Process for the asymmetric catalytic synthesis of oxygen-containing polycyclic bridged compounds

Abstract

The application discloses a method for asymmetric catalytic synthesis of oxygen-containing multi-bridged ring compounds and belongs to the field of organic synthesis. The method uses 2-hydroxycinnamaldehyde or a derivative thereof 1 and beta-nitroketone 2 as raw materials, chiral secondary amine as a catalyst, and reacts in an organic solvent under the action of an organic base; after the reaction is completed, the target product 4 is obtained through silica gel column chromatography separation and purification. The method starts from simple and easily available 2-hydroxycinnamaldehyde or a derivative thereof and nitroketone, completes the synthesis of chiral oxygen-containing multi-bridged ring compounds, has wide substrate applicability, and provides a new method for the construction of multi-substituted oxygen-containing multi-bridged ring and other chiral heterocyclic skeletons. The application develops a new reaction path, realizes the diversified synthesis of chiral bridged ring compounds through an addition / elimination / cyclization reaction sequence in one step, and has the advantages of mild reaction conditions, easily available substrates and catalysts, simple and clean reaction system, and the ability to obtain the target product in a high yield and excellent enantioselectivity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a method for synthesizing oxygen-containing multi-bridged ring compounds by using organic asymmetric catalysis. BACKGROUND

[0002] Chiral oxygen-containing multi-bridged ring skeleton is widely present in natural products with biological activity, and plays a variety of different physiological roles as a core skeleton (Trost, B. M.; Shen, H. C; Dong L; Surivet, J-P.; 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 multi-bridged ring skeleton also serves as an important pharmacophore, and provides a structural basis for the pharmacological activity of many clinically applied drugs. The synthesis of such compounds has been an important research topic of interest to medicinal chemists and pharmacologists.

[0003] In the field of asymmetric organocatalysis, chiral secondary amine compounds are a special class of small organic 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 with high enantioselectivity in many asymmetric transformations (List, B.; Lerner, R. A.; Barbas, C. F., Proline-Catalyzed Direct Asymmetric Aldol Reactions. J. Am. Chem. Soc. 2000, 122, 2395-2396.). In recent years, there have been many discoveries about the use of 2-hydroxy cinnamaldehyde in secondary amine catalysis to construct oxygen-containing polycyclic heterocyclic structures (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 Situ Formed 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 subject group of the present application also reported a number of various oxygen-containing polycyclic heterocyclic compounds synthesized by 2-hydroxy cinnamaldehyde ((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 these structures mostly contain only a single skeleton, and the synthesis method of more complex compounds such as bridged ring, multi-fused ring, etc. has been reported, but the long reaction route, multiple reaction steps and other shortcomings limit its further research. Therefore, it is of great research significance and practical value to develop a simple and efficient method to construct oxygen-containing multi-bridged ring compounds containing pharmacophore skeletons.

[0004] In summary, although the existing method can be used to synthesize oxygen-containing multi-bridged ring compounds, the substrate has a narrow applicable range, the structural skeleton is simple and single, and the synthesis of raw materials is complex, which seriously limits the further derivation and use of oxygen-containing multi-bridged ring skeletons. SUMMARY

[0005] In view of the above problems, the purpose of the present application is to provide a simple, efficient, easily available raw material, good substrate universality, mild reaction condition, high yield and excellent diastereoselectivity of one-step synthesis of oxygen-containing multi-bridged ring compound method.

[0006] The application directly obtains the target compound by constructing a high-functional oxygen-containing multi-bridge ring skeleton through a series of addition / semi-acetalization / elimination / addition reactions based on 2-hydroxycinnamaldehyde or its derivative and beta-nitroketone as raw materials. Based on the structural characteristics of 2-hydroxycinnamaldehyde containing phenolic hydroxyl and enal structure and multiple reaction sites, the Michael addition reaction of the beta-carbon of beta-nitroketone and the double bond of 2-hydroxycinnamaldehyde or its derivative can be carried out under the catalysis of secondary amine to provide an electrophilic site and a nucleophile to react, and the secondary amine is used as one of substrates for synthesizing compounds containing chromane structure; the beta-nitroketone and the 2-hydroxycinnamaldehyde are selected to react, the polarity of the beta-nitroketone is reversed after HNO2 is removed, the beta-carbon is changed from nucleophilic to electrophilic, and the beta-nitroketone can further be ring-closed with the 2-hydroxycinnamaldehyde, so that the single six-membered oxygen ring structure is enriched, and the complex multi-bridge ring structure is obtained, thereby a new method for constructing the complex multi-bridge ring containing potential pharmacological activity is provided. The method can not only synthesize the target product with high yield, but also meet the characteristics of simple operation, high efficiency, environmental protection and good substrate universality.

