CN102101868B - 1,1'-bicarboline N,N'-dioxocompound and synthesis and application thereof - Google Patents
1,1'-bicarboline N,N'-dioxocompound and synthesis and application thereof Download PDFInfo
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Abstract
The invention discloses a 1,1'-bicarboline N,N'-dioxocompound shown as a formula (I) and a racemic modification and an enantiomer thereof. In the formula (I), a group represented by X is selected from methyl, ethyl, propyl, butyl and benzyl; a group represented by R is selected from hydrogen, COOR1 and C(R2)2OR3; R1 is methyl, ethyl, propyl, isopropyl or butyl; R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or phenyl; and R3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, benzyl, acetyl, propiono, butyryl or benzoyl. The compound shown as the formula (I) serves as a catalyst applied in asymmetric catalysis. The invention also discloses the synthesis of the compound shown as the formula (I).
Description
Technical field
The invention belongs to catalysis technical field, more particularly, relate to 1,1 '-two carbolines
N, N '-dioxy compounds, its synthetic method, it is as catalyzer, and the application aspect asymmetry catalysis.
Background technology
The chirality factor has played extremely important effect in chemistry, biology and other multiple subject and technical field.Along with nature evolution, the generation of life and development, chirality in vivo becomes universal phenomenon.Different optical isomers has different biological activitys, operative mechanism and possible pathways metabolism and reads.The character of a pair of enantiomer in the achirality environment is identical, and in chiral environment often performance be not quite similar, sometimes even completely contradict.A famous example is exactly " thalidomide " event, " thalidomide " is a kind of tranquilizer, this medicine of initial listing is racemic modification, people thought once that the optical isomer that does not wherein play drug effect only was the physiology inertia, found afterwards that this kind isomer took the rear fetal malformation that easily causes to the gravid woman, people just recognize thus, and in organism, different optical isomers will be treated cautiously as different compounds.When FDA required to declare chiral drug from 1992, all will set forth clearly to the physiological action of each isomer, similar regulation has also been made by the European Community.World's medicine gross sales (GS) was 3,900 hundred million dollars in 2000, and wherein chiral drug is 1,325 hundred million dollars, accounting for more than 2/3 with the sale of individual isomer form in the chiral drug.
Along with the intensification to chirality understanding, the originally research in medicine industry also expands to each field such as agricultural chemicals, spices and organic materials gradually, through the development of four more than ten years, has formed the ambit of special what is called " asymmetric synthesis ".The acquisition of chipal compounds is generally by following several means:
First: the fractionation of raceme.Racemic modification is separated with physics, chemistry or biological method;
Second: utilize the natural chiral compound to carry out asymmetric synthesis as starting raw material or chiral auxiliary;
The the 3rd: utilize chiral catalyst to carry out asymmetry catalysis and synthesize.
Asymmetry catalysis is synthetic to refer generally to utilize the chiral catalyst (catalytic amount) of appropriate design or biological enzyme is controlled reactant as chiral template antipodal faces, with a large amount of prochirality substrate selectives change into the product of particular configuration, realize Chiral amplification and chiral multiplication.Briefly, exactly by come the product of a large amount of chirality features of Stereoselective production with the chirality hyle of catalysis magnitude.Its reaction conditions is gentle, and stereoselectivity is good, and (R) isomer or (S)-isomer is easy to produce equally, and latent chiral substrates wide material sources, is most economical and the most practical technology for producing a large amount of chipal compounds.Therefore, chiral catalyst is paid much attention to by whole world organic chemist.
Summary of the invention
The object of the present invention is to provide described 1, the 1 '-two carbolines of formula (I)
N, N '-dioxy compounds, its synthetic method and the application in asymmetric catalysis field.
In order to realize above-mentioned purpose of the present invention, the invention provides following technical scheme:
1,1 '-two carbolines shown in the formula (I)
N, N '-dioxy compounds, its racemic modification, enantiomer,
（I）
Wherein, the group of X representative is selected from: methyl, ethyl, propyl group, butyl, benzyl;
The group of R representative is selected from: hydrogen, COOR
1, C (R
2)
2OR
3, R wherein
1Be methyl, ethyl, propyl group, sec.-propyl, butyl; R
2Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, phenyl; R
3Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, benzyl, ethanoyl, propionyl, butyryl radicals, benzoyl.
Above-mentioned formula (I) compound is preferably the compound shown in structural formula IA, IB, the IC:
Wherein, X is selected from: methyl, ethyl, propyl group, butyl, benzyl;
R
1Be selected from methyl, ethyl, propyl group, sec.-propyl, butyl;
R
2Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, phenyl;
R
3Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, benzyl, ethanoyl, propionyl, butyryl radicals, benzoyl.
Formula (I) compound is as the application of catalyzer.
The application of formula (I) compound in asymmetry catalysis.
