Preparation method and application of phosphorus center chiral heterocyclic compound

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a phosphorus center chiral compound, and a synthetic route is shown as a reaction formula I. Secondary phosphine borane which is stable in air and easy to operate is used as a raw material, under the catalysis of cheap metal copper and a commercial chiral ethylenediamine ligand, the trivalent phosphorus center chiral benzophosphorus heterocyclic ring protected by borane is directly synthesized by utilizing a dynamic kinetic resolution C-P (III) coupling / cyclization reaction strategy, a borane protecting group can be removed by utilizing N-methyl piperazine and the like, and the chiral benzophosphorus heterocyclic ring is obtained. And obtaining the product. The method is simple to operate, the conversion rate of the raw material secondary phosphoborane is high, the directly synthesized product is trivalent phosphorus center chiral benzo-phosphorus heterocyclic ring, and the enantioselectivity of the product is high.

Description

Technical Field

[0001] The invention belongs to the field of chiral compound synthesis, and specifically relates to a preparation method and application of a phosphorus-centered chiral heterocyclic compound. Background Art

[0002] Since Knowles' pioneering work on the development of the chiral monodentate phosphine ligand CAPMP in asymmetric catalytic hydrogenation in the last century, a series of phosphorus-centered chiral ligands have been synthesized and widely used in asymmetric hydrogenation reactions and coupling reactions. Some ligands have become dominant ligands in the field of chiral synthesis, such as CAPMP, DIPAMP, BisP*, QuinoxP*, and cyclic DuanPhos / Tang-Phos / ZhangPhos-type ligands, BI-DIME / BOP-type ligands, and DuPhos / BeePhos-type ligands, etc. (Glueck, D S Chem. Eur. J. 2008, 14, 7108-7177; Xu, RL; Yang, H.; Fu, W Z; Tang, W J ACS Catal. 2016, 6, 8, 4814–4858; Tang, W J Chin. J. Org. Chem. 2020, 40, 1409-1422).

[0003] Compared with phosphine ligands with chiral skeletons, the chiral sites of phosphorus-centered chiral ligands are closer to the active centers of metal catalysts and have stronger chiral induction control capabilities. The phosphorus-centered chiral benzoheterocyclic skeleton has become an advantageous skeleton for designing chiral phosphine ligands due to its rigidity and electron-richness. However, the chiral phosphorus heterocyclic ligand skeleton is currently mainly limited to benzo five-membered phosphorus heterocycles, and there is a lack of methods for preparing and synthesizing phosphorus-centered chiral mesocyclic (6-10-membered) skeletons (Xu, GQ; Senanayake CH; Tang, WJ Acc. Chem. Res. 2019, 52, 4, 1101–1112; Cao, Z.; He, DY; Tang, WJ Org. Process Res. Dev. 2024, 28, 4, 949–977; Imamoto, T. Chem. Rev. 2024, 124, 14, 8657–8739).

[0004] In addition, the synthesis of cyclic phosphorus-centered chiral ligands mainly relies on classical chiral resolution of diastereomers or chiral auxiliary group synthesis, which is time-consuming, labor-intensive, and consumes a large amount of chiral resolution agents or chiral auxiliary groups. The synthetic raw materials used are phosphine chloride and secondary phosphine, which have strong odors and are air-sensitive and difficult to operate. Although the Glueck team used the Pd / Me-DuPhos catalytic system to catalyze the secondary phosphine and secondary phosphine borane to synthesize benzopentacyclic phosphorus, the Pd metal catalyst is expensive, and the product can only obtain 70% ee at most. The substrate preparation route requires the use of primary phosphine-borane, which is difficult to synthesize and difficult to operate (Brunker, TJ; Anderson, BJ; Blank, NFetc. Org. Lett. 2007, 9 (6), 1109-1112). In the early stage, our team used secondary phosphine oxide as raw material to catalyze the asymmetric synthesis of chiral benzophosphine oxide compounds with phosphorus centers. However, it is difficult to further reduce phosphine oxide compounds to more applicable trivalent phosphine compounds. There is a lack of general reduction methods, and the reduction process often reduces the optical purity of the phosphorus chiral center (Liu, BX; Liu, P.; Wang, X. etc. Org. Lett. 2023, 25 (13), 2178-2183). At present, there is a lack of methods for catalytic asymmetric synthesis of trivalent phosphorus chiral center compounds with high enantioselectivity. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a method for directly synthesizing a borane-protected trivalent phosphorus-centered chiral benzophosphorus heterocycle (6-10-membered ring) by using air-stable and easy-to-operate secondary phosphine borane as a raw material, cheap metal copper and commercial chiral ethylenediamine ligand as a catalytic system through a dynamic kinetic resolution CP (III) coupling / cyclization reaction; the borane protecting group on the product can be removed by using N-methylpiperazine or the like, without affecting the optical activity of the phosphorus chiral center and with high yield.

