CN118271228A - 一种手性吲哚甘氨酸衍生物的合成方法 - Google Patents
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Abstract
本发明提供了一种手性吲哚甘氨酸衍生物的合成方法,所述方法包括以下步骤:以吲哚衍生物A和叔丁基亚磺酰亚胺B为原料,在路易斯酸催化剂作用下的发生傅克烷基化反应,制得手性吲哚甘氨酸衍生物C。本发明所提供的硼催化傅克烷基化反应反应条件温和,步骤简单、易操作,区域选择性高,立体选择性高,且以较高的收率得到一类之前方法难以得到手性吲哚甘氨酸衍生物,适用于工业化生产,因此,在合成上,尤其是在生物碱类天然产物的合成上具有很好的应用前景。
Description
技术领域
本发明涉及有机化工领域,特别涉及一种吲哚氨基酸衍生物的合成方法。
技术背景
吲哚甘氨酸衍生物是重要的天然产物和药物合成中间体,例如,吲哚甘氨酸被成功用于dragmacidins(Organic Letters,2000,2,3027.)和hamacanthins(Tetrahedron,2005,61,2309.)等多种吲哚生物碱的合成。因此,发展新的技术方法来合成吲哚甘氨酸衍生物具有重要研究意义。
吲哚3-位C-H和甘氨酸衍生物氮的a-位C-H之间在金属氧化剂催化下发生交叉脱氢偶联直接构筑吲哚甘氨酸衍生物(CN 106316920 B;CN 106478485 B)是目前常用的方法之一。此外,吲哚和亚胺通过金属催化的曼尼希型傅克(Mannich-type Friedel-Crafts)反应得到(Chemical Communications,2010,46,1550;Journal ofOrganic Chemistry,2016,81,9227.)手性吲哚甘氨酸衍生物的方法由于其反应高效,手性选择性高,被广泛用于手性吲哚甘氨酸的构建。
然而,已有的交叉脱氢偶联方法和传统的曼尼希型傅克反应往往需要使用铜、锌等金属催化剂,或需要使用到强氧化剂、钌或铱作为光敏催化剂,其中,铜、锌等金属催化剂容易存在金属残留问题,钌等光敏催化剂价格昂贵,并且强氧化剂的使用存在一定安全隐患。因此,上述合成方法还存在一定局限。
发明内容
为克服以上现有技术中存在的缺陷与不足,本发明旨在利用硼催化傅克烷基化反应,提供一种简单、高区域选择性和高立体选择性的手性吲哚甘氨酸衍生物构建方法。
本发明的技术方案是合成路线如下:
并且,所述方法包括以下步骤:
以化合物A和叔丁基亚磺酰亚胺B为起始原料,在路易斯酸催化剂作用下的发生傅克烷基化反应,制得手性吲哚甘氨酸衍生物C。
根据上述合成方法,可制备的化合物的结构通式为C:
并且,所述结构通式C具有以下特点:
(1)R为芳香胺,脂肪胺,烷氧基,烷基,芳烃基,杂环芳烃基;
(2)R1、R2和R3为碳环或杂环,或者R1、R2和R3各自独立选自:H,烷基,酯基,卤素,烯基,硝基,炔基,烷氧基,芳烃基,烷氧基,芳烃基,杂环芳烃基;
(3)化合物中叔丁基可以替代为2,4,6-三甲基苯基(Mes)、甲基苯基(Tol)、苯基(Ph)或异丙基(i-pr);
(4)亚磺酰基的构型是R或S。
优选地,通式C中:
(1)R可优选为芳香胺和脂肪胺;
(2)取代基R1可优选为H,烷基,卤素,烷氧基,酯基,硝基;
(3)取代基R2可优选为H,烷基,芳烃基;
(4)取代基R3可优选为H,烷基。
优选地,所述化合物合成方法包括以下步骤:
将化合物A溶于溶剂中,依次加入叔丁基亚磺酰亚胺B,路易斯酸催化剂反应,后处理,制得目标产物C。
优选地,在上述合成方法中,步骤为:
将化合物A溶于乙腈中,依次加入叔丁基亚磺酰亚胺B和路易斯酸催化剂反应,在-78℃-100℃反应,后处理,制得目标产物C。
优选地,在上述合成方法中,步骤为:
将化合物A溶于乙腈中,依次加入叔丁基亚磺酰亚胺B和路易斯酸催化剂反应,在0℃反应0.5-3小时,后处理,制得目标产物C。
优选地,所述路易斯酸催化剂可优选为B(C6F5)3。
另外,在上述合成方法中,反应步骤中所述的“后处理”均为本领域技术人员根据本步反应条件做出的合理后处理,这些后处理旨在除去反应杂质与溶剂,并在一定程度上保证获得纯净产物。
可选地,步骤中的后处理指的是:反应完毕后,向反应液中加入饱和食盐水,用乙酸乙酯萃取3次,合并有机相经无水硫酸钠干燥,抽滤、浓缩后用快速柱层析分离,即得目标产物C。
有益效果:本发明所提供的硼催化傅克烷基化反应反应条件温和,步骤简单、易操作,区域选择性高,立体选择性高,且以较高的收率得到一类之前方法难以得到手性吲哚甘氨酸衍生物,适用于工业化生产,因此,在合成上,尤其是在生物碱类天然产物的合成上具有很好的应用前景。
附图说明
