CN111203277B - Application of chiral bidentate phosphite ligand, conia-Ene reaction catalyst and method for constructing chiral quaternary carbon center - Google Patents

Application of chiral bidentate phosphite ligand, conia-Ene reaction catalyst and method for constructing chiral quaternary carbon center Download PDF

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CN111203277B
CN111203277B CN202010122511.6A CN202010122511A CN111203277B CN 111203277 B CN111203277 B CN 111203277B CN 202010122511 A CN202010122511 A CN 202010122511A CN 111203277 B CN111203277 B CN 111203277B
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张攀科
冯笑甜
王志武
薄冰
赵清国
卢宇萍
郝晓方
赵文龙
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Abstract

The invention provides application of a chiral bidentate phosphite ligand, a Conia-Ene reaction catalyst and a method for constructing a chiral quaternary carbon center, belonging to the technical field of organic synthesis. The invention provides an application of chiral bidentate phosphite ligand in a Conia-Ene reaction, and the chiral bidentate phosphite ligand and copper salt are matched to be used as a catalyst of the Conia-Ene reaction, so that the chiral bidentate phosphite ligand can be used for catalyzing cyclization reaction of a substrate containing a delta-alkynyl enol silyl ether structure or a gamma-alkynyl enol silyl ether structure to construct a chiral quaternary carbon center. The Conia-Ene reaction catalyst obtained by matching the chiral bidentate phosphite ester ligand with the copper salt has mild reaction conditions, high selectivity, separation yield of over 75 percent, high reaction activity and wide substrate universality, and can synthesize compounds containing chiral quaternary carbon centers with different structures.

Description

Application of chiral bidentate phosphite ligand, conia-Ene reaction catalyst and method for constructing chiral quaternary carbon center
Technical Field
The invention relates to the technical field of organic synthesis, in particular to application of a chiral bidentate phosphite ligand, a Conia-Ene reaction catalyst and a method for constructing a chiral quaternary carbon center.
Background
Many natural products contain chiral quaternary carbon centers, most of which are in the form of spiro atoms. Although spiro compounds are of great interest because of their unique conformational characteristics and their particular significance in biological systems, the construction of carbocyclic containing quaternary carbon atom chiral centers remains a significant challenge. The widespread presence of carbocyclic ring-containing quaternary carbon atom chiral centers in a variety of natural products has greatly contributed to the interest in the development of carbocyclic ring-containing quaternary carbon atom chiral centers.
The construction of carbon-carbon bonds by enolization is one of the most efficient and widely used methods. Initially, the coia-Ene reaction can convert γ -alkynones to spiro compounds via thermal cyclization, but its high temperature conditions limit the scope of application of the reaction. With the development, the method for constructing the quaternary carbon atom chiral center by a catalytic system developed on the basis of the Conia-Ene reaction is mature. Therefore, a series of metal-based catalysts are successfully applied to the construction reaction of quaternary carbon atom chiral centers, metal elements in the commonly used catalysts are mainly copper, silver, gold and palladium, ligands in the catalysts are mainly monophosphine ligands, diphosphine ligands and nitrogen ligands, but the method for constructing the quaternary carbon atom chiral centers by using the catalysts is complex, the selected ligands are sensitive to air and water, the reaction conditions are harsh, the catalysts used are often noble metals when the selectivity is good, and the experiment cost is high.
Disclosure of Invention
The invention aims to provide application of a chiral bidentate phosphite ligand, a Conia-Ene reaction catalyst and a method for constructing a chiral quaternary carbon center, and provides novel application of the chiral bidentate phosphite ligand in a Conia-Ene reaction.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an application of chiral bidentate phosphite ligand in a Conia-Ene reaction, wherein the chiral bidentate phosphite ligand is a compound shown as a formula I or a formula II:
Figure BDA0002393400520000021
the application also provides an application of the chiral bidentate phosphite ligand in a reaction for constructing a chiral quaternary carbon center, wherein the chiral bidentate phosphite ligand is a compound shown in an application formula I or a formula II in the technical scheme.
The application also provides a Conia-Ene reaction catalyst, which comprises chiral bidentate phosphite ligand and copper salt, wherein the chiral bidentate phosphite ligand is a compound shown as a formula I or a formula II in the application of the technical scheme.
Preferably, the molar ratio of the copper salt to the chiral bidentate phosphite ligand is 1.2 to 2.
Preferably, the copper salt is at least one of cupric chloride, cupric bromide, copper trifluoromethanesulfonate, copper acetylacetonate, cupric sulfate, cuprous bromide, cuprous cyanide, cuprous iodide and cuprous acetate.
The invention also provides application of the Conia-Ene reaction catalyst in the technical scheme in the reaction for constructing the chiral quaternary carbon center.
The invention also provides a method for constructing the chiral quaternary carbon center, which comprises the following steps:
mixing alkynyl enol silyl ether compounds, a catalyst and a solvent, and carrying out Conia-Ene reaction to obtain a compound containing a chiral quaternary carbon center; the catalyst is the Conia-Ene reaction catalyst in the technical scheme; the alkynyl enol silyl ether compound is a compound containing a delta-alkynyl enol silyl ether structure or a compound containing a gamma-alkynyl enol silyl ether structure.
Preferably, the temperature of the Conia-Ene reaction is 20 to 80 ℃.
Preferably, the mol ratio of the alkynyl enol silyl ether compound to the copper salt in the catalyst is 1.
