CN107474032B - 一种合成手性3,4-二氢香豆素的方法 - Google Patents

一种合成手性3,4-二氢香豆素的方法 Download PDF

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CN107474032B
CN107474032B CN201610403147.4A CN201610403147A CN107474032B CN 107474032 B CN107474032 B CN 107474032B CN 201610403147 A CN201610403147 A CN 201610403147A CN 107474032 B CN107474032 B CN 107474032B
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周永贵
吴波
陈木旺
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Abstract

一种合成手性3,4‑二氢香豆素的方法：从磺酰烷基取代的苯酚和5‑取代‑2(3H)‑呋喃酮出发，在无机碱和有机催化剂的作用下反应可以得到含各种取代基的手性3,4‑二取代二氢香豆素。本发明操作简便实用，产率高，非对映选择性好，对映选择性高。

Description

一种合成手性3,4-二氢香豆素的方法
技术领域
本发明涉及二氢香豆素，具体地说是一种应用有机催化体系高度对映选择性、非对映选择性地合成手性3,4-二氢香豆素的方法
背景技术
手性3,4-二氢香豆素衍生物是一类重要的化合物，具有光谱的生理活性和药物活性[1]，例如醛糖还原酶活性，蛋白激酶抑制活性，抗癌活性，抗氧化活性，抗炎活性以及抗微生物活性，它广泛应用于药物、天然产物的合成中。因此，手性3,4-二氢香豆素在医药、农药、精细化学品领域有着十分重要的作用。目前，已经发展了很多合成手性3,4-二氢香豆素的方法[2]。这些一般为使用金属催化的方法，或是有机催化的方法。(文献1：a)R.D.H.Murray,J.Mendez,S.A.Brown,The Natural Coumarin:Occurrence,Chemistry,andBiochemistry,Wiley,New York,1982；b)R.O’Kennedy,R.D.Thornes,Coumarins:Biology,Applications,and Mode of Action,Wiley,Chichester,UK,1st edn,1997；c)C.A.Kontogiorgis,D.J.Hadjipavlou-Litina,J.Med.Chem.2005,48,6400.文献2：a)B.C.Hong,P.Kotame,G.H.Lee,Org.Lett.2011,13,5758；b)X.H.Li,P.Fang,D.Chen,X.L.Hou,Org.Chem.Front.2014,1,969；c)E.Alden-Danforth,M.T.Scerba,T.Lectka,Org.Lett.2008,10,4951；d)H.Lv,L.You,S.Ye,Adv.Synth.Catal.2009,351,2822；e)A.Lee,K.A.Scheidt,Chem.Commun.2015,51,3407；f)H.Hu,Y.Liu,J.Guo,L.Lin,Y.Xu,X.Liu,X.Feng,Chem.Commun.2015,51,3835；g)S.-Y.Zhang,M.Lv,S.-J.Yin,N.-K.Li,J.-Q.Zhang,X.-W.Wang,Adv.Synth.Catal.2016,358,143.)
由于大多数合成手性3,4-二氢香豆素的方法存在着反应的非对映选择性和对映选择性差、产率低、反应试剂或催化剂昂贵、反应条件比较苛刻、反应操作复杂缺点，阻止了这些方法的广泛应用。因此发展一种简便、有效、高收率、高非对映选择性、高对映选择性的方法合成手性3,4-二氢香豆素是一个极具吸引力的研究方向。
发明内容
本发明的目的是提供一类含各种取代基的手性3,4-二氢香豆素的合成方法。
本发明的技术方案如下：
本发明提供的是一类具有不同立体和电子效应取代基的手性3,4-二氢香豆素的合成，其合成路线如下：
Figure BDA0001012465080000021
所述反应物和产物中取代基Ar为苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基中的一种或二种以上。R1为苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基中的一种或二种以上；R2为C1-C10的烷基。
具体反应步骤为:
将化合物1溶于有机溶剂中，化合物1于有机溶剂中的溶度为0.01-1.0mol/L，向该体系按化合物1：化合物2的摩尔比1:0.01-1:3加入化合物2，接着向该体系按化合物1：无机碱的摩尔比1:1-1:5加入无机碱，然后向该体系按化合物1：有机催化剂的摩尔比1:0.01-1:0.2加入有机催化剂，30-70℃下反应，5天以上后，加入水淬灭反应；静置分液，水层用二氯甲烷萃取2-8次，合并二氯甲烷层后，无水硫酸钠干燥，过滤，减压去除溶剂，硅胶柱层析得到产品化合物3。
所用的有机溶剂为四氢呋喃、乙醚、二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、苯、对二甲苯、1,4-二氧六环、乙酸乙酯、N,N-二甲基甲酰胺、乙醇。
