CN114524789A - Method for enantioselectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone - Google Patents
Method for enantioselectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone Download PDFInfo
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- CN114524789A CN114524789A CN202210183143.5A CN202210183143A CN114524789A CN 114524789 A CN114524789 A CN 114524789A CN 202210183143 A CN202210183143 A CN 202210183143A CN 114524789 A CN114524789 A CN 114524789A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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Abstract
The invention relates to the technical field of organic synthesis, and discloses a method for enantioselectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone, which takes cheaper copper salt and chiral phosphine ligand as catalysts to enantioselectively catalyze and synthesize the 3, 3-disubstituted isobenzofuran-1 (3H) -ketone.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for enantioselectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone.
Background
Isobenzofuran-1 (3H) -one, also known as phthalide. Natural products containing such structures often possess important biological and pharmaceutical activities. For example, 3-butylphthalide (NBP) separated from celery seeds can inhibit platelet aggregation, improve microcirculation and relieve ischemic brain injury, and becomes an effective antiplatelet medicament for treating ischemic stroke, and chiral L-butylphthalide is more effective under certain conditions; isoochracinic acid isolated from Alternaria chrysanthemi and Herbaric acid isolated from Cladosporium polycephalum have antibacterial and antimicrobial activities; DermacozineD isolated from dermatophytes exhibited toxicity to different tumor cells; the compounds isolated from the endophytic fungus anthrax CR1535-02 are cytotoxic to HepG2 cell line and have potent antioxidant properties.
Currently, there are few methods for the synthesis of 3, 3-disubstituted isobenzofuran-1 (3H) -ones. Tanaka et al use Rh (COD)2BF4Solphos as catalyst, through the reaction of 1, 6-diyne with propargyl alcohol in the presence of [2+2 ]]Reacting and transferring esterification, and enantioselectively generating chiral 3, 3-disubstituted isobenzofuran-1 (3H) -ketone, wherein the ee value can reach 94%, but a noble metal Rh catalyst is needed. Youn et al report a method for preparing 3, 3-disubstituted isobenzofuran-1 (3H) -one by using NHC formed by in-situ deprotonation of triazolate to catalyze the oxidation of air to o-alkenylbenzaldehyde and the oxa-Michael addition, and the chiral cinchonine is adopted to replace triethylamine in the system, so that the 3, 3-disubstituted isobenzofuran-1 (3H) -one is synthesized with medium to high yield and ee value, but the catalyst dosage is higher, and the reaction time is as long as 6.7-15 days. Sala et al in KOH or K3PO4And dibenzo-18-crown-6, an aryl michael reaction of 3-arylphthalide and an α, β -unsaturated ketone was developed to yield the corresponding 3, 3-disubstituted isobenzofuran-1 (3H) -one in high yield and diastereoselectivity, but without enantioselectivity.
At present, the method for synthesizing chiral 3, 3-disubstituted isobenzofuran-1 (3H) -ketone compounds has some defects, such as the need of noble metal catalysts, more catalyst consumption, overlong reaction time and low enantioselectivity.
Disclosure of Invention
In order to make up the defects of the prior art, the invention provides a method for enantioselectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone, which takes cheaper copper salt and chiral phosphine ligand as catalysts to enantioselectively catalyze and synthesize the 3, 3-disubstituted isobenzofuran-1 (3H) -ketone, so as to effectively solve the technical problems of needing to adopt noble metal, slow reaction and lack of enantioselectivity in the background technology, and is realized by the following technical scheme:
under the action of a catalyst formed by a copper salt-chiral phosphine ligand, silane is used as a reducing agent to carry out conjugate reduction/Aldol addition/lactonization cascade reaction on o-acyl benzoate (I) and alpha, beta-unsaturated acid ester (II) to obtain 3, 3-disubstituted isobenzofuran-1 (3H) -ketone (III). The method uses a catalytic amount of Cu-phosphine catalyst, Cu-phosphine L1-L6 or an enantiomer thereof, and has the advantages of mild reaction conditions, quick reaction and higher enantiomer selectivity.
A method for selectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone comprises the following steps:
further, the substrate of formula I and R in the compound of formula III1Is C1-C12Alkyl of (C)6-C12One of aryl groups; compounds of formula II and R in compounds of formula III2Is C1-C12Alkyl groups of (a); r3Is H or C1-C5Alkyl groups of (a); r4Is H or C1-C5Alkyl group of (1).
