A method for synthesizing (±)-cycloclavine analogs by base-catalyzed dearomatization reaction

Abstract

The application discloses a series of compounds with various cyclopropyl spirocyclohexanedione skeletons synthesized by base-assisted p / ortho-bromophenol and active olefin (methylene malonate) [2+1] de-aromatic reaction. With bromonaphthol and methylene malonate as raw materials, de-aromatic Michael addition occurs in the presence of a base, followed by intramolecular free radical SRN1 dehalogenation cyclopropanation, and then derivatization and ring closure to obtain (±)‑cycloclavine analogues. The method has the advantages of good chemical selectivity and high yield, and the product contains a chiral quaternary carbon center.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing (±)-cycloclavine analogues by [2+1] de-aromatization of bromonaphthol with electron-deficient olefins, belonging to the technical field of asymmetric synthesis in organic chemistry. BACKGROUND

[0002] Cycloclavine, a special ergot alkaloid, was first isolated from the seeds of ipomoea hildebrandtii by Hoffman et al. in 1969. It belongs to the clavine group of ergot alkaloids. The main difference between cycloclavine and ergot alkaloids and their derivatives is that it has a pentacyclic structure with three consecutive chiral centers (5R, 8R, 10R), including two quaternary carbons on the cyclopropane ring, and a methyl group at the C8 position. Due to its consecutive chiral centers and fused polycyclic skeleton, synthesis is a great challenge. Many studies on the synthesis of ergot alkaloids (±)-cycloclavine and related alkaloid skeletons are based on the key intermediate Uhle ketone. For example: In 2008, the Szántay group started from the known α-bromo-Uhle ketone and completed the first total synthesis of (±)-cycloclavine in 8 steps with a total yield of 1.1%. However, this route has several reactions with low yield, and the synthesis of α-bromo-Uhle ketone also requires 7 steps.

[0003]

[0004] In 2016, the Opatz research group published a modular form synthesis of (±)-cycloclavine. The Szántay intermediate A was obtained in 7 steps with a yield of 17%, and then the cyclopropanation by the Szántay research group could complete the synthesis of (±)-cycloclavine.

[0005]

[0006] In 2017, the Cao research group first asymmetrically synthesized Szántay's amine (+)-2 from 4-bromoindole through 11 steps with a total yield of 19.7% by sulfoximine and rhodium-catalyzed C=C bond isomerization, which is a key precursor for obtaining (+)-cycloclavine directly.

[0007]

[0008]

[0009] However, a new method for synthesizing (±)-cycloclavine analogues by constructing a cyclopropane spirocyclohexenone has not been reported. SUMMARY

[0010] To solve the above problems, the application provides a method for synthesizing (±)-cycloclavine analogues by [2+1] de-aromatization reaction of bromine-containing naphthol and electron-deficient olefin. The bromine-containing naphthol 1 and electron-deficient olefin 2 are used as raw materials, and under the action of a base, [2+1] de-aromatization reaction is carried out to synthesize cyclopropane spiro cyclohexene ketone, and (±)-cycloclavine analogues 3 are further derived. The method provides a mild, simple and efficient way for product synthesis.

[0011] The method for synthesizing cyclopropane spiro cyclohexene ketone by [2+1] de-aromatization reaction provided by the application comprises the following steps: using p- / o-bromophenol 1 and electron-deficient olefin 2 as raw materials, and in the presence of a base, [2+1] de-aromatization reaction is carried out to synthesize cyclopropane spiro cyclohexene ketone compound 3. The reaction equation is represented as:

[0012]

[0013] wherein: EWG=CO2 i Pr, CO2Et, CO2 t Bu, CO2Me, CN; R1 is selected from H, C1-C4 alkyl, C1-C4 alkoxy, halogen; R2 is selected from H, phenyl.

[0014] Further, in the above technical solution, the base is selected from Cs2CO3, K3PO4, Na2CO3, K2CO3, Et3N, KOH or NaH.

[0015] Further, in the above technical solution, the reaction is carried out in an organic solvent, and the organic solvent is selected from acetonitrile, diethyl ether, chlorobenzene, tetrahydrofuran. The preferred solvent is tetrahydrofuran.

[0016] Further, in the above technical solution, the molar ratio of the bromine-containing naphthol 1, methylene malonate 2 and base is 1:2:2.

