CN107698590A - A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral - Google Patents
A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral Download PDFInfo
- Publication number
- CN107698590A CN107698590A CN201710903808.4A CN201710903808A CN107698590A CN 107698590 A CN107698590 A CN 107698590A CN 201710903808 A CN201710903808 A CN 201710903808A CN 107698590 A CN107698590 A CN 107698590A
- Authority
- CN
- China
- Prior art keywords
- chiral
- yuan
- synthesis
- cyclization
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
- C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/36—Sulfur atom
- C07D473/38—Sulfur atom attached in position 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a kind of method of asymmetric [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral, belong to asymmetric syntheses field in organic chemistry.Using the acrylate and MBH carbonic esters of α purine substitution as raw material, using chiral SITCP as catalyst, chirality five-membered homocyclic nucleus glycosides compound being obtained after reaction, reacting cis-selectivity and enantioselectivity is good, high income is up to 93%.
Description
Technical field
The present invention relates to the synthetic method of chiral carbocyclic ring purine nucleosides, and in particular to a kind of asymmetry [3+2] cyclization
The method of five yuan of carbocyclic purine nucleosides of synthesis of chiral, the asymmetric syntheses field belonged in organic chemistry.
Background technology
Chirality five-membered carbocyclic purine nucleosides class compound has extensive physiologically active, such as Abacavir,
Entecavir and Carbovir may be respectively used for treating HIV and HBV.Other chirality five-membered carbocyclic ring ring nucleosides are such as：
Noraristeromycin, Aristeromycin, Neplanocin A and HNPA have different pharmaceutical activity.It is meanwhile chiral
The product configuration of class compound has very big influence to its bioactivity, so synthesizing, preparing optically pure chiral compound
Thing and it is carried out some physiological and pharmacologicals activity test, research there is larger application prospect and meaning.
Traditional chirality five-membered carbocyclic nucleoside of structure has two kinds of approach.The first approach is that first a well-designed warp is more
Step reaction obtain have spatial configuration and the chiral carbocyclic ring containing different functional groups, then with the base of purine or pyrimidine
Connected by the method for chemistry, so as to form five yuan of carbocyclic nucleosides of chirality, the method for introducing chiral carbocyclic ring mainly has parent
Core substitution reaction, the ring-opening reaction of epoxide, four kinds of the coupling reaction of pi-allyl etc. of Mitsunobu reactions and palladium chtalyst
Method.Second of approach is one amino of introducing on above-mentioned described chirality five-membered ring, and purine or phonetic is constructed from amino
Pyridine base, so as to synthesis of chiral homocyclic nucleus glycosides compound.But two kinds of approach are all to need the chiral source of equivalent, by multistep
Reaction, could five yuan of carbocyclic nucleosides of synthesis of chiral.And chiral substrates be relatively difficult to prepare, cost it is higher.Comparatively, selection is low
Cost, achiral starting material cheap and easy to get is by asymmetric [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral
Method, there is significant meaning.
The content of the invention
In order to overcome drawbacks described above, the present invention use the acrylate 1 that α-purine substitutes and MBH carbonic esters 2 as raw material,
Five yuan of homocyclic nucleus glycosides compounds of synthesis of chiral in the presence of chiral monophosphorus catalyst.This method is five yuan of carbocyclic rings of synthesis of chiral
Nucleoside compound provides a kind of easy, cheap, efficient approach.
A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral, it is characterised in that including
Following operation：It is raw material with the acrylate 1 and MBH carbonic esters 2 of α-purine substitution, solvent is added, in chiral monophosphorus catalyst
In the presence of, reaction obtains chirality five-membered homocyclic nucleus glycosides compound 3 or its enantiomter.
