CN110590486B - Method for synthesizing chiral heteronucleoside analogue through asymmetric cycloaddition reaction - Google Patents
Method for synthesizing chiral heteronucleoside analogue through asymmetric cycloaddition reaction Download PDFInfo
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Abstract
The invention discloses a method for synthesizing chiral heteronucleoside analogues through asymmetric cycloaddition reaction, and belongs to the field of asymmetric synthesis in organic chemistry. Purine substituted olefin 1 and epoxybutene 2 are used as raw materials, in the presence of a palladium catalyst and chiral diphosphine ligand SegPHOS or MeOBIPHEP, chiral heteronucleoside analogue 3 is obtained by asymmetric cycloaddition reaction, dr is 1/1-7/1 with the highest ee reaching 95%, and various functional group substituted chiral heteronucleosides 7-11 are obtained after derivatization. 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 by asymmetric cycloaddition 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 routes require equivalent chiral sources, and chiral isonucleosides are obtained through multi-step 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 material through the asymmetric cycloaddition reaction becomes the most direct and effective reaction way.
Disclosure of Invention
In order to overcome the defects, the invention adopts alpha-azacyclo-substituted electron-deficient olefin 1 and epoxybutene 2 as raw materials to synthesize the chiral heteronucleoside compound with high yield and high enantioselectivity under the action of metal and chiral phosphine ligand. The method provides a simple, convenient, cheap and efficient way for synthesizing the chiral heteronucleoside compound.
A method for synthesizing chiral heteronucleoside by asymmetric [3+2] cyclization reaction is characterized by comprising the following operations: substituted olefin 1 and epoxybutene 2 are used as raw materials, and are reacted in the presence of a palladium catalyst and a chiral diphosphine ligand to obtain a chiral isocucleoside analogue 3, wherein the reaction equation is as follows: the reaction equation is as follows:
wherein R is 1 Is purine with different substituents and pyrimidine with different substituents; r 2 Is C1-C8 alkyl, phenyl or substituted phenyl. More preferably, the C1-C8 alkyl group is selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, or the like.
Further, in the above technical solution, the palladium catalyst is selected from Pd (PPh) 3 ) 4 Or Pd 2 (dba) 3 Etc., preferably Pd (PPh) 3 ) 4 。
Further, in the above technical scheme, the chiral diphosphine ligand has the following representative structure:
among the above-mentioned bisphosphine ligands, axially chiral bisphosphine ligands are preferred, and L6 (SegPHOS for short), L11 (BINAP for short) and L12(MeOBIPHEP) ligands are most preferred.
Further, in the technical scheme, the molar ratio of the substituted 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, 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; the compound 6 is reduced by olefin to obtain the isonucleoside 11.
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 reaction equation is as follows:
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-purine or pyrimidine substituted acrylate as a substrate, and generates asymmetric cycloaddition reaction under the action of a palladium catalyst and an axial chiral diphosphine ligand, thereby providing a simple, 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, and the chiral heteronucleoside compound 3 is obtained after the reaction, and dr is 1/1-7/1, and the highest ee reaches 95%. Pyrimidine substituted alkenes are significantly superior to purine substituted alkenes in diastereoselectivity.
Detailed Description
Example 1
a Unless 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. b The isolation yield. c dr values the crude product was tested by nuclear magnetic testing. d The ee values were separated by high performance liquid chromatography.
In the reaction condition screening process, the influence of the ligand on the reaction (reference numerals 1 to 14), the influence of the reaction solvent on the reaction (reference numerals 15 to 18), and the influence of the temperature on the reaction (reference numerals 19 to 21) were examined. Finally, Pd (PPh) is determined 3 ) 4 For the best metal, ligand L6 was the best ligand, and toluene was the best solvent.
Examination of reaction conditions: in a 10mL vacuum tube, alpha-5-methyluracil-substituted methyl acrylate 1a (31.4mg,0.1mmol), Pd (PPh) was added 3 ) 4 (5.8mg,5 mol%) and L6(3.6mg,6 mol%). After 3 times replacement with nitrogen, 0.5mL of dichloromethane was added, and stirring was carried out for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of dichloromethane and added to the reaction tube. The reaction tube was left at room temperature for 1 day. Tracking the reaction by TLC, terminating the reaction, adding dichloromethane/water for extraction, drying the organic phase with anhydrous sodium sulfate, concentrating the organic phase in vacuo, and subjecting to column chromatography to obtain the target compound 3a with a yield of 89%, 6:1dr and 94%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:
2.5mol％Pd(PPh 3 ) 4 /3mol％L6 yield：40％-50％；6:1-7:1dr；86％-91％ee。5mol％Pd(PPh 3 ) 4 /6mol％L6 yield：80％-90％；6:1-7:1dr；90％-94％ee。10mol％PdPd(PPh 3 ) 4 /12mol％L6 yield：80％-95％；6:1-7:1dr；90％-94％ee。
example 2:
in a 10mL vacuum tube, alpha-5-ethyluracil substituted methyl acrylate 1b (32.8mg,0.1mmol), Pd (PPh) was added 3 ) 4 (5.7mg,5 mol%) and L6(3.7mg,6 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene 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 target compound 3b in 90% yield, 6:1dr and 92% ee.
