A method for preparing chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives

Abstract

The present invention relates to a preparation method of a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative, comprising the following steps: step 1, under an inert gas atmosphere, a soluble nickel salt and a chiral oxazoline ligand are mixed in an organic solvent to obtain a nickel metal complex chiral catalyst solution; step 2, under an inert gas atmosphere, the nickel metal complex chiral catalyst solution, a photocatalyst, a β-ketoester shown in formula I and a vinyl azide shown in formula II are mixed, and then reacted under blue light to obtain a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative, wherein the photocatalyst is selected from one or more of 4CzIPN, [Ru(bpy)3]Cl2·6H2O, and Mes-Acr(ClO4). The method of the present invention can obtain a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative of a nitrogen-containing heterocyclic compound with optical activity, and the method has short steps, mild conditions, and is economical and efficient, thereby solving the problems of high economic cost, difficult operation, and low enantioselectivity in the prior art.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative. Background Art

[0002] Chiral polycyclic 3,4-dihydro-2H-pyrrole and its derivatives are an important class of compounds found in nature, widely used in chemistry, biology, and medicine. Existing methods for synthesizing similar skeletons require multiple steps and harsh conditions (requiring temperatures as low as -78°C and ammonia), or use expensive palladium as a catalyst at 80°C. These methods have drawbacks due to their cost and operational complexity, and both methods only yield racemic products.

[0003] Cycloaddition reactions are powerful tools for constructing cyclic structures. Visible light, a safe, clean, and green energy source, has evolved over the past few decades from photochemical cycloaddition reactions using ultraviolet light to current visible light catalysis. These reactions offer milder reaction conditions and a wider range of substrates, providing a promising pathway for the synthesis of cyclic compounds. However, relatively few reports exist on the use of 3+2 cycloadditions for the construction of five-membered ring compounds, particularly five-membered nitrogen-containing heterocyclic compounds. Furthermore, a major challenge facing photocatalytic cycloaddition reactions is the control of stereoselectivity.

[0004] Therefore, it is of great significance to explore methods for selectively preparing chiral polycyclic 3,4-dihydro-2H-pyrrole and its derivatives through non-cycloaddition reactions under photochemical conditions. Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a method for preparing chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives to obtain chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives as optically active nitrogen-containing heterocyclic compounds. The method has short steps, mild conditions, and is economical and efficient, thus solving the problems of high economic cost, difficult operation and low enantiomeric selectivity in the prior art for the synthesis of pyrrole derivative skeletons.

[0006] The specific solution provided by the present invention includes the following steps:

[0007] The present invention provides a method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative, comprising the following steps:

[0008] Step 1: Under an inert gas atmosphere, a soluble nickel salt and a chiral oxazoline ligand are mixed in an organic solvent to react to obtain a nickel metal complex chiral catalyst solution;

[0009] Step 2: Under an inert gas atmosphere, a nickel metal complex chiral catalyst solution, a photocatalyst, a β-ketoester represented by formula I, and a vinyl azide represented by formula II are mixed, and then reacted under blue light to obtain a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative represented by formula III, wherein the photocatalyst is selected from one or more of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile 4CzIPN, terpyridine ruthenium chloride hexahydrate [Ru(bpy)3]Cl2·6H2O, and 10-methyl-9-mesityl acridine perchlorate Mes-Acr(ClO4);

[0010]

[0011] Wherein, n is 1 or 2;

[0012] R 1 is selected from tert-butoxy, tert-butylamino or 1-adamantanylamino;

[0013] R 2 is selected from H, halogen, alkyl or alkoxy;

[0014] R 3 The substituents in the substituted phenyl group and the substituted thienyl group are selected from one or more of halogen, hydroxyl, substituted or unsubstituted alkyl, alkoxy, phenyl, trifluoromethyl, acetonitrile or ester groups.

[0015] The technical solution of the present invention has the following beneficial effects:

[0016] Based on the method of the present invention, under the synergistic catalysis of a photocatalyst and a nickel metal complex chiral catalyst, an asymmetric 3+2 cycloaddition reaction of vinyl azide and β-ketoester is achieved, and a series of chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives are constructed. The method is short in steps and under mild conditions, and achieves the efficient and high enantioselective synthesis of optically active chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives.

[0017] On the basis of the above scheme, the present invention can also be improved as follows:

[0018] Furthermore, the soluble nickel salt is selected from one or more of Ni(acac)2, Ni(OTf)2 or NiBr2.

[0019] Preferably, the soluble nickel salt is selected from Ni(acac)2, which has higher yield and enantiomeric selectivity.

[0020] Furthermore, the chiral oxazoline ligand is selected from one or more of the following structures:

[0021]

[0022] Preferably, the chiral oxazoline ligand is one or more of L5, L7, L8, L9 or L10.

[0023] More preferably, the chiral oxazoline ligand is L10.

[0024] Furthermore, the organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, chloroform, trifluoromethylbenzene, 1,2-dichloroethane, ether, acetone or methanol.

[0025] Preferably, the organic solvent is selected from acetonitrile, tetrahydrofuran or acetone.

[0026] Furthermore, the molar ratio of the soluble nickel salt to the chiral oxazoline ligand is 1:(1-1.5).

[0027] Furthermore, in step 2, the ratio of the amount of β-ketoester, vinyl azide, nickel metal complex chiral catalyst and photocatalyst substance is 1: (1-3): (5%-25%): (0.5%-5%).

[0028] Furthermore, the nickel metal complex chiral catalyst solution, the photocatalyst, the β-ketoester represented by Formula I and the vinyl azide represented by Formula II are mixed, the mixed reaction solution is degassed with liquid nitrogen, and then reacted under blue light irradiation.

[0029] Furthermore, the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative represented by formula III is selected from any one of the following structures:

[0030]

[0031] Preferably, the vinyl azide represented by formula II is selected from one of the following structures:

[0032]

[0033] Preferably, the β-ketoester represented by formula I is selected from one of the following structures:

[0034]

[0035] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0036] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0037] The technical problem solved by the present invention is to provide a method for preparing chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives to obtain chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives of optically active nitrogen-containing heterocyclic compounds. The method has short steps, mild conditions, and is economical and efficient, thus solving the problems of high economic cost, difficult operation and low enantiomeric selectivity in the prior art.

[0038] The specific solution provided by the present invention includes the following steps:

[0039] The present invention provides a method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative, comprising the following steps:

[0040] Step 1: Under an inert gas atmosphere, a soluble nickel salt and a chiral oxazoline ligand are mixed in an organic solvent to react to obtain a nickel metal complex chiral catalyst solution;

[0041] Step 2: Under an inert gas atmosphere, a nickel metal complex chiral catalyst solution, a photocatalyst, a β-ketoester represented by Formula I, and a vinyl azide represented by Formula II are mixed, and then reacted under blue light to obtain a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative represented by Formula III, wherein the photocatalyst is selected from one or more of 4CzIPN, [Ru(bpy)3]Cl2·6H2O, and Mes-Acr(ClO4);

[0042]

[0043] Wherein, n is 1 or 2;

[0044] R 1 is selected from tert-butoxy, tert-butylamino or 1-adamantanylamino;

[0045] R 2 is selected from H, halogen, alkyl or alkoxy;

[0046] R 3 It is selected from one of substituted or unsubstituted phenyl and thienyl, and the substituent in the substituted phenyl and substituted thienyl is selected from one or more of halogen, hydroxyl, substituted or unsubstituted alkyl, alkoxy, phenyl, trifluoromethyl, acetonitrile or ester.

[0047] Preferably, the substituent in the substituted alkyl group is selected from one or more of halogen, hydroxyl, alkoxy, phenyl, trifluoromethyl, acetonitrile or ester.

