CN106631740B - 一种高非对映选择性的环戊-2-烯酮-4-醇化合物及其制备方法 - Google Patents

一种高非对映选择性的环戊-2-烯酮-4-醇化合物及其制备方法 Download PDF

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CN106631740B
CN106631740B CN201611009921.XA CN201611009921A CN106631740B CN 106631740 B CN106631740 B CN 106631740B CN 201611009921 A CN201611009921 A CN 201611009921A CN 106631740 B CN106631740 B CN 106631740B
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麻生明
马登科
傅春玲
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Zhejiang University ZJU
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Abstract

本发明公开了一种高非对映选择性的环戊‑2‑烯酮‑4‑醇化合物及其制备方法，在氮气保护下向干燥的史兰克反应瓶中依次加入碱，氮杂环卡宾前体和溶剂，室温下搅拌10分钟后冷却至反应温度，加入芳香醛，α‑联烯酮和溶剂，加完后在反应温度下反应，反应结束后，再乙酸乙酯冲硅胶短柱，浓缩，快速柱层析，得到高非对映选择性的环戊‑2‑烯酮‑4‑醇类化合物。本发明制备方法克服传统方法的弊端，操作简单，原料和试剂易得，反应条件温和，反应具有高度的立体选择性，官能团兼容性较好，催化量反应，产物易分离纯化，直接得到环戊‑2‑烯酮‑4‑醇类化合物。

Description

一种高非对映选择性的环戊-2-烯酮-4-醇化合物及其制备 方法
技术领域
本发明属于化学合成技术领域，具体涉及一种高非对映选择性的环戊-2-烯酮-4-醇化合物及其制备方法。
背景技术
环戊-2-烯酮-4-醇结构存在于报道的一些天然产物和具有生物活性的化合物中((a)M.Naganuma,M.Nishida,K.Kuramochi,F.Sugawara,H.Yoshida and Y.Mizushina,Bioorg.Med.Chem.,2008,16,2939；(b)A.H.Aly,R.Edrada-Ebel,I.D.Indriani,V.Wray,W.E.G.Müller,F.Totzke,U.Zirrgiebel,C.M.H.G.Kubbutat,W.H.Lin,P.Proksch and R.Ebel,J.Nat.Prod.,2008,71,972；(c)P.Jiao,J.B.Gloer,J.Campbelland C.A.Shearer,J.Nat.Prod.,2006,69,612；(d)W.A.Ayer and J.S.Racok,Can.J.Chem.,1990,68,2085.)，具有潜在的合成应用。因此，发展高效的合成方法一直是化学家感兴趣的领域((a)S.P.Roche and D.J.Aitken,Eur.J.Org.Chem.,2010,5339；(b)D.J.Aitken,H.Eijsberg,A.Frongia,J.Ollivier,P.P.Piras,Synthesis,2014,46,1；(c)S.P.Simeonov,J.P.M.Nunes,K.Guerra,V.B.Kurteva and C.A.M.Afonso,Chem.Rev.,2016,116,5744.)。从非环状的原料出发的方法包括1,2-二酮与3-羰基羧酸酯或酰胺的环化反应((a)E.Holtz,V.B.Appel and P.Langer,Eur.J.Org.Chem.,2005,532；(b)M.Sher,C.Fischer,H.Reinkea and P.Langer,Tetrahedron,2007,63,4080.),1,2-二酮与酮的环化反应((a)C.F.H.Allen and E.W.Spanagel,J.Am.Chem.Soc.,1932,54,4338；(b)F.R.Japp and G.D.Lander,J.Chem.Soc.,Trans.,1897,123；(c)F.R.Japp and J.Knox,J.Chem.Soc.,Trans.,1905,673；(d)F.R.Japp and A.N.Meldrum,J.Chem.Soc.,Trans.,1901,1024；(e)I.V.Mikhura,A.A.Formanovskii and A.S.Shashkov,Russ.J.Org.Chem.,2010,46,1116；(f)K.Marjani,M.Mousavi,O.Arazi,A.Ashouri,S.Bourghani andM.Rajabi,Monatsh.Chem.,2009,140,1331.),1,2-二酮与1,3-双三甲基硅氧-1,3-二烯的环化反应((a)P.Langer and V.Org.Lett.,2000,2,1597；(b)E.Holtz,V.B.Appel and P.Langer,Eur.J.Org.Chem.,2005,532),1,2-二酮与2-三甲基硅氧烯丙基三甲基硅烷的环化反应(A.Hosomi,H.Hayashida and Y.Tominaga,J.Org.Chem.,1989,54,3254.)