CN1314673C - Multidentate oxazoline ligand having chirality and its compounding product with main group metal or transition metal, synthesis method and its use - Google Patents

Multidentate oxazoline ligand having chirality and its compounding product with main group metal or transition metal, synthesis method and its use Download PDF

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CN1314673C
CN1314673C CNB021123543A CN02112354A CN1314673C CN 1314673 C CN1314673 C CN 1314673C CN B021123543 A CNB021123543 A CN B021123543A CN 02112354 A CN02112354 A CN 02112354A CN 1314673 C CN1314673 C CN 1314673C
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oxazoline
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CN1513847A (en
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唐勇
周剑
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to a multidentate oxazoline ligand with chirality, a compounding product of the oxazoline ligand and the metal of a main family or the transition metal of a third family to a thirteenth family, a synthesis method of the compounding product and an application of the compounding product for catalyzing asymmetric synthesis. The structural formula of the compounding product is disclosed in the specification, wherein m1, m2 or m3 is 0 or an alkylene of C1-3, and m1, m2 and m3 can be identical or different. M is a metal atom of the main family or a transition metal atom of the third family to an eleventh family; X is anions, X can comprise halogen atoms comprising fluorine, chlorine, bromine or iodine., and oxygen-comprising base groups, fluorine-comprising base groups or boron-comprising base groups, and a plurality of X can be identical or different. N is 1, 2 or 3; A and B are oxygen atoms, sulphur atoms, selenium atoms, phosphorus atoms or nitrogen atoms; R, R1, R1', R2, R2', R3, R3', R4, R5, R6 and R7 are the alkyls of C1-30 or the alkyls of C1-30 comprising oxygen or nitrogen, and R, R1, R1', R2, R2', R3, R3', R4, R5, R6 and R7 can be identical or different or mutually formed into ring forming keys. The base groups can be the chiral base groups or can not be the chiral base groups, the coordination capability of the base groups is not stronger than that of N atoms in an oxazoline ring in a ligand framework, and an arrowhead toward right direction represents a single key or double keys. The oxygen-comprising base groups are oxygen-comprising acid radix negative ions comprising trifluoromethanesulfonic acid radix negative ions, sulfate radix negative ions or perchloric acid radix negative ions, the fluorine-comprising base groups are fluorine-comprising acid radix negative ions comprising fluoroboric acid radix negative ions, hexafluoro antimonic acid radix negative ions or hexafluoro phosphate radix negative ions, the boron-comprising.

Description

Have chirality Duo Chi oxazoline part and with title complex, the preparation method and use of main group metal or transition metal
Technical field
The present invention relates to a class have chirality many teeth oxazoline part and with title complex, synthetic method and the purposes in the catalysis asymmetric synthesis thereof of main group metal or three races's to the 13 group 4 transition metals.
Background technology
As everyone knows, the enantioselectivity of asymmetric catalysis and reactive behavior depend primarily on the character of catalyzer, and this is the character decision by chiral ligand to a great extent.Therefore, the synthetic effective chiral ligand of a class of the design asymmetric reaction key of achieving success often.Has C 2One symmetric bisoxazoline part was the more important part of a class: since 1986; containing has had the part of oxazoline ring first Application since asymmetry catalysis, the countless parts that include the few Yi oxazoline ring of Zhi are synthesized out, and in very short time, be successfully applied to the catalytic reaction of a series of organo-metallic, this be because: 1, the oxazoline ring is to the stability of hydrolysis and oxidation; 2, the oxazoline ring can with a series of transition-metal coordinations, and the chiral centre in the part and metal ion are very approaching, thus to the steric course of reaction apply directly, intense influence.3,, oxazoline is a neutral ligand, and can not weaken its lewis acidity after the metal center coordination, thereby keeps the high catalytic activity of metal complexes.4,, oxazoline can be convenient synthetic from the chiral amino acid that is easy to obtain.(P.Braunstein, F.Naud Angew.Chem., Int.Ed.2001,40,680.) typical part is as follows:
Figure C0211235400061
Wherein, title complex with Bisoxazoline/Cu (II) is the most effective, be widely used in the asymmetric catalysis of the many carbon-carbon bond formation of DA reaction, HDA reaction, Aldol reaction, cyclopropanization reaction, Mukaiyama-Micheael addition reaction, Fu Ke alkylated reaction, Michael addition or the like, shown good asymmetric induction ability (%ee is greater than 95% usually), and catalytic activity is (in the HAD reaction, catalyst levels can be reduced to 0.05%, can compare U.S. with enzyme.)(Evans.D.A.；Rovis，T.；Johnson，J.S.Pure?Appl.Chem.，1999，71，1407.(b)J_rgensen，K.A.；Johannsen，M.；Yao，S.；Audrian，H.；Thorhauge，J.Acc.Chem.Res.1999，32，605.(c)Johnson，J.S.；Evans，D.A.Acc.Chem.Res.2000，JJ，325.)。
But in most cases, the Bisoxazoline that has only the expensive tertiary butyl to replace (R=tert-Bu) just can obtain good result; And mantoquita also needs the copper trifluoromethanesulfcomposite to water sensitive, or need close that metaantimmonic acid silver and anhydrous cupric chloride reaction obtain that hexafluoro closes metaantimmonic acid copper and more loaded down with trivial details from photosensitive hexafluoro during preparation.This makes catalyzer very expensive, and operation simultaneously also has trouble.
Along with the expansion of range of application, even the title complex of tert-Butyl-Bisoxazoline/Cu (II) in some new reactions, can not be obtained good result.As the Fu Ke alkylated reaction of electron rich aromatic ring system to the activatory malonate derivative.(Zhuang，W；Hansen，T.；J_rgensen，K.A.Chem.Commun.2001.347.)。
Summary of the invention
The object of the present invention is to provide a class asymmetric synthesis catalyzer, promptly be used for asymmetric catalysis, have chirality many teeth oxazoline part and with the title complex of main group metal or three races's to the 13 group 4 transition metals, this title complex is catalyzer or catalyst system.
Many teeth oxazoline part that two of purpose of the present invention is to provide above-mentioned with chirality and with the synthetic method of the title complex of main group metal or three races's to the 13 group 4 transition metals.
Many teeth oxazoline part that three of purpose of the present invention is to provide above-mentioned with chirality and with the purposes of the title complex of main group metal or three races's to the 13 group 4 transition metals, promptly be used for the catalyzer of the asymmetric catalysis that a series of carbon-carbon bonds and carbon-heteroatom bond form.This catalyzer uses cheap chiral source and the cheap moisture salt of metal, has shown good catalytic activity and asymmetric induction effect in some reactions, and has not needed strict anhydrous condition.
Multiple tooth chirality provided by the invention uh the structural formula of azoles quinoline title complex or catalyzer be:
Figure C0211235400071
m 1, m 2Or m 3Be 0 or C 1-3Alkylidene group, m 1, m 2And m 3Can be identical between the three also can be inequality;
M is the transition metal atoms of ten gangs of three races to the, especially copper, zinc, nickel, iron, magnesium, manganese, cobalt, chromium;
X is a negatively charged ion, can be halogen atom, oxy radical, fluoro-containing group or the boron-containing group that comprises fluorine, chlorine, bromine or iodine, and several X can be identical, also can be different;
N is 1,2, or 3;
A and B are Sauerstoffatom, sulphur atom, selenium atom, phosphorus atom or nitrogen-atoms;
R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4And R 5, R 6And R 7Be alkyl, each other can be identical, also can be inequality, can also be each other in encircling into key; Can be chiral radicals, can not be chiral radicals also;
→: refer to singly-bound or two key;
* be that this atom has chirality.
Further above-mentioned title complex or catalyst system are elaborated below:
(1) chiral coordination compound or catalyzer (I), above-mentioned title complex or catalyst system are chiralitys, structural formula is as follows:
Wherein →, m 1, m 2And m 3A, B, M, X and n; R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4And R 5With identical in the aforementioned structural formula (I).