Reaction equation is as follows：
Wherein, R1Represent one kind in following groups：Cl, H, Ph, piperidines, diethylin, methoxyl group, rosickyite base；R2Under representative
One kind in row group：Cl、H；R3Represent one kind in following groups：Methyl, ethyl, the tert-butyl group；R4Represent one in following groups
Kind：Methyl, ethyl, the tert-butyl group, benzyl；R5Represent one kind in following groups：Phenyl, 2-ClC6H4、 3-FC6H4、3-ClC6H4、
3-BrC6H4、4-NO2C6H4、4-CNC6H4、4-CH3C6H4、 4-CH3OC6H4、
Further, in the above-mentioned technical solutions, described chiral monophosphorus catalyst is derived from SITCP, and every kind of part all wraps
Include two kinds of R types and S types.R type SITCP structures are：Or S type SITCP structures are：
Further, in SITCP parts, Ar preferably is selected from phenyl, 4- methoxyphenyls or 3,5- di-t-butyl -4- first
Phenyl.Using S type SITCP parts as representative, concrete structure is as follows：
Further, in the above-mentioned technical solutions, the α-acrylate 1 of purine substitution, MBH carbonic esters 2, chirality
The mol ratio of single phosphine catalyst is 1:1-2:0.05-0.20.
Further, in the above-mentioned technical solutions, reaction dissolvent is selected from 1,2- dichloroethanes, toluene, dichloromethane, chlorine
It is imitative.
Further, in the above-mentioned technical solutions, reaction temperature is selected from -10 DEG C to 30 DEG C.
Further, in the above-mentioned technical solutions, whole course of reaction needs to operate under inert gas shielding, inert gas
It is preferred that nitrogen.
Further, obtain chirality five-membered homocyclic nucleus glycosides compound 3 can further derive it is different types of to obtain
Derivative products, using NaBH4Or DIBAL-H is reduced, the product for reducing the ester group list being connected with nitrogen-atoms is respectively obtained
Or the product of two ester group Restore Alls.Such as five yuan of carbocyclic purine nucleosides products 3ca and NaBH4Reduction obtains monohydroxy chemical combination
Thing 4ca, reduce to obtain dihydroxyl compound 5ca with DIBAL-H.
Invention beneficial effect：
The present invention provides a kind of easy, cheap, efficient synthesis for the method for five yuan of carbocyclic purine nucleosides of synthesis of chiral
Method, reaction raw materials are easy to get, and product structure enriches, and product stereoselectivity is high, and chirality five-membered homocyclic nucleus glycoside is obtained after reaction
Compound, yield reach as high as 93%.
Embodiment
Embodiment 1
aUnless stated otherwise, the step of reaction is as follows:Under nitrogen atmosphere, catalyst (20mol%), 1 (0.05 mmol),
2 (0.06mmol) are in CH2Cl24 days of reaction in (1.0mL)bDr values test crude product by nuclear-magnetism.cSeparation yield.dEe values pass through
High performance liquid chromatography separation..
In the screening process of reaction condition, influence (entries 1-8) of the phosphine catalyst to reaction has been primarily looked at.
Simultaneously by compareing influence of the different ligands to reaction and considering price factor, it is optimal ligand that part P6, which is finally determined,.
The investigation of reaction condition：In 10mL vacuum tube, the 6- chloracrylic acid ethyl esters 1a of α-purine substitution is added
(23.8mg, 0.1mmol), (S)-SITCP (3.5mg, 20mmol%) and phenyl MBH methyl carbonates 2a (35.1mg,
0.12mmol).By nitrogen displacement 3 times so that nitrogen is full of in reaction tube, then adds 1mL dichloromethane.Sealing reaction
Pipe, reaction tube is placed in -10 DEG C of cryogenic pump and reacted 4 days.Tracked and reacted with TLC, after terminating reaction, addition dichloromethane/
Water is extracted, anhydrous sodium sulfate drying organic phase, is concentrated in vacuo organic phase, then obtains target compound 3aa through column chromatography
Yield 83%, 9:1dr and 91%ee.
In the case where other conditions are fixed, influence of the dosage of catalyst to reaction is only investigated, with 1a and 2a reaction lifes
Into exemplified by 3aa, 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%.
In the case where other conditions are fixed, only influence of the steric hindrance of examination substitution substrate substituent to reaction,
Reaction equation is as follows：
aUnless stated otherwise, the step of reaction is as follows:Under nitrogen atmosphere, catalyst (20mol%), 1 (0.05mmol),
2 (0.06mmol) are in CH2Cl2Reaction 4 days in (1.0mL).bDr values test crude product by nuclear-magnetism.cSeparation yield.dEe values pass through
High performance liquid chromatography separation.
