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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 PDF

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CN117800900A
CN117800900A CN202311755843.8A CN202311755843A CN117800900A CN 117800900 A CN117800900 A CN 117800900A CN 202311755843 A CN202311755843 A CN 202311755843A CN 117800900 A CN117800900 A CN 117800900A
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bicyclo
substituted
chiral
hexane
phenyl
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吕馨馨
江智勇
赵筱薇
付倩倩
王家豪
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Henan Normal University
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Abstract

The invention discloses a polysubstituted chiral bicyclo [2.1.1] hexane compound and a synthesis method thereof, belonging to the field of organic synthesis. 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 invention expands intermolecular chiral [2+2] photocycloaddition reaction by utilizing a strategy of photocatalysis and chiral Bronsted acid synergistic catalysis, provides various structural units, and provides possibility for various applications of bicyclo [2.1.1] hexane chiral bridged compounds.

Description

一种多取代手性双环[2.1.1]己烷类化合物及其合成方法A multi-substituted chiral bicyclo[2.1.1]hexane compound and its synthesis method

技术领域Technical Field

本发明具体涉及多取代手性双环[2.1.1]己烷类化合物及其合成方法，属于有机合成技术领域。The present invention specifically relates to a polysubstituted chiral bicyclo[2.1.1]hexane compound and a synthesis method thereof, belonging to the technical field of organic synthesis.

背景技术Background technique

多取代手性双环[2.1.1]己烷类化合物及其衍生物，由于结构中含有特殊的双环[2.1.1]己烷这种桥环骨架，作为生物同分酯(具有与其所取代的生物性质相似基团)在药物研究中具有重要的研究价值，作为具有潜在应用的候选功能分子具有重要的研究意义。Multi-substituted chiral bicyclo[2.1.1]hexane compounds and their derivatives, because the structure contains a special bridged ring skeleton of bicyclo[2.1.1]hexane, are bioisoesters (with the substituted Groups with similar biological properties) have important research value in drug research and have important research significance as candidate functional molecules with potential applications.

多取代手性双环[2.1.1]己烷类衍生物的构建主要是通过分子间化学反应合成，已有方法采用光直接激发能量转移的方式来完成，目前其消旋反应能够较好的实现，但是手性产物的合成目前仅有使用手性诱导方法实现，即使用超过当量手性催化剂获得相应手性产物，采用催化量手性布朗斯特酸催化剂通过光氧化还原的方式实现该反应目前尚未报道。The construction of multi-substituted chiral bicyclic [2.1.1] hexane derivatives is mainly synthesized through intermolecular chemical reactions. Existing methods use direct light excitation energy transfer to complete the process. At present, the racemization reaction can be better realized. , but the synthesis of chiral products is currently only achieved using the chiral induction method, that is, using more than an equivalent amount of chiral catalyst to obtain the corresponding chiral product, and using a catalytic amount of chiral Bronsted acid catalyst to achieve the reaction through photoredox. Currently, Not reported yet.

因此，研究并开发多取代手性双环[2.1.1]己烷类化合物的绿色高效合成方法，利用该方法合成系列相应化合物，具有重要的理论意义和实用前景。Therefore, it is of great theoretical significance and practical prospect to study and develop a green and efficient synthesis method of multi-substituted chiral bicyclo[2.1.1]hexane compounds, and to use this method to synthesize a series of corresponding compounds.

发明内容Contents of the invention

为了解决上述技术问题，本发明提供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。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。该合成方法具有高效、高立体选择性、底物适用范围广等优点。In order to solve the above technical problems, the present invention provides a polysubstituted chiral bicyclo[2.1.1]hexane compound and a synthesis method thereof. A polysubstituted bicyclo[1.1.0]butane compound 1 and a vinyl azaaromatic compound 2 are used as raw materials, and an asymmetric photoredox [2+2] cycloaddition reaction is carried out under light induction and in the presence of a chiral Brønsted acid to obtain a polysubstituted chiral bicyclo[2.1.1]hexane compound 3. The synthesis method has the advantages of high efficiency, high stereoselectivity, and a wide range of substrate applicability.

本发明所述多取代手性双环[2.1.1]己烷类化合物，其结构通式为：The multi-substituted chiral bicyclo[2.1.1]hexane compound of the present invention has a general structural formula:

其中：R1为氢、C1-4烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R2为氢或C1-4烷基，R3为1-甲基苯并咪唑、吡啶基或取代吡啶基，取代吡啶基芳环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R4为C1-4烷基或C3-6环烷烃，R5为萘基、呋喃、吲哚、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。Among them: R 1 is hydrogen, C 1-4 alkyl, phenyl or substituted phenyl, the substituent on the substituted phenyl phenyl ring is 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 substituents on the substituted pyridyl aromatic ring are C 1-4 alkyl, C 1-4 alkyl Oxygen or halogen, R 4 is C 1-4 alkyl or C 3-6 cycloalkane, R 5 is naphthyl, furan, indole, phenyl or substituted phenyl, the substituent on the substituted phenyl phenyl ring is C 1-4 alkyl, C 1-4 alkoxy or halogen.

本发明所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于，包括如下操作：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反应，得到多取代手性双环[2.1.1]己烷类化合物3。反应方程式为：The synthesis method of multi-substituted chiral bicyclo[2.1.1]hexane compounds according to the present invention is characterized in that it includes the following operations: using multi-substituted bicyclo[1.1.0]butane compounds 1 and vinyl azaarenes Compound 2 was used as raw material, and reacted in the presence of light induction and chiral Brønsted acid to obtain multi-substituted chiral bicyclo[2.1.1]hexane compound 3. The reaction equation is:

其中：R1为氢、C1-4烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R2为氢或C1-4烷基，R3为1-甲基苯并咪唑、吡啶基或取代吡啶基，取代吡啶基芳环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R4为C1-4烷基或C3-6环烷烃，R5为萘基、呋喃、吲哚、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。Among them: R 1 is hydrogen, C 1-4 alkyl, phenyl or substituted phenyl, the substituent on the substituted phenyl phenyl ring is 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 substituents on the substituted pyridyl aromatic ring are C 1-4 alkyl, C 1-4 alkyl Oxygen or halogen, R 4 is C 1-4 alkyl or C 3-6 cycloalkane, R 5 is naphthyl, furan, indole, phenyl or substituted phenyl, the substituent on the substituted phenyl phenyl ring is C 1-4 alkyl, C 1-4 alkoxy or halogen.

