Method for asymmetric catalytic synthesis of oxygen-containing multi-element bridged ring compound

Abstract

The invention discloses a method for asymmetric catalytic synthesis of an oxygen-containing multi-element bridged ring compound, and belongs to the field of organic synthesis. According to the method, 2-hydroxycinnamaldehyde or a derivative 1 thereof and beta-nitroketone 2 are taken as raw materials, chiral secondary amine is taken as a catalyst, and reaction is performed in an organic solvent under the action of organic alkali; and after the reaction is finished, separating and purifying by silica gel column chromatography to obtain a target product 4. The synthesis of the chiral oxygen-containing multi-element bridged ring compound is completed from simple and easily available 2-hydroxycinnamyl aldehyde or a derivative thereof and nitroketone, the method has wide substrate applicability, and a new method is provided for construction of chiral heterocyclic skeletons such as multi-substituted oxygen-containing multi-element bridged rings; a new reaction path is developed, and diversified synthesis of the functional group-oriented chiral bridged ring compound is realized in one step through an addition / elimination / cyclization reaction sequence; the reaction conditions are mild, the substrate and the catalyst are easy to obtain, the reaction system is simple and clean, and the target product can be obtained with higher yield and excellent enantioselectivity.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing oxygen-containing multi-bridged ring compounds by adopting organic asymmetric catalysis. Background Art

[0002] Chiral oxygen-containing polycyclic bridge skeletons are widely present in natural products with biological activity, and as core skeletons, they play a variety of different physiological roles (Trost, BM; Shen, HC; Dong L; Surivet, JP.; Sylvain, C. Synthesis of Chiral Chromans by the Pa-Catalyzed Asymmetric Allylic Alkylation (AAA): Scope, Mechanism, and Applications. J. Am. Chem. Soc. 2004, 126, 11966-11983.). The polycyclic bridge skeleton is also an important pharmacophore, providing a structural basis for the pharmacological activity of many drugs used in clinical practice. The synthesis of such compounds has always been an important research topic of concern to medicinal chemists and pharmacologists.

[0003] In the field of asymmetric organic catalysis, chiral secondary amine compounds are a special class of organic small molecule catalysts. Secondary amine compounds can form enamines with aldehyde compounds to activate nucleophiles or form imine salt active intermediates to activate electrophiles, thereby catalyzing various asymmetric reactions and having high enantioselectivity in many asymmetric transformations (List, B.; Lerner, RA; Barbas, CF, Proline-Catalyzed Direct Asymmetric Aldol Reactions. J. Am. Chem. Soc. 2000, 122, 2395-2396.). In recent years, there have been many discoveries at home and abroad on the use of 2-hydroxycinnamaldehyde in the construction of oxygen-containing polycyclic structures under the catalysis of secondary amines ((a) Yu, C.; Huang, H.; Li, X.; Zhang, Y.; Li, H.; Wang, W. Aniline-Promoted Cyclization-Replacement Cascade Reactions of 2-Hydroxycinnamaldehydes with Various Carbonic Nucleophiles through In SituFormed N, O-Acetals. Chem.-Eur. J. 2016, 22(27), 9240-9246. (b) Liu, M.-M.; Chen, X.-Y.; Huang, Y.-Q.; Feng, P.; Guo, Y.-L.; Yang, G. et al. Hybrids of Phenylsulfonylfuroxan and Coumarin as Potent Antitumor Agents. J. Med. Chem. 2014, 57(22), 9343-9356.).The research group of the present invention has also reported a number of various oxygen-containing polycyclic heterocyclic compounds synthesized from 2-hydroxycinnamaldehyde ((a) Pei, J.-P.; Chen, Y.-H.; Liu, Y.-K. Asymmetric Organocatalytic Sequential Reaction of Structurally Complex Cyclic Hemiacetals and Functionalized Nitro-olefins To Synthesize Diverse Heterocycles. Org. Lett. 2018, 20, 3609–3612. (b) Chen, Y.-H.; Lv, X.-J.; You, Z.-H.; Liu, Y.-K. Asymmetric Organocatalyzed Reaction Sequence of 2-Hydroxy Cinnamaldehydes And Acyclic N-Sulfonyl Ketimines to Construct Diverse Chiral Bridged Polycyclic Aminals.Org.Chem.Front.2019,6,3725–3730.), but most of these structures contain only a single skeleton. Although the synthesis methods of more complex compounds such as bridge rings and polycondensed rings have been reported, the disadvantages of long reaction routes and many reaction steps limit their further research. Therefore, developing a simple and efficient method to construct oxygen-containing polycyclic bridge compounds with pharmacophore skeletons has important research significance and practical value.

[0004] In summary, although the existing methods can be used to synthesize oxygen-containing polycyclic bridged compounds, they have a narrow substrate applicability range, a simple and single structural skeleton, and complex raw material synthesis, which seriously limits the further derivation and use of oxygen-containing polycyclic bridged skeletons. Summary of the invention

[0005] In view of the above problems, the purpose of the present invention is to provide a method for synthesizing oxygen-containing polycyclic bridged compounds by organic asymmetric catalysis in one step, which is simple, efficient, has readily available raw materials, good substrate universality, mild reaction conditions, high yield and excellent diastereoselectivity.