Example 3:
in a 10mL vacuum tube, alpha-5-fluorouracil-substituted methyl acrylate 1c (32.8mg,0.1mmol), Pd (PPh) was added 3 ) 4 (11.4mg,10 mol%) and L6(7.4mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene 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 3c in 81% yield, 6:1dr and 91% ee. HPLC CHIRALCEL IA n-hexane/isopropanol 90/10, flow rate 0.8mLMin, column temperature 25 deg.C, wavelength 250nm, retention time 34.007min (major),37.667min (minor). 1 H NMR(600MHz,CDCl 3 ):δ7.90(d,J＝7.8Hz,2H),7.73(d,J＝6.6Hz,1H),7.69-7.67(m,1H),7.53-7.50(m,2H),5.61-5.54(m,1H),5.52-5.43(m,2H),4.84(d,J＝10.8Hz,1H),4.16-4.14(m,2H),3.91(t,J＝9.6Hz,1H),3.80(s,3H),3.41(dd,J＝17.4,8.4Hz,1H). 13 C NMR(150MHz,CDCl 3 ):δ169.3,166.5,155.6(J C-F ＝27.0Hz),149.6,140.7,139.1,135.7,130.8,130.3,130.2(J C-F ＝184.5Hz),125.5(J C-F ＝34.5Hz),122.8,77.5,74.4,71.5,53.6,51.8.HRMS(ESI):m/z calcd.for C 19 H 17 FN 2 O 6 Na[M+Na] + :441.0963,found441.0957.
Example 4:
in a 10mL vacuum tube, alpha-5-hydrouracil substituted methyl acrylate 1d (30.0mg,0.1mmol), Pd (PPh) was added 3 ) 4 (5.7mg,5 mol%) and L6(3.7mg,6 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene 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 target compound 3d in 85% yield, 7:1dr and 90% ee.
Example 5:
in a 10mL vacuum tube, alpha-p-bromobenzoyl protected 5-methyluracil substituted methyl acrylate 1i (39.2mg,0.1mmol), Pd (PPh) 3 ) 4 (5.7mg,5 mol%) and L6(3.7mg,6 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene 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 stopped, 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 target compound 3i in 90% yield, 6:1dr and 94% ee. HPLC CHIRALCEL IA, 70/30 for n-hexane/2-propanol, 0.6mL/min for flow rate, columntemperature＝25℃,λ＝250nm,retention time:10.583min(minor),12.139min(major). 1 HNMR(600MHz,CDCl 3 ):δ7.74(d,J＝8.6Hz,2H),7.63(d,J＝8.6Hz,2H),7.44(s,1H),5.65-5.55(m,1H),5.47-5.41(m,2H),4.84(d,J＝10.8Hz,1H),4.18-4.13(m,1H),4.11(d,J＝10.2Hz,1H),3.96-3.87(m,1H),3.78(s,3H),3.48(q,J＝9.0Hz,1H),1.98(s,3H). 13 C NMR(100MHz,CDCl 3 ):δ169.7,167.7,162.4,151.0,136.4,132.7,131.9,130.9,130.4,122.0,110.6,77.7,74.2,71.5,53.4,51.3,13.1.HRMS(ESI):m/z calcd.for C 20 H 19 BrN 2 O 6 Na[M+Na] + :485.0319,found485.0316
Example 6:
in a 10mL vacuum tube, 1l of α -5-methyluracil-substituted tert-butyl acrylate (35.6mg,0.1mmol), Pd (PPh) was added 3 ) 4 (5.7mg,5 mol%) and L6(3.7mg,6 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene 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 target compound 3l in 91% yield, 3:1dr and 92% ee.
Example 7:
in a 10mL vacuum tube, alpha-6-chloropurine substituted methyl acrylate 4a (23.8mg,0.1mmol), Pd (PPh) 3 ) 4 (11.4mg,10 mol%) and L6(7.4mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene 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 5a in 85% yield, 1:1dr and 90%/92% ee.
Example 8:
in a 10mL vacuum tube, alpha-2-chloro-6-N, N-dimethylpurine-substituted methyl acrylate 4c was added(28.1mg,0.1mmol),Pd(PPh 3 ) 4 (11.4mg,10 mol%) and L6(7.4mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene 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 target compound 5c in 83% yield, 1:1.5dr and 80/85% ee.
