新颖的手性伯氨类催化剂在Aldol反应中的应用
|
摘要
不对称有机合成是当代有机合成中最具有吸引力的领域之一,作为不对称合成的一个新方法,对映选择性的有机催化已经成为越来越普遍应用的方法,因此探寻新颖并且有效的小分子催化剂已经成为了有机合成化学中的一项挑战。不对称Aldol反应是C-C键形成的重要反应之一,其反应生成的β-羟基羰基化合物是许多药物合成的中间体,在目前的研究成果中,大部分的小分子催化剂都是脯氨酸或其衍生物,脯氨酸是仲氨,而设计合成伯氨类催化剂并取得良好催化效果的却很少。
本文以廉价易得的天然氨基酸为原料,合成了一系列的新型的伯氨类催化剂Va-Vg,并通过加入少量的添加剂,在底物的适用性方面较系统研究了丙酮和3-戊酮与各种芳香醛的反应,取得了满意的结果。
1.通过一种简单易行的路线合成了催化剂Va-Vg,并考查了它们对催化剂活性和对映选择性的影响。
2.从添加剂的种类和用量、溶剂、温度、催化剂的用量等几方面研究了最好的催化剂Vf在有机相中对Aldol反应的催化活性和对映选择性产生的影响。
3.多步条件的优化,结果表明,不同的添加剂对产物的ee值有很大的影响,其中2,4-二硝基酚是最适合的,它把产物的ee值由56%提高到了93%;添加剂和催化剂的用量对结果影响不大;降低温度能提高其对映选择性。最重要的是,我们利用这类催化剂扩展了底物的范围,催化3-戊酮与芳香醛的Aldol反应在纯3-戊酮中能以高产率和良好的非对应选择性和对应选择性得到syn异构体。
Asymmetric organic synthesis is one of the most attractive research areas in organic synthesis. As a new method for asymmetric synthesis, enantioselective organocataiysis is more and more popular, so it has become a chemical challenges to explore many new and effective small molecular catalysts. The asymmetric aldol reaction is considered to be one of the important reaction of the carbon-carbon bond forming. It provides an atom-economic approach toβ-hydroxy-carbonyls which make up a large family of chiral intermediates for synthesis of many drugs. In previous research, most of the small molecular catalysts are proline or their derivatives, proline is second amine but few first amine catalysts were reported.
In this thesis, a series of new primary amine catalysts were synthesized from readily available amino acid. Moreover, extension of acetone and 3-pentylone to aryl aldehydes are observed by addition of optimal additives.
1. A series of catalysts Va-Vg were synthesized and the effects on the catalytic activity and enantioselectivity were studied.
2. The catalytic activity and enantioselectivety of the suitable catalyst V f have been studied in organic phase in the influence of the type and amount of the additives, different solvents, temperature and the amount of catalyst etc.
3. The results indicated that different additives have great effects on the enantioselectivity . 2, 4-dinitrophenol is the optimal additive among them which can raise the ee from 56% to 93%. The amount of additive and catalyst make little effect on the results. Low temperature can increase enantioselectivity. The most important is that we expand the scope of the substrate , the aldol reaction of 3-pentylone and aryl aldehydes leads to the formation of syn product with high yield, excellent diastereoselectivity and enantioselectivity in neat 3-pentylone.
本文以廉价易得的天然氨基酸为原料,合成了一系列的新型的伯氨类催化剂Va-Vg,并通过加入少量的添加剂,在底物的适用性方面较系统研究了丙酮和3-戊酮与各种芳香醛的反应,取得了满意的结果。
1.通过一种简单易行的路线合成了催化剂Va-Vg,并考查了它们对催化剂活性和对映选择性的影响。
2.从添加剂的种类和用量、溶剂、温度、催化剂的用量等几方面研究了最好的催化剂Vf在有机相中对Aldol反应的催化活性和对映选择性产生的影响。
3.多步条件的优化,结果表明,不同的添加剂对产物的ee值有很大的影响,其中2,4-二硝基酚是最适合的,它把产物的ee值由56%提高到了93%;添加剂和催化剂的用量对结果影响不大;降低温度能提高其对映选择性。最重要的是,我们利用这类催化剂扩展了底物的范围,催化3-戊酮与芳香醛的Aldol反应在纯3-戊酮中能以高产率和良好的非对应选择性和对应选择性得到syn异构体。
Asymmetric organic synthesis is one of the most attractive research areas in organic synthesis. As a new method for asymmetric synthesis, enantioselective organocataiysis is more and more popular, so it has become a chemical challenges to explore many new and effective small molecular catalysts. The asymmetric aldol reaction is considered to be one of the important reaction of the carbon-carbon bond forming. It provides an atom-economic approach toβ-hydroxy-carbonyls which make up a large family of chiral intermediates for synthesis of many drugs. In previous research, most of the small molecular catalysts are proline or their derivatives, proline is second amine but few first amine catalysts were reported.
