CN117800900A - A multi-substituted chiral bicyclo[2.1.1]hexane compound and its synthesis method - Google Patents
A multi-substituted chiral bicyclo[2.1.1]hexane compound and its synthesis method Download PDFInfo
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Abstract
本发明公开了一种多取代手性双环[2.1.1]己烷类化合物及其合成方法，属于有机合成领域。以多取代双环[1.1.0]丁烷类化合物1和乙烯基氮杂芳烃化合物2为原料，在光诱导和手性布朗斯特酸存在下不对称光氧化还原[2+2]环加成反应，得到多取代手性双环[2.1.1]己烷类化合物3。本发明利用光催化和手性布朗斯特酸协同催化的策略将分子间手性[2+2]光环加成反应进行拓展，提供了多种结构单元，为双环[2.1.1]己烷类手性桥环化合物的多方面应用提供了可能。The invention discloses a multi-substituted chiral bicyclo[2.1.1]hexane compound and a synthesis method thereof, and belongs to the field of organic synthesis. Using multi-substituted bicyclo[1.1.0]butane compounds 1 and vinyl azaarene compounds 2 as raw materials, asymmetric photoredox [2+2] cycloaddition was carried out in the presence of light induction and chiral Bronsted acid. reaction to obtain polysubstituted chiral bicyclo[2.1.1]hexane compound 3. The present invention utilizes the strategy of photocatalysis and chiral Bronsted acid synergistic catalysis to expand the intermolecular chiral [2+2] photocycloaddition reaction and provides a variety of structural units, which are bicyclo[2.1.1] hexane. Chiral bridged ring compounds provide possibilities for various applications.
Description
Technical Field
The invention particularly relates to a polysubstituted chiral bicyclo [2.1.1] hexane compound and a synthesis method thereof, belonging to the technical field of organic synthesis.
Background
The polysubstituted chiral bicyclo [2.1.1] hexane compound and the derivative thereof have important research value in medicine research as biological isopolyester (with similar groups to the biological properties of the polysubstituted chiral bicyclo [2.1.1] hexane) due to the fact that the structure of the polysubstituted chiral bicyclo [2.1.1] hexane compound contains a special bicyclo [2.1.1] hexane bridged ring skeleton, and have important research significance as candidate functional molecules with potential application.
The construction of polysubstituted chiral bicyclo [2.1.1] hexane derivatives is mainly synthesized by intermolecular chemical reaction, the existing method is completed by directly exciting energy transfer by light, the racemization reaction can be better realized at present, but the synthesis of chiral products is only realized by using a chiral induction method at present, namely, corresponding chiral products are obtained by using more than equivalent chiral catalysts, and the reaction is realized by adopting a catalytic amount chiral Bronsted acid catalyst in a photooxidation reduction mode, which has not been reported at present.
Therefore, a green high-efficiency synthesis method of the polysubstituted chiral bicyclo [2.1.1] hexane compound is researched and developed, and the method is used for synthesizing a series of corresponding compounds, so that the method has important theoretical significance and practical prospect.
Disclosure of Invention
In order to solve the technical problems, the invention provides a polysubstituted chiral bicyclo [2.1.1] hexane compound and a synthesis method thereof. The polysubstituted bicyclo [1.1.0] butane compound 1 and the vinyl aza-aromatic compound 2 are used as raw materials, and the polysubstituted chiral bicyclo [2.1.1] hexane compound 3 is obtained through asymmetric photooxidation reduction [2+2] cycloaddition reaction in the presence of photoinduction and chiral Bronsted acid. The synthesis method has the advantages of high efficiency, high stereoselectivity, wide substrate application range and the like.
The structural general formula of the polysubstituted chiral bicyclo [2.1.1] hexane compound is as follows:
wherein: r is R 1 Is hydrogen, C 1-4 Alkyl, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl being C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 2 Is hydrogen or C 1-4 Alkyl, R 3 Is 1-methylbenzimidazole, pyridyl or substituted pyridyl, and the substituent on the aryl ring of the substituted pyridyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 4 Is C 1-4 Alkyl or C 3-6 Cycloalkanes, R 5 Is naphthyl, furan, indole, phenyl or substituted phenyl, the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen.
The invention relates to a synthesis method of a polysubstituted chiral bicyclo [2.1.1] hexane compound, which is characterized by comprising the following operations: the polysubstituted bicyclo [1.1.0] butane compound 1 and the vinyl aza-aromatic compound 2 are used as raw materials to react in the presence of photoinduction and chiral Bronsted acid to obtain the polysubstituted chiral bicyclo [2.1.1] hexane compound 3. The reaction equation is:
wherein: r is R 1 Is hydrogen, C 1-4 Alkyl, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl being C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 2 Is hydrogen or C 1-4 Alkyl, R 3 Is 1-methylbenzimidazole, pyridyl or substituted pyridyl, and the substituent on the aryl ring of the substituted pyridyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 4 Is C 1-4 Alkyl or C 3-6 Cycloalkanes, R 5 Is naphthyl, furan, indole, phenyl or substitutedPhenyl, the substituent on the phenyl ring of the substituted phenyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen.
Further, in the above technical solution, the light is selected from 360-445nm wavelength. The specific wavelength is preferably from 365nm, 395nm, 410nm, 430nm or 445nm.
Further, in the above technical scheme, the chiral bronsted acid is selected from (S) -3,3' -bis (1-pyrenyl) -1,1' -binaphthol phosphate, (S) -3,3' -bis (1-pyrenyl) -5,5', 6', 7', 8' -octahydro-1, 1' -binaphthol phosphate, (S) -1, 9-dimethyl-3, 7-bis (1-pyrenyl) spiro-diphenol phosphate, (S) -10,10,13,13-tetramethyl-3, 7-bis (1-pyrenyl) spiro-diphenol phosphate or (S) -6,6' -diaryl substituted spiro-diphenol phosphate, wherein: the aryl substituent of the (S) -6,6' -diaryl substituted spiro diphenol phosphate is 10-phenylanthracene-9-yl, 9-anthryl, 9-phenanthryl, 3-fluoranthryl or 4-isopropylbenzene.
Further, in the technical scheme, the molar ratio of the polysubstituted bicyclo [1.1.0] butane compound 1, the vinyl aza-aromatic compound 2 and the chiral Bronsted acid is 1-2.5:1-2:0.1.
Further, in the above technical scheme, the reaction is performed in an organic solvent, and the organic solvent plays a role in dissolving the raw materials. The organic solvent is selected from dichloromethane, 1, 2-dichloroethane, chloroform, toluene, fluorobenzene, chlorobenzene, acetonitrile or diethyl ether. Preferably methylene chloride.
Further, in the above technical scheme, the reaction temperature is-50 ℃ to-10 ℃.
Further, in the above technical scheme, the reaction is performed under the protection of inert gas (nitrogen or argon).
The invention has the beneficial effects that:
1) The substituted chiral bicyclo [2.1.1] hexane compound has novel structure, takes the polysubstituted bicyclo [1.1.0] butane compound 1 and the vinyl aza-aromatic compound 2 as raw materials, and can be efficiently synthesized into the polysubstituted chiral bicyclo [2.1.1] hexane compound 3 by intermolecular [2+2] light cycloaddition reaction under the existence of photoinduction and chiral Bronsted acid.
2) The synthesis method has the advantages of high efficiency, high stereoselectivity, wide substrate application range and the like. Meanwhile, the photocatalysis advantage is fully utilized, and various structural units are obtained from polysubstituted bicyclo [1.1.0] butane derivatives through cycloaddition reaction, so that the method provides possibility for various applications of bicyclo [2.1.1] hexane chiral bridged compounds.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
The general method comprises the following steps: adding a compound 1a, a compound 2a and a chiral Bronsted acid catalyst into a 25mL reaction tube, adding dichloromethane to dissolve, performing pumping gas to fill argon, placing in a low-temperature refrigerator, keeping the temperature for 30 minutes without light stirring, placing LED lamp beads for irradiation, and stirring for reaction. After the reaction, the temperature was returned to room temperature, transferred to a reaction flask, spin-dried, and separated by silica gel column (petroleum ether/ethyl acetate=40/1-10/1) to give the product 3a.
