CN110204468B - Asymmetric synthesis method of chiral alpha-thiocyano cyclic ketonic acid ester compound - Google Patents

Asymmetric synthesis method of chiral alpha-thiocyano cyclic ketonic acid ester compound Download PDF

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CN110204468B
CN110204468B CN201910473151.1A CN201910473151A CN110204468B CN 110204468 B CN110204468 B CN 110204468B CN 201910473151 A CN201910473151 A CN 201910473151A CN 110204468 B CN110204468 B CN 110204468B
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acid ester
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CN110204468A (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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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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

Abstract

The invention discloses a method for synthesizing a chiral alpha-thiocyano cyclic ketonic acid ester compound shown as a formula (III): in the formula (I)The cyclic ketonic acid ester compound and the N-thiocyano phthalimide shown in the formula (II) are used as raw materials, under the action of a chiral catalyst, asymmetric thiocyanation reaction is carried out in an organic solvent until the reaction is complete, and after the reaction is finished, reaction liquid is subjected to post-treatment to obtain a corresponding product, namely the chiral alpha-thiocyano cyclic ketonic acid ester compound shown in the formula (III). The efficient synthesis method of the chiral alpha-thiocyano cyclic ketonic acid ester compound provided by the invention has the advantages of high yield, good enantioselectivity, wide range of reaction substrates, cheap and easily available reaction reagents and important application value.

Description

Asymmetric synthesis method of chiral alpha-thiocyano cyclic ketonic acid ester compound
Technical Field
The invention relates to a method for synthesizing a chiral alpha-thiocyano cyclic ketonic acid ester compound.
Background
Asymmetric catalysis is one of the most active fields of chemical development at present, and provides an effective strategy for synthesizing compounds such as chiral drugs, pesticides, natural products, spices and the like. Among them, chiral transition metal catalysis has been widely paid attention to due to its high catalytic efficiency and excellent chiral induction capability. In the traditional asymmetric catalytic process, adverse factors such as harsh temperature conditions, long reaction time, large catalyst amount and the like often appear, so that the development of an efficient and mild asymmetric synthesis method is necessary.
Compounds with thiocyano, sulfamide or sulfimine as core skeleton are widely present in many drugs, pesticides and natural products, such as: ibrumebradine (Eflucimibe) is used for treating or preventing atherosclerosis and reducing blood lipid. Amoxicillin (Amoxicillin) acts as a broad-spectrum antibiotic due to its potent bactericidal effect. Penicillin (Penicillin G) is used for the treatment of pneumonia, meningitis, endocarditis, diphtheria, anthracnose, and the like. Natural products, namely, Fascicularin, 9-Thiocyanato Pupuakenane, Psamaplin B, (S) - (-) -Spirobransinin, Fusaperazine A, wherein (+) -1,1' -dideoxy vertecillin A has a significant toxic activity on human colon cancer HCT-116 cells, and the like. The molecular structural formulas of the clinical medicine, the pesticide and the natural products are shown as follows:
Figure BDA0002081335910000021
in medicinal chemistry, sulfur-containing compounds have significant biological activity. In addition, the thiocyano-containing chiral quaternary carbon compound can be converted into other chiral compounds containing important functional groups, such as thiotrifluoromethyl, thiodifluoromethyl, mercapto, disulfide, thio-sulfide, tetrazole, thiazolinone, and the like. At present, only chenxue theme group reports an asymmetric thiocyanation reaction of a cyclic ketonic acid ester compound catalyzed by a cinchona alkaloid derivative in Organic Letters,2018.20,1600, but the reaction needs to be carried out at-78 ℃, and the reaction needs an ester group with large steric hindrance on a substrate to realize good chiral control. Therefore, the development of a high-efficiency and simple synthetic strategy for synthesizing the chiral alpha-thiocyano cyclic ketonic acid ester compound is particularly important.
Disclosure of Invention
The invention aims to provide a high-efficiency synthesis method of chiral alpha-thiocyano cyclic ketonic acid ester compounds.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthetic method of chiral alpha-thiocyano cyclic ketonic acid ester compounds shown as a formula (III) is characterized by comprising the following steps:
taking a beta-keto acid ester compound shown in a formula (I) and N-thiocyanatophthalimide (NTP) shown in a formula (II) as raw materials, carrying out asymmetric thiocyanation reaction in an organic solvent under the action of a chiral catalyst until the reaction is complete, and after the reaction is finished, carrying out post-treatment on reaction liquid to obtain a corresponding product, namely the chiral alpha-thiocyanatocyclic keto acid ester compound shown in the formula (III); the chiral catalyst is a chiral complex formed by a chiral compound taking oxazoline as a functional group and copper salt; the ratio of the amounts of the cyclic beta-keto acid ester compound represented by the formula (I) and the N-thiocyanatophthalimide (NTP) represented by the formula (II) is 1: 1.0 to 2.0; the amount ratio of the chiral catalyst to the cyclic beta-keto ester compound shown in the formula (I) is 1-10: 100, respectively;
Figure BDA0002081335910000031
in the formula (I) or the formula (III),
R1is methyl, methoxy, fluorine, chlorine, bromine, 5, 6-dimethoxy or 5, 6-methylenedioxy;
R2is methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopentyloxy, cyclohexyloxy, benzyloxy, adamantyloxy or anilino;
n is 1,2 or 3.
