A method for highly stereoselectively constructing nitrogen-nitrogen axial chiral bipyrrole compounds

Abstract

The present invention belongs to the field of asymmetric organic synthesis, and discloses a method for highly stereoselectively constructing nitrogen-nitrogen axially chiral bipyrrole compounds. The present invention uses chiral rhodium as a catalyst, diazo compounds and bipyrrole derivatives as raw materials, and a method for highly stereoselectively constructing nitrogen-nitrogen axially chiral bipyrrole compounds by using a desymmetrization strategy. The advantages of the method of the present invention are as follows: novel nitrogen-nitrogen axially chiral bipyrrole compounds can be constructed quickly and efficiently. The reaction conditions are mild, the operation is simple, the substrate generality is good, the reaction efficiency is high, and the enantioselectivity is good, up to 99% ee.

Description

Technical Field

[0001] The present invention belongs to the field of asymmetric catalysis, and specifically relates to a method for generating rhodium carbene in situ from a diazo compound under the action of a chiral rhodium catalyst, and performing a highly stereoselective C-H bond insertion reaction on an N-N axially chiral bipyrrole compound to generate an optically active N-N axially chiral bipyrrole compound. Background Art

[0002] Axially chiral ligands and catalysts are very common and have important applications in asymmetric catalysis. For example, BINAP has been industrialized for multiple asymmetric catalytic reactions, and axially chiral phosphoric acids have shown excellent catalytic performance and application prospects in organocatalysis. The research on constructing axially chiral skeletons has received increasing attention.

[0003] N-heterocyclic compounds containing axially chiral N-N bonds are widely present in natural products, functional materials, chiral ligands and bioactive molecules. For example, the structures of BIMIP, schischkiniin, and antibiotics all contain N-N chiral axes. However, compared with the research on carbon-carbon axial chirality, there are few synthetic methods for nitrogen-nitrogen atomic axial chirality. The reported methods include: catalytic asymmetric construction of N-N bonds through enantioselective N-allyl alkylation reactions (Lu, Y., et al.; Chem. 2021, 7, 2743–2757.); formation of enantioselective N-heterocycles through chiral phosphoric acid or Lewis acid catalysis (Li, X., et al.; Chem. Sci. 2022, 13, 141–148.); and desymmetrization of meso-bipyrroles using asymmetric Friedel-Crafts reactions (Liu, R.-R., et al.; J. Am. Chem. Soc. 2021, 143, 15005–15010.).

[0004] Compared with the Friedel-Crafts reaction, the C-H bond insertion reaction of carbene is a very fast and efficient method for constructing C-H bonds. In the present invention, a metal carbene generated by catalysis with a suitable chiral catalyst is highly selectively inserted into the Sp 2 -H bond of a heteroaromatic ring to achieve selective desymmetrization, thereby constructing N-N axial chirality, which will be a very direct and effective method. The present invention provides a new method for constructing an optically active N-N bipyrrole compound by chiral rhodium-catalyzed diazo compounds inserting into the C-H bond of a prochiral N-N bipyrrole compound. Summary of the Invention

[0005] The present invention discloses a new method for constructing chiral N-N bipyrrole compounds by chiral rhodium-catalyzed C-H bond insertion of diazo derivatives into prochiral N-N bipyrrole compounds, which can obtain N-N axis chiral bipyrrole compounds in excellent yields and enantioselectivities. The possible reaction process is as follows: The diazo compound generates chiral rhodium carbene under the catalysis of chiral rhodium, forms an amphoteric ion intermediate with the N-N bipyrrole compound, and then undergoes stereoselective proton migration and aromatization to construct the N-N chiral axis.

[0006] A method for constructing nitrogen-nitrogen axis chiral bipyrrole compounds with high stereoselectivity is carried out specifically according to the following steps: Under the protection of argon, a chiral rhodium catalyst, a bipyrrole derivative (1), a diazo derivative (2) and a solvent are added into a reaction tube, and then stirred and reacted at a certain temperature for a certain time to obtain an N-N axis chiral bipyrrole compound (3).

[0007] The specific reaction general formula of the present invention is as follows:

[0008]

[0009] Wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclohexyl; R 2 is methyl, ethyl, tert-butyl; R 3 is hydrogen, methyl; R 4 is methyl, ethyl; R 5 is hydrogen, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4-nitro, 4-phenyl, 3-methyl, 3-chloro, 2-methoxy, 3,4-dichloro, naphthalen-1-yl.

[0010] Furthermore, the bipyrrole derivative includes the following structural formulas:

[0011]

[0012] Furthermore, the diazo derivative includes the following structural formulas:

[0013]

[0014] The preferred diazo derivative is the following structural formula:

[0015]

[0016] Further, the chiral rhodium catalyst is: Rh2(S-BTPCP)4, Rh2(S-TFPTTL)4, Rh2(S-PTAD)4, Rh2(S-NTTL)4, Rh2(S-MSP)4, Rh2(S-PTTL)4, Rh2(S-4-Br-NTTL)4, Rh2(S-4-Cl-NTTL)4, and the further preferably catalyst is: Rh2(S-NTTL)4

[0017]

[0018] Further, the reaction solvents are: dichloromethane, dichloroethane, chloroform, toluene, trifluorotoluene, methanol, 1,4-dioxane, etc., and the optimal solvent is: dichloroethane (DCE).

[0019] Further, the molar ratio of the chiral rhodium catalyst, bipyrrole derivative (1), and diazo derivative (2) in the reaction is: 0.01 - 0.02:1:1.1 - 5, and the optimal molar ratio is: 0.01:1:3.

[0020] Further, the reaction solution concentration is: 0.05 - 0.6 mol / L, and the optimal reaction concentration is: 0.4 mol / L.

[0021] Further, the reaction temperature is: -20 - 25 °C, and the best temperature is: 0 °C.

[0022] Further, the reaction time is: 10 minutes - 3 hours, and the best time is: 30 minutes.

[0023] The synthesized optically pure N-N axially chiral bipyrrole derivative can be easily derivatized to obtain optically pure N-N axially chiral bipyrrole derivatives with more rich structures, further enriching the molecular library of this kind of compounds.

[0024] Beneficial effects

[0025] The present invention discloses a method for constructing N-N axially chiral biaryl compounds by the stereoselective insertion reaction of diazo compounds into the C-H bond of prochiral N-N bipyrrole derivatives catalyzed by chiral rhodium. The axial chirality construction is efficiently completed in one step through the carbene transfer strategy. The advantages of the method of the present invention are: mild reaction conditions, simple operation, good substrate generality, high reaction efficiency, and good enantioselectivity. Description of the drawings

[0026] Figure 1 1H-NMR (proton nuclear magnetic resonance) of 3a obtained in Example 1 1 1H-NMR (proton nuclear magnetic resonance);

[0027] Figure 2 1H-NMR (proton nuclear magnetic resonance) of 3a obtained in Example 1 13C-NMR (Carbon-13 Nuclear Magnetic Resonance);

[0028] Figure 3 The HRMS (High Resolution Mass Spectrometry) of 3a obtained in Example 1;

[0029] Figure 4 The HPLC (High Performance Liquid Chromatography, the upper figure is the racemic product, the lower figure is the chiral product) of 3a obtained in Example 1. Detailed Embodiments

[0030] The present invention will be further described below through specific examples, and the present invention is not limited to the following examples:

[0031] Example 1:

[0032]

[0033] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 hours. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (82.8 mg, 91%, 93% ee). Melting point: 73 - 75 °C. HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.89 min (minor), 9.15 min (major), 93% ee. [α] D 25 : 18.72° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.10 (m, 3H), 6.93 (s, 1H), 6.91 - 6.80 (m, 2H), 6.09 (s, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 2.80 - 2.62 (m, 2H), 1.87 (s, 3H), 1.83 (s, 3H), 1.09 (t, J = 7.5 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 169.0, 165.1, 143.7, 132.5, 130.0, 128.8, 128.0, 127.3, 126.7, 125.8, 110.8, 110.5, 108.0, 106.3, 52.8, 51.3, 49.9, 17.9, 13.7, 11.0, 9.2. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 29 N2O6 453.2020; Found 453.2020.

