A process for the preparation of polysubstituted chiral cyclobutenes

Abstract

The application discloses a preparation method of a polysubstituted chiral cyclobutene, which comprises the following steps: in a glove box filled with a protective gas, adding a metal catalyst, a chiral ligand and a solvent into a reaction bottle, fully stirring, adding a vinyl-carbonyl-bicyclobutane and an imine, and stirring at a certain temperature until the reaction is completed to obtain the polysubstituted chiral cyclobutene, wherein the metal catalyst is Pd2(dba)3, and the solvent is selected from dichloromethane, 1,2-dichloroethane, ethyl acetate, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, toluene or trifluorotoluene. The application realizes the addition / β-H elimination reaction of the bicyclobutane and the imine, can accurately control the stereo and chemical selectivity of the reaction, and can stably obtain the target product with a high ee value and a high dr value; the method is completed in one step, the steps are short, the conditions are mild, and the substrate application range is wide.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, and in particular relates to a method for preparing polysubstituted chiral cyclobutene. Background Technology

[0002] Chiral polysubstituted cyclobutene skeletons are widely found in natural products and bioactive molecules. The unique ring strain and double bond characteristics of this type of skeleton endow it with rich functionalization, making it an important chiral building block (Namyslo, JC, Kaufmann, DE Chem. Rev. 2003, 103, 1485−1538). To date, the asymmetric synthesis of this type of framework has mainly been achieved through transition metal catalysis, photocatalysis, and organocatalysis (Parsutkar, MM, Pagar, VV, Rajan Babu, TVJ Am. Chem. Soc. 2019, 141, 15367−15377; Zhang, M., Wang, X.-C. Angew. Chem., Int. Ed. 2021, 60, 17185−17190; Lin, S.-L., Chen, Y.-H., Liu, H.-H., Xiang, SH, Tan, BJ Am. Chem. Soc. 2023, 145, 21152−21158; Pravin, K., Díaz-Salazar, H., Iagarmina, A., Woźniak, Ł. J. Am. Chem. Soc.2026, However, this type of method currently has limitations, including a single catalytic activation mode, difficulty in controlling multi-chiral centers, limited substrate range, and harsh reaction conditions.

[0003] In recent years, cyclobutenes have often appeared as byproducts or reaction intermediates in cycloaddition reactions involving bicyclobutane (Qin, T., He, M., Zi, W. Nat. Synth. 2025, 4, 124−133). Given the importance of polysubstituted chiral cyclobutenes in synthetic chemistry, and the continued challenges in their efficient preparation, there is an urgent need to develop a method for the efficient asymmetric synthesis of polysubstituted chiral cyclobutenes from bicyclobutane. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing polysubstituted chiral cyclobutenes by palladium-catalyzed addition reaction of vinyl-carbonyl-bicyclobutane (VC-BCB) with imines, which has excellent chemoselectivity, enantioselectivity and diastereoselectivity.

[0005] Therefore, the present invention adopts the following technical solution:

[0006] A method for preparing polysubstituted chiral cyclobutenes, the reaction formula and reaction process are as follows:

[0007]

[0008] In a glove box filled with protective gas, a metal catalyst, a chiral ligand, and a solvent are added to a reaction flask. After thorough stirring, vinyl-carbonyl-bicyclobutane and an imine are added. The mixture is stirred at a certain temperature until the reaction is complete, yielding polysubstituted chiral cyclobutene.

[0009] in:

[0010] The metal catalyst is Pd2(dba)3;

[0011] The chiral ligand has one of the following structures:

[0012] , , .

[0013] Preferably, R1 is an alkyl, aryl, substituted aryl, or heteroaryl group.

[0014] Preferably, for R1: the alkyl group is n-butyl or tert-butyl; the heteroaryl group is furanyl, thiophene, benzofuranyl, piperonyl, or quinolinyl; the aryl group is phenyl or naphthyl; the substituted aryl group is a substituted phenyl group, wherein the substituent is methyl, methoxy, trifluoromethyl, bromine, chlorine, or fluorine.

[0015] Preferably, R2 is alkenyl, aryl, substituted aryl, or heteroaryl.

[0016] Preferably, for R2: the alkenyl group is styryl; the heteroaryl group is furanyl, thiophene, benzothiophene, benzofuranyl, piperyl, or quinolinyl; the aryl group is phenyl or naphthyl; the substituted aryl group is a substituted phenyl group, wherein the substituent is alkynyl, esteryl, thiomethyl, methyl, tert-butyl, methoxy, chlorine, or fluorine.

[0017] Preferably, R3 is p-toluylsulfonyl, p-methoxyphenylsulfonyl, p-fluorophenylsulfonyl, or phenylsulfonyl.

[0018] Preferably, the solvent is selected from dichloromethane, 1,2-dichloroethane, ethyl acetate, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, toluene, or trifluorotoluene.

[0019] In the above preparation method, the molar ratio of the metal catalyst to bicyclobutane is (1.25-5):100; the molar ratio of the chiral ligand to bicyclobutane is (4-12):100; and the equivalence ratio of the imine to bicyclobutane is 1:1.

[0020] Preferably, the reaction time is 10 to 24 hours; the specific temperature is -15℃ to 80℃, preferably 0℃ to 40℃.

[0021] This invention uses tris(dibenzylacetone)dipalladium (Pd2(dba)3) as a catalyst and a chiral phosphoramidite ligand or Trost ligand as a chiral ligand. After pre-stirring to form a metal complex, it coordinates with vinyl-carbonyl-bicyclobutane to obtain an allylpalladium zwitterionic intermediate. Then, after reacting with an unsaturated acceptor imine, the intermediate undergoes β-hydrogen elimination to dissociate palladium, yielding the target product, chiral cyclobutene.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. This invention utilizes a transition metal palladium and a chiral ligand catalytic system to achieve, for the first time, the addition / β-H elimination reaction of bicyclobutane with an imine. It can precisely control the stereoselectivity and chemoselectivity of the reaction, and can stably obtain target products with high ee and high dr values. The chiral configuration is precisely controllable, with very few stereo impurities. It eliminates the need for complex purification processes such as chiral resolution and recrystallization, greatly simplifying the process and improving the optical purity and synthesis efficiency of the product.

[0024] 2. The vinyl-carbonyl-bicyclobutane and imine used in this invention can both be prepared from simple and inexpensive commercial raw materials, and there are extensive literature reports on them, which is beneficial for industrial scale-up production;

[0025] 3. This invention employs a one-step palladium-catalyzed process, which is concise, operates under mild conditions, and has a wide range of applicable substrates, avoiding the problems of long, low-yield, and highly polluting traditional multi-step synthetic routes. Furthermore, it boasts high catalytic efficiency, low palladium catalyst loading, redox neutrality, atom economy, and gram-scale selectivity with no attenuation.

[0026] 4. This invention can be used for late-stage functionalization modification of drug molecules containing chiral multi-substituted cyclobutene structures. It can be applied to drug research and development and production. Moreover, the chiral skeleton is stable and the configuration is fixed, which can efficiently carry out various transformations such as ring opening, ring expansion, and cycloaddition modification. It can derive a variety of chiral cyclic intermediates, drug lead compounds and functional material monomers, with strong structural extensibility and versatility.

[0027] 5. It has a wide range of substrate compatibility, including alkyl, aryl, heterocyclic, and multifunctional groups. VC-BCB is compatible with various imines, and sensitive functional groups do not require protection, allowing for the introduction of amino substitution sites in one step.

[0028] 6. Based on the ring strain of bicyclobutane (BCB) to drive ring opening, the substrate has high activity and is safe to store without the risk of explosion. The built-in carbonyl-guided precise control of multiple continuous chiral centers can efficiently construct fully heterosubstituted complex cyclobutene skeletons containing quaternary carbons.

[0029] 7. The product has multiple reaction sites including double bonds, carbonyl groups, and amino groups. The subsequent derivatization process has a stable stereoconfiguration, which can rapidly construct the core three-dimensional framework of natural products and chiral drugs. The synthetic route is short, produces less waste, and has low industrial production cost. It solves the industry bottleneck of existing methods that make it difficult to efficiently prepare high stereopurity multi-substituted chiral cyclobutene building blocks in large quantities. Detailed Implementation

[0030] To better understand the technical solution of the present invention, the following embodiments will further illustrate the method provided by the present invention. However, the present invention is not limited to the listed embodiments, but should also include any other well-known modifications within the scope of the claims of the present invention.

[0031] In the reaction formulas of the following examples:

[0032] Pd2(dba)3 (tris(dibenzylacetone)dipalladium) is the catalyst; -Ts is... .

[0033] L1, L2, and L3 are chiral ligands, with the following structural formulas:

[0034] , , .

