WO2020177654A1 - 膦配体及其制备方法和催化合成邻位四取代联芳烃的应用 - Google Patents

膦配体及其制备方法和催化合成邻位四取代联芳烃的应用 Download PDF

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WO2020177654A1
WO2020177654A1 PCT/CN2020/077397 CN2020077397W WO2020177654A1 WO 2020177654 A1 WO2020177654 A1 WO 2020177654A1 CN 2020077397 W CN2020077397 W CN 2020077397W WO 2020177654 A1 WO2020177654 A1 WO 2020177654A1
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汤文军
杨贺
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中国科学院上海有机化学研究所
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Definitions

  • the invention relates to a phosphine ligand, a preparation method thereof, and application of catalyzed synthesis of ortho-tetra-substituted biaromatic hydrocarbons.
  • Korupensamine A has high antimalarial activity.
  • Michellamine B has been used as a clinical drug because of its strong anti-HIV activity (J.Nat.Prod.1997,60,677; J.Med.Chem.1991,34,3402; Chem.Rev.2011,111,563).
  • the ortho-four-substituted chiral biaryl structure with axial chirality is also widely present in many natural products and drug molecules, such as gonytolide A, a natural product of chromone lactones.
  • Gonytolide A can significantly stimulate the activity of mammalian innate immune response (Org. Lett. 2011, 13, 4624).
  • the pyranoquinone dimer cardinalin 3 shows strong in vivo cytotoxicity to certain leukemia cells (J. Chem. Soc., Perkin Trans. 1997, 6, 919; Nat. Prod. Lett. 1994, 5, 211; Aust. J .Chem.1997,50,1081).
  • Gossypol is a natural product of polyphenols.
  • gossypol was marketed in China as a male contraceptive (J. Am. Oil Chem. Soc. 2006, 83, 269).
  • a series of biological activities of gossypol and its derivatives including anti-insect, anti-malarial, anti-tumor and virus inhibition activities, were successively reported (Future Med.Chem.2017,9,11; Science.1982,218,288; Carbohydr.Res.2011,346,2070; J.Med.Chem.1998,41,3879; Cancer Res.1990,50,6936; Bioorg.Med.Chem.Lett.2012,22,1415; Bioorg.Med.Chem .2016,24,474; Bioorg.Med.Chem.Lett.2018,28,49; Mol.Carcinogen.2018,57,1213; Front.Pharmacol.2018,9,728).
  • the preparation methods of ortho-tetra-substituted biaryl compounds with axial chirality mainly include resolution of racemic compounds, induction by chiral reagents or auxiliary groups, and asymmetric catalysis.
  • the resolution of racemic compounds consumes 50% of the raw materials, and the chiral reagent or auxiliary group induction consumes the chiral source.
  • the asymmetric catalysis method uses a catalytic amount of chiral catalyst, which shows obvious high efficiency and economy.
  • Asymmetric coupling is one of the most efficient and practical methods in the existing asymmetric catalytic methods for the synthesis of chiral biaryl groups.
  • the method of synthesizing ortho-four-substituted biaryl compounds by asymmetric coupling has been studied (Angew.Chem.Int.Ed.2017,56,4777; J.Am.Chem.Soc.2002,124,13396; Eur.J.Org.Chem.2014,6676;Chem.Eur.J.2006,12,9346;Org.Lett.2010,12,1072.), but the existing methods still have many shortcomings, and the reaction substrate structure is single , Poor tolerance of functional groups, insufficient coupling efficiency or enantioselectivity, etc.
  • the following chiral phosphine ligands are used to synthesize ortho-tetrasubstituted 2,2'-dimethyl-1.1'-binaphthyl with axial chirality, although certain phosphine ligands can obtain a certain yield and ee value, but the general applicability of these chiral phosphine ligands in the synthesis of ortho-tetra-substituted biaryl structures with axial chirality has not been studied in depth, so the chiral ortho-tetra-substituted biaryls obtained
  • the base structure is relatively simple.
  • the technical problem to be solved by the present invention is to overcome the defects of low yield, low optical purity, or single type of substituents in the synthesis of ortho-tetra-substituted biaryl compounds in the prior art, and a phosphine ligand and The preparation method and application of the catalyzed synthesis of ortho-tetra-substituted biaromatic hydrocarbons.
  • the phosphine ligand of the present invention is applied to the asymmetric Suzuki-Miyaura coupling reaction, and the ortho-tetra-substituted biaryl compound with various substituents can be obtained in high yield, especially the ortho-tetrasubstituted biaryl compound with high selectivity can be obtained.
  • the four-substituted biaryl compound at the position, and the reaction conditions are mild.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a phosphine ligand, which is a compound represented by formula I or a racemate thereof:
  • R 1, R 3 and R 5 are independently hydrogen, C 1 ⁇ 10 alkyl group, C 1 ⁇ 10 heteroalkyl, C 3 ⁇ 30 cycloalkyl , R 1-1a substituted C 3 ⁇ 30 cycloalkyl group, C 6 ⁇ 30 aryl group or R 1-1b substituted C 6 ⁇ 30 aryl group;
  • a hetero atom heteroalkyl C 1 ⁇ 10 alkyl group is selected from One or more of O, S and N, the number is 1, 2, 3, 4, 5 or 6; when the number of heteroatoms is more than one, the heteroatoms are the same or different;
  • R 2 and R 4 are independently C 1 ⁇ 10 alkyl group, C 1 ⁇ 10 heteroalkyl, C 3 ⁇ 30 cycloalkyl group, R 2-1a substituted C 3 ⁇ 30 cycloalkyl group, C 6 ⁇ 30 aryl Group or R 2-1b substituted C 6-30 aryl group;
  • the heteroatoms in the C 1-10 heteroalkyl group are selected from one or more of O, S and N, the number is 1, 2, 3, 4, 5 or 6; when the number of heteroatoms is more than one, the heteroatoms are the same or different;
  • Each R 1-1a and each R 2-1a is independently a C 1-10 alkyl group; the number of R 1-1a and R 2-1a is one or more; when R 1-1a and R 2-1a The number is independently multiple, and R 1-1a and R 2-1a are independently the same or different;
  • Each R 1-1b and each R 2-1b is independently C 1-10 alkyl, C 1-10 alkoxy or C 6-30 aryl; when each R 1-1b and each R 2 The number of -1b is independently multiple, and R 1-1b and R 2-1b are independently the same or different;
  • R 6 and R 7 are independently H, C 1 ⁇ 10 alkyl, hydroxy-substituted C 1 ⁇ 10 alkyl group, C 3 ⁇ 30 cycloalkyl or C 6 ⁇ 30 aryl group;
  • R 8 is a hydroxyl group, a C 1-10 alkyl group, a hydroxyl-substituted C 1-10 alkyl group, a C 1-10 alkoxy group, C 3 ⁇ 30 cycloalkyl group, a mercapto group or a C 6 ⁇ 30 aryl group, wherein, R 10 and R 11 are independently H or C 1 ⁇ 4 alkyl group;
  • R 9 is a C 1-10 alkyl group, a C 3-30 cycloalkyl group or a C 6-30 aryl group.
  • the C 1-10 alkyl group may be a C 1-6 alkyl group, preferably a C 1-3 alkyl group.
  • the C 1-3 alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl or isopropyl.
  • the C 1-10 heteroalkyl group may be a C 1-6 heteroalkyl group.
  • the C 3-30 cycloalkyl group may be a C 3-10 cycloalkyl group.
  • R 1-1a substituted C 3 ⁇ 30 cycloalkyl group a substituted cycloalkyl group R 1-1a in C C 3 ⁇ 30 3 ⁇ 30
  • the cycloalkyl group may be a C 3-10 cycloalkyl group.
  • the C 6-30 aryl group may be a C 6-14 aryl group.
  • R 1-1b substituted C 6 ⁇ 30 aryl group When the R 1, R 3 and R 5 are independently R 1-1b substituted C 6 ⁇ 30 aryl group, said R 1-1b substituted C 6 ⁇ 30 aryl group of C 6 ⁇ 30 aryl group It can be a C 6-14 aryl group.
  • the C 1-10 alkyl group may be a linear C 1-10 alkyl group or a branched C 3-10 alkyl group, preferably a branched chain C 3-10 alkyl.
  • the linear C 1-10 alkyl group may be a linear C 1-6 alkyl group, preferably a linear C 1-3 alkyl group.
  • the branched C 3-10 alkyl group may be a branched C 3-6 alkyl group, preferably a branched C 3-5 alkyl group.
  • the branched C 3 ⁇ 5 alkyl group may be isopropyl, Preferably isopropyl or
  • the C 3-30 cycloalkyl group may be a C 3-10 cycloalkyl group, preferably a C 3-6 cycloalkyl group.
  • R 2 and R 4 are independently R 2-1a substituted C 3 ⁇ 30 cycloalkyl group
  • R 2-1a substituted C 3 ⁇ 30 cycloalkyl group, C 3 ⁇ 30 cycloalkyl group may be C 3-10 cycloalkyl, preferably C 3-6 cycloalkyl.
  • the C 3-6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl.
  • R 2 and R 4 are independently R 2-1a substituted C 3 ⁇ 30 cycloalkyl group
  • said R 2-1a substituted C 3 ⁇ 30 cycloalkyl group may be the number of R 2-1a It is 1, 2, 3 or 4, preferably 4.
  • the R 2-1a is preferably the same.
  • the C 1-10 alkyl group may be a C 1-6 alkyl group, preferably a C 1-3 alkyl group.
  • the C 1-3 alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
  • R 2 and R 4 are independently R 2-1a substituted C 3 ⁇ 30 cycloalkyl group
  • said R 2-1a substituted C 3 ⁇ 30 cycloalkyl group may be substituted with C 1 ⁇ 3 alkyl group C 3-6 cycloalkyl group, more preferably
  • a C 6 ⁇ 30 aryl group may be a C 6 ⁇ 20 aryl group, preferably C 6 ⁇ 14 aryl group, more preferably a phenyl group.
  • R 1, R 2, R 3 , R 4 and R 5 are independently R 2-1b substituted C 6 ⁇ 30 aryl group
  • said R 2-1b substituted C 6 ⁇ 30 aryl group C 6 ⁇ 30 aryl group may be a C 6 ⁇ 20 aryl group, preferably C 6 ⁇ 14 aryl group.
  • the C 1-10 alkyl group may be a C 1-6 alkyl group, preferably a C 1-3 alkyl group.
  • the C 1-3 alkyl group may be methyl, ethyl, n-propyl or isopropyl.
  • the C 1-10 alkyl group in the hydroxy-substituted C 1-10 alkyl group may be a C 1-6 alkyl group, Preferably, C 1-3 alkyl.
  • the C 1-3 alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
  • R 6 and R 7 are independently a C 3-30 cycloalkyl group
  • the C 3-30 cycloalkyl group may be a C 3-10 cycloalkyl group.
  • a C 6 ⁇ 30 aryl group may be a C 6 ⁇ 20 aryl group.
  • the C 1-10 alkyl group may be a C 1-6 alkyl group, preferably a C 1-3 alkyl group.
  • the C 1-3 alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
  • the C 1-10 alkyl group in the hydroxy-substituted C 1-10 alkyl group may be a C 1-6 alkyl group, preferably C 1-3 alkyl.
  • the C 1-3 alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
  • the number of hydroxy groups in the hydroxy-substituted C 1-10 alkyl group may be one.
  • the C 1-10 alkoxy group may be a C 1-6 alkoxy group, preferably a C 1-3 alkoxy group.
  • the C 1-3 alkoxy group may be methoxy, ethoxy, n-propoxy or isopropoxy, preferably methoxy.
  • R 8 is a C 3-30 cycloalkyl group
  • the C 3-30 cycloalkyl group may be a C 3-10 cycloalkyl group.
  • a C 6 ⁇ 30 aryl group may be a C 6 ⁇ 20 aryl group.
  • the C 1-10 alkyl group may be a linear C 1-10 alkyl group or a branched C 3-10 alkyl group, preferably a branched C 3-10 alkyl group.
  • the linear C 1-10 alkyl group may be a linear C 1-6 alkyl group, preferably a linear C 1-3 alkyl group.
  • the branched C 3-10 alkyl group may be a branched C 3-6 alkyl group, preferably a branched C 3-4 alkyl group.
  • the branched C 3-4 alkyl group may be isopropyl, Or tert-butyl, or tert-butyl.
  • the C 3-30 cycloalkyl group may be a C 3-10 cycloalkyl group.
  • a C 6 ⁇ 30 aryl group may be a C 6 ⁇ 20 aryl group.
  • the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, Or tert-butyl.
  • the compound represented by formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 and R 5 are independently C 1-10 alkyl.
  • R 1 and R 5 are the same.
  • R 2 and R 4 are independently C 1 ⁇ 10 alkyl group, C 3 ⁇ 30 cycloalkyl group, R 2-1a substituted C 3 ⁇ 30 cycloalkyl or C 6 ⁇ 30 aryl base.
  • R 2 and R 4 are independently C 3 ⁇ 30 cycloalkyl or R 2-1a substituted C 3 ⁇ 30 cycloalkyl group.
  • R 2 and R 4 are the same.
  • R 3 is hydrogen
  • R 6 and R 7 are independently H, C 1-10 alkyl or hydroxy-substituted C 1-10 alkyl.
  • R 6 and R 7 are independently C 1-10 alkyl.
  • R 8 is hydroxy, C 1-10 alkyl, C 1-10 alkoxy or
  • R 8 is hydroxyl
  • R 9 is a C 1-10 alkyl group.
  • R 1 and R 5 are independently C 1 ⁇ 10 alkyl group
  • R 2 and R 4 are independently C 1 ⁇ 10 alkyl group, C 3 ⁇ 30 cycloalkyl group, R 2-1a substituted C 3 ⁇ 30 cycloalkyl or C 6 ⁇ 30 aryl group
  • R 3 is hydrogen
  • R 6 and R 7 are independently H, C 1 ⁇ 10 alkyl group or a hydroxy-substituted C 1 ⁇ 10 alkyl group;
  • R 8 is hydroxy, C 1 ⁇ 10 alkyl group, C 1 ⁇ 10 alkoxy group, or
  • R 9 is a C 1-10 alkyl group.
  • R 1 and R 5 are independently C 1 ⁇ 10 alkyl group;
  • R 2 and R 4 are independently C 3 ⁇ 30 cycloalkyl or R 2-1a substituted C 3 ⁇ 30 cycloalkyl Alkyl;
  • R 3 is hydrogen;
  • R 6 and R 7 are independently C 1-10 alkyl;
  • R 8 is hydroxy;
  • R 9 is C 1-10 alkyl.
  • the compound represented by formula I may optionally be any of the following compounds:
  • the present invention also provides a method for preparing the compound represented by formula I or its racemate, which comprises the following steps: in the presence of a reducing agent, the compound II is subjected to a reduction reaction of the following formula in an organic solvent, To obtain compound I, that is;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are the same as described above.
  • the reducing agent may be a conventional reducing agent for this type of reaction in the art, preferably a halogenated silane reducing agent and/or a polysilane reducing agent.
  • the halogenated silane reducing agent may be trichlorosilane.
  • the polysilane-based reducing agent may be polymethoxyhydrosilane.
  • the amount of the reducing agent can be a conventional amount.
  • the molar ratio of the reducing agent to the compound II is 1-10, such as 8.
  • the reduction reaction is preferably carried out in the presence of an acid binding agent.
  • the acid binding agent may be a conventional acid binding agent, preferably an inorganic weak base and/or an organic weak base, more preferably an organic weak base, and further preferably a tertiary amine organic weak base.
  • the reducing agent is a polysilane-based reducing agent
  • the reduction reaction is preferably carried out in the presence of tetraisopropyl titanate.
  • the organic solvent may be a conventional solvent for such reactions, preferably aromatic hydrocarbon solvents and/or ether solvents.
  • aromatic hydrocarbon solvent can be toluene or benzene, or toluene.
  • the amount of the organic solvent may not be specifically limited, as long as it does not affect the progress of the reaction.
  • the temperature of the reduction reaction may be a conventional temperature of this type of reaction in the art, preferably 60-80°C, for example 70°C.
  • the compound II is preferably
  • the monitoring method for the progress of the reduction reaction can be a conventional monitoring method in the art (for example, TLC, HPLC, LC-MS), and generally the disappearance or no reaction of compound II is used as the end point of the reaction.
  • the time of the reduction reaction is preferably 8-24 hours, for example 12 hours.
  • the following post-processing steps may also be included: cooling the reaction liquid after the reaction to room temperature, adjusting the reaction liquid to neutral, extraction (the extraction solvent is preferably ethyl acetate), drying, concentration and column chromatography (The eluent is preferably petroleum ether-ethyl acetate, and the volume ratio is 20:1-10:1, for example 15:1).
  • extraction solvent is preferably ethyl acetate
  • concentration and column chromatography The eluent is preferably petroleum ether-ethyl acetate, and the volume ratio is 20:1-10:1, for example 15:1).
  • the present invention also provides a compound represented by formula II or its racemate:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are the same as described above.
  • the compound represented by Formula II or its racemate is preferably any one of the following compounds:
  • the present invention also provides a method for preparing the compound represented by formula II or its racemate, which comprises the following steps:
  • X is halogen;
  • R 12a and R 12b are independently H, C 1 ⁇ 10 alkyl, hydroxy-substituted C 1 ⁇ 10 alkyl group, C 3 ⁇ 30 cycloalkyl or C 6 ⁇ 30 aryl group;
  • R 13a R 13b and R 13b are independently H or C 1-4 alkyl, R 13a and R 13b are not H at the same time;
  • R 14 is C 1-10 alkyl, hydroxy-substituted C 1-10 alkyl or C 1-10 alkane Oxy group;
  • "*" R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the same definitions as described above.
  • halogen is Cl, Br or I.
  • the C 1-10 alkyl group may independently be a C 1-6 alkyl group, preferably a C 1-3 alkyl group, more preferably methyl, ethyl, n-propyl or isopropyl, More preferably, methyl, ethyl, or isopropyl.
  • the hydroxy-substituted C 1 ⁇ 10 alkyl group of C 1 ⁇ 10 alkyl group independently may be C 1 ⁇ 6 alkyl, preferably C 1 ⁇ 3 alkyl group, more preferably methyl, Ethyl, n-propyl or isopropyl, more preferably methyl.
  • the C 3-30 cycloalkyl group may be a C 3-10 cycloalkyl group, preferably a C 3-6 cycloalkyl group.
  • the C 6-30 aryl group may be a C 6-18 aryl group, preferably a C 6-14 aryl group.
  • the C 1-4 alkyl group may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, Or tert-butyl, preferably methyl.
  • the C 1-10 alkyl group may be a C 1-6 alkyl group, preferably a C 1-3 alkyl group, more preferably methyl, ethyl, n-propyl or isopropyl, and still more preferably methyl .
  • the C 1-10 alkoxy group may be a C 1-6 alkoxy group, preferably a C 1-3 alkoxy group, and more preferably a methoxy group, ethoxy group, n-propoxy group or isopropoxy group The group is more preferably a methoxy group.
  • the alkaline reagent may be a conventional alkaline reagent in the art, preferably lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide And one or more of sodium bis(trimethylsilyl)amide or sodium hydride, more preferably lithium diisopropylamide or lithium bis(trimethylsilyl)amide.
  • the molar ratio of the alkaline reagent to the compound III may be a conventional ratio of this type of reaction in the art, preferably 1.0-5.0, such as 4.0.
  • the organic solvent may be a conventional organic solvent for such reactions in the field, preferably aromatic hydrocarbon solvents (such as toluene), ether solvents (such as tetrahydrofuran, dioxane, diethyl ether) and halogenated hydrocarbon solvents (E.g., dichloromethane), more preferably ether solvents.
  • aromatic hydrocarbon solvents such as toluene
  • ether solvents such as tetrahydrofuran, dioxane, diethyl ether
  • halogenated hydrocarbon solvents E.g., dichloromethane
  • the amount of the organic solvent may not be specifically limited as long as it does not affect the reaction.
  • the molar ratio of the compound A to the compound III may be a conventional ratio of this type of reaction in the art, preferably 1 to 5.0, such as 2.0.
  • the reaction temperature may be a temperature conventional in the art, preferably -78-30°C.
