CN114085201A - 一种手性双环γ-丁内酯类化合物的制备方法 - Google Patents
一种手性双环γ-丁内酯类化合物的制备方法 Download PDFInfo
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Abstract
本申请公开了一种手性双环γ‑丁内酯类化合物的制备方法,手性双环γ‑丁内酯类化合物是许多类化合物和药物分子的主要骨架,是重要的活性中间体,例如,天然产物鬼臼毒素及其衍生物作为抗肿瘤药物广泛应用于临床治疗;上市药物硫酸沃拉帕沙也作为首创口服PAR‑1抑制剂。本申请通过(1S,2S)‑1,2‑二苯乙二胺催化的γ‑双甲基呋喃酮与α,β‑不饱和酮的双Michael加成反应,一步反应快速获得功能性的产率高达80%、立体选择性>20:1和较高er值的手性双环γ‑丁内酯类化合物,为合成药物活性中间体提供方法思路,解决了目前医药研发领域的该化合物合成难点。
Description
技术领域
本发明属于医药化合物合成领域,尤其涉及一种手性双环γ-丁内酯类化合物的制备方法。
背景技术
手性双环γ-丁内酯类化合物是许多萜类化合物和药物分子的主要骨架,如已有上市药物伊托泊苷和替尼泊苷等,作为拓扑异构酶Ⅱ抑制剂,具有抗肿瘤的药理作用;硫酸沃拉帕沙是一种首创的蛋白激酶受体1拮抗剂,是一种抗血小板制剂的抗血栓药物;另有天然产物如鬼臼毒素及其类似物和半日花内酯类化合物,也具有多种生物活性。因此,多手性中心的双环γ-丁内酯类化合物广泛存在于具有生物活性的各种萜类和药物分子中。已有文献报道在手性胺类催化剂存在下α,β-不饱和酮与硝基烯烃、α,β-不饱和酮、α,β-不饱和酯等底物发生多步串联反应构筑多手性中心官能团的六元碳环,但是目前还未见到手性伯胺催化的α,β-不饱和酮与呋喃酮反应构筑手性双环γ-丁内酯类化合物的相关报道。
目前,依托泊苷和替尼泊苷的半合成方法基本是通过天然提取得到的鬼臼毒素来合成表鬼臼毒素,将所得的表鬼臼毒素与葡萄糖衍生物反应生成。如中国发明专利CN111138443A《一种4’-去甲基表鬼臼毒素全合成的制备方法》公开了一种抗肿瘤药物木盒的工艺方法,其涉及一种表鬼臼毒素的制备方法:采用丁香醛作为初始物料,与4-乙烯基二氢呋喃-2-酮反应得到中间体,合成方法步骤复杂。
在本发明人之前的报道的口头报告《基于呋喃酮的反应:手性二伯胺催化呋喃酮与α、β-不饱和酮的不对称D-A反应》提出,利用呋喃酮与α、β-不饱和酮发生不对称反应,但在现有技术里面没有之前报道产物的绝对构型及具体实例。
本发明人于2020年申请的发明专利CN111233795A《一种手性γ-丁内酯类化合物及其衍生物的制备方法及其应用》,利用醛类化合物与2-呋喃酮进行有机催化不对称Michael加成反应,该发明提供一种方法可使得手性γ-丁内酯与三个连续的手性碳;发明专利CN111303090A《一种手性γ,γ-双取代丁烯酸内酯类化合物及其制备方法》,通过双官能团硫脲类催化剂催化的γ-二聚体呋喃酮与α、β-不饱和硝基烯烃的Vinylogous Michael加成反应。对比现有技术,本发明利用α,β-不饱和酮与呋喃酮,在不同手性二伯胺类催化剂作用下,通过双Michael加成反应得到手性双环γ-丁内酯类化合物。
所以目前亟需一种简便高效的方法能一步构建手性双环γ-丁内酯类化合物,以解决目前医药研发领域中的合成难点。
发明内容
首先,本发明人成功地发现了以手性二伯胺类催化剂催化双γ-二甲基-α-乙酯呋喃酮与α,β-不饱和酮的双Michael加成反应,能够高效、简便地合成手性双环γ-丁内酯类化合物,本申请人在此基础上开展了一系列大量的反应工作之后,得到手性双环γ-丁内酯类化合物的制备方法。
进一步地,一种手性双环γ-丁内酯类化合物的制备方法,其步骤如下:
取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a-d(0.25mmol)和2aa-bd(0.5mmol),室温搅拌反应13-14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3aa-bd。
本申请所述的一种手性双环γ-丁内酯类化合物制备方法中,手性二伯胺类催化剂结构如下:
其中,手性二伯胺类催化剂优选(1S,2S)-1,2-二苯基乙二胺。其他手性胺类催化剂如(1S,2S)-(+)-1,2-环己二胺、(S)-1-苯基-3-(哌啶-1-基)-2-丙胺等也可实现。
进一步地,本申请所述的一种手性双环γ-丁内酯类化合物的制备方法中所述溶剂选自甲苯、正己烷、异丙醇、二氯甲烷、甲醇或乙醇中一种或多种的混合物,其中最优选为异丙醇。
进一步地,本申请所述的一种手性双环γ-丁内酯类化合物的制备方法中,所述化合物1a-d和化合物2aa-2bd的摩尔量之比为1:2。
进一步地,本申请所述的一种手性双环γ-丁内酯类化合物的制备方法中,化合物1a-d和手性胺类催化剂的摩尔比为1:0.5。
另外,本申请所述的一种手性双环γ-丁内酯类化合物易于得到重结晶化合物3aa-bd,其er值提高至99:1。
进一步的,本申请所述的一种手性双环γ-丁内酯类化合物,其结构式为:
其中,R1=甲基、乙基;R1,R2=环己基;R2=甲基、乙基;R3=苯基、苄基、对苯甲氧基、间苯甲氧基、邻苯甲氧基、3,4-二甲氧基、3,4,5-三甲氧基、对苯硝基、间苯硝基、对苯氰基、三氟苯甲基、对苯甲酯基、对苯卤素基、间苯卤素基、邻苯卤素基、萘基、呋喃基、噻吩基、2-甲基吡咯基、2-甲基吲哚基或吡啶基。
进一步地,本申请所述的一种手性双环γ-丁内酯类化合物,化合物的结构式如下:
附图说明
图1是本发明实施例1中化合物3aa的核磁共振氢谱的示意图;
图2是本发明实施例1中化合物3aa的核磁共振碳谱的示意图;
图3是本发明实施例1中化合物3aa的高效液相色谱消旋产物的示意图;
图4是本发明实施例1中化合物3aa的高效液相色谱手性产物的示意图;
图5是本发明实施例1中化合物3aa的X-单晶衍射法的示意图。
有益效果:
本申请公开的一种手性双环γ-丁内酯类化合物是许多萜类化合物和药物分子的主要骨架,如已有上市药物伊托泊苷、替尼泊苷及沃拉帕沙,天然产物如鬼臼毒素和半日花内酯类化合物,具有多种生物活性,本申请通过(1S,2S)-1,2-二苯乙二胺催化的γ-双甲基呋喃酮与α,β-不饱和酮的双Michael加成反应,合成了一系列产率高达80%、立体选择性>20:1和较好er值的手性双环γ-丁内酯类化合物。该成果是药物发现的迫切需要,在医药、化工领域具有很大的应用前景。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明了,下面结合具体实施方式并参照附图,对本发明进一步详细说明。应该理解,这些描述只是示例性的,而并非要限制本发明的范围。此外,在以下说明中,省略了对公知结构和技术的描述,以避免不必要地混淆本发明的概念。
本发明所述的手性二伯胺类催化剂结构式为:
1.化合物3aa:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2aa(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3aa。
产率:88.4%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.45(d,J=7.1Hz,2H),7.32(dt,J=6.9Hz,4.7Hz,3H),3.89(dq,J=10.7Hz,7.1Hz,1H),3.28–3.16(m,2H),2.64(1H dd,J=16.5Hz,4.7Hz,),2.58–2.44(m,2H),1.42(s,3H),1.38(s,3H),0.91–0.82(m,3H);13C NMR(100MHz,CDCl3)δ208.4,172.9,169.8,136.9,129.5,128.1,127.9,82.9,62.4,60.34,46.8,42.2,42.0,37.8,28.5,24.5,13.3;HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=13.570min,tR1(minor)=25.385min).dr>20:1.=92.9:7.1 er.ES-HRMS:Calcdfor C19H22O5[M+H],331.1540,Found 331.1540.
2.化合物3ab:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2bb(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ab。
产率:99.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.20(d,J=5.9Hz,1H),7.05(d,J=8.0Hz,1H),3.83(dq,J=10.7,7.1Hz,1H),3.73–3.63(m,1H),3.59(dd,J=14.0,3.0Hz,1H),3.20–3.05(m,1H),2.54(dd,J=16.5,4.8Hz,1H),2.42(ddd,J=13.6,7.7,4.6Hz,1H),2.25(s,1H),1.32(s,1H),1.29(s,1H),0.82(t,J=7.2Hz,1H).13C NMR(100MHz,CDCl3)δ208.6,172.9,169.8,137.6,133.7,129.2,128.7,82.8,62.3,60.2,46.8,42.1,41.9,37.8,28.5,24.5,21.0,13.3.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=13.364min,tR1(minor)=17.685min).dr>20:1.=91.9:8.1 er.ES-HRMS:Calcd forC20H25O5[M+H],345.1696,Found 345.1696.
3.化合物3ac:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ac(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分
产率:94.3%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.27(d,J=8.8Hz,2H),6.77(d,J=8.8Hz,2H),3.83(dq,J=10.7,7.1Hz,1H),3.71(d,J=6.9Hz,3H),3.68(dd,J=10.7,7.2Hz,1H),3.58(dd,J=14.2,2.9Hz,1H),3.18–2.98(m,2H),2.53(dd,J=16.4,4.7Hz,1H),2.41(ddd,J=13.8,7.8,4.7Hz,2H),1.32(s,3H),1.28(s,3H),0.84(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ207.5,171.9,168.8,158.1,129.5,127.7,112.3,81.8,61.3,59.3,54.2,45.8,41.1,40.4,36.7,27.4,23.4,12.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=14.463min,tR1(minor)=21.009min).dr>20:1.=93.2:6.8 er.ES-HRMS:Calcdfor C20H24O6[M+H],361.1646,Found 361.1656.
4.化合物3ad:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ad(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ad。
产率:93.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.19(d,J=8.8Hz,2H),6.60(d,J=8.8Hz,2H),3.85(dq,J=10.7,7.1Hz,1H),3.70(dq,J=10.7,7.2Hz,1H),3.54(dd,J=14.0,3.0Hz,1H),3.16–3.04(m,2H),2.85(s,6H),2.56–2.35(m,3H),1.32(s,3H),1.29(s,3H),0.86(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ209.0,173.1,169.9,150.2,130.0,124.2,112.0,82.7,62.3,60.4,46.9,42.3,41.6,40.5,37.8,28.5,24.5,13.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=8.388min,tR1(minior)=13.469min).dr>20:1.=95.1:4.9 er.ES-HRMS:Calcd for C21H27NO5[M+H],374.1962,Found 374.1956.
5.化合物3ae:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ae(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分
产率:99.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.07(d,J=2.1Hz,1H),6.81(dd,J=8.4,2.1Hz,1H),6.73(d,J=8.4Hz,1H),3.82(s,4H),3.79(s,3H),3.67(dq,J=10.7,7.2Hz,1H),3.58(dd,J=14.1,3.0Hz,1H),3.15–3.04(m,2H),2.59–2.32(m,3H),1.33(s,3H),1.29(s,3H),0.85(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ208.4,173.0,169.9,148.6,148.2,129.1,121.2,113.4,110.5,82.8,62.3,60.4,55.9,55.8,47.0,42.1,41.7,37.8,28.4,24.5,13.4.HPLC(DaicelChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=27.245min,tR1(minor)=33.019min).dr>20:1.=92.3:7.7 er.ES-HRMS:Calcd for C21H26O7[M+H],391.1751,Found 391.1745.
6.化合物3af:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2af(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3af。
产率:98.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ6.64(s,2H),3.85–3.71(m,11H),3.57(dd,J=14.1,3.0Hz,1H),3.16–3.06(m,2H),2.59–2.38(m,3H),1.31(d,J=14.7Hz,6H),0.86(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ208.1,172.9,169.9,152.6,137.6,132.2,106.8,82.8,62.4,60.8,60.3,56.2,46.9,42.2,42.0,37.8,28.4,24.5,13.4.HPLC(Daicel ChiralPak AD-H,210nm,hexane:i-PrOH=70:30,1.0mL/min:tR1(minior)=6.953min,tR1(major)=11.560min).dr>20:1.=97.3:1.7 er.ES-HRMS:Calcd for C22H28O8[M+H],421.1857,Found 421.1853.
7.化合物3ag:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ag(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ag。
产率:91.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.38(d,J=8.6Hz,1H),7.25(d,J=8.5Hz,1H),3.84(dq,J=10.7,7.1Hz,1H),3.69(dq,J=10.7,7.2Hz,1H),3.57(dd,J=14.2,2.9Hz,1H),3.19–3.00(m,1H),2.55(dd,J=16.5,4.6Hz,1H),2.47–2.33(m,1H),1.33(s,2H),1.29(s,2H),0.85(t,J=7.2Hz,2H);13C NMR(100MHz,CDCl3)δ207.8,172.8,169.7,135.8,131.2,131.2,122.1,83.0,62.6,60.1,46.9,41.7,41.6,37.7,28.5,24.5,13.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=14.463min,tR1(minor)=21.009min).dr>20:1.=90.3:9.7 er.ES-HRMS:Calcd for C19H22BrO5[M+H],409.0645,Found409.0643.8.化合物3ah:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ah(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ah。
产率:98.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.34–7.28(m,2H),7.25–7.21(m,2H),3.84(dq,J=10.7,7.1Hz,1H),3.69(dq,J=10.7,7.2Hz,1H),3.59(dd,J=14.3,2.9Hz,1H),3.18–3.04(m,2H),2.55(dd,J=16.5,4.6Hz,1H),2.41(ddd,J=14.0,7.9,4.9Hz,2H),1.33(s,3H),1.29(s,3H),0.85(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ207.8,172.8,169.7,135.2,133.9,130.9,128.2,83.0,62.5,60.2,46.9,41.8,41.5,37.7,28.4,24.4,13.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=17.454min,tR1(minor)=21.683min).dr>20:1.=95.1:4.9 er.ES-HRMS:Calcd for C19H22ClO5[M+H],365.1150,Found 365.1145.
9.化合物3ai:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ai(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ai。
产率96.2%:。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.40–7.32(m,2H),6.94(t,J=8.7Hz,2H),3.83(dq,J=10.7,7.1Hz,1H),3.72–3.56(m,2H),3.16–3.05(m,2H),2.55(dd,J=16.5,4.6Hz,1H),2.41(dt,J=16.3,7.5Hz,2H),1.31(d,J=16.3Hz,6H),0.84(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ208.0,172.9,169.8,162.4(d,J=247.1Hz),132.5(d,J=3.1Hz),131.2(d,J=8.0Hz),114.9(d,J=21.4Hz),82.9,62.4,60.3,46.9,42.0,41.4,37.7,28.4,24.5,13.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=12.815min,tR1(minior)=15.075min).dr>20:1.=90.1:9.9 er.ES-HRMS:Calcd forC19H21FO5[M+H],349.1446,Found 349.1439.
10.化合物3aj:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2aj(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3aj。
产率:57.8%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ8.18(t,J=2.0Hz,1H),8.10(ddd,J=8.2,2.2,1.0Hz,1H),7.83(d,J=7.8Hz,1H),7.46(t,J=8.0Hz,1H),3.87(dq,J=10.8,7.1Hz,1H),3.76–3.67(m,2H),3.17(ddd,J=18.6,15.7,9.5Hz,2H),2.59(dd,J=16.5,4.6Hz,1H),2.46(ddd,J=17.9,12.3,8.6Hz,2H),1.35(s,3H),1.31(s,3H),0.86(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ205.8,171.5,168.4,147.0,137.9,135.5,128.0,122.8,122.0,82.2,61.7,59.0,46.0,40.8,40.4,36.7,27.5,23.4,12.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=90:10,1.0mL/min:tR1(major)=51.216min,tR1(minior)=77.303min).dr>20:1.=95.6:4.4 er.ES-HRMS:Calcd for C19H21NO7[M+H],376.1391,Found 376.1403.
11.化合物3ak:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ak(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ak。
产率:80.7%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.54(q,J=8.5Hz,4H),3.84(dq,J=10.8,7.1Hz,1H),3.73–3.58(m,2H),3.13(ddd,J=14.5,10.2,6.5Hz,2H),2.57(dd,J=16.5,4.6Hz,1H),2.42(ddd,J=14.1,8.0,5.0Hz,2H),1.34(s,3H),1.30(s,3H),0.83(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ207.0,172.6,169.5,142.2,131.7,130.5,118.4,111.9,83.2,62.6,60.1,47.0,42.0,41.3,37.7,28.4,24.4,13.4.HPLC(Daicel ChiralPak AD-H,210nm,hexane:i-PrOH=90:10,1.0mL/min:tR1(minior)=28.470min,tR1(major)=58.594min).dr>20:1.=88.5:11.5er.ES-HRMS:Calcd for C20H21NO5[M+H],356.1492,Found 356.1489.
12.化合物3al:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2al(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3al。
产率:96.2%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.51(s,1H),3.80(dq,J=10.7,7.1Hz,1H),3.72–3.58(m,1H),3.21–3.07(m,1H),2.56(dd,J=16.5,4.6Hz,1H),2.44(ddd,J=14.0,8.0,5.0Hz,1H),1.34(s,1H),1.29(s,1H),0.78(t,J=7.2Hz,1H);13C NMR(101MHz,CDCl3)δ207.4,172.7,169.6,140.9,130.3,130.0,125.3,124.9(q,J=3.7Hz),83.1,62.5,60.2,46.9,41.8,41.5,37.7,28.4,24.4,13.2.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=12.554min,tR1(minior)=16.282min).dr>20:1.=92.7:7.3 er.ES-HRMS:Calcdfor C20H21FO5[M+H],399.1414,Found 399.1408.
13.化合物3am:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2am(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5
产率:80.6%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.92(d,J=8.5Hz,2H),7.45(d,J=8.4Hz,2H),3.87–3.80(m,4H),3.64(tdd,J=14.3,9.3,5.1Hz,2H),3.21–3.08(m,2H),2.56(dd,J=16.5,4.7Hz,1H),2.50–2.37(m,2H),1.34(s,3H),1.30(s,3H),0.80(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ207.6,172.6,169.6,166.7,142.0,129.7,129.6,129.3,83.0,62.5,60.2,52.1,46.9,42.2,41.7,37.8,28.5,24.5,13.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=70:30,1.0mL/min:tR1(major)=13.670min,tR1(minor)=17.265min).dr>20:1.=92.3:7.7 er.ES-HRMS:Calcd for C21H24O7[M+H],389.1595,Found 389.1597.
14.化合物3an:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2an(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3an。
产率:95.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.55(d,J=8.0Hz,1H),7.19–7.03(m,3H),4.45(dd,J=9.9,4.9Hz,1H),4.11–3.98(m,2H),3.36(t,J=7.4Hz,1H),3.08(dd,J=18.0,10.0Hz,1H),2.62(d,J=7.5Hz,2H),2.42(dd,J=18.0,4.9Hz,1H),1.41(d,J=5.6Hz,6H),0.97(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ207.4,170.8,169.4,137.2,133.7,129.2,128.3,127.4,126.2,84.2,62.6,58.4,47.3,42.9,42.1,38.5,29.9,24.6,13.5.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=10.027min,tR1(minor)=19.945min).dr>20:1.=95.1:4.9 er.ES-HRMS:Calcd for C19H22BrO5[M+H],409.0645,Found 409.0651.15.化合物3ao:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ao(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ao。
产率:92.6%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.38(d,J=8.6Hz,1H),7.25(d,J=8.6Hz,1H),3.84(dq,J=10.7,7.1Hz,1H),3.69(dq,J=10.7,7.2Hz,1H),3.57(dd,J=14.2,3.0Hz,1H),3.17–3.03(m,1H),2.55(dd,J=16.5,4.6Hz,1H),2.41(ddd,J=14.0,8.0,4.9Hz,1H),1.33(s,1H),1.29(s,1H),0.85(t,J=7.2Hz,1H);13C NMR(100MHz,CDCl3)δ207.8,172.8,169.7,135.8,131.2,131.2,122.1,83.0,62.5,60.1,46.9,41.7,41.6,37.7,28.5,24.4,13.4.HPLC(Daicel ChiralPakOD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=14.687min,tR1(minor)=21.768min).dr>20:1.=90.8:9.2 er.ES-HRMS:Calcd for C19H22BrO5[M+H],409.0645,Found 409.0641.
16.化合物3ap:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ap(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ap。
产率:78.8%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.39–7.34(m,1H),7.14(d,J=2.0Hz,3H),4.46(dd,J=10.1,4.8Hz,1H),4.04(dd,J=10.3,7.1Hz,2H),3.37(t,J=7.5Hz,1H),3.09(dd,J=18.1,10.1Hz,1H),2.62(d,J=7.5Hz,2H),2.41(dd,J=18.1,4.8Hz,1H),1.42(s,3H),1.39(s,3H),0.97(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ206.5,169.8,168.4,134.5,134.2,129.3,127.9,127.2,125.6,83.1,61.6,57.5,46.1,40.9,39.0,37.5,28.8,23.6,12.5.HPLC(DaicelChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=6.245min,tR1(minor)=11.433min).dr>20:1.=96.1:3.9 er.ES-HRMS:Calcd for C19H22ClO5[M+H],365.1150,Found 365.1149.
17.化合物3aq:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2aq(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3aq。
产率:95.8%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.45–7.29(m,4H),3.95(dq,J=10.7Hz,7.1Hz,1H),3.83(dq,J=10.8Hz,7.2Hz,1H),3.67(dd,J=14.2Hz,3.0Hz,1H),3.23(dd,J=9.7Hz,4.1Hz,1H),3.18(dd,J=13.4Hz,10.1Hz,1H),2.64(dd,J=16.5Hz,4.6Hz,1H),2.51(m,2H),1.42(s,3H),1.39(s,3H),0.95(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ207.6,172.7,169.7,138.9,134.0,129.3,129.2,128.2,128.1,83.0,62.6,60.2,46.9,41.9,41.7,37.8,28.5,24.5,13.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=8.195min,tR1(minor)=12.440min).dr>20:1.=92.3:7.7 er.ES-HRMS:Calcdfor C19H22ClO5[M+H],365.1150,Found 365.1149.
18.化合物3ar:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ar(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ar。
产率:87.9%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ8.18(t,J=1.9Hz,1H),8.10(dd,J=8.2,1.2Hz,1H),7.83(d,J=7.8Hz,1H),7.46(t,J=8.0Hz,1H),3.87(dq,J=10.8,7.1Hz,1H),3.71(ddd,J=9.0,7.1,5.1Hz,2H),3.17(ddd,J=18.6,15.7,9.5Hz,2H),2.64–2.43(m,3H),1.35(s,3H),1.31(s,3H),0.86(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ206.8,172.6,169.5,148.0,138.9,136.5,129.0,123.9,123.0,83.3,62.7,60.0,47.0,41.8,41.5,37.7,28.5,24.4,13.4.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=11.713min,tR1(minor)=15.669min).dr>20:1.=92.7:7.3 er.ES-HRMS:Calcd forC19H21NO7[M+H],376.1391,Found 376.1399.
19.化合物3as:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2as(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3as。
产率:64.1%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.25–7.04(m,4H),4.17–4.04(m,2H),4.03–3.93(m,1H),3.50(dd,J=9.5Hz,6.5Hz,1H),3.05(dd,J=18.1Hz,10.6Hz,1H),2.73(dd,J=16.4Hz,6.4Hz,1H),2.64(dd,J=16.3Hz,9.7Hz,1H),2.48(d,J=4.2Hz,1H),2.43(s,3H),1.46(d,J=5.6Hz,6H),1.00(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ208.3,171.9,169.8,137.4,136.4,131.3,127.5,126.5,125.8,83.8,62.6,59.7,46.9,42.9,39.5,38.5,29.4,24.6,20.1,13.5;HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=13.364min,tR1(minor)=17.685min).dr>20:1.=90.4:9.6 er.ES-HRMS:Calcd forC20H25O5[M+H],345.1696,Found 345.1693.
20.化合物3at:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2at(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分
产率:68.8%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.26–7.21(m,1H),7.12–7.08(m,1H),6.91–6.85(m,12H),4.46(dd,J=9.7Hz,5.0Hz,1H),4.13–4.00(m,2H),3.80(s,3H),3.47(t,J=7.4Hz,1H),3.12(dd,J=17.9Hz,9.7Hz,1H),2.70(dd,J 16.2,7.4,1H),2.61(dd,J 16.2,7.4,1H),2.44(dd,J=17.9Hz,4.9Hz,1H),1.48(s,3H),1.46(s,3H),1.04(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ208.5,171.4,169.5,157.4,128.9,128.1,126.4,120.2,110.9,84.1,62.4,58.7,55.3,47.1,41.8,38.5,37.3,29.9,24.6,13.6.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=14.463min,tR1(minor)=21.009min).dr>20:1.=93.4:6.6 er.ES-HRMS:Calcd for C20H24O6[M+H],361.1646,Found 361.1672.
20.化合物3au:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2au(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3au。
产率:85.8%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.15(t,J=8.0Hz,1H),7.00–6.96(m,1H),6.89(d,J=7.8Hz,1H),6.75(dd,J=8.2,1.9Hz,1H),3.84(dq,J=10.7,7.1Hz,1H),3.74(s,3H),3.73–3.67(m,1H),3.61(dd,J=13.9,3.1Hz,1H),3.19–3.04(m,2H),2.47(tdd,J=24.1,16.5,9.2Hz,3H),1.33(s,3H),1.30(s,3H),0.83(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ207.3,171.8,168.7,158.2,137.3,127.9,120.4,114.4,112.4,81.8,61.4,59.2,54.2,45.7,41.2,41.0,36.8,27.5,23.5,12.3.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=14.463min,tR1(minor)=21.009min).dr>20:1.=93.7:6.3er.ES-HRMS:Calcd for C20H24O6[M+H],361.1646,Found 361.1662.
22.化合物3av:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2av(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3av。
产率:48.1%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ8.00(d,J=8.5Hz,1H),7.79(d,J=8.0Hz,1H),7.70(d,J=8.2Hz,1H),7.47(dtd,J=15.9,6.8,1.2Hz,2H),7.32–7.26(m,1H),7.21(s,1H),4.92(t,J=6.0Hz,1H),3.95–3.83(m,2H),3.82–3.73(m,1H),3.02(dd,J=18.7,6.6Hz,1H),2.79(dd,J=16.8,7.4Hz,1H),2.65–2.53(m,2H),1.47(s,3H),1.39(s,3H),0.68(t,J=7.1Hz,3H).13CNMR(100MHz,CDCl3)δ208.1,172.2,169.2,134.8,134.1,131.3,129.1,128.6,126.5,126.0,124.4,124.3,123.5,84.9,62.7,60.1,45.5,43.1,39.6,38.8,29.7,24.9,13.3.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(major)=20.786min,tR1(minior)=24.069min).dr>20:1.=98.4:1.6 er.ES-HRMS:Calcdfor C23H24O5[M+H],381.1696,Found381.1689.
23.化合物3aw:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2aw(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3aw。
产率:83.3%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.88–7.74(m,4H),7.65(dd,J=8.7Hz,1.0Hz,1H),7.49(dd,J=6.2Hz,3.1Hz,2H),3.94–3.68(m,2H),3.60(dq,J=10.7Hz,7.2Hz,1H),3.42–3.22(m,2H),2.75–2.47(m,3H),1.44(s,3H),1.40(s,3H),0.67(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ208.3,172.9,169.9,134.5,133.0,132.9,128.2,128.1,127.7,127.6,127.5,126.2,126.1,83.0,62.4,60.5,46.9,42.4,42.2,37.9,28.6,24.5,13.2.HPLC(Daicel ChiralPakOD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=9.945min,tR1(minior)=22.925min).dr>20:1.=92.4:7.6 er.ES-HRMS:Calcd for C23H24O5[M+H],381.1696,Found381.1697.
24.化合物3ax:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ax(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ax。
产率:98.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.30–7.25(m,1H),6.30–6.21(m,2H),4.09–3.98(m,2H),3.93(dd,J=9.7,4.3Hz,1H),3.64(qd,J=7.0,0.8Hz,1H),3.31(dd,J=9.3,6.3Hz,1H),2.96(dd,J=18.7,9.8Hz,1H),2.53(ddd,J=25.6,17.6,5.2Hz,2H),2.41(dd,J=16.4,9.5Hz,1H),1.35(s,3H),1.31(s,3H),1.08(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ207.7,172.1,169.0,151.0,142.1,110.7,108.9,84.1,62.9,58.9,45.5,40.2,38.1,37.8,29.2,24.5,13.7.HPLC(Daicel ChiralPak AD-H,210nm,hexane:i-PrOH=80:20,1.0mL/min:tR1(minior)=9.842min,tR1(major)=11.213min).dr>20:1.=90.6:9.4 er.ES-HRMS:Calcdfor C17H20O6[M+H],321.1333,Found 321.1323.
25.化合物3ay:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ay(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ay。
产率:99.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.26(d,J=5.0Hz,1H),7.13(d,J=3.1Hz,1H),7.01–6.90(m,1H),4.07–3.84(m,3H),3.32–3.09(m,2H),2.71(dd,J=18.0Hz,3.2Hz,1H),2.63(dd,J=16.3Hz,4.7Hz,1H),2.49(dd,J=15.9Hz,13.7Hz,1H),1.41(s,3H),1.40(s,3H),1.01(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ207.3,172.8,169.6,139.5,127.6,126.4,125.6,83.2,62.6,60.2,46.8,42.7,38.2,37.9,28.6,24.5,13.5.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=9.842min,tR1(minior)=11.213min).dr>20:1.=98.9:1.1 er.ES-HRMS:Calcd for C17H20O5S[M+H],337.1104,Found 337.1110.
26.化合物3az:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2az(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3az。
产率:92.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ6.48(s,1H),5.93(t,J=3.1Hz,1H),5.85–5.74(m,1H),3.97(qq,J=10.7,7.1Hz,1H),3.74(dd,J=10.7,4.0Hz,1H),3.60(s,1H),3.34(dd,J=10.5,5.8Hz,1H),2.90(dd,J=18.6,10.7Hz,1H),2.66(ddd,J=16.4,5.8,1.1Hz,1H),2.43(ddd,J=19.2,10.2,5.9Hz,1H),1.34(d,J=11.5Hz,2H),0.97(t,J=7.1Hz,1H);13C NMR(100MHz,CDCl3)δ208.0,172.7,169.3,128.8,122.7,107.7,106.9,83.9,62.6,60.7,45.9,43.0,38.3,35.3,34.3,29.1,24.5,13.6.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(minior)=6.128min,tR1(major)=12.0559min).dr>20:1.=93.7:6.3 er.ES-HRMS:Calcd for C18H23NO5[M+H],334.1649,Found 334.1647.
27.化合物3ba:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2ba(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3ba。
产率:51.2%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.60(d,J=8.1Hz,1H),7.16–7.10(m,1H),7.07–7.01(m,1H),6.99(s,1H),4.04(dd,J=11.8,3.7Hz,1H),3.86–3.75(m,1H),3.68(s,1H),3.37–3.24(m,1H),2.70–2.42(m,1H),1.35(s,1H),1.34(s,1H),0.71(t,J=7.1Hz,1H);13C NMR(100MHz,CDCl3)δ208.7,172.8,170.4,136.7,128.6,127.1,121.8,120.2,119.3,110.5,109.2,83.2,62.3,59.8,46.5,42.8,38.0,36.4,32.8,28.9,24.5,13.2.HPLC(Daicel ChiralPakAS-H,210nm,hexane:i-PrOH=60:40,1.0mL/min:tR1(minior)=18.132min,tR1(major)=21.169min).dr>20:1.=92.2:7.8 er.ES-HRMS:Calcd for C22H25NO5[M+H],384.1806,Found 384.1806.
28.化合物3bb:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1a(0.25mmol)和2bb(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3bb。
产率:80.0%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ8.37(d,J=4.5Hz,1H),7.59(td,J=7.7,1.6Hz,1H),7.30(d,J=7.9Hz,1H),7.09(dd,J=7.1,5.1Hz,1H),4.21–4.14(m,1H),3.93(q,J=7.1Hz,2H),3.69(t,J=6.6Hz,1H),2.93(dd,J=18.9,6.5Hz,1H),2.71(dd,J=17.0,7.1Hz,1H),2.47(ddd,J=23.2,17.9,5.6Hz,2H),1.48(s,3H),1.31(s,3H),0.86(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ208.7,173.3,168.7,158.6,148.3,136.7,124.0,122.2,85.5,62.3,59.3,45.5,45.0,42.3,39.6,29.7,24.9,13.4.HPLC(Daicel ChiralPak AS-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=9.036min,tR1(minior)=17.756min).dr>20:1.=94.2:5.8 er.ES-HRMS:Calcd for C19H22O6[M+H],332.1492,Found 332.1477.
29.化合物3bc:取化合物(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)催化剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1b(0.25mmol)和2bc(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分离纯化,旋干,得化合物3bc。
产率:93.7%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.23(d,J=8.8Hz,2H),6.78(d,J=8.8Hz,2H),3.72(s,3H),3.56(dd,J=14.2,3.0Hz,1H),3.31(s,3H),3.17–3.01(m,2H),2.58–2.32(m,3H),1.32(s,3H),1.27(s,3H).13C NMR(101MHz,CDCl3)δ207.3,171.8,169.4,158.1,129.3,127.6,112.4,81.8,59.2,54.1,52.0,45.9,41.1,40.7,36.6,27.5,23.3.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=8.388min,tR1(minior)=13.469min).dr>20:1.=95.1:4.9 er.ES-HRMS:Calcd for C19H22O6[M+H],347.1489,Found 347.1485.
30.化合物3bd:取催化剂(1S,2S)-1,2-二苯基乙二胺(0.05mmol)和N-Boc-L-Phg(0.05mmol)酸性添加剂溶于溶剂异丙醇(2.0mL),预先反应15分钟,向体系中加入1c(0.25mmol)和2bd(0.5mmol),室温搅拌反应14天,反应结束后,饱和氯化铵淬灭,用乙酸乙酯萃取,抽滤,旋干,柱层析分离,洗脱剂为乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱,分
产率:86.9%。硅胶柱层析(乙酸乙酯:石油醚=1:20、1:10、1:5梯度洗脱);1H NMR(400MHz,CDCl3)δ7.27(d,J=8.6Hz,2H),6.77(d,J=8.8Hz,2H),3.88–3.76(m,1H),3.71(d,J=1.1Hz,3H),3.65(dd,J=10.7,7.2Hz,1H),3.57(dd,J=14.1,2.7Hz,1H),3.11(ddd,J=27.0,13.1,9.4Hz,2H),2.57–2.34(m,3H),1.72–1.26(m,10H),0.83(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ207.9,172.0,168.8,158.1,129.5,127.8,112.3,83.2,61.2,58.9,54.2,44.5,41.2,40.5,36.0,35.7,31.9,28.6,23.6,21.4,21.4,12.3.HPLC(Daicel ChiralPak OD-H,210nm,hexane:i-PrOH=50:50,1.0mL/min:tR1(major)=8.388min,tR1(minior)=13.469min).dr>20:1.=91.1:8.9 er.ES-HRMS:Calcd forC23H28O6[M+H],401.1959,Found 401.1948.
31.化合物3aa-3ap,3as,3au-3bd的外细胞毒性初筛实验。
取出细胞生长良好的各组细胞的培养皿,用胰蛋白酶消化后收集细胞,经离心后得到细胞沉淀。使用含10%FBS的培养基重悬,充分混匀后制成单细胞悬液,然后使用全自动细胞计数仪进行细胞计数。按一定的倍数稀释细胞悬液,调整细胞浓度至1×105/ml。用移液器吸取100μL(1×104个)稀释后的细胞悬液,加入96孔板,在最外围一圈孔内加入200μL PBS溶液,避免液体挥发影响实验结果。将待测化合物分别用DMSO配成20mM的母液,分别取出1μL加入到999μL相应培养基中,混匀。12h(细胞贴壁后)吸出原有培养基,依次加入上述浓度的培养基100μL于96孔板中,每个化合物设置三个复孔,每板设置一个空白对照。置入37℃的CO2培养箱中孵育,72h后取出,并向各孔中分别加入10u L CCK-8溶液,放入培养箱中孵育2小时后,将酶标仪测定在450nm处的吸光度,进行吸光度测量得各孔OD值。计算细胞存活率。
注:“-”表示该化合物有对细胞无抑制活性。
32.化合物3aa-bd的产率、er值、dr值的表格:
由上表可知,本发明成功地合成了一系列产率高达99%、立体选择性>20:1dr和较好的er值的手性双环γ-丁内酯类化合物,开发了利用手性二伯胺类催化剂的γ-双甲基-α-乙酯呋喃酮(式Ⅱ)与α,β-不饱和酮(式Ⅲ)的双Michael加成反应,从而可以一步反应快速获得功能性手性双环γ-丁内酯类化合物,为合成药物活性中间体提供思路和方法,解决目前医药研发领域的化合物合成难点。同时,化合物3aw对MCF-7细胞系有超过50%的抑制活性。
应当理解的是,本发明的上述具体实施方式仅仅用于示例性说明或解释本发明的原理,而不构成对本发明的限制。因此,在不偏离本发明的精神和范围的情况下所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。此外,本发明所附权利要求旨在涵盖落入所附权利要求范围和边界、或者这种范围和边界的等同形式内的全部变化和修改例。
Claims (8)
4.根据权利要求1所述的一种手性双环γ-丁内酯类化合物的制备方法,其特征在于,手性双环γ-丁内酯类化合物3aa-bd易于重结晶,重结晶后的手性双环γ-丁内酯类化合物3aa-bd的er值提高至99:1。
6.根据权利要求5所述一种手性双环γ-丁内酯类化合物的制备方法,其特征在于,化合物1a-d和手性胺类催化剂的摩尔量之比为1:0.5。
7.根据权利要求1所述一种手性双环γ-丁内酯类化合物的制备方法,其特征在于,所述溶剂选自甲苯、正己烷、异丙醇、二氯甲烷、甲醇或乙醇中的一种或多种的混合物。
8.根据权利要求1所述一种手性双环γ-丁内酯类化合物的制备方法,其特征在于,化合物1a-d和化合物2aa-2bd的摩尔量之比为1:2。
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