[0034] Example 2:

[0035] Racemic product: Under argon protection, Rh2(esp)2 (1.5 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain a white solid product 3a': (49.7 mg, 55%), melting point: 73 - 75 °C.

[0036] Example 3:

[0037] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCM (2.0 mL) were added to a reaction tube, and the reaction was stirred at 25 °C for 3 h. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain a white solid product 3a: (45.2 mg, 50%, 78% ee).

[0038] Example 4:

[0039] Under argon protection, Rh2(S-TFPTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCM (2.0 mL) were added to a reaction tube, and the reaction was stirred at 25 °C for 3 h. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain a white solid product 3a: (68.7 mg, 76%, 0% ee), melting point: 73 - 75 °C.

[0040] Example 5:

[0041] Under argon protection, Rh2(S-PTAD)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCM (2.0 mL) were added to the reaction tube, and the reaction was stirred at 25 °C for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (68.7 mg, 52%, 59% ee), melting point: 73 - 75 °C.

[0042] Example 6:

[0043] Under argon protection, Rh2(S-MSP)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCM (2.0 mL) were added to the reaction tube, and the reaction was stirred at 25 °C for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (36.1 mg, 40%, 0% ee), melting point: 73 - 75 °C.

[0044] Example 7:

[0045] Under argon protection, Rh2(S-4-Br-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCM (2.0 mL) were added to the reaction tube, and the reaction was stirred at 25 °C for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (36.1 mg, 48%, 69% ee), melting point: 73 - 75 °C.

[0046] Example 8:

[0047] Under argon protection, Rh2(S-4-Cl-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCM (2.0 mL) were added to the reaction tube, and the reaction was stirred at 25 °C for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (36.1 mg, 48%, 69% ee), melting point: 73 - 75 °C.

[0048] Example 9:

[0049] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCM (2.0 mL) were added to a reaction tube, and the reaction was stirred at 10 °C for 3 hours. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (66.9 mg, 74%, 79% ee), melting point: 73 - 75 °C.

[0050] Example 10:

[0051] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCE (2.0 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 3 hours. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (54.2 mg, 60%, 88% ee), melting point: 73 - 75 °C.

[0052] Example 11:

[0053] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (63.2 mg, 0.4 mmol) and DCE (1.0 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 3 hours. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (67.8 mg, 75%, 90% ee), melting point: 73 - 75 °C.

[0054] Example 12:

[0055] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 10 minutes. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the white solid product 3a: (66.0 mg, 73%, 93% ee), melting point: 73 - 75 °C.

[0056] Example 13:

[0057]

[0058] To a toluene solution (18.0 ml) of 1,4-dione (547.0 mg, 4.8 mmol, 1 equiv.) was added (S2) (1.5 g, 5.8 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an oil bath at 80 °C for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the white solid product 1b (269.0 mg, 17%), melting point: 70 - 72 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.03 (d, J = 8.0 Hz, 2H), 6.88 (s, 1H), 6.79 (d, J = 8.0 Hz, 2H), 5.88 (s, 2H), 3.87 (s, 3H), 2.67 (q, J = 7.4 Hz, 2H), 2.28 (s, 3H), 1.88 (s, 6H), 1.09 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 165.1, 143.5, 137.0, 132.6, 129.5, 127.9, 127.4, 125.6, 110.5, 107.3, 105.2, 51.1, 21.1, 17.9, 13.7, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 21 H 25 N2O2 337.1911; Found 337.1908.

[0059] Example 14:

[0060]

[0061] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1b (67.0 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to give the colorless oily product 3b: (56.4 mg, 60%, 83% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.14 min (minor), 8.23 min (major), 83% ee. [α] D25 : 19.20° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.16 - 6.91 (m, 2H), 6.88 (s, 1H), 6.85 - 6.62 (m, 2H), 6.08 (s, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.83 - 2.57 (m, 2H), 2.28 (s, 3H), 1.85 (s, 3H), 1.83 (s, 3H), 1.08 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 167.9, 167.9, 164.0, 142.3, 136.0, 131.5, 128.4, 126.9, 126.1, 125.6, 124.5, 109.6, 109.3, 106.3, 105.1, 51.7, 50.1, 48.9, 28.7, 20.1, 16.8, 12.6, 9.9, 8.1. HRMS (ESI) m / z: [M + H] + calcd for C 26 H 31 N2O6 467.2177; Found 467.2181.

[0062] Example 15:

[0063]

[0064] To a toluene solution (20.0 ml) of 1,4-dione (615.0 mg, 5.4 mmol, 1 equiv.) was added (S3) (1.8 g, 5.8 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the white solid product 1c (269.0 mg, 17%), melting point: 70 - 72 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 6.75 (dd, J = 7.0, 2.0 Hz, 3H), 6.71 - 6.63 (m, 2H), 5.79 (s, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 2.59 (q, J = 7.4 Hz, 2H), 1.79 (s, 6H), 1.01 (t, J = 7.4 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 165.2, 158.8, 143.2, 132.4, 127.9, 127.2, 122.9, 114.1, 110.4, 106.7, 105.2, 55.2, 51.1, 17.9, 13.7, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 21 H 25 N2O3 353.1860; Found 353.1857.

[0065] Example 16:

[0066]

[0067] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1c (70.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure, and purified by thin-layer chromatography (eluent: PE:EA = 5:1) to obtain a colorless oily product 3c: (75.4 mg, 78%, 91% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 20 / 80, flow rate = 1.0 mL / min, I = 215 nm) t R = 6.80 min (minor), 7.66 min (major), 91% ee. [α] D 25 : 19.76° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) (400 MHz, Chloroform-d) δ 6.84 - 6.71 (m, 3H), 6.71 - 6.63 (m, 2H), 5.79 (s, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 2.59 (q, J = 7.4 Hz, 2H), 1.79 (s, 6H), 1.01 (t, J = 7.4 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 169.04, 169.0, 165.2, 158.9, 143.1, 132.5, 128.0, 127.3, 126.8, 122.7, 114.2, 110.6, 110.4, 106.8, 106.2, 55.2, 52.8, 51.2, 49.9, 17.9, 13.8, 11.0, 9.2. HRMS (ESI) m / z: [M+H] + calcd for C 26 H 31 N2O7 483.2126; Found 483.2130.

[0068] Example 17:

[0069]

[0070] To a toluene solution (23.0 ml) of 1,4-dione (718.0 mg, 6.3 mmol, 1 equiv.) was added (S4) (2 g, 7.5 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the white solid product 1d (870.0 mg, 17%), mp: 64 - 66 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 6.94 - 6.83 (m, 5H), 5.88 (s, 2H), 3.87 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 1.87 (s, 6H), 1.09 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 165.0, 163.2, 160.7, 143.7, 131.5, 127.8, 127.5 (d, J C-F = 7.9 Hz), 126.4 (d, J C-F = 3.4 Hz), 115.7 (d, J C-F = 21.7 Hz), 110.6, 107.7, 105.4, 51.2, 17.9, 13.6, 11.1. 19 19F NMR (376 MHz, Chloroform-d) δ -114.5. HRMS (ESI) m / z: [M+H] + calcd for C 20 H 22FN2O2341.1660; Found 341.1658.

