CN107382823B - Chiral tetrahydro carbazole analog derivative and preparation method thereof - Google Patents
Chiral tetrahydro carbazole analog derivative and preparation method thereof Download PDFInfo
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- 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
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Abstract
The invention discloses chiral tetrahydro carbazole analog derivatives and preparation method thereof, belong to technical field of organic synthesis, it is with structure shown in structural formula I, preparation method is that 3- nitroindoline II, Nazarov reagent III and chiral catalyst A are dissolved in reaction dissolvent, is stirred at -10 DEG C -25 DEG C, after reacting 48-96 h, end of reaction, chloroacetic chloride and alkali is added, obtains product I to after completion of the reaction, isolate and purify；Present invention firstly discloses a new class of tetrahydrocarbazole compounds, provide richer candidate molecules for clinical new medicament screen, and preparation method of the invention has many advantages, such as that novel, simple and direct, easy to operate, reaction condition is mild, high income, stereoselectivity are high.
Description
Technical field
The present invention relates to organic synthesis fields, more particularly to chiral tetrahydro carbazole analog derivative and preparation method thereof.
Background technique
Carbazole is the core skeleton for constituting many natural products and drug, 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 alkaloid and compound with pharmaceutical activity, as follows, compound (-)-
Aspidospermine is that the late 19th century is isolated from aspidospermine, have antibacterial, diuresis, promote vessel retraction and
Respiratory stimulant isoreactivity；Vindoline and Minovincine has anticancer activity.Therefore, develop effective method to close
At 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 type that this kind of compound can also be greatly enriched simultaneously, provides more candidate molecules for new medicament screen.
Currently, reported chirality tetrahydro carbazole 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.
Summary of the invention
An object of the present invention, in that a new class of chiral tetrahydro carbazole analog derivative is provided, to solve above-mentioned ask
Topic.
To achieve the goals above, the technical solution adopted by the present invention is that such: chiral tetrahydro carbazole analog derivative, institute
Chiral tetrahydro carbazole analog derivative is stated with 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.
The Ar is selected from phenyl, p-methylphenyl, p-methoxyphenyl, Chloro-O-Phenyl, right as a preferred technical solution,
One of chlorphenyl, m-bromophenyl, p-bromophenyl, p-nitrophenyl, 2- thienyl, 2- furyl, 1- naphthalene；The R1Choosing
From one of 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 tert-butyl.
Present invention firstly discloses a new class of chiral tetrahydrocarbazole compounds, and there are three continuous hands for compound tool
Property center and easy functionalizing group, be convenient for other Chiral polycyclic compounds of derivative synthesis, can research and development for new drug and drug
Screening provides more candidate molecules.
The second object of the present invention is to provide a kind of preparation methods of above-mentioned chiral tetrahydro carbazole analog derivative, adopt
Technical solution is 3- nitroindoline II, Nazarov reagent III and chiral catalyst A to be dissolved in reaction dissolvent, -10
It is stirred at DEG C -25 DEG C, after reacting 48-96h, end of reaction is added chloroacetic chloride and alkali, obtains to after completion of the reaction, isolate and purify
Product I.
In above-mentioned reaction equation, " Cat A " i.e. " chiral catalyst A ", in chiral catalyst A such as above-mentioned reaction equation of the invention
Structural formula, be chiral thiourea catalyst；" solvent " i.e. " reaction dissolvent ", " Base " i.e. " alkali "；
The molar ratio of 3- nitroindoline II and Nazarov reagent III is 1:1-1:4 as a preferred technical solution,.
The reaction dissolvent is selected from toluene, mesitylene, methylene chloride, chloroform, tetrahydro as a preferred technical solution,
Furans, ether, acetonitrile, ethyl alcohol, methanol, 1,4- dioxane, chlorobenzene.
The reaction dissolvent is chloroform as a preferred technical solution, using chloroform as reaction dissolvent yield more
It is high.
The molar ratio of the chiral catalyst A and 3- nitroindoline II is 1:5-1:20 as a preferred technical solution,.
Every II compound represented of 0.1mmol structural formula as a preferred technical solution, consumption of organic solvent 0.1-
4mL。
As a preferred technical solution, the alkali be selected from triethylamine, diisopropyl ethyl amine, potassium carbonate, sodium phosphate, carbon
Sour caesium.
