CN104059083B - A kind of method of asymmetric synthesis of chirality bicyclo-caprolactam compounds - Google Patents

A kind of method of asymmetric synthesis of chirality bicyclo-caprolactam compounds Download PDF

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CN104059083B
CN104059083B CN201410229778.XA CN201410229778A CN104059083B CN 104059083 B CN104059083 B CN 104059083B CN 201410229778 A CN201410229778 A CN 201410229778A CN 104059083 B CN104059083 B CN 104059083B
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phenyl
chirality
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bicyclo
ethyl acetate
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CN104059083A (en
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夏爱宝
吴超
许丹倩
徐振元
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Abstract

The invention provides the method for asymmetric synthesis of a kind of chirality bicyclo-caprolactam compounds as shown in formula (I), described synthetic method is: by chirality secondary amine catalyst, alkaline matter, organic solvent mixing, α shown in formula (II) is added under stirring condition, α carbonyl amide derivatives shown in β beta-unsaturated carbonyl compounds and formula (III), 12～84h are reacted at 20～60 DEG C, after reaction terminates, reactant liquor post processing obtains the chirality bicyclo-caprolactam compounds shown in formula (I)；It is an advantage of the current invention that: chirality bicyclo-caprolactam compounds of the present invention has chirality；One kettle way decreases purification step, improves product yield, is particularly suited for commercial production, can apply to the field such as organic synthesis, material；

Description

A kind of method of asymmetric synthesis of chirality bicyclo-caprolactam compounds
(1) technical field
The present invention relates to the method for asymmetric synthesis of a kind of chirality bicyclo-caprolactam compounds.
(2) background technology
Catalysis asymmetric synthesis is to realize asymmetric increment, obtains optically active substance most efficient method with chemical means, wherein Including the chemical reaction of the metal-chiral ligand catalysis accounting for a small amount of enzymic catalytic reaction and the overwhelming majority, but enzymatic height Specificity limits its range of application, and in the reaction system of metal catalytic, the metal participating in reaction is difficult to remove after the reaction Fall, easily to environment.Organocatalysis achieves the most asymmetric of chiral material by mimetic enzyme catalysis Catalyze and synthesize, the shortcoming overcoming enzymatic high specificity with its wider universality, solve from source meanwhile Applied metal catalyst in catalytic reaction and the toxic residue problem brought, and organocatalysis also have low price, Reaction condition is gentle, easily prepare and be easily recycled etc. advantage, and therefore the little Journal of Molecular Catalysis of organic functions is increasingly becoming organic conjunction Become reaction, the study hotspot of asymmetric catalysis.
After numerous organic micromolecule catalysts is synthesized, recently, use organic micromolecule catalyst, pass through cascade reaction Realize the important research direction (Chem.Rev., 2014,114,2390) being configured to organic asymmetry catalysis of multiple chemical bond. Cascade reaction is then the means using " one kettle way ", keep identical reaction condition with under identical catalyst system and catalyzing, without The separation of intermediate product builds two processes even more than chemical bond successively, and this is the process of an Atom economy, and subtracts Lack the time loss of protection and deprotection, it is to avoid the separation process of intermediate product, meet the developing direction of Green Chemistry.
Chirality bicyclo-caprolactam is the important intermediate (Tetrahedron, 1994,50,4215) of synthesis iminosugar, is The important chiral building block (Bull.Chem.Soc.Jpn., 1977,50,2375) of numerous natural products and medicine intermediate.This The diphenylprolinol silica ether compound that invention uses chiral proline derivative is organic micromolecule catalyst, at toluene solvant Middle catalysis α, beta-unsaturated aldehyde and alpha-keto amide, go here and there through asymmetric Michael-hemiaminalization-hemiacetalization Connection reaction, successfully achieves " one kettle way " synthesis of chirality bicyclo-caprolactam.
(3) summary of the invention
It is an object of the invention to provide the method for asymmetric synthesis of a kind of chirality bicyclo-caprolactam compounds.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of method of asymmetric synthesis of the chirality bicyclo-caprolactam compounds as shown in formula (I), described synthetic method For:
By chirality secondary amine catalyst, alkaline matter, organic solvent mixing, under stirring condition, add α shown in formula (II), β-insatiable hunger With alpha-carbonyl amide derivatives shown in carbonyl compound and formula (III), at-20～60 DEG C, react 12～84h, after reaction terminates, Reactant liquor post processing obtains the chirality bicyclo-caprolactam compounds shown in formula (I)；
In formula (I), formula (II) or formula (III), R1、R3Each stand alone as the alkyl of H, C1～C20,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, phenyl, the fluorine-based phenyl of 2-, The fluorine-based phenyl of 3-, the fluorine-based phenyl of 4-, 2-chloro phenyl, 3-chloro phenyl, 4-chloro phenyl, 2-bromo phenyl, 3-bromo phenyl, 4-bromo phenyl, 2-nitrobenzophenone, 3-nitrobenzophenone, 4-nitrobenzophenone, 2-trifluoromethyl, 3-trifluoromethyl, 4- Trifluoromethyl, furyl, thienyl, 3,5-trifluoromethyl or 3,5-trimethoxyphenyl；R2For H or C1～C20 Alkyl.
Further, described chirality bicyclo-caprolactam compounds is the compound shown in formula (Ia):
More preferred, in formula (I), formula (Ia), formula (II) or formula (III), described R1For 2-chloro phenyl, 2-bromine Base phenyl, 2-methoxyphenyl, the fluorine-based phenyl of 3-, 3-chloro phenyl, 3-methoxyphenyl, the fluorine-based phenyl of 4-, 4-chloro phenyl, 4-bromo phenyl, 4-methoxyphenyl, 4-aminomethyl phenyl, phenyl, furyl, propyl group or isopropyl；R2For methyl, propyl group Or isopropyl；R3For phenyl, 3,5-bis-trifluoromethyl or 3,5-Dimethoxyphenyl.
