CN111909016B - 2’-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法 - Google Patents

2’-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法 Download PDF

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CN111909016B
CN111909016B CN202010993867.7A CN202010993867A CN111909016B CN 111909016 B CN111909016 B CN 111909016B CN 202010993867 A CN202010993867 A CN 202010993867A CN 111909016 B CN111909016 B CN 111909016B
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柴国利
张苹
郭蓉
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Abstract

本发明公开了2'‑羟基‑α,β‑不饱和酮与1,3‑二烯环加成反应合成光学活性环己烯类化合物的方法，属于有机化学技术领域。采用2'‑羟基‑α,β‑不饱和酮1与1,3‑二烯2作为原料，在手性四苯并环辛四烯类配体或手性联萘酚类配体、硼酸三苯酯和分子筛存在下，发生环加成反应得到光学活性环己烯类化合物3。本发明合成方法具有以下优势：底物适用性广，反应原料易得，催化剂结构新颖，催化剂用量少，催化效率高，反应条件温和，后处理简单，得到的活性环己烯类化合物对映选择性(高达99％ee)和非对映选择性(endo/exo高达>20/1)均非常优秀。

Description

2’-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环 己烯类化合物的方法
技术领域
本发明属于有机化学中的不对称合成技术领域，具体涉及2’-羟基-α,β-不饱和酮与双烯体的不对称D-A环加成反应合成光学活性环己烯类化合物的方法。
背景技术
研究发现，从桑科植物中分离提取得到的含环己烯母核结构的天然产物具有抗氧化、抗肿瘤和抗HIV等药理活性，然而由于分离提取成本较高，严重阻碍其药理活性的研究，因此，通过有机合成方法高效、高立体选择性合成具有生物活性的环己烯母核结构化合物可以为手性药物的开发奠定基础(Angew.Chem.Int.Ed.2002,41,1668.)。不对称D-A反应是构建碳-碳键的一类重要反应，该反应具有原子经济性、高效性和立体专一性等特点，可立体选择性构建最多含4个连续立体中心的六元环状化合物，在手性药物和天然产物的全合成领域具有广泛的应用前景。
许多具有生物活性的六元环状化合物可通过α,β-不饱和羰基化合物与双烯体发生D-A反应来得到，促进α,β-不饱和羰基化合物参与的不对称D-A反应的方法主要包括：(1)手性底物诱导，(2)手性Lewis酸催化，(3)氢键作用催化，(4)手性胺催化。其中，手性配体与金属形成的Lewis酸催化剂在不对称D-A反应中得到广泛应用(Chem.Rev.2013,113,5515.)。
2000年，Wipf小组将手性BINOL衍生物-硼络合物促进的D-A反应应用于萘醌型天然产物(+)-diepoxinσ的全合成中(J.Org.Chem.2000,65,6319.)。雷晓光课题组报道使用新型手性VANOL配体-硼络合物促进2’-羟基查尔酮与双烯体发生不对称Diels-Alder反应，合成一系列具有不同取代基的环己烯核心骨架化合物，并将其应用于(-)-panduratin A等天然产物的全合成(J.Org.Chem.2016,81,458；Org.Lett.2016,18,360；Angew.Chem.Int.Ed.2014,53,9257.)。该项研究工作可为D-A类型天然产物的全合成提供指导，同时也为后继天然产物导向的化学生物学研究奠定基础。
到目前为止，催化不对称D-A反应的研究已经取得了很大进展，然而α,β-不饱和羰基化合物与双烯体参与的不对称D-A反应仍存在诸多亟待解决的问题，底物适用性及反应通用性不太理想，环合产物的区域选择性和立体选择性较难控制，催化剂用量较大。因此，设计简单高效的新型手性催化剂，开发实用的催化体系，拓展结构丰富多样的反应底物，得到一系列光学活性的环己烯类化合物，具有重要的研究意义。
