手性奎宁硫脲的应用的制作方法

本发明涉及手性螺环化合物的合成，具体涉及手性奎宁硫脲在催化靛红衍生β,γ-不饱和α-酮酸酯化合物和3-羟基-4氢-色烯-4-酮反应中的应用。

背景技术：

手性氧杂螺环羟吲哚类化合物广泛存在于天然产物和药物分子中，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。手性螺环羟吲哚-苯并吡喃-酮并-3,4-二氢-吡喃化合物，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氧杂螺环羟吲哚半缩酮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。手性的氧杂螺环羟吲哚半缩酮化合物具有连续的共轭结构，这种连续共轭结构使其容易发生电子转移和跃迁，故氧杂螺环羟吲哚半缩酮化合物在电子转移、光电材料方面也具有潜在的应用价值。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氧杂螺环羟吲哚类化合物的方法报道的比较少。β,γ-不饱和α-酮酸酯作为一个具有多反应位点、缺电子的β,γ-不饱和体系和活化的α-羰基的骨架的应用受到了广泛的关注和报道，而靛红衍生β,γ-不饱和α-酮酸酯骨架参与的化学反应的报道比较少。施敏课题组在2014年报道了以(dhq)2aqn为催化剂，靛红衍生β,γ-不饱和α-酮酸酯和联烯酯的不对称[3+2]环加成反应，能以56%‒99%的收率和76%‒98%的对映选择性得到手性氧杂螺环羟吲哚类化合物。(h.-b.yang,y.-z.zhao,r.sang,y.wei,m.shi,asymmetricsynthesisofbioxindole-substitutedhexahydro-furo[2,3-b]furansviahydroquinineanthraquinone-1,4-diyldi-ether-catalyzeddominoannulationofacylidenoxindoles/isatins,acylidenoxindolesandallenoates.adv.synth.catal.,2014,356,3799-380),但该反应的催化剂用量较大，反应的非对映选择性不是很高，从而限制了该反应的进一步应用价值。

因此很有必要寻找一种新的合成手性螺环羟吲哚-苯并吡喃-酮并-3,4-二氢-吡喃化合物的方法，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。

技术实现要素：

本发明的目的是提供一种手性螺环羟吲哚-苯并吡喃-酮并-3,4-二氢-吡喃化合物的催化合成方法及由此制备的手性螺环羟吲哚-苯并吡喃-酮并-3,4-二氢-吡喃化合物。

为达到上述发明目的，本发明采用的技术方案是：一种氧杂螺环羟吲哚半缩酮化合物的合成方法，具体为：以靛红衍生β,γ-不饱和α-酮酸酯化合物和3-羟基-4氢-色烯-4-酮为反应物，以手性奎宁硫脲为催化剂，在卤代烃类溶剂中，反应得到产物手性螺环羟吲哚-苯并吡喃-酮并-3,4-二氢-吡喃化合物；

所述靛红衍生β,γ-不饱和α-酮酸酯化合物的化学结构式为，其中r¹选自：甲基、甲氧基甲基、苄基、烯丙基、苄氧羰基中的一种；r²选自：氢、5-氟、5-氯、5-溴、5-甲基、5-甲氧基、6-氯、6-溴、6-甲氧基、7-氟、7-甲基、5,6-二氟、5,7-二甲基中的一种；r³选自：甲基、乙基中的一种；

所述3-羟基-4氢-色烯-4-酮化合物的化学结构式为，其中r为氢、6-氟、6-溴、6-甲基、7-甲氧基中的一种；

所述手性螺环羟吲哚-苯并吡喃-酮并-3,4-二氢-吡喃化合物的结构式为：

。

优选的技术方案中，以摩尔量计，所述催化剂的用量为靛红衍生β,γ-不饱和α-酮酸酯化合物的2-10%；进一步优选为5%。

优选的技术方案中，以摩尔量计，3-羟基-4氢-色烯-4-酮化合物的用量为靛红衍生β,γ-不饱和α-酮酸酯化合物的1-2倍；进一步优选为1.5倍。

优选的技术方案中，反应温度低于室温，比如-30℃至室温；反应时间为36-41小时。优选-20℃反应40小时。

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下，向反应瓶中依次加入催化剂、靛红衍生β,γ-不饱和α-酮酸酯化合物、溶剂，搅拌15-35分钟后加入3-羟基-4氢-色烯-4-酮化合物进行反应，反应结束后，粗产物通过简单的柱层析（洗脱剂优选为石油醚∶乙酸乙酯=2：1～1:1）即可得到目标产物；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。手性的氧杂螺环羟吲哚半缩酮化合物具有连续的共轭结构，这种连续共轭结构使其容易发生电子转移和跃迁，故氧杂螺环羟吲哚半缩酮化合物可以用做电子转移、光电材料。

本发明进一步公开上述手性奎宁硫脲在催化靛红衍生β,γ-不饱和α-酮酸酯化合物和3-羟基-4氢-色烯-4-酮反应中的应用。

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3-羟基-4氢-色烯-4-酮化合物和靛红衍生β,γ-不饱和α-酮酸酯化合物为反应物、手性多功能奎宁硫脲为催化剂合成手性螺环羟吲哚-苯并吡喃-酮并-3,4-二氢-吡喃化合物的方法，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氧杂螺环羟吲哚半缩酮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-环化串联反应，体系中没有副产物生成；

3．本发明公开的合成氧杂螺环羟吲哚半缩酮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(5.9mg，0.01mmol)，和1a(25.9mg,0.1mmol)，2a(16.2mg,0.1mmol)，加入1ml二氯甲烷，在室温条件下反应12小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3a(36.6mg)，黄色固体，mp:198-201℃,收率为87%，>20/1dr，87%ee。

反应瓶中依次加入奎宁硫脲(5.9mg，0.01mmol)，和1a(25.9mg,0.1mmol)，2a(16.2mg,0.1mmol)，加入1ml二氯甲烷，在零摄氏度条件下反应12小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3a(33.3mg)，黄色固体，mp:198-201℃,收率为79%，>20/1dr，96%ee。

反应瓶中依次加入奎宁硫脲(3.0mg，0.005mmol)，和1a(25.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下搅拌20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3a(40.8mg)，黄色固体，mp:198-201℃,收率为97%，>20/1dr，98%ee。

