A method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization

Abstract

This application discloses an asymmetric photocatalytic spirocyclic synthesis method for constructing chiral spirocyclic amines, belonging to the field of organic synthesis. This method utilizes a dual-catalyst system composed of chiral phosphoric acid (CPA) and fac-Ir(ppy)3 photosensitizer. Under visible light irradiation, using alkenylsulfonyl oximes I and vinyl azide II substituted with imine-nitro-aromatic hydrocarbons as starting materials, a series of imine-nitro-nitro-aromatic hydrocarbon-functionalized spirocyclic amines were synthesized in high yield and with high enantioselectivity. The key innovation of this invention lies in using a sulfonyl group to replace the traditional ester group to protect the nitrogen atom of the oxime. This improvement promotes the energy transfer (EnT) mechanism rather than the single electron transfer (SET) mechanism. In this way, the reaction efficiency is significantly improved, while providing an ideal reaction environment for chiral hydrogen bonding catalysis.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization. Background Technology

[0002] Visible light-driven photocatalytic synthesis has become a powerful tool in the field of 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 wide range of functional groups. In particular, chemists have successfully achieved enantiomeric differentiation in various radical reactions by introducing exogenous chiral catalysts, thus effectively utilizing photocatalysis to synthesize enantiomeric chiral molecules. Therefore, 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 remains 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 over the past few decades due to their widespread presence in natural products, bioactive compounds, and chiral ligands. The advantages of photocatalytic synthesis have led to significant advancements 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 Trifunctionalizing ipso-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 via ipso-spirocyclization with vinyl azides, providing an efficient route for the synthesis of high-value spirocyclic amine derivatives. However, research on asymmetric reaction systems is relatively limited. One major challenge is the competitive photocycloaddition reaction between azides and triplet photosensitizers via an energy transfer (EnT) pathway. Furthermore, after the nitrogen radical intermediate completes 5-exo-trig cyclization, these species may undergo single-electron oxidation instead of addition with vinyl azides. These competing side reactions often result in yields below 50%, which are difficult to significantly improve even with system optimization. Clearly, the stringent reaction conditions required for optimal chemoselectivity make achieving high enantioselectivity with exogenous chiral catalysts a significant challenge. This problem stems from the rapid orbital flipping of radicals, complicating the precise enantioselectivity control typically dependent on specific reaction conditions. Moreover, the inherent complexity of multi-step cascade radical transformations further hinders chiral catalysts from achieving sufficient enantiodiscrimination, as these systems often contain multiple reaction intermediates simultaneously, and persistent racemic background reactions further weaken the enantioselectivity in these photocatalytic systems. Therefore, these challenges highlight the necessity of innovative strategies to overcome these obstacles and fully exploit the potential of asymmetric radical chemistry.

[0004] This application focuses on using imine-containing azaaryl hydrocarbons as substrates to achieve various radical-based chemical transformations via asymmetric photocatalysis. Azaaryl hydrocarbon derivatives are widely used in drug synthesis and materials science, especially in ligand design, and have significant research value. Notably, many N,N,N-type chiral ligands based on azaaryl hydrocarbons have been developed, exhibiting excellent catalytic performance in various important reactions. Against this backdrop, this application aims to explore the asymmetric photocatalytic reactions of imine-containing azaaryl hydrocarbon-substituted alkenylsulfonyl oximes I and vinyl azides II. This application not only verifies the feasibility of asymmetric photocatalysis in constructing spiroquaternary carbon stereocenters but also provides a convenient and modular method for synthesizing a novel class of N,N,N-type chiral ligands, thereby further enriching the field of asymmetric catalysis. Summary of the Invention

[0005] The purpose of this invention is to provide a method for constructing chiral spirocyclic amines through asymmetric photocatalytic spirocyclic cyclization.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclization is presented below:

[0008]

[0009] The alkenylsulfonyl oxime of Formula I and the vinyl azide of Formula II were added to an organic solvent. Under the action of the photocatalyst fac-Ir(ppy)3, the chiral catalyst C1, a base, and additives, the reaction was carried out under visible light irradiation at room temperature with stirring until complete. The resulting chiral spirocyclic amine compound III was obtained after separation and purification. 1 for G 1 H, F, Cl, Br, C1-C4 saturated alkyl groups, methoxy groups, CF3, Ph, Ar 2 for G 2 Selected from H, F, Cl, Br, C1-C4 saturated alkyl groups, methoxy groups, CF3, Ph, COOEt, OCF3, Trimethylsilyl or triphenylsilyl, where R is methyl, ethyl, propyl, benzyl, or a C4-C12 cycloalkyl group composed of two Rs.

