CN104860911A - 一种手性3,4-二氢香豆素衍生化合物合成方法 - Google Patents
一种手性3,4-二氢香豆素衍生化合物合成方法 Download PDFInfo
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Abstract
本发明公开了一种手性3,4-二氢香豆素衍生化合物的合成方法,具体为以邻羟基查尔酮与吖内酯为反应物,在手性多功能手性奎宁硫脲催化下,在溶剂中合成得到产物。本发明公开的方法原料简单易得,反应条件温和,后处理简单方便,适用的底物范围广,收率高,对映选择性高;由此合成得到的产物可用以合成药物和杀虫剂的中间体。
Description
技术领域
本发明涉及手性季碳化合物的合成,具体涉及一种手性3,4-二氢香豆素衍生化合物的催化合成方法。
背景技术
手性季碳类化合物,具有抗肿瘤、抗植物病毒、植物生长调节、除草、杀菌、抑制酶活性、抗氧化及防辐射、破坏生物细胞膜等广泛的生物活性,而受到很多科学家的关注。手性的3,4-二氢香豆素衍生化合物作为手性季碳类化合物,同样具有类似的潜在应用价值,因此选择高效的方法合成手性的含氧缩醛胺化合物吸引了许多化学家的极大兴趣,近来涌现出了许多合成方法。
在有机合成领域,通过不对称小分子催化的反应由于仅用少量的手性催化剂就可获得大量新的活性物质而成为最有效、有经济价值的合成手性化合物的方法。
现有技术中合成手性的3,4-二氢香豆素衍生化合物的方法报道的比较少。Hayashi课题组在2005报道了以(R)-Segphos为配体,铑金属催化的香豆素和芳基硼酸的不对称1,4-加成反应,能够以45%‒94%的收率和99.1%‒99.7%的对映选择性得到3,4-二氢香豆素的目标产物,但因使用了金属,加上配体比较贵,所以成本比较高(G.
Chen, N. Tokunaga, T. Hayashi, Rhodium-catalyzed asymmetric 1,4-addition of
arylboronic acids to coumarins: Asymmetric synthesis of (R)-Tolterodine.
Org.Lett. 2005, 7, 2285.);叶松课题组2009年也报道了不饱和酮QM-1a与烯酮的环加成反应,用的催化剂为氮杂卡宾,能够以30%‒96%的收率,2/1‒9/1的顺反比以及51%‒99%和86%‒96%对映选择性分别得到顺式和反式的3,4-二氢香豆素,但底物和催化都比较难合成(H.
Lv, L. You, S. Ye, Enantioselective synthesis of dihydrocoumarins via
n-heterocyclic carbene-catalyzed cycloaddition of ketenesand o-Quinone
methides. Adv. Synth. Catal. 2009, 351, 2822.)。
因此很有必要寻找一种新的合成手性3,4-二氢香豆素衍生化合物的方法,该方法不仅收率高、对映选择性优秀,同时还需底物易合成,成本低,反应条件温和,操作简单。
发明内容
本发明的目的是提供一种手性3,4-二氢香豆素衍生化合物的催化合成方法。
为达到上述发明目的,本发明采用的技术方案是:一种手性3,4-二氢香豆素衍生化合物的合成方法,具体为:在反应器中,以邻羟基查尔酮化合物、吖内酯化合物为反应物,以手性硫脲化合物为催化剂,在苯类溶剂中,于-30℃~-5℃反应得到产物手性3,4-二氢香豆素衍生化合物;
所述邻羟基查尔酮化合物的化学结构式为
1,其中R1选自:5-氯、氢、5-甲基、4-甲氧基中的一种;R2选自:甲基、苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-碘苯基、4-三氟甲基苯基、4-甲基苯基、4-叔丁基苯基、4-苯基苯基、4-正戊基苯基、3-氟苯基、3-氯苯基、3-甲氧基苯基、2-氟苯基、3,4-2氟苯基、1-萘基、2-呋喃基,2-噻吩基中的一种;
所述吖内酯化合物的化学结构式为,其中R3为苄基、异丁基或者2-甲硫基乙基;R4为苯基、4-氟苯基或者4-甲基苯基;
所述3,4-二氢香豆素衍生化合物的结构式为:
。
上述技术方案中,所述苯类溶剂为间二甲苯。
上述技术方案中,以摩尔量计,所述催化剂的用量为邻羟基查尔酮的5-20%;吖内酯的用量为邻羟基查尔酮的1-2倍。
优选的技术方案中,所述催化剂为手性奎宁硫脲;其化学结构式如下所示:
上述技术方案中,反应过程包括在低温-30℃~-5℃下,向反应器中依次加入催化剂、邻羟基查尔酮、吖内酯,搅拌后再加入溶剂,TLC跟踪反应结束后,粗产物通过简单的柱层析(洗脱剂优选为二氯甲烷∶石油醚=1~2:1)即可得到目标产物手性3,4-二氢香豆素衍生化合物;该类化合物是很多抗菌药物,抗病毒剂和酶抑制剂的类似物,有巨大的潜在应用价值。
优选的技术方案中,反应体系中加入4Å分子筛为添加剂,以提高反应收率。
进一步优选的方案中,以质量计,所述4Å分子筛的用量为邻羟基查尔酮用量的20%。
优选的,所述反应时间为12个小时;反应温度为-5℃。此条件下,反应能耗小、产物收率高。
上述反应过程如下所示:
由于上述技术方案运用,本发明与现有技术相比具有下列优点:
1.本发明首次实现了以邻羟基查尔酮化合物和吖内酯化合物为反应物、手性多功能奎宁硫脲为催化剂合成手性3,4-二氢香豆素衍生化合物的方法,该方法操作简便,收率高,立体选择性好。
2.本发明所公开的合成手性3,4-二氢香豆素衍生化合物的反应后处理简单,反应不存在动力学拆分过程,属于Michael加成反应,体系中没有副产物生成。
3.本发明公开的合成3,4-二氢香豆素衍生化合物的方法适用底物范围很广,原料均为工业化、廉价易得的产品,无污染;并且官能团兼容性高,对应选择性优秀,收率高。
具体实施方式
下面结合实施例对本发明作进一步描述:
实施例一:
反应瓶中依次加入奎宁硫脲 (2.8
mg,0.005 mmol),和2a (25.9mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),搅拌,加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4a (15.9 mg),白色固体,收率为60%,>20/1 dr,80%
ee。
反应瓶中依次加入奎宁硫脲 (5.6 mg,0.01 mmol),和2a (25.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),搅拌,加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4a (29.0 mg),白色固体,收率为75%,>20/1 dr,79%
ee。
反应瓶中依次加入奎宁硫脲 (11.2 mg,0.02 mmol),和2a (25.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),搅拌,加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4a (48.0 mg),白色固体,收率为91%,>20/1 dr,91%
ee。
对产物4a进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 9.244, t (minor)= 8.276]; [α]D 26
= –14.00 (c 0.50, CHCl3); 1H
NMR (400MHz, CDCl3): δ7.96
(d, J = 8 Hz, 2H), 7.62–7.59 (m, 1H),
7.50–7.46 (m, 2H), 7.43–7.40 (m, 2H), 7.31–7.29
(m, 3H), 7.22–7.16 (m, 2H), 7.07–6.97 (m, 5H), 5.73 (m, 1H), 4.24 (d, J = 8 Hz,
1H), 3.73–3.68 (m, 2H), 3.48–3.36 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 195.71, 166.67, 166.09, 165.22 (J =
252 Hz), 149.62, 136.11, 134.09, 134.04, 130.49, 129.66, 129.53, 129.44,
129.28, 129.03 (J = 5 Hz), 128.91, 128.37, 127.97, 126.33, 117.72,
115.96 (J = 22 Hz), 60.12, 38.52, 38.05, 35.04; IR (KBr) νmax: 3415.6, 3065.7, 1770.8, 1684.1,
1666.0, 1603.4, 1581.1, 1527.3, 1236.5, 1001.6, 984.5, 757.6, 602.8, 532.3 cm−1;
HRMS-CI: [M]+ Calcd for C31H23ClFNO4,
527.1300, found: 527.1292.