对产物3a进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=13.936,t(minor)=24.650];[α]d²⁵=+63.0(c=0.51,chcl3);¹hnmr(400mhz,cdcl3)δ8.83(s,0.5h),8.21(ddd,j=13.2,8.0,1.2hz,1h),7.89(d,j=7.6hz,1h),7.54–7.49(m,1h),7.45(td,j=8.0,1.2hz,0.5h),7.38(td,j=8.0,1.2hz,1h),7.33–7.29(m,1h),7.23–7.18(m,1h),7.15–7.03(m,2h),6.98(d,j=7.8hz,0.5h),5.05(s,0.5h),4.42–4.32((dq,j=7.2,6.8hz,2h)),3.38(d,j=8.0hz,3h),3.31(d,j=14.0hz,0.5h),3.07(d,j=14.8hz,0.5h),2.69(d,j=14.8hz,0.5h),2.33(d,j=14.0hz,0.5h),1.38(dt,j=15.8,7.1hz,3h);¹³cnmr(101mhz,cdcl3)δ177.71,175.47,171.97,171.84,168.43,167.33,155.05,154.99,147.63,145.48,143.87,143.78,137.11,136.67,133.58,133.44,130.23,129.86,129.54,128.80,127.69,126.32,126.08,124.78,124.77,124.60,123.76,123.74,123.71,123.41,118.07,117.87,109.66,108.61,94.90,93.63,63.71,62.80,50.16,49.56,37.60,37.51,27.41,27.25,14.15,14.08;ir:3276.4,2961.7,1740.5,1714.4,1627.4,1611.0,1468.6,1260.0,1192.0,1034.8,1020.7,796.4,758.9,692.5cm^-1;hrmscalcd.forc23h19nnao7[m+na]⁺444.1054,found:444.1065；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(3.0mg，0.005mmol)，和1b(28.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.6:1）即可得到目标产物3b(42.8mg)，黄色固体，mp:141-144℃,收率为95%，>20/1dr，98%ee。

对产物3b进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=12.362,t(minor)=17.090];[α]d²⁵=+98.0(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.48(s,0.3h),8.22(d,j=7.2hz,0.4h),8.18(d,j=7.6hz,0.6h),7.93(d,j=7.6hz,0.6h),7.51–7.49(m,1h),7.42(t,j=7.2hz,0.3h),7.36(t,j=7.6hz,0.7h),7.33–7.28(m,1h),7.23(d,j=2.9hz,0.3h),7.21–7.15(m,1h),7.11–7.04(m,1.7h),5.29(s,0.7h),5.29(t,j=10.1hz,1h),5.21(dd,j=10.8,5.2hz,1h),4.36(dq,j=12.7,5.7hz,2h),3.42(d,j=7.6hz,3h),3.30(d,j=13.6hz,0.7h),3.11(d,j=14.8hz,0.3h),2.72(d,j=14.8hz,0.3h),2.39(d,j=14.0hz,0.35h),1.37(dt,j=14.2,7.1hz,3h);¹³cnmr(101mhz,cdcl3)δ178.59,176.28,171.92,171.75,168.29,167.22,155.00,154.96,147.42,145.43,142.10,141.90,136.94,136.49,133.73,133.58,130.34,129.65,129.37,128.27,127.82,126.40,126.18,125.12,124.86,124.67,123.90,123.84,123.74,123.70,117.73,117.61,110.10,110.06,94.80,93.64,72.17,71.95,63.68,62.88,56.61,56.37,50.50,49.96,37.78,37.62,14.14,14.07;ir:3514.9,3282.1,2961.4,2928.7,1738.7,1720.6,1631.9,1620.9,1484.3,1467.9,1368.6,1341.2,1217.1,1194.4,1147.4,1103.9,1039.2,977.2,923.7,860.6,775.0,758.9,701.2,660.5,613.3cm^-1;hrmscalcd.forc24h22no8[m+h]⁺452.1340,found:452.1348。

实施例三：

反应瓶中依次加入奎宁硫脲(0.002mmol)，和1c(33.5mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应38小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3c(48.3mg)，白色固体，mp:141-144°c,收率为91%，>20/1dr，96%ee。

反应瓶中依次加入奎宁硫脲(3.0mg，0.005mmol)，和1c(33.5mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应36小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3c(48.7mg)，白色固体，mp:141-144℃,收率为98%，>20/1dr，99%ee。

对产物3c进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=17.371,t(minor)=25.698];[α]d²⁵=+114.0(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.83(s,0.4h),8.23(d,j=8.0hz,0.45h),8.18(d,j=8.0hz,0.55h),7.94(d,j=7.6hz,0.55h),7.55–7.50(m,1h),7.42–7.33(m,5h),7.32–7.30(m,1h),7.23(d,j=8.4hz,1h),7.12(t,j=7.6hz,0.5h),7.06(d,j=7.6hz,0.7h),7.02(d,j=3.2hz,0.5h),7.00(d,j=4.4hz,0.3h),6.92(d,j=8.0hz,0.4h),6.85(d,j=7.6hz,0.55h),5.33(s,0.6h),5.26(t,j=15.6hz,1h),4.81(t,j=15.2hz,1h),4.37(dq,j=7.2,5.2hz,2h),3.38(dd,j=14.0,2.0hz,0.6h),3.13(d,j=15.2hz,0.4h),2.76(d,j=14.8hz,0.4h),2.42(d,j=14.0hz,0.6h),1.38(dt,j=7.2,5.2hz,3h);¹³cnmr(101mhz,cdcl3)δ177.95,175.64,171.97,171.81,168.39,167.31,154.00,154.96,147.84,145.80,136.90,136.45,135.44,134.53,133.66,133.48,130.15,129.87,129.44,129.13,128.94,128.71,128.32,127.99,127.78,127.32,127.30,126.37,126.13,124.80,124.70,124.60,123.79,123.75,123.69,123.43,117.76,117.60,110.65,109.59,94.90,93.66,63.64,62.83,50.17,49.55,44.63,44.46,37.42,37.37,14.13,14.07;ir:3484.2,3281.4,2959.1,2923.7,1739.1,1714.4,1632.2,1610.4,1485.9,1466.6,1364.0,1346.3,1284.3,1263.4,1216.9,1197.6,1182.2,1145.9,1081.0,1038.4,974.7,947.8,883.8,808.3,753.4,734.7,698.6,630.1cm^-1;hrmscalcd.forc29h24no7[m+h]⁺498.1547,found:498.1545，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(3.0mg，0.005mmol)，和1d(28.5mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3d(46.0mg)，白色固体，mp:158-160℃,收率为97%，>20/1dr，99%ee。