[0048] Based on the method of the present invention, under the synergistic catalytic conditions of a photocatalyst and a nickel metal complex chiral catalyst, an asymmetric 3+2 cycloaddition reaction of vinyl azide and β-ketoester is achieved, and a series of chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives are constructed. The method is short in steps and under mild conditions, and optically active chiral polycyclic 3,4-dihydro-2H-pyrrole derivatives are synthesized efficiently and with high enantioselectivity.

[0049] Based on the preparation method of the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to the embodiment of the present invention, the soluble nickel salt is selected from one or more of Ni(acac)2, Ni(OTf)2 or NiBr2.

[0050] Preferably, the soluble nickel salt is selected from Ni(acac)2, which has higher yield and enantiomeric selectivity.

[0051] According to the preparation method of the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to the embodiment of the present invention, the chiral oxazoline ligand is selected from one or more of the following structures:

[0052]

[0053] Preferably, the chiral oxazoline ligand is one or more of L5, L7, L8, L9 or L10.

[0054] More preferably, the chiral oxazoline ligand is L10.

[0055] According to the preparation method of the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to the embodiment of the present invention, the organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, chloroform, trifluoromethylbenzene, 1,2-dichloroethane, ether, acetone or methanol.

[0056] Preferably, the organic solvent is selected from acetonitrile, tetrahydrofuran or acetone.

[0057] According to the method for preparing the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to the embodiment of the present invention, the molar ratio of the soluble nickel salt to the chiral oxazoline ligand is 1:(1-1.5).

[0058] According to the preparation method of the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to the embodiment of the present invention, in step 2, the ratio of the amount of β-ketoester, vinyl azide, nickel metal complex chiral catalyst and photocatalyst substance is 1: (1 to 3): (5% to 25%): (0.5% to 5%).

[0059] According to the preparation method of the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to the embodiment of the present invention, a nickel metal complex chiral catalyst solution, a photocatalyst, a β-ketoester represented by Formula I, and a vinyl azide represented by Formula II are mixed, and the mixed reaction solution is degassed with liquid nitrogen to remove trace oxygen in the system as much as possible, and then reacted under blue light irradiation.

[0060] According to the preparation method of the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to the embodiment of the present invention, the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative represented by Formula III is selected from any one of the following structures:

[0061]

[0062] Preferably, the vinyl azide represented by formula II is selected from one of the following structures:

[0063]

[0064] Preferably, the β-ketoester represented by formula I is selected from one of the following structures:

[0065]

[0066] Example 1

[0067] Preparation of compound III-1:

[0068]

[0069] The preparation steps are as follows:

[0070] At room temperature, Ni(acac)2 (0.015 mmol, 15 mol%) and ligand L10 (0.018 mmol, 18 mol%) were dissolved in 0.5 mL of acetonitrile and stirred under argon for 0.5 h. Subsequently, 4CzIPN (0.002 mmol, 2 mol%), a β-ketoester substrate (0.1 mmol, 1.0 equiv.), and a vinyl azide substrate (0.15 mmol, 1.5 equiv.) were added. The mixture was then degassed three times with liquid nitrogen. The reaction mixture was irradiated with a 10W blue light for 2 h. TLC confirmed the reaction was complete. The reaction mixture was then purified by column chromatography (gradient elution: petroleum ether / ethyl acetate = 20:1-4:1, V / V ratio) to directly yield the corresponding target product. Compound III-1 was prepared from the β-ketoester substrate I-1 and the vinyl azide substrate II-1.

[0071] The product yield was 73% and the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column; mobile phase: isopropanol:n-hexane 85:15, v:v), mobile phase flow rate was 1.0 mL / min, detection wavelength was 210 nm, column temperature was 25°C, retention time was t R (major)=15.09min,t R (minor)=12.07min.

[0072] Product structure characterization data:

[0073] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.82 (d, J = 6.8Hz, 2H), 7.66 (d, J = 7.2Hz, 1H), 7.41 (t, J = 7.6Hz, 1H), 7.35 (t, J = 7.6Hz ,2H),7.28-7.19(m,3H),5.00(s,1H),3.95(dd,J=25.2,17.2Hz,2H),2.96(dd,J=21.6,16.4Hz,2H),1.46(s,9H).

[0074] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.55,172.48,142.51,140.43,133.23,131.24,129.25,128.38,1 28.11,127.49,124.79,124.75,115.68,81.68,61.21,47.79,40.32,27.97.HRMS(EI):m / z[M+H] + calcd for C 22 H 24 NO3 + :350.1757,found:350.1751.

[0075] Example 2

[0076] Preparation of compound III-2

[0077]

[0078] The preparation steps are the same as those in Example 1, except that compound III-2 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-2.

[0079] The product yield was 70%, the enantiomeric excess was 90%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 210 nm, 25 ° C, retention time was t R (major)=18.46min,t R (minor)=13.68min.

[0080] Product structure characterization data:

[0081] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.68 (t, J = 8.4Hz, 3H), 7.25 (t, J = 4.0Hz, 1H), 7.21 (t, J = 5.6Hz, 2H), 7.14 (d, J = 8.0Hz,2H),5.31(s,1H),3.95(t,J=17.6Hz,2H),2.94(dd,J=26.0,16.4Hz,2H),2.34(s,3H),1.45(s,9H).

[0082] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.48, 142.69, 141.62, 140.42, 130.48, 129.11, 129.07, 128.1 1,127.42,124.75,115.63,81.54,61.20,47.67,40.27,27.95,21.47.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO3 + :364.1907,found:364.1904.

[0083] Example 3

[0084] Preparation of compound III-3

[0085]

[0086] The preparation steps are the same as those in Example 1, except that compound III-3 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-3.

[0087] The product yield was 63%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 220 nm, 25 ° C, retention time was t R(major)=33.06min,t R (minor)=20.12min.

[0088] Product structure characterization data:

[0089] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.77 (d, J = 8.8Hz, 2H), 7.67 (d, J = 7.2Hz, 1H), 7.26 (s, 1H), 7.21 (t, J = 6.8Hz, 2H), 6.8 4(d,J=8.4Hz,2H),5.24(s,1H),3.94(t,J=16.8Hz,2H),3.80(s,3H),2.93(dd,J=27.2,16.8Hz,2H),1.46(s,9H).

[0090] 13 C NMR(100MHz,CDCl3)δ(ppm)172.53,171.83,161.96,142.83,140.41,129.92,129.06,127.41,1 25.91,124.73,115.62,113.66,81.51,61.26,55.28,47.56,40.30,27.96.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO4 + :380.1856,found:380.1854.

[0091] Example 4

[0092] Preparation of compound III-4

[0093]

[0094] The preparation steps are the same as those in Example 1, except that compound III-4 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-4.

[0095] The product yield was 72%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 220 nm, 25 ° C, retention time was t R (major)=35.47min,t R (minor)=18.33min.

[0096] Product structure characterization data:

[0097] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.74 (d, J = 8.3Hz, 2H), 7.66 (d, J = 7.6Hz, 1H), 7.36 (d, J = 8.4Hz, 2H), 7.25 (s, 1H), 7.22- 7.17(m,2H),5.22(s,1H),3.94(dd,J=21.6,17.6Hz,2H),2.94(dd,J=24.4,16.8Hz,2H),1.46(s,9H),1.29(s,9H).

[0098] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.53,172.34,154.66,142.69,140.34,130.47,129.08,127.94,127.41,1 25.32,124.79,124.72,115.59,81.56,61.16,47.74,40.23,34.84,31.07,27.98.HRMS(ESI):m / z[M+H] + calcd for C 26 H 32 NO3 + :406.2377,found:406.2367.

[0099] Example 5

[0100] Preparation of compound III-5

[0101]

[0102] The preparation steps are the same as those in Example 1, except that compound III-5 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-5.

