CN116891405A - 一种手性α，α-二芳基酮类化合物及其制备方法和应用 - Google Patents

一种手性α，α-二芳基酮类化合物及其制备方法和应用 Download PDF

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CN116891405A
CN116891405A CN202310656705.8A CN202310656705A CN116891405A CN 116891405 A CN116891405 A CN 116891405A CN 202310656705 A CN202310656705 A CN 202310656705A CN 116891405 A CN116891405 A CN 116891405A
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张祥志
刘宏福
李保琼
张艺瑞
吴腾飞
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Wuyi University
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Abstract

本发明公开了一种手性α，α‑二芳基酮类化合物及其制备方法和应用，其具有式Ⅰ所示的结构：其中，R1选自萘基、蒽基、喹啉基、未取代或被一个或多个C1～6的烷基、C1～6的烷氧基卤素、苯基、C2～10的炔基、硝基、氰基、三氟甲磺酸基、C2～10的酯基、醛基、C2～10的酮基、C1～6的卤代烷基取代的苯基；R2选自萘基、C2～10的酯基、C2～15的炔基、未取代或被一个或多个卤素、苯基、二甲基叔丁基硅醚基取代的C1～10的烷基、未取代或取代的苯基；R3选自H、C1～6的烷基、卤素。本发明提供的手性α，α‑二芳基酮类化合物可以用于吡啶菌酰胺、二芳基环氧丙烷和BRL‑15572类似物的立体选择性合成。

Description

一种手性α，α-二芳基酮类化合物及其制备方法和应用
技术领域
本发明涉及有机合成技术领域，尤其是涉及一种手性α，α-二芳基酮类化合物及其制备方法和应用。
背景技术
α，α-二芳基酮分子骨架广泛存在于许多具有重要生物活性的天然产物、有机功能材料以及人工合成的药物分子中。例如从龙脑香科植物茎部分离得到的Pauciflorol E，以及从扯根菜的保肝水煎剂中分离得到的Penchinones C与Penchinones D和用于治疗结核病的药物分子Volixibat Pharmacophore。局限于产物难以制备并且在羰基加成反应或储存期间可能会发生外消旋化，很少有有效的方法来对映选择性构建这种特定骨架，其原因在于α-H受到羰基的影响，表现出了相当强的酸性，导致在碱性或酸性条件下烯醇化从而引发外消旋，这一固有性质造成立体选择性极难控制。
基于此，有必要开发一系列新的手性α，α-二芳基酮类化合物。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明第一方面提出一种手性α，α-二芳基酮类化合物，可以用于天产物分子的修饰；或者用于吡啶菌酰胺(florylpicoxamid)、二芳基环氧丙烷(2-(diarylmethyl)oxirane)和人5-HT1D受体拮抗剂(BRL-15572)类似物的立体选择性合成。
本发明第二方面还提供一种α，α-二芳基酮类化合物的制备方法
本发明第三方面还提供一种α，α-二芳基酮类化合物的应用。
根据本发明的第一方面实施例提供的一种手性α，α-二芳基酮类化合物，具有式Ⅰ所示的结构：
其中，R1选自萘基、蒽基、喹啉基、未取代或被一个或多个C1～6的烷基、C1～6的烷氧基卤素、苯基、C2～10的炔基、硝基、氰基、三氟甲磺酸基、C2～10的酯基、醛基、C2～10的酮基、C1～6的卤代烷基取代的苯基；
R2选自萘基、C2～10的酯基、C2～15的炔基、未取代或被一个或多个卤素、苯基、二甲基叔丁基硅醚基取代的C1～10的烷基、未取代或被一个或多个C1～6的烷基、C1～6的烷氧基、苯基、C2～6的烯基、卤素取代的苯基；
R3选自H、C1～6的烷基、卤素。
根据本发明实施例的手性α，α-二芳基酮类化合物，至少具有如下有益效果：
本发明提供的手性α，α-二芳基酮类化合物可以用于天然产物分子的修饰；或者用于吡啶菌酰胺(florylpicoxamid)、二芳基环氧丙烷(2-(diarylmethyl)oxirane)和人5-HT1D受体拮抗剂(BRL-15572)类似物的立体选择性合成。
根据本发明的一些实施例，R2选自萘基、C4～7的酯基、C7～15的炔基、未取代或被一个或多个F、Cl、Br、苯基、二甲基叔丁基硅醚基取代的C1～10的烷基、未取代或被一个或多个C1～6的烷基、C1～6的烷氧基、苯基、C2～6的烯基、F、Cl、Br取代的苯基。
根据本发明的一些实施例，所述手性α，α-二芳基酮类化合物选自以下结构中的一种：
根据本发明的第二方面实施例提供的上述所述的手性α，α-二芳基酮类化合物的制备方法，包括如下步骤：
S1、将化合物1、化合物3和溶剂在可见光照射下反应得到中间体；
S2、将中间体、化合物2和手性磷酸催化剂混合进行反应，即得手性α，α-二芳基酮类化合物；
其中化合物1、化合物2和化合物3的结构式如下：
R4和R5独立地选自C1～6的烷基、苄基。
根据本发明实施例的手性α，α-二芳基酮类化合物的制备方法，至少具有如下有益效果：
现有技术难以制备并且在羰基加成反应或反应完成后的过程中可能会发生外消旋化，很少有有效的方法来对映选择性构建这种特定骨架，其原因在于α-H受到羰基的影响，表现出了相当强的酸性，导致在碱性或酸性条件下烯醇化从而引发外消旋，这一固有性质造成立体选择性极难控制。
本发明提供了一种简单实用的策略，以商业可得的炔烃化合物1、苯醌为原料，通过光催化形成醌式中间体后，化合物2作为氢源，手性磷酸(CPA)催化剂催化下完成了手性α，α-二芳基酮类化合物的制备，且该反应具有较高的收率和对映选择性。
根据本发明的一些实施例，所述可见光的波长为400nm～600nm。
根据本发明的一些实施例，所述手性磷酸催化剂选自以下结构式中的一种：
根据本发明的一些实施例，所述化合物2选自以下结构中的一种：
根据本发明的一些实施例，步骤S2中，所述反应的温度为-78℃～25℃。降低反应温度能够提高对映选择性，温度不能太低，温度太低会引起手性磷酸催化剂的反应活性降低。由此，反应的温度为-78℃～25℃。
根据本发明的一些实施例，步骤S2中，所述反应的时间为60～300min。
根据本发明的一些实施例，所述反应的制备原料中还加入了的分子筛。加入分子筛以减少体系含水量。
根据本发明的一些实施例，所述化合物1、化合物2、苯醌和手性磷酸催化剂的摩尔比为1：(0.5～4)：(0.5～4)：(0.01～1)。
根据本发明的一些实施例，所述反应中还加入了溶剂，所述溶剂选自氯苯、二氯甲烷、乙腈、甲苯或二氯乙烷中的至少一种。
本发明第三方面提供一种手性α，α-二芳基酮类化合物在制备吡啶菌酰胺、二芳基环氧丙烷或人5-HT1D受体拮抗剂类似物中的应用。
定义和一般术语
“C1～6的烷基”表示碳原子总数为1～6的烷基，包括C1～6的直链烷基、C1～6的支链烷基和C3～6的环烷基，例如可以为碳原子总数为1、2、3、4、5或6的直链烷基、碳原子总数为1、2、3、4、5或6的支链烷基或者碳原子总数为3、4、5或6的环烷基，例如可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、甲基环丙基、乙基环丙基、环戊基、甲基环戊基、环己基等。针对“C1～10的烷基”具有与此相似的解释，所不同的是，碳原子数不同。
“C1～6的烷氧基”表示碳原子总数为1-6的烷氧基，包括C1-6的直链烷氧基、C1-6的支链烷氧基和C2-6的环烷氧基，例如可以为碳原子总数为1、2、3、4、5或6的直链烷氧基、碳原子总数为1、2、3、4、5或6的支链烷氧基或者碳原子总数为2、3、4、5或6的环烷氧基，例如可以为甲氧基、乙氧基、正丙氧基、异丙氧基等。
“卤素”包括氟、氯、溴、碘中的任意一个或两个以上。
“C1～6的卤代烷基”与“C1～6的烷基”的定义相似，所不同的是，烷基中任意一个H原子由任意的卤素取代。
“C2～10的炔基”表示具有一个或多个三键的直链或支链的烃基，并且该炔基的碳原子总数为2-10，该基团中的三键可以在任意位置。“C2～15的炔基”具有相似的解释，所不同的是，碳原子数不同。
“C2～6的烯基”表示具有一个或多个双键的直链或支链的烃基，并且该烯基的碳原子总数为2-6，该基团中的双键可以在任意位置。
“C2～10的酯基”表示为碳原子总数为2～10的酯基，代表性的实例包括甲酸甲酯基、甲酸乙酯基、乙酸乙酯基、乙酸甲酯基等。
本发明的其它特征和优点将在随后的说明书中阐述，并且，部分地从说明书中变得显而易见，或者通过实施本发明而了解。
具体实施方式
以下是本发明的具体实施例，并结合实施例对本发明的技术方案作进一步的描述，但本发明并不限于这些实施例。
本发明所采用的试剂、方法和设备，如无特殊说明，均为本技术领域常规试剂、方法和设备。
本发明的制备的产物的ee值通过高效液相色谱(HPLC)分析测定得到。
实施例1
实施例1提供一种手性α，α-二芳基酮类化合物，其反应方程式和制备方法如下：
S1、室温下将化合物1(0.20mmol)、苯醌(0.10mmol)、二氯甲烷(2mL)，2×35W蓝色LEDs室温照射4h；生成醌式中间体；
S2、然后加入化合物2-1(0.15mmol)和手性磷酸催化剂(S)-C4(5mol％)，室温下反应30min，即得手性α，α-二芳基酮类化合物(收率为99％，ee值为52％)。
实施例2～8
实施例2～8提供一系列手性α，α-二芳基酮类化合物，其反应方程式和制备方法同实施例1，其区别在于，实施例2～8的手性磷酸催化剂不同，手性磷酸催化剂的结构式如下：其收率和ee值如表1。
表1
实施例9～13
实施例9～13提供一系列手性α，α-二芳基酮类化合物，其反应方程式和制备方法同实施例1，其区别在于，实施例9～13的化合物2的结构式不同，其结构式如下，收率和ee值见
表2：
表2
实施例14～16
实施例14～16提供一系列手性α，α-二芳基酮类化合物，其反应方程式和制备方法同实施例13，其区别在于，步骤S2的反应温度和添加剂不同，具体如下表3：