[0006] The present invention adopts the following technical solution:

[0007] A method for copper-catalyzed asymmetric synthesis of trivalent phosphorus-centered chiral compounds, the synthesis route of which is shown in Reaction Formula I:

[0008]

[0009] In reaction formula I, R 1 is selected from hydrogen, C1-5 alkyl, halogen, C1-5 alkoxy, trifluoromethyl, R 2 is selected from C1-C10 alkyl, phenyl or substituted phenyl, aryl or substituted aryl, alkenyl or substituted alkenyl, n is an integer of 1 to 5, X is a halogen I, Y is an oxygen atom or a carbon atom, and the chiral ligand L* is any one or a combination of compounds L1-L11 (chiral diamine ligands or amino acid ligands),

[0010]

[0011] The trivalent phosphorus-centered chiral compound is compound 3. The trivalent phosphorus-centered chiral compound has a trivalent phosphorus-centered chiral benzophosphorus heterocycle (6-10 membered ring) structure.

[0012] Preferably, the Cu catalyst is selected from one or more of CuBr, CuCl, CuI, CuO, CuOTf, Cu(MeCN)4PF6, Cu(MeCN)4BF4, CuOH, CuCl2, CuBr2, CuSO4, and Cu(OAc)2.

[0013] Preferably, the solvent is selected from one or more of N,N-dimethylformamide, thionyl chloride, dichloromethane, tetrahydrofuran, hexane, ethyl acetate, methyl tert-butyl ether, toluene, chlorobenzene, xylene, hexane, ether, dioxane, ethylene dichloride, acetone, isopropanol, and methanol.

[0014] Preferably, the base is selected from Na2CO3, K2CO3, Cs2CO3, NaOH, CsF, Na3PO4, K3PO4, Et3N, sodium tert-butoxide, sodium hydride.

[0015] Preferably, the specific steps of the method are:

[0016] 1): Under the protection of inert gas, raw material compound 1 (secondary phosphoborane), Cu catalyst, chiral ligand L*, base and solvent are added to the reactor, and stirred at 0-60° C. for 1-15 hours to generate compound 2 (a chiral benzo 6-10-membered phosphorus heterocycle with a trivalent phosphorus center);

[0017] 2): Add compound 2 to a reactor, add an organic solvent such as tetrahydrofuran or toluene to dissolve it, then add nitrogen methylpiperazine or triethylamine, and stir at a temperature range of 0-50° C. for 0.5-2 hours to generate compound 3.

[0018] The trivalent phosphorus-centered chiral compound described in the present invention has a trivalent phosphorus-centered chiral benzophosphorus heterocycle (6-10-membered ring) structure, which is compound 2 or compound 3, that is: a trivalent phosphorus-centered chiral benzo six-membered phosphorus heterocycle and its borane complex, a trivalent phosphorus-centered chiral benzo seven-membered phosphorus heterocycle and its borane complex, a trivalent phosphorus-centered chiral benzo eight-membered phosphorus heterocycle and its borane complex, a trivalent phosphorus-centered chiral benzo nine-membered phosphorus heterocycle and its borane complex, or a trivalent phosphorus-centered chiral benzo ten-membered phosphorus heterocycle and its borane complex.

[0019] Preferably, the molar ratio of compound 1:Cu catalyst:chiral ligand L* is: 1:0.02-0.2:0.02-0.2.

[0020] Preferably, in the reactor of step 1), the concentration of compound 1 is 0.02-2.0 mol / L.

[0021] Preferably, the compound 1 is prepared by reducing the secondary phosphine oxide with a borane complex such as borane dimethyl sulfide or borane tetrahydrofuran, using the following reaction formula II (reference method M. Stankevic, KM Pietrusiewicz. Synlett 2003, 7, 1012-1016):

[0022]

[0023] The present invention also provides a trivalent phosphorus-centered chiral compound, characterized in that its structural formula is as shown in compound 3,

[0024]

[0025] In the structural formula, R 1 is selected from hydrogen, C1-5 alkyl, halogen, C1-5 alkoxy, trifluoromethyl, R 2 It is selected from C1-C10 alkyl, phenyl or substituted phenyl, aryl or substituted aryl, alkenyl or substituted alkenyl, n is an integer of 1 to 5, and Y is an oxygen atom or a carbon atom.

[0026] The present invention also provides application of the trivalent phosphorus-centered chiral compound in metal-catalyzed asymmetric catalytic reactions.

[0027] Compared with the prior art, the beneficial effects of the present invention include at least:

[0028] 1. Using air-stable and easy-to-operate secondary phosphine borane as raw material, under the catalysis of cheap copper metal and commercial chiral ethylenediamine ligand, the dynamic kinetic resolution CP (III) coupling / cyclization reaction strategy is used to directly synthesize borane-protected trivalent phosphorus-centered chiral benzophosphorus heterocycles. This method is simple to operate, the conversion rate of the raw material secondary phosphine borane is high, and the direct synthesis product is a trivalent phosphorus-centered chiral benzophosphorus heterocycle, and the product has high enantioselectivity.

