Chiral annular nitrone and preparation method thereof

Abstract

The invention provides chiral annular nitrone and a preparation method thereof, and belongs to the technical field of organic synthetic chemistry. The method comprises the following steps: by taking alkenyl oxime and aryl halide as raw materials, adding a palladium catalyst, a chiral ligand and alkali, then adding an organic solvent under the protection of inert gas, and reacting at 50-100 DEG C for 12-24 hours. And after the reaction is finished, carrying out silica gel column chromatography separation to obtain the chiral annular nitrone. According to the invention, the palladium catalyst is combined with the chiral ligand to realize intermolecular cyclization of alkenyl oxime and aryl halide to generate chiral annular nitrone. The reaction enantioselectivity is good, generation of a Heck product and an oxygen heterocyclic ring product oxime ether is avoided, the highest yield can reach 90%, the highest ee value can reach 98%, the conditions are mild, the yield is high, and the method has a very good application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a chiral cyclic nitrone and a preparation method thereof. Background Art

[0002] Nitrones are a class of compounds containing nitrogen-oxygen dipole structures. As 1,3-dipole reagents in organic synthesis, nitrones can undergo intramolecular or intermolecular cycloaddition reactions to form C-C and C-O bonds, introducing multiple stereoselective chiral centers. Nitrones also possess lipid-lowering, antioxidant, and anti-free radical properties in medicine. In chemistry, they can serve as free radical scavengers and therapeutic agents. Cyclic nitrones, a major class of nitrone compounds, are not only key building blocks in natural products but also play an important role in synthetic and medicinal chemistry. Cyclic nitrones are widely found in biologically active natural products and serve as intermediates in the synthesis of biologically active compounds. Nitrones are also widely used as free radical scavengers in biochemical reactions, as biological reagents, and as intermediates for certain nitrogen heterocyclic structures.

[0003] Although cyclic nitrone has a wide range of applications, so far, there are few reports on the synthesis of chiral cyclic nitrone, especially the method of catalytic synthesis of chiral nitrone is very lacking. In 1999, the Goti group first reported the synthesis of chiral cyclic nitrone. Although the corresponding nitrone yield was only 25% and the ee value was only 36%, it was of great significance to the development of the synthesis of chiral cyclic nitrone [Cicchi Stefano, Francesca Cardona, Alberto Brandi, Massiom Corsi, Andre Goti, Tetrahedron Letters, 1999, 40, 1989-1992.]. In 2019, the research groups of Zhao Jinbo and Zhang Qian reported the copper-catalyzed Cope-type non-activated olefin hydroamination reaction to generate cyclic nitrone. In this catalytic system, the copper catalyst has poor control over the enantioselectivity of the reaction, but it provides important reference for the asymmetric synthesis of cyclic nitrones [Meng-RuZhang, Shuang Liu, He-Xin Li, Na Li, Mei-Hui Guan and Mehfooz Haroon, Chemistry–A European Journal, 2019, 25(54): 12620-12627.]. In 2021, the Carreira group reported a highly enantioselective and chemoselective iridium-catalyzed N-allylation reaction of oximes to synthesize chiral cyclic nitrones. The reaction has good substrate universality and high ee value, and the authors synthesized the marine natural product (+)-halichlorine through this reaction form [Sandmeier T, Carreira E M. Angewandte Chemie International Edition, 2021, 60(18): 9913-9918.].

[0004] In summary, the palladium-catalyzed cyclization of alkenyl oximes to chiral cyclic nitrones is an important area of research in synthetic chemistry. Current progress is limited to unimolecular reactions, but achieving two-component reactions through coupling reactions could significantly improve synthetic efficiency. However, a literature review reveals no reports of two-component reactions for the catalytic synthesis of chiral cyclic nitrones. Developing efficient synthetic strategies for chiral cyclic nitrones remains a challenging yet significant task. Summary of the Invention

[0005] The present invention aims to provide a chiral cyclic nitrone and a preparation method thereof. The method uses readily available alkenyl oxime and aryl halide as starting materials, and through the regulation of enantioselectivity by different chiral ligands, the chiral cyclic nitrone is prepared with good yield and excellent enantioselectivity.

[0006] In order to achieve the above purpose, the following technical solutions are adopted:

[0007] The present invention first provides a chiral cyclic nitrone, the structural formula of which is shown in Formula 7:

[0008]

[0009] In formula 7, A 1 A is selected from phenyl, 4-chlorophenyl, 4-methoxyphenyl, biphenyl, 3,5-dimethylphenyl, ethyl, naphthyl or benzyl; 2 A is selected from methyl, cyclopentyl, phenyl or allyl; 3 A is selected from methyl, cyclopentyl, phenyl or allyl; 4 Any one of the following atoms or groups: carbon, oxygen or ethyl, A 8 Any one selected from the following groups: hydrogen, 4-chloro, 4-fluoro, 4-ester, 4-trifluoromethyl, 4-methoxy, 4-dimethylamino, 3,5-dimethoxy, 3,5-di-tert-butyl-4-methoxy, estrone or 2-methylformyl.

[0010] Preferably, the structural formula of the chiral cyclic nitrone is as follows:

[0011]

[0012] The present invention also provides a method for preparing a chiral cyclic nitrone, which comprises dissolving a palladium catalyst, a chiral ligand, and a base in an organic solvent in an inert atmosphere to carry out an amine palladium reaction, thereby converting an alkenyl oxime and an aryl (pseudo) halide into a chiral cyclic nitrone.

