Preparation of cinchona alkaloid-metal complex and application of cinchona alkaloid-metal complex in asymmetric cyanidation reaction

Abstract

The invention relates to preparation of a cinchona alkali-metal complex and application of the cinchona alkali-metal complex in an asymmetric cyanidation reaction. The invention belongs to the technical field of fine chemical synthesis. The method comprises the following steps: modifying quinine, quinidine, cinchonine and cinchonidine to introduce an amino group capable of being additionally coordinated to a C9 site, introducing a hydroxyl group capable of being additionally coordinated to a C6 site, reacting the amino group introduced to the C9 site with sulfonyl chloride to introduce more coordination groups, and then coordinating with a cheap alkaline metal reagent to obtain the cinchona alkali-metal complex. The cinchona alkaloid-metal complex catalyst disclosed by the invention can catalyze an asymmetric cyanidation addition reaction of an alpha, beta-unsaturated carbonyl compound to obtain a cyanidation addition product with high enantioselectivity, and is expected to be used as a chiral ligand to realize more asymmetric catalytic reactions; the preparation method disclosed by the invention has the advantages of high yield, low raw material cost, short reaction route, mild reaction conditions and the like, and has a wide application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to the preparation of a cinchona alkaloid-metal complex and the application of the complex in asymmetric cyanation. Background Art

[0002] Asymmetric synthesis and asymmetric catalysis are the main methods for obtaining optically pure compounds. Asymmetric catalysis methods include biocatalysis, chiral metal ligand catalysis, asymmetric electrocatalysis and organic small molecule catalysis. Among them, chiral metal ligand catalysis has the advantages of a wide range of chemical bond activation and the ability to activate inert chemical bonds, and has gradually become a research hotspot in the field of asymmetric catalysis.

[0003] Cinchona alkaloids and their derivatives have multiple chiral centers in their structures. The rigid structures of quinine and quinoline rings give the substances chiral pockets similar to enzymes, thus providing a chiral environment. Therefore, they are widely used as organic catalysts for catalytic asymmetric synthesis. Cinchona alkaloids and their derivatives can also coordinate with metals with empty orbitals to form metal complexes for catalytic asymmetric synthesis. However, the current research on cinchona alkaloids and their derivatives as ligands for catalytic asymmetric synthesis is not rich enough, and their application in asymmetric synthesis is still relatively scarce.

[0004] Representative research results of cinchona alkali and its derivatives as chiral ligands and metal coordination catalysis asymmetric synthesis include the use of cinchona alkali / tetraisopropoxytitanium / biphenol in situ to generate catalysts, realizing the asymmetric cyanation reaction of aldehydes, ketones, aldimines and ketimines by Feng Xiaoming's research group; the first case of palladium-catalyzed asymmetric α-arylation reaction involving quinine as a chiral ligand; Zhang Shengyong and He Wei's research groups applied chiral Schiff base ligands derived from cinchona alkali to the asymmetric Henry reaction of aldehydes and nitromethane. The chiral ligands of cinchona alkali and its derivatives reported so far need to be complexed with expensive metals, and the preparation methods are complicated, the yield is low, the asymmetric catalytic system is complex, and the asymmetric catalytic reaction conditions are harsh. Therefore, it is necessary to develop complexes of cinchona alkali and cheap metals as new catalysts for asymmetric catalytic reactions. Summary of the invention

[0005] In order to overcome the deficiencies of the above-mentioned prior art, the present invention provides a simple and efficient preparation method for a novel cinchona alkali-metal complex, which uses cheap alkali metals and alkaline earth metals instead of expensive metals to greatly reduce the preparation cost, and can also solve the problems of slow reaction rate, complex catalytic system, high catalytic cost, etc. in the existing chiral ligand and metal-catalyzed asymmetric reaction, which has important reference significance for the research and application of cinchona alkali chiral ligands in the field of asymmetric catalysis; at the same time, the cinchona alkali-metal complex is used to catalyze the asymmetric cyanation addition reaction of α, β-unsaturated carbonyl compounds to obtain a cyanation addition product with high enantioselectivity, which enriches the research and application of cinchona alkali and its derivatives as ligands in the field of asymmetric synthesis.