Embodiment 2：
In 10mL vacuum tube, the 6- piperidines methyl acrylate (28.7mg, 0.1mmol) of α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and phenyl MBH methyl carbonates (35.1 mg, 0.12mmol).By nitrogen displacement 3 times so that
Nitrogen is full of in reaction tube, then adds 1mL dichloromethane.Reaction tube is sealed, reaction tube is placed in -10 DEG C of cryogenic pump
Reaction 4 days.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous sodium sulfate drying is organic
Phase, organic phase is concentrated in vacuo, then obtains target compound 3ea yields 87% through column chromatography, 9:1dr and 90%ee.
Embodiment 3：
In 10mL vacuum tube, the 6- rosickyite bases methyl acrylate (27.8 mg, 0.1mmol) of α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and phenyl MBH methyl carbonates (35.1mg, 0.12mmol).By nitrogen displacement 3 times so that
Nitrogen is full of in reaction tube, then adds 1mL dichloromethane.Reaction tube is sealed, reaction tube is placed in -10 DEG C of cryogenic pump
Reaction 4 days.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous sodium sulfate drying is organic
Phase, organic phase is concentrated in vacuo, then obtains target compound 3ea yields 85% through column chromatography, 9:1dr and 90%ee.
Representative compound characterize data is as follows：
3ea White solid；85%yield, 9:1dr, 90%ee. [α]D 20=66.1 (c=0.5, CH2Cl2)
.HPLC CHIRALCEL IA, n-hexane/isopropanol=70/30, the mL/min of flow velocity=0.5, column temperature=25 DEG C, λ=254nm,
Retention time:26.267min,33.839 min.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, found
475.1414.
Embodiment 4：
In 10mL vacuum tube, the 6- hydracrylic acids methyl esters (20.4mg, 0.1mmol) of α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and phenyl MBH methyl carbonates (35.1 mg, 0.12mmol).By nitrogen displacement 3 times so that
Nitrogen is full of in reaction tube, then adds 1mL dichloromethane.Reaction tube is sealed, reaction tube is placed in -10 DEG C of cryogenic pump
Reaction 4 days.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous sodium sulfate drying is organic
Phase, organic phase is concentrated in vacuo, then obtains target compound 3ia yields 92% through column chromatography, 10:1dr and 90%ee.
Embodiment 5：
In 10mL vacuum tube, 2, the 6- chloracrylic acids methyl esters (27.1mg, 0.1mmol) of α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and phenyl MBH methyl carbonates (35.1 mg, 0.12mmol).By nitrogen displacement 3 times so that
Nitrogen is full of in reaction tube, then adds 1mL dichloromethane.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump instead
Answer 5 days.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous sodium sulfate drying organic phase,
Organic phase is concentrated in vacuo, then obtains target compound 3ja yields 82% through column chromatography, 10:1dr and 92%ee.
Embodiment 6：
In 10mL vacuum tube, the 6- chloracrylic acids methyl esters (23.8 mg, 0.1mmol) of addition α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and a fluorophenyl MBH methyl carbonate (51.6mg, 0.12mmol).By nitrogen displacement 3 times,
So that being full of nitrogen in reaction tube, 1mL dichloromethane is then added.Reaction tube is sealed, reaction tube is placed in -10 DEG C of low temperature
Reacted 4 days in pump.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous sodium sulfate drying has
Machine phase, organic phase is concentrated in vacuo, then obtains target compound 3cb yields 82% through column chromatography, 9:1dr and 90%ee.
Representative compound characterize data is 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 velocity=0.5mL/min, column temperature=25 DEG C, 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.
Embodiment 7：
In 10mL vacuum tube, the 6- chloracrylic acids methyl esters (23.8 mg, 0.1mmol) of addition α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and Chloro-O-Phenyl MBH methyl carbonates (53.5mg, 0.12mmol).By nitrogen displacement 3 times,
So that being full of nitrogen in reaction tube, 1mL dichloromethane is then added.Reaction tube is sealed, reaction tube is placed in -10 DEG C of low temperature
Reacted 4 days in pump.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous sodium sulfate drying has
Machine phase, organic phase is concentrated in vacuo, then obtains target compound 3ce yields 73% through column chromatography, 10:1dr and 92%ee.