Synthesizing of formula (I) compound:
1) use first following methods synthesis type (II) compound:
（II）
Tryptophan methyl ester is dissolved in anhydrous CH
2Cl
2In, add the 4A molecular sieve, stir the lower glyoxal dimethyl base acetal that drips, r.t reacts 6 h, and suction filtration removes solvent under reduced pressure, upper silica gel column chromatography, methylene dichloride: methyl alcohol=140:1 wash-out obtains formula (II) compound;
2) use again following methods synthesis type (III) compound:
（Ⅲ）
Compound shown in the formula (II) is dissolved in CH
2Cl
2In, adding DDQ in batches, r.t reacts 10 min, and water washing is colourless to water layer, anhydrous Na
4SO
4Drying, steaming desolventizes, and obtains the formula III compound;
Or compound shown in the formula (II) is dissolved in the dry DMF, adding TCCA under 0 ℃ in batches, this thermotonus 2 h obtain formula (III) compound;
3) use again following methods synthesis type (IV) compound:
（Ⅳ）
The described compound of formula (III) is dissolved in acetone, adds the acetone soln of p-methyl benzenesulfonic acid, r.t stirs 2 h, adds saturated NaHCO
3, remove acetone under reduced pressure, the suction filtration precipitation, drying gets formula (IV) compound;
4) again with the synthetic formula V compound of following methods:
（V）
The described compound of formula (IV) is dissolved in anhydrous CH
2Cl
2In, adding tryptophan methyl ester, stirring at room adds 4A molecular sieve r.t and reacts 12 h to dissolving, 0 ℃ of lower trifluoroacetic acid that slowly drips, r.t reacts 12 h, adds saturated NaHCO
3Alkalization, suction filtration is removed molecular sieve, saturated NaCl washing, anhydrous Na SO
4Drying, steaming desolventizes and obtains the formula V compound;
5) use again following methods synthesis type (VI) compound:
（VI）
The described compound of formula V is dissolved in anhydrous CH
2Cl
2, adding DDQ in batches, r.t reacts 0.5 h, gets buff powder, and sodium hydride is suspended in the dry DMF, adds buff powder, is stirred to the suspended substance dissolving under 0 ℃, slowly drips haloalkane, and reaction 3 h get formula (VI) compound under this temperature;
6) use again following methods synthesis type (VII) compound:
（VII）
LiAlH
4Be suspended among the anhydrous THF, the described compound of adding formula (VI), r.t reacts 1 h, adds successively H under the ice bath
2O, 15 % NaOH solution, H
2O, reactant diatomite filtration, evaporate to dryness obtain formula (VII) compound;
Work as R
2During for alkane,
Formula (VI) compound is dissolved among the anhydrous THF Ar
2Protection is lower to drip Grignard reagent, and r.t reacts 8 h, adds saturated ammonium chloride cancellation reaction under the ice bath, ethyl acetate dilution, saturated NaCl washing, anhydrous anhydrous Na SO
4Drying, evaporate to dryness obtains buff powder, upper silicagel column, sherwood oil: the ethyl ester wash-out obtains formula (VII) compound;
7) use again following methods synthesis type (VIII) compound:
（VIII）
Formula (VII) or compound are dissolved in anhydrous CH
2Cl
2Or among the DMF, add successively alkali, haloalkane or acyl chlorides, and r.t reacts 12 h, removes solvent under reduced pressure, and silicagel column on the residue obtains formula (VIII) compound;
8) use at last following methods synthesis type (I) compound:
Formula VI compound or formula (VIII) compound are dissolved in CH
2Cl
2In, adding metachloroperbenzoic acid, r.t reacts 24 h, adds saturated sodium bicarbonate solution, stirs 10 min, branch vibration layer, organic phase is washed with saturated NaCl, anhydrous Na SO
4Drying, steaming desolventizes, silica gel column chromatography, methylene dichloride: methyl alcohol obtains formula (I) compound.
Specific implementation method:
The purpose that the below enumerates the embodiment of the invention is to illustrate further essentiality content of the present invention, but does not limit the present invention with this.
Embodiment 1:
Synthesizing of formula of the present invention (I) compound:
(1) compound 1-dimethyl formal group-beta-tetrahydro carboline-3-methyl-formiate (
1) synthetic:
Tryptophan methyl ester (8 mmol) is dissolved in anhydrous CH
2Cl
2In (100 mL), add the 4A molecular sieve, stir lower dropping glyoxal dimethyl base acetal (8.8 mmol), r.t reacts 6 h, and suction filtration removes solvent under reduced pressure, upper silica gel column chromatography, and methylene dichloride: methyl alcohol=140:1 wash-out obtains respectively compound
1Two isomer, this isomer can be directly used in compound without separation
2Synthetic.
Cis -ESI,
m/z 305 [M+H]
+.
1H NMR (500 MHz, CDCl
3)
δ 2.88 (1H, dd,
J = 8.5, 7.5 Hz), 3.18 (1H, dd,
J = 10.1, 3.5 Hz), 3.55 (3H, s, O
CH 3 ), 3.63 (3H, s, O
CH 3 ), 3.79 (1H, m), 3.82 (3H, s, COO
CH 3 ), 4.29 (1H, d,
J = 5.7 Hz), 4.50 (1H, d,
J = 6.1 Hz,), 7.11 (1H, t,
J = 7.4 Hz), 7.18 (1H, t,
J = 7.7 Hz), 7.35 (1H, d,
J = 7.8 Hz), 7.50 (1H, d,
J = 7.9 Hz), 8.59 (1H, s).
