CN109111391A - The chiral pyrrolidine derivative and its synthetic method of a kind of ring skeleton containing ternary and application - Google Patents
The chiral pyrrolidine derivative and its synthetic method of a kind of ring skeleton containing ternary and application Download PDFInfo
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract
The present invention relates to organic chemistry fileds, to solve the problems, such as that it is seldom that the chiral pyrrolidine derivative of the ring skeleton containing ternary has synthesis, it is catalyst that the invention proposes the chiral pyrrolidine derivatives and its synthetic method of a kind of ring skeleton containing ternary using metal, under the collective effect of Phosphine ligands and alkali additive, it is synthesized by 1,3- dipole [3+2] cycloaddition reaction of azomethine ylide and compound cyclopropene.The synthetic method of the invention is easy to operate, reaction condition is mild, and substrate universality is strong, and products collection efficiency is high and enantioselectivity is high.The compound that the present invention synthesizes is that a kind of important nitrogen-containing heterocycle compound can be widely applied to various organic syntheses, medicine, materials chemistry and field of fine chemical.
Description
Technical field
The present invention relates to organic chemistry fileds, and in particular to a kind of pyrrolidin derivatives of the ring skeleton containing ternary and its synthesis
Method and application.
Background technique
Nitrogen-containing heterocycle compound is many kinds of, is prevalent in drug molecule and natural products.Wherein, pyrrolidines is one
The important penta azacyclo compound of class, it has the characteristics that ring strain is small, stability is high.Chiral pyrrolidine unit is many days
The important component of right alkaloid, pharmaceutical activity molecule.Some drug molecules containing pyrrolidine scaffold have antibiotic, kill
The practical values such as microbial inoculum, additive, this makes them, and demand is increasing in the market, therefore, chiral pyrrolidine chemical combination
The synthesis of object causes the extensive concern of organic synthesis worker.This kind of compound is initially mainly extracted out of organism and is separated
It arrives, but with the continuous development of chiral technology, it is more and more containing pyrrolidine scaffold and with natural, the non-day of pharmaceutical activity
Right compound is also found.Early in Shin-ya kaitocephalin separating obtained from Eupenicillium sp in 1997 be a kind of use
In the natural antagonist for the treatment of epilepsy and cerebral ischemia, it can be effectively avoided Kainate toxin and damages certain neurons；(+)-
Conessine is a kind of tellicherry bark category class kurchinine, and isolated from disease-resistant wood skin, this kind of steroid biology has critically important
Bioactivity, oneself is through being used for the treatment of dysentery.The common structural feature of these compounds is all to contain pyrrolidine scaffold unit.
Natural products and bioactive molecule containing chiral pyrrolidine unit are in fields such as medicine, pesticide, food, chemical industries
Suffer from critically important application.In general, the composed structure of molecule decides the properties such as its physics, chemistry and optics, and then influence
Its generated effect in various substances, such as the antiviral property that generates in organism, antibiotic property, inhibition physiology is living
Property, it is the light sensitivity of high molecular material, electric conductivity, steady the effects of the lubricant that generates in household chemicals, preservative, additive
The functions such as qualitative, magnetic.Therefore, more efficient, practical chiral pyrrolidine derivatives are designed and synthesized with highly important
Realistic meaning.
Early in twentieth century initial stage, Willststter and Robinson pyrrolidines just reports the synthetic method of pyrrolidines.
The classical way of synthesis of pyrrolidine includes: alkylated reaction, condensation reaction, the reduction of succinimide, cyclic annular enamine and pyrroles,
Azepine Cope-Mannich tandem reaction and other synthetic methods etc..Pyrrolidines unit is also used as chiral ligand or organic
Micromolecule catalyst, the functionalized pyrrolidines of stereoselective syntheses become the pith in organic synthesis.A large amount of mapping choosings
Selecting property synthesis of pyrrolidine document oneself through being reported, such as aminating reaction, hydrogenation, Micheal addition-reduction reaction, ring
Addition reaction etc..But contained by the mode of transition metal-catalyzed asymmetry 1,3- dipole [3+2] cycloaddition reaction to synthesize
The chiral pyrrolidine derivative synthetic method of ternary ring skeleton is not reported but.
Summary of the invention
Chiral pyrrolidine derivative to solve the problems, such as the ring skeleton containing ternary is seldom in the presence of synthesizing, and the invention proposes one
The chiral pyrrolidine derivative and its synthetic method of kind of the ring skeleton containing ternary, it is easy to operate, reaction condition is mild, substrate universality
By force, products collection efficiency is high and enantioselectivity is high.
The invention also provides the chiral pyrrolidine derivatives of ternary ring skeleton in organic synthesis, medicine, materialized simultaneously
Application in and field of fine chemical.
The present invention is achieved by the following technical solutions: a kind of chiral pyrrolidine derivative of the ring skeleton containing ternary has
The structural formula as shown in (I):
In formula, R1、R2、R3、R4It is respectively and independently selected from hydrogen, aryl, a kind of in alkyl, preferably, R1、R2、R3、R4Respectively
Be independently selected from H-, CH3-, Ph-, m-ClPh-, p-ClPh-, p-BrPh, 2-naphthyl, 2-furyl, 2-thiopheneyl,
It is a kind of in p-MePh2SiPh-, Cy-, i-Pr-.
The synthetic method are as follows: azomethine ylide and compound cyclopropene are anti-by 1,3- dipole [3+2] cycloaddition
The chiral pyrrolidine derivative of the ring skeleton containing ternary should be synthesized, reaction structure formula is as follows:
The synthetic method is following steps: under inert gas protection, azomethine ylide and ring being added in container
Propene compound, metallic catalyst, Phosphine ligands, alkali additive, in reaction medium, in 0 DEG C~react 24-48h at room temperature,
It is extracted with ethyl acetate, solvent is evaporated off after organic phase is dry, obtains crude product, then isolates and purifies, obtain ternary ring skeleton
Chiral pyrrolidine derivative.
The molar ratio of cyclopropene compound and azomethine ylide is 1: 1~1: 1.2.Preferably, reactant first is sub-
The concentration of ammonium ylide and cyclopropene compound is respectively the solution of 0.1-1.3mol/L.Azomethine ylide and cyclopropene
Compound is readily synthesized as raw material, and substrate universality is strong, and obtained products collection efficiency is high and enantioselectivity is high.
