CN107602559B - A method for the synthesis of chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanation initiated by Michael addition - Google Patents

Abstract

The invention discloses a kind of methods of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition, belong to the field of asymmetric synthesis in organic chemistry.The acrylate and Bromo-t-butylacetate replaced using α-purine obtains chiral cyclopropane carbocyclic purine nucleosides after the catalysis reaction of the Chiral Amine derived from quinine, reaction enantioselectivity is good, and yield is medium to outstanding as raw material.

Description

A Michel Addition-Initiated Asymmetric Cyclopropanation for the Synthesis of Chiral Three-membered Carbocycles nucleoside method

technical field

The invention relates to a synthesis method of chiral carbocyclic purine nucleosides, in particular to a method for synthesizing chiral three-membered carbocyclic nucleosides through asymmetric cyclopropanization triggered by Michael addition, which belongs to the field of asymmetric synthesis in organic chemistry .

Background technique

Chiral cyclopropane carbocyclic purine nucleoside compounds have a wide range of physiological activities, such as Besifovir, MBX1616 and A5021 have shown high drug activity (reference: Boutureira, O.; Matheu, M.I.; Díaz, Y.; Castillón, S. Chem. Soc. Rev. 2013, 42, 5056). For example, the currently known LB80317, LB80380 and A-5021 all pass a cyclopropane and a cyclopropane. They are linked to bases and exhibit good antiviral activity. They have been used in Phase II clinical trials to treat hepatitis B virus and herpes simplex virus. At the same time, compounds with different configurations will also produce medicinal effects (reference: Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17 and Oh, C.H.; Hong, J.H., Nucleosides Nucleotides. 2007, 26, 403). The construction of chiral cyclopropane purine nucleoside analogs has broad research prospects and significance.

There are two traditional approaches to construct chiral cyclopropanes. The first approach is to carefully design and synthesize a chiral three-membered carbocycle, introduce an amino group on the three-membered carbocycle, and construct a purine base or a pyrimidine base from the amino group, thereby forming a chiral three-membered carbocyclic nucleoside. The second approach is through a multi-step design, a multi-step synthesis at the purine base followed by intramolecular cyclopropanation under the action of a chiral rhodium catalyst. However, the methods for constructing cyclopropane nucleoside derivatives by these two methods are too complicated and the synthesis cost is relatively high. Relatively speaking, the method for preparing chiral cyclopropane carbocyclic nucleosides by using low-cost, cheap and easy-to-obtain raw materials is of high value.

Contents of the invention

In order to overcome the above defects, the present invention uses α-purine substituted acrylate 1 and bromoacetate 2 as raw materials, and synthesizes chiral cyclopropane carbocyclic nucleoside compounds under the action of quinine-derived chiral amine catalysts . This method provides a simple, cheap and efficient way for the synthesis of chiral cyclopropane carbocyclic nucleosides.

A method for synthesizing chiral cyclopropane carbocyclic purine nucleosides by asymmetric cyclization, characterized in that it comprises the following steps: using α-purine substituted acrylate 1 and bromoacetate 2 as raw materials, adding solvent and Base, in the presence of a quinine-derived chiral amine catalyst, react to obtain a chiral three-membered carbocyclic purine nucleoside 3 or its enantiomer, and the reaction equation is as follows:

Wherein, R ¹ represents one of the following groups: Cl, dimethylamino, diethylamino, methoxy, ethoxy, H, Ph, propylthio, piperidine, morpholine, pyrrole; R ² Represents one of the following groups: Cl, H; R ³ represents one of the following groups: methyl, ethyl, isopropyl, tert-butyl, benzyl; R ⁴ represents one of the following groups Species: methyl, ethyl, isopropyl, tert-butyl, benzyl;

Further, in the above technical scheme, the parent structure of the chiral amine catalyst derived from quinine is taken from chiral quinine, each catalyst includes two types of R type and S type, and the specific structure of the catalyst is as follows:

Further, in the above technical solution, the molar ratio of the α-purine substituted acrylate 1, tert-butyl bromoacetate 2, and chiral amine catalyst is 1:1-2:0.05-0.20.

Further, in the above technical scheme, the reaction base is selected from potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate, and silver carbonate. The molar ratio of base to α-purine substituted acrylate 1 is 1:1-2.

Further, in the above technical scheme, the reaction solvent is selected from the solvents selected from acetonitrile, tetrahydrofuran, 1,2-dichloroethane, toluene, chlorobenzene, dioxane, dichloromethane, ether or chloroform or Several kinds. Acetonitrile, tetrahydrofuran, 1,2-dichloroethane, dichloromethane or a mixed solvent of dichloromethane and acetonitrile is preferred.