Preferably, the solvent is at least one of toluene, dichloromethane, tetrahydrofuran, dioxane, 1, 2-dichloroethane, N-dimethylformamide, methanol and water; the compound containing delta-alkynyl enol silyl ether is any one of compounds shown in formulas III-1 to III-8, and the compound containing a gamma-alkynyl enol silyl ether structure is a compound shown in a formula III-9 or a formula III 10:
Figure BDA0002393400520000031
wherein,
Figure BDA0002393400520000033
the invention provides an application of chiral bidentate phosphite ligand in a Conia-Ene reaction, the chiral bidentate phosphite ligand is matched with copper salt to be used as a catalyst of the Conia-Ene reaction, the chiral bidentate phosphite ligand can be used for catalyzing a cyclization reaction of a compound containing a delta-alkynyl enol silicon ether structure or a compound containing a gamma-alkynyl enol silicon ether structure to construct a chiral quaternary carbon center, specifically, in a reaction system, copper salt and the chiral bidentate phosphite ligand are combined to form a complex with large steric hindrance, the complex and a carbon-carbon triple bond in a raw material are subjected to oxidation insertion reaction, then, under the induction of the chiral bidentate phosphite ligand, enol silicon ether negative ions in molecules selectively attack the carbon-carbon triple bond to form a cyclic transition state, and then, the reduction elimination of metal copper salt is carried out, and a target product is generated. The Conia-Ene reaction catalyst obtained by matching the chiral bidentate phosphite ligand with the copper salt has mild reaction conditions, high selectivity, separation yield of over 75 percent, high reaction activity and wide substrate universality, and can be used for synthesizing compounds containing chiral quaternary carbon centers with different structures.
Detailed Description
The invention provides an application of chiral bidentate phosphite ligand in a Conia-Ene reaction, wherein the chiral bidentate phosphite ligand is a compound shown as a formula I or a formula II:
Figure BDA0002393400520000041
the use is particularly preferred when chiral bidentate phosphite ligands are complexed with copper salts as catalysts for the Conia-Ene reaction.
The invention also provides an application of the chiral bidentate phosphite ligand in a reaction for constructing the chiral quaternary carbon center, wherein the chiral bidentate phosphite ligand is a compound shown in the formula I or the formula II in the application of the technical scheme; the application is particularly preferably that the chiral bidentate phosphite ligand is matched with copper salt to be used as a catalyst for the reaction for constructing the chiral quaternary carbon center; the chiral quaternary carbon center is preferably a carbocyclic ring-containing chiral quaternary carbon center.
The invention also provides a Conia-Ene reaction catalyst, which comprises chiral bidentate phosphite ester ligand and copper salt, wherein the chiral bidentate phosphite ester ligand is a compound shown in a formula I or a compound shown in a formula II in the application of the technical scheme.
In the present invention, the molar ratio of the copper salt to the chiral bidentate phosphite ligand is preferably 1.2 to 2.
In the present invention, the copper salt is preferably at least one of copper chloride, copper bromide, copper trifluoromethanesulfonate, copper acetylacetonate, copper sulfate, cuprous bromide, cuprous cyanide, cuprous iodide and cuprous acetate; more preferably copper chloride, copper bromide, copper trifluoromethanesulfonate, copper acetylacetonate, copper sulfate, cuprous bromide, cuprous cyanide, cuprous iodide or cuprous acetate, and most preferably copper chloride, cuprous iodide or cuprous cyanide.
In the present invention, the preparation method of the Conia-Ene reaction catalyst is not particularly limited, and the components of the Conia-Ene reaction catalyst may be added to the reaction system separately, or the components may be added to the reaction system directly after being mixed.
The invention also provides the application of the Conia-Ene reaction catalyst in the technical scheme in the reaction for constructing the chiral quaternary carbon center; the chiral quaternary carbon center is preferably a carbocyclic ring-containing chiral quaternary carbon center; the compound containing the chiral quaternary carbon center containing the carbocyclic ring is preferably any one of the compounds shown in formulas IV-1 to IV-10:
Figure BDA0002393400520000051
Figure BDA0002393400520000052
wherein
Figure BDA0002393400520000061
The invention also provides a method for constructing the chiral quaternary carbon center, which comprises the following steps:
mixing alkynyl enol silyl ether compounds, a catalyst and a solvent, and carrying out Conia-Ene reaction to obtain a compound containing a chiral quaternary carbon center; the catalyst is the Conia-Ene reaction catalyst in the technical scheme; the alkynyl enol silyl ether compound is a compound containing a delta-alkynyl enol silyl ether structure or a compound containing a gamma-alkynyl enol silyl ether structure.