[0071] Example 18:

[0072]

[0073] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1d (68.0 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the colorless oily product 3d: (92.0 mg, 97%, 91% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.36 min (minor), 8.46 min (major), 91% ee. [α] D 25 : 18.80° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 6.97 - 6.85 (m, 3H), 6.85 - 6.74 (m, 2H), 6.08 (d, J = 1.1 Hz, 1H), 4.51 (s, 1H), 3.87 (s, 3H), 3.77 (d, J = 6.7 Hz, 6H), 2.83 - 2.60 (m, 2H), 1.89 - 1.84 (m, 3H), 1.82 (s, 3H), 1.09 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.9 (d, J C-F = 20.5 Hz), 164.9, 163.2, 160.7, 143.5, 131.6, 127.9, 127.7 (d, J C-F = 7.7 Hz), 126.6, 126.2 (d, J C-F = 3.4 Hz), 115.7 (d, J C-F = 21.5 Hz), 110.7 (d, J C-F = 7.4 Hz), 107.7, 106.4, 53.0, 52.7, 51.2, 49.8, 17.9, 13.7, 10.9, 9.1. 1919F NMR (376 MHz, Chloroform-d) δ -114.4. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 28 FN2O6 471.1926; Found 471.1925.

[0074] Example 19:

[0075]

[0076] To a toluene solution (23.0 ml) of 1,4-dione (399.0 mg, 3.5 mmol, 1 equiv.) was added (S5) (1.2 g, 4.2 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the white solid product 1e (900.0 mg, 72%), mp: 56 - 58 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 7.18 (d, J = 8.7 Hz, 2H), 6.93 (s, 1H), 6.85 - 6.71 (m, 2H), 5.89 (s, 2H), 3.87 (s, 3H), 2.69 (q, J = 7.5 Hz, 2H), 1.87 (s, 6H), 1.10 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 164.9, 144.1, 133.0, 131.2, 129.0, 128.7, 127.8, 126.8, 110.8, 108.1, 105.5, 51.2, 17.9, 13.6, 11.0. HRMS (ESI) m / z: [M+H] + calcd for C 20 H 22 ClN2O2 357.1364; Found 357.1362.

[0077] Example 20:

[0078]

[0079] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1e (71.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure, and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the colorless oily product 3d: (84.0 mg, 86%, 97% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 6.95 min (minor), 7.81 min (major), 97% ee. [α] D 25 : 74.16° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.24 - 7.11 (m, 2H), 6.93 (s, 1H), 6.81 - 6.68 (m, 2H), 6.10 (d, J = 1.2 Hz, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 2.71 (dd, J = 19.1, 7.4 Hz, 2H), 1.86 (s, 3H), 1.81 (s, 3H), 1.09 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.9, 164.8, 143.9, 133.1, 131.2, 128.9, 128.4, 127.9, 126.9, 126.6, 110.9, 110.7, 108.2, 106.5, 52.8, 52.7, 51.2, 49.8, 17.9, 13.6, 10.9, 9.1. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 28 ClN2O6 487.1630; Found 487.1634.

[0080] Example 21:

[0081]

[0082] To a toluene solution (11.0 ml) of 1,4-dione (376.0 mg, 3.3 mmol, 1 equiv.) was added (S6) (1.3 g, 4.0 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the white solid product 1f (700.0 mg, 54%), melting point: 75 - 77 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.51 - 7.43 (m, 2H), 7.42 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 7.27 - 7.20 (m, 1H), 6.95 - 6.90 (m, 1H), 6.88 - 6.81 (m, 2H), 5.84 (s, 2H), 3.80 (s, 3H), 2.62 (q, J = 7.5 Hz, 2H), 1.83 (s, 6H), 1.03 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 164.9, 144.2, 131.9, 131.2, 129.1, 127.8, 127.0, 121.2, 110.8, 108.2, 105.5, 51.2, 17.9, 13.6, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 20 H 22 BrN2O2 401.0859; Found 401.0861.

[0083] Example 22:

[0084]

[0085] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1f (80.0 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated to remove the solvent under reduced pressure and purified by thin layer chromatography (eluent: PE:EA = 7:1) to give the colorless oily product 3f: (92.0 mg, 87%, 94% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R= 7.18 min (minor), 8.10 min (major), 94% ee. [α] D 25 : 20.16° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J = 8.7 Hz, 2H), 6.94 (s, 1H), 6.68 (d, J = 8.7 Hz, 2H), 6.10 (d, J = 1.1 Hz, 1H), 4.51 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 2.81 - 2.61 (m, 2H), 1.86 (s, 3H), 1.81 (s, 3H), 1.09 (t, J = 7.4 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.9, 168.9, 164.8, 143.9, 131.9, 131.2, 128.8, 127.8, 127.1, 126.6, 121.2, 110.9, 110.8, 108.2, 106.5, 52.8, 52.7, 51.2, 49.8, 17.9, 13.6, 10.9, 9.1. HRMS (ESI) m / z: [M+Na] + calcd for C 25 H 27 BrN2NaO6 553.0945; Found 553.0939.

[0086] Example 23:

[0087]

[0088] To a toluene solution (10.0 ml) of 1,4-dione (307.0 mg, 2.7 mmol, 1 equiv.) was added (S7) (900.0 mg, 3.3 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give 1 g (300.0 mg, 32%) of a white solid product, melting point: 79 - 81 °C. 11H NMR (400 MHz, Chloroform-d) δ 7.63 - 7.34 (m, 2H), 7.11 (s, 1H), 7.01 - 6.68 (m, 2H), 5.94 (s, 2H), 3.89 (s, 3H), 2.71 (q, J = 7.5 Hz, 2H), 1.87 (s, 6H), 1.11 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 164.6, 145.5, 134.4, 132.7, 130.2, 127.7, 125.4, 118.8, 111.5, 110.3, 110.2, 106.0, 51.4, 18.0, 13.6, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 21 H 22 N3O2 348.1707; Found 348.1704.

[0089] Example 24:

[0090]

[0091] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1g (69.4 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by distillation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 3:1) to obtain the white solid product 3g: (52.0 mg, 54%, 95% ee), melting point: 126 - 128 °C. HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 20 / 80, flow rate = 1.0 mL / min, I = 215 nm) t R = 8.63 min (minor), 9.40 min (major), 95% ee. [α] D 25 : 33.5° (c: 0.25, CH2Cl2). 11H NMR (400 MHz, Chloroform-d) δ 7.54 - 7.41 (m, 2H), 7.10 (s, 1H), 6.91 - 6.78 (m, 2H), 6.13 (s, 1H), 4.53 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.79 (s, 3H), 2.73 (dd, J=12.1, 7.4 Hz, 2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.11 (t, J=7.4 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.9, 164.6, 145.3, 134.1, 132.8, 130.3, 127.8, 126.6, 125.5, 118.9, 111.6, 111.4, 110.4, 110.3, 107.0, 53.0, 52.9, 51.5, 49.9, 18.0, 13.7, 10.9, 9.2. HRMS (ESI) m / z: [M+H] + calcd for C 26 H 28 N3O6 478.1973; Found 478.1977.

[0092] Example 25:

[0093]

[0094] To a toluene solution (10.0 ml) of 1,4-diketone (473.0 mg, 4.3 mmol, 1 equiv.) was added (S8) (1.5 g, 5 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the yellow solid product 1h (150.0 mg, 10%), melting point: 141 - 143 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 8.11 - 8.05 (m, 2H), 7.17 (s, 1H), 6.92 (d, J = 9.0 Hz, 2H), 5.96 (s, 2H), 3.90 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H), 1.88 (s, 6H), 1.11 (d, J = 7.6 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 164.5, 146.0, 145.8, 136.2, 129.9, 127.6, 125.3, 124.3, 111.6, 110.9, 106.1, 51.4, 17.9, 13.5, 11.0. HRMS (ESI) m / z: [M+H] + calcd for C 20 H 22 N3O4 368.1605; Found 368.1609.

