WO2020238559A1 - 一种去c2-对称性二苯胺型手性双噁唑啉配体及其合成方法与应用 - Google Patents

一种去c2-对称性二苯胺型手性双噁唑啉配体及其合成方法与应用 Download PDF

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WO2020238559A1
WO2020238559A1 PCT/CN2020/088254 CN2020088254W WO2020238559A1 WO 2020238559 A1 WO2020238559 A1 WO 2020238559A1 CN 2020088254 W CN2020088254 W CN 2020088254W WO 2020238559 A1 WO2020238559 A1 WO 2020238559A1
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formula
reaction
chloride
solution
copper
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PCT/CN2020/088254
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French (fr)
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许丹倩
王益锋
王彪
徐振元
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浙江工业大学
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Definitions

  • the invention relates to a diphenylamine type chiral bisoxazoline ligand with de-C 2 -symmetry, and a synthesis method and application thereof.
  • the present invention provides a diphenylamine type chiral bisoxazoline ligand with no C 2 -symmetry.
  • This kind of ligand realizes the ligand by introducing different groups on the diphenylamine skeleton and removing the C 2 -symmetry
  • the precise control of the "electronic effect" of the skeleton, the C 2 -symmetry diphenylamine chiral bisoxazoline ligand is more excellent than the C 2 -symmetric diphenylamine chiral bisoxazoline ligand
  • the three-dimensional control capability and a wider range of applications have important practical application value.
  • One of the objectives of the present invention is to provide a C 2 -symmetric diphenylamine type chiral bisoxazoline ligand.
  • the present invention provides a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand represented by formula 3:
  • R 1 and R 2 are each independently hydrogen, C 1 ⁇ 4 alkyl, phenyl, benzyl, 1-naphthyl, 2-naphthyl, substituted phenyl, or R 1 ⁇ R 2 are both 2,3-di hydrogen indenyl; H of the phenyl is substituted on the phenyl ring by C 1 ⁇ 4 alkyl, halo, trifluoromethyl, mono- or di-substituted;
  • R 3 and R 4 are each independently hydrogen, C 1 ⁇ 4 alkyl, C 1 ⁇ 4 alkoxy, halogen, trifluoromethyl, nitro, sulfonic acid, hydroxyl, amino or N,N-bis(C 1 to 4 ) Alkylamino.
  • the second objective of the present invention is to provide a method for synthesizing the diphenylamine type chiral bisoxazoline ligand.
  • reaction formulas of the pathway (1) and pathway (2) are as follows:
  • organic solvent A at a temperature of 80-200°C, use the anthranilic acid derivatives of formula I and the orthochlorobenzoic acid derivatives of formula II as raw materials, and then add Carbonate, copper and cuprous iodide are subjected to coupling reaction for 1-24 hours, and the reaction solution A is obtained after cooling and filtering.
  • the compound shown; the ratio of the amount of the anthranilic acid derivatives represented by formula I and the orthochlorobenzoic acid derivatives represented by formula II and the amount of carbonate, copper and cuprous iodide is 1: 1: 1-2: 0.01-0.5: 0.01-0.5;
  • step (2) Mix the compound of formula 1 obtained in step (1) with thionyl chloride, heat to reflux for 4 hours, distill off excess SOCl 2 to obtain diacid chloride, and add the diacid chloride to organic solvent B to obtain diacid chloride.
  • Acid chloride solution add chiral amino alcohol and basic substance A to organic solvent B to obtain a mixed solution, add diacid chloride solution dropwise to the mixed solution at -20-20°C, return to room temperature, and react for 1-24 hours ,
  • the obtained reaction solution B was quenched with aqueous ammonium chloride solution, extracted three times with water, saturated NaHCO 3 solution, and saturated brine.
  • step (3) Mix the ⁇ -bishydroxyamide shown in formula 2 obtained in step (2), methanesulfonyl chloride, and basic substance B in an organic solvent C at a temperature of 0-30°C, and react 1-24 After hours, the reaction solution C was evaporated to remove the solvent to obtain a crude product, and further column chromatography was separated to obtain the C 2 -symmetry diphenylamine type chiral bisoxazoline ligand shown in formula 3; ⁇ shown in formula 2 -The ratio of the amount of bishydroxy amide to methylsulfonyl chloride and basic substance B is 1:2-3:1-6.
  • the carbonate is sodium carbonate, potassium carbonate or cesium carbonate.
  • the organic solvent A is N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, toluene, chlorine Benzene, tetrahydrofuran, chloroform, carbon tetrachloride, dichloromethane, 1,4-dioxane or pyridine;
  • the added amount of the organic solvent A is the substance of the anthranilic acid derivative represented by formula I The amount is 1-20mL/mmol.
  • the organic solvent B is toluene, xylene, chlorobenzene, tetrahydrofuran, chloroform, carbon tetrachloride, methylene chloride, 1,4-dioxane or pyridine;
  • the amount of organic solvent B added is 1-10 mL/mmol based on the amount of the compound represented by Formula 1.
  • the basic substance A or the basic substance B is each independently triethylamine, tripropylamine, tributylamine, N,N-diisopropylmethylamine, N , N-Diisopropylethylamine, tetramethyldiethylamine, sodium carbonate or potassium carbonate.
  • the organic solvent C is toluene, xylene, chlorobenzene, tetrahydrofuran, chloroform, carbon tetrachloride or dichloromethane; the addition amount of the organic solvent C is the ⁇ -bishydroxyamide shown in formula 2. The amount of the substance is 1-10mL/mmol.
  • step (2') is different from step (2) in the route (1), the other steps are the same as the route one.
  • the organic phase is Water sodium sulfate is dried, desolventized, separated by column chromatography, eluted with a mixture of PE/EA with a volume ratio of 2 to 5:1 as the eluent, and collected the eluent containing the target product and evaporated the solvent to obtain
  • the amount of salt and 1-hydroxybenzotriazole is 1:2-3:2-3:2-3.
  • the organic solvent D is toluene, xylene, chlorobenzene, tetrahydrofuran, chloroform, carbon tetrachloride or dichloromethane; the addition amount of the organic solvent D is the same as that of the compound represented by formula 1.
  • the amount of substance is 1-10 ml/mmol.
  • the method for synthesizing the C 2 -symmetric diphenylamine-type chiral bisoxazoline ligand provided by the present invention is not limited to this. Regardless of whether the substituent is introduced unilaterally or different substituents are introduced bilaterally on the diphenylamine skeleton, or C 2- Based on the symmetric diphenylamine skeleton, the C 2 -symmetry diphenylamine-type chiral bisoxazoline ligands with different groups introduced on the oxazole ring are all within the scope of the present invention.
  • the third object of the present invention is to provide a diphenylamine-type chiral bisoxazoline ligand without C 2 -symmetry coordinated with copper, zinc, nickel, iron or rhodium salts Catalyst.
  • the copper salt is: copper chloride, copper sulfate, copper bromide, copper acetate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper acetylacetonate or copper perchlorate;
  • the zinc salt is Zinc chloride, zinc sulfate, zinc bromide, zinc acetate, zinc trifluoroacetate, zinc trifluoromethanesulfonate, zinc acetylacetonate or zinc perchlorate;
  • the nickel salt is nickel chloride, nickel sulfate, bromide Nickel, nickel acetate, nickel trifluoromethanesulfonate, nickel trifluoroacetate, nickel acetylacetonate or nickel perchlorate;
  • the iron salt is ferrous chloride, ferrous sulfate, ferrous bromide, ferrous acetate, Ferrous trifluoroacetate, ferrous trifluoromethanesulfonate, ferrous acetylacet
  • the catalyst is applied to asymmetric catalytic reactions.
  • the asymmetric catalytic reaction is the asymmetric chlorination, bromination and dearomatization of ⁇ -naphthol derivatives, and the asymmetric fluorination, chlorination, bromination, and bromination of 1,3-dicarbonyl compounds.
  • the limitation of the present invention includes common asymmetric reactions catalyzed by chiral bisoxazoline metal complexes.
  • the present invention has the following beneficial effects:
  • the present invention provides a kind of novel ligands, the synthesis method of this kind of ligands is simple, the conditions are mild, and it is suitable for industrial application.
  • This type of ligand introduces different groups on the diphenylamine skeleton, which can realize the adjustment and control of the "electronic effect" of the ligand skeleton to adapt to the specific electronic effects of different types of catalytic reactions when the ligand is applied to different catalytic reactions. Requirements, so as to achieve the purpose of improving the enantioselectivity of asymmetric catalytic.