By changing reaction conditions such as reaction concentration, chiral Bronsted acid catalyst, material proportion, reaction temperature and the like, the reaction result is as follows:
TABLE 1 Synthesis of 3a under different conditions a
Example 2
To a 25mL reaction tube, 1a (0.25 mmol,2.5 eq), 2a (0.10 eq) and chiral Bronsted acid catalyst C7 (0.01 mmol,0.1 eq) were added, and then 2mL of anhydrous dichloromethane was added, thoroughly mixed, cooled, and then the mixture was purged with argon three times, placed in a low temperature refrigerator, kept at-40℃for 30 minutes without light stirring, and then, at-40℃to-50℃under controlled temperature, one 3W,365nm wavelength LED lamp bead was placed at 3 cm for 24-72 hours. At the end of the reaction, the temperature was returned to room temperature, transferred to a reaction flask, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=40/1-10/1) to give a yellow solid product 3a (30.0 mg, 77%).
Example 3
Following the procedure and procedure of example 2, the reaction was carried out by merely changing reactant 1 and reactant 2 to give polysubstituted chiral bicyclo [2.1.1] hexane-based compounds 3a-3p,3x-3zl, with the following specific results:
representative compound characterization data are as follows:
naphthalen-2-yl((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3a):yellow oil；30.0mg,77％yield；93％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.53(d,J＝4.5Hz,1H),8.16(s,1H),7.91–7.76(m,5H),7.61–7.46(m,3H),7.44–7.32(m,5H),7.28–7.22(m,2H),7.00(t,J＝7.1Hz,2H),4.25(dd,J＝8.9,3.6Hz,1H),2.90(dd,J＝9.3,6.9Hz,1H),2.86–2.79(m,1H),2.68–2.61(m,1H),2.58(dd,J＝9.3,6.6Hz,1H),2.41(dd,J＝6.5,2.9Hz,1H),2.26(dd,J＝4.9,1.9Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.4,161.2,149.0,142.6,136.1,135.3,134.9,132.5,130.1,129.7,128.5,128.3,128.2,127.8,126.6,126.6,126.2,124.6,123.5,121.7,60.8,52.4,51.6,50.1,42.5,40.2；HRMS(ESI)m/z 390.1856(M+H + ),calc.for C 28 H 24 NO + 390.1852.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:10.0min(major)and 18.1min(minor).
(6-methoxynaphthalen-2-yl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3b):white solid；Mp 156.3–157.5℃；31.2mg,74％yield；91％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.56–8.51(m,1H),8.08(d,J＝1.6Hz,1H),7.83(dd,J＝8.6,1.8Hz,1H),7.69(dd,J＝29.0,8.8Hz,2H),7.41–7.31(m,5H),7.27–7.22(m,1H),7.16(dd,J＝8.9,2.5Hz,1H),7.10(d,J＝2.5Hz,1H),7.01–6.96(m,1H),4.22(ddd,J＝9.1,4.2,1.5Hz,1H),3.93(s,3H),2.92(dd,J＝9.4,6.8Hz,1H),2.86(ddd,J＝10.9,4.3,3.0Hz,1H),2.62(ddd,J＝11.1,8.9,2.6Hz,1H),2.56(dd,J＝9.3,6.5Hz,1H),2.40(dd,J＝6.5,2.9Hz,1H),2.24(ddd,J＝6.8,2.7,1.6Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ201.9,161.2,159.7,149.0,142.7,137.0,136.1,132.8,131.3,130.1,128.4,127.8,126.9,126.6,126.3,125.3,123.6,121.7,119.6,105.8,60.8,55.5,52.5,51.6,50.0,42.5,40.1；HRMS(ESI)m/z 420.1958(M+H + ),calc.for C 29 H 26 NO 2 + 420.1958.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:12.8min(major)and 17.1min(minor).
phenyl((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3c):yellow oil；17.9mg,53％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.50(d,J＝4.6Hz,1H),7.73(d,J＝7.8Hz,2H),7.47–7.42(m,2H),7.36–7.34(m,6H),7.25–7.23(m,1H),7.05(t,J＝6.4Hz,1H),7.01(d,J＝7.0Hz,1H),4.19(dd,J＝9.0,4.1Hz,1H),2.80–2.70(m,2H),2.61(t,J＝9.3Hz,1H),2.48(dd,J＝9.2,6.7Hz,1H),2.35(dd,J＝6.9,2.6Hz,1H),2.20(d,J＝6.2Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ202.5,161.1,148.8,142.5,137.6,136.3,132.4,128.50,128.45,128.4,126.6,126.2,123.4,121.7,60.5,52.0,51.5,50.1,42.3,40.4；HRMS(ESI)m/z 340.1701(M+H + ),calc.for C 24 H 22 NO + 340.1696.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:8.6min(major)and 8.1min(minor).
(4-fluorophenyl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3d):yellow oil；22.2mg,62％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.50(d,J＝4.3Hz,1H),7.76(dd,J＝8.7,5.6Hz,2H),7.44(td,J＝7.7,1.8Hz,1H),7.36–7.32(m,4H),7.29–7.21(m,1H),7.09–6.95(m,4H),4.15(dd,J＝9.0,4.1Hz,1H),2.82–2.70(m,2H),2.61(ddd,J＝11.1,8.9,2.7Hz,1H),2.46(dd,J＝9.3,6.5Hz,1H),2.33(dd,J＝6.6,2.9Hz,1H),2.19(dt,J＝7.0,2.0Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ200.9,165.3(d,J F-C ＝254.1Hz),161.0,148.9,142.4,136.3,133.9(d,J F-C ＝3.1Hz),131.2(d,J F-C ＝8.9Hz),128.5,126.6,126.2,123.4,121.8,115.4(d,J F-C ＝22.0Hz),60.3,52.1,51.3,50.1,42.5,40.3； 19 F NMR(376MHz,CDCl 3 )δ-106.1；HRMS(ESI)m/z 358.1607(M+H + ),calc.for C 24 H 21 FNO + 358.1602.The ee was determined by HPLC analysis:CHIRALPAK IE(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:10.6min(major)and 10.0min(minor).
(4-chlorophenyl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3e):white solid；Mp 102.2–103.3℃；27.0mg,69％yield；92％ee； (c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.49(d,J＝4.5Hz,1H),7.71–7.63(m,2H),7.52–7.43(m,2H),7.41–7.28(m,8H),7.26–7.22(m,1H),7.10–7.01(m,2H),4.17(dd,J＝9.0,4.4Hz,1H),2.77–2.68(m,1H),2.67–2.57(m,1H),2.45(dd,J＝9.3,6.5Hz,1H),2.32(dd,J＝6.5,2.8Hz,1H),2.20(dt,J＝7.0,2.1Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ201.3,160.9,148.8,142.3,138.8,136.5,135.9,130.0,128.7,128.5,126.7,126.2,123.4,121.9,60.2,52.0,51.2,50.2,42.5,40.5；HRMS(ESI)m/z 374.1312(M+H + ),calc.for C 24 H 21 ClNO + 374.1306.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:9.4min(major)and 10.2min(minor).
((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(4-(trimethylsilyl)phenyl)methanone(3f):yellow oil；28.5mg,69％yield；92％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J＝4.1Hz,1H),7.70(d,J＝8.0Hz,2H),7.51(d,J＝8.0Hz,2H),7.48–7.41(m,1H),7.35–7.34(m,4H),7.25–7.19(m,1H),7.09–6.98(m,2H),4.20(dd,J＝8.4,3.6Hz,1H),2.80–2.69(m,2H),2.66–2.56(m,1H),2.47(dd,J＝9.2,6.6Hz,1H),2.34(dd,J＝6.4,2.7Hz,1H),2.19(d,J＝6.7Hz,1H),0.27(s,9H)； 13 C NMR(101MHz,CDCl 3 )δ201.6,160.1,147.7,145.4,141.5,136.6,135.5,132.3,127.5,126.4,125.6,125.2,122.4,120.7,59.5,50.9,50.5,49.1,41.3,39.4,-2.2；HRMS(ESI)m/z 412.2094(M+H + ),calc.for C 27 H 30 NOSi + 412.2091.The ee was determined by HPLC analysis:CHIRALPAK ID(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:7.6min(major)and 17.7min(minor).
