CN107382823A - Chiral tetrahydro carbazole analog derivative and preparation method thereof - Google Patents

Chiral tetrahydro carbazole analog derivative and preparation method thereof Download PDF

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CN107382823A
CN107382823A CN201710559437.2A CN201710559437A CN107382823A CN 107382823 A CN107382823 A CN 107382823A CN 201710559437 A CN201710559437 A CN 201710559437A CN 107382823 A CN107382823 A CN 107382823A
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preparation
chiral
analog derivative
reaction
tetrahydro carbazole
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CN107382823B (en
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徐小英
岳登峰
赵建强
袁伟成
刘斌
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LIKAI CHIRALITY TECHNOLOGY Co Ltd CHENGDU
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LIKAI CHIRALITY TECHNOLOGY Co Ltd CHENGDU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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Abstract

The invention discloses chiral tetrahydro carbazole analog derivative and preparation method thereof, belong to technical field of organic synthesis, it has structure shown in structural formula I, its preparation method stirs, after reacting 48 96 h for 3 nitroindolines II, Nazarov reagents III and chiral catalyst A are dissolved in reaction dissolvent at 10 DEG C 25 DEG C, reaction finishes, add chloroacetic chloride and alkali, after question response, isolate and purify to obtain product I；Present invention firstly discloses a kind of new tetrahydrocarbazole compound, provide more rich candidate molecules for clinical new medicament screen, and the preparation method of the present invention has the advantages that novel, simple and direct, simple to operate, reaction condition is gentle, high income, stereoselectivity are high.

Description

Chiral tetrahydro carbazole analog derivative and preparation method thereof
Technical field
The present invention relates to organic synthesis field, more particularly to chiral tetrahydro carbazole analog derivative and preparation method thereof.
Background technology
Carbazole is the core skeleton for forming many natural products and medicine, most in these natural molecules and drug molecule Number is found to have good bioactivity, is the important sources of developing new drug.Wherein, chiral hydride carbazole skelton is even more extensive It is present in many natural alkaloids and has in the compound of pharmaceutical activity, it is as follows, compound (-)- Aspidospermine is that the late 19th century is isolated from aspidospermine, has an antibacterial, diuresis, promote vessel retraction and Respiratory stimulant isoreactivity；Vindoline and Minovincine has active anticancer.Therefore, effective method is developed to close Into the multi-ring heterocyclic compound containing this class formation, not only new thinking and method can be provided for the synthesis of such compound, The species of this kind of compound can also be greatly enriched simultaneously, and more candidate molecules are provided for new medicament screen.
At present, the chiral tetrahydro carbazole reported is mostly 1,2,3,4- tetrahydro carbazole skeletons, and for chiral 1a, 3,4, The report of 4a- tetrahydro carbazole molecule of the skeleton is also fewer.Based on tetrahydrocarbazole compound medicine and other fields extensive use, Therefore exploitation novel chiral carbazole compound tool has very important significance.
The content of the invention
An object of the present invention, in that a kind of new chiral tetrahydro carbazole analog derivative is provided, to solve above-mentioned ask Topic.
To achieve these goals, the technical solution adopted by the present invention is such：Chiral tetrahydro carbazole analog derivative, institute Stating chiral tetrahydro carbazole analog derivative has structure shown in structural formula I：
Wherein, Ar is aryl, R1For sulfonyl, acyl group or alkoxy acyl, R2For H, halogen atom or alkyl, R3For alkane Base.
As preferable technical scheme, the Ar is selected from phenyl, p-methylphenyl, p-methoxyphenyl, Chloro-O-Phenyl, right One kind in chlorphenyl, m-bromophenyl, p-bromophenyl, p-nitrophenyl, 2- thienyls, 2- furyls, 1- naphthyls；The R1Choosing One kind from p-toluenesulfonyl, benzenesulfonyl, methoxycarbonyl group, carbethoxyl group, benzyloxycarbonyl group, tertbutyloxycarbonyl, acetyl group； The R2Selected from hydrogen or 5- methyl；The R3Selected from methyl or ethyl or the tert-butyl group.
Present invention firstly discloses a kind of new chiral tetrahydrocarbazole compound, the compound has three continuous hands Property center and easy functionalizing group, be easy to other Chiral polycyclic compounds of derivative synthesis, can be research and development and the medicine of new drug Screening provides more candidate molecules.