[0103] The product yield was 54%, the enantiomeric excess was 93%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 220 nm, 25 ° C, retention time was t R (major)=40.81min,t R (minor)=37.95min.

[0104] Product structure characterization data:

[0105] 1H NMR (400MHz, CDCl3) δ (ppm) 7.89 (d, J = 8.0Hz, 2H), 7.68 (d, J = 7.2Hz, 1H), 7.59 (d, J = 8.0Hz, 4H), 7.44 (t, J = 7.6Hz, 2H), 7. 37(d,J=7.2Hz,1H),7.29-7.21(m,3H),4.91(s,1H),3.98(dd,J=31.6,17.2Hz,2H),2.99(t,J=16.8Hz,2H),1.47(s,9H).

[0106] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.51,172.19,143.88,142.52,140.43,140.11,132.13,129.29,128.82,128.62,12 7.84,127.54,127.08,127.03,124.83,124.76,115.72,81.74,61.25,47.84,40.36,28.00.HRMS(ESI):m / z[M+H] + calcd for C 28 H 28 NO3 + :426.2064,found:426.2034.

[0107] Example 6

[0108] Preparation of compound III-6

[0109]

[0110] The preparation steps are the same as those in Example 1, except that compound III-6 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-6.

[0111] The product yield was 71%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 210 nm, 25 ° C, retention time was t R (major)=14.97min,t R (minor)=13.35min.

[0112] Product structure characterization data:

[0113] 1H NMR (400MHz, CDCl3) δ (ppm) 7.81 (dd, J = 8.4, 5.2Hz, 2H), 7.65 (d, J = 8.0Hz, 1H), 7.26 (s, 1H), 7.22 (q, J = 4.0Hz, 2H ),7.02(t,J=8.8Hz,2H),5.31(s,1H),3.95(dd,J=17.2,14.0Hz,2H),2.94(dd,J=34.4,16.8Hz,2H),1.46(s,9H).

[0114] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.33, 171.46, 164.60 (d, J = 250.0Hz), 142.51, 140.42, 130.34 (d, J = 8.0Hz), 129.44 (d, J=3.0Hz),129.29,127.50,124.86,124.68,115.70,115.50(d,J=22.0Hz),81.70,77.00,61.39,47.68,40.21,27.95. 19 F NMR(376MHz, CDCl3)δ(ppm)-108.25.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 FNO3 + :368.1656,found:368.1653.

[0115] Example 7

[0116] Preparation of compound III-7

[0117]

[0118] The preparation steps are the same as those in Example 1, except that compound III-7 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-7.

[0119] The product yield was 78%, and the enantiomeric excess was 94%. (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 220 nm, 25°C, and the retention time was t R (major)=32.65min,t R (minor)=16.63min.

[0120] Product structure characterization data:

[0121] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.74 (d, J = 8.0Hz, 2H), 7.65 (d, J = 7.6Hz, 1H), 7.31 (d, J = 8.0Hz, 2H), 7.27 (d, J = 7.2Hz, 1H),7.22(t,J=5.6Hz,2H),5.28(s,1H),3.94(dd,J=17.6,8.0Hz,2H),2.93(dd,J=38.8,16.8Hz,2H),1.46(s,9H).

[0122] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.25,171.55,142.39,140.42,137.41,131.63,129.43,129.35,12 8.67,127.53,124.89,124.68,115.73,81.74,61.38,47.66,40.21,27.96.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 ClNO3 + :384.1361,found:384.1359.

[0123] Example 8

[0124] Preparation of compound III-8

[0125]

[0126] The preparation steps are the same as those in Example 1, except that compound III-8 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-8.

[0127] The product yield was 70%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral IC-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 230 nm, 25 ° C, retention time was t R (major)=11.57min,t R (minor)=19.56min.

[0128] Product structure characterization data:

[0129] 1H NMR (400MHz, CDCl3) δ (ppm) 7.65 (t, J = 8.0Hz, 3H), 7.47 (d, J = 8.4Hz, 2H), 7.29 (t, J = 7.2Hz, 1H), 7.22 (t ,J=6.4Hz,2H),5.21(s,1H),3.93(dd,J=17.6,6.8Hz,2H),2.93(dd,J=39.6,16.8Hz,2H),1.45(s,9H).

[0130] 13 C NMR(100MHz,CDCl3)δ(ppm)172.24,171.66,142.34,140.41,132.07,131.64,129.60,129.37,12 7.54,125.95,124.90,124.67,115.74,81.76,61.37,47.63,40.20,27.96.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 BrNO3 + :428.0856,found:428.0861.

[0131] Example 9

[0132] Preparation of compound III-9

[0133]

[0134] The preparation steps are the same as those in Example 1, except that compound III-9 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-9.

[0135] The product yield was 70%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 220 nm, 25 ° C, retention time was t R (major)=23.59min,t R (minor)=12.43min.

[0136] Product structure characterization data:

[0137] 1H NMR (400MHz, CDCl3) δ (ppm) 7.91 (d, J = 8.0Hz, 2H), 7.65 (d, J = 7.6Hz, 1H), 7.60 (d, J = 8.4Hz, 2H), 7.30 (t, J = 7.6Hz ,1H),7.23(t,J=7.2Hz,2H),5.28(s,1H),3.97(t,J=17.2Hz,2H),2.97(dd,J=34.8,16.8Hz,2H),1.46(s,9H).13C NMR (100MHz, CDCl3) δ (ppm) 172.18, 171.56, 142.15, 140.42, 136.39, 132.75 (q, J = 33.0Hz), 129.52, 128.40 ,127.61,125.39(d,J=4.0Hz),,125.00,124.67,122.36,115.77,81.92,77.00,61.41,47.83,40.11,27.94.

[0138] 19 F NMR(376MHz, CDCl3)δ(ppm)-62.94.HRMS(ESI):m / z[M+H] + calcd for C 23 H 23 F3NO3 + :418.1625,found:418.1619.

[0139] Example 10

[0140] Preparation of compound III-10

[0141]

[0142] The preparation steps are the same as those in Example 1, except that compound III-10 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-10.

[0143] The product yield was 72%, the enantiomeric excess was 89%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=28.80min,t R (minor)=33.40min.

[0144] Product structure characterization data:

[0145] 1H NMR (400MHz, CDCl3) δ (ppm) 7.92 (d, J = 8.4Hz, 2H), 7.66 (d, J = 8.0Hz, 2H), 7.62 (d, J = 7.6Hz, 1H), 7. 34-7.23(m,3H),4.77(s,1H),3.95(t,J=17.2Hz,2H),2.97(dd,J=38.8,16.8Hz,2H),1.46(s,9H).

[0146] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.20,171.07,141.85,140.39,137.16,132.22,129.71,128.58,127.7 2,125.05,124.63,118.24,115.81,114.57,82.15,61.32,47.80,40.25,27.94.HRMS(ESI):m / z[M+H] + calcd for C 23 H 23 N2O3 + :375.1703,found:375.1701.

[0147] Example 11

[0148] Preparation of compound III-11

[0149]

[0150] The preparation steps are the same as those in Example 1, except that compound III-11 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-11.

[0151] Yield 69%, enantiomeric excess 90%, (determined by chiral HPLC; HPLC analysis was performed on a chiral IC-H column, isopropanol:n-hexane 85:15, v:v), 1.0 mL / min, 210 nm, 25 ° C, retention time t R (major)=19.33min,t R (minor)=32.09min.

[0152] Product structure characterization data:

[0153] 1H NMR (400MHz, CDCl3) δ (ppm) 8.03 (d, J = 8.0Hz, 2H), 7.89 (d, J = 8.0Hz, 2H), 7.65 (d, J = 7.2Hz, 1H), 7.32-7.22(m,3H),4.67(s,1H),4.01-3.90(m,5H),2.98(dd,J=23.2,16.8Hz,2H),1.46(s,9H).