As further preferred technical solution, the alkali is triethylamine, and more preferable using triethylamine reaction effect, yield is more
It is high.
Compared with the prior art, the advantages of the present invention are as follows: present invention firstly discloses a new class of Tetrahydrocarbazolesands
Object is closed, provides richer candidate molecules for clinic new medicament screen, novel, simple and direct, operation that preparation method of the invention has
Simply, the advantages that reaction condition is mild, high income, high stereoselectivity.
Detailed description of the invention
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.
Specific embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment one: synthesis compound (I-a)
- 3 nitroindoline of 1- p-toluenesulfonyl (II) (31.6mg, 0.1mmol) is added in a horminess glass tube,
(4E) -3- carbonyl -5- phenyl -4- pentenoic acid ethyl ester (III) (48.2mg, 0.2mmol), chiral catalyst A (14mg,
0.02mmol), -10 DEG C are cooled to, 0.5ml chloroform is then added, mixture stirs 72h at -10 DEG C, triethylamine is then added
(0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reaction mixture continue that 20min is stirred at room temperature.Fully reacting
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.
The optically-active of gained compound I-a, fusing point, hydrogen spectrum, 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: synthesis compound (I-b)
- 3 nitroindoline of 1- methoxycarbonyl group (II) (22.0mg, 0.1mmol) is added in a horminess glass tube, (4E)-
3- carbonyl -5- phenyl -4- pentenoic acid ethyl ester (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) is added, acetyl
Chlorine (0.2mmol, 15.7mg) reaction mixture continues that 20min is stirred at room temperature.After fully reacting, evaporated under reduced pressure solvent, which obtains, slightly to be produced
Product.Crude product obtains compound I-b (white solid, yield 90%, > 20:1dr, 94%ee) through column chromatography separating purification.
The optically-active of gained compound I-b, fusing point, hydrogen spectrum, 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: synthesis compound (I-c)
- 3 nitroindoline of 1- carbethoxyl group (II) (23.4mg, 0.1mmol) is added in a horminess glass tube, (4E)-
3- carbonyl -5- phenyl -4- pentenoic acid ethyl ester (III) (48.2mg, 0.2mmol), catalyst A (14mg, 0.005mmol), then plus
Enter 0.5ml chloroform, mixture stirs 72h at 25 DEG C.Then triethylamine (0.2mmol, 20mg) is added, chloroacetic chloride
(0.2mmol, 15.7mg) reaction mixture continues that 20min is stirred at room temperature.After fully reacting, evaporated under reduced pressure solvent, which obtains, slightly to be produced
Product.Crude product obtains compound I-c (white solid, yield 95%, > 20:1dr, 92%ee) through column chromatography separating purification.
The optically-active of gained compound I-c, fusing point, hydrogen spectrum, 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: synthesis compound (I-d)
- 3 nitroindoline of 1- tertbutyloxycarbonyl (II) (26.2mg, 0.1mmol) is added in a horminess glass tube,
(4E) -3- carbonyl -5- phenyl -4- pentenoic acid ethyl ester (III) (48.2mg, 0.1mmol), catalyst A (14mg, 0.02mmol), drop
Then 0.5ml tetrahydrofuran is added to -10 DEG C in temperature, mixture stirs 72h at -10 DEG C.Then diisopropyl ethyl amine is added
(0.2mmol, 25.8mg), chloroacetic chloride (0.2mmol, 15.7mg) reaction mixture continue that 20min is stirred at room temperature.Fully reacting
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；
The optically-active of gained compound I-d, fusing point, hydrogen spectrum, 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: synthesis compound (I-e)
- 3 nitroindoline of 1- benzyloxycarbonyl group (II) (29.6mg, 0.1mmol) is added in a horminess glass tube, (4E)-
3- carbonyl -5- phenyl -4- pentenoic acid ethyl ester (III) (48.2mg, 0.4mmol), catalyst A (14mg, 0.01mmol), be cooled to -
10 DEG C, 0.5ml acetonitrile is then added, mixture stirs 72h at -10 DEG C.Then sodium carbonate (0.2mmol, 21.2mg) is added,
Chloroacetic chloride (0.2mmol, 15.7mg) reaction mixture continues that 20min is stirred at room temperature.After fully reacting, evaporated under reduced pressure solvent is obtained
Crude product.Crude product obtains compound I-e (white solid, yield 86%, > 20:1dr, 97%ee) through column chromatography separating purification.On
It states in structural formula I-e, Cbz is benzyloxycarbonyl group；
The optically-active of gained compound I-e, fusing point, hydrogen spectrum, 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: synthesis compound (I-f)
- 3 nitroindoline of 1- acetyl group (II) (20.4mg, 0.1mmol) is added in a horminess glass tube, (4E) -3-
Carbonyl -5- phenyl -4- pentenoic acid ethyl ester (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) reaction mixture continues that 20min is stirred at room temperature.After fully reacting, evaporated under reduced pressure solvent is obtained
Crude product.Crude product obtains compound I-f (yellow oil, yield 90%, > 20:1dr, 95%ee) through column chromatography separating purification.