[0010] Furthermore, the molar ratio of the alkenylsulfonyl oxime shown in Formula I to the vinyl azide shown in Formula II is 1:(2-4), the amount of photocatalyst fac-Ir(ppy)3 added is 1-5% of the molar amount of alkenylsulfonyl oxime, and the amount of chiral catalyst C1 added is 10-20% of the molar amount of alkenylsulfonyl oxime.

[0011] Further, the alkali is one or more of K2CO3, KHCO3 and K3PO4 in any proportion, and the amount of alkali added is 1 to 3 times the molar amount of 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 is 0.025 mL for every 0.1 mmol of alkenylsulfonyl oxime raw material.

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

[0014] Furthermore, the visible light is provided by one or two 3W blue LEDs.

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

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

[0017]

[0018]

[0019]

[0020] The application of the above-mentioned chiral spirocyclic amine compounds as chiral ligands in catalytic reactions, wherein the reaction refers to the asymmetric alkynylation reaction of quinoline of 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 CuBr and isobutyl chloroformate (ClCO2). i In the presence of Bu), N,N-diisopropylethylamine (DIPEA) and chiral spirocyclic amine 14, dichloromethane was used as a solvent, and the reaction was stirred at -15 to -25 °C until complete. The target chiral compound C was then 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] This application describes the successful synthesis of a series of pyridine-functionalized spirocyclic amines (3-26) by reacting a series of 1-aryl vinyl azides with substrate I under predetermined reaction conditions, with yields ranging from 43% to 94% and enantiomeric excess (ee) ranging from 83% to 99%.

[0025] Notably, the introduction of electron-withdrawing or electron-donating groups (e.g., 4-10 and 11-22) at the para, meta, or ortho positions of the vinyl azide aromatic ring did not significantly affect the enantioselectivity. The lower yields of some products (e.g., 13 and 21) may be attributed to reduced reactivity of radical addition to the vinyl azide, as some of the vinyl azide is consumed to form the corresponding nitrogen-containing heterocyclic propylene. Importantly, the trimethylsilyl (TMS) group in compound 13 exhibits remarkable compatibility in reaction systems containing KF. Furthermore, the high tolerance of the allyl group in compound 20 further highlights the precise chemoselectivity of this reaction among different olefins.

[0026] This application also investigated some vinyl azides with polycyclic aromatic hydrocarbons (23, 24) and heterocyclic aromatic hydrocarbons (25, 26), obtaining high yields and high ee values, further demonstrating the broad applicability of the method.

[0027] Subsequently, this application investigated the reaction of 1-(1-azidovinyl)-2-bromobenzene with a series of aza-aryl substituted 4-(trifluoromethyl)benzenesulfonyl oximes. This vinyl azide was chosen because the ortho-substitution presents a challenge, making it difficult to achieve satisfactory yields and enantioselectivity, while also providing a strong basis for assessing the synthetic diversity of this strategy. Furthermore, the bromine functional group can accommodate 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; the yields of the corresponding products (27-33) ranged from 56% to 75%, with ee values ​​exceeding 90%. More importantly, the pyridine group in the products could be tuned by quinoline (e.g., 34) and isoquinoline (e.g., 35), further broadening the range of these tridentate ligands. Furthermore, substituents on the chiral ligand ring can effectively control the spatial configuration, which is crucial for the wider application of chiral ligands. Against this backdrop, replacing 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) yielded 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 from these molecules, and the products can be obtained with satisfactory yields and enantioselectivity.

