Method for constructing chiral spiro amine through asymmetric photocatalytic spirocyclization

Abstract

The invention discloses a method for constructing chiral spiro amine through asymmetric photocatalytic spirocyclization, and belongs to the field of organic synthesis. According to the method, a dual-catalyst system consisting of chiral phosphoric acid (CPA) and a fac-Ir (ppy) 3 photosensitizer is adopted, and under the irradiation of visible light, alkenyl sulfonyl oxime I # imgabs0 # and vinyl azide II # imgabs1 # substituted by imine-containing aza-aromatic hydrocarbon are used as raw materials, and are subjected to a one-step synthesis to obtain the chiral chiral aza-aromatic compound. The key innovation of the invention lies in that sulfonyl is adopted to replace a traditional ester group to protect nitrogen atoms of oxime, and the improvement promotes the development of an energy transfer (EnT) mechanism instead of a single electron transfer (SET) mechanism. In this way, the reaction efficiency is remarkably improved, and meanwhile an ideal reaction environment is provided for chiral hydrogen bond catalysis.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for constructing chiral spirocyclic amine by asymmetric photocatalytic spirocyclization. Background Art

[0002] Visible light-driven photocatalytic synthesis has become a powerful tool in the field of free radical chemistry, enabling the efficient construction of complex and valuable molecules. This method has attracted widespread attention due to its reliance on simple starting materials, its ability to achieve efficient transformations under mild reaction conditions, and its excellent compatibility with a variety of functional groups. In particular, chemists have successfully achieved enantiomeric discrimination in a variety of free radical reactions by introducing exogenous chiral catalysts, thereby effectively utilizing photocatalytic synthesis of enantiomerically enriched chiral molecules. As a result, this technology has become an important driving force for the development of synthetic chemistry and pharmacology. However, compared with racemic synthesis methods, research on asymmetric photocatalytic synthesis is still relatively limited, especially in the asymmetric synthesis of spiroquaternary carbon stereocenters, where there is a significant gap in the relevant literature and this goal has not yet been achieved.

[0003] The synthesis of helical chiral molecules has attracted much attention in the past few decades because they are widely present in natural products, bioactive compounds and chiral ligands. The advantages of photocatalytic synthesis have made significant progress in its application in this field. For example, in 2021, Yi, Du, Fu and their team (Qi, Z.; Zhang, Z.; Yang, L.; Zhang, D.; Lu, J.; Wei, J.; Wei, S.; Fu, Q.; Du, X.; Yi, D. Nitrogen-Radical-Triggered Trifunctionalizingipso-Spirocyclization of Unactivated Alkenes with Vinyl Azides: A Modular Access to Spiroaminal Frameworks. Adv. Synth. Catal. 2021, 363, 3762-3768.) reported the successful photoredox-catalyzed trifunctionalization of unactivated alkenyl oxime esters through ipso-spirocyclization with vinyl azides, providing an efficient route for the synthesis of high-value spirocyclic amine derivatives. However, relatively few studies have been conducted on asymmetric reaction systems. One of the main issues is the competitive photocycloaddition of azides with triplet photosensitizers via an energy transfer (EnT) pathway. In addition, after the 5-exo-trig cyclization of nitrogen radical intermediates, these species may undergo single-electron oxidation instead of addition reaction with vinyl azides. These competitive side reactions often result in yields below 50%, which are difficult to improve significantly even after system optimization. Obviously, the stringent reaction conditions required to achieve optimal chemoselectivity make it a major challenge to use exogenous chiral catalysts to achieve high enantioselectivity. The root of this problem lies in the rapid orbital flipping of radicals, which complicates the precise enantioselectivity control that usually relies on specific reaction conditions. In addition, the intrinsic complexity of multi-step cascade radical transformations further hinders chiral catalysts from achieving sufficient enantioselectivity, as multiple reaction intermediates are often present simultaneously in these systems, and the persistent racemic background reaction further weakens the enantioselectivity in these photocatalytic systems. Therefore, these challenges highlight the need for innovative strategies to overcome obstacles and fully explore the potential of asymmetric radical chemistry.