[0007] The specific technical scheme of the application is as follows:

[0008] 2-hydroxycinnamaldehyde or its derivative 1 and beta-nitroketone 2 are used as raw materials, chiral secondary amine is used as a catalyst, and 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 obtained through silica gel column chromatography separation and purification, and the reaction formula is as follows:

[0009]

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

[0011] R is selected from hydrogen, methyl, methoxy and halogen; the halogen is one of fluorine, chlorine, bromine and iodine. 2 R is selected from hydrogen, methyl, methoxy and halogen; the halogen is one of fluorine, chlorine, bromine and iodine.

[0012] The reaction mechanism of the application is as follows: under the catalysis of chiral secondary amine, the Michael addition reaction of the beta-carbon of beta-nitroketone and the double bond of 2-hydroxycinnamaldehyde or its derivative occurs, then the ring-closing reaction of the phenolic hydroxyl and the aldehyde carbonyl generates a ring semi-acetal, in the presence of an organic base, the increase of the acidity of the alpha position of the carbonyl promotes the elimination of HNO2, the beta-carbon of the beta-nitroketone is polarized and changes from nucleophilic to electrophilic, and the intramolecular oza-Michael addition reaction of the hydroxyl to the beta-carbon occurs to obtain an oxygen-containing multi-bridge ring 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 triethylene diamine, 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, diethyl 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, and 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-nitro ketone is 1.0:(0.8-1.5), preferably 1.0:1.2.

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

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

[0022] (1) Starting from simple and readily available 2-hydroxycinnamaldehyde or its derivative and nitro ketone, the synthesis of chiral oxygen-containing polycyclic bridged compounds is completed, which has wide substrate applicability and provides a new method for the construction of polysubstituted oxygen-containing polycyclic bridged and other chiral bridged skeletons.

[0023] (2) The present application develops a new reaction path, which realizes the diversification synthesis of chiral bridged compounds through addition / elimination / cyclization reaction sequence in one step.

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

[0025] The present application will be further described below in combination with specific examples.

[0026] Example 1:

[0027]

[0028] Table 1. Organic solvent screening

[0029]

[0030] [a] Unless otherwise noted, reactions were performed at 25 °C in 0.2 mL of solvent on a 0.1 mmol scale with a 1.0:1.2 molar ratio of 1a and 2a, a 1.0:0.2 molar ratio of 1a to 3a, and a 1.0:0.2 molar ratio of 1a to base. [b] Isolated yield. [c] ee determined by chiral HPLC analysis.

[0031] A screening of the reaction solvent was performed at 25 °C with 20 mol% of 3a as catalyst and 20 mol% of TEA as organic base using 2-hydroxy cinnamaldehyde 1a and β-nitro ketone 2a (Table 1). When 2-methyltetrahydrofuran was used as solvent, the reaction was complete in 11 h with a 46% yield of product 4a and 96% ee.

[0032] Table 2. Catalyst screening

[0033]

[0034] [a] Unless otherwise noted, reactions were performed at 25 °C in 0.2 mL of solvent on a 0.1 mmol scale with a 1.0:1.2 molar ratio of 1a and 2a, a 1.0:0.2 molar ratio of 1a to 3a, and a 1.0:0.2 molar ratio of 1a to base. [b] Isolated yield. [c] ee determined by chiral HPLC analysis.

[0035] A screening of the catalyst was performed at 25 °C with 2-methyltetrahydrofuran as solvent, 20 mol% of 3 as catalyst and 20 mol% of TEA as base using 2-hydroxy cinnamaldehyde 1a and β-nitro ketone 2a (Table 2). When 3a was used as catalyst, the reaction was complete in 11 h with a 46% yield of product 4a and 96% ee.

[0036] Table 3. Organic base screening

[0037]

[0038] [a] Unless otherwise noted, reactions were performed at 25 °C in 0.2 mL of solvent on a 0.1 mmol scale with a 1.0:1.2 molar ratio of 1a and 2a, a 1.0:0.2 molar ratio of 1a to 3a, and a 1.0:0.2 molar ratio of 1a to base. [b] Isolated yield. [c] ee determined by chiral HPLC analysis.

[0039] The reaction was screened with 2-methyltetrahydrofuran as solvent, 20 mol% of 3a as catalyst, 20 mol% of organic base as base, and 2-hydroxycinnamaldehyde la and β-nitroketone 2a (Table 3) at 25 °C. When (S)-B3 was used as the organic base, the reaction was completed in 48 hours, and the yield of 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 la to β-nitroketone 2a

[0041]

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

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

[0044] Table 5. Screening of reaction temperature

[0045]

[0046] [a] Unless otherwise stated, the reaction was carried out at 25 °C, 0.2 mL of 2-methyltetrahydrofuran solvent, 20 mol% of 3a as catalyst, 20 mol% of (S)-B3 as organic base, 0.1 mmol standard. [b] Isolated yield. [c] ee determined by chiral HPLC analysis.