((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(p-tolyl)methanone(3g):white solid；Mp 104.1–105.4℃；22.6mg,64％yield；90％ee；(c1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J＝4.6Hz,1H),7.66(d,J＝7.9Hz,2H),7.47–7.44(m,1H),7.35(d,J＝4.3Hz,4H),7.27–7.22(m,1H),7.15(d,J＝7.9Hz,2H),7.09–7.00(m,2H),4.20(dd,J＝8.0,3.3Hz,1H),2.78–2.73(m,2H),2.63(t,J＝9.2Hz,1H),2.49(dd,J＝9.2,6.6Hz,1H),2.37(s,3H),2.36–2.33(m,1H),2.19(d,J＝6.8Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ201.8,161.0,148.6,143.3,142.5,136.6,134.8,129.1,128.7,128.4,126.6,126.2,123.4,121.8,60.5,51.9,51.6,49.9,42.3,40.4,21.7；HRMS(ESI)m/z 354.1858(M+H + ),calc.for C 25 H 24 NO + 354.1852.The ee was determined by HPLC analysis:CHIRALPAK ID(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；reten tion time:16.3min(major)and 40.7min(minor).
(4-(tert-butyl)phenyl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3h):yellow oil；25.1mg,64％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.52(d,J＝4.2Hz,1H),7.69(d,J＝8.1Hz,2H),7.48–7.31(m,7H),7.27–7.20(m,1H),7.06–7.02(m,2H),4.20(dd,J＝8.8,4.1Hz,1H),2.78–2.74(m,2H),2.61(t,J＝8.8Hz,1H),2.48(dd,J＝9.3,6.6Hz,1H),2.34(d,J＝4.6Hz,1H),2.19(d,J＝6.3Hz,1H),1.31(s,9H)； 13 C NMR(150MHz,CDCl 3 )δ201.9,161.1,156.2,148.7,142.5,136.4,134.8,128.5,128.4,126.6,126.2,125.4,123.5,121.7,60.5,51.9,51.5,50.0,42.4,40.4,35.2,31.2；HRMS(ESI)m/z 396.2322(M+H + ),calc.for C 28 H 30 NO + 396.2322.The ee was determined by HPLC analysis:CHIRALPAK ID(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:11.0min(major)and25.0min(minor).
(4-methoxyphenyl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3i):yellow oil；19.6mg,53％yield；89％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J＝4.4Hz,1H),7.74(d,J＝8.8Hz,2H),7.44(t,J＝7.3Hz,1H),7.35–7.32(m,4H),7.28–7.20(m,1H),7.09–7.01(m,2H),6.82(d,J＝8.8Hz,2H),4.18(dd,J＝9.1,4.2Hz,1H),3.83(s,3H),2.83–2.75(m,2H),2.61(t,J＝9.2Hz,1H),2.48(dd,J＝9.2,6.7Hz,1H),2.34(dd,J＝6.5,2.8Hz,1H),2.18(d,J＝6.7Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ200.6,163.1,161.0,148.7,142.6,136.5,130.9,130.3,128.4,126.6,126.2,123.5,121.8,113.6,60.5,55.5,52.1,51.5,49.8,42.4,40.2；HRMS(ESI)m/z 370.1808(M+H + ),calc.for C 25 H 24 NO 2 + 370.1802.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:13.9min(major)and 15.9min(minor).
(3-fluorophenyl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3j):yellow oil；25.0mg,70％yield；94％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.49(d,J＝4.3Hz,1H),7.55–7.40(m,3H),7.38–7.28(m,5H),7.25–7.22(m,1H),7.18–7.13(m,1H),7.08–6.99(m,2H),4.16(dd,J＝8.5,4.1Hz,1H),2.77–2.67(m,2H),2.66–2.57(m,1H),2.46(dd,J＝9.3,6.6Hz,1H),2.33(dd,J＝6.5,2.7Hz,1H),2.20(d,J＝6.8Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ201.3,162.6(d,J F-C ＝247.5Hz),160.9,148.8,142.3,139.7(d,J F-C ＝6.6Hz),136.4,130.0(d,J F-C ＝7.6Hz),128.5,126.7,126.2,124.2(d,J F-C ＝3.2Hz),123.3,121.8,119.4(d,J F-C ＝21.8Hz),115.3(d,J F-C ＝22.1Hz),60.2,52.0,51.2,50.2,42.4,40.5； 19 F NMR(376MHz,CDCl 3 )δ-112.2；HRMS(ESI)m/z 358.1603(M+H + ),calc.for C 24 H 21 FNO + 358.1602.The ee was determined by HPLC analysis:CHIRALPAK ID(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:9.1min(major)and 14.8min(minor).
((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(m-tolyl)methanone(3k):white solid；Mp 106.5–107.8℃；20.8mg,59％yield；90％ee；(c1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J＝4.0Hz,1H),7.55–7.48(m,2H),7.46–7.39(m,1H),7.35–7.34(m,4H),7.29–7.18(m,3H),7.08–6.97(m,2H),4.17(dd,J＝8.5,3.7Hz,1H),2.84–2.68(m,2H),2.65–2.56(m,1H),2.47(dd,J＝9.3,6.6Hz,1H),2.35–2.34(m,1H),2.33(s,3H),2.18(d,J＝6.3Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ202.6,161.1,148.8,142.5,138.1,137.5,136.3,133.3,129.0,128.4,128.2,126.6,126.2,125.7,123.5,121.7,60.6,52.0,51.5,50.0,42.4,40.3,21.5；HRMS(ESI)m/z 354.1853(M+H + ),calc.for C 25 H 24 NO + 354.1852.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:6.7min(major)and 7.3min(minor).
(3-(tert-butyl)phenyl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3l):yellow oil；28.9mg,73％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J＝4.4Hz,1H),7.74(s,1H),7.52(dd,J＝19.0,7.8Hz,2H),7.46–7.38(m,1H),7.38–7.27(m,5H),7.26–7.20(m,1H),7.08–6.97(m,2H),4.18(dd,J＝8.6,3.9Hz,1H),2.89–2.74(m,2H),2.60(ddd,J＝11.1,8.9,2.7Hz,1H),2.47(dd,J＝9.3,6.5Hz,1H),2.34(dd,J＝6.5,2.9Hz,1H),2.20(d,J＝6.6Hz,1H),1.29(s,9H)； 13 C NMR(150MHz,CDCl 3 )δ203.1,161.1,151.3,148.9,142.5,137.5,136.3,129.6,128.4,128.1,126.6,126.2,125.6,125.6,123.6,121.7,60.4,52.1,51.6,50.1,42.5,40.1,34.9,31.4.HRMS(ESI)m/z 396.2326(M+H + ),calc.for C 28 H 30 NO + 396.2322.The ee was determined by HPLC analysis:CHIRALPAK IE(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:8.1min(major)and 8.8min(minor).benzo[d][1,3]dioxol-5-yl((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3m):yellow oil；20.3mg,53％yield；91％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.52(d,J＝4.5Hz,1H),7.46(t,J＝7.8Hz,1H),7.36–7.32(m,5H),7.24–7.22(m,2H),7.10–7.01(m,2H),6.72(d,J＝8.1Hz,1H),5.99(s,2H),4.15(dd,J＝9.0,4.2Hz,1H),2.80–2.74(m,2H),2.60(t,J＝9.4Hz,1H),2.49–2.43(m,1H),2.33(d,J＝6.3Hz,1H),2.16(d,J＝6.3Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ200.2,161.0,151.4,148.8,148.0,142.5,136.5,132.0,128.5,126.6,126.2,124.9,123.5,121.8,108.5,107.8,101.8,60.5,52.2,51.6,49.8,42.5,40.3；HRMS(ESI)m/z 384.1597(M+H + ),calc.for C 25 H 22 NO 3 + 384.1594.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:12.0min(major)and 13.3min(minor).
