Asymmetric catalytic synthesis method of oxime ether compound with high optical purity

Abstract

The invention relates to an asymmetric catalytic synthesis method of an oxime ether compound with high optical purity. According to the method, a catalytic system formed by combining monovalent rhodium metal and a chiral olefin ligand is adopted, and an aryl or alkenyl diazo compound is used as a carbene precursor to carry out asymmetric insertion reaction on an O-H bond of oxime, so that efficient asymmetric catalytic synthesis of a series of oxime ether compounds with high optical purity is realized.

Description

Technical Field

[0001] The invention belongs to the field of synthetic chemistry and relates to an asymmetric catalytic synthesis method of high optical purity oxime ether compounds. Background Art

[0002] Oxime ether compounds occupy an important position in the organic chemistry system, not only because of their outstanding efficacy in medicinal chemistry, but also because of their building block function in organic synthetic chemistry. In particular, molecules containing oxime ether structures are ubiquitous in a variety of drugs, demonstrating their excellent pharmacological properties. For example, oxime ether compounds play a central role in some drugs used to treat bacterial infections, including the antifungal drug methoxazole and the antibacterial drug roxithromycin with oxime ether structural motifs. Another example is phentuximab, a broad-spectrum acaricide. In addition, fluvoxamine is known for its therapeutic effect on obsessive-compulsive disorder and antidepressant activity. Enoxabiodinium is a strobilurin fungicide with broad-spectrum fungicidal activity. It entered the market in 2007 and is currently one of the largest-selling pesticide varieties. In view of these rich biological activities, efficient and practical methods for the synthesis of oxime ethers have become the research focus in the field of synthetic organic chemistry. In the past few decades, new methods for the synthesis of oxime ethers have emerged continuously, attracting great attention from industry and academia. The synthesis of traditional oxime ether compounds is usually achieved through the condensation of carbonyl compounds and hydroxylamine, or through the cross-coupling reaction of oxime with arylboronic acid or organic halide. In addition, the method of using transition metal catalysts to replace allyl groups on oximes has also attracted attention. However, these methods usually require the use of transition metal catalysts at relatively high reaction temperatures, and all of the resulting oxime ether compounds are racemic.

[0003] In recent years, the visible light-promoted OH functionalization reaction of aromatic diazo esters with oximes has been found to be useful for the synthesis of a series of oxime ether skeleton compounds, but all of them are racemic products. The synthesis of optically pure chiral compounds by asymmetric catalysis has become a core frontier of synthetic chemistry, but the methods for the preparation of chiral oxime ether compounds are rarely explored. It can be said that there is still no efficient asymmetric synthesis method for obtaining oxime ether compounds with high chemical purity. Summary of the invention

[0004] In a first aspect, the present invention provides a method for preparing a carbon-centered chiral high optical purity oxime ether compound, wherein the method comprises the following steps: using a monovalent rhodium metal and a chiral diene ligand L as catalysts, a diazo compound 1 and an oxime compound 2 as reaction substrates, and obtaining a reaction product oxime ether compound 3 or ent-3 under the protection of an inert gas;

[0005]

[0006] In the formula,

[0007] R1 is substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 5-7 membered heteroaryl;

[0008] R 2 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-30 Aryl;

[0009] R 3 , R 4 are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-30 Aryl;

[0010] Unless otherwise specified, the heteroaryl group contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the substitution refers to the hydrogen atoms on the group being substituted mono- or poly-substituted, and the substituents are independently selected from: halogen, nitro (NO2), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, 6-10 membered aryl; the halogen is F, Cl, Br or I.

[0011] As described in the method of the first aspect of the present invention, the chiral diene ligand has the following structural formula:

[0012]

[0013] wherein compound L and compound ent-L are enantiomers of each other;

[0014] Ar 1 or Ar 2 are each independently selected from substituted or unsubstituted C 6-30 Aryl, where Ar 1 and Ar 2 The groups may be the same or different; the substitution means that the hydrogen atoms on the group are replaced by one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, nitro (NO2), cyano (CN); the halogen is F, Cl, Br or I.

[0015] In another preferred embodiment, the chiral diene ligand has any structure selected from the following group:

[0016]

[0017]

[0018] The above-mentioned ligands can be prepared by methods known in the art, for example, by referring to the method of Chen D, Zhang X, Qi WY, Xu B, Xu MH. Rhodium (I)-catalyzed asymmetric carbene insertion into B-Hbonds: highly enantioselective access to functionalized organoboranes. J Am Chem Soc. 2015Apr 29; 137(16): 5268-71. doi: 10.1021 / jacs.5b00892. Epub 2015Mar4. PMID: 25726987.

[0019] In another preferred embodiment, the monovalent rhodium metal catalyst is selected from the following group: [Rh(C2H4)2Cl]2, [Rh(C2H4)2OH]2, [Rh(COE)2Cl]2, [Rh(COE)2OH]2, or a combination thereof.

[0020] In another preferred embodiment, the diazo compound has the structure shown in Compound 1:

[0021]

[0022] in:

[0023] R 1 is substituted or unsubstituted C 6-30 Aryl, substituted or unsubstituted 5-7 membered heteroaryl;

[0024] R 2 is substituted or unsubstituted C 6-30 Aryl; preferably substituted or unsubstituted phenyl; more preferably, methyl-substituted phenyl; most preferably 2,4,6-trimethylphenyl;

[0025] In another preferred embodiment, the diazo compound 1 is selected from the following group:

[0026]

[0027] In another preferred embodiment, the oxime compound has a structure as shown in Compound 2:

[0028]

[0029] in:

[0030] R 3 is substituted or unsubstituted C6-30 Aryl;

[0031] R 4 For hydrogen.

[0032] In another preferred embodiment, the oxime compound is 4-methylbenzoyl oxime, benzoyl oxime, 4-fluorobenzoyl oxime, 4-chlorobenzoyl oxime, 4-bromobenzoyl oxime, 4-trifluoromethylbenzoyl oxime, 3-methylbenzoyl oxime, 2-methylbenzoyl oxime, 2-fluorobenzoyl oxime, 1-naphthoyl oxime, and 2-naphthoyl oxime.

[0033] In another preferred embodiment, based on the amount of the diazo compound 1, the amount of the oxime compound 2 is 100 mol% to 300 mol%.