  • Using the chiral complex formed by the ligand and the metal salt of the present invention as a catalyst has superior enantioselectivity and a wider range of applications in asymmetric catalytic reactions, and has important application value.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-methoxy-2-((R)-4-phenyl-4,5-dihydro of the present invention -Oxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-fluoro-2-((R)-4-phenyl-4,5-dihydro-oxazol Azol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • reaction was quenched with ammonium chloride solution, extracted three times with water, saturated sodium bicarbonate solution and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the short column filtration was used directly for the next reaction.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-bromo-2-((R)-4-phenyl-4,5-dihydro-oxaline of the present invention Azol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • reaction was quenched with ammonium chloride solution, extracted three times with water, saturated sodium bicarbonate solution and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the short column filtration was used directly for the next reaction.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-trifluoromethyl-2-((R)-4-phenyl-4,5-di Hydro-oxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • reaction was quenched with ammonium chloride solution, extracted three times with water, saturated sodium bicarbonate solution and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the short column filtration was used directly for the next reaction.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-nitro-2-((R)-4-phenyl-4,5-dihydro- Oxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-amino-2-((R)-4-phenyl-4,5-dihydro-oxaline of the present invention Azol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • reaction was quenched with ammonium chloride solution, extracted three times with water, saturated sodium bicarbonate solution and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the short column filtration was used directly for the next reaction.
  • the product of the reaction is the C 2 -symmetric diphenylamine-type chiral bisoxazoline ligand 4-bromo-2-((4R,5R)-4-phenyl-4,5-dihydro of the present invention -Oxazol-2-yl)-N-(2-((4R,5R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • reaction was quenched with ammonium chloride solution, extracted three times with water, saturated sodium bicarbonate solution and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the short column filtration was used directly for the next reaction.
  • the product of the reaction is the C 2 -symmetric diphenylamine-type chiral bisoxazoline ligand 5-nitro-2-((R)-4-phenyl-4,5-dihydro- Oxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • reaction was quenched with ammonium chloride solution, extracted three times with water, saturated sodium bicarbonate solution and saturated brine respectively, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the short column filtration was used directly for the next reaction.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 2-nitro-2-((R)-4-phenyl-4,5-dihydro- Oxazol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand of the present invention, 3-fluoro-2-((R)-4-phenyl-4,5-dihydro-oxaline Azol-2-yl)-N-(2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)phenyl)aniline.
  • the product of the reaction is the C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-methyl-N-(4-nitro-2-((R)-4-phenyl) of the present invention -4,5-Dihydro-oxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)aniline.
  • the product of the reaction is the C 2 -symmetric diphenylamine-type chiral bisoxazoline ligand 4-methoxy-N-(4-nitro-2-((R)-4-benzene) of the present invention Yl-4,5-dihydro-oxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)aniline.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-fluoro-N-(4-nitro-2-((R)-4-phenyl- 4,5-Dihydro-oxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)aniline.
  • the product of the reaction is a de-C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-bromo-N-(4-nitro-2-((R)-4-phenyl- 4,5-Dihydro-oxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)aniline.
  • the reaction solution was slowly added dropwise to ice water, extracted with dichloromethane three times, and the organic phases were combined, dried with anhydrous sodium sulfate, and dissolved.
  • the product of the reaction is a C 2 -symmetric diphenylamine type chiral bisoxazoline ligand 4-hydroxy-N-(4-nitro-2-((R)-4-phenyl- 4,5-Dihydro-oxazol-2-yl)phenyl)-2-((R)-4-phenyl-4,5-dihydro-oxazol-2-yl)aniline.
  • reaction formula is:
  • reaction formula is:
  • reaction formula is:
  • reaction formula is:
  • the chiral complex formed by 0.01 mmol of oxazoline ligand 3-d and copper trifluoroacetate was used as a chiral catalyst, 1-oxo-2,3-indanone-2-carboxylic acid methyl ester (1 mmol ), N-fluorobisbenzenesulfonamide (1.2mmol), add it to a 10mL test tube, and then add 4mL of dichloromethane to dissolve it. After the dosing is completed, the reaction is stirred at room temperature for 8h. The reaction solution is concentrated under reduced pressure and separated on a silica gel column.
  • reaction formula is:
  • reaction formula is:

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Abstract