In structure above I-f, Cbz is acetyl group；
The optically-active of gained compound I-f, fusing point, hydrogen spectrum, 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: synthesis compound (I-g)
- 3 nitroindoline of 1- p-toluenesulfonyl (II) (31.6mg, 0.1mmol) is added in a horminess glass tube,
(4E) -3- carbonyl -5- phenyl -4- amylene tert-butyl acrylate (III) (49.2mg, 0.2mmol), catalyst A (14mg, 0.02mmol),
- 10 DEG C are cooled to, 0.5ml methylene chloride is then added, mixture stirs 96h at -10 DEG C.Then triethylamine is added
(0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reaction mixture continue that 20min is stirred at room temperature.Fully reacting
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).
The optically-active of gained compound I-g, fusing point, hydrogen spectrum, 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: synthesis compound (I-h)
- 3 nitroindoline of 1- acetyl group (II) (20.4mg, 0.1mmol) is added in a horminess glass tube, (4E) -3-
Carbonyl -5- (4- aminomethyl phenyl) -4- amylene tert-butyl acrylate (III) (46.5mg, 0.2mmol), catalyst A (14mg,
0.02mmol), -10 DEG C are cooled to, 0.5ml ether is then added, mixture stirs 96h at -10 DEG C.Then triethylamine is added
(0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reaction mixture continue that 20min is stirred at room temperature.Fully reacting
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).
The optically-active of gained compound I-h, hydrogen spectrum, carbon is composed and mass spectrometric data is 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: synthesis compound (I-i)
- 3 nitroindoline of 1- acetyl group (II) (20.4mg, 0.1mmol) is added in a horminess glass tube, (4E) -3-
Carbonyl -5- (4- chlorphenyl) -4- amylene tert-butyl acrylate (III) (50.5mg, 0.2mmol), catalyst A (14mg, 0.02mmol),
- 10 DEG C are cooled to, 0.5ml ethyl alcohol is then added, mixture stirs 96h at -10 DEG C.Then be added triethylamine (0.2mmol,
20mg), chloroacetic chloride (0.2mmol, 15.7mg) reaction mixture continues that 20min is stirred at room temperature.After fully reacting, 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).
The optically-active of gained compound I-i, hydrogen spectrum, carbon is composed and mass spectrometric data is 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:
- 3 nitroindoline (II) (21.8mg, 0.1mmol) of 1- acetyl group -5- methyl is added in a horminess glass tube,
(4E) -3- carbonyl -5- (4- phenyl) -4- pentenoic acid ethyl ester (III) (43.2mg, 0.2mmol), catalyst A (14mg,
0.02mmol), -10 DEG C are cooled to, 0.5ml chlorobenzene is then added, mixture stirs 96h at -10 DEG C.Then triethylamine is added
(0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reaction mixture continue that 20min is stirred at room temperature.Fully reacting
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).
The optically-active of gained compound I-j, hydrogen spectrum, carbon is composed and mass spectrometric data is 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 nitroindoline (II) (28.1mg, 0.1mmol) of 1- acetyl group -7- is added in a horminess glass tube,
(4E) -3- carbonyl -5- (4- phenyl) -4- pentenoic acid ethyl ester (III) (43.2mg, 0.2mmol), catalyst A (14mg,
0.02mmol), -10 DEG C are cooled to, 0.5ml1,4- dioxane is then added, mixture stirs 96h at -10 DEG C.Then plus
Enter triethylamine (0.2mmol, 20mg), chloroacetic chloride (0.2mmol, 15.7mg) reaction 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 (yellow oil, receipts through column chromatography separating purification
Rate 81%, > 20:1dr, 90%ee).