进一步地，在上述技术方案中，所述光选自360-445nm波长。具体波长优选自365nm、395nm、410nm、430nm或445nm。Furthermore, in the above technical solution, the light is selected from a wavelength of 360-445 nm, and the specific wavelength is preferably selected from 365 nm, 395 nm, 410 nm, 430 nm or 445 nm.

进一步地，在上述技术方案中，所述手性布朗斯特酸选自(S)-3,3'-双(1-芘基)-1,1'-联萘酚磷酸酯、(S)-3,3'-双(1-芘基)-5,5',6,6',7,7',8,8'-八氢-1,1'-联萘酚磷酸酯、(S)-1,9-二甲基-3,7-双(1-芘基)螺环二酚磷酸酯、(S)-10,10,13,13-四甲基-3,7-双(1-芘基)螺环二酚磷酸酯或(S)-6,6'-二芳基取代螺环二酚磷酸酯，其中：(S)-6,6'-二芳基取代螺环二酚磷酸酯的芳基取代基为10-苯基蒽-9-基、9-蒽基、9-菲基、3-荧蒽基或4-异丙基苯。Further, in the above technical solution, the chiral Bronsted acid is selected from (S)-3,3'-bis(1-pyrenyl)-1,1'-binaphthyl phosphate, (S) -3,3'-bis(1-pyrenyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl 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: (S)-6,6'-diaryl substituted spirocyclic diphenol phosphate The aryl substituent of the phenolic phosphate is 10-phenylanthracen-9-yl, 9-anthracenyl, 9-phenanthrenyl, 3-fluoranthyl or 4-isopropylbenzene.

进一步地，在上述技术方案中，所述多取代双环[1.1.0]丁烷类化合物1、乙烯基氮杂芳烃化合物2与手性布朗斯特酸摩尔比为1-2.5:1-2:0.1。Further, in the above technical solution, the molar ratio of the polysubstituted bicyclo[1.1.0]butane compound 1, vinyl azaarene compound 2 and chiral Brønsted acid is 1-2.5:1-2: 0.1.

进一步地，在上述技术方案中，反应在有机溶剂中进行，有机溶剂为起到溶解原料的作用。有机溶剂选自二氯甲烷、1,2-二氯乙烷、氯仿、甲苯、氟苯、氯苯、乙腈或乙醚。优选条件下为二氯甲烷。Further, in the above technical solution, the reaction is carried out 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. Dichloromethane is preferred under preferred conditions.

进一步地，在上述技术方案中，反应温度为-50℃至-10℃。Furthermore, in the above technical solution, the reaction temperature is -50°C to -10°C.

进一步地，在上述技术方案中，反应在惰性气体(氮气或氩气)保护下进行。Furthermore, in the above technical solution, the reaction is carried out under the protection of an inert gas (nitrogen or argon).

发明有益效果：Beneficial effects of the invention:

1)取代手性双环[2.1.1]己烷类化合物结构新颖，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分子间[2+2]光环加成反应，即可高效合成得到多取代手性双环[2.1.1]己烷类化合物3。1) The structure of substituted chiral bicyclo[2.1.1]hexane compounds is novel. It uses multi-substituted bicyclo[1.1.0]butane compounds 1 and vinyl azaarenes compounds 2 as raw materials. Multi-substituted chiral bicyclo[2.1.1]hexane compounds 3 can be efficiently synthesized through the intermolecular [2+2] photocycloaddition reaction in the presence of Ster's acid.

2)其合成方法具有高效、高立体选择性、底物适用范围广等优点。同时充分利用光催化优势，从多取代双环[1.1.0]丁烷衍生物出发通过环加成反应获得多种结构单元，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。2) Its synthesis method has the advantages of high efficiency, high stereoselectivity, and wide substrate application range. At the same time, we make full use of the advantages of photocatalysis to obtain a variety of structural units through cycloaddition reactions starting from multi-substituted bicyclo[1.1.0]butane derivatives, which is a multi-faceted bicyclo[2.1.1]hexane chiral bridged ring compound. Applications provide possibilities.

具体实施方式Detailed ways

以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。The above-mentioned contents of the present invention will be further described in detail below through examples, but this should not be understood to mean that the scope of the above-mentioned subject of the present invention is limited to the following examples. All technologies implemented based on the above-mentioned contents of the present invention belong to the scope of the present invention.

实施例1Example 1

通用方法：向25mL反应管中，加入化合物1a、化合物2a和手性布朗斯特酸催化剂后，加入二氯甲烷溶解，进行抽换气，使其充满氩气，置于低温冰箱中保持温度无光搅拌30分钟后放置LED灯珠照射，搅拌反应。反应结束，温度恢复至室温，转移至反应瓶，旋干，硅胶柱分离(石油醚/乙酸乙酯＝40/1-10/1)得到产物3a。General method: Add compound 1a, compound 2a and chiral Brønsted acid catalyst to a 25mL reaction tube, add methylene chloride to dissolve, ventilate until it is filled with argon, and place it in a low-temperature refrigerator to keep the temperature stable. After stirring for 30 minutes, place the LED lamp beads to illuminate and stir for reaction. At the end of the reaction, the temperature returned to room temperature, transferred to a reaction bottle, spun dry, and separated on a silica gel column (petroleum ether/ethyl acetate = 40/1-10/1) to obtain product 3a.