Further, in the above technical solution, the reaction temperature is selected from -10°C to 30°C.

Further, in the above technical scheme, the whole reaction process does not need to be operated under the protection of inert gas.

Further, in the above scheme, the product _3ac can be further reduced by NaBH4 to obtain the monohydroxyl compound 4ac, and reduced by DIBAL-H to obtain the dihydroxyl compound 5ac.

It is found by research that under the above reaction conditions, after purification, the separation yields for different substrates are 72%-98%.

Beneficial effects of the invention:

The present invention provides a simple, cheap and efficient synthetic method for the synthesis of chiral cyclopropane carbocyclic purine nucleosides, the reaction raw materials are easy to obtain, the product structure is rich, the stereoselectivity of the product is high, and chiral cyclopropane is obtained after the reaction Carbocyclic purine nucleosides with moderate to excellent yields.

Detailed ways

Example 1

^a Unless otherwise stated, the reaction conditions were as follows: α-purine-substituted acrylate 1a (0.1 mmol), tert-butyl bromoacetate 2c (0.11 mmol), quinine-based catalyst (10 mol%) and base (1.1 eq) in 1 mL of solvent React at 0°C. ^bIsolation yield. ^c Determined by chiral HPLC analysis. ^dReact at room temperature. ^e Increase the amount of base to 2 equivalents, the yield increases to 52%, ee=92%. ^f catalyst consumption is 5mol%. ^g at -10°C. ^h at -20°C.

In the process of screening the reaction conditions, the influence of amine catalysts on the reaction was firstly investigated (markers 1-6). At the same time, by comparing the effects of different catalysts on the reaction, the best catalyst for catalyst 4f was determined.

Investigation of reaction conditions: In a 10mL vacuum tube, add α-purine-substituted 6-Cl ethyl acrylate 1a (25.2mg, 0.1mmol), (DHQD) ₂ AQN (8.6mg, 10mol%), cesium carbonate (36mg, 0.11 mmol) and tert-butyl bromoacetate 2a (17 μL, 0.11 mmol). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was tracked by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3ac was obtained by column chromatography with a yield of 95% and an ee value of 97%.

When other conditions are fixed, only the influence of the amount of catalyst on the reaction is investigated. Taking 1a and 2a to form 3ac as an example, the reaction equation is as follows:

5%mmol(DHQD) ₂ AQN yield: 30%-40%; ee: 94%-98%;

15%mmol(DHQD) ₂ AQN yield: 80%-90%; ee: 94%-98%;

20%mmol(DHQD) ₂ AQN yield: 90%-98%; ee: 94%-98%;

When other conditions are fixed, only the influence of different bases on the reaction is examined, and the reaction equation is as follows:

^a Unless otherwise stated, the reaction conditions were as follows: α-purine-substituted acrylate 1a (0.1 mmol), tert-butyl bromoacetate 2 (0.11 mmol), quinine-based catalyst (10 mol%) and base (1.1 eq) in 1 mL of solvent React at 0°C. ^bIsolation yield. ^c Determined by chiral HPLC analysis.

When other conditions are fixed, only the influence of different solvents on the reaction is examined, and the reaction equation is as follows:

^a Unless otherwise stated, the reaction conditions are as follows: α-purine substituted acrylate 1a (0.1 mmol), tert-butyl bromoacetate 2c (0.11 mmol), quinine catalyst (10 mol%) and base (1.1 equivalents, entry 1 -4 base is 2 equivalents), 1 mL of solvent was reacted at 0°C. ^bIsolation yield. ^c Determined by chiral HPLC analysis.

Example 2:

In a 10 mL vacuum tube, α-purine substituted 6-dimethylaminoacrylate (26.1 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol ). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was tracked by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3fc was obtained by column chromatography with a yield of 84%, 97% ee.

Example 3:

In a 10 mL vacuum tube, α-purine substituted 6-diethylaminoacrylate (28.9 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol ). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3gc was obtained by column chromatography with a yield of 87%, 94% ee.