[0047] The reaction was screened with 2-methyltetrahydrofuran as solvent, 20 mol% of 3a as catalyst, 20 mol% of (S)-B3 as base, and 2-hydroxycinnamaldehyde la and β-nitroketone 2a (Table 5) at 25 °C. When the equivalent ratio of 2-hydroxycinnamaldehyde la and β-nitroketone 2a was 1.0:1.2, the reaction was completed in 48 hours, and the yield of product 4a was 57%, and the ee value was 99%. Increasing or decreasing the equivalent ratio of both did not improve the yield and ee value.

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

[0049] 1H NMR (400 MHz, CDC13) δ 7.84 - 7.76 (m, 2H), 7.56 - 7.51 (m, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.14 (ddd, J = 8.0, 7.3, 1.8 Hz, 1H), 6.85 - 6.83 (m, 1H), 6.82 (t, J = 1.7 Hz, 1H), 6.74 (td, J = 7.4, 1.2 Hz, 1H), 5.75 (d, J = 3.0 Hz, 1H), 4.79 (ddd, J = 8.4, 5.3, 3.2 Hz, 1H), 3.46 (td, J = 3.5, 1.3 Hz, 1H), 3.33 (dd, J = 17.8, 5.3 Hz, 1H), 2.80 (dd, J = 17.8, 8.2 Hz, 1H), 2.38 - 2.33 (m, 1H), 2.31 (dd, J = 11.5, 1.4 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 198.2, 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, 33.1 ppm. HRMS: [M + H] + calcd for C 18 H 17 O3 + 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) = 14.980 min, t R (minor) = 10.787 min, ee = 99%.

[0050] Thus, the general reaction conditions for chiral oxygen-containing polycyclic bridged derivatives 4 were obtained: β-nitroketone 2 (0.12 mmol, 1.2 eq) was added to a solution of 2-hydroxycinnamaldehyde 1 (0.1 mmol, 1.0 eq), 3a (0.02 mmol, 0.2 eq), (S)-B3 (0.02 mmol, 0.2 eq) in 2-Me-THF (0.2 mL), the reaction was stirred at 25 °C for 48 h, then the product 4 was obtained by silica gel column chromatography 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] Example 2:

[0053]

[0054] Following the procedure of Example 1, using starting material 2b instead of 2a, and otherwise as described, compound 4b was obtained by silica gel column chromatography eluting with petroleum ether: ethyl acetate (10:1), 10 mg, 36% yield, ee = 96%.

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

[0056] 1 H NMR (400 MHz, CDC13) δ 7.19 - 7.13 (m, 1H), 6.84 - 6.79 (m, 3H), 5.69 (d, J = 2.7 Hz, 1H), 4.58 (ddd, J = 7.6, 6.0, 3.2 Hz, 1H), 3.30 (td, J = 3.3, 1.6 Hz, 1H), 2.69 (dd, J = 17.8, 5.9 Hz, 1H), 2.30 - 2.22 (m, 5H), 1.49 (p, J = 7.5 Hz, 2H), 1.33 - 1.16 (m, 6H), 0.86 (t, J = 7.1 Hz, 3H) ppm. 13 C NMR (100 MHz, CDC13) δ 209.2, 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, 13.9 ppm. HRMS: [M + H] + calcd for C 17 H 25 O3 + 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) = 9.940 min, t R (minor) = 8.440 min, ee = 96%.

[0057] Example 3:

[0058]

[0059] Following the procedure of Example 1, using starting material 2c instead of 2a, and otherwise as described, compound 4c was obtained by silica gel column chromatography eluting with petroleum ether: ethyl acetate (20:1), 21 mg, 74% yield, ee = 96%.

[0060] Test data for compound 4c are as follows:

[0061] 1 H NMR (400 MHz, CDC13) δ 7.80 (td, J = 7.6, 1.9 Hz, 1H), 7.48 (dddd, J = 8.7, 7.1, 5.0, 1.9 Hz, 1H), 7.19 (td, J = 7.6, 1.1 Hz, 2H), 7.12 (dd, J = 7.9, 1.8 Hz, 2H), 7.04 (ddd, J = 11.2, 8.3, 1.1 Hz, 1H), 6.85 (dd, J = 7.4, 1.8 Hz, 1H), 6.81 (dd, J = 8.0, 2.7 Hz, 2H), 6.76 (td, J = 7.4, 1.2 Hz, 1H), 5.74 (d, J = 3.0 Hz, 1H), 4.78 (dq, J = 8.3, 3.1 Hz, 1H), 3.42 (t, J = 2.8 Hz, 1H), 3.29 (ddd, J = 18.7, 5.8, 2.8 Hz, 1H), 2.84 (ddd, J = 18.6, 7.5, 2.9 Hz, 1H), 2.34 (dt, J = 11.6, 3.4 Hz, 1H), 2.29 (dd, J = 11.5, 1.4 Hz, 2H) ppm. 13 C NMR (100 MHz, CDC13) δ 196.1, 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, 33.0 ppm. 19 F NMR (375 MHz, CDC13) δ -109.1. HRMS: [M + H] + calcd for C 18 H 16 FO3 + 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) = 16.013 min, t R (minor) = 15.273 min, ee = 98%.

