WO2020007017A1 - Chiral bisamino-ether compounds, and method of preparation and use thereof - Google Patents

Chiral bisamino-ether compounds, and method of preparation and use thereof Download PDF

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WO2020007017A1
WO2020007017A1 PCT/CN2019/000044 CN2019000044W WO2020007017A1 WO 2020007017 A1 WO2020007017 A1 WO 2020007017A1 CN 2019000044 W CN2019000044 W CN 2019000044W WO 2020007017 A1 WO2020007017 A1 WO 2020007017A1
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substituted phenyl
bis
methoxy
naphthyl
iso
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Xiaojian Jiang
Ying Yeung YEUNG
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Jinan University
University of Jinan
Chinese University of Hong Kong CUHK
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Jinan University
University of Jinan
Chinese University of Hong Kong CUHK
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to novel chiral bisamino-ether compounds, and method of preparation and use thereof.
  • chiral aminomethanol compounds are used as starting materials to react with halogenated aryl compounds in the presence of a base to give a variety of chiral bisamino-ether compounds.
  • the novel chiral bisamino-ether compounds can be used for asymmetric fluorocyclization of unsaturated heterocyclic compounds with excellent enantioselectivity and great potentials for industrial applications.
  • the materials of such bis-quinine or bis-quinidine compounds were derived from the natural product of quinine or quinidine.
  • the quinine or quinidine as a natural product, has a single structure rather than being a pair of mirror-image of enantiomers. Consequently, the compounds are difficult to be structurally modified, and thus that the R and S enantiomeric products cannot be ensured to have the same ee value.
  • the present invention provided synthesis of various of chiral aminomethanol intermediates 1 using D or L type amino acids as starting materials (Jiang, X.; Tan, CK; Zhou, L.; Yeung, Y. -Y. Angew. Chem. Int. Ed. Engl. 2012, 51, 7771) .
  • the natural L-proline or D-proline which is inexpensive and readily available, was used as a starting material to carry out oxidation and Grignard reaction to give the compound C or F each having two chiral centers, and then through column chromatography purification, four chiral aminomethanol compounds 1 having different stereo configurations can be obtained (as shown in the scheme below) as the raw materials in the present invention.
  • the variability of the groups R 1 and R 2 allows the final product chiral bisamino-ether compound (I) of the present invention to have multiple tunable sites to form a variable spatial structure for the needs of different reactions, and the presence of D and L types of amino acids shall ensure that both R and S enantiomeric products with the same ee value can be obtained. It is indicated that the chiral bisamino-ether compounds (I) of the present invention have broad industrial utilities.
  • the present invention provides novel chiral bisamino-ether compounds, and method of preparation and use thereof.
  • the novel chiral bisamino-ether compounds can be used for asymmetric fluorocyclization of unsaturated heterocyclic compounds with excellent enantioselectivity for broad industrial applications.
  • the present invention provides a chiral bisamino-ether compound having the structure of formula (I) :
  • n 1 or 2; chiral center *has (R) or (S) configuration; and is one of the following moieties:
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 9 unsaturated alkyl, haloalkyl, C 1 -C 8 alkoxyl, phenyl, C 1 -C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1 -C 8 alkyl) amino substituted phenyl, C 1 -C 8 alkoxyl substituted phenyl, C 1 -C 8 acyl substituted phenyl, (C 1 -C 8 acyl) amino substituted phenyl, C 2 -C 8 ester group-substituted phenyl, and C 2 -C 8 acyloxyl substituted phenyl;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 9 unsaturated alkyl, haloalkyl, C 1 -C 8 alkoxyl, phenyl, C 1 -C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1 -C 8 alkyl) amino substituted phenyl, C 1 -C 8 alkoxyl substituted phenyl, C 1 -C 8 acyl substituted phenyl, (C 1 -C 8 acyl) amino substituted phenyl, C 2 -C 8 ester group-substituted phenyl, C 2 -C 8 acyloxyl substituted phenyl, naphthyl, pyridyl, quinolyl, isoquinolinyl, furyl, and thienyl;
  • R 3 , R 4 , R 5 , R 6 and R 7 may be the same or different, and are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 9 unsaturated alkyl, haloalkyl, C 1 -C 8 alkoxyl, C 1 -C 8 acyl, C 2 -C 8 acyloxyl, C 2 -C 8 ester group, (C 1 -C 8 acyl) amino, di (C 1 -C 8 alkyl) amino, halogen, amino, phenyl, C 1 -C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1 -C 8 alkyl) amino substituted phenyl, C 1 -C 8 alkoxyl substituted phenyl, C 1 -C 8 acyl substituted phenyl, (C 1 -C 8 acyl) amino
  • the C 1 -C 8 alkyl is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isoamyl, neopentyl, sec-pentyl, tert-amyl, cyclopentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, cyclohexyl, n-heptyl, isoheptyl, neoheptyl , n-heptyl, tert-heptyl, cycloheptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert
  • the C 1 -C 9 unsaturated alkyl is allyl, 2-methylpropyl, cis-n-butenyl, trans-2-butenyl, 3, 3-dimethylallyl, cis-2-pentenyl, trans-2-pentenyl, propargyl, benzyl, or 1-phenyl-1-propenyl;
  • haloalkyl is halogenated alkyl with halogen being fluorine, chlorine, bromine or iodine;
  • the C 1 -C 8 alkoxy is methoxyl, ethoxyl, n-propoxyl, isopropoxyl, cyclopropoxyl, n-butoxyl, iso-butoxyl, sec-butoxyl, tert-butoxyl, cyclobutoxyl, n-pentyloxyl, iso-pentyloxyl, neo-pentyloxyl, sec-pentyloxyl, tert-pentyloxyl, eyclopentyloxyl, n-hexyloxyl, iso-hexyloxyl, neo-hexyloxyl, sec-hexyloxyl, tert-hexyloxyl, cyclohexyloxyl, n-heptyloxyl, iso-heptyloxyl, neo-heptyloxyl, sec-heptyloxyl, tert-heptyloxyl,
  • the C 1 -C 8 acyl is formyl, acetyl, propionyl, n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, neo-valeryl, sec-valeryl, n-hexanoyl, iso-hexanoyl, neo-hexanoyl , sec-hexanoyl, n-heptanoyl, iso-heptanoyl, neo-heptanoyl, sec-heptanoyl, n-octanoyl, iso-octanoyl, neo-octanoyl, sec-octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylformyl, 1-cyclohexylformyl, or 1-cycloheptylcarbonyl;
  • the C 2 -C 8 acyloxyl is acetoxyl, propionyloxyl, n-butyryloxyl, iso-butyryloxyl, n-pentanoyloxyl, iso-valeryloxyl, sec-pentanoyloxyl, nco-pentanoyloxyl, n-hexanoyloxyl, iso-hexanoyloxyl, sec-hexanoyloxyl, neo-hexanoyloxyl, n-heptanoyloxyl, iso-heptanoyloxyl, sec-heptanoyloxyl, neo-heptanoyloxyl, n-octanoyloxyl, iso-octanoyloxyl, sec-octanoyloxyl, neo-octanoyloxyl, 1-cyclopropylcarbonyloxyl, 1-cycl
  • the C 2 -C 8 ester group is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, iso-butoxycarbonyl, n-pentyloxycarbonyl, iso-pentyloxycarbonyl, neo-pentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, iso-hexyloxycarbonyl, sec-hexyloxycarbonyl, neo-hexyloxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, iso-heptyloxycarbonyl, neo-heptyloxycarbonyl, sec-heptyloxycarbonyl
  • the chiral bisamino-ether compound (I) as described herein, comprises a racemate, dextroisomer and laevoisomer having same chemical formula but different stereo structures and optical rotation properties.
  • the present invention provides a method of preparation of the chiral bisamino-ether compound, and the method comprises: chiral amino-methanol compound 1 (2 mmol) being reacted with a base (2-4 mmol) in an organic solvent for 5-30 minutes, and then further reacted with halogenated aryl compound 2 (1-2 mmol) at 0-160 °C for 2-96 hours to give a chiral bisamino-ether compound (I) with different substituent groups:
  • n 1 or 2; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are defined as in formula (I) ; the halogenated aryl compound 2 is selected from the group consisting of:
  • the organic solvent is dimethylformamide, dichloromethane, dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, or any combination thereof.
  • the base is sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or any combination thereof.
  • the present invention provides a use of the chiral bisamino-ether compound, wherein the use comprises: using the chiral bisamino-ether compound I in asymmetric fluorocyclization of unsaturated heterocyclic compound 3:
  • R 8 and R 9 may be the same or different, and are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 9 unsaturated alkyl, halogen, haloalkyl, C 1 -C 8 alkoxyl, phenyl, C 1 -C 8 alkyl substituted phenyl, halophenyl, hydroxy substituted phenyl, amino substituted phenyl, di (C 1 -C 8 alkyl) amino substituted phenyl, C 1 -C 8 alkoxy substituted phenyl, C 1 -C 8 acyl substituted phenyl, (C 1 -C 8 acyl) amino substituted phenyl, C 2 -C 8 ester group-substituted phenyl, C 2 -C 8 acyloxy substituted phenyl, or naphthyl; the fluoro reagent is bis (tetrafluoroborate) salt of 1-ch
  • the reaction is carried out by adding the chiral bisamino-ether compound (I) and the substrate 3 into a round bottom flask, adding an additive and a solvent, adding the fluoro reagent, and then stirring the reaction at a specified temperature until the completion of the reaction.