The specific synthesis method comprises the following steps: adding copper salt and phosphine ligand into a Sheliang bottle 1, adding a substrate of a formula I into a Sheliang bottle 2, vacuumizing, and adding N2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding a compound of the formula II into the Shelang bottle 2, and then respectively adding reaction solvents into the Shelang bottle 1 and the Shelang bottle 2 and stirring for 10 min; adding silane into a Huliang bottle 1 and stirring for 20 min; adding the solution in the Huliang bottle 2 into the Huliang bottle 1 through a double-ended needle, and reacting for 4-6H to synthesize the compound 3, 3-disubstituted isobenzofuran-1 (3H) -ketone in the formula III.
Further, the copper salt is CuF (PPh)3)3·2MeOH、R5CO2Cu、(R5CO2)2Cu、(R5CO2)2Cu·mH2One of O, m is 1 or 2 or 3, R5Is C1-C10Alkyl or C1-C10Substituted alkyl of (a); or CuX, CuX2One of CuI and NaOR5Or CuX, CuX2One of CuI and KOR5Wherein X is one of F, Cl and Br.
Further, the phosphine ligand is one of phosphine compounds L1-L6 with the following structures or one of enantiomers thereof;
in L1-L6, R6Is one of phenyl or substituted phenyl, wherein the substituted phenyl refers to phenyl with one to all H atoms substituted on the phenyl, and the substituent is C1-C4Straight chain alkyl group of (1), C3-C4Branched alkyl of C1-C4One or more of alkoxy and halogen.
Further, said silane comprises R8SiH3、R8 2SiH2、R8 3SiH、Ph2MeSiH、(SiHMe2)2O、(MeO)3SiH、(SiHMe2)2NH、((CH3)2OSi)n、R9(OSiHMe)pOR9One of (1); p is an integer of 1,2,3, …,100, R8Is Me, Et or Ph, R9Is H, Si (CH)3)3Or Si (CH)3)2But。
Further, the reaction solvent is ethers, aromatic hydrocarbons or alkyl halides, including but not limited to one or more of ethyl ether, butyl ether, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, ethylbenzene, xylene, dichloromethane, and 1, 2-dichloroethane.
Further, the mass of the substrate of formula I is (1-1000) mL/g.
Furthermore, the molar ratio of the copper salt, the phosphine ligand, the silane, the compound shown in the formula I and the compound shown in the formula II is (0.02-0.08): (0.02-0.16): (2-5): 1: (2-3).
Further, when copper salt and phosphine ligand are respectively added into the Huliang bottle 1, the temperature in the Huliang bottle is-20-45 ℃.
Compared with the prior art, the invention has the beneficial effects that:
the invention adopts proper chiral phosphine ligand L1-L6, can enantioselectively synthesize chiral 3, 3-disubstituted isobenzofuran-1 (3H) -ketone, and the ee value of the product is as high as 99%.
The invention can selectively prepare 3, 3-disubstituted isobenzofuran-1 (3H) -ketone by enantiomer, and the used raw materials are all commercially available raw materials which are easy to obtain; the method only uses a catalytic amount of cheap metal Cu compound as the metal part of the catalyst, does not need a noble metal catalyst, and has low cost.
The reaction of the invention is fast, and the reaction can be completed in 4-6 hours.
Drawings
FIG. 1 is an HPLC chromatogram of the product of example 1;
FIG. 2 is an HPLC chromatogram of the product of example 2;
FIG. 3 is an HPLC chromatogram of the product of example 3.
Detailed Description
The invention is described in more detail below with reference to specific examples, without limiting the scope of the invention. Unless otherwise specified, the experimental methods adopted by the invention are all conventional methods, and experimental equipment, materials, reagents and the like used in the experimental method can be obtained from commercial sources.
When R is1-R4When the alkyl, aryl and substituted aryl are the same type, the preparation method is the same, and the difference is only in the number of carbon, and the description is omitted.