发明内容
本发明的目的在于提供一种2’-羟基-α,β-不饱和酮与双烯体的不对称D-A环加成反应合成光学活性环己烯类化合物的方法。
基于上述目的，本发明采用2’-羟基-α,β-不饱和酮1与1,3-二烯2作为原料，在手性四苯并环辛四烯类配体或手性联萘酚类配体、硼酸三苯酯和分子筛存在下，发生环加成反应得到光学活性环己烯类化合物3。反应方程式如下：
Figure BDA0002691823590000021
其中：R1选自苯基、C1-C3烷基、C1-C3烷氧基、卤素或硝基；Ar选自苯基、C1-C3烷基取代苯基、C1-C3烷氧基取代苯基、卤素取代苯基、三氟甲基取代苯基、萘基或噻吩基；R2选自氢、甲基或2-甲基-2-戊烯基
Figure BDA0002691823590000022
R3选自氢或甲基，R4选自氢、苯基、C1-C3烷基取代苯基或卤素取代苯基。
进一步地，在上述技术方案中，所述手性配体选自(S)-2,15-二氯-1,16-二羟基四苯并环辛四烯L1：(S)-2,15-Cl2-DHTP，(S,S)-1,8,9,16-四羟基四苯并环辛四烯L2：(S,S)-THTP，(S)-1,16-二羟基四苯并环辛四烯L3：(S)-DHTP，(S)-2,15-二苯基-1,16-二羟基四苯并环辛四烯L4：(S)-2,15-Ph2-DHTP或(S)-2,15-二溴-1,16-二羟基四苯并环辛四烯L5：(S)-2,15-Br2-DHTP中的一种；对应具体结构如下：
Figure BDA0002691823590000023
进一步地，在上述技术方案中，所述手性配体还可为手性联萘酚类化合物，具体结构如下：
Figure BDA0002691823590000024
进一步地，在上述技术方案中，所述分子筛选自
Figure BDA0002691823590000031
或
Figure BDA0002691823590000032
分子筛。分子筛优选
Figure BDA0002691823590000033
分子筛。
进一步地，在上述技术方案中，所述2’-羟基-α,β-不饱和酮1、双烯体2、硼酸三苯酯、手性配体的摩尔比为1:1.0-10.0:0.10-0.15:0.10-0.15，每0.1mmol 2’-羟基-α,β-不饱和酮1中分子筛的用量为100mg。
进一步地，在上述技术方案中，所述反应溶剂为甲苯、三氟甲苯、邻二甲苯(o-xylene)、1,2-二氯乙烷(DCE)或甲基叔丁基醚(MTBE)。优选反应溶剂为1,2-二氯乙烷。
进一步地，在上述技术方案中，反应温度为20-40℃，优选30℃。
进一步地，在上述技术方案中，整个反应在氮气或氩气气氛下进行。
发明有益效果
本发明反应原料易得，反应条件温和，后处理简单，催化剂可回收再利用，产物收率和对映选择性良好至优秀。
具体实施方式
以下结合具体实施例对本发明的技术方案作进一步详细说明，但本发明的保护范围并不局限于此。
实施例1：
Figure BDA0002691823590000034
Figure BDA0002691823590000035
Figure BDA0002691823590000041
a反应条件：2’-羟基查尔酮1a(0.1mmol)、双烯体2a(0.2mmol)、B(OPh)3(0.01mmol)、手性配体(0.012mmol)、
Figure BDA0002691823590000042
分子筛(100mg)和1.0mL无水溶剂在N2气氛下搅拌.bendo/exo比例为粗品核磁氢谱数据.cendo-异构体分离产率.dee值通过手性柱HPLC分析.e不加
Figure BDA0002691823590000043
分子筛.f
Figure BDA0002691823590000044
分子筛(100mg)代替
Figure BDA0002691823590000045
分子筛.g
Figure BDA0002691823590000046
分子筛(100mg)代替
Figure BDA0002691823590000047
分子筛.hBH3·THF(10mol％)代替B(OPh)3.iBH3·SMe2(10mol％)代替B(OPh)3.jB(OPh)3(5mol％)、手性配体(6mol％).