All right further its structural formula of following description of chiral coordination compound or catalyzer (I):
Wherein:
m 1, m 2And m 3A, B, M, X and n; R, R 1, R 1 ', R 2, R 2 ', R 3, R 4And R 5With identical in the aforementioned structural formula (I).
(IA-1～IA-4) will help to more clearly understand chiral coordination compound of the present invention or catalyzer (IA) to structural formula.
Figure C0211235400091
M wherein 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4And R 5With identical in the aforementioned structural formula (I).
Figure C0211235400092
M wherein 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6And R 7With identical in the aforementioned structural formula (I).
M wherein 1, m 2And m 3M, X and n; R, R 1, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6And R 7With identical in the aforementioned structural formula (I).
Figure C0211235400094
M wherein 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4And R 5With identical in the aforementioned structural formula (I), S can be a chirality, can not be chirality also.
M wherein 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', and R 4With identical in the aforementioned structural formula (I).
(2) chiral coordination compound or catalyzer (IB)
Figure C0211235400102
M wherein 1, m 2And m 3A, B, M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5And R 6With identical in the aforementioned structural formula (I).
(IB-1～IB-4) will help to more clearly understand chiral coordination compound of the present invention or catalyzer to structural formula.
Figure C0211235400103
Wherein:
m 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5And R 6With identical in the aforementioned structural formula (I).
Wherein:
m 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5And R 6With identical in the aforementioned structural formula (I).
Figure C0211235400111
Wherein:
m 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5And R 6With identical in the aforementioned structural formula (I).
Figure C0211235400112
Wherein:
m 1, m 2And m 3M, X and n; R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5And R 6With identical in the aforementioned structural formula (I).
To the part term that foregoing partly uses be described as follows below, these explanations will help clearer understanding content of the present invention.
X: each X is negatively charged ion, can be halogen atom, oxy radical, fluoro-containing group or the boron-containing group that comprises fluorine, chlorine, bromine or iodine, and several X can be identical, also can be different; The oxy radical here refers to oxygen acid root negative ion, as trifluoromethanesulfonic acid root negative ion (OTf -), sulfate radical negative ion (SO 4 2-), perchlorate's negative ion (ClO 4 -); Fluoro-containing group refers to fluorine-containing acid radical anion, as tetrafluoroborate negative ion (BF 4 -), hexafluoro closes metaantimmonic acid root negative ion (SbF 6 -), hexafluoro closes phosphate radical negative ion (PF 6 -) or the like, boron-containing group refers to the boracic acid radical anion, as tetraphenylboron acid group negative ion (Ph 4B -) or the like.R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6And R 7Be alkyl, each other can be identical, also can be inequality, can also be each other in encircling into key; Can be chiral radicals, can not be chiral radicals also.Alkyl refers to carbon containing, hydrogen, and the group of oxygen or nitrogen specializes as nothing, refers generally to contain the group of 1～30 carbon atom.These groups may have coordination with metal center, also may not have coordination.But the coordination ability of these groups and metal is not better than N atom in the part Gu Jia Zhong oxazoline ring, and promptly these groups should not replace the coordination of nitrogen and metal in the Suo Xi Wang De oxazoline ring.
Among the present invention, the synthetic method of used part is method (Vorbr ü ggen, the H. according to the He oxazoline part of classics; Krolikiewicz, K.Tetrahedron 1993,49, and 9353; Ghosh, A.K.; Mathivavan, P.; Capiello, J.Tetrahedron:Asymmetry, 1998,9,1), make trioazole quinoline part from corresponding carboxylic acid, acyl chlorides, ester, or after making basic De bisoxazoline skeleton, make corresponding polydentate ligand by substitution reaction again.
Specifically, in organic solvent, make respectively with following three kinds of methods:
A kind of synthetic method of Duo Chi oxazoline part of chirality is characterized in that making respectively with following three kinds of methods in organic solvent:
(1) be part as follows for structural formula:
Figure C0211235400121
The time, and when the substituting group on the San oxazoline ring is identical, by the corresponding structure formula be Tribasic carboxylic acid, being respectively with the oxalyl chloride mol ratio is 1: during 3-20, make acyl chlorides 0-25 ℃ of reaction after 2-40 hour; The acyl chlorides of gained and structural formula are
Figure C0211235400123
The mol ratio of amino alcohol be 1: during 3-20, reaction obtained corresponding amide in 2-40 hour under 0-25 ℃ of temperature; The acid amides of gained under 0-25 ℃ of temperature, respectively is 1 with the organic amine compound mol ratio that contains lone-pair electron on Tosyl chloride, the nitrogen-atoms: 3-6 again: during 3-50, reacted 20-50 hour;
Perhaps from the derivative methyl esters or the ethyl ester of corresponding above-mentioned triprotic acid, under high boiling solvent or condition of no solvent, be with structural formula
Figure C0211235400124
Amino alcohol be 1 with mol ratio: during 3-20,50-250 ℃ the reaction 30-200 hour, obtain corresponding amide; The organic amine compound and the tetracol phenixin that contain lone-pair electron on the acid amides of gained and triphenyl phosphorus, the nitrogen-atoms, respectively with 1: 3-10: 3-60: the mol ratio of 3-50, reaction is 20-60 hour under 0-25 ℃ of temperature;
When the substituting group on the San oxazoline ring of above-mentioned part is inequality, be to use
Figure C0211235400125
At the organic or inorganic alkali of monovalence metal according to 1: the molar ratio reaction of 1-2 obtained corresponding negative ion in 0.5-2 hour in-78-0 ℃ a reaction; The gained negative ion with According to mol ratio is 1: during 1.0-2 ,-78-0 ℃ following the reaction 0.5-20 hour;
(2) for part:
Figure C0211235400132
The time, with following 1)-4), 1) and 5), perhaps 1), 5) and 6) three kinds of methods make respectively:
1) uses At the organic or inorganic alkali of monovalence metal according to 1: the mol ratio of 1-3 ,-78 ℃ down reaction obtained negative ion in 0.5-5 hour; 2) this negative ion and formaldehyde are 1 with mol ratio: the ratio of 5-10 is in-78 ℃ of down reactions 0.5-20 hour, 3) add again with the Tosyl chloride of mol ratio such as above-mentioned negative ion 0-25 ℃ down reaction be converted into corresponding after 0.5-20 hour
Figure C0211235400134
4) with structural formula be again
Figure C0211235400135
Negative ion with 1: the mol ratio of 1-3,0-25 ℃ temperature range internal reaction 1-40 hour;
5) or 1) negative ion that obtains and the C of bromoacetic acid 1-10Hydrocarbyl carbonate compound mol ratio is followed successively by 1: during 1-2, reacted 0.5-20 hour down at-78 ℃, obtain respective ligand;
Perhaps 6) by 5) part and the corresponding C of gained 1-10Alkylmetal reagent reaction ,-78 ℃ of reactions 0.5-20 hour down, obtain respective ligand;
Wherein, m 1, m 2, m 3, X, n, A, B, R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6Or R 7According to claim 1.
The synthetic method of the title complex of a kind of many teeth of chirality oxazoline part and main group metal or three races's to the 13 group 4 transition metals is characterized in that in organic solvent among the present invention, with anhydrous metal salt or contain the metal-salt MX of crystal water nFH 2O and part mol ratio are 1: 0.5-2.0 at room temperature reacted 0.1-5 hour, the following structural formula of described part:
Figure C0211235400141
Wherein f is 0-12, m 1, m 2, m 3, X, n, A, B, R, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6Or R 7As mentioned above.
Described part can also be following structural formula:
R wherein 1, R 1 ', R 2, R 2 ', R 3Or R 3 'As mentioned above.