[0034] In another preferred embodiment, based on the amount of the diazo compound 1, the amount of the monovalent rhodium metal catalyst is 0.1 to 8 mol%.

[0035] In another preferred embodiment, based on the amount of the diazo compound 1, the amount of the chiral diene ligand is 0.1-10 mol%.

[0036] In another preferred embodiment, the method comprises one or more features selected from the following group:

[0037] (1) The reaction is carried out in an organic solvent. Preferably, the organic solvent is selected from the group consisting of dichloromethane, dichloroethane, ether, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, or a combination thereof;

[0038] (2) The reaction is carried out in the presence of an additive, preferably, the additive is a compound selected from the group consisting of HCl, H2SO4, H3PO4, CH3COOH, Et3N·3HCl, Et3N·3HF, Et3N·HBr, or a combination thereof; more preferably, the additive is used in an amount of 50 mol% to 500 mol%, based on the amount of the diazo compound 1;

[0039] (3) The reaction temperature is 0 to 60°C;

[0040] (4) The reaction time is 1 to 24 hours.

[0041] In another preferred embodiment, the oxime ether compound is selected from the following group:

[0042]

[0043]

[0044] The second aspect of the present invention provides an oxime ether compound selected from the following group:

[0045]

[0046] DETAILED DESCRIPTION

[0047] The invention provides an asymmetric catalytic synthesis method for oxime ether compounds with high optical purity. Specifically, a catalytic system of a combination of monovalent rhodium metal and chiral olefin ligands is adopted, and aromatic vinyl diazo is used as a carbene precursor, so that a highly efficient asymmetric insertion reaction of the OH bond of the rhodium (I) carbene to the oxime compound can be achieved, thereby conveniently obtaining various substituted oxime ether compounds with high optical purity.

[0048] the term

[0049] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0050] As used herein, the term “C 6-30 The term "aryl" refers to an aromatic group having 6 to 30 carbon atoms, including monocyclic or polycyclic aromatic groups, such as phenyl, naphthyl, or the like.

[0051] The term "5-7 membered heteroaryl" refers to a heteroaryl group having 5-7 ring atoms (having 1-7 heteroatoms selected from N, O or S in the backbone), pyrrolyl, pyridyl, furanyl, or the like.

[0052] The term "C 1-6 The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0053] The term "C 1-6 The term "haloalkyl" refers to an alkyl group having 1 to 6 carbon atoms in which one or more hydrogen atoms are replaced by halogen atoms (F, Cl, Br, I), such as fluoromethyl, trifluoromethyl, trichloromethyl, or the like.

[0054] The term "C 1-6 The term "haloalkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms in which one or more hydrogen atoms are replaced by halogen atoms (F, Cl, Br, I), such as fluoromethoxy, fluoroethoxy, or the like.

[0055] Method for preparing high optical purity oxime ether compounds containing carbon center chirality

[0056] The present invention provides a method for preparing a high optical purity oxime ether compound containing a carbon center chirality. Specifically, the method comprises: under the protection of an inert gas, a monovalent rhodium catalyst and a chiral diene ligand are dissolved in an organic solvent, and stirred at room temperature for 30 minutes. Subsequently, a diazo compound, an oxime compound and an additive are added in sequence, and the stirring reaction is continued for 1 to 24 hours. After the reaction is completed, conventional post-treatment is performed, and the chiral oxime ether compound with high optical purity is obtained by separation and purification by silica gel column chromatography.

[0057] The main technical advantages of the present invention are embodied in the following aspects:

[0058] (1) The present invention uses a specific complex composed of monovalent rhodium metal / diene ligand as a catalyst, and under specific conditions, realizes for the first time the efficient asymmetric OH bond carbene insertion reaction of diazo compounds on oxime substrates. The reaction process has mild conditions, simple operation, and exhibits unique chemical properties.

[0059] (2) The method provided by the present invention exhibits excellent substrate universality, and can achieve good chemical transformation effects regardless of the substituent types of oxime substrates and alkenyldiazo substrates, as well as their derivatives;

[0060] (3) The reaction strategy adopted by the present invention has excellent stereoselectivity and can effectively prepare chiral oxime ether compounds with high optical purity. These products can be further converted into important compounds such as chiral hydroxylamine and chiral alcohol, showing excellent application potential and practical prospects.

[0061] In summary, the method of the present invention realizes the catalytic asymmetric synthesis of oxime ether compounds, the process is simple and efficient, and the obtained products can be further converted into various important compounds such as chiral hydroxylamine and chiral alcohol, and has broad application prospects.

[0062] The following part describes the specific implementation of the present invention in detail in combination with examples to further illustrate the technical details of the present invention. It should be understood that the contents described in the examples provided by the present invention are for further explanation of the present invention and are not intended to limit the scope of protection of the present invention.

[0063] Example 1 Synthesis of Compound 3a

[0064] Experiment 1: Under argon protection, alkenyl diazo substrate 1a (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3a (yellow solid, 92% yield, 96% ee).

[0065]

[0066] 1 H NMR (600MHz, CDCl3) δ8.19 (s, 1H), 7.46 (d, J = 8.0Hz, 2H), 7.44-7.37 (m, 5H), 7.37-7.33 (m, 1H), 7.17 (d, J = 7.9Hz, 2 H),6.86(s,2H),6.33(dd,J=15.8,1.6Hz,1H),5.92(dd,J=5.0,1.4Hz,1H),2.36(s,3H),2.26(s,3H),2.10(s,6H). 13 C NMR (151MHz, CDCl3) δ164.30,150.08,148.44,145.94,140.51,138.37,135.46,129.92,129.56,12 9.33,129.23,128.91,128.68,127.78,127.33,120.91,84.17,21.61,20.91,16.42.HRMS(ESI)forC 27 H 27 NO3[M+H] + :calcd.414.2064,found 414.2065.

[0067] Experiment 2: The ligand (1R,4R)-L1 used in Experiment 1 was replaced by (1R,4R)-L2. The rest of the experimental operations were the same as Experiment 1 to obtain product 3a as a yellow solid with a yield of 54% and an ee of 86%.

