CN103272638A - Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof - Google Patents

Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof Download PDF

Info

Publication number
CN103272638A
CN103272638A CN2013102189704A CN201310218970A CN103272638A CN 103272638 A CN103272638 A CN 103272638A CN 2013102189704 A CN2013102189704 A CN 2013102189704A CN 201310218970 A CN201310218970 A CN 201310218970A CN 103272638 A CN103272638 A CN 103272638A
Authority
CN
China
Prior art keywords
reaction
chirality
guanidine
phenyl
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN2013102189704A
Other languages
Chinese (zh)
Other versions
CN103272638B (en
Inventor
王保民
邹立伟
穆宏芳
张焕瑞
曲景平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian University of Technology
Original Assignee
Dalian University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dalian University of Technology filed Critical Dalian University of Technology
Priority to CN201310218970.4A priority Critical patent/CN103272638B/en
Publication of CN103272638A publication Critical patent/CN103272638A/en
Application granted granted Critical
Publication of CN103272638B publication Critical patent/CN103272638B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a series of chiral guanidine catalysts based on a tartaric acid skeleton and a preparation method thereof, and asymmetric catalytic application thereof, and belongs to the field of a catalyst technology and preparation methods of catalysts. The chiral guanidine catalysts have a structure shown in a general formula I or II; the basic skeletons heptatomic ring and five-membered ring respectively contain guanidyl and ketal structure units; and alpha, alpha'- of guanidyl on the heptatomic ring are respectively connected with two aryl groups. The invention provides a method for preparing chiral guanidine of the tartaric acid skeleton from chiral thiourea based on the tartaric acid skeleton and amine under promotion of cuprous chloride. The reaction temperature is 40 DEG C; the reaction time is 4-72 hours; and the yield is 50-99%. The chiral thiourea is prepared from tartrate by the steps of condensation, grignard reaction, chloro, azidation and reduction into chiral diamine and reaction with carbon disulfide.

