Planar chiral phosphine oxazole ligand compound based on cycloarane skeleton as well as synthesis method and application of planar chiral phosphine oxazole ligand compound

Abstract

The invention discloses a planar chiral phosphine oxazole ligand compound based on a cycloarane skeleton as well as a synthesis method and application thereof, the cycloarane skeleton phosphorus-containing nitrogen oxide compound is selected from at least one of compounds with a structural formula as shown in formula I: # imgabs0 #, R is independently selected from phenyl, C7-C8 substituted aryl and cyclohexyl, and R is independently selected from phenyl, C7-C8 substituted aryl and cyclohexyl. The substituent group of the substituted aryl is selected from one of methyl, methoxyl, trifluoromethyl and fluorine atoms; ar is selected from one of a benzene ring, a substituted aromatic ring and a naphthalene ring, and a substituent group of the substituted aromatic ring is selected from one of methyl and fluorine atoms. According to the invention, a novel cycloarane skeleton-based phosphorus-containing nitrogen oxide compound with planar chirality can be effectively synthesized, and the compound as a ligand shows excellent catalytic activity and enantioselective control ability in the enantioselective synthesis of palladium-catalyzed 1, 3-disubstituted isoindoline. The method is simple and easy to operate, mild in reaction condition, low in energy consumption, environment-friendly and good in yield.

Description

Technical Field

[0001] The present application relates to a class of planar chiral phosphine oxazole ligand compounds based on a cyclophane skeleton, a preparation method and application thereof, and a preparation method of a chiral 1,3-disubstituted isoindoline, belonging to the technical field of organic synthesis. Background Art

[0002] Transition metal-catalyzed asymmetric synthesis plays an important role in the field of modern synthetic chemistry and is a direct and effective method for constructing chiral compounds. Since ligands affect the spatial and electronic properties of metal catalysts, the development of new and efficient chiral ligands is the core of asymmetric catalysis.

[0003] Chiral nitrogen-phosphorus compounds are an important class of chiral ligands, which are widely used in various metal-catalyzed asymmetric syntheses. However, in some asymmetric reactions, there are still scientific problems such as the inability to precisely control the elementary reactions and stereoselectivity. Therefore, it is necessary and urgent to develop new chiral nitrogen-phosphorus ligands to achieve the regulation of elementary reaction types and high stereoselectivity control in asymmetric reactions. This has important theoretical significance and application value, and is also an important supplement to existing chiral nitrogen-phosphorus ligands.

[0004] Chiral isoindolines are common structural motifs in a variety of natural products and pharmaceutical compounds, and exhibit a wide range of biological activities, including antianxiety, antipsychotic, antitumor, and multidrug resistance reversal activities. To date, several research groups have achieved a variety of synthetic schemes for constructing heterocyclic systems, but only a few methods can obtain disubstituted dihydroisoindolines with high enantio- and diastereoselectivities. However, all of these methods are limited to the use of a large amount of organic catalysts (≥10 mol%), low catalytic efficiency, and due to the characteristics of the reaction mechanism, the type of nucleophilic reagents is strictly restricted, resulting in a limited range of substrates. Therefore, developing a simple, effective, high-yield, and highly enantioselective method for synthesizing chiral 1,3-disubstituted isoindolines is a very promising research direction. Summary of the invention

[0005] The purpose of the present application is to provide a class of planar chiral phosphine oxazole ligand compounds based on a cyclophane skeleton, a synthesis method and application thereof, and a method for preparing a chiral 1,3-disubstituted isoindoline.

[0006] In order to expand the types of chiral nitrogen-phosphorus bidentate ligands and explore their more possibilities in asymmetric catalysis, the present invention designs a series of phosphine-oxazole bidentate ligands with face chirality based on a cycloarene skeleton, which is a class of phosphorus-containing nitrogen oxide compounds based on a cycloarene skeleton. Its synthesis uses optically pure 5-hydroxy-4-amino[2.2]-cycloarene as a raw material, and this type of compound can be obtained by coupling it with diaryl phosphine, coupling it with diaryl phosphine oxide, or exchanging bromine with n-butyl lithium and then replacing it with dicyclohexyl chlorophosphine. As a ligand, this compound exhibits excellent catalytic activity and enantioselective control ability in the palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindoline.

[0007] According to one aspect of the present application, a class of planar chiral phosphinothiazole ligand compounds based on a cyclophane skeleton is provided, wherein the planar chiral phosphinothiazole ligand compound based on a cyclophane skeleton is selected from at least one of the compounds having the structural formula shown in Formula I:

[0008]

[0009] Wherein, R is independently selected from phenyl, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 substituted phenyl) and cyclohexyl, the substituent of the substituted aryl (such as substituted phenyl) is selected from one of methyl, methoxy, trifluoromethyl and fluorine atom; Ar is selected from benzene ring, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 The substituent of the substituted aryl group (such as a substituted phenyl group) and a naphthalene ring is selected from one of a methyl group and a fluorine atom.

[0010] Optionally, the cycloarene skeleton phosphorus-containing nitrogen oxide compound is a planar chiral phosphine oxazole ligand compound having a racemic cycloarene skeleton, (R p )-cyclophane skeleton planar chiral phosphine oxazole ligand compound, (S p )-One of the planar chiral phosphine oxazole ligand compounds with a cyclophane skeleton.

[0011] According to another aspect of the present application, a method for preparing the above-mentioned cyclophane skeleton planar chiral phosphine oxazole ligand compound is provided, and the preparation method at least comprises:

[0012] Preparation of the compound shown in formula II:

[0013]

[0014] Under an inert atmosphere, a mixed solution a containing a compound represented by formula III, a compound represented by formula a1, an acid and a solvent W is subjected to a condensation reaction a in an inert atmosphere to obtain a compound represented by formula II;

[0015]

[0016] The reaction formula is as follows:

[0017]

[0018] Wherein, Ar is selected from benzene ring, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 The substituent of the substituted aryl group (such as a substituted phenyl group) and a naphthalene ring is selected from one of a methyl group and a fluorine atom.

[0019] Optionally, the molar ratio of the compound represented by formula III to the compound represented by formula a1 is 1:1.1 to 1:1.3;

[0020] Optionally, the reaction conditions of the condensation reaction a are a temperature of 90 to 110°C and a reaction time of 24 to 48 hours; optionally, the temperature of the condensation reaction a is selected from any value of 90°C, 100°C, 110°C or any value between any two of the above points; optionally, the reaction time of the condensation reaction a is selected from any value of 24 hours, 36 hours, 48 ​​hours or any value between any two of the above points.

[0021] Optionally, the inert atmosphere in the condensation reaction a is selected from at least one of nitrogen and argon.

[0022] Optionally, the acid is selected from at least one of methanesulfonic acid, p-toluenesulfonic acid monohydrate, and acetic acid.

[0023] Optionally, the solvent W is selected from at least one of methanol, tetrahydrofuran, diethyl ether and dioxane.

[0024] Optionally, the concentration of the compound represented by formula III in the solvent W is 0.2 to 1.0 mol / L.

[0025] The preparation method of the above-mentioned cyclophane skeleton planar chiral phosphine oxazole ligand compound is prepared by method 1;

[0026] The method comprises a compound represented by formula II, a diarylphosphine (Ar 2 'PH), cuprous iodide (CuI), N,N-dimethylethylenediamine (MeNHCH 2 CH 2 NHMe), cesium carbonate (Cs 2 CO 3) and a mixture of solvent X, undergoing a coupling reaction b in an inert atmosphere to obtain a planar chiral compound of formula I;

[0027] Wherein, Ar 2 ' is independently selected from phenyl, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 The substituents of the substituted aryl (e.g., substituted phenyl) are selected from C 1 ~C 4 One of an alkyl group, a methoxy group, a trifluoromethyl group, and a fluorine atom;

[0028] The reaction formula is as follows:

[0029]

[0030] Wherein, Ar is selected from benzene ring, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 The substituent of the substituted aryl group (such as a substituted phenyl group) and a naphthalene ring is selected from one of a methyl group and a fluorine atom.

