Method for constructing chiral nitrogen heterocycle through palladium-catalyzed asymmetric dynamic kinetics C-N coupling

Abstract

The invention discloses a method for constructing a chiral nitrogen heterocyclic ring through palladium-catalyzed asymmetric dynamic kinetics C-N coupling, and belongs to the technical field of organic synthesis. The invention relates to a method for constructing a chiral nitrogen heterocyclic ring by palladium-catalyzed asymmetric dynamic kinetics C-N coupling, which comprises the following steps: uniformly mixing a palladium catalyst, a ligand, alkali and a solvent, adding a compound with a saturated racemic nitrogen heterocyclic ring and an aryl halide, and mixing for reaction to obtain the compound with the chiral nitrogen heterocyclic ring. According to the method disclosed by the invention, the used substrate is a compound with a saturated racemic azacyclo-ring, the substrate synthesis steps are simple and efficient, and the problem that a high-purity chiral alcohol raw material needs to be used in a traditional synthesis method or a substrate preparation method is complicated is solved; the method is mild in reaction condition, easy in reaction condition control, strong in chiral control capability, wide in substrate applicability and very good in applicability to heterocyclic ring substrates, the ee value of most of the compounds is 90% or above, and various compounds with chiral nitrogen heterocyclic rings can be synthesized.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for constructing a chiral nitrogen heterocycle through palladium-catalyzed asymmetric dynamic kinetic CN coupling. Background Art

[0002] Chiral nitrogen-containing heterocyclic structures are widely present in natural products and pharmaceuticals and serve as important synthetic building blocks for the construction of numerous high-value-added functional molecules. For example, niraparib is a poly(adenosine diphosphate) ribose polymerase (PARP) inhibitor used to treat ovarian cancer; larotrectinib has been approved for the treatment of cancer; and ezetimibe has lipid-lowering properties. The successful launch of these drugs fully demonstrates the importance and enormous potential of chiral nitrogen-containing heterocyclic rings in drug development. Therefore, the efficient and precise construction of such structures has important research significance and application value, and will play a vital role in the synthesis of natural products, pharmaceutical molecules, and material molecules.

[0003] Several techniques have been developed for the asymmetric synthesis of α-substituted chiral nitrogen-containing heterocycles, including intramolecular stereospecific substitution reactions, asymmetric hydrogenation of imines, transition-metal-catalyzed asymmetric reductive amination, and asymmetric C-H activation reactions. While extensive research has focused on catalytic system design (e.g., metallo / enzyme / photocatalysis) and substrate activation methods (e.g., Negishi coupling, C–H functionalization), these synthetic strategies still face several pressing challenges. First, they require high-purity chiral alcohol substrates (e.g., a substrate (S:R) = 93:7), resulting in cumbersome synthesis steps and generally low yields. Second, asymmetric hydrogenation and reductive amination reactions often require precise control of reaction temperature, hydrogen pressure, and specialized solvents, resulting in demanding, time-consuming, and tedious reactions. Third, kinetic resolution methods using amines are generally applicable only to substrates with specific structural characteristics, limiting their applicability. Furthermore, these methods offer a theoretical maximum yield of only 50%, resulting in reduced atom economy. Therefore, there is an urgent need to find a synthesis method with low substrate purity requirements, simple synthesis steps, easy-to-control reaction conditions, wide applicability and high product yield. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for constructing chiral nitrogen heterocycles by palladium-catalyzed asymmetric dynamic kinetic CN coupling, so as to solve the problems existing in the above-mentioned prior art.

[0005] To achieve the above object, the present invention provides the following solutions:

[0006] One of the technical solutions of the present invention: a method for constructing a chiral nitrogen heterocycle by palladium-catalyzed asymmetric dynamic kinetic CN coupling, comprising the following steps:

[0007] After uniformly mixing a palladium catalyst, a ligand, a base, and a solvent, a compound having a saturated racemic nitrogen heterocycle (R:S=50:50) and an aryl halide are added, mixed and reacted to obtain a compound having a chiral nitrogen heterocycle;

[0008] The structure of the ligand is:

[0009] wherein R1 is selected from one of substituted phenyl, pyridyl, substituted pyridyl and substituted benzyl;

[0010] R2 is selected from one of tert-butyl, isopropyl, benzyl, phenyl and pyridyl.

[0011] The present invention uses a compound having a saturated racemic nitrogen heterocycle as a substrate, complexes it with a palladium catalyst and a chiral ligand, and generates a palladium ammonia intermediate through oxidative addition and anion exchange. The dominant intermediate forms a chiral nitrogen heterocycle product through reduction elimination; while the non-dominant intermediate tends to undergo β-H elimination to form an imine, and then the non-dominant intermediate is converted into a chiral nitrogen heterocycle through re-migration insertion. The reasonable ligand design of the present invention facilitates the conversion of the non-dominant intermediate into the chiral nitrogen heterocycle.

[0012] The method of the present invention is a method for synthesizing chiral nitrogen heterocycles using a saturated, non-activated racemic nitrogen heterocycle (i.e., a compound having a saturated racemic nitrogen heterocycle) as a starting material through a single ligand-controlled palladium-catalyzed asymmetric dynamic kinetic CN coupling reaction. The chiral nitrogen heterocycles prepared by the method of the present invention have advantages such as high yield, good enantioselectivity, and structural diversity.

[0013] Preferably, the ligand (S configuration, the palladium catalyst and the ligand are complexed under solvent conditions to form a metal ligand complex, which reacts with the aryl halide and the nitrogen heterocycle through a series of oxidative additions to form a palladium amino intermediate. Different ligand structures can regulate the CN coupling reaction process to form a chiral nitrogen heterocycle, and the palladium catalyst and the ligand are reduced and eliminated to return to the state of the metal ligand complex) is selected from any one of the following compounds:

[0014]

[0015]

[0016] Preferably, the palladium catalyst comprises Pd 2(dba)3 (tris(dibenzylideneacetone)dipalladium), Pd(OAc)2 (palladium acetate), PdCl2 (palladium chloride), Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium), [Pd(allyl)Cl]2 (allylpalladium chloride dimer), Pd(PPh3)2Cl2 (dichlorobis(triphenylphosphine)palladium) and Pd(MeCN)2Cl2 (dichlorodiacetonitrile palladium); more preferably [Pd(allyl)Cl]2 (allylpalladium chloride dimer).

[0017] Preferably, the molar amount of the palladium catalyst is 1 to 10% of the molar amount of the compound having a saturated racemic nitrogen heterocycle;

[0018] The molar amount of the ligand is 3 to 20% of the molar amount of the compound having a saturated racemic nitrogen heterocycle;

[0019] The molar ratio of the base to the compound having a saturated racemic nitrogen heterocycle is (1-2.5):1.

[0020] Preferably, the molar ratio of the palladium catalyst to the ligand is 1:3, 5:10, 5:12.5, 5:15, 5:20, 10:10, 10:15 or 10:20; more preferably 5:15.

[0021] Preferably, the base is selected from potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), sodium tert-butoxide (NaO t Bu), potassium tert-butoxide (KO t Bu), lithium tert-butoxide (LiO t Bu), potassium phosphate (K3PO4), potassium acetate (KOAc), sodium acetate (NaOAc), lithium fluoride (LiF), cesium fluoride (CsF), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), lithium tetrafluoroborate (LiBF4) and sodium methoxide (CH3ONa); more preferably sodium tert-butoxide (NaO t Bu).

[0022] Preferably, the molar ratio of the base to the compound having a saturated racemic nitrogen heterocycle is 1:1, 1.5:1, 2.0:1, 2.5:1 or 3:1; more preferably 2:1.

[0023] Preferably, the solvent is selected from tetrahydrofuran (THF), chloroform (CHCl3), methyl tert-butyl ether (MTBE), toluene, acetonitrile (MeCN), 1,4-dioxane, dichloromethane (DCM), 1,2-dichlorobenzene, tert-butyl alcohol ( tThe solvent is preferably selected from the group consisting of BuOH, ethyl acetate (EtOAc), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), cyclohexane, trifluorotoluene (Benzotrifluoride) and chlorobenzene (Chlorobenzene); more preferably methyl tert-butyl ether (MTBE).

[0024] Preferably, the concentration of the compound having a saturated racemic nitrogen heterocycle in the solvent is 0.05M, 0.1M, 0.15M or 0.2M; more preferably 0.1M.

[0025] Preferably, the compound having a saturated racemic nitrogen heterocycle is selected from any one of the following compounds:

[0026]

[0027]

[0028] Wherein, R is selected from one of hydrogen atom, halogen atom, trifluoromethyl group, cyano group, nitro group, aldehyde group, methoxycarbonyl group, methyl group, isopropyl group, tert-butyl group, methoxy group, trifluoromethoxy group, dimethylamino group and acetoxy group.

[0029] Preferably, the halogen atom is F, Cl or Br.

[0030] Preferably, the aryl halide is selected from any one of the following compounds:

[0031]

[0032] Among them, Me is a methyl group, MeO is a methoxy group, BnO is a benzyloxy group, CN is a cyano group, Bpin is a pinacol borate group, i-Pr is an isopropyl group; and I / Br represents an I atom or a Br atom.