The second object of the present invention, it is to provide a kind of preparation method of above-mentioned chiral tetrahydro carbazole analog derivative, adopts Technical scheme is 3- nitroindolines II, Nazarov reagents III and chiral catalyst A to be dissolved in reaction dissolvent, -10 Stirred at DEG C -25 DEG C, after reacting 48-96h, reaction finishes, and adds chloroacetic chloride and alkali, after question response, isolates and purifies to obtain Product I.
In above-mentioned reaction equation, " Cat A " are " in chiral catalyst A ", chiral catalyst A of the invention such as above-mentioned reaction equation Structural formula, be chiral thiourea catalyst；" solvent " i.e. " reaction dissolvent ", " Base " i.e. " alkali "；
As preferable technical scheme, the mol ratio of 3- nitroindolines II and Nazarov reagents III is 1:1-1:4.
As preferable technical scheme, described reaction dissolvent is selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrochysene Furans, ether, acetonitrile, ethanol, methanol, 1,4- dioxane, chlorobenzene.
As preferable technical scheme, described reaction dissolvent is chloroform, using chloroform as reaction dissolvent yield more It is high.
As preferable technical scheme, the chiral catalyst A and 3- nitroindolines II mol ratio is 1:5-1:20.
As preferable technical scheme, per the compound shown in 0.1mmol structural formulas II, consumption of organic solvent 0.1- 4mL。
As preferable technical scheme, the alkali be selected from triethylamine, diisopropyl ethyl amine, potassium carbonate, sodium phosphate, carbon Sour caesium.
As further preferred technical scheme, the alkali is triethylamine, and more preferable using triethylamine react effect, yield is more It is high.
Compared with prior art, the advantage of the invention is that：Present invention firstly discloses a kind of new Tetrahydrocarbazolesand Compound, more rich candidate molecules are provided for clinical new medicament screen, novel, simple and direct, operation that preparation method of the invention has Simply, the advantages that reaction condition is gentle, high income, high stereoselectivity.
Brief description of the drawings
Fig. 1 is the hydrogen spectrogram of I-a made from embodiment 1；
Fig. 2 is the carbon spectrogram of I-a made from embodiment 1；
Fig. 3 is the high resolution mass spectrum figure of I-a made from embodiment 1；
Fig. 4 is the mono-crystalline structures figure of I-a made from embodiment 1.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment one：Synthesize compound (I-a)
The nitroindoline (II) (31.6mg, 0.1mmol) of 1- p-toluenesulfonyls -3 is added in a horminess glass tube, (4E) -3- carbonyl -5- phenyl -4- pentenoic acid ethyl esters (III) (48.2mg, 0.2mmol), chiral catalyst A (14mg, 0.02mmol), -10 DEG C are cooled to, then adds 0.5ml chloroforms, mixture stirs 72h at -10 DEG C, then adds triethylamine (0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continue that 20min is stirred at room temperature.Reaction is complete Afterwards, evaporated under reduced pressure solvent obtains crude product.Crude product through column chromatography separating purification obtain compound I-a (white solid, yield 95%,> 20:1dr, 95%ee), in structure above I-a, Ts is p-toluenesulfonyl.
Gained compound I-a optically-active, fusing point, hydrogen is composed, carbon is composed and mass spectrometric data is as follows：
[α]D 20=-7.5 (c 3.25, CH2Cl2)；m.p.189.7-191.3℃；HPLC(AD-H,ethanol/n- Hexane=25/75, flow rate=1.0mL/min, λ=254nm) tR=9.8min (minor), 14.0min (major)；1H NMR(300MHz,DMSO-d6) δ 1.32 (t, J=7.1Hz, 3H), 2.02 (s, 3H), 2.29 (s, 3H), 2.38 (d, J= 17.9Hz, 1H), 2.72 (dd, J=17.9,5.7Hz, 1H), 4.27 (q, J=7.1Hz, 2H), 4.66 (d, J=5.4Hz, 1H), 6.35 (s, 1H), 7.26-7.41 (m, 8H), 7.55-7.62 (m, 4H), 8.01 (d, J=7.8Hz, 1H)；13C NMR(75MHz, DMSO-d6)δ14.0,20.3,21.0,32.6,44.8,61.4,63.3,96.9,117.3,119.2,125.8,126.6, 127.1,127.5,127.7,128.2,128.8,129.9,133.1,134.2,137.8,140.6,144.9,151.0, 163.7,167.5；HRMS(ESI)calcd.for C30H28N2NaO8S[M+Na]+599.1459,found:599.1459.