[0029] 2. Compared with the preparation route using secondary phosphine oxide as raw material, the present invention overcomes the technical problems of difficulty in reducing phosphine oxide compounds, lack of universal reduction methods, and reduction process reducing the optical purity of the phosphorus chiral center. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The single crystal structure of compound 2c (7-membered phosphorus heterocycle);

[0031] Figure 2 The single crystal structure of compound 2e (9-membered phosphorus heterocycle);

[0032] Figure 3 is the H NMR spectrum of compound 3c (7-membered phosphorus heterocycle);

[0033] Figure 4 is the carbon NMR spectrum of compound 3c (7-membered phosphorus heterocycle);

[0034] Figure 5 is the H NMR spectrum of compound 2f (10-membered phosphorus heterocycle);

[0035] Figure 6 is the carbon NMR spectrum of compound 2f (10-membered phosphorus heterocycle);

[0036] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of compound 7 prepared in Example 12. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical scheme and beneficial effects of the present invention clearer, the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. Examples of the embodiments are shown in the accompanying drawings. It should be understood that the specific embodiments described in the following embodiments of the present invention are only exemplary descriptions of the specific embodiments of the present invention, and are intended to be used to explain the present invention, but do not constitute a limitation of the present invention.

[0038] The endpoints of ranges and any values ​​disclosed herein are not limited to the exact range or value, and these ranges or values ​​should be understood to include approximations to these ranges.

[0039] Example 1: Preparation of Compound 1b Secondary Phosphine Borane

[0040]

[0041] Phosphine oxide 4b (15 mmol), THF (180 mL) were added to the reaction bottle, followed by H2O (90 mol, 6.0 equiv) and BH3·SMe2 complex (90 mmol, 2.0 M THF) and reacted at room temperature under argon atmosphere for 1.0 h. Water (50 mL) was then added, and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The crude product was loaded on a silica gel column and purified with petroleum ether / dichloromethane (8:1 to 4:1) to give pure product 1b.

[0042] Compound 1b: 81% yield, colorless oil; 31 P NMR (CDCl3, 162MHz): δ–3.5 (dm, J=430.9Hz); 1H NMR (CDCl3, 400MHz): δ7.81–7.83 (m, 1H), 7.69–7.74 (m, 2H), 7.54–7.58 (m, 1H), 7. 48–7.52(m, 2H), 7.28–7.30(m, 1H), 7.16–7.18(m, 1H), 6.88–6.93(m, 1H), 5.48(m, J H-P =368.0Hz, 1H), 2.71–2.74(m, 2H), 1.97–2.10(m, 2H), 1.68–1.69(m, 4H), 0.83(m, 3H, BH3); 13 C{ 1 H}NMR (CDCl3, 100MHz): δ144.4, 139.6, 132.9 (d, 3 J P–C =8.6Hz, 2C), 131.8(d, 4 J P–C =2.2Hz), 129.5, 129.2(d, 2 J P–C =9.9Hz, 2C), 128.5, 128.0, 125.7(d, 1 J P–C =55.0Hz), 100.6, 40.3, 31.2(d, 2 J P–C =11.8Hz), 24.1(d, 3 J P–C =2.6Hz), 23.6(d, 1 J P–C =31.7Hz); HRMS(ESI):m / z[M+Na] + Calculate for C 16 H 21 BIPNa + :405.0411, found405.0412.

[0043] Example 2: Preparation of Compound 1c Secondary Phosphine Borane

[0044]

[0045] Phosphine oxide 4c (15 mmol), THF (180 mL) were added to the reaction bottle, followed by H2O (90 mol, 6.0 equiv) and BH3·SMe2 complex (90 mmol, 2.0 M THF) and reacted at room temperature under argon atmosphere for 1.0 h. Water (50 mL) was then added, and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The crude product was loaded on a silica gel column and purified with petroleum ether / dichloromethane (8:1 to 4:1) to give pure product 1c.

[0046] Compound 1c: 38% yield, colorless oil; 31 P NMR (CDCl3, 162MHz): δ–6.0 (dm, J=362.9Hz); 1 H NMR (CDCl3, 400MHz): δ7.81–7.83 (m, 1H), 7.62–7.66 (m, 2H), 7.27–7.30 (m, 1H), 7.16–7.18 (m, 1H), 7.00–7.02 (m, 2H), 6.88–6.93 (m, 1H), 5.47 (m, J H-P =368.0Hz, 1H), 3.88(s, 3H), 2.70–2.74(m, 2H), 1.94–2.03(m, 2H), 1.64–1.72(m, 4H), 0.80(m, 3H, BH3); 13 C{ 1 H}NMR(CDCl3, 100MHz): δ162.5(d, 4 J P–C =2.1Hz), 144.4, 139.6, 134.7(d, 3 J P–C =9.9Hz, 2C), 129.5, 128.5, 128.0, 115.9(d, 1 J P–C =59.5Hz), 114.8(d, 2 J P–C =10.9Hz, 2C), 100.6, 55.5, 40.3, 31.2(d, 2 J P–C =12.0Hz), 23.9(d, 1 J P–C =35.1Hz), 24.0(d, 3 J P–C =2.3Hz); HRMS(ESI):m / z[M+Na] + Calculate for C 17 H23 BIOPNa + :435.0516, found 435.0517.

