CN116178312A - 一种手性环醚的合成方法 - Google Patents

一种手性环醚的合成方法 Download PDF

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CN116178312A
CN116178312A CN202310102776.3A CN202310102776A CN116178312A CN 116178312 A CN116178312 A CN 116178312A CN 202310102776 A CN202310102776 A CN 202310102776A CN 116178312 A CN116178312 A CN 116178312A
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cyclic ether
nickel
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孔望清
许盛
平媛媛
李炜
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Wuhan University WHU
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Abstract

本发明公开了一种手性环醚的合成方法，属于有机合成技术领域。本发明方法包括以下步骤：芳基或者烯基溴代物和环醚，通过光催化剂与手性镍催化剂的催化，在紫光照射下反应完全，得到手性环醚。本发明利用光/镍协同催化的策略，实现环醚氧邻位碳氢键的立体选择性的芳基化、烯基化。该方法不仅条件温和、底物适应性广，而且由于直接使用环醚为原料，该方法还具有成本低廉原子利用率高的优势。通过后续的转化，所合成的手性环醚可以实现多种市售药物的合成，具有巨大的合成价值。

Description

一种手性环醚的合成方法
技术领域
本发明属于有机合成技术领域，具体涉及一种手性环醚的合成方法。
背景技术
手性环醚不仅是众多生物活性天然产物和市售药物的核心单元，还是应用广泛的合成砌块，因此发展手性环醚结构的方法学具有重要的研究意义。
然而以往手性环醚的合成依赖于手性醇的分子内亲核取代关环或者使用手性拆分的方式，面临着反应成本高、原料难以制备、底物普适性低以及原子经济性差等缺点。
发明内容
本发明目的在于克服现有技术存在的缺点与不足，提供一种新颖的手性环醚的合成方法。该方法以芳基或者烯基溴代物A和环醚B为原料，利用可见光促进的氢原子转移(HAT)过程直接断裂环醚B的碳氢键产生环醚自由基，接着在手性镍催化剂的协同催化下与芳基或者烯基溴代物A偶联，得到手性环醚。本发明利用光/镍协同催化的策略，实现环醚氧邻位碳氢键的立体选择性的芳基化、烯基化。通过后续的转化，所合成的手性环醚可以实现多种市售药物的合成，具有巨大的合成价值。
本发明的目的通过下述技术方案实现：
一种手性环醚的合成方法，包括以下步骤：芳基或者烯基溴代物A和环醚B，通过光催化剂与手性镍催化剂的催化，在紫光照射下反应完全，得到手性环醚C。所述的紫光优选为390nm的紫光，所述的反应条件优选为-15-5℃反应60-80小时。
一种手性环醚的合成方法，包括以下步骤：在惰性气体的保护下，将镍催化剂、配体、光催化剂、芳基或烯基溴代物A、环醚B、碱加到有机溶剂中，在紫光照射下反应完全，经柱层析分离得到手性环醚C。
优选的，所述的芳基或者烯基溴代物A选自以下结构：
Figure BDA0004073655880000021
优选的，所述的环醚B选自以下结构，
Figure BDA0004073655880000022
优选的，所述的镍催化剂包括但不限于氯化镍、溴化镍、氯化镍乙二醇二甲醚、溴化镍乙二醇二甲醚、环辛二烯镍、乙酰丙酮镍、高氯酸镍、碘化镍和醋酸镍四水合物，优选为氯化镍乙二醇二甲醚。
优选的，所述的配体选自以下结构，优先为D和E。
Figure BDA0004073655880000023
优选的，所述的光催化剂以下结构，优选为F。
Figure BDA0004073655880000031
优选的，所述的碱包括但不限于碳酸钠、碳酸钾、磷酸钾、磷酸一氢钾、磷酸二氢钾、碳酸氢钠、碳酸锂、碳酸铯、磷酸钠和醋酸钠，优选为碳酸钠。
优选的，所述的有机溶剂包括但不限于乙酸乙酯、四氢呋喃、四氢吡喃、1,4-二氧六环、环氧丁烷、γ-丁内酯、三氟甲苯、乙腈、丙酮和二甲亚砜的一种或多种组成的混合溶剂。
优选的，所述的芳基或烯基溴代物A、环醚B、镍催化剂、配体、光催化剂、碱的摩尔比例为1:10:0.1:0.15:0.2:2，其中芳基或烯基溴代物A的浓度为0.1～0.5mol/L。
本发明的优点和有益效果：本发明提供了一种利用光促氢原子转移和镍协同催化策略，直接断裂环醚的碳氢键实现对映选择性芳基化和烯基化，制备一系列手性环醚。该方法直接使用廉价易得的环醚作为原料，光催化剂廉价且能回收再利用，大大降低了合成成本。此外，反应条件温和，官能团耐受性好，底物适用范围广，是一种高效、绿色、廉价合成手性环醚的方法。
具体实施方法
通过下述实施例将有助于理解本发明，但并不限制本发明的内容。
实施例1
Figure BDA0004073655880000032
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物1a(45.8mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物1c(33.1mg,75％yield,90％ee)。
1H NMR(400MHz,CDCl3)δ8.04–7.97(m,2H),7.43–7.36(m,2H),4.94(t,J＝7.2Hz,1H),4.37(q,J＝7.1Hz,2H),4.11(dt,J＝8.2,6.8Hz,1H),3.95(dt,J＝8.2,7.0Hz,1H),2.41–2.30(m,1H),2.06–1.96(m,2H),1.82–1.72(m,1H),1.39(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ166.5,148.8,129.5,129.2,125.3,80.1,68.8,60.8,34.7,25.9,14.3.