[0006] The technical solution of the present invention is as follows:

[0007] One of the objects of the present invention is to provide a method for preparing a cinchona alkali-metal complex, which is as follows:

[0008] By modifying quinine, quinidine, cinchonine, and cinchonidine, the C6 position is modified to a hydroxyl group, and the C9 position is modified to an amine group. The amine group at the C9 position can also react with sulfonyl chloride to introduce more coordination groups, and then coordinate with a cheap alkaline metal reagent to obtain a cinchona alkali-metal complex;

[0009] The cinchona alkaloid-metal complex catalyst of the invention can catalyze the asymmetric cyanation addition reaction of α,β-unsaturated carbonyl compounds to obtain cyanation addition products with high enantioselectivity.

[0010] Further defined, the general structure formula of the cinchona alkaloid derivative ligand is:

[0011]

[0012] It is further defined that the method for preparing the cinchona alkaloid-metal complex comprises the following steps:

[0013] S1. The preparation method of cinchona alkaloid derivatives is as follows:

[0014] a. Using quinine, quinidine, cinchonine, and cinchonidine as raw materials, solvent, diethyl azodicarboxylate, and triphenylphosphine were added under nitrogen protection, diphenylphosphoazide was added dropwise under an ice-water bath, and heated to reflux. After the reaction was complete, the cinchona alkaloid derivative ligands Ic to If were obtained by separation and purification;

[0015] b. Using cinchona alkali derivative ligands Ia to If as raw materials, dichloromethane as solvent, quinoline-8-sulfonyl chloride or p-toluenesulfonyl chloride is added, triethylamine is added under an ice-water bath, and the reaction is restored to room temperature. After the reaction is complete, the cinchona alkali derivative ligands Ig to Ir are obtained by separation and purification;

[0016] S2. Under nitrogen protection, cinchona alkaloid derivative ligands Ia~Ir and alkaline metal reagents are added to a solvent at room temperature and stirred thoroughly to obtain the corresponding cinchona alkaloid-metal complex ligands.

[0017] It is further defined that in step S1a, the solvent is one of tetrahydrofuran, dichloromethane, and 1,2-dichloroethane; the feeding ratio is: the cinchona alkali raw material is 1 equivalent, the diethyl azodicarboxylate, triphenylphosphine, and diphenylphosphoazide are 1-2 equivalents, 2-4 equivalents, and 1-2 equivalents, respectively, and the amount of solvent is 1-4 ml per mmol of cinchona alkaloid raw material.

[0018] The most preferred embodiment is that the solvent used is tetrahydrofuran, the ratio of the cinchona alkaloid raw material to diethyl azodicarboxylate, triphenylphosphine, and diphenylphosphoryl azide is 1:1.4:2.8:1.4; and the amount of solvent used is 2.5 ml per mmol of cinchona alkaloid raw material.

[0019] It is further defined that in step S1a, the separation and purification method is: after the reaction is complete, concentrate under reduced pressure, add dichloromethane to dilute, add an appropriate amount of dilute hydrochloric acid to adjust the pH value and then wash with dichloromethane, then add an appropriate amount of ammonia water to adjust the pH value and then extract with dichloromethane, wash the organic phase with saturated brine and then dry it with anhydrous magnesium sulfate, filter and concentrate.

[0020] It is further defined that in step S1b, the separation and purification method is: after the reaction is completed, water is added to quench, followed by extraction with dichloromethane, the organic phase is washed with water and saturated brine in sequence, dried over anhydrous magnesium sulfate, and then concentrated to obtain a crude product, and the crude product is purified by recrystallization with dichloromethane and ethyl acetate.

[0021] It is further defined that the alkaline metal reagent described in the preparation method of cinchona alkali-metal complex is cesium carbonate, potassium carbonate, sodium amide, dibutyl magnesium, lithium amide; and the solvent is dichloromethane, 1,2-dichloroethane, chloroform, toluene.

[0022] It is further defined that the cinchona alkali-metal complex catalyst can catalyze the asymmetric cyanation reaction of α,β-unsaturated carbonyl compound II to obtain a highly enantioselective cyanation product III, the general formula of which is as follows:

[0023]

[0024] Compared with the prior art, the present invention has the following advantages:

[0025] The method of the invention uses cinchona alkali and its derivatives as raw materials, introduces an additional coordinated amine group at the C9 position and an additional coordinated hydroxyl group at the C6 position by modifying the cinchona alkali, and the amine group introduced at the C9 position can react with sulfonyl chloride to introduce more coordinated groups, thereby obtaining a cinchona alkali derivative with specific functions, and then replaces expensive metals with cheap alkali metals and alkaline earth metals to synthesize cinchona alkali-metal complexes, which has the advantages of high yield, low raw material cost, short reaction route, mild reaction conditions, etc.; can be used to catalyze the asymmetric cyanation addition reaction of α, β-unsaturated carbonyl compounds to obtain a cyanation addition product with high enantioselectivity, has good substrate adaptability, and can be widely used in the research of asymmetric catalysis. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Cinchona alkaloid derivative Ia 1 H NMR spectrum;