表3
实施例17
实施例17提供一种手性α，α-二芳基酮类化合物，其反应方程式和制备方法同实施例15，其区别在于，采用手性磷酸催化剂(R)-C11替代手性磷酸催化剂(S)-C4；制备得到的手性α，α-二芳基酮类化合物(收率为99％，ee值为90％)。
实施例18～60
实施例18～60提供了一系列手性α，α-二芳基酮类化合物，其化合物的结构式如下，其制备方法同实施例17，其区别在于化合物1的结构式不同，制备的手性α，α-二芳基酮类化合物、收率及ee值的数值见表4。
表4
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实施例1以及实施例18～60的表征数据如下：
实施例1； 1H NMR(500MHz,CDCl3)δ7.30(t,J＝7.4Hz,2H),7.27–7.21(m,1H),7.21–7.15(m,2H),7.02(d,J＝8.6Hz,2H),6.73(d,J＝8.6Hz,2H),6.35(s,1H),5.05(s,1H),2.22(s,3H).13C{1H}NMR(126MHz,CDCl3)δ208.5,155.1,138.3,130.1,129.7,128.8,128.7,127.2,115.7,64.2,29.9.HRMS(ESI)m/z:[M+Na]+Calcd forC15H14O2Na249.0886；Found 249.0887.The ee value was determined by the chiralHPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝13.5min,tmajor＝12.4min).
实施例18； 1H NMR(500MHz,CDCl3)δ7.13(d,J＝8.0Hz,2H),7.08(d,J＝8.1Hz,2H),7.03(d,J＝8.6Hz,2H),6.74(d,J＝8.5Hz,2H),5.01(s,1H),2.31(s,3H),2.22(s,3H).13C{1H}NMR(126MHz,CDCl3)δ208.2,155.0,136.9,135.4,130.1,129.4,128.7,115.6,63.9,29.9,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C16H17O2241.1223；Found241.1224.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝12.6min,tmajor＝11.3min)./>
实施例19； 1H NMR(500MHz,CDCl3)δ7.28(d,J＝8.5Hz,2H),7.11(d,J＝8.4Hz,2H),7.04(d,J＝8.5Hz,2H),6.77(d,J＝8.6Hz,2H),5.76(s,1H),5.02(s,1H),2.24(s,3H).13C{1H}NMR(126MHz,CDCl3)δ207.4,155.2,137.0,133.1,130.2,130.1,129.5,128.8,115.8,63.4,30.0.HRMS(ESI)m/z:[M+Na]+Calcd for C15H13ClO2Na283.0496；Found 283.0498.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝7.7min,tmajor＝7.0min).
实施例20； 1H NMR(500MHz,CDCl3)δ7.63(d,J＝8.4Hz,2H),7.04(d,J＝8.5Hz,2H),6.93(d,J＝8.3Hz,2H),6.77(d,J＝8.6Hz,2H),5.62(s,1H),4.99(s,1H),2.23(s,3H).13C{1H}NMR(126MHz,CDCl3)δ207.2,155.1,138.2,137.7,130.8,130.1,129.5,115.8,92.9,63.6,30.0.HRMS(ESI)m/z:[M+Na]+Calcd for C15H13IO2Na374.9852；Found 374.9851.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝16.8min,tmajor＝15.4min).
实施例21； 1H NMR(500MHz,CDCl3)δ7.31(t,J＝7.3Hz,2H),7.27–7.17(m,3H),7.05(d,J＝8.5Hz,2H),6.73(d,J＝8.6Hz,2H),5.08(s,1H),2.57(q,J＝7.3Hz,2H),1.05(t,J＝7.3Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ210.7,154.9,138.7,130.3,130.1,128.8,128.6,127.1,115.6,63.1,36.1,8.1.HRMS(ESI)m/z:[M+Na]+Calcd for C16H16O2Na 263.1043；Found 263.1044.The ee value was determined by thechiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝95:5,v＝1mL/min-1,λ＝254.0nm；tminor＝20.8min,tmajor＝22.8min).
实施例22；熔点为175-176℃, 1H NMR(500MHz,CDCl3)δ7.30(t,J＝7.4Hz,2H),7.27–7.16(m,3H),7.00(d,J＝8.5Hz,2H),6.70(d,J＝8.6Hz,2H),5.42(s,1H),5.20(s,1H),2.06–1.95(m,1H),1.13–1.07(m,2H),0.90–0.83(m,2H).13C{1H}NMR(126MHz,CDCl3)δ210.6,155.2,138.7,130.2,129.9,129.1,128.6,127.1,115.7,64.5,21.2,12.3.HRMS(ESI)m/z:[M+H]+Calcd for C17H17O2 253.1223；Found 253.1221.The eevalue was determined by the chiral HPLC analysis(CHIRALPAK IG,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝12.9min,tmajor＝14.4min).
实施例23； 1H NMR(500MHz,CDCl3)δ7.31(t,J＝7.4Hz,2H),7.27–7.16(m,3H),7.04(d,J＝8.6Hz,2H),6.73(d,J＝8.6Hz,2H),5.07(s,1H),2.54(t,J＝7.4Hz,2H),1.56(dt,J＝20.6,7.5Hz,2H),1.32–1.18(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ210.2,155.0,138.6,130.2,130.1,128.8,128.6,127.1,115.6,63.3,42.6,26.1,22.2,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C18H21O2 269.1536；Found 269.1537.The ee value was determined by the chiral HPLC analysis(CHIRALPAK IC,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝245.0nm；tminor＝12.1min,tmajor＝10.7min).
实施例24； 1H NMR(500MHz,CDCl3)δ7.17–6.99(m,6H),6.73(d,J＝8.5Hz,2H),5.03(s,1H),2.52(t,J＝7.4Hz,2H),2.31(s,3H),1.55(dt,J＝15.1,7.5Hz,2H),1.33–1.18(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ210.1,154.9,136.8,135.6,130.5,130.1,129.4,128.7,115.6,62.9,42.5,26.1,22.2,21.0,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C19H23O2 283.1698；Found 283.1696.The ee valuewas determined by the chiral HPLC analysis(CHIRALPAK IC,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝230.0nm；tminor＝11.8min,tmajor＝12.9min).
实施例25； 1H NMR(500MHz,CDCl3)δ7.60–7.49(m,4H),7.41(t,J＝7.6Hz,2H),7.32(t,J＝7.4Hz,1H),7.25(d,J＝8.2Hz,2H),7.08(d,J＝8.6Hz,2H),6.76(d,J＝8.6Hz,2H),5.10(s,1H),2.56(t,J＝7.4Hz,2H),1.66–1.48(m,2H),1.32–1.21(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ210.2,155.1,140.6,139.9,137.7,130.1,129.2,128.7,127.3,127.2,127.0,115.7,62.9,42.6,26.1,22.2,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C24H25O2 345.1849；Found 345.1847.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝8.6min,tmajor＝7.3min).