实施例2
Figure BDA0004073655880000041
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物2a(42.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物2c(24.5mg,60％yield,93％ee)。
1H NMR(600MHz,CDCl3)δ7.84(dd,J＝8.0,0.7Hz,1H),7.50–7.47(m,1H),7.46–7.42(m,1H),5.28(s,2H),4.99(t,J＝7.3Hz,1H),4.13–4.07(m,1H),4.00–3.94(m,1H),2.44–2.37(m,1H),2.07–1.98(m,2H),1.79–1.72(m,1H)；13C NMR(151MHz,CDCl3)δ171.0,150.9,147.0,126.6,125.6,124.5,118.8,80.1,69.6,68.9,34.9,25.9.HRMS:(ESI)calcdfor C12H13O3 +[M+H]+205.0859；found 205.0860.
实施例3
Figure BDA0004073655880000042
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物3c(35.0mg,92％yield,92％ee)。
1H NMR(600MHz,CDCl3)δ7.96–7.89(m,2H),7.45–7.38(m,2H),4.95(t,J＝7.2Hz,1H),4.13–4.08(m,1H),3.99–3.94(m,1H),2.59(s,3H),2.41–2.32(m,1H),2.04–1.98(m,2H),1.80–1.73(m,1H)；13C NMR(151MHz,CDCl3)197.9,149.2,136.1,128.5,125.6,80.2,68.9,34.7,26.6,26.0.
实施例4
Figure BDA0004073655880000051
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物4a(36.8mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物4c(23.6mg,67％yield,90％ee)。
1H NMR(600MHz,CDCl3)δ9.99(s,1H),7.87–7.82(m,2H),7.52–7.47(m,2H),4.97(t,J＝7.2Hz,1H),4.14–4.09(m,1H),4.00–3.95(m,1H),2.42–2.36(m,1H),2.05–1.99(m,2H),1.81–1.74(m,1H)；13C NMR(151MHz,CDCl3)δ192.1,150.9,135.4,129.9,126.1,80.2,69.0,34.8,26.0.
实施例5
Figure BDA0004073655880000052
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物5a(36.2mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物5c(28.7mg,83％yield,92％ee)。
1H NMR(600MHz,CDCl3)δ7.64–7.58(m,2H),7.46–7.39(m,2H),4.93(t,J＝7.2Hz,1H),4.12–4.06(m,1H),4.00–3.93(m,1H),2.41–2.34(m,1H),2.05–1.97(m,2H),1.77–1.70(m,1H)；13C NMR(151MHz,CDCl3)δ149.2,132.1,126.1,119.0,110.7,79.8,68.9,34.7,25.9.
实施例6
Figure BDA0004073655880000061
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物6a(46.8mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物6c(32.5mg,72％yield,92％ee)。
1H NMR(600MHz,CDCl3)δ7.91–7.85(m,2H),7.53–7.49(m,2H),4.96(t,J＝7.2Hz,1H),4.12–4.07(m,1H),3.98–3.93(m,1H),3.03(s,3H),2.42–2.35(m,1H),2.05–1.96(m,2H),1.78–1.71(m,1H)；13C NMR(151MHz,CDCl3)δ150.2,139.0,127.4,126.3,79.7,68.9,44.5,34.7,25.9.HRMS:(ESI)calcd for C11H15O3S+[M+H]+227.0736；found 227.0735.
实施例7
Figure BDA0004073655880000062
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物7a(44.8mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物7c(29.8mg,69％yield,90％ee)。
1H NMR(600MHz,CDCl3)δ7.62–7.55(m,2H),7.48–7.41(m,2H),4.95(t,J＝7.2Hz,1H),4.11(dt,J＝8.4,6.8Hz,1H),3.96(dt,J＝8.3,7.0Hz,1H),2.37(dq,J＝12.1,6.7Hz,1H),2.01(dq,J＝8.1,6.9Hz,2H),1.77(dq,J＝12.3,7.8Hz,1H)；13C NMR(151MHz,CDCl3)δ147.8,129.3(q,J＝32.2Hz),125.8,125.3(q,J＝3.8Hz),124.3(q,J＝271.8Hz),80.0,68.9,34.8,26.0；19F NMR(565MHz,CDCl3)δ-62.37.
实施例8
Figure BDA0004073655880000071
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物8a(34.8mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物8c(22.2mg,67％yield,88％ee)。
1H NMR(600MHz,CDCl3)δ7.33–7.27(m,2H),7.05–6.97(m,2H),4.85(t,J＝7.2Hz,1H),4.12–4.05(m,1H),3.95–3.89(m,1H),2.34–2.26(m,1H),2.06–1.96(m,2H),1.81–1.72(m,1H)；13C NMR(151MHz,CDCl3)δ162.0(d,J＝244.7Hz),139.1(d,J＝3.2Hz),127.3(d,J＝7.9Hz),115.1(d,J＝21.3Hz),80.1,68.6,34.7,26.0；19F NMR(565MHz,CDCl3)δ-115.9.
