CN1539838A - Recoverable repeatable use chirality cinchona alkaloid ligand and application - Google Patents

Recoverable repeatable use chirality cinchona alkaloid ligand and application Download PDF

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CN1539838A
CN1539838A CNA2003101058586A CN200310105858A CN1539838A CN 1539838 A CN1539838 A CN 1539838A CN A2003101058586 A CNA2003101058586 A CN A2003101058586A CN 200310105858 A CN200310105858 A CN 200310105858A CN 1539838 A CN1539838 A CN 1539838A
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孙晓莉
张生勇
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Fourth Military Medical University FMMU
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Abstract

A recoverable and cyclically used chiral cinchona alkaloid ligand and its application in the asymmetrical bihydroxylation or aminohydroxylation of olefin and disclosed.

Description

Recyclable and reusable chirality cinchona alkaloid ligand and application thereof
Technical field
The present invention relates to a class recyclable and reusable small molecules chirality cinchona alkaloid ligand and in the asymmetric dihydroxylation of alkene and the application in the Asymmetric Aminohydroxylation Reaction.
Background technology
Chirality is one of natural feature, also is the basis of all life, and biological phenomena depends on the existence and the chiral recognition of chirality.All animals and plants and human body all have accurate chiral recognition ability to medicine.The configuration difference of chiral drug, their physiologically active is also different with toxicity.The L-DOPA is the Parkinsonian good medicine of treatment, but the D-DOPA has serious toxic side effect.(S)-drug effect of Naproxen Base is 35 times of (R)-isomer.So how obtaining chipal compounds just becomes the severe challenge that the chemist faces.Can obtain optical pure compound though the racemic modification by classics splits and chiral source is synthetic, the catalysis asymmetric synthesis that the seventies grows up is the most economical and scientific methods of acquisition chipal compounds.
Asymmetry catalysis synthetic key is how to design and synthesize the catalyzer of high enantioselectivity and catalytic activation, and its core work is the design of chiral ligand and synthesizes.
Asymmetric dihydroxylation reaction (AD) can be represented by the formula:
Figure A20031010585800031
Asymmetric Aminohydroxylation Reaction (AA) is represented with following formula:
Figure A20031010585800032
The adjacent two pure and mild chirality beta-alkamines of the product chirality of these two kinds of reactions are the important synthetic drugs and the intermediate of chirality natural product, and raw material olefin is a latent chirality function based raw material cheap and easy to get.Because the part that uses costs an arm and a leg and can not reclaim and reuse at present, thereby limited the suitability for industrialized production of these two kinds of reactions.The key that determines this reaction is chiral ligand and metal complex thereof, and in recent ten years, people further investigate this reaction, and constantly releases new part to improve optical yields.So far, best small molecules part all is the biologically-derived thing of quinine that Sharpless successively reports, and its structure is represented with A, B, C respectively.
ALK *=DHQ (hydroquinine) or DHQD (dihydro-quinidine)
Yet they all can not reclaim and reuse, and therefore, cost is higher.In order to reduce cost, people have developed callable macromolecular ligand, and have obtained comparatively ideal optical yields.Mainly contain three class macromolecular ligands: 1. insoluble organic polymer load part.2. the cinchona alkaloid ligand of inorganic carrier load.3. the cinchona alkaloid ligand of solubility polymer-supported.But there is following shortcoming in they: 1. synthesis step is long, the cost height; 2. molecule is too big, and movement velocity is slow, so reactive behavior descends; 3. because of molecular weight is big, add-on is too big for substrate; When 4. reclaiming, consumption of organic solvent is big.
Summary of the invention
One of purpose of the present invention provides the new callable small molecules chirality cinchona alkaloid ligand of a class.
Another object of the present invention provides the purposes of above-mentioned part in AD reaction and AA reaction, since reusable, production cost reduced effectively, have good industrial prospect.