在反应条件的筛选过程中，首先考察了不同的手性配体对反应的影响(entries1-9)，最终选用L1为最佳配体。随后，考察了不同溶剂对反应的影响(entries 10-16)，最终选用1,2-二氯乙烷(DCE)作溶剂。同时考察了分子筛、Lewis酸、催化剂用量对反应的影响(entries 17-22)，最终选择
Figure BDA0002691823590000048
分子筛作添加剂、硼酸三苯酯作为Lewis酸，催化剂用量为10mol％。
反应条件的考察(以entry 12为例)：
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000049
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基查尔酮1a(22.4mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1a消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3aa，收率为93％，>99％ee。
3aa白色固体(34.4mg,产率93％)；熔点130-131℃；HPLC(Daicel Chiralpak IG,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝5.4min,tR(major)＝6.6min,ee＝>99％；[α]D 20＝–114.4(c 2.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.80(s,1H),8.05-8.02(m,1H),7.50-7.46(m,1H),7.23-7.16(m,7H),7.19-7.08(m,1H),7.01-6.96(m,1H),6.93-6.88(m,3H),5.60(d,J＝4.8Hz,1H),4.46(dd,J＝6.0,11.6Hz,1H),4.02(t,J＝5.6Hz,1H),3.47(td,J＝6.0,11.6Hz,1H),2.51(dd,J＝5.6,18.0Hz,1H),2.28(dd,J＝10.4,17.2Hz,1H),1.87(s,3H)；HRMS(ESI-TOF)calcd.for C26H24O2Na([M+Na]+):391.1669,found:391.1657.
实施例2：
Figure BDA0002691823590000051
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000052
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1b(23.8mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1b消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ba，收率为92％，99％ee。
3ba白色固体(35.4mg,产率92％)；熔点160-162℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.5mL/min,λ＝254nm)tR(minor)＝9.4min,tR(major)＝9.74min,ee＝99％；[α]D 26＝–99.4(c 2.0,CHCl3)；1H NMR(600MHz,CDCl3)δ11.64(s,1H),7.79(s,1H),7.29(d,J＝7.8Hz,1H),7.23-7.17(m,7H),7.11-7.08(m,1H),6.91-6.89(m,2H),6.82(d,J＝8.4Hz,1H),5.61(d,J＝5.4Hz,1H),4.45(dd,J＝5.4,11.4Hz,1H),4.02(t,J＝6.0Hz,1H),3.46(td,J＝5.4,11.4Hz,1H),2.51(dd,J＝6.0,18.0Hz,1H),2.42(s,3H),2.29(dd,J＝10.8,18.0Hz,1H),1.88(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ206.2,160.6,145.3,139.9,137.3,135.3,129.3,128.9,128.6,128.14,128.11,127.3,126.2,122.4,120.0,118.7,50.6,45.9,40.3,36.8,23.3,20.9；HRMS(ESI-TOF)calcd.for C27H26O2Na([M+Na]+):405.1825,found:405.1817.
实施例3：
Figure BDA0002691823590000061
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000063
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1c(25.4mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1c消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/4-1/2)分离纯化得到目标产物3ca，收率为92％，99％ee。
3ca白色固体(36.6mg,产率92％)；熔点107-109℃；HPLC(Daicel Chiralpak IG,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝7.1min,tR(major)＝9.1min,ee＝94％；[α]D 27＝–105.6(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ12.32(s,1H),7.93(d,J＝8.8Hz,1H),7.23-7.15(m,7H),7.11-7.07(m,1H),6.93-6.91(m,2H),6.52(dd,J＝2.8,9.2Hz,1H),6.35(d,J＝2.4Hz,1H),5.59(d,J＝3.2Hz,1H),4.34(dd,J＝5.6,11.6Hz,1H),3.96(t,J＝5.6Hz,1H),3.84(s,3H),3.45(td,J＝6.0,11.2Hz,1H),2.49(dd,J＝5.6,18.0Hz,1H),2.25(dd,J＝11.2,17.6Hz,1H),1.86(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ204.4,165.9,165.6,145.4,140.1,135.2,130.9,129.4,128.5,128.1 127.3,127.2,126.2,122.4,114.7,107.8,101.3,55.7,50.4,45.9,40.3,36.8,23.3；HRMS(ESI-TOF)calcd.for C27H26O3Na([M+Na]+):421.1774,found:421.1759.