In the invention, the compound containing delta-alkynyl enol silyl ether is preferably any one of compounds shown in formulas III-1 to III-8, and the compound containing gamma-alkynyl enol silyl ether structure is preferably a compound shown in a formula III-9 or a formula III 10:
Figure BDA0002393400520000062
wherein,
Figure BDA0002393400520000072
the source of the alkynyl enol silyl ether compound is not particularly limited, and the alkynyl enol silyl ether compound can be prepared by a method conventional in the art, such as the compounds shown in formulas III-2, III-3, III-4, III-5, III-6, III-8, III-9 and III-10 prepared by a method disclosed in the prior art of "A Conia-Ene-Type Cyclization under Basic Conditions Enable an instant Synthesis of (-) -Lycosurramine R [ J ]" (Felix W.W.Hartrap, takayuki Furukawa, and Dirk trap, angew. Chem.int. Ed.2017,56, 893-896), and the specific examples are as follows:
adding magnesium strips (49.0mg, 2.00mmol and 4.00eq.) into tetrahydrofuran (5 mL), dropwise adding three drops of dibromoethane, then cooling the reaction liquid to room temperature, dropwise adding (4-bromobutane-1 alkynyl-) trimethylsilane (1.50mmol and 3.00eq.) into the reaction liquid, stirring the reaction liquid at the temperature of 50 ℃ for 1.5 hours, and then cooling the reaction liquid to-78 ℃; adding CuB into the reaction solutionr·SMe 2 (cuprous bromide dimethyl sulfide, 21mg,0.10mmol, 0.20eq.) stirring for 15min, then adding 1.0mL of ketene (0.5mmol, 1.0eq.) tetrahydrofuran solution with a concentration of 0.5mmol/L, TMSCl (trimethylchlorosilane, 126. Mu.L, 1.0mmol, 2.0eq.) and HMPA (hexamethylphosphoric triamide, 174. Mu.L, 1.0mmol, 2.0eq.) and continuing the reaction. The progress of the reaction was monitored by TLC (thin layer chromatography) until the starting material had reacted to completion, followed by saturated NH 4 The reaction was quenched with Cl solution (4 mL), the resulting reaction was warmed to room temperature, and H was added 2 Diluted with O (4 mL), extracted with diethyl ether (3X 5 mL), and the resulting organic layer was washed with water (10 mL), with saturated NaCl solution (10 mL), and with anhydrous MgSO 4 Drying and rotary evaporation concentration to obtain a crude product; dissolving the crude product in THF (5 mL), cooling to 0 ℃, dropwise adding 1.5mL of 1M TBAF (tetrabutylammonium fluoride, 1.50mmol, 3.00eq.) tetrahydrofuran solution, heating the reaction solution to room temperature, and stirring for reaction until TCL analysis shows that the reaction is complete; adding saturated NH to the obtained reaction solution 4 Cl (10 mL) and water (5 mL) then extracted with diethyl ether (3X 15 mL); the organic layer obtained by the extraction was successively washed with water (10 mL), saturated NaCl solution (20 mL), and anhydrous MgSO 4 Drying, rotary evaporation and concentration to obtain a crude final product, purifying the crude final product by column chromatography to obtain alkynone, and reacting the alkynone with TBSOTf (tert-butyldimethylsilyl trifluoromethanesulfonate) or TIPSOTf (triisopropylsilyltrifluoromethanesulfonate) to obtain a compound shown in a formula III-2, III-3, III-4, III-5, III-6, III-8, III-9 or III-10; wherein the ketenes used for the preparation of formulae III-2, III-3, III-4, III-5, III-6, III-8, III-9 and III-10 are (2-methyl-2-cyclopentenyl) -1-one (2-methyl-2-cyclopenten-1-one), (5-methyl-2-cyclohexenyl) -1-one (5-methyl-2-cyclohexen-1-one), 2- (4-Methoxyphenyl) -2-cyclohexen-1-one (2- (4-Methoxyphenyl) -2-cyclohexen-1-one), respectively 2- (4-bromophenyl) -2-cyclohexen-1-one (2- (4-bromophenyl) -2-cyclohexen-1-one), 2-methyl-5- (1-methylvinyl) cyclohexen-1-one (2-methyl-5- (prop-1-en-2-yl) cyclohexen-1-one), 2-allyl-2-cyclohexen-1-one (2-allyl-2-cyclohexen-1-one), 2- (2-iodophenyl) -2-cyclohexen-1-one (5-methyl-2- (2-iodophenyl) -2-cyclohexen-1-one) and (2-methyl-2-cyclohexenyl-1-one) ) -1-one (2-m)ethyl-2-cyclohexen-1-one); the non-commercial reagents used therein are prepared by methods well known in the art, such as 2-allyl-2-cyclohexen-1-one prepared according to the following prior art: angew. Chem. Int. Ed.2007,46,7671-7673; the starting material (R) -2-iodo-5-methyl-2-cyclohexen-1-one ((R) -2-iodo-5-methylcyclohexohex-2-en-1-one) required for the preparation of 2-allyl-2-cyclohexen-1-one and 2- (2-iodophenyl) -2-cyclohexen-1-one was prepared according to the following prior art: chem.commu.2006, 4928; (4-bromobut-1-yn-1-yl) trimethylsilane (4-bromobutan-1-ynyl-) trimethylsilane was prepared according to the following prior art: chem.commun.2013,49,4012;2- (4-methoxyphenyl) -2-cyclohexen-1-one and 2- (4-bromophenyl) -2-cyclohexen-1-one were prepared according to the following prior art: chem.2005,70,8575;
the compounds of formula III-1 are prepared with reference to the prior art "Cobalt-Copper Dual Light-drive Catalytic Reduction of Aldehydes and Aromatic Ketone in Aqueous Media [ J ]" (Arnau C., carla C., ferran A., alicia C., julio L., chem.Sci.2017,8, 4739-4749), and specifically include the following steps:
mixing 1-phenyl-1- (4-pentenyl) ketone (CAS number: 3240-29, 4.8g,30mmol, 1.0eq.) with 50mL of anhydrous ethanol and 2.25g of sodium ethoxide (33mmol, 1.1eq.), stirring for 15min, dropwise adding 4-bromo-1-butyne (3.7g, 33mmol, 1.1eq.) at 0 ℃, reacting at room temperature for 24h, filtering the obtained reaction solution, taking the filtrate, performing rotary evaporation and concentration on the obtained filtrate to remove most of the solvent (ethanol), adding 50mL of water into the concentrated solution, extracting with dichloromethane (3 x 50 mL), drying the obtained organic phase with anhydrous magnesium sulfate, concentrating the organic phase, and removing dichloromethane to obtain an eneyne product; the eneyne product and TBSOTf (triisopropylsilyl trifluoromethanesulfonate) react in one step to obtain a compound shown in a formula III-1;
the compound shown in the formula III-7 can be obtained by one-step reaction of 3,4-dihydro-2- (3-pentynyl) - (2H) -Naphthalenone (3, 4-dihydro-2- (3-pentyn-1-yl) -1 (2H) -naphalenone with CAS number: 1565554-72-4) and TBSOTf (tert-butyldimethylsilyl trifluoromethanesulfonate).