More specifically, described chirality bicyclo-caprolactam compounds is one of following: (1) (1R, 2R, 3R, 5S)-1-hydroxyl Base-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (2) (1R, 2R, 3R, 5S)-3-(2-chloro phenyl)-1- Hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (3) (1R, 2R, 3R, 5S)-3-(2-bromo phenyl)-1- Hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (4) (1R, 2R, 3R, 5S)-1-hydroxyl-3-(2-first Phenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (5) ((1R, 2R, 3R, 5S)-3-(3-fluorine Base phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (6) ((1R, 2R, 3R, 5S)-3-(3- Chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (7) (1R, 2R, 3R, 5S)-1- Hydroxyl-3-(3-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (8) (1R, 2R, 3R, 5S)-3-(the fluorine-based phenyl of 4-)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (9) (1R, 2R, 3R, 5S)-3-(4-chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (10) (1R, 2R, 3R, 5S)-3-(4-bromo phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (11) (1R, 2R, 3R, 5S)-1-hydroxyl-3-(4-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone, (12) (1R, 2R, 3R, 5S)-1-hydroxyl-3-(4-aminomethyl phenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone, (13) (1R, 2R, 3R, 5S)-3-(furan-2-alkyl)-1-hydroxy-2-methyl-6-phenyl-8-oxa--6-azabicyclic [3,2,1] Octane-7-ketone, (14) (1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-6-phenyl-3-propyl group-8-oxa--6-azabicyclic [3,2,1] Octane-7-ketone, (15) (1R, 2R, 3S, 5S)-1-hydroxyl-3-isopropyl-2-methyl-6-phenyl-8-oxa--6-azabicyclic [3,2,1] Octane-7-ketone, (16) (1R, 2R, 3R, 5S)-1-hydroxyl-2-isopropyl-3,6-diphenyl-8-oxa--6-azabicyclic [3,2,1] is pungent Alkane-7-ketone, (17) (1R, 2R, 3R, 5S)-6-phenyl-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azabicyclic [3,2,1] octane -7-ketone, (18) (1R, 2R, 3R, 5S)-6-(3,5-bis-(trifluoromethyl) phenyl)-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azepine Bicyclo-[3,2,1] octane-7-ketone, (19) (1R, 2R, 3R, 5S)-6-(3,5-Dimethoxyphenyl)-1-hydroxy-2-methyl-3-phenyl-8- Oxa--6-azabicyclic [3,2,1] octane-7-ketone.
Synthetic method of the present invention, described alpha-carbonyl amide derivatives (III) and α, the throwing of beta-unsaturated carbonyl compound (II) The amount ratio of material material can be 1:1～3, preferably 1:1.2.
Synthetic method of the present invention, described chirality secondary amine catalyst is proline derivative, is selected from formula (IV)～(X) institute One of compound shown, the preferably compound shown in formula (VI)；Described alpha-carbonyl amide derivatives (III) is secondary with chirality The ratio of the amount of the material that feeds intake of amine catalyst can be 1:0.05～0.3, preferably 1:0.2.
Synthetic method of the present invention, described alkaline matter be selected from DIPEA, triethylene diamine, 1,8-phenodiazine Miscellaneous bicyclo-[5.4.0] 11 carbon-7-alkene, DMAP, potassium carbonate, Schweinfurt green, triethylamine, quinine, cinchonine, Kui Ning Ding, cinchonine are fixed, sodium hydroxide or cyclohexanediamine, preferably triethylamine；Described alpha-carbonyl amide derivatives (III) and alkali The ratio of the amount of the material that feeds intake of property material can be 1:0.05～0.3, preferably 1:0.2.
Synthetic method of the present invention, described organic solvent can be dichloromethane, chloroform, ether, diisopropyl ether, oxolane, Isosorbide-5-Nitrae-dioxane, ethyl acetate, toluene, dimethylbenzene, benzotrifluoride, thionyl chloride, DMF, second Nitrile, methanol, ethanol or isopropanol, preferably toluene；The volumetric usage of described organic solvent is with alpha-carbonyl amide derivatives (III) The gauge of material can be 0.5～5mL/mmol, preferably 2.5mL/mmol.
Synthetic method of the present invention, preferred reaction conditions is reaction 48h at 0 DEG C.
Synthetic method of the present invention, the method for described reactant liquor post processing is: after reaction terminates, reactant liquor is extracted with ethyl acetate, After extract distillation desolvation, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate With the mixed liquor of petroleum ether volume ratio 1:3, collecting the eluent containing target compound, concentrate drying obtains the hands shown in formula (I) Property bicyclo-caprolactam compounds.
The synthetic method of chirality bicyclo-caprolactam compounds of the present invention, the synthetic method described in concrete recommendation is:
By the chirality secondary amine catalyst shown in formula (IV), triethylamine, toluene mixing, add shown in formula (II) under stirring condition Alpha-carbonyl amide derivatives shown in α, beta-unsaturated carbonyl compound and formula (III), reacts 48h at 0 DEG C, after reaction terminates, Reactant liquor post processing obtains the chirality bicyclo-caprolactam compounds shown in formula (I)；Described chirality secondary amine catalyst is formula (VI) compound shown in；Described alpha-carbonyl amide derivatives (III) and α, beta-unsaturated carbonyl compound (II) Feed intake the amount of material than for 1:1.2；The material that feeds intake of described alpha-carbonyl amide derivatives (III) and chirality secondary amine catalyst The ratio of amount is 1:0.2；Described alpha-carbonyl amide derivatives (III) is 1:0.2 with the ratio of the amount of the material that feeds intake of triethylamine；Institute The volumetric usage stating toluene is calculated as 2.5mL/mmol with the amount of the material of alpha-carbonyl amide derivatives (III)；
After reaction terminates, the method for reactant liquor post processing is: after reaction terminates, reactant liquor is extracted with ethyl acetate, and extract steams After evaporating desolvation, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether The mixed liquor of volume ratio 1:3, collects the eluent containing target compound, and concentrate drying obtains chirality two hexamethylene shown in formula (I) Lactam analog compound.