[0068] Experiment 3: The ligand (1R,4R)-L1 used in Experiment 1 was replaced by (1R,4R)-L3. The rest of the experimental operations were the same as Experiment 1 to obtain product 3a as a yellow solid with a yield of 70% and 97% ee.

[0069] Experiment 4: The ligand (1R,4R)-L1 used in Experiment 1 was replaced by (1R,4R)-L4. The rest of the experimental operations were the same as Experiment 1 to obtain product 3a as a yellow solid with a yield of 65% and an ee of 97%.

[0070] Experiment 5: The ligand (1R,4R)-L1 used in Experiment 1 was replaced by (1R,4R)-L5. The rest of the experimental operations were the same as Experiment 1 to obtain product 3a as a yellow solid with 85% yield and 96% ee.

[0071] Experiment 6: The ligand (1R,4R)-L1 used in Experiment 1 was replaced by (1R,4R)-L6. The rest of the experimental operations were the same as Experiment 1 to obtain product 3a as a yellow solid with 83% yield and 96% ee.

[0072] Experiment 7: The ligand (1R,4R)-L1 used in Experiment 1 was replaced by (1R,4R)-L7. The rest of the experimental operations were the same as Experiment 1 to obtain product 3a as a yellow solid with a yield of 60% and 97% ee.

[0073] Example 2 Synthesis of Compound ent-3a

[0074] Under the protection of argon, the alkenyl diazo substrate 1a (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), and the chiral diene ligand (1S,4S)-L1 (0.0055mmol, 5.5mol%) with the opposite configuration in Example 1 were sequentially put into the reaction bottle, and the solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the product ent-3a with the opposite configuration (yellow solid, 91% yield, 96% ee).

[0075]

[0076] 1H NMR (600 MHz, CDCl3) δ8.18 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.44-7.36 (m, 5H), 7.37-7.33 (m, 1H), 7.16 (d, J = 7.9 Hz, 2H), 6.85 (s, 2H), 6.33 (dd, J = 15.8, 1.6 Hz, 1H), 5.91 (dd, J = 5.0, 1.4 Hz, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 2.10 (s, 6H). The above results show that when ligands with different configurations are used, products with chirality inversion can be obtained, and the reaction efficiency is basically the same as that when ligands with corresponding configurations are used.

[0077] Example 3 Synthesis of Compound 3b

[0078] Under argon protection, alkenyldiazo substrate 1b (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(C2H4)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3b (yellow solid, 85% yield, 97% ee).

[0079]

[0080] 1 H NMR (600MHz, CDCl3) δ8.17(s,1H),7.46(d,J=7.9Hz,2H),7.39(dd,J=15.7,5.0Hz,1H),7.32(d,J=7.8Hz,2H),7.25(s,1H),7.21(d,J=7.8H z,2H),7.16(d,J=7.9Hz,2H),6.86(s,2H),6.32(d,J=15.8Hz,1H),5.88(d,J=5.0Hz,1H),2.36(d,J=4.4Hz,6H),2.25(s,3H),2.09(s,6H). 13C NMR (151MHz, CDCl3) δ164.33,149.96,148.64,145.95,140.44,138.56,135.43,135.33,129.93,129.5 9,129.54,129.32,129.29,127.79,127.32,120.76,84.05,21.61,21.37,20.92,16.42.HRMS(ESI)for C 28 H 29 NO3[M+H] + :calcd.428.2220,found 428.2225.

[0081] Example 4 Synthesis of Compound 3c

[0082] Under argon protection, alkenyldiazo substrate 1c (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L5 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3c (yellow solid, 91% yield, 95% ee).

[0083]

[0084] 1 H NMR (400MHz, CDCl3) δ8.19(s,1H),7.49(d,J=8.1Hz,2H),7.44(d,J=5.0Hz,1H),7.38(dd,J=9.9,3.4Hz,3H),7.19(d,J=8.0Hz,2H),6.99- 6.93(m,2H),6.89(s,2H),6.34(dd,J=15.8,1.7Hz,1H),5.89(dd,J=5.0,1.6Hz,1H),3.85(s,3H),2.38(s,3H),2.28(s,3H),2.12(s,6H). 13C NMR (101MHz, CDCl3) δ164.22,159.82(s),149.79,148.54,145.81,140.31,135.29,130.21,129.78, 129.41,129.18,129.14,127.17,120.59,114.16,83.66,55.32,21.47,20.77,16.28.HRMS(ESI)for C 28 H 29 NO4[M+Na] + :calcd.466.1989,found466.1982.

[0085] Example 5 Synthesis of Compound 3d

[0086] Under argon protection, alkenyl diazo substrate 1d (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L7 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3d (yellow solid, 75% yield, 97% ee).

[0087]

[0088] 1 H NMR (600MHz, CDCl3) δ8.18 (s, 1H), 7.45 (d, J = 8.1Hz, 2H), 7.40-7.35 (m, 4H), 7.34 (dd, J = 15.1, 4.4Hz, 1H), 7.17 (d, J = 7. 9Hz, 2H), 6.86 (s, 2H), 6.32 (dd, J=15.8, 1.6Hz, 1H), 5.88 (dd, J=5.0, 1.4Hz, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 2.09 (s, 6H). 13C NMR (101MHz, CDCl3) δ164.15,150.32,147.73,145.88,140.66,137.02,135.52,134.53,129.8 6,129.59,129.35,129.11,129.03,127.35,121.23,83.34,21.62,20.91,16.41.HRMS(ESI)for C 27 H 26 ClNO3[M+H] + :calcd.448.1674,found 448.1675.

[0089] Example 6 Synthesis of Compound 3e

[0090] Under argon protection, alkenyldiazo substrate 1e (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3e (yellow solid, 73% yield, 97% ee).

[0091]

[0092] 1 H NMR (400MHz, CDCl3) δ8.18(s,1H),7.53(d,J=8.4Hz,2H),7.45(d,J=8.0Hz,2H),7.37-7.27(m,3H),7.17(d,J=8.0 Hz,2H),6.86(s,2H),6.32(dd,J=15.8,1.6Hz,1H),5.86(d,J=3.8Hz,1H),2.36(s,3H),2.26(s,3H),2.09(s,6H); 13 C NMR (101MHz, CDCl3) δ164.14,150.35,147.64,145.88,140.68,137.56,135.53,132.06,129.86,12 9.60,129.41,129.35,129.02,127.35,122.71,121.26,83.38,21.62,20.91,16.41.HRMS(ESI)forC27 H 26 BrNO3[M+H] + :calcd.492.1169,found 492.1175.