实施例26； 1H NMR 1H NMR(500MHz,CDCl3)δ7.45–7.28(m,2H),7.11(d,J＝8.2Hz,2H),7.02(d,J＝8.5Hz,2H),6.73(d,J＝8.6Hz,2H),5.68(s,1H),5.03(s,1H),2.52(t,J＝7.4Hz,2H),2.39(t,J＝7.1Hz,2H),1.66–1.40(m,6H),1.31–1.17(m,2H),0.93(t,J＝7.3Hz,3H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.7,155.0,138.0,131.8,130.1,128.7,122.9,115.6,90.7,80.2,63.0,42.6,30.8,26.1,22.2,22.0,19.1,13.8,13.6.HRMS(ESI)m/z:[M+H]+Calcd for C24H29O2 349.2162；Found349.2159.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝240.0nm；tminor＝10.0min,tmajor＝11.0min).
实施例27； 1H NMR(500MHz,CDCl3)δ7.42(d,J＝8.2Hz,2H),7.05(dd,J＝12.7,8.4Hz,4H),6.75(d,J＝8.3Hz,2H),5.64(s,1H),5.02(s,1H),2.65–2.41(m,2H),1.70–1.48(m,2H),1.39–1.12(m,2H),0.84(t,J＝7.3Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.5,155.1,137.8,131.6,130.5,130.0,129.7,121.1,115.8,62.5,42.6,26.0,22.1,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C18H20O2Br 347.0647；Found347.0651.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIC,n-hexane/2-propanol＝95:5,v＝1mL/min-1,λ＝254.0nm；λ＝254.0nm；tminor＝16.6min,tmajor＝15.4min).
实施例28； 1H NMR(500MHz,CDCl3)δ7.27(d,J＝8.5Hz,2H),7.12(d,J＝8.5Hz,2H),7.03(d,J＝8.6Hz,2H),6.75(d,J＝8.6Hz,2H),5.04(s,1H),2.63–2.45(m,2H),1.63–1.47(m,2H),1.33–1.17(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.7,155.1,137.2,133.0,130.2,130.0,129.8,128.7,115.8,62.5,42.6,26.0,22.1,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C18H20ClO2 303.1146；Found303.1144.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIG,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝6.5min,tmajor＝5.8min)./>
实施例29； 1H NMR(500MHz,CDCl3)δ7.15(dd,J＝8.6,5.4Hz,2H),7.04(d,J＝8.5Hz,2H),6.99(t,J＝8.7Hz,2H),6.76(d,J＝8.6Hz,2H),5.64(s,1H),5.05(s,1H),2.60–2.47(m,2H),1.61–1.50(m,2H),1.31–1.18(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.8,161.9(d,1JC-F＝245.9Hz),155.0,134.5,134.5,130.4,130.3,130.1,130.0,115.7,115.5,115.3,62.4,42.5,26.1,22.2,13.8.19FNMR(471MHz,CDCl3)δ-115.6.HRMS(ESI)m/z:[M+H]+Calcd for C18H20FO2 287.1442；Found287.1440.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIC,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝225.0nm；tminor＝8.0min,tmajor＝7.4min).
实施例30； 1H NMR(500MHz,CDCl3)δ7.25(dd,J＝14.0,7.9Hz,1H),7.05(d,J＝8.5Hz,2H),6.99–6.84(m,3H),6.76(d,J＝8.6Hz,2H),6.02(s,1H),5.06(s,1H),2.67–2.46(m,2H),1.66–1.47(m,2H),1.33–1.17(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.7,162.8(d,1JC-F＝246.2Hz),155.2,141.2,141.1,130.1,130.0,129.9,129.4,124.5,124.5,116.0,115.8,115.8,114.1,113.9,62.8,42.6,26.0,22.1,13.7.19F NMR(471MHz,CDCl3)δ-112.7.HRMS(ESI)m/z:[M+H]+Calcd forC18H20FO2 287.1442；Found 287.1439.The ee value was determined by the chiralHPLC analysis(CHIRALPAK IC,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝235.0nm；tminor＝7.2min,tmajor＝7.9min).
实施例31； 1H NMR(500MHz,CDCl3)7.24–7.17(m,1H),7.13–6.94(m,5H),6.79(d,J＝8.6Hz,2H),6.18(s,1H),5.31(s,1H),2.69–2.44(m,2H),1.68–1.48(m,2H),1.36–1.17(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.4,160.3(d,1JC-F＝245.4Hz),155.4,130.6,130.1,130.1,128.8,128.7,127.7,126.7,126.5,124.0,124.0,115.9,115.2,115.0,56.2,56.1,42.2,26.0,22.1,13.7.19F NMR(471MHz,CDCl3)δ-116.3.HRMS(ESI)m/z:[M+H]+Calcd for C18H20FO2 287.1442；Found287.1440.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane/2-propanol＝98:2,v＝1mL/min-1,λ＝254.0nm；tminor＝47.1min,tmajor＝49.5min).
实施例32； 1H NMR(500MHz,CDCl3)δ7.07(d,J＝8.6Hz,2H),6.80(d,J＝8.6Hz,2H),6.75–6.64(m,3H),5.53(s,1H),5.02(s,1H),2.68–2.44(m,2H),1.65–1.47(m,2H),1.34–1.18(m,2H),0.85(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.6,163.0(d,1JC-F＝248.4Hz),162.8(d,1JC-F＝248.4Hz),155.3,142.6,130.1,128.9,116.0,111.9,111.9,111.8,111.7,102.7,102.5,102.3,62.5,42.7,26.0,22.1,13.7.19F NMR(471MHz,CDCl3)δ-109.7.HRMS(ESI)m/z:[M-H]-Calcd for C18H17F2O2303.1202；Found 303.1197.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝5.1min,tmajor＝5.7min).
实施例33； 1H NMR(500MHz,CDCl3)δ7.13–6.96(m,4H),6.93–6.85(m,1H),6.78(d,J＝8.6Hz,2H),5.92(s,1H),5.02(s,1H),2.64–2.45(m,2H),1.67–1.47(m,2H),1.37–1.15(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.4,155.3,149.8(dd,1JC-F＝248.1,93.5Hz),149.7(dd,1JC-F＝248.0,93.3Hz),135.8,135.8,135.7,130.0,129.3,124.8,124.7,124.7,124.7,117.9,117.8,117.2,117.0,115.9,62.1,42.6,26.0,22.1,13.7.19F NMR(471MHz,CDCl3)δ-137.27,-137.32,-140.1,-140.2.HRMS(ESI)m/z:[M+H]+Calcd for C18H19F2O2 305.1348；Found 305.1344.The eevalue was determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝85:15,v＝1mL/min-1,λ＝254.0nm；tminor＝6.7min,tmajor＝7.6min).
实施例34； 1H NMR(500MHz,CDCl3)δ7.36(d,J＝8.3Hz,1H),7.29–7.20(m,1H),7.11–6.98(m,3H),6.80(d,J＝8.5Hz,2H),5.21(s,1H),5.00(s,1H),2.70–2.40(m,2H),1.63–1.50(m,2H),1.34–1.19(m,2H),0.85(t,J＝7.3Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.4,155.2,139.1,132.5,131.2,130.8,130.3,130.1,129.3,128.2,116.0,62.1,42.6,26.0,22.2,13.8.HRMS(ESI)m/z:[M–H]-Calcd for C18H17Cl2O2335.0611；Found335.0609.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IG,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝9.8min,tmajor＝9.0min).
实施例35； 1H NMR(500MHz,CDCl3)δ7.52(t,J＝1.7Hz,1H),7.25(d,J＝1.7Hz,2H),7.05(d,J＝8.6Hz,2H),6.79(d,J＝8.6Hz,2H),5.99(s,1H),4.98(s,1H),2.73–2.37(m,2H),1.66–1.46(m,2H),1.36–1.14(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.8,155.5,142.6,132.7,130.6,130.1,128.5,122.9,116.1,62.2,42.6,25.9,22.1,13.7.HRMS(ESI)m/z:[M–H]-Calcd for C18H17Br2O2424.9580；Found424.9574.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝5.2min,tmajor＝5.9min).
实施例36； 1H NMR(500MHz,CDCl3)δ7.26(d,J＝8.8Hz,2H),7.19(d,J＝8.8Hz,2H),7.06(d,J＝8.5Hz,2H),6.79(d,J＝8.6Hz,2H),5.91(s,1H),5.09(s,1H),2.65–2.46(m,2H),1.66–1.47(m,2H),1.33–1.17(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.3,155.4,148.5,139.4,130.6,130.1,129.2,121.3,118.7(q,1JC-F＝320.7Hz),116.0,62.3,42.6,26.0,22.1,13.7.19F NMR(471MHz,CDCl3)δ-72.9.HRMS(ESI)m/z:[M+H]+Calcd for C19H20F3O5S 417.0938；Found 417.0972.The eevalue was determined by the chiral HPLC analysis(CHIRALPAK IG,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝240.0nm；tminor＝10.3min,tmajor＝8.7min).