本发明公开了一种如式3所示的去C2-对称性的二苯胺型手性双噁唑啉配体、合成方法及其在不对称催化反应中的应用。所述的配体通过在二苯胺骨架上引入不同的基团去除其C2-对称性，实现配体骨架"电子效应"的精确调控。该类配体通过邻氨基苯甲酸类衍生物和邻氯苯甲酸类衍生物为起始原料制得式1所示的化合物，然后与式4所示的手性氨基醇化合物反应得到式2所示的化合物β-双羟基酰胺，接着β-双羟基酰胺缩合制得式3所示的化合物去C2-对称性的二苯胺型手性双噁唑啉配体。本发明同时还提供了利用该去C2-对称性二苯胺型手性双噁唑啉配体与与铜盐、锌盐、镍盐、铁盐或铑盐配位形成的催化剂在不对称催化反应中的应用。

Description

一种去C 2-对称性二苯胺型手性双噁唑啉配体及其合成方法与应用 技术领域
本发明涉及一种具有去C 2-对称性二苯胺型手性双噁唑啉配体及其合成方法与应用。
背景技术
金属络合物作为最为普遍的化学催化剂，因其高效的催化效能和优异的手性诱导能力受到广泛关注，其中手性配体作为手性源发挥了至关重要的作用。90年代初，Nishiyama等人首次报道了第一个手性双噁唑啉配体Pybox并将其应用于简单酮类的不对称硅氢化反应，获得了优异的结果(Organometallics,1991,10:2706-2708)。至此，相继发展了各种不同骨架结构的手性双噁唑啉配体。自从Guiry课题组2002年首次将二苯胺骨架引入双噁唑啉配体中(Tetrahedron Letters,1995,36:8745-8748)以来，该类配体亦被广泛应用于多种不对称反应。2015年，Rovis课题组报道了一种二苯胺骨架上修饰的具C 2-对称性的二苯胺型手性双噁唑啉配体，并将其应用于催化1-氮杂二烯与硝基烯烃不对称[4+2]环加成反应来合成哌啶类衍生物，取得了很好的对映选择性(Journal of the American Chemical Society,2015,137:4445-4452)。但是现有的该类手性配体骨架电子效应单一，在应用于不对称催化反应时，对反应的对映选择性还有进一步提高的空间，对催化的反应类型也有待进一步拓展。
发明内容
本发明提供一种去C 2-对称性的二苯胺型手性双噁唑啉配体，该类配体通过在二苯胺骨架上引入不同的基团，去除其C 2-对称性实现配体骨架“电子效应”的精确调控，这种去C 2-对称性的二苯胺型手性双噁唑啉配体比C 2-对称的二苯胺型手性双噁唑啉配体具有更优异的立体控制能力及更广的应用范围，具有重要的实际应用价值。
本发明的目的之一就是提供一种去C 2-对称性二苯胺型手性双噁唑啉配体。
本发明提供了一种式3所示的去C 2-对称性二苯胺型手性双噁唑啉配体：
Figure PCTCN2020088254-appb-000001
其中，
R 1、R 2各自独立为氢、C 1～ 4的烷基、苯基、苄基、1-萘基、2-萘基、取代苯基或R 1～R 2同时为2,3-二氢茚基；所述的取代苯基为苯环上的H被C 1～ 4烷基、 卤素、三氟甲基单取代或二取代；
R 3、R 4各自独立为氢、C 1～ 4烷基、C 1～ 4烷氧基、卤素、三氟甲基、硝基、磺酸基、羟基、氨基或N，N-二(C 1～ 4)烷基氨基。
本发明的目的之二就是提供该种二苯胺型手性双噁唑啉配体的合成方法。
本发明所述的式3所示的去C 2-对称性二苯胺型手性双噁唑啉配体的合成方法是由以下两种途径合成：
途径(一)：以式Ⅰ所示的邻氨基苯甲酸类衍生物和式Ⅱ所示的邻氯苯甲酸类衍生物通过偶联反应制得式1所示的化合物，然后将式1所示的化合物经酰氯化，再与式4所示的手性氨基醇化合物反应制得式2所示的β-双羟基酰胺化合物，所述的式2所示的化合物进一步环合得到去C 2-对称性二苯胺型手性双噁唑啉配体。
途径(二)与途径(一)所述方法的不同在于式2所示的β-双羟基酰胺化合物的合成方法不同，其为式1所示的化合物在1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI·HCl)和1-羟基苯并三唑(HOBt)的存在下制得式2所示的化合物β-双羟基酰胺。
所述的途径(一)和途径(二)的反应式如下：
Figure PCTCN2020088254-appb-000002
具体的制备步骤是：
途径(一)：
(1)在有机溶剂A中，在80～200℃的温度条件下，以式Ⅰ所示的邻氨基苯甲酸类衍生物和式Ⅱ所示的邻氯苯甲酸类衍生物为原料，然后加入碳酸盐、铜和碘化亚铜，进行偶联反应1-24小时，得到反应液A冷却后过滤，向滤液中加入稀盐酸至溶液呈pH＝1～4，搅拌、过滤得到式1所示的化合物；所述的式Ⅰ所示的邻氨基苯甲酸类衍生物和式Ⅱ所示的邻氯苯甲酸类衍生物以及碳酸盐、铜和碘化亚铜的物质的量之比为1：1：1-2：0.01-0.5：0.01-0.5；
(2)将步骤(1)所得式1所示的化合物与氯化亚砜混合，加热回流4小时，蒸除多余的SOCl 2得到二酰氯，将所述的二酰氯加入有机溶剂B中得到二酰氯溶液，将手性氨基醇和碱性物质A加入有机溶剂B得到混合液，在-20-20℃下，向所述的混合液中滴加二酰氯溶液，恢复至室温，反应1-24小时，得到反应液B用氯化铵水溶液淬灭，用水、饱和NaHCO 3溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥、脱溶，通过柱层析分离(PE/EA＝5:1～2:1)，得到式2所示的中间体β-双羟基酰胺；所述的式1所示的化合物与氯化亚砜的物质的量之为1：5-10；所述的二酰氯与氨基醇、碱的物质的量之为1：2-3：1-6，所述的二酰氯的物质的量以式1所示的化合物的物质的量来计；
(3)在有机溶剂C中，0-30℃的温度条件下，将步骤(2)所得式2所示的β-双羟基酰胺、甲基磺酰氯及碱性物质B混合，反应1-24小时，反应液C经蒸除溶剂得粗品，进一步柱层析分离得到式3所示的去C 2-对称性的二苯胺型手性双噁唑啉配体；所述式2所示的β-双羟基酰胺与甲基磺酰氯、碱性物质B的物质的量之比为1：2-3：1-6。
进一步，步骤(1)中，所述的碳酸盐为碳酸钠、碳酸钾或碳酸铯。
进一步，步骤(1)中，所述的有机溶剂A为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲苯、氯苯、四氢呋喃、氯仿、四氯化碳、二氯甲烷、1,4-二氧六环或吡啶；所述的有机溶剂A的加入量以式Ⅰ所示的邻氨基苯甲酸类衍生物的物质的量计为1-20mL/mmol。
进一步，步骤(2)中，所述的有机溶剂B为甲苯、二甲苯、氯苯、四氢呋喃、氯仿、四氯化碳、二氯甲烷、1,4-二氧六环或吡啶；所述的有机溶剂B的加入量以式1所示的化合物的物质的量计为1-10mL/mmol。
进一步，步骤(2)或(3)中，所述的碱性物质A或碱性物质B各自独立为三乙胺、三丙胺、三丁胺、N,N-二异丙基甲胺、N,N-二异丙基乙胺、四甲基二乙胺、碳酸钠或碳酸钾。
进一步，所述的有机溶剂C为甲苯、二甲苯、氯苯、四氢呋喃、氯仿、四氯化碳或二氯甲烷；所述的有机溶剂C的加入量以式2所示的β-双羟基酰胺的物质的量计为1-10mL/mmol。
途径(二)：
除步骤(2′)与所述的途径(一)中的步骤(2)不同以外，其余步骤与路线一均相同。
(2′)在室温条件下，将手性氨基醇、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑溶于有机溶剂D中，然后加入步骤(1)所得式1所示的化合物，在室温条件下反应1-24小时，得到反应液D用氯化铵水溶液淬灭，用水洗涤反应液、萃取，有机相用无水硫酸钠干燥、脱溶，通过柱层析分离，以 体积比为2～5:1的PE/EA的混合液为洗脱剂进行洗脱，收集含目标产物的洗脱液蒸除溶剂得到式2所示的中间体β-双羟基酰胺；所述的式1所示的化合物、手性氨基醇、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与1-羟基苯并三唑的物质的量之为1：2-3：2-3：2-3。
进一步，所述的有机溶剂D为甲苯、二甲苯、氯苯、四氢呋喃、氯仿、四氯化碳或二氯甲烷；所述的有机溶剂D的加入量以所述的式1所示的化合物的物质的量计为1-10ml/mmol。
本发明提供的去C 2-对称性二苯胺型手性双噁唑啉配体的合成方法不限于此，二苯胺骨架上不论单边引入取代基或双边引入不同取代基或以去C 2-对称性二苯胺骨架为基础，噁唑环上引入不同基团的去C 2-对称性二苯胺型手性双噁唑啉配体均在本发明的限制范围内。
本发明的目的之三在于提供一种由所述的去C 2-对称性的二苯胺型手性双噁唑啉配体与铜盐、锌盐、镍盐、铁盐或铑盐配位形成的催化剂。
进一步，所述的铜盐为：氯化铜、硫酸铜、溴化铜、醋酸铜、三氟乙酸铜、三氟甲磺酸铜、乙酰丙酮铜或高氯酸铜；所述的锌盐为氯化锌、硫酸锌、溴化锌、醋酸锌、三氟乙酸锌、三氟甲磺酸锌、乙酰丙酮锌或高氯酸锌；所述的镍盐为氯化镍、硫酸镍、溴化镍、醋酸镍、三氟甲磺酸镍、三氟乙酸镍、乙酰丙酮镍或高氯酸镍；所述的铁盐为氯化亚铁、硫酸亚铁、溴化亚铁、醋酸亚铁、三氟乙酸亚铁、三氟甲磺酸亚铁、乙酰丙酮亚铁或高氯酸亚铁；所述的铑盐为氯化铑、三氟乙酸铑、氯化羰基铑、双(三苯基膦)合氯化羰基铑、三(三苯基膦)羰基氢化铑或三苯基膦氯化铑。
再进一步，所述的催化剂应用于不对称催化反应中。
更进一步，所述的不对称催化反应为β-萘酚衍生物的不对称氯化，溴化去芳构化反应，1，3-二羰基化合物的不对称氟化、氯化、溴化、氧化、硫氰基化或三氟甲硫基化官能团化反应，1，3-二羰基化合物的不对称Michael加成反应或吲哚与硝基烯烃的不对称傅克反应。
本发明的限制范围包括常见的基于手性双噁唑啉金属络合物催化的不对称反应。
与现有技术相比，本发明的有益效果在于：
本发明提供了一类新颖的配体，该类配体的合成方法简便、条件温和、适用于工业化应用。该类配体通过在二苯胺骨架上引入不同的基团，从而可以实现配体骨架“电子效应”的调节控制，以适应配体在应用于不同催化反应时，不同催化反应类型特有的电子效应要求，从而达到提高不对称催化对映选择性的目的。
以本发明所述的配体物与金属盐形成的手性络合物为催化剂，在不对称催化反应中具有更优越的对映选择性和更广泛的用途，具有重要的应用价值。
具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此。
实施例1：
Figure PCTCN2020088254-appb-000003
将5.48g邻氨基苯甲酸、7.44g 2-氯-5-甲氧基苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-5-甲氧基苯甲酸。
将1.35g(R)-(-)-2-苯基甘氨醇、2.20g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1.55g 1-羟基苯并三唑溶于THF中，然后加入1.44g 2-((2-羧基苯基)氨基)-5-甲氧基苯甲酸。在室温条件下反应12小时。用氯化铵溶液淬灭反应、减压脱溶、加入乙酸乙酯溶解、用水洗涤、萃取三次，有机相用硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体1.96g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-甲氧基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-a:[α]D 20＝-261(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,CDCl 3)δ10.78(s,1H),7.91–7.86(m,1H),7.50(d,J＝9.0Hz,1H),7.42(d,J＝3.1Hz,1H),7.31–7.20(m,11H),7.13(dd,J＝7.3,2.0Hz,2H),7.01(dd,J＝9.0,3.1Hz,1H),6.84(ddd,J＝8.1,5.5,2.8Hz,1H),5.26(dd,J＝9.9,8.1Hz,1H),5.17(dd,J＝10.0,8.3Hz,1H),4.55(dd,J＝10.0,8.3Hz,1H),4.45(dd,J＝10.1,8.4Hz,1H),4.07(t,J＝8.1Hz,1H),3.94(t,J＝8.3Hz,1H),3.85(s,3H)； 13C NMR(126MHz,CDCl 3)δ164.35,164.14,145.36,142.39,131.83,130.39,128.51,127.29,126.66,123.35,118.75,117.85,115.13,114.09,112.60,74.22,73.32,70.10,69.89,55.74；熔点：70-72℃；高分辨C 31H 27N 3O 3Na([M+Na] +),计算值:512.1945；实测值:512.1939.