  • the reaction conditions include: the solvent is acetone, acetonitrile, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, 1, 2-dichloroethane, chloroform, or a combination thereof; the chiral bisamino-ether compound (I) is in an amount of 10-120 mol%; the substrate 3 is in a concentration of 0.01-10 M; the additive is sodium hydrogencarbonate, potassium hydrogencarbonate, cesium carbonate, sodium carbonate, potassium carbonate, or a combination thereof; the reaction temperature is -78 to 40°C; the reaction time is 2-96 hours.
  • a chiral aminomethanol compound 1 is used as a starting material to react with a halogenated aryl compound 2 in the presence of a base to obtain a substituent-containing chiral bisamino-ether compound (I) .
  • the novel chiral bisamino-ether compound (I) can be used for the asymmetric fluorocyclization of the unsaturated heterocyclic compound 3.
  • the compounds of the invention showed some advantageous features, which include: having excellent effects with a wide range of substrates for a series of unsaturated heterocyclic compounds; having high tolerance to functional groups; having high enantioselectivity; and being able to obtain both R and S enantiomeric products with the same ee value.
  • the above features indicate that the novel chiral bisamino-ether compound of the invention is superior over the previous bis-quinine or bis-quinidine compounds and can find broad applications in industry.
  • Me refers to methyl
  • Et refers to ethyl
  • Allyl refers to allyl
  • Ph refers to phenyl
  • Mes refers to 2, 4, 6-trimethylphenyl
  • Bn refers to benzyl
  • Ts refers to p-toluenesulfonyl
  • Boc refers to tert-butoxycarbonyl
  • NMR nuclear magnetic resonance
  • HRMS high resolution mass spectrometry
  • chiral HPLC refers to high performance liquid chromatography with a chiral column
  • ee value refers to enantiomer excess value
  • Selectfluor refers to 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt
  • NFSI refers to N-fluorobis benzene sulfonamide.
  • the compounds obtained by the synthesis described herein are all prepared with the same process, and thus, for the sake of brevity, only the process for preparing the compound Ia is specifically described below, while the process for other subsequently listed compounds is omitted.
  • the chiral aminomethanol compound (R, S) -1a (482 mg, 2 mmol) was dissolved in dimethylformamide (6 mL) , and then added with 60%sodium hydride (120 mg, 3 mmol) at room temperature for 15 min. Then, halogenated aryl compound 2b (239 mg, 1.2 mmol) was added, and the reaction was run at 50 °C in an oil bath for 24 hours. After the reaction being completed, the reaction mixture was concentrated and cooled to room temperature, and added with water (6 mL) , and then was extracted with ethyl acetate (15 mL ⁇ 3) . The organic phase was combined and dried over anhydrous sodium sulfate, and then filtrated.
  • Example 8 Asymmetric fluorocyclization of the Substrate 3aa-an

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Abstract

The present invention provides novel chiral bisamino-ether compounds, and method of preparation and use thereof. The chiral bisamino-ether compounds have the structure of formula (I). The method of preparation includes: using chiral aminomethanol compounds as starting materials to react with halogenated aryl compounds in the presence of a base to give a variety of chiral bisamino-ether compounds. The novel chiral bisamino-ether compounds can be used for asymmetric fluorocyclization of unsaturated heterocyclic compounds with excellent enantioselectivity and great potentials for industrial applications.

Description

CHIRAL BISAMINO-ETHER COMPOUNDS, AND METHOD OF PREPARATION AND USE THEREOF FIELD OF THE INVENTION
The present invention relates to novel chiral bisamino-ether compounds, and method of preparation and use thereof. Specifically, chiral aminomethanol compounds are used as starting materials to react with halogenated aryl compounds in the presence of a base to give a variety of chiral bisamino-ether compounds. The novel chiral bisamino-ether compounds can be used for asymmetric fluorocyclization of unsaturated heterocyclic compounds with excellent enantioselectivity and great potentials for industrial applications.
BACKGROUND OF THE INVENTION
In the past few decades, natural bis-quinine or bis-quinidine has been used as a catalyst or reactant in a variety of asymmetric reactions to prepare important chiral compounds (Behrens, C.H.; Sharpless, K.B. Aldrichimica Acta 1983, 16, 67; Kolb, H.C.; van Nieuwenhze, M.S.; Sharlpless, K.B. Chem. Rev. 1994, 94, 2483; Li, G.G.; Chang, H.T.; Sharpless, K.B. Angew. Chem. Int. Ed. Engl. 1996, 35, 451; Jaganathan, A.; Garzan, A.; Whitehead, D.C.; Staples, R.J.; Borhan, B. Angew. Chem. Int. Ed. Engl. 2011, 50, 2593; Whitehead, D.C.; Yousefi, R.; Jaganathan, A.; Borhan, B.J. Am. Chem. Soc. 2010, 132, 3298; Lozano, O.; Blessley, G.; del Campo, T.M.; Thompson, A.L.; Giuffredi, G.T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur, V. Angew. Chem. Int. Ed. Engl. 2011, 50, 8105; Yu, P.A. Handbook of Reagents for Organic Synthesis: Catalytic Oxidation Reagents 2013, 483) .
In the past, the materials of such bis-quinine or bis-quinidine compounds were derived from the natural product of quinine or quinidine. However, the quinine or quinidine, as a natural product, has a single structure rather than being a pair of mirror-image of enantiomers. Consequently, the compounds are difficult to be structurally modified, and thus that the R and S enantiomeric products cannot be ensured to have the same ee value.
SUMMARY OF THE INVENTION
To overcome the above disadvantages of the natural products of quinine or quinidine, the present invention provided synthesis of various of chiral aminomethanol intermediates 1 using D or L type amino acids as starting materials (Jiang, X.; Tan, CK; Zhou, L.; Yeung, Y. -Y. Angew. Chem. Int. Ed. Engl. 2012, 51, 7771) . For example, the natural L-proline or D-proline, which is inexpensive and readily available, was used as a starting material to carry out oxidation and Grignard reaction to give the compound C or F each having two chiral centers, and then through  column chromatography purification, four chiral aminomethanol compounds 1 having different stereo configurations can be obtained (as shown in the scheme below) as the raw materials in the present invention. The variability of the groups R 1 and R 2 allows the final product chiral bisamino-ether compound (I) of the present invention to have multiple tunable sites to form a variable spatial structure for the needs of different reactions, and the presence of D and L types of amino acids shall ensure that both R and S enantiomeric products with the same ee value can be obtained. It is indicated that the chiral bisamino-ether compounds (I) of the present invention have broad industrial utilities.
Figure PCTCN2019000044-appb-000001
Therefore, in order to solve the problems associated with the natural bis-quinine or bis-quinidine compounds, the present invention provides novel chiral bisamino-ether compounds, and method of preparation and use thereof. The novel chiral bisamino-ether compounds can be used for asymmetric fluorocyclization of unsaturated heterocyclic compounds with excellent enantioselectivity for broad industrial applications.
In one aspect, the present invention provides a chiral bisamino-ether compound having the structure of formula (I) :
Figure PCTCN2019000044-appb-000002
wherein:
n = 1 or 2; chiral center *has (R) or (S) configuration; and
Figure PCTCN2019000044-appb-000003
is one of the following moieties:
Figure PCTCN2019000044-appb-000004
R 1 is selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, haloalkyl, C 1-C 8 alkoxyl, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxyl substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, and C 2-C 8 acyloxyl substituted phenyl;
R 2 is selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, haloalkyl, C 1-C 8 alkoxyl, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxyl substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, C 2-C 8 acyloxyl substituted phenyl, naphthyl, pyridyl, quinolyl, isoquinolinyl, furyl, and thienyl;
R 3, R 4, R 5, R 6 and R 7 may be the same or different, and are each independently selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, haloalkyl, C 1-C 8 alkoxyl, C 1-C 8 acyl, C 2-C 8 acyloxyl, C 2-C 8 ester group, (C 1-C 8 acyl) amino, di (C 1-C 8 alkyl) amino, halogen, amino, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxyl substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, C 2-C 8 acyloxyl substituted phenyl, naphthyl, pyridyl, quinolyl, isoquinolinyl, furyl and thienyl.