实施例4：
Figure BDA0002691823590000062
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000064
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1d(24.2mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1d消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3da，收率为97％，>99％ee。
3da白色固体(37.6mg,产率97％)；熔点168-169℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.5mL/min,λ＝214nm)tR(minor)＝10.2min,tR(major)＝12.8min,ee＝>99％；[α]D 27＝–110.1(c 2.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.51(s,1H),7.67(dd,J＝3.2,9.2Hz,1H),7.24-7.15(m,8H),7.12-7.08(m,1H),6.90-6.86(m,3H),5.61-5.58(m,1H),4.33(dd,J＝6.0,11.6Hz,1H),4.00(t,J＝5.6Hz,1H),3.45(td,J＝6.0,11.2Hz,1H),2.51(dd,J＝6.0,18.4Hz,1H),2.28(dd,J＝11.2,18.0Hz,1H),1.87(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ205.6,158.8,155.1(d,J＝238.5Hz),145.0,139.7,135.3,129.3,128.6,127.4,127.3,126.4,123.9(d,J＝24.0Hz),122.1,120.3(d,J＝7.5Hz),119.7(d,J＝6.0Hz),114.3(d,J＝24.0Hz),51.0,45.8,40.0,36.9,23.3；19F{1H}NMR(376MHz,CDCl3)δ–124.0；HRMS(ESI-TOF)calcd.for C26H23FO2Na([M+Na]+):409.1574,found:409.1569.
实施例5：
Figure BDA0002691823590000071
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000072
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1e(30.3mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1e消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ea，收率为89％，98％ee。
3ea白色固体(39.8mg,产率89％)；熔点184-186℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.5mL/min,λ＝220nm)tR(minor)＝9.8min,tR(major)＝11.4min,ee＝98％；[α]D 26＝–65.7(c 2.0,CHCl3)；1H NMR(600MHz,CDCl3)δ11.71(s,1H),8.09(s,1H),7.55(d,J＝8.4Hz,1H),7.22-7.09(m,8H),6.90-6.89(m,2H),6.82(d,J＝9.0Hz,1H),5.61(d,J＝4.8Hz,1H),4.35(dd,J＝6.0,11.4Hz,1H),3.99(t,J＝5.4Hz,1H),3.45(td,J＝6.0,11.4Hz,1H),2.51(dd,J＝6.0,18.0Hz,1H),2.29(dd,J＝11.4,18.0Hz,1H),1.88(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ205.6,161.6,144.9,139.7,139.0,135.3,131.5,129.3,128.6,128.2,127.4,127.3,126.4,122.1,121.5,121.1,110.7,51.0,45.9,40.0,36.8,23.3；HRMS(ESI-TOF)calcd.for C26H23BrO2Na([M+Na]+):469.0774,found:469.0772.
实施例6：
Figure BDA0002691823590000081
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000083
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1f(26.9mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1f消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/4-1/2)分离纯化得到目标产物3fa，收率为93％，95％ee。
3fa白色固体(38.6mg,产率93％)；熔点193-195℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝90:10,流速1.0mL/min,λ＝254nm)tR(minor)＝6.1min,tR(major)＝7.7min,ee＝95％；[α]D 26＝–67.5(c 2.0,CHCl3)；1H NMR(600MHz,CDCl3)δ12.43(s,1H),8.93(s,1H),8.34(d,J＝9.0Hz,1H),7.22-7.17(m,7H),7.12-7.10(m,1H),7.00(d,J＝9.0Hz,1H),6.89-6.87(m,2H),5.61-5.60(m,1H),4.47(dd,J＝6.0,11.4Hz,1H),4.00(t,J＝6.0Hz,1H),3.49(td,J＝6.0,11.4Hz,1H),2.53(dd,J＝5.4,18.0Hz,1H),2.34(dd,J＝11.4,18.6Hz,1H),1.89(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ206.4,167.5,144.6,139.8,139.6,135.4,130.9,129.2,128.7,128.4,127.6,127.3,126.6,125.8,121.9,120.0,119.0,51.3,46.0,39.6,37.0,23.3；HRMS(ESI-TOF)calcd.for C26H23NO4Na([M+Na]+):436.1519,found:436.1512.