[0095] Example 26:

[0096]

[0097] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1h (73.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 3:1) to obtain the yellow liquid product 3h: (72.8 mg, 73%, 94% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 20 / 80, flow rate = 1.0 mL / min, I = 215 nm) t R = 9.07 min (minor), 10.76 min (major), 94% ee. [α] D 25 : 61.50° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 9.1 Hz, 2H), 7.17 (s, 1H), 6.89 (d, J = 9.1 Hz, 2H), 6.15 (s, 1H), 4.53 (s, 1H), 3.90 (s, 3H), 3.80 (s, 6H), 2.83 - 2.66 (m, 2H), 1.87 (s, 3H), 1.83 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 168.8, 164.4, 146.1, 145.5, 129.9, 127.7, 126.5, 125.4, 124.3, 111.7, 111.4, 111.0, 107.0, 52.9, 52.8, 51.4, 49.8, 17.9, 13.5, 10.8, 9.1. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 28 N3O6 498.1871; Found 498.1873.

[0098] Example 27:

[0099]

[0100] To a toluene solution (30.0 ml) of 1,4-dione (900.0 mg, 7.9 mmol, 1 equiv.) was added (S9) (3.0 g, 9.5 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the yellow oily product 1i (500.0 mg, 10%). 1 1H NMR (400 MHz, Chloroform-d) δ 7.26 (d, J = 8.5 Hz, 1H), 7.03 - 6.97 (m, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.60 (dd, J = 8.5, 2.3 Hz, 1H), 5.94 (s, 2H), 3.88 (s, 3H), 2.71 (q, J = 7.5 Hz, 2H), 1.88 (s, 6H), 1.11 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 164.7, 144.5, 132.9, 130.9, 130.7, 130.0, 129.9, 127.6, 127.2, 124.3, 111.0, 108.9, 105.8, 51.2, 17.9, 13.6, 11.0. HRMS (ESI) m / z: [M+H] + calcd for C 20 H 21 Cl2N2O2 391.0975; Found 391.0976.

[0101] Example 28:

[0102]

[0103] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1i (78.0 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the yellow liquid product 3i: (88.0 mg, 84%, 93% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.06 min (minor), 8.85 min (major), 93% ee. [α] D 25 : 27.20° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 8.12 - 8.07 (m, 3H), 8.04 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.4, 1.2 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.50 - 7.38 (m, 5H), 6.60 (dd, J = 7.4, 3.4 Hz, 1H), 0.35 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 168.8, 168.8, 164.6, 144.4, 132.9, 131.1, 130.8, 129.9, 129.8, 127.7, 127.3, 126.4, 124.4, 111.1, 111.0, 108.9, 106.8, 52.8, 52.8, 51.3, 49.8, 17.9, 13.6, 10.8, 9.1. HRMS (ESI) m / z: [M + H] + calcd for C 25 H 27 Cl2N2O6 521.1241; Found 521.1243.

[0104] Example 29:

[0105]

[0106] To a toluene solution (17.0 ml) of 1,4-dione (581.0 mg, 5.1 mmol, 1 equiv.) was added (S10) (2.0 g, 6.2 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the product 1j as a yellow oil (800.0 mg, 40%), melting point: 105 - 107 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.51 - 7.43 (m, 2H), 7.42 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 7.27 - 7.20 (m, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.86 (dd, J = 8.6, 2.1 Hz, 2H), 5.84 (s, 2H), 3.80 (s, 3H), 2.62 (q, J = 7.5 Hz, 2H), 1.83 (s, 6H), 1.03 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 165.1, 144.0, 140.3, 139.6, 132.0, 129.1, 128.8, 127.9, 127.4, 127.36, 126.8, 125.8, 110.8, 107.9, 105.4, 51.2, 17.9, 13.7, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 26 H 27 N2O2 399.2067; Found 399.2068.

[0107] Example 30:

[0108]

[0109] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1j (79.6 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated to remove the solvent under reduced pressure and purified by thin layer chromatography (eluent: PE:EA = 7:1) to give the yellow liquid product 3j: (90.0 mg, 85%, 92% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) tR = 9.88 min (minor), 10.66 min (major), 92% ee. [α] D 25 : 17.76° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.57 - 7.53 (m, 2H), 7.47 - 7.38 (m, 4H), 7.35 - 7.29 (m, 1H), 7.00 (d, J = 5.9 Hz, 1H), 6.91 (dd, J = 8.6, 2.0 Hz, 2H), 6.12 (s, 1H), 4.54 (s, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 2.82 - 2.63 (m, 2H), 1.91 (s, 3H), 1.85 (s, 3H), 1.10 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.0, 168.9, 143.8, 140.3, 139.7, 132.0, 128.9, 128.8, 127.9, 127.4, 127.4, 126.8, 126.7, 125.8, 110.9, 110.6, 108.0, 106.3, 52.8, 52.7, 51.2, 49.9, 17.9, 13.7, 10.9, 9.2. HRMS (ESI) m / z: [M + H] + calcd for C 31 H 33 N2O6 529.2333; Found 529.2335.

[0110] Example 31:

[0111]

[0112] To a toluene solution (11.0 ml) of 1,4-diketone (353.0 mg, 3.1 mmol, 1 equiv.) was added (S11) (1.0 g, 3.7 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1), to give the yellow solid product 1k (469.0 mg, 29%), melting point: 49 - 51 °C. 11H NMR (400 MHz, Chloroform-d) δ 7.09 (t, J = 7.6 Hz, 1H), 7.04 - 6.97 (m, 1H), 6.92 (s, 1H), 6.77 (m, 1H), 6.69 - 6.42 (m, 1H), 5.88 (s, 2H), 3.87 (s, 3H), 2.69 (q, J = 7.6 Hz, 2H), 2.24 (s, 3H), 1.88 (s, 6H), 1.10 (t, J = 7.6 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 165.1, 143.7, 138.2, 132.6, 130.1, 128.6, 127.9, 126.6, 122.4, 110.5, 107.7, 105.2, 51.1, 21.5, 17.9, 13.7, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 21 H 25 N2O2 337.1911; Found 337.1907.

[0113] Example 32:

[0114]

[0115] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1k (67.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube. The reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the yellow liquid product 3k: (68.4 mg, 73%, 92% ee). HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.32 min (minor), 8.92 min (major), 92% ee. [α] D 25 : 22.32° (c: 0.25, CH2Cl2). 11H NMR (400 MHz, Chloroform-d) δ 7.08 (t, J = 7.7 Hz, 1H), 6.99 (ddt, J = 7.5, 1.8, 0.9 Hz, 1H), 6.92 (s, 1H), 6.70 (d, J = 1.8 Hz, 1H), 6.63 (dt, J = 7.8, 1.6 Hz, 1H), 6.09 (d, J = 1.1 Hz, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 2.82 - 2.58 (m, 2H), 2.23 (s, 3H), 1.86 (s, 3H), 1.83 (s, 3H), 1.08 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.9, 165.0, 143.6, 138.3, 132.5, 129.8, 128.6, 128.0, 127.9, 126.6, 126.4, 122.6, 110.7, 110.3, 107.7, 106.1, 52.8, 52.7, 51.2, 49.9, 21.4, 17.9, 13.6, 10.9, 9.2. HRMS (ESI) m / z: [M + H] + calcd for C 26 H 31 N2O6 467.2177; Found 467.2176.

[0116] Example 33:

[0117]

[0118] To a toluene solution (6.0 ml) of 1,4-dione (192.0 mg, 1.7 mmol, 1 equiv.) was added (S12) (600.0 mg, 2.1 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 50:1 - 20:1) to give the product 1l as a yellow oil (600.0 mg, 99%). 1 1H NMR (400 MHz, Chloroform-d) δ 7.30 - 7.07 (m, 2H), 6.98 (s, 1H), 6.92 - 6.80 (m, 1H), 6.67 (dt, J = 6.2, 2.0 Hz, 1H), 5.92 (s, 2H), 3.88 (s, 3H), 2.70 (q, J = 7.2 Hz, 2H), 1.88 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H).13 C NMR (101 MHz, Chloroform-d) δ 164.8, 144.4, 134.7, 131.8, 130.9, 130.0, 127.7, 127.1, 125.7, 123.2, 110.9, 108.7, 105.6, 51.2, 17.9, 13.6, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 20 H 22 ClN2O2 357.1364; Found 357.1367.