Embodiment two：Synthesize compound (I-b)
The nitroindoline (II) (22.0mg, 0.1mmol) of addition 1- methoxycarbonyl groups -3 in a horminess glass tube, (4E) - 3- carbonyl -5- phenyl -4- pentenoic acid ethyl esters (III) (48.2mg, 0.2mmol), catalyst A (14mg, 0.01mmol), are cooled to 0 DEG C, 0.5ml toluene is then added, mixture stirs 72h at 0 DEG C.Then potassium carbonate (0.2mmol, 27.6mg), acetyl are added Chlorine (0.2mmol, 15.7mg) reactant mixture continues that 20min is stirred at room temperature.After reaction completely, evaporated under reduced pressure solvent, which obtains, slightly to be produced Product.Crude product through column chromatography separating purification obtain compound I-b (white solid, yield 90%,>20:1dr, 94%ee).
Gained compound I-b optically-active, fusing point, hydrogen is composed, carbon is composed and mass spectrometric data is as follows：
[α]D 20=+29.2 (c 2.28, CH2Cl2)；m.p.115.2-116.3℃；HPLC(AD-H,ethanol/n- Hexane=20/80, flow rate=1.0mL/min, λ=254nm) tR=11.0min (minor), 23.4min (major)；1H NMR(300MHz,DMSO-d6) δ 1.25 (t, J=7.1Hz, 3H), 2.00 (s, 3H), 2.44-2.50 (m, 1H), 2.83-2.92 (m, 1H), 3.77 (s, 3H), 4.18-4.28 (m, 2H), 4.87 (d, J=5.3Hz, 1H), 6.32 (d, J= 1.1Hz, 1H), 7.29-7.44 (m, 6H), 7.54-7.59 (m, 1H), 7.72 (d, J=7.9Hz, 1H), 8.08 (d, J= 7.4Hz,1H)；13C NMR(75MHz,DMSO-d6)δ14.0,20.2,32.4,42.5,53.4,60.7,61.4,96.6, 116.9,118.2,124.5,125.6,126.4,127.9,128.2,129.0,132.8,138.1,140.8,150.1, 152.1,164.1,167.5；HRMS(ESI)calcd.for C25H24N2NaO8[M+Na]+503.1425,found: 503.1428。
Embodiment three：Synthesize compound (I-c)
The nitroindoline (II) (23.4mg, 0.1mmol) of addition 1- carbethoxyl groups -3 in a horminess glass tube, (4E) - 3- carbonyl -5- phenyl -4- pentenoic acid ethyl esters (III) (48.2mg, 0.2mmol), catalyst A (14mg, 0.005mmol), Ran Houjia Enter 0.5ml chloroforms, mixture stirs 72h at 25 DEG C.Then triethylamine (0.2mmol, 20mg), chloroacetic chloride are added (0.2mmol, 15.7mg) reactant mixture continues that 20min is stirred at room temperature.After reaction completely, evaporated under reduced pressure solvent, which obtains, slightly to be produced Product.Crude product through column chromatography separating purification obtain compound I-c (white solid, yield 95%,>20:1dr, 92%ee).
Gained compound I-c optically-active, fusing point, hydrogen is composed, carbon is composed and mass spectrometric data is as follows：
[α]D 20=+22.3 (c 2.27, CH2Cl2)；m.p.163.5-165.0℃；HPLC(AD-H,ethanol/n- Hexane=20/80, flow rate=1.0mL/min, λ=254nm) tR=10.3min (minor), 22.6min (major)；1H NMR(300MHz,DMSO-d6)δ1.21-1.29(m,6H)2.00(s,3H),2.44-2.50(m,1H),2.88 (dd, J=18.3, J=6.2Hz, 1H), 4.10-4.33 (m, 4H), 4.87 (d, J=5.5Hz, 1H), 6.33 (s, 1H), 7.28- 7.43 (m, 6H), 7.54-7.59 (m, 1H), 7.69 (d, J=8.0Hz, 1H), 8.07 (d, J=7.6Hz, 1H)；13C NMR (75MHz,DMSO-d6)δ14.0,14.1,20.2,32.3,42.4,60.6,61.3,62.5,96.5,117.1,118.2, 124.4,125.5,126.5,127.9,128.2,129.0,132.7,138.1,140.8,150.0,151.7,164.1, 167.5；HRMS(ESI)calcd.for C26H26N2NaO8[M+Na]+517.1581,found:517.1579.
