WO2022218391A1 - 手性螺环铵盐化合物及其制备方法和应用 - Google Patents

手性螺环铵盐化合物及其制备方法和应用 Download PDF

Info

Publication number
WO2022218391A1
WO2022218391A1 PCT/CN2022/086917 CN2022086917W WO2022218391A1 WO 2022218391 A1 WO2022218391 A1 WO 2022218391A1 CN 2022086917 W CN2022086917 W CN 2022086917W WO 2022218391 A1 WO2022218391 A1 WO 2022218391A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
unsubstituted
formula
group
Prior art date
Application number
PCT/CN2022/086917
Other languages
English (en)
French (fr)
Inventor
邓力
许亚楠
罗济生
Original Assignee
西湖大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 西湖大学 filed Critical 西湖大学
Publication of WO2022218391A1 publication Critical patent/WO2022218391A1/zh

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/794—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring
    • C07C49/796—Ketones containing a keto group bound to a six-membered aromatic ring having unsaturation outside an aromatic ring polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the technical field of organic synthesis, and in particular relates to a chiral spirocyclic ammonium salt compound with a spirobidihydroindene skeleton.
  • Chiral spiro compounds are C2-symmetric axial chiral compounds similar to chiral binaphthyl compounds, but they are more rigid and have smaller dihedral angles than chiral binaphthyl compounds, and they have greater advantages in asymmetric catalysis.
  • the potential to induce a better chiral induction effect (Ding, K.; Han, Z.; Wang, Z. Chem. Asian J., 2009, 4, 32-41).
  • chiral spiro compounds are widely used as chiral ligands and organic small molecule catalysts in asymmetric synthesis, and great progress has been made [(a) Rahman, A.; Lin, X. Org. Biomol. Chem ., 2018, 16, 4753-4777.
  • the purpose of the present invention is to provide a quaternary ammonium salt compound with a chiral spiro skeleton that can be used for asymmetric catalytic oxy-Cope rearrangement reactions.
  • the first aspect of the present invention provides a chiral spirocyclic ammonium salt compound, the compound has the structure shown in general formula I:
  • R 1 and R 2 are each independently selected from the following group: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 1-naphthyl, substituted or unsubstituted 1-naphthyl 2-naphthyl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted benzyl, wherein the R 1 and R 2 may be the same or different;
  • R 1 , R 2 and the connected N + together form a 6-20-membered ring structure (including saturated or partially unsaturated heterocycles)
  • R 3 and R 4 are one or more substituents located on the corresponding benzene ring, each independently selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1 -C6 benzyloxy, substituted or unsubstituted C1-C6 silyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, Substituted or unsubstituted phenyl, substituted or unsubstituted 1-naphthyl, substituted or unsubstituted 2-naphthyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted benzyl; wherein , the R 3 and R 4 can be the same or different
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted Phenyl, substituted or unsubstituted 1-naphthyl, substituted or unsubstituted 2-naphthyl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted benzyl; or C1-C10 alkoxy or R 5 to R 6 , R 6 to R 7 , and R 7 to R 8 are C3 to C7 aliphatic rings; wherein, the R 5 , R 6 , R 7 , and R 8 may be the same or different;
  • R 5 , R 6 , R 7 or R 8 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring and connected in parallel with the carbon-carbon bond to which it is attached , substituted or unsubstituted 5-10-membered heteroaromatic ring, substituted or unsubstituted 5-10-membered saturated or partially unsaturated carbocyclic ring, substituted or unsubstituted 5-10-membered saturated or partially unsaturated heterocycle;
  • X is each independently selected from the group consisting of chloride, bromide, iodide, triflate, p-toluenesulfonate, phosphate, borate;
  • substitution refers to substitution by a substituent selected from the group consisting of C1-C10 alkyl, C1-C6 alkoxy, phenyl, nitro, and halogen.
  • the heteroaryl group is selected from the group consisting of furyl, thienyl or pyridyl.
  • the compound of formula I is selected from the following group:
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, and a substituted or unsubstituted C1-C4 alkyl group.
  • the R 3 and R 4 are one or more substituents located on the corresponding benzene ring, each of which is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl groups , substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 1-naphthyl, substituted or unsubstituted 2-naphthyl , substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted benzyl.
  • the R 1 , R 2 are each independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, or the R 1 , R 2 and the connected N + are common Forms a 6-20-membered cyclic structure (including saturated or partially unsaturated heterocycles).
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention, the method comprising the steps of:
  • the method further comprises the steps:
  • Y is one or more groups located on the corresponding phenyl group, and the Y is selected from the following group: H or halogen; LG is selected from Cl, Br, I, OTs, Oms; the definitions of the remaining groups As described in the first aspect of the present invention.
  • the inert solvent is selected from the group consisting of methylene chloride, toluene, tetrahydrofuran, chloroform, methanol, dimethyl sulfoxide, diethyl ether, N,N-dimethylformamide, acetonitrile, petroleum ether, ethyl acetate, or a combination thereof.
  • the step (2) is carried out at 70-90°C.
  • reaction time of the step (2) is 5-40h.
  • the step (3) is carried out at 60-80°C.
  • reaction time of the step (3) is 8-16h.
  • the step (4) is carried out at 60-80°C.
  • reaction time of the step (4) is 5-10h.
  • the method includes the steps:
  • the inert solvent is selected from the group consisting of methylene chloride, toluene, tetrahydrofuran, chloroform, methanol, dimethyl sulfoxide, diethyl ether, N,N-dimethylformamide, acetonitrile, petroleum ether, ethyl acetate, or a combination thereof.
  • the solvent is diethyl ether.
  • the step (1a) is carried out at 30-40°C.
  • reaction time of the step (1a) is 18-32h.
  • the method includes the steps:
  • the compound of formula I-1 is reacted with thionyl chloride and methanol successively, and then reacted with diisobutylaluminum hydride to obtain the compound of formula I-2; wherein, the Y is halogen (preferably I).
  • the inert solvent is selected from the group consisting of methylene chloride, toluene, tetrahydrofuran, chloroform, methanol, dimethyl sulfoxide, diethyl ether, N,N-dimethylformamide, acetonitrile, petroleum ether, ethyl acetate, or a combination thereof.
  • the inert solvent is methanol.
  • the inert solvent is toluene.
  • the step (1b) is first performed at 70-90°C, and then performed at -70-(-85)°C.
  • reaction time of the step (1b) is 15-25h.
  • described method when described Y is halogen (preferably I), described method also comprises the steps:
  • the inert solvent is selected from the group consisting of methylene chloride, toluene, tetrahydrofuran, chloroform, methanol, dimethyl sulfoxide, diethyl ether, N,N-dimethylformamide, acetonitrile, petroleum ether, ethyl acetate, or a combination thereof.
  • the alkali is sodium acetate.
  • the palladium catalyst is palladium acetate.
  • step (iv) is carried out at 90-110°C.
  • reaction time of the step (iv) is 24-48h.
  • the method further comprises the steps:
  • the compound of formula I-5 is reacted with trifluoromethanesulfonic anhydride to obtain the compound of formula I-6; preferably, the solvent is DCM; the reaction is carried out in the presence of pyridine;
  • the palladium catalyst is palladium acetate;
  • the ligand is dppp;
  • the inert solvent is a mixed solvent of DMSO, MeOH and Et 3 N;
  • the inert solvent is selected from the group consisting of methylene chloride, toluene, tetrahydrofuran, chloroform, methanol, dimethyl sulfoxide, diethyl ether, N,N-dimethylformamide, acetonitrile, petroleum ether, ethyl acetate, or a combination thereof.
  • step (i) is carried out at 0-40°C.
  • reaction time of the step (i) is 6-18h.
  • step (ii) is carried out at 90-100°C.
  • reaction time of the step (ii) is 24-48h.
  • step (iii) is carried out at 90-110°C.
  • reaction time of the step (iii) is 8-12h.
  • the third aspect of the present invention provides the use of the compound according to the first aspect of the present invention, which is used for catalyzing the oxy-Cope rearrangement reaction.
  • the compound is used to catalyze the enantioselective [3,3]-sigma rearrangement of 1,5-hexadien-3-ols to obtain chiral ⁇ , ⁇ -unsaturated carbonyl compounds.
  • the inventors After long-term and in-depth research, the inventors have prepared a class of quaternary ammonium salt compounds with a chiral spiro-ring skeleton that can be used for asymmetric catalytic oxy-Cope rearrangement reactions.
  • the quaternary ammonium salt compound has a simple preparation method and good chiral induction effect, and can be used for the oxy-Cope rearrangement reaction that cannot be catalyzed by a common chiral ammonium salt phase transfer catalyst. Based on the above findings, the inventors have completed the present invention.
  • the object of the present invention is to provide a new class of chiral spirocyclic ammonium salt compounds.
  • this kind of chiral spirocyclic ammonium salt compound has a more rigid framework and smaller dihedral angle, and has a greater potential to induce better asymmetric catalysis. chiral induction effect.
  • the chiral spirocyclic ammonium salt compound provided by the present invention is a compound of formula I or an enantiomer or racemate of the compound.
  • R 1 and R 2 are each independently selected from the following group: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 1-naphthyl, substituted or unsubstituted 1-naphthyl 2-naphthyl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted benzyl, wherein the R 1 and R 2 may be the same or different;
  • R 1 , R 2 and the connected N + together form a 6-20-membered ring structure (including saturated or partially unsaturated heterocycles)
  • R 3 and R 4 are one or more substituents located on the corresponding benzene ring, each independently selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1 -C6 benzyloxy, substituted or unsubstituted C1-C6 silyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, Substituted or unsubstituted phenyl, substituted or unsubstituted 1-naphthyl, substituted or unsubstituted 2-naphthyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted benzyl; wherein , the R 3 and R 4 can be the same or different
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted Phenyl, substituted or unsubstituted 1-naphthyl, substituted or unsubstituted 2-naphthyl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted benzyl; or C1-C10 alkoxy or R 5 to R 6 , R 6 to R 7 , and R 7 to R 8 are C3 to C7 aliphatic rings; wherein, the R 5 , R 6 , R 7 , and R 8 may be the same or different;
  • R 5 , R 6 , R 7 or R 8 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring and connected in parallel with the carbon-carbon bond to which it is attached , substituted or unsubstituted 5-10-membered heteroaromatic ring, substituted or unsubstituted 5-10-membered saturated or partially unsaturated carbocycle, substituted or unsubstituted 5-10-membered saturated or partially unsaturated heterocycle;
  • X is each independently selected from the group consisting of chloride, bromide, iodide, triflate, p-toluenesulfonate, phosphate, borate;
  • Preferred chiral spirocyclic ammonium salt compounds are selected from the following compounds and their enantiomers or racemates:
  • the invention also provides a preparation method of a chiral spirocyclic ammonium salt compound, which is characterized in that: starting with racemic or optically active 1,1'-spirobisindane-7,7'-diphenol The raw material is prepared through the following reaction formula:
  • R 1 , R 2 , R 3 , R 4 , and X are as defined in the first aspect of the present invention, and LG is selected from Cl, Br, I, OTs, and OMs.
  • compound 4 is reduced with lithium aluminum hydride to obtain compound 6A; compound 6A is reacted with thionyl chloride in an organic solvent to obtain compound 7A; under nitrogen atmosphere, under palladium catalysis, compound 4 is in an organic solvent with the original
  • the iodine reagent synthesized in situ was reacted for 36 hours to prepare compound 5; after compound 5 was reacted with thionyl chloride, it was directly reacted with methanol, and then reduced with diisobutylaluminum hydride to obtain compound 6B; compound 6A was mixed with chloride in an organic solvent Sulfoxide reaction affords compound 7B.
  • compound 7 is reacted with secondary amine to prepare compound IA-IG; under nitrogen atmosphere, under palladium catalysis, compound IA-IG is reacted with coupling reagent in organic solvent for 5-10 hours to prepare compound IH -IQ.
  • the organic solvent can be dichloromethane, toluene, tetrahydrofuran, chloroform, methanol, dimethyl sulfoxide, diethyl ether, N,N-dimethylformamide, acetonitrile, petroleum ether, ethyl acetate One of the esters or a mixed solvent of several of them.
  • the chiral spirocyclic ammonium salt compound of the present invention can be used for asymmetric catalysis oxy-Cope rearrangement reaction, and is characterized in that it passes through the following reaction formula:
  • R is a C1-C6 alkyl group or a C6-C10 aryl group
  • R 1 and R 2 are independently selected from C1-C6 alkyl group, phenyl group, and substituted phenyl group, and the substituent on the phenyl group is an alkyl group.
  • aryl, R 1 , R 2 can be the same or different;
  • R 3 , R 4 are independently selected from H, C1-C6 alkyl;
  • R 3 ⁇ R 4 are C3 ⁇ C7 aliphatic rings, R 3 , R 4 can be The same can also be different.
  • the method comprises: in an organic solvent, using a compound having the general formula I as a chiral catalyst, in the presence of a base, using 1,5-hexadien-3-ol
  • a compound having the general formula I as a chiral catalyst
  • 1,5-hexadien-3-ol The chiral ⁇ , ⁇ -unsaturated carbonyl compounds with high enantioselectivity can be obtained by performing the oxy-Cope rearrangement reaction as the reaction reagent. Under the most optimal conditions, this method can achieve a yield of 90%, ee value 92%.
  • Magnetium, potassium carbonate (14mg, 0.1mmol), compound 7A (16mg, 0.05mmol) were successively added to a 10mL Schlenk tube, the system was replaced with a nitrogen atmosphere, di-n-butylamine (8mg, 0.06mmol), acetonitrile (0.5mg) were added. mL), reacted at 70°C for 12 hours. After the reaction, add water (2mL) to dilute, extract with dichloromethane (3 ⁇ 5mL), and combine the organic phases. The organic phase was washed successively with 50% sodium hydroxide, 10% hydrobromic acid, saturated sodium bromide, and dried over anhydrous sodium sulfate.
  • Example 26 Asymmetric catalysis of oxy-Cope rearrangement by chiral spirocyclic ammonium salts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明涉及一种手性螺环铵盐化合物及其制备方法和应用，具体地，所述的化合物具有如下的结构式I的光学纯或消旋化合物。本发明还提供了该化合物的合成方法，所述方法可以高产率的合成该类手性螺环铵盐化合物。该类化合物作为潜在的手性相转移催化剂在不对称合成方面具有广阔的应用前景。

