CN113443987B - 一种铜不对称催化构建手性四取代环外α-羟基联烯酸酯的方法 - Google Patents

一种铜不对称催化构建手性四取代环外α-羟基联烯酸酯的方法 Download PDF

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CN113443987B
CN113443987B CN202110650147.5A CN202110650147A CN113443987B CN 113443987 B CN113443987 B CN 113443987B CN 202110650147 A CN202110650147 A CN 202110650147A CN 113443987 B CN113443987 B CN 113443987B
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孙江涛
许光洋
邵莺
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Abstract

本发明属于不对称催化合成技术领域，具体公开了一种铜不对称催化构建手性四取代环(二氢茚环或者四氢萘环)外α‑羟基联烯酸酯的方法。使用铜/手性噁唑啉体系催化芳炔醛或芳炔酮与重氮化合物经过分子间、分子内串联环化反应，合成光学纯的含有中心手性和轴手性四取代环(二氢茚环或者四氢萘环)外α‑羟基联烯酸酯的方法，其中对映选择性高达97％ee，非对映选择性高达>19:1dr。本发明方法的优点有：反应条件简单温和、底物适用范围广、产率高、对映选择性和非对映选择性好。

Description

一种铜不对称催化构建手性四取代环外α-羟基联烯酸酯的 方法
技术领域
本发明属于不对称催化有机合成技术领域，涉及铜不对称催化构建手性四取代环(二氢茚环或者四氢萘环)外α-羟基联烯酸酯的方法，具体涉及一种使用铜/噁唑啉催化芳炔醛或芳炔酮与重氮酯反应以高对映和非对映选择性合成同时含有中心手性和轴手性的四取代环(二氢茚环或者四氢萘环)外α-羟基联烯酸酯的方法。
背景技术
联烯是重要的有机合成子，在天然产物、药物分子和功能材料中广泛存在，联烯衍生物具有独特的生物活性和药物活性，如含联烯母核的化合物被用作抗肿瘤和抗病毒药物(Matthews,D.P.；Bitonti,A.J.；Edwards,M.L.；McCarthy,J.R. US5607925A,1997)、具有抗HIV病毒逆转录作用(Megati,S.；Goren,Z.；Silverton, J.V.；Orlina,J.；Nishimura,H.；Shirasaki,T.；Mitsuya,H.；Zemlicka,J.J.Med. Chem.1992,35,4098.)。联烯是具有轴手性的化合物，因此不对称催化合成光学纯的轴手性联烯具有重要意义。
重氮化合物作为常用的卡宾前体可以与末端炔烃偶联构建联烯骨架，为联烯化合物合成提供一个直接有效的方法。(Tang,Y.；Chen,Q.；Liu,X.；Wang,G.； Lin,L.；Feng,X.Angew.Chem.Int.Ed.2015,54,9512.Chu,W.-D.；Zhang,L.； Zhang,Z.；Zhou,Q.；Mo,F.；Zhang,Y.；Wang,J.J.Am.Chem.Soc.2016,138,14558. Tang,Y.；Xu,J.；Yang,J.；Lin,L.；Feng,X.)只能构建二或者三取代的手性联烯。而 Liu课题组(Liu X.Chem 2018,4,1658.)虽然成功构建了环外四取代手性联烯，但局限在必须使用昂贵的靛红衍生物作为原料，还需要使用难合成的配体来控制立体选择性，并且加入毒性较大的YBr3作为添加剂。
发明内容
本发明提供了一种铜/噁唑啉体系催化芳炔醛或芳炔酮与重氮酯反应，以高对映和非对映选择性合成同时含有中心手性和轴手性的四取代环(二氢茚环或者四氢萘环)外α-羟基联烯酸酯的方法，其中反应的立体选择性通过改变催化剂、配体进行控制。反应可能的历程是首先形成炔基铜卡宾物种，经过炔基迁移插入形成中心手性有机炔铜物种，再与亲电试剂(醛、酮)发生炔基Aldol反应得到产物，或者是先经过1，3-铜迁移得到亲核性的轴手性联烯铜物种，被分子内引入的亲电试剂捕获生成四取代环(二氢茚环或者四氢萘环)外轴手性α-羟基联烯酸酯。本发明具体的反应通式如下：
Figure BDA0003110864590000021