[0033] Preferably, the molar ratio of the compound having a saturated racemic nitrogen heterocycle to the aryl halide is (1-2): (1-2); more preferably 1:1.5;

[0034] The temperature of the mixed reaction is 0-80° C., and the time is 8-18 hours.

[0035] Preferably, the structure of the compound having a chiral nitrogen heterocycle (S configuration) is as follows:

[0036]

[0037]

[0038] The second technical solution of the present invention: a compound having a chiral nitrogen heterocycle prepared by the above preparation method.

[0039] The third technical solution of the present invention: an application of the above-mentioned compound having a chiral nitrogen heterocycle as a pharmaceutical intermediate.

[0040] Preferably, the compound having a chiral nitrogen heterocycle can be used as a synthetic and other drug intermediates.

[0041] The present invention discloses the following technical effects:

[0042] (1) The substrate used in the method of the present invention is a compound having a saturated racemic nitrogen heterocycle. The substrate synthesis step is simple and efficient, avoiding the problem of using high-purity chiral alcohol raw materials or complex substrate preparation methods in traditional synthesis methods. In addition, the method of the present invention has mild reaction conditions, easy control of reaction conditions, strong chirality control ability, and most of the ee values are above 90%. In addition, the substrate has wide applicability and has good applicability to heterocyclic substrates, and can synthesize a variety of compounds having chiral nitrogen heterocycles.

[0043] (2) Traditional palladium-catalyzed intermolecular CN coupling relies on a kinetic resolution strategy, which is limited by thermodynamic equilibrium (theoretical yield ≤ 50%), resulting in the waste of half of the raw materials. However, the method of the present invention uses a compound having a saturated racemic nitrogen heterocycle as a raw material, and through a single ligand-controlled palladium-catalyzed asymmetric dynamic kinetic CN coupling reaction, the racemic substrate is racemized and asymmetrically transformed, thereby achieving complete conversion of the raw material and constructing an intermolecular CN bond with high stereoselectivity. It has the advantages of good atom economy, strong chirality control ability, high yield (up to 88%), and high stereoselectivity (up to 94%).

[0044] (3) In the traditional palladium-catalyzed CN coupling strategy between molecules, the palladium-amino intermediate (Pd-NR2) is prone to β-H elimination / reinsertion to trigger product racemization, which has low enantioselectivity (i.e., leads to low stereoselectivity). However, the present invention uses ligand design to precisely regulate the two competitive elementary reactions of "β-H elimination (dynamic equilibrium)" and "reductive elimination (stereoselectivity)" at the same time, which has the advantages of good enantioselectivity and new reaction mechanism. DETAILED DESCRIPTION

[0045] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0046] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0047] It should be pointed out that the matters not described in detail in the present invention are conventional operating means in this field and are not the focus of the present invention.

[0048] Example 1

[0049] Palladium-catalyzed asymmetric dynamic kinetic CN coupling method for the construction of chiral nitrogen heterocycles:

[0050] General Method A: In a nitrogen-filled glove box, [Pd(allyl)Cl]2 (3.6 mg, 0.01 mmol, 5 mol%), ligand 3s (15.4 mg, 0.03 mmol, 15 mol%), sodium tert-butoxide (38.4 mg, 0.4 mmol, 2.0 equiv), and 2.0 mL of anhydrous methyl tert-butyl ether were added sequentially to a Shrek tube. After stirring at room temperature for 15 minutes, an aryl halide (0.3 mmol, 1.5 equiv) and a compound containing a saturated racemic nitrogen heterocycle (0.2 mmol, 1.0 equiv) were added sequentially. The mixture was removed from the glove box and reacted at 60°C for 8 hours. After completion of the reaction, the precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) to obtain the desired product.

[0051] General Method B: In a nitrogen-filled glove box, [Pd(allyl)Cl]2 (3.6 mg, 0.01 mmol, 5 mol%), ligand 3s (15.4 mg, 0.03 mmol, 15 mol%), sodium tert-butoxide (38.4 mg, 0.4 mmol, 2.0 equiv), and 2.0 mL of anhydrous methyl tert-butyl ether were added sequentially to a Shrek tube. After stirring at room temperature for 15 minutes, an aryl halide (0.3 mmol, 1.5 equiv) and a compound containing a saturated racemic nitrogen heterocycle (0.2 mmol, 1.0 equiv) were added sequentially. The mixture was removed from the glove box and reacted at 40°C for 16 hours. After completion of the reaction, the precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) to obtain the desired product.

[0052] General Method C: In a nitrogen-filled glove box, [Pd(allyl)Cl]2 (3.6 mg, 0.01 mmol, 5 mol%), ligand 3s (15.4 mg, 0.03 mmol, 15 mol%), sodium tert-butoxide (38.4 mg, 0.4 mmol, 2.0 equiv), and 2.0 mL of anhydrous methyl tert-butyl ether were added sequentially to a Shrek tube. After stirring at room temperature for 15 minutes, an aryl halide (0.3 mmol, 1.5 equiv) and a compound containing a saturated racemic nitrogen heterocycle (0.2 mmol, 1.0 equiv) were added sequentially. The mixture was removed from the glove box and allowed to react at 10°C for 8 hours. After completion of the reaction, the precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) to obtain the desired product.

[0053] General Method D: In a nitrogen-filled glove box, [Pd(allyl)Cl]2 (3.6 mg, 0.01 mmol, 5 mol%), ligand 3s (15.4 mg, 0.03 mmol, 15 mol%), sodium tert-butoxide (38.4 mg, 0.4 mmol, 2.0 equiv), and 2.0 mL of anhydrous methyl tert-butyl ether were added sequentially to a Shrek tube. After stirring at room temperature for 15 minutes, an aryl halide (0.3 mmol, 1.5 equiv) and a compound containing a saturated racemic nitrogen heterocycle (0.2 mmol, 1.0 equiv) were added sequentially. The mixture was removed from the glove box and allowed to react at 0°C for 18 hours. After completion of the reaction, the precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) to obtain the desired product.

[0054] General Method E: In a nitrogen-filled glove box, [Pd(allyl)Cl]2 (3.6 mg, 0.01 mmol, 5 mol%), ligand 3s (15.4 mg, 0.03 mmol, 15 mol%), sodium tert-butoxide (38.4 mg, 0.4 mmol, 2.0 equiv), and 2.0 mL of anhydrous methyl tert-butyl ether were added sequentially to a Shrek tube. After stirring at room temperature for 15 minutes, an aryl halide (0.3 mmol, 1.5 equiv) and a compound containing a saturated racemic nitrogen heterocycle (0.2 mmol, 1.0 equiv) were added sequentially. The mixture was removed from the glove box and allowed to react at 15°C for 18 hours. After completion of the reaction, the precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) to obtain the desired product.

[0055] The structural formula of 3s in general methods A to E is:

[0056] Compound 4a Prepared according to general method A, 31.7 mg of white solid with a yield of 83% and an ee value of 90%.

[0057] 1 H NMR (400MHz, CDCl3) δ7.31(dd,J=7.7,6.9Hz,2H),7.25–7.23(m,3H),7.16(dd,J=8.7,7.3Hz,2H),6.65(t,J=7.3Hz,1H),6.54– 6.48(m,2H),4.74(dd,J=8.3,1.8Hz,1H),3.79–3.67(m,1H),3.42(td,J=9.1,6.8Hz,1H),2.47–2.33(m,1H),2.14–1.92(m,3H). 13 C NMR(101MHz, CDCl3)δ147.24,144.72,129.11,128.59,126.73,126.03,115.85,112.43,63.01,49.20,36.18,23.19.HRMS(ESI)m / z calculated for C 16 H 18 N + [M+H] + 224.1439,found 224.1444.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 6.3 min, t R (minor) = 8.8min, ee value is 90% ee.

[0058] Compound 4b Prepared according to general method A, 18.9 mg of white solid with a yield of 40% and an ee value of 88%.

[0059] 1H NMR(400MHz, CDCl3)δ7.34(d,J=7.2Hz,2H),7.24(dd,J=10.2,4.7Hz,2H),7.18–7 .14(m,1H),7.14–7.09(m,1H),6.97(dd,J=11.2,4.1Hz,1H),6.85(d,J=7.9Hz,1H ),6.80(t,J=7.3Hz,1H),4.69(dd,J=9.1,6.3Hz,1H),4.00–3.86(m,1H),2.97–3. 02(m,J=8.8,4.4Hz,1H),2.38–2.44(m,4H),2.13–2.01(m,1H),1.85–1.98(m,2H). 13 C NMR (101MHz, CDCl3) δ152.32,148.54,143.84,131.38,130.80,128.39,126.7 1,126.06,121.10,118.00,64.52,54.25,37.17,24.62,20.25.HRMS(ESI)m / z calculated forC 16 H 18 N + [M+H] + 238.1596,found238.1595.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 9.3 min, t R (minor) = 9.8min, ee value is 88%.

[0060] Compound 4c Prepared according to general method A, 37.5 mg of white solid with a yield of 79% and an ee value of 90%.