[0047] Example 3: Preparation of Compound 1d Secondary Phosphine Borane

[0048]

[0049] Phosphine oxide 4d (15 mmol), THF (180 mL) were added to the reaction bottle, followed by H2O (90 mol, 6.0 equiv) and BH3·SMe2 complex (90 mmol, 2.0 M THF) and reacted at room temperature under argon atmosphere for 1.0 h. Water (50 mL) was then added, and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The crude product was loaded on a silica gel column and purified with petroleum ether / dichloromethane (8:1 to 4:1) to give pure product 1d.

[0050] Compound 1d is a colorless oil; 31 P NMR (CDCl3, 162MHz): δ–2.8 (d, J=374.2Hz); 1 H NMR (CDCl3, 400MHz): δ7.66–7.73 (m, 3H), 7.43–7.52 (m, 3H), 7.23–7.25 (m, 1H), 6.65–6.68 (m, 1H), 5.50 (m, J H-P =367.6Hz, 1H), 3.93–3.96 (m, 2H), 1.62–2.00 (m, 8H), 0.86 (m, 3H, BH3); 13 C{ 1 H}NMR (CDCl3, 100MHz): δ156.5, 138.6, 132.9 (d, 2 J P–C =8.7Hz, 2C), 131.8(d, J P–C =1.4Hz), 129.3(d, 3 J P–C =7.7Hz, 2C), 129.1, 126.4, 125.7(d, 1 J P–C =54.8Hz), 112.5, 86.9, 69.2, 28.6, 27.3(d, 2 J P–C =12.4Hz), 24.1(d, 3 J P–C =2.0Hz), 23.7(d, 1J P–C =35.3Hz); HRMS(ESI):m / z[M+Na] + Calculate for C 17 H 22 BClIOPNa + :469.0127, found469.0123.

[0051] Example 4: Preparation of Compound 2a from Compound 1a

[0052]

[0053] Compound 1a (0.3 mmol, 1.0 equiv), CuI (5.7 mg, 0.03 mmol, 10 mmol%), L1 (10.8 mg, 0.045 mmol, 15 mmol%) and Cs2CO3 (195.5 mg, 0.6 mmol, 2.0 equiv) were added to the reaction vessel, and then 2 mL of methylcyclopentane solvent was added under argon atmosphere and stirred at room temperature for 24 hours. 5.0 mL of ethyl acetate was then added to the mixture. The resulting suspension was filtered through celite, and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was loaded onto a silica gel column and purified with petroleum ether / dichloromethane (10:1 to 4:1) to obtain pure product 2a.

[0054] 80% yield, colorless oil; 31 P NMR (CDCl3, 162MHz): δ–3.3 (dm, J=390.4Hz); 1 H NMR (CDCl3, 400MHz): δ7.78–7.80 (m, 1H), 7.65–7.70 (m, 2H), 7.51–7.55 (m, 1H), 7. 44–7.48(m, 2H), 7.24–7.28(m, 1H), 7.13–7.16(m, 1H), 6.87–6.91(m, 1H), 5.47(m, J H-P =368.4Hz, 1H), 2.76–2.80 (m, 2H), 1.97–2.06 (m, 2H), 1.81–1.90 (m, 2H), 0.81 (m, 3H, BH3); 13 C{ 1 H}NMR (CDCl3, 100MHz): δ143.3, 139.7, 132.9 (d, 3 J P–C =8.6Hz, 2C), 131.8(d, 4 J P–C =2.2Hz), 129.6, 129.2(d, 2 JP–C =9.9Hz, 2C), 128.6, 128.3, 125.5(d, 1 J P–C =55.1Hz), 100.6, 41.4(d, 2 J P–C =12.3Hz), 24.9(d, 3 J P–C =2.2Hz), 23.1(d, 1 J P–C =35Hz); HRMS(ESI):m / z[M+Na] + calcdfor C 14 H 17 BIPNa + :391.0254, found 391.0255.

[0055] Example 5: Preparation of Compound 2b from Compound 1b

[0056]

[0057] Compound 1b (0.3 mmol, 1.0 equiv), CuI (5.7 mg, 0.03 mmol, 10 mmol%), L1 (10.8 mg, 0.045 mmol, 15 mmol%) and Cs2CO3 (195.5 mg, 0.6 mmol, 2.0 equiv) were added to the reaction vessel, and then 2 mL of methylcyclopentane solvent was added under argon atmosphere and stirred at room temperature for 24 hours. 5.0 mL of ethyl acetate was then added to the mixture. The resulting suspension was filtered through celite, and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was loaded onto a silica gel column and purified with petroleum ether / dichloromethane (10:1 to 4:1) to obtain pure product 2b.