[0006] The present invention uses 2-hydroxycinnamaldehyde or its derivatives and β-nitroketone, which are easily available, as raw materials, and constructs a highly functional oxygen-containing multi-bridged ring skeleton through a series reaction of addition / hemiacetalization / elimination / addition to directly obtain the target compound. Based on the structural characteristics of 2-hydroxycinnamaldehyde containing phenolic hydroxyl groups and olefinic aldehyde structures and multiple reaction sites, the present invention can form unsaturated imine ions under the catalysis of secondary amines to provide electrophilic sites and react with nucleophilic reagents, serving as one of the substrates for synthesizing compounds containing chroman structures; β-nitroketone with multiple reaction sites is selected to react with 2-hydroxycinnamaldehyde, and β-nitroketone is used to remove HNO 2 After the polarity reversal reactivity, the β-carbon changes from nucleophilic to electrophilic, and can further close the ring with 2-hydroxycinnamaldehyde, thereby enriching the single six-membered oxygen ring structure and obtaining a complex bridge ring structure, providing a new method for constructing complex multi-membered bridge rings with potential pharmacological activity. This method can not only synthesize the target product with a high yield, but also meet the characteristics of simple operation, high efficiency and environmental protection, and good substrate universality.

[0007] The specific technical solutions of the present invention are as follows:

[0008] 2-Hydroxycinnamaldehyde or its derivative 1 and β-nitroketone 2 are used as raw materials and chiral secondary amine is used as catalyst. The reaction is carried out in an organic solvent under the action of an organic base. After the reaction is completed, the target product 4 is separated and purified by silica gel column chromatography. The reaction formula is as follows:

[0009]

[0010] Among them, R 1 One selected from hydrogen, methyl, methoxy and halogen; the halogen is one selected from fluorine, chlorine, bromine and iodine.

[0011] R 2 is an aryl or substituted aryl or pentyl group; the aryl or substituted aryl group is selected from one of phenyl, 2-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-bromophenyl, 4-methoxyphenyl, 2-furyl, 2-naphthyl, 2-benzothienyl, 3-N-Ts-indolyl and styryl.

[0012] The reaction mechanism of the present invention is: under the catalysis of chiral secondary amine, the β-carbon of β-nitroketone and the double bond of 2-hydroxycinnamaldehyde or its derivative undergo Michael addition reaction, followed by cyclization reaction between phenolic hydroxyl group and aldehyde carbonyl group to generate cyclic hemiacetal, and in the presence of organic base, the acidity of α position of carbonyl group increases to promote HNO 2 The β-carbon of β-nitroketone undergoes polarity reversal, changing from nucleophilic to electrophilic, and the hydroxyl group attacks the β-carbon to undergo an intramolecular oza-Michael addition reaction to obtain an oxygen-containing polycyclic bridge compound.

[0013] The chiral secondary amine is selected from the following compounds:

[0014]

[0015] The organic base is one of TEA, DBU, DABCO, Quinine or thiourea tertiary amine derivatives. Among them, TEA is triethylamine, DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, DABCO is triethylenediamine, Quinine is quinine, and the thiourea tertiary amine derivative is selected from the following compounds:

[0016]

[0017] The organic solvent is one of tetrahydrofuran, 1,2-dichloroethane, ether, ethyl acetate, toluene, 2-methyltetrahydrofuran or acetone.

[0018] The molar ratio of the 2-hydroxycinnamaldehyde or its derivative to the chiral secondary amine catalyst is 1.0:0.2; the molar ratio of the 2-hydroxycinnamaldehyde or its derivative to the organic base is 1.0:0.2.

[0019] The molar ratio of the 2-hydroxycinnamaldehyde or its derivative to the β-nitroketone is 1.0:(0.8-1.5), and the preferred molar ratio is 1.0:1.2.

[0020] The reaction temperature is 0-40°C, preferably 25°C.

[0021] The reaction of the present invention has the following advantages:

[0022] (1) Starting from the simple and readily available 2-hydroxycinnamaldehyde or its derivatives and nitroketones, the synthesis of chiral oxygen-containing polycyclic bridged ring compounds was completed, which has a wide range of substrate applicability and provides a new method for the construction of chiral bridged ring skeletons such as polysubstituted oxygen-containing polycyclic bridged rings.

[0023] (2) The present invention develops a new reaction pathway, which achieves the diversified synthesis of functional group-directed chiral bridged ring compounds in one step through an addition / elimination / cyclization reaction sequence.

[0024] (3) The reaction conditions of the present invention are mild, the substrate and catalyst are easily available, the reaction system is simple and clean, and the target product can be obtained with high yield and excellent enantioselectivity. DETAILED DESCRIPTION

[0025] The present invention will be further described below in conjunction with specific embodiments.

[0026] Embodiment 1:

[0027]

[0028] Table 1. Organic solvent screening

[0029]

[0030] [a]: Unless otherwise stated, the reactions were carried out at 25°C in 0.2 mL of solvent with a 0.1 mmol standard. The molar ratio of 1a to 2a was 1.0:1.2, the molar ratio of 1a to 3a was 1.0:0.2, and the molar ratio of 1a to base was 1.0:0.2. [b]: Isolated yield. [c]: ee determined by chiral HPLC analysis.

[0031] At 25°C, 20 mol% of 3a was used as a catalyst, 20 mol% of TEA was used as an organic base, and 2-hydroxycinnamaldehyde 1a and β-nitroketone 2a were used to screen the reaction solvent (Table 1). When 2-methyltetrahydrofuran was used as the solvent, the reaction was completed after 11 hours, and the yield of the product 4a was 46% and the ee value was 96%.

[0032] Table 2. Catalyst screening

[0033]

[0034] [a]: Unless otherwise stated, the reactions were carried out at 25°C in 0.2 mL of solvent with a 0.1 mmol standard. The molar ratio of 1a to 2a was 1.0:1.2, the molar ratio of 1a to 3 was 1.0:0.2, and the molar ratio of 1a to base was 1.0:0.2. [b]: Isolated yield. [c]: ee determined by chiral HPLC analysis.