The chirality bicyclo-caprolactam compounds that the present invention prepares has antibiotic property, can be as the precursor of some pharmaceutical intermediates.
Compared with prior art, it is an advantage of the current invention that: chirality bicyclo-caprolactam compounds of the present invention has hands Levying property；One kettle way decreases purification step, improves product yield, is particularly suited for commercial production, can apply to organic conjunction The fields such as one-tenth, material.
(4) detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited to that.
The specific embodiment of the present invention has synthesized compound as described below:
(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone；
(1R, 2R, 3R, 5S)-3-(2-chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-3-(2-bromo phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-1-hydroxyl-3-(2-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-3-(the fluorine-based phenyl of 3-)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-3-(3-chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-1-hydroxyl-3-(3-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-3-(the fluorine-based phenyl of 4-)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-3-(4-chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-3-(4-bromo phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-1-hydroxyl-3-(4-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-1-hydroxyl-3-(4-aminomethyl phenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-3-(furan-2-alkyl)-1-hydroxy-2-methyl-6-phenyl-8-oxa--6-azabicyclic [3,2,1] octane-7- Ketone；
(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-6-phenyl-3-propyl group-8-oxa--6-azabicyclic [3,2,1] octane-7-ketone；
(1R, 2R, 3S, 5S)-1-hydroxyl-3-isopropyl-2-methyl-6-phenyl-8-oxa--6-azabicyclic [3,2,1] octane-7-ketone；
(1R, 2R, 3R, 5S)-1-hydroxyl-2-isopropyl-3,6-diphenyl-8-oxa--6-azabicyclic [3,2,1] octane-7-ketone；
(1R, 2R, 3R, 5S)-6-phenyl-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azabicyclic [3,2,1] octane-7-ketone；
(1R, 2R, 3R, 5S)-6-(3,5-bis-(trifluoromethyl) phenyl)-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azabicyclic [3, 2,1] octane-7-ketone；
(1R, 2R, 3R, 5S)-6-(3,5-Dimethoxyphenyl)-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azabicyclic [3,2,1] Octane-7-ketone.
Embodiment 1:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.0494g, yield 80% 99%, 98%, dr value 5.7:1),1H NMR(500MHz,CDCl3): δ=7.596-7.580 (m, 2H), 7.396-7.364 (m, 2H),7.334-7.304(m,2H),7.249-7.144(m,4H),5.951(s,1H),4.584(s,1H),3.295-3.250(m,1H), 2.480-2.363 (m, 2H), 2.050-2.009 (m, 1H), 0.867-0.863 (d, J=6.5Hz, 3H)；13C NMR(125MHz, CDCl3): δ=170.348,139.857,135.850,129.504 (× 2), 128.551 (× 2), 127.632 (× 2), 126.839,125.428, 118.717(×2),101.856,85.858,38.199,38.147,25.892,6.754ppm。
Embodiment 2:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (IV) (0.013g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 25 DEG C of reaction 24h of co-catalysis, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.0488g, yield 79% 94%, 97%, dr value 2.8:1).
Embodiment 3:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (IV) (0.015g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 25 DEG C of reaction 24h of co-catalysis, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.050g, yield 81% 95%, 95%, dr value 2.5:1).
Embodiment 4:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (VII) (0.015g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 25 DEG C of reaction 24h of co-catalysis, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.058g, yield 94% 88%, 96%, dr value 2.6:1).
Embodiment 5:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (VIII) (0.017g, 0.04mmol) and triethylamine (0.004g, The lower 25 DEG C of reaction 24h of co-catalysis 0.04mmol), are extracted with ethyl acetate (3 × 2mL), and extract distillation removing is molten After agent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio The mixed liquor of 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.057g, yield 93%, Ee value is 93%, 96%, dr value 2.8:1).
Embodiment 6:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (IX) (0.026g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 25 DEG C of reaction 24h of co-catalysis, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.046g, yield 93% 91%, 90%, dr value 3.2:1).
Embodiment 7:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (X) (0.024g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 25 DEG C of reaction 24h of co-catalysis, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.034g, yield 93% 91%, 99%, dr value 11:1).
Embodiment 8:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL benzotrifluoride mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, The lower 0 DEG C of reaction 24h of co-catalysis 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation desolvation After, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio 1:3 Mixed liquor, collect containing the eluent of target compound, concentrate drying obtains target compound (0.0362g, yield 99%, Ee Value is 98%, 98%, dr value 1.5:1).
Embodiment 9:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3, the system of 6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Standby
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL1,2-dichloroethanes mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, The lower 0 DEG C of reaction 24h of co-catalysis 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation desolvation After, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio 1:3 Mixed liquor, collect containing the eluent of target compound, concentrate drying obtains target compound (0.0358g, yield 98%, Ee Value is 95%, 96%, dr value 1.3:1).
Embodiment 10:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL ethyl acetate mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, The lower 0 DEG C of reaction 24h of co-catalysis 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation desolvation After, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio 1:3 Mixed liquor, collect containing the eluent of target compound, concentrate drying obtains target compound (0.0274g, yield 75%, Ee Value is 82%, 99%, dr value 3.1:1).
Embodiment 11:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL diisopropyl ether mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, The lower 0 DEG C of reaction 24h of co-catalysis 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation desolvation After, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio 1:3 Mixed liquor, collect containing the eluent of target compound, concentrate drying obtains target compound (0.0292g, yield 80%, Ee Value is 66%, 99%, dr value 1.4:1).
Embodiment 12:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 Mmol) and 0.5mL diisopropyl ether, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and N, N-diisopropyl The lower 0 DEG C of reaction 24h of co-catalysis of base ethamine (0.001g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extraction After liquid distillation desolvation, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and stone The mixed liquor of oil ether volume ratio 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.0281g, Yield 77%, Ee value is 96%, 99%, dr value 1.4:1).