(2-fluorophenyl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3n):yellow oil；17.0mg,48％yield；84％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.48(d,J＝4.3Hz,1H),7.54(t,J＝7.4Hz,1H),7.46(td,J＝7.4,1.8Hz,1H),7.41–7.27(m,5H),7.25–7.20(m,J＝6.7,1H),7.14–7.01(m,4H),4.16(q,J＝4.7Hz,1H),2.67(ddd,J＝11.6,9.4,2.7Hz,1H),2.49–2.38(m,3H),2.39–2.30(m,1H),2.28–2.21(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ201.8,161.7,159.7(d,J F-C ＝252.1Hz),148.6(d,J F-C ＝5.2Hz),142.6,136.5,132.7,132.7,130.2(d,J F-C ＝3.6Hz),128.5,126.7,126.2,124.2(d,J F-C ＝3.5Hz),123.4,121.7,116.3(d,J F-C ＝22.5Hz),60.7,50.4(d,J F-C ＝4.2Hz),50.1(d,J F-C ＝1.0Hz),49.8,41.7,41.6； 19 F NMR(376MHz,CDCl 3 )δ-112.3；HRMS(ESI)m/z 358.1606(M+H + ),calc.for C 24 H 21 FNO + 358.1602.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:11.4min(major)and 7.7min(minor).
(1-methyl-1H-indol-6-yl)((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3p):yellow oil；25.9mg,66％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.56(d,J＝4.4Hz,1H),7.74(s,1H),7.59–7.50(m,2H),7.41–7.32(m,5H),7.25–7.21(m,1H),7.19(d,J＝3.0Hz,1H),7.04–7.00(m,2H),6.48(d,J＝3.0Hz,1H),4.27(s,1H),3.80(s,3H),2.92–2.86(m,2H),2.66–2.62(m,1H),2.57(dd,J＝9.3,6.6Hz,1H),2.39(dd,J＝6.6,2.9Hz,1H),2.22(d,J＝6.9Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.2,161.2,148.6,142.7,136.5,136.2,132.6,132.0,130.8,128.4,126.5,126.3,123.8,121.8,120.4,119.9,110.9,101.4,61.0,52.3,52.0,49.8,42.7,40.1,33.1；HRMS(ESI)m/z 393.1961(M+H + ),calc.for C 27 H 25 N 2 O + 393.1960.The ee was determined by HPLC analysis:CHIRALPAK IE(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:29.8min(major)and 36.4min(minor).
((1R,2R,4S)-2-(3-chloropyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3y):yellow oil；30.1mg,71％yield；93％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.38(dd,J＝4.7,1.6Hz,1H),8.23(s,1H),7.94(dd,J＝8.6,1.7Hz,1H),7.82(q,J＝8.6Hz,3H),7.59–7.45(m,2H),7.41(dd,J＝8.0,1.5Hz,1H),7.36–7.30(m,4H),7.28–7.19(m,1H),6.95(dd,J＝8.0,4.6Hz,1H),4.54(ddd,J＝9.1,4.5,1.5Hz,1H),2.88–2.70(m,2H),2.56–2.44(m,2H),2.41(dt,J＝7.0,2.2Hz,1H),2.37(dd,J＝6.6,2.9Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.5,158.7,146.5,142.5,136.8,135.6,135.0,132.44,132.31,129.8,129.6,128.5,128.0,127.8,127.8,126.6,126.5,126.1,125.0,122.6,59.3,50.4,50.3,49.0,43.8,41.4；HRMS(ESI)m/z 424.1469(M+H + ),calc.for C 28 H 23 ClNO + 424.1463.The ee was determined by HPLC analysis:CHIRALPAK IC(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:8.9min(major)and 9.7min(minor).
2-((1R,2R,4S)-1-(2-naphthoyl)-4-phenylbicyclo[2.1.1]hexan-2-yl)isonicotinonitrile(3zb):yellow oil；27.1mg,65％yield；88％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.66(d,J＝5.0Hz,1H),8.23(s,1H),7.88–7.84(m,4H),7.57(dt,J＝31.0,7.3Hz,2H),7.39–7.36(m,4H),7.29–7.26(m,1H),7.21–7.20(m,2H),4.25(dd,J＝9.0,4.2Hz,1H),2.80(dd,J＝9.2,7.3Hz,1H),2.73(dt,J＝11.5,3.7Hz,1H),2.68(t,J＝10.0Hz,1H),2.58(dd,J＝9.3,6.7Hz,1H),2.47(d,J＝5.5Hz,1H),2.32(d,J＝6.6Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ201.5,163.1,149.9,142.0,135.4,134.8,132.5,129.9,129.6,128.6,128.5,127.9,126.9,126.8,126.1,126.1,125.1,124.4,123.1,120.5,116.5,60.8,52.0,51.3,50.3,42.5,40.4；HRMS(ESI)m/z 415.1804(M+H + ),calc.for C 29 H 23 N 2 O + 415.1805.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:14.0min(major)and 22.4min(minor).
naphthalen-2-yl((1R,2R,4S)-4-phenyl-2-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3zd):white solid；Mp 126.3–127.2℃；27.5mg,60％yield；99％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,Chloroform-d)δ8.65(d,J＝5.1Hz,1H),8.19(s,1H),7.89–7.78(m,4H),7.63–7.48(m,2H),7.39–7.34(m,4H),7.29–7.24(m,1H),7.19(d,J＝5.2Hz,1H),7.16(s,1H),4.33–4.23(m,1H),2.83–2.73(m,2H),2.68(ddd,J＝11.0,8.9,2.6Hz,1H),2.58(dd,J＝9.3,6.6Hz,1H),2.46(dd,J＝6.6,2.8Hz,1H),2.33(dt,J＝7.2,2.0Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ201.9,162.9,149.9,142.2,138.3,135.3,135.0,132.5,129.8,129.6,128.8(t,J＝14.8Hz),128.5,128.4,128.4,127.9,126.8,126.2,124.4,122.8(q,J＝275.9Hz),119.2(q,J＝3.4Hz),117.3(q,J＝3.1Hz),60.8,52.2,51.3,50.3,42.5,40.4； 19 F NMR(376MHz,Chloroform-d)δ-65.0；HRMS(ESI)m/z 458.1722(M+H + ),calc.for C 29 H 23 F 3 NO + 458.1726.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:7.8min(major)and 18.6min(minor).
((1R,2R,4S)-2-(4-methylpyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zf):yellow oil；40.0mg,99％yield；93％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.37(d,J＝4.9Hz,1H),8.16(s,1H),7.90–7.76(m,4H),7.63–7.47(m,2H),7.42–7.32(m,4H),7.28–7.22(m,1H),6.86–6.78(m,2H),4.18(dd,J＝8.8,3.7Hz,1H),2.91(dd,J＝9.3,6.9Hz,1H),2.85–2.75(m,1H),2.67–2.59(m,1H),2.56(dd,J＝9.3,6.6Hz,1H),2.40(dd,J＝6.5,2.9Hz,1H),2.26(d,J＝6.6Hz,1H),2.07(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ202.6,160.9,148.7,147.1,142.6,135.2,135.1,132.5,130.0,129.7,128.4,128.3,128.1,127.8,126.6,126.6,126.3,124.6,124.4,122.8,60.8,52.2,51.5,50.0,42.6,40.2,20.9；HRMS(ESI)m/z 404.2011(M+H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:9.7min(major)and 20.8min(minor).
((1R,2R,4S)-2-(4-methoxypyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zg):yellow oil；42.0mg,99％yield；94％ee；(c1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝5.6Hz,1H),8.21(s,1H),7.93–7.76(m,4H),7.62–7.47(m,2H),7.39–7.34(m,4H),7.28–7.20(m,1H),6.56–6.52(m,2H),4.19(dd,J＝9.3,4.2Hz,1H),3.58(s,3H),2.89(dd,J＝9.3,6.8Hz,1H),2.80(dt,J＝10.8,3.6Hz,1H),2.70–2.61(m,1H),2.57(dd,J＝9.2,6.6Hz,1H),2.41(dd,J＝6.4,2.8Hz,1H),2.28(d,J＝6.7Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.4,165.9,162.8,149.9,142.5,135.3,134.9,132.5,130.0,129.7,128.4,128.3,128.2,127.8,126.6,126.6,126.2,124.5,109.1,108.4,60.7,55.0,52.4,51.5,50.0,42.7,40.3；HRMS(ESI)m/z 420.1960(M+H + ),calc.for C 29 H 26 NO 2 + 420.1958.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:12.4min(major)and 30.8min(minor).