The chirality cinchona alkaloid ligand has following general structure:
Figure A20031010585800042
R wherein 1Be
Figure A20031010585800043
Or
Figure A20031010585800044
R 2, R 3Be selected from following radicals:
1. R 2And R 3Be the alkyl of 2-10 carbon atom one of arbitrarily; R 2And R 3It is the alkyl that contains 2-10 carbon atom of 1-2 hydroxyl; R 2And R 3It is the hydroxyl sulfuryl alkyl of 2-10 carbon atom; R 2And R 3It is the carboxyl sulfuryl alkyl of 2-10 carbon atom; R 2And R 3It is the ester group sulfuryl alkyl of 3-10 carbon atom; R 2And R 3It is the carboxyalkyl of a carboxyl or 2-10 carbon atom; R 2And R 3It is the ester group of 2-10 carbon atom; R 2And R 3It is the carbonylic alkyl of 2-10 carbon atom; R 2And R 3It is the haloalkyl (halogen is F, Cl, Br, I) of 2-10 carbon atom;
2. work as R 2=R 3=-CH (OH) CH 2During OH,
Figure A20031010585800051
Specify as follows:
1. R 2And R 3Can be the alkyl of 2-10 carbon atom, but R 2And R 3Be not alkyl simultaneously, for example if R 2Be alkyl-CH 2CH 3Or-CH 2CH 2CH 3, R then 3Be a polar group, as-CH 2CH 2SO 2CH 2CH 2OH;
2. R 2, R 3Be the alkyl that contains 2-10 carbon atom of 1-2 hydroxyl, as-CH 2OH ,-CH (OH) CH 3,-CH (OH) CH 2OH ,-CH 2CH (OH) CH 2OH;
3. R 2, R 3Be the hydroxyl sulfuryl alkyl of 2-10 carbon atom, as-CH 2CH 2SO 2CH (CH 2OH) 2,-CH 2CH 2SO 2CH 2CH 2OH ,-CH 2CH 2SO 2CH 2CH (OH) CH 2OH;
4. R 2, R 3Be the carboxyl sulfuryl alkyl of 2-10 carbon atom, as-CH 2CH 2SO 2CH 2CH 2COOH;
5. R 2, R 3Be the ester group sulfuryl alkyl of 3-10 carbon atom, as-CH 2CH 2SO 2CH 2CH 2COOCH 3
6. R 2, R 3Be the carboxyalkyl of a carboxyl or 2-10 carbon atom, as-COOH, CH 2COOH;
7. R 2, R 3Be the ester group of 2-10 carbon atom, as-COOCH 3,-COOCH (OH) CH 2OH;
8. R 2, R 3Be the carbonylic alkyl of 2-10 carbon atom, as-COCH 3
9. R 2, R 3Be the haloalkyl (halogen is F, Cl, Br, I) of 2-10 carbon atom, as-CH (Br) CH 2Br ,-CH (Br) CH 3
The preparation of part
Instrument and condition that experiment is used: the micro-fusing point instrument of XRC-1; The automatic polarimeter of PERKIN-ELMER 343 types; VARIAN INOVA-400 type nuclear magnetic resonance spectrometer; Bruker Apex II and ZAB-HS type mass spectrograph; Viro EL III type elemental analyser; The efficient liquid of Waters 600E type Hunan chromatographic instrument (Turbochrom data processing; Detect wavelength 220nm); Daicel Chiralcel, OD, AD, chiral chromatographic column; WatersALC/GPC type gel permeation chromatograph (Ultrastyragel post group: 100A, 500A, 10 3A, 10 4A).
1. intermediate 1 and 2 preparation method
The structure of intermediate 1 and intermediate 2 is as follows:
The method for making of the method for making of intermediate 1 and intermediate 2 is similar, and the synthetic route of intermediate 1 is:
Use 3,6-dichloro-pyridazine and quinine or quinidine reaction obtain.
Intermediate 2, synthetic route is:
Figure A20031010585800062
Synthesizing of intermediate 1
In the 100mL three-necked bottle, add 4g (0.0268mmol) 3,6-dichloro-pyridazine, 11.13g (0.0343mmol) quinine; add 35mLDMF again, under the nitrogen protection, add 4.2g (0.175mmol) NaH; 60～80 ℃ of reactions of magnetic agitation 8h, TLC check only to have and seldom measure quinine residue, stopped reaction.Add 150mL ethyl acetate and 100mL water extracting and demixing, water layer is used ethyl acetate extraction (100mL * 3) again, merges the ester layer and washes (100mL * 3), anhydrous MgSO with water 4Drying, suction filtration, evaporated under reduced pressure gets solid 15g, gets white needle-like crystals with re-crystallizing in ethyl acetate, and vacuum-drying gets intermediate 17.6g, productive rate 60%. 1HNMR is consistent with structure.