实施例7：
Figure BDA0002691823590000082
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000084
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1g(23.8mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1g消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ga，收率为95％，99％ee。
3ga白色固体(36.5mg,产率95％)；熔点140-142℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝5.4min,tR(major)＝6.2min,ee＝99％；[α]D 26＝–103.7(c 2.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.82(s,1H),8.02(d,J＝7.6Hz,1H),7.49-7.45(m,1H),7.22-7.18(m,3H),7.07-7.05(m,2H),6.99-6.88(m,6H),5.59-5.57(m,1H),4.43(dd,J＝5.6,11.6Hz,1H),3.99(t,J＝5.6Hz,1H),3.43(td,J＝6.0,11.2Hz,1H),2.49(dd,J＝6.0,18.4Hz,1H),2.29-2.25(m,1H),2.23(s,3H),1.86(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ206.5,162.7,142.2,140.0,136.2,135.7,135.3,129.36,129.32,129.28,128.1,127.3,127.1,122.3,120.4,119.1,118.9,50.8,45.9,40.3,36.3,23.3,21.1；HRMS(ESI-TOF)calcd.for C27H26O2Na([M+Na]+):405.1825,found:405.1823.
实施例8：
Figure BDA0002691823590000091
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000092
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1h(25.4mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1h消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ha，收率为96％，98％ee。
3ha白色固体(38.1mg,产率96％)；熔点57-59℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝90:10,流速1.0mL/min,λ＝254nm)tR(minor)＝4.9min,tR(major)＝5.8min,ee＝98％；[α]D 26＝–106.0(c 2.0,CHCl3)；1H NMR(400MHz,CDCl3)δ11.84(s,1H),8.02-8.00(m,1H),7.49-7.45(m,1H),7.22-7.19(m,3H),7.11-7.07(m,2H),6.99-6.97(m,1H),6.93-6.88(m,3H),6.74-6.70(m,2H),5.60-5.57(m,1H),4.40(dd,J＝5.6,11.6Hz,1H),3.99(t,J＝5.6Hz,1H),3.71(s,3H),3.42(td,J＝6.0,11.6Hz,1H),2.48(dd,J＝6.0,18.0Hz,1H),2.26(dd,J＝11.2,18.0Hz,1H),1.86(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ206.5,162.7,157.9,140.0,137.3,136.2,135.3,129.4,129.3,128.2,128.1,127.3,122.3,120.4,119.1,118.9,114.0,55.3,51.0,45.9,40.2,35.9,23.3；HRMS(ESI-TOF)calcd.for C27H26O3Na([M+Na]+):421.1774,found:421.1766.
实施例9：
Figure BDA0002691823590000101
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000102
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1i(24.2mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1i消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ia，收率为97％，98％ee。
3ia无色油状液体(37.5mg,产率97％)；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.5mL/min,λ＝254nm)tR(minor)＝9.4min,tR(major)＝11.1min,ee＝98％；[α]D 27＝–112.2(c 2.0,CHCl3)；1H NMR(600MHz,CDCl3)δ11.79(s,1H),8.01(d,J＝7.8Hz,1H),7.49(t,J＝7.8Hz,1H),7.24-7.12(m,5H),6.98(t,J＝7.8Hz,1H),6.94-6.85(m,5H),5.60-5.59(m,1H),4.40(dd,J＝5.4,12.0Hz,1H),4.03-4.01(m,1H),2.49(dd,J＝6.0,18.6Hz,1H),2.25(dd,J＝11.4,18.0Hz,1H),1.87(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ206.3,162.7,161.3(d,J＝243.0Hz),140.8(d,J＝4.5Hz),139.8,136.4,135.1,129.30,129.28,128.7(d,J＝9.0Hz),128.2,127.4,122.3,120.3,119.1,119.0,115.3(d,J＝21.0Hz),51.0,45.9,40.1,36.1,23.3；19F{1H}NMR(564MHz,CDCl3)δ–117.0；HRMS(ESI-TOF)calcd.for C26H23FO2Na([M+Na]+):409.1574,found:409.1573.