The organic or inorganic alkali of described monovalence metal is di-isopropyl amination lithium, C 4-12Lithium alkylide, sodium hydride or potassium hydride KH.
The organic amine compound that contains lone-pair electron on the described nitrogen-atoms is benzyl lauryl amine, triethylamine, Tributylamine, trioctylamine, pyridine, bipyridine, 1,8-diazacyclo [4.3.0]-5-nonene, 4-(N, N-dimethyl)-pyridine or 1,4-diazacyclo [2.2.2] octane.
Described corresponding C 1-10Alkylmetal reagent be C 1-10Azoviolet, zincon, cadion or lithium reagent.
The catalyzer that part of the present invention and metal-salt form can also can use after the load, can also use additive.
On-the-spot catalyzer of the present invention can be used in a series of asymmetric synthesis, comprises in the asymmetric catalysis of DA reaction, HDA reaction, Aldol reaction, cyclopropanization reaction, Mukaiyama-Micheael addition reaction, Fu Ke alkylated reaction, Michael addition or the like many carbon-carbon bonds and carbon-heteroatom bond formation.The operation steps of reaction be familiar with by people and document in a large amount of reports have been arranged, for example (Evans, D.A.; Rovis, T.; Kozlowski, M C.; Downey, C.W.; Tedrow, J.S.J.Am.Chem.Soc.2000,122,9134; Kanemasa, S, Oderaotoshi, Y.; Sakaguchi, S.H.; Yamamoto, J.Tanaka, E.Wada, Curran, D.P.J.Am.Chem.Soc.1998,120,3074; Juhl.K.; Gathergood, N.; J_rgensen, K.A.Angew.Chem.Int.Ed.2001,40,2995.)
The general step of reaction is (1) Preparation of Catalyst: be respectively 1 according to mol ratio in the reaction tubes: 1-2 adds metal-salt and part, adds appropriate solvent again, stirs 2 hours under the room temperature; (2) activation of substrate; After Preparation of Catalyst is good, add needs and the catalyzer substrate of complex activation in advance, stirring at room is as cold as assigned temperature after half an hour again; (3) add remaining reactant, reaction.
Be reflected in the common organic solvent and carry out, aromatic hydrocarbons for example, alcohols, the haloalkane kind solvent also has other, and be exemplified below but be not limited in this, as acetone, CH 3CN or the like.Select different solvent conditions according to different reactions.
The temperature maintenance of reaction arrives in the temperature range that refluxes at-78 ℃.For reaching good catalytic activity and asymmetric induction effect, temperature maintenance is best at-78 ℃ to 0 ℃.
Catalyst concn maintains 10 -2About M.
Additive is a molecular sieve, water, and alcohols, ketone, amine also have some inorganic minerals, are exemplified below but are not limited to this, as Al 2O 3, Magnesium Silicate q-agent or the like.Additive generally adds in substrate activatory process.Additive does not add in the process of catalyst activation preparation, in order to avoid cause unnecessary activity decay.
Asymmetric synthesis is generally carried out in reaction unit commonly used.
Brief summary:
The invention provides a class asymmetric synthesis chiral catalyst, preparation method and use.This catalyzer be a class new tridentate ligand and with main group metal or three races's to the 13 group 4 transition metal complexes, prepare in organic solvent by above-mentioned part metallizing thing.This catalyzer provided by the invention can be used for the applied research in the catalysis asymmetric synthesis.This catalyzer has showed the distinguishing feature of following several respects in asymmetric synthesis:
1. part is easily synthetic, and the raw material of synthetic ligands cheaply is easy to get;
2. catalyzer has the character of well water-fast and anti-air, prepares simple and convenient;
3. catalyzer has good catalytic activity and asymmetric induction effect;
4. catalyzer is applied widely, can be used in the asymmetric catalysis of a series of carbon-carbon bonds and carbon-heteroatom bond formation.
Specific implementation method
Below exemplifying embodiment the present invention will better be described, but what need to emphasize is that the present invention never only limits to the represented content of these several exemplifying embodiments.
Following example has shown not ipsilateral of the present invention, comprises the synthetic of part, the operation of catalyzer on-site preparation, the operation of asymmetric synthesis and reaction conditions; Given data comprise the data of part and product.The preparation of part should be under the exsiccant atmosphere of inert gases, and the part that makes should be at cryopreservation under the atmosphere of inert gases.The operation of all asymmetric reactions, comprise weighing, Preparation of Catalyst and reaction can be carried out in air atmosphere.Enantioselectivity is measured by HPLC.
Embodiment 1
Ligand L 1Synthetic:
Figure C0211235400161
Add 3.72g 1 (17mmol) in 25ml Schlenk bottle, L-Valinol 7.04g (68mmol) is warming up to 80 ℃, reactant is tied to form transparent and homogeneous solution, stirs every heating 12 hours, be chilled to 30 ℃ of final vacuums and took out methyl alcohol about one hour, accumulative total was reacted 80 hours.Stopped reaction, after a small amount of methylene dichloride dissolving, direct flash chromatography, eluent (ethyl acetate/methanol=30/1), getting product S1 is white solid 4.52g, productive rate 61%.[α] D 20＝20.5°(c＝1.09，HCCl 3)； 1H?NMR(300MHz，CDCl 3)：δ0.93(m，18H)，1.60(s，3H)，1.65-1.90(m，3H)，2.50(ABd，J＝14.1Hz，1H)，3.25(ABd，J＝14.1Hz，1H)，3.32-3.42(m，1H)，3.45-3.65(m，3H)，3.67-3.90(m，8h)，6.93(d，J＝9.2Hz，1H)，8.2(d，J＝9.0Hz，1H)，8.8(d，J＝8.1Hz，1H)； 13C?NMR(75MHz，CDCl 3)：174.33.173.44，173.30，63.39，62.90，62.73，60.424，57.51，57.23，57.11，53.752，42.87，29.43，29.18，29.10，27.21，27.14，19.67，19.65，19.56，18.83，18.70，18.68；IR(KBr)：3706，3624，3170，2966，2350，1766，1739，1609，1564，1465，1399MS(ESI)：432.4(M+H) +，454.4(M+Na) +；Anal.Calcd.for?C 21H 41O 3N 3：C，58.16；H，9.58；N，9.74.Found：C，58.16；H，9.40；N，9.47.