In the present invention, the solvent is preferably at least one of toluene, dichloromethane, tetrahydrofuran, dioxane, 1, 2-dichloroethane, N-dimethylformamide, methanol and water, and more preferably at least one of dichloromethane, N-dimethylformamide, methanol and water; when the solvent is a mixed solution, the invention has no special limitation on the proportion of the components in the mixed solution, and can dissolve the raw materials to ensure that the reaction is smoothly carried out.
The dosage of the solvent is not particularly limited, and the smooth reaction can be ensured, in the embodiment of the invention, the dosage ratio of the solvent to the alkynyl enol silyl ether compound is preferably 8-1201mmol.
In the present invention, the compound containing a chiral quaternary carbon center is preferably any one of the compounds represented by formulas IV-1 to IV-10.
In the present invention, the molar ratio of the alkynyl enol silyl ether compound to the copper salt in the catalyst is preferably 1.
In the embodiment of the invention, the alkynyl enol silyl ether compound is preferably dissolved in the solvent first, and then the catalyst is added.
In the present invention, the temperature of the Conia-Ene reaction is preferably 20 to 80 ℃, more preferably 20 to 50 ℃.
After the Conia-Ene reaction is finished, the solvent in the reaction liquid obtained by the Conia-Ene reaction is preferably removed, and then the reaction liquid is subjected to column chromatography separation to obtain a compound containing a chiral quaternary carbon center; the method for removing the solvent is not particularly limited, and any method for removing the solvent can be adopted, such as reduced pressure distillation; in the present invention, the skilled person can select the eluent for column chromatography and the column for column chromatography according to conventional technical means, and in the present embodiment, the column for column chromatography is preferably a silica gel column; the eluent is preferably a mixed solution obtained by mixing hexane and ethyl acetate according to the volume ratio of 5; when the compound containing the chiral quaternary carbon center is a compound shown as a formula IV-2, a compound shown as a formula IV-8 or a compound shown as a formula IV-9, the eluent is preferably a mixed solution obtained by mixing petroleum ether and ethyl acetate according to a volume ratio of 5; when the compound containing the chiral quaternary carbon center is a compound shown as a formula IV-3, the eluent is preferably a mixed solution obtained by mixing petroleum ether and ethyl acetate according to a volume ratio of 13; when the compound containing the chiral quaternary carbon center is a compound shown as a formula IV-4, the eluent is preferably a mixed solution obtained by mixing petroleum ether and ethyl acetate according to a volume ratio of 6; when the compound containing the chiral quaternary carbon center is a compound shown as a formula IV-5, the eluent is preferably a mixed solution obtained by mixing petroleum ether and ethyl acetate according to a volume ratio of 7; when the compound containing the chiral quaternary carbon center is a compound shown as a formula IV-6, the eluent is preferably a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 1; when the compound containing the chiral quaternary carbon center is a compound shown as a formula IV-7, the eluent is preferably a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 1; when the compound containing the chiral quaternary carbon center is a compound shown in a formula IV-10, the elution mode of the column chromatographic separation is gradient elution, and the eluent used in the gradient elution is preferably a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 6 to 3.
The following examples are provided to illustrate the use of chiral bidentate phosphite ligands, conia-Ene reaction catalysts and methods of constructing chiral quaternary carbon centers of the present invention in detail, but should not be construed as limiting the scope of the invention.
Example 1
Figure BDA0002393400520000101
A compound represented by the formula III-1 (170.3mg, 0.5 mmol) was dissolved in 5mL of a mixed solvent obtained by mixing methylene chloride and water at a volume ratio of 4 2 (8.5mg, 0.05mmol), carrying out Conia-Ene reaction at 30 ℃, monitoring the reaction progress by TLC (thin layer chromatography) until the raw materials are completely reacted, and carrying out rotary evaporation on the obtained reaction liquid to remove the solvent to obtain a crude product; and (2) performing column chromatography on the obtained crude product to obtain a cycloisomerized product (namely the compound containing the chiral quaternary carbon center), wherein the column chromatography is a silica gel column, and the eluent is a mixed solution obtained by mixing hexane and ethyl acetate according to the volume ratio of 5. The cycloisomerized product obtained in this example was tested for 95% purity and was calculated to yield 81% isolated.
By HPLC, a Chiralcel OJ chiral column was selected, and the ee value of the product was measured under conditions of a detection wavelength of 230nm, a column temperature of room temperature, mobile phases of hexane and isopropanol (98V/V), and a flow rate of 1mL/min, and was 95%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(400MHz,CDCl 3 )δ7.56(d,J＝8.1,2H).7.34(t,J＝8.1,1H),7.25(t,J＝8.1,2H),5.67(m,1H),5.21(t,J＝2.4,1H),5.16(s,1H),5.15(m,1H),5.10(t,J＝2.4,1H),2.66(m,1H),2.54(m,2H),2.22(m,1H),2.14(m,1H),1.85-1.62(m,3H)；
13 C NMR(100MHz,CDCl 3 )δ205.6,153.8,138.7,132.5,130.1,125.4,128.7,115.8,107.4,60.8,45.0,36.8,34.7,25.6。
from the above nuclear magnetic data analysis, it was found that the cycloisomerized product obtained in this example had the structure shown in formula IV-1 in equation (1).