实施例37； 1H NMR(500MHz,CDCl3)δ8.14(d,J＝8.8Hz,2H),7.35(d,J＝8.7Hz,2H),7.09(d,J＝8.5Hz,2H),6.82(d,J＝8.6Hz,2H),5.55(s,1H),5.16(s,1H),2.70–2.46(m,2H),1.69–1.49(m,2H),1.35–1.15(m,2H),0.85(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.3,155.5,146.8,146.3,130.1,129.7,128.8,123.6,116.1,62.8,42.7,26.0,22.1,13.7.HRMS(ESI)m/z:[M–H]-Calcd for C18H18NO4 312.1241；Found 312.1239.The ee value was determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝235.1nm；tminor＝22.3min,tmajor＝24.1min).
实施例38； 1H NMR(500MHz,CDCl3)δ7.57(d,J＝8.3Hz,2H),7.29(d,J＝8.3Hz,2H),7.06(d,J＝8.6Hz,2H),6.81(d,J＝8.6Hz,2H),5.12(s,1H),2.70–2.46(m,2H),1.69–1.48(m,2H),1.33–1.18(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.6,155.6,144.4,132.2,130.1,129.6,128.6,118.7,116.1,110.6,63.0,42.7,25.9,22.1,13.7.HRMS(ESI)m/z:[M–H]-Calcd for C19H18NO2 292.1343；Found292.1340.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane/2-propanol＝85:15,v＝1mL/min-1,λ＝254.0nm；tminor＝11.6min,tmajor＝12.8min).
实施例39； 1H NMR(500MHz,CDCl3)δ7.97(d,J＝8.4Hz,2H),7.27(d,J＝8.3Hz,2H),7.05(d,J＝8.5Hz,2H),6.79(d,J＝8.6Hz,2H),5.11(s,1H),3.89(s,3H),2.64–2.46(m,2H),1.66–1.49(m,2H),1.33–1.18(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.2,209.1,167.2,167.2,155.5,155.4,144.2,130.1,129.8,128.9,128.6,115.8,63.1,52.2,42.6,26.0,22.1,13.7.HRMS(ESI)m/z:[M+H]+Calcd for C20H23O4 327.1591；Found 327.1589.The ee value was determined by thechiral HPLC analysis(CHIRALPAK IG,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝43.3min,tmajor＝38.6min).
实施例40； 1H NMR(500MHz,CDCl3)δ9.96(s,1H),7.82(d,J＝8.2Hz,2H),7.36(d,J＝8.2Hz,2H),7.09(d,J＝8.6Hz,2H),6.81(d,J＝8.6Hz,2H),5.14(s,1H),2.65–2.48(m,2H),1.63–1.50(m,2H),1.34–1.19(m,2H),0.85(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.7,192.2,155.4,146.0,135.0,130.1,130.0,129.5,129.1,115.9,63.2,42.7,26.0,22.1,13.8.HRMS(ESI)m/z:[M–H]-Calcd for C19H19O3 295.1340；Found295.1335.The ee value was determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝9.0min,tmajor＝10.2min).
实施例41； 1H NMR 1H NMRδ7.84–7.69(m,4H),7.63–7.52(m,1H),7.45(t,J＝7.7Hz,2H),7.31(d,J＝8.3Hz,2H),7.08(d,J＝8.6Hz,2H),6.82(d,J＝8.6Hz,2H),6.65(s,1H),5.15(s,1H),2.71–2.46(m,2H),1.68–1.48(m,2H),1.35–1.17(m,2H),0.85(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.2,196.9,155.6,143.9,137.3,136.0,132.6,130.4,130.1,130.0,129.0,128.8,128.3,115.9,63.1,42.7,26.0,22.1,13.8.HRMS(ESI)m/z:[M–H]-Calcd for C25H23O3 371.1653；Found 371.1648.The eevalue was determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝12.3min,tmajor＝14.1min).
实施例42； 1H NMR(500MHz,CDCl3)δ7.82(dd,J＝8.2,5.6Hz,2H),7.71(d,J＝8.1Hz,2H),7.32(d,J＝8.0Hz,2H),7.21–7.03(m,4H),6.81(d,J＝8.4Hz,2H),5.82(s,1H),5.14(s,1H),2.65–2.48(m,2H),1.69–1.50(m,2H),1.37–1.15(m,2H),0.86(t,J＝7.3Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.9,195.2,165.4(d,1JC-F＝254.3Hz),155.4,143.8,136.0,133.6,133.6,132.7,132.6,130.2,130.1,129.4,128.9,115.9,115.5,115.4,63.1,42.7,26.0,22.2,13.8.19F NMR(471MHz,CDCl3)δ-105.7.HRMS(ESI)m/z:[M+H]+Calcd for C25H24FO3 391.1704；Found 391.1700.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝13.3min,tmajor＝16.7min).
实施例43； 1H NMR(500MHz,CDCl3)δ7.72(dd,J＝8.4,6.2Hz,4H),7.43(d,J＝8.6Hz,2H),7.31(d,J＝8.2Hz,2H),7.10(d,J＝8.6Hz,2H),6.81(d,J＝8.6Hz,2H),5.98(s,1H),5.14(s,1H),2.70–2.46(m,2H),1.64–1.52(m,2H),1.32–1.19(m,2H),0.85(t,J＝7.3Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.2,195.6,155.6,144.1,139.0,135.7,135.6,131.4,130.2,130.1,129.0,128.9,128.6,115.9,63.1,42.7,26.0,22.1,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C25H24ClO3 407.1408；Found 407.1407.Theee value was determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝9.0min,tmajor＝12.1min).
实施例44； 1H NMR(500MHz,CDCl3)δ7.72(d,J＝8.3Hz,2H),7.36(d,J＝8.4Hz,1H),7.25(d,J＝8.3Hz,2H),7.07(d,J＝8.6Hz,2H),6.80(d,J＝8.6Hz,2H),6.61–6.41(m,2H),5.79(s,1H),5.11(s,1H),3.86(s,3H),3.69(s,3H),2.65–2.45(m,2H),1.63–1.49(m,2H),1.36–1.15(m,2H),0.85(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.8,195.4,163.4,159.6,155.3,143.6,137.4,132.3,130.1,130.1,129.6,128.6,121.2,115.8,104.4,98.8,63.2,55.6,55.5,42.6,26.0,22.2,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C27H29O5 433.2010；Found 433.2007.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IG,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝44.7min,tmajor＝60.9min).
实施例45； 1H NMR(500MHz,CDCl3)δ7.95(d,J＝8.3Hz,2H),7.80(d,J＝15.7Hz,1H),7.67–7.58(m,2H),7.49(d,J＝15.7Hz,1H),7.44–7.37(m,3H),7.33(d,J＝8.3Hz,2H),7.08(d,J＝8.5Hz,2H),6.82(d,J＝8.6Hz,2H),6.36(s,1H),5.14(s,1H),2.65–2.47(m,2H),1.66–1.48(m,2H),1.35–1.19(m,2H),0.85(t,J＝7.3Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.0,190.6,155.5,145.2,144.2,136.7,134.7,130.7,130.1,129.2,129.8,128.9,128.8,128.5,121.9,115.9,63.1,42.7,26.0,22.1,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C27H27O3 399.1955；Found 399.1953.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IG,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝23.4min,tmajor＝26.9min).
实施例46； 1H NMR(500MHz,CDCl3)δ7.90(d,J＝8.3Hz,2H),7.29(d,J＝8.3Hz,2H),7.08(d,J＝8.5Hz,2H),6.81(d,J＝8.6Hz,2H),5.12(s,1H),2.63–2.49(m,5H),1.63–1.50(m,2H),1.32–1.21(m,2H),0.85(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ208.8,198.3,155.4,144.5,135.7,130.1,129.3,129.1,128.6,115.9,63.1,42.7,26.6,26.0,22.2,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C20H23O3 311.1642；Found 311.1638.The ee value was determined by the chiral HPLC analysis(CHIRALPAK ID,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝12.1min,tmajor＝10.9min)./>
实施例47； 1H NMR(500MHz,CDCl3)δ7.96–7.87(m,1H),7.84(dd,J＝6.2,3.0Hz,1H),7.77(d,J＝8.2Hz,1H),7.53–7.37(m,3H),7.20(d,J＝7.1Hz,1H),7.00(d,J＝8.5Hz,2H),6.68(d,J＝8.5Hz,2H),5.86(s,1H),5.79(s,1H),2.70–2.51(m,2H),1.67–1.52(m,2H),1.33–1.17(m,2H),0.82(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ210.6,155.0,134.5,134.1,131.8,130.4,129.5,129.0,128.1,126.5,126.4,125.7,125.3,123.3,115.6,59.6,42.6,26.3,22.2,13.8.HRMS(ESI)m/z:[M–H]-Calcd forC22H21O2 317.1547；Found 317.1541.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IC,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝230.0nm；tminor＝8.0min,tmajor＝6.1min).