Complex compound is formed in situ in metallic catalyst and Phosphine ligands, easy to operate.
The metallic catalyst be selected from four acetonitrile copper of tetrafluoro boric acid, silver acetate, four acetonitrile copper of hexafluorophosphoric acid, copper acetate,
One of copper trifluoromethanesulfcomposite, usage amount are the 1~10% of cyclopropene compound mole.
The Phosphine ligands are selected from chiral phosphine ligand diphosphine compound, and usage amount is the 2 of cyclopropene compound mole
~11%.The Phosphine ligands have one of structural formula as shown in (II):
The alkali additive is selected from potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, diisopropylamine, N, N- diisopropyl second
Amine, 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene (DBU), a kind of in 4-dimethylaminopyridine (DMAP), usage amount is
The 10-100% of cyclopropene compound mole.
The reaction medium is a kind of in toluene, tetrahydrofuran, methylene chloride, ether.
Above-mentioned room temperature is 20 DEG C ± 5 DEG C, and reaction temperature of the present invention is 0 DEG C~room temperature, and reaction temperature mild condition reduces anti-
Answer difficulty.
Preferably, crude product is concentrated under reduced pressure after being cleaned by silica gel column chromatography can obtain sterling, convenient post-treatment, and product
Enantioselectivity and cis-selectivity it is very high.
The present invention is anti-through [3+2] cycloaddition using the azomethine ylide and cyclopropene compound being readily synthesized as raw material
It should can efficiently synthesize the chiral pyrrolidine derivative of the serial ring skeleton containing ternary.The compound of synthesis contain multiple functional groups and
Multiple chiral centers are a kind of important nitrogen-containing heterocycle compounds, have potential bioactivity, can be used as among fine chemistry industry
Body is widely used in various organic syntheses, medicine, materials chemistry and field of fine chemical, has considerable application value.
Compared with prior art, the beneficial effects of the present invention are: synthetic method is easy to operate, reaction condition is mild, substrate
Universality is strong, and products collection efficiency is high and enantioselectivity is high.
Specific embodiment
Below by embodiment, invention is further described in detail, raw materials used commercially available in embodiment or use
Conventional method preparation.
Embodiment 1
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL dichloromethane
Alkane stirs 30min in advance at room temperature.Glycine Schiff base 5a (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.2mmol), continues that reaction is stirred at room temperature for 24 hours.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6a, yellow oily
72mg, yield 92%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.39 (d, J=7.3Hz, 2H), 7.36-7.26 (m,
6H), 7.26-7.16 (m, 2H), 4.71 (s, 1H), 4.37 (s, 1H), 3.62 (s, 3H), 3.50 (t, J=24.9Hz, 4H),
2.74 (s, 1H), 2.43 (s, 2H), 1.17 (t, J=7.1Hz, 3H), 0.77 (t, J=7.1Hz, 3H)13C NMR (100MHz,
CDCl3) δ 174.2,168.1,144.3,138.9,128.7,128.4,126.9,126.8,126.7,126.2,62.8,61.5,
52.0,41.7,38.7,35.2,13.2,12.6.HRMS (ESI) m/z:[M+H]+ calculated for C24H29N2O3:
393.2173, found:393.2170.Enantiomeric excess was determined by HPLC with a
Phenomenex chiral INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, > 99%
ee)；major enantiomer tr=17.16min, minor enantiomer tr=22.46min.
Embodiment 2:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(13.0mg, 0.011mmol) and metallic catalyst Cu (CH3CN)4BF4(3.15mg, 0.01mmol) adds 2.0mL solvent four
Hydrogen furans, stirs 30min in advance at room temperature.Glycine Schiff base 5b (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.2mmol), continues that reaction 26h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6b, orange oily
74mg, yield 88%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.21 (dd, J=8.5,5.7Hz, 6H), 7.14
(dd, J=8.9,4.4Hz, 1H), 6.77 (d, J=8.5Hz, 2H), 4.57 (s, 1H), 4.26 (s, 1H), 3.70 (s, 3H),
3.55 (s, 3H), 3.40 (d, J=25.8Hz, 4H), 2.66 (s, 1H), 2.23 (d, J=38.8Hz, 2H), 1.09 (t, J=
7.0Hz, 3H), 0.69 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.3,168.1,158.6,138.9,
136.5,128.7,127.8,126.8,126.1,113.7,62.2,61.4,55.3,52.1,41.6,38.6,35.1,13.2,
12.6.HRMS (ESI) m/z:[M+Na]+ calculated for C25H30N2NaO4: 445.2098, found:
445.2112.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=80: 20,1.0mL/min, 210nm, > 99%ee)；major
enantiomer tr=15.44min, minor enantiomer tr=26.47min.
Embodiment 3:
Under nitrogen atmosphere, the Phosphine ligands L4:(R weighed up is added into ready test tube)-DM-SegPhos
(15.9mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL solvent two
Chloromethanes stirs 30min in advance at room temperature.Glycine Schiff base 5c (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.2mmol), continues that reaction 28h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6c, colorless oil
92mg, yield 93%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.60-7.51 (m, 4H), 7.50-7.38 (m, 4H),
7.31 (d, J=4.3Hz, 4H), 7.27-7.19 (m, 2H), 4.78 (s, 1H), 4.39 (s, 1H), 3.65 (s, 3H), 3.50 (d, J
=24.6Hz, 4H), 2.76 (s, 1H), 2.43 (s, 2H), 1.18 (t, J=7.0Hz, 3H), 0.78 (t, J=7.0Hz, 3H)13C
NMR (101MHz, CDCl3) δ 174.2,168.1,143.3,141.0,139.9,138.9,128.8,128.7,127.2,
127.2,127.1,127.1,126.9,126.2,62.6,61.5,52.1,41.7,38.7,35.3,13.2,12.6.HRMS
(ESI) m/z:[M+H]+ calculated for C30H33N2O3: 469.2486, found:469.2476.Enantiomeric
Excess was determined by HPLC with a Phenomenex chiral INA column (hexanes:2-
Propanol=85: 15,1.0mL/min, 210nm, > 99%ee)；major enantiomer tr=16.91min, minor
enantiomer tr=21.80min.