13C NMR (125 MHz, CDCl
3)
δ 25.6, 52.3, 54.5, 55.2, 56.0, 56.3, 107.0, 108.8, 111.0, 118.0, 119.3, 121.8, 126.8, 131.4, 135.9, 173.4.
Trans-1 MS
-ESI,
m/z 305 [M+H]
+.
1H NMR (500 MHz, CDCl
3)
δ 3.10-3.19 (2H, m), 3.51 (3H, s, O
CH 3 ), 3.56 (3H, s, O
CH 3 ), 3.72 (3H, s, COO
CH 3 ), 4.06 (1H, m), 4.39 (1H, d,
J = 7.1 Hz), 4.43 (1H, d,
J = 7.1 Hz,), 7.10 (1H, t,
J = 7.5 Hz), 7.17 (1H, t,
J = 7.7 Hz), 7.34 (1H, d,
J = 8.0 Hz), 7.50 (1H, d,
J = 7.8 Hz), 8.41 (1H, s).
13C NMR (125 MHz, CDCl
3)
δ 24.4, 51.2, 52.1, 53.3, 54.3, 55.6, 106.6, 107.9, 110.9, 118.1, 119.2, 121.7, 126.8, 130.8, 135.9, 174.1.
(2) compound 1-dimethyl formal group-β-carboline-3-methyl-formiate (
2) synthetic:
Compound
1(5.6 mmol) is dissolved in CH
2Cl
2In (50 mL), add DDQ(11.2 mmol in batches), r.t reacts 10 min, and water washing is colourless to water layer, anhydrous Na
4SO
4Drying, steaming desolventizes, and obtains compound
2
Compound
2MS-ESI,
M/z301 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ3.54 (6H, s, O
CH 3 ), 4.07 (3H, s, COO
CH 3 ), 7.35 (1H, t,
J=7.4 Hz), 7.56-7.62 (2H, m), 8.18 (1H, d,
J=7.9 Hz), 8.89 (1H, s), 9.45 (1H, br s).
13C NMR (100 MHz, CDCl
3)
δ52.7,54.9,106.9,111.9,118.2,120.8,121.3,121.8,129.1,130.1,134.9,136.7,140.5,140.5,166.6.
(3) compound 1-carboxaldehyde radicals-β-carboline-3-methyl-formiate (
3) synthetic:
Compound
2(4.3 mmol) is dissolved in the acetone (40 mL), adds the acetone soln (8.6 mmol, 40 mL) of p-methyl benzenesulfonic acid, and r.t stirs 2 h, adds saturated NaHCO
3(20 mL) removes acetone under reduced pressure, and the suction filtration precipitation is washed three times, and drying obtains compound
3
Compound
3MS-ESI,
M/z255 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ4.12 (3H, s, COO
CH 3 ), 7.44 (1H, t,
J=7.4 Hz), 7.64-7.71 (2H, m), 8.23 (1H, d,
J=7.9 Hz), 9.07 (1H, s), 10.33 (1H, br s), 10.45 (1H, s).
13C NMR (100 MHz, CDCl
3)
δ53.1,112.4,120.7,121.5,122.1,122.2,130.2,132.1,135.0,136.2,138.1,141.5,165.8,195.4.
(4) compound 1-(β-carboline-3-methyl-formiate)-beta-tetrahydro carboline-3-methyl-formiate (
4) synthetic:
Compound
3(2.83 mmol) is dissolved in anhydrous CH
2Cl
2In, adding tryptophan methyl ester (2.83 mmol), stirring at room is dissolving extremely, adds 4A molecular sieve r.t and reacts 12 h, and (2.83 mmol are dissolved in 3 mL CH to 0 ℃ of lower slowly dropping trifluoroacetic acid
2Cl
2), r.t reacts 12 h, adds saturated NaHCO
3Alkalization, suction filtration is removed molecular sieve, saturated NaCl washing, anhydrous Na SO
4Drying, steaming desolventizes and obtains compound
4
Cis -ESI,
m/z 455 [M+H]
+.
1H NMR (400 MHz, DMSO)
δ 3.12 (1H, dd,
J =14.9 Hz, 3.2 Hz, H-4), 3.47 (1H, dd,
J =11.2 Hz, 3.0 Hz, H-4), 3.64 (3H, s, COO
CH 3 ), 3.85 (br s, 1H, NH), 3.88 (3H, s, COO
CH 3 ), 4.37 (1H, br s, H-3), 6.00 (1H, s, H-1), 6.91–6.98 (2H, m, H-6, H-7), 7.14 (1H, d,
J = 7.8 Hz, H-8), 7.28 (1H, t,
J = 7.5 Hz, H-6`), 7.46 (1H, d,
J = 6.9 Hz, H-5), 7.56 (1H, t,
J = 7.6 Hz, H-7`), 7.73 (1H, d,
J = 8.2 Hz, H-8`), 8.35 (1H, d,
J =7.8 Hz, H-5`), 8.87 (1H, s, H-4`), 10.29 (1H, s,
NH), 11.39 (1H, s,
NH);
13C NMR (100 MHz, DMSO)
δ24.0, 51.9, 52.1, 53.2, 54.8, 106.5, 111.5, 113.0, 117.2, 117.8, 118.5, 120.4, 120.9, 121.0, 121.9, 126.7, 128.7, 128.7, 132,7, 135.2, 135.8, 136.4, 140.8, 145.5, 166.2, 174.4.
