CN114436935A - 不对称共轭加成合成光学活性β-氨基酮衍生物的方法 - Google Patents
不对称共轭加成合成光学活性β-氨基酮衍生物的方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Organic Chemistry (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了不对称共轭加成合成光学活性β‑氨基酮衍生物的方法,属于有机化学中技术领域。以β‑酰亚胺丙烯酮1和有机硼酸2为原料,在手性联二萘酚类或四苯并环辛四烯类催化剂、分子筛存在下,有机溶剂中经过不对称共轭加成反应得到β‑氨基酮衍生物3。本方法反应原料易得,催化剂结构简单,催化效率高,反应条件温和,后处理简单。
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共轭加成合成光学活性β-氨基酮衍生物的方法。
背景技术
手性β-氨基酮衍生物广泛存在于医药和具有生物活性天然产物中,例如抗癌药物紫杉醇(Taxol)侧链、蛋白质磷酸酶抑制剂Motu porin环肽结构和免疫响应调节剂Bestatin等。因此,开发合成光学活性的β-氨基酮衍生物的新方法引起了化学家极大兴趣。近年来,有机小分子催化有机硼化物与α,β-不饱和羰基化合物不对称共轭加成反应是构筑C-C键的重要合成方法(Molecules 2018,23,2317–2353),该方法存在很多优点,例如催化剂低毒性、易于制备、稳定性好;所使用的有机硼化物(烃基硼酸、有机硼酸酯和有机硼酸盐)低毒、廉价易得和良好的官能团耐受性,以及反应操作简单和不存在反应后金属残留等优点在现代有机合成中发挥重要作用。
到目前为止,用于该反应的手性催化剂种类还比较少。仅有毛斌等人报道使用光学活性联萘酚衍生物催化炔基三氟硼酸钾盐与β-邻苯二甲酰亚胺丙烯酮类化合物发生不对称1,4-加成反应得到手性β-氨基酮衍生物(Org.Lett.2020,22,7427),该反应所使用一种新多氟联萘酚骨架催化剂,且需要溴化锂和三氟化硼***络合物作为添加剂下-35℃下反应,而且对于不同反应底物反应条件不同。
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,实现简单易得、相对稳定的有机硼酸与β-氨基不饱和酮不对称共轭加成反应,得到一系列光学活性β-氨基酮衍生物就显得非常必要。
发明内容
为了克服上述技术缺陷,本发明提供了不对称共轭加成合成光学活性β-氨基酮衍生物的方法。采用有机硼酸与β-邻苯二甲酰亚胺丙烯酮作为原料,在手性联萘酚类化合物或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共轭加成反应,以高收率、高对映选择性一步合成光学活性β-氨基酮衍生物。
本发明所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,包括如下步骤:以β-酰亚胺丙烯酮1和有机硼酸2为原料,在手性联二萘酚类或手性四苯并环辛四烯类催化剂和分子筛存在下,有机溶剂中反应得到β-氨基酮类化合物3。反应方程式如下:
其中:R1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;R2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;β-二甲酰亚胺丙烯酮选自β-邻苯二甲酰亚胺丙烯酮或β-琥珀酰亚胺丙烯酮。
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、2-萘基、甲基或环己基;R2为苯乙烯基、对甲基苯乙烯基、对氯苯乙烯基、对溴苯乙烯基、对三氟甲基苯乙烯基、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,所述手性联二萘酚类催化剂为
3,5-(CF3)2C6H4;优选条件下,手性联二萘酚类催化剂为如下四种:
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两种:
进一步地,在上述技术方案中,所述β-邻苯二甲酰亚胺丙烯酮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,所述有机溶剂选自甲苯、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、***、甲基叔丁基醚、乙腈或1,4-二氧六环。
进一步地,在上述技术方案中,反应温度为0至30℃,优选25℃。
进一步地,在上述技术方案中,整个反应过程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、对映选择性良好至优秀。
具体实施方式
实施例1
aβ-邻苯二甲酰亚胺丙烯酮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cee通过HPLC手性柱分析d 0℃e无Mg(OtBu)2 f MeOH(0.01mmol,10mol%)替代Mg(OtBu)2(0.01mmol,10mol%)g无分子筛分子筛(100mg)分子筛(100mg)jCat 1(0.005mmol,5mol%)kCat 12(0.01mmol,10mol%).