采用5-取代-2(3H)-呋喃酮为反应物，用量为每1毫摩尔化合物1用1:1.2毫摩尔5-取代-2(3H)-呋喃酮。
采用无机碱作为反应促进剂，用量为每1毫摩尔化合物1用1:1.2无机碱。
采用有机催化剂作为反应催化剂，用量为每1毫摩尔化合物1用1:0.1有机催化剂。
方法中所用的无机碱剂为碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、碳酸铯、磷酸钠、磷酸钾中的一种或两种以上混合。
方法中所用的有机催化剂为奎宁，奎尼丁，辛可宁，辛可宁丁，硫脲，方酰胺中的一种或两种以上。
反应温度为30℃。
本发明从磺酰烷基取代的苯酚和5-取代-2(3H)-呋喃酮出发，经过一步反应可以高产率、高非对映选择性地得到一系列含各种取代基的手性3,4-二氢香豆素。
本发明从各种磺酰基取代的苯酚出发，与各种5-取代-2(3H)-呋喃酮反应生成手性3,4-二氢香豆素，该反应采用无机碱作为促进剂，有机催化剂作为催化剂，反应条件温和，产率高，非对映选择性好，对映选择性高。本发明原料廉价易得，操作简便，体系简单，为后处理提供了便利，大大提高了反应效率，反应能容忍各种不同的取代基和官能团。
本发明具有以下优点：
1.原料简单易得。
2.反应活性高，原料转化完全，核磁氢谱检测到副产物含量较低或不存在，分离方便，能获得高纯度的产物。
3.反应的非对映选择性好，能高非对映选择性地得到顺式非对映异构体。
4.能高对映选择性地得到含各种取代基的手性3,4-二氢香豆素。
5.反应条件温和。
具体实施方式
本发明将化合物1，在有机溶剂中和各种5-取代-2(3H)-呋喃酮2反应，使用无机碱作为促进剂，有机催化剂作为催化剂，其合成路线如下：
Figure BDA0001012465080000031
其中：
取代基Ar为苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基中的一种或二种以上。R1为苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基中的一种或二种以上；R2为C1-C10的烷基。
下面通过实施例详述本发明；但本发明并不限于下述的实施例。
实施例1：条件优化
向3mL反应瓶中加入磺酰基取代萘酚1a(39毫克,0.10毫摩尔)，呋喃酮2a(12毫克,11微升,0.12毫摩尔),碳酸钠(13毫克,0.12毫摩尔),有机催化剂(0.01毫摩尔)和1.5毫升溶剂，30℃下搅拌反应6天，加入10毫升水淬灭反应。静置分液，水层用二氯甲烷萃取三次(20mL×3)，合并有机层后，无水硫酸钠干燥，过滤。减压去除溶剂，硅胶柱层析得到产物，反应结构式如下：
Figure BDA0001012465080000041
产物的产率为分离的两个非对映异构体的总产率，dr值为顺式非对映异构体与反式非对映异构体的比例，ee值为顺式非对映异构体的对映体过量百分率，见表1。
表1.合成手性3,4-二氢香豆素3a的条件优化
Figure BDA0001012465080000042
实施例2：手性3,4-二氢香豆素3的合成
向3mL反应瓶中加入磺酰烷基取代萘酚1(0.10毫摩尔)，呋喃酮2(0.12毫摩尔),碳酸钠(13毫克,0.12毫摩尔),有机催化剂4b(6.3毫克,0.01毫摩尔)和1.5毫升氯仿，30℃下搅拌反应6天，加入10毫升水淬灭反应。静置分液，水层用二氯甲烷萃取三次(20mL×3)，合并有机层后，无水硫酸钠干燥，过滤。减压去除溶剂，硅胶柱层析得到产物，反应式如下：
产物的产率为分离的两个非对映异构体的总产率，dr值为顺式非对映异构体与反式非对映异构体的比例，ee值为顺式非对映异构体的对映体过量百分率，见表1。
表2.手性3,4-二氢香豆素3的合成
Figure BDA0001012465080000051
各个化合物的实验数据如下：
(3S,4S)-3-(2-Oxopropyl)-4-phenyl-3,4-dihydro-2H-benzo[h]chro men-2-one(3a):unknown compound,97％yield,9.2:1dr,97％ee,[α]20 D＝+360.16(c 0.54,CHCl3),white solid,mp＝150-151℃,Rf＝0.60(petroleum ether/ethyl acetate 10/1).1H NMR(400MHz,CDCl3)δ8.31(t,J＝8.6Hz,1H),7.81(d,J＝7.9Hz,1H),7.65-7.44(m,3H),7.32-7.24(m,3H),7.22-7.16(m,1H),7.10-6.97(m,2H),4.40(d,J＝6.8Hz,1H),3.85(dd,J＝13.1,6.8Hz,1H),3.03(dd,J＝18.4,5.9Hz,1H),2.41(dd,J＝18.4,7.0Hz,1H),2.19(s,3H)；13C NMR(100MHz,CDCl3)δ206.2,169.8,146.1,138.7,133.9,129.4,128.1,128.0,127.8,127.0,126.9,125.8,124.7,123.9,121.5,121.2,45.7,41.1,40.4,30.6.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 11.9 min and 14.9 min(maj).HRMS Calculated for C22H19O3[M+H]+331.1329,found 331.1331.