以上数据证明目的产物合成成功。
实施例二:
反应瓶中依次加入奎宁硫脲 (11.2
mg,0.02 mmol),和2b (27.7mg, 0.1 mmol),3a
(26.9 mg, 0.1 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4b (21.8 mg),白色固体,收率为65%,>20/1 dr,91%
ee。
反应瓶中依次加入奎宁硫脲 (11.2 mg,0.02 mmol),和2b (27.7 mg, 0.1 mmol),3a
(40.3 mg, 0.15 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4b (32.7 mg),白色固体,收率为78%,>20/1 dr,90%
ee。
反应瓶中依次加入奎宁硫脲 (11.2 mg,0.02 mmol),和2b (27.7mg, 0.1 mmol),3a (53.8
mg, 0.2 mmol),4Å分子筛 (150
mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4b (54.0
mg),白色固体,收率为99%,>20/1
dr,92% ee。
对产物4b进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 11.310, t (minor)= 10.397]; [α]D 26
= –24.56 (c 0.29, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.93–7.89 (m, 2H), 7.36–7.32
(m, 2H), 7.21–7.16 (m, 3H), 7.10–7.03 (m, 4H), 7.00–6.97
(m, 2H), 6.94–6.88 (m, 3H), 5.84 (s, 1H), 4.20–4.11 (m, 1H), 3.63–3.57
(m, 2H), 3.42–3.26 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 194.27, 166.69,
166.29 (J = 255 Hz), 166.13, 165.18 (J = 252 Hz), 163.92, 149.56,
133.99, 132.56 (J = 3 Hz), 131.12 (J = 9 Hz), 130.47, 129.63,
129.49 (J = 9 Hz), 129.28, 129.02, 127.96, 126.26, 117.72, 116.14 (J
= 21 Hz), 115.92 (J = 22 Hz), 60.16, 38.39, 38.04, 35.11; IR (KBr) νmax: 3421.4, 2956.2, 2925.7, 1771.5,
1640.6, 1601.4, 1496.9, 1384.3, 1288.8, 1156.9, 1011.9, 764.8, 699.9, 605.3 cm−1;
HRMS-ESI: [M+H]+ Calcd for C31H23ClF2NO4,
546.1205, found: 546.1280.
以上数据证明目的产物合成成功。
实施例三:
反应瓶中依次加入奎宁硫脲 (11.2
mg, 0.02 mmol),和2c (29.3 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150mg),加入1.5 mL 间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4c (52.4 mg),白色固体,收率为95%,>20/1 dr,92%
ee。
反应瓶中依次加入奎宁硫脲 (11.2 mg,0.02 mmol),和2c (29.3 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),加入1.5 mL间二甲苯,在零下10摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4c (27.6 mg),白色固体,收率为72%,>20/1 dr,96%
ee。
对产物4c进行分析,结果如下:用HPLC测定 [Daicel Chiralcel IA, hexane/i-PrOH(70:30) , flow rate:
1.0 mL·min-1, λ = 254 nm, t (major) = 12.521, t (minor)= 11.625]; [α]D 26 = –36.40 (c 0.25, CH2Cl2); 1H
NMR (400MHz, CDCl3): δ7.81
(d, J = 8 Hz, 2H), 7.36–7.32 (m, 3H),
7.21–7.15 (m, 4H), 7.10–6.99 (m, 2H), 6.99–6.98
(m, 2H), 6.94–6.88 (m, 3H), 5.83 (s, 1H), 4.21–4.11 (m, 1H), 3.63–3.55
(m, 2H), 3.38–3.26 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 194.74, 166.66,
166.14, 165.19 (J = 252 Hz), 149.54, 140.62, 134.38, 133.94, 130.45,
129.78, 129.68, 129.48 (J = 9 Hz), 129.29, 129.04, 128.34, 127.98,
126.20, 125.41, 117.74, 115.93 (J = 22 Hz), 60.20, 38.42, 38.02, 35.11;
IR (KBr) νmax: 3442.1,
2988.0, 1770.9, 1639.0, 1489.4, 1384.5, 1173.5, 1004.0, 786.0, 624.3, 525.0 cm−1;
HRMS-ESI: [M+H]+ Calcd for C31H23Cl2FNO4,
562.0910, found: 562.0980.
以上数据证明目的产物合成成功。
实施例四:
反应瓶中依次加入奎宁硫脲 (11.2
mg,0.02 mmol),和2d (33.8 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4d (49.2 mg),白色固体,收率为81%,>20/1 dr,90%
ee。
对产物4d进行分析,结果如下:用HPLC测定 [Daicel Chiralcel IA, hexane/i-PrOH(70:30) , flow rate:
1.0 mL·min-1, λ = 254 nm, t (major) = 13.308, t (minor)= 12.405]; [α]D 26 = –35.67 (c 0.3, CH2Cl2); 1H
NMR (400MHz, CDCl3): δ7.90
(d, J = 8 Hz, 2H), 7.69 (d, J = 8 Hz, 2H), 7.52–7.49 (m, 2H), 7.39–7.32
(m, 4H), 7.28–7.19 (m, 1H), 7.17–7.05 (m, 5H), 5.95 (s, 1H), 4.36–4.28 (m, 1H), 3.79–3.72
(m, 2H), 3.53–3.43 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 194.94, 166.64,
166.14, 165.22 (J = 252 Hz), 149.54, 134.78, 133.92, 132.31, 130.45,
129.85, 129.48 (J = 9 Hz), 129.35, 129.07, 128.72, 128.35, 128.02,
126.17, 125.42, 117.77, 115.96 (J = 22 Hz), 60.20, 38.40, 38.04, 35.05;
IR (KBr) νmax: 3395.9,
2956.4, 2925.5, 1779.3, 1726.9, 1685.3, 1603.7, 1051.1, 1009.3, 981.3, 764.8,
702.8, 586.5 cm−1; HRMS-ESI: [M+H]+ Calcd for C31H23BrClFNO4,
606.0405, found: 606.0497.