[0062] Example 4:

[0063]

[0064] The procedure of Example 1 was followed using starting material 2d instead of 2a, and the other conditions and procedures were the same, to give compound 4d, 21 mg, yield 67%, ee = 98% by silica gel column chromatography, eluted with petroleum ether: ethyl acetate (25: 1).

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

[0066] 1 H NMR (400 MHz, CDC13) δ 7.76 (t, J = 1.9 Hz, 1H), 7.61 (dt, J = 7.8, 1.3 Hz, 1H), 7.48 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.13 (ddd, J = 8.1, 7.2, 1.8 Hz, 1H), 6.81 (dd, J = 8.4, 1.3 Hz, 1H), 6.80 - 6.77 (m, 1H), 6.73 (td, J = 7.3, 1.2 Hz, 1H), 5.72 (d, J = 3.0 Hz, 1H), 4.74 (ddd, J = 8.4, 5.5, 3.2 Hz, 1H), 3.42 (td, J = 3.4, 1.3 Hz, 1H), 3.26 (dd, J = 17.8, 5.4 Hz, 1H), 2.74 (dd, J = 17.8, 8.1 Hz, 1H), 2.35 - 2.30 (m, 1H), 2.30 - 2.26 (m, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 196.8, 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, 33.0 ppm. HRMS: [M + H] + calcd for C 18 H 16 ClO3 + 315.0782, found 315.0780. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 210 nm, t R( major) = 12.047 min, t R (minor) = 9.833 min, ee = 98%.

[0067] Example 5:

[0068]

[0069] The procedure of Example 1 was followed using starting material 2e instead of 2a, with otherwise identical conditions and procedures, to give compound 4e, 18 mg, 58% yield, ee = 99%, by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (20: 1).

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

[0071] 1 H NMR (400 MHz, CDC13) δ 7.31 (d, J = 2.0 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.27 - 7.20 (m, 1H), 7.10 (ddd, J = 8.1, 7.4, 1.8 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.81 - 6.79 (m, 1H), 6.78 (d, J = 1.5 Hz, 1H), 6.71 (td, J = 7.4, 1.2 Hz, 1H), 5.70 (d, J = 3.1 Hz, 1H), 4.73 (ddd, J = 8.4, 5.3, 3.2 Hz, 1H), 3.77 (s, 3H), 3.41 (dq, J = 4.1, 1.3 Hz, 1H), 3.27 (dd, J = 17.8, 5.3 Hz, 1H), 2.74 (dd, J = 17.8, 8.2 Hz, 1H), 2.31 (dt, J = 11.6, 3.4 Hz, 1H), 2.28 - 2.23 (m, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 197.9, 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, 33.1 ppm. HRMS: [M + H] + calcd for C 19 H 19 O4 + 311.1278, found 311.1279. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 220 nm, t R( major) = 18.887 min, t R (minor) = 12.673 min, ee = 99%.

[0072] Example 6:

[0073]

[0074] The procedure of Example 1 was followed using starting material 2f instead of 2a, with otherwise identical conditions and procedures, to give compound 4f, 22 mg, 61% yield, ee = 98%, by silica gel column chromatography eluting with petroleum ether: ethyl acetate (25: 1).

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

[0076] 1 H NMR (400 MHz, CDC13) δ 7.66 - 7.62 (m, 2H), 7.56 - 7.51 (m, 2H), 7.14 (ddd, J = 8.1, 7.2, 1.8 Hz, 1H), 6.83 (dd, J = 8.1, 1.1 Hz, 1H), 6.80 (dd, J = 7.4, 1.9 Hz, 1H), 6.74 (td, J = 7.3, 1.2 Hz, 1H), 5.74 (d, J = 3.0 Hz, 1H), 4.76 (ddd, J = 8.4, 5.5, 3.2 Hz, 1H), 3.43 (td, J = 3.5, 1.3 Hz, 1H), 3.26 (dd, J = 17.7, 5.5 Hz, 1H), 2.75 (dd, J = 17.7, 8.0 Hz, 1H), 2.35 (dt, J = 11.6, 3.3 Hz, 1H), 2.30 (dd, J = 11.5, 1.4 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 197.1, 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, 33.0 ppm. HRMS: [M + H] + calcd for C 18 H 16 BrO3 + 359.0277, found 359.0278. HPLC analysis: DAICEL CHIRALPAK OD-H, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 260 nm, t R( major) = 11.840 min, t R (minor) = 9.907 min, ee = 98%.

[0077] Example 7:

[0078]

[0079] Following the procedure of Example 1, using starting material 2g instead of 2a, and otherwise as described, compound 4g was obtained by column chromatography on silica gel eluting with petroleum ether: ethyl acetate (10:1) in 15 mg, 48% yield, ee = 97%.