In the chiral bisamino-ether compound (I) :
the C 1-C 8 alkyl is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isoamyl, neopentyl, sec-pentyl, tert-amyl, cyclopentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, cyclohexyl, n-heptyl, isoheptyl, neoheptyl , n-heptyl, tert-heptyl, cycloheptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert-octyl, or cyclooctyl;
the C 1-C 9 unsaturated alkyl is allyl, 2-methylpropyl, cis-n-butenyl, trans-2-butenyl, 3, 3-dimethylallyl, cis-2-pentenyl, trans-2-pentenyl, propargyl, benzyl, or 1-phenyl-1-propenyl;
the haloalkyl is halogenated alkyl with halogen being fluorine, chlorine, bromine or iodine;
the C 1-C 8 alkoxy is methoxyl, ethoxyl, n-propoxyl, isopropoxyl, cyclopropoxyl, n-butoxyl, iso-butoxyl, sec-butoxyl, tert-butoxyl, cyclobutoxyl, n-pentyloxyl, iso-pentyloxyl, neo-pentyloxyl, sec-pentyloxyl, tert-pentyloxyl, eyclopentyloxyl, n-hexyloxyl, iso-hexyloxyl, neo-hexyloxyl, sec-hexyloxyl, tert-hexyloxyl, cyclohexyloxyl, n-heptyloxyl, iso-heptyloxyl, neo-heptyloxyl,  sec-heptyloxyl, tert-heptyloxyl, cycloheptyloxyl, n-octyloxyl, iso-octyloxyl, neo-octyloxyl, sec-octyloxyl, tert-octyloxyl, or cyclooctyloxyl;
the C 1-C 8 acyl is formyl, acetyl, propionyl, n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, neo-valeryl, sec-valeryl, n-hexanoyl, iso-hexanoyl, neo-hexanoyl , sec-hexanoyl, n-heptanoyl, iso-heptanoyl, neo-heptanoyl, sec-heptanoyl, n-octanoyl, iso-octanoyl, neo-octanoyl, sec-octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylformyl, 1-cyclohexylformyl, or 1-cycloheptylcarbonyl;
the C 2-C 8 acyloxyl is acetoxyl, propionyloxyl, n-butyryloxyl, iso-butyryloxyl, n-pentanoyloxyl, iso-valeryloxyl, sec-pentanoyloxyl, nco-pentanoyloxyl, n-hexanoyloxyl, iso-hexanoyloxyl, sec-hexanoyloxyl, neo-hexanoyloxyl, n-heptanoyloxyl, iso-heptanoyloxyl, sec-heptanoyloxyl, neo-heptanoyloxyl, n-octanoyloxyl, iso-octanoyloxyl, sec-octanoyloxyl, neo-octanoyloxyl, 1-cyclopropylcarbonyloxyl, 1-cyclobutylcarbonyloxyl, 1-cyclopentylcarbonyl, 1-cyclohexylcarbonyloxyl, or 1-cycloheptylcarbonyl;
the C 2-C 8 ester group is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, iso-butoxycarbonyl, n-pentyloxycarbonyl, iso-pentyloxycarbonyl, neo-pentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, iso-hexyloxycarbonyl, sec-hexyloxycarbonyl, neo-hexyloxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, iso-heptyloxycarbonyl, neo-heptyloxycarbonyl, sec-heptyloxycarbonyl, tert-heptyloxycarbonyl, or cycloheptyloxycarbonyl.
The chiral bisamino-ether compound (I) , as described herein, comprises a racemate, dextroisomer and laevoisomer having same chemical formula but different stereo structures and optical rotation properties.
In another aspect, the present invention provides a method of preparation of the chiral bisamino-ether compound, and the method comprises: chiral amino-methanol compound 1 (2 mmol) being reacted with a base (2-4 mmol) in an organic solvent for 5-30 minutes, and then further reacted with halogenated aryl compound 2 (1-2 mmol) at 0-160 ℃ for 2-96 hours to give a chiral bisamino-ether compound (I) with different substituent groups:
Figure PCTCN2019000044-appb-000005
wherein: n = 1 or 2; R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are defined as in formula (I) ; the halogenated aryl compound 2 is selected from the group consisting of:
Figure PCTCN2019000044-appb-000006
In some embodiments, the organic solvent is dimethylformamide, dichloromethane, dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, or any combination thereof.
In some embodiments, the base is sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or any combination thereof.
In yet another aspect, the present invention provides a use of the chiral bisamino-ether compound, wherein the use comprises: using the chiral bisamino-ether compound I in asymmetric fluorocyclization of unsaturated heterocyclic compound 3:
Figure PCTCN2019000044-appb-000007
YH = NHBoc, NHTs, NHCOOBn, NHCOOMe, OH
wherein: R 8 and R 9 may be the same or different, and are each independently selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, halogen, haloalkyl, C 1-C 8 alkoxyl, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxy substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxy substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, C 2-C 8 acyloxy substituted phenyl, or naphthyl; the fluoro reagent is bis (tetrafluoroborate) salt of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane or N-fluorobisbenzenesulfonamide; and the position marked by asterisk (*) is a chiral center.
In particular, in the use, the reaction is carried out by adding the chiral bisamino-ether compound (I) and the substrate 3 into a round bottom flask, adding an additive and a solvent, adding the fluoro reagent, and then stirring the reaction at a specified temperature until the completion of the reaction.
In the use, the reaction conditions include: the solvent is acetone, acetonitrile, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, 1, 2-dichloroethane, chloroform, or a combination thereof; the chiral bisamino-ether compound (I) is in an amount of 10-120 mol%; the substrate 3 is in a concentration of 0.01-10 M; the additive is sodium hydrogencarbonate, potassium hydrogencarbonate, cesium carbonate, sodium carbonate, potassium carbonate, or a  combination thereof; the reaction temperature is -78 to 40℃; the reaction time is 2-96 hours.
In the present invention, a chiral aminomethanol compound 1 is used as a starting material to react with a halogenated aryl compound 2 in the presence of a base to obtain a substituent-containing chiral bisamino-ether compound (I) . The novel chiral bisamino-ether compound (I) can be used for the asymmetric fluorocyclization of the unsaturated heterocyclic compound 3. The compounds of the invention showed some advantageous features, which include: having excellent effects with a wide range of substrates for a series of unsaturated heterocyclic compounds; having high tolerance to functional groups; having high enantioselectivity; and being able to obtain both R and S enantiomeric products with the same ee value. The above features indicate that the novel chiral bisamino-ether compound of the invention is superior over the previous bis-quinine or bis-quinidine compounds and can find broad applications in industry.
DETAILED DESCRIPTION OF EMBODIMENTS
The invention will be further understood through the following examples, which should not be construed as limiting the scope of the invention. It should be understood that all of the techniques implemented based on the above teachings of the present invention are within the scope of the present invention.
It should be noted that the abbreviations used in the examples have the following meanings: Me refers to methyl, Et refers to ethyl, Allyl refers to allyl, Ph refers to phenyl, Mes refers to 2, 4, 6-trimethylphenyl, Bn refers to benzyl, Ts refers to p-toluenesulfonyl, Boc refers to tert-butoxycarbonyl, NMR refers to nuclear magnetic resonance, HRMS refers to high resolution mass spectrometry, chiral HPLC refers to high performance liquid chromatography with a chiral column, ee value refers to enantiomer excess value, Selectfluor refers to 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt, and NFSI refers to N-fluorobis benzene sulfonamide.
Example 1: Preparation of the chiral bisamino-ether compounds
In this example, the compounds obtained by the synthesis described herein are all prepared with the same process, and thus, for the sake of brevity, only the process for preparing the compound Ia is specifically described below, while the process for other subsequently listed compounds is omitted.
1, 4-Bis ( (R) - ( (S) -1-methyl-2-pyrrolyl) (1-naphthyl) methoxy) phthalazine (Ia) :
Figure PCTCN2019000044-appb-000008
The chiral aminomethanol compound (R, S) -1a (482 mg, 2 mmol) was dissolved in dimethylformamide (6 mL) , and then added with 60%sodium hydride (120 mg, 3 mmol) at room temperature for 15 min. Then, halogenated aryl compound 2b (239 mg, 1.2 mmol) was added, and the reaction was run at 50 ℃ in an oil bath for 24 hours. After the reaction being completed, the reaction mixture was concentrated and cooled to room temperature, and added with water (6 mL) , and then was extracted with ethyl acetate (15 mL×3) . The organic phase was combined and dried over anhydrous sodium sulfate, and then filtrated. The filtrate was concentrated via rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 2: 1, v/v) to give a light yellow solid 438 mg; mp 90-91℃; yield 72%. 
Figure PCTCN2019000044-appb-000009
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.45-7.33 (m, 20H) , 3.15-3.10 (m, 2H) , 3.03-2.98 (m, 2H) , 2.51 (s, 6H) , 2.45-2.24 (m, 4H) , 2.02-1.93 (m, 2H) , 1.78-1.58 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.8, 135.6, 133.8, 131.9, 130.6, 128.8, 127.9, 125.9, 125.5, 125.3, 123.5, 123.2, 123.1, 122.9; HRMS (TOF +) calcd. for C 40H 40N 4O 2 [M+H]  + 609.3579, found 609.3577.