Trans-4 MS
-ESI,
m/z 455 [M+H]
+.
1H NMR (400 MHz, DMSO)
δ 3.12 (1H, dd,
J =14.7 Hz, 3.1 Hz, H-4), 3.47 (1H, dd,
J =11.0 Hz, 2.8 Hz, H-4), 3.65 (3H, s, COO
CH 3 ), 3.89 (3H, s, COO
CH 3 ), 4.38 (1H, br s, H-3), 6.00 (1H, s, H-1), 6.92–6.98 (2H, m, H-6, H-7), 7.14 (1H, d,
J = 7.8 Hz, H-8), 7.28 (1H, t,
J = 7.5 Hz, H-6`), 7.46 (1H, d,
J = 6.9 Hz, H-5), 7.56 (1H, t,
J = 7.6 Hz, H-7`), 7.73 (1H, d,
J = 8.2 Hz, H-8`), 8.36 (1H, d,
J =7.7 Hz, H-5`), 8.96 (1H, s, H-4`), 10.27 (1H, s,
NH), 11.47 (1H, s,
NH).
(5) compound 1,1'-β-two carbolines-9, and 9'-dimethyl-3, the 3'-methyl-formiate (
5) synthetic:
Compound
4(2 mmol) is dissolved in anhydrous CH
2Cl
2In, add DDQ (4 mmol) in batches, r.t reacts 0.5 h, in the reaction solution impouring 40 mL frozen water, suction filtration, filter cake be water, ethanol, washed with dichloromethane successively, gets buff powder, this yellow powder adding is suspended with sodium hydride (80% in oil, 2.67 in dry DMF mmol), be stirred to the suspended substance dissolving under 0 ℃, slowly drip methyl iodide (4 mmol), reaction 3 h under this temperature, in the reaction solution impouring 30 mL frozen water, suction filtration, filter cake be water, 50 % washing with alcohol successively, drying obtains compound
5
Compound
5MS-ESI,
M/z479 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ3.44 (3H * 2, s, 2 * N
CH 3 ), 4.03 (3H * 2, s, COO
CH 3 ), 7.42 (1H * 2, t,
J=7.4 Hz), 7.47 (1H * 2, d,
J=8.4 Hz), 7.68 (1H * 2, t,
J=7.7 Hz), 8.30 (1H * 2, d,
J=7.8 Hz), 9.06 (1H * 2, s).
13C NMR (100 MHz, CDCl
3)
δ32.7,52.8,110.0,118.1,120.9,121.2,121.8,129.2,130.6,135.9,137.6,139.8,142.9,166.6.
(6) compound 1,1'-β-two carbolines-9, and 9'-dimethyl-3,3'-methyl alcohol (
6) synthetic:
LiAlH
4(1.5 mmol) is suspended in (20 mL) among the anhydrous THF, drips compound
5THF solution (1 mmol is dissolved among the anhydrous THF of 10 mL), r.t reacts 1 h, adds successively 0.6 mL H under the ice bath
2O, 0.6 mL, 15 % NaOH solution, 0.6 mL H
2O, reactant diatomite filtration, evaporate to dryness obtain the buff powder compound
6
Compound
6MS-ESI,
M/z423 [M+H]
+.
1H NMR (500 MHz, DMSO)
δ3.31 (3H * 2, s, N
CH 3 ), 4.76 (2H * 2, s,
CH 2 OH), 7.31 (1H * 2, m), 7.61 (2H * 2, m), 8.34 (1H * 2, s), 8.38 (1H * 2, d,
J=7.9 Hz),
13C NMR (100 MHz, DMSO)
δ32.0,64.6,110.4,111.4,119.8,120.5,121.9,128.8,130.1,134.5,139.9,142.5,149.6.
(7) compound
7a-7dSynthetic:
Method
A: compound
6(1 mmol) is dissolved in anhydrous CH
2Cl
2In (50 mL), add successively triethylamine (2.2 mmol), acyl chlorides (2.2 mmol), r.t reacts 12 h, removes solvent under reduced pressure, silicagel column on the residue, sherwood oil: ethyl ester: methylene dichloride=4:1:1 wash-out obtains compound
7a-7b
Compound
7a R 3 =COCH
3, 1,1'-β-two carbolines-9,9'-dimethyl-3,3'-methyl acetate base, MS-ESI,
M/z507 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ2.17 (3H * 2, s, 2 * CO
CH 3 ), 3.30 (3H * 2, s, 2 * N
CH 3 ), 5.46 (2H * 2, d,
J=16.0 Hz, Ar
CH 2 ), 7.35 (1H * 2, t,
J=7.4 Hz), 7.41 (1H * 2, d,
J=8.3 Hz), 7.63 (1H * 2, t,
J=7.3 Hz), 8.22 (1H * 2, s), 8.25 (1H * 2, d,
J=8.0 Hz).
13C NMR (100 MHz, CDCl
3)
δ21.1,31.9,67.8,109.7,114.1,120.0,120.8,121.7,128.9,130.9,135.5,140.1,142.9,143.4,170.9.
