WO2017107789A1 - 手性螺二氢茚骨架化合物及其制备方法 - Google Patents

手性螺二氢茚骨架化合物及其制备方法 Download PDF

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WO2017107789A1
WO2017107789A1 PCT/CN2016/109383 CN2016109383W WO2017107789A1 WO 2017107789 A1 WO2017107789 A1 WO 2017107789A1 CN 2016109383 W CN2016109383 W CN 2016109383W WO 2017107789 A1 WO2017107789 A1 WO 2017107789A1
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compound
formula
group
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reaction
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丁奎岭
曹予曦
郑治尧
崇庆雷
王正
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浙江九洲药业股份有限公司
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Priority to US16/060,424 priority Critical patent/US11325875B2/en
Priority to JP2018533768A priority patent/JP6990183B2/ja
Priority to EP16877600.3A priority patent/EP3395788A4/en
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Definitions

  • the present invention specifically relates to a chiral spiroindoline skeleton compound and a process for the preparation thereof.
  • Compounds containing a chiral full-carbon spiro structure are a special class of chiral molecules, namely chiral spirocyclones.
  • the chemical bond of the spiro carbon atom has a tetrahedral orientation characteristic, and its two rings are respectively in two planes close to each other perpendicular to each other, and the formed rigid structure limits the spiro compound.
  • the two rings are free to rotate, so that when the ring contains a substituent, it has an axial chirality.
  • a spiro compound containing a full carbon spiro structure is an important structural unit of some biologically active compounds, and is found in natural products such as ⁇ -vetivone, acorenone B, fredericamycin, and the like. Widely available (specific reference R. Rios, Chem. Soc. Rev. 2012, 41, 1060.).
  • the chiral spiro compound is more rigid and is generally less prone to racemization, so the spiro skeleton having the above advantages is
  • a class of ideal chiral ligand skeletons has been greatly developed in the synthesis and asymmetric catalysis of chiral ligands in the last ten years.
  • several excellent chiral ligands represented by chiral spiroindoline skeleton ligands in recent years have exhibited better catalysis and stereo in other types of asymmetric catalytic reactions than other chiral frameworks.
  • the chemical control effect is considered to be the chiral ligand of the "privileged structures" in the current asymmetric catalysis field (S.-F.Zhu, Q.-L. Zhou, in Privileged Chiral Ligands and Catalysts, Ed .: Q.-L. Zhou, Wiley-VCH, Weinheim, 2011, pp. 137-170.).
  • S.-F.Zhu Q.-L. Zhou
  • the current synthesis of chiral spiroalkanes is often quite cumbersome (see review literature: [1] M. Sannigrahi, Tetrahedron 1999, 55, 9007; [2] R.
  • chiral ligands and catalysts based on spiroindoline there are more than 100 chiral ligands and catalysts based on spiroindoline, and the chiral starting materials used in the synthesis are optically pure (R)- or (S)-1,1'- Spiro-indane-7,7'-diphenol or a derivative thereof ([1] Zhou, Qilin; Fu, Yu; Xie, Jianhua; Wang, Lixin; Zhou, Hai.
  • CN 1342652A [2] Zhou, Qilin ;Xie,Jianhua;Cheng,Xu;Fu,Yu;Wang,Lixin.CN 1439643A;[3]Zhou,Qilin;Duan,Haifeng;Shi,Wenjian;Wang,Lixin;Xie,Jianhua.CN 1760198A.[4]Zhou , Qilin; Hou, Guohua; Xie, Jianhua; Wang, Lixin. CN 1887893A; [5] Zhou, Qilin; Zhu, Shoufei; Li, Shen; Wang, Lixin; Song, Song.
  • WO 2009129700A1 [6] Zhou, Qilin ;Xie,Jianhua;Liu,Xiaoyan;Xie,Jianbo;Wang,Lixin.
  • WO 2012065571A1 [7] Lin Xufeng, Zhao Yanyan, Qu Haijun, Li Xuejian, CN 102516302A.).
  • the technical problem to be solved by the present invention is to overcome the prior art method for preparing a chiral fused ring spiroindoline skeleton compound, which requires an expensive chiral starting material or a chiral resolving agent, and requires a chiral separation step.
  • the cumbersome steps, the high cost of raw materials and processes, the poor economic and environmental protection, and the low catalytic efficiency of the asymmetric hydrogenation catalyst in the prior art provide a chiral spiroindoline skeleton compound and a preparation method thereof.
  • the preparation method of the chiral fused ring spiroindoline skeleton compound of the invention does not require the use of chiral starting materials or chiral resolving reagents, does not require chiral resolution steps, is simple in method, simple in post-treatment, economical and environmentally friendly,
  • the product yield is high, and the product optical purity and chemical purity are high.
  • the transition metal-catalyzed asymmetric reaction catalyst prepared by using the chiral fused ring spiroindoline skeleton compound of the invention has a remarkable catalytic effect, the product yield is >99%, and the product ee value is as high as >99%.
  • the present invention provides a chiral fused ring spiroindoline skeleton compound of the formula I, or an enantiomer or diastereomer thereof;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, a C 1 -C 10 alkyl group, a C 3 -C 10 cycloalkyl group, Alkoxy, aryl, fluorine, chlorine, bromine, iodine or a hydroxyl group of C 1 to C 4 ;
  • R 1 , R 4 , R 5 and R 8 are each independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 4 alkoxy, aryl , fluorine, chlorine, bromine, iodine or a hydroxyl group;
  • R 2 and R 3 are bonded together with a carbon atom on the molecular skeleton to which they are attached to form an aromatic ring, and the aromatic ring is bonded to the molecular skeleton to which R 2 and R 3 are attached
  • the benzene ring in which the carbon atom is located is a concentric ring structure;
  • R 6 and R 7 are bonded together with the carbon atom on the molecular skeleton to which they are attached to form an aromatic ring, and the aromatic ring is bonded to the molecule to which R 6 and R 7 are attached.
  • the benzene ring in which the carbon atom on the skeleton is located is a concentric ring structure
  • the chiral fused ring spiroindoline skeleton compound represented by Formula I is not a compound represented by Formula I-n;
  • said R 1 is the same as R 8 .
  • said R 2 is the same as R 7 .
  • said R 3 is the same as R 6 .
  • said R 4 is the same as R 5 .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a C 1 -C 10 alkyl group
  • the C 1 -C 10 The alkyl group is a C 1 - C 6 alkyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a C 1 -C 6 alkyl group
  • the C 1 -C 6 The alkyl group is a C 1 - C 3 alkyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a C 1 -C 3 alkyl group
  • the C 1 -C 3 The alkyl group is a methyl group, an ethyl group or a propyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a C 3 -C 10 cycloalkyl group
  • the C 3 -C The cycloalkyl group of 10 is a C 3 - C 6 cycloalkyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a C 3 -C 6 cycloalkyl group
  • the C 3 -C The cycloalkyl group of 6 is a cyclopropyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a C 1 -C 4 alkoxy group
  • the C 1 -C The alkoxy group of 4 is a C 1 - C 3 alkoxy group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a C 1 -C 3 alkoxy group
  • the C 1 -C The alkoxy group of 3 is a methoxy group, an ethoxy group or a propoxy group.
  • the aryl group is a C 6 -C 20 aryl group.
  • the C 6 -C 20 aryl group is a C 6 -C 12 aryl group.
  • the C 6 -C 12 aryl group is a phenyl or naphthyl group.
  • the aromatic ring is a C 6 - C 20 aromatic ring.
  • the C 6 -C 20 aromatic ring is a C 6 -C 12 aromatic ring.
  • the C 6 -C 12 aromatic ring is a benzene ring or a naphthalene ring.
  • the aromatic ring is a C 6 - C 20 aromatic ring.
  • the C 6 -C 20 aromatic ring is a C 6 -C 12 aromatic ring.
  • the C 6 -C 12 aromatic ring is a benzene ring or a naphthalene ring.
  • said n 0, 1, 2 or 3.
  • the C 1 -C 10 alkyl group is a C 1 -C 4 alkyl group.
  • the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a propyl group or a tert-butyl group.
  • the C 3 -C 10 cycloalkyl group is a C 3 -C 6 cycloalkyl group.
  • the C 3 -C 6 cycloalkyl group is a cyclopropyl group.
  • the aryl group is a C 6 -C 20 aryl group.
  • the C 6 -C 20 aryl group is a C 6 -C 12 aryl group.
  • the C 6 -C 12 aryl group is a phenyl or naphthyl group.
  • Y 1 and Y 2 are each independently a C 1 -C 4 alkoxy group
  • the C 1 -C 4 alkoxy group is a methoxy group or an ethoxy group.
  • the chiral fused ring spiroindoline skeleton compound represented by Formula I is any one of the following compounds:
  • the present invention also provides a phosphoramidite ligand as shown in Formula I', or an enantiomer or diastereomer thereof;
  • the R 1 'and R 2 ' are each independently a C 1 -C 10 alkyl group or a C 3 -C 10 cycloalkyl group; or the R 1 'and R 2 ' together with the N atom to which they are attached Linked to a C 2 -C 10 azacycloalkane ring.
  • the C 1 -C 10 alkyl group is a C 1 -C 3 alkyl group.
  • the C 1 -C 3 alkyl group is a methyl group, an ethyl group or a propyl group.
  • R 1 ' and R 2 ' are each independently a C 3 -C 10 cycloalkyl group
  • the C 3 -C 10 cycloalkyl group is a C 3 -C 6 cycloalkyl group.
  • R 1 ' and R 2 ' are each independently a C 3 -C 6 cycloalkyl group
  • the C 3 -C 6 cycloalkyl group is a cyclopropyl group.
  • the C 2 -C 10 azacycloalkyl ring is a C 3 -C 6 azacycloalkane ring.
  • the C 3 -C 6 azacycloalkane is a tetrahydropyrazolidine.
  • the phosphoramidite ligand as shown in formula I' is any of the following compounds:
  • the present invention also provides a process for the preparation of a compound of formula I, which comprises the steps of: subjecting a compound of formula III to an intramolecular Friedel-Crafts reaction in a solvent under the action of a catalyst; a compound of formula I; said catalyst is a Brnsted acid or a Lewis acid; said X, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same As mentioned above;
  • the Brnsted acid is one of hydrochloric acid, phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and phosphotungstic acid or A variety.
  • the Lewis acid is cesium trifluoromethanesulfonate, aluminum trichloride, tin tetrachloride, iron trichloride, boron trifluoride, titanium tetrachloride, titanium tetraisopropoxide, and three One or more of indium fluoromethanesulfonate and copper trifluoromethanesulfonate.
  • the Lewis acid is titanium tetrachloride.
  • the method for preparing the compound of formula I may further comprise the steps of: mixing the solvent and the compound of formula III, adding the catalyst at 0 ° C and The reaction is carried out for 1 to 100 minutes (preferably 30 minutes), and the temperature is naturally raised to 15 to 40 ° C (preferably 25 ° C) and the reaction is continued for 1 to 20 hours (preferably 5 to 6 hours).
  • the addition to the catalyst is preferably a dropwise addition; more preferably a slow addition.
  • the slow drop rate of the slow addition is from 0.1 mL/min to 1.5 mL/min (preferably 0.5 mL/min).
  • the 0 ° C condition is preferably achieved by ice bath cooling.
  • the continuing reaction is carried out under agitation.
  • the intramolecular Friedel-Crafts reaction is carried out under anhydrous anaerobic conditions.
  • the intramolecular Friedel-Crafts reaction is carried out under protective gas conditions.
  • the protective gas may be a conventional protective gas for such reactions in the art, preferably argon and/or nitrogen.
  • the molar ratio of the compound of formula III to the catalyst is from 100:1 to 1:100; more preferably from 2:1 to 1:10; for example from 1:4 to 1:1. Another example is 1:2.
  • the solvent of the intramolecular Friedel-Crafts reaction can be a conventional solvent for such reactions in the art.
  • the solvent of the intramolecular Friedel-Crafts reaction is one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether solvent, an alcohol solvent, an amide solvent, and a sulfoxide solvent.
  • the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene.
  • the halogenated hydrocarbon solvent is one or more of dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane.
  • the ether solvent is diethyl ether and/or tetrahydrofuran.
  • the alcohol solvent is methanol and/or ethanol.
  • the amide solvent is N,N-dimethylformamide.
  • the sulfoxide solvent is dimethyl sulfoxide.
  • the molar volume ratio of the compound of the formula III to the solvent of the intramolecular Friedel-Crafts reaction is from 0.02 mol/L to 0.2 mol/L, such as 0.05 mol/L or 0.1 mol/ L.
  • the temperature of the intramolecular Friedel-Crafts reaction may be a conventional temperature for such a reaction in the art, preferably from -40 ° C to 100 ° C; more preferably from 0 to 40 ° C; most preferably from 0 to 25 °C; for example 5, 10 or 25 °C.
  • the progress of the intramolecular Friedel-Crafts reaction can be monitored by a conventional test method (such as TLC, HPLC, GC or NMR) in the art, generally When the compound shown in Formula III disappears as the end point of the reaction, the intramolecular Friedel-Crafts reaction time
  • the interval is preferably from 0.1 to 48 hours; more preferably from 1 to 24 hours; for example from 0.5 to 12 hours; for example, 2 hours, 4 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 8 hours, 10 hours , 12 hours or 20 hours.
  • the post-treatment operation may be further included.
  • the method and conditions for the post-treatment may be conventional methods and conditions for post-treatment of such reactions in the art.
  • the reaction is quenched, extracted, dried, filtered, and concentrated.
  • the quenching is preferably water quenching.
  • the amount of water is preferably such that its volume is from 0.4 to 0.5 times the volume of the reaction solvent.
  • the extracted extractant is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the volume ratio of the extracted single extraction extractant to the reaction solvent is from 0.5 to 10.
  • the extraction is preferably carried out three times.
  • the dried desiccant is preferably anhydrous sodium sulfate.
  • the concentration is preferably a vacuum distillation.
  • the step of column chromatography may be further included.
  • the column chromatography is preferably carried out using a silica gel column.
  • the column chromatography eluent is preferably a mixture of petroleum ether and an ester solvent.
  • the volume of the petroleum ether and the ester solvent is preferably from 1:100 to 100:1 (more preferably 50:1).
  • the ester solvent is preferably ethyl acetate.
  • the method for preparing the compound of formula I further comprises the steps of: asymmetrically hydrogenating a compound of formula II with hydrogen under the action of a catalyst to obtain the a compound as shown in formula III;
  • the asymmetric hydrogenation catalyst may be a conventional asymmetric hydrogenation catalyst for such reactions in the art, preferably a transition metal of ruthenium, osmium, iridium and palladium.
  • the metal complex is chiral or achiral; more preferably a phosphine-nitrogen ligand complex of hydrazine.
  • the phosphine-nitrogen ligand complex of hydrazine is a chiral phosphine-nitrogen ligand complex of Ir.
  • the chiral phosphine-nitrogen ligand complex of Ir is a chiral monovalent quinone/phosphine-oxazoline complex.
  • the monovalent ruthenium/phosphine-oxazoline complex is preferably IrI/(S)-tBu-PHOX, Ir I /(R,S)-Bn-SpinPHOX and Ir I /() represented by the following formula: S,S)-Bn-SpinPHOX and one or more of their respective enantiomers and diastereomers;
  • the molar ratio of the catalyst for the asymmetric hydrogenation reaction to the compound of the formula II is 0.0001 to 0.1; more preferably 0.005 to 0.02; optimally 0.01 to 0.02.
  • the solvent of the asymmetric hydrogenation reaction may be a conventional solvent for such a reaction in the art, preferably a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, or an ether.
  • a solvent an alcohol solvent, an amide solvent, and a sulfoxide solvent.
  • the halogenated hydrocarbon solvent is dichloromethane, One or more of chloroform, carbon tetrachloride, and 1,2-dichloroethane.
  • the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene.
  • the ether solvent is diethyl ether and/or tetrahydrofuran.
  • the alcohol solvent is methanol and/or ethanol.
  • the amide solvent is N,N-dimethylformamide.
  • the sulfoxide solvent is dimethyl sulfoxide.
  • the volume-mass ratio of the solvent of the asymmetric hydrogenation reaction to the compound of the formula II is from 1 ml/g to 20 ml/g, for example, 12.0 ml/g. ⁇ 50 ml/g, for example, 12.5 ml/g.
  • the pressure of the hydrogen of the asymmetric hydrogenation reaction may be a conventional pressure for such a reaction in the art; preferably from 1 to 100 atm; more preferably from 30 to 50 atm. .
  • the temperature of the asymmetric hydrogenation reaction may be a conventional temperature for such a reaction in the art, preferably from -78 to 80 ° C; more preferably from 10 to 35 °C.
  • the progress of the asymmetric hydrogenation reaction can be monitored by a conventional test method (such as TLC, HPLC, GC or NMR) in the art, generally as in Formula II.
  • a conventional test method such as TLC, HPLC, GC or NMR
  • the time of the asymmetric hydrogenation reaction is preferably from 1 to 48 hours; more preferably from 6 to 12 hours; further, for example, from 6 to 8 hours.
  • the method for preparing the compound of the formula I, after the end of the asymmetric hydrogenation reaction preferably further comprises a post-treatment operation.
  • the methods and conditions for the post-treatment may be conventional methods and conditions for post-treatment of such reactions in the art, preferably: concentration, column chromatography.
  • concentration is preferably a vacuum distillation.
  • the column chromatography preferably employs a silica gel column.
  • the column chromatography eluent is preferably a mixture of petroleum ether and an ester solvent having a volume ratio of 1:100 to 100:1 (for example, 20).
  • the ester solvent is ethyl acetate.
  • the method for preparing the compound of the formula I after the end of the asymmetric hydrogenation reaction, without post-treatment, directly reacts the reaction system with the solvent of the Friedel-Crafts reaction, The catalyst and the compound of formula III are mixed and the intramolecular Friedel-Crafts reaction is carried out.
  • the method for preparing the compound of formula I further comprises the step of: subjecting a compound of formula V, formula VI and formula VII to an aldol condensation reaction as shown below, in a solvent, Producing the compound of formula II;
  • the method and conditions of the aldol condensation reaction may be conventional methods and conditions for such reactions in the art, and the present invention preferably has the following conditions:
  • the aldol condensation reaction is carried out under basic conditions.
  • the basic condition is the addition of an inorganic base.
  • the inorganic base is as described above.
  • the solvent of the aldol condensation reaction is a mixed solvent of an alcohol solvent and water.
  • the alcohol solvent is one or more of methanol, ethanol and propanol.
  • the volume ratio of the alcohol solvent to water in the mixed solvent of the alcohol solvent and water is from 1:1 to 1:10.
  • the molar ratio of the solvent of the aldol condensation reaction to the compound of the formula VI is from 10,000 ml/mol to 1 ml/mol.
  • the temperature of the aldol condensation reaction is from 10 to 35 °C.
  • the progress of the aldol condensation reaction can be monitored by a conventional test method (such as TLC, HPLC, GC or NMR) in the art, generally as in the formula.
  • a conventional test method such as TLC, HPLC, GC or NMR
  • the time of the substitution reaction is preferably from 1 to 12 hours (for example, 10 hours).
  • the post-treatment operation may be further included.
  • the methods and conditions for the post-treatment may be conventional methods and conditions for post-treatment such reactions in the art, preferably: filtration, washing, and drying.
  • the filtration is preferably suction filtration.
  • the washing is preferably first washed with water and then with an alcohol solvent such as ethanol.
  • the invention also provides a process for the preparation of a compound of formula I', which comprises the steps of: substituting a compound of formula I with a compound of formula IV in a solvent under basic conditions; Reacting to produce a compound of formula I'; wherein W 1 and W 2 are each independently halogen; said X, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 1 ' and R 2 ' are as described above;
  • the halogen is preferably fluorine, chlorine, bromine or iodine.
  • the C 1 -C 10 alkyl group is a C 1 -C 6 alkyl group; more preferably a C 1 -C 3 alkyl group.
  • the C 1 -C 3 alkyl group is a methyl group, an ethyl group or a propyl group.
  • the method and conditions of the substitution reaction may be conventional methods and conditions in the art, and the present invention preferably has the following conditions:
  • the method for preparing the compound represented by the formula I' further comprises the steps of: mixing the compound of the formula I with the solvent under alkaline conditions, and cooling to -40 to 10 ° C. Then, it is mixed with the compound shown in Formula IV, and the substitution reaction is carried out after the temperature is raised to 10 to 35 °C.