一种铜不对称催化构建手性四取代环(二氢茚环或者四氢萘环)外α-羟基联烯酸酯的方法，具体按照下述步骤进行：氩气保护下，将芳炔醛或芳炔酮(1) (使用廉价的邻溴苯甲醛或酮先用乙二醇保护后，将溴进行卤锂交换后与3-溴 -1-三甲基硅基-1-丙炔亲核取代，再脱保护即可获得Chem.Asian J.2018，13， 3885.)、铜催化剂、噁唑啉配体(L＊)(市售)及溶剂在室温下预搅拌1小时，再加入重氮酯(2)(使用芳基乙酸酯用市售的对甲苯磺酸叠氮进行重氮化简便获得ACS Catal.2013，3，1144.)，之后反应搅拌2-72小时得到手性四取代环(二氢茚环或者四氢萘环)外α-羟基联烯酸酯(3)。对本发明内容的具体说明如下：
铜催化剂为：碘化亚铜，溴化亚铜，三氟甲磺酸亚铜，三氟甲磺酸铜，六氟磷酸四(乙腈)铜，四氟硼酸四(乙腈)铜，溴化铜，三氟乙酸铜，三氟乙酰丙酮化铜(Cu(tfacac)2)等，其中最优催化剂二价铜盐：三氟乙酰丙酮化铜。
其中的配体为手性噁唑啉配体，具体结构如下：
Figure BDA0003110864590000031
最优的噁唑啉配体为L4。
对于得到的同时含有中心手性和轴手性的四取代环(二氢茚环或者四氢萘环)外α-羟基联烯酸酯(3)中取代基：R1为Ph，4-MeC6H4，4-FC6H4，4-C1C6H4， 4-BrC6H4，4-PhC6H4，4-CF3OC6H4，4-CF3C6H4，3-C1C6H4，2-FC6H4，2-萘基， 3-噻吩基，胡椒环，3-(N-Boc吲哚)基；R2为Me，Et，iPr，tBu，Bn等；R3为 4-F，5-MeO，5-Me，6-C1，6-MeO，7-C1，4，5-并苯环，5，6-OCH2O；R4为氢、烷基；n＝1，2。
反应的溶剂为：二氯甲烷，二氯乙烷，氯仿，甲苯，乙腈，正己烷等，其中最优的溶剂为二氯甲烷。
反应中铜催化剂、噁唑啉配体、炔醛或炔酮(1)、重氮酯(2)的摩尔比为： 0.05～0.10∶0.055～0.11：1∶1.2～1.5，最优的摩尔比为：0.05∶0.055∶1∶1.5。
反应液浓度为：0.02～0.10mol/L，最佳浓度为0.025mo1/L。
反应的温度为：25-60℃，其中最佳温度为40℃。
反应还可以加入添加剂，具体为
Figure BDA0003110864590000032
分子筛，
Figure BDA0003110864590000033
分子筛或
Figure BDA0003110864590000034
分子筛，其中
Figure BDA0003110864590000035
分子筛最好，其添加量为60mg/0.1mmol。
有益效果和优点
本发明公开了一种铜不对称催化构建手性四取代环(二氢茚环或者四氢萘环)外α-羟基联烯酸酯的方法，通过选用合适的铜盐催化剂和配体对反应进行调控同时克服了反应的非对映选择性和对映选择性难题，丰富和发展了基于铜卡宾转移反应构建轴手性联烯衍生物的合成方法。
本发明方法的优点有：反应条件简单温和、底物适用范围广、产率高、对映选择性和非对映选择性好。
附图说明
图1为实施例1得到的3aa的1H-NMR(核磁氢谱)；
图2为实施例1得到的3aa的13C-NMR(核磁碳谱)；
图3为实施例1得到的3aa的HRMS(高分辨质谱)；
图4为实施例1得到的3aa的HPLC(高效液相色谱)。
具体实施方式
下面将通过具体实施例对本发明做进一步说明，本发明并不局限于以下的实施例：
实施例1：
Figure BDA0003110864590000041
氩气保护下，向反应管中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000042
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌12小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa(27.8mg,87％yield,97％ee)。HPLC检测条件:Daicel Chiralpak IC column, n-hexane/i-PrOH＝80/20,flow rate 1mL/min,λ＝254nm,tR＝5.77min(major)and 6.57min(minor).[α]D 20:-131.6°(c＝0.50,CH2Cl2).1HNMR(300MHz,CDCl3)δ 7.62-7.44(m,3H),7.43-7.21(m,6H),5.89(s,1H),5.11(hept,J＝6.2Hz,1H),4.08 (d,J＝19.9Hz,1H),3.89(d,J＝19.9Hz,1H),2.58(s,1H),1.27(d,J＝6.2Hz,3H), 1.26(d,J＝6.2Hz,3H).13C NMR(75MHz,CDCl3)δ207.2,165.7,142.8,139.9,132.8,129.3,128.7,128.4,128.0,127.7,125.5,124.9,111.7,107.5,77.3,69.2,34.9,21.9.HRMS(ESI)m/z:[M+Na]+Calcd for C21H20NaO3 343.1305；Found 343.1305.