Further, preferably, R is1Is methyl, methoxy, fluorine, chlorine or bromine; r2Is isopropoxy, tert-butoxy or adamantyloxy; n is 1 or 2.
Further, the chiral catalyst of the invention is a chiral complex formed by one of the compounds shown in formula (IV), formula (V), formula (VI) or formula (VII) and copper salt:
Figure BDA0002081335910000041
in formula (IV), formula (V), formula (VI) or formula (VII), the carbon atom marked with x is a chiral carbon atom;
R3、R4each independently is C3～4Alkyl, phenyl or benzyl of (a);
R5、R6each independently of the other being methyl or C4～5Cycloalkyl groups of (a); m is 1 or 2;
R7、R8each independently is C3～4Alkyl, phenyl or benzyl of (a);
R9、R10each independently is C3～4Alkyl, phenyl or benzyl of (a);
R11、R12、R13、R14each independently is hydrogen, C3～4Alkyl, phenyl, benzyl, 3, 5-dimethylphenyl, 3, 5-di-tert-butylphenyl, 2-naphthyl or R11～R14Are each 2, 3-dihydroindenyl;
x is imino, azomethyl or sulfur;
R15、R16each independently hydrogen, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, nitro, amino or hydroxy.
Still further, preferably, said R3、R4、R7、R8、R9、R10、R12、R13Each independently is phenyl, benzyl, isopropyl or tert-butyl; the R is5、R6Are all hydrogen; said R11、R14Each independently is hydrogen or phenyl; r15、R16Each independently is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl or nitro; and X is imino, azomethyl or sulfur.
Further, the chiral alpha-thiocyano cyclic ketonic acid ester compound is preferably a compound represented by the formula (III):
Figure BDA0002081335910000051
in the formula (III), R1、R2And n is as defined in formula (I).
Further, the chiral catalyst of the present invention is more preferably one of the following chiral complexes with copper salts:
Figure BDA0002081335910000052
Figure BDA0002081335910000061
further, the copper salt is cupric bromide, cupric acetate, copper trifluoromethanesulfonate, copper acetylacetonate, copper tetrafluoroborate, or cupric perchlorate, cuprous tetraacetonitrile tetrafluoroborate or cuprous tetraacetonitrile hexafluorophosphate.
Further, the volume usage amount of the organic solvent is 5 to 20mL/mmol based on the amount of the cyclic β -keto acid ester compound represented by the formula (I).
Further, the organic solvent is ethyl acetate, acetonitrile, dichloromethane, trichloromethane, carbon tetrachloride, toluene, tetrahydrofuran, m-xylene or 1, 2-dichloroethane.
Further, the temperature of the asymmetric thiocyanation reaction is-78-25 ℃, and the reaction time is 12 hours.
Generally, the post-treatment method of the reaction solution of the present invention is: after the reaction is finished, extracting the reaction liquid by using ethyl acetate, distilling the organic phase to remove the solvent, performing column chromatography separation on the residue by using 200-300-mesh silica gel, performing gradient elution by using a mixed liquid of the ethyl acetate and petroleum ether in a volume ratio of 1: 1-10 as an eluent, collecting an eluent containing the target compound, evaporating the solvent, and drying to obtain the chiral alpha-thiocyano cyclic ketonic acid ester compound shown in the formula (III).
Compared with the prior art, the invention has the beneficial effects that:
the efficient synthesis method of the chiral alpha-thiocyano cyclic ketonic acid ester compound provided by the invention has the advantages of high yield, good asymmetric selectivity, wide range of reaction substrates, cheap and easily available reaction reagents and important application value.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1:
the reaction formula is as follows:
Figure BDA0002081335910000071
adding 0.02mmol of oxazoline ligand (VII) -a complex and copper trifluoromethanesulfonate tert-butyl indanone (0.2mmol) into a 10mL test tube, adding 2mL dichloromethane for dissolving, stirring at 0 ℃ for 10 minutes, then adding N-thiocyanatophthalimide (1.5equiv) shown in formula (II) into the system, reacting at 0 ℃ for 12 hours, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, performing gradient elution by using an eluent with the volume ratio of petroleum ether to ethyl acetate of 1-10: 1 as the eluent, collecting the eluent, evaporating the solvent to obtain a white solid product (yield 96%), [ alpha ]]D20＝60°(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 analysis with Daicel Chiralpak AD-H,2-propanol: hexane 2:98, flow rate1.0mL/min,285 nm; t is tR＝14.759min,15.852min.98％ee.HRMS:m/z＝312.0663[M+Na]+.