((1R,2R,4S)-2-(5-methylpyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zj):white solid；Mp 75.2–76.9℃；39.0mg,97％yield；97％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.35(d,J＝0.8Hz,1H),8.14(s,1H),7.84(ddd,J＝20.2,10.1,5.1Hz,4H),7.59–7.46(m,2H),7.40–7.31(m,4H),7.28–7.21(m,2H),7.14(dd,J＝7.9,1.8Hz,1H),6.88(d,J＝7.9Hz,1H),4.20(dd,J＝8.8,3.9Hz,1H),2.88(dd,J＝9.2,6.9Hz,1H),2.85–2.78(m,1H),2.66–2.59(m,1H),2.56(dd,J＝9.3,6.6Hz,1H),2.41(dd,J＝6.5,2.9Hz,1H),2.24(d,J＝6.7Hz,1H),2.15(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ202.4,158.1,149.4,142.7,136.7,135.3,134.8,132.5,131.1,130.1,129.7,128.4,128.3,128.1,127.8,126.6,126.6,126.3,124.6,122.9,60.9,52.0,51.5,50.0,42.5,40.2,18.0；HRMS(ESI)m/z 404.2010(M+H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:10.8min(major)and 14.5min(minor).
((1R,2R,4S)-2-(6-methylpyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zk):yellow oil；35.1mg,87％yield；86％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.26(s,1H),7.97–7.78(m,4H),7.61–7.47(m,2H),7.39–7.21(m,6H),6.87(d,J＝7.5Hz,1H),6.84(d,J＝7.6Hz,1H),4.25(t,J＝7.0Hz,1H),2.79(dd,J＝9.3,6.8Hz,1H),2.69(d,J＝6.4Hz,2H),2.55(dd,J＝9.4,6.5Hz,1H),2.42(s,3H),2.40–2.27(m,2H)； 13 C NMR(150MHz,CDCl 3 )δ202.4,160.5,157.6,142.7,136.4,135.2,135.1,132.5,130.1,129.6,128.5,128.2,128.0,127.8,126.6,126.6,126.2,124.9,121.1,119.9,60.2,52.1,51.5,50.2,42.7,40.7,24.3；HRMS(ESI)m/z 404.2013(M+H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:7.1min(major)and 10.7min(minor).
((1R,2R,4S)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zl):yellow oil；27.0mg,61％yield；97％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.87(d,J＝8.1Hz,1H),7.79(dd,J＝8.6,1.7Hz,1H),7.71–7.61(m,3H),7.49–7.33(m,5H),7.31–7.25(d,J＝6.2Hz,3H),7.21(t,J＝7.6Hz,1H),7.02(t,J＝7.6Hz,1H),6.83(d,J＝8.0Hz,1H),4.20(dd,J＝8.6,3.9Hz,1H),3.40(t,J＝8.2Hz,1H),3.34(s,3H),3.19(dt,J＝10.9,3.6Hz,1H),2.69(ddd,J＝11.1,8.8,2.6Hz,1H),2.51(dd,J＝9.4,6.9Hz,1H),2.41(dd,J＝7.0,3.0Hz,1H),2.34(d,J＝6.6Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.4,155.0,141.8,135.8,135.7,135.1,133.7,132.1,130.4,129.6,128.5,128.2,127.4,126.8,126.5,126.4,126.4,123.9,122.6,122.3,119.3,109.1,60.4,50.6,49.9,44.3,42.1,40.6,29.8；HRMS(ESI)m/z 443.2121(M+H + ),calc.for C 31 H 27 N 2 O + 443.2118.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:16.3min(major)and 10.6min(minor).
example 4
To a 25mL reaction tube, 1 (0.10 mmol), 2a (0.20 mmol,2.0 eq) and chiral Bronsted acid catalyst C7 (0.01 mmol,0.1 eq) were added, and then 2mL of anhydrous dichloromethane was added, thoroughly mixed, cooled, and then the mixture was purged three times with argon, placed in a low temperature refrigerator, kept at-40℃for 30 minutes without light stirring, and then, at-40℃under controlled temperature, one 3W,430nm wavelength LED bead was placed at 3 cm for 48 hours of stirring. After the reaction, the temperature is restored to room temperature, the mixture is transferred to a reaction bottle, the mixture is dried by spin, and silica gel column separation (petroleum ether/ethyl acetate=40/1-10/1) is carried out to obtain a polysubstituted chiral bicyclo [2.1.1] hexane product 3q-3w, and the specific results are as follows:
representative compounds are characterized as follows:
((1R,2R,4S)-4-(4-fluorophenyl)-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3q):white solid；Mp 111.5–112.7℃；36.5mg,90％yield；90％ee；(c 1.0,CHCl 3 )； 1 HNMR(400MHz,CDCl 3 )δ8.54(d,J＝4.5Hz,1H),8.14(s,1H),7.90–7.76(m,4H),7.62–7.46(m,2H),7.42–7.29(m,3H),7.10–6.96(m,4H),4.24(dd,J＝8.6,3.8Hz,1H),2.89(dd,J＝9.3,6.9Hz,1H),2.86–2.80(m,1H),2.66–2.58(m,1H),2.55(dd,J＝9.3,6.6Hz,1H),2.38(dd,J＝6.5,2.9Hz,1H),2.22(d,J＝6.7Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.2,161.7(d,J F-C ＝244.3Hz),160.9,148.9,138.3(d,J F-C ＝3.1Hz),136.3,135.3,134.8,132.5,130.1,129.7,128.4,128.2,127.8,127.7,126.7,124.5,123.6,121.8,115.2(d,J F-C ＝21.1Hz),60.7,52.3,51.7,49.5,42.6,40.2； 19 F NMR(376MHz,CDCl 3 )δ-116.4；HRMS(ESI)m/z 430.1582(M+Na + ),calc.for C 28 H 22 FNNaO + 430.1578.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:14.2min(major)and 21.4min(minor).
naphthalen-2-yl((1R,2R,4S)-2-(pyridin-2-yl)-4-(4-(trimethylsilyl)phenyl)bicyclo[2.1.1]hexan-1-yl)methanone(3r):white solid；Mp 101.4–102.8℃；41.9mg,91％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.54(d,J＝3.6Hz,1H),8.18(s,1H),7.92–7.75(m,4H),7.62–7.49(m,4H),7.39–7.37(m,3H),7.03–7.00(m,2H),4.27(d,J＝5.3Hz,1H),2.93–2.80(m,2H),2.67(t,J＝9.8Hz,1H),2.59(t,J＝7.7Hz,1H),2.43(d,J＝5.3Hz,1H),2.27(d,J＝5.9Hz,1H),0.29(s,9H)； 13 C NMR(150MHz,CDCl 3 )δ202.3,161.1,148.9,143.1,138.5,136.3,135.3,134.8,133.5,132.5,130.1,129.7,128.3,128.2,127.8,126.6,125.7,124.6,123.5,121.8,60.8,52.3,51.5,50.0,42.5,40.3,-0.9；HRMS(ESI)m/z 462.2247(M+H + ),calc.for C 31 H 32 NOSi + 462.2248.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:8.1min(major)and 11.6min(minor).naphthalen-2-yl((1R,2R,4S)-2-(pyridin-2-yl)-4-(p-tolyl)bicyclo[2.1.1]hexan-1-yl)methanone(3s):white solid；Mp 138.8–139.4℃；24.3mg,60％yield；85％ee； (c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.53(d,J＝4.6Hz,1H),8.16(s,1H),7.86–7.79(m,4H),7.57–7.50(m,2H),7.37(t,J＝7.6Hz,1H),7.29–7.14(m,4H),7.02–6.98(m,2H),4.24(d,J＝5.0Hz,1H),2.90–2.83(m,1H),2.80(d,J＝10.8Hz,1H),2.63(t,J＝9.8Hz,1H),2.58–2.53(m,1H),2.39(d,J＝6.3Hz,1H),2.24(d,J＝6.2Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ202.4,161.2,149.0,139.5,136.2,136.2,135.3,134.9,132.5,130.1,129.7,129.1,128.3,128.2,127.8,126.6,126.2,124.6,123.5,121.7,60.7,52.4,51.7,49.8,42.6,40.3,21.2；HRMS(ESI)m/z 404.2010(M+H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:12.0min(major)and 18.2min(minor).
