CN112811996A - 不对称双共轭加成合成光学活性酮类化合物的方法 - Google Patents
不对称双共轭加成合成光学活性酮类化合物的方法 Download PDFInfo
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Abstract
本发明公开了不对称双共轭加成合成光学活性酮类化合物的方法,属于有机化学中的不对称合成技术领域。具体步骤如下:以二烯酮1和有机硼酸2为原料,在手性联二萘酚或手性四苯并环辛四烯类催化剂和分子筛存在下,经过不对称共轭加成反应得到酮类化合物3。反应方程式如下:
Description
技术领域
本发明属于有机化学中的不对称合成技术领域,具体涉及一种不对称双共轭加成合成光学活性酮类化合物的方法。
背景技术
有机硼化物与α,β-不饱和羰基化合物的不对称共轭加成反应是构筑C-C键的重要合成方法。有机硼化物(烃基硼酸、有机硼酸酯和有机硼酸盐)以其低毒、廉价易得、稳定性好和良好的官能团耐受性等优点在现代有机合成中发挥重要作用,有机小分子催化有机硼化物与α,β-不饱和羰基化合物的不对称共轭加成反应具有很多优点,例如催化剂低毒性、易于制备、价格便宜、稳定性好、操作简单和不存在反应后金属残留等。
到目前为止,用于该反应的手性催化剂种类还比较少,而且大多需要使用不太稳定的有机硼酸酯和有机硼酸盐,直接使用简单易得、相对稳定的有机硼酸的报道还比较少。2014年,Sugiura等人报道使用光学活性酒石酸衍生物催化苯乙烯基硼酸与二烯酮发生不对称共轭加成反应,主要得到单苯乙烯基加成的酮类化合物,双共轭加成产物较少(Org.Lett.2014,16,5172–5175)。
因此,发展一种无过渡金属参与、反应活性好、操作简单的催化体系,实现有机硼酸与二烯酮的不对称双共轭加成反应,得到一系列光学活性的酮类衍生物是本发明重点解决的技术问题。
发明内容
为了克服上述技术缺陷,本发明提供了不对称双共轭加成反应合成光学活性酮类化合物的方法。采用有机硼酸与二烯酮作为原料,在手性联萘酚类化合物或手性四苯并环辛四烯类化合物作为催化剂,分子筛作为添加剂下经过不对称双共轭加成反应,以高收率、高非对映选择性和对映选择性一步合成光学活性酮类化合物。
本发明所述不对称双共轭加成合成光学活性酮类化合物的方法,包括如下步骤:以二烯酮1和有机硼酸2为原料,在手性联二萘酚或手性四苯并环辛四烯类化合物和分子筛催化下,反应得到酮类化合物3。反应方程式如下:
其中:R1,R2各自独立选自取代苯基、萘基、呋喃基、噻吩基、C1-C6烷基或取代苯基乙基,所述取代苯基中取代基为氢、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基、C1-C4烷氧羰基或硝基;R3选自取代苯乙烯基、呋喃基、苯丙呋喃基、噻吩基、苯并噻吩基或C1-C8烷烯基,所述所述取代苯中取代基为氢、C1-C4烷基、C1-C4烷氧基、卤素、三氟甲基、C1-C4烷氧羰基或硝基。
进一步地,在上述技术方案中,R1为取代苯基、2-噻吩基、2-呋喃基、1-萘基或2-萘基;R2为取代苯基、2-噻吩基、2-呋喃基、1-萘基、2-萘基、正丙基或苯乙基;R3为苯乙烯基、对甲基苯乙烯基、2-呋喃基、2-苯并呋喃基、2-噻吩基、2-苯并噻吩基或正辛烯基。
进一步地,在上述技术方案中,所述手性1,1'-联二萘酚类催化剂为R=H、F、Cl、Br、I、Ph、3,5-Me2C6H4、3,5-(MeO)2C6H4、3,5-(CF3)2C6H4;优选条件下手性1,1'-联二萘酚类催化剂为如下三种:
进一步地,在上述技术方案中,所述手性四苯并环辛四烯酚类催化剂为R=H、F、Cl、Br、I、Ph、3,5-Me2C6H4、3,5-(MeO)2C6H4、3,5-(CF3)2C6H4;优选条件下手性四苯并环辛四烯酚类催化剂为如下三种:
进一步地,在上述技术方案中,所述二烯酮1、有机硼酸2与催化剂摩尔比为1:2-4:0.05-0.20。
进一步地,在上述技术方案中,所述反应溶剂为甲苯、二氯甲烷、四氢呋喃、三氟甲苯、邻二甲苯、间二甲苯、氯苯、1,2-二氯乙烷、二异丙基醚或1,4-二氧六环。
进一步地,在上述技术方案中,整个反应过程需要在氮气或氩气下进行,优选氮气。
发明有益效果:
本发明反应原料易得,反应条件温和,后处理简单,催化剂可回收再利用,产物收率、非对映选择性和对映选择性良好至优秀。
具体实施方式