Example 9:
in a 10mL vacuum tube was added α -2-amino-6-benzyloxypurine substituted methyl acrylate 4f (32.5mg,0.1mmol), Pd (PPh) 3 ) 4 (11.4mg,10 mol%) and L6(7.4mg,12 mol%). After 3 times replacement with nitrogen, 0.5mL of toluene was added, and the mixture was stirred for half an hour, epoxybutene 2(9.0mg,0.12mmol) was dissolved in 0.5mL of toluene and added to the reaction tube. The reaction tube was left at room temperature for 1 day. The reaction was followed by TLC, after termination of the reaction, extraction was performed by addition of dichloromethane/water, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo and then subjected to column chromatography to give the title compound 5f in 87% yield, 1:1.5dr and 80/90% ee. TLC, Rf 0.24(PE/EA 1:1), 5f1 HPLCCHIRALCEL IA, n-hexane/2-propanol 80/20, flow rate 0.6mL/min, column temperature 25 ℃, λ 250nm, retentition time 19.461min (minor),21.383min (major). 1 H NMR(400MHz,CDCl 3 )δ7.71(s,1H),7.44(d,J＝7.0Hz,2H),7.34–7.22(m,3H),5.47(d,J＝2.5Hz,2H),5.32-5.23(m,1H),5.00(d,J＝19.2Hz,1H),4.86(d,J＝10.4Hz,1H),4.72-4.70(br,2H),4.54(d,J＝10.0Hz,1H),4.28–4.19(m,2H),3.95(q,J＝7.8Hz,1H),3.83(dd,J＝8.8,7.6Hz,1H),3.67(s,3H).5f2:HPLCCHIRALCEL ODH,n-hexane/2-propanol＝60/40,flow rate＝1.0mL/min,column temperature＝25℃,λ＝250nm,retention time:15.328min(minor),22.245min(major). 1 H 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). 13 CNMR(150MHz,CDCl 3 ):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.for C 20 H 22 N 5 O 4 [M+H] + :396.1666,found 396.1672.
Example 10:
according to the reaction conditions and operations of examples 2 to 9, only the reaction substrate was changed, and the reaction results were shown by the following structural formulae:
example 11:
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. 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 column chromatographed to give 20.6mg white solid 6ba in 75% yield 90% ee. m.p. 165.2-167.5 ℃, HPLC CHIRALCEL OD, n-hexane/isopropanol 70/30, flow rate of 0.8mL/min, column temperature of 25 ℃, wavelength of 250nm, retention time of 7.241min (major),10.182min (minor). 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(150MHz,CDCl 3 ):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 C 13 H 17 N 4 O 3 [M+H] + :277.1295,found277.1287.
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) 2 PHAL (3.9mg,0.005mmol), methanesulfonamide (9.5mg,0.1mmol) and K 2 OsO 2 (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 added 2 S 2 O 3 Adding dichloromethane/water under stirring for 2h for extraction, drying with anhydrous sodium sulfate, vacuum concentrating organic phase, and performing column chromatography to obtain 11.6mg white solid 7ba 76% yield,20:1dr and 90% ee, m.p.:204.5-207.3 deg.C, TLC: R f ＝0.27(DCM:CH 3 OH＝30:1)[UV].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). 1 H NMR(400MHz,CD 3 OD):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). 13 C NMR(150MHz,CD 3 OD):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 C 13 H 18 N 4 O 5 Na[M+Na] + :333.1169,found333.1164.