[0035] Example 1

[0036] A method for preparing product 1, comprising the following reaction formula and steps:

[0037]

[0038] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 78 mg of product 1, which was a white foam with a yield of 89%, an ee value of 94%, and a dr value > 20:1.

[0039] The product is characterized as follows:

[0040] [α] 25 D = -14.3 (c 1.1, CHCl3).

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 8.2, 2.0 Hz, 2H), 7.40 (t, J =7.4 Hz, 1H), 7.32 (d, J = 7.7 Hz, 2H), 7.28 – 7.22 (m, 2H), 7.05 (ddd, J =32.2, 15.3, 8.2 Hz, 7H), 6.35 (d, J = 7.4 Hz, 1H), 6.26 (dd, J = 17.3, 10.5Hz, 1H), 6.06 (s, 1H), 5.12 (dd, J = 29.4, 13.9 Hz, 2H), 4.85 (d, J = 7.6 Hz,1H), 2.94 – 2.72 (m, 2H), 2.27 (s, 3H).

[0042] 13 C NMR (101 MHz, CDCl3) δ 203.5, 147.7, 142.8, 137.5, 137.5, 136.9,132.5, 130.2, 129.1, 128.6, 128.1, 128.1, 127.6, 127.5, 127.1, 118.6, 63.3,60.1, 37.7, 21.4.

[0043] HRMS (ESI) calcd. For C27 H 25 NNaO3S + [M + Na] + = 466.1447, Found:466.1445.

[0044] t r (major) = 45.465 min, t r (minor) = 53.632 min, (Chiralcel IC, λ =254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0045] Example 2

[0046] A method for preparing product 2, the reaction formula and steps are as follows:

[0047]

[0048] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 50.4 mg of 2a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 87 mg of product 2, which was a white foam with a yield of 85%, an ee value of 92%, and a dr value > 20:1.

[0049] The product is characterized as follows:

[0050] [α] 25 D = -6.9 (c 1.2, CHCl3).

[0051] 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 10.4, 8.1 Hz, 4H), 7.29 (d, J= 7.4 Hz, 2H), 7.08 – 6.98 (m, 3H), 6.93 (t, J = 6.4 Hz, 4H), 6.30 (t, J =8.2 Hz, 1H), 6.18 (ddd, J = 17.3, 10.3, 3.1 Hz, 1H), 5.95 (d, J = 2.8 Hz,1H), 5.14 – 4.99 (m, 2H), 4.77 (dd, J = 8.1, 3.6 Hz, 1H), 2.76 (d, J = 4.0Hz, 2H), 2.20 (s, 3H).

[0052] 13 C NMR (101 MHz, CDCl3) δ 202.1, 147.1, 142.0, 138.9, 136.4, 136.3,132.5 (q, J = 32.3 Hz), 129.0, 128.5, 128.1, 127.6, 127.2, 126.8, 126.4,126.0, 125.9 (q, J = 273.7 Hz), 124.1(q, J = 4.0 Hz), 118.0, 62.2, 59.2,36.8, 20.3.

[0053] 19 F NMR (376 MHz, CDCl3) δ -63.1.

[0054] HRMS (ESI) calcd. For C 28 H 24 F3NNaO3S + [M + Na] + = 534.1321, Found:534.1317.

[0055] the ee value was 92%, t r (major) = 19.885 min, t r (minor) = 24.898min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0056] Example 3

[0057] A method for preparing product 3, the reaction formula and steps are as follows:

[0058]

[0059] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 42.8 mg of 3a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 89 mg of product 3, which was a white foam with a yield of 94%, an ee value of 92%, and a dr value > 20:1.

[0060] The product is characterized as follows:

[0061] [α] 25 D = -44.5 (c 1.0, CHCl3).

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.05 (ddd, J = 29.0, 12.8, 7.3 Hz, 7H), 6.72 (d, J = 8.6 Hz, 2H), 6.35 – 6.19 (m, 2H), 6.08 (s, 1H), 4.80 (d, J = 7.0 Hz, 1H), 3.79 (s, 3H), 2.95 – 2.68 (m, 2H), 2.27 (s, 3H).

[0063] 13C NMR (101 MHz, CDCl3) δ 201.2, 163.1, 147.7, 142.8, 137.7, 137.5,131.3, 130.4, 130.3, 129.6, 129.1, 128.0, 127.6, 127.5, 127.1, 118.4, 113.4,63.5, 60.0, 55.4, 38.0, 21.4.

[0064] HRMS (ESI) calcd. For C 28 H 27 NNaO4S + [M + Na] + = 496.1553, Found: 496.1549.

[0065] The ee value was 92%, t r (major) = 35.811 min, t r (minor) = 18.070min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0066] Example 4

[0067] A method for preparing product 4, the reaction formula and steps are as follows:

[0068]

[0069] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 52.4 mg of 4a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 83 mg of product 4, which was a white foam with a yield of 80%, an ee value of 91%, and a dr value > 20:1.

[0070] The product is characterized as follows:

[0071] [α] 25D = -52.9 (c 1.1, CHCl3).

[0072] 1 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 8.4, 2.3 Hz, 2H), 7.31 (dd, J= 8.7, 2.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.96 (ddd, J = 29.6, 13.5, 7.4Hz, 7H), 6.30 (t, J = 7.4 Hz, 1H), 6.16 (ddd, J = 17.4, 10.6, 2.4 Hz, 1H),5.97 (s, 1H), 5.03 (dd, J = 33.6, 13.8 Hz, 2H), 4.75 (d, J = 7.6 Hz, 1H),2.81 – 2.62 (m, 2H), 2.19 (d, J = 2.4 Hz, 3H).

[0073] 13 13C NMR (101 MHz, CDCl3) δ 202.3, 147.8, 143.0, 137.4, 135.5, 131.5,130.2, 130.1, 129.8, 129.2, 128.1, 127.8, 127.7, 127.5, 127.1, 118.8, 63.2,60.2, 37.7, 21.4.

[0074] HRMS (ESI) calcd. For C 27 H 24 BrNNaO3S + [M + Na] + = 544.0552, Found:544.0552.

[0075] the ee value was 91%, t r (major) = 34.460 min, t r (minor) = 42.703min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0076] Example 5

[0077] A method for preparing product 5, the reaction formula and steps are as follows:

[0078]

[0079] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 43.6 mg of 5a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 76 mg of product 5, which was a colorless liquid with a yield of 80%, an ee value of 92%, and a dr value > 20:1.

[0080] The product is characterized as follows:

[0081] [α] 25 D = -39.7 (c 1.0, CHCl3).

[0082] 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H), 7.24 (dt, J =14.5, 5.4 Hz, 4H), 7.15 – 6.95 (m, 7H), 6.37 – 6.20 (m, 2H), 6.04 (d, J = 1.9Hz, 1H), 5.14 (dd, J = 33.6, 13.9 Hz, 2H), 4.81 (dd, J = 7.6, 2.4 Hz, 1H), 2.92 – 2.73 (m, 2H), 2.28 (s, 3H).

[0083] 13 C NMR (101 MHz, CDCl3) δ 202.2, 148.0, 143.0, 138.9, 137.4, 135.2,130.1, 129.8, 129.2, 128.4, 128.1, 127.8, 127.4, 127.1, 118.9, 63.3, 60.1,37.9, 21.4.

[0084] HRMS (ESI) calcd. For C 27 H 24 ClNNaO3S + [M + Na] + = 500.1058, Found:500.1056.

[0085] The ee value was 90%, t r (major) = 21.670 min, t r (minor) = 25.412min, (Chiralcel ID, λ = 254 nm, hexanes: i PrOH = 95: 5, flow rate = 1.0 mL / min).

[0086] Example 6

[0087] A method for preparing product 6, the reaction formula and steps are as follows:

[0088]

[0089] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 40.4 mg of 6a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 83 mg of product 6, which was a white foam with a yield of 78%, an ee value of 91%, and a dr value > 20:1.

[0090] The product is characterized as follows:

[0091] [α] 25 D = -14.5 (c 1.0, CHCl3).

[0092] 1¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J = 8.0 Hz, 2H), 7.29 (ddd, J =9.0, 5.4, 2.3 Hz, 2H), 7.11 – 6.88 (m, 7H), 6.84 (t, J = 8.5 Hz, 2H), 6.21 (dq, J = 17.3, 10.5, 8.8 Hz, 2H), 5.98 (s, 1H), 5.17 – 4.94 (m, 2H), 4.74 (d, J = 7.5 Hz, 1H), 2.85 – 2.65 (m, 2H), 2.20 (s, 3H).