[0004] The research focus of this application is to use azaarenes containing imine groups as substrates to achieve a variety of free radical-based chemical transformations through asymmetric photocatalysis. Azaarene derivatives are widely used in drug synthesis and materials science, especially in ligand design, and have important research value. It is worth noting that many N,N,N-type chiral ligands based on azaarenes have been developed, and these ligands have shown excellent catalytic performance in a variety of important reactions. In this context, this application aims to explore the asymmetric photocatalytic reaction of imine-containing azaarenes substituted olefin sulfonyl oxime I and vinyl azide II. This application not only verifies the feasibility of asymmetric photocatalysis in constructing spiroquaternary carbon stereocenters, but also provides a convenient and modular method to synthesize a new type of N,N,N-type chiral ligands, thereby further enriching the field of asymmetric catalysis. Summary of the invention

[0005] The purpose of the present invention is to provide a method for constructing chiral spirocyclic amine by asymmetric photocatalytic spirocyclization.

[0006] Based on the above purpose, the present invention adopts the following technical solutions:

[0007] A method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization, the synthetic route is as follows:

[0008]

[0009] The alkenylsulfonyl oxime of formula I and the vinyl azide of formula II are added to an organic solvent, and under the action of a photocatalyst fac-Ir(ppy)3, a chiral catalyst C1, a base, and an additive, the reaction is completed by stirring at room temperature under visible light irradiation, and the target chiral spirocyclic amine compound III is obtained by separation and purification; Ar 1 for G 1 H, F, Cl, Br, C1-C4 saturated alkyl, methoxy, CF 3 , Ph, Ar 2 for G 2 Selected from H, F, Cl, Br, C 1 ~C4 saturated alkyl, methoxy, CF 3 、Ph、COOEt、OCF 3 , trimethylsilyl or triphenylsilyl, R is methyl, ethyl, propyl, benzyl or two Rs form a C4-C12 cycloalkyl group,

[0010] Furthermore, the molar ratio of the olefin sulfonyl oxime represented by formula I to the vinyl azide represented by formula II is 1:(2-4), and the photocatalyst fac-Ir(ppy) 3 The amount of the added catalyst is 1 to 5% of the molar amount of the alkenylsulfonyl oxime, and the amount of the added catalyst C1 is 10 to 20% of the molar amount of the alkenylsulfonyl oxime.

[0011] Further, the base is K 2 CO 3 , KHCO 3 and K 3 PO 4 One or a mixture of two or more of the above in any proportion, wherein the amount of the base added is 1 to 3 times the molar amount of the alkenylsulfonyl oxime.

[0012] Furthermore, the additives are KF and water, the amount of KF added is 1 to 2 times the molar amount of alkenylsulfonyl oxime, and the amount of water added per 0.1 mmol of alkenylsulfonyl oxime raw material is 0.025 mL.

[0013] Furthermore, the additive is the organic solvent which is one or a mixture of two or more of dichloromethane, ethylbenzene and t-BuPh in any proportion.

[0014] Furthermore, the visible light is provided by 1 to 2 3W blue LED lamps.

[0015] The chiral spirocyclic amine compound prepared by the above method.

[0016] Specifically, the present application synthesized the following chiral spirocyclic amine compounds:

[0017]

[0018]

[0019]

[0020] The chiral spirocyclic amine compound is used as a chiral ligand in a catalytic reaction, wherein the reaction refers to an asymmetric alkynylation reaction of quinoline described in formula A with phenylacetylene in the presence of CuBr. The specific process is as follows:

[0021]

[0022] The quinoline of formula A and the phenylacetylene of formula B are reacted in the presence of CuBr, isobutyl chloroformate (ClCO 2 iBu), N,N-diisopropylethylamine (DIPEA) and chiral spirocyclic amine 14, dichloromethane was used as solvent, the reaction was stirred at -15 to -25°C until complete, and the target chiral compound C was separated and purified.

[0023] Furthermore, the molar ratio of quinoline to phenylacetylene is (1-2):(1-2), the amount of CuBr added is 4-6% of the molar amount of quinoline, the amount of chiral spirocyclic amine added is 5-6% of the molar amount of quinoline, the amount of isobutyl chloroformate added is 1-1.5 times the molar amount of quinoline, and the amount of N,N-diisopropylethylamine added is 1-1.5 times the molar amount of quinoline.