((1R,2R,4S)-4-([1,1'-biphenyl]-4-yl)-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3t):white solid；Mp 146.5–148.0℃；25.9mg,56％yield；87％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.55(d,J＝4.7Hz,1H),8.18(s,1H),7.92–7.74(m,4H),7.64–7.50(m,6H),7.48–7.32(m,6H),7.07–6.98(m,2H),4.29(dd,J＝9.2,4.0Hz,1H),2.93(dd,J＝9.4,6.9Hz,1H),2.88(dt,J＝11.0,3.5Hz,1H),2.73–2.67(m,1H),2.61(dd,J＝9.3,6.6Hz,1H),2.46(dd,J＝6.4,2.8Hz,1H),2.30(d,J＝6.8Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.2,161.0,148.8,141.6,141.1,139.6,136.5,135.3,134.8,132.5,130.1,129.7,128.9,128.4,128.2,127.8,127.3,127.2,127.2,126.7,126.7,124.6,123.6,121.9,60.8,52.2,51.7,49.9,42.7,40.3；HRMS(ESI)m/z 466.2160(M+H + ),calc.for C 34 H 28 NO + 466.2165.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:16.0min(major)and 24.6min(minor).
((1R,2R,4S)-4-(3-fluorophenyl)-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3u):yellow oil；30.6mg,75％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.54(d,J＝4.6Hz,1H),8.14(s,1H),7.85–7.79(m,4H),7.56–7.51(m,2H),7.37(t,J＝7.5Hz,1H),7.31(dd,J＝14.5,7.2Hz,1H),7.14(d,J＝7.6Hz,1H),7.06(d,J＝9.9Hz,1H),7.00(t,J＝7.8Hz,2H),6.94(t,J＝8.4Hz,1H),4.24(d,J＝5.0Hz,1H),2.95–2.89(m,1H),2.84(d,J＝10.8Hz,1H),2.63(t,J＝9.8Hz,1H),2.59–2.53(m,1H),2.39(d,J＝5.5Hz,1H),2.24(d,J＝6.3Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ202.0,163.1(d,J F-C ＝245.6Hz),160.8,148.9,145.2(d,J F-C ＝6.8Hz),136.3,135.3,134.7,132.5,130.1,130.0(d,J F-C ＝8.6Hz),129.7,128.4,128.2,127.8,126.7,124.5,123.6,121.9,121.9,113.5(d,J F-C ＝21.1Hz),113.3(d,J F-C ＝21.3Hz),60.7,52.1,51.5,49.8,42.5,40.1； 19 F NMR(376MHz,CDCl 3 )δ-113.4；HRMS(ESI)m/z 408.1755(M+H + ),calc.for C 28 H 23 FNO + 408.1758.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:11.6min(major)and 21.8min(minor).
naphthalen-2-yl((1R,2R,4S)-2-(pyridin-2-yl)-4-(m-tolyl)bicyclo[2.1.1]hexan-1-yl)methanone(3v):yellow oil；31.2mg,77％yield；87％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J＝4.6Hz,1H),8.15(s,1H),7.91–7.74(m,4H),7.56–7.48(m,2H),7.40–7.32(m,1H),7.25–7.13(m,3H),7.10–6.94(m,3H),4.23(dd,J＝9.3,4.2Hz,1H),2.87(dd,J＝9.2,7.0Hz,1H),2.81(dt,J＝10.7,3.5Hz,1H),2.67–2.59(m,1H),2.56(dd,J＝9.2,6.6Hz,1H),2.39(dd,J＝6.5,2.8Hz,1H),2.36(s,3H),2.23(d,J＝6.6Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.4,161.2,149.0,142.5,138.0,136.2,135.3,134.9,132.5,130.1,129.7,128.4,128.3,128.2,127.8,127.3,127.0,126.6,124.6,123.5,123.2,121.7,60.7,52.4,51.5,50.0,42.6,40.3,21.6；HRMS(ESI)m/z 404.2013(M+H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:9.2min(major)and 21.9min(minor).
((1R,2R,4S)-4-(3-(tert-butyl)phenyl)-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3w):yellow oil；24.9mg,56％yield；83％ee；(c1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.54(d,J＝4.6Hz,1H),8.18(s,1H),7.93–7.78(m,4H),7.57–7.54(m,2H),7.42–7.28(m,4H),7.20(d,J＝5.4Hz,1H),7.07–6.97(m,2H),4.26(d,J＝4.9Hz,1H),2.92–2.78(m,2H),2.68(t,J＝9.7Hz,1H),2.62–2.55(m,1H),2.43(d,J＝5.9Hz,1H),2.28(d,J＝6.4Hz,1H),1.35(s,9H)； 13 C NMR(150MHz,CDCl 3 )δ202.5,161.2,151.3,149.0,142.1,136.3,135.3,134.9,132.5,130.1,129.7,128.3,128.2,128.1,127.8,126.6,124.6,123.7,123.5,123.4,123.0,121.7,60.7,52.4,51.8,50.3,42.6,40.4,34.9,31.6；HRMS(ESI)m/z 468.2306(M+Na + ),calc.for C 32 H 31 NNaO + 468.2298.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:6.4min(major)and 13.5min(minor).
example 5
To a 25mL reaction tube, 1a (0.25 mmol,2.5 eq), 2a (0.10 eq) and chiral Bronsted acid catalyst C7 (0.01 mmol,0.1 eq) were added, and then 2mL of anhydrous dichloromethane was added, thoroughly mixed, cooled, and then the mixture was purged with argon three times, placed in a low temperature refrigerator, kept at-40℃for 30 minutes without light stirring, and then, at-40℃under controlled temperature, one 3W,365nm wavelength LED bead was placed at 3 cm, and stirred for 24-48 hours. After the reaction, the temperature is restored to room temperature, the mixture is transferred to a reaction bottle, the mixture is dried by spin, and silica gel column separation (petroleum ether/ethyl acetate=40/1-10/1) is carried out to obtain polysubstituted chiral bicyclo [2.1.1] hexane products 4a-4m, and the specific results are as follows:
representative compounds are characterized as follows:
((1R,2R,4S)-2-methyl-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4a):white solid；Mp 137.5–138.6℃；31.1mg,77％yield；95％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.36(d,J＝4.0Hz,1H),8.05(s,1H),7.80(dd,J＝21.2,8.7Hz,4H),7.58–7.44(m,3H),7.35–7.27(m,5H),7.22(ddd,J＝8.5,4.2,1.9Hz,1H),7.03(dd,J＝6.9,5.1Hz,1H),3.20(dd,J＝10.8,2.6Hz,1H),2.75(dd,J＝9.5,7.1Hz,1H),2.45(dd,J＝9.5,6.8Hz,1H),2.28(dd,J＝6.7,2.8Hz,1H),2.24–2.17(m,2H),1.78(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ203.1,166.2,148.0,142.6,136.5,136.2,134.9,132.4,130.6,129.6,128.4,128.0,127.7,127.5,126.5,126.4,126.1,125.6,122.0,121.3,61.3,55.4,49.4,47.8,47.7,46.8,27.3；HRMS(ESI)m/z 404.2012(M+H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:9.6min(major)and 12.1min(minor).、
((1R,2R,4S)-2-butyl-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4b):yellow oil；37.1mg,83％yield；95％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.39(d,J＝4.7Hz,1H),7.85–7.80(m,2H),7.77–7.68(m,3H),7.54(t,J＝7.5Hz,1H),7.46(dt,J＝19.3,7.6Hz,2H),7.35(d,J＝4.4Hz,4H),7.27–7.21(m,2H),7.06–7.00(m,1H),3.33(d,J＝11.1Hz,1H),2.88–2.79(m,1H),2.45(t,J＝8.0Hz,1H),2.33(td,J＝12.5,4.9Hz,1H),2.26–2.14(m,4H),1.34–1.23(m,3H),0.81(t,J＝7.0Hz,3H),0.80–0.73(m,1H)； 13 C NMR(150MHz,CDCl 3 )δ202.4,163.4,148.4,142.7,136.1,135.6,135.0,132.3,130.8,129.7,128.4,128.1,127.7,127.5,126.5,126.4,126.1,125.3,122.8,121.3,62.4,59.1,49.1,48.2,46.2,43.0,37.6,27.7,23.4,14.2；HRMS(ESI)m/z 446.2470(M+H + ),calc.for C 32 H 32 NO + 446.2478.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:7.8min(major)and 8.4min(minor).