[0093] Example 7 Synthesis of Compound 3f

[0094] Under argon protection, alkenyl diazo substrate 1f (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent Dioxane (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3f (yellow solid, 76% yield, 99% ee).

[0095]

[0096] 1 H NMR (400MHz, CDCl3) δ8.21(s,1H),7.67(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),7.45(d,J=8.1Hz,2H),7.34(dd,J=15.8,5.1Hz,1H ),7.17(d,J=7.9Hz,2H),6.87(s,2H),6.34(dd,J=15.8,1.7Hz,1H),5.96(d,J=4.0Hz,1H),2.36(s,3H),2.26(s,3H),2.09(s,6H). 13 C NMR(101MHz, CDCl3)δ164.04(s),150.56(s),147.22(s),145.86(s),142.59(s),140.79(s),135.57(s),129.84(s),129.62(s),129.37(s) ,128.91(s),127.95(s),127.38(s),125.89(q,J=3.7Hz),122.78(s),121.55(s),83.34(s),21.63(s),20.92(s),16.41(s).HRMS(ESI)for C 27 H 26 BrNO3[M+H] +:calcd.492.1169,found 492.1175.

[0097] Example 8 Synthesis of Compound 3g

[0098] Under the protection of argon, 1g (0.1mmol) of alkenyldiazo substrate, 4-methylbenzaldehyde oxime (0.12mmol), [Rh(C2H4)2Cl]2 (2.5mol%, 0.005mmol of rhodium), and chiral diene ligand (1R,4R)-L5 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, and solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain 3g of the target product (yellow solid, 86% yield, 98% ee).

[0099]

[0100] 1 H NMR (400MHz, CDCl3) δ8.19(s,1H),7.47(d,J=8.1Hz,2H),7.39(dd,J=15.7,5.1Hz,1H),7.28(d,J=7.4Hz,1H),7.22(d,J=8.5Hz,2H),7.17(d ,J=8.0Hz,3H),6.86(s,2H),6.32(dd,J=15.7,1.6Hz,1H),5.88(dd,J=5.1,1.4Hz,1H),2.38(s,3H),2.36(s,3H),2.26(s,3H),2.10(s,6H). 13 C NMR(101MHz, CDCl3)δ164.34(s),150.02(s),148.61(s),145.94(s),140.47(s),138.62(s),138.20(s),135.43(s),129.92(s),129.55(s), 129.46(s),129.32(s),128.80(s),128.42(s),127.33(s),124.84(s),120.78(s),84.26(s),21.61(s),20.91(s),16.42(s).HRMS(ESI)for C 27 H 25 F2NO3[M+H] + :calcd.450.1875,found450.1876.

[0101] Example 9 Synthesis of Compound 3h

[0102] Under the protection of argon, the alkenyl diazo substrate 1h (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), and chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, and solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3h (yellow solid, 72% yield, 97% ee).

[0103]

[0104] 1 H NMR (400MHz, CDCl3) δ8.20 (s, 1H), 7.46 (d, J = 8.1Hz, 2H), 7.42 (s, 1H), 7.33 (ddd, J = 10.3, 6.4, 4.2Hz, 4H), 7.17 (d, J = 8. 0Hz,2H),6.87(s,2H),6.33(dd,J=15.8,1.6Hz,1H),5.88(dd,J=5.1,1.5Hz,1H),2.36(s,3H),2.26(s,3H),2.10(s,7H). 13 C NMR (101MHz, CDCl3) δ164.01,150.30,147.38,145.76,140.57,140.44,135.40,134.68,130.06,129.7 5,129.47,129.23,128.67,127.67,127.25,125.67,121.23,83.24,21.50,20.79,16.30.HRMS(ESI)for C 27 H 26 ClNO3[M+H] + :calcd.448.1674,found448.1668.

[0105] Example 10 Synthesis of Compound 3i

[0106] Under argon protection, alkenyl diazo substrate 1i (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and HOAc (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3i (white solid, 71% yield, 99% ee).

[0107]

[0108] 1 H NMR(400MHz, CDCl3)δ8.20(s,1H),7.46(d,J=8.1Hz,2H),7.33-7.24(m,4H),7.18(d,J=8.0Hz,2H),6.96(dd,J=7.8,2.0Hz,2H),6 .87(s,2H),6.83-6.74(m,1H),6.34(dd,J=15.8,1.7Hz,1H),5.87(dd,J=5.1,1.5Hz,1H),2.37(s,3H),2.26(s,3H),2.10(s,6H). 13 C NMR (151MHz, CDCl3) δ164.14 (d, J = 12.5Hz), 163.98, 162.49 (d, J = 12.3Hz), 150.71, 146.65, 145.85, 142.65 (d, J = 8.6Hz), 140.86, 135.59, 12 9.85,129.64,129.38,128.84,127.42,121.73,110.46(dd,J=20.6,5.4Hz),103.98(t,J=25.2Hz),82.84,21.64,20.92,16.42.HRMS(ESI)for C 27 H 25 F2NO3[M+Na] + :calcd.472.1695,found472.1688.

[0109] Example 11 Synthesis of Compound 3j

[0110] Under argon protection, alkenyl diazo substrate 1j (0.1 mmol), 4-methylbenzaldehyde oxime (0.12 mmol), [Rh(COE)2Cl]2 (2.5 mol%, 0.005 mmol of rhodium), chiral diene ligand (1R,4R)-L7 (0.0055 mmol, 5.5 mol%) were sequentially put into a reaction bottle, solvent DCM (1.0 ml) and Et3N·3HF (0.1 mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3j (yellow solid, 90% yield, 93% ee).