对产物3d进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=15.593,t(minor)=19.550];[α]d²⁵=+97.3(c=0.52,chcl3);¹hnmr(400mhz,cdcl3)δ8.79(s,0.45h),8.21(dd,j=17.2,7.6hz,1h),7.93(d,j=7.6hz,0.50h),7.54–7.50(m,1h),7.41(t,j=7.6hz,0.6h),7.36–7.29(m,1.4h),7.25(d,j=7.2hz,0.5h),7.17(t,j=7.6hz,0.5h),7.11–7.01(m,2h),6.94(d,j=7.6hz,0.5h),5.99–5.88(m,1h),5.34(dd,j=16.8,10.6hz,2h),5.21(s,0.55h),4.60(dd,j=16.8,3.6hz,1h),4.36(dt,j=7.6,5.6hz,3h),3.33(d,j=14.0hz,0.55h),3.11(d,j=14.8hz,0.45h),2.72(d,j=14.8hz,0.45h),2.38(d,j=14.0hz,0.55h),1.38(dt,j=14.4,7.1hz,3h);¹³cnmr(101mhz,cdcl3)δ177.59,175.22,171.98,171.82,168.42,167.32,155.02,149.97,147.72,145.61,143.07,142.90,136.98,136.52,133.66,133.50,130.76,130.16,129.96,129.83,129.45,128.72,127.78,126.37,126.12,124.80,124.70,124.61,123.82,123.74,123.70,123.37,118.00,117.85,117.68,117.44,110.51,109.49,94.88,93.64,63.69,62.83,50.16,49.53,43.05,42.92,37.50,37.47,14.15,14.08;ir:3544.6,3259.4,2963.1,2854.3,1740.2,1710.8,1625.9,1609.6,1487.0,1467.4,1432.8,1280.3,1260.9,1238.1,1198.6,1186.3,1107.0,1039.8,1004.7,977.5,943.9,884.7,855.7,797.5,761.9,702.3,668.9,655.5,636.0,619.9cm^-1;hrmscalcd.forc25h22no7[m+h]⁺448.1391,found:448.1393；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(3.0mg，0.005mmol)，和1e(37.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应30分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3e(39.4mg)，黄色固体，mp:196-198℃,收率为73%，>20/1dr，99%ee。

对产物3e进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=28.027,t(minor)=41.336];[α]d²⁵=+98.4(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.82(s,0.45h),8.23(dd,j=14.8,7.6hz,1h),7.93(d,j=7.6hz,0.55h),7.54(t,j=7.6hz,1h),7.40–7.29(m,6.45h),7.23–7.01(m,3h),6.92(d,j=7.6hz,0.5h),6.85(d,j=7.6hz,0.5h),5.27(t,j=15.6hz,1h),5.11(s,0.55h),4.82(t,j=14.0hz,1h),4.39(dq,j=12.4,7.2hz,2h),3.39(d,j=14.0hz,0.55h),3.14(d,j=14.8hz,0.45h),2.75(d,j=15.2hz,0.45h),2.41(d,j=14.0hz,0.55h),1.40(dt,j=12.4,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ178.00,175.66,171.99,171.85,168.45,167.34,155.07,155.02,147.80,143.05,142.86,136.95,136.50,135.47,134.56,133.69,133.54,130.18,129.89,129.50,129.18,128.99,128.78,128.38,128.04,127.80,127.37,127.36,126.46,126.22,124.86,124.75,124.67,123.84,123.78,123.47,117.81,117.64,110.66,109.64,94.93,93.64,63.78,62.90,50.21,49.56,44.69,44.52,37.46,14.18,14.12;ir:3482.3,3279.6,2960.8,2922.9,1743.1,1715.8,1640.6,1609.8,1488.3,1467.7,1432.2,1369.4,1282.4,1262.1,1196.7,1184.7,1146.1,1109.0,1040.2,1013.5,972.1,860.0,772.8,753.5,728.6,696.9,630.7cm^-1;hrmscalcd.forc30h24no9[m+h]⁺542.1146,found:542.1153；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(3.0mg，0.005mmol)，和1f(28.7mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3f(24.2mg)，黄色固体，mp:150-153℃,收率为54%，>20/1dr，98%ee。

对产物3f进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=15.747,t(minor)=20.035];[α]d²⁵=+113.3(c=0.30,chcl3);¹hnmr(400mhz,cdcl3)δ8.34(d,j=8.0hz,0.8h),8.31(d,j=6.4hz,0.2h),8.23–8.21(m,1h),7.95(d,j=7.6hz,0.7h),7.56(dd,j=7.2,1.2hz,1h),7.95(d,j=2.8hz,0.3h),7.47–7.40(m,1h),7.34–7.29(m,1h),7.23(d,j=8.0hz,0.7h),7.18(d,j=8.4hz,0.7h),7.14(d,j=8.4hz,0.3h),5.10(s,0.7h),4.38(dq,j=15.6,7.2hz,2h),3.32(d,j=14.0hz,0.8h),3.08(d,j=15.2hz,0.2h),2.81(d,j=15.2hz,0.3h),2.74(d,j=5.7hz,3h),2.47(d,j=14.0hz,0.7h),1.38(dt,j=15.2,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ177.06,171.94,170.71,168.06,155.10,147.08,140.19,136.56,133.94,133.82,129.91,128.76,127.90,127.28,126.85,126.41,126.22,125.96,125.62,125.08,124.91,123.69,123.42,118.05,117.96,117.37,116.65,94.46,93.56,63.93,63.21,50.70,50.51,38.87,38.56,27.35,27.01,14.17,14.13;ir:3350.2,2926.9,2924.5,1760.2,1741.5,1724.4,1640.9,1613.6,1465.6,1434.8,1370.1,1339.0,1306.9,1268.1,1198.3,1147.9,1107.9,1063.4,973.7,802.7,763.4cm^-1;hrmscalcd.forc24h20no8[m+h]⁺450.1183,found:450.1188；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(3.0mg，0.005mmol)，和1g(27.7mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3g(35.9mg)，微红色固体，mp:114-116℃,收率为82%，>20/1dr，99%ee。

对产物3g进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(85:15),flowrate:1.0ml·min^-1,λ=254nm,t(major)=30.576];[α]d²⁵=+135.8(c=0.46,chcl3);¹hnmr(400mhz,cdcl3)δ8.75(s,0.3h),8.22(dd,j=8.0,1.6hz,0.3h),8.18(dd,j=8.0,1.6hz,0.7h),7.69(dd,j=8.4,2.4hz,0.7h),7.55–7.50(m,1h),7.34–7.27(m,1h),7.13(dd,j=8.8,2.4hz,1h),7.10–7.05(m,1h),7.00–6.96(m,0.7h),6.89(dd,j=8.4,4.0hz,0.7h),5.28(d,j=2.2hz,0.7h),4.36(m,2h),3.35(dt,j=14.4,7.1hz,2h),3.31(d,j=2.4hz,0.3h),3.27(d,j=2.4hz,0.3h),3.02(d,j=14.8hz,0.3h),2.70(d,j=14.8hz,0.3h),2.34(d,j=14.0hz,0.7h),2.09(s,0.6h),1.37(dt,j=14.4,7.1hz,3h);¹³cnmr(101mhz,cdcl3)δ177.40,175.14,171.96,171.75,168.21,167.19,160.22(j=243.2hz),154.50(j=239.6hz),155.02,154.09,147.07,144.79,139.79,139.77,137.16,136.60,133.72,133.57,131.23,131.14,130.71(j=6.4hz)130.66(j=6.9hz),128.94,126.36,126.12,124.90,124.72,123.71,123.68,118.00,117.84,116.75(j=23.6hz),116.08(j=26.1hz),115.93(j=23.6hz),112.15(j=25.4hz),110.44(j=8.1hz),109.03(j=8.1hz),94.79,93.59,63.73,62.89,50.41(j=1.7hz),49.86(j=1.6hz),37.43,27.58,27.41,14.14,14.07;ir:3298.6,2927.8,1747.9,1722.8,1636.2,1613.7,1492.8,1469.3,1352.8,1258.6,1198.5,1151.0,1105.5,1030.8,972.2,866.1,797.3,734.3,683.5cm^-1;hrmscalcd.forc23h19fno7[m+h]⁺440.1140,found:440.1146；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(3.0mg，0.005mmol)，和1h(29.3mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.6:1）即可得到目标产物3h(42.7mg)，黄色固体，mp:128-131℃,收率为77%，>20/1dr，94%ee。