Embodiment 13:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL diisopropyl ether mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylene diamine (0.004g, The lower 0 DEG C of reaction 24h of co-catalysis 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation desolvation After, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio 1:3 Mixed liquor, collect containing the eluent of target compound, concentrate drying obtains target compound (0.0266g, yield 77%, Ee Value is 97%, 99%, dr value 1.0:1).
Embodiment 14:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 Mmol) and 0.5mL diisopropyl ether, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and 1,8-diazabicylo The lower 0 DEG C of reaction 24h of co-catalysis of [5.4.0] 11 carbon-7-alkene (0.006g, 0.04mmol), is extracted with ethyl acetate (3 × 2 ML), after extract distillation desolvation, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is second Acetoacetic ester and the mixed liquor of petroleum ether volume ratio 1:3, collect the eluent containing target compound, and concentrate drying obtains target compound (Ee value is 87%, 80%, dr value 1.7:1 for 0.0193g, yield 56%).
Embodiment 15:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 Mmol) and 0.5mL diisopropyl ether, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and 4-dimethylamino pyrrole The lower 0 DEG C of reaction 24h of co-catalysis of pyridine (0.005g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), and extract steams After evaporating desolvation, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether The mixed liquor of volume ratio 1:3, collects the eluent containing target compound, and concentrate drying obtains target compound (0.0327g, yield 95%, Ee value is 96%, 99%, dr value 1.1:1).
Embodiment 16:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL diisopropyl ether mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and potassium carbonate (0.006g, The lower 0 DEG C of reaction 24h of co-catalysis 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation desolvation After, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio 1:3 Mixed liquor, collect containing the eluent of target compound, concentrate drying obtains target compound (0.0113g, yield 33%, Ee Value is 86%, 91%, dr value 1.8:1).
Embodiment 17:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 72h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.0274g, yield 80% 99%, 98%, dr value 5.7:1).
Embodiment 18:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0273g, 0.2 And 0.5mL toluene mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 60 DEG C of reaction 24h of co-catalysis, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.026g, yield 76% 95%, 96%, dr value 1:2.3).
Embodiment 19:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.1mL toluene mmol), chirality secondary amine catalyst (VI) (0.004g, 0.01mmol) and triethylamine (0.001g, 0.01 Mmol) under co-catalysis ,-20 DEG C of reaction 84h, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.017g, yield 50% 87%, 90%, dr value 2:1).
Embodiment 20:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-3,6-diphenyl-8-oxygen-6-azabicyclic [3,2,1] octane-7-ketone Preparation
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), cinnamic aldehyde (0.082g, 0.6 And 3mL toluene mmol), chirality secondary amine catalyst (VI) (0.024g, 0.06mmol) and triethylamine (0.006g, 0.06 Mmol) the lower 25 DEG C of reaction 12h of co-catalysis, are extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, Gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and what eluant was ethyl acetate with petroleum ether volume ratio 1:3 is mixed Closing liquid, collect the eluent containing target compound, concentrate drying obtains target compound, and (Ee value is for 0.030g, yield 87% 97%, 90%, dr value 2.7:1).
Embodiment 21:(1R, 2R, 3R, 5S)-3-(2-chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 2-chlorocinnamaldehyde (0.0399g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, The lower 0 DEG C of reaction 48h of co-catalysis 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation desolvation After, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio 1:3 Mixed liquor, collect containing the eluent of target compound, concentrate drying obtains target compound (0.0645g, yield 94%, Ee Value is 99%, 99%, dr value 2.1:1),1H NMR(500MHz,CDCl3): δ=7.559-7.540 (m, 2H), 7.362-7.324 (m,3H),7.243-7.160(m,4H),5.925(s,1H),5.271(s,1H),3.725-3.700(m,1H),2.676-2.624(m, 1H), 2.504-2.447 (m, 1H), 1.868-1.828 (m, 1H), 0.868-0.855 (d, J=6.5Hz, 3H) ppm；13C NMR (125MHz,CDCl3): δ=170.574,136.903,135.627,134.229,129.987,129.410 (× 2), 128.928, 128.064,126.552,125.465,119.150(×2),101.978,85.734,35.488,34.846,25.792,7.102ppm
Embodiment 22:(1R, 2R, 3R, 5S)-3-(2-bromo phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 2-bromocinnamaldehyde (0.0504g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 99% for 0.0604g, yield 78%, 99%, dr value 1.7:1),1H NMR(500MHz,CDCl3): δ=7.592-7.548 (m, 3H), 7.395-7.363 (m, 2H), 7.305-7.291(m,1H),7.211-7.173(m,2H),7.126-7.092(m,1H),5.949-5.942(m,1H),4.572(s 1H),3.731-3.685(m,1H),2.696-2.644(m,1H),2.496-2.430(m,1H),1.890-1.850(m,1H), 0.874-0.860 (d, J=7.0Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.359,138.407,135.657, 133.444,129.490(×2),129.216,128.451,127.190,125.564,125.113,119.369(×2),101.828, 85.864,38.160,34.938,26.036,6.992ppm。
Embodiment 23:(1R, 2R, 3R, 5S)-1-hydroxyl-3-(2-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,
1] preparation of octane-7-ketone
2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 2-methoxycinnamic aldehyde is added in 10mL test tube (0.0389g, 0.24mmol) and 0.5mL toluene, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine The lower 0 DEG C of reaction 48h of co-catalysis of (0.004g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation removing After solvent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio The mixed liquor of 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.0658g, yield 97%, Ee value is 93%, 90%, dr value 3.0:1),1H NMR(500MHz,CDCl3): δ=7.571-7.555 (m, 2H), 7.360-7.328(m,2H),7.239-7.205(m,1H),7.168-7.102(m,2H),6.937-6.907(m,1H), 6.840-6.824(m,1H),5.904(s,1H),4.946(s,1H),3.768(s,3H),3.676-3.630(m,1H), 2.672-2.619 (m, 1H), 2.513-2.456 (m, 1H), 1.878-1.829 (m, 1H), 0.836-0.822 (d, J=7.0Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.801,157.145,135.998129.316 (× 2), 128.112,127.742, 125.196,120.058,118.891(×2),110.199,102.170,86.001,55.243,35.186,32.224,29.691,25.764, 7.215ppm。
Embodiment 24:(1R, 2R, 3R, 5S)-3-(the fluorine-based phenyl of 3-)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 3-fluorine cinnamic aldehyde (0.0360g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 98% for 0.0582g, yield 89%, 96%, dr value 5.1:1),1H NMR(500MHz,CDCl3): δ=7.560-7.545 (m, 2H), 7.360-7.328 (m, 2H), 7.296-7.251(m,1H),7.181-7.151(m,1H),6.945-6.908(m,2H),6.871-6.851(m,1H),5.919(s, 1H),5.282(s,1H),3.270-3.224(m,1H),2.415-2.346(m,2H),2.026-1.986(m,1H),0.880-0.866 (d, J=7.0Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.598,162.973 (d,1JC-F=244.6Hz), 142.672(d,3JC-F=6.9Hz), 135.676,129.979 (d,3JC-F=8.3Hz), 129.435 (× 2), 125.440,123.259, 118.643(×2),114.548(d,2JC-F=21.8Hz), 113.660 (d,2JC-F=20.8Hz), 101.994,85.463,37.896 (d,4JC-F=9.9Hz), 29.693,25.783,6.768ppm.