In the 50ml three-necked bottle, add 503mg (1.17mmol) S1, triphenyl phosphorus 1.84g (7mmol), the anhydrous tetracol phenixin of 5ml, the anhydrous CH of 13ml 3CN, stirring at room is treated solution clarification back injection 5ml triethylamine, is warming up to 25 ℃, stir, white casse appears immediately, yellowing muddiness soon, so react 24 hours after, solution becomes the brownish black muddiness, add the 10ml ethyl acetate, the 3ml saturated sodium bicarbonate solution is stirred to white precipitate and occurs, tell organic phase, behind the aqueous phase dissolved white precipitate, use 5 * 3ml ethyl acetate extraction again] merge organic phase behind the water, wash twice with saturated aqueous common salt 3ml, organic phase with anhydrous sodium sulfate drying after, the flash chromatography purifying, eluent (sherwood oil/acetone=4/1) gets product L 1Be colourless liquid, be total to 358mg, productive rate 81.4%.[α] D 20＝-121.9°(21mg/2mL，CHCl 3)， 1H?NMR(300MHz，CDCl 3)：δ0.84-0.96(m，18H)，1.61(s，3H)，1.70-1.81(m，3H)，2.95(ABd，J＝14.6Hz，1H)，3.09(ABd，J＝14.6Hz，1H)，3.83-4.18(m，6H)，4.18-4.26(m，3H)。 13C?NMR(75MHz，CDCl 3)：167.01，163.68，72.26，72.06，71，65，70.41，70.06，69.82，40.90，34.99，32.59，32.45，32.19，21.31，18.91，18.86，18.55，18.23，17.91，17.6917.45。IR(KBr)：2958，2900，2873，1661，1468，1384，1356，1235，1169，1095，983，903cm -1。MS(ESI)：378(M+H) +，400(M+Na) +；Anal.calcd.for?C 21H 35O 3N 3：C，66.81；H，9.34；N，11.13.Found：C，66.56；H，9.29；N，11.12。
Embodiment 2
Ligand L 2Synthetic:
Add 2.45g (11.2mmol) 1 in 25ml Schlenk bottle, L-Isoleucinol 5.2g (45.0mmol) is warming up to 70 ℃, reactant is tied to form transparent and homogeneous solution, stirs every heating 12 hours, be chilled to 30 ℃ of final vacuums and took out methyl alcohol about one hour, accumulative total was reacted 80 hours.Stopped reaction, after a small amount of methylene dichloride dissolving, direct flash chromatography, eluent (ethyl acetate/methanol=30/1) gets product S 2Be white solid 2.26g, productive rate 43.5%. 1H?NMR(300MHz，CDCl 3)：δ0.94(m，18H)，1.05-1.12(m，3H)，1.38-1.58(m，6H)，1.58(s，3H)，1.90(br，3H)，2.49(ABd，J＝14.1Hz，1H)，3.22(ABd，J＝14.1Hz，1H)，3.3-4.0(m，9H)，6.95(d，J＝8.2Hz，1H)，8.18(d，J＝8.6Hz，1H)，8.86(d，J＝9.2Hz，1H).MS(m/z)：474(M+1) +，(2)，357，(100)，313(67)，295(48)，69(40)，41(34)，55(26)，196(24)，339(24).
In the 50ml three-necked bottle, add S 2750mg (1.6mmol), triphenyl phosphorus 2.50g (9.5mmol), the anhydrous tetracol phenixin of 7.5ml, the anhydrous CH of 18ml 3CN, stirring at room is treated solution clarification back injection 7.5ml triethylamine, is warming up to 25 ℃, stir, white casse appears immediately, yellowing muddiness soon, so react 24 hours after, solution becomes the brownish black muddiness, add the 20ml ethyl acetate, the 8ml saturated sodium bicarbonate solution is stirred to white precipitate and occurs, tell organic phase, behind the aqueous phase dissolved white precipitate, use 10 * 3ml ethyl acetate extraction again] merge organic phase behind the water, wash twice with saturated aqueous common salt 3ml, organic phase with anhydrous sodium sulfate drying after, the flash chromatography purifying, eluent (sherwood oil/acetone=4/1) gets product L 2Be colourless liquid, be total to 536mg, productive rate 80%. 1H?NMR(300MHz，CDCl 3)：δ0.8(m，9H)，0.94(m，9H)，1.18(m，3H)，1.36-1.56(m，6H)，1.6(s，3H)，2.95(ABd，J＝14.7Hz，1H)，3.08(ABd，J＝14.7Hz，1H)，3.82-4.4(m，9H).MS(m/z)：419(M +，5)，362(100)，225(37)，363(18)，235(19)，262(15)，155(13)，55(12)，223(11).
Embodiment 3
Ligand L 3Synthetic:
Figure C0211235400172
Add 1.33g (6.1mmol) 1 in 25ml Schlenk bottle, D-phenyl glycinol 3.72g (27mmol) is warming up to 90 ℃, reactant is tied to form transparent and homogeneous solution, stirs every heating 12 hours, be chilled to 30 ℃ of final vacuums and took out methyl alcohol about one hour, accumulative total was reacted 60 hours.Stopped reaction, after a small amount of methylene dichloride dissolving, direct flash chromatography, eluent (ethyl acetate/methanol=25/1), getting product S3 is white solid 1.06g, productive rate 32.6%.[α] D 20＝-102.3°(c＝1.14，HCCl 3)； 1H?NMR(300MHz，CDCl 3)：δ1.54(s，3H)；1.63(br，s，3H)，2.63(ABd，J＝15.0Hz，1H)，3.2(AB，J＝15.0Hz，1H)，3.6-4.1(m，6H)，5.1-5.28(m，3H)，7.28(m，15H)，7.47(d，J＝9.5Hz，1H)，8.63(d，J＝8.1Hz，1H)，9.45(d，J＝8.3，1H)， 13CNMR(75MHz，CDCl 3)：173.6，173.1，172.7，138.6，138.4，128.73，128.66，127.7，127.6，126.73，126.71，126.43，66.43，65.69，65.51，56.05，55.60，53.38，42.71，25.74；IR：3323.5，3061.6，3029.8，2937，1651，1537，1495，1453，1372，1239，1068，1039，756，700，637；MS(m/z)：534(M+1) +(47)，106(100)，397(89)，365(73)，103(51)，516(42)，104(42)，77(41).Anal.calcd.forC 30H 35O 6N 3：C，67.53；H，6.61；N，7.87.Found：C，67.12；H，6.50；N，7.43.
In the 50ml three-necked bottle, add S 3452mg (0.85mmol), triphenyl phosphorus 1.34g (5.1mmol), the anhydrous tetracol phenixin of 3.6ml, the anhydrous CH of 10ml 3CN, stirring at room is treated solution clarification back injection 3.6ml triethylamine, is warming up to 25 ℃, stir, white casse appears immediately, yellowing muddiness soon, so react 24 hours after, solution becomes the brownish black muddiness, add the 10ml ethyl acetate, the 3ml saturated sodium bicarbonate solution is stirred to white precipitate and occurs, tell organic phase, behind the aqueous phase dissolved white precipitate, use 5 * 3ml ethyl acetate extraction again] merge organic phase behind the water, wash twice with saturated aqueous common salt 3ml, organic phase with anhydrous sodium sulfate drying after, the flash chromatography purifying, eluent (sherwood oil/THF=3/2), get product L 3Be white solid, be total to 347mg, productive rate 85%. 1H?NMR(300MHz，CDCl 3)：δ1.86(s，3H)，3.31(ABd，J＝14.1Hz，1H)，3.25(ABd，J＝14.1Hz，1H)，4.03-4.19(m，3H)，4.67-4.70(m，3H)，5.10-5.32(m，3H)，7.23-7.31(m，15H)， 13CNMR(75MHz，CDCl 3)：168.29，168.25，164.61，142.01，142.00，141.98，128.38，128.32，127.20，126.59，126.42，75.31，74.22，69.60，69.41，69.28，41.053，34.9，30.1，21.52；MS(m/z)：479(M +，10)，480(M+1) +(14)，205(100)，265(48)，220(35)，104(30)，201(30).HRMS：calcud.479.22090；found.479.21840.