以下结合具体实施例对本发明的技术方案作进一步详细说明,但本发明的保护范围并不局限于此。
实施例1
a二烯酮1a(0.1mmol)、反式-2-苯基乙烯基硼酸2a(0.2mmol)、催化剂(0.01mmol,10mol%)、Mg(OtBu)2(0.01mmol,10mol%)、分子筛(100mg)、1.0mL无水溶剂在N2气氛下b分离产率cdl/meso通过HPLC手性柱分析dee通过HPLC手性柱分析e2a(0.3mmol)f不加Mg(OtBu)2 g在0℃hCat 5(0.005mmol,5mol%)分子筛(100mg)j不加分子筛k二烯酮1a(0.1mmol)、反式-2-苯基乙烯基硼酸2a(0.3mmol)、Cat 9(0.01mmol,10mol%)、分子筛(100mg)、1.0mL甲苯在N2气氛下25℃.
在反应条件的筛选过程中,考察了不同手性催化剂对反应的影响(标号1-10),确定了Cat 2、3、5和Cat 8、9、10为最佳催化剂。接着考察了不同溶剂对反应影响(标号12-19),最终选用甲苯作溶剂。同时考察了投料比例、Mg(OtBu)2、温度、催化剂用量和分子筛对反应的影响(标号11和20-24),最终选择反应温度为25℃,催化剂用量为10mol%。反应条件的考察典型操作(以标号23为例):
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1a(23.4mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1a消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到产物3aa,收率为97%。白色固体(42.8mg);mp 102-103℃;HPLC(Daicel Chiral pak IB,正己烷/异丙醇=90:10,流速0.8 mL/min,λ=254 nm)tR(1)=15.4min,tR(2)=18.6min,tR(3)=26.2min,dl-/meso-=95.8:4.2,>99%ee;[α]D 25=–8.2(c 2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.29-7.16(m,20H),6.31-6.20(m,4H),4.05(q,J=6.8Hz,2H),2.89-2.85(m,4H);13C NMR(100MHz,CDCl3)δ206.9,143.1,137.2,132.4,130.1,128.8,128.6,127.8,127.4,126.8,126.4,49.5,43.8;HRMS(ESI)m/z:[M+Na]+Calcd forC33H30ONa 465.2189;Found 465.2168.
实施例2
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1b(26.2mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1b消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到产物3ba,收率为99%。白色固体(46.8mg);mp 75-77℃;HPLC(Daicel Chiral pak IB,正己烷/异丙醇=90:10,流速0.8 mL/min,λ=254 nm)tR(1)=12.5min,tR(2)=13.8min,tR(3)=16.7min,dl-/meso-=97.0:3.0,>99%ee;[α]D 25=–10.1(c 2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.25-7.21(m,8H),7.19-7.16(m,2H),7.10-7.05(m,8H),6.29-6.18(m,4H),4.02(q,J=6.8Hz,2H),2.91-2.79(m,4H),2.29(s,6H);13C NMR(100MHz,CDCl3)δ207.1,140.0,137.3,136.3,132.7,129.9,129.5,128.5,127.6,127.3,126.4,49.5,43.4,21.1;HRMS(ESI)m/z:[M+Na]+Calcd for C35H34O Na 493.2502;Found493.2500.