[0058] Compound 2b: 81% yield, white solid, mp 60.8–62.3°C; [α] D 25 =+31.0 (c=0.26, CHCl3, 95%ee); HPLC (Chiralpak AD-H, hexane / i-PrOH=98 / 2, flow rate=1.0mL / min, l=230nm), τ major =8.4min, τ minor =7.4min; 31 P NMR (CDCl3, 162MHz): δ21.1 (m); 1H NMR (CDCl3, 400MHz): δ7.70–7.75 (m, 1H), 7.40–7.51 (m, 6H), 7.30 (t, J=7.6Hz, 1H), 7.22–7.24 (m, 1H), 2.96–3.02 (m, 1H), 2.66 –2.73(m, 1H), 2.30–2.40(m, 1H), 2.17–2.54(m, 1H), 1.89–2.06(m, 2H), 1.73–1.78(m, 1H), 1.64–1.69(m, 1H), 0.87(m, 3H, BH3); 13 C{ 1 H}NMR(CDCl3, 100MHz): δ146.6(d, 2 J P–C =3.8Hz), 135.7(d, 2 J P–C =15.4Hz), 132.1(d, 4 J P–C =2.1Hz), 131.6(d, 3 J P–C =8.7Hz, 2C), 130.8(d, 4 J P–C =2.2Hz), 130.8(d, 1 J P–C =53.9Hz), 130.3(d, 3 J P–C =7.9Hz), 129.0(d, 2 J P–C =9.7Hz, 2C), 127.4(d, 1 J P–C =52.1Hz), 126.7(d, 3 J P–C =11.9Hz), 34.9, 27.7, 25.7(d, 1 J P–C =35.8Hz), 23.4(d, 2 J P–C =5.9Hz); HRMS(ESI):m / z[M+Na] + calcdfor C 16 H 20 BNa + :277.1288, found 277.1289.

[0059] Example 6: Preparation of Compound 2c from Compound 1c

[0060]

[0061] Compound 1c (0.3 mmol, 1.0 equiv), CuI (5.7 mg, 0.03 mmol, 10 mmol%), L1 (10.8 mg, 0.045 mmol, 15 mmol%) and Cs2CO3 (195.5 mg, 0.6 mmol, 2.0 equiv) were added to the reaction vessel, and then 2 mL of methylcyclopentane solvent was added under an argon atmosphere and stirred at room temperature for 24 hours. 5.0 mL of ethyl acetate was then added to the mixture. The resulting suspension was filtered through diatomaceous earth, and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was loaded onto a silica gel column and purified with petroleum ether / dichloromethane (10:1 to 4:1) to obtain pure product 2c. Taking 2c as an example, its single crystal structure is shown in the figure below. Figure 1 shown.

[0062] 76% yield, white solid, [α] D 25 =–16.3 (c=0.26, CHCl3, 93%ee); HPLC (Chiralpak AD-H, hexane / i-PrOH=98 / 2, flow rate=1.0mL / min, l=230nm), τ major =16.4min, τ minor =10.7min; 31 P NMR (CDCl3, 162MHz): δ13.9 (m); 1 HNMR (CDCl3, 400MHz): δ7.74 (dd, J=8.4Hz, 13.2Hz, 1H), 7.54–7.59 (m, 2H), 7.45–7.49 (m, 1H), 7.17–7.21 (m, 1H), 7.12–7.14 (m, 1 H), 6.92–6.93(m, 2H), 4.33–4.38(m, 1H), 3.93–3.98(m, 1H), 3.81(s, 3H), 2.38–2.45(m, 1H), 2.08–2.16(m, 3H), 0.85(m, 3H, BH3); 13 C{ 1 H}NMR(CDCl3, 100MHz): δ162.7(d, 4 J P–C =1.2Hz), 161.9(d, 3 J P–C =2.3Hz), 136.0(d, 2 J P–C =13.9Hz), 133.9(d, 3 J P–C=10.7Hz, 2C), 133.7(d, 4 J P–C =2.2Hz), 124.8(d, 2 J P–C =11.4Hz), 122.5(d, 3 J P–C =5.0Hz), 122.3(d, 1 J P–C =51.9Hz), 120.1(d, 1 J P–C =60.4Hz), 114.5(d, 2 J P–C =11.1Hz, 2C), 74.0(d, 3 J P–C =2.2Hz), 55.4, 25.5(d, 2 J P–C =6.1Hz), 25.0(d, 1 J P–C =37.4Hz); HRMS(ESI):m / z[M+Na] + calcdfor C 16 H 20 BO2PNa + :309.1186, found 309.1185.

[0063] Example 7: Preparation of Compound 2d from Compound 1d

[0064]

[0065] Compound 1d (0.3 mmol, 1.0 equiv), CuI (5.7 mg, 0.03 mmol, 10 mmol%), L1 (10.8 mg, 0.045 mmol, 15 mmol%) and K2CO3 (82.8 mg, 0.6 mmol, 2.0 equiv) were added to the reaction vessel, and then 2 mL of toluene solvent was added under argon atmosphere and stirred at 30°C for 24 hours. 5.0 mL of ethyl acetate was then added to the mixture. The resulting suspension was filtered through celite, and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was loaded onto a silica gel column and purified with petroleum ether / dichloromethane (10:1 to 4:1) to obtain pure product 2d.