Embodiment 25:((1R, 2R, 3R, 5S)-3-(3-chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 3-chlorocinnamaldehyde (0.0398g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 99% for 0.0652g, yield 95%, 90%, dr value 4.6:1),1H NMR(500MHz,CDCl3): δ=7.546-7.544 (m, 2H), 7.369-7.336 (m, 2H), 7.250-7.143(m,4H),7.045-7.030(m,1H),5.920(s,1H),4.997(s,1H),3.252-3.206(m,1H), 2.413-2.357 (m, 2H), 2.024-1.984 (m, 1H), 0.887-0.873 (d, J=7.0Hz, 3H) ppm；13C NMR(125 MHz,CDCl3): δ=170.464,142.068,135.664,134.484,129.751,129.437 (× 2), 127.742,126.986, 125.837,125.440,118.600(×2),101.903,85.459,37.901(×2),25.709,6.776ppm。
Embodiment 26:(1R, 2R, 3R, 5S)-1-hydroxyl-3-(3-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2, 1] preparation of octane-7-ketone
2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 3-methoxycinnamic aldehyde is added in 10mL test tube (0.0389g, 0.24mmol) and 0.5mL toluene, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine The lower 0 DEG C of reaction 48h of co-catalysis of (0.004g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation removing After solvent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio The mixed liquor of 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.0644g, yield 95%, Ee value is 98%, 95%, dr value 4.0:1),1H NMR(500MHz,CDCl3): δ=7.572-7.555 (m, 2H), 7.372-7.340(m,2H),7.276-7.170(m,2H),6.785-6.735(m,2H),6.695-6.692(m,1H),5.981(s, 1H),4.941(s,1H),3.793(s,3H),3.256-3.210(m,1H),2.431-2.366(m,2H),2.030-1.989(m,1H), 0.888-0.875 (d, J=6.5Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.614,159.780,141.587, 135.768,129.454,129.422(×2),125.390,119.889,119.829,118.698(×2),113.653,111.923, 102.021,85.697,55.224,38.082,25.864,6.783ppm。
Embodiment 27:(1R, 2R, 3R, 5S)-3-(the fluorine-based phenyl of 4-)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 4-fluorine cinnamic aldehyde (0.0360g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 95% for 0.0484g, yield 74%, 99%, dr value 5.3:1),1H NMR(500MHz,CDCl3): δ=7.557-7.535 (m, 2H), 7.382-7.329 (m, 2H), 7.177-7.156(m,3H),7.009-6.974(m,2H),5.868(s,1H),5.813(s,1H),2.606-2.517(m,1H), 2.312-2.249 (m, 1H), 2.185-2.107 (m, 2H), 0.963-0.949 (d, J=7.0Hz, 3H) ppm；13C NMR(125 MHz,CDCl3): δ=169.026,161.777 (d,1JC-F=243.6Hz), 137.329 (d,4JC-F=3.1Hz), 135.800, 129.416(×2,d,3JC-F=6.4Hz), 129.390,125.385 (× 2), 118.753 (× 2), 115.512 (× 2, d,2JC-F=21.0Hz), 102.366,85.565,43.465,41.791,35.408,12.173ppm。
Embodiment 28:((1R, 2R, 3R, 5S)-3-(4-chloro phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 4-chlorocinnamaldehyde (0.0398g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 99% for 0.0583g, yield 85%, 96%, dr value 4.3:1),1H NMR(500MHz,CDCl3): δ=7.545-7.527 (m, 2H), 7.363-7.275 (m, 4H), 7.166-7.124(m,1H),7.081-7.014(m,2H),5.903(s,1H),5.591(s,1H),3.229-3.183(m,1H), 2.395-2.332 (m, 2H), 1.992-1.951 (m, 1H), 0.862-0.848 (d, J=7.0Hz, 3H) ppm；13C NMR(125 MHz,CDCl3): δ=170.796,138.465,135.635,132.546,129.384 (× 2), 128.952 (× 2), 128.622 (× 2), 125.412,118.627(×2),102.134,85.425,37.892,37.582,25.804,6.781ppm。
Embodiment 29:(1R, 2R, 3R, 5S)-3-(4-bromo phenyl)-1-hydroxy-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 4-bromocinnamaldehyde (0.0504g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 99% for 0.0613g, yield 79%, 96%, dr value 3.7:1),1H NMR(500MHz,CDCl3): δ=7.576-7.560 (m, 2H), 7.449-7.433 (m, 2H), (7.411-7.357 m, 2H), 7.226-7.140 (m, 1H), 7.031-7.015 (d, J=8.0Hz, 2H), 5.931 (s, 1H), 3.233-3.188 (m, 1H), 2.378-2.335 (m, 2H), 2.015-1.980 (m, 1H), 0.864-0.850 (d, J=7.0Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.401,138.926,135.723,131.640 (× 2), 129.501 (× 2), 129.335(×2),125.483,120.678,118.642(×2),101.845,85.569,37.933,37.733,25.839,6.748 ppm。
Embodiment 30:(1R, 2R, 3R, 5S)-1-hydroxyl-3-(4-methoxyphenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2, 1] preparation of octane-7-ketone
2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 4-methoxycinnamic aldehyde is added in 10mL test tube (0.0389g, 0.24mmol) and 0.5mL toluene, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine The lower 0 DEG C of reaction 48h of co-catalysis of (0.004g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation removing After solvent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio The mixed liquor of 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.0576g, yield 85%, Ee value is 90%, 92%, dr value 3.0:1),1H NMR(500MHz,CDCl3): δ=7.557-7.541 (m, 2H), 7.368-7.336(m,2H),7.193-7.163(m,1H),7.120-7.102(m,2H),6.856-6.839(m,2H), 5.824-5.805(m,1H),5.655(s,1H),3.793(s,3H),2.552-2.495(m,1H),2.302-3.227(m,1H), 2.134-2.116 (m, 2H), 0.964-0.950 (d, J=7.0Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=169.050,158.542,135.909,133.667,129.366 (× 2), 128.906 (× 2), 125.302,118.773 (× 2), 114.083(×2),102.404,85.719,55.263,43.315,41.902,35.467,12.185ppm。