Description

Based on chirality guanidine catalyst of tartaric acid skeleton and its preparation method and application
Technical field
The present invention relates to a kind of chirality guanidine catalyst based on the tartaric acid skeleton and preparation method thereof, and the application in the asymmetric 'alpha '-hydroxylation reaction of catalysis beta-dicarbonyl compound.Belong to catalyst technology and preparation method thereof field.
Background technology
Chirality (Chirality) is one of natural essential attribute.As the large biological molecule of vital movement important foundation, as protein, polysaccharide, nucleic acid and enzyme etc., almost be chirality entirely, these molecules often have important physiological function in vivo.In recent years, along with the development of synthetic method, increasing chipal compounds can obtain by chemical synthesis.Asymmetry catalysis synthetic oneself become the important means of obtaining chiral material, be one of chiral drug suitability for industrialized production key technology that must break through.Be that people are known with enzyme as catalyst, its high reaction activity and highly-solid selectively are the targets that people dream of always.Organic micromolecule catalyst has been considered to the broad-spectrum chiral catalyst of the 3rd class after enzyme and chiral metal complex compound catalyst, is new and a receive much concern field in chiral molecules synthetic.Guanidine radicals functional group is present in the various natural molecules more widely because guanidine radicals has very strong alkalescence, can with
Figure BDA00003301635600011
The mode of alkali activates multiple reaction substrate, therefore, (other organic micromolecule catalysts comprise L-proline and derivative thereof to chirality guanidine catalyst with high activity and high selectivity as one of important member of organic catalyst, quinine and derivative thereof, the chirality phosphonic acids, the chirality thiocarbamide, N-heterocyclic carbine etc.) be widely used in the asymmetric syntheses.Therefore, the new chirality guanidine catalyst of development and be applied to asymmetry catalysis and receive much concern in recent years.
The chirality guanidine catalyst of having reported mainly comprises: amino acid derived five yuan of dicyclo chirality guanidine catalysts (E.J.Corey Org.Lett.1999,1,157-160; C.H.Tan Tetrahedron Lett.2006,47,1007-1010), amino acid derived five yuan of monocycle chirality guanidine catalyst (T.Ishikawa Chem.Commun.2001,245-246), amino acid derived bis-thiourea chain guanidinesalt (K.Nagasawa Adv.Synth.Catal.2005,347,1643-1648), BINOL monocycle chirality guanidine catalyst (the M.Terada J.Am.Chem.Soc.2006 that derives, 128,16044-16045), chirality cyclohexanediamine chain guanidinesalt (the E.N.Jacobsen J.Am.Chem.Soc.2008 that derives, 130,9228-9229), proline bifunctional chiral guanidine catalyst (the X.M.Feng Angew.Chem.Int.Ed.2009 that derives, 48,5195-5198), serine dicyclo bifunctional chiral guanidine catalyst (the T.Misaki and T.Sugimura J.Am.Chem.Soc.2010 that spreads out, 132,6286-6287).
In general, though there have been a lot of chirality guanidine catalysts to be developed, the kind of chirality guanidine is still limited, and its catalytic performance awaits to excavate fully.Therefore, the development structure novelty, have the chirality guanidine catalyst of high activity and highly-solid selectively and be applied to synthetic one of the important goal in asymmetric organic synthesis field that remains of chirality.
Summary of the invention
The present invention is conceived to the synthetic and application on asymmetry catalysis of design of novel chiral guanidine.Be raw material with tartrate cheap and easy to get, synthesized a series of novel chiral guanidine catalysts based on the tartaric acid skeleton through the reaction of seven steps; And be different from the elder generation that reports in the document from the traditional route of the synthetic isothiourea of thiocarbamide and then synthesis of chiral guanidine catalyst, the thiocarbamide that the present invention is derived by tartaric acid under the effect of stannous chloride and potash and amine react a step synthesized chirality guanidine catalyst, and reaction condition gentleness (40 ℃), be applicable to various kinds of amine (primary amine: alkylamine, benzylamine, alpha substituted benzylamine, aniline, substituted-phenyl amine, amino alcohol; Secondary amine: cyclohexylamine).
The object of the present invention is to provide a kind of chirality guanidine catalyst based on the tartaric acid skeleton, it is the compound with general formula I or II:
Figure BDA00003301635600021
Ⅰ
Figure BDA00003301635600022
Ⅱ
Wherein,
R 1Be C 1～C 4Alkyl or phenyl;
R 2Be selected from hydrogen, C 1-6Alkyl, aromatic group, halogen, C 1-6Alkoxyl and C 1-6A kind of in the haloalkyl;
R 3Be C 1-6The residual chain of alkyl, aromatic group or amino alcohol;
In the general formula II, n=0,1 or 2.
Contain guanidine radicals and ketal construction unit in the basic framework heptatomic ring of chirality guanidine catalyst of the present invention and the five-membered ring respectively; The α of guanidine radicals on the heptatomic ring, α '-position is connected with two aromatic yl groups respectively.
Among chirality guanidine catalyst general formula I of the present invention and the general formula I I, R 1Be C 1～C 4Alkyl or phenyl is preferably methyl.
Among chirality guanidine catalyst general formula I of the present invention and the general formula I I, R 2Be selected from hydrogen, C 1-6Alkyl, aromatic group, halogen, C 1-6Alkoxyl and C 1-6A kind of in the haloalkyl is preferably methyl, isopropyl, the tert-butyl group, phenyl, 4-position or 3,5-position substituted-phenyl, methoxyl group or trifluoromethyl, more preferably hydrogen or phenyl.
Among chirality guanidine catalyst general formula I of the present invention and the general formula I I, R 2Be the substituting group that replaces arbitrarily.R 2Group replaces and to comprise single replace and polysubstituted, replace comprise the phenyl neighbour,, the replacement of contraposition.
Among chirality guanidine catalyst general formula I of the present invention and the general formula I I, R 3Be C 1-6The residual chain of alkyl, aromatic group or amino alcohol is preferably methyl, cyclohexyl, phenyl, 4-position or 3,5-position substituted-phenyl, benzyl, 4-position or 3,4,5-position substituted benzyl is more preferably to methyl-benzyl, 3,4,5-trimethoxy benzyl, 2,6-diisopropyl phenyl, 3, the 5-di-tert-butyl-phenyl, uncle's L-leucinol or (1S, 2S)-cyclohexylamine alcohol.
Among the chirality guanidine catalyst general formula I I of the present invention, n=0,1 or 2, preferred n=1.
Among chirality guanidine catalyst general formula I of the present invention and the general formula I I, R 2Or R 3Group described 4-position or 3,5-position substituted-phenyl or 4-position, 3,4, in the substituted benzyl of 5-position, the substituting group on phenyl or the benzyl is preferably methyl, isopropyl, the tert-butyl group, methoxyl group, trifluoromethyl, fluorine and chlorine etc.
The residual chain of amino alcohol of the present invention refers to the part except deaminizing in the amino alcohol that amino acid reduction obtains.For example, uncle's L-leucinol that the reduction of L-Terleu obtains, the residual chain of amino acid is the both 1-tert-butyl group-2-hydroxyl-ethyls of the residual chain of uncle's L-leucinol.
Figure BDA00003301635600031
Chirality guanidine catalyst typical compound of the present invention is listed in table 1.R in the table 1 2Group comprises two kinds of two kinds of compounds of finger that replace mode, as 4-Me, 3, and 5-(Me) 2Refer to R 2Be 4-Me or R 2Be 3,5-(Me) 2Two kinds of compounds.
Compound structure shown in table 1 general structure (I, II)
Figure BDA00003301635600051
Figure BDA00003301635600061
Figure BDA00003301635600071
Figure BDA00003301635600081
Figure BDA00003301635600101
Table 2 compound structure, physical property and characterization data
Figure BDA00003301635600102
Chirality guanidine catalyst of the present invention is preferably selected from a kind of of following numbering 1～12 compound:
Chirality guanidine catalyst 1:R 1=CH 3, R 2=H, R 3=(1S)-the 1-tert-butyl group-2-hydroxyethyl;
Chirality guanidine catalyst 2:R 1=CH 3, R 2=H, R 3=(1S, 2S)-the 2-hydroxy-cyclohexyl;
Chirality guanidine catalyst 3:R 1=CH 3, R 2=H, R 3=2,6-diisopropyl phenyl;
Chirality guanidine catalyst 4:R 1=CH 3, R 2=H, R 3=3,5-di-tert-butyl-phenyl;
Chirality guanidine catalyst 5:R 1=CH 3, R 2=H, R 3=3,4,5-trimethoxy benzyl;