实施例9
Figure BDA0004073655880000081
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物9a(38.0mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物9c(23.3mg,64％yield,90％ee)。
1H NMR(600MHz,CDCl3)δ7.31–7.24(m,4H),4.86(t,J＝7.2Hz,1H),4.11–4.06(m,1H),3.95–3.90(m,1H),2.35–2.28(m,1H),2.03–1.97(m,2H),1.79–1.71(m,1H)；13C NMR(151MHz,CDCl3)δ142.0,132.7,128.4,127.0,80.0,68.7,34.7,26.0.
实施例10
Figure BDA0004073655880000082
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物10a(53.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物10c(34.8mg,67％yield,89％ee)。
1H NMR(600MHz,CDCl3)δ8.08(d,J＝8.2Hz,1H),7.56–7.52(m,1H),7.41–7.36(m,1H),4.94(t,J＝7.2Hz,1H),4.12–4.07(m,1H),3.99–3.94(m,1H),3.25(s,3H),2.43–2.36(m,1H),2.06–1.96(m,2H),1.78–1.71(m,1H)；13C NMR(151MHz,CDCl3)δ152.0,136.3,132.6,130.9,128.8,124.4,79.1,69.1,42.8,34.7,25.9.HRMS:(ESI)calcd forC11H14ClO3S+[M+H]+261.0347；found 261.0347.
实施例11
Figure BDA0004073655880000091
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物11a(41.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物11c(27.6mg,69％yield,88％ee)。
1H NMR(600MHz,CDCl3)δ7.38(dd,J＝7.1,2.2Hz,1H),7.20–7.15(m,1H),7.08(t,J＝8.7Hz,1H),4.83(t,J＝7.2Hz,1H),4.11–4.05(m,1H),3.95–3.89(m,1H),2.34–2.28(m,1H),2.03–1.97(m,2H),1.77–1.70(m,1H)；13C NMR(151MHz,CDCl3)δ157.1(d,J＝247.5Hz),140.6(d,J＝3.8Hz),127.8,125.3(d,J＝7.1Hz),120.8(d,J＝17.6Hz),116.3(d,J＝21.0Hz),79.5,68.8,34.7,25.9；19F NMR(565MHz,CDCl3)δ-118.2.HRMS:(ESI)calcd forC10H11ClFO+[M+H]+201.0477；found 201.0480.
实施例12
Figure BDA0004073655880000092
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物12a(31.4mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物12c(19.2mg,65％yield,91％ee)。
1H NMR(600MHz,CDCl3)δ7.37–7.30(m,4H),7.28–7.23(m,1H),4.90(t,J＝7.2Hz,1H),4.13–4.08(m,1H),3.94(td,J＝7.9,6.3Hz,1H),2.36–2.30(m,1H),2.06–1.97(m,2H),1.85–1.78(m,1H)；13C NMR(151MHz,CDCl3)δ143.5,128.3,127.1,125.7,80.7,68.7,34.6,26.1.
实施例13
Figure BDA0004073655880000101
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物13a(46.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物13c(27.3mg,61％yield,88％ee)。
1H NMR(600MHz,CDCl3)δ7.64–7.57(m,4H),7.48–7.41(m,4H),7.38–7.34(m,1H),4.96(t,J＝7.2Hz,1H),4.17–4.12(m,1H),4.01–3.96(m,1H),2.41–2.34(m,1H),2.10–2.00(m,2H),1.91–1.83(m,1H)；13C NMR(151MHz,CDCl3)δ142.5,141.0,140.1,128.7,127.1,127.1,126.1,80.4,68.7,34.6,26.1.
实施例14
Figure BDA0004073655880000102
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物14a(31.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物14c(18.7mg,63％yield,91％ee)。
1H NMR(600MHz,CDCl3)δ8.57(d,J＝2.3Hz,1H),8.51(dd,J＝4.8,1.7Hz,1H),7.70–7.64(m,1H),7.29–7.25(m,1H),4.92(t,J＝7.2Hz,1H),4.14–4.07(m,1H),3.99–3.92(m,1H),2.41–2.34(m,1H),2.07–2.01(m,2H),1.84–1.76(m,1H)；13C NMR(151MHz,CDCl3)δ148.6,147.6,138.8,133.3,123.4,78.5,68.8,34.6,26.0.
实施例15
Figure BDA0004073655880000111
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物15a(45.2mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物15c(33.0mg,76％yield,91％ee)。
1H NMR(600MHz,CDCl3)δ8.66(d,J＝2.0Hz,1H),7.84(dd,J＝8.2,2.1Hz,1H),7.64(dd,J＝8.1,0.8Hz,1H),4.99(t,J＝7.2Hz,1H),4.13–4.07(m,1H),4.00–3.94(m,1H),2.47–2.39(m,1H),2.09–1.98(m,2H),1.81–1.74(m,1H)；13C NMR(151MHz,CDCl3)δ147.8,147.0(q,J＝34.6Hz),142.4,121.6(q,J＝273.7Hz),120.2(q,J＝2.7Hz),77.9,69.0,34.7,25.9；19F NMR(565MHz,CDCl3)δ-67.7.
