CN107698590B - A method for the synthesis of chiral five-membered carbocyclic purine nucleosides by asymmetric [3+2] cyclization - Google Patents

Abstract

The invention discloses a method for synthesizing chiral five-membered carbocyclic purine nucleoside through asymmetric [3+2] cyclization reaction, which belongs to the field of asymmetric synthesis in organic chemistry. α -purine substituted acrylate and MBH carbonate are taken as raw materials, chiral SITCP is taken as a catalyst, and a chiral five-membered carbocyclic nucleoside compound is obtained after reaction, so that the reaction diastereoselectivity and enantioselectivity are good, and the yield is up to 93%.

Description

An asymmetric [3+2] cyclization for the synthesis of chiral five-membered carbocyclic purine nucleosides method

technical field

The invention relates to a method for synthesizing chiral carbocyclic purine nucleosides, in particular to a method for synthesizing chiral five-membered carbocyclic purine nucleosides by asymmetric [3+2] cyclization reaction, and belongs to the field of asymmetric synthesis in organic chemistry .

Background technique

Chiral five-membered carbocyclic purine nucleosides have a wide range of physiological activities, such as Abacavir, Entecavir and Carbovir can be used to treat HIV and HBV, respectively. Other chiral five-membered carbocyclic nucleosides such as Noraristeromycin, Aristeromycin, Neplanocin A and HNPA have different pharmacological activities. At the same time, the product configuration of chiral compounds has a great influence on their biological activity, so the synthesis and preparation of optically pure chiral compounds and the testing and research of some physiological and pharmacological activities have great application prospects and significance. .

There are two traditional ways to construct chiral five-membered carbocyclic nucleosides. The first way is to carefully design a chiral carbocyclic ring with stereo configuration and different functional groups obtained by multi-step reactions, and then chemically link it with the base of purine or pyrimidine to form a chiral carbocyclic ring. Five-membered carbocyclic nucleosides can be introduced into chiral carbocycles by four methods: nucleophilic substitution reaction, ring-opening reaction of epoxy compounds, Mitsunobu reaction and palladium-catalyzed allyl coupling reaction. The second approach is to introduce an amino group into the above-mentioned chiral five-membered ring, and construct a purine or pyrimidine base from the amino group, thereby synthesizing chiral carbocyclic nucleoside compounds. However, both approaches require equivalent chiral sources, and after multi-step reactions, chiral five-membered carbocyclic nucleosides can be synthesized. Moreover, chiral substrates are relatively difficult to prepare and have high cost. Relatively speaking, the method of synthesizing chiral five-membered carbocyclic purine nucleosides through asymmetric [3+2] cyclization using low-cost, inexpensive and readily available achiral raw materials is of great significance.

SUMMARY OF THE INVENTION

In order to overcome the above defects, the present invention uses α-purine substituted acrylate 1 and MBH carbonate 2 as raw materials to synthesize chiral five-membered carbocyclic nucleoside compounds under the action of a chiral monophosphine catalyst. This method provides a facile, inexpensive and efficient way to synthesize chiral five-membered carbocyclic nucleosides.

A method for synthesizing a chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization, characterized in that the method comprises the following operations: using α-purine-substituted acrylate 1 and MBH carbonate 2 as raw materials, A solvent is added to react in the presence of a chiral monophosphine catalyst to obtain a chiral five-membered carbocyclic nucleoside compound 3 or its enantiomer.