实施例3
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1c(29.4mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1c消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/2-1/1)分离纯化得到目标产物3ca,收率为96%。白色固体(48.3mg);mp 75-76℃;HPLC(Daicel Chiralpak ID,正己烷/异丙醇=90:10,流速0.8mL/min,λ=254nm)tR(1)=17.7min,tR(2)=19.1min,tR(3)=23.4min,dl-/meso-=95.6:4.4,>99%ee;[α]D 26=–20.5(c 2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.26-7.14(m,14H),6.89-6.83(m,4H),6.37-6.28(m,4H),4.44(q,J=6.8Hz,2H),3.79(s,6H),2.96-2.86(m,4H);13C NMR(100MHz,CDCl3)δ207.9,156.9,137.6,131.9,131.5,130.1,128.5,128.4,127.7,127.1,126.4,120.8,111.0,55.5,48.1,38.2;HRMS(ESI)m/z:[M+Na]+Calcd for C35H34O3Na 525.2400;Found525.2368.
实施例4
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1d(29.4mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1d消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/2-1/1)分离纯化得到目标产物3da,收率为96%。白色固体(46.0mg);mp 68-69℃;HPLC(DaicelChiralpak IB,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=7.6min,tR(2)=14.1min,tR(3)=18.3min,dl-/meso-=94.0:6.0,>99%ee;[α]D 27=–6.9(c2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.28-7.10(m,14H),6.95-6.91(m,4H),6.31-6.16(m,4H),4.04(q,J=6.8Hz,2H),2.91-2.79(m,4H);13C NMR(100MHz,CDCl3)δ206.5,161.7(d,J=244.0Hz,),138.6(d,J=3.0Hz),137.0,132.1,130.3,129.2(d,J=8.0Hz),128.6,127.6,126.3,115.6(d,J=21.0Hz),49.5,42.9;19FNMR(376MHz,CDCl3)δ–116.1;HRMS(ESI)m/z:[M+Na]+Calcd for C33H28F2ONa 501.2000;Found 501.1990.
实施例5
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1e(30.3mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥的甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1e消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3ea,收率为92%。白色固体(47.1mg);mp 51-52℃;HPLC(Daicel Chiralpak IB,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=9.7min,tR(2)=17.5min,tR(3)=24.9min,dl-/meso-=96.3:3.7,>99%ee;[α]D 23=–8.5(c2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.28-7.17(m,14H),7.12-7.07(m,4H),6.31-6.15(m,4H),4.03(q,J=10.2Hz,2H),2.93-2.77(m,4H);13C NMR(150MHz,CDCl3)δ206.2,141.5,137.0,132.6,131.8,130.6,129.2,128.9,128.7,127.6,126.4,49.3,43.1;HRMS(ESI)m/z:[M+Na]+Calcd for C33H28Cl2ONa 533.1409;Found 533.1390.
实施例6
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1f(39.2mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥的甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1f消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/2-1/1)分离纯化得到目标产物3fa,收率为92%。白色固体(55.4mg);mp 103-104℃;HPLC(Daicel Chiralpak IB,正己烷/异丙醇=70:30,流速1.0mL/min,λ=254nm)tR(1)=9.9min,tR(2)=16.7min,tR(3)=23.2min,dl-/meso-=96.5:3.5,>99%ee;[α]D 25=–6.2(c2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.38-7.35(m,4H),7.29-7.20(m,10H),7.06-7.04(m,4H),6.28-6.14(m,4H),4.01(q,J=7.2Hz,2H),2.93-2.77(m,4H);13C NMR(100MHz,CDCl3)δ206.2,141.9,136.9,131.9,131.6,130.6,129.6,128.7,127.6,126.4,120.6,49.2,43.1;HRMS(ESI)m/z:[M+Na]+Calcd for C33H28Br2ONa 621.0399;Found 621.0401.
实施例7
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1g(33.3mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1g消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/2-1/1)分离纯化得到目标产物3ga,收率为99%。白色固体(53.7mg);mp 136-138℃;HPLC(Daicel Chiralpak IB,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=23.4min,tR(2)=28.4min,tR(3)=30.0min,dl-/meso-=97.2:2.8,>99%ee;[α]D 20=–14.2(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.77-7.70(m,6H),7.61(s,2H),7.44-7.40(m,4H),7.32-7.30(m,2H),7.23-7.14(m,10H),6.34-6.25(m,4H),4.24-4.21(m,2H),3.06-2.92(m,4H);13C NMR(150MHz,CDCl3)δ206.7,140.5,137.2,133.7,132.5,132.3,130.4,128.6,128.5,127.9,127.8,127.4,126.37,126.31,126.22,126.17,125.7,49.4,43.8;HRMS(ESI)m/z:[M+Na]+Calcd for C41H34ONa 565.2502;Found 565.2487.