Example 2
Figure BDA0002393400520000111
Dissolving a compound represented by formula III-2 (153mg, 0.5 mmol) in 5mL of a mixed solvent obtained by mixing dichloromethane and methanol at a volume ratio of 4; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 5. The cycloisomerized product obtained in this example was tested for 96% purity and was calculated to yield 75% isolated.
The cyclic isomerization product obtained in this example was tested for ee value by the detection method in example 1, and the result was 90%.
The nuclear magnetic analysis of the product of the cycloisomerization product obtained in this example showed the following results:
1 H NMR(600MHz,CDCl 3 )δ＝5.23(t,J＝2.3,1H),4.89(t,J＝2.4,1H),2.45–2.40(m,2H),2.40–2.35(m,1H),2.38–2.34(m,1H),2.19(ddd,J＝18.5,9.5,8.7,1H),2.14–1.93(m,2H),1.71–1.65(m,2H),1.23(s,3H)；
13 C NMR(150MHz,CDCl 3 )δ＝230.5,161.0,112.5,60.9,53.0,38.7.0,32.6,27.0,23.6,21.8。
from the above nuclear magnetic data analysis, it is understood that the cycloisomerized product obtained in this example has the structure shown in formula IV-2 in formula (2), and is (1R) -1-methyl-8-methylenebis [2.2.0] octan-2-one, i.e., (6R) -6 a-methyl-6-methyl-hexahydropentalen-1 (2H) -one.
Example 3
Figure BDA0002393400520000121
Dissolving a compound represented by the formula III-3 (167.8 mg,0.5 mmol) in a mixed solvent obtained by mixing 50mL of dichloromethane and water at a volume ratio of 5, then adding a compound represented by the formula I (43mg, 0.08mmol) and CuI (16mg, 0.08mmol), carrying out a Conia-Ene reaction at 20 ℃, monitoring the reaction progress by a TLC method (thin layer chromatography) until the reaction of the raw materials is completed, and carrying out rotary evaporation on the obtained reaction liquid to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 13. The purity of the cycloisomerized product obtained in this example was tested to be 98%, and the isolated yield was calculated to be 87%.
By HPLC, a Chiralcel AD chiral column was selected, and the ee value of the product was measured under conditions of a detection wavelength of 230nm, a column temperature of room temperature, mobile phases of hexane and isopropanol (99.5V/V), and a flow rate of 1mL/min, and was 92%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(800MHz,CDCl 3 )δ＝5.27(t,J＝2.5,1H),5.15(t,J＝2.4,1H),5.12(t,J＝2.1,1H),4.77(t,J＝2.5,1H),2.67(ddd,J＝14.9,4.4,1.7,1H),2.58(dtd,J＝12.5,4.9,2.4,1H),2.54–2.49(m,1H),2.49–2.42(m,2H),2.41–2.34(m,2H),2.33–2.28(m,1H),2.13–2.16(m,2H),2.07–1.96(m,1H),1.92(ddd,J＝14.2,4.4,3.8,1H),1.89–1.82(m,2H),1.80–1.74(m,3H),1.74–1.69(m,1H),1.59–1.54(m,1H),1.54–1.48(m,1H),1.32(ddd,J＝12.8,8.7,4.4,1H),1.29(ddd,J＝12.2,9.4,3.5,1H),1.03–0.97(m,15H),0.80(s,3H)；
13 C NMR(200MHz,CDCl 3 )δ＝220.4,215.7,163.6,154.8,112.0,101.4,62.4,62.3,53.5,47.4,45.6,45.3,37.3,35.9,32.8,32.3,31.9,31.5,30.4,30.3,30.2,29.9,27.7,27.2,24.6,23.1,21.8,21.8。
as is apparent from the above nuclear magnetic data analysis, the cycloisomerized product obtained in this example has the structure shown in formula IV-3 in the reaction formula (3), and is (R) 1,1-dimethyl-4-methylenespiro [4.5] decan-6-one, i.e. (R) -1,1-dimethyl-4-methylenespiro [4.5] can-6-one.
Example 4
Figure BDA0002393400520000131
Dissolving a compound represented by formula III-4 (206.3mg, 0.5 mmol) in 8mL of a mixed solvent obtained by mixing dichloromethane and water in a volume ratio of 3, then adding a compound represented by formula II (80g, 0.08mmol) and CuI (10mg, 0.05mmol), carrying out a Conia-Ene reaction at 30 ℃, monitoring the reaction progress by a TLC method (thin layer chromatography) until the reaction of the raw materials is completed, and subjecting the resulting reaction liquid to rotary evaporation to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to a volume ratio of 6. The purity of the cycloisomerized product obtained in the example is tested to be 98%, and the isolated yield is calculated to be 80%.
The cyclic isomerization product obtained in this example was tested for ee value by the detection method in example 3, and the result was 97%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(800MHz,CDCl 3 )δ＝7.13(d,J＝8.8,2H),6.79(d,J＝8.8,2H),5.43(t,J＝2.2,1H),4.68(t,J＝2.5,1H),3.64(s,3H),2.78(ddd,J＝11.0,9.4,5.2,1H),2.71–2.63(m,1H),2.37(dddd,J＝14.8,9.6,5.1,2.7,2H),2.31(dddd,J＝14.7,6.3,4.7,1.3,1H),2.16–2.11(m,1H),1.89–1.78(m,1H),1.71–1.65(m,2H),1.62–1.57(m,2H)；
13 C NMR(200MHz,CDCl 3 )δ＝220.9,155.4,150.8,131.3,127.1,115.7,109.3,69.5,52.3,49.2,37.8。
as is clear from the above nuclear magnetic data analysis, the cycloisomerized product obtained in this example has the structure shown in formula IV-4 in formula (4), and is (1R) 1-p-methoxyphenyl-9-methylenebis [2.2.0] nonan-2-one, namely (3 aR) -3a- (4-methoxyphenyl) -3-methyleneoco-hydro-4H-inden-4-one.