Example IV：Synthesize compound (I-d)
The nitroindoline (II) (26.2mg, 0.1mmol) of 1- tertbutyloxycarbonyls -3 is added in a horminess glass tube, (4E) -3- carbonyl -5- phenyl -4- pentenoic acid ethyl esters (III) (48.2mg, 0.1mmol), catalyst A (14mg, 0.02mmol), drop Then temperature adds 0.5ml tetrahydrofurans to -10 DEG C, mixture stirs 72h at -10 DEG C.Then diisopropyl ethyl amine is added (0.2mmol, 25.8mg), chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continue that 20min is stirred at room temperature.Reaction is complete Afterwards, evaporated under reduced pressure solvent obtains crude product.Crude product through column chromatography separating purification obtain compound I-d (white solid, yield 88%,> 20:1dr, 98%ee).In structure above I-d, Boc is tertbutyloxycarbonyl；
Gained compound I-d optically-active, fusing point, hydrogen is composed, carbon is composed and mass spectrometric data is as follows：
[α]D 20=+13.6 (c 2.29, CH2Cl2)；m.p.122.8-125.3℃；HPLC(OD-H,ethanol/n- Hexane=5/95, flow rate=1.0mL/min, λ=254nm) tR=6.9min (minor), 8.3min (major)；1H NMR(300MHz,DMSO-d6) δ 1.24 (t, J=7.1Hz, 3H) 1.49 (s, 9H), 2.00 (s, 3H), 2.44 (d, J= 18.2Hz, 1H), 2.88 (dd, J=17.7,5.5Hz, 1H), 4.11-4.31 (m, 2H), 4.84 (d, J=5.7Hz, 1H), 6.28 (s, 1H), 7.26-7.44 (m, 6H), 7.51-7.60 (m, 2H), 8.05 (d, J=7.7Hz, 1H)；13C NMR(75MHz,DMSO- d6)δ14.0,20.2,27.7,32.3,42.3,60.5,61.3,82.4,96.3,117.4,118.5,124.2,125.4, 126.7,127.9,128.2,129.0,132.7,138.2,140.9,149.4,150.7,164.2,167.5；HRMS(ESI) calcd.for C28H30N2NaO8[M+Na]+545.1894,found:545.1891.
Embodiment five：Synthesize compound (I-e)
The nitroindoline (II) (29.6mg, 0.1mmol) of addition 1- benzyloxycarbonyl groups -3 in a horminess glass tube, (4E) - 3- carbonyl -5- phenyl -4- pentenoic acid ethyl esters (III) (48.2mg, 0.4mmol), catalyst A (14mg, 0.01mmol), be cooled to - 10 DEG C, 0.5ml acetonitriles are then added, mixture stirs 72h at -10 DEG C.Then sodium carbonate (0.2mmol, 21.2mg) is added, Chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continues that 20min is stirred at room temperature.After reaction completely, evaporated under reduced pressure solvent obtains Crude product.Crude product through column chromatography separating purification obtain compound I-e (white solid, yield 86%,>20:1dr, 97%ee).On State in structural formula I-e, Cbz is benzyloxycarbonyl group；
Gained compound I-e optically-active, fusing point, hydrogen is composed, carbon is composed and mass spectrometric data is as follows：
[α]D 20=-8.1 (c 2.4, CH2Cl2)；m.p.125.9-127.4℃；HPLC(AD-H,ethanol/n-hexane =20/80, flow rate=1.0mL/min, λ=254nm) tR=15.9min (minor), 29.2min (major)；1H NMR (300MHz,CDCl3) δ 1.25 (t, J=7.0Hz, 3H), 2.04 (s, 3H), 2.43-2.50 (m, 1H), 2.98-3.07 (m, 1H), 4.06-4.15 (m, 2H), 4.48 (d, J=5.0Hz, 1H), 5.20 (d, J=12.4Hz, 1H), 5.36 (d, J= 12.3Hz, 1H), 6.61 (d, J=1.0Hz, 1H), 7.17-7.23 (m, 1H), 7.31-7.46 (m, 11H), 7.72 (d, J= 7.3Hz,2H),；13C NMR(75MHz,CDCl3)δ14.0,20.4,32.9,44.1,61.1,61.4,68.1,96.1,118.2, 119.0,124.3,124.3,126.7,128.0,128.1,128.3,128.4,128.5,129.1,132.4,135.5, 137.2,141.6,150.6,152.3,164.2,167.5；HRMS(ESI)calcd.for C31H28N2NaO8[M+Na]+ 579.1738,found:579.1735.