Embodiment 31:(1R, 2R, 3R, 5S)-1-hydroxyl-3-(4-aminomethyl phenyl)-2-methyl-6-phenyl-8-oxygen-6-azabicyclic [3,2,1] The preparation of octane-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 4-methyl cinnamic aldehyde (0.0350g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 99% for 0.0388g, yield 60%, 98%, dr value 3.6:1),1H NMR(500MHz,CDCl3): δ=7.574-7.557 (m, 2H), 7.396.7.364 (m, 2H), 7.211-7.181(m,1H),7.134-7.084(m,4H),5.846-5.820(m,1H),5.092(s,1H),2.584-2.526(m, 1H), 2.333-2.298 (m, 4H), 2.157-2.137 (m, 2H), 0.965-0.952 (d, J=7.0Hz, 3H) ppm；13C NMR (125MHz,CDCl3): δ=168.889,138.554,136.651,135.962,129.428 (× 2), 129.389 (× 2), 127.864(×2),125.340,118.790(×2),102.266,85.866,43.772,41.694,35.462,20.985,12.214 ppm。
Embodiment 32:(1R, 2R, 3R, 5S)-3-(furan-2-alkyl)-1-hydroxy-2-methyl-6-phenyl-8-oxa--6-azabicyclic [3,2, 1] preparation of octane-7-ketone
2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 3-(furyl-2-base) propylene is added in 10mL test tube Aldehyde (0.0293g, 0.24mmol) and 0.5mL toluene, in chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and three second The lower 0 DEG C of reaction 48h of co-catalysis of amine (0.004g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), and extract distillation is de- After solvent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume The ratio mixed liquor of 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.0454g, yield 76%, Ee value is 98%, 67%, dr value 5.6:1),1H NMR(500MHz,CDCl3): δ=7.550-7.534 (m, 2H), 7.370-7.332 (m, 3H), 7.188-7.158 (m, 1H), 6.292-6.282 (m, 1H), 6.018-6.012 (d, J=6.0Hz, 1H), 5.872(s,1H),4.868(s,1H),3.323-3.277(m,1H),2.526-2.474(m,1H),2.318-2.261(m,1H), 2.052-2.011 (m, 1H), 0.932-0.919 (d, J=6.5Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.279,154.386,141.599,135.632,129.410 (× 2), 125.430,118.758 (× 2), 109.933,105.915, 101.469,85.535,36.298,32.946,25.160,7.137,ppm。
Embodiment 33:(1R, 2R, 3R, 5S)-1-hydroxy-2-methyl-6-phenyl-3-propyl group-8-oxa--6-azabicyclic [3,2,1] octane-7- The preparation of ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 2-hexenoic aldehyde (0.024g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 89% for 0.0512g, yield 93%, 79%, dr value 7.7:1),1H NMR(500MHz,CDCl3): δ=7.499-7.480 (m, 2H), 7.344-7.311 (m, 2H), 7.163-7.134(m,1H),5.717(s,1H),4.994(s,1H),2.114-2.062(m,1H),1.847-1.798(m,1H), 1.740-1.699 (m, 1H), 1.663-1.608 (m, 1H), 1.333-1.123 (m, 4H), 1.079-1.065 (d, J=7.0Hz, 3H) 0.852-0.824 (t, J=7.0Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.794,135.863, 129.282(×2),125.124,118.700(×2),102.304,85.940,35.293,33.894,32.064,28.518,19.584, 14.030,5.608ppm。
Embodiment 34:(1R, 2R, 3S, 5S)-1-hydroxyl-3-isopropyl-2-methyl-6-phenyl-8-oxa--6-azabicyclic [3,2,1] octane The preparation of-7-ketone
Add in 10mL test tube 2-carbonyl-N-phenylbutanamides (0.0354g, 0.2mmol), 4-methyl-2-pentenal serving (0.024g, 0.24mmol) and 0.5mL toluene, chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 98% for 0.0369g, yield 67%, 87%, dr value 7.0:1),1H NMR(500MHz,CDCl3): δ=7.501-7.483 (m, 2H), 7.360-7.328 (m, 2H), 7.175-7.146(m,1H),5.741(s,1H),4.856(s,1H),2.208-2.170(m,1H),1.864-1.832(m,1H), 1.636-1.553 (m, 2H), 1.352-1.307 (m, 1H), 1.097-1.084 (d, J=6.5Hz, 3H), 0.868-0.855 (d, J=6.5Hz, 3H), 0.784-0.771 (d, J=6.5Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.677, 135.855,129.320(×2),125.168,118.732(×2),102.341,85.949,39.819,34.381,28.427,26.659, 20.667,19.819,5.765ppm。
Embodiment 35:(1R, 2R, 3R, 5S)-1-hydroxyl-2-isopropyl-3,6-diphenyl-8-oxa--6-azabicyclic [3,2,1] octane-7- The preparation of ketone
Add in 10mL test tube 2-carbonyl-N-propyloxy phenyl amide (0.0410g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 98% for 0.0398g, yield 59%, 99%, dr value 9.5:1),1H NMR(500MHz,CDCl3): δ=7.563-7.540 (m, 2H), 7.391-7.355 (m, 2H), 7.326-7.296 (m, 2H), 7.254-7.177 (m, 4H), 5.754-5.747 (t, J=1.5Hz1H), 5.084 (s, 1H), 3.076-3.018 (m1H), 2.441-2.414 (m, 1H), 2.212-2.096 (m, 3H), 0.997-0.983 (d, J=7.0Hz3H), 0.698-0.683 (d, J=7.5Hz3H) ppm；13C NMR(125MHz,CDCl3): δ=167.748,142.797,136.028, 129.421(×2)128.685(×2)128.125(×2),126.877,125.285,118.777(×2),102.436,85.556,51.601, 39.152,37.053,26.570,21.503,20.052ppm。
Embodiment 36:(1R, 2R, 3R, 5S)-6-phenyl-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azabicyclic [3,2,1] octane-7- The preparation of ketone