[0066] Compound 2d, 38% yield, white solid, mp 110.6–111.4 °C; [α] D 25=–100.0(c=0.08,CHCl3,96%ee);HPLC(ChiralpakAD-H,hexane / i-PrOH=98 / 2,flow rate=1.0mL / min,l=230nm),τ major =10.5min,τ minor =8.4min; 31 P NMR(CDCl3,162MHz):δ16.7(m); 1 H NMR(CDCl3,400MHz):δ7.67–7.70(m,1H),7.59–7.64(m,2H),7.38–7.46(m,4H),7.07–7.10(m,1H),4.35(t,J=11.6Hz,1H),4.11–4.14(m,1H),3.09–3.20(m,1H),2.20–2.30(m,1H),1.80–2.11(m,3H),1.50–1.53(m,1H),0.86(m,3H,BH3); 13 C{ 1 H}NMR(CDCl3,100MHz):δ158.2(d, 2 J P–C =1.4Hz),134.2(d, 2 J P–C =15.4Hz),133.6(d, 3 J P–C =2.0Hz),131.9(d, 3 J P–C =9.3Hz,2C),131.2(d, 3 J P–C =2.5Hz),131.4(d, 1 J P–C =56.7Hz),130.4,130.3,128.9(d, 2 J P–C =10.1Hz,2C),127.7(d, 1 J P–C =48.7Hz),76.0,28.3(d, 1 J P–C =36.9Hz),23.6(d, 3 J P–C =3.3Hz),22.0(d, 2 J P–C =3.6Hz);HRMS(ESI):m / z[M+Na] + calcd for C 16 H19 BClOPNa + :327.0847, found327.0844.

[0067] Example 8: Preparation of Compound 2e from Compound 1e

[0068]

[0069] Compound 1e (0.3 mmol, 1.0 equiv), CuI (5.7 mg, 0.03 mmol, 10 mmol%), L1 (10.8 mg, 0.045 mmol, 15 mmol%) and K2CO3 (82.8 mg, 0.6 mmol, 2.0 equiv) were added to the reaction vessel, and then 2 mL of toluene solvent was added under an argon atmosphere and stirred at 30°C for 24 hours. 5.0 mL of ethyl acetate was then added to the mixture. The resulting suspension was filtered through diatomaceous earth, and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was loaded onto a silica gel column and purified with petroleum ether / dichloromethane (10:1 to 4:1) to obtain pure product 2e. Taking 2e as an example, its single crystal structure is shown in the figure below. Figure 2 shown.

[0070] Compound 2e: 76% yield, white solid; [α] D 25 =–48.3 (c=0.48, CHCl3, 90%ee); HPLC (Chiralpak AD-H, hexane / i-PrOH=98 / 2, flow rate=1.0mL / min, l=230nm), τ major =11.3min, τ minor =7.6min; 31 P NMR (CDCl3, 162MHz): δ20.9 (m); 1 H NMR (CDCl3, 400MHz): δ7.69–7.74 (m, 2H), 7.58 (d, J=13.6Hz, 1H), 7.35–7.43 (m, 3H), 7.26–7.29 (m, 1H), 6.95–6.97 (m, 1H), 4.40–4.45 (m, 1H), 4.11–4.16 (m, 1H), 2.68–2.77 (m, 1H), 2.28 (s, 3H), 2.09–2.18 (m, 1H), 1.85–2.00 (m, 2H), 1.47–1.78 (m, 4H), 0.85 (m, 3H, BH3); 13 C{ 1 H}NMR(CDCl3, 100MHz): δ159.4(d, 2 JP–C =1.9Hz), 136.5(d, 2 J P–C =14.7Hz), 134.1(d, 4 J P–C =2.3Hz), 132.6(d, 3 J P–C =11.9Hz), 132.0(d, 1 J P–C =55.2Hz), 132.0(d, 3 J P–C =9.2Hz, 2C), 130.8(d, 4 J P–C =2.4Hz), 128.6(d, 2 J P–C =9.9Hz, 2C), 118.4(d, 1 J P–C =53.4Hz), 117.2(d, 3 J P–C =4.6Hz), 73.5, 27.3(d, 2 J P–C =6.7Hz), 26.5, 24.8(d, 1 J P–C =39.4Hz), 21.4(d, 3 J P–C =3.3Hz), 20.8; HRMS(ESI):m / z[M+Na] + Calculate for C 18 H 24 BOPNa + :321.1550, found 321.1546.

[0071] Example 9: Preparation of Compound 2f from Compound 1f

[0072]

[0073] Compound 1f (0.3 mmol, 1.0 equiv), CuI (5.7 mg, 0.03 mmol, 10 mmol%), L1 (10.8 mg, 0.045 mmol, 15 mmol%) and K2CO3 (82.8 mg, 0.6 mmol, 2.0 equiv) were added to the reaction vessel, and then 2 mL of toluene solvent was added under argon atmosphere and stirred at 30°C for 24 hours. 5.0 mL of ethyl acetate was then added to the mixture. The resulting suspension was filtered through celite, and the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was loaded onto a silica gel column and purified with petroleum ether / dichloromethane (10:1 to 4:1) to obtain pure product 2f.

