CN111646948A - 不对称环丙烷化合成手性嘧啶取代双酯基环丙烷的方法 - Google Patents

不对称环丙烷化合成手性嘧啶取代双酯基环丙烷的方法 Download PDF

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CN111646948A
CN111646948A CN202010635935.2A CN202010635935A CN111646948A CN 111646948 A CN111646948 A CN 111646948A CN 202010635935 A CN202010635935 A CN 202010635935A CN 111646948 A CN111646948 A CN 111646948A
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王海霞
张蜜蜜
李文朋
谢明胜
郭海明
渠桂荣
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Henan Normal University
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Abstract

本发明公开了一种不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷，属于有机化学中的不对称合成领域。以N1‑乙烯基嘧啶和苯基碘叶立德为原料，在铜盐催化剂和手性双噁唑啉配体存在下，以高达97％收率和99％ee得到手性嘧啶取代的双酯基环丙烷，进一步与苯甲醛、乙醛酸乙酯或炔丙醇进行[3+2]环加成反应，还可得到更多手性嘧啶核苷类似物，本发明为该类手性嘧啶核苷类似物的合成提供了一种简洁的新路径。

Description

不对称环丙烷化合成手性嘧啶取代双酯基环丙烷的方法
技术领域
本发明涉及不对称环丙烷化合成手性嘧啶取代双酯基环丙烷的方法，属于有机化学中的不对称合成领域。
背景技术
嘧啶核苷类化合物通常具有抗病毒活性，在药物化学中具有广泛的应用。自从发现嘧啶核苷具有良好的抗病毒活性以来,嘧啶核苷的合成便成了研究热点。例如Besifovir具有季碳中心的三元环嘧啶核苷作为anti-HBV(乙型肝炎病毒)药物，氟尿嘧啶、Brivudine、Idoxuridine都是比较典型的手性五元糖环嘧啶核苷类药物。
目前，手性嘧啶三元碳环核苷的合成方法，主要集中在嘌呤或嘧啶的碱基引入一个手性三元碳环。然而，手性三元碳环由于构建困难，合成步骤多，导致产物总收率较低。此外，对于合成手性非天然嘧啶核苷的途径，除了天然核苷的衍生化以外，主要途径是通过手性糖环与活化的嘧啶碱基之间的糖基化，但面临着控制非对映选择性的挑战。
因此，开发一种简单、高效的不对称合成手性嘧啶核苷非常有必要。
发明内容
为克服上述缺陷，本发明利用苯基碘叶立德和N1-乙烯基嘧啶为原料在铜催化剂和手性配体作用下，不对称合成了手性嘧啶取代双酯基环丙烷。该方法为合成手性嘧啶取代的环丙烷提供了一种高效、便捷的途径。此外，将手性嘧啶取代的双酯基环丙烷分别与苯甲醛、乙醛酸乙酯、炔丙醇的进一步发生[3+2]环加成反应，还可合成不同的手性嘧啶核苷类似物。
本发明所述不对称环丙烷化合成手性嘧啶取代双酯基环丙烷的方法，其反应方程式为：
Figure BDA0002568161020000021
其中，R选自氢、卤素、C1-C4烷基、含杂原子C1-C4烷基、C1-C4烷氧基、苯乙炔基；R1选自C1-C4烷基；Pg选自苯甲酰基、对卤苯甲酰基、Boc。
包括以下步骤：以N1-乙烯基嘧啶1和苯基碘叶立德2为原料在铜催化剂和手性配体的作用下反应得到嘧啶取代的双酯基环丙烷3。