实施例16
Figure BDA0004073655880000112
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物16a(41.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物16c(29.9mg,75％yield,92％ee)。
1H NMR(600MHz,CDCl3)δ8.86(dd,J＝4.2,1.7Hz,1H),8.15–8.10(m,1H),8.06(d,J＝8.7Hz,1H),7.80–7.75(m,1H),7.65(dd,J＝8.7,2.0Hz,1H),7.37(dd,J＝8.2,4.2Hz,1H),5.07(t,J＝7.2Hz,1H),4.16(dt,J＝8.2,6.8Hz,1H),3.99(dt,J＝8.2,6.9Hz,1H),2.43–2.37(m,1H),2.07–2.01(m,2H),1.89–1.82(m,1H)；13C NMR(151MHz,CDCl3)δ150.0,147.7,141.8,136.0,129.4,128.0,127.6,123.7,121.2,80.3,68.9,34.6,26.0.
实施例17
Figure BDA0004073655880000121
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物17a(52.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物17c(33.5mg,66％yield,88％ee)。
1H NMR(600MHz,CDCl3)δ8.21–8.17(m,1H),8.16(dt,J＝1.5,0.7Hz,1H),7.87–7.84(m,1H),7.83–7.80(m,1H),7.48–7.44(m,2H),7.44–7.41(m,1H),5.08(t,J＝7.2Hz,1H),4.24–4.17(m,1H),4.02(td,J＝8.0,6.3Hz,1H),2.45–2.39(m,1H),2.12–2.03(m,2H),1.93–1.86(m,1H)；13C NMR(151MHz,CDCl3)δ139.9,139.7,138.1,135.5,135.4,126.6,124.6,124.2,122.8,122.6,121.6,118.5,80.7,68.7,35.0,26.0.HRMS:(ESI)calcd forC16H15OS+[M+H]+255.0838；found 255.0838.
实施例18
Figure BDA0004073655880000122
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物18a(72.2mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物18c(46.6mg,66％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.73–7.66(m,2H),7.41–7.36(m,2H),7.31–7.23(m,3H),7.16–7.10(m,2H),6.60(d,J＝7.5Hz,1H),5.11–5.06(m,1H),4.93(t,J＝7.2Hz,1H),4.12–4.07(m,1H),3.98–3.93(m,1H),3.76(s,3H),3.29(dd,J＝13.9,5.8Hz,1H),3.22(dd,J＝13.9,5.4Hz,1H),2.39–2.32(m,1H),2.04–1.97(m,2H),1.77–1.73(m,1H)；13C NMR(151MHz,CDCl3)δ172.1,166.7,147.8,135.9,132.6,129.4,128.7,127.2,127.1,125.7,80.1,68.9,53.5,52.5,37.9,34.7,26.0.HRMS:(ESI)calcd for C21H24NO4 +[M+H]+354.1700；found354.1689.
实施例19
Figure BDA0004073655880000131
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物19a(67.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物19c(40.9mg,62％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ8.04–7.96(m,2H),7.43–7.35(m,2H),5.00–4.88(m,2H),4.14–4.07(m,1H),3.99–3.93(m,1H),2.40–2.32(m,1H),2.15–2.09(m,1H),2.04–1.92(m,3H),1.80–1.69(m,3H),1.58–1.51(m,2H),1.17–1.06(m,2H),0.91(dd,J＝8.2,6.8Hz,6H),0.78(d,J＝7.0Hz,3H)；13C NMR(151MHz,CDCl3)δ166.0,148.8,129.7,129.6,125.3,80.2,74.7,68.9,47.3,41.0,34.8,34.3,31.5,26.5,26.0,23.7,22.1,20.8,16.5.
实施例20
Figure BDA0004073655880000141
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物20a(88.4mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物20c(67.7mg,78％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ8.00–7.93(m,2H),7.42–7.38(m,2H),5.94(d,J＝3.6Hz,1H),5.48(d,J＝2.8Hz,1H),4.94(t,J＝7.2Hz,1H),4.62(d,J＝3.6Hz,1H),4.37–4.30(m,2H),4.12–4.06(m,3H),3.98–3.93(m,1H),2.39–2.32(m,1H),2.03–1.96(m,2H),1.77–1.71(m,1H),1.54(s,3H),1.40(s,3H),1.30(s,3H),1.25(s,3H)；13C NMR(151MHz,CDCl3)δ165.1,149.8,129.8,128.2,125.6,112.4,109.4,105.1,83.4,80.1,79.9,76.5,72.6,68.9,67.2,34.8,26.8,26.7,26.2,26.0,25.2.HRMS:(ESI)calcd for C23H31O8 +[M+H]+435.2013；found 435.2005.