((1S,2S,4R)-2-cyclopropyl-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4c):yellow oil；40.0mg,76％yield；96％ee；(c1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.57(d,J＝4.0Hz,1H),8.45(s,1H),8.14–7.99(m,4H),7.80–7.65(m,3H),7.58–7.47(m,4H),7.46–7.40(m,2H),7.31–7.20(m,1H),3.23(dd,J＝9.4,6.8Hz,1H),2.99(dd,J＝11.2,2.6Hz,1H),2.54–2.35(m,3H),2.23(dd,J＝11.2,3.0Hz,1H),1.82(tt,J＝8.4,5.7Hz,1H),0.94(tdd,J＝17.5,9.6,5.3Hz,2H),0.44(dq,J＝9.1,5.1,4.6Hz,1H),0.10(dq,J＝10.9,5.4Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.9,164.8,147.9,142.6,137.1,135.9,134.9,132.4,130.4,129.6,128.4,127.8,127.8,127.4,126.6,126.4,126.0,125.9,122.7,121.4,62.7,58.8,49.4,47.4,46.5,40.9,19.0,4.9,1.3；HRMS(ESI)m/z430.2166(M+H + ),calc.for C 31 H 28 NO + 430.2165.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:11.3min(major)and 16.3min(minor).
((1S,2S,4R)-2-cyclopentyl-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4d):yellow oil；32.2mg,70％yield；99％ee；(c1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.24(s,1H),8.14(s,1H),7.84(d,J＝8.2Hz,1H),7.80–7.76(m,3H),7.59–7.53(m,2H),7.48(t,J＝7.5Hz,1H),7.36–7.29(m,3H),7.27(d,J＝6.9Hz,2H),7.21(t,J＝7.1Hz,1H),7.06(t,J＝6.1Hz,1H),2.90(d,J＝11.0Hz,1H),2.83(dt,J＝16.7,9.2Hz,2H),2.46(d,J＝11.3Hz,1H),2.34(p,J＝6.3Hz,1H),2.22(d,J＝6.2Hz,1H),2.12–2.03(m,2H),1.68–1.49(m,3H),1.43–1.33(m,1H),1.24(dt,J＝18.9,9.0Hz,2H),1.01(dq,J＝14.5,8.1,6.2Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ202.8,165.7,148.2,142.8,136.7,135.5,134.8,132.5,130.7,129.6,128.4,127.9,127.7,127.2,126.5,126.3,126.1,126.0,122.8,121.2,62.5,61.8,49.0,48.13,48.09,47.5,41.7,31.3,29.8,25.4,23.9；HRMS(ESI)m/z 458.2480(M+H + ),calc.for C 33 H 32 NO + 458.2478.The ee was determined by HPLC analysis:CHIRALPAK IE(4.6mm i.d.x 250mm)；Hexane/2-propanol＝95/05；flow rate 1.0mL/min；20℃；254nm；retention time:33.5min(major)and 41.8min(minor).
((1S,2S,4R)-2-cyclohexyl-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4e):yellow oil；33.2mg,70％yield；99％ee；(c1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.30(s,1H),8.13(s,1H),7.88–7.75(m,4H),7.60–7.47(m,3H),7.37–7.26(m,5H),7.23–7.19(m,1H),7.09(t,J＝6.3Hz,1H),2.93(d,J＝11.1Hz,1H),2.84(dd,J＝9.6,7.1Hz,1H),2.55(d,J＝11.0Hz,2H),2.39(tt,J＝11.6,2.8Hz,1H),2.22–2.05(m,3H),1.88(d,J＝13.3Hz,1H),1.64–1.42(m,4H),1.30–0.99(m,3H),0.60–0.47(m,1H)； 13 C NMR(100MHz,CDCl 3 )δ203.5,165.6,159.8,148.2,142.8,136.6,135.4,134.9,132.4,130.9,129.7,128.4,128.0,127.7,127.3,126.5,126.4,126.0,123.2,121.2,64.0,62.0,48.44,48.39,48.35,45.8,42.1,31.2,30.5,27.4,27.0,26.7；HRMS(ESI)m/z 472.2639(M+H + ),calc.for C 34 H 34 NO + 472.2635.The ee was determined by HPLC analysis:CHIRAL PAK IG(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:13.8min(major)and 10.2min(minor).
((1S,2R,4R)-2-methyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4f):yellow oil；20.4mg,62％yield；85％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.33(d,J＝4.3Hz,1H),7.98(s,1H),7.85–7.71(m,4H),7.53(t,J＝7.4Hz,1H),7.50–7.41(m,2H),7.25–7.24(m,1H),7.01–6.97(m,1H),2.95(dd,J＝10.9,2.2Hz,1H),2.52(s,1H),2.33–2.20(m,1H),2.09–2.02(m,2H),1.96(dd,J＝9.5,6.0Hz,2H),1.69(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ203.6,166.5,147.8,136.5,136.1,134.8,132.4,130.5,129.6,127.9,127.7,127.4,126.3,125.6,122.1,121.1,64.9,53.6,44.1,42.6,41.9,35.3,27.2；HRMS(ESI)m/z 328.1702(M+H + ),calc.for C 23 H 22 NO + 328.1696.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:11.4min(major)and 16.8min(minor).
((1S,2R,4R)-2-methyl-2-(6-methylpyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4g):white solid；Mp 99.9–100.6℃；26.9mg,79％yield；96％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.13(s,1H),7.84(dd,J＝11.5,4.5Hz,2H),7.78(t,J＝9.4Hz,2H),7.54(t,J＝7.2Hz,1H),7.48(t,J＝7.3Hz,1H),7.41(t,J＝7.7Hz,1H),7.09(d,J＝7.9Hz,1H),6.82(d,J＝7.5Hz,1H),2.76(d,J＝10.9Hz,1H),2.50(s,1H),2.22(dd,J＝9.6,7.2Hz,1H),2.12–2.07(m,1H),2.01(s,3H),1.99(dt,J＝11.3,5.7Hz,2H),1.83(dd,J＝9.7,6.9Hz,1H),1.65(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ203.3,166.3,157.0,136.8,136.4,134.8,132.5,130.7,129.6,127.8,127.7,127.2,126.3,126.1,120.5,118.6,64.2,54.2,43.8,43.1,42.3,35.4,27.9,23.6；HRMS(ESI)m/z 342.1854(M+H + ),calc.for C 24 H 24 NO + 342.1852.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:5.1min(major)and 6.5min(minor).
((1S,2R,4R)-2-methyl-2-(4-methylpyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4h):yellow oil；33.2mg,97％yield；90％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.17(d,J＝5.0Hz,1H),7.95(s,1H),7.81(d,J＝8.1Hz,1H),7.75(ddd,J＝12.4,8.4,2.6Hz,3H),7.55–7.51(m,1H),7.49–7.44(m,1H),7.00(s,1H),6.79(d,J＝4.9Hz,1H),3.01–2.94(m,1H),2.51(d,J＝1.3Hz,1H),2.25(dd,J＝9.7,7.1Hz,1H),2.07(s,3H),2.06–2.00(m,2H),1.95(dd,J＝9.7,6.9Hz,1H),1.92(ddd,J＝10.9,2.4,1.2Hz,1H),1.66(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ203.8,166.2,147.6,146.9,136.6,134.8,132.4,130.5,129.6,127.9,127.6,127.3,126.3,125.6,123.1,122.2,65.0,53.4,44.1,42.7,41.7,35.3,27.1,21.1；HRMS(ESI)m/z 342.1855(M+H + ),calc.for C 24 H 24 NO + 342.1852.The ee was determined by HPLC analysis:CHIRALPAK IE(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:11.6min(major)and 17.2min(minor).