Description

手性螺环铵盐化合物及其制备方法和应用 技术领域
本发明属于有机合成技术领域，具体涉及一种具有螺双二氢茚骨架的手性螺环铵盐化合物。
背景技术
近几十年来，手性季铵盐催化剂由于其特有的结构和性质，已经被广泛应用于手性中心的构建、天然产物和药物分子的催化合成中。其中，金鸡纳碱和联萘骨架的季铵盐在许多不对称催化反应中展现出了十分高效的催化活性[(a)Novacek,J.；Waser,M.Eur.J.Org.Chem.2013,2013,637-648.(b)Shirakawa,S.；Maruoka,K.Angew.Chem.,Int.Ed.2013,52,4312-4348.(c)Jew,S.；Park,H.Chem.Commun.2009,7090-7103.]；近年来发展的氨基酸衍生的手性季铵盐催化剂也在各种不对称加成反应中具有独特的催化效果(Wang,H.；Zheng,C.；Zhao,G.Chin.J.Chem.2019,37,1111-1119.)。但是，目前高效的手性季铵盐催化剂的种类仍然很少，并且在很多不对称反应中，其活性及对映选择性并不理想。目前为止，仍需要发展新型高效的手性季铵盐催化剂，去解决实际存在的很多问题。
Figure PCTCN2022086917-appb-000001
手性螺环化合物是与手性联萘化合物相似的C2-对称的轴手性化合物，但其又比联萘化合物更加的刚性、有更小的二面角，在不对称催化中有更大的潜力诱导产生更好的手性诱导效果(Ding,K.；Han,Z.；Wang,Z.Chem.Asian J.,2009,4,32-41)。目前，手性螺环化合物作为手性配体、有机小分子催化剂被广泛应用于不对称合成中，并取得了巨大的进展[(a)Rahman,A.；Lin,X.Org.Biomol.Chem.,2018,16,4753-4777.(b)Xu,C.；Hu,W.Chem.J.Chinese.U.2020,41,2153-2173.]。然而，手性螺环骨架的季铵盐化合物的制备方法仍未见报道，而该类化合物作为潜在的手性相转移催化剂在不对称合成方面具有广阔的应用前景。
发明内容
本发明的目的是提供一种能够用于不对称催化oxy-Cope重排反应的手性螺环骨架的季铵盐化合物。
本发明的第一方面，提供了一种手性螺环铵盐化合物，所述的化合物具有通式I所示的结构：
Figure PCTCN2022086917-appb-000002
其中，R 1、R 2各自独立地选自下组：取代或未取代的C1～C10的烷基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基，其中，所述的R 1、R 2可以相同或不同；
或所述的R 1、R 2与相连的N +共同构成6-20元环状结构(包括饱和或部分不饱和杂环)
R 3、R 4为一个或多个位于对应苯环上的取代基，其各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6苄氧基、取代或未取代的C1-C6硅基、取代或未取代的C1～C10烷基、取代或未取代的C1-C6烯基、取代或未取代的C1-C6炔基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基；其中，所述的R 3、R 4可以相同或不同；
R 5、R 6、R 7、R 8各自独立地选自下组：H、取代或未取代的C1～C10的烷基、取代或未取代的C1-C10烷氧基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基；或C1～C10烷氧基；或R 5～R 6、R 6～R 7、R 7～R 8并为C3～C7脂肪环；其中，所述的R 5、R 6、R 7、R 8可以相同或不同；
或一个或多个R 5、R 6、R 7或R 8共同形成与其相连的碳碳键并联的选自下组的环状结构：取代或未取代的苯环、取代或未取代的萘环、取代或未取代的5-10元杂芳环、取代或未取代的5-10元饱和或部分不饱和碳环、取代或未取代的5-10元饱和或部分不饱和杂环；
X各自独立地选自下组：氯离子、溴离子、碘离子、三氟甲磺酸根离子、对甲苯磺酸根离子、磷酸根离子、硼酸根离子；
除非特别说明，所述的取代指被选自下组的取代基取代：C1～C10的烷基、C1-C6烷氧基、苯基、硝基、卤素。
在另一优选例中，所述的杂芳基选自下组：呋喃基、噻吩基或吡啶基。
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2022086917-appb-000003
在另一优选例中，所述的R 5、R 6、R 7、R 8各自独立地选自下组：H、取代或未取代的C1～C4的烷基。
在另一优选例中，所述的R 3、R 4为一个或多个位于对应苯环上的取代基，其各自独立地选自下组：H、取代或未取代的C1～C6烷基、取代或未取代的C1-C6烯基、取代或未取代的C1-C6炔基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基。
在另一优选例中，所述的R 1、R 2各自独立地选自下组：取代或未取代的C1～C6的烷基，或所述的R 1、R 2与相连的N +共同构成6-20元环状结构(包括饱和或部分不饱和杂环)。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2022086917-appb-000004
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的制备方法，所述的方法包括步骤：
Figure PCTCN2022086917-appb-000005
(2)在惰性溶剂中，用式I-2化合物与氯化亚砜反应，得到式I-3化合物；
Figure PCTCN2022086917-appb-000006
(3)在惰性溶剂中，在氮气气氛下，用式I-3化合物与R 1R 2NH反应，得到式I-4化合物；
且当Y不为H时，所述的方法还包括步骤：
Figure PCTCN2022086917-appb-000007
(4)在惰性溶剂中，在氮气气氛下，用钯催化剂催化偶联试剂与I-4进行反应，得到式I化合物；
其中，Y为一个或多个位于对应苯基上的基团，且所述的Y选自下组：H或卤素；LG选自Cl、Br、I、OTs、Oms；其余各基团的定义如本发明第一方面中所述。
在另一优选例中，所述的惰性溶剂选自下组：二氯甲烷、甲苯、四氢呋喃、氯仿、甲醇、二甲基亚砜、乙醚、N，N-二甲基甲酰胺、乙腈、石油醚、乙酸乙酯，或其组合。
在另一优选例中，所述的步骤(2)在70-90℃下进行。
在另一优选例中，所述的步骤(2)的反应时间为5-40h。
在另一优选例中，所述的步骤(3)在60-80℃下进行。
在另一优选例中，所述的步骤(3)的反应时间为8-16h。
在另一优选例中，所述的步骤(4)在60-80℃下进行。
在另一优选例中，所述的步骤(4)的反应时间为5-10h。
在另一优选例中，所述的方法包括步骤：
Figure PCTCN2022086917-appb-000008
(1a)在惰性溶剂中，用式I-1化合物与氢化铝锂反应，得到式I-2化合物；其中，所述的Y为H。
在另一优选例中，所述的惰性溶剂选自下组：二氯甲烷、甲苯、四氢呋喃、氯仿、甲醇、二甲基亚砜、乙醚、N，N-二甲基甲酰胺、乙腈、石油醚、乙酸乙酯，或其组合。
在另一优选例中，所述的溶剂为乙醚。
在另一优选例中，所述的步骤(1a)在30-40℃下进行。
在另一优选例中，所述的步骤(1a)的反应时间为18-32h。
在另一优选例中，所述的方法包括步骤：
Figure PCTCN2022086917-appb-000009
(1b)在惰性溶剂中，用式I-1化合物与氯化亚砜和甲醇先后进行反应，然后与二异丁基氢化铝反应，得到式I-2化合物；其中，所述的Y为卤素(优选为I)。
在另一优选例中，所述的惰性溶剂选自下组：二氯甲烷、甲苯、四氢呋喃、氯仿、甲醇、二甲基亚砜、乙醚、N，N-二甲基甲酰胺、乙腈、石油醚、乙酸乙酯，或其组合。
在另一优选例中，所述的惰性溶剂为甲醇。
在另一优选例中，所述的惰性溶剂为甲苯。
在另一优选例中，所述的步骤(1b)先在70-90℃下进行，后在-70-(-85)℃下进行。
在另一优选例中，所述的步骤(1b)的反应时间为15-25h。
在另一优选例中，当所述的Y为卤素(优选为I)时，所述的方法还包括步骤：
Figure PCTCN2022086917-appb-000010
(iv)在惰性溶剂中，在钯催化剂和碱存在下，用式I-8化合物与碘试剂进行反应，得到式I-1化合物；较佳地，所述的溶剂为DMF，所述的碘试剂为碘/醋酸碘苯。
在另一优选例中，所述的惰性溶剂选自下组：二氯甲烷、甲苯、四氢呋喃、氯仿、甲醇、二甲基亚砜、乙醚、N，N-二甲基甲酰胺、乙腈、石油醚、乙酸乙酯，或其组合。
在另一优选例中，所述的碱为醋酸钠。
在另一优选例中，所述的钯催化剂为醋酸钯。
在另一优选例中，所述的步骤(iv)在90-110℃下进行。
在另一优选例中，所述的步骤(iv)的反应时间为24-48h。
在另一优选例中，所述的方法还包括步骤：
Figure PCTCN2022086917-appb-000011
(i)在惰性溶剂中，用式I-5化合物与三氟甲磺酸酐反应，得到式I-6化合物；较佳地，所述的溶剂为DCM；所述的反应在吡啶存在下进行；
Figure PCTCN2022086917-appb-000012
(ii)在惰性溶剂中，在钯催化剂存在下，用式I-6化合物与一氧化碳反应，得到式I-7化合物；较佳地，所述的钯催化剂为醋酸钯；所述的配体为dppp；更佳地，所述的惰性溶剂为DMSO、MeOH和Et 3N的混合溶剂；
Figure PCTCN2022086917-appb-000013