  • the method of mixing with the compound of formula IV is such that the compound of formula IV is added to the reaction system.
  • the manner of addition is a drop. It is preferred that the dropwise addition be slow.
  • the substitution reaction is carried out under stirring.
  • the substitution reaction is carried out under anhydrous anaerobic conditions.
  • the substitution reaction is carried out under protective gas conditions.
  • the protective gas is argon and/or nitrogen.
  • the basic condition is that the reaction is carried out under the action of a base.
  • the base is an organic base and/or an inorganic base.
  • the organic base is pyridine, imidazole, pyrazine, anthraquinone, anthraquinone, morpholine, piperidine, piperazine, tertiary amine, aniline and anthraquinone organic base.
  • the tertiary amine organic base is one or more of trimethylamine, triethylamine, tributylamine, N-ethyldiisopropylamine and N,N-dimethylbenzylamine. .
  • the aniline organic base is N,N-dimethylaniline.
  • the pyridine organic base is one or more of pyridine, methylpyridine, ethylmethylpyridine, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine.
  • the piperidine organic base is N-methyl piperidine.
  • the porphyrin organic base is N-methylmorpholine.
  • the piperazine-based organic base is 1,4-ethylene piperazine (DABCO).
  • the steroidal organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and/or 1,5-diazabicyclo[4.3 .0] indole-5-ene (DBN).
  • the inorganic base is an alkali metal or alkaline earth metal hydride, an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal alkoxide, an alkali metal or alkaline earth metal amide, an alkali metal Or one or more of an alkaline earth metal carbonate, an alkali metal or alkaline earth metal hydrogencarbonate, an alkali metal or alkaline earth metal carboxylate, and ammonium carbonate.
  • the alkali metal or alkaline earth metal hydride is sodium hydride and/or potassium hydride.
  • the alkali metal or alkaline earth metal hydroxide is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • the alkali metal or alkaline earth metal alkoxide is one or more selected from the group consisting of sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide, sodium t-steroxide and potassium t-steroxide.
  • the alkali metal or alkaline earth metal amide is sodium amide and/or lithium diisopropylamide.
  • the alkali metal or alkaline earth metal carbonate is one or more of potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate.
  • the alkali metal or alkaline earth metal hydrogencarbonate is potassium hydrogencarbonate and/or sodium hydrogencarbonate.
  • the alkali metal or alkaline earth metal carboxylate is sodium acetate.
  • the solvent for the substitution reaction is one or more of an ether solvent, a halogenated alkane solvent, and an aromatic hydrocarbon solvent.
  • the ether solvent is tetrahydrofuran.
  • the molar volume ratio of the compound of the formula I to the solvent is from 0.05 mol/L to 0.5 mol/L; more preferably 0.1 mol/L.
  • the molar ratio of the compound of the formula I to the compound of the formula IV is from 1:1.1 to 1:3; more preferably from 1:1.1 to 1:1.3. .
  • the temperature of the substitution reaction is from 0 to 35 ° C; more preferably from 0 to 25 ° C.
  • the progress of the substitution reaction can be monitored by a conventional test method (such as TLC, HPLC, GC or NMR) in the art, generally as in Formula I.
  • a conventional test method such as TLC, HPLC, GC or NMR
  • the time of the substitution reaction is preferably from 1 to 12 hours.
  • the post-treatment operation may be further included.
  • the methods and conditions for the post-treatment may be conventional methods and conditions for post-treatment of such reactions in the art, preferably: concentration, column chromatography.
  • concentration is preferably a vacuum distillation.
  • the column chromatography preferably employs a silica gel column.
  • the column chromatography eluent is preferably a mixture of petroleum ether and a fatty amine solvent having a volume ratio of from 100:1 to 10:1 (for example, 20).
  • the fatty amine solvent is triethylamine.
  • room temperature means an ambient temperature of 20 to 30 °C.
  • alkyl means a saturated linear or branched hydrocarbon moiety, such as -CH 3 or -CH (CH 3) 2.
  • alkoxy refers to a group formed by linking an alkyl group to an oxygen atom, such as -OCH 3 , -OCH 2 CH 3 .
  • cycloalkyl denotes a saturated cyclic hydrocarbyl moiety, such as cyclohexyl.
  • aryl refers to a hydrocarbyl moiety containing one or more aromatic rings including, but not limited to, phenyl, phenylene, naphthyl, naphthylene, anthracenyl, fluorenyl, phenanthryl.
  • alkyl, alkoxy, cycloalkyl, and aryl groups described herein include both substituted and unsubstituted moieties.
  • Possible substituents on the alkyl, alkoxy, cycloalkyl, and aryl groups include, but are not limited to, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2- C6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 1 -C 6 alkoxy, aryl, hydroxy, halogen, amino.
  • the preparation method of the chiral fused ring spiroindoline skeleton compound of the invention does not require the use of chiral starting materials or chiral resolving reagents, does not require chiral resolution steps, is simple in method, simple in post-treatment, and economical. Environmental protection, high product yield, high optical purity and chemical purity.
  • the transition metal complex prepared by using the chiral fused ring spiroindoline skeleton compound of the invention has the catalytic effect as a catalyst for asymmetric hydrogenation reaction, the product yield is >99%, and the product ee value is up to >99. %.
  • the method for preparing compound II by the aldol condensation reaction of the invention can reach >90%, and the post-treatment is simpler.
  • Fig. 1 is a chart showing the X-ray crystal structure of the chiral fused ring spiroindoline skeleton compound I-g obtained in Example 20.
  • anti and syn are used to distinguish cis-trans isomers, wherein anti refers to a compound of a trans configuration of a pair of cis-trans isomer compounds, and syn refers to a pair of cis-transforms.
  • the dr value indicates the molar ratio between diastereomers.
  • the ee value indicates an enantiomeric excess.
  • the ee value (RS) / (R + S) * 100%, That is, the ratio of the difference in molar amount of the two compounds to the sum of the molar amounts of the two compounds; and vice versa.
  • the yield or yield refers to the isolated yield, that is, the yield obtained after separation and purification of the product by post-treatment, rather than the conversion of the reaction before the post-treatment.
  • t R indicates the peak time of the main product
  • t R indicates the peak time of the by-product
  • the by-products are generally diastereomeric of the cis-trans configuration of the main product. isomer.
  • IR absorbent
  • IR indicates infrared detection of a pure product sample unless otherwise specified.
  • Chiralcel OD-H column indicates the Chiralcel OD-H chiral column of the Japanese company.
  • the compounds II-a to II-m prepared from Example 2 were respectively a hydrogenated substrate, and 1.0% of a phosphine-oxazoline ligand ruthenium complex Ir I /(S)- t Bu -PHOX is a catalyst (percentage is the percentage of mole of catalyst to the molar amount of compound II), according to the experimental method described in Example 3, only the hydrogenation substrate is changed, the hydrogen pressure is changed to 30 atm, and the reaction time is changed to 8 The reaction was carried out in an hour to obtain hydrogenated products III-a to III-m as shown below. The dr values of these products were measured to be anti/syn > 19:1.
  • IR(neat) ⁇ 2996 , 2920, 2847, 2349, 1604, 1495, 1463, 1451, 1406, 1330, 1295, 1278, 1260, 1242, 1207, 1184, 1116, 1077, 1063, 1024, 996, 943, 880, 853, 786, 768, 732, 701, 671, 665, 609 cm -1 .
  • Example 7 (i.e., Comparative Example 1)
  • the experiment was carried out in accordance with the method of Example 6 except that the amount of the substrate compound III-h (0.2 mmol in this example), the type and amount of the catalyst, the kind of the solvent and the amount (the solvent in this example) were used according to the conditions shown in Table 2.
  • the dosage was 2.0 mL
  • the reaction temperature was changed, and the yield and ee value are shown in Table 2.
  • the molar equivalents in Table 2 represent the multiples of the molar amount of the catalyst relative to the molar amount of the compound III-h.
  • "-" indicates no solvent.
  • ee value in Table 2 indicates that it cannot be measured.
  • reaction time was 12 h.
  • the catalysts in this example are all common proton acids of the Bronsted type. It can be seen that the protonic acid of the Bronsted type is not suitable as a catalyst for the stereoselective ring closure of the compound III-h.
  • CPA chiral phosphoric acid
  • the experiment was carried out in accordance with the method of Example 6 except that the amount of the substrate compound III-h (0.2 mmol in this example), the type and amount of the catalyst, the kind of the solvent and the amount (the solvent in this example) were used according to the conditions shown in Table 3.
  • the dosage was 2.0 mL
  • the reaction temperature was changed, and the yield and ee value are shown in Table 3.
  • the molar equivalents in Table 3 represent the multiples of the molar amount of the catalyst relative to the molar amount of the compound III-h. In the column of ee value in Table 3, "-" indicates that it cannot be measured.
  • reaction time was 12 h.
  • the experiment was carried out in accordance with the method of Example 6 except that the amount of the substrate compound III-h (0.2 mmol in this example), the type and amount of the catalyst, the kind and amount of the solvent (the solvent in this example) were as shown in Table 4.
  • the dosage was 2.0 mL
  • the reaction temperature was changed, and the yield and ee value are shown in Table 4.
  • the molar equivalents in Table 4 represent the multiples of the molar amount of the catalyst relative to the molar amount of the compound III-h.
  • reaction time was 12 h.
  • the experiment was carried out in the same manner as in Example 6 except that the amount of the substrate compound III-h (0.2 mmol in this example), the type and amount of the catalyst (the catalyst in the present embodiment was TiCl 4 , the amount of the catalyst was 0.4 mmol), and the solvent.
  • the type and amount (the solvent in the present example were all dichloromethane, the amount was 2.0 mL) were changed, and the reaction temperature and reaction time were changed according to the conditions shown in Table 5.
  • the yield and ee value are shown in Table 5.
  • the experiment was carried out in the same manner as in Example 6 except that the amount of the substrate compound III-h (0.2 mmol in this example), the type and amount of the catalyst (the catalyst in the present embodiment was TiCl 4 , the amount of the catalyst was 0.4 mmol), and the solvent.
  • the amount (the amount of the solvent used in the present embodiment was 2.0 mL) was changed, and the solvent type, the reaction temperature, and the reaction time were changed according to the conditions shown in Table 6, and the yield and ee value are shown in Table 6.
  • the experiment was carried out in the same manner as in Example 6 except that the amount of the substrate compound III-h (0.2 mmol in this example), the type and amount of the catalyst (the catalyst in the present embodiment was TiCl 4 ), and the solvent type (in this example)
  • the solvent was changed by dichloromethane), and the amount of the catalyst, the substrate concentration (i.e., the ratio of the molar amount (mol/L) of the substrate compound III-h to the solvent), and the reaction time were changed according to the conditions shown in Table 7.
  • the yield and ee values are shown in Table 7.
  • the molar equivalents represent a multiple of the molar amount of the catalyst relative to the molar amount of the substrate compound III-h.
  • Example 13 Using the compound III-a (>99% ee) obtained in Example 5 as a substrate, the procedure of Example 13 was carried out, and III-a was in 2 molar equivalents of TiCl 4 (relative to the molar equivalent of the compound III-a). Under the action of intramolecular asymmetric cyclization, a chiral fused ring spiroindoline skeleton compound Ia is obtained.
  • III-b (>99% ee) obtained in Example 5 as a substrate, and operating in the same manner as in Example 13, III-b undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Ib is obtained.
  • IR(neat) ⁇ 3016 , 2921, 2852, 2834, 1918, 1856, 1795, 1595, 1459, 1446, 1377, 1319, 1261, 1210, 1196, 1158, 1141, 1094, 1076, 1032, 953, 930, 896, 871, 790, 779, 756, 720, 711, 668, 645, 619 cm -1 .
  • III-c (>99% ee) obtained in Example 5 as a substrate, and operating in the same manner as in Example 13, III-c undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Ic is obtained.
  • Example 13 Using the compound III-d (>99% ee) obtained in Example 5 as a substrate, the experimental procedure in Example 13 was carried out, and III-d undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • the chiral fused ring spiroindoline skeleton compound Id is obtained.
  • III-e (>99% ee) obtained in Example 5 as a substrate, and operating in the same manner as in Example 13, III-e undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Ie is obtained.
  • III-f (>99% ee) obtained in Example 5 as a substrate, and operating in the same manner as in Example 13, III-f undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound If is obtained.
  • III-g (>99% ee) obtained in Example 5 as a substrate, referring to the experimental method in Example 13, III-g undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Ig is obtained.
  • Fig. 1 The X-ray crystal diffraction molecular structure of the chiral fused ring spiroindoline skeleton compound I-g is shown in Fig. 1.
  • III-h (>99% ee) obtained in Example 5 as a substrate, according to the experimental method in Example 13, III-h undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • the chiral fused ring spiroindoline skeleton compound Ih is obtained.
  • III-i (>99% ee) obtained in Example 5 as a substrate, and operating in the same manner as in Example 13, III-i undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Ii is obtained.
  • III-j (>99% ee) obtained in Example 5 as a substrate, referring to the experimental method in Example 13, III-j undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Ij is obtained.
  • III-k (99% ee) obtained in Example 5 as a substrate, and operating according to the experimental method in Example 13, III-k undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Ik is obtained.
  • III-1 (>99% ee) obtained in Example 5 as a substrate, and operating in the same manner as in Example 13, III-1 was subjected to intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Il is obtained.
  • III-m (>99% ee) obtained in Example 5 as a substrate, referring to the experimental method in Example 13, III-m undergoes intramolecular asymmetric cyclization under the action of 2 molar equivalents of TiCl 4 .
  • a chiral fused ring spiroindoline skeleton compound Im is obtained.
  • the compound III-s (>99% ee) was prepared according to the method of Example 5, and the compound III-s was used as a substrate.
  • the procedure of Example 13 was followed, and the intramolecular reaction was carried out under the action of 2 molar equivalents of TiCl 4 .
  • the cyclization reaction is carried out to obtain a chiral fused ring spiroindoline skeleton compound I-s'.
  • the compound III-q (>99% ee) was prepared by the method of Example 5, and the compound III-q was used as a substrate.
  • the procedure of Example 13 was followed, and the intramolecular reaction was carried out under the action of 2 molar equivalents of TiCl 4 .
  • the cyclization reaction is carried out to obtain a chiral fused ring spiroindoline skeleton compound I-q'.
  • the compound III-r (>99% ee) was obtained by the method of Example 5, and the compound III-r was used as a substrate.
  • the procedure of Example 13 was followed, and intramolecular reaction was carried out under the action of 2 molar equivalents of TiCl 4 .
  • the cyclization reaction is carried out to obtain a chiral fused ring spiroindoline skeleton compound I-r'.
  • the compound II can be used as a raw material, and an asymmetric hydrogenation and a closed-loop one-pot method can be used.
  • the intermediate compound III can be directly separated, and an appropriate amount of TiCl 4 can be directly added to the hydrogenation reaction mixture to synthesize the compound I.
  • a compound I-h one-pot asymmetric hydrogenation-ring-closing reaction to synthesize compound Ih is taken as an example to illustrate a typical experimental procedure for the synthesis of compound I by one-pot method from compound II.
  • the hydrogenation bottle (150-mL) was treated with anhydrous anaerobic treatment under an argon atmosphere, and the catalyst (S) -t BuPHOX/Ir(I) (96.0 mg, 0.061 mmol) and the substrate II-h (6.15 g, 12.55 mmol) and anhydrous dichloromethane (75 mL).
  • the hydrogenation bottle was transferred to the autoclave in a glove box. After replacing the hydrogen three times, hydrogen was charged to 50 atm. The reaction was carried out for 12 hours at room temperature.
  • the second step is to remove the Ih methyl group with BBr 3 : after the Schlenk bottle (100 mL) is anhydrous and anaerobic, add (1S, 2S, 2'S)-Ih (5.02g, 10.55) under argon atmosphere. Methyl acetate (35.0 mL) was cooled to -78 °C. BBr 3 (4M in CH 2 Cl 2 ) (6.59 mL, 26.38 mmol) was added dropwise. After the addition is completed, slowly increase to room temperature. After stirring for an additional 12 hours, it was quenched by the addition of water (100 mL). With dichloromethane (20mL ⁇ 3).
  • Example 29 In the same manner as in Example 28, starting from II-h, using the (R) -t BuPHOX/Ir(I) catalyst, a one-pot asymmetric hydrogenation/cyclization, the obtained product was debrominated according to the method of Example 29. Thereafter, the enantiomer ent-Io of the compound Io can be obtained.
  • the corresponding monodentate phosphoramidite ligand It can be synthesized by reacting diphenol ent-Io with dimethylaminodichlorophosphorus under basic conditions as shown in the following formula.
  • the complex formed by the chiral fused ring spiroindoline skeleton phosphoramidite ligand It and [Rh(COD) 2 OTf] is a chiral catalyst, and the catalyzed ⁇ -dehydroamino acid methyl ester is not
  • a symmetric hydrogenation reaction is used to exemplify the use of the chiral fused ring spiroindoline skeleton compound in the present invention for asymmetric catalysis.