Chirality guanidine catalyst 6:R 1=CH 3, R 2=Ph, R 3=to methyl-benzyl;
Chirality guanidine catalyst 7:R 1=CH 3, R 2=Ph, R 3=(1S)-the 1-tert-butyl group-2-hydroxyethyl;
Chirality guanidine catalyst 8:R 1=CH 3, R 2=Ph, R 3=2,6-diisopropyl phenyl;
Chirality guanidine catalyst 9:n=1, R 2=H, R 3=(1S)-the 1-tert-butyl group-2-hydroxyethyl;
Chirality guanidine catalyst 10:n=1, R 2=H, R 3=3,5-di-tert-butyl-phenyl;
Chirality guanidine catalyst 11:n=1, R 2=Ph, R 3=(1S)-the 1-tert-butyl group-2-hydroxyethyl;
Chirality guanidine catalyst 12:n=1, R 2=Ph, R 3=3,5-di-tert-butyl-phenyl;
Another object of the present invention is to provide a kind of preparation method of above-mentioned chirality guanidine catalyst based on the tartaric acid skeleton.
Wherein, the preparation method of compound of Formula I is undertaken by following process route:
The preparation method of general formula I I compound is identical with compound of Formula I preparation method process route.
In the method for the invention, general formula I I compound is pressed and compound of Formula I same process path of preparing, is undertaken by following route:
May further comprise the steps:
1. condensation reaction: with tartrate and ketone or ketal in molar ratio 1:1～1:1.5 under lewis acidic catalysis, in benzene or reflux in toluene reaction 12～24h; The gained reactant liquor adds sodium acid carbonate, water treatment, extraction, washing, drying, concentrate at last enriched product;
2. grignard reaction: with step 1. gained condensation product and RMgBr in molar ratio 1:4.5～1:5 in oxolane, under counterflow condition, reacted 30～90 minutes; Cooling, cancellation, extraction, washing, drying, concentrated, recrystallization from ethyl acetate/petroleum ether gets product;
3. chlorination reaction: with step 2. gained grignard reaction product be dissolved in the carrene, with thionyl chloride, triethylamine 1:3:4.2～1:3.5:7 in molar ratio, in room temperature to reflux temperature, reaction 3～12h; Reaction steams solvent after finishing, and obtains chlorizate;
4. azido reaction: with step 3. gained chlorination reaction product be dissolved in N, in the dinethylformamide, with sodium azide 1:4 in molar ratio, in 80 ℃ of reaction 72h; Cooling, reactant liquor is poured in the water, use extracted with diethyl ether, organic layer washing, dry, filter, concentrated, rapid column chromatography obtains solid, with ether be recrystallized product;
5. reduction reaction: with step 4. gained Azide product be dissolved in the oxolane, with Lithium Aluminium Hydride 1:6 in molar ratio, in 0 ℃ of reaction 1.5～6h; Cancellation, extraction, washing, drying, concentrate, ether/n-hexane be recrystallized product;
6. the preparation that has the chirality thiocarbamide of tartaric acid skeleton: with step 5. the gained reduzate be dissolved in the pyridine, with carbon disulfide 1:2 in molar ratio, in 60 ℃ of reaction 12～24h; Cooling, reactant liquor is poured in the water, uses dichloromethane extraction; Organic layer washing, dry, filter, concentrate, carrene/n-hexane be recrystallized product;
7. the preparation that has the chirality guanidine catalyst of tartaric acid skeleton: with step 6. gained thiocarbamide and amine, stannous chloride, potash in molar ratio 1:1.2:2:4～1:10:2.1:15 add in the oxolane, in 40 ℃ of reaction 4～72h; Cooling, cancellation, extraction, filtration, washing, drying, concentrated, column chromatography obtains solid product.
Another purpose of the present invention provides the application of above-mentioned chirality guanidine catalyst in the asymmetric 'alpha '-hydroxylation reaction of catalysis beta-dicarbonyl compound.
A kind of asymmetric 'alpha '-hydroxylation reaction of beta-dicarbonyl compound comprises the steps:
Under the blanket of nitrogen, with beta-dicarbonyl compound and above-mentioned chirality guanidine catalyst in molar ratio 1:0.1～1:0.01 be dissolved in the toluene.Be cooled to-78 ℃.Add oxidant (mol ratio of oxidant and beta-dicarbonyl compound is 1.2:1).-78 ℃ of reactions.Benzinum and ethyl acetate are eluant, eluent, and column chromatography for separation obtains asymmetric 'alpha '-hydroxylation product.
Beta-dicarbonyl compound comprises: indone derive beta-ketoester and beta-diketon, tetralone derive beta-ketoester and beta-diketon etc.
Unless otherwise indicated, term used herein has following implication.
Term used herein " alkyl " comprises straight chained alkyl and branched alkyl.As mention single alkyl as " propyl group ", and then only refer in particular to straight chained alkyl, as mention single branched alkyl as " isopropyl ", then only refer in particular to branched alkyl.For example, " C 1-6Alkyl " comprise C 1-4Alkyl, C 1-3Alkyl, methyl, ethyl, n-pro-pyl, isopropyl and the tert-butyl group.Similarly rule also is applicable to other group that uses in this specification.
Term used herein " halogen " comprises fluorine, chlorine, bromine and iodine.
Beneficial effect of the present invention is: 1) synthetic a series of novel chiral guanidine catalysts based on the tartaric acid skeleton; 2) developed the new method that is used for the preparation of chirality guanidine catalyst; The novel chiral guanidine catalyst based on the tartaric acid skeleton that 3) will prepare is applied to the asymmetric 'alpha '-hydroxylation reaction of beta-dicarbonyl compound, obtain almost quantitative yield and extraordinary enantioselectivity, for the Alpha-hydroxy-beta-dicarbonyl compound of synthesis of optically active provides important asymmetric organic catalysis method.
The specific embodiment
The following examples can make those of ordinary skill in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 1:
Figure BDA00003301635600171
Reaction reagent and condition: a) 2, the 2-dimethoxy propane, p-methyl benzenesulfonic acid, benzene refluxes 12h; B) bromobenzene, the magnesium powder, oxolane refluxes 1.5h, productive rate 91%(two-step reaction); C) thionyl chloride, triethylamine, carrene refluxes 3h, productive rate 65%; D) Sodium azide, N, dinethylformamide, 80 ℃, 72h, productive rate 77%; E) Lithium Aluminium Hydride, oxolane, 0 ℃, 4h, productive rate 93%; F) carbon disulfide, pyridine, 60 ℃, productive rate 98%; G) replace amine, stannous chloride, potash, oxolane, 40 ℃, 4-30h, productive rate 87-95%.
1.G1-1 synthetic:
Under the blanket of nitrogen, in the 250mL there-necked flask, add successively anhydrous benzene (148mL), L-ethyl tartrate (12.4g, 60mmol), 2, the 2-dimethoxy propane (9.4g, 11mL, 90mmol, 1.5eq.), p-methyl benzenesulfonic acid (0.12g).Be warming up to backflow, reaction 12h.Cool to room temperature adds NaHCO 3(1.5 g) continues to stir 30min.Add water (100mL), tell organic phase, water twice of ethyl acetate extraction (60mL * 2), merge organic phase, washing (50mL * 1), saturated sodium-chloride water solution is washed (50mL * 1), anhydrous sodium sulfate drying, steaming solvent, to get ketal be yellow oil 14.8g, productive rate 100%.
Under the blanket of nitrogen, the new system RMgBr will be housed { by bromobenzene 47.1g(300mmol, 5.0eq.), magnesium powder 8.0g(330mmol, 5.5eq.) and oxolane (180mL) make the 250mL there-necked flask place ice-water bath, slowly drip and be dissolved with above-mentioned gained ketal (14.8g, 60mmol, oxolane 1.0eq.) (15mL) solution.Add and be warming up to backflow, reaction 1.5h.Cool to room temperature adds saturated aqueous ammonium chloride (400mL) cancellation reaction.Tell organic phase, water ethyl acetate extraction (300mL * 1,100mL * 2), merge organic phase, washing (100mL * 1), saturated sodium-chloride water solution is washed (100mL * 1), and anhydrous sodium sulfate drying steams solvent, recrystallization from ethyl acetate/petroleum ether gets white solid G1-125.6g, productive rate 91%. 1H?NMR(400MHz,CDCl 3/TMS):δ7.52(dd,J=7.8,1.3Hz,4H),7.33-7.22(m,16H),4.59(s,2H),3.92(s,2H),1.03(s,6H)。
2.G1-2 synthetic:
Under the blanket of nitrogen, to being dissolved with G1-1(4.7g, 10mmol, in the 250mL there-necked flask of carrene 1.0eq.) (60mL) solution, dripping thionyl chloride (1.8g, 30mmol, 3.0eq.).Reactant liquor is warming up to backflow, slowly drips and be dissolved with triethylamine (4.2g, 42mmol, carrene 4.2eq.) (60mL) solution, TLC detection reaction.Cool to room temperature after reacting completely in the saturated sodium bicarbonate that the reactant liquor impouring is cold (200mL) solution, stirs 2h.Tell organic phase, the water carrene is got (100mL * 1), merges organic phase, and saturated sodium-chloride water solution is washed (100mL * 1), and anhydrous sodium sulfate drying steams solvent rapid column chromatography (petroleum ether/ethyl ether=10/1) and gets brown solid.Crude product carrene/benzinum be recrystallized white solid G1-23.3g, productive rate 65%. 1H?NMR(400MHz,CDCl 3/TMS):δ7.48-7.41(m,8H),7.33-7.16(m,12H),5.45(s,2H),0.97(s,6H)。