Compound
7b R 3 =COPh, 1,1'-β-two carbolines-9,9'-dimethyl-3,3'-methyl benzoate base, MS-ESI,
M/z631 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ3.30 (3H * 2, s, 2 * N
CH 3 ), 5.74 (2H * 2, d,
J=4.8 Hz, Ar
CH 2 ), 7.31-7.37 (2H * 2, m), 7.45 (2H * 2, t,
J=7.5 Hz), 7.56-7.61 (2H * 2, m), 8.13 (2H * 2, d,
J=8.3 Hz), 8.24 (1H * 2, d,
J=7.9 Hz), 8.32 (1H * 2, s).
13C NMR (100 MHz, CDCl
3)
δ31.9,68.2,109.6,114.2,119.9,120.9,121.8,128.4,128.9,129.8,130.1,131.1,133.1,133.1,135.6,140.0,142.9,143.6,166.5.
Method
B: sodium hydride (4.3 mmol) is suspended in the dry DMF (20 mL), adds compound
42(1.4 mmol), 0 ℃ of lower 10 min that stir slowly drips Benzyl Chloride (4.3 mmol), and r.t reacts 12 h, in the reaction solution impouring 60 mL frozen water, ethyl acetate extraction 3 times merges organic phase, saturated NaCl washing 6 times, anhydrous sodium sulfate drying, upper silicagel column, sherwood oil: ethyl acetate: methylene dichloride=8:1:2 obtains
7c-7d
Compound
7c R 3 =CH
2Ph, 1,1'-β-two carbolines-9,9'-dimethyl-3, the 3'-methyl benzyl ether, MS-ESI,
M/z603 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ3.24 (3H * 2, s, 2 * N
CH 3 ), 4.76 (2H * 2, s), 4.97 (2H * 2, s), 5.74 (2H * 2, d,
J=4.8 Hz, Ar
CH 2 ), 7.25-7.39 (5H * 2, m), 7.45 (2H * 2, t,
J=7.5 Hz), 7.59 (1H * 2, t,
J=7.7 Hz), 8.24 (1H * 2, d,
J=7.9 Hz), 8.33 (1H * 2, s).
13C NMR (100 MHz, CDCl
3)
δ31.8,72.8,73.6,109.5,112.7,119.7,121.0,121.8,127.7,127.9,128.4,128.6,131.0,135.4,138.2,139.8,142.9,146.4.
Compound
7d R 3 =CH
3, 1,1'-β-two carbolines-9,9'-dimethyl-3, the 3'-dme, MS-ESI,
M/z451 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ3.25 (3H * 2, s, 2 * N
CH 3 ), 3.57 (3H * 2, s, 2 * O
CH 3 ), 4.86 (2H * 2, d,
J=3.5 Hz), 7.32 (1H * 2, t,
J=7.9 Hz), 7.37 (1H * 2, d,
J=8.3 Hz), 7.60 (1H * 2, t,
J=7.3 Hz), 8.24 (1H * 2, d,
J=7.9 Hz), 8.27 (1H * 2, s).
13C NMR (100 MHz, CDCl
3)
δ31.8,58.7,75.9,109.5,112.6,119.8,120.9,121.7,128.6,130.9,135.4,139.8,142.9,146.2.
(8) compound 1,1'-β-two carbolines-9, and 9'-dimethyl-3, the 3'-Virahol (
8) synthetic:
Compound
5(1 mmol) is dissolved in (40 mL) among the anhydrous THF, Ar
2Protection is lower to drip methyl-magnesium-bromide (8 mmol), and r.t reacts 8 h, adds saturated ammonium chloride cancellation reaction under the ice bath, ethyl acetate dilution, saturated NaCl washing, anhydrous anhydrous Na SO
4Drying, evaporate to dryness obtains buff powder, upper silicagel column, sherwood oil: ethyl ester=3:1 wash-out obtains compound
8
Compound
8MS-ESI,
M/z479 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ1.73 (3H * 2, s), 1.74 (3H * 2, s), 3.36 (3H * 2, s, 2 * N
CH 3 ), 7.34 (1H * 2, t,
J=7.5 Hz), 7.41 (1H * 2, d,
J=8.1 Hz), 7.63 (1H * 2, t,
J=7.4 Hz), 8.17 (1H * 2, s), 8.26 (1H * 2, d,
J=7.8 Hz).
13C NMR (100 MHz, CDCl
3)
δ30.7,30.9,31.6,72.1,109.3,119.8,120.7,121.5,121.6,128.9,131.6,134.9,137.8,143.2,153.9.
(9) compound
9a-9hSynthetic:
Compound
5,Or
6,Or
7,Or
8(1 mmol) is dissolved in CH
2Cl
2In (50 mL), add metachloroperbenzoic acid (3 mmol, content 70%), r.t reacts 24 h, adds 20 mL saturated sodium bicarbonate solutions, stirs 10 min, branch vibration layer, organic phase is washed with saturated NaCl, anhydrous Na SO
4Drying, steaming desolventizes, silica gel column chromatography, methylene dichloride: methanol-eluted fractions obtains compound
9a-9h
Compound
9a(
R)-(+)-1,1'-β-two carbolines-
N, N '-dioxy-9,9'-dimethyl-3, the 3'-methyl-formiate, HPLC splits, Chiralpak-IC post, 250 * 10 mm, CH
2Cl
2: CH
3OH=40:60.