[0027] Figure 2 is the infrared spectrum of cinchona alkaloid derivative Ia;

[0028] Figure 3 This is the infrared spectrum of the Ia-Li metal complex prepared in Example 1;

[0029] Figure 4 is the HPLC chromatogram of IIIa prepared in Example 20;

[0030] Figure 5 is the HPLC chromatogram of racemic IIIa;

[0031] Figure 6 The IIIa prepared in Example 20 1 H NMR spectrum. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0033] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained through commercial channels by those skilled in the art.

[0034] The terms "comprising," "including," "having," "containing," or any other variations thereof, as used in the following examples, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus comprising the listed elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

[0035] Example 1, Preparation of Ia-Li cinchona alkali-metal complex

[0036] Take Ia as raw material, add cinchona alkaloid derivative Ia (0.1 mmol), 5 ml 1,2-dichloroethane and lithium amide (0.4 mmol) under nitrogen atmosphere, stir well for half an hour to obtain Ia-Li cinchona alkaloid-metal complex.

[0037] Cinchona alkaloid derivative ligand Ia: 1 H NMR (300MHz, Methanol-d 4 )δ8.61(d,J=4.7Hz,1H),7.92(d,J=9.1Hz,1H),7.56(dd,J=10.3,3.6Hz,2H),7.39(dd,J=9.1,2.5Hz,1H),5.87(ddd,J=17.1,10.3,7.5Hz,1H ),5.07(t,J=1.5Hz,1H),5.01(t,J=1.5Hz,1H),4.98(t,J=1.4Hz,1H),4.66(d,J=10.4Hz,1H),3.36(d,J=4.4Hz,1H),3.34–3.29(m,1H),3.29–

[0038] 3.16(m,1H),2.92–2.76(m,2H),2.36(s,1H),1.61–1.55(m,3H),1.46(t,J=12.0Hz,1H),1.26(d,J=11.9Hz,1H),0.76(dd,J=13.5,7.4Hz,1H).

[0039] Embodiment 2-5

[0040] The lithium amide in Example 1 was replaced by cesium carbonate, potassium carbonate, sodium amide, and dibutyl magnesium, and the other steps and parameters were the same as those in Example 1 to obtain Ia-Cs, Ia-K, Ia-Na, and Ia-Mg cinchona alkali-metal complexes.

[0041] Embodiment 6-8

[0042] The 1,2-dichloroethane in Example 1 was replaced by dichloromethane, chloroform, and toluene, and the other steps and parameters were the same as those in Example 1 to obtain the Ia-Li cinchona alkali-metal complex in the dichloromethane, chloroform, and toluene solution system.

[0043] Example 9, Preparation of Ib-Li cinchona alkaloid-metal complex

[0044] Ia in Example 1 was replaced by Ib, and the other steps and parameters were the same as those in Example 1 to obtain Ib-Li cinchona alkaloid-metal complex.

[0045] Cinchona alkaloid derivative ligand Ib: 1 H NMR (300 MHz, DMSO-d 6 )δ9.09(s,1H),8.76(d,J=7.6Hz,1H),7.92(d,J=7.5Hz,1H),7.54–7.42(m,2H),7.33(dd,J=7.5,1.5Hz,1H),5.73(dd d,J=16.4,10.1,6.2Hz,1H),5.04(ddd,J=13.8,10.1,1.0Hz,1H),4.79(ddd,J=16.7,13.8,1.0Hz,1H),4.03(d,J=7.0H z,1H),3.38(dt,J=12.4,7.1Hz,1H),3.17–2.97(m,2H),2.90(q,J=7.0Hz,1H),2.71(dd,J=12.4,7.0Hz,1H),2.58–2.4 3(m,3H),1.95(h,J=7.0Hz,1H),1.83–1.65(m,1H),1.45(ddt,J=13.8,11.3,7.0Hz,2H),1.29(dt,J=13.2,7.0Hz,1H).