实施例48； 1H NMR(500MHz,CDCl3)δ7.81–7.72(m,3H),7.61(s,1H),7.47–7.40(m,2H),7.31(dd,J＝8.5,1.8Hz,1H),7.06(d,J＝8.6Hz,2H),6.73(d,J＝8.6Hz,2H),5.93(s,1H),5.22(s,1H),2.57(t,J＝7.4Hz,2H),1.58(dt,J＝20.7,7.5Hz,2H),1.34–1.19(m,2H),0.83(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ210.4,155.0,136.2,133.4,132.4,130.2,130.1,128.3,127.8,127.6,127.4,127.1,126.2,125.9,115.6,63.3,42.7,26.1,22.2,13.8.HRMS(ESI)m/z:[M–H]-Calcd for C22H21O2 317.1547；Found 317.1542.The ee value was determined by the chiral HPLC analysis(CHIRALPAK IC,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝6.6min,tmajor＝7.5min).
实施例49； 1H NMR(500MHz,CDCl3)δ8.72(d,J＝8.1Hz,1H),8.64(d,J＝8.2Hz,1H),7.95(d,J＝8.1Hz,1H),7.79(d,J＝8.2Hz,1H),7.71–7.52(m,4H),7.45(s,1H),7.08(d,J＝8.5Hz,2H),6.73(d,J＝8.5Hz,2H),5.79(s,1H),5.39(s,1H),2.80–2.53(m,2H),1.67–1.58(m,2H),1.33–1.21(m,2H),0.84(t,J＝7.3Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ210.1,155.0,132.8,131.2,131.1,130.8,130.5,130.0,129.4,128.8,127.5,126.9,126.9,126.9,126.5,124.1,123.4,122.4,115.6,59.9,42.8,26.3,22.2,13.8.HRMS(ESI)m/z:[M–H]-Calcd for C26H23O2 367.1704；Found 367.1699.The ee valuewas determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝7.7min,tmajor＝6.2min).
实施例50； 1H NMR(500MHz,CDCl3)δ8.83(dd,J＝4.3,1.6Hz,1H),8.20(d,J＝7.6Hz,1H),7.84–7.79(m,2H),7.48–7.38(m,2H),7.07(d,J＝8.5Hz,2H),6.82(d,J＝8.6Hz,2H),5.25(s,1H),2.64–2.49(m,2H),1.68–1.48(m,2H),1.36–1.17(m,2H),0.84(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.2,157.0,149.5,147.1,142.2,136.8,130.3,128.6,127.8,127.7,127.3,127.1,121.1,116.2,63.4,42.5,26.1,22.2,13.8.HRMS(ESI)m/z:[M+H]+Calcd for C21H22NO2 320.1645；Found320.1643.The ee value was determined by the chiral HPLC analysis(CHIRALPAKID,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝18.1min,tmajor＝16.6min).
实施例51； 1H NMR(500MHz,CDCl3)δ7.36–7.24(m,3H),7.24–7.16(m,2H),7.07(d,J＝8.4Hz,2H),6.78(d,J＝8.5Hz,2H),5.33(s,1H),4.19(s,2H).13C{1H}NMR(126MHz,CDCl3)δ201.0,155.2,137.4,130.2,129.0,128.9,128.8,127.6,115.8,60.0,48.0.HRMS(ESI)m/z:[M–H]-Calcd for C15H12ClO2 259.0531；Found259.0529.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIG,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝280.0nm；tminor＝15.3min,tmajor＝14.1min).
实施例52； 1H NMR(500MHz,CDCl3)δ7.57(d,J＝8.2Hz,2H),7.32(d,J＝8.1Hz,2H),7.09(d,J＝8.5Hz,2H),6.81(d,J＝8.5Hz,2H),5.24(s,1H),5.13(s,1H),3.67–3.39(m,2H),2.85–2.62(m,2H),2.17–1.97(m,2H).13C{1H}NMR(126MHz,CDCl3)δ207.6,155.3,142.5,130.1,129.5,129.3,129.2,129.1,125.5,125.5,124.0(q,1JC-F＝272.1Hz),116.0,63.1,44.2,39.5,26.4.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)m/z:[M–H]-Calcd for C18H15ClF3O2 355.0718；Found 355.0713.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝6.8min,tmajor＝7.4min).
实施例53； 1H NMR(500MHz,CDCl3)δ7.55(d,J＝8.2Hz,2H),7.30(d,J＝8.2Hz,2H),7.06(d,J＝8.6Hz,2H),6.78(d,J＝8.6Hz,2H),5.12(s,1H),2.64–2.49(m,2H),1.66–1.50(m,2H),1.32–1.18(m,2H),0.85(t,J＝7.4Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.3,155.3,142.8,130.1,129.4,129.3,129.2,125.4,125.4,124.1(q,1JC-F＝272.0Hz),115.9,62.9,42.7,26.0,22.1,13.7.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)m/z:[M–H]-Calcd for C19H18F3O2 335.1264；Found 335.1262.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝215.0nm；tminor＝8.9min,tmajor＝9.8min).
实施例54； 1H NMR(500MHz,CDCl3)δ7.55(d,J＝8.2Hz,2H),7.31(d,J＝8.2Hz,2H),7.07(d,J＝8.6Hz,2H),6.78(d,J＝8.6Hz,2H),5.54(s,1H),5.12(s,1H),2.66–2.45(m,2H),1.68–1.49(m,2H),1.35–1.12(m,6H),0.84(t,J＝7.0Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ209.3,155.3,142.8,130.1,129.4,129.3,129.2,129.2,125.5,125.5,125.4,125.4,124.1(q,1JC-F＝272.1Hz),115.9,62.9,43.0,31.4,28.7,23.9,22.4,14.0.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)m/z:[M–H]-Calcd forC21H22F3O2 363.1577；Found 363.1574.The ee value was determined by the chiralHPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝5.1min,tmajor＝5.8min).
实施例55； 1H NMR(500MHz,CDCl3)δ7.55(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz,2H),7.06(d,J＝8.4Hz,2H),6.78(d,J＝8.4Hz,2H),5.08(s,1H),2.42(d,J＝6.8Hz,2H),1.96–1.78(m,1H),1.77–1.49(m,5H),1.33–1.17(m,2H),1.09(dt,J＝15.6,8.3Hz,1H),0.97–0.77(m,2H).13C{1H}NMR(126MHz,CDCl3)δ208.7,155.3,142.7,130.2,129.4,129.2,129.2,125.4,124.1(q,1JC-F＝272.2Hz),115.9,63.4,50.5,33.9,33.1,32.9,26.1,25.0,25.9.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)m/z:[M–H]-Calcdfor C22H22F3O2375.1577；Found 375.1572.The ee value was determined by the chiralHPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝5.3min,tmajor＝6.5min).
实施例56； 1H NMR(500MHz,CDCl3)δ7.64(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),7.15(d,J＝8.5Hz,2H),6.87(d,J＝8.6Hz,2H),5.27(s,1H),4.38–3.52(m,2H),2.96–2.70(m,2H),0.96(s,9H),0.133(s,3H),0.131(s,3H).13C{1H}NMR(126MHz,CDCl3)δ207.6,155.2,145.7,142.6,136.4,130.4,129.4,129.3,129.2,129.1,128.4,125.4,125.4,124.1(q,1JC-F＝271.9Hz),119.5,115.9,63.7,59.0,45.3,25.9,18.3,-5.5.HRMS(ESI)m/z:[M–H]-Calcd for C23H28F3O3Si 437.1765；Found 437.1759.19FNMR(471MHz,CDCl3)δ-62.5.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IG,n-hexane/2-propanol＝85:15,v＝1mL/min-1,λ＝254.0nm；tminor＝4.3min,tmajor＝3.8min).
实施例57； 1H NMR(500MHz,CDCl3)δ7.55(d,J＝8.2Hz,2H),7.31(d,J＝8.2Hz,2H),7.08(d,J＝8.5Hz,2H),6.79(d,J＝8.6Hz,2H),5.37(s,1H),5.11(s,1H),3.56(t,J＝6.3Hz,2H),2.65–2.50(m,2H),1.68–1.60(m,2H),1.52–1.39(m,2H),0.87(s,9H),0.02(s,6H).13C{1H}NMR(126MHz,CDCl3)δ208.6,155.3,142.8,130.1,129.4,129.3,129.2,125.5,125.4,124.1(q,1JC-F＝271.9Hz),115.9,62.8,62.8,42.7,31.9,25.9,20.4,18.3,-5.4.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)m/z:[M–H]-Calcdfor C25H32F3O3Si465.2078；Found 465.2072.The ee value was determined by thechiral HPLC analysis(CHIRALPAK IG,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝5.0min,tmajor＝4.5min).
实施例58； 1H NMR(500MHz,CDCl3)δ7.55(d,J＝8.1Hz,2H),7.31(d,J＝8.1Hz,2H),7.06(d,J＝8.5Hz,2H),6.77(d,J＝8.5Hz,2H),6.05(s,1H),5.17(s,1H),4.12(q,J＝7.1Hz,2H),2.86(t,J＝6.5Hz,2H),2.71–2.50(m,2H),1.23(t,J＝7.1Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ207.2,174.3,173.1,155.5,142.6,130.2,129.5,129.2,129.2,128.9,125.5,125.48,125.45,125.42,125.40,124.1(q,1JC-F＝272.0Hz),115.9,106.3,63.0,61.0,37.2,28.4,14.1.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)m/z:[M+H]+Calcd for C20H20F3O4 381.1308；Found 381.1306.The ee value was determinedby the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝254.0nm；tminor＝13.9min,tmajor＝16.6min).