图1是化合物C1的H谱核磁数据图;
图2是化合物C1的C谱核磁数据图;
图3是化合物C2的H谱核磁数据图;
图4是化合物C2的C谱核磁数据图;
图5是化合物C3的H谱核磁数据图;
图6是化合物C3的C谱核磁数据图;
图7是化合物C4的H谱核磁数据图;
图8是化合物C4的C谱核磁数据图;
图9是化合物C5的H谱核磁数据图;
图10是化合物C5的C谱核磁数据图;
图11是化合物C6的H谱核磁数据图;
图12是化合物C6的C谱核磁数据图;
图13是化合物C7的H谱核磁数据图;
图14是化合物C7的C谱核磁数据图;
图15是化合物C7的F谱核磁数据图;
图16是化合物C8的H谱核磁数据图;
图17是化合物C8的C谱核磁数据图;
图18是化合物C9的H谱核磁数据图;
图19是化合物C9的C谱核磁数据图;
图20是化合物C10的H谱核磁数据图;
图21是化合物C10的C谱核磁数据图;
图22是化合物C11的H谱核磁数据图;
图23是化合物C11的C谱核磁数据图;
图24是化合物C12的H谱核磁数据图;
图25是化合物C12的C谱核磁数据图;
图26是化合物C13的H谱核磁数据图;
图27是化合物C13的C谱核磁数据图;
图28是化合物C14的H谱核磁数据图;
图29是化合物C14的C谱核磁数据图;
图30是化合物C15的H谱核磁数据图;
图31是化合物C15的C谱核磁数据图;
图32是化合物C16的H谱核磁数据图;
图33是化合物C16的C谱核磁数据图;
图34是化合物C17的H谱核磁数据图;
图35是化合物C17的C谱核磁数据图;
图36是化合物C17的F谱核磁数据图;
图37是化合物C18的H谱核磁数据图;
图38是化合物C18的C谱核磁数据图;
图39是化合物C19的H谱核磁数据图;
图40是化合物C19的C谱核磁数据图;
图41是化合物C20的H谱核磁数据图;
图42是化合物C20的C谱核磁数据图;
图43是化合物C21的H谱核磁数据图;
图44是化合物C21的C谱核磁数据图;
图45是化合物C22的H谱核磁数据图;
图46是化合物C22的C谱核磁数据图;
图47是化合物C22的F谱核磁数据图;
图48是化合物C23的H谱核磁数据图;
图49是化合物C23的C谱核磁数据图;
图50是化合物C24的H谱核磁数据图;
图51是化合物C24的C谱核磁数据图。
具体实施方式
下面的实施实例是对本发明的进一步说明,而不是限制本发明的范围。本发明的第一方面,提供了一种硼催化傅克烷基化反应构建手性吲哚甘氨酸衍生物的方法,其合成路线如下:
并且,所述合成方法包括以下步骤:
以化合物A和叔丁基亚磺酰亚胺B为起始原料,在路易斯酸催化剂作用下的发生傅克烷基化反应,制得手性吲哚甘氨酸衍生物C。
本发明的第二方面,提供了一类新型手性吲哚甘氨酸衍生物C,该新型手性吲哚甘氨酸衍生物是根据本发明第一方面所述的合成方法制得的目标产物C。
实例1:化合物C1的合成
操作步骤:在圆底烧瓶中,向化合物A1(0.14g,1.20mmol)和B(C6F5)3(0.06g,0.12mmol)在MeCN(5mL)中的混合物中加入B1(0.27g,1.00mmol),在氩气环境中,将其冷却至0℃。经过0.5小时,底物完全消耗后(通过TLc分析监测),用水(20mL)洗涤反应混合物,用乙酸乙酯(3x20mL)萃取混合物。将合并的有机相用Na2SO4干燥,并在真空中浓缩。残留物在硅胶(石油醚∶乙酸乙酯=1∶3)上通过快速柱色谱法纯化得红棕色油状化合物C1(329mg,86%yield):[α]D 20=+127.5(c 0.5,MeOH).IR(KBr)Vmax:3441,3281,3052,2962,2914,2878,1645,1573,1537,1452,1362,1259,1061,929,748,682cm-1.1H NMR(400MHz,Chloroform-d)δ9.67(s,1H),7.52(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7.13(q,J=6.6,6.0Hz,5H),7.08–6.98(m,3H),6.59(t,J=6.1Hz,1H),5.19–5.15(m,1H),5.05(s,1H),4.30(qd,J=15.1,5.8Hz,2H),1.11(s,9H).13C NMR(100MHz,Chloroform-d)δ171.2,137.7,137.2,128.6,127.4,126.4,125.2,122.6,119.9,112.0,110.0,55.6,54.7,43.7,22.7.HRMS(ESI)calculated for C21H26N3O2S+[M+H]+:384.1740,found 384.1742.