(iii)在惰性溶剂中，在碱存在下(优选氢氧化钠)，用式I-7化合物反应得到式I-8化合物；较佳地，所述的溶剂为甲醇。
在另一优选例中，所述的惰性溶剂选自下组：二氯甲烷、甲苯、四氢呋喃、氯仿、甲醇、二甲基亚砜、乙醚、N，N-二甲基甲酰胺、乙腈、石油醚、乙酸乙酯，或其组合。
在另一优选例中，所述的步骤(i)在0-40℃下进行。
在另一优选例中，所述的步骤(i)的反应时间为6-18h。
在另一优选例中，所述的步骤(ii)在90-100℃下进行。
在另一优选例中，所述的步骤(ii)的反应时间为24-48h。
在另一优选例中，所述的步骤(iii)在90-110℃下进行。
在另一优选例中，所述的步骤(iii)的反应时间为8-12h。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物的用途，其用于催化oxy-Cope重排反应。
在另一优选例中，所述的化合物用于催化1,5-己二烯-3-醇类化合物对映选择性[3,3]-sigma重排从而获得手性δ,ε-不饱和羰基化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，制备得到了一类能够用于不对称催化oxy-Cope重排反应的手性螺环骨架的季铵盐化合物。所述的季铵盐化合物制备方法简单，手性诱导效果好，能够用于常见的手性铵盐相转移催化剂无法催化的oxy-Cope重排反应。基于上述发现，发明人完成了本发明。
新型手性螺环铵盐化合物
本发明的目的在于提供一类新型手性螺环铵盐化合物。相对于文献报道的手性铵盐相转移催化剂，这类手性螺环铵盐化合物具有更加刚性的骨架、有更小的二面角，在不对称催化中有更大的潜力诱导产生更好的手性诱导效果。本发明提供的手性螺环铵盐化合物，是具有式I的化合物或所述化合物的对映体、消旋体。
Figure PCTCN2022086917-appb-000014
其中，R 1、R 2各自独立地选自下组：取代或未取代的C1～C10的烷基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基，其中，所述的R 1、R 2可以相同或不同；
或所述的R 1、R 2与相连的N +共同构成6-20元环状结构(包括饱和或部分不饱和杂环)
R 3、R 4为一个或多个位于对应苯环上的取代基，其各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6苄氧基、取代或未取代的C1-C6硅基、取代或未取代的C1～C10烷基、取代或未取代的C1-C6烯基、取代或未取代的C1-C6炔基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基；其中，所述的R 3、R 4可以相同或不同；
R 5、R 6、R 7、R 8各自独立地选自下组：H、取代或未取代的C1～C10的烷基、取代或未取代的C1-C10烷氧基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基；或C1～C10烷氧基；或R 5～R 6、R 6～R 7、R 7～R 8并为C3～C7脂肪环；其中，所述的R 5、R 6、R 7、R 8可以相同或不同；
或一个或多个R 5、R 6、R 7或R 8共同形成与其相连的碳碳键并联的选自下组的环状结构：取代或未取代的苯环、取代或未取代的萘环、取代或未取代的5-10元杂芳环、 取代或未取代的5-10元饱和或部分不饱和碳环、取代或未取代的5-10元饱和或部分不饱和杂环；
X各自独立地选自下组：氯离子、溴离子、碘离子、三氟甲磺酸根离子、对甲苯磺酸根离子、磷酸根离子、硼酸根离子；
优选的手性螺环铵盐化合物选自如下化合物及其对映体或消旋体：
Figure PCTCN2022086917-appb-000015
手性螺环铵盐化合物的制备
本发明还提供了一种手性螺环铵盐化合物的制备方法，其特征在于：以消旋或旋光活性的1，1'-螺双二氢化茚-7，7'-二酚为起始原料，经过下述反应式制备得到：
Figure PCTCN2022086917-appb-000016
其中：R 1、R 2、R 3、R 4、X如本发明第一方面所定义,LG选自Cl、Br、I、OTs、OMs。
化合物1在有机溶剂中与三氟甲磺酸酐室温下反应12小时制备得到化合物2；在一氧化碳氛围下，钯催化下，化合物2在有机溶剂中反应24-48小时制备得到化合物3。化合物3在碱性条件下水解得到化合物4。
在氮气氛围下,化合物4用氢化铝锂还原，得到化合物6A；化合物6A在有机溶剂中与氯化亚砜反应得到化合7A；在氮气氛围下,钯催化下，化合物4在有机溶剂中与原位合成的碘试剂反应36小时制备得到化合物5；化合物5与氯化亚砜反应后，直接与甲醇反应，随后用二异丁基氢化铝还原得到化合物6B；化合物6A在有机溶剂中与氯化亚砜反应得到化合7B。
在氮气氛围下,化合物7与二级胺反应制备得到化合物IA-IG；在氮气氛围下,钯催化下，化合物IA-IG在有机溶剂中与偶联试剂反应5-10小时，制备得到化合物IH-IQ。
在上述合成方法中，所述的有机溶剂可为二氯甲烷、甲苯、四氢呋喃、氯仿、甲醇、二甲基亚砜、乙醚、N，N-二甲基甲酰胺、乙腈、石油醚、乙酸乙酯中的一种或其中几种的混合溶剂。
上述方法中各个步骤条件温和，且中间体7A和7B适合大量制备，因此该方法预期还可以用于制备在7A和7B基础上侧链进行进一步修饰的化合物。
不对称催化oxy-Cope重排反应
本发明的手性螺环铵盐化合物可以用于不对称催化oxy-Cope重排反应，其特征是经过下述反应式：
Figure PCTCN2022086917-appb-000017
其中，R为C1-C6烷基或C6-C10芳基，R 1，R 2分别独立选自C1-C6烷基、苯基、取代苯基，所述的苯基上的取代基为烷基、芳基，R 1、R 2可以相同也可以不同；R 3，R 4独立选自H、C1-C6烷基；R 3～R 4并为C3～C7脂肪环，R 3、R 4可以相同也可以不同。
在本发明的一个优选实施方式下，所述的方法包括：在有机溶剂中，用具有通式I的化合物作为手性催化剂，在碱存在下，用1,5-己二烯-3-醇类化合物为反应试剂进行oxy-Cope重排反应，就可以获得高对映选择性的手性δ,ε-不饱和羰基化合物，在最优选的条件下，该方法可以达到90％收率，ee值92％。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：螺环化合物2的合成
Figure PCTCN2022086917-appb-000018
在250mL烧瓶中先后加入磁子、化合物1(8.0g,31.7mmol),吡啶(11.2mL,139.5mmol)，二氯甲烷(160mL),冷却至0℃，在此温度下，缓慢加入三氟甲磺酸酐(13.1mL,70.0mmol)，加入完毕后，移至室温，在室温下反应12小时。反应结束后，除去体系溶剂。随后，体系中加入乙酸乙酯(130mL),先后用5％盐酸溶液、饱和碳酸氢钠、饱和氯化钠洗涤一次。无水硫酸钠干燥有机相，过滤，减压浓缩，经柱层析分离(洗脱剂：二氯甲烷)，得到目标产物2，白色固体(95％，15.5g)。 1H NMR(500MHz,CDCl 3)δ7.32-7.26(m,4H),7.13(dd,J＝6.5,1.5Hz,2H),3.17-3.05(m,4H),2.42-2.28(m,4H)。
实施例2：螺环化合物3的合成
Figure PCTCN2022086917-appb-000019
在氮气氛围下，在250mL三口烧瓶中先后加入磁子，化合物2(5.2g,10.0mmol),醋酸钯(0.23g,1.0mmol)，1,3-双(二苯基膦)丙烷(0.43g,1.0 mmol)，二甲基亚砜(90mL),甲醇(30mL),三乙胺(24mL)，加入完毕后，撤去氮气，改用一氧化碳向反应体系鼓泡半小时，在一氧化碳氛围下，70℃下搅拌至反应完全(薄层色谱点板监测反应)。反应完成后，冷却至室温，减压浓缩，除去体系中溶剂。经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝8：1)，得到目标产物3，白色固体(72％，2.4g)。 1H NMR(500MHz,CDCl 3)δ7.60(d,J＝8.0Hz,2H),7.43(d,J＝7.0Hz,2H),7.22(t,J＝7.5Hz,2H),3.16(m,6H),3.13-3.00(m,4H),2.62-2.52(m,2H),2.33-2.27(m,2H)。
实施例3：螺环化合物4的合成
Figure PCTCN2022086917-appb-000020
在100mL烧瓶中先后加入磁子，化合物3(4.3g,12.8mmol),甲醇(25mL),30％氢氧化钠水溶液(25mL),搅拌回流10小时后，冷却至室温。加水稀释，用6M的盐酸水溶液调节体系pH至5～6，用乙酸乙酯萃取(3х40mL),合并有机相，有机相用水和饱和氯化钠各洗涤一次，无水硫酸钠干燥，过滤。减压浓缩，经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1:1)，得到目标产物4,白色固体(93％,3.7g)。 1H NMR(500
MHz,CDCl 3)δ7.63(d,J＝7.5Hz,2H),7.39(d,J＝7.0Hz,2H),7.13(t,J＝7.5Hz,2H),3.13-2.97(m,4H),2.53-2.44(m,2H),2.28-2.22(m,2H)。
实施例4：螺环化合物5的合成
Figure PCTCN2022086917-appb-000021