[0013] The structural formula of the alkenyl oxime is shown in Formula 1-3:

[0014]

[0015] In formula 1, A 1 A is selected from phenyl, 4-chlorophenyl, 4-methoxyphenyl, biphenyl, 3,5-dimethylphenyl, ethyl, naphthyl or benzyl; 2 A is selected from methyl, cyclopentyl, phenyl or allyl; 3 A is selected from methyl, cyclopentyl, phenyl or allyl; 4 Any one of the following atoms or groups: carbon, oxygen or ethyl; A 5 A is selected from hydrogen or methyl; 6 is selected from hydrogen or triisopropylsilyl;

[0016] Preferably, the structural formula of the alkenyl oxime is as follows:

[0017]

[0018] The aryl (pseudo) halide is 6-bromoquinoline, 6-bromobenzofuran, methyl o-bromobenzoate, 1-bromopyrene, (bromoethynyl)benzene or the structure shown in Formula 4:

[0019]

[0020] In formula 4, A 7 Selected from iodine or bromine, A 8 Any one selected from the following groups: hydrogen, 4-chloro, 4-fluoro, 4-ester, 4-trifluoromethyl, 4-methoxy, 4-dimethylamino, 3,5-dimethoxy, 3,5-di-tert-butyl-4-methoxy, estrone or 2-methylformyl;

[0021] Preferably, the structure of the aryl (pseudo) halide is as follows:

[0022]

[0023] The chiral ligand is a chiral tert-butylsulfenylamide phosphine ligand (SadPhos) or a chiral tert-butylsulfenylamide phosphine ligand based on a XantPhos skeleton, and the structural formula is shown in Formula 5-6:

[0024]

[0025] In formula 5, R 1 is selected from hydrogen or methoxy; R 2 R is selected from hydrogen, 3-phenyl, 4-phenyl, 3,5-diphenyl, 3,5-di-tert-butyl-4-methoxy, 3,5-di-tert-butyl-4-butoxy, or the N-α aromatic substituent is 9-phenanthrenyl, 1-naphthyl or 2-naphthyl; 3 is selected from hydrogen, methyl, n-butyl or cyclopropyl; R 4 Selected from diphenylphosphine, dicyclohexylphosphine, diadamantylphosphine or di-tert-butylphosphine;

[0026]

[0027] In formula 6: R 5 is selected from hydrogen, 3-phenyl, 4-phenyl, 3,5-diphenyl, 3,5-di-tert-butyl-4-methoxy, 3,5-di-tert-butyl-4-butoxy, or R 5 The N-α aromatic substituent is 9-phenanthrenyl, 1-naphthyl, 2-naphthyl or 9-phenanthrenyl; R 6 is selected from hydrogen or methyl; R 7 Selected from diphenylphosphine, dicyclohexylphosphine, diadamantylphosphine or di-tert-butylphosphine.

[0028] Preferably, the structural formula of the chiral ligand is as shown in Formula L1-L4:

[0029]

[0030] Preferably, the palladium catalyst is: palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium or bis(dibenzylideneacetone)palladium.

[0031] Preferably, the base is cesium carbonate, cesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium tert-butoxide or sodium methoxide.

[0032] Preferably, the organic solvent is tetrahydrofuran, diethyl ether, methyl tert-butyl ether, toluene, n-hexane or 1,4-dioxane.

[0033] Preferably, the molar ratio of the alkenyl oxime to the aryl (pseudo) halide is 1:(1.2-3).

[0034] Preferably, the amount of the palladium catalyst is 2.5%-10% of the molar amount of alkenyl oxime, the amount of the chiral ligand is 6%-20% of the molar amount of alkenyl oxime, and the amount of the base is 1-3 times the molar amount of alkenyl oxime.

[0035] Preferably, the reaction temperature is 50-100° C., and the reaction time is 8-72 h.

[0036] Beneficial effects of the present invention

[0037] The present invention provides a chiral cyclic nitrone and a preparation method thereof. The method is to use alkenyl oxime and aryl (pseudo) halide as raw materials, add a palladium catalyst, a chiral ligand, and a base, and then add an organic solvent under the protection of an inert gas to react to obtain a chiral cyclic nitrone. The present invention combines the palladium catalyst with the chiral ligand to achieve intermolecular cyclization of alkenyl oxime and aryl halide to generate a chiral cyclic nitrone. Compared with the prior art, the reaction conditions of the present invention are mild. The catalyst, chiral ligand, base, and solvent in the reaction conditions are all commercially available. The reaction process is an intermolecular cyclization reaction of alkenyl oxime and aryl halide, with a wide substrate universality, a high reaction yield, and excellent enantioselectivity. In the reaction, there is no generation of competitive reaction products, multi-substituted olefins (Heck products) and oxime ethers (carbon etherification products), and the yield can reach up to 90%, and the ee value can reach up to 98%. In addition, the nitrone obtained by the reaction can be converted into a pharmaceutically active nitrogen heterocyclic intermediate through a classic reduction reaction, which has reference significance for research directions such as chemical and pharmaceutical industries. In summary, the present invention has the advantages of cheap and readily available raw materials, mild reaction conditions, simple process operation, good enantioselectivity, and high reaction yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 11 is the hydrogen spectrum of the nitrone product obtained in Example 1;