实例2:化合物C2的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得黄色油状产物C2(134mg,90%yield):[α]D 20=-1329.76(c 0.1,MeOH).IR(KBr)Vmax:3552,3287,2950,2908,2866,1783,1722,1705,1638,1548,1500,1440,1422,1368,1319,1254,1037,905,802,748,700,598cm-1.1H NMR(400MHz,Chloroform-d)δ8.49–8.40(m,1H),7.45(d,J=8.1Hz,1H),7.23–7.15(m,5H),7.07(dd,J=7.2,2.4Hz,2H),6.93(dd,J=8.2,1.4Hz,1H),6.24–6.13(m,1H),5.22(d,J=1.7Hz,1H),5.02(d,J=1.8Hz,1H),4.48(dd,J=15.0,6.3Hz,1H),4.30(dd,J=15.1,5.7Hz,1H),2.45(s,3H),1.18(s,9H).13C NMR(100MHz,Chloroform-d)δ170.8,137.7,137.5,132.8,128.6,127.4,125.4,122.9,122.0,119.8,111.6,110.5,55.4,54.3,43.8,22.7,21.7.HRMS(ESI)calculated for C22H28N3O2S+[M+H]+:398.1897,found 398.1899.
实例3:化合物C3的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得浅黄色油状产物C3(137mg,92%yield):[α]D 20=+62.90(c0.1MeOH).IR(KBr)Vmax:3552,3245,3112,3058,2950,2920,2860,1855,1711,1645,1513,1458,1362,1344,1265,1103,1025,905,748,694,598cm-1.1H NMR(400MHz,Chloroform-d)δ8.78(s,1H),7.31(d,J=2.6Hz,1H),7.23(td,J=5.0,1.9Hz,3H),7.16–7.04(m,3H),6.89(d,J=7.1Hz,1H),6.19(s,1H),5.27(s,1H),5.16(s,1H),4.56(dd,J=14.9,6.5Hz,1H),4.26(dd,J=14.9,5.5Hz,1H),2.50(s,3H),1.19(s,9H).13C NMR(100MHz,CDCl3)δ171.7,137.6,131.0,128.6,127.6,127.5,124.4,123.0,122.1,109.3,55.3,54.5,43.8,22.7,20.8.HRMS(ESI)calculated for C22H28N3O2S+[M+H]+:398.1898,found 398.1897.
实例4:化合物C4的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得浅黄色油状产物C4(134mg,86%yield):[α]D 20=+77.10(c0.04MeOH).IR(KBr)Vmax:3554,3292,2947,2918,2857,2820,1788,1720,1639,1550,1502,1444,1424,1369,1323,1257,1039,903,700,598cm-1.1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),7.29(s,1H),7.25–7.18(m,4H),7.12–7.08(m,2H),7.04(t,J=7.9Hz,1H),6.68(d,J=7.7Hz,1H),6.25(t,J=6.0Hz,1H),5.25(d,J=1.8Hz,1H),5.05(d,J=1.8Hz,1H),4.48(dd,J=15.1,6.1Hz,1H),4.34(dd,J=15.1,5.8Hz,1H),3.95(s,3H),1.20(s,9H).13C NMR(100MHz,CDCl3)δ170.8,146.3,137.7,128.6,127.6,127.4,126.5,125.3,120.7,112.7,111.2,102.6,55.4,55.3,54.2,43.7,22.7.HRMS(ESI)calculated for C22H28N3O3S+[M+H]+:414.1846,found 414.1847.
实例5:化合物C5的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得浅黄色油状产物C5(104mg,63%yield):[α]D 20=-1102.94(c 0.1,MeOH).IR(KBr)Vmax:3438,2956,2842,1782,1627,1513,1446,1079,1013,872,795cm-1.1HNMR(400MHz,Chloroform-d)δ9.87–9.77(m,1H),8.11(d,J=1.4Hz,1H),7.73(dd,J=8.5,1.4Hz,1H),7.55(d,J=8.4Hz,1H),7.37(d,J=2.6Hz,1H),7.16(dd,J=5.2,1.9Hz,3H),7.04(dd,J=6.9,2.7Hz,2H),6.55(t,J=6.1Hz,1H),5.21(d,J=2.7Hz,1H),5.04(d,J=2.8Hz,1H),4.35(d,J=6.0Hz,2H),3.89(s,3H),1.13(s,9H).13C NMR(100MHz,Chloroform-d)δ170.7,168.0,137.5,136.4,129.4,128.7,128.6,127.5,127.4,124.3,120.9,119.4,114.4,110.8,55.7,54.6,52.0,43.8,22.7.HRMS(ESI)calculated for C23H28N3O4S+[M+H]+:442.1795,found 442.1798.