在100mL封管中，先后加入磁子、化合物4(1.32g,4.3mmol),醋酸钯(0.19g,0.86mmol),碘(2.72g,10.75mmol),醋酸碘苯(3.46g,10.75mmol),醋酸钠(1.17g,8.6mmol),N,N-二甲基甲酰胺(40mL),向体系中氮气鼓泡半小时。体系在100℃下反应36小时。冷却至室温，减压浓缩，用饱和亚硫酸钠(30mL)淬灭。用2N的盐酸溶液(30mL)酸化至酸性,二氯甲烷萃取(3х30mL)，合并有机相。无水硫酸钠干燥，过滤，减压浓缩，经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝1:1)，得到目标产物5，白色固体(70％,1.69g)。 1H NMR(500MHz,CDCl 3)δ7.63(d,J＝7.5Hz,2H),6.98(d,J＝8.0Hz,2H),3.04-2.87(m,4H),2.48-2.39(m,2H),2.25-2.19(m,2H)。
实施例5：螺环化合物6A的合成
Figure PCTCN2022086917-appb-000022
在100mL三口烧瓶中先后加入磁子、氢化铝锂(0.5g,13.2mmol),体系置换成氮气氛围，加入乙醚(12mL)，随后冷却至0℃。在此温度下，向体系中缓慢加入化合物4(0.4g,1.3mmol)的乙醚(24mL)溶液。加料完毕后，0℃下继续搅拌半小时。然后在加热回流条件下反应24小时。反应完毕后，冷却至室温，先后向反应体系中缓慢加入水(1mL),50％氢氧化钠水溶液(2mL),水(2mL),乙酸乙酯(20mL)。用装有少量硅藻土的沙星漏斗过滤，滤渣用乙酸乙酯洗涤(2х10mL),合并有机相。有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝2:1)，得到目标产物6A，白色固体(83％，0.3g)。 1H NMR(500MHz,CDCl 3)δ7.30(d,J＝7.5Hz,2H),7.28-7.23(m,2H),7.22(d,J＝7.5Hz,2H),4.23(d,J＝12.0Hz,2H),4.17(d,J＝12.0Hz,2H),3.06-2.98(m,4H),2.60(br,2H),2.36-2.29(m,2H),2.06-1.96(m,2H)。
实施例6：螺环化合物6B的合成
Figure PCTCN2022086917-appb-000023
在100mL两口瓶中，先后加入磁子、化合物5(0.56g,1.0mmol),体系置换成氮气氛围，加入氯化亚砜(10mL)溶解,反应移至80℃下反应8小时。反应完毕后，冷却至室温，减压浓缩，加入甲醇(5mL),继续在80℃下反应4小时。反应结束后，冷却至室温，减压浓缩，经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝30:1),得到中间产物，白色固体(85％,0.5g)。 1H NMR(500MHz,CDCl 3)δ7.67(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),3.25(s,6H),3.04-2.91(m,4H),2.66-2.57(m,2H),2.26-2.19(m,2H)。
在50mL三口瓶中先后加入磁子、上述中间产物(0.56g,0.85mmol),反应置换成氮气氛围，加入甲苯(10mL)溶解，冷却至-78℃。加入二异丁基氢化铝(1.5M甲苯溶液,3.8mL),在此温度下继续搅拌3小时后，移至室温下反应5小时。反应结束后，用饱和氯化铵溶液淬灭(20mL),乙酸乙酯萃取(3х20mL)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝4:1),得到目标产物6B，白色固体(90％,0.41g)。 1H NMR(500MHz,CDCl 3)δ7.75(d,J＝6.5Hz,2H),6.95(d,J＝6.5Hz,2H),4.41(d,J＝10.0Hz,2H),4.23(d,J＝10.0Hz,2H),3.10(br,2H),3.03-2.91(m,4H),2.33-2.27(m,2H),2.06-1.98(m,2H)。
实施例7：螺环化合物7A的合成
Figure PCTCN2022086917-appb-000024
在25mL的烧瓶中，先后加入磁子、化合物6A(0.3g,1.07mmol),吡啶(87μL,1.07mmol),氯仿(10mL)。在0℃下，向体系中缓慢加入氯化亚砜(0.78mL,10.7mmol)的氯仿溶液(8mL),继续搅拌半小时。然后加热回流条件下搅拌5小时。反应完成后，冷却至室温。向反应体系中缓慢加水(20mL)淬灭。分液后，水相用氯仿萃取(3х10mL),合并有机相。有机相分别用饱和碳酸氢钠和饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩。经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝20:1)，得到目标产物7A,白色固体(80％,0.27g)。 1H NMR(500MHz,CDCl 3)δ7.29-7.23(m,6H),4.16(d,J＝12.0Hz,2H),4.13(d,J＝12.0Hz,2H),3.08-3.03(m,4H),2.38-2.29(m,2H),2.29-2.22(m,2H)。
实施例8：螺环化合物7B的合成
具体操作参考实例7
Figure PCTCN2022086917-appb-000025
7B，白色固体,0.44g,收率：78％, 1H NMR(500MHz,CDCl 3)δ7.81(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),4.29(d,J＝11.5Hz,2H),4.24(d,J＝11.5Hz,2H),3.08-2.93(m,4H),2.39-2.27(m,4H)； 13C NMR(125MHz,CDCl 3)δ149.4,144.8,140.1,135.9,127.4,101.6,63.9,47.7,38.9,30.4。
实施例9：螺环化合物IA的合成
Figure PCTCN2022086917-appb-000026
在10mL Schlenk管中先后加入磁子、碳酸钾(14mg,0.1mmol),化合物7A(16mg,0.05mmol),体系置换成氮气氛围，加入二正丁基胺(8mg,0.06mmol),乙腈(0.5mL)，在70℃条件下反应12小时。反应结束后，加水(2mL)稀释，二氯甲烷萃取(3х5mL),合并有机相。有机相先后用50％氢氧化钠、10％氢溴酸、饱和溴化钠洗涤，无水硫酸钠干燥。过滤，减压浓缩，经柱层析分离(洗脱剂：二氯甲烷：甲醇＝10:1)，得到相应的目标产物IA,白色固体，18mg,收率：82％。 1H NMR(500MHz,CDCl 3)δ7.40-7.34(m,4H),7.32-7.28(m,2H),4.67(d,J＝13.5Hz,2H),4.21(d,J＝13.5Hz,2H),3.28(td,J＝13.5,5.0Hz,2H),3.14-3.05(m,2H),2.96-2.85(m,4H),2.32-2.26(m,2H),2.18-2.11(m, 2H),1.94-1.84(m,2H),1.84-1.76(m,2H),1.45-1.36(m,4H),1.00(t,J＝7.5Hz,6H)； 13C NMR(125MHz,CDCl 3)δ150.9,144.7,131.7,128.2,127.8,121.7,61.2,58.3,57.1,38.9,30.2,24.8,19.8,13.7；HRMS(ESI)calcd for C 27H 36BrN,(M-Br)+374.2842,found 374.2846.
实施例10：螺环化合物IB的合成
具体操作参考实例9
Figure PCTCN2022086917-appb-000027
白色固体，15mg,收率：80％， 1H NMR(500MHz,CDCl 3)δ7.47(d,J＝7.0Hz,2H),7.39(d,J＝7.5Hz,2H),7.32(t,J＝7.5Hz,2H),4.59(d,J＝13.0Hz,2H),4.28(d,J＝12.5Hz,2H),3.25(s,6H),3.15-3.06(m,2H),2.94-2.87(m,2H),2.35-2.29(m,2H),1.94-1.85(m,2H)； 13C NMR(125MHz,CDCl 3)δ150.7,144.6,132.5,128.3,127.8,122.3,61.4,61.2,50.2,38.9,30.3；HRMS(ESI)calcd for C 21H 24BrN(M-Br)+290.1903,found 290.1908.
实施例11：螺环化合物IC的合成
具体操作参考实例9
Figure PCTCN2022086917-appb-000028
白色固体，15mg,收率：76％， 1H NMR(500MHz,CDCl 3)δ7.46(d,J＝7.5Hz,2H),7.38(d,J＝7.5Hz,2H),7.29(t,J＝7.5Hz,2H),5.31(d,J＝12.5Hz,2H),4.26-4.14(m,6H),3.88-3.80(m,2H),3.48-3.42(m,2H),3.14-3.00(m,2H),2.92-2.85(m,2H),2.34-2.28(m,2H),1.94-1.85(m,2H)； 13C NMR(125MHz,CDCl 3)δ151.1,144.8,132.3,128.4,127.9,121.3,61.2,60.7,57.9,56.5,39.0,30.3；HRMS(ESI)calcd for C 23H 26NOBr,(M-Br)+332.2009,found 332.2013.
实施例12：螺环化合物ID的合成
具体操作参考实例9
Figure PCTCN2022086917-appb-000029