实施例8
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1h(21.4mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1h消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3ha,收率为94%。白色固体(39.7mg);mp 86-88℃;HPLC(DaicelChiralpak ID,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=8.5min,tR(2)=10.8min,tR(3)=11.7min,dl-/meso-=93.8:6.2,>99%ee;[α]D 24=26.6(c2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.32-7.19(m,12H),6.40-6.38(m,2H),6.25-6.17(m,4H),6.04-6.02(m,2H),4.18(q,J=10.8Hz,2H),3.00(d,J=10.2Hz,25.2Hz,2H),2.87-2.80(m,2H);13C NMR(150MHz,CDCl3)δ205.9,155.8,141.6,137.1,131.5,129.3,128.6,127.6,126.5,110.4,105.7,47.1,37.7;HRMS(ESI)m/z:[M+Na]+Calcd for C29H26O3Na445.1774;Found 445.1765.
实施例9
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1i(26.4mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1i消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/2-1/1)分离纯化得到目标产物3ia,收率为85%。白色固体(40.3mg);mp 70-71℃;HPLC(DaicelChiralpak IB,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=10.6min,tR(2)=13.0min,tR(3)=16.2min,tR(4)=17.8min,d.r.=96.9:3.1,>99%ee;[α]D 27=–12.3(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.28-7.22(m,10H),7.20-7.15(m,5H),7.12-7.09(m,2H),6.81-6.78(m,2H),6.31-6.19(m,4H),4.08-3.98(m,2H),3.75(s,3H),2.91-2.80(m,4H);13C NMR(150MHz,CDCl3)δ207.1,158.4,143.1,137.32,137.28,135.1,132.9,132.5,130.2,129.9,128.81,128.77,128.6,127.8,127.40,127.36,126.8,126.4,114.2,55.4,49.6,49.5,43.8,43.0;HRMS(ESI)m/z:[M+Na]+Calcd for C34H32O2Na495.2295;Found 495.2274.
实施例10
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 5(7.1mg,0.01mmol,10mol%)、二烯酮1j(20.0mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0equiv),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1j消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/2-1/1)分离纯化得到目标产物3ja,收率为68%。无色油状液体(27.8mg);HPLC(DaicelChiralpak IB,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=6.0min,tR(2)=6.4min,tR(3)=7.5min,tR(4)=8.4min,d.r.=82.0:18.0,>99%ee;[α]D 21=14.7(c 1.0,CHCl3);1H NMR(400MHz,CDCl3)mixture ofdiastereomersδ7.30-7.15(m,15H),6.37-6.25(m,3H),5.96-5.90(m,1H),4.08(q,J=6.8Hz,1H),2.92-2.90(m,2H),2.76-2.67(m,1H),2.51-2.39(m,2H),1.33-1.23(m,4H),0.85-0.82(m,3H);13C NMR(150MHz,CDCl3)mixtureof diastereomersδ208.0,143.2,143.1,137.5,137.2,133.34,133.33,132.6,130.4,130.3,130.1,128.79,128.78,128.6,127.83,127.79,127.4,127.2,126.8,126.3,126.2,49.54,49.51,49.46,49.3,43.9,38.5,37.3,20.5,20.4,14.1;HRMS(ESI)m/z:[M+Na]+Calcd for C30H32ONa 431.2345;Found 431.2334.
实施例11
根据实施例10反应条件,采用不同二烯酮类化合物1与不同有机硼酸类化合物2,反应结果如下:
实施例12
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 9(4.9mg,0.01mmol,10mol%)、二烯酮1k(37.2mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1k消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3ka',收率为72%。无色油状物(53.7mg);HPLC(DaicelChiralpak IB,正己烷/异丙醇=80:20,流速0.8mL/min,λ=254nm)tR(1)=14.2min,tR(2)=18.8min,tR(3)=27.8min,dl-/meso-=98.2:1.8,>99%ee;[α]D 19=19.8(c 2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.35(t,J=1.2Hz,2H),7.28-7.18(m,10H),7.15-7.13(m,4H),6.32-6.17(m,4H),4.52(q,J=6.8Hz,2H),2.99-2.89(m,4H);13C NMR(100MHz,CDCl3)δ205.4,138.9,136.8,134.5,133.0,131.4,129.9,129.7,129.5,128.7,127.7,127.5,126.4,47.7,39.8;HRMS(ESI)m/z:[M+Na]+Calcd forC33H26Cl4ONa 601.0630;Found601.0613.