Representative compound characterization data are as follows:

3gc colorless oily liquid, 87% yield, 94% ee. [α] ²⁵ _D = -80.1 (c = 1.2, CH ₂ Cl ₂ ); Ee value was detected by chiral HPLC (mobile phase, n-hexane/2- propanol＝80/20, flow rate: 0.6mL/min, detection wavelength: 250nm, retention time: 13.924min, 18.512min.); ¹ H NMR (600MHz, CDCl ₃ ): 8.30(s, 1H), 7.66(s, 1H), 4.13-4.16(m, 2H), 3.96(br, 4H), 2.98(br, 1H), 2.05-2.45(m, 2H), 1.26(t, J=6.6Hz, 6H), 1.18(s ,9H), 1.15 (t, J=6.6Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): 168.6, 166.5, 153.9, 152.9, 151.9, 139.0, 119.2, 82.3, 62.8, 43.1, 41.3, 28.1 , 27.6, 20.5, 14.1, 13.6; HRMS calcd for C ₂₀ H ₂₉ N ₅ NaO ₄ [M+Na] ⁺ 426.2112, found 426.2113.

Example 4:

In a 10 mL vacuum tube, α-purine substituted 6-pyrrole acrylate (28.7 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was tracked by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3hc was obtained by column chromatography with a yield of 87%, 97% ee.

Example 5:

In a 10 mL vacuum tube, α-purine substituted 6-morpholine acrylate (30.3 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mmol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol) . Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3jc was obtained by column chromatography with a yield of 98%, 96% ee.

Embodiment 6:

In a 10 mL vacuum tube, α-purine substituted 6-methoxyacrylate (24.8 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol ). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3kc was obtained by column chromatography with a yield of 94%, 96% ee.

Representative compound characterization data are as follows:

3kc Colorless oil, 92% yield, 96% ee. [α] ²⁵ _D = -98.7 (c = 1.4, CH ₂ Cl ₂ );

The Ee value is detected by chiral HPLC (mobile phase, n-hexane/2-propanol=80/20, flow rate: 0.6mL/min, detection wavelength: 250nm, retention time: 11.557min, 16.991min.); ¹ H NMR ( 600 MHz, CDCl ₃ ):8.53(s,1H),7.87(s,1H),4.18(s,3H),4.10-4.18(m,2H),2.96(br,1H),2.10-2.50(m, 2H), 1.18(s, 9H), 1.129(t, J=6.6Hz, 3H); ¹³ C NMR (150MHz, CDCl ₃ ): 168.2, 166.2, 161.2, 153.3, 152.5, 143.3, 121.3, 82.6, 63.0, 54.3, 41.4, 27.7, 20.5, 14.0; HRMS calcd for C ₁₇ H ₂₂ N ₄ NaO ₅ [M+Na] ⁺ 385.1482, found 385.1486.

Embodiment 7:

In a 10 mL vacuum tube, α-purine substituted 6-ethoxyacrylate (26.2 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol ). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3lc was obtained by column chromatography with a yield of 86%, 95% ee.

Embodiment 8:

In a 10 mL vacuum tube, α-purine substituted 6-propylthioacrylate (29.2 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol ). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was tracked by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3mc was obtained by column chromatography with a yield of 92%, 96% ee.

Representative compound characterization data are as follows:

3mc colorless oily liquid, 92% yield, 96% ee. [α] ²⁵ _D = -84.4 (c = 1.2, CH ₂ Cl ₂ ); Ee value was detected by chiral HPLC (mobile phase, n-hexane/2- propanol＝80/20, flow rate: 0.6mL/min, detection wavelength: 250nm, retention time: 12.683min, 23.804min.); ¹ H NMR (600MHz, CDCl ₃ ): 8.66 (s, 1H), 7.88 (s, 1H),4.09-4.17(m,2H),3.29-3.37(m,2H),2.93,(br,1H),2.07-2.5(m,2H),1.76-1.82(m,2H),1.15(s ,9H), 1.11(t, J=7.2Hz, 3H), 1.05(t, J=7.2Hz, 3H); ¹³ C NMR(150MHz, CDCl ₃ ): 168.1, 166.2, 161.9, 152.2, 149.6, 143.6, 131.2, 82.6, 63.1, 41.3, 30.7, 27.6, 22.9, 20.5, 14.0, 13.5; HRMS calcd for C ₁₉ H ₂₆ N ₄ NaO ₄ S[M+Na] ⁺ 429.1567, found 429.1573.

Embodiment 9:

In a 10 mL vacuum tube, α-purine substituted 6-phenylacrylate (29.4 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol) . Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3nc was obtained by column chromatography with a yield of 90%, 97% ee.

Example 10:

In a 10 mL vacuum tube, α-purine substituted 6-hydroacrylate (29.4 mg, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and tert-butyl bromoacetate (17 μL, 0.11 mmol). Then 0.66 mL of dichloromethane and 0.34 mL of acetonitrile were added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound 3oc was obtained by column chromatography with a yield of 72% and 96% ee.