The reaction equation is as follows:

Wherein, R ¹ represents one of the following groups: Cl, H, Ph, piperidine, diethylamino, methoxy, propylthio; R ² represents one of the following groups: Cl, H; R ³ represents one of the following groups: methyl, ethyl, tert-butyl; R ⁴ represents one of the following groups: methyl, ethyl, tert-butyl, benzyl; R ⁵ represents the following groups One of the groups: phenyl, 2-ClC ₆ H ₄ , 3-FC ₆ H ₄ , 3-ClC ₆ H ₄ , 3-BrC ₆ H ₄ , 4-NO ₂ C ₆ H ₄ , 4-CNC ₆ H ₄ , 4-CH ₃ C ₆ H ₄ , 4-CH ₃ OC ₆ H ₄ ,

Further, in the above technical scheme, the chiral monophosphine catalyst is taken from SITCP, and each ligand includes two types, R-type and S-type. The R-type SITCP structure is: Or the S-type SITCP structure is:

Further, in the SITCP ligand, Ar is preferably selected from phenyl, 4-methoxyphenyl or 3,5-di-tert-butyl-4-methoxyphenyl. Represented by S-type SITCP ligand, the specific structure is as follows:

Further, in the above technical solution, the molar ratio of the α-purine-substituted acrylate 1, the MBH carbonate 2, and the chiral monophosphine catalyst is 1:1-2:0.05-0.20.

Further, in the above technical scheme, the reaction solvent is selected from 1,2-dichloroethane, toluene, dichloromethane and chloroform.

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

Further, in the above technical solution, the entire reaction process needs to be operated under the protection of an inert gas, and the inert gas is preferably nitrogen.

Further, the obtained chiral five-membered carbocyclic nucleoside compound 3 can be further derivatized to obtain different types of derivative products, which can be reduced by NaBH ₄ or DIBAL-H to obtain the products of single reduction of the ester group connected to the nitrogen atom, respectively. Or the product of the reduction of both ester groups. For example, the five-membered carbocyclic purine nucleoside product 3ca was reduced with NaBH ₄ to obtain the monohydroxy compound 4ca, and the reduction with DIBAL-H gave the dihydroxy compound 5ca.

Invention Beneficial Effects:

The invention provides a simple, cheap and efficient synthesis method for the method for synthesizing chiral five-membered carbocyclic purine nucleosides, the reaction raw materials are easily obtained, the product structure is abundant, the product stereoselectivity is high, and the chiral five-membered nucleoside is obtained after the reaction. Carbocyclic nucleoside compounds with a yield of up to 93%.

Detailed ways

Example 1

^a Unless otherwise specified, the reaction steps were as follows: under nitrogen atmosphere, catalyst (20mol%), 1 (0.05 mmol), 2 (0.06 mmol) were reacted in CH ₂ Cl ₂ (1.0 mL) for 4 days. ^b dr values by NMR Test the crude product. ^c Isolated yield. The ^dee values were separated by high performance liquid chromatography. .

During the screening of reaction conditions, the effect of phosphine catalysts on the reaction was first investigated (entries 1-8). At the same time, by comparing the influence of different ligands on the reaction and considering the price factor, the ligand P6 was finally determined as the best ligand.

Investigation of reaction conditions: In a 10 mL vacuum tube, add α-purine-substituted ethyl 6-chloroacrylate 1a (23.8 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and phenyl MBH methyl carbonate Ester 2a (35.1 mg, 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3aa was obtained by column chromatography in a yield of 83%, 9:1dr and 91 %ee.

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

5% mmol(S)-SITCP yield: 25%-30%; ee: 90%-93%.

10% mmol(S)-SITCP yield: 37%-42%; ee: 90%-93%.

20% mmol(S)-SITCP yield: 82%-85%; ee: 90%-93%.

When other conditions are fixed, only the influence of the steric hindrance of the substituent of the substituted substrate on the reaction is examined, and the reaction equation is as follows:

^a Unless otherwise specified, the reaction steps were as follows: under nitrogen atmosphere, catalyst (20 mol%), 1 (0.05 mmol), 2 (0.06 mmol) were reacted in CH ₂ Cl ₂ (1.0 mL) for 4 days. The ^bdr value of the crude product was tested by NMR. ^c Isolated yield. The ^dee values were separated by high performance liquid chromatography.

