CN110642843A - Method for synthesizing chiral heteronucleoside analogue through asymmetric [3+2] cyclization reaction - Google Patents
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Abstract
The invention discloses a method for synthesizing chiral heteronucleoside analogues through asymmetric [3+2] cyclization reaction, belonging to the field of asymmetric synthesis in organic chemistry. Using nitrogen heterocyclic ring substituted olefin 1 and epoxybutene 2 as raw materials, and obtaining a chiral heteronucleoside analogue 3 in the presence of a palladium catalyst and a chiral ferrocene oxazoline derivative nitrogen phosphine ligand, wherein the dr value is 19:1, enantioselectivity was highest at 98% ee. The product 3 is further derived to obtain various functional group substituted chiral heteronucleosides 7-11 with high yield. The method provides a simple, convenient, cheap and efficient way for synthesizing chiral heteronucleoside compounds.
Description
Technical Field
The invention relates to a method for synthesizing chiral isonucleoside, in particular to a method for synthesizing chiral isonucleoside analogue by asymmetric [3+2] cyclization reaction, belonging to the field of asymmetric synthesis in organic chemistry.
Background
Natural nucleoside drugs are susceptible to hydrolysis and enzymatic degradation due to the presence of an aminal structure. In order to increase the stability, the base of the isonucleoside is shifted, and a novel nucleoside compound called isonucleoside is constructed. Chiral heteronucleoside compounds have important roles in biology and medicinal chemistry, for example, the isocucleoside compound Iso-ddA shows that the anti-HIV activity and selectivity are equivalent to those of the nucleoside compound ddA. However, the types of the existing discovered and applied heteronucleoside structures are very few, and the further structural modification of the heteronucleoside structures to change or enhance the antiviral or antitumor activity of the heteronucleoside structures has very important significance. Meanwhile, the product configuration of the chiral compound has great influence on the biological activity of the chiral compound, so that the research on synthesizing and preparing the optically pure chiral compound has great research value.
There are two approaches to the traditional construction of chiral heteronucleosides. The first approach is to elaborate a chiral tetrahydrofuran ring with three-dimensional configuration and different functional groups obtained by multi-step reaction, and then to chemically link with the base to form chiral isonucleoside. The second approach is to introduce an amino group on the above chiral tetrahydrofuran ring, and construct a base from the amino group, thereby synthesizing the chiral isocucleoside compound. However, both approaches require equivalent amounts of chiral source and the chiral heteronucleoside is obtained through multiple reactions. The method has low yield, and the chiral substrate is difficult to prepare and has higher cost.
Therefore, the method for synthesizing the chiral isonucleoside by selecting the low-cost, cheap and easily-obtained achiral raw materials to carry out asymmetric [3+2] cyclization reaction becomes the most direct and effective reaction path.
Disclosure of Invention
In order to overcome the defects, the invention adopts nitrogen heterocyclic ring substituted olefin 1 and epoxybutene 2 as raw materials to synthesize the chiral heteronucleoside compound 3 in the presence of a palladium catalyst and a chiral ferrocene derived nitrogen phosphine ligand. The method provides a simple, cheap and efficient way for synthesizing the chiral heteronucleoside compound, and has the advantages of high product yield and good enantioselectivity.
A method for synthesizing chiral heteronucleoside by asymmetric [3+2] cyclization reaction comprises the following operations: the method comprises the following steps of taking nitrogen heterocyclic ring substituted olefin 1 and epoxybutene 2 as raw materials, and reacting in the presence of a palladium catalyst and a chiral ligand to obtain a chiral isocucleoside analogue 3, wherein the reaction equation is as follows:
wherein at least one of X, Y, A, B is nitrogen; r1Is one or more substituent groups, and R is C1-C8 alkyl or phenyl.
Further, in the above technical scheme, the nitrogen-containing heterocycle is selected from purine with different substituents, benzotriazole, substituted benzimidazole, 4-azaindole, 4-azabenzimidazole, 7-azabenzimidazole or substituted imidazole; r is selected from methyl, ethyl, isopropyl, tertiary butyl, benzyl and phenyl with different substituents.