Embodiment 4:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 0.5mL solvent two
Chloromethanes stirs 30min in advance at room temperature.Glycine Schiff base 5d (0.22mmol) and alkali additive K are sequentially added after 30min2CO3
(0.04mmol) adds cyclopropene compound 4a (0.20mmol), continues that reaction 30h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6d, yellow oil
Shape 84mg, yield 99%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.39-7.19 (m, 9H), 4.74 (s, 1H), 4.30
(s, 1H), 3.65 (s, 3H), 3.61-3.28 (m, 4H), 2.76 (s, 1H), 2.30 (s, 2H), 1.17 (t, J=7.1Hz, 3H),
0.76 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.1,168.0142.8,138.6,132.6,128.8,
128.4,128.2,127.0,126.1,62.3,61.5,52.2,41.7,38.8,35.2,13.2,12.6.HRMS (ESI) m/z:
[M+H]+ calculated for C24H28ClN2O3: 427.1783, found:427.1780.Enantiomeric excess
Was determined by HPLC with a Phenomenex chiral INA column (hexanes:2-propanol
=90: 10,1.0mL/min, 210nm, > 99%ee)；major enantiomer tr=22.94min, minor
enantiomer tr=37.72min.
Embodiment 5:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4PF6(7.5mg, 0.02mmol) adds 2.0mL solvent two
Chloromethanes stirs 30min in advance at room temperature.Glycine Schiff base 5e (0.24mmol) and alkali additive are sequentially added after 30min such as
K2CO3(0.02mmol) adds cyclopropene compound 4a (0.20mmol), continues that reaction 32h is stirred at room temperature.Reaction
It (is monitored after the completion by TLC), mixture is concentrated, it is white later by silica gel column purification crude product to obtain corresponding product 6e
Color solid 72mg, yield 93%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.43 (d, J=8.4Hz, 2H), 7.37-7.18 (m,
7H), 4.74 (s, 1H), 4.30 (s, 1H), 3.66 (s, 3H), 3.58-3.31 (m, 4H), 2.76 (s, 1H), 2.30 (s, 2H),
1.17 (t, J=7.1Hz, 3H), 0.75 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.1168.0,
143.3,138.6,131.3,128.8,128.6,127.0,126.1,120.7,62.3,61.5,52.2,41.7,38.8,
35.2,13.2,12.6.HRMS (ESI) m/z:[M+H]+ calculated for C24H28BrN2O3: 471.1278, found:
471.1299.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, > 99%ee)；major
enantiomer tr=24.15min, minor enantiomer tr=40.69min.
Embodiment 6:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (OTf)27.2mg, 0.02mmol), add 0.8mL solvent dichloromethane
Alkane stirs 30min in advance at room temperature.Glycine Schiff base 5f (0.22mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.20mmol), continues that reaction 34h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6f, yellow is solid
Body 77mg, yield 95%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) 67.30 (d, J=4.3Hz, 4H), 7.25-7.14 (m,
4H), 7.03 (d, J=6.7Hz, 1H), 4.66 (s, 1H), 4.36 (s, 1H), 3.63 (s, 3H), 3.51 (t, J=22.6Hz,
4H), 2.74 (s, 1H), 2.32 (d, J=9.1Hz, 5H), 1.17 (t, J=7.1Hz, 3H), 0.76 (t, J=7.1Hz, 3H)13C
NMR (100MHz, CDCl3) δ 174.2,168.2,144.2,138.9,137.9,128.7,128.3,127.6,127.5,
126.8,126.2,123.7,62.8,61.5,52.0,41.7,38.7,35.2,21.5,13.2,12.6.HRMS (ESI) m/z:
[M+H]+ calculated for C25H31N2O3: 407.2329, found:407.2328.Enantiomeric excess
Was determined by HPLC with a Phenomenex chiral INA column (hexanes:2-propanol
=90: 10,1.0mL/min, 210nm, > 99%ee)；minor enantiomer tr=11.45min, major
enantiomer tr=12.75min.
Embodiment 7:
Under nitrogen atmosphere, the Phosphine ligands L3:(R weighed up is added into ready test tube)-SegPhos (13.4mg,
0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL solvent toluene, at room temperature
30min is stirred in advance.Glycine Schiff base 5g (0.20mmol) and alkali additive K are sequentially added after 30min2CO3(0.02mmol), then
It is added cyclopropene compound 4a (0.2mmol), continues that reaction 36h is stirred at room temperature.It (is supervised after the reaction was completed by TLC
Survey), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6g, colorless oil 72mg, yield is
84%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.35 (s, 1H), 7.27-7.09 (m, 8H), 4.67
(s, 1H), 4.25 (s, 1H), 3.61 (s, 3H), 3.40 (d, J=20.6Hz, 4H), 2.68 (s, 1H), 2.16 (d, J=
21.1Hz, 2H), 1.09 (t, J=7.1Hz, 3H), 0.68 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3)δ
175.0,168.0,146.4,138.6,134.2,129.6,128.8,127.0,126.9,126.1,124.9,62.5,61.5,
52.2,41.7,38.8,35.2,13.1,12.6.HRMS (ESI) m/z: [M+H]+ calculated for C24H28ClN2NaO3
: 427.1783, found: 427.1780.Enantiomeric excess was determined by HPLC with a
Phenomenex chiral INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, > 99%
ee)；minor enantiomer tr=10.84min, major enantiomer tr=12.77min.
Embodiment 8:
Under nitrogen atmosphere, be added the Phosphine ligands L4 weighed up: (R)-DM-SegPhos into ready test tube (8.2mg,
0.012mmol) and metallic catalyst Cu (CH3CN)4BF4(3.3mg, 0.011mmol) adds 2.0mL methylene chloride,
Stir 30min in advance at room temperature.Glycine Schiff base 5h (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.2mmol), continues that reaction 38h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6h, colorless oil
82mg, yield 87%, 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.59 (s, 1H), 7.40-7.13 (m, 8H), 4.75
(s, 1H), 4.32 (s, 1H), 3.71 (s, 3H), 3.65-3.21 (m, 4H), 2.78 (s, 1H), 2.33 (s, 2H), 1.18 (t, J=
7.1Hz, 3H), 0.76 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 172.9,167.0,145.6,137.5,
128.87,128.82,128.8,127.8,125.9,125.1,124.4,121.5,61.4,60.5,51.2,40.7,37.7,
34.2,12.1,11.6.HRMS (ESI) m/z:[M+H]+ calculated for C24H28BrN2O3: 471.1278, found:
471.1291.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, 99%ee)；minor enantiomer
tr=11.91min, major enantiomer tr=13.00min.