[0080] Test data for compound 4g are as follows:

[0081] 1 H NMR (400 MHz, CDC13) δ 7.73 - 7.67 (m, 2H), 7.06 (ddd, J = 9.0, 7.5, 1.8 Hz, 1H), 6.81 - 6.77 (m, 2H), 6.76 (d, J = 1.5 Hz, 1H), 6.74 (d, J = 1.5 Hz, 1H), 6.67 (td, J = 7.4, 1.2 Hz, 1H), 5.67 (d, J = 3.0 Hz, 1H), 4.70 (ddd, J = 8.4, 5.3, 3.2 Hz, 1H), 3.76 (s, 3H), 3.37 (td, J = 3.5, 1.2 Hz, 1H), 3.20 (dd, J = 17.5, 5.3 Hz, 1H), 2.67 (dd, J = 17.5, 8.2 Hz, 1H), 2.27 (dt, J = 11.6, 3.4 Hz, 1H), 2.22 (dd, J = 11.5, 1.4 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 196.6, 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, 33.1 ppm. HRMS: [M + H] + calcd for C 19 H 19 O4 + 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) = 27.953 min, t R (minor) = 19.307 min, ee = 97%.

[0082] Example 8:

[0083]

[0084] The procedure of Example 1 was followed using starting material 2h instead of 2a, with otherwise identical conditions and procedures, to give compound 4h, 22 mg, 81% yield, ee = 99%, by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (10: 1).

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

[0086] 1 H NMR (400 MHz, CDC13) δ 7.52 (dd, J = 1.8, 0.8 Hz, 1H), 7.15 (ddd, J = 8.0, 7.3, 1.7 Hz, 1H), 7.04 (dd, J = 3.5, 0.8 Hz, 1H), 6.87 (dd, J = 7.4, 1.7 Hz, 1H), 6.83 (dd, J = 8.2, 1.1 Hz, 1H), 6.78 (td, J = 7.3, 1.2 Hz, 1H), 6.47 (dd, J = 3.6, 1.7 Hz, 1H), 5.73 (d, J = 2.9 Hz, 1H), 4.74 (ddd, J = 7.8, 5.9, 3.2 Hz, 1H), 3.38 (td, J = 3.4, 1.4 Hz, 1H), 3.15 (dd, J = 17.3, 5.8 Hz, 1H), 2.66 (dd, J = 17.2, 7.8 Hz, 1H), 2.36 - 2.31 (m, 1H), 2.30 (d, J = 2.4 Hz, 1H) ppm. 13 CNMR (100 MHz, CDC13) δ 186.6, 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, 33.0 ppm. HRMS: [M + H] + calcd for C 16 H 15 O4 + 271.0965, found 271.0968. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 260 nm, t R( major) = 16.247 min, t R (minor) = 12.353 min, ee = 99%.

[0087] Example 9:

[0088]

[0089] The procedure of Example 1 was followed using starting material 2i instead of 2a, with otherwise identical conditions and procedures, to give compound 4i, 20 mg, 61% yield, ee = 99%, by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (25: 1).

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

[0091] 1 H NMR (400 MHz, CDC13) δ 8.26 (s, 1H), 7.90 (t, J = 8.5 Hz, 2H), 7.84 (dd, J = 9.0, 2.3 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.89 - 6.83 (m, 2H), 6.73 (t, J = 7.4 Hz, 1H), 5.78 (t, J = 2.6 Hz, 1H), 4.85 (ddt, J = 8.3, 5.3, 2.5 Hz, 1H), 3.53 - 3.44 (m, 2H), 2.94 (ddd, J = 17.6, 8.4, 2.1 Hz, 1H), 2.42 - 2.35 (m, 1H), 2.33 (d, J = 11.5 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 198.1, 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, 33.2 ppm. HRMS: [M + H] + calcd for C 22 H 19 O3 + 331.1329, found 331.1331. HPLC analysis: DAICEL CHIRALPAK AD-H, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 240 nm, t R( major) = 19.007 min, t R (minor) = 17.387 min, ee = 99%.

[0092] Example 10:

[0093]

[0094] The procedure of Example 1 was followed using starting material 2j instead of 2a, and the other conditions and procedures were the same, to give compound 4j, 16 mg, yield 48%, ee = 99% by silica gel column chromatography, eluted with petroleum ether: ethyl acetate (20: 1).

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

[0096] 1 H NMR (400 MHz, CDC13) δ 7.83 (dd, J = 11.9, 8.1 Hz, 2H), 7.69 (d, J = 1.7 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.87 (dd, J = 10.5, 7.9 Hz, 2H), 6.77 (t, J = 7.4 Hz, 1H), 5.76 (t, J = 2.2 Hz, 1H), 4.79 (tt, J = 5.1, 3.1 Hz, 1H), 3.46 - 3.41 (m, 1H), 3.37 (ddd, J = 17.1, 5.6, 1.6 Hz, 1H), 2.85 (ddd, J = 17.1, 8.1, 1.7 Hz, 1H), 2.39 - 2.27 (m, 2H) ppm. 13 C NMR (100 MHz, CDC13) δ 192.4, 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, 33.1 ppm. HRMS: [M + H] + calcd for C 20 H 17 O3S + 337.0893, found 337.0895. HPLC analysis: DAICEL CHIRALPAK IB, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 205 nm, t R( major) = 14.773 min, t R (minor) = 10.993 min, ee = 99%.