Example 1
0.0050g of Cu (PPh) was added to the dried Huliang bottle 1 in this order3)3F.2 MeOH and 0.0054g enantiomerically pure L1 (R)6Ph), 0.0400g of methyl benzoylbenzoate was added to Sheliang bottle 2, which was then evacuated, N2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding 0.0340g of methyl methacrylate into the Huliang bottle 2, then respectively adding 0.5mL of anhydrous toluene into the Huliang bottles 1 and 2, cooling to 0 ℃, and stirring for 10 min; adding 3equiv of PMHS into the Huliang bottle 1 and stirring for 20 min; the solution in the hough flask 2 was added to the hough flask 1 via a double-ended needle. After 6h of reaction, 3mL of saturated aqueous ammonium chloride was added and stirred for 1h, filtered, separated and the aqueous phase extracted twice with 3mL of ethyl acetate. The combined organic phases were washed twice with 2mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated and purified by column chromatography to give the product 3-phenyl-3- (1-methyl-1-methoxyacyl) ethyl isobenzofuran-1 (3H) -one (iii-1).
Example 2
0.0058g of Cu (PPh) was added in this order to the dried Huliang bottle 13)3F.2 MeOH and 0.0062g enantiomerically pure L1 (R)6Ph), 0.0502g of methyl benzoylbenzoate were added to Sheliang bottle 2, vacuum was applied, and N2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding 0.0560g of ethyl methacrylate into the Huliang bottle 2, then respectively adding 0.8mL of anhydrous toluene into the Huliang bottles 1 and 2, cooling to 0 ℃, and stirring for 10 min; adding 3equiv of PMHS into the Huliang bottle 1 and stirring for 20 min; the solution in the hough flask 2 was added to the hough flask 1 via a double-ended needle. After 5h of reaction, 3mL of saturated aqueous ammonium chloride was added and stirred for 1h, filtered, separated and the aqueous phase extracted twice with 3mL of ethyl acetate. The combined organic phases were washed twice with 2mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated and purified by column chromatography to give the product 3-phenyl-3- (1-methyl-1-ethoxyacyl) ethyl isobenzofuran-1 (3H) -one (iii-2).
Example 3
0.0058g of Cu (PPh) was added in this order to the dried Huliang bottle 13)3F.2 MeOH and 0.0065g enantiomerically pure L1 (R)6Ph), 0.0480g of methyl o-benzoylbenzoate was added to Sheliang bottle 2, vacuum was applied, and N2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding 0.0711g of benzyl methacrylate into the Huliang bottle 2, then respectively adding 0.8mL of anhydrous tetrahydrofuran into the Huliang bottles 1 and 2, cooling to 0 ℃, and stirring for 10 min; adding 3equiv of PMHS into the Huliang bottle 1 and stirring for 20 min; the solution in the hough flask 2 was added to the hough flask 1 via a double-ended needle. After 4h of reaction, 3mL of saturated aqueous ammonium chloride was added and stirred for 1h, filtered, separated and the aqueous phase extracted twice with 3mL of ethyl acetate. The combined organic phases were washed twice with 2mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated and purified by column chromatography to give the product 3-phenyl-3- (1-methyl-1-benzyloxyacyl) ethyl isobenzofuran-1 (3H) -one (iii-3).
Example 4
0.0048g of Cu (PPh) was added to the dried Huliang bottle 1 in sequence3)3F.2 MeOH and 0.0082g enantiomerically pure L1 (R)6Ph), 0.0490g of methyl o-benzoylbenzoate was added to Sheliang bottle 2, vacuum was applied, and N2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding 0.1060g of lauryl methacrylate into the Huliang bottle 2, then respectively adding 0.8mL of anhydrous toluene into the Huliang bottles 1 and 2, cooling to-10 ℃, and stirring for 10 min; 3equiv of Ph were added2SiH2Putting into a Huliang bottle 1 and stirring for 20 min; the solution in the hough flask 2 was added to the hough flask 1 via a double-ended needle. After 6h of reaction, 3mL of saturated aqueous ammonium chloride was added and stirred for 1h, filtered, separated and the aqueous phase extracted twice with 3mL of ethyl acetate. The combined organic phases were washed twice with 2mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated and purified by column chromatography to give the product 3-phenyl-3- (1-methyl-1-dodecyloxyacyl) ethyl isobenzofuran-1 (3H) -one (iii-4).