实例6:化合物C6的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得黄绿色固体产物C6(117mg,73%yield):[α]D 20=+65.3(c 0.005,MeOH).IR(KBr)Vmax:3448,2962,2934,2867,2822,1798,1742,1713,1550,1463,1452,1368,1335,1263,1021,896cm-1.1H NMR(400MHz,Chloroform-d)δ9.43(s,1H),8.26(d,J=2.0Hz,1H),7.90(dd,J=9.0,2.0Hz,1H),7.54(d,J=8.8Hz,1H),7.47(d,J=2.6Hz,1H),7.19(s,2H),7.17–7.14(m,4H),7.05–7.01(m,2H),6.21(s,1H),5.18(d,J=2.4Hz,1H),4.93(s,1H),4.35(qd,J=14.8,5.9Hz,2H),1.12(s,9H).13C NMR(100MHz,CDCl3)δ169.9,143.9,137.3,135.5,131.2,129.8,128.7,127.7,127.5,120.0,115.6,108.7,55.8,54.1,44.0,22.7.HRMS(ESI)calculated for C21H25N4O4S+[M+H]+:429.1591,found 429.1593.
实例7:化合物C7的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得浅黄色油状产物C7(131mg,87%yield):[α]D 20=+43.60(c 0.005,MeOH).IR(KBr)Vmax:3454,2954,2921,2847,1660,1641,1611,1531,1459,1316,1278,1028,888,808,756,685,584cm-1.1H NMR(400MHz,Chloroform-d)δ9.37–9.30(m,1H),7.24–7.18(m,3H),7.16–7.09(m,5H),7.01(dd,J=7.4,2.1Hz,2H),6.86(td,J=9.0,2.5Hz,1H),6.33(t,J=6.0Hz,1H),5.09(d,J=2.1Hz,1H),4.94(d,J=2.1Hz,1H),4.31(dd,J=8.1,6.0Hz,2H),1.10(s,9H).13C NMR(100MHz,CDCl3)δ170.8,146.3,137.7,128.6,127.6,127.4,126.5,125.3,120.7,112.7,111.2,102.6,55.4,55.3,54.2,43.7,22.7.19F NMR(376MHz,CDCl3)δ-123.5.HRMS(ESI)calculated for C21H24FN3O2S+[M+H]+:402.1647,found402.1648.
实例8:化合物C8的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C8(142mg,82%yield):[α]D 20=+63.4(c 0.005,MeOH).IR(KBr)Vmax:3456,3264,2957,2929,2840,1662,1648,1619,1558,1526,1459,1329,1236,1030,884,801,752,689,581cm-1.1H NMR(400MHz,Chloroform-d)δ9.16(s,1H),7.64(d,J=1.8Hz,1H),7.23–7.12(m,6H),7.09(d,J=2.5Hz,1H),7.04–7.00(m,2H),6.26(t,J=6.0Hz,1H),5.07(d,J=2.1Hz,1H),4.92(s,1H),4.35–4.30(m,2H),1.11(s,9H).13C NMR(150MHz,CDCl3)δ170.4,137.5,135.7,128.7,127.5,127.4,127.3,126.7,125.8,122.7,113.5,113.3,109.9,55.7,54.4,43.8,22.7.HRMS(ESI)calculated forC21H25BrN3O2S+[M+H]+:462.0845,found 462.0847.
实例9:化合物C9的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得淡黄色油状产物C9(144mg,83%yield):[α]D 20=-1096.23(c 0.1,MeOH).IR(KBr)Vmax:3452,3263,2956,2920,2842,1657,1645,1614,1554,1524,1458,1326,1235,1025,886,802,754,688,580cm-1.1H NMR(400MHz,Chloroform-d)δ9.11(s,1H),7.53(d,J=1.7Hz,1H),7.40(d,J=8.5Hz,1H),7.24–7.13(m,5H),7.06(dd,J=7.2,2.4Hz,2H),6.29(t,J=5.9Hz,1H),5.17(d,J=2.0Hz,1H),5.00(d,J=2.1Hz,1H),4.38(qd,J=15.0,6.0Hz,2H),1.17(s,9H).13C NMR(100MHz,CDCl3)δ170.5,137.9,137.5,128.6,127.5,127.4,126.7,123.9,123.5,121.2,116.5,114.8,110.7,55.6,54.3,43.8,22.7.HRMS(ESI)calculated for C21H25BrN3O2S+[M+H]+:462.0845,found 462.0848.