1, 4-Bis ( (R) - ( (S) -1-allyl-2-pyrrolyl) (1-naphthyl) methoxy) phthalazine (Ib) :
Figure PCTCN2019000044-appb-000010
449 mg, yield 68%, light yellow solid; mp 94-95 ℃; 
Figure PCTCN2019000044-appb-000011
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 7.93-7.48 (m, 16H) , 6.15-6.02 (m, 2H) , 5.69 (s, broad, 2H) , 5.42-5.25 (m, 4H) , 3.83-3.77 (m, 2H) , 3.29-3.10 (m, 6H) , 2.48-2.39 (m, 2H) , 1.81-1.60 (m, 8H) , 1.19-1.12 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 136.7, 135.6, 133.6, 130.1, 129.0, 127.4, 125.7, 125.6, 125.3, 123.3, 122.6, 117.6, 67.3, 67.1, 57.0, 54.8, 24.4, 23.4; HRMS (TOF +) calcd. for C 44H 44N 4O 2 [M+H]  + 661.3534, found 661.3537.
1, 4-Bis ( (R) - ( (S) -1-methyl-2-pyrrolyl) (4-trifluoromethylphenyl) methoxy) phthalazine (Ic) :
Figure PCTCN2019000044-appb-000012
405 mg, yield 63%, light yellow solid; mp 86-87 ℃; 
Figure PCTCN2019000044-appb-000013
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.32-6.51 (m, 14H) , 3.12-3.06 (m, 2H) , 2.36 (s, 6H) , 2.33-2.26 (m, 2H) , 2.22-2.15 (m, 2H) , 1.88-1.72 (m, 6H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.8, 143.8, 132.1, 129.8, 129.3, 127.0, 125.2 (q, J= 3.8 Hz) , 123.1, 122.8, 76.1, 70.6, 57.5, 41.6, 25.9, 23.5; HRMS (TOF +) calcd. for C 34H 34F 6N 4O 2 [M+H]  + 645.3755, found 645.3764.
1, 4-Bis ( (R) - (2-methoxyphenyl) ( (S) -1-methyl-2-pyrrolyl) methoxy) phthalazine (Id) :
Figure PCTCN2019000044-appb-000014
364 mg, yield 64%, light yellow solid; mp 82-83℃; 
Figure PCTCN2019000044-appb-000015
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.39-6.72 (m, 14H) , 3.90 (s, 6H) , 3.15-3.12 (m, 2H) , 3.35-3.33 (m, 2H) , 2.26 (s, 6H) , 1.88-1.63 (m, 8H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.9, 156.6, 131.6, 128.6, 128.2, 127.2, 123.2, 122.8, 120.4, 110.7, 74.9, 68.4, 58.6, 55.6, 43.6, 28.3, 24.1; HRMS (TOF +) calcd. for C 34H 40N 4O 4 [M+H]  + 569.6761, found 569.6759.
4, 6-Bis ( (R) - ( (S) -1-methyl-2-pyrrolyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Ie) :
Figure PCTCN2019000044-appb-000016
426 mg, yield 60%, light yellow solid; mp 137-138℃; 
Figure PCTCN2019000044-appb-000017
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.33-7.07 (m, 26H) , 3.11-3.06 (m, 2H) , 2.94-2.91 (m, 2H) , 2.40 (s, 6H) , 2.33-2.24 (m, 2H) , 2.16-2.08 (m, 2H) , 1.76-1.59 (m, 6H) , ;  13C NMR (CDCl 3, 75 MHz) : δ 166.8, 160.6, 137.3, 136.2, 133.7, 131.8, 131.2, 130.7, 129.9, 129.0, 128.9, 128.0, 127.9, 127.6, 127.3, 126.0, 125.4, 124.1, 123.2, 104.7, 74.1, 69.3, 57.7, 41.5, 26.0, 23.1; HRMS (TOF +) calcd. for C 48H 46N 4O 2 [M+H]  + 711.4181, found 711.4183.
4, 6-Bis ( (R) - ( (S) -1-allyl-2-pyrrolyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (If) :
Figure PCTCN2019000044-appb-000018
465.4 mg, yield 61%, light yellow solid; mp 149-150℃; 
Figure PCTCN2019000044-appb-000019
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.39-7.09 (m, 26H) , 5.73-5.60 (m, 2H) , 5.05-4.95 (m 4H) , 3.25-3.19 (m, 4H) , 3.08-3.04 (m, 2H) , 2.95-2.88 (m, 2H) , 2.40-2.32 (m, 2H) , 2.11-2.04 (m, 2H) , 1.75-1.59 (m, 6H) ;  13C NMR (CDCl 3, 75 MHz) : δ 159.8, 153.5, 130.2, 129.3, 126.6, 124.0, 123.9, 122.9, 121.7, 120.9, 120.7, 120.6, 120.2, 118.6, 118.3, 118.2, 117.4, 116.8, 109.2, 97.5, 68.7, 59.7, 50.8, 47.5, 19.7, 16.3; HRMS (TOF +) calcd. for C 52H 50N 4O 2 [M+H]  + 763.4007, found 763.4039.
1, 4-Bis ( (R) - ( (S) -1-methyl-2-piperidinyl) (1-naphthyl) methoxy) phthalazine (Ig) :
Figure PCTCN2019000044-appb-000020
509 mg, yield 80%, light yellow solid; mp 91-92℃; 
Figure PCTCN2019000044-appb-000021
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.53-7.28 (m, 20H) , 3.01-2.88 (m, 3H) , 2.66 (s, 6H) , 2.57-2.53 (m, 2H) , 2.19-2.12 (m, 2H) , 2.05-1.95 (m, 1H) , 1.78-1.54 (m, 6H) , 1.10-0.97 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.7, 134.9, 133.9, 132.0, 128.9, 127.9, 125.9, 125.5, 125.0, 123.8, 123.6, 123.5, 123.1, 71.7, 62.3, 58.2, 43.7, 25.8, 24.7, 24.5; HRMS (TOF +) calcd. for C 42H 44N 4O 2 [M+H]  + 637.5579, found 637.5590.
1, 4-Bis ( (R) - ( (S) -1-allyl-2-piperidyl) (1-naphthyl) methoxy) phthalazine (Ih) :
Figure PCTCN2019000044-appb-000022
530.4 mg, yield 77%, light yellow solid; mp 96-97℃; 
Figure PCTCN2019000044-appb-000023
 (c 1.0, CHCl 3) ;  1H NMR  (CDCl 3, 300 MHz) : δ 8.53-7.36 (m, 20H) , 5.80-5.67 (m, 2H) , 5.12-4.92 (m 4H) , 3.92-3.86 (m, 2H), 3.26-2.94 (m, 6H) , 2.26-2.20 (m, 2H) , 2.05-1.97 (m, 2H) , 1.82-1.78 (m, 2H) , 1.66-1.49 (m, 6H), 1.22-1.05 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.7, 135.4, 133.9, 131.9, 130.6, 128.8, 127.9, 125.9, 125.5, 125.0, 124.1, 124.0, 123.5, 123.1, 117.6, 72.4, 64.0, 56.9, 52.3, 25.2, 24.9, 24.2; HRMS (TOF +) calcd. for C 46H 48N 4O 2 [M+H]  + 689.6225, found 689.6237.
3, 6-Bis ( (R) - ( (S) -1-methyl-2-piperidinyl) (1-naphthyl) methoxy) pyridazine (Ii) :
Figure PCTCN2019000044-appb-000024
433.9 mg, yield 74%, light yellow solid; mp 85-86℃; 
Figure PCTCN2019000044-appb-000025
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.12-7.28 (m, 20H) , 3.73-3.65 (m, 1H) , 3.17-3.13 (m, 2H) , 2.75 (s, 6H) , 2.61-2.58 (m, 2H) , 2.32-2.24 (m, 2H) , 1.94-1.86 (m, 2H) , 1.77-1.47 (m, 8H) , 1.10-0.98 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 163.6, 151.2, 133.9, 133.2, 130.8, 130.3, 129.1, 128.4, 126.5, 124.9, 124.1, 122.8, 121.2, 72.8, 66.8, 53.1, 43.1, 25.3, 24.4, 24.1; HRMS (TOF +) calcd. for C 38H 42N 4O 2 [M+H]  + 587.7352, found 587.7361.