实施例21
Figure BDA0004073655880000142
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物21a(97.4mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物21c(69.1mg,72％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.49–7.44(m,2H),7.40–7.40(m,1H),7.38–7.35(m,1H),7.35–7.29(m,3H),7.23–7.17(m,1H),7.11–7.04(m,1H),7.01–6.92(m,1H),6.87–6.72(m,1H),6.08–4.95(m,1H),4.94–4.86(m,1H),4.26–4.12(m,1H),4.12–4.05(m,1H),3.98–3.90(m,1H),2.89–2.69(m,3H),2.40–2.29(m,1H),2.11–2.03(m,1H),2.03–1.98(m,2H),1.98–1.85(m,2H),1.82–1.66(m,2H)；13C NMR(151MHz,CDCl3)δ172.9,172.5,147.0,146.8,145.3,145.1,138.4,137.8,135.8,135.7,135.3,132.4,132.3,131.1,130.9,130.7,130.6,130.3,130.2,130.12,130.09,128.1,128.0,127.9,127.8,127.6,127.5,127.3,127.1,126.6,126.3,126.1,125.7,80.3,68.9,58.6,52.8,43.1,42.7,34.8,34.6,33.2,30.1,30.0,29.0,26.0,26.0,22.5,21.1.HRMS:(ESI)calcd for C28H28Cl2NO2 +[M+H]+480.1492；found 480.1475.
实施例22
Figure BDA0004073655880000151
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物22a(80.2mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物22c(48.8mg,62％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.41–7.28(m,4H),5.27(d,J＝11.9Hz,1H),5.15(d,J＝11.9Hz,1H),4.90(t,J＝7.2Hz,1H),4.59(dd,J＝4.3,2.1Hz,1H),4.40(s,1H),4.12–4.07(m,1H),3.97–3.92(m,1H),3.48(dd,J＝16.2,4.3Hz,1H),3.43(dd,J＝16.2,2.1Hz,1H),2.37–2.30(m,1H),2.04–1.98(m,2H),1.81–1.73(m,1H),1.55(s,3H),1.27(s,3H)；13C NMR(151MHz,CDCl3)δ170.8,166.9,144.6,133.1,129.0,126.1,80.3,68.8,68.1,63.2,62.8,61.0,38.3,34.7,26.0,20.2,18.6.HRMS:(ESI)calcd for C19H24NO6S+[M+H]+394.1319；found 394.1306.
实施例23
Figure BDA0004073655880000152
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物23a(113.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物23c(76.2mg,68％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ8.04–7.96(m,2H),7.42–7.34(m,2H),5.43–5.39(m,1H),4.94(t,J＝7.2Hz,1H),4.88–4.81(m,1H),4.13–4.08(m,1H),3.98–3.92(m,1H),2.49–2.42(m,2H),2.39–2.32(m,1H),2.05–1.95(m,5H),1.93–1.88(m,1H),1.88–1.80(m,1H),1.80–1.69(m,2H),1.62–1.42(m,6H),1.41–1.04(m,14H),1.04–0.95(m,3H),0.92(d,J＝6.5Hz,3H),0.87(d,J＝2.8Hz,3H),0.86(d,J＝2.8Hz,3H),0.68(s,3H)；13C NMR(151MHz,CDCl3)δ165.9,148.8,139.7,129.7,129.6,125.3,122.8,80.2,74.5,68.9,56.7,56.1,50.0,42.3,39.7,39.5,38.2,37.1,36.7,36.2,35.8,34.8,32.0,31.9,28.3,28.1,27.9,26.0,24.3,23.9,22.9,22.6,21.1,19.4,18.8,11.9.
实施例24
Figure BDA0004073655880000161
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物24a(90.4mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物24c(56.8mg,64％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ8.20–8.09(m,2H),7.50–7.42(m,2H),7.33(dd,J＝8.6,1.1Hz,1H),6.98(dd,J＝8.5,2.6Hz,1H),6.94(d,J＝2.4Hz,1H),4.98(t,J＝7.2Hz,1H),4.16–4.10(m,1H),4.01–3.95(m,1H),2.97–2.87(m,2H),2.56–2.48(m,1H),2.46–2.37(m,2H),2.35–2.29(m,1H),2.19–2.12(m,1H),2.10–2.00(m,4H),2.00–1.95(m,1H),1.83–1.76(m,1H),1.68–1.43(m,7H),0.92(s,3H)；13C NMR(151MHz,CDCl3)δ220.9,165.4,149.8,148.9,138.1,137.4,130.3,128.4,126.5,125.6,121.7,118.9,80.2,68.9,50.5,48.0,44.2,38.0,35.9,34.8,31.6,29.5,26.4,26.0,25.8,21.6,13.9.HRMS:(ESI)calcd forC29H33O4 +[M+H]+445.2373；found445.2365.
实施例25
Figure BDA0004073655880000171
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，烯基溴代物25a(39.0mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物25c(26.0mg,70％yield,91％ee)。
1H NMR(600MHz,CDCl3)δ7.45–7.40(m,1H),7.35–7.31(m,1H),7.27–7.23(m,1H),7.18–7.13(m,1H),6.75–6.70(m,1H),4.84(td,J＝7.0,1.3Hz,1H),4.04–3.98(m,1H),3.92–3.86(m,1H),3.41(d,J＝1.6Hz,2H),2.25–2.17(m,1H),2.06–1.95(m,2H),1.90–1.83(m,1H)；13C NMR(151MHz,CDCl3)δ150.5,144.7,143.3,126.7,126.4,124.3,123.7,120.7,77.8,68.3,38.1,32.2,26.1.