(+)-9a [α]
D +750 (
c =0.27, CHCl
3). MS-ESI,
m/z 511 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ 3.44 (3H × 2, s, 2 × N
CH 3 ), 4.01 (3H × 2, s, COO
CH 3 ), 7.36-7.39 (2H × 2, m), 7.57 (1H × 2, t,
J = 7.2 Hz), 8.08 (1H × 2, d,
J = 7.7 Hz), 8.55 (1H × 2, s).
13C NMR (100 MHz, CDCl
3)
δ29.4, 53.1, 109.8, 119.4, 120.1, 120.9, 121.1, 121.7, 126.2, 128.4, 133.1, 139.3, 143.5, 163.1.
Compound
9b(
R)-(+)-1,1'-β-two carbolines-
N-oxygen-9,9'-dimethyl-3, the 3'-methyl-formiate, HPLC splits, Chiralpak-IC post, 250 * 10 mm, CH
2Cl
2: CH
3OH=60:40.
(+)-9b [α]
D +605 (
c = 0.25, CHCl
3). MS-ESI,
m/z 517 [M+Na]
+.
1H NMR (400 MHz, CDCl
3)
δ 3.16 (3H, s, N
CH 3 ), 3.62 (3H, s, N
CH 3 ), 4.00 (3H, s, COO
CH 3 ), 4.03 (3H, s, COO
CH 3 ), 7.34-7.47 (4H, m), 7.57 (1H, t,
J = 7.4 Hz), 7.68 (1H, t,
J = 7.4 Hz), 8.11 (1H, d,
J = 7.8 Hz), 8.28 (1H, d,
J = 7.8 Hz), 8.49 (1H, s), 9.08 (1H, s).
13C NMR (100 MHz, CDCl
3)
δ. 29.5, 31.9, 52.8, 53.1, 109.8, 110.1, 118.2, 118.9, 120.8, 120.9, 121.1, 121.1, 121.6, 121.8, 128.4, 129.3, 129.8, 132.1, 133.0, 133.2, 136.9, 136.9, 138.1, 138.8, 142.7, 143.6, 163.3, 166.4.
Compound
9cR
1=R
2=R
3=H, (
R)-(+)-1,1'-β-two carbolines-
N, N '-dioxy-9,9'-dimethyl-3,3'-methyl alcohol, HPLC splits, Chiralcel-OD-H post, 250 * 10 mm, CH
3OH.(+)-
9c: [α]
D = +434 (
c =0.23, CHCl
3). MS-ESI,
m/z 455 [M+H]
+. HR-MS
m/z calcd for C
26H
23N
4O
4 [M+H]
+ 455.1719, found 455.1709.
1H NMR (400 MHz, CDCl
3)
δ 3.22 (3H × 2, s, N
CH 3 ), 4.91 (1H × 2, d,
J = 12.7 Hz, ArC
H 2 ), 5.07 (1H × 2, d,
J = 13.4 Hz, ArC
H 2 ), 7.11 (1H × 2, t,
J = 7.6 Hz), 7.21 (1H × 2, d,
J = 8.1 Hz), 7.41 (1H × 2, t,
J = 7.6 Hz), 7.91 (1H × 2, d,
J = 7.1 Hz), 8.26 (1H × 2, s).
13C NMR (100 MHz, CDCl
3)
δ29.2, 61.2, 109.3, 115.6, 120.6, 120.8, 121.2, 122.7, 124.9, 128.3, 136.9, 142.3, 143.3.
Compound
9dR
1=R
2=H, R
3=COCH
3, (
R)-(+)-1,1'-β-two carbolines-
N, N '-dioxy-9,9'-dimethyl-3,3'-methyl acetate base HPLC splits, Chiralpak-IC post, 250 * 10 mm, CH
2Cl
2: CH
3OH=40:60.
(+)-9d [α]
D +353 (
c = 0.15, CHCl
3). MS-ESI,
m/z 561 [M+Na]
+.
1H NMR (400 MHz, CDCl
3)
δ2.53 (3H × 2, s, CH
2OCO
CH 3 ), 3.31 (3H × 2, s, 2 × N
CH 3 ), 5.48 (1H × 2, d,
J = 14.6 Hz, C
H 2 OCOCH
3), 5.69 (1H × 2, d,
J = 14.6 Hz, C
H 2 OCOCH
3), 7.32-7.36 (2H × 2, m), 7.55 (1H × 2, t,
J = 7.7 Hz), 8.11 (1H × 2, d,
J = 7.6 Hz), 8.19 (1H × 2, s).
13C NMR (100 MHz, CDCl
3)
δ21.1, 29.3, 61.1, 109.5, 115.9, 120.9, 120.9, 121.0, 121.0, 125.4, 128.1, 137.7, 137.9, 143.3, 170.6.
Compound
9eR
1=R
2=H, R
3=COPh, (
R)-(+)-1,1'-β-two carbolines-
N, N '-dioxy-9,9'-dimethyl-3,3'-methyl benzoate base, HPLC splits, Chiralpak-IC post, 250 * 10 mm, THF:CH
3OH=75:25.(+)-
9e: [α]
D = +190 (
c =0.21, CHCl
3). MS-ESI,
m/z 663 [M+H]
+. HR-MS
m/z calcd for C
40H
31N
4O
6 [M+H]
+ 663.2243, found 663.2250.