[0093] 13 ¹³C NMR (101 MHz, CDCl₃) δ 201.7, 165.1 (d, J = 256.5 Hz), 147.9, 142.9, 137.4, 133.2, 131.4 (d, J = 9.1 Hz), 130.1, 130.0, 129.2, 128.1, 127.7, 127.5, 127.1, 118.8, 115.3 (d, J = 21.2 Hz) , 63.4, 60.1, 37.9, 21.4.

[0094] 19 ¹⁹F NMR (376 MHz, CDCl₃) δ -105.2.

[0095] HRMS (ESI) calcd. for C 27 H 24 FNNaO₃S + [M + Na] + = 484.1353, Found: 484.1350.

[0096] the ee value was 91%, t r (major) = 26.843 min, t r (minor) = 14.914 min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70:30, flow rate = 0.8 mL / min).

[0097] Example 7

[0098] A method for preparing product 7, the reaction formula and steps are as follows:

[0099]

[0100] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 39.6 mg of 7a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 78 mg of product 7, which was a white foam with a yield of 85%, an ee value of 92%, and a dr value > 20:1.

[0101] The product is characterized as follows:

[0102] [α] 25 D = -25.9 (c 1.2, CHCl3).

[0103] 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1Hz, 2H), 7.05 – 6.87 (m, 9H), 6.27 (d, J = 7.2 Hz, 1H), 6.17 (dd, J = 17.3,10.5 Hz, 1H), 5.98 (s, 1H), 5.11 – 4.93 (m, 2H), 4.75 (d, J = 7.3 Hz, 1H), 2.89 – 2.60 (m, 2H), 2.23 (s, 3H), 2.19 (s, 3H).

[0104] 13 C NMR (101 MHz, CDCl3) δ 201.8, 146.6, 142.3, 141.8, 136.5, 136.4,133.2, 129.3, 129.2, 128.1, 127.8, 127.8, 127.0, 126.6, 126.5, 126.0, 117.4,62.3, 62.3, 59.0, 36.7, 20.5, 20.3.

[0105] HRMS (ESI) calcd. For C 28 H 27 NNaO3S + [M + Na] + = 480.1604, Found:480.1601.

[0106] The ee value was 92%, t r (major) = 31.570 min, t r (minor) = 17.606min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0107] Example 8

[0108] A method for preparing product 8, the reaction formula and steps are as follows:

[0109]

[0110] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 46.8 mg of 8a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 84 mg of product 8, which was a white foam with a yield of 85%, an ee value of 91%, and a dr value > 20:1.

[0111] The product is characterized as follows:

[0112] [α] 25 D = -69.5 (c 1.2, CHCl3).

[0113] 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.52 (m, 4H), 7.38 (ddd, J = 16.4,8.1, 5.0 Hz, 5H), 7.00 (q, J = 6.8, 5.0 Hz, 5H), 6.89 – 6.71 (m, 2H), 6.46 – 6.22 (m, 1H), 6.20 – 5.98 (m, 2H), 4.99 (ddd, J = 20.8, 14.0, 3.6 Hz, 2H), 4.85 (t, J = 7.6 Hz, 1H), 2.96 – 2.60 (m, 2H), 2.06 (s, 3H).

[0114] 13 C NMR (101 MHz, CDCl3) δ 202.0, 146.6, 146.6, 141.8, 136.7, 136.3,133.9, 132.9, 132.9, 130.9, 129.5, 129.2, 129.1, 128.5, 128.1, 127.5, 127.1,126.9, 126.7, 126.6, 126.5, 126.0, 125.7, 123.4, 117.5, 62.4, 62.3, 59.3,36.9, 20.2.

[0115] HRMS (ESI) calcd. For C 31 H 27 NNaO3S + [M + Na] + = 516.1604, Found: 516.1600.

[0116] The ee value was 91%, t r (major) = 26.899 min, t r (minor) = 21.062min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.5mL / min).

[0117] Example 9

[0118] A method for preparing product 9, the reaction formula and steps are as follows:

[0119]

[0120] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 47.0 mg of 9a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 87 mg of product 9, which was a white foam with a yield of 88%, an ee value of 90%, and a dr value > 20:1.

[0121] The product is characterized as follows:

[0122] [α] 25 D = -290.8 (c 1.3, CHCl3).

[0123] 1 H NMR (400 MHz, CDCl3) δ 10.04 (d, J = 4.2 Hz, 1H), 9.44 – 8.98 (m,1H), 8.33 (dd, J = 8.4, 2.4 Hz, 1H), 7.94 (dt, J = 6.7, 3.7 Hz, 1H), 7.62 (t,J = 7.8 Hz, 3H), 7.53 (q, J = 3.5, 2.9 Hz, 2H), 7.40 (dd, J = 6.4, 2.9 Hz,2H), 7.27 – 7.15 (m, 5H), 5.87 (dd, J = 17.4, 10.5 Hz, 1H), 5.72 (s, 1H),5.10 – 5.01 (m, 1H), 4.90 (dd, J = 10.5, 3.1 Hz, 1H), 4.77 (d, J = 17.3 Hz, 1H), 2.48 – 2.28 (m, 5H).

[0124] 13C NMR (101 MHz, CDCl3) δ 210.3, 150.2, 147.0, 144.2, 142.7, 138.9,137.8, 137.7, 136.8, 130.3, 129.7, 129.2, 129.1, 128.5, 128.0, 127.6, 127.5,127.2, 126.7, 122.2, 117.8, 61.5, 60.6, 36.4, 21.6.

[0125] HRMS (ESI) calcd. For C 30 H 26 N2NaO3S + [M + Na] + = 517.1556, Found:517.1553.

[0126] The ee value was 90%, t r (major) = 30.845 min, t r (minor) = 18.085min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0127] Example 10

[0128] A method for preparing product 10, comprising the following reaction formula and steps:

[0129]

[0130] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 34.8 mg of 10a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 79 mg of product 10, which was a white foam with a yield of 91%, an ee value of 92%, and a dr value > 20:1.

[0131] The product is characterized as follows:

[0132] [α] 25 D = -25.1 (c 1.1, CHCl3).

[0133] 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 1.7Hz, 1H), 7.10 – 6.91 (m, 8H), 6.45 – 6.22 (m, 3H), 6.07 (s, 1H), 5.26 – 5.06(m, 2H), 4.80 (d, J = 7.9 Hz, 1H), 3.01 – 2.66 (m, 2H), 2.28 (s, 3H).

[0134] 13 C NMR (101 MHz, CDCl3) δ 189.5, 151.9, 148.3, 146.6, 142.8, 137.5,137.2, 130.3, 129.8, 129.1, 127.8, 127.5, 127.4, 127.0, 119.2, 118.8, 112.2,63.2, 59.2, 37.0, 21.4.

[0135] HRMS (ESI) calcd. For C 25 H 23 NNaO4S + [M + Na] + = 456.1240, Found:456.1237.

[0136] The ee value was 92%, t r (major) = 48.644 min, t r (minor) = 27.724min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0137] Example 11

[0138] A method for preparing product 11, comprising the following reaction formula and steps:

[0139]

[0140] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 38.0 mg of 11a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 81 mg of product 11, which was a white foam with a yield of 91%, an ee value of 92%, and a dr value > 20:1.

[0141] The product is characterized as follows:

[0142] [α] 25 D = -26.1 (c 1.2, CHCl3).

[0143] 1 H NMR (400 MHz, CDCl3) δ 7.49 – 7.28 (m, 4H), 7.03 – 6.76 (m, 8H), 6.49 (d, J = 8.4 Hz, 1H), 6.29 (dd, J = 17.3, 10.5 Hz, 1H), 6.02 (s, 1H), 5.12 (dd, J = 26.9, 13.9 Hz, 2H), 4.68 (d, J = 8.5 Hz, 1H), 2.98 – 2.67 (m,2H), 2.17 (s, 3H).

[0144] 13 C NMR (101 MHz, CDCl3) δ 194.4, 149.0, 142.8, 142.5, 137.6, 137.2,134.3, 133.5, 130.3, 129.1, 128.0, 127.9, 127.7, 127.4, 127.0, 119.2, 64.1,60.0, 38.2, 21.4.

[0145] HRMS (ESI) calcd. For C 25 H 23 NNaO3S2 + [M + Na] + = 472.1012, Found:472.1009.

[0146] The ee value was 92%, t r (major) = 26.043 min, t r (minor) = 17.273min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0147] Example 12

[0148] A method for preparing product 12, the reaction formula and steps are as follows:

[0149]

[0150] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 45.6 mg of 12a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 78 mg of product 12, which was a white foam with a yield of 81%, an ee value of 91%, and a dr value > 20:1.

[0151] The product is characterized as follows:

[0152] [α] 25 D = -57.5 (c 1.3, CHCl3).