((1S,2R,4R)-2-(5-fluoropyridin-2-yl)-2-methylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4i):yellow oil；28.0mg,81％yield；94％ee；(c 1.0,CHCl 3 )； 1 H NMR(600MHz,CDCl 3 )δ8.17(s,1H),7.99(s,1H),7.85–7.72(m,4H),7.56–7.48(m,2H),7.24–7.11(m,2H),2.92(d,J＝10.8Hz,1H),2.53(s,1H),2.27(t,J＝8.4Hz,1H),2.06(dd,J＝10.1,7.3Hz,2H),1.95(dd,J＝13.9,9.4Hz,2H),1.66(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ203.5,162.5(d,J F-C ＝3.5Hz),158.0(d,J F-C ＝254.5Hz),136.4,135.6(d,J F-C ＝23.0Hz),134.9,132.4,130.5,129.6,128.1,127.7,127.6,126.5,125.4,123.0(d,J F-C ＝1.6Hz),122.9(d,J F-C ＝12.6Hz),65.1,53.1,44.2,42.6,42.3,35.4,27.3； 19 F NMR(565MHz,CDCl 3 )δ-131.5；HRMS(ESI)m/z 346.1606(M+H + ),calc.for C 23 H 21 FNO + 346.1602.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:5.7min(major)and 7.2min(minor).
((1S,2R,4R)-2-methyl-2-(5-methylpyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4j):white solid；Mp 91.9–92.9℃；26.0mg,76％yield；97％ee；(c 1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.90(s,1H),7.77(ddd,J＝22.6,15.0,8.4Hz,4H),7.50(dt,J＝24.8,7.1Hz,2H),7.22(dd,J＝8.1,1.6Hz,1H),7.10(d,J＝8.1Hz,1H),2.97(d,J＝10.8Hz,1H),2.52(s,1H),2.26(t,J＝8.1Hz,1H),2.17(s,3H),2.06–1.97(m,3H),1.92(d,J＝10.8Hz,1H),1.65(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ203.7,163.5,148.1,136.6,136.5,134.9,132.4,130.6,130.4,129.6,127.9,127.7,127.4,126.3,125.6,121.5,65.2,53.0,44.2,42.6,41.9,35.3,27.1,18.0；HRMS(ESI)m/z 342.1854(M+H + ),calc.for C 24 H 24 NO + 342.1852.The ee was determinedby HPLC analysis:CHIRALPAK IE(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；reten tiontime:11.4min(major)and 15.3min(minor).
the foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
Claims (10)
1. The polysubstituted chiral bicyclo [2.1.1] hexane compound is characterized by having the following structural general formula:
wherein: r is R 1 Is hydrogen, C 1-4 Alkyl, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl being C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 2 Is hydrogen or C 1-4 Alkyl, R 3 Is 1-methylbenzimidazole, pyridyl or substituted pyridyl, and the substituent on the aryl ring of the substituted pyridyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 4 Is C 1-4 Alkyl or C 3-6 Cycloalkanes, R 5 Is naphthyl, furan, indole, phenyl or substituted phenyl, the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen.
2. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 1, which is characterized by comprising the following operations: taking a polysubstituted bicyclo [1.1.0] butane compound 1 and a vinyl aza-aromatic compound 2 as raw materials, and reacting in the presence of photoinduction and chiral Bronsted acid to obtain a polysubstituted chiral bicyclo [2.1.1] hexane compound 3; the reaction equation is expressed as:
wherein: r is R 1 Is hydrogen, C 1-4 Alkyl, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl being C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 2 Is hydrogen or C 1-4 Alkyl, R 3 Is 1-methylbenzimidazole, pyridyl or substituted pyridylThe substituent on the aryl ring of the substituted pyridyl group being C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 4 Is C 1-4 Alkyl or C 3-6 Cycloalkanes, R 5 Is naphthyl, furan, indole, phenyl or substituted phenyl, the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen.
3. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 2, wherein the method is characterized in that: the light is selected from the group consisting of wavelengths of 360-445 nm.
4. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 3, wherein the method is characterized in that: the wavelength of light is selected from 365nm, 395nm, 410nm, 430nm or 445nm.
5. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 2, wherein the method is characterized in that: chiral bronsted acids are selected from (S) -3,3' -bis (1-pyrenyl) -1,1' -binaphthol phosphate, (S) -3,3' -bis (1-pyrenyl) -5,5', 6', 7', 8' -octahydro-1, 1' -binaphthol phosphate, (S) -1, 9-dimethyl-3, 7-bis (1-pyrenyl) spirocyclic diphenol phosphate, (S) -10,10,13,13-tetramethyl-3, 7-bis (1-pyrenyl) spirocyclic diphenol phosphate, or (S) -6,6' -diaryl substituted spirocyclic diphenol phosphate; wherein: the aryl substituent of the (S) -6,6' -diaryl substituted spiro diphenol phosphate is 10-phenylanthracene-9-yl, 9-anthryl, 9-phenanthryl, 3-fluoranthryl or 4-isopropylbenzene.
6. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 2, wherein the method is characterized in that: the reaction is carried out in an organic solvent selected from dichloromethane, 1, 2-dichloroethane, chloroform, toluene, fluorobenzene, chlorobenzene, acetonitrile or diethyl ether.
7. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 6, wherein the method is characterized in that: the organic solvent is selected from dichloromethane.
8. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 2, wherein the method is characterized in that: the molar ratio of the polysubstituted bicyclo [1.1.0] butane compound 1, the vinyl aza-aromatic compound 2 and the chiral Bronsted acid is 1-2.5:1-2:0.1.
9. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to claim 2, wherein the method is characterized in that: the reaction temperature is-50 ℃ to-10 ℃.
10. The method for synthesizing the polysubstituted chiral bicyclo [2.1.1] hexane compound according to any one of claims 2 to 9, which is characterized in that: the reaction is carried out under the protection of inert gas.
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| CN118496128A (en) * | 2024-04-12 | 2024-08-16 | 西北大学 | A method for preparing a polysubstituted 2-aminobicyclo[2.1.1]hexene compound |
| CN119504443A (en) * | 2024-11-15 | 2025-02-25 | 浙江工业大学 | A bicyclo[2.1.1]hexene compound and its preparation and application |
| CN119954611A (en) * | 2025-01-24 | 2025-05-09 | 华东理工大学 | Polyhydroxyphenol crosslinking agent and preparation method and application method thereof |
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| US20080058535A1 (en) * | 2006-07-25 | 2008-03-06 | Zhengming Chen | Methods and compositions for production, formulation and use of 1 aryl-3-azabicyclo[3.1.0]hexanes |
| TW201129700A (en) * | 2009-11-18 | 2011-09-01 | Taisho Pharmaceutical Co Ltd | Method for producing optically active bicyclo [310] hexane derivative using oxygen |
| CN102531911A (en) * | 2011-12-22 | 2012-07-04 | 浙江工业大学 | Chiral dicyclic compound and asymmetric syntheses method thereof |
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| US20080058535A1 (en) * | 2006-07-25 | 2008-03-06 | Zhengming Chen | Methods and compositions for production, formulation and use of 1 aryl-3-azabicyclo[3.1.0]hexanes |
| TW201129700A (en) * | 2009-11-18 | 2011-09-01 | Taisho Pharmaceutical Co Ltd | Method for producing optically active bicyclo [310] hexane derivative using oxygen |
| CN102531911A (en) * | 2011-12-22 | 2012-07-04 | 浙江工业大学 | Chiral dicyclic compound and asymmetric syntheses method thereof |
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| CN118496128A (en) * | 2024-04-12 | 2024-08-16 | 西北大学 | A method for preparing a polysubstituted 2-aminobicyclo[2.1.1]hexene compound |
| CN119504443A (en) * | 2024-11-15 | 2025-02-25 | 浙江工业大学 | A bicyclo[2.1.1]hexene compound and its preparation and application |
| CN119504443B (en) * | 2024-11-15 | 2025-10-28 | 浙江工业大学 | A bicyclo[2.1.1]hexene compound and its preparation and application |
| CN119954611A (en) * | 2025-01-24 | 2025-05-09 | 华东理工大学 | Polyhydroxyphenol crosslinking agent and preparation method and application method thereof |
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