进一步地，在上述技术方案中，所述催化剂选自Cu(OTf)2、Cu(SbF6)2、Cu[(MeCN)4]PF6等。
进一步地，在上述技术方案中，所述手性配体为L5，其结构式如下:
Figure BDA0002568161020000022
进一步地，在上述技术方案中，所述反应溶剂选自二氯甲烷、甲苯、氟苯、1,3-二氯苯、氟苯、1,3-二氯苯中的一种或多种。最佳溶剂为氟苯/1,3-二氯苯为1/2(v/v)混合。
进一步地，在上述技术方案中，所述铜催化剂和配体摩尔比为1:1-1.2。
进一步地，在上述技术方案中，所述反应温度为0℃至-20℃，优选反应温度为-20℃。
进一步地，在上述技术方案中，所述反应体系加入分子筛，优选加入4A分子筛。
进一步地，在上述技术方案中，所述手性嘧啶取代双酯基环丙烷3可以继续进行衍生，从而得到更多类型的手性嘧啶核苷类似物。例如与苯甲醛、乙醛酸乙酯、炔丙醇进一步发生[3+2]环加成反应分别生成化合物4、化合物5/化合物6和化合物7；对应结构如下：
Figure BDA0002568161020000031
进一步地，在上述技术方案中，与苯甲醛反应时，在SnCl4催化剂存在下进行，与乙醛酸乙酯反应时，在MgI2催化剂存在下进行，与丙炔醇反应时，在Sc(OTf)2催化剂存在下进行。
发明有益效果
本发明提供了一种构建手性嘧啶取代D-A环丙烷的有效方法，通过对映选择性地将N1-乙烯基嘧啶与苯碘化叶立德在铜/双噁唑啉配体催化下反生环丙化，生成手性嘧啶取代环丙烷，收率83-97％，71-99％ee。产物进一步衍生，通过[3+2]环加成反应可得到不同手性嘧啶核苷类似物。
具体实施方式
实施例1:
Figure BDA0002568161020000041
Figure BDA0002568161020000051
在反应条件的筛选过程中，考察了配体和温度和反应的影响，最终确定了L5为最佳配体，-20℃为最佳反应温度，选定了Cu(OTf)2为催化剂，混合溶剂氟苯/1,3二氯苯＝1/2。
反应条件的考察：在干燥Schlenk反应管中，加入N1-乙基胸腺嘧啶(0.05mmol)、Cu(OTf)2(0.005mmol,0.12eq)和配体L5(0.006mmol,0.12eq)，塞上橡胶塞并用封口膜进行严格密封，用真空泵进行置换氮气三次，加入0.5mL混合溶剂氟苯/1,3二氯苯＝1:2(体积比)，室温下搅拌2h。待金属和手性配体充分配位后，将反应管放进-20℃低温反应浴中搅拌20分钟，接着在氮气氛围下加入醋酸碘苯(0.2mmol)。TLC跟踪反应结束，真空浓缩有机相，柱层析(PE/EA＝2:1)，得到18.7mg白色固体3aa。m.p.:181.1-183.6℃.97％yield,,99％ee.[α]D 25＝-20.7(c＝1.4,CH2Cl2)。HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flowrate＝0.8mL/min,λ＝254nm,retention time:13.750min,15.275min.1H NMR(400MHz,CD3OD)δ7.91(d,J＝7.6Hz,2H),7.72(t,J＝6.8Hz,1H),7.56(t,J＝7.6Hz,3H),4.01(t,J＝7.6HZ,1H),3.74(s,3H),3.62(s,3H),2.32(t,J＝6.4Hz,1H),2.01(t,J＝7.6Hz,1H),1.92(s,3H).13C NMR(150MHz,CDCl3)δ168.4,167.6,166.9,162.8,150.2,139.0,135.2,131.6,130.7,129.2,111.1,53.4,53.4,42.8,35.0,20.4,12.7.HRMS(ESI):m/z calcd.for:C19H18N2O7Na+[M+Na]+:409.1006,found 409.1006.