Embodiment 9:
Under nitrogen atmosphere, the Phosphine ligands L2:(R weighed up is added into ready test tube)-BINAP (13.6mg,
0.011mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.01mmol) adds 0.5mL solvent such as methylene chloride,
Stir 30min in advance at room temperature.Glycine Schiff base 5i (0.42mmol) and alkali additive K are sequentially added after 30min2CO3
(0.04mmol) adds cyclopropene compound 4a (0.40mmol), continues that reaction 40h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6i, colorless oil
Shape 154mg, yield 82%, 98%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.73 (dd, J=7.8,1.2Hz, 1H), 7.63-
7.48 (m, 1H), 7.37-7.21 (m, 6H), 7.11 (td, J=7.8,1.4Hz, 1H), 4.83 (s, 1H), 4.69 (s, 1H),
3.93-3.75 (m, 2H), 3.68 (s, 3H), 3.45 (m, 1H), 3.34-3.08 (m, 1H), 2.61 (s, 1H), 2.50 (s, 1H),
2.32 (d, J=8.2Hz, 1H), 1.17 (t, J=7.1Hz, 3H), 0.72 (t, J=7.1Hz, 3H)13C NMR (100MHz,
CDCl3) δ 174.5,167.9,143.1,138.8,132.8,128.8,128.6,128.6,127.5,126.9,126.6,
122.9,62.6,61.9,52.1,42.2,38.7,35.3,13.2,12.7.HRMS (ESI) m/z:[M+H]+ calculated
for C24H28N2BrO3: 471.1278, found:471.1296.Enantiomeric excess was determined by
HPLC with a Phenomenex chiral INA column (hexanes:2-propanol=90: 10,1.0mL/min,
210nm, 98%ee)；minor enantiomer tr=8.69min, major enantiomer tr=12.23min.
Embodiment 10:
Under nitrogen atmosphere, the Phosphine ligands L2:(R weighed up is added into ready test tube)-BINAP (13.6mg,
0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL methylene chloride, room
30min is stirred under temperature in advance.Glycine Schiff base 5j (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.2mmol), continues that reaction 42h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6j, colorless oil
62mg, yield 76%, 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.46 (d, J=7.2Hz, 1H), 7.29 (dd, J=
15.2,6.3Hz, 4H), 7.25-7.09 (m, 4H), 4.91 (s, 1H), 4.41 (s, 1H), 3.64 (s, 3H), 3.61-3.27 (m,
4H), 2.76 (s, 1H), 2.42 (s, 3H), 2.32 (s, 2H), 1.18 (t, J=7.1Hz, 3H), 0.74 (t, J=7.1Hz, 3H)
.13C NMR (100MHz, CDCl3) δ 174.1,168.0,142.2,139.0,134.8,130.4,128.7,126.9,126.8,
126.3,126.0,126.0,61.5,59.3,52.1,41.7,38.6,35.5,19.7,13.2,12.6.HRMS (ESI) m/z:
[M+H]+ calculated for C25H31N2O3: 407.2329, found:407.2297.Enantiomeric excess
Was determined by HPLC with a Phenomenex chiral INA column (hexanes:2-propanol
=90: 10,1.0mL/min, 210nm, 99%ee)；minor enantiomer tr=9.89min, major enantiomer
tr=12.98min.
Embodiment 11:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(5.2mg, 0.0044mmol) and metallic catalyst Cu (CH3CN)4BF4(1.26mg, 0.0040mmol) adds 1.0mL solvent
Ether stirs 15min in advance at room temperature.Glycine Schiff base 5k (0.20mmol) and alkali additive K are sequentially added after 15min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.2mmol), continues that reaction 48h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6k, yellow oily
81mg, yield 95%, 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.77 (dd, J=7.7,1.1Hz, 1H), 7.44-
7.12 (m, 8H), 4.86 (s, 1H), 4.70 (s, 1H), 3.80 (dd, J=28.3,23.3Hz, 1H), 3.75-3.57 (m, 4H),
3.54-3.33 (m, 1H), 3.22 (dd, J=13.0,6.5Hz, 1H), 2.60 (s, 1H), 2.42 (d, J=24.3Hz, 2H),
1.16 (t, J=7.1Hz, 3H), 0.73 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.4,168.0,
141.7,138.8,132.4,129.4,128.7,128.4,128.2,126.9,126.9,126.5,61.9,60.5,52.0,
42.0,38.7,35.3,13.2,12.6.HRMS (ESI) m/z:[M+H]+ calculated for C24H28ClN2O3:
427.1783, found:427.1740.Enantiomeric excess was determined by HPLC with a
Phenomenex chiral INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, 99%
ee)；minor enantiomer tr=9.15min, major enantiomer tr=12.02min.
Embodiment 12:
Under nitrogen atmosphere, the Phosphine ligands L3:(R weighed up is added into ready test tube)-SegPhos (3.35mg,
0.0055mmol) and metallic catalyst Cu (CH3CN)4BF4(1.58mg, 0.0050mmol) adds 2.0mL solvent tetrahydro furan
It mutters, stirs 30min in advance at room temperature.Glycine Schiff base 51 (0.22mmol) and alkali additive cesium carbonate are sequentially added after 30min
(0.02mmol) adds cyclopropene compound 4a (0.20mmol), continues that reaction 46h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 61, colorless oil
Shape 71mg, yield 80%, 97%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.80 (s, 1H), 7.76-7.69 (m, 3H), 7.45-
7.32 (m, 3H), 7.28-7.13 (m, 5H), 4.82 (s, 1H), 4.32 (s, 1H), 3.53 (s, 3H), 3.51-3.21 (m, 4H),
2.72 (s, 1H), 2.42 (s, 2H), 1.13 (t, J=7.1Hz, 3H), 0.72 (t, J=7.1Hz, 3H)13C NMR (100MHz,
CDCl3) δ 174.2,168.2,141.6,138.8,133.4,132.6,128.8,128.1,128.0,127.6,126.9,
126.2,126.0,125.6,125.3,125.1,63.0,61.6,53.5,52.1,41.7,38.7,35.3,13.2,
12.7.HRMS (ESI) m/z:[M+H]+ calculated for C28H31N2O3: 443.2329, found:
443.2406.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=80: 20,1.0mL/min, 210nm, 97%ee)；major enantiomer
tr=11.71min, minor enantiomer tr=13.09min.
