v) = 100:1) to obtain chiral allene 3a as a colorless liquid in 67% yield with an ee 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] Figure 9 This is the chiral HPLC spectrum of chiral allene 3a racemate (rac-3a). Figure 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 is carried out in the same steps as in Example 5.

[0103] Example 7

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

[0105] Comparative Example 1

[0106] The commonly used ligand Bn-Pybox was used as a catalyst ligand in the copper-catalyzed chiral synthesis of allene 3a. The specific steps were 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 tetrahydrofuran was replaced by toluene in step (2), and no target product was generated after the reaction was completed.

[0112] Comparative Example 4

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

[0114] Comparative Example 5

[0115] The same as Example 1, except that tetrahydrofuran was replaced by ether in step (2), and no target product was generated after the reaction was 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. Yields and ee values ​​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 shown in 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 high yield and high enantioselectivity in the catalytic synthesis of chiral allene 3a. Pyridine oxazoline compounds in the prior art, such as 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 α position 2 on the quinine fragment have certain acidity, which easily produces weak hydrogen bond interactions with the intermediate product generated by the chiral allene, better stabilizing 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 purpose 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 a 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: Under an inert gas atmosphere, NaH is washed with n-hexane. After washing, the n-hexane is removed, and an anhydrous organic solvent and quinine are added to the NaH, and the reaction is stirred for 0.5 to 2 hours. Then, a pyridine oxazoline represented by formula S is added, and the reaction is stirred at 60 to 70° C. for 4 to 6 hours to react to produce a novel chiral multidentate ligand containing a quinine fragment represented by 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 minutes, 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 n-hexane includes: standing still after stirring, and after the NaH solid is completely precipitated, sucking out the n-hexane with a pipette, 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, and then the system is extracted with DCM 2 to 4 times. The organic phases are combined and extracted once with saturated brine. An appropriate amount of anhydrous sodium sulfate is added to the obtained organic solution for drying, and the solution is filtered with suction. The filtrate is mixed with silica gel and spin-dried. 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.

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 fragments as claimed in claim 1 as a catalyst ligand in metal-catalyzed synthesis of chiral allenes.

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