CN110204468A - A kind of method of asymmetric synthesis of chiral alpha-thiocyanogen cyclic ketone acid esters compound - Google Patents

A kind of method of asymmetric synthesis of chiral alpha-thiocyanogen cyclic ketone acid esters compound Download PDF

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CN110204468A
CN110204468A CN201910473151.1A CN201910473151A CN110204468A CN 110204468 A CN110204468 A CN 110204468A CN 201910473151 A CN201910473151 A CN 201910473151A CN 110204468 A CN110204468 A CN 110204468A
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formula
reaction
thiocyanogen
chiral
acid esters
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CN110204468B (en
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王益锋
王彪
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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/02—Thiocyanates
    • C07C331/14—Thiocyanates having sulfur atoms of thiocyanate groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

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Abstract

The invention discloses one kind chiral alpha as shown in formula (III)-thiocyanogen cyclic ketone acid esters compound synthetic methods: using N- thiocyanogen phthalimide shown in cyclic ketone acid esters compound shown in formula (I) and formula (II) as raw material, under the action of chiral catalyst, asymmetric thiocyanogenization reaction is carried out in organic solvent until the reaction is complete, reaction solution is post-treated after reaction obtains corresponding product, that is chiral alpha shown in formula (III)-thiocyanogen cyclic ketone acid esters compound, this kind of compound can be used as a kind of important organic biological active intermediate and be applied to medicine, the fields such as pesticide.This chiral alpha provided by the invention-thiocyanogen cyclic ketone acid esters compound high-efficiency synthesis method, high income, enantioselectivity are good, reaction substrate is in extensive range, reaction reagent is cheap and easy to get, have important application value.

Description

A kind of method of asymmetric synthesis of chiral alpha-thiocyanogen cyclic ketone acid esters compound
Technical field
The present invention relates to a kind of chiral alpha-thiocyanogen cyclic ketone acid esters compound synthetic methods.
Background technique
Asymmetry catalysis is current chemical developer one of field the most active, to carry out synthesis of chiral drug, pesticide, day The right compounds such as product and fragrance provide effective strategy.And wherein chiral transition metal is catalyzed, because of its efficient catalysis effect The extensive concern of energy and excellent chiral induction ability by everybody.In traditional asymmetry catalysis process, it often will appear temperature The unfavorable factors such as degree condition is harsh, the reaction time is long, catalytic amount is big, therefore develop a kind of efficiently mild asymmetric syntheses side Method seems very necessary.
Many drugs, pesticide and day are widely present in by the compound of core skeleton of thiocyanogen, sulphamide or sulfilimine In right product, such as: Yi Lumaibu (Eflucimibe) is for treating or preventing atherosclerosis, reducing blood lipid.Amoxicillin (Amoxicillin) as broad-spectrum antibiotic due to its strong bactericidal effect.Penicillin (Penicillin G) for treat pneumonia, Meningitis, endocarditis, diphtheria, anthracnose, etc..Natural products Fasicularin, 9-Thiocyanato Pupukeanane, Psammaplin B, (S)-(-)-Spirobrassinin, Fusaperazine A, wherein (+) -1,1'- Dideoxyverticillin A has significant cytotoxic activity, etc. to human colon carcinoma HCT-116 cell.These clinical medicines, The molecular structural formula of pesticide and natural products is as follows:
In pharmaceutical chemistry, the compound of sulfur-bearing has significant bioactivity.In addition, the chiral quaternary carbon containing thiocyanogen Other chipal compounds containing important functional group can be converted by closing object, such as sulphur trifluoromethyl, sulphur difluoromethyl, sulfydryl, two sulphur Key, sulphur phosphorus key, tetrazolium, thiazolinone etc..Currently, only Chen Fuxue seminar is in Organic Letters, 2018.20, The asymmetric thiocyanogenization reaction of an example cinchona alkaloid-derived ligands catalysis cyclic ketone acid esters compound is reported in 1600, but should Reaction must be reacted under the conditions of -78 DEG C, and the reaction ester group that needs substrate to contain big steric hindrance be just able to achieve it is good Good chiral control.Therefore develop a kind of synthesis plan of efficiently simple synthesis of chiral α-thiocyanogen cyclic ketone acid esters compound Slightly it is particularly important.
Summary of the invention
The object of the present invention is to provide a kind of chiral alpha-thiocyanogen cyclic ketone acid esters compound high-efficiency synthesis methods.
To achieve the above object, the technical scheme adopted by the invention is as follows:
One kind chiral alpha as shown in formula (III)-thiocyanogen cyclic ketone acid esters compound synthetic method, it is characterised in that The method carries out in accordance with the following steps:
It is original with N- thiocyanogen phthalimide (NTP) shown in beta-keto acid ester type compound shown in formula (I) and formula (II) Material carries out asymmetric thiocyanogenization reaction until the reaction is complete, reaction knot under the action of chiral catalyst in organic solvent Shu Hou, reaction solution is post-treated to obtain corresponding product, i.e. formula (III) institute chiral alpha-thiocyanogen cyclic ketone acid esters compound； The chiral catalyst is the chiral complex formed using oxazoline as the chipal compounds of functional group and mantoquita；The formula (I) amount of the substance of N- thiocyanogen phthalimide (NTP) shown in ring-type beta-keto acid ester type compound shown in and formula (II) it Than for 1:1.0~2.0；The ratio between the amount of substance of ring-type beta-keto acid ester type compound shown in the chiral catalyst and formula (I) For 1~10:100；
In formula (I) or formula (III),
R1For methyl, methoxyl group, fluorine, chlorine, bromine, 5,6- dimethoxy or 5,6- methylenedioxy；
R2For methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, cyclopentyloxy, cyclohexyloxy, benzyloxy, Buddha's warrior attendant alcoxyl Base or anilino-；
N is 1,2 or 3.