[0154] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.37,171.81,166.44,142.08,140.43,137.20,132.29,129.62,129.55,1 28.04,127.66,124.95,124.69,115.79,81.98,61.25,52.30,47.96,40.32,27.95.HRMS(ESI):m / z[M+H] + calcd for C 24 H 26 NO5 + :408.1805,found:408.1800.

[0155] Example 12

[0156] The preparation steps are as follows:

[0157]

[0158] At room temperature, Ni(acac)2 (0.015 mmol, 15 mol%) and ligand L10 (0.018 mmol, 18 mol%) were dissolved in 0.5 mL of acetonitrile and stirred under argon for 0.5 h. Mec-Acr (0.002 mmol, 2 mol%), β-ketoester substrate I (0.1 mmol, 1.0 equiv.), and vinyl azide substrate II (0.15 mmol, 3.0 equiv.) were then added. The mixture was then degassed three times with liquid nitrogen. The reaction mixture was irradiated with a 10W blue light for 8 h. TLC confirmed the reaction was complete. The reaction mixture was then purified by column chromatography using a mixture of petroleum ether (V) and ethyl acetate (V) ratios of 20:1 to 4:1 to obtain the desired product. Compound III-12 was prepared from β-ketoester substrate I-1 and vinyl azide substrate II-13.

[0159] The product yield was 62%, and the enantiomeric excess was 96%. (determined by chiral HPLC; HPLC analysis was performed on a chiral IC-H column, isopropanol:n-hexane ratio was 85:15, v:v), 1.0 mL / min, 250 nm, 25°C, and the retention time was tR (major)=6.92min,t R (minor)=8.81min.

[0160] Product structure characterization data:

[0161] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.64 (d, J = 7.2Hz, 1H), 7.54-7.58 (m, 2H), 7.37-7.20 (m, 4H), 7.14-7.0 9(m,1H),4.80(s,1H),3.93(dd,J=17.6,12.4Hz,2H),2.95(dd,J=35.6,16.8Hz,2H),1.46(s,9H).

[0162] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.35, 171.51 (d, J = 3.0Hz), 162.61 (d, J = 245.0Hz), 142.18, 140.40, 135.43 (d, J = 7.0Hz), 130.00 (d, J = 8.0Hz), 1 29.45,127.60,124.90,124.68,123.85(d,J=3.0Hz),118.22(d,J=21.0 Hz), 115.65, 114.87 (d, J = 22.0Hz), 81.91, 61.25, 47.85, 40.28, 27.95.

[0163] 19 F NMR(376MHz, CDCl3)δ-112.50.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 FNO3 + :368.1656,found:368.1652.

[0164] Example 13

[0165] Preparation of compound III-13

[0166]

[0167] The preparation steps are the same as those in Example 1, except that compound III-13 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-14.

[0168] Yield 70%, enantiomeric excess 91%, (determined by chiral HPLC; HPLC analysis was performed on a chiral IC-H column, isopropanol:n-hexane 90:10, v:v), 1.0 mL / min, 250 nm, 25°C, retention time t R (major)=9.78min,t R (minor)=14.67min.

[0169] Product structure characterization data:

[0170] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.82 (s, 1H), 7.69 (d, J = 7.6Hz, 1H), 7.64 (d, J = 7.2Hz, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.31-7.2 6(m,3H),7.22(d,J=7.2Hz,1H),4.65(s,1H),3.92(dd,J=17.2,9.6Hz,2H),2.95(dd,J=34.8,16.4Hz,2H),1.46(s,9H).

[0171] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.36, 171.36, 142.10, 140.37, 134.98, 134.51, 131.21, 129.71, 129.50, 12 8.12,127.63,126.17,124.91,124.66,115.65,81.95,61.21,47.82,40.29,27.96.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 ClNO3 + :384.1361,found:384.1347.

[0172] Example 14

[0173] Preparation of compound III-14

[0174]

[0175] The preparation steps are the same as those in Example 1, except that compound III-14 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-15.

[0176] The product yield was 70%, the enantiomeric excess was 91%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 210 nm, 25 ° C, retention time was t R (major)=17.75min,t R (minor)=12.29min.

[0177] Product structure characterization data:

[0178] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.67 (d, J = 7.6Hz, 2H), 7.57 (d, J = 6.4Hz, 1H), 7.29-7.19 (m, 5H), 4 .78(s,1H),3.93(t,J=17.6Hz,2H),2.95(dd,J=20.8,16.8Hz,2H),2.31(s,3H),1.45(s,9H).

[0179] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.68, 172.53, 142.49, 140.41, 138.07, 133.19, 132.02, 129.24, 128.63, 128.2 4,127.49,125.27,124.77,124.74,115.58,81.68,61.17,47.86,40.33,27.97,21.21.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO3 + :364.1907,found:364.1903.

[0180] Example 15

[0181] Preparation of compound III-15

[0182]

[0183] The preparation steps are the same as those in Example 1, except that compound III-15 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-16.

[0184] The product yield was 75%, the enantiomeric excess was 93%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 250 nm, 25°C, and the retention time was tR (major)=8.08min,t R (minor)=9.34min.

[0185] Product structure characterization data:

[0186] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.06-8.01 (m, 1H), 7.64 (d, J = 6.8Hz, 1H), 7.44-7.36 (m, 1H), 7.34-7.27 (m, 2H), 7.14 (t,J=7.2Hz,1H),7.06(dd,J=11.2,8.4Hz,1H),4.34(s,1H),4.03-3.79(m,2H),3.13-2.95(m,2H),1.46(s,6H).

[0187] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.61, 170.18 (d, J = 2.0Hz), 161.80 (d, J = 252.0Hz), 142.04, 140.48, 132.87 (d, J = 9.0Hz), 130.67 (d, J = 3.0Hz), 129.48, 127.62,124.97,124.68,124.30(d,J=3.0Hz),121.39(d,J=12.0Hz),116.1 7(d,J=23.0Hz),114.30,81.89,61.33,61.31,51.12,51.04,40.05,27.97.

[0188] 19 F NMR(376MHz, CDCl3)δ-112.17.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 FNO3 + :368.1656,found:368.1651.

[0189] Example 16

[0190] Preparation of compound III-16

[0191]

[0192] The preparation steps are the same as those in Example 12, except that compound III-16 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-17.

[0193] The product yield was 52%, the enantiomeric excess was 96%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=10.13min,t R (minor)=8.60min.

[0194] Product structure characterization data:

[0195] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.69-7.59 (m, 2H), 7.38-7.20 (m, 6H), 4.43 (s, 1H) ), 3.93 (dd, J=50.4, 18.0Hz, 2H), 3.06 (dd, J=26.4, 18.0Hz, 2H), 1.47 (s, 9H).

[0196] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.72, 172.31, 141.80, 140.45, 133.61, 132.55, 131.15, 130.86, 130.23, 12 9.49,127.59,126.84,124.95,124.66,114.55,81.92,61.84,51.07,39.78,28.00.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 ClNO3 + :384.1361,found:384.1358.

[0197] Example 17

[0198] Preparation of compound III-17

[0199]

[0200] The preparation steps are the same as those in Example 1, except that compound III-17 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-18.

[0201] The product yield was 75%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 210 nm, 25 ° C, retention time was t R(major)=6.62min,t R (minor)=7.48min.

[0202] Product structure characterization data:

[0203] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.60 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.33-7.16 (m, 6H), 4.1 8(s,1H),3.90(dd,J=16.8,5.2Hz,2H),2.94(dd,J=54.8,16.8Hz,2H),2.48(s,3H),1.48(s,9H).

[0204] 13 C NMR (100MHz, CDCl3) δ (ppm) 174.35, 172.56, 142.31, 140.21, 137.66, 133.41, 131.32, 129.73, 129.40, 128.6 7,127.61,125.51,124.95,124.67,115.99,81.86,60.96,51.54,39.75,28.02,21.52.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO3 + :364.1907,found:364.1901.