3.G1-3 synthetic:
Under the blanket of nitrogen, to being dissolved with G1-2(2.5g, 5mmol, N 1.0eq.), in the 50mL there-necked flask of dinethylformamide (15mL) solution, add sodium azide (1.3g, 20mmol, 4.0eq.).Reactant liquor is warming up to 80 ℃, reaction 72h.Cool to room temperature after reacting completely in the water that the reactant liquor impouring is cold (100mL), is told organic phase, and the water ether is got (50mL * 3) three times.Merge organic phase, wash three times (35mL * 3), anhydrous sodium sulfate drying steams solvent, the crude product ether be recrystallized white solid G1-32.0g, productive rate 77%. 1H?NMR(400MHz,CDCl 3/TMS):δ7.34-7.24(m,10H),4.92(s,2H),1.11(s,6H)。
4.G1-4 synthetic:
Under the blanket of nitrogen, with LiAlH4(1.6g, 42mmol 6.0eq.) is suspended in the oxolane (40mL), is cooled to 0 ℃.Slowly drip and be dissolved with G1-3(3.6g, 7mmol, oxolane 1.0eq.) (40mL) solution.0 ℃ of reaction 4h.After reacting completely, 1M NaOH(5mL) the cancellation reaction.Reactant liquor adds diethyl ether after (20mL) dilution, adds anhydrous sodium sulfate (20g), stirring at room 2h.The filtering solid, the Anhydrous potassium carbonate drying steams solvent, crude product ether/n-hexane be recrystallized white solid G1-43.0g, productive rate 93%. 1H?NMR(400MHz,CDCl 3/TMS):δ7.55-7.53(m,4H),7.36-7.29(m,6H),7.20-7.13(m,10H),4.92(s,2H),2.30(brs,4H),1.11(s,6H)。
5.G1-5 synthetic:
Under the blanket of nitrogen, to being dissolved with G1-4(1.393g, 3mmol, add in pyridine 1.0eq.) (5mL) solution carbon disulfide (361 μ L, 6mmol, 2.0eq.).Reactant liquor is warming up to 60 ℃, reaction 18h.The back cool to room temperature reacts completely, add methylene chloride (20mL) and water (10mL) in reactant liquor, 1M HCl transfers pH=2, tells organic phase, the water carrene is got (50mL * 3) three times, merge organic phase, 1M NaOH solution is washed (50mL * 1), and saturated nacl aqueous solution is washed (60mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product carrene/n-hexane be recrystallized white solid G1-51.489g, productive rate 98%.Mp277.4-278.6℃;[α] D 24=-191.3(c0.31,CH 2Cl 2); 1H?NMR(400MHz,CDCl 3/TMS):δ7.63-7.61(m,4H),7.44-7.39(m,6H),7.28(m,6H),7.15(m,4H),6.85(s,2H),4.59(s,2H),1.20(s,6H); 13C?NMR(101MHz,CDCl 3/TMS):δ185.9,143.4,139.6,129.3,128.8,128.5,128.1,128.0,127.7,110.8,78.0,70.5,26.9;IR(KBr):3386,3062,2983,2904,1515,1495,1457,1444,1164,1105,755,698,681;HRMS(ESI)Calcd.for?C 32H 30N 2O 2NaS +([M+Na] +)529.1926,Found529.1921。
5. the chirality guanidine is synthetic:
1) chirality guanidine 2 is synthetic:
Under the blanket of nitrogen, add successively in the 50mL reaction bulb Anhydrous potassium carbonate (165.9mg, 1.2mmol, 6.0eq.), stannous chloride (41.6mg, 0.42mmol, 2.1eq.), oxolane (2mL), G1-5(101.3mg, 0.2mmol, 1.0eq.).Behind the stirring at room 10min, add 1S, 2S, (60.7mg, 0.4mmol 2.0eq.), are warming up to 40 ℃ to-cyclohexylamine alcohol hydrochloride, reaction 30h.The back cool to room temperature reacts completely, in reactant liquor, add saturated ammonium chloride solution (30mL), 1M HCl transfers pH=4, carrene is got (30mL * 3) three times, merge organic phase and filter, the filtrate saturated nacl aqueous solution is washed (20mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product column chromatography (methylene chloride=50/1) gets white solid.The gained solid is dissolved in the carrene (25mL), adds 2M NaOH solution (5mL), stirring at room 2h.The water carrene is got (5mL * 2), merges organic phase, and saturated nacl aqueous solution is washed (10mL * 1), and the Anhydrous potassium carbonate drying steams solvent and gets white solid 2102.3mg, productive rate 87%.
2) chirality guanidine 13 is synthetic:
Under the blanket of nitrogen, in the 50mL reaction bulb, add Anhydrous potassium carbonate (276.4mg, 2.0mmol successively, 4.0eq.), stannous chloride (104.0mg, 1.05mmol, 2.1eq.), oxolane (5mL), G1-5(235.3mg, 0.5mmol, 1.0eq.), behind the stirring at room 10min, add (S)-phenyl ethylamine (72.7mg, 76.5 μ L, 0.6mmol, 1.2eq.).Be warming up to 40 ℃, reaction 4h.The back cool to room temperature reacts completely, in reactant liquor, add saturated ammonium chloride solution (30mL), 1M HCl transfers pH=4, carrene is got (30mL * 3) three times, merge organic phase and filter, the filtrate saturated nacl aqueous solution is washed (20mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product column chromatography (methylene chloride=50/1) gets white solid.The gained solid is dissolved in the carrene (30mL), add 2M NaOH solution (5mL), stirring at room 2h, the water carrene is got (5mL * 2), merge organic phase, saturated nacl aqueous solution is washed (10mL * 1), Anhydrous potassium carbonate drying, steam solvent and get white solid 13282.3mg, productive rate 95%.
Embodiment 2:
Figure BDA00003301635600201
Reaction reagent and condition: a) 2, the 2-dimethoxy propane, p-methyl benzenesulfonic acid, benzene refluxes 12h; B) 4-phenyl bromobenzene, the magnesium powder, oxolane refluxes 1.5h, productive rate 95%(two-step reaction); C) thionyl chloride, triethylamine, carrene refluxes 3h; D) Sodium azide, N, dinethylformamide, 80 ℃, 72h, productive rate 79%(two-step reaction); E) Lithium Aluminium Hydride, oxolane, 0 ℃, 4h, productive rate 84%; F) carbon disulfide, pyridine, 60 ℃, productive rate 99%; G) replace amine, stannous chloride, potash, oxolane, 40 ℃, 15-48h, productive rate 71-85%.
1.G2-1 synthetic:
Under the blanket of nitrogen, add successively in the 250mL there-necked flask anhydrous benzene (148mL), L-ethyl tartrate (4.1g, 20mmol), 2, the 2-dimethoxy propane (3.1g, 3.7mL, 30mmol, 1.5eq.), p-methyl benzenesulfonic acid (0.03g).Be warming up to backflow, reaction 12h.Cool to room temperature adds NaHCO 3(0.5g) continue to stir 30min.Add water (40mL), tell organic phase, twice of water ethyl acetate extraction (30mL * 2), merge organic phase, washing (30mL * 1), saturated sodium-chloride water solution is washed (30mL * 1), anhydrous sodium sulfate drying, steaming solvent, to get ketal be yellow oil 4.9g, productive rate 100%.
Under the blanket of nitrogen, will be equipped with the new system grignard reagent by to bromo biphenyl (22.4g, 96mmol, 4.8eq.); The magnesium powder (2.6g, 106mmol, 5.3eq.) and oxolane (85mL) make the 250mL there-necked flask place ice-water bath.Slowly drip and be dissolved with above-mentioned gained ketal (4.9g, 20mmol, oxolane 1.0eq.) (10mL) solution.Add and be warming up to backflow, reaction 1.5h.Cool to room temperature adds saturated aqueous ammonium chloride (100mL) cancellation reaction.Tell organic phase, three (150mL extractions 1 time of water ethyl acetate extraction, 100mL extraction 2 times is expressed as 150mL * 1,100mL * 2, down together), merge organic phase, washing (80mL * 1), saturated sodium-chloride water solution is washed (100mL * 1), anhydrous sodium sulfate drying, steam solvent ethyl acetate/benzinum be recrystallized white solid G2-114.6g, productive rate 95%. 1H?NMR(400MHz,CDCl 3/TMS):δ7.67-7.56(m,12H),7.53-7.29(m,24H),4.72(s,2H),4.23(brs,1H),1.16(s,3H)。
2.G2-2 synthetic:
Under the blanket of nitrogen, to being dissolved with G2-1(1.54g, 2mmol, in the 100mL there-necked flask of carrene 1.0eq.) (15mL) solution, dripping thionyl chloride (0.71g, 3mmol, 3.0eq.).Reactant liquor is warming up to backflow, slowly drips and be dissolved with triethylamine (0.85g, 8.4mmol, carrene 4.2eq.) (20mL) solution, TLC detection reaction.Cool to room temperature after reacting completely steams solvent and gets the pitchy solid.Add N, dinethylformamide (15mL), and sodium azide (0.52g, 8mmol, 4.0eq.).Adding is warming up to 80 ℃ with reactant liquor, reaction 72h.Cool to room temperature after reacting completely in reactant liquor impouring cold water (100mL), is told organic phase, water extracted with diethyl ether three times (50mL * 3).Merge organic phase, washing (35mL * 3), anhydrous sodium sulfate drying steams solvent, the crude product ether be recrystallized white solid G2-21.29g, productive rate 79%.Mp142.1-143.9℃;[α] D 24=-38.162(c0.36,CH 2Cl 2); 1H?NMR(400MHz,CDCl 3/TMS):δ7.65-7.54(m,16H),7.47-7.31(m,20H),5.08(s,2H),1.25(s,6H); 13C?NMR(101MHz,CDCl 3/TMS)δ140.7,140.5,140.5,140.4,139.2,130.0,128.9,128.8,128.7,127.6,127.4,127.1,127.1,126.8,126.4,110.8,80.8,73.0,27.6;IR(KBr):3061,3025,2986,2936,2106,1493,1447,1382,1372,1255,1216,1167,1070,978,764,745,703;Calcd.for?C 55H 44N 6O 2Na +([M+Na] +)843.3423,Found843.3452。