In this thesis, a series of new primary amine catalysts were synthesized from readily available amino acid. Moreover, extension of acetone and 3-pentylone to aryl aldehydes are observed by addition of optimal additives.
1. A series of catalysts Va-Vg were synthesized and the effects on the catalytic activity and enantioselectivity were studied.
2. The catalytic activity and enantioselectivety of the suitable catalyst V f have been studied in organic phase in the influence of the type and amount of the additives, different solvents, temperature and the amount of catalyst etc.
3. The results indicated that different additives have great effects on the enantioselectivity . 2, 4-dinitrophenol is the optimal additive among them which can raise the ee from 56% to 93%. The amount of additive and catalyst make little effect on the results. Low temperature can increase enantioselectivity. The most important is that we expand the scope of the substrate , the aldol reaction of 3-pentylone and aryl aldehydes leads to the formation of syn product with high yield, excellent diastereoselectivity and enantioselectivity in neat 3-pentylone.
引文
[1]林国强,陈耀全,陈新滋,李月明 手性合成--不对称反应及其应用科学出版社,北京,2000,p2-p49
[2]BERKESSEL,A;GROGER,H.Asymmetric Organocatalysis[M].2005
[3]尤田耙,林国强 不对称合成 科学出版社,北京,2000,p2-p17
[4]Noyori,R.Angew.Chem.Int.Ed.2002,41,2008
[5]Sharpless,K.B.Angew.Chem.Int.Ed.2002,41,2023
[6]Anastas,P.T.;Kirchhoff,M.Acc.Chem.Res.2002,35,686
[7]List B,Pojarliev P,Castcllo C.[J].Org Lett,2001,3(4),573
[8]Z.G.Hajos.D.R.Parrish.J.Org.Chem,1974,39,1615-1621
[9]C.PIDATHALA.L.HOANG.N.VIGNOLA.B.LIST.Angew.Chem,2003,115,2891-2894.
[10]List B,Lerner R A,Barbas C F.J Am Chem Soc,2000,122,2395-2396
[11]Sakthivel,K.;Notz,W.;Bui.T.:Barbas.C.F.J.Am.Chem.Soc.2001,123,5260-5267
[12]List,B.;Pojarliev,P.;Castello,C.Org.Lett,2001,3,573-575
[13]Anders Bogevig,Nagaswamy Kumaragurubaran,Karl Anker JF rgensen,Chem.Comm,2002,620-621
[14]Benaglia M,Cinquini M,Cozzi F,etal.Adv.Synth.Catal.2002,344,533
[15]Swapandeep Singh Chimnian,Dinesh Mahajan.Tetrahedron,2005,61,5019-5025
[16]Casaa J.;Sunden H.;Cordova A.Tetradron Lett,2004,45,6117
[17]Zhong G.;Fan J.;BarbasⅢ C.F.Tetrahedron Lett,2004,45,5681
[18]Cordova A.;NotzW.;BarbasⅢ C.E J.Org.Chem,2002,67,301
[19]Chowdari,N.S.;Ramachary D.B.;Cordova A.;BarbasⅢC.F.Tetrahedron Lett,2002,43,9591
[20]Kawana M,Emoto S.Tetrahedron Lett.,1972,48,4850
[21]Tang,Z.;Jiang,F.;Yu,L.-T.;Cui,X.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.;Wu,Y.-D.J.Am.Chem.Soc,2003,125,5262
[22]Kotrusz.;Kmentova.;Gotov,B.;Toma,S.;Soleaniova,E.Chem.Commun,2002,21,2510-2511
[23]Cordova,A.Tetrahedron Lett,2000,4,3949- 3952.