实施例2：
Figure BDA0003110864590000051
氩气保护下，向反应管中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L1(2.2 mg)、
Figure BDA0003110864590000052
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌3小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物 3aa(25.3mg,79％yield,95％ee)。
实施例3：
Figure BDA0003110864590000053
氩气保护下，向反应管中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L7(2.2 mg)、
Figure BDA0003110864590000054
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌20小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa(13.1mg,41％yield,96％ee)。
实施例4：
Figure BDA0003110864590000061
氩气保护下，向反应管中加入1a(14.4mg)、Cu(MeCN)4BF4(1.6mg)、L1 (2.2mg)、
Figure BDA0003110864590000062
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌3小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa(7.7mg,24％yield,94％ee)。
实施例5：
Figure BDA0003110864590000063
氩气保护下，向反应管中加入1a(14.4mg)、CuI(0.9mg)、L1(2.2mg)、
Figure BDA0003110864590000064
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a (30.6mg)，反应混合物在40℃油浴中搅拌15小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa (10.5mg,33％yield,57％ee)。
实施例6：
Figure BDA0003110864590000065
氩气保护下，向反应管中加入1a(14.4mg)、CuBr2(1.1mg)、L1(2.2mg)、
Figure BDA0003110864590000071
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入 2a(30.6mg)，反应混合物在40℃油浴中搅拌3小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa (4.8mg,15％yield,50％ee)。
实施例7：
Figure BDA0003110864590000072
氩气保护下，向反应管中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3mg) 和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌20小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa(25.3mg,79％ yield,93％ee)。
实施例8：
Figure BDA0003110864590000073
氩气保护下，向反应管中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000074
分子筛(60mg)和甲苯(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌12小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa(18.9mg,59％yield,76％ee)。
实施例9：
Figure BDA0003110864590000081
氩气保护下，向反应管中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000082
分子筛(60mg)和DCM(2mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌12小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa(28.8mg,90％yield,94％ee)。
实施例10：
Figure BDA0003110864590000083
氩气保护下，向反应管中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000084
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在45℃油浴中搅拌12小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物3aa(28.8mg,90％yield,92％ee)。
实施例11：
Figure BDA0003110864590000085
氩气保护下，向反应管中中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000086
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2b(42.4mg)，反应混合物在40℃油浴中搅拌12小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到白色固体产物3ab (35.1mg,88％yield,95％ee)，熔点：106-108℃。HPLC检测条件:Daicel Chiralpak IC column,n-hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,λ＝254nm,tR＝7.48 min(major)and 8.36min(minor).[α]D 20:-126.2°(c＝0.90,CH2Cl2).1H NMR(400 MHz,CDCl3)δ7.52(d,J＝6.4Hz,1H),7.47(d,J＝8.5Hz,2H),7.42(d,J＝8.5Hz, 2H),7.39-7.27(m,3H),5.90(s,1H),5.12(hept,J＝6.2Hz,1H),4.08(d,J＝19.9Hz, 1H),3.90(d,J＝19.9Hz,1H),2.47(s,1H),1.26(t,J＝6.2Hz,6H).13C NMR(100 MHz,CDCl3)δ207.3,165.3,142.7,139.7,131.7,131.6,130.3,129.5,127.8,125.5,124.9,122.1,112.1,106.6,77.4,69.4,34.8,21.9.HRMS(ESI)m/z:[M+Na]+ Calcd forC21H19 79BrNaO3 421.0410；Found 421.0410；Calcd for C21H19 81BrNaO3 423.0389；Found423.0392.