[0074] Compound 2f: 16% yield, white solid, 16% yield, [α] D 25 =–71.5 (c=0.26, CHCl3, 97%ee); HPLC (Chiralpak AD-H, hexane / i-PrOH=95 / 5, flow rate=1.0mL / min, l=230nm), τ major =13.6min, τ minor =12.4min; 31 P NMR (CDCl3, 162MHz): δ21.1 (m); 1 H NMR (CDCl3, 400MHz): δ7.71–7.77 (m, 1H), 7.57–7.62 (m, 2H), 7.35–7.51 (m, 4H), 6.94–7.04 (m, 2H), 4.08–4 .22(m, 2H), 2.51–2.61(m, 1H), 1.98–2.07(m, 1H), 1.58–1.82(m, 6H), 1.42–1.48(m, 2H), 0.85(m, 3H, BH3); 13 C{ 1 H}NMR (CDCl3, 100MHz): δ160.8, 136.8(d, 2 J P–C =13.7Hz), 133.4(d, 4 J P–C =1.8Hz), 132.2(d, 3 J P–C =9.3Hz, 2C), 131.1(d, 1 J P–C =56.3Hz), 130.6(d, 3 J P–C =2.7Hz), 128.5(d, 2 JP–C =10.5Hz, 2C), 121.4(d, 2 J P–C =11.7Hz), 117.5(d, 1 J P–C =52.1Hz), 111.9(d, 2 J P–C =4.1Hz), 70.2, 28.1(d, 2 J P–C =9.5Hz), 26.2, 24.2(d, 1 J P–C =37.6Hz), 24.0, 21.3(d, 3 J P–C =4.4Hz); HRMS(ESI):m / z[M+Na] + Calculate for C 18 H 24 BOPNa + :321.1550, found321.1551.

[0075] Example 10: Preparation of Compound 3b from Compound 2b

[0076]

[0077] Compound 2b (51 mg, 0.2 mmol, 95% ee) and PhMe (2 mL) were added to the reaction vessel, N-methylpiperazine (101 mg, 1.0 mmol) was added to the reaction liquid, and the mixture was stirred at 30 ° C for 5 hours under an argon atmosphere. Water (1.0 mL) was then added to quench the reaction, and the aqueous layer was extracted with EtOAc (8 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Flash column chromatography eluted with hexane / dichloromethane gave compound 3 (46 mg, 96% yield)

[0078] Compound 3: 1 HNMR (CDCl3, 400MHz): δ7.56–7.57 (m, 2H), 7.44 (s, 3H), 7.15–7.18 (m, 2H), 6.99–7.03 (m, 1H), 6.70–6.7 3(m, 1H), 3.03–3.09(m, 1H), 2.88–2.93(m, 1H), 2.09–2.31(m, 3H), 1.95–2.01(m, 2H), 1.44–1.53(m, 1H); 13 C{ 1 H}NMR (CDCl3, 100MHz): δ146.4 (d, J P–C=16.5Hz), 141.3(d, J P–C =14.4Hz), 137.6(d, J P–C =9.1Hz), 134.1(d, J P–C =19.9Hz, 2C), 131.2(d, J P–C =10.1Hz), 129.4, 129.4 (d, J P–C =1.7Hz), 128.8(d, J P–C =7.3Hz, 2C), 127.8, 125.7 (d, J P–C =3.6Hz), 36.3(d, J P–C =7.5Hz)), 28.6(d, J P–C =9.8Hz), 28.5(d, J P–C =2.1Hz), 27.1(d, J P–C =11.1Hz);

[0079] Example 11: Preparation of Compound 3c from Compound 2c

[0080]

[0081] Compound 2c (51 mg, 0.2 mmol, 94% ee) and PhMe (2 mL) were added to the reaction vessel, N-methylpiperazine (101 mg, 1.0 mmol) was added to the reaction liquid, and the mixture was stirred at 30 ° C for 5 hours under an argon atmosphere. Water (1.0 mL) was then added to quench the reaction, and the aqueous layer was extracted with EtOAc (8 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. Flash column chromatography eluted with hexane / dichloromethane gave compound 3c (46 mg, 95% yield).