[0153] 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 2H), 7.11 – 6.77 (m,9H), 6.55 (d, J = 8.2 Hz, 1H), 6.34 – 6.23 (m, 1H), 6.25 – 6.09 (m, 1H), 6.00(s, 1H), 5.86 (d, J = 2.8 Hz, 2H), 5.00 (dd, J = 33.5, 13.8 Hz, 2H), 4.76 (d,J = 7.4 Hz, 1H), 2.83 – 2.52 (m, 2H), 2.19 (s, 3H).

[0154] 13 C NMR (101 MHz, CDCl3) δ 200.5, 151.4, 147.8, 147.4, 142.9, 137.5,137.4, 131.0, 130.2, 129.1, 128.0, 127.7, 127.6, 127.1, 125.4, 118.4, 108.8,107.5, 101.9, 63.2, 60.0, 37.7, 21.4.

[0155] HRMS (ESI) calcd. For C 28 H 25 NNaO5S + [M + Na] + = 510.1346, Found:510.1344.

[0156] The ee value was 91%, t r (major) = 54.644 min, t r (minor) = 18.299min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0157] Example 13

[0158] A method for preparing product 13, the reaction formula and steps are as follows:

[0159]

[0160] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 44.8 mg of 13a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 82 mg of product 13, which was a white foam with a yield of 85%, an ee value of 90%, and a dr value > 20:1.

[0161] The product is characterized as follows:

[0162] [α] 25 D = 73.4 (c 0.9, CHCl3).

[0163] 1 H NMR (400 MHz, CDCl3) δ 7.60 – 7.47 (m, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.25 (s, 2H), 7.07 – 6.94 (m, 5H), 6.90 (d, J = 8.0 Hz, 2H), 6.63 (d, J= 2.3 Hz, 1H), 6.29 – 6.13 (m, 2H), 6.04 (s, 1H), 5.05 (dd, J = 29.3, 13.9Hz, 2H), 4.79 (dd, J = 7.0, 2.2 Hz, 1H), 2.90 – 2.65 (m, 2H), 2.16 (s, 3H).

[0164] 13 C NMR (101 MHz, CDCl3) δ 202.9, 156.9, 147.7, 146.3, 142.9, 137.7,137.4, 132.3, 130.3, 130.2, 129.1, 128.1, 127.7, 127.5, 127.1, 125.5, 123.1,118.6, 111.1, 107.3, 63.6, 60.1, 38.2, 21.3.

[0165] HRMS (ESI) calcd. For C 29 H25 NNaO4S + [M + Na] + = 506.1397, Found: 506.1393.

[0166] The ee value was 90%, t r (major) = 43.042 min, t r (minor) = 17.002min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0167] Example 14

[0168] A method for preparing product 14, comprising the following reaction formula and steps:

[0169]

[0170] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 32.8 mg of 14a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 76 mg of product 14, which was a white foam with a yield of 90%, an ee value of 91%, and a dr value > 20:1.

[0171] The product is characterized as follows:

[0172] [α] 25 D = 122.0 (c 0.9, CHCl3).

[0173] 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 2H), 7.13 – 7.03 (m,3H), 6.98 (dd, J = 13.3, 7.6 Hz, 4H), 6.83 (d, J = 9.1 Hz, 1H), 6.43 (dd, J =17.3, 10.5 Hz, 1H), 5.87 (s, 1H), 5.36 – 5.24 (m, 2H), 4.56 (d, J = 9.2 Hz, 1H), 2.95 – 2.60 (m, 2H), 2.40 – 2.31 (m, 1H), 2.30 (s, 3H), 2.00 – 1.87 (m,1H), 1.36 – 1.26 (m, 2H), 1.20 – 1.06 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H).

[0174] 13 C NMR (101 MHz, CDCl3) δ 214.6, 149.0, 142.6, 138.0, 137.4, 130.4,130.0, 129.0, 128.0, 127.3, 127.2, 126.9, 118.8, 63.8, 59.4, 40.5, 37.2,25.1, 21.9, 21.3, 13.8.

[0175] HRMS (ESI) calcd. For C 25 H 29 NNaO3S + [M + Na] + = 446.1760, Found: 446.1757.

[0176] The ee value was 91%, t r (major) = 36.112 min, t r (minor) = 26.204min, (Chiralcel IF, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0177] Example 15

[0178] A method for preparing product 15, comprising the following reaction formula and steps:

[0179]

[0180] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 32.8 mg of 15a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 70 mg of product 15, which was a white foam with a yield of 80%, an ee value of 90%, and a dr value > 20:1.

[0181] The product is characterized as follows:

[0182] [α] 25 D = 32.3 (c 1.1, CHCl3).

[0183] 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.1 Hz, 2H), 7.06 – 6.88 (m,7H), 6.50 (d, J = 8.7 Hz, 1H), 6.26 (dd, J = 17.3, 10.5 Hz, 1H), 5.59 (s,1H), 5.24 – 4.98 (m, 2H), 4.49 (d, J = 8.8 Hz, 1H), 2.67 (d, J = 3.1 Hz, 2H), 2.21 (s, 3H), 1.23 (s, 9H).

[0184] 13 C NMR (101 MHz, CDCl3) δ 172.0, 145.9, 141.6, 137.0, 136.4, 129.6,128.9, 128.0, 126.9, 126.3, 126.2, 126.2, 125.9, 116.9, 80.9, 61.8, 53.8,36.0, 26.7, 20.3.

[0185] HRMS (ESI) calcd. For C 25 H 29 NNaO4S+ [M + Na] + = 462.1710, Found: 462.1706.

[0186] The ee value was 90%, t r (major) = 56.209 min, t r (minor) = 36.043min, (Chiralcel IF, λ = 254 nm, hexanes: i PrOH = 90: 10, flow rate = 0.5 mL / min).

[0187] Example 16

[0188] A method for preparing product 16, comprising the following reaction formula and steps:

[0189]

[0190] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 55.0 mg of 2b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 77 mg of product 16, which was a white foam with a yield of 90%, an ee value of 96%, and a dr value > 20:1.

[0191] The product is characterized as follows:

[0192] [α] 25 D = -28.2 (c 0.6, CHCl3).

[0193] 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.5 Hz, 2H), 7.38 – 7.26 (m,3H), 7.17 (t, J = 7.6 Hz, 2H), 7.09 – 6.87 (m, 5H), 6.57 (d, J = 8.6 Hz, 2H), 6.39 – 6.25 (m, 1H), 6.17 (dd, J = 17.3, 10.5 Hz, 1H), 6.00 (s, 1H), 5.02(dd, J = 27.9, 13.8 Hz, 2H), 4.78 (dd, J = 7.5, 2.4 Hz, 1H), 3.64 (d, J = 1.9Hz, 3H), 2.90 – 2.43 (m, 2H).

[0194] 13 C NMR (101 MHz, CDCl3) δ 202.2, 161.4, 146.6, 136.4, 135.7, 131.5,131.0, 129.2, 129.1, 128.1, 127.6, 127.1, 127.0, 126.6, 126.5, 117.5, 112.7,62.2, 59.1, 54.5, 36.6, 36.5.

[0195] HRMS (ESI) calcd. For C 27 H 25 NNaO4S + [M + Na] + = 482.1397, Found: 482.1395.

[0196] The ee value was 96%, t r (major) = 40.349 min, t r (minor) = 46.777min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0197] Example 17

[0198] A method for preparing product 17, comprising the following reaction formula and steps:

[0199]

[0200] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 52.6 mg of 3b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 71 mg of product 17, which was a white foam with a yield of 80%, an ee value of 90%, and a dr value > 20:1.

[0201] The product is characterized as follows:

[0202] [α] 25 D = 4.0 (c 1.0, CHCl3).

[0203] 1 H NMR (400 MHz, CDCl3) δ 7.59 – 7.50 (m, 2H), 7.42 (dd, J = 8.1, 6.3Hz, 1H), 7.34 – 7.29 (m, 2H), 7.25 (t, J = 7.7 Hz, 2H), 7.15 – 7.03 (m, 3H),7.03 – 6.96 (m, 2H), 6.83 (t, J = 8.6 Hz, 2H), 6.50 (d, J = 7.6 Hz, 1H), 6.28(dd, J = 17.4, 10.5 Hz, 1H), 6.08 (s, 1H), 5.25 – 5.07 (m, 2H), 4.86 (d, J =7.7 Hz, 1H), 2.90 (d, J = 3.2 Hz, 2H).

[0204] 13C NMR (101 MHz, CDCl3) δ 203.9, 164.7(d, J = 256.5 Hz), 147.8,137.1, 137.0, 136.7 (d, J = 4.0 Hz), 132.6, 130.2, 130.0, 129.7, 129.6,128.5, 128.2, 127.9, 127.5, 118.8, 115.6 (d, J = 23.2 Hz), 63.8, 59.8, 38.2.