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Abstract

本发明公开了一种手性螺二氢茚骨架化合物及其制备方法。本发明的手性稠环螺二氢茚骨架化合物如式I或I'所示；本发明的手性螺二氢茚骨架化合物的制备方法，其包括如下步骤：溶剂中，催化剂作用下，将如式III所示的化合物进行分子内傅里德-克拉夫茨反应，制得如式I所示的化合物；所述催化剂为布朗斯特酸或路易斯酸。本发明的制备方法，不需采用手性起始原料或手性拆分试剂、无须进行手性拆分步骤、方法简单、后处理简便、经济环保、产物收率高、产物光学纯度和化学纯度高。采用本发明的手性稠环螺二氢茚骨架化合物制得的过渡金属催化的不对称反应的催化剂，催化效果显著，产物收率＞99％，产物ee值高达＞99％。

Description

手性螺二氢茚骨架化合物及其制备方法
本申请要求于2015年12月22日提交中国专利局、申请号为201510974151.1、发明名称为“手性螺二氢茚骨架化合物及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明具体涉及手性螺二氢茚骨架化合物及其制备方法。
背景技术
含有手性全碳螺环结构的化合物是一类特殊的手性分子，即手性螺烷分子。在这类螺烷分子的结构中，其螺碳原子的化学成键具有四面体取向特征，它的两个环分别处于两个相互接近垂直的平面，所形成的刚性结构限制了螺环化合物中两个环的自由旋转，故当环上含有取代基时便具有了轴向手性。含有全碳螺环结构的螺烷化合物是一些生物活性化合物的重要结构单元，在天然产物如岩兰酮(β-vetivone)、菖蒲烯酮(acorenone B)、菲特霉素(fredericamycin)等中广泛存在(具体参考文献R.Rios,Chem.Soc.Rev.2012,41,1060.)。另外，由于螺烷分子中两个环是通过σ-键连接在一个季碳中心上，所以手性螺环化合物刚性较强，且通常不易发生消旋化，因此具有上述优点的螺烷骨架是一类理想的手性配体骨架，在最近十余年手性配体的合成和不对称催化应用中有了较大的发展。例如，近年来出现的若干以手性螺二氢茚骨架配体为代表的优秀手性配体，在多种类型的不对称催化反应中表现出比以往其它手性骨架更好的催化和立体化学控制效果，被认为是当前不对称催化领域中的“优势结构”(privileged structures)的手性配体(S.-F.Zhu,Q.-L.Zhou,in Privileged Chiral Ligands and Catalysts,Ed.:Q.-L.Zhou,Wiley-VCH,Weinheim,2011,pp.137-170.)。然而，目前手性螺烷分子的合成过程通常相当繁琐(参见综述文献：[1]M.Sannigrahi,Tetrahedron 1999,55,9007；[2]R.Pradhan et al,Tetrahedron2006,62,779；[3]S.Kotha et al,Synthesis 2009,165；[4]V.A.D'yakonov et al,Chem.Rev.2014,114,5775.)，不仅底物应用范围有限，而且在大多数情况下只能得到外消旋的产物。光学纯的螺烷骨架分子的获得大多经过消旋体或非对映异构体的拆分过程，成本高且操作繁琐，还会带来环境污染，因此极大地限制了其实际应用。目前以螺二氢茚为骨架的手性配体和催化剂已有百余个，其合成中所采用的手性起始原料都是光学纯(R)-或(S)-1,1’-螺环二氢化茚-7,7’-二酚或其衍生物([1]Zhou,Qilin；Fu,Yu；Xie,Jianhua；Wang,Lixin；Zhou,Hai.CN 1342652A；[2]Zhou,Qilin；Xie,Jianhua；Cheng,Xu；Fu,Yu；Wang,Lixin.CN 1439643A；[3]Zhou,Qilin；Duan,Haifeng；Shi,Wenjian；Wang,Lixin；Xie,Jianhua.CN 1760198A.[4]Zhou,Qilin；Hou,Guohua；Xie,Jianhua；Wang,Lixin.CN 1887893A；[5]Zhou,Qilin；Zhu,Shoufei；Li,Shen；Wang,Lixin；Song,Song.WO 2009129700A1；[6]Zhou,Qilin；Xie,Jianhua；Liu,Xiaoyan；Xie,Jianbo；Wang,Lixin.WO 2012065571A1；[7]林旭峰，赵彦彦，屈海军，李雪健，CN 102516302A.)。到目前为止，此类光学纯的螺二氢茚骨架手性源,即光学纯(R)-或(S)-1,1’-螺环二氢化茚-7,7’-二酚或酯，无一例外都是通过非对映体化学衍生或手性包结结晶等手性拆分方法所获得的(参见文献：[1]V.B.Birman et al,Tetrahedron-Asymmetry 1999,10,125；[2]J.H.Zhang et al,Tetrahedron-Asymmetry 2002,13,1363；[3]Z.Li et al,Tetrahedron-Asymmetry2004,15,665；[4]M.Venugopal et al,Tetrahedron-Asymmetry 2004,15,3427.)， 拆分过程繁琐操作复杂，耗费大量的手性拆分试剂，且不经济环保，这些缺陷提高了配体的成本，给其大量制备带来了困难，因此一定程度上限制了它们的应用。
因此，发展一种高效不对称催化、不使用手性拆分试剂、无须进行手性拆分步骤、方法简单、后处理简便、经济环保、产物收率高、产物光学纯度和化学纯度高的制备手性稠环螺二氢茚骨架化合物的方法，及开发一种具有较高催化活性的含有手性稠环螺二氢茚骨架化合物配体的手性催化剂是本领域亟待解决的问题。
发明内容
本发明要解决的技术问题是为了克服现有技术中手性稠环螺二氢茚骨架化合物的制备方法需要采用昂贵的手性起始原料或手性拆分试剂、需要进行手性拆分步骤、步骤繁琐、原料及工艺成本高、经济环保性差的缺陷，及现有技术中不对称氢化催化剂催化效率低等缺陷，而提供了一种手性螺二氢茚骨架化合物及其制备方法。本发明的手性稠环螺二氢茚骨架化合物的制备方法，不需采用手性起始原料或手性拆分试剂、无须进行手性拆分步骤、方法简单、后处理简便、经济环保、产物收率高、产物光学纯度和化学纯度高。采用本发明的手性稠环螺二氢茚骨架化合物制得的过渡金属催化的不对称反应的催化剂，催化效果显著，产物收率>99％，产物ee值高达>99％。
本发明技术方案之一：
本发明提供了一种如式I所示的手性稠环螺二氢茚骨架化合物，或它们的对映体或非对映异构体；
Figure PCTCN2016109383-appb-000001
其中，R1、R2、R3、R4、R5、R6、R7和R8各自独立地为氢、C1～C10的烷基、C3～C10的环烷基、C1～C4的烷氧基、芳基、氟、氯、溴、碘或羟基；
或者，R1、R4、R5和R8各自独立地为氢、C1～C10的烷基、C3～C10的环烷基、C1～C4的烷氧基、芳基、氟、氯、溴、碘或羟基；R2和R3与它们所连接的分子骨架上的碳原子一起连接成芳环，且该芳环与“R2和R3所连接的分子骨架上的碳原子所在的苯环”是并环结构；R6和R7与它们所连接的分子骨架上的碳原子一起连接成芳环，且该芳环与“R6和R7所连接的分子骨架上的碳原子所在的苯环”是并环结构；
X为CY1Y2、NY1、O或S；n＝0～3；其中Y1和Y2各自独立地为氢、C1～C10的烷基、C3～C10的环烷基、芳基或C1～C4的烷氧基；
并且，所述如式I所示的手性稠环螺二氢茚骨架化合物不为如式I-n所示的化合物；
Figure PCTCN2016109383-appb-000002
较佳地，所述R1与R8相同。较佳地，所述R2与R7相同。较佳地，所述R3与R6相同。较佳地，所述R4与R5相同。
较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C10的烷基时，所述C1～C10的烷基为C1～C6的烷基。较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C6的烷基时，所述C1～C6的烷基为C1～C3的烷基。较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C3的烷基时，所述C1～C3的烷基为甲基、乙基或丙基。
较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C3～C10的环烷基时，所述C3～C10的环烷基为C3～C6的环烷基。较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C3～C6的环烷基时，所述C3～C6的环烷基为环丙基。
较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C4的烷氧基时，所述C1～C4的烷氧基为C1～C3的烷氧基。较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C3的烷氧基时，所述C1～C3的烷氧基为甲氧基、乙氧基或丙氧基。
较佳地，所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为芳基时，所述芳基为C6～C20芳基。较佳地，所述C6～C20芳基为C6～C12芳基。较佳地，所述C6～C12芳基为苯基或萘基。
较佳地，所述R2和R3与它们所连接的分子骨架上的碳原子一起连接成芳环时，所述芳环为C6～C20芳环。较佳地，所述C6～C20芳环为C6～C12芳环。较佳地，所述C6～C12芳环为苯环或萘环。
较佳地，所述R6和R7与它们所连接的分子骨架上的碳原子一起连接成芳环时，所述芳环为C6～C20芳环。较佳地，所述C6～C20芳环为C6～C12芳环。较佳地，所述C6～C12芳环为苯环或萘环。
较佳地，所述n＝0、1、2或3。
较佳地，所述Y1和Y2各自独立地为C1～C10的烷基时，所述C1～C10的烷基为C1～C4烷基。较佳地，所述C1～C4烷基为甲基、乙基、丙基或叔丁基。
较佳地，所述Y1和Y2各自独立地为C3～C10的环烷基时，所述C3～C10的环烷基为C3～C6的环烷基。较佳地，所述C3～C6的环烷基为环丙基。
较佳地，所述Y1和Y2各自独立地为芳基时，所述芳基为C6～C20芳基。较佳地，所述C6～C20芳基为C6～C12芳基。较佳地，所述C6～C12芳基为苯基或萘基。
较佳地，所述Y1和Y2各自独立地为C1～C4的烷氧基时，所述C1～C4的烷氧基为甲氧基或乙氧基。
较佳地，所述如式I所示的手性稠环螺二氢茚骨架化合物为如下任一化合物：
Figure PCTCN2016109383-appb-000003
Figure PCTCN2016109383-appb-000004
Figure PCTCN2016109383-appb-000005
本发明技术方案之二：
本发明还提供了一种如式I’所示的亚磷酰胺配体，或它们的对映体或非对映异构体；
Figure PCTCN2016109383-appb-000006
所述X、n、R1、R2、R3、R6、R7和R8同前所述。
所述R1’和R2’各自独立地为C1～C10的烷基或C3～C10的环烷基；或者所述R1’和R2’与它们所连接的N原子一起连接成C2～C10氮杂烷环。
较佳地，所述R1’和R2’各自独立地为C1～C10的烷基时，所述C1～C10的烷基为C1～C3的烷基。较佳地，所述R1’和R2’各自独立地为C1～C3的烷基时，所述C1～C3的烷基为甲基、乙基或丙基。
较佳地，所述R1’和R2’各自独立地为C3～C10的环烷基时，所述C3～C10的环烷基为C3～C6的环烷基。较佳地，所述R1’和R2’各自独立地为C3～C6的环烷基时，所述C3～C6的环烷基为环丙基。
较佳地，所述C2～C10氮杂烷环为C3～C6氮杂烷环。较佳地，所述C3～C6氮杂烷环为四氢吡唑烷。
较佳地，所述如式I’所示的亚磷酰胺配体为如下任一化合物：
Figure PCTCN2016109383-appb-000007
本发明技术方案之三：
本发明还提供了一种如式I所示的化合物的制备方法，其包括如下步骤：溶剂中，催化剂作用下，将如式III所示的化合物进行分子内傅里德－克拉夫茨反应，制得如式I所示的化合物；所述催化剂为布朗斯特酸或路易斯酸；所述X、n、R1、R2、R3、R4、R5、R6、R7和R8同前所述；
Figure PCTCN2016109383-appb-000008
较佳地，所述布朗斯特酸为盐酸、磷酸、多聚磷酸、甲基磺酸、三氟甲基磺酸、醋酸、三氟乙酸、对甲苯磺酸和磷钨酸中的一种或多种。
较佳地，所述路易斯酸为三氟甲基磺酸钪、三氯化铝、四氯化锡、三氯化铁、三氟化硼、四氯化钛、四异丙氧基钛、三氟甲基磺酸铟和三氟甲基磺酸铜中的一种或多种。
更佳地，所述路易斯酸为四氯化钛。
较佳地，所述如式I所示的化合物的制备方法还可进一步包括如下步骤：将所述溶剂和所述如式III所示的化合物进行混合，0℃条件下，加入所述催化剂并反应1～100分钟(较佳地为30分钟)，自然升温至15℃～40℃(较佳地为25℃)并继续反应1～20小时(较佳地为5～6小时)。
所述加入所述催化剂中的加入较佳地为滴加；更佳地为缓慢滴加。所述缓慢滴加的滴加速率为0.1mL/min～1.5mL/min(较佳为0.5mL/min)。
所述0℃条件较佳地为冰浴冷却达到。
较佳地，所述继续反应是在搅拌条件下进行。
较佳地，所述分子内傅里德－克拉夫茨反应在无水无氧条件下进行。
较佳地，所述分子内傅里德－克拉夫茨反应在保护性气体条件下进行。所述保护性气体可为本领域此类反应的常规保护性气体，较佳地为氩气和/或氮气。
较佳地，所述如式III所示的化合物与所述催化剂的摩尔比为100:1～1:100；更佳地为2:1～1:10；例如1:4～1:1，再例如1:2。
所述分子内傅里德－克拉夫茨反应的溶剂可为本领域此类反应的常规溶剂。较佳地，所述分子内傅里德－克拉夫茨反应的溶剂为芳烃类溶剂、卤代烃类溶剂、醚类溶剂、醇类溶剂、酰胺类溶剂和亚砜类溶剂中的一种或多种。较佳地，所述芳烃类溶剂为苯、甲苯和二甲苯中的一种或多种。较佳地，所述卤代烃类溶剂为二氯甲烷、氯仿、四氯化碳和1,2-二氯乙烷中的一种或多种。较佳地，所述醚类溶剂为乙醚和/或四氢呋喃。较佳地，所述醇类溶剂为甲醇和/或乙醇。较佳地，所述酰胺类溶剂为N,N-二甲基甲酰胺。较佳地，所述亚砜类溶剂为二甲基亚砜。
较佳地，所述如式III所示的化合物与所述分子内傅里德－克拉夫茨反应的溶剂的摩尔体积比值为0.02mol/L～0.2mol/L，例如0.05mol/L或0.1mol/L。
所述分子内傅里德－克拉夫茨反应的温度可为本领域此类反应的常规温度，较佳地为-40℃～100℃；更佳地为0～40℃；最佳地为0～25℃；例如5、10或25℃。
所述如式I所示的化合物的制备方法中，所述分子内傅里德－克拉夫茨反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR)进行监控，一般以如式III所示的化合物消失时作为反应终点，所述分子内傅里德－克拉夫茨反应的时 间较佳地为0.1～48小时；更佳地为1～24小时；例如0.5～12小时；再例如2小时、4小时、5小时、5.5小时、6小时、6.5小时、8小时、10小时、12小时或20小时。
所述如式I所示的化合物的制备方法中，在所述分子内傅里德－克拉夫茨反应结束后，较佳地，还可进一步包含后处理的操作。所述的后处理的方法和条件可为本领域此类反应后处理常规的方法和条件，较佳地为：将反应淬灭、萃取、干燥、过滤、浓缩，即可。所述淬灭较佳地为水淬灭。所述水的用量较佳地为其体积是反应溶剂体积的0.4～0.5倍。所述萃取的萃取剂较佳地为卤代烃类溶剂；所述卤代烃类溶剂较佳地为二氯甲烷。所述萃取的单次萃取的萃取剂的体积与反应溶剂的体积比值为0.5～10。所述萃取较佳地进行三次。所述干燥的干燥剂较佳地为无水硫酸钠。所述浓缩较佳地为减压蒸馏。
所述如式I所示的化合物的制备方法中，在所述分子内傅里德－克拉夫茨反应结束后，较佳地，还可进一步包含柱层析的步骤。所述柱层析较佳地为采用硅胶柱进行。所述柱层析的淋洗液较佳地为石油醚与酯类溶剂的混合液。所述石油醚与酯类溶剂的混合液中，所述石油醚与酯类溶剂的体积比较佳地为1:100～100:1(更佳地为50：1)。所述酯类溶剂较佳地为乙酸乙酯。
较佳地，所述如式I所示的化合物的制备方法，还进一步包括如下步骤：溶剂中，催化剂作用下，将如式II所示的化合物与氢气进行不对称氢化反应，制得所述如式III所示的化合物；
Figure PCTCN2016109383-appb-000009
所述如式I所示的化合物的制备方法中，所述不对称氢化反应的催化剂可为本领域此类反应常规的不对称氢化催化剂，较佳地为钌、铑、铱和钯的过渡金属络合物中的一种或多种；所述金属络合物为手性或非手性的；更佳地为铱的膦-氮配体络合物。较佳地，所述铱的膦-氮配体络合物为Ir的手性膦-氮配体络合物。较佳地，所述Ir的手性膦-氮配体络合物为手性一价铱/膦-噁唑啉络合物。所述一价铱/膦-噁唑啉络合物较佳地为如下式所示的IrI/(S)-tBu-PHOX、IrI/(R,S)-Bn-SpinPHOX和IrI/(S,S)-Bn-SpinPHOX及它们各自的对映异构体和非对映异构体中的一种或多种；
Figure PCTCN2016109383-appb-000010
所述如式I所示的化合物的制备方法中，较佳地，所述不对称氢化反应的催化剂与所述如式II所示的化合物的摩尔比值为0.0001～0.1；更佳地为0.005～0.02；最佳地为0.01～0.02。
所述如式I所示的化合物的制备方法中，所述不对称氢化反应的溶剂可为本领域此类反应常规的溶剂，较佳地为卤代烃类溶剂、芳香烃类溶剂、醚类溶剂、醇类溶剂、酰胺类溶剂和亚砜类溶剂中的一种或多种。较佳地，所述卤代烃类溶剂为二氯甲烷、 氯仿、四氯化碳和1,2-二氯乙烷中的一种或多种。较佳地，所述芳香烃类溶剂为苯、甲苯和二甲苯中的一种或多种。较佳地，所述醚类溶剂为乙醚和/或四氢呋喃。较佳地，所述醇类溶剂为甲醇和/或乙醇。较佳地，所述酰胺类溶剂为N,N-二甲基甲酰胺。较佳地，所述亚砜类溶剂为二甲基亚砜。
所述如式I所示的化合物的制备方法中，所述不对称氢化反应的溶剂与所述如式II所示的化合物的体积质量比值为1ml/g～20ml/g，例如12.0ml/g～50ml/g，再例如12.5ml/g。
所述如式I所示的化合物的制备方法中，所述不对称氢化反应的氢气的压力可为本领域此类反应的常规压力；较佳地为1～100atm；更佳地为30～50atm。
所述如式I所示的化合物的制备方法中，所述不对称氢化反应的温度可为本领域此类反应的常规温度，较佳地为-78～80℃；更佳地为10～35℃。
所述如式I所示的化合物的制备方法中，所述不对称氢化反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR)进行监控，一般以如式II所示的化合物消失时作为反应终点，所述不对称氢化反应的时间较佳地为1～48小时；更佳地为6～12小时；再例如6～8小时。
所述的如式I所示的化合物的制备方法，在所述的不对称氢化反应结束后，较佳地，还可进一步包含后处理的操作。所述的后处理的方法和条件可为本领域此类反应后处理常规的方法和条件，较佳地为：浓缩、柱层析。所述浓缩较佳地为减压蒸馏。所述柱层析较佳地采用硅胶柱。所述柱层析的淋洗剂较佳地为体积比值为1:100～100:1(例如20)的石油醚和酯类溶剂的混合液。较佳地，所述酯类溶剂为乙酸乙酯。
较佳地，所述的如式I所示的化合物的制备方法，在所述的不对称氢化反应结束后，不进行后处理，直接将反应体系和所述傅里德－克拉夫茨反应的溶剂、催化剂及所述如式III所示的化合物混合，并进行所述分子内傅里德－克拉夫茨反应。
较佳地，所述如式I所示的化合物的制备方法，还进一步包括如下步骤：溶剂中，将如式V、式VI和式VII所示的化合物进行如下所示的羟醛缩合反应，制得所述如式II所示的化合物；
Figure PCTCN2016109383-appb-000011
所述如式I所示的化合物的制备方法中，所述羟醛缩合反应的方法和条件均可为本领域此类反应的常规方法和条件，本发明优选如下条件：
较佳地，所述羟醛缩合反应在碱性条件下进行。
较佳地，所述碱性条件是添加无机碱。较佳地，所述无机碱同前所述。
较佳地，所述羟醛缩合反应的溶剂为醇类溶剂和水的混合溶剂。较佳地，所述醇类溶剂为甲醇、乙醇和丙醇中的一种或多种。较佳地，所述醇类溶剂和水的混合溶剂中醇类溶剂和水的体积比为1:1～1:10。
较佳地，所述羟醛缩合反应的溶剂与所述如式VI所示的化合物的体积摩尔比值为10000ml/mol～1ml/mol。
较佳地，所述羟醛缩合反应的温度为10～35℃。
所述的如式I所示的化合物的制备方法中，所述的羟醛缩合反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR)进行监控，一般以如式VI所示的化合物消失时作为反应终点，所述的取代反应的时间较佳地为1～12小时(例如10小时)。
所述的如式I所示的化合物的制备方法中，在所述的羟醛缩合反应结束后，较佳地，还可进一步包含后处理的操作。所述的后处理的方法和条件可为本领域此类反应后处理常规的方法和条件，较佳地为：过滤、洗涤、干燥。所述过滤较佳地为抽滤。所述洗涤较佳地先用水洗涤，然后用醇类溶剂(例如乙醇)洗涤。
本发明技术方案之四：
本发明还提供了一种如式I’所示的化合物的制备方法，其包括如下步骤：碱性条件下，溶剂中，将如式I所示的化合物与如式IV所示的化合物进行取代反应，制得如式I’所示的化合物；所述W1和W2各自独立地为卤素；所述X、n、R1、R2、R3、R4、R5、R6、R7、R8、R1’和R2’同前所述；
Figure PCTCN2016109383-appb-000012
较佳地，所述取代反应中，所述卤素较佳地为氟、氯、溴或碘。
较佳地，所述取代反应中，所述C1～C10烷基为C1～C6烷基；更佳地为C1～C3烷基。较佳地，所述C1～C3烷基为甲基、乙基或丙基。
所述取代反应的方法和条件可为本领域常规的方法和条件，本发明优选下列条件：
较佳地，所述如式I’所示的化合物的制备方法还包括如下步骤：碱性条件下，将所述如式I所示的化合物与所述溶剂混合，冷却至-40～10℃，然后与所述如式IV所示的化合物混合，温度升至10～35℃后进行所述取代反应。
较佳地，所述与所述如式IV所示的化合物混合的方法为将所述如式IV所示的化合物加入反应体系。较佳地，所述加入的方式为滴加。所述滴加以缓慢为宜。
较佳地，所述取代反应在搅拌条件下进行。
较佳地，所述取代反应在无水无氧条件下进行。
较佳地，所述取代反应在保护性气体条件下进行。较佳地，所述保护性气体为氩气和/或氮气。