  • the compound III is preferably
  • the compound A is preferably acetone or
  • the monitoring method of the progress of the reaction can be a conventional monitoring method in the art (for example, TLC, HPLC, LC-MS), and generally the disappearance or no reaction of compound III is used as the end point of the reaction.
  • the time of the reduction reaction is preferably 1 to 5 hours, for example 2 hours.
  • the reaction may also include the following post-treatment steps: cooling the reaction solution after the reaction, quenching (the quenching reagent is saturated ammonium chloride), extraction (the extraction solvent is preferably ethyl acetate), and water washing ( Wash with saturated brine), dry, concentrate and column chromatography (the eluent is preferably petroleum ether-ethyl acetate, and the volume ratio is 1:1 to 5:1, for example 2:1).
  • quenching the quenching reagent is saturated ammonium chloride
  • extraction is preferably ethyl acetate
  • water washing Wash with saturated brine
  • the present invention also provides a compound represented by formula III:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 9 are the same as described above.
  • the compound shown in formula III can be any compound shown in formula III.
  • the Suzuki-Miyaura coupling reaction includes the following steps: In the presence of a palladium catalyst, the compound I and a basic reagent, the compound C and the compound D are subjected to a Suzuki-Miyaura coupling reaction in a solvent to obtain compound E or compound ent-E;
  • the Suzuki-Miyaura coupling reaction includes the following steps: in the presence of a palladium catalyst, the compound I racemate and an alkaline reagent, the compound C and the compound D are subjected to the Suzuki-Miyaura coupling reaction in a solvent , Get compound E and compound ent-E;
  • R 15 , R 19 , R 20 and R 24 are independently F, C 1-10 alkyl (for example, C 1-6 alkyl, or C 1-3 alkyl, or methyl), C 1-10 Alkoxy (e.g. C 1-6 alkoxy, or C 1-3 alkoxy, or methoxy), C 6-30 aryl (e.g. C 6-14 aryl, or phenyl) , R 15-1 substituted C 6-30 aryl (for example, C 6-14 aryl), phenoxy, R 15-2 substituted phenoxy, -CHO or -OSO 2 F;
  • C 1-10 alkyl for example, C 1-6 alkyl, or C 1-3 alkyl, or methyl
  • C 1-10 Alkoxy e.g. C 1-6 alkoxy, or C 1-3 alkoxy, or methoxy
  • C 6-30 aryl e.g. C 6-14 aryl, or phenyl
  • R 15-1 substituted C 6-30 aryl for example, C 6-14
  • R 16 , R 17 , R 18 , R 21 , R 22 and R 23 are independently H, F, C 1-10 alkyl (e.g. C 1-6 alkyl, or C 1-3 alkyl, for example Methyl), C 1-10 alkoxy (e.g. C 1-6 alkoxy, another example of C 1-3 alkoxy, another example of methoxy), C 6-30 aryl (e.g.
  • C 6-14 Aryl such as phenyl), R 16-1 substituted C 6-30 aryl (for example C 6-14 aryl), phenoxy, R 16-2 substituted phenoxy, C 1-10 silane Group (C 1-6 silyl group, another example of C 1-3 silyl group, another example of trimethylsilyl group), NHPiv, -CHO or -OSO 2 F; or, any of R 16 , R 17 and R 18
  • the adjacent two groups are formed together with the carbon atom to which they are connected
  • any two adjacent groups of R 21 , R 22 and R 23 are formed together with the carbon atom to which they are connected
  • C 6-10 aryl group e.g., C 6 ⁇ 14 aryl group, e.g. phenyl another
  • R 15-3 substituted C 6-10 aryl group e.g. C 6 ⁇ 14 aryl group, e.g. phenyl another
  • C 5-10 cycloalkyl C 3-10 heteroaryl group (e.g., C 3 ⁇ 10 heteroaryl, another example pyridyl) or a C 5-10 heterocycle alkyl
  • C 3-10 hetero atoms of said heteroaryl and said C 5- 10 heterocycloalkyl group selected from N, S and O, one or more of the number 2, 3 or 4;
  • R 18 and R 19 together with the carbon atom to which they are connected form a C 6-10 aryl group (e.g., C 6-14 aryl group, and another example, phenyl), or a C 6-10 aryl group substituted by R 18-1 (e.g. C 6 ⁇ 14 aryl group, e.g.
  • C 5-10 cycloalkyl C 3-10 heteroaryl group (e.g., C 3 ⁇ 10 aryl group, another example pyridyl) or a C 5-10 heterocycloalkyl
  • C 3-10 heteroaryl group e.g., C 3 ⁇ 10 aryl group, another example pyridyl
  • the heteroatoms in the C 3-10 heteroaryl group and the C 5-10 heterocycloalkyl group are selected from one or more of N, S and O, the number is 1, 2, 3 or 4 A
  • R 20 and R 21 together with the carbon atom to which they are connected form a C 6-10 aryl group (e.g., C 6-14 aryl group, and another example phenyl), or a C 6-10 aryl group substituted by R 20-1 (e.g. C 6 ⁇ 14 aryl group, e.g.
  • C 5-10 cycloalkyl C 3-10 heteroaryl group (e.g., C 3 ⁇ 10 aryl group, another example pyridyl) or a C 5-10 heterocycloalkyl
  • C 3-10 heteroaryl group e.g., C 3 ⁇ 10 aryl group, another example pyridyl
  • the heteroatoms in the C 3-10 heteroaryl group and the C 5-10 heterocycloalkyl group are selected from one or more of N, S and O, the number is 1, 2, 3 or 4 A
  • R 23 and R 24 together with the carbon atom to which they are connected form a C 6-10 aryl group (e.g., C 6-14 aryl group, and another example, phenyl), or a C 6-10 aryl group substituted by R 23-1 (e.g. C 6 ⁇ 14 aryl group, e.g.
  • C 5-10 cycloalkyl C 3-10 heteroaryl group (e.g., C 3 ⁇ 10 aryl group, another example pyridyl) or a C 5-10 heterocycloalkyl
  • C 3-10 heteroaryl group e.g., C 3 ⁇ 10 aryl group, another example pyridyl
  • the heteroatoms in the C 3-10 heteroaryl group and the C 5-10 heterocycloalkyl group are selected from one or more of N, S and O, the number is 1, 2, 3 or 4 A
  • R 15-1 , R 15-2 , R 16-1 , and R 16-2 are independently C 1-10 alkyl, C 1-10 alkoxy, phenyl, nitro, -CHO or -OSO 2 F ;
  • R 15-3 , R 18-1 , R 20-1 and R 23-1 are independently phenyl, R 15-3-1 substituted phenyl or R 15- 3-1 are independently C 1 ⁇ 10 alkyl group or a halogen-substituted C 1 ⁇ 10 alkyl group (e.g., F substituted alkyl group of C 1 ⁇ 3, another example trifluoromethyl);
  • the R 15-1 , R 15-2 , R 16-1 , R 16-2 , R 15-3 , R 18-1 , R 20-1 and R 23-1 and R 15-3-1 The number is one or more, and when there are more than one, the same or different.
  • the ee value of the compound E is preferably >86%, more preferably >90%; most preferably >93%.
  • the conditions and operations of the Suzuki-Miyaura coupling reaction can be conventional conditions and operations of this type of reaction in the art.
  • the following conditions are preferred in the present invention:
  • the palladium catalyst is preferably one of palladium chloride, palladium hydroxide, bis(acetonitrile) palladium chloride, tris(dibenzylideneacetone) dipalladium, and palladium acetate.
  • the palladium catalyst is preferably one of palladium chloride, palladium hydroxide, bis(acetonitrile) palladium chloride, tris(dibenzylideneacetone) dipalladium, and palladium acetate.
  • One or more, preferably tris(dibenzylideneacetone)dipalladium is preferably one of palladium chloride, palladium hydroxide, bis(acetonitrile) palladium chloride, tris(dibenzylideneacetone) dipalladium, and palladium acetate.
  • One or more, preferably tris(dibenzylideneacetone)dipalladium is preferably one of palladium chloride, palladium hydroxide,
  • the molar ratio of the palladium catalyst to the compound C is preferably 0.0005 to 0.01, such as 0.001, or 0.005.
  • the molar ratio of the compound represented by formula I to the compound C is preferably 0.001 to 0.02, such as 0.002, or 0.01.
  • the basic reagent is preferably an inorganic weak base.
  • the inorganic weak base is preferably one or more of alkali metal carbonate, alkali metal fluoride salt and alkali metal phosphate, more preferably alkali metal phosphate, and further preferably potassium phosphate.
  • the molar ratio of the alkaline reagent to the compound C is preferably 1 to 5, such as 3.
  • the molar ratio of the compound D to the compound C is preferably 1 to 4, such as 2.
  • the amount of the solvent is not specifically limited, as long as it does not affect the progress of the reaction.
  • the solvent is preferably a mixed solvent of an organic solvent and water.
  • the organic solvent is preferably one or more of aromatic hydrocarbon solvents, alcohol solvents, amide solvents, ether solvents and sulfoxide solvents, more preferably aromatic hydrocarbon solvents.
  • the aromatic hydrocarbon solvent is preferably toluene.
  • the alcohol solvent is preferably n-butanol and/or 3-pentanol.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the ether solvent is preferably tetrahydrofuran and/or dioxane.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the volume ratio of the organic solvent to water is preferably 10:1 to 4:1, such as 5:1.
  • the reaction temperature is preferably 40-100°C, more preferably 55-80°C.
  • the compound C is preferably any one of the following compounds:
  • the compound D is preferably any one of the following compounds:
  • the monitoring method for the progress of the reaction can be a conventional monitoring method in the art (such as TLC, HPLC, LC-MS), and generally the disappearance of compound III or no longer reacting is used as the end point of the reaction.
  • the reaction time is preferably 4-24 hours, more preferably 8-20 hours.
  • the present invention also provides a compound represented by formula E or its enantiomer ent-E:
  • the compound represented by formula E or its enantiomer is preferably any one of the following compounds:
  • the present invention also provides a compound represented by formula Y:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 9 are the same as described above.
  • the present invention also provides an application of the compound represented by formula Y as a catalyst in the Suzuki-Miyaura coupling reaction:
  • the Suzuki-Miyaura coupling reaction includes the following steps: under the catalysis of the compound Y, the compound C and the compound D are subjected to the Suzuki-Miyaura coupling reaction in a solvent in the presence of a basic reagent to obtain the compound E or the compound ent-E is fine;
  • the single crystal parameters of the compound represented by formula Y-1 are shown in Table 1:
  • the phosphine ligands of the present invention can not only synthesize a series of ortho positions in high yields in the asymmetric Suzuki-Miyaura coupling reaction (especially the coupling reaction with large steric hindrance).
  • Four-substituted biaryl compounds The use of a single configuration of phosphine ligands can also produce ortho-four-substituted biaryl compounds with high optical purity (ee value>86%) in high yield, and has high compatibility with substrates of different functional groups (especially aldehyde groups). ) And mild reaction conditions (no need for high temperature or strong alkali).
  • the ortho-four-substituted biaryl compounds with axial chirality that have been reported so far are usually through resolution or desymmetrical strategies, which often requires obtaining achiral or racemic biaryl compounds first.
  • the synthesis steps are relatively cumbersome; the chiral prosthetic group strategy requires a stoichiometric chiral source.
  • the chemical reaction economy is relatively low; for the use of asymmetric aromatic cyclization strategy to construct chiral neighbors
  • the reaction substrate is often more complicated and poor in practicality.
  • the chiral biaryl compound obtained by the invention has higher optical purity and simple and easy-to-obtain raw materials, and has a strong economical and practical type.
  • the present invention has been completed on this basis.
  • the term "chiral atom” means that when different substituents are attached to the atom C or P, the atom C or P at this time is called a chiral atom.
  • "R-S configuration" is a term in the R-S system nomenclature in the nomenclature of chiral atoms. The specific nomenclature of the R-S system is as follows: when the a, b, c, d attached to the central C or P atom are different groups, the molecule is chiral.
  • alkyl is not specifically specified, and is a saturated linear or branched monovalent hydrocarbon group with the specified number of carbon atoms.
  • C 1 -C 10 alkyl means having 1-10 carbon atoms ⁇ alkyl.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl, isopropyl), butyl (such as n-butyl, isobutyl, s-butyl, t-butyl) and pentyl (such as n-pentyl, isopentyl, neopentyl).
  • alkoxy or "phenoxy” refers to an alkyl group or a phenyl group connected to other parts of the molecule through an oxygen bridge.
  • cycloalkyl or “cycloalkane” refers to a non-aromatic saturated or unsaturated cyclic hydrocarbon group with a specified number of ring carbon atoms.
  • the cycloalkyl group can be monocyclic or polycyclic (for example Two-ring and three-ring), which can be combined ring, spiro ring and bridged ring structure.
  • the cycloalkyl group optionally contains one or more double bonds or triple bonds.
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-ene Group, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclo Nonyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • Cycloalkyl also includes polycyclic cycloalkyl structures, where the polycyclic structure optionally includes saturated or partially fused saturated or partially unsaturated cycloalkyl or heterocyclyl or aryl or heteroaryl rings Unsaturated cycloalkyl.
  • the bicyclic carbocyclic ring with 7 to 12 atoms can be arranged as a bicyclic [4,5], [5,5], [5,6] or [6,6] system, for example, or as a bridged ring system such as bi[2.2 .1]Heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
  • heterocyclic ring refers to a non-aromatic saturated or partially non-aromatic saturated or partially non-aromatic compound formed by replacing at least one ring carbon atom in a cycloalkane (as defined in the present invention) by a heteroatom selected from N, O and S. Saturated cyclic hydrocarbon group.
  • aryl or “aromatic ring” refers to any stable monocyclic or polycyclic (such as bicyclic or tricyclic) carbocyclic ring with up to 7 atoms in each ring, in which at least one ring is Aromatic ring.
  • aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl, or acenaphthyl. It is understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
  • heteroaryl or “heteroaromatic ring” refers to a stable monocyclic or polycyclic (such as bicyclic or tricyclic) carbocyclic ring with up to 7 atoms in each ring, at least one of which is aromatic Ring and contain at least one heteroatom selected from O, N and S.
  • Heteroaryl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the compound of formula I or its racemate of the present invention, as a metal ligand in the Suzuki-Miyaura coupling reaction, can obtain tetra-substituted in a high yield (yield of more than 75%) Aryl compounds.
  • the single-configuration compound represented by formula I is used as the metal ligand in the Suzuki-Miyaura coupling reaction to obtain a tetra-substituted aryl compound with axial chirality in high yield (ee value above 83%).
  • Fig. 1 is an X-single crystal diffraction pattern of the compound represented by formula Y-1 in Example 7.
  • the eluent is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 1:1.
  • the eluent containing the product (e) is concentrated and spin-dried to obtain a colorless oily liquid, which solidifies after standing to obtain a colorless waxy solid with a yield of 0.66 g and a yield of 87%.
  • the reaction mixture was stirred at 70°C for 12 hours and then cooled to room temperature. Under an ice water bath, a degassed 30% sodium hydroxide solution (15 mL) was slowly added dropwise to the reaction system, and then the reaction system was raised to room temperature and stirred for 2 hours. Add ethyl acetate (10mL) to the reaction solution, shake well and separate the organic phase. The aqueous phase was extracted with ethyl acetate (10mL ⁇ 4). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated at 20°C.
  • Reference Example 1 prepared 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-diisopropylphenyl)-2, 3-Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol.
  • Reference Example 1 prepared 3-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-bis(3,3,4,4- Tetramethylcyclopentyl)phenyl)-2,3-dihydrobenzo[d][1,3]oxy, phosphine-pentanyl)-pentanol.
  • the reaction mixture was stirred at 70°C for 12 hours and then cooled to room temperature. Under an ice water bath, a degassed 30% sodium hydroxide solution (10 mL) was slowly added dropwise to the reaction system, and then the reaction system was raised to 60° C. and stirred for 30 minutes. After cooling to room temperature, ethyl acetate (10 mL) was added to the reaction solution. After shaking well, the organic phase was separated. The aqueous phase was extracted with ethyl acetate (10 mL ⁇ 4). The organic phases were combined and dried over anhydrous sodium sulfate.
  • the raw material a was replaced with the raw material ent-a, referring to the preparation method of Example 1, the enantiomer 2-((2R,3R)-3-tert-butyl-4-(2,6) of the ligand I-6 was prepared.
  • Culturing single crystals by volatilization method weigh 25 mg of compound Y product into a 10 mL test tube, add 0.5 mL of dichloromethane to dissolve, and then add 2 mL of n-hexane. Place the test tube in an Erlenmeyer flask containing n-hexane, seal the Erlenmeyer flask and place it at 0°C for crystallization.
  • reaction steps are as follows: 2-bromo-3,4-dimethoxybenzaldehyde (13a, 60mg, 0.24mmol), 2-formyl-6-methoxyphenyl potassium trifluoroborate (14a, 68mg, 0.28 mmol) and potassium phosphate (156mg, 0.72mmol) were added to a 10mL Schlenk tube, and the air in the Schlenk tube was replaced with nitrogen for three times.
  • the crude product is purified by silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 4:1.
  • the eluent containing product (15a) is concentrated and spin-dried to obtain a colorless waxy solid (S)-5,6,6'-trimethoxybiphenyl-2,2'-dialdehyde (E-15a), yield 63mg, yield 86%.
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (I-6, BaryPhos) is used as a chiral ligand.
  • the aromatics are catalyzed by transition metal palladium.
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium Substitute 13d and potassium arylfluoroborate 14a participate in the asymmetric Suzuki-Miyaura coupling reaction to prepare ortho-tetra-substituted biaryl compound E-15d with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium Substitute 13e and potassium arylfluoroborate 14b participate in the asymmetric Suzuki-Miyaura coupling reaction to prepare ortho-tetrasubstituted biaryl compound E-15e with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13f and potassium arylfluoroborate 14a prepares the ortho-tetra-substituted biaryl compound E-15f with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13g and potassium arylfluoroborate 14b prepares the ortho-tetra-substituted biaryl compound E-15g with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitution 13i and potassium arylfluoroborate 14c prepares the ortho-tetra-substituted biaryl compound E-15i with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitution 13k and potassium arylfluoroborate 14a prepares the ortho-tetra-substituted biaryl compound E-15k with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13l and potassium arylfluoroborate 14a prepares the ortho-tetra-substituted biaryl compound E-15l with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitution 13m and potassium arylfluoroborate 14a prepares the ortho-tetra-substituted biaryl compound E-15m with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13n and potassium arylfluoroborate 14b prepares the ortho-tetra-substituted biaryl compound E-15n with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13o and potassium arylfluoroborate 14a prepares the ortho-tetra-substituted biaryl compound E-15o with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium Substitute 13q and potassium arylfluoroborate 14a participate in the asymmetric Suzuki-Miyaura coupling reaction to prepare ortho-tetra-substituted biaryl compound E-15q with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium The asymmetric Suzuki-Miyaura coupling reaction involving the substitution 13r and potassium arylfluoroborate 14b prepares the ortho-tetra-substituted biaryl compound E-15r with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugated)-propanol (6, BaryPhos) is used as a chiral ligand, through transition metal palladium catalyzed aryl halide 13e and aryl boronic acid 14d.
  • the asymmetric Suzuki-Miyaura coupling reaction to prepare the ortho-four-substituted biaryl compound E-15s with axial chirality (the reaction route is shown below).
  • reaction steps are as follows: N-(3-bromo-2-formyl-4,5-dimethoxyphenyl) pivalamide (13e, 82mg, 0.24mmol), 2-methoxy-1-naphthaleneboronic acid (14d, 97mg, 0.48mmol) and potassium phosphate (156mg, 0.72mmol) were added to a 10mL Schlenk tube, and the air in the Schlenk tube was replaced with nitrogen for three times.
  • the crude product is purified by silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1.
  • the eluent containing the product (15s) is concentrated and spin-dried to obtain a white solid (S)-N-(2-formyl-4,5-dimethoxy-3-(2-methoxy-1-naphthyl) ) Phenyl) pivalamide (E-15s), yield 83mg, yield 82%.