[0039] Figure 2 This is the carbon spectrum of the nitrone product obtained in Example 1;

[0040] Figure 3 1 is the HPLC analysis spectrum of the nitrone product obtained in Example 1;

[0041] Figure 4 1 is the hydrogen spectrum of the nitrone product obtained in Example 2;

[0042] Figure 5 This is the carbon spectrum of the nitrone product obtained in Example 2;

[0043] Figure 6 1 is the HPLC analysis spectrum of the nitrone product obtained in Example 2;

[0044] Figure 7 is the hydrogen spectrum of the nitrone product obtained in Example 3;

[0045] Figure 8 This is the carbon spectrum of the nitrone product obtained in Example 3;

[0046] Figure 9 1 is the HPLC analysis spectrum of the nitrone product obtained in Example 3;

[0047] Figure 10 1 is the hydrogen spectrum of the nitrone product obtained in Example 4;

[0048] Figure 11 This is the carbon spectrum of the nitrone product obtained in Example 4;

[0049] Figure 12 4 is the HPLC analysis spectrum of the nitrone product obtained in Example 4;

[0050] Figure 13 is the hydrogen spectrum of the nitrone product obtained in Example 5;

[0051] Figure 14 This is the carbon spectrum of the nitrone product obtained in Example 5;

[0052] Figure 15 1 is the HPLC analysis spectrum of the nitrone product obtained in Example 5;

[0053] Figure 16 1 is the hydrogen spectrum of the nitrone product obtained in Example 6;

[0054] Figure 17 This is the carbon spectrum of the nitrone product obtained in Example 6;

[0055] Figure 18 HPLC analysis spectrum of the nitrone product obtained in Example 6;

[0056] Figure 19 is the hydrogen spectrum of the nitrone product obtained in Example 7;

[0057] Figure 20 This is the carbon spectrum of the nitrone product obtained in Example 7;

[0058] Figure 21 HPLC analysis spectrum of the nitrone product obtained in Example 7;

[0059] Figure 22 is the hydrogen spectrum of the nitrone product obtained in Example 8;

[0060] Figure 23 This is the carbon spectrum of the nitrone product obtained in Example 8;

[0061] Figure 24 HPLC analysis spectrum of the nitrone product obtained in Example 8;

[0062] Figure 25 1 is the hydrogen spectrum of the nitrone product obtained in Example 9;

[0063] Figure 26 This is the carbon spectrum of the nitrone product obtained in Example 9;

[0064] Figure 27 1 is the HPLC analysis spectrum of the nitrone product obtained in Example 9;

[0065] Figure 28 1 is the hydrogen spectrum of the nitrogen heterocyclic product obtained in Example 10;

[0066] Figure 29 This is the carbon spectrum of the nitrogen heterocyclic product obtained in Example 10;

[0067] Figure 30 1 is the HPLC analysis spectrum of the nitrogen heterocyclic product obtained in Example 10;

[0068] Figure 31 1 is the hydrogen spectrum of the nitrogen heterocyclic product obtained in Example 11;

[0069] Figure 32 This is the carbon spectrum of the nitrogen heterocyclic product obtained in Example 11;

[0070] Figure 33 This is the HPLC analysis spectrum of the nitrogen heterocyclic product obtained in Example 11. DETAILED DESCRIPTION

[0071] In order to make the creative features, technical means and purpose of the present invention easier to understand, the present invention is further described below in conjunction with specific embodiments. The following specific description is illustrative rather than restrictive and should not be used to limit the scope of protection of the present invention.

[0072] Example 1. Synthesis of Chiral Five-membered Ring Nitrones (I)

[0073] Alkenyl oxime (48.7 mg, 1.0 equiv.), p-chlorobromobenzene (45.9 mg, 1.2 equiv.), bis(dibenzylideneacetone)palladium (5.7 mg, 5 mol%), chiral ligand L1 (7.7 mg, 6 mol%), and cesium carbonate (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the tube was then replaced with argon. Methyl tert-butyl ether (2 mL) was added via syringe under argon. The tube was sealed and reacted at 50°C for 12 h. After the reaction was terminated, the nitrone was isolated by column chromatography in 68% yield and 94% ee.

[0074]

[0075] (R)-1-Benzyl-3-(4-chlorobenzyl)-2-azaspiro[4.4]non-1-ene-2-oxide: yellow solid. 1 H NMR (400MHz, CDCl3) δ7.29-7.24(m,4H),7.24-7.17(m,3H),7.17-7.09(m,2H),4.41-4.17(m,1H),3.89(d,J=14.3Hz,1H),3.61(d,J=14.4H z,1H),3.31(dd,J=13.8,3.4Hz,1H),3.16(dd,J=13.7,7.7Hz,1H),1.97(dd,J=12.8,8.3Hz,1H),1.86(d,J=18.4Hz,1H),1.75-1.36(m,8H); 13 C NMR (101MHz, CDCl3) δ151.07,136.44,134.95,132.62,131.19,128.74,128.60,128.52,126.6 3,70.94,52.89,38.02,37.52,36.91,36.59,30.25,24.02,23.62; HRMS(ESI-TOF)(m / z):Calcd for C 22 H 25 ClNO + ([M+H] + ), 354.1620; found 354.1622; HPLCconditions: Daicel Chiralpak AD-H, Hex / i-PrOH=85 / 15, 0.8·mL / min; t R =15.3min(minor);16.6min(major).[α]D 24 =-3.7 (c = 0.3, CHCl3), such as Figure 1-3 shown.