[24]Loh,T.- P.;Feng,L-C.;Yang,H.-Y.;Yang,J.-Y.Tetrahedron Lett,2002,43,8714-8743
[25]Chowdari,N.S.;Ramachary,D.B.;Barbas,C.FIII.Synlett,2003,1906-1909
[26]Chandrasekhar,S.;Narsihmulu,.C.;Reddy,N.R.TetrahedronLett,2004,45,4581-4582
[27]Yin-SuWu,Wei-Yan Shao,Chuan-Qi Zheng,Zhong-Li Huang,Jiwen Cai,and Qin-Ying Deng M.H.C.Acta 2004,87,1377-1384
[28]Yi YP,Qiu PD,Zu C,et al[J].Tetrahedron Lett,2003,44,3871.
[29]Tang,Z.;Jiang,F.;Yu,L.-T.;Cui,X.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.;Wu,Y.-D,J.Am.Chem.Soc,2003,125,5262
[30]Tang,Z.;Yang,Z.-H.;Chen,X.-H.;Cun,L.-F.;Mi,A.-Q.;Jiang,Y.-Z.;Gong,L.-Z J.Am.Chem.Soc,2005,127,9285
[31]Tang,Z.;Jiang,F.;Cui,X.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.;Wu,Y.-D.PNAS.2004,10,15755
[32]Albercht.Berkessel,Burkhard Koch,Johann Lex.Synth.Catal,2004,346,1141-1146.
[33]Wu,Y.-Y.;Zhang,Y.-Z.;Yu,M.-L;Zhao,G.;Wang,S.-W.Org.Lett,2006,8,4417
[34]Philipp,Krattiger,Roman,Kovasy,Jefferso.D.Revell,Stanisav.Ivan,Org.Lett,2005,7,1101-1103
[35]List,B.;Lerner,R.A.;Barbas,C.F.,J.Am.Chem.Soc,2000,122,2395
[36]Hayashi,Y.;Sumiya,T.;Takahashi,J.;Gotoh,H.;Urushima,T.;Shoji,M.Angew.Chem.Int.Ed,2006,45,958
[37]Evagelos Bellis.George Kokotos,Tetrahedron,2005,61,8669-8676.
[38]Evagelos Bellis.George Kokotos,J.M.Cata.A:Chemical,2005,241,166-174.
[39]Gu,L.Q.;Yu,M.L;Wu,X.Y.;Zhang,Y.Z.;Zhao,G.,Adv.Synth.Catal,2006,348,2223
[40]Nakadai,M.;Saito,S.;Yamamoto,H.Tetrahedron,2002,58,8167-8177.
[41]Luo,S.Z.;Xu,H.;Li J.-Y.;Zhang,L.;Cheng,J.-P.,J.Am.Chem.Soc.2007,129,3074
[42]Mohamed Amedjkouh.Tetrahedron:Asymmetry.2005,16,1411-1414
[43]Zhaoqin,Jiang;Zhian,Liang;Xiaoyu,Wu.;Yixi,Lu,Chem.Commun,2006,2,801-2803
[44]Kofoed,J.;Nielsenb,J.;Reymonda,J-L,,Bioorganic & Medicinal Chemistry Lett,2003,13,2445-2447
[45]Marc R.M.Andreae and Anthony P.Davis,Tetrahedron:Asymmetry 2005,16,2487-2492
[46]Tang,Z.;Yang,Z.-H.;Cun,L.-F.;Gong,L-Z;Mi,A-Q.;Jiang,Y.-Z.,Org.Lett,2004,6,2285-2287
[47]Philipp Krattiger,Roman Kovasy,Jefferson D.Revell,Stanisav Ivan and Helma.Wennemers.Org.Lett.2005,7,1101-1103.