[0205] 19 F NMR (376 MHz, CDCl3) δ -106.3.

[0206] HRMS (ESI) calcd. For C 26 H 22 FNNaO3S + [M + Na] + = 470.1197, Found:470.1197.

[0207] The ee value was 90%, t r (major) = 28.439 min, t r (minor) = 19.347min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.5mL / min).

[0208] Example 18

[0209] A method for preparing product 18, the reaction formula and steps are as follows:

[0210]

[0211] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 49.0 mg of 4b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 72 mg of product 18, which was a white foam with a yield of 84%, an ee value of 87%, and a dr value > 20:1.

[0212] The product is characterized as follows:

[0213] [α] 25 D = -7.9 (c 1.1, CHCl3).

[0214] 1 H NMR (400 MHz, CDCl3) δ 7.67 – 7.57 (m, 2H), 7.44 (t, J = 7.3 Hz,1H), 7.36 (dd, J = 15.0, 7.5 Hz, 3H), 7.27 (dd, J = 14.6, 7.4 Hz, 4H), 7.16 –7.01 (m, 5H), 6.53 (dd, J = 7.6, 2.4 Hz, 1H), 6.31 (dd, J = 17.4, 10.5 Hz,1H), 6.10 (s, 1H), 5.28 – 5.05 (m, 2H), 4.91 (d, J = 7.6 Hz, 1H), 3.06 – 2.75(m, 2H).

[0215] 13 C NMR (101 MHz, CDCl3) δ 203.8, 147.8, 140.5, 137.3, 137.1, 132.5,132.2, 130.2, 130.2, 128.6, 128.2, 127.8, 127.4, 127.0, 118.7, 63.6, 60.1,38.0.

[0216] HRMS (ESI) calcd. For C 26 H 23 NNaO3S +[M + Na] + = 452.1291, Found:452.1291.

[0217] The ee value was 87%, t r (major) = 23.437 min, t r (minor) = 18.303min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.5mL / min).

[0218] Example 19

[0219] A method for preparing product 19, comprising the following reaction formula and steps:

[0220]

[0221] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 57.8 mg of 5b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 83 mg of product 19, which was a white foam with a yield of 88%, an ee value of 97%, and a dr value > 20:1.

[0222] The product is characterized as follows:

[0223] [α] 25 D = -12.4 (c 1.3, CHCl3).

[0224] 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.40 (m, 5H), 7.31 (t, J = 7.7 Hz, 2H), 7.01 (dd, J = 29.9, 8.2 Hz, 4H), 6.63 (d, J = 8.4 Hz, 2H), 6.29 (dd, J =17.2, 9.7 Hz, 2H), 6.11 (s, 1H), 5.24 – 5.04 (m, 2H), 4.86 (d, J = 7.4 Hz, 1H), 3.72 (s, 3H), 3.02 – 2.63 (m, 2H), 2.31 (s, 3H).

[0225] 13 C NMR (101 MHz, CDCl3) δ 203.2, 159.1, 147.7, 142.8, 137.6, 136.8,132.5, 130.2, 129.7, 129.1, 128.7, 128.7, 128.2, 127.1, 118.5, 113.5, 62.6,60.4, 55.2, 37.4, 21.4.

[0226] HRMS (ESI) calcd. For C 28 H 27 NNaO4S + [M + Na] + = 496.1553, Found: 496.1549.

[0227] The ee value was 97%, t r (major) = 45.912 min, t r (minor) = 41.036min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.3mL / min).

[0228] Example 20

[0229] A method for preparing product 20, comprising the following reaction formula and steps:

[0230]

[0231] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 67.4 mg of 6b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 80 mg of product 20, which was a white foam with a yield of 77%, an ee value of 93%, and a dr value > 20:1.

[0232] The product is characterized as follows:

[0233] [α] 25 D = 4.6 (c 1.1, CHCl3).

[0234] 1 H NMR (400 MHz, CDCl3) δ 7.54 – 7.42 (m, 5H), 7.33 (t, J = 7.8 Hz,2H), 7.22 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.3 Hz,2H), 6.43 (d, J = 7.6 Hz, 1H), 6.29 (dd, J = 17.3, 10.4 Hz, 1H), 6.10 (s,1H), 5.28 – 5.02 (m, 2H), 4.85 (d, J = 7.6 Hz, 1H), 3.05 – 2.69 (m, 2H), 2.35 (s, 3H).

[0235] 13 C NMR (101 MHz, CDCl3) δ 202.8, 148.0, 143.2, 137.2, 136.5, 132.7,131.1, 130.1, 129.7, 129.5, 129.3, 128.6, 128.3, 127.1, 121.7, 118.9, 62.7,59.8, 37.4, 21.5.

[0236] HRMS (ESI) calcd. For C 27 H 24 BrNNaO3S+ [M + Na] + = 544.0552, Found:544.0548.

[0237] The ee value was 93%, t r (major) = 25.493 min, t r (minor) = 20.025min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.5mL / min).

[0238] Example 21

[0239] A method for preparing product 21, comprising the following reaction formula and steps:

[0240]

[0241] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 54.6 mg of 7b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 79 mg of product 21, which was a white foam with a yield of 87%, an ee value of 90%, and a dr value > 20:1.

[0242] The product is characterized as follows:

[0243] [α] 25 D = 0.2 (c 1.0, CHCl3).

[0244] 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.37 (m, 5H), 7.30 (t, J = 7.7 Hz, 2H), 7.09 – 6.91 (m, 5H), 6.80 (td, J = 8.0, 7.1, 2.4 Hz, 1H), 6.35 (d, J =7.3 Hz, 1H), 6.25 (dd, J = 17.3, 10.5 Hz, 1H), 6.08 (s, 1H), 5.25 (d, J = 7.3Hz, 1H), 5.19 – 5.01 (m, 2H), 3.02 – 2.73 (m, 2H), 2.36 (s, 3H), 2.29 (s, 3H).

[0245] 13 C NMR (101 MHz, CDCl3) δ 204.2, 147.0, 142.7, 137.5, 137.2, 135.9,135.3, 132.4, 130.3, 130.2, 130.0, 129.0, 128.7, 128.1, 127.7, 127.5, 126.9,125.9, 118.4, 60.1, 58.3, 38.4, 21.4, 20.0.

[0246] HRMS (ESI) calcd. For C 28 H 27 NNaO3S + [M + Na] + = 480.1604, Found:480.1601.

[0247] The ee value was 90%, t r (major) = 27.581 min, t r (minor) = 32.513min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0248] Example 22

[0249] A method for preparing product 22, the reaction formula and steps are as follows:

[0250]

[0251] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 55.4 mg of 8b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 83 mg of product 22, which was a white foam with a yield of 90%, an ee value of 92%, and a dr value > 20:1.

[0252] The product is characterized as follows:

[0253] [α] 25 D = -18.8 (c 1.2, CHCl3).

[0254] 1 H NMR (400 MHz, CDCl3) δ 7.54 – 7.41 (m, 5H), 7.32 (t, J = 7.7 Hz, 2H), 7.06 (dd, J = 8.2, 5.3 Hz, 4H), 6.80 (t, J = 8.4 Hz, 2H), 6.42 – 6.22(m, 2H), 6.10 (s, 1H), 5.16 (dd, J = 34.4, 13.9 Hz, 2H), 4.88 (d, J = 7.2 Hz,1H), 3.03 – 2.69 (m, 2H), 2.33 (s, 3H).

[0255] 13 C NMR (101 MHz, CDCl3) δ 203.0, 162.2 (d, J = 247.5 Hz), 147.9,143.1, 137.3, 136.6, 133.4, 132.7, 130.1, 129.8, 129.4, 129.3 (d, J = 6.1Hz), 128.6, 128.3, 127.1, 118.8, 114.9 (d, J = 21.2 Hz), 62.6, 60.0, 37.5,21.4.

[0256] 19F NMR (376 MHz, CDCl3) δ -113.9.

[0257] HRMS (ESI) calcd. For C 27 H 24 FNNaO3S + [M + Na] + = 484.1353, Found:484.1350.

[0258] The ee value was 92%, t r (major) = 36.078 min, t r (minor) = 31.023min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.3mL / min).

[0259] Example 23

[0260] A method for preparing product 23, the reaction formula and steps are as follows:

[0261]

[0262] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 63.4 mg of 9b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 82 mg of product 23, which was a white foam with a yield of 82%, an ee value of 92%, and a dr value > 20:1.

[0263] The product is characterized as follows:

[0264] [α] 25 D = -10.5 (c 1.2, CHCl3).