4, 6-Bis ( (R) - ( (S) -1-methyl-2-piperidyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Ij) :
Figure PCTCN2019000044-appb-000026
450 mg, yield 61%, light yellow solid; mp 150-151℃; 
Figure PCTCN2019000044-appb-000027
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.32-7.02 (m, 27H) , 3.05-3.01 (m, 2H) , 2.64-2.61 (m, 2H) , 2.39-2.27 (m, 2H), 1.78-1.47 (m, 10H) , 1.11-0.96 (m, 2H) , ;  13C NMR (CDCl 3, 75 MHz) : δ 176.1, 166.6, 160.6, 136.9, 135.0, 133.7, 131.4, 130.3, 130.1, 129.1, 127.9, 127.8, 127.6, 126.3, 125.5, 125.1, 124.6, 122.9, 104.9, 72.7, 66.0, 56.9, 24.6, 23.7, 23.3, 22.6; HRMS (TOF +) calcd. for C 50H 50N 4O 2 [M+H]  + 739.4007, found 739.3988.
2-Methyl-4, 6-bis ( (R) - ( (S) -1-methyl-2-piperidinyl) (1-naphthyl) methoxy) pyrimidine (Ik) :
Figure PCTCN2019000044-appb-000028
456 mg, yield 76%, light yellow solid; mp 85-86℃; 
Figure PCTCN2019000044-appb-000029
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.12-7.38 (m, 16H) , 6.32 (s, 1H) , 3.04-2.97 (m, 2H) , 2.67 (s, 6H) , 2.22-2.12 (m, 2H) , 2.04 (s, 3H) , 1.90-1.52 (m, 7H) , 1.40-1.36 (m, 2H) , 1.01-0.92 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 170.3, 166.9, 134.7, 133.7, 130.2, 129.0, 127.8, 126.1, 125.4, 126.3, 124.7, 123.0, 90.6, 71.4, 66.7, 58.2, 43.2, 25.8, 24.6, 24.3; HRMS (TOF +) calcd. for C 39H 44N 4O 2 [M+H]  + 601.3537, found 601.3530.
1, 4-Bis ( (R) - (1-naphthyl) ( (S) -1-propyl-2-piperidyl) methoxy) phthalazine (II) :
Figure PCTCN2019000044-appb-000030
505 mg, yield 73%, light yellow solid; mp 100-101℃; 
Figure PCTCN2019000044-appb-000031
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.50-7.33 (m, 20H) , 3.19-3.07 (m, 4H) , 2.90-2.87 (m, 2H) , 2.47-2.38 (m, 2H), 2.18-1.94 (m, 4H) , 1.81-1.75 (m, 2H) , 1.64-1.50 (m, 6H) , 1.42-1.08 (m, 4H) , 0.52 (t, J= 9.0 Hz, 6H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.6, 135.6, 133.9, 131.9, 130.6, 128.8, 127.7, 125.8, 125.4, 125.0, 124.1, 124.0, 123.0, 72.6, 64.4, 55.3, 52.5, 25.1, 24.8, 24.1, 20.0, 11.6; HRMS (TOF +) calcd. for C 46H 52N 4O 2 [M+H]  + 693.6384, found 693.6391.
4, 6-Bis ( (R) - ( (S) -1-allyl-2-piperidyl) (1-naphthyl) methoxy) -2-methylpyrimidine (Im) :
Figure PCTCN2019000044-appb-000032
515 mg, yield 79%, light yellow solid; mp 97-98℃; 
Figure PCTCN2019000044-appb-000033
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.23-7.43 (m, 16H) , 6.20-6.06 (m, 2H) , 5.44-5.30 (m 4H) , 3.81-3.75 (m,  2H), 3.50-3.42 (m, 2H) , 3.14-3.10 (m, 2H) , 2.83-2.79 (m, 2H) , 2.41-2.33 (m, 2H) , 2.15 (s, 3H) , 1.92-1.61 (m, 8H) , 1.39-1.32 (m, 3H) , 1.10-0.89 (m, 3H) ;  13C NMR (CDCl 3, 75 MHz) : δ 170.4, 167.0, 135.2, 133.7, 130.5, 128.9, 127.8, 125.9, 125.4, 125.3, 125.0, 123.5, 118.2, 90.8, 71.8, 63.0, 57.1, 53.4, 25.9, 25.6, 25.3, 24.3; HRMS (TOF +) calcd. for C 43H 48N 4O 2 [M+H]  + 653.4977, found 653.4980.
3, 6-Bis ( (R) - ( (S) -1-allyl-2-piperidyl) (1-naphthyl) methoxy) pyridazine (In) :
Figure PCTCN2019000044-appb-000034
440 mg, yield 69%, brown oil; 
Figure PCTCN2019000044-appb-000035
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.21-7.23 (m, 16H) , 6.15-6.02 (m, 2H) , 5.46-5.31 (m 4H) , 3.86-3.79 (m, 2H) , 3.48-3.41 (m, 2H) , 3.16-3.12 (m, 2H) , 2.89-2.85 (m, 2H) , 2.41-2.32 (m, 2H) , 21.90-1.61 (m, 9H) , 1.48-1.43 (m, 3H) , 1.13-1.00 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 163.7, 151.1, 133.8, 130.7, 130.6, 131.0, 129.0, 128.2, 126.2, 125.7, 124.9, 124.3, 123.3, 121.1, 73.4, 63.1, 57.2, 53.5, 25.4, 25.1, 24.1; HRMS (TOF +) calcd. for C 42H 46N 4O 2 [M+H]  + 639.5690, found 639.5692.
1, 4-Bis ( (S) - ( (S) -1-methyl-2-pyrrolyl) (phenyl) methoxy) phthalazine (Io) :
Figure PCTCN2019000044-appb-000036
396 mg, yield 78%, light yellow solid; mp 81-82℃; 
Figure PCTCN2019000044-appb-000037
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.29-6.37 (m, 16H) , 3.12-3.02 (m, 4H) , 2.52 (s, 6H) , 2.40-2.32 (m, 2H) , 1.71-1.64 (m, 8H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.5, 139.5, 131.7, 127.9, 127.6, 123.0, 122.8, 80.0, 69.2, 58.1, 43.1, 28.3, 23.4; HRMS (TOF +) calcd. for C 32H 36N 4O 2 [M+H]  + 509.4573, found 509.4576.
1, 4-Bis ( (S) - ( (S) -1-methyl-2-pyrrolyl) (1-naphthyl) methoxy) phthalazine (Ip) :
Figure PCTCN2019000044-appb-000038
389 mg, yield 64%, light yellow solid; mp 89-90℃; 
Figure PCTCN2019000044-appb-000039
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.54-6.99 (m, 20H) , 3.35-3.28 (m, 2H) , 3.13-3.08 (m, 2H) , 2.36-2.30 (m, 6H), 2.27 (s, 6H) , 1.86-1.69 (m, 2H) , 1.64-1.60 (m, 6H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.7, 135.9, 133.9, 131.7, 131.3, 128.7, 128.1, 125.8, 125.6, 125.3, 125.2, 124.7, 123.1, 122.8, 79.1, 69.0, 58.5, 43.6, 29.2, 23.9; HRMS (TOF +) calcd. for C 40H 40N 4O 2 [M+H]  + 609.3579, found 609.3576.
1, 4-Bis ( (S) - ( (S) -1-allyl-2-pyrrolyl) (1-naphthyl) methoxy) phthalazine (Iq) :
Figure PCTCN2019000044-appb-000040
437 mg, yield 66%, light yellow solid; mp. 93-94℃; 
Figure PCTCN2019000044-appb-000041
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.47-7.28 (m, 16H) , 5.81-5.68 (m, 2H) , 4.99-4.93 (m, 4H) , 3.77-3.62 (m, 2H), 3.1-3.24 (m, 4H) , 3.01-2.95 (m, 2H) , 2.57-2.45 (m, 2H) , 1.82-1.64 (m, 10H) , 1.30-1.26 (m, 2H);  13C NMR (CDCl 3, 75 MHz) : δ 156.9, 133.7, 131.9, 131.0, 128.6, 128.2, 125.8, 125.3, 125.2, 124.4, 123.2, 122.8, 66.7, 59.1, 54.5, 29.7, 28.9, 24.2; HRMS (TOF +) calcd. for C 44H 44N 4O 2 [M+H]  + 661.3534, found 661.3532.
1, 4-Bis ( (S) - ( (S) -1-methyl-2-pyrrolyl) (4-trifluoromethylphenyl) methoxy) phthalazine (Ir) :
Figure PCTCN2019000044-appb-000042
418.6 mg, yield 65%, light yellow solid; mp 88-89℃; 
Figure PCTCN2019000044-appb-000043
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.31-6.39 (m, 14H) , 3.09-3.00 (m, 4H) , 2.51 (s, 6H) , 2.37-2.29 (m, 2H) , 1.77-1.49 (m, 8H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.5, 143.3, 132.1, 130.2, 129.8, 129.3, 128.9, 127.8, 124.8, 122.9, 122.6, 124.8 (q, J= 3.8 Hz) , 122.9, 122.6, 79.3, 68.9, 57.9, 42.9, 27.9, 23.6;  HRMS (TOF +) calcd. for C 34H 34F 6N 4O 2 [M+H]  + 645.3755, found 645.3761.