通过改变反应反应浓度、手性布朗斯特酸催化剂、物料配比和反应温度等反应条件，反应结果如下：By changing the reaction conditions such as reaction concentration, chiral Bronsted acid catalyst, material ratio and reaction temperature, the reaction results are as follows:

表1不同条件下3a的合成a Table 1 Synthesis of 3a under different conditionsa

实施例2Example 2

向25mL反应管中，加入1a(0.25mmol,2.5eq)、2a(0.10mmol)和手性布朗斯特酸催化剂C7(0.01mmol,0.1eq)后，加入无水二氯甲烷2mL充分混合，冷却后抽换气三次，使其充满氩气，置于低温冰箱中保持-40℃温度下无光搅拌30分钟后，控温-40℃至-50℃下，放置一枚3W，365nm波长LED灯珠于3厘米处照射，搅拌24-72小时。反应结束，温度恢复至室温，转移至反应瓶，旋干，硅胶柱分离(石油醚/乙酸乙酯＝40/1-10/1)得到黄色固体产物3a(30.0mg,77％)。To a 25mL reaction tube, add 1a (0.25mmol, 2.5eq), 2a (0.10mmol) and chiral Bronsted acid catalyst C7 (0.01mmol, 0.1eq), then add 2mL of anhydrous dichloromethane, mix thoroughly, and cool. Then pump and ventilate three times to make it full of argon. Place it in a low-temperature refrigerator and keep it at -40°C without light for 30 minutes. After stirring for 30 minutes, control the temperature from -40°C to -50°C and place a 3W, 365nm wavelength LED lamp. The beads were irradiated at 3 cm and stirred for 24-72 hours. After the reaction was completed, the temperature returned to room temperature, transferred to a reaction bottle, spun dry, and separated on a silica gel column (petroleum ether/ethyl acetate = 40/1-10/1) to obtain yellow solid product 3a (30.0 mg, 77%).

实施例3Example 3

依照实施例2的方法和步骤，仅仅通过改变反应物1和反应物2进行反应，得到多取代手性双环[2.1.1]己烷类化合物3a-3p,3x-3zl,具体结果如下：According to the method and steps of Example 2, only by changing reactant 1 and reactant 2 to carry out the reaction, poly-substituted chiral bicyclo[2.1.1]hexane compounds 3a-3p, 3x-3zl were obtained. The specific results are as follows:

代表性化合物表征数据如下：Characterization data of representative compounds 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C28H24NO+390.1852.The eewas 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).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 ) δ 202.4, 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 eewas determined by HPLC analysis: CHIRALPAK IA (4.6mm idx 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C29H26NO2 +420.1958.Theee 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).(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 ,142.7,137.0,136.1,132.8,131.3,130.1,128.4,127.8,126.9,126.6,126.3,125.3,123.6,121.7,119.6,105.8,60.8,55.5,52.5,51.6,50.0,4 2.5,40.1; HRMS(ESI )m/z 420.1958(M+H + ),calc.for C 29 H 26 NO 2 + 420.1958.Theee was determined by HPLC analysis: CHIRALPAK IA (4.6mm idx 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,CHCl3)；1HNMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C24H22NO+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).phenyl((1R,2R,4S)-4-phenyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)methanone(3c): yellow oil; 17.9 mg, 53% yield; 90%ee; (c 1.0, CHCl 3 ); 1 HNMR (600MHz, CDCl 3 ) δ8.50 (d, J = 4.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 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 ) δ 202.5, 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 idx 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)δ200.9,165.3(d,JF-C＝254.1Hz),161.0,148.9,142.4,136.3,133.9(d,JF-C＝3.1Hz),131.2(d,JF-C＝8.9Hz),128.5,126.6,126.2,123.4,121.8,115.4(d,JF-C＝22.0Hz),60.3,52.1,51.3,50.1,42.5,40.3；19F NMR(376MHz,CDCl3)δ-106.1；HRMS(ESI)m/z 358.1607(M+H+),calc.for C24H21FNO+358.1602.The ee was determined by HPLCanalysis:CHIRALPAK IE(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:10.6min(major)and 10.0min(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 = 4.3 Hz, 1H), 7.76 (dd, J = 8.7, 5.6 Hz, 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 ) δ 200.9, 165.3 (d, J FC = 254.1Hz), 161.0, 148.9, 142.4, 136.3, 133.9 (d ,J FC =3.1Hz),131.2(d,J FC =8.9Hz),128.5,126.6,126.2,123.4,121.8,115.4(d,J FC =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 HPLCanalysis: CHIRALPAK IE (4.6mm idx 250mm); Hexane/2-propanol=80/20; flow rate1.0mL/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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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.forC24H21ClNO+374.1306.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mmi.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retention time:9.4min(major)and 10.2min(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.forC 24 H 21 ClNO + 374.1306.The ee was determined by HPLC analysis: CHIRALPAK IA (4.6mmi.dx 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(101MHz,CDCl3)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 C27H30NOSi+412.2091.The ee was determined byHPLC analysis:CHIRALPAK ID(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flowrate 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)(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 = 4.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz,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＝8.4,3.6 Hz,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 idx 250mm); Hexane/2-propanol=80/20; flowrate 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C25H24NO+354.1852.The ee was determined byHPLC analysis:CHIRALPAK ID(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flowrate 1.0mL/min；20℃；254nm；reten tion time:16.3min(major)and 40.7min(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 = 4.6 Hz, 1H), 7.66 (d, J = 7.9 Hz, 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 idx 250mm); Hexane/2-propanol=80/20; flowrate 1.0mL/min; 20℃; 254nm; retention 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C28H30NO+396.2322.The ee was determined by HPLC analysis:CHIRALPAK ID(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:11.0min(major)and25.0min(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 = 4.2 Hz, 1H), 7.69 (d, J = 8.1 Hz, 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＝8.8 Hz,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 idx250mm); Hexane/2-propanol ＝80/20; flow rate 1.0mL/min; 20℃; 254nm; retention time: 11.0min (major) and 25.0min (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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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/z370.1808(M+H+),calc.for C25H24NO2 +370.1802.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:13.9min(major)and 15.9min(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 = 7.3 Hz,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/z370.1808(M+H + ),calc.for C 25 H 24 NO 2 + 370.1802.The ee was determined by HPLC analysis: CHIRALPAK IA (4.6mm idx 250mm); Hexane/2-propanol=80/20; flow rate1.0mL/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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)δ201.3,162.6(d,JF-C＝247.5Hz),160.9,148.8,142.3,139.7(d,JF-C＝6.6Hz),136.4,130.0(d,JF-C＝7.6Hz),128.5,126.7,126.2,124.2(d,JF-C＝3.2Hz),123.3,121.8,119.4(d,JF-C＝21.8Hz),115.3(d,JF-C＝22.1Hz),60.2,52.0,51.2,50.2,42.4,40.5；19F NMR(376MHz,CDCl3)δ-112.2；HRMS(ESI)m/z 358.1603(M+H+),calc.for C24H21FNO+358.1602.The ee was determinedby 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).(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 ) δ 201.3, 162.6 (d, J FC = 247.5Hz), 160.9, 148.8, 142.3, 139.7 (d, J FC = 6.6Hz), 136.4, 130.0 (d, J FC = 7.6Hz), 128.5,126.7,126.2,124.2(d,J FC =3.2Hz),123.3,121.8,119.4(d,J FC =21.8Hz),115.3(d,J FC =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 idx 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C25H24NO+354.1852.The ee was determined by HPLC analysis:CHIRALPAKIA(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).((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 (400 MHz, CDCl 3 )δ8.52(d, J＝4.0 Hz, 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, 3.7 Hz, 1H),2.84–2.68(m, 2H),2.65–2.56(m, 1H),2.47(dd, J＝9.3, 6.6 Hz, 1H),2.35–2.34(m, 1H),2.33(s, 3H),2.18(d, J＝6.3 Hz, 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 2 5 H 2 4 NO + 354.1852.The ee was determined by HPLC analysis:CHIRALPAKIA(4.6mm idx 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C28H30NO+396.2322.The eewas 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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/z384.1597(M+H+),calc.for C25H22NO3 +384.1594.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:12.0min(major)and 13.3min(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＝6.5,2.9 Hz, 1H), 2.20 (d, J = 6.6Hz, 1H), 1.29 (s, 9H); 13 C NMR (150MHz, CDCl 3 ) δ 203.1, 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 eewas determined by HPLC analysis: CHIRALPAK IE (4.6mm idx 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; 20.3 mg, 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/z384.1597(M+H + ),calc.for C 25 H 22 NO 3 + 384.1594.The ee was determined by HPLCanalysis:CHIRALPAK IA( 4.6mm idx 250mm); Hexane/2-propanol=80/20; flow rate1.0mL/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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)δ201.8,161.7,159.7(d,JF-C＝252.1Hz),148.6(d,JF-C＝5.2Hz),142.6,136.5,132.7,132.7,130.2(d,JF-C＝3.6Hz),128.5,126.7,126.2,124.2(d,JF-C＝3.5Hz),123.4,121.7,116.3(d,JF-C＝22.5Hz),60.7,50.4(d,JF-C＝4.2Hz),50.1(d,JF-C＝1.0Hz),49.8,41.7,41.6；19F NMR(376MHz,CDCl3)δ-112.3；HRMS(ESI)m/z 358.1606(M+H+),calc.for C24H21FNO+358.1602.The ee was determined byHPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flowrate 1.0mL/min；20℃；254nm；retention time:11.4min(major)and 7.7min(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 FC =252.1Hz),148.6(d,J FC =5.2Hz),142.6,136.5,132.7,132.7,130.2(d,J FC =3.6Hz),128.5,126.7 ,126.2,124.2(d,J FC =3.5Hz),123.4,121.7,116.3(d,J FC =22.5Hz),60.7,50.4(d,J FC =4.2Hz),50.1(d,J FC =1.0 Hz), 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 idx 250mm); Hexane/2-propanol=80/20; flowrate 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C27H25N2O+393.1960.The ee wasdetermined 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)and36.4min(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 ) δ 202.2, 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 idx 250mm); Hexane/2-propanol=80/20; flow rate 1.0mL/min; 20℃; 254nm; retention time: 29.8min (major)and36.4min(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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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/z424.1469(M+H+),calc.for C28H23ClNO+424.1463.The ee was determined by HPLCanalysis:CHIRALPAK IC(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:8.9min(major)and 9.7min(minor).((1R,2R,4S)-2-(3-chloropyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3y):yellow oil; 30.1 mg, 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 ) δ 202.5, 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/ z424.1469(M+H + ),calc.for C 28 H 23 ClNO + 424.1463.The ee was determined by HPLCanalysis: CHIRALPAK IC (4.6mm idx 250mm); Hexane/2-propanol=80/20; flow rate1. 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C29H23N2O+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).2-((1R,2R,4S)-1-(2-naphthoyl)-4-phenylbicyclo[2.1.1]hexan-2-yl)isonicotinonitrile(3zb): yellow oil; 27.1 mg, 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 ) δ 201.5, 163.1, 149.9, 142.0, 135.4, 134.8 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 idx 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,CHCl3)；1H 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)；13C NMR(150MHz,CDCl3)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；19F NMR(376MHz,Chloroform-d)δ-65.0；HRMS(ESI)m/z 458.1722(M+H+),calc.for C29H23F3NO+458.1726.The ee was determined byHPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flowrate 1.0mL/min；20℃；254nm；retention time:7.8min(major)and 18.6min(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 (400 MHz, Chloroform-d) δ8.65 (d, J＝5.1 Hz, 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＝5.2 Hz, 1H), 7.1 6 (s, 1H), 4.33–4.23 (m, 1H), 2.83–2.73 (m, 2H), 2.68 (ddd, J = 11.0, 8.9, 2.6 Hz, 1H), 2.58 (dd, J = 9.3, 6.6 Hz, 1H), 2.46 (dd, J = 6.6, 2.8 Hz, 1H), 2.33 (dt, J = 7.2, 2.0 Hz, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 201.9, 162.9, 149.9, 142.2, 138.3, 135.3, 135.0, 132.5, 129.8, 129.6, 128.8 (t, J = 14.8 Hz), 128.5, 128.4, 128.4, 127.9, 126.8, 126.2, 124.4, 122.8 (q, J = 275.9 Hz), 119.2 (q, J = 3.4 Hz), 117.3 (q, J = 3.1 Hz), 60.8, 52.2, 51.3, 50.3, 42.5, 40.4; 19 F NMR (376 MHz, 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 (4.6 mm idx 250 mm); Hexane/2-propanol = 80/20; flow rate 1.0 mL/min; 20°C; 254 nm; retention time: 7.8 min (major) and 18.6 min (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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C29H26NO+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-methylpyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zf):yellow oil; 40.0 mg, 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 404.2 011(M+ H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis: CHIRALPAK IA (4.6mm idx 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C29H26NO2 +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-(4-methoxypyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zg):yellow oil; 42.0 mg, 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 idx 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13CNMR(100MHz,CDCl3)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 C29H26NO+404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:10.8min(major)and 14.5min(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 CNMR (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(4.6 mm idx250mm); 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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/z404.2013(M+H+),calc.for C29H26NO+404.2009.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:7.1min(major)and 10.7min(minor).((1R,2R,4S)-2-(6-methylpyridin-2-yl)-4-phenylbicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3zk):yellow oil; 35.1 mg, 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 )δ202.4,160.5,157.6,142.7,136.4,135.2,135.1,132.5,130.1,129.6,128.5,128.2,128.0,127.8,126.6,126.6,126.2,124.9,121.1,11 9.9,60.2,52.1,51.5, 50.2,42.7,40.7,24.3; HRMS(ESI)m/z404.2013(M+H + ),calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm idx 250mm) ; Hexane/2-propanol=80/20; flow rate1.0mL/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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C31H27N2O+443.2118.The ee was determined byHPLC analysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flowrate 1.0mL/min；20℃；254nm；retention time:16.3min(major)and 10.6min(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 idx 250mm); Hexane/2-propanol=80/20; flowrate 1.0mL/min; 20℃; 254nm; retention time :16.3min(major)and 10.6min(minor).