以上数据证明目的产物合成成功。
实施例五:
反应瓶中依次加入奎宁硫脲 (11.2
mg,0.02 mmol),和2e (38.4 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4e (62.0 mg),白色固体,收率为95%,>20/1 dr,88%
ee。
对产物4e进行分析,结果如下:用HPLC测定 [Daicel Chiralcel IA, hexane/i-PrOH(70:30) , flow rate:
1.0 mL·min-1, λ = 254 nm, t (major) = 14.221, t (minor)= 13.063]; [α]D 26 = –31.20 (c 0.375, CH2Cl2); 1H
NMR (400MHz, CDCl3): δ7.84
(d, J = 8 Hz, 2H), 7.66 (d, J = 12 Hz, 2H), 7.43–7.39 (m, 2H), 7.31–7.29
(m, 3H), 7.21–7.18 (m, 2H), 7.06–6.98 (m, 5H), 5.76 (s, 1H), 4.32–4.29 (m, 1H), 3.68–3.63
(m, 2H), 3.43–3.35 (m, 2H); 13C NMR (101
MHz, DMSO-d6) δ 196.71, 165.87,
165.16, 164.12 (J = 247 Hz), 149.39, 137.66, 135.36, 134.82, 131.69,
131.49, 130.54, 130.16 (J = 9 Hz), 129.99, 128.65, 128.08, 128.01,
127.30, 126.88, 117.02, 115.26 (J = 22 Hz), 102.43, 65.01, 29.99, 18.65,
13.54; IR (KBr) νmax:
3424.2, 2956.7, 2925.3, 1777.7, 1719.7, 1685.2, 1604.0, 1560.5, 1481.4, 1287.9,
1005.0, 981.7, 765.3, 703.3, 603.1 cm−1; HRMS (ESI): m/z = (calcd
for (C31H22ClFINO4+H)+). HRMS-ESI:
[M+H]+ Calcd for C31H23ClFINO4,
654.0266, found: 654.0349.
以上数据证明目的产物合成成功。
实施例六:
反应瓶中依次加入奎宁硫脲 (11.2
mg,0.02 mmol),和2f (32.7 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4f (57.2 mg),白色固体,收率为96%,>20/1 dr,92%
ee。
对产物4f进行分析,结果如下:用HPLC测定 [Daicel Chiralcel AD-H, hexane/i-PrOH(70:30) , flow
rate: 1.0 mL·min-1, λ = 254 nm, t (major) = 10.524, t (minor)= 12.695]; [α]D 26 =–16.00 (c 0.425, CH2Cl2); 1H
NMR (400MHz, CDCl3): δ8.07
(d, J = 8 Hz, 2H), 7.74 (d, J = 8 Hz, 2H), 7.54–7.52 (m, 1H), 7.42–7.40
(m, 2H), 7.32–7.30 (m, 3H), 7.20–7.18 (m, 2H), 7.06–7.00
(m, 4H), 5.81 (s, 1H), 4.31–4.28 (m, 1H),
3.78–3.61 (m, 2H), 3.51–3.37 (m, 2H); 13C NMR (101 MHz, DMSO-d6)
δ 196.72, 166.05, 165.21, 164.15 (J =
248 Hz), 149.46, 139.24, 134.82, 133.05, 132.73, 130.58, 130.19 (J = 9
Hz), 129.19, 128.12, 128.03 127.27, 126.92, 125.69 (J = 4 Hz), 123.75 (J
= 272 Hz), 122.39, 117.06, 115.27 (J = 22 Hz), 60.12, 36.49, 35.65,
14.00; IR (KBr) νmax:
3422.7, 2957.3, 1774.5, 1691.3, 1604.2, 1535.1, 1408.1, 1275.9, 1156.8, 1014.2,
985.4, 764.4, 702.3, 621.4, 604.1 cm−1; HRMS-ESI: [M+H]+
Calcd for C32H23ClF4NO4, 596.1173,
found: 596.1263.
以上数据证明目的产物合成成功。
实施例七:
反应瓶中依次加入奎宁硫脲 (11.2
mg,0.02 mmol),和2g (27.2 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:10)即可得到目标产物4g (50.3 mg),白色固体,收率为93%,>20/1 dr,88%
ee。
对产物4g进行分析,结果如下:用HPLC测定 [Daicel Chiralcel IA, hexane/i-PrOH(70:30) , flow rate:
1.0 mL·min-1, λ = 254 nm, t (major) = 10.162, t (minor)= 8.641]; [α]D 26 = –30.52 (c 0.485, CH2Cl2); 1H
NMR (400MHz, CDCl3): δ7.85
(d, J = 8 Hz, 2H), 7.43–7.40 (m, 2H),
7.29–7.25 (m, 5H), 7.22–7.21 (m, 1H), 7.18–7.12
(m, 1H), 7.11–7.05 (m, 2H), 7.02–6.95 (m, 3H), 5.80 (s, 1H), 4.24–4.19 (m, 1H), 3.72–3.63
(m, 2H), 3.45–3.35 (m, 2H), 2.41 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ
195.28, 166.71, 166.06, 165.20 (J = 251 Hz), 149.63, 145.11, 134.09,
133.68, 130.51, 129.65, 129.60, 129.49 (J = 9 Hz), 129.22, 129.02,
128.72, 128.48, 127.93, 126.41, 117.67, 115.93 (J = 22 Hz), 60.09,
38.41, 38.09, 35.04, 21.83; IR (KBr) νmax:
3378.4, 3030.7, 2957.1, 2808.6, 1773.9, 1678.6, 1604.4, 1538.4, 1456.1, 1407.7,
1181.8, 1014.5, 978.1, 764.2, 701.2, 604.8 cm−1; HRMS-ESI: [M+H]+
Calcd for C32H26ClFNO4, 542.1456, found:
542.1512.
以上数据证明目的产物合成成功。
实施例八:
反应瓶中依次加入奎宁硫脲 (11.2
mg,0.02 mmol),和2h (31.5 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛(150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4h (54.9 mg),白色固体,收率为94%,>20/1 dr,92%
ee。
对产物4h进行分析,结果如下:用HPLC测定 [Daicel Chiralcel IA, hexane/i-PrOH(70:30) , flow rate:
1.0 mL·min-1, λ = 254 nm, t (major) = 8.029, t (minor)= 6.714]; [α]D 26 = –25.62 (c 0.32, CH2Cl2); 1H
NMR (400MHz, CDCl3): δ7.90
(d, J = 8 Hz, 2H), 7.48–7.42 (m, 4H),
7.28–7.15 (m, 5H), 7.06–6.95 (m, 5H), 5.83 (s, 1H), 4.33–4.17 (m, 1H), 3.71–3.65
(m, 2H), 3.48–3.35 (m, 2H), 1.33 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ
195.26, 166.73, 166.03, 165.18 (J = 252 Hz), 158.03, 149.61, 134.10,
133.54, 130.52, 129.51 (J = 9 Hz), 129.19, 129.00, 128.73, 128.71,
128.37, 127.91, 126.43, 125.92, 117.66, 115.92 (J = 22 Hz), 60.07,
38.49, 38.00, 35.34, 35.08, 31.14.; IR (KBr) νmax:
3430.3, 2959.8, 2869.4, 1780.4, 1676.9, 1604.3, 1500.6, 1406.3, 1010.9, 984.2,
849.1, 764.0, 702.1, 540.4 cm−1; HRMS-ESI: [M+H]+ Calcd
for C35H32ClFNO4, 584.1926, found: 584.2023.