Example 2:

In a 10 mL vacuum tube, α-purine-substituted methyl 6-piperidine acrylate (28.7 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and phenyl MBH methyl carbonate (35.1 mg, 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3ea was obtained by column chromatography in a yield of 87%, 9:1dr and 90 %ee.

Example 3:

In a 10 mL vacuum tube, α-purine-substituted methyl 6-propylthioacrylate (27.8 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and phenyl MBH methyl carbonate (35.1 mg, 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo, and then the target compound 3ea was obtained by column chromatography in a yield of 85%, 9:1dr and 90 %ee.

Representative compound characterization data are as follows:

3ea White solid; 85% yield, 9:1dr, 90% ee. [α] _D ²⁰ = 66.1 (c=0.5, CH ₂ Cl ₂ ). HPLC CHIRALCEL IA, n-hexane/isopropanol = 70/30, flow rate =0.5 mL/min, column temperature=25℃, λ=254nm, retention time: 26.267min, 33.839min. ¹ H NMR (400MHz, CDCl ₃ ): 8.57(s, 1H), 7.65(s, 1H), 7.02 -7.01(m,1H),6.94-6.90(m,3H),6.80-6.78(m,2H),5.38(s,1H),3.90(d,J＝18.6Hz,1H),3.73(s,3H ), 3.64(s, 3H), 3.37(dd, J=3.0, 18.6Hz, 1H), 3.33-3.23(m, 2H), 1.81-1.72(m, 2H), 1.05(t, J=7.2Hz, 1H). ¹³ C NMR (151MHz, CDCl ₃ ): 171.1, 163.7, 161.5, 151.6, 148.6, 140.5, 139.7, 137.6, 135.0, 131.1, 128.3, 128.3, 128.1, 72.2, 55.9, 53.7, 52.0, 40.9, 3 ,22.9, 13.6.HRMS(ESI):m/z calcd.for C ₂₃ H ₂₄ N ₄ O ₄ SNa[M+Na] ⁺ :475.1410, found475.1414.

Example 4:

In a 10 mL vacuum tube, α-purine substituted methyl 6-hydroacrylate (20.4 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and phenyl MBH methyl carbonate (35.1 mg, 0.12 mmol) ). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3ia was obtained by column chromatography in a yield of 92%, 10:1dr and 90 %ee.

Example 5:

In a 10 mL vacuum tube, α-purine-substituted methyl 2,6-chloroacrylate (27.1 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and phenyl MBH methyl carbonate (35.1 mg, 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at 0°C for 5 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo, and then the target compound 3ja was obtained by column chromatography in a yield of 82%, 10:1dr and 92 %ee.

Example 6:

In a 10 mL vacuum tube, α-purine-substituted methyl 6-chloroacrylate (23.8 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and m-fluorophenyl MBH methyl carbonate (51.6 mg) were added , 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3cb was obtained by column chromatography in a yield of 82%, 9:1dr and 90 %ee.

Representative compound characterization data are as follows:

3cb White solid; 82% yield, 9:1dr, 90% ee. [α] _D ²⁰ = 57.1 (c=0.5, CH ₂ Cl ₂ ). HPLC CHIRALCEL ODH, n-hexane/isopropanol = 70/30, flow rate =0.5mL/min, column temperature=25℃, λ=254nm, retention time: 11.066min, 13.742min. ¹ H NMR (400MHz, CDCl ₃ ): 8.64(s, 1H), 7.89(s, 1H), 7.07 -7.05(m, 1H), 6.89-6.83(m, 1H), 6.70-6.68(m, 1H), 6.60-6.57(m, 1H), 6.52-6.50(m, 1H), 5.42(s, 1H) , 3.93(dt, J=2.0, 18.8Hz, 1H), 3.76(s, 3H), 3.67(s, 3H), 3.42(dd, J=2.8, 18.8Hz, 1H). ¹³ C NMR(151MHz, CDCl ₃ ): 170.4, 163.3, 161.7, 151.8, 151.8, 151.2, 143.0, 139.3, 137.8, 131.4, 130.6, 129.6, 115.4, 115.2, 72.4, 55.7, 54.0, 52.2, 41.1.HRMS(ESId): m/z calcd .for C ₂₀ H ₁₇ ClFN ₄ O ₄ [M+H] ⁺ :431.0917, found 431.0916.