[0024] In the present application, a series of 1-aryl vinyl azides were reacted with substrate I under given reaction conditions to successfully synthesize a series of pyridine-functionalized spirocyclic amines (3-26) with yields ranging from 43% to 94% and enantiomeric excesses (ee) ranging from 83% to 99%.

[0025] It is noteworthy that the introduction of electron-withdrawing or electron-donating groups at the para-, meta-, or ortho-positions of the vinyl azide aromatic ring (e.g., 4-10 and 11-22) did not significantly affect the enantioselectivity. The lower yields of some products (e.g., 13 and 21) may be attributed to the reduced reactivity of the radical addition to the vinyl azide, as part of the vinyl azide was consumed to form the corresponding aziridine. Importantly, the trimethylsilyl (TMS) group in compound 13 showed remarkable compatibility in the reaction system containing KF. In addition, the high tolerance of the allyl group in compound 20 further highlights the exquisite chemoselectivity of this reaction between different olefins.

[0026] This application also studied some vinyl azides with condensed aromatic rings (23, 24) and heteroaromatic rings (25, 26), and obtained high yields and high ee values, further demonstrating the wide applicability of this method.

[0027] Subsequently, the present application studies the reaction of 1-(1-azidovinyl)-2-bromobenzene with a series of azaarene-substituted 4-(trifluoromethyl)benzenesulfonyl oximes. The reason for choosing this vinyl azide is the challenge of ortho-substitution, which makes it difficult to obtain satisfactory yields and enantioselectivities, and also provides a strong basis for measuring the synthetic diversity of this strategy. In addition, the bromine functional group can be adapted to a variety of subsequent modifications, further enriching the diversity of these important chiral ligands.

[0028] Notably, the introduction of substituents with different electronic properties at the 3-, 4-, 5-, and 6-positions of the 2-pyridine ring of the oxime substrate did not adversely affect the excellent enantioselectivity, and the corresponding products (27-33) were obtained in yields ranging from 56% to 75% with ee values ​​exceeding 90%. More importantly, the pyridine group in the products can be tuned by quinoline (e.g., 34) and isoquinoline (e.g., 35), further broadening the types of these tridentate ligands. In addition, the substituents on the chiral ligand ring can effectively regulate the spatial configuration, which is crucial for the wider application of chiral ligands. In this context, the replacement of the two methyl groups in compound I with various linear alkyl chains (e.g., 36, 37), benzyl groups (e.g., 38), and cyclic structures (e.g., 39-48) gave a series of structurally attractive spirocyclic amines.

[0029] It is worth mentioning that various saturated carbon rings, including four-membered rings (39), five-membered rings (40,41), six-membered rings (42-46), seven-membered rings (47), and twelve-membered rings (48), can be easily constructed in these molecules, and the products can be obtained with satisfactory yields and enantioselectivities.

[0030] Subsequently, the present application evaluated the potential of these nitrogen-based spirocyclic amine products as chiral ligands in metal catalysis to demonstrate the synthetic practicality of the compounds of the present application. The present application studies the asymmetric alkynylation reaction of quinoline A with phenylacetylene in the presence of 5 mol% CuBr. The reaction conditions are 1.0 equivalent of isobutylcarbonochloridate, 1.4 equivalents of N,N-diisopropylethylamine (DIPEA), chiral spirocyclic amine compound 14 as a ligand, and dichloromethane as a solvent, and the reaction is carried out at -20°C. The target product C was successfully obtained with a yield of 56% and an ee of 90%, thereby effectively avoiding the use of the axial chiral P,N ligand (S)-StackPhos, which requires a cumbersome preparation method.

[0031] In summary, this application reports for the first time an asymmetric photocatalytic spirocyclization reaction involving reactions of alkenylsulfonyl oximes and vinyl azides substituted with imine-containing azaarenes. This method successfully synthesized a series of azaarene-functionalized chiral spiroamines with yields up to 94% and enantioselectivities up to 99% ee. The key to the success of this method is the use of sulfonyl as a protecting group for the oxime, making energy transfer an alternative mechanism to initiate the reaction transformation. This strategy not only improves the reaction activity and chemical selectivity, but also creates an optimal environment for enantioselective control. The synthetic significance of this study is further demonstrated by demonstrating the potential of these products as a new class of chiral ligands, and preliminary studies have shown that they have good catalytic effects in asymmetric alkynylation reactions. DETAILED DESCRIPTION

[0032] The present invention is further described in detail below in conjunction with the examples. It should be understood that the examples described in this specification are only for explaining the present invention, not for limiting the present invention, and the parameters, proportions, etc. of the examples can be selected according to local conditions without substantial impact on the results.