[0111]

[0112] 1 H NMR (400MHz, CDCl3) δ8.23(s,1H),7.49(d,J=8.1Hz,2H),7.38(dd,J=15.7,5.1Hz,1H),7.20(d,J=8.0Hz,2H),6.89(s,2H),6.60(d,J=2.3Hz,2H),6 .46(t,J=2.3Hz,1H),6.37(d,J=1.7Hz,1H),6.33(d,J=1.7Hz,1H),5.86(d d,J=5.1,1.6Hz,1H),3.83(s,6H),2.39(s,3H),2.28(s,3H),2.12(s,6H). 13 C NMR (101MHz, CDCl3) δ164.29,161.18,150.17,148.15,145.93,140.69,140.54,135.46,129.91,129.5 6,129.33,129.18,127.36,120.95,105.66,100.47,84.11,55.55,21.62,20.91,16.42.HRMS(ESI)for C29H31NO5[M+H] + :calcd.474.2275,found 474.2277.

[0113] Example 12 Synthesis of Compound 3k

[0114] Under argon protection, alkenyl diazo substrate 1k (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3k (yellow solid, 75% yield, 92% ee).

[0115]

[0116] 1 H NMR (600MHz, CDCl3) δ8.19(s,1H),7.52(d,J=1.9Hz,1H),7.48(d,J=8.3Hz,1H),7.45(d,J=8.0Hz,2H),7.29(dd,J=15.8,5.1Hz,1H),7.27 -7.24(m,2H),7.18(d,J=7.9Hz,2H),6.87(s,2H),6.33(dd,J=15.8,1.6Hz,1H),5.88-5.81(m,1H),2.36(s,3H),2.26(s,3H),2.10(s,6H). 13 C NMR(151MHz, CDCl3)δ164.01(s),150.64(s),146.93(s),145.86(s),140.83(s),138.89(s),135.59(s),133.09(s),132.74(s),130.92(s), 129.85(s),129.63(s),129.37(s),128.86(s),127.40(s),126.94(s),121.64(s),82.73(s),21.63(s),20.92(s),16.42(s).HRMS(ESI)for C 27 H 25 Cl2NO3[M+H] + :calcd.482.1284,found482.1276.

[0117] Example 13 Synthesis of Compound 31

[0118] Under argon protection, alkenyldiazo substrate 1l (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3l (yellow solid, 70% yield, 95% ee).

[0119]

[0120] 1 H NMR (400MHz, CDCl3) δ8.23 (s, 1H), 7.52-7.44 (m, 3H), 7.44-7.32 (m, 2H), 7.21 (ddd, J = 8.0, 6.2, 1.7Hz, 3H), 7.17-7.10 (m,1H),6.89(s,2H),6.37(dd,J=15.8,1.6Hz,1H),6.28(dd,J=5.0,1.6Hz,1H),2.38(s,3H),2.28(s,3H),2.12(s,6H). 13 C NMR (101MHz, CDCl3) δ164.34,150.02,148.61,145.94,140.47,138.62,138.20,135.43,129.92,129.55,12 9.46,129.32,129.25,128.80,128.42,127.33,124.84,120.78,84.26,21.61,20.91,16.42.HRMS(ESI)for C 27 H 26 FNO3[M+H] + :calcd.432.1969,found432.1969.

[0121] Example 14 Synthesis of Compound 3m

[0122] Under the protection of argon, alkenyl diazo substrate 1m (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L2 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3m (yellow solid, 65% yield, 95% ee).

[0123]

[0124] 1 H NMR (400MHz, CDCl3) δ8.24(s,1H),7.49(d,J=8.1Hz,2H),7.33(dd,J=15.8,4.9Hz,1H),7.20(d,J=8.1Hz,2H),7.19 -7.14(m,2H),7.10(td,J=9.0,4.4Hz,1H),7.06-6.99(m,1H),6.89(s,2H),2.39(s,3H),2.28(s,3H),2.12(s,7H). 13 C NMR(151MHz, CDCl3)δ164.09(s),150.66(s),146.18(s),145.87(s),140.81(s),135.54(s),129.88(s),129.62(s),129.35(s),12 7.43(s),121.44(s),116.74(ddd,J=63.7,24.5,8.4Hz),115.25(dd,J=25.2,4.0Hz),21.63(s),20.91(s),16.40(s).HRMS(ESI)for C 27 H 25 F2NO3[M+H] + :calcd.450.1875,found 450.1876.

[0125] Example 15 Synthesis of Compound 3n

[0126] Under argon protection, alkenyl diazo substrate 1n (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3n (yellow solid, 70% yield, 94% ee).

[0127]

[0128] 1 H NMR (400MHz, CDCl3) δ8.23(s,1H),8.21(d,J=8.5Hz,1H),7.93-7.84(m,2H),7.58(ddd,J=7.5,6.8,3.0Hz,3H),7.53(dd,J=11.4,4.7Hz,2H),7.48(d ,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),6.86(s,2H),6.65(dd,J=4.5,1.8Hz ,1H),6.40(dd,J=15.8,1.8Hz,1H),2.36(s,3H),2.25(s,3H),2.09(s,7H); 13 C NMR (101MHz, CDCl3) δ164.30,150.18,148.40,145.93,140.56,135.45,134.21,133.97,131.21,129.91,129.57,129.54,12 9.32,129.19,129.04,127.37,126.70,126.28,126.04,125.49,124.02,121.38,81.82,21.62,20.92,16.43.HRMS(ESI)for C 31 H 29 NO3[M+H] + :calcd.464.2220,found 464.2227.

[0129] Example 16 Synthesis of Compound 3o

[0130] Under argon protection, alkenyl diazo substrate 1o (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3o (yellow solid, 75% yield, 95% ee).

[0131]

[0132] 1 H NMR (400MHz, CDCl3) δ8.52(d,J=8.0Hz,1H),8.21(s,1H),8.05(dd,J=8.3,1.1Hz,1H),7.80(dd,J=15.9,3.8Hz,1H),7.59-7.53(m,1H),7.53- 7.47(m,1H),7.42(d,J=8.1Hz,1H),7.12(d,J=8.0Hz,1H),6.82(s,1H),6.26(dd,J=15.9,2.2Hz,1H),2.33(s,1H),2.23(s,1H),2.04(s,2H). 13 C NMR (101MHz, CDCl3) δ164.28,149.92,149.60,145.88,140.47,135.41,131.86,130.14,129.88,129.51,12 9.47,129.44,129.29,129.13,127.32,126.37,125.14,120.94,80.36,21.59,20.89,16.36.HRMS(ESI)for C 35 H 31 NO3[M+H] + :calcd.514.2377,found 514.2382.