[0035] At 25°C, 2-methyltetrahydrofuran was used as solvent, 20 mol% of 3 was used as catalyst, 20 mol% of TEA was used as base, 2-hydroxycinnamaldehyde 1a and β-nitroketone 2a were used to screen the catalyst (Table 2). When 3a was used as catalyst, the reaction was completed after 11 hours, and the yield of product 4a was 46% and the ee value was 96%.

[0036] Table 3. Organic base screening

[0037]

[0038] [a]: Unless otherwise stated, the reactions were carried out at 25°C in 0.2 mL of solvent with a 0.1 mmol standard. The molar ratio of 1a to 2a was 1.0:1.2, the molar ratio of 1a to 3a was 1.0:0.2, and the molar ratio of 1a to base was 1.0:0.2. [b]: Isolated yield. [c]: ee determined by chiral HPLC analysis.

[0039] At 25°C, 2-methyltetrahydrofuran was used as the solvent, 20 mol% of 3a was used as the catalyst, and 20 mol% of the organic base was used as the base. 2-Hydroxycinnamaldehyde 1a and β-nitroketone 2a were used to screen the organic base (Table 3). When (S)-B3 was used as the organic base, the reaction was completed after 48 hours, and the yield of the product 4a was increased to 57%, and the ee value was increased to 99%.

[0040] Table 4. Screening of the molar ratio of 2-hydroxycinnamaldehyde 1a to β-nitroketone 2a

[0041]

[0042] [a]: Unless otherwise stated, the reaction was carried out at 25°C in 0.2 mL of 2-methyltetrahydrofuran solvent, 20 mol% of 3a as catalyst, 20 mol% of (S)-B3 as organic base, and 0.1 mmol standard. [b]: Isolated yield. [c]: Chiral HPLC analysis to determine ee.

[0043] At 25°C, with 2-methyltetrahydrofuran as solvent, 20 mol% 3a as catalyst, and 20 mol% (S)-B3 as base, the equivalent ratio of 2-hydroxycinnamaldehyde 1a and β-nitroketone 2a was screened (Table 4). When the equivalent ratio of 2-hydroxycinnamaldehyde 1a and β-nitroketone 2a was 1.0:1.2, the reaction was completed after 48 hours, and the yield of product 4a was 57% and the ee value was 99%. Increasing or decreasing the equivalent ratio of the two did not increase the yield and ee value.

[0044] Table 5. Reaction temperature screening

[0045]

[0046] [a]: Unless otherwise stated, the reaction was carried out in 0.2 mL of 2-methyltetrahydrofuran solvent, 0.1 mmol standard, the molar ratio of 1a to 2a was 1.0:1.2, the molar ratio of 1a to 3a was 1.0:0.2, and the molar ratio of 1a to base was 1.0:0.2. [b]: Isolated yield. [c]: ee was determined by chiral HPLC analysis.

[0047] Using 2-methyltetrahydrofuran as solvent, 20 mol% of 3a as catalyst, 20 mol% of (S)-B3 as base, 2-hydroxycinnamaldehyde 1a and β-nitroketone 2a, the temperature was screened (Table 5), and the reaction temperature was 0-40° C., and the preferred reaction temperature was 25° C. Further increasing or decreasing the temperature could not improve the reaction yield and ee value.

[0048] The test data of compound 4a are as follows:

[0049] 1H NMR (400 MHz, CDCl 3 )δ7.84–7.76(m,2H),7.56–7.51(m,1H),7.40(t,J=7.7Hz,2H),7.14(ddd,J=8.0,7.3,1.8H z,1H),6.85–6.83(m,1H),6.82(t,J=1.7Hz,1H),6.74(td,J=7.4,1.2Hz,1H),5.75(d,J=3.0 Hz,1H),4.79(ddd,J=8.4,5.3,3.2Hz,1H),3.46(td,J=3.5,1.3Hz,1H),3.33(dd,J=17.8,5. 3Hz,1H),2.80(dd,J=17.8,8.2Hz,1H),2.38–2.33(m,1H),2.31(dd,J=11.5,1.4Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ198.2,151.6,136.7,133.3,128.9,128.6,128.0,128.0,125.1,120.6,116.4,99.1,84.8,40.8,39.6,33.1ppm.HRMS:[M+H] + Calculate for C 18 H 17 O 3 + 281.1172, found 281.1173. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=240 nm, t R( major)=14.980min,t R (minor)=10.787min, ee=99%.

[0050] Thus, the general reaction conditions for chiral oxygen-containing polycyclic bridged derivative 4 were obtained: β-nitroketone 2 (0.12 mmol, 1.2 equiv) was added to a solution of 2-hydroxycinnamaldehyde 1 (0.1 mmol, 1.0 equiv), 3a (0.02 mmol, 0.2 equiv) and (S)-B3 (0.02 mmol, 0.2 equiv) in 2-Me-THF (0.2 mL), and the reaction was stirred at 25 °C for 48 hours. The product 4 was obtained by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (20:1).

[0051] The above optimal reaction conditions were applied to the reaction of 2-hydroxycinnamaldehyde 1 and β-nitroketone 2 in the following examples.

[0052] Embodiment 2:

[0053]

[0054] According to the method of Example 1, 2a was replaced by 2b, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether:ethyl acetate (10:1) to obtain compound 4b, 10 mg, with a yield of 36% and ee=96%.

[0055] The test data of compound 4b are as follows:

[0056] 1 H NMR (400 MHz, CDCl 3 )δ7.19–7.13(m,1H),6.84–6.79(m,3H),5.69(d,J=2.7Hz,1H),4.58(ddd,J=7.6,6.0,3.2Hz,1H),3.30(td,J=3.3,1.6Hz, 1H),2.69(dd,J=17.8,5.9Hz,1H),2.30–2.22(m,5H),1.49(p,J=7.5Hz,2H),1.33–1.16(m,6H),0.86(t,J=7.1Hz,3H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ209.2,151.6,128.9,127.9,125.1,120.5,116.4,99.2,99.1,84.1,44.8,43.4,39.4,33.0,31.3,23.3,22.4,13.9ppm.HRMS:[M+H] + calcdfor C 17 H 25 O 3 + 275.1642, found 275.1640. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=9.940min,t R (minor)=8.440min, ee=96%.