白色固体，11mg,收率：39％， 1H NMR(500MHz,CDCl 3)δ7.61-7.56(m,4H),7.45-7.42(m,8H),4.79(d,J＝13.5Hz,4H),3.87(d,J＝13.5Hz,4H),3.11-3.02(m,4H),2.98-2.91(m,4H),2.17-2.11(m,4H),2.09-1.96(m,4H)； 13C NMR(125MHz,CDCl 3)δ151.1,144.8,134.2,128.4,127.5,120.7,61.8,60.6,38.8,29.8；HRMS(ESI)calcd for C 38H 36BrN,(M-Br)+506.2842,found 506.2845.
实施例13：螺环化合物IE的合成
具体操作参考实例9
Figure PCTCN2022086917-appb-000030
白色固体，25mg,收率：71％， 1H NMR(500MHz,CDCl 3)δ7.82(d,J＝9.0Hz,2H),7.14(d,J＝9.0Hz,2H),4.93(d,J＝14.0Hz,2H),4.61(d,J＝14.0Hz,2H),3.85(td,J＝13.0,4.0Hz,2H),3.05-2.95(m,4H),2.95-2.87(m,2H),2.19-2.12(m,4H),2.01-1.92(m,4H),1.66-1.50(m,2H),1.47-1.38(m,2H),1.01(t,J＝7.5Hz,6H)； 13C NMR(125MHz,CDCl 3)δ152.9,145.5,140.1,130.1,123.7,102.6,64.4,62.6,57.7,39.1,29.8,24.0,20.0,13.7.HRMS(ESI)calcd for C 27H 34BrI 2N，(M-Br)+626.0775,found 626.0796.
实施例14：螺环化合物IF的合成
具体操作参考实例9
Figure PCTCN2022086917-appb-000031
白色固体，25mg,收率：79％， 1H NMR(500MHz,CDCl 3)δ7.88(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),4.68-4.59(m,4H),3.43(s,6H),3.08-2.99(m,2H),2.96-2.89(m,2H),2.25-2.19(m,2H),2.00-1.95(m,2H)；HRMS(ESI)calcd for C 21H 26BrI 2N，(M-Br)+541.9836,found 541.9833.
实施例15：螺环化合物IG的合成
具体操作参考实例9
Figure PCTCN2022086917-appb-000032
淡黄色固体，15mg,收率：44％， 1H NMR(500MHz,CDCl 3)δ7.92(d,J＝8.0Hz,1H),7.74-7.68(m,3H),7.53-7.49(m,3H),7.17(d,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H), 5.51(d,J＝12.5Hz,1H),5.15(d,J＝14.0Hz,1H),4.80(d,J＝14.0Hz,1H),4.58(d,J＝13.5Hz,1H),4.36(d,J＝13.5Hz,1H),3.98(d,J＝12.5Hz,1H),3.34(s,3H),3.10-2.91(m,4H),2.26-2.19(m,2H),2.09-2.00(m,2H)； 13C NMR(125MHz,CDCl 3)δ152.7,145.0,144.9.141.1,140.1,134.1,131.1,130.1,129.8,129.5,126.3,125.2,124.0,103.0,102.2,66.3,65.8,64.3,59.7,47.2,39.5,38.6,29.9,29.7；HRMS(ESI)calcd for C 27H 26BrI 2N,(M-Br)+618.0149,found 618.0184.
实施例16：螺环化合物IH的合成
Figure PCTCN2022086917-appb-000033
在10mL Schlenk管中先后加入磁子、化合物IE(35mg,0.05mmol),四三苯基膦钯(6mg,0.005mmol),苯硼酸(30mg,0.25mmol),体系置换成氮气氛围，加入甲苯(0.3mL)，碳酸钾(2M,0.2mL),在70℃条件下反应5～10小时。反应结束后，加水(2mL)稀释，二氯甲烷萃取(3х5mL),合并有机相。有机相先后用50％氢氧化钠、10％氢溴酸、饱和溴化钠洗涤，无水硫酸钠干燥。过滤，减压浓缩，经柱层析分离(洗脱剂：二氯甲烷：甲醇＝10:1)，得到相应的目标产物IH。白色固体，15mg,收率：48％， 1H NMR(500MHz,CDCl 3)δ7.49-7.35(m,12H),7.30(d,J＝8.0Hz,2H),4.64(d,J＝13.5Hz,2H),4.56(d,J＝13.5Hz,2H),3.18-3.04(m,4H),2.45-2.27(m,6H),1.94-1.86(m,2H),1.29-1.25(m,2H),1.22-1.11(m,2H),0.94-0.85(m,2H),0.69(t,J＝7.0Hz,6H),0.61-0.56(m,2H)； 13C NMR(125MHz,CDCl 3)δ152.8,144.4,144.2,140.3,130.7,130.4,128.2,118.6,63.1,57.0,55.3,39.4,30.1,23.2,19.7,13.4；HRMS(ESI)calcd for C 39H 44BrN,(M-Br)+526.3468,found 526.3509.
实施例17：螺环化合物II的合成
具体操作参考实例16
Figure PCTCN2022086917-appb-000034
淡黄色固体，5mg,收率：15％， 1H NMR(500MHz,CDCl 3)δ7.44(d,J＝6.0Hz,2H),7.29(d,J＝6.0Hz,2H),7.27(d,J＝7.5Hz,4H),6.99(d,J＝7.5Hz,4H),4.65(d,J＝11.5Hz,2H),4.47(d,J＝11.5Hz,2H),3.16-3.08(m,2H),3.07-3.01(m,2H),2.43-2.34(m,4H),2.28-2.20(m,2H),2.05(s,6H),2.04-1.97(m,6H),1.19-1.11(m,2H),0.98-0.92(m,2H),0.72(t,J＝6.0Hz,6H)； 13C NMR(125MHz,CDCl 3)δ159.5,152.8,144.3,143.7,132.6,131.5,130.8,128.0,118.7,63.1,57.1,55.7,55.2,39.3,29.5,22.8,19.7,13.5；HRMS (ESI)calcd for C 41H 48BrNO 2,(M-Br)+586.3680,found 586.3691.
实施例18：螺环化合物IJ的合成
具体操作参考实例16
Figure PCTCN2022086917-appb-000035
黄色固体，4mg,收率：10％， 1H NMR(500MHz,CD 3OD)δ8.37(d,J＝8.5Hz,4H),7.68(d,J＝8.5Hz,4H),7.62(d,J＝7.5Hz,2H),7.42(d,J＝8.0Hz,2H),4.53(d,J＝12.0Hz,2H),4.45(d,J＝12.0Hz,2H),3.29-3.22(m,2H),3.10-3.04(m,2H),2.52-2.47(m,2H),2.46-2.38(m,2H),2.28-2.21(m,2H),2.21-2.16(m,2H),2.05-1.94(m,4H),1.15-1.08(m,2H),0.98-0.92(m,2H),0.70(t,J＝7.0Hz,6H)； 13C NMR(125MHz,CD 3OD)δ152.9,147.5,146.7,145.3,142.4,131.1,130.6,127.9,118.5,62.9,57.3,54.8,38.7,29.5,22.8,19.1,12.1；HRMS(ESI)calcd for C 39H 42BrN 3O 4,(M-Br)+616.3170,found 616.31717.
实施例19：螺环化合物IK的合成
具体操作参考实例16
Figure PCTCN2022086917-appb-000036
淡黄色固体，13mg,收率：40％， 1H NMR(500MHz,CDCl 3)δ7.45(d,J＝9.0Hz,2H),7.29(d,J＝9.0Hz,2H),7.02(br,2H),6.95(br,4H),4.71(d,J＝13.5Hz,2H),4.47(d,J＝13.5Hz,2H),3.18-3.10(m,2H),3.10-3.01(m,2H),2.41-2.33(m,6H),2.33(s,12H),2.28-2.20(m,2H),1.98-1.90(m,2H),1.16-1.08(m,2H),0.97-0.87(m,2H),0.72(t,J＝7.0Hz,6H)； 13C NMR(125MHz,CDCl 3)δ152.7,144.7,144.0,140.2,130.5,129.7,128.1,118.5,63.0,56.9,55.1,39.4,30.1,23.1,21.4,19.6,13.3；HRMS(ESI)calcd for C 43H 52BrN,(M-Br)+582.4094,found 582.4101.
实施例20：螺环化合物IL的合成
具体操作参考实例16
Figure PCTCN2022086917-appb-000037