Further, in the above technical solution, the palladium catalyst is selected from Pd (PPh)3)4Or Pd2(dba)3Etc., preferably Pd (PPh)3)4。
Further, in the above technical scheme, the chiral ligand is selected from chiral diphosphine or azaphosphine ligands, and the representative structure is as follows:
from the comprehensive consideration of reaction enantioselectivity and diastereoselectivity, the L10 ligand is the most effective ligand in the oxazoline ligand L7-L10 derived from ferrocene.
Further, in the technical scheme, the molar ratio of the olefin 1 to the epoxybutene 2 to the palladium catalyst to the chiral ligand is 1:0.2-1.2:0.05-0.20: 0.06-0.22.
Further, in the above technical scheme, the reaction is carried out in a solvent, and the organic solvent is selected from dichloromethane, 1, 2-dichloroethane, chloroform, chlorobenzene, toluene or mesitylene.
Further, in the above technical scheme, the reaction temperature is selected from-40 ℃ to 60 ℃.
In order to expand the application range of the method, the chiral heteronucleoside analogue 3 prepared by the method can be further derivatized by reduction, bromination, dihydroxylation and the like to obtain various types of derivative products, such as chiral heteronucleoside analogues 7-11, so that the product types are enriched, and the practicability of the method is improved.
Specifically, the chiral isonucleoside product 3 is reduced by a reducing agent to obtain an isonucleoside 6 containing one hydroxyl group; carrying out dihydroxylation reaction on the compound 6 to obtain an isonucleoside 7 containing three hydroxyl groups; reacting the compound 6 with a fluorinating reagent to obtain a product 8; the compound 6 is subjected to monohydroxyation reaction to obtain an isonucleoside compound 9 containing two hydroxyl groups; brominating the compound 6 to obtain bicyclic heteronucleoside 10; compound 6 is reduced with an olefin to give the isonucleoside 11.
The reaction equation is as follows:
wherein the reducing agent is selected from sodium borohydride, the hydrogenation reduction is carried out by palladium carbon under the condition of hydrogen, the bromination is carried out by N-bromosuccinimide, the fluorinating agent is selected from diethylaminosulfur trifluoride, the hydroxylation is carried out by 9-BBN, and the dihydroxylation is carried out by potassium ferricyanide, potassium osmate, methanesulfonamide and potassium carbonate.
The invention has the beneficial effects that:
the prior art methods are mostly limited to electron deficient olefins with a double activating group and a single activating group (i.e. olefins with two electron withdrawing groups on the same carbon atom, such as double activation of the same carboxylate). The electron-deficient olefin having an electron donating amino group and an electron withdrawing carboxylate at one end of a double bond is not reported in the literature because of its chemical inertness.
The invention takes the alpha-heterocyclic substituted acrylate as a substrate, and generates asymmetric [3+2] cycloaddition reaction under the action of a palladium catalyst and a ferrocene derived nitrogen phosphine ligand, thereby providing a simple, convenient, cheap and efficient synthesis method for synthesizing the chiral heteronucleoside compound, wherein the reaction raw materials are easy to obtain, the product structure is rich, the product stereoselectivity is high, the chiral heteronucleoside compound 3 is obtained after the reaction, and the enantioselectivity can reach 98% ee to the maximum extent. Meanwhile, the product 3 is derived to obtain chiral heteronucleoside substituted by various functional groups at high yield, thereby further expanding the practicability of the method.
Detailed Description
Example 1
aUnless otherwise stated, the reaction was carried out under a nitrogen atmosphere in a solvent of metal (10 mol%), ligand (12 mol%), 1a (0.1mmol),2(0.12mmol) for 1 day.bThe isolation yield.cdr values the crude product was tested by nuclear magnetic testing.dThe ee values were separated by high performance liquid chromatography.
In the screening of the reaction conditions, the influence of the ligand on the reaction (reference numerals 1 to 10), the influence of the metal on the reaction (reference numerals 10 to 12), and the influence of the reaction solvent on the reaction (reference numerals 13 to 15) were examined. Finally, Pd (PPh) is determined3)4For the best metal, ligand L10 is the best ligand, and dichloromethane is the best ligandA solvent.
Examination of reaction conditions: in a 10mL vacuum tube, α -benzimidazole substituted methyl acrylate 1a (20.2mg,0.1mmol), Pd (PPh)3)4(11.5mg,10 mol%) and L10(5.9mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of methylene chloride was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of methylene chloride and added to the reaction tube. The reaction tube was left at room temperature for 1 day. 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 then subjected to column chromatography to give the title compound 3a in 93% yield, 19:1dr and 90% ee.