Embodiment 13:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (OAc)2(3.6mg, 0.02mmol) adds 1.2mL solvent dichloromethane
Alkane stirs 30min in advance at room temperature.Glycine Schiff base 5m (0.21mmol) and alkali additive potassium tert-butoxide are sequentially added after 30min
(0.01mmol) adds cyclopropene compound 4a (0.2mmol), continues that reaction 48h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6m, yellow oily
57mg, yield 72%, 98%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.32 (d, J=3.8Hz, 4H), 7.24 (dd, J=
7.7,3.8Hz, 1H), 7.16 (d, J=4.8Hz, 1H), 6.97-6.89 (m, 2H), 4.97 (s, 1H), 4.24 (s, 1H), 3.63
(s, 3H), 3.47 (d, J=17.1Hz, 4H), 2.82 (s, 1H), 2.47 (s, 2H), 1.15 (t, J=6.9Hz, 3H), 0.75 (t,
J=6.9Hz, 3H)13C NMR (100MHz, CDCl3) δ 173.6,167.9,149.0,138.6,128.8,126.9,126.8,
126.3,124.2,123.5,61.1,58.5,52.1,41.6,38.7,35.2,13.2,12.6.HRMS (ESI) m/z:[M+H]+
calculated for C22H27N2O38:399.1737, found:399.1693.Enantiomeric excess was
Determined by HPLC with a Phenomenex chiral INA column (hexanes:2-propanol=90
: 10,1.0mL/min, 210nm, 98%ee)；major enantiomer tr=19.78min, minor enantiomer tr
=25.69min.
Embodiment 14:
Under nitrogen atmosphere, the Phosphine ligands L4:(R weighed up is added into ready test tube)-DM-SegPhos
(14.45mg, 0.020mmol) and metallic catalyst Cu (CH3CN)4PF6(7.45mg, 0.02mmol) adds 2.0mL solvent
Ether stirs 30min in advance at room temperature.Glycine Schiff base 5n (0.20mmol) and alkali additive DBU are sequentially added after 30min
(0.04mmol) adds cyclopropene compound 4a (0.2mmol), is transferred at 0 DEG C and is stirred to react 48h.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6n, colorless oil
54mg, yield 68%, 83%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.38-7.12 (m, 5H), 4.27 (s, 1H), 3.73
(s, 3H), 3.43 (s, 4H), 3.06 (s, 1H), 2.14 (t, J=46.5Hz, 4H), 1.92-1.55 (m, 4H), 1.29-1.06
(m, 7H), 1.03-0.78 (m, 2H), 0.72 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.9,168.4,
139.3,128.6,126.6,126.0,65.5,61.1,52.0,42.5,41.5,38.5,34.7,30.8,30.2,26.6,
26.2,26.1,13.1,12.5.HRMS (ESI) m/z:[M+H]+ calculated for C24H35N2O3: 399.2642,
Found:399.2610.Enantiomeric excess was determined by HPLC with a Phenomenex
Chiral INA column (hexanes:2-propanol=95: 5,1.0mL/min, 210nm, 83%ee)；minor
enantiomer tr=8.83min, major enantiomer tr=18.74min.
Embodiment 15:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (OTf)2(7.3mg, 0.02mmol) adds 2.0mL solvent toluene, room
30min is stirred under temperature in advance.Glycine Schiff base 5o (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4a (0.2mmol), is transferred at 0 DEG C and is stirred to react 48h.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6o, yellow oily
38mg, yield 53%, 75%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.37-7.13 (m, 5H), 4.25 (s, 1H), 3.73
(s, 3H), 3.42 (s, 4H), 3.05 (s, 1H), 2.43 (s, 1H), 2.31-2.05 (m, 2H), 1.57 (dd, J=13.8,
6.9Hz, 1H), 1.12 (t, J=7.1Hz, 3H), 0.97 (t, J=6.4Hz, 6H), 0.73 (t, J=7.1Hz, 3H)13C NMR
(100MHz, CDCl3) δ 174.8,168.3,139.3,128.6,126.6,126.1,66.9,61.2,52.0,41.5,38.6,
34.8,33.0,20.1,19.8,13.1,12.5.HRMS (ESI) m/z:[M+H]+ calculated for C21H31N2O3:
359.2329, found:359.2311.Enantiomeric excess was determined by HPLC with a
Phenomenex chiral INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, 75%
ee)；minor enantiomer tr=6.30min, major enantiomer tr=8.68min.
Embodiment 16:
Under nitrogen atmosphere, the Phosphine ligands L2:(R weighed up is added into ready test tube)-BINAP (6.85mg,
0.011mmol) and metallic catalyst Cu (CH3CN)4BF4(3.15mg, 0.01mmol) adds 1.0mL methylene chloride,
Stir 30min in advance at room temperature.Glycine Schiff base 5a (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4b (0.2mmol), continues that reaction 28h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6p, faint yellow oil
Shape 56mg, yield 65%, 98%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.28 (m, 9H), 4.70 (s, 1H), 4.36 (s,
1H), 3.63 (s, 3H), 3.47 (d, J=25.4Hz, 4H), 2.74 (s, 1H), 2.42 (s, 2H), 1.18 (t, J=7.1Hz,
3H), 0.82 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.0,167.4,143.9,141.1,134.7,
130.0,128.4,127.08,127.06,126.7,126.2,124.5,62.8,61.4,52.1,41.6,38.7,34.9,
13.3,12.5.HRMS (ESI) m/z:[M+H]+ calculated for C24H28ClN2O3: 427.1783, found:
427.1764.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, 98%ee)；minor enantiomer
tr=9.05min, major enantiomer tr=10.08min.
Embodiment 17:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 1.0mL solvent four
Hydrogen furans, stirs 30min in advance at room temperature.Glycine Schiff base 5a (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4c (0.2mmol), continues that reaction 30h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6q, colorless oil
73mg, yield 85%, 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.29 (m, 9H), 4.69 (s, 1H), 4.35 (s,
1H), 3.62 (s, 3H), 3.47 (d, J=27.1Hz, 4H), 2.71 (s, 1H), 2.43 (s, 2H), 1.17 (t, J=7.1Hz,
3H), 0.80 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.0,167.6,144.0,137.6,132.8,
128.9,128.4,127.6,127.0,126.7,62.7,61.3,52.1,41.6,38.7,34.7,13.4,12.6.HRMS
(ESI) m/z:[M+H]+ calculated for C24H28ClN2O3: 427.1783, found:
427.1737.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=85: 15,1.0mL/min, 210nm, 99%ee)；major enantiomer
tr=12.93min, minor enantiomer tr=18.67min.