[0057] Embodiment 3:

[0058]

[0059] According to the method of Example 1, 2a was replaced by 2c, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether: ethyl acetate (20: 1) to obtain compound 4c, 21 mg, with a yield of 74% and ee = 96%.

[0060] The test data of compound 4c are as follows:

[0061] 1 H NMR (400 MHz, CDCl 3 )δ7.80(td,J=7.6,1.9Hz,1H),7.48(dddd,J=8.7,7.1,5.0,1.9Hz,1H),7.19(td,J=7.6,1.1Hz,2H),7.12(dd,J=7. 9,1.8Hz,2H),7.04(ddd,J=11.2,8.3,1.1Hz,1H),6.85(dd,J=7.4,1.8Hz,1H),6.81(dd,J=8.0,2.7Hz,2H),6.76(t d,J=7.4,1.2Hz,1H),5.74(d,J=3.0Hz,1H),4.78(dq,J=8.3,3.1Hz,1H),3.42(t,J=2.8Hz,1H),3.29(ddd,J=18.7, 5.8,2.8Hz,1H),2.84(ddd,J=18.6,7.5,2.9Hz,1H),2.34(dt,J=11.6,3.4Hz,1H),2.29(dd,J=11.5,1.4Hz,2H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ196.1,196.1,151.5,134.8,134.7,130.4,130.3,128.9,127.9,125.1,124.4, 124.4,120.6,116.9,116.6,116.4,99.2,84.3,84.2,45.8,45.8,39.6,33.0ppm. 19 F NMR (375MHz, CDCl 3 )δ-109.1.HRMS:[M+H] + Calculate for C 18 H 16 FO 3 + 299.1078, found 299.1078. HPLC analysis: DAICEL CHIRALPAK OD-H, n-hexane / isopropanol=98 / 2, 1.0 mL / min, λ=205 nm, t R(major)=16.013min,t R (minor)=15.273min,ee=98%.

[0062] Embodiment 4:

[0063]

[0064] According to the method of Example 1, 2a was replaced by 2d, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether:ethyl acetate (25:1) to obtain compound 4d, 21 mg, with a yield of 67% and ee=98%.

[0065] The test data of compound 4d are as follows:

[0066] 1 H NMR (400 MHz, CDCl 3 )δ7.76(t,J=1.9Hz,1H),7.61(dt,J=7.8,1.3Hz,1H),7.48(ddd,J=8.0,2.1,1.1Hz,1H),7.31(t,J=7. 9Hz,1H),7.13(ddd,J=8.1,7.2,1.8Hz,1H),6.81(dd,J=8.4,1.3Hz,1H),6.80–6.77(m,1H),6.73(td,J =7.3,1.2Hz,1H),5.72(d,J=3.0Hz,1H),4.74(ddd,J=8.4,5.5,3.2Hz,1H),3.42(td,J=3.4,1.3Hz,1H) ,3.26(dd,J=17.8,5.4Hz,1H),2.74(dd,J=17.8,8.1Hz,1H),2.35–2.30(m,1H),2.30–2.26(m,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ196.8,151.6,138.2,135.0,133.2,129.9,129.0,128.0,127.9,126.2, 126.1,124.9,120.7,116.5,99.1,84.5,41.0,39.6,33.0ppm.HRMS:[M+H] + Calculate for C 18 H 16 C1O 3 +315.0782, found 315.0780. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=210 nm, t R( major)=12.047min,t R (minor)=9.833min, ee=98%.

[0067] Embodiment 5:

[0068]

[0069] According to the method of Example 1, 2a was replaced by 2e, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether: ethyl acetate (20: 1) to obtain compound 4e, 18 mg, with a yield of 58%, ee = 99%.

[0070] The test data of compound 4e are as follows:

[0071] 1 H NMR (400 MHz, CDCl 3 )δ77.31(d,J=2.0Hz,1H),7.30–7.27(m,1H),7.27–7.20(m,1H),7.10(ddd,J=8.1,7.4,1.8Hz,1H), 7.06–7.01(m,1H),6.81–6.79(m,1H),6.78(d,J=1.5Hz,1H),6.71(td,J=7.4,1.2Hz,1H),5.70(d,J= 3.1Hz,1H),4.73(ddd,J=8.4,5.3,3.2Hz,1H),3.77(s,3H),3.41(dq,J=4.1,1.3Hz,1H),3.27(dd,J= 17.8,5.3Hz,1H),2.74(dd,J=17.8,8.2Hz,1H),2.31(dt,J=11.6,3.4Hz,1H),2.28–2.23(m,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ197.9,159.7,151.6,138.1,129.6,128.9,128.0,125.1,120.7,120.6 ,119.9,116.4,112.1,99.1,84.8,55.4,40.9,39.6,33.1ppm.HRMS:[M+H] + Calculate for C 19 H 19 O4 + 311.1278, found 311.1279. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=220 nm, t R( major)=18.887min,t R (minor)=12.673min,ee=99%.

[0072] Embodiment 6:

[0073]

[0074] According to the method of Example 1, 2a was replaced by 2f, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether: ethyl acetate (25:1) to obtain compound 4f, 22 mg, with a yield of 61% and ee = 98%.