[0031] In the method 1:

[0032] Optionally, the molar ratio of the compound represented by formula II to the diaryl phosphine is 1:1.6 to 1:2.0;

[0033] The molar ratio of the compound represented by formula II to cuprous iodide is 1:0.1 to 1:0.2;

[0034] The molar ratio of the compound represented by formula II to N,N-dimethylethylenediamine is 1:0.8 to 1:1;

[0035] The molar ratio of the compound represented by formula II to cesium carbonate is 1:3.5 to 1:4.0.

[0036] Optionally, the mixture further contains a solvent X, and the solvent X is selected from at least one of toluene, p-xylene and m-xylene.

[0037] Optionally, the reaction conditions of the coupling reaction b are a temperature of 100°C to 110°C and a reaction time of 5 to 7 hours; optionally, the temperature of the condensation reaction a is selected from any value of 100°C, 105°C, 110°C or any value between any two of the above points; optionally, the reaction time of the condensation reaction a is selected from any value of 5 hours, 6 hours, 7 hours or any value between any two of the above points.

[0038] Optionally, the inactive atmosphere in the coupling reaction b is selected from at least one of nitrogen and argon.

[0039] The preparation method of the above-mentioned cyclophane skeleton planar chiral phosphine oxazole ligand compound is prepared by method 2;

[0040] The method 2 includes coupling reaction c and reduction reaction;

[0041] The coupling reaction c is: containing the compound shown in formula II, diarylphosphine oxide (Ar 2 ” P(O)H), a mixed solution c of a palladium catalyst, a bisphosphine ligand, a base and a solvent Y, undergoes a coupling reaction c in an inactive atmosphere to obtain a compound represented by formula c2;

[0042] Wherein, Ar 2 " is independently selected from phenyl and C 7 ~C 8 The substituted aryl group is selected from C 1 ~C 4 One of an alkyl group, a methoxy group, a trifluoromethyl group, and a fluorine atom;

[0043]

[0044] The reduction reaction is as follows: the compound represented by formula c2, trichlorosilane (HSiCl 3 ), a mixture of a base and a solvent Z is subjected to a reduction reaction in an inactive atmosphere to obtain a planar chiral compound of formula I.

[0045] The reaction formula is as follows:

[0046]

[0047] Wherein, Ar is selected from benzene ring, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 The substituent of the substituted aryl group (such as a substituted phenyl group) and a naphthalene ring is selected from one of a methyl group and a fluorine atom.

[0048] In the coupling reaction c of the method 2:

[0049] Optionally, the molar ratio of the compound represented by formula II to the diaryl phosphine oxide is 1:1.5 to 1:2.0;

[0050] Optionally, the molar ratio of the compound represented by formula II to the palladium catalyst is 1:0.05 to 1:0.1;

[0051] Optionally, the molar ratio of the compound represented by formula II to the bisphosphine ligand is 1:0.05 to 1:0.1;

[0052] Optionally, the molar ratio of the compound represented by formula II to the base is 1:2 to 1:4;

[0053] Optionally, the reaction conditions of the coupling reaction c are 90-110°C and the reaction time is 8-12 hours; optionally, the temperature of the condensation reaction a is selected from any value of 90°C, 100°C, 110°C or any value between any two of the above points; optionally, the reaction time of the condensation reaction a is selected from any value of 8 hours, 10 hours, 12 hours or any value between any two of the above points.

[0054] Optionally, the inactive atmosphere in the coupling reaction c is selected from at least one of nitrogen and argon.

[0055] Optionally, the palladium catalyst is selected from at least one of palladium acetate and palladium trifluoroacetate.

[0056] Optionally, the bisphosphine ligand is selected from at least one of 1,4-bis(diphenylphosphino)butane, 1,3-bis(diphenylphosphino)propane and 1,2-bis(diphenylphosphino)ethane.

[0057] Optionally, the base is selected from at least one of N,N-diisopropylethylamine, diisopropylamine and triethylamine.

[0058] Optionally, the solvent Y is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide.

[0059] Optionally, the concentration of the compound represented by formula II in solvent Y is 0.1 mol / L to 0.3 mol / L.

[0060] In the reduction reaction of the second method:

[0061] Optionally, the molar ratio of the compound represented by formula C2 to trichlorosilane is 1:5 to 1:10.

[0062] Optionally, the molar ratio of the compound represented by formula C2 to the base is 1:5 to 1:10.

[0063] Optionally, the reduction reaction is carried out at a temperature of 100 to 120°C for 12 to 24 hours; optionally, the temperature of the condensation reaction a is selected from any value of 100°C, 110°C, 120°C or any value between any two of the above points; optionally, the reaction time of the condensation reaction a is selected from any value of 12 hours, 18 hours, 24 hours or any value between any two of the above points.

[0064] Optionally, the inactive atmosphere in the reduction reaction is selected from at least one of nitrogen and argon.

[0065] Optionally, the base is selected from at least one of N,N-diisopropylethylamine, diisopropylamine and triethylamine.

[0066] Optionally, the solvent Z is selected from at least one of p-xylene, m-xylene and toluene.

[0067] Optionally, the concentration of the compound represented by formula c2 in solvent Z is 0.02 mol / L to 0.2 mol / L.

[0068] The preparation method of the above-mentioned cyclophane skeleton planar chiral phosphine oxazole ligand compound is prepared by method three;

[0069] The third method is to prepare a mixed solution d containing the compound shown in formula II, n-butyl lithium (n-BuLi), N,N,N,N-tetramethylethylenediamine (TMEDA) and solvent S, and to perform a bromine-lithium exchange reaction in an inactive atmosphere, and then add a disubstituted chlorophosphine (R 2 PC1) undergoes a substitution reaction d to obtain a planar chiral compound shown in formula I;

[0070] The reaction formula is as follows:

[0071]

[0072] Wherein, R is independently selected from phenyl, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 substituted phenyl) and cyclohexyl, the substituent of the substituted aryl (such as substituted phenyl) is selected from one of methyl, methoxy, trifluoromethyl and fluorine atom; Ar is selected from benzene ring, C 7 ~C 8 Substituted aromatic groups (such as C 7 ~C 8 The substituent of the substituted aryl group (such as a substituted phenyl group) and a naphthalene ring is selected from one of a methyl group and a fluorine atom.

[0073] Specifically, the disubstituted chlorophosphine (R 2 PCl) is diarylphosphine chloride (Ar 2 ”' 2 PCl) or dicyclohexylphosphine chloride (Cy 2 PCl), the diarylphosphine chloride (Ar 2 ”' 2 Ar in PCl 2 "' is independently selected from phenyl, C 7 ~C 8Substituted aromatic groups (such as C 7 ~C 8 The substituent of the substituted aryl group (such as substituted phenyl) is selected from one of methyl, methoxy, trifluoromethyl and fluorine atom.