实施例2:
根据实施例1中最佳反应条件，仅仅将反应底物进行改变，得到如下反应结果及结构式：
Figure BDA0002568161020000061
典型化合物表征数据如下：
3ca:Colorless oil；96％yield,18.72mg,98％ee.[α]D 25＝-44.2(c＝1.6.,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:14.867min,16.927min.1H NMR(600MHz,CDCl3)δ7.91(d,J＝7.8Hz,2H),7.66(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,2H),7.35(d,J＝5.4Hz,1H),3.98(t,J＝7.2Hz,1H),3.76(s,3H),3.67(s,3H),2.17(t,J＝6.6Hz,1H),2.00(t,J＝7.8Hz,1H)；13CNMR(150MHz,CDCl3)δ167.2,166.8,166.7,156.1(d,JC-F＝114Hz),148.8,140.7,139.1,135.7,130.9,130.9,129.3,128.0(d,JC-F＝138Hz),53.5,53.4,43.0,34.9,20.5；19F NMR(376MHz,CDCl3)δ–163.85；HRMS(ESI):m/z calcd.for:C18H15N2O7Na+[M+Na]+:413.0756,found 413.0756.
3da:Colorless oil；93％yield,18.88mg,87％ee.[α]D 25＝-32.61(c＝1.2,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:14.640min,18.120min.1H NMR(600MHz,CDCl3)δ7.90(d,J＝7.8Hz,2H),7.65(t,J＝7.8Hz,1H),7.49(t,J＝7.8Hz,3H),4.00(t,J＝7.2Hz,1H),3.77(s,3H),3.67(s,3H),2.21(t,J＝6.6Hz,1H),2.02((t,J＝7.2Hz,1H)).13C NMR(150MHz,CDCl3)δ167.2,167.0,166.8,158.0,149.3,140.1,135.6,131.0,130.9,129.3,109.2,53.5,53.5,43.0,34.8,20.4.HRMS(ESI):m/z calcd.for:C18H15N2O7Na+[M+Na]+:429.0460,found429.0458.
3ea:Colorless oil；94％yield,21.15mg,90％ee.[α]D 25＝-43.69(c＝0.6,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:15.412min,18.795min.1H NMR(600MHz,CDCl3)δ7.90(d,J＝7.8Hz,2H),7.65(t,J＝7.2Hz,1H),7.60(s,1H),7.49(t,J＝7.2Hz,2H),3.99(d,J＝6.6Hz,1H),3.77(s,3H),3.67(s,3H),2.21(t,J＝6.6Hz,1H),2.02(t,J＝7.2Hz,1H).13C NMR(150MHz,CDCl3)δ167.2,167.0,166.7,149.5,142.5,135.5,131.0,130.9,129.3,96.8,53.5,53.5,43.0,34.8,20.5；HRMS(ESI):m/z calcd.for:C18H15BrN2O7Na+[M+Na]+:472.9955,found472.9953.
3ga:Colorless oil；91％yield,20.02mg,93％ee.[α]D 25＝-26.4(c＝1.2,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:9.917min,11.863min.1H NMR(600MHz,CDCl3)δ7.89(d,J＝7.8Hz,2H),7.74(s,1H),7.66(t,J＝7.2Hz,1H),7.50(t,J＝7.8Hz,2H),4.02(t,J＝7.2Hz,1H),3.77(s,3H),3.67(s,3H),2.19(t,J＝6.0Hz,1H),2.06(t,J＝7.4Hz,1H).13C NMR(150MHz,CDCl3)δ167.0,166.8,157.4,149.2,144.2(q,JC-F＝24.0Hz),135.7,130.9,130.8,129.4,122.4,120.6,105.5(q,JC-F＝132.0Hz),53.5,43.1,34.6,20.4；19F NMR(376MHz,CDCl3)δ–63.28(s)；HRMS(ESI):m/z calcd.for:C19H15F3N2O7Na+[M+Na]+:463.0724,found 463.0724.