Further, it is preferable that the R1For methyl, methoxyl group, fluorine, chlorine or bromine；R2For isopropoxy, tert-butoxy or gold Rigid alkoxy；N is 1 or 2.
Further, chiral catalyst of the present invention be formula (IV), formula (V), compound shown in formula (VI) or formula (VII) One of with mantoquita formed chiral complex:
In formula (IV) formula (V), formula (VI) or formula (VII), the carbon atom for indicating * is asymmetric carbon atom；
R3、R4Respectively stand alone as C3~4Alkyl, phenyl or benzyl；
R5、R6Respectively stand alone as methyl or C4~5Naphthenic base；M is 1 or 2；
R7、R8Respectively stand alone as C3~4Alkyl, phenyl or benzyl；
R9、R10Respectively stand alone as C3~4Alkyl, phenyl or benzyl；
R11、R12、R13、R14Respectively stand alone as hydrogen, C3~4Alkyl, phenyl, benzyl, 3,5- 3,5-dimethylphenyl, 3,5- bis- Tert-butyl-phenyl, 2- naphthalene or R11~R14It is 2,3- dihydro indenyl；
The X is imino group, N-methyl or sulphur；
R15、R16Respectively stand alone as hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, nitro, amino or hydroxyl.
Further, it is preferable that the R3、R4、R7、R8、R9、R10、R12、R13Respectively stand alone as phenyl, benzyl, isopropyl Or tert-butyl；The R5、R6It is hydrogen；The R11、R14Respectively stand alone as hydrogen or phenyl；R15、R16Respectively stand alone as hydrogen, first Base, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, nitro；The X is imino group, N-methyl or sulphur.
Further, the preferably described chiral alpha-thiocyanogen cyclic ketone acid esters compound is formula (III) compound represented:
In formula (III), R1、R2, n the same formula of definition (I).
Further, chiral catalyst of the present invention be more preferably chiral complex that following compounds and mantoquita are formed it One:
Further, the mantoquita be copper bromide, copper acetate, copper trifluoromethanesulfcomposite, acetylacetone copper, copper tetrafluoroborate or Cupric perchlorate, four acetonitrile of tetrafluoro boric acid are cuprous or four acetonitrile of hexafluorophosphoric acid is cuprous.
Further, the volumetric usage of organic solvent of the present invention is with ring-type beta-keto acid ester type compound shown in formula (I) The amount of substance be calculated as 5~20mL/mmol.
Further, organic solvent of the present invention be ethyl acetate, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, Toluene, tetrahydrofuran, meta-xylene or 1,2- dichloroethanes.
Further, asymmetric thiocyanogen reaction temperature of the present invention is -78~25 DEG C, the reaction time 12 hours.
In general, the post-processing approach of reaction solution of the present invention are as follows: after reaction, reaction solution is extracted with ethyl acetate, After taking organic phase distillation removing solvent, residue carries out column chromatography for separation with 200~300 mesh silica gel, and eluant, eluent is ethyl acetate Mixed liquor with petroleum ether volume ratio 1:1~10 is that eluant, eluent carries out gradient elution, collects the eluent containing target compound, steams Except solvent and drying is to get chiral alpha shown in formula (III)-thiocyanogen cyclic ketone acid esters compound.
Compared with prior art, the beneficial effects of the present invention are:
This chiral alpha provided by the invention-thiocyanogen cyclic ketone acid esters compound high-efficiency synthesis method, yield High, asymmetric selectivity is good, reaction substrate is in extensive range, reaction reagent is cheap and easy to get, has important application value.
Specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in This.
Embodiment 1:
Reaction equation are as follows:
By the complex compound of 0.02mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 2mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in 0 DEG C, then to N- thiocyanogen phthalimide (1.5equiv) shown in formula (II) is added in above-mentioned system, reacts 12 hours, will react under the conditions of 0 DEG C Liquid is concentrated under reduced pressure, and upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is elution Agent carries out gradient elution, collects eluent and boils off solvent, obtains white solid product (yield 96%), [α] D20=60 ° of (c= 1.0,CH2Cl2).1H NMR(500MHz,CDCl3) δ=7.88 (d, J=7.7Hz, 1H), 7.73 (td, J=7.7,1.0Hz, 1H), 7.55-7.47 (m, 2H), 4.06 (d, J=18.0Hz, 1H), 3.63 (d, J=18.0Hz, 1H), 1.45 (s, 9H)13C NMR(126MHz,CDCl3) δ=194.97,150.98,136.74,133.11,128.80,126.18,125.80,86.07, 64.19,40.38,27.65ppm. by chiral HPLC, and concrete analysis condition is Daicel Chiralpak AD-H, 2- Propanol:hexane=2:98, flow rate 1.0mL/min, 285nm；tR=14.759min, 15.852min.98% Ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-a:
Reaction equation are as follows:
By the complex compound of 0.02mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 2mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in -78 DEG C, then N- thiocyanogen phthalimide (1.5equiv) shown in formula (II) is added into above-mentioned system, is reacted 12 hours under the conditions of -78 DEG C, it will Reaction solution is concentrated under reduced pressure, upper silica gel column chromatography post separation, and the eluent that the volume ratio with petroleum ether and ethyl acetate is 1~10:1 is Eluant, eluent carries out gradient elution, collects eluent and boils off solvent, obtains white solid product (yield 95%), pass through chiral HPLC Analysis, concrete analysis condition are Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate1.0mL/min,285nm；tR=14.759min, 15.852min.33%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-b:
Reaction equation are as follows:
By the complex compound of 0.02mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 2mL methylene chloride is added, is placed in and stirs 10 minutes at room temperature, state then up N- thiocyanogen phthalimide (1.5equiv) shown in formula (II) is added in system, reacts 12 hours under room temperature, by reaction solution It is concentrated under reduced pressure, upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is eluant, eluent Gradient elution is carried out, eluent is collected and boils off solvent, obtain white solid product (yield 94%), by chiral HPLC, Concrete analysis condition is Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0mL/ min,285nm；tR=14.759min, 15.852min.96%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-c:
Reaction equation are as follows:
By the complex compound of 0.002mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 2mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in 0 DEG C, then to N- thiocyanogen phthalimide (1.5equiv) shown in formula (II) is added in above-mentioned system, reacts 12 hours, will react under the conditions of 0 DEG C Liquid is concentrated under reduced pressure, and upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is elution Agent carries out gradient elution, collects eluent and boils off solvent, obtain white solid product (yield 93%), passes through chiral HPLC points Analysis, concrete analysis condition are Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0mL/min,285nm；tR=14.759min, 15.852min.34%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-d:
Reaction equation are as follows:
By the complex compound of 0.04mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 2mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in 0 DEG C, then to N- thiocyanogen phthalimide (1.5equiv) shown in formula (II) is added in above-mentioned system, reacts 12 hours, will react under the conditions of 0 DEG C Liquid is concentrated under reduced pressure, and upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is elution Agent carries out gradient elution, collects eluent and boils off solvent, obtain white solid product (yield 95%), passes through chiral HPLC points Analysis, concrete analysis condition are Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0mL/min,285nm；tR=14.759min, 15.852min.98%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-e:
Reaction equation are as follows:
By the complex compound of 0.02mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 4mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in 0 DEG C, then to N- thiocyanogen phthalimide (1.5equiv) shown in formula (II) is added in above-mentioned system, reacts 12 hours, will react under the conditions of 0 DEG C Liquid is concentrated under reduced pressure, and upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is elution Agent carries out gradient elution, collects eluent and boils off solvent, obtain white solid product (yield 96%), passes through chiral HPLC points Analysis, concrete analysis condition are Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0mL/min,285nm；tR=14.759min, 15.852min.92%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-f:
Reaction equation are as follows:
By the complex compound of 0.02mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 1mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in 0 DEG C, then to N- thiocyanogen phthalimide (1.5equiv) shown in formula (II) is added in above-mentioned system, reacts 12 hours, will react under the conditions of 0 DEG C Liquid is concentrated under reduced pressure, and upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is elution Agent carries out gradient elution, collects eluent and boils off solvent, obtain white solid product (yield 96%), passes through chiral HPLC points Analysis, concrete analysis condition are Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0mL/min,285nm；tR=14.759min, 15.852min.98%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-g:
Reaction equation are as follows:
By the complex compound of 0.02mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 4mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in 0 DEG C, then to N- thiocyanogen phthalimide (1.0equiv) shown in formula (II) is added in above-mentioned system, reacts 12 hours, will react under the conditions of 0 DEG C Liquid is concentrated under reduced pressure, and upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is elution Agent carries out gradient elution, collects eluent and boils off solvent, obtain white solid product (yield 86%), passes through chiral HPLC points Analysis, concrete analysis condition are Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0mL/min,285nm；tR=14.759min, 15.852min.95%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 1-h:
Reaction equation are as follows:
By the complex compound of 0.02mmol oxazoline ligand (VII)-a and copper trifluoromethanesulfcomposite, indone tert-butyl acrylate (0.2mmol) is added in 10mL test tube, and the dissolution of 4mL methylene chloride is added, stirs 10 minutes under the conditions of being placed in 0 DEG C, then to N- thiocyanogen phthalimide (2.0equiv) shown in formula (II) is added in above-mentioned system, reacts 12 hours, will react under the conditions of 0 DEG C Liquid is concentrated under reduced pressure, and upper silica gel column chromatography post separation, the eluent that the volume ratio using petroleum ether and ethyl acetate is 1~10:1 is elution Agent carries out gradient elution, collects eluent and boils off solvent, obtain white solid product (yield 96%), passes through chiral HPLC points Analysis, concrete analysis condition are Daicel Chiralpak AD-H, 2-propanol:hexane=2:98, flow rate 1.0mL/min,285nm；tR=14.759min, 15.852min.98%ee.HRMS:m/z=312.0663 [M+Na]+.
Embodiment 2-42
Take reactant same as Example 1, under identical operating procedure, reaction is placed under the conditions of 0 DEG C, respectively with 0.02mmol or less catalyst alternative catalysts (VII)-a, different mantoquitas and the different organic solvents under (VII)-a catalysis The asymmetric thiocyanogenization reaction of middle progress, the results are shown in Table 1:
The corresponding asymmetric thiocyanogen response data of 1 differential responses object of table
Embodiment 43:
Difference from Example 1 is: keto ester used be indone acid methyl esters, other reaction conditions and step with react Embodiment 1 is identical, obtains white solid product (yield 98%).[α]D20=15 ° of (c=1.0, CH2Cl2).1H NMR (500MHz,CDCl3) δ=7.89 (d, J=7.6Hz, 1H), 7.76 (t, J=7.5Hz, 1H), 7.57-7.49 (m, 2H), 4.13 (d, J=18.1Hz, 1H), 3.83 (s, 3H), 3.65 (d, J=18.1Hz, 1H)13C NMR(126MHz,CDCl3) δ= 194.26,166.73,150.80,136.98,132.81,128.97,128.97,126.26,125.98,109.17,63.38, 54.56,40.32ppm；By chiral HPLC, condition of making a concrete analysis of is Daicel Chiralpak ID-H, 2- Propanol:hexane=10:90, flow rate 1.0mL/min, 254nm；tR=26.585min, 28.278min.82% Ee.HRMS:m/z=270.0198 [M+Na]+.