[0017] Further, in the above technical solution, the reaction temperature is selected from 0-50℃. The preferred temperature is 25℃.

[0018] Further, the product cyclopropyl spiro cyclohexanedione skeleton compound 3b is hydrolyzed in the presence of an inorganic base, then condensed in the presence of EDCI to obtain compound 12, and then cyclized in the presence of sodium hydride to obtain (±)-cycloclavine analogue 13.

[0019]

[0020] Further, in the above technical solution, the inorganic base is selected from sodium carbonate, sodium hydroxide, potassium carbonate or potassium hydroxide.

[0021] Advantages of the Invention:

[0022] 1. The [2+1] de-aromatic reaction of bromonaphthol 1 and electron-deficient olefin 2 under the action of base to obtain cyclopropyl spirocyclohexanedione skeleton compound 3. The raw materials of the present application are easy to obtain, the selectivity of the product is high, and the reaction yield can reach 96% at most.

[0023] 2. Compound 3b is hydrolyzed in the presence of base and condensed in the presence of EDCI to obtain compound 12, and then cyclized in the presence of sodium hydride to obtain (±)-cycloclavine analogue 13. It has a chiral quaternary carbon center, and the reaction is novel. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 It is a single crystal X-ray diffraction spectrum of compound 3e in Example 5;

[0025] Figure 2 It is a single crystal X-ray diffraction spectrum of compound 3g in Example 6;

[0026] Figure 3 It is a single crystal X-ray diffraction spectrum of compound 7c in Example 11; DETAILED DESCRIPTION

[0027] Example 1

[0028] Take the reaction of p / o-bromophenol 1a and electron-deficient olefin 2a to generate 3a as an example, and carry out reaction condition optimization, wherein 4a and 5 are by-products generated in the reaction, and the reaction equation is as follows:

[0029]

[0030]

[0031] a Unless otherwise specified, the reaction conditions are as follows: 1a (0.2 mmol), 2a (0.4 mmol), base (2.0 equiv) in 2 mL of solvent, room temperature for 3 hours. b NMR yield is 1,3,5-trimethoxybenzene as an internal standard. c -40℃ overnight. d Temperature-78℃ overnight. d Separation yield.

[0032] During the reaction condition screening process, the effects of different bases and organic solvents on the reaction were investigated, and finally Cs2CO3 was determined as the best base and tetrahydrofuran was determined as the best reaction solvent.

[0033] To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1a (44.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), and the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate. The organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 3a (61.7 mg, 90%). TLC: Rf = 0.5 (PE / EA = 5: 1). f 1 H NMR (600 MHz, CDC13) δ 8.24 (d, J = 7.4 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.28 (d, J = 10.3 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 10.2 Hz, 1H), 5.06 (hept, J = 6.2 Hz, 1H), 4.70 (hept, J = 6.3 Hz, 1H), 2.71 (d, J = 6.4 Hz, 1H), 2.56 (d, J = 6.4 Hz, 1H), 1.24 (d, J = 6.0 Hz, 3H), 1.23 (d, J = 5.9 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H), 0.49 (d, J = 6.2 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 184.9, 166.8, 165.3, 147.1, 139.0, 133.8, 131.9, 130.9, 127.7, 127.6, 123.1, 70.9, 69.7, 48.5, 35.3, 26.8, 21.9, 21.7, 21.3, 20.8. HRMS (ESI) m / z: [M + Na] + calcd for C 20 H 22 NaO5365.1359; found 365.1359.

[0034] Example 2:

[0035]

[0036] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1a (44.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of methylenemalonate 2b (57.7 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), and the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate. The organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 3b (52.7 mg, 92%). TLC: Rf= 0.2 (PE / EA = 5: 1). f 1 H NMR (600 MHz, CDC13) δ 8.24 (dd, J = 7.7, 1.7 Hz, 1H), 7.49 (td, J = 7.6, 1.7 Hz, 1H), 7.45 (td, J = 7.5, 1.2 Hz, 1H), 7.21 (d, J = 10.3 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 10.4 Hz, 1H), 3.77 (s, 3H), 3.35 (s, 3H), 2.75 (d, J = 6.6 Hz, 1H), 2.62 (d, J = 6.6 Hz, 1H). 13 C NMR (101 MHz, CDC13) δ 184.5, 167.4, 166.3, 146.4, 138.6, 133.7, 131.9, 131.2, 127.9, 127.7, 122.5, 53.7, 52.9, 48.0, 35.4, 27.0. HRMS (ESI) m / z: [M + Na] + calcd for C 16 H 14 NaO5309.0733; found 309.0736.