[0205] Example 18

[0206] Preparation of compound III-18

[0207]

[0208] The preparation steps are the same as those in Example 12, except that compound III-18 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-12.

[0209] The product yield was 65%, the enantiomeric excess was 96%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 70:30, v:v), 1.0 mL / min, 254 nm, 25°C, retention time was t R (major)=35.96min,t R (minor)=13.28min.

[0210] Product structure characterization data:

[0211] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.72 (d, J = 8.0Hz, 2H), 7.67 (d, J = 6.8Hz, 1H), 7.27 (d, J = 8.0Hz, 4H), 7.21 (d, J = 7.2Hz ,1H),4.84(s,1H),4.65(s,1H),3.93(t,J=18.0Hz,2H),2.94(dd,J=21.2,16.8Hz,2H),2.67(s,1H),1.44(s,9H).

[0212] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.50,172.47,144.42,142.40,140.49,132.23,129.32,128.23,127.5 3,126.63,124.80,124.70,115.68,81.77,64.47,61.18,47.74,40.44,27.95.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO4 + :380.1856,found:380.1855.

[0213] Example 19

[0214] Preparation of compound III-19

[0215]

[0216] The preparation steps are the same as those in Example 1, except that compound III-19 is prepared from β-ketoester substrate I-1 and vinyl azide substrate II-19.

[0217] The product yield was 43%, the enantiomeric excess was 88%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=27.17min,t R (minor)=17.10min.

[0218] Product structure characterization data:

[0219] 1H NMR (400MHz, CDCl3) δ (ppm) 7.72-7.67 (m, 1H), 7.68-7.63 (m, 1H), 7.58 (d, J = 5.1Hz, 1H), 7.29 (d, J = 3.2Hz, 3H) ,7.21(q,J=4.7,4.2Hz,1H),4.25(s,1H),3.89(dd,J=17.2,11.6Hz,2H),2.95(t,J=16.4Hz,2H),1.45(s,9H).

[0220] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.63,167.62,142.31,140.44,136.71,129.41,128.72,127.61,12 6.99,126.19,124.78,124.72,115.86,81.89,60.99,48.50,40.64,27.97.HRMS(ESI):m / z[M+H] + calcd for C 20 H 22 NO3S + :356.1315,found:356.1309.

[0221] Example 20

[0222] Preparation of compound III-20

[0223]

[0224] The preparation steps are the same as those in Example 12, except that compound III-20 is prepared from β-ketoester substrate I-2 and vinyl azide substrate II-1.

[0225] The product yield was 85%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 230 nm, 25 ° C, retention time was t R (major)=14.74min,t R (minor)=11.63min.

[0226] Product structure characterization data:

[0227] 1H NMR (400MHz, CDCl3) δ (ppm) 7.81 (d, J = 7.6Hz, 2H), 7.53 (d, J = 7.6Hz, 1H), 7.41 (t, J = 7.2Hz, 1H), 7.35 (t, J = 7.6Hz, 2H), 7.05 (d, J=8.0Hz,1H),7.02(s,1H),4.68(s,1H),3.92(dd,J=35.6,17.6Hz,2H),2.93(dd,J=16.4,8.4Hz,2H),2.32(s,3H),1.45(s,9H).

[0228] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.60,172.21,140.59,139.76,139.26,133.39,131.15,128.49,128.3 4,128.07,125.30,124.40,115.60,81.67,61.38,47.88,40.25,27.99,21.41.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO3 + :364.1907,found:364.1901.

[0229] Example 21

[0230] Preparation of compound III-21

[0231]

[0232] The preparation steps are the same as those in Example 12, except that compound III-21 is prepared from β-ketoester substrate I-3 and vinyl azide substrate II-1.

[0233] The product yield was 68%, and the enantiomeric excess was 90%. (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 250 nm, 25°C, and the retention time was t R (major)=20.43min,t R (minor)=18.15min.

[0234] Product structure characterization data:

[0235] 1H NMR (400MHz, CDCl3) δ (ppm) 7.84 (d, J = 8.0Hz, 2H), 7.54 (d, J = 8.4Hz, 1H), 7.43 (d, J = 7.2Hz, 1H), 7.38 (t, J = 7.2Hz, 2H) ,6.84(d,J=8.0Hz,1H),6.72(s,1H),3.91(dd,J=35.2,17.6Hz,3H),3.79(s,3H),2.95(d,J=17.2Hz,2H),1.45(s,9H).

[0236] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.65, 171.96, 161.02, 142.21, 134.80, 133.45, 131.22, 128.40, 128.0 4,125.53,115.38,114.20,109.38,81.88,61.55,55.41,47.96,40.54,28.00.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO4 + :380.1856,found:380.1853.

[0237] Example 22

[0238] Preparation of compound III-22

[0239]

[0240] The preparation steps are the same as those in Example 12, except that compound III-22 is prepared from β-ketoester substrate I-4 and vinyl azide substrate II-1.

[0241] The product yield was 76%, and the enantiomeric excess was 94%. (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 250 nm, 25°C, and the retention time was t R (major)=11.92min,t R (minor)=10.55min.

[0242] Product structure characterization data:

[0243] 1H NMR (400MHz, CDCl3) δ (ppm) 7.80 (d, J = 7.6Hz, 2H), 7.61 (dd, J = 9.2, 4.8Hz, 1H), 7.43 (t, J = 7.6Hz, 1H), 7.35 (t, J = 7 .6Hz,2H),6.89(d,J=8.0Hz,2H),5.45(s,1H),3.95(dd,J=37.6,17.6Hz,2H),2.94(d,J=17.6Hz,2H),1.46(s,9H).

[0244] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.79, 172.03, 163.69 (d, J = 245.0Hz), 142.90 (d, J = 9.0Hz), 138.47, 132.93, 131.44 ,128.46,128.13,126.22(d,J=9.0Hz),114.90,114.67,111.41(d,J=22.0Hz),81.76,61.67,47.52,40.12,27.94.

[0245] 19 F NMR(376MHz, CDCl3)δ-113.28.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 FNO3 + :368.1656,found:368.1651.

[0246] Example 28

[0247] Preparation of compound III-23

[0248]

[0249] The preparation steps are the same as those in Example 12, except that compound III-23 is prepared from β-ketoester substrate I-5 and vinyl azide substrate II-1.

[0250] The product yield was 66%, and the enantiomeric excess was 86%. (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 254 nm, 25°C, and the retention time was t R (major)=27.34min,t R (minor)=15.10min.

[0251] Product structure characterization data:

[0252] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.80 (d, J = 6.8Hz, 2H), 7.57 (d, J = 8.0Hz, 1H), 7.43 (t, J = 7.2Hz, 1H), 7.36 (t, J = 7.6H z,2H),7.18(d,J=8.4Hz,2H),5.19(s,1H),3.94(dd,J=40.8,17.6Hz,2H),2.94(d,J=17.6Hz,2H),1.45(s,9H).

[0253] 13 C NMR(100MHz,CDCl3)δ(ppm)172.98,172.03,142.48,141.12,135.03,132.97,131.50,128.49,12 8.13,127.85,125.95,124.88,115.04,81.92,61.39,47.59,40.17,27.97.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 ClNO3 + :384.1361,found:384.1353.

[0254] Example 24

[0255] Preparation of compound III-24

[0256]

[0257] The preparation steps are the same as those in Example 12, except that compound III-24 is prepared from β-ketoester substrate I-6 and vinyl azide substrate II-1.

[0258] The product yield was 64%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=17.72min,t R (minor)=19.17min.