Example 7:

In a 10 mL vacuum tube, α-purine-substituted methyl 6-chloroacrylate (23.8 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and o-chlorophenyl MBH methyl carbonate (53.5 mg) were added , 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3ce was obtained by column chromatography in a yield of 73%, 10:1dr and 92 %ee.

Example 8:

In a 10 mL vacuum tube, α-purine-substituted methyl 6-chloroacrylate (23.8 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and methyl 1-naphthyl MBH carbonate (55.4 mg) were added , 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo, and then the target compound 3cj was obtained by column chromatography in a yield of 87%, 10:1dr and 96 %ee.

Representative compound characterization data are as follows:

3cj White solid; 87% yield, 10:1 dr, 96% ee. [α] _D ²⁰ = 60.2 (c=0.5, CH ₂ Cl ₂ ). HPLC CHIRALCEL IA, n-hexane/isopropanol = 70/30, flow rate =0.5mL/min, column temperature=25℃, λ=254nm, retention time: 36.264min, 46.357min. ¹ H NMR (600MHz, CDCl ₃ ): 8.43(s, 1H), 7.92-7.90(m, 1H) ,7.60-7.57(m,1H),7.37(s,1H),7.26-7.25(m,1H),7.15-7.14(m,3H),7.00-6.99(m,1H),6.23(s,1H) , 3.95(d, J=18.6Hz, 1H), 3.87(s, 3H), 3.60(s, 3H), 3.51(dd, J=3.0, 18.6Hz, 1H). ¹³ C NMR (151MHz, CDCl ₃ ) :170.7,163.7,151.9,151.1, 150.5,143.2,139.3,138.1,133.8,131.3,131.2,130.9,129.3,128.6,125.9,125.4,124.6,124.3,123.5,72.1,54.0 (ESI): m/z calcd.for C ₂₄ H ₂₀ ClN ₄ O ₄ [M+H] ⁺ : 463.1168, found 463.1167

Example 9:

In a 10 mL vacuum tube, add α-purine-substituted methyl 6-chloroacrylate (23.8 mg, 0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and 3,4-dimethylphenyl MBH carbonic acid Methyl ester (52.8 mg, 0.12 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed and placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound was obtained by column chromatography in a yield of 85% in 3cm, 10:1dr and 96 %ee.

Example 10:

In a 10 mL vacuum tube, α-purine substituted methyl acrylate 1 (0.1 mmol), (S)-SITCP (3.5 mg, 20 mmol%) and aryl MBH methyl carbonate 2 (0.12 mmol) were added. The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of dichloromethane was added. The reaction tube was sealed, and the reaction tube was placed in a cryopump at -10°C for 4 days. The reaction was followed by TLC, after the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then the target compound 3 was obtained by column chromatography. By changing the substituents of the substrate, different products 3 can be obtained.

The specific reaction results are as follows:

Example 11:

In a 50 mL round-bottomed flask, the five-membered carbocyclic nucleoside analog 3ca (82.4 mg, 0.2 mmol) was added, and 20 mL of methanol was added, the reaction was brought to room temperature, and NaBH ₄ (22.8 mg, 0.6 mmol). Checked by TLC , quenched with saturated NH ₄ Cl after complete reaction. After terminating the reaction, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo, and then the target compound 4ca was obtained by column chromatography (CH ₂ Cl ₂ /MeOH=50:1) (yield 92%, 93%ee).