较佳地，所述碱性条件为反应在碱作用下进行。较佳地，所述碱为有机碱和/或无机碱。较佳地，所述的有机碱为吡啶类、咪唑类、吡嗪类、吲哚类、嘌呤类、吗啉类、哌啶类、哌嗪类、叔胺类、苯胺类和脒类有机碱中的一种或多种。较佳地，所述的叔胺类有机碱为三甲胺、三乙胺、三丁胺、N-乙基二异丙基胺和N,N-二甲基苄胺中的一种或多种。较佳地，所述的苯胺类有机碱为N,N-二甲基苯胺。较佳地，所述的吡啶类有机碱为吡啶、甲基吡啶、乙基甲基吡啶、4-二甲氨基吡啶和2-甲基-5-乙基吡啶中的一种或多种。较佳地，所述的哌啶类有机碱为N-甲基哌啶。较佳地，所述的吗 啉类有机碱为N-甲基吗啉。较佳地，所述的哌嗪类有机碱为1,4-亚乙基哌嗪(DABCO)。较佳地，所述的脒类有机碱为1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)和/或1,5-二氮杂二环[4.3.0]壬-5-烯(DBN)。较佳地，所述的无机碱为碱金属或碱土金属的氢化物、碱金属或碱土金属的氢氧化物、碱金属或碱土金属的烷氧化物、碱金属或碱土金属的氨基化物、碱金属或碱土金属的碳酸盐、碱金属或碱土金属的碳酸氢盐、碱金属或碱土金属的羧酸盐和碳酸铵中的一种或多种。较佳地，所述的碱金属或碱土金属的氢化物为氢化钠和/或氢化钾。较佳地，所述的碱金属或碱土金属的氢氧化物为氢氧化钠、氢氧化钾和氢氧化锂中的一种或多种。较佳地，所述的碱金属或碱土金属的烷氧化物为甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠、叔戌醇钠和叔戌醇钾中的一种或多种。较佳地，所述的碱金属或碱土金属的氨基化物为氨基化钠和/或二异丙氨基锂。较佳地，所述的碱金属或碱土金属的碳酸盐为碳酸钾、碳酸钠、碳酸锂和碳酸铯中的一种或多种。较佳地，所述的碱金属或碱土金属的碳酸氢盐为碳酸氢钾和/或碳酸氢钠。较佳地，碱金属或碱土金属的羧酸盐为乙酸钠。
较佳地，所述取代反应的溶剂为醚类溶剂、卤代烷烃类溶剂和芳烃类溶剂中的一种或多种。较佳地，所述醚类溶剂为四氢呋喃。
较佳地，所述取代反应中，所述如式I所示的化合物与所述溶剂的摩尔体积比值为0.05mol/L～0.5mol/L；更佳地为0.1mol/L。
较佳地，所述取代反应中，所述如式I所示的化合物与如式IV所示的化合物的摩尔比为1：1.1～1：3；更佳地为1：1.1～1：1.3。
较佳地，所述取代反应的温度为0～35℃；更佳地为0～25℃。
所述的如式I’所示的化合物的制备方法中，所述的取代反应的进程可以采用本领域中的常规测试方法(如TLC、HPLC、GC或NMR)进行监控，一般以如式I所示的化合物消失时作为反应终点，所述的取代反应的时间较佳地为1～12小时。
所述的如式I’所示的化合物的制备方法中，在所述的取代反应结束后，较佳地，还可进一步包含后处理的操作。所述的后处理的方法和条件可为本领域此类反应后处理常规的方法和条件，较佳地为：浓缩、柱层析。所述浓缩较佳地为减压蒸馏。所述柱层析较佳地采用硅胶柱。所述柱层析的淋洗剂较佳地为体积比值为100:1～10:1(例如20)的石油醚和脂肪胺类溶剂的混合液。较佳地，所述脂肪胺类溶剂为三乙胺。
本发明中，室温指环境温度为20～30℃。
术语“烷基”表示饱和的线性或支链烃部分，如-CH3或-CH(CH3)2。术语“烷氧基”表示指烷基与氧原子连结后的生成基团，如-OCH3，-OCH2CH3。术语“环烷基”表示饱和的环状烃基部分，例如环己基。术语“芳基”表示包含一个或多个芳环的烃基部分，包括但不限于苯基、亚苯基、萘基、亚萘基、芘基、蒽基、菲基。
除非另外说明，本文所述的烷基、烷氧基、环烷基、和芳基同时包括取代的和未取代的部分。烷基、烷氧基、环烷基、和芳基上可能的取代基包括，但不限于：C1-C6烷基,C1-C6卤代烷基,C2-C6烯基,C2-C6炔基,C3-C10环烷基,C3-C10环烯基,C1-C6烷氧基,芳基,羟基,卤素,氨基。
在符合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。
若非特别指明，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：
1、本发明的手性稠环螺二氢茚骨架化合物的制备方法，不需采用手性起始原料或手性拆分试剂、无须进行手性拆分步骤、方法简单、后处理简便、经济环保、产物收率高、产物光学纯度和化学纯度高。
2、采用本发明的手性稠环螺二氢茚骨架化合物制得的过渡金属络合物，作为不对称氢化反应的催化剂，催化效果显著，产物收率>99％，产物ee值高达>99％。
3、本发明的羟醛缩合反应制备化合物II的方法产率可达到>90％，后处理更简单。
附图说明
图1为实施例20得到的手性稠环螺二氢茚骨架化合物I-g的X射线晶体衍射分子结构图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明中，按照本领域常识，anti和syn是用以区分顺反异构体的，其中anti指一对顺反异构体化合物中反式构型的化合物，而syn指一对顺反异构体化合物中顺式构型的化合物。
本发明中，按照本领域常识，dr值表示非对映异构体之间的摩尔比值。例如，若非对映异构体为顺反异构体，且非对映异构体中反式构型化合物与顺式构型化合物的摩尔量大，则dr值＝anti/syn*100％，即dr值为非对映异构体中反式构型化合物与顺式构型化合物的摩尔比值；反之亦然。
本发明中，按照本领域常识，ee值表示对映体过量。例如，若一对对映异构体分别为R构型和S构型，且R构型化合物摩尔量大于S构型化合物，则ee值＝(R-S)/(R+S)*100％，即两个化合物的摩尔量的差值与两个化合物的摩尔量之和的比值；反之亦然。
以下实施例中，若无特殊说明，收率或产率均指分离收率，即产物经过后处理分离纯化后所得收率，而非后处理之前的反应的转化率。
以下实施例中，若无特殊说明，tR(major)表示主产物出峰时间，tR(minor)表示副产物出峰时间，且副产物一般为主产物的顺反构型的非对映异构体。
以下实施例中，若无特殊说明，IR(neat)表示纯的产物样品的红外检测。
以下实施例中，若无特殊说明，calcd.For表示化合物质谱数据的计算值，Found表示质谱数据的实验值。
以下实施例中，若无特殊说明，Chiralcel OD-H column表示日本大赛璐公司的型号为Chiralcel OD-H的手性柱。
实施例1
如下式的反应路线所示，以化合物II-a的制备为例，在本实施例详细说明本发明所述的α,α’-二(亚芳基)酮化合物(通式II)的通用制备方法：
Figure PCTCN2016109383-appb-000013
向250-mL茄形瓶中加入氢氧化钠(1.6g,40mmol)，1/1(v/v)的乙醇/水溶液(100mL)，室温下搅拌溶解后，依次加入环己酮(1.03mL,10mmol)和苯甲醛(2.2mL,22mmol)，室温搅拌10小时。反应体系中析出大量黄色固体，抽滤，所得固体用大量水(4×100mL)洗涤，少量乙醇(10mL)洗涤，干燥得到黄色粉末状固体产物II-a(产 率85％)。
II-a:M.P.115-117℃,1H NMR(400MHz,CDCl3)δ7.80(s,2H),7.47-7.32(m,10H),2.95-2.91(m,4H),1.82-1.75(m,2H)ppm.13C NMR(100MHz,CDCl3)δ190.4,136.9,136.1,135.9,130.3,128.6,128.4,28.4,23.0ppm.
实施例2
按照实施例1的制备方法,仅改变反应底物的如式2a所示化合物上的取代基，分别制备如下所示的α,α’-二(亚芳基)酮类化合物II-a～II-m：
Figure PCTCN2016109383-appb-000014
如式II-b所示化合物的收率及结构鉴定数据：
黄色固体,92％.M.P.142-144℃,1H NMR(400MHz,CDCl3)δ7.91(s,2H),7.26-7.18(m,8H),2.77-2.75(m,4H),2.34(s,6H),1.73-1.67(m,2H),13C NMR(100MHz,CDCl3)δ190.4,137.9,136.7,136.0,135.1,130.1,129.0,128.4,125.3,28.4,23.5,20.0.IR(neat)ν2932,1664,1590,1463,1400,1277,1240,1195,1165,1138,1018,996,968,929,860,814,783,759,736,721,607cm-1.HRMS(ESI)m/z:calcd.for C22H23O+:303.1743,Found:303.1747([M+H]+).
如式II-c所示化合物的收率及结构鉴定数据：
黄色固体,收率85％,M.P.83-85℃,1H NMR(400MHz,CDCl3)δ7.77(s,2H),7.31-7.24(m,6H),7.16-7.14(m,2H),2.94-2.91(m,4H),2.38(s,6H),1.80-1.74(m,2H). 13C NMR(100MHz,CDCl3)δ109.3,137.9,137.0,136.0,135.9,131.1,129.4,128.2,127.4,28.5,23.0,21.4.IR(neat)ν2939,1659,1597,1490,1428,1276,1227,1180,1162,1143,1072,1050,971,946,885,835,786,758,737,717,690,616cm-1.HRMS(ESI)m/z:calcd.for C22H23O+:303.1743,Found:303.1751([M+H]+).
如式II-d所示化合物的收率及结构鉴定数据：
黄色固体，收率90％.M.P.179-181℃,1H NMR(400MHz,CDCl3)δ7.78(s,2H),7.38(d,J＝8.0Hz,4H),7.21(d,J＝8.4Hz,4H),2.92(t,J＝6Hz,4H),2.38(s,6H),1.81-1.75(m,2H).13C NMR(100MHz,CDCl3)δ190.4,138.8,136.8,135.4,133.1,130.4,129.1,28.5,23.0,21.4.IR(neat)ν2938,2915,1660,1598,1564,1507,1311,1266,1197,1154,1139,1016,958,935,867,817,757,729,706,660cm-1.HRMS(ESI)m/z:calcd.for C22H23O+:303.1743,Found:303.1749([M+H]+).
如式II-e所示化合物的收率及结构鉴定数据：
黄色固体,收率95％,1H NMR(400MHz,CDCl3)δ7.76(s,2H),7.32(t,J＝8.0Hz,2H),7.06(d,J＝7.6Hz,2H),6.99(s,2H),6.89(dd,J＝8,2.4Hz,2H),3.83(s,6H),2.94-2.91(m,4H),1.81-1.75(m,2H).13C NMR(100MHz,CDCl3)δ190.3,159.4,137.2,136.8,136.4,129.3,122.8,115.7,114.2,55.2,28.4,22.9,IR(neat)ν2934,2834,1690,1601,1571,1491,1445,1426,1316,1270,1220,1185,1162,1094,1045,993,947,921,883,868,822,769,751,674,626cm-1.HRMS(ESI)m/z:calcd.for C22H23O3 +:335.1642,Found:335.1646([M+H]+).
如式II-f所示化合物的收率及结构鉴定数据：
黄色固体,收率90％,M.P.167-169℃,1H NMR(400MHz,CDCl3)δ7.76(s,2H),7.44(d,J＝8.8Hz,4H),6.92(d,J＝8.8Hz,4H),3.82(s,6H),2.89(t,J＝5.2Hz,4H),1.83-1.75(m,2H).13C NMR(100MHz,CDCl3)δ190.0,159.8,136.4,134.2,132.1,128.6,113.8,55.2,28.4,22.9.IR(neat)ν2939,2829,1657,1591,1553,1505,1451,1416,1313,1301,1276,1247,1182,1159,1138,1112,1022,965,948,868,832,809,754,731,663cm-1.HRMS(ESI)m/z:calcd.for C22H23O3 +:335.1642,Found:335.1647([M+H]+).
如式II-g所示化合物的收率及结构鉴定数据：
黄色固体,收率75％,M.P.186-188℃,1H NMR(400MHz,CDCl3)δ7.98-7.95(m,4H),δ7.88-7.83(m,6H),δ7.60-7.58(m,2H),δ7.52-7.50(m,4H),13C NMR(100MHz,CDCl3)δ190.3,137.1,136.4,133.5,133.1,133.0,130.2,128.4,127.9,127.7,127.6,126.8,126.4,28.6,23.0.IR(neat)ν3050,2961,2932,2847,2451,1950,1665,1605,1576,1500,1451,1432,1371,1349,1332,1309,1282,1269,1239,1178,1164,1139,1124,1064,1015,987,968,946,921,893,882,860,820,773,750,728,655,640,630,611cm-1.HRMS-EI(m/z)M+calcd.for C28H22O+374.1665found 374.1673[M+].、
如式II-h所示化合物的收率及结构鉴定数据：
黄色固体,收率95％,M.P.165-166℃,1H NMR(400MHz,CDCl3)δ7.79(s,2H),7.50(d,J＝8.8Hz,2H),6.84(d,J＝2.8Hz,2H),6.75(dd,J＝8.4,2.8Hz,2H),3.80(s,3H),2.76(t,J＝5.6Hz,4H),1.79-1.72(m,2H),13C NMR(100MHz,CDCl3)δ189.3,158.2,137.4,136.7,136.2,133.3,116.3,115.4,115.1,55.4,28.2,22.9.IR(neat)ν3071,3000,2961,2941,2872,2847,2829,1656,1590,1566,1462,1438,1398,1299,1280,1263,1238,1193,1165,1145,1111,1041,1017,995,858,825,813,750,733,694,606cm-1；EI-MS(70eV),m/z＝492([M]+),411,331,317,301,289,274,166,128,115,102；calcd.for C22H20Br2O3:C,53.68；H,4.10％；Found:C,53.67；H,4.08％.
如式II-i所示化合物的收率及结构鉴定数据：
黄色固体(Yellow powder),收率75％,M.P.160-162℃,1H NMR(400MHz,CDCl3)δ7.76(s,2H),7.12-7.10(m,2H),7.02(s,2H),6.90(d,J＝8.4Hz,2H),3.91(d,J＝1Hz,12H),2.94(t,J＝5.2Hz,4H),1.85-1.81(m,2H).13C NMR(100MHz,CDCl3)δ189.9,149.5,148.5,136.7,134.4,128.8,123.8,113.6,110.7,55.8,55.8,28.4,22.9.IR(neat)ν2940,2838,1652,1595,1511,1446,1420,1331,1246,1138,1067,1017,991,935,920,908,865,849,806,759,719,611cm-1.HRMS(ESI)m/z:calcd.for C24H27O5 +:395.1853,Found:395.1860([M+H]+).
如式II-j所示化合物的收率及结构鉴定数据：
黄色固体,收率90％,M.P.142-144℃,1H NMR(400MHz,CDCl3)δ7.88(s,2H),7.13-7.04(m,6H),2.76(m,4H),2.33(s,6H),2.29(s,6H),1.72-1.70(m,2H).13C NMR(100MHz,CDCl3)δ190.4,136.6,136.1,134.9,134.8,134.7,130.0,129.5,129.1,28.4,23.5,21.0,19.6.IR(neat)ν2931,1669,1613,1588,1488,1433,1310,1275,1230,1166,1137,1034,928,904,810,780,751,719cm-1.HRMS(ESI)m/z:calcd.for C24H27O+:331.2056,Found:331.2063([M+H]+).
如式II-k所示化合物的收率及结构鉴定数据：
黄色固体,收率85％,M.P.75-77℃,1H NMR(400MHz,CDCl3)δ7.85(s,2H),7.12(d,J＝8.8,2H),6.79-6.78(m,4H),3.78(s,6H),2.76(t,J＝4.8Hz,4H),2.25(s,6H),1.73-1.69(m,2H).13C NMR(100MHz,CDCl3)δ190.2,157.1,136.8,136.0,135.9,130.9,129.9,114.7,113.4,55.3,28.4,23.4,19.0.IR(neat)ν2919,2834,1663,1605,1582,1491,1466,1444,1411,1282,1250,1235,1211,1159,1138,1116,1038,992,950,912,884,859,819,803,749,731,706cm-1.HRMS(ESI)m/z:calcd.for C24H27O3 +:363.1955,Found:363.1961([M+H]+).
如式II-l所示化合物的收率及结构鉴定数据：
黄色固体,收率92％,M.P.145-147℃.1H NMR(400MHz,CDCl3)δ7.93(s,2H),6.88-6.85(m,6H),3.80(s,6H),3.79(s,6H),2.85(t,J＝5.2Hz,4H),1.77-1.74(m,2H),13C NMR(100MHz,CDCl3)δ190.4,152.7,136.8,132.3,125.8,116.3,114.3,111.5,56.0,55.8,28.7,23.4.IR(neat)ν2945,2832,1663,1600,1491,1462,1414,1280,1249,1218,1180,1155,1141,1036,991,934,864,809,754,732,718,698cm-1.HRMS(ESI)m/z:calcd.for C24H27O5 +:395.1853,Found:395.1849([M+H]+).
如式II-m所示化合物的收率及结构鉴定数据：
黄色固体,收率85％,M.P.180-182℃,1H NMR(400MHz,CDCl3)δ7.92(s,2H),7.08(d,J＝8.8Hz,2H),6.69(d,J＝8.4Hz,2H),3.90-3.89(m,18H),2.85-2.82(m,4H),1.77-1.75(m,2H).13C NMR(100MHz,CDCl3)δ190.1,154.2,153.4,142.1,135.7,131.8,125.1,123.0,106.5,61.4,60.8,55.9,28.8,23.4.IR(neat)ν2938,1660,1587,1490,1456,1410,1264,1204,1160,1137,1090,1041,1017,967,943,921,879,861,820,732,698,651cm-1.
实施例3
Figure PCTCN2016109383-appb-000015
在氩气氛围中，将氢化瓶(150-mL)无水无氧处理后，加入实施例2制备的化合物II-h(6.0g,12.2mmol)、催化剂IrI/(S)-tBu-PHOX(0.061mmol)、以及无水二 氯甲烷(75mL)。在手套箱中将氢化瓶转移至高压釜中，置换氢气三次后，充入氢气至30atm，室温下反应6～8小时。在通风橱中小心放空残余氢气，打开反应釜，减压除去溶剂，混合物取样用1H NMR测定II-h的转化率>99％和产物III-h的顺反比例(d.r.＝anti/syn)>95:5。剩余混合物减压除去溶剂，残余物用硅胶柱层析分离纯化(石油醚/乙酸乙酯20:1)，得无色油状液体III-h。
制得化合物III-h，产物为无色油状液体,收率92％,ee值>99％,[α]D 20＝-18.79(c 1.0,CHCl3).产物的ee值由手性高效液相色谱测定,手性柱为日本大赛璐公司的型号为Chiralcel AS-H的手性柱；(流动相,异丙醇/正己烷(v/v)＝5:95,温度为室温.；流动相流速:0.5mL/min；紫外-可见光检测,检测波长λ＝230nm)；化合物III-h的保留时间tR(major)＝17.49min；化合物III-h的顺式构型异构体的保留时间tR(minor)＝19.31min.
化合物III-h结构鉴定数据：1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.4Hz,2H),6.72(d,J＝3.2Hz,2H),6.61(dd,J＝8.8,2.8Hz,2H),3.73(s,3H),3.18(dd,J＝13.6,3.0Hz,2H),2.97-2.90(m,2H),2.72(dd,J＝14.0,8.4Hz,2H),1.96-1.88(m,2H),1.83-1.77(m,2H),1.70-1.62(m,2H),13C NMR(100MHz,CDCl3)δ213.7,158.6,139.9,133.2,116.9,114.9,113.5,55.3,48.9,36.4,32.2,20.6,IR(纯样品)ν2992,2959,2920,2854,2834,1571,1466,1457,1437,1315,1286,1271,1256,1174,1102,1079,1035,967,800,607cm-1；EI-MS(70eV),m/z:496([M]+),415,336,215,199,187,137,121,91,77；HRMS-EI(m/z):计算值C22H24O3Br2 +:494.0092,实测值:494.0096([M]+).