在反应条件筛选过程中,考察了不同手性催化剂对反应的影响(标号1-11),确定了Cat 1、2和Cat 6、7、8、11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Mg(OtBu)2、温度、催化剂用量和分子筛对反应的影响(标号20-26),最终选择反应温度为25℃,催化剂用量为10mol%。反应条件典型操作(以标号1为例):
在氮气保护下,向Schlenk管(无水无氧处理,下同)中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到42.3mg无色液体3aa,收率99%。HPLC(Daicel Chiralpak IF,hexane/i-PrOH=80:20,flow rate1.0mL/min,λ=254nm)tR(minor)=22.4min,tR(major)=23.6min,98%ee;[α]D 26=–19.0(c1.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.97-7.95(m,2H),7.84-7.81(m,2H),7.70-7.68(m,2H),7.55-7.53(m,1H),7.46-7.42(m,2H),7.38-7.36(m,2H),7.31-7.27(m,2H),7.25-7.21(m,1H),6.71(d,J=16.0Hz,1H),6.59(dd,J=8.0,15.6Hz,1H),5.69-5.63(m,1H),4.14(dd,J=8.8,17.6Hz,1H),3.65(dd,J=5.6,17.6Hz,1H);HRMS(ESI)m/z:[M+Na]+Calcd forC25H19N O3Na 404.1257;Found 404.1256.
实施例2
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1b(29.1mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。
TLC显示1b消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到46.1mg无色液体3ba,收率99%。HPLC(Daicel Chiralpak IF,正己烷/异丙醇=70:30,flow rate 1.0mL/min,λ=254nm)tR(minor)=20.5min,tR(major)=22.1min,97%ee;[α]D 29=–14.2(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.86-7.81(m,4H),7.69-7.68(m,2H),7.36(d,J=7.8Hz,2H),7.29-7.21(m,5H),6.70(d,J=15.6Hz,1H),6.59(dd,J=7.8,15.6Hz,1H),5.67-5.64(m,1H),4.10(dd,J=9.0,17.4Hz,1H),3.62(dd,J=5.4,17.4Hz,1H),2.38(s,3H);13C NMR(150MHz,CDCl3)δ196.4,168.1,144.3,136.2,134.2,134.1,133.3,132.1,129.5,128.7,128.4,128.1,126.8,126.0,123.4,49.2,40.7,21.8;HRMS(ESI)m/z:[M+Na]+Calcd for C26H21NO3Na 418.1414;Found 418.1410.
实施例3
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1c(30.7mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1c消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/3)分离纯化得到38.2mg白色固体3ca,收率93%。mp 102-103℃;HPLC(Daicel Chiralpak IB,正己烷/异丙醇=70:30,flowrate 1.0mL/min,λ=254nm)tR(minor)=10.2min,tR(major)=15.5min,97%ee;[α]D 29=–23.1(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.95-7.93(m,2H),7.83-7.81(m,2H),7.70-7.67(m,2H),7.38-7.36(m,2H),7.30-7.27(m,2H),7.24-7.21(m,1H),6.92-6.90(m,2H),6.70(d,J=16.2Hz,1H),6.59(dd,J=7.8,15.6Hz,1H),5.67-5.63(m,1H),4.08(dd,J=8.4,17.4Hz,1H),3.85(s,3H),3.59(dd,J=6.0,17.4Hz,1H);13C NMR(150MHz,CDCl3)δ195.2,168.1,163.8,136.2,134.0,133.2,132.1,130.5,129.8,128.6,128.1,126.8,126.1,123.4,113.9,55.6,49.3,40.4;HRMS(ESI)m/z:[M+Na]+Calcd for C26H21NO4Na434.1363;Found 434.1360.