Synthesizing of intermediate 2
In the exsiccant there-necked flask, add 7.2g (0.022mol) quinine (QN), 2.2g (0.011mol) 1,4-two chloro-2,4.5g anhydrous K 2CO 3With 60mL dry toluene, N 2Protection down, oil bath reflux 2h adds 1.8g KOH then, reflux water-dividing 15h (use acetone: ethyl acetate: triethylamine=make developping agent at 45: 5: 3.5, TLC follows the tracks of reaction) adds 20mL water after being chilled to room temperature.Then, use CH 2Cl 2Extraction (30mL * 3) is washed till neutrality with 20mL water and 20mL salt solution with organic layer, anhydrous MgSO more successively 4Drying, drain crude product 9.6g.Separate with above-mentioned developping agent rapid column chromatography, get intermediate 26.2g, productive rate 72.9%.
1H NMR (CDCl 3, interior mark TMS): δ: 8.65 (d, J=5.3Hz, 2H, Ar-H), 8.33 (m, 2H, Ar-H), 7.98 (d, J=9.2Hz, 2H, Ar-H), 7.96 (m, 2H, Ar-H), 7.58 (s, 2H, Ar-H), 7.44 (d, J=5.2Hz, 2H, Ar-H), 7.38 (m, 2H, Ar-H), 7.03 (br, 2H, HC-O), 5.83 (m, 2H, HC=C), 4.99 (m, 4H, H 2C=C), 3.93 (s, 6H, CH 3O), 3.50 (m, 2H), 3.13 (m, 4H), 2.60 (m, 4H), 2.26 (s, 2H), 1.40-1.89 (m, 10H). 13C?NMR(CDCl 3，100MHz)：δ：157.70，156.90，147.38，144.75，141.95，132.37，131.60，127.20，122.80，122.60，122.47，121.96，118.49，114.39，101.90，77.22，60.14，56. 73，55. 73，42.68，39.90，27.72，23.85，15.29。MS(FAB)：m/z?775.1(M+H +)，307.2，136.1。
Although intermediate 1 and intermediate 2 also are to have the outstanding active part of AD catalytic reaction, their solubleness in non-polar solvent is fine, is difficult to reclaim with usual way.According to the similar principle that mixes, the contriver introduces polar group at intramolecularly, to reduce the solubleness of part in non-polar solvent, just R 2, R 3All replaced arbitrarily one or both of by polar group.
Estimating a small molecules part in the AD reaction during active and stereoselectivity, the contriver adopts the method for Sharpless, i.e. 1mmol alkene, 3mmol K 3Fe (CN) 6, 3mmol K 3CO 3, 0.002mmolK 2OsO 2(OH) 4(substrate 0.2%), 0.01mmol part (substrate 1%), the trimethyl carbinol: water=reaction in 1: 1, product is through column chromatography for separation.Potassium osmate original position in this system generates OsO 4, form catalyzer with part.Need add a certain amount of CH for non-terminal olefine 3SO 2NH 2, to promote osmium VIThe hydrolysis of Monoethylene Glycol (MEG) ester.React as follows:
R＝H，Ph，COOR
When R=H, osmium VIAcid Monoethylene Glycol (MEG) ester itself is easy to hydrolysis, need not add CH 3SO 2NH 2
The AD that the contriver has examined or check 2 pairs of multiple alkene of part with aforesaid method reacts, and the results are shown in table 1.