实例10:化合物C10的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得淡黄色固体产物C10(124mg,79%yield):[α]D 20=+258.25(c0.04,MeOH).IR(KBr)Vmax:3460,2957,2840,1662,1648,1618,1559,1524,1452,1235,801,752,689cm-1.1HNMR(400MHz,Chloroform-d)δ8.97(s,1H),7.39(d,J=7.9Hz,1H),7.26(d,J=2.5Hz,1H),7.15–7.10(m,4H),6.99(dd,J=6.9,2.5Hz,2H),6.94(t,J=7.8Hz,1H),6.24(t,J=5.9Hz,1H),5.14(d,J=2.0Hz,1H),4.95(d,J=2.0Hz,1H),4.30(qd,J=15.0,5.9Hz,2H),1.08(s,9H).13CNMR(150MHz,CDCl3)δ170.3,137.5,134.2,128.5,127.4,127.3,126.5,126.5,122.2,120.9,118.7,117.0,111.9,55.5,54.1,43.7,22.6.HRMS(ESI)calculated for C21H25ClN3O2S+[M+H]+:418.1351,found 418.1354.
实例11:化合物C11的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得淡黄色固体产物C11(124mg,79%yield)as a pale yellowsolid:[α]D 20=+42.25(c 0.02,MeOH).IR(KBr)Vmax:.3454,2840,1663,1652,1556,1522,1452,1233,800,764,752,689cm-1.1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),7.54(s,1H),7.36(s,1H),7.20–7.12(m,4H),7.06(s,1H),7.03–6.99(m,2H),6.31(t,J=6.0Hz,1H),5.03(s,1H),4.91(s,1H),4.32–4.28(m,2H),1.10(s,9H).13C NMR(150MHz,CDCl3)δ170.3,137.4,135.8,128.7,128.1,127.4,126.8,124.7,120.9,113.4,109.9,55.8,54.3,43.9,22.7.HRMS(ESI)calculated for C20H22Cl2N3O2S+[M+H]+:451.0888,found 451.0890.
实例12:化合物C12的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得淡黄色油状产物C12(193mg,87%yield):[α]D 20=+82.22(c 0.2,MeOH).IR(KBr)Vmax:3317,3209,3041,2944,2848,2757,1645,1524,1446,1416,1410,1362,1265,1194,1103,1079,1013,965,941,869,778,736,712,646,586,550cm-1.1H NMR(400MHz,Chloroform-d)δ9.01(s,1H),7.20(d,J=6.4Hz,3H),7.14(d,J=8.7Hz,1H),7.09–7.04(m,2H),6.87(d,J=2.6Hz,1H),6.74(dd,J=8.8,2.4Hz,1H),6.35(t,J=6.1Hz,1H),5.18(s,1H),5.00(s,1H),4.52–4.20(m,2H),3.67(s,3H),2.31(s,3H),1.16(s,9H).13CNMR(100MHz,CDCl3)δ171.1,154.1,137.8,137.0,130.7,128.6,127.4,127.4,126.9,111.7,111.6,105.1,100.9,55.7,55.2,52.8,43.7,22.7,22.1,11.7.HRMS(ESI)calculated for C23H30N3O3S+[M+H]+:428.2002,found 428.2004.
实例13:化合物C13的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得淡黄色油状产物C13(139mg,93%yield):[α]D 20=-511(c 0.2,MeOH).IR(KBr)Vmax:3419,3293,3058,2968,2908,2854,1651,1560,1518,1464,1404,1344,1326,1235,1151,1049,892,808,736,694,586cm-1.1H NMR(400MHz,Chloroform-d)δ7.57(d,J=8.0Hz,1H),7.31(d,J=8.2Hz,1H),7.25(d,J=2.3Hz,1H),7.23–7.17(m,3H),7.16(s,1H),7.13–7.05(m,3H),6.30(t,J=6.0Hz,1H),5.22(d,J=2.1Hz,1H),5.02(d,J=2.1Hz,1H),4.45(dd,J=15.0,6.1Hz,1H),4.31(dd,J=15.0,5.9Hz,1H),3.75(s,3H),1.16(s,9H).13CNMR(100MHz,CDCl3)δ170.9,137.8,137.7,130.3,128.6,127.4,127.4,125.7,122.5,120.3,119.9,109.7,109.2,55.4,54.2,43.7,32.9,22.7.HRMS(ESI)calculatedfor C22H28N3O2S+[M+H]+:398.1897,found 398.1899.
实例14:化合物C14的合成
使用化合物C1所示步骤,以化合物B1(0.10g,0.38mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得白色固体产物C14(141mg,82%yield)as a white solid:[α]D 20=+47.0(c 0.04,MeOH).IR(KBr)Vmax:2971,2854,1651,1560,1518,1464,1404,1344,1326,1235,1151,1049,892,808,736,694,586cm-1.1H NMR(400MHz,Chloroform-d)δ7.55(d,J=7.9Hz,1H),7.47(d,J=8.2Hz,1H),7.41–7.37(m,4H),7.17–7.11(m,6H),7.07(d,J=7.6Hz,1H),7.02(dd,J=7.4,1.9Hz,2H),6.24(t,J=6.1Hz,1H),5.22(d,J=2.1Hz,1H),4.96(d,J=2.2Hz,1H),4.38(d,J=5.9Hz,1H),4.29(d,J=5.8Hz,1H),1.10(s,9H).13C NMR(100MHz,CDCl3)δ170.4,139.0,137.7,136.9,129.7,129.0,128.6,127.5,126.9,126.5,124.3,123.3,120.9,120.4,112.2,111.0,55.6,54.2,43.8,22.7.HRMS(ESI)calculatedfor C27H30N3O2S+[M+H]+:460.2053,found 460.2055.