[48]Kawana M,Emoto.S.Tetrahedron Lett.,1972,48,4850
[49]Kiyooka S,Kido Y,Kaneko Y.Tetrahedron Lett,1994,35,29,5243
[50]Benaglia M,Cinquini M,Cozzi F,etal.,Adv.Synth.Catal.2002,344,533
[51]Benaglia M,Cinquini M,Cozzi F,etal.,J.Molecu.Cat.A:Chem,2003,204-205,157
[52]Szollsi G,London G,Balaspiri L,etal.Chirality,2003,15,90
[53]Machajewski,T.D.;Wong,C.H.Angew.Chem.Int.Ed.2000,39,1352
[54]Xiao-Ying Xu,Yan-Zhao Wang,and Liu-Zhu Gong,Org.Lett,2007,9,4247-4249
[55]S.S.V.Ramasastry,Klaus Albertshofer,Naoto Utsumi,and Carlos F.Barbas Ⅲ,Org.Lett,2008,10,51621-1624
[56]B.List.Synlett,2001,1675-1686
[57]K.Sakthivel.W.Notz.T.Bui C.F.Barbas Ⅲ.J.Am.Chem.Soc.2001,123,5260-52
[58]Yan Zhou,Zixing Shan Tetrahedron,2006,62,5692-5696
[59]Tang,Z.;Yang,Z.-H.;Chen,X.-H.;Cun,L.-F.;Mi,A.-Q.;Jiang,Y.-Z.;Gong,L.-Z.J.Am.Chem.Soc.,2005,127,9285-9289
[60]Yan Zhou and Zixing ShanTetrahedron:Asymmetry,2006,17,1671-1677
[61]Guo,H.-M.;Cun,L.-F.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.Chem.Commun.2005,
[2]BERKESSEL,A;GROGER,H.Asymmetric Organocatalysis[M].2005
[3]尤田耙,林国强 不对称合成 科学出版社,北京,2000,p2-p17
[4]Noyori,R.Angew.Chem.Int.Ed.2002,41,2008
[5]Sharpless,K.B.Angew.Chem.Int.Ed.2002,41,2023
[6]Anastas,P.T.;Kirchhoff,M.Acc.Chem.Res.2002,35,686
[7]List B,Pojarliev P,Castcllo C.[J].Org Lett,2001,3(4),573
[8]Z.G.Hajos.D.R.Parrish.J.Org.Chem,1974,39,1615-1621
[9]C.PIDATHALA.L.HOANG.N.VIGNOLA.B.LIST.Angew.Chem,2003,115,2891-2894.
[10]List B,Lerner R A,Barbas C F.J Am Chem Soc,2000,122,2395-2396
[11]Sakthivel,K.;Notz,W.;Bui.T.:Barbas.C.F.J.Am.Chem.Soc.2001,123,5260-5267
[12]List,B.;Pojarliev,P.;Castello,C.Org.Lett,2001,3,573-575
[13]Anders Bogevig,Nagaswamy Kumaragurubaran,Karl Anker JF rgensen,Chem.Comm,2002,620-621
[14]Benaglia M,Cinquini M,Cozzi F,etal.Adv.Synth.Catal.2002,344,533
[15]Swapandeep Singh Chimnian,Dinesh Mahajan.Tetrahedron,2005,61,5019-5025
[16]Casaa J.;Sunden H.;Cordova A.Tetradron Lett,2004,45,6117
[17]Zhong G.;Fan J.;BarbasⅢ C.F.Tetrahedron Lett,2004,45,5681
[18]Cordova A.;NotzW.;BarbasⅢ C.E J.Org.Chem,2002,67,301
[19]Chowdari,N.S.;Ramachary D.B.;Cordova A.;BarbasⅢC.F.Tetrahedron Lett,2002,43,9591
[20]Kawana M,Emoto S.Tetrahedron Lett.,1972,48,4850
[21]Tang,Z.;Jiang,F.;Yu,L.-T.;Cui,X.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.;Wu,Y.-D.J.Am.Chem.Soc,2003,125,5262
[22]Kotrusz.;Kmentova.;Gotov,B.;Toma,S.;Soleaniova,E.Chem.Commun,2002,21,2510-2511
[23]Cordova,A.Tetrahedron Lett,2000,4,3949- 3952.
[24]Loh,T.- P.;Feng,L-C.;Yang,H.-Y.;Yang,J.-Y.Tetrahedron Lett,2002,43,8714-8743
[25]Chowdari,N.S.;Ramachary,D.B.;Barbas,C.FIII.Synlett,2003,1906-1909
[26]Chandrasekhar,S.;Narsihmulu,.C.;Reddy,N.R.TetrahedronLett,2004,45,4581-4582
[27]Yin-SuWu,Wei-Yan Shao,Chuan-Qi Zheng,Zhong-Li Huang,Jiwen Cai,and Qin-Ying Deng M.H.C.Acta 2004,87,1377-1384
[28]Yi YP,Qiu PD,Zu C,et al[J].Tetrahedron Lett,2003,44,3871.