1H NMR (400 MHz, CDCl
3)
δ 3.32 (3H × 2, s, N
CH 3 ), 5.74 (1H × 2, d,
J = 14.9 Hz, ArC
H 2 ), 6.00 (1H × 2, d,
J = 14.9 Hz, ArC
H 2 ), 7.32 (2H × 2, m), 7.52 (3H × 2, m), 7.64 (1H × 2, t,
J = 7.4 Hz), 8.08 (1H × 2, d,
J = 7.9 Hz), 8.21 (2H × 2, d,
J = 7.4 Hz), 8.25 (1H × 2, s).
13C NMR (100 MHz, CDCl
3)
δ29.3, 61.4, 109.5, 115.6, 120.9, 121.0, 121.0, 121.1, 125.4, 128.1, 128.6, 129.7, 129.9, 133.4, 137.7, 138.1, 143.3, 166.2.
Compound
9fR
1=R
2=H, R
3=CH
2Ph, (
R)-(+)-1,1'-β-two carbolines-
N, N '-dioxy-9,9'-dimethyl-3, the 3'-methyl benzyl ether, HPLC splits, Chiralpak-IC post, 250 * 10 mm, THF:CH
3OH=80:20.(+)-
9f: [α]
D = +160 (
c =0.25, CHCl
3). MS-ESI,
m/z 635 [M+H]
+. HR-MS
m/z calcd for C
40H
35N
4O
4 [M+H]
+ 635.2658, found 635.2668.
1H NMR (400 MHz, CDCl
3)
δ 3.23 (3H × 2, s, N
CH 3 ), 4.83 (2H × 2, s, O
CH 2 Ph), 5.00 (1H × 2, d,
J = 15.8 Hz, ArC
H 2 ), 5.04 (1H × 2, d,
J = 15.7 Hz, ArC
H 2 ), 7.29-7.36 (3H × 2, m), 7.41 (2H × 2, t,
J = 7.5 Hz), 7.51 (3H × 2, m), 8.11 (1H × 2, d,
J = 7.7 Hz), 8.35 (1H × 2, s).
13C NMR (100 MHz, CDCl
3)
δ 29.5, 67.0, 73.8, 109.4, 114.4, 120.8, 121.0, 121.1, 121.5, 125.1, 127.9, 128.0, 128.0, 128.6, 137.2, 137.7, 140.8, 143.3.
Compound
9gR
1=R
2=H, R
3=CH
3, (
R)-(+)-1,1'-β-two carbolines-
N, N '-dioxy-9,9'-dimethyl-3, the 3'-dme, HPLC splits, Chiralpak-IC post, 250 * 10 mm, THF:CH
3OH=50:50.(+)-
9g: [α]
D = +235 (
c =0.26, CHCl
3). MS-ESI,
m/z 483 [M+H]
+. HR-MS
m/z calcd for C
28H
27N
4O
4 [M+H]
+ 483.2032, found 483.2028.
1H NMR (400 MHz, CDCl
3)
δ 3.25 (3H × 2, s, N
CH 3 ), 3.67 (3H × 2, s, O
CH 3 ), 4.89 (1H × 2, d,
J = 15.6 Hz, ArC
H 2 ), 4.96 (1H × 2, d,
J = 15.5 Hz, ArC
H 2 ), 7.2 (2H × 2, m), 7.53 (1H × 2, t,
J = 7.8 Hz), 8.12 (1H × 2, d,
J = 7.8 Hz), 8.29 (1H × 2, s).
13C NMR (100 MHz, CDCl
3)
δ 29.4, 59.5, 69.2, 109.4, 114.2, 120.8, 120.9, 121.1, 121.4, 125.2, 127.9, 137.2, 140.6, 143.3.
Compound
9hR
1=R
2=CH
3, R
3=H, (
R)-(+)-1,1'-β-two carbolines-
N, N '-dioxy-9,9'-dimethyl-3, the 3'-Virahol, HPLC splits, Chiralpak-IC post, 250 * 10 mm, CH
2Cl
2: CH
3OH=90:10.
(+)-9h [α]
D +547 (
c = 0.27, CHCl
3). MS-ESI,
m/z 511 [M+H]
+.
1H NMR (400 MHz, CDCl
3)
δ 1.87 (6H × 2, s), 3.33 (3H × 2, s, 2 × N
CH 3 ), 7.37 (2H × 2, m), 7.59 (1H × 2, t,
J = 7.3 Hz), 8.13 (1H × 2, d,
J = 7.8 Hz), 8.19 (1H × 2, s).
13C NMR (100 MHz, CDCl
3)
δ28.1, 28.3, 29.2, 72.1, 109.7, 113.4, 120.9, 121.0, 121.1, 122.6, 126.1, 128.6, 136.9, 143.6, 146.1, 172.1.
