CN101569864A - 手性磺胺类有机小分子催化剂及其应用 - Google Patents
手性磺胺类有机小分子催化剂及其应用 Download PDFInfo
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Abstract
本发明涉及一种手性磺胺类有机小分子催化剂、其合成方法以及在不对称共轭加成反应中的应用。本发明提供了结构通式为(I)的手性磺胺类有机小分子催化剂。本发明提供的式(I)所示手性磺胺类有机小分子催化剂的合成方法是以手性或者非手性胺为原料,在有机碱存在下,与邻苯二酚磺酸酯反应,得到的化合物与等当量的手性胺在溶剂中回流,得到式(I)所示的磺胺类有机小分子催化剂。本发明提供的手性磺胺类有机小分子催化剂能够催化醛、酮与硝基烯烃的不对称共轭加成反应,获得了良好的化学产率和高度的对映选择性。反应具有操作简便、对映选择性高等优点,反应产物可以用于很多手性药物和天然产物的合成中。
Description
技术领域
本发明涉及一类手性磺胺有机小分子催化剂、其合成方法以及在不对称共轭加成反应中的应用,属于不对称合成、催化反应、有机合成领域。
技术背景
有机小分子催化是继金属催化和生物催化之后又一种有效的催化方法。有机小分子催化可以避免使用价格昂贵、毒性较大的金属,不需要无水无氧条件,操作简单易行。该类催化剂可以应用于多种类型的催化反应,底物范围宽,对映选择性高。因此有机小分子催化既避免了金属催化的毒性问题,又克服了生物催化底物范围窄的缺点,具有很高的应用前景。
在酶和有机小分子催化的反应中,普遍通过氢键作用加速反应的进行和控制反应的立体选择性。手性脲和硫脲是近年来发展的两类最重要的氢键给体有机小分子催化剂,Jacobsen研究小组设计合成了多种手性脲和硫脲小分子催化剂用于Strecker反应、nitro-Mannich反应、Michael反应及醛的硅氰化反应等多种不对称催化反应中(J.Am.Chem.Soc.1998,120,4901;Angew.Chem.Int.Ed.2000,39,1279;Angew.Chem.Int.Ed.2005,44,466;J.Am.Chem.Soc.2006,128,7170;Adv,Synth.Catal.2006,348,826),获得了很高的对映选择性和优秀的化学收率。Corey和Grogan应用二环胍类有机小分子催化剂作为双氢给体,催化Strecker反应(OrgLett.1999,1,157)。手性Amidinium和内酰胺类有机小分子催化剂可以作为双氢键给体催化Diels-Alder反应(Org.Lett.2000,2,179)和光诱导环加成反应(Angew.Chem.Int.Ed.2004,43,5849)。尽管如此,手性双氢键给体类催化剂的种类还是非常有限制的,发展新结构的双氢键给体手性有机小分子催化剂和扩展应用的反应类型是今后重要的研究方向。
本发明应用磺胺基团作为新的双氢键给体,通过引入恰当的手性结构,制备了具有良好催化性能的手性磺胺类有机小分子催化剂,在醛、酮与硝基烯烃的共轭加成反应中获得了高度的对映选择性和较好的化学收率,反应产物能够应用于手性药物和天然产物的合成中。
发明概述
本发明提供式(I)所示的手性磺胺类有机小分子催化剂:
式(I)
其中R1为取代或未取代的烷基、取代或未取代的芳香基;R2为氢、取代或未取代的烷基;R3、R4独立地为取代或未取代的烷基、取代或未取代的芳香基;
本发明还提供上述式(I)所示手性磺胺类有机小分子催化剂的合成方法。该合成方法包括如下步骤:
手性或者非手性烷基胺与邻苯二酚磺酸酯在有机碱及DMF存在下,反应2-72小时得到式(II)的化合物;式(II)的化合物与手性胺在溶剂中回流2-4小时得到上述式(1)的化合物。
式(II)
本发明进一步提供上述式(I)所示手性磺胺类有机小分子催化剂在醛、酮与硝基烯烃的不对称共轭加成反应中的应用。
发明详述
本文所用术语有如下定义:
“烷基”表示1-12个碳的饱和或不饱和,直链或支链,取代或未取代的烷烃链,包括甲基、乙基、异丙基、叔丁基、烯丙基、戊基、异戊基、叔戊基、己基、异己基、溴甲基、金刚烷基等。
“芳香基”表示芳香烃类化合物,包括苯基、萘基、取代的苯基、取代的萘基以及杂环芳香基;
“取代的烷基或者取代的芳香基”表示上述的“芳香基”、“烷基”可被任选的卤原子、烷基、烷氧基、杂环、羟基、保护的羟基、甲酰基、酰氧基、氨基、酰胺基、硝基、氰基、酯或者醚等基团取代。
“手性”表示该化合物或取代基具有与其镜像不能重叠的性质,并且是以其中一种对映异构体纯的或者过量的形式存在。
式(I)所示的手性磺胺类有机小分子催化剂可按如下的流程制备:
(1)手性或者非手性烷基胺,有机碱与DMF的二氯甲烷溶液,慢慢滴加邻苯二酚磺酸酯的二氯甲烷溶液,滴加完毕搅拌至反应原料转化完全,酸洗,饱和食盐水洗涤,干燥浓缩,柱层析得到式(II)的化合物;
式(II)
(2)式(II)的化合物与等当量的手性胺在溶剂中反应2-4小时,得到式(I)的化合物。
式(I)
R1为取代或未取代的烷基、取代或未取代的芳香基;R2为氢、取代或未取代的烷基;R3、R4独立地为取代或未取代的烷基、取代或未取代的芳香基,两者也可以联结成环。
其中:
R1代表性的基团可为苯基、硝基苯基、卤代苯基、萘基、金刚烷基、甲胺酰基等;优选为苯基、萘基、甲胺酰基及金刚烷基。
R2代表性的基团可为氢、甲基、乙基、异丙基、叔丁基等;优选为氢、甲基、叔丁基。
R3、R4独立地为取代的烷基、取代或未取代的芳香基,也可以联结构成碳环或杂环;优选为手性的2-氨基环己基、2-乙酰胺基环己基、2-氨基-1,2-二苯基乙基、2-羟基-1,2-二苯基乙基、吡咯烷基等。
步骤(1)中手性或者非手性烷基胺可为苄胺、α-甲基苄胺、硝基取代苄胺、卤素取代苄胺、1-萘甲胺、2-氨基-N,3,3-三甲基丁酰胺或者金刚烷胺;
步骤(1)中有机碱可为三乙胺、二异丙基乙胺、DMAP、DCU、咪唑、吗啡啉、吡啶、哌啶等,优选为三乙胺;
步骤(1)中的反应温度为0-50℃,其中滴加时温度优选为0℃,滴加完后温度优选为20℃;反应时间为2-72小时,优选为24小时;
步骤(2)中手性胺可为(1R,2R)-环己二胺、(1S,2S)-环己二胺、(1R,2S)-1,2-二苯基乙二胺、(S)-3-氨甲基吡咯、(1R,2S)-2-氨基-1,2-二苯基乙醇等;
步骤(2)中反应温度为80-140℃,优选为120℃;反应时间为2-4小时,优选为2.5小时;
本发明(I)式所示手性磺胺类有机小分子催化剂中,代表性的化合物如下:
以下结合实施例对本发明做进一步的阐明,但这些实施例不是对本发明的任何限制。在实施例中,熔点用WRS-2A微机熔点仪测定;NMR用Varian Mercury 300测定,化学位移以δ(ppm)表示;高分辨质谱用(MAT95XP型)磁电双聚焦质谱仪测定。
实施例1
在50mL圆底反应瓶中加入苄胺(214mg,2.0mmol),三乙胺(240mg,1.2mmol),DMF(5mL)和二氯甲烷(20mL)。将反应瓶置于冰浴下搅拌,慢慢滴加邻苯二酚磺酸酯(344mg,2.0mmol)与二氯甲烷(10mL)的溶液,加完后于室温搅拌1天。反应液用1N盐酸洗涤(20mL×3),饱和食盐水洗一次(20mL),有机相用无水Na2SO4干燥。蒸干溶剂后得到粗产物,用柱层析纯化得到N-2-羟基苯基-N’-苄基磺胺556mg,收率99%。
N-2-羟基苯基-N’-苄基磺胺(584mg,2.1mmol),(1R,2R)-环己二胺(274mg,2.4mmol)溶于二氧六环(15mL)中,回流2.5h。冷却至室温,浓缩除去溶剂。加入乙酸乙酯(50mL),有机相分别用水洗(20mL×1),2%氢氧化钠水溶液洗(20mL×3)和饱和食盐水洗(20mL×1)。用无水Na2SO4干燥,浓缩后得到粗产物,用柱层析纯化得到白色固体SA-1(290mg),收率为49%。熔点为148-149℃, (C=2.0,CH3OH)。MS(FAB+):284,154,149,136,115,107,91;1H NMR(300Hz,CD3OD)δ:7.39-7.25(m,5H,Ar-H),4.17(d,J=9.1Hz,2H,CH2),2.81-2.81(m,1H,CH),2.41-2.33(m,1H,CH),2.09-2.06(m,2H,CH2),1.73-1.71(m,2H,CH2),1.30-1.22(m,4H,2CH2);13C NMR(75Hz,CD3OD)δ:136.6,126.7,126.1,112.5,58.1,53.1,45.1,32.0,31.2,23.8,23.2;HRMS(FAB+)(C13H22O2N3S1)[M+H]+:理论值284.1427,实验值284.1425。
实施例2
(S)-α-甲基苄胺(242mg,2.0mmol),三乙胺(254mg,2.5mmol),DMF(5mL)加入50mL反应瓶中,加入DCM(20mL),于冰浴下搅拌。慢慢滴加邻苯二酚磺酸酯(344mg,2.0mmol)与DCM(10mL)的溶液,加完后于室温搅拌1天。反应后处理方式同实施例1,得到N-2-羟基苯基-N’-(1-苯基乙基)磺胺564mg,收率96.2%
N-2-羟基苯基-N’-(1-苯基乙基)磺胺(564mg,1.9mmol),(1R,2R)-环己二胺(200mg,1.9mmol)溶于二氧六环(15mL)中,回流2.5h。反应后处理方式同实施例2,得到白色固体SA-2(200mg),收率38.4%。熔点为115-118℃, (C=2.3,CH3OH)。MS(FAB+):298,280,149,136,115,105,57;1HNMR(300Hz,CD3OD)δ:7.38-7.22(m,5H,Ar-H),4.48(d,1H,J=6.9Hz,CH),2.67-2.64(m,1H,CH),2.28-2.27(m,1H,CH),1.90-1.60(m,4H,CH2),1.49(d,3H,J=6.9Hz,CH3),1.25-1.01(m,4H,2CH2);13C NMR(75Hz,CD3OD)δ:144.6,128.4,127.0,126.1,59.8,54.8,53.6,33.6,32.6,25.3,24.8,24.1;HRMS(FAB+)(C14H24O2N3S1)[M+H]+:理论值298.1584,实验值298.1558。
实施例3
1-萘甲胺(785mg,5.0mmol),三乙胺(600mg,6.0mmol),DMF(10mL)加入50mL反应瓶中,加入DCM(20mL),冰浴下搅拌,称取邻苯二酚磺酸酯(860mg,5.0mmol)溶于DCM(15mL)后慢慢滴加到上述反应液中,加完后于室温搅拌1天。反应后处理方式同实施例1,得到N-2-羟基苯基-N’-1-萘甲基磺胺1.65g,收率100%。
N-2-羟基苯基-N’-1-萘甲基磺胺(666mg,2.0mmol),(1R,2R)-环己二胺(240g,2.1mmol)溶于二氧六环(30mL)中,回流2.5h。反应后处理方式同实施例2,得到白色固体SA-3(311mg),收率46.1%。熔点为150-152℃, (C=2.0,CH3OH)。MS(FAB+):334,307,279,219,205,149,136,115,107,77,57;1H NMR(300Hz,CD3OD)δ:8.19-7.41(m,7H,Ar-H),4.64(q,2H,CH2),2.84-2.81(m,1H,CH),2.44-2.36(m,1H,CH),2.05-1.91(m,2H,CH2),1.69-1.68(m,2H,CH2),1.29-1.15(m,4H,2CH2);13C NMR(75Hz,CD3OD)δ:132.4,131.6,129.9,127.0,126.9,126.7,124.7,124.6,124.1,121.9,57.8,53.2,43.2,31.8,31.2,23.7,23.1;HRMS(FAB+)(C17H24O2N3S1)[M+H]+:理论值334.1584,实验值334.1580。
实施例4
2-氨基-N,3,3-三甲基丁酰胺盐酸盐(540mg,3.0mmol),三乙胺(720mg,7.2mmol),DMF(8mL)加入50mL反应瓶中,加入DCM(15mL),冰浴下搅拌,称取邻苯二酚磺酸酯(516mg,3.0mmol)溶于DCM(12mL)后慢慢滴加到上述反应液中,加完后于室温搅拌1天。反应后处理方式同实施例1,得到(S)-2-羟基苯基-3,3-二甲基-1-甲胺-1-氧丁基-2-磺胺475mg,收率50.1%
(S)-2-羟基苯基-3,3-二甲基-1-甲胺-1-氧丁基-2-磺胺(200mg,0.6mmol),(1R,2R)-环己二胺(72mg,0.6mmol)溶于二氧六环(10mL)中,回流2.5h。反应后处理方式同实施例2,得到白色固体SA-4(100mg),收率52.1%。熔点为101-105℃,MS(ESI):321(M+1);1H NMR(300Hz,CD3OD)δ:3.53(d,1H,J=1.2Hz,CH),2.95-2.87(m,1H,CH),2.72(dd,3H,J1=0.9Hz,J2=3.6Hz,CH3),2.67-2.59(m,1H,CH),2.03-1.98(m,2H,CH2),1.75-1.73(m,2H,CH2),1.29-1.21(m,4H,2CH2),0.97(d,6H,J=0.9Hz,2CH3),0.95(d,3H,J=0.9Hz,CH3).
实施例5
N-2-羟基苯基-N’-苄基磺胺(279mg,1.0mmol),(1R,2R)-2-乙酰胺基-1-环己基胺(114mg,1.0mmol)溶于二氧六环(15mL)中,回流2.5小时。反应后处理方式同实施例2,得到白色固体SA-5(238mg),收率72.3%。熔点为181-182℃, (C=2.0,CH3OH)。MS(FAB+):326,279,149,136,120,91,77,57;1H NMR(300Hz,CD3OD)δ:7.34-7.20(m,5H,Ar-H),4.12(d,2H,J=2.4Hz,CH2),3.61-3.53(m,1H,CH),3.06-3.98(m,1H,CH),2.11-2.08(m,2H,CH2),1.93(s,3H,CH3),1.73-1.71(m,2H,CH2),1.31-1.29(m,4H,2CH);13C NMR(75Hz,CD3OD)δ:170.6,136.5,126.7,126.1,125.6,55.6,51.4,45.1,31.9,30.7,23.3,23.0,20.3;HRMS(FAB+)(C15H24O3N3S1)[M+H]+:理论值326.1533,实验值326.1531。
实施例6
硝基苯乙烯(45mg,0.3mmol),苯甲酸(4mg,0.03mmol),SA-1(17mg,0.06mmol),丙酮(0.5mL)加入到5mL反应瓶中,室温搅拌1d。减压除去溶剂后,用柱层析分离得到5-硝基-4-苯基-2-酮62mg,收率99%,74%ee。MS(EI):207,160,145,104,77,43;1H NMR(300MHz,CDCl3)δ:7.31-7.18(m,5H,Ar-H),4.72-4.55(m,2H,CH2NO2),4.59(dd,1H,J=7.6,12.0Hz,CH2NO2),4.00(t,1H,J=6.9Hz,CH),2.91(d,2H,J=6.9Hz,CH2CO),2.12(s,3H,CH3).
实施例7
硝基苯乙烯(45mg,0.3mmol),三乙胺(4mg,0.03mmol),SA-1(17mg,0.06mmol),丙醛(0.5mL)加入到5mL反应瓶中,室温搅拌8d。减压除去溶剂后,用柱层析分离得到2-甲基-4-硝基-3-苯基丁醛38mg,收率61%,74%ee,66%de。MS(EI):207,160,145,131,117,104,91,77;1HNMR(300MHz,CDCl3)δ:9.71(d,1H,J=1.8Hz,CHO),7.34-7.15(m,5H,Ar-H),4.82-4.65(m,2H,CH2),3.88-3.78(m,1H,CH),2.82-2.76(m,1H,CH),1.01(m,3H,CH3)。
实施例8
硝基苯乙烯(45mg,0.3mmol),二异丙基乙基胺(DIPEA)(8mg,0.6mmol),SA-1(17mg,0.06mmol),异丁醛(0.2mL)加入到5mL反应瓶中,室温搅拌1d。减压除去溶剂后,用柱层析分离得到无色油状物2,2-二甲基-4-硝基-3-苯基丁醛49mg,收率73%,98%ee。 (C=3.0,CHCl3);MS(EI):221,187,170,159,145,117,105,91,77,72;1H NMR(300MHz,CDCl3)δ:9.51(s,1H,CHO),7.24(m,5H,Ar-H),4.85(dd,1H,J=12.9,11.1Hz,CH),4.68(dd,1H,J=12.9,4.2Hz,CH2),3.78(dd,1H,J=11.1,4.2Hz,CH2),1.14(s,3H,CH3),1.01(s,3H,CH3)。
附表:手性磺胺类有机小分子催化剂催化醛与硝基乙烯类化合物的共轭加成反应
Claims (9)
2.根据权利要求1所述的化合物,其中R1、R2中的两个相联结构成碳环或杂环;
3.根据权利要求1所述的化合物,其中R3、R4相联结构成碳环或杂环;优选为R3、R4相联结构成含有取代或未取代氨基的手性烷基;
5.根据权利要求4所述的合成方法,其特征在于手性或者非手性烷基胺为苄胺、α-甲基苄胺、萘甲胺、3-吡咯烷胺、2-氨基-N,3,3-三甲基丁酰胺、金刚烷胺等,优选为苄胺、萘甲胺、2-氨基-N,3,3-三甲基丁酰胺;
6.根据权利要求4所述的合成方法,其特征在于有机碱为三乙胺、二异丙基乙胺、DMAP、DCU、咪唑、吗啡啉、吡啶、哌啶等,优选为三乙胺;
7.根据权利要求4所述的合成方法,其特征在于溶剂为二氧六环;
8.根据权利要求4所述的合成方法,其特征在于手性胺为手性环己二胺、手性二苯基乙二胺、手性吡咯烷基胺、辛可宁、手性2-羟基-1,2-二苯基乙基胺等;
9.根据权利要求1所述的化合物的应用,其特征在于该类化合物能够作为催化剂应用于醛、酮与硝基烯烃的不对称共轭加成反应中。
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