Embodiment 8：
In 10mL vacuum tube, the 6- chloracrylic acids methyl esters (23.8 mg, 0.1mmol) of addition α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and 1- naphthyl MBH methyl carbonates (55.4mg, 0.12mmol).By nitrogen displacement 3 times, make
Obtain in reaction tube and be full of nitrogen, then add 1mL dichloromethane.Reaction tube is sealed, reaction tube is placed in -10 DEG C of cryogenic pump
Middle reaction 4 days.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous sodium sulfate drying is organic
Phase, organic phase is concentrated in vacuo, then obtains target compound 3cj yields 87% through column chromatography, 10:1dr and 96%ee.
Representative compound characterize data is as follows：
3cj White solid；87%yield, 10:1dr, 96%ee. [α]D 20=60.2 (c=0.5, CH2Cl2).
HPLC CHIRALCEL IA, n-hexane/isopropanol=70/30, flow velocity=0.5mL/min, column temperature=25 DEG C, λ=254nm, protect
Stay the time:36.264min,46.357min.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
Embodiment 9：
In 10mL vacuum tube, the 6- chloracrylic acids methyl esters (23.8 mg, 0.1mmol) of addition α-purine substitution, (S)-
SITCP (3.5mg, 20mmol%) and 3,4- 3,5-dimethylphenyl MBH methyl carbonates (52.8mg, 0.12mmol).Put by nitrogen
Change 3 times so that nitrogen is full of in reaction tube, then adds 1mL dichloromethane.Reaction tube is sealed, reaction tube is placed in -10
DEG C cryogenic pump in react 4 days.Tracked and reacted with TLC, after terminating reaction, added methylene chloride/water and extracted, anhydrous slufuric acid
Sodium dries organic phase, is concentrated in vacuo organic phase, then obtains target compound 3cm yields 85% through column chromatography, and 10:1dr and
96%ee.
Embodiment 10：
In 10mL vacuum tube, the methyl acrylate 1 (0.1mmol) of α-purine substitution, (S)-SITCP are added
(3.5mg, 20mmol%) and aryl MBH methyl carbonates 2 (0.12mmol).By nitrogen displacement 3 times so that be full of in reaction tube
Nitrogen, then add 1mL dichloromethane.Reaction tube is sealed, reaction tube is placed in -10 DEG C of cryogenic pump and reacted 4 days.With
TLC tracking is reacted, and after terminating reaction, is added methylene chloride/water and is extracted, anhydrous sodium sulfate drying organic phase, is concentrated in vacuo
Organic phase, then obtain target compound 3 through column chromatography.The substituent of substrate is changed, different products 3 can be obtained.
Its specific reaction result is as follows：
Embodiment 11：
In 50mL round-bottomed flask, five yuan of Carbocyclic nucleoside analogues 3ca (82.4mg, 0.2 mmol) are added, and add
20mL methanol, by reaction as room temperature, add NaBH4(22.8mg, 0.6mmol) is detected with TLC, after complete reaction, is used
Saturation NH4Cl is quenched.After terminating reaction, addition methylene chloride/water is extracted, anhydrous sodium sulfate drying organic phase, and vacuum is dense
Contracting organic phase, then through column chromatography (CH2Cl2/ MeOH=50:1) target compound 4ca (yield 92%, 93%ee) is obtained.
Representative compound characterize data is as follows：
4ca White solid；92%yield, 93%ee. [α]D 20=-32.9 (c=0.3, CH2Cl2).HPLC
CHIRALCEL IA, n-hexane/isopropanol=80/20, flow velocity=0.6mL/min, column temperature=25 DEG C, λ=254nm, during reservation
Between:28.511min,31.936min.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.for
C19H17ClN4O3Na[M+Na]+:407.0881, found 407.0884.
Embodiment 12：
In 10mL vacuum tube, five yuan of carbocyclic purine nucleosides 4ca (38.4mg, 0.1 mmol) are added.Put by nitrogen
Change 3 times so that nitrogen is full of in reaction tube, then under nitrogen flowing, adds 1mL tetrahydrofuran.Reaction tube is sealed, will be reacted
Pipe is placed in -20 DEG C.It is slowly added to DIBAL-H (3equiv, 1.1M in cyclohexane).Tracked and reacted with TLC, terminated anti-
Ying Hou, the ammonium chloride solution of saturation is added, dichloromethane extraction, anhydrous sodium sulfate drying organic phase, is concentrated in vacuo organic phase, so
Target compound 5ca, yield 57%, ee values 91% are obtained by column chromatography.
Representative compound characterize data is as follows：
5ca Colourless liquid；57%yield, 91%ee. [α]D 20=-8.6 (c=0.63, CH2Cl2).