[0119] Example 34:

[0120]

[0121] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1l (71.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube. The reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by evaporation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the yellow liquid product 3l: (76.7 mg, 79%, 91% ee). HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 8.38 min (minor), 10.76 min (major), 90% ee. [α] D 25 : 27.64° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.13 (q, J = 8.2 Hz, 2H), 6.97 (s, 1H), 6.89 (s, 1H), 6.62 (d, J = 7.1 Hz, 1H), 6.13 (s, 1H), 4.53 (s, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.71 (tq, J = 14.0, 7.3 Hz, 2H), 1.87 (s, 3H), 1.84 (s, 3H), 1.09 (t, J = 7.5 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 169.0, 168.9, 164.8, 144.3, 134.7, 131.7, 130.9, 130.1, 127.8, 127.3, 126.5, 125.7, 123.4, 111.0, 110.8, 108.8, 106.6, 52.9, 52.8, 51.3, 49.9, 17.9, 13.7, 11.0, 9.2. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 28 ClN2O6 487.1630; Found 487.1630.

[0122] Example 35:

[0123]

[0124] To a toluene solution (5.6 ml) of 1,4-dione (182.0 mg, 1.6 mmol, 1 equiv.) was added (S13) (600.0 mg, 2.0 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the product 1m as a yellow oil (300.0 mg, 40%). 1 1H NMR (400 MHz, Chloroform-d) δ 7.71 (m, 2H), 7.61 - 7.53 (m, 1H), 7.43 - 7.35 (m, 2H), 7.29 (dd, J = 8.6, 1.8 Hz, 1H), 7.11 (d, J = 6.5 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 5.95 (s, 2H), 3.89 (s, 3H), 2.75 (q, J = 7.5 Hz, 2H), 1.90 (s, 6H), 1.13 (t, J = 7.5 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 165.1, 144.2, 133.7, 132.3, 132.2, 128.4, 128.2, 128.0, 127.4, 127.4, 126.2, 126.1, 124.2, 123.6, 110.8, 108.4, 105.5, 51.2, 18.0, 13.7, 11.2. HRMS (ESI) m / z: [M+H] + calcd for C 24 H 25N2O2 373.1911; Found 373.1908.

[0125] Example 36:

[0126]

[0127] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1m (74.4 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin layer chromatography (the eluent was PE:EA = 7:1) to obtain the yellow liquid product 3m: (78.0 mg, 78%, 91% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 8.87 min (minor), 10.35 min (major), 91% ee. [α] D 25 : 48.32° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.80 - 7.64 (m, 2H), 7.60 (dd, J = 6.2, 3.4 Hz, 1H), 7.40 (dt, J = 6.2, 3.4 Hz, 2H), 7.36 - 7.28 (m, 1H), 7.10 (s, 1H), 6.81 (s, 1H), 6.17 (s, 1H), 4.56 (s, 1H), 3.90 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 2.87 - 2.63 (m, 2H), 1.89 (s, 3H), 1.87 (s, 3H), 1.21 - 1.05 (m, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.1, 169.0, 144.1, 133.8, 132.3, 132.2, 128.7, 128.3, 128.0, 127.4, 127.1, 126.7, 126.3, 126.2, 124.4, 123.3, 110.8, 108.6, 106.5, 52.8, 51.3, 50.0, 18.0, 13.8, 11.0, 9.3. HRMS (ESI) m / z: [M + H] + calcd for C 29 H 31 N2O6 503.2177; Found 503.2178.

[0128] Example 37:

[0129]

[0130] To a toluene solution (28.0 ml) of 1,4-diketone (855.0 mg, 1.6 mmol, 1 equiv.) was added (S14) (2.5 g, 9.0 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the yellow solid product 1n (1.5 g, 57%). Melting point: 63 - 65 °C 1 H NMR (400 MHz, Chloroform-d) δ 7.14 (t, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.74 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.67 (dt, J = 8.0, 1.3 Hz, 1H), 6.27 (s, 1H), 5.90 (s, 2H), 3.87 (s, 3H), 3.64 (s, 3H), 2.69 (q, J = 7.4 Hz, 2H), 1.89 (s, 6H), 1.10 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 165.0, 159.8, 143.9, 132.0, 131.4, 129.7, 127.9, 118.4, 113.7, 110.6, 109.8, 108.0, 105.3, 55.1, 51.2, 17.9, 13.6, 11.1. HRMS (ESI) m / z: [M + H] + calcd for C 21 H 25 N2O3 353.1860; Found 353.1859.

[0131] Example 38:

[0132]

[0133] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1n (70.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure, and purified by thin-layer chromatography (eluent: PE:EA = 5:1) to obtain the yellow liquid product 3n: (74.0 mg, 76%, 60% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 20 / 80, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.94 min (minor), 10.91 min (major), 60% ee. [α] D 25 : 1.76° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.21 (ddd, J = 8.4, 7.3, 1.9 Hz, 1H), 7.02 - 6.55 (m, 4H), 5.94 (s, 1H), 4.45 (s, 1H), 3.86 (s, 3H), 3.73 (s, 6H), 3.70 (s, 3H), 2.68 (qd, J = 7.4, 2.7 Hz, 2H), 1.86 (s, 3H), 1.84 (s, 3H), 1.04 (t, J = 7.4 Hz, 3H). 13 C NMR Unknown NMR (101 MHz, Chloroform-d) δ 169.0, 168.9, 165.3, 157.2, 143.0, 130.2, 129.3, 128.9, 128.2, 126.9, 120.3, 110.8, 110.6, 110.3, 109.7, 105.6, 55.3, 52.7, 52.6, 51.1, 50.0, 18.1, 13.6, 11.1, 9.3. HRMS (ESI) m / z: [M+H] + calcd for C 26 H 31 N2O7 483.2126; Found 483.2128.

[0134] Example 39:

[0135]

[0136] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1o (61.4 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure to remove the solvent and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the yellow liquid product 3o: (77.0 mg, 87%, 84% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 8.62 min (minor), 9.64 min (major), 84% ee. [α] D 25 : 10.48° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.13 (m, 3H), 6.96 - 6.85 (m, 3H), 6.08 (s, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 2.27 (s, 3H), 1.85 (s, 3H), 1.84 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.0, 165.4, 138.0, 132.5, 130.0, 128.8, 127.9, 127.3, 126.5, 125.6, 111.3, 110.5, 107.6, 106.2, 53.5, 52.8, 51.3, 49.9, 10.9, 10.4, 9.1. HRMS (ESI) m / z: [M+H] + calcd for C 24 H 27 N2O6 439.1864; Found 439.1862.

[0137] Example 40:

[0138]

[0139] To a toluene solution (15.0 ml) of 1,4-dione (436.0 mg, 3.8 mmol, 1 equiv.) was added (S16) (1.2 g, 4.6 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an oil bath at 80 °C for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the yellow solid product 1p (1.0 g, 78%). Melting point: 93 - 95 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.14 (m, 3H), 7.05 - 6.73 (m, 3H), 5.88 (s, 2H), 3.87 (s, 3H), 2.76 - 2.53 (m, 2H), 1.87 (s, 6H), 1.52 - 1.45 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 165.2, 142.5, 132.5, 130.2, 128.7, 127.8, 127.2, 125.7, 111.0, 107.8, 105.3, 51.1, 26.5, 22.6, 14.3, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 21 H 25 N2O2 337.1911; Found 337.1908.