[0075] The test data of compound 4f are as follows:

[0076] 1 H NMR (400 MHz, CDCl 3 )δ7.66–7.62(m,2H),7.56–7.51(m,2H),7.14(ddd,J=8.1,7.2,1.8Hz,1H),6.83(dd,J=8.1, 1.1Hz,1H),6.80(dd,J=7.4,1.9Hz,1H),6.74(td,J=7.3,1.2Hz,1H),5.74(d,J=3.0Hz,1H),4 .76(ddd,J=8.4,5.5,3.2Hz,1H), 3.43(td,J=3.5,1.3Hz,1H), 3.26(dd,J=17.7,5.5Hz,1H), 2.75(dd,J=17.7,8.0Hz,1H), 2.35(dt,J=11.6,3.3Hz,1H), 2.30(dd,J=11.5,1.4Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ197.1,151.6,135.4,131.9,129.5,128.9,128.5,127.9,125.0,120.7,116.4,99.1,84.6,40.8,39.6,33.0ppm.HRMS:[M+H] + Calculate for C 18 H 16 B O 3+ 359.0277, found 359.0278. HPLC analysis: DAICELCHIRALPAK OD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=260 nm, t R( major)=11.840min,t R (minor)=9.907min,ee=98%.

[0077] Embodiment 7:

[0078]

[0079] According to the method of Example 1, the raw material 2g was used to replace 2a, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether: ethyl acetate (10:1) to obtain compound 4g, 15 mg, with a yield of 48%, ee = 97%.

[0080] The test data of compound 4g are as follows:

[0081] 1 H NMR (400 MHz, CDCl 3 )δ7.73–7.67(m,2H),7.06(ddd,J=9.0,7.5,1.8Hz,1H),6.81–6.77(m,2H),6.76(d,J=1.5Hz ,1H),6.74(d,J=1.5Hz,1H),6.67(td,J=7.4,1.2Hz,1H),5.67(d,J=3.0Hz,1H),4.70(ddd,J= 8.4,5.3,3.2Hz,1H),3.76(s,3H),3.37(td,J=3.5,1.2Hz,1H),3.20(dd,J=17.5,5.3Hz,1H), 2.67(dd,J=17.5,8.2Hz,1H), 2.27(dt,J=11.6,3.4Hz,1H), 2.22(dd,J=11.5,1.4Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ196.6,163.6,151.6,130.3,129.9,128.8,128.1,125.2,120.6,116.3,113.7,99.1,85.0,55.5,40.4,39.6,33.1ppm.HRMS:[M+H] + Calculate for C 19 H 19 O 4 +311.1278, found 311.1276. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=220 nm, t R( major)=27.953min,t R (minor)=19.307min,ee=97%.

[0082] Embodiment 8:

[0083]

[0084] According to the method of Example 1, 2a was replaced by 2h, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether:ethyl acetate (10:1) to obtain compound 4h, 22 mg, with a yield of 81% and ee=99%.

[0085] The test data of compound 4h are as follows:

[0086] 1 H NMR (400 MHz, CDCl 3 )δ7.52(dd,J=1.8,0.8Hz,1H),7.15(ddd,J=8.0,7.3,1.7Hz,1H),7.04(dd,J=3.5,0.8Hz,1H),6.87 (dd,J=7.4,1.7Hz,1H),6.83(dd,J=8.2,1.1Hz,1H),6.78(td,J=7.3,1.2Hz,1H),6.47(dd,J=3.6,1. 7Hz,1H),5.73(d,J=2.9Hz,1H),4.74(ddd,J=7.8,5.9,3.2Hz,1H),3.38(td,J=3.4,1.4Hz,1H),3.15 (dd,J=17.3,5.8Hz,1H),2.66(dd,J=17.2,7.8Hz,1H),2.36–2.31(m,1H),2.30(d,J=2.4Hz,1H)ppm. 13 CNMR (100MHz, CDCl 3 )δ186.6,152.3,151.6,146.7,128.9,128.2,125.0,120.6,117.7,116.4,112.2,99.1,84.2,40.6,39.7,33.0ppm.HRMS:[M+H] + Calculate for C 16 H 15 O 4 +271.0965, found 271.0968. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=260 nm, t R( major)=16.247min,t R (minor)=12.353min, ee=99%.

[0087] Embodiment 9:

[0088]

[0089] According to the method of Example 1, 2a was replaced by 2i, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether: ethyl acetate (25:1) to obtain compound 4i, 20 mg, with a yield of 61% and ee = 99%.

[0090] The test data of compound 4i are as follows:

[0091] 1 H NMR (400 MHz, CDCl 3 )δ8.26(s,1H),7.90(t,J=8.5Hz,2H),7.84(dd,J=9.0,2.3Hz,2H),7.58(t,J=7.4Hz ,1H),7.52(t,J=7.6Hz,1H),7.15(t,J=7.8Hz,1H),6.89–6.83(m,2H),6.73(t,J=7. 4Hz,1H),5.78(t,J=2.6Hz,1H),4.85(ddt,J=8.3,5.3,2.5Hz,1H),3.53–3.44(m,2H ),2.94(ddd,J=17.6,8.4,2.1Hz,1H),2.42–2.35(m,1H),2.33(d,J=11.5Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ198.1,151.7,135.7,134.1,132.5,130.0,129.7,129.0,128.7,128.5,128.2,127 .8,126.9,125.2,123.6,120.7,116.5,99.2,85.0,40.9,39.7,33.2ppm.HRMS:[M+H] + Calculate for C 22 H 19 O 3 +331.1329, found 331.1331. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=240 nm, t R( major)=19.007min,t R (minor)=17.387min,ee=99%.

[0092] Embodiment 10:

[0093]

[0094] According to the method of Example 1, the raw material 2j was used to replace 2a, and the other conditions and steps were the same. The compound 4j was obtained by silica gel column chromatography and eluted with petroleum ether: ethyl acetate (20: 1). The yield was 48%, and the ee was 99%.