[0074] When the disubstituted chlorophosphine (R 2 PCl) is dicyclohexylphosphine chloride (Cy 2 PCl), the method 3 is to prepare a mixed solution d containing the compound shown in formula II, n-butyl lithium (n-BuLi), N,N,N,N-tetramethylethylenediamine (TMEDA) and solvent S, and to perform a bromine-lithium exchange reaction in an inactive atmosphere, and then add dicyclohexylphosphine chloride (Cy 2 PC1) undergoes a substitution reaction d to obtain a planar chiral compound shown in formula I;

[0075] The reaction formula is as follows:

[0076]

[0077] In the third method:

[0078] Optionally, the molar ratio of the compound represented by formula II to n-butyl lithium is 1:1.2 to 1:1.4;

[0079] Optionally, the molar ratio of the compound represented by formula II to N,N,N,N-tetramethylethylenediamine is 1:1.2 to 1:1.4;

[0080] Optionally, the molar ratio of the compound represented by formula II to dicyclohexylphosphine chloride is 1:2 to 1:3;

[0081] The reaction conditions of the bromine-lithium exchange are a temperature of -90 to -60°C, preferably -78°C, and a reaction time of 2 to 4 hours;

[0082] The reaction conditions of the substitution reaction d are a temperature of -90 to -60°C, preferably -78°C, and a reaction time of 1 to 2 hours; then the temperature is raised to room temperature, and optionally, the reaction time is 8 to 12 hours; optionally, the reaction time of the substitution reaction d is selected from any value of 8 hours, 10 hours, 12 hours, or any value between any two of the above points.

[0083] Optionally, the inactive atmosphere in the lithium bromide exchange and substitution reaction c is selected from at least one of nitrogen and argon.

[0084] Optionally, the solvent S is selected from at least one of tetrahydrofuran and diethyl ether.

[0085] According to another aspect of the present application, there is provided a use of at least one of the above-mentioned cyclopentane skeleton planar chiral phosphinothazole ligand compound and the cyclopentane skeleton planar chiral phosphinothazole ligand compound prepared by the above-mentioned preparation method as a ligand in the enantioselective synthesis of 1,3-disubstituted isoindolines catalyzed by palladium.

[0086] A method for preparing a chiral cis-1,3-disubstituted isoindoline, comprising subjecting a mixture A containing a compound represented by formula IV, a compound represented by formula V, an additive and a catalyst to an asymmetric boronic acid addition reaction, and then adding a base to cause a Michael addition reaction, so that the asymmetric boronic acid addition reaction is connected in series with the Michael addition reaction to obtain a chiral cis-1,3-disubstituted isoindoline represented by formula VI;

[0087]

[0088] The reaction formula is as follows:

[0089]

[0090] Where: R 1 is selected from phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is independently selected from at least one of methyl, methoxy and nitro;

[0091] R 2 Selected from methyl or ethyl;

[0092] Ar 1 is selected from phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is independently selected from at least one of methyl, fluorine and chlorine;

[0093] Ar 2 is selected from phenyl, naphthyl or substituted phenyl, and the substituent of the substituted phenyl is selected from one of methyl, ethyl, isopropyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, benzyloxy, hydroxyl, dimethylamino and bromine;

[0094] The catalyst is a planar chiral nitrogen-phosphorus complex of palladium, and the planar chiral nitrogen-phosphorus complex of palladium refers to a mixture B containing a palladium precursor and a planar chiral nitrogen-phosphorus compound L in a solvent J, which is coordinated to form the chiral nitrogen-phosphorus complex of palladium, and then the solvent J is removed; the planar chiral nitrogen-phosphorus compound is at least one of the planar chiral phosphinothiazole ligand compound of the above-mentioned cyclopentane skeleton and the planar chiral phosphinothiazole ligand compound of the cyclopentane skeleton prepared by the above-mentioned preparation method.

[0095] Optionally, the palladium precursor is selected from palladium acetate or palladium trifluoroacetate.

[0096] Optionally, the molar ratio of the palladium precursor to the planar chiral nitrogen-phosphorus compound is 1:1.1 to 1:2.

[0097] Optionally, the reaction temperature of the coordination reaction between the palladium precursor and the planar chiral nitrogen-phosphorus compound is 15° C. to 35° C., and the reaction time is 30 to 90 min.

[0098] Optionally, the solvent J is selected from at least one of acetone, dichloromethane and tetrahydrofuran;

[0099] The molar concentration of the palladium precursor in the solvent J is 0.002-0.01 mol / L.

[0100] Optionally, the molar ratio of the compound represented by formula IV to the compound represented by formula V is 1:1 to 1:3, the molar ratio of the compound represented by formula IV to the additive is 1:0.05 to 1:0.1, and the molar ratio of the compound represented by formula IV to the planar chiral nitrogen-phosphorus complex of palladium is 1:0.02 to 1:0.1.

[0101] Optionally, the additive is selected from metal Lewis acids; preferably, the additive is selected from silver acetate, silver nitrate and copper acetate.

[0102] Optionally, the base is selected from an inorganic base; preferably, the base is selected from cesium carbonate, potassium carbonate or potassium phosphate.

[0103] Optionally, the mixture A contains a solvent T, and the solvent T is selected from at least one of trifluoroethanol, hexafluoroisopropanol, methanol and ethanol.

[0104] Optionally, the concentration of the compound represented by formula IV in the solvent T is 0.02 mol / L to 0.2 mol / L.

[0105] Optionally, the temperature of the first step (asymmetric boronic acid addition reaction) of the tandem reaction is 30-60°C, and the temperature of the second step (Michael addition reaction) is 30-60°C.

[0106] Optionally, the first step (asymmetric boronic acid addition reaction) of the tandem reaction takes 1 to 5 hours, and the second step (Michael addition reaction) takes 8 to 12 hours.

[0107] On the other hand, the present invention provides a class of chiral cis-1,3-disubstituted isoindoline compounds having the structure shown in Formula VI:

[0108]

[0109] In Formula VI: R 1 is selected from phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is independently selected from at least one of methyl, methoxy and nitro;

[0110] R 2 Selected from methyl or ethyl;

[0111] Ar1 is selected from phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is independently selected from at least one of methyl, fluorine and chlorine;

[0112] Ar 2 The substituted phenyl group is selected from phenyl, naphthyl or substituted phenyl, and the substituent of the substituted phenyl group is selected from one of methyl, ethyl, isopropyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, benzyloxy, hydroxyl, dimethylamino and bromine.

[0113] Optionally, the chiral cis-1,3-disubstituted isoindoline compound is selected from any one of the structures shown in 6aa, 6ba, 6ca, 6da, 6ea, 6fa, 6ga, 6ha, 6ab, 6ac, 6ad, 6ae, 6af, 6ag, 6ah, 6ai, 6aj, 6ak, 6al, 6am, 6an, 6ao, 6ap, and 6aq;

[0114]

[0115]

[0116] The beneficial effects of this application include:

[0117] 1) The present invention can effectively synthesize a new type of planar chiral phosphine oxazole ligand compound based on a cyclophane skeleton with planar chirality, and the synthesis route is short, and the target compound can be obtained with a high yield.

[0118] 2) The planar chiral oxazole phosphine ligand compound based on the cyclophane skeleton synthesized by the present invention is a chirally pure reagent.

[0119] 3) The planar chiral oxazole phosphine ligand compound based on the cyclopentane skeleton synthesized by the present invention can be applied to the enantioselective synthesis of 1,3-disubstituted isoindoline catalyzed by palladium, and has excellent catalytic activity and enantioselective controllability. BRIEF DESCRIPTION OF THE DRAWINGS

[0120] Figure 1 This is the X-ray single crystal diffraction test pattern of compound 6aa of the present invention. DETAILED DESCRIPTION

[0121] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0122] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0123] As a specific implementation, the present invention is implemented by the following technical solutions:

[0124] A type of planar chiral phosphine oxazole ligand compound based on a cyclophane skeleton and a synthesis method thereof, wherein the compound may be racemic or optically active, and the structural formula of the planar chiral phosphine oxazole ligand compound based on a cyclophane skeleton is the structure of the compound of formula I below:

[0125]

[0126] in:

[0127] R is independently selected from phenyl, C 7 ~C 8 substituted aromatic group and cyclohexyl; the substituent of the substituted aromatic group is selected from one of methyl, methoxy, trifluoromethyl and fluorine atom; Ar is selected from one of benzene ring, substituted aromatic ring and naphthalene ring; the substituent of the substituted aromatic ring is selected from one of methyl and fluorine atom.