[0037] Example 3:

[0038]

[0039] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1a (44.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of ethyl methylene malonate 2c (68.9 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), and the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate. The organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 3c (52.7 mg, 92%). TLC: Rf = 0.4 (PE / EA = 5: 1). f 1 H NMR (600 MHz, CDC13) δ 8.23 (dd, J = 7.7, 1.7 Hz, 1H), 7.47 (td, J = 7.6, 1.7 Hz, 1H), 7.44 (td, J = 7.4, 1.3 Hz, 1H), 7.23 (d, J = 10.3 Hz, 1H), 6.93 (dd, J = 7.8, 1.2 Hz, 1H), 6.61 (d, J = 10.3 Hz, 1H), 4.24 - 4.19 (m, 2H), 3.95 - 3.89 (m, 1H), 3.73 - 3.67 (m, 1H), 2.73 (d, J = 6.5 Hz, 1H), 2.58 (d, J = 6.6 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 184.7, 167.1, 165.9, 146.8, 138.8, 133.8, 131.8, 131.0, 127.7, 127.6, 122.8, 62.8, 62.0, 48.3, 35.3, 26.8, 14.0, 13.6. HRMS (ESI) m / z: [M + Na] + calcd for C 16 H 14 NaO5337.1046; found 337.1045.

[0040] Example 4:

[0041]

[0042] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1a (44.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of tert-butyl methylene malonate 2d (91.3 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), and the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate. The organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 3d (61.7 mg, 86%). TLC: Rf = 0.6 (PE / EA = 5: 1). f 1 H NMR (400 MHz, CDC13) δ 8.26 - 8.21 (m, 1H), 7.51 - 7.43 (m, 2H), 7.20 (d, J = 10.3 Hz, 1H), 7.02 (dd, J = 7.5, 1.6 Hz, 1H), 6.61 (d, J = 10.3 Hz, 1H), 2.64 (d, J = 6.4 Hz, 1H), 2.51 (d, J = 6.4 Hz, 1H), 1.47 (s, 9H), 1.11 (s, 9H). 13 C NMR (151 MHz, CDC13) δ 185.1, 166.3, 164.7, 147.7, 139.2, 133.8, 132.0, 130.6, 127.5, 127.4, 123.9, 83.8, 82.6, 49.9, 35.1, 28.2, 28.04, 27.97, 27.6, 26.4. HRMS (ESI) m / z: [M + Na] + calcd for C 22 H 26 NaO5393.1672; found 393.1672.

[0043] Example 5:

[0044]

[0045] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1a (44.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of 2-benzylidene malononitrile 2e (61.7 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube. The test tube was sealed with a rubber septum. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 3e (41.4 mg, 70%). TLC: Rf = 0.3 (PE / EA = 5: 1). f = 0.3 (PE / EA = 5: 1). 1 H NMR (400 MHz, CDC13) δ 8.39 (dd, J = 7.8, 1.6 Hz, 1H), 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.69 (td, J = 7.6, 1.1 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.42 - 7.37 (m, 3H), 6.82 (d, J = 10.5 Hz, 1H), 6.55 (d, J = 10.5 Hz, 1H), 4.36 (s, 1H). 13 C NMR (101 MHz, CDC13) δ 182.9, 140.3, 133.8, 133.4, 133.1, 130.0, 129.9, 129.8, 129.7, 128.5, 128.4, 123.8, 112.1, 111.4, 43.2, 40.7, 22.8. HRMS (ESI) m / z: [M + Na] + calcd for C 20 H 12 NNaO 319.0842; found 319.0836.