[0061] 1H NMR (400MHz, CDCl3) δ7.32(dd,J=9.8,4.9Hz,2H),7.27–7.22(m,3H),7.05(t,J=7.8Hz,1H),6.50(d,J=7.4Hz,1H),6.38(s,1H),6.31(dd, J=8.2,2.3Hz,1H),4.79–4.71(m,1H),3.77–3.68(m,1H),3.43(td,J=9.0,6.8Hz,1H),2.45–2.33(m,1H),2.28(s,3H),2.10–1.91(m,3H). 13 C NMR (101MHz, CDCl3) δ147.40,144.88,138.78,128.99,128.55,126.66,126.04,116 .89,113.01,109.79,62.99,49.25,36.17,23.17,21.99.HRMS(ESI)m / zcalculated for C 17 H 20 N + [M+H] + 238.1596,found 238.1593.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.4 min, t R (minor) = 9.5min, ee value is 90%.

[0062] Compound 4d Prepared according to general method A, 32.3 mg of white solid with a yield of 68% and an ee value of 90%.

[0063] 1 H NMR (400MHz, CDCl3) δ7.31–7.25(m,2H),7.20(dd,J=12.3,7.1Hz,3H),6.95(d,J=8.5Hz,2H),6.40(d,J=8.5Hz,2H),4 .67(dd,J=8.3,1.7Hz,1H),3.74–3.61(m,1H),3.34–3.40(m,1H),2.34–2.38(m,1H),2.20(s,3H),2.08–1.87(m,3H). 13C NMR(101MHz, CDCl3)δ145.23,145.01,129.64,128.56,126.65,126.05,124.83,112.40,63.12,49.40,36.24,23.28,20.38.HRMS(ESI)m / z calculated for C 17 H 20 N + [M+H] + 238.1596,found238.1593.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.1 min, t R (minor) = 6.1min, ee value is 90%.

[0064] Compound 4e Prepared according to general method B, 34.6 mg of white solid, with a yield of 62% and an ee value of 90%.

[0065] 1 H NMR (400MHz, CDCl3) δ7.25–7.33(m,4H),7.23(dd,J=5.1,3.5Hz,1H),7.21–7.17(m,2H),6.47(d,J=8.5Hz,2H),4.69(dd, J=8.4,2.0Hz,1H),3.72(t,J=7.2Hz,1H),3.39(td,J=9.1,6.7Hz,1H),2.43–2.24(m,1H),2.11–1.87(m,3H),1.26(s,9H). 13 C NMR(101MHz, CDCl3)δ145.21,138.42,128.57,126.70,126.08,125.93,112.04,63.34,49.41,36.23,33.85,31.68,23.32.HRMS(ESI)m / z calculated for C 20 H 26 N + [M+H] + 280.2065,found 280.2071.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, tR (major) = 4.4 min, t R (minor) = min, ee value is 90%.

[0066] Compound 4f Prepared according to general method A, 24.6 mg of yellow oily liquid, with a yield of 51% and an ee value of 91%.

[0067] 1 H NMR (400MHz, CDCl3) δ7.34–7.28(m,2H),7.22(t,J=6.1Hz,3H),6.89–6.80(m,2H),6.41(s,2H),4.65(dd,J= 8.2,2.1Hz,1H),3.70(t,J=7.0Hz,1H),3.37(dd,J=15.8,8.8Hz,1H),2.36–2.44(m,1H),2.12–1.91(m,3H). 13 C NMR (101MHz, CDCl3) δ155.03 (d, J = 234.3Hz), 144.68, 143.94, 128.65, 126.83, 1 26.00, 115.47 (d, J = 22.2Hz), 112.79 (d, J = 7.1Hz), 63.44, 49.73, 36.36, 23.36. 19 F NMR(376MHz,CDCl3)δ-130.47.HRMS(ESI)m / zcalculated for C 16 H 17 FN + [M+H] + 242.1345, found 242.1341.Optical Rotation: [α] 23D = -88.9 (c = 0.06, CHCl3).HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH = 99 / 1, t R (major) = 5.6 min, t R (minor) = 6.8min, ee value is 91%.

[0068] Compound 4g Prepared according to general method A, 42.8 mg of white solid, with a yield of 83% and an ee value of 90%.

[0069] 1H NMR (400MHz, CDCl3) δ7.33–7.27(m,2H),7.24–7.20(m,1H),7.17–7.20(m,2H),7.09–7.03(m,2H),6.43–6.34(m,2H) ,4.68(dd,J=8.2,2.1Hz,1H),3.73–3.61(m,1H),3.38(td,J=8.9,7.1Hz,1H),2.48–2.31(m,1H),2.11–1.89(m,3H). 13 C NMR(101MHz, CDCl3)δ145.75,144.17,128.87,128.69,126.92,125.96,120.66,113.47,63.12,49.38,36.25,23.23.HRMS(ESI)m / z calculated for C 16 H 17 C1N + [M+H] + 258.1050,found258.1046.Optical Rotation: (c=0.68, CHCl3). HPLC analysis: OD-H, 254nm, flow rate 0.9mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.9 min, t R (minor) = 7.5min, ee value is 90%.

[0070] Compound 4h Prepared according to general method A, 45.3 mg of white solid with a yield of 75% and an ee value of 90%.

[0071] 1 H NMR (400MHz, CDCl3) δ7.32–7.22(m,3H),7.22–7.15(m,4H),6.34(t,J=6.1Hz,2H),4.67(dd,J=8.2, 1.8Hz,1H),3.74–3.60(m,1H),3.37(dd,J=16.0,8.9Hz,1H),2.48–2.31(m,1H),2.08–1.90(m,3H). 13C NMR(101MHz, CDCl3)δ146.08,144.04,131.72,128.69,126.93,125.94,114.04,107.76,63.04,49.31,36.22,23.19.HRMS(ESI)m / z calculated for C 16 H 17 BrN + [M+H] + 302.0550,found 302.0544.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 6.0 min, t R (minor) = 7.5min, ee value is 90%.

[0072] Compound 4i Prepared according to general method C, 43.7 mg of colorless liquid, with a yield of 75% and an ee value of 90%.

[0073] 1 H NMR (400MHz, CDCl3) δ7.35(d,J=8.8Hz,2H),7.31(t,J=7.5Hz,2H),7.24(dd,J=9.8,4.0Hz,1H),7.17(d,J=7.2Hz,2H),6.49 (d,J=8.7Hz,2H),4.86–4.72(m,1H),3.81–3.65(m,1H),3.46(dd,J=16.3,8.8Hz,1H),2.37–2.46(m,1H),2.12–1.92(m,3H). 13 C NMR (101MHz, CDCl3) δ149.19, 143.52, 128.78, 127.07, 126.35 (q, J = 3.0Hz), 125.89, 117.50, 117.17, 111.85, 62.96, 49.18, 36.10, 23.05. 19 F NMR(376MHz,CDCl3)δ-60.60.HRMS(ESI)m / zcalculated for C 17 H 17 F3N + [M+H] + 292.1313,found 292.1309.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.8 min, t R (minor) = 8.9min, ee value is 90%.

[0074] Compound 4j Prepared according to general method A, 28.4 mg of yellow oily liquid, with a yield of 53% and an ee value of 90%.

[0075] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=7.9Hz,1H),7.24(dd,J=12.9,4.8Hz,3H),7.20–7.16(m,1H),7.11(t,J=7.2Hz,3H),6.60(dd,J =8.2,1.7Hz,1H),4.72(d,J=6.9Hz,1H),3.77–3.63(m,1H),3.42(dd,J=16.2,8.8Hz,1H),2.50–2.30(m,1H),2.09–1.87(m,3H). 13 C NMR (101MHz, CDCl3) δ149.35,147.63,143.18,129.53,128.88,127.25,125.89,118.35,110.53,106.49,63.24,49.51,36.22,23.12.HRMS (ESI) m / z calculated forC 16 H 17 N2O2 + [M+H] + 269.1290,found 269.1291.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 11.6 min, t R (minor) = 28.7min, ee value is 90%.

[0076] Compound 4k Prepared according to general method A, 49.2 mg of white solid with a yield of 80% and an ee value of 82%.

[0077] 1H NMR (600MHz, CDCl3) δ7.22(t,J=7.5Hz,2H),7.14(dd,J=11.8,4.4Hz,1H),7.10(d,J=7.4Hz,2H),6.99(t,J=8.2Hz,1H),6.39(d,J=8.0Hz,1H),6.27(d d,J=8.4,1.7Hz,1H),6.23(s,1H),4.68–4.58(m,1H),3.59(td,J=8.9,2.3H z,1H),3.32(dd,J=16.1,9.1Hz,1H),2.30–2.34(m,1H),2.03–1.82(m,3H). 13 C NMR (151MHz, CDCl3) δ150.43,148.50,143.86,129.89,128.73,127.00,125.94 ,120.65(q,J=175.2Hz),110.91,107.62,104.85,63.20,49.35,36.18,23.12. 19 F NMR(565MHz,CDCl3)δ-57.45.HRMS(ESI)m / zcalculated for C 17 H 17 F3NO + [M+H] + 308.1262,found 308.1260.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 4.9 min, t R (minor) = 8.4min, ee value is 82%.

[0078] Compound 4l Prepared according to general method A, 44.8 mg of white solid, with a yield of 79% and an ee value of 90%.