(3R,4S)-3-(2-Oxopropyl)-4-phenyl-3,4-dihydro-2H-benzo[h]chro men-2-one(3a’):unknown compound,3.9:1 dr,79％ee,[α]20 D＝+50.00(c 0.12,CHCl3),colorless oil,Rf＝0.65(petroleum ether/ethyl acetate10/1).1H NMR(400MHz,CDCl3)δ8.30(d,J＝8.3Hz,1H),7.84-7.75(m,1H),7.64-7.30(m,6H),7.24-7.15(m,2H),6.74(d,J＝8.6Hz,1H),4.41(d,J＝12.2Hz,1H),3.61(ddd,J＝12.1,7.0,4.3Hz,1H),2.85(dd,J＝17.7,7.0Hz,1H),2.52(dd,J＝17.6,4.3Hz,1H),2.14(s,3H)；13C NMR(100MHz,CDCl3)δ205.7,169.9,146.3,139.4,133.8,129.5,129.1,128.2,127.7,127.0,126.9,125.4,124.1,123.6,121.6,120.8,45.5,42.3,41.4,30.5.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 20.1 min(maj)and25.5 min.HRMS Calculated for C22H19O3[M+H]+331.1329,found 331.1331.
(3S,4S)-3-(2-Oxopropyl)-4-p-tolyl-3,4-dihydro-2H-benzo[h]chro men-2-one(3b):unknown compound,97％yield,9.2:1 dr,97％ee,[α]20 D＝+389.44(c 0.56,CHCl3),colorless oil,Rf＝0.60(petroleum ether/ethyl acetate 10/1).1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.3Hz,1H),7.81(d,J＝7.7Hz,1H),7.63-7.49(m,3H),7.20(d,J＝8.4Hz,1H),7.07(d,J＝7.9Hz,2H),6.93(d,J＝8.1Hz,2H),4.36(d,J＝7.0Hz,1H),3.83(dd,J＝13.0,7.0Hz,1H),3.03(dd,J＝18.5,5.9Hz,1H),2.42(dd,J＝18.5,7.1Hz,1H),2.28(s,3H),2.19(s,3H)；13C NMR(100MHz,CDCl3)δ206.3,169.9,146.1,137.9,135.7,133.9,130.1,127.9,127.9,127.0,126.9,125.9,124.7,124.0,121.6,121.4,45.4,41.2,40.5,30.6,21.2.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 11.7 min and 14.7 min(maj).HRMS Calculatedfor C23H21O3[M+H]+345.1485,found 345.1486.