实施例26
Figure BDA0004073655880000172
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，烯基溴代物26a(35.0mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物26c(20.0mg,60％yield,90％ee)。
1H NMR(600MHz,CDCl3)δ6.07–6.06(m,1H),4.40(t,J＝7.4Hz,1H),3.92(m,1H),3.86(m,1H),2.39–2.35(m,2H),2.33–2.26(m,1H),2.24(dd,J＝6.6,5.0Hz,1H),2.22–2.13(m,1H),2.04–1.96(m,2H),1.95–1.88(m,2H),1.72–1.63(m,1H)；13C NMR(151MHz,CDCl3)δ199.9,165.8,123.2,80.4,68.9,37.8,31.3,25.81,25.78,22.7.HRMS:(ESI)calcd forC10H14O2 +[M+H]+167.1067；found:167.1066.
实施例27
Figure BDA0004073655880000181
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，烯基溴代物27a(51.2mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物27c(36.0mg,71％yield,88％ee)。
1H NMR(600MHz,CDCl3)δ5.61(s,1H),4.22(t,J＝7.4Hz,1H),3.87(m,2H),3.83–3.73(m,2H),3.56(d,J＝12.5Hz,1H),3.46–3.36(m,1H),2.06(d,J＝21.4Hz,2H),2.00–1.93(m,1H),1.93–1.83(m,2H),1.70–1.59(m,1H),1.48–1.42(m,9H)；13C NMR(151MHz,CDCl3)δ154.9,126.6,118.6,81.7,79.5,68.4,43.4,39.6,30.2,28.5,26.0,24.3.HRMS:(ESI)calcd for C9H16NO+[M+H-Boc]+154.1226；found:154.1225.
实施例28
Figure BDA0004073655880000182
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚28b(320mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物28c(31.9mg,81％yield,94％ee)。
1H NMR(600MHz,CDCl3)δ7.94–7.91(m,2H),7.44–7.40(m,2H),2.59(s,3H)；13CNMR(151MHz,CDCl3)δ197.9,149.2,136.1,128.5,125.6,26.6.HRMS:(ESI)calcd for C12H8D7O2 +[M+H]+198.1506；found 198.1497.
实施例29
Figure BDA0004073655880000191
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚29b(344mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物29c(17.1mg,42％yield,d.r.＝3.5:1,eemajor＝87％,eeminor＝93％)。
1H NMR(600MHz,CDCl3)δ7.94–7.89(m,2H),7.46–7.39(m,2H),5.11–4.92(m,1H),4.39–4.17(m,1H),2.61–2.58(m,3H),2.46–2.31(m,1H),2.18–2.07(m,1H),1.86–1.79(m,1H),1.68–1.62(m,1H),1.39–1.32(m,3H).13C NMR(151MHz,CDCl3)δ197.94,197.92,149.8,149.3,136.1,136.0,128.47,128.53,125.8,125.5,80.4,79.8,76.33,76.28,35.6,34.7,34.2,33.0,29.7,26.6,21.5,21.3.HRMS:(ESI)calcd for C14H17O4 +[M+H]+205.1223；found205.1224.
实施例30
Figure BDA0004073655880000192
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚30b(520mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物30c(34.7mg,70％yield,d.r.>25:1)。
1H NMR(600MHz,CDCl3)δ7.94–7.90(m,2H),7.44–7.40(m,2H),5.25(t,J＝7.1Hz,1H),4.78(dd,J＝7.9,6.1Hz,1H),3.78(s,3H),2.59(s,3H),2.46–2.36(m,2H),2.18–2.13(m,1H),1.86–1.80(m,1H).13C NMR(151MHz,CDCl3)δ197.8,173.6,147.6,136.3,128.5,125.6,81.4,52.2,34.3,30.2,26.7.HRMS:(ESI)calcd for C14H17O4 +[M+H]+249.1121；found 249.1120.
实施例31
Figure BDA0004073655880000201
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚31b(344mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物31c(26.1mg,64％yield,92％ee)。
1H NMR(600MHz,CDCl3)δ8.01–7.97(m,2H),7.52–7.46(m,2H),5.35(dd,J＝9.6,6.5Hz,1H),4.29–4.24(m,1H),4.04(d,J＝17.0Hz,1H),2.94–2.88(m,1H),2.61(s,3H),2.54–2.46(m,1H)；13C NMR(151MHz,CDCl3)δ213.3,197.6,145.3,137.0,128.8,125.9,78.8,71.7,44.6,26.7.HRMS:(ESI)calcd for C12H13O3 +[M+H]+205.0859；found 205.0856.
实施例32
Figure BDA0004073655880000202
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(氰基)苯基)甲酮(9.5mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，γ-丁内酯32b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物32c(24.4mg,60％yield,r.r.＝5:1,93％ee)。
1H NMR(600MHz,CDCl3)δ8.00–7.97(m,2H),7.45–7.42(m,2H),5.58–5.54(m,1H),2.76–2.65(m,3H),2.61(s,3H),2.20–2.14(m,1H)；13C NMR(151MHz,CDCl3)δ197.5,176.5,144.6,137.1,128.9,125.3,80.4,30.9,28.7,26.7.HRMS:(ESI)calcd for C12H13O3 +[M+H]+205.0859；found 205.0857.