Example 1-a:
the reaction formula is as follows:
Figure BDA0002081335910000081
adding 0.02mmol of oxazoline ligand (VII) -a complex and copper trifluoromethanesulfonate tert-butyl indanone (0.2mmol) into a 10mL test tube, adding 2mL dichloromethane for dissolving, stirring at-78 ℃ for 10 minutes, then adding N-thiocyanatophthalimide (1.5equiv) shown in the formula (II) into the system, reacting at-78 ℃ for 12 hours, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, performing gradient elution by using eluent of petroleum ether and ethyl acetate with the volume ratio of 1-10: 1 as eluent, collecting the eluent, evaporating the solvent to obtain a white solid product (yield 95%), analyzing by chiral HPLC,the specific analysis conditions are Daicel Chiralpak AD-H,2-propanol: hexane ═ 2:98, flow rate1.0mL/min,285 nm; t is tR＝14.759min,15.852min.33％ee.HRMS:m/z＝312.0663[M+Na]+.
Example 1-b:
the reaction formula is as follows:
Figure BDA0002081335910000091
adding 0.02mmol of oxazoline ligand (VII) -a complex compound and copper trifluoromethanesulfonate tert-butyl indenone (0.2mmol) into a 10mL test tube, adding 2mL dichloromethane for dissolving, stirring at room temperature for 10 minutes, then adding N-thiocyanatophthalimide (1.5equiv) shown in the formula (II) into the system, reacting at room temperature for 12 hours, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, performing gradient elution by using eluent with the volume ratio of petroleum ether to ethyl acetate being 1-10: 1, collecting the eluent, evaporating and removing the solvent to obtain a white solid product (yield 94%), and analyzing by chiral HPLC (chiral HPLC), wherein the specific analysis conditions are Daicel Chiralpak AD-H, 2-propenol: hexane ═ 2:98, flow rate1.0mL/min and 285 nm; t is tR＝14.759min,15.852min.96％ee.HRMS:m/z＝312.0663[M+Na]+.
Example 1-c:
the reaction formula is as follows:
Figure BDA0002081335910000092
adding 0.002mmol of oxazoline ligand (VII) -a complex and copper trifluoromethanesulfonate tert-butyl indanone (0.2mmol) into a 10mL test tube, adding 2mL of dichloromethane for dissolving, stirring at 0 ℃ for 10 minutes, then adding N-thiocyanophthalimide (1.5equiv) shown in formula (II) into the system, reacting at 0 ℃ for 12 hours, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, performing gradient elution by using an eluent of which the volume ratio of petroleum ether to ethyl acetate is 1-10: 1 as the eluent, collecting the eluent and evaporating the solvent to obtain a white solid product(yield 93%), and chiral HPLC analysis, wherein the specific analysis conditions are Daicel Chiralpak AD-H,2-propanol: hexane ═ 2:98, flow rate1.0mL/min,285 nm; t is tR＝14.759min,15.852min.34％ee.HRMS:m/z＝312.0663[M+Na]+.
Examples 1-d:
the reaction formula is as follows:
Figure BDA0002081335910000101
adding 0.04mmol of oxazoline ligand (VII) -a complex compound and copper trifluoromethanesulfonate tert-butyl indenone (0.2mmol) into a 10mL test tube, adding 2mL of dichloromethane for dissolving, stirring for 10 minutes at 0 ℃, then adding N-thiocyanophthalimide (1.5equiv) shown in the formula (II) into the system, reacting for 12 hours at 0 ℃, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, performing gradient elution by using eluent with the volume ratio of petroleum ether to ethyl acetate being 1-10: 1 as eluent, collecting the eluent, evaporating the solvent to obtain a white solid product (yield 95%), analyzing by chiral HPLC (specific analysis conditions are Daicel Chiralpak AD-H,2-propanol: hexane ═ 2:98, flow rate1.0mL/min, and 285 nm); t is tR＝14.759min,15.852min.98％ee.HRMS:m/z＝312.0663[M+Na]+.
Examples 1-e:
the reaction formula is as follows:
Figure BDA0002081335910000111
adding 0.02mmol of oxazoline ligand (VII) -a complex and copper trifluoromethanesulfonate tert-butyl indenone (0.2mmol) into a 10mL test tube, adding 4mL dichloromethane for dissolving, stirring at 0 ℃ for 10 minutes, adding N-thiocyanatophthalimide (1.5equiv) shown in formula (II) into the system, reacting at 0 ℃ for 12 hours, concentrating the reaction solution under reduced pressure, separating by using a silica gel chromatographic column, performing gradient elution by using an eluent of petroleum ether and ethyl acetate in a volume ratio of 1-10: 1 as an eluent, collecting the eluent, and elutingThe solvent was evaporated to give a white solid product (96% yield) which was analyzed by chiral HPLC under the specific conditions of Daicel Chiralpak AD-H,2-propanol: hexane ═ 2:98, flow rate1.0mL/min,285 nm; t is tR＝14.759min,15.852min.92％ee.HRMS:m/z＝312.0663[M+Na]+.