Implement 44:
Difference from Example 1 is: keto ester used be indone acetoacetic ester, other reaction conditions and step with react Embodiment 1 is identical, obtains white solid product (yield 95%).[α] D20=82 ° of (c=1.0, CH2Cl2) .1H NMR δ=7.89 (500MHz, CDCl3) (d, J=7.8Hz, 1H), 7.76 (t, J=7.5Hz, 1H), 7.57-7.49 (m, 2H), 4.29 (q, J=7.1Hz, 2H), 4.12 (d, J=18.1Hz, 1H), 3.65 (d, J=18.1Hz, 1H), 1.28 (t, J=7.1Hz, 3H) .13C NMR (125MHz, CDCl3) δ=194.46,166.23,150.87,136.92,132.90,128.93,126.25, 125.95,109.30,64.16,63.43,40.33,13.88ppm. are by chiral HPLC, concrete analysis condition DaicelChiralpak OD-H, 2-propanol:hexane=5:95, flow rate 1.0mL/min, 254nm；TR= 15.172min, 16.225min.87%ee.HRMS:m/z=284.0351 [M+Na]+
Embodiment 45:
Difference from Example 1 is: keto ester used is indone isopropyl propionate, other reaction conditions and step and anti- It answers embodiment 1 identical, obtains white solid product (yield 97%).[α] D20=69 ° of (c=1.0, CH2Cl2) .1HNMR δ=7.89 (500MHz, CDCl3) (d, J=7.7Hz, 1H), 7.78-7.72 (m, 1H), 7.53 (dd, J=19.7,7.5Hz, 2H), 5.11 (hept, J=6.2Hz, 1H), 4.09 (d, J=18.0Hz, 1H), 3.64 (d, J=18.0Hz, 1H), 1.27 (dd, J=9.1,6.3Hz, 6H) .13C NMR (125MHz, CDCl3) δ=194.59,165.74,150.91,136.85,132.97, 128.89,126.23,125.92,109.41,72.62,63.49,40.30,21.42ppm；By chiral HPLC, specifically Analysis condition is Daicel Chiralpak AS-Hcolumn at 285nm, 2-propanol:hexane=2:98, flow rate 1.0mL/min；TR=33.718min, 37.719min.93%ee.HRMS:m/z=298.0509 [M+Na]+
Embodiment 46:
Difference from Example 1 is: keto ester used is indone acid ring pentyl ester, other reaction conditions and step and anti- It answers embodiment 1 identical, obtains white solid product (yield 97%).[α] D20=60 ° of (c=1.0, CH2Cl2) .1H NMR δ=7.88 (500MHz, CDCl3) (d, J=7.7Hz, 1H), 7.75 (t, J=7.5Hz, 1H), 7.55-7.49 (m, 2H), 4.08 (d, J=18.0Hz, 1H), 3.62 (d, J=18.0Hz, 1H), 1.84 (dq, J=13.8,7.3Hz, 2H), 1.74-1.68 (m, 2H), 1.66-1.57 (m, 4H) .13C NMR (125MHz, CDCl3) δ=194.50,165.85,150.86,136.83, 132.96,128.89,126.20,125.86,109.40,81.65,63.46,40.22,32.50,23.46ppm；Pass through chirality HPLC analysis, concrete analysis condition is Daicel Chiralpak AD-H column at 265nm, 2-propanol: Hexane=5:95, flow rate 1.0mL/min；TR=19.465min, 21.345min.90%ee.HRMS:m/z= 324.0667[M+Na]+.
Embodiment 47:
Difference from Example 1 is: keto ester used is indone acid cyclohexyl, other reaction conditions and step and anti- It answers embodiment 1 identical, obtains colorless oil as product (yield 97%).[α] D20=82 ° of (c=1.0, CH2Cl2) .1H NMR δ=7.89 (500MHz, CDCl3) (d, J=7.7Hz, 1H), 7.75 (td, J=7.7,1.1Hz, 1H), 7.56-7.49 (m, 2H), 4.91 (tt, J=8.1,3.7Hz, 1H), 4.09 (d, J=18.0Hz, 1H), 3.65 (d, J=18.0Hz, 1H), 1.78 (ddd, J=11.4,7.3,3.6Hz, 2H), 1.65-1.56 (m, 2H), 1.54-1.42 (m, 3H), 1.39-1.25 (m, 4H) .13C NMR (125MHz, CDCl3) δ=194.57,150.91,136.81,133.01,128.86,126.20,125.85, 76.83,63.75,40.37,30.87,30.76,25.02,22.96ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AD-H column at 285nm, 2-propanol:hexane=2:98, flow rate 1.0mL/min；TR=28.958min, 31.478min.85%ee.HRMS:m/z=338.0817 [M+Na]+
Embodiment 48:
Difference from Example 1 is: keto ester used be indone acid benzyl ester, other reaction conditions and step with react Embodiment 1 is identical, obtains colorless oil as product (yield 95%).[α] D20=42 ° of (c=1.0, CH2Cl2) .1H NMR δ=7.89 (500MHz, CDCl3) (dd, J=8.1,2.5Hz, 1H), 7.75 (td, J=7.8,1.1Hz, 1H), 7.56-7.48 (m, 2H), 7.40-7.32 (m, 3H), 7.30-7.26 (m, 2H), 5.30-5.20 (m, 2H), 4.09 (d, J=18.0Hz, 1H), 3.64 (d, J=18.0Hz, 1H) .13C NMR (125MHz, CDCl3) δ=194.20,166.14,150.79,136.95, 134.32,134.11,132.87,128.98,128.81,128.72,128.12,126.26,126.00,123.59,69.36, 40.29ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak OD-H columnat 256nm, 2-propanol:hexane=2:98, flow rate 1.0mL/min；TR=73.958min, 85.920min.92% Ee.HRMS:m/z=346.0510 [M+Na]+