Embodiment 18:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL solvent two
Chloromethanes stirs 30min in advance at room temperature.Glycine Schiff base 5a (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.10mmol) adds cyclopropene compound 4d (0.2mmol), continues that reaction 18h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6r, colorless oil
92mg, yield 98%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.43 (d, J=8.5Hz, 2H), 7.32 (dt, J=
21.5,7.0Hz, 4H), 7.21 (dd, J=15.8,7.9Hz, 3H), 4.69 (s, 1H), 4.33 (d, J=18.5Hz, 1H), 3.62
(s, 3H), 3.58-3.20 (m, 4H), 2.71 (s, 1H), 2.37 (s, 2H), 1.16 (t, J=7.0Hz, 3H), 0.81 (t, J=
7.0Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.0,167.6,144.0,138.1,131.8,128.4,128.0,
127.0,126.7,120.8,62.7,61.3,52.1,41.6,38.7,34.8,13.4,12.6.HRMS (ESI) m/z:[M+H]+
calculated for C24H28BrN2O3: 471.1278, found:471.1227.Enantiomeric excess was
Determined by HPLC with a Phenomenex chiral INA column (hexanes:2-propanol=90
: 10,1.0mL/min, 210nm, > 99%ee)；major enantiomer tr=20.50min, minor enantiomer
tr=31.23min.
Embodiment 19:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL solvent four
Hydrogen furans, stirs 30min in advance at room temperature.Three second of glycine Schiff base 5c (0.20mmol) and alkali additive is sequentially added after 30min
Amine (0.22mmol) adds cyclopropene compound 4e (0.2mmol), continues that reaction 44h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6s, colorless oil
Shape 74mg, yield 91%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.54 (dd, J=16.3,7.7Hz, 4H), 7.44-
7.37 (m, 4H), 7.31 (dd, J=12.7,5.4Hz, 1H), 4.51 (s, 1H), 4.11 (s, 1H), 3.68 (s, 2H), 3.57 (s,
3H), 3.52-3.25 (m, 2H), 2.31 (d, J=6.2Hz, 1H), 2.25 (s, 1H), 1.88 (d, J=6.3Hz, 1H), 1.36
(s, 3H), 1.29 (t, J=7.1Hz, 3H), 1.14 (t, J=7.1Hz, 3H) .13CNMR (100MHz, CDCl3) δ 174.3,
170.0,143.4,141.0,139.7,128.7,127.2,127.0,127.0,61.7,60.6,52.0,41.2,38.1,
26.8,21.5,14.5,12.7.HRMS (ESI) m/z:[M+H]+ calculated for C25H31N2O3: 407.2329,
Found:407.2341.Enantiomeric excess was determined by HPLC with a Phenomenex
Chiral INA column (hexanes:2-propanol=85: 15,1.0mL/min, 210nm, > 99%ee)；major
enantiomer tr=10.26min, minor enantiomer tr=11.75min.
Embodiment 20:
Under nitrogen atmosphere, the Phosphine ligands L3:(R weighed up is added into ready test tube)-SegPhos (6.7mg,
0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(3.10mg, 0.02mmol) adds 2.5mL methylene chloride,
Stir 30min in advance at room temperature.Glycine Schiff base 5a (0.24mmol) and alkali additive K are sequentially added after 30min2CO3
(0.04mmol) adds cyclopropene compound 4f (0.2mmol), continues that reaction 36h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6t, white solid
68mg, yield 87%, 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.40 (d, J=7.4Hz, 1H), 7.35-7.18 (m,
8H), 4.70 (s, 1H), 4.34 (s, 1H), 3.64 (s, 3H), 3.60 (t, J=6.6Hz, 2H), 3.45-3.35 (m, 1H),
3.35-3.25 (m, 1H), 2.71 (d, J=6.5Hz, 1H), 2.49 (s, 1H), 2.34 (d, J=6.5Hz, 1H), 1.94-1.75
(m, 4H)13C NMR (100MHz, CDCl3) δ 174.2,167.5,144.4,138.4,128.8,128.4,127.0,126.8,
126.7,125.9,63.0,61.5,52.1,47.1,46.0,39.7,36.5,36.4,26.2,24.1.HRMS (ESI) m/z:[M
+H]+ calculated for C24H27N2O3: 391.2016, found:391.1973.Enantiomeric excess was
Determined by HPLC with a Phenomenex chiral INA column (hexanes:2-propanol=90
: 10,1.0mL/min, 210nm, 99%ee)；major enantiomer tr=30.06min, minor enantiomer tr
=34.31min.
Embodiment 21:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (OAc)2(3.6mg, 0.02mmol) adds 2.0mL solvent dichloromethane
Alkane stirs 30min in advance at room temperature.Glycine Schiff base 5a (0.20mmol) and alkali additive diisopropylamine are sequentially added after 30min
(0.1mmol) adds cyclopropene compound 4g (0.20mmol), continues that reaction 38h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6u, white solid
46mg, yield 59%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.44-7.16 (m, 10H), 5.70 (s, 1H), 4.76
(s, 1H), 4.33 (s, 1H), 3.59 (s, 3H), 3.38-3.13 (m, 2H), 2.72 (d, J=6.6Hz, 1H), 2.42 (s, 1H),
2.27 (d, J=6.6Hz, 1H), 1.58-1.39 (m, 2H), 1.29 (m, 2H), 0.89 (t, J=7.3Hz, 3H)13C NMR
(100MHz, CDCl3) δ 174.1,168.9,144.0,139.8,128.8,128.4,127.6,127.3,127.1,126.8,
62.1,60.6,52.1,39.6,38.2,37.6,34.4,31.6,20.1,13.7.HRMS (ESI) m/z:[M+H]+
calculated for C24H29N2O3: 393.2173, found:393.2135.Enantiomeric excess was
Determined by HPLC with a Phenomenex chiral INA column (hexanes:2-propanol=90
: 10,1.0mL/min, 210nm, > 99%ee)；major enantiomer tr=14.55min, minor enantiomer
tr=23.86min.