实施例4
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、N-邻苯二甲酰-β-烯胺酮1d(29.5mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1d消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到42.0mg白色固体3da,收率99%。mp 106-107℃;HPLC(Daicel Chiralpak IB,正己烷/异丙醇=70:30,flow rate1.0mL/min,λ=254nm)tR(minor)=7.9min,tR(major)=11.3min,97%ee;[α]D 26=–8.6(c2.0,CHCl3);1H NMR(600MHz,CDCl3)δ8.00-7.98(m,2H),7.83-7.82(m,2H),7.71-7.69(m,2H),7.37(d,J=7.8Hz,2H),7.30-7.22(m,3H),7.11(t,J=8.4Hz,2H),6.71(d,J=16.2Hz,1H),6.58(dd,J=8.4,16.2Hz,1H),5.66-5.63(m,1H),4.11(dd,J=9.0,18.0Hz,1H),3.61(dd,J=5.4,18.0Hz,1H);13C NMR(150MHz,CDCl3)δ168.1,166.0(d,J=253.5Hz,),136.2,134.2,135.5,133.1(d,J=3.0Hz),132.0,130.9(d,J=10.5Hz),128.7,128.2,126.8,125.7,123.5,115.9(d,J=22.5Hz),49.2,40.8;19F NMR(564MHz,CDCl3)δ–104.6;HRMS(ESI)m/z:[M+Na]+Calcd for C25H18FNO3Na 422.1163;Found 422.1161.
实施例5
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1e(30.3mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1e消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到45.9mg无色液体3ea,收率99%。HPLC(Dai cel Chiral pak IF,正己烷/异丙醇=70:30,flow rate 1.0mL/min,λ=254nm)tR(minor)=18.2min,tR(major)=20.5min,97%ee;[α]D 29=–16.8(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.90(d,J=8.4Hz,1H),7.83-7.82(m,2H),7.70-7.69(m,2H),7.42-7.36(m,4H),7.30-7.28(m,2H),7.24-7.22(m,1H),6.70(d,J=16.2Hz,1H),6.57(dd,J=7.8,15.6Hz,1H),5.66-5.62(m,1H),4.11(dd,J=9.0,18.0Hz,1H),3.61(dd,J=5.4,17.4Hz,1H);13C NMR(150MHz,CDCl3)δ195.6,168.1,140.0,136.1,135.0,134.2,133.5,132.0,129.7,129.2,128.7,128.3,126.8,125.7,123.5,49.1,40.8;HRMS(ESI)m/z:[M+Na]+Calcd for C25H18Cl NO3Na 438.0867;Found 438.0865.
实施例6
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1f(35.5mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1f消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到45.1mg白色固体3fa,收率98%。mp 65-66℃;HPLC(Daicel Chiralpak IB,hexane/i-PrOH=70:30,flowrate 1.0mL/min,λ=254nm)tR(minor)=9.5min,tR(major)=17.2min,97%ee;[α]D 28=–13.7(c 2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.84-7.80(m,4H),7.71-7.69(m,2H),7.60-7.57(m,2H),7.38-7.35(m,2H),7.31-7.27(m,2H),7.25-7.23(m,1H),6.71(d,J=16.0Hz,1H),6.57(dd,J=8.0,15.6Hz,1H),5.66-5.62(m,1H),4.10(dd,J=8.8,17.6Hz,1H),3.60(dd,J=5.6,17.6Hz,1H);13C NMR(150MHz,CDCl3)δ195.8,168.1,136.1,135.4,134.2,133.6,132.1,132.0,129.8,128.8,128.7,128.3,126.8,125.7,123.5,49.1,40.8;HRMS(ESI)m/z:[M+Na]+Calcd for C25H18NO3BrNa 482.0362;Found 482.0361.
实施例7
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1g(32.7mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1g消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到46.1mg无色液体3ga,收率99%。HPLC(Daicel Chiral pak IB,正己烷/异丙醇=60:40,flow rate 1.0mL/min,λ=254nm)tR(minor)=8.6min,tR(major)=11.6min,96%ee;[α]D 28=–29.5(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ8.50(s,1H),8.01-7.99(m,1H),7.95(d,J=7.8Hz,1H),7.86-7.80(m,4H),7.68-7.65(m,2H),7.59-7.52(m,2H),7.39-7.37(m,2H),7.30-7.27(m,2H),7.23-7.21(m,1H),6.74(d,J=15.6Hz,1H),6.64(dd,J=7.8,15.6Hz,1H),5.75-5.71(m,1H),4.27(dd,J=9.0,18.0Hz,1H),3.78(dd,J=5.4,17.4Hz,1H);13C NMR(150MHz,CDCl3)δ196.7,168.2,136.2,135.9,134.1,134.0,133.4,132.6,132.1,130.1,129.8,128.8,128.7,128.2,127.9,127.0,126.8,126.0,123.8 123.5,49.3,40.9;HRMS(ESI)m/z:[M+Na]+Calcd for C29H21NO3Na 454.1414;Found 454.1414.
实施例8
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1h(26.7mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,3.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1h消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到35.3mg无色液体3ha,收率95%。HPLC(Daicel Chiralpak IB,正己烷/异丙醇=60:40,flow rate 1.0mL/min,λ=254nm)tR(minor)=7.8min,tR(major)=10.0min,95%ee;[α]D 26=+0.3(c 2.0,CHCl3);1H NMR(400MHz,CDCl3)δ7.86-7.80(m,2H),7.71-7.61(m,2H),7.56(d,J=1.2Hz,1H),7.38-7.35(m,2H),7.30-7.27(m,2H),7.24-7.21(m,2H),6.70(d,J=16.0Hz,1H),6.58(dd,J=8.0,15.6Hz,1H),6.51(dd,J=1.6,3.6Hz,1H),5.64-5.58(m,1H),3.90(dd,J=8.8,16.8Hz,1H),3.55(dd,J=6.0,16.8Hz,1H);13C NMR(100MHz,CDCl3)δ185.7,168.0,152.5,146.8,136.2,134.1,133.5,132.1,128.7,128.2,126.8,125.7,123.4,117.8,112.5,49.1,40.8;HRMS(ESI)m/z:[M+Na]+Calcd for C23H17NO4Na 394.1050;Found394.1050.
实施例9
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1i(21.5mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1i消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到32.4mg无色液体3ia,收率99%。HPLC(Daicel Chiral pak IB,正己烷/异丙醇=60:40,flow rate 1.0mL/min,λ=254nm)tR(minor)=6.5min,tR(major)=7.0min,98%ee;[α]D 28=+2.8(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.84-7.81(m,2H),7.71-7.69(m,2H),7.36-7.34(m,2H),7.29-7.26(m,2H),7.24-7.21(m,1H),6.65(d,J=15.6Hz,1H),6.47(dd,J=8.4,15.6Hz,1H),5.46-5.43(m,1H),3.52(dd,J=8.4,17.4Hz,1H),3.16(dd,J=6.0,17.4Hz,1H),2.17(s,3H);13C NMR(150MHz,CDCl3)δ205.2,168.0,136.1,134.1,133.3,132.0,128.7,128.2,126.8,125.6,123.4,48.8,45.6,30.4;HRMS(ESI)m/z:[M+Na]+Calcd for C20H17NO3Na342.1101;Found 342.1094.