对产物3h进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(85:15),flowrate:1.0ml·min^-1,λ=254nm,t(major)=30.714,t(minor)=28.046];[α]d²⁵=+188.8(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.63(s,0.3h),8.21(dd,j=14.0,8.0hz,1h),7.90(d,j=1.6hz,0.7h),7.55–7.51(m,1h),7.42(dd,j=8.0,1.6hz,0.3h),7.35(dd,j=8.4,2.0hz,0.77h),7.32–7.28(m,1h),7.21(d,j=1.6hz,0.3h),7.14(d,j=8.4hz,0.7h),7.10(d,j=8.8hz,0.3h),6.97(d,j=8.4hz,0.3h),6.90(d,j=8.4hz,0.7h),5.18(s,0.7h),4.37(dq,j=14.8,7.2hz,2h),3.35(d,j=9.5hz,3h),3.28(d,j=14.0hz,0.7h),3.03(d,j=14.8hz,0.3h),2.69(d,j=14.8hz,0.3h),2.33(d,j=14.0hz,0.7h),1.37(dt,j=14.8,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ177.30,175.04,171.93,171.73,168.17,167.16,155.02,154.96,146.91,144.69,142.39,137.18,136.63,133.73,133.59,131.22,131.04,130.38,130.30,130.25,129.57,128.84,128.26,126.39,126.15,124.92,124.75,124.39,123.71,118.03,117.90,110.64,109.52,94.77,93.55,63.78,62.93,50.18,49.64,37.44,27.57,27.39,14.16,14.09;ir:3474.2,2932.3,1746.1,1728.2,1632.8,1611.2,1489.4,1468.1,1429.9,1345.7,1189.4,1148.1,1104.3,1030.5,977.3,834.7,808.9,762.2,703.7,676.4cm^-1;hrmscalcd.forc23h19clno7[m+h]⁺456.0845,found:456.0832；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(3.0mg，0.005mmol)，和1i(36.5mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3i(46.9mg)，白色固体，mp:124-127℃,收率为89%，>20/1dr，93%ee。

对产物3i进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=22.013,t(minor)=19.790];[α]d²⁵=+78.6(c=0.60,chcl3);¹hnmr(400mhz,cdcl3)δ8.61(s,0.3h),8.22(dd,j=8.0,1.6hz,0.3h),8.18(dd,j=8.0,1.2hz,0.7h),8.03(d,j=1.6hz,0.7h),7.57–7.48(m,2h),7.34(d,j=2.0hz,0.3h),7.31(d,j=8.0hz,0.7h),7.13(d,j=8.4hz,0.7h),7.10(d,j=8.4hz,0.3h),6.92(d,j=8.4hz,0.3h),6.85(d,j=8.0hz,0.7h),5.22(s,0.7h),4.36(dq,j=14.4,7.2hz,2h),3.35(d,j=9.7hz,3h),3.29(d,j=2.0hz,0.3h),3.26(d,j=2.4hz,0.3h),3.03(d,j=14.8hz,0.3h),2.68(d,j=14.8hz,0.3h),2.33(d,j=14.0hz,0.7h),1.36(dt,j=14.4,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ177.18,174.93,171.91,171.70,168.14,167.15,154.99,154.94,146.89,144.69,142.90,142.87,137.17,136.62,133.72,133.57,133.20,132.46,131.54,130.94,130.66,127.09,126.35,126.12,124.90,124.73,123.72,123.69,,118.02,117.91,117.38,116.15,111.09,110.03,94.76,93.55,63.75,62.91,50.10,49.56,37.46,37.44,27.54,27.36,14.15,14.08;ir:3494.2,3280.2,2961.3,1723.3,1364.5,1610.4,1480.4,1467.2,1339.7,1282.0,1218.4,1173.6,1146.4,1106.2,1040.3,977.1,961.1,813.5,797.2,764.6,747.7,669.0,643.9cm^-1;hrmscalcd.forc23h19clno7[m+h]⁺500.0339,found:500.0339；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(3.0mg，0.005mmol)，和1j(27.3mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应38小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3j(41.7mg)，白色固体，mp:226-228℃,收率为99%，>20/1dr，96%ee。

对产物3j进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=17.666,t(minor)=15.895];[α]d²⁵=+24.2(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.89(s,0.5h),8.22(dd,j=8.0,1.6hz,0.5h),8.18(dd,j=8.0,1.6hz,0.5h),7.69(s,0.5h),7.53–7.48(m,1h),7.32–7.28(m,1h),7.22(d,j=8.0hz,0.5h),7.17–7.13(m,1h),7.09(d,j=8.4hz,0.5h),7.02(s,0.5h),6.91(d,j=7.6hz,0.5h),6.85(d,j=8.0hz,0.5h),5.08(d,j=2.2hz,0.5h),4.35(dt,j=7.2,5.0hz,2h),3.34(d,j=8.0hz,3h),3.29(dd,j=14.0,2.4hz,0.5h),3.04(d,j=14.8hz,0.5h),2.66(d,j=14.8hz,0.5h),2.31(d,j=14.0hz,0.5h),2.30(d,j=8.8hz,3h),1.37(dt,j=16.6,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ177.59,175.37,171.98,171.84,168.48,167.37,155.04,154.99,147.87,145.70,141.43,141.36,137.05,136.59,134.65,133.52,133.38,132.99,130.47,129.86,128.74,128.73,128.38,126.28,126.03,124.71,124.55,124.47,123.74,123.71,118.11,117.94,109.39,108.30,94.91,93.64,63.66,62.76,50.18,49.61,37.59,27.41,27.25,21.32,21.23,14.14,14.07;ir:3494.7,3282.8,2961.6,1745.8,1718.6,1636.8,1611.3,1499.5,1359.2,1282.1,1260.8,1196.1,1103.7,1037.9,977.5,964.8,811.7,796.6,760.2,699.6,669.8,647.7cm^-1;hrmscalcd.forc24h22no7[m+h]⁺436.1391,found:436.1396；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(3.0mg，0.005mmol)，和1k(28.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.8:1）即可得到目标产物3k(44.2mg)，白色固体，mp:191-193℃,收率为98%，>20/1dr，98%ee。