Example 12:
in a 10mL vacuum tube, the isonucleoside compound 6ba (13.8mg,0.05mmol) was added dissolved in dichloromethane, the reaction was left at room temperature, DAST (13 μ L,2equiv) was added, the reaction was followed by TLC, after termination, dichloromethane/water was added for extraction, anhydrous sodium sulfate was dried, the organic phase was concentrated in vacuo, and column chromatography gave 11.0mg of colorless liquid 8ba, 79% yield, 90% 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). 1 H NMR(400MHz,CDCl 3 ):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). 13 C NMR(150MHz,CDCl 3 ):δ161.5,152.1,151.9,140.9,132.5,122.3,120.8,82.5(J C-F ＝177.0Hz),73.1(J C-F ＝0.3Hz),72.1,69.9(J C-F ＝16.5Hz),54.4,51.2(J C-F ＝1.5Hz). 19 F NMR(564MHz,CDCl 3 ):δ-224.5(s)HRMS(ESI):m/z calcd.for C 13 H 16 FN 4 O 2 [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), H 2 O 2 (30% water, 30. mu.L), and stirred at room temperature for two hours. Dichloromethane/water was added for extraction, dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo and column chromatographed to give 11.6mg of a white solid 9ba, 79% yield, 90% ee, m.p. 163.2-165.4 deg.c, HPLC CHIRALCEL ID, n-hexane/isopropanol 50/50, flow rate 1.0mL/min, column temperature 25 deg.c, wavelength 250nm, retention time 10.617min (major),12.869min (minor). 1 H NMR(400MHz,CD 3 OD):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). 13 C NMR(150MHz,CD 3 OD):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 C 13 H 19 N 4 O 4 [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/waterExtracting, drying with anhydrous sodium sulfate, vacuum concentrating organic phase, column chromatography to obtain 15mg colorless liquid 10ba, 85% yield,>20:1dr, 90% ee, HPLC CHIRALCEL ODH, 50/50 n-hexane/isopropanol, 1.0mL/min flow rate, 25 ℃ column temperature, 250nm wavelength, 10.177min (minor),12.073min (major). 1 H NMR(600MHz,CDCl 3 ):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). 13 C NMR(150MHz,CDCl 3 ):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.for C 13 H 15 BrN 4 O 3 Na[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 H 2 (1 atm.) the reaction was stirred overnight. After the reaction is completed, the mixture is dried by spinning after passing through diatomite, and column chromatography is carried out to obtain 11.8mg of white solid 11ba, 86% yield, 90% ee, m.p. 142.1-144.7 ℃ TLC R f ＝0.36(DCM:CH 3 OH＝50:1)[UV].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). 1 H NMR(600MHz,CD 3 OD):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). 13 C NMR(150MHz,CD 3 OD):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 C 13 H 19 N 4 O 3 [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 given by way of illustration 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 such changes and modifications are within the scope of the present invention.
Claims (8)
1. A method for synthesizing chiral heteronucleoside analogues through asymmetric [3+2] cyclization reaction is characterized by comprising the following steps: substituted olefin 1 and epoxybutene 2 are used as raw materials and react in the presence of a palladium catalyst and an axial chiral diphosphine ligand to obtain a chiral isocucleoside analogue 3; the reaction equation is as follows:
the axially chiral diphosphine ligand is selected from
Wherein R is 1 Is composed of
R 2 Is C1-C8 alkyl and phenyl.
2. The method for the synthesis of chiral heteronucleoside analogs by asymmetric [3+2] cyclization according to claim 1, wherein: C1-C8 alkyl is selected from methyl, ethyl, isopropyl, tert-butyl or benzyl.
3. The method for synthesizing chiral heteronucleoside analogs according to claim 1, comprising the step of asymmetric [3+2] cyclization, wherein: the reaction is carried out in an organic solvent selected from dichloromethane, chlorobenzene, toluene or mesitylene.
4. The asymmetry [3+2] of claim 1]Synthesis of chiral heteronucleoside analogs by cyclizationA method of manufacturing a product, comprising: the palladium catalyst is selected from Pd (PPh) 3 ) 4 Or Pd 2 (dba) 3 。
5. The method for synthesizing chiral heteronucleoside analogs according to claim 1, comprising the step of asymmetric [3+2] cyclization, wherein: the reaction temperature is selected from-40 ℃ to 60 ℃.
6. The method for synthesizing chiral heteronucleoside analogs according to any one of claims 1-5, by asymmetric [3+2] cyclization, characterized in that: the molar ratio of the substituted olefin 1 to the epoxybutene 2 to the palladium catalyst to the axial chiral diphosphine ligand is 1:0.2-1.2:0.05-0.20: 0.06-0.22.
7. A method for synthesizing chiral heteronucleoside analogues 7-11, characterized by: preparing an isopurine nucleoside analogue 3 by the method as described in claim 1, followed by performing different derivatizations using the isopurine nucleoside analogue 3 as a raw material to obtain chiral isopurine nucleoside analogues 7-11, according to the reaction equation:
8. the method of claim 7, 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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Non-Patent Citations (4)
| Title |
|---|
| A Straightforward Entry to Chiral Carbocyclic Nucleoside Analogues via Enantioselective [3+2] Cycloaddition of α-Nucleobase Substituted Acrylates;Ming-Sheng Xie 等;《Chemical Communications》;20150626;第51卷;第12451-12454页 * |
| Electron-Deficient Alkynes as Dipolarophile in Pd-Catalyzed;Wen-Ping Ding等;《Organic Letters》;20190813;第21卷;全文 * |
| Ming-Sheng Xie 等.A Straightforward Entry to Chiral Carbocyclic Nucleoside Analogues via Enantioselective [3+2] Cycloaddition of α-Nucleobase Substituted Acrylates.《Chemical Communications》.2015,第51卷第12451-15454页. * |
| Trisubstituted alkenes with a single activator as dipolarophiles in a highly diastereo- and enantioselective [3+2] cycloaddition with vinyl epoxides under Pd-catalysis;Juan Du等;《Chem. Commun.》;20181031;第54卷;全文 * |
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