4, 6-bis ( (S) - ( (S) -1-methyl-2-pyrrolyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Is) :
Figure PCTCN2019000044-appb-000044
433 mg, yield 61%, light yellow solid; mp 136-137℃; 
Figure PCTCN2019000044-appb-000045
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.50-6.76 (m, 26H) , 3.22-3.08 (m, 2H) , 2.38-2.30 (m, 2H) , 2.26 (s, 6H) , 1.86-1.77 (m, 2H) , 1.65-1.53 (m, 4H) , 1.43-1.38 (m, 2H) ;  13C NMR (CDCl 3, 75 MHz) : δ 167.0, 162.7, 159.3, 136.1, 133.9, 132.5, 131.3, 131.0, 130.2, 129.0, 128.7, 128.5, 128.4, 128.3, 128.1, 126.2, 125.3, 124.5, 118.9, 81.6, 69.5, 58.4, 43.2, 28.6, 23.5; HRMS (TOF +) calcd. for C 48H 46N 4O 2 [M+H]  + 711.4181, found 711.4186.
4, 6-bis ( (S) - ( (S) -1-allyl-2-pyrrolyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (It) :
Figure PCTCN2019000044-appb-000046
480 mg, yield 63%, light yellow solid; mp 147-148℃; 
Figure PCTCN2019000044-appb-000047
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.58-6.71 (m, 26H) , 5.84-5.70 (m, 2H) , 5.04-4.96 (m 4H) , 3.44-3.33 (m, 4H) , 3.11-3.06 (m, 2H) , 2.93-2.86 (m, 2H) , 2.44-2.36 (m, 2H) , 1.79-1.69 (m, 2H) , 1.60-1.40 (m, 6H) ;  13C NMR (CDCl 3, 75 MHz) : δ 166.8, 161.2, 137.6, 137.1, 136.2, 133.9, 132.4, 131.6, 131.0, 129.0, 128.3, 128.0, 127.6, 125.8, 125.3, 124.9, 116.4, 104.6, 80.5, 66.8, 59.1, 54.5, 28.5, 24.0; HRMS (TOF +) calcd. for C 52H 50N 4O 2 [M+H]  + 763.4007, found 763.4038.
1, 4-Bis ( (S) - ( (S) -1-methyl-2-piperidinyl) (1-naphthyl) methoxy) phthalazine (Iu) :
Figure PCTCN2019000044-appb-000048
477 mg, yield 75%, light yellow solid; mp. 93-94℃; 
Figure PCTCN2019000044-appb-000049
 (c 1.0, CHCl 3) ;  1H NMR  (CDCl 3, 300 MHz) : δ 8.66-7.11 (m, 20H) , 3.41-3.35 (m, 2H) , 2.95-2.91 (m, 2H) , 2.43 (s, 6H) , 2.49-2.39 (m, 2H) , 1.56-1.51 (m, 6H) , 1.18-1.03 (m, 6H) ;  13C NMR (CDCl 3, 75 MHz) : δ 156.1, 135.7, 134.0, 131.8, 131.6, 128.7, 128.4, 127.1, 125.9, 125.4, 125.3, 123.1, 122.8, 78.4, 66.3, 55.6, 42.9, 27.3, 24.2, 23.5; HRMS (TOF +) calcd. for C 42H 44N 4O 2 [M+H]  + 637.5579, found 637.5584.
4, 6-Bis ( (S) - ( (S) -1-methyl-2-piperidyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Iv) :
Figure PCTCN2019000044-appb-000050
472 mg, yield 64%, light yellow solid; mp 150-151℃; 
Figure PCTCN2019000044-appb-000051
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.40-7.10 (m, 26H) , 3.67-3.56 (m, 1H) , 3.06-2.88 (m, 3H) , 3.00 (s, 3H), 2.94 (s, 3H) , 2.42-2.30 (m, 2H) , 1.67-1.48 (m, 5H) , 1.28-0.86 (m, 5H) ;  13C NMR (CDCl 3, 75 MHz) : δ 165.5, 164.3, 162.7, 154.7, 133.7, 132.4, 132.0, 131.3, 131.0, 130.8, 130.4, 128.9, 128.8, 128.5, 128.1, 128.0, 127.9, 127.6, 127.3, 126.2, 125.7, 125.3, 124.9, 105.9, 67.4, 56.9, 43.9, 36.5, 31.5, 27.8, 24.5, 23.6; HRMS (TOF +) calcd. for C 50H 50N 4O 2 [M+H]  + 739.4007, found 739.4005.
1, 4-Bis ( (S) - ( (S) -1-methyl-2-piperidyl) (1-naphthyl) methoxy) -9, 10-nonanedione (Iw) :
Figure PCTCN2019000044-appb-000052
407 mg, yield 57%, brown solid; mp 149-148℃; 
Figure PCTCN2019000044-appb-000053
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 300 MHz) : δ 8.66-6.80 (m, 22H) , 3.63-3.55 (m, 2H) , 3.29-3.25 (m, 1H) , 2.80-2.70 (m, 2H), 2.06 (s, 6H) , 1.92-1.37 (m, 8H) , 1.21-0.95 (m, 3H) ;  13C NMR (CDCl 3, 75 MHz) : δ 182.6, 182.1, 176.8, 155.8, 138.5, 134.2, 134.0, 133.9, 133.6, 133.0, 131.5, 131.4, 129.6, 129.1, 127.3, 126.8, 126.4, 126.3, 125.5, 123.9, 123.8, 120.7, 69.2, 57.6, 43.8, 27.5, 23.9, 23.4, 22.9; HRMS (TOF +) calcd. for C 48H 46N 2O 4 [M+H]  + 715.5179, found 715.5172.
1, 4-Bis ( (R) - ( (R) -1-allyl-2-piperidyl) (1-naphthyl) methoxy) phthalazine (Ix) :
Figure PCTCN2019000044-appb-000054
523.6 mg, yield 76%, light yellow solid; mp 97-98℃; 
Figure PCTCN2019000044-appb-000055
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 400 MHz) : δ 8.53-7.32 (m, 20H) , 6.09-5.99 (m, 2H) , 5.42-5.25 (m 4H) , 3.98-3.93 (m, 2H), 3.53-3.50 (m, 2H) , 3.20-3.04 (m, 4H) , 2.41-2.35 (m, 2H) , 2.13-2.05 (m, 2H) , 1.86-1.82 (m, 2H), 1.64-1.59 (m, 4H) , 1.21-1.12 (m, 3H) , 0.91-0.87 (m, 3H) ;  13C NMR (CDCl 3, 100 MHz) : δ 157.8, 156.5, 133.9, 131.9, 131.8, 130.7, 128.8, 128.0, 126.0, 125.5, 125.0, 124.1, 123.8, 123.5, 123.2, 122.8, 122.6, 72.2, 63.7, 62.8, 56.9, 53.0, 24.9, 24.1; HRMS (TOF +) calcd. for C 46H 48N 4O 2 [M+H]  + 689.6225, found 689.6231.
1, 4-Bis ( (S) - ( (R) -1-allyl-2-piperidyl) (1-naphthyl) methoxy) phthalazine (Iy) :
Figure PCTCN2019000044-appb-000056
523.6 mg, yield 76%, light yellow solid; mp 96-97℃; 
Figure PCTCN2019000044-appb-000057
 (c 1.0, CHCl 3) ;  1H NMR (CDCl 3, 400 MHz) : δ 8.53-7.32 (m, 20H) , 6.09-5.99 (m, 2H) , 5.42-5.25 (m 4H) , 3.98-3.93 (m, 2H), 3.53-3.50 (m, 2H) , 3.20-3.04 (m, 4H) , 2.41-2.35 (m, 2H) , 2.13-2.05 (m, 2H) , 1.86-1.82 (m, 2H), 1.64-1.59 (m, 4H) , 1.21-1.12 (m, 3H) , 0.91-0.87 (m, 3H) ;  13C NMR (CDCl 3, 100 MHz) : δ 157.8, 156.5, 133.9, 131.9, 131.8, 130.7, 128.8, 128.0, 126.0, 125.5, 125.0, 124.1, 123.8, 123.5, 123.2, 122.8, 122.6, 72.2, 63.7, 62.8, 56.9, 53.0, 24.9, 24.1; HRMS (TOF +) calcd. for C 46H 48N 4O 2 [M+H]  + 689.6225, found 689.6231.
Example 2: Different Chiral Bisamino-ether Compounds Used for Asymmetric Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000058
In a 10 mL round-bottom flask were added 3a (27.6 mg, 0.1 mmol) , sodium bicarbonate (NaHCO 3, 10.1 mg, 0.12 mmol) , chiral bisamino-ether compound I (0.12 mmol) and 2.5 mL of  acetone, and the mixture was stirred at -78 ℃ for 15 minutes. Then, a bis (tetrafluoroborate) salt of 1-4-fluoro-1, 4-diazabicyclo [2.2.2] octane (Selectfluor, 42.5 mg, 0.12 mmol) was added. After the reaction being completed, the reaction mixture was concentrated by rotary evaporation at room temperature, and then water (1 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3) , and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 6: 1, v/v) to give 4a. The ee value was analyzed by chiral HPLC, and the experimental results are shown in Table 1.