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium
  • the asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13u and the aryl boronic acid 14d prepares the ortho-tetra-substituted biaryl compound E-15x with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium
  • the asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13v and the aryl boronic acid 14d prepares the ortho-tetra-substituted biaryl compound E-15z with axial chirality (the reaction route is shown below).
  • the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)-2,3- Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) is used as a chiral ligand.
  • aryl halide catalyzed by transition metal palladium
  • the asymmetric Suzuki-Miyaura coupling reaction involving the substitute 13x and the aryl boronic acid 14f prepares the ortho-tetrasubstituted biaryl compound E-15ad with axial chirality (the reaction route is shown below).
  • the yield was 87%.
  • the enantiomeric excess value (ee) was determined by chiral high pressure liquid phase, and the measured ee value was 86%; high pressure liquid phase conditions: chiral AD-H column, 25°C, flow rate: 1 mL/min, n-hexane/isopropyl Alcohol: 70/30, 210nm, 6.70min(S), 9.67min(R);
  • the yield was 83%.
  • the enantiomeric excess value (ee) is determined by the chiral high pressure liquid phase, and the measured ee value is 90%; the high pressure liquid phase conditions: chiral AD-H column, 25°C, flow rate: 1 mL/min, n-hexane/isopropyl Alcohol: 70/30, 210nm, 6.70min(S), 9.67min(R);
  • the yield was 83%.
  • the enantiomeric excess value (ee) was determined by chiral high pressure liquid phase, and the measured ee value was 64%; high pressure liquid phase conditions: chiral AD-H column, 25°C, flow rate: 1 mL/min, n-hexane/isopropyl Alcohol: 70/30, 210nm, 6.70min(S), 9.67min(R).
  • the yield was 75%.
  • the enantiomeric excess (ee) was determined by the chiral high pressure liquid phase, and the measured ee value was 84%; the high pressure liquid phase conditions: chiral AD-H column, 25°C, flow rate: 1 mL/min, n-hexane/isopropyl Alcohol: 70/30, 210nm, 6.70min(S), 9.67min(R).
  • Example 1 the compound 2-((2S,3S)-3-tert-butyl-4-(2,6-dimethoxy-3,5-dicyclopentylphenyl)- 2,3-Dihydrobenzo[d][1,3]oxy, phosphine-pentyl conjugate)-propanol (6, BaryPhos) racemate.
  • this racemate as a ligand, referring to the preparation method of Example 8 or Example 26, asymmetric Suzuki-Miyaura coupling of aryl halide and aryl boronic acid or potassium aryl fluoroborate catalyzed by transition metal palladium
  • the racemic biaryl compound is prepared by the reaction, and the yield is 80-92%.
  • This example is mainly used to prepare the racemate in the example, which serves as a control for determining the enantiomeric excess (ee) of a chiral sample.
  • the yield is similar to that of the chiral product in the above example.
  • reaction steps are as follows: 2-bromo-3,4-dimethoxybenzaldehyde (13a, 60mg, 0.24mmol), 2-formyl-6-methoxyphenyl potassium trifluoroborate (14a, 68mg, 0.28 mmol) and potassium phosphate (156mg, 0.72mmol) were added to a 10mL Schlenk tube, and the air in the Schlenk tube was replaced with nitrogen for three times. Under the protection of nitrogen, degassed toluene (4 mL), deionized water (0.8 mL), and metal complex Y-1 (2.0 mg, 0.0012 mmol) were sequentially added. The reaction system was stirred at 60°C for 15 hours and then cooled to room temperature.
  • the enantiomeric excess value (ee) was determined by chiral high pressure liquid phase, and the measured ee value was 92%; high pressure liquid phase conditions: chiral AD-H column, 25°C, flow rate: 1 mL/min, n-hexane/isopropyl Alcohol: 70/30, 210nm, 6.70min(S), 9.67min(R).
  • the use of metal complex Y-1 as a chiral catalyst has the same ee value as the biaryl product obtained in Example 8.

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Abstract

本发明公开了一种膦配体及其制备方法和催化合成邻位四取代联芳烃的应用。本发明的膦配体的结构如式I所示。本发明的膦配体或其消旋体可作为金属配体，可高收率或者高光学纯度得到多种官能团的邻位四取代联芳基类化合物。

Description

膦配体及其制备方法和催化合成邻位四取代联芳烃的应用
本申请要求申请日为2019年3月5日的中国专利申请201910165339X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种膦配体及其制备方法和催化合成邻位四取代联芳烃的应用。
背景技术
许多天然产物和药物分子具有轴手性的联芳基结构，例如，在萘异喹啉类生物碱大家族中，如Korupensamine A、Korupensamine B和Michellamine B。Korupensamine A和Korupensamine B均有较高的抗疟活性。Michellamine B因为具有较强的抗HIV活性曾用作临床药物(J.Nat.Prod.1997,60,677；J.Med.Chem.1991,34,3402；Chem.Rev.2011,111,563)。与此同时，具有轴手性的邻位四取代手性联芳基结构也广泛存在于许多天然产物和药物分子中，例如，色酮内酯类天然产物gonytolide A。Gonytolide A可显著的激发哺乳动物天然免疫反应的活性(Org.Lett.2011,13,4624)。吡喃萘醌二聚体cardinalin 3对某些白血病细胞显示出很强的体内细胞毒性(J.Chem.Soc.,Perkin Trans.1997,6,919；Nat.Prod.Lett.1994,5,211；Aust.J.Chem.1997,50,1081)。棉酚是一个多酚类天然产物。在二十世纪中期，棉酚作为一个男性避孕药在中国上市(J.Am.Oil Chem.Soc.2006,83,269)。之后，棉酚及其衍生物的一系列生物活性，包括抗虫、抗疟疾、抗肿瘤和病毒抑制等活性，相继被报道(Future Med.Chem.2017,9,11；Science.1982,218,288；Carbohydr.Res.2011,346,2070；J.Med.Chem.1998,41,3879；Cancer Res.1990,50,6936；Bioorg.Med.Chem.Lett.2012,22,1415；Bioorg.Med.Chem.2016,24,474；Bioorg.Med.Chem.Lett.2018,28,49；Mol.Carcinogen.2018,57,1213；Front.Pharmacol.2018,9,728)。
具有轴手性的邻位四取代联芳基化合物的制备方法主要有拆分消旋化合物、用手性试剂或辅助基团诱导、以及不对称催化。拆分消旋化合物要消耗50％的原料，用手性试剂或辅助基团诱导要消耗手性源。与它们相比，不对称催化方法利用催化量的手性催化剂，表现出明显的高效性和经济性。
不对称偶联是现有合成手性联芳基不对称催化方法中效率最高、实用性最强的方法之一。尽管用不对称偶联合成邻位四取代联芳基化合物的方法已有所研究(Angew.Chem.Int.Ed.2017,56,4777；J.Am.Chem.Soc.2002,124,13396；Eur.J.Org.Chem.2014,6676；Chem.Eur.J.2006,12,9346；Org.Lett.2010,12,1072.)，但现有方法仍然存在许多缺点，反应底物结构单一、官能团容忍性差、偶联效率或者对映选择性不够高等等。例如，下述手性膦配体被用于合成具有轴手性的邻位四取代2,2’-二甲基-1.1’-联萘，虽然某些膦配体 可以得到一定的产率和ee值，但这些手性膦配体在合成具有轴手性的邻位四取代联芳基结构中的取代基的普适性并没有深入研究，因而所得到的手性邻位四取代联芳基结构较为单一。
Figure PCTCN2020077397-appb-000001
尤其是，对于含有醛基的手性邻位四取代联苯基类化合物的报道更少。目前报道的含有醛基的手性邻位四取代联苯基类化合物的收率和对映选择性也一般。
Figure PCTCN2020077397-appb-000002
综上所述，本领域急需开发一类具有实用性更强、效率更高的催化剂，以便高效合成多种官能团的邻位四取代联芳基类化合物，尤其具有轴手性的邻位四取代联芳基类化合物。
发明内容
本发明所要解决的技术问题是为了克服现有技术中合成邻位四取代联芳基类化合物，收率低、光学纯度低、或者取代基种类单一的缺陷，而提供的一种膦配体及其制备方法和催化合成邻位四取代联芳烃的应用。本发明的膦配体应用到不对称Suzuki-Miyaura偶联反应中，可高收率得到多种取代基的邻位四取代联芳基化合物，尤其是高选择性的得到具有轴手性的邻位四取代联芳基化合物，而且反应条件温和。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种膦配体，其为如式I所示的化合物或其消旋体：
Figure PCTCN2020077397-appb-000003
其中，“*”表示此处的原子为手性原子；R 1、R 3和R 5独立地为氢、C 1～10烷基、C 1～10杂烷基、C 3～30环烷基、R 1-1a取代的C 3～30环烷基、C 6～30芳基或R 1-1b取代的C 6～30芳基；所述C 1～10杂烷基中的杂原子选自O、S和N中的一种或多种，个数为1、2、3、4、5或6；当杂原子的个数为多个时，杂原子相同或不相同；
R 2和R 4独立地为C 1～10烷基、C 1～10杂烷基、C 3～30环烷基、R 2-1a取代的C 3～30环烷基、C 6～30芳基或R 2-1b取代的C 6～30芳基；所述C 1～10杂烷基中的杂原子选自O、S和N中的一种或多种，个数为1、2、3、4、5或6；当杂原子的个数为多个时，杂原子相同或不相同；
每个R 1-1a和每个R 2-1a独立为C 1～10烷基；R 1-1a和R 2-1a个数为1个或多个；当R 1-1a和R 2-1a个数独立地为多个，R 1-1a和R 2-1a独立地相同或不相同；
每个R 1-1b和每个R 2-1b独立地为C 1～10烷基、C 1～10烷氧基或C 6～30芳基；当每个R 1-1b和每个R 2-1b个数独立地为多个，R 1-1b和R 2-1b独立地相同或不相同；
R 6和R 7独立地为H、C 1～10烷基、羟基取代的C 1～10烷基、C 3～30环烷基或C 6～30芳基；
R 8为羟基、C 1～10烷基、羟基取代的C 1～10烷基、C 1～10烷氧基、
Figure PCTCN2020077397-appb-000004
C 3～30环烷基、巯基或C 6～30芳基，其中，R 10和R 11独立地为H或C 1～4烷基；
R 9为C 1～10烷基、C 3～30环烷基或C 6～30芳基。
当所述R 1、R 3和R 5独立地为C 1～10烷基时，所述C 1～10烷基可为C 1～6烷基，优选C 1～3烷基。所述C 1～3烷基可为甲基、乙基、正丙基或异丙基，优选甲基或异丙基。
当所述R 1、R 3和R 5独立地为C 1～10杂烷基时，所述C 1～10杂烷基可为C 1～6杂烷基。
当所述R 1、R 3和R 5独立地为C 3～30环烷基时，所述C 3～30环烷基可为C 3～10环烷基。
当所述R 1、R 3和R 5独立地为R 1-1a取代的C 3～30环烷基时，所述R 1-1a取代的C 3～30环烷基中的C 3～30环烷基可为C 3～10环烷基。
当所述R 1、R 3和R 5独立地为C 6～30芳基时，所述C 6～30芳基可为C 6～14芳基。
当所述R 1、R 3和R 5独立地为R 1-1b取代的C 6～30芳基时，所述R 1-1b取代的C 6～30芳基 中的C 6～30芳基可为C 6～14芳基。
当所述R 2和R 4独立地为C 1～10烷基时，所述C 1～10烷基可为直链C 1～10烷基或支链C 3～10烷基，优选支链C 3～10烷基。其中，所述直链C 1～10烷基可为直链C 1～6烷基，优选直链C 1～3烷基。所述支链C 3～10烷基可为支链C 3～6烷基，优选支链C 3～5烷基。所述支链C 3～5烷基可为异丙基、
Figure PCTCN2020077397-appb-000005
Figure PCTCN2020077397-appb-000006
优选异丙基或
Figure PCTCN2020077397-appb-000007
当所述R 2和R 4独立地为C 3～30环烷基时，所述C 3～30环烷基可为C 3～10环烷基，优选C 3～6环烷基。
当所述R 2和R 4独立地为R 2-1a取代的C 3～30环烷基时，R 2-1a取代的C 3～30环烷基中的C 3～30环烷基可为C 3～10环烷基，优选C 3～6环烷基。所述C 3～6环烷基可为环丙基、环丁基、环戊基或环己基，优选环戊基。
当所述R 2和R 4独立地为R 2-1a取代的C 3～30环烷基时，所述R 2-1a取代的C 3～30环烷基中的R 2-1a个数可为1、2、3或4个，优选4个。当所述R 2-1a取代的个数为多个时，所述R 2-1a优选相同。
当所述R 2-1a为C 1～10烷基时，所述C 1～10烷基可为C 1～6烷基，优选C 1～3烷基。所述C 1～3烷基可为甲基、乙基、正丙级或异丙基，优选甲基。
当所述R 2和R 4独立地为R 2-1a取代的C 3～30环烷基时，所述R 2-1a取代的C 3～30环烷基可为C 1～3烷基取代的C 3～6环烷基，进一步优选
Figure PCTCN2020077397-appb-000008
当所述R 2和R 4独立地为C 6～30芳基时，所述C 6～30芳基可为C 6～20芳基，优选C 6～14芳基，进一步优选为苯基。
当所述R 1、R 2、R 3、R 4和R 5独立地为R 2-1b取代的C 6～30芳基时，所述R 2-1b取代的C 6～30芳基中的C 6～30芳基可为C 6～20芳基，优选C 6～14芳基。
当所述R 6和R 7独立地为C 1～10烷基时，所述C 1～10烷基可为C 1～6烷基，优选C 1～3烷基。所述C 1～3烷基可为甲基、乙基、正丙基或异丙基。
当所述R 6和R 7独立地为羟基取代的C 1～10烷基时，所述羟基取代的C 1～10烷基中的C 1～10烷基可为C 1～6烷基，优选C 1～3烷基。所述C 1～3烷基可为甲基、乙基、正丙基或异丙基，优选甲基。
当所述R 6和R 7独立地为C 3～30环烷基时，所述C 3～30环烷基可为C 3～10环烷基。
当所述R 6和R 7独立地C 6～30芳基时，所述C 6～30芳基可为C 6～20芳基。
当所述R 8为C 1～10烷基时，所述C 1～10烷基可为C 1～6烷基，优选C 1～3烷基。所述C 1～3 烷基可为甲基、乙基、正丙基或异丙基，优选甲基。
当所述R 8为羟基取代的C 1～10烷基时，所述羟基取代的C 1～10烷基中的C 1～10烷基可为C 1～6烷基，优选C 1～3烷基。所述C 1～3烷基可为甲基、乙基、正丙基或异丙基，优选甲基。
当所述R 8为羟基取代的C 1～10烷基时，所述羟基取代的C 1～10烷基中的羟基的个数可为1个。
当所述R 8独立地为C 1～10烷氧基时，所述C 1～10烷氧基可为C 1～6烷氧基，优选C 1～3烷氧基。所述C 1～3烷氧基可为甲氧基、乙氧基、正丙氧基或异丙氧基，优选甲氧基。
当所述R 8为
Figure PCTCN2020077397-appb-000009
时，所述
Figure PCTCN2020077397-appb-000010
可为
Figure PCTCN2020077397-appb-000011
Figure PCTCN2020077397-appb-000012
优选
Figure PCTCN2020077397-appb-000013
当所述R 8为C 3～30环烷基时，所述C 3～30环烷基可为C 3～10环烷基。
当所述R 8为C 6～30芳基时，所述C 6～30芳基可为C 6～20芳基。
当R 9为C 1～10烷基时，所述C 1～10烷基可为直链C 1～10烷基或支链C 3～10烷基，优选支链C 3～10烷基。其中，所述直链C 1～10烷基可为直链C 1～6烷基，优选直链C 1～3烷基。所述支链C 3～10烷基可为支链C 3～6烷基，优选支链C 3～4烷基。所述支链C 3～4烷基可为异丙基、
Figure PCTCN2020077397-appb-000014
或叔丁基，又可为叔丁基。
当所述R 9为C 3～30环烷基时，所述C 3～30环烷基可为C 3～10环烷基。
当所述R 9为C 6～30芳基时，所述C 6～30芳基可为C 6～20芳基。
当所述R 10和R 11独立地为C 1～4烷基时，所述C 1～4烷基为甲基、乙基、正丙基、异丙基、正丁基、
Figure PCTCN2020077397-appb-000015
或叔丁基。
在本发明一实施方案中，所述的如式I所示化合物为
Figure PCTCN2020077397-appb-000016
在本发明一实施方案中，R 1和R 5独立地为C 1～10烷基。
在本发明一实施方案中，R 1和R 5相同。
在本发明一实施方案中，R 2和R 4独立地为C 1～10烷基、C 3～30环烷基、R 2-1a取代的C 3～30环烷基或C 6～30芳基。
在本发明一实施方案中，R 2和R 4独立地为C 3～30环烷基或R 2-1a取代的C 3～30环烷基。
在本发明一实施方案中，R 2和R 4相同。
在本发明一实施方案中，R 3为氢。
在本发明一实施方案中，R 6和R 7独立地为H、C 1～10烷基或羟基取代的C 1～10烷基。
在本发明一实施方案中，R 6和R 7独立地为C 1～10烷基。
在本发明一实施方案中，R 8为羟基、C 1～10烷基、C 1～10烷氧基或
Figure PCTCN2020077397-appb-000017
在本发明一实施方案中，R 8为羟基。
在本发明一实施方案中，R 9为C 1～10烷基。
在本发明一实施方案中，
Figure PCTCN2020077397-appb-000018
为
Figure PCTCN2020077397-appb-000019
Figure PCTCN2020077397-appb-000020
在本发明一实施方案中，
Figure PCTCN2020077397-appb-000021
为
Figure PCTCN2020077397-appb-000022
在本发明一实施方案中，所述如式I所示化合物中，
Figure PCTCN2020077397-appb-000023
为
Figure PCTCN2020077397-appb-000024
Figure PCTCN2020077397-appb-000025
在本发明一实施方案中，所述如式I所示化合物中，
Figure PCTCN2020077397-appb-000026
为
Figure PCTCN2020077397-appb-000027
Figure PCTCN2020077397-appb-000028
在本发明一实施方案中，R 1和R 5独立地为C 1～10烷基；R 2和R 4独立地为C 1～10烷基、C 3～30环烷基、R 2-1a取代的C 3～30环烷基或C 6～30芳基；R 3为氢；
R 6和R 7独立地为H、C 1～10烷基或羟基取代的C 1～10烷基；R 8为羟基、C 1～10烷基、 C 1～10烷氧基或
Figure PCTCN2020077397-appb-000029
和，R 9为C 1～10烷基。
在本发明一实施方案中，R 1和R 5独立地为C 1～10烷基；R 2和R 4独立地为C 3～30环烷基或R 2-1a取代的C 3～30环烷基；R 3为氢；R 6和R 7独立地为C 1～10烷基；R 8为羟基；和，R 9为C 1～10烷基。
所述如式I所示化合物任选如下任一化合物：
Figure PCTCN2020077397-appb-000030
本发明还提供了一种所述如式I所示的化合物或其消旋体的制备方法，其包括如下步骤：在还原剂存在下，将化合物II在有机溶剂中进行如下式的还原反应，得到化合物I，即可；
Figure PCTCN2020077397-appb-000031
其中，“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义均同前所述。
所述还原反应中，所述还原剂可以为本领域该类反应常规的还原剂，优选卤代硅烷类还原剂和/或聚硅烷类还原剂。所述卤代硅烷类还原剂可为三氯硅烷。所述聚硅烷类还原剂可为聚甲氧基氢硅烷。所述还原剂的用量可为常规用量，优选所述还原剂与所述化合物II的摩尔比值为1～10，例如8。
