CN107698590B - Method for synthesizing chiral five-membered carbocyclic purine nucleoside through asymmetric [3+2] cyclization reaction - Google Patents
Method for synthesizing chiral five-membered carbocyclic purine nucleoside through asymmetric [3+2] cyclization reaction Download PDFInfo
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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
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 through asymmetric [3+2] cyclization reaction, belonging to the field of asymmetric synthesis in organic chemistry.
Background
Chiral five-membered carbocyclic purine nucleosides have a wide range of physiological activities, such as Abacavir, Entecavir and Carbovir can be used for the treatment of HIV and HBV, respectively. Other chiral five-membered carbocyclic nucleosides such as: noraristeromycin, Aristomycin, Neplanocin A and HNPA have different pharmaceutical activities. Meanwhile, the product configuration of the chiral compound has great influence on the biological activity of the compound, so that the synthesis and preparation of the optically pure chiral compound and the test and research on the physiological and pharmacological activities of the compound have great application prospects and significance.
There are two approaches to the traditional construction of chiral five-membered carbocyclic nucleosides. The first approach is to elaborate a chiral carbocycle which is obtained through multi-step reactions and has a three-dimensional configuration and different functional groups, and then to chemically connect the chiral carbocycle with bases of purine or pyrimidine to form chiral five-membered carbocyclic nucleoside, wherein the chiral carbocycle introduction method mainly comprises four methods, namely nucleophilic substitution reaction, ring opening reaction of epoxy compound, Mitsunobu reaction, palladium-catalyzed allyl coupling reaction, and the like. The second approach is to introduce an amino group on the chiral five-membered ring, and construct purine or pyrimidine base from the amino group, thereby synthesizing the chiral carbocyclic nucleoside compound. However, both approaches require an equivalent amount of chiral source and can synthesize chiral five-membered carbocyclic nucleosides through multi-step reactions. And the chiral substrate is relatively difficult to prepare and has higher cost. Relatively speaking, the method for synthesizing the chiral five-membered carbocyclic purine nucleoside by using the low-cost, cheap and easily-obtained achiral raw material through the asymmetric [3+2] cyclization reaction has obvious significance.
Disclosure of Invention
In order to overcome the defects, α -purine substituted acrylate 1 and MBH carbonate 2 are used as raw materials to synthesize the chiral five-membered carbocyclic nucleoside compound under the action of a chiral monophosphine catalyst.
A method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization reaction is characterized by comprising the following steps of taking α -purine substituted acrylate 1 and MBH carbonate 2 as raw materials, adding a solvent, and reacting in the presence of a chiral monophosphine catalyst to obtain chiral five-membered carbocyclic nucleoside compound 3 or an enantiomer thereof.
The reaction equation is as follows:
wherein R is1Represents in the following groupsOne of them is: cl, H, Ph, piperidine, diethylamino, methoxy and propylthio; r2Represents one of the following groups: cl and H; r3Represents one of the following groups: methyl, ethyl, tert-butyl; r4Represents one of the following groups: methyl, ethyl, tert-butyl, benzyl; r5Represents one of the following groups: phenyl, 2-ClC6H4、 3-FC6H4、3-ClC6H4、3-BrC6H4、4-NO2C6H4、4-CNC6H4、4-CH3C6H4、 4-CH3OC6H4、
Further, in the above technical scheme, the chiral monophosphine catalyst is taken from SITCP, and each ligand comprises R type and S type. The R-type SITCP structure is as follows:or the S-type SITCP structure is as follows:
further, in the SITCP ligand, Ar is preferably selected from phenyl, 4-methoxyphenyl or 3, 5-di-tert-butyl-4-methoxyphenyl. The specific structure of the S-type SITCP ligand is as follows:
further, in the technical scheme, 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 scheme, the reaction temperature is selected from-10 ℃ to 30 ℃.
Further, in the above technical scheme, the whole reaction process needs to be operated under the protection of inert gas, and the inert gas is preferably nitrogen.
Further, the obtained chiral five-membered carbocyclic nucleoside compound 3 can be further derived to obtain different types of derived products, and NaBH is adopted4Or DIBAL-H, to obtain a product in which the ester group attached to the nitrogen atom is mono-reduced or a product in which both ester groups are fully reduced, respectively. For example, the five-membered carbocyclic purine nucleoside product 3ca with NaBH4Reducing to obtain a monohydroxy compound 4ca, and reducing with DIBAL-H to obtain a dihydroxy compound 5 ca.