实例15:化合物C15的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C15(282mg,88%yield):[α]D 20=+46.7(c 0.2,MeOH).IR(KBr)Vmax:3453,3122,2920,1855,1711,1645,1458,1362,1265,1103,1025,901,751,598cm-1.1H NMR(400MHz,Chloroform-d)δ8.78–8.69(m,1H),7.57(d,J=8.0Hz,1H),7.38(d,J=8.2Hz,1H),7.25(d,J=3.2Hz,1H),7.21(t,J=7.6Hz,1H),7.09(t,J=7.5Hz,1H),7.02(d,J=7.9Hz,2H),6.95(d,J=7.9Hz,2H),6.19(t,J=6.0Hz,1H),5.22(d,J=1.9Hz,1H),5.02(s,1H),4.42(dd,J=14.9,6.0Hz,1H),4.28(dd,J=14.9,5.7Hz,1H),2.27(s,3H),1.17(s,9H).13C NMR(100MHz,CDCl3)δ170.7,137.1,137.0,134.6,129.2,127.4,125.9,125.2,122.8,120.2,120.1,111.7,110.7,55.5,54.3,43.6,22.7,22.1.HRMS(ESI)calculated for C22H28N3O2S+[M+H]+:398.1897,found 398.1899.
实例16:化合物C16的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C16(270mg,82%yield):[α]D 20=+67.8(c 0.2,MeOH).IR(KBr)Vmax:3252,2981,2928,1649,1509,1455,1362,1224,1158,1049,1012,821,736,568cm-1.1H NMR(400MHz,Chloroform-d)δ9.39–9.27(m,1H),7.51(d,J=8.0Hz,1H),7.36(d,J=8.2Hz,1H),7.29(d,J=8.2Hz,2H),7.21–7.15(m,2H),7.07(t,J=7.5Hz,1H),6.91(d,J=8.2Hz,2H),6.54(t,J=6.1Hz,1H),5.19(d,J=2.3Hz,1H),4.99(d,J=2.3Hz,1H),4.28(t,J=5.9Hz,2H),1.15(s,9H).13C NMR(100MHz,CDCl3)δ171.1,137.1,136.8,131.6,129.1,126.1,125.1,122.7,121.2,120.1,119.9,111.9,110.3,55.6,54.6,43.1,22.7,22.1.HRMS(ESI)calculated for C21H25BrN3O2S+[M+H]+:462.0845,found 462.0848.
实例17:化合物C17的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C17(225mg,79%yield):[α]D 20=+72.5(c 0.2,MeOH).IR(KBr)Vmax:3251,3065,2981,2926,1657,1627,1537,1506,1452,1410,1362,1338,1224,1157,1091,1049,1007,821,736,568cm-1.1H NMR(400MHz,Chloroform-d)δ9.72(s,1H),7.50(d,J=8.0Hz,1H),7.34(d,J=8.2Hz,1H),7.19–7.10(m,2H),7.03(ddd,J=8.0,7.0,1.0Hz,1H),7.00–6.93(m,2H),6.83–6.77(m,2H),6.76–6.70(m,1H),5.17(d,J=2.7Hz,1H),5.02(d,J=2.7Hz,1H),4.39–4.08(m,2H),1.11(s,9H).13C NMR(100MHz,CDCl3)δ171.2,163.2,160.8,137.2,133.6,133.5,129.1,129.0,126.3,125.1,122.6,119.9,119.8,115.4,115.2,112.0,110.1,55.6,54.8,43.0,22.7.HRMS(ESI)calculated forC21H25FN3O2S+[M+H]+:402.1646,found 402.1648.
实例18:化合物C18的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C18(286mg,87%yield):[α]D 20=+120.5(c 0.2,MeOH).IR(KBr)Vmax:3287,3065,2963,2908,2848,1663,1543,1500,1434,1404,1326,1265,1067,1019,718,652cm-1.1H NMR(400MHz,Chloroform-d)δ9.01(s,1H),7.50(dd,J=8.0,2.6Hz,1H),7.40(ddd,J=18.7,8.0,2.7Hz,2H),7.23–7.16(m,2H),7.14(t,J=3.6Hz,2H),7.05(tq,J=7.3,3.4,2.8Hz,2H),6.52–6.41(m,1H),5.22(d,J=2.5Hz,1H),4.98(d,J=2.6Hz,1H),4.43(dd,J=6.2,2.6Hz,2H),1.17(d,J=2.7Hz,9H).13C NMR(100MHz,CDCl3)δ171.0,137.1,136.6,132.7,129.6,129.1,127.5,126.2,125.1,123.4,122.7,120.1,120.0,111.8,110.2,55.5,54.4,44.1,29.7,22.7.HRMS(ESI)calculated forC21H25BrN3O2S+[M+H]+:462.0845,found 462.0848.