[0076] Example 2. Synthesis of Chiral Five-membered Ring Nitrones (II)

[0077] Alkenyl oxime (48.7 mg, 1.0 equiv.), p-chlorobromobenzene (45.9 mg, 1.2 equiv.), bis(dibenzylideneacetone)palladium (5.7 mg, 5 mol%), chiral ligand L1 (7.7 mg, 6 mol%), and cesium carbonate (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the tube was then replaced with argon. Methyl tert-butyl ether (2 mL) was added via syringe under argon. The tube was sealed and reacted at 60°C for 12 h. After the reaction was terminated, the nitrone was isolated by column chromatography in an overall yield of 59.3%, a 1.2 / 1 dr, 70% ee, and >99% ee.

[0078]

[0079] (2R,4S)-4-Allyl-2-(4-chlorobenzyl)-5-ethyl-4-phenyl-3,4-dihydropyrrole-1-oxide: yellow oily liquid. 1 H NMR (400MHz, CDCl3) δ7.37-7.23(m,14H),7.22-7.13(m,11H),6.56(dd,J=6.2,2.7Hz,2H),5.72(dt,J=16.3,9.1Hz,1H),5.39-5.26(m,3H) ,5.22(dd,J=20.4,7.8Hz,1H),5.09-4.93(m,4H),4.41(dd,J=7.0,3.7Hz,2H),4.30(s,1H),3.58(dd,J=13.9,5.9Hz,1H),3.32(dd,J=13.8, 7.1Hz,2H),3.23(dd,J=13.8,3.7Hz,2H),2.97(dd,J=13.9,3.5Hz,1H),2.75(dd,J=11.8,5.8Hz,1H),2.68(dd,J=14.9,8.1Hz,2H),2.44-2 .30(m,4H),2.30-2.17(m,4H),2.13(dd,J=14.3,5.7Hz,2H),2.05(dd,J=13.5,8.6Hz,3H),1.96(dd,J=13.6,8.3Hz,1H),1.04-0.93(m,8H); 13C NMR (101MHz, CDCl3) δ152.85,152.70,144.31,143.94,134.69,134.31,132.85 ,132.81,132.67,132.54,131.94,131.35,128.84,128.63,128.55,128.40,127 .17,126.97,126.26,125.75,120.16,119.43,70.94,70.86,53.38,52.97,41.1 0,40.25,36.94,36.42,35.98,35.92,19.30,8.98; HRMS(ESI-TOF)(m / z):Calcd for C 22 H 25 ClNO + ([M+H] + ), 354.1620; found 354.1618; HPLCconditions: Daicel Chiralpak OD-H, Hex / i-PrOH=95 / 5, 0.4·mL / min; minordiastereomer:t R =27.69min(major),29.36min(minor); major diastereomer:t R =36.67min(major),53.09min(minor). Figure 4-6 shown.

[0080] Example 3. Synthesis of Chiral Five-membered Ring Nitrones (III)

[0081] Silane-protected alkenyl oxime (74.7 mg, 1.0 equiv.), iodobenzene (94.2 mg, 3 equiv.), bis(dibenzylideneacetone)palladium (5.7 mg, 5 mol%), chiral ligand L1 (7.7 mg, 6 mol%), and cesium fluoride (45.6 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the reaction tube was then replaced with argon. Tetrahydrofuran (2 mL) was added via syringe under argon, and the reaction tube was sealed and reacted at 60°C for 72 h. After the reaction was terminated, the nitrone was isolated by column chromatography in 87% yield and 98% ee.

[0082]

[0083] (R)-2-Benzyl-2,4,4-trimethyl-5-phenyl-3,4-dihydro-2H-pyrrole-1-oxide: white solid. 1HNMR (400MHz, CDCl3) δ7.62(d,J=7.0Hz,2H),7.46-7.35(m,2H),7.34-7.27(m,3H),7.27-7.22(m,1H),3.62(d,J=13.6 Hz,1H),2.60(d,J=13.7Hz,1H),2.15(d,J=13.4Hz,1H),1.84(d,J=13.3Hz,1H),1.67(s,3H),1.26(s,3H),0.54(s,3H); 13 C NMR (101MHz, CDCl3) δ148.02,136.75,130.58,129.65,129.05,128.36,128.22,128.19 ,126.87,76.21,43.97,43.82,41.39,30.14,28.00,27.63; HRMS(ESI-TOF)(m / z):Calcd for C 22 H 23 ClNO + ([M+H] + ), 294.1853; found 294.1852; HPLC conditions: Daicel Chiralpak AD-H, Hex / i-PrOH=90 / 10, 0.5·mL / min; t R =27.2min(minor);25.7min(major).[α] D 14 =-150.7 (c = 1.0, CHCl3). Figure 7-9 shown.