[0046] Example 10. Preparation of Ic-Li cinchona alkaloid-metal complex

[0047] Preparation of cinchona alkaloid derivative Ic: Quinine (6mmol), triphenylphosphine (8.4mmol), 15ml tetrahydrofuran, diethyl azodicarboxylate (8.4mmol) were added under argon atmosphere, stirred at 0°C for 10min, diphenylphosphine (8.4mmol) was added dropwise, the temperature was raised to room temperature and stirred for 24 hours, reacted at 50°C for 3 hours, triphenylphosphine (8.4mmol) was added again, the reaction was continued at 50°C for 3 hours, cooled to room temperature, 2ml water was added and stirred overnight. The mixture was concentrated under reduced pressure, dichloromethane was added to dissolve, an appropriate amount of dilute hydrochloric acid was added to adjust the pH value, and then washed with dichloromethane, an appropriate amount of ammonia water was added to adjust the pH value, and then extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain product Ic, 1.82g, yellow solid, with a yield of 93.6%.

[0048] Ia in Example 1 was replaced by Ic, and the other steps and parameters were the same as those in Example 1 to obtain Ic-Li cinchona alkaloid-metal complex.

[0049] Cinchona alkaloid derivative ligand Ic: 1H NMR (300MHz, DMSO-d6) δ8.75 (d, J = 7.5Hz, 1H), 7.99 (d, J = 7.5Hz, 1H), 7.64 (d, J = 7.5Hz, 1H), 7.40 (d, J = 1.6Hz, 1H), 7.27 (dd, J = 7.4, 1.4Hz, 1H), 5.73 (ddd, J = 16.4, 10.1, 6.2Hz, 1H), 5.04 (ddd, J = 13.9, 10.1, 1.0Hz, 1H), 4.79 (ddd, J = 16.7, 13.8, 1.0Hz, 1 H),4.31(d,J=7.0Hz,1H),3.80(s,3H),3.42(dd,J=12.5,7.0Hz,1H),3.32–3.06(m,2H),2.94(q,J=7.0Hz,1H),2.62(dd,J=12 .5,7.0Hz,1H),2.41–2.26(m,3H),1.84(h,J=7.0Hz,1H),1.72–1.54(m,2H),1.55–1.37(m,1H),1.25(dt,J=13.1,7.0Hz,1H).

[0050] Examples 11-12

[0051] The solvent in Example 10 was replaced by dichloromethane and 1,2-dichloroethane. The other steps and parameters were the same as those in the preparation method of cinchona alkaloid derivatives in Example 10. The yields of Ic were dichloromethane (31.6%) and 1,2-dichloroethane (56.1%).

[0052] Example 13. Preparation of Id-Li cinchona alkaloid-metal complex

[0053] Preparation of cinchona alkaloid derivative Id: Quinine was replaced by quinidine, and the other steps and parameters were the same as those in Example 10 to obtain product Id, 1.81 g, yellow solid, with a yield of 93.3%.

[0054] Ia in Example 1 is replaced by Id, and the other steps and parameters are the same as those in Example 1 to obtain Id-Li cinchona alkaloid-metal complex.

[0055] Cinchona alkaloid derivative ligand Id: 1 H NMR (300 MHz, DMSO-d 6 )δ8.75(d,J=7.5Hz,1H),7.99(d,J=7.5Hz,1H),7.61(d,J=7.5Hz,1H),7.37(d,J=1.6Hz,1H),7.27(dd,J=7.4,1.4Hz,1 H),5.73(ddd,J=16.4,10.1,6.2Hz,1H),5.04(ddd,J=13.9,10.1,1.0Hz,1H),4.79(ddd,J=16.7,13.8,1.0Hz,1H),4.07 (d,J=7.0Hz,1H),3.80(s,3H),3.50–3.33(m,1H),3.19–2.99(m,2H),2.86(q,J=7.0Hz,1H),2.72(dd,J=12.5,7.0Hz,1 H),2.53(s,2H),2.34(dtd,J=8.0,7.0,6.0Hz,1H),1.90–1.65(m,2H),1.59–1.38(m,2H),1.29(dt,J=13.2,7.0Hz,1H).

[0056] Example 14. Preparation of Ie-Li cinchona alkaloid-metal complex

[0057] Preparation of cinchona alkaloid derivative Ie: Quinine was replaced by cinchona, and the other steps and parameters were the same as those in Example 10, to obtain product Ie, 1.58 g, yellow solid, with a yield of 89.8%.

[0058] Ia in Example 1 is replaced by Ie, and the other steps and parameters are the same as those in Example 1 to obtain Ie-Li cinchona alkaloid-metal complex.