实施例59； 1H NMR(500MHz,CDCl3)δ7.54(dd,J＝14.3,8.2Hz,4H),7.44(d,J＝8.1Hz,2H),7.31(d,J＝8.1Hz,2H),7.08(d,J＝8.5Hz,2H),6.79(d,J＝8.5Hz,2H),5.30(s,1H),5.12(s,1H),2.76–2.53(m,2H),2.38(t,J＝7.0Hz,2H),1.92–1.66(m,2H),1.63–1.45(m,2H).13C{1H}NMR(126MHz,CDCl3)δ208.2,155.2,142.7,131.7,130.1,129.5,129.5,129.4,129.2,129.2,129.1,127.6,125.5,125.5,125.4,125.1,125.1,125.1,124.04(q,1JC-F＝270.1Hz),123.97(q,1JC-F＝270.1Hz),115.9,92.3,79.92,62.9,42.2,27.7,23.1,19.2.19F NMR(471MHz,CDCl3)δ-62.5,-62.7.HRMS(ESI)m/z:[M–H]-Calcd for C28H21F6O2503.1451；Found 503.1447.The ee value was determined by thechiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝6.7min,tmajor＝8.0min)/>
实施例60； 1H NMR(500MHz,CDCl3)δ7.51(d,J＝8.2Hz,2H),7.29–7.15(m,5H),7.12–7.08(m,2H),6.98(d,J＝8.6Hz,2H),6.74(d,J＝8.6Hz,2H),5.61(s,1H),5.01(s,1H),2.99–2.80(m,4H).13C{1H}NMR(126MHz,CDCl3)δ208.0,155.2,142.4,140.4,130.1,129.2,129.0,128.5,128.4,126.2,125.4,125.4,124.0(q,1JC-F＝272.0Hz),63.3,44.2,30.0.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)m/z:[M–H]-Calcdfor C23H18F3O2383.1264；Found 383.1260.The ee value was determined by the chiralHPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝6.9min,tmajor＝8.8min).
实施例61
实施例61提供一种手性α，α-二芳基酮类化合物，其反应方程式和制备方法如下：
S1、室温下将化合物1(0.20mmol)、苯醌(0.10mmol)、二氯甲烷(2mL)，2×35W蓝色LEDs室温照射4h；生成醌式中间体；
S2、然后加入化合物2-6(0.15mmol)、MS(60mg)和手性磷酸催化剂(R)-C2(5mol％)，-60℃下反应3h，即得手性α，α-二芳基酮类化合物(收率为95％，ee值为91％)。
实施例62～67
实施例62～67提供了一系列的手性α，α-二芳基酮类化合物，其采用实施例61的制备方法制备下列化合物，结构式、收率和ee值如下：
其实施例61～67的数据表征如下：
实施例61； 1H NMR(500MHz,CDCl3)δ7.96(d,J＝7.6Hz,2H),7.42(t,J＝7.4Hz,1H),7.38–7.12(m,7H),7.02(d,J＝8.5Hz,2H),6.82(s,1H),6.67(d,J＝8.5Hz,2H),5.96(s,1H).13C{1H}NMR(126MHz,CDCl3)δ199.9,155.0,139.1,136.4,133.2,130.3,130.1,128.9,128.6,128.6,127.0,115.7,58.5.HRMS(ESI)m/z:[M+H]+Calcdfor C20H17O2 289.1223；Found 289.1222.The ee value was determined by the chiralHPLC analysis(CHIRALPAK IF,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝7.3min,tmajor＝8.1min).
实施例62； 1H NMR(500MHz,CDCl3)δ7.97(d,J＝8.9Hz,2H),7.15(d,J＝8.7Hz,2H),7.05(d,J＝8.6Hz,2H),6.85(dd,J＝15.0,8.8Hz,4H),6.71(d,J＝8.6Hz,2H),5.88(s,1H),5.83(s,1H),3.81(s,3H),3.74(s,3H).13C{1H}NMR(126MHz,CDCl3)δ198.0,163.4,158.5,154.8,131.7,131.5,131.3,130.1,130.0,129.6,115.6,114.1,113.8,57.4,55.4,55.2.HRMS(ESI)m/z:[M+H]+Calcd for C22H21O4 349.1434；Found349.1432.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝23.3min,tmajor＝26.4min).
实施例63； 1H NMR(500MHz,CDCl3)δ7.89(d,J＝8.3Hz,2H),7.19(d,J＝8.0Hz,2H),7.15–7.06(m,6H),6.73(d,J＝8.6Hz,2H),5.91(s,1H),5.11(s,1H),2.36(s,3H),2.29(s,3H).13C{1H}NMR(126MHz,CDCl3)δ198.6,154.6,143.9,136.7,136.5,134.2,131.5,130.3,129.4,129.3,129.1,128.9,115.6,58.1,21.6,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C22H21O2 317.1536；Found 317.1533.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝12.7min,tmajor＝15.2min).
实施例64； 1H NMR(500MHz,CDCl3)δ7.92(d,J＝8.3Hz,2H),7.21(d,J＝8.3Hz,2H),7.18–7.06(m,6H),6.72(d,J＝8.6Hz,2H),5.93(s,1H),5.91–5.75(m,2H),5.34(s,1H),5.09–4.90(m,4H),2.75–2.69(m,2H),2.69–2.61(m,2H),2.41–2.28(m,4H).13C{1H}NMR(126MHz,CDCl3)δ198.8,154.7,147.7,140.6,138.1,137.4,136.9,134.6,131.3,130.3,129.2,128.9,128.7,128.7,115.6,115.4,114.8,58.1,35.3,35.3,34.9,34.9.HRMS(ESI)m/z:[M+H]+Calcd for C28H29O2 397.2168；Found 397.2169.The eevalue was determined by the chiral HPLC analysis(CHIRALPAK IF,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝7.4min,tmajor＝8.3min).
实施例65； 1H NMR(500MHz,DMSO)δ9.42(d,J＝9.5Hz,1H),8.23–8.00(m,2H),7.41–7.21(m,4H),7.22–7.05(m,4H),6.72(dd,J＝13.3,5.3Hz,2H),6.30(s,1H),3.41(s,1H).13C{1H}NMR(126MHz,DMSO)δ196.9,165.9,164.9(d,1JC-F＝252.3Hz),161.0(d,1JC-F＝243.2Hz),136.2,136.2,132.9,132.9,131.8,131.8,130.9,130.9,129.9,129.2,115.9,115.7,115.6,115.1,114.9,56.0.19F NMR(471MHz,DMSO)δ-105.7,-116.3.HRMS(ESI)m/z:[M+Na]+Calcd for C20H14F2O2Na 347.0854；Found347.0857.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝8.9min,tmajor＝11.1min).
实施例66；熔点为213–214℃, 1H NMR(500MHz,DMSO)δ8.16(d,J＝8.5Hz,2H),7.79(d,J＝8.4Hz,2H),7.72(d,J＝7.3Hz,2H),7.62(dd,J＝11.2,7.8Hz,4H),7.54–7.31(m,8H),7.15(d,J＝8.5Hz,2H),6.72(d,J＝8.5Hz,2H),6.35(s,1H).13C{1H}NMR(126MHz,DMSO)δ197.9,144.6,139.9,139.4,138.8,138.5,135.2,130.0,129.6,129.6,129.1,128.9,128.4,127.4,127.0,127.0,126.7,126.6,115.6,56.6.HRMS(ESI)m/z:[M+H]+Calcd for C32H25O2 441.1849；Found 441.1848.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IF,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝18.4min,tmajor＝17.0min).