[0082] White solid.[α] D 25 =+26.0 (c 0.30, CHCl3, 94%ee); 31 P NMR (CDCl3, 162MHz4.): δ–12.2(m); 1 H NMR (CDCl3, 400MHz): δ7.52–7.56 (m, 2H), 7.41 (s, 3H), 7.20–7.24 (m, 1H), 7.02–7.05 (m, 1H), 6.95 (t, J=7 .6Hz, 1H), 6.85–6.89(m, 1H), 4.33–4.37(m, 1H), 3.85–3.90(m, 1H), 2.03–2.33(m, 3H), 1.96–2.03(m, 1H); 13C{ 1 H}NMR (CDCl3, 100MHz): δ163.1(d, J P–C =8.1Hz), 137.4(d, J P–C =10.3Hz), 133.7(d, J P–C =19.9Hz, 2C), 133.5(d, J P–C =15.5Hz), 133.2(d, J P–C =16.2Hz), 129.7, 129.3, 128.8 (d, J P–C =7.2Hz, 2C), 123.8(d, J P–C =5.3Hz), 121.7, 74.2 (d, J P–C =5.4Hz), 21.9(d, J P–C =7.4Hz), 25.2(d, J P–C =11.7Hz); HRMS(ESI):m / z[M+Na]+calcd for C 16 H 18 P + :241.1141, found 241.1138.

[0083] Example 12: Application of compound 2c as a ligand in metal-catalyzed coupling reactions

[0084]

[0085] Compound 5 (0.2 mmol), compound 6 (0.22 mmol), Pd(OAc)2 (0.004 mmol), ligand 3c (0.006 mmol), Na2CO3 (0.4 mmol), and 2 ml of toluene were added to the reaction flask and reacted at 60°C for 8 hours to obtain compound 7 (72% yield, 52% ee).

[0086] White solid.[α] D 25 =+27.1 (c 0.30, CHCl3, 52%ee); 1 HNMR (CDCl3, 400MHz):

[0087] 8.00-8.04 (m, 2H), 7.93-7.96 (m, 1H), 7.87 (d, J = 9.2 Hz, 2H), 7.60 (m, 1H), 7.51 (m, 1H), 7.19-7.40 (m, 12H), 7.05-7.14 (m, 4H). H NMR spectrum Figure 7 shown.

[0088] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention and do not constitute a limitation on the content of the present invention. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for copper-catalyzed asymmetric synthesis of trivalent phosphorus-centered chiral compounds, characterized in that: Its synthetic route is shown in reaction formula I. In reaction formula I, R 1 is selected from hydrogen, C1-5 alkyl, halogen, C1-5 alkoxy, trifluoromethyl, R 2 is selected from C1-C10 alkyl, phenyl or substituted phenyl, aryl or substituted aryl, alkenyl or substituted alkenyl, n is an integer of 1 to 5, X is a halogen I, Y is an oxygen atom or a carbon atom, and the chiral ligand L* is any one or a combination of compounds L1-L11, The trivalent phosphorus-centered chiral compound is compound 3.

2. The method according to claim 1, characterized in that The Cu catalyst is selected from one or more of CuBr, CuCl, CuI, CuO, CuOTf, Cu(MeCN)4PF6, Cu(MeCN)4BF4, CuOH, CuCl2, CuBr2, CuSO4, and Cu(OAc)2.

3. The method according to claim 1, characterized in that The solvent is selected from one or more of N,N-dimethylformamide, thionyl chloride, dichloromethane, tetrahydrofuran, hexane, ethyl acetate, methyl tert-butyl ether, toluene, chlorobenzene, xylene, hexane, ether, dioxane, ethylene dichloride, acetone, isopropanol, and methanol.

4. The method according to claim 1, characterized in that The base is selected from Na2CO3, K2CO3, Cs2CO3, NaOH, CsF, Na3PO4, K3PO4, Et3N, sodium tert-butoxide, and sodium hydride.

5. The method according to any one of claims 1 to 4, characterized in that: The specific steps of the method are: 1): Under the protection of inert gas, raw material compound 1, Cu catalyst, chiral ligand L*, base and solvent are added to the reactor, and stirred at 0-60° C. for 1-15 hours to generate compound 2; 2) Add compound 2 to a reactor, add tetrahydrofuran or toluene to dissolve it, then add nitrogen methylpiperazine or triethylamine, and stir at a temperature range of 0-50° C. for 0.5-2 hours to generate compound 3.

6. The method according to claim 5, characterized in that The molar ratio of compound 1: Cu catalyst: chiral ligand L* is: 1: 0.02~0.2: 0.02~0.

2.

7. The method according to claim 5, characterized in that In the reactor of step 1), the concentration of the compound 1 is 0.02-2.0 mol / L.

8. The method according to claim 5, characterized in that The compound 1 is prepared by reducing the secondary phosphine oxide with borane dimethyl sulfide or borane tetrahydrofuran, using the following reaction formula II:

9. A trivalent phosphorus-centered chiral compound, characterized in that: Its structural formula is shown in compound 3. In the structural formula, R 1 is selected from hydrogen, C1-5 alkyl, halogen, C1-5 alkoxy, trifluoromethyl, R 2 It is selected from C1-C10 alkyl, phenyl or substituted phenyl, aryl or substituted aryl, alkenyl or substituted alkenyl, n is an integer of 1 to 5, and Y is an oxygen atom or a carbon atom.

10. Use of a trivalent phosphorus-centered chiral compound as claimed in claim 9 in a metal-catalyzed asymmetric catalytic reaction.

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