[0084] Example 4. Synthesis of Chiral Five-Membered Ring Nitrones (IV)

[0085] Alkenyl oxime (40.6 mg, 1.0 equiv.), 1-bromopyrene (67.5 mg, 1.2 equiv.), bis(dibenzylideneacetone)palladium (5.7 mg, 5 mol%), chiral ligand L1 (7.7 mg, 6 mol%), and cesium carbonate (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the tube was then replaced with argon. Methyl tert-butyl ether (2 mL) was added via syringe under argon. The tube was sealed and reacted at 60°C for 12 h. After the reaction was terminated, the nitrone was isolated by column chromatography in 87% yield and 96% ee.

[0086]

[0087] (R)-4,4-Dimethyl-5-phenyl-2-(1-pyrenylmethyl)-3,4-dihydro-2H-pyrrole-1-oxide: colorless oily liquid. 1 H NMR (400MHz, CDCl3) δ8.44(d,J=9.3Hz,1H),8.19-8.05(m,4H),7.98(d,J=5.7Hz,2H),7.93(dd,J=13.3,7.3Hz,4H),7.45(t,J=7. 4Hz,2H),7.39(t,J=7.3Hz,1H),4.86-4.43(m,2H),3.48(dd,J=13.4,9.2Hz,1H),1.86(d,J=8.1Hz,2H),1.18(s,3H),1.13(s,3H); 13 C NMR (101MHz, CDCl3) δ148.16,131.16,131.04,130.65,130.33,129.42,129.16,128.91,128.24,128.18,128.05,127.79,127.25,1 26.97,125.86,125.02,124.93,124.91,124.64,123.12,71.64,42.92,41.16,35.78,27.95,26.72; HRMS(ESI-TOF)(m / z):Calcdfor C 29 H 26 NO + ([M+H] + ), 404.2009; found 404.2010; HPLC conditions: Daicel Chiralpak AD-H, Hex / i-PrOH=80 / 20, 0.8·mL / min; t R =13.8min(minor);16.3min(major);[α] D 24 =-144.9 (c = 1.0, CHCl3). Figure 10-12 shown.

[0088] Example 5. Synthesis of Chiral Five-Membered Ring Nitrones (V)

[0089] Alkenyl oxime (40.8 mg, 1.0 equiv.), (bromoacetyl)benzene (72.4 mg, 2 equiv.), bis(dibenzylideneacetone)palladium (5.7 mg, 5 mol%), chiral ligand L2 (7.0 mg, 6 mol%), and cesium carbonate (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the reaction tube was then replaced with argon. Hexane (2 mL) was added via syringe under argon, and the tube was sealed and reacted at 50°C for 24 h. After the reaction was terminated, the nitrone was isolated by column chromatography in an 11% yield and 85% ee.

[0090]

[0091] (R)-4,4-Dimethyl-5-phenyl-2-(3-phenylprop-2-yn-1-yl)-3,4-dihydro-2H-pyrrole-1-oxide: yellow oily liquid. 1 H NMR(400MHz, CDCl3) δ7.89(d,J=7.1Hz,2H),7.51-7.32(m,5H),7.28(d,J=2.2Hz,3H),4.41(dd,J=9.6,4.1Hz,1 H),3.18(d,J=5.4Hz,2H),2.33(dd,J=12.8,8.0Hz,1H),2.17(dd,J=12.7,9.0Hz,1H),1.45(s,3H),1.37(s,3H); 13 C NMR (101MHz, CDCl3) δ148.84,131.60,129.53,128.92,128.31,128.28,128.20,127.93,12 3.26,84.60,83.35,69.03,43.14,40.55,28.11,27.48,23.52; HRMS(ESI-TOF)(m / z):Calcd forC 21 H 22 NO + ([M+H] + ), 304.1696; found 304.1699; HPLC conditions: Daicel Chiralpak AD-H, Hex / i-PrOH=80 / 20, 0.5·mL / min; t R =19.53min(minor);17.91min(major).[α] D 21 =-26.5 (c = 0.3, CHCl3). Figure 13-15 shown.

[0092] Example 6. Synthesis of Chiral Six-membered Ring Nitrones (VI)

[0093] Alkenyl oxime (43.4 mg, 1.0 equiv.), p-chlorobromobenzene (57.4 mg, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium (7.3 mg, 4 mol%), chiral ligand L3 (16.6 mg, 10 mol%), and cesium carbonate (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the reaction tube was then replaced with argon. Diethyl ether (2 mL) was added via syringe under argon, and the reaction tube was sealed and reacted at 80°C for 12 h. After the reaction was terminated, the nitrone was isolated by column chromatography in 90% yield and 90% ee.

[0094]

[0095] (S)-2-(4-Chlorobenzyl)-5,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine-1-oxide: white solid. 1 H NMR (400MHz, CDCl3) δ7.48-7.41(m,2H),7.41-7.34(m,1H),7.34-7.28(m,2H),7.28-7.21(m,2H),7.17-7.11(m,2H),4.17-4.07(m,1H) ),3.41(dd,J=13.4,7.9Hz,1H),3.31(dd,J=13.4,3.2Hz,1H),2.02(m,1H),1.94-1.81(m,1H),1.66(m,1H),1.03(s,3H),0.91(s,3H); 13 C NMR (101MHz, CDCl3) δ153.58,135.73,133.69,132.58,131.29,128.50,128.37,128.07 ,127.99,68.09,37.66,36.92,32.47,28.27,27.38,22.47; HRMS(ESI-TOF)(m / z):Calcd for C 20 H 23 ClNO + ([M+H] + ), 328.1463; found 328.1472; HPLC conditions: DaicelChiralpak AD-H, Hex / i-PrOH=80 / 20, 0.8mL / min; t R =8.6min(minor);9.9min(major);[α] D23 =-128.8 (c = 1.0, CHCl3). Figure 16-18 shown.