[0046] Example 6:

[0047]

[0048] To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1 g (60.4 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 3 g (78.4 mg, 93%). TLC: Rf = 0.5 (PE / EA = 5: 1). f 1 H NMR (600 MHz, CDC13) δ 8.06 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.4, 1.7 Hz, 1H), 7.20 (d, J = 10.3 Hz, 1H), 7.07 (d, J = 1.7 Hz, 1H), 6.58 (d, J = 10.3 Hz, 1H), 5.03 (hept, J = 6.2 Hz, 1H), 4.80 (hept, J = 6.3 Hz, 1H), 2.63 (d, J = 6.6 Hz, 1H), 2.56 (d, J = 6.6 Hz, 1H), 1.23 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H), 0.64 (d, J = 6.3 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 183.9, 166.3, 164.9, 146.8, 140.8, 132.5, 131.0, 130.6, 129.1, 127.4, 126.3, 71.0, 70.1, 48.7, 34.6, 26.9, 21.8, 21.6, 21.4, 20.9. HRMS (ESI) m / z: [M + Na] + calcd for C 20 H 21 BrNaO5443.0465; found 443.0462.

[0049] Example 7:

[0050]

[0051] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1i (59.8 mg, 0.2 mmol, 1.0 eq) and Cs2CO3(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate, the organic layer was dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the pure product 3i (68.5 mg, 82%). TLC: Rf = 0.4 (PE / EA = 5:1). f 1 H NMR (400 MHz, CDC13) δ 8.30 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 8.1, 1.7 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.52 - 7.45 (m, 2H), 7.44 - 7.36 (m, 1H), 7.30 (d, J = 10.4 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 6.64 (d, J = 10.3 Hz, 1H), 5.07 (hept, J = 6.3 Hz, 1H), 4.71 (hept, J = 6.3 Hz, 1H), 2.83 (d, J = 6.5 Hz, 1H), 2.60 (d, J = 6.6 Hz, 1H), 1.26 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H), 0.44 (d, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 184.6, 166.6, 165.3, 146.9, 144.6, 139.8, 139.2, 132.5, 130.9, 129.2, 128.4, 128.1, 127.3, 126.3, 121.7, 70.8, 69.6, 48.7, 35.5, 26.5, 21.8, 21.6, 21.2, 20.7. HRMS (ESI) m / z: [M + Na] + calcd for C 26 H 26 NaO5441.1673; found 441.1667.

[0052] Example 8:

[0053]

[0054] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 1j (47.4 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube. The test tube was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 3j (52.7 mg, 87%). TLC: Rf = 0.4 (PE / EA = 10: 1). f 1 H NMR (400 MHz, CDC13) δ 8.29 - 8.21 (m, 1H), 7.49 - 7.40 (m, 2H), 7.03 (m, 1H), 6.98 - 6.91 (m, 1H), δ 5.06 (hept, J = 6.2 Hz, 1H), 4.70 (hept, J = 6.3 Hz, 1H), 2.67 (d, J = 6.4 Hz, 1H), 2.52 (d, J = 6.4 Hz, 1H), 2.06 (d, J = 1.4 Hz, 3H), 1.23 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H), 0.50 (d, J = 6.3 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 185.6, 166.9, 165.6, 142.3, 139.1, 137.7, 133.7, 131.5, 127.7, 127.6, 123.0, 70.8, 69.7, 48.1, 35.0, 26.4, 21.8, 21.7, 21.4, 20.8, 16.6. HRMS (ESI) m / z: [M + Na] + calcd for C 21 H 24 NaO5379.1516; found 379.1514.

[0055] Example 9:

[0056]

[0057] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 6a (44.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), and the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, and the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 7a (52.0 mg, 76%). TLC: Rf = 0.4 (PE / EA = 5: 1). f 1 H NMR (400 MHz, CDC13) δ 7.55 (d, J = 9.8 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.33 - 7.26 (m, 2H), 7.15 - 7.07 (m, 1H), 6.30 (d, J = 9.8 Hz, 1H), 4.97 (hept, J = 6.2 Hz, 1H), 4.74 (hept, J = 6.2 Hz, 1H), 2.86 (d, J = 5.7 Hz, 1H), 2.55 (d, J = 5.7 Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H), 0.68 (d, J = 6.3 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 194.4, 164.8, 163.8, 145.0, 134.7, 132.0, 129.7, 128.9, 127.6, 125.8, 125.7, 70.1, 69.7, 54.2, 41.9, 21.6, 21.4, 21.3, 21.2, 20.6. HRMS (ESI) m / z: [M + Na] + calcd for C 20 H 22 NaO5365.1359; found 365.1363.