Representative compound characterization data are as follows:

4ca White solid; 92% yield, 93% ee. [α] _D ²⁰ = -32.9 (c=0.3, CH ₂ Cl ₂ ). HPLC CHIRALCEL IA, n-hexane/isopropanol = 80/20, flow rate = 0.6 mL/ min, column temperature=25℃, λ=254nm, retention time: 28.511min, 31.936min. ¹ H NMR (600 MHz, CDCl ₃ ): 8.63(s, 1H), 7.73(s, 1H), 7.09-7.09( m, 1H), 7.01-6.94(m, 3H), 6.85(m, 2H), 4.82(s, 1H), 4.73(br, 1H), 4.41(d, J＝12.3Hz, 1H), 4.14(d , J=12.4Hz, 1H), 3.66 (s, 3H), 3.58 (d, J=18.5Hz, 1H), 3.20 (d, J=18.5Hz, 1H). ¹³ C NMR (151MHz, CDCl ₃ ): 164.0, 151.5, 151.3, 150.9, 145.4, 139.6, 138.7, 136.3, 131.6, 128.5, 128.0, 74.1, 66.6, 54.9, 52.0, 40.6.HRMS(ESI):m/z calcd.forC ₁₉ H ₁₇ ClN ₄ O ₃ Na[M+Na] ⁺ :407.0881, found 407.0884.

Example 12:

In a 10 mL vacuum tube, the five-membered carbocyclic purine nucleoside 4ca (38.4 mg, 0.1 mmol) was added. The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then 1 mL of tetrahydrofuran was added under nitrogen flow. The reaction tube was sealed and placed at -20°C. DIBAL-H (3equiv, 1.1M in cyclohexane) was added slowly. The reaction was followed by TLC. After terminating the reaction, saturated ammonium chloride solution was added, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo, and then the target compound 5ca was obtained by column chromatography with a yield of 57%. ee value 91%.

Representative compound characterization data are as follows:

5ca Colourless liquid; 57% yield, 91% ee. [α] _D ²⁰ = -8.6 (c = 0.63, CH ₂ Cl ₂ ). HPLC CHIRALCEL IE, n-hexane/isopropanol = 80/20, flow rate = 0.5 mL /min, column temperature=25℃, λ=254nm, retention time: 32.633min, 35.508min. ¹ H NMR (600 MHz, CDCl ₃ ): 8.58(s, 1H), 7.82(s, 1H), 6.97-6.93 (m, 3H), 6.83-6.82(m, 2H), 6.02(s, 1H), 5.02(s, 1H), 4.54(s, 1H), 4.34(d, J=12.2Hz, 1H), 4.17- 4.09 (m, 3H), 3.39 (d, J=16.6Hz, 1H), 2.98 (d, J=16.7Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ): 151.5, 151.1, 150.6, 146.6, 145.7 ,136.3,131.6, 128.5,127.9,122.9,74.6,67.1,60.8,55.9,40.1.HRMS(ESI):m/z calcd. for C ₁₈ H ₁₇ ClN ₄ O ₂ Na[M+Na] ⁺ :379.0932, found 379.0942.

Example 13:

In a 10 mL reaction tube, the five-membered carbocyclic nucleoside analog 3ca (82.4 mg, 0.2 mmol), NaIO ₄ (44.6 mg, 2 equiv) was dissolved in 0.1 mL of water and added to the reaction tube. The reaction was placed at ₀ °C and _RuCl3.3H2O (2.8 mg, 0.1 equiv) was added. Ethyl acetate (0.2 mL) and acetonitrile (0.3 mL) were then added. Substrate 3ca (41.2 mg, 0.1 mmol) was dissolved in ethyl acetate (0.3 mL) and added slowly. The reaction was detected by TLC. After the reaction was completed, 10% NaHCO ₃ (0.7 mL) and saturated Na ₂ SO ₃ solution (2.0 mL) were added. After the reaction was stirred for 10 min, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo, and then the target compound 6ca was obtained by column chromatography in 81% yield, 16:1 dr. Representative compound characterization data are as follows:

6ca: Colourless liquid; 81% yield, 16: 1dr. ¹ H NMR (600MHz, CDCl ₃ ): 8.41 (s, 1H), 8.21 (s, 1H), 6.99 (m, 1H), 6.93 (m, 2H) ,6.72(m,2H),5.09(s,1H), 5.02(t,J=5.8Hz,1H),3.79(dd,J=15.1,6.9Hz,1H),3.72(s,3H),3.43( s, 3H), 3.16 (dd, J=15.1, 5.1 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ): 171.8, 171.2, 152.1, 151.5, 150.9, 144.2, 133.1, 131.1, 129.4, 128.3, 85.9 ,73.3,70.4,61.8,54.2,52.9,41.2.HRMS(ESI):m/z calcd.forC ₂₀ H ₁₉ ClN ₄ NaO ₆ [M+Na] ⁺ :469.0885,found 469.0881.

The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments. The above-mentioned embodiments and descriptions only illustrate the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will also have various Variations and improvements all fall within the scope of the present invention.

Claims (6)

1. a method for asymmetric [3+2] cyclization reaction synthesis of chiral five-membered carbocyclic purine nucleosides, is characterized in that, comprises the steps: the acrylate 1 and MBH carbonate 2 that replace with α-purine are The raw material is added with a solvent, and in the presence of a chiral monophosphine catalyst, the reaction obtains a chiral five-membered carbocyclic purine nucleoside 3 or its enantiomer. The reaction equation is as follows:

Wherein, R ¹ is selected from: Cl, H, Ph, piperidinyl, diethylamino, methoxy or propylthio; R ² is selected from: Cl, H; R ³ is selected from: methyl, ethyl or tert-butyl; R ⁴ is selected from: methyl, ethyl, tert-butyl, benzyl; R ⁵ is selected from: phenyl, 2-ClC ₆ H ₄ , 3-FC ₆ H ₄ , 3-ClC ₆ H ₄ , 3-BrC ₆ H ₄ , 4-NO ₂ C ₆ H ₄ , 4-CNC ₆ H ₄ , 4-CH ₃ C ₆ H ₄ , 4-CH ₃ OC ₆ H ₄ ,

The chiral monophosphine catalyst is selected from R-type SITCP:

or S-type SITCP:

Wherein, Ar is selected from phenyl, 4-methoxyphenyl or 3,5-di-tert-butyl-4-methoxyphenyl. 2. the method for synthesizing chiral five-membered carbocyclic purine nucleosides according to a kind of asymmetric [3+2] cyclization reaction in claim 1, is characterized in that: reaction solvent is selected from 1,2-dichloroethane, toluene , dichloromethane or chloroform. 3. the method for synthesizing chiral five-membered carbocyclic purine nucleosides according to a kind of asymmetric [3+2] cyclization reaction in claim 1, is characterized in that: described α-purine substituted acrylate 1, MBH carbonate 2. The molar ratio of the chiral monophosphine catalyst is 1:1-2:0.05-0.20. 4. A method for synthesizing chiral five-membered carbocyclic purine nucleosides according to an asymmetric [3+2] cyclization reaction in claim 1, wherein the reaction temperature is selected from -10°C to 30°C. 5. A method for synthesizing a chiral five-membered carbocyclic purine nucleoside according to an asymmetric [3+2] cyclization reaction in claim 1, wherein the entire reaction process is operated under the protection of an inert gas. 6. according to a kind of method of asymmetric [3+2] cyclization reaction synthesis chiral five-membered carbocyclic purine nucleoside in claim 1, it is characterized in that: chiral five-membered carbocyclic purine nucleoside product 3ca and NaBH ₄ Reduction to obtain monohydroxy compound 4ca, and reduction with DIBAL-H to obtain dihydroxy compound 5ca;