对产物3k进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=22.303,t(minor)=27.639];[α]d²⁵=+141.6(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.95(s,0.5h),8.20–8.16(m,1h),7.55(d,j=2.0hz,0.5h),7.53–7.49(m,1h),7.29(t,j=1.2hz,1h),7.11(dd,j=19.6,8.4hz,1h),6.93(s,1h),6.89(d,j=2.4hz,0.5h),6.84(d,j=18.8hz,1h),5.07(d,j=1.6hz,0.5h),4.34(dq,j=15.6,7.2hz,2h),3.74(d,j=8.0hz,3h),3.33(d,j=7.6hz,3h),3.28(d,j=2.0hz,0.5h),3.04(d,j=14.8hz,0.5h),2.67(d,j=14.8hz,0.5h),2.32(d,j=14.0hz,0.5h),1.36(dt,j=15.6,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ177.27,175.05,171.92,171.81,168.41,167.37,157.49,156.38,155.02,154.97,147.62,145.52,137.15,137.06,136.99,136.59,136.59,133.54,133.42,130.97,129.96,126.24,126.02,124.73,124.57,123.71,123.69,118.08,117.92,114.82,114.58,114.29,110.57,110.22,108.92,94.91,93.60,63.69,62.77,55.95,55.82,50.51,49.89,37.63,37.45,27.47,27.31,14.14,14.06;ir:3350.6,2963.2,2922.7,1748.1,1714.7,1652.5,1637.1,1611.6,1497.2,147.0,1363.4,1339.6,1260.9,1236.3,1202.1,1160.5,1144.2,1108.8,1039.5,1025.3,977.0,806.5,758.1,694.3,679.9,646.6cm^-1;hrmscalcd.forc24h22no8[m+h]⁺452.1340,found:452.1352；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(3.0mg，0.005mmol)，和1l(29.3mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3l(39.1mg)，黄色固体，mp:111-113℃,收率为86%，>20/1dr，97%ee。

对产物3l进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=22.883,t(minor)=30.794];[α]d²⁵=+57.2(c=0.65,chcl3);¹hnmr(400mhz,cdcl3)δ8.58(s,0.3h),8.22(dd,j=8.0,1.2hz,0.3h),8.18(dd,j=8.0,1.6hz,0.7h),7.82(d,j=8.0hz,0.7h),7.55–7.51(m,1h),7.34–7.28(m,1h),7.15(d,j=7.4hz,1h),7.10(d,j=8.4hz,0.3h),7.05–7.03(m,1h),6.97(d,j=2.0hz,0.7h),5.19(s,0.7h),4.36(dq,j=11.1,5.6hz,2h),3.35(d,j=9.2hz,3h),3.27(d,j=14.4hz,0.7h),3.03(d,j=14.8hz,0.3h),2.67(d,j=14.8hz,0.3h),2.31(d,j=14.0hz,0.7h),1.36(dt,j=11.1,5.6hz,3h);¹³cnmr(101mhz,cdcl3)δ177.76,175.49,171.96,171.77,168.28,167.21,155.03,154.97,147.06,145.02,144.88,137.15,136.64,136.18,135.45,133.74,133.61,128.85,128.11,127.09,126.39,126.13,124.92,124.81,123.74,124.67,123.73,123.69,123.29,118.03,117.85,110.51,109.38,94.80,93.58,63.79,62.93,49.84,49.25,37.57,37.40,27.56,27.38,14.16,14.09;ir:3348.8,3277.2,2961.0,2923.4,1722.4,1365.8,1607.2,1468.0,1365.6,1281.9,1260.5,1188.7,1147.4,1103.4,1078.4,1025.5,971.2,798.4,759.1,645.0,621.5cm^-1;hrmscalcd.forc23h19clno7[m+h]⁺456.0845,found:456.0833；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(3.0mg，0.005mmol)，和1m(33.7mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3m(42.9mg)，黄色固体，mp:105-107℃,收率为86%，>20/1dr，97%ee。

对产物3m进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=22.846,t(minor)=31.330];[α]d²⁵=+245.2(c=0.25,chcl3);¹hnmr(400mhz,cdcl3)δ8.57(s,0.3h),8.22(dd,j=8.0,1.6hz,0.3h),8.18(dd,j=8.0,1.6hz,0.7h),7.76(d,j=8.4hz,0.7h),7.55–7.51(m,1h),7.32–7.28(m,1.3h),7.21(d,j=2.0hz,0.3h),7.19(d,j=1.6hz,0.7h),7.15(d,j=8.4hz,0.7h),7.12(d,j=1.6hz,0.7h),7.09(d,j=1.6hz,0.3h),5.13(d,j=2.0hz,0.7h),4.36(dt,j=14.4,7.1hz,2h),3.35(d,j=9.3hz,3h),3.28(dd,j=14.4,1.6hz,0.7h),3.02(d,j=14.8hz,0.3h),2.67(d,j=15.2hz,0.3h),2.30(d,j=14.0hz,0.7h),1.37(dt,j=14.4,7.1hz,3h);¹³cnmr(101mhz,cdcl3)δ177.63,175.35,171.89,171.72,168.25,167.19,155.01,154.96,146.91,145.14,144.77,137.16,136.67,133.73,133.60,129.17,128.66,127.69,1127.61,126.37,126.23,126.13,125.12,124.90,124.73,123.86,123.70,123.30,118.02,117.85,113.27,112.16,94.79,93.55,63.80,62.91,49.89,49.29,37.49,37.34,27.55,27.37,14.15,14.09;ir:3396.7,3280.6,2961.7,2924.1,1723.6,1636.6,1602.5,1468.6,1365.5,1282.9,1260.5,1188.9,1149.5,1101.7,1025.4,970.9,798.9,759.3,707.0,643.9,620.5cm^-1;hrmscalcd.forc23h19brno7[m+h]⁺500.0339,found:500.0346；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(3.0mg，0.005mmol)，和1n(28.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3n(33.4mg)，微红色固体，mp:210-211℃,收率为74%，>20/1dr，>99%ee。

对产物3n进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=26.010];[α]d²⁵=+186.0(c=0.20,chcl3);¹hnmr(400mhz,cdcl3)δ8.77(s,0.4h),8.24–8.19(m,1h),7.76(d,j=8.0hz,0.5h),7.52(t,j=7.6hz,1h),7.30(dd,j=14.4,7.2hz,1h),7.15(d,j=8.4hz,0.5h),7.10(d,j=8.4hz,1h),6.66–6.59(m,1h),6.56–6.54(m,1h),4.94(d,j=1.8hz,0.6h),4.36(dd,j=14.9,7.3hz,2h),3.86(d,j=7.6hz,3h),3.34(d,j=6.0hz,3h),3.28(dd,j=14.0,2.0hz,0.6h),3.02(d,j=15.2hz,0.4h),2.65(d,j=15.2hz,0.4h),2.29(d,j=14.0hz,0.6h),1.38(dd,j=14.9,7.3hz,3h);¹³cnmr(101mhz,cdcl3)δ178.34,176.05,171.99,171.89,168.52,167.41,161.64,161.11,155.07,155.03,147.89,145.81,145.16,136.54,133.43,128.53,126.36,126.11,124.75,124.60,124.56,123.76,121.88,120.28,118.11,117.91,108.28,106.82,97.87,96.71,94.98,93.67,63.75,62.82,55.88,55.72,49.74,49.13,37.77,37.68,27.42,27.28,14.18,14.11;ir:3334.4,2962.9,2938.6,1740.2,1707.5,1629.4,1612.5,1470.9,1456.4,1373.9,1288.0,1262.2,1194.5,1149.8,1101.2,1062.6,969.3,927.7,877.8,804.3,758.7,691.5,649.3,639.4,617.3cm^-1;hrmscalcd.forc24h22no8[m+h]⁺452.1340,found:452.1353；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(3.0mg，0.005mmol)，和1o(27.7mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3o(43.5mg)，黄色固体，mp:190-192℃,收率为99%，>20/1dr，99%ee。