Embodiment 49:
Difference from Example 1 is: keto ester used is indone acid Buddha's warrior attendant alkyl ester, other reaction conditions and step with It is identical to react embodiment 1, obtains white solid product (yield 98%).[α] D20=60 ° of (c=1.0, CH2Cl2) .1H NMR δ=7.88 (500MHz, CDCl3) (d, J=7.7Hz, 1H), 7.73 (td, J=7.6,1.1Hz, 1H), 7.55-7.48 (m, 2H), 4.06 (d, J=18.0Hz, 1H), 3.63 (d, J=18.0Hz, 1H), 2.18 (s, 3H), 2.06 (d, J=3.1Hz, 6H), 1.64 (d, J=2.8Hz, 6H) .13C NMR (125MHz, CDCl3) δ=151.02,136.67,128.75,126.14, 125.80,86.13,64.34,40.88,40.47,35.81,30.94ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak OD-H column at 270nm, 2-propanol:hexane=10:90, flow rate 1.0mL/min；TR=12.399min, 13.572min.99%ee.HRMS:m/z=390.1132 [M+Na]+
Embodiment 50:
Difference from Example 1 is: keto ester used is 6- methyl indone tert-butyl acrylate, other reaction conditions and step Suddenly identical as reaction embodiment 1, obtain white solid product (yield 94%).[α] D20=70 ° of (c=1.0, CH2Cl2) .1H δ=7.66 (s, 1H) NMR (500MHz, CDCl3), 7.56-7.52 (m, 1H), 7.41 (d, J=7.8Hz, 1H), 4.00 (d, J= 17.9Hz, 1H), 3.57 (d, J=17.9Hz, 1H), 2.44 (s, 3H), 1.45 (s, 9H) .13CNMR (125MHz, CDCl3) δ= 194.98,165.21,148.44,138.97,138.06,133.24,125.59,109.74,85.92,64.53,40.11, 27.63,21.09ppm；By chiral HPLC, condition of making a concrete analysis of is Daicel Chiralpak OJ-H, 2- Propanol at254nm, hexane=5:95, flow rate 1.0mL/min；TR=24.425min, 30.864min.98%ee.HRMS:m/z=326.0820 [M+Na]+
Embodiment 51:
Difference from Example 1 is: keto ester used be 6- methoxyl group indone tert-butyl acrylate, other reaction conditions and Step is identical as reaction embodiment 1, obtains white solid product (yield 90%).D20=40 ° of [α] (c=1.0, CH2Cl2) .1H δ=7.41 (d, J=8.4Hz, 1H) NMR (500MHz, CDCl3), 7.31 (dd, J=8.4,2.5Hz, 1H), 7.28- 7.27 (m, 1H), 3.96 (d, J=17.7Hz, 1H), 3.87 (s, 3H), 3.54 (d, J=17.7Hz, 1H), 1.45 (s, 9H) .13C NMR (126MHz, CDCl3) δ=194.96,165.17,160.28,143.96,134.38,126.85,126.38, 106.48,86.00,64.88,55.70,39.87,27.65ppm；By chiral HPLC, concrete analysis condition is DaicelChiralpak OJ-H column at 254nm, 2-propanol:hexane=5:95, flow rate1.0mL/ min；TR=40.584min, 44.743min.96%ee.HRMS:m/z=342.0770 [M+Na]+
Embodiment 52:
Difference from Example 1 is: keto ester used is 6- fluorine indone tert-butyl acrylate, other reaction conditions and step It is identical as reaction embodiment 1, obtain white solid product (yield 95%).[α] D20=55 ° of (c=1.0, CH2Cl2) .1H δ=7.52 (dt, J=6.6,3.1Hz, 2H) NMR (500MHz, CDCl3), 7.45 (td, J=8.4,2.4Hz, 1H), 4.02 (d, J=18.7Hz, 1H), 3.57 (s, 1H), 1.46 (s, 9H) .13C NMR (125MHz, CDCl3) δ=164.71,146.48, 134.93,127.73,127.67,124.71,124.52,111.60,111.42,109.46,86.41,64.78,39.86, 27.63ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak ID-H column at 254nm, 2-propanol:hexane=2:98, flow rate 1.0mL/min；TR=29.571min, 32.104min.96%ee.HRMS:m/z=330.0568 [M+Na]+
Embodiment 53:
Difference from Example 1 is: keto ester used is 6- chlorine indone tert-butyl acrylate, other reaction conditions and step It is identical as reaction embodiment 1, obtain white solid product (yield 95%).[α] D20=67 ° of (c=1.0, CH2Cl2) .1H δ=7.86-7.82 (m, 1H) NMR (500MHz, CDCl3), 7.69 (dd, J=7.9,1.4Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 4.02 (d, J=18.1Hz, 1H), 3.59 (d, J=18.1Hz, 1H), 1.46 (s, 9H) .13C NMR (125MHz, CDCl3) δ=193.86,136.73,135.23,134.56,127.33,125.36,109.40,86.44,7 7.28,64.47, 39.94,27.61ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AS-H column At254nm, 2-propanol:hexane=10:90, flow rate 1.0mL/min；TR=12.786min, 13.799min.92%ee.HRMS:m/z=346.0276 [M+Na]+