The invention has the beneficial effects that:
the invention provides a simple, cheap and efficient synthesis method for synthesizing chiral five-membered carbocyclic purine nucleoside, reaction raw materials are easy to obtain, the product structure is rich, the product stereoselectivity is high, the chiral five-membered carbocyclic nucleoside compound is obtained after reaction, and the yield can reach 93 percent at most.
Detailed Description
Example 1
aUnless otherwise stated, the reaction was carried out under a nitrogen atmosphere with the catalyst (20 mol%), 1(0.05mmol),2(0.06mmol) in CH2Cl2(1.0mL) for 4 days.bdr values the crude product was tested by nuclear magnetic testing.cThe isolation yield.dThe ee values were separated by high performance liquid chromatography. .
During the screening of the reaction conditions, the effect of the phosphine catalyst on the reaction was first examined (entries 1-8). Meanwhile, the ligand P6 is finally determined as the optimal ligand by comparing the influence of different ligands on the reaction and considering the price factor.
Examination of reaction conditions in a 10mL vacuum tube, α -purine-substituted ethyl 6-chloroacrylate 1a (23.8mg,0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl phenyl MBH carbonate 2a (35.1mg,0.12mmol) were added, the reaction tube was filled with nitrogen by nitrogen substitution 3 times, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ for reaction 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 83 aa yield, 9:1dr and 91% ee.
Under other fixed conditions, only the influence of the amount of the catalyst on the reaction is considered, and 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%。
with the other conditions fixed, the effect of steric hindrance of the substituent on the reaction was examined only, and the reaction equation is as follows:
aunless otherwise stated, the reaction was carried out under a nitrogen atmosphere with the catalyst (20 mol%), 1(0.05mmol),2(0.06mmol) in CH2Cl2(1.0mL) for 4 days.bdr valueThe crude product was tested by nuclear magnetic resonance.cThe isolation yield.dThe ee values were separated by high performance liquid chromatography.
Example 2:
α -purine-substituted methyl 6-piperidinecarboxylate (28.7mg, 0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl phenyl MBH carbonate (35.1mg,0.12mmol) were replaced 3 times by nitrogen in a 10mL vacuum tube to fill the reaction tube with nitrogen, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ for 4 days, the reaction was followed by TLC, after termination of the reaction, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and then subjected to column chromatography to give the desired compound 3ea yield 87%, 9:1dr and 90% ee.
Example 3:
α -purine-substituted methyl 6-propylsulfanylacrylate (27.8 mg,0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl phenyl MBH carbonate (35.1mg,0.12mmol) were placed in a 10mL vacuum tube 3 times by nitrogen substitution so that the reaction tube was filled with nitrogen, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ for 4 days, the reaction was followed by TLC, after the termination of the reaction, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and then column chromatography was performed to obtain 85% yield of the objective compound 3ea, 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, CH2Cl2) HPLC CHIRALCEL IA, 70/30 of n-hexane/isopropanol, 0.5mL/min of flow rate, 25 ℃ of column temperature, 254nm of lambda, 26.267min of retention time, 33.839 min of retention time.1H NMR(400MHz,CDCl3):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).13C NMR (151MHz,CDCl3):171.1,163.7,161.5,151.6,148.6,140.5,139.7,137.6, 135.0,131.1,128.3,128.3,128.1,72.2,55.9,53.7,52.0,40.9,30.7,22.9, 13.6.HRMS(ESI):m/z calcd.for C23H24N4O4SNa[M+Na]+:475.1410, found475.1414.
Example 4:
α -purine-substituted methyl 6-hydrocrylate (20.4mg, 0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl phenyl MBH carbonate (35.1mg,0.12mmol) were replaced 3 times by nitrogen in a 10mL vacuum tube, so that the reaction tube was filled with nitrogen, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ for 4 days, the reaction was followed by TLC, after termination of the reaction, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and then subjected to column chromatography to obtain the desired compound 3ia yield 92%, 10:1dr and 90% ee.
Example 5:
α -purine-substituted methyl 2, 6-chloroacrylate (27.1mg, 0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl phenyl MBH carbonate (35.1mg,0.12mmol) were placed in a 10mL vacuum tube 3 times by nitrogen substitution so that the reaction tube was filled with nitrogen, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a 0 ℃ cryopump for 5 days, the reaction was followed by TLC, after termination of the reaction, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and then column chromatography was performed to obtain the desired compound 3ja yield 82%, 10:1dr and 92% ee.