Example 11

According to the reaction conditions of the examples, in a 10 mL vacuum tube, α-purine substituted acrylate derivatives (lac-1rc, 1ag-1ad, 0.1 mmol), (DHQD) ₂ AQN (8.6 mg, 10 mol%) and bromine tert-butyl acetate (17 μL, 0.11 mmol). Then 1 mL of solvent was added. Seal the reaction tube, and place the reaction tube in a cryopump at 0°C for 2 days. The reaction was followed by TLC. After the reaction was terminated, the reaction solution was concentrated in vacuo, and then the target compound was obtained by column chromatography. Only the reaction substrate is changed, and the following reaction results are obtained:

^a Reaction for 3 days. ^b The solvent is tetrahydrofuran.

Example 12:

In a 10mL reaction tube, add cyclopropane carbocyclic nucleoside analog 3ac (36.6mg, 0.1mmol), and add methanol, react to -10°C, and add NaBH ₄ (11.7mg, 0.3mmol). Detection by TLC , after the reaction was complete, it was quenched with saturated NH ₄ Cl. The reaction was extracted with CH ₂ Cl ₂ (3×10 mL), the organic phases were combined and spin-dried. The product was passed through a column (CH ₂ Cl ₂ /MeOH=50:1) The product 4ac was obtained (92% yield, 97% ee).

Representative compound characterization data are as follows:

4ac White solid, 92% yield, 97% ee. [α] ²⁵ _D = -73.0 (c = 2.4, CH ₂ Cl ₂ );

The Ee value is detected by chiral HPLC (mobile phase, n-hexane/2-propanol=80/20, flow rate: 0.6mL/min, detection wavelength: 250nm, retention time: 10.636min, 13.960min.); ¹ H NMR ( 600 MHz, CDCl ₃ ): 8.69(s,1H), 8.12(s,1H), 4.04(d, J＝11.4Hz, 1H), 3.83(d, J＝12Hz, 1H), 3.74(s, 1H) ,2.35(q,1H)2.07(t,J=6Hz,1H),1.72(q,1H),1.14(s,9H); ¹³ C NMR(150MHz,CDCl ₃ ):167.8,152.5,152.1,150.9, 146.9, 131.4, 82.2, 67.0, 45.2, 27.7, 25.0, 17.3; HRMS calcd for C ₁₄ H ₁₇ ClN ₄ NaO ₃ [M+Na] ⁺ 347.0881, found 347.0872.

Example 13:

In a 10 mL vacuum tube, cyclopropane carbocyclic purine nucleoside 3ac (36.6 mg, 0.1 mmol) was added. The reaction tube was filled with nitrogen gas by replacing it with nitrogen gas three times, and then 1 mL of dichloromethane was added under nitrogen gas flow. Seal the reaction tube and place the reaction tube at -40 °C. DIBAL-H (7 equiv, 1.0M in cyclohexane) was slowly added. Track the reaction with TLC, after terminating the reaction, add saturated ammonium chloride solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase in vacuo, then obtain the target compound 5ac through column chromatography, the yield is 42%, The ee value is 97%.

Representative compound characterization data are as follows:

5ac Colorless oil, 42% yield, 97% ee. [α] ²⁵ _D = -60.6 (c = 1.0, MeOH);

The Ee value is detected by chiral HPLC (mobile phase, n-hexane/2-propanol=80/20, flow rate: 0.6mL/min, detection wavelength: 250nm, retention time: 22.917min, 29.932min.); ¹ H NMR ( 600 MHz, CD ₃ OD): 8.75(s, 1H), 8.61(s, 1H), 8.34(d, J＝9.6Hz, 1H), 3.63(d, J＝10.8Hz, 1H), 3.56(d, J＝6.0Hz, 1H), 3.23(t, J＝9.6Hz, 1H), 1.74-1.79(m, 1H), 1.48(t, J＝6.6 Hz, 1H), 1.44(t, J＝6.6Hz, 1H); ¹³ C NMR (150MHz, CD ₃ OD): 152.8, 151.5, 150.0, 149.2, 131.3, 66.1, 60.0, 47.2, 23.7, 12.8; HRMS calcd for C ₁₀ H ₁₁ ClN ₄ NaO ₂ [M+Na] ⁺ 277.0463,found 277.0471.

Example 14:

In a 10 mL pressure-resistant tube, add cyclopropane bishydroxycarbocyclic purine nucleoside 5ac (25.4 mg, 0.1 mmol). Subsequently, 2 mL of ammonia-methanol solution was added to seal the reaction tube, and the reaction tube was placed at 110°C. The reaction was tracked by TLC. After the reaction was terminated for 24 h, the reaction solution was concentrated in vacuo, and then the target compound 6ac was obtained by column chromatography with a yield of 52%, 95% ee.