实施例33
Figure BDA0004073655880000211
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚33b(232mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物33c(26.4mg,75％yield,86％ee)。
1H NMR(600MHz,CDCl3)δ8.03–7.93(m,2H),7.55–7.47(m,2H),5.86(t,J＝7.6Hz,1H),4.89–4.83(m,1H),4.71–4.66(m,1H),3.12–3.05(m,1H),2.66–2.57(m,4H)；13C NMR(151MHz,CDCl3)δ197.8,148.9,136.5,128.7,125.1,82.2,68.5,30.6,26.7.HRMS:(ESI)calcd for C11H13O2 +[M+H]+177.0910；found 177.0906.
实施例34
Figure BDA0004073655880000212
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚34b(344mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物34c(22.8mg,56％yield,62％ee)。
1H NMR(600MHz,CDCl3)δ7.92(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),4.38(dd,J＝11.3,2.4Hz,1H),4.20–4.12(m,1H),3.67–3.58(m,1H),2.59(s,3H),1.99–1.92(m,1H),1.89–1.82(m,1H),1.73–1.66(m,2H),1.63–1.49(m,2H)；13C NMR(151MHz,CDCl3)δ198.0,148.8,136.1,128.5,125.8,79.5,68.9,34.1,26.7,25.8,23.9.
实施例35
Figure BDA0004073655880000221
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚35b(576mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物35c(33.0mg,63％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.97–7.93(m,2H),7.47–7.44(m,2H),5.15–5.12(m,1H),4.84–4.79(m,2H),4.79(dd,J＝6.3,2.1Hz,1H),4.12(dd,J＝10.6,1.5Hz,1H),4.00(dd,J＝10.7,4.1Hz,1H),2.60(s,3H),1.60(s,3H),1.37(s,3H)；13C NMR(151MHz,CDCl3)δ197.7,144.3,136.4,128.7,125.7,113.5,87.1,85.3,81.1,73.0,26.8,26.7,25.1.HRMS:(ESI)calcd for C15H19O4 +[M+H]+263.1278；found 263.1283.
实施例36
Figure BDA0004073655880000222
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚36b(776mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，水解，快速柱层析，得无色液体产物36c(27.6mg,67％yield,r.r.>20:1,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.96–7.91(m,2H),7.46–7.40(m,2H),5.23(dd,J＝10.2,5.8Hz,1H),4.65(t,J＝4.9Hz,1H),4.25(dd,J＝9.9,4.3Hz,1H),3.97–3.92(m,1H),2.60(s,3H),2.42–2.36(m,1H),2.15(s,1H),1.93–1.87(m,1H)；13C NMR(151MHz,CDCl3)δ198.0,148.0,136.3,128.6,125.7,79.0,76.5,72.7,44.6,26.7.HRMS:(ESI)calcd for C12H15O3 +[M+H]+207.1016；found 207.1013.
实施例37
Figure BDA0004073655880000231
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aR,8aS)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚37b(808mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物37c(40.0mg,62％yield,r.r.＝11:1,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.95–7.91(m,2H),7.44–7.41(m,2H),4.70(d,J＝4.2Hz,1H),4.22–4.18(m,1H),4.16–4.09(m,2H),2.59(s,3H),2.16–2.09(m,1H),1.93–1.88(m,1H),0.88(s,9H),-0.02(d,J＝7.2Hz,6H)；13C NMR(151MHz,CDCl3)δ197.9,146.8,136.3,128.4,125.8,87.1,79.6,67.6,34.9,26.7,25.7,18.0.HRMS:(ESI)calcd for C18H29O3Si+[M+H]+321.1881；found 321.1877.
实施例38
Figure BDA0004073655880000232
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aR,8aS)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物3a(39.8mg,0.2mmol)，环醚38b(472mg,2.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，水解，快速柱层析，得无色液体产物38c(46.0mg,65％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.94–7.88(m,2H),7.45–7.39(m,2H),5.16(dd,J＝9.7,2.4Hz,1H),2.59(s,3H),2.35–2.27(m,1H),2.10–2.04(m,1H),1.85–1.78(m,1H),1.68–1.56(m,5H),1.42–1.31(m,4H),1.25(s,3H),1.19–1.10(m,1H),1.00(dd,J＝12.5,2.6Hz,1H),0.95–0.89(m,1H),0.88(s,3H),0.86(s,3H),0.83(s,3H)；13C NMR(151MHz,CDCl3)δ198.0,150.9,135.8,128.4,125.8,82.2,58.6,57.3,42.4,39.8,36.2,33.6,33.1,32.3,26.7,21.7,21.1,20.6,18.3,15.1.HRMS:(ESI)calcd for C24H35O2 +[M+H]+355.2632；found355.2628.
实施例39
Figure BDA0004073655880000241
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物39a(56.6mg,0.2mmol)和四氢呋喃1b(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物39c(34.1mg,62％yield,91％ee)。
1H NMR(600MHz,CDCl3)δ7.78(d,J＝7.8Hz,2H),7.34(d,J＝7.8Hz,2H),4.92(t,J＝7.2Hz,1H),4.10(dt,J＝8.0,6.8Hz,1H),3.97–3.92(m,1H),2.33(dtd,J＝12.6,7.2,5.9Hz,1H),1.99(pd,J＝7.3,6.8,2.0Hz,2H),1.78(dq,J＝12.3,7.8Hz,1H),1.34(s,12H).13C NMR(151MHz,CDCl3)δ146.8,134.8,124.8,83.7,80.6,68.7,34.7,25.9,24.8,24.8.