[0265] 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.71 (m, 2H), 7.47 (dd, J = 10.6, 7.7Hz, 5H), 7.37 – 7.23 (m, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.0 Hz,2H), 6.64 – 6.41 (m, 1H), 6.26 (dd, J = 17.3, 10.5 Hz, 1H), 6.12 (s, 1H), 5.20 – 5.02 (m, 2H), 4.96 (dd, J = 7.8, 2.1 Hz, 1H), 3.89 (s, 3H), 2.96 –2.68 (m, 2H), 2.28 (s, 3H).

[0266] 13 C NMR (101 MHz, CDCl3) δ 202.5, 166.7, 147.8, 143.2, 142.6, 137.2,136.4, 132.7, 130.0, 129.6, 129.4, 129.2, 128.6, 128.3, 127.8, 127.0, 118.8,62.8, 59.8, 52.1, 37.3, 21.3.

[0267] HRMS (ESI) calcd. For C 29 H 27 NNaO5S + [M + Na] + = 524.1502, Found:524.1503.

[0268] The ee value was 92%, t r (major) = 43.056 min, t r (minor) = 51.889min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0269] Example 24

[0270] A method for preparing product 24, the reaction formula and steps are as follows:

[0271]

[0272] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 61.0 mg of 10b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 81 mg of product 24, which was a white foam with a yield of 83%, an ee value of 96%, and a dr value > 20:1.

[0273] The product is characterized as follows:

[0274] [α] 25 D = 3.0 (c 1.0, CHCl3).

[0275] 1 H NMR (400 MHz, CDCl3) δ 7.55 – 7.39 (m, 5H), 7.31 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.97 (s, 4H), 6.44 – 6.21 (m, 2H), 6.11 (s,1H), 5.29 – 5.03 (m, 2H), 4.85 (dd, J = 7.5, 2.2 Hz, 1H), 3.06 – 2.71 (m,2H), 2.41 (s, 3H), 2.32 (s, 3H).

[0276] 13 C NMR (101 MHz, CDCl3) δ 203.1, 147.8, 142.9, 138.0, 137.4, 136.7,134.3, 132.6, 130.2, 130.0, 129.2, 128.7, 128.2, 128.1, 127.1, 126.1, 118.7,62.8, 60.1, 37.4, 21.4, 15.8.

[0277] HRMS (ESI) calcd. For C 28 H 27 NNaO3S2 + [M + Na]+ = 512.1325, Found:512.1322.

[0278] The ee value was 96%, t r (major) = 38.528 min, t r (minor) = 46.242min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.8 mL / min).

[0279] Example 25

[0280] A method for preparing product 25, the reaction formula and steps are as follows:

[0281]

[0282] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 57.4 mg of 11b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 80 mg of product 25, which was a white foam with a yield of 85%, an ee value of 86%, and a dr value > 20:1.

[0283] The product is characterized as follows:

[0284] [α] 25 D = -6.1 (c 1.0, CHCl3).

[0285] 1H NMR (400 MHz, CDCl3) δ 7.32 – 6.96 (m, 7H), 6.80 (d, J = 8.0 Hz,2H), 6.51 (s, 1H), 6.32 (s, 2H), 6.15 – 5.97 (m, 2H), 5.84 (s, 1H), 5.04 –4.73 (m, 2H), 4.54 (d, J = 7.5 Hz, 1H), 2.79 – 2.52 (m, 2H), 2.08 (s, 3H), 1.86 (s, 6H).

[0286] 13 C NMR (101 MHz, CDCl3) δ 203.9, 147.8, 142.6, 137.7, 137.5, 137.2,137.0, 132.3, 130.5, 130.3, 129.2, 128.9, 128.6, 128.0, 127.0, 125.4, 118.5,63.6, 60.0, 38.0, 21.3, 21.1.

[0287] HRMS (ESI) calcd. For C 29 H 29 NNaO3S + [M + Na] + = 494.1760, Found: 494.1759.

[0288] The ee value was 86%, t r (major) = 58.841 min, t r (minor) = 54.934min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.3 mL / min).

[0289] Example 26

[0290] A method for preparing product 26, the reaction formula and steps are as follows:

[0291]

[0292] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 57.0 mg of 12b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 80 mg of product 26, which was a white foam with a yield of 85%, an ee value of 95%, and a dr value > 20:1.

[0293] The product is characterized as follows:

[0294] [α] 25 D = -2.9 (c 1.0, CHCl3).

[0295] 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 8.2, 1.4 Hz, 2H), 7.73 – 7.67(m, 2H), 7.58 – 7.50 (m, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.30 – 7.21 (m, 3H),7.15 – 7.04 (m, 4H), 6.40 (dd, J = 17.3, 10.5 Hz, 1H), 6.26 – 6.13 (m, 2H),5.87 (dd, J = 15.8, 8.2 Hz, 1H), 5.77 (d, J = 8.5 Hz, 1H), 5.39 – 5.07 (m,2H), 4.39 (t, J = 8.4 Hz, 1H), 3.06 (d, J = 13.7 Hz, 1H), 2.92 (d, J = 13.6Hz, 1H), 2.24 (s, 3H).

[0296] 13C NMR (101 MHz, CDCl3) δ 202.3, 148.8, 143.2, 137.9, 136.6, 136.0,133.5, 132.7, 130.5, 130.3, 129.4, 128.7, 128.4, 128.4, 127.9, 127.4, 126.5,125.0, 118.9, 62.0, 60.1, 36.6, 21.3.

[0297] HRMS (ESI) calcd. For C 29 H 27 NNaO3S + [M + Na] + = 492.1604, Found:492.1601.

[0298] The ee value was 95%, t r (major) = 18.543 min, t r (minor) = 35.867min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.5mL / min).

[0299] Example 27

[0300] A method for preparing product 27, the reaction formula and steps are as follows:

[0301]

[0302] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 61.8 mg of 13b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 74 mg of product 27, which was a white foam with a yield of 75%, an ee value of 88%, and a dr value > 20:1.

[0303] The product is characterized as follows:

[0304] [α]25 D = 22.8 (c 1.0, CHCl3).

[0305] 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 7.8,1.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.42 (tt, J =5.6, 3.0 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.29 – 7.16 (m, 5H), 7.07 (t, J = 7.7Hz, 1H), 6.81 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 7.7 Hz, 1H), 6.31 (dd, J =17.3, 10.5 Hz, 1H), 5.99 (s, 1H), 5.87 (d, J = 7.7 Hz, 1H), 5.29 – 5.06 (m,2H), 2.98 (s, 2H), 2.21 (s, 3H).

[0306] 13 C NMR (101 MHz, CDCl3) δ 204.8, 147.2, 142.6, 137.5, 137.3, 133.6,133.5, 132.3, 131.2, 130.7, 130.3, 128.8, 128.6, 128.0, 128.0, 126.9, 126.3,125.8, 125.6, 124.9, 123.1, 118.5, 60.5, 57.9, 39.2, 21.2.

[0307] HRMS (ESI) calcd. For C 31 H 27 NNaO3S + [M + Na] + = 516.1604, Found:516.1600.

[0308] the ee value was 88%, t r (major) = 57.398 min, t r(minor) = 74.468min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0309] Example 28

[0310] A method for preparing product 28, the reaction formula and steps are as follows:

[0311]

[0312] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 61.8 mg of 14b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 77 mg of product 28, which was a white foam with a yield of 78%, an ee value of 88%, and a dr value > 20:1.

[0313] The product is characterized as follows:

[0314] [α] 25 D = 2.6 (c 1.1, CHCl3).

[0315] 1 H NMR (400 MHz, CDCl3) δ 7.79 – 7.66 (m, 1H), 7.64 – 7.59 (m, 1H), 7.58 – 7.39 (m, 9H), 7.33 – 7.24 (m, 2H), 7.20 (dd, J = 8.7, 2.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 6.70 – 6.55 (m, 1H), 6.30 (dd, J = 17.3, 10.5 Hz, 1H), 6.21 (d, J = 3.9 Hz, 1H), 5.23 – 5.00 (m, 3H), 3.08 – 2.84 (m, 2H), 2.08(s, 3H).

[0316] 13C NMR (101 MHz, CDCl3) δ 203.2, 147.7, 142.9, 137.4, 136.8, 134.6,132.7, 132.6, 130.2, 129.0, 128.7, 128.2, 128.0, 127.8, 127.5, 127.1, 127.0,126.0, 125.4, 118.6, 63.5, 60.3, 37.6, 21.2.

[0317] HRMS (ESI) calcd. For C 31 H 27 NNaO3S + [M + Na] + = 516.1604, Found: 516.1600.

[0318] The ee value was 88%, t r (major) = 26.630 min, t r (minor) = 20.285min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.5mL / min).

[0319] Example 29

[0320] A method for preparing product 29, the reaction formula and steps are as follows:

[0321]

[0322] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 63.0 mg of 15b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 70 mg of product 29, which was a white foam with a yield of 71%, an ee value of 90%, and a dr value > 20:1.