[0097] Example 11:

[0098]

[0099] The procedure of Example 1 was followed using starting material 2k instead of 2a, with otherwise identical conditions and procedures, to give compound 4k, 21 mg, 45% yield, ee = 99%, by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (9: 1).

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

[0101] 1 H NMR (400 MHz, CDC13) δ 8.31 - 8.26 (m, 1H), 7.94 - 7.89 (m, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.40 - 7.30 (m, 3H), 7.28 (s, 1H), 7.21 (td, J = 7.8, 1.8 Hz, 1H), 6.90 (dd, J = 8.1, 1.1 Hz, 1H), 6.87 (dd, J = 7.4, 1.7 Hz, 1H), 6.77 (td, J = 7.5, 1.2 Hz, 1H), 5.75 (d, J = 2.5 Hz, 1H), 4.78 (ddd, J = 7.5, 6.1, 3.2 Hz, 1H), 3.40 (td, J = 3.3, 1.7 Hz, 1H), 3.19 (dd, J = 16.5, 6.1 Hz, 1H), 2.74 (dd, J = 16.6, 7.6 Hz, 1H), 2.37 (s, 3H), 2.35 - 2.31 (m, 2H) ppm. 13 C NMR (100 MHz, CDC13) δ 193.7, 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, 21.7 ppm. HRMS: [M + H] + calcd for C 27 H 24 NO5S + 474.1370, found 474.1370. HPLC analysis: DAICEL CHIRALPAK IB, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 205 nm, t R( major) = 17.080 min, t R (minor) = 16.073 min, ee = 99%.

[0102] Example 12:

[0103]

[0104] Following the procedure of Example 1, using starting material 2l instead of 2a, and otherwise as described, compound 4l was obtained by column chromatography on silica gel eluting with petroleum ether: ethyl acetate (12:1), 22 mg, 72% yield, ee = 99%.

[0105] Test data for compound 4l are as follows:

[0106] 1 H NMR (400 MHz, CDC13) δ 7.50 - 7.46 (m, 2 H), 7.43 - 7.33 (m, 4 H), 7.17 (td, J = 7.9, 1.8 Hz, 1 H), 6.88 (dd, J = 7.4, 1.8 Hz, 1 H), 6.85 - 6.77 (m, 2 H), 6.62 (d, J = 16.2 Hz, 1 H), 5.74 (d, J = 2.9 Hz, 1 H), 4.71 (ddd, J = 7.9, 5.7, 3.2 Hz, 1 H), 3.37 (td, J = 3.4, 1.4 Hz, 1 H), 3.00 (dd, J = 17.3, 5.7 Hz, 1 H), 2.54 (dd, J = 17.4, 7.9 Hz, 1 H), 2.38 - 2.31 (m, 1 H), 2.31 - 2.26 (m, 1 H) ppm. 13 C NMR (100 MHz, CDC13) δ 198.0, 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, 33.0 ppm. HRMS: [M + H] + calcd for C 20 H 19 O3 + 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) = 13.873 min, t R (minor) = 9.733 min, ee = 99%.

[0107] Example 13:

[0108]

[0109] The procedure of Example 1 was followed using starting material 1b instead of 1a, with otherwise identical conditions and procedures, to give compound 4m, 15 mg, 50% yield, ee = 99%, by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (20: 1).

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

[0111] 1 H NMR (400 MHz, CDC13) δ 7.80 (dd, J = 8.4, 1.3 Hz, 2H), 7.57 - 7.50 (m, 1H), 7.41 (t, J = 7.7 Hz, 2H), 6.94 (ddd, J = 10.7, 8.1, 1.6 Hz, 1H), 6.67 (td, J = 7.8, 4.6 Hz, 1H), 6.61 (dt, J = 7.5, 1.3 Hz, 1H), 5.84 (d, J = 3.1 Hz, 1H), 4.79 (ddd, J = 8.4, 5.1, 3.2 Hz, 1H), 3.54 (td, J = 3.3, 1.5 Hz, 1H), 3.37 (dd, J = 17.9, 5.1 Hz, 1H), 2.78 (dd, J = 17.9, 8.5 Hz, 1H), 2.39 (dt, J = 11.8, 3.5 Hz, 1H), 2.32 (dd, J = 11.8, 1.2 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 198.0, 152.7, 150.3, 139.7, 139.6, 136.7, 133.5, 128.7, 128.0, 127.8, 123.2, 123.2, 120.6, 120.5, 116.0, 115.8, 99.4, 85.0, 40.7, 39.5, 33.1 ppm. 19 F NMR (375 MHz, CDC13) δ -136.3. HRMS: [M + H] + calcd for C 18 H 16 FO3 + 299.1078, found 299.1079. HPLC analysis: DAICEL CHIRALPAK IG, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 205 nm, t R( major) = 43.007 min, t R (minor) = 17.567 min, ee = 99%.