实施例10
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-琥珀酰丙烯酮1j(22.9mg,0.1mmol)和有机硼酸2a(29.6mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1j消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/3-1/2)分离纯化得到29.2mg白色固体3ja,收率为88%。mp117-118℃;HPLC(Daicel Chiralpak IF,正己烷/异丙醇=70:30,flow rate 1.0mL/min,λ=254nm)tR(minor)=13.8min,tR(major)=16.0min,97%ee;[α]D 29=–10.4(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.94(d,J=7.8Hz,1H),7.58-7.56(m,1H),7.47-7.45(m,2H),7.37(d,J=7.2Hz,2H),7.31-7.29(m,2H),7.26-7.23(m,1H),6.68(d,J=15.6Hz,1H),6.53(dd,J=8.4,16.2Hz,1H),5.49-5.45(m,1H),4.07(dd,J=9.0,17.4Hz,1H),3.51(dd,J=5.4,17.4Hz,1H),2.66(s,4H);13C NMR(150MHz,CDCl3)δ197.0,177.1,136.6,136.1,133.9,133.6,128.8,128.7,128.3,128.2,126.8,125.1,50.1,39.9,28.2;HRMS(ESI)m/z:[M+Na]+Calcd for C21H19N O3Na 356.1257;Found 356.1256.
实施例11
根据实施例10反应条件,采用β-邻苯二甲酰亚胺丙烯酮1a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Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2b(32.4mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/3)分离纯化得到39.7mg白色固体3ab,收率99%。mp 110-111℃;HPLC(Daicel Chiral pak IC,正己烷/异丙醇=90:10,flowrate 1.0mL/min,λ=254nm)tR(minor)=27.4min,tR(major)=29.4min,95%ee;[α]D 28=–3.7(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.96-7.95(m,2H),7.83-7.80(m,2H),7.70-7.67(m,2H),7.56-7.53(m,1H),7.45-7.43(m,2H),7.27-7.25(m,2H),7.09(d,J=8.4Hz,2H),6.67(d,J=15.6Hz,1H),6.54(dd,J=7.8,15.6Hz,1H),5.66-5.62(m,1H),4.14(dd,J=8.4,17.4Hz,1H),3.63(dd,J=6.0,18.0Hz,1H),2.31(s,3H);13C{1H}NMR(150MHz,CDCl3)δ196.9,168.1,138.1,136.7,134.1,133.5,133.4,133.3,132.1,129.4,128.8,128.3,126.7,124.8,123.4,49.3,40.9,21.3;HRMS(ESI)m/z:[M+Na]+Calcd for C26H21NO3Na418.14 14;Found 418.1411.
实施例13
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2c(33.18mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/3)分离纯化得到39.8mg白色固体3ac,收率99%。mp 120-121℃;HPLC(Daicel Chiral pak IB,正己烷/异丙醇=80:20,flowrate 1.0mL/min,λ=254nm)tR(major)=9.3min,tR(minor)=10.4min,97%ee;[α]D 28=–8.0(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.96(d,J=7.2Hz,2H),7.85-7.82(m,2H),7.71-7.69(m,2H),7.56(t,J=7.2Hz,1H),7.45(t,J=7.8Hz,2H),7.25-7.23(m,1H),7.12(d,J=7.8Hz,1H),7.08-7.06(m,1H),6.94-6.90(m,1H),6.67(d,J=16.2Hz,1H),6.59(dd,J=7.8,15.6Hz,1H),5.68-5.65(m,1H),4.11(dd,J=8.4,17.4Hz,1H),3.67(dd,J=6.0,18.0Hz,1H);13C NMR(150MHz,CDCl3)δ196.7,168.1,163.1(d,J=244.5Hz),138.6(d,J=7.5Hz),136.6,134.2,133.6,132.2(d,J=1.5Hz),132.0,130.1(d,J=9.0Hz),128.8,128.3,127.4,123.5,122.7(d,J=3.0Hz),115.0(d,J=21.0Hz),113.2(d,J=21.0Hz),48.9,40.8;19F NMR(564MHz,CDCl3)δ–133.4;HRMS(ESI)m/z:[M+Na]+Calcd forC25H18NO3FNa 422.1163;Found 422.1161.