淡黄色固体，14mg,收率：32％， 1H NMR(500MHz,CDCl 3)δ7.85-7.83(m,2H),7.66-7.49(m,14H),7.48-7.35(m,14H),4.81(d,J＝12.5Hz,2H),4.56(d,J＝13.0Hz,2H),3.22-3.13(m,2H),3.11-3.03(m,2H),2.49-2.40(m,4H),2.28-2.02(m,4H),2.03-1.99(m,4H),1.88-1.79(m,2H),1.68-1.59(m,2H),0.45(t,J＝7.0Hz,6H)； 13C NMR(125MHz,CDCl 3)δ152.8,144.6,144.2,141.3,130.8,130.2,129.9,129.2,128.4,128.3,127.7,127.1,125.5,118.3,63.1,56.9,54.9,39.3,30.1,22.8,19.6,13.3；HRMS(ESI)calcd for C 63H 60BrN,(M-Br)+830.4720,found 830.4757.
实施例21：螺环化合物IM的合成
具体操作参考实例16
Figure PCTCN2022086917-appb-000038
淡黄色固体，8mg,收率：24％， 1H NMR(500MHz,CDCl 3)δ7.93(d,J＝8.5Hz,2H),7.88-7.83(m,2H),7.70-7.64(m,2H),7.57-7.44(m,10H),7.39(d,J＝8.0Hz,2H),4.78-4.62(m,4H),3.22-3.07(m,4H),2.49-2.35(m,6H),2.03-1.98(m,1H),1.89-1.81(m,2H),1.65-1.59(m,1H),1.18-0.98(m,4H),0.78-0.72(m,2H),0.55-0.28(m,6H)； 13C NMR(125MHz,CDCl 3)δ152.9,144.4,132.5,132.23,132.16,132.1,132.0,131.1,129.3,128.6,128.5,128.2,127.9,127.1,126.9,118.7,63.1,60.5,57.0,39.4,30.1,22.9,19.4,13.0；HRMS(ESI)calcd for C 47H 48BrN,(M-Br)+626.3781,found 626.3786.
实施例22：螺环化合物IN的合成
具体操作参考实例16
Figure PCTCN2022086917-appb-000039
黄色固体，12mg,收率：45％， 1H NMR(500MHz,CDCl 3)δ7.51-7.44(m,6H),7.42-7.37(m,2H),7.33-7.28(m,6H),4.50(d,J＝13.5Hz,2H),4.46(d,J＝13.5Hz,2H),3.19-3.11(m,2H),3.08-3.01(m,2H),2.45-2.39(m,2H),2.37(s,6H),2.25-2.12(m,2H)； 13C NMR(125MHz,CDCl 3)δ152.3,145.2,143.7,139.3,131.2,130.2,129.7,128.5,128.0,119.3,62.9,58.0,51.4,39.5,30.1；HRMS(ESI)calcd for C 33H 32BrN,(M-Br)+442.2529,found 442.2549.
实施例23：螺环化合物IO的合成
具体操作参考实例16
Figure PCTCN2022086917-appb-000040
淡黄色固体，10mg,收率：34％， 1H NMR(500MHz,CDCl 3)δ7.52-7.48(m,3H),7.45-7.41(m,2H),7.39-7.33(m,3H),7.32-7.26(m,2H),7.22(d,J＝7.5Hz,1H),7.17-7.12(m,2H),7.06-7.01(m,3H),7.98-6.94(m,2H),6.92-6.85(m,1H),5.23(d,J＝13.5Hz,1H),4.60(d,J＝13.5Hz,1H),4.20(d,J＝12.5Hz,1H),4.13(d,J＝13.0Hz,1H),3.47(d,J＝12.5Hz,2H),3.23-3.11(m,2H),3.10-3.02(m,2H),2.46-2.40(m,2H),2.33(s,3H),2.30-2.21(m,1H),2.17-2.09(m,1H)； 13C NMR(125MHz,CDCl 3)δ152.5,145.6,144.8,143.60,143.56,139.3,139.2,133.0,131.5,130.34,130.32,129.9,128.8,128.5,127.9,127.4,126.3,120.0,118.8,65.4,63.0,59.1,51.7,46.3,40.2,38.8,30.2,30.1；HRMS(ESI)calcd for C 39H 36BrN,(M-Br)+518.2842,found 518.2855.
实施例24：螺环化合物IP的合成
Figure PCTCN2022086917-appb-000041
在10mL Schlenk管中先后加入磁子、化合物IE(35mg,0.05mmol),二(三苯基膦)氯化钯(4mg,0.005mmol),碘化亚铜(1mg,0.005mmol),体系置换成氮气氛围，先后加入苯乙炔(5mg,0.05mmol),三乙胺(0.2mL),四氢呋喃(0.3mL)，在60℃条件下反应12小时。反应结束后，加水(2mL)稀释，二氯甲烷萃取(3х5mL),合并有机相。有机相先后 用11％氢溴酸、饱和溴化钠洗涤，无水硫酸钠干燥。过滤，减压浓缩，经柱层析分离(洗脱剂：二氯甲烷：甲醇＝10:1)，得到相应的目标产物IP。淡黄色固体，16mg,收率：50％， 1H NMR(500MHz,CDCl 3)δ7.58(d,J＝7.5Hz,2H),7.52-7.48(m,4H),7.44(d,J＝8.0Hz,2H),7.41-7.36(m,6H),4.89(s,4H),3.73-3.65(m,2H),3.19-3.02(m,6H),2.32-2.26(m,2H),2.20-2.12(m,2H),1.56-1.43(m,4H),1.34-1.23(m,4H),0.87(t,J＝7.5Hz,6H)； 13C NMR(125MHz,CDCl 3)δ151.7,146.0,132.9,131.4,129.3,128.9,128.1,124.8,122.4,122.1,94.9,88.0,62.5,57.7,57.5,38.9,30.4,24.4,20.1,13.6；HRMS(ESI)calcd for C 43H 44BrN,(M-Br)+574.3468,found 574.3473.
实施例25：螺环化合物IQ的合成
具体操作参考实例24
Figure PCTCN2022086917-appb-000042
淡黄色固体，17mg,收率：61％， 1H NMR(500MHz,CDCl 3)δ7.74-7.70(m,4H),7.59(d,J＝8.0Hz,2H),7.42(d,J＝7.5Hz,2H),7.41-7.36(m,6H),4.86(d,J＝13.5Hz,2H),4.58(d,J＝13.5Hz,2H),3.38(s,6H),3.17-3.10(m,2H),3.01-2.94(m,2H),2.35-2.29(m,2H),2.05-1.97(m,4H)； 13C NMR(125MHz,CDCl 3)δ151.1,145.0,133.5,132.2,129.4,128.8,128.0,125.7,122.8,121.8,95.9,86.7,62.4,59.9,52.5,38.8,30.3；HRMS(ESI)calcd for C 37H 32BrN,(M-Br)+490.2529,found 490.2542.
实施例26：手性螺环铵盐化合物不对称催化oxy-Cope重排反应
Figure PCTCN2022086917-appb-000043
向反应管中依次加入催化剂(0.005mmol),氢氧化钾(0.5mg,0.01mmol),四氢呋喃(1.0mL),1,5-己二烯-3-醇类化合物(28mg,0.1mmol),在-20℃下反应3小时后，加入饱和氯化铵淬灭，乙酸乙酯萃取(3х2mL),合并有机相。无水硫酸钠干燥。过滤，减压浓缩，经柱层析分离(洗脱剂：石油醚：乙酸乙酯＝20:1)，得到相应的目标产物。无色液体，24mg,收率：88％， 1H NMR(500MHz,CDCl 3)δ7.84-7.80(m,2H),7.48-7.43(m,1H),7.38-7.32(m,2H),7.22-7.14(m,4H),7.12-7.07(m,1H),5.01-4.95(m,1H),3.37-3.29(m,1H),3.26-3.14(m,2H),2.39-2.31(m,1H),2.28-2.20(m,1H),1.54(s,3H),1.45(s,3H)；使用高效液相色谱分析原料和目标产物的光学纯度，所得实验结果见下表：
Entry 催化剂 原料产率(％) 原料ee(％) 产物产率(％) 产物ee(％)
1 无 98 0 0 0
2 C-1 80 0 18 0
3 C-2 85 0 10 0
4 M 40 0 55 0
5 S 50 0 42 0
6 IA 0 - 98 0
7 IH 10 50 88 31
Figure PCTCN2022086917-appb-000044
从表可知，目前最常用的手性铵盐相转移金鸡纳碱类催化剂C1/C2、联萘类催化剂M、酒石酸类的催化剂S，在oxy-Cope重排反应中都没有手性诱导效果，而手性螺环铵盐类化合物在此反应中表现出了较高的手性诱导效果，足以证明该类催化剂在不对称催化方面具有广阔的应用前景。
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 (10)

