CN114853744A - 一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法 - Google Patents
一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法 Download PDFInfo
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- CN114853744A CN114853744A CN202210560924.1A CN202210560924A CN114853744A CN 114853744 A CN114853744 A CN 114853744A CN 202210560924 A CN202210560924 A CN 202210560924A CN 114853744 A CN114853744 A CN 114853744A
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- heterocycle
- substituted
- catalysis
- conjugated olefin
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- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 36
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- -1 olefin compound Chemical class 0.000 claims abstract description 22
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- 125000003118 aryl group Chemical group 0.000 claims description 10
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
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- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
-
- 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
- C07D405/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
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Abstract
本发明公开了一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,它以手性磷酸为催化剂,在氧化剂、添加剂和有机溶剂存在下,如式I所示的含杂环共轭烯烃化合物在手性磷酸催化剂的催化作用下,被氧化剂氧化为如式II所示的含杂环手性环氧化合物,反应式如下:
Description
技术领域
本发明涉及一种有机小分子催化含杂环共轭烯烃的不对称环氧化反应方法。
背景技术
带有立体中心的芳香N-杂环结构片段普遍存在于天然产物和生物活性化合物中[Bagher Eftekhari-Sis.;Maryam,Zirak.;Ali Akbari.Chem.Rev.2013,113,2958–3043.],其不对称构建在合成界具有重要意义。前手性的杂环烯烃的直接对映选择性官能团化在原子经济性方面是一种有吸引力的策略[Daniel Best.;Hon WaiLam.J.Org.Chem.2014,79,831–845.]。
手性环氧化合物不仅是用途极为广泛的合成中间体,其结构单元也存在于大量的天然产物、药物和生物活性分子中[Jiayun He.;Jesse Ling.;PaulineChiu.Chem.Rev.2014,114,8037-8128.]。烯烃的不对称环氧化反应是合成手性环氧化物最直接有效的方法之一。金属催化烯烃的不对称环氧化取得了很大的成功,过渡金属催化的氧化体系实现了对烯丙醇[Giorgio De Faveri.;Gennadiy Ilyashenko.;MichaelWatkinson.Chem.Soc.Rev.2011,40,1722–1760.]含杂原子烯烃[Carlota Claraso.;LaiaVicens.;Alfonso Polo.;Miquel Costas.Org.Lett.2019,21,2430-2435.]、非官能团化烯烃[Konstantin P.Bryliakov.Chem.Rev.2017,117,11406-11459.]以及缺电子烯烃[OlafCusso.;Marco Cianfanelli.;Xavi Ribas.;Robertus J.M.Klein Gebbink.;MiquelCostas.J.Am.Chem.Soc.2016,138,2732-2738]的不对称环氧化反应。除此,烯烃的不对称环氧化反应利用有机催化剂也能很好的实现,1999年,Yian Shi等以果糖衍生的手性酮催化H2O2对某些烯烃进行不对称环氧化反应,ee值达73%[J.DavidWarren.;YianShi.J.Org.Chem.1999,64,7675–7677];1998年,Page等以手性亚胺盐和过氧单磺酸钾实现对某些烯烃的环氧化,ee值达73%[Philip C.Bulman Page.;Gerasimos A.Rassias.;Donald Bethell.;Mark B.Schilling.J.Org.Chem.1998,63,2774–2777];2014年,ScottJ.Miller等报道了多肽催化剂和过氧化氢对烯丙醇类化合物的区域选择性(>100:1:1)和对映选择性环氧化(86%ee)[Nadia C.Abascal.;Phillip A.Lichtor.;MichaelW.Giuliano.;Scott J.Miller.Chem.Sci.,2014,5,4504–4511];2008年,List等报道了手性离子对导向烯醛的不对称环氧化反应,TBHP作为氧化剂,其中含有手性磷酸盐的胺盐为最佳催化剂,ee值达96%[Manuel Mahlau.;Prof.Dr.BenjaminList.Angew.Chem.Int.Ed.2013,52,518–533.];2008年,List等使用包含手性二胺和手性或非手性酸的离子对催化剂,过氧化氢为氧化剂实现了对环烯酮的不对称环氧化(95:5e.r.)[Xingwang Wang.;Corinna M.Reisinger.;Benjamin List.J.Am.Chem.Soc.2008,130,6070–6071];2012年,Shibata等发现甲基肼、碱和金鸡纳碱的相转移催化剂组成的有机催化体系可以实现具有β-三氟甲基-β,β双取代烯酮的不对称氧化反应,ee值达99%[Hiroyuki Kawai.;Satoshi Okusu.;Zhe Yuan.;Etsuko Tokunaga.;Akihito Yamano.;Motoo Shiro.;Norio Shibata.Angew.Chem.Int.Ed.2013,52,2221–2225];2018年,Nagasawad等开发了一种胍-双脲双功能的肽类有机催化剂,实现了2-取代的1,4-萘醌与TBHP的对映选择性亲核环氧化,相应的环氧化合物以85:15-95:5er获得[MasakiKawaguchi.;Katsuhiro Nakano.;Keisuke Hosoya.;Tatsuya Orihara.;MasahiroYamanaka.;Minami Odagi.;Kazuo Nagasawa.Org.Lett.2018,20,2811-2815];2005年,报道了第一个手性脯氨酸衍生的催化剂催化的烯基醛的不对称环氧化反应,对映体过量值达到96%[Mauro Marigo.;Johan Franze′n.;Thomas B.Poulsen.;Wei Zhuang.;Karl Anker J.Am.Chem.Soc.2005,127,6964-6965.];2015年,AlessandraLattanz等报道了由多功能金鸡纳碱硫脲/CHP催化体系,实现了亚烷基丙二腈的首次不对称氧化[Sara Meninno.;Andreu Vidal-Albalat.;Alessandra Lattanzi.Org.Lett.2015,17,4348-4351.];2017年,Alessandra Lattanzi等以手性胺-硫脲作为催化剂,TBHP为氧化剂,实现了β,β’-取代的不饱和吡唑啉酮的非对映选择性和对映选择性环氧化[SaraMeninno.;Angelo Roselli.;Amedeo Capobianco.;Jacob Overgaard.;AlessandraLattanzi.Org.Lett.2017,19,5030-5033]。
综上文献调研发现,目前烯烃的不对称环氧化反应可通过过渡金属催化或者有机催化实现;高效的有机催化剂为烯烃的不对称环氧化提供了多种可能,主要包括α,β-不饱和羰基化合物、硝基烯烃、丙烯腈的不对称氧化,所适用的底物范围有限并且有机催化剂通常需要较高的催化剂负载量(5-20mol%)。此外,含氮杂芳基烯烃不对称环氧化反应进展缓慢,尽管该类产物在手性药物中间体的合成中具有潜在的应用前景。开发一种条件温和、催化体系适用范围广泛、廉价环保的不对称有机催化方法,实现各类芳杂环取代烯烃的高效对映选择性环氧化是本发明着力解决的技术问题。
发明内容
针对现有技术存在的上述技术问题,本发明的目的在于提供一种有机小分子催化的含氮杂芳环共轭烯烃的不对称环氧化方法,本发明利用过氧化氢为氧化剂,以手性磷酸为催化剂,以无水硫酸镁为添加剂,在较简单的条件下对含杂环共轭烯烃进行不对称催化环氧化反应,得到高光学活性和产率的手性环氧化合物。
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化反应方法,其特征在于以手性磷酸为催化剂,在有机溶剂、氧化剂及添加剂存在下,如式I所示的含杂环共轭烯烃化合物在手性磷酸催化剂的催化作用下,被氧化剂氧化为如式II所示的含杂环手性环氧化合物,反应式如下:
X选自下列之一:NTs、NBoc、S、O;优选为NTs;
Y选自下列之一:C、N;
Z选自下列之一:C、N;
R1选自下列之一:氢原子、C1~C6烷烃基或取代烷烃基、C5~C6烯基、芳基或杂芳基;
R2选自下列之一:氢原子、C1~C6脂肪烃基或取代脂肪烃基、C1-C6烷氧基、C1-C6烯基、取代炔基、芳基或杂芳基、取代氨基、酯基、硝基、氰基、卤素;
R3选自下列之一:氢原子、甲基、骈环杂环基。
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于所述R1中,C1~C6烷烃基或取代烷烃基为甲基、正丙基、异丙基、正己基、氯丙基、氯丁基、取代甲基或取代乙基,取代甲基的取代基为NPhth或OBn,取代乙基的取代基为OTBS、苯基或酯基;C5~C6烯基为戊烯基;芳基为苯基或对氯苯基;
所述R2中,C1~C6脂肪烃基或取代脂肪烃基为甲基或三氟甲基,C1-C6烷氧基为甲氧基,C1-C6烯基为戊烯基,TIPS炔基为TIPS取代的乙炔基,芳基或杂芳基为苯基或N-Boc-2-吡咯基,取代氨基为Ts保护的氨基,酯基为甲酸乙酯,卤素为F、Cl或Br;
所述R3中,骈环杂环基为骈环己基。
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于式I所示的含杂环共轭烯烃化合物选自下列之一:
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于氧化剂为TBHP、m-CPBA、CHP或H2O2,优选为H2O2;氧化剂与式I所示化合物的物质的量比为1.2~2.5:1.0,优选为2.0:1.0。
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于反应温度为0℃~50℃,优选为25℃~35℃;所述有机溶剂为苯、甲苯、三氟甲苯、氯苯、邻二甲苯、间二甲苯、对二甲苯、均三甲苯、二氯甲烷、氯仿、四氯化碳、正己烷、乙腈、甲基叔丁基醚、乙酸乙酯中的至少一种,优选为甲苯、乙酸乙酯或者甲苯-乙酸乙酯混合溶剂,甲苯-乙酸乙酯混合溶剂中甲苯与乙酸乙酯的体积比是1~3:1,优选为2:1。
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于催化剂与式I所示化合物的物质的量比为5~20:100,优选为10:100;式I所示化合物的物质的量与有机溶剂的体积之比为0.025~0.5:1,优选为0.1:1,物质的量单位为mmol,体积单位为mL。
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于所述添加剂为无水硫酸钠或无水硫酸镁,优选为无水硫酸镁;所述无水硫酸镁的质量与式I所示化合物的物质的量之比为0.3~2.4:1,优选为1.2:1,质量的单位为g,物质的量单位为mmol。
所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于手性磷酸催化剂选自下列之一:
与现有技术相比,本发明具有如下有益效果:
(1)本发明在一定程度上突破了现有技术的局限,相对于以过渡金属、手性离子对或相转移催化剂组成的有机催化体系,本发明单独利用手性磷酸作为催化剂,采用无水硫酸镁为添加剂,通过氧化可以实现含杂环手性环氧化合物高对映选择性的制备,避免了过渡金属以及其他碱等化学物质的使用。
(2)本发明采用过氧化氢为氧化剂,价格低廉,唯一副反应是水,环境友好,原子经济性好。其反应条件简单温和,具有经济、环保的优点,顺应绿色化学发展的大趋势。
(3)本发明扩大了烯烃的范围,报道了第一个手性磷酸催化的杂环烯烃对映选择性环氧化反应,底物范围可以进一步扩展到苯并咪唑、苯并噻唑、苯并恶唑取代的多种烯烃。
(4)本发明报道了一种高对映选择性合成含杂环手性环氧化合物方法,反应步骤简便,只需一步反应即可得到高光学活性的杂环手性环氧化合物,其经过开环或官能团化反应生成一系列生物活性化合物和医药的重要中间体,具有较好的应用前景和社会价值。总而言之,本发明在原子经济性、步骤经济性、高效性、绿色性和多样性导向合成等方面具有较大的优势。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。
分析仪器:使用海能技术MP430视频熔点仪测定熔点。包括1H NMR,13C NMR光谱在内的NMR数据是在Bruker 400MHz或600MHz仪器上记录的。所有的13C NMR光谱都是宽带质子去耦的。1H NMR相对于溶剂的残留信号以ppm为单位报道化学位移。使用ESI或EI作为离子源,在Agilent 6210 TOF LC/MS上记录了高分辨率质(HRMS)。使用AUTOPOLV自动旋光仪测定旋光度。通过使用配备有Daicel Chiralpak IA,IB,IC,ID,IE,IF,IG,IJ色谱柱的Agilent 1100 HPLC分析确定对映体过量值(ee值)。
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手性磷酸催化剂G是本申请自制,其合成路线如下:
手性磷酸催化剂G的1H NMR和13C NMR检测数据如下:
1H NMR(600MHz,CDCl3)δ8.42(s,2H),8.20(d,J=1.2Hz,2H),8.08–8.01(m,2H),7.94(s,2H),7.84(d,J=8.4Hz,2H),7.77–7.72(m,4H),7.69(ddd,J=8.0,2.4,1.4Hz,8H),7.53(dd,J=8.6,1.4Hz,2H),7.49–7.34(m,18H),7.28(d,J=1.8Hz,2H),7.15(d,J=1.8Hz,2H),6.79(t,J=7.6Hz,2H),6.76–6.71(m,2H),2.88(p,J=6.8Hz,2H),2.69(p,J=6.8Hz,2H),1.24(s,18H),1.13(d,J=6.8Hz,6H),1.01(d,J=6.8Hz,6H),0.94(d,J=6.8Hz,6H),0.72(d,J=6.8Hz,6H).
13C NMR(150MHz,CDCl3)δ148.6,147.9,146.5,138.5,138.0,137.8,136.7,136.7,134.6,134.6,133.6,133.1,133.0,132.9,132.1,131.5,131.4,130.6,130.3,130.1,129.5,128.5,123.0,127.9,127.9,127.2,126.8,126.4,125.8,125.7,125.2,125.0,122.2,31.4,30.9,29.0,26.3,25.3,23.7,23.1,19.0.HRMS(ESI)m/z calcd.forC104H96O4PSi2[M-H]-:1495.6590;found 1495.6663.
手性磷酸催化剂H是本申请自制,其合成路线如下:
手性磷酸催化剂H的1H NMR检测数据如下:
1HNMR(400MHz,CDCl3)δ8.12(s,2H),8.06(s,2H),7.85(s,2H),7.81(d,J=8.4Hz,2H),7.77–7.69(m,4H),7.68–7.60(m,8H),7.60(d,J=8.7Hz,2H),7.53(d,J=8.6Hz,2H),7.48–7.31(m,16H),7.24(d,J=8.8Hz,2H),7.06–6.86(m,4H),1.25(s,18H).
13C NMR(100MHz,CDCl3)δ138.2,136.7,136.7,134.6,134.5,134.2,133.4,133.1,133.0,131.4,131.3,131.0,130.8,130.4,129.5,128.6,128.0,127.9,127.8,127.8,127.4,126.4,126.3,126.0,125.1,125.0,122.4,29.1,19.1.HRMS(ESI)m/z calcd.forC80H64O4PSi2[M-H]-:1175.4086;found 1175.4122.
手性磷酸催化剂I是本申请自制,其合成路线如下:
手性磷酸催化剂I的1H NMR和13C NMR检测数据如下:
1H NMR(400MHz,CDCl3)δ8.15(s,2H),7.94(s,2H),7.82–7.72(m,6H),7.68(ddt,J=5.6,3.9,1.6Hz,8H),7.57(ddd,J=7.0,4.3,2.3Hz,4H),7.52(dd,J=7.3,1.6Hz,2H),7.52–7.30(m,22H),7.24–7.16(m,4H),7.14–7.01(m,4H),1.29(s,18H).
13C NMR(150MHz,CDCl3)δ147.1,147.0,138.9,138.2,138.0,136.7,136.7,134.7,134.5,134.4,133.5,133.2,133.1,131.6,131.4,131.2,131.1,130.9,130.4,130.2,129.8,129.7,129.5,128.5,128.3,127.9,127.5,127.2,126.6,126.3,126.2,125.8,125.0,124.7,124.5,122.3,29.1,19.1.HRMS(ESI)m/z calcd.for C92H72O4PSi2[M-H]-:1327.4712;found 1327.4715.
本发明以化合物I-1为底物,进行了大量手性磷酸催化剂的筛选。
实验步骤:在N2保护下,将反应体系密闭进行无水无氧处理,并调整温度为25℃,在10mL的反应瓶中依次加入化合物I-1(0.1mmol,1.0equiv)、手性催化剂A1-K(0.01mmol,0.1equiv)、添加剂无水硫酸镁(120mg)、溶剂为甲苯(1mL,0.1M),最后通过微量进样器逐滴加入H2O2(30%水溶液,0.2mmol,2.0equiv),进行反应。通过TLC分析监测反应直至反应完成后,将反应体系通过硅藻土过滤并浓缩,所得浓缩粗产品用柱层析分离纯化,洗脱剂为石油醚/乙酸乙酯=10/1(v/v),得到目标化合物II-1为白色固体。按照上述操作方式,手性催化剂分别选用A1-K时相对应的反应时间、目标化合物II-1的收率及ee值分别如下所示:
通过对比和筛选,最终确定(S)-J作为最优催化剂参与不对称环氧化反应。
实施例1:产物II-1的合成
实验步骤:在N2保护下,将反应体系密闭进行无水无氧处理,并调整温度为25℃,在10mL的反应瓶中依次加入化合物I-1(0.1mmol,1.0equiv)、手性螺环催化剂(S)-J(0.01mmol,0.1equiv)、添加剂无水硫酸镁(120mg)、溶剂为甲苯(0.66mL,0.066M)和乙酸乙酯(0.33mL,0.033M),最后通过微量进样器逐滴加入H2O2(30%水溶液,0.2mmol,2.0equiv),进行反应。通过TLC分析监测反应直至反应完成后,将反应体系通过硅藻土过滤并浓缩,所得浓缩粗产品用柱层析分离纯化,洗脱剂为石油醚/乙酸乙酯=10/1(v/v),得到目标化合物II-1为白色固体,反应时间12h,收率94%,ee值为90%。[α]D 20=+125.6(c 1.0,CHCl3)。1HNMR(400MHz,CDCl3)δ8.00(dd,J=7.8,1.2Hz,1H),7.92(d,J=8.4Hz,2H),7.74–7.62(m,1H),7.43–7.26(m,4H),4.42(d,J=2.0Hz,1H),3.62(qd,J=5.2,2.0Hz,1H),2.38(s,3H),1.58(d,J=5.2Hz,3H).13C NMR(150MHz,CDCl3)δ150.3,146.4,141.8,135.0,133.0,130.4,127.3,125.8,125.2,120.9,113.5,77.5,77.2,76.8,56.8,52.8,21.8,17.4.HRMS(ESI)m/zcalcd.for C17H17N2O3S[M+H]+:329.0954;found 329.0941.
对照例1:产物II-1的合成
将实施例1中的手性联萘酚催化剂(S)-J替换为同等摩尔量的手性联萘酚催化剂(R)-A1,混合溶剂甲苯(0.66mL,0.066M)和乙酸乙酯(0.33mL,0.33M)替换为甲苯(1mL,0.1M),不添加无水硫酸镁,其余操作步骤同实施例1,最终得到相应的化合物II-1。
目标化合物II-1为白色固体,反应时间22h,收率84%,ee值为38%。
对照例2:产物II-1的合成
将实施例1中的H2O2替换为同等摩尔量的TBHP,手性联萘酚催化剂(S)-J替换为同等摩尔量的手性联萘酚催化剂(R)-A1,混合溶剂甲苯(0.66mL,0.066M)和乙酸乙酯(0.33mL,0.33M)替换为甲苯(1mL,0.1M),不添加无水硫酸镁,其余操作步骤同实施例1,最终得到相应的化合物II-1。
目标化合物II-1为白色固体,反应时间36h,收率70%,ee值为44%。
对照例3:产物II-1的合成
将实施例1中的H2O2替换为同等摩尔量的m-CPBA,手性联萘酚催化剂(S)-J替换为同等摩尔量的手性联萘酚催化剂(R)-A1,混合溶剂甲苯(0.66mL,0.066M)和乙酸乙酯(0.33mL,0.33M)替换为甲苯(1mL,0.1M),不添加无水硫酸镁,其余操作步骤同实施例1,最终得到相应的化合物II-1。
目标化合物II-1为白色固体,反应时间24h,收率81%,ee值为3%。
对照例4:产物II-1的合成
将实施例1中的H2O2替换为同等摩尔量的CHP,手性联萘酚催化剂(S)-J替换为同等摩尔量的手性联萘酚催化剂(R)-A1,混合溶剂甲苯(0.66mL,0.066M)和乙酸乙酯(0.33mL,0.33M)替换为甲苯(1mL,0.1M),其余操作步骤同实施例1,最终得到相应的化合物II-1。
目标化合物II-1为白色固体,反应时间36h,收率46%,ee值为11%。
对照例5:产物II-1的合成
将实施例1中的无水硫酸镁替换为同等质量的无水硫酸钠,手性联萘酚催化剂(S)-J替换为同等摩尔量的手性联萘酚催化剂(R)-A1,混合溶剂甲苯(0.66mL,0.066M)和乙酸乙酯(0.33mL,0.33M)替换为甲苯(1mL,0.1M),其余操作步骤同实施例1,最终得到相应的化合物II-1。
目标化合物II-1为白色固体,反应时间24h,收率57%,ee值为41%。
实施例2:产物II-2的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-2所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-2。
得到产物II-2为黄色固体,反应时间24h,产率47%,ee值为82%。[α]D 20=–11.2(c1.0,CHCl3)。1H NMR(400MHz,CDCl3)δ7.97–7.84(m,1H),7.76–7.65(m,1H),7.37–7.28(m,2H),4.35(d,J=2.0Hz,1H),3.50(qd,J=5.2,2.0Hz,1H),1.72(s,9H),1.54(d,J=5.2Hz,3H).13C NMR(100MHz,CDCl3)δ151.9,148.7,142.0,132.9,125.2,124.6,120.5,114.8,86.3,57.1,54.2,28.2,17.7.HRMS(ESI)m/z calcd.for C15H18N2NaO3[M+Na]+:297.1210;found 297.1210.
实施例3:II-3的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-3所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-3。
得到产物II-3为白色固体,反应时间10h,产率82%,ee值为94%。[α]D 20=–201.7(c 1.0,CHCl3)。1H NMR(600MHz,CDCl3)δ8.13(d,J=1.4Hz,1H),7.99–7.86(m,2H),7.75(d,J=1.2Hz,1H),7.35(d,J=8.2Hz,2H),4.36(t,J=1.6Hz,1H),3.64–3.52(m,1H),2.41(s,3H),1.57(d,J=5.2Hz,3H).13C NMR(150MHz,CDCl3)δ152.2,147.1,141.2,134.5,132.1,130.7,130.1,129.6,127.4,122.0,115.0,57.0,52.4,21.0,17.4.HRMS(ESI)m/zcalcd.forC17H15Cl2N2O3S[M+H]+:397.0175;found 397.0189.
实施例4:产物II-4的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-4所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-4。
得到产物II-4为白色固体,反应时间16h,产率95%,ee值为88%。[α]D 20=-192.7(c 1.0,CHCl3)。1H NMR(600MHz,CDCl3)δ7.93–7.87(m,2H),7.76(s,1H),7.41(s,1H),7.29(d,J=8.0Hz,2H),4.38(s,1H),3.64–3.57(m,1H),2.39(s,3H),2.37(s,3H),2.31(s,3H),1.56(d,J=5.2Hz,3H).13C NMR(150MHz,CDCl3)δ149.4,146.2,140.3,135.2,134.3,131.5,130.3,127.2,120.9,113.7,56.7,52.9,21.8,20.9,20.3,17.4.HRMS(ESI)m/zcalcd.forC19H21N2O3S[M+H]+:357.1267;found 357.1278.
实施例5:产物II-5的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-5所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-5。
得到产物II-5为无色油状液体,反应时间10h,产率75%,ee值为91%。[α]D 20=–132.3(c 1.0,CHCl3)。1H NMR(600MHz,CDCl3)δ8.18(d,J=1.8Hz,1H),7.91(d,J=8.6Hz,2H),7.53(d,J=8.6Hz,1H),7.45(dd,J=8.6,1.8Hz,1H),7.34(d,J=8.2Hz,2H),4.37(d,J=2.0Hz,1H),3.59(qd,J=5.2,2.0Hz,1H),2.40(s,3H),1.56(d,J=5.2Hz,3H).13C NMR(150MHz,CDCl3)δ150.9,146.8,140.8,134.7,134.0,130.6,128.7,127.4,122.0,119.3,116.6,56.9,52.6,21.9,17.4.HRMS(ESI)m/z calcd.for C17H15BrN2NaO3S[M+Na]+:428.9879;found 428.9879.
实施例6:产物II-6的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-6所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-6。
得到产物II-6为无色油状液体,反应时间8h,产率84%,ee值为92%。[α]D 20=–135.1(c 1.0,CHCl3)。1H NMR(600MHz,CDCl3)δ7.88(dd,J=10.2,8.6Hz,3H),7.81(d,J=2.0Hz,1H),7.49(dd,J=8.8,2.0Hz,1H),7.31(d,J=8.2Hz,2H),4.39(d,J=2.0Hz,1H),3.59(qd,J=5.2,2.0Hz,1H),2.39(s,3H),1.57(d,J=5.2Hz,3H).13C NMR(150MHz,CDCl3)δ151.5,146.8,143.1,134.7,132.1,130.5,128.8,127.3,123.8,118.3,114.7,57.0,52.6,21.9,17.4.HRMS(ESI)m/z calcd.for C17H15BrN2NaO3S[M+Na]+:428.9879;found428.9891.
实施例7:产物II-7的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-7所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-7。
得到产物II-7为无色油状液体,反应时间20h,产率78%,ee值为90%。[α]D 20=–95.7(c 1.0,CHCl3)。1H NMR(600MHz,CDCl3)δ7.89(d,J=8.4Hz,2H),7.87(d,J=9.0Hz,1H),7.29(d,J=8.2Hz,2H),7.13(d,J=2.6Hz,1H),6.99(dd,J=9.0,2.6Hz,1H),4.39(d,J=2.0Hz,1H),3.80(s,3H),3.61(qd,J=5.2,2.0Hz,1H),2.38(s,3H),1.56(d,J=5.2Hz,3H).13C NMR(150MHz,CDCl3)δ157.9,150.8,146.3,143.0,135.0,130.4,127.2,115.1,114.0,103.2,56.8,55.8,52.7,21.8,17.5.HRMS(ESI)m/z calcd.for C18H18N2NaO4S[M+Na]+:381.0879;found 381.0894.
实施例8:产物II-8的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-8所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-8。
得到产物II-8为无色油状液体,反应时间36h,产率71%,ee值为75%。[α]D20=–68.9(c 1.0,CHCl3)。1H NMR(400MHz,CDCl3)δ7.92(d,J=8.4Hz,2H),7.82(d,J=8.4Hz,1H),7.32–7.22(m,3H),7.12(d,J=7.4Hz,1H),4.43(d,J=2.0Hz,1H),3.68(qd,J=5.2,2.0Hz,1H),2.55(s,3H),2.36(s,3H),1.58(d,J=5.2Hz,3H).13C NMR(100MHz,CDCl3)δ149.3,146.2,141.0,135.0,132.7,131.1,130.3,127.3,125.6,125.6,110.9,56.6,52.9,21.8,17.4,16.7.HRMS(ESI)m/z calcd.for C18H18N2NaO3S[M+Na]+:365.0930;found365.0930.
实施例9:产物II-9的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-9所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-9。
得到产物II-9为无色油状液体,反应时间18h,产率78%,ee值为88%。[α]D 20=–299.8(c 1.0,CHCl3)。1H NMR(600MHz,CDCl3)δ7.94–7.88(m,3H),7.57(d,J=8.4Hz,1H),7.37(dd,J=8.4,1.6Hz,1H),7.30(d,J=8.2Hz,2H),6.50(d,J=15.8Hz,1H),6.30(dt,J=15.8,6.8Hz,1H),4.39(d,J=2.0Hz,1H),3.61(qd,J=5.2,2.0Hz,1H),2.38(s,3H),2.23(qd,J=7.2,1.6Hz,2H),1.56(d,J=5.2Hz,3H),1.55–1.50(m,2H),0.98(t,J=7.4Hz,3H).13C NMR(150MHz,CDCl3)δ150.2,146.4,140.9,136.3,135.1,133.6,132.1,130.4,129.8,127.3,123.3,120.7,110.8,56.7,52.8,35.3,22.6,21.8,17.4,13.9.HRMS(ESI)m/zcalcd.for C22H25N2O3S[M+H]+:397.1580;found 397.1593.
实施例10:产物II-10的合成
将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-10所示化合物,其余操作步骤同实施例1,最终得到相应的化合物II-10。
得到产物II-10为无色油状液体,反应时间24h,产率85%,ee值为95%。[α]D 20=–153.4(c 1.0,CHCl3)。1H NMR(400MHz,CDCl3)δ7.99(dd,J=7.8,1.2Hz,1H),7.95–7.88(m,2H),7.72–7.65(m,1H),7.42–7.32(m,2H),7.30(d,J=8.4Hz,2H),5.83(ddt,J=16.8,10.2,6.6Hz,1H),5.06(dq,J=17.2,1.6Hz,1H),5.00(ddt,J=10.2,2.2,1.2Hz,1H),4.47(d,J=2.0Hz,1H),3.57(ddd,J=6.6,4.4,2.0Hz,1H),2.38(s,3H),2.19(q,J=7.2Hz,2H),1.99–1.82(m,1H),1.81–1.59(m,3H).13C NMR(100MHz,CDCl3)δ150.4,146.4,141.8,138.2,134.9,133.0,130.4,127.3,125.7,125.2,120.9,115.3,113.5,60.8,51.8,33.5,31.2,25.2,21.8.HRMS(ESI)m/z calcd.for C21H22N2NaO3S[M+Na]+:405.1243;found 405.1251.
实施例11-46
本发明具有广泛的底物实用性,按照实施例1中的反应条件,多种底物能参与该反应,高收率、高立体选择性地获得含杂环手性环氧化合物。
实施例11-46中未作特殊说明的实验方法重复实施例1,不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的式I所示的含杂环共轭烯烃化合物”,其余操作步骤同实施例1,最终得到相应的式II所示的含杂环手性环氧化合物,反应式如下:
上述反应式中,式II结构式中的取代基R1、R2、R3均与式I结构式中相同。其中,实施例11-46中使用的含杂环共轭烯烃化合物的分子结构式分别如I-11~I-46所示,反应结果见表1中。
表1
表1中,a表示反应的混合溶剂甲苯(0.66mL,0.066M)和乙酸乙酯0.33mL,0.33M)替换为甲苯(1mL,0.1M),温度25℃替换为35℃。b表示反应的手性催化剂J替换为同等摩尔量的G。c表示反应的温度25℃替换为35℃。d表示反应的混合溶剂甲苯(0.66mL,0.066M)和乙酸乙酯(0.33mL,0.33M)替换为乙酸乙酯(1mL,0.1M),温度25℃替换为35℃。e表示反应的H2O2替换为同等摩尔量的m-CPBA。
本说明书所述的内容仅仅是对发明构思实现形式的列举,本发明的保护范围不应当被视为仅限于实施例所陈述的具体形式。
Claims (8)
1.一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于以手性磷酸为催化剂,在氧化剂、添加剂和有机溶剂存在下,如式I所示的含杂环共轭烯烃化合物在手性磷酸催化剂的催化作用下,被氧化剂氧化为如式II所示的含杂环手性环氧化合物,反应式如下:
X选自下列之一:NTs、NBoc、S、O;优选为NTs;
Y选自下列之一:C、N;
Z选自下列之一:C、N;
R1选自下列之一:氢原子、C1~C6烷烃基或取代烷烃基、C5~C6烯基、芳基;
R2选自下列之一:氢原子、C1~C6脂肪烃基或取代脂肪烃基、C1-C6烷氧基、C1-C6烯基、TIPS炔基、芳基或杂芳基、取代氨基、酯基、硝基、氰基、卤素;
R3选自下列之一:氢原子、甲基、骈环杂环基。
2.如权利要求1所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于所述R1中,C1~C6烷烃基或取代烷烃基为甲基、正丙基、异丙基、正己基、氯丙基、氯丁基、取代甲基或取代乙基,取代甲基的取代基为NPhth或OBn,取代乙基的取代基为OTBS、苯基或酯基;C5~C6烯基为戊烯基;芳基为苯基或对氯苯基;
所述R2中,C1~C6脂肪烃基或取代脂肪烃基为甲基或三氟甲基,C1-C6烷氧基为甲氧基,C1-C6烯基为戊烯基,TIPS炔基为TIPS取代的乙炔基,芳基或杂芳基为苯基或N-Boc-2-吡咯基,取代氨基为Ts保护的氨基,酯基为甲酸乙酯,卤素为F、Cl或Br;
所述R3中,骈环杂环基为骈环己基。
4.如权利要求1所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于氧化剂为TBHP、m-CPBA、CHP或H2O2,优选为H2O2;氧化剂与式I所示化合物的物质的量比为1.2~2.5:1.0,优选为2.0:1.0。
5.如权利要求1所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于反应温度为0℃~50℃,优选为25℃~35℃;所述有机溶剂为苯、甲苯、三氟甲苯、氯苯、邻二甲苯、间二甲苯、对二甲苯、均三甲苯、二氯甲烷、氯仿、四氯化碳、正己烷、乙腈、甲基叔丁基醚、乙酸乙酯中的至少一种,优选为甲苯、乙酸乙酯或者甲苯-乙酸乙酯混合溶剂,甲苯-乙酸乙酯混合溶剂中甲苯与乙酸乙酯的体积比是1~3:1,优选为2:1。
6.如权利要求1所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于催化剂与式I所示化合物的物质的量比为5~20:100,优选为10:100;式I所示化合物的物质的量与有机溶剂的体积之比为0.025~0.5:1,优选为0.1:1,物质的量单位为mmol,体积单位为mL。
7.如权利要求1所述的一种有机小分子催化含杂环共轭烯烃的不对称环氧化方法,其特征在于所述添加剂为无水硫酸钠或无水硫酸镁,优选为无水硫酸镁;所述无水硫酸镁的质量与式I所示化合物的物质的量之比为0.3~2.4:1,优选为1.2:1,质量的单位为g,物质的量单位为mmol。
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