[0095] The test data of compound 4j are as follows:

[0096] 1 H NMR (400 MHz, CDCl 3 )δ7.83(dd,J=11.9,8.1Hz,2H),7.69(d,J=1.7Hz,1H),7.45(t,J=7.6Hz,1H),7.38(t ,J=7.6Hz,1H),7.17(t,J=7.7Hz,1H),6.87(dd,J=10.5,7.9Hz,2H),6.77(t,J=7.4Hz ,1H),5.76(t,J=2.2Hz,1H),4.79(tt,J=5.1,3.1Hz,1H),3.46–3.41(m,1H),3.37(dd d,J=17.1,5.6,1.6Hz,1H),2.85(ddd,J=17.1,8.1,1.7Hz,1H),2.39–2.27(m,2H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ192.4,151.7,143.4,142.6,139.1,129.7,129.1,128.3,127.6,126.2,125 .1,125.0,123.0,120.8,116.5,99.3,84.6,41.4,39.7,33.1ppm.HRMS:[M+H] + Calculate for C 20 H 17 O 3 S +337.0893, found 337.0895. HPLC analysis: DAICEL CHIRALPAK IB, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=14.773min,t R (minor)=10.993min, ee=99%.

[0097] Embodiment 11:

[0098]

[0099] According to the method of Example 1, the raw material 2k was used to replace 2a, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether: ethyl acetate (9:1) to obtain compound 4k, 21 mg, with a yield of 45%, ee = 99%.

[0100] The test data of compound 4k are as follows:

[0101] 1 H NMR (400 MHz, CDCl 3 )δ8.31–8.26(m,1H),7.94–7.89(m,2H),7.79(d,J=8.5Hz,2H),7.40–7.30(m,3H),7.28(s,1H),7. 21(td,J=7.8,1.8Hz,1H),6.90(dd,J=8.1,1.1Hz,1H),6.87(dd,J=7.4,1.7Hz,1H),6.77(td,J=7. 5,1.2Hz,1H),5.75(d,J=2.5Hz,1H),4.78(ddd,J=7.5,6.1,3.2Hz,1H),3.40(td,J=3.3,1.7Hz,1H ), 3.19(dd,J=16.5,6.1Hz,1H),2.74(dd,J=16.6,7.6Hz,1H),2.37(s,3H),2.35–2.31(m,2H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ193.7,151.6,146.0,134.8,134.4,132.5,130.2,129.1,128.2,127.4,127.2,125.8,125.1 ,124.9,123.0,121.1,120.7,116.5,113.1,99.2,84.5,42.2,39.8,33.1,21.7ppm.HRMS:[M+H] + Calculate for C27 H 24 NO 5 S + 474.1370, found 474.1370. HPLC analysis: DAICELCHIRALPAK IB, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=17.080min,t R (minor)=16.073min, ee=99%.

[0102] Embodiment 12:

[0103]

[0104] According to the method of Example 1, the raw material 21 was used to replace 2a, and the other conditions and steps were the same. The compound 41 was obtained by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (12:1), 22 mg, with a yield of 72% and ee=99%.

[0105] The test data of compound 41 are as follows:

[0106] 1 H NMR (400 MHz, CDCl 3 )δ7.50–7.46(m,2H),7.43–7.33(m,4H),7.17(td,J=7.9,1.8Hz,1H),6.88(dd,J= 7.4,1.8Hz,1H),6.85–6.77(m,2H),6.62(d,J=16.2Hz,1H),5.74(d,J=2.9Hz,1H), 4.71(ddd,J=7.9,5.7,3.2Hz,1H),3.37(td,J=3.4,1.4Hz,1H),3.00(dd,J=17.3,5 .7Hz,1H),2.54(dd,J=17.4,7.9Hz,1H),2.38–2.31(m,1H),2.31–2.26(m,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ198.0,151.6,143.2,134.3,130.7,129.0,128.9,128.4,128.1,126.2,125.1,120.6,116.4,99.2,84.6,42.8,39.6,33.0ppm.HRMS:[M+H] + calcdfor C 20 H 19 O 3+ 307.1329, found 307.1330. HPLC analysis: DAICEL CHIRALPAK IB, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=220 nm, t R( major)=13.873min,t R (minor)=9.733min,ee=99%.

[0107] Embodiment 13:

[0108]

[0109] According to the method of Example 1, 1a was replaced by 1b, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether: ethyl acetate (20: 1) to obtain compound 4m, 15 mg, with a yield of 50%, ee = 99%.

[0110] The test data of compound 4m are as follows:

[0111] 1 H NMR (400 MHz, CDCl 3 )δ7.80(dd,J=8.4,1.3Hz,2H),7.57–7.50(m,1H),7.41(t,J=7.7Hz,2H),6.94(ddd,J=10.7,8 .1,1.6Hz,1H),6.67(td,J=7.8,4.6Hz,1H),6.61(dt,J=7.5,1.3Hz,1H),5.84(d,J=3.1Hz,1H) ,4.79(ddd,J=8.4,5.1,3.2Hz,1H),3.54(td,J=3.3,1.5Hz,1H),3.37(dd,J=17.9,5.1Hz,1H) ,2.78(dd,J=17.9,8.5Hz,1H),2.39(dt,J=11.8,3.5Hz,1H),2.32(dd,J=11.8,1.2Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ198.0,152.7,150.3,139.7,139.6,136.7,133.5,128.7,128.0,127.8,1 23.2,123.2,120.6,120.5,116.0,115.8,99.4,85.0,40.7,39.5,33.1ppm. 19 F NMR (375MHz, CDCl 3 )δ-136.3.HRMS:[M+H]+ Calculate for C 18 H 16 FO 3 + 299.1078, found 299.1079. HPLC analysis: DAICEL CHIRALPAK IG, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=43.007min,t R (minor)=17.567min,ee=99%.