实施例67； 1H NMR(500MHz,CDCl3)δ8.56(s,1H),8.07(dd,J＝8.7,1.7Hz,1H),7.94–7.65(m,7H),7.61–7.36(m,5H),7.17(d,J＝8.5Hz,2H),6.77(d,J＝8.6Hz,2H),6.28(s,1H).13C{1H}NMR(126MHz,CDCl3)δ198.9,155.0,137.0,135.5,134.0,133.4,132.4,131.0,130.8,130.5,129.7,128.6,128.5,128.5,127.9,127.7,127.6,127.6,127.3,126.7,126.1,125.9,124.6,115.8,58.7.HRMS(ESI)m/z:[M+H]+Calcd forC28H21O2 389.1536；Found 389.1533.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IF,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝254.0nm；tminor＝12.3min,tmajor＝14.1min).应用例1
吡啶菌酰胺类似物的合成
Florylpicoxamid是陶氏益农公司开发的第2代吡啶酰胺类杀菌剂，该剂可用于谷物、葡萄、果树、坚果、蔬菜等防治壳针孢属、葡萄孢属、链核盘菌属、链格孢属真菌引起的病害以及白粉病、炭疽病、斑点病等，其作用于真菌复合体III Qi泛醌(即辅酶Q)键合位点，通过抑制线粒体呼吸作用而致效。
本发明通过一系列反应成功实现该药物的不对称合成，合成路线如下：
制备步骤如下：
室温氮气保护下，芳基炔烃化合物1(4mmol，2.0equiv)和苯醌(2mmol，1.0equiv)溶于CH2Cl2(40mL)溶液中，蓝色LED(2×35W)下照射4h，然后将反应混合物冷却至–60℃，将MS(1.2g)、(R)-C11(0.1mmol,5mol％)和化合物2-6(3mmol,1.5equiv)依次添加到体系中。将所得混合物在–60℃下搅拌3h。待反应完成后，将混合物真空浓缩，直接进行硅胶柱层析(洗脱液：石油醚/乙酸乙酯＝3:1)得到化合物Ⅰ-102；
在0℃下向化合物Ⅰ-102(390.8mg，1.6mmol)的甲醇(16mL)溶液中加入NaBH4(90.8mg，2.4mmol)。反应混合物在室温下搅拌1h，待反应完成后，DCM萃取。有机层经Na2SO4干燥，减压浓缩，残余物通过硅胶柱层析(洗脱液：石油醚/乙酸乙酯/二氯甲烷3:1:3至1:1:1)纯化得到产物Ⅰ-103和Ⅰ-103'；
在0℃下，向化合物Ⅰ-103(123.1mg，0.5mmol)的CH2Cl2(5mL)溶液中依次加入Et3N(105ul，0.75mmol)，4-甲苯磺酰氯(114.4mg，0.6mmol)，0℃下搅拌1h。反应完全后，将混合物真空浓缩，直接进行硅胶柱层析(洗脱液：石油醚/乙酸乙酯2:1)得到化合物Ⅰ-104。
室温下，Ⅰ-104(195mg，0.49mmol)、DMAP(6mg，0.049mmol)、(S)-2-((叔丁氧基羰基)氨基)丙酸(111.3mg，0.588mmol)溶于CH2Cl2(5mL)溶液中，0℃下加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDCI)(187.9mg,0.9mmol)。室温下反应12h。真空浓缩，直接进行硅胶柱层析(洗脱液：石油醚/乙酸乙酯1:1)得化合物Ⅰ-105；
室温下，向化合物Ⅰ-105(171.5mg，0.3mmol)的1,4-二氧六环(2mL)溶液中加入HCl(1mL，4mol，4N)。将反应搅拌过夜，然后真空浓缩得到粘稠物。加入乙醚(10mL)后混合物剧烈搅拌30分钟。过滤混合物，用乙醚冲洗，然后用正己烷冲洗，真空干燥后得到粗产物丙氨酸盐酸盐。向丙氨酸盐酸盐、3-羟基-4-甲氧基吡啶甲酸Ⅰ-106(55.8mg,0.33mmol)的DCM(3mL)混合溶液中加入PyBOP(171.7mg,0.33mmol)和N,N-二异丙基乙胺(183uL,10.5mmol)，室温下反应搅拌24h，真空浓缩后直接进行硅胶柱层析(洗脱液：石油醚/乙酸乙酯1:2)，得白色泡沫状固体产物Ⅰ-107；
将化合物Ⅰ-107(62.3mg,0.1mmol)、三乙胺(0.5mL)和乙酸酐(0.5mL,5mol)加入到25ml烧瓶中。室温搅拌1h，真空浓缩后直接进行硅胶柱层析(洗脱液：石油醚/乙酸乙酯1:1)得到产物Ⅰ-108。
产物表征：
化合物Ⅰ-102； 1H NMR(500MHz,CDCl3)δ7.21–7.10(m,2H),7.10–6.91(m,4H),6.77(d,J＝8.5Hz,2H),5.61(s,1H),5.04(s,1H),2.24(s,3H).13C{1H}NMR(126MHz,CDCl3)δ207.7,δ161.9(d,1JC-F＝246.3Hz),155.1,134.2,134.2,130.4,130.4,130.1,115.8,115.6,115.4,63.3,29.9.19F NMR(471MHz,CDCl3)δ-115.4.HRMS(ESI)m/z:[M+Na]+Calcd for C15H13FO2Na 267.0792；Found 267.0789.The ee value was determinedby the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝90:10,v＝1mL/min-1,λ＝210.0nm；tminor＝13.9min,tmajor＝12.6min).
化合物Ⅰ-103；熔点为124-125℃,94％ee, 1H NMR(500MHz,DMSO)1H NMR(500MHz,DMSO)δ9.11(s,1H),7.29(dd,J＝8.7,5.7Hz,2H),7.14(d,J＝8.5Hz,2H),7.05(t,J＝8.9Hz,2H),6.64(d,J＝8.5Hz,2H),4.48(d,J＝5.3Hz,1H),4.40–4.23(m,1H),3.65(d,J＝8.4Hz,1H),0.96(d,J＝6.1Hz,3H).13C{1H}NMR(126MHz,DMSO)δ160.5(d,1JC-F＝241.8Hz),155.4,140.9,140.9,133.5,129.8,129.8,129.5,114.9,114.8,7.18,57.8,22.8.19F NMR(471MHz,DMSO)δ-117.6.HRMS(ESI)m/z:[M-H]-Calcd for C15H14FO2245.0983；Found 245.0981.The ee value was determined by the chiral HPLCanalysis(CHIRALPAK IA,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝6.6min,tmajor＝5.4min).
化合物Ⅰ-104； 1H NMR(500MHz,CDCl3)δ7.70(d,J＝8.3Hz,2H),7.37–7.22(m,4H),7.22–7.11(m,2H),7.06–6.88(m,4H),4.54–4.27(m,1H),3.78(d,J＝8.2Hz,1H),2.44(s,3H),1.15(d,J＝6.2Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ161.5(d,1JC-F＝245.5Hz),148.3,145.4,140.3,137.7,137.7,132.4,129.8,129.7,129.6,129.6,128.4,122.6,115.6,115.4,69.9,58.6,21.7,21.6.19F NMR(471MHz,CDCl3)δ-115.9.HRMS(ESI)m/z:[M-H]-Calcd for C22H20FO4S 399.1072；Found 399.1072.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝80:20,v＝1mL/min-1,λ＝240.0nm；tminor＝11.6min,tmajor＝9.9min).
化合物Ⅰ-105； 1H NMR(500MHz,CDCl3)δ7.67(d,J＝8.3Hz,2H),7.29(d,J＝8.0Hz,2H),7.24–7.14(m,4H),6.98(t,J＝8.6Hz,2H),6.90(d,J＝8.6Hz,2H),5.98–5.47(m,1H),4.96(d,J＝7.6Hz,1H),4.18–4.05(m,1H),4.01(d,J＝10.1Hz,1H),2.44(s,3H),1.42(s,9H),1.19(d,J＝6.2Hz,3H),0.78(d,J＝7.2Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ172.6,δ161.7(d,1JC-F＝246.3Hz),154.9,148.3,145.3,140.2,136.3,132.4,129.7,129.5,129.4,129.1,128.3,122.4,115.8,115.6,79.7,72.7,56.3,49.0,28.2,21.6,19.1,18.0.19F NMR(471MHz,CDCl3)δ-115.2.HRMS(ESI)m/z:[M+Cl]-Calcd forC30H34FNO7SCl606.1729；Found 606.1741.
化合物Ⅰ-107；1H NMR(500MHz,CDCl3)δ12.05(s,1H),8.33(d,J＝7.9Hz,1H),7.98(d,J＝5.2Hz,1H),7.67(d,J＝8.3Hz,2H),7.29(d,J＝8.0Hz,2H),7.24–7.14(m,4H),6.98(t,J＝8.6Hz,2H),6.92–6.83(m,3H),5.81–5.54(m,1H),4.62–4.39(m,1H),4.03(d,J＝9.9Hz,1H),3.95(s,3H),2.43(s,3H),1.22(d,J＝6.2Hz,3H),1.00(d,J＝7.2Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ171.4,168.5,161.7(d,1JC-F＝246.1Hz),155.3,148.6,148.2,145.3,140.4,140.0,136.1,136.1,132.3,130.1,129.7,129.5,129.4,129.1,128.3,122.3,115.7,115.6,109.4,73.1,56.2,56.0,47.7,21.6,18.9,17.5.19F NMR(471MHz,CDCl3)δ-115.2.HRMS(ESI)m/z:[M+H]+Calcd for C32H32FN2O8S 623.1858；Found 623.1851.