[0140] Example 41:

[0141]

[0142] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1p (67.0 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated to remove the solvent under reduced pressure and purified by thin layer chromatography (eluent: PE:EA = 7:1) to give the yellow solid product 3p: (82.8 mg, 89%, 97% ee). Melting point: 73 - 75 °C. HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.64 min (minor), 9.06 min (major), 97% ee. [α] D 25: 7.36° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.24 - 7.14 (m, 3H), 6.92 (s, 1H), 6.89 - 6.82 (m, 2H), 6.09 (s, 1H), 4.51 (s, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.75 (s, 3H), 2.70 (ddd, J=13.7, 9.2, 6.7 Hz, 1H), 2.59 (ddd, J=13.7, 9.2, 6.7 Hz, 1H), 1.85 (s, 3H), 1.82 (s, 3H), 1.52 - 1.42 (m, 2H), 0.90 (t, J=7.4 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.0, 168.9, 165.1, 142.3, 132.4, 130.0, 128.7, 127.9, 127.2, 126.6, 125.7, 111.2, 110.5, 107.8, 106.2, 52.7, 51.2, 49.9, 26.5, 22.6, 14.3, 10.9, 9.2. HRMS (ESI) m / z: [M + H] + calcd for C 26 H 31 N2O6 467.2177; Found 467.2178.

[0143] Example 42:

[0144]

[0145] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1q (67.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by distillation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain a colorless oily product 3q: (81.4 mg, 87%, 67% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.46 min (minor), 8.36 min (major), 67% ee. [α] D 25 : 20.88° (c: 0.25, CH2Cl2). 11H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.14 (m, 3H), 6.97 (s, 1H), 6.91 - 6.82 (m, 2H), 6.08 (s, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 2.69 (p, J = 7.1 Hz, 1H), 1.88 (s, 3H), 1.85 (s, 3H), 1.36 (dd, J = 7.1, 4.3 Hz, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.0, 164.7, 147.1, 131.9, 130.1, 128.8, 128.4, 127.3, 127.1, 125.8, 110.8, 110.5, 109.2, 106.2, 52.8, 51.3, 49.9, 25.2, 20.3, 20.2, 10.9, 9.2. HRMS (ESI) m / z: [M+H] + calcd for C 26 H 31 N2O6 467.2177; Found 467.2180.

[0146] Example 43:

[0147]

[0148] To a toluene solution (6.7 ml) of 1,4-dione (275.0 mg, 2.4 mmol, 1 equiv.) was added (S18) (800.0 mg, 2.9 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 10:1) to give the white solid product 1r (600 mg, 71%). Melting point: 89 - 91 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 7.34 - 7.09 (m, 3H), 7.06 - 6.79 (m, 3H), 3.86 (s, 3H), 3.03 - 2.34 (m, 2H), 1.87 (s, 6H), 1.42 (dt, J = 19.8, 7.6 Hz, 2H), 1.30 (dt, J = 15.2, 7.6 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 165.1, 142.7, 132.4, 130.3, 128.7, 127.8, 127.2, 125.7, 110.9, 107.8, 105.3, 51.1, 31.2, 24.2, 22.8, 13.7, 11.1. HRMS (ESI) m / z: [M+H] + calcd for C 22 H 27 N2O2 351.2067; Found 351.2064.

[0149] Example 44:

[0150]

[0151] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1r (70.0 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure to remove the solvent and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain a colorless oily product 3r: (65.6 mg, 68%, 95% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.09 min (minor), 8.49 min (major), 95% ee. [α] D 25 : 27.20° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.12 (m, 3H), 6.92 (s, 1H), 6.89 - 6.82 (m, 2H), 6.09 (s, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.80 - 3.70 (m, 6H), 2.71 (ddd, J = 13.6, 9.6, 6.2 Hz, 1H), 2.61 (ddd, J = 13.6, 9.6, 6.2 Hz, 1H), 1.86 (s, 3H), 1.82 (s, 3H), 1.46 - 1.36 (m, 2H), 1.30 (q, J = 7.3 Hz, 2H), 0.83 (t, J = 7.3 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 169.0, 165.2, 142.6, 132.5, 130.1, 128.8, 128.0, 127.3, 126.6, 125.8, 111.1, 110.6, 107.9, 106.3, 52.8, 52.7, 51.2, 50.0, 31.2, 24.2, 22.7, 13.6, 11.0, 9.3. HRMS (ESI) m / z: [M+H] + calcd for C 27 H 33 N2O6 481.2333; Found 481.2334.

[0152] Example 45:

[0153]

[0154] To a toluene solution (16.0 ml) of 1,4-dione (478.0 mg, 4.2 mmol, 1 equiv.) was added (S19) (1.5 mg, 5.0 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the white solid product 1s (1.0 g, 68%). Melting point: 70 - 72 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 7.30 - 7.09 (m, 3H), 7.04 - 6.74 (m, 3H), 5.88 (s, 2H), 3.86 (s, 3H), 2.69 (dd, J = 9.2, 4.8 Hz, 2H), 1.86 (s, 6H), 1.75 - 1.61 (m, 1H), 0.86 (dd, J = 6.9, 4.2 Hz, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 165.3, 141.2, 132.7, 130.3, 128.7, 127.7, 127.2, 125.8, 112.0, 107.9, 105.4, 51.1, 33.2, 28.1, 22.5, 11.2. HRMS (ESI) m / z: [M+H] + calcd for C 22 H 27 N2O2 351.2067; Found 351.2065.

[0155] Example 46:

[0156]

[0157] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1s (67.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube. The reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure to remove the solvent and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the yellow oily product 3s: (80.0 mg, 83%, 96% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 7.15 min (minor), 8.44 min (major), 96% ee. [α] D 25 : 22.40° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.23 - 7.13 (m, 3H), 6.89 (s, 1H), 6.88 - 6.81 (m, 2H), 6.08 (s, 1H), 4.52 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 2.78 - 2.55 (m, 2H), 1.87 (s, 3H), 1.83 (s, 3H), 1.61 (s, 9H), 1.12 - 1.05 (m, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 169.0, 169.0, 141.1, 132.7, 130.1, 128.8, 127.9, 127.3, 126.5, 126.0, 112.2, 110.6, 108.0, 106.4, 52.8, 51.2, 50.0, 33.2, 28.2, 22.5, 11.1, 9.4. HRMS (ESI) m / z: [M+H] + calcd for C 27 H 33 N2O6 481.2333; Found 481.2334.

[0158] Example 47:

[0159]

[0160] To a toluene solution (16.0 ml) of 1,4-dione (376.0 mg, 3.3 mmol, 1 equiv.) was added (S20) (1.2 g, 4.0 mmol, 1.2 equiv.) and pyridinium 4-methylbenzenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the yellow solid product 1t (470.0 mg, 38%). Melting point: 73 - 75 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.12 (m, 3H), 6.97 (s, 1H), 6.92 (d, J = 6.4 Hz, 2H), 5.87 (s, 2H), 3.86 (s, 3H), 2.22 (s, 3H), 1.88 (s, 6H), 1.76 (dt, J = 13.2, 3.2 Hz, 2H), 1.66 - 1.53 (m, 3H), 1.39 - 1.24 (m, 1H), 1.22 - 1.07 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 164.8, 146.6, 131.9, 130.3, 128.7, 128.2, 127.2, 125.8, 110.8, 109.1, 105.2, 51.2, 35.9, 29.5, 26.9, 25.5, 11.1. HRMS (ESI) m / z: [M + H] + calcd for C 24 H 29 N2O2 377.2224; Found 377.2223.

[0161] Example 48:

[0162]

[0163] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1t (75.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to give the yellow oily product 3t: (73.4 mg, 72%, 98% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R= 4.58 min (minor), 5.09 min (major), 98% ee. [α] D 25 : 24.00° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.14 (m, 3H), 6.96 (s, 1H), 6.94 - 6.86 (m, 2H), 6.08 (s, 1H), 4.52 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 2.32 - 2.12 (m, 3H), 1.86 (s, 3H), 1.85 (s, 3H), 1.75 (d, J = 13.1 Hz, 2H), 1.63 - 1.49 (m, 3H), 1.29 (ddd, J = 16.0, 8.0, 3.2 Hz, 1H), 1.21 - 1.07 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.1, 169.0, 146.5, 132.1, 128.8, 128.4, 127.3, 127.1, 125.9, 111.0, 110.5, 109.2, 106.3, 52.8, 51.3, 50.0, 36.0, 29.7, 29.6, 27.0, 26.9, 25.6, 10.9, 9.3. HRMS (ESI) m / z: [M + H] + calcd for C 29 H 35 N2O6 507.2490; Found 507.2493.