[0128] The present invention provides a design and synthesis of a planar chiral phosphine oxazole ligand compound based on a cyclophane skeleton, and the synthesis route is as follows:

[0129]

[0130] Wherein: Ar represents a phenyl group or an aromatic group having a substituent on the other benzene ring.

[0131] Reaction steps:

[0132] Synthesis of compound 2:

[0133]

[0134] Condensation reaction: Under nitrogen protection, compound 1, 2-bromobenzoyl chloride compounds, methanesulfonic acid and 1,4-dioxane were added to the reaction bottle and reacted at 100° C. for 36 hours to obtain compounds 2a-e.

[0135] Method 1:

[0136]

[0137] Coupling reaction: Under nitrogen protection, add compound 2 and diphenylphosphine (Ph 2 PH), cuprous iodide (CuI), N,N-dimethylethylenediamine (MeNHCH 2 CH 2 NHMe), cesium carbonate (Cs 2 CO 3 ) and toluene (Toluene), react at 110°C for 6 hours, and then stop the reaction to obtain compounds L1-L3.

[0138] Method 2:

[0139]

[0140] Coupling reaction: Under nitrogen protection, add compound 2 and diarylphosphine oxide (Ar" 2 P(O)H), palladium acetate (Pd(OAc) 2 ), 1,4-bis(diphenylphosphino)butane (DPPB), N,N-diisopropylethylamine (DIPEA) and dimethyl sulfoxide (DMSO) were reacted at 100°C for 12 hours to obtain the phosphine oxide compound 3.

[0141] Reduction reaction: Under nitrogen protection, add compound 3 and trichlorosilane (HSiCl 3 ), N,N-diisopropylethylamine (DIPEA) and toluene (Toluene), react at 120°C for 24 hours to obtain compound L4-11.

[0142] Method 3:

[0143]

[0144] Substitution reaction: Under nitrogen protection, compound 2a, n-butyl lithium (n-BuLi), N,N,N,N-tetramethylethylenediamine (TMEDA) and tetrahydrofuran (THF) were added to the reaction flask and reacted at -78°C for 3 hours, followed by the addition of dicyclohexylphosphine chloride (Cy 2 PC1), and then the temperature was raised to room temperature and reacted for 12 hours to obtain compound L12.

[0145] As one of the preferred embodiments, the specific reaction steps of the palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindoline are as follows: under nitrogen protection, palladium trifluoroacetate and the compound shown in formula I are added to a sealed tube, acetone is added, and the reaction is stirred at room temperature for 60 minutes, and the acetone is removed under reduced pressure. The compound shown in formula IV, the compound shown in formula V, solvent T and additives are added under nitrogen, and the reaction is stirred at 30° C. or 60° C. for 3-5 hours, and cesium carbonate is added. The reaction is carried out at 30° C. for 10 hours, the solvent T is spin-dried, and the pure chiral cis-1,3-disubstituted isoindoline is separated by column chromatography.

[0146] The term "C 1 ~C 4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms; preferably "C 1 ~C 4 The "alkyl" includes methyl, ethyl, n-propyl, isopropyl and the like.

[0147] In the present invention, C 1 ~C 4 , C 7 ~C 8The numbers refer to the number of carbon atoms in the group.

[0148] In the present invention, "alkyl" is a group formed by losing any hydrogen atom from an alkane compound molecule. The alkane compound includes straight-chain alkanes, branched-chain alkanes, cycloalkanes, and branched cycloalkanes.

[0149] In the present invention, "aryl" is a group formed by losing a hydrogen atom on the aromatic ring of an aromatic compound molecule; the aromatic compound includes a compound containing an aromatic ring and a compound in which at least one hydrogen atom on the aromatic ring is replaced by an alkyl group.

[0150] In the present invention, "phenyl group" refers to a phenyl group formed by toluene losing a hydrogen atom on the benzene ring.

[0151] The analysis method in the embodiment of the present invention is as follows:

[0152] H NMR 1 H-NMR was measured on a Bruker 400 MHz NMR spectrometer.

[0153] The ee values ​​in the examples of the present invention were measured on an Agilent LC 1100 liquid chromatograph.

[0154] The room temperature in the embodiments of the present invention refers to 25°C.

[0155] Synthesis of optically pure 5-hydroxy-4-amino[2.2]paracyclophane compound 1 as starting material in the following examples References (a) Cipiciani, A.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Ruzziconi, RJ Org. Chem. 2002, 67, 2665-2670. (b) Friedmann, CJ; Ay, S.; SJ Org. Chem. 2010, 75, 4612-4614.

[0156] The synthesis references of the raw material olefin imine compounds 4a-4h in the following examples are (a) Takizawa, S.; Sako, M; Abozeid, MA; Kishi, K.; Wathsala, HDP; Hirata, S.; Murai, K.; Fujioka, H.; Sasai, H. Org. Lett. 2017, 19, 5426–5429. (b) Enders, D.; Narine, AA; Toulgoat, F.; Bisschops, T. Angew. Chem. Int. Ed. 2008, 47, 5661-5665.

[0157] The synthesis of the raw material 2-bromobenzoyl chloride compounds in the following examples is referenced in (a) Seth, K.; Purohit, P.; Chakraborti, AK Org. Lett. 2014, 16, 2334–2337.

[0158] Example 1: Synthesis of Compound 2a

[0159]

[0160] Under nitrogen protection, compound 1 (0.239 g, 1.0 mmol), o-bromobenzoyl chloride (0.263 g, 1.2 mmol), 2.0 mL of dioxane, and 0.2 mL of methanesulfonic acid were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 36 hours. The solvent was removed by vacuum evaporation. 5 mL of ethyl acetate was added for dilution, and 5 mL of saturated sodium bicarbonate solution was used to quench the reaction. Ethyl acetate was used for extraction, and anhydrous Na 2 SO 4 After drying, filtering, and removing the solvent under reduced pressure, column chromatography was performed to obtain 0.352 g of a white solid with a yield of 87%.

[0161] Example 2: Synthesis of Compound 2b

[0162]

[0163] Under nitrogen protection, compound 1 (0.239 g, 1.0 mmol), 3-methyl-2-bromobenzoyl chloride (0.280 g, 1.2 mmol), 2.0 mL of dioxane, and 0.2 mL of methanesulfonic acid were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 36 hours. The solvent was removed by vacuum evaporation. 5 mL of ethyl acetate was added for dilution, and 5 mL of saturated sodium bicarbonate solution was used to quench the reaction. Ethyl acetate was used for extraction, and anhydrous Na 2 SO 4 After drying and filtering, the solvent was removed under reduced pressure and column chromatography was performed to obtain 0.189 g of a white solid with a yield of 45%.