[0059] Cinchona alkaloid derivative ligand Ie: 1H NMR (300MHz, DMSO-d6) δ8.81 (d, J = 7.5Hz, 1H), 8.22–8.06 (m, 2H), 7.76–7.56 (m, 3H), 5.73 (ddd, J = 16.4, 10.1, 6.1Hz, 1H), 5.04 (ddd, J = 13.8, 10.1, 1.0Hz, 1H), 4.79 (ddd, J = 16.6, 13.8, 1.0Hz, 1H), 4.13 (d, J = 7.0Hz, 1H), 3.31 (dd, J = 12.4, 6.9Hz, 1H), 3.17(dt,J=12.5,7.1Hz,1H),3.04(dt,J=12.5,7.1Hz,1H),2.89(q,J=7.0Hz,1H),2.73(dd,J=12.4,7.0Hz,1H),2.55(dtd,J =8.0,6.9,5.9Hz,1H),2.35(s,2H),1.90(h,J=7.0Hz,1H),1.60(ddt,J=13.9,8.0,6.9Hz,2H),1.40(dt,J=13.3,7.1Hz,2H).

[0060] Example 15. Preparation of If-Li cinchona alkali-metal complex

[0061] Preparation of cinchona alkaloid derivative If: Quinine was replaced by cinchonidine, and the other steps and parameters were the same as those in Example 10, to obtain product If, 1.67 g, yellow solid, with a yield of 94.9%.

[0062] Replace Ia in Example 1 with If, and the other steps and parameters are the same as in Example 1 to obtain If-Li cinchona alkaloid-metal complex.

[0063] Cinchona alkaloid derivative ligand If: 1 H NMR (300 MHz, DMSO-d 6)δ8.81(d,J=7.5Hz,1H),8.26–8.09(m,2H),7.65(tt,J=6.5,2.4Hz,3H),5.73(ddd,J=16.4,10.1,6.2Hz,1 H),5.04(ddd,J=13.8,10.1,1.0Hz,1H),4.79(ddd,J=16.6,13.8,1.0Hz,1H),4.03(d,J=7.0Hz,1H),3.40( dt,J=12.4,7.0Hz,1H),3.17–3.01(m,2H),2.89(q,J=7.0Hz,1H),2.73(dd,J=12.5,7.0Hz,1H),2.53(s,2H ),2.43–2.27(m,1H),1.91–1.63(m,2H),1.45(ddt,J=13.8,11.9,6.8Hz,2H),1.28(dt,J=13.2,7.0Hz,1H).

[0064] Example 16. Preparation of Ig-Li cinchona alkaloid-metal complex

[0065] Preparation of cinchona alkaloid derivative Ig: Cinchona alkaloid derivative Ia (6.0 mmol) was used as raw material. Under a nitrogen atmosphere, 30 ml of dichloromethane was added, and quinoline-8-sulfonyl chloride (6.3 mmol) was added. Triethylamine (7.2 mmol) was added dropwise in an ice-water bath. The reaction was stirred at room temperature overnight and monitored by TLC. After the reaction of the raw material was complete, water was added to quench the reaction. Then, dichloromethane was added to extract the organic phase. The organic phase was washed with water and saturated brine in turn, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was purified by recrystallization with dichloromethane and ethyl acetate to obtain product Ig, 2.79 g, as a yellow solid. The yield was 93.0%.

[0066] Ia in Example 1 was replaced by Ig, and the other steps and parameters were the same as those in Example 1 to obtain an Ig-Li cinchona alkaloid-metal complex.

[0067] Cinchona alkaloid derivative ligand Ig: 1H NMR(300MHz,Chloroform-d)δ9.07(dd,J=7.5,1.5Hz,1H),8.71(d,J=7.5Hz,1H),8.22(ddt,J=20.3,7.6,1.6Hz,3H),8.00(d,J=7.5H z,1H),7.76(t,J=7.5Hz,1H),7.55(d,J=7.5Hz,1H),7.45–7.31(m,2H),7.16(d,J=1.5Hz,1H),6.85(s,1H),5.82–5.64(m,1H),5.04( ddd,J=13.8,10.1,0.9Hz,1H),4.79(ddd,J=16.7,13.8,0.9Hz,1H),4.62(s,1H),4.37(d,J=7.0Hz,1H),3.78(dt,J=12.5,7.0Hz,1H) ,3.12(q,J=7.0Hz,1H),2.87(dt,J=12.5,7.1Hz,1H),2.71–2.54(m,1H),2.35–2.16(m,2H),1.89(h,J=6.9Hz,1H),1.79–1.42(m,4H).