Embodiment 4
Ligand L 4Synthetic:
Add 0.39g (1.8mmol) 1 in 25ml Schlenk bottle, L-phenylalaninol 1.0g (6.6mmol) is warming up to 90 ℃, reactant is tied to form transparent and homogeneous solution, stirs every heating 12 hours, be chilled to 30 ℃ of final vacuums and took out methyl alcohol about one hour, accumulative total was reacted 80 hours.Stopped reaction, after a small amount of methylene dichloride dissolving, direct flash chromatography, eluent (ethyl acetate/methanol=30/1) gets product S 4Be white solid 207mg, productive rate 20%. 1H?NMR(300MHz，CDCl 3)：δ1.1(s，3H)，2.22(ABd，J＝14.6Hz，1H)，2.6-2.9(m，8H)，3.3-3.5(m，8H)，3.58-3.75(m，3H)，4.05-4.25(m，5H)，6.89(d，J＝8.5Hz，1H)，7.20(m，15H)，7.60(d，J＝8.6Hz，1H)，8.60(d，J＝8.6Hz，1H)；MS(ESI)：576.5[M+H +]，598.5[M+Na +]；IR(KBr)，3305，3026，2939，1651，1538，1496，1454，1373，1240，1039，840，746，700
In the 50ml three-necked bottle, add S 417mg (0.03mmol), triphenyl phosphorus 50mg (0.19mmol), the anhydrous tetracol phenixin of 0.2ml, the anhydrous CH of 0.5ml 3CN, stirring at room, treat solution clarification back injection 0.2ml triethylamine, be warming up to 25 ℃, stir, occur white casse immediately, soon yellowing muddiness, so reaction is after 48 hours, and solution becomes the brownish black muddiness, adds the 10ml ethyl acetate, the 3ml saturated sodium bicarbonate solution, be stirred to white precipitate and occur, tell organic phase, behind the aqueous phase dissolved white precipitate, use 5 * 3ml ethyl acetate extraction again] merge organic phase behind the water, 3ml washes twice with saturated aqueous common salt, organic phase with anhydrous sodium sulfate drying after, the flash chromatography purifying, eluent (pure ethyl acetate), after removing most of triphen oxygen phosphorus, use eluent (petrol ether/ethyl acetate/acetone=5: 3: 1) to be further purified again, get product L 4Be light yellow liquid, be total to 10mg, productive rate 65%. 1H?NMR(300MHz，CDCl 3)：δ1.56(s，3H)，2.52-2.72(m，3H)，2.95-3.18(m，5H)，3.90-3.96(t，J＝7.4Hz，1H)，3.98-4.06(m，2H)，4.1-4.23(m，3H)，4.38(m，3H)，7.22(m，15H).MS(m/z)：521(M +，3)，522(M+1) +(2)，430(100)，429(99)，431(29)，293(28)，117(22)，269(17).
Embodiment 5
Ligand L 5Synthetic:
Add 0.232g 1 (1mmol) in 25ml Schlenk bottle, L-Valinol 0.41g (4mmol) is warming up to 80 ℃, reactant is tied to form transparent and homogeneous solution, stirs every heating 12 hours, be chilled to 30 ℃ of final vacuums and took out methyl alcohol about one hour, accumulative total was reacted 50 hours.Stopped reaction, after a small amount of methylene dichloride dissolving, direct flash chromatography, eluent (ethyl acetate/methanol=30/1) gets product S 5Be white solid 0.21g, productive rate 47%.； 1H?NMR(300MHz，CDCl 3)：δ0.93(m，18H)，1.53(s，3H)，1.74-1.86(m，3H)，2.17-2.34(m，4H)，3.32-3.42(m，1H)，3.48-3.65(m，3H)，3.69-3.84(m，8H)，4.21-4.45(m，br，3H)，7.21(d，J＝9.3Hz，1H)，7.42(d，J＝9.0Hz，1H)，8.43(d，J＝9.3Hz，1H)；
In the 50ml three-necked bottle, add 195mg (0.45mmol) S 5, triphenyl phosphorus 0.71g (2.7mmol), the anhydrous tetracol phenixin of 1.7ml, the anhydrous CH of 4ml 3CN, stirring at room is treated solution clarification back injection 1.7ml triethylamine, is warming up to 25 ℃, stir, white casse appears immediately, yellowing muddiness soon, so react 24 hours after, solution becomes the brownish black muddiness, add the 10ml ethyl acetate, the 3ml saturated sodium bicarbonate solution is stirred to white precipitate and occurs, tell organic phase, behind the aqueous phase dissolved white precipitate, use 5 * 3ml ethyl acetate extraction again] merge organic phase behind the water, wash twice with saturated aqueous common salt 3ml, organic phase with anhydrous sodium sulfate drying after, the flash chromatography purifying, eluent (sherwood oil/acetone=4/1) gets product L 5Be colourless liquid, be total to 95mg, productive rate 54%. 1H?NMR(300MHz，CDCl 3)：4.14-4.21(m，3H)，3.81-4.00(m，6H)，2.21-2.37(m，4H)，1.67-1.78(m，3H)，1.49(s，3H)，0.88-0.95(m，18H).
Embodiment 6
Ligand L 6Synthetic:
In the 50ml three-necked bottle, add diisopropylamine (0.5mmol), butyllithium (0.4ml, 0.6mmol) ,-78 ℃ down stir half an hour after, add compound S 6(126mg, 0.5mmol) ,-78 ℃ down stir half an hour after, (88mg 0.5mmol), reacts and is warming up to room temperature after one hour, spends the night to add the 2-bromo methyl cycloheptapyridine.By the usual method processing reaction, obtain product L behind the purifying 6Be weak yellow liquid, (125mmg, productive rate are 73%). 1H?NMR(300MHz，CDCl 3)：δ0.96(m，12H)，1.60(s，3H)，1.75-1.84(m，3H)，3.07(ABd，J＝14.6Hz，1H)，3.38(ABd，J＝14.6Hz，1H)，3.83-4.18(m，4H)，4.18-4.26(m，2H)，7.40-7.60(m，2H)，7.98-8.02(m，2H)。
Embodiment 7
Ligand L 7Synthetic:
In the 50ml three-necked bottle, add diisopropylamine (0.5mmol), butyllithium (0.4ml, 0.6mmol) ,-78 ℃ down stir half an hour after, add compound S 6(126mg, 0.5mmol) ,-78 ℃ down stir half an hour after, (98mg 0.5mmol), reacts and is warming up to room temperature after one hour, spends the night to add bromo-acetic acid tert-butyl.By the usual method processing reaction, obtain product L behind the purifying 7Be weak yellow liquid, (125mmg, productive rate are 73%). 1H?NMR(300MHz，CDCl 3)：δ0.96(m，21H)，1.60(s，3H)，1.75-1.84(m，3H)，2.78(ABd，J＝14.6Hz，1H)，2.94(ABd，J＝14.6Hz，1H)，3.83-4.18(m，4H)，4.18-4.26(m，2H)，
Embodiment 8
Ligand L 8Synthetic:
Figure C0211235400202
In the 50ml three-necked bottle, add diisopropylamine (0.5mmol), butyllithium (0.4ml, 0.6mmol) ,-78 ℃ down stir half an hour after, add compound S 6(126mg, 0.5mmol) ,-78 ℃ down stir half an hour after, (98mg 0.5mmol), reacts and is warming up to room temperature after one hour, spends the night to add methyl bromoacetate.After the removal of solvent under reduced pressure, drip phenyl grignard reagent (3mmol), stirring at room is after one hour, again temperature rising reflux stopped reaction after three hours.After the usual method processing, obtain product L behind the purifying 8Be weak yellow liquid, (160mg, productive rate are 71%). 1H?NMR(300MHz，CDCl 3)：δ0.96(m，21H)，1.60(s，3H)，1.75-1.84(m，3H)，2.46(s，br，1H)，2.98(ABd，J＝14.6Hz，1H)，3.16(ABd，J＝14.6Hz，1H)，3.83-4.18(m，4H)，4.18-4.26(m，2H)，7.18-7.30(m，10H)。