Embodiment 2:
The compound that the present invention relates to
9a-9hApplication in asymmetric reaction, the catalytic effect in the asymmetric allylation of phenyl aldehyde is as follows:
Embodiment 3:
The compounds of this invention
9aApplication in asymmetric reaction, the catalytic effect in the asymmetric allylation of various aldehyde is as follows:
Claims (5)
1. 1,1 ' shown in the formula (I)-two carboline N, N '-dioxy compounds, its racemic modification, enantiomer,
Wherein, the group of X representative is selected from: methyl, ethyl, propyl group, butyl, benzyl;
The group of R representative is selected from: hydrogen, COOR
1, C (R
2)
2OR
3, R wherein
1Be methyl, ethyl, propyl group, sec.-propyl, butyl; R
2Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, phenyl; R
3Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, benzyl, ethanoyl, propionyl, butyryl radicals, benzoyl.
2. formula as claimed in claim 1 (I) compound is shown in structural formula IA, IB, IC
Wherein, X is selected from: methyl, ethyl, propyl group, butyl, benzyl;
R
1Be selected from methyl, ethyl, propyl group, sec.-propyl, butyl;
R
2Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, phenyl;
R
3Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, benzyl, ethanoyl, propionyl, butyryl radicals, benzoyl.
3. formula claimed in claim 1 (I) compound is as the application of catalyzer.
4. the application of formula claimed in claim 1 (I) compound in asymmetry catalysis.
5. formula claimed in claim 1 (I) compound is synthetic:
1) synthetic following structural formula formula shown (II) compound:
Tryptophan methyl ester is dissolved in anhydrous CH
2Cl
2In, add the 4A molecular sieve, stir the lower glyoxal dimethyl base acetal that drips, r.t reacts 6 h, and suction filtration removes solvent under reduced pressure, upper silica gel column chromatography, methylene dichloride: methyl alcohol=140:1 wash-out obtains formula (II) compound;
2) synthetic following structural formula formula shown (III) compound:
Compound shown in the formula (II) is dissolved in CH
2Cl
2In, adding DDQ in batches, r.t reacts 10 min, and water washing is colourless to water layer, anhydrous Na
4SO
4Drying, steaming desolventizes, and obtains the formula III compound;
Or compound shown in the formula (II) is dissolved in the dry DMF, adding TCCA under 0 ℃ in batches, this thermotonus 2 h obtain formula (III) compound;
3) synthetic following structural formula formula shown (IV) compound:
The described compound of formula (III) is dissolved in acetone, adds the acetone soln of p-methyl benzenesulfonic acid, r.t stirs 2 h, adds saturated NaHCO
3, remove acetone under reduced pressure, the suction filtration precipitation, drying gets formula (IV) compound;
4) formula V compound shown in the synthetic following structural formula:
The described compound of formula (IV) is dissolved in anhydrous CH
2Cl
2In, adding tryptophan methyl ester, stirring at room adds 4A molecular sieve r.t and reacts 12 h to dissolving, 0 ℃ of lower trifluoroacetic acid that slowly drips, r.t reacts 12 h, adds saturated NaHCO
3Alkalization, suction filtration is removed molecular sieve, saturated NaCl washing, anhydrous Na SO
4Drying, steaming desolventizes and obtains the formula V compound;
5) synthetic following structural formula formula shown (VI) compound:
The described compound of formula V is dissolved in anhydrous CH
2Cl
2, adding DDQ in batches, r.t reacts 0.5 h, gets buff powder, and sodium hydride is suspended in the dry DMF, adds buff powder, is stirred to the suspended substance dissolving under 0 ℃, slowly drips haloalkane, and reaction 3 h get formula (VI) compound under this temperature;
6) synthetic following structural formula formula shown (VII) compound:
LiAlH
4Be suspended among the anhydrous THF, the described compound of adding formula (VI), r.t reacts 1 h, adds successively H under the ice bath
2O, 15 % NaOH solution, H
2O, reactant diatomite filtration, evaporate to dryness obtain formula (VII) compound;
Work as R
2During for alkane,
Formula (VI) compound is dissolved among the anhydrous THF Ar
2Protection is lower to drip Grignard reagent, and r.t reacts 8 h, adds saturated ammonium chloride cancellation reaction under the ice bath, ethyl acetate dilution, saturated NaCl washing, anhydrous anhydrous Na SO
4Drying, evaporate to dryness obtains buff powder, upper silicagel column, sherwood oil: the ethyl ester wash-out obtains formula (VII) compound;
7) synthetic following structural formula formula shown (VIII) compound:
Formula (VII) or compound are dissolved in anhydrous CH
2Cl
2Or among the DMF, add successively alkali, haloalkane or acyl chlorides, and r.t reacts 12 h, removes solvent under reduced pressure, and silicagel column on the residue obtains formula (VIII) compound;
8) finally synthesize formula claimed in claim 1 (I) compound:
Formula (VI) compound or formula (VIII) compound are dissolved in CH
2Cl
2In, adding metachloroperbenzoic acid, r.t reacts 24 h, adds saturated sodium bicarbonate solution, stirs 10 min, branch vibration layer, organic phase is washed with saturated NaCl, anhydrous Na SO
4Drying, steaming desolventizes, silica gel column chromatography, methylene dichloride: methyl alcohol obtains formula (I) compound, continues to get final product with chirality HPLC fractionation.
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