Example 5
Figure BDA0002393400520000141
Dissolving a compound represented by the formula III-5 (230.8mg, 0.5mmol) in 60mL of dichloromethane, adding a compound represented by the formula I (0.65g, 1.2mmol) and CuCN (2.5mg, 0.025mmol), carrying out Conia-Ene reaction at 40 ℃, monitoring the reaction progress by a TLC method (thin layer chromatography) until the reaction of the raw materials is completed, and carrying out rotary evaporation on the obtained reaction liquid to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 7. The purity of the cycloisomerized product obtained in this example was tested to be 98%, and the isolated yield was calculated to be 77%.
The ee value of the cycloisomerized product obtained in this example was measured by the detecting method in example 3, and the result was 98%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(400MHz,CDCl 3 )δ＝7.53–7.42(m,2H),7.19–7.01(m,2H),5.32(t,J＝2.2,1H),4.53(t,J＝2.6,1H),2.69(dq,J＝11.0,4.9,1H),2.59(dtt,J＝17.5,8.5,2.2,2H),2.49–2.38(m,3H),2.11–1.98(m,1H),1.89–1.72(m,2H),1.65–1.56(m,2H)；
13 C NMR(100MHz,CDCl 3 )δ＝220.3,155.9,146.7,132.5,128.0,115.3,68.6,51.3,38.6,28.7,27.3,26.9,25.2。
as is clear from the above nuclear magnetic data analysis, the cycloisomerized product obtained in this example has the structure shown in formula IV-5 in formula (5), and is (R) 1-p-bromophenyl-9-methylenebisbridge [2.2.0] nonan-2-one, namely (3 aR) -3a- (4-bromophenyl) -3-methylisoctahydro-4H-inden-4-one.
Example 6
Figure BDA0002393400520000151
The compound represented by the formula III-6 (160mg, 0.5 mmol) was dissolved in 5mL of dimethyl sulfoxide, and then the compound represented by the formula I (43.2mg, 0.08mmol) and CuCl were added 2 (8.5mg, 0.05mmol), conia-Ene reaction at room temperature, monitoring the reaction progress by TLC (thin layer chromatography) until the reaction of the raw materials is completed, and rotary evaporation of the obtained reaction liquid to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 1. The purity of the cycloisomerized product obtained in this example was tested to be 98%, and the isolated yield was calculated to be 82%.
By HPLC, a Chiralcel WHELK-O chiral column was selected, and the ee value of the product was determined to be 89% under the conditions of a detection wavelength of 230nm, a column temperature of room temperature, mobile phases of hexane and isopropanol (98V/V), and a flow rate of 1 mL/min.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(400MHz,CDCl 3 )δ＝5.12(t,J＝2.2,1H),4.78–4.76(m,2H),4.69–4.63(m,1H),2.63(q,J＝6.2,1H),2.47–2.38(m,4H),2.28–2.19(m,1H),1.88–1.79(m,3H),1.69(dt,J＝1.4,0.6,3H),1.49(ddd,J＝12.5,6.5,2.4,1H),1.34(s,3H)；
13 C NMR(100MHz,CDCl 3 )δ215.8,158.7,146.3,112.8,109.5,75.3,46.5,42.6,41.8,34.7,32.1,31.6,24.1,22.3。
as is clear from the above nuclear magnetic data analysis, the cycloisomerized product obtained in this example has the structure shown in formula IV-6 in equation (6), and is (R) 1-methyl-9-methylene-4- (1-methylvinyl) di-bridge [2.2.0] anthan-2-one (i.e., (3aR, 6R) -3 a-methyl-3-methyl-6- (prop-1-en-2-yl) octahydro-4H-inden-4-one).
Example 7
Figure BDA0002393400520000161
Dissolving a compound represented by formula III-7 (163mg, 0.5 mmol) in 5mL of dichloromethane, adding a compound represented by formula II (80mg, 0.08mmol) and CuI (6mg, 0.03mmol), carrying out Conia-Ene reaction at 30 ℃, monitoring the reaction progress by a TLC method (thin layer chromatography) until the reaction of the raw materials is completed, and carrying out rotary evaporation on the obtained reaction liquid to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 1. The purity of the cycloisomerized product obtained in this example was tested to be 94%, and the isolated yield was calculated to be 91%.
The cyclic isomerization product obtained in this example was tested for ee value by the detection method in example 3, and found to be 81%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(300MHz,CDCl 3 )δ8.24(d,J＝7.5,1H).7.35(t,J＝7.5,1H),7.20(t,J＝7.5,1H),7.13(d,J＝7.5,1H),5.12(s,1H),4.56(s,1H),3.21(m,2H),2.55(m,2H),2.32(m,2H),1.89(m,1H),1.75(m,3H)；
13 C NMR(100MHz,CDCl 3 )δ220.8,165.6,148.0,135.4,130.8,127.0,126.4,125.9,105.4,56.3,35.8,33.4,32.5,26.5,23.1。
from the above nuclear magnetic data analysis, it was found that the cycloisomerized product obtained in this example has the structure shown in formula IV-7 in equation (7), and is 2-methylene-3',4' -dihydro-1' -spiro [ cyclopentane-1,2' naphthalene ] -1-one (i.e., 2-methyl-3 ',4' -dihydro-1' H-spiro [ cyclopropentane-1, 2' -naphtalen ] -1' -one).