3.G2-3 synthetic:
Under the blanket of nitrogen, with LiAlH 4(173.1mg, 4.6mmol 6.0eq.) are suspended in the oxolane (8mL), are cooled to 0 ℃.Slowly drip and be dissolved with G2-2(626.7mg, 0.76mmol, oxolane 1.0eq.) (8mL) solution.0 ℃ of reaction 4h.After reacting completely, 1M NaOH(2mL) cancellation reaction, reactant liquor add diethyl ether after (10mL) dilution, add anhydrous sodium sulfate (4g), stirring at room 2h.The filtering solid, the Anhydrous potassium carbonate drying steams solvent, crude product ether/n-hexane be recrystallized white solid G2-3493.1mg, productive rate 84%.Mp276.1-277.7℃;[α] D 24=-28.4(c0.34,CH 2Cl 2); 1H?NMR(400MHz,CDCl 3/TMS):δ7.71-7.25(m,36H),4.39(s,2H),2.46(brs,4H),1.20(s,6H); 13C?NMR(101MHz,CDCl 3/TMS):δ148.9,142.9,140.7,140.7,139.6,139.3,129.7,128.9,128.7,127.9,127.4,127.2,127.0,126.8,126.0,107.7,81.9,62.4,27.3;IR(KBr):3365,3166,3054,3026,2979,2869,1599,1486,1378,1369,1235,1219,1171,1072,1007,844,833,766,745,698;HRMS(ESI)Calcd.for?C 55H 49N 2O 2 +([M+H] +)769.3794,Found769.3782。
4.G2-4 synthetic:
Under the blanket of nitrogen, to being dissolved with G2-3(768.9mg, 1mmol, add in pyridine 1.0eq.) (2mL) solution carbon disulfide (120 μ L, 2mmol, 2.0eq.).Reactant liquor is warming up to 60 ℃, reaction 18h.The back cool to room temperature reacts completely, add methylene chloride (20mL) and water (20mL) in reactant liquor, 1M HCl transfers pH=2, tells organic phase, the water carrene is got (50mL * 3) three times, merge organic phase, 1MNaOH solution is washed (50mL * 1), and saturated nacl aqueous solution is washed (60mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product carrene/n-hexane be recrystallized white solid G2-4810mg, productive rate 99%.Mp322.9-324.3℃;[α] D 24=-131.1(c0.339,CH 2Cl 2); 1H?NMR(400MHz,CDCl 3/TMS):δ7.79-7.71(m,12H),7.55-7.28(m,24H),6.96(s,2H),4.74(s,2H),1.32(s,6H); 13C?NMR(101MHz,CDCl 3/TMS):δ186.1,142.110,141.510,140.7,140.2,140.1,138.6,129.8,129.0,128.9,128.2,127.7,127.6,127.1,127.1,126.6,111.1,78.3,70.3,27.1;IR(KBr):3383,3055,3028,2989,2985,15189,1487,1421,1166,1099,837,765,696;HRMS(ESI)Calcd.for?C 56H 47N 3O 2S +([M+H] +)811.3358,Found811.3355。
4. the chirality guanidine is synthetic:
1) chirality guanidine 6 is synthetic:
Under the blanket of nitrogen, in the 50mL reaction bulb, add Anhydrous potassium carbonate (276.4mg, 2.0mmol successively, 4.0eq.), stannous chloride (104.0mg, 1.05mmol, 2.1eq.), oxolane (5mL), G2-4(405.5mg, 0.5mmol, 1.0eq.), behind the stirring at room 10min, add methylbenzylamine (84.8mg, 0.7mmol, 1.4eq.), be warming up to 40 ℃, reaction 15h.The back cool to room temperature reacts completely, in reactant liquor, add saturated ammonium chloride solution (30mL), 1M HCl transfers pH=4, dichloromethane extraction three times (40mL * 3), merge organic phase and filter, the filtrate saturated nacl aqueous solution is washed (20mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product column chromatography (methylene chloride=20/1) gets white solid.The gained solid is dissolved in the carrene (40mL), add 2M NaOH solution (8mL), stirring at room 2h, water dichloromethane extraction (5mL * 2), merge organic phase, saturated nacl aqueous solution is washed (10mL * 1), Anhydrous potassium carbonate drying, steam solvent and get white solid 6332.9mg, productive rate 85%.
2) chirality guanidine 7 is synthetic:
Under the blanket of nitrogen, add successively in the 50mL reaction bulb Anhydrous potassium carbonate (55.3mg, 10.4mmol, 4.0eq.), stannous chloride (20.8mg, 0.21mmol, 2.1eq.), oxolane (1mL), G2-4(81.1mg, 0.1mmol, 1.0eq.).Behind the stirring at room 10min, (23.4mg, 0.2mmol 2.0eq.), are warming up to 40 ℃, reaction 48h to add uncle's L-leucinol.The back cool to room temperature reacts completely, in reactant liquor, add saturated ammonium chloride solution (15mL), 1M HCl transfers pH=4, carrene is got (20mL * 3) three times, merge organic phase and filter, the filtrate saturated nacl aqueous solution is washed (10mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product column chromatography (methylene chloride=50/1) white solid.The gained solid is dissolved in the carrene (25mL), add 2M NaOH solution (5mL), stirring at room 2h, water dichloromethane extraction (5mL * 2), merge organic phase, saturated nacl aqueous solution is washed (5mL * 1), Anhydrous potassium carbonate drying, steam solvent and get white solid 763.5mg, productive rate 71%.
Embodiment 3:
Figure BDA00003301635600231
Reaction reagent and condition: a) cyclohexanone, p-methyl benzenesulfonic acid, zinc chloride, benzene refluxes 18h; B) bromobenzene, the magnesium powder, oxolane refluxes 1.5h, productive rate 75%(two-step reaction); C) thionyl chloride, triethylamine, carrene refluxes 3h; D) Sodium azide, N, dinethylformamide, 80 ℃, 72h, productive rate 71%(two-step reaction); E) Lithium Aluminium Hydride, oxolane, 0 ℃, 4h, productive rate 84%; F) carbon disulfide, pyridine, 60 ℃, productive rate 83%; G) to methylbenzylamine, stannous chloride, potash, oxolane, 40 ℃, 12h, productive rate 62%.
1.G3-1 synthetic:
Under the blanket of nitrogen, add successively in the 250mL there-necked flask anhydrous benzene (200mL), L-ethyl tartrate (11.5g, 56mmol), cyclohexanone (8.2g, 8.7mL, 84mmol, 1.5eq.), p-methyl benzenesulfonic acid (0.35g), zinc dichloride (0.35g).Be warming up to backflow, reaction 18h.Cool to room temperature adds NaHCO 3(1.4g) continue to stir 30min.Add water (100mL), tell organic phase, twice of water ethyl acetate extraction (100mL * 2), merge organic phase, washing (100mL * 1), saturated sodium-chloride water solution is washed (100 mL * 1), anhydrous sodium sulfate drying, steaming solvent, to get ketal be yellow oil 16g, productive rate 100%.
Under the blanket of nitrogen, will be equipped with the new system grignard reagent by bromobenzene (12.6g, 80mmol, 5.0eq.), the magnesium powder (2.1g, 88mmol, 5.5eq.) and oxolane (60mL) make the 250mL there-necked flask place ice-water bath.Slowly drip and be dissolved with above-mentioned gained ketal (4.6g, 216mmol, oxolane 1.0eq.) (4mL) solution.Adding room temperature reaction spends the night.Add saturated aqueous ammonium chloride (100mL) cancellation reaction.Tell organic phase, water ethyl acetate extraction three times (100mL * 3) merges organic phase, washing (80mL * 1), saturated sodium-chloride water solution is washed (100mL * 1), anhydrous sodium sulfate drying, steam solvent ethyl acetate/benzinum be recrystallized white solid G3-16.1g, productive rate 75%. 1H?NMR(400MHz,CDCl 3/TMS):δ7.57-7.47(m,4H),7.39-7.21(m,16H),4.55(s,2H),3.73(brs,2H),1.50-1.31(m,4H),1.31-1.07(m,6H)。
2.G3-2 synthetic:
Under the blanket of nitrogen, to being dissolved with G2-1(1.52g, 3mmol, in the 100mL there-necked flask of carrene 1.0eq.) (20mL) solution, dripping thionyl chloride (1.07g, 9mmol, 3.0eq.).Reactant liquor is warming up to backflow, slowly drips and be dissolved with triethylamine (1.21g, 18mmol, carrene 6eq.) (20mL) solution, TLC detection reaction.Cool to room temperature after reacting completely steams solvent and gets the pitchy solid.Add N, dinethylformamide (12mL), sodium azide (0.78g, 12mmol, 4.0eq.).Adding is warming up to 80 ℃ with reactant liquor, reaction 72h.The back cool to room temperature reacts completely, in the water that the reactant liquor impouring is cold (100m), tell organic phase, water extracted with diethyl ether three times (100mL * 1,60mL * 2), merge organic phase, washing (50mL * 3), anhydrous sodium sulfate drying steams solvent, crude product column chromatography (petrol ether/ethyl acetate=50/1) gets white solid G3-21.19g, productive rate 71%.Mp162.1-163.7℃; 1H?NMR(400MHz,CDCl 3)δ7.40-7.18(m,20H),4.90(s,2H),1.49-1.39(m,4H),1.30-1.22(m,6H); 13C?NMR(101MHz,CDCl 3)δ142.0,140.2,129.6,128.3,128.1,127.8,127.7,127.6,110.7,80.0,73.2,36.7,25.0,24.1;IR(KBr):3446,3060,2929,2853,2120,1376,1366,1267,1107,756,737,698;HRMS(ESI)Calcd.for?C 34H 32N 6O 2Na +([M+Na] +)579.2484,Found579.2473。
3.G3-3 synthetic:
Under the blanket of nitrogen, with LiAlH 4(455.4mg, 12mmol 6.0eq.) are suspended in the oxolane (15mL), are cooled to 0 ℃.Slowly drip and be dissolved with G3-2(1113.7mg, 2mmol, oxolane 1.0eq.) (15mL) solution.0 ℃ of reaction 4h.After reacting completely, 1M NaOH(8mL) cancellation reaction, reactant liquor add diethyl ether after (15mL) dilution, add anhydrous sodium sulfate (8g), stirring at room 2h.The filtering solid, the Anhydrous potassium carbonate drying steams solvent, and crude product column chromatography (methylene chloride=20/1) gets white solid G3-3851.1mg, productive rate 84%.Mp228.4-231.7℃; 1H?NMR(400MHz,CDCl 3)δ?7.55-7.50(m,4H),7.35-7.29(m,6H),7.24-7.10(m,10H),4.20(s,2H),2.21(brs,4H),1.51-1.36(m,4H),1.28-1.22(m,6H);IR(KBr):3359,2942,2858,1493,1367,1352,1122,767,740,704;HRMS(ESI)Calcd.for?C 34H 37N 2O 2 +([M+H] +)505.2855,Found505.2863。