The optically-active of gained compound I-k, hydrogen spectrum, carbon is composed and mass spectrometric data is 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 in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (9)
1. chiral tetrahydro carbazole analog derivative, which is characterized in that the chirality tetrahydro carbazole analog derivative has shown in structural formula I
Structure:
Wherein, the Ar is selected from phenyl, p-methylphenyl, p-methoxyphenyl, Chloro-O-Phenyl, rubigan, m-bromophenyl, right
One of bromophenyl, p-nitrophenyl, 2- thienyl, 2- furyl, 1- naphthalene；The R1Selected from p-toluenesulfonyl, benzene
One of sulfonyl, methoxycarbonyl group, carbethoxyl group, benzyloxycarbonyl group, tertbutyloxycarbonyl, acetyl group；The R2Selected from hydrogen or 5-
Methyl or 7- bromine；The R3Selected from methyl or ethyl or tert-butyl.
2. the preparation method of chirality tetrahydro carbazole analog derivative described in claim 1, which is characterized in that by 3- nitroindoline
II, Nazarov reagent III and chiral catalyst A are dissolved in reaction dissolvent, are stirred at -10 DEG C -25 DEG C, after reacting 48-96 h,
End of reaction is added chloroacetic chloride and alkali, obtains product I to after completion of the reaction, isolate and purify；
The Ar be selected from phenyl, p-methylphenyl, p-methoxyphenyl, Chloro-O-Phenyl, rubigan, m-bromophenyl, to bromobenzene
One of base, p-nitrophenyl, 2- thienyl, 2- furyl, 1- naphthalene；The R1Selected from p-toluenesulfonyl, benzene sulfonyl
One of base, methoxycarbonyl group, carbethoxyl group, benzyloxycarbonyl group, tertbutyloxycarbonyl, acetyl group；The R2Selected from hydrogen or 5- methyl
Or 7- bromine；The R3Selected from methyl or ethyl or tert-butyl.
3. preparation method according to claim 2, which is characterized in that 3- nitroindoline II and Nazarov reagent III rubs
You are than being 1:1-1:4.
4. preparation method according to claim 2, which is characterized in that the reaction dissolvent be selected from toluene, mesitylene,
Methylene chloride, chloroform, tetrahydrofuran, ether, acetonitrile, ethyl alcohol, methanol, 1,4- dioxane, chlorobenzene.
5. the preparation method according to claim 4, which is characterized in that the reaction dissolvent is chloroform.
6. preparation method according to claim 2, which is characterized in that the chiral catalyst A and 3- nitroindoline II
Molar ratio is 1:5-1:20.
7. preparation method according to claim 2, which is characterized in that every 0.1 mmol structural formula, II compound represented,
Consumption of organic solvent is 0.1-4 mL.
8. preparation method according to claim 2, which is characterized in that the alkali be selected from triethylamine, diisopropyl ethyl amine,
Potassium carbonate, sodium phosphate, cesium carbonate.
9. preparation method according to claim 8, which is characterized in that the alkali is triethylamine.
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| Asymmetric Michael/Cyclization Cascade Reaction of 3-Isothiocyanato Oxindoles and 3-Nitroindoles with Amino-Thiocarbamate Catalysts: Enantioselective Synthesis of Polycyclic Spirooxindoles;Jian-Qiang Zhao et al.;《Organic Letters》;20150415;第17卷;2238-2241 |
| Organocatalytic asymmetric double Michael reaction of Nazarov reagents with alkylidene azlactones for the construction of spiro-fused cyclohexanone/5-oxazolone system;Ming-Qiang Zhou et al.;《Tetrahedron》;20140617;第70卷;5787-5793 |
| Zn-Catalyzed Diastereo- and Enantioselective Cascade Reaction of 3-Isothiocyanato Oxindoles and 3-Nitroindoles: Stereocontrolled Syntheses of Polycyclic Spirooxindoles;Jian-Qiang Zhao et al.;《Organic Letters》;20150928;第17卷;5020-5023 |
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