  1. 一种手性螺环铵盐化合物，其特征在于，所述的化合物具有通式I所示的结构：
    Figure PCTCN2022086917-appb-100001
    其中，R 1、R 2各自独立地选自下组：取代或未取代的C1～C10的烷基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基，其中，所述的R 1、R 2可以相同或不同；
    或所述的R 1、R 2与相连的N +共同构成6-20元环状结构(包括饱和或部分不饱和杂环)；
    R 3、R 4为一个或多个位于对应苯环上的取代基，其各自独立地选自下组：H、卤素、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6苄氧基、取代或未取代的C1-C6硅基、取代或未取代的C1～C10烷基、取代或未取代的C1-C6烯基、取代或未取代的C1-C6炔基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基；其中，所述的R 3、R 4可以相同或不同；
    R 5、R 6、R 7、R 8各自独立地选自下组：H、取代或未取代的C1～C10的烷基、取代或未取代的C1-C10烷氧基、取代或未取代的苯基、取代或未取代的1-萘基、取代或未取代的2-萘基、取代或未取代的5-10元杂芳基、取代或未取代的苄基；或C1～C10烷氧基；或R 5～R 6、R 6～R 7、R 7～R 8并为C3～C7脂肪环；其中，所述的R 5、R 6、R 7、R 8可以相同或不同；
    或一个或多个R 5、R 6、R 7或R 8共同形成与其相连的碳碳键并联的选自下组的环状结构：取代或未取代的苯环、取代或未取代的萘环、取代或未取代的5-10元杂芳环、取代或未取代的5-10元饱和或部分不饱和碳环、取代或未取代的5-10元饱和或部分不饱和杂环；
    X各自独立地选自下组：氯离子、溴离子、碘离子、三氟甲磺酸根离子、对甲苯磺酸根离子、磷酸根离子、硼酸根离子；
    除非特别说明，所述的取代指被选自下组的取代基取代：C1～C10的烷基、C1-C6烷氧基、苯基、硝基、卤素。
  2. 如权利要求1所述的化合物，其特征在于，所述的杂芳基选自下组：呋喃基、噻吩基或吡啶基。
  3. 如权利要求1所述的化合物，其特征在于，所述的式I化合物选自下组：
    Figure PCTCN2022086917-appb-100002
  4. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2022086917-appb-100003
  5. 如权利要求1所述的化合物的制备方法，其特征在于，所述的方法包括步骤：
    Figure PCTCN2022086917-appb-100004
    (2)在惰性溶剂中，用式I-2化合物与氯化亚砜反应，得到式I-3化合物；
    Figure PCTCN2022086917-appb-100005
    (3)在惰性溶剂中，在氮气气氛下，用式I-3化合物与R 1R 2NH反应，得到式I-4化合物；
    且当Y不为H时，所述的方法还包括步骤：
    Figure PCTCN2022086917-appb-100006
    (4)在惰性溶剂中，在氮气气氛下，用钯催化剂催化偶联试剂与I-4进行反应，得到式I化合物；
    其中，Y为一个或多个位于对应苯基上的基团，且所述的Y选自下组：H或卤素；LG选自Cl、Br、I、OTs、Oms；其余各基团的定义如权利要求1中所述。
  6. 如权利要求5所述的制备方法，其特征在于，所述的方法包括步骤：
    Figure PCTCN2022086917-appb-100007
    (1a)在惰性溶剂中，用式I-1化合物与氢化铝锂反应，得到式I-2化合物；其中，所述的Y为H。
  7. 如权利要求5所述的制备方法，其特征在于，所述的方法包括步骤：
    Figure PCTCN2022086917-appb-100008
    (1b)在惰性溶剂中，用式I-1化合物与氯化亚砜和甲醇先后进行反应，然后与二异丁基氢化铝反应，得到式I-2化合物；其中，所述的Y为卤素。
  8. 如权利要求5所述的制备方法，其特征在于，当所述的Y为卤素时，所述的方法还包括步骤：
    Figure PCTCN2022086917-appb-100009
    (iv)在惰性溶剂中，在钯催化剂和碱存在下，用式I-8化合物与碘试剂进行反应，得到式I-1化合物。
  9. 如权利要求8所述的制备方法，其特征在于，所述的方法还包括步骤：
    Figure PCTCN2022086917-appb-100010
    (i)在惰性溶剂中，用式I-5化合物与三氟甲磺酸酐反应，得到式I-6化合物；
    Figure PCTCN2022086917-appb-100011
    (ii)在惰性溶剂中，在钯催化剂存在下，用式I-6化合物与一氧化碳反应，得到式I-7化合物；
    Figure PCTCN2022086917-appb-100012
    (iii)在惰性溶剂中，在碱存在下(优选氢氧化钠)，用式I-7化合物反应得到式I-8化合物。
  10. 如权利要求1所述的化合物的用途，其特征在于，用于催化oxy-Cope重排反应。
PCT/CN2022/086917 2021-04-14 2022-04-14 手性螺环铵盐化合物及其制备方法和应用 WO2022218391A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110402629.9A CN115197145B (zh) 2021-04-14 2021-04-14 手性螺环铵盐化合物及其制备方法和应用
CN202110402629.9 2021-04-14

