CN107056777A - 基于金鸡纳生物碱骨架的手性胍有机催化剂及其制备方法和应用 - Google Patents

基于金鸡纳生物碱骨架的手性胍有机催化剂及其制备方法和应用 Download PDF

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CN107056777A
CN107056777A CN201710148213.2A CN201710148213A CN107056777A CN 107056777 A CN107056777 A CN 107056777A CN 201710148213 A CN201710148213 A CN 201710148213A CN 107056777 A CN107056777 A CN 107056777A
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cinchona alkaloid
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chiral
guanidine
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CN107056777B (zh
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何炜
袁佳妮
冀楠
刘玉龙
张俊娜
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Fourth Military Medical University FMMU
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Abstract

本发明涉及一种基于金鸡纳生物碱骨架的新型手性胍类化合物及其制备和应用。该类新型手性胍可以用价廉易得的金鸡纳生物碱为原料，通过超声波法制备而得。新型手性胍可作为有机小分子催化剂用于催化不对称Michael加成反应，得到优异的催化效果和优良的对映选择性。

Description

基于金鸡纳生物碱骨架的手性胍有机催化剂及其制备方法和 应用
技术领域
本发明涉及一种基于金鸡纳生物碱骨架的新型手性胍有机催化剂及其在不对称Michael加成反应中的应用，属于有机合成手性催化技术领域。
背景技术
胍是指含有一个碳原子与三个氮原子形成不饱和四价键骨架的一类有机化合物。如果结构中有手性因素的胍即为手性胍。胍类化合物的共轭酸稳定，表现出强碱性，被广泛地应用于有机合成中。尤其是基于手性胍类化合物的有机小分子催化剂结构形式多样，可简单分为开链胍，单环胍，双环胍以及其他的胍盐，这些手性胍不仅在构象上有巨大的差别，在化学特性以及合成中也有差别，它们在不对称催化的过渡态中可以灵活的实现反应底物的活化和产物的构型控制，从而达到非常高的立体选择性和对映选择性。
金鸡纳生物碱类骨架由于具备多个手性中心、刚性的构型、特殊电子效应方面的特征以及分子结构的复杂性等特点，在不对称催化领域早已备受关注，作为不对称催化剂的“优势骨架”，得到了广泛的发展。然而，基于金鸡纳生物碱骨架的手性胍类化合物尚未有国内外文献报道。
发明内容
本发明的目的在于提供一类催化活性高、手性诱导作用强的金鸡纳生物碱衍生的新型双功能手性胍类催化剂及其制备方法，并将其应用于不对称Michacel加成反应；
本发明实现过程如下：
结构通式（I）所示的化合物，
其中，R1和R2独立地选自C1-C6的烷基、环烷基、芳基或取代芳基；
所述芳基选自苯基、苄基、萘基；
所述取代基选自硝基、巯基、卤素、C1-C6的烷基、甲氧基、羟基；
R3选自甲氧基或者氢。
结构通式（I）所示的化合物为：
金鸡纳骨架可以是奎宁、辛克宁、奎尼丁或辛可尼丁，结构如下：
上述化合物的制备方法包括如下步骤：以金鸡纳生物碱原料，在叠氮酸、偶氮二甲酸二异丙酯、三苯基膦条件下生成9-氨基-金鸡纳生物碱；
上述第一步产物与二硫化碳、二环己基碳二亚胺反应生成金鸡纳生物碱异硫氰酸酯；
上述金鸡纳生物碱异硫氰酸酯和胺反应得到金鸡纳生物碱硫脲；
（4）上述金鸡纳生物碱硫脲和相应的伯胺在氯化亚铜、碳酸铯作用下反应得到结构通式（I）所示的化合物，
。
上述制备方法中，可以选用不同的金鸡纳生物碱为原料制得手性胍催化剂，路线相同。
以不同的胺和硫脲反应可以得到各种不同的新型手性胍催化剂。
在硫脲和胺反应这一步，可以采用超声波（500w-850w）作用下，反应温度30-60℃反应，高产率地得到预期产物。
上述化合物在如下反应所示的硫代丙二酸酯和反式-β-硝基苯乙烯的不对称反应中的应用。
式中R1=Me, Et, t-Bu, OMe, CF3等; R2=Ph, 4-MeOPh, n-propyl等; X=O, S；n=1,2。