其中，当所述还原剂为卤硅烷类还原剂时，所述还原反应优选在缚酸剂存在下进行还原反应。所述缚酸剂可为常规的缚酸剂，优选无机弱碱和/或有机弱碱，更优选有机弱碱，进一步优选叔胺类有机弱碱。当所述还原剂为聚硅烷类还原剂时，所述还原反应优选在钛酸四异丙酯存在下进行还原反应。
所述还原反应中，所述有机溶剂可为本领此类反应的常规溶剂，优选芳烃类溶剂和/或醚类溶剂。所述芳烃类溶剂可为甲苯好或苯，又可为甲苯。所述有机溶剂的用量可不做具体的限定，只要不影响反应进行即可。
所述还原反应中，所述还原反应的温度可为本领域此类反应的常规温度，优选60～80℃，例如70℃。
所述化合物II优选
Figure PCTCN2020077397-appb-000032
Figure PCTCN2020077397-appb-000033
所述还原反应中，所述还原反应的进程的监测方法可为本领域常规的监测方法(例如TLC、HPLC、LC-MS)，一般以化合物II消失或者不再反应作为反应的终点。所述还原反应的时间优选8～24小时，例如12小时。
所述还原反应结束后，还可包括以下后处理步骤：将反应结束后的反应液冷却至室温，调节反应液至中性，萃取(萃取溶剂优选乙酸乙酯)、干燥、浓缩和柱层析(洗脱剂 优选石油醚-乙酸乙酯，其体积比20:1～10:1，例如15:1)。
本发明还提供了一种如式II所示的化合物或其消旋体：
Figure PCTCN2020077397-appb-000034
其中，“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义均同前所述。
所示如式II所示的化合物或其消旋体优选如下任一化合物：
Figure PCTCN2020077397-appb-000035
本发明还提供了一种上述如式II所示的化合物或其消旋体的制备方法，其包括以下步骤：
在碱性试剂作用下，将化合物III与化合物A在有机溶剂中进行如下式的反应，得到化合物II即可；
Figure PCTCN2020077397-appb-000036
其中，X为卤素；R 12a和R 12b独立地为H、C 1～10烷基、羟基取代的C 1～10烷基、C 3～30 环烷基或C 6～30芳基；R 13a和R 13b独立地为H或C 1～4烷基，R 13a和R 13b不同时为H；R 14为C 1～10烷基、羟基取代的C 1～10烷基或C 1～10烷氧基；“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义均同前所述。
X中，所述卤素为Cl、Br或I。
R 12a和R 12b中，所述C 1～10烷基独立地可为C 1～6烷基，优选C 1～3烷基，进一步优选甲基、乙基、正丙基或异丙基，更进一步优选甲基、乙基或异丙基。
R 12a和R 12b中，所述羟基取代的C 1～10烷基中的C 1～10烷基独立地可为C 1～6烷基，优选C 1～3烷基，进一步优选甲基、乙基、正丙基或异丙基，更进一步优选甲基。
R 12a和R 12b中，所述C 3～30环烷基可为C 3～10环烷基，优选C 3～6环烷基。
R 12a和R 12b中，所述C 6～30芳基可为C 6～18芳基，优选C 6～14芳基。
R 13a和R 13b中，所述C 1～4烷基独立可为甲基、乙基、正丙基、异丙基、正丁基、
Figure PCTCN2020077397-appb-000037
Figure PCTCN2020077397-appb-000038
或者叔丁基，优选甲基。
R 14中，所述C 1～10烷基可为C 1～6烷基，优选C 1～3烷基，进一步优选甲基、乙基、正丙基或异丙基，更进一步优选甲基。
R 14中，所述C 1～10烷氧基可为C 1～6烷氧基，优选C 1～3烷氧基，进一步优选甲氧基、乙氧基、正丙氧基或异丙氧基，更进一步优选甲氧基。
所述反应中，所述碱性试剂可为本领域常规的碱性试剂，优选二异丙基胺基锂、双(三甲基硅基)氨基锂、双(三甲基硅基)氨基钾和双(三甲基硅基)氨基钠或氢化钠中一种或多种，更优选二异丙基胺基锂或双(三甲基硅基)氨基锂。
所述反应中，所述碱性试剂与所述化合物III的摩尔比值可为本领域此类反应常规的比值，优选1.0～5.0，例如4.0。
所述反应中，所述有机溶剂可为本领域此类反应常规的有机溶剂，优选芳烃类溶剂(例如甲苯)、醚类溶剂(例如四氢呋喃、二氧六环、乙醚)和卤代烃类溶剂(例如二氯甲烷)中的一种或多种，更优选醚类溶剂。所述有机溶剂的用量可不做具体的限定，只要不影响反应即可。
所述反应中，所述化合物A与所述化合物III的摩尔比值可为本领域此类反应常规的比值，优选1～5.0，例如2.0。
所述反应中，所述反应的温度可为本领域常规的温度，优选-78～30℃。
所述化合物III优选
Figure PCTCN2020077397-appb-000039
所述化合物A优选丙酮或
Figure PCTCN2020077397-appb-000040
所述反应的进程的监测方法可为本领域常规的监测方法(例如TLC、HPLC、LC-MS)，一般以化合物III消失或者不再反应作为反应的终点。所述还原反应的时间优选1～5小时，例如2小时。
所述反应结束后，其还可包括以下后处理步骤：将反应结束后的反应液冷却，淬灭(淬灭的试剂为饱和氯化铵)、萃取(萃取溶剂优选乙酸乙酯)、水洗(采用饱和食盐水进行水洗)、干燥、浓缩和柱层析(洗脱剂优选石油醚-乙酸乙酯，其体积比1:1～5:1，例如2:1)。
本发明还提供了一种如式III所示的化合物：
Figure PCTCN2020077397-appb-000041
其中，R 1、R 2、R 3、R 4、R 5和R 9均同前所述。
所示如式III所示的化合物可为
Figure PCTCN2020077397-appb-000042
本发明还提供了一种上述的如式I所示的化合物或消旋体在Suzuki-Miyaura偶联反应中作为金属配体的应用：所述Suzuki-Miyaura偶联反应，其包括以下步骤：在钯催化剂、所述化合物I和碱性试剂存在下，将化合物C和化合物D在溶剂中进行Suzuki-Miyaura偶联反应，得到化合物E或者化合物ent-E即可；
Figure PCTCN2020077397-appb-000043
或者，所述Suzuki-Miyaura偶联反应，其包括以下步骤：在钯催化剂、所述化合物I消旋体和碱性试剂存在下，将化合物C和化合物D在溶剂中进行Suzuki-Miyaura偶联反应，得到化合物E和化合物ent-E即可；
Figure PCTCN2020077397-appb-000044
其中，“
Figure PCTCN2020077397-appb-000045
与
Figure PCTCN2020077397-appb-000046
”和“
Figure PCTCN2020077397-appb-000047
与
Figure PCTCN2020077397-appb-000048
”，均表示此基团具有轴手性；Q为C或N；当Q为N时，R 18不存在；X为卤素(例如Cl、Br或I)；M为
Figure PCTCN2020077397-appb-000049
或-BF 3K(例如
Figure PCTCN2020077397-appb-000050
或-BF 3K)；
R 15、R 19、R 20和R 24独立地为F、C 1～10烷基(例如C 1～6烷基，又例如C 1～3烷基，再例如甲基)、C 1～10烷氧基(例如C 1～6烷氧基，又例如C 1～3烷氧基，再例如甲氧基)、C 6～30芳基(例如C 6～14芳基，再例如苯基)、R 15-1取代的C 6～30芳基(例如C 6～14芳基)、苯氧基、R 15-2取代的苯氧基、-CHO或-OSO 2F；
R 16、R 17、R 18、R 21、R 22和R 23独立地为H、F、C 1～10烷基(例如C 1～6烷基，又例如C 1～3烷基，再例如甲基)、C 1～10烷氧基(例如C 1～6烷氧基，又例如C 1～3烷氧基，再例如甲氧基)、C 6～30芳基(例如C 6～14芳基，再例如苯基)、R 16-1取代的C 6～30芳基(例如C 6～14芳 基)、苯氧基、R 16-2取代的苯氧基、C 1～10硅烷基(C 1～6硅烷基，又例如C 1～3硅烷基，再例如三甲基硅烷基)、NHPiv、-CHO或-OSO 2F；或者，R 16、R 17和R 18中任意相邻的两个基团与其相连的碳原子一起形成
Figure PCTCN2020077397-appb-000051
或者，R 21、R 22和R 23中任意两个相邻的两个基团与其相连的碳原子一起形成
Figure PCTCN2020077397-appb-000052
或者，R 15和R 16与其相连的碳原子一起共同形成C 6-10芳基(例如C 6～14芳基，再例如苯基)、R 15-3取代的C 6-10芳基(例如C 6～14芳基，再例如苯基)、C 5-10环烷基、C 3-10杂芳基(例如C 3～10杂芳基，再例如吡啶基)或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5- 10杂环烷基中的杂原子选自N、S和O中的一个或多个，个数为1、2、3或4个；
或者，R 18和R 19与其相连的碳原子一起共同形成C 6-10芳基(例如C 6～14芳基，再例如苯基)、R 18-1取代的C 6-10芳基(例如C 6～14芳基，再例如苯基)、C 5-10环烷基、C 3-10杂芳基(例如C 3～10芳基，再例如吡啶基)或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5-10杂环烷基中的杂原子选自N、S和O中的一个或多个，个数为1、2、3或4个；
或者，R 20和R 21与其相连的碳原子一起共同形成C 6-10芳基(例如C 6～14芳基，再例如苯基)、R 20-1取代的C 6-10芳基(例如C 6～14芳基，再例如苯基)、C 5-10环烷基、C 3-10杂芳基(例如C 3～10芳基，再例如吡啶基)或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5-10杂环烷基中的杂原子选自N、S和O中的一个或多个，个数为1、2、3或4个；
或者，R 23和R 24与其相连的碳原子一起共同形成C 6-10芳基(例如C 6～14芳基，再例如苯基)、R 23-1取代的C 6-10芳基(例如C 6～14芳基，再例如苯基)、C 5-10环烷基、C 3-10杂芳基(例如C 3～10芳基，再例如吡啶基)或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5-10杂环烷基中的杂原子选自N、S和O中的一个或多个，个数为1、2、3或4个；
R 15-1、R 15-2、R 16-1、R 16-2独立地为C 1～10烷基、C 1～10烷氧基、苯基、硝基、-CHO或-OSO 2F；
所述R 15-3、R 18-1、R 20-1和R 23-1独立地为苯基、R 15-3-1取代的苯基或
Figure PCTCN2020077397-appb-000053
R 15- 3-1独立地为C 1～10烷基或者卤素取代的C 1～10烷基(例如F取代的C 1～3烷基，再例如三氟甲基)；
所述R 15-1、R 15-2、R 16-1、R 16-2、R 15-3、R 18-1、R 20-1和R 23-1和R 15-3-1的个数为一个或多个，当为多个时，相同或不同。
所述的应用中，所述化合物E的ee值优选>86％，更优选>90％；最优选>93％。
所述的应用中，所述Suzuki-Miyaura偶联反应的条件和操作可以为本领域该类反应的常规条件和操作，本发明优选以下条件：
所述Suzuki-Miyaura偶联反应中，所述钯催化剂优选钯催化剂为氯化钯、氢氧化钯、二(乙腈)氯化钯、三(二亚苄基丙酮)二钯和醋酸钯中的一种或多种，优选三(二亚苄基丙酮)二钯。
所述Suzuki-Miyaura偶联反应中，所述钯催化剂与所述化合物C的摩尔比值优选0.0005～0.01，例如0.001，又例如0.005。
所述Suzuki-Miyaura偶联反应中，所述如式I所示的化合物与所述化合物C的摩尔比值优选0.001～0.02，例如0.002，又例如0.01。
所述Suzuki-Miyaura偶联反应中，碱性试剂优选无机弱碱。所述无机弱碱优选碱金属碳酸盐、碱金属氟化盐和碱金属磷酸盐中的一种或多种，更优选碱金属磷酸盐，进一步优选磷酸钾。
所述Suzuki-Miyaura偶联反应中，所述碱性试剂与所述化合物C的摩尔比值优选1～5，例如3。
所述Suzuki-Miyaura偶联反应中，所述化合物D与所述化合物C的摩尔比值优选1～4，例如2。
所述Suzuki-Miyaura偶联反应中，所述溶剂的用量不做具体的限定，只要不影响反应进行即可。
所述Suzuki-Miyaura偶联反应中，所述溶剂优选有机溶剂与水的混合溶剂。所述有机溶剂优选芳烃类溶剂、醇类溶剂、酰胺类溶剂、醚类溶剂和亚砜类溶剂中的一种或多种，更优选芳烃类溶剂。所述芳烃类溶剂优选甲苯。所述醇类溶剂优选正丁醇和/或3-戊醇。所述酰胺类溶剂优选N,N-二甲基甲酰胺。所述醚类溶剂优选四氢呋喃和/或二氧六环。所述亚砜类溶剂优选二甲亚砜。所述有机溶剂与水的体积比优选10:1～4：1，例如5:1。
所述Suzuki-Miyaura偶联反应中，所述的反应温度优选40-100℃，更优选55-80℃。
所述Suzuki-Miyaura偶联反应中，所述化合物C优选如下任一化合物：
Figure PCTCN2020077397-appb-000054
所述Suzuki-Miyaura偶联反应中，所述化合物D优选如下任一化合物：
Figure PCTCN2020077397-appb-000055
所述Suzuki-Miyaura偶联反应中，所述反应的进程的监测方法可为本领域常规的监测方法(例如TLC、HPLC、LC-MS)，一般以化合物III消失或者不再反应作为反应的终点。所述的反应时间优选4-24小时，更优选8-20小时。
本发明还提供了一种如式E所示的化合物或其对映体ent-E：
Figure PCTCN2020077397-appb-000056
其中，“
Figure PCTCN2020077397-appb-000057
与
Figure PCTCN2020077397-appb-000058
”和“
Figure PCTCN2020077397-appb-000059
与
Figure PCTCN2020077397-appb-000060
”，均表示该基团具有轴手性；Q、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22和R 23和R 24均同前所述。
所述如式E所示的化合物或其对映体优选如下任一化合物：
Figure PCTCN2020077397-appb-000061
Figure PCTCN2020077397-appb-000062
本发明还提供了一种如式Y所示的化合物：
Figure PCTCN2020077397-appb-000063
其中，“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 9的定义均同前所述。
本发明还提供了一种上述如式Y所示的化合物在Suzuki-Miyaura偶联反应中作为催化剂的应用：
所述Suzuki-Miyaura偶联反应，其包括以下步骤：在所述化合物Y催化下，碱性试剂存在下，将化合物C和化合物D在溶剂中进行Suzuki-Miyaura偶联反应，得到化合物E或者化合物ent-E即可；
Figure PCTCN2020077397-appb-000064
其中，“
Figure PCTCN2020077397-appb-000065
与
Figure PCTCN2020077397-appb-000066
”和“
Figure PCTCN2020077397-appb-000067
与
Figure PCTCN2020077397-appb-000068
”，均表示此基团具有轴手性；M、Q、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24均同前所述。
本发明还提供了一种如式Y-1所示的化合物的单晶，其晶系属于单斜晶系，C 2空间群，晶胞参数为
Figure PCTCN2020077397-appb-000069
α＝γ＝90°，β＝113.055(2)°；
Figure PCTCN2020077397-appb-000070
优选，所述如式Y-1所示的化合物的单晶参数如表1所示：
表1如式Y-1所示的化合物的单晶参数
Figure PCTCN2020077397-appb-000071
Figure PCTCN2020077397-appb-000072
发明人经过持久而深入的研究，发现本发明的膦配体在进行不对称Suzuki-Miyaura偶联反应(尤其是大位阻的偶联反应)中，不仅可以高收率地合成一系列邻位四取代联芳基化合物。采用单一构型的膦配体还可高收率得到具有高光学纯度(ee值>86％)的邻位四取代联芳基化合物，而且对不同官能团的底物兼容性高(尤其是醛基)以及反应条件温和(无需高温或者强碱)。目前已报道的具有轴手性的邻位四取代联芳基化合物，通常是通过拆分或去对称化策略往往需要先得到非手性或消旋的联芳基化合物。其合成步骤较为繁琐；手性辅基策略则需要化学计量的手性源，和不对称催化偶联相比，化学反应经济性相对较低；对于利用不对称的芳香环化策略构建手性邻位四取代化合物方面，反应底物往往比较复杂，实用性较差。(Org.Biomol.Chem.,2006,4,3197；Chem.Soc.Rev.,2015,44,3418；Org.Biomol.Chem.,2017,15,4506；Acc.Chem.Res.2018,51,534)。本发明所得到的手性联芳基化合物的光学纯度更高且原料简单易得，具有很强的经济实用型。在此基础上完成了本发明。
在本发明中，术语“手性原子”是指当原子C或P上连有不同的取代基时，此时的原子C或P称为手性原子。本发明中“R-S构型”是对手性原子命名中R-S系统命名法中的术语。R-S系统具体命名法如下：当连接到中心C或P原子上的a、b、c、d是不同基团时，分子是手性的。假设分子中四个取代基按CIP顺序规则以a>b>c>d顺序排列，如果将最小d基团置于离观察者最远的位置，按a-b-c的先后顺序观察其他三个基团，观察到a→b→c是顺时针方向，则这个碳中心的构型被定义为R(拉丁文rectus)；否则就认定为S(拉丁文sinister)。
在本发明中，术语“烷基”没有特别指明，均为指定数目碳原子的饱和的直链或支链的一价烃基，例如C 1-C 10烷基是指具有1-10个碳原子的烷基。烷基的例子包括但不限于甲基(Me)、乙基(Et)、丙基(如正丙基、异丙基)、丁基(如正丁基、异丁基、s-丁基、t-丁基)和戊基(如n-戊基、异戊基、新戊基)。
在本发明中，术语“烷氧基”或者“苯氧基”均是指通过氧桥连接到分子其他部分的烷基或苯基。
在本发明中，术语“环烷基”或“环烷烃”是指具有指定数目环碳原子数的非芳香族的饱和或不饱和的环烃基，环烷基可以为单环或多环(例如二环和三环)，可以为并环、螺环和桥环结构。环烷基内任选包含一个或多个双键或三键。单环的环烷基包括但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基。环烷基还包括多环的环烷基结构，其中多环的结构任选地包括与饱和或部分不饱和的环烷基或杂环基或芳基或杂芳基环稠合的饱和或部分不饱和的环烷基。具有7到12个原子的双环碳环可以布置为例如双环[4,5]、[5,5]、[5,6]或[6,6]系统，或布置为桥接环系统例如双[2.2.1]庚烷、双环[2.2.2]辛烷和双环[3.2.2]壬烷。
在本发明中，术语“杂环”是指环烷烃(如本发明中所定义)内的至少一个环碳原子被选自N、O和S的杂原子代替形成的非芳香族的饱和或部分不饱和的环烃基。
在本发明中，术语“芳基”或“芳环”是指任何稳定的在各环中可高达7个原子的单环或者多环(例如双环或三环)碳环，其中至少一个环是芳香环。芳基的实例包括不限于苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基或者苊基(acenaphthyl)。可以理解，在芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳环进行的。
在本发明中，术语“杂芳基”或“杂芳环”是指各环中可高达7个原子的稳定单环或者多环(例如双环或三环)碳环，其中至少一个环是芳香环并且含有至少一个选自O、N和S的杂原子。杂芳基可以通过其中的杂原子或碳原子连接到分子中的其他部分。杂芳基的例子包括但不限于吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的如式I所示的化合物或其消旋体，作为Suzuki-Miyaura偶联反应中金属配体，可以高收率(收率75％以上)得到四取代芳基类化合物。将单一构型的如式I所示的化合物作为Suzuki-Miyaura偶联反应中金属配体，可高收率得到具有轴手性的四取代芳基类化合物(ee值83％以上)。
附图说明
图1为实施例7中如式Y-1所示的化合物的X-单晶衍射图。
图2为实施例7中如式Y-1所示的化合物的X-单晶衍射图的局部放大图。
具体实施方式
实施例1 2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(I-6，BaryPhos)的制备
Figure PCTCN2020077397-appb-000073
S1.(S)-4-(2,6-二甲氧基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(c)的制备
按照已知的文献方法，将a转化为(S)-4-(2,6-二甲氧基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(c)(Org.Lett.2010,12,176；Angew.Chem.,Int.Ed.2010,49,5879)。
S2.(S)-4-(3,5-二溴-2,6-二甲氧基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(d)的制备
按照已知的文献方法，将c转化为(S)-4-(3,5-二溴-2,6-二甲氧基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(d)(Adv.Syn.Catal.2016,358,3522)。
S3.(S)-4-(2,6-二甲氧基-3,5-二环戊基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(III-1)的制备
将(S)-4-(3,5-二溴-2,6-二甲氧基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(d,0.80g,1.59mmol)，环戊烯基硼酸频哪醇酯(0.93g,4.77mmol)和磷酸钾(1.68g,4.77mmol)加入到25mL的Schlenk管中，抽换气三次用氮气置换Schlenk管中的空气。在氮气保护下依次加入1,4-二氧六环(3mL)，去离子水(0.6mL)，三(二亚苄基丙酮)二钯(44mg,0.048mmol)和2-双环己基膦-2',6'-二甲氧基联苯(39mg,0.096mmol)。反应体系在80℃搅拌10小时后冷却至室温。将反应混合物用硅藻土过滤，滤渣用乙酸乙酯洗三次。滤液合并后浓缩，粗产品通过硅胶柱层析纯化，淋洗剂是体积比为1:1的石油醚和乙酸乙酯混合溶剂。含有产物(e)的洗脱剂浓缩旋干后得到无色油状液体，静置后固化得到无色蜡状固体，产量0.66g，产率87％。
向含有e(0.66g,1.38mmol)的甲醇溶液中加入20％氢氧化钯碳(0.10g,15wt％)。反应体系在一个大气压的氢气氛围下搅拌48小时。将反应混合物用硅藻土过滤，催化剂用乙酸乙酯洗三次。滤液合并后浓缩，粗产品通过硅胶柱层析纯化，淋洗剂是体积比为1:1的石油醚和乙酸乙酯混合溶剂。含有产物(f)的洗脱剂浓缩旋干后得到无色泡沫状固体，产量0.61g，产率92％。
f: 1H NMR(500MHz,CDCl 3)δ7.45(t,J＝7.8Hz,1H),7.15(s,1H),6.98(dd,J＝7.3,3.1Hz,1H),6.93(dd,J＝8.3,2.9Hz,1H),4.49(dd,J＝13.7,2.3Hz,1H),4.34(dd,J＝13.7,10.7Hz,1H),3.58(s,3H),3.46(s,3H),3.35–3.17(m,2H),2.11(dt,J＝8.4,5.6Hz,1H),2.07–1.90(m,3H),1.89–1.48(m,12H),1.40–1.30(m,1H),0.94(d,J＝16.2Hz,8H)； 13C NMR(126MHz,CDCl 3)δ165.6(d,J＝19.1Hz),154.9,153.9,139.6(d,J＝5.9Hz),135.6,134.5,133.3(d,J＝1.4Hz),127.6(d,J＝2.0Hz),125.5,124.5(d,J＝8.2Hz),115.4(d,J＝90.2Hz),112.8(d,J＝5.4Hz),65.8(d,J＝60.7Hz),62.0(d,J＝81.4Hz),38.7,38.4,35.4,34.6,34.3,34.2,33.9,33.4,25.7,25.6,25.6,25.5,24.0； 31P NMR(162MHz,CDCl 3)δ62.4；HRMS(ESI)Calcd.for C 29H 40O 4P[M+H] +:483.2664；Found:483.2660.