Example 6:
in a 10mL vacuum tube, α -purine-substituted methyl 6-chloroacrylate (23.8mg,0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl m-fluorophenyl MBH carbonate (51.6mg,0.12mmol) were added, the reaction tube was purged with nitrogen by 3 times, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ 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 column chromatography was performed to obtain 82% yield of the objective compound 3cb, 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,CH2Cl2) HPLC CHIRALCEL ODH, n-hexane/isopropanol 70/30, flow rate 0.5mL/min, column temperature 25 ℃, λ 254nm, retention time 11.066min,13.742min.1H NMR(400MHz,CDCl3):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).13C NMR(151MHz,CDCl3):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(ESI):m/z calcd.for C20H17ClFN4O4[M+H]+:431.0917,found 431.0916.
Example 7:
in a 10mL vacuum tube, α -purine-substituted methyl 6-chloroacrylate (23.8mg,0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl o-chlorophenyl MBH carbonate (53.5mg,0.12mmol) were added, the reaction tube was purged with nitrogen by 3 times, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ 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 column chromatography was performed to obtain the desired compound 3ce yield 73%, 10:1dr, and 92% ee.
Example 8:
α -purine-substituted methyl 6-chloroacrylate (23.8mg,0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl 1-naphthyl MBH carbonate (55.4mg,0.12mmol) were added to a 10mL vacuum tube, the reaction tube was filled with nitrogen by nitrogen substitution 3 times, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ for reaction 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 column chromatography was performed to obtain the objective compound 3cj in 87%, 10:1dr and 96% ee.
Representative compound characterization data are as follows:
3cj White solid;87%yield,10:1dr,96%ee.[α]D 20=60.2(c=0.5,CH2Cl2) HPLC CHIRALCEL IA, 70/30 of n-hexane/isopropanol, 0.5mL/min of flow rate, 25 ℃ of column temperature, 254nm of lambda, 36.264min of retention time, 46.357min of retention time.1H NMR (600MHz,CDCl3):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).13C NMR(151MHz,CDCl3):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, 125.9,125.4,124.6,124.3,123.5,72.8,54.0,52.1,50.5,41.9.HRMS(ESI): m/z calcd.for C24H20ClN4O4[M+H]+:463.1168,found 463.1167
Example 9:
α -purine-substituted methyl 6-chloroacrylate (23.8mg,0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and methyl 3, 4-dimethylphenyl MBH carbonate (52.8mg,0.12mmol) were added to a 10mL vacuum tube, the reaction tube was filled with nitrogen by nitrogen substitution 3 times, then 1mL of dichloromethane was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ for reaction 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, concentrated in vacuo, and the objective compound was subjected to column chromatography in 85% yield of 3cm, 10:1dr and 96% ee.
Example 10:
α -purine-substituted methyl acrylate 1(0.1mmol), (S) -SITCP (3.5mg,20 mmol%) and aryl MBH methyl carbonate 2(0.12mmol) were charged into a 10mL vacuum tube, the reaction tube was filled with nitrogen by nitrogen substitution 3 times, then 1mL of methylene chloride was added, the reaction tube was sealed, the reaction tube was placed in a cryopump at-10 ℃ for 4 days, the reaction was followed by TLC, after the reaction was terminated, extraction was performed by adding methylene chloride/water, the organic phase was dried with anhydrous sodium sulfate, concentrated in vacuo, and then subjected to column chromatography to obtain the objective compound 3, the substituent of the substrate was replaced, and a different product 3 could be obtained.
The specific reaction results are shown below:
example 11:
in a 50mL round bottom flask, the five-membered carbocyclic nucleoside analog 3ca (82.4mg,0.2 mmol) was added, 20mL of methanol was added, the reaction was allowed to warm to room temperature, and NaBH was added4(22.8mg, 0.6 mmol.) detection by TLC, after complete reaction, saturated NH was added4And (4) quenching by Cl. After the reaction was terminated, dichloromethane/water was added for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo and then subjected to column Chromatography (CH)2Cl2MeOH ═ 50:1) yielded the title compound 4ca (92% yield, 93% ee).
Representative compound characterization data are as follows:
4ca White solid;92%yield,93%ee.[α]D 20=-32.9(c=0.3,CH2Cl2) HPLCCHIRALCEL IA, 80/20 of n-hexane/isopropanol, 0.6mL/min of flow rate, 25 ℃ of column temperature, 254nm of lambda, 28.511min of retention time, 31.936min of retention time.1H NMR(600 MHz,CDCl3):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).13C NMR(151MHz,CDCl3):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.forC19H17ClN4O3Na[M+Na]+:407.0881, found 407.0884.