Add in 10mL test tube 2-carbonyl-N-benzyl butyramide (0.0382g, 0.2mmol), cinnamic aldehyde (0.0328g, 0.24 And 0.5mL toluene mmol), chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine (0.004g, 0.04 Mmol) the lower 0 DEG C of reaction 48h of co-catalysis, is extracted with ethyl acetate (3 × 2mL), after extract distillation desolvation, and institute Obtaining concentrate and carry out column chromatography for separation with 200～300 mesh silica gel, eluant is the mixing of ethyl acetate and petroleum ether volume ratio 1:3 Liquid, collects containing the eluent of target compound, concentrate drying obtain target compound (Ee value is 99% for 0.0375g, yield 58%, 79%, dr value 1.6:1),1H NMR(500MHz,CDCl3): δ=7.365-7.119 (m, 10H), 5.237 (s, 1H), 4.922-4.892 (d, J=15Hz, 1H), 4.370 (s, 1H), 4.142-4.112 (d, J=15Hz, 1H), 3.152-3.106 (m, 1H), 2.323-2.298 (m, 1H), 2.260-2.204 (m, 1H), 1.618-1.577 (m, 1H), 0.808-0.795 (d, J=6.5Hz, 3H), ppm；13C NMR(125MHz,CDCl3): δ=171.659,140.020,134.542,128.969 (× 2), 128.484 (× 2), 128.282,128.185(×2),127.675(×2),126.745,101.418,84.452,44.758,38.357,38.266,25.343, 6.645ppm。
Embodiment 37:(1R, 2R, 3R, 5S)-6-(3,5-bis-(trifluoromethyl) phenyl)-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azepine The preparation of bicyclo-[3,2,1] octane-7-ketone
2-carbonyl-N-3,5-two trifluoromethyl butyramide (0.0626g, 0.2mmol), cinnamic aldehyde is added in 10mL test tube (0.0328g, 0.24mmol) and 0.5mL toluene, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine The lower 0 DEG C of reaction 48h of co-catalysis of (0.004g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation removing After solvent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio The mixed liquor of 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.0846g, yield 95%, Ee value is 62%, dr value 49:1),1H NMR(500MHz,CDCl3): δ=8.060-8.026 (m, 2H), 7.668-7.625 (m, 1H),7.350-7.321(m,2H),7.284-7.255(m,1H),7.227-7.211(m,2H),5.973(s,1H),5.474(s,1H), 2.560-2.485(m,1H),2.408-2.372(m,1H),2.330-2.266(m,1H),2.210-2.156(m,1H), 0.974-0.961 (d, J=6.5Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=169.958,140.759, 137.294,132.963 (× 2, m), 128.858 (× 2), 127.936 (× 2), 127.376,122.766 (× 2, m), 118.282 (m), 117.207(×2,m),102.539,85.487,44.053,41.494,34.947,12.030ppm。
Embodiment 38:(1R, 2R, 3R, 5S)-6-(3,5-Dimethoxyphenyl)-1-hydroxy-2-methyl-3-phenyl-8-oxa--6-azabicyclic [3, 2,1] preparation of octane-7-ketone
2-carbonyl-N-3,5-Dimethoxyphenyl butyramide (0.0474g, 0.2mmol), cinnamic aldehyde is added in 10mL test tube (0.0328g, 0.24mmol) and 0.5mL toluene, at chirality secondary amine catalyst (VI) (0.017g, 0.04mmol) and triethylamine The lower 0 DEG C of reaction 48h of co-catalysis of (0.004g, 0.04mmol), is extracted with ethyl acetate (3 × 2mL), extract distillation removing After solvent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio The mixed liquor of 1:3, collects containing the eluent of target compound, concentrate drying obtain target compound (0.0664g, yield 90%, Ee value is 92%, 89%, dr value 1.3:1),1H NMR(500MHz,CDCl3): δ=7.326-7.276 (m, 2H), 7.242-7.213 (m, 1H), 7.147-7.133 (m, 2H), 6.787-6.783 (m, 2H), 6.268-6.260 (t, J=2.0Hz, 1H), 5.877(s,1H),4.723(s,1H),3.789(s,6H),3.249-3.203(m,1H),2.429-2.336(m,2H), 2.060-2.012 (m, 1H), 0.864-0.851 (d, J=6.5Hz, 3H) ppm；13C NMR(125MHz,CDCl3): δ=170.607,161.332 (× 2), 139.877,137.460,128.512 (× 2), 127.622 (× 2), 126.792,102.152, 97.097(×2),85.704,55.447(×2),38.109,37.999,29.710,25.741,6.773ppm。

Claims (9)

1. the method for asymmetric synthesis of the chirality bicyclo-caprolactam compounds as shown in formula (I), it is characterised in that institute The synthetic method stated is:
By chirality secondary amine catalyst, alkaline matter, organic solvent mixing, under stirring condition, add α shown in formula (II), β-insatiable hunger With alpha-carbonyl amide derivatives shown in carbonyl compound and formula (III), at-20～60 DEG C, react 12～84h, after reaction terminates, Reactant liquor post processing obtains the chirality bicyclo-caprolactam compounds shown in formula (I)；
In formula (I), formula (II) or formula (III), R1、R3Each stand alone as the alkyl of H, C1～C20,2-methoxybenzene Base, 3-methoxyphenyl, 4-methoxyphenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, phenyl, the fluorine-based benzene of 2- The fluorine-based phenyl of base, 3-, the fluorine-based phenyl of 4-, 2-chloro phenyl, 3-chloro phenyl, 4-chloro phenyl, 2-bromo phenyl, 3-bromo Phenyl, 4-bromo phenyl, 2-nitrobenzophenone, 3-nitrobenzophenone, 4-nitrobenzophenone, 2-trifluoromethyl, 3-trifluoromethylbenzene Base, 4-trifluoromethyl, furyl, thienyl, 3,5-bis-trifluoromethyl or 3,5-Dimethoxyphenyl；R2For H Or the alkyl of C1～C20；