实施例2：
Figure PCTCN2020088254-appb-000004
将5.48g邻氨基苯甲酸、6.98g 2-氯-5-氟苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-5-氟苯甲酸。
将1.35g(R)-(-)-2-苯基甘氨醇、2.20g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1.55g 1-羟基苯并三唑溶于THF中，然后加入1.10g 2-((2-羧基苯基)氨基)-5-氟苯甲酸。在室温条件下反应12小时。用氯化铵溶液淬灭反应、减压脱溶、加入乙酸乙酯溶解、用水洗涤、萃取三次，有机相用硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体1.55g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-氟-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-b:[α]D 20＝-260(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,CDCl 3)δ10.93(s,1H),7.87(dd,J＝7.9,1.4Hz,1H),7.53(ddd,J＝33.1,9.2,3.9Hz,2H),7.42–7.00(m,13H),6.89(t,J＝7.5Hz,1H),5.16(q,J＝10.3Hz,2H),4.47(ddd,J＝13.3,10.0,8.4Hz,2H),4.04–3.93(m,2H)； 13C NMR(126MHz,CDCl 3)δ142.53,131.68,128.50,128.48,127.29,126.59,126.57,119.28,118.49,116.67,116.65,73.98,73.54,70.00； 19F NMR(376MHZ,CDCl 3)δ-122.66；熔点：55-58℃；高分辨C 30H 24FN 3O 2Na([M+Na] +),计算值:500.1745；实测值:500.1742.
实施例3：
Figure PCTCN2020088254-appb-000005
将5.48g邻氨基苯甲酸、9.42g 2-氯-5-溴苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-5-溴苯甲酸。
将1.68g 2-((2-羧基苯基)氨基)-5-溴苯甲酸和10mL SOCl 2加入圆底烧 瓶中，加热回流4小时，旋蒸除去多余的SOCl 2，将脱溶所得的二酰氯加入到二氯甲烷中。在冰浴条件下，将二酰氯的二氯甲烷溶液滴加入含1.35g(R)-(-)-2-苯基甘氨醇、3.8mL三乙胺的二氯甲烷溶液中。待滴加完毕后，在室温下搅拌20小时。用氯化铵溶液淬灭反应，用水、饱和碳酸氢钠溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体2.15g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-溴-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-c:[α]D 20＝-223(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ11.13(s,1H),8.04–7.99(m,1H),7.90(dd,J＝7.8,1.5Hz,1H),7.52(dd,J＝8.4,1.1Hz,1H),7.41(d,J＝2.0Hz,2H),7.28–7.23(m,8H),7.16–7.14(m,4H),7.01–6.97(m,1H),5.18(ddd,J＝10.5,8.2,2.8Hz,2H),4.50(dd,J＝9.9,8.5Hz,2H),4.01(dt,J＝10.0,8.2Hz,2H). 13C NMR(126MHz,Chloroform-d)δ163.00,142.46,142.40,134.27,132.95,131.59,130.71,128.56,128.53,127.40,127.35,126.62,120.66,119.14,118.72,116.73,111.08,73.79,70.10；熔点：75-78℃,高分辨C 30H 24BrN 3O 2Na([M+Na] +),计算值:538.1125；实测值:538.1126.
实施例4：
Figure PCTCN2020088254-appb-000006
将5.48g邻氨基苯甲酸、8.98g 2-氯-5-溴苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-5-三氟甲基苯甲酸。
将1.63g 2-((2-羧基苯基)氨基)-5-三氟甲基苯甲酸和10mL SOCl 2加入圆底烧瓶中，加热回流4小时，旋蒸除去多余的SOCl 2，将脱溶所得的二酰氯加入到二氯甲烷中。在冰浴条件下，将二酰氯的二氯甲烷溶液滴加入含1.35g(R)-(-)-2-苯基甘氨醇、3.8mL三乙胺的二氯甲烷溶液中。待滴加完毕后，在室温下搅拌20小时。用氯化铵溶液淬灭反应，用水、饱和碳酸氢钠溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵 溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到淡黄色固体2.29g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-三氟甲基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-d:[α]D 20＝-259(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,CDCl 3)δ11.42(s,1H),8.18(s,1H),7.93(dd,J＝7.8,1.6Hz,1H),7.60(d,J＝8.3Hz,1H),7.52(d,J＝1.9Hz,2H),7.43(td,J＝8.4,7.9,1.6Hz,1H),7.31–7.17(m,9H),7.15–7.09(m,3H),5.20(ddd,J＝25.4,10.0,8.3Hz,2H),4.52(ddd,J＝39.1,10.1,8.3Hz,2H),4.10(t,J＝8.2Hz,1H),3.98(t,J＝8.3Hz,1H)； 13C NMR(126MHz,CDCl 3)δ163.77,163.21,146.99,142.35,142.21,140.92,131.48,130.83,128.60,128.51,128.37,128.35,128.03,128.00,127.47,127.36,126.61,126.58,122.36,121.13,118.94,115.43,112.78,74.08,73.57,70.23,69.98； 19F NMR(376MHZ,CDCl 3)δ-61.64；熔点：66-68℃,高分辨C 31H 24F 3N 3O 2Na([M+Na] +),计算值:550.1713；实测值:550.1712.
实施例5：
Figure PCTCN2020088254-appb-000007
将5.48g邻氨基苯甲酸、8.06g 2-氯-5-硝基苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-5-硝基苯甲酸。
将1.51g 2-((2-羧基苯基)氨基)-5-硝基苯甲酸和10mL SOCl 2加入圆底烧瓶中，加热回流4小时，旋蒸除去多余的SOCl 2，将脱溶所得的二酰氯加入到二氯甲烷中。在冰浴条件下，将二酰氯的二氯甲烷溶液滴加入含1.35g(R)-(-)-2-苯基甘氨醇、3.8mL三乙胺的二氯甲烷溶液中。待滴加完毕后，在室温下搅拌20小时。用氯化铵溶液淬灭反应，用水、饱和碳酸氢钠溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体2.32g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-e:[α]D 20＝-139(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,CDCl 3)δ11.80(s,1H),8.83(d,J＝2.8Hz,1H),8.14(dd,J＝9.4,2.8Hz,1H),7.96(dd,J＝7.8,1.5Hz,1H), 7.61–7.55(m,1H),7.50(td,J＝8.2,7.8,1.6Hz,1H),7.32(d,J＝9.4Hz,1H),7.28–7.25(m,8H),7.20(dd,J＝7.6,1.7Hz,2H),7.10(dd,J＝6.5,3.0Hz,2H),5.19(ddd,J＝27.0,10.0,8.3Hz,2H),4.60(dd,J＝10.1,8.4Hz,1H),4.48(dd,J＝10.2,8.4Hz,1H),4.17(t,J＝8.3Hz,1H),3.97(t,J＝8.3Hz,1H)； 13C NMR(126MHz,CDCl 3)δ162.75,144.95,141.89,141.07,131.94,131.62,130.91,128.65,128.54,127.56,127.40,126.58,122.26,119.76；熔点：153-156℃,高分辨C 30H 24N 4O 4Na([M+Na] +),计算值:527.1690；实测值:527.1691.
实施例6：
Figure PCTCN2020088254-appb-000008
将0.18g 10％Pd/C、0.50g 4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺和无水乙醇加入反应釜中，用N 2置换釜内空气三次，然后用H 2置换釜内N 2三次，充入H 2(2.5MPa)开始反应，直至反应结束。取出反应液、用硅藻土过滤、脱溶。柱层析分离(PE/EA＝20:1～10:1)，得到黄色产物0.39g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-氨基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-f:[α]D 20＝-233(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ10.60(s,1H),7.86(dd,J＝7.9,1.5Hz,1H),7.37(d,J＝8.6Hz,1H),7.28(s,7H),7.26(d,J＝2.9Hz,2H),7.24(d,J＝3.0Hz,3H),7.23(s,1H),7.19(d,J＝8.5Hz,1H),7.10(dd,J＝7.3,1.9Hz,2H),6.83–6.75(m,2H),5.29(dd,J＝9.9,8.0Hz,1H),5.13(dd,J＝9.9,8.4Hz,1H),4.57(dd,J＝10.0,8.3Hz,1H),4.41(dd,J＝10.1,8.4Hz,1H),4.09(t,J＝8.1Hz,1H),3.90(t,J＝8.3Hz,1H). 13C NMR(126MHz,Chloroform-d)δ163.28,162.82,150.61,146.29,142.82,142.24,141.48,131.94,130.31,128.54,128.51,127.33,127.30,126.70,124.65,119.80,118.93,117.71,114.42,110.56,73.22,70.14；熔点：85-89℃,高分辨C 30H 26N 4O 2Na([M+Na] +),计算值:475.2129；实测值:475.2128.