Embodiment six：Synthesize compound (I-f)
The nitroindoline (II) (20.4mg, 0.1mmol) of 1- acetyl group -3, (4E) -3- are added in a horminess glass tube Carbonyl -5- phenyl -4- pentenoic acid ethyl esters (III) (48.2mg, 0.2mmol), catalyst A (14mg, 0.02mmol), are cooled to -10 DEG C, 0.5ml mesitylene is then added, mixture stirs 72h at -10 DEG C.Then cesium carbonate (0.2mmol, 65mg) is added, Chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continues that 20min is stirred at room temperature.After reaction completely, evaporated under reduced pressure solvent obtains Crude product.Crude product through column chromatography separating purification obtain compound I-f (yellow oil, yield 90%,>20:1dr, 95%ee). In structure above I-f, Cbz is acetyl group；
Gained compound I-f optically-active, fusing point, hydrogen is composed, carbon is composed and mass spectrometric data is as follows：
[α]D 20=-68.6 (c 2.26, CH2Cl2)；HPLC (AD-H, ethanol/n-hexane=20/80, flow Rate=1.0mL/min, λ=254nm) tR=20.4min (minor), 27.6min (major)；1H NMR(300MHz,DMSO- d6) δ 1.22 (t, J=7.1Hz, 3H), 2.02 (s, 3H), 2.35 (s, 3H), 2.49-2.61 (m, 1H), 2.93 (d, J= 18.9Hz, 1H), 4.19 (q, J=6.9Hz, 2H), 4.82 (d, J=6.3Hz, 1H), 6.32 (s, 1H), 7.29-7.47 (m, 6H), 7.49-7.87 (m, 2H), 8.11 (d, J=7.7Hz, 1H)；13C NMR(75MHz,DMSO-d6)δ13.9,20.3,22.8, 32.3,41.2,54.9,61.4,96.3,118.0,119.8,125.1,125.6,127.9,128.3,129.0,129.2, 131.9,132.4,138.0,141.2,164.0,167.5,168.5；HRMS(ESI)calcd.for C25H24N2NaO7[M+Na ]+487.1476,found:487.1464.
Embodiment seven：Synthesize compound (I-g)
The nitroindoline (II) (31.6mg, 0.1mmol) of 1- p-toluenesulfonyls -3 is added in a horminess glass tube, (4E) -3- carbonyl -5- phenyl -4- amylenes tert-butyl acrylates (III) (49.2mg, 0.2mmol), catalyst A (14mg, 0.02mmol), - 10 DEG C are cooled to, then adds 0.5ml dichloromethane, mixture stirs 96h at -10 DEG C.Then triethylamine is added (0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continue that 20min is stirred at room temperature.Reaction is complete Afterwards, evaporated under reduced pressure solvent obtains crude product.Crude product through column chromatography separating purification obtain compound I-g (white solid, yield 65%,> 20:1dr,>99%ee).
Gained compound I-g optically-active, fusing point, hydrogen is composed, carbon is composed and mass spectrometric data is as follows：
[α]D 20=-58.3 (c 1.6, CH2Cl2)；m.p.91.7-93.3℃；HPLC(OD-H,ethanol/n-hexane =20/80, flow rate=1.0mL/min, λ=254nm) tR=4.6min (minor), 5.0min (major)；1H NMR (300MHz,DMSO-d6) δ 1.42 (s, 9H), 2.03 (s, 3H), 2.34 (s, 3H), 2.40-2.51 (m, 1H), 2.87 (d, J= 16.4Hz, 1H), 4.79 (d, J=6.4Hz, 1H), 6.37 (s, 1H), 7.25-7.49 (m, 6H), 7.49-7.89 (m, 2H), (8.10 d, J=7.7Hz, 1H)；13C NMR(75MHz,DMSO-d6)δ20.2,22.8,27.5,31.7,41.5,60.7,82.3, 95.9,119.3,124.9,125.5,127.9,128.2,128.9,132.3,138.0,141.2,163.3,167.2,167.9； HRMS(ESI)calcd.for C27H28N2NaO7[M+H]+515.1789,found:515.1787.