Example 1-f:
the reaction formula is as follows:
Figure BDA0002081335910000121
adding 0.02mmol of oxazoline ligand (VII) -a complex compound and copper trifluoromethanesulfonate tert-butyl indenone (0.2mmol) into a 10mL test tube, adding 1mL of dichloromethane for dissolving, stirring at 0 ℃ for 10 minutes, then adding N-thiocyanophthalimide (1.5equiv) shown in the formula (II) into the system, reacting at 0 ℃ for 12 hours, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, performing gradient elution by using eluent with the volume ratio of petroleum ether to ethyl acetate being 1-10: 1 as eluent, collecting the eluent and evaporating the solvent to obtain a white solid product (yield is 96%), analyzing by chiral HPLC (specific analysis conditions are Daicel Chiralpak AD-H,2-propanol: hexane ═ 2:98, flow rate1.0mL/min and 285 nm); t is tR＝14.759min,15.852min.98％ee.HRMS:m/z＝312.0663[M+Na]+.
Example 1-g:
the reaction formula is as follows:
Figure BDA0002081335910000122
adding 0.02mmol of oxazoline ligand (VII) -a complex and copper trifluoromethanesulfonate tert-butyl indenone (0.2mmol) into a 10mL test tube, adding 4mL dichloromethane for dissolving, stirring at 0 ℃ for 10 minutes, then adding N-thiocyanatophthalimide (1.0equiv) shown in formula (II) into the system, reacting at 0 ℃ for 12 hours, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, and taking an eluent with the volume ratio of petroleum ether to ethyl acetate of 1-10: 1 as the eluentEluting with eluent, collecting eluent, evaporating solvent to obtain white solid product (yield 86%), and analyzing by chiral HPLC (high performance liquid chromatography) under the specific analysis conditions of Daicel Chiralpak AD-H,2-propanol: hexane ═ 2:98, flow rate1.0mL/min,285 nm; t is tR＝14.759min,15.852min.95％ee.HRMS:m/z＝312.0663[M+Na]+.
Examples 1-h:
the reaction formula is as follows:
Figure BDA0002081335910000131
adding 0.02mmol of oxazoline ligand (VII) -a complex compound and copper trifluoromethanesulfonate tert-butyl indenone (0.2mmol) into a 10mL test tube, adding 4mL of dichloromethane for dissolving, stirring at 0 ℃ for 10 minutes, then adding N-thiocyanophthalimide (2.0equiv) shown in the formula (II) into the system, reacting at 0 ℃ for 12 hours, decompressing and concentrating the reaction liquid, separating by using a silica gel chromatographic column, performing gradient elution by using eluent with the volume ratio of petroleum ether to ethyl acetate being 1-10: 1 as eluent, collecting the eluent and evaporating the solvent to obtain a white solid product (yield is 96%), analyzing by chiral HPLC (specific analysis conditions are Daicel Chiralpak AD-H,2-propanol: hexane ═ 2:98, flow rate1.0mL/min and 285 nm); t is tR＝14.759min,15.852min.98％ee.HRMS:m/z＝312.0663[M+Na]+.
Examples 2 to 42
The same reactants as in example 1 were taken, the reaction was carried out at 0 ℃ in the same operation procedure, and asymmetric thiocyanidation reactions were carried out with 0.02mmol of the following catalysts instead of the catalyst (VII) -a, with different copper salts and in different organic solvents under the catalysis of (VII) -a, and the results are shown in Table 1:
TABLE 1 asymmetric thiocyanatoxidation data for different reactants
Figure BDA0002081335910000141
Figure BDA0002081335910000151
Example 43:
Figure BDA0002081335910000152
the difference from the embodiment 1 is that: the ketonic acid ester used was methyl indenoate, and the reaction conditions and procedure were the same as in reaction example 1, whereby a white solid product was obtained (yield 98%). [ alpha ] to]D20＝15°(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 194.26,166.73,150.80,136.98,132.81,128.97,128.97,126.26,125.98,109.17,63.38,54.56,40.32 ppm; analyzing by chiral HPLC, wherein the specific analysis conditions are Daicel Chiralpak ID-H,2-propanol, hexane ═ 10:90, flow rate1.0mL/min and 254 nm; t is tR＝26.585min,28.278min.82％ee.HRMS:m/z＝270.0198[M+Na]+.