(3S,4S)-3-(2-Oxopropyl)-4-m-tolyl-3,4-dihydro-2H-benzo[h]chro men-2-one(3c):unknown compound,97％yield,11.2:1 dr,98％ee,[α]20 D＝+402.04(c 0.58,CHCl3),colorless oil,Rf＝0.60(petroleum ether/ethyl acetate 10/1).1H NMR(400MHz,CDCl3)δ8.38-8.31(m,1H),7.83(d,J＝7.7Hz,1H),7.67-7.46(m,3H),7.24-7.11(m,2H),7.06(d,J＝7.5Hz,1H),6.91-6.78(m,2H),4.37(d,J＝7.2Hz,1H),3.86(td,J＝7.2,6.1Hz,1H),3.04(dd,J＝18.4,6.0Hz,1H),2.43(dd,J＝18.3,7.2Hz,1H),2.27(s,3H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ206.3,169.8,146.1,139.2,138.7,133.9,129.3,128.9,128.6,127.8,127.0,126.9,125.9,125.2,124.7,123.9,121.6,121.3,45.7,41.2,40.3,30.5,21.6.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 11.4 minand 14.1 min(maj).HRMS Calculatedfor C23H21O3[M+H]+345.1485,found 345.1486.
(3S,4S)-3-(2-Oxopropyl)-4-o-tolyl-3,4-dihydro-2H-benzo[h]chromen-2-one(3d):unknown compound,97％yield,6.2:1 dr,98％ee,[α]20 D＝+402.47(c 0.48,CHCl3),colorless oil,Rf＝0.60(petroleum ether/ethyl acetate 10/1).1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.3Hz,1H),7.81(d,J＝7.9Hz,1H),7.70-7.45(m,3H),7.24-6.86(m,5H),4.80(d,J＝7.3Hz,1H),3.94(d,J＝6.7Hz,1H),3.07(dd,J＝18.5,5.7Hz,1H),2.46(s,3H),2.34(dd,J＝18.5,6.8Hz,1H),2.18(s,3H)；13C NMR(100MHz,CDCl3)δ206.3,167.0,146.0,137.8,135.5,133.8,131.2,127.8,127.8,127.7,127.6,127.0,126.9,125.8,124.7,124.1,121.9,121.5,40.8,40.3,30.4,20.5.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time12.5 minand 14.3 min(maj).HRMS Calculated for C23H21O3[M+H]+345.1485,found 345.1486.
(3S,4S)-4-(3,5-Dimethylphenyl)-3-(2-oxopropyl)-3,4-dihydro-2H-benzo[h]chromen-2-one(3e):unknown compound,97％yield,11.3:1 dr,98％ee,[α]20 D＝+424.63(c 0.58,CHCl3),white solid,mp＝196-197℃,Rf＝0.60(petroleum ether/ethylacetate 10/1).1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.2Hz,1H),7.82(d,J＝7.8Hz,1H),7.65-7.46(m,3H),7.20(d,J＝8.3Hz,1H),6.87(s,1H),6.63(s,2H),4.31(d,J＝7.0Hz,1H),3.83(dd,J＝13.0,7.0Hz,1H),3.03(dd,J＝18.5,5.9Hz,1H),2.42(dd,J＝18.5,7.1Hz,1H),2.22(s,6H),2.19(s,3H)；13C NMR(100MHz,CDCl3)δ206.4,169.9,146.0,139.0,138.7,133.9,129.8,127.8,127.0,126.9,126.0,125.7,124.6,124.0,121.6,121.4,45.6,41.2,40.3,30.6,21.5.HPLC:Chiralpak IC column,230nm,30 ℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 10.8 minand 13.9 min(maj).HRMSCalculated for C24H23O3[M+H]+359.1645,found 359.1643.
(3S,4S)-4-(3,4-Dimethylphenyl)-3-(2-oxopropyl)-3,4-dihydro-2H-benzo[h]chromen-2-one(3f):unknown compound,97％yield,9.6:1 dr,98％ee,[α]20 D＝+392.73(c 0.58,CHCl3),colorless oil,Rf＝0.60(petroleum ether/ethyl acetate 10/1).1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.3Hz,1H),7.82(d,J＝8.1Hz,1H),7.56(dq,J＝13.8,7.0Hz,3H),7.20(d,J＝8.3Hz,1H),7.02(d,J＝8.2Hz,1H),6.86-6.71(m,2H),4.33(d,J＝7.0Hz,1H),3.83(q,J＝6.6Hz,1H),3.03(dd,J＝18.5,5.9Hz,1H),2.43(dd,J＝18.5,7.1Hz,1H),2.20(s,3H),2.19(s,3H),2.16(s,3H)；13C NMR(100MHz,CDCl3)δ206.4,167.0,146.0,137.8,136.5,136.1,133.8,130.6,129.1,127.8,126.9,126.9,125.9,125.5,124.7,123.9,121.6,121.5,45.3,41.2,40.4,30.6,20.1,19.6.HPLC:ChiralpakICcolumn,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time11.6 min and 14.6 min(maj).HRMS Calculated for C24H23O3[M+H]+359.1645,found359.1645.