[0112] Embodiment 14:

[0113]

[0114] According to the method of Example 1, 1a was replaced by 1c, and other conditions and steps were the same. 4n was obtained by silica gel column chromatography with petroleum ether: ethyl acetate (25:1) as eluent, 18 mg, with a yield of 56% and ee = 99%.

[0115] The test data of compound 4n are as follows:

[0116] 1 H NMR (400 MHz, CDCl 3 )δ7.81(d,J=8.2Hz,2H),7.55(t,J=7.4Hz,1H),7.42(t,J=7.2Hz,2H),6. 87–6.81(m,1H),6.80–6.69(m,2H),5.74(t,J=2.4Hz,1H),4.76(qd,J=5. 0,2.2Hz,1H),3.48(s,1H),3.37(ddd,J=17.9,5.2,1.7Hz,1H),2.78(ddd,J=17.9,8.5,1.8Hz,1H),2.41–2.32(m,1H),2.26(d,J=11.7Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ197.9,152.5,136.6,134.0,133.5,128.8,128.7,128.0,123.8,120.8,116.9,99.2,84.8,40.7,39.3,33.1ppm.HRMS:[M+H] + Calculate for C 18 H 16 C1O 3 +315.0782, found 315.0781. HPLC analysis: DAICEL CHIRALPAK IC, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=240 nm, t R( major)=11.227min,t R (minor)=7.947min, ee=99%.

[0117] Embodiment 15:

[0118]

[0119] According to the method of Example 1, the raw material 1d was used to replace 1a, and other conditions and steps were the same. The product was purified by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (20:1) to obtain compound 4o, 16 mg, with a yield of 52% and ee = 98%.

[0120] The test data of compound 4o are as follows:

[0121] 1 H NMR (400 MHz, CDCl 3 )δ7.84–7.78(m,2H),7.53(ddt,J=8.1,6.9,1.3Hz,1H),7.45–7.38(m,2H),6.72(d,J=8.3 Hz,1H),6.41(d,J=2.5Hz,1H),6.31(dd,J=8.3,2.5Hz,1H),5.72(d,J=3.2Hz,1H),4.75(dd d,J=8.2,5.3,3.1Hz,1H),3.73(s,3H),3.43–3.39(m,1H),3.32(dd,J=17.8,5.3Hz,1H),2. 81(dd,J=17.8,8.1Hz,1H),2.32(dt,J=11.6,3.5Hz,1H),2.26(dd,J=11.5,1.3Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ198.1,160.2,152.4,136.7,133.3,128.6,128.4,128.0,117.3,106.5,102.0,99.1,84.8,55.3,40.8,38.9,33.4ppm.HRMS:[M+H] + Calculate for C 19 H 19 O 4 +311.1278, found 311.1278. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=16.513min,t R (minor)=15.240min, ee=98%.

[0122] Embodiment 16:

[0123]

[0124] According to the method of Example 1, 1a was replaced by 1e, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether:ethyl acetate (25:1) to obtain compound 4p, 20 mg, with a yield of 56% and ee=99%.

[0125] The test data of compound 4p are as follows:

[0126] 1 H NMR (400 MHz, CDCl 3 )δ7.81(d,J=8.0Hz,2H),7.59–7.51(m,1H),7.43(t,J=7.4Hz,2H),7.28–7.20(m ,1H),6.97(t,J=2.1Hz,1H),6.71(dd,J=8.6,1.6Hz,1H),5.76–5.70(m,1H),4.7 8(tq,J=5.0,2.7,2.3Hz,1H),3.46–3.40(m,1H),3.34(dd,J=17.6,5.5Hz,1H),2 .81(ddd,J=17.7,8.0,1.6Hz,1H),2.39–2.32(m,1H),2.26(d,J=11.7Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ198.1,150.9,136.8,133.5,131.8,130.7,128.7,128.1,127.3,118.3,112.8,99.2,84.8,40.7,39.6,32.9ppm.HRMS:[M+H] + Calculate for C 18 H 16 B O 3 +359.0277, found 359.0278. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=12.420min,t R (minor)=11.120min, ee=99%.

[0127] Embodiment 17:

[0128]

[0129] According to the method of Example 1, 1a was replaced by 1f, and other conditions and steps were the same. 4q was obtained by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (25:1). The yield was 54%, and the ee was 98%.

[0130] The test data of compound 4q are as follows:

[0131] 1 H NMR (400 MHz, CDCl 3 )δ7.79(d,J=8.5Hz,2H),7.53(t,J=7.6Hz,1H),7.41(t,J=7.4Hz,2H),6.93(d,J=7.8 Hz,1H),6.73(dd,J=8.2,2.4Hz,1H),6.63–6.57(m,1H),5.75–5.70(m,1H),4.78(ddt, J=8.4,5.3,2.7Hz,1H),3.38(d,J=3.3Hz,1H),3.30(dd,J=17.6,4.9Hz,1H),2.82(ddd ,J=17.6,8.3,2.4Hz,1H),2.36–2.30(m,1H),2.28(d,J=10.3Hz,1H),2.08(s,3H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ198.5,149.3,137.0,133.3,129.9,129.4,128.6,128.0,124.9,116.1,99.2,84.9,40.9,39.6,33.2,20.4ppm.HRMS:[M+H] + Calculate for C 19 H 19 O 3 +295.1329, found 295.1329. HPLC analysis: DAICEL CHIRALPAK IB, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=7.607min,t R (minor)=6.927min, ee=98%.