Implementation 44:
Figure BDA0002081335910000153
the difference from the embodiment 1 is that: the ketonic acid ester used was ethyl indenoate, and the reaction conditions and procedure were the same as in reaction example 1, whereby a white solid product was obtained (yield 95%). [ α ] D20 ═ 82 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.89(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 by chiral HPLC analysis, specifically analysis conditions dareak-heipaol H, chipalk ═ 2 nm, 5nm, polik:, 0.95 nm; tR 15.172min,16.225 min.87% ee.hrms M/z 284.0351[ M + Na ] +.
Example 45:
Figure BDA0002081335910000154
the difference from the embodiment 1 is that: the keto ester used was isopropyl indanone, and the other reaction conditions and procedure were the same as in reaction example 1, to obtain a white solid product (yield 97%). [ α ] D20 ═ 69 ° (C ═ 1.0, CH2Cl2).1HNMR (500MHz, CDCl3) δ ═ 7.89(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 ═ 194.59,165.74,150.91,136.85,132.97,128.89,126.23,125.92,109.41,72.62,63.49,40.30,21.42 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AS-Hcolumn at285nm,2-propanol, hexane ═ 2:98 and flow rate of 1.0 mL/min; tR 33.718min,37.719 min.93% ee.hrms M/z 298.0509[ M + Na ] +.
Example 46:
Figure BDA0002081335910000161
the difference from the embodiment 1 is that: the keto ester used was cyclopentyl indenoate, and the reaction conditions and procedure were the same as in reaction example 1, yielding a white solid product (yield 97%). α D20 ═ 60 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.88(D, J ═ 7.7Hz,1H),7.75(t, J ═ 7.5Hz,1H),7.55 to 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 to 1.68(m,2H),1.66 to 1.57(m,4H).13C NMR (125MHz, CDCl3) δ 194.50,165.85,150.86,136.83,132.96,128.89,126.20,125.86,109.40,81.65,63.46,40.22,32.50,23.46 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AD-H column at 265nm,2-propanol: hexane ═ 5:95, and flow rate of 1.0 mL/min; tR 19.465min,21.345 min.90% ee.hrms M/z 324.0667[ M + Na ] +.
Example 47:
Figure BDA0002081335910000171
the difference from the embodiment 1 is that: the ketonate used was cyclohexyl indonoate, and the other reaction conditions and procedure were the same as in reaction example 1, whereby a colorless oily product was obtained (yield 97%). α D20 ° (C1.0, CH2Cl2) 1H NMR (500MHz, CDCl3) δ 7.89(D, J7.7 Hz,1H),7.75(td, J7.7, 1.1Hz,1H), 7.56-7.49 (m,2H),4.91(tt, J8.1, 3.7Hz,1H),4.09(D, J18.0 Hz,1H),3.65(D, J18.0 Hz,1H),1.78(ddd, J11.4, 7.3,3.6Hz,2H), 1.65-1.56 (m,2H), 1.54-1.42 (m,3H), 1.39-1.25 (m,4H), 13.6 Hz,2H), 3663, 3675 ppm 3675, 3675 ppm, 78(D, J18.0 Hz, 1H); performing chiral HPLC analysis, wherein the specific analysis conditions are Daicel Chiralpak AD-H column at285nm,2-propanol: hexane ═ 2:98, and flow rate1.0 mL/min; tR 28.958min,31.478 min.85% ee.hrms M/z 338.0817[ M + Na ] +.
Example 48:
Figure BDA0002081335910000172
the difference from the embodiment 1 is that: the ketonic acid ester used was benzyl indenonate, and the other reaction conditions and procedure were the same as in reaction example 1, whereby a colorless oily product was obtained (yield 95%). α D20 ═ 42 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.89(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 194.20,166.14,150.79,136.95,134.32,134.11,132.87,128.98,128.81,128.72,128.12,126.26,126.00,123.59,69.36,40.29 ppm; analyzing by chiral HPLC, wherein the specific analysis conditions are that Daicel Chiralpak OD-H columnat 256nm,2-propanol, hexane ═ 2:98, and flow rate is 1.0 mL/min; tR 73.958min,85.920 min.92% ee.hrms M/z 346.0510[ M + Na ] +.
Example 49:
Figure BDA0002081335910000181
the difference from the embodiment 1 is that: the keto ester used was adamantyl indenoate and the other reaction conditions and procedure were the same as in reaction example 1 to give the product as a white solid (yield 98%). α D20 ═ 60 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.88(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 ═ 151.02,136.67,128.75,126.14,125.80,86.13,64.34,40.88,40.47,35.81,30.94 ppm; performing chiral HPLC analysis under the specific analysis conditions of 270nm Daicel Chiralpak OD-H column at, 10:90 hexane 2-propanol and 1.0mL/min flow rate; tR 12.399min,13.572 min.99% ee.hrms M/z 390.1132[ M + Na ] +.