以上数据证明目的产物合成成功。
实施例九:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2i(33.5 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛(150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4i (59.2 mg),白色固体,收率为98%,>20/1 dr,94%
ee。
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02
mmol),和2i (33.5 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛(150 mg),加入1.5 mL间二甲苯,在零下30摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4i (29.9 mg),白色固体,收率为79%,>20/1 dr,98%
ee。
对产物4i进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel AD-H, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 16.125, t (minor)= 14.439]; [α]D 26
= –28.33 (c 0.3, CH2Cl2);
1H NMR (400MHz, CDCl3): δ8.03
(d, J = 8 Hz, 2H), 7.68 (d, J = 8 Hz, 2H), 7.61 (d, J = 8
Hz, 2H), 7.49–7.39 (m, 5H), 7.30–7.29 (m, 3H), 7.26–7.24
(m, 1H), 7.19–7.16 (m, 1H), 7.14–7.08 (m, 2H), 7.02–6.97
(m, 3H), 5.84 (s, 1H), 4.28–4.19 (m, 1H),
3.75–3.69 (m, 2H), 3.53–3.37 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 195.31, 166.71, 166.09, 165.21 (J =
252 Hz), 149.62, 146.78, 139.64, 134.75, 134.06, 130.52, 129.66, 129.50 (J =
9 Hz), 129.28, 129.16, 129.05, 128.99, 128.72, 128.63, 127.97, 127.56, 127.41,
126.36, 117.72, 115.95 (J = 22 Hz), 60.14, 38.57, 38.10, 35.07; IR (KBr)
νmax: 3396.6,
3031.0, 1772.7, 1676.5, 1496.4, 1406.7, 1288.5, 1157.0, 1007.1, 984.2, 764.1,
698.3, 527.8 cm−1; HRMS-ESI: [M+H]+ Calcd for C37H28ClFNO4,
604.1613, found: 604.1698.
以上数据证明目的产物合成成功。
实施例十:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2j (32.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=1:10)即可得到目标产物4j (47.8 mg),白色固体,收率为80%,>20/1 dr,91%
ee。
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02
mmol),和2j (32.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下20摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4j (29.9 mg),白色固体,收率为80%,>20/1 dr,95%
ee。
对产物4j进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 8.608, t (minor)= 7.407]; [α]D 26
= –25.60 (c 0.25, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.87
(d, J = 8 Hz, 2H), 7.44–7.40 (m, 2H),
7.29–7.25 (m, 5H), 7.22–7.14 (m, 2H), 7.07–7.06
(m, 2H), 7.02–6.95 (m, 3H), 5.81 (s, 1H), 4.24–4.21 (m, 1H), 3.72–3.64
(m, 2H), 3.47–3.34 (m, 2H), 2.65 (t, J = 8 Hz,
2H), 1.66–1.58 (m, 2H), 1.32–1.26 (m, 4H), 0.91–0.86
(m, 3H); 13C NMR (101 MHz, CDCl3) δ 195.27, 166.72, 166.04, 165.18 (J = 252 Hz),
150.05, 149.63, 134.11, 133.83, 130.52, 129.57, 129.50 (J = 9 Hz),
129.26, 129.23, 129.20, 129.00, 128.52, 127.90, 126.42, 117.65, 115.92 (J
= 22 Hz), 60.06, 38.46, 38.05, 36.10, 35.06, 31.51, 30.88, 22.59, 14.10.; IR
(KBr) νmax: 3386.1,
3026.4, 2929.4, 2857.5, 1773.1, 1676.5, 1604.4, 1534.0, 1497.1, 1288.6, 1181.1,
1013.9, 984.5, 764.2, 700.8, 669.8, 495.3 cm−1; HRMS-ESI: [M+H]+
Calcd for C36H34ClFNO4, 598.2082, found:
598.2168.
以上数据证明目的产物合成成功。
实施例十一:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2k (27.7 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4k (49.3 mg),白色固体,收率为97%,>20/1 dr,90%
ee。
对产物4k进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 9.547, t (minor)= 8.319]; [α]D 26
= –28.36 (c 0.275, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.83
(d, J = 4 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.56–7.50 (m, 3H), 7.37–7.32
(m, 5H), 7.15–7.05 (m, 5H), 6.02 (s, 1H), 4.40–4.27 (m, 1H), 3.81–3.71
(m, 2H), 3.55–3.42 (m, 2H).; 13C NMR (101
MHz, CDCl3) δ 194.73, 166.65,
166.18, 165.35 (J = 222 Hz), 162.86 (J = 217 Hz), 149.54, 138.13,
133.91, 130.72 (J = 8 Hz), 130.45, 129.71, 129.50 (J = 9 Hz),
129.32, 129.05, 128.01, 126.19, 124.18, 121.21, 121.00, 117.76, 115.94 (J =
22 Hz), 115.13 (J = 22 Hz), 60.22, 38.59, 37.95, 35.20; IR (KBr) νmax: 3423.7, 3032.8, 2991.2, 2923.9,
1772.8, 1685.4, 1603.6, 1533.7, 1407.5, 1288.4, 1156.8, 1012.5, 850.1, 763.8,
700.9, 535.6 cm−1; HRMS-ESI: [M+H]+ Calcd for C31H23ClF2NO4,
546.1205, found: 546.1280.
以上数据证明目的产物合成成功。
实施例十二:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2l (29.3 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛(150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物5l(51.9 mg),白色固体,收率为94%,>20/1 dr,91%
ee。
对产物4l进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 10.053, t (minor)= 8.440]; [α]D 26
= –33.77 (c 0.225, CH2Cl2);
1H NMR (400MHz, DMSO-d6): δ8.45
(s, 1H), 8.09 (s, 1H), 7.97 (d, J = 8 Hz, 1H), 7.74–7.69 (m, 2H), 7.58–7.54
(m, 1H), 7.29–7.21 (m, 6H), 7.13–7.07 (m, 3H), 6.95 (d, J = 8 Hz, 2H), 4.64–4.08 (m, 1H), 3.94–3.53
(m, 2H), 3.40–3.34 (m, 2H).; 13C NMR (101
MHz, DMSO-d6) δ 196.22, 165.96,
165.17, 164.13 (J = 248 Hz), 149.41, 137.89, 134.83, 133.70, 133.30,
130.66, 130.55, 130.18 (J = 9 Hz), 129.06, 128.88, 128.22, 128.07,
128.00, 127.30, 126.88, 126.82, 117.03, 115.26 (J = 22 Hz), 60.58,
54.44, 35.60, 13.99; IR (KBr) νmax:
3407.9, 3031.0, 2925.9, 1773.1, 1686.0, 1603.5, 1571.4, 1481.9, 1288.4, 1157.4,
1013.7, 889.4, 764.1, 701.6, 603.4, 495.7 cm−1; HRMS-ESI: [M+H]+
Calcd for C31H23Cl2FNO4, 562.0910,
found: 562.1002.以上数据证明目的产物合成成功。
实施例十三:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2m (28.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4m (35.7 mg),白色固体,收率为74%,>20/1 dr,86%
ee。
对产物4m进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 10.262, t (minor)= 8.918]; [α]D 26
= –44.80 (c 0.25, CH2Cl2);
1H NMR (400MHz, DMSO): δ7.53
(d, J = 8 Hz, 1H), 7.47–7.46 (m, 1H),
7.43–7.40 (m, 2H), 7.38–7.36 (m, 1H), 7.39–7.29
(m, 3H), 7.21–7.12 (m, 4H), 7.07–7.05 (m, 2H), 7.03–6.97
(m, 3H), 5.78 (s, 1H), 4.26–4.19 (m, 1H),
3.84 (s, 1H), 3.70–3.65 (m, 2H),
3.47–3.34 (m, 2H).; 13C NMR (101
MHz, CDCl3) δ 195.60, 166.61,
166.08, 165.21 (J = 252 Hz), 160.13, 149.60, 137.44, 134.00, 130.49,
130.00, 129.67, 129.49 (J = 9 Hz), 129.28, 129.17, 129.07, 127.99,
126.33, 120.97, 120.63, 117.73, 115.95 (J = 22 Hz), 112.50, 60.13,
55.65, 38.58, 38.05, 35.08.; IR (KBr) νmax:
3427.1, 3071.3, 2988.0, 1772.3, 1642.4, 1603.3, 1406.7, 1288.3, 1259.0, 1157.4,
1093.4, 787.1, 763.6, 700.8, 496.2 cm−1; HRMS-ESI: [M+H]+
Calcd for C32H26ClFNO5, 558.1405, found:
558.1491.