Embodiment 54:
Difference from Example 1 is: keto ester used is 6- bromindion tert-butyl acrylate, other reaction conditions and step It is identical as reaction embodiment 1, obtain white solid product (yield 93%).[α] D20=87 ° of (c=1.0, CH2Cl2) .1H δ=7.99 (d, J=1.7Hz, 1H) NMR (500MHz, CDCl3), 7.83 (dd, J=8.2,1.9Hz, 1H), 7.43 (d, J= 8.2Hz, 1H), 3.99 (d, J=18.2Hz, 1H), 3.56 (d, J=18.2Hz, 1H), 1.45 (s, 9H) .13C NMR (125MHz, CDCl3) δ=193.73,164.61,149.51,139.49,134.85,128.48,127.64,122.94, 109.39,86.46,64.33,40.00,27.62ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak ID-Hcolumn at 254nm, 2-propanol:hexane=5:95, flow rate 1.0mL/min；tR =20.972min, 23.718min, 92%ee.HRMS:m/z=389.9773 [M+Na]+
Embodiment 55:
Difference from Example 1 is: keto ester used be 5- methoxyl group indone tert-butyl acrylate, other reaction conditions and Step is identical as reaction embodiment 1, obtains white solid product (yield 95%).D20=26 ° of [α] (c=1.0, CH2Cl2) .1H δ=7.80 (d, J=8.6Hz, 1H) NMR (500MHz, CDCl3), 7.01 (dd, J=8.6,2.1Hz, 1H), 6.93 (s, 1H), 4.00 (d, J=18.0Hz, 1H), 3.93 (s, 3H), 3.58 (d, J=18.0Hz, 1H), 1.46 (s, 9H) .13C NMR (125MHz, CDCl3) δ=166.92,127.59,126.12,123.59,117.03,109.96,109.25,85.89, 64.82,55.92,40.39,27.67ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AD-Hcolumn at 265nm, 2-propanol:hexane=5:95, flow rate 1.0mL/min；TR= 22.125min, 23.245min.96%ee.HRMS:m/z=342.0775 [M+Na]+
Embodiment 56:
Difference from Example 1 is: keto ester used is 5- fluorine indone tert-butyl acrylate, other reaction conditions and step It is identical as reaction embodiment 1, obtain white solid product (yield 96%).[α] D20=71 ° of (c=1.0, CH2Cl2) .1H δ=7.90 (dd, J=9.1,5.2Hz, 1H) NMR (500MHz, CDCl3), 7.24-7.17 (m, 2H), 4.05 (d, J= 18.2Hz, 1H), 3.62 (d, J=18.2Hz, 1H), 1.46 δ=164.77 (s, 9H) .13C NMR (125MHz, CDCl3), 153.96,128.34,128.25,117.48,117.29,113.22,113.04,109.54,86.37,64.42,40.18, 27.64ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AS-H column at 290nm, 2-propanol:hexane=5:95, flow rate 1.0mL/min；TR=17.492min, 19.785min.96%ee.HRMS:m/z=330.0571 [M+Na]+
Embodiment 57:
Difference from Example 1 is: keto ester used is 5- chlorine indone tert-butyl acrylate, other reaction conditions and step It is identical as reaction embodiment 1, obtain white solid product (yield 96%).[α] D20=31 ° of (c=1.0, CH2Cl2) .1H δ=7.81 (d, J=8.2Hz, 1H) NMR (500MHz, CDCl3), 7.55-7.51 (m, 1H), 7.48 (dd, J=8.2,1.5Hz, 1H), 4.03 (d, J=18.2Hz, 1H), 3.61 (d, J=18.2Hz, 1H), 1.46 (s, 9H) .13C NMR (125MHz, CDCl3) δ=193.63,164.71,152.33,143.59,131.57,129.74,126.81,126.45,86.43,64.26, 40.01,27.65ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AS-H column At285nm, 2-propanol:hexane=10:90, flow rate 1.0mL/min；TR=16.212min, 20.052min.96%ee.HRMS:m/z=346.0279 [M+Na]+
Embodiment 58:
Difference from Example 1 is: keto ester used is 5- bromindion tert-butyl acrylate, other reaction conditions and step It is identical as reaction embodiment 1, obtain white solid product (yield 94%).[α] D20=19 ° of (c=1.0, CH2Cl2) .1H δ=7.73 (d, J=8.5Hz, 2H) NMR (500MHz, CDCl3), 7.67-7.62 (m, 1H), 4.04 (d, J=18.2Hz, 1H), (3.61 d, J=18.2Hz, 1H), 1.45 (s, 9H) .13C NMR (125MHz, CDCl3) δ=193.87,164.66,152.34, 132.56,131.95,129.52,126.79,109.44,86.43,64.13,39.91,27.63ppm；Pass through chiral HPLC points Analysis, concrete analysis condition is Daicel Chiralpak AS-H column at 285nm, 2-propanol:hexane=5: 95,flow rate 1.0mL/min；TR=16.212min, 20.052min.96%ee.HRMS:m/z=389.9771 [M+ Na]+.