[0033] Example 1

[0034] Synthesis of compound 3:

[0035]

[0036] In a 25 mL Schlenk tube, olefin sulfonyl oxime 1 (0.1 mmol, 1.0 equivalent), chiral catalyst C1 (0.015 mmol, 0.15 equivalent), K 2 CO 3 (0.15mmol, 1.5 equivalents), KF (0.1mmol, 1.0 equivalents), water (0.025mL), photocatalyst fac-Ir(ppy)3 (0.002mmol, 0.02 equivalents), 1-(1-azidovinyl)-4-methylbenzene 2 (0.3mmol, 3.0 equivalents) and ethylbenzene (3.0mL). The reaction mixture was degassed three times using a freeze-pump-melt method. The Schlenk tube was then placed about 2.0 cm away from a 3W blue LED (wavelength 445nm) lamp and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure and the target product 3 was purified by flash column chromatography on a silica gel column and gradient elution with petroleum ether / ethyl acetate / tetrahydrofuran (15:1:1 to 10:1:1) to obtain the target product 3 as a white solid with a yield of 70% and 90% ee.

[0037] The NMR data of compound 3 are: 1 H NMR (400 MHz, CDCl 3 )δ8.71–8.55(m,1H),8.16(d,J=7.9Hz,1H),7.76(d,J=8.1Hz,2H),7.70(td,J=7.7,1.8H z,1H),7.30(ddd,J=7.5,4.9,1.2Hz,1H),7.19(d,J=8.0Hz,2H),3.39(dt,J=16.9,8.4Hz ,1H),3.22(ddd,J=12.8,9.7,3.9Hz,2H),2.87(d,J=15.9Hz,1H),2.37(s,3H),2.30(ddd ,J=12.6,8.8,3.5Hz,1H),2.15(ddd,J=13.3,9.3,7.9Hz,1H),1.15(s,3H),1.06(s,3H). 13C NMR (101 MHz, CDCl 3 )δ174.6,174.4,153.6,149.1,140.9,136.2,132.3,129.1,127.9,124.7,122.7,111.2,50.1,45.0,35.3,28.5,25.1,22.0,21.6.

[0038] The synthesis process of compounds 4 to 48 is the same as that of Example 1.

[0039] Example 2

[0040] Compound 11 was a white solid with a yield of 87% and 90% ee.

[0041] The NMR data of compound 11 are: 1 H NMR (600 MHz, CDCl 3 )δ8.64(d,J=4.4Hz,1H),8.16(d,J=7.9Hz,1H),7.87(d,J=7.0Hz,2H),7.68( td,J=7.7,1.7Hz,1H),7.44–7.35(m,3H),7.31–7.27(m,1H),3.40(dt,J=17.0 ,8.4Hz,1H),3.24(ddd,J=15.1,9.6,3.5Hz,2H),2.88(d,J=15.9Hz,1H),2.3 5–2.26(m,1H),2.15(ddd,J=13.3,9.3,8.0Hz,1H),1.17(s,3H),1.07(s,3H); 13 C NMR (101 MHz, CDCl 3 )δ174.8,174.,153.5,149.1,136.2,135.0,130.7,128.4,127.9,124.7,122.7,111.3,50.1,45.0,35.3,28.5,25.1,21.9.

[0042] Example 3

[0043] Compound 14 was a white solid with a yield of 73% and 90% ee.