实施例3:
Figure BDA0002568161020000081
向反应管中，加入3ba(37.2mg,0.1mmol)、TFA/DCM(v/v＝1/1,1.0mL)混合溶液，并在室温下搅拌3小时。TLC跟踪反应完毕，加入NaHCO3终止反应，并将混合物用DCM(3×10mL)萃取，合并有机相Na2SO4干燥，经柱层析(DCM/MeOH＝15/1)得到21.71mg白色固体3aa-1(81％,84％ee)。[α]D 25＝-14.26(c＝1.56,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:15.363min,18.775min.m.p.:172.1-175.8℃.1H NMR(600MHz,DMSO-d6)δ11.3(s,1H),7.58(d,J＝8.4Hz,1H),5.52(d,J＝8.4Hz,1H),3.97(t,J＝7.2Hz,1H),3.71(s,3H),3.56(s,3H),2.34(t,J＝6.6Hz,1H),1.93(t,J＝7.8Hz,1H).13CNMR(150MHz,DMSO-d6)δ168.0,166.4,163.8,150.5,144.8,101.3,53.3,53.2,34.8,19.5；HRMS(ESI):m/z calcd.for:C22H24N2O7Na+[M+Na]+:291.0588,found:291.0586.
实施例4:
Figure BDA0002568161020000091
在氮气保护条件下，向反应管中加入3aa(0.1mmol)、苯甲醛5a(0.12mmol,1.2eq)和溶剂DCM(1mL)在-78℃反应过夜，TCL跟踪反应结束，加入2mL水，将混合物用DCM(5mL×3)萃取,合并有机相，经Na2SO4干燥并在真空下浓缩，通过柱层析(PE/EA＝2/1)，得到所需产物4aa(68％收率，50％ee)。Colorless oil；68％yield,33.45mg,50％ee.[α]D 25＝0.72(c＝-9.14,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:12.173min,19.650min.1H NMR(600MHz,CDCl3)δ8.07(s,1H),7.95(d,J＝7.8Hz,2H),7.64(t,J＝7.2Hz,1H),7.48(dd,J＝18.0,7.2Hz,4H),7.38-7.33(m,3H),6.36(t,J＝7.2Hz,1H),5.61(s,1H),3.80(s,3H),3.15(s,3H),2.99(dd,J＝8.4,7.2Hz,1H),2.80(dd,J＝14.4,7.8Hz,1H),2.10(s,3H).13C NMR(150MHz,CDCl3)δ170.0,169.9,168.9,136.0,135.2,131.7,130.7,129.3,129.0,128.3,126.7,112.2,82.6,81.7,63.9,53.3,52.9,39.3,13.1.HRMS(ESI):m/z calcd.for:C26H24N2O8Na+[M+Na]+:515.1425,found:515.1423.
实施例5:
Figure BDA0002568161020000101
在氮气保护条件下，向反应管中加入3aa(38.6mg,0.1mmol)、乙二酸乙酯(甲苯中约50％的溶剂，0.12mmol,23.8μL)和溶剂DCM(1mL)在0℃反应2小时。TCL跟踪反应结束，加入水(2mL)，并将混合物用DCM(5mL×3)萃取。合并有机相，经Na2SO4干燥并在真空下浓缩,通过柱层析(PE/EA＝1/1)，得到产物5aa和6aa。5aa,Colorless oil；35％yield,17.09mg,86％ee.[α]D 25＝-6.49(c＝0.81,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:12.955min,14.542min.1H NMR(400MHz,CDCl3)δ8.13(d,J＝1.2Hz,1H),7.96–7.87(m,2H),7.64(t,J＝7.6Hz,1H),7.49(t,J＝8.4Hz,2H),6.26(dd,J＝8.0,5.6Hz,1H),5.18(s,1H),4.32–4.20(m,2H),3.84(s,3H),3.76(s,3H),2.97(dd,J＝13.6,5.6Hz,1H),2.86(dd,J＝13.6,8.4Hz,1H),2.01(d,J＝1.3Hz,3H),1.33(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ169.8,168.9,168.4,167.1,162.8,149.6,135.8,135.8,135.2,131.7,130.6,129.3,111.6,85.4,80.4,63.2,62.4,54.2,53.7,38.3,14.2,12.9；HRMS(ESI):m/z calcd.for:C23H24N2O10Na+[M+Na]+:511.1323,found:511.1322.6aa,Colorless oil；37％yield,18.06mg,93％ee.