实施例12：
Figure BDA0003110864590000091
氩气保护下，向反应管中中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000092
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2c(37.2mg)，反应混合物在40℃油浴中搅拌12小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:10-1:4)得到淡黄色粘稠油状产物3ac(20.0mg,55％yield,96％ee)。HPLC检测条件:Daicel Chiralpak ID column, n-hexane/i-PrOH＝60/40,flow rate 2mL/min,λ＝254nm,tR＝5.86min(major)and 9.66min(minor).[α]D 20:-179.6°(c＝0.50,CH2Cl2).1HNMR(300MHz,CDCl3)δ 7.55-7.49(m,1H),7.39-7.27(m,3H),7.09-6.99(m,2H),6.80(d,J＝8.0Hz,1H), 5.96(s,2H),5.88(s,1H),5.12(hept,J＝6.0Hz,1H),4.06(d,J＝19.9Hz,1H),3.88 (d,J＝19.9Hz,1H),2.46(s,1H),1.27(d,J＝6.0Hz,3H),1.25(d,J＝6.0Hz,3H). 13CNMR(75MHz,CDCl3)δ206.7,165.7,147.7,147.5,142.8,139.9,129.4,127.7, 126.3,125.5,124.9,122.5,111.7,109.1,108.3,107.2,101.3,77.3,69.2,34.9,21.9. HRMS(ESI)m/z:[M+Na]+Calcd for C22H20NaO5 387.1203；Found 387.1202.
实施例13：
Figure BDA0003110864590000101
氩气保护下，向反应管中中加入1a(14.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000102
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2d(51.4mg)，反应混合物在40℃油浴中搅拌6小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到白色固体产物3ad(29.9 mg,65％,95％ee)，熔点：147-149℃。HPLC检测条件:Daicel Chiralpak ID column, n-hexane/i-PrOH＝70/30,flow rate 1mL/min,λ＝254nm,tR＝6.77min(minor) and 8.26min(major).[α]D 20:-146.3°(c＝0.60,CH2Cl2).1HNMR(300MHz,CDCl3) δ8.22(d,J＝8.2Hz,1H),8.17(s,1H),7.73(d,J＝7.8Hz,1H),7.62-7.51(m,1H), 7.43-7.29(m,4H),7.21(t,J＝7.8Hz,1H),5.96(d,J＝5.9Hz,1H),5.17(hept,J＝ 6.2Hz,1H),4.15(d,J＝20.1Hz,1H),3.97(d,J＝20.1Hz,1H),2.52(d,J＝5.9Hz, 1H),1.68(s,9H),1.30(d,J＝6.2Hz,3H),1.29(d,J＝6.2Hz,3H).13C NMR(75 MHz,CDCl3)δ207.2,165.6,149.6,142.8,139.8,135.5,129.4,128.8,127.8,126.3, 125.6,124.9,124.8,123.0,119.8,115.4,112.5,110.8,100.5,84.0,77.8,69.4,35.5, 28.3,22.0.HRMS(ESI)m/z:[M+Na]+Calcd for C28H29NNaO5 482.1938；Found 482.1936.
实施例14：
Figure BDA0003110864590000111
氩气保护下，向反应管中中加入1b(17.4mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000112
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在40℃油浴中搅拌12小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:10-1:4)得到淡黄色粘稠油状产物3ba(28.0mg,80％yield,96％ee)。HPLC检测条件:Daicel Chiralpak ID column, n-hexane/i-PrOH＝60/40,flow rate 2mL/min,λ＝254nm,tR＝4.31min(major)and 7.05min(minor).[α]D 20:-136.5°(c＝0.55,CH2Cl2).1HNMR(400MHz,CDCl3)δ 7.53(d,J＝7.4Hz,2H),7.42(d,J＝8.4Hz,1H),7.35(t,J＝7.4Hz,2H),7.32-7.26 (m,1H),6.88(d,J＝8.4Hz,1H),6.81(s,1H),5.84(s,1H),5.14(hept,J＝6.2Hz, 1H),4.06(d,J＝19.9Hz,1H),3.85(d,J＝19.9Hz,1H),3.82(s,3H),2.41(s,1H),1.28(d,J＝6.2Hz,3H),1.27(d,J＝6.2Hz,3H).13C NMR(75MHz,CDCl3)δ 207.3,165.6,160.9,141.7,135.1,132.8,128.7,128.4,128.0,126.3,114.3,112.0, 109.4,107.3,76.9,69.2,55.6,34.9,21.9.HRMS(ESI)m/z:[M+Na]+Calcd for C22H22NaO4 373.1410；Found 373.1410.