[0133] Example 17 Synthesis of Compound 3p

[0134] Under argon protection, alkenyl diazo substrate 1p (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3p (yellow solid, 65% yield, 96% ee).

[0135]

[0136] 1 H NMR (400MHz, CDCl3) δ8.19 (s, 1H), 7.53-7.48 (m, 3H), 7.43 (dd, J = 15.8, 5.2Hz, 1H), 7.28 (s, 1H), 7.21 (d, J = 7. 9Hz,2H),6.90(s,2H),6.49-6.40(m,3H),6.00(dd,J=5.2,1.6Hz,1H),2.39(s,3H),2.29(s,3H),2.14(s,6H). 13 C NMR (151MHz, CDCl3) δ164.09,150.77,150.29,145.91,145.09,143.54,140.63,135.51,129.90,12 9.59,129.35,129.10,127.39,122.37,110.70,109.93,77.28,21.63,20.92,16.42.HRMS(ESI)for C 25 H 25 NO4[M+H] + :calcd.404.1856,found 404.1864.

[0137] Example 18 Synthesis of Compound 3q

[0138] Under argon protection, alkenyl diazo substrate 1q (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L2 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3q (white solid, 79% yield, 92% ee).

[0139]

[0140] 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),7.49(d,J=8.1Hz,2H),7.45(dd,J=15.7,5.2Hz,1H),7.37(dd,J=5.1,1.2Hz,1H),7.19(d,J=8.0Hz,2H),7.14(d,J=3 .5Hz,1H),7.04(dd,J=5.1,3.5Hz,1H),6.87(s,2H),6.39(dd,J=15.7,1.6H z,1H),6.15(dd,J=5.2,1.1Hz,1H),2.37(s,3H),2.26(s,3H),2.11(s,6H). 13 C NMR(151MHz, CDCl3)δ164.13(s),150.30(s),147.19(s),145.92(s),140.81(s),140.62(s),135.49(s),129.90(s),129.59(s),129.3 4(s),129.12(s),127.39(s),127.02(s),126.85(s),126.80(s),121.59(s),79.31(s),21.63(s),20.91(s),16.41(s).HRMS(ESI)for C 25 H 25 SNO3[M+H] + :calcd.420.1628,found420.1621.

[0141] Example 19 Synthesis of Compound 3r

[0142] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), benzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3r (yellow solid, 90% yield, 96% ee).

[0143]

[0144] 1 H NMR (400MHz, CDCl3) δ8.23 (s, 1H), 7.58 (dd, J = 6.6, 3.0Hz, 2H), 7.50-7.32 (m, 10H), 6.87 (s ,2H),6.34(dd,J=15.8,1.7Hz,1H),5.94(dd,J=5.1,1.6Hz,1H),2.26(s,3H),2.10(s,7H). 13 C NMR (151MHz, CDCl3) δ164.28,150.07,148.30,145.93,138.29,135.47,132.01,130.25,129.90 ,129.33,128.92,128.84,128.72,127.79,127.38,120.97,84.30,20.91,16.41.HRMS(ESI)for C 26 H 25 NO3[M+H] + :calcd.400.1907,found400.1907.

[0145] Example 20 Synthesis of Compound 3s

[0146] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 4-fluorobenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3s (yellow solid, 83% yield, 95% ee).

[0147]

[0148] 1 H NMR (600MHz, CDCl3) δ8.19(s,1H),7.59-7.52(m,1H),7.44-7.40(m,1H),7.41-7.34(m,1H),7.06(t,J=8.7 Hz,1H),6.86(s,1H),6.33(dd,J=15.8,1.7Hz,1H),5.91(dd,J=5.1,1.7Hz,1H),2.26(s,1H),2.10(s,2H). 13 C NMR (151MHz, CDCl3) δ164.80,164.25,163.14,148.88,148.20,145.91,138.22,135.49,129.88,129.34,129.25,1 29.19,128.94,128.76,128.23(d,J=3.2Hz),127.77,121.00,116.08,115.94,84.34,20.91,16.40.HRMS(ESI)for C 26 H 24 FNO3[M+H] + :calcd.418.1813,found 418.1813.

[0149] Example 21 Synthesis of Compound 3t

[0150] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 4-chlorobenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L10 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3t (yellow solid, 79% yield, 94% ee).

[0151]

[0152] 1 H NMR(400MHz, CDCl3)δ8.21(s,1H),7.56-7.51(m,2H),7.47-7.44(m,4H),7.43-7.34(m,4H),6. 89(s,2H),6.35(dd,J=15.8,1.7Hz,1H),5.95(dd,J=5.1,1.7Hz,1H),2.29(s,3H),2.13(s,6H). 13 C NMR (151MHz, CDCl3) δ164.22,148.88,148.09,145.90,138.14,136.15,135.50,130.51,129.87, 129.35,129.14,128.96,128.80,128.54,127.77,121.06,84.46,20.91,16.41(s).HRMS(ESI)for C 26 H 24 ClNO3[M+H] + :calcd.434.1517,found434.1519.

[0153] Example 22 Synthesis of Compound 3u

[0154] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 4-bromobenzaldehyde oxime (0.12mmol), [Rh(COD)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3u (yellow solid, 80% yield, 94% ee).

[0155]

[0156] 1 H NMR (600MHz, CDCl3) δ8.16(s,1H),7.50(d,J=8.1Hz,2H),7.44(d,J=8.4Hz,2H),7.42(d,J=4.2Hz,4H),7.39( dd,J=15.5,5.0Hz,2H),6.87(s,2H),6.32(d,J=15.8Hz,1H),5.92(d,J=5.1Hz,1H),2.26(s,4H),2.10(s,6H). 13 C NMR (151MHz, CDCl3) δ164.23,148.98,148.07,145.90,138.11,135.51,132.09,130.94,129.87 ,129.35,128.96,128.81,128.77,127.77,124.48,121.06,84.48,20.91,16.41.HRMS(ESI)for C 26 H 24 BrNO3[M+H] + :calcd.478.1012,found 478.1014.

[0157] Example 23 Synthesis of Compound 3v

[0158] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 4-trifluoromethylbenzaldehyde oxime (0.12mmol), [Rh(COD)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3v (yellow solid, 76% yield, 92% ee).