Embodiment 22:
Under nitrogen atmosphere, the Phosphine ligands L2:(R weighed up is added into ready test tube)-BINAP (13.6mg,
0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL methylene chloride, room
30min is stirred under temperature in advance.Glycine Schiff base 5e (0.22mmol) and alkali additive K are sequentially added after 30min2CO3
(0.03mmol) adds cyclopropene compound 4c (0.20mmol), continues that reaction 40h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6v, white is solid
Body 90mg, yield 89%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.43 (d, J=8.3Hz, 2H), 7.33-7.21 (m,
6H), 4.72 (s, 1H), 4.29 (s, 1H), 3.65 (s, 3H), 3.47 (d, J=5.5Hz, 4H), 2.72 (s, 1H), 2.41 (s,
1H), 2.27 (s, 1H), 1.16 (t, J=7.1Hz, 3H), 0.79 (t, J=7.1Hz, 3H)13C NMR (100MHz, CDCl3)δ
173.9,167.5,143.0,137.3,132.9,131.4,128.9,128.5,127.5,120.8,62.3,61.4,52.2,
41.7,38.8,34.7,13.3,12.6.HRMS (ESI) m/z:[M+Na]+ calculated for C24H26BrClN2NaO3:
527.0677, found:527.0681.Enantiomeric excess was determined by HPLC with a
Phenomenex chiral INA column (hexanes:2-propanol=80: 20,1.0mL/min, 210nm, > 99%
ee)；major enantiomer tr=17.24min, minor enantiomer tr=33.42min.
Embodiment 23:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL solvent second
Ether stirs 30min in advance at room temperature.Glycine Schiff base 5c (1.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.10mmol) adds cyclopropene compound 4c (1.00mmol), continues that reaction 42h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6w, colorless oil
Shape 495mg, yield 98%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.56 (t, J=8.6Hz, 4H), 7.43 (dd, J=
12.6,7.8Hz, 4H), 7.37-7.21 (m, 5H), 4.75 (s, 1H), 4.37 (s, 1H), 3.65 (s, 3H), 3.49 (d, J=
21.6Hz, 4H), 2.74 (s, 1H), 2.41 (s, 2H), 1.18 (t, J=7.0Hz, 3H), 0.81 (t, J=7.0Hz, 3H)13C
NMR (100MHz, CDCl3) δ 174.1,167.7,143.1,140.9,140.0,137.5,132.8,128.9,128.8,
127.62,127.2,127.15 (s), 127.1,62.5,61.4,52.2,41.7,38.8,34.8,13.4,12.6.HRMS
(ESI) m/z:[M+H]+ calculated for C30H32ClN2O3: 503.2096, found:
503.2070.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, > 99%ee)；major
enantiomer tr=35.85min, minor enantiomer tr=51.19min.
Embodiment 24:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL solvent four
Hydrogen furans, stirs 30min in advance at room temperature.Glycine Schiff base 5c (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4d (0.2mmol), continues that reaction 44h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6x, white solid
107mg, yield 98%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.56 (t, J=8.6Hz, 4H), 7.44 (t, J=
9.1Hz, 6H), 7.34 (t, J=7.3Hz, 1H), 7.20 (d, J=8.5Hz, 2H), 4.75 (s, 1H), 4.36 (s, 1H), 3.65
(s, 3H), 3.49 (d, J=18.9Hz, 4H), 2.74 (s, 1H), 2.44 (s, 2H), 1.18 (t, J=7.0Hz, 3H), 0.81 (t,
J=7.0Hz, 3H)13C NMR (100MHz, CDCl3) δ 174.0,167.6,143.0,140.9,134.0,138.0,131.9,
128.8,128.0,127.2,127.2,127.1,120.9,62.6,61.4,52.3,41.7,38.8,34.8,13.4,
12.6.HRMS (ESI) m/z:[M+H]+ calculated for C30H32BrN2O3: 547.1591, found:
547.1555.Enantiomeric excess was determined by HPLC with a Phenomenex chiral
INA column (hexanes:2-propanol=90: 10,1.0mL/min, 210nm, > 99%ee)；major
enantiomer tr=45.37min, minor enantiomer tr=65.87min.
Embodiment 25:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 2.0mL solvent two
Chloromethanes stirs 30min in advance at room temperature.Glycine Schiff base 5p (0.20mmol) and alkali additive DMAP are sequentially added after 30min
(0.01mmol) adds cyclopropene compound 4c (0.2mmol), continues that reaction 46h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6y, colorless oil
59mg, yield 54%, 98%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.54-7.43 (m, 4H), 7.39-7.20 (m, 9H),
4.66 (s, 1H), 4.36 (s, 1H), 3.61 (s, 3H), 3.45 (d, J=25.4Hz, 4H), 2.68 (s, 1H), 2.35 (s, 2H),
1.16 (t, J=7.1Hz, 3H), 0.80 (t, J=7.0Hz, 3H), 0.53 (s, 6H)13C NMR (100MHz, CDCl3)δ
176.4,170.0,147.3,140.7,139.9,139.1,136.8,136.5,135.2,131.5,131.23,130.2,
129.9,128.5,65.2,63.8,54.5,44.0,41.1,37.1,15.7,15.0,0.00.HRMS (ESI) m/z: [M+H]+
calculated for C32H38C1N2O3Si:561.2335, found:561.2259.Enantlomeric excess was
Determined by HPLC with a Phenomenex chlral INA column (hexanes:2-propanol=90
: 10,1.0mL/min, 210nm, 98%ee)；minor enantiomer tr=15.78min, major enantiomer tr
=23.32min.
Embodiment 26:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 3.0mL solvent four
Hydrogen furans, stirs 30min in advance at room temperature.Glycine Schiff base 5c (0.20mmol) and alkali additive K are sequentially added after 30min2CO3
(0.02mmol) adds cyclopropene compound 4h (0.2mmol), continues that reaction 48h is stirred at room temperature.Reaction is completed
It (is monitored afterwards by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6z, yellow is solid
Body 92mg, yield 84%, > 99%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.56 (t, J=7.5Hz, 4H), 7.49-7.38 (m,
6H), 7.34 (d, J=7.3Hz, 1H), 7.19 (d, J=8.5Hz, 2H), 4.76 (s, 1H), 4.32 (s, 1H), 3.76-3.53
(m, 9H), 3.41 (s, 2H), 2.78 (s, 1H), 2.42 (d, J=42.8Hz, 2H)13C NMR (100MHz, CDCl3) δ 173.7,
167.1,142.6,140.8,140.2,137.6,132.1,128.78,127.73,127.2,127.15,127.1,121.1,
66.6,62.2,60.9,52.2,46.5,42.3,34.5.HRMS (ESI) m/z:[M+H]+ calculated for
C30H30BrN2O4: 561.1383, found:561.1402.Enantiomeric excess was determined by HPLC
With a Daicel chiral IA column (hexanes:2-propanol=70: 30,1.0mL/min, 254nm, >
99%ee)；major enantiomer tr=64.87min, minor enantiomer tr=71.65min.