Embodiment eight：Synthesize compound (I-h)
The nitroindoline (II) (20.4mg, 0.1mmol) of 1- acetyl group -3, (4E) -3- are added in a horminess glass tube Carbonyl -5- (4- aminomethyl phenyls) -4- amylenes tert-butyl acrylate (III) (46.5mg, 0.2mmol), catalyst A (14mg, 0.02mmol), -10 DEG C are cooled to, then adds 0.5ml ether, mixture stirs 96h at -10 DEG C.Then triethylamine is added (0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continue that 20min is stirred at room temperature.Reaction is complete Afterwards, evaporated under reduced pressure solvent obtains crude product.Crude product obtains compound I-g (yellow oil, yield through column chromatography separating purification 87%,>20:1dr,>99%ee).
Gained compound I-h optically-active, hydrogen are composed, carbon spectrum and mass spectrometric data are as follows：
[α]D 20=-72.4 (c 2.2, CH2Cl2)；HPLC (AD-H, ethanol/n-hexane=20/80, flow rate =1.0mL/min, λ=254nm) tR=28.0min (minor), 31.0min (major)；1H NMR(300MHz,DMSO-d6)δ 1.21 (t, J=7.1Hz, 3H), 2.02 (s, 3H), 2.28 (s, 3H), 2.34 (s, 3H), 2.39-2.50 (m, 1H), 2.90 (d, J =17.1Hz, 1H), 4.18 (q, J=6.9Hz, 2H), 4.76 (d, J=6.3Hz, 1H), 6.25 (s, 1H), 7.18 (d, J= 8.0Hz, 2H), 7.27-7.40 (m, 3H), 7.48-7.79 (m, 2H), 8.08 (d, J=7.7Hz, 1H)；13C NMR(75MHz, DMSO-d6)δ13.9,20.3,20.6,22.8,32.4,54.9,61.4,79.2,96.1,117.9,119.7,125.1, 125.6,127.7,127.9,129.6,132.3,134.9,137.7,141.23,164.0,167.4,168.5；HRMS(ESI) calcd.for C26H26N2NaO7[M+Na]+501.1632,found:501.1633.
Embodiment nine：Synthesize compound (I-i)
The nitroindoline (II) (20.4mg, 0.1mmol) of 1- acetyl group -3, (4E) -3- are added in a horminess glass tube Carbonyl -5- (4- chlorphenyls) -4- amylenes tert-butyl acrylate (III) (50.5mg, 0.2mmol), catalyst A (14mg, 0.02mmol), - 10 DEG C are cooled to, then adds 0.5ml ethanol, mixture stirs 96h at -10 DEG C.Then add triethylamine (0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continues that 20min is stirred at room temperature.After reaction completely, evaporated under reduced pressure Solvent obtains crude product.Crude product through column chromatography separating purification obtain compound I-g (yellow oil, yield 86%,>20:1dr, 90%ee).
Gained compound I-i optically-active, hydrogen are composed, carbon spectrum and mass spectrometric data are as follows：
[α]D 20=-56.1 (c 2.3, CH2Cl2)；HPLC (OD-H, i-propanol/n-hexane=20/80, flow Rate=1.0mL/min, λ=254nm) tR=7.6min (major), 8.5min (minor)；1H NMR(300MHz,DMSO- d6) δ 1.21 (t, J=7.1Hz, 3H), 2.02 (s, 3H), 2.35 (s, 3H), 2.50-2.59 (m, 1H), 2.88 (d, J= 17.8Hz, 1H), 4.18 (q, J=6.9Hz, 2H), 4.88 (d, J=6.2Hz, 1H), 6.34 (s, 1H), 7.31-7.40 (m, 1H), 7.41-7.76 (m, 6H), 8.09 (d, J=7.7Hz, 1H)；13C NMR(75MHz,DMSO-d6)δ13.9,20.3,22.9, 32.0,61.4,96.1,118.1,125.1,125.6,127.7,129.0,129.8,132.4,133.1,136.9,141.1, 163.9,167.5,168.5；HRMS(ESI)calcd.for C25H23ClN2NaO7[M+Na]+521.1086,found: 521.1092。
Embodiment ten：
The nitroindoline (II) (21.8mg, 0.1mmol) of 1- acetyl group -5- methyl -3 is added in a horminess glass tube, (4E) -3- carbonyls -5- (4- phenyl) -4- pentenoic acid ethyl esters (III) (43.2mg, 0.2mmol), catalyst A (14mg, 0.02mmol), -10 DEG C are cooled to, then adds 0.5ml chlorobenzenes, mixture stirs 96h at -10 DEG C.Then triethylamine is added (0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continue that 20min is stirred at room temperature.Reaction is complete Afterwards, evaporated under reduced pressure chloroform obtains crude product.Crude product obtains compound I-j (yellow oil, yield through column chromatography separating purification 85%,>20:1dr, 93%ee).