With other conditions fixed, only the effect of the amount of catalyst on the reaction was examined, taking the reaction of 1a and 2 to form 3a as an example, the reaction equation is as follows:
5mol％Pd(0)/6mol％L10yield：40％-62％；17:1-18:1dr；86％-89％ee。
10mol％Pd(0)/12mol％L10yield：82％-93％；19:1dr；88％-91％ee。
20mol％Pd(0)/22mol％L10yield：90％-95％；19:1dr；90％-92％ee。
example 2:
in a 10mL vacuum tube, α -4, 5-diphenylimidazole-substituted methyl acrylate 1c (30.4mg,0.1mmol), Pd (PPh)3)4(11.5mg,10 mol%) and L10(5.9mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of methylene chloride was added and the mixture was stirred for half an hour, followed by addition of a solution of epoxybutene 2(9.0mg,0.12mmol) in methylene chloride (0.5mL) and stirring at room temperature for 1 day. The reaction was followed by TLC, after termination of the reaction dichloromethane/water was added for extraction, dried over anhydrous sodium sulphate, the organic phase was concentrated in vacuo and the column chromatographed to give 32.8mg of colourless liquid 3c in 88% yield, 7:1dr, 94% ee.
Example 3:
in a 10mL vacuum tube, the alpha-benzotriazole substituted propaneMethyl enoate 1e (20.3mg,0.1mmol), Pd (PPh)3)4(11.5mg,10 mol%) and L10(5.9mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of methylene chloride was added and the mixture was stirred for half an hour, followed by addition of a solution of epoxybutene 2(9.0mg,0.12mmol) in methylene chloride (0.5mL) and stirring at room temperature for 1 day. The reaction was followed by TLC, after termination of the reaction dichloromethane/water was added for extraction, dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo and column chromatographed to give 24.6mg of 3e as a colourless liquid in 90% yield, 13:1dr, 98% ee. HPLC CHIRALCEL IE, n-hexane/isopropanol 60/40, flow rate of 1.0mL/min, column temperature of 25 ℃, wavelength of 254nm, retention time of 29.351min (minor),35.251min (major).1H NMR(600MHz,CDCl3):δ8.11(d,J＝8.4Hz,1H),7.50-7.45(m,1H),7.42-7.37(m,1H),7.30(d,J＝8.4Hz,1H),6.02-5.96(m,1H),5.41(d,J＝16.8Hz,1H),5.32(d,J＝10.4Hz,1H),4.85(d,J＝9.6Hz,1H),4.73(q,J＝7.2Hz,1H),4.53(d,J＝9.6Hz,1H),4.40(dd,J＝9.0,7.2Hz,1H),4.03(dd,J＝8.4,6.0Hz,1H),3.63(s,3H).13C NMR(150MHz,CDCl3):δ168.6,146.9,133.0,132.5,128.0,124.4,120.7,120.5,109.8,76.7,74.9,72.7,53.3,50.8.HRMS(ESI):m/z calcd.for C14H16N3O3[M+H]+:274.1186,found 274.1183.
Example 4:
in a 10mL vacuum tube, α -7-azabenzimidazole-substituted methyl acrylate 1f (20.3mg,0.1mmol), Pd (PPh)3)4(11.5mg,10 mol%) and L10(5.9mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of methylene chloride was added and the mixture was stirred for half an hour, followed by addition of a solution of epoxybutene 2(9.0mg,0.12mmol) in methylene chloride (0.5mL) and stirring at room temperature for 1 day. Follow the reaction by TLC, after the reaction is terminated, add dichloromethane/water for extraction, dry with anhydrous sodium sulfate, concentrate the organic phase in vacuo, and carry out column chromatography to obtain the target compound 3f with 88% yield, 6:1dr, 96% ee.