4.G3-4 synthetic:
Under the blanket of nitrogen, to being dissolved with G3-3(850mg, 1.68mmol, add in pyridine 1.0eq.) (2mL) solution carbon disulfide (204 μ L, 3.37mmol, 2.0eq.).Reactant liquor is warming up to 60 ℃, reaction 20h.The back cool to room temperature reacts completely, add methylene chloride (50mL) and water (20mL) in reactant liquor, 1M HCl transfers pH=2, tells organic phase, water dichloromethane extraction three times (20mL * 3), merge organic phase, 1M NaOH solution is washed (20mL * 1), and saturated nacl aqueous solution is washed (30mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product column chromatography (petrol ether/ethyl acetate=10/1) gets white solid G3-4762mg, productive rate 83%.Mp258.3-261.2℃;[α] D 24=-197.5(c0.11,CH 2Cl 2); 1H?NMR(400MHz,CDCl 3)δ7.60-7.57(m,4H),7.44-7.34(m,6H),7.29-7.26(m,6H),7.20-7.11(m,4H),6.87(s,2H),4.58(s,2H),1.55-1.22(m,10H); 13C?NMR(101MHz,CDCl 3)δ185.7,143.6,139.8,129.3,128.8,128.4,128.0,127.9,127.7,111.3,77.3,70.7,36.3,24.9,23.7;IR(KBr):3378,3058,2935,1635,1447,1366,1119,755,699;HRMS(ESI)Calcd.for?C 35H 34N 2O 2SNa +([M+Na] +)569.2239,Found569.2216。
4. chirality guanidine 20 is synthetic:
Under the blanket of nitrogen, in the 50mL reaction bulb, add Anhydrous potassium carbonate (55.3mg, 20.4mmol successively, 4.0eq.), stannous chloride (20.8mg, 0.21mmol, 2.1eq.), oxolane (1mL), G3-4(54.7mg, 0.1mmol, 1.0eq.), behind the stirring at room 10min, add methylbenzylamine (18.2mg, 0.15mmol, 1.5eq.), be warming up to 40 ℃, reaction 12h.The back cool to room temperature reacts completely, in reactant liquor, add saturated ammonium chloride solution (25mL), 1M HCl transfers pH=4, dichloromethane extraction three times (25mL * 3), merge organic phase and filter, the filtrate saturated nacl aqueous solution is washed (15mL * 1), anhydrous sodium sulfate drying, steam solvent, crude product column chromatography (methylene chloride=20/1) gets white solid.The gained solid is dissolved in the carrene (20mL), add 2M NaOH solution (4mL), stirring at room 2h, the water carrene is got (5mL * 2), merge organic phase, saturated nacl aqueous solution is washed (5mL * 1), Anhydrous potassium carbonate drying, steam solvent and get white solid 2039.4mg, productive rate 62%.
The catalytic applications example
Optically active Alpha-hydroxy-beta-dicarbonyl structure extensively is present in natural products, medicine and the chemistry of pesticide product molecule, also is the key intermediate of more synthetic chipal compounds.Asymmetry catalysis oxidation beta-dicarbonyl compound is to obtain one of effective method of this type of construction unit.In the organic catalysis, existing only have the asymmetric 'alpha '-hydroxylation reaction of cinchona alkaloid catalysis beta-ketoester to realize industrialization, can obtain yield and medium enantioselectivity preferably.Therefore continue to develop the cheap effectively chiral organic micromolecule catalyst with novel skeleton structure and have important significance for theories and using value.This patent has prepared a series of novel chiral guanidine catalysts based on the tartaric acid skeleton, and the asymmetric 'alpha '-hydroxylation that is applied to beta-dicarbonyl compound reacts, obtain almost quantitative yield and extraordinary enantioselectivity (table 3), for the Alpha-hydroxy-beta-dicarbonyl structure of synthesis of optically active provides important catalysis process.
Table 3: under the blanket of nitrogen, 21(1.0eq.), 6(0.1eq.) and 22(1.2eq.) in toluene ,-78 ℃ of reaction 0.5～13h, benzinum and ethyl acetate are eluant, eluent, column chromatography for separation obtains product 23.
Figure BDA00003301635600261
Figure BDA00003301635600262
When the asymmetric 'alpha '-hydroxylation of investigation beta-ketoester reacted, the size of ester group group had very big influence (entries1-5) to the enantioselectivity of reaction.The beta-keto acid methyl esters provides extraordinary 93%ee(entry1 as a result).Along with the change of beta-ketoester ester group group is big, reactivity and enantioselectivity all descend to some extent.Beta-keto acid tert-butyl ester 13h reacts completely, the productive rate with 96%, and 86% ee value obtains product (entry4).The cloud density of beta-ketoester substrate phenyl ring and substituting group position have influenced the enantioselectivity (entries6-11) of 'alpha '-hydroxylation reaction.No. 5 positions of phenyl ring be connected with electron-withdrawing substituent (F, Cl, Br) or can both provide fine yield and enantioselectivity (entries6-11) during electron donating group (OMe).Yet the enantioselectivity that reacts when being connected with substituting group 4 or No. 6 positions decreases (entries10,11).When reaction substrate was the beta-ketoester of hexatomic ring, reactivity reduced (12h reacts completely), enantioselectivity obviously descend (55%ee).When the asymmetric 'alpha '-hydroxylation of the beta-diketon that the investigation indone is derived reacted, the size of the outer acyl group of ring influenced not quite the enantioselectivity of reaction.Acetyl group, propiono and bytyry have all obtained close productive rate and ee value (entries13-15).Yet when No. 5 positions of phenyl ring are connected with substituting group, no matter be that (F, Cl still are electron donating group (OMe) Br) to electron-withdrawing substituent, though the enantioselectivity of reaction all descends to some extent, still obtained having the enantioselectivity product (entries16-19) of synthetic use.
The catalytic reaction products data
Figure BDA00003301635600271
min,t minor=27.2min).
Figure BDA00003301635600272
mL/min,t major=15.8min,t minor=18.9min).
Figure BDA00003301635600273
λ=254nm,30°C,0.8mL/min,t major=12.6min,t minor=14.3min).
Figure BDA00003301635600274
(determined?by?HPLC?using?chiral?OD-H?column,hexane/2-propanol=95/5,λ=254nm,30°C,0.8mL/min,t major=9.9min,t minor=11.0min).
Figure BDA00003301635600281
hexane/2-propanol=95/5,λ=254nm,30°C,0.8mL/min,t major=27.5min,t minor=33.6min).
Figure BDA00003301635600282
80.5,53.6,39.1(d,J=2.0Hz);IR(KBr):3398,1752,1719,1205,1182,798,656cm -1;HRMS(ESI)Calcd.for?C 11H 8O 4F([M-H] -)223.0407,Found223.0411;Enantiomeric?excess?was?determined?to?be91%(determined?by?HPLC?using?chiral?OD-H?column,hexane/2-propanol=95/5,λ=254nm,30°C,0.8mL/min,t major=23.3min,t minor=29.7min).
Figure BDA00003301635600283
24.3min,t minor=30.9min).
Figure BDA00003301635600284
31.3min).
Figure BDA00003301635600285
856,657cm -1;HRMS(ESI)Calcd.for?C 12H 12O 5Na([M+Na] +)259.0582,Found259.0572;Enantiomeric?excess?was?determined?to?be91%(determined?by?HPLC?using?chiral?OD-H?column,hexane/2-propanol=9/1,λ=254nm,30°C,0.8mL/min,t major=20.5min,t minor=24.6min).
Figure BDA00003301635600286
53.4,38.2,17.8.IR(KBr):3423,1749,1714,1260,1200,1179,769,677cm -1;HRMS(ESI)Calcd.for?C 12H 12O 4Na([M+Na] +)243.0633,Found243.0640;Enantiomeric?excess?was?determined?to?be80%(determined?by?HPLC?using?chiral?OD-H?column,hexane/2-propanol=95/5,λ=254nm,30°C,0.8mL/min,t major=19.1min,t minor=22.2min).
Figure BDA00003301635600291
t major=19.9min,t minor=23.9min).
Figure BDA00003301635600292
mL/min,t major=16.1min,t minor=18.2min).
Figure BDA00003301635600293
27.3min).
39.0,29.8,7.5;IR(KBr):3407,1724,1703,1130,1109,781,735,667cm -1;HRMS(ESI)Calcd.for?C 12H 12O 3Na([M+Na] +)227.0684,Found227.0689;Enantiomeric?excess?was?determined?to?be88%(determined?by?HPLC?using?chiral?AS-H?column,hexane/2-propanol=8/2,λ=254nm,30°C,0.7mL/min,t minor=11.0min,t major=19.8min).
Figure BDA00003301635600295
16.9,13.4;IR(Neat):3427,1727,1704,1124,1064,733cm -1;HRMS(ESI)Calcd.for?C 13H 14O 3Na([M+Na] +)241.0841,Found241.0838;Enantiomeric?excess?was?determined?to?be86%(determined?by?HPLC?using?chiral?AS-H?column,hexane/2-propanol=8/2,λ=254nm,30°C,0.7mL/min,t minor=11.7min,t major=20.3min).
Figure BDA00003301635600301
1699,1255,1128,624cm -1;HRMS(ESI)Calcd.for?C 11H 9O 3FNa([M+Na] +)231.0433,Found231.0437;Enantiomeric?excess?was?determined?to?be79%(determined?by?HPLC?using?chiral?AS-H?column,hexane/2-propanol=8/2,λ=254nm,30°C,0.7mL/min,t minor=13.0min,t major=29.0min).
Figure BDA00003301635600302
min).
Figure BDA00003301635600303
excess?was?determined?to?be81%(determined?by?HPLC?using?chiral?AS-H?column,hexane/2-propanol=8/2,λ=254nm,30°C,0.7mL/min,t minor=13.3min,t major=28.3min).
243.0633,Found243.0629;Enantiomeric?excess?was?determined?to?be80%(determined?by?HPLC?using?chiral?AS-H?column,hexane/2-propanol=7/3,λ=254nm,30°C,0.4mL/min,t minor=14.7min,t major=31.1min)。

Claims (10)

1. chirality guanidine catalyst based on the tartaric acid skeleton, for having the compound of general formula I or II:
Figure FDA00003301635500011
Ⅰ
Figure FDA00003301635500012
Ⅱ
Wherein:
R 1Be C 1～C 4Alkyl or phenyl;
R 2Be selected from hydrogen, C 1-6Alkyl, aromatic group, halogen, C 1-6Alkoxyl and C 1-6A kind of in the haloalkyl;
R 3Be C 1-6The residual chain of alkyl, aromatic group or amino alcohol;
In the general formula II, n=0,1 or 2.
2. according to the described chirality guanidine catalyst of claim 1, it is characterized in that: n=1.
3. according to the described chirality guanidine catalyst of claim 1, it is characterized in that: R 1Be methyl.
4. according to the described chirality guanidine catalyst of the arbitrary claim of claim 1～3, it is characterized in that: R 2Be methyl, isopropyl, the tert-butyl group, phenyl, 4-position or 3,5-position substituted-phenyl, methoxyl group or trifluoromethyl.
5. according to the described chirality guanidine catalyst of the arbitrary claim of claim 1～3, it is characterized in that: R 3Be methyl, cyclohexyl, phenyl, 4-position or 3,5-position substituted-phenyl, benzyl, 4-position or 3,4,5-position substituted benzyl.
6. according to the described chirality guanidine catalyst of claim 4, it is characterized in that: R 2Be hydrogen atom or phenyl.
7. according to the described chirality guanidine catalyst of claim 5, it is characterized in that: R 3For to methyl-benzyl, 3,4,5-trimethoxy benzyl, 2,6-diisopropyl phenyl, 3, the 5-di-tert-butyl-phenyl, (1S)-the 1-tert-butyl group-2-hydroxyethyl or (1S, 2S)-the 2-hydroxy-cyclohexyl.
8. according to the described chirality guanidine catalyst of claim 1, it is characterized in that: described catalyst is selected from a kind of of following numbering 1～12 compound:
Figure FDA00003301635500021
9. preparation method based on the chirality guanidine catalyst of tartaric acid skeleton, it is characterized in that: the preparation method of compound of Formula I is undertaken by following process route:
Figure FDA00003301635500031
The preparation method of general formula I I compound is identical with compound of Formula I preparation method process route.
10. preparation method according to claim 9 is characterized in that: may further comprise the steps:
1. condensation reaction: with tartrate and ketone or ketal in molar ratio 1:1～1:1.5 under lewis acidic catalysis, in benzene or reflux in toluene reaction 12～24h; The gained reactant liquor adds sodium acid carbonate, water treatment, extraction, washing, drying, concentrate at last enriched product;
2. grignard reaction: with step 1. gained condensation product and RMgBr in molar ratio 1:4.5～1:5 in oxolane, under counterflow condition, reacted 30～90 minutes; Cooling, cancellation, extraction, washing, drying, concentrated, recrystallization from ethyl acetate/petroleum ether gets product;
3. chlorination reaction: with step 2. gained grignard reaction product be dissolved in the carrene, with thionyl chloride, triethylamine 1:3:4.2～1:3.5:7 in molar ratio, in room temperature to reflux temperature, reaction 3～12h; Reaction steams solvent after finishing, and obtains chlorizate;
4. azido reaction: with step 3. gained chlorination reaction product be dissolved in N, in the dinethylformamide, with sodium azide 1:4 in molar ratio, in 80 ℃ of reaction 72h; Cooling, reactant liquor is poured in the water, use extracted with diethyl ether, organic layer washing, dry, filter, concentrated, rapid column chromatography obtains solid, with ether be recrystallized product;
5. reduction reaction: with step 4. gained Azide product be dissolved in the oxolane, with Lithium Aluminium Hydride 1:6 in molar ratio, in 0 ℃ of reaction 1.5～6h; Cancellation, extraction, washing, drying, concentrate, ether/n-hexane be recrystallized product;
6. the preparation that has the chirality thiocarbamide of tartaric acid skeleton: with step 5. the gained reduzate be dissolved in the pyridine, with carbon disulfide 1:2 in molar ratio, in 60 ℃ of reaction 12～24h; Cooling, reactant liquor is poured in the water, uses dichloromethane extraction; Organic layer washing, dry, filter, concentrate, carrene/n-hexane be recrystallized product;
7. the preparation that has the chirality guanidine catalyst of tartaric acid skeleton: with step 6. gained thiocarbamide and amine, stannous chloride, potash in molar ratio 1:1.2:2:4～1:10:2.1:15 add in the oxolane, in 40 ℃ of reaction 4～72h; Cooling, cancellation, extraction, filtration, washing, drying, concentrated, column chromatography obtains solid product.
CN201310218970.4A 2013-06-04 2013-06-04 Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof Expired - Fee Related CN103272638B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310218970.4A CN103272638B (en) 2013-06-04 2013-06-04 Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310218970.4A CN103272638B (en) 2013-06-04 2013-06-04 Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN103272638A true CN103272638A (en) 2013-09-04
CN103272638B CN103272638B (en) 2015-04-22

Family

ID=49055318

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310218970.4A Expired - Fee Related CN103272638B (en) 2013-06-04 2013-06-04 Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN103272638B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107721969A (en) * 2017-11-08 2018-02-23 天津狄克特科技有限公司 Chiral catalyst part TADDOLs preparation method in a kind of asymmetric syntheses
CN108440534A (en) * 2018-04-04 2018-08-24 南开大学 Efficiently synthesize β chiral bicyclic or polycyclic imidazole derivatives
CN112645839A (en) * 2020-12-23 2021-04-13 安徽泽升科技有限公司 Bilateral asymmetric substituent substituted tartaric acid skeleton compound and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102658199A (en) * 2012-05-14 2012-09-12 惠州市莱佛士制药技术有限公司 Novel asymmetric phase-transfer catalyst pentaazabicyclo and preparation method thereof
CN102718768A (en) * 2012-06-26 2012-10-10 惠州市莱佛士制药技术有限公司 Chiral five-membered bicyclic guanidine compound, preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102658199A (en) * 2012-05-14 2012-09-12 惠州市莱佛士制药技术有限公司 Novel asymmetric phase-transfer catalyst pentaazabicyclo and preparation method thereof
CN102718768A (en) * 2012-06-26 2012-10-10 惠州市莱佛士制药技术有限公司 Chiral five-membered bicyclic guanidine compound, preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHRISTOPHER UYEDA ET AL: "Enantioselective Claisen Rearrangements with a Hydrogen-Bond Donor Catalyst", 《J. AM. CHEM. SOC.》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107721969A (en) * 2017-11-08 2018-02-23 天津狄克特科技有限公司 Chiral catalyst part TADDOLs preparation method in a kind of asymmetric syntheses
CN107721969B (en) * 2017-11-08 2020-02-11 天津狄克特科技有限公司 Preparation method of chiral catalyst ligand TADDOLs in asymmetric synthesis
CN108440534A (en) * 2018-04-04 2018-08-24 南开大学 Efficiently synthesize β chiral bicyclic or polycyclic imidazole derivatives
CN108440534B (en) * 2018-04-04 2021-05-28 南开大学 Efficient synthesis of beta-chiral bicyclic or polycyclic imidazole derivatives
CN112645839A (en) * 2020-12-23 2021-04-13 安徽泽升科技有限公司 Bilateral asymmetric substituent substituted tartaric acid skeleton compound and application thereof

Also Published As

Publication number Publication date
CN103272638B (en) 2015-04-22

Similar Documents

Publication Publication Date Title
WO2021129082A1 (en) METHOD FOR SYNTHESIZING α-ACRYLIC ACID COMPOUND BY USING PALLADIUM TO CATALYZE CARBON DIOXIDE AND ALKYNE
Balsells et al. Synthesis of chiral sulfonamide/Schiff base ligands
CN103087105A (en) Chiral phosphine ligand and metal catalyst comprising same and application of chiral phosphine ligand and metal catalyst
CN103272638B (en) Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof
CN105111208A (en) Preparation method of tetrahydro 1, 8-naphthyridine compound and chiral product prepared by adopting preparation method
Liu et al. Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides using amino acid auxiliary
CN106986800A (en) A kind of preparation method of β carbonyls thioether
CN110494439B (en) Chiral biphenyl diphosphine ligand and preparation method thereof
CN109180682A (en) A kind of chiral aza ring carbene precursor compound and preparation method thereof with bicyclic skeleton
CN111072605B (en) Preparation method of fluoroalkyl-substituted benzofuran derivative or indole derivative
CN109908954A (en) A kind of chiral aldehydes catalyst and preparation method and the method for being catalyzed asymmetric nucleophilic addition
CN106905227A (en) The preparation method of aryl-linking compound
CN104109174B (en) A kind of biphenyl ligand and synthetic method thereof and the application in the reaction of racemize propargyl alcohol carbonic ether Infectious disease thereof
CN103402973A (en) Compound and method for producing same, as well as method for producing oseltamivir phosphate
CN106748802B (en) A method of preparing fluorine-containing secondary amine
CN106866480A (en) Many cyclophane selenide analog derivatives and preparation method thereof
Muzalevskiy et al. Synthesis of α-trifluoromethyl-phenethylamines from α-trifluoromethyl β-aryl enamines and β-chloro-β-(trifluoromethyl) styrenes
CN103044467A (en) Method for preparing intermediate used for synthesizing bortezomib
CN100588656C (en) Forcipated diimidazoline palladium compound and its application in Suzuki reaction
CN103601779B (en) The synthetic method of 7-denitrification-2 '-deoxidation-7-halogen 9 substituted guanine nucleosides
CN109320538B (en) Synthesis method of 3-bromo-5-aryl-2- (trimethylsilyl) -1- (N, N-dimethyl sulfonamide) pyrrole
CN107056674A (en) A kind of method of suzuki cyclisation coupling one-step synthesis dihydro pyrrole derivates
CN111138338A (en) Synthesis method of photocatalytic fluoroalkyl indoline
CN111057080A (en) Preparation method of boron-containing indolinone derivative
CN111808041B (en) Difluoroalkyl aryl oxazolidinone compound and preparation method thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20150422

Termination date: 20180604

CF01 Termination of patent right due to non-payment of annual fee