Example 8
Figure BDA0002393400520000171
Dissolving a compound represented by formula III-8 (312.95mg, 1.0 mmol) in 8mL of a mixed solvent obtained by mixing dichloromethane and water at a volume ratio of 4:1, then adding a compound represented by formula I (81mg, 0.15mmol) and CuI (5mg, 0.025mmol), carrying out a Conia-Ene reaction at 45 ℃, monitoring the progress of the reaction by TLC (thin layer chromatography) until the reaction of the raw materials is completed, and subjecting the resulting reaction liquid to rotary evaporation to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, the elution process is gradient elution, and an eluant used is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 6 to 3. The cycloisomerized product obtained in this example was tested for 98% purity and was calculated to yield 88%.
By HPLC, a Chiralcel OJ chiral column was selected, and the ee value of the product was determined under conditions of a detection wavelength of 230nm, a column temperature of room temperature, mobile phases of hexane and isopropanol (98V/V), and a flow rate of 1mL/min, and was 98%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 HNMR(400MHz,CDCl 3 )δ＝5.81(t,J＝2.2,1H),2.62(dtd,J＝17.7,9.0,2.2,1H),2.50-2.37(m,2H),2.36(dtd,J＝12.3,4.0,1.6,1H),2.11-2.02(m,1H),2.02-1.83(m,2H),1.66-1.53(m,2H),1.53-1.46(m,1H),1.46-1.31(m,1H),1.15(s,3H)；
13 C NMR(101MHz,CDCl 3 )δ＝211.1,145.9,112.8,58.4,52.7,39.2,28.5,28.5,27.8,26.1,19.2。
from the above nuclear magnetic data analysis, it is understood that the cycloisomerized product obtained in this example has the structure shown in formula IV-8 in reaction formula (8), and is (1S) 1-methyl-9-chloroethylenedindolichopper [3.4] nonan-2-one (i.e., (1S) -3- (chloromethyl) -3 a-methyctahydro-4H-inden-4-one).
Example 9
Figure BDA0002393400520000181
Dissolving a compound represented by the formula III-9 (285.3mg, 0.5mmol) in 10mL of a mixed solvent obtained by mixing dichloromethane and methanol at a volume ratio of 10; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 5. The cycloisomerized product obtained in this example was tested for 92% purity and was calculated to have an isolated yield of 90%.
By HPLC, a Chiralcel WHELK-O chiral column was selected, and the ee value of the product was determined under conditions of a detection wavelength of 230nm, a column temperature of room temperature, mobile phases of hexane and isopropanol (98V/V), and a flow rate of 1mL/min, and was 96%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(400MHz,CDCl 3 )δ7.89(dd,J＝7.5,1.2,1H),7.53(m,2H),7.47-7.35(m,3H),7.13(dt,J＝7.5,1.2,1H),6.86(dd,J＝7.5,1.6,1H),6.74(dt,J＝7.5,1.6,1H),6.42(t,J＝2.4,1H),3.68(d,J＝14.5,1H),3.31(d,J＝14.5,1H),2.73(m,1H),2.68(ddd,J＝15.1,7.5,1.5,1H),2.35(m,1H),2.21-1.86(m,3H),1.63-1.48(m,2H),0.99(d,J＝6.8,3H)；
13 C NMR(100MHz,CDCl 3 )δ218.36,145.87,142.43,138..46,136.68,132.71,130.25,127.68,126.48,125.53,125.65,124.61,104.75,68.85,46.40,44.57,41.93,39.86,36.73,27.96,21.92。
as is apparent from the above nuclear magnetic data analysis, the ring-isomerized product obtained in this example has the structure represented by formula IV-9 in reaction formula (9), and is (1R, 4R) -4-methyl-1- (2-iodophenyl) -8-en-9-phenylbis [3.4] nonan-2-one (i.e., (3aS, 6R) -3a- (2-iodobenzyl) -6-methyl-3-phenyl-1,3a,5,6,7 a-hexahydro-4H-inden-4-one).
Example 10
Figure BDA0002393400520000191
Dissolving a compound represented by the formula III-10 (152mg, 0.5 mmol) in 8mLN, N-dimethylformamide, adding a compound represented by the formula I (65mg, 0.12mmol) and CuI (12mg, 0.06mmol), carrying out Conia-Ene reaction at 40 ℃, monitoring the progress of the reaction by TLC (thin layer chromatography) until the reaction of the raw materials is completed, and carrying out rotary evaporation on the obtained reaction liquid to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 5. The cycloisomerized product obtained in this example was tested for 98% purity and was calculated to yield 83%.
The cyclic isomerization product obtained in this example was tested for ee by the detection method in example 3, and found to be 92%.
The nuclear magnetic analysis of the cycloisomerized product obtained in this example gave the following results:
1 H NMR(400MHz,CDCl 3 )δ5.91(m,1H),5.81-5.75(m,2H),5.16(s,1H),5.12(m,1H),2.63-2.48(m,5H),2.31-1.99(m,3H),1.68(dq,J＝13.5,2.4,1H),1.57(m,1H),0.99(d,J＝7.0,3H)；
13 C NMR(100MHz,CDCl 3 )δ218.57,135.52,133.25,132.72,116.83,63.19,48.39,41.33,40.66,37.36,34.55,26.81,22.34。
as is apparent from the above nuclear magnetic data analysis, the cycloisomerized product obtained in this example has the formula IV-10 shown in the reaction formula (10), and is (1R, 4R) 1-allyl-4-methyl-8-enedibridge [3.4] nonan-2-one (i.e., (3aS, 6R) -3a-allyl-6-methyl-1,3a,5,6,7 a-hexahydro-4H-inden-4-one).