实施例13
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 9(4.9mg,0.01mmol,10mol%)、二烯酮1l(45.2mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1l消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3la',收率为72%。白色固体(47.4mg);mp 112-113℃;HPLC(Daicel Chiralpak ID,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=12.2min,tR(2)=13.4min,tR(3)=23.9min,dl-/meso-=97.9:2.1,>99%ee;[α]D 19=7.3(c2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.42(d,J=13.2Hz,2H),7.27-7.16(m,10H),6.78(d,J=4.2Hz,2H),6.63-6.61(m,2H),6.38-6.19(m,4H),4.54(q,J=10.2Hz,2H),3.73(s,6H),2.99-2.89(m,4H);13C NMR(100MHz,CDCl3)δ205.7,159.2,143.1,137.0,133.9,131.2,130.3,128.6,127.5,126.5,115.1,114.9,113.3,55.6,48.0,42.6;HRMS(ESI)m/z:[M+Na]+Calcd for C35H32Br2O3Na681.0610;Found 681.0610.
实施例14
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 9(4.9mg,0.01mmol,10mol%)、二烯酮1l(45.2mg,0.1mmol)和有机硼酸2b(48.6mg,0.3mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1l消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3lb',收率为99%。无色油状液体(68.8mg);HPLC(DaicelChiralpakID,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=12.3min,tR(2)=13.3min,tR(3)=20.1min,dl-/meso-=93.2:6.8,>99%ee;[α]D 19=5.1(c 2.0,CHCl3);1HNMR(600MHz,CDCl3)δ7.43-7.41(m,2H),7.16-7.14(m,4H),7.05-7.03(m,4H),6.78-6.77(m,2H),6.63-6.61(m,2H),6.33-6.30(m,2H),6.20-6.16(m,2H),4.53-4.51(m,2H),3.73-3.73(m,6H),2.93-2.91(m,4H),2.30(s,6H);13C NMR(150MHz,CDCl3)δ205.8,159.2,143.3,137.3,134.3,133.9,131.1,129.3,126.4,115.1,114.9,113.4,55.6,48.1,42.7,21.3;HRMS(ESI)m/z:[M+Na]+Calcd for C37H36Br2O3Na 709.0923;Found 709.0904.
实施例15
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 9(4.9mg,0.01mmol,10mol%)、二烯酮1l(45.2mg,0.1mmol)和有机硼酸2c(33.6mg,0.3mmol,3.0equiv),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1l消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3lc',收率为85%。无色油状液体(49.8mg);HPLC(Daicel ChiralpakID,正己烷/异丙醇=80:20,流速1.0mL/min,λ=220nm)tR(1)=10.8min,tR(2)=13.2min,tR(3)=16.5min,dl-/meso-=86.1:13.9,>99%ee;[α]D 23=13.7(c 2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.44-7.41(m,2H),7.30-7.26(m,2H),6.65-6.62(m,4H),6.27-6.24(m,2H),6.01-5.99(m,2H),5.06-5.01(m,2H),3.71-3.72(d,6H),3.21-3.14(m,2H),3.00-2.95(m,2H);13C NMR(100MHz,CDCl3)δ204.5,159.2,154.6,142.0,141.8,133.8,115.3(115.2),114.5,113.7(113.8),110.4,107.0,55.5,46.6,39.5;HRMS(ESI)m/z:[M+Na]+Calcd for C27H24Br2O5Na 608.9883;Found 608.9873.