[0112] Example 14:

[0113]

[0114] Following the procedure of Example 1, replacing starting material 1a with 1c, and otherwise as described, compound 4n was obtained by silica gel column chromatography eluting with petroleum ether: ethyl acetate (25:1), 18 mg, 56% yield, ee = 99%.

[0115] Test data for compound 4n are as follows:

[0116] 1 H NMR (400 MHz, CDC13) δ 7.81 (d, J = 8.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 6.87 - 6.81 (m, 1H), 6.80 - 6.69 (m, 2H), 5.74 (t, J = 2.4 Hz, 1H), 4.76 (qd, J = 5.0, 2.2 Hz, 1H), 3.48 (s, 1H), 3.37 (ddd, J = 17.9, 5.2, 1.7 Hz, 1H), 2.78 (ddd, J = 17.9, 8.5, 1.8 Hz, 1H), 2.41 - 2.32 (m, 1H), 2.26 (d, J = 11.7 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 197.9, 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, 33.1 ppm. HRMS: [M + H] + calcd for C 18 H 16 ClO3 + 315.0782, found 315.0781. HPLC analysis: DAICEL CHIRALPAK IC, n-hexane / isopropyl alcohol = 90 / 10, 1.0 mL / min, λ = 240 nm, t R( major) = 11.227 min, t R (minor) = 7.947 min, ee = 99%.

[0117] Example 15:

[0118]

[0119] Following the procedure of Example 1, replacing starting material 1a with 1d, and otherwise as described, compound 4o was obtained by silica gel column chromatography eluting with petroleum ether: ethyl acetate (20:1), 16 mg, 52% yield, ee = 98%.

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

[0121] 1 H NMR (400 MHz, CDC13) δ 7.84 - 7.78 (m, 2H), 7.53 (ddt, J = 8.1, 6.9, 1.3 Hz, 1H), 7.45 - 7.38 (m, 2H), 6.72 (d, J = 8.3 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 6.31 (dd, J = 8.3, 2.5 Hz, 1H), 5.72 (d, J = 3.2 Hz, 1H), 4.75 (ddd, J = 8.2, 5.3, 3.1 Hz, 1H), 3.73 (s, 3H), 3.43 - 3.39 (m, 1H), 3.32 (dd, J = 17.8, 5.3 Hz, 1H), 2.81 (dd, J = 17.8, 8.1 Hz, 1H), 2.32 (dt, J = 11.6, 3.5 Hz, 1H), 2.26 (dd, J = 11.5, 1.3 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 198.1, 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, 33.4 ppm. HRMS: [M+H] + calcd for C 19 H 19 O4 + 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) = 16.513 min, t R (minor) = 15.240 min, ee = 98%.

[0122] Example 16:

[0123]

[0124] Following the procedure of Example 1, replacing 1a with 1e, and keeping other conditions and procedures the same, compound 4p was obtained by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (25: 1), 20 mg, yield 56%, ee = 99%.

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

[0126] 1 H NMR (400 MHz, CDC13) δ 7.81 (d, J = 8.0 Hz, 2H), 7.59 - 7.51 (m, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.28 - 7.20 (m, 1H), 6.97 (t, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.6, 1.6 Hz, 1H), 5.76 - 5.70 (m, 1H), 4.78 (tq, J = 5.0, 2.7, 2.3 Hz, 1H), 3.46 - 3.40 (m, 1H), 3.34 (dd, J = 17.6, 5.5 Hz, 1H), 2.81 (ddd, J = 17.7, 8.0, 1.6 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.26 (d, J = 11.7 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 198.1, 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, 32.9 ppm. HRMS: [M + H] + calcd for C 18 H 16 BrO3 + 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) = 12.420 min, t R (minor) = 11.120 min, ee = 99%.

[0127] Example 17:

[0128]

[0129] Following the procedure of Example 1, replacing starting material 1a with 1f, and following the same conditions and procedures, compound 4q was obtained by silica gel column chromatography eluted with petroleum ether: ethyl acetate (25: 1), 16 mg, yield 54%, ee = 98%.

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

[0131] 1H NMR (400 MHz, CDC13) δ 7.79 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 6.93 (d, J = 7.8 Hz, 1H), 6.73 (dd, J = 8.2, 2.4 Hz, 1H), 6.63 - 6.57 (m, 1H), 5.75 - 5.70 (m, 1H), 4.78 (ddt, J = 8.4, 5.3, 2.7 Hz, 1H), 3.38 (d, J = 3.3 Hz, 1H), 3.30 (dd, J = 17.6, 4.9 Hz, 1H), 2.82 (ddd, J = 17.6, 8.3, 2.4 Hz, 1H), 2.36 - 2.30 (m, 1H), 2.28 (d, J = 10.3 Hz, 1H), 2.08 (s, 3H) ppm. 13 C NMR (100 MHz, CDC13) δ 198.5, 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, 20.4 ppm. HRMS: [M + H] + calcd for C 19 H 19 O3 + 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) = 7.607 min, t R (minor) = 6.927 min, ee = 98%.