本发明将超声波辐射法用于合成新型双功能手性胍类化合物，相比较于传统的回流加热法，缩短了反应时间，大大提高了转化率和化学产率。
本发明把金鸡纳生物碱和不同的胺通过胍基连接在一起，构建一种新型的手性胍催化剂，得到既具有胍的碱性强，多氢键的结构特点，又具有金鸡纳生物碱复杂的手性环境，可高效的催化多种不对称反应，是一类全新结构的手性催化剂。本发明将价廉易得的金鸡纳生物碱引入新型双功能手性胍类催化剂，由于设计中引入胍基可提供强碱性和多氢键环境，这类有机催化剂空间位阻和电子效应等精细结构具有很好的可调控性，用于催化不对称反应，可获得高的催化活性和对映选择性。
具体实施方式
下面通过实施例对本发明进行详述，但本发明并不限于这些实施例。
手性胍化合物的合成：以1a, 1b, 1c, 1d, 1e, 1f的合成为例进行详细说明。
实施例1
实施例1 金鸡纳生物碱硫脲1-((S)-(6-methoxyquinolin-4-yl)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)-3-neopentylthiourea的合成
称取奎宁(12 g, 36.98 mmol)和三苯基磷(12.12 g, 46.23 mmol)于250mL锡纸包裹的圆底烧瓶中，加入THF（70 mL），置于0℃低温反应器中，快速加入DIAD（9.16 mL, 46.23mmol)，反应液变黄色透明液体。搅拌五分钟后，继续保持冰浴，向反应液中缓慢滴入叠氮酸的三氯甲烷溶液(65mL, 46.23 mmol)，溶液变为白色浑浊。搅拌过夜，加热至50℃，反应液白色浑浊变为黄色透明液体，搅拌24h。再向反应液中加入三苯基磷(12.12 g, 46.23mmol)，加热至溶液有气泡放出。凉至室温，加入30mL蒸馏水。搅拌24h，旋蒸有机相，用DCM（150 mL）和2M HCl (150 mL)稀释反应液。水相用DCM (50 mL×3)洗涤，2M NaOH调节PH为12，随着NaOH的加入溶液变为白色浑浊，当PH达到12时有黄色油状物析出，用DCM萃取水相，合并有机相，无水硫酸钠干燥过夜，除去溶剂，硅胶柱层析得到棕黄色油状物9-氨基-奎宁(10.5 g, yield 87%).
在-10℃低温反应器中，称取9-氨基-奎宁(6g, 18.55 mmol)的THF(40 mL)溶液中，用恒压滴液漏斗缓慢滴加CS2(6.72 mL, 111.3 mmol)的THF溶液， 一次性加入DCC (3.83g,18.55 mmol)。搅拌过夜，除去溶剂。将粗产物硅胶柱层析纯化，得到淡黄色固体，9-氨基表奎宁异硫氰酸酯(6.5 g, 95%).
称取9-氨基表奎宁异硫氰酸酯（2.5 g, 6.8 mmol）于100 mL圆底烧瓶中，加入新蒸THF，加入（1.25 mL, 10.26 mmol）新戊胺，反应24小时后，TLC检测原料消失，除去溶剂，用二氯甲烷和石油醚重结晶得到2.4 g白色固体9-氨基表奎宁硫脲，产率84%
新型双功能手性胍类催化剂1f 2-((S)-(6-methoxyquinolin-4-yl)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)-1-(4-methylbenzyl)-3-neopentylguanidine的合成
称取氯化亚铜（130 mg，1.3 mmol），碳酸铯（1.56 g, 5.2 mmol）于100 mL烧瓶中，加入新蒸THF，抽真空，补氮气置于超声波清洗仪中，加入9-氨基表奎宁硫脲，超声反应20 min,TLC检查原料点小时，新点生成，加入4-甲基苄胺（0.25 mL, 1,5 mmol），超声反应一个小时，产物生成，加入饱和氯化铵淬灭反应，2 M盐酸调节PH到5，室温搅拌半个小时，用二氯甲烷萃取，合并有机相，硅藻土过滤，用饱和氯化钠洗涤，无水硫酸钠干燥2个小时，除去溶剂，硅胶柱层析，得到白色固体452 mg, 用加入2 M 氢氧化钠10 mL,室温搅拌2小时，分离有机相，二氯甲烷萃取水相，饱和氯化钠洗涤，无水碳酸钾干燥，过滤，除去溶剂得到淡黄色固体590 mg，产率85%。
催化剂1a