实施例4
在氩气氛围中，将氢化瓶(150-mL)无水无氧处理后，加入实施例2制备的化合物II-h(0.1g,0.2mmol)、催化剂A(0.002mmol)、以及无水二氯甲烷(5mL)。在手套箱中将氢化瓶转移至高压釜中，置换氢气三次后，充入氢气，室温下反应12小时。在通风橱中小心放空残余氢气，打开反应釜，减压除去溶剂，混合物取样用1H NMR测定II-h的转化率和产物III-h的顺反比例(d.r.＝anti/syn)。剩余混合物减压除去溶剂，残余物用硅胶柱层析分离纯化(石油醚/乙酸乙酯20:1)，得无色油状液体III-h,产物ee值和dr值均按照实施例3中的手性高效液相色谱方法进行测定。催化剂种类和氢气压力、产物收率和dr值及ee值如表1所示。
表1
催化剂A 氢气压力(atm) 收率(％) anti/syn[c] ee(％)
IrI/(S)-tBu-PHOX 50 93 >19:1 99
IrI/(R,S)-Bn-SpinPHOX 50 90 19:1 99
IrI/(S,S)-Bn-SpinPHOX 50 85 >19:1 99
IrI/(S)-tBu-PHOX 30 93 >19:1 99
表1中的催化剂A的各个化合物的结构如下所示：
Figure PCTCN2016109383-appb-000016
从表1可以得知，采用上述几种不同的手性铱(I)/膦-噁唑啉络合物作为催化剂， 催化效果相近，都能以优秀的dr值(anti/syn≥19:1)和99％ee得到相应的不对称氢化产物III-h。产物收率略有差异，其中IrI/(S)-tBu-PHOX的综合效果最佳，在30atm氢气压力下室温反应12小时，以>19:1的dr值、99％ee和93％的分离收率得到III-h。
实施例5
Figure PCTCN2016109383-appb-000017
如上式所示，分别以由实施例2制备的化合物II-a～II-m为氢化底物，以1.0％的膦-噁唑啉配体铱络合物IrI/(S)-tBu-PHOX为催化剂(百分比为催化剂的摩尔量占化合物II摩尔量的百分比)，按照实施例3所述的实验方法，仅将氢化底物改变、将氢气压力变为30atm、将反应时间变为8小时，进行反应，制得如下所示的氢化产物III-a～III-m。测得这些产物的dr值均为anti/syn>19:1。
氢化产物III-a～III-m相关的收率及结构分析表征数据如下：
Figure PCTCN2016109383-appb-000018
白色固体,收率90％.>99％ee,[α]D 20＝-56.5(c 1.00,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝2:98,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝13.22min；tR(minor)＝20.22min.1H NMR(400MHz,CDCl3)δ7.28-7.11(m,10H),3.10(dd,J＝13.6,5.6Hz,2H),2.80-2.75(m,2H),2.60(dd,J＝13.6,9.2Hz,2H),1.90-1.84(m,2H),1.77-1.71(m,2H),1.63-1.57(m,2H)ppm.13C NMR(100MHz,CDCl3)δ214.7,139.6,129.0,128.4,126.2,50.7,36.2,31.8,20.3ppm.
Figure PCTCN2016109383-appb-000019
无色液体,收率94％.>99％ee,[α]D 20＝-38.0(c 0.97,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-Hcolumn；流动相,异丙醇/正己烷(v/v)＝5:95,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝9.52min；tR(minor)＝11.27min.The absolute configuration was assigned by analogy.1H NMR(400MHz,CDCl3)δ7.08-6.99(m,8H),3.08(dd,J＝14.0,5.2Hz,2H),2.73-2.71(m,2H),2.56(dd,J＝13.6,9.2Hz,2H),2.26(s,6H),1.87-1.82(m,2H),1.71-1.68(m,2H),1.59-1.55(m,2H).13C NMR(100MHz,CDCl3)δ 214.0,137.5,135.8,130.1,129.5,126.1,125.5,49.0,33.1,31.6,20.3,19.2.IR(neat)ν3016,2929,2860,2349,2323,1703,1604,1492,1454,1379,1270,1143,1120,1031,941,919,898,867,833,741,671,665cm-1.HRMS(ESI)m/z:calcd.for C22H30NO+:324.2322,Found:324.2321([M+NH4]+).
Figure PCTCN2016109383-appb-000020
无色液体,收率82％,>99％ee,[α]D 20＝-56.3(c 1.02,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-Hcolumn；流动相,异丙醇/正己烷(v/v)＝5:95,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝9.20min；tR(minor)＝12.30min.1H NMR(400MHz,CDCl3)δ7.15-7.11(m,2H),6.99-6.89(m,6H),3.05(dd,J＝14.0,6.0Hz,2H),2.75-2.72(m,2H),2.54(dd,J＝13.2,8.8Hz,2H),2.29(s,6H),1.87-1.82(m,2H),1.70-1.67(m,2H),1.57-1.54(m,2H).13C NMR(100MHz,CDCl3)δ214.5,139.4,137.7,129.6,128.1,126.7,125.8,50.5,35.9,31.6,21.2,20.1.IR(neat)ν2925,2859,1705,1608,1488,1446,1377,1117,1037,921,852,782,766,743,699cm-1.HRMS-EI(m/z)M+calcd.for C22H26O+306.1978found 306.1988[M+].
Figure PCTCN2016109383-appb-000021
白色固体，收率90％,>99％ee,M.P.71-73℃,[α]D 20＝-46.2(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝5:95,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝9.45min；tR(minor)＝11.26min.1H NMR(400MHz,CDCl3)δ7.08(d,J＝8.0Hz,4H),7.01(d,J＝7.6Hz,4H),3.05(dd,J＝13.6,5.6Hz 2H),2.76-2.72(m,2H),2.56(dd,J＝13.6,9.2Hz,2H),2.32(s,6H),1.90-1.85(m,2H),1.74-1.71(m,2H),1.60-1.55(m,2H).13C NMR(100MHz,CDCl3)δ215.0,136.5,135.6,129.1,128.9,50.8,35.7,31.8,21.0,20.3.IR(neat)ν3007,2928,2854,1902,1695,1516,1441,1344,1320,1286,1258,1231,1150,1091,1022,943,921,904,868,798,772,752,708,644,613cm-1.HRMS(ESI)m/z:calcd.for C22H30NO+:324.2322,Found:324.2319([M+NH4]+).
Figure PCTCN2016109383-appb-000022
无色液体,收率97％,>99％ee,[α]D 20＝-48.2(c 1.01,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝10:90,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220 nm；tR(major)＝14.19min；tR(minor)＝19.48min.1H NMR(400MHz,CDCl3)δ7.16(t,J＝7.6Hz,2H),6.74-6.69(m,6H),3.75(s,6H),3.06(dd,J＝13.6,5.2Hz,2H),2.76-2.73(m,2H),2.56(dd,J＝13.6,9.2Hz,2H),1.88-1.84(m,2H),1.72-1.69(m,2H),1.61-1.54(m,2H).13C NMR(100MHz,CDCl3)δ214.4,159.4,141.0,129.2,121.2,114.6,111.2,54.9,50.4,36.0,31.6,20.1.IR(neat)ν2930,1703,1583,1488,1453,1257,1152,1118,1041,853,780,747cm-1.HRMS-EI(m/z)M+calcd.for C22H26O3 +338.1876found338.1876.
Figure PCTCN2016109383-appb-000023
白色固体,收率95％,>99％ee,M.P.68-70℃.[α]D 20＝-30.6(c 1.03,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝10:90,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝230nm；tR(major)＝16.16min；tR(minor)＝20.49min.1H NMR(400MHz,CDCl3)δ7.03(d,J＝8.4Hz,4H),6.80(d,J＝8.4Hz,4H),3.74(s,6H),3.04(dd,J＝14,6.4Hz,2H),2.75-2.72(m,2H),2.55(dd,J＝13.6,8.4Hz,2H),1.89-1.83(m,2H),1.73-1.70(m,2H),1.60-1.55(m,2H).13C NMR(100MHz,CDCl3)δ214.3,157.6,131.2,129.5,113.4,54.7,50.6,35.0,31.6,20.0.IR(neat)ν2936,2860,2838,1888,1692,1610,1583,1509,1457,1440,1420,1359,1342,1321,1300,1279,1243,1231,1174,1136,1114,1099,1074,1028,959,916,893,871,846,831,810,776,759,736,708,683,623cm-1.HRMS(ESI)m/z:calcd.for C22H30NO3 +:335.2220,Found:335.2216([M+NH4]+).
Figure PCTCN2016109383-appb-000024
白色固体,收率95％,>99％ee,M.P.108-110℃.[α]D 20＝-0.1(c 1.2,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝10:90,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝12.98min；tR(minor)＝15.58min.1H NMR(400MHz,CDCl3)δ7.73-7.71(m,2H),7.65(d,J＝8.4Hz,4H),7.49(s,2H),7.39-7.34(m,4H),7.19(dd,J＝8.0,1.2Hz,2H),3.21(dd,J＝14.0,6.0Hz,2H),2.86-2.82(m,2H),2.69(dd,J＝13.6,8.8Hz,2H),1.83-1.78(m,2H),1.63-1.60(m,2H),1.55-1.50(m,2H).13C NMR(100MHz,CDCl3)δ214.3,137.0,133.3,131.9,127.9,127.4,127.3,127.3,127.2,125.8,125.2,50.5,36.2,31.8,20.1.IR(neat)ν3055,2922,2858,2349,2323,1948,1703,1632,1600,1505,1470,1448,1358,1312,1274,1247,1211,1157,1123,1107,1083,1067,1015,989,974,949,921,900,876,861,826,817,773,742,687,671,665,650,622,610cm-1.HRMS(ESI)m/z:calcd.for C28H30NO+:396.2322,Found:396.2320([M+H]+).
Figure PCTCN2016109383-appb-000025
无色油状液体,收率92％,>99％ee,[α]D 20＝-18.79(c 1.0,CHCl3).The enantiomeric excess was determined by HPLC on a Chiralcel AS-H column；(流动相,异丙醇/正己烷(v/v)＝5:95,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝230nm)；tR(major)＝17.49min；tR(minor)＝19.31min.1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.4Hz,2H),6.72(d,J＝3.2Hz,2H),6.61(dd,J＝8.8,2.8Hz,2H),3.73(s,6H),3.18(dd,J＝13.6,6.0Hz,2H),2.97-2.90(m,2H),2.72(dd,J＝14.0,8.4Hz,2H),1.96-1.88(m,2H),1.83-1.77(m,2H),1.70-1.62(m,2H)ppm；13C NMR(100MHz,CDCl3)δ213.7,158.6,139.9,133.2,116.9,114.9,113.5,55.3,48.9,36.4,32.2,20.6ppm；EI-MS(70eV),m/z:496([M]+),415,336,215,199,187,137,121,91,77；HRMS-EI(m/z):calcd.for C22H24O3Br2 +:494.0087,found:494.0096([M]+).
Figure PCTCN2016109383-appb-000026
白色固体,收率95％,>99％ee,M.P.102-104℃,[α]D 20＝-44.1(c 1.10,CHCl3),>99％ee.产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝10:90,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝26.73min；tR(minor)＝34.04min.1H NMR(400MHz,CDCl3)δ6.58-6.45(m,6H),3.65(s,12H),2.88(dd,J＝13.6,6.4Hz,2H),2.61-2.58(m,2H),2.39(dd,J＝13.6,8.4Hz,2H),1.75-1.70(m,2H),1.60-1.57(m,2H),1.46-1.41(m,2H).13C NMR(100MHz,CDCl3)δ214.0,148.1,146.7,131.4,120.2,111.5,110.4,55.0,55.0,50.2,35.2,31.4,19.7.IR(neat)ν2996,2920,2847,2349,1604,1495,1463,1451,1406,1330,1295,1278,1260,1242,1207,1184,1116,1077,1063,1024,996,943,880,853,786,768,732,701,671,665,609cm-1.HRMS-EI(m/z)M+calcd.for C24H30O5 +398.2088found 398.2099[M+].
Figure PCTCN2016109383-appb-000027
白色固体,收率95％,>99％ee,M.P.103-105℃,[α]D 20＝-30.5(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝5:95,温度，室温。流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝8.03min；tR(minor)＝8.94min.1H NMR(400MHz,CDCl3)δ7.20-7.06(m,6H),3.26(dd,J＝14,4.8Hz,2H),2.93-2.91(m,2H), 2.74(dd,J＝14,9.6Hz 2H),2.45(s,6H),2.43(s,6H),2.09-2.05(m,2H),1.93-1.90(m,2H),1.83-1.76(m,2H).13C NMR(100MHz,CDCl3)δ214.2,137.5,134.8,132.7,130.3,130.1,126.8,49.2,33.2,31.6,20.7,20.4,18.8.IR(neat)ν3002,2929,2852,2349,1894,1698,1615,1503,1455,1370,1339,1297,1261,1244,1235,1178,1157,1143,1121,1094,1075,1051,1032,949,921,895,855,810,709,671,664,615cm-1.HRMS(ESI)m/z:calcd.for C24H34NO+:352.2635Found:352.2634([M+NH4]+).
Figure PCTCN2016109383-appb-000028
黄色固体,收率90％,M.P.88-90℃,[α]D 20＝-41.9(c 1.10,CHCl3),99％ee.产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝10:90,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝12.17min；tR(minor)＝13.82min.1H NMR(400MHz,CDCl3)δ7.04(d,J＝8.0Hz,2H),6.67-6.64(m,2H),3.74(s,6H),3.06(dd,J＝13.6,4.4Hz,2H),2.76-2.73(m,2H),2.57(dd,J＝13.6,9.6Hz,2H),2.22(s,6H),1.91-1.87(m,2H),1.76-1.73(m,2H),1.64-1.59(m,2H).13C NMR(100MHz,CDCl3)δ214.5,157.5,138.9,131.0,128.0,115.6,111.0,55.0,49.1,33.5,31.6,20.4,18.5.IR(neat)ν2998,2957,2925,2849,2834,2349,2323,2073,1694,1607,1580,1499,1442,1382,1361,1338,1307,1289,1273,1249,1215,1204,1160,1121,1096,1056,1030,996,973,930,895,870,853,833,816,802,757,725,715,691,671,665,652,613cm-1.HRMS-EI(m/z)M+calcd.for C24H30O3 +366.2189found 366.2197.
Figure PCTCN2016109383-appb-000029
无色油状液体,收率89％,[α]D 20＝-15.9(c 1.15,CHCl3),>99％ee.产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝10:90,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝20.94min；tR(minor)＝23.53min.1H NMR(400MHz,CDCl3)δ6.76-6.69(m,6H),3.75(s,6H),3.72(s,6H),3.11(dd,J＝13.2,5.6Hz,2H),2.90-2.88(m,2H),2.62(dd,J＝13.2,9.2Hz,2H),1.87-1.83(m,2H),2.73(m,2H),1.60-1.57(m,2H).13C NMR(100MHz,CDCl3)δ214.8,152.9,151.5,129.0,116.8,110.8,110.7,55.3,55.1,48.8,32.3,30.9,20.2.IR(neat)ν2931,2833,1702,1590,1497,1463,1426,1282,1219,1179,1158,1127,1045,1024,934,854,800,733,712cm-1.HRMS(ESI)m/z:calcd.for C24H34NO5 +:416.2429,Found:416.2431([M+NH4]+).
Figure PCTCN2016109383-appb-000030
无色油状液体,收率94％,>99％ee,[α]D 20＝-8.7(c 1.00,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel AS-H column；流动相,异丙醇/正己烷(v/v)＝10:90,温度，室温.；流动相流速,0.5mL/min；紫外-可见光检测，波长λ＝220nm；tR(major)＝15.51min；tR(minor)＝16.71min.1H NMR(400MHz,CDCl3)δ6.64(d,J＝8.4Hz,2H),6.45(d,J＝8.4Hz,2H),3.77(s,6H),3.74(s,6H),3.70(s,6H),2.91(dd,J＝13.6,6.4Hz,2H),2.73-2.70(m,2H),2.47(dd,J＝13.2,8Hz,2H),1.78-1.74(m,2H),1.66-1.63(m,2H),1.50-1.46(m,2H).13C NMR(100MHz,CDCl3)δ214.6,151.7,151.5,141.6,125.0,124.1,106.5,60.2,60.1,55.3,49.4,32.1,30.0,20.1.IR(neat)ν2932,2854,1703,1601,1493,1464,1416,1274,1257,1233,1199,1163,1094,1039,1015,950,904,854,795,752,682,665cm-1.