Embodiment 9
Ligand L 9Synthetic:
Figure C0211235400211
Ligand L 9Synthetic:
In the 50ml three-necked bottle, add diisopropylamine (0.5mmol), butyllithium (0.4ml, 0.6mmol) ,-78 ℃ down stir half an hour after, add compound S 6(126mg, 0.5mmol) ,-78 ℃ down stir half an hour after, add and newly steam formaldehyde (0.5ml 5mmol), reacts and is warming up to room temperature after one hour, spends the night.After the removal of solvent under reduced pressure, behind the adding 15ml methylene dichloride, (95mg, 0.5mmol) with the 1ml pyridine, stirring at room is after one hour to add p-TsCl.Other gets a 100ml flask, and (50mg, 2.0mmol), 0 ℃ adds 2ml Ph down to add metal Na 2PCl (90 μ L, 0.5mmol) 1, the 4-dioxane solution.After stirring half an hour, the above-mentioned drips of solution that makes is added to fills Ph again 2In the flask of Pna, stirring at room is after 30 minutes, stopped reaction.After the usual method processing, obtain product L behind the purifying 9Be weak yellow liquid, (98mmg, productive rate are 39%). 1H?NMR(300MHz，CDCl 3)：δ0.96(m，21H)，1.60(s，3H)，1.75-1.84(m，3H)，2.91(ABd，J＝14.6Hz，1H)，3.07(ABd，J＝14.6Hz，1H)，3.83-4.18(m，4H)，4.18-4.26(m，2H)，7.18-7.30(m，10H)。
Embodiment 10
Ligand L 10Synthetic
In the 50ml three-necked bottle, add diisopropylamine (0.5mmol), butyllithium (0.4ml, 0.6mmol) ,-78 ℃ down stir half an hour after, add compound S 6(126mg, 0.5mmol) ,-78 ℃ down stir half an hour after, add and newly steam formaldehyde (0.5ml 5mmol), reacts and is warming up to room temperature after one hour, spends the night.After the removal of solvent under reduced pressure, behind the adding 15ml methylene dichloride, (95mg, 0.5mmol) with the 1ml pyridine, stirring at room is after one hour to add p-TsCl.Other gets a 100ml flask, under-78 ℃, at the scene Zhi Bei LDA (from diisopropylamine (0.5mmol), butyllithium (0.4ml, 0.6mmol) in make), drip (S)-aminomethyl phenyl sulfanilamide (SN) (60mg, 0.5mmol) ,-78 ℃ down stir half an hour after, drip the above-mentioned solution that makes, react after five hours ,-78 ℃ drip 1ml ammonium chloride solution termination reaction.After the usual method processing, obtaining product L10 behind the purifying is yellow liquid, (98mmg, productive rate are 25%). 1H?NMR(300MHz，CDCl 3)：δ0.96(m，21H)，1.60(s，3H)，1.75-1.84(m，3H)，2.91(ABd，J＝14.6Hz，1H)，3.07(ABd，J＝14.6Hz，1H)，3.83-4.18(m，4H)，4.18-4.26(m，2H)，7.18-7.30(m，5H)。
Embodiment 11～embodiment 20 has shown the catalysis characteristics that the present invention shows in the asymmetric Michael addition reaction of indoles to activatory Arylidene Malonates, be under the air atmosphere, (20～20 ℃) have good catalytic activity in quite wide temperature range.The enantioselectivity of product is good, and the productive rate height is expected application in tryptophan derivative synthetic.
Embodiment 11
In the exsiccant reaction tubes, add Cu (ClO 4) 26H 2O 9mg (0.025mmol), add ligand L 112mg (0.03mmol) and acetone 2ml again, stir after 2 hours under the room temperature, inject the solution 1ml of Benzylidene Malonate71mg (0.25mmol), be cooled to-20 ℃ of afterreactions 80 hours, by obtaining product behind the usual method purifying is white solid, and productive rate 56%, enantioselectivity are 92.5%ee..(annotate: product can obtain optically pure product by recrystallization).[α] D 20＝+63.4(20.5mg/2mL?CHCl 3). 1H?NMR(300MHz，CDCl 3)，δ1.00(m，6H)，3.99(m，4H)，4.29(d，J＝11.4Hz，1H)，5.08(d，J＝11.7Hz，1H)，7.03-7.06(m，1H)，7.10-7.30(m，6H)，7.36(d，J＝6.9Hz，2H)，7.55(d，J＝7.8Hz，1H)，8.06(s，br，1H)；mp?168-170℃
Embodiment 12
Figure C0211235400222
Operation steps is with embodiment 11: product is a white solid, and productive rate 98%, enantioselectivity are 87.8%ee.[α] D 20=+62.6 (19.8mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3) δ 3.52 (s, 3H), 3.56 (s, 3H), 4.31 (d, J=11.7Hz, 1H), 5.09 (d, J=12.0Hz, 1H), 7.11-7.17 (m, 4H), 7.21-7.36 (m, 5H), 7.51 (d, J=7.8Hz, 1H), 8.06 (s, br, 1H); Mp 148-150 ℃
Embodiment 13
Operation steps is with embodiment 11: product is a white solid, productive rate 98%, enantioselectivity is: 91.8%ee.[α] D 20=+43.5 (24.4mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3) δ 0.92 (t, J=6.9,7.2Hz, 3H), 1.00 (t, J=6.9,7.2Hz, 3H), 3.94 (q, J=6.9,7.2Hz, 2H), 4.00 (q, J=6.9,7.2Hz, 2H), 4.41 (d, J=11.7Hz, 1H), 5.67 (d, J=11.7Hz, 1H), 7.01-7.12 (m, 5H), 7.20 (m, 1H), 7.30 (dd, J=0.9,7.5Hz, 1H), 7.38 (dd, J=1.2,7.5Hz, 1H), 7.69 (d, J=7.5Hz, 1H), 8.27 (s, br, 1H); Mp 124-126 ℃
Embodiment 14
Operation steps is with embodiment 11: product is a white solid, productive rate 73%, enantioselectivity is: 90.7%ee.[α] D 20=+5.4 (20.2mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3) δ 0.97-1.02 (m, 6H), 3.77 (s, 3H), 3.94-4.05 (m, 4H), 4.26 (d, J=11.7Hz, 1H), 5.02 (d, J=11.7Hz, 1H), 6.78 (dd, J=2.4,5.7Hz, 1H), 6.96 (d, J=2.4Hz, 1H), 7.11-7.17 (m, 3H), and 7.20-7.25 (m, 2H), 7.37-7.38 (m, 2H), 7.99 (s, br, 1H); Mp144-146 ℃
Embodiment 15
Operation steps is with embodiment 11: product is a yellow solid, productive rate 98%, enantioselectivity is: 90.6%ee.[α] D 20=+3.8 (22.1mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3), δ 1.00 (t, J=7.2Hz, 3H), 1.06 (t, J=7.2Hz, 3H), 4.02 (q, J=7.2Hz, 4H), 4.32 (d, J=11.7Hz, 2H), 5.20 (d, J=11.7Hz, 1H), 7.05 (t, J=7.2Hz, 1H), and 7.16-7.22 (m, 2H), 7.30-7.33 (d, J=8.1Hz, 1H) 7.47 (d, J=8.1Hz, 1H), 7.54 (d, J=8.4Hz, 2H), 8.10 (d, J=8.7Hz, 2H), 8.20 (s, br, 1H); 13C NMR (75MHz, CDCl 3); 167.43,167.36,149.18,146.56,136.13,129.02,126.12,123.56,122.51,121.23,119.75,118.73,115.1,111.25,61.75,61.74,57.54,42.38,13.78,13.64, IR (film) 3450,3103,3004,2985,2905,1752,1724,1603,1523,1462,1368,1281,1228cm -1MS (EI, m/z): 410 (M +, 12), 251 (100), 205 (21), 252 (18), 204 (17), 217 (7), 291 (6); Anal.Calcd for C 22H 22N 2O 6: C, 64.38; H, 5.40; N, 6.83.Found:C, 64.48, H, 5.62, N, 6.65.mp 139-140 ℃
Embodiment 16