实施例40
Figure BDA0004073655880000251
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aR,8aS)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物40a(38.6mg,0.2mmol)，环醚37b(808mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，脱保护，快速柱层析，得无色液体产物40c(23.2mg,58％yield,r.r.>20:1,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.20–7.09(m,2H),7.08–7.03(m,1H),4.71(d,J＝3.5Hz,1H),4.24–4.16(m,2H),4.15–4.09(m,1H),2.21–2.12(m,1H),2.07(d,J＝4.4Hz,1H),1.99–1.92(m,1H)；13C NMR(151MHz,CDCl3)δ150.4(dd,J＝248.3,12.7Hz),149.7(dd,J＝247.6,12.7Hz),138.0(dd,J＝5.0,3.7Hz),121.3(dd,J＝6.4,3.6Hz),117.2(d,J＝17.3Hz),114.5(d,J＝18.0Hz),86.2,78.8,67.3,34.3；19F NMR(376MHz,CDCl3)δ-137.4,-139.6.HRMS:(ESI)calcd for C10H11F2O2 +[M+H]+201.0722；found 201.0719.
实施例41
Figure BDA0004073655880000252
在惰性(氩气)气氛下向装有磁子的透明反应管中加入(4-甲氧基苯基)(4-(三氟甲基)苯基)甲酮(11.2mg,0.04mmol)，(3aS,8aR)-2-(2-(二苯基膦基)-5-(三氟甲基)苯基)-3a,8a-二氢-8H-茚并[1,2-d]噁唑(14.6mg,0.03mmol)，氯化镍乙二醇二甲醚(4.2mg,0.02mmol)，碳酸钠(42.4mg,0.4mmol)，芳基溴代物41a(58.6mg,0.2mmol)，环醚30b(520mg,4.0mmol)和乙酸乙酯(2mL)。紫光灯(10w,390nm)照射下-5℃反应65小时，浓缩，快速柱层析，得无色液体产物41c(46.5mg,68％yield,d.r.>95:5)。
1H NMR(600MHz,CDCl3)δ7.84–7.74(m,3H),5.29(t,J＝7.3Hz,1H),4.81(dd,J＝8.1,6.2Hz,1H),3.80(s,3H),2.55–2.47(m,1H),2.47–2.40(m,1H),2.25–2.17(m,1H),1.89–1.79(m,1H)；13C NMR(151MHz,CDCl3)δ173.3,144.8,131.7(q,J＝33.3Hz),125.8(q,J＝3.9Hz),123.3(q,J＝272.6Hz),121.4(p,J＝3.8Hz),80.5,77.4,52.3,34.3,30.1；19FNMR(565MHz,CDCl3)δ-62.85.HRMS:(ESI)calcd for C14H13F6O3 +[M+H]+343.0763；found343.0759.
以上列举的仅是本发明的几个具体实施例，显然，本发明不仅限于以上实施例，还可以有诸多变形，本领域的普通技术人员能从本发明公开的内容直接导出或间接联想到的所有变形，均应认为是本发明的保护范围。

Claims (10)

1.一种手性环醚的合成方法，其特征在于，包括以下步骤：芳基或者烯基溴代物和环醚，通过光催化剂与手性镍催化剂的催化，在紫光照射下反应完全，得到手性环醚。
2.根据权利要求1所述的方法，其特征在于，包括以下步骤：在惰性气体的保护下，将镍催化剂、配体、光催化剂、芳基或烯基溴代物、环醚、碱加到有机溶剂中，在紫光照射下反应完全，得到手性环醚。
3.根据权利要求1或2所述的制备方法，其特征在于：所述的芳基或者烯基溴代物选自以下结构：
Figure FDA0004073655870000011
4.根据权利要求1或2所述的制备方法，其特征在于：所述的环醚选自以下结构：
Figure FDA0004073655870000012
5.根据权利要求1或2所述的制备方法，其特征在于：所述的镍催化剂包括但不限于氯化镍、溴化镍、氯化镍乙二醇二甲醚、溴化镍乙二醇二甲醚、环辛二烯镍、乙酰丙酮镍、高氯酸镍、碘化镍和醋酸镍四水合物。
6.根据权利要求2所述的制备方法，其特征在于：所述的配体选自以下结构：
Figure FDA0004073655870000021
7.根据权利要求1或2所述的制备方法，其特征在于：所述的光催化剂选自以下结构：
Figure FDA0004073655870000022
8.根据权利要求2所述的制备方法，其特征在于：所述的碱包括但不限于碳酸钠、碳酸钾、磷酸钾、磷酸一氢钾、磷酸二氢钾、碳酸氢钠、碳酸锂、碳酸铯、磷酸钠和醋酸钠。
9.根据权利要求2所述的制备方法，其特征在于：所述的有机溶剂包括但不限于乙酸乙酯、四氢呋喃、四氢吡喃、1,4-二氧六环、环氧丁烷、γ-丁内酯、三氟甲苯、乙腈、丙酮和二甲亚砜一种或多种组成的混合溶剂。
10.根据权利要求2所述的制备方法，其特征在于：芳基或烯基溴代物、环醚、镍催化剂、配体、光催化剂、碱的摩尔比例为1:10:0.1:0.15:0.2:2，其中芳基或烯基溴代物的浓度为0.1～0.5mol/L。
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