化合物Ⅰ-108； 1H NMR(500MHz,CDCl3)δ8.40(s,1H),8.32(d,J＝5.4Hz,1H),7.67(d,J＝8.3Hz,2H),7.29(d,J＝8.0Hz,2H),7.23–7.10(m,4H),7.07–6.92(m,3H),6.88(d,J＝8.7Hz,2H),5.80–5.58(m,1H),4.65–4.40(m,1H),4.02(d,J＝9.8Hz,1H),3.91(s,3H),2.43(s,3H),2.38(s,3H),1.20(d,J＝6.2Hz,3H),0.92(d,J＝7.2Hz,3H).13C{1H}NMR(126MHz,CDCl3)δ172.0,168.8,162.3,161.7(d,1JC-F＝246.1Hz),159.4,148.3,146.6,145.3,141.3,140.1,137.4,136.3,136.3,132.3,129.7,129.6,129.5,129.2,128.3,122.4,115.8,115.6,109.8,72.9,56.3,56.2,47.7,21.6,20.7,19.0,18.0.19F NMR(471MHz,CDCl3)δ-115.3.HRMS(ESI)m/z:[M+H]+Calcd for C34H34FN2O9S665.1964；Found 665.1954.
应用例2
葛兰素史克公司的BRL-15572类似物的制备：
S1、将实施例51制备的化合物(R)-Ⅰ-51或(S)-Ⅰ-51'(208.6mg,0.8mmol)的甲醇(8mL)溶液中加入NaBH4(45.4mg,1.2mmol)，室温下搅拌1h。待反应完全后，反应混合物用CH2Cl2萃取。有机层经Na2SO4干燥，减压浓缩，残余物直接硅胶柱层析(洗脱液：石油醚/乙酸乙酯/二氯甲烷5:1:5至2:1:2)纯化得到还原产物SⅠ-51。
S2、在装有磁性搅拌子的25mL圆形烧瓶中依次加入SⅠ-51(26.3mg,0.1mmol)、哌嗪2-110(29.5mg,25uL,0.15mmol)、K2CO3(55.3mg,0.2mmol)和KI(3.3mg,0.02mmol)，乙腈(1mL)，反应混合物在90℃下反应24h。真空浓缩后直接进行硅胶柱层析(洗脱液：石油醚/乙酸乙酯2:1至1:1)得产物2-111，即得到BRL-15572类似物。
其BRL-15572类似物的表征数据如下：
化合物(R,S)-2-111为白色泡沫状固体，分离收率为93％(39.2mg),92％ee, 1H NMR(500MHz,CDCl3)δ7.69–6.99(m,8H),6.99–6.51(m,5H),4.68–4.25(m,1H),3.79(d,J＝8.1Hz,1H),3.44–2.96(m,4H),2.92–2.65(m,2H),2.62–2.44(m,2H),2.43–2.22(m,2H).13C{1H}NMR(126MHz,CDCl3)δ154.4,152.1,141.9,134.9,133.8,130.0,129.3,128.6,128.5,126.5,119.5,115.8,115.5,113.9,68.6,62.5,55.8,52.9,48.7.HRMS(ESI)m/z:[M+H]+Calcd for C25H28ClN2O2 423.1834；Found 423.1826.The eevalue was determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝9.1min,tmajor＝10.8min).
化合物(R,R)-2-111为白色泡沫状固体，分离收率为98％(41.4mg),92％ee, 1H NMR(500MHz,CDCl3)δ7.34–7.08(m,4H),6.91–6.70(m,1H),6.64(d,J＝8.5Hz,1H),4.57–4.33(m,1H),3.78(d,J＝8.4Hz,1H),3.33–2.97(m,2H),2.88–2.63(m,1H),2.54–2.43(m,1H),2.41–2.26(m,1H).13C{1H}NMR(126MHz,CDCl3)δ154.4,152.1,142.0,134.9,133.4,130.0,129.6,128.7,128.1,126.6,119.5,115.8,115.5,113.9,68.5,62.5,56.0,52.9,48.7.HRMS(ESI)m/z:[M+H]+Calcd for C25H28ClN2O2 423.1834；Found423.1826.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝13.4min,tmajor＝7.7min).
化合物(S,R)-2-111为白色泡沫状固体，分离收率为96％(40.4mg),92％ee, 1H NMR(500MHz,CDCl3)δ7.69–6.99(m,8H),6.99–6.51(m,5H),4.68–4.25(m,1H),3.79(d,J＝8.1Hz,1H),3.44–2.96(m,4H),2.92–2.65(m,2H),2.62–2.44(m,2H),2.43–2.22(m,2H).13C{1H}NMR(126MHz,CDCl3)δ154.4,152.1,141.9,134.9,133.8,130.0,129.3,128.6,128.5,126.5,119.5,115.8,115.5,113.9,68.6,62.5,55.8,52.9,48.7.HRMS(ESI)m/z:[M+H]+Calcd for C25H28ClN2O2 423.1834；Found 423.1826.The eevalue was determined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝10.8min,tmajor＝9.0min).
化合物(S,S)-2-111为白色泡沫状固体，分离收率为98％(41.4mg),93％ee, 1H NMR(500MHz,CDCl3)δ7.34–7.08(m,4H),6.91–6.70(m,1H),6.64(d,J＝8.5Hz,1H),4.57–4.33(m,1H),3.78(d,J＝8.4Hz,1H),3.33–2.97(m,2H),2.88–2.63(m,1H),2.54–2.43(m,1H),2.41–2.26(m,1H).13C{1H}NMR(126MHz,CDCl3)δ154.4,152.1,142.0,134.9,133.4,130.0,129.6,128.7,128.1,126.6,119.5,115.8,115.5,113.9,68.5,62.5,56.0,52.9,48.7.HRMS(ESI)m/z:[M+H]+Calcd for C25H28ClN2O2 423.1834；Found423.1826.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane/2-propanol＝70:30,v＝1mL/min-1,λ＝254.0nm；tminor＝7.7min,tmajor＝13.5min).
由此，本发明制备的手性α，α-二芳基酮类化合物合成了吡啶菌酰胺类似物的杀菌剂以及葛兰素史克公司的BRL-15572类似物。本发明的手性α，α-二芳基酮类化合物的应用不限于此，也可以用于天然产物的的结构修饰、2-(二芳基甲基)环氧乙烷的制备。
上面结合本发明实施例作了详细说明，但本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。

Claims (10)

1.一种手性α，α-二芳基酮类化合物，其特征在于，具有式Ⅰ所示的结构：
其中，R1选自萘基、蒽基、喹啉基、未取代或被一个或多个C1～6的烷基、C1～6的烷氧基、卤素、苯基、C2～10的炔基、硝基、氰基、三氟甲磺酸基、C2～10的酯基、醛基、C2～10的酮基、C1～6的卤代烷基取代的苯基；
R2选自萘基、C2～10的酯基、C2～15的炔基、未取代或被一个或多个卤素、苯基、二甲基叔丁基硅醚基取代的C1～10的烷基、未取代或被一个或多个C1～6的烷基、C1～6的烷氧基、苯基、C2～6的烯基、卤素取代的苯基；
R3选自H、C1～6的烷基、卤素。
2.根据权利要求1所述的手性α，α-二芳基酮类化合物，其特征在于，R2选自萘基、C4～7的酯基、C7～15的炔基、未取代或被一个或多个F、Cl、Br、苯基、二甲基叔丁基硅醚基取代的C1～10的烷基、未取代或被一个或多个C1～6的烷基、C1～6的烷氧基、苯基、C2～6的烯基、F、Cl、Br取代的苯基。
3.根据权利要求1所述的手性α，α-二芳基酮类化合物，其特征在于，所述手性α，α-二芳基酮类化合物选自以下结构中的一种：
4.根据权利要求1～3任一项所述的手性α，α-二芳基酮类化合物的制备方法，其特征在于，包括如下步骤：
S1、将化合物1、化合物3和溶剂在可见光照射下反应得到中间体；
S2、将中间体、化合物2和手性磷酸催化剂混合进行反应，即得手性α，α-二芳基酮类化合物；
其中化合物1、化合物2和化合物3的结构式如下：
R4和R5独立地选自C1～6的烷基、苄基。
5.根据权利要求4所述的手性α，α-二芳基酮类化合物的制备方法，其特征在于，所述手性磷酸催化剂选自以下结构式中的一种：
6.根据权利要求4所述的手性α，α-二芳基酮类化合物的制备方法，其特征在于，所述化合物2选自以下结构中的一种：
7.根据权利要求4所述的手性α，α-二芳基酮类化合物的制备方法，其特征在于，所述反应的温度为-78℃～25℃。
8.根据权利要求4所述的手性α，α-二芳基酮类化合物的制备方法，其特征在于，步骤S2中，所述反应的制备原料中还加入了的分子筛。
9.根据权利要求4所述的手性α，α-二芳基酮类化合物的制备方法，其特征在于，所述溶剂选自氯苯、二氯甲烷、四氢呋喃、乙腈、甲苯或二氯乙烷中的至少一种。
10.权利要求1～3任一项所述的手性α，α-二芳基酮类化合物在制备吡啶菌酰胺、二芳基环氧丙烷或人5-HT1D受体拮抗剂类似物中的应用。
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