[0058] Example 10:

[0059]

[0060] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 6b (60.4 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 7b (73.3 mg, 87%). TLC: Rf = 0.4 (PE / EA = 5:1). f 1 H NMR (400 MHz, CDC13) δ 7.51 (d, J = 9.8 Hz, 1H), 7.45 (dd, J = 8.1, 1.9 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.32 (d, J = 9.8 Hz, 1H), 4.98 (hept, J = 6.3 Hz, 1H), 4.83 (hept, J = 6.3 Hz, 1H), 2.89 (d, J = 5.9 Hz, 1H), 2.51 (d, J = 5.9 Hz, 1H), 1.23 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.2 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 193.3, 164.5, 163.5, 144.0, 136.8, 130.9, 130.8, 130.7, 129.1, 126.0, 123.8, 70.5, 69.9, 41.5, 21.6, 21.5, 21.3, 21.2, 21.17. HRMS (ESI) m / z: [M + Na] + calcd for C 20 H 21 BrNaO5443.0465; found 443.0466.

[0061] Example 11:

[0062]

[0063] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 6c (50.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube. The test tube was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 7c (64.8 mg, 87%). TLC: Rf = 0.3 (PE / EA = 5:1). f 1 H NMR (600 MHz, CDC13) δ 7.51 (d, J = 9.7 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.3, 2.5 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.18 (d, J = 9.8 Hz, 1H), 4.98 (hept, J = 6.2 Hz, 1H), 4.79 (hept, J = 6.2 Hz, 1H), 3.83 (s, 3H), 2.87 (d, J = 5.7 Hz, 1H), 2.49 (d, J = 5.8 Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.09 (d, J = 6.3 Hz, 3H), 0.76 (d, J = 6.2 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 194.1, 164.7, 163.8, 160.5, 145.1, 137.1, 131.2, 125.1, 123.1, 112.8, 112.1, 70.0, 69.6, 55.6, 54.5, 42.0, 21.6, 21.4, 21.21, 21.19, 21.16. HRMS (ESI) m / z: [M + Na] + calcd for C 21 H 24 NaO6395.1465; found 395.1465.

[0064] Example 12:

[0065]

[0066] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 6j (44.8 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber stopper. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 7j (64.8 mg, 87%). TLC: Rf = 0.2 (PE / EA = 5: 1). f 1 H NMR (400 MHz, CDC13) δ 8.43 (dd, J = 4.9, 1.7 Hz, 1H), 7.67 (dd, J = 7.7, 1.7 Hz, 1H), 7.58 (d, J = 9.9 Hz, 1H), 7.20 (dd, J = 7.7, 4.8 Hz, 1H), 6.41 (d, J = 9.9 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.88 (hept, J = 6.3 Hz, 1H), 2.93 (d, J = 3.9 Hz, 1H), 2.66 (d, J = 3.9 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.3 Hz, 3H) 13 C NMR (101 MHz, CDC13) δ 193.4, 164.2, 164.1, 148.8, 142.9, 136.0, 127.1, 126.6, 121.8, 70.0, 69.7, 56.2, 43.2, 29.0, 21.7, 21.59, 21.56, 21.4. HRMS (ESI) m / z: [M + Na] + calcd for C 19 H 21 NNaO5366.1312; found 366.1312.

[0067] Example 13:

[0068]

[0069] ​To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 8a (34.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber septum. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 9a (46.8 mg, 80%). TLC: Rf = 0.3 (PE / EA = 5: 1). f 1 H NMR (400 MHz, CDC13) δ 6.73 (d, J = 10.2 Hz, 2H), 6.47 (d, J = 10.2 Hz, 2H), 5.10 (hept, J = 6.3 Hz, 2H) 2.32 (s, 2H), 1.28 (d, J = 6.3 Hz, 6H), 1.25 (d, J = 6.2 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 185.8, 166.7, 145.9, 131.8, 70.7, 46.1, 36.2, 28.0, 21.70, 21.66. HRMS (ESI) m / z: [M + Na] + calcd for C 16 H 20 NaO5315.1203; found 315.1209.