实例19:化合物C19的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得乳白色油状产物C19(260mg,89%yield):[α]D 20=+115(c 0.2,MeOH).IR(KBr)Vmax:3317,3263,3197,3079,2962,2872,1651,1560,1452,1350,1205,1049,754,688cm-1.1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),7.56(d,J=8.0Hz,1H),7.40(d,J=8.2Hz,1H),7.29(d,J=6.8Hz,1H),7.25–7.19(m,3H),7.18–7.13(m,2H),7.09(t,J=7.5Hz,1H),6.22(d,J=8.2Hz,1H),5.16(d,J=2.1Hz,1H),4.95(s,1H),4.84(q,J=7.6Hz,1H),1.67–1.53(m,2H),1.17(s,9H),0.62(t,J=7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ170.1,141.7,137.0,128.6,127.4,126.5,126.0,125.1,122.8,120.2,120.0,111.7,110.8,55.5,54.5,28.8,22.7,10.4.HRMS(ESI)calculated for C23H30N3O2S+[M+H]+:412.2053,found 412.2056.
实例20:化合物C20的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得黄棕色固体产物C20(267mg,91%yield):[α]D 20=+131(c 0.2,MeOH).IR(KBr)Vmax:3414,3275,3071,2981,2914,2842,1711,1687,1638,1543,1513,1428,1368,1272,1175,1043,808,730cm-1.1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),7.55(d,J=8.0Hz,1H),7.38(d,J=8.2Hz,1H),7.24–7.14(m,2H),7.09(t,J=7.6Hz,1H),7.02–6.96(m,2H),6.78–6.69(m,2H),6.22(t,J=5.9Hz,1H),5.20(d,J=1.9Hz,1H),5.03(d,J=2.0Hz,1H),4.39(dd,J=14.8,6.0Hz,1H),4.26(dd,J=14.8,5.7Hz,1H),3.74(s,3H),1.17(s,9H).13C NMR(100MHz,Chloroform-d)δ170.6,158.9,137.0,129.8,128.8,126.0,125.1,122.8,120.1,114.0,111.7,110.6,55.3,54.4,43.3,22.7.HRMS(ESI)calculated for C22H28N3O3S+[M+H]+:414.1846,found 414.1850.
实例21:化合物C21的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得黄棕色油状产物C21(234mg,89%yield):[α]D 20=+180.91(c 0.1,MeOH).IR(KBr)Vmax:3428,3251,3071,2932,2848,1692,1603,1548,1518,1358,1319,1254,1164,1049,899,760,694cm-1.1H NMR(400MHz,Chloroform-d)δ9.35(s,1H),8.30(dd,J=7.2,4.0Hz,1H),7.59(d,J=8.0Hz,1H),7.36(t,J=7.4Hz,3H),7.22–7.12(m,4H),7.08–6.95(m,2H),5.32(d,J=3.3Hz,1H),5.02(s,1H),1.18(s,9H).13C NMR(100MHz,Chloroform-d)δ169.4,137.3,137.1,128.9,126.1,125.2,124.7,122.7,120.3,120.2,119.7,112.0,110.3,60.5,55.8,22.7.HRMS(ESI)calculated for C20H24N3O2S+[M+H]+:370.1584,found 370.1587.
实例22:化合物C22的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C22(234mg,87%yield):[α]D 20=+86.70(c 0.2,MeOH).IR(KBr)Vmax:2981,1767,1685,1643,1547,1368,1052,667cm-1.1H NMR(400MHz,Chloroform-d)δ9.21(t,J=8.8Hz,1H),8.57(t,J=7.9Hz,1H),7.61(d,J=8.0Hz,1H),7.35(d,J=8.2Hz,1H),7.33–7.29(m,2H),7.20–7.15(m,2H),7.08(t,J=7.5Hz,1H),6.84(t,J=8.5Hz,2H),5.35(d,J=4.0Hz,1H),5.02(d,J=3.7Hz,1H),1.18(s,9H).13C NMR(100MHz,CDCl3)δ169.4,160.7,158.3,137.0,133.4,125.7,125.3,122.8,122.0,121.9,120.3,119.6,115.5,115.3,111.9,110.7,56.0,55.8,22.7.19F NMR(376MHz,Chloroform-d)δ-117.34.HRMS(ESI)calculated for C20H23FN3O2S+[M+H]+:388.1490,found 388.1494.