[0096] Example 7. Synthesis of Chiral Six-membered Ring Nitrones (VII)

[0097] Alkenyl oxime (40.4 mg, 1.0 equiv.), p-chlorobromobenzene (57.4 mg, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium (7.3 mg, 4 mol%), chiral ligand L4 (14.8 mg, 10 mol%), and cesium carbonate (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the reaction tube was then replaced with argon. Diethyl ether (2 mL) was added via syringe under argon, and the reaction tube was sealed and reacted at 100°C for 12 h. After the reaction was terminated, the nitrone was isolated by column chromatography in 85% yield and 84% ee.

[0098]

[0099] (R)-3-(4-Chlorophenyl)-6,6-dimethyl-5-phenyl-3,6-dihydro-2H-1,4-oxazine-4-oxide: yellow solid. 1 H NMR (400MHz, CDCl3) δ7.50-7.38(m,3H),7.36-7.21(m,6H),4.06(dd,J=12.6,3.2Hz,1H),3.99-3.91(m,1H),3.8 3(dd,J=12.6,2.5Hz,1H),3.47(dd,J=13.3,3.2Hz,1H),3.31(dd,J=13.2,9.7Hz,1H),1.39(s,3H),1.26(s,3H); 13 C NMR (101MHz, CDCl3) δ149.15,135.26,132.87,132.15,131.13,128.91,128.74,128 .72,128.33,76.10,67.47,60.08,35.86,27.01,24.75; HRMS(ESI-TOF)(m / z):Calcd for C 19 H 21 ClNO2 + ([M+H] + ), 330.1256; found 330.1250; HPLC conditions: Daicel Chiralpak AD-H, Hex / i-PrOH=80 / 20, 0.8·mL / min; t R=11.1min(minor);15.8min(major).[α] D 24 =61.2(c=1.0,CHCl3). Figure 19-21 shown.

[0100] Example 8. Synthesis of Chiral Six-Membered Ring Nitrones (VIII)

[0101] Alkenyl oxime (85.9 mg, 1.0 equiv.), p-chlorobromobenzene (57.4 mg, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium (7.3 mg, 4 mol%), chiral ligand L3 (16.6 mg, 10 mol%), and cesium carbonate (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the reaction tube was then replaced with argon. Diethyl ether (2 mL) was added via syringe under argon, and the reaction tube was sealed and reacted at 50°C for 24 h. After the reaction was terminated, the nitrone was isolated by column chromatography in a 33% yield and 72% ee.

[0102]

[0103] (R)-5-((tert-Butyldiphenylsilyl)oxy)-3-(4-chlorobenzyl)-6-methyl-3,4-dihydroisoquinoline-2-oxide: yellow oily liquid. 1 H NMR (400MHz, CDCl3) δ7.70-7.50(m,5H),7.49-7.37(m,2H),7.37-7.23(m,4H),7.17(d,J=8.1Hz,2H),6.95(dd,J=15.3,7.9Hz,3H),6.68(d,J=7 .6Hz,1H),3.78(dd,J=9.6,4.5Hz,1H),3.11(dd,J=13.4,3.9Hz,1H),2.77-2.62(m,2H),2.57(dd,J=16.8,6.2Hz,1H),2.07(s,3H),1.01(s,9H); 13 C NMR (101MHz, CDCl3) δ151.66,134.92,133.65,133.21,132.57,131.21,130.70,130.35,130.06,128.67,127.7 4,127.72,127.24,119.00,118.68,68.32,35.65,27.05,26.65,19.99,19.34; HRMS(ESI-TOF)(m / z):Calcdfor C 33 H 35 ClNO2Si+ ([M+H] + ),540.2121; found540.2123; HPLC conditions: DaicelChiralpak AD-H, Hex / i-PrOH=80 / 20, 0.8mL / min; t R =6.5min(minor);7.2min(major).[α] D 24 =28.8(c=1.0,CHCl3). Figure 22-24 shown.

[0104] Example 9 Synthesis of Chiral Six-membered Ring Nitrones (IX)

[0105] Alkenyl oxime (48.9 mg, 1.0 equiv.), p-chlorobromobenzene (57.4 mg, 1.5 equiv.), Pd(dba) (7.3 mg, 4 mol%), L3 (16.6 mg, 10 mol%), and CsCO (78.2 mg, 1.2 equiv.) were weighed and added to a 25 mL sealed tube. The air in the tube was then replaced with argon. EtO (2 mL) was added via syringe under argon, and the tube was sealed and reacted at 50°C for 24 h. After the reaction was terminated, the nitrone was isolated by column chromatography in 88% yield and 64% ee.