[0164] Example 3: Synthesis of Compound 2c

[0165]

[0166] Under nitrogen protection, compound 1 (0.239 g, 1.0 mmol), 4-methyl-2-bromobenzoyl chloride (0.280 g, 1.2 mmol), 2.0 mL of dioxane, and 0.2 mL of methanesulfonic acid were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 36 hours. The solvent was removed by vacuum evaporation. 5 mL of ethyl acetate was added for dilution, and 5 mL of saturated sodium bicarbonate solution was used to quench the reaction. Ethyl acetate was used for extraction, and anhydrous Na 2 SO 4After drying, filtering, and removing the solvent under reduced pressure, column chromatography was performed to obtain 0.202 g of a white solid with a yield of 48%.

[0167] Example 4: Synthesis of Compound 2d

[0168]

[0169] Under nitrogen protection, compound 1 (0.717 g, 3.0 mmol), 5-fluoro-2-bromobenzoyl chloride (0.855 g, 3.6 mmol), 6.0 mL of dioxane, and 0.6 mL of methanesulfonic acid were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 36 hours. The solvent was removed by vacuum evaporation. 10 mL of ethyl acetate was added for dilution, and 10 mL of saturated sodium bicarbonate solution was used to quench the reaction. Ethyl acetate was used for extraction, and anhydrous Na 2 SO 4 After drying and filtering, the solvent was removed under reduced pressure and column chromatography was performed to obtain 1.025 g of a white solid with a yield of 81%.

[0170] Example 5: Synthesis of Compound 2e

[0171]

[0172] Under nitrogen protection, compound 1 (0.388 g, 1.62 mmol), 3-bromo-2-naphthoyl chloride (0.523 g, 1.94 mmol), 3.0 mL of dioxane, and 0.3 mL of methanesulfonic acid were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 36 hours. The solvent was removed by vacuum evaporation. 5 mL of ethyl acetate was added for dilution, and 5 mL of saturated sodium bicarbonate solution was used to quench the reaction. Ethyl acetate was used for extraction, and anhydrous Na 2 SO 4 After drying, filtering, and removing the solvent under reduced pressure, column chromatography was performed to obtain 0.385 g of a white solid with a yield of 52%.

[0173] Example 6: Synthesis of Compound L1

[0174]

[0175] Under nitrogen protection, cuprous iodide (0.083 g, 0.44 mmol), diphenylphosphine (1.2 mL, 6.58 mmol), N,N-dimethylethylenediamine (0.33 mL, 3.06 mmol), and 15 mL of toluene were added to a 100 mL reaction bottle, and stirred at room temperature for 20 minutes. Compound 2a (1.415 g, 3.5 mmol), cesium carbonate (4.276 g, 13.13 mmol), and 15 mL of toluene were added, and the mixture was reacted at 110 ° C for 6 hours. The mixture was filtered, washed with dichloromethane, and the solvent was removed under reduced pressure. 1.522 g of white solid was obtained by column chromatography with a yield of 88%.

[0176] Example 7: Synthesis of Compound L2

[0177]

[0178] Under nitrogen protection, cuprous iodide (0.036 g, 0.19 mmol), diphenylphosphine (0.25 mL, 1.41 mmol), N,N-dimethylethylenediamine (0.14 mL, 1.31 mmol), and 3.5 mL of toluene were added to a 50 mL reaction bottle, and stirred at room temperature for 20 minutes. Compound 2b (0.314 g, 0.75 mmol), cesium carbonate (0.916 g, 2.81 mmol), and 3.5 mL of toluene were added, and the mixture was reacted at 110 ° C for 6 hours. The mixture was filtered, washed with dichloromethane, and the solvent was removed under reduced pressure by column chromatography to obtain 0.210 g of a white solid with a yield of 53%.

[0179] Example 8: Synthesis of Compound L3

[0180]

[0181] Under nitrogen protection, cuprous iodide (0.011 g, 0.056 mmol), diphenylphosphine (0.16 mL, 0.91 mmol), N,N-dimethylethylenediamine (0.045 mL, 0.85 mmol), and 2 mL of toluene were added to a 50 mL reaction bottle, and stirred at room temperature for 20 minutes. Compound 2c (0.202 g, 0.45 mmol), cesium carbonate (0.586 g, 1.8 mmol), and 2 mL of toluene were added, and the mixture was reacted at 110 ° C for 6 hours. The mixture was filtered, washed with dichloromethane, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain 0.188 g of a white solid with a yield of 75%.

[0182] Example 9: Synthesis of Compound L4

[0183]

[0184] Under nitrogen protection, compound 2a (0.404 g, 1.0 mmol), di(2-methylphenyl)phosphine oxide (0.461 g, 2.0 mmol), palladium acetate (0.011 g, 0.05 mmol), 1,4-bis(diphenylphosphino)butane (0.021 g, 0.05 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and 6.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 12 hours, and then 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and anhydrous Na 2 SO 4 The mixture was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain compound 3d.

[0185] Under nitrogen protection, compound 3d, N,N-diisopropylethylamine (1.7 mL, 10.0 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.50 mL, 5.0 mmol) was added dropwise. The mixture was reacted at 120 °C for 24 h, and 4 mL of saturated sodium bicarbonate solution was added to quench the mixture. The mixture was filtered through celite, and the solvent was removed under reduced pressure. After column chromatography, 0.297 g of a white solid was obtained. The yield was 55%.

[0186] Example 10: Synthesis of Compound L5

[0187]

[0188] Under nitrogen protection, compound 2a (0.202 g, 0.5 mmol), di(4-methylphenyl)phosphine oxide (0.230 g, 1.0 mmol), palladium acetate (0.006 g, 0.025 mmol), 1,4-bis(diphenylphosphino)butane (0.011 g, 0.025 mmol), N,N-diisopropylethylamine (0.35 mL, 2.0 mmol), and 3.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 12 hours, and 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and anhydrous Na 2 SO 4 The product was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain compound 3e.

[0189] Under nitrogen protection, compound 3e, N,N-diisopropylethylamine (0.85 mL, 5.0 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.25 mL, 2.5 mmol) was added dropwise. The mixture was reacted at 120 °C for 24 h, and 4 mL of saturated sodium bicarbonate solution was added to quench the mixture. The mixture was filtered through celite, and the solvent was removed under reduced pressure. 0.262 g of a white solid was obtained by column chromatography. The yield was 99%.

[0190] Example 11: Synthesis of Compound L6

[0191]

[0192] Under nitrogen protection, compound 2a (0.202 g, 0.5 mmol), di(4-methoxyphenyl)phosphine oxide (0.246 g, 1.0 mmol), palladium acetate (0.006 g, 0.025 mmol), 1,4-bis(diphenylphosphino)butane (0.011 g, 0.025 mmol), N,N-diisopropylethylamine (0.35 mL, 2.0 mmol), 3.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, reacted at 100 ° C for 12 hours, added 15 mL of water to dilute, extracted with ethyl acetate, washed with saturated sodium chloride solution, anhydrous Na2 SO 4 The mixture was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain compound 3f.

[0193] Under nitrogen protection, compound 3f, N,N-diisopropylethylamine (0.85 mL, 5.0 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.25 mL, 2.5 mmol) was added dropwise. The mixture was reacted at 120 °C for 24 h, and 4 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was filtered through celite, and the solvent was removed under reduced pressure. After column chromatography, 0.534 g of a white solid was obtained. The yield was 94%.

[0194] Example 12: Synthesis of Compound L7

[0195]

[0196] Under nitrogen protection, compound 2a (0.404 g, 1.0 mmol), di(3,5-dimethylphenyl)phosphine oxide (0.517 g, 2.0 mmol), palladium acetate (0.011 g, 0.05 mmol), 1,4-bis(diphenylphosphino)butane (0.021 g, 0.05 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and 6.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 12 hours, and 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and anhydrous Na 2 SO 4 The product was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain 3 g of compound.