[0259] Product structure characterization data:

[0260] 1H NMR (400MHz, CDCl3) δ (ppm) 7.78 (d, J = 7.2Hz, 2H), 7.52 (d, J = 8.4Hz, 1H), 7.43 (t, J = 7.2Hz, 1H), 7.38-7.32 (m, 3H ),7.30(d,J=8.0Hz,1H),5.66(s,1H),3.95(dd,J=36.4,17.6Hz,2H),2.93(dd,J=16.8,5.6Hz,2H),1.46(s,9H).

[0261] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.14,171.87,142.84,141.71,132.82,131.51,130.61,128.47,12 8.13,127.86,126.31,123.15,115.07,81.81,61.35,47.45,39.99,27.95.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 BrNO3 + :428.0856,found:428.0852.

[0262] Example 25

[0263] Preparation of compound III-25

[0264]

[0265] The preparation steps are the same as those in Example 1, except that compound III-30 is prepared from β-ketoester substrate I-7 and vinyl azide substrate II-1.

[0266] The product yield was 72%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=21.67min,t R (minor)=12.37min.

[0267] Product structure characterization data:

[0268] 1H NMR (400MHz, CDCl3) δ (ppm) 7.84 (d, J = 7.6Hz, 2H), 7.46-7.40 (m, 2H), 7.36 (t, J = 7.2Hz, 2H), 7.09 (s ,2H),4.40(s,1H),3.91(dd,J=44.0,17.6Hz,2H),2.94(d,J=17.6Hz,2H),2.30(s,3H),1.45(s,9H).

[0269] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.69, 172.41, 142.38, 137.36, 137.33, 133.34, 131.22, 130.39, 128.3 6,128.10,125.02,124.55,115.64,81.76,61.41,47.94,40.10,27.98,21.19.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO3 + :364.1907,found:364.1906.

[0270] Example 26

[0271] Preparation of compound III-26

[0272]

[0273] The preparation steps are the same as those in Example 12, except that compound III-26 is prepared from β-ketoester substrate I-8 and vinyl azide substrate II-1.

[0274] The product yield was 73%, the enantiomeric excess was 92%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 80:20, v:v), 1.0 mL / min, 254 nm, 25°C, retention time was t R (major)=36.71min,t R (minor)=16.38min.

[0275] Product structure characterization data:

[0276] 1H NMR (400MHz, CDCl3) δ (ppm) 7.84 (d, J = 7.6Hz, 2H), 7.43 (t, J = 7.6Hz, 1H), 7.37 (t, J = 6.8Hz, 2H), 7.20 (s, 1H), 7.09 (d, J = 8.0Hz, 1H), 6 .85(d,J=8.4Hz,1H),4.58(s,1H),3.97(d,J=17.6Hz,2H),3.81(d,J=16.4Hz,2H),3.76(s,3H),2.94(t,J=18.4Hz,2H),1.45(s,9H).

[0277] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.70,172.52,159.55,143.55,133.28,132.08,131.29,128.40,128.1 0,125.50,117.22,115.56,108.15,81.82,61.56,55.42,47.93,39.92,27.96.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO4 + :380.1856,found:380.1850.

[0278] Example 27

[0279] Preparation of compound III-27

[0280]

[0281] The preparation steps are the same as those in Example 12, except that compound III-27 is prepared from β-ketoester substrate I-9 and vinyl azide substrate II-1.

[0282] The product yield was 67%, the enantiomeric excess was 88%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 254 nm, 25°C, retention time was t R (major)=31.57min,t R (minor)=10.91min.

[0283] Product structure characterization data:

[0284] 1H NMR (400MHz, CDCl3) δ (ppm) 7.80 (d, J = 8.0Hz, 2H), 7.56 (d, J = 7.6Hz, 1H), 7.42 (t, J = 7.2Hz, 1H), 7.34 (t, J = 7.2Hz, 2H), 7.2 5(d,J=7.6Hz,1H),7.15(t,J=7.6Hz,1H),5.64(s,1H),3.98(dd,J=46.0,17.6Hz,2H),2.99(t,J=15.6Hz,2H),1.46(s,9H).

[0285] 13 C NMR(100MHz,CDCl3)δ(ppm)173.30,171.92,144.68,138.80,132.87,131.50,130.56,129.17,12 8.97,128.46,128.19,123.13,116.07,81.87,60.71,47.66,39.70,27.95.HRMS(ESI):m / z[M+H] + calcd for C 22 H 23 ClNO3 + :384.1361,found:384.1362.

[0286] Example 28

[0287] Preparation of compound III-33

[0288]

[0289] The preparation steps are the same as those in Example 12, except that compound III-28 is prepared from β-ketoester substrate I-10 and vinyl azide substrate II-1.

[0290] The product yield was 51%, the enantiomeric excess was 90%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 70:30, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=32.17min,t R (minor)=20.77min.

[0291] Product structure characterization data:

[0292] 1H NMR (400MHz, CDCl3) δ (ppm) 7.85 (d, J = 7.2Hz, 2H), 7.48-7.36 (m, 3H), 7.17 (s, 1H), 6.6 9(s,1H),4.10(s,1H),4.01-3.78(m,8H),2.96(dd,J=26.0,17.6Hz,2H),1.46(s,9H).

[0293] 13 C NMR (100MHz, CDCl3) δ (ppm) 172.79,172.10,150.59,149.16,134.03,133.37,132.13,131.27,128.41,1 28.04,116.08,106.94,106.61,81.92,61.43,55.98,55.93,48.13,40.58,27.99.HRMS(ESI):m / z[M+H] + calcd for C 24 H 28 NO5 + :410.1962,found:410.1962.

[0294] Example 29

[0295] Preparation of compound III-29

[0296]

[0297] The preparation steps are the same as those in Example 12, except that compound III-29 is prepared from β-ketoester substrate I-11 and vinyl azide substrate II-1.

[0298] The product yield was 70%, the enantiomeric excess was 96%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=10.02min,t R (minor)=13.45min.

[0299] Product structure characterization data:

[0300] 1H NMR (400MHz, CDCl3) δ (ppm) 8.25 (s, 1H), 7.76 (d, J = 7.6Hz, 2H), 7.64 (d, J = 7.6Hz, 1H), 7.40 (t, J = 7.2Hz, 1H), 7.32-7.20 (m, 4H), 7 .13(t,J=7.2Hz,1H),4.14(d,J=18.0Hz,1H),3.61(d,J=16.8Hz,1H),3.16(d,J=16.8Hz,1H),2.97(d,J=18.0Hz,1H),1.35(s,9H).

[0301] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.61, 172.73, 143.55, 139.77, 132.67, 131.56, 129.03, 128.42, 12 8.24,127.61,124.82,124.68,111.55,60.62,50.96,47.26,42.69,28.72.HRMS(ESI):m / z[M+H] + calcd for C 22 H 25 N2O2 + :349.1911,found:349.1908.

[0302] Example 30

[0303] Preparation of compound III-30

[0304]

[0305] The preparation steps are the same as those in Example 12, except that compound III-30 is prepared from β-ketoester substrate I-12 and vinyl azide substrate II-1.

[0306] The product yield was 63%, the enantiomeric excess was 91%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=16.50min,t R (minor)=21.36min.

[0307] Product structure characterization data:

[0308] 1H NMR (400MHz, CDCl3) δ (ppm) 8.30 (s, 1H), 7.75 (d, J = 7.6Hz, 2H), 7.65 (d, J = 7.6Hz, 1H), 7.39 (t, J = 7.2Hz, 1H), 7.29 (t, J = 7.6Hz, 2H), 7.23-7.09 (m,3H),4.12(d,J=17.6Hz,1H),3.62(d,J=16.8Hz,1H),3.16(d,J=16.8Hz,1H),2.95(d,J=17.6Hz,1H),2.04(s,3H),2.01(s,6H),1.66(s,6H).

[0309] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.57,172.49,143.57,139.77,132.67,131.51,128.99,128.38,128.24,1 27.58,124.79,124.71,111.49,60.63,51.67,47.29,42.60,41.48,36.35,29.36.HRMS(ESI):m / z[M+H] + calcd for C 28 H 31 N2O2 + :427.2380,found:427.2380.