Gained compound I-j optically-active, hydrogen are composed, carbon spectrum and mass spectrometric data are as follows：
[α]D 20=-64.4 (c 2.3, CH2Cl2)；m.p.171.1-173.2℃；HPLC(AD-H,ethanol/n- Hexane=20/80, flow rate=1.0mL/min, λ=254nm) tR=9.8min (minor), 17.8min (major)；1H NMR(300MHz,DMSO-d6) δ 1.21 (t, J=7.0Hz, 3H), 2.02 (s, 3H), 2.32 (s, 3H), 2.41 (s, 3H), 2.49-2.60 (m, 1H), 2.75-3.12 (m, 1H), 4.04-4.31 (m, 2H), 4.79 (d, J=6.4Hz, 1H), 6.31 (s, 1H),7.24-7.71(m,7H),7.93(s,1H)；13C NMR(75MHz,DMSO-d6)δ13.9,20.3,20.6,22.8, 32.3,41.6,55.7,61.3,96.2,118.0,125.6,127.8,128.3,129.0,132.7,134.6,138.1, 139.0,164.0,167.4,168.3；HRMS(ESI)calcd.for C26H26N2NaO7[M+Na]+501.1632,found: 501.1636.
Embodiment 11：
Bromo- 3 nitroindolines (II) (28.1mg, 0.1mmol) of 1- acetyl group -7- are added in a horminess glass tube, (4E) -3- carbonyls -5- (4- phenyl) -4- pentenoic acid ethyl esters (III) (43.2mg, 0.2mmol), catalyst A (14mg, 0.02mmol), -10 DEG C are cooled to, then adds 0.5ml1,4- dioxane, mixture stirs 96h at -10 DEG C.Then plus Enter triethylamine (0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reactant mixture continues that 20min is stirred at room temperature.Instead After answering completely, evaporated under reduced pressure solvent obtains crude product.Crude product obtains compound I-k through column chromatography separating purification and (yellow oil, received Rate 81%,>20:1dr, 90%ee).
Gained compound I-k optically-active, hydrogen are composed, carbon spectrum and mass spectrometric data are as follows：
[α]D 20=-62.4 (c 2.5, CH2Cl2)；m.p.61.5-62.8℃；HPLC(OD-H,i-propanol/n- Hexane=20/80, flow rate=1.0mL/min, λ=254nm) tR=7.6min (major), 8.3min (minor)；1H NMR(300MHz,DMSO-d6) δ 1.22 (t, J=7.1Hz, 3H), 2.05 (s, 3H), 2.36 (s, 3H), 2.47-2.62 (m, 1H), 2.94 (dd, J=19.9,5.9Hz, 1H), 4.20 (q, J=7.0Hz, 2H), 4.81 (d, J=6.4Hz, 1H), 6.28 (s, 1H), 7.24-7.48 (m, 5H), 7.59 (dd, J=8.2,1.7Hz, 1H), 7.88 (s, 1H), 8.09 (d, J=8.3Hz, 1H)；13C NMR(75MHz,DMSO-d6)δ13.9,20.4,22.7,32.2,61.5,95.9,117.6,121.6,125.3,127.3, 127.5,127.8,128.0,128.4,129.1,137.7,142.5,163.9,167.4,168.7；HRMS(ESI) calcd.for C25H23BrN2NaO7[M+Na]+565.0581,found:565.0585.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention All any modification, equivalent and improvement made within refreshing and principle etc., should be included in the scope of the protection.