[0106]

[0107] (R)-3-(4-Chlorobenzyl)-8-methoxy-1-methyl-3,4-dihydropyrazino[1,2-a]indole-2-oxide: yellow oily liquid. 1 H NMR (400MHz, CDCl3) δ7.29 (d, J = 8.3Hz, 2H), 7.14-7.00 (m, 4H), 7.00-6.93 (m, 1H), 6.62 (s, 1H), 4.51-4. 27(m,1H),4.07(s,2H),3.86(s,3H),3.49(dd,J=13.3,3.7Hz,1H),2.82(t,J=12.2Hz,1H),2.46(s,3H); 13C NMR (101MHz, CDCl3) δ154.73,136.50,134.46,133.22,132.63,130.78,130.74,129.21,129.00, 114.91,109.36,102.63,102.16,69.21,55.68,41.11,35.67,13.47; HRMS(ESI-TOF)(m / z):Calcd for C 20 H 20 Cl2NO2 + ([M+H] + ), 355.1208; found 355.1206; HPLC conditions: Daicel Chiralpak OD-H, Hex / i-PrOH=80 / 20, 0.8mL / min; t R =22.2min(minor);18.2min(major).[α] D 25 =-26.8 (c = 1.0, CHCl3). Figures 25-27 shown.

[0108] Example 10 Synthesis of Chiral Six-membered Cyclic Imine (X)

[0109] (S)-2-(4-chlorobenzyl)-5,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine-1-oxide (98.4 mg, 1.0 equiv.) was weighed and added to a 100 mL eggplant-shaped flask. MeOH (10 mL) and TiCl₃ (115.7 mg, 0.75 mmol, 2.5 equiv., 15.0-20.0 wt% TiCl₃ in 30% HCl) were then added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the imine was isolated by column chromatography in 81% yield and 90% ee.

[0110]

[0111] (S)-2-(4-chlorophenyl)-5,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine: colorless oily liquid 1HNMR (400MHz, CDCl3) δ7.32(t,J=6.5Hz,3H),7.25(t,J=6.8Hz,4H),7.18(d,J=8.3Hz,2H),3.90-3.62(m,1H),3.22(dd,J=13.3, 4.3Hz,1H),2.73(dd,J=13.3,9.0Hz,1H),1.70-1.60(m,1H),1.57(t,J=5.4Hz,2H),1.48-1.34(m,1H),1.06(s,3H),1.04(s,3H); 13 C NMR (101MHz, CDCl3) δ176.34,141.28,137.91,131.74,130.92,128.08,127.71,1 27.41,59.95,42.77,35.67,35.50,28.22,27.23,23.74; HRMS(ESI)(m / z):Calcd for C 20 H 23 C1N + ([M+H] + ), 312.1514; found 312.1514; HPLC conditions: Daicel Chiralpak OD-H, Hex / i-PrOH = 97 / 3, 0.5·mL / min; tr = 10.2 min (minor); 10.9min (major).[α] D 25 =-69.7 (c = 1.0, CHCl3). Figures 28-30 shown.

[0112] Example 11 Synthesis of Chiral Six-membered Cyclic Imine (XI)

[0113] (S)-2-(4-chlorophenyl)-5,5-dimethyl-6-phenyl-2,3,4,5-tetrahydropyridine (98.4 mg, 1.0 equiv.) was weighed and added to a 25 mL branched reaction tube. The air in the tube was then replaced with argon, and hexane (2 mL) was added via syringe. The mixture was stirred and refrigerated at -78°C. DIBAL-H (3.2 mL, 3.2 mmol, 4 equiv., 1 M in hexane) was then slowly added dropwise via syringe under argon. After the reaction was completed, the reaction was quenched with EA, the liquid phases were separated, washed, dried, and concentrated, and the crude cyclic amine was directly used for the next reaction.

[0114] NaH (24 mg, 0.6 mmol, 1.5 equiv., 60% in kerosene) was weighed and added to a 25 mL branched reaction tube. The air in the reaction tube was then replaced with argon, and THF (5 mL) was added via syringe. The mixture was stirred and refrigerated at 0°C. The crude cyclic amine (125.5 mg, 0.4 mmol, 1 equiv.) dissolved in THF (3 mL) was then slowly added dropwise under argon via syringe. After 1 hour, (Boc)2O (174.6 mg, 0.8 mmol, 2 equiv.) was added to the reaction tube. After completion of the reaction, the nitrogen heterocyclic product was isolated by column chromatography in 70% yield and 91% ee.

[0115]

[0116] Tert-Butyl (2R, 6S)-6-(4-chlorophenyl)-3,3-dimethyl-2-phenylpiperidin-1-carbonate: colorless oily liquid. 1 H NMR (400MHz, CDCl3) δ7.34-7.17(m,7H),7.12(d,2H),3.37(s,1H),2.91-2.77(m,1H),2. 77-2.66(m,1H),2.68-2.54(m,1H),1.52(s,6H),1.48(s,3H),0.84(s,3H),0.72(s,3H); 13 C NMR (101MHz, CDCl3) δ146.68,142.11,137.79,131.81,130.48,128.59,128.41,127.33,126.79 ,85.07,70.79,59.31,43.10,40.45,33.71,29.13,28.77,27.34,19.36; HRMS(ESI)(m / z):Calcd for C 25 H 33 ClNO2 + ([M+H] + ), 414.2195; found 414.2203; HPLC conditions: Daicel Chiralpak OD-H, Hex / i-PrOH=95 / 5, 0.8·mL / min; tr=5.9min (minor); 5.1min (major).[α] D 18 =37.6(c=1.0,CHCl3). Figures 31-33 shown.