[0310] Example 31

[0311] Preparation of compound III-31

[0312]

[0313] The preparation steps are the same as those in Example 1, except that compound III-31 is prepared from β-ketoester substrate I-13 and vinyl azide substrate II-1.

[0314] The product yield was 66%, and the enantiomeric excess was 87%. (Determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 90:10, v:v), 1.0 mL / min, 250 nm, 25°C, and the retention time was t R (major)=29.85min,t R (minor)=12.40min.

[0315] Product structure characterization data:

[0316] 1H NMR (400MHz, CDCl3) δ (ppm) 8.01 (d, J = 7.6Hz, 1H), 7.88 (d, J = 7.6Hz, 2H), 7.44 (t, J = 6.8Hz,1H),7.38(t,J=7.6Hz,2H),7.32(t,J=7.2Hz,1H),7.21(t,J=7.6Hz,1H),7.07 (d,J=7.6Hz,1H),4.12(s,1H),3.73(d,J=17.2Hz,1H),3.02(d,J=16.8Hz,1H),2.97 -2.90(m,1H),2.74-2.67(m,1H),2.38-2.31(m,1H),1.97-1.90(m,1H),1.46(s,9H).

[0317] 13 C NMR (100MHz, CDCl3) δ (ppm) 173.74, 172.93, 138.86, 135.79, 133.62, 131.24, 128.53, 128.31, 127.9 7,127.76,127.71,126.91,100.25,81.97,55.79,44.66,30.97,27.96,25.96.HRMS(ESI):m / z[M+H] + calcd for C 23 H 26 NO3 + :364.1907,found:364.1904.

[0318] Example 32

[0319] Preparation of compound III-32

[0320]

[0321] The preparation steps are the same as those in Example 1, except that compound III-32 is prepared from β-ketoester substrate I-14 and vinyl azide substrate II-1.

[0322] The product yield was 67%, the enantiomeric excess was 80%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 254 nm, 25 ° C, retention time was t R (major)=18.49min,t R (minor)=6.10min.

[0323] Product structure characterization data:

[0324] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.86 (d, J = 6.8Hz, 2H), 7.49-7.39 (m, 2H), 4.51 (s, 1H), 3.96 (d, J = 18.0Hz, 1H), 2.86 (d, J = 18.0Hz, 1H) ,2.62-2.54(m,1H),2.28-2.23(m,1H),2.08-2.01(m,1H),1.81-1.74(m,1H),1.71-1.66(m,1H),1.50(s,9H),1.43-1.31(m,1H).

[0325] 13 C NMR(100MHz,CDCl3)δ(ppm)173.42,171.91,133.20,131.20,128.41,128.14,1 15.57,81.29,59.24,47.96,39.93,37.57,28.02,22.82.HRMS(ESI):m / z[M+H] + calcd for C 18 H 24 NO3 + :302.1751,found:302.1753.

[0326] Example 33

[0327] Preparation of compound III-33

[0328]

[0329] The preparation steps are the same as those in Example 1, except that compound III-33 is prepared from β-ketoester substrate I-15 and vinyl azide substrate II-1.

[0330] The product yield was 74%, the enantiomeric excess was 87%, (determined by chiral HPLC; HPLC analysis was performed on a chiral AZ-H column, isopropanol:n-hexane was 85:15, v:v), 1.0 mL / min, 254 nm, 25°C, retention time was t R (major)=24.48min,t R (minor)=11.42min.

[0331] Product structure characterization data:

[0332] 1H NMR (400MHz, CDCl3) δ (ppm) 7.88 (d, J = 7.6Hz, 2H), 7.47 (t, J = 7.2Hz, 1H), 7.41 (t, J = 7.6Hz, 2H), 5.19 (s, 1H), 3.74 (d, J = 16.4Hz, 1H), 2.81 (d, J = 1 6.8Hz,1H),2.19-2.12(m,1H),2.07(d,J=14.0Hz,1H),1.99-1.92(m,1H ),1.72-1.63(m,2H),1.52(s,9H),1.44-1.35(m,1H),1.33-1.18(m,2H).

[0333] 13 C NMR (100MHz, CDCl3) δ (ppm) 175.09, 173.47, 133.95, 131.25, 128.38, 127.95, 99. 56,81.06,55.02,45.53,34.90,33.95,28.09,21.81,21.36.HRMS(ESI):m / z[M+H] + calcd for C 19 H 26 NO3 + :316.1907,found:316.1904.

[0334] Example 34

[0335] Preparation of compound III-34

[0336]

[0337] The preparation steps are as follows:

[0338] At room temperature, Ni(acac)2 (0.015 mmol, 15 mol%) and ligand L10 (0.018 mmol, 18 mol%) were dissolved in 0.5 mL of acetonitrile and stirred under argon for 0.5 h. 4CzIPN (0.002 mmol, 2 mol%) and vinyl azide substrate II (0.15 mmol, 1.5 equiv) were then added. The mixture was then degassed three times with liquid nitrogen. β-ketoester I was dissolved in 0.5 mL of acetonitrile and added to the reaction system in ten portions (50 μL at a time, with 10-minute intervals). The reaction mixture was irradiated with 10W blue light for 2 h. TLC confirmed the reaction was complete. The reaction mixture was then purified by column chromatography using a mixture of petroleum ether / ethyl acetate (V:V) ratios of 20:1 to 10:1 to directly obtain the corresponding target product. Compound III-34 was prepared from β-ketoester substrate I-16 and vinyl azide substrate II-1.

[0339] The product yield was 62%, and the enantiomeric excess was 74%. (determined by chiral HPLC; HPLC analysis was performed on a chiral AD-H column, isopropanol:n-hexane ratio was 85:15, v:v), 1.0 mL / min, 254 nm, 25°C, and the retention time was t R (major)=13.06min,t R (minor)=11.45min.

[0340] Product structure characterization data:

[0341] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.83 (d, J = 7.2Hz, 2H), 7.61 (d, J = 7.6Hz, 1H), 7.47 (t, J = 7.2Hz, 1H), 7.39 (t, J = 7.5Hz, 2H), 7.29-7.2 5(m,2H),6.98(t,J=7.2Hz,1H),6.90(d,J=8.0Hz,1H),4.58(s,1H),4.18(d,J=18.8Hz,1H),3.46(d,J=18.8Hz,1H),1.50(s,9H). 13 C NMR (100MHz, CDCl3) δ (ppm) 172.90,168.24,159.32,132.52,131.88,130.94,128.58,128.39 ,126.98,124.85,121.86,114.25,110.67,94.70,83.36,46.90,27.96.HRMS(ESI):m / z[M+H] + calcd for C 21 H 21 NaNO4 + :374.1363,found:374.1366.

[0342] Example 35

[0343] Preparation of compound III-1:

[0344] The preparation steps are as follows:

[0345] At room temperature, Ni(acac)2 (0.015 mmol, 15 mol%) and ligand L10 (0.018 mmol, 18 mol%) were dissolved in 0.5 mL of acetonitrile and stirred under argon for 0.5 h. Subsequently, [Ru(bpy)3]Cl2·6H2O (0.002 mmol, 2 mol%), a β-ketoester substrate (0.1 mmol, 1.0 equiv.), and a vinyl azide substrate (0.15 mmol, 1.5 equiv.) were added. The mixture was then degassed three times with liquid nitrogen. The reaction mixture was irradiated with a 10W blue light for 2 h. TLC confirmed the reaction was complete. The reaction mixture was then purified by column chromatography using a mixture of petroleum ether (V) and ethyl acetate (V) (20:1-4:1) to directly obtain the desired product. Compound III-1 was prepared from the β-ketoester substrate I-1 and the vinyl azide substrate II-1. The yield was 56% and the enantiomeric excess was 86%.