(3S,4S)-4-(Naphthalen-2-yl)-3-(2-oxopropyl)-3,4-dihydro-2H-ben zo[h]chromen-2-one(3g):unknown compound,97％yield,8.1:1 dr,98％ee,[α]20 D＝+514.96(c0.66,CHCl3),colorless oil,Rf＝0.70(petroleum ether/ethyl acetate 5/1).1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.3Hz,1H),7.90-7.68(m,4H),7.66-7.49(m,4H),7.49-7.40(m,2H),7.24-7.11(m,2H),4.58(d,J＝7.1Hz,1H),3.92(d,J＝6.2Hz,1H),3.03(dd,J＝18.5,6.0Hz,1H),2.43(dd,J＝18.5,7.1Hz,1H),2.15(s,3H).13C NMR(100MHz,CDCl3)δ206.3,169.8,146.1,136.3,133.9,133.6,133.0,129.5,128.0,127.9,127.9,127.1,127.1,127.0,126.8,126.5,125.9,125.5,124.8,124.0,121.6,121.0,45.9,41.2,40.4,30.6.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 13.9 min and 16.3 min(maj).HRMS Calculated forC26H21O3[M+H]+381.1485,found 381.1485.
(3S,4S)-4-(4-Chlorophenyl)-3-(2-oxopropyl)-3,4-dihydro-2H-ben zo[h]chromen-2-one(3h):unknown compound,97％yield,8.6:1 dr,98％ee,[α]20 D＝+354.65(c0.62,CHCl3),colorless oil,Rf＝0.60(petroleum ether/ethyl acetate 5/1).1H NMR(400MHz,CDCl3)δ8.31(dd,J＝8.1,0.7Hz,1H),7.83(d,J＝7.5Hz,1H),7.65-7.51(m,3H),7.26-7.13(m,3H),7.04-6.93(m,2H),4.41(d,J＝7.0Hz,1H),3.85(dt,J＝13.1,6.6Hz,1H),3.05(dd,J＝18.4,5.9Hz,1H),2.39(dd,J＝18.5,7.2Hz,1H),2.21(s,3H)；13C NMR(100MHz,CDCl3)δ206.0,169.4,146.1,137.2,134.1,134.0,129.7,129.4,127.9,127.2,127.1,125.6,124.9,123.9,121.5,120.7,45.0,41.1,40.3,30.6.HPLC:Chiralpak ICcolumn,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time10.7 min and 13.4 min(maj).HRMS Calculated for C22H18ClO3[M+H]+365.0939,found365.0942.
(3S,4S)-3-(2-Oxopropyl)-4-(4-(trifluoromethyl)phenyl)-3,4-dihyd ro-2H-benzo[h]chromen-2-one(3i):unknown compound,98％yield,8.1:1 dr,97％ee,[α]20 D＝+302.57(c 0.58,CHCl3),colorless oil,Rf＝0.60(petroleum ether/ethyl acetate5/1).1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.3Hz,1H),7.84(d,J＝7.6Hz,1H),7.70-7.48(m,5H),7.19(d,J＝8.3Hz,3H),4.51(d,J＝7.0Hz,1H),3.90(dd,J＝13.0,7.0Hz,1H),3.06(dd,J＝18.5,6.0Hz,1H),2.38(dd,J＝18.5,7.2Hz,1H),2.21(s,3H)；13C NMR(100MHz,CDCl3)δ205.9,169.3,146.2,142.8,142.8,134.1,128.5,127.9,127.3,127.2,126.5(q,J＝3.9Hz),125.5,125.0,123.9,121.6,120.3,45.4,41.0,40.3,30.6；19F NMR(376MHz,CDCl3)δ-62.69.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 8.4 min and 10.5min(maj).HRMS Calculated forC23H18F3O3[M+H]+399.1203,found 399.1204.