Example 5
To a dry Huliang bottle 1 were added 0.0018g of CuBr followed by 0.0092g of enantiomerically pure L2 (R)6Ph), and 0.0470g KOBut0.0480g of o-benzoylbenzoic acid methyl ester is added into a Huliang bottle 2, vacuum pumping is carried out, and N is added2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding 0.0570g of allyl methacrylate into the Hough flask 2, and then respectively adding 0.8mL of anhydrous toluene into the Hough flasks 1 and 2 and stirring for 10 min; 3equiv of (Me) were added2SiH)2O, putting into a Huliang bottle 1 and stirring for 20 min; the solution in the hough flask 2 was added to the hough flask 1 via a double-ended needle. After 6h of reaction, 3mL of saturated aqueous ammonium chloride was added and stirred for 1h, filtered, separated and the aqueous phase extracted twice with 3mL of ethyl acetate. The combined organic phases were washed twice with 2mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated and purified by column chromatography to give the chiral 3-phenyl-3- (1-methyl-1-allyloxyacyl) ethyl isobenzofuran-1 (3H) -one (iii-5) product.
Example 6
0.0019g Cu (OAc) was added to the dried Huliang bottle 1 in order2And 0.0035g L3 (R)6Ph), 0.0350g of methyl o-valerylbenzoate was added to Shehang bottle 2, and the mixture was evacuated to dryness under reduced pressure2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding 0.0320g of methyl methacrylate into the Hough flask 2, then respectively adding 0.8mL of anhydrous tetrahydrofuran into the Hough flasks 1 and 2, cooling to 0 ℃, and stirring for 10 min; adding 3equiv of PMHS into the Huliang bottle 1 and stirring for 20 min; the solution in the hough flask 2 was added to the hough flask 1 via a double-ended needle. After 6h of reaction, 3mL of saturated aqueous ammonium chloride was added and stirred for 1h, filtered, separated and the aqueous phase extracted twice with 3mL of ethyl acetate. The combined organic phases were passed through 2mL of saturated sodium chloride solutionWashing twice, drying with anhydrous sodium sulfate, rotary steaming, and purifying by column chromatography to obtain chiral 3-n-butyl-3- (1-methyl-1-methoxyacyl) ethyl isobenzofuran-1 (3H) -ketone (III-6).
Comparative example 1
0.003g Cu (PPh) was added to a Huliang bottle3)3F.2 MeOH, 0.023g methyl o-benzoylbenzoate, vacuum/N2After three times of substitution, a solution of 0.022g of methyl methacrylate/0.5 mL of anhydrous toluene was added thereto, the temperature was reduced to 0 ℃ and stirred for 10min, 3equiv of PMHS was slowly added thereto, after 6 hours of reaction, 3mL of a saturated aqueous ammonium chloride solution was added and stirred for 1 hour, and filtration, liquid separation and extraction of the aqueous phase with 3mL of ethyl acetate were carried out twice. The combined organic phases were washed twice with 2mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to give 0.017g of 3-phenyl-3- (1-methyl-1-methoxyacyl) ethyl isobenzofuran-1 (3H) -one (iii-6) in 57% yield.
While the invention has been described with reference to specific embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (9)
1. A method for selectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -ketone is characterized in that the synthetic route is as follows:
the substrate of formula I and R in the compound of formula III1Is C1-C12Alkyl of (C)6-C12One of aryl groups; compounds of formula II and IIIR in the compound2Is C1-C12Alkyl groups of (a); r is3Is H or C1-C5Alkyl groups of (a); r4Is H or C1-C5Alkyl group of (1).
2. The method for selectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -one as claimed in claim 1, wherein the specific synthesis method comprises: adding copper salt and phosphine ligand into a Sheliang bottle 1, adding a substrate of a formula I into a Sheliang bottle 2, vacuumizing, and adding N2Displacement is carried out for three times; keeping the nitrogen atmosphere, adding a compound of the formula II into the Shelang bottle 2, and then respectively adding reaction solvents into the Shelang bottle 1 and the Shelang bottle 2 and stirring for 10 min; adding silane into the Sheliang bottle 1 and stirring for 20 min; adding the solution in the Huliang bottle 2 into the Huliang bottle 1 through a double-ended needle, and reacting for 4-6H to synthesize the compound 3, 3-disubstituted isobenzofuran-1 (3H) -ketone in the formula III.