HPLC CHIRALCEL IE, n-hexane/isopropanol=80/20, flow velocity=0.5mL/min, column temperature=25 DEG C, λ=254nm, protect
Stay the time:32.633min,35.508min.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.
Embodiment 13：
In 10mL reaction tube, five yuan of Carbocyclic nucleoside analogues 3ca (82.4mg, 0.2 mmol), NaIO are added4
(44.6mg, 2equiv) is dissolved in 0.1mL water, is added into reaction tube.Reaction is placed in 0 DEG C and adds RuCl3·
3H2O (2.8mg, 0.1equiv) then adds ethyl acetate (0.2mL) and acetonitrile (0.3mL).By substrate 3ca (41.2mg,
0.1 mmol) (0.3mL) is dissolved in ethyl acetate, it is slowly added to.Detected and reacted with TLC, after question response is complete, add 10%
NaHCO3(0.7mL) and saturation Na2SO3After solution (2.0mL) reaction stirrings 10min, it is extracted with ethyl acetate, anhydrous sodium sulfate
Dry organic phase, be concentrated in vacuo organic phase, then through column chromatography obtain target compound 6ca, yield 81%, 16:1dr.Represent
Property characterization of compound 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.for
C20H19ClN4NaO6 [M+Na]+:469.0885,found 469.0881.
Embodiment above describes the general principle of the present invention, main features and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (9)
- A kind of 1. method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral, it is characterised in that including such as Lower step：It is raw material with the acrylate 1 and MBH carbonic esters 2 of α-purine substitution, adds solvent, deposited in chiral monophosphorus catalyst Under, reaction obtains chirality five-membered carbocyclic purine nucleosides 3 or its enantiomter, reaction equation are as follows：
- 2. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 1, its It is characterised by：R1It is selected from：Cl, H, Ph, piperidines, diethylin, methoxyl group or rosickyite base；R2It is selected from：Cl、H；R3It is selected from：Methyl, Ethyl or the tert-butyl group；R4It is selected from：Methyl, ethyl, the tert-butyl group, benzyl；R5It is selected from：Phenyl, 2-ClC6H4、3-FC6H4、3-ClC6H4、 3-BrC6H4、4-NO2C6H4、4-CNC6H4、4-CH3C6H4、4-CH3OC6H4、
- 3. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 1, its It is characterised by：The chiral monophosphorus catalyst is selected from R types SITCP：Or S types SITCP：
- 4. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 3, its It is characterised by：In the SITCP parts, Ar is selected from phenyl, 4- methoxyphenyls or 3,5- di-t-butyl -4- methoxyphenyls.
- 5. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 1, its It is characterised by：Reaction dissolvent is selected from 1,2- dichloroethanes, toluene, dichloromethane or chloroform.
- 6. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 1, its It is characterised by：The acrylate 1 of the α-purine substitution, MBH carbonic esters 2, the mol ratio of chiral monophosphorus catalyst are 1:1-2: 0.05-0.20。
- 7. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 1, its It is characterised by：Reaction temperature is selected from -10 DEG C to 30 DEG C.
- 8. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 1, its It is characterised by：Whole course of reaction operates under inert gas shielding.