Example 50:
Figure BDA0002081335910000191
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 6-methylindenoate, and the reaction conditions and procedure were the same as in reaction example 1, whereby a white solid product was obtained (yield 94%). α D20 ° 70 ° (c 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ 7.66(s,1H), 7.56-7.52 (m,1H),7.41(D, J7.8 Hz,1H),4.00(D, J17.9 Hz,1H),3.57(D, J17.9 Hz,1H),2.44(s,3H),1.45(s,9H).13CNMR (125MHz, CDCl3) δ 194.98,165.21,148.44,138.97,138.06,133.24,125.59,109.74,85.92,64.53,40.11,27.63,21.09 ppm; analyzing by chiral HPLC, wherein the specific analysis conditions are Daicel Chiralpak OJ-H,2-propanol at254nm, hexane ═ 5:95 and flow rate1.0 mL/min; tR 24.425min,30.864 min.98% ee.hrms M/z 326.0820[ M + Na ] +.
Example 51:
Figure BDA0002081335910000192
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 6-methoxyindenone, and other reaction conditions and procedures were the same as in reaction example 1, whereby a white solid product was obtained (yield 90%). α D20 ═ 40 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.41(D, J ═ 8.4Hz,1H),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 ═ 194.96,165.17,160.28,143.96,134.38,126.85,126.38,106.48,86.00,64.88,55.70,39.87,27.65 ppm; performing chiral HPLC analysis under the specific analysis conditions of DaicelChiralpak OJ-H column at254nm,2-propanol, hexane ═ 5:95, and flow rate of 1.0 mL/min; tR 40.584min,44.743 min.96% ee.hrms M/z 342.0770[ M + Na ] +.
Example 52:
Figure BDA0002081335910000201
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 6-fluoroindanone, and other reaction conditions and procedures were the same as in reaction example 1, whereby a white solid product was obtained (yield 95%). α D20 ═ 55 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.52(dt, J ═ 6.6,3.1Hz,2H),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 ═ 164.71,146.48,134.93,127.73,127.67,124.71,124.52,111.60,111.42,109.46,86.41,64.78,39.86,27.63 ppm; analyzing by chiral HPLC, wherein the specific analysis conditions are Daicel Chiralpak ID-H column at254nm,2-propanol: hexane ═ 2:98, and flow rate1.0 mL/min; tR 29.571min,32.104 min.96% ee.hrms M/z 330.0568[ M + Na ] +.
Example 53:
Figure BDA0002081335910000211
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 6-chloroindanone, and the reaction conditions and procedure were the same as in reaction example 1, whereby a white solid product was obtained (yield 95%). α ] D20 ═ 67 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.86-7.82 (m,1H),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 ═ 193.86,136.73,135.23,134.56,127.33,125.36,109.40,86.44,77.28,64.47,39.94,27.61 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AS-H column at254nm,2-propanol: hexane ═ 10:90, and flow rate of 1.0 mL/min; tR 12.786min,13.799 min.92% ee.hrms: M/z 346.0276[ M + Na ] +.
Example 54:
Figure BDA0002081335910000212
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 6-bromoindanone, and other reaction conditions and procedures were the same as in reaction example 1, whereby a white solid product was obtained (yield 93%). α ] D20 ═ 87 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.99(D, J ═ 1.7Hz,1H),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 ═ 193.73,164.61,149.51,139.49,134.85,128.48,127.64,122.94,109.39,86.46,64.33,40.00,27.62 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak ID-Hcolumn at254nm,2-propanol: hexane ═ 5:95, and flow rate of 1.0 mL/min; tR-20.972 min,23.718min, 92% ee.hrms: M/z 389.9773[ M + Na ] +.
Example 55:
Figure BDA0002081335910000221
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 5-methoxyindenone, and other reaction conditions and procedures were the same as in reaction example 1, whereby a white solid product was obtained (yield 95%). [ α ] D20 ═ 26 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.80(D, J ═ 8.6Hz,1H),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 ═ 166.92,127.59,126.12,123.59,117.03,109.96,109.25,85.89,64.82,55.92,40.39,27.67 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AD-Hcolumn at 265nm,2-propanol: hexane ═ 5:95, and flow rate of 1.0 mL/min; tR 22.125min,23.245 min.96% ee.hrms M/z 342.0775[ M + Na ] +.
Example 56:
Figure BDA0002081335910000222
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 5-fluoroindanone, and other reaction conditions and procedures were the same as in reaction example 1, whereby a white solid product was obtained (yield 96%). α D20 ° (C1.0, CH2Cl2), 1H NMR (500MHz, CDCl3) δ 7.90(dd, J9.1, 5.2Hz,1H), 7.24-7.17 (m,2H),4.05(D, J18.2 Hz,1H),3.62(D, J18.2 Hz,1H),1.46(s,9H), 13C NMR (125MHz, CDCl3) δ 164.77,153.96,128.34,128.25,117.48,117.29,113.22,113.04,109.54,86.37,64.42,40.18,27.64 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AS-H column at 290nm,2-propanol: hexane ═ 5:95, and flow rate of 1.0 mL/min; tR 17.492min,19.785 min.96% ee.hrms M/z 330.0571[ M + Na ] +.