[29]Tang,Z.;Jiang,F.;Yu,L.-T.;Cui,X.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.;Wu,Y.-D,J.Am.Chem.Soc,2003,125,5262
[30]Tang,Z.;Yang,Z.-H.;Chen,X.-H.;Cun,L.-F.;Mi,A.-Q.;Jiang,Y.-Z.;Gong,L.-Z J.Am.Chem.Soc,2005,127,9285
[31]Tang,Z.;Jiang,F.;Cui,X.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.;Wu,Y.-D.PNAS.2004,10,15755
[32]Albercht.Berkessel,Burkhard Koch,Johann Lex.Synth.Catal,2004,346,1141-1146.
[33]Wu,Y.-Y.;Zhang,Y.-Z.;Yu,M.-L;Zhao,G.;Wang,S.-W.Org.Lett,2006,8,4417
[34]Philipp,Krattiger,Roman,Kovasy,Jefferso.D.Revell,Stanisav.Ivan,Org.Lett,2005,7,1101-1103
[35]List,B.;Lerner,R.A.;Barbas,C.F.,J.Am.Chem.Soc,2000,122,2395
[36]Hayashi,Y.;Sumiya,T.;Takahashi,J.;Gotoh,H.;Urushima,T.;Shoji,M.Angew.Chem.Int.Ed,2006,45,958
[37]Evagelos Bellis.George Kokotos,Tetrahedron,2005,61,8669-8676.
[38]Evagelos Bellis.George Kokotos,J.M.Cata.A:Chemical,2005,241,166-174.
[39]Gu,L.Q.;Yu,M.L;Wu,X.Y.;Zhang,Y.Z.;Zhao,G.,Adv.Synth.Catal,2006,348,2223
[40]Nakadai,M.;Saito,S.;Yamamoto,H.Tetrahedron,2002,58,8167-8177.
[41]Luo,S.Z.;Xu,H.;Li J.-Y.;Zhang,L.;Cheng,J.-P.,J.Am.Chem.Soc.2007,129,3074
[42]Mohamed Amedjkouh.Tetrahedron:Asymmetry.2005,16,1411-1414
[43]Zhaoqin,Jiang;Zhian,Liang;Xiaoyu,Wu.;Yixi,Lu,Chem.Commun,2006,2,801-2803
[44]Kofoed,J.;Nielsenb,J.;Reymonda,J-L,,Bioorganic & Medicinal Chemistry Lett,2003,13,2445-2447
[45]Marc R.M.Andreae and Anthony P.Davis,Tetrahedron:Asymmetry 2005,16,2487-2492
[46]Tang,Z.;Yang,Z.-H.;Cun,L.-F.;Gong,L-Z;Mi,A-Q.;Jiang,Y.-Z.,Org.Lett,2004,6,2285-2287
[47]Philipp Krattiger,Roman Kovasy,Jefferson D.Revell,Stanisav Ivan and Helma.Wennemers.Org.Lett.2005,7,1101-1103.
[48]Kawana M,Emoto.S.Tetrahedron Lett.,1972,48,4850
[49]Kiyooka S,Kido Y,Kaneko Y.Tetrahedron Lett,1994,35,29,5243
[50]Benaglia M,Cinquini M,Cozzi F,etal.,Adv.Synth.Catal.2002,344,533
[51]Benaglia M,Cinquini M,Cozzi F,etal.,J.Molecu.Cat.A:Chem,2003,204-205,157
[52]Szollsi G,London G,Balaspiri L,etal.Chirality,2003,15,90
[53]Machajewski,T.D.;Wong,C.H.Angew.Chem.Int.Ed.2000,39,1352
[54]Xiao-Ying Xu,Yan-Zhao Wang,and Liu-Zhu Gong,Org.Lett,2007,9,4247-4249
[55]S.S.V.Ramasastry,Klaus Albertshofer,Naoto Utsumi,and Carlos F.Barbas Ⅲ,Org.Lett,2008,10,51621-1624
[56]B.List.Synlett,2001,1675-1686
[57]K.Sakthivel.W.Notz.T.Bui C.F.Barbas Ⅲ.J.Am.Chem.Soc.2001,123,5260-52
[58]Yan Zhou,Zixing Shan Tetrahedron,2006,62,5692-