[0197] Under nitrogen protection, compound 3 g, N,N-diisopropylethylamine (1.7 mL, 10.0 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.50 mL, 5.0 mmol) was added dropwise. The mixture was reacted at 120 ° C for 24 hours, and 4 mL of saturated sodium bicarbonate solution was added to quench the mixture. The mixture was filtered through celite, and the solvent was removed under reduced pressure. After column chromatography, 0.529 g of a white solid was obtained. The yield was 93%.

[0198] Example 13: Synthesis of Compound L8

[0199]

[0200] Under nitrogen protection, compound 2a (0.404 g, 1.0 mmol), di(4-fluorophenyl)phosphine oxide (0.476 g, 2.0 mmol), palladium acetate (0.011 g, 0.05 mmol), 1,4-bis(diphenylphosphino)butane (0.021 g, 0.05 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and 6.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 12 hours, and 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and anhydrous Na 2 SO 4 The mixture was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain compound 3h.

[0201] Under nitrogen protection, compound 3h, N,N-diisopropylethylamine (1.7 mL, 10.0 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.50 mL, 5.0 mmol) was added dropwise. The mixture was reacted at 120 °C for 24 h, and 4 mL of saturated sodium bicarbonate solution was added to quench the mixture. The mixture was filtered through celite, and the solvent was removed under reduced pressure. 0.397 g of a white solid was obtained by column chromatography. The yield was 78%.

[0202] Example 14: Synthesis of Compound L9

[0203]

[0204] Under nitrogen protection, compound 2a (0.404 g, 1.0 mmol), bis(3,5-ditrifluoromethylphenyl)phosphine oxide (0.676 g, 2.0 mmol), palladium acetate (0.011 g, 0.05 mmol), 1,4-bis(diphenylphosphino)butane (0.021 g, 0.05 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and 6.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, and the mixture was reacted at 100 °C for 12 hours, and 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and anhydrous Na 2 SO 4 The mixture was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain compound 3i.

[0205] Under nitrogen protection, compound 3i, N,N-diisopropylethylamine (1.7 mL, 10.0 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.50 mL, 5.0 mmol) was added dropwise. The mixture was reacted at 120 °C for 24 h, and 4 mL of saturated sodium bicarbonate solution was added to quench the mixture. The mixture was filtered through celite, and the solvent was removed under reduced pressure. 0.490 g of a white solid was obtained by column chromatography. The yield was 64%.

[0206] Example 15: Synthesis of Compound L10

[0207]

[0208] Under nitrogen protection, compound 2d (0.422 g, 1.0 mmol), diphenylphosphine oxide (0.404 g, 2.0 mmol), palladium acetate (0.011 g, 0.05 mmol), 1,4-bis(diphenylphosphino)butane (0.021 g, 0.05 mmol), N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and 6.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, and the mixture was reacted at 100 ° C for 12 hours, and 15 mL of water was added for dilution, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and anhydrous Na 2 SO 4 The product was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain compound 3j.

[0209] Under nitrogen protection, compound 3j, N,N-diisopropylethylamine (1.7 mL, 10.0 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.50 mL, 5.0 mmol) was added dropwise. The mixture was reacted at 120 °C for 24 h, and 4 mL of saturated sodium bicarbonate solution was added to quench the mixture. The mixture was filtered through celite, and the solvent was removed under reduced pressure. After column chromatography, 0.345 g of a white solid was obtained. The yield was 65%.

[0210] Example 16: Synthesis of Compound L11

[0211]

[0212] Under nitrogen protection, compound 2e (0.385 g, 0.85 mmol), diphenylphosphine oxide (0.344 g, 1.7 mmol), palladium acetate (0.010 g, 0.043 mmol), 1,4-bis(diphenylphosphino)butane (0.018 g, 0.043 mmol), N,N-diisopropylethylamine (0.59 mL, 3.4 mmol), 5.0 mL of dimethyl sulfoxide were added to a 50 mL reaction bottle, reacted at 100 ° C for 12 hours, added 15 mL of water to dilute, extracted with ethyl acetate, washed with saturated sodium chloride solution, anhydrous Na 2 SO 4 The product was dried, filtered, and the solvent was removed under reduced pressure and then column chromatography was performed to obtain compound 3k.

[0213] Under nitrogen protection, compound 3k, N,N-diisopropylethylamine (1.5 mL, 8.5 mmol), and 15 mL of toluene were added to a 50 mL sealed tube, and trichlorosilane (0.42 mL, 4.25 mmol) was added dropwise. The mixture was reacted at 120 °C for 24 h, and 4 mL of saturated sodium bicarbonate solution was added to quench the mixture. The mixture was filtered through celite, and the solvent was removed under reduced pressure. After column chromatography, 0.272 g of a white solid was obtained in a yield of 62%.

[0214] Example 17: Synthesis of Compound L12

[0215]

[0216] Under nitrogen protection, compound 2a (0.404 g, 1.0 mmol), N,N,N,N-tetramethylethylenediamine (0.20 mL, 1.3 mmol), and 20 mL of anhydrous tetrahydrofuran were added to a 100 mL reaction bottle, cooled to -78 °C, and n-butyl lithium (2.5 M n-hexane solution, 0.52 mL, 1.3 mmol) was slowly added (within 10 minutes), and stirred for 3 hours; then, dicyclohexylphosphine chloride (0.44 mL, 2.0 mmol) was slowly added (within 10 minutes), and reacted at -78 °C for 1 hour, and slowly (within 1 hour) warmed to room temperature, and stirred for 10 hours. After the solvent was removed under reduced pressure, column chromatography was performed to obtain 0.513 g of a yellow solid with a yield of 98%.

[0217] Example 18: Palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindolines 6aa

[0218]

[0219] Under nitrogen protection, palladium trifluoroacetate (0.005mmol), chiral nitrogen-phosphorus ligand L1 (0.005mmol) and 1mL acetone were added to a 10mL sealed tube, stirred at room temperature for 1 hour, the solvent was removed under reduced pressure, sulfonimide 4a (0.1mmol), arylboronic acid 5a (0.2mmol) and 1.5mL trifluoroethanol were added, and the mixture was moved into a 30°C oil bath and stirred for 5min, and then silver acetate (0.005mmol) was added. After stirring and reacting at 30°C for 3 hours, cesium carbonate (0.3mmol) was added, and the mixture was stirred and reacted at 30°C for 10 hours. After the reaction was complete, the solvent was dried, internal standard trimethoxybenzene (0.1mmol) was added, and the H NMR spectrum was measured. The H NMR yield was 92%, the enantiomeric excess was >99%, and the diastereomeric ratio was >20:1.

[0220] Examples 19-29: Palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindolines 6aa

[0221] 1,3-Disubstituted isoindoline was prepared by the same method as in Example 18, except that the type of chiral nitrogen and phosphorus ligand was changed. The results are shown in Table 1.

[0222]

[0223] Table 1. Condition parameters and results of Examples 19 to 29

[0224]

[0225] Example 30: Palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindolines 6aa

[0226]

[0227] Under nitrogen protection, palladium trifluoroacetate (0.01mmol), chiral nitrogen-phosphorus ligand L2 (0.012mmol) and 2mL acetone were added to a 10mL sealed tube, stirred at room temperature for 1 hour, the solvent was removed under reduced pressure, sulfonimide 4a (0.2mmol), arylboronic acid 5a (0.4mmol) and 1.5mL trifluoroethanol were added, and the mixture was moved into a 30°C oil bath and stirred for 5min, and then silver acetate (0.01mmol) was added, stirred at 30°C for 3 hours, and cesium carbonate (0.6mmol) was added, and stirred at 30°C for 10 hours. After the reaction was complete, the solvent was dried, tetrahydrofuran was added to dissolve, filtered on silica gel, the solvent was dried again, and column chromatography was used to separate the pure chiral cis-1,3-disubstituted isoindoline 6aa, with a yield of 90%, an enantiomeric excess of >99%, and a diastereomeric ratio of >20:1.