[0164]

[0165] To a toluene solution (9.6 ml) of 1,4-dione (330.0 mg, 2.9 mmol, 1 equiv.) was added (S22) (1.0 g, 3.4 mmol, 1.2 equiv.) and pyridinium p-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 50:1 - 20:1) to give the product 1v as a colorless oil (120.0 mg, 12%). 11H NMR (400 MHz, Chloroform-d) δ 7.18 - 7.03 (m, 3H), 6.92 - 6.70 (m, 3H), 5.79 (s, 2H), 2.56 (q, J = 7.4 Hz, 2H), 1.79 (s, 6H), 1.52 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 164.2, 142.9, 132.1, 130.4, 128.7, 127.9, 127.0, 125.6, 112.6, 108.1, 105.2, 80.0, 28.5, 17.9, 13.9, 11.1. HRMS (ESI) m / z: [M + H] + calcd for C 23 H 29 N2O2 365.2224; Found 365.2220.

[0166] Example 49:

[0167]

[0168] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1v (72.8 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was evaporated under reduced pressure and purified by thin-layer chromatography (the eluent was PE:EA = 7:1) to obtain the yellow oily product 3v: (64.0 mg, 65%, 94% ee). HPLC detection conditions: HPLC (OD-H, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 6.83 min (minor), 10.64 min (major), 94% ee. [α] D 25 : 7.60° (c: 0.25, CH2Cl2). 1 1H NMR (400 MHz, Chloroform-d) δ 7.23 - 7.13 (m, 3H), 6.89 (s, 1H), 6.88 - 6.81 (m, 2H), 6.08 (s, 1H), 4.52 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 2.78 - 2.55 (m, 2H), 1.87 (s, 3H), 1.83 (s, 3H), 1.61 (s, 9H), 1.12 - 1.05 (m, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 170.0, 169.0, 164.1, 142.7, 132.1, 130.1, 128.7, 128.0, 127.1, 126.7, 125.6, 112.6, 110.3, 108.2, 106.1, 80.1, 52.7, 49.9, 28.4, 17.9, 13.9, 10.9, 9.2. HRMS (ESI) m / z: [M+H] + calcd for C 28 H 35 N2O6 495.2490; Found 495.2487.

[0169] Example 50:

[0170]

[0171] To a toluene solution (9.6 ml) of 1,4-dione (330.0 mg, 2.9 mmol, 1 equiv.) was added (S22) (1.0 g, 3.4 mmol, 1.2 equiv.) and pyridinium 4-toluenesulfonate (PPTS, 5 mol%). The resulting mixture was heated in an 80 °C oil bath for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 50:1 - 20:1) to give the product 1w as a colorless oil (120.0 mg, 12%). 1 1H NMR (400 MHz, Chloroform-d) δ 7.24 (m, 3H), 7.08 - 6.94 (m, 2H), 5.73 (s, 2H), 3.87 (s, 3H), 2.63 (q, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.88 (s, 6H), 1.06 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 166.1, 142.6, 130.6, 129.9, 129.5, 128.2, 128.1, 127.5, 117.3, 110.0, 104.6, 50.8, 18.3, 13.8, 12.3, 11.3. HRMS (ESI) m / z: [M+H] + calcd for C 21 H 25 N2O2 337.1911; Found 337.1911.

[0172] Example 51:

[0173]

[0174] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1q (67.2 mg, 0.2 mmol), 2a (94.8 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The reaction solution was evaporated under reduced pressure, and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the yellow solid product 3w: (56 mg, 60%, 99% ee). Melting point: 41 - 43 °C. HPLC detection conditions: HPLC (IC, i-PrOH / n-hexane = 20 / 80, flow rate = 1.0 mL / min, I = 215 nm) t R = 9.20 min (minor), 10.32 min (major), 99% ee. [α] D 25 : 10.48° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.23 (dq, J = 5.0, 3.1, 2.4 Hz, 3H), 7.09 - 6.84 (m, 2H), 5.92 (d, J = 1.2 Hz, 1H), 4.43 (s, 1H), 3.87 (s, 3H), 3.73 (s, 3H), 3.69 (s, 3H), 2.73 - 2.55 (m, 2H), 2.31 (s, 3H), 1.85 (s, 3H), 1.82 (s, 3H), 1.05 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 169.1, 169.0, 166.1, 142.5, 129.7, 129.6, 128.3, 128.1, 127.6, 126.9, 117.5, 110.2, 109.8, 105.7, 52.7, 50.9, 50.0, 18.4, 13.9, 12.3, 11.2, 9.5. HRMS (ESI) m / z: [M+H] + calcd for C 26 H 31 N2O6 467.2177; Found 467.2180.

[0175] Example 52:

[0176] Gram-scale reaction: Under argon protection, Rh2(S-NTTL)4 (62.2 mg, 0.043 mmol), 1w (1.44 g, 4.3 mmol), 2a (2 g, 12.9 mmol) and DCE (10.75 mL) were added to a reaction tube. The reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by distillation under reduced pressure and purified by column chromatography (eluent: PE:EA = 5:1) to obtain the yellow solid product 3w: (1.2 g, 60%, 99% ee). Melting point: 41 - 43 °C.

[0177] Example 53:

[0178]

[0179] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2b (111.6 mg, 0.6 mmol) and DCE (0.5 mL) were added to a reaction tube. The reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by distillation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 5:1) to obtain the colorless oily product 3x: (57.4 mg, 60%, 60% ee). HPLC detection conditions: HPLC (IC, i-PrOH / n-hexane = 10 / 90, flow rate = 1.0 mL / min, I = 215 nm) t R = 10.63 min (minor), 11.64 min (major), 60% ee. [α] D 25 : 7.28° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.13 (m, 3H), 6.93 (s, 1H), 6.90 - 6.83 (m, 2H), 6.10 (s, 1H), 4.48 (s, 1H), 4.27 - 4.16 (m, 4H), 3.87 (s, 3H), 2.85 - 2.50 (m, 2H), 1.87 (s, 3H), 1.84 (s, 3H), 1.26 (td, J = 7.1, 2.4 Hz, 6H), 1.08 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.6, 165.1, 143.8, 132.5, 130.1, 128.8, 127.8, 127.3, 126.6, 125.8, 110.8, 107.9, 106.4, 61.6, 51.3, 50.4, 17.9, 14.2, 13.7, 11.0, 9.3. HRMS (ESI) m / z: [M+H]+ Calculated for C 27 H 33 N2O6 481.2333; Found 481.2336.

[0180] Example 54:

[0181]

[0182] To a solution of 3w (28.0 mg, 0.06 mmol, 1.0 equiv) in DMF (0.6 mL) was added NBS (12.4 mg, 0.07 mmol, 1.2 equiv), and the resulting mixture was stirred in a water bath at 25 °C until the reaction was complete (monitored by TLC). The reaction mixture was added to water (3.6 mL) and extracted with EtOAc. The organic phase was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 5:1) to give the target compound 4 as a white solid (27.0 mg, 83%, 98% ee). Melting point: 92 - 95 °C. HPLC detection conditions: HPLC (IA, i-PrOH / n-hexane = 1 / 99, flow rate = 0.3 mL / min, I = 215 nm) t R = 18.53 min (major), 20.15 min (minor), 98% ee. [α] D 25 : 37.84° (c: 0.25, CHCl3). 1 H NMR (400 MHz, Chloroform-d) δ 7.28 - 7.21 (m, 3H), 7.05 - 6.86 (m, 2H), 4.70 (s, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.66 (s, 3H), 2.65 (dd, J = 17.0, 7.4 Hz, 2H), 2.30 (s, 3H), 1.87 (s, 3H), 1.86 (s, 3H), 1.06 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.5, 168.4, 165.9, 142.3, 130.6, 129.5, 129.3, 128.5, 128.4, 127.8, 126.1, 117.7, 110.5, 110.0, 96.9, 52.8, 52.8, 51.0, 49.5, 18.4, 13.8, 12.3, 10.4, 10.3. HRMS (ESI) m / z: [M + H] + Calculated for C 26 H30 BrN2O6545.1282; Found 545.1287.