[0044] The NMR data of compound 14 are: 1 H NMR (600 MHz, CDCl 3)δ8.61–8.44(m,1H),8.11(d,J=7.8Hz,1H),7.63(td,J=7.7,1.7Hz,1H),7. 37(d,J=7.4Hz,1H),7.22(ddd,J=7.4,4.9,1.0Hz,1H),7.20–7.15(m,1H),7. 12(t,J=5.8Hz,2H),3.29–3.15(m,3H),2.66(d,J=16.1Hz,1H),2.42(s,3H) ,2.30–2.19(m,1H),2.05(dt,J=13.1,9.0Hz,1H),1.10(s,3H),1.02(s,3H); 13 C NMR (151 MHz, CDCl 3 )δ177.2,174.9,153.7,149.1,137.0,136.2,135.7,131.1,129.2,128. 7,125.6,124.8,122.7,111.5,53.7,44.8,35.2,28.5,25.1,21.5,21.2.

[0045] Example 4

[0046] Compound 16 was a white solid with a yield of 61% and 90% ee.

[0047] The NMR data of compound 16 are: 1 H NMR (600 MHz, CDCl 3 )δ8.65(d,J=4.7Hz,1H),8.18(d,J=7.9Hz,1H),7.95(d,J=8.3Hz,2H),7.70(td,J=7.7,1.7 Hz,1H),7.63(dd,J=10.1,7.9Hz,4H),7.44(t,J=7.7Hz,2H),7.36(t,J=7.4Hz,1H),7.30(d dd,J=7.3,4.9,0.9Hz,1H),3.42(dt,J=17.0,8.4Hz,1H),3.32–3.21(m,2H),2.92(d,J=15. 9Hz,1H),2.38–2.27(m,1H),2.17(ddd,J=13.3,9.3,8.0Hz,1H),1.19(s,3H),1.09(s,3H); 13 C NMR (151 MHz, CDCl 3)δ174.8,174.3,153.5,149.1,143.5,140.5,136.3,133.9,128.9,128.5,12 7.8,127.2,127.1,124.8,122.7,111.3,50.1,45.1,35.3,28.5,25.2,22.0.

[0048] Example 5

[0049] Compound 23 was a white solid with a yield of 89% and 87% ee.

[0050] The NMR data of compound 23 are: 1 H NMR (600MHz, CD 3 OD)δ8.64(d,J=4.6Hz,1H),8.34(s,1H),8.13(d,J=8.0Hz,1H),8.03(dd,J=8.6,1 .5Hz,1H),7.98(d,J=7.6Hz,1H),7.92–7.88(m,2H),7.86(dd,J=7.8,1.5Hz,1H),7 .55(dq,J=6.8,5.7Hz,2H),7.50–7.42(m,1H),3.49–3.40(m,2H),3.31–3.27(m,1H ),3.17(d,J=16.4Hz,1H),2.30(dt,J=13.8,4.6Hz,2H),1.22(s,3H),1.13(s,3H); 13 C NMR (151 MHz, CD 3 OD)δ178.1,177.3,153.5,150.2,138.1,136.1,134.2,132.6,130.3,129.8,129.2,1 28.6,128.5,127.6,126.6,124.8,123.5,112.4,50.9,45.4,36.3,28.7,25.3,21.5.

[0051] Example 6

[0052] Compound 34 was obtained as a white solid with a yield of 68% and 77% ee.

[0053] The NMR data of compound 34 are: 1 H NMR (400 MHz, CDCl 3)δ8.34(d,J=8.5Hz,1H),8.15(d,J=8.4Hz,2H),7.82(dd,J=8.1,1.1Hz,1H),7.72( ddd,J=8.4,6.9,1.4Hz,1H),7.62–7.50(m,3H),7.31(td,J=7.5,1.2Hz,1H),7.25–7 .18(m,1H),3.55–3.42(m,2H),3.42–3.33(m,1H),3.01(d,J=16.4Hz,1H),2.37(dd d,J=13.1,8.0,3.7Hz,1H),2.19(dt,J=13.2,8.9Hz,1H),1.20(s,3H),1.18(s,3H); 13 C NMR (151 MHz, CDCl 3 )δ177.2,175.9,153.8,147.9,137.9,135.9,133.4,130.6,130.5,130.1,129.5,12 8.7,127.7,127.4,127.4,121.3,120.2,111.2,53.4,45.8,35.2,28.3,24.8,21.8.

[0054] Example 7

[0055] Compound 37 was obtained as a white solid with a yield of 60% and 90% ee.