S4.2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭-3-氧)-丙醇(II-1)的制备
氮气氛围下，将二异丙基胺基锂的四氢呋喃溶液(2.5mol/L,1.66mL,4.16mmol)缓慢滴加到干冰/丙酮浴冷却的(S)-4-(2,6-二甲氧基-3,5-二环戊基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(f)(0.50g,1.04mmol)的无水四氢呋喃(8mL)溶液中。在-78℃搅拌1小时后，向反应体系中加入干燥新蒸的丙酮(0.61mL,8.28mmol)。反应体系在-78℃搅拌一小时后缓慢升至室温，然后在室温继续搅拌1小时。向反应液中加入饱和氯化铵溶液(15mL)，水层用乙酸乙酯(15mL×2)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥后，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯＝2:1)，得到无色油状液 体2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭-3-氧)-丙醇(g,0.48g,85％)。
g: 1H NMR(500MHz,CDCl 3)δ7.47(t,J＝7.8Hz,1H),7.15(s,1H),7.00–6.92(m,2H),4.24–4.17(m,2H),3.57(s,3H),3.43(s,3H),3.38–3.29(m,1H),3.26–3.17(m,1H),2.13–1.47(m,15H),1.42(s,3H),1.36(s,3H),1.38–1.30(m,1H),0.98(d,J＝16.2Hz,9H)； 13C NMR(126MHz,CDCl 3)δ164.9(d,J＝19.5Hz),154.6,153.9,139.7(d,J＝5.5Hz),135.5,134.4,133.6(d,J＝1.7Hz),127.1(d,J＝2.0Hz),125.5,124.8(d,J＝8.3Hz),114.9,114.2,112.4(d,J＝5.4Hz),78.2(d,J＝60.2Hz),73.5(d,J＝2.0Hz),62.2,61.2,38.5(d,J＝11.2Hz),35.1(d,J＝74.2Hz),34.4(d,J＝13.2Hz),33.9(d,J＝70.4Hz),29.3,28.5(d,J＝5.7Hz),25.7,25.6,25.6,25.6,24.7(d,J＝2.8Hz),23.6； 31P NMR(162MHz,CDCl 3)δ65.7；HRMS(ESI)Calcd.for C 32H 46O 5P[M+H] +:541.3083；Found:541.3085.
S5.2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6,BaryPhos)的制备
氮气氛围下，向冰水浴冷却的2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭-3-氧)-丙醇(g)(0.40g,0.74mmol)的干燥甲苯(5mL)溶液中依次加入三乙基胺(1.65mL,11.84mmol)和三氯硅烷(0.60mL,5.93mmol)。反应体系在0℃下搅拌10分钟，然后加热到70℃。将反应混合液在70℃搅拌12小时后冷却至室温。冰水浴下将脱气的30％氢氧化钠溶液(15mL)缓慢滴加到反应体系中，随后将反应体系升至室温并搅拌2小时。向反应液中加入乙酸乙酯(10mL)，充分震荡后分出有机相，水相用乙酸乙酯(10mL×4)萃取，有机相合并，无水硫酸钠干燥后，20℃下浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯＝15:1)，得到白色泡沫状固体2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6,0.32g,82％)。
6: 1H NMR(500MHz,CDCl 3)δ7.30(t,J＝7.8Hz,1H),7.13(s,1H),6.99(dd,J＝7.3,3.0Hz,1H),6.92(d,J＝8.1Hz,1H),4.63(s,1H),3.69(s,3H),3.38–3.21(m,2H),3.18(s,3H),2.41(s,1H),2.14–2.02(m,2H),2.02–1.91(m,2H),1.90–1.75(m,4H),1.74–1.49(m,7H),1.43–1.34(m,1H),1.26(d,J＝7.4Hz,6H),0.73(d,J＝12.3Hz,9H)； 13C NMR(126MHz,CDCl 3)δ164.5,154.4,153.7,139.7(d,J＝17.4Hz),135.3,134.6,130.1,129.0,124.6(d,J＝3.1Hz),124.5,123.2(d,J＝4.0Hz),109.2,91.3(d,J＝30.4Hz),73.5(d,J＝19.4Hz),62.5,60.7,38.9,38.7(s),35.5,34.4,34.2,34.1,30.8,30.6,26.9,26.8,25.7,25.6,25.6,25.5,24.9,24.8； 31P NMR(162MHz,CDCl 3)δ-1.1；HRMS(ESI)Calcd.for C 32H 46O 4P[M+H] +:525.3134；Found:525.3131.
实施例2 2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二异丙基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(I-3)的制备
Figure PCTCN2020077397-appb-000074
参考实施例1的制备方法制备了2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二异丙基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇。
1H NMR(500MHz,CDCl 3)δ7.31(t,J＝7.8Hz,1H),7.11(s,1H),7.00(dd,J＝7.3,3.0Hz,1H),6.92(d,J＝8.1Hz,1H),4.62(s,1H),3.69(s,3H),3.27(ddd,J＝28.8,13.7,6.8Hz,2H),3.17(s,3H),1.31(d,J＝6.9Hz,3H),1.29–1.21(m,12H),1.12(d,J＝6.8Hz,3H),0.72(d,J＝12.3Hz,9H)； 13C NMR(126MHz,CDCl 3)δ164.5,153.5,153.0,139.7(d,J＝17.5Hz),137.9,137.2,130.1,129.1(d,J＝1.1Hz),124.6(d,J＝16.4Hz),123.3,123.1(d,J＝4.3Hz),109.2,91.3(d,J＝30.6Hz),73.6(d,J＝19.4Hz),62.5,60.6,30.6(d,J＝19.0Hz),26.8(d,J＝51.6Hz),26.8(d,J＝15.0Hz),25.4(d,J＝7.0Hz),24.8(d,J＝8.1Hz),24.4,24.3,23.1(d,J＝38.4Hz)； 31P NMR(121MHz,CDCl 3)δ0.2.
实施例3 3-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二(3,3,4,4-四甲基环戊基)苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-戊醇(I-7)的制备
Figure PCTCN2020077397-appb-000075
参考实施例1的制备方法制备了3-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二(3,3,4,4-四甲基环戊基)苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-戊醇。
1H NMR(500MHz,CDCl 3)δ7.35(s,1H),7.28(t,J＝8.0Hz,1H),6.95(dd,J＝7.4,3.3Hz,1H),6.88(d,J＝8.1Hz,1H),4.82(s,1H),3.68(s,3H),3.65–3.58(m,2H),3.16(s,3H),2.05(ddd,J＝31.8,13.1,9.9Hz,3H),1.95–1.88(m,3H),1.84(dd,J＝13.2,9.1Hz,1H),1.77–1.70(m,3H),1.69–1.61(m,4H),1.54(dd,J＝13.1,9.0Hz,1H),1.05–0.94(m,30H),0.73(d,J＝12.3Hz,9H)； 13C NMR(126MHz,CDCl 3)δ164.8,154.1,153.5,139.5(d,J＝17.7Hz),136.7,135.8,130.0,128.8,125.4,124.4(d,J＝14.9Hz),123.0(d,J＝4.5Hz),109.1,88.9(d,J＝29.5Hz),77.1(d,J＝14.3Hz),62.6,60.8,50.0,49.2,48.7,48.2,43.6,43.4,43.3,43.2,33.4,27.0,26.9,25.7,25.6,25.5,25.2,24.7,24.6,24.6,24.5； 31P NMR(121MHz,CDCl 3)δ-3.2.
实施例4(2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二苯基苯基)-2-异丙基-2,3-二氢苯并[d][1,3]氧，膦-戊轭(I-10)的制备
Figure PCTCN2020077397-appb-000076
参考实施例1的制备方法制备了3-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二苯基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-戊醇(I-10)。
1H NMR(500MHz,CDCl 3)δ7.58-7.40(m,10H),7.35(s,1H),7.28(t,J＝8.0Hz,1H),6.95(dd,J＝7.4,3.3Hz,1H),6.88(d,J＝8.1Hz,1H),4.82(s,1H),3.68(s,3H),3.16(s,3H),1.90(s,3H),1.73(s,3H),0.72(d,J＝12.3Hz,9H)； 31P NMR(121MHz,CDCl 3)δ-2.9.
实施例5(2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2-异丙基-2,3-二氢苯并[d][1,3]氧，膦-戊轭(I-5)的制备
Figure PCTCN2020077397-appb-000077
S4.参考实施例1的制备方法制备了(S)-4-(2,6-二甲氧基-3,5-二环戊基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(f)。
S5.(2S,3S)-2-异丙基-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭-3-氧(h)的制备
氮气氛围下，将二异丙基胺基锂的四氢呋喃溶液(1.5mol/L,0.5mL,0.75mmol)缓慢滴加到干冰/丙酮浴冷却的(S)-4-(2,6-二甲氧基-3,5-二环戊基苯基)-3-叔丁基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(f)(0.18g,0.38mmol)的无水四氢呋喃(8mL)溶液中。在-78℃搅拌1小时后，向反应体系中加入2-碘代异丙烷(0.12mL,1.14mmol)。反应体系在-78℃搅拌一小时后缓慢升至室温，然后在室温继续搅拌1小时。向反应液中加入饱和氯化铵溶液(15mL)，水层用乙酸乙酯(15mL×2)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥后，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯＝3:1)，得到无色油状液体(2S,3S)-2-异丙基-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭-3-氧(h,0.16g,82％)。
1H NMR(500MHz,CDCl 3)δ7.44(t,J＝7.8Hz,1H),7.14(s,1H),6.95–6.90(m,2H),4.14(dd,J＝6.5,4.7Hz,1H),3.56(s,3H),3.49(s,3H),3.37–3.29(m,1H),3.22(ddd,J＝17.3,9.6,7.6Hz,1H),2.33(qd,J＝13.4,6.7Hz,1H),2.15–1.98(m,4H),1.94(ddd,J＝11.9,7.6,3.8Hz,1H),1.89–1.74(m,4H),1.73–1.62(m,5H),1.55(ddt,J＝20.7,18.2,8.8Hz,2H),1.13(d,J＝6.7Hz,3H),1.09(d,J＝6.7Hz,3H),0.96(d,J＝15.8Hz,9H)； 13C NMR(126MHz,CDCl 3)δ164.4(d,J＝19.5Hz),154.7,153.8,139.8(d,J＝5.4Hz),135.4,134.3,133.1,127.5(d,J＝2.0Hz),125.4,124.4(d,J＝8.1Hz),115.5,114.8,112.2(d,J＝5.3Hz),78.8(d,J＝60.7Hz),61.8(d,J＝74.8Hz),38.6,38.4,35.4,34.7,34.6,34.4,33.9,33.3,29.8,25.7,25.7,25.6,23.8,20.0(d,J＝5.1Hz),18.1(d,J＝5.0Hz)； 31P NMR(162MHz,CDCl 3)δ60.7；HRMS(ESI)Calcd.for C 32H 46PO 4[M+H] +:525.3134；Found:525.3131.
S6.(2S,3S)-2-异丙基-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭(I-5)的制备
氮气氛围下，向冰水浴冷却的(2S,3S)-2-异丙基-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭-3-氧(h)(0.16g,0.31mmol)的干燥四氢呋喃(5mL)溶液中依次加入聚甲基氢硅氧烷(1.0g)和钛酸四异丙酯(0.70mL,2.36mmol)。反应体系在0℃下搅拌10分钟，然后加热到70℃。将反应混合液在70℃搅拌12小时后冷却至室温。冰水浴下将脱气的30％氢氧化钠溶液(10mL)缓慢滴加到反应体系中，随后将反应体系升至60℃并搅拌30分钟。冷却至室温后，向反应液中加入乙酸乙酯(10mL)，充分震荡后分出有机相，水相用乙酸乙酯(10mL×4)萃取，有机相合并，无水硫酸钠干燥后，20℃下减压浓缩除去有机溶剂，硅胶柱层析纯化(石油醚:乙酸乙酯＝30:1)，得到白色泡沫状固体(2S,3S)-2-异丙基-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭(I-5,0.13g,84％)。
1H NMR(500MHz,cdcl 3)δ7.28(d,J＝7.8Hz,1H),7.12(s,1H),6.96(d,J＝6.9Hz,1H), 6.88(d,J＝7.9Hz,1H),4.65(d,J＝4.9Hz,1H),3.66(s,3H),3.37(dt,J＝16.8,8.4Hz,1H),3.30–3.25(m,1H),3.25(s,3H),2.01(ddd,J＝31.1,16.3,9.7Hz,6H),1.89–1.54(m,10H),1.00(d,J＝8.7Hz,3H),0.98(d,J＝7.2Hz,3H),0.72(d,J＝11.9Hz,9H)； 13C NMR(126MHz,cdcl 3)δ164.5,154.4,153.7,139.6(d,J＝17.3Hz),135.2,134.4,129.7,129.0,124.5(d,J＝18.3Hz),124.4,123.0(d,J＝3.7Hz),109.0,89.1(d,J＝28.8Hz),62.3,60.8,38.8,38.7,35.5(s),34.4(s),34.3,34.2,34.1,33.9,30.6,30.5,27.0,26.9,25.8,25.6,25.6,25.5,18.8(d,J＝11.1Hz),18.0(d,J＝8.9Hz)； 31P NMR(162MHz,CDCl 3)δ0.8.
实施例6 2-((2R,3R)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(I-ent 6)的制备
Figure PCTCN2020077397-appb-000078
将原料a替换为原料ent-a，参考实施例1的制备方法，制备了配体I-6的对映体2-((2R,3R)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(I-ent 6)。
实施例7
如式Y-1所示的化合物的制备
氮气保护下，向芳基氯代物13ac(10.3mg,0.052mmol)的脱气的正己烷中依次加入钯催化剂(cod)Pd(CH 2SiMe 3) 2(20.0mg,0.052mmol)和实施例6制得的配体I-ent6(27.0mg,0.052mmol)。该混合物在室温下搅拌1小时候得到澄清溶液。将此反应体系室温搅拌10小时，有白色沉淀析出。将混合物在氮气氛围下过滤，固体用干燥脱气的正己烷洗涤三次(每次3ml)。得到的浅黄色固体真空干燥后即得氧化加成的钯络合物，产量29mg,产率69％。
1H NMR(400MHz,CDCl 3)δ9.48(s,2H),7.35(t,J＝7.7Hz,2H),7.21(s,2H),7.12(d,J＝8.4Hz,2H),6.90(d,J＝8.1Hz,2H),6.84(dd,J＝7.3,3.2Hz,2H),6.46(d,J＝8.4Hz,2H),4.74(s,2H),3.79(s,6H),3.75(s,6H),3.68(s,3H),3.40–3.34(m,2H),3.33(s,6H),2.99(dd,J＝16.2,8.7Hz,2H),2.25–1.42(m,44H),0.77(d,J＝16.5Hz,18H)。
Figure PCTCN2020077397-appb-000079
如式Y所示的化合物的单晶制备
通过挥发法培养单晶：称取25mg化合物Y产物于10mL试管中，加入0.5mL二氯甲烷溶解后，再加入2mL正己烷。将试管置于装有正己烷的锥形瓶中，将锥形瓶封口后放置在0℃下结晶，即可。
检测方法X-射线单晶衍射
经检测，式Y-1所示的化合物的晶系属于单斜晶系，C 2空间群，晶胞参数为
Figure PCTCN2020077397-appb-000080
Figure PCTCN2020077397-appb-000081
α＝γ＝90°,β＝113.055(2)°；其单晶参数如表2所示；其X-射线单晶衍射如图1所示。
表2如式Y-1所示的化合物的单晶参数
Figure PCTCN2020077397-appb-000082
Figure PCTCN2020077397-appb-000083
由所得X-射线单晶衍射的表征结果表明，可以确定化合物Y的构型为
Figure PCTCN2020077397-appb-000084
从而可以推导出实施例5产物的构型为
Figure PCTCN2020077397-appb-000085
按照发明人之前研究结果发现(J.Am.Chem.Soc.2014,136,570-573；Org.Lett.2012,14,2258-2261)，
Figure PCTCN2020077397-appb-000086
结构中，磷氧五元环上的取代基M与P原子上的叔丁基位于氮碳氧形成的平面的两侧。实施例1中原料a的立体构型确定后，根据发明人之前的研究结果以及实施例5产物的构型，可以推导出实施例1产物的构型为
Figure PCTCN2020077397-appb-000087
实施例8
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(I-6，BaryPhos)作为手性配体，通过过渡金属钯催化的芳基卤代物13a和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具 有轴手性的邻位四取代联芳基化合物E-15a(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000088
反应步骤如下：将2-溴-3,4-二甲氧基苯甲醛(13a,60mg,0.24mmol)，2-甲酰基-6-甲氧基苯基三氟硼酸钾(14a,68mg,0.28mmol)和磷酸钾(156mg,0.72mmol)加入到10mL的Schlenk管中，抽换气三次用氮气置换Schlenk管中的空气。在氮气保护下依次加入脱气的甲苯(4mL)，去离子水(0.8mL)，三(二亚苄基丙酮)二钯(2.2mg,0.0024mmol)和手性膦配体6(2.6mg,0.0049mmol)。反应体系在60℃搅拌15小时后冷却至室温。向反应体系中加入饱和食盐水，混合物用乙酸乙酯萃取三次。有机相合并后用无水硫酸钠干燥，过滤并浓缩。粗产品通过硅胶柱层析纯化，淋洗剂是体积比为4:1的石油醚和乙酸乙酯混合溶剂。含有产物(15a)的洗脱剂浓缩旋干后得到无色蜡状固体(S)-5,6,6’-三甲氧基联苯-2,2’-二醛(E-15a)，产量63mg，产率86％。
对映体过量值(ee)由手性高压液相测定，测得ee值为92％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,210nm,6.70min(S),9.67min(R)； 1H NMR(500MHz,CDCl 3)δ9.70(s,1H),9.50(s,1H),7.85(d,J＝8.6Hz,1H),7.68(dd,J＝7.8,1.0Hz,1H),7.56(t,J＝7.8Hz,1H),7.23(dd,J＝8.2,0.8Hz,1H),7.11(d,J＝8.6Hz,1H),3.99(s,3H),3.76(s,3H),3.50(s,3H)； 13C NMR(126MHz,CDCl 3)δ191.2,190.2,157.6,157.3,146.6,135.7,131.3,129.8,128.5,125.6,125.5,120.0,115.6,111.9,77.3,77.0,76.7,60.2,56.0；HRMS(ESI)Calcd.for C 17H 17O 5[M+H] +:301.1076；Found:301.1081.