The AD reaction of table 1 part 2
Substrate reactions thermotonus time productive rate ee
(℃) (h) (％) (％) b
0 24 92.0 96.6
Figure A20031010585800073
25 24 92.1 96.9
Figure A20031010585800074
0 24 90.1 97.6
Figure A20031010585800075
25 24 91.0 90.3
Figure A20031010585800076
0 24 86.1 89.0
Figure A20031010585800077
25 24 82.7 98.0
25 24 90.4 92.4
Embodiment 1: the preparation (R of part 3 2And R 3One of be the situation of the alkyl of 2-10 carbon atom)
Figure A20031010585800081
Use reagent and reaction conditions: (a) NaH, DMF, 50 ℃, 10h, productive rate 85%
(b)DHQ，NaH，DMF，70℃，8h，76％
(c) α-mercaptoethanol, AIBN, backflow 15h, 70%
(d) NMO, OsO 4, backflow 20h, 94%
Embodiment 2: the preparation (R of part 4,5 2, R 3Be the situation of alkyl that contains 2-10 carbon atom of 1-2 hydroxyl)
Figure A20031010585800082
Embodiment 3: the preparation (R of part 6,7,8 2, R 3Be the situation of the hydroxyl sulfuryl alkyl of 2-10 carbon atom)
In the 100mL there-necked flask, successively add 262.4mg (1.6mmol) Diisopropyl azodicarboxylate (AIBN), 0.3mL (4.2mmol) mercaptoethanol, 3.1g (4mmol) is (QN) 2PHAL 2 and 20mL CHCl 3Under the nitrogen protection, the oil bath heating, 67 ℃ of backflow 36h use CHCl 3: CH 3OH: Et 3N=5: do carry out agent at 1: 1, TLC checks two new dot generation, still has raw material point residue.Be cooled to room temperature, add 20mL water, use CHCl 3Extraction (30mL * 3), combining extraction liquid, with the saturated common salt washing once, anhydrous MgSO 4Drying, the pressure reducing and steaming solvent gets crude product, and crude product uses column chromatography (CH 3OH: Et 3N=5: 1), the component of winning (raw material) 0.3g, second component product (monoether) 1.7g, productive rate 50.1%, m.p.126.5～128 ℃ also obtain the 3rd component (bis ether) 0.71g simultaneously, productive rate 19%, m.p.134～135.5 ℃.
In the 100mL round-bottomed flask, successively add 1.7g (2.0mmol) monoether, 0.7g (6mmol) NMO, 20mL THF, 8mL tBuOH.Stir and drip 100mg/mL OsO down 4Toluene solution 0.24mL.Stir 12h under the room temperature, solution has precipitation to generate from light to dark, last blackening.Add NaHSO 36g stirs 2h.The anhydrous MgSO of suction filtration, filtrate 4Dried overnight.The pressure reducing and steaming solvent, remaining solid uses column chromatography (CHCl 3: Et 3N=5: 1), get part 6 (1.32g), productive rate 70%.m.p.164.5～166℃。
Figure A20031010585800091
Part 7 and 8 synthetic method are similar with synthetic 6.
Embodiment 4: the preparation (R of part 9,10 2, R 3Be the type of the carboxyl sulfuryl alkyl of 2-10 carbon atom)
Embodiment 5: the preparation (R of ligand 11 2, R 3Be the type of the ester group sulfuryl alkyl of 3-10 carbon atom)
Figure A20031010585800102
With part 9 is that raw material can synthetic ligands 11 with conventional esterification process.
Embodiment 6: the preparation (R of ligand 12 2, R 3Be the type of the carboxyalkyl of 1-10 carbon atom)
Figure A20031010585800103
Can be oxidized to ligand 12 with 1 easily with oxygenant commonly used.
Embodiment 7: the preparation (R of ligand 13 2, R 3Be the type of the ester group of 2-10 carbon atom)
Figure A20031010585800104
With ligand 12 is that raw material can synthetic ligands 13 with conventional esterification process.
Embodiment 8: the preparation (R of ligand 14 2, R 3Be the carbonylic alkyl of 2-10 carbon atom)
Can be oxidized to ligand 14 with 5 easily with oxygenant commonly used.
Embodiment 9: the preparation (R of ligand 15,16 2, R 3Be the type of the haloalkyl of 2-10 carbon atom)
Figure A20031010585800112
With ordinary method is available Br 2, HBr by addition reaction from 1 the preparation 15,16.
Embodiment 10: the experimental result and the recovering state of part 3 catalysis AD reaction
In the 50mL three-necked bottle, add K 3[Fe (CN) 6] 0.980g (3mmol), K 2CO 30.410g (3mmol), part 0.0084g (0.01mmol), K 2OsO 2(OH) 40.0008g (0.002mmol), CH 3SO 2NH 20.095g (1mmol) (end alkene does not add), alkene 1mmol adds the 6mL water and the 6mL trimethyl carbinol, the stirring at room reaction.TLC detects, and after reaction finishes, adds 1.5g Na 2SO 3Stir 1h, add the 10mL ethyl acetate, stir layering.Water layer merges organic layer with ethyl acetate extraction (15mL * 3), washes (end alkene is without KOH) with 2M KOH 10mL, and water is washed till neutrality with the ester layer then.(end alkene washes with water 3 times), organic layer adds anhydrous MgSO 4Drying, concentrating under reduced pressure, silica gel column chromatography separates, and experimental result is listed in table 2.