[0070] Example 14:

[0071]

[0072] To a 10 mL dry test tube equipped with a magnetic stir bar was added bromonaphthol 8n (40.6 mg, 0.2 mmol, 1.0 eq) and Cs2C03(130.3 mg, 0.4 mmol, 2.0 eq). Then a solution of isopropyl methylene malonate 2a (80.1 mg, 0.4 mmol, 2.0 eq) in dry THF (2 mL) was added to the test tube, which was sealed with a rubber septum. The reaction mixture was stirred at room temperature for 3 h. The reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate, the organic layer was dried over Na2S04. After removal of the solvent under reduced pressure, the crude product was purified by silica gel column chromatography to give the pure product 9n (49.0 mg, 76%). TLC: Rf = 0.3 (PE / EA = 5: 1). f ​= 0.4 (petroleum ether / ethyl acetate = 2: 1). 1 H NMR (600 MHz, CDC13) δ 6.71 (d, J = 10.1 Hz, 1H), 6.29 (dd, J = 10.2, 2.3 Hz, 1H), 5.60 (d, J = 2.3 Hz, 1H), 5.09 - 5.02 (m, 2H), 3.78 (s, 3H), 2.44 (d, J = 4.0 Hz, 1H), 2.26 (d, J = 4.0 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H), 1.24 (d, J = 6.6 Hz, 3H) 1.20 (d, J = 6.3 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 192.7, 171.8, 166.6, 165.0, 138.7, 123.4, 100.7, 70.7, 69.2, 60.0, 50.1, 41.8, 30.7, 21.8, 21.7, 21.6, 21.5. HRMS (ESI) m / z: [M + Na] + calcd for C 17 H 22 NaO6345.1309; found 345.1309.

[0073] Example 15:

[0074]

[0075] To a 25 mL dry round bottom flask equipped with a magnetic stir bar was added KOH (250 mg, 4.4 mmol, 1.1 eq) and H20 (3.6 mL). After KOH dissolved, the resulting solution was cooled to 0 °C and 3b (1.145 g, 4 mmol, 1.0 eq) in MeOH (2 mL) was added by dropwise addition. The reaction mixture was stirred at room temperature for 12 hours. The reaction was complete (monitored by TLC), the reaction mixture was washed with Et20 and the pH was adjusted to 1 by the addition of 1 M aqueous HC1. The mixture was extracted with EtOAc and the organic layers were combined, dried over Na2S04and concentrated under reduced pressure to give the crude product.

[0076] In a 100 mL round bottom flask containing a magnetic stir bar, the crude product was dissolved in DCM (25 mL). To this solution was added EDCI (1.146 g, 6.0 mmol) and DMAP (244 mg, 2.0 mmol) sequentially. The mixture was stirred at room temperature for 30 minutes. Then BnNH2(470 mg, 4.4 mmol) was added to the reaction mixture, which was stirred at room temperature overnight. The reaction mixture was diluted with H2O and extracted with DCM (3 x 50 mL). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (eluent: PE / EA = 10 / 1) to give pure intermediate 12 (530 mg, 36% yield over two steps).

[0077] To a 25 mL round bottom flask containing a magnetic stir bar was added intermediate 12 (250 mg, 1.5 mmol, 1.1 eq) and dry THF (15 mL). The solution was cooled to 0 °C and NaH (1.5 mmol, 1.0 eq) was added slowly. The mixture was stirred at room temperature for 30 minutes. The reaction was complete (monitored by TLC), the reaction mixture was quenched with H2O and extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (eluent: PE / EA = 10 / 1) to give pure product 13 (285 mg, 52%).12(R f = 0.4, PE / EA = 2:1); 1 H NMR (400 MHz, CDC13) δ 8.19 (dd, J = 7.8, 1.6 Hz, 1H), 7.56 (t, J = 5.9 Hz, 1H), 7.48 (td, J = 7.7, 1.7 Hz, 1H), 7.41 (td, J = 7.5, 1.2 Hz, 1H), 7.31 - 7.18 (m, 5H), 7.04 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 10.2 Hz, 1H), 6.51 (d, J = 10.2 Hz, 1H), 4.51 (dd, J = 14.9, 6.1 Hz, 1H), 4.34 (dd, J = 14.9, 5.6 Hz, 1H), 3.55 (s, 3H), 2.90 (d, J = 6.7 Hz, 1H), 2.77 (d, J = 6.6 Hz, 1H). 13 C NMR (101 MHz, CDC13) δ 184.1, 167.4, 163.1, 147.5, 138.0, 137.5, 133.7, 131.7, 131.1, 128.6, 127.7, 127.48, 127.45, 127.4, 122.6, 52.8, 48.4, 44.2, 35.7, 23.5. HRMS (ESI) m / z: [M + Na]+ Calculated for C 22 H 19 NNaO4 384.1207; found 384.1207.13(R f = 0.3, petroleum ether / ethyl acetate = 2:1); 1 1H NMR (600 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.55–7.51 (m, 1H), 7.37–7.32 (m, 3H), 7.31–7.27 (m, 1H), 7.25–7.21 (m, 3H), 5.04 (d, J = 14.9 Hz, 1H), 3.95 (d, J = 14.9 Hz, 1H), 3.93 (dd, J = 12.0, 5.1 Hz, 1H), 3.71 (s, 3H), 3.25 (dd, J = 15.0, 5.1 Hz, 1H), 2.61 (dd, J = 15.0, 12.0 Hz, 1H), 2.55 (d, J = 5.8 Hz, 1H), 1.54 (d, J = 5.8 Hz, 1H). 13 13C NMR (101 MHz, CDCl3) δ 193.6, 169.0, 165.3, 135.9, 135.8, 134.3, 133.3, 129.0, 128.2, 128.1, 127.7, 127.0, 125.0, 56.2, 53.0, 44.0, 43.8, 43.3, 34.2, 24.3. HRMS (ESI) m / z: [M+Na] + Calculated for C 22 H 19 NNaO4 384.1207; found 384.1207.