实施例4Example 4

向25mL反应管中，加入1(0.10mmol)、2a(0.20mmol,2.0eq)和手性布朗斯特酸催化剂C7(0.01mmol,0.1eq)后，加入无水二氯甲烷2mL充分混合，冷却后抽换气三次，使其充满氩气，置于低温冰箱中保持-40℃温度下无光搅拌30分钟后，控温-40℃下，放置一枚3W，430nm波长的LED灯珠于3厘米处照射，搅拌48小时。反应结束，温度恢复至室温，转移至反应瓶，旋干，硅胶柱分离(石油醚/乙酸乙酯＝40/1-10/1)得到多取代手性双环[2.1.1]己烷类产物3q-3w，具体结果如下：In a 25mL reaction tube, 1 (0.10mmol), 2a (0.20mmol, 2.0eq) and chiral Bronsted acid catalyst C7 (0.01mmol, 0.1eq) were added, and then 2mL of anhydrous dichloromethane was added and mixed thoroughly. After cooling, the mixture was vented three times to fill it with argon gas, and then placed in a low-temperature refrigerator to maintain a temperature of -40°C without light and stirred for 30 minutes. Then, a 3W, 430nm wavelength LED lamp bead was placed at 3 cm to irradiate at -40°C and stirred for 48 hours. After the reaction was completed, the temperature was restored to room temperature, and the mixture was transferred to a reaction bottle, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate = 40/1-10/1) to obtain multi-substituted chiral bicyclo[2.1.1]hexane products 3q-3w. The specific results are as follows:

代表性化合物表征如下：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,CHCl3)；1HNMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)δ202.2,161.7(d,JF-C＝244.3Hz),160.9,148.9,138.3(d,JF-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,JF-C＝21.1Hz),60.7,52.3,51.7,49.5,42.6,40.2；19F NMR(376MHz,CDCl3)δ-116.4；HRMS(ESI)m/z 430.1582(M+Na+),calc.for C28H22FNNaO+430.1578.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:14.2min(major)and 21.4min(minor).((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 FC ＝244.3Hz),160.9,148.9,138.3(d, JFC ＝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 FC =21.1Hz),60.7,52.3,51.7,49.5,42.6,40.2; 19F 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 idx250mm ); 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C31H32NOSi+462.2248.The eewas 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C29H26NO+404.2009.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:12.0min(major)and 18.2min(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 eewas determined by HPLC analysis:CHIRALPAK IA( 4.6mm idx 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 idx250mm); Hexane/2-propanol＝80/20; flow rate 1.0mL/min; 20℃; 254nm; retentiontime:12.0min(major)and 18.2 min(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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C34H28NO+466.2165.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:16.0min(major)and 24.6min(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 HPLCanalysis: CHIRALPAK IA (4.6mm idx 250mm); Hexane/2-propanol=80/20; flow rate1.0mL/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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)δ202.0,163.1(d,JF-C＝245.6Hz),160.8,148.9,145.2(d,JF-C＝6.8Hz),136.3,135.3,134.7,132.5,130.1,130.0(d,JF-C＝8.6Hz),129.7,128.4,128.2,127.8,126.7,124.5,123.6,121.9,121.9,113.5(d,JF-C＝21.1Hz),113.3(d,JF-C＝21.3Hz),60.7,52.1,51.5,49.8,42.5,40.1；19F NMR(376MHz,CDCl3)δ-113.4；HRMS(ESI)m/z 408.1755(M+H+),calc.for C28H23FNO+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).((1R,2R,4S)-4-(3-fluorophenyl)-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(3u): yellow oil; 30.6 mg, 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 ) δ 202.0, 163.1 (d, J FC ＝ 245.6Hz), 160.8, 148.9, 145.2 (d, J FC ＝ 6.8Hz), 136.3, 135.3, 134.7 ,132.5,130.1,130.0(d,J FC =8.6Hz),129.7,128.4,128.2,127.8,126.7,124.5,123.6,121.9,121.9,113.5(d,J FC =21.1Hz),113.3(d,J FC = 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 idx 250mm); Hexane/2-propanol=80/20; flow rate 1.0mL/min; 20℃; 254nm; retention time: 11.6 min(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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C29H26NO+404.2009.The ee was determined by HPLC analysis:CHIRALPAKIA(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).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 (400 MHz, CDCl 3 ) δ8.52 (d, J＝4.6 Hz, 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, 4.2 Hz, 1H), 2.8 7 (dd, J = 9.2, 7.0 Hz, 1H), 2.81 (dt, J = 10.7, 3.5 Hz, 1H), 2.67–2.59 (m, 1H), 2.56 (dd, J = 9.2, 6.6 Hz, 1H), 2.39 (dd, J = 6.5, 2.8 Hz, 1H), 2.36 (s, 3H), 2.23 (d, J = 6.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 202.4, 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: CHIRALPAKIA (4.6mm idx 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C32H31NNaO+468.2298.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:6.4min(major)and 13.5min(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; 24.9 mg, 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 idx250mm); Hexane/2-propanol＝80/20; flow rate 1.0mL/min; 20℃; 254nm; retention time: 6.4min (major) and 13.5min(minor).

实施例5Example 5

向25mL反应管中，加入1a(0.25mmol,2.5eq)、2a(0.10mmol)和手性布朗斯特酸催化剂C7(0.01mmol,0.1eq)后，加入无水二氯甲烷2mL充分混合，冷却后抽换气三次，使其充满氩气，置于低温冰箱中保持-40℃温度下无光搅拌30分钟后，控温-40℃下，放置一枚3W，365nm波长的LED灯珠于3厘米处照射，搅拌24-48小时。反应结束，温度恢复至室温，转移至反应瓶，旋干，硅胶柱分离(石油醚/乙酸乙酯＝40/1-10/1)得到多取代手性双环[2.1.1]己烷类产物4a-4m，具体结果如下：To a 25mL reaction tube, add 1a (0.25mmol, 2.5eq), 2a (0.10mmol) and chiral Bronsted acid catalyst C7 (0.01mmol, 0.1eq), then add 2mL of anhydrous dichloromethane, mix thoroughly, and cool. Then pump and ventilate three times to make it full of argon. Place it in a low-temperature refrigerator and keep it at -40°C without light for 30 minutes. After stirring for 30 minutes, control the temperature at -40°C and place a 3W, 365nm wavelength LED lamp bead at 3 Centimeter, stir for 24-48 hours. After the reaction is completed, the temperature returns to room temperature, transferred to the reaction bottle, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate = 40/1-10/1) to obtain polysubstituted chiral bicyclo[2.1.1]hexane products. 4a-4m, the specific results are as follows:

代表性化合物表征如下：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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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/z404.2012(M+H+),calc.for C29H26NO+404.2009.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:9.6min(major)and 12.1min(minor).、((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/z404.2012(M+H + ) ,calc.for C 29 H 26 NO + 404.2009.The ee was determined by HPLC analysis: CHIRALPAK IA (4.6mm idx 250mm); Hexane/2-propanol=80/20; flow rate1.0mL/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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C32H32NO+446.2478.The ee wasdetermined 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).((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 idx 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C31H28NO+430.2165.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:11.3min(major)and 16.3min(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 (400 MHz, CDCl 3 )δ8.57 (d, J＝4.0 Hz, 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, 6.8 Hz, 1H), 2.99 (dd, J＝11.2, 2.6 Hz, 1H), 2.54–2.35 (m, 3H), 2.23 (dd, J = 11.2, 3.0 Hz, 1H), 1.82 (tt, J = 8.4, 5.7 Hz, 1H), 0.94 (tdd, J = 17.5, 9.6, 5.3 Hz, 2H), 0.44 (dq, J = 9.1, 5.1, 4.6 Hz, 1H), 0.10 (dq, J = 10.9, 5.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 202.9, 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/z 430.2166 (M+H + ), calc. for C 31 H 28 NO + 430.2165. The ee was determined by HPLC analysis: CHIRALPAK IA (4.6 mm idx250 mm); Hexane/2-propanol=80/20; flow rate 1.0 mL/min; 20°C; 254 nm; retention time: 11.3 min (major) and 16.3 min (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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C33H32NO+458.2478.The ee was determined by HPLC analysis:CHIRALPAK IE(4.6mm i.d.x250mm)；Hexane/2-propanol＝95/05；flow rate 1.0mL/min；20℃；254nm；retentiontime:33.5min(major)and 41.8min(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 .8,165.7,148.2,142.8,136.7,135.5,134.8,132.5,130.7,129.6,128.4,127.9,127.7,127.2,126.5,126.3,126.1,126.0,122.8,121.2,62.5,6 1.8,49.0,48.13,48.09,47.5 ,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 idx250mm); 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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C34H34NO+472.2635.The ee wasdetermined 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,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＝13.3 Hz,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 idx 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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 C23H22NO+328.1696.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:11.4min(major)and 16.8min(minor).((1S,2R,4R)-2-methyl-2-(pyridin-2-yl)bicyclo[2.1.1]hexan-1-yl)(naphthalen-2-yl)methanone(4f):yellow oil; 20.4 mg,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 )δ203.6,166.5,147.8,136.5,136.1,134.8,132.4,130.5,129.6,127.9,127.7,127.4,126.3,125.6,122.1,121.1,64.9,53.6,44.1,4 2.6,41.9,35.3,27.2 ; 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 idx250mm); 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(150MHz,CDCl3)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/z342.1854(M+H+),calc.for C24H24NO+342.1852.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm i.d.x 250mm)；Hexane/2-propanol＝80/20；flow rate1.0mL/min；20℃；254nm；retention time:5.1min(major)and 6.5min(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 )δ203.3,166.3,157.0,136.8,136.4,134.8,132.5,130.7,129.6,127.8,127.7,127.2,126.3,126.1,120.5,118.6,64.2,54.2,43.8,4 3.1,42.3,35.4,27.9 ,23.6; HRMS(ESI)m/z342.1854(M+H + ),calc.for C 24 H 24 NO + 342.1852.The ee was determined by HPLCanalysis:CHIRALPAK IA(4.6mm idx 250mm); Hexane/2- propanol=80/20; flow rate1.0mL/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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C24H24NO+342.1852.The ee was determined by HPLC analysis:CHIRALPAKIE(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-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 = 5.0 Hz, 1H), 7.95 (s, 1H), 7.81 (d, J = 8.1 Hz, 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 ) δ203.8,166.2,147.6,146.9,136.6,134.8,132.4,130.5,129.6,127.9,127.6,127.3,126.3,125.6,123.1,122.2,65.0,53.4,44.1,42.7,41.7,3 5.3,27.1,21.1; HRMS( ESI)m/z 342.1855(M+H + ),calc.for C 24 H 24 NO + 342.1852.The ee was determined by HPLC analysis: CHIRALPAKIE (4.6mm idx 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,CHCl3)；1H NMR(600MHz,CDCl3)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)；13CNMR(150MHz,CDCl3)δ203.5,162.5(d,JF-C＝3.5Hz),158.0(d,JF-C＝254.5Hz),136.4,135.6(d,JF-C＝23.0Hz),134.9,132.4,130.5,129.6,128.1,127.7,127.6,126.5,125.4,123.0(d,JF-C＝1.6Hz),122.9(d,JF-C＝12.6Hz),65.1,53.1,44.2,42.6,42.3,35.4,27.3；19F NMR(565MHz,CDCl3)δ-131.5；HRMS(ESI)m/z 346.1606(M+H+),calc.for C23H21FNO+346.1602.The ee was determined by HPLC analysis:CHIRALPAK IA(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flow rate 1.0mL/min；20℃；254nm；retentiontime:5.7min(major)and 7.2min(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 (600 MHz, 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=10.8 Hz, 1H), 2.53 (s, 1H), 2.27 (t, J=8.4 Hz, 1H), 2.06 (dd, J=10.1, 7.3 Hz, 2H), 1.95 (dd, J=13.9, 9.4 Hz, 2H), 1.66 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ203.5, 162.5 (d, J FC ＝3.5 Hz), 158.0 (d, J FC ＝254.5Hz), 136.4,135.6(d,J FC ＝23.0Hz), 134.9,132.4,130.5,129.6,128.1,127.7,127.6,126.5,125.4,123.0(d,J FC ＝1.6Hz),122.9(d,J FC ＝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 (4.6 mm idx250 mm); Hexane/2-propanol=80/20; flow rate 1.0 mL/min; 20°C; 254 nm; retention time: 5.7 min (major) and 7.2 min (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,CHCl3)；1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)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 C24H24NO+342.1852.The ee was determinedbyHPLC analysis:CHIRALPAK IE(4.6mm i.d.x250mm)；Hexane/2-propanol＝80/20；flowrate 1.0mL/min；20℃；254nm；reten tiontime:11.4min(major)and 15.3min(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 ) δ 203.7, 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 determined by HPLC analysis:CHIRALPAK IE(4.6mm idx250mm ); Hexane/2-propanol=80/20; flowrate 1.0mL/min; 20℃; 254nm; retention time: 11.4min (major) and 15.3min (minor).

以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the industry should understand that the present invention is not limited by the above embodiments. The above embodiments and descriptions only illustrate the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will also have various modifications. Changes and improvements, these changes and improvements all fall within the scope of protection of the present invention.