Table 1: Different Chiral Bisamino-ether Compounds Used for Asymmetric Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000059
Example 3: Different Solvents Used for Asymmetric Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000060
In a 10 mL round-bottom flask were added 3a (27.6 mg, 0.1 mmol) , NaHCO 3 (10.1 mg, 0.12 mmol) , chiral bisamino-ether compound Ih (82.6 mg, 0.12 mmol) and a solvent (2.5 mL) , and the mixture was stirred at -78 ℃ for 15 minutes. Then, Selectfluor (42.5 mg, 0.12 mmol) was added. After the reaction being completed, the reaction mixture was concentrated by rotary evaporation at room temperature, and then water (1 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3) , and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 6: 1, v/v) to give 4a. The ee value was analyzed by chiral HPLC, and the experimental results are shown in Table 2.
Table 2: Different Solvents for Asymmetric Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000061
Example 4: Different Additives for Asymmetric Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000062
In a 10 mL round-bottom flask were added 3a (27.6 mg, 0.1 mmol) , an additive (0.12 mmol) , chiral bisamino-ether compound Ih (82.6 mg, 0.12 mmol) , and acetone (2.5 mL) , and the mixture was stirred at -78 ℃ for 15 minutes. Then, Selectfluor (42.5 mg, 0.12 mmol) was added. After the reaction being completed, the reaction mixture was concentrated by rotary evaporation room temperature, and then water (1 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3) , and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 6: 1, v/v) to give 4a. The ee value was analyzed by chiral HPLC, and the experimental results are shown in Table 3.
Table 3: Different Additives for Asymmetric Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000063
Example 5: Different Temperatures for Asymmetric fluorocyclization of 3a
Figure PCTCN2019000044-appb-000064
In a 10 mL round-bottom flask were added 3a (27.6 mg, 0.1 mmol) , NaHCO 3 (10.1 mg, 0.12 mmol) , chiral bisamino-ether compound Ih (82.6 mg, 0.12 mmol) , and acetone (2.5 mL) , and the mixture was stirred at different temperatures for 15 minutes. Then, Selectfluor (42.5 mg, 0.12 mmol) was added. After the reaction being completed, the reaction mixture was concentrated by rotary evaporation at room temperature, and then water (1 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3) , and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 6: 1, v/v) to give 4a. The ee value was analyzed by chiral HPLC, and the experimental results are shown in Table 4:
Table 4: Different Temperatures for Asymmetric Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000065
Example 6: Chiral Bisamino-ether Compound Ih for Catalytic Enantioselective Fluorocyclization of 3a
Figure PCTCN2019000044-appb-000066
Ina 10 mL round-bottom flask were added 3a (27.6 mg, 0.1 mmol) , K 2CO 3 (20.7 mg, 0.15 mmol) , chiral bisamino-ether compound Ih (13.8 mg, 0.02 mmol) and acetone (1 mL) , and the mixture was stirred at -78 ℃ for 15 minutes. Then, N-fluorobisbenzenesulfonamide (NFSI, 37.8 mg, 0.12 mmol) was added and reacted for 72 hours. The reaction mixture was concentrated by rotary evaporation at room temperature, and then water (1 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3) , and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 6: 1, v/v) to give 25.1 mg of 4a, with yield of 86%and ee value of 89%as analyzed with chiral HPLC.
Example 7: Asymmetric Fluorocyclization of the Substrate 3a-s
In a 10 mL round-bottom flask were added 3 (0.1 mmol) , sodium bicarbonate (NaHCO 3, 10.1 mg, 0.12 mmol) , chiral bisamino-ether compound Ih (82.6 mg, 0.12 mmol) and acetone (2.5 mL) , and the mixture was stirred at -78 ℃ for 15 minutes. Then a bis (tetrafluoroborate) salt of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane (Selectfluor, 42.5 mg, 0.12 mmol) was added. After the reaction being completed, the reaction mixture was concentrated by rotary evaporation at room temperature, and then water (1 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3) , and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 6: 1, v/v) to give 4. The ee value was analyzed by chiral HPLC, and the experimental results are shown in Table 7.
Example 8: Asymmetric fluorocyclization of the Substrate 3aa-an
In a 10 mL round-bottom flask were added 3 (0.1 mmol) , sodium bicarbonate (NaHCO 3, 10.1 mg, 0.12 mmol) , chiral bisamino-ether compound Ig (76.3 mg, 0.12 mmol) and acetone (2.5 mL) , and the mixture was stirred at -78 ℃ for 15 minutes. Then a bis (tetrafluoroborate) salt of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane (Selectfluor, 42.5 mg, 0.12 mmol) was added. After the reaction being completed, the reaction mixture was concentrated by rotary evaporation at room temperature, and then water (1 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3) , and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated by rotary evaporation to remove solvent. The residue was separated with silica gel column chromatography (petroleum ether/ethyl acetate = 6: 1, v/v) to give 4. The ee value was analyzed by chiral HPLC, and the experimental results are shown in Table 7.
Table 7: Results of Asymmetric Fluorocyclization for Substrate 3
Figure PCTCN2019000044-appb-000067
Figure PCTCN2019000044-appb-000068
Figure PCTCN2019000044-appb-000069
Figure PCTCN2019000044-appb-000070
Although particular embodiments and examples have been herein described in detail, the above description has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the invention. In particular, it is contemplated by the inventor that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as claimed.

Claims (10)

  1. A chiral bisamino-ether compound, having a structure of formula (I) :
    Figure PCTCN2019000044-appb-100001
    wherein:
    n = 1 or 2; chiral center *has (R) or (S) configuration; and
    Figure PCTCN2019000044-appb-100002
    is one of the following moieties:
    Figure PCTCN2019000044-appb-100003
    R 1 is selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, haloalkyl, C 1-C 8 alkoxyl, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxyl substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, and C 2-C 8 acyloxyl substituted phenyl;
    R 2 is selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, haloalkyl, C 1-C 8 alkoxyl, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxyl substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, C 2-C 8 acyloxyl substituted phenyl, naphthyl, pyridyl, quinolyl, isoquinolinyl, furyl, and thienyl;
    R 3, R 4, R 5, R 6 and R 7 may be the same or different, and are each independently selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, haloalkyl, C 1-C 8 alkoxyl, C 1-C 8 acyl, C 2-C 8 acyloxyl, C 2-C 8 ester group, (C 1-C 8 acyl) amino, di (C 1-C 8 alkyl) amino, halogen, amino, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxyl substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxyl substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, C 2-C 8 acyloxyl substituted phenyl, naphthyl, pyridyl, quinolyl, isoquinolinyl, furyl and thienyl.
  2. The chiral bisamino-ether compound of claim 1, wherein:
    the C 1-C 8 alkyl is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isoamyl, neopentyl, sec-pentyl, tert-amyl, cyclopentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, cyclohexyl, n-heptyl, isoheptyl, neoheptyl , n-heptyl, tert-heptyl, cycloheptyl, n-octyl, isooctyl, neooctyl, sec-octyl, tert-octyl, or cyclooctyl;
    the C 1-C 9 unsaturated alkyl is allyl, 2-methylpropyl, cis-n-butenyl, trans-2-butenyl, 3, 3-dimethylallyl, cis-2-pentenyl, trans-2-pentenyl, propargyl, benzyl, or  1-phenyl-l-propenyl;
    the haloalkyl is halogenated alkyl with halogen being fluorine, chlorine, bromine or iodine;
    the C 1-C 8 alkoxy is methoxyl, ethoxyl, n-propoxyl, isopropoxyl, cyclopropoxyl, n-butoxyl, iso-butoxyl, sec-butoxyl, tert-butoxyl, cyclobutoxyl, n-pentyloxyl, iso-pentyloxyl, neo-pentyloxyl, sec-pentyloxyl, tert-pentyloxyl, cyclopentyloxyl, n-hexyloxyl, iso-hexyloxyl, neo-hexyloxyl, sec-hexyloxyl, tert-hexyloxyl, cyclohexyloxyl, n-heptyloxyl, iso-heptyloxyl, neo-heptyloxyl, sec-heptyloxyl, tert-heptyloxyl, cycloheptyloxyl, n-octyloxyl, iso-octyloxyl, neo-octyloxyl, sec-octyloxyl, tert-octyloxyl, or cyclooctyloxyl;
    the C 1-C 8 acyl is formyl, acetyl, propionyl, n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, neo-valeryl, sec-valeryl, n-hexanoyl, iso-hexanoyl, neo-hexanoyl , sec-hexanoyl, n-heptanoyl, iso-heptanoyl, neo-heptanoyl, sec-heptanoyl, n-octanoyl, iso-octanoyl, neo-octanoyl, sec-octanoyl, 1-cyclopropylformyl, 1-cyclobutylformyl, 1-cyclopentylformyl, 1-cyclohexylformyl, or 1-cycloheptylcarbonyl;
    the C 2-C 8 acyloxyl is acetoxyl, propionyloxyl, n-butyryloxyl, iso-butyryloxyl, n-pentanoyloxyl, iso-valeryloxyl, sec-pentanoyloxyl, neo-pentanoyloxyl, n-hexanoyloxyl, iso-hexanoyloxyl, sec-hexanoyloxyl, neo-hexanoyloxyl, n-heptanoyloxyl, iso-heptanoyloxyl, sec-heptanoyloxyl, neo-heptanoyloxyl, n-octanoyloxyl, iso-octanoyloxyl, sec-octanoyloxyl, neo-octanoyloxyl, 1-cyclopropylcarbonyloxyl, 1-cyclobutylcarbonyloxyl, 1-cyclopentylcarbonyl, 1-cyclohexylcarbonyloxyl, or 1-cycloheptylcarbonyl;
    the C 2-C 8 ester group is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, iso-butoxycarbonyl, n-pentyloxycarbonyl, iso-pentyloxycarbonyl, neo-pentyloxycarbonyl, sec-pentyloxycarbonyl, tert-pentyloxycarbonyl, cyclopentyloxycarbonyl, n-hexyloxycarbonyl, iso-hexyloxycarbonyl, sec-hexyloxycarbonyl, neo-hexyloxycarbonyl, tert-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, iso-heptyloxycarbonyl, neo-heptyloxycarbonyl, sec-heptyloxycarbonyl, tert-heptyloxycarbonyl, or cycloheptyloxycarbonyl.