Comparative example 1
A compound represented by the formula IV-1 was prepared according to the method of example 1, except that the compound represented by the formula II was not added and the progress of the reaction was monitored by TLC (thin layer chromatography), and the formation of the objective product was not detected at all times.
Comparative example 2
A compound represented by the formula IV-1 was prepared as in example 1, except that CuCl was not added 2 And the progress of the reaction was monitored by TLC (thin layer chromatography), and the formation of the desired product was not detected at all times.
Comparative example 3
A compound represented by the formula IV-1 was prepared as in example 1, except that the compound represented by the formula II was replaced with an equimolar amount of triphenylphosphine (26mg, 0.1mmol), the progress of the reaction was monitored by TLC (thin layer chromatography), and after completion of the reaction of the starting materials, the resulting reaction solution was subjected to rotary evaporation to remove the solvent to obtain a crude product; and (3) carrying out column chromatography separation on the obtained crude product to obtain a cycloisomerization product, wherein a chromatographic column used for the column chromatography separation is a silica gel column, and an eluent used for the column chromatography separation is a mixed solution obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 5. The purity of the cycloisomerized product obtained by the comparative example is 96% through testing, the separation yield is 85% through calculation, the optical rotation of the obtained cycloisomerized product is measured by a polarimeter, and the test result shows that the optical rotation of the product is equal to zero, namely the ee value is 0.
From examples 1 to 10, it can be seen that the compound of formula I or formula II is used for catalyzing Conia-Ene reaction by combining with copper salt, and the compound containing chiral quaternary carbon center with higher ee value is obtained, and simultaneously, the yield is higher and is more than 75%. As can be seen from comparative examples 1 and 2, copper salts and compounds represented by formula I or II need to be coordinated to catalyze the Conia-Ene reaction, but neither of them is necessary. And as can be seen from comparative example 3, when the catalyst obtained by matching other conventional achiral phosphine ligand with copper salt is used for catalyzing Conia-Ene reaction, the ee value of the obtained product is equal to zero, which indicates that the Conia-Ene reaction catalyst provided by the invention has excellent selectivity.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (7)

  1. Use of a Conia-Ene reaction catalyst in a reaction to build a chiral quaternary carbon center, the Conia-Ene reaction catalyst comprising a chiral bidentate phosphite ligand and a copper salt, the chiral bidentate phosphite ligand being a compound of formula I or formula II:
    Figure FDA0003878215570000011
  2. 2. the use according to claim 1, wherein the molar ratio of the copper salt to the chiral bidentate phosphite ligand is 1.2 to 2.
  3. 3. Use according to claim 1 or 2, wherein the copper salt is at least one of cupric chloride, cupric bromide, cupric trifluoromethanesulfonate, cupric acetylacetonate, cupric sulfate, cuprous bromide, cuprous cyanide, cuprous iodide and cuprous acetate.
  4. 4. A method for constructing a chiral quaternary carbon center is characterized by comprising the following steps:
    mixing alkynyl enol silyl ether compounds, a catalyst and a solvent, and carrying out Conia-Ene reaction to obtain a compound containing a chiral quaternary carbon center; the catalyst is a Conia-Ene reaction catalyst for use according to any one of claims 1 to 3; the alkynyl enol silyl ether compound is a compound containing a delta-alkynyl enol silyl ether structure or a compound containing a gamma-alkynyl enol silyl ether structure.
  5. 5. The method according to claim 4, wherein the temperature of the Conia-Ene reaction is 20 to 80 ℃.
  6. 6. The method according to claim 4, wherein the molar ratio of the alkynyl enol silyl ether compound to the copper salt in the catalyst is 1.
  7. 7. The method of claim 4, wherein the solvent is at least one of toluene, dichloromethane, tetrahydrofuran, dioxane, 1, 2-dichloroethane, N-dimethylformamide, methanol, and water; the compound containing delta-alkynyl enol silyl ether is any one of compounds shown in formulas III-1 to III-8, and the compound containing the structure of gamma-alkynyl enol silyl ether is a compound shown in a formula III-9 or a formula III 10:
    Figure FDA0003878215570000021
    Figure FDA0003878215570000022
    wherein,
    Figure FDA0003878215570000023
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DE10352757A1 (en) * 2003-11-12 2005-06-16 Studiengesellschaft Kohle Mbh Chiral di- and triphosphites
CN101298460A (en) * 2008-06-25 2008-11-05 中国科学院上海有机化学研究所 Bidentate phosphite ester ligand, synthetic method and use thereof in alkene unsymmetrical catalysis hydroformylation reaction
CN104710476A (en) * 2013-12-16 2015-06-17 中国科学院兰州化学物理研究所 Chiral bidentate phosphite ligand and preparation method and application thereof
CN107827931B (en) * 2017-11-21 2019-05-31 郑州大学 Using '-biphenyl diphenol as bidentate phosphite ester ligand of structural unit and preparation method thereof
CN107915757B (en) * 2017-11-21 2019-05-31 郑州大学 Using trans cvclohexvl glycol as bidentate phosphite ester ligand of connection structure and preparation method thereof

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