[0068] Example 17, Preparation of Ih-Li cinchona alkaloid-metal complex

[0069] Preparation of cinchona alkaloid derivative Ih: Replace cinchona alkaloid derivative Ia with Ib, and the other steps and parameters are the same as Example 16 to obtain product Ih, 2.86 g, yellow solid, with a yield of 95.3%.

[0070] Ia in Example 1 is replaced by Ih, and the other steps and parameters are the same as those in Example 1 to obtain Ih-Li cinchona alkaloid-metal complex.

[0071] Cinchona alkaloid derivative ligand Ih: 1H NMR(300MHz,Chloroform-d)δ9.08(dd,J=7.5,1.5Hz,1H),8.71(d,J=7.5Hz,1H),8.28–8.08(m,3H),7.97(d,J=7.5Hz,1H),7.70 (t,J=7.5Hz,1H),7.58(d,J=7.5Hz,1H),7.45–7.26(m,2H),7.14(d,J=1.4Hz,1H),6.44(s,1H),5.82–5.64(m,1H),5.04(ddd,J=1 4.0,10.0,0.8Hz,1H),4.79(ddd,J=16.7,13.8,0.9Hz,1H),4.63(s,1H),4.41(d,J=7.0Hz,1H),3.68(dt,J=12.5,7.1Hz,1H),3.1 0(q,J=7.0Hz,1H),2.86(dt,J=12.5,7.1Hz,1H),2.69–2.53(m,1H),2.34–2.16(m,2H),1.88(h,J=6.9Hz,1H),1.79–1.42(m,4H).

[0072] Example 18, Preparation of Ii-Li Cinchona Alkaloid-Metal Complex

[0073] Preparation of cinchona alkaloid derivative Ii: Substitute p-toluenesulfonyl chloride for quinoline-8-sulfonyl chloride, and the other steps and parameters are the same as those in Example 16 to obtain product Ii, 2.54 g, yellow solid, with a yield of 91.4%.

[0074] Ia in Example 1 is replaced by Ii, and the other steps and parameters are the same as those in Example 1 to obtain Ii-Li cinchona alkaloid-metal complex.

[0075] Cinchona alkaloid derivative ligand Ii: 1H NMR(300MHz,Chloroform-d)δ8.76(d,J=7.5Hz,1H),7.93(d,J=7.5Hz,1H),7.71–7.56(m,3H),7.34(ddd,J= 28.7,7.4,1.4Hz,3H),7.17(d,J=1.5Hz,1H),5.73(ddd,J=16.4,10.1,6.1Hz,1H),5.60(s,1H),5.04(ddd,J= 13.8,10.1,1.0Hz,1H),4.88–4.70(m,2H),4.45(d,J=7.0Hz,1H),3.43(dt,J=12.5,7.1Hz,1H),3.08(q,J=7. 0Hz,1H),2.86–2.59(m,2H),2.46–2.32(m,4H),2.32–2.16(m,1H),1.95(h,J=7.0Hz,1H),1.79–1.42(m,4H).

[0076] Example 19, Ij-Li Preparation of Cinchona Alkaloid-Metal Complex

[0077] Preparation of cinchona alkaloid derivative Ij: Replace cinchona alkaloid derivative Ia with Ib, replace quinoline-8-sulfonyl chloride with p-toluenesulfonyl chloride, and the other steps and parameters are the same as in Example 16 to obtain product Ij, 2.57 g, yellow solid, with a yield of 92.5%.

[0078] Replace Ia in Example 1 with Ij, and the other steps and parameters are the same as in Example 1 to obtain Ij-Li cinchona alkaloid-metal complex.

[0079] Cinchona alkaloid derivative ligand Ij: 1H NMR(300MHz,Chloroform-d)δ8.76(d,J=7.5Hz,1H),7.93(d,J=7.5Hz,1H),7.71–7.56(m,3H),7.34(ddd,J= 28.7,7.4,1.4Hz,3H),7.17(d,J=1.5Hz,1H),5.73(ddd,J=16.4,10.1,6.1Hz,1H),5.60(s,1H),5.04(ddd,J= 13.8,10.1,1.0Hz,1H),4.88–4.70(m,2H),4.45(d,J=7.0Hz,1H),3.43(dt,J=12.5,7.1Hz,1H),3.08(q,J=7. 0Hz,1H),2.86–2.59(m,2H),2.46–2.32(m,4H),2.32–2.16(m,1H),1.95(h,J=7.0Hz,1H),1.79–1.42(m,4H).