Claims (10)

1. chiral tetrahydro carbazole analog derivative, it is characterised in that the chiral tetrahydro carbazole analog derivative has shown in structural formula I Structure：
Wherein, Ar is aryl, R1For sulfonyl, acyl group or alkoxy acyl, R2For H, halogen atom or alkyl, R3For alkyl.
2. chiral tetrahydro carbazole analog derivative according to claim 1, it is characterised in that the Ar is selected from phenyl, to first Base phenyl, p-methoxyphenyl, Chloro-O-Phenyl, rubigan, m-bromophenyl, p-bromophenyl, p-nitrophenyl, 2- thienyls, One kind in 2- furyls, 1- naphthyls；The R1Selected from p-toluenesulfonyl, benzenesulfonyl, methoxycarbonyl group, carbethoxyl group, benzyl One kind in oxygen carbonyl, tertbutyloxycarbonyl, acetyl group；The R2Selected from hydrogen or 5- methyl or 7- bromines；The R3Selected from methyl or second Base or the tert-butyl group.
3. the preparation method of the chiral tetrahydro carbazole analog derivative described in any one of claim 1 or 2, it is characterised in that will 3- nitroindolines II, Nazarov reagents III and chiral catalyst A are dissolved in reaction dissolvent, are stirred at -10 DEG C -25 DEG C, reaction After 48-96 h, reaction finishes, addition chloroacetic chloride and alkali, after question response, isolates and purifies to obtain product I.
4. preparation method according to claim 3, it is characterised in that 3- nitroindolines II and Nazarov reagents III rub You are than being 1:1-1:4.
5. preparation method according to claim 3, it is characterised in that described reaction dissolvent be selected from toluene, mesitylene, Dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4- dioxane, chlorobenzene.
6. preparation method according to claim 5, it is characterised in that described reaction dissolvent is chloroform.
7. according to the preparation method described in right 3, it is characterised in that the catalyst amount A and 3- nitroindolines II mole Than for 1:5-1:20.
8. according to the preparation method described in right 3, it is characterised in that the compound shown in every 0.1 mmol structural formulas II, it is organic Solvent load is 0.1-4 mL.
9. according to the preparation method described in right 3, it is characterised in that the alkali is selected from triethylamine, diisopropyl ethyl amine, carbonic acid Potassium, sodium phosphate, cesium carbonate.
10. according to the preparation method described in right 9, it is characterised in that the alkali is triethylamine.
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CN111606924A (en) * 2020-06-03 2020-09-01 成都大学 Chiral thiopyranoindolophenylthiolsulfone derivatives and preparation method thereof
CN112194548A (en) * 2020-10-12 2021-01-08 成都大学 Alpha-amino-gamma-butyrolactone compound and preparation method thereof
CN114292277A (en) * 2022-01-12 2022-04-08 成都大学 Indoline tetrahydropyrane compound and preparation method thereof

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JIAN-QIANG ZHAO ET AL.: "Asymmetric Michael/Cyclization Cascade Reaction of 3-Isothiocyanato Oxindoles and 3-Nitroindoles with Amino-Thiocarbamate Catalysts: Enantioselective Synthesis of Polycyclic Spirooxindoles", 《ORGANIC LETTERS》 *
JIAN-QIANG ZHAO ET AL.: "Zn-Catalyzed Diastereo- and Enantioselective Cascade Reaction of 3-Isothiocyanato Oxindoles and 3-Nitroindoles: Stereocontrolled Syntheses of Polycyclic Spirooxindoles", 《ORGANIC LETTERS》 *
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CN111606924A (en) * 2020-06-03 2020-09-01 成都大学 Chiral thiopyranoindolophenylthiolsulfone derivatives and preparation method thereof
CN111548298A (en) * 2020-06-18 2020-08-18 成都大学 Chiral trifluoromethyl substituted maleimide derivative and preparation method thereof
CN111548298B (en) * 2020-06-18 2023-03-21 成都大学 Chiral trifluoromethyl substituted maleimide derivative and preparation method thereof
CN112194548A (en) * 2020-10-12 2021-01-08 成都大学 Alpha-amino-gamma-butyrolactone compound and preparation method thereof
CN112194548B (en) * 2020-10-12 2023-01-13 成都大学 Alpha-amino-gamma-butyrolactone compound and preparation method thereof
CN114292277A (en) * 2022-01-12 2022-04-08 成都大学 Indoline tetrahydropyrane compound and preparation method thereof

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