Example 57:
Figure BDA0002081335910000231
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 5-chloroindanone, and the reaction conditions and procedure were the same as in reaction example 1, whereby a white solid product was obtained (yield 96%). α D20 ° (C1.0, CH2Cl2) 1H NMR (500MHz, CDCl3) δ 7.81(D, J8.2 Hz,1H), 7.55-7.51 (m,1H),7.48(dd, J8.2, 1.5Hz,1H),4.03(D, J18.2 Hz,1H),3.61(D, J18.2 Hz,1H),1.46(s,9H), 13C NMR (125MHz, CDCl3) δ 193.63,164.71,152.33,143.59,131.57,129.74,126.81,126.45,86.43,64.26,40.01,27.65 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AS-H column at285nm,2-propanol: hexane ═ 10:90, and flow rate of 1.0 mL/min; tR 16.212min,20.052 min.96% ee.hrms: M/z 346.0279[ M + Na ] +.
Example 58:
Figure BDA0002081335910000241
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 5-bromoindanone, and other reaction conditions and procedures were the same as in reaction example 1, whereby a white solid product was obtained (yield 94%). α D20 ═ 19 ° (C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.73(D, J ═ 8.5Hz,2H), 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 ═ 193.87,164.66,152.34,132.56,131.95,129.52,126.79,109.44,86.43,64.13,39.91,27.63 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AS-H column at285nm,2-propanol: hexane ═ 5:95, and flow rate of 1.0 mL/min; tR 16.212min,20.052 min.96% ee.hrms: M/z 389.9771[ M + Na ] +.
Example 59:
Figure BDA0002081335910000242
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 4-bromoindanone, and other reaction conditions and procedures were the same as in reaction example 1, whereby a white solid product was obtained (yield 95%). α ] D20 ═ 82(C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.90(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 ═ 194.38,164.61,150.66,139.37,135.06,130.53,124.55,121.39,109.29,86.53,63.87,41.35,27.65 ppm; performing chiral HPLC analysis, wherein the specific analysis conditions are Daicel Chiralpak AD-Hcolumn at 237nm,2-propanol, hexane ═ 5:95, and flow rate1.0 mL/min; tR 9.786min,11.399 min.99% ee.hrms M/z 389.9765[ M + Na ] +.
Example 60:
Figure BDA0002081335910000251
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 5, 6-dimethoxyindanone, and other reaction conditions and procedures were the same as in reaction example 1, to obtain a white solid product (yield 92%). α D20 ═ 5(C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.23(s,1H),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 ═ 193.22,165.32,157.19,150.36,147.00,125.80,109.94,106.77,105.41,85.80,64.84,56.43,56.12,40.19,27.60 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AS-H column at 230nm,2-propanol: hexane ═ 10:90, and flow rate of 1.0 mL/min; tR 23.532min,27.731 min.99% ee.hrms M/z 396.0876[ M + Na ] +.
Example 61:
Figure BDA0002081335910000252
the difference from the embodiment 1 is that: the keto ester used was tert-butyl 5, 6-methylenedioxyindanone, and other reaction conditions and steps were the same as in reaction example 1, whereby the product was obtained as a white solid (yield 94%). α D20 ═ 29(C ═ 1.0, CH2Cl2), 1HNMR (500MHz, CDCl3), δ ═ 7.17(s,1H),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 ═ 192.66,165.13,156.11,149.36,127.67,123.53,109.87,105.22,103.60,102.90,85.94,64.88,40.28,27.62 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AD-H column at248nm,2-propanol, hexane ═ 10:90, and flow rate of 1.0 mL/min; tR 18.225min,19.199 min.94% ee.hrms M/z 356.0567[ M + Na ] +.
Example 62:
Figure BDA0002081335910000261
the difference from the embodiment 1 is that: the ketonic acid ester used was benzylamine indonate, and the other reaction conditions and procedure were the same as in reaction example 1, whereby a white solid product was obtained (yield 91%). α D20 ═ 13(C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl 3). δ ═ 7.86(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, CDCl 3). δ ═ 197.57,164.23,150.69,137.45,136.92,132.67,128.93,128.84,127.78,127.68,126.58,125.86,108.55,58.13,44.60,37.94 ppm; performing chiral HPLC analysis under the specific analysis conditions of Daicel Chiralpak AD-H column at254nm,2-propanol: hexane ═ 10:90, and flow rate of 1.0 mL/min; tR 55.980min,59.845 min.30% ee.hrms M/z 347.0460[ M + Na ] +.