实施例6
在氩气氛围中，向一个50-mL施伦克管(Schlenk管)中加入化合物III-h(ee,>99％,247mg,0.5mmol)和无水二氯甲烷(10mL)，溶液在冰浴中冷却至0℃,缓慢加入催化剂(本实施例催化剂为TiCl4)(0.11mL,1.0mmol)，在0℃下搅拌30分钟后，缓慢升至室温，继续搅拌5小时，TLC监测至反应完毕后，加入5mL水猝灭反应。反应混合物用二氯甲烷(5mL×3)萃取三次，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压除溶剂后，残余物用硅胶柱层析分离纯化(石油醚/乙酸乙酯＝50:1)，得白色固体(1S,2S,2'S)-I-h，产物ee值用手性HPLC测定[Chiralcel OD-H column；流动相,异丙醇/正己烷＝0:100,温度，室温.；流动相流速,0.8mL/min；紫外-可见光检测波长λ＝230nm；tR(major)＝15.80min；tR(minor)＝23.00min.]。
实施例7(即对比例1)
Figure PCTCN2016109383-appb-000031
按照实施例6的方法进行实验，仅按照表2所示的条件对底物化合物III-h用量(本实施例中为0.2mmol)、催化剂种类和用量、溶剂种类和用量(本实施例中溶剂用量均为2.0mL)、反应温度进行改变，收率和ee值见表2。表2中的摩尔当量表示催化剂的摩尔量相对于化合物III-h的摩尔量的倍数。表2溶剂一栏，“-”表示无溶剂。表2中ee值一栏，“-”表示无法测得。
本实施例中，反应时间均为12h。
表2
Figure PCTCN2016109383-appb-000032
Figure PCTCN2016109383-appb-000033
从表2的数据可以看出，当使用多聚磷酸(PPA)或甲烷磺酸时，反应在加热条件下可以顺利进行，分别以72％和70％的收率得到关环产物，但遗憾的是产物没有光学活性(见表2中编号为1和2的两行中的ee值数据)，这很可能是因为化合物III-h在这些质子酸的环境中发生了消旋化。当使用磷钨酸H3[W12PO40]在甲苯中回流时，反应产率较低，仅有25％，同样得到了完全消旋的关环产物I-h。而采用手性磷酸(CPA)或手性磷酸和4A分子筛(CPA/4A MS)催化时，则未得到相应的关环产物。
本实施例中的催化剂均为常见的布伦斯特(Bronsted)类型的质子酸，可见，Bronsted类型的质子酸不宜作为化合物III-h立体选择性关环的催化剂。
本发明中，手性磷酸(CPA)的结构如下式所示：
Figure PCTCN2016109383-appb-000034
实施例8(对比例2)
按照实施例6的方法进行实验，仅按照表3所示的条件对底物化合物III-h用量(本实施例中为0.2mmol)、催化剂种类和用量、溶剂种类和用量(本实施例中溶剂用量均为2.0mL)、反应温度进行改变，收率和ee值见表3。表3中的摩尔当量表示催化剂的摩尔量相对于化合物III-h的摩尔量的倍数。表3中ee值一栏，“-”表示无法测得。
本实施例中，反应时间均为12h。
Figure PCTCN2016109383-appb-000035
表3
编号 催化剂(摩尔当量) 溶剂 反应温度(℃) 收率(％) ee(％)
1 Sc(OTf)3(2) CH2Cl2 40 0 --
2 In(OTf)3(2) CH2Cl2 40 0 --
3 Cu(OTf)2(2) CH2Cl2 40 0 --
4 AlCl3(2) CH2Cl2 40 0 --
5 SnCl4(2) CH2Cl2 40 0 --
6 FeCl3(2) CH2Cl2 40 0 --
7 Ti(iPrO)4(2) CH2Cl2 40 0 --
8 Cp2TiCl2(2) CH2Cl2 40 0 --
9 TiCl4/(±)BINOL(2) CH2Cl2 40 0 --
10 Ti(iPrO)4(0.1) 甲苯 80 微量 --
11 Sc(OTf)3(0.2) 甲苯 80 0 --
12 Ti(iPrO)4(1) 甲苯 80 0 --
13 SnCl4/(±)BINOL(1.2/0.2) CH2Cl2 25 0 --
14 Cp2TiCl2(1) 甲苯 80 0 --
15 AlCl3(1.5) DCE 80 0 --
16 Cu(OTf)2(0.5) DCE 80 0 --
实施例9
按照实施例6的方法进行实验，仅按照表4所示的条件对底物化合物III-h用量(本实施例中为0.2mmol)、催化剂种类和用量、溶剂种类和用量(本实施例中溶剂用量均为2.0mL)、反应温度进行改变，收率和ee值见表4。表4中的摩尔当量表示催化剂的摩尔量相对于化合物III-h的摩尔量的倍数。
本实施例中，反应时间为12h。
Figure PCTCN2016109383-appb-000036
表4
编号 催化剂(摩尔当量) 溶剂 反应温度(℃) 收率(％) ee(％)
1 TiCl4(2) CH2Cl2 40 51 99
从表3和表4中可以看出，表3中的一系列路易斯酸(Lewis酸)性金属盐对关环反应都没有任何促进作用，没有得到相应产物。但是，在表4中的强Lewis酸TiCl4的作用下，反应能够顺利进行，以51％的收率得到(1S,2S,2'S)-I-h，并且原料的光学纯度基本得到保持，(1S,2S,2'S)-I-h的ee值达到99％。
实施例10
Figure PCTCN2016109383-appb-000037
按照实施例6的方法进行实验，仅对底物化合物III-h用量(本实施例中为0.2mmol)、催化剂种类和用量(本实施例中催化剂为TiCl4，催化剂用量为0.4mmol)、溶剂种类和用量(本实施例中溶剂均为二氯甲烷，用量均为2.0mL)进行改变，及按照表5所示的条件对反应温度、反应时间进行改变，收率和ee值见表5。
表5
编号 反应温度(℃) 反应时间(h) 收率(％) ee(％)
1 40 2 52 99
2 25 2 55 99
3 10 8 72 >99
4 5 12 70 >99
5 0 20 62 >99
6 0～25 6 84 >99
从表5可以看出，对于二氯甲烷中TiCl4催化的III-h不对称脱水环化反应，温度在25℃～40℃时，反应2小时产物收率中等，产物ee值达99％。在10℃时反应8小时，产物收率提高到72％，产物的ee值略升高至>99％。继续降低温度到5℃，反应12小时产物收率基本不变，产物ee值也得到保持。进一步降低温度至0℃，反应体系较干净，但活性降低，延长反应时间至20小时，产率只有62％。当反应从初始的0℃缓慢恢复至室温时，副反应也得到有效抑制，以84％的产率和>99％ee得到关环产物I-h。
实施例11
Figure PCTCN2016109383-appb-000038
按照实施例6的方法进行实验，仅对底物化合物III-h用量(本实施例中为0.2mmol)、催化剂种类和用量(本实施例中催化剂为TiCl4，催化剂用量为0.4mmol)、溶剂用量(本实施例中溶剂用量均为2.0mL)进行改变，及按照表6所示的条件对溶剂种类、反应温度、反应时间进行改变，收率和ee值见表6。
表6
编号 溶剂 反应时间(h) 收率(％) ee(％)
1 CH2Cl2 6 84 >99
2 DCE 10 52 >99
3 CHCl3 8 65 >99
4 甲苯 12 56 >99
从表6可以看出，不同的溶剂对此关环反应的产物收率影响很大。在1,2-二氯乙烷(DCE)和氯仿(CHCl3)为溶剂时，反应产物收率分别降低到52％和65％，但对映选择性依然保持>99％ee。甲苯为溶剂的反应较缓慢，反应体系也较复杂，产物收率降到56％，但仍能获得>99％ee值的产物。因此，二氯甲烷为最优的反应溶剂。
实施例12
Figure PCTCN2016109383-appb-000039
按照实施例6的方法进行实验，仅对底物化合物III-h用量(本实施例中为0.2mmol)、催化剂种类和用量(本实施例中催化剂为TiCl4)、溶剂种类(本实施例中溶剂均为二氯甲烷)进行改变，及按照表7所示的条件对催化剂用量、底物浓度(即底物化合物III-h与溶剂的摩尔体积(mol/L)比值)、反应时间进行改变，收率和ee值见表7。表7中，摩尔当量表示催化剂的摩尔量相对于底物化合物III-h摩尔量的倍数。
表7
编号 TiCl4(摩尔当量) 底物浓度(mol/L) 反应时间(h) 收率(％) ee(％)
1 2 0.2 4 75 >99
2 2 0.1 6 84 >99
3 2 0.05 6 93 >99
4 2 0.02 6 91 >99
5 4 0.05 4 72 >99
6 1 0.05 6 81 >99
从表7可以看出，在0℃缓慢恢复至室温的温度条件下，底物的浓度及TiCl4用量的变化对反应活性有一定的影响，而对产物的光学纯度影响不大(>99％ee)。当底物浓度提高到0.2M时，副反应增多，反应收率降低到75％。而降低底物浓度至0.05M时，副反应基本得到抑制，产物I-h收率提高至93％。这说明较低的反应物浓度对分 子内的关环反应很有利。继续降低底物浓度至0.02M，反应速度变慢。TiCl4用量对产物收率也有影响。当TiCl4用量从2eq.增加到4eq.时，收率显著地降低。而TiCl4用量降至1eq.时，底物未转化完全，产率降至81％。
实施例13
Figure PCTCN2016109383-appb-000040
在氩气氛围中，将Schlenk管(50mL)无水无氧处理，加入光学纯的化合物III-h(>99％ee)(247mg,0.5mmol)和无水二氯甲烷(10mL)，冷却至0℃，缓慢滴加TiCl4(0.11mL,1.0mmol)，在0℃下反应30分钟后，缓慢恢复至室温，继续搅拌5小时，加入5mL水猝灭反应，用二氯甲烷(5mL×3)萃取三次，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压除溶剂后，残余物用硅胶柱层析分离纯化(石油醚/乙酸乙酯＝50:1)，得白色固体I-h(220mg,93％)，产物ee值用HPLC测定。
实施例14
Figure PCTCN2016109383-appb-000041
以实施例5中得到的化合物III-a(>99％ee)为底物，参照实施例13中的实验方法操作，III-a在2摩尔当量TiCl4(相对于化合物III-a的摩尔当量)作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-a。
产物化合物I-a的性状及结构鉴定数据：无色液体,收率83％,96％ee,[α]D 20＝131.1(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel OD-H column；eluent,2-propanol/hexane 5:95；temp,r.t.；flow rate,0.5mL/min；uv-vis detection,λ＝210nm；tR(minor)＝8.52min；tR(major)＝9.97min.1H NMR(400MHz,CDCl3)δ7.31-7.06(m,6H),δ6.76(d,J＝7.6Hz,2H),δ3.10(dd,J＝15.6,7.2Hz,2H),δ2.75(dd,J＝15.2,5.6Hz,2H),δ2.62-2.55(m 2H),δ1.61-1.49(m,4H),δ1.43-1.37(m,2H)ppm.13C NMR(100MHz,CDCl3)δ149.0,142.8,126.5,126.3,124.9,123.1,61.0,43.6,36.1,27.4,19.6ppm.IR(neat)ν3065,3017,2922,2847,2661,2310,1944,1905,1600,1474,1456,1260,1025,934,880,800,747,727,706,661,635cm-1.HRMS-EI(m/z)calcd.for C20H20 +260.1560,found 260.1568[M+].
实施例15
Figure PCTCN2016109383-appb-000042
以实施例5中得到的化合物III-b(>99％ee)为底物，参照实施例13中的实验方法操作，III-b在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-b。
产物化合物I-b的性状及结构鉴定数据：白色固体,收率85％,>99％ee,M.P.151-153℃,[α]D 20＝225.0(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel PA-2column；eluent,acetonitrile/water 80:20；temp,r.t.；flow rate,0.7mL/min；uv-vis detection,λ＝230nm；tR(major)＝9.54min；tR(minor)＝10.21min.1H NMR(400MHz,CDCl3)δ7.01-6.98(m,4H),δ6.59-6.57(m,2H),δ3.01(dd,J＝15.6,7.2Hz,2H),δ2.65(dd,J＝15.6,5.6Hz,2H),δ2.57-2.54(m2H),δ2.31(s,6H),δ1.60-1.50(m,4H),δ1.43-1.36(m,2H).13C NMR(100MHz,CDCl3)δ148.9,141.4,134.1,127.4,126.5,120.4,61.3,43.3,34.7,27.6,19.7,19.1.IR(neat)ν3016,2921,2852,2834,1918,1856,1795,1595,1459,1446,1377,1319,1261,1210,1196,1158,1141,1094,1076,1032,953,930,896,871,790,779,756,727,711,668,645,619cm-1.HRMS-EI(m/z)calcd.for C22H24 +288.1873,found 288.1874[M+].
实施例16
Figure PCTCN2016109383-appb-000043
以实施例5中得到的化合物III-c(>99％ee)为底物，参照实施例13中的实验方法操作，III-c在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-c。
产物的性状及结构鉴定数据：无色液体(Cololess liquid),收率75％,96％ee,[α]D 20＝168.5(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel PA-2column；eluent,acetonitrile/water 80:20；temp,r.t.；flow rate,0.7mL/min；uv-vis detection,λ＝230nm；tR(major)＝10.21min；tR(minor)＝12.39min.1H NMR(400MHz,CDCl3)δ7.11(s,2H),6.89(d,J＝8.0Hz,2H),6.65(d,J＝8.0Hz,2H),3.04(dd,J＝15.2,6.8Hz,2H),2.69(dd,J＝15.2,6Hz,2H),2.55-2.52(m,2H),2.32(s,6H),1.57-1.48(m,4H),1.39-1.36(m,2H).13C NMR(100MHz,CDCl3)δ146.3,142.8,136.0,127.1,125.7,122.8,60.3,43.9,36.1,27.5,21.3,19.7.IR(neat)ν3004,2920,2847,1614,1485,1447,1377,1357,1299,1260,1217,1191,1136,1082,1037,956,930,879,810,799,756,708,680,668,626cm-1.
实施例17
Figure PCTCN2016109383-appb-000044
以实施例5中得到的化合物III-d(>99％ee)为底物，参照实施例13中的实验方法操作，III-d在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-d。
产物的性状及结构鉴定数据：白色固体，收率70％,93％ee,M.P.102-104℃,[α]D 20＝31.3(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel PC-3column；eluent,acetonitrile/water 60:40；temp,r.t.；flow rate,0.5mL/min；uv-vis detection,λ＝230nm；tR(minor)＝27.33min；tR(major)＝29.00min.1H NMR(400MHz,CDCl3)δ7.19(d,J＝7.6Hz,2H),6.98(d,J＝7.6Hz,2H),6.57(s,2H),3.05(dd,J＝15.6,7.2Hz,2H),2.69(dd,J＝19.2,9.2Hz,2H),2.57-2.54(m,2H),2.23(s,6H),1.59-1.47(m,4H),1.41-1.35(m,2H).13C NMR(100MHz,CDCl3)δ149.2,139.7,135.8,127.3,124.6,123.8,60.8,43.9,35.8,27.5,21.4,19.7.IR(neat)ν3003,2919,2848,2350,1892,1756,1612,1488,1447,1377,1312,1260,1207,1137,1080,1022,948,930,879,847,810,796,727,706,632cm-1.HRMS-EI(m/z)M+calcd.for C22H24 +288.1873found 288.1873[M+].
实施例18
Figure PCTCN2016109383-appb-000045
以实施例5中得到的化合物III-e(>99％ee)为底物，参照实施例13中的实验方法操作，III-e在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-e。
产物的性状及结构鉴定数据：白色固体,收率65％,97％ee,M.P.94-96℃,[α]D 20＝138.1(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel OD-H column；eluent,2-propanol/hexane 2:98；temp,r.t.；flow rate,0.5mL/min；uv-vis detection,λ＝220nm；tR(minor)＝10.52min；tR(major)＝11.62min.1H NMR(400MHz,CDCl3)δ6.85(s,2H),6.67-6.60(m,4H),3.76(s,6H),3.04(dd,J＝15.6,7.2Hz,2H),2.69(dd,J＝15.6,6.0Hz,2H),2.55-2.51(m,2H),1.58-1.46(m,4H),1.40-1.34(m,2H).13C NMR(100MHz,CDCl3)δ158.7,144.0,141.5,123.5,111.8,110.4,59.4,55.2,44.1,36.2.27.4,19.6.IR(neat)ν2919,2845,1605,1584,1484,1463,1308,1246,1219,1193,1142,1116,1033,913,839,799,750.HRMS-EI(m/z)M+calcd.for C22H24O2 +320.1771found 320.1780[M+].
实施例19
Figure PCTCN2016109383-appb-000046
以实施例5中得到的化合物III-f(>99％ee)为底物，参照实施例13中的实验方法操作，III-f在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-f。
产物的性状及结构鉴定数据：白色固体,收率60％,79.9％ee,M.P.146℃,[α]D 20＝67.3(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel OD-H column；eluent,2-propanol/hexane 2:98；temp,r.t.；flow rate,0.5mL/min；uv-vis detection,λ＝220nm；tR(minor)＝10.05min；tR(major)＝16.65min.1H NMR(400MHz,CDCl3)δ7.24(d,J＝8.0Hz,2H),6.76(dd,J＝8.0,2.4Hz,2H),6.39(d,J＝2.8Hz,2H),3.73(s,6H),3.07(dd,J＝14.8,6.8Hz,2H),2.72(dd,J＝15.2,6Hz,2H),2.62-2.59(m,2H),1.64-1.54(m,4H),1.46-1.43(m,2H).13C NMR(100MHz,CDCl3)δ158.7,150.3,134.6,125.4,111.9,109.0,61.4,55.2,44.1,35.3,27.5,19.6.IR(neat)ν2995,2927,2852,1605,1584,1482,1462,1327,1283,1273,1240,1228,1215,1199,1151,1141,1121,1086,1061,1032,930,866,845,823,808,768,755,704,672cm-1.HRMS(ESI)m/z:calcd.for C22H25O2 +:321.1849,Found:321.1851([M+H]+).
实施例20
Figure PCTCN2016109383-appb-000047
以实施例5中得到的化合物III-g(>99％ee)为底物，参照实施例13中的实验方法操作，III-g在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-g。
产物的性状及结构鉴定数据：无色固体,收率57％,M.P.248-250℃,[α]D 20＝-151.0(c 1.10,CHCl3),99％ee.1H NMR(400MHz,CDCl3)δ7.82-7.79(m,4H),7.61(d,J＝8.0Hz,2H),7.41-7.33(m,3H),7.31(s,1H),7.19(s,2H),3.33(dd,J＝16,7.2Hz,2H),2.97(dd,J＝15.6,6.4Hz,2H),2.78-2.75(m,2H),1.68-1.56(m,4H),1.46-1.42(m,2H).13C NMR(100MHz,CDCl3)δ148.5,142.1,133.2,133.0,127.8,127.3,125.1,124.9,123.1,121.5,60.4,43.8,35.6,27.3,19.6.HPLC[(column,Chiralcel PC-2；eluent,acetonitrile/water 60:40；temp,r.t.；flow rate,0.7mL/min；detection,230nm light)；tR(R)＝125.33min；tR(S)＝131.56min].IR(neat)ν3050,2952,2925,2902,2847,2349,2323,1951,1701,1634,1604,1498,1447,1432,1336,1289,1261,1208,1143,1096,1037,1018,951,930,886,868,801,750,671,665,623,614.HRMS-EI(m/z)M+calcd.for C28H28 +360.1873found 360.1880[M+].
手性稠环螺二氢茚骨架化合物I-g的X射线晶体衍射分子结构图见图1所示。
实施例21
Figure PCTCN2016109383-appb-000048
以实施例5中得到的化合物III-h(>99％ee)为底物，按照实施例13中的实验方法操作，III-h在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-h。
产物的性状及结构鉴定数据：白色固体,收率93％,M.P.192-193℃,[α]D 20＝189.70(c 1.0,CHCl3)>99.6％ee.产物的ee值由手性高效液相色谱测定,Chiralcel OD-H column；eluent,2-propanol/hexane 0:100,temp,r.t.；flow rate,0.8mL/min；uv-vis detection,λ＝230nm；tR(major)＝15.80min；tR(minor)＝23.00min.1H NMR(400MHz,CDCl3)δ7.24(d,J＝8.4Hz,2H),6.50(d,J＝8.4Hz,2H),3.44(s,6H),3.09(dd,J＝15.6,7.6Hz,2H),2.92-2.88(m,2H),2.73(dd,J＝15.6,6.4Hz,2H),1.56-1.51(m,4H),1.46-1.44(m,2H)；13C NMR(100MHz,CDCl3)δ156.25,145.89,136.70,130.30,111.47,111.09,64.30,55.49,41.92,39.46,26.18,17.88.
实施例22
Figure PCTCN2016109383-appb-000049
以实施例5中得到的化合物III-i(>99％ee)为底物，参照实施例13中的实验方法操作，III-i在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-i。
产物的性状及结构鉴定数据：无色液体,收率45％,96％ee,[α]D 20＝81.3(c 1.10,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel PC-3column；eluent,acetonitrile/water 70:30；temp,r.t.；flow rate,0.7mL/min；uv-visdetection,λ＝230nm；tR(major)＝6.34min；tR(minor)＝6.97min.1H NMR(400MHz,CDCl3)δ6.85(s,2H),6.31(s,2H),3.88(s,6H),3.72(s,6H),3.03(dd,J＝15.2,7.2Hz,2H),2.67(dd,J＝15.2,6Hz,2H),2.54-2.51(m,2H),1.59-1.49(m,4H),1.41-1.37(m,2H).13C NMR(100MHz,CDCl3)δ147.9,147.8,140.8,133.8,108.0,106.3,60.9,55.8,55.8,44.3,36.0,27.5,19.5.IR(neat)ν3001,2933,2857,2834,1702,1607,1590,1513,1463,1451,1417,1337,1258,1235,1192,1155,1140,1026,944,854,805,749,665,638cm-1.HRMS-EI(m/z)M+calcd.for C24H28O4 +380.1982found 380.1985[M+].
实施例23
Figure PCTCN2016109383-appb-000050
以实施例5中得到的化合物III-j(>99％ee)为底物，参照实施例13中的实验方法操作，III-j在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-j。
产物的性状及结构鉴定数据：无色固体(Colorless solid),收率80％,99％ee,M.P.128-130℃,[α]D 20＝90.0(c 1.00,CHCl3).产物的ee值由手性高效液相色谱测定,Chiralcel PC-1column；eluent,acetonitrile/water 80:20；temp,r.t.；flow rate,0.7mL/min；uv-vis detection,λ＝230nm；tR(major)＝16.66min；tR(minor)＝17.67min.1H NMR(400MHz,CDCl3)δ6.92(d,J＝7.2Hz,2H),6.80(d,J＝7.2Hz,2H),2.95-2.81(m,4H),2.66-2.61(m,2H),2.25(s,6H),1.86-1.79(m,2H),1.70(s,6H),1.66-1.53(m,4H).13C NMR(100MHz,CDCl3)δ146.5,142.2,131.6,131.2,128.9,127.4,63.8,43.0,34.9,20.0,18.9,17.9,14.6.IR(neat)ν2921,2847,1488,1448,1217,1039,879,807,753,667cm-1.HRMS-EI(m/z)M+calcd.for C24H28 +316.2186,found 316.2187[M+].
实施例24
Figure PCTCN2016109383-appb-000051
以实施例5中得到的化合物III-k(99％ee)为底物，参照实施例13中的实验方法操作，III-k在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-k。
产物的性状及结构鉴定数据：白色固体,收率78％,M.P.73-75℃,[α]D 20＝109.7(c 1.05,CHCl3),94％ee.产物的ee值由手性高效液相色谱测定,Chiralcel PC-1column；eluent,acetonitrile/water 80:20；temp,r.t.；flow rate,0.7mL/min；uv-vis detection,λ＝230nm；tR(major)＝13.17min；tR(minor)＝15.42min.1H NMR(400MHz,CDCl3)δ6.94(d,J＝8.4Hz,2H),6.57(d,J＝8.4Hz),3.41(s,6H),3.04(dd,J＝15.2,7.6Hz,2H),2.97-2.94(m,2H),2.64(dd,J＝14.8,6.0Hz,2H),2.25(s,6H),1.60-1.55(m,2H),1.49-1.45(m,2H).13C NMR(100MHz,CDCl3)δ155.4,145.1,135.4,127.9,126.1,110.2,62.3,55.9,42.4,36.8,26.9,18.5,18.4.IR(neat)ν2919,2848,1977,1602,1490,1463,1437,1378,1313,1255,1220,1183,1161,1087,1034,964,937,870,844,795,754,721,666,611.HRMS-EI(m/z)calcd.for C28H28O2 +348.2084；found 348.2089 [M+].