[α]D 25＝-8.62(c＝1.18,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:16.382min,19.677min.1H NMR(400MHz,CDCl3)δ7.92-7.90(m,2H),7.65(t,J＝7.5Hz,1H),7.49(t,J＝8.0Hz,2H),7.29(d,J＝1.2Hz,1H),6.35(dd,J＝6.8,4.4Hz,1H),5.44(s,1H),4.27(m,2H),3.82(s,3H),3.76(s,3H),3.32(dd,J＝14.4,7.2Hz,1H),2.78(dd,J＝14.4,4.4Hz,1H),1.97(d,J＝1.2Hz,3H),1.29(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ169.3,168.8,168.3,167.2,162.8,149.2,135.3,135.2,131.6,130.6,129.3,111.0,87.7,82.1,62.9,62.3,54.1,53.7,39.3,29.8,14.2,12.8.HRMS(ESI):m/z calcd.for:C23H24N2O10Na+[M+Na]+:511.1323,found:511.1322.
实施例6:
Figure BDA0002568161020000111
在氮气保护条件下，向反应管中加入3ba(37.2mg，0.1mmol)、乙二酸乙酯(甲苯中约50％溶剂，0.12mmol,23.8μL)和溶剂THF(0.5mL)。将另外将MgI2(2.8mg,0.01mmol)溶解在0.5mL THF中，并在氮气气氛下于0℃通过注射器将其加入上述反应体系中，继续搅拌2小时，TLC跟踪反应结束，加入2mL水，并将混合物用DCM(5mL×3)萃取。合并有机相，经Na2SO4干燥并在真空下浓缩，通过柱层析(PE/EA＝1/1)，得到所需产物5ba(47％,80％ee)和6ba(24％,88％ee)。5ba Colorless oil；47％yield,22.28mg,80％ee.[α]D 25＝-8.47(c＝0.68,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:16.090min,21.082min.1H NMR(600MHz,CDCl3)δ8.31(d,J＝7.8Hz,1H),7.93(d,J＝7.8Hz,2H),7.65(t,J＝7.2Hz,1H),7.49(t,J＝7.8Hz,2H),6.21(t,J＝6.6Hz,1H),5.90(d,J＝8.4Hz,1H),5.18(s,1H),4.35-4.17(m,2H),3.83(s,3H),3.76(s,3H),3.00(dd,J＝13.8,5.4Hz,1H),2.88(dd,J＝13.8,7.8Hz,1H),1.32(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ169.7,168.6,168.3,167.1,162.0,149.5,140.1,135.3,131.5,130.6,129.3,102.8,85.9,80.7,63.1,62.5,54.2,53.8,38.7,14.1；HRMS(ESI):m/z calcd.for:C22H22N2O10Na+[M+Na]+:497.1167,found:497.1167；6ba,Colorlessoil；21％yield,9.96mg,88％ee.[α]D 25＝-7.69(c＝0.65,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:18.915min,28.347min.1H NMR(600MHz,CDCl3)δ7.92(d,J＝7.2Hz,2H),7.66(t,J＝7.2Hz,1H),7.50(t,J＝8.4Hz,3H),6.32(s,1H),5.83(d,J＝8.4Hz,1H),5.44(s,1H),4.25-4.17(m,2H),3.82(s,3H),3.76(s,3H),3.34(dd,J＝14.4,7.2Hz,1H),2.81(s,1H),1.29(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ169.2,168.5,168.3,167.0,149.1,139.4,135.4,131.5,130.6,129.4,102.2,88.1,82.2,62.7,62.4,54.2,53.8,39.4,29.8,14.1；HRMS(ESI):m/z calcd.for:C22H22N2O10Na+[M+Na]+:497.1167,found:497.1167.