[0056] The NMR data of compound 37 are: 1 H NMR (400MHz, CD 3 OD)δ8.64(dd,J=4.8,0.7Hz,1H),8.16(d,J=7.9Hz,1H),7.90(ddd,J=7.7,4.6,1.4Hz,1H),7.6 6(d,J=8.0Hz,1H),7.51–7.43(m,2H),7.41(t,J=7.4Hz,1H),7.36–7.29(m,1H),3.30(ddd,J=2 3.0,14.9,11.2Hz,3H),3.11(d,J=17.2Hz,1H),2.42–2.29(m,2H),1.79–1.62(m,3H),1.56–1. 46(m,1H),1.38–1.24(m,3H),1.22–1.11(m,1H),0.96(t,J=7.2Hz,3H),0.85(t,J=7.2Hz,3H); 13 C NMR (151 MHz, CD 3OD)δ179.3,177.1,153.6,150.2,138.1,137.9,134.4,132.1,131.1,128.5,126.6 ,123.6,121.5,112.3,52.5,51.2,36.9,36.8,35.9,30.0,19.4,19.0,15.2,15.2.

[0057] Example 8

[0058] Compound 38 was obtained as a white solid with a yield of 57% and 90% ee.

[0059] The NMR data of compound 38 are: 1 H NMR (600MHz, CD 3 OD)δ8.68–8.64(m,1H),8.28(d,J=7.9Hz,1H),7.93(dt,J=7.8,3.9Hz,1H),7.56(d,J=8.0Hz,1H),7.54 –7.49(m,1H),7.28(d,J=7.7Hz,2H),7.25–7.20(m,4H),7.16–7.13(m,4H),7.10(d,J=7.1Hz,2H),6.52( dd,J=7.7,1.4Hz,1H),3.84(d,J=16.8Hz,1H),3.38–3.33(m,1H),3.27(d,J=13.1Hz,1H),3.24(s,1H),3 .05(d,J=16.8Hz,1H),2.93(d,J=14.0Hz,1H),2.90–2.83(m,2H),2.56–2.49(m,1H),2.38–2.31(m,1H); 13 C NMR (151 MHz, CD 3 OD)δ179.1,176.8,153.7,150.2,140.2,139.8,138.1,137.3,134.1,132.0,131.6,131.4,1 29.2,128.9,127.9,127.2,126.6,123.8,121.3,112.5,56.0,40.9,40.9,36.2,30.7,29.5.

[0060] Example 9

[0061] Compound 39 was obtained as a white solid with a yield of 61% and 63% ee.

[0062] The NMR data of compound 39 are: 1 H NMR (600MHz, CD 3OD)δ8.66(dd,J=4.8,0.6Hz,1H),8.20(d,J=7.9Hz,1H),7.90(td,J=7.8,1.7Hz,1H),7.65(d,J=8.0Hz,1H),7 .52–7.47(m,1H),7.45(dd,J=7.6,1.7Hz,1H),7.42(dd,J=10.8,4.2Hz,1H),7.33(td,J=7.9,1.8Hz,1H),3.5 4(d,J=17.2Hz,1H),3.43–3.39(m,1H),3.39–3.29(m,2H),2.47(ddd,J=13.4,9.4,6.7Hz,1H),2.37–2.26(m, 1H),2.26–2.19(m,1H),2.16(ddd,J=13.7,9.2,4.9Hz,1H),2.04–1.93(m,3H),1.76(dt,J=13.0,6.6Hz,1H); 13 C NMR (151 MHz, CD 3 OD)δ178.9,178.7,153.3,150.2,138.2,138.1,134.1,132.1,130.6,128 .6,126.7,123.7,121.4,110.7,53.4,52.9,36.5,30.4,29.6,28.5,16.8.

[0063] Example 10

[0064] Compound 45 was obtained as a white solid with a yield of 43% and 90% ee.