Embodiment 27:
Under nitrogen atmosphere, the Phosphine ligands L5:(R weighed up is added into ready test tube)-DTBM-SegPhos
(26.0mg, 0.022mmol) and metallic catalyst Cu (CH3CN)4BF4(6.3mg, 0.02mmol) adds 3.0mL solvent second
Ether stirs 30min in advance at room temperature.Glycine Schiff base 5c (0.20mmol) and alkali additive potassium tert-butoxide are sequentially added after 30min
(0.02mmol) adds cyclopropene compound 4i (0.2mmol), continues that reaction 28h is stirred at room temperature.After the reaction was completed
(being monitored by TLC), mixture is concentrated, later by silica gel column purification crude product to obtain corresponding product 6aa, pale yellow colored solid
Body 100mg, yield 92%, 98%ee.
The physical and chemical index of the product:1H NMR (400MHz, CDCl3) δ 7.56 (t, J=8.7Hz, 4H), 7.42 (dd, J=
17.0,8.8Hz, 5H), 7.36-7.21 (m, 4H), 4.81 (s, 1H), 4.44 (s, 1H), 3.76-3.17 (m, 7H), 2.75 (s,
1H), 2.44 (s, 2H), 1.81 (s, 2H), 1.56-1.27 (m, 8H)13C NMR (100MHz, CDCl3) δ 174.0,168.1,
143.0,140.91,140.88,140.0,134.7,123.0,128.8,127.3,127.2,127.2,127.1,125.2,
62.5,61.4,52.2,49.7,46.6,35.7,26.9,26.7,26.0,25.7,23.0.HRMS (ESI) m/z:[M+H]+
calculated for C33H36ClN2O3: 543.2409, found:543.2419.Enantiomeric excess was
Determined by HPLC with a Daicel chiral IB column (hexanes:2-propanol=85: 15,
1.0mL/min, 254nm, 98%ee)；minor enantiomer tr=13.51min, major enantiomer tr=
33.88min.
In short, the foregoing is merely presently preferred embodiments of the present invention, it is all according to equalization made by scope of the present invention patent
Variation and modification, shall all be covered by the patent of the invention.
Claims (10)
1. a kind of chiral pyrrolidine derivative of ring skeleton containing ternary, which is characterized in that the chiral pyrrolidine derivative tool
Just like structural formula shown in (I):
In formula, R1、R2、R3、R4It is respectively and independently selected from hydrogen, aryl, a kind of in alkyl.
2. a kind of synthetic method of the chiral pyrrolidine derivative of the ring skeleton containing ternary as described in claim 1, feature exist
In the synthetic method are as follows: azomethine ylide and compound cyclopropene synthesize bone containing three-membered ring by cycloaddition reaction
The chiral pyrrolidine derivative of frame, reaction structure formula are as follows:
3. a kind of synthetic method of the chiral pyrrolidine derivative of ring skeleton containing ternary according to claim 2, feature
It is, the synthetic method is following steps: under inert gas protection, azomethine ylide and cyclopropylene is added in container
Class compound, metallic catalyst, Phosphine ligands, alkali additive, in reaction medium, in 0 DEG C~react 24-48h at room temperature, use second
Acetoacetic ester extraction is evaporated off solvent after organic phase is dry, obtains crude product, then isolate and purify again, obtain the hand of ternary ring skeleton
Property pyrrolidin derivatives.
4. a kind of synthetic method of the chiral pyrrolidine derivative of ring skeleton containing ternary according to claim 3, feature
It is, the molar ratio of cyclopropene compound and azomethine ylide is 1: 1~1: 1.2.
5. a kind of synthetic method of the chiral pyrrolidine derivative of ring skeleton containing ternary according to claim 3, feature
It is, the metallic catalyst is selected from four acetonitrile copper of tetrafluoro boric acid, silver acetate, four acetonitrile copper of hexafluorophosphoric acid, copper acetate, trifluoro
One of copper methane sulfonate, usage amount are the 1~10% of cyclopropene compound mole.
6. a kind of synthetic method of the chiral pyrrolidine derivative of ring skeleton containing ternary according to claim 3, feature
Be, the Phosphine ligands be selected from chiral phosphine ligand diphosphine compound, usage amount be cyclopropene compound mole 2~
11%.
7. a kind of synthetic method of the chiral pyrrolidine derivative of ring skeleton containing ternary according to claim 6, feature
It is, the Phosphine ligands have one of structural formula as shown in (II):
8. a kind of synthetic method of the chiral pyrrolidine derivative of ring skeleton containing ternary according to claim 3, feature
It is, alkali additive is selected from potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, diisopropylamine, n,N-diisopropylethylamine, 1,8-
A kind of in 11 carbon -7- alkene of diazabicyclo [5.4.0], 4-dimethylaminopyridine, usage amount is cyclopropene compound mole
The 10-100% of amount.
9. a kind of synthetic method of the chiral pyrrolidine derivative of ring skeleton containing ternary according to claim 3, feature
It is, reaction medium is a kind of in toluene, tetrahydrofuran, methylene chloride, ether.
10. a kind of chiral pyrrolidine derivative of the ring skeleton containing ternary as described in claim 1 is in organic synthesis, medicine, material
Application in material chemistry and field of fine chemical.
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| CN114957087A (en) * | 2022-04-13 | 2022-08-30 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of intermediate of palovaried |
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| CN110256479A (en) * | 2019-04-25 | 2019-09-20 | 杭州师范大学 | A kind of chiral pyrrolidine derivative and preparation method thereof of siliceous acyl group skeleton |
| CN110256479B (en) * | 2019-04-25 | 2022-01-25 | 杭州师范大学 | Chiral pyrrolidine derivative containing silicon acyl skeleton and preparation method thereof |
| CN114957087A (en) * | 2022-04-13 | 2022-08-30 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of intermediate of palovaried |
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