实施例7:
Figure BDA0002568161020000121
在氮气保护条件下，向反应管中加入3aa(38.6mg,0.1mmol)、炔丙醇(12μL,0.12mmol,1.2eq)、Sc(OTf)3(2.5mg,5mol％)和DCM(1mL)在-10℃反应12小时,通过TLC跟踪反应结束，加入2mL水，混合物用DCM(5mL×3)萃取。合并有机相，Na2SO4干燥并在真空下浓缩，柱层析(PE/EA＝1/1)得到27.85mg白色固体7aa(63％,89％ee)。m.p.:95.8-96.9℃.[α]D 25＝-13.51(c＝0.93,CH2Cl2).HPLC CHIRALCEL IA,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝254nm,retention time:12.290min,15.593min.1H NMR(600MHz,CDCl3)δ7.93(d,J＝6.6Hz,2H),7.65(t,J＝7.8Hz,1H),7.50(t,J＝7.8Hz,2H),7.24(s,1H),5.95(dd,J＝8.4,4.8Hz,1H),4.20(d,J＝2.4Hz,2H),3.74(s,6H),3.56(t,J＝7.2Hz,1H),2.55-2.50(m,2H),2.39-2.35(m,1H),1.99(s,3H).13C NMR(150MHz,CDCl3)δ168.9,168.8,168.6,162.7,149.9,135.2,134.4,131.7,130.6,129.3,112.1,82.8,76.2,57.5,53.2,53.1,47.9,33.9,12.8；HRMS(ESI):m/z calcd.for:C22H22N2O8Na+[M+Na]+:465.1268,found:465.1267.
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。

Claims (9)

1.不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷的方法，其特征在于，包括以下步骤：以N1-乙烯基嘧啶1和苯基碘叶立德2为原料，在铜盐催化剂和手性双噁唑啉配体的作用下，有机溶剂中反应，得到嘧啶取代的双酯基环丙烷3；其反应方程式如下：
Figure FDA0002568161010000011
其中，R选自氢、卤素、C1-C4烷基、含杂原子C1-C4烷基、C1-C4烷氧基、苯乙炔基；R1选自C1-C4烷基；Pg选自苯甲酰基、对卤苯甲酰基、Boc。
2.根据权利要求1所述不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷的方法，其特征在于：所述铜盐催化剂选自Cu(OTf)2、Cu(SbF6)2或Cu[(MeCN)4]PF6。
3.根据权利要求1所述不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷的方法，其特征在于：手性双噁唑啉配体为
Figure FDA0002568161010000012
4.根据权利要求1所述不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷的方法，其特征在于：所述反应溶剂选自二氯甲烷、甲苯、氟苯、1,3-二氯苯、氟苯、1,3-二氯苯中的一种或多种。
5.所述不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷的方法，其特征在于：所述铜催化剂和配体摩尔比为1:1-1.2。
6.所述不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷的方法，其特征在于：反应温度为0℃至-20℃。
7.根据权利要求1所述所述不对称环丙烷化合成手性嘧啶取代的双酯基环丙烷的方法，其特征在于：反应体系加入分子筛。
8.一种手性嘧啶取代双酯基环丙烷3的应用，其特征在于：包括采用权利要求1-8中任意一项得到手性嘧啶取代双酯基环丙烷3，然后手性嘧啶取代双酯基环丙烷3与苯甲醛、乙醛酸乙酯、炔丙醇进一步发生[3+2]环加成反应分别生成化合物4、化合物5/化合物6和化合物7；对应结构如下：
Figure FDA0002568161010000021
9.根据权利要求8中所述的应用，其特征在于：与苯甲醛反应时，在SnCl4催化剂存在下进行，与乙醛酸乙酯反应时，在MgI2催化剂存在下进行，与丙炔醇反应时，在Sc(OTf)2催化剂存在下进行。
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