[0079] 1H NMR (600MHz, CDCl3) δ7.22–7.15(m,2H),7.12(t,J=8.2Hz,3H),5.76(s,1H),5.62(s,2H),4.66–4.57(m,1H),3.60(d,J=9 .1Hz,1H),3.59(s,6H),3.33(dd,J=16.1,9.0Hz,1H),2.28–2.31(m,1H),1.95(dd,J=15.1,6.3Hz,1H),1.92–1.81(m,2H). 13 C NMR(151MHz, CDCl3)δ161.47,149.04,144.62,128.61,126.75,125.96,91.86,88.31,63.27,55.15,49.43,36.10,23.14.HRMS(ESI)m / z calculated for C 18 H 22 NO2 + [M+H] + 284.1651,found 284.1653.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 8.5 min, t R (minor) = 10.5min, ee value is 90%.

[0080] Compound 4m Prepared according to general method A, 35.2 mg of white solid with a yield of 73% and an ee value of 90%.

[0081] 1 H NMR (600MHz, CDCl3) δ7.21(t,J=7.5Hz,2H),7.14(d,J=7.8Hz,1H),7.11(t,J=7 .3Hz,2H),6.96(dd,J=15.5,7.9Hz,1H),6.23(dd,J=11.7,4.8Hz,1H),6.15(d, J=8.3Hz,1H),6.10(d,J=12.5Hz,1H),4.62(d,J=7.9Hz,1H),3.58(dd,J=11.9, 4.7Hz,1H),3.31(dd,J=16.1,9.0Hz,1H),2.27–2.34(m,1H),2.01–1.79(m,3H). 13C NMR (151MHz, CDCl3) δ164.06 (d, J = 241.6Hz), 148.91 (d, J = 12.1Hz), 144.08, 130.05 (d, J = 10.6Hz), 128.69, 1 26.93, 125.94, 108.28 (d, J = 3.0Hz), 102.38 (d, J = 21.1Hz), 99.41 (d, J = 27.2Hz), 63.16, 49.36, 36.15, 23.09. 19 F NMR(565MHz,CDCl3)δ-112.86–-113.00(m).HRMS(ESI)m / z calculated for C 16 H 17 FN + [M+H] + 242.1345,found 242.1344.OpticalRotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.9 min, t R (minor) = 17.7min, ee value is 90%.

[0082] Compound 4n Prepared according to general method A, 40.7 mg of white solid, with a yield of 68% and an ee value of 92%.

[0083] 1 H NMR (600MHz, CDCl3) δ7.40 (d, J=7.3Hz, 2H), 7.29 (dd, J=15.3, 7.8Hz, 2H), 7.24 –7.18(m,3H),7.16(d,J=7.4Hz,2H),7.15–7.08(m,2H),6.78(d,J=7.5Hz,1H),6 .64(s,1H),6.38(d,J=8.0Hz,1H),4.73–4.64(m,1H),3.72–3.63(m,1H),3.39(d d,J=15.9,8.9Hz,1H),2.28–2.33(m,1H),1.86–1.91(m,1H),1.93–1.83(m,2H). 13C NMR (151MHz, CDCl3) δ147.56,144.62,142.31,142.20,129.45,128.64,127.38,127.0 9,126.81,126.07,115.15,111.70,111.30,63.19,49.38,36.22,23.25.HRMS(ESI)m / z calculated forC 22 H 22 N + [M+H] + 300.1758,found 300.1752.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 8.1 min, t R (minor) = 26.5min, ee value is 92%.

[0084] Compound 4o Prepared according to general method A, 42.1 mg of white solid, with a yield of 77% and an ee value of 90%.

[0085] 1 H NMR (600MHz, CDCl3) δ8.30(d,J=8.3Hz,1H),7.67(d,J=8.0Hz,1H),7.39(t,J=7.1Hz,1H) ,7.34(dd,J=10.9,3.9Hz,1H),7.29(dd,J=15.8,7.8Hz,3H),7.13–7.04(m,3H),7.01(t,J =7.3Hz,1H),6.79(d,J=7.5Hz,1H),4.63(t,J=7.6Hz,1H),4.14–4.02(m,1H),3.00(t,J=7 .1Hz,1H),2.37(dd,J=6.8,4.3Hz,1H),2.09–1.98(m,1H),1.88(dd,J=17.6,11.5Hz,2H). 13 C NMR (151MHz, CDCl3) δ146.74,143.40,134.96,129.48,128.41,128.29,126.81,126.69,125.89, 125.60,124.89,124.59,121.88,114.00,64.58,56.73,36.81,24.48.HRMS(ESI)m / zcalculated for C20 H 20 N + [M+H] + 274.1596,found274.1600.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 6.4 min, t R (minor) = 7.6min, ee value is 90%.

[0086] Compound 4p Prepared according to general method A, 41.0 mg of white solid with a yield of 75% and an ee value of 82%.

[0087] 1 H NMR (600MHz, CDCl3) δ7.67(d,J=8.1Hz,1H),7.61(t,J=9.0Hz,2H),7.34(dd,J =12.0,7.1Hz,3H),7.29(d,J=6.6Hz,2H),7.26(t,J=7.2Hz,1H),7.17(t,J=7. 3Hz,1H),6.93–6.88(m,1H),6.79(s,1H),4.93(d,J=7.3Hz,1H),3.87(t,J=7. 3Hz, 1H), 3.58 (dd, J=16.1, 9.0Hz, 1H), 2.47–2.51 (m, 1H), 2.19–1.98 (m, 3H). 13 C NMR (151MHz, CDCl3) δ145.11,144.60,135.16,128.77,128.65,127.65,126.84,126.2 1,126.10,126.01,121.55,116.30,105.65,63.03,49.44,36.23,23.19.HRMS(ESI)m / z calculated for C 20 H 20 N + [M+H] + 274.1596,found 274.1601.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 9.0 min, tR (minor) = 13.9min, ee value is 82%.

[0088] Compound 4q Prepared according to general method D, 36.1 mg of yellow oily liquid with a yield of 71% and an ee value of 90%.

[0089] 1 H NMR (400MHz, CDCl3) δ7.31–7.24(m,3H),7.23–7.18(m,3H),5.94(d,J=7.8Hz,1H),5.77(d,J=8.0Hz,1H),4.95( dd,J=8.1,2.1Hz,1H),3.91–3.80(m,1H),3.71(s,3H),3.63–3.69(m,1H),2.46–2.33(m,1H),2.09–1.89(m,3H). 13 C NMR(101MHz, CDCl3)δ163.27,156.06,144.98,139.50,128.40,126.53,125.88,98.52,95.91,61.99,52.96,48.22,35.97,23.21.HRMS(ESI)m / z calculated for C 16 H 19 N2O + [M+H] + 255.1497,found255.1523.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.8 min, t R (minor) = 17.8min, ee value is 90%.

[0090] Compound 4r Prepared according to general method A, 22.8 mg of white solid with a yield of 48% and an ee value of 84%.

[0091] 1H NMR(600MHz, CDCl3) δ7.23(d,J=7.4Hz,1H),7.20–7.14(m,3H),7.12(dd,J=12.1,7.0Hz,2H),6.67(t,J=7.2Hz,1H),6.46(d,J=8.0Hz,2H),4 .88(dd,J=8.4,1.3Hz,1H),3.77(t,J=7.5Hz,1H),3.44–3.48(m,1H),2.47(s,3H),2.45–2.36(m,1H),2.14–1.99(m,2H),1.93–1.84(m,1H). 13 C NMR (151MHz, CDCl3) δ147.08,142.09,134.21,130.68,129.13,126.65,126.17,125 .60,115.85,112.35,60.50,49.17,33.98,23.15,19.43.HRMS(ESI)m / zcalculated for C 17 H 20 N + [M+H] + 238.1596,found 238.1595.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 6.0 min, t R (minor) = 9.1min, ee value is 84%.

[0092] Compound 4s Prepared according to general method A, 34.2 mg of white solid with a yield of 72% and an ee value of 90%.

[0093] 1 H NMR (600MHz, CDCl3) δ7.24–7.16(m,3H),7.07(dd,J=13.1,7.2Hz,3H),6.67(t,J=7.2Hz,1H),6.54(d,J=7.8Hz,2H),4.72(d,J=7.5 Hz,1H),3.74(t,J=7.6Hz,1H),3.43(dd,J=16.0,9.1Hz,1H),2.44–2.37(m,1H),2.36(s,3H),2.13–2.03(m,1H),2.04–1.94(m,2H). 13C NMR (151MHz, CDCl3) δ147.38,144.86,138.17,129.10,128.47,127.56,126.6 7,123.12,115.84,112.47,63.15,49.27,36.20,23.22,21.70.HRMS(ESI)m / z calculatedfor C 17 H 20 N + [M+H] + 238.1596,found 238.1592.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.3 min, t R (minor) = 12.6min, ee value is 90%.

[0094] Compound 4t Prepared according to general method A, 32.3 mg of white solid with a yield of 68% and an ee value of 90%.

[0095] 1 H NMR (600MHz, CDCl3) δ7.19–7.11(m,6H),6.65(t,J=6.9Hz,1H),6.52(d,J=7.0Hz,2H),4.77–4.68(m,1H) ,3.71(t,J=7.3Hz,1H),3.41(dd,J=16.0,9.1Hz,1H),2.36-2.40(m,1H),2.34(s,3H),2.11–1.89(m,3H). 13 C NMR (151MHz, CDCl3) δ147.32,141.73,136.27,129.46,129.30,129.11,125.99,115.80,112.44,62.80,49.19,36.25,23.20,21.20.HRMS(ESI) m / z calculated for C 17 H 20 N + [M+H] + 238.1596,found 238.1593.OpticalRotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.1 min, t R (minor) = 11.7min, ee value is 90%.

[0096] Compound 4u Prepared according to general method A, 28.6 mg of white solid, with a yield of 57% and an ee value of 90%.

[0097] 1 H NMR (600MHz, CDCl3) δ7.17(dd,J=8.6,7.4Hz,2H),6.86(d,J=5.2Hz,3H),6.65(t,J=7.2Hz,1H),6.53(d,J=7.8Hz,2H),4.68–4.62 (m,1H),3.71(t,J=7.6Hz,1H),3.39(td,J=9.2,6.9Hz,1H),2.40–2.34(m,1H),2.29(s,6H),2.10–2.02(m,1H),2.00–1.87(m,2H). 13 CNMR(151MHz, CDCl3)δ147.53,145.03,138.05,129.09,128.51,123.77,115.78,112.48,63.27,49.32,36.22,23.25,21.57.HRMS(ESI)m / z calculated for C 18 H 22 N + [M+H] + 252.1752,found252.1752.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 4.7 min, t R (minor) = 8.8min, ee value is 90%.

[0098] Compound 4v Prepared according to general method A, 32.8 mg of colorless liquid with a yield of 68% and an ee value of 92%.

[0099] 1H NMR (600MHz, CDCl3) δ7.15–7.21(m,4H),6.99(t,J=8.7Hz,2H),6.67(t,J=7.2Hz,1H),6.49(d,J=7.9Hz,2H), 4.71(d,J=7.2Hz,1H),3.78–3.65(m,1H),3.41(dd,J=16.3,8.9Hz,1H),2.37-2.40(m,1H),2.09–1.86(m,3H). 13 C NMR (151MHz, CDCl3) δ161.82 (d, J = 244.6Hz), 147.14, 140.33, 129.16, 127.51 (d ,J=7.6Hz),116.12,115.40(d,J=21.1Hz),112.52,62.46,49.24,36.25,23.16. 19 F NMR(565MHz,CDCl3)δ-116.72.HRMS(ESI)m / z calculated for C 16 H 17 FN + [M+H] + 242.1345,found 242.1342.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.9 min, t R (minor) = 22.1min, ee value is 92%.

[0100] Compound 4w Prepared according to general method A, 33.5 mg of white solid, with a yield of 65% and an ee value of 90%.

[0101] 1 H NMR (600MHz, CDCl3) δ7.17(t,J=7.0Hz,2H),7.07(dd,J=12.5,5.2Hz,4H),6.57(t,J=7.2Hz,1H),6.39(d,J=8.0Hz,2H),4.64–4.56(m ,1H),3.62(dd,J=12.3,6.5Hz,1H),3.32(dd,J=16.6,8.6Hz,1H),2.36–2.24(m,1H),1.89–1.92(m,2H),1.82(dd,J=7.4,4.6Hz,1H). 13C NMR(151MHz, CDCl3)147.06,143.30,132.36,129.18,128.75,127.48,116.23,112.53,62.54,49.26,36.15.HRMS(ESI)m / z calculated for C 16 H 17 C1N + [M+H] + 258.1050,found258.1050.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 6.5 min, t R (minor) = 28.2min, ee value is 90%.

[0102] Compound 4x Prepared according to general method A, 36.9 mg of white solid, with a yield of 61% and an ee value of 90%.

[0103] 1 H NMR (600MHz, CDCl3) δ7.42(d,J=8.4Hz,2H),7.16(dd,J=8.2,7.5Hz,2H),7.12(d,J=8.3Hz,2H),6.67(t,J=7.2Hz,1H),6.48(d,J=8.0Hz,2H),4 .68(dd,J=8.2,1.6Hz,1H),3.75–3.68(m,1H),3.41(dd,J=16.6,8.5Hz,1H),2.44–2.35(m,1H),1.99–2.02(m,2H),1.91(dd,J=7.5,4.7Hz,1H). 13 C NMR(151MHz, CDCl3)δ147.03,143.84,131.70,129.19,127.89,120.44,116.26,112.55,62.61,49.28,36.10,23.19.HRMS(ESI)m / zcalculated for C 16 H 17 BrN + [M+H] + 302.0544,found302.0543.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 6.6 min, t R (minor) = 28.4min, ee value is 90%.

[0104] Compound 4y Prepared according to general method A, 39.0 mg of white solid with a yield of 67% and an ee value of 85%.

[0105] 1 H NMR (600MHz, CDCl3) δ7.56(d,J=8.1Hz,2H),7.36(d,J=8.0Hz,2H),7.17(dd,J=8.4,7.5Hz,2H),6.68(t,J=7.3Hz,1H),6.48(d,J=8. 0Hz,2H),4.77(d,J=8.0Hz,1H),3.79–3.70(m,1H),3.44(q,J=8.4Hz,1H),2.41–2.47(m,1H),2.05–1.98(m,2H),1.98–1.91(m,1H). 13 C NMR (151MHz, CDCl3) δ148.99, 146.97, 129.25, 126.43, 125.65 (q, J = 6.5Hz), 125.31, 123.51, 116.45, 112.58, 62.85, 49.35, 36.07, 23.23. 19 F NMR(565MHz,CDCl3)δ-62.27.HRMS(ESI)m / z calculated for C 17 H 17 F3N + [M+H] + 292.1307, found 292.1318. Optical Rotation: [α] 23D = -67.7 (c = 0.45, CHCl3). HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH = 99 / 1, t R (major) = 6.2 min, t R (minor) = 31.3min, ee value is 85%.

[0106] Compound 4z Prepared according to general method A, 37.0 mg of white solid with a yield of 73% and an ee value of 90%.

[0107] 1 H NMR (600MHz, CDCl3) δ7.15(t,J=7.8Hz,4H),6.84(d,J=8.6Hz,2H),6.64(t,J=6.5Hz,1H),6.51(d,J=6.8Hz,2H),4.69(d,J=7. 5Hz,1H),3.79(s,3H),3.69(d,J=6.9Hz,1H),3.40(dd,J=16.1,9.0Hz,1H),2.33–2.39(m,1H),1.99(dd,J=50.6,25.5Hz,3H). 13 CNMR(151MHz, CDCl3)δ158.47,147.32,136.73,129.11,127.08,115.82,113.97,112.45,62.47,55.37,49.17,36.29,23.19.HRMS(ESI)m / z calculated for C 17 H 20 NO + [M+H] + 254.1545,found254.1544.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 7.5 min, t R (minor) = 19.4min, ee value is 90%.

[0108] Compound 4ab Prepared according to general method A, 38.1 mg of white solid with a yield of 62% and an ee value of 90%.

[0109] 1 H NMR (600MHz, CDCl3) δ7.16(d,J=8.4Hz,2H),7.12–7.03(m,4H),6.59(t,J=7.2Hz,1H),6.40(d,J=8.0Hz,2H),4.64(d,J=7.0Hz,1H ),3.63(dd,J=12.2,6.4Hz,1H),3.33(dd,J=16.5,8.6Hz,1H),2.38–2.25(m,1H),2.01–1.87(m,2H),1.84(dd,J=7.3,4.7Hz,1H). 13CNMR (151MHz, CDCl3) δ148.06, 147.06, 143.43, 129.22, 127.37, 121.17, 120.64 (q, J = 256.7Hz, 1H), 116.31, 112.56, 62.51, 49.29, 36.13, 23.18. 19 F NMR(565MHz,CDCl3)δ-57.84.HRMS(ESI)m / z calculated for C 17 H 18 F3NO + [M+H] + 308.1256, found 308.1265. Optical Rotation: [α] 23D = -61.5 (c = 0.37, CHCl3). HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH = 99 / 1, t R (major) = 5.7 min, t R (minor) = 26.6min, ee value is 90%.

[0110] Compound 4ac Prepared according to general method A, 37.8 mg of white solid with a yield of 63% and an ee value of 92%.

[0111] 1 H NMR (600MHz, CDCl3) δ7.60–7.55(m,2H),7.53(d,J=8.2Hz,2H),7.43(t,J=7.7Hz,2H),7 .33(d,J=7.4Hz,1H),7.30(d,J=8.0Hz,2H),7.17(dd,J=8.5,7.4Hz,2H),6.66(t,J=7.1 Hz,1H),6.55(d,J=7.1Hz,2H),4.77(d,J=7.0Hz,1H),3.75(t,J=7.5Hz,1H),3.44(td,J =9.1,6.9Hz,1H),2.47–2.37(m,1H),2.08(dd,J=20.2,11.1Hz,1H),2.04–1.97(m,2H). 13CNMR(151MHz,CDCl3)δ147.26,143.84,141.11,139.73,129.17,128.85,127.37,1 27.23,127.17,126.54,116.00,112.55,62.86,49.30,36.19,23.29.HRMS(ESI)m / z calculated for C 22 H 22 N + [M+H] + 300.1752,found 300.1756.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 8.0 min, t R (minor) = 22.4min, ee value is 92%.

[0112] Compound 4ad Prepared according to general method A, 32.3 mg of white solid with a yield of 67% and an ee value of 90%.

[0113] 1 H NMR (600MHz, CDCl3) δ7.17(dd,J=13.8,7.9Hz,1H),7.07(t,J=7.9Hz,2H),6.94(d,J=7.6Hz,1H),6.80–6.86(m,2H),6.58(t,J=7.2Hz,1H),6.41( d,J=8.1Hz,2H),4.61(d,J=7.2Hz,1H),3.67–3.60(m,1H),3.31(dd,J=16 .1,9.0Hz,1H),2.26–2.33(m,1H),2.01–1.88(m,2H),1.88–1.78(m,1H). 13 C NMR (151MHz, CDCl3) δ163.30 (d, J = 246.1Hz), 147.87, 147.08, 130.13 (d, J = 7.6Hz), 129.17, 121.63 (d ,J=3.0Hz),116.27,113.67(d,J=21.1Hz),112.97(d,J=21.1Hz),112.54,62.79,49.27,36.05,23.21. 19F NMR(565MHz, CDCl3)δ-113.07(dd,J=15.1,8.7Hz).HRMS(ESI)m / z calculated for C 16 H 17 FN + [M+H] + 242.1345,found242.1337.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 6.1 min, t R (minor) = 24.8min, ee value is 90%.

[0114] Compound 4ae Prepared according to general method A, 38.5 mg of white solid, with a yield of 66% and an ee value of 90%.

[0115] 1 H NMR (600MHz, CDCl3) δ7.43(s,1H),7.42–7.37(m,1H),7.32(d,J=5.5Hz,2H),7.08(t,J=7.9Hz,2H),6.59(t,J=7.3Hz,1H),6.40(d,J=8.1Hz,2 H),4.67(dd,J=8.3,1.6Hz,1H),3.70–3.62(m,1H),3.34(q,J=8.5Hz,1H),2.32–2.36(m,1H),1.99–1.89(m,2H),1.85(dd,J=7.5,4.6Hz,1H). 13 C NMR (151MHz, CDCl3) δ146.59 (d, J = 158.6Hz), 131.05 (q, J = 33.2Hz), 129.42, 129.23, 129.11, 125.27, 123 .80(dd,J=7.4,3.4Hz),123.46,122.84(dd,J=7.3,3.5Hz),116.47,112.62,62.97,49.42,36.16,23.19. 19 F NMR(565MHz,CDCl3)δ-62.38.HRMS(ESI)m / z calculated for C 17 H 17 F3N + [M+H] +292.1313, found 292.1310. Optical Rotation: [α] 23D = -38.6 (c = 0.28, CHCl3). HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH = 99 / 1, t R (major) = 5.7 min, t R (minor) = 20.4min, ee value is 90%.

[0116] Compound 4af Prepared according to general method A, 32.7 mg of white solid, with a yield of 63% and an ee value of 87%.

[0117] 1 H NMR(600MHz, CDCl3)δ7.09(t,J=7.9Hz,2H),6.94(td,J=9.2,4.3Hz,1H),6.77–6.80(m,1H),6.73–6.76(m,1H),6.61(t,J=7.3Hz,1H),6 .40(d,J=8.1Hz,2H),4.87(d,J=8.4Hz,1H),3.63(t,J=7.7Hz,1H),3.30(dd,J=15.8,8.9Hz,1H),2.36–2.26(m,1H),1.99–1.85(m,3H). 13 C NMR(151MHz, CDCl3)δ157.50(qd,J=219.3,1.8Hz),146.84,133.55(dd,J=16.2,6.4Hz),129.27,116.63,11 6.57, 116.43 (d, J = 8.6Hz), 114.62 (q, J = 8.7Hz), 114.46 (t, J = 8.9Hz), 112.47, 57.19, 49.01, 34.35, 23.31. 19 F NMR(565MHz, CDCl3)δ-118.64–-118.71(m),-124.36–-124.59(m).HRMS(ESI)m / z calculated for C 16 H 16 F2N + [M+H] + 260.1251,found260.1252.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, tR (major) = 5.1 min, t R (minor) = 8.2min, ee value is 87%.

[0118] Compound 4ag Prepared according to general method A, 38.3 mg of white solid with a yield of 70% and an ee value of 90%.

[0119] 1 H NMR (600MHz, CDCl3) δ8.03(d,J=8.4Hz,1H),7.81(d,J=8.0Hz,1H),7.64(d,J=8.0Hz ,1H),7.51–7.46(m,1H),7.43(dd,J=11.0,3.9Hz,1H),7.27–7.19(m,2H),7.02(t,J =8.0Hz,2H),6.54(t,J=7.3Hz,1H),6.38(d,J=8.1Hz,2H),5.35(d,J=8.6Hz,1H),3. 75–3.66(m,1H),3.39(dd,J=16.9,8.8Hz,1H),2.51–2.34(m,1H),2.04–1.85(m,3H). 13 CNMR(151MHz,CDCl3)δ147.11,138.62,134.34,130.52,129.18,129.15,127.41,125.99,1 25.72,125.53,123.30,123.28,115.97,112.52,60.33,49.06,34.45,23.53.HRMS(ESI)m / z calculated for C 20 H 20 N + [M+H] + 274.1596,found 274.1601.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 8.0 min, t R (minor) = 9.2min, ee value is 90%.

[0120] Compound 4ah Prepared according to general method A, 28.3 mg of yellow oily liquid, with a yield of 63% and an ee value of 90%.

[0121] 1 H NMR (600MHz, CDCl3) δ8.56 (s, 1H), 8.49 (d, J = 3.6Hz, 1H), 7.53 (d, J = 7.8Hz, 1H) ,7.23(dd,J=7.6,4.9Hz,1H),7.16(dd,J=8.6,7.4Hz,2H),6.67(t,J=7.3Hz,1H) ,6.47(d,J=8.0Hz,2H),4.77(dd,J=8.3,1.7Hz,1H),3.77–3.69(m,1H),3.42(d d,J=16.3,8.7Hz,1H),2.41–2.48(m,1H),2.06–1.99(m,2H),1.97–1.91(m,1H). 13 C NMR(151MHz, CDCl3)δ147.99,147.97,146.88,140.30,134.16,129.27,123.70,116.52,112.59,60.85,49.28,36.03,23.22.HRMS(ESI)m / z calculated for C 15 H 17 N2 + [M+H] + 225.1392,found225.1393.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=50 / 50, t R (major) = 6.9 min, t R (minor) = 15.0min, ee value is 90%.

[0122] Compound 4ai Prepared according to general method E, 32.7 mg of white liquid, with a yield of 78% and an ee value of 94%.

[0123] 1H NMR (600MHz, CDCl3) δ7.48(d,J=7.4Hz,2H),7.38(t,J=7.6Hz,2H),7.29(t,J=7.3Hz,1H),7.16(t,J=7.9Hz,2H),6.74(t,J=7.3Hz,1H) ,6.45(d,J=7.8Hz,2H),4.93(t,J=7.9Hz,1H),4.10–3.99(m,1H),3.75(dd,J=15.3,8.3Hz,1H),2.70–2.56(m,1H),2.32–2.38(m,1H). 13 C NMR(151MHz, CDCl3)δ152.20,143.80,128.97,128.79,127.49,126.00,118.10,112.26,67.61,49.49,28.01.HRMS(ESI)m / z calculated for C 15 H 16 N + [M+H] + 210.1283,found210.1278.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=50 / 50, t R (major) = 6.3 min, t R (minor) = 9.6min, ee value is 94%.

[0124] Compound 4aj Prepared according to general method A, 50.2 mg of white solid, with a yield of 88% and an ee value of 91%.

[0125] 1 H NMR (600MHz, CDCl3) δ7.23–7.14 (m, 8H), 7.11 (dd, J = 10.3, 3.7Hz, 2H), 6.79 (s ,2H),6.69(s,1H),5.75(s,1H),3.72–3.60(m,1H),3.45(s,1H),2.88(s,2H). 13C NMR (151MHz, CDCl3) δ149.67,143.19,137.99,135.87,129.32,128.39,128.24,127.95,127. 46,127.23,126.98,126.33,117.59,113.96,62.98,43.99,28.14.HRMS(ESI)m / zcalculated for C 21 H 20 N + [M+H] + 286.1596,found 286.1598.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 39.8 min, t R (minor) = 43.5min, ee value is 91%.

[0126] Compound 4ak Prepared according to general method A, 45.7 mg of white solid with a yield of 67% and an ee value of 94%.

[0127] 1 H NMR (400MHz, CDCl3) δ7.33(d,J=1.9Hz,1H,),7.28–7.17(m,8H,),7.10(d,J=7.9Hz,1H),6.85(d,J=8.1Hz,2H),6.75(t,J= 7.3Hz,1H),5.84(s,1H),3.72(dt,J=10.9,5.3Hz,1H),3.51(ddd,J=11.2,9.2,5.0Hz,1H),2.98–2.80(m,2H),1.34(s,9H). 13 C NMR (101MHz, CDCl3) δ149.67,149.22,143.34,137.53,132.91,129.30,128.36,127.71,127.2 7,126.83,124.90,124.11,117.29,113.56,63.18,44.06,34.61,31.59,27.63.HRMS(ESI)m / z calculated for C 25 H 27 N[M+H] + 342.2216,found 342.2206.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.8 min, t R (minor) = 7.2min, ee value is 94%.

[0128] Compound 4al Prepared according to general method A, 46.7 mg of white solid, with a yield of 77% and an ee value of 91%.

[0129] 1 H NMR (400MHz, CDCl3) δ7.22–7.10(m,7H),7.07–6.99(m,1H),6.95–6.87(m,1H),6.81(ddd,J=23.1,11.3,5.2Hz ,3H),6.69(t,J=7.2Hz,1H),5.71(s,1H),3.59(dd,J=11.4,5.7Hz,1H),3.50–3.32(m,1H),2.95–2.71(m,2H). 13 C NMR (101MHz, CDCl3) δ161.21(d,J=245.4Hz),149.54,142.61,139.58(d,J=6.1Hz),131.41,129.72(d,J=3.5Hz),129.35,1 29.12,128.79,128.47,127.52,127.21,118.11,114.69(d,J=10.6Hz),114.46,114.08(d,J=10.6Hz),62.89,43.85,27.37. 19 F NMR(376MHz,CDCl3)δ-116.38,-116.40.HRMS(ESI)m / z calculated for C 21 H 18 FN[M+H] + 304.1496,found304.1498.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 4.6 min, t R (minor) = 9.7min, ee value is 91%.

[0130] Compound 4am Prepared according to general method A, 53.1 mg of white solid, with a yield of 83% and an ee value of 91%.

[0131] 1 H NMR (400MHz, CDCl3) δ7.13(ddd,J=16.6,8.8,3.1Hz,9H),7.00(d,J=8.1Hz,1H),6.77(d,J=8.1Hz,2H), 6.69(t,J=7.2Hz,1H),5.70(s,1H),3.58(dt,J=11.4,5.7Hz,1H),3.48–3.36(m,1H),2.92–2.67(m,2H). 13 C NMR (101MHz, CDCl3) δ149.48,142.49,139.51,134.34,131.74,129.72,129.35,128.47 ,127.88,127.57,127.27,127.23,118.18,114.51,62.67,43.54,27.44.HRMS(ESI)m / z calculated for C 21 H 19 ClN[M+H] + 320.1201,found 320.1199.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 4.7 min, t R (minor) = 14.3min, ee value is 91%.

[0132] Compound 4an Prepared according to general method A, 47.9 mg of white solid, with a yield of 76% and an ee value of 90%.

[0133] 1 H NMR (400MHz, CDCl3) δ7.23–7.06(m,7H),6.99(d,J=8.2Hz,1H),6.83–6.73(m,3H),6.68(dt,J=11.8,5. 2Hz,2H),5.70(s,1H),3.71(s,3H),3.60(dt,J=11.1,5.4Hz,1H),3.49–3.34(m,1H),2.88–2.64(m,2H). 13C NMR (101MHz, CDCl3) δ157.99,149.72,143.11,138.87,129.29,129.13,128.36,128.01,12 7.48,126.97,117.65,114.11,113.46,112.75,63.05,55.48,44.09,27.18.HRMS(ESI)m / z calculated for C 22 H 21 NO[M+H] + 316.1696,found 316.1687.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.3 min, t R (minor) = 9.4min, ee value is 90%.

[0134] Compound 4ao Prepared according to general method A, 34.1 mg of white solid with a yield of 57% and an ee value of 92%.

[0135] 1 H NMR (400MHz, CDCl3) δ7.24–7.12(m,7H),7.03(dd,J=13.7,7.8Hz,4H),6.82(t,J=7.3Hz,1H),6.72(d,J=7.6Hz,1H),5.90(s ,1H),3.73–3.62(m,1H),3.55–3.42(m,1H),2.95(ddd,J=16.6,10.9,5.7Hz,1H),2.69(dt,J=16.6,3.7Hz,1H),2.38(s,3H). 13 C NMR (101MHz, CDCl3) δ150.24,142.17,137.88,136.43,136.25,130.73,129.95,129.24,129.18,12 8.79,127.17,126.74,126.08,125.36,119.54,117.70,59.64,43.71,25.95,19.90.HRMS(ESI)m / z calculated for C 22 H 21 N + [M+H] +300.1747,found 300.1732.OpticalRotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.4 min, t R (minor) = 9.7min, ee value is 92%.

[0136] Compound 4ap Prepared according to general method A, 52.6 mg of white solid, with a yield of 77% and an ee value of 90%.

[0137] 1 H NMR (400MHz, CDCl3) δ7.38–7.20(m,10H),6.93(d,J=8.1Hz,2H),6.81(t,J=7.3Hz,1H),5.90(s,1H) ,3.79(dt,J=11.1,5.5Hz,1H),3.58(ddd,J=11.4,8.5,5.4Hz,1H),3.07–2.91(m,2H),1.34(s,9H). 13 C NMR (101MHz, CDCl3) δ149.65,149.61,140.11,138.16,135.92,129.28,128.17,127.91,127.0 9,127.01,126.20,125.25,117.32,113.67,62.42,43.82,34.47,31.48,28.00.HRMS(ESI)m / z calculated for C 25 H 27 N + [M+H] + 342.2216,found 342.2206.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 2.8 min, t R (minor) = 3.9min, ee value is 90%.

[0138] Compound 4aq Prepared according to general method A, 48.5 mg of white solid, with a yield of 80% and an ee value of 90%.

[0139] 1H NMR (400MHz, CDCl3) δ7.13(ddd,J=13.9,10.6,6.9Hz,8H),6.83(t,J=8.6Hz,2H),6.76(d,J=8.1Hz,2H),6.69(t, J=7.2Hz,1H),5.72(s,1H),3.59(dt,J=11.1,5.5Hz,1H),3.41(ddd,J=11.4,8.7,4.9Hz,1H),2.96–2.67(m,2H). 13 C NMR (101MHz, CDCl3) δ161.92 (d, J = 246.4Hz), 149.61, 138.91, 138.89, 137.75, 135.82, 129.35, 129.11 ,129.03,128.38,127.89,127.30,126.36,117.99,115.10(d,J=21.2Hz),114.34,62.44,43.83,28.13. 19 F NMR(376MHz,CDCl3)δ-116.32.HRMS(ESI)m / z calculated for C 21 H 18 FN[M+H] + 304.1496,found 304.1498.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.0 min, t R (minor) = 6.5min, ee value is 90%.

[0140] Compound 4ar Prepared according to general method A, 49.8 mg of white solid with a yield of 78% and an ee value of 92%.

[0141] 1 H NMR (400MHz, CDCl3) δ7.21–7.05(m,10H),6.83–6.64(m,3H),5.69(s,1H),3.59( dd,J=11.1,5.5Hz,1H),3.47–3.30(m,1H),2.84(ddd,J=14.1,12.2,8.1Hz,2H). 13C NMR (101MHz, CDCl3) δ149.52,141.80,137.51,135.82,132.76,129.36,128.86,128.48,128. 35,127.84,127.39,126.42,118.01,114.24,62.53,43.97,28.19.HRMS(ESI)m / zcalculated for C 21 H 18 ClN[M+H] + 320.1201,found 320.1199.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 10.3 min, t R (minor) = 11.8min, ee value is 92%.

[0142] Compound 4as Prepared according to general method A, 59.0 mg of white solid with a yield of 81% and an ee value of 88%.

[0143] 1 H NMR (400MHz, CDCl3) δ7.43–7.37(m,2H),7.27(pd,J=6.7,4.0Hz,5H),7.22(dd,J=7.9,4.3Hz,1H),7.18(t,J=5.3Hz,2H),6.88(d,J= 8.1Hz,2H),6.83(t,J=7.3Hz,1H),5.81(s,1H),3.73(dd,J=11.2,5.6Hz,1H),3.53(ddd,J=11.3,9.0,4.9Hz,1H),3.07–2.76(m,2H). 13 C NMR (101MHz, CDCl3) δ149.45,142.32,137.41,135.79,131.40,129.34,129.19,128.31,127. 79,127.37,126.41,120.88,117.97,114.15,62.54,43.96,28.18.HRMS(ESI)m / zcalculated for C 21 H 18 BrN[M+H] +364.0695,found 364.0689.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 9.9 min, t R (minor) = 10.5min, ee value is 88%.

[0144] Compound 4at Prepared according to general method A, 60.1 mg of white solid with a yield of 85% and an ee value of 87%.

[0145] 1 H NMR (400MHz, CDCl3) δ7.51(d,J=8.3Hz,2H),7.40(d,J=8.2Hz,2H),7.28(ddt,J=7.4,5.3,3.4Hz,5H),7.22–7.17(m,1H),6.87–6 .75(m,3H),5.86(s,1H),3.74(dt,J=10.9,5.3Hz,1H),3.52(ddd,J=11.2,9.4,4.8Hz,1H),2.95(ddd,J=14.8,12.6,8.0Hz,2H). 13 C NMR (101MHz, CDCl3) δ149.40,147.45,137.20,135.91,129.42,128.38,127.85,127.7 1,127.59,126.55,125.39,125.35(q,J=4.0Hz),118.09,114.05,62.82,44.17,28.24. 19 F NMR(376MHz,CDCl3)δ-62.39.HRMS(ESI)m / z calculated for C 22 H 18 F3N[M+H] + 354.1464,found 354.1465.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 21.4 min, t R (minor) = 22.9min, ee value is 87%.

[0146] Compound 4au Prepared according to general method A, 46.7 mg of white solid, with a yield of 74% and an ee value of 90%.

[0147] 1 H NMR (400MHz, CDCl3) δ7.35–7.26(m,5H),7.22(d,J=8.7Hz,3H),6.94(d,J=8.2Hz,2H),6.88–6.80(m,3H),5. 88(s,1H),3.79(s,3H),3.75(dd,J=11.4,5.7Hz,1H),3.57(ddd,J=11.5,8.4,5.2Hz,1H),3.08–2.90(m,2H). 13 C NMR (101MHz, CDCl3) δ158.52,149.69,138.15,135.74,135.21,129.24,128.55,128.24,12 7.83,127.02,126.19,117.61,114.18,113.62,62.35,55.25,43.64,28.06.HRMS(ESI)m / z calculated for C 22 H 21 NO[M+H] + 316.1696,found316.1687.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 30.3 min, t R (minor) = 32.3min, ee value is 90%.

[0148] Compound 4av Prepared according to general method A, 44.2 mg of white solid, with a yield of 71% and an ee value of 90%.

[0149] 1H NMR (400MHz, CDCl3) δ7.27–7.00(m,10H),6.77(d,J=8.0Hz,2H),6.66(dd,J=20.3,13.3Hz,1H),6.58(dd,J=17.5,10.9Hz,1H),5. 73(s,1H),5.60(d,J=17.6Hz,1H),5.11(d,J=10.8Hz,1H),3.64(dd,J=10.9,5.4Hz,1H),3.43(d,J=5.0Hz,1H),2.95–2.77(m,2H). 13 CNMR(101MHz, CDCl3)δ149.66,142.95,137.92,136.56,136.34,135.87,129.31,128.25,127.89,1 27.62,127.22,126.34,126.25,117.67,114.05,113.76,62.82,43.99,29.85,28.24.HRMS(ESI)m / z calculated for C 23 H 21 N + [M+H] + 312.1747,found312.1747.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 13.2 min, t R (minor) = 14.3min, ee value is 90%.

[0150] Compound 4aw Prepared according to general method A, 47.6 mg of white solid, with a yield of 77% and an ee value of 89%.

[0151] 1H NMR (400MHz, CDCl3) δ7.43–7.37(m,2H),7.27(pd,J=6.7,4.0Hz,5H),7.22(d d,J=7.9,4.3Hz,1H),7.18(t,J=5.3Hz,2H),6.88(d,J=8.1Hz,2H),6.83(t,J= 7.3Hz,1H),5.83(s,1H),3.73(dd,J=11.2,5.6Hz,1H),3.63(ddd,J=11.3,9.0 ,4.9Hz,1H),3.04(s,1H),2.95(ddd,J=14.8,12.6,8.0Hz,2H).HRMS(ESI)m / z calculated for C 23 H 19 N[M+H] + 310.1590,found310.1592.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 5.2 min, t R (minor) = 6.9min, ee value is 89%.

[0152] Compound 4ax Prepared according to general method A, 48.5 mg of white solid, with a yield of 88% and an ee value of 70%.

[0153] 1 H NMR (400MHz, CDCl3) δ7.27–6.99(m,7H),6.86(d,J=7.4Hz,2H),6.69(t,J=6.7Hz,1H),6 .13(s,1H),5.87(s,1H),5.76(s,1H),3.53(s,2H),2.90(ddd,J=45.2,15.3,5.3Hz,2H). 13 C NMR (101MHz, CDCl3) δ155.90,149.47,142.18,135.67,135.15,129.27,128.59,128.10,127. 29,126.14,118.29,114.84,110.06,107.87,57.73,42.79,27.87.HRMS(ESI)m / zcalculated for C 19 H 17 NO[M+H] +276.1383,found 276.1363.OpticalRotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 3.5 min, t R (minor) = 4.8min, ee value is 70%.

[0154] Compound 4ay Prepared according to general method A, 44.3 mg of white solid, with a yield of 76% and an ee value of 90%.

[0155] 1 H NMR (400MHz, CDCl3) δ7.25–7.04(m,7H),6.82(d,J=7.8Hz,3H),6.74(s,1H),6.69(t ,J=7.1Hz,1H),5.78(s,1H),3.62–3.33(m,2H),2.86(ddd,J=45.8,15.5,7.7Hz,2H). 13 CNMR (101MHz, CDCl3) δ149.61,144.80,137.61,135.65,129.35,128.50,127.66,127.4 7,127.18,126.20,125.66,122.44,117.92,114.51,59.71,43.11,27.88.HRMS(ESI)m / z calculated for C 19 H 17 NS[M+H] + 292.1154,found 292.1139.Optical Rotation: HPLC analysis: OD-H, 254 nm, flow rate 0.9 mL / min, n-hexane / i-PrOH=99 / 1, t R (major) = 4.1 min, t R (minor) = 4.7min, ee value is 90%.

[0156] Example 2

[0157] Palladium-catalyzed asymmetric dynamic kinetic CN coupling method for the construction of chiral nitrogen heterocycles:

[0158] In a nitrogen-filled glove box, [Pd(allyl)Cl]2 (3.6 mg, 0.01 mmol, 5 mol%), ligand 3a (15.4 mg, 0.03 mmol, 15 mol%), sodium tert-butoxide (38.4 mg, 0.4 mmol, 2.0 equiv), and 2.0 mL of anhydrous methyl tert-butyl ether were added sequentially to a Shrek tube. After stirring at room temperature for 15 minutes, aryl halide 2d (0.3 mmol, 1.5 equiv) and compound 1a (0.2 mmol, 1.0 equiv) containing a saturated racemic nitrogen heterocycle were added sequentially. The mixture was then removed from the glove box and allowed to react at 60°C for 8 hours. After completion of the reaction, the precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) to afford 33.4 mg of a white solid 4a in 75% yield and 83% ee.

[0159] Wherein, R in compound 1a is H.

[0160] Example 3

[0161] The same as Example 2, except that the ligand was ligand 3n. Purification by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) gave 26.8 mg of white solid 4a with a yield of 60% and an ee value of 78%.

[0162] Example 4

[0163] The same as Example 2, except that the ligand was ligand 3p; purification by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) gave 32.6 mg of white solid 4a with a yield of 73% and an ee value of 84%.

[0164] Example 5

[0165] The same as Example 2, except that the ligand was ligand 3u; purification by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) gave 24.5 mg of white solid 4a with a yield of 55% and an ee value of 77%.

[0166] Example 6

[0167] The same as Example 2, except that the ligand was ligand 3t; purification by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) gave 26.8 mg of white solid 4a with a yield of 60% and an ee value of 92%.

[0168] Example 7

[0169] The same as Example 2 except that the ligand was ligand 3v. Purification by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) gave 37.0 mg of white solid 4a with a yield of 83% and an ee value of 87%.

[0170] Comparative Example 1

[0171] Same as Example 2, except that the ligand is: (S configuration); purified by silica gel flash column chromatography (mobile phase: n-hexane:ethyl acetate = 50:1) to give 26.8 mg of white solid 4a with a yield of 60% and an ee value of 17%.

[0172] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

Claims

1. A method for constructing chiral nitrogen heterocycles by palladium-catalyzed asymmetric dynamic kinetic CN coupling, characterized in that: The following steps are involved: After uniformly mixing a palladium catalyst, a ligand, a base and a solvent, a compound having a saturated racemic nitrogen heterocycle and an aryl halide are added, mixed and reacted to obtain a compound having a chiral nitrogen heterocycle; The structure of the ligand is: wherein R1 is selected from one of substituted phenyl, pyridyl, substituted pyridyl and substituted benzyl; R2 is selected from one of tert-butyl, isopropyl, benzyl, phenyl and pyridyl.

2. The method according to claim 1, characterized in that The ligand is selected from any one of the following compounds:

3. The method according to claim 1, characterized in that The palladium catalyst includes one of Pd2(dba)3, Pd(OAc)2, PdCl2, Pd(PPh3)4, [Pd(allyl)Cl]2, Pd(PPh3)2Cl2 and Pd(MeCN)2Cl2.

4. The method according to claim 1, wherein The molar amount of the palladium catalyst is 1 to 10% of the molar amount of the compound having a saturated racemic nitrogen heterocycle; and / or, the molar amount of the ligand is 3 to 20% of the molar amount of the compound having a saturated racemic nitrogen heterocycle; And / or, the molar ratio of the base to the compound having a saturated racemic nitrogen heterocycle is (1-2.5):

1.

5. The method according to claim 1, characterized in that The compound having a saturated racemic nitrogen heterocycle is selected from any one of the following compounds: Wherein, R is selected from one of hydrogen atom, halogen atom, trifluoromethyl group, cyano group, nitro group, aldehyde group, methoxycarbonyl group, methyl group, isopropyl group, tert-butyl group, methoxy group, trifluoromethoxy group, dimethylamino group and acetoxy group.

6. The method according to claim 1, characterized in that The aryl halide is selected from any one of the following compounds:

7. The method according to claim 1, characterized in that The molar ratio of the compound having a saturated racemic nitrogen heterocycle and the aryl halide is (1-2): (1-2); And / or, the temperature of the mixing reaction is 0 to 80° C., and the time is 8 to 18 hours.

8. The method according to claim 1, characterized in that The compound having a chiral nitrogen heterocycle is any one of the following compounds:

9. A compound having a chiral nitrogen heterocycle prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the compound having a chiral nitrogen heterocycle according to claim 9 as a pharmaceutical intermediate.

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