，膦促进的1,2-二酮与2,3-联烯酸酯的环化反应(A.Jose,K.C.S.Lakshmi,E.Sureshand V.Nair,Org.Lett.,2013,15,1858.)；过渡金属催化的3-三乙基硅氧-5-三丁基锡-4(Z)-戊烯羧酸硫乙酯的分子内偶联反应，随后脱硅基保护(A.Morita and S.Kuwahara,Org.Lett.,2006,8,1613.)，5位羟基叔丁基二甲基硅或者叔丁基二苯基硅保护的1,6-二烯-3-庚酮的关环复分解反应，产物可以进一步脱保护(J.Toueg and J.Prunet,Org.Lett.,2008,10,45.)，β-苯硫基丙酰硅烷与烯醇锂盐的串联Aldol-Brook环化反应，随后进一步的脱硅和消除苯硫基(K.Takeda,M.Fujisawa,T.Makino and E.Yoshii,J.Am.Chem.Soc.,1993,115,9351.)，5位羟基叔丁基二甲基硅保护的3-羰基-6-庚烯羧酸叔丁酯的臭氧Knoevenagel环化反应，产物可以进一步脱保护(A.S.Batsanov,J.P.Knowles,A.P.Lightfoot,G.Maw,C.E.Thirsk,S.J.R.Twiddle and A.Whiting,Org.Lett.,2007,9,5565.)，(E)-4-甲氧甲基-1-硅氧-1,4,5-己三烯-3-醇的Nazarov环化脱硅反应((a)L.Wanand M.A.Tius,Org.Lett.,2007,9,647；(b)M.A.Tius,H.Hu,J.K.Kawakami and J.Busch-Petersen,J.Org.Chem.,1998,63,5971；(c)M.A.Tius,Acc.Chem.Res.,2003,36,284.)，还有涉及到顺式-2-烯-1,4-二酮(For direct cycliczation of cis-2-en-1,4-dicarbonylcompounds,see:(a)C.Nájera and M.Yus,J.Org.Chem.,1988,53,4708；(b)A.M.Celli,L.R.Lampariello,S.Chimichi,R.Nesi and M.Scotton,Can.J.Chem.,1982,60,1327；(c)F.Bonadies,A.Scettri and C.D.Campli,Tetrahedron Lett.,1996,37,1899；foroxidation-cyclization of furans,see:(d)T.Shono,Y.Matsumura,H.Hamaguchi andK.Nakamura,Chem.Lett.,1976,1249；(e)G.Adembri,G.Giorgi,R.L.Lampariello,M.L.Paoli and A.Sega,J.Chem.Soc.,Perkin Trans.1,2000,2649；(f)S.Al-Busafi,J.R.Doncaster,M.G.B.Drew,A.C.Regan and R.C.Whitehead,J.Chem.Soc.,PerkinTrans.1,2002,476；(g)S.Al-Busafi and R.C.Whitehead,Tetrahedron Lett.,2000,41,3467；(h)D.Kalaitzakis,M.Triantafyllakis,I.Alexopoulou,M.Sofiadis andG.Vassilikogiannakis,Angew.Chem.Int.Ed.,2014,53,13201.)或者(Z)-4-羰基-2-戊烯醛的反应(P.R.Hamann and A.Wissner,Syn.Commum.,1989,19,1509.)等。尽管有如此多的报道，发展一种由简单易得的原料出发，条件温和的合成环戊-2-烯酮-4-醇类化合物的新方法仍然具有重要的意义。
发明内容
本发明通过芳香醛和α-联烯酮出发，在氮杂环卡宾的催化下高立体选择性地合成环戊-2-烯酮-4-醇类化合物。本发明方法操作简单，原料和试剂易得，反应具有高立体选择性，官能团兼容性较好，产物易分离纯化，可直接得到高非对映选择性的环戊-2-烯酮-4-醇类化合物，本发明是通过以下技术方案来实现的：
本发明公开了一种高非对映选择性的环戊-2-烯酮-4-醇类化合物，所述环戊-2-烯酮-4-醇类化合物的结构如式(Ⅰ)所示：
式(Ⅰ)中，Ar为芳基；当R1为直链烷基、末端苄氧基取代的直链烷基、支链烷基或苄基时，R2为氢；或者R1、R2为环状的环戊基，立体上具有反式选择性。
本发明还公开了一种高非对映选择性地合成环戊-2-烯酮-4-醇化合物的新方法，芳香醛和α-联烯酮在氮杂环卡宾的催化下反应，得到环戊-2-烯酮-4-醇类化合物，制备方法的反应式(a)如下：
反应式(a)中，Ar为芳基；当R1为直链烷基、末端苄氧基取代的直链烷基、支链烷基或者苄基时，R2为氢，或者R1、R2为环状的环戊基。
作为进一步地改进，本发明所述制备方法包括如下步骤：
在氮气保护下向干燥的史兰克反应瓶中依次加入碱，氮杂环卡宾前体和溶剂，室温下搅拌10分钟后冷却至反应温度，加入芳香醛，α-联烯酮和溶剂，加完后在反应温度下反应，反应结束后，再乙酸乙酯冲硅胶短柱，浓缩，快速柱层析，得到高非对映选择性的环戊-2-烯酮-4-醇类化合物。
作为进一步地改进，本发明所述方法中，氮杂环卡宾前体为1-乙基-3-甲基咪唑四氟硼酸盐。
作为进一步地改进，本发明所述的碱为碳酸铯。
作为进一步地改进，本发明所述的溶剂为1,4-二氧六环和二氯甲烷的混合溶剂，所述的1,4-二氧六环/二氯甲烷为3/1。
作为进一步地改进，本发明所述反应温度为-10度。
作为进一步地改进，本发明芳香醛与α-联烯酮的摩尔比为1.2/1。
本发明公开一种高非对映选择性地合成环戊-2-烯酮-4-醇的新方法，该方法是通过氮杂环卡宾催化的芳香醛和α-联烯酮的反应，高效地构建环戊-2-烯酮-4-醇的合成方法。本发明制备方法克服传统方法的弊端，包括以下优点：操作简单，原料和试剂易得，反应条件温和，反应具有高度的立体选择性，官能团兼容性较好，催化量反应，产物易分离纯化，直接得到环戊-2-烯酮-4-醇类化合物。
具体实施方式
结合以下具体实施例和反应式，对本发明作进一步的详细说明，本发明保护不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。以下实施例有助于理解本发明，但不限制本发明保护范围。
注：以下实施例反应式中的equiv.表示当量；mmol表示毫摩尔；M表示mol/L；表示1-乙基-3-甲基咪唑四氟硼酸盐；Cs2CO3表示碳酸铯；dioxane表示1,4-二氧六环；DCM表示二氯甲烷。
实施例1 3-甲基-4-(4-溴苯基)-5-戊基环戊-2-烯酮-4-醇(001)的合成
取一支干燥的史兰克反应瓶，氮气下抽换气三次。在氮气保护下，在反应瓶中依次加入碳酸铯(65.1mg,0.2mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(40.3mg,0.2mmol)，1,4-二氧六环(3.75mL)，和二氯甲烷(1.25mL)。室温搅拌10分钟后冷却至-10度，氮气保护下依次加入对溴苯甲醛(226.8mg,1.2mmol)，二氯甲烷(1.25mL)和1,2-二烯-4-癸酮(152.3mg,1mmol)，1,4-二氧六环(3.75mL)。19.5小时后，乙酸乙酯(20mL×3)冲硅胶短柱过滤，旋去溶剂后快速柱层析分离(石油醚(30℃～60℃，重蒸)/乙酸乙酯＝10/1(440mL)to 5/1(480mL×2)to 3/1(400mL))得到3-甲基-4-(4-溴苯基)-5-戊基环戊-2-烯酮-4-醇(0.1796g,53％,dr>99:1)(通过核磁分析粗产品的dr是95:5)，液体：1H NMR(300MHz,CDCl3)δ7.47(d,J＝8.7Hz,2H,ArH),7.13(brs,2H,ArH),6.13(q,J＝1.3Hz,1H,＝CH),2.72(s,1H,OH),2.58(dd,J1＝9.0Hz,J2＝5.4Hz,1H,CH),1.90(d,J＝1.5Hz,3H,CH3),1.59-1.46(m,1H,oneproton from CH2),1.40-0.94(m,6H,CH2×3),0.89-0.72(m,4H,CH3+one proton fromCH2)；13C NMR(75MHz,CDCl3)δ206.1,176.1,138.4,131.3,130.1,127.5,121.6,85.2,61.4,31.6,27.1,25.9,22.1,13.9,13.6；IR(neat)ν(cm-1)3435,2954,2930,2859,1693,1625,1589,1572,1487,1466,1456,1434,1397,1375,1307,1297,1245,1232,1205,1164,1075,1010；MS(70ev,EI)m/z(％)338(M+(81Br),4.15),336(M+(79Br),4.56),265(100)；HRMScalcd for C17H21 79BrO2(M+):336.0725,found:336.0728.
实施例2 3-甲基-4-苯基-5-戊基环戊-2-烯酮-4-醇(002)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：苯甲醛(127.4mg,1.2mmol)，1,2-二烯-4-癸酮(153.0mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(40.0mg,0.2mmol)，碳酸铯(65.3mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应11小时，得到3-甲基-4-苯基-5-戊基环戊-2-烯酮-4-醇(0.1966g,76％,dr＝99:1)(石油醚(60℃～90℃,重蒸)/乙酸乙酯＝10/1(440mL)to 5/1(480mL)to 3/1(400mL))(通过核磁分析粗产品的dr是96:4)，液体：1H NMR(300MHz,CDCl3)δ7.51-6.97(m,5H,ArH),6.14(q,J＝1.3Hz,1H,＝CH),2.81(s,1H,OH),2.60(dd,J1＝9.2Hz,J2＝5.3Hz,1H,CH),1.91(d,J＝1.5Hz,3H,CH3),1.59-1.45(m,1H,one proton from CH2),1.38-0.91(m,6H,CH2×3),0.90-0.78(m,1H,one proton fromCH2),0.75(t,J＝6.8Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ206.3,176.1,139.2,130.1,128.2,127.5,125.5,85.6,61.4,31.7,27.1,25.8,22.1,13.9,13.7；IR(neat)ν(cm-1)3439,3087,3060,3028,2955,2930,2859,1693,1626,1601,1491,1448,1374,1301,1246,1232,1205,1165,1131,1093,1066,1015；MS(70ev,EI)m/z(％)258(M+,14.47),187(100)；Elemental analysis calcd(％)for C17H22O2:C,79.03；H,8.58；Found:C,79.00；H,8.81.
实施例3 3-甲基-4-苯基-5-丙基环戊-2-烯酮-4-醇(003)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：苯甲醛(127.6mg,1.2mmol)，1,2-二烯-4-辛酮(124.3mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(39.9mg,0.2mmol)，碳酸铯(65.1mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应15.5小时得到3-甲基-4-苯基-5-丙基环戊-2-烯酮-4-醇(0.1461g,63％,dr＝99:1)(石油醚(30℃～60℃)/乙酸乙酯＝10/1(440mL)to 5/1(480mL×2+180mL)to 3/1(400mL))(通过核磁分析粗产品的dr是95:5)，液体(固体，熔点79～81度(乙醇))：1H NMR(300MHz,CDCl3)δ7.47-6.99(m,5H,ArH),6.13(q,J＝1.4Hz,1H,＝CH),3.18(s,1H,OH),2.64(dd,J1＝8.7Hz,J2＝5.4Hz,1H,CH),1.91(d,J＝1.5Hz,3H,CH3),1.55-1.39(m,1H,one proton from CH2),1.39-1.14(m,2H,CH2),0.89-0.75(m,1H,one proton from CH2),0.69(t,J＝7.4Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ206.7,176.6,139.3,129.9,128.2,127.5,125.5,85.5,61.1,28.1,20.8,13.9,13.7；IR(neat)ν(cm-1)3435,3087,3060,3028,2958,2933,2871,1694,1626,1601,1491,1465,1448,1375,1319,1301,1249,1220,1194,1170,1131,1096,1066,1034,1002；MS(70ev,EI)m/z(％)230(M+,9.35),187(100)；HRMS calcd for C15H18O2(M+):230.1307,found:230.1310.
实施例4 3-甲基-4-苯基-5-苄基环戊-2-烯酮-4-醇(004)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：苯甲醛(127.8mg,1.2mmol)，1-苯基-4,5-二烯-3-己酮(173.0mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(40.1mg,0.2mmol)，碳酸铯(65.1mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应22小时，得到3-甲基-4-苯基-5-苄基环戊-2-烯酮-4-醇(0.1598g,57％,dr＝92:8)(石油醚(30℃～60℃)/乙酸乙酯＝10/1(440mL)to 5/1(480mL)to 3/1(600mL))(通过核磁分析粗产品的dr是92:8)，液体：1H NMR(300MHz,CDCl3)δ7.37-7.26(m,3H,ArH),7.25-6.97(m,5H,ArH),6.81-6.70(m,2H,ArH),[6.14(q,J＝1.3Hz,0.92H),6.12(q,J＝1.2Hz,0.08H),1H,＝CH],3.27-3.04(m,2H,CH2),[2.42(s,0.08H),2.30(s,0.83H),1H,OH],2.26-2.14(m,1H,CH),1.90-1.82(m,3H,CH3)；IR(neat)ν(cm-1)3418,3086,3061,3028,2948,2916,2855,1694,1625,1602,1496,1448,1434,1374,1304,1243,1211,1162,1088,1065,1014；MS(70ev,EI)m/z(％)278(M+,57.11),187(100)；Elemental analysis calcd(％)forC19H18O2:C,81.99,H,6.52；Found:C,81.69；H,6.47.
实施例5 3-甲基-4-苯基-5-(4-苄氧丁基)环戊-2-烯酮-4-醇(005)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：苯甲醛(128.0mg,1.2mmol)，1,2-二烯-9-苄氧-4-壬酮(244.3mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(40.3mg,0.2mmol)，碳酸铯(65.1mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应11.5h得到3-甲基-4-苯基-5-(4-苄氧丁基)环戊-2-烯酮-4-醇(0.2337g,65％,purity＝98％,dr＝99:1)(石油醚(60℃～90℃)/乙酸乙酯＝10/1(440mL)to 5/1(420mL+600mL)to3/1(400mL))(通过核磁分析粗产品的dr是96:4)，液体：1H NMR(300MHz,CDCl3)δ7.43-6.99(m,10H,ArH),6.11(q,J＝1.4Hz,1H,＝CH),4.42(s,2H,CH2),3.49-3.16(m,3H,OH+CH2),2.65(dd,J1＝9.0Hz,J2＝5.1Hz,1H,CH),1.87(d,J＝1.2Hz,3H,CH3),1.63-1.19(m,5H,CH2×2+one proton from CH2),1.01-0.82(m,1H,one proton from CH2)；13C NMR(75MHz,CDCl3)δ206.5,176.8,139.3,138.2,129.6,128.2,128.1,127.6,127.44,127.36,125.5,85.1,72.6,69.9,60.9,28.9,25.4,23.7,13.6；IR(neat)ν(cm-1)3439,3086,3061,3029,2938,2862,2793,1694,1626,1601,1492,1448,1372,1301,1240,1203,1162,1097,1068,1028；MS(70ev,EI)m/z(％)350(M+,3.28),91(100)；HRMS calcd for C23H26O3(M+):350.1882,found:350.1878.
实施例6(4R*,5S*)-3-甲基-4-(4-苯基苯基)-5-戊基环戊-2-烯酮-4-醇(4R*,5S*-006)和(4R*,5R*)-3-甲基-4-(4-苯基苯基)-5-戊基环戊-2-烯酮-4-醇(4R*,5R*-006)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：对苯基苯甲醛(225.5mg,1.2mmol)，1,2-二烯-4-癸酮(152.9mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(40.0mg,0.2mmol)，碳酸铯(65.5mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应8.5小时得到不纯的(4R*,5S*)-3-甲基-4-(4-苯基苯基)-5-戊基环戊-2-烯酮-4-醇(18.4mg)和纯的(4R*,5R*)-3-甲基-4-(4-苯基苯基)-5-戊基环戊-2-烯酮-4-醇(241.0mg,72％)(石油醚(30℃～60℃)/乙酸乙酯＝10/1(440mL+400mL)to 5/1(480mL+200mL)to 3/1(400mL))(通过核磁分析粗产品的dr是94:6)。不纯的(4R*,5S*)-3-甲基-4-(4-苯基苯基)-5-戊基环戊-2-烯酮-4-醇进一步过柱得到纯的样品(8.9mg,3％)(二氯甲烷(400mL))。
(4R*,5S*)-3-甲基-4-(4-苯基苯基)-5-戊基环戊-2-烯酮-4-醇，小极性异构体，液体：1HNMR(300MHz,CDCl3)δ7.62-7.57(m,4H,ArH),7.49-7.34(m,5H,ArH),6.10(q,J＝1.3Hz,1H,＝CH),2.61(dd,J1＝8.7Hz,J2＝5.7Hz,1H,CH),2.01(s,1H,OH),1.92(d,J＝1.5Hz,3H,CH3),1.83-1.59(m,2H,CH2),1.51-1.32(m,2H,CH2),1.31-1.14(m,4H,CH2×2),0.81(t,J＝6.9Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ208.6,177.2,142.4,140.4,140.1,130.5,128.8,127.4,127.3,127.0,125.0,82.8,59.7,31.8,27.3,26.8,22.3,14.1,14.0；IR(neat)ν(cm-1)3444,3057,3029,2954,2927,2857,1694,1626,1600,1486,1435,1405,1374,1298,1263,1213,1195,1180,1133,1076,1007；MS(70ev,EI)m/z(％)334(M+,14.35),263(100)；HRMS calcd for C23H26O2(M+):334.1933,found:334.1929.
(4R*,5R*)-3-甲基-4-(4-苯基苯基)-5-戊基环戊-2-烯酮-4-醇，大极性异构体，液体：1H NMR(300MHz,CDCl3)δ7.64-7.51(m,4H,ArH),7.50-7.19(m,5H,ArH),6.17(q,J＝1.3Hz,1H,＝CH),2.66(s,1H,OH),2.63(dd,J1＝9.0Hz,J2＝5.1Hz,1H,CH),1.95(d,J＝1.5Hz,3H,CH3),1.64-1.49(m,1H,one proton from CH2),1.41-1.19(m,2H,CH2),1.19-0.83(m,5H,2×CH2+oneproton from CH2),0.74(t,J＝7.1Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ206.9,177.0,140.3,140.1,138.3,129.8,128.7,127.3,126.9,126.7,126.1,85.3,61.4,31.6,27.1,25.9,22.0,13.82,13.80；IR(neat)ν(cm-1)3448,3057,3029,2953,2929,2858,1691,1625,1600,1560,1486,1435,1404,1374,1317,1301,1267,1232,1207,1196,1180,1164,1132,1076,1007；MS(70ev,EI)m/z(％)334(M+,18.23),263(100)；HRMScalcd for C23H26O2(M+):334.1933,found:334.1929.
实施例7 3-甲基-4-对甲苯基-5-丙基环戊-2-烯酮-4-醇(007)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：对甲基苯甲醛(145.0mg,1.2mmol)，1,2-二烯-4-辛酮(124.4mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(39.8mg,0.2mmol)，碳酸铯(65.4mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应32.5小时得到3-甲基-4-对甲苯基-5-丙基环戊-2-烯酮-4-醇(0.1612g,65％,purity98％,dr＝99:1)(石油醚(30℃～60℃)/乙酸乙酯＝10/1(440mL)to 5/1(480+120mL)to 3/1(400mL))(通过核磁分析粗产品的dr是94:6)，液体：1H NMR(300MHz,CDCl3)δ7.38-6.77(m,4H,ArH),6.11(q,J＝1.3Hz,1H,＝CH),3.19(s,1H,OH),2.63(dd,J1＝8.7Hz,J2＝5.4Hz,1H,CH),2.34(s,3H,CH3),1.91(d,J＝1.2Hz,3H,CH3),1.54-1.15(m,3H,CH2+one proton fromCH2),0.93-0.76(m,1H,one proton from CH2),0.71(t,J＝7.2Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ206.8,176.8,137.1,136.3,129.7,128.9,125.4,85.4,61.0,28.0,20.9,20.8,14.0,13.7；IR(neat)ν(cm-1)3443,3051,3024,2958,2932,2871,1693,1625,1511,1465,1434,1409,1375,1316,1300,1286,1248,1220,1193,1170,1131,1111,1078,1038,1021,1008；MS(70ev,EI)m/z(％)244(M+,16.88),201(100)；HRMS calcd for C16H20O2(M+):244.1463,found:244.1472.
实施例8 3-甲基-4-(2-萘基)-5-苄基环戊-2-烯酮-4-醇(008)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：2-萘甲醛(191.5mg,1.2mmol)，1-苯基-4,5-二烯-3-己酮(173.0mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(40.0mg,0.2mmol)，碳酸铯(65.1mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应13小时得到3-甲基-4-(2-萘基)-5-苄基环戊-2-烯酮-4-醇(0.1866g,57％,dr＝91:9)(石油醚(30℃～60℃)/乙酸乙酯＝10/1(440mL)to 5/1(480mL+180mL)to 3/1(400mL+200mL))(通过核磁分析粗产品的dr是92:8)，液体：1HNMR(300MHz,CDCl3)δ7.92-7.59(m,4H,ArH),7.59-7.40(m,2H,ArH),7.20-6.90(m,4H,ArH),6.81-6.57(m,2H,ArH),[6.20(q,J＝1.3Hz,0.91H),6.17(q,J＝1.3Hz,0.09H),1H,＝CH],3.30-3.06(m,2H,CH2),[2.67(s,0.08H),2.57(s,0.89H),1H,OH],2.22(dd,J1＝14.4Hz,J2＝9.9Hz,1H,CH),1.88(d,J＝1.2Hz,3H,CH3)；IR(neat)ν(cm-1)3432,3084,3059,3027,2978,2947,2918,2853,1691,1625,1601,1507,1497,1454,1434,1373,1357,1304,1271,1247,1211,1196,1161,1115,1077,1034,1019；MS(70ev,EI)m/z(％)328(M+,14.99),237(100)；Elementalanalysis calcd(％)for C23H20O2:C,84.12,H,6.14；Found:C,83.69；H,6.25.
实施例9(4R*,5S*)-3-甲基-4-(2-萘基)-5-异丙基环戊-2-烯酮-4-醇(4R*,5S*-009)和(4R*,5R*)-3-甲基-4-(2-萘基)-5-异丙基环戊-2-烯酮-4-醇(4R*,5R*-009)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：2-萘甲醛(191.6mg,1.2mmol)，1,2-二烯-6-甲基-4-庚酮(124.5mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(39.9mg,0.2mmol)，碳酸铯(65.1mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10度反应22.5小时得到(4R*,5S*)-3-甲基-4-(2-萘基)-5-异丙基环戊-2-烯酮-4-醇(3.8mg,1％)和(4R*,5R*)-3-甲基-4-(2-萘基)-5-异丙基环戊-2-烯酮-4-醇(156.3mg,55％)(石油醚(30℃～60℃)/乙酸乙酯＝60/1(400mL×2)to 10/1(440mL)to 5/1(480mL×3)to 3/1(400mL))(通过核磁分析粗产品的dr是95:5)。
(4R*,5S*)-3-甲基-4-(2-萘基)-5-异丙基环戊-2-烯酮-4-醇，小极性异构体，液体：1HNMR(300MHz,CDCl3)δ7.95-7.91(m,1H,ArH),7.89-7.79(m,3H,ArH),7.54-7.46(m,2H,ArH),7.28(dd,J1＝8.7Hz,J2＝2.1Hz,1H,ArH),6.14(q,J＝1.3Hz,1H,＝CH),2.60(d,J＝4.5Hz,1H,CH),2.35-2.21(m,2H,one proton from CH2+OH),1.89(d,J＝1.5Hz,3H,CH3),1.11(d,J＝6.6Hz,3H,CH3),1.06(d,J＝6.6Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ208.0,177.1,141.3,133.1,132.5,131.7,128.7,128.1,127.6,126.5,126.2,123.3,122.6,83.6,64.5,27.8,22.0,19.8,13.8；IR(neat)ν(cm-1)3445,3057,2957,2929,2872,1688,1628,1599,1507,1466,1435,1385,1368,1296,1272,1231,1199,1160,1132,1078,1020；MS(70ev,EI)m/z(％)280(M+,10.47),237(100)；HRMS calcd for C19H20O2(M+):280.1463,found:280.1466.
(4R*,5R*)-3-甲基-4-(2-萘基)-5-异丙基环戊-2-烯酮-4-醇，大极性异构体，固体，熔点147～149℃(乙酸乙酯):1H NMR(300MHz,CDCl3)δ8.12-7.67(m,4H,ArH),7.60-6.90(m,3H,ArH),6.11(q,J＝1.3Hz,1H,＝CH),2.56(s,1H,OH),2.52(d,J＝8.7Hz,1H,CH),1.87(d,J＝1.2Hz,3H,CH3),1.84-1.73(m,1H,CH),1.04(d,J＝6.6Hz,3H,CH3),0.73(d,J＝6.6Hz,3H,CH3)；13C NMR(75MHz,CDCl3)δ205.7,175.5,137.3,133.0,132.5,130.2,128.2,127.8,127.5,126.3,126.2,125.1,123.7,85.3,67.4,26.5,21.8,20.5,13.3；IR(neat)ν(cm-1)3453,3057,2957,2920,2870,1687,1629,1599,1507,1470,1435,1386,1373,1301,1270,1254,1234,1195,1162,1123,1094,1041,1030；MS(70ev,EI)m/z(％)280(M+,7.79),237(100)；Elemental analysiscalcd(％)for C19H20O2:C,81.40,H,7.19；Found:C,81.42；H,7.24.
实施例10 3-甲基-4-羟基-4-苯基螺[4.5]癸-2-烯-1-酮(010)的合成
按实施例1所述的方法，不同的是所用底物和试剂为：苯甲醛(126.9mg,1.2mmol)，1-环己基-2,3-二烯-1-丁酮(150.7mg,1mmol)，1-乙基-3-甲基咪唑四氟硼酸盐(40.0mg,0.2mmol)，碳酸铯(65.0mg,0.2mmol)，1,4-二氧六环(7.5mL)和二氯甲烷(2.5mL)在-10℃反应32小时，再升温至50℃反应14.5小时，得到3-甲基-4-羟基-4-苯基螺[4.5]癸-2-烯-1-酮(0.1281g,50％)(石油醚(60℃～90℃,重蒸)/乙酸乙酯＝40/1(400mL)to 30/1(480mL×2+300mL)to 10/1(300mL)to 5/1(420mL)to 3/1(400mL))，液体：1H NMR(300MHz,CDCl3)δ7.72-6.67(m,5H,ArH),6.13(q,J＝1.4Hz,1H,＝CH),2.51(brs,1H,OH),1.92(d,J＝1.5Hz,3H,CH3),1.85-1.40(m,6H,from cyclohexyl group),1.38-1.06(m,3H,from cyclohexylgroup),0.91-0.78(m,1H,from cyclohexyl group)；13C NMR(75 MHz,CDCl3)δ210.5,173.9,140.6,129.6,128.0,127.4,125.9,87.5,56.3,32.9,30.0,25.4,22.4,21.6,14.1；IR(neat)ν(cm-1)3462,3085,3058,3027,2933,2861,1686,1631,1600,1490,1449,1374,1361,1310,1266,1226,1194,1147,1127,1105,1069,1031；MS(70 ev,EI)m/z(％)256(M+,77.01),151(100)；HRMS calcd for C17H20O2(M+):256.1463,found:256.1459.

Claims (7)

1.一种高非对映选择性地合成环戊-2-烯酮-4-醇化合物的方法，其特征在于，环戊-2-烯酮-4-醇类化合物的结构如式(Ⅰ)所示：
芳香醛和α-联烯酮在氮杂环卡宾的催化下反应，得到式(Ⅰ)的环戊-2-烯酮-4-醇类化合物，所述制备方法的反应式(a)如下：
所述反应式(a)中，Ar为芳基；当R1为直链烷基、末端苄氧基取代的直链烷基、支链烷基或者苄基时，R2为氢，或者R1、R2为环状的环戊基。
2.根据权利要求1所述的方法，其特征在于，所述制备方法包括如下步骤：
在氮气保护下向干燥的史兰克反应瓶中依次加入碱，氮杂环卡宾前体和溶剂，室温下搅拌10分钟后冷却至反应温度，加入芳香醛，α-联烯酮和溶剂，加完后在反应温度下反应，反应结束后，再乙酸乙酯冲硅胶短柱，浓缩，快速柱层析，得到式(Ⅰ)的环戊-2-烯酮-4-醇类化合物。
3.如权利要求1或2所述的方法，其特征在于，所述方法中，氮杂环卡宾前体为1-乙基-3-甲基咪唑四氟硼酸盐。
4.如权利要求1或2所述的方法，其特征在于，所述方法中，碱为碳酸铯。
5.如权利要求3所述的方法，其特征在于，所述方法中，所述的溶剂为1,4-二氧六环和二氯甲烷的混合溶剂，所述的1,4-二氧六环/二氯甲烷为3/1。
6.如权利要求4所述的方法，其特征在于，所述方法中，所述反应温度为-10度。
7.如权利要求1或2或5或6所述的方法，其特征在于，所述方法中，芳香醛与α-联烯酮的摩尔比为1.2/1。
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