Operation steps is with embodiment 11: product is a white solid, productive rate 92%, enantioselectivity is: 92.9%ee.[α] D 20=+37.9 (26.2mg/2mL CH 2Cl 2), 1H NMR (300MHz, CDCl 3) δ 1.00 (m, 6H), 2.38 (s, 3H), 3.98 (m, 4H), 4.27 (d, J=12.3Hz, 1H), 5.04 (d, J=11.7Hz, 1H), 6.95 (m, 1H), 7.11-7.25 (m, 5H), 7.33-7.38 (m, 3H), 7.96 (s, br, 1H); 13C NMR (75MHz, CDCl 3): 167.98,167.85,141.4,134.4,128.63,128.28,128.11,126.87,126.64,123.8,120.9,118.9,116.4,110.57,76.6,61.43,61.37,58.44,42.77,21.5,13.75,13.72; MS (EI, m/z): 379 (M +, 12), 220 (100), 221 (20), 204 (7), 218 (7), 217 (6), 260 (5), 219 (4); IR (CHCl 3), 3418,3141,3066,3008,2981,2935,1745,1717,1584,1498,1455,1371,1306,1271,1175,1026,812,701,508,429; Anal.Calcd for C 25H 25NO 4: C, 72.80; H, 6.64; N, 3.69; Found:C, 72.62, H, 6.79, N, 3.81; Mp 180-184 ℃
Embodiment 17
Operation steps is with embodiment 11: product is a yellow solid, productive rate 99%, enantioselectivity is: 90.9%ee.[α] D 20=+9.3 (19.9mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3) δ 3.57 (s, 3H), 3.59 (s, 3H), 4.34 (d, J=11.4Hz, 1H), 5.21 (d, J=11.7Hz, 1H), 7.05 (t, J=7.2Hz, 1H), 7.17 (dt, J=0.9,8.1Hz, 1H), 7.22 (d, J=2.4Hz, 1H), 7.33 (d, J=8.1Hz, 1H), 7.44 (d, J=7.8Hz, 1H), 7.53 (d, J=8.7Hz, 2H), 8.11 (d, J=8.7Hz, 2H), 8.19 (s, br, 1H); Mp 90-91 ℃
Embodiment 18
Figure C0211235400242
Operation steps is with embodiment 11: product is a white solid, productive rate 84%, enantioselectivity is: 89.6%ee.Analytical data for:[α] D 20=+37.3 (21.6mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3) δ 0.98 (t, J=6.9,7.2Hz, 3H), 1.04 (t, J=6.9,7.2Hz, 3H), and 3.96-4.04 (m, 4H), 4.56 (dd, J=11.7,0.6Hz, 1H), 5.06 (d, J=11.7Hz, 1H), 7.03 (t, J=7.8,7.2Hz, 1H), 7.10-7.13 (m, 2H), 7.15-7.20 (m, 2H), 7.28-7.30 (m, 3H), 7.48 (d, J=8.1Hz, 1H), 8.20 (s, br, 1H); 13C NMR (75MHz, CDCl 3): 167.9,167.8,140,136,132,129.6,128.5,126.4,122.4,120.9,119.6,119.2,116.3,111.2,61.7,58.1,42.2,13.85,13.76; MS (EI, m/z): 399 (M +, 13), 400[(M+1) +, 4.7], 240 (100), 239 (60), 241 (36), 242 (34), 204 (16), 203 (11), 280 (8); IR (CHCl 3), 3408,3130,3060.2985,2938,2901,1744,1616,1596,1549,1494,1459,1421,1392,1371,1311,1247,850,742,582; Anal.Calcd for C 22H 22ClNO 4: C, 66.08; H, 5.55; N, 3.50; Cl, 8.87; Found:C, 66.24, H, 5.67, N, 3.44, Cl, 9.05; Mp 154-156 ℃
Embodiment 19
Operation steps is with embodiment 11: product is a white solid, productive rate 84%, enantioselectivity is: 59.7%ee.[α] D 20=+1.3 (54.1mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3), δ 0.91 (t, J=6.9Hz, 3H), 1.26 (t, J=6.9Hz, 3H), 1.45 (d, J=6.6Hz, 3H), 3.81 (d, J=6.9Hz, 1H), and 3.86-3.93 (m, 3H), 4.22 (q, J=6.9Hz, 1H), 7.00 (d, J=2.7Hz, 1H), 7.10-7.18 (m, 2H), 7.31 (d, J=7.5Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 8.18 (s, br, 1H); Mp53-55 ℃.
Embodiment 20
Operation steps is with embodiment 11: product is a white solid, productive rate 84%, enantioselectivity is: 90.2%ee.[α] D 20=+26.1 (37.6mg/2mL CHCl 3) 1H NMR (300MHz, CDCl 3) δ 0.97 (t, J=6.9,7.2Hz, 3H), 1.04 (t, J=6.9,7.2Hz, 3H), 3.95-4.04 (m, 4H), 4.25 (d, J=11.7Hz, 2H), 5.04 (d, J=11.7Hz, 1H), and 7.02-7.05 (m, 1H), 7.05-7.12 (m, 2H), 7.21-7.27 (m, 3H), 7.32-7.35 (m, 2H), 7.48 (d, J=7.5Hz, 1H), 8.22 (s, br, 1H); Mp 146-148 ℃
Embodiment 21～embodiment 24 has shown the catalysis characteristics that the present invention shows in Asymmetric Diels-Alder Reaction, promptly under the air atmosphere, (20～20 ℃) have good catalytic activity in quite wide temperature range.The enantioselectivity of product is good, and productive rate is good.
Embodiment 21
In the exsiccant reaction tubes, add Cu (ClO 4) 26H 2O 9mg (0.025mmol), add ligand L 212mg (0.03mmol) and acetone 2ml again, stir the solution 1ml of Zhu Ru oxazoline ketone (71mg0.50mmol) after 2 hours under the room temperature, stir half an hour after being cooled to-78 ℃, the new steaming cyclopentadiene 250ul that adds-78 ℃, stir, after the TLC demonstration reacts completely, cross a short column, after 150ml (petrol ether/ethyl acetate 1: 1) drip washing, flash chromatography purifying again, product is a white solid, productive rate 60%, products obtained therefrom determines that through HPLC the ratio of exo and endo is 13: 1, and the ee% value of endo type product is 81%.(ChiracelOD-H post, 95: 5 normal butanes: Virahol).
Embodiment 22
Figure C0211235400253
In the exsiccant reaction tubes, add Cu (ClO 4) 26H 2O 9mg (0.025mmol), add ligand L 212mg (0.03mmol) and acetone 2ml again, stir after 2 hours under the room temperature, inject the solution 1ml of Jia oxazolin ketone 78mg (0.50mmol), stir half an hour after being cooled to 0 ℃, the new steaming cyclopentadiene 250ul that adds 0 ℃, stir, show through TLC and react, cross a short column near after complete, after 150ml (petrol ether/ethyl acetate 1: 1) drip washing, flash chromatography purifying again, product is a white solid, productive rate 70%, products obtained therefrom determines that through HPLC the ratio of exo and endo is 98: 2, and the ee% value of endo type product is 75%.(Chiracel OD-H post, 99: 1 normal butanes: Virahol).
1H?NMR(300MHz，CDCl 3)：δ1.48(d，J＝7Hz，1H)，1.70(d，J＝7Hz，1H)，2.1(m，1H)，2.54(s，1H)，3.28(s，1H)3.54(m，1H)，3.91-4.43(m，2H)，4.38-4.43(t，J＝8.1Hz，2H)，5.78(m，1H)，6.38(dd，J＝3.3，5.5Hz，1H)，
Embodiment 23
In the exsiccant reaction tubes, add Cu (ClO 4) 26H 2O 9mg (0.025mmol), add ligand L 212mg (0.03mmol) and acetone 2ml again, stir after 2 hours under the room temperature, inject the solution 1ml of Ben oxazolin ketone 108mg (0.50mmol), stir half an hour after being cooled to 25 ℃, the new steaming cyclopentadiene 250ul that adds 25 ℃, stir, show through TLC and react, cross a short column near after complete, after 150ml (petrol ether/ethyl acetate 1: 1) drip washing, flash chromatography purifying again, product is a white solid, productive rate 50%, products obtained therefrom determines that through HPLC the ratio of exo and endo is 98: 2, and the ee% value of endo type product is 65%.(ChiracelOD-H post, 95: 5 normal butanes: Virahol).
