CN102101868A - 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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- CN102101868A CN102101868A CN 201110075166 CN201110075166A CN102101868A CN 102101868 A CN102101868 A CN 102101868A CN 201110075166 CN201110075166 CN 201110075166 CN 201110075166 A CN201110075166 A CN 201110075166A CN 102101868 A CN102101868 A CN 102101868A
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- 0 CC1C=C(c2cc(C(*)(*)O)nc(-c3nc(C(*)(*)O)cc4c3[n](*)c3ccccc43)c2N2*)C2=CC1 Chemical compound CC1C=C(c2cc(C(*)(*)O)nc(-c3nc(C(*)(*)O)cc4c3[n](*)c3ccccc43)c2N2*)C2=CC1 0.000 description 1
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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 important role 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 " incident, " thalidomide " is a kind of tranquilizer, this medicine of initial listing is a racemic modification, people thought once that the optical isomer that does not wherein play drug effect only was the physiology inert, found afterwards to cause baby's deformity easily after this kind isomer is taken 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 research in medicine industry originally 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 natural chipal compounds to carry out asymmetric synthesis as starting raw material or chirality prothetic group;
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 that chirality is amplified and chirality is bred.Briefly, come the product of a large amount of chirality features of Stereoselective production by the chirality hyle that uses the catalysis magnitude exactly.Its reaction conditions gentleness, 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 Application of Catalyst.
The application of formula (I) compound in asymmetry catalysis.
Synthesizing of formula (I) compound:
1) earlier in order to following method synthesis type (II) compound:
（II）
Tryptophan methyl ester is dissolved in anhydrous CH
2Cl
2In, add the 4A molecular sieve, stir and drip glyoxal dimethyl base acetal down, r.t reacts 6 h, and suction filtration removes solvent under reduced pressure, last silica gel column chromatography, methylene dichloride: methyl alcohol=140:1 wash-out obtains formula (II) compound;
2) again in order to following method 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) again in order to following method 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 in order to following method synthesis type (V) compound:
（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, and 0 ℃ slowly drips trifluoroacetic acid down, and 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) again in order to following method synthesis type (VI) compound:
（VI）
The described compound of formula V is dissolved in anhydrous CH
2Cl
2, add DDQ in batches, r.t reacts 0.5 h, buff powder, sodium hydride is suspended in the dry DMF, adds buff powder, is stirred to the suspended substance dissolving under 0 ℃, slowly drips haloalkane, reaction 3 h under this temperature, formula (VI) compound;
6) again in order to following method 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 H under the ice bath successively
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 drips Grignard reagent down, and r.t reacts 8 h, and ice bath adds saturated ammonium chloride cancellation reaction down, ethyl acetate dilution, saturated NaCl washing, anhydrous anhydrous Na SO
4Drying, evaporate to dryness obtains buff powder, last silicagel column, sherwood oil: the ethyl ester wash-out obtains formula (VII) compound;
7) again in order to following method synthesis type (VIII) compound:
（VIII）
Formula (VII) or compound are dissolved in anhydrous CH
2Cl
2Or among the DMF, add alkali, haloalkane or acyl chlorides successively, and r.t reacts 12 h, removes solvent under reduced pressure, and silicagel column on the residue obtains formula (VIII) compound;
8) at last in order to following method 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 of enumerating the embodiment of the invention below 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) is synthetic:
Tryptophan methyl ester (8 mmol) is dissolved in anhydrous CH
2Cl
2In (100 mL), add the 4A molecular sieve, stir and drip glyoxal dimethyl base acetal (8.8 mmol) down, r.t reacts 6 h, and suction filtration removes solvent under reduced pressure, last silica gel column chromatography, methylene dichloride: methyl alcohol=140:1 wash-out, obtain two isomer of compound 1 respectively, this isomer can be directly used in the synthetic of compound 2 without separation.
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-Ka Lin-3-methyl-formiate (2) is 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 2 MS-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-Ka Lin-3-methyl-formiate (3) is synthetic:
Compound 2(4.3 mmol) be dissolved in the acetone (40 mL), add the acetone soln (8.6 mmol, 40 mL) of p-methyl benzenesulfonic acid, 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 3 MS-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-Ka Lin-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 slow down 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-3,3'-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 5 MS-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 the THF solution (1 mmol is dissolved among the anhydrous THF of 10 mL) of compound 5, and r.t reacts 1 h, adds 0.6 mL H under the ice bath successively
2O, 0.6 mL, 15 % NaOH solution, 0.6 mL H
2O, reactant diatomite filtration, evaporate to dryness obtain buff powder compound 6.