实施例10：
Figure BDA0002691823590000111
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000113
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1j(30.3mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1j消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ja，收率为98％，>99％ee。
3ja白色固体(44.0mg,产率98％)；熔点194-196℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝6.4min,tR(major)＝7.4min,ee＝>99％；[α]D 27＝–90.3(c 2.0,CHCl3)；1H NMR(600MHz,CDCl3)δ11.77(s,1H),8.01(d,J＝7.8Hz,1H),7.49(t,J＝7.8Hz,1H),7.31-7.29(m,2H),7.22-7.21(m,3H),7.07-6.87(m,6H),5.60(s,1H),4.41-4.38(m,1H),4.03-4.01(m,1H),3.47-3.42(m,1H),2.48(dd,J＝6.0,18.0Hz,1H),2.24(dd,J＝11.4,18.0Hz,1H),1.87(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ206.1,162.7,144.3,139.7,136.4,135.0,131.6,129.3 129.1,128.2,127.4,122.4,120.2,119.9,119.2,119.1,50.8,45.9,39.9,36.4,23.3；HRMS(ESI-TOF)calcd.forC26H23BrO2Na([M+Na]+):469.0774,found:469.0767.
实施例11：
Figure BDA0002691823590000112
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000114
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基α,β-不饱和酮1k(27.4mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(0.8mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2a的甲苯溶液(0.2mL，0.2mmol，1M)，然后30℃恒温搅拌。TLC点板跟踪至原料1k消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ka，收率为97％，98％ee。
3ka白色固体(40.8mg,产率97％)；熔点104-106℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝8.1min,tR(major)＝11.4min,ee＝98％；[α]D 26＝–83.2(c 2.0,CHCl3)；1H NMR(600MHz,CDCl3)δ11.75(s,1H),8.07(d,J＝7.8Hz,1H),7.73-7.64(m,4H),7.48-7.45(m,1H),7.40-7.34(m,3H),7.26-7.21(m,3H),7.01-6.88(m,4H),5.64-5.63(m,1H),4.58(dd,J＝6.0,11.4Hz,1H),4.06(t,J＝5.4Hz,1H),3.65(td,J＝6.0,11.4Hz,1H),2.57(dd,J＝6.0,18.6Hz,1H),2.39(dd,J＝10.8,18.0Hz,1H),1.89(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ206.3,162.7,142.7,139.9,136.3,135.2,133.6,132.3 129.3(m),128.3 128.2,127.71,127.66,127.4,126.0,125.8,125.4,122.4,120.3,119.1,119.0,50.9,45.9,40.0,36.9,23.4；HRMS(ESI-TOF)calcd.forC30H26O2Na([M+Na]+):441.1825,found:441.1825.
实施例12：
Figure BDA0002691823590000121
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000122
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基查尔酮1a(22.4mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(1.0mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2b(68.1mg，1.0mmol)，然后30℃恒温搅拌。TLC点板跟踪至原料1a消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ab，收率为96％，95％ee。
3ab无色油状液体(28.1mg,产率96％)；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝6.4min,tR(major)＝7.0min,ee＝95％；[α]D 26＝–12.9(c 2.0,CHCl3)；1H NMR(600MHz,CDCl3)δ12.34(s,1H),7.83-7.81(m,1H),7.42-7.39(m,1H),7.42-7.39(m,3H),7.20-7.17(m,4H),7.10-7.08(m,1H),6.88-6.84(m,2H),5.51-5.50(m,1H),3.98(td,J＝5.4,10.8Hz,1H),3.35(td,J＝6.6,10.8Hz,1H),2.42-2.27(m,4H),1.74(s,3H)；HRMS(ESI)calcd.for C20H20O2Na([M+Na]+):315.1356,found:315.1350.