Embodiment 59:
Difference from Example 1 is: keto ester used is 4- bromindion tert-butyl acrylate, other reaction conditions and step It is identical as reaction embodiment 1, obtain white solid product (yield 95%).[α] D20=82 (c=1.0, CH2Cl2) .1H NMR δ=7.90 (500MHz, CDCl3) (d, J=7.8Hz, 1H), 7.84 (d, J=7.6Hz, 1H), 7.42 (t, J=7.7Hz, 1H), 3.96 (d, J=18.5Hz, 1H), 3.53 (d, J=18.5Hz, 1H), 1.47 (s, 9H) .13C NMR (126MHz, CDCl3) δ= 194.38,164.61,150.66,139.37,135.06,130.53,124.55,121.39,109.29,86.53,63.87, 41.35,27.65ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AD-Hcolumn at 237nm, 2-propanol:hexane=5:95, flow rate 1.0mL/min；TR=9.786min, 11.399min.99% Ee.HRMS:m/z=389.9765 [M+Na]+
Embodiment 60:
Difference from Example 1 is: keto ester used is 5,6- dimethoxy indone tert-butyl acrylate, other reaction items Part and step are identical as reaction embodiment 1, obtain white solid product (yield 92%).[α] D20=5 (c=1.0, CH2Cl2) δ=7.23 (s, 1H) .1H NMR (500MHz, CDCl3), 6.91 (s, 1H), 4.01 (s, 3H), 3.93 (s, 4H), 3.54 (d, J=17.8Hz, 1H), 1.45 (s, 9H) .13C NMR (126MHz, CDCl3) δ=193.22,165.32,157.19, 150.36,147.00,125.80,109.94,106.77,105.41,85.80,64.84,56.43,56.12,40.19, 27.60ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AS-H column at 230nm, 2-propanol:hexane=10:90, flow rate 1.0mL/min；TR=23.532min, 27.731min.99%ee.HRMS:m/z=396.0876 [M+Na]+
Embodiment 61:
Difference from Example 1 is: keto ester used is 5,6- methylene dioxy indone tert-butyl acrylate, other reactions Condition and step are identical as reaction embodiment 1, obtain white solid product (yield 94%).[α] D20=29 (c=1.0, CH2Cl2) δ=7.17 (s, 1H) .1HNMR (500MHz, CDCl3), 6.87 (s, 1H), 6.14 (d, J=5.1Hz, 2H), 3.92 (d, J=17.9Hz, 1H), 3.50 (d, J=17.9Hz, 1H), 1.45 (s, 9H) .13C NMR (126MHz, CDCl3) δ= 192.66,165.13,156.11,149.36,127.67,123.53,109.87,105.22,103.60,102.90,85.94, 64.88,40.28,27.62ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak AD-H Column at248nm, 2-propanol:hexane=10:90, flow rate 1.0mL/min；TR=18.225min, 19.199min.94%ee.HRMS:m/z=356.0567 [M+Na]+
Embodiment 62:
Difference from Example 1 is: keto ester used is indone acid benzylamine ester, other reaction conditions and step and anti- It answers embodiment 1 identical, obtains white solid product (yield 91%).[α] D20=13 (c=1.0, CH2Cl2) .1H NMR δ=7.86 (500MHz, CDCl3) (d, J=7.7Hz, 1H), 7.76 (t, J=7.3Hz, 1H), 7.53 (dt, J=23.3, 6.5Hz, 3H), 7.33 (tt, J=13.1,7.2Hz, 5H), 4.63-4.47 (m, 2H), 4.38 (d, J=18.7Hz, 1H), 3.40 (d, J=18.7Hz, 1H) .13C NMR (126MHz, CDCl3) δ=197.57,164.23,150.69,137.45,136.92, 132.67,128.93,128.84,127.78,127.68,126.58,125.86,108.55,58.13,44.60,37.94ppm； By chiral HPLC, condition of making a concrete analysis of is Daicel Chiralpak AD-H column at 254nm, 2- Propanol:hexane=10:90, flow rate 1.0mL/min；TR=55.980min, 59.845min.30% Ee.HRMS:m/z=347.0460 [M+Na]+
Embodiment 63:
Difference from Example 1 is: keto ester used is 1-tetralone Buddha's warrior attendant alkyl ester, other reaction conditions and step Suddenly identical as reaction embodiment 1, obtain colorless oil as product (yield 94%).[α] D20=74 (c=1.0, CH2Cl2) .1H δ=8.06-8.02 (m, 1H) NMR (500MHz, CDCl3), 7.57 (td, J=7.6,1.3Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 7.29 (d, J=9.6Hz, 1H), 3.24-3.08 (m, 3H), 2.58 (ddd, J=14.3,11.5,5.8Hz, 1H), 2.16 (s, 3H), 2.06 (s, 6H), 1.62 (s, 6H) .13C NMR (126MHz, CDCl3) δ=189.55,142.55,134.78, 130.60,128.85,128.19,127.43,110.51,85.46,66.33,40.84,35.84,34.06,30.88, 27.06ppm；By chiral HPLC, concrete analysis condition is Daicel Chiralpak OD-H columnat 254nm, 2-propanol:hexane=10:90, flow rate 1.0mL/min；TR=10.346min, 11.946min.96% Ee.HRMS:m/z=404.1295 [M+Na]+
Embodiment 64:
Difference from Example 1 is: keto ester used be 1- benzosuberone Buddha's warrior attendant alkyl ester, other reaction conditions and Step is identical as reaction embodiment 1, obtains colorless oil as product (yield 92%).[α] D20=36 (c=1.0, CH2Cl2) .1H δ=7.58 (dd, J=7.7,1.5Hz, 1H) NMR (500MHz, CDCl3), 7.45 (td, J=7.6,1.5Hz, 1H), 7.33 (td, J=7.6,1.2Hz, 1H), 7.20 (d, J=7.7Hz, 1H), 3.06-2.99 (m, 2H), 2.96-2.91 (m, 1H), 2.32 (ddd, J=14.1,8.0,4.9Hz, 1H), 2.21-2.14 (m, 1H), 2.13-2.10 (m, 3H), 2.09-2.03 (m, 1H), 1.98-1.94 (m, 3H), 1.88-1.84 (m, 3H), 1.60 (d, J=3.2Hz, 6H) .13C NMR (126MHz, CDCl3) δ= 197.55,164.70,139.69,136.74,132.49,130.66,129.89,126.58,110.78,84.88,72.15, 40.56,35.85,33.89,30.80,26.96,24.83ppm；By chiral HPLC, concrete analysis condition is Daicel ChiralpakOD-H column at 254nm, 2-propanol:hexane=10:90, flow rate 1.0mL/min；tR =9.000min, 11.213min.74%ee.HRMS:m/z=418.1447 [M+Na]+

Claims (10)

1. a kind of synthetic method of the chiral alpha as shown in formula (III)-thiocyanogen cyclic ketone acid esters compound, it is characterised in that: institute Method is stated to carry out in accordance with the following steps:
Using N- thiocyanogen phthalimide shown in beta-keto acid ester type compound shown in formula (I) and formula (II) as raw material, in chirality Under the action of catalyst, asymmetric thiocyanogenization reaction is carried out in organic solvent until the reaction is complete, after reaction, reaction Liquid is post-treated to obtain corresponding product, i.e. formula (III) institute chiral alpha-thiocyanogen cyclic ketone acid esters compound；The chirality Catalyst is the chiral complex formed using oxazoline as the chipal compounds of functional group and mantoquita；β-shown in the formula (I) The ratio between amount of substance of N- thiocyanogen phthalimide shown in ketone acid ester type compound and formula (II) is 1:1.0~2.0；Described The ratio between chiral catalyst and the amount of substance of beta-keto acid ester type compound shown in formula (I) are 1~10:100；
In formula (I) or formula (III),
R1For methyl, methoxyl group, fluorine, chlorine, bromine, 5,6- dimethoxy or 5,6- methylenedioxy；
R2For methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, cyclopentyloxy, cyclohexyloxy, benzyloxy, Buddha's warrior attendant alkoxy or Anilino-；
N is 1,2 or 3.
2. the method as described in claim 1, it is characterised in that: the R1For methyl, methoxyl group, fluorine, chlorine or bromine；R2For isopropyl Oxygroup, tert-butoxy or Buddha's warrior attendant alkoxy；N is 1 or 2.
3. the method as described in claim 1, it is characterised in that: the chiral catalyst is formula (IV), formula (V), formula (VI) Or the chiral complex that one of compound shown in formula (VII) is formed with mantoquita:
In formula (IV) formula (V), formula (VI) or formula (VII), the carbon atom for indicating * is asymmetric carbon atom；
R3、R4Respectively stand alone as C3~4Alkyl, phenyl or benzyl；
R5、R6Respectively stand alone as methyl or C4~5Naphthenic base；M is 1 or 2；
R7、R8Respectively stand alone as C3~4Alkyl, phenyl or benzyl；
R9、R10Respectively stand alone as C3~4Alkyl, phenyl or benzyl；
R11、R12、R13、R14Respectively stand alone as hydrogen, C3~4Alkyl, phenyl, benzyl, 3,5- 3,5-dimethylphenyl, 3,5- di-t-butyl Phenyl, 2- naphthalene or R11~R14It is 2,3- dihydro indenyl；
The X is imino group, N-methyl or sulphur；
R15、R16Respectively stand alone as hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, nitro, amino or hydroxyl.
4. method as claimed in claim 3, it is characterised in that: the R3、R4、R7、R8、R9、R10、R12、R13Respectively stand alone as benzene Base, benzyl, isopropyl or tert-butyl；The R5、R6It is hydrogen；The R11、R14Respectively stand alone as hydrogen or phenyl；R15、R16Respectively From standing alone as hydrogen, methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, nitro；The X is imino group, N-methyl or sulphur.
5. method as claimed in claim 3, it is characterised in that: the chiral catalyst is one of following compounds and mantoquita shape At chiral complex:
6. method as claimed in claim 1 or 3, it is characterised in that: the mantoquita is copper bromide, copper acetate, trifluoromethanesulfonic acid Copper, acetylacetone copper, copper tetrafluoroborate or cupric perchlorate, four acetonitrile of tetrafluoro boric acid is cuprous or four acetonitrile of hexafluorophosphoric acid is cuprous.
7. the method as described in claim 1, it is characterised in that: the volumetric usage of the organic solvent is with ring shown in formula (I) The amount of the substance of shape beta-keto acid ester type compound is calculated as 5~20mL/mmol.
8. the method as described in claim 1, it is characterised in that: the organic solvent be ethyl acetate, acetonitrile, methylene chloride, Chloroform, carbon tetrachloride, toluene, tetrahydrofuran, meta-xylene or 1,2- dichloroethanes.
9. the method as described in claim 1, it is characterised in that: the asymmetry thiocyanogen reaction temperature is -78~25 DEG C, Reaction time 12 hours.
10. the method as described in claim 1, it is characterised in that: the post-processing approach of the reaction solution are as follows: after reaction, Reaction solution is extracted with ethyl acetate, and after taking organic phase distillation removing solvent, residue carries out column chromatography with 200~300 mesh silica gel Separation, eluant, eluent are that the mixed liquor of ethyl acetate and petroleum ether volume ratio 1:1~10 is that eluant, eluent carries out gradient elution, and collection contains Solvent is evaporated off and dry to get chiral alpha-thiocyanogen cyclic ketone acid esters compound in the eluent of target compound.
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