3. The process as claimed in claim 2, wherein the copper salt is CuF (PPh)3)3·2MeOH、R5CO2Cu、(R5CO2)2Cu、(R5CO2)2Cu·mH2One of O, m is 1 or 2 or 3, R5Is C1-C10Alkyl or C1-C10Substituted alkyl of (a); or CuX, CuX2One of CuI and NaOR5Or CuX, CuX2One of CuI and KOR5Wherein X is one of F, Cl and Br.
4. The process according to claim 2, wherein the phosphine ligand is one of phosphine compounds L1-L6, or one of its enantiomers;
in L1-L6, R6Is one of phenyl or substituted phenyl, wherein the substituted phenyl refers to phenyl with one to all H atoms substituted on the phenyl, and the substituent is C1-C4Straight chain alkyl group of (1), C3-C4Branched alkyl of (2), C1-C4One or more of alkoxy and halogen.
5. The process of claim 2 for the selective synthesis of 3, 3-disubstituted isobenzofuran-1 (3H) -one wherein said silane comprises R8SiH3、R8 2SiH2、R8 3SiH、Ph2MeSiH、(SiHMe2)2O、(MeO)3SiH、(SiHMe2)2NH、((CH3)2OSi)n、R9(OSiHMe)pOR9One of (1); p is an integer of 1,2,3, …,100, R8Is Me, Et or Ph, R9Is H, Si (CH)3)3Or Si (CH)3)2But。
6. The method as claimed in claim 2, wherein the reaction solvent is ether, aromatic or alkyl halide, including but not limited to diethyl ether, dibutyl ether, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, ethylbenzene, xylene, dichloromethane, 1, 2-dichloroethane.
7. A process for the selective synthesis of 3, 3-disubstituted isobenzofuran-1 (3H) -one according to claim 2, characterized in that the mass of the substrate of formula i is (1-1000) mL/g.
8. The method for selectively synthesizing 3, 3-disubstituted isobenzofuran-1 (3H) -one as claimed in claim 2, wherein the molar ratio of the copper salt, the phosphine ligand, the silane, the compound of formula I and the compound of formula II is (0.02-0.08): (0.02-0.16): 2-5): 1 (2-3).
9. The process as claimed in claim 2, wherein the temperature in the Shelang flask 1 is-20 to 45 ℃ when the copper salt and phosphine ligand are added to the Shelang flask 1.
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Citations (4)
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| CN104250236A (en) * | 2014-07-14 | 2014-12-31 | 大连大学 | Synthetic method of gamma-alkyl oxyacyl methyl-gamma-butyrolactone and delta- alkyl oxyacyl methyl-delta-valerolactone |
| CN106831665A (en) * | 2016-12-14 | 2017-06-13 | 大连大学 | Enantioselective synthesis γ replaces the method that gamma butyrolactone and δ replace δ valerolactones |
| CN107746403A (en) * | 2017-06-26 | 2018-03-02 | 中国科学院昆明植物研究所 | Serial open loop Diterpene class compound and its pharmaceutical composition and its application in pharmacy |
| CN113200948A (en) * | 2021-05-24 | 2021-08-03 | 大连大学 | Method for synthesizing chiral phthalide |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104250236A (en) * | 2014-07-14 | 2014-12-31 | 大连大学 | Synthetic method of gamma-alkyl oxyacyl methyl-gamma-butyrolactone and delta- alkyl oxyacyl methyl-delta-valerolactone |
| CN106831665A (en) * | 2016-12-14 | 2017-06-13 | 大连大学 | Enantioselective synthesis γ replaces the method that gamma butyrolactone and δ replace δ valerolactones |
| CN107746403A (en) * | 2017-06-26 | 2018-03-02 | 中国科学院昆明植物研究所 | Serial open loop Diterpene class compound and its pharmaceutical composition and its application in pharmacy |
| CN113200948A (en) * | 2021-05-24 | 2021-08-03 | 大连大学 | Method for synthesizing chiral phthalide |
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| ZIA UD DIN ET AL.: "Intramolecular Rearrangements of 1-Ethoxypropenyl Esters of γ- and δ-Keto Acids", 《J. ORG. CHEM.》, vol. 36, no. 19, pages 2740 - 2743 * |
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