[0117] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the appended claims.

Claims

1. A chiral cyclic nitrone, characterized in that The structural formula is shown in Formula 7: In formula 7, A 1 A is selected from phenyl, 4-chlorophenyl, 4-methoxyphenyl, biphenyl, 3,5-dimethylphenyl, ethyl, naphthyl or benzyl; 2 A is selected from methyl, cyclopentyl, phenyl or allyl; 3 A is selected from methyl, cyclopentyl, phenyl or allyl; 4 Any one of the following atoms or groups: carbon, oxygen or ethyl, A 8 Any one selected from the following groups: hydrogen, 4-chloro, 4-fluoro, 4-ester, 4-trifluoromethyl, 4-methoxy, 4-dimethylamino, 3,5-dimethoxy, 3,5-di-tert-butyl-4-methoxy, estrone or 2-methylformyl.

2. A chiral cyclic nitrone according to claim 1, characterized in that The structural formula of the chiral cyclic nitrone is as follows:

3. The method for preparing a chiral cyclic nitrone according to claim 1, wherein The method comprises the following steps: dissolving a palladium catalyst, a chiral ligand and a base in an organic solvent in an inert atmosphere to carry out an amine palladium reaction, thereby converting an alkenyl oxime and an aryl (pseudo) halide into a chiral cyclic nitrone; The structural formula of the alkenyl oxime is shown in Formula 1-3: In formula 1, A 1 A is selected from phenyl, 4-chlorophenyl, 4-methoxyphenyl, biphenyl, 3,5-dimethylphenyl, ethyl, naphthyl or benzyl; 2 A is selected from methyl, cyclopentyl, phenyl or allyl; 3 A is selected from methyl, cyclopentyl, phenyl or allyl; 4 Any one of the following atoms or groups: carbon, oxygen or ethyl; A 5 A is selected from hydrogen or methyl; 6 is selected from hydrogen or triisopropylsilyl; The aryl (pseudo) halide is 6-bromoquinoline, 6-bromobenzofuran, methyl o-bromobenzoate, 1-bromopyrene, (bromoethynyl)benzene or the structure shown in Formula 4: In formula 4, A 7 Selected from iodine or bromine, A 8 Any one selected from the following groups: hydrogen, 4-chloro, 4-fluoro, 4-ester, 4-trifluoromethyl, 4-methoxy, 4-dimethylamino, 3,5-dimethoxy, 3,5-di-tert-butyl-4-methoxy, estrone or 2-methylformyl; The chiral ligand is a chiral tert-butylsulfenylamide phosphine ligand (SadPhos) or a chiral tert-butylsulfenylamide phosphine ligand based on a XantPhos skeleton, and the structural formula is shown in Formula 5-6: In formula 5, R 1 is selected from hydrogen or methoxy; R 2 R is selected from hydrogen, 3-phenyl, 4-phenyl, 3,5-diphenyl, 3,5-di-tert-butyl-4-methoxy, 3,5-di-tert-butyl-4-butoxy, or the N-α aromatic substituent is 9-phenanthrenyl, 1-naphthyl or 2-naphthyl; 3 is selected from hydrogen, methyl, n-butyl or cyclopropyl; R 4 Selected from diphenylphosphine, dicyclohexylphosphine, diadamantylphosphine or di-tert-butylphosphine; In formula 6: R 5 is selected from hydrogen, 3-phenyl, 4-phenyl, 3,5-diphenyl, 3,5-di-tert-butyl-4-methoxy, 3,5-di-tert-butyl-4-butoxy, or R 5 The N-α aromatic substituent is 9-phenanthrenyl, 1-naphthyl, 2-naphthyl or 9-phenanthrenyl; R 6 is selected from hydrogen or methyl; R 7 Selected from diphenylphosphine, dicyclohexylphosphine, diadamantylphosphine or di-tert-butylphosphine.

4. The method for preparing a chiral cyclic nitrone according to claim 3, wherein The structural formula of the alkenyl oxime is as follows:

5. The method for preparing a chiral cyclic nitrone according to claim 3, wherein The structure of the aryl (pseudo) halide is as follows:

6. The method for preparing a chiral cyclic nitrone according to claim 3, wherein The structural formulas of the chiral ligands are shown in Formulas L1-L4:

7. The method for preparing a chiral cyclic nitrone according to claim 3, wherein The palladium catalyst is: palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium or bis(dibenzylideneacetone)palladium.

8. The method for preparing a chiral cyclic nitrone according to claim 3, wherein The molar ratio of the alkenyl oxime to the aryl (pseudo) halide is 1:(1.2-3).

9. The method for preparing a chiral cyclic nitrone according to claim 3, wherein The amount of the palladium catalyst is 2.5%-10% of the molar amount of the alkenyl oxime, the amount of the chiral ligand is 6%-20% of the molar amount of the alkenyl oxime, and the amount of the base is 1-3 times the molar amount of the alkenyl oxime.

10. The method for preparing a chiral cyclic nitrone according to claim 3, characterized in that: The reaction temperature is 50-100° C., and the reaction time is 8-72 hours.

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