Publications (1)

Publication Number Publication Date
WO2022218391A1 true WO2022218391A1 (zh) 2022-10-20

Family

ID=83574203

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/086917 WO2022218391A1 (zh) 2021-04-14 2022-04-14 手性螺环铵盐化合物及其制备方法和应用

Country Status (2)

Country Link
CN (1) CN115197145B (zh)
WO (1) WO2022218391A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116063232B (zh) * 2023-02-28 2024-01-30 浙江九洲药业股份有限公司 一种螺双二氢茚配体及其制备方法与应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007622A2 (ja) * 2003-07-23 2005-01-27 Tosoh Corporation 光学活性四級アンモニウム塩、その製造法、並びにそれを用いた光学活性α−アミノ酸誘導体の製造方法
CN101671365A (zh) * 2009-09-18 2010-03-17 南开大学 手性螺环胺基膦配体化合物与合成方法及其应用
CN102391306A (zh) * 2011-08-31 2012-03-28 南开大学 螺环苄胺-膦和制备方法及其应用
CN111116474A (zh) * 2019-12-17 2020-05-08 浙江大学 一种基于螺二氢茚骨架的手性胺-脲类化合物及其制备方法和应用
CN111468183A (zh) * 2019-11-25 2020-07-31 天津大学 多氟代三芳基手性螺环磷酸催化剂及其制备方法、用途
CN112916042A (zh) * 2021-01-29 2021-06-08 兰州交通大学 基于四甲基螺二氢茚骨架的手性季铵盐相转移催化剂及制备方法
CN114262295A (zh) * 2021-12-21 2022-04-01 天津大学 螺二氢茚骨架手性季铵盐及制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111689887B (zh) * 2019-03-12 2022-04-01 武汉大学 铜/铱协同催化不对称烯丙基化/2-氮杂-Cope重排反应及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007622A2 (ja) * 2003-07-23 2005-01-27 Tosoh Corporation 光学活性四級アンモニウム塩、その製造法、並びにそれを用いた光学活性α−アミノ酸誘導体の製造方法
CN101671365A (zh) * 2009-09-18 2010-03-17 南开大学 手性螺环胺基膦配体化合物与合成方法及其应用
CN102391306A (zh) * 2011-08-31 2012-03-28 南开大学 螺环苄胺-膦和制备方法及其应用
CN111468183A (zh) * 2019-11-25 2020-07-31 天津大学 多氟代三芳基手性螺环磷酸催化剂及其制备方法、用途
CN111116474A (zh) * 2019-12-17 2020-05-08 浙江大学 一种基于螺二氢茚骨架的手性胺-脲类化合物及其制备方法和应用
CN112916042A (zh) * 2021-01-29 2021-06-08 兰州交通大学 基于四甲基螺二氢茚骨架的手性季铵盐相转移催化剂及制备方法
CN114262295A (zh) * 2021-12-21 2022-04-01 天津大学 螺二氢茚骨架手性季铵盐及制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PAINTER PHILLIP P., WONG BONNIE M., TANTILLO DEAN J.: "Facilitating the Cope Rearrangement by Partial Protonation: Implications for Synthesis and Biosynthesis", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, vol. 16, no. 18, 19 September 2014 (2014-09-19), US , pages 4818 - 4821, XP055977297, ISSN: 1523-7060, DOI: 10.1021/ol5023036 *
XU CHANGMING, QI YINSHENG, YANG XINSHUANG, LI XIANGFAN, LI ZHENPENG, BAI LEI: "Development of C 2 -Symmetric Chiral Spirocyclic Phase-Transfer Catalysts: Synthesis and Application to Asymmetric Alkylation of Glycinate Schiff Base", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, vol. 23, no. 8, 16 April 2021 (2021-04-16), US , pages 2890 - 2894, XP055977295, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.1c00535 *

Also Published As

Publication number Publication date
CN115197145A (zh) 2022-10-18
CN115197145B (zh) 2024-02-13

Similar Documents

Publication Publication Date Title
Wang et al. Novel chiral ammonium ionic liquids as efficient organocatalysts for asymmetric Michael addition of aldehydes to nitroolefins
WO2018086197A1 (zh) 手性螺环二酚衍生物的催化不对称合成方法
CN112916042B (zh) 基于四甲基螺二氢茚骨架的手性季铵盐相转移催化剂及制备方法
WO2022218391A1 (zh) 手性螺环铵盐化合物及其制备方法和应用
CN112920066A (zh) 一种α-取代-α-氨基酸酯类化合物及其制备方法
CN110117237B (zh) 一种芳香腈或烯基腈类化合物的制备方法
JP7464234B2 (ja) 軸不斉を有する高光学活性アレンカルボン酸系化合物を製造する方法
CA2272380A1 (en) Process of preparing substituted acrylamides
CN112479982A (zh) 一种手性吲哚-2,3-并八元碳环化合物的制备方法
CN112538033B (zh) 一种环芳烷类面手性化合物的拆分方法
WO2007064869A2 (en) Catalysts for aryl sulfide synthesis and method of producing aryl sulfides
CN106977455A (zh) 一种医药中间体异喹啉酮化合物的制备方法
CN112824372A (zh) 铜催化烯烃的不对称环丙烷化方法及其应用
JP2010207767A (ja) 光学活性アルコール化合物の製法
WO2020220651A1 (zh) 一种手性2-羟基-1，4-二羰基化合物和泛解酸内酯的合成方法
CN106854125B (zh) 一种制备含有两个手性中心α-氟-β-乙炔基酮化合物的方法
CN114437060B (zh) 一种(r)-和(s)-3-奎宁环醇的制备方法
CN111925308B (zh) 一种光催化合成n-取代砜二亚胺的方法
CN110183298B (zh) 一种二苯并戊烯衍生物的制备方法
CN111825508B (zh) 一种二氢化9-菲胺类化合物的制备方法及其制得的手性产品
KR20180124088A (ko) S-거울상 이성질체를 이의 라세미체 형태로 전환하는 방법
CN110590641B (zh) 一种3-羟基异吲哚-1-酮系列化合物的绿色制备方法
KR20090051776A (ko) 아자비시클로알칸올 유도체의 제조 방법
WO2023046096A1 (zh) 一种基于金卡宾催化体系室温条件下1,3-二取代联烯类化合物的制备方法
CN115784906A (zh) 一种高选择性傅克芳基化反应制备三芳基甲烷衍生物的方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22787613

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22787613

Country of ref document: EP

Kind code of ref document: A1