以上数据证明目的产物合成成功。
实施例十四:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2n (27.7 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4n (57.9 mg),白色固体,收率为95%,>20/1 dr,96%
ee。
对产物4n进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel AD-H, hexane/i-PrOH(80:20) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 13.238, t (minor)= 14.299]; [α]D 26
= –24.00 (c 0.25, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.96–7.92 (m, 1H), 7.66–7.61
(m, 1H), 7.53–7.50 (m, 2H), 7.38–7.37 (m, 3H), 7.34–7.31
(m, 1H), 7.29–7.28 (m, 1H), 7.24–7.21 (m, 1H), 7.17–7.15
(m, 2H), 7.10–7.05 (m, 3H), 5.95 (s, 1H), 4.51–4.27 (m, 1H), 3.85–3.66
(m, 2H), 3.56–3.36 (m, 2H).; 13C NMR (101
MHz, CDCl3) δ 194.28, 166.36,
166.15, 165.16 (J = 252 Hz), 162.16 (J = 253 Hz), 163.43, 160.90,
149.52, 135.59 (J = 9 Hz), 133.84, 130.90 (J = 2 Hz), 130.43,
129.66, 129.48 (J = 9 Hz), 129.15, 129.06, 128.58, 128.02, 126.40,
124.90 (J = 3 Hz), 124.82 (J = 5 Hz), 117.75, 117.04 (J =
23 Hz), 115.89 (J = 22 Hz), 60.26, 42.94, 37.60, 35.45; IR (KBr) νmax: 3364.8, 3031.5, 2932.7, 2873.5,
1776.7, 1723.3, 1687.9, 1605.6, 1579.6, 1496.3, 1383.5, 1288.0, 1103.3, 1013.7,
985.9, 742.6, 604.2 cm−1; HRMS-ESI: [M+H]+ Calcd for C31H23ClF2NO4,
546.1205, found: 546.1270.
以上数据证明目的产物合成成功。
实施例十五:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2o (29.5 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4o(41.7 mg),白色固体,收率为79%,>20/1 dr,91%
ee。
对产物4o进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 11.817, t (minor)= 10.674]; [α]D 26
= –21.60 (c 0.25, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.83–7.78 (m, 1H), 7.75–7.70
(m, 1H), 7.44–7.41 (m, 2H), 7.31–7.27 (m, 4H), 7.23–7.20
(m, 1H), 7.18–7.16 (m, 2H), 7.09–7.03 (m, 3H), 7.01–6.98
(m, 2H), 5.86 (s, 1H), 4.30–4.17 (m, 1H),
3.71–3.61 (m, 2H), 3.43–3.34 (m, 2H).; 13C NMR (101 MHz, CDCl3)
δ 193.48, 168.30, 166.61, 166.21, 165.26
(J = 252 Hz), 149.52, 133.84, 130.42, 129.80, 129.48 (J = 9 Hz),
129.21 (J = 3 Hz), 129.11, 128.73, 128.63, 128.08, 127.34, 126.07,
125.51, 118.04, 117.86, 117.83, 116.00 (J = 22 Hz), 60.27, 38.34, 38.04,
35.05; IR (KBr) νmax:
3420.1, 3068.1, 1772.7, 1686.0, 1517.3, 1496.8, 1285.7, 1157.5, 1109.8, 1013.5,
893.3, 764.5, 701.3, 497.7 cm−1; HRMS-ESI: [M+H]+ Calcd
for C31H22ClF3NO4, 564.1111, found:
564.1191.
以上数据证明目的产物合成成功。
实施例十六:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2p (30.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4p(43.1 mg),白色固体,收率为95%,>20/1 dr,87%
ee。
对产物5p进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel AD-H, hexane/i-PrOH(70:30) , flow rate: 1.0 mL•min-1, λ = 254 nm, t
(major) = 17.484, t (minor)= 21.355]; [α]D26
= 26.47 (c 0.34, CHCl3); 1H NMR (400MHz, CDCl3): δ7.83
(d, J = 8 Hz, 2H), 7.67 (d, J = 4 Hz, 2H), 7.48-7.32 (m, 11H), 7.10–7.00 (m, 2H), 6.81 (s, 1H), 5.31(d, J = 8 Hz, 1H), 3.60
(d, J = 16 Hz, 1H), 3.50 (dd, J = 8 Hz, J = 8 Hz, 1H); 13C NMR (101 MHz, DMSO):
δ 197.26, 166.72, 165.93, 150.16, 136.04,
135.54, 133.54, 131.72, 128.75, 128.46, 128.36, 128.20, 128.07, 127.87, 127.71,
127.21, 125.50, 124.63, 115.67, 99.52, 63.04, 37.88, 36.98; IR (KBr) νmax: 3377.0, 2922.3, 1759.1, 1670.2, 1589.2, 1514.2,
1400.5, 1011.7, 948.1, 756.4, 694.8, 564.0 cm−1; HRMS (CI): m/z = 495.1237
(calcd for C30H22ClNO4).
以上数据证明目的产物合成成功。
实施例十七:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2q (24.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4q (48.7 mg),白色固体,收率为94%,>20/1 dr,90%
ee。
对产物4q进行分析,结果如下: 用HPLC测定0.35, CH2Cl2);
[Daicel Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 11.161, t (minor)= 8.750]; [α]D 26
= –13.14 (c 0.35, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.60–7.53 (m, 1H), 7.44–7.41
(m, 2H), 7.29–7.26 (m, 3H), 7.22–7.17 (m, 3H), 7.10–7.08
(m, 2H), 7.01–6.96 (m, 3H), 6.54–6.53 (m, 1H), 5.84 (s, 1H), 4.27–4.19 (m, 1H), 3.67–3.51
(m, 2H), 3.37–3.30 (m, 2H).; 13C NMR (101
MHz, CDCl3) δ 184.99, 166.03,
165.18 (J = 251 Hz), 152.08, 149.54, 147.16, 133.88, 130.51, 129.64,
129.60 (J = 9 Hz), 129.29, 129.22, 129.03, 127.98, 126.04, 118.27,
117.73, 115.90 (J = 22 Hz), 112.83, 60.07, 38.28, 37.67, 35.16; IR (KBr)
νmax: 3415.9,
3071.3, 2925.0, 1771.9, 1668.1, 1568.0, 1496.0, 1408.5, 1288.3, 1157.4, 1013.2,
904.7, 763.6, 701.8, 593.1 cm−1; HRMS-ESI: [M+H]+ Calcd
for C29H22ClFNO5, 518.1092, found: 518.1158.