Example 63:
Figure BDA0002081335910000271
the difference from the embodiment 1 is that: the keto ester used was adamantane 1-tetralone ester, and the other reaction conditions and procedure were the same as in reaction example 1, whereby a colorless oily product was obtained (yield 94%). α ] D20 ═ 74(C ═ 1.0, CH2Cl 2.1H NMR (500MHz, CDCl3) δ ═ 8.06-8.02 (m,1H),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, 3906, 30.88 ppm; analyzing by chiral HPLC, wherein the specific analysis conditions are Daicel Chiralpak OD-H columnat 254nm,2-propanol, hexane ═ 10:90 and flow rate1.0 mL/min; tR 10.346min,11.946 min.96% ee.hrms M/z 404.1295[ M + Na ] +.
Example 64:
Figure BDA0002081335910000272
the difference from the embodiment 1 is that: the keto ester used was adamantane-1-benzocycloheptanate, and the other reaction conditions and procedure were the same as in reaction example 1, to give a colorless oily product (yield 92%). [ α ] D20 ═ 36(C ═ 1.0, CH2Cl2).1H NMR (500MHz, CDCl3) δ ═ 7.58(dd, J ═ 7.7,1.5Hz,1H),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, 1.0, 4.9Hz,1H), 2.21-2.14 (m,1H), 2.13-2.10 (m,3H), 2.09-2.03 (m,1H), 1.84H, 3.78 (m, 3.42, 3.78, 3H), 3.42H, 3.8.8.8, 3.8, 3H, 3.8, 3H, 3.8, 3H, 3; performing chiral HPLC analysis under the specific analysis conditions of Daicel ChiralpakOD-H column at254nm,2-propanol: hexane ═ 10:90, and flow rate of 1.0 mL/min; tR 9.000min,11.213 min.74% ee.hrms: M/z 418.1447[ M + Na ] +.

Claims (7)

1. A synthetic method of chiral alpha-thiocyano cyclic ketonic acid ester compounds shown in formula (III) is characterized by comprising the following steps: the method comprises the following steps:
taking a beta-keto acid ester compound shown in a formula (I) and N-thiocyanatophthalimide shown in a formula (II) as raw materials, carrying out asymmetric thiocyanation reaction in an organic solvent under the action of a chiral catalyst until the reaction is complete, and after the reaction is finished, carrying out post-treatment on reaction liquid to obtain a corresponding product, namely a chiral alpha-thiocyanatocyclic keto acid ester compound shown in a formula (III);
the chiral catalyst is a chiral complex formed by one of the following compounds and copper salt:
Figure FDA0002806001710000011
Figure FDA0002806001710000021
the mass ratio of the beta-keto acid ester compound shown in the formula (I) to the N-thiocyanatophthalimide shown in the formula (II) is 1: 1.0 to 2.0; the amount ratio of the chiral catalyst to the beta-keto ester compound shown in the formula (I) is 1-10: 100, respectively;
Figure FDA0002806001710000022
in the formula (I) or the formula (III),
R1is methyl, methoxy, fluorine, chlorine, bromine, 5, 6-dimethoxy or 5, 6-methylenedioxy;
R2is methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopentyloxy, cyclohexyloxy, benzyloxy, adamantyloxy or anilino;
n is 1,2 or 3.
2. The method of claim 1, wherein: the R is1Is methyl, methoxy, fluorine, chlorine or bromine; r2Is isopropoxy, tert-butoxy or adamantyloxy; n is 1 or 2.
3. The method of claim 1, wherein: the copper salt is cupric bromide, cupric acetate, copper trifluoromethanesulfonate, copper acetylacetonate, copper tetrafluoroborate, or cupric perchlorate, cuprous tetraacetonitrile tetrafluoroborate or cuprous tetraacetonitrile hexafluorophosphate.
4. The method of claim 1, wherein: the volume usage amount of the organic solvent is 5-20 mL/mmol based on the amount of the cyclic beta-keto acid ester compound shown in the formula (I).
5. The method of claim 1, wherein: the organic solvent is ethyl acetate, acetonitrile, dichloromethane, trichloromethane, carbon tetrachloride, toluene, tetrahydrofuran, m-xylene or 1, 2-dichloroethane.
6. The method of claim 1, wherein: the temperature of the asymmetric thiocyanation reaction is-78-25 ℃, and the reaction time is 12 hours.
7. The method of claim 1, wherein: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, extracting the reaction liquid by using ethyl acetate, distilling the organic phase to remove the solvent, performing column chromatography separation on the residue by using 200-300-mesh silica gel, performing gradient elution by using a mixed liquid of the ethyl acetate and petroleum ether in a volume ratio of 1: 1-10 as an eluent, collecting an eluent containing a target compound, evaporating the solvent, and drying to obtain the chiral alpha-thiocyano cyclic ketonic acid ester compound.
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