实施例9
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(I-6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13b和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15b(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000089
(S)-3-氟-6,6’-二甲氧基联苯基-2,2’-二醛(15b):白色固体(78％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性AD- H柱，25℃，流速:1mL/min,正己烷/异丙醇：85/15,250nm,8.00min(S),12.55min(R)； 1H NMR(400MHz,CDCl 3)δ9.96(s,1H),9.68(s,1H),7.64(dd,J＝7.8,1.0Hz,1H),7.53(t,J＝8.0Hz,1H),7.26–7.14(m,3H),3.73(s,3H),3.68(s,3H)； 13C NMR(126MHz,CDCl 3)δ191.4,188.3,158.8,156.8(d,J＝6.4Hz),153.3(d,J＝2.3Hz),135.3,129.7,125.5(d,J＝74.2Hz),120.3,117.0(d,J＝10.4Hz),116.9(d,J＝2.9Hz),116.0(s),56.4(d,J＝2.8Hz),56.0(d,J＝3.2Hz)； 19F NMR(376MHz,CDCl 3)δ-128.7；HRMS(ESI)Calcd.for C 16H 14FO 4[M+H] +:289.0876；Found:289.0870.
实施例10
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13c和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15c(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000090
(S)-5,6,6’-三甲氧基-3-硝基苯基-2,2’-二醛(E-15c):白色固体(84％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,8.38min(S),14.42min(R)； 1H NMR(600MHz,CDCl 3)δ9.91(s,1H),9.78(s,1H),7.70(s,1H),7.61(dd,J＝7.7,1.1Hz,1H),7.56(t,J＝7.9Hz,1H),7.20(dd,J＝8.2,1.0Hz,1H),4.04(s,4H),3.78(s,4H),3.60(s,3H)； 13C NMR(151MHz,CDCl 3)δ191.2,187.5,130.2,122.1,116.0,107.9,77.2,77.0,76.8,56.5,56.0；HRMS(ESI)Calcd.for C 17H 16NO 7[M+H] +:346.0927；Found:346.0929.
实施例11
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13d和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15d(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000091
(S)-6,6’-二甲氧基联苯基-2,2’-二醛(E-15d):白色固体(83％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,8.67min(S),17.82min(R)； 1H NMR(500MHz,CDCl 3)δ9.66(s,2H),7.67(d,J＝7.8Hz,2H),7.54(t,J＝8.0Hz,2H),7.22(d,J＝8.2Hz,2H),3.73(s,6H)； 13C NMR(126MHz,CDCl 3)δ191.7,157.2,135.8,129.8,125.4,119.7,115.9,77.3,77.0,76.7,56.0；HRMS(ESI)Calcd.for C 16H 14NaO 4[M+Na] +:293.0790；Found:293.0786.
实施例12
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13e和芳基氟硼酸钾14b参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15e(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000092
(S)-N-(2,6’-二甲酰基-2，3‘，5，6-四甲氧基联苯基-3-)叔丁酰胺(E-15e):白色固体(67％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,230nm,6.01min(S),7.01min(R)； 1H NMR(500MHz,CDCl 3)δ12.06(s,1H),9.59(s,1H),9.38(s,1H),8.72(s,1H),7.84(d,J＝8.6Hz,1H),7.13(d,J＝8.7Hz,1H),4.03(s,3H),4.01(s,3H),3.67(s,3H),3.54(s,3H),1.36(s,9H)； 13C NMR(126MHz,CDCl 3)δ192.9,189.7,179.2,158.8,157.6,146.7,140.8,133.2,130.9,128.5,126.0,113.8,112.2,103.4,60.6,60.5,56.1,56.0,40.6,27.6；HRMS(ESI)Calcd.for C 23H 28NO 7[M+H] +:430.1866；Found:430.1864.
实施例13
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备 方法，通过过渡金属钯催化的芳基卤代物13f和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15f(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000093
(S)-3,6,6’-三甲氧基-4-苯基联苯基-2,2’-二醛(E-15f):白色固体(73％产率)；86％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为86％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,7.20min(S),8.68min(R)； 1H NMR(400MHz,CDCl 3)δ10.21(s,1H),9.72(s,1H),7.65(t,J＝7.6Hz,3H),7.48(td,J＝7.8,1.7Hz,3H),7.44–7.39(m,1H),7.17(d,J＝8.2Hz,1H),7.15(s,1H),3.74(s,3H),3.68(s,3H),3.47(s,3H)； 13C NMR(126MHz,CDCl 3)δ192.0,191.0,156.6,153.5,153.3,137.1,136.7,135.3,130.2,129.1,129.0,128.6,128.0,127.7,122.8,119.6,118.2,115.9,62.5,56.3,56.0；HRMS(ESI)Calcd.for C 23H 21O 5[M+H] +:377.1389；Found:377.1390.
实施例14
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13g和芳基氟硼酸钾14b参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15g(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000094
(S)-5,5’,6,6’-四甲氧基联苯基-2,2’-二醛(E-15g):白色固体(80％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,230nm,7.08min(S),9.49min(R)； 1H NMR(400MHz,CDCl 3)δ9.56(s,2H),7.85(d,J＝8.6Hz,2H),7.13(d,J＝8.6Hz,2H),4.01(s,6H),3.61(s,6H)； 13C NMR(126MHz,CDCl 3)δ189.9,157.5,146.5,131.3,128.4,125.9,111.9,77.3,77.0,76.7,60.4,56.0；HRMS(ESI)Calcd.for C 18H 19O 6[M+H] +:331.1182； Found:331.1175.
实施例15
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13h和芳基氟硼酸钾14c参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15h(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000095
(S)-6’-苄氧基-4,5,5’,6-四甲氧基联苯基-2,2’-二醛(E-15h):白色固体(71％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,6.15min(S),8.32min(R)； 1H NMR(600MHz,CDCl 3)δ9.61(s,1H),9.50(s,1H),7.87(d,J＝8.7Hz,1H),7.34(s,1H),7.22–7.11(m,4H),6.93(dd,J＝7.6,1.6Hz,2H),4.83(d,J＝11.2Hz,1H),4.78(d,J＝11.1Hz,1H),4.01(s,3H),3.98(s,3H),3.89(s,3H),3.61(s,3H)； 13C NMR(151MHz,CDCl 3)δ190.1,189.9,157.7,153.9,151.4,147.3,145.9,137.0,131.2,130.2,129.0,128.1(d,J＝11.0Hz),127.8,127.7,126.1,125.1,112.0,105.6,74.5,61.0,60.8,56.2,56.1；HRMS(ESI)Calcd.for C 25H 24NaO 7[M+Na] +:459.1420；Found:459.1418.
实施例16
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13i和芳基氟硼酸钾14c参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15i(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000096
(S)-6-苄氧基-5,6’-二甲氧基联苯基-2,2’-二醛(E-15i):白色固体(80％产率)；93％ ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为93％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,230nm,6.78min(S),11.84min(R)； 1H NMR(600MHz,CDCl 3)δ9.66(d,J＝4.7Hz,1H),9.56–9.46(m,1H),7.88(d,J＝8.6Hz,1H),7.66(d,J＝7.8Hz,1H),7.54(t,J＝8.0Hz,1H),7.2–7.10(m,5H),6.86(d,J＝7.0Hz,2H),4.84(d,J＝11.1Hz,1H),4.59(d,J＝11.1Hz,1H),4.00(s,3H),3.68(s,3H)； 13C NMR(151MHz,CDCl 3)δ191.3,190.3,157.8,157.2,145.4,136.8,135.9,131.8,129.8,128.6,128.1,127.7,125.6,125.6,119.8,115.5,111.9,74.6,56.0,55.9；HRMS(ESI)Calcd.for C 23H 21O 5[M+H] +:377.1389；Found:377.1378.
实施例17
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13j和芳基氟硼酸钾14b参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15j(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000097
(S)-5,5’,6,6’-四甲氧基-3-甲基联苯基-2,2’-二醛(E-15j):白色固体(83％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,230nm,5.89min(S),8.02min(R)； 1H NMR(600MHz,CDCl 3)δ9.71(s,1H),9.55(s,1H),7.83(d,J＝8.6Hz,1H),7.10(d,J＝8.6Hz,1H),6.86(s,1H),4.00(s,3H),3.99(s,3H),3.64(s,3H),3.56(s,3H),2.69(s,3H)； 13C NMR(151MHz,CDCl 3)δ191.6,190.1,157.5,156.0,146.4,144.5,138.7,133.1,132.6,128.4,126.0,125.7,115.3,111.8,60.5,60.4,56.0,55.8,21.7；HRMS(ESI)Calcd.for C 19H 21O 6[M+H] +:345.1338；Found:345.1337.
实施例18
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13k和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15k(其反应路线如下所 示)。
Figure PCTCN2020077397-appb-000098
(S)-2-(2-甲酰基-6-甲氧基苯基)-1-甲氧基-9-甲基-3-咔唑甲醛(E-15k):白色固体(90％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,230nm,9.84min(S),14.12min(R)； 1H NMR(400MHz,CDCl 3)δ9.75(s,1H),9.70(s,1H),8.65(s,1H),8.17(d,J＝7.7Hz,1H),7.77(dd,J＝7.8,1.0Hz,1H),7.65–7.55(m,2H),7.47(d,J＝8.2Hz,1H),7.35(t,J＝7.1Hz,1H),7.27(d,J＝9.7Hz,1H),4.16(s,3H),3.79(s,3H),3.42(s,3H)； 13C NMR(126MHz,CDCl 3)δ191.78,191.1,157.7,143.4,142.5,136.7,135.9,130.0,127.4,127.2,126.7,126.4,125.5,123.4,120.7,119.7,117.8,115.5,109.3,61.2,56.0,31.3；HRMS(ESI)Calcd.for C 23H 20NO 4[M+H] +:374.1392；Found:374.1385.
实施例19
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13l和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15l(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000099
(R)-6-甲氧基-6’-甲基联苯基-2,2’-二甲醛(E-15l):白色固体(83％产率)；92％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为92％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,5.76min(S),9.13min(R)； 1H NMR(600MHz,CDCl 3)δ9.64(d,J＝0.6Hz,1H),9.58(d,J＝0.7Hz,1H),7.90(dd,J＝7.7,0.7Hz,1H),7.68(dd,J＝7.8,1.0Hz,1H),7.59–7.55(m,2H),7.49(t,J＝7.6Hz,1H),7.27–7.24(m,1H),3.75(s,3H),2.01(s,3H)； 13C NMR(151MHz,CDCl 3)δ191.8,191.2,157.0,138.3,136.8,135.5,135.5,135.0,129.9,129.2,128.5,125.8,120.1,116.0,56.0,19.8；HRMS(ESI)Calcd.for C 16H 14NaO 3[M+Na] +:277.0841；Found:277.0830.
实施例20
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13m和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15m(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000100
(S)-6-氟-6’-甲基联苯基-2,2’-二甲醛(E-15m):白色固体(86％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：80/20,250nm,8.00min(S),12.46min(R)； 1H NMR(500MHz,CDCl 3)δ9.79(d,J＝1.2Hz,1H),9.68(s,1H),7.86(dd,J＝7.8,1.0Hz,1H),7.68(dd,J＝7.8,1.1Hz,1H),7.61(t,J＝8.0Hz,1H),7.59–7.54(m,1H),7.43–7.39(m,1H),7.26(dd,J＝8.2,0.9Hz,1H),3.76(s,3H)； 13C NMR(126MHz,CDCl 3)δ190.8,190.3(d,J＝3.7Hz),159.9(d,J＝247.0Hz),157.4,136.4(d,J＝2.3Hz),135.8,130.6,130.1(d,J＝8.3Hz),124.4(d,J＝17.6Hz),123.9(d,J＝3.3Hz),122.0,121.3,120.8(d,J＝23.0Hz),116.1,56.1； 19F NMR(282MHz,CDCl 3)δ-113.9；HRMS(EI)Calcd.for C 15H 11FO 3[M] +:258.0692；Found:258.0690.
实施例21
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13n和芳基氟硼酸钾14b参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15n(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000101
(S)-3,4-二甲氧基-2-(2-甲氧基萘基-1-)苯甲醛(E-15n):白色固体(90％产率)；93％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为93％；高压液相条件：手性OD- H柱，25℃，流速:1mL/min,正己烷/异丙醇：95/5,230nm,27.22min(S),30.24min(R)； 1H NMR(400MHz,CDCl 3)δ9.29(s,1H),7.97(d,J＝9.1Hz,1H),7.93(d,J＝8.7Hz,1H),7.87–7.81(m,1H),7.39(d,J＝9.1Hz,1H),7.36–7.31(m,2H),7.25–7.20(m,1H),7.14(d,J＝8.7Hz,1H),4.01(s,3H),3.85(s,3H),3.46(s,3H)； 13C NMR(126MHz,CDCl 3)δ191.3,158.0,154.5,147.1,135.03(s),134.0,130.3,128.7(d,J＝1.8Hz),128.0,127.0,124.7,124.4,123.7,115.8,112.7,111.5,77.3,77.0,76.8,60.5,56.3,55.9；HRMS(ESI)Calcd.for C 20H 19O 4[M+H] +:323.1283；Found:323.1279.
实施例22
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13o和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15o(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000102
(S)-5-(2-甲酰基-6-甲氧基苯基)-6-甲氧基-2-萘甲醛(E-15o):白色固体(84％产率)；89％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为89％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,7.14min(S),8.14min(R)； 1H NMR(600MHz,CDCl 3)δ10.11(s,1H),9.49(s,1H),8.35(d,J＝1.4Hz,1H),8.14(d,J＝9.0Hz,1H),7.79(dd,J＝8.8,1.6Hz,1H),7.73(dd,J＝7.8,0.9Hz,1H),7.59(t,J＝8.0Hz,1H),7.48(d,J＝9.1Hz,1H),7.31(d,J＝8.2Hz,1H),7.28(d,J＝8.8Hz,1H),3.87(s,3H),3.69(s,3H)； 13C NMR(151MHz,CDCl 3)δ192.3,191.9,157.7,157.2,137.2,135.8,135.0,132.3,132.2,129.5,127.7,125.8,123.7,119.4,116.6,116.5,113.6,56.4,56.1；HRMS(ESI)Calcd.for C 20H 17O 4[M+H] +:321.1127；Found:321.1129.
实施例22
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13p和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15p(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000103
(S)-2-(2,6-二甲氧基萘基-1-)-3-甲氧基苯甲醛(E-15p):白色固体(79％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性OD-H柱，25℃，流速:0.8mL/min,正己烷/异丙醇：90/10,230nm,10.11min(S),13.32min(R)； 1H NMR(600MHz,CDCl 3)δ9.47(s,1H),7.84(d,J＝9.0Hz,1H),7.71(dd,J＝7.8,1.0Hz,1H),7.55(dd,J＝14.3,6.1Hz,1H),7.35(d,J＝9.0Hz,1H),7.29(d,J＝8.2Hz,1H),7.15(d,J＝2.6Hz,1H),7.10(d,J＝9.2Hz,1H),7.01(dd,J＝9.2,2.6Hz,1H),3.91(s,3H),3.79(s,3H),3.69(s,3H)； 13C NMR(151MHz,CDCl 3)δ192.9,157.9,156.1,153.3,135.9,129.7,129.6,129.3,129.1,128.8,126.4,119.7,119.0,116.4,116.4,113.7,105.9,56.6,56.1,55.3；HRMS(ESI)Calcd.for C 20H 19O 4[M+H] +:323.1283；Found:323.1278.
实施例24
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13q和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15q(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000104
(S)-3-甲氧基-2-(6-甲氧基喹啉-5-基)苯甲醛(E-15q):白色固体(80％产率)；89％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为89％；高压液相条件：手性AD-H柱，25℃，流速:0.8mL/min,正己烷/异丙醇：85/15,230nm,16.60min(S),21.61min(R)； 1H NMR(500MHz,CDCl 3)δ9.50(s,1H),8.79(s,1H),8.23(d,J＝9.2Hz,1H),7.72(d,J＝7.8Hz,1H),7.62–7.53(m,4H),7.29(d,J＝8.2Hz,1H),7.25(dd,J＝7.6,2.6Hz,2H),3.85(s,3H),3.68(s,3H)； 13C NMR(126MHz,CDCl 3)δ192.3,157.7,154.7,148.2,143.7,136.0,133.1,131.5,129.5,129.0,127.8,121.6,119.3,116.4,116.2,115.8,56.5,56.0；HRMS(ESI)Calcd.for C 18H 16NO 3[M+H] +:294.1130；Found:294.1125.
实施例25
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)- 2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13r和芳基氟硼酸钾14b参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15r(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000105
(2S)-2-(6-(1-羟基异丙-2-基)-2-甲氧基萘-1-基)-3,4-二甲氧基苯甲醛(E-15r):白色固体(92％产率)；91％de。
立体异构体过量值(de)由手性高压液相测定，测得de值为89％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,5.76min,6.41min； 1H NMR(600MHz,CDCl 3)δ9.29(s,1H),7.93(d,J＝8.7Hz,2H),7.68(s,1H),7.38(d,J＝9.1Hz,1H),7.23(dd,J＝8.8,1.7Hz,1H),7.19(d,J＝8.7Hz,1H),7.14(d,J＝8.7Hz,1H),4.02(s,3H),3.85(s,3H),3.79–3.74(m,2H),3.47(s,3H),3.08(dq,J＝13.8,6.9Hz,1H),1.34(d,J＝7.0Hz,3H)； 13C NMR(151MHz,CDCl 3)δ191.4,158.0,154.3,147.0,138.7,135.0,133.0,130.0,128.8,128.6,127.0,126.2,125.3,124.5,115.7,112.9,111.6,68.5,60.6,56.3,55.9,42.2,17.5；HRMS(ESI)Calcd.for C 23H 25O 5[M+H] +:381.1702；Found:381.1699.
实施例26
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，通过过渡金属钯催化的芳基卤代物13e和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15s(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000106
反应步骤如下：将N-(3-溴-2-甲酰基-4,5-二甲氧基苯基)特戊酰胺(13e,82mg,0.24mmol)，2-甲氧基-1-萘硼酸(14d,97mg,0.48mmol)和磷酸钾(156mg,0.72mmol)加入到10mL的Schlenk管中，抽换气三次用氮气置换Schlenk管中的空气。在氮气保护下依次加入脱气的甲苯(4mL)，三(二亚苄基丙酮)二钯(2.2mg,0.0024mmol)和手性膦配体6(2.6mg,0.0049mmol)。反应体系在60℃搅拌15小时后冷却至室温。向反应体系中加入饱和食盐水，混合物用乙酸乙酯萃取三次。有机相合并后用无水硫酸钠干燥，过滤并浓缩。粗 产品通过硅胶柱层析纯化，淋洗剂是体积比为3:1的石油醚和乙酸乙酯混合溶剂。含有产物(15s)的洗脱剂浓缩旋干后得到白色固体(S)-N-(2-甲酰基-4,5-二甲氧基-3-(2-甲氧基-1-萘基)苯基)特戊酰胺(E-15s)，产量83mg，产率82％。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：80/20,250nm,4.72min(S),5.84min(R)； 1H NMR(400MHz,CDCl 3)δ12.13(s,1H),9.21(s,1H),8.74(s,1H),7.97(d,J＝9.0Hz,1H),7.86–7.82(m,1H),7.41–7.32(m,3H),7.26–7.22(m,1H),4.05(s,3H),3.87(s,3H),3.39(s,3H),1.37(s,9H)； 13C NMR(126MHz,CDCl 3)δ194.6,179.1,159.3,154.4,142.2,140.8,136.3,133.9,130.4,128.7,128.0,127.1,124.7,123.8,115.9,113.9,112.6,103.0,60.5,56.3,56.1,40.6,27.6；HRMS(ESI)Calcd.for C 25H 28NO 5[M+H] +:422.1967；Found:422.1962.