[0323] The product is characterized as follows:

[0324] [α] 25 D = 9.3 (c 1.0, CHCl3).

[0325] 1 H NMR (400 MHz, CDCl3) δ 7.51 – 7.45 (m, 2H), 7.41 (ddt, J = 8.7,6.4, 2.2 Hz, 1H), 7.29 – 7.19 (m, 4H), 7.08 – 7.03 (m, 2H), 7.00 (d, J = 8.0Hz, 2H), 6.95 – 6.86 (m, 2H), 6.53 – 6.21 (m, 2H), 6.07 (s, 1H), 5.41 – 5.01(m, 2H), 4.82 (dd, J = 7.7, 2.1 Hz, 1H), 2.98 – 2.69 (m, 2H), 2.29 (s, 3H),1.24 (s, 9H).

[0326] 13 C NMR (101 MHz, CDCl3) δ 204.1, 150.6, 147.9, 142.5, 137.7, 137.3,134.4, 132.3, 130.5, 130.3, 129.0, 128.6, 128.0, 127.1, 127.1, 124.9, 118.5,63.5, 60.2, 38.1, 34.4, 31.3, 21.4.

[0327] HRMS (ESI) calcd. For C 31 H 33 NNaO3S + [M + Na] + =522.2073, Found:522.2069.

[0328] the ee value was 90%, t r (major) = 22.824 min, t r (minor) = 18.530min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 80: 20, flow rate = 0.5mL / min).

[0329] Example 30

[0330] A method for preparing product 30, comprising the following reaction formula and steps:

[0331]

[0332] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 71.0 mg of 16b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 86 mg of product 30, which was a white foam with a yield of 81%, an ee value of 90%, and a dr value > 20:1.

[0333] The product is characterized as follows:

[0334] [α] 25 D = 41.6 (c 1.2, CHCl3).

[0335] 1 H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 7.6 Hz, 5H), 7.11 (t, J = 7.7Hz, 2H), 6.97 (d, J = 7.8 Hz, 2H), 6.79 (dd, J = 14.7, 7.9 Hz, 4H), 6.22 (t,J = 6.7 Hz, 1H), 6.13 – 6.00 (m, 1H), 5.88 (d, J = 1.7 Hz, 1H), 5.04 – 4.80(m, 2H), 4.66 (dd, J = 7.7, 3.0 Hz, 1H), 2.80 – 2.47 (m, 2H), 2.11 (s, 3H),0.05 (s, 9H).

[0336] 13C NMR (101 MHz, CDCl3) δ 203.1, 147.8, 143.1, 137.8, 137.3, 136.7,132.7, 131.6, 130.1, 129.8, 129.2, 128.6, 128.3, 127.6, 127.0, 122.4, 118.8,104.7, 94.6, 63.1, 59.9, 37.6, 21.4.

[0337] HRMS (ESI) calcd. For C 32 H 33 NNaO3SSi + [M + Na] + = 562.1843, Found: 562.1838.

[0338] The ee value was 90%, t r (major) = 27.920 min, t r (minor) = 33.136min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0339] Example 31

[0340] A method for preparing product 31, the reaction formula and steps are as follows:

[0341]

[0342] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 49.8 mg of 17b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 74 mg of product 31, which was a white foam with a yield of 86%, an ee value of 94%, and a dr value > 20:1.

[0343] The product is characterized as follows:

[0344] [α]25 D = -53.4 (c 1.0, CHCl3).

[0345] 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.62 – 7.56 (m, 2H),7.52 – 7.45 (m, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.19 – 7.01 (m, 4H), 6.32 (dd,J = 17.3, 10.5 Hz, 1H), 6.12 (d, J = 8.4 Hz, 2H), 5.99 (dd, J = 2.0, 0.9 Hz,1H), 5.26 – 5.04 (m, 2H), 4.86 (d, J = 8.6 Hz, 1H), 3.02 (d, J = 13.5 Hz,1H), 2.78 (d, J = 13.6 Hz, 1H), 2.34 (s, 3H).

[0346] 13 C NMR (101 MHz, CDCl3) δ 202.4, 148.6, 143.2, 142.8, 140.3, 137.6,136.6, 132.7, 130.7, 130.3, 129.3, 128.6, 128.4, 127.1, 122.7, 118.7, 109.5,60.5, 54.9, 36.2, 21.5.

[0347] HRMS (ESI) calcd. For C 25 H 23 NNaO4S + [M + Na] + = 456.1240, Found:456.1237.

[0348] the ee value was 94%, t r (major) = 29.599 min, t r (minor) = 32.995min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0349] Example 32

[0350] A method for preparing product 32, the reaction formula and steps are as follows:

[0351]

[0352] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 53.0 mg of 18b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 71 mg of product 32, which was a white foam with a yield of 79%, an ee value of 95%, and a dr value > 20:1.

[0353] The product is characterized as follows:

[0354] [α] 25 D = -30.8 (c 1.2, CHCl3).

[0355] 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H), 7.49 (dd, J = 7.8,4.6 Hz, 3H), 7.34 (t, J = 7.7 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.03 (dd, J= 5.0, 3.0 Hz, 1H), 6.88 (d, J = 3.0 Hz, 1H), 6.70 (d, J = 5.0 Hz, 1H), 6.45– 6.22 (m, 2H), 6.12 (s, 1H), 5.30 – 5.11 (m, 2H), 5.00 (d, J = 8.2 Hz, 1H),3.03 – 2.80 (m, 2H), 2.36 (s, 3H).

[0356] 13C NMR (101 MHz, CDCl3) δ 203.5, 148.4, 142.9, 139.0, 137.7, 137.1,132.5, 130.6, 130.3, 129.2, 128.5, 128.2, 127.0, 126.7, 125.7, 122.9, 118.8,60.2, 59.3, 37.3, 21.5.

[0357] HRMS (ESI) calcd. For C 25 H 23 NNaO3S2 + [M + Na] + = 472.1012, Found:472.1009.

[0358] The ee value was 95%, t r (major) = 41.233 min, t r (minor) = 47.718min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0359] Example 33

[0360] A method for preparing product 33, the reaction formula and steps are as follows:

[0361]

[0362] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 63.4 mg of 19b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 69 mg of product 33, which was a white foam with a yield of 69%, an ee value of 94%, and a dr value > 20:1.

[0363] The product is characterized as follows:

[0364] [α] 25D = -12.3 (c 1.1, CHCl3).

[0365] 1 H NMR (400 MHz, CDCl3) δ 7.56 – 7.41 (m, 5H), 7.32 (t, J = 7.8 Hz,2H), 7.10 (d, J = 8.0 Hz, 2H), 6.36 – 6.22 (m, 3H), 6.11 (d, J = 8.5 Hz, 2H),5.89 (s, 2H), 5.26 – 5.10 (m, 2H), 4.76 (d, J = 7.2 Hz, 1H), 3.62 (s, 3H),3.01 – 2.74 (m, 2H), 2.34 (s, 3H).

[0366] 13 C NMR (101 MHz, CDCl3) δ 203.3, 148.4, 148.1, 143.1, 143.0, 137.6,136.9, 134.7, 132.6, 132.1, 130.2, 130.2, 129.1, 128.7, 128.2, 127.1, 118.8,107.2, 102.0, 101.5, 63.4, 60.1, 56.3, 37.8, 21.4.

[0367] HRMS (ESI) calcd. For C 29 H 27 NaNO5S + [M + Na] + = 524.1502, Found:524.1502.

[0368] The ee value was 94%, t r (major) = 60.819 min, t r (minor) = 70.935min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0369] Example 34

[0370] A method for preparing product 34, the reaction formula and steps are as follows:

[0371]

[0372] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 62.0 mg of 20b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 80 mg of product 34, which was a white foam with a yield of 81%, an ee value of 92%, and a dr value > 20:1.

[0373] The product is characterized as follows:

[0374] [α] 25 D = -9.1 (c 1.1, CHCl3).

[0375] 1 H NMR (400 MHz, CDCl3) δ 8.92 (dd, J = 4.1, 2.0 Hz, 1H), 8.07 (dd, J= 8.4, 2.1 Hz, 1H), 7.89 (d, J = 3.5 Hz, 1H), 7.58 – 7.51 (m, 3H), 7.50 –7.43 (m, 3H), 7.41 – 7.36 (m, 1H), 7.33 – 7.26 (m, 3H), 6.86 (dd, J = 8.3,2.2 Hz, 2H), 6.77 – 6.60 (m, 1H), 6.27 – 6.16 (m, 2H), 5.10 (ddd, J = 13.0,8.6, 3.2 Hz, 2H), 4.97 (dd, J = 17.5, 3.4 Hz, 1H), 3.01 – 2.75 (m, 2H), 2.11(s, 3H).