[0228] Compound 6aa was subjected to a graphene monochromatic Mo-Kα radiation. After X-ray single crystal diffraction test (test condition: 293K) on BRUKER D8 VENTURE diffractometer, the structure was analyzed by Olex2 1.2. The structure was confirmed by single crystal. Figure 1 As shown; the compound 6aa crystal belongs to the orthorhombic system, the space group is P 21, and the unit cell parameters are Z=4.

[0229] Examples 31-37: Palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindolines 6

[0230] The same method and conditions as in Example 30 were used to prepare cis-1,3-disubstituted isoindoline 6 with different structures, and only the type of sulfonimide 4 in the reaction was changed to obtain chiral cis-1,3-disubstituted isoindoline 3ba, 3ca, 3da, 3ea, 3fa, 3ga, and 3ha in sequence. The structure of sulfonimide 4 is as follows:

[0231]

[0232] Examples 38-45: Palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindolines 6

[0233] The same method and conditions as in Example 30 were used to prepare cis-1,3-disubstituted isoindoline 6 of different structures, and only the type of aryl boronic acid 5 in the reaction was changed to obtain chiral cis-1,3-disubstituted isoindoline 6ab, 6ac, 6ad, 6ae, 6af, 6ag, 6ah, 6ai in sequence. The structure of aryl boronic acid 5 is as follows:

[0234]

[0235] Example 46: Palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindolines 6aj

[0236]

[0237] Under nitrogen protection, palladium trifluoroacetate (0.01mmol), chiral nitrogen-phosphorus ligand L2 (0.012mmol) and 2mL acetone were added to a 10mL sealed tube, stirred at room temperature for 1 hour, the solvent was removed under reduced pressure, sulfonimide 4a (0.2mmol), arylboronic acid 5j (0.4mmol) and 3.0mL trifluoroethanol were added, and the mixture was moved into a 60℃ oil bath and stirred for 5min, and then silver acetate (0.02mmol) was added. After stirring and reacting at 60℃ for 3 hours, cesium carbonate (0.6mmol) was added, and the mixture was stirred and reacted at 30℃ for 10 hours. After the reaction was complete, the solvent was dried by spin drying, tetrahydrofuran was added to dissolve, silica gel was filtered, the solvent was dried again, and column chromatography was used to separate the pure chiral cis-1,3-disubstituted isoindoline 6aj, with a yield of 81%, an enantiomeric excess of >99%, and a diastereomeric ratio of >20:1.

[0238] Examples 47-53: Palladium-catalyzed enantioselective synthesis of 1,3-disubstituted isoindolines 6

[0239] The same method and conditions as in Example 46 were used to prepare cis-1,3-disubstituted isoindoline 6 with different structures, and only the type of aryl boronic acid 5 in the reaction was changed to obtain chiral cis-1,3-disubstituted isoindoline 6ak, 6al, 6am, 6an, 6ao, 6ap, and 6aq in sequence. The structure of aryl boronic acid 5 is as follows:

[0240]

[0241] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

Claims

1. A type of planar chiral phosphine oxazole ligand compound based on a cyclophane skeleton, It is characterized in that The cyclophane skeleton planar chiral phosphine oxazole ligand compound is selected from at least one of the compounds having the structural formula shown in Formula I: Wherein, R is independently selected from phenyl, C 7 ~C 8 The substituents of the substituted aryl are selected from C 1 ~C 4 One of an alkyl group, a methoxy group, a trifluoromethyl group, and a fluorine atom; Ar is independently selected from a benzene ring, a substituted aromatic ring and a naphthalene ring, and the substituent of the substituted aromatic ring is selected from a methyl group and a fluorine atom.

2. The cyclophane skeleton-containing planar chiral phosphine oxazole ligand compound according to claim 1, It is characterized in that The cycloarene skeleton planar chiral phosphine oxazole ligand compound is a cycloarene skeleton planar chiral phosphine oxazole ligand compound having a racemic p )-cyclophane skeleton planar chiral phosphine oxazole ligand compound, (S p )-One of the planar chiral phosphine oxazole ligand compounds with a cyclophane skeleton.

3. A method for preparing a type of planar chiral phosphine oxazole ligand compound based on a cyclophane skeleton as claimed in any one of claims 1 to 2, It is characterized in that The preparation method at least comprises: Preparation of the compound shown in formula II: A mixed solution a containing a compound represented by formula III, a compound represented by formula a1, an acid and a solvent W is subjected to a condensation reaction a in an inert atmosphere to obtain a compound represented by formula II; The reaction formula is as follows:

4. The preparation method according to claim 3, It is characterized in that The molar ratio of the compound represented by formula III to the compound represented by formula a1 is 1:1.1 to 1:1.3; The reaction conditions of the condensation reaction a are a temperature of 90 to 110° C. and a reaction time of 24 to 48 hours; The inert atmosphere in the condensation reaction a is selected from at least one of nitrogen and argon; The acid is selected from at least one of methanesulfonic acid, p-toluenesulfonic acid monohydrate, and acetic acid; The solvent W is selected from at least one of methanol, tetrahydrofuran, ether and dioxane; The concentration of the compound represented by formula III in the solvent W is 0.2-1.0 mol / L.

5. The preparation method according to claim 3, It is characterized in that The preparation method at least comprises: Prepared by method 1; The first method is to prepare a mixed solution b containing a compound shown in formula II, a diaryl phosphine, cuprous iodide, N,N-dimethylethylenediamine, cesium carbonate and a solvent X, and to perform a coupling reaction b in an inactive atmosphere to obtain a planar chiral compound shown in formula I; Wherein, the diaryl phosphine is Ar 2 'PH, Ar 2 ' is independently selected from phenyl, C 7 ~C 8 The substituted aryl group is selected from C 1 ~C 4 One of the alkyl, methoxy, trifluoromethyl and fluorine atoms; the reaction formula is as follows:

6. The preparation method according to claim 5, It is characterized in that The molar ratio of the compound represented by formula II to the diaryl phosphine is 1:1.6 to 1:2.0; The molar ratio of the compound represented by formula II to cuprous iodide is 1:0.1 to 1:0.2; The molar ratio of the compound represented by formula II to N,N-dimethylethylenediamine is 1:0.8 to 1:1; The molar ratio of the compound represented by formula II to cesium carbonate is 1:3.5 to 1:4.0; The solvent X is selected from at least one of toluene, p-xylene and m-xylene. The concentration of the compound represented by formula III in solvent X is 0.05-0.5 mol / L. The reaction conditions of the coupling reaction b are a temperature of 100° C. to 110° C. and a reaction time of 5 to 7 hours; the inactive atmosphere in the coupling reaction b is selected from at least one of nitrogen and argon.