- 9. according to a kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral in claim 1, its It is characterised by：Chirality five-membered carbocyclic purine nucleosides product 3ca and NaBH4Reduction obtains monohydroxy compound 4ca, with DIBAL-H Reduction obtains dihydroxyl compound 5ca.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710903808.4A CN107698590B (en) | 2017-09-29 | 2017-09-29 | Method for synthesizing chiral five-membered carbocyclic purine nucleoside through asymmetric [3+2] cyclization reaction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710903808.4A CN107698590B (en) | 2017-09-29 | 2017-09-29 | Method for synthesizing chiral five-membered carbocyclic purine nucleoside through asymmetric [3+2] cyclization reaction |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107698590A true CN107698590A (en) | 2018-02-16 |
| CN107698590B CN107698590B (en) | 2020-02-18 |
Family
ID=61176229
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710903808.4A Active CN107698590B (en) | 2017-09-29 | 2017-09-29 | Method for synthesizing chiral five-membered carbocyclic purine nucleoside through asymmetric [3+2] cyclization reaction |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107698590B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558882A (en) * | 2018-04-12 | 2018-09-21 | 河南师范大学 | A method of five yuan of carbocyclic purine nucleosides of [3+2] cycloaddition synthesis of chiral based on connection olefin(e) acid ester |
| CN108774229A (en) * | 2018-07-18 | 2018-11-09 | 河南师范大学 | A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center |
| CN108864115A (en) * | 2018-08-08 | 2018-11-23 | 河南师范大学 | The method of the non-aromatic purine nucleosides of [3+2] cycloaddition asymmetry dearomatization synthesis of chiral |
| CN108912123A (en) * | 2018-08-17 | 2018-11-30 | 河南师范大学 | A method of passing through asymmetric [3+3] cyclization synthesis of chiral six-membered carbon ring purine nucleosides |
| CN109369661A (en) * | 2018-12-05 | 2019-02-22 | 河南师范大学 | The method of [3+2] cycloaddition dearomatization synthesis of chiral hydrogenation benzofuran compounds |
| CN110156730A (en) * | 2019-07-05 | 2019-08-23 | 河南师范大学 | A kind of synthetic method of chiral tricyclic benzofuran compounds |
| CN110590781A (en) * | 2019-10-14 | 2019-12-20 | 河南师范大学 | Method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric allylamine reaction |
| CN112300176A (en) * | 2020-11-27 | 2021-02-02 | 河南师范大学 | Method for synthesizing chiral five-membered thiaheterocyclic nucleoside analogue by asymmetric [3+2] cyclization reaction |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592236A (en) * | 2014-10-14 | 2015-05-06 | 河南师范大学 | Method for synthesis of chiral heterocyclic nucleoside analogue by asymmetric [3+2] cycloaddition |
| CN105037366A (en) * | 2015-07-30 | 2015-11-11 | 河南师范大学 | Method for synthesizing chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition |
| CN105732631A (en) * | 2016-01-28 | 2016-07-06 | 河南师范大学 | N9 vinylpurine and synthesis method thereof, and method for synthesizing polysubstituted chiral azacyclonucleoside analogs from N9 vinylpurine |
-
2017
- 2017-09-29 CN CN201710903808.4A patent/CN107698590B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592236A (en) * | 2014-10-14 | 2015-05-06 | 河南师范大学 | Method for synthesis of chiral heterocyclic nucleoside analogue by asymmetric [3+2] cycloaddition |
| CN105037366A (en) * | 2015-07-30 | 2015-11-11 | 河南师范大学 | Method for synthesizing chiral pentabasic carbocyclic nucleoside analog by asymmetric [3+2] cycloaddition |
| CN105732631A (en) * | 2016-01-28 | 2016-07-06 | 河南师范大学 | N9 vinylpurine and synthesis method thereof, and method for synthesizing polysubstituted chiral azacyclonucleoside analogs from N9 vinylpurine |
Non-Patent Citations (2)
| Title |
|---|
| MING-SHENG XIE等: "A straightforward entry to chiral carbocyclic nucleoside analogues via the enantioselective [3+2] cycloaddition of a-nucleobase substituted acrylates", 《CHEM. COMMUN.》 * |
| SOPHIE RACINE等: "Synthesis of (Carbo)nucleoside Analogues by [3+2] Annulation of Aminocyclopropanes", 《ANGEW. CHEM. INT. ED.》 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558882A (en) * | 2018-04-12 | 2018-09-21 | 河南师范大学 | A method of five yuan of carbocyclic purine nucleosides of [3+2] cycloaddition synthesis of chiral based on connection olefin(e) acid ester |
| CN108558882B (en) * | 2018-04-12 | 2020-08-04 | 河南师范大学 | Method for synthesizing chiral five-membered carbocyclic purine nucleoside through [3+2] cycloaddition based on allenoic acid ester |