Claims (10)

1.多取代手性双环[2.1.1]己烷类化合物，其特征在于，结构通式如下：1. Multi-substituted chiral bicyclo[2.1.1]hexane compounds, characterized in that the general structural formula is as follows: 其中：R1为氢、C1-4烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R2为氢或C1-4烷基，R3为1-甲基苯并咪唑、吡啶基或取代吡啶基，取代吡啶基芳环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R4为C1-4烷基或C3-6环烷烃，R5为萘基、呋喃、吲哚、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。Wherein: R1 is hydrogen, C1-4 alkyl, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl is C1-4 alkyl, C1-4 alkoxy or halogen, R2 is hydrogen or C1-4 alkyl, R3 is 1-methylbenzimidazole, pyridyl or substituted pyridyl, the substituent on the aromatic ring of the substituted pyridyl is C1-4 alkyl, C1-4 alkoxy or halogen, R4 is C1-4 alkyl or C3-6 cycloalkane, R5 is naphthyl, furan, indole, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl is C1-4 alkyl, C1-4 alkoxy or halogen. 2.如权利要求1所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于，包括如下操作：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反应，得到多取代手性双环[2.1.1]己烷类化合物3；反应方程式表示为：2. The method for synthesizing a polysubstituted chiral bicyclo[2.1.1]hexane compound as claimed in claim 1, characterized in that it comprises the following operations: using a polysubstituted bicyclo[1.1.0]butane compound 1 and a vinyl azaaromatic compound 2 as raw materials, reacting under light induction and in the presence of a chiral Bronsted acid to obtain a polysubstituted chiral bicyclo[2.1.1]hexane compound 3; the reaction equation is expressed as: 其中：R1为氢、C1-4烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R2为氢或C1-4烷基，R3为1-甲基苯并咪唑、吡啶基或取代吡啶基，取代吡啶基芳环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R4为C1-4烷基或C3-6环烷烃，R5为萘基、呋喃、吲哚、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素。Among them: R 1 is hydrogen, C 1-4 alkyl, phenyl or substituted phenyl, the substituent on the substituted phenyl phenyl ring is 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 substituents on the substituted pyridyl aromatic ring are C 1-4 alkyl, C 1-4 alkyl Oxygen or halogen, R 4 is C 1-4 alkyl or C 3-6 cycloalkane, R 5 is naphthyl, furan, indole, phenyl or substituted phenyl, the substituent on the substituted phenyl phenyl ring is C 1-4 alkyl, C 1-4 alkoxy or halogen. 3.根据权利要求2所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：所述光选自360-445nm波长。3. The method for synthesizing multi-substituted chiral bicyclo[2.1.1]hexane compounds according to claim 2, characterized in that: the light is selected from the wavelength of 360-445nm. 4.根据权利要求3所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：光波长选自365nm、395nm、410nm、430nm或445nm。4. The method for synthesizing multi-substituted chiral bicyclo[2.1.1]hexane compounds according to claim 3, characterized in that: the light wavelength is selected from 365nm, 395nm, 410nm, 430nm or 445nm. 5.根据权利要求2所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：手性布朗斯特酸选自(S)-3,3'-双(1-芘基)-1,1'-联萘酚磷酸酯、(S)-3,3'-双(1-芘基)-5,5',6,6',7,7',8,8'-八氢-1,1'-联萘酚磷酸酯、(S)-1,9-二甲基-3,7-双(1-芘基)螺环二酚磷酸酯、(S)-10,10,13,13-四甲基-3,7-双(1-芘基)螺环二酚磷酸酯或(S)-6,6'-二芳基取代螺环二酚磷酸酯；其中：(S)-6,6'-二芳基取代螺环二酚磷酸酯的芳基取代基为10-苯基蒽-9-基、9-蒽基、9-菲基、3-荧蒽基或4-异丙基苯。5. The method for synthesizing multi-substituted chiral bicyclo[2.1.1]hexane compounds according to claim 2, characterized in that: the chiral Bronsted acid is selected from (S)-3,3'-bis(1 -Pyrenyl)-1,1'-binaphthyl phosphate, (S)-3,3'-bis(1-pyrenyl)-5,5',6,6',7,7',8, 8'-Octahydro-1,1'-binaphthol phosphate, (S)-1,9-dimethyl-3,7-bis(1-pyrenyl)spirodiphenol 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 (S)-6,6'-diaryl-substituted spirocyclic diphenol phosphate is 10-phenylanthracene-9-yl, 9-anthracenyl, 9-phenanthrenyl, 3- Fluoranthene or 4-isopropylbenzene. 6.根据权利要求2所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：反应在有机溶剂中进行，有机溶剂选自二氯甲烷、1,2-二氯乙烷、氯仿、甲苯、氟苯、氯苯、乙腈或乙醚。6. The method for synthesizing a polysubstituted chiral bicyclo[2.1.1]hexane compound according to claim 2, characterized in that the reaction is carried out in an organic solvent selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, fluorobenzene, chlorobenzene, acetonitrile or ether. 7.根据权利要求6所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：有机溶剂选自二氯甲烷。7. The method for synthesizing multi-substituted chiral bicyclo[2.1.1]hexane compounds according to claim 6, characterized in that: the organic solvent is selected from dichloromethane. 8.根据权利要求2所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：所述多取代双环[1.1.0]丁烷类化合物1、乙烯基氮杂芳烃化合物2与手性布朗斯特酸摩尔比为1-2.5:1-2:0.1。8. The method for synthesizing a polysubstituted chiral bicyclo[2.1.1]hexane compound according to claim 2, characterized in that the molar ratio of the polysubstituted bicyclo[1.1.0]butane compound 1, the vinyl nitrogen aromatic compound 2 and the chiral Bronsted acid is 1-2.5:1-2:0.1. 9.根据权利要求2所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：反应温度为-50℃至-10℃。9. The method for synthesizing multi-substituted chiral bicyclo[2.1.1]hexane compounds according to claim 2, characterized in that the reaction temperature is -50°C to -10°C. 10.根据权利要求2-9任意一项所述多取代手性双环[2.1.1]己烷类化合物的合成方法，其特征在于：反应在惰性气体保护下进行。10. The method for synthesizing the polysubstituted chiral bicyclo[2.1.1]hexane compounds according to any one of claims 2 to 9, characterized in that the reaction is carried out under the protection of an 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

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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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TW201129700A (en) * 2009-11-18 2011-09-01 Taisho Pharmaceutical Co Ltd Method for producing optically active bicyclo [310] hexane derivative using oxygen
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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
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