[0065] The NMR data of compound 45 are: 1 H NMR (400MHz, CD 3 OD)δ8.69–8.60(m,1H),8.20–8.10(m,1H),7.91(td,J=7.8,1.6Hz,1H),7.67(d, J=7.8Hz,1H),7.53–7.46(m,1H),7.46–7.38(m,2H),7.35(ddd,J=8.2,6.4,2.9H z,1H),3.93(s,4H),3.39(d,J=17.1Hz,1H),3.32–3.28(m,2H),3.23(d,J=17.1H z,1H),2.36–2.19(m,2H),1.95(d,J=9.9Hz,1H),1.76(s,5H),1.64–1.58(m,2H). 13 C NMR (101 MHz, CD 3OD)δ180.0,177.7,153.5,150.2,138.2,138.0,134.2,132.2,130.8,128.6, 126.6,123.7,121.4,112.1,109.4,65.1,65.1,35.9,33.7,32.4,29.2,28.8.

[0066] Embodiment 11

[0067] Compound 48 was obtained as a white solid with a yield of 43% and 91% ee.

[0068] The NMR data of compound 48 are: 1 H NMR (600MHz, CD 3 OD)δ8.64(d,J=4.7Hz,1H),8.15(d,J=7.9Hz,1H),7.96–7.78(m,1H),7.6 4(d,J=8.0Hz,1H),7.53–7.43(m,1H),7.43–7.34(m,2H),7.34–7.23(m,1H ),3.36–3.28(m,2H),3.21(d,J=17.3Hz,1H),3.10(d,J=17.3Hz,1H),2.32 (dd,J=8.0,4.3Hz,2H),1.83(dd,J=11.3,6.3Hz,2H),1.54–1.21(m,20H); 13 CNMR(151MHz,CD 3 OD)δ179.5,177.6,153.6,150.2,138.2,138.1,134.1,132.0,130.7,128.5,126.6,123.6,121.3 ,112.6,52.4,51.3,35.4,30.6,30.3,28.8,27.9,27.8,27.0,23.7,23.6,23.3,22.8,20.7,20.4.

[0069] Application Examples

[0070]

[0071] In a glove box, CuBr (0.005 mmol, 5% equiv) was added to a flask, which was then removed and placed under a dry nitrogen atmosphere after the stopper was sealed. Next, a solution of chiral spirocyclic amine 14 (99% ee, 0.0055 mmol, 5.5% equiv) in dichloromethane (1.0 mL) after a single recrystallization was added to the flask and stirred at room temperature for 30 minutes. Thereafter, compound 50 (0.1 mmol, 1.0 equiv) was added to the flask. During the stirring process, isobutyl chloroformate (0.1 mmol, 1.0 equiv) was added to a solution of 7-methoxyquinoline 49 (0.1 mmol, 1.0 equiv) in dichloromethane (1.0 mL) and stirred at room temperature for 5 minutes. The obtained quinoline salt was then transferred to a flask containing a copper catalyst and an alkyne, and N,N-diisopropylethylamine (DIPEA, 0.14 mmol, 1.4 equivalents) was added via a syringe, and the mixture was cooled to -20°C, and the reaction progress was monitored by thin layer chromatography (TLC). After the reaction was completed, the mixture was directly subjected to flash column chromatography (silica gel column) using ethyl acetate / petroleum ether (10:1) as the mobile phase to finally obtain the target product 51 as a colorless oil with a yield of 56% and 90% ee.

[0072] The NMR data of compound 51 are: 1 H NMR (600 MHz, CDCl 3 )δ7.35(s,1H),7.33–7.29(m,2H),7.23(dd,J=10.3,7.1Hz,3H),7.05(d,J=8.4Hz,1H),6.67(dd,J=8.4,2.5Hz,1H),6.51(d,J=9.3Hz, 1H),6.08(d,J=5.5Hz,1H),5.95(dd,J=9.1,6.3Hz,1H),4.12–3.98(m,2H),3.82(s,3H),2.08–1.99(m,1H),1.00(s,3H),0.99(s,3H); 13 C NMR (151 MHz, CDCl 3 )δ159.4,135.7,132.0,128.41,128.2,127.5,125.7,122.7),119.9,110.6,86.2,83.2,77.3,77.1,76.9,72.8,55.5,44.8,28.0,19.3.