Described chirality secondary amine catalyst is selected from one of compound shown in formula (IV)～(X):
2. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that institute The R stated1For 2-chloro phenyl, 2-bromo phenyl, 2-methoxyphenyl, the fluorine-based phenyl of 3-, 3-chloro phenyl, 3-methoxybenzene The fluorine-based phenyl of base, 4-, 4-chloro phenyl, 4-bromo phenyl, 4-methoxyphenyl, 4-aminomethyl phenyl, phenyl, furyl, Propyl group or isopropyl；R2For methyl, propyl group or isopropyl；R3For phenyl, 3,5-bis-trifluoromethyl or 3,5-dimethoxy Phenyl.
3. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that institute The alkaline matter stated is N, N-diisopropylethylamine, triethylene diamine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 4-bis- Methylamino pyridine, potassium carbonate, Schweinfurt green, triethylamine, quinine, cinchonine, quinine set, cinchonine are fixed, sodium hydroxide or ring Hexamethylene diamine.
4. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that institute The organic solvent stated is dichloromethane, chloroform, ether, diisopropyl ether, oxolane, 1,4-dioxane, ethyl acetate, first Benzene, dimethylbenzene, benzotrifluoride, thionyl chloride, N,N-dimethylformamide, acetonitrile, methanol, ethanol or isopropanol；Described The volumetric usage of organic solvent be calculated as 0.5～5mL/mmol with the amount of the material of alpha-carbonyl amide derivatives (III).
5. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that institute The alpha-carbonyl amide derivatives (III) stated and α, the amount of the material that feeds intake of beta-unsaturated carbonyl compound (II) is than for 1:1～3.
6. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that institute The alpha-carbonyl amide derivatives (III) stated is 1:0.05～0.3 with the ratio of the amount of the material that feeds intake of chirality secondary amine catalyst.
7. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that institute The alpha-carbonyl amide derivatives (III) stated is 1:0.05～0.3 with the ratio of the amount of the material that feeds intake of alkaline matter.
8. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that anti- After should terminating, the method for reactant liquor post processing is: after reaction terminates, reactant liquor is extracted with ethyl acetate, extract distillation removing After solvent, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether volume ratio The mixed liquor of 1:3, collects the eluent containing target compound, and concentrate drying obtains the chirality bicyclo-caprolactam class shown in formula (I) Compound.
9. the method for asymmetric synthesis of chirality bicyclo-caprolactam compounds as claimed in claim 1, it is characterised in that institute The synthetic method stated is:
By the chirality secondary amine catalyst shown in formula (VI), triethylamine, toluene mixing, add shown in formula (II) under stirring condition Alpha-carbonyl amide derivatives shown in α, beta-unsaturated carbonyl compound and formula (III), reacts 48h at 0 DEG C, after reaction terminates, Reactant liquor post processing obtains the chirality bicyclo-caprolactam compounds shown in formula (I)；Described alpha-carbonyl amide derivatives (III) With α, the amount of the material that feeds intake of beta-unsaturated carbonyl compound (II) is than for 1:1.2；Described alpha-carbonyl amide derivatives (III) It is 1:0.2 with the ratio of the amount of the material that feeds intake of chirality secondary amine catalyst；Described alpha-carbonyl amide derivatives (III) and triethylamine The ratio of amount of the material that feeds intake be 1:0.2；The volumetric usage of described toluene is with the amount of the material of alpha-carbonyl amide derivatives (III) It is calculated as 2.5mL/mmol；
After reaction terminates, the method for reactant liquor post processing is: after reaction terminates, reactant liquor is extracted with ethyl acetate, and extract steams After evaporating desolvation, gained concentrate carries out column chromatography for separation with 200～300 mesh silica gel, and eluant is ethyl acetate and petroleum ether The mixed liquor of volume ratio 1:3, collects the eluent containing target compound, and concentrate drying obtains chirality two hexamethylene shown in formula (I) Lactam analog compound.
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