Example 5:
in a 10mL vacuum tube, α -6-chloropurine-substituted methyl acrylate 4a (23.8mg,0.1mmol), Pd (PPh)3)4(11.5mg,10 mol%) and L10(5.9mg,12 mol%). After 3 times of replacement with nitrogen, 0.5mL of methylene chloride was added and the mixture was stirred for half an hour,then, a solution of epoxybutene 2(9.0mg,0.12mmol) in methylene chloride (0.5mL) was added, and the reaction was stirred at room temperature for 1 day. The reaction was followed by TLC, after the reaction was stopped, dichloromethane/water was added for extraction, dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo and column chromatographed to give the title compound 5a in 91% yield, 7:1dr, 97% ee. HPLC CHIRALCEL ODH, n-hexane/2-propanol 70/30, flow rate 0.8mL/min, column temperature 25 ℃, lambda 250nm, retention time 11.208min (major),17.574min (minor), TLC, Rf 0.35 (petri ether: ethyl acetate 2:1) [ UV].1H NMR(400MHz,CDCl3):δ8.70(s,1H),8.36(s,1H),5.86-5.71(m,1H),5.52(d,J＝16.8Hz,1H),5.44(d,J＝10.4Hz,1H),5.05(d,J＝10.4Hz,1H),4.55(d,J＝10.4Hz,1H),4.31(t,J＝8.0Hz,1H),4.01(t,J＝9.0Hz,1H),3.87-3.84(m,1H),3.70(s,3H).13C NMR(150MHz,CDCl3):δ168.8,152.4,152.2,151.7,143.0,131.7,131.2,122.2,76.2,72.7,72.0,53.5,52.9.HRMS(ESI):m/z calcd.for C13H13ClN4O3Na[M+Na]+:331.0568,found331.0559.
Example 6:
in a 10mL vacuum tube, 4g (41.9mg,0.1mmol) of α -Boc protected adenine substituted methyl acrylate, Pd (PPh)3)4(11.5mg,10 mol%) and L10(5.9mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of methylene chloride was added and the mixture was stirred for half an hour, followed by addition of a solution of epoxybutene 2(9.0mg,0.12mmol) in methylene chloride (0.5mL) and stirring at room temperature for 1 day. The reaction was followed by TLC, after the reaction was stopped, dichloromethane/water was added for extraction, dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo and column chromatographed to give the title compound 5g, 89% yield, 7:1dr, 98% ee.
Example 7:
in a 10mL vacuum tube, α -2-amino-6-benzyloxypurine substituted methyl acrylate 4m (32.5mg,0.1mmol), Pd (PPh)3)4(11.5mg,10 mol%) and L10(5.9mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of methylene chloride was added and the mixture was stirred for half an hour, followed by addition of a solution of epoxybutene 2(9.0mg,0.12mmol) in methylene chloride (0.5mL) and stirring at room temperature for 1 day. Follow the reaction by TLC, after the reaction is stopped, add dichloroExtraction with methane/water, drying over anhydrous sodium sulfate, vacuum concentration of the organic phase, and column chromatography gave the title compound 5a in 88% yield, 6:1dr, 95% ee. HPLCCHIRALCEL ODH, n-hexane/isopropanol 60/40, flow rate of 1.0mL/min, column temperature of 25 ℃, wavelength of 250nm, retention time of 15.328min (minor),22.245min (major).1H NMR(400MHz,CDCl3):δ7.76(s,1H),7.48-7.40(m,2H),7.36-7.22(m,3H),5.73-5.64(m,1H),5.48(s,2H),5.36(d,J＝17.2Hz,1H),5.29(d,J＝10.4Hz,1H),4.91(d,J＝10.0Hz,1H),4.73(br,2H),4.36(d,J＝10.0Hz,1H),4.16(dd,J＝8.8,7.6Hz,1H),3.88(t,J＝8.8Hz,1H),3.72(q,J＝8.4Hz,1H),3.60(s,3H).13C NMR(150MHz,CDCl3):δ169.7,161.2,159.1,154.8,136.8,136.6,131.7,128.5,128.4,128.1,121.4,115.7,76.5,71.8,71.8,68.2,53.1,52.4.HRMS(ESI):m/z calcd.forC20H22N5O4[M+H]+:396.1666,found 396.1672
Example 8
According to the reaction conditions and operations of examples 2 to 7, only the reaction substrate was changed, and the reaction results were shown by the following structural formulae:
example 9:
in a 10mL vacuum tube, the isonucleoside compound 5b (30.4mg,0.1mmol) was dissolved in methanol, the reaction was left at room temperature, and sodium borohydride (15.2mg,0.4mmol) was added. Tracking the reaction by TLC, terminating the reaction, adding dichloromethane/water for extraction, drying with anhydrous sodium sulfate, concentrating the organic phase in vacuo, and performing column chromatography to obtain 21.8mg of white solid 6ba, [ alpha ]]D 26Yield 79% yield, 96% ee, 32.8(c ═ 0.25, MeOH). 165.2-167.5 ℃, HPLC CHIRALCEL OD, 70/30 of normal hexane/isopropanol, 0.8mL/min of flow rate, 25 ℃ of column temperature, 250nm of wavelength, 7.241min (major),10.182min (minor).1H NMR(400MHz,CDCl3):δ8.45(s,1H),8.14(s,1H),6.17-6.01(m,1H),5.38-5.28(m,2H),4.76(s,1H),4.49-4.35(m,3H),4.14(s,3H),4.14-4.02(m,2H),3.90(dd,J＝8.8,6.0Hz,1H),3.62-3.56(q,J＝7.6Hz,1H).13C NMR(150MHz,CDCl3):δ161.1,151.7,151.5,141.7,133.3,121.7,119.7,74.4,72.8,72.1,63.4,54.4,52.0.HRMS(ESI):m/z calcd.for C13H17N4O3[M+H]+:277.1295,found 277.1287.
To a solvent of tert-butanol/water (2:1,1mL) was added potassium ferricyanate (49.4mg,0.15mmol), potassium carbonate (20.7mg,0.15mmol), (DHQD)2PHAL (3.9mg,0.005mmol), methanesulfonamide (9.5mg,0.1mmol) and K2OsO2(OH)4(0.3mg,0.001mmol) and after stirring the reaction at room temperature for half an hour, substrate 6ba (13.8mg,0.05mmol) was added. The reaction was left to stir at room temperature overnight. After the reaction is completed, Na is added2S2O3Adding dichloromethane/water to extract after stirring for 2h, drying with anhydrous sodium sulfate, concentrating the organic phase in vacuum, and performing column chromatography to obtain 11.9mg of white solid 7ba 77% yield,20:1dr and 96% ee, m.p.:204.5-207.3 ℃. [ alpha ]]D 26＝6.6(c＝0.4,MeOH).TLC:Rf＝0.27(DCM:CH3OH＝30:1).HPLC CHIRALCEL IE,n-hexane/2-propanol＝50/50,flow rate＝1.0mL/min,column temperature＝25℃,λ＝250nm,retention time:8.121min(major),11.465min(minor).1H NMR(400MHz,CD3OD):δ8.50(s,1H),8.38(s,1H),4.72(d,J＝10.8Hz,1H),4.64(d,J＝11.8Hz,1H),4.37-4.28(m,2H),4.21-4.15(m,2H),4.17(s,3H),4.04(t,J＝8.8Hz,1H),3.45-3.40(m,2H),3.35(s,1H),3.31-3.30(m,1H).13C NMR(150MHz,CD3OD):δ160.8,152.0,151.1,142.4,121.5,73.3,72.7,68.2,67.1,64.9,60.8,53.3.HRMS(ESI):m/z calcd.for C13H18N4O5Na[M+Na]+:333.1169,found 333.1164.
Example 10:
in a 10mL vacuum tube, the isonucleoside compound 6ba (13.8mg,0.05mmol) was added dissolved in dichloromethane,the reaction was allowed to stand at room temperature, DAST (13. mu.L, 2equiv) was added, the reaction was followed by TLC, after termination of the reaction, dichloromethane/water was added for extraction, dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo, and column chromatography gave 10.9mg of colorless liquid 8ba, 79% yield, 96% ee.HPLC CHIRALCEL ID, n-hexane/isopropanol 50/50, flow rate 1.0mL/min, column temperature 25 ℃, wavelength 250nm, retention time 18.906min (major),27.240min (minor).1H NMR(400MHz,CDCl3):δ8.52(s,1H),8.15(s,1H),6.04-5.90(m,1H),5.42(d,J＝17.2Hz,1H),5.37(d,J＝10.4Hz,1H),5.21(dd,J＝46.8,10.0Hz,1H),4.81(dd,J＝46.8,10.4Hz,1H),4.69(dd,J＝10.8,3.6Hz,1H),4.44(d,J＝10.8Hz,1H),4.19(s,3H),4.16(d,J＝8.0Hz,1H),3.92-3.85(m,1H),3.80(q,J＝8.0Hz,1H).13C NMR(150MHz,CDCl3):δ161.5,152.1,151.9,140.9,132.5,122.3,120.8,82.5(JC-F＝177.0Hz),73.1(JC-F＝0.3Hz),72.1,69.9(JC-F＝16.5Hz),54.4,51.2(JC-F＝1.5Hz).19F NMR(564MHz,CDCl3):δ-224.5(s)HRMS(ESI):m/z calcd.for C13H16FN4O2[M+H]+:279.1252,found 279.1250.