[0080] Example 20: Preparation of asymmetric cyanation product IIIa catalyzed by Ia-Li metal complex

[0081] Under nitrogen protection, IIa (0.5 mmol) and acetone cyanohydrin (1.0 mmol) were added to the cinchona alkali derivative ligand Ia-Li cinchona alkali-metal complex, heated to 60°C, reacted for 4 h, and monitored by TLC. After the raw materials reacted completely, they were washed with water, then extracted with dichloromethane, and the organic phase was washed with water and saturated brine in sequence, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to column chromatography using ethyl acetate: n-hexane (v:v) = 1:10 to obtain IIIa, 111 mg, as a white solid powder with a yield of 95.2% and an ee value of 93.4%.

[0082] IIIa: 1 H NMR(300MHz,Chloroform-d)δ7.97–7.92(m,2H),7.66–7.57(m,1H),7.55–7.32(m,7H),4. 59(dd,J=7.9,6.0Hz,1H), 3.75(dd,J=17.9,7.9Hz,1H), 3.53(dd,J=17.9,6.0Hz,1H)ppm.

[0083] Example 21. Preparation of asymmetric cyanation product IIIb catalyzed by Ia-Li metal complex

[0084] The difference between this example and Example 20 is that the substrate is changed from IIa to IIb, and the other steps and parameters are the same as those in Example 20. The obtained product IIIb, 97 mg, is a white solid powder with a yield of 76.7% and an ee value of 83.3%.

[0085] IIIb: 1 H NMR(300MHz,Chloroform-d)δ7.96(td,J=7.6,1.9Hz,1H),7.66–7.53(m,

[0086] 1H),7.49–7.23(m,7H),4.67–4.49(m,1H),3.84–3.45(m,2H).

[0087] Example 22: Preparation of asymmetric cyanation product IIIc catalyzed by Ia-Li metal complex

[0088] The difference between this example and Example 20 is that the substrate is changed from IIa to IIc, and the other steps and parameters are the same as those in Example 20. The obtained product IIIc, 103 mg, is a white solid powder with a yield of 81.4% and an ee value of 87.0%.

[0089] IIIc: 1 H NMR (300MHz, Chloroform-d) δ8.09–7.87(m,2H),7.69–7.55(m,1H),7.56–7.33(m,4H),7.10(t,J=8.6Hz,2H),4.59(t,J=6.9Hz,1H),3.85–3.37(m,2H).

[0090] Example 23: Preparation of asymmetric cyanation product IIId catalyzed by Ia-Li metal complex

[0091] The difference between this example and Example 20 is that the substrate is replaced by IId from IIa, and the other steps and parameters are the same as those in Example 20. The obtained product IIId, 115 mg, yellow solid powder, has a yield of 86.7% and an ee value of 82.5%.

[0092] IIId: 1 H NMR (300MHz, Chloroform-d) δ7.95 (dd, J=7.7, 2.6Hz, 2H), 7.62 (dd, J=8.7,

[0093] 6.1Hz,1H),7.49(dd,J=9.2,6.6Hz,2H),7.38–7.29(m,1H),7.07–6.94(m,2H), 6.89(dd,J=8.6,2.4Hz,1H),4.66–4.47(m,1H),3.84(s,3H),3.79–3.44(m,2H).

[0094] Example 24: Preparation of asymmetric cyanation product IIIe catalyzed by Ia-Li metal complex

[0095] The difference between this example and Example 20 is that the substrate is replaced by IIf from IIa, and the other steps and parameters are the same as those in Example 20. The obtained product IIIe, 113 mg, is a white solid powder with a yield of 90.7% and an ee value of 83.4%.

[0096] IIIe: 1 H NMR(300MHz,Chloroform-d)δ8.04–7.85(m,2H),7.69–7.56(m,1H),7.54–7.44(m,2H),7.39– 7.30(m,2H),7.26–7.17(m,2H),5.31(s,3H),4.55(dd,J=7.9,6.1Hz,1H),3.81–3.42(m,2H).

[0097] As can be seen from Examples 1-19, the method of the present invention starts from the cheap and readily available cinchona alkalinity, and by modifying quinine, quinidine, cinchonine, and cinchonidine, the C6 position is modified to a hydroxyl group, and the C9 position is modified to an amine group. The amine group at the C9 position can also react with sulfonyl chloride to introduce more coordinating groups, and then coordinate with cheap alkali metals to obtain a cinchona alkali-metal complex. This method has the advantages of high yield, low raw material cost, short reaction route, and mild reaction conditions. As can be seen from Examples 20-24, the cinchona alkali-metal complex of the present invention can be used to catalyze the asymmetric cyanation addition reaction of α, β-unsaturated carbonyl compounds to obtain a cyanation addition product with high enantioselectivity, thereby realizing the application of the cinchona alkali-metal complex in the field of asymmetric cyanation.