[0073] In summary, this application successfully developed the first dual catalyst system combining a photosensitizer and a chiral Bronsted acid for asymmetric photochemical spirocyclization reactions. This method achieves the efficient reaction of a series of imine-containing nitrogen heteroaromatic substituted alkenylsulfonyl oximes with vinyl azides to generate nitrogen heteroaromatic functionalized spiroamines with high yields and excellent enantioselectivity. By using the sulfonyl group as a protecting group for the oxime, the reaction can be initiated through an energy transfer (EnT) mechanism rather than the previously reported single electron transfer (SET) mechanism. This innovative reaction mechanism enables the reaction to be carried out efficiently under mild conditions and achieves significant enantioselectivity.

[0074] The construction of spiroquaternary carbon stereocenters through an asymmetric radical addition process marks a significant progress in this field. In addition, the synthesized product was successfully used as a chiral ligand in an asymmetric alkynylation reaction, indicating that azaarene functionalized spirocyclic amines, as an important class of N,N,N-type chiral ligands, can greatly enrich the toolbox of asymmetric metal catalysis, highlighting the great potential and value of this method in catalytic chemistry.

Claims

1. A method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization, characterized in that: The synthetic route is as follows: The alkenylsulfonyl oxime of formula I and the vinyl azide of formula II are added to an organic solvent, and under the action of a photocatalyst fac-Ir(ppy)3, a chiral catalyst C1, a base, and an additive, the reaction is completed by stirring at room temperature under visible light irradiation, and the target chiral spirocyclic amine compound III is obtained by separation and purification; Ar 1 for G 1 H, F, Cl, Br, C1-C4 saturated alkyl, methoxy, CF3, Ph, Ar 2 for G 2 Selected from H, F, Cl, Br, C1-C4 saturated alkyl, methoxy, CF3, Ph, COOEt, OCF3, trimethylsilyl or triphenylsilyl, R is methyl, ethyl, propyl, benzyl or two Rs form a C4-C12 cycloalkyl, 2. The method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization according to claim 1, characterized in that: The molar ratio of the alkenylsulfonyl oxime shown in formula I to the vinyl azide shown in formula II is 1:(2-4), the added amount of the catalyst fac-Ir(ppy)3 is 1-5% of the molar amount of the alkenylsulfonyl oxime, and the added amount of the chiral catalyst C1 is 10-20% of the molar amount of the alkenylsulfonyl oxime.

3. The method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization according to claim 1, characterized in that: The base is one of K2CO3, KHCO3 and K3PO4 or a mixture of two or more of them in any proportion, and the added amount of the base is 1 to 3 times the molar amount of olefin sulfonyl oxime.

4. The method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization according to claim 1, characterized in that: The additives are KF and water, the amount of KF added is 1 to 2 times the molar amount of alkenylsulfonyl oxime, and the amount of water added per 0.1 mmol of alkenylsulfonyl oxime raw material is 0.02 to 0.05 mL.

5. The method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization according to claim 1, characterized in that: The organic solvent is one of dichloromethane, ethylbenzene and t-BuPh or a mixture of two or more of them in any proportion.

6. The method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization according to claim 1, characterized in that: The visible light is provided by 1 to 2 3W blue LED lamps.

7. A chiral spirocyclic amine compound obtained by the method according to any one of claims 1 to 6.

8. Use of the chiral spirocyclic amine compound according to claim 7 as a chiral ligand in a catalytic reaction, characterized in that: The reaction refers to the asymmetric alkynylation reaction of quinoline described in formula A with phenylacetylene in the presence of CuBr, 9. The use according to claim 8, characterized in that: The specific process is as follows: The quinoline of formula A and the phenylacetylene of formula B are reacted in the presence of CuBr, isobutyl chloroformate, N,N-diisopropylethylamine (DIPEA) and a chiral spiroamine with dichloromethane as a solvent at -15 to -25°C with stirring until the reaction is complete, and the target chiral compound III is separated and purified.

10. The use according to claim 9, characterized in that: The molar ratio of quinoline to phenylacetylene is (1-2):(1-2), the added amount of CuBr is 4-6% of the molar amount of quinoline, the added amount of chiral spirocyclic amine is 5-6% of the molar amount of quinoline, the added amount of isobutyl chloroformate is 1-1.5 times the molar amount of quinoline, and the added amount of N,N-diisopropylethylamine is 1-1.5 times the molar amount of quinoline.

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