In a 10mL vacuum tube, add the isonucleoside compound 6ba (13.8mg,0.05mmol) dissolved in dry tetrahydrofuran, react at 0 deg.C, add 9-BBN (0.5M in THF,0.2mmol, 400. mu.L) to the reaction, stir overnight, add aqueous NaOH (3N, 120. mu.L), H2O2(30% water, 30. mu.L) and stirred at room temperature for two hours. Extracting with dichloromethane/water, drying with anhydrous sodium sulfate, vacuum concentrating organic phase, and performing column chromatography to obtain 11.9mg white solid 9ba, 81% yield,11.9mg, 98% ee, m.p. 163.2-165.4 ℃. [ alpha. ]]D 264.8(c 0.25 MeOH), HPLC CHIRALCEL ID, n-hexane/isopropanol 50/50, flow rate 1.0mL/min, column temperature 25 ℃, wavelength 250nm, retention time 10.617min (major),12.869min (minor).1H NMR(400MHz,CD3OD):δ8.50(s,1H),8.41(s,1H),4.73(d,J＝10.2Hz,1H),4.40(d,J＝11.6Hz,1H),4.28-4.19(m,2H),4.17(s,3H),4.03(d,J＝11.6Hz,1H),3.73(dd,J＝8.8,7.6Hz,1H),3.67-3.57(m,2H),3.25-3.17(m,1H),2.34-2.27(m,1H),1.73-1.64(m,1H).13C NMR(150MHz,CD3OD):δ162.3,153.5,152.6,143.8,122.7,74.48,74.3,73.2,62.4,61.4,54.7,45.0,31.9.HRMS(ESI):m/z calcd.for C13H19N4O4[M+H]+:295.1401,found 295.1395.
In a 10mL vacuum tube, the isonucleoside compound 6ba (13.8mg,0.05mmol) was dissolved in 1mL dichloromethane, the reaction was left at room temperature, NBS (10.6mg,0.06mmol) was added to the reaction solution, and the reaction was stirred overnight. Adding dichloromethane/water for extraction, drying with anhydrous sodium sulfate, vacuum concentrating organic phase, performing column chromatography to obtain 15mg colorless liquid 10ba, 85% yield,>20:1dr, 98% ee, HPLC CHIRALCEL ODH, n-hexane/isopropanol 50/50, flow rate of 1.0mL/min, column temperature of 25 ℃, wavelength of 250nm, retention time of 10.177min (minor),12.073min (major).1H NMR(600MHz,CDCl3):δ8.51(s,1H),8.13(s,1H),4.58-4.53(m,2H),4.19(s,3H),4.17-4.13(m,1H),4.08-3.98(m,4H),3.74-3.66(m,2H),3.56(t,J＝6.4Hz,1H).13C NMR(150MHz,CDCl3):δ177.2,161.5,152.2,152.2,140.2,85.1,77.1,75.2,72.4,55.2,54.5,33.1,29.7.HRMS(ESI):m/z calcd.forC13H15BrN4O3Na[M+Na]+:377.0220,found 377.0225.