白色固体, 产率为80% 。熔点：83.2-86.2℃ [a]D 25 = -79.4 (c = 0.5, CHCl3); 1HNMR(400 MHz, CD3OD) s 8.61(d, J = 3.2 Hz, 1 H), 7.98(d, J = 9.2 Hz, 1 H),7.92(s, 1 H), 7.77(s, 1 H), 7.50(d, J = 9.2 Hz, 1 H), 7.45(s, 1 H), 7.18-7.10(m, 4 H), 5.86-5.77(m, 1 H), 5.34(br s, 1 H), 5.05-4.95(m, 2 H), 4.00(s, 3H),3.93(s, 1 H), 3.78(d, J = 9.6 Hz, 1 H), 3.53(t, J = 9.6 Hz, 1 H), 3.32-3.24(m, 3 H), 2.89-2.81(m, 3 H), 2.62-2.49(m, 3 H), 2.33(s, 1 H), 1.65(s, 4H), 1.37-1.30(m, 3 H), 1.02-0.87(m, 1 H), 0.28(s, 9 H) ppm; 13C NMR(400MHz ,CD3OD):s159.77, 156.57, 148.44, 145.28, 145.25, 142.95, 140.02, 131.80,130.19, 129.59, 127.50, 123.42, 114.95, 67.78, 59.24, 56.71, 56.55, 55.43,42.04, 41.10, 38.58, 32.33, 29.01, 26.55 ppm;IR (KBr): ν 3232, 3174, 3070,2931, 2866, 1620, 1508, 1473, 1434, 1353, 1080, 1029, 914, 736, 702cm-1; HRMScalcd for C35H47N5O2, ([M+H+]) ：570.3803；found：570.3798
催化剂1b
白色固体, 产率为77%，熔点：83.6-86.8℃ [a]D 25 = -89.6 (c = 0.5, CHCl3);1HNMR(400 MHz, CD3OD) s 8.65(d, J = 4.4 Hz, 1 H), 7.97(d, J = 9.2 Hz, 1 H),7.70(s, 1 H), 7.56(d, J = 4.4 Hz, 1 H), 7.47(d, J = 9.2 Hz, 1 H), 7.29-7.25(m, 2 H), 7.22-7.17(m, 3 H), 5.83-5.75(m, 1 H), 5.05(br s, 1 H), 5.03-4.95(m,2 H), 3.97(s, 3 H),3.80(s, 1 H), 3.59-3.55(m, 1 H), 3.43-3.38(m, 1 H), 3.27-3.21(m, 3 H), 3.06(s, 1 H), 2.84-2.81(m, 2 H), 2.69-2.64(m, 3 H), 2.32(br s,1 H), 1.61(s, 4 H), 1.28(s, 2 H), 0.99-0.89(m, 2 H), 0.52(s, 9 H) ppm; 13C NMR(400MHz , CD3OD):s 160.8, 158.2, 146.9, 143.6, 141.1, 137.6, 130.0, 129.0,127.5，122.1, 113.6, 102.4, 71.4, 64.3, 55.1, 54.9, 53.4, 41.7, 40.5, 39.2,27.3, 27.2, 26.1, 25.9, 25.0 ppm; IR (KBr): ν 3321 , 2947, 2862, 1620, 1508,1473, 1454, 1357, 1242, 1226, 1033, 914, 829, 736, 702cm-1; HRMS calcd forC35H47N5O2 ([M+H+]) 570.3803；found：570.3795
催化剂1c
淡黄色固体，产率为90%， 熔点：71.2-74.1℃[a]D 25 = -90.0 (c = 0.5, CHCl3); 1HNMR(400 MHz, CD3OD) s 8.59(d, J = 4.8 Hz, 1 H), 7.96 (d, J = 9.2 Hz, 1 H),7.76(s, 1 H), 7.47-7.43(m, 2 H), 7.04(s, 2 H), 6.89(t, J = 8.4 Hz, 2 H),5.78-5.69(m, 1 H), 5.24-5.17(m, 1 H), 4.99-4.91(m, 2 H), 4.30-4.19(q, J =15.6 Hz, 2 H), 3.91(s, 3 H), 3.20-3.14(m, 1 H), 3.06(br s, 2 H), 2.93-2.84(m,1 H), 2.71(d, J = 12.8 Hz, 2 H), 2.61-2.54 (m, 1 H), 2.28(br s, 1 H), 1.66-1.60(m, 3 H), 1.30-1.24(m, 1 H), 1.17(t, J = 6.8 Hz, 1 H),1.07-0.97(m, 2 H),0.80(s, 1 H), 0.47(s, 9 H) ppm; 13C NMR(400MHz , CD3OD): s 164.45, 162.04,159.65, 