实施例7：
Figure PCTCN2020088254-appb-000009
将5.48g邻氨基苯甲酸、9.42g 2-氯-5-溴苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3 小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-5-溴苯甲酸。
将1.68g 2-((2-羧基苯基)氨基)-5-溴苯甲酸和10mL SOCl 2加入圆底烧瓶中，加热回流4小时，旋蒸除去多余的SOCl 2，将脱溶所得的二酰氯加入到二氯甲烷中。在冰浴条件下，将二酰氯的二氯甲烷溶液滴加入含2.13g(1R,2S)-2-氨基-1,2-二苯基乙醇、3.8mL三乙胺的二氯甲烷溶液中。待滴加完毕后，在室温下搅拌20小时。用氯化铵溶液淬灭反应，用水、饱和碳酸氢钠溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体2.15g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-溴-2-((4R，5R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((4R，5R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-g:[α]D 20＝-73(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,CDCl 3)δ11.34(s,1H),8.09(dd,J＝1.8,0.8Hz,1H),8.01(d,J＝7.4Hz,1H),7.59(d,J＝8.4Hz,1H),7.47(d,J＝1.8Hz,2H),7.45–7.41(m,1H),7.33(td,J＝4.6,1.4Hz,6H),7.18(qd,J＝6.8,3.0Hz,11H),7.05(ddd,J＝7.7,5.4,1.8Hz,5H),5.14–5.11(m,2H),4.94(dd,J＝12.9,7.7Hz,2H). 13C NMR(126MHz,Chloroform-d)δ162.19,143.05,140.30,132.96,131.79,130.89,128.79,128.76,128.57,128.38,128.30,127.40,126.41,126.38,125.87,125.77,119.37,119.28,111.10,88.00,78.71；熔点：86-89℃,高分辨C 42H 32BrN 3O 2Na([M+Na] +),计算值:690.1750；实测值:690.1749.
实施例8：
Figure PCTCN2020088254-appb-000010
将5.48g邻氨基苯甲酸、8.06g 2-氯-4-硝基苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-4-硝基苯甲酸。
将1.51g 2-((2-羧基苯基)氨基)-4-硝基苯甲酸和10mL SOCl 2加入圆底烧瓶中，加热回流4小时，旋蒸除去多余的SOCl 2，将脱溶所得的二酰氯加入到二氯甲烷中。在冰浴条件下，将二酰氯的二氯甲烷溶液滴加入含1.35g(R)-(-)-2-苯基甘氨醇、3.8mL三乙胺的二氯甲烷溶液中。待滴加完毕后，在室温下搅拌20 小时。用氯化铵溶液淬灭反应，用水、饱和碳酸氢钠溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到橙色固体2.07g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体5-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-h:[α]D 20＝-358(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,CDCl 3)δ11.48(s,1H),8.34(s,1H),8.02(d,J＝8.6Hz,1H),7.95(dd,J＝7.9,1.6Hz,1H),7.65(dd,J＝8.6,2.2Hz,1H),7.63–7.58(m,1H),7.47(ddd,J＝8.4,7.4,1.6Hz,1H),7.29–7.23(m,8H),7.18–7.12(m,4H),5.18(ddd,J＝10.1,8.2,5.2Hz,2H),4.52(dt,J＝10.1,8.3Hz,2H),4.05(dt,J＝38.5,8.3Hz,2H)； 13C NMR(126MHz,CDCl 3)δ163.68,141.05,131.92,131.61,130.89,128.65,128.53,127.56,127.39,126.58,122.24,119.75,118.65,112.62,110.75,73.97,73.77,70.28,70.03；熔点：76-78℃,高分辨C 30H 24N 4O 4Na([M+Na] +),计算值:527.1690；实测值:527.1684.
实施例9：
Figure PCTCN2020088254-appb-000011
将5.48g邻氨基苯甲酸、8.06g 2-氯-3-硝基苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-3-硝基苯甲酸。
将1.51g 2-((2-羧基苯基)氨基)-3-硝基苯甲酸和10mL SOCl 2加入圆底烧瓶中，加热回流4小时，旋蒸除去多余的SOCl 2，将脱溶所得的二酰氯加入到二氯甲烷中。在冰浴条件下，将二酰氯的二氯甲烷溶液滴加入含1.35g(R)-(-)-2-苯基甘氨醇、3.8mL三乙胺的二氯甲烷溶液中。待滴加完毕后，在室温下搅拌20小时。用氯化铵溶液淬灭反应，用水、饱和碳酸氢钠溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到橙色固体1.69g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体2-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-i:[α]D 20＝-142(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ11.55(d,J＝72.1Hz,1H),8.13–8.10(m,1H),7.92(d,J＝7.4Hz,1H),7.47–7.34(m,2H),7.28(s,8H),7.18–7.07(m,3H),6.98–6.84(m,2H),5.47(s,1H),5.07(s,1H),4.69(d,J＝44.5Hz,1H),4.47(s,1H),4.18(t,J＝8.1Hz,1H),3.97(s,1H),3.68(s,1H). 13C NMR(126MHz,Chloroform-d)δ164.11,164.08,143.58,139.90,136.10,131.87,130.17,128.60,128.57,127.52,127.37,126.58,126.53,124.37,124.33,123.26,121.26,120.12,114.16,113.71,74.47,74.46,70.06,70.03；熔点：115-118℃,高分辨C 30H 24N 4O 4Na([M+Na] +),计算值:527.1690；实测值:527.1684.
实施例10：
Figure PCTCN2020088254-appb-000012
将5.48g邻氨基苯甲酸、6.98g 2-氯-6-氟苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基苯基)氨基)-6-氟苯甲酸。
将1.35g(R)-(-)-2-苯基甘氨醇、2.20g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1.55g 1-羟基苯并三唑溶于THF中，然后加入1.10g 2-((2-羧基苯基)氨基)-5-氟苯甲酸。在室温条件下反应12小时。用氯化铵溶液淬灭反应、减压脱溶、加入乙酸乙酯溶解、用水洗涤、萃取三次，有机相用硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到淡黄色固体1.29g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体3-氟-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)-N-(2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)苯胺。
3-j:[α]D 20＝-298(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,CDCl 3)δ10.92(s,1H),7.86(d,J＝6.8Hz,1H),7.52(ddd,J＝32.5,9.2,3.9Hz,2H),7.42–6.99(m,14H),6.88(t,J＝7.3Hz,1H),5.16(q,J＝10.3Hz,2H),4.47(ddd,J＝13.3,10.0,8.5Hz,2H),3.98(dt,J＝17.0,8.2Hz,3H)； 13C NMR(126MHz,CDCl 3)δ164.10,163.16,142.52,142.19,131.68,130.53,128.48,127.29,126.56,121.02,120.94,119.27,118.71,118.49,116.67,116.43,113.84,73.98,73.54,70.00； 19F NMR(376MHZ,CDCl 3)δ-122.68；熔点：68-71℃；高分辨C 30H 24FN 3O 2Na([M+Na] +),计算值:500.1745；实测值:500.1739.
实施例11：
Figure PCTCN2020088254-appb-000013
将7.28g 2-氨基-5-硝基苯甲酸、6.82g 2-氯-5-甲基苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基-4-甲基苯基)氨基)-5-甲氧基苯甲酸。
将1.35g(R)-(-)-2-苯基甘氨醇、2.20g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1.55g 1-羟基苯并三唑溶于THF中，然后加入1.58g 2-((2-羧基-4-甲基苯基)氨基)-5-硝基苯甲酸。在室温条件下反应12小时。用氯化铵溶液淬灭反应、减压脱溶、加入乙酸乙酯溶解、用水洗涤、萃取三次，有机相用硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体2.07g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-甲基-N-(4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯胺。
3-k:[α]D 20＝-169(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ11.63(s,1H),8.82(d,J＝2.6Hz,1H),8.11(dd,J＝9.4,2.6Hz,1H),7.79(s,1H),7.44(d,J＝8.2Hz,1H),7.31–7.20(m,11H),7.12–7.08(m,2H),5.26(t,J＝9.1Hz,1H),5.16(t,J＝9.2Hz,1H),4.66–4.59(m,1H),4.49–4.42(m,1H),4.18(t,J＝8.2Hz,1H),3.95(t,J＝8.3Hz,1H),2.40(s,3H). 13C NMR(126MHz,Chloroform-d)δ163.56,162.97,150.73,142.12,141.95,137.75,136.40,132.44,132.44,131.40,128.71,128.56,127.65,127.52,127.48,127.40,126.59,126.52,124.31,121.61,113.22,110.31,74.42,73.45,70.36,69.87,20.76；熔点：85-86℃；高分辨C 31H 26N 4O 4Na([M+Na] +),计算值:541.1846；实测值:541.1847.