[0030] Subsequently, this application evaluated the potential of these spirocyclic amine products based on nitrogen-containing aromatic hydrocarbons as chiral ligands in metal catalysis to demonstrate the synthetic practicality of the compounds in this application. This application investigated the asymmetric alkynylation reaction of quinoline A with phenylacetylene in the presence of 5 mol% CuBr. The reaction conditions were 1.0 equivalent of isobutylcarbonochloridate, 1.4 equivalent of N,N-diisopropylethylamine (DIPEA), chiral spirocyclic amine compound 14 as the ligand, and dichloromethane as the solvent, and the reaction was carried out at -20 °C. The target product C was successfully obtained in 56% yield and 90% ee, thus effectively avoiding the use of axially chiral P,N ligands (S)-StackPhos, which require cumbersome preparation methods.

[0031] In summary, this application reports for the first time an asymmetric photocatalytic spirocyclic reaction involving the reaction of imine-containing aza-aryl substituted alkenyl sulfonyl oximes and vinyl azides. This method successfully synthesized a series of aza-aryl functionalized chiral spirocyclic amines in high yields (up to 94%) and with enantioselectivity up to 99% ee. The key to this success lies in using the sulfonyl group as the protecting group of the oxime, allowing energy transfer to become an alternative mechanism for initiating the reaction transformation. This strategy not only improves the reactivity and chemoselectivity but also creates an optimal environment for enantioselective control. The synthetic significance of this study is further demonstrated by showcasing the potential of these products as a novel class of chiral ligands, with preliminary studies indicating their excellent catalytic performance in asymmetric alkynylation reactions. Detailed Implementation

[0032] The present invention will be further described in detail below with reference to embodiments. It should be understood that the embodiments described in this specification are merely for explaining the present invention and are not intended to limit the present invention. The parameters, proportions, etc. of the embodiments can be selected according to local conditions without having a substantial impact on the results.

[0033] Example 1

[0034] Synthesis of compound 3:

[0035]

[0036] In a 25 mL Schlenk tube, the following were added sequentially: alkenylsulfonyl oxime 1 (0.1 mmol, 1.0 equivalent), chiral catalyst C1 (0.015 mmol, 0.15 equivalent), K₂CO₃ (0.15 mmol, 1.5 equivalent), KF (0.1 mmol, 1.0 equivalent), water (0.025 mL), photocatalyst fac-Ir(ppy)₃ (0.002 mmol, 0.02 equivalent), 1-(1-azidovinyl)-4-methylbenzene 2 (0.3 mmol, 3.0 equivalent), and ethylbenzene (3.0 mL). The reaction mixture was degassed three times using a freeze-pump-melt method. The Schlenk tube was then placed approximately 2.0 cm away from a 3W blue LED (445 nm wavelength) and stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the target product 3 was purified by flash column chromatography on a silica gel column using a gradient elution of petroleum ether / ethyl acetate / tetrahydrofuran (15:1:1 to 10:1:1). The product was a white solid with a yield of 70% and an ee of 90%.

[0037] The NMR data for compound 3 are as follows: 1 H NMR (400MHz, CDCl3) δ8.71–8.55(m,1H),8.16(d,J=7.9Hz,1H),7.76(d,J=8.1Hz,2H),7.70(t d,J=7.7,1.8Hz,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 (101MHz, CDCl3) δ174.6,174.4,153.6,149.1,140.9,136.2,132.3,12 9.1,127.9,124.7,122.7,111.2,50.1,45.0,35.3,28.5,25.1,22.0,21.6.

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

[0039] Example 2

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

[0041] The NMR data for compound 11 are as follows: 1 H NMR (600MHz, CDCl3) δ8.64(d,J=4.4Hz,1H),8.16(d,J=7.9Hz,1H),7.87(d,J=7.0 Hz,2H),7.68(td,J=7.7,1.7Hz,1H),7.44–7.35(m,3H),7.31–7.27(m,1H),3.40(d t,J=17.0,8.4Hz,1H),3.24(ddd,J=15.1,9.6,3.5Hz,2H),2.88(d,J=15.9Hz,1H) ,2.35–2.26(m,1H),2.15(ddd,J=13.3,9.3,8.0Hz,1H),1.17(s,3H),1.07(s,3H); 13 C NMR (101MHz, CDCl3) 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 is a white solid with a yield of 73% and an ee of 90%.