实施例13：
Figure BDA0002691823590000131
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000133
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基查尔酮1a(22.4mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(1.0mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2c(82.1mg，1.0mmol)，然后30℃恒温搅拌。TLC点板跟踪至原料1a消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ac，收率为96％，93％ee。
3ac无色油状液体(29.5mg,产率96％)；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝5.9min,tR(major)＝7.1min,ee＝83％；[α]D 26＝–18.6(c 2.0,CHCl3)；1H NMR(400MHz,CDCl3)δ12.37(s,1H),7.86-7.83(m,1H),7.43-7.39(m,1H),7.19-7.18(m,4H),7.11-7.08(m,1H),6.90-6.85(m,2H),4.05(td,J＝5.6,10.8Hz,1H),3.35-3.28(m,1H),2.41-2.27(m,4H),1.69(s,6H)；HRMS(ESI-TOF)calcd.for C21H22O2Na([M+Na]+):329.1512,found:329.1505.
实施例14：
Figure BDA0002691823590000132
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入100mg
Figure BDA0002691823590000134
分子筛、手性配体L1(4.9mg，0.012mmol，12mol％)、硼酸三苯酯(2.9mg，0.01mmol，5mol％)、和2’-羟基查尔酮1a(22.4mg，0.1mmol)，抽换气3次，再加入干燥的甲苯(1.0mL)，特氟龙塞子拧紧反应管，100℃搅拌2h。冷却至室温(25-30℃)，在氮气保护下向反应瓶中加入1,3-二烯2d(136.2mg，1.0mmol)，然后30℃恒温搅拌。TLC点板跟踪至原料1a消失，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5-1/3)分离纯化得到目标产物3ad，收率为89％，93％ee。
3ad无色油状液体(32.2mg,产率89％)；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝5.5min,tR(major)＝6.4min,ee＝93％；[α]D 27＝–10.8(c 1.0,CHCl3)；1H NMR(400MHz,CDCl3)δ12.36(s,1H),7.84(d,J＝8.0Hz,1H),7.43-7.39(m,1H),7.20-7.07(m,5H),6.89-6.85(m,2H),5.54-5.52(m,1H),5.14(t,J＝6.8Hz,1H),4.00(td,J＝5.2,10.8Hz,1H),3.34(td,J＝6.0,10.8Hz,1H),2.49-2.03(m,8H),1.72(s,3H),1.63(s,3H)；HRMS(ESI-TOF)calcd.for C25H28O2Na([M+Na]+):383.1982,found:383.1979.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (6)

1.2'-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法，其特征在于，包括如下步骤：
Figure FDA0003685504450000011
采用2'-羟基-α,β-不饱和酮1与1,3-二烯2作为原料，在手性四苯并环辛四烯类配体、硼酸三苯酯和分子筛存在下，发生环加成反应得到光学活性环己烯类化合物3；其中：R1选自苯基、C1-C3烷基、C1-C3烷氧基、卤素或硝基；Ar选自苯基、C1-C3烷基取代苯基、C1-C3烷氧基取代苯基、卤素取代苯基、三氟甲基取代苯基、萘基或噻吩基；R2选自氢、甲基或2-甲基-2-戊烯基； R3选自氢或甲基，R4选自氢、苯基、C1-C3烷基取代苯基或卤素取代苯基；手性四苯并环辛四烯类配体为
Figure FDA0003685504450000012
X＝Cl或Br；所述反应溶剂选自甲苯、三氟甲苯、邻二甲苯、1,2-二氯乙烷或甲基叔丁基醚；分子筛选自
Figure FDA0003685504450000013
或
Figure FDA0003685504450000014
分子筛。
2.根据权利要求1所述2'-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法，其特征在于：分子筛选自
Figure FDA0003685504450000015
分子筛。
3.根据权利要求1所述2'-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法，其特征在于：所述2'-羟基-α,β-不饱和酮1、1,3-二烯2、硼酸三苯酯、手性配体的摩尔比为1:1.0-10.0:0.10-0.15:0.10-0.15。
4.根据权利要求1所述2'-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法，其特征在于：所述反应溶剂为1,2-二氯乙烷。
5.根据权利要求1-4任意一项所述2'-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法，其特征在于：反应温度为20-40℃。
6.根据权利要求1-4任意一项所述2'-羟基-α,β-不饱和酮与双烯体环加成反应合成光学活性环己烯类化合物的方法，其特征在于：整个反应过程在氮气或氩气气氛下进行。
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