[0098] The above are only preferred specific embodiments of the present invention, which are all different implementations based on the overall concept of the present invention, and the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A preparation of a cinchona alkali-metal complex and its application in asymmetric cyanation reaction, characterized in that: By modifying the structures of quinine, quinidine, cinchonine and cinchonidine, the C6 position is modified to a hydroxyl group and the C9 position is modified to an amine group. The amine group at the C9 position can also react with sulfonyl chloride to introduce more coordination groups to obtain a variety of cinchona alkaloid derivatives, which are then coordinated with cheap alkaline metal reagents to obtain cinchona alkaloid-metal complexes. The cinchona alkaloid-metal complex catalyst of the invention is used for catalyzing the asymmetric cyanation addition reaction of α,β-unsaturated carbonyl compounds, and can obtain a cyanation addition product with high enantioselectivity.

2. The method according to claim 1, characterized in that General structural formula of cinchona alkaloid derivative ligands Ia~Ir 3. The method for preparing the cinchona alkali-metal complex according to claims 1 to 2, characterized in that: The following steps are involved: S1. The preparation method of cinchona alkaloid derivatives is as follows: a. Using quinine, quinidine, cinchonine and cinchonidine as raw materials, adding solvent, diethyl azodicarboxylate and triphenylphosphine under nitrogen protection, adding diphenylphosphoazide dropwise under ice water bath, heating to reflux, separating and purifying after the reaction is complete to obtain cinchona alkaloid derivative ligands Ⅰc~If; b. Using cinchona alkali derivative ligands Ia to If as raw materials, dichloromethane as solvent, quinoline-8-sulfonyl chloride or p-toluenesulfonyl chloride is added, triethylamine is added under an ice-water bath, and the reaction is restored to room temperature. After the reaction is complete, the cinchona alkali derivative ligands Ig to Ir are obtained by separation and purification; S2. Under nitrogen protection, cinchona alkaloid derivative ligands Ia~Ir and alkaline metal reagents are added to a solvent at room temperature and stirred thoroughly to obtain the corresponding cinchona alkaloid-metal complex.

4. The method for preparing the cinchona alkali-metal complex according to claim 3, characterized in that: In step S1a, the solvent is one of tetrahydrofuran, dichloromethane, and 1,2-dichloroethane; the feeding ratio is: the cinchona alkaloid raw material is 1 equivalent, the diethyl azodicarboxylate, triphenylphosphine, and diphenylphosphoazide are 1-2 equivalents, 2-4 equivalents, and 1-2 equivalents, respectively, and the amount of solvent is 1-4 ml per mmol of cinchona alkaloid raw material.

5. The method for preparing the cinchona alkali-metal complex according to claim 3, characterized in that: In step S1a, the separation and purification method is: after the reaction is complete, concentrate under reduced pressure, add dichloromethane to dilute, add an appropriate amount of dilute hydrochloric acid to adjust the pH value and then wash with dichloromethane, then add an appropriate amount of ammonia water to adjust the pH value and then extract with dichloromethane, wash the organic phase with saturated brine, dry it with anhydrous magnesium sulfate, filter and concentrate. In step S1b, the separation and purification method is: after the reaction is completed, water is added to quench, followed by extraction with dichloromethane, the organic phase is washed with water and saturated brine in sequence, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product, and the crude product is purified by recrystallization with dichloromethane and ethyl acetate.

6. The method for preparing the cinchona alkali-metal complex according to claim 3, characterized in that: The alkaline metal reagent described in step S2 is cesium carbonate, potassium carbonate, n-butyl lithium, sodium amide, lithium hydride, dibutyl magnesium, lithium amide; the solvent is dichloromethane, 1,2-dichloroethane, chloroform, toluene.

7. The method according to claim 1, characterized in that The cinchona alkali-metal complex catalyst can catalyze the asymmetric cyanation reaction of α, β-unsaturated carbonyl compound II to obtain a highly enantioselective cyanation product III, the general structural formula of which is:

8. Use of the cinchona alkaloid-metal complex ligand prepared by the preparation method according to any one of claims 1 to 6 in an asymmetric cyanation reaction.

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