[0132] Embodiment 18:

[0133]

[0134] According to the method of Example 1, 1a was replaced by 1g, and other conditions and steps were the same. 4r was obtained by silica gel column chromatography and eluted with petroleum ether:ethyl acetate (25:1). The yield was 52%, and the ee was 98%.

[0135] The test data of compound 4r are as follows:

[0136] 1 H NMR (400 MHz, CDCl 3 )δ7.78(d,J=7.1Hz,2H),7.55–7.48(m,1H),7.40(t,J=7.2Hz,2H),7.09(td,J=8.2,2.1Hz ,1H),6.49(dd,J=8.3,2.0Hz,1H),6.32(dd,J=8.3,2.0Hz,1H),5.73(t,J=2.6Hz,1H),4.8 9(tt,J=5.9,2.5Hz,1H),3.76(q,J=2.9Hz,1H),3.41(s,3H),3.09(ddd,J=17.4,6.2,2.1H z,1H),3.00(ddd,J=17.4,7.3,2.1Hz,1H),2.38–2.27(m,1H),2.20(d,J=11.6Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ197.9,156.5,152.4,137.1,133.1,128.7,128.6,128.0,113.6,109.4,102.5,99.2,85.0,55.1,40.0,32.9,32.8ppm.HRMS:[M+H] + Calculate for C 19 H 19 O 4 +311.1278, found 311.1277. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=26.460min,t R (minor)=20.067min,ee=98%.

[0137] Embodiment 19:

[0138]

[0139] According to the method of Example 1, 1a was replaced by 1h, and other conditions and steps were the same. Silica gel column chromatography was performed and eluted with petroleum ether:ethyl acetate (25:1) to obtain compound 4s, 15 mg, with a yield of 42%, ee=99%.

[0140] The test data of compound 4s are as follows:

[0141] 1 H NMR (400 MHz, CDCl 3 )δ7.82(d,J=7.6Hz,2H),7.53(t,J=7.4Hz,1H),7.41(td,J=7.9,1.9Hz,2H ),7.11(d,J=7.9Hz,1H),7.04(td,J=8.0,1.9Hz,1H),6.80(d,J=8.1Hz,1H) ,5.74(t,J=2.6Hz,1H),4.94(tt,J=5.9,2.5Hz,1H),3.85(d,J=3.9Hz,1H), 3.10(dd,J=6.2,2.0Hz,2H),2.46–2.36(m,1H),2.25(d,J=11.8Hz,1H)ppm. 13 C NMR (100 MHz, CDCl 3 )δ197.7,152.9,137.0,133.3,129.8,128.6,128.2,125.3,124.8,123.2,116.1,99.3,84.5,40.3,39.4,33.0ppm.HRMS:[M+H] + Calculate for C 18 H 16 B O 3 +359.0277, found 359.0280. HPLC analysis: DAICEL CHIRALPAK IG, n-hexane / isopropanol=90 / 10, 1.0 mL / min, λ=205 nm, t R( major)=29.147min,t R (minor)=33.053min, ee=99%.

[0142] Example 20: Scale-up test

[0143] In order to verify the application of this reaction, the preparative scale synthesis of product 4a was carried out under the optimal reaction conditions. The results showed that the reaction could obtain product 4a with excellent yield (155 mg, 55%) and maintain excellent enantioselectivity (98% ee), indicating that the reaction has industrial application value.

[0144]

[0145] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed in the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for asymmetric catalytic synthesis of oxygen-containing multi-bridged ring compounds, characterized in that: The method comprises the following steps: using 2-hydroxycinnamaldehyde or its derivative 1 and β-nitroketone 2 as raw materials and a chiral secondary amine as a catalyst, reacting in an organic solvent under the action of an organic base; after the reaction is completed, separating and purifying by silica gel column chromatography to obtain the target product 4, and the reaction formula is as follows: Among them, R 1 is selected from one of hydrogen, methyl, methoxy and halogen; the halogen is one of fluorine, chlorine, bromine and iodine; R 2 is an aryl or substituted aryl or pentyl group; the aryl or substituted aryl group is selected from one of phenyl, 2-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-bromophenyl, 4-methoxyphenyl, 2-furyl, 2-naphthyl, 2-benzothienyl, 3-N-Ts-indolyl and styryl.

2. The method for synthesizing an oxygen-containing polybasic bridged ring compound according to claim 1, characterized in that: The chiral secondary amine is selected from the following compounds:

3. The method for synthesizing an oxygen-containing polybasic bridged ring compound according to claim 1, characterized in that: The organic base is one of TEA, DBU, DABCO, Quinine or thiourea tertiary amine derivatives.

4. The method for synthesizing an oxygen-containing polybasic bridged ring compound according to claim 3, characterized in that: The thiourea tertiary amine derivative is selected from the following compounds:

5. The method for synthesizing an oxygen-containing polybasic bridged ring compound according to claim 1, characterized in that: The organic solvent is one of tetrahydrofuran, 1,2-dichloroethane, ether, ethyl acetate, toluene, 2-methyltetrahydrofuran or acetone.

6. The method for synthesizing an oxygen-containing polybasic bridged ring compound according to claim 1, characterized in that: The molar ratio of the 2-hydroxycinnamaldehyde or its derivative to the chiral secondary amine catalyst is 1.0:0.2; the molar ratio of the 2-hydroxycinnamaldehyde or its derivative to the organic base is 1.0:0.

2.

7. The method for synthesizing an oxygen-containing polybasic bridged ring compound according to claim 1, characterized in that: The molar ratio of the 2-hydroxycinnamaldehyde or its derivative to the β-nitroketone is 1.0:(0.8-1.5).

8. The method for synthesizing an oxygen-containing polybasic bridged ring compound according to claim 1, characterized in that: The reaction temperature is 0-40°C.

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