Productive rate is 33.5%. 1H NMR (300MHz, CDCl 3): δ 1.60 (d, 1H), 1.95 (d, 1H), 3.00 (s, 1H) 3.34 (m, 1H), 3.47 (s, 1H), 3.96-4.07 (m, 2H), 4.20 (m, 1H), 4.36-4.43 (m, 2H), 5.92 (dd, and 1H) 6.53 (dd, 1H), 7.15-7.30 (m, 5H)
Embodiment 24
In the exsiccant reaction tubes, add Cu (ClO 4) 26H 2O 18mg (0.05mmol), add ligand L 223mg (0.03mmol) and acetone 2ml again, stir after 2 hours under the room temperature, inject the solution 1ml of dienophile 95mg (0.50mmol), stir half an hour after being cooled to-20 ℃, the new steaming cyclopentadiene 400ul that adds-20 ℃, stir, show through TLC and react, cross a short column near after complete, after 150ml (petrol ether/ethyl acetate 20: 1) drip washing, flash chromatography purifying again, product is colourless liquid 87mg, productive rate 77%, products obtained therefrom determines that through HPLC the ratio of exo and endo is 92: 8, and the ee% value of endo type product is 50%.(Chiracel AD post, 50: 1 normal butanes: Virahol).
Productive rate is 71%. 1H NMR (300MHz, CDCl 3): δ 1.65 (br, 1H), 1.95 (br, 1H), 3.08 (br, 1H), 3.25 (br, 1H), 3.52 (br, 1H), 3.75 (m, 1H), 3.84 (m, 3H), 5.94 (m, 1H), 6.44 (1H), 7.1-7.4 (m, 5H).

Claims (5)

1, a kind of Duo Chi of chirality oxazoline part has following structural formula:
M wherein 1, m 2Or m 3Be 0 or C 1-3Alkylidene group, m 1, m 2And m 3Be identical or inequality between the three:
A is Sauerstoffatom, sulphur atom, selenium atom, phosphorus atom or nitrogen-atoms;
B carbon atom or sulphur atom;
R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6And R 7Be C 1-30Alkyl, described alkyl is the group that contains carbon, hydrogen, oxygen or nitrogen, and is mutually the same or inequality, wherein, R 4, R 5, R 6And R 7Be chiral radicals or achirality group; But the coordination ability of these groups and metal is not better than N atom in the part Gu Jia Zhong oxazoline ring.
2, a kind of Duo Chi of chirality oxazoline part is characterized in that having following structural formula:
Figure C021123540003C1
M wherein 1, m 2, m 3, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6And R 7According to claim 1.
3, a kind of Duo Chi of chirality as claimed in claim 2 oxazoline part is characterized in that described part is following structural formula:
Figure C021123540003C2
Wherein R, R 1, R 1 ', R 2, R 2 ', R 3Or R 3 'According to claim 1.
4, the synthetic method of a kind of Duo Chi of chirality as claimed in claim 1 oxazoline part is characterized in that making respectively with following two kinds of steps in organic solvent:
(1) be part as follows for structural formula:
Figure C021123540003C3
The time, and when the substituting group on the San oxazoline ring is identical, by the corresponding structure formula be
Figure C021123540003C4
Tribasic carboxylic acid, being respectively with the oxalyl chloride mol ratio is 1: during 3-20, make acyl chlorides 0-25 ℃ of reaction after 2-40 hour; The acyl chlorides of gained and structural formula are
Figure C021123540004C1
The mol ratio of amino alcohol be 1: during 3-20, reaction obtained corresponding amide in 2-40 hour under 0-25 ℃ of temperature; The acid amides of gained under 0-25 ℃ of temperature, respectively is 1 with the organic amine compound mol ratio that contains lone-pair electron on Tosyl chloride, the nitrogen-atoms: 3-6 again: during 3-50, reacted 20-50 hour;
Perhaps from the derivative methyl esters or the ethyl ester of corresponding above-mentioned triprotic acid, under high boiling solvent or condition of no solvent, be with structural formula
Figure C021123540004C2
Amino alcohol be 1 with mol ratio: during 3-20,50-250 ℃ the reaction 30-200 hour, obtain corresponding amide; The organic amine compound and the tetracol phenixin that contain lone-pair electron on the acid amides of gained and triphenyl phosphorus, the nitrogen-atoms, respectively with 1: 3-10: 3-60: the mol ratio of 3-50, reaction is 20-60 hour under 0-25 ℃ of temperature;
When the substituting group on the San oxazoline ring of above-mentioned part is inequality, be to use At the organic or inorganic alkali of monovalence metal according to 1: the molar ratio reaction of 1-2 obtained corresponding negative ion in 0.5-2 hour in-78-0 ℃ a reaction; The gained negative ion with
Figure C021123540004C4
According to mol ratio is 1: during 1.0-2 ,-78-0 ℃ following the reaction 0.5-20 hour;
(2) for part: The time, with following 1)-4), 1) and 5), perhaps 1), 5) and 6) three kinds of methods make respectively:
1) uses At the organic or inorganic alkali of monovalence metal according to 1: the mol ratio of 1-3 ,-78 ℃ down reaction obtained negative ion in 0.5-5 hour; 2) this negative ion and formaldehyde are 1 with mol ratio: the ratio of 5-10 is in-78 ℃ of down reactions 0.5-20 hour, 3) add again with the Tosyl chloride of mol ratio such as above-mentioned negative ion 0-25 ℃ down reaction be converted into corresponding after 0.5-20 hour 4) with structural formula be again Negative ion with 1: the mol ratio of 1-3,0-25 ℃ temperature range internal reaction 1-40 hour;
Perhaps 5) be 1) negative ion that obtains and the C of bromoacetic acid 1-10Hydrocarbyl carbonate compound mol ratio is followed successively by 1: during 1-2, reacted 0.5-20 hour down at-78 ℃, obtain respective ligand;
Perhaps 6) by 5) part and the corresponding C of gained 1-10Alkylmetal reagent reaction ,-78 ℃ of reactions 0.5-20 hour down, obtain respective ligand;
Wherein, m 1, m 2, m 3, A, B, R, R 1, R 1 ', R 2, R 2 ', R 3, R 3 ', R 4, R 5, R 6Or R 7According to claim 1;
The organic or inorganic alkali of described monovalence metal is di-isopropyl amination lithium, C 4-12Lithium alkylide, sodium hydride or potassium hydride KH; The organic amine compound that contains lone-pair electron on the described nitrogen-atoms is benzyl lauryl amine, triethylamine, Tributylamine, trioctylamine, pyridine, bipyridine, 1,8-diazacyclo [4.3.0]-5-nonene, 4-(N, N-dimethyl)-pyridine or 1,4-diazacyclo [2.2.2] octane.
5, the purposes of a kind of Duo Chi of chirality as claimed in claim 1 oxazoline part, the Duo Chi oxazoline part and the metal-salt that it is characterized in that the described chirality of claim 1 form catalyzer, and this catalyzer is used for the asymmetric catalysis of C-C and carbon-heteroatom bond formation.
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JPH09255668A (en) * 1996-03-28 1997-09-30 Sumitomo Chem Co Ltd Production of bisoxazolines
CN1353718A (en) * 1999-04-08 2002-06-12 得克萨斯农业及机械体系综合大学 Novel ligands for chiral catalysis

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JPH08283248A (en) * 1995-02-15 1996-10-29 Sumitomo Chem Co Ltd Oxazolines, their production and production of asymmetric cyclopropanecarboxylic acids using the same
JPH09255668A (en) * 1996-03-28 1997-09-30 Sumitomo Chem Co Ltd Production of bisoxazolines
CN1353718A (en) * 1999-04-08 2002-06-12 得克萨斯农业及机械体系综合大学 Novel ligands for chiral catalysis

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