| CN108774229A (en) * | 2018-07-18 | 2018-11-09 | 河南师范大学 | A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center |
| CN108864115A (en) * | 2018-08-08 | 2018-11-23 | 河南师范大学 | The method of the non-aromatic purine nucleosides of [3+2] cycloaddition asymmetry dearomatization synthesis of chiral |
| CN108864115B (en) * | 2018-08-08 | 2019-12-20 | 河南师范大学 | Method for synthesizing chiral non-aromatic purine nucleoside through [3+2] cycloaddition asymmetric dearomatization |
| CN108912123A (en) * | 2018-08-17 | 2018-11-30 | 河南师范大学 | A method of passing through asymmetric [3+3] cyclization synthesis of chiral six-membered carbon ring purine nucleosides |
| CN109369661A (en) * | 2018-12-05 | 2019-02-22 | 河南师范大学 | The method of [3+2] cycloaddition dearomatization synthesis of chiral hydrogenation benzofuran compounds |
| CN109369661B (en) * | 2018-12-05 | 2020-05-08 | 河南师范大学 | Method for synthesizing chiral hydrogenated benzofuran compound by (3 + 2) cycloaddition dearomatization |
| CN110156730A (en) * | 2019-07-05 | 2019-08-23 | 河南师范大学 | A kind of synthetic method of chiral tricyclic benzofuran compounds |
| CN110156730B (en) * | 2019-07-05 | 2020-07-17 | 河南师范大学 | Synthesis method of chiral tricyclic benzofuran compound |
| CN110590781A (en) * | 2019-10-14 | 2019-12-20 | 河南师范大学 | Method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric allylamine reaction |
| CN112300176A (en) * | 2020-11-27 | 2021-02-02 | 河南师范大学 | Method for synthesizing chiral five-membered thiaheterocyclic nucleoside analogue by asymmetric [3+2] cyclization reaction |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107698590B (en) | 2020-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107698590A (en) | A kind of method of asymmetry [3+2] cyclization five yuan of carbocyclic purine nucleosides of synthesis of chiral | |
| Zhang et al. | Novel chiral P, N-ferrocene ligands in palladium-catalyzed asymmetric allylic alkylations | |
| Nagao et al. | Asymmetric trifluoromethylation of ketones with (trifluoromethyl) trimethylsilane catalyzed by chiral quaternary ammonium phenoxides | |
| CN104592236A (en) | Method for synthesis of chiral heterocyclic nucleoside analogue by asymmetric [3+2] cycloaddition | |
| CN109761984B (en) | Method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric hydrogen transfer | |
| CN108314655B (en) | Method for synthesizing three-membered carbocyclic pyrimidine nucleoside analogue through rhodium-catalyzed asymmetric cyclopropanation | |
| CN107602559B (en) | A method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition | |
| Zhang et al. | Application of asymmetric aminohydroxylation to heteroaromatic acrylates | |
| CN110642843B (en) | Method for synthesizing chiral heteronucleoside analogue through asymmetric [3+2] cyclization reaction | |
| CN105732648B (en) | The nitrogen-containing heterocycle compound and synthetic method of a kind of pyrrolo- furans | |
| CN108558882B (en) | Method for synthesizing chiral five-membered carbocyclic purine nucleoside through [3+2] cycloaddition based on allenoic acid ester | |
| CN106316871B (en) | A kind of amino acid derivativges of chiral beta 2 and preparation method thereof | |
| CN105732631A (en) | N9 vinylpurine and synthesis method thereof, and method for synthesizing polysubstituted chiral azacyclonucleoside analogs from N9 vinylpurine | |
| CN110437277B (en) | Synthetic method of phosphoalkenyl ester compound | |
| CN104860911B (en) | Synthesis method of chiral 3,4-dihydrocoumarin derivative compound | |
| CN109666041B (en) | Chiral monophosphine ligand HP-Phos with diphenyl ether skeleton, preparation method and application thereof | |
| CN107474017B (en) | Synthesis of chiral N by asymmetric allylation reaction1Process for preparing (E) -allylpyrimidine | |
| CN109705014B (en) | Novel chiral amine oxide ligand and preparation method thereof | |
| CN108912123B (en) | Method for synthesizing chiral hexa-membered carbocyclic purine nucleoside through asymmetric [3+3] cyclization reaction | |
| CN104193667A (en) | Synthesis method of divergently oriented azacycles | |
| CN115108926B (en) | Intermediate compound for preparing erdasatinib and preparation method | |
| CN115057885B (en) | Styrene axis chiral phosphine ligand and synthetic method and application thereof | |
| CN112898253B (en) | Method for synthesizing 3-coumaranone compound containing chiral tertiary alcohol structure | |
| CN110128363B (en) | Cyclosporine derivatives and process for preparing same | |
| CN111393476B (en) | Chiral bidentate nitrogen phosphine ligand Rong-Phos and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |