CN102675049B - 光学活性轴手性α-联烯醇、合成方法和用途 - Google Patents

光学活性轴手性α-联烯醇、合成方法和用途 Download PDF

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CN102675049B
CN102675049B CN201210193176.4A CN201210193176A CN102675049B CN 102675049 B CN102675049 B CN 102675049B CN 201210193176 A CN201210193176 A CN 201210193176A CN 102675049 B CN102675049 B CN 102675049B
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麻生明
叶俊涛
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

本发明涉及一种光学活性轴手性α-联烯醇、合成方法和用途，通过二溴化锌促进剂，通过叔丁基二甲基硅基保护的炔丙醇、醛和手性α,α-二苯基脯氨醇制备高光学活性轴手性α-联烯醇的方法。该轴手性α-联烯醇具有如下的结构式：

Description

光学活性轴手性α-联烯醇、合成方法和用途
技术领域
本发明涉及一种高光学活性轴手性α-联烯醇、简单高效合成的方法和用途，具体涉及一种二溴化锌促进的，通过叔丁基二甲基硅基保护的炔丙醇、醛和手性α,α-二苯基脯氨醇制备高光学活性轴手性α-联烯醇的方法。
背景技术
α-联烯醇是一类非常重要的有机合成中间体，广泛应用于2,5-二氢呋喃(R.Gelin,S.Gelin,M.Albrand,Bull.Soc.Chim.Fr.1972,1946;L.-I.Olsson,A.Claesson,Synthesis 1979,743;S.S.Nikam,K.-H.Chu,K.K.Wang,J.Org.Chem.1986,51,745;J.A.Mashall,X.-J.Wang,J.Org.Chem.1990,55,2995;J.A.Mashall,X.-J.Wang,J.Org.Chem.1991,56,4913;J.A.Mashall,K.G.Pinney,J.Org.Chem.1993,58,7180;J.A.Mashall,R.H.Yu,J.F.Perkins,J.Org.Chem.1995,60,5550;J.A.Mashall,C.A.Sehon,J.Org.Chem.1995,60,5966)、2(5H)-呋喃酮(E.Yoneda,T.Kaneko,S.-W.Zhang,K.Onitsuka,S.Takahashi,Org.Lett.2000,2,441;X.Cheng,X.Jiang,Y.Yu,S.Ma,J.Org.Chem.2008,73,8960)、乙烯基氧杂环丙烷(R.W.Friesen,M.Blouin,J.Org.Chem.1993,58,1653;S.-K.Kang,T.Yamaguchi,S.-J.Pyun,Y.-T.Lee,T.-G..Bail,Tetrahedron Lett.1998,39,2127;S.Ma,S.Zhao,J.Am.Chem.Soc.1999,121,7943)、β-卤素-β,γ-烯醛或者烯酮(J.Li,C.Fu,G.Chen,G.Chai,S.Ma,Adv.Synth.Catal.2008,350,1376;C.Fu,J.Li,S.Ma,Chem.Commun.2005,4119;J.-Q.He,D.Shibata,C.Ohno,S.Okamoto,Tetrahedron Lett.2008,49,6724)、1,3-共轭二烯(S.Ma,G.Wang,Tetrahedron Lett.2002,43,5723;Y.Deng,X.Jin,S.Ma,J.Org.Chem.2007,72,5901)和烯丙醇(Z.Lu,S.Ma,Adv.Synth.Catal.2007,349,1225)等有机化合物的合成。同时，α-联烯醇还是合成一系列官能团化的联烯如联烯胺(C.Sahlberg,S.B.Ross,I.Fagervall,A.-L.Ask,A.Claesson,J.Med.Chem.1983,26,103;Y.Imada,M.Nishida,K.Kutsuwa,S.-I.Murahashi,T.Naota,Org.Lett.2005,7,5837;B.M.Trost,D.R.Fandrick,D.C.Dinh,J.Am.Chem.Soc.2005,127,14186)、联烯丙二酸酯(M.Ogasawara,H.Ikeda,T.Nagano,T.Hayashi,J.Am.Chem.Soc.2001,123,2089;Y.Imada,K.Ueno,K.Kutsuwa,S.-I.Murahashi,Chem.Lett.2002,140;S.Ma,N.Jiao,S.Zhao,H.Hou,J.Org.Chem.,2002,67,2837;)、联烯硫醇(N.Morita,N.Krause,Angew.Chem.,Int.Ed.2006,45,1897)和联烯醛或酮(S.Ma,S.Yu,S.Yin,J.Org.Chem.2003,68,8996;b)S.Ma,J.Liu,S.Li,B.Chen,J.Cheng,J.Kuang,Y.Liu,B.Wan,Y.Wang,J.Ye,Q.Yu,W.Yuan,S.Yu,Adv.Synth.Catal.2011,353,1005)等化合物的重要前体。在一系列α-联烯醇中，轴手性的α-联烯醇尤为重要，因为其轴手性能够通过手性转移的策略转化为产物的中心手性，从而为合成光学活性的化合物提供了一种有效的途径。因此，发展一种简单高效合成高光学活性轴手性α-联烯醇的方法意义十分重大。根据文献报道，合成轴手性α-联烯醇需要很繁琐的步骤，反应条件比较苛刻，总产率低，且大部分方法需要使用危险的化学品如正丁基锂(n-BuLi)或乙基溴化镁(EtMgBr)以及氢化锂铝(LiAlH4)，操作不方便，不利于大规模合成(L.-I.Olsson,A.Claesson,Acta Chem.Scand.1977,B31,614;A.Claesson,L.-I.Olsson,J.Am.Chem.Soc.1979,101,7302;R.A.Smith,R.L.White,A.Krantz,J.Med.Chem.1988,31,1558;J.Stichler-Bonaparte,H.Kruth,R.Lunkwitz,C.Tschierske,Liebigs Ann.1996,1375)。
本发明克服了现有技术中合成步骤长，产率低，需要使用危险化学品、操作不方便等缺陷，提供了一种二溴化锌促进的，利用叔丁基二甲基硅基保护的炔丙醇、醛和手性α,α-二苯基脯氨醇简单高效制备高光学活性轴手性α-联烯醇的方法。该方法与传统方法相比，具有合成路线短、产率高、操作方便、适用大规模合成等优点。
发明内容
本发明的目的在于提供一种高光学活性轴手性α-联烯醇、简单高效合成方法和用途。
本发明提供的一种轴手性α-联烯醇具有如下的结构式：
Figure BDA00001755563300031
其中，R1=C1～C10的烃基，如直链烷基、环状烷基或苯基等；R2=H或C1～C10的烃基等，如直链烷基、环状烷基或苯基；联烯的轴手性为R或S型，与羟基相连的碳原子可以是非手性、R或S型；当所述的C1～C10的烃基为脂肪基时，ee值大于96%。
本发明提供的一种轴手性α-联烯醇的合成方法，反应式如下：
Figure BDA00001755563300041
其中，PG表示硅基保护基团，R1、R2、联烯的轴手性以及与羟基相连的碳原子的构型如前所述。
在100-130℃下和有机溶剂中，以锌盐为促进剂，以(S)-3或其对映体为手性仲胺，与硅基保护的炔丙醇和醛反应5-15小时，过短硅胶柱后用四正丁基氟化铵脱去硅基保护基即可得到轴手性α-联烯醇产物；其中，所述硅基保护的炔丙醇：醛：手性仲胺：锌盐：四正丁基氟化铵的摩尔比为1～3：1～3：1：0.5～1.5：1～5；所述的硅基为三甲基硅基、三异丙基硅基、叔丁基二甲基硅基和叔丁基二苯基硅基，优选叔丁基二甲基硅基；所述的手性仲胺为(S)-3a-e或其对映体，优选(S)-3a或其对映体；所述的锌盐为氯化锌、溴化锌、碘化锌、醋酸锌和三氟甲磺酸锌，优选溴化锌；所述的四正丁基氟化铵为四正丁基氟化铵三水合物和四正丁基氟化铵的四氢呋喃溶液；上述的有机溶剂为苯、甲苯、氯苯、对二甲苯、邻二甲苯、间二甲苯或均三甲苯；优选甲苯。
进一步的描述方法可以是：
在干燥的反应器中加入锌盐、手性仲胺、硅基保护的炔丙醇、醛和干燥的有机溶剂，在100-130℃下搅拌5-20小时。反应结束后，过短硅胶柱得到粗产物，将其溶于有机溶剂，0℃下加入四正丁基氟化铵，然后在室温下搅拌1-15小时。反应结束后向反应体系中加入水洗涤，有机溶剂萃取，无水硫酸钠干燥，浓缩，柱层析分离方法纯化得到轴手性α-联烯醇。
本发明设计一种高效合成轴手性α-联烯醇的方法，以二溴化锌为促进剂，从叔丁基二甲基硅基保护的炔丙醇、醛和手性α,α-二苯基脯氨醇出发，经过两步操作即可获得高光学活性的轴手性α-联烯醇。利用该方法，可以简单高效地合成带有不同取代基的轴手性α-联烯伯醇及仲醇。使用S构型的α,α-二苯基脯氨醇，可以得到联烯的轴手性为R构型的产物，而使用R构型的α,α-二苯基脯氨醇便可以制备联烯的轴手性为S构型的产物。当以光学活性的叔丁基二甲基硅基保护的炔丙醇为起始原料时，通过使用不同构型的起始原料和α,α-二苯基脯氨醇，可以方便地合成同时具有轴手性和中心手性的轴手性α-联烯仲醇的全部四个异构体。
利用本发明方法合成的高光学活性的轴手性α-联烯醇，可以很方便的合成具有中心手性且手性完全保持的2,5-二氢呋喃类化合物，同时还可以合成手性完全保持的轴手性联烯胺和联烯丙二酸酯类化合物。
本发明方法具有合成路线短、操作简单、原料易得、分离纯化方便、底物普适性广、总产率较高、对应选择性以及非对映选择性高等优点。本发明克服了现有技术中合成步骤长，产率低，反应条件比较苛刻、需要使用危险化学品、操作不方便等缺陷。
具体实施方式
以下实施例有助于理解本发明，但不限于本发明的内容。
实施例1
Figure BDA00001755563300051
其中，equiv表示当量，mol表示摩尔，TBS(tert-butyldimethylsilyl)表示叔丁基二甲基硅基，Cy(cyclohexyl)表示环己基，TBAF(tetrabutylammonium fluoride)表示四正丁基氟化铵，toluene表示甲苯，THF表示四氢呋喃，rt表示室温，ee表示对映体过量，de表示非对映体过量
在惰性气体的保护下，向干燥的反应管中加入ZnBr2(169.3mg,0.75mmol)，热烘枪烘干，然后依次加入α,α-二苯基脯氨醇(S)-3a(258.7mg,1.0mmol,98%),叔丁基二甲基硅基保护的炔丙醇1a(188.2mg,1.1mmol)，干燥的甲苯(2mL),新蒸环己基甲醛2a(168.6mg,1.5mmol)和干燥的甲苯(1mL)。然后在反应管上插入回流冷凝管，放置到事先已加热到130℃的油浴中回流搅拌10小时。冷至室温后，用短的硅胶柱过滤，20mL乙醚洗涤，浓缩后过一根短柱(石油醚/乙醚=50/1)得到叔丁基二甲基硅基保护的联烯醇粗产物。将该粗产物直接溶于四氢呋喃(3mL)，0°C下加入TBAF·3H2O(316.0mg,1.0mmol)，自然升至室温搅拌1.5小时后，向体系加入10mL乙醚和10mL水，分出有机层，水层乙醚萃取(10mL×3)，合并有机层，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙酸乙酯=10/1)得液体轴手性α-联烯醇(R)-4aa(104.0mg,68%):99%ee(HPLC测定条件:ChiralcelAS-H柱,正己烷/异丙醇=98/2,0.6mL/min,λ=214nm,tR(大峰)=16.0min,tR(小峰)=19.2min);[α]22 D=-99.8(c=1.01,CHCl3);1H NMR(300MHz,CDCl3)δ=5.41-5.24(m,2H,CH=C=CH),4.10(d,J=2.7Hz,2H,OCH2),2.08-1.88(m,2H,OH and CH from Cy),1.82-1.57(m,5H,protons from Cy),1.37-0.97(m,5H,protons from Cy);13C NMR(75MHz,CDCl3)δ=201.9,99.7,92.5,60.8,37.0,33.0,32.9,26.0,25.9;MS(EI)m/z(%):152(M+,0.70),55(100);IR(neat):v=3326,2923,2850,1961,1448,1302,1259,1214,1062,1008cm-1;HRMS[M+]计算值:152.1201,实测值:152.1203.
实施例2
Figure BDA00001755563300071
操作参考实施例1。ZnBr2(1.6912g,7.5mmol)，α,α-二苯基脯氨醇(S)-3a(2.5857g,10mmol),叔丁基二甲基硅基保护的炔丙醇1a(1.8738g,11mmol)，新蒸环己基甲醛2a(1.6831g,15mmol)，干燥的甲苯(30mL)，TBAF·3H2O(3.1563g,10mmol)和四氢呋喃(30mL)。柱层析(石油醚/乙酸乙酯=15/1(800mL)→10:1)得液体轴手性α-联烯醇(R)-4aa(1.0624,70%):99%ee(HPLC测定条件:ChiralcelAS-H柱,正己烷/异丙醇=98/2,0.6mL/min,λ=214nm,tR(大峰)=11.9min,tR(小峰)=12.9min);[α]22 D=-100.3(c=1.00,CHCl3);1H NMR(300MHz,CDCl3)δ=5.42-5.26(m,2H,CH=C=CH),4.11(s,2H,OCH2),2.07-1.94(m,1H,CH fromCy),1.82-1.49(m,6H,OH and protons from Cy),1.36-1.00(m,5H,protons fromCy).
实施例3
Figure BDA00001755563300072
操作参考实施例1。ZnBr2(506.8mg,2.25mmol)，α,α-二苯基脯氨醇(S)-3a(775.4mg,3.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(562.4mg,3.3mmol)，新蒸异戊醛2b(388.1mg,4.5mmol)，干燥的甲苯(9mL)，TBAF·3H2O(947.3mg,3.0mmol)和四氢呋喃(5mL)。柱层析(石油醚/乙酸乙酯=15/1)得液体轴手性α-联烯醇(R)-4ab(171.2mg,45%):98%ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇=200/1,1.0mL/min,λ=214nm,tR(大峰)=20.4min,tR(小峰)=25.3min);[α]22 D=-80.3(c=1.01,CHCl3);1H NMR(300MHz,CDCl3)δ=5.35-5.18(m,2H,CH=C=CH),4.11(s,2H,OCH2),2.03-1.79(m,3H,OH and CH2),1.76-1.58(m,1H,CH),0.92(d,J=6.6Hz,6H,two CH3);13C NMR(75MHz,CDCl3)δ=203.6,92.2,90.9,60.8,38.1,28.3,22.1;MS(EI)m/z(%):126(M+,0.21),55(100);IR(neat):v=3326,2955,2928,2870,1963,1466,1384,1367,1262,1056,1013cm-1;HRMS[M+]计算值:126.1045,实测值:126.1044.
实施例4
Figure BDA00001755563300081
操作参考实施例1。ZnBr2(169.7mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.8mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(188.2mg,1.1mmol)，新蒸正己醛2c(150.4mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(316.2mg,1.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=10/1)得液体轴手性α-联烯醇(R)-4ac(83.0mg,59%):98%ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇=98/2,0.5mL/min,λ=214nm,tR(大峰)=12.2min,tR(小峰)=13.1min);[α]21 D=-78.4(c=1.03,CHCl3);1H NMR(300MHz,CDCl3)δ=5.36-5.23(m,2H,CH=C=CH),4.11(s,2H,OCH2),2.09-1.90(m,3H,OH and CH2),1.49-1.23(m,6H,three CH2),0.89(t,J=6.5Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ=203.0,93.7,91.6,60.7,31.2,28.7,28.5,22.4,14.0;MS(EI)m/z(%):140(M+,0.15),55(100);IR(neat):v=3345,2956,2928,2857,1963,1464,1417,1379,1206,1137,1111,1057,1011cm-1;HRMS[M+]计算值:140.1201,实测值:140.1202.
实施例5
Figure BDA00001755563300091
操作参考实施例1。ZnBr2(169.4mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.2mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(188.2mg,1.1mmol)，新蒸环戊基甲醛2d(147.3mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(316.4mg,1.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=10/1)得液体轴手性α-联烯醇(R)-4ad(81.9mg,59%):98%ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇=98/2,0.6mL/min,λ=214nm,tR(大峰)=13.8min,tR(小峰)=15.3min);[α]20 D=-97.2(c=1.02,CHCl3);1H NMR(300MHz,CDCl3)δ=5.39-5.27(m,2H,CH=C=CH),4.10(d,J=2.7Hz,2H,OCH2),2.56-2.39(m,1H,CH from cyclopentyl),2.07(s,1H,OH),1.86-1.72(m,2H,CH2),1.72-1.47(m,4H,two CH2),1.46-1.28(m,2H,CH2);13C NMR(75MHz,CDCl3)δ=201.8,98.6,92.4,60.7,39.0,32.7,24.8;MS(EI)m/z(%):138(M+,0.28),79(100);IR(neat):v=3321,2951,2867,1961,1451,1420,1207,1009cm-1;HRMS[M+]计算值:138.1045,实测值:138.1044.
实施例6
Figure BDA00001755563300092
操作参考实施例1。ZnBr2(169.5mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.3mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(188.2mg,1.1mmol)，新蒸正辛醛2e(192.5mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(315.7mg,1.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=15/1)得液体轴手性α-联烯醇(R)-4ae(109.8mg,65%):97%ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇=98/2,0.6mL/min,λ=214nm,tR(大峰)=11.1min,tR(小峰)=12.2min);[α]20 D=-66.1(c=1.03,CHCl3);1H NMR(300MHz,CDCl3)δ=5.37-5.22(m,2H,CH=C=CH),4.11(d,J=1.2Hz,2H,OCH2),2.07-1.95(m,2H,CH2),1.91(s,1H,OH),1.47-1.17(m,10H,five CH2),0.88(t,J=6.5Hz,3H,CH2);13C NMR(75MHz,CDCl3)δ=202.9,93.8,91.6,60.7,31.8,29.08,29.06,29.0,28.6,22.6,14.0;MS(ESI):m/z 191(M+Na+),168(M+);IR(neat):v=3320,2956,2925,2855,1964,1463,1420,1379,1140,1056,1012cm-1;HRMS[M+]计算值:168.1514,实测值:168.1515.
实施例7
Figure BDA00001755563300101
操作参考实施例1。ZnBr2(169.7mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.6mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(187.9mg,1.1mmol)，新蒸苯丙醛2f(202.1mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(315.7mg,1.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=15/1(320mL)→10:1)得液体轴手性α-联烯醇(R)-4af(105.1mg,60%):96%ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇=100/1,1.0mL/min,λ=214nm,tR(大峰)=19.0min,tR(小峰)=20.5min);[α]20 D=-38.7(c=1.05,CHCl3);1H NMR(300MHz,CDCl3)δ=7.32-7.13(m,5H,Ar-H),5.34-5.21(m,2H,CH=C=CH),3.97(d,J=1.2Hz,2H,OCH2),2.83-2.64(m,2H,CH2),2.45-2.24(m,2H,CH2),1.78(s,1H,OH);13C NMR(75MHz,CDCl3)δ=203.2,141.3,128.4,128.2,125.8,92.7,92.1,60.4,35.0,29.9;MS(EI)m/z(%):174(M+,0.12),91(100);IR(neat):v=3341,3026,2923,2856,1963,1495,1453,1062,1008cm-1;HRMS[M+]计算值:174.1045,实测值:174.1044.
实施例8
Figure BDA00001755563300111
操作参考实施例1。ZnBr2(169.2mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.7mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(188.1mg,1.1mmol)，新蒸2-乙基丁醛2g(150.4mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(315.8mg,1.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=15/1)得液体轴手性α-联烯醇(R)-4ag(88.7mg,63%):98%ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇=200/1,1.0mL/min,λ=214nm,tR(大峰)=19.0min,tR(小峰)=22.0min);[α]20 D=-92.5(c=1.01,CHCl3);1H NMR(300MHz,CDCl3)δ=5.32(q,J=6.1Hz,1H,one protonfrom CH=C=CH),5.14-5.04(m,1H,one proton fromCH=C=CH),4.11(d,J=3.6Hz,2H,OCH2),2.05(s,1H,OH),1.95-1.80(m,1H,CH),1.53-1.20(m,4H,two CH2),0.90(t,J=7.4Hz,6H,two CH3);13C NMR(75MHz,CDCl3)δ=202.9,97.3,91.5,61.0,42.7,27.5,27.3,11.54,11.46;MS(EI)m/z(%):140(M+,0.15),93(100);IR(neat):v=3323,2988,2871,1963,1459,1381,1359,1141,1011cm-1;HRMS[M+]计算值:140.1201,实测值:140.1199.
实施例9
Figure BDA00001755563300121
操作参考实施例1，第一步反应温度为120°C。ZnBr2(169.7mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.3mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(188.0mg,1.1mmol)，新蒸苯甲醛2h(159.5mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(315.7mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=8/1)得液体轴手性α-联烯醇(R)-4ah(37.0mg,25%):93%ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇=98/2,1.0mL/min,λ=214nm,tR(小峰)=20.1min,tR(大峰)=21.5min;[α]20 D=-217.1(c=0.45,CHCl3);1H NMR(300MHz,CDCl3)δ=7.35-7.14(m,5H,Ar-H),6.35-6.27(m,1H,CH=C=CH),4.11(q,J=5.8Hz,1H,OCH),4.24(t,J=2.4Hz,1H,OCH),1.84(s,1H,OH);13C NMR(75MHz,CDCl3)δ=204.2,133.7,128.6,127.2,126.8,97.1,95.8,60.3;MS(EI)m/z(%):146(M+,23.71),55(100);IR(neat):v=3327,3031,2928,2871,1950,1598,1494,1459,1408,1264,1205,1112,1072,1009cm-1;HRMS[M+]计算值:146.0732,实测值:146.0731.
实施例10
Figure BDA00001755563300122
操作参考实施例1。ZnBr2(169.4mg,0.75mmol)，α,α-二苯基脯氨醇(R)-3a(258.3mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇1a(188.3mg,1.1mmol)，新蒸环己基甲醛2a(169.0mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(315.8mg,1.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=10/1)得液体轴手性α-联烯醇(S)-4aa(99.9mg,66%):99%ee(HPLC测定条件:Chiralcel AS-H柱,正己烷/异丙醇=98/2,0.6mL/min,λ=214nm,tR(小峰)=16.0min,tR(大峰)=19.0min);[α]21 D=100.9(c=1.04,CHCl3);1H NMR(300MHz,CDCl3)δ=5.41-5.26(m,2H,CH=C=CH),4.11(s,2H,OCH2),2.08-1.94(m,1H,CH from Cy),1.82-1.57(m,6H,OH and protons from Cy),1.37-1.00(m,5H,protons from Cy);13C NMR(75MHz,CDCl3)δ=201.8,99.9,92.6,60.8,37.0,33.03,32.97,26.0,25.9;MS(EI)m/z(%):152(M+,1.15),55(100);IR(neat):v=3321,2923,2850,1961,1448,1417,1348,1062,1009cm-1;HRMS[M+]计算值:152.1201,实测值:152.1202.
实施例11
反应式箭下面的61%表示产率；de值，表示非对映体过量。后面实施例相同符号表示相同的意思。
操作参考实施例1。ZnBr2(169.3mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.5mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(±)-1b(277.9mg,1.1mmol)，新蒸环己基甲醛2a(168.2mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(946.9mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=25/1)得液体轴手性α-联烯醇5ba(143.5mg,61%):(Ra，S)-5ba(98%de,99%ee),(Ra，R)-5ba(99%de,98%ee)(HPLC测定条件:Chiralcel PC-2柱,正己烷/异丙醇=98/2,0.5mL/min,λ=214nm,tR(小峰)=9.4min,tR(大峰)=10.3min,tR(大峰)=11.5min,tR(小峰)=12.6min);[α]21 D=-81.8(c=1.01,CHCl3);1H NMR(300MHz,CDCl3)δ=5.33-5.19(m,2H,CH=C=CH),3.87(s,1H,OCH),2.06-1.57(m,12H,OH and protons from Cy),1.49-0.94(m,11H,protons from Cy);13C NMR(75MHz,CDCl3)δ=201.4,200.9,100.3,99.8,95.1,94.9,74.5,73.9,44.08,43.97,37.12,37.09,33.04,33.01,32.97,28.73,28.70,28.3,28.2,26.5,26.11,26.07,26.05,26.00,25.98,25.91;MS(EI)m/z(%):234(M+,2.25),55(100);IR(neat):v=3376,2922,2851,1960,1448,1083,1009cm-1;HRMS[M+]计算值:234.1984,实测值:234.1980.
实施例12
Figure BDA00001755563300141
操作参考实施例1。ZnBr2(169.3mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.8mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(±)-1c(295.7mg,1.1mmol)，新蒸环己基甲醛2a(168.5mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(947.2mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=25/1)得液体轴手性α-联烯醇5ca(175.8mg,70%):(Ra,S)-5ca(97%de,98%ee),(Ra，R)-5ca(98%de,97%ee)(HPLC测定条件:Chiralcel IC柱,正己烷/异丙醇=100/1,0.5mL/min,λ=214nm,tR(小峰)=14.0min,tR(大峰)=14.8min,tR(大峰)=16.8min,tR(小峰)=17.4min);[α]21 D=-70.2(c=1.03,CHCl3);1H NMR(300MHz,CDCl3)δ=5.32-5.19(m,2H,CH=C=CH),4.10(s,1H,OCH),2.07-1.48(m,9H,OH andprotons from Cy and n-C7H15),1.48-0.99(m,15H,protons from Cy and n-C7H15),0.88(t,J=5.7Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ=201.1,200.7,100.4,99.8,96.8,96.6,70.3,69.8,37.6,37.5,37.1,33.04,32.99,31.7,29.5,29.4,29.2,26.0,25.9,25.44,25.39,22.6,14.0;MS(EI)m/z(%):250(M+,0.61),55(100);IR(neat):v=3346,2923,2852,1961,1448,1134,1047,1017cm-1;HRMS[M+]计算值:250.2297,实测值:250.2298.
实施例13
Figure BDA00001755563300151
操作参考实施例1。ZnBr2(169.4mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.5mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(±)-1d(271.4mg,1.1mmol)，新蒸环己基甲醛2a(169.1mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(947.2mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=15/1)得液体轴手性α-联烯醇5da(167.2mg,73%):(Ra，S)-5da(99%de,99%ee),(Ra,R)-5da(99%de,99%ee)(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇=98/2,0.8mL/min,λ=214nm,tR(大峰)=13.3min,tR(小峰)=15.8min,tR(小峰)=19.7min,tR(大峰)=22.4min);[α]21 D=-61.9(c=1.02,CHCl3);1H NMR(300MHz,CDCl3)δ=7.39-7.21(m,5H,Ar-H),5.47-5.39(m,1H,one proton fromHC=C=CH),5.37-5.29(m,1H,one proton from HC=C=CH),5.21-5.14(m,1H,PhCH),2.36(d,J=3.0Hz,1H,OH),2.07-1.93(m,1H,CH from Cy),1.81-1.57(m,5H,protons from Cy),1.35-0.97(m,5H,protons from Cy);13C NMR(75MHz,CDCl3)δ=201.2,200.9,143.1,143.0,128.2,127.45,127.38,126.1,125.9,101.0,100.6,96.93,96.85,72.3,72.1,37.04,37.01,32.8,25.95,25.85;MS(EI)m/z(%):228(M+,3.11),107(100);IR(neat):v=3355,2923,2850,1962,1493,1449,1013cm-1.
实施例14
Figure BDA00001755563300161
操作参考实施例1。ZnBr2(169.5mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.3mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(R)-1b(277.9mg,1.1mmol)，新蒸环己基甲醛2a(168.4mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(947.2mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=25/1)得液体轴手性α-联烯醇(Ra,R)-5ba(131.8mg,56%):>99%de,>99%ee(HPLC测定条件:Chiralcel PC-2柱,正己烷/异丙醇=98/2,0.5mL/min,λ=214nm,tR(小峰)=10.0min,tR(大峰)=11.4min;[α]21 D=-118.8(c=1.03,CHCl3);1H NMR(300MHz,CDCl3)δ=5.28-5.15(m,2H,CH=C=CH),3.84(t,J=5.7Hz,1H,OCH),2.04-1.54(m,12H,OH and protons from Cy),1.46-0.90(m,11H,protons from Cy);13C NMR(75MHz,CDCl3)δ=201.4,99.7,94.9,74.5,43.9,37.1,33.01,32.96,28.7,28.3,26.5,26.1,26.00,25.97,25.9;MS(EI)m/z(%):234(M+,1.93),55(100);IR(neat):v=3373,2922,2851,1960,1448,1083,1008cm-1;HRMS[M+]计算值:234.1984,实测值:234.1985.
实施例15
Figure BDA00001755563300171
操作参考实施例1。ZnBr2(169.7mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.3mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(R)-1c(295.5mg,1.1mmol)，新蒸环己基甲醛2a(168.4mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(947.2mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=25/1)得液体轴手性α-联烯醇(Ra,R)-5ca(178.3mg,71%):99%de,>99%ee(HPLC测定条件:Chiralcel IC柱,正己烷/异丙醇=100/1,0.5mL/min,λ=214nm,tR(小峰)=12.5min,tR(小峰)=13.1min,tR(大峰)=14.9min;[α]21 D=-80.8(c=1.04,CHCl3);1HNMR(300MHz,CDCl3)δ=5.32-5.18(m,2H,CH=C=CH),4.10(d,J=6.0Hz,1H,OCH),2.06-1.92(m,2H,OH and proton from Cy),1.81-0.99(m,22H,protons fromCy and n-C7H15),0.88(t,J=6.6Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ=201.1,99.7,96.5,70.3,37.4,37.1,33.01,32.97,31.7,29.4,29.2,26.0,25.9,25.4,22.6,14.0;MS(EI)m/z(%):250(M+,0.56),55(100);IR(neat):v=3345,2923,2852,1962,1448,1047,1017cm-1;HRMS[M+]计算值:250.2297,实测值:250.2296.
实施例16
Figure BDA00001755563300172
操作参考实施例1。ZnBr2(169.7mg,0.75mmol)，α,α-二苯基脯氨醇(R)-3a(258.4mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(R)-1c(295.7mg,1.1mmol)，新蒸环己基甲醛2a(168.6mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(947.2mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=25/1)得液体轴手性α-联烯醇(Sa,R)-5ca(171.1mg,68%):99%de,>99%ee(HPLC测定条件:Chiralcel IC柱,正己烷/异丙醇=100/1,0.5mL/min,λ=214nm,tR(大峰)=14.8min,tR(小峰)=17.6min,tR(小峰)=18.3min;[α]22 D=61.8(c=1.07,CHCl3);1HNMR(300MHz,CDCl3)δ=5.33-5.18(m,2H,CH=C=CH),4.10(t,J=2.6Hz,1H,OCH),2.07-1.93(m,1H,proton from Cy),1.89(s,1H,OH),1.82-1.00(m,22H,protons from Cy and n-C7H15),0.88(t,J=6.8Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ=200.7,100.1,96.7,69.7,37.5,37.0,33.0,32.9,31.7,29.4,29.2,26.0,25.9,25.4,22.5,13.9;MS(EI)m/z(%):250(M+,0.96),55(100);IR(neat):v=3334,2923,2852,1962,1449,1047,1019cm-1;HRMS[M+]计算值:250.2297,实测值:250.2299.
实施例17
操作参考实施例1。ZnBr2(169.6mg,0.75mmol)，α,α-二苯基脯氨醇(S)-3a(258.5mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(S)-1c(295.7mg,1.1mmol)，新蒸环己基甲醛2a(168.5mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(947.4mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=25/1)得液体轴手性α-联烯醇(Ra,S)-5ca(186.2mg,74%):99%de,99%ee(HPLC测定条件:Chiralcel IC柱,正己烷/异丙醇=100/1,0.5mL/min,λ=214nm,tR(小峰)=16.5min,tR(大峰)=17.9min,tR(小峰)=20.0min,tR(小峰)=20.9min;[α]20 D=-58.2(c=1.04,CHCl3);1H NMR(300MHz,CDCl3)δ=5.32-5.18(m,2H,CH=C=CH),4.09(s,1H,OCH),2.07-1.90(m,2H,OH and proton from Cy),1.82-1.00(m,22H,protons from Cy andn-C7H15),0.88(t,J=6.6Hz,3H,CH3);13C NMR(75MHz,CDCl3)δ=200.7,100.2,96.7,69.7,37.5,37.1,33.0,32.9,31.7,29.5,29.2,26.0,25.9,25.4,22.6,14.0;MS(EI)m/z(%):250(M+,0.55),55(100);IR(neat):v=3336,2923,2852,1962,1448,1121,1047,1019cm-1;HRMS[M+]计算值:250.2297,实测值:250.2295.
实施例18
Figure BDA00001755563300191
操作参考实施例1。ZnBr2(169.4mg,0.75mmol)，α,α-二苯基脯氨醇(R)-3a(258.3mg,1.0mmol),叔丁基二甲基硅基保护的炔丙醇(S)-1c(295.2mg,1.1mmol)，新蒸环己基甲醛2a(168.5mg,1.5mmol)，干燥的甲苯(3mL)，TBAF·3H2O(947.2mg,3.0mmol)和四氢呋喃(3mL)。柱层析(石油醚/乙酸乙酯=25/1)得液体轴手性α-联烯醇(Sa,S)-5ca(162.3mg,65%):99%de,>99%ee(HPLC测定条件:Chiralcel IC柱,正己烷/异丙醇=100/1,0.5mL/min,λ=214nm,tR(小峰)=16.5min,tR(小峰)=17.5min,tR(小峰)=20.1min,tR(大峰)=21.0min;[α]20 D=79.4(c=1.04,CHCl3);1H NMR(300MHz,CDCl3)δ=5.31-5.19(m,2H,CH=C=CH),4.11(d,J=6.0Hz,1H,OCH),2.06-1.91(m,1H,proton from Cy),1.88(s,1H,OH),1.81-0.99(m,22H,protons from Cy and n-C7H15),0.88(t,J=6.6Hz,3H,CH3);13CNMR(75MHz,CDCl3)δ=201.1,99.8,96.6,70.3,37.5,37.1,33.03,32.98,31.8,29.4,29.2,26.0,25.9,25.4,22.6,14.0;MS(EI)m/z(%):250(M+,0.71),55(100);IR(neat):v=3343,2923,2852,1962,1448,1120,1048,1020cm-1;HRMS[M+]计算值:250.2297,实测值:250.2303.
实施例19
Figure BDA00001755563300201
向干燥的反应管中依次加入轴手性α-联烯醇(R)-4aa(76.2mg,0.5mmol,99%ee),丙酮(3mL)和0.05摩尔/升的AgNO3溶液(1mL,0.05mmol).然后在反应管中插入回流冷凝管，放置到事先已加热到50℃的油浴中搅拌18小时。冷至室温后,向反应管中加入乙酸乙酯(10mL)和饱和食盐水(10mL)，分出有机层，水层乙酸乙酯萃取(10mL×3)，合并有机层，饱和食盐水洗涤(10mL)，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙醚=40/1)得液体化合物(R)-6(59.7mg,78%):99%ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇=400/1,0.5mL/min,λ=214nm,tR(大峰)=10.2min,tR(小峰)=11.5min);[α]22 D=-161.8(c=1.05,CHCl3);1HNMR(300MHz,CDCl3)δ=5.90(d,J=6.6Hz,1H,one proton from CH=CH),5.79(d,J=6.0Hz,1H,one proton from CH=CH),4.60(s,3H,OCH and OCH2),1.83-1.59(m,5H,proton from Cy),1.54-1.38(m,1H,proton from Cy),1.32-0.90(m,5H,protons from Cy);13C NMR(75MHz,CDCl3)δ=128.0,126.7,90.6,75.2,43.4,28.6,28.4,26.5,26.13,26.10;MS(EI)m/z(%):152(M+,0.84),69(100);IR(neat):v=2924,2851,1449,1350,1083,1068,1021cm-1;HRMS[M+]计算值:152.1201，实测值：152.1202.(参考文献：J.A.Mashall，X.-J.Wang，J.Org.Chem.1991，56，4913；C.M.Sapu，J.E.
Figure BDA00001755563300211
，J.Deska，Angew.Chem.Int.Ed.2011，50，9731)
实施例20
Figure BDA00001755563300212
向干燥的反应管中依次加入轴手性α-联烯醇(R)-4aa(76.5mg，0.5mmol，99％ee)和2mL二氯甲烷，然后在-15℃下加入N-碘代丁二酰亚胺(124.0mg，0.55mmol)和1mL二氯甲烷.加完后继续在-15℃下搅拌12小时.反应结束后加入Na2S2O3(10mL)淬灭反应.分出有机层，水层二氯甲烷萃取(10mLx3)。合并有机层，饱和食盐水洗涤(10mL)，无水硫酸钠十燥，浓缩，柱层析(石油醚/乙醚＝50/1)得液体化合物(R)-7(110.3mg，79％)：99％ee(HPLC测定条件：ChiralcelAD-H柱，正己烷/异丙醇＝100/1，0.3 mL/min，λ＝214nm，tR(大峰)＝12.3min，tR(小峰)＝13.1min)；[α]22 D＝+6.0(c＝1.04，CHCl3)；1H NMR(300MHz，CDCl3)δ＝6.26(s，1H，C＝CH)，4.66-4.44(m，3 H，OCH and OCH2)，1.83-1.57(m，5H，proton from Cy)，1.52-0.95(m，6 H，protons from Cy)；13C NMR(75 MHz，CDCl3)δ＝135.1，93.5，91.0，76.9，40.6，30.1，26.7，26.3，26.0，24.2；MS(EI)m/z(％)：278(M+，11.82)，195(100)；IR(neat)：v＝2924，2850，1613，1449，1342，1311，128l，1234，1178，1102，1087，1067，1019 cm-1；HRMS[M+]计算值：278.0168，实测值：278.0169.(参考文献：C.J.T.Hyland，L.S.Hegedus，J.Org.Chem.2006，71，8658；B.Lü，X.Jiang，C.Fu，S.Ma，J. Org.Chem.2009，74，438；J.Deska，J.E.，Org.Biomol.Chem.2009，7，3379)
实施例21
Figure BDA00001755563300221
在惰性气体的保护下，向干燥的反应管中依次加入三苯基磷(197.2mg,0.75mmol),叔丁氧羰基保护的对甲苯磺酰胺(163.0mg,0.6mmol),轴手性α-联烯醇(R)-4aa(76.3mg,0.5mmol,99%ee)和干燥的四氢呋喃(2mL)。然后将偶氮二甲酸二乙酯(131.1mg,0.75mmol)溶于1mL干燥的四氢呋喃，在0℃下利用注射器在20分钟内滴加到反应体系中。加完后，自然升至室温搅拌12小时。反应结束后，浓缩，柱层析(石油醚/乙酸乙酯/二氯甲烷=15/1/0.1)得到叔丁氧羰基保护的联烯胺。然后直接将其溶解在3mL二氯甲烷中，10°C下加入0.15mL三氟乙酸。搅拌2.5小时后再加入0.15mL三氟乙酸，继续搅拌2.5小时。反应结束后，浓缩除去大部分三氟乙酸，然后加入10mL二氯甲烷和20mL饱和NaHCO3溶液。分出有机层，水层二氯甲烷萃取(10mLx3)。合并有机层，饱和食盐水洗涤(10mL)，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙酸乙酯=9/1)得液体化合物(R)-8(134.9mg,88%,两步总产率):99%ee(HPLC测定条件:Chiralcel AD-H柱,正己烷/异丙醇=95/5,0.5mL/min,λ=214nm,tR(大峰)=36.3min,tR(小峰)=38.4min);[α]22 D=-105.5(c=1.07,CHCl3);1H NMR(300MHz,CDCl3)δ=7.77(d,J=7.8Hz,2H,Ar-H),7.30(d,J=7.5Hz,2H,Ar-H),5.21-5.12(m,1H,CH=C=CH),5.11-5.01(m,1H,CH=C=CH),4.92(t,J=5.3Hz,1H,NH),3.59-3.50(m,2H,NCH2),2.42(s,3H,CH3),1.98-1.83(m,1H,protonfrom Cy),1.75-1.53(m,5H,protons from Cy),1.33-0.89(m,5H,protons from Cy);13C NMR(75MHz,CDCl3)δ=202.2,143.2,137.0,129.5,127.0,100.3,88.4,42.0,36.7,32.8,32.7,25.9,25.7,21.4;MS(EI)m/z(%):305(M+,2.03),55(100);IR(neat):v=3280,2923,2850,1963,1598,1447,1421,1325,1158,1093cm-1;HRMS[M+]计算值:305.1450,实测值:305.1451.(参考文献：O.Mitsunobu,M.Yamada,Bull.Chem.Soc.Jpn.1967,40,2380;O.Mitsunobu,Synthesis 1981,1)
实施例22
Figure BDA00001755563300231
在惰性气体的保护下，向干燥的反应管中依次加入对二甲基氨基吡啶(6.2mg,0.05mmol),干燥的三乙胺(76.1mg,0.75mmol),轴手性α-联烯醇(R)-4aa(76.2mg,0.5mmol,99%ee)和干燥的DCM(3mL)。然后在0℃下利用注射器将甲基磺酰氯(47ul,d=1.475,0.6mmol)在15分钟内滴加到反应体系中。加完后继续在0℃下搅拌1小时。反应结束后加入10mL水和10mL二氯甲烷，分出有机层，水层二氯甲烷萃取(10mL×3)，合并有机层，向其中加入约2克碎冰，然后依次用1M HCl(10mL)，饱和NaHCO3溶液(10mL)和饱和食盐水(10mL)洗涤，无水硫酸钠干燥，浓缩后直接投下一步反应。在另外一个反应管中加入氢化钠(24.1mg,0.6mmol,60%)，然后在0°C下依次加入干燥的四氢呋喃(1mL),干燥的DMSO(0.25mL),和丙二酸二甲酯(145.5mg,1.1mmol)，加完后升至室温搅拌30分钟。然后将上一步制备的粗产品溶于1mL干燥的四氢呋喃，室温下利用注射器在30min内滴加到上述反应体系中。加完后室温搅拌24小时，反应结束后，0℃下加入10mL饱和NH4Cl淬灭反应，然后加入10mL乙醚，分出有机层，水层乙醚萃取(10mL×3)，合并有机层，饱和食盐水洗涤(10mL)，无水硫酸钠干燥，浓缩，柱层析(石油醚/乙醚=25/1)(87.1mg,65%,两步总产率)得液体化合物(R)-9:99%ee(HPLC测定条件:Chiralcel OD-H柱,正己烷/异丙醇=100/1,1mL/min,λ=214nm,tR(小峰)=7.2min,tR(大峰)=7.9min);[α]22 D=-85.4(c=1.05,CHCl3);1H NMR(300MHz,CDCl3)δ=5.20-5.09(m,2H,CH=C=CH),3.74(s,6H,two CH3),3.51(t,J=7.2Hz,1H,CH),2.64-2.52(m,2H,CH2),2.01-1.85(m,1H,proton from Cy),1.79-1.58(m,5H,protons from Cy),1.36-0.96(m,5H,protons from Cy);13C NMR(75MHz,CDCl3)δ=202.7,169.34,169.29,98.9,88.2,52.44,52.42,51.2,37.1,32.9,32.8,28.1,26.0,25.9;MS(EI)m/z(%):266(M+,19.00),91(100);IR(neat):v=2924,2851,1962,1736,1437,1342,1262,1231,1150,1035cm-1;HRMS[M+]计算值:266.1518,实测值:266.1516.(参考文献：Z.Zhang,C.F.Bender,R.A.Widenhoefer,J.Am.Chem.Soc.2007,129,14148)

Claims (4)

1.一种轴手性α-联烯醇的合成方法，其特征是通过下述步骤获得：
Figure FDA0000395970380000011
其中，R1=C1～C10的烃基，R2=H或C1～C10的烃基，联烯的轴手性为R或S型，与羟基相连的碳原子可以是非手性、R或S型；当所述的C1～C10的烃基为脂肪基时，ee值大于96；
在100-130℃下和有机溶剂中，以锌盐为促进剂，以(S)-3a-e或其对映体为手性仲胺，与硅基保护的炔丙醇和醛反应5-15小时，过短硅胶柱后用四正丁基氟化铵三水合物或四正丁基氟化铵的四氢呋喃溶液脱去硅基保护基即可得到轴手性α-联烯醇产物；
其中，所述硅基保护的炔丙醇：醛：手性仲胺：锌盐：四正丁基氟化铵的摩尔比为1～3：1～3：1：0.5～1.5：1～5；所述的硅基PG为三甲基硅基、三异丙基硅基、叔丁基二甲基硅基或叔丁基二苯基硅基；所述的手性仲胺为具有如下结构式的(S)-3a-e或其对映体：
Figure FDA0000395970380000012
所述的锌盐为氯化锌、溴化锌、碘化锌、醋酸锌或三氟甲磺酸锌。
2.如权利要求1所述的轴手性α-联烯醇的合成方法，其特征是在干燥的反应器中加入锌盐、手性仲胺、硅基保护的炔丙醇、醛和干燥的有机溶剂，在100-130℃下搅拌5-15小时；反应结束后，过短硅胶柱得到粗产物，将其溶于有机溶剂，0℃下加入四正丁基氟化铵三水合物或四正丁基氟化铵的四氢呋喃溶液，然后在室温下搅拌1-15小时。
3.如权利要求1或2所述的轴手性α-联烯醇的合成方法，其特征是所述的有机溶剂为苯、甲苯、氯苯、对二甲苯、邻二甲苯、间二甲苯或均三甲苯。
4.如权利要求1或2所述的轴手性α-联烯醇的合成方法，其特征是反应产物经过水洗涤，有机溶剂萃取，干燥，浓缩或柱层析分离纯化。
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US5238832A (en) * 1992-06-08 1993-08-24 Board Of Governors Of Wayne State University Aryl aliphatic acids

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