实施例16
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 9(4.9mg,0.01mmol,10mol%)、二烯酮1l(45.2mg,0.1mmol)和有机硼酸2d(48.6mg,0.3mmol,3.0equiv),抽换气3次,再加入干燥的甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1l消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3ld',收率为86%。白色固体(59.1mg);mp 70-72℃;HPLC(DaicelChiralpak IB,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=8.1min,tR(2)=9.2min,tR(3)=10.1min,dl-/meso-=83.8:16.2,>99%ee;[α]D 23=13.7(c2.0,CHCl3);1H NMR(400MHz,CDCl3)mixture of diastereomersδ7.46-7.33(m,6H),7.22-7.13(m,4H),6.74-6.73(m,2H),6.66-6.62(m,2H),6.34-6.33(m,2H),5.22-5.18(m,2H),3.68-3.67(d,6H),3.38-3.30(m,2H),3.15-3.09(m,2H);13C NMR(100MHz,CDCl3)mixtureof diastereomersδ204.10,204.05,159.3,157.6,157.55,157.53,154.9,141.1,141.0,133.89,133.87,128.50,128.48,123.9,122.8,120.89,120.86,115.49,115.45,114.65,114.64,113.9,113.8,111.2,104.2,104.1,55.5,46.4,39.9;HRMS(ESI)m/z:[M+Na]+Calcdfor C35H28Br2O5Na 709.0196;Found 709.0189.
实施例17
在氮气保护下,向经过无水无氧处理25mL Schlenk管中加入100mg分子筛、手性催化剂Cat 9(4.9mg,0.01mmol,10mol%)、二烯酮1m(37.2mg,0.1mmol)和有机硼酸2a(44.4mg,0.3mmol,3.0equiv),抽换气3次,再加入干燥的甲苯(1.0mL),25℃搅拌24h。TLC点板跟踪至原料1m消失,减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/3-1/1)分离纯化得到目标产物3ma',收率为97%。无色油状液体(56.1mg);HPLC(DaicelChiralpak IB,正己烷/异丙醇=80:20,流速1.0mL/min,λ=254nm)tR(1)=6.5min,tR(2)=19.3min,tR(3)=21.9min,dl-/meso-=96.0:4.0,>99%ee;[α]D 19=1.3(c2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.47-7.43(m,4H),7.39-7.32(m,4H),7.28-7.18(m,10H),6.35-6.17(m,4H),4.13(q,J=10.8Hz,2H),3.01-2.83(m,4H);13C NMR(150MHz,CDCl3)δ205.6,144.0,136.8,131.3,131.2,131.1(q,J=31.5Hz),131.0,129.3,128.7,127.7,126.4,124.4(q,J=4.5Hz),124.2(q,J=271.5Hz),123.8(q,J=6.0Hz),49.2,43.5;19F{1H}NMR(376MHz,CDCl3)δ–62.5;HRMS(ESI)m/z:[M+Na]+Calcd for C35H28F6ONa601.1937;Found 601.1922.
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 (10)
2.根据权利要求1所述不对称双共轭加成合成光学活性酮类化合物的方法,其特征在于:R1为取代苯基、2-噻吩基、2-呋喃基、1-萘基或2-萘基;R2为取代苯基、2-噻吩基、2-呋喃基、1-萘基、2-萘基、正丙基或苯乙基;R3为苯乙烯基、对甲基苯乙烯基、2-呋喃基、2-苯并呋喃基、2-噻吩基、2-苯并噻吩基或正辛烯基。
4.根据权利要求1所述不对称双共轭加成合成光学活性酮类化合物的方法,其特征在于:手性1,1'-联二萘酚类催化剂催化剂选自R=Br、I或3,5-(CF3)2C6H4。
5.根据权利要求1所述不对称双共轭加成合成光学活性酮类化合物的方法,其特征在于:手性四苯并环辛四烯酚类催化剂选自R=Cl、Br或Ph。
6.根据权利要求1所述不对称双共轭加成合成光学活性酮类化合物的方法,其特征在于:所述α,β-不饱和酮1、有机硼酸2与催化剂摩尔比为1:2-4:0.05-0.20。
7.根据权利要求1所述不对称双共轭加成合成光学活性酮类化合物的方法,其特征在于:所述反应溶剂选自甲苯、二氯甲烷、四氢呋喃、三氟甲苯、邻二甲苯、1,2-二氯乙烷、二异丙基醚或1,4-二氧六环。
8.根据权利要求1所述不对称共轭加成合成光学活性酮类化合物的方法,其特征在于:反应温度为0至25℃。
10.根据权利要求1-9任意一项所述不对称双共轭加成合成光学活性酮类化合物的方法,其特征在于:整个反应过程需要在氮气或氩气下进行。
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