(3S,4S)-4-(4-Fluorophenyl)-3-(2-oxopropyl)-3,4-dihydro-2H-ben zo[h]chromen-2-one(3j):unknown compound,97％yield,9.3:1 dr,98％ee,[α]20 D＝+379.97(c0.50,CHCl3),colorless oil,Rf＝0.60(petroleum ether/ethyl acetate 10/1).1H NMR(400MHz,CDCl3)δ8.31(d,J＝8.2Hz,1H),7.82(d,J＝7.9Hz,1H),7.70-7.45(m,3H),7.18(d,J＝8.4Hz,1H),7.10-6.83(m,4H),4.42(d,J＝6.8Hz,1H),3.84(dd,J＝13.1,6.8Hz,1H),3.04(dd,J＝18.5,6.0Hz,1H),2.39(dd,J＝18.5,7.2Hz,1H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ206.1,169.6,162.5(d,JC-F＝247.2Hz),146.0,134.50(d,JC-F＝3.7Hz),134.0,129.7(d,JC-F＝8.1Hz).127.9,127.2,127.0,125.6,124.9,123.9,121.5,121.0,116.4(d,JC-F＝21.3Hz),44.9,41.1,40.5,30.5；19F NMR(376MHz,CDCl3)δ-114.02.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 10.5 min and 13.2 min(maj).HRMS Calculated for C22H18FO3[M+H]+349.1234,found 349.1233.
(3S,4S)-7-Methoxy-3-(2-oxopropyl)-4-phenylchroman-2-one(3k):unknowncompound,52％yield,2.6:1 dr,90％ee,[α]20 D＝+144.49(c 0.20,CHCl3),colorlessoil,Rf＝0.45(petroleum ether/ethyl acetate 5/1).1H NMR(400MHz,CDCl3)δ7.31-7.21(m,3H),7.02(dd,J＝25.9,7.6Hz,3H),6.74-6.61(m,2H),4.22(d,J＝6.7Hz,1H),3.80(s,3H),3.72(q,J＝6.7Hz,1H),2.95(dd,J＝18.5,6.0Hz,1H),2.34(dd,J＝18.4,7.0Hz,1H),2.17(s,3H)；13C NMR(100MHz,CDCl3)δ206.2,169.8,160.2,151.9,139.4,129.4,129.4,127.9,127.8,118.5,111.3,102.5,55.7,44.8,41.2,40.5,30.5.HPLC:Chiralpak ICcolumn,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time18.6 minand 22.9 min(maj).HRMS Calculated for C19H19O4[M+H]+311.1278,found311.1278.
(3R,4S)-7-Methoxy-3-(2-oxopropyl)-4-phenylchroman-2-one(3k’):unknowncompound,2.6:1 dr,42％ee,[α]20 D＝+33.75(c 0.08,CHCl3),colorless oil,Rf＝0.50(petroleum ether/ethyl acetate 5/1).1H NMR(400MHz,CDCl3)δ7.46-7.30(m,3H),7.18(d,J＝7.2Hz,2H),6.67(d,J＝2.1Hz,1H),6.60-6.47(m,2H),4.17(d,J＝12.7Hz,1H),3.79(s,3H),3.55-3.43(m,1H),2.79(dd,J＝17.7,7.3Hz,1H),2.42(dd,J＝17.7,3.9Hz,1H),2.12(s,3H)；13C NMR(100MHz,CDCl3)δ205.9,170.2,160.1,151.9,139.3,129.5,129.2,129.1,128.2,118.8,110.7,102.3,55.7,44.6,42.2,41.2,30.5.HPLC:Chiralpak IAcolumn,230nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time10.7 min(maj)and 11.8 min.HRMS Calculated for C19H19O4[M+H]+311.1278,found311.1279.
(3S,4S)-3-(2-Oxobutyl)-4-phenyl-3,4-dihydro-2H-benzo[h]chrom en-2-one(3l):unknown compound,94％yield,8.1:1 dr,97％ee,[α]20 D＝+368.72(c 0.56,CHCl3),pale yellow oil,Rf＝0.80(petroleum ether/ethyl acetate 5/1).1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.3Hz,1H),7.82(d,J＝7.9Hz,1H),7.66-7.45(m,3H),7.34-7.25(m,2H),7.22(t,J＝7.1Hz,2H),7.10-6.97(m,2H),4.41(d,J＝7.0Hz,1H),3.89(dd,J＝13.1,7.0Hz,1H),3.00(dd,J＝18.2,5.9Hz,1H),2.60-2.30(m,3H),1.08(t,J＝7.3Hz,3H)；13CNMR(100MHz,CDCl3)δ209.1,169.9,146.1,138.8,133.9,129.4,128.1,128.1,127.8,127.0,126.9,125.8,124.7,123.9,121.5,121.2,45.7,40.4,40.0,36.5,8.0.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 10.9 min and 12.7 min(maj).HRMS Calculated for C23H21O3[M+H]+345.1285,found 345.1286.