[0159]

[0160] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),7.71(d,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),7.53-7.34(m,6H) ,6.89(s,2H),6.36(dd,J=15.8,1.7Hz,1H),5.98(dd,J=5.1,1.7Hz,1H),2.29(s,3H),2.13(s,6H). 13 C NMR (151MHz, CDCl3) δ164.18,148.65,147.85,145.90,137.98,135.54,135.42,132.46-131.26(m),129 .86,129.36,129.00,128.89,127.79,127.55,125.81(d,J=3.7Hz),84.72,20.91,16.41.HRMS(ESI)for C 27 H 24 F3NO3[M+H] + :calcd.468.1781,found 468.1783.

[0161] Example 24 Synthesis of Compound 3w

[0162] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 3-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3w (yellow solid, 90% yield, 94% ee).

[0163]

[0164] 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.52-7.33(m,9H),7.31-7.23(m,2H),7.19(d,J=7.6Hz,1H),6.87(s ,2H),6.34(dd,J=15.8,1.7Hz,1H),5.94(dd,J=5.1,1.7Hz,1H),2.36(s,3H),2.27(s,3H),2.11(s,6H). 13 C NMR (151MHz, CDCl3) δ164.28,150.28,148.37,145.93,138.57,138.30,135.46,131.89,131.10,129.9 0,129.33,128.92,128.73,128.70,127.76,124.77,120.95,84.24,21.43,20.91,16.41.HRMS(ESI)for C 27 H 28 NO3[M+H] + :calcd.414.2064,found 414.2064.

[0165] Example 25 Synthesis of Compound 3x

[0166] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 2-methylbenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L5 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3x (yellow solid, 80% yield, 92% ee).

[0167]

[0168] 1 H NMR(400MHz, CDCl3)δ8.50)((s,1H),7.69-7.64(m,1H),7.52-7.35(m,7H),7.32-7.26(m,3H),7.21(t,J=7.3Hz,2 H),6.89(s,2H),6.38(dd,J=15.8,1.7Hz,1H),5.96(dd,J=5.2,1.6Hz,1H),2.44(s,3H),2.29(s,3H),2.13(s,6H). 13 C NMR (151MHz, CDCl3) δ164.28,149.21,148.36,145.94,138.27,137.14,135.47,131.03,130.23,129.98,12 9.91,129.34,128.94,128.75,127.85,127.44,126.26,121.05,84.27,20.92,20.19,16.41.HRMS(ESI)for C 27 H 28 NO3[M+H] + :calcd.414.2064,found 414.2065.

[0169] Example 26 Synthesis of Compound 3y

[0170] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 2-fluorobenzaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, and solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3y (white solid, 87% yield, 94% ee).

[0171]

[0172] 1 H NMR (600MHz, CDCl3) δ8.48(s,1H),7.79(s,1H),7.42(dt,J=5.0,4.5Hz,5H),7.39-7.32(m,3H),7.13(t,J=7.6Hz,1 H),7.07(t,J=9.2Hz,1H),6.86(s,2H),6.34(dd,J=15.8,1.5Hz,1H),5.98-5.80(m,1H),2.26(s,3H),2.10(s,6H). 13 C NMR (151MHz, CDCl3) δ 164.25, 161.05 (d, J = 252.0Hz), 148.08, 145.93, 143.79 (d, J = 4.4Hz), 138.16, 135.49, 131.83 (d, J = 8.5Hz), 129. 90,129.34,128.95,128.78,127.78,127.05,124.46(d,J=3.4Hz),121.06,119.86,116.09,115.95,84.52,20.91,16.42.HRMS(ESI)for C 26 H 24 FNO3[M+H] + :calcd.418.1813,found 418.1814.

[0173] Example 27 Synthesis of Compound 3z

[0174] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 1-naphthaldehyde oxime (0.12mmol), [Rh(COE)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L5 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCM (1.0ml) and Et3N·3HF (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3z (white solid, 81% yield, 95% ee).

[0175]

[0176] 1 H NMR (600MHz, CDCl3) δ8.85(s,1H),8.52(d,J=8.3Hz,1H),7.88(dd,J=11.8,4.8Hz,2H),7.73(d,J=7.0Hz,1H),7.57-7.52(m,2H),7.5 2-7.42(m,6H),7.40-7.36(m,1H),6.87(s,2H),6.43(dd,J=15.8,1.6Hz,1H),6.04(dd,J=5.2,1.4Hz,1H),2.26(s,3H),2.11(s,6H). 13 C NMR (101MHz, CDCl3) δ164.29,150.15,148.35,145.92,138.26,135.47,133.96,130.91,130.73,129.89,129.33,12 8.97,128.86,128.80,128.17,127.89,127.33,126.34,125.37,124.86,121.10,84.38,20.92,16.43.HRMS(ESI)for C 30 H 27 NO3[M+H] + :calcd.450.2064,found 450.2064.

[0177] Example 28 Synthesis of Compound 3aa

[0178] Under argon protection, alkenyldiazo substrate 1a (0.1mmol), 2-naphthaldehyde oxime (0.12mmol), [Rh(C2H4)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3aa (white solid, 86% yield, 95% ee).

[0179]

[0180] 1 H NMR (600MHz, CDCl3) δ8.37(s,1H),7.87(s,1H),7.86-7.79(m,4H),7.53-7.49(m,2H),7.48-7.46(m,2H),7.43(ddd,J=9.0,5.1, 2.9Hz,3H),7.39-7.34(m,1H),6.86(s,2H),6.37(dd,J=15.8,1.7Hz,1H),5.98(dd,J=5.1,1.6Hz,1H),2.26(s,3H),2.10(s,6H). 13 C NMR (101MHz, CDCl3) δ164.30,150.23,148.32,145.91,138.26,135.48,134.33,133.25,129.90,129.67,129.33,128.95 ,128.91,128.76,128.70,128.47,128.00,127.81,127.18,126.75,123.10,121.00,84.39,20.92,16.43.HRMS(ESI)for C 30 H 27 NO3[M+H] + :calcd.450.2064,found 450.2065.

[0181] Example 29 Synthesis of Compound 3ab

[0182] Under argon protection, alkenyl diazo substrate 1r (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(C2H4)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3ab (white solid, 85% yield, 95% ee).