[0078] Example 16:

[0079] The present application is directed to a series of synthetic racemic compounds, and the anti-tumor activity of the above compounds is tested in vitro by using Cell Counting Kit-8 (CCK-8) method. The CCK-8 method is used to evaluate the anti-tumor activity of the synthetic compounds in vitro. Cells are seeded into a 96-well plate (5x103 cells / well), and after the cells adhere, various gradient dilution concentrations of compounds are added, with 5-FU group and blank control group, 100 μL per well, 37℃, 5% CO2 incubator for 48h, CCK-8 10 μL is added, and placed in a 37℃, 5% CO2 incubator for 1.5h, and the absorbance is measured by a microplate reader (Multiskan FC / Thermo) at 450nm wavelength, repeated three times. The data is analyzed by GraphPadPism 6 software. The results of the anti-tumor activity of representative compounds are as follows:

[0080]

[0081] The above examples describe the basic principles, main features and advantages of the present application. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the scope of the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. A method for synthesizing a compound 3 of a cyclopropyl spirocyclohexanedione skeleton by base-catalyzed dearomatization, characterized by, The method comprises the following steps: reacting bromonaphthol 1 and methylenemalonate 2 in the presence of a base to obtain a cyclopropyl spirocyclohexanedione skeleton compound 3 containing a quaternary carbon center; and a reaction equation is shown as follows: wherein: EWG = CO2 i Pr, CO2Et, CO2 t Bu, CO2Me, CN; R1is selected from H, C1-C4alkyl, C1-C4alkoxy, halogen; R2is selected from H, phenyl.

2. The method of synthesizing cyclopropyl spirocyclohexanedione backbone compound 3 according to claim 1, characterized by: The base is selected from KOH, Cs2CO3, K3PO4, Na2CO3, K2CO3, Et3N or NaH.

3. The method of synthesizing cyclopropyl spirocyclohexanedione backbone compound 3 according to claim 1, characterized by: The reaction is carried out in an organic solvent selected from acetonitrile, diethyl ether, chlorobenzene and tetrahydrofuran.

4. The method of synthesizing cyclopropyl spirocyclohexanedione backbone compound 3 according to claim 1, characterized by: The molar ratio of the bromonaphthol 1, the methylenemalonate 2 and the base is 1:2:

2.

5. The method of synthesizing cyclopropyl spirocyclohexanedione backbone compound 3 according to claim 1, characterized by: The reaction temperature is 0-50 DEG C.

6. A method of synthesizing a (±)-cycloclavine analogue 13, characterized by, The method comprises the following steps: The cyclopropyl spirocyclohexanedione skeleton compound 3b is obtained by any one of the methods in claims 1-5, then the compound 3b is hydrolyzed in the presence of an inorganic base, then condensed in the presence of EDCI to obtain a compound 12, and then cyclized in the presence of sodium hydride to obtain a (±)-cycloclavine analogue 13.

7. The method of synthesizing the (±)-cycloclavine analog 13 according to claim 6, wherein: The inorganic base is selected from sodium carbonate, sodium hydroxide, potassium carbonate or potassium hydroxide.

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