[0044] The NMR data for compound 14 are as follows: 1H NMR (600MHz, CDCl3) 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 (151MHz, CDCl3) δ177.2,174.9,153.7,149.1,137.0,136.2,135.7,131.1,12 9.2,128.7,125.6,124.8,122.7,111.5,53.7,44.8,35.2,28.5,25.1,21.5,21.2.

[0045] Example 4

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

[0047] The NMR data for compound 16 are as follows: 1 H NMR (600MHz, CDCl3) 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=7.7,1.7Hz,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(ddd,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); 13C NMR (151MHz, CDCl3) δ174.8,174.3,153.5,149.1,143.5,140.5,136.3,133.9,128.9, 128.5,127.8,127.2,127.1,124.8,122.7,111.3,50.1,45.1,35.3,28.5,25.2,22.0.

[0048] Example 5

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

[0050] The NMR data for compound 23 are as follows: 1 H NMR (600MHz, CD3OD) 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=7.8,1.5H z,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(151MHz,CD3OD)δ178.1,177.3,153.5,150.2,138.1,136.1,134.2,132.6,130.3,129.8, 129.2,128.6,128.5,127.6,126.6,124.8,123.5,112.4,50.9,45.4,36.3,28.7,25.3,21.5.

[0051] Example 6

[0052] Compound 34 is a white solid with a yield of 68% and an ee of 77%.

[0053] The NMR data for compound 34 are as follows: 1H NMR (400MHz, CDCl3) δ8.34(d,J=8.5Hz,1H),8.15(d,J=8.4Hz,2H),7.82(dd,J=8.1,1.1 Hz,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),2.3 7(ddd,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 (151MHz, CDCl3) δ177.2,175.9,153.8,147.9,137.9,135.9,133.4,130.6,130.5,130.1, 129.5,128.7,127.7,127.4,127.4,121.3,120.2,111.2,53.4,45.8,35.2,28.3,24.8,21.8.

[0054] Example 7

[0055] Compound 37 is a white solid with a yield of 60% and an ee of 90%.

[0056] The NMR data for compound 37 are as follows: 1 H NMR (400MHz, CD3OD) 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),7.66(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=23.0,14.9,11.2Hz,3H),3.11(d,J=17.2Hz,1H),2.42–2.29(m,2H),1.79–1.62(m,3H),1.5 6–1.46(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); 13C NMR (151MHz, CD3OD) 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 is a white solid with a yield of 57% and an ee of 90%.

[0059] The NMR data for compound 38 are as follows: 1 H NMR (600MHz, CD3OD) 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=8.0H z,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,1 H),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(151MHz,CD3OD)δ179.1,176.8,153.7,150.2,140.2,139.8,138.1,137.3,134.1,132.0,131.6, 131.4,129.2,128.9,127.9,127.2,126.6,123.8,121.3,112.5,56.0,40.9,40.9,36.2,30.7,29.5.

[0060] Example 9

[0061] Compound 39 is a white solid with a yield of 61% and an ee of 63%.

[0062] The NMR data for compound 39 are as follows: 1H NMR (600MHz, CD3OD) 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),3.54(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),2.37–2.2 6(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 (151MHz, CD3OD) δ178.9,178.7,153.3,150.2,138.2,138.1,134.1,132.1,13 0.6,128.6,126.7,123.7,121.4,110.7,53.4,52.9,36.5,30.4,29.6,28.5,16.8.

[0063] Example 10

[0064] Compound 45 is a white solid with a yield of 43% and an ee of 90%.

[0065] The NMR data for compound 45 are as follows: 1 H NMR(400MHz,CD3OD)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 .4,2.9Hz,1H),3.93(s,4H),3.39(d,J=17.1Hz,1H),3.32–3.28(m,2H),3.23(d,J=17 .1Hz,1H),2.36–2.19(m,2H),1.95(d,J=9.9Hz,1H),1.76(s,5H),1.64–1.58(m,2H). 13C NMR (101MHz, CD3OD) 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] Example 11

[0067] Compound 48 is a white solid with a yield of 43% and an ee of 91%.