实施例12：
Figure PCTCN2020088254-appb-000014
将7.28g 2-氨基-5-硝基苯甲酸、7.46g 2-氯-5-甲氧基苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽 滤得到固体产物2-((2-羧基-4-甲氧基苯基)氨基)-5-甲氧基苯甲酸。
将1.35g(R)-(-)-2-苯基甘氨醇、2.20g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1.55g 1-羟基苯并三唑溶于THF中，然后加入1.66g 2-((2-羧基-4-甲氧基苯基)氨基)-5-硝基苯甲酸。在室温条件下反应12小时。用氯化铵溶液淬灭反应、减压脱溶、加入乙酸乙酯溶解、用水洗涤、萃取三次，有机相用硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到橘黄色固体1.98g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-甲氧基-N-(4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯胺。
3-l:[α]D 20＝-121(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ11.47(s,1H),8.82(s,1H),8.10(d,J＝12.2Hz,1H),7.48(d,J＝3.0Hz,1H),7.42(d,J＝8.9Hz,1H),7.29–7.23(m,9H),7.10–7.07(m,3H),7.02(d,J＝9.4Hz,1H),5.28(dd,J＝9.9,8.3Hz,1H),5.18(dd,J＝10.0,8.4Hz,1H),4.63(dd,J＝10.0,8.4Hz,1H),4.48(dd,J＝10.1,8.5Hz,1H),4.19(t,J＝8.2Hz,1H),3.95(t,J＝8.4Hz,1H),3.88(s,3H). 13C NMR(126MHz,Chloroform-d)δ163.28,163.14,156.99,151.50,141.97,137.41,131.65,128.72,128.58,127.67,127.53,127.44,127.02,126.59,126.51,123.91,118.44,114.96,112.62,109.54,74.55,73.39,70.34,69.95,55.79；熔点：80-81℃；高分辨C 31H 26N 4O 5Na([M+Na] +),计算值:557.1795；实测值:557.1793.
实施例13：
Figure PCTCN2020088254-appb-000015
将7.28g 2-氨基-5-硝基苯甲酸、6.98g 2-氯-5-氟苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基-4-氟苯基)氨基)-5-甲氧基苯甲酸。
将1.35g(R)-(-)-2-苯基甘氨醇、2.20g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1.55g 1-羟基苯并三唑溶于THF中，然后加入1.66g 2-((2-羧基-4-氟苯基)氨基)-5-硝基苯甲酸。在室温条件下反应12小时。用氯化铵溶液淬灭反应、减压脱溶、加入乙酸乙酯溶解、用水洗涤、萃取三次，有机相用硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺 酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体1.85g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-氟-N-(4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯胺。
3-m:[α]D 20＝-149(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ11.65(s,1H),8.83(d,J＝2.7Hz,1H),8.13(dd,J＝9.4,2.7Hz,1H),7.67(dd,J＝8.9,3.0Hz,1H),7.52(dd,J＝8.9,4.9Hz,1H),7.27(dt,J＝6.3,4.0Hz,7H),7.23–7.18(m,3H),7.15(d,J＝9.4Hz,1H),7.10–7.06(m,2H),5.21(ddd,J＝27.6,10.0,8.4Hz,2H),4.62(dd,J＝10.0,8.4Hz,1H),4.50(dd,J＝10.2,8.5Hz,1H),4.18(t,J＝8.2Hz,1H),3.98(t,J＝8.4Hz,1H). 13C NMR(126MHz,Chloroform-d)δ162.87,162.24,160.09,156.14,150.57,141.82,138.02,135.17,128.71,128.59,127.68,127.58,127.56,127.37,126.56,126.44,126.22,126.16,123.49,123.43,118.86,118.68,117.63,117.43,112.98,110.55,74.48,73.49,70.32,70.05. 19F NMR(376MHZ,CDCl 3)δ-122.69；熔点：85-86℃；高分辨C 30H 23FN 4O 4Na([M+Na] +),计算值:545.1596；实测值:545.1598.
实施例14：
Figure PCTCN2020088254-appb-000016
将7.28g 2-氨基-5-硝基苯甲酸、9.42g 2-氯-5-溴苯甲酸、5.52g K 2CO 3、0.378g铜粉和1.14g CuI加入到圆底烧瓶中混合，然后加入DMF，置于回流温度下反应3小时。冷却后过滤，向滤液中加入稀盐酸至溶液呈弱酸性，搅拌、抽滤得到固体产物2-((2-羧基-4-溴苯基)氨基)-5-甲氧基苯甲酸。
将1.35g(R)-(-)-2-苯基甘氨醇、2.20g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1.55g 1-羟基苯并三唑溶于THF中，然后加入1.66g 2-((2-羧基-4-溴苯基)氨基)-5-硝基苯甲酸。在室温条件下反应12小时。用氯化铵溶液淬灭反应、减压脱溶、加入乙酸乙酯溶解、用水洗涤、萃取三次，有机相用硫酸钠干燥，除去溶剂，短柱过滤直接用于下一步反应。
在冰浴条件下，向溶有上步所得产品的二氯甲烷溶液中加入0.9mL甲基磺酰氯和3.3mL三乙胺，待体系稳定后置于室温下反应10小时，用饱和氯化铵溶液淬灭反应，盐水洗涤、无水硫酸钠干燥，脱溶得到粗产物。通过柱层析分离(PE/EA＝10:1～5:1)，得到黄色固体2.47g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-溴-N-(4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯胺。
3-n:[α]D 20＝-149(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ11.82(s,1H),8.82(d,J＝2.7Hz,1H),8.15(dd,J＝9.4,2.8Hz,1H),8.10(d,J＝2.4Hz,1H), 7.58(dd,J＝8.7,2.4Hz,1H),7.46(d,J＝8.7Hz,1H),7.32(d,J＝9.4Hz,1H),7.27(dt,J＝7.0,2.9Hz,7H),7.18(dd,J＝7.5,1.7Hz,2H),7.09(dd,J＝6.5,3.0Hz,2H),5.18(ddd,J＝26.5,10.0,8.4Hz,2H),4.61(dd,J＝10.0,8.4Hz,1H),4.49(dd,J＝10.1,8.4Hz,1H),4.16(t,J＝8.3Hz,1H),3.99(t,J＝8.4Hz,1H). 13C NMR(126MHz,Chloroform-d)δ162.65,162.12,149.47,141.85,138.64,134.46,133.64,128.71,128.61,127.67,127.56,127.39,127.30,126.55,126.46,124.35,122.18,116.44,114.01,111.81,74.38,73.61,70.35,70.06；熔点：87-89℃；高分辨C 30H 23BrN 4O 4Na([M+Na] +),计算值:605.0795；实测值:605.0794.
实施例15：
Figure PCTCN2020088254-appb-000017
在N 2条件下，向三口圆底烧瓶中加入0.53g 4-甲氧基-N-(4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯胺和二氯甲烷，将体系置于-78℃条件下，接着缓慢逐滴滴加4M溶于二氯甲烷的BBr 3溶液。滴加完毕后，将体系置于室温下反应12小时。将反应液缓慢滴加到冰水中，用二氯甲烷萃取三次，合并有机相、用无水硫酸钠干燥、脱溶。柱层析分离(PE/EA＝20:1～10:1)，得到橙色产物0.34g。反应的产物即本发明的一种去C 2-对称性二苯胺型手性双噁唑啉配体4-羟基-N-(4-硝基-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯基)-2-((R)-4-苯基-4，5-二氢-噁唑-2-基)苯胺。
3-o:[α]D 20＝-52(c＝1.0,CH 2Cl 2)； 1H NMR(500MHz,Chloroform-d)δ11.25(s,1H),8.81(s,1H),8.08(d,J＝11.6Hz,1H),7.36–7.33(m,1H),7.32–7.17(m,11H),7.05(d,J＝5.0Hz,2H),6.90–6.84(m,2H),5.36(t,J＝9.0Hz,1H),5.15(t,J＝9.1Hz,1H),4.69(t,J＝9.2Hz,1H),4.42(t,J＝9.4Hz,1H),4.23(t,J＝8.2Hz,1H),3.89(t,J＝8.3Hz,1H). 13C NMR(126MHz,Chloroform-d)δ165.12,163.36,151.77,141.91,137.28,130.37,128.78,128.72,127.85,127.83,127.79,127.71,127.38,126.61,126.45,123.98,119.84,117.54,112.42,108.92,75.14,73.39,70.31,69.04；熔点：119-122℃；高分辨C 30H 24N 4O 5Na([M+Na] +),计算值:521.1819；实测值:521.1815.