(3S,4S)-3-(2-Oxohexyl)-4-phenyl-3,4-dihydro-2H-benzo[h]chrom en-2-one(3m):unknown compound,97％yield,8.0:1 dr,98％ee,[α]20 D＝+345.13(c 0.64,CHCl3),colorless oil,Rf＝0.70(petroleum ether/ethyl acetate 10/1).1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.3Hz,1H),7.82(d,J＝7.7Hz,1H),7.66-7.46(m,3H),7.37-7.25(m3H),7.24-7.17(m,1H),7.04(dd,J＝7.7,1.7Hz,2H),4.42(d,J＝7.0Hz,1H),3.88(td,J＝7.1,5.9Hz,1H),3.01(dd,J＝18.3,5.8Hz,1H),2.56-2.29(m,3H),1.64-1.51(m,2H),1.38-1.29(m,2H),0.91(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ208.8,169.9,146.1,138.8,133.9,129.4,128.1,127.8,127.0,126.9,125.9,124.7,123.9,121.5,121.3,45.7,43.1,40.4,40.3,26.0,22.5,14.0.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 9.9 min and 11.9 min(maj).HRMSCalculated for C25H25O3[M+H]+373.1798,found 373.1799.
(3S,4S)-3-(2-Oxo-3-phenylpropyl)-4-phenyl-3,4-dihydro-2H-benzo[h]chromen-2-one(3n):unknown compound,98％yield,11.1:1 dr,99％ee,[α]20 D＝+311.30(c 0.68,CHCl3),colorless oil,Rf＝0.70(petroleum ether/ethyl acetate 10/1).1HNMR(400MHz,CDCl3)δ8.31(d,J＝8.2Hz,1H),7.81(d,J＝7.7Hz,1H),7.66-7.50(m,3H),7.39-7.27(m,3H),7.24-7.09(m,6H),6.88(dd,J＝7.6,1.8Hz,2H),4.36(d,J＝6.8Hz,1H),3.91-3.61(m,3H),3.11(dd,J＝18.7,5.1Hz,1H),2.49(dd,J＝18.6,7.9Hz,1H)；13C NMR(100MHz,CDCl3)δ206.0,169.8,146.1,138.4,133.9,133.8,129.7,129.4,129.0,128.0,128.0,127.9,127.4,127.0,126.9,125.8,124.7,123.9,121.5,121.2,50.5,45.3,40.5,39.7.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 11.3 min and 17.0 min(maj).HRMS Calculated forC28H23O3[M+H]+407.1642,found 407.1641.
(3S,4S)-3-(2-Oxo-2-phenylethyl)-4-phenyl-3,4-dihydro-2H-benzo [h]chromen-2-one(3o):unknown compound,97％yield,2.1:1 dr,98％ee,[α]20 D＝+357.47(c0.44,CHCl3),pale yellow oil,Rf＝0.75(petroleum ether/ethyl acetate 10/1).1HNMR(400MHz,CDCl3)δ8.36(d,J＝8.3Hz,1H),7.88(dd,J＝36.1,7.6Hz,3H),7.70-7.36(m,6H),7.33-7.12(m,5H),7.03(dd,J＝6.5,2.9Hz,2H),4.57(d,J＝6.8Hz,1H),4.08(ddd,J＝8.2,7.2,4.5Hz,1H),3.63(dd,J＝18.6,4.5Hz,1H),3.00(dd,J＝18.6,8.3Hz,1H)；13C NMR(100MHz,CDCl3)δ197.7,167.0,146.2,138.6,136.6,133.9,133.7,129.4,128.9,128.3,128.2,128.1,127.9,127.0,126.9,126.0,124.7,123.9,121.5,121.4,45.5,40.7,36.3.HPLC:Chiralpak IC column,230nm,30℃,n-hexane/i-propanol＝75/25,flow＝0.7mL/min,retention time 11.9 min and 14.8 min(maj).HRMS Calculated forC27H21O3[M+H]+393.1485,found 393.1488.