7. The preparation method according to claim 3, It is characterized in that The preparation method at least comprises: preparing by method 2; The method 2 includes coupling reaction c and reduction reaction; The coupling reaction c is: a mixed solution c containing a compound shown in formula II, a diaryl phosphine oxide, a palladium catalyst, a bisphosphine ligand, a base and a solvent Y undergoes a coupling reaction c in an inactive atmosphere to obtain a compound shown in formula c2; wherein the diaryl phosphine oxide is Ar 2 ”P(O)H,Ar 2 " is independently selected from phenyl and C 7 ~C 8 The substituted aryl group is selected from C 1 ~C 4 One of alkyl, methoxy, trifluoromethyl and fluorine atoms; the reduction reaction is: a mixed solution c containing the compound represented by formula c2, trichlorosilane, a base and a solvent Z undergoes a reduction reaction in an inactive atmosphere to obtain a planar chiral compound represented by formula I; The reaction formula is as follows:

8. The preparation method according to claim 7, It is characterized in that In the coupling reaction c of the method 2: The molar ratio of the compound represented by formula II to the diaryl phosphine oxide is 1:1.5 to 1:2.0; The molar ratio of the compound represented by formula II to the palladium catalyst is 1:0.05 to 1:0.1; The molar ratio of the compound represented by formula II to the diphosphine ligand is 1:0.05 to 1:0.1; The molar ratio of the compound represented by formula II to the base is 1:2 to 1:4; The reaction conditions of the coupling reaction c are 90-110° C. and 8-12 hours; The inactive atmosphere in the coupling reaction c is selected from at least one of nitrogen and argon; The palladium catalyst is selected from at least one of palladium acetate and palladium trifluoroacetate; The bisphosphine ligand is selected from at least one of 1,4-bis(diphenylphosphino)butane, 1,3-bis(diphenylphosphino)propane, and 1,2-bis(diphenylphosphino)ethane; The base is selected from at least one of N,N-diisopropylethylamine, diisopropylamine and triethylamine; The solvent Y is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide; The concentration of the compound represented by formula II in solvent Y is 0.1 mol / L to 0.3 mol / L; In the reduction reaction of the method 2: The molar ratio of the compound represented by formula c2 to trichlorosilane is 1:5 to 1:10; The molar ratio of the compound represented by formula c2 to the base is 1:5 to 1:10; The reduction reaction is carried out at 100-120°C for 12-24 hours; The inactive atmosphere in the reduction reaction is selected from at least one of nitrogen and argon; The base is selected from at least one of N,N-diisopropylethylamine, diisopropylamine and triethylamine; The solvent Z is selected from at least one of p-xylene, m-xylene and toluene; The concentration of the compound represented by formula c2 in the solvent Z is 0.02 mol / L to 0.2 mol / L.

9. The preparation method according to claim 3, It is characterized in that The preparation method at least comprises: Prepared by method 3; The third method is to carry out a bromine-lithium exchange reaction in an inert atmosphere on a mixed solution d containing a compound shown in formula II, n-butyl lithium, N,N,N,N-tetramethylethylenediamine and a solvent S, and then add a disubstituted chlorophosphine to carry out a substitution reaction d to obtain a planar chiral compound shown in formula I; Wherein, the disubstituted chlorophosphine is R 2 PCl; The reaction formula is as follows:

10. The preparation method according to claim 9, It is characterized in that In the third method: The molar ratio of the compound represented by formula II to n-butyl lithium is 1:1.2 to 1:1.4; The molar ratio of the compound represented by formula II to N,N,N,N-tetramethylethylenediamine is 1:1.2 to 1:1.4; The molar ratio of the compound represented by formula II to the disubstituted chlorophosphine is 1:2 to 1:3; The reaction conditions of the bromine-lithium exchange are a temperature of -90 to -60°C and a reaction time of 2 to 4 hours; The reaction conditions of the substitution reaction d are a temperature of -90 to -60°C for 1 to 2 hours, followed by a temperature rise of 15 to 35°C for 8 to 12 hours; The inactive atmosphere in the lithium bromide exchange and substitution reaction c is selected from at least one of nitrogen and argon; The solvent S is selected from at least one of tetrahydrofuran and diethyl ether; The concentration of the compound represented by formula II in the solvent Z is 0.01 mol / L to 0.1 mol / L.

11. Use of at least one of the planar chiral phosphinothazole ligand compound with a cyclophane skeleton as described in any one of claims 1 to 2 and the planar chiral phosphinothazole ligand compound with a cyclophane skeleton prepared by the preparation method of any one of claims 3 to 10 as a ligand in the enantioselective synthesis of 1,3-disubstituted isoindolines catalyzed by palladium.

12. A method for preparing chiral cis-1,3-disubstituted isoindoline. It is characterized in that A mixture A containing a compound represented by formula IV, a compound represented by formula V, an additive, and a catalyst undergoes an asymmetric boric acid addition reaction, and then a base is added to undergo a Michael addition reaction to obtain a chiral cis-1,3-disubstituted isoindoline represented by formula VI; The reaction formula is as follows: Where: R 1 is selected from phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is independently selected from at least one of methyl, methoxy and nitro; R 2 Selected from methyl or ethyl; Ar 1 is selected from phenyl or substituted phenyl, wherein the substituents of the substituted phenyl are independently selected from at least one of methyl, fluorine and chlorine; Ar 2 is selected from phenyl, naphthyl or substituted phenyl, and the substituent of the substituted phenyl is selected from one of methyl, ethyl, isopropyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, benzyloxy, hydroxyl, dimethylamino and bromine atoms; The catalyst is a chiral nitrogen-phosphorus complex of palladium; The chiral nitrogen-phosphorus complex of palladium is prepared by combining a palladium precursor and a planar chiral nitrogen-phosphorus compound in a solvent J to form the chiral nitrogen-phosphorus complex of palladium; The planar chiral nitrogen-phosphorus compound is at least one of the planar chiral phosphinothiazole ligand compound of the cyclophane skeleton described in any one of claims 1 to 2 and the planar chiral phosphinothiazole ligand compound of the cyclophane skeleton prepared by the preparation method described in any one of claims 3 to 10.

13. The method according to claim 12, It is characterized in that The palladium precursor is selected from palladium acetate or palladium trifluoroacetate; The molar ratio of the palladium precursor to the planar chiral nitrogen-phosphorus compound is 1:1.1 to 1:2; The solvent J is selected from at least one of acetone, dichloromethane and tetrahydrofuran; The molar concentration of the palladium precursor in the solvent J is 0.05-0.2 mol / L; The coordination reaction temperature is 15°C to 35°C and the time is 30 to 90 minutes; The molar ratio of the compound represented by formula IV to the compound represented by formula V is 1:1 to 1:3, the molar ratio of the compound represented by formula IV to the additive is 1:0.05 to 1:0.1, and the molar ratio of the compound represented by formula IV to the chiral nitrogen-phosphorus complex of palladium is 1:0.02 to 1:0.1; The additive is selected from metal Lewis acids; preferably, the additive is selected from silver acetate, silver nitrate and copper acetate; The base is selected from an inorganic base; preferably, the additive is selected from cesium carbonate, potassium carbonate or potassium phosphate; The mixture A contains a solvent T, and the solvent T is selected from at least one of trifluoroethanol, hexafluoroisopropanol, methanol, and ethanol; The concentration of the compound represented by formula IV in the solvent T is 0.02 mol / L to 0.2 mol / L; The temperature of the asymmetric boric acid addition reaction is 30°C to 60°C, and the temperature of the Michael addition reaction is 30°C to 60°C; The time of the asymmetric boronic acid addition reaction is 1 hour to 5 hours, and the time of the Michael addition reaction is 8 hours to 12 hours; Preferably, the chiral cis-1,3-disubstituted isoindoline is selected from any one of the structures shown in 6aa, 6ba, 6ca, 6da, 6ea, 6fa, 6ga, 6ha, 6ab, 6ac, 6ad, 6ae, 6af, 6ag, 6ah, 6ai, 6aj, 6ak, 6al, 6am, 6an, 6ao, 6ap, and 6aq;

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