[0183]

[0184] 1 H NMR (400MHz, CDCl3) δ8.23 (s, 1H), 7.54-7.35 (m, 8H), 7.20 (d, J = 8.0Hz, 2H), 7.08 (s ,3H),6.38(dd,J=15.8,1.7Hz,1H),5.95(d,J=5.0Hz,1H),2.39(s,3H),2.17(s,6H). 13 C NMR (151MHz, CDCl3) δ163.94,149.98,148.49,148.09,140.40,138.2,130.25,129.45,129.0 9,128.80,128.57,128.55,127.66,127.21,125.87,120.69,84.04,21.49,16.38.MS(ESI)for C 26 H 26 NO3[M+H] + :calcd.400.2,found 400.2.

[0185] Example 30 Synthesis of Compound 3ac

[0186] Under argon protection, alkenyl diazo substrate 1s (0.1mmol), 4-methylbenzaldehyde oxime (0.12mmol), [Rh(C2H4)2Cl]2 (2.5mol%, 0.005mmol of rhodium), chiral diene ligand (1R,4R)-L1 (0.0055mmol, 5.5mol%) were sequentially put into a reaction bottle, solvent DCE (1.0ml) and HCl (0.1mmol) were added, and the reaction was stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction solution was collected, concentrated by rotary evaporator, and separated by silica gel column chromatography to obtain the target product 3ac (white solid, 87% yield, 81% ee).

[0187]

[0188] 1 H NMR(400MHz, CDCl3) δ8.17(s,1H),7.46(d,J=8.1Hz,2H),7.42-7.32(m,10H),7.24(dd,J=15.8,5.3Hz,1H),7.18 (d,J=7.9Hz,2H),6.16(dd,J=15.8,1.6Hz,1H),5.85(dd,J=5.3,1.6Hz,1H),5.20(d,J=2.1Hz,2H),2.38(s,3H). 13 C NMR (151MHz, CDCl3) δ166.06,149.84,147.06,140.30,138.25,135.84,129.39,129.09,128.6 9,128.57,128.45,128.34,128.26,127.59,127.17,121.62,84.00,66.41,21.46.MS(ESI)for C 25 H 24 NO3[M+H] + :calcd.386.1,found 386.2.

[0189] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a high optical purity oxime ether compound containing a carbon center chirality, characterized in that: The method comprises the following steps: under the protection of an inert gas, using a monovalent rhodium metal and a chiral diene ligand as catalysts, a diazo compound 1 and an oxime compound 2 as reaction substrates, and obtaining an oxime ether compound 3 or ent-3 as a reaction product; In the formula, R 1 is substituted or unsubstituted C 6-30 Aryl, or substituted or unsubstituted 5-7 membered heteroaryl; R 2 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-30 Aryl; R 3 , R 4 are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-30 Aryl; Unless otherwise specified, the heteroaryl group contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the substitution refers to the replacement of hydrogen atoms on the group by one or more substituents, and the substituents are independently selected from: halogen, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, benzyloxy, C 6-10 Aryl; the halogen is F, Cl, Br or I.

2. The method according to claim 1, characterized in that The chiral diene ligand has the following structure: Wherein, compound L and compound ent-L are enantiomers of each other; Ar 1 or Ar 2 are each independently selected from substituted or unsubstituted C 6-30 Aryl, and Ar 1 and Ar 2 The groups may be the same or different; the substitution means that the hydrogen atoms on the group are replaced by one or more substituents selected from the following groups: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, nitro, cyano; the halogen is F, Cl, Br or I.

3. The method according to claim 1, characterized in that The chiral diene ligand has any structure selected from the following group:

4. The method according to claim 1, characterized in that The monovalent rhodium metal catalyst is selected from the following group: [Rh(C2H4)2Cl]2, [Rh(C2H4)2OH]2, [Rh(COE)2Cl]2, [Rh(COE)2OH]2, or a combination thereof.

5. The method according to claim 1, characterized in that The diazo compound has a structure as shown in compound 1: in: R 1 is substituted or unsubstituted C 6-30 Aryl, or substituted or unsubstituted 5-7 membered heteroaryl; R 2 is substituted or unsubstituted C 6-30 Aryl; preferably substituted or unsubstituted phenyl; More preferably, the diazo compound 1 is selected from the following group:

6. The method according to claim 1, characterized in that The oxime compound has a structure as shown in compound 2: in: R 3 is substituted or unsubstituted C 6-30 Aryl; R 4 is hydrogen; Preferably, the oxime compound is 4-methylbenzoyl oxime, benzoyl oxime, 4-fluorobenzoyl oxime, 4-chlorobenzoyl oxime, 4-bromobenzoyl oxime, 4-trifluoromethylbenzoyl oxime, 3-methylbenzoyl oxime, 2-methylbenzoyl oxime, 2-fluorobenzoyl oxime, 1-naphthoyl oxime, or 2-naphthoyl oxime.

7. The method according to claim 1, characterized in that The method further comprises one or more features selected from the group consisting of: Based on the amount of the diazo compound 1, the amount of the oxime compound 2 is 100 mol% to 300 mol%; Based on the amount of the diazo compound 1, the amount of the monovalent rhodium metal catalyst is 0.1 to 8 mol%; Based on the amount of the diazo compound 1, the amount of the chiral diene ligand is 0.1 to 10 mol%.

8. The method according to claim 1, characterized in that The method further comprises one or more features selected from the group consisting of: (1) The reaction is carried out in an organic solvent. Preferably, the organic solvent is selected from the group consisting of dichloromethane, dichloroethane, ether, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, or a combination thereof; (2) The reaction is carried out in the presence of an additive, preferably, the additive is a compound selected from the group consisting of HCl, H2SO4, H3PO4, CH3COOH, Et3N·3HCl, Et3N·3HF, Et3N·HBr, or a combination thereof; more preferably, the additive is used in an amount of 50 mol% to 500 mol%, based on the amount of the diazo compound 1; (3) The reaction temperature is 0 to 60°C; (4) The reaction time is 1 to 24 hours.

9. The method according to claim 1, characterized in that The oxime ether compound is selected from the following group:

10. An oxime ether compound selected from the group consisting of:

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