[0068] The NMR data for compound 48 are as follows: 1 H NMR(600MHz,CD3OD)δ8.64(d,J=4.7Hz,1H),8.15(d,J=7.9Hz,1H),7.96–7.78 (m,1H),7.64(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,CD3OD)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% equivalent) was added to a flask, which was then sealed with a stopper and placed under a dry nitrogen atmosphere. Next, a 1.0 mL solution of a single-crystallized chiral spirocyclic amine 14 (99% ee, 0.0055 mmol, 5.5% equivalent) in dichloromethane was added to the flask, and the mixture was stirred at room temperature for 30 minutes. Subsequently, compound 50 (0.1 mmol, 1.0 equivalent) was added to the flask. While stirring, isobutyl chloroformate (0.1 mmol, 1.0 equivalent) was added to a 1.0 mL solution of 7-methoxyquinoline 49 (0.1 mmol, 1.0 equivalent) in dichloromethane, and the mixture was 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 equivalence) was added via syringe. The mixture was then cooled to -20 °C, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the mixture was directly subjected to flash column chromatography (silica gel column) using ethyl acetate / petroleum ether (10:1) as the mobile phase, finally yielding the target product 51 as a colorless oil with a yield of 56% and an ee of 90%.

[0072] The NMR data for compound 51 are as follows: 1 H NMR (600MHz, CDCl3) 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 (151MHz, CDCl3) 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 Brønsted acid for asymmetric photochemical spirocyclic reactions. This method achieved highly efficient reactions of a series of imine-containing alkylene-substituted alkenylsulfonyl oximes with vinyl azides, generating alkylene-functionalized spirocyclic amines in high yields with excellent enantioselectivity. By using the sulfonyl group as the protecting group of the oxime, this reaction can be initiated via an energy transfer (EnT) mechanism, rather than the previously reported single-electron transfer (SET) mechanism. This innovative reaction mechanism enables the reaction to proceed efficiently under mild conditions and achieves significant enantioselectivity.

[0074] The construction of spiroquaternary carbon stereocenters via asymmetric radical addition processes marks a significant advancement in this field. Furthermore, the synthesized products have been successfully applied as chiral ligands in asymmetric alkynylation reactions, demonstrating that the functionalization of spirocyclic amines with aza-aromatics, as an important class of N,N,N-type chiral ligands, can greatly enrich the toolbox of asymmetric metal catalysis, highlighting the immense potential and value of this method in catalytic chemistry.

Claims

1. A method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclic cyclization, characterized in that, The synthesis route is as follows: ， ， ， The alkenylsulfonyl oxime of Formula I and the vinyl azide of Formula II were added to an organic solvent. Under the action of the photocatalyst fac-Ir(ppy)3, the chiral catalyst C1, a base, and additives, the reaction was carried out under visible light irradiation at room temperature with stirring until complete. The resulting chiral spirocyclic amine compound III was obtained after separation and purification. 1 for G 1 H, F, Cl, Br, C1~C4 saturated alkyl groups, methoxy groups, CF3, Ar 2 for G 2 The additive is selected from H, F, Cl, Br, C1~C4 saturated alkyl groups, methoxy groups, CF3, COOEt, OCF3, and R is methyl, ethyl, or propyl, wherein the additive is KF and water.

2. The method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclic cyclization 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 amount of catalyst fac-Ir(ppy)3 added is 1~5% of the molar amount of alkenylsulfonyl oxime, and the amount of chiral catalyst C1 added is 10~20% of the molar amount of alkenylsulfonyl oxime.

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

4. The method for constructing chiral spirocyclic amines by asymmetric photocatalytic spirocyclic hydration according to claim 1, characterized in that, The amount of KF added is 1 to 2 times the molar amount of alkenylsulfonyl oxime, and the amount of water added for each 0.1 mmol of alkenylsulfonyl oxime feedstock is 0.02 to 0.05 mL.

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

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

7. The chiral spirocyclic amine compound obtained by the method of claim 1.

8. The application of chiral spirocyclic amine compounds as chiral ligands in catalytic reactions, characterized in that, The catalytic reaction is as follows: The structure of the chiral helical ring is as follows: , The quinoline of Formula A and the phenylacetylene of Formula B were reacted in the presence of CuBr, isobutyl chloroformate, N,N-diisopropylethylamine and chiral spirocyclic amine, with dichloromethane as solvent, and stirred at -15 to -25°C until complete. The target chiral compound C was obtained by separation and purification.

9. The application according to claim 8, characterized in that, 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.

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