  3. The chiral bisamino-ether compound of claim 1, comprising a racemate, dextroisomer and laevoisomer having same chemical formula but different stereo structures and optical rotation properties.
  4. The chiral bisamino-ether compound of claim 1, the compound being selected form the group consisting of:
    1, 4-Bis ( (R) - ( (S) -1-methyl-2-pyrrolyl) (1 -naphthyl) methoxy) phthalazine (Ia) ;
    1, 4-Bis ( (R) - ( (S) -1 -allyl-2-pyrrolyl) (1 -naphthyl) methoxy) phthalazine (Ib) ;
    1, 4-Bis ( (R) - ( (S) -1 -methyl-2-pyrrolyl) (4-trifluoromethylphenyl) methoxy) phthalazine (Ic) ;
    1, 4-Bis ( (R) - (2-methoxyphenyl) ( (S) -1-methyl-2-pyrrolyl) methoxy) phthalazine (Id) ;
    4, 6-Bis ( (R) - ( (S) -1-methyl-2-pyrrolyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Ie) ;
    4, 6-Bis ( (R) - ( (S) -1 -allyl-2-pyrrolyl) (1 -naphthyl) methoxy) -2, 5-diphenylpyrimidine (If) ;
    1, 4-Bis ( (R) - ( (S) -1 -methyl-2-piperidinyl) (1-naphthyl) methoxy) phthalazine (Ig) ;
    1, 4-Bis ( (R) - ( (S) -1 -allyl-2-piperidyl) (1-naphthyl) methoxy) phthalazine (Ih) ;
    3, 6-Bis ( (R) - ( (S) -1 -methyl-2-piperidinyl) (1-naphthyl) methoxy) pyridazine (Ii) ;
    4, 6-Bis ( (R) - ( (S) -1-methyl-2-piperidyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Ij) ;
    2-Methyl-4, 6-bis ( (R) - ( (S) -1-methyl-2-piperidinyl) (1-naphthyl) methoxy) pyrimidine (Ik) ;
    1, 4-Bis ( (R) - (1-naphthyl) ( (S) -1-propyl-2-piperidyl) methoxy) phthalazine (Il) ;
    4, 6-Bis ( (R) - ( (S) -1 -allyl-2-piperidyl) (1-naphthyl) methoxy) -2-methylpyrimidine (Im) ;
    3, 6-Bis ( (R) - ( (S) -1-allyl-2-piperidyl) (1-naphthyl) methoxy) pyridazine (In) ;
    1, 4-Bis ( (S) - ( (S) -1-methyl-2-pyrrolyl) (phenyl) methoxy) phthalazine (Io) ;
    1, 4-Bis ( (S) - ( (S) -1 -methyl-2-pyrrolyl) (1 -naphthyl) methoxy) phthalazine (Ip) ;
    1, 4-Bis ( (S) - ( (S) -1 -allyl-2-pyrrolyl) (1-naphthyl) methoxy) phthalazine (Iq) ;
    1, 4-Bis ( (S) - ( (S) -1-methyl-2-pyrrolyl) (4-trifluoromethylphenyl) methoxy) phthalazine (Ir) ;
    4, 6-bis ( (S) - ( (S) -1-methyl-2-pyrrolyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Is) ;
    4, 6-bis ( (S) - ( (S) -1-allyl-2-pyrrolyl) (1 -naphthyl) methoxy) -2, 5-diphenylpyrimidine (It) ;
    1, 4-Bis ( (S) - ( (S) -1-methyl-2-piperidinyl) (1-naphthyl) methoxy) phthalazine (Iu) ;
    4, 6-Bis ( (S) - ( (S) -1-methyl-2-piperidyl) (1-naphthyl) methoxy) -2, 5-diphenylpyrimidine (Iv) ;
    1, 4-Bis ( (S) - ( (S) -1 -methyl-2-piperidyl) (1 -naphthyl) methoxy) -9, 10-nonanedione (Iw) ;
    1, 4-Bis ( (R) - ( (R) -l-allyl-2-piperidyl) (1-naphthyl) methoxy) phthalazine (Ix) ; and
    1, 4-Bis ( (S) - ( (R) -1-allyl-2-piperidyl) (1-naphthyl) methoxy) phthalazine (Iy) .
  5. A method of preparation of the chiral bisamino-ether compound of claim 1, the method comprising: chiral amino-methanol compound 1, 2 mmol, being reacted with a base, 2-4 mmol, in an organic solvent for 5-30 minutes, and then further reacted with halogenated aryl compound 2, 1-2 mmol, at 0-160 ℃ for 2-96 hours to give a chiral bisamino-ether compound (I) with different substituent groups:
    Figure PCTCN2019000044-appb-100004
    wherein: n = 1 or 2; R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are defined as in claim 1; the halogenated aryl compound 2 is selected from the group consisting of:
    Figure PCTCN2019000044-appb-100005
  6. The method of claim 5, wherein the organic solvent is dimethylformamide, dichloromethane, dichloroethane, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, or any combination thereof.
  7. The method of claim 5, wherein the base is sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or any combination thereof.
  8. A use of the chiral bisamino-ether compound of claim 1, wherein the use comprises: using the chiral bisamino-ether compound I in asymmetric fluorocyclization of unsaturated heterocyclic compound 3:
    Figure PCTCN2019000044-appb-100006
    wherein: R 8 and R 9 may be the same or different, and are each independently selected from the group consisting of hydrogen, C 1-C 8 alkyl, C 1-C 9 unsaturated alkyl, halogen, haloalkyl, C 1-C 8 alkoxyl, phenyl, C 1-C 8 alkyl substituted phenyl, halophenyl, hydroxy substituted phenyl, amino substituted phenyl, di (C 1-C 8 alkyl) amino substituted phenyl, C 1-C 8 alkoxy substituted phenyl, C 1-C 8 acyl substituted phenyl, (C 1-C 8 acyl) amino substituted phenyl, C 2-C 8 ester group-substituted phenyl, C 2-C 8 acyloxy substituted phenyl, or naphthyl; the fluoro reagent is bis (tetrafluoroborate) salt of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane or  N-fluorobisbenzenesulfonamide; and the position marked by asterisk (*) is a chiral center.
  9. The use of claim 8, wherein reaction being carried out by adding the chiral bisamino-ether compound (I) and the substrate 3 into a round bottom flask, adding an additive and a solvent, adding the fluoro reagent, and then stirring the reaction at a specified temperature until the completion of the reaction.
  10. The use of claim 8, wherein reaction conditions comprising: the solvent is acetone, acetonitrile, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, 1, 2-dichloroethane, chloroform, or a combination thereof; the chiral bisamino-ether compound (I) is in an amount of 10-120 mol%; the substrate 3 is in a concentration of 0.01-10 M; the additive is sodium hydrogencarbonate, potassium hydrogencarbonate, cesium carbonate, sodium carbonate, potassium carbonate, or a combination thereof; the reaction temperature is -78 to 40℃; the reaction time is 2-96 hours.
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FUJIWARA,T. ET AL.: "Synthesis of 10b-fluorinated analogues of protubonine A and its 11a- epimer via fluorocyclisation of tryptophan-containing dipeptides", RSC ADV., vol. 5, 8 December 2014 (2014-12-08), pages 5464 - 5473, ISSN: 2046-2069 *
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