对产物3o进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=19.841,t(minor)=40.459];[α]d²⁵=+132.9(c=0.54,chcl3);¹hnmr(400mhz,cdcl3)δ8.65(s,0.4h),8.21(dd,j=8.0,1.2hz,0.4h),8.17(dd,j=8.0,1.2hz,0.6h),7.71(d,j=7.2hz,0.6h),7.55–7.50(m,1h),7.33–7.28(m,1h),7.18–7.16(m,1h),7.16(d,j=8.4hz,1h),7.14(d,j=2.4hz,0.4h),7.12–7.07(m,1h),7.02–6.97(m,1h),5.20(s,0.6h),4.35(dq,j=14.6,7.2hz,3h),3.56(d,j=2.8hz,3h),3.28(dd,j=14.4,1.6hz,0.6h),3.03(d,j=14.8hz,0.4h),2.70(d,j=14.8hz,0.4h),2.34(d,j=14.0hz,0.6h),1.36(dt,j=14.6,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ177.34,175.14,171.93,171.75,168.27,167.19,155.02,154.97,148.02(d,j=244.8hz),147.84(d,j=242.0hz),147.11,137.02,136.57,133.71,136.57,132.35(d,j=2.5hz),131.41(d,j=2.7hz),130.56(d,j=8.4hz),130.53(d,j=8.8hz),126.33,126.08,125.45(d,j=6.5hz),124.86,124.67,123.84(d,j=8.6hz),123.68(d,j=4.2hz),123.58(d,j=3.2hz),119.65(d,j=3.3hz),118.28(d,j=19.0hz),118.03,117.85,117.47(d,j=18.8hz),94.81,93.54,63.72,62.86,50.33(d,j=1.9hz),49.69(d,j=2.1hz),37.76,37.59,30.02(d,j=5.8hz),29.84(d,j=6.2hz),14.13,14.06;ir:3516.5,3277.3,2961.2,2922.7,1736.5,1715.6,1624.6,1610.9,1477.8,1466.6,1364.9,1336.3,1284.1,1260.1,1245.1,1196.8,1108.1,1080.2,1048.3,1023.4,988.0,963.4,800.7,758.6,702.5,642.4,628.9cm^-1;hrmscalcd.forc23h19fno7[m+h]⁺440.1140,found:440.1151；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(3.0mg，0.005mmol)，和1p(27.3mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3p(43.0mg)，黄色固体，mp:191-194℃,收率为99%，>20/1dr，>99%ee。

对产物3p进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=31.735];[α]d²⁵=+92.0(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.92(s,0.65h),8.21(dd,j=8.0,1.2hz,0.65h),8.17(dd,j=8.0,1.6hz,0.35h),7.73(d,j=7.2hz,0.35h),7.53–7.49(m,1h),7.29(t,j=7.2hz,1h),7.18–7.12(m,1h),7.10–7.07(m,0.35h),7.05–7.02(m,1h),6.93(t,j=7.6hz,0.35h),5.07(s,0.35h),4.34(dt,j=16.0,7.2hz,2h),3.62(s,3h),3.28(d,j=14.0hz,0.35h),2.99(d,j=14.8hz,0.35h),2.66(d,j=3.2hz,3h),2.62(d,j=14.4hz,0.65h),2.30(d,j=14.4hz,0.35h),1.36(dt,j=16.0,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ178.28,176.32,171.95,171.83,168.44,167.33,155.06,155.00,147.92,145.78,141.50,141.46,137.04,137.64,133.93,133.53,133.38,133.31,130.50,129.38,126.25,126.01,125.51,124.71,124.59,124.55,123.70,123.18,121.64,121.33,120.03,118.10,117.90,94.91,93.63,63.63,62.73,49.61,49.04,38.10,37.95,30.79,30.75,19.40,19.01,14.14.05;ir:3503.2,3277.8,2960.2,2924.9,1736.6,1694.9,1667.7,1648.6,1634.0,1612.0,1466.3,1377.1,1361.1,1287.1,1260.5,1195.2,1145.4,1111.1,1071.5,1021.2,965.3,909.4,795.5,763.3,749.9,699.7,643.2,623.9cm^-1;hrmscalcd.forc23h19fno7[m+h]⁺436.1391,found:436.1400；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(3.0mg，0.005mmol)，和1q(28.7mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.7:1）即可得到目标产物3q(35.9mg)，黄色固体，mp:200-202℃,收率为80%，>20/1dr，98%ee。

对产物3q进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=21.379,t(minor)=19.769];[α]d²⁵=+45.0(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.98(s,0.7h),8.22(dd,j=8.0,1.6hz,0.7h),8.18(dd,j=8.0,1.6hz,0.3h),7.54–7.50(m,1.3h),7.32(d,j=0.8hz,0.2h),7.29(d,j=8.0hz,0.8h),7.18(d,j=8.4hz,0.3h),7.14(d,j=8.4hz,0.7h),6.94(s,0.7h),6.89(s,0.3h),6.82(s,0.7h),5.03(d,j=2.0hz,0.3h),4.35(dq,j=16.8,7.2hz,3h),3.59(s,3h),3.27(dd,j=14.0,2.4hz,1h),2.98(d,j=14.8hz,0.7h),2.63(d,j=11.2hz,0.6h),2.62(s,3h),2.29(d,j=14.4hz,0.4h),2.23(d,j=7.2hz,3h),1.36(dt,j=16.8,7.2hz,3h);¹³cnmr(101mhz,cdcl3)δ178.16,176.23,171.99,171.87,168.52,167.41,155.08,155.03,148.16,146.01,139.04,139.00,137.00,136.59,134.37,133.76,133.48,133.35,132.69,130.61,129.42,126.26,126.11,126.01,124.68,124.53,123.74,122.28,120.99,118.17,117.99,94.94,93.64,63.64,62.73,49.67,49.12,38.10,38.06,30.72,20.97,20.88,19.23,18.84,14.14,14.07;ir:3151.5,2961.7,2921.9,1757.4,1710.4,1660.6,1632.5,1612.4,1485.3,1468.8,1442.9,1371.2,1287.2,1260.4,1200.4,1139.1,1099.0,1077.0,1025.7,961.6,870.6,800.3,761.7,695.9,648.9cm^-1;hrmscalcd.forc25h24no7[m+h]⁺450.1547,found:450.1558；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(3.0mg，0.005mmol)，和1r(29.5mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.7:1）即可得到目标产物3r(42.5mg)，黄色固体，mp:113-115℃,收率为96%，>20/1dr，93%ee。