Example 12:
in a 10mL vacuum tube, the five-membered carbocyclic purine nucleoside 4ca (38.4mg,0.1 mmol) was added. The reaction tube was filled with nitrogen by replacing it with nitrogen 3 times, and then 1mL of tetrahydrofuran was added under a nitrogen stream. The reaction tube was sealed and placed at-20 ℃. DIBAL-H (3equiv,1.1M in cyclohexane) was added slowly. The reaction was followed by TLC, after the reaction was terminated, a saturated ammonium chloride solution was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and then subjected to column chromatography to obtain the target compound 5ca in a yield of 57% and an ee value of 91%.
Representative compound characterization data are as follows:
5ca Colourless liquid;57%yield,91%ee.[α]D 20=-8.6(c=0.63,CH2Cl2) HPLC CHIRALCEL IE, 80/20 of n-hexane/isopropanol, 0.5mL/min of flow rate, 25 ℃ of column temperature, 254nm of lambda, 32.633min of retention time, 35.508min of retention time.1H NMR(600 MHz,CDCl3):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).13C NMR(151MHz,CDCl3):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 C18H17ClN4O2Na[M+Na]+:379.0932,found 379.0942.
Example 13:
in a 10mL reaction tube, five-membered carbocyclic nucleoside analogue 3ca (82.4mg,0.2 mmol), NaIO was added4(44.6mg,2equiv) was dissolved in 0.1mL of water, which was added to the reaction tube. The reaction was left at 0 ℃ and RuCl was added3·3H2O (2.8mg,0.1 equiv.) Ethyl acetate (0.2mL) and acetonitrile (0.3mL) were then added. Substrate 3ca (41.2mg,0.1 mmol) was dissolved in ethyl acetate (0.3mL) and added slowly. By usingDetecting the reaction by TLC, and adding 10% NaHCO after the reaction is completed3(0.7mL) and saturated Na2SO3Solution (2.0mL), reaction stirred for 10min, extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, concentrated in vacuo, and then subjected to column chromatography to obtain the target compound 6ca in 81% yield 16:1 dr. Representative compound characterization data are as follows:
6ca:Colourless liquid;81%yield,16:1dr.1H NMR(600MHz,CDCl3):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=15.1,5.1Hz,1H).13C NMR(151MHz,CDCl3):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.forC20H19ClN4NaO6[M+Na]+:469.0885,found 469.0881.
the foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (6)
1. A method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric [3+2] cyclization reaction is characterized by comprising the following steps of taking α -purine substituted acrylate 1 and MBH carbonate 2 as raw materials, adding a solvent, and reacting in the presence of a chiral monophosphine catalyst to obtain the chiral five-membered carbocyclic purine nucleoside 3 or an enantiomer thereof, wherein the reaction equation is as follows:
wherein R is1Selected from: cl, H, Ph, piperidinyl, diethylamino, methoxy or propylthio; r2Selected from: cl、H;R3Selected from: methyl, ethyl or tert-butyl; r4Selected from: methyl, ethyl, tert-butyl, benzyl; r5Selected from: phenyl, 2-ClC6H4、3-FC6H4、3-ClC6H4、3-BrC6H4、4-NO2C6H4、4-CNC6H4、4-CH3C6H4、4-CH3OC6H4、
2. The method for synthesizing chiral five-membered carbocyclic purine nucleoside according to claim 1, wherein the asymmetric [3+2] cyclization reaction comprises: the reaction solvent is selected from 1, 2-dichloroethane, toluene, dichloromethane or chloroform.
3. The method for synthesizing chiral five-membered carbocyclic purine nucleoside according to claim 1, wherein the molar ratio of α -purine substituted acrylate 1, MBH carbonate 2 and chiral monophosphine catalyst is 1:1-2: 0.05-0.20.
4. The method for synthesizing chiral five-membered carbocyclic purine nucleoside according to claim 1, wherein the asymmetric [3+2] cyclization reaction comprises: the reaction temperature is selected from-10 ℃ to 30 ℃.
5. The method for synthesizing chiral five-membered carbocyclic purine nucleoside according to claim 1, wherein the asymmetric [3+2] cyclization reaction comprises: the whole reaction process is operated under the protection of inert gas.
6. An asymmetry [3+2] according to claim 1]The method for synthesizing chiral five-membered carbocyclic purine nucleoside by cyclization reaction is characterized by comprising the following steps: chiral five-membered carbocyclic purine nucleoside product 3ca and NaBH4Reducing to obtain a monohydroxy compound 4ca, and reducing with DIBAL-H to obtain a dihydroxy compound 5 ca;
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