[0183] Example 55:

[0184]

[0185] Thiourea (22.8 mg, 0.3 mmol, 6.0 equiv) was added to a solution of 3w (26.0 mg, 0.05 mmol, 1.0 equiv) in dry DMSO (1.0 mL). Then, a solution of 1 M potassium tert-butoxide (12.3 mg, 0.11 mmol, 2.2 equiv) was added dropwise. After stirring in an oil bath at 60 °C for 10 h, the reaction mixture was diluted with EA (2.5 mL) and washed with 1 N hydrochloric acid solution. The phases were separated by extraction, and the aqueous phase was extracted with EA. The collected organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 10:1) to give the target compound 5 as a colorless oil (16.1 mg, 67%, 99% ee). HPLC detection conditions: HPLC (AD-H, i-PrOH / n-hexane = 2 / 98, flow rate = 1 mL / min, λ = 215 nm) t R = 6.49 min (minor), 9.10 min (major), 99% ee. [α] D 25 : 32.16° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 3H), 7.22 (d, J = 7.4 Hz, 3H), 7.02 - 6.92 (m, 2H), 5.75 (s, 1H), 3.87 (s, 3H), 3.35 (s, 2H), 2.64 (q, J = 7.4 Hz, 2H), 2.31 (s, 3H), 1.84 (s, 6H), 1.06 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 190.1, 176.9, 166.1, 142.5, 130.6, 129.7, 129.5, 128.2, 127.9, 127.6, 126.2, 117.3, 109.9, 109.7, 106.1, 50.8, 32.2, 18.3, 13.8, 12.2, 11.0, 9.3. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 27N4O4S 479.1748; Found 479.1746.

[0186] Example 56:

[0187]

[0188] Under argon, (CuOTf)2·Tol (5.0 mg, 10 mol%), BINAP (8.5 mg, 11 mol%) and CH2Cl2 (0.5 mL) were added to a dry tube equipped with a magnetic stir bar, and the reaction mixture was stirred at room temperature for 30 minutes. Under anaerobic conditions, DTBP (2.0 equiv) was added to a suspension of 3w (25 mg, 0.05 mmol, 1.0 equiv), 7 (38 mg, 0.08 mmol, 1.5 equiv) and CH2Cl2 (0.5 mL) in another dry 25 mL Schlenk tube. After the reaction mixture was stirred at room temperature for 5 minutes, the above copper catalyst-containing mixture was transferred to this Schlenk tube and stirred in an oil bath at 60 °C for 4.5 hours. After the reaction was completed (monitored by TLC), the solvent was removed under vacuum, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 5:1) to obtain the target compound 6 as a colorless oil (11.4 mg, 42%, 99% ee). HPLC detection conditions: HPLC (IC, i-PrOH / n-hexane = 5 / 95, flow rate = 1 mL / min, I = 215 nm) t R = 13.20 min (major), 14.33 min (minor), 99% ee. [α] D 25 : 24.40° (c: 0.25, CH2Cl2). 1 H NMR (400 MHz, Chloroform-d) δ 7.36 (dd, J = 8.1, 6.8 Hz, 2H), 7.29 - 7.26 (m, 1H), 7.24 (dd, J = 5.1, 2.0 Hz, 3H), 7.17 - 7.09 (m, 2H), 7.04 - 6.96 (m, 2H), 4.56 (s, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 3.61 (s, 3H), 2.77 (qd, J = 7.4, 1.6 Hz, 2H), 2.34 (s, 3H), 1.91 (s, 3H), 1.78 (s, 3H), 1.13 (t, J = 7.4 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 169.2, 169.1, 142.3, 134.4, 130.6, 130.3, 129.6, 129.5, 128.3, 128.1, 127.8, 127.4, 126.5, 124.8, 121.0, 117.5, 110.1, 108.9, 52.6, 52.5, 50.8, 48.6, 18.4, 13.9, 12.3, 10.2, 9.9. HRMS (ESI) m / z: [M+H] + calcd for C 32 H 35 N2O6 543.2490; Found 543.2493.

[0189] Example 57:

[0190]

[0191] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2f (85.2 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. The solvent of the reaction solution was removed by distillation under reduced pressure and purified by thin-layer chromatography (eluent: PE:EA = 7:1) to obtain the yellow oily product 3y (<5%, 0% ee).

[0192] Example 58:

[0193]

[0194] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2c (128.4 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. 3ac (yield <5%).

[0195] Example 59:

[0196]

[0197] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2d (145.2 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. 3ad (yield <5%).

[0198] Example 60:

[0199]

[0200] Under argon protection, Rh2(S-NTTL)4 (2.8 mg, 0.002 mmol), 1a (64.4 mg, 0.2 mmol), 2e (68.4 mg, 0.6 mmol) and DCE (0.5 mL) were added to the reaction tube, and the reaction was stirred at 0 °C for 0.5 h. 3ae (yield < 5%).

Claims

1. A method for highly stereoselectively constructing nitrogen-nitrogen axial chiral bipyrrole compounds, characterized in that: Under argon protection, using chiral rhodium as a catalyst, bipyrrole derivatives and diazo compounds as raw materials, adding a solvent, and stirring and reacting at 0-25 °C to obtain a nitrogen-nitrogen axially chiral bipyrrole compound; ； wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclohexyl; R 2 is methyl, ethyl, tert-butyl; R 3 is hydrogen, methyl; R 4 is methyl, ethyl; R 5 is hydrogen, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-cyano, 4-nitro, 4-phenyl, 3-methyl, 3-chloro, 2-methoxy, 3,4-dichloro; the chiral rhodium catalyst is one of Rh2( S -NTTL)4, Rh2(S-4-Br-NTTL)4, Rh2(S-4-Cl-NTTL)4; the solvent is dichloroethane or dichloromethane; 。 2. The method for constructing a nitrogen-nitrogen axial chiral bipyrrole compound with high stereoselectivity according to claim 1, characterized in that, The chiral rhodium catalyst is Rh2( S -NTTL)4; the amount of the chiral rhodium catalyst used is 1-2% of the molar amount of the bipyrrole derivative.

3. The method for constructing a nitrogen-nitrogen axially chiral bipyrrole compound with high stereoselectivity according to claim 1, wherein: The bipyrrole derivatives include the following structural formulas: 。 4. The method for constructing a nitrogen-nitrogen axially chiral bipyrrole compound with high stereoselectivity according to claim 1, characterized in that: The diazo compound is the following structural formula: 。 5. The method for constructing a nitrogen-nitrogen axially chiral bipyrrole compound with high stereoselectivity according to claim 1, characterized in that: The reaction solvent is dichloroethane; the concentration of the bipyrrole derivative in the solvent is 0.05-0.6 mol / L.

6. The method for constructing a nitrogen-nitrogen axial chiral bipyrrole compound with high stereoselectivity according to claim 1, characterized in that: In the reaction, the molar ratio of the chiral rhodium catalyst, bipyrrole derivative, and diazo compound is: 0.01-0.02:1:1.1-5.

7. The method for constructing a nitrogen-nitrogen axial chiral bipyrrole compound with high stereoselectivity according to claim 1, wherein: The reaction time is: 10 minutes - 3 hours.

Images