对产物3r进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(80:20),flowrate:1.0ml·min^-1,λ=254nm,t(major)=22.295,t(minor)=27.049];[α]d²⁵=+98.2(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.54(s,0.2h),8.20(dd,j=8.0,1.2hz,0.2h),8.16(dd,j=8.0,1.6hz,0.8h),7.82(dd,j=10.0,8.0hz,0.8h),7.55–7.51(m,1h),7.29(t,j=8.0hz,1h),7.14(d,j=8.4hz,0.8h),7.10(t,j=8.0hz,0.2h),6.90(dd,j=9.2,6.0hz,2h),6.80(dd,j=9.6,6.4hz,0.8h),5.51(s,0.8h),4.36(dq,j=13.6,6.4hz,2h),3.34(d,j=10.2hz,3h),3.25(dd,j=14.0,1.6hz,0.8h),3.00(d,j=14.8hz,0.2h),2.69(d,j=15.2hz,0.2h),2.33(d,j=14.4hz,0.8h),1.36(dt,j=13.6,6.4hz,3h);¹³cnmr(101mhz,cdcl3)δ17.54,175.30,171.96,171.70,168.10,167.14,154.98,154.93,151.39,(d,j=248.2hz),151.25(d,j=248.1hz),146.83(d,j=241.4hz),146.76,146.71(d,j=244.3hz),140.26(d,j=11.6hz),137.19,136.55,136.55,133.82,133.68,126.38(s),126.13,124.99(d,j=2.9hz),124.92(d,j=4.0hz),124.80,123.68,123.62,118.01(d,j=11.7hz),117.95,117.83(d,j=42.0hz),98.90,98.67,94.76,93.61,63.73,62.96,50.06,49.52,37.53,37.41,27.69,27.51,14.12,14.06;ir:3279.2,3070.6,2961.2,2161.1,2031.0,1979.4,1626.2,1613.7,1506.3,1428.2,1391.7,1368.7,1283.9,1252.0,1185.7,1152.3,1096.7,1024.9,1007.6,960.4,873.5,786.3,758.8,688.3,645.2,618.4cm^-1;hrmscalcd.forc23h18f2no7[m+h]⁺458.1046,found:458.1048；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(3.0mg，0.005mmol)，和1s(24.5mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2a(24.3mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3s(35.8mg)，微红色固体，mp:205-207℃,收率为98%，>20/1dr，98%ee。

对产物3s进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=20.279,t(minor)=32.183];[α]d²⁵=+71.5(c=0.52,chcl3);¹hnmr(400mhz,cdcl3)δ8.88(s,0.55h),8.22(dd,j=8.0,1.2hz,0.6h),8.19(dd,j=8.4,1.6hz,0.4h),7.87(d,j=7.6hz,0.4h),7.53–7.49(m,1h),7.44(td,j=7.6,1.2hz,0.6h),7.38(dt,j=8.0,1.2hz,0.45h),7.33–7.29(m,1h),7.20(dd,j=12.0,6.4hz,1h),7.15–7.12(m,0.55h),7.09–7.06(m,1h),7.04(d,j=8.0hz,0.6h),6.97(d,j=7.6hz,0.4h),5.01(d,j=2.0hz,0.45h),3.91(s,3h),3.37(d,j=10.8hz,3h),3.30(dd,j=14.0,2.4hz,0.45h),3.07(d,j=14.8hz,0.55h),2.69(d,j=15.2hz,1h),2.33(d,j=14.0hz,0.45h);¹³cnmr(101mhz,cdcl3)δ177.71,175.38,171.94,171.84,168.87,167.82,155.06,155.00,147.64,145.48,143.86,143.00,137.03,136.56,133.62,133.47,130.27,129.82,129.57,128.71,127.64,126.33,126.08,124.81,124.79,124.63,123.75,123.72,123.69,123.43,118.08,117.88,109.69,108.62,94.97,93.72,54.07,53.52,50.15,49.49,37.64,37.48,27.43,27.25;ir:3316.0,2961.4,2922.7,1752.1,1725.6,1637.8,1610.0,1468.3,1432.1,1366.3,1351.3,1280.3,1270.1,1260.5,1219.0,1188.0,1146.9,1124.0,1070.1,979.7,966.8,945.6,811.9,801.2,760.7,746.8,660.7,640.5,616.8cm^-1;hrmscalcd.forc30h24no9[m+h]⁺408.1078,found:408.1084；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(3.0mg，0.005mmol)，和1a(25.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2b(27.0mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3t(37.4mg)，微红色固体，mp:170-173℃,收率为88%，>20/1dr，93%ee。

对产物3t进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=12.258,t(minor)=22.094];[α]d²⁵=+80.2(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.81(s,0.5h),7.88(dd,j=7.6,0.8hz,0.5h),7.84(dd,j=8.0,2.8hz,0.5h),7.80(dd,j=8.0,2.8hz,0.5h),7.45(td,j=7.6,1.2hz,0.5h),7.38(td,j=7.6,1.2hz,0.5h),7.24–7.21(m,1h),7.20–7.13(m,1h),7.04(d,j=7.6hz,0.5h),6.97(d,j=7.6hz,0.5h),5.17(s,0.5h),4.35(tq,j=14.4,7.2hz,2h),3.36(d,j=9.6hz,3h),3.28(d,j=14.0hz,0.5h),3.05(d,j=15.2hz,0.5h),2.68(d,j=15.2hz,1h),2.33(d,j=14.4hz,0.5h),1.37(dt,j=14.4,7.2hz,3h);¹³cnmr(100mhz,cdcl3)δ177.58,175.35,171.24,171.11,168.33,167.22,159.24(j=245.3hz),159.17(j=245.1hz),151.33,151.25,148.05,145.86,143.82,143.73,136.77,136.35,130.33,129.73,129.63,128.63,127.70,124.86,124.84(j=6.3hz),124.75(j=4.6hz),123.78,123.48,120.06(j=14.6hz),121.75(j=14.5hz),120.26(j=8.1hz),120.06(j=8.0hz),110.94(j=27.1hz),10.70(j=26.9hz),109.72,108.67,100.09,94.97,93.70,63.75,62.86,50.16,49.57,37.64,37.48,27.44,27.27,14.14,14.08;ir:3430.1,2987.5,1755.6,1711.6,1610.3,1483.3,1469.4,1369.7,1259.8,1186.1,1163.3,1100.0,1022.9,994.4,852.4,831.0,799.5,757.7,691.1,642.2cm^-1;hrmscalcd.forc23h19fno7[m+h]⁺440.1140,found:440.1143；以上数据证明目的产物合成成功。