实例23:化合物C23的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C23(199mg,87%yield):[α]D 20=+179.89(c 0.2,MeOH).IR(KBr)Vmax:3252,2981,2928,1768,1742,1509,1455,1224,1158,1049,821,742cm-1.1H NMR(400MHz,Chloroform-d)δ8.64(s,1H),7.64(dt,J=7.9,0.9Hz,1H),7.37(dt,J=8.2,0.9Hz,1H),7.22–7.15(m,2H),7.11(ddd,J=8.1,7.0,1.0Hz,1H),5.33(d,J=4.6Hz,1H),4.52(d,J=4.6Hz,1H),4.24(dq,J=10.8,7.1Hz,1H),4.13(dq,J=11.2,7.1Hz,1H),1.21(s,9H),1.18(t,J=7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ171.9,136.6,125.6,124.2,122.5,119.9,119.6,111.5,62.0,55.8,54.3,22.7,14.0.HRMS(ESI)calculated for C16H23N2O3S+[M+H]+:323.1424,found 323.1425.
实例24:化合物C24的合成
使用化合物C1所示步骤,以化合物A1(0.10g,0.85mmol)为原料,经硅胶柱层析(石油醚:乙酸乙酯=1:3)得红棕色油状产物C24(195mg,85%yield):[α]D 20=-95.24(c0.003,MeOH).IR(KBr)Vmax:3252,2981,1768,1744,1501,1450,1225,1169,1052,820,740cm-1.1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),7.64(dd,J=7.9,1.0Hz,1H),7.37(dt,J=8.2,0.9Hz,1H),7.24–7.16(m,2H),7.11(ddd,J=8.0,7.0,1.1Hz,1H),5.32(d,J=4.7Hz,1H),4.53(d,J=4.7Hz,1H),4.29–4.19(m,1H),4.13(dq,J=10.8,7.1Hz,1H),1.21(s,9H),1.18(t,J=7.1Hz,3H).13C NMR(100MHz,Chloroform-d)δ171.9,136.7,125.6,124.2,122.4,119.9,119.6,111.5,62.0,55.8,54.4,22.7,14.0.HRMS(ESI)calculatedfor C16H23N2O3S+[M+H]+:323.1424,found 323.1425.
以上对本发明的具体实例进行了详细描述,但其只是作为范例,本发明并不限制于以上描述的具体实例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所做的均等变换和修改,都应涵盖在本发明的范畴内。
Claims (6)
1.一种手性吲哚甘氨酸衍生物的合成方法,其特征在于,包括以下步骤:
以吲哚衍生物A和叔丁基亚磺酰亚胺B为原料,在路易斯酸催化剂作用下的发生傅克烷基化反应,制得手性吲哚甘氨酸衍生物C;
所述吲哚甘氨酸衍生物C的结构通式为C:
所述结构通式C具有以下特点:
(1)所述叔丁基亚磺酰亚胺B中的R为芳香胺,脂肪胺,烷氧基,烷基,芳烃基,杂环芳烃基;
(2)吲哚衍生物A中的R1、R2和R3为碳环或杂环,或R1、R2和R3各自独立选自:H,烷基,酯基,卤素,烯基,硝基,炔基,烷氧基,芳烃基,烷氧基,芳烃基,杂环芳烃基;
(3)所述叔丁基亚磺酰亚胺B中叔丁基可替代为2,4,6-三甲基苯基(Mes)、甲基苯基(Tol)、苯基(Ph)或异丙基(i-pr);
(4)所述叔丁基亚磺酰亚胺B中的亚磺酰基的构型是R或S。
2.如权利要求1所述手性吲哚甘氨酸衍生物的合成方法,其特征在于,所述合成方法包括以下步骤:
将吲哚衍生物A溶于溶剂中,依次加入叔丁基亚磺酰亚胺B,路易斯酸催化剂反应,后处理,制得目标产物C;
(1)R为芳香胺和脂肪胺的一种或两种;
(2)取代基R1为H,烷基,卤素,烷氧基,酯基,硝基的任意一种或多种;
(3)取代基R2为H,烷基,芳烃基的任意一种或多种;
(4)取代基R3为H,烷基的任意一种或两种。
3.如权利要求1所述手性吲哚甘氨酸衍生物的合成方法,其特征在于,所述步骤为:
将吲哚衍生物A溶于乙腈中,依次加入叔丁基亚磺酰亚胺B和路易斯酸催化剂反应,在-78℃-100℃反应,后处理,制得目标产物C。
4.如权利要求1所述的合成方法,其特征在于,所述步骤为:
将吲哚衍生物A溶于乙腈中,依次加入叔丁基亚磺酰亚胺B和路易斯酸催化剂反应,在0℃反应0.5-3小时,后处理,制得目标产物C。
5.如权利要求3或4所述手性吲哚甘氨酸衍生物的合成方法,其特征在于,所述路易斯酸催化剂为B(C6F5)3。
6.如权利要求3或4所述手性吲哚甘氨酸衍生物的合成方法,其特征在于,所述步骤中的后处理指的是:反应完毕后,向反应液中加入饱和食盐水,用乙酸乙酯萃取3次,合并有机相经无水硫酸钠干燥,抽滤、浓缩后用快速柱层析分离,即得目标产物C。
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