[0346] Example 36

[0347] Preparation of compound III-1:

[0348] The preparation steps are as follows:

[0349] At room temperature, Ni(acac)2 (0.015 mmol, 15 mol%) and ligand L10 (0.018 mmol, 18 mol%) were dissolved in 0.5 mL of acetonitrile and stirred under argon for 0.5 h. Mes-Acr(ClO4) (0.002 mmol, 2 mol%), a β-ketoester substrate (0.1 mmol, 1.0 equiv.), and a vinyl azide substrate (0.3 mmol, 3 equiv.) were then added. The mixture was then degassed three times with liquid nitrogen. The reaction mixture was irradiated with a 10W blue light for 8 h. TLC confirmed the reaction was complete. The reaction mixture was then purified by column chromatography using a mixture of petroleum ether (V) and ethyl acetate (V) (20:1-4:1) to directly obtain the desired product. Compound III-1 was prepared from the β-ketoester substrate I-1 and the vinyl azide substrate II-1. The yield was 71% and the enantiomeric excess was 95%.

[0350] Examples 37-52

[0351] Preparation of compound III-1

[0352] The preparation steps are the same as those in Example 1, except that different ligands are used. For details, see Table 1.

[0353] Example 53

[0354] Preparation of compound III-1

[0355] The preparation steps are as follows:

[0356] At room temperature, Ni(acac)2 (0.010 mmol, 10 mol%) and ligand L9 (0.012 mmol, 12 mol%) were dissolved in 0.5 mL of acetonitrile and stirred under argon for 0.5 h. 4CzIPN (0.002 mmol, 2 mol%), a β-ketoester substrate (0.1 mmol, 1.0 equiv.), and a vinyl azide substrate (0.15 mmol, 1.5 equiv.) were then added. The mixture was then degassed three times with liquid nitrogen. The reaction mixture was irradiated with a 10W blue light for 2 h. TLC confirmed the reaction was complete. The reaction mixture was then purified by column chromatography (gradient elution: petroleum ether / ethyl acetate = 20:1-4:1, V / V ratio) to directly yield the corresponding target product. Compound III-1 was prepared from the β-ketoester substrate I-1 and the vinyl azide substrate II-1.

[0357] The product yield was 63% and the enantiomeric excess was 86% (determined using a chiral HPLC instrument; HPLC analysis was performed using a chiral AD-H column; the mobile phase was isopropanol:n-hexane in a ratio of 85:15, v:v), the mobile phase flow rate was 1.0 mL / min, the detection wavelength was 210 nm, the column temperature was 25°C, and the retention time was t R (major)=15.09min,t R (minor)=12.07min.

[0358] Examples 54-60

[0359] The preparation steps are the same as those in Example 53, except that different solvents are used. See Table 2 for details.

[0360] Examples 61-62

[0361] Preparation of compound III-1

[0362] The preparation steps are the same as those in Example 1, except that Ni(acac)2 is replaced by other metal salts, see Table 3.

[0363] Comparative Examples 1-5

[0364] The preparation steps are the same as those in Example 1, except that Ni(acac)2 is replaced by other metal salts, see Table 3.

[0365] Comparative Example 6

[0366] The preparation steps are the same as those in Example 1, except that no photocatalyst 4CzIPN is added.

[0367] Comparative Example 7

[0368] The preparation steps are the same as those in Example 1, except that no blue light irradiation is performed.

[0369] Comparative Example 8

[0370] The preparation steps are the same as those in Example 1, except that ligand L10 is not added.

[0371] Comparative Example 9

[0372] The preparation steps are the same as those in Example 1, except that the ligand L10 and Ni(acac)2 are not added.

[0373] Table 1. Product yields and enantiomeric excess (ee values) under different ligands

[0374]

[0375] As shown in Table 1, compared with other chiral oxazoline ligands, chiral bisoxazoline ligands with a substituent with a larger steric hindrance (such as benzyl and tert-butylbenzyl) have higher enantioselectivity.

[0376] Table 2. Product yields and ee values ​​under different organic solvents

[0377]

[0378]

[0379] As shown in Table 2, when acetonitrile, tetrahydrofuran, trifluorotoluene or acetone is used as solvent, the yield and enantiomeric selectivity are relatively high, while when methanol, ether or dichloroethane is used as solvent, the yield is relatively low.

[0380] Table 3. Product yields and ee values ​​under different metal salts

[0381]

[0382] As shown in Table 3, under the action of metal nickel salt, the reaction has a high enantiomeric selectivity, and when the metal nickel salt is nickel acetylacetonate, the yield is higher than that of other nickel salts.

[0383] Table 4. Product yield and ee value under different experimental conditions

[0384]

[0385] As shown in Table 4, the reaction cannot occur without light or a photocatalyst. In the absence of a ligand or nickel salt, the yield is very low, and only a racemic product is obtained. Based on the method of the present invention, under blue light illumination, the combined action of a photocatalyst and a chiral nickel metal complex catalyst, a β-ketoester and a vinyl azide cycloaddition reaction occurs to form polycyclic 3,4-dihydro-2H-pyrrole derivatives with high enantioselectivity.

[0386] Although the embodiments of the present invention have been described in detail above, those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and purpose of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims

1. A method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative, characterized in that: The steps include: Step 1: Under an inert gas atmosphere, a soluble nickel salt and a chiral oxazoline ligand are mixed in an organic solvent to react to obtain a nickel metal complex chiral catalyst solution; Step 2: Under an inert gas atmosphere, a nickel metal complex chiral catalyst solution, a photocatalyst, a β-ketoester represented by Formula I, and a vinyl azide represented by Formula II are mixed, and then reacted under blue light to obtain a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative represented by Formula III, wherein the photocatalyst is selected from one or more of 4CzIPN, [Ru(bpy)3]Cl2·6H2O, and Mes-Acr(ClO4); Where n is 1 or 2; R 1 is selected from tert-butoxy, tert-butylamino or 1-adamantanylamino; R 2 is selected from H, halogen, alkyl or alkoxy; R 3 One selected from substituted or unsubstituted phenyl and thienyl, wherein the substituents in the substituted phenyl and substituted thienyl are selected from one or more of halogen, hydroxyl, alkyl, alkoxy, phenyl, trifluoromethyl, cyano or ester groups; The soluble nickel salt is selected from one or more of Ni(acac)2, Ni(OTf)2 or NiBr2; The chiral oxazoline ligand is selected from one or more of the following structures:

2. The method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to claim 1, wherein: The chiral oxazoline ligand is one or more of L5, L7, L8, L9 or L10.

3. The method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to claim 1, wherein: The organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, chloroform, trifluoromethylbenzene, 1,2-dichloroethane, ether, acetone or methanol.

4. The method for preparing the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to claim 3, characterized in that: The organic solvent is selected from acetonitrile, tetrahydrofuran or acetone.

5. The method for preparing the chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to claim 1, characterized in that: The molar ratio of the soluble nickel salt to the chiral oxazoline ligand is 1:(1-1.5).

6. The method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to claim 1, wherein: In step 2, the ratio of the amount of β-ketoester, vinyl azide, nickel metal complex chiral catalyst and photocatalyst substance is 1: (1-3): (5%-25%): (0.5%-5%).

7. The method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to claim 1, wherein: A nickel metal complex chiral catalyst solution, a photocatalyst, a β-ketoester represented by Formula I and a vinyl azide represented by Formula II are mixed, and the mixed reaction solution is degassed with liquid nitrogen and then reacted under blue light irradiation.

8. The method for preparing a chiral polycyclic 3,4-dihydro-2H-pyrrole derivative according to claim 1, wherein: The chiral polycyclic 3,4-dihydro-2H-pyrrole derivative represented by formula III is selected from any one of the following structures:

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