[0376] 13C NMR (101 MHz, CDCl3) δ 202.1, 150.8, 147.8, 147.4, 142.9, 137.0,136.1, 135.8, 132.7, 130.0, 129.7, 129.1, 128.8, 128.5, 128.3, 127.5, 127.1,126.2, 121.3, 118.7, 63.0, 60.1, 37.1, 21.2.

[0377] HRMS (ESI) calcd. For C 30 H 26 N2NaO3S + [M + Na] + = 517.1556, Found:517.1552.

[0378] The ee value was 92%, t r (major) = 15.846 min, t r (minor) = 23.823min, (Chiralcel OD-3, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5mL / min).

[0379] Example 35

[0380] A method for preparing product 35, the reaction formula and steps are as follows:

[0381]

[0382] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 59.8 mg of 21b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 88 mg of product 35, which was a white foam with a yield of 91%, an ee value of 83%, and a dr value > 20:1.

[0383] The product is characterized as follows:

[0384] [α] 25 D = -8.2 (c 1.0, CHCl3).

[0385] 1 H NMR (400 MHz, CDCl3) δ 7.71 – 7.62 (m, 3H), 7.57 (dd, J = 8.3, 2.3Hz, 2H), 7.54 – 7.45 (m, 2H), 7.38 – 7.20 (m, 4H), 6.94 (d, J = 8.0 Hz, 2H),6.82 (d, J = 2.6 Hz, 1H), 6.51 – 6.34 (m, 2H), 6.21 (d, J = 2.5 Hz, 1H), 5.34– 4.92 (m, 3H), 3.14 – 2.87 (m, 2H), 2.15 (s, 3H).

[0386] 13 13C NMR (101 MHz, CDCl3) δ 202.4, 154.3, 153.4, 148.5, 143.1, 137.3,136.9, 132.6, 130.6, 130.3, 129.1, 128.5, 128.3, 127.6, 127.0, 124.2, 122.8,121.0, 119.0, 111.0, 105.4, 59.3, 57.6, 37.1, 21.3.

[0387] HRMS (ESI) calcd. For C 29 H 25 NNaO4S + [M + Na] + = 506.1397, Found:506.1393.

[0388] the ee value was 83%, t r (major) = 31.542 min, t r (minor) = 28.947min, (Chiralcel IC, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.5 mL / min).

[0389] Example 36

[0390] A method for preparing product 36, the reaction formula and steps are as follows:

[0391]

[0392] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of toluene solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 63.0 mg of 22b (0.2 mmol, 1.0 equiv) were added. The mixture was cooled to 0 °C and stirred for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 83 mg of product 36, which was a white foam with a yield of 83%, an ee value of 97%, and a dr value > 20:1.

[0393] The product is characterized as follows:

[0394] [α] 25 D = -20.5 (c 1.2, CHCl3).

[0395] 1 H NMR (400 MHz, CDCl3) δ 7.7 – 7.6 (m, 3H), 7.6 (dd, J = 8.3, 2.3 Hz,2H), 7.5 – 7.5 (m, 2H), 7.4 – 7.2 (m, 4H), 6.9 (d, J = 8.0 Hz, 2H), 6.8 (d, J= 2.6 Hz, 1H), 6.5 – 6.3 (m, 2H), 6.2 (d, J = 2.5 Hz, 1H), 5.3 – 5.1 (m, 3H), 3.1 – 2.9 (m, 2H), 2.2 (s, 3H).

[0396] 13 C NMR (101 MHz, CDCl3) δ 203.1, 149.1, 143.1, 141.4, 139.7, 138.7,137.4, 137.0, 132.6, 130.6, 130.2, 129.0, 128.5, 128.3, 127.1, 124.3, 124.2,123.8, 123.4, 122.1, 119.3, 60.3, 37.3, 21.2.

[0397] HRMS (ESI) calcd. For C 29 H 25 NNaO3S2 + [M + Na] + = 522.1168, Found: 522.1167.

[0398] The ee value was 97%, t r (major) = 48.859 min, t r (minor) = 27.205min, (Chiralcel IA, λ = 254 nm, hexanes: i PrOH = 70: 30, flow rate = 0.3 mL / min).

[0399] Example 37

[0400] A method for preparing product 1, comprising the following reaction formula and steps:

[0401]

[0402] In an argon-filled glove box, 4.6 mg of Pd2(dba)3 (0.005 mmol, 2.5 mol%), 9.8 mg of chiral ligand L2 (0.012 mmol, 6.0 mol%), and 1.0 mL of tetrahydrofuran solvent were added to the reaction flask. After stirring thoroughly for half an hour, 36.8 mg of 1a (0.2 mmol, 1.0 equiv) and 51.8 mg of 1b (0.2 mmol, 1.0 equiv) were added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain 72 mg of product 1, which was a white foam with a yield of 81%, an ee value of 80%, and a dr value > 20:1.

[0403] Examples 38 and 39

[0404] The following examples are all methods for preparing product 1, and their steps and reaction conditions are roughly the same as those in Example 1, except that:

[0405]

[0406] The dosage of ligand L1 was 8.3 mg (0.012 mmol, 6.0 mol%), and the dosage of ligand L3 was 9.5 mg (0.011 mmol, 5.5 mol%).

[0407] Examples 40-51

[0408] The following examples are all methods for preparing product 1. The steps and reaction conditions are roughly the same as in Example 1, except that the solution and stirring temperatures are different, as detailed below:

[0409]

[0410] Examples 40-51 investigated the effects of different solvents and temperatures on the reaction. When toluene was used as the reaction solvent at room temperature, a high yield and excellent ee value (yield: 91%, ee value: 92%) were maintained. Furthermore, when the solvent was changed to trifluorotoluene, ethyl acetate, or dichloroethane, excellent yields and ee values ​​were still maintained. When dichloromethane, 1,4-dioxane, or ethylene glycol dimethyl ether were used, the ee value remained at a moderately high level. After toluene was determined to be the optimal solvent, increasing the temperature to 60°C did not significantly change the yield and ee value; decreasing the temperature to -15°C also showed almost no significant change in yield and ee value. This demonstrates that the reaction conditions of this invention are mild, less affected by solvents and temperatures, and exhibit excellent process resistance.

Claims

1. A process for the preparation of a polysubstituted chiral cyclobutene, characterized in that, The reaction formula and reaction process are as follows: In a glove box filled with protective gas, a metal catalyst, a chiral ligand, and a solvent are added to a reaction flask. After thorough stirring, vinyl-carbonyl-bicyclobutane and an imine are added. The mixture is stirred at a certain temperature until the reaction is complete, yielding polysubstituted chiral cyclobutene. in: The metal catalyst is Pd2(dba)3; The chiral ligand has one of the following structures: 、 、 。 2. The method of claim 1, wherein: R1 is an alkyl, aryl, substituted aryl, or heteroaryl group.

3. The preparation method according to claim 2, characterized in that, For R1: the alkyl group is n-butyl or tert-butyl; the heteroaryl group is furanyl, thiophene, benzofuranyl, piperonyl or quinolinyl; the aryl group is phenyl or naphthyl; the substituted aryl group is a substituted phenyl group, wherein the substituent is methyl, methoxy, trifluoromethyl, bromine, chlorine or fluorine.

4. The preparation method according to claim 1, characterized in that: R2 is an alkenyl, aryl, substituted aryl, or heteroaryl group.

5. The preparation method according to claim 4, characterized in that, For R2: the alkenyl group is styryl; the heteroaryl group is furanyl, thiophene, benzothiophene, benzofuranyl, piperyl, or quinolinyl; the aryl group is phenyl or naphthyl; the substituted aryl group is a substituted phenyl group, wherein the substituent is alkynyl, esteryl, thiomethyl, methyl, tert-butyl, methoxy, chlorine, or fluorine.

6. The preparation method according to claim 1, characterized in that: R3 is p-toluylsulfonyl, p-methoxyphenylsulfonyl, p-fluorophenylsulfonyl, or phenylsulfonyl.

7. The preparation method according to claim 1, characterized in that: The solvent is selected from dichloromethane, 1,2-dichloroethane, ethyl acetate, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, toluene, or trifluorotoluene.

8. The preparation method according to any one of claims 1-7, characterized in that: The molar ratio of the metal catalyst to bicyclobutane is (1.25-5):100; The molar ratio of the chiral ligand to bicyclobutane is (4-12):100; The equivalence ratio of the imine to bicyclobutane is 1:

1.

9. The preparation method according to claim 8, characterized in that: The reaction time is 10 to 24 hours, and the specific temperature is -15℃ to 80℃.

10. The preparation method according to claim 8, characterized in that: The specified temperature is 0℃~40℃.

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