实施例25
Figure PCTCN2016109383-appb-000052
以实施例5中得到的化合物III-l(>99％ee)为底物，参照实施例13中的实验方法操作，III-l在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-l。
产物的性状及结构鉴定数据：无色油状液体,收率85％,[α]D 20＝95.2(c 1.10,CHCl3),90％ee.产物的ee值由手性高效液相色谱测定,Chiralcel PC-2column；eluent,acetonitrile/water 60:40；temp,r.t.；flow rate,0.7mL/min；uv-vis detection,λ＝230nm；tR(minor)＝33.33min；tR(major)＝35.19min.1H NMR(400MHz,CDCl3)δ6.65(d,J＝8.8Hz,2H),6.59(d,J＝8.8Hz,2H),3.82(s,6H),3.40(s,6H),3.09(dd,J＝15.2,7.6Hz,2H),2.94-2.91(m,2H),2.67(dd,J＝15.6,6.4Hz,2H),1.59-1.52(m,4H),1.48-1.45(m,2H).13C NMR(100MHz,CDCl3)δ151.6,150.4,137.6,133.9,110.7,108.8,62.7,56.3,55.7,42.8,34.5,26.6,18.3.IR(neat)ν2999,2919,2850,2832,2050,1810,1596,1488,1460,1448,1436,1329,1312,1297,1254,1239,1213,1186,1164,1117,1094,1073,1049,1003,987,975,953,929,908,875,795,751,714,652,637cm-1.HRMS(ESI)m/z:calcd.for C24H32NO4 +:398.2326,Found:398.2324([M+NH4]+).
实施例26
Figure PCTCN2016109383-appb-000053
以实施例5中得到的化合物III-m(>99％ee)为底物，参照实施例13中的实验方法操作，III-m在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-m。
产物的性状及结构鉴定数据：无色油状液体,收率56％,[α]D 20＝51.8(c 1.10,CHCl3),59.9％ee.产物的ee值由手性高效液相色谱测定,Chiralcel PA-2column；eluent,acetonitrile/water 60:40；temp,r.t.；flow rate,0.7mL/min；uv-vis detection,λ＝230nm；tR(major)＝8.89min；tR(minor)＝14.31min.1H NMR(400MHz,CDCl3)δ6.11(s,2H),3.94(s,6H),3.87(s,6H),3.71(s,6H),3.04(dd,J＝15.6,7.2Hz,2H),2.68(dd,J＝15.6,6.0Hz,2H),2.51-2.49(m,2H),1.64-1.50(m,4H),1.42-1.37(m,2H).13C NMR(100MHz,CDCl3)δ152.8,150.0,144.4,140.3,126.3,102.4,61.8,61.0,60.5,56.1,43.8,32.9,27.5,19.5.IR(neat)ν2927,2849,1586,1463,1411,1324,1299,1229,1196,1115,1096,1034,947,910,831,793,750cm-1.
实施例26-1
Figure PCTCN2016109383-appb-000054
参照实施例5的方法制得化合物III-s(>99％ee)，以化合物III-s为底物，参照实施例13中的实验方法操作，在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-s’。
产物的性状及结构鉴定数据：白色固体,收率82％,[α]D 20＝141.7(c 1.10,CHCl3),>99％ee.产物的ee值由手性高效液相色谱测定,Chiralcel IA-3column；eluent,2-propanol/hexane 10:90；temp,r.t.；flow rate,0.5mL/min；uv-vis detection,λ＝214nm；tR(major)＝7.38min；tR(minor)＝8.54min.1H NMR(400MHz,CDCl3)δ7.32-7.15(m,7H),6.60(d,J＝8.8Hz,1H),6.49(d,J＝8.8Hz,1H),4.06-3.99(m,1H),3.64(s,3H),3.36-3.29(m,4H),3.12-2.99(m,2H),2.93-2.87(m,1H),2.55(d,J＝16.0Hz,1H),2.42-2.36(m,1H),1.95-1.91(m,1H),1.86-1.83(m,1H),1.77-1.69(m,1H),1.41-1.31(m,1H).13C NMR(100MHz,CDCl3)δ157.2,155.9,148.1,146.9,144.2,138.8,133.2,130.7,130.4,128.3,126.9,126.0,112.3,111.3,111.21,111.17,64.0,55.7,55.5,45.4,42.1,40.3,38.8,38.1,36.4,33.4.IR(neat)ν2923,1574,1469,1259,1191,1082,1021,971,849,797,759,698,671,659,642cm-1.HRMS-EI(m/z)calcd.for C28H26Br2O2 +:552.0294,found:552.0298[M+].
实施例26-2
Figure PCTCN2016109383-appb-000055
参照实施例5的方法制得化合物III-q(>99％ee)，以化合物III-q为底物，参照实施例13中的实验方法操作，在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-q’。
产物的性状及结构鉴定数据：白色固体,收率78％,[α]D 20＝210.6(c 1.10,CHCl3),>99％ee.产物的ee值由手性高效液相色谱测定,Chiralcel IA-3column；eluent,2-propanol/hexane 10:90；temp,r.t.；flow rate,0.5mL/min；uv-vis detection,λ＝214nm；tR(major)＝7.66min；tR(minor)＝8.23min.1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.8Hz,1H),7.20(d,J＝8.4Hz,1H),6.55(d,J＝8.8Hz,1H),6.44(d,J＝8.4Hz,1H),3.81-3.75(m,1H),3.60(s,3H),3.29-3.24(m,4H),3.01(dd,J＝16.0,8.4Hz,1H),2.85(dd,J＝16.0,10.8Hz,1H),2.51(d,J＝15.6Hz,1H),2.27-2.21(m,1H),1.77-1.59(m,3H),1.18-1.11(m,1H),0.87-0.78(m,4H).13C NMR(100MHz,CDCl3)δ157.1,155.9, 148.1,144.5,139.0,133.6,130.6,130.3,112.2,111.3,111.25,111.20,64.3,55.7,55.5,44.8,42.1,40.2,39.5,38.4,34.4,24.7,22.5.IR(neat)ν2946,1573,1470,1274,1257,1188,1099,1077,1047,987,960,805,796,764,670,614cm-1.HRMS-EI(m/z)calcd.for C23H24Br2O2 +:490.0138,found:490.0141[M+].
实施例26-3
Figure PCTCN2016109383-appb-000056
参照实施例5的方法制得化合物III-r(>99％ee)，以化合物III-r为底物，参照实施例13中的实验方法操作，在2摩尔当量TiCl4作用下发生分子内不对称环化反应，得到手性稠环螺二氢茚骨架化合物I-r’。
产物的性状及结构鉴定数据：白色固体,收率75％,[α]D 20＝13.2(c 1.10,CHCl3),97％ee.产物的ee值由手性高效液相色谱测定,Chiralcel IA-3column；eluent,2-propanol/hexane 10:90；temp,r.t.；flow rate,0.5mL/min；uv-vis detection,λ＝214nm；tR(major)＝7.38min；tR(minor)＝8.54min.1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.4Hz,1H),7.21(d,J＝8.4Hz,1H),6.55(d,J＝8.8Hz,1H),6.45(d,J＝8.4Hz,1H),3.77-3.60(m,1H),3.60(s,3H),3.37-3.32(m,4H),3.08(dd,J＝16.0,8.4Hz,1H),2.82(dd,J＝16.0,9.6Hz,1H),2.53(d,J＝15.6Hz,1H),2.26-2.20(m,1H),1.72-1.61(m,2H),1.37-1.23(m,2H),0.95-0.86(m,1H),0.83(s,9H).13C NMR(100MHz,CDCl3)δ157.1,155.9,147.9,144.5,138.8,133.9,130.5,130.3,112.0,111.2,111.17,111.12,64.6,55.6,55.5,45.5,42.6,40.3,40.2,39.0,32.4,32.3,27.7,27.4.IR(neat)ν2922,1573,1470,1274,1258,1098,1077,961,796,766,670,615cm-1.HRMS-EI(m/z)calcd.for C26H30Br2O2 +:532.0607,found:532.0621[M+].
实施例27
以化合物II为原料，可以采用不对称氢化和关环一锅法，不需分离中间体化合物III,直接向氢化反应混合物中加入适量TiCl4,合成化合物I。本实施例中，以化合物II-h一锅法不对称氢化-关环反应合成化合物I-h为例，说明从化合物II出发一锅法合成化合物I的实验操作典型方法。
Figure PCTCN2016109383-appb-000057
在氩气氛围中，将氢化瓶(150-mL)无水无氧处理，加入催化剂(S)-tBuPHOX/Ir(I)(96.0mg,0.061mmol)、底物II-h(6.15g,12.55mmol)和无水二氯甲烷(75mL)。在手套箱中将氢化瓶转移至高压釜中。置换氢气三次后，充入氢气至50atm。室温下反应12小时。小心放空氢气后，在氩气保护下，将浅黄色反应液用注射器迅速转移 至另一无水无氧处理过的三口瓶(500-mL)中，加入无水二氯甲烷175mL，冰浴冷却，缓慢滴加TiCl4(2.75mL,25.1mmol)，在0℃下反应30分钟后，缓慢恢复至室温，继续搅拌6小时，加入100mL水猝灭反应，二氯甲烷(50mL×3)萃取三次，合并有机相，无水硫酸钠干燥，过滤除去干燥剂，滤液减压除溶剂后，残余物用硅胶柱层析分离纯化(石油醚/乙酸乙酯＝50:1)，得白色固体I-h(5.02g,收率84％,>99％ee)。
实施例28(7,7’-二溴取代的手性稠环螺二氢茚骨架螺环二酚I-n的制备)
Figure PCTCN2016109383-appb-000058
如上式所示，第一步，采用实施例27所述的方法，以化合物II-h为起始原料，一锅法不对称氢化-关环反应，以两步84％总收率和>99％ee合成得到化合物I-h。
第二步，用BBr3脱除I-h甲基的操作方法：将Schlenk瓶(100mL)无水无氧处理后，在氩气气氛下，加入(1S,2S,2'S)-I-h(5.02g,10.55mmol)，二氯甲烷(35.0mL)，冷却至-78℃。逐滴加入BBr3(4M in CH2Cl2)(6.59mL,26.38mmol)。滴加完毕缓慢升至室温。再搅拌12小时后，加入水(100mL)猝灭。用二氯甲烷(20mL×3)萃取，合并有机相，无水Na2SO4干燥，过滤除去干燥剂，滤液减压除去溶剂，粗产物经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝5:1)，得白色固体I-n(4.02g,85％)。
产物性状及结构鉴定数据：白色固体,收率85％,M.p.132-133℃，[α]D 20＝+301.63(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.25(d,J＝8.0Hz,2H),6.50(d,J＝8.8Hz,2H),4.58(s,2H),3.07-3.00(m,2H),2.90-2.81(m,4H),1.72-1.66(m,2H),1.60-1.55(m,4H)；13C NMR(75MHz,CDCl3)δ152.36,145.39,132.19,132.16,116.85.111.34,62.75,42.60,38.43,23.00,16.09；IR(neat)ν3470,3392,2921,2913,2851,1573,1461,1422,1291,1211,1184,1084,1065,1045,806,718,677,660,627cm-1；EI-MS(70eV),m/z＝450([M]+),369,290,263,184,145,124,115,107,94；HRMS-EI(m/z)calcd.for C20H18O2Br2 +,447.9668,found,447.9670[M]+.
实施例29(手性稠环螺二氢茚骨架螺环二酚I-o的制备)
Figure PCTCN2016109383-appb-000059
从实施例28所合成的化合物I-n出发，通过Pd/C催化氢解脱溴反应，以95％的收率得到手性稠环螺二氢茚二酚I-o。具体操作方法如下：在一个氢化瓶(100mL)中加入(1S,2S,2'S)-I-n(4.02g,8.97mmol)、甲醇(20.0mL)、醋酸(6mL)及10％Pd/C(0.40g)，转移至反应釜中，置换三次氢气后，充入氢气至20atm。室温下反应12小时，小心放空氢气，过滤除去Pd/C，滤液减压除去乙醇，加入饱和NaHCO3(100mL)，乙酸乙酯(20mL×3)萃取三次，合并有机相，无水硫酸钠干燥，过滤除去干 燥剂，滤液减压除去溶剂后得到(1S,2S,2'S)-I-o(2.54g)。
产物性状及结构鉴定数据：无色液体,收率95％,>99％ee.[α]D 20＝157.9(c 1.0,CHCl3).产物I-o的ee值由手性高效液相色谱测定,Chiralcel AD-H column.Conditions:hexane/isopropanol＝80:20；flow rate＝1.0mL/min；UV detection at 230nm；tR＝4.84min(minor),9.42min(major).1H NMR(400MHz,CDCl3)δ7.14(t,J＝7.6Hz,2H),6.89(d,J＝7.6Hz,2H),6.61(d,J＝8.0Hz,2H),4.60(s,2H),3.03(dd,J＝18.4,10.8Hz,2H),2.94-2.89(m,4H),1.67-1.55(m,6H)；13C NMR(100MHz,CDCl3)δ153.50,145.67,130.72,129.40,118.02,114.76,60.20,43.65,36.92,24.05,16.90；IR(KBr pellet)ν3588,3568,2924,2846,1609,1586,1485,1460,1340,1261,1225,1190,1137,1107,986,933,779,734cm-1；EI-MS(70eV),m/z＝292([M]+),290,207,184,169,78,51；HRMS-EI(m/z)[M]+calcd for C20H20O2,292.1463,found,292.1465.Anal.calcd.for C20H20O2:C,82.16；H,6.89％；Found:C,82.46；H,7.04％.
实施例30
参照实施例28和29所述的实验方法操作，用(R)-tBuPHOX/Ir(I)作为不对称氢化催化剂，得到手性稠环螺二氢茚骨架二酚I-p。
Figure PCTCN2016109383-appb-000060
(1R,2R,2'R)-I-p:白色固体，收率66％；>99％ee,M.p.53-54℃.[α]D 20＝-201.7(c 0.70,CHCl3)；1H NMR(400MHz,CDCl3)δ7.16(t,J＝7.6Hz,2H),6.85(d,J＝7.2Hz,2H),6.64(d,J＝7.6Hz,2H),4.41(s,6H),3.44(dd,J＝16.8,9.2Hz,2H),3.00-2.98(m,2H),2.80(dd,J＝17.2,4.8Hz,2H),2.05-2.01(m,2H),1.60-1.56(m,2H)；13C NMR(100MHz,CDCl3)δ152.95,145.09,131.90,129.52,117.52,114.14,70.50,50.85,38.76,33.15,；IR(neat)ν3514,3031,2952,2936,2915,1849,2837,1610,1585,1479,1462,1271,1161,989,780,772,742,721cm-1；EI-MS(70eV),m/z＝278([M]+),250,231,202,189,171,165,145,115,91,77；HRMS-EI(m/z)calcd for C19H18O2,278.1307,found,278.1310[M]+.Anal.calcd.for C19H18O2:C,81.99；H,6.52％；Found:C,81.82；H,6.62％.
实施例31
参照实施例28和29所述的实验方法操作，用(R)-tBuPHOX/Ir(I)作为不对称氢化催化剂，得到手性稠环螺二氢茚骨架二酚I-q。
Figure PCTCN2016109383-appb-000061
(1R,2R,2'R)-I-q:白色固体，收率59％；>99％ee.M.p.132-133℃,[α]D 20＝ -217.6(c 0.74,CHCl3)；1H NMR(400MHz,CDCl3)δ7.18(t,J＝7.6Hz,1H),7.05(t,J＝7.6Hz,1H),6.95(d,J＝7.6Hz,1H),6.84(d,J＝7.2Hz,1H),6.59(d,J＝8.0Hz,1H),6.53(d,J＝8.0Hz,1H),4.89(s,1H),4.46(s,1H),3.74-3.71(m,1H),3.31(dd,J＝15.6,6.8Hz,1H),3.06(dd,J＝15.6,12.0Hz,1H),2.85(dd,J＝15.6,8.4Hz,1H),2.57(d,J＝8.0Hz,1H),2.39-2.33(m,1H),1.82-1.77(m,2H),1.65-1.57(m,1H),1.25-1.17(m,1H),0.90-0.81(m,4H)；13C NMR(100MHz,CDCl3)δ154.38,152.94,146.58,144.73,132.74,129.84,128.86,128.31,118.99,117.20,115.44,114.58,45.80,42.85,39.34,38.26,35.99,33.72,24.53,22.60；IR(neat)ν3452,3387,2924,2898,1583,1472,1456,1286,1248,1233,1199,981,776,734cm-1；EI-MS(70eV),m/z＝306([M]+),249,231,199,189,157,145,115,107,91,71,57,41；HRMS-EI(m/z)calcd for C21H22O2,302.1620,found,306.1617[M]+.
实施例32
参照实施例28和29所述的实验方法操作，用(R)-tBuPHOX/Ir(I)作为不对称氢化催化剂，得到手性稠环螺二氢茚骨架二酚I-r。
Figure PCTCN2016109383-appb-000062
(1R,2R,2'R)-I-r:白色固体，收率50％；>99％ee,M.p.112-113℃,[α]D 20＝-167.4(c 0.835,CHCl3)；1H NMR(400MHz,CDCl3)δ7.01(t,J＝7.6Hz,1H),6.95(t,J＝7.6Hz,1H),6.82(d,J＝7.6Hz,1H),6.76(d,J＝7.2Hz,1H),6.45(d,J＝7.6Hz,1H),6.31(d,J＝8.0Hz,1H),5.55(s,1H),4.57(s,1H),3.90-3.88(m,1H),3.28(dd,J＝16.0,6.4Hz,1H),3.01(dd,J＝15.2,12.0Hz,1H),2.78(dd,J＝15.6,8.0Hz,1H),2.46(d,J＝8.0Hz,1H),2.27-2.23(m,1H),1.77-1.73(m,1H),1.62-1.58(m,1H),1.39-1.35(m,1H),1.29-1.24(m,1H),0.88-0.80(m,10H)；13C NMR(100MHz,CDCl3)δ154.80,152.60,146.44,144.76,133.35,129.87,128.92,118.80,117.49,115.64,114.62,60.94,46.92,42.52,40.05,39.74,36.21,32.19,31.89,27.62,26.74；IR(neat)ν3503,3461,2930,2854,1609,1584,1458,1279,1225,1197,1155,990,776,733,721cm-1；EI-MS(70eV),m/z＝348([M]+),291,241,231,202,185,165,145,107,57,41；HRMS-EI(m/z)calcd for C24H28O2,348.2089,found,348.2093[M]+.
实施例33
参照实施例28和29所述的实验方法操作，用(R)-tBuPHOX/Ir(I)作为不对称氢化催化剂，得到手性稠环螺二氢茚骨架二酚I-s。
Figure PCTCN2016109383-appb-000063
(1R,2R,2'R)-I-s:白色固体，收率50％；>99％ee,M.p.93-94℃,[α]D 20＝-222.5(c 0.545,CHCl3)；1H NMR(300MHz,CDCl3)δ7.13-7.28(m,6H),7.05(t,J＝10.0Hz,1H),6.93(d,J＝9.6Hz,1H),6.86(d,J＝10.0Hz,1H),6.54(t,J＝9.2Hz,2H),5.04(s,1H),4.49(s,1H),3.98(m,1H),3.35(dd,J＝21.2,8.4Hz,1H),3.21(dd,J＝20.4,16.8Hz,1H),3.00-2.86(m,2H),2.57-2.44(m,2H),2.02-1.93(m,1H),1.84-1.72(m,2H),1.34(dd,J＝33.2,16.4Hz,1H)；13C NMR(75MHz,CDCl3)δ154.57,152.89,146.68,146.47,144.48,132.79,129.97,128.54,128.34,128.32,126.90,125.99,119.06,117.30,115.61,114.72,60.55,46.39,42.57,39.34,38.00,36.27,35.86,32.82；IR(neat)ν3327,3026,2921,2845,1604,1457,1435,1345,1328,1267,988,779,764,753,737,699cm-1；EI-MS(70eV),m/z＝368([M]+),261,250,231,202,127,107,85,71,57,43；HRMS-EI(m/z)calcd for C26H24O2,368.1776,found,368.1771[M]+.