Representative compound characterization data are as follows:

6ac White soil, 52% yield, 95% ee. [α] ²⁵ _D = -60.6 (c = 0.9, MeOH);

The Ee value is detected by chiral HPLC (mobile phase, n-hexane/2-propanol=70/30, flow rate: 0.8mL/min, detection wavelength: 250nm, retention time: 19.895min, 38.407min.); ¹ H NMR ( 600 MHz, CD ₃ OD): 8.75(s, 1H), 8.62(s, 1H), 3.84(d, J=9.6Hz, 1H), 3.62(d, J=12.0Hz, 1H), 3.56(d, J＝6.6Hz, 1H), 3.23(d, J＝8.4Hz, 1H), 1.74-1.79(m, 1H), 1.48(t, J＝6.6Hz, 1H), 1.44(t, J＝6.6Hz, 1H); ¹³ C NMR (150MHz, CD ₃ OD): 157.5, 153.7, 151.3, 145.1, 120.4, 67.6, 61.7, 44.1, 25.1, 14.2; HRMS calcd for C ₁₀ H ₁₃ N ₅ NaO ₂ [M+Na] ⁺ 258.0961,found 258.0967.

The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the industry should understand that the present invention is not limited by the above-mentioned embodiments, and that described in the above-mentioned embodiments and the specification only illustrates the principle of the present invention, and the present invention also has various aspects without departing from the scope of the principle of the present invention. Changes and improvements, these changes and improvements all fall within the protection scope of the present invention.

Claims (7)

1. A method for synthesizing chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanization initiated by Michael addition, characterized in that: comprising the steps of: α-purine substituted acrylate 1 and bromoacetate 2 Add a base and a solvent, and in the presence of a quinine-derived chiral amine catalyst, react to obtain a chiral three-membered carbocyclic purine nucleoside 3 or its enantiomer, and the reaction equation is as follows: Wherein, R is selected from ^: chlorine, dimethylamino, diethylamino, methoxy, ethoxy, ^hydrogen , phenyl, propylthio, piperidine, morpholine or pyrrole; R is selected from: chlorine, Hydrogen; ^R is selected from: methyl, ethyl, isopropyl, tert ^- butyl or benzyl; R is selected from: methyl, ethyl, isopropyl, tert-butyl or benzyl; the quinine The derivatized chiral amine catalyst is selected from (DHQD) ₂ PYR, (DQHD) ₂ PHAL or (DHQD) ₂ AQN. 2. according to a kind of method for the synthesis of chiral three-membered carbocyclic nucleosides through the asymmetric cyclopropanization that Michael addition causes among the claim 1, it is characterized in that: described solvent is selected from acetonitrile, tetrahydrofuran, 1,2-bis One or more of ethyl chloride, toluene, chlorobenzene, dioxane, methylene chloride, ether or chloroform. 3. according to a kind of method for synthesizing chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanization initiated by Michael addition in claim 1 or 2, it is characterized in that: described solvent is selected from acetonitrile, tetrahydrofuran, 1,2 - Dichloroethane, dichloromethane or a mixed solvent of dichloromethane and acetonitrile. 4. according to a kind of method that the asymmetric cyclopropanization that Michael addition causes in claim 1 synthesizes chiral three-membered carbocyclic nucleoside, it is characterized in that: described alkali is selected from potassium carbonate, cesium carbonate, tert-butanol Potassium, Potassium Phosphate, Silver Carbonate. 5. according to a kind of method that the asymmetric cyclopropanization that causes by Michael addition causes chiral three-membered carbocyclic nucleoside in claim 1, it is characterized in that: described α-purine substituted acrylate 1, bromoacetic acid The molar ratio of tert-butyl ester 2, chiral amine catalyst and base is 1:1-2:0.05-0.20:1-2. 6. A method for synthesizing chiral three-membered carbocyclic nucleosides by asymmetric cyclopropanation initiated by Michael addition according to claim 1, characterized in that: the reaction temperature is -10°C to 30°C. 7. According to claim 1, a method for synthesizing chiral three-membered carbocyclic nucleosides through asymmetric cyclopropanization initiated by Michael addition, characterized in that: the product chiral three-membered carbocyclic purine nucleoside 3ac Reduction with NaBH4 _affords the monohydroxyl compound 4ac Reduction with DIBAL-H affords the dihydroxy compound 5ac