(3R,4S)-3-(2-Oxo-2-phenylethyl)-4-phenyl-3,4-dihydro-2H-benzo[h]chromen-2-one(3o’):unknown compound,2.1:1 dr,82％ee,[α]20 D＝+154.53(c 0.22,CHCl3),pale yellow solid,mp＝145-146 ℃,Rf＝0.70(petroleum ether/ethyl acetate10/1).1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.3Hz,1H),7.94-7.84(m,2H),7.80(d,J＝7.6Hz,1H),7.66-7.20(m,11H),6.79(d,J＝8.6Hz,1H),4.55(d,J＝11.2Hz,1H),3.83(s,1H),3.45(dd,J＝17.8,6.3Hz,1H),3.08(dd,J＝17.8,4.8Hz,1H)；13C NMR(100MHz,CDCl3)δ197.0,169.9,146.4,139.8,136.7,133.9,133.5,129.5,129.0,128.8,128.3,128.2,127.7,127.1,126.9,125.7,124.2,123.6,121.7,120.5,45.7,42.5,37.1.HPLC:ChiralpakIC column,230nm,30℃,n-hexane/i-propanol＝60/40,flow＝0.7mL/min,retentiontime 16.1 min(maj)and 24.5 min.HRMS Calculated for C27H21O3[M+H]+393.1485,found393.1488。

Claims (5)

1.一种合成手性3,4-二氢香豆素的方法，其反应式和条件如下：
Figure DEST_PATH_IMAGE001
所述反应物和产物中取代基Ar为苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基中的一种或二种以上；
R1为苯基、取代苯基或萘基，取代苯基上的取代基为C1-C6的烷基、卤素、甲氧基中的一种或二种以上；
R2为C1-C10的烷基；
采用无机碱作为反应促进剂，用量为每1毫摩尔化合物1用1:1.2无机碱；
所述无机碱为碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、磷酸钠、磷酸钾中的一种或两种以上混合；
采用有机催化剂作为反应催化剂，用量为每1毫摩尔化合物1用1:0.1有机催化剂；
所述有机催化剂为奎宁，奎尼丁，辛可宁，辛可宁丁，硫脲，方酰胺中的一种或两种以上；
所述硫脲为：
Figure 209439DEST_PATH_IMAGE002
或
Figure DEST_PATH_IMAGE003
或
Figure 877311DEST_PATH_IMAGE004
；
所述方酰胺为：
Figure DEST_PATH_IMAGE005
或
Figure 283147DEST_PATH_IMAGE006
。
2.如权利要求1所述的方法，其特征在于：
具体反应步骤为:
将化合物1溶于有机溶剂中，化合物1于有机溶剂中的溶度为0.01-1.0 mol/L，向该体系按化合物1：化合物2的摩尔比1:0.01-1:3加入化合物2，接着向该体系按化合物1：无机碱的摩尔比1:1-1:5加入无机碱，然后向该体系按化合物1：有机催化剂的摩尔比1:0.01-1:0.2加入有机催化剂，30-70 oC下反应，5天以上后，加入水淬灭反应；静置分液，水层用二氯甲烷萃取2-8次，合并二氯甲烷层后，无水硫酸钠干燥，过滤，减压去除溶剂，硅胶柱层析得到产品化合物3。
3.如权利要求1所述的方法，其特征在于：
所用的有机溶剂为四氢呋喃、乙醚、二氯甲烷、氯仿、1,2-二氯乙烷、甲苯、苯、对二甲苯、1,4-二氧六环、乙酸乙酯、N,N-二甲基甲酰胺、乙醇中的一种或二种以上。
4.如权利要求1或2所述的方法，其特征在于：
采用化合物2为反应物，用量为每1毫摩尔化合物1用1:1.2毫摩尔化合物2。
5.如权利要求1或2所述的方法，其特征在于：
反应温度为30 oC。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892557A (zh) * 2015-03-31 2015-09-09 淮海工学院 一种不对称合成手性二氢香豆素衍生物的方法
CN105541774A (zh) * 2016-01-13 2016-05-04 华中师范大学 3,4-二氢香豆素类化合物及其制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892557A (zh) * 2015-03-31 2015-09-09 淮海工学院 一种不对称合成手性二氢香豆素衍生物的方法
CN105541774A (zh) * 2016-01-13 2016-05-04 华中师范大学 3,4-二氢香豆素类化合物及其制备方法和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Catalytic Asymmetric Addition of Meldrum’s Acid, Malononitrile, and 1,3-Dicarbonyls to ortho-Quinone Methides Generated In Situ Under Basic Conditions;Lorenzo Caruana et al.;《Chem. Eur. J.》;20150315;第21卷;6037-6041 *

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