实施例15：
Figure BDA0003110864590000113
氩气保护下，向反应管中中加入1c(15.8mg)、Cu(tfacac)2(1.8mg)、L4(2.3 mg)、
Figure BDA0003110864590000121
分子筛(60mg)和DCM(4mL)并在25℃搅拌1小时，之后在氩气下加入2a(30.6mg)，反应混合物在60℃油浴中搅拌2小时。反应液减压蒸除溶剂、柱层析纯化(淋洗剂为乙酸乙酯：石油醚＝1:20-1:5)得到淡黄色粘稠油状产物 3ca(21.0mg,63％yield,80％ee)。HPLC检测条件:Daicel Chiralpak ID column, n-hexane/i-PrOH＝60/40,flow rate 2mL/min,λ＝254nm,tR＝2.24min(minor) and 2.67min(major).[α]D 20:-109.2°(c＝0.50,CH2Cl2).1HNMR(400MHz,CDCl3) δ7.57(d,J＝7.4Hz,2H),7.50-7.44(m,1H),7.39-7.26(m,6H),5.14(hept,J＝6.2 Hz,1H),4.07(d,J＝20.0Hz,1H),3.93(d,J＝20.0Hz,1H),2.62(s,1H),1.75(s, 3H),1.27(d,J＝6.2Hz,3H),1.26(d,J＝6.2Hz,3H).13C NMR(100MHz,CDCl3) δ206.2,165.7,146.7,138.6,132.7,129.2,128.5,128.4,128.0,127.8,124.9,123.6, 116.3,108.5,83.2,69.2,34.3,29.0,22.0.HRMS(ESI)m/z:[M+Na]+Calcd for C22H22NaO3357.1461；Found 357.1461.

Claims (5)

1.一种铜不对称催化构建手性四取代环外α-羟基联烯酸酯的方法，其特征在于，所述方法为：氩气保护下，将芳炔醛或芳炔酮(1)、铜催化剂、手性噁唑啉配体及溶剂在室温下预搅拌1小时，再加入重氮酯(2)，之后搅拌反应得到手性四取代环外α-羟基联烯酸酯(3)；
Figure FDA0003848889630000011
其中，R1为Ph，4-MeC6H4，4-FC6H4，4-ClC6H4，4-BrC6H4，4-PhC6H4，4-CF3OC6H4，4-CF3C6H4，3-ClC6H4，2-FC6H4，2-萘基，3-噻吩基，胡椒环，3-(N-Boc吲哚)基；R2为Me，Et，iPr，tBu，Bn；R3为4-F，5-MeO，5-Me，6-Cl，6-MeO，7-Cl，4,5-并苯环，5,6-OCH2O；R4为氢、烷基；n＝1,2；
所述铜催化剂为：三氟乙酰丙酮化铜；
所述手性噁唑啉配体的结构如下式所示：
Figure FDA0003848889630000012
所述反应的温度为：25-60℃，反应时间为2-72小时。
2.根据权利要求1所述的铜不对称催化构建手性四取代环外α-羟基联烯酸酯的方法，其特征在于，所述溶剂为：二氯甲烷，二氯乙烷，氯仿，甲苯，乙腈，正己烷。
3.根据权利要求1所述的铜不对称催化构建手性四取代环外α-羟基联烯酸酯的方法，其特征在于，铜催化剂、噁唑啉配体、芳炔醛或芳炔酮、重氮酯的摩尔比：0.05～0.10:0.055～0.11:1:1.2～1.5。
4.根据权利要求1所述的铜不对称催化构建手性四取代环外α-羟基联烯酸酯的方法，其特征在于，所述反应液浓度为：0.02～0.10mol/L。
5.根据权利要求1所述的铜不对称催化构建手性四取代环外α-羟基联烯酸酯的方法，其特征在于，所述反应的添加剂为
Figure FDA0003848889630000021
分子筛，
Figure FDA0003848889630000022
分子筛或
Figure FDA0003848889630000023
分子筛。
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