以上数据证明目的产物合成成功。
实施例十八:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2r (25.9 mg, 0.1 mmol),3a
(51.0mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4r (51.3 mg),白色固体,收率为96%,>20/1 dr,88%
ee。
对产物4r进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 11.791, t (minor)= 9.362]; [α]D 26
= –47.50 (c 0.2, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.72–7.68 (m, 2H), 7.43–7.39
(m, 2H), 7.32–7.30 (m, 3H), 7.22–7.19 (m, 1H), 7.18–7.13
(m, 2H), 7.09–7.08 (m, 2H), 7.04–6.97 (m, 3H), 5.69 (s, 1H), 4.23–4.20 (m, 1H), 3.72–3.61
(m, 2H), 3.39–3.32 (m, 2H); 13C NMR (101
MHz, DMSO-d6) δ 190.01, 166.00,
165.19, 164.13 (J = 248 Hz), 149.43, 143.07, 135.65, 134.82, 134.17, 130.59,
130.17 (J = 9 Hz), 129.06, 128.88, 128.16, 128.04, 127.12, 126.91,
117.06, 115.27 (J = 22 Hz), 99.52, 59.90, 54.45, 36.95, 35.55; IR (KBr) νmax: 3424.3, 3026.4, 2978.4, 1763.9,
1654.6, 1603.4, 1534.5, 1414.2, 1384.4, 1290.6, 1157.0, 1011.7, 935.2, 763.5,
700.5, 484.9 cm−1; HRMS-ESI: [M+H]+ Calcd for C29H22ClFNO4S,
534.0864, found: 534.0940.
以上数据证明目的产物合成成功。
实施例十九:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2s (16.2 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4s(33.2 mg),白色固体,收率为87%,>20/1 dr,88%
ee。
对产物4s进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 8.633, t (minor)= 11.288]; [α]D 26
= –0.280 (c 0.45, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.75 – 7.71 (m, 2H), 7.68 – 7.64
(m, 1H), 7.41 – 7.35 (m, 3H), 7.33 – 7.26 (m, 3H), 7.08 (t, J = 8 Hz), 6.94 (d, J
= 8 Hz, 1H), 6,69–6.62 (m, 2H),
5.24 (dd, J = 4 Hz, J = 12 Hz, 1H), 3.45 (dd, J = 8 Hz, J
= 16 Hz, 1H), 3.38 (dd, J = 8 Hz, J = 12 Hz, 1H), 2.41 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ13C NMR
(101 MHz, CDCl3) δ 198.94, 170.56,
166.42, 165.15 (J = 251 Hz), 149.15, 136.54, 135.42, 131.42, 129.77,
129.61 (J = 9 Hz), 129.42, 129.14, 127.79, 127.57, 127.50, 126.91,
122.78, 115.90 (J = 22 Hz), 54.17, 37.67, 27.30; IR (KBr) νmax: 3446.9, 3067.9, 2859.7, 1770.4,
1719.5, 1647.2, 1575.4, 1516.0, 1484.4, 1450.6, 1384.3, 1261.2, 1210.3, 1067.2,
988.9, 761.9, 697.1, 473.6 cm−1; HRMS-ESI: [M+H]+ Calcd
for C26H23FNO4, 432.1533, found: 432.1611.
以上数据证明目的产物合成成功。
实施例二十:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2t (22.4 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4t (45.8 mg),白色固体,收率为93%,>20/1 dr,94%
ee。
对产物4t进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel AD-H, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 12.074, t (minor)= 14.296]; [α]D 26
= –8.80 (c 0.25, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.95
(d, J = 4Hz, 2H), 7.60 – 7.56 (m, 1H),
7.47 – 7.43 (m, 2H), 7.39 – 7.35 (m, 2H), 7.28 – 7.26
(m, 3H), 7.24 – 7.18 (m, 2H), 7.10 – 7.09 (m, 2H), 7.05 – 7.02
(m, 1H), 7.00 – 6.95 (m, 3H), 5.84 (s, 1H), 4.28 – 4.19 (m, 1H), 3.73 – 3.68
(m, 2H), 3.54 – 3.40 (m, 2H).; 13C NMR (101
MHz, CDCl3) δ 196.19, 167.21,
166.16, 165.08 (J = 251 Hz), 151.02, 136.31, 134.38, 133.90, 130.51,
129.40 (J = 9 Hz), 129.31, 128.94, 128.92, 128.71, 128.32, 127.77,
124.65, 124.51, 116.42, 115.85 (J = 22 Hz), 60.60, 38.58, 38.34, 34.77.;
IR (KBr) νmax: 3424.1,
3064.9, 2981.6, 1768.3, 1680.3, 1647.3, 1602.9, 1533.0, 1491.6, 1454.1, 1384.3,
1288.0, 1156.9, 1001.9, 984.2, 752.3, 602.3 cm−1; HRMS-ESI: [M+H]+
Calcd for C31H25FNO4, 494.1689, found:
494.1767.
实施例二十一:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2u (24.2 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4u (47.6 mg),白色固体,收率为93%,>20/1 dr,89%
ee。
对产物4u进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 13.817, t (minor)= 17.246]; [α]D 26
= –22.53 (c 0.25, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.99–7.95 (m, 2H), 7.39–7.35
(m, 2H), 7.29–7.28 (m, 3H), 7.26–7.20 (m, 1H), 7.18–7.13
(m, 2H), 7.11–7.08 (m, 3H), 7.05–6.94 (m, 4H), 5.88 (s, 1H), 4.29–4.19 (m, 1H), 3.70–3.66
(m, 2H), 3.51–3.39 (m, 2H).; 13C NMR (101
MHz, CDCl3) δ 194.74, 167.19,
166.20 (J = 254 Hz), 166.19, 165.09 (J = 251 Hz), 150.97, 134.31,
132.78 (J = 3 Hz), 131.06 (J = 9 Hz), 130.47, 129.39 (J =
9 Hz), 129.36, 129.15, 128.95, 128.34, 127.80, 125.41, 124.68, 124.41, 116.31 (J
= 27 Hz), 115.85 (J = 22 Hz), 60.64, 38.40, 34.76, 21.57; IR (KBr) νmax: 3427.1, 3032.8, 2984.8, 1767.5,
1642.9, 1600.8, 1529.3, 1491.9, 1384.4, 1288.3, 1156.9, 1011.0, 847.2, 798.2,
700.5, 494.2 cm−1; HRMS-ESI: [M+H]+ Calcd for C31H24F2NO4,
512.1595, found: 512.1674.
以上数据证明目的产物合成成功。
实施例二十二:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2v (25.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4v(50.7 mg),白色固体,收率为96%,>20/1 dr,90%
ee。
对产物4v进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 16.150, t (minor)= 20.965]; [α]D 26
= –33.33 (c 0.225, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.88
(d, J = 8Hz, 2H), 7.42 (d, J = 8Hz, 2H), 7.39–7.35 (m, 2H), 7.29–7.28
(m, 3H), 7.26–7.21 (m, 1H), 7.16–7.14 (m, 1H), 7.10–7.08
(m, 2H), 7.06–6.95 (m, 4H), 5.89 (s, 1H), 4.30–4.19 (m, 1H), 3.70–3.66
(m, 2H), 3.51–3.39 (m, 2H).; 13C NMR (101
MHz, CDCl3) δ 195.22, 167.18,
166.22, 165.10 (J = 251 Hz), 150.95, 140.44, 134.62, 134.27, 130.47,
129.75, 129.39 (J = 9 Hz), 129.40, 129.23, 128.97, 128.67, 127.83,
124.71, 124.36, 116.47, 115.86 (J = 22 Hz), 60.69, 38.48, 38.39, 34.77.;
IR (KBr) νmax: 3415.9,
3026.4, 1767.3, 1681.8, 1603.0, 1571.5, 1491.2, 1401.2, 1288.4, 1157.0, 1092.9,
984.2, 794.3, 700.8, 670.6, 528.0 cm−1; HRMS-ESI: [M+H]+
Calcd for C31H24ClFNO4, 528.1300, found:
528.1387.