实施例二十一：

反应瓶中依次加入奎宁硫脲(3.0mg，0.005mmol)，和1a(25.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2c(35.8mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.5:1）即可得到目标产物3u(37.4mg)，微红色固体，mp:136-138℃,收率为65%，>20/1dr，92%ee。

对产物3u进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=15.695,t(minor)=31.396];[α]d²⁵=+355.0(c=0.61,chcl3);¹hnmr(400mhz,cdcl3)δ8.82(s,0.5h),8.32(d,j=2.4hz,0.5h),8.27(d,j=2.0hz,0.5h),7.88(d,j=7.6hz,0.5h),7.58(dt,j=8.8,2.4hz,1h),7.47–7.36(m,1h),7.24–7.18(m,1h),7.10–7.04(m,1h),7.03(d,j=4.8hz,0.5h),6.99–6.96(m,1h),5.22(s,0.5h),4.35(dq,j=7.2,4.4hz,3h),3.36(d,j=10.0hz,3h),3.27(d,j=14.0hz,0.5h),3.05(d,j=15.2hz,0.5h),2.68(d,j=15.2hz,0.5h),2.34(d,j=14.4hz,0.5h),1.36(dt,j=14.6,7.1hz,3h);¹³cnmr(101mhz,cdcl3)δ177.52,175.27,170.73,170.59,168.29,167.18,153.81,153.75,148.11,145.88,143.81,143.71,137.27,136.81,136.58,136.42,130.36,129.65,128.70,128.53,128.46,127.73,125.00,124.98,124.88,123.80,123.51,120.07,119.87,118.24,118.06,109.73,108.67,95.01,93.73,63.75,62.88,50.15,49.57,37.66,37.46,27.45,27.28,14.15,14.08;ir:3331.6,2926.6,1741.1,1723.1,1626.8,1606.3,1467.2,1418.4,1352.2,1242.0,1227.8,1098.5,1074.8,987.5,963.1,835.7,754.6,660.7cm^-1;hrmscalcd.forc23h19brno7[m+h]⁺500.0339,found:500.0337；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(3.0mg，0.005mmol)，和1a(25.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2d(26.4mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.4:1）即可得到目标产物3v(42.2mg)，黄色固体，mp:106-108℃,收率为97%，>20/1dr，98%ee。

对产物3v进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=19.812,t(minor)=41.106];[α]d²⁵=+52.8(c=0.60,chcl3);¹hnmr(400mhz,cdcl3)δ8.81(s,0.5h),7.97(dd,j=18.8,1.2hz,0.5h),7.88(d,j=7.6hz,0.5h),7.43(td,j=8.0,1.2hz,0.5h),7.36(td,j=8.0,1.2hz,0.5h),7.32–7.29(m,1h),7.21–7.14(m,1h),7.07(dd,j=7.6,0.8hz,0.5h),7.02(d,j=8.4hz,0.5h),6.97(d,j=3.2hz,0.5h),6.95(d,j=2.4hz,0.5h),5.15(s,0.5h),4.39(dq,j=16.8,7.2hz,2h),3.35(d,j=8.4hz,3h),3.28(d,j=14.0hz,0.5h),3.04(d,j=14.8hz,0.5h),2.66(d,j=14.8hz,0.5h),2.36(d,j=5.6hz,3h),2.32(d,j=14.0hz,0.5h),1.36(dt,j=16.8,7.2hz,2h);¹³cnmr(101mhz,cdcl3)δ177.74,175.52,172.02,171.88,168.45,167.35,153.37,153.30,147.52,145.35,143.84,143.75,136.96,136.51,134.90,134.77,134.74,134.52,130.17,129.93,129.47,128.85,127.68,125.43,125.18,124.73,123.72,123.37,117.79,117.60,109.62,108.56,94.85,93.63,63.62,62.76,50.15,49.56,37.62,37.51,27.38,27.21,20.86,14.13,14.06;ir:3283.4,2936.0,1717.8,1611.6,1488.4,1471.8,1368.8,1278.3,1191.7,1161.4,1129.7,1031.4,961.7,692.2,662.7cm^-1;hrmscalcd.forc24h22no7[m+h]⁺436.1391,found:436.1381；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(3.0mg，0.005mmol)，和1a(25.9mg,0.1mmol)，加入1ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2e(28.8mg,0.15mmol)，继续反应40小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.4:1）即可得到目标产物3w(44.6mg)，黄色固体，mp:218-220℃,收率为99%，>20/1dr，99%ee。

反应瓶中依次加入奎宁硫脲(90.65mg，0.005mmol)，和1a(906.5mg,3.5mmol)，加入5ml二氯甲烷，在零下20摄氏度条件下反应20分钟，加入2e(1.51g5.25mmol)，继续反应41小时，反应体系通过简单的柱层析（洗脱剂为石油醚：乙酸乙酯=1.4:1）即可得到目标产物3w(1.76g)，黄色固体，mp:218-220℃,收率为92%，>20/1dr，99%ee。

对产物3w进行分析，结果如下：用hplc测定[daicelchiralpakia,hexane/i-proh(70:30),flowrate:1.0ml·min^-1,λ=254nm,t(major)=16.022,t(minor)=23.611];[α]d²⁵=+43.6(c=0.50,chcl3);¹hnmr(400mhz,cdcl3)δ8.80(s,0.5h),8.11(d,j=9.2hz,0.5h),8.05(d,j=8.8hz,0.5h),7.92(d,j=7.2hz,0.5h),7.45(t,j=8.4hz,0.5h),7.39(t,j=7.2hz,0.5h),7.24–7.17(m,1h),7.11–7.04(m,1h),6.98(d,j=8.0hz,0.5h),6.85(ddd,j=15.6,8.8,2.0hz,1h),6.49(d,j=2.4hz,0.5h),6.44(d,j=2.0hz,0.5h),5.41(s,0.5h),4.36(q,j=7.2hz,2h),3.77(s,3h),3.37(d,j=8.0hz,3h),3.25(d,j=14.0hz,0.5h),3.04(d,j=14.8hz,0.5h),2.67(d,j=14.8hz,0.5h),2.34(d,j=14.0hz,0.5h),1.37(dt,j=16.9,7.1hz,3h);¹³cnmr(101mhz,cdcl3)δ177.74,175.61,171.50,171.27,168.44,167.36,164.14,164.03,,156.86,156.77,147.09,144.90,143.83,143.73,137.00,136.50,130.16,129.94,129.44,128.86,127.77,127.58,127.27,124.75,123.76,123.40,117.60,117.49,114.60,114.49,109.65,108.65,99.92,94.86,93.72,63.52,62.76,55.89,55.85,50.07(,49.53,37.76,37.60,27.40,27.24,14.12,14.05;ir:3287.6,2962.2,1733.3,1609.8,1446.5,1422.9,1368.4,1265.9,1167.8,1153.7,1100.4,1028.0,973.5,833.4,748.5,694.1,635.9cm^-1;hrmscalcd.forc24h22no8[m+h]⁺452.1340,found:452.1343；以上数据证明目的产物合成成功。