实施例27
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13s和芳基硼酸14e参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15t(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000107
(S)-3-苄氧基-2-(2,3-二甲氧基-1-萘基)-4-甲氧基苯甲醛(E-15t):白色固体(87％产率)；96％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为96％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：80/20,250nm,7.82min,11.81min； 1H NMR(400MHz,CDCl 3)δ9.40(s,1H),7.96(d,J＝8.7Hz,1H),7.76(d,J＝8.1Hz,1H),7.36(t,J＝7.3Hz,1H),7.28(s,1H),7.23–7.14(m,3H),7.06(dt,J＝14.1,6.9Hz,3H),6.70(d,J＝6.6Hz,2H),4.83(d,J＝10.7Hz,1H),4.57(d,J＝10.6Hz,1H),4.02(s,6H),3.69(s,3H)； 13C NMR(126MHz,CDCl 3)δ190.9,158.2,152.0,147.4,146.0,137.2,135.1,131.0,129.0,128.7,127.8,127.5,127.4,126.7,125.4,125.3,124.7,124.57,123.17,111.77,107.9,74.6,60.6,56.0,55.7；HRMS(ESI)Calcd.for C 27H 25O 5[M+H] +:429.1702；Found:429.1695.
实施例28
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13h和芳基硼酸14e参与的不对称Suzuki- Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15u(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000108
(S)-2-(2,3-二甲氧基-1-萘基)-3,4,5-三甲氧基苯甲醛(E-15u):白色固体(91％产率)；93％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为93％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,250nm,5.37min，6.16min； 1H NMR(400MHz,CDCl 3)δ9.38(s,1H),7.77(d,J＝8.1Hz,1H),7.46(s,1H),7.41–7.36(m,1H),7.29(s,1H),7.27–7.21(m,1H),7.17(d,J＝8.3Hz,1H),4.04(s,3H),4.02(s,3H),4.01(s,3H),3.71(s,3H),3.56(s,3H)； 13C NMR(126MHz,CDCl 3)δ191.0,153.5,151.89,151.9,147.8,147.6,130.9,130.0,129.4,128.3,126.8,125.4,125.2,124.5,122.9,107.8,105.0,61.0,61.0,60.6,56.1,55.6；HRMS(ESI)Calcd.for C 22H 23O 6[M+H] +:383.1495；Found:383.1494.
实施例29
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13b和芳基硼酸14e参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15v(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000109
(S)-2-(2,3-二甲氧基-1-萘基)-6-氟-3甲氧基苯甲醛(E-15v):白色固体(89％产率)；92％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为92％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：80/20,230nm,7.13min，8.38min； 1H NMR(600MHz,CDCl 3)δ9.64(s,1H),7.76(d,J＝8.1Hz,1H),7.38(t,J＝7.5Hz,1H),7.27(d,J＝7.4Hz,2H),7.24–7.21(m,2H),7.10(d,J＝8.4Hz,1H),4.03(s,2H),3.68(s,3H),3.66(s,3H)； 13C NMR(151MHz,CDCl 3)δ189.3,157.4,155.7,153.8(d,J＝2.2Hz),151.9,147.0,131.0,129.1,128.4,126.9,125.4,124.6,124.5,124.0(d,J＝8.2Hz),123.0,117.1(d,J＝9.4Hz),116.7 (d,J＝22.8Hz),107.9,60.5,56.4,55.6； 19F NMR(376MHz,cdcl 3)δ-127.0(dd,J＝9.4,4.6Hz)；HRMS(ESI)Calcd.for C 20H 18FO 4[M+H] +:341.1189；Found:341.1185.
实施例30
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13t和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15w(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000110
(S)-2,6-二甲氧基-4-甲酰基-3-(2-甲氧基-1-萘基)吡啶(E-15w):白色固体(83％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性AD-H柱，25℃，流速:0.3mL/min,正己烷/异丙醇：98/2,230nm,32.19min，36.93min； 1H NMR(500MHz,CDCl 3)δ9.48(s,1H),7.96(d,J＝9.0Hz,1H),7.85(dd,J＝11.5,5.4Hz,1H),7.40–7.34(m,3H),7.29–7.26(m,1H),6.92(s,1H),4.04(s,3H),3.85(s,3H),3.83(s,3H)； 13C NMR(126MHz,CDCl 3)δ191.9,163.2,161.9,155.1,145.5,134.0,130.5,128.9,128.2,126.9,124.6,123.8,114.5,112.9,96.6,56.4,54.1(d,J＝2.0Hz)；HRMS(ESI)Calcd.for C 19H 17NNaO 4[M+Na] +:346.1055；Found:346.1051.
实施例31
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13u和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15x(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000111
(S)-2,6-二甲氧基-4-甲酰基-3-(2-甲氧基-1-萘基)吡啶(E-15x):白色固体(92％产率)；81％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为81％；高压液相条件：手性AD-H柱，25℃，流速:0.3mL/min,正己烷/异丙醇：99/1,230nm,11.15min，12.31min； 1H NMR(500MHz,CDCl 3)δ9.46(s,1H),7.98–7.94(m,2H),7.86(d,J＝7.6Hz,1H),7.61(d,J＝7.3Hz,1H),7.49(t,J＝7.7Hz,1H),7.39(d,J＝9.1Hz,1H),7.34(pd,J＝6.8,1.4Hz,2H),7.08(d,J＝8.3Hz,1H),3.83(s,3H),1.95(s,3H)； 13C NMR(126MHz,cdcl 3)δ193.1,154.1,140.2,138.8,135.6,135.0,133.6,130.2,128.8,128.2,127.9,127.2,124.6,124.4,123.8,118.5,112.7,56.3,19.4；HRMS(ESI)Calcd.for C 19H 17O 2[M+H] +:277.1229；Found:277.1225.
实施例32
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13o和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15y(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000112
(S)-2,2’-二甲氧基-1,1’-联萘基-6-甲醛(E-15y):白色固体(81％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：80/20,230nm,6.63min，7.21min； 1H NMR(500MHz,CDCl 3)δ10.11(s,1H),8.37(d,J＝1.2Hz,1H),8.15(d,J＝9.0Hz,1H),8.01(d,J＝9.0Hz,1H),7.89(d,J＝8.2Hz,1H),7.69(dd,J＝8.8,1.5Hz,1H),7.55(d,J＝9.1Hz,1H),7.47(d,J＝9.1Hz,1H),7.34(t,J＝7.4Hz,1H),7.26–7.20(m,2H),7.07(d,J＝8.5Hz,1H),3.82(s,3H),3.78(s,3H)； 13C NMR(126MHz,CDCl 3)δ192.0,157.7,154.9,137.4,135.0,133.7,132.2,131.4,129.8,129.2,128.1,128.1,126.5,126.3,124.8,123.6,123.3,120.0,118.5,114.6,114.0,56.8,56.6；HRMS(ESI)Calcd.for C 23H 19O 3[M+H] +:343.1334；Found:343.1322.
实施例33
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13v和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15z(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000113
(S)-2’-甲氧基-1,1’-联萘基-2-磺酰氟(E-15z):白色固体(65％产率)；93％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为93％；高压液相条件：手性AD-H柱，25℃，流速:0.6mL/min,正己烷/异丙醇：96/4,250nm,12.22min，13.00min； 1H NMR(600MHz,CDCl 3)δ8.06(d,J＝8.5Hz,1H),8.05(d,J＝8.2Hz,1H),7.98(d,J＝8.3Hz,1H),7.89(d,J＝8.2Hz,1H),7.65(d,J＝8.4Hz,1H),7.54(ddd,J＝8.1,6.8,1.1Hz,1H),7.46(d,J＝9.1Hz,1H),7.35(td,J＝8.3,1.1Hz,2H),7.29(d,J＝8.5Hz,1H),7.25–7.23(m,1H),6.99(d,J＝8.4Hz,1H),3.81(s,3H)； 13C NMR(151MHz,CDCl 3)δ155.0,146.2,133.5,133.4,132.6,131.0,130.3,128.8,128.2,128.1,127.5,127.0,126.9,126.8,126.5,124.6,123.7,119.0,114.9,112.9,56.3；HRMS(EI)Calcd.for C 21H 15FO 4S[M] +:382.0675；Found:382.0677.
实施例34
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13w和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15aa(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000114
(S)-6-甲氧基-5-(2-甲氧基-1-萘基)喹啉(E-15aa):白色固体(92％产率)；91％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为91％；高压液相条件：手性OD-H柱，25℃，流速:0.8mL/min,正己烷/异丙醇：90/10,250nm,11.51min，14.97min； 1H NMR(500MHz,CDCl 3)δ8.77(d,J＝3.8Hz,1H),8.25(d,J＝9.2Hz,1H),8.00(d,J＝9.1Hz,1H),7.88(d,J＝8.2Hz,1H),7.69(d,J＝9.3Hz,1H),7.46(dd,J＝8.8,3.7Hz,2H),7.34(t,J＝7.4Hz,1H),7.26–7.22(m,1H),7.14(dd,J＝8.5,4.0Hz,1H),7.08(d,J＝8.5Hz,1H),3.81(s,3H),3.78(s,3H)； 13C NMR(126MHz,CDCl 3)δ155.0(d,J＝6.1Hz),148.1,144.2,133.9,133.6,130.6,129.9,129.1(d,J＝12.4Hz),128.0,126.6,124.9,123.6,121.2,119.3,118.1,117.3,113.9,56.8(d,J＝9.2Hz)；HRMS(EI)Calcd.for C 21H 17NO 2[M] +:315.1259；Found:315.1252.
实施例35
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13n和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15ab(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000115
(S)-2,2’-二甲氧基-1,1’-联萘(E-15ab):白色固体(89％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性OD-H柱，25℃，流速:0.7mL/min,正己烷/异丙醇：99/1,250nm,10.79min，11.93min； 1H NMR(500MHz,CDCl 3)δ7.99(d,J＝9.0Hz,2H),7.88(d,J＝8.2Hz,2H),7.47(d,J＝9.0Hz,2H),7.32(t,J＝7.4Hz,2H),7.22(t,J＝7.6Hz,2H),7.12(d,J＝8.4Hz,2H),3.78(s,6H)； 13C NMR(126MHz,CDCl 3)δ155.0,134.0,129.4,129.2,127.9,126.3,125.2,123.5,119.6,114.3,56.9；HRMS(EI)Calcd.for C 22H 18O 2[M] +:314.1307；Found:314.1303.
实施例36
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13p和芳基硼酸14e参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15ac(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000116
(S)-2,2’-二甲氧基-1,1’-联萘(E-15ac):白色固体(89％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性AD-H柱，25℃，流速:0.8mL/min,正己烷/异丙醇：95/5,230nm,8.18min，9.97min； 1H NMR(600MHz,CDCl 3)δ7.84(d,J＝9.0Hz,2H),7.40(d,J＝9.0Hz,2H),7.16(d,J＝2.6Hz,2H),7.02(d,J＝9.2Hz,2H),6.90(dd,J＝9.2,2.6Hz,2H),3.88(s,6H),3.72(s,6H)； 13C NMR(151MHz,CDCl 3)δ156.1,153.6,130.1,129.4,128.0,126.9,120.2,119.2,115.1,106.1,105.9,57.2,55.3,30.2,29.8,14.2；
HRMS(EI)Calcd.for C 24H 22O 4[M] +:374.1518；Found:374.1509.
实施例37
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13x和芳基硼酸14f参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15ad(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000117
(S)-2,2’-二甲氧基-1,1’-联萘(E-15ad):白色固体(87％产率)；85％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为85％；高压液相条件：手性AD-H柱，25℃，流速:0.8mL/min,正己烷/异丙醇：95/5,250nm,5.39min，6.38min； 1H NMR(400MHz,CDCl 3)δ7.82–7.75(m,5H),7.61(d,J＝8.1Hz,4H),7.45(t,J＝7.4Hz,5H),7.37(dd,J＝13.8,7.1Hz,4H),7.23(s,2H),3.94(s,6H)； 13C NMR(126MHz,CDCl 3)δ155.3,138.4,134.0,132.4,130.0,129.7,128.8,128.0,127.7,127.2,126.3,126.3,123.9,105.7,55.5；HRMS(EI)Calcd.for C 34H 26O 2[M] +:466.1933；Found:466.1936.
实施例38
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13y和芳基硼酸14g参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15ae(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000118
(S)-2,2’,3,3’-四甲氧基-1,1’-联萘(E-15ae):白色固体(90％产率)；95％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为95％；高压液相条件：手性AD-H柱，25℃，流速:0.8mL/min,正己烷/异丙醇：95/5,230nm,12.79min，18.81min； 1H NMR(500MHz,CDCl 3)δ7.81(d,J＝8.2Hz,2H),7.40–7.32(m,4H),7.12(q,J＝8.8Hz,4H),4.08(s,6H),3.66(s,6H)； 13C NMR(126MHz,CDCl 3)δ152.4,147.4,131.2,129.0,126.6, 126.0,125.7,125.2,124.0,107.3,60.7,55.6；HRMS(EI)Calcd.for C 24H 22O 4[M] +:374.1518；Found:374.1494.
实施例39
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13z和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15af(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000119
(S)-2-(2,2’-二甲氧基-1,1’-联萘-6-基)-4H-色满-4-酮(E-15af):白色固体(75％产率)；92％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为92％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：75/25,230nm,17.48min，23.31min； 1H NMR(600MHz,CDCl 3)δ8.54(s,1H),8.25(d,J＝7.9Hz,1H),8.13(d,J＝9.0Hz,1H),7.90(d,J＝9.1Hz,1H),7.71(dd,J＝11.3,4.2Hz,1H),7.66(dd,J＝9.0,1.8Hz,1H),7.62(d,J＝8.3Hz,1H),7.55(d,J＝9.0Hz,1H),7.45(d,J＝15.9Hz,2H),7.43(d,J＝14.2Hz,1H),7.23(d,J＝9.0Hz,1H),7.20(d,J＝2.5Hz,1H),7.00(d,J＝9.2Hz,1H),6.95–6.90(m,2H),3.91(s,3H),3.83(s,3H),3.76(s,3H)； 13C NMR(151MHz,CDCl 3)δ178.5,163.8,156.7,156.4,156.1,153.5,135.6,133.7,130.8,130.1,129.2,128.5,128.4,127.3,126.5,126.4,126.3,125.7,125.2,124.0,123.0,119.8,119.4,119.1,118.1,114.8,107.2,106.0,57.1,56.7,55.3；HRMS(EI)Calcd.for C 32H 24O 5[M] +:488.1624；Found:488.1616.
实施例40
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13aa和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15ag(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000120
(S)-(2,2’-二甲氧基-1,1’-联萘-3-基)三甲基硅烷(E-15ag):白色固体(79％产率)；94％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为94％；高压液相条件：手性IC柱，25℃，流速:0.7mL/min,正己烷/异丙醇：100/0,250nm,6.91min，8.01min； 1H NMR(600MHz,CDCl 3)δ8.03(s,1H),8.01(d,J＝9.0Hz,1H),7.87(dd,J＝8.1,3.6Hz,2H),7.46(d,J＝9.1Hz,1H),7.34(td,J＝7.8,0.9Hz,2H),7.27–7.24(m,1H),7.21(ddd,J＝8.0,6.8,1.0Hz,1H),7.18(d,J＝8.5Hz,1H),7.13(d,J＝8.5Hz,1H),3.82(s,3H),3.24(s,3H),0.42–0.35(m,9H)； 13C NMR(151MHz,CDCl 3)δ161.2,155.1,136.3,135.3,134.1,133.8,130.4,130.0,129.3,128.3,128.0,126.8,126.5,125.5,125.2,124.3,123.8,121.7,120.0,113.8,60.4,56.7,-0.3；HRMS(EI)Calcd.for C 25H 26O 2Si[M] +:386.1702；Found:386.1699.
实施例41
以实施例1制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)作为手性配体，参考实施例26的制备方法，通过过渡金属钯催化的芳基卤代物13ab和芳基硼酸14d参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15ah(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000121
(S)-5-(3,5-二三氟甲基苯基)-2,2’-二甲氧基-1,1’-联萘(E-15ah):白色固体(88％产率)；90％ee。
对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性PC柱，25℃，流速:0.7mL/min,乙腈/水：80/20,214nm,6.53min，7.22min； 1H NMR(500MHz,CDCl 3)δ8.12–7.97(m,4H),7.90(d,J＝8.0Hz,1H),7.84(d,J＝9.2Hz,1H),7.48(dd,J＝14.0,9.3Hz,2H),7.35(t,J＝7.2Hz,1H),7.31–7.20(m,4H),7.13(d,J＝8.2Hz,1H),3.82(s,3H),3.78(s,3H)； 13C NMR(126MHz,CDCl 3)δ155.2,155.0,143.4,137.0,134.5,133.9, 131.7(q,J＝33.4Hz),130.3(d,J＝4.1Hz),129.7(d,J＝0.6Hz),129.2,128.0(d,J＝0.7Hz),126.7,126.5,126.4,126.4,125.8,125.1,125.1,123.6,121.6–120.6(m),120.2,119.2,114.7,114.1,56.9,56.7； 19F NMR(376MHz,cdcl 3)δ-62.7；HRMS(EI)Calcd.for C 30H 20F 6O 2[M] +:526.1367；Found:526.1363.