In a 10mL vacuum tube, add the isonucleoside compound 6ba (13.8mg,0.05mmol) dissolved in 1mL methanol, let the reaction stand at room temperature, add Pd/C (2.7mg, 10%) to the reaction and fill with H2(1 atm.) the reaction was stirred overnight. After the reaction is completed, the mixture is dried by spinning after passing through diatomite, and the column chromatography is carried out to obtain 12.3mg of white solid 11ba, 89% yield, 98% ee, m.p. 142.1-144.7 ℃ alpha]D 26＝4.3(c＝0.2,CH2Cl2).TLC:Rf＝0.36(DCM:CH3OH＝50:1).HPLC CHIRALCEL IE,n-hexane/2-propanol＝50/50,flow rate＝1.0mL/min,column temperature＝25℃,λ＝250nm,retention time:16.566min(major),23.525min(minor).1H NMR(600MHz,CD3OD):δ8.49(s,1H),8.36(s,1H),4.77(d,J＝10.4Hz,1H),4.46(d,J＝11.8Hz,1H),4.17(d,J＝10.4Hz,1H),4.16(s,3H),4.16-4.12(m,1H),3.99(d,J＝11.8Hz,1H),3.72(dd,J＝9.0,6.4Hz,1H),3.04-2.94(m,1H),2.09-2.05(m,1H),1.52-1.40(m,1H),0.96(t,J＝7.4Hz,3H).13C NMR(150MHz,CD3OD):δ162.2,153.4,152.5,143.9,122.8,74.3,74.0,73.7,62.2,54.7,49.5,22.4,12.9.HRMS(ESI):m/z calcd.for C13H19N4O3[M+H]+:279.1452,found 279.1445.
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 (9)
1. A method for synthesizing chiral heteronucleoside 3 by asymmetric [3+2] cyclization reaction is characterized by comprising the following steps: using nitrogen heterocyclic ring substituted olefin 1 and epoxybutene 2 as raw materials, and reacting in the presence of a palladium catalyst and a chiral ferrocene derived nitrogen phosphine ligand to obtain a chiral heteronucleoside analogue 3, wherein the reaction equation is as follows:
wherein at least one of X, Y, A, B is nitrogen; r1Is one or more substituents, R2Is C1-C8 alkyl and phenyl.
2. A method for the synthesis of chiral heteronucleoside analogues according to the asymmetric [3+2] cyclization reaction of claim 1, characterized in that: the nitrogen-containing heterocycle is selected from purine with different substituents, benzotriazole, substituted benzimidazole, 4-azaindole, 4-azabenzimidazole, 7-azabenzimidazole or substituted imidazole; r is selected from methyl, ethyl, isopropyl, tertiary butyl, benzyl and phenyl with different substituents.
3. Asymmetry [3+2] according to claim 1]A method for synthesizing chiral isonucleosides through cyclization reaction, which is characterized in that: the chiral ferrocene-derived nitrogen phosphine ligand is selected from
4. A method for the synthesis of chiral heteronucleoside analogues according to the asymmetric [3+2] cyclization reaction of claim 1, characterized in that: the reaction is carried out in an organic solvent selected from dichloromethane, 1, 2-dichloroethane, chloroform, chlorobenzene, toluene or mesitylene.
5. A method for the synthesis of chiral heteronucleoside analogues according to the asymmetric [3+2] cyclization reaction of claim 1, characterized in that: the reaction temperature is selected from-40 ℃ to 60 ℃.
6. Asymmetry [3+2] according to claim 1]A method for synthesizing chiral heteronucleoside analogues by cyclization reaction is characterized in that: the palladium catalyst is selected from Pd (PPh)3)4Or Pd2(dba)3。
7. The method for synthesizing chiral heteronucleosides according to any one of claims 1-6, characterized in that: the mol ratio of the olefin 1, the epoxybutene 2, the palladium catalyst and the nitrogen-phosphine ligand is 1:0.2-1.2:0.05-0.20: 0.06-0.22.
8. A method for synthesizing chiral heteronucleoside analogues 7-11, characterized by: taking the product 3 obtained in the claim 1 as a raw material, carrying out different derivatizations to obtain chiral heteronucleoside analogues 7-11, wherein the reaction equation is as follows:
9. the method as set forth in claim 8, wherein: the reducing agent is selected from sodium borohydride, the hydrogenation reduction is carried out by palladium carbon under the condition of hydrogen, the bromination is carried out by N-bromosuccinimide, the fluorinating agent is selected from diethylamido sulfur trifluoride, the hydroxylation is carried out by 9-BBN, and the dihydroxylation is carried out by potassium ferricyanide, potassium osmate, methanesulfonamide and potassium carbonate.
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