155.35, 148.35, 148.27, 148.22, 148.18, 145.31, 142.82, 142.68,138.08, 131.69, 130.14, 123.43, 116.05, 115.84, 103.74, 56.75, 56.42, 55.52,41.74, 41.09, 32.72, 28.97, 27.61, 26.53 ppm; IR (KBr): ν 3309, 2947, 2866,1643, 1620, 1508, 1473, 1357, 1226, 1153, 1080, 1033, 991, 914, 852, 829, 736cm-1; HRMS calcd for C33H42FN5O ([M+H+]) 544.3466；found：544.3452
催化剂1d
淡黄色固体，产率为87%，熔点：68.2-70.6℃ [a]D 25 = -99.0 (c = 0.5, CHCl3); 1HNMR(400 MHz, CD3OD) s 8.67(d, J = 4.8 Hz, 1 H), 8.00 (d, J = 9.6 Hz, 1 H),7.79(s, 1 H), 7.66(d, J = 4.4 Hz, 1 H), 7.51-7.48(dd, J 1 = 2.4 Hz, J 2 = 9.2Hz, 1 H), 5.86-5.77(m, 1 H), 5.28-5.27(m, 1 H), 5.05-4.95(m, 2 H), 4.02(s, 3H), 3.53-3.48(q, J = 7.2 Hz, 1 H), 3.40-3.36(m, 1 H), 3.32-3.27(m, 2 H),2.88-2.84(m, 2 H), 2.70(d, J = 13.2Hz, 1 H), 2.37(br s, 1 H), 1.90 (d, J =12Hz, 1 H), 1.75-1.60(m, 7 H), 1.39-0.96(m, 4 H), 0.48(s, 9 H) ppm; 13C NMR(400MHz , CD3OD): s 158.17, 153.02, 146.87, 143.84, 141.31, 130.27, 128.57,121.82, 113.55, 102.25, 55.27, 54.95, 54.80, 51.82, 40.48, 39.58, 33.59,31.49, 27.48, 26.13, 25.22, 25.10, 24.25 ppm; IR (KBr): ν 3328, 3074, 2931,2858, 1650, 1620, 1508, 1473, 1357, 1242, 1226, 1130, 1080, 1033, 987, 914,852, 736 cm-1;
HRMS calcd for C32H47N5O([M+H+]):518.3853；found：518.3848
催化剂1e
淡黄色固体， 产率为86%，熔点：68.2-71.4℃[a]D 25 = -103 (c = 0.5, CHCl3); 1HNMR(400 MHz, CD3OD) s 8.56(d, J = 4.4 Hz, 1 H), 7.95(d, J = 9.2 Hz, 1 H),7.74(s, 1 H), 7.43(d, J = 9.2 Hz, 1 H), 7.31(s, 1 H), 7.27(d, J = 8.0 Hz, 2H), 7.03(d, J = 7.2 Hz, 2 H), 5.77-5.68(m, 1 H), 5.20(br s, 1 H), 4.97(d, J =17.2 Hz, 1 H), 4.89(s, 1 H), 4.33-4.23(m, 2 H), 3.90(s, 3 H), 3.18-3.12(m, 1H), 3.02(br s, 2 H), 2.90(d, J = 12.8 Hz, 1 H), 2.74-2.65(m, 2 H), 2.56-2.50(m, 1 H), 2.27(brs, 1 H), 1.67-1.59( m, 3 H), 1.31(s, 9 H), 1.29-1.22(m, 2H), 1.05-0.97(m, 1 H), 0.40(s, 9 H) ppm; 13C NMR(400MHz , CD3OD): s 180.23,170.26, 160.22, 156.10, 152.56, 148.46, 145.42, 142.47, 134.73, 133.78,133.05, 132.28, 129.94, 128.40, 126.99, 123.59, 115.15, 102.96, 60.18, 56.49,56.17, 54.06, 41.36, 40.81, 35.50, 32.57, 31.82, 28.63, 24.33, 22.31, 14.73ppm; IR (KBr): ν 3433, 3305, 2950, 2866, 1650, 1620, 1508, 1473, 1361, 1226,1134, 1080, 1033, 987, 914, 852, 736, 617 cm-1; HRMS calcd for C37H51N5O ([M+H+])：582.4166；found：582.4175