Compound 6 MS-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-7d's is synthetic:
Method A: compound 6(1 mmol) be dissolved in anhydrous CH
2Cl
2In (50 mL), add triethylamine (2.2 mmol), acyl chlorides (2.2 mmol) successively, 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), and 0 ℃ is stirred 10 min down, slowly drip Benzyl Chloride (4.3 mmol), r.t reacts 12 h, in the reaction solution impouring 60 mL frozen water, and ethyl acetate extraction 3 times, merge organic phase, saturated NaCl washing 6 times, anhydrous sodium sulfate drying, last 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-3,3'-Virahol (8) synthetic:
Compound 5(1 mmol) is dissolved in (40 mL) among the anhydrous THF, Ar
2Protection drips methyl-magnesium-bromide (8 mmol) down, and r.t reacts 8 h, and ice bath adds saturated ammonium chloride cancellation reaction down, ethyl acetate dilution, saturated NaCl washing, anhydrous anhydrous Na SO
4Drying, evaporate to dryness obtains buff powder, last silicagel column, sherwood oil: ethyl ester=3:1 wash-out obtains compound 8.
Compound 8 MS-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-9h's is synthetic:
Compound 5 or 67 or 8(1 mmol) be 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 9c R
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 9d R
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 9e R
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 9f R
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 9g R
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 9h R
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 application of compound 9a-9h in asymmetric reaction that the present invention relates to, the catalytic effect in the asymmetric allylation of phenyl aldehyde is as follows:
Embodiment 3:
The application of The compounds of this invention 9a in asymmetric reaction, the catalytic effect in the asymmetric allylation of various aldehyde is as follows:
Claims (5)
1. 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.
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. the described formula of claim 1 (I) compound is as Application of Catalyst.
4. the application of the described formula of claim 1 (I) compound in asymmetry catalysis.
5. the described formula of claim 1 (I) compound is synthetic:
1) synthetic following structural formula formula shown (II) compound:
（II）
Tryptophan methyl ester is dissolved in anhydrous CH
2Cl
2In, add the 4A molecular sieve, stir and drip glyoxal dimethyl base acetal down, r.t reacts 6 h, and suction filtration removes solvent under reduced pressure, last 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:
（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) synthetic following structural formula formula shown (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) formula V compound shown in the synthetic following structural formula:
（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, and 0 ℃ slowly drips trifluoroacetic acid down, and 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:
（VI）
The described compound of formula V is dissolved in anhydrous CH
2Cl
2, add DDQ in batches, r.t reacts 0.5 h, buff powder, sodium hydride is suspended in the dry DMF, adds buff powder, is stirred to the suspended substance dissolving under 0 ℃, slowly drips haloalkane, reaction 3 h under this temperature, formula (VI) compound;
6) synthetic following structural formula formula shown (VII) compound:
（VII）
LiAlH
4Be suspended among the anhydrous THF, the described compound of adding formula (VI), r.t reacts 1 h, adds H under the ice bath successively
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 drips Grignard reagent down, and r.t reacts 8 h, and ice bath adds saturated ammonium chloride cancellation reaction down, ethyl acetate dilution, saturated NaCl washing, anhydrous anhydrous Na SO
4Drying, evaporate to dryness obtains buff powder, last silicagel column, sherwood oil: the ethyl ester wash-out obtains formula (VII) compound;
7) synthetic following structural formula formula shown (VIII) compound:
（VIII）
Formula (VII) or compound are dissolved in anhydrous CH
2Cl
2Or among the DMF, add alkali, haloalkane or acyl chlorides successively, and r.t reacts 12 h, removes solvent under reduced pressure, and silicagel column on the residue obtains formula (VIII) compound;
8) the finally synthetic described formula of 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.
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| CN114933599A (en) * | 2022-06-17 | 2022-08-23 | 中国人民解放军空军军医大学 | Bis-beta-carboline compound and medicinal salt thereof, preparation method and application |
| CN114933599B (en) * | 2022-06-17 | 2023-08-01 | 中国人民解放军空军军医大学 | Double beta-carboline compound and medicinal salt, preparation method and application thereof |
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