实施例16：
反应式为：
Figure PCTCN2020088254-appb-000018
将0.02mmol噁唑啉配体3-e和醋酸铜的络合物，2-羟基-1-萘甲酸甲酯(0.2mmol)加入到10mL试管中，加入2mL甲苯溶解，置于0℃条件下搅拌10分钟，然 后向上述体系中加入式(II)所示1,3-二氯-5,5-二甲基海因(1.2equiv.)，0℃条件下搅拌反应18小时，将反应液减压浓缩，上硅胶层析柱分离，以石油醚和乙酸乙酯的体积比为1～10:1的洗脱液为洗脱剂进行梯度洗脱，收集洗脱液蒸去溶剂，得到淡黄色固体产物(收率98％)，[α]D 20＝79°(c＝1.0,CH 2Cl 2). 1H NMR(500MHz,Chloroform-d)δ7.55–7.50(m,2H),7.49–7.43(m,2H),7.39(dd,J＝7.3,1.7Hz,1H),6.29(d,J＝10.0Hz,1H),3.78(s,3H)； 13C NMR(126MHz,Chloroform-d)δ189.81,166.77,145.59,137.44,131.01,130.03,129.94,128.96,128.39,123.28,67.35,54.21ppm.通过手性HPLC分析，具体分析条件为Daicel Chiralpak OJ-H,正己烷/异丙醇＝70:30，流速为1.0mL/min，检测波长为320nm，t R1＝14.679min(大峰)，t R2＝20.812min(小峰)。90％ee。高分辨实测值:259.0132。
取与上述相同的反应物，分别以0.02mmol以下配体替代配体3-e，相同的反应条件和操作步骤进行不对称氯化去芳构化反应，结果如下表所示：
Figure PCTCN2020088254-appb-000019
表1不同配体对应的实验数据
Figure PCTCN2020088254-appb-000020
实施例17：
反应式为：
Figure PCTCN2020088254-appb-000021
将0.02mmol噁唑啉配体3-a和三氟甲磺酸铜的络合物，加入2mL二氯甲烷溶解，先室温搅拌0.5h，再将反应体系冷却至-45℃，然后将2-羟基-1-萘甲酸甲酯(0.2mmol)加入到10mL试管中，向上述体系中加入式(II)所示1,3-二溴-5,5-二甲基海因(1.2equiv)，搅拌反应0.5h，将反应液减压浓缩，上硅胶层析柱分离，以石油醚和乙酸乙酯的体积比为1～10:1的洗脱液为洗脱剂进行梯度洗脱，收集洗脱液蒸去溶剂，得到淡黄色固体产物(收率90％)， 1H NMR(500MHz,CDCl 3)δ＝7.50(d,J＝10.0Hz,1H),7.48–7.46(m,1H),7.46–7.41(m,2H),7.41–7.38(m,1H),6.32(d,J＝10.1Hz,1H),3.82(s,3H). 13C NMR(126MHz,CDCl 3)δ＝189.87,166.67,144.99,138.05,131.05,130.12,129.97,129.17,127.95,123.26,60.22,54.46ppm.通过手性HPLC分析，具体分析条件为Daicel Chiralpak OD-H,2-propanol:hexane＝10:90,flow rate 1.0mL/min,254nm)；t R＝15.11min,20.37min.97％ee.。HRMS:m/z＝280.9811[M+Na] +
实施例18：
反应式为：
Figure PCTCN2020088254-appb-000022
将0.02mmol噁唑啉配体3-n和三氟甲磺酸铜的络合物，3-氧代-2,3-二氢苯并呋喃-2-羧酸甲酯(0.2mmol)加入到10mL试管中，加入4mL甲苯溶解，室温搅拌10min，用进样针向上述体系中加入α,β-不饱和烯酮(1.2mmol)，室温搅拌反应8h，将反应液减压浓缩，上硅胶层析柱分离，以石油醚和乙酸乙酯的体积比为1～10:1的洗脱液为洗脱剂进行梯度洗脱，收集洗脱液蒸去溶剂，得到黄色液体产物(收率75％)， 1H NMR(500MHz,Chloroform-d)δ＝7.70-7.64(m,2H),7.20(d,J＝8.7Hz,1H),7.15(t,J＝7.4Hz,1H),3.77(s,3H),2.64-2.58(m,1H),2.52-2.49(m,2H),2.42-2.34(m,3H),1.03(t,J＝7.3Hz,3H)ppm. 13C NMR(125MHz,Chloroform-d)δ＝208.88,195.53,172.04,166.06,138.67,125.02,122.83,119.41,113.50,90.28,53.36,35.83,35.73,27.90,7.68ppm通过手性HPLC分析，具体分析条件为Daicel Chiralpak OD-H,2-propanol:hexane＝10:90,flow rate 1.0mL/min,254nm)；t R＝18.2min(次),20.5min(主).96％ee.。
实施例19：
反应式为：
Figure PCTCN2020088254-appb-000023
将0.01mmol噁唑啉配体3-d与三氟乙酸铜形成的手性络合物为手性催化剂，1-氧代-2,3-二氢茚酮-2-羧酸甲酯(1mmol)，N-氟代双苯磺酰胺(1.2mmol)，加入10mL试管中，再加入4mL二氯甲烷溶解，投料完毕，室温搅拌反应8h，将反应液减压浓缩，上硅胶层析柱分离，以石油醚和乙酸乙酯的体积比为1～10:1的洗脱液为洗脱剂进行梯度洗脱，收集洗脱液蒸去溶剂得到白色固体产物(收率97％)， 1H NMR(500MHz,CDCl 3):δ7.85(d,J＝7.7Hz,1H),7.72(t,J＝8.0Hz,1H),7.53–7.46(m,2H),3.82(s,3H),3.81(dd,J＝11.7,17.7Hz,1H),3.80(d,J＝11.3Hz,1H),3.45(dd,J＝23.3,17.6Hz,3H)； 13C NMR(125MHz,CDCl 3):δ195.02(d,J CF＝18.2Hz),167.74(d,J CF＝27.9Hz),150.80(d,J CF＝3.6Hz),136.72,133.32,128.67,126.61,125.68,94.64(d,J CF＝201.8Hz),38.29(d,J CF＝24.0Hz).通过手性HPLC分析，具体分析条件为Daicel Chiralpak OD-H,Hexane:iPrOH＝90:10,flow rate 1.0ml/min,254nm:t R(主)＝12.2min,t R(次)＝14.1min,99％ee。
实施例20：
反应式为：
Figure PCTCN2020088254-appb-000024
将0.02mmol噁唑啉配体3-a和三氟甲磺酸铜的络合物，茚酮酸叔丁酯(0.2mmol)加入到10mL试管中，加入2mL二氯甲烷溶解，置于0℃条件下搅拌10分钟，然后向上述体系中加入式(II)所示N-硫氰基酞酰亚胺(1.5equiv)，0℃条件下反应12小时，将反应液减压浓缩，上硅胶层析柱分离，以石油醚和乙酸乙酯的体积比为1～10:1的洗脱液为洗脱剂进行梯度洗脱，收集洗脱液蒸去溶剂，得到白色固体产物(收率90％)，[α]D 20＝60°(c＝1.0,CH 2Cl 2). 1H NMR(500MHz,CDCl 3)δ＝7.88(d,J＝7.7Hz,1H),7.73(td,J＝7.7,1.0Hz,1H),7.55–7.47(m,2H),4.06(d,J＝18.0Hz,1H),3.63(d,J＝18.0Hz,1H),1.45(s,9H). 13C NMR(126MHz,CDCl 3)δ＝194.97,150.98,136.74,133.11,128.80,126.18,125.80,86.07,64.19,40.38,27.65ppm.通过手性HPLC分析，具体分析条件为Daicel Chiralpak AD-H,2-propanol:hexane＝2:98,flow rate 1.0mL/min,285nm；t R＝14.759min,15.852min.96％ee.HRMS:m/z＝312.0663[M+Na] +.