以上数据证明目的产物合成成功。
实施例二十三:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2w (30.3 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4w(25.7 mg),白色固体,收率为95%,>20/1 dr,>99%
ee。
对产物4w进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 17.579]; [α]D 26
= –56.00 (c 0.25, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.80
(d, J = 8Hz, 2H), 7.58 (d, J = 8Hz, 2H), 7.39–7.35 (m, 2H), 7.28–7.21
(m, 4H), 7.15–7.14 (m, 1H), 7.09–7.04 (m, 3H), 7.01–6.95
(m, 3H), 5.89 (s, 1H), 4.30–4.21 (m, 1H),
3.70–3.66 (m, 2H), 3.50–3.39 (m, 2H).; 13C NMR (101 MHz, CDCl3)
δ 195.43, 167.16, 166.21, 165.09 (J
= 252 Hz), 150.94, 135.01, 134.25, 132.23, 130.46, 129.82, 129.40, 129.39 (J
= 9 Hz), 129.20, 128.97, 127.83, 124.72, 124.34, 116.48, 115.86 (J = 22
Hz), 60.70, 38.46, 38.38, 34.76; IR (KBr) νmax:
3419.8, 3064.8, 2959.2, 2923.9, 1768.4, 1603.0, 1585.2, 1532.0, 1491.3, 1454.7,
1288.3, 1156.9, 1009.4, 983.5, 813.1, 700.8, 458.5 cm−1; HRMS-ESI:
[M+H]+ Calcd for C31H24BrFNO4,
572.0794, found: 572.0894.
以上数据证明目的产物合成成功。
实施例二十四:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2x (35.0 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为乙酸乙酯:石油醚=1:10)即可得到目标产物4x(40.3 mg),白色固体,收率为75%,>20/1 dr,>99%
ee。
对产物4x进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 19.995]; [α]D 26
= –36.19 (c 0.21, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.81
(d, J = 8Hz, 2H), 7.64 (d, J = 8Hz, 2H), 7.44–7.37 (m, 2H), 7.29–7.24
(m, 4H), 7.15–7.14 (m, 1H), 7.08–7.04 (m, 3H), 7.00–6.98
(m, 3H), 5.85 (s, 1H), 4.28–4.20 (m, 1H),
3.68–3.64 (m, 2H), 3.49–3.39 (m, 2H).; 13C NMR (101 MHz, CDCl3)
δ 195.74, 167.16, 166.20, 165.12 (J
= 251 Hz), 150.95, 138.25, 135.53, 134.25, 130.46, 129.65, 129.39 (J = 9
Hz), 129.16, 128.99, 128.64, 128.35, 127.85, 124.74, 124.33, 116.51, 115.89 (J
= 21 Hz), 102.09, 60.69, 38.40, 34.72; IR (KBr) νmax:
3427.2, 3029.6, 2988.0, 2923.9, 1767.0, 1642.0, 1603.2, 1580.8, 1529.1, 1454.4,
1384.5, 1288.1, 1156.7, 1005.3, 982.5, 756.1, 700.4, 498.0 cm−1;
HRMS-ESI: [M+H]+ Calcd for C31H24FINO4,
620.0656, found: 620.0724.
以上数据证明目的产物合成成功。
实施例二十五:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2y (23.8 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4y (48.3mg),白色固体,收率为95%,>20/1 dr,88%
ee。
对产物4y进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel AD-H, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 9.549, t (minor)= 11.305]; [α]D 26
= –28.51 (c 0.27, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.95
(d, J = 8Hz, 2H), 7.60–7.56 (m, 1H),
7.48–7.44 (m, 2H), 7.40–7.37 (m, 2H), 7.29–7.26
(m, 2H), 7.10–7.08 (m, 2H), 7.01–6.92 (m, 5H), 5.82 (s, 1H), 4.30–4.19 (m, 1H), 3.72–3.68
(m, 2H), 3.52–3.39 (m, 2H), 2.21 (s, 3H).; 13C
NMR (101 MHz, CDCl3) δ
196.24, 167.39, 166.13, 165.06 (J = 250 Hz), 148.90, 136.37, 134.48,
134.25, 133.85, 130.51, 129.74, 129.71, 129.51, 129.42 (J = 9 Hz),
129.24, 128.90, 128.32, 127.73, 124.14, 116.13, 115.82 (J = 22 Hz),
60.62, 38.68, 38.24, 34.66, 20.91; IR (KBr) νmax:
3415.7, 3064.9, 2956.0, 2925.0, 1765.8, 1683.9, 1602.8, 1448.3, 1384.2, 1288.8,
1157.9, 1012.5, 984.8, 849.6, 747.3, 700.4, 566.7 cm−1; HRMS-ESI:
[M+H]+ Calcd for C32H27FNO4,
508.1846, found: 508.1933.
以上数据证明目的产物合成成功。
实施例二十六:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2z (25.9 mg, 0.1 mmol),3a
(53.8 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4z(62.5 mg),白色固体,收率为96%,>20/1 dr,90%
ee。
对产物4z进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 27.337, t (minor)= 31.478]; [α]D 26
= –20.83 (c 0.24, CH2Cl2);
1H NMR (400MHz, CDCl3): δ7.81
(d, J = 8Hz, 2H), 7.63 (d, J = 8Hz, 2H), 7.42–7.39 (m, 2H), 7.29–7.26
(m, 3H), 7.08–6.98 (m, 5H), 6.60–6.53 (m, 2H), 5.82 (s, 1H), 4.34–4.14 (m, 2H), 3.72 (s, 3H), 3.68–3.61 (m, 2H), 3.44–3.38
(m, 2H).; 13C NMR (101 MHz, CDCl3) δ 195.90, 167.23, 165.01 (J = 224 Hz), 160.45,
151.81, 138.24, 135.61, 134.40, 130.48, 129.65, 129.43 (J = 9 Hz),
128.97, 127.80, 115.93, 115.91 (J = 22 Hz), 110.34, 102.38, 102.06,
60.73, 55.65, 38.77, 37.92, 34.61. IR (KBr) νmax:
3406.5, 3063.9, 2931.5, 2956.0, 1770.1, 1684.0, 1626.8, 1560.6, 1445.4, 1442.1,
1394.1, 1192.2, 1158.3, 1005.5, 984.2, 763.1, 700.7, 572.2 cm−1;
HRMS-ESI: [M+H]+ Calcd for C32H26FINO5,
650.0761, found: 650.0859.