[0132] Example 18:

[0133]

[0134] Following the procedure of Example 1, replacing la with starting material 1g, and following the same conditions and procedures, compound 4r was obtained by silica gel column chromatography eluted with petroleum ether: ethyl acetate (25: 1), 16 mg, yield 52%, ee = 98%.

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

[0136] 1H NMR (400 MHz, CDC13) δ 7.78 (d, J = 7.1 Hz, 2H), 7.55 - 7.48 (m, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.09 (td, J = 8.2, 2.1 Hz, 1H), 6.49 (dd, J = 8.3, 2.0 Hz, 1H), 6.32 (dd, J = 8.3, 2.0 Hz, 1H), 5.73 (t, J = 2.6 Hz, 1H), 4.89 (tt, J = 5.9, 2.5 Hz, 1H), 3.76 (q, J = 2.9 Hz, 1H), 3.41 (s, 3H), 3.09 (ddd, J = 17.4, 6.2, 2.1 Hz, 1H), 3.00 (ddd, J = 17.4, 7.3, 2.1 Hz, 1H), 2.38 - 2.27 (m, 1H), 2.20 (d, J = 11.6 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 197.9, 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, 32.8 ppm. HRMS: [M + H] + calcd for C 19 H 19 O4 + 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) = 26.460 min, t R (minor) = 20.067 min, ee = 98%.

[0137] Example 19:

[0138]

[0139] Following the procedure of Example 1, replacing starting material 1a with 1h, and following the same conditions and procedures, compound 4s was obtained by silica gel column chromatography eluted with petroleum ether: ethyl acetate (25: 1), 15 mg, yield 42%, ee = 99%.

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

[0141] 1H NMR (400 MHz, CDC13) δ 7.82 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.41 (td, J = 7.9, 1.9 Hz, 2H), 7.11 (d, J = 7.9 Hz, 1H), 7.04 (td, J = 8.0, 1.9 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.74 (t, J = 2.6 Hz, 1H), 4.94 (tt, J = 5.9, 2.5 Hz, 1H), 3.85 (d, J = 3.9 Hz, 1H), 3.10 (dd, J = 6.2, 2.0 Hz, 2H), 2.46 - 2.36 (m, 1H), 2.25 (d, J = 11.8 Hz, 1H) ppm. 13 C NMR (100 MHz, CDC13) δ 197.7, 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, 33.0 ppm. HRMS: [M + H] + calcd for C 18 H 16 BrO3 + 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) = 29.147 min, t R (minor) = 33.053 min, ee = 99%.

[0142] Example 20: Scale-up experiment

[0143] To verify the use of the reaction, a preparation scale synthesis of product 4a was carried out under the optimal reaction conditions, which 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 merely describes the specific embodiments of the present application, but the protection scope of the present application is not limited thereto, any changes or replacements within the technical range disclosed by the present application can be easily thought by any person skilled in the art, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A method for asymmetric catalytic synthesis of oxygen-containing multi-component bridged ring compounds, characterized in that, The process includes 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, the reaction is carried out in an organic solvent under the action of an organic base; after the reaction, the target product 4 is obtained by silica gel column chromatography for separation and purification. The reaction formula is as follows: ； Among them, R 1 Selected from hydrogen, methyl, methoxy, and halogen; wherein the halogen is one of fluorine, chlorine, bromine, and iodine; R 2 It is one of pentyl, phenyl, 2-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-bromophenyl, 4-methoxyphenyl, 2-furanyl, 2-naphthyl, 2-benzothiophenyl, 3-N-Ts-indolyl, and styrylyl; The chiral secondary amine is selected from the following compounds: ； The organic base is one of TEA, DBU, DABCO, quinine, or a thiourea tertiary amine derivative. The thiourea tertiary amine derivative is selected from the following compounds: 。 2. The method for synthesizing oxygen-containing multi-component bridged ring compounds according to claim 1, characterized in that, The organic solvent is one of tetrahydrofuran, 1,2-dichloroethane, diethyl ether, ethyl acetate, toluene, 2-methyltetrahydrofuran, or acetone.

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

2.

4. The method for synthesizing oxygen-containing multi-component bridged ring compounds according to claim 1, characterized in that, The molar ratio of 2-hydroxycinnamaldehyde or its derivative to β-nitroketone is 1.0:(0.8-1.5).

5. The method for synthesizing oxygen-containing multi-component bridged ring compounds according to claim 1, characterized in that, The reaction temperature is 0-40℃.

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