In the 50mL three-necked bottle, add K 3[Fe (CN) 6] 1.960g (6mmol), K 2CO 30.820g (6mmol), part 0.084g (0.1mmol), CH 3SO 2NH 20.190g (2mmol), ethyl cinnamate 0.352g (2mmol) adds the 10mL water and the 10mL trimethyl carbinol.Stir and add OsO down 4Toluene solution (50mg/100mL) 52 μ l room temperature reaction 20h.The TLC monitoring, reaction adds 2.5g NaSO after finishing 3Stir 1h.The pressure reducing and steaming trimethyl carbinol.Water layer CH 2Cl 2Extraction (30mL * 3), CH 2Cl 2Layer washes with water again, and organic phase adds anhydrous MgSO 4Drying is evaporated to 1mL, adds the 20mL anhydrous diethyl ether, and the adularescent precipitation is separated out the recovery part 80% of sand core funnel suction filtration.Ether layer TLC detects no remaining part.Reclaim part and repeat catalyzed reaction again 5 times.
Table 2 part 3 catalysis AD reaction results
Sequence number. olefin product time chemicals rate optical yields
(％) (％)
1 16 75 98
2 15 74 96
3
Figure A20031010585800123
10 86 ＞99
4 20 91 ＞99
5 5 85 88
6
Figure A20031010585800126
10 79 92
Embodiment 11: the AD reaction result of part 4
The AD reaction experiment the results are shown in Table 3.
Table 3 part 4 catalysis AD reaction results
Sequence number alkene time chemical yield (%) optical yields. (%)
1 16 72 98
2
Figure A20031010585800128
15 82 96
3
Figure A20031010585800129
10 90 99
4 ?20 90 99
5
Figure A200310105858001211
5 79 88
6 10 94 92
Embodiment 1:: the AD reaction result of part 6 and recovery experiment (seeing Table 4)
Table 4 part 6 catalysis AD reaction results
Ask the isolated yield optical yields during substrate temperature
(℃) (h) (％) (％)
26 24 97.8 99.0
Figure A20031010585800132
26 24 82.2 92.5
Figure A20031010585800133
26 24 97.3 97.1
Figure A20031010585800134
26 24 98.1 95.2
Figure A20031010585800135
26 6 ＞99 99.0
Figure A20031010585800136
26 10 99.0 99.5
The recovery experiment of part 6---ethyl cinnamate is made substrate recovery part
In 25mL single port bottle, add 1.96g (6.0mmol) K 3Fe (CN) 6, 0.82g (6.0mmol) K 2CO 3, 0.19g (2.0mmol) CH 3SO 2NH 2, 52 μ L (0.01mmol) OsO 4Toluene solution (50mg/mL), 0.0918g (0.1mmol) part 6, reactor is placed magnetic stirring apparatus, add 0.352g (2mmol) trans-cinnamic acid ethyl ester, 10mL water is stirred to the inorganics CL, adds the 10mL trimethyl carbinol again, after reacting 8h under 26 ℃, TLC checks that no raw material point has only a new dot generation.Add 2.5gNa 2SO 3Stir 1h.The pressure reducing and steaming trimethyl carbinol, water layer have insoluble inorganic salt, add 2mL water again.Use CH 2Cl 2Organic layer is told in extraction (15mL * 3).Merge organic layer, anhydrous MgSO 4Drying, suction filtration, concentrating under reduced pressure filtrate slowly drips exsiccant anhydrous diethyl ether 25mL to 0.5mL, and the adularescent precipitation produces immediately, places 30min, with G-5 sand core funnel suction filtration, with solid vacuum-drying, reclaims part 60.091g, the rate of recovery 99%.Check filtrate with TLC, no part exists.The placement of diethyl ether solution room temperature is spent the night, and volatilization gets needle-like crystal next day naturally, and decompressing and extracting gets solid 0.418g, productive rate 99.5%, and it is 99% that the HPLC chiral column is measured the ee value.
The part that reclaims through a little be supplemented to 0.1mmol once more catalysis measure substrate equally, repeat catalysis 6 times.