实施例42
以实施例2制备的化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二异丙基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(I-3)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13a和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15a(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000122
产率87％。对映体过量值(ee)由手性高压液相测定，测得ee值为86％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,210nm,6.70min(S),9.67min(R)；
实施例43
以实施例3制备的化合物3-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二(3,3,4,4-四甲基环戊基)苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-戊醇(I-7)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13a和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15a(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000123
产率83％。对映体过量值(ee)由手性高压液相测定，测得ee值为90％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,210nm,6.70min(S),9.67min(R)；
实施例44
以实施例4备的化合物(2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二苯基苯基)-2-异丙基-2,3-二氢苯并[d][1,3]氧，膦-戊轭(I-10)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13a和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联 反应制备具有轴手性的邻位四取代联芳基化合物E-15a(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000124
产率83％。对映体过量值(ee)由手性高压液相测定，测得ee值为64％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min，正己烷/异丙醇：70/30,210nm,6.70min(S),9.67min(R)。
实施例45
以实施例5制备的化合物(2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2-异丙基-2,3-二氢苯并[d][1,3]氧，膦-戊轭(I-5)作为手性配体，参考实施例8的制备方法，通过过渡金属钯催化的芳基卤代物13a和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15a(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000125
产率75％。对映体过量值(ee)由手性高压液相测定，测得ee值为84％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,210nm,6.70min(S),9.67min(R)。
实施例46
按照实施例1的制备方法，制备得到化合物2-((2S,3S)-3-叔丁基-4-(2,6-二甲氧基-3,5-二环戊基苯基)-2,3-二氢苯并[d][1,3]氧，膦-戊轭)-丙醇(6，BaryPhos)的消旋体。以此消旋体作为配体，参考实施例8或实施例26的制备方法，通过过渡金属钯催化的芳基卤代物和芳基硼酸或芳基氟硼酸钾参与的不对称Suzuki-Miyaura偶联反应制备消旋的联芳基化合物，其产率为80～92％。
该实施例中主要用于制备个实施例中的消旋体，其作为测定手性样品对映体过量值(ee)的对照。其产率和上述实施例中手性产物的产率类似。
实施例47
以实施例7制备的含有手性配体的钯金属络合物Y-1作为手性催化剂，通过芳基卤代物13a和芳基氟硼酸钾14a参与的不对称Suzuki-Miyaura偶联反应制备具有轴手性的邻位四取代联芳基化合物E-15a(其反应路线如下所示)。
Figure PCTCN2020077397-appb-000126
反应步骤如下：将2-溴-3,4-二甲氧基苯甲醛(13a,60mg,0.24mmol)，2-甲酰基-6-甲氧基苯基三氟硼酸钾(14a,68mg,0.28mmol)和磷酸钾(156mg,0.72mmol)加入到10mL的Schlenk管中，抽换气三次用氮气置换Schlenk管中的空气。在氮气保护下依次加入脱气的甲苯(4mL)，去离子水(0.8mL)，和金属络合物Y-1(2.0mg,0.0012mmol)。反应体系在60℃搅拌15小时后冷却至室温。向反应体系中加入饱和食盐水，混合物用乙酸乙酯萃取三次。有机相合并后用无水硫酸钠干燥，过滤并浓缩。粗产品通过硅胶柱层析纯化，淋洗剂是体积比为4:1的石油醚和乙酸乙酯混合溶剂。含有产物(15a)的洗脱剂浓缩旋干后得到无色蜡状固体(R)-5,6,6’-三甲氧基联苯-2,2’-二醛(E-15a)，产量60mg，产率82％。
对映体过量值(ee)由手性高压液相测定，测得ee值为92％；高压液相条件：手性AD-H柱，25℃，流速:1mL/min,正己烷/异丙醇：70/30,210nm,6.70min(S),9.67min(R)。利用金属络合物Y-1作为手性催化剂和实施例8所得到的联芳基产物的ee值一致。
对比例1～3
参考实施例8的制备方法，以不同的膦配体作为配体，制备具有光学活性的联芳基化合物15a。
Figure PCTCN2020077397-appb-000127
反应结果如表1所示：
表1
编号 配体 收率 ee％
对比例1 L8 62％ 32％
对比例2 L9 66％ 36％
对比例3 L11 60％ 45％
实施例5 I-6 86％ 92％
由上表可知，不同取代基的膦配体作为金属配体应用到不对称Suzuki-Miyaura偶联反应，其得到产物的收率和选择性得到显著提高，尤其是在对映选择性方面(ee值相差最高可达60％，最低也在47％)。这一结果充分显示出：本发明的配体应用到不对称Suzuki-Miyaura偶联反应中，可高效制备手性邻位四取代联芳基类化合物。

Claims (15)

  1. 一种膦配体，其为如式I所示的化合物或其消旋体：
    Figure PCTCN2020077397-appb-100001
    其中，“*”表示此处的原子为手性原子；R 1、R 3和R 5独立地为氢、C 1～10烷基、C 1～10杂烷基、C 3～30环烷基、R 1-1a取代的C 3～30环烷基、C 6～ 30芳基或R 1-1b取代的C 6～ 30芳基；所述C 1～10杂烷基中的杂原子选自O、S和N中的一种或多种，个数为1、2、3、4、5或6；当杂原子的个数为多个时，杂原子相同或不相同；
    R 2和R 4独立地为C 1～10烷基、C 1～10杂烷基、C 3～30环烷基、R 2-1a取代的C 3～30环烷基、C 6～ 30芳基或R 2-1b取代的C 6～ 30芳基；所述C 1～10杂烷基中的杂原子选自O、S和N中的一种或多种，个数为1、2、3、4、5或6；当杂原子的个数为多个时，杂原子相同或不相同；
    每个R 1-1a和每个R 2-1a独立为C 1～10烷基；R 1-1a和R 2-1a个数为1个或多个；当R 1-1a和R 2-1a个数独立地为多个，R 1-1a和R 2-1a独立地相同或不相同；
    每个R 1-1b和每个R 2-1b独立地为C 1～10烷基、C 1～10烷氧基或C 6～ 30芳基；当每个R 1-1b和每个R 2-1b个数独立地为多个，R 1-1b和R 2-1b独立地相同或不相同；
    R 6和R 7独立地为H、C 1～10烷基、羟基取代的C 1～10烷基、C 3～30环烷基或C 6～ 30芳基；
    R 8为羟基、C 1～10烷基、羟基取代的C 1～10烷基、C 1～10烷氧基、
    Figure PCTCN2020077397-appb-100002
    C 3～30环烷基、巯基或C 6～ 30芳基，其中，R 10和R 11独立地为H或C 1～4烷基；
    R 9为C 1～10烷基、C 3～30环烷基或C 6～ 30芳基。
  2. 如权利要求1所述如式I所示的化合物或其消旋体，其特征在于，当所述R 1、R 3和R 5独立地为C 1～10烷基时，所述C 1～10烷基为C 1～6烷基，优选C 1～3烷基；
    和/或，当所述R 1、R 3和R 5独立地为C 1～10杂烷基时，所述C 1～10杂烷基为C 1～6杂烷基；
    和/或，当所述R 1、R 3和R 5独立地为C 3～30环烷基时，所述C 3～30环烷基为C 3～10环烷基；
    和/或，当所述R 1、R 3和R 5独立地为R 1-1a取代的C 3～30环烷基时，所述R 1-1a取代的C 3～30环烷基中的C 3～30环烷基为C 3～10环烷基；
    和/或，当所述R 1、R 3和R 5独立地为C 6～ 30芳基时，所述C 6～ 30芳基为C 6～14芳基；
    和/或，当所述R 1、R 3和R 5独立地为R 1-1b取代的C 6～ 30芳基时，所述R 1-1b取代的C 6～ 30芳基中的C 6～ 30芳基为C 6～14芳基；
    和/或，当所述R 2和R 4独立地为C 1～10烷基时，所述C 1～10烷基为直链C 1～10烷基或支链C 3～10烷基，优选支链C 3～10烷基；
    和/或，当所述R 2和R 4独立地为C 3～30环烷基时，所述C 3～30环烷基为C 3～10环烷基，优选C 3～6环烷基；
    和/或，当所述R 2和R 4独立地为R 2-1a取代的C 3～30环烷基时，R 2-1a取代的C 3～30环烷基中的C 3～30环烷基为C 3～10环烷基，优选C 3～6环烷基；
    和/或，当所述R 2和R 4独立地为R 2-1a取代的C 3～30环烷基时，所述R 2-1a取代的C 3～30环烷基中的R 2-1a个数为1、2、3或4个，优选4个；
    和/或，当所述R 2-1a为C 1～10烷基时，所述C 1～10烷基为C 1～6烷基，优选C 1～3烷基；
    和/或，当所述R 2和R 4独立地为C 6～ 30芳基时，所述C 6～ 30芳基为C 6～20芳基，优选C 6～14芳基；
    和/或，当所述R 1、R 2、R 3、R 4和R 5独立地为R 2-1b取代的C 6～ 30芳基时，所述R 2-1b取代的C 6～ 30芳基中的C 6～ 30芳基为C 6～20芳基，优选C 6～14芳基；
    和/或，当所述R 6和R 7独立地为C 1～10烷基时，所述C 1～10烷基为C 1～6烷基，优选C 1～3烷基；
    和/或，当所述R 6和R 7独立地为羟基取代的C 1～10烷基时，所述羟基取代的C 1～10烷基中的C 1～10烷基为C 1～6烷基，优选C 1～3烷基；
    和/或，当所述R 6和R 7独立地为C 3～30环烷基时，所述C 3～30环烷基为C 3～10环烷基；
    和/或，当所述R 6和R 7独立地C 6～ 30芳基时，所述C 6～ 30芳基为C 6～ 20芳基；
    和/或，当所述R 8为C 1～10烷基时，所述C 1～10烷基为C 1～6烷基，优选C 1～3烷基；
    和/或，当所述R 8为羟基取代的C 1～10烷基时，所述羟基取代的C 1～10烷基中的C 1～10烷基为C 1～6烷基，优选C 1～3烷基；
    和/或，当所述R 8为羟基取代的C 1～10烷基时，所述羟基取代的C 1～10烷基中的羟基的个数为1个；
    和/或，当所述R 8独立地为C 1～10烷氧基时，所述C 1～10烷氧基为C 1～6烷氧基，优选C 1～3烷氧基；
    和/或，当所述R 8为
    Figure PCTCN2020077397-appb-100003
    R 10和R 11独立地为C 1～4烷基时，所述C 1～4烷基为甲基、乙基、正丙基、异丙基、正丁基、
    Figure PCTCN2020077397-appb-100004
    或叔丁基；
    和/或，当所述R 8为C 3～30环烷基时，所述C 3～30环烷基为C 3～10环烷基；
    和/或，当所述R 8为C 6～ 30芳基时，所述C 6～ 30芳基为C 6～ 20芳基；
    和/或，当R 9为C 1～10烷基时，所述C 1～10烷基为直链C 1～10烷基或支链C 3～10烷基，优选支链C 3～10烷基；
    和/或，当所述R 9为C 3～30环烷基时，所述C 3～30环烷基为C 3～10环烷基；
    和/或，当所述R 9为C 6～ 30芳基时，所述C 6～ 30芳基为C 6～ 20芳基；
    和/或，所述的如式I所示化合物为
    Figure PCTCN2020077397-appb-100005
  3. 如权利要求2所述如式I所示的化合物或其消旋体，其特征在于，当所述R 1、R 3和R 5独立地为C 1～3烷基时，所述C 1～3烷基为甲基、乙基、正丙基或异丙基，优选甲基或异丙基；
    和/或，当所述R 2和R 4独立地为直链C 1～10烷基时，所述直链C 1～10烷基为直链C 1～6烷基，优选直链C 1～3烷基；
    和/或，当所述R 2和R 4独立地为支链C 3～5烷基时，所述支链C 3～5烷基为异丙基、
    Figure PCTCN2020077397-appb-100006
    优选异丙基或
    Figure PCTCN2020077397-appb-100007
    和/或，当所述R 2和R 4独立地为R 2-1a取代的C 3～30环烷基，R 2-1a取代的C 3～30环烷基中的C 3～30环烷基为C 3～6环烷基时，所述C 3～6环烷基为环丙基、环丁基、环戊基或环己基，优选环戊基；
    和/或，当所述R 2-1a取代的个数为多个时，所述R 2-1a为相同；
    和/或，当所述R 2-1a为C 1～3烷基时，所述C 1～3烷基为甲基、乙基、正丙级或异丙基，优选甲基；
    和/或，当所述R 2和R 4独立地为C 6～14芳基时，所述C 6～14芳基为苯基；
    和/或，当所述R 6和R 7独立地为C 1～3烷基时，所述C 1～3烷基为甲基、乙基、正丙基或异丙基；
    和/或，当所述R 6和R 7独立地为羟基取代的C 1～10烷基，所述羟基取代的C 1～10烷基中的C 1～10烷基为C 1～3烷基时，所述C 1～3烷基为甲基、乙基、正丙基或异丙基，优选甲基；
    和/或，当所述R 8为C 1～3烷基时，所述C 1～3烷基为甲基、乙基、正丙基或异丙基，优 选甲基；
    和/或，当所述R 8为羟基取代的C 1～10烷基，所述羟基取代的C 1～10烷基中的C 1～10烷基为C 1～3烷基时，所述C 1～3烷基为甲基、乙基、正丙基或异丙基，优选甲基；
    和/或，当所述R 8独立地为C 1～3烷氧基时，所述C 1～3烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基，优选甲氧基；
    和/或，当R 9为直链C 1～10烷基时，所述直链C 1～10烷基为直链C 1～6烷基，优选直链C 1～3烷基；
    和/或，当R 9为支链C 3～10烷基时，所述支链C 3～10烷基为支链C 3～6烷基，优选支链C 3～4烷基，进一步优选为异丙基、
    Figure PCTCN2020077397-appb-100008
    或叔丁基，更进一步优选叔丁基。
  4. 如权利要求1～3中至少一项所述如式I所示的化合物或其消旋体，其特征在于，R 1和R 5独立地为C 1～10烷基；
    和/或，R 2和R 4独立地为C 1～10烷基、C 3～30环烷基、R 2-1a取代的C 3～30环烷基或C 6～ 30芳基，优选C 3～30环烷基或R 2-1a取代的C 3～30环烷基；
    和/或，R 3为氢；
    和/或，R 6和R 7独立地为H、C 1～10烷基或羟基取代的C 1～10烷基，优选C 1～10烷基；
    和/或，R 8为羟基、C 1～10烷基、C 1～10烷氧基或
    Figure PCTCN2020077397-appb-100009
    优选羟基；
    和/或，R 9为C 1～10烷基。
  5. 如权利要求1所述如式I所示的化合物或其消旋体，其特征在于，R 1和R 5相同；
    和/或，R 2和R 4相同；
    和/或，
    Figure PCTCN2020077397-appb-100010
    为
    Figure PCTCN2020077397-appb-100011
    优选
    Figure PCTCN2020077397-appb-100012
    和/或，
    Figure PCTCN2020077397-appb-100013
    为
    Figure PCTCN2020077397-appb-100014
    Figure PCTCN2020077397-appb-100015
    优选
    Figure PCTCN2020077397-appb-100016
  6. 如权利要求1～5中至少一项所述如式I所示的化合物或其消旋体，其特征在于，所述如式I所示的化合物任选如下任一化合物：
    Figure PCTCN2020077397-appb-100017
  7. 一种如权利要求1～6中至少一项所述如式I所示的化合物或其消旋体的制备方法，其特征在于，其包括如下步骤：在还原剂存在下，将化合物II在有机溶剂中进行如下式的还原反应，得到化合物I，即可；
    Figure PCTCN2020077397-appb-100018
    其中，“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义均如权利要求1～6中至少一项所述。
  8. 如权利要求7所述如式I所示的化合物或其消旋体的制备方法，其特征在于，所述 还原反应中，所述还原剂为卤代硅烷类还原剂和/或聚硅烷类还原剂；
    和/或，所述还原剂与所述化合物II的摩尔比值为1～10；
    和/或，所述还原反应中，所述有机溶剂为芳烃类溶剂和/或醚类溶剂；
    和/或，所述还原反应中，所述还原反应的温度为60～80℃。
  9. 一种如式II所示的化合物或其消旋体：
    Figure PCTCN2020077397-appb-100019
    其中，“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9的定义均同权利要求1～6中至少一项所述。
  10. 如权利要求9所述如式II所示的化合物或其消旋体，其特征在于，所述的化合物II为如下任一化合物：
    Figure PCTCN2020077397-appb-100020
  11. 一种如权利要求9或10所述的化合物II的制备方法，其特征在于，其包括以下步骤：在碱性试剂作用下，将化合物III与化合物A在有机溶剂中进行如下式的反应，得到化合物II即可；
    Figure PCTCN2020077397-appb-100021
    其中，X为卤素；R 12a和R 12b独立地为H、C 1～10烷基、羟基取代的C 1～10烷基、C 3～30环烷基或C 6～ 30芳基；R 13a和R 13b独立地为H或C 1～4烷基，R 13a和R 13b不同时为H；R 14为C 1～10烷基、羟基取代的C 1～10烷基或C 1～10烷氧基；“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9均同权利要求1～7中至少一项所述。
  12. 一种如权利要求1～6中至少一项所述如式I所示的化合物或其消旋体在Suzuki-Miyaura偶联反应中作为金属配体的应用：
    所述Suzuki-Miyaura偶联反应，其包括以下步骤：在钯催化剂、所述化合物I和碱性试剂存在下，将化合物C和化合物D在溶剂中进行Suzuki-Miyaura偶联反应，得到化合物E或者化合物ent-E即可；
    Figure PCTCN2020077397-appb-100022
    或者，所述Suzuki-Miyaura偶联反应，其包括以下步骤：在钯催化剂、所述化合物I消旋体和碱性试剂存在下，将化合物C和化合物D在溶剂中进行Suzuki-Miyaura偶联反应，得到化合物E和化合物ent-E即可；
    Figure PCTCN2020077397-appb-100023
    其中，“
    Figure PCTCN2020077397-appb-100024
    与
    Figure PCTCN2020077397-appb-100025
    ”和“
    Figure PCTCN2020077397-appb-100026
    与
    Figure PCTCN2020077397-appb-100027
    ”，均表 示此基团具有轴手性；Q为C或N；当Q为N时，R 18不存在；X为卤素；M为
    Figure PCTCN2020077397-appb-100028
    Figure PCTCN2020077397-appb-100029
    或-BF 3K；
    R 15、R 19、R 20和R 24独立地为F、C 1～10烷基、C 1～10烷氧基、C 6～30芳基、R 15-1取代的C 6～30芳基、苯氧基、R 15-2取代的苯氧基、-CHO或-OSO 2F；
    R 16、R 17、R 18、R 21、R 22和R 23独立地为H、F、C 1～10烷基、C 1～10烷氧基、C 6～30芳基、R 16-1取代的C 6～30芳基、苯氧基、R 16-2取代的苯氧基、C 1～10硅烷基、NHPiv、-CHO或-OSO 2F；
    或者，R 16、R 17和R 18中任意两个相邻的两个基团与其相连的碳原子一起形成
    Figure PCTCN2020077397-appb-100030
    或者，R 21、R 22和R 23中任意两个相邻的两个基团与其相连的碳原子一起形成
    Figure PCTCN2020077397-appb-100031
    或者，R 15和R 16与其相连的碳原子一起共同形成C 6-10芳基、R 15-3取代的C 6-10芳基、C 5-10环烷基、C 3-10杂芳基或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5-10杂环烷基中的杂原子独立地选自N、S和O中的一个或多个，个数为1、2、3或4个；
    或者，R 18和R 19与其相连的碳原子一起共同形成C 6-10芳基、R 18-1取代的C 6-10芳基、C 5-10环烷基、C 3-10杂芳基或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5-10杂环烷基中的杂原子独立地选自N、S和O中的一个或多个，个数为1、2、3或4个；
    或者，R 20和R 21与其相连的碳原子一起共同形成C 6-10芳基、R 20-1取代的C 6-10芳基、C 5-10环烷基、C 3-10杂芳基或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5-10杂环烷基中的杂原子独立地选自N、S和O中的一个或多个，个数为1、2、3或4个；
    或者，R 23和R 24与其相连的碳原子一起共同形成C 6-10芳基、R 23-1取代的C 6-10芳基、C 5-10环烷基、C 3-10杂芳基或C 5-10杂环烷基；所述C 3-10杂芳基和所述C 5-10杂环烷基中的杂原子独立地选自N、S和O中的一个或多个，个数为1、2、3或4个；
    R 15-1、R 15-2、R 16-1、R 16-2独立地为C 1～10烷基、C 1～10烷氧基、苯基、硝基、-CHO或-OSO 2F；
    所述R 15-3、R 18-1、R 20-1和R 23-1独立地为苯基、R 15-3-1取代的苯基或
    Figure PCTCN2020077397-appb-100032
    R 15-3-1独立地为C 1～10烷基或者卤素取代的C 1～10烷基；
    所述R 15-1、R 15-2、R 16-1、R 16-2、R 15-3、R 18-1、R 20-1和R 23-1和R 15-3-1的个数独立地为一个或多个，当为多个时，相同或不同。
  13. 一种如式Y所示的化合物：
    Figure PCTCN2020077397-appb-100033
    其中，“*”、R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 9的定义均如权利要求1～6中至少一项所述。
  14. 一种如权利要求13所述如式Y所示的化合物在Suzuki-Miyaura偶联反应中作为催化剂的应用：
    所述Suzuki-Miyaura偶联反应，其包括以下步骤：在所述化合物Y催化下，碱性试剂存在下，将化合物C和化合物D在溶剂中进行Suzuki-Miyaura偶联反应，得到化合物E或者化合物ent-E即可；
    Figure PCTCN2020077397-appb-100034
    其中，“
    Figure PCTCN2020077397-appb-100035
    与
    Figure PCTCN2020077397-appb-100036
    ”和“
    Figure PCTCN2020077397-appb-100037
    与
    Figure PCTCN2020077397-appb-100038
    ”，均表示此基团具有轴手性；M、Q、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24均如权利要求13所述。
  15. 一种如式Y-1所示的化合物的单晶，其晶系属于单斜晶系，C 2空间群，晶胞参数为
    Figure PCTCN2020077397-appb-100039
    α＝γ＝90°，β＝113.055(2)°；
    Figure PCTCN2020077397-appb-100040
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