催化剂1f
白色固体，产率为87%， [a]D 25 = -105.0 (c = 0.5, CHCl3); 1H NMR(400 MHz,CD3OD)：s 8.54(d, J = 4.4 Hz, 1 H), 7.94 (d, J = 9.6 Hz, 1 H), 7.73(s, 1 H),7.43-7.40(dd, J = 2.8 Hz, 9.2 Hz, 1 H), 7.34(d, J = 4 Hz, 1 H), 7.03-6.97(m,4 H), 5.76-5.68(m, 1 H), 5.19(brs, 1 H), 4.96(d, J = 13.6 Hz, 1 H), 4.88(s, 1H), 4.30-4.19(q, J = 15.6 Hz, 2 H), 3.90(s, 3 H), 3.18-3.12(m, 1 H), 3.09(brs, 1 H),2.99(s, 1 H), 2.88(d, J = 12.8 Hz, 1 H), 2.72-2.65 (m, 2 H), 2.59-2.52(m, 1 H), 2.30(s, 3 H), 1.64-1.58(m, 3 H), 1.27-1.15(m, 2 H), 1.04-0.96(m, 2 H),0.42(s, 9 H) ppm; 13C NMR(400MHz , CD3OD): s 159,57, 155.28, 148.27,145.27, 142.84, 138.95, 137.49, 131.58, 130.17, 130.06, 128.38, 123.40,114.92, 103.65, 56.74, 56.34, 55.80, 41.72, 41.09, 32.65, 28.97, 27.54,26.52, 21.24 ppm IR (KBr): ν 3440, 3317, 2939, 2862, 1635, 1620, 1504, 1473,1353, 1253, 1226, 1134, 1080, 1033, 987, 914, 852, 736, 617 cm-1;
HRMS：C34H45N5O calcd for ([M+H+]): 540.3697; found:540.3703
应用实例
本发明的新型手性胍催化剂在不对称Michael反应中的应用：
称取0.2 mmol的丙二酸二硫酚酯和0.2 mmol的反式硝基苯乙烯于10ml具塞反应试管，加入5% mol 的手性胍催化剂，加入2mL 的对二甲苯，20℃下搅拌5小时，反应结束后经快速柱层析分离得到Michael反应产物（产率90%），95% ee。1H NMR( CDCl3, 400MHz) δ: 7.43-7.35(m, 9H), 7.19-7.16(m, 4H), 6.87(d, J = 8.8 Hz, 2H), 4.81-4.79(m, 2H),4.45(d, J = 9.6 Hz, 1 H), 4.38-4.32(m, 1H), 3.79(s, 3H)， ee 值由手性HPLC测定。HPLC分析（OD-H column, = 214 nm, eluent: n-hexane/i-propanol=70/30, 流速:1.0mL /min）；tR = 18.37(major), 27.57(minor)。
表1. 与实施例1相同条件下以奎宁骨架为例手性胍化合物的合成

Claims (4)

1.结构通式（I）所示的化合物，
其中，R1和R2独立地选自C1-C6的烷基、环烷基、芳基或取代芳基；
所述芳基选自苯基、苄基、萘基；
所述取代基选自硝基、巯基、卤素、C1-C6的烷基、甲氧基、羟基；
R3选自甲氧基或者氢。
2.根据权利要求1所述的化合物，其特征在于结构通式（I）所示的化合物为：
。
3.权利要求1所示化合物的制备方法，包括如下步骤：以金鸡纳生物碱原料，在叠氮酸、偶氮二甲酸二异丙酯、三苯基膦条件下生成9-氨基-金鸡纳生物碱；
上述第一步产物与二硫化碳、二环己基碳二亚胺反应生成金鸡纳生物碱异硫氰酸酯；
上述金鸡纳生物碱异硫氰酸酯和胺反应得到金鸡纳生物碱硫脲；
（4）上述金鸡纳生物碱硫脲和相应的伯胺在氯化亚铜、碳酸铯作用下反应得到结构通式（I）所示的化合物，
。
4.权利要求1所示化合物作为双功能手性胍催化剂在Michael加成中的应用。
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