实施例34(手性稠环螺二氢茚骨架亚磷酰胺配体I-t的合成)
采用与实施例28相同的方法，从II-h出发，采用(R)-tBuPHOX/Ir(I)催化剂，通过一锅法不对称氢化/环化，所得产物按照实施例29的方法脱溴后，即可得到化合物I-o的对映异构体ent-I-o。如下式所示，将二酚ent-I-o与二甲基胺基二氯磷在碱性条件下反应，可合成得到相应的单齿亚磷酰胺配体I-t。
Figure PCTCN2016109383-appb-000064
操作方法：将Schlenk管(15mL)无水无氧处理后，在氩气气氛下，加入螺环二酚ent-I-o(0.30mmol)、THF(3.5mL)和Et3N(0.15mL)，冷却至0℃。缓慢加入二甲基胺基二氯磷(37.9μL,0.33mmol)，滴加完毕后反应液缓慢升至室温。室温下再搅拌12小时后，反应溶液减压除去大部分溶剂，用溶剂(石油醚/三乙胺＝20:1)冲洗硅胶柱，残余物经硅胶柱层析分离纯化(淋洗剂，石油醚/三乙胺＝20:1)，油泵抽干得产物I-t。
产物化合物I-t，白色固体,收率86％,M.p.89-90℃,[α]D 20＝+234.95(c 0.50,CHCl3)；1H NMR(400MHz,CDCl3)δ7.11(t,J＝7.6Hz,1H),7.03(t,J＝7.6Hz,1H),6.93-6.88(m,3H),6.54(d,J＝8.0Hz,1H),3.26-3.16(m,2H),2.90-2.69(m,4H),2.19(d,J＝8.8Hz,6H),1.95-1.88(m,2H),1.68-1.63(m,2H)；13C NMR(100MHz,CDCl3)δ149.18(d,J＝5.3Hz),145.88(d,J＝5.6Hz),145.57(d,J＝2.1Hz),144.80,128.72(d,J＝2.0Hz),128.59,121.29(d, J＝1.7Hz),121.03(d,J＝6.5Hz),120.56(d,J＝2.5Hz),119.46(d,J＝0.8Hz),61.09,46.10,45.85(d,J＝1.1Hz),36.57,35.98,35.16,34.97,19.04,19.01,14.93；31P NMR(161MHz,CDCl3)δ125.38；IR(neat)ν2926,2891,2883,2864,2841,1582,1459,1441,1290,1235,1224,1190,1159,1140,1027,972,925,803,790,775,742,725,692,678cm-1；ESI-MS(m/z):365([M]+)；HRMS-ESI(m/z):calcd.for C22H25NO2P+:366.1617,found:366.1626([M+H]+).
实施例35(Rh(I)/手性稠环螺二氢茚骨架亚磷酰胺配体I-t催化的α-脱氢氨基酸甲酯的不对称氢化)
本实施例以手性稠环螺二氢茚骨架亚磷酰胺配体I-t与[Rh(COD)2OTf]现场形成的络合物为手性催化剂，催化的α-脱氢氨基酸甲酯的不对称氢化反应，用来例举说明本发明中手性稠环螺二氢茚骨架化合物在不对称催化中的应用。
Figure PCTCN2016109383-appb-000065
操作方法：在氩气气氛中，将氢化瓶无水无氧处理，加入[Rh(COD)2]OTf(1.17mg,0.0025mmol)和I-t(0.0050mmol)，置换氩气三次后，加入CH2Cl2(2.5mL)。将氢化瓶转入手套箱中，加入α-脱氢氨基酸甲酯底物1’(54.8mg,0.25mmol)，并放入高压釜中。置换氢气三次后，充入氢气至20atm，室温搅拌12h，停止搅拌，小心放掉氢气，反应溶液减压除去溶剂，用1H NMR测定转化率，残余物用乙酸乙酯过一硅胶短柱分离得到氢化产物2’。白色固体,收率>99％,M.p.85-87℃,96％ee,[α]D 20＝-97.92(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.21-7.31(m,3H),7.09-7.12(m,2H),6.22(d,J＝6.4Hz,1H),4.84-4.90(m,1H),3.71(s,3H),3.04-3.16(m,2H),1.97(s,3H).产物2’的ee值由手性高效液相色谱测定,Chiralcel AD column.Conditions:hexane/isopropanol＝92:8；flow rate＝1.0mL/min；UV detection at 230nm；tR＝14.50min(major),18.99min(minor).
实施例36(手性稠环螺二氢茚骨架亚磷酰胺配体I-u的合成)
Figure PCTCN2016109383-appb-000066
将Schlenk瓶(100-mL)无水无氧处理后，加入THF(30mL)和吡咯烷(20.0mmol)，冷却至-78℃，逐滴加入n-BuLi(2.4M in Hexanes)(9.17mL,22mmol)，滴加完毕后缓慢升至室温。在另一无水无氧处理的Schlenk瓶中加入THF(10mL)和PCl3(2.27mL)，冷却至-78℃。移取胺锂溶液至PCl3的THF溶液中，缓慢升至室温后再搅拌12小时。反应体系减压除去溶剂，用THF(10mL×3)洗涤-抽干，除去过量的PCl3。最后加入THF(10mL)配成溶液。
将Schlenk瓶(15mL)无水无氧处理后，在氩气气氛下，加入二酚I-p(0.55mmol)、THF(5.0mL)和Et3N(0.40mL)，冷却至0℃。缓慢加入上述胺基二氯磷(1.70mL)， 滴加完毕缓慢升至室温。再搅拌12h后，停止反应，反应体系减压除去大部分溶剂，用溶剂(石油醚/三乙胺＝20:1)冲洗硅胶柱，残余物经柱层析分离纯化(石油醚/三乙胺＝20:1)，油泵抽干得固体产物(1R,2R,2’R)-I-u。白色固体,收率49％,M.p.87-88℃,[α]D 20＝-237.2o(c 0.565,CHCl3)；1H NMR(400MHz,CDCl3)δ7.18(t,J＝8.0Hz,1H),7.08(t,J＝8.0Hz,1H),6.93-6.85(m,3H),6.57(d,J＝8.0Hz,1H),3.27-3.17(m,2H),2.89-2.78(m,4H),2.73(dd,J＝17.2,5.2Hz,2H),2.34-2.26(m,2H),1.99-1.85(m,2H),1.68-1.64(m,4H),1.55-1.52(m,2H)；13C NMR(100MHz,CDCl3)δ149.67(d,J＝4.8Hz),146.13(d,J＝5.9Hz),145.48(d,J＝2.0Hz),144.96,142.82(d,J＝3.6Hz),141.21(d,J＝1.2Hz),128.75(d,J＝2.0Hz),128.00,121.69(d,J＝1.6Hz),120.90(d,J＝6.3Hz),120.47(d,J＝2.4Hz),119.36(d,J＝0.8Hz),71.34,53.18,52.68(d,J＝1.2Hz),45.25,45.10,40.90,40.52,31.51,31.32,25.80,25.75；31P NMR(161MHz,CDCl3)δ124.43；IR(neat)ν2922,2850,1732,1582,1460,1293,1227,1206,1075,1006,981,804,780,726,676cm-1；EI-MS(70eV),m/z:377([M]+),348,308,280,202,189,101,70,43；HRMS-EI(m/z):calcd.for C23H24NO2P:377.1545,found:377.1543.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。
此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (18)

  1. 一种如式I所示的手性稠环螺二氢茚骨架化合物，或它们的对映体或非对映异构体；
    Figure PCTCN2016109383-appb-100001
    其中，R1、R2、R3、R4、R5、R6、R7和R8各自独立地为氢、C1～C10的烷基、C3～C10的环烷基、C1～C4的烷氧基、芳基、氟、氯、溴、碘或羟基；
    或者，R1、R4、R5和R8各自独立地为氢、C1～C10的烷基、C3～C10的环烷基、C1～C4的烷氧基、芳基、氟、氯、溴、碘或羟基；R2和R3与它们所连接的分子骨架上的碳原子一起连接成芳环，且该芳环与“R2和R3所连接的分子骨架上的碳原子所在的苯环”是并环结构；R6和R7与它们所连接的分子骨架上的碳原子一起连接成芳环，且该芳环与“R6和R7所连接的分子骨架上的碳原子所在的苯环”是并环结构；
    X为CY1Y2、NY1、O或S；n＝0～3；其中Y1和Y2各自独立地为氢、C1～C10的烷基、C3～C10的环烷基、芳基或C1～C4的烷氧基；
    并且，所述如式I所示的手性稠环螺二氢茚骨架化合物不为如式I-n所示的化合物；
    Figure PCTCN2016109383-appb-100002
  2. 如权利要求1所述的化合物，其特征在于：
    所述R1与R8相同；和/或，所述R2与R7相同；和/或，所述R3与R6相同；和/或，所述R4与R5相同；和/或，所述n＝0、1、2或3。
  3. 如权利要求1或2所述的化合物，其特征在于：
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C10的烷基时，所述C1～C10的烷基为C1～C6的烷基；
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C3～C10的环烷基时，所述C3～C10的环烷基为C3～C6的环烷基；
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C4的烷氧基时，所述C1～C4的烷氧基为C1～C3的烷氧基；
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为芳基时，所述芳基为C6～C20芳基；
    所述R2和R3与它们所连接的分子骨架上的碳原子一起连接成芳环时，所述芳环为C6～C20芳环；
    所述R6和R7与它们所连接的分子骨架上的碳原子一起连接成芳环时，所述芳环为 C6～C20芳环；
    所述Y1和Y2各自独立地为C1～C10的烷基时，所述C1～C10的烷基为C1～C4烷基；
    所述Y1和Y2各自独立地为C3～C10的环烷基时，所述C3～C10的环烷基为C3～C6的环烷基；
    所述Y1和Y2各自独立地为芳基时，所述芳基为C6～C20芳基；
    所述Y1和Y2各自独立地为C1～C4的烷氧基时，所述C1～C4的烷氧基为甲氧基或乙氧基。
  4. 如权利要求3所述的化合物，其特征在于：
    所述R1、R2、R3、R4、R6、R6、R7和R8各自独立地为C1～C6的烷基时，所述C1～C6的烷基为C1～C3的烷基；
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C3～C6的环烷基时，所述C3～C6的环烷基为环丙基；
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C3的烷氧基时，所述C1～C3的烷氧基为甲氧基、乙氧基或丙氧基；
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为所述C6～C20芳基时，所述C6～C20芳基为C6～C12芳基；
    所述R2和R3与它们所连接的分子骨架上的碳原子一起连接成所述C6～C20芳环时，所述C6～C20芳环为C6～C12芳环；
    所述R6和R7与它们所连接的分子骨架上的碳原子一起连接成C6～C20芳环时，所述C6～C20芳环为C6～C12芳环；
    所述Y1和Y2各自独立地为C1～C4烷基时，所述C1～C4烷基为甲基、乙基、丙基或叔丁基；
    所述Y1和Y2各自独立地为C3～C6的环烷基时，所述C3～C6的环烷基为环丙基；
    所述Y1和Y2各自独立地为C6～C20芳基时，所述C6～C20芳基为C6～C12芳基。
  5. 如权利要求4所述的化合物，其特征在于：
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为C1～C3的烷基时，所述C1～C3的烷基为甲基、乙基或丙基；
    所述R1、R2、R3、R4、R5、R6、R7和R8各自独立地为所述C6～C12芳基时，所述C6～C12为苯基或萘基；
    所述R2和R3与它们所连接的分子骨架上的碳原子一起连接成所述C6～C12芳环时，所述C6～C12芳环为苯环或萘环；
    所述R6和R7与它们所连接的分子骨架上的碳原子一起连接成C6～C12芳环时，所述C6～C12芳环为苯环或萘环；
    所述Y1和Y2各自独立地为C6～C12芳基时，所述C6～C12芳基为苯基或萘基。
  6. 如权利要求1所述的化合物，其特征在于：所述如式I所示的手性稠环螺二氢茚骨架化合物为如下任一化合物：
    Figure PCTCN2016109383-appb-100003
    Figure PCTCN2016109383-appb-100004
    Figure PCTCN2016109383-appb-100005
  7. 一种如式I’所示的亚磷酰胺配体，或它们的对映体或非对映异构体；
    Figure PCTCN2016109383-appb-100006
    所述X、n、R1、R2、R3、R6、R7和R8同权利要求1～6中任一项所述；
    所述R1’和R2’各自独立地为C1～C10的烷基或C3～C10的环烷基；或者所述R1’和R2’与它们所连接的N原子一起连接成C2～C10氮杂烷环。
  8. 如权利要求7所述的如式I’所示的亚磷酰胺配体，或它们的对映体或非对映异构体，其特征在于：
    所述R1’和R2’各自独立地为C1～C10的烷基时，所述C1～C10的烷基为C1～C3的烷基；
    所述R1’和R2’各自独立地为C3～C10的环烷基时，所述C3～C10的环烷基为C3～C6的环烷基；
    所述R1’和R2’与它们所连接的N原子一起连接成C2～C10氮杂烷环时，所述C2～C10氮杂烷环为C3～C6氮杂烷环。
  9. 如权利要求8所述的如式I’所示的亚磷酰胺配体，或它们的对映体或非对映异构体，其特征在于：
    所述R1’和R2’各自独立地为C1～C3的烷基时，所述C1～C3的烷基为甲基、乙基或丙基；
    所述R1’和R2’各自独立地为C3～C6的环烷基时，所述C3～C6的环烷基为环丙基；
    所述R1’和R2’与它们所连接的N原子一起连接成C3～C6氮杂烷环时，所述C3～C6氮杂烷环为四氢吡唑烷。
  10. 如权利要求7所述的如式I’所示的亚磷酰胺配体，或它们的对映体或非对映异构体，其特征在于：所述如式I’所示的亚磷酰胺配体为如下任一化合物：
    Figure PCTCN2016109383-appb-100007
  11. 一种如式I所示的化合物的制备方法，其特征在于，其包括如下步骤：溶剂中，催化剂作用下，将如式III所示的化合物进行分子内傅里德-克拉夫茨反应，制得如式I所示的化合物；所述催化剂为布朗斯特酸或路易斯酸；所述X、n、R1、R2、R3、R4、R5、R6、R7和R8同权利要求1～6中任一项所述；
    Figure PCTCN2016109383-appb-100008
  12. 如权利要求11所述的制备方法，其特征在于：
    所述布朗斯特酸为盐酸、磷酸、多聚磷酸、甲基磺酸、三氟甲基磺酸、醋酸、三氟乙酸、对甲苯磺酸和磷钨酸中的一种或多种；所述路易斯酸为三氟甲基磺酸钪、三氯化铝、四氯化锡、三氯化铁、三氟化硼、四氯化钛、四异丙氧基钛、三氟甲基磺酸铟和三氟甲基磺酸铜中的一种或多种；
    和/或，所述如式I所示的化合物的制备方法还可进一步包括如下步骤：将所述溶剂和所述如式III所示的化合物进行混合，0℃条件下，加入所述催化剂并反应1～100分钟，自然升温至15℃～40℃并继续反应1～20小时；
    和/或，所述分子内傅里德-克拉夫茨反应在无水无氧条件下进行；
    和/或，所述分子内傅里德-克拉夫茨反应在保护性气体条件下进行；
    和/或，所述如式III所示的化合物与所述催化剂的摩尔比为100∶1～1∶100；
    和/或，所述分子内傅里德-克拉夫茨反应的溶剂为芳烃类溶剂、卤代烃类溶剂、醚类溶剂、醇类溶剂、酰胺类溶剂和亚砜类溶剂中的一种或多种；
    和/或，所述如式III所示的化合物与所述分子内傅里德-克拉夫茨反应的溶剂的摩尔体积比值为0.02mol/L～0.2mol/L；
    和/或，所述分子内傅里德-克拉夫茨反应的温度为-40℃～100℃；
    和/或，所述分子内傅里德-克拉夫茨反应的时间为0.1～48小时。
  13. 如权利要求11或12所述的制备方法，其特征在于：所述如式I所示的化合物的制备方法，还进一步包括如下步骤：溶剂中，催化剂作用下，将如式II所示的化合物与氢气进行不对称氢化反应，制得所述如式III所示的化合物；
    Figure PCTCN2016109383-appb-100009
  14. 如权利要求13所述的制备方法，其特征在于：
    所述如式I所示的化合物的制备方法中，所述不对称氢化反应的催化剂为钌、铑、铱和钯的过渡金属络合物中的一种或多种；所述金属络合物为手性或非手性的；
    和/或，所述如式I所示的化合物的制备方法中，所述不对称氢化反应的催化剂与所述如式II所示的化合物的摩尔比值为0.0001～0.1；
    和/或，所述如式I所示的化合物的制备方法中，所述不对称氢化反应的溶剂为卤代烃类溶剂、芳香烃类溶剂、醚类溶剂、醇类溶剂、酰胺类溶剂和亚砜类溶剂中的一种或多种；
    和/或，所述如式I所示的化合物的制备方法中，所述不对称氢化反应的溶剂与所述如式II所示的化合物的体积质量比值为1ml/g～20ml/g；
    和/或，所述如式I所示的化合物的制备方法中，所述不对称氢化反应的氢气的压力为1～100atm；
    和/或，所述如式I所示的化合物的制备方法中，所述不对称氢化反应的温度为-78～80℃；
    和/或，所述如式I所示的化合物的制备方法中，所述不对称氢化反应的时间为1～48小时；
    和/或，所述的如式I所示的化合物的制备方法，在所述的不对称氢化反应结束后，不进行后处理，直接将反应体系和所述傅里德-克拉夫茨反应的溶剂、催化剂及所述如式III所示的化合物混合，并进行所述分子内傅里德-克拉夫茨反应。
  15. 如权利要求13或14所述的制备方法，其特征在于：所述如式I所示的化合物的制备方法，还进一步包括如下步骤：溶剂中，将如式V、式VI和式VII所示的化合物进行如下所示的羟醛缩合反应，制得所述如式II所示的化合物；
    Figure PCTCN2016109383-appb-100010
  16. 如权利要求15所述的制备方法，其特征在于；
    所述羟醛缩合反应在碱性条件下进行；
    和/或，所述羟醛缩合反应的溶剂为醇类溶剂和水的混合溶剂；
    和/或，所述羟醛缩合反应的溶剂与所述如式VI所示的化合物的体积摩尔比值为10000ml/mol～1ml/mol；
    和/或，所述羟醛缩合反应的温度为10～35℃；
    和/或，所述的取代反应的时间为1～12小时。
  17. 一种如式I’所示的化合物的制备方法，其特征在于，其包括如下步骤：碱性条件下，溶剂中，将如式I所示的化合物与如式IV所示的化合物进行取代反应，制得如式I’所示的化合物；所述W1和W2各自独立地为卤素；所述X、n、R1、R2、R3、 R4、R5、R6、R7、R8、R1’和R2’同权利要求7～10中任一项所述；
    Figure PCTCN2016109383-appb-100011
  18. 如权利要求17所述的制备方法，其特征在于：
    所述如式I’所示的化合物的制备方法还包括如下步骤：碱性条件下，将所述如式I所示的化合物与所述溶剂混合，冷却至-40～10℃，然后与所述如式IV所示的化合物混合，温度升至10～35℃后进行所述取代反应；
    和/或，所述取代反应在无水无氧条件下进行；
    和/或，所述取代反应在保护性气体条件下进行；
    和/或，所述碱性条件为反应在碱作用下进行；
    和/或，所述取代反应的溶剂为醚类溶剂、卤代烷烃类溶剂和芳烃类溶剂中的一种或多种；
    和/或，所述取代反应中，所述如式I所示的化合物与所述溶剂的摩尔体积比值为0.05mol/L～0.5mol/L；
    和/或，所述取代反应中，所述如式I所示的化合物与如式IV所示的化合物的摩尔比为1∶1.1～1∶3；
    和/或，所述取代反应的温度为0～35℃；
    和/或，所述的取代反应的时间为1～12小时。
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