实施例14
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2d(36.5mg,0.2mmol,2.0equiv),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/3)分离纯化得到41.5mg白色固体3ad,收率99%。mp 136-138℃;HPLC(Daicel Chiral pak IB,正己烷/异丙醇=80:20,flow rate 1.0mL/min,λ=254nm)tR(major)=9.9min,tR(minor)=12.2min,97%ee;[α]D 28=–7.1(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.96-7.95(m,2H),7.84-7.82(m,2H),7.71-7.69(m,2H),7.57-7.54(m,1H),7.46-7.43(m,2H),7.30-7.24(m,4H),6.65(d,J=16.2Hz,1H),6.56(d,J=8.4,16.2Hz,1H),5.67-5.64(m,1H),4.10(dd,J=8.4,17.4Hz,1H),3.67(dd,J=6.0,18.0Hz,1H);13C NMR(150MHz,CDCl3)δ196.3,168.1,144.5,134.8,134.2,134.1,133.8,132.1,129.5,128.9,128.4,128.0,126.7,123.5,49.1,40.7,21.8;HRMS(ESI)m/z:[M+Na]+Calcd for C25H18NO3ClNa 438.0867;Found 438.0862.
实施例15
在氮气保护下,向Schlenk管中加入100mg分子筛、手性催化剂Cat 1(4.1mg,0.01mmol、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2e(45.4mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/3)分离纯化得到45.2mg白色固体3ae,收率为98%。mp 131-133℃;HPLC(Daicel Chiral pak IF,正己烷/异丙醇=80:20,flow rate1.0mL/min,λ=254nm)tR(major)=20.0min,tR(minor)=23.3min,98%ee;[α]D 28=+2.6(c2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.96-7.95(m,2H),7.84-7.82(m,2H),7.72-7.69(m,2H),7.57-7.54(m,1H),7.46-7.40(m,4H),7.24-7.22(m,2H),6.64(d,J=16.2Hz,1H),6.57(dd,J=7.8,15.6Hz,1H),5.67-5.63(m,1H),4.10(dd,J=8.4,18.0Hz,1H),3.67(dd,J=5.4,17.4Hz,1H);13C NMR(150MHz,CDCl3)δ196.7,168.1,136.6,135.2,134.2,133.6,132.2,132.0,131.8,128.9,128.33,128.27,126.7,123.5,122.0,49.0,40.8;HRMS(ES I)m/z:[M+Na]+Calcd for C25H18NO3BrNa 482.0362;Found 482.0360.
实施例16
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2f(32.4mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚体积比1/5-1/3)分离纯化得到41.7mg白色固体3af,收率99%。mp 108-110℃;HPLC(Daicel Chiralpak IF,正己烷/异丙醇=70:30,flow rate 1.0mL/min,λ=254nm)tR(minor)=16.1min,tR(major)=20.6min,90%ee;[α]D28=–1.5(c2.0,CHCl3);1H NMR(600MHz,CDCl3)δ8.02-8.00(m,2H),7.85-7.83(m,2H),7.72-7.70(m,2H),7.60-7.57(m,1H),7.51-7.42(m,4H),7.25-7.23(m,1H),7.20-7.17(m,1H),6.75(s,1H),6.33-6.31(m,1H),4.49(dd,J=9.0,18.0Hz,1H),4.04(dd,J=5.4,18.6Hz,1H);13C NMR(150MHz,CDCl3)δ196.0,167.8,154.8,154.4,136.3,134.2,133.7,131.9,128.9,128.3,128.2,124.5,123.6,123.0,121.2,111.5,104.5,44.4,38.7;HRMS(ESI)m/z:[M+Na]+Calcd for C25H17NO4Na 418.1050;Found 418.1050.