以上数据证明目的产物合成成功。
实施例二十七:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2a (25.9 mg, 0.1 mmol),3b
(50.2 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4aa(41.2 mg),白色固体,收率为81%,>20/1 dr,89%
ee。
对产物4aa进行分析,结果如下: 用HPLC测定 [Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 8.287, t (minor)= 7.543]; [α]D26
= –5.92 (c 0.35, CHCl3); 1H NMR
(400MHz, CDCl3): δ7.97–7.95 (m, 2H), 7.62-7.59 (m, 1H), 7.50-7.45 (m, 3H), 7.42–7.40 (m, 2H), 7.36–7.32
(m, 2H), 7.30–7.29 (m, 3H), 7.23 (d, J = 4 Hz,
1H), 7.18–7.16 (m, 1H), 7.08–7.05 (m, 2H), 6.97 (d, J = 12 Hz, 1H), 5.77 (s,
1H), 4.18(d, J = 12 Hz, 1H), 3.75–3.69
(m, 2H), 3.47–3.37 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 195.66, 167.11,
166.74, 149.71, 136.15, 134.13, 134.07, 133.09, 132.34, 130.53, 129.60, 129.28,
129.04, 129.01, 128.86, 128.37, 127.92, 127.05, 126.36, 117.71, 60.02, 38.61,
38.10, 34.99; IR (KBr) νmax:
3408.3, 2956.8, 1773.7, 1682.6, 1481.4, 1408.5, 1238.2, 1182.0, 1092.3, 982.7,
756.5, 634.7, 585.9 cm−1; HRMS-CI: [M]+ Calcd for C31H24ClNO4,
509.1394, found: 509.1396.
以上数据证明目的产物合成成功。
实施例二十八:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2a (25.9 mg, 0.1 mmol),3c
(46.2 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为乙酸乙酯:石油醚=1:10)即可得到目标产物4ab(40.1 mg),白色固体,收率为82%,>20/1 dr,84%
ee。
对产物4ab进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 12.058, t (minor)= 8.995]; [α]D 26
= –30.76 (c 0.26, CHCl3); 1H
NMR (400MHz, CDCl3): δ8.10
(d, J = 8 Hz, 2H), 7.74–7.71 (m, 1H),
7.65 (d, J = 8 Hz, 2H), 7.61–7.53
(m, 2H), 7.37–7.24 (m, 4H), 7.17–7.12 (m, 1H), 6.63 (s, 1H), 4.89 (d, J = 4 Hz,
1H), 3.69 (d, J = 8 Hz, 1H), 3.57 (dd, J = 12 Hz, J = 8
Hz, 1H), 2.25–2.20 (m, 2H), 1.98–1.95(m, 1H), 1.18 (d, J = 4 Hz, 2H), 1.07 (d, J
= 4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 196.79, 167.38, 167.04, 149.26, 142.72, 136.10, 133.86,
130.70, 129.81, 129.42, 129.00, 128.88, 128.72, 128.36, 128.16, 127.04, 126.84,
126.16, 117.70, 60.67, 38.82, 37.90, 37.69, 24.44, 24.13, 24.08, 21.55; IR
(KBr) νmax: 3398.4,
2926.2, 2870.6, 1780.8, 1686.5, 1612.3, 1481.4, 1448.7, 1187.2, 1001.6, 974.4,
688.7, 570.6, 535.2 cm−1; HRMS-CI: [M]+ Calcd for C29H28ClNO4,
489.1707, found: 489.1713.
以上数据证明目的产物合成成功。
实施例二十九:
反应瓶中依次加入奎宁硫脲(11.2 mg,0.02 mmol),和2a (25.9 mg, 0.1 mmol),3d
(47.0 mg, 0.2 mmol),4Å分子筛 (150 mg),加入1.5 mL间二甲苯,在零下5摄氏度条件下反应12小时,反应体系通过简单的柱层析(洗脱剂为二氯甲烷:石油醚=2:1)即可得到目标产物4ac (42.9 mg),白色固体,收率为87%,>20/1 dr,84%
ee。
对产物4ac进行分析,结果如下: 用HPLC测定[Daicel
Chiralcel IA, hexane/i-PrOH(70:30) , flow rate: 1.0 mL·min-1, λ =
254 nm, t (major) = 9.697, t (minor)= 7.396]; [α]D 26
= –44.76 (c 0.42, CHCl3); 1H
NMR (400MHz, CDCl3): δ7.93–7.91 (m, 2H), 7.63–7.61
(m, 2H), 7.59–7.55 (m, 1H), 7.51–7.48 (m, 1H), 7.45–7.37
(m, 4H), 7.24–7.21 (m, 1H), 7.18 (d, J = 4 Hz,
1H), 7.02–6.99 (m, 1H), 4.75–4.71 (m, 1H), 3.45–3.42
(m, 2H), 2.70–2.59 (m, 2H), 2.43–2.27(m, 2H), 2.12 (s, 3H); 13C NMR (101 MHz,
DMSO) δ 197.22, 166.43, 165.89, 149.34, 136.09,
133.65, 133.21, 131.76, 128.84, 128.77, 128.66, 128.32, 128.22, 127.66, 127.62,
127.52, 127.41, 117.44, 59.23, 37.47, 37.33, 31.16, 27.46, 14.72; IR (KBr) νmax: 3290.9, 2915.6, 1745.2, 1695.7,
1661.8, 1597.0, 1474.2, 1229.5, 1193.1, 1001.1, 990.3, 757.5, 627.3, 549.8,
537.7 cm−1; HRMS-CI: [M]+ Calcd for C27H24ClNO4S,
493.1115, found: 493.1108.
以上数据证明目的产物合成成功。
Claims (10)
1.一种手性3,4-二氢香豆素衍生化合物合成方法,其特征在于,包括以下步骤:在反应器中,以邻羟基查尔酮化合物和吖内酯化合物为反应物,以手性硫脲化合物为催化剂,在苯类溶剂中,于-30℃~-5℃反应得到3,4-二氢香豆素衍生化合物;
所述邻羟基查尔酮化合物的化学结构式为
,其中R1选自:5-氯、氢、5-甲基、4-甲氧基中的一种;R2选自:甲基、苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-碘苯基、4-三氟甲基苯基、4-甲基苯基、4-叔丁基苯基、4-苯基苯基、4-正戊基苯基、3-氟苯基、3-氯苯基、3-甲氧基苯基、2-氟苯基、3,4-2氟苯基、1-萘基、2-呋喃基,2-噻吩基中的一种;
所述吖内酯化合物的化学结构式为,其中R3为苄基、异丁基或者2-甲硫基乙基;R4为苯基、4-氟苯基或者4-甲基苯基;
所述3,4-二氢香豆素衍生化合物的结构式为:
。
2.根据权利要求1所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于: 所述苯类溶剂为间二甲苯。
3.根据权利要求1所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于: 以摩尔量计,所述催化剂的用量为邻羟基查尔酮化合物的5~20%;吖内酯化合物的用量为邻羟基查尔酮化合物的1~2倍。
4.根据权利要求1所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于: 向反应器中依次加入催化剂、邻羟基查尔酮化合物、吖内酯化合物,搅拌后再加入苯类溶剂进行反应。
5.根据权利要求1所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于:所述催化剂为手性奎宁硫脲。
6.根据权利要求1所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于: 所述反应时间为12个小时;反应温度为-5℃。
7.根据权利要求1所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于:反应结束后,反应液通过简单的柱层析即可得到所述手性3,4-二氢香豆素衍生化合物;所述柱层析时洗脱剂为体积比为1∶(1~2)的二氯甲烷/石油醚混合液。
8.根据权利要求1所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于:反应体系中加入4Å分子筛为添加剂。
9.根据权利要求8所述手性3,4-二氢香豆素衍生化合物合成方法,其特征在于: 以质量计,所述4Å分子筛的用量邻羟基查尔酮化合物用量的20%。
10.根据权利要求1~9所述任意一种合成方法制备的手性3,4-二氢香豆素衍生化合物。
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