实施例21：
反应式为：
Figure PCTCN2020088254-appb-000025
将0.02mmol噁唑啉配体3-e和三氟甲磺酸锌的络合物，吲哚(0.2mmol)，β-硝基苯乙烯(0.2mmol)加入到10mL试管中，加入4mL甲苯溶解，置于室温条件下搅拌12h，将反应液减压浓缩，上硅胶层析柱分离，以石油醚和乙酸乙酯的体积比为1～10:1的洗脱液为洗脱剂进行梯度洗脱，收集洗脱液蒸去溶剂，得到油状液体产物(收率93％)。 1H NMR(300MHz,Chloroform-d)δ8.02(s,1H),7.43(d,J＝7.8Hz,1H)7.31-7.15(m,7H),7.06(t,J＝7.6Hz,1H),6.94(d,J＝2.4Hz,1H),5.17(t,J＝8.1Hz,1H),5.02(dd,J＝12.4,7.6Hz,1H),4.90(dd,J＝12.4,8.6Hz,1H).； 13C NMR(75MHz,Chloroform-d)δ139.1,136.4,128.9,127.7,127.5,126.0,122.7,121.6,119.9,118.8,114.3,111.4,79.5,41.6.通过手性HPLC分析，具体分析条件为Daicel Chiralpak OD-H,正己烷/异丙醇＝70:30，流速为1.0mL/min，检测波长为254nm，t R1＝24.8min(大峰)，t R2＝20.4min(小峰)，98％ee。

Claims (13)

  1. 一种如式3所示的去C 2-对称性二苯胺型手性双噁唑啉配体：
    Figure PCTCN2020088254-appb-100001
    其中，
    R 1、R 2各自独立为氢、C 1～ 4的烷基、苯基、苄基、1-萘基、2-萘基、取代苯基或R 1～R 2同时为2,3-二氢茚基；所述的取代苯基为苯环上的H被C 1～ 4烷基、卤素、三氟甲基单取代或二取代；
    R 3、R 4各自独立为氢、C 1～ 4烷基、C 1～ 4烷氧基、卤素、三氟甲基、硝基、磺酸基、羟基、氨基或N，N-二(C 1～ 4)烷基氨基。
  2. 一种如权利要求1所述的去C 2-对称性二苯胺型手性双噁唑啉配体的制备方法，其特征在于：所述的方法按照如下步骤进行：
    (1)在有机溶剂A中，在80～200℃的温度条件下，以式Ⅰ所示的邻氨基苯甲酸类衍生物和式Ⅱ所示的邻氯苯甲酸类衍生物为原料，然后加入碳酸盐、铜和碘化亚铜，进行偶联反应1-24小时，得到反应液A冷却后过滤，向滤液中加入稀盐酸至溶液呈pH＝1～4，搅拌、过滤得到式1所示的化合物；所述的式Ⅰ所示的邻氨基苯甲酸类衍生物和式Ⅱ所示的邻氯苯甲酸类衍生物以及碳酸盐、铜和碘化亚铜的物质的量之比为1：1：1-2：0.01-0.5：0.01-0.5；
    (2)将步骤(1)所得式1所示的化合物与氯化亚砜混合，加热回流4小时，蒸除多余的SOCl 2得到二酰氯，将所述的二酰氯加入有机溶剂B中得到二酰氯溶液，将手性氨基醇和碱性物质A加入有机溶剂B得到混合液，在-20-20℃下，向所述的混合液中滴加二酰氯溶液，恢复至室温，反应1-24小时，得到反应液B用氯化铵水溶液淬灭，用水、饱和NaHCO 3溶液、饱和食盐水分别萃取三次，有机相用无水硫酸钠干燥、脱溶，通过柱层析分离，得到式2所示的中间体β-双羟基酰胺；所述的式1所示的化合物与氯化亚砜的物质的量之为1：5-10；所述的二酰氯与氨基醇、碱的物质的量之为1：2-3：1-6，所述的二酰氯的物质的量以式1所示的化合物的物质的量来计；
    (3)在有机溶剂C中，0-30℃的温度条件下，将步骤(2)所得式2所示的β-双羟基酰胺、甲基磺酰氯及碱性物质B混合，反应1-24小时，反应液C经蒸除溶剂得粗品，进一步柱层析分离得到式3所示的去C 2-对称性的二苯胺型手性双噁唑啉配体；所述式2所示的β-双羟基酰胺与甲基磺酰氯、碱性物质B的物质的量之比为1：2-3：1-6；
    Figure PCTCN2020088254-appb-100002
  3. 如权利要求2所述的方法，其特征在于：步骤(1)中，所述的碳酸盐为碳酸钠、碳酸钾或碳酸铯。
  4. 如权利要求2所述的方法，其特征在于：步骤(1)中，所述的有机溶剂A为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲苯、氯苯、四氢呋喃、氯仿、四氯化碳、二氯甲烷、1,4-二氧六环或吡啶；所述的有机溶剂A的加入量以式Ⅰ所示的邻氨基苯甲酸类衍生物的物质的量计为1-20ml/mmol。
  5. 如权利要求2所述的方法，其特征在于：步骤(2)中，所述的有机溶剂B为甲苯、二甲苯、氯苯、四氢呋喃、氯仿、四氯化碳、二氯甲烷、1,4-二氧六环或吡啶；所述的有机溶剂B的加入量以式1所示的化合物的物质的量计为1-10mL/mmol。
  6. 如权利要求2所述的方法，其特征在于：步骤(2)或(3)中，所述的碱性物质A或碱性物质B各自独立为三乙胺、三丙胺、三丁胺、N,N-二异丙基甲胺、N,N-二异丙基乙胺、四甲基二乙胺、碳酸钠或碳酸钾。
  7. 如权利要求2所述的方法，其特征在于：步骤(3)中，所述的有机溶剂C为甲苯、二甲苯、氯苯、四氢呋喃、氯仿、四氯化碳或二氯甲烷；所述的有机溶剂C的加入量以式2所示的β-双羟基酰胺的物质的量计为1-10mL/mmol。
  8. 如权利要求2所述的方法，其特征在于：步骤(2)中，所述的式2所示的中间体β-双羟基酰胺的制备方法为：
    在室温条件下，将手性氨基醇、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑溶于有机溶剂D中，然后加入步骤(1)所得式1所示的化合物，在室温条件下反应1-24小时，得到反应液D用氯化铵水溶液淬灭，用水洗涤反应液、萃取，有机相用无水硫酸钠干燥、脱溶，通过柱层析分离，以体积比为2～5:1的PE/EA的混合液为洗脱剂进行洗脱，收集含目标产物的洗脱液蒸除溶剂得到式2所示的中间体β-双羟基酰胺；所述的式1所示的化合物、手性氨基醇、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与1-羟基苯并三唑的物质的量之为1：2-3：2-3：2-3。
  9. 如权利要求8所述的方法，其特征在于：所述的有机溶剂D为甲苯、二甲苯、氯苯、四氢呋喃、氯仿、四氯化碳或二氯甲烷；所述的有机溶剂D的加入量以所述的式1所示的化合物的物质的量计为1-10mL/mmol。
  10. 一种如权利要求1所述的去C 2-对称性二苯胺型手性双噁唑啉配体与铜盐、锌盐、镍盐、铁盐或铑盐配位形成的催化剂。
  11. 如权利要求10所述的催化剂，其特征在于：所述的铜盐为：氯化铜、硫酸铜、溴化铜、醋酸铜、三氟乙酸铜、三氟甲磺酸铜、乙酰丙酮铜或高氯酸铜；所述的锌盐为氯化锌、硫酸锌、溴化锌、醋酸锌、三氟乙酸锌、三氟甲磺酸锌、乙酰丙酮锌或高氯酸锌；所述的镍盐为氯化镍、硫酸镍、溴化镍、醋酸镍、三氟甲磺酸镍、三氟乙酸镍、乙酰丙酮镍或高氯酸镍；所述的铁盐为氯化亚铁、硫酸亚铁、溴化亚铁、醋酸亚铁、三氟乙酸亚铁、三氟甲磺酸亚铁、乙酰丙酮亚铁或高氯酸亚铁；所述的铑盐为氯化铑、三氟乙酸铑、氯化羰基铑、双(三苯基膦)合氯化羰基铑、三(三苯基膦)羰基氢化铑或三苯基膦氯化铑。
  12. 一种如权利要求10所述的催化剂在不对称催化反应中的应用。
  13. 如权利要求12所述的应用，其特征在于：所述的不对称催化反应为β-萘酚衍生物的不对称氯化，溴化去芳构化反应，1，3-二羰基化合物的不对称氟化、氯化、溴化、氧化、硫氰基化或三氟甲硫基化官能团化反应，1，3-二羰基化合物的不对称Michael加成反应或吲哚与硝基烯烃的不对称傅克反应。
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