实施例17
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2g(25.6mg,0.2mmol,2.0equiv),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/5-1/3)分离纯化得到32.3mg无色液体3ag,收率90%。HPLC(Daicel Chiralpak IF,正己烷/异丙醇=80:20,flow rate 1.0mL/min,λ=254nm)tR(minor)=18.3min,tR(major)=19.5min,94%ee;[α]D 28=–40.2(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.98-7.97(m,2H),7.82-7.79(m,2H),7.69-7.66(m,2H),7.58-7.55(m,1H),7.45(t,J=7.8Hz,2H),7.23-7.22(m,2H),6.95(dd,J=3.6,5.4Hz,1H),6.36(dd,J=5.4,9.6Hz,1H),4.58(dd,J=9.6,18.0Hz,1H),3.89(dd,J=4.8,18.0Hz,1H);13C{1H}NMR(150MHz,CDCl3)δ196.3,167.9,142.1,136.4,134.2,133.7,131.9,128.8,128.3,126.9,126.6,125.6,123.5,45.6,41.6;HRMS(ESI)m/z:[M+Na]+Calcd forC21H15NO3SNa 384.0665;Found 384.0662.
实施例18
在氮气保护下,向Schlenk管中加入100mg分子筛、催化剂Cat 1(4.1mg,0.01mmol)、β-邻苯二甲酰亚胺丙烯酮1a(27.7mg,0.1mmol)和有机硼酸2h(31.2mg,0.2mmol,2.0eq),抽换气3次,再加入干燥甲苯(1.0mL),25℃搅拌24h。TLC显示1a消失,减压除去溶剂后快速硅胶柱层析(乙酸乙酯/石油醚1/8-1/5)分离纯化得到24.0mg无色液体3ah,收率62%。HPLC(Daicel Chiralpak IF,正己烷/异丙醇=80:20,flow rate 1.0mL/min,λ=254nm)tR(minor)=10.4min,tR(major)=11.0min,98%ee;[α]D 29=–32.7(c 2.0,CHCl3);1H NMR(600MHz,CDCl3)δ7.95-7.93(m,2H),7.82-7.79(m,2H),7.67-7.66(m,2H),7.55-7.53(m,1H),7.45-7.42(m,2H),5.86-5.75(m,2H),5.46-5.42(m,1H),4.02(dd,J=8.4,17.4Hz,1H),3.52(dd,J=6.0,17.4Hz,1H),2.00(q,J=7.2Hz,2H),1.34-1.23(m,8H),0.85-0.83(m,3H);13C NMR(150MHz,CDCl3)δ197.1,168.1,136.8,135.0,134.0,133.4,132.1,128.8,128.2,126.4,123.3,49.1,40.9,32.2,31.7,28.92,28.89,22.7,14.2;HRMS(ESI)m/z:[M+Na]+Calcd for C25H27NO3Na 412.1883;Found 412.1884.
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)
1.不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于,包括如下步骤:以β-酰亚胺丙烯酮1和有机硼酸2为原料,在手性联二萘酚类或手性四苯并环辛四烯类催化剂和分子筛存在下,有机溶剂中反应得到β-氨基酮衍生物3;反应方程式表示为:
其中:R1选自取代苯基、萘基、呋喃基、噻吩基、C1-C6烷基或环己基,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;R2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;β-二甲酰亚胺丙烯酮选自β-邻苯二甲酰亚胺丙烯酮或β-琥珀酰亚胺丙烯酮。
3.根据权利要求2所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于:手性联二萘酚类催化剂中,R选自Cl、Br、I或3,5-(CF3)2C6H4。
4.根据权利要求2所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于:手性四苯并环辛四烯酚类催化剂中,R选自Cl或Br。
5.根据权利要求1所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于:所述β-酰亚胺丙烯酮1、有机硼酸2与催化剂摩尔比为1:2-4:0.05-0.20。
6.根据权利要求1所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于:所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、三氟甲苯、邻二甲苯、1,2-二氯乙烷、***、甲基叔丁基醚、乙腈或1,4-二氧六环。
7.根据权利要求1所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于:反应温度为0至30℃。
8.根据权利要求1所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于:反应中加入叔丁醇镁、甲醇、异丙醇或叔丁醇。
10.根据权利要求1-9任意一项所述不对称共轭加成合成光学活性β-氨基酮衍生物的方法,其特征在于:整个反应过程在氮气或氩气下进行。
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