The rate of recovery reclaims part productive rate glycol amount optical yields
Recovered frequency
(％) (g) (％) (g) (％) *
1 99.1 0.091 99.5 0.418 99
2 98.0 0.090 99.2 0.417 99
3 98.0 0.090 99.0 0.416 99
4 98.0 0.090 99.2 0.417 99
5 98.0 0.090 99.0 0.415 99
6 99.1 0.091 99.0 0.415 99
Embodiment 12: the AA reaction of part 6
The AA reaction of vinylbenzene, trans-cinnamic acid ester
In the 25ml round-bottomed flask, (0.469g, 3.1mmol) 7.5ml of solution and new preparation is dissolved with NaOH (0.122g, aqueous solution 3.05mmol) to add the benzyl carbamate that is dissolved in the 4ml n-propyl alcohol.Drip freshly prepd t-butyl hypochlorate 0.35ml (3.05mmol).Place 25 ℃ of water-baths, magnetic agitation.Behind the several minutes, add the 3.5ml n-propyl alcohol solution that is dissolved with part 6 (0.05mmol).This moment, reaction solution was a homogeneous phase.Behind the 5min, add alkene (1mmol) and K 2OsO 2(OH) 4 (14.7mg, 0.04mmol), it is green that reaction solution is.Reaction finishes back (TCL monitoring), and reaction mixture cools off with ice-water bath, adds the 20ml saturated sodium bisulfite solution, continues to stir 15min, rises to room temperature, restir 30min.Leave standstill layering.Water merges organic phase with ethyl acetate extraction (15ml * 3), uses 20ml water and the water washing of 50ml salt respectively, the MgSO4 drying, and concentrating under reduced pressure is used the chromatography separated product.
The AA reaction of β-naphthalene ethene
Replace vinylbenzene with β-naphthalene ethene, other charging capacity is the same.Be reflected under 0 ℃ and carry out.After the reaction end, (～4 ℃) standing over night has solid to separate out in refrigerator, filters, with the cold n-propyl alcohol-water of 3ml (v/v1: 1) wash, filter, get white solid 207.6mg, productive rate 65%.Crude product is dissolved in ethyl acetate, and by filtered through silica gel, the pressure reducing and steaming solvent gets pure product 191.0mg.

Claims (3)

1. chirality cinchona alkaloid ligand has following general structure:
Figure A2003101058580002C1
R wherein 1Be Or
R 2, R 3Be selected from following radicals:
1. R 2And R 3Be the alkyl of 2-10 carbon atom one of arbitrarily; R 2And R 3It is the alkyl that contains 2-10 carbon atom of 1-2 hydroxyl; R 2And R 3It is the hydroxyl sulfuryl alkyl of 2-10 carbon atom; R 2And R 3It is the carboxyl sulfuryl alkyl of 2-10 carbon atom; R 2And R 3It is the ester group sulfuryl alkyl of 3-10 carbon atom; R 2And R 3It is the carboxyalkyl of a carboxyl or 2-10 carbon atom; R 2And R 3It is the ester group of 2-10 carbon atom; R 2And R 3It is the carbonylic alkyl of 2-10 carbon atom; R 2And R 3It is the haloalkyl of 2-10 carbon atom;
2. work as R 2=R 3=-CH (OH) CH 2During OH,
2. the application of the described part of claim 1 in the asymmetric dihydroxylation reaction of alkene.
3. the application of the described part of claim 1 in the Asymmetric Aminohydroxylation Reaction of alkene.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1310914C (en) * 2005-08-24 2007-04-18 中国人民解放军第四军医大学 Acid absorbing agent for preparing cinchona alkaloids ligand
CN101029049B (en) * 2007-03-23 2011-04-13 中国人民解放军第四军医大学 Use of recovered and reutilized quinine derivative derivative ligand in synthesizing paclitaxel and polyene paclitaxel sided chain

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1310914C (en) * 2005-08-24 2007-04-18 中国人民解放军第四军医大学 Acid absorbing agent for preparing cinchona alkaloids ligand
CN101029049B (en) * 2007-03-23 2011-04-13 中国人民解放军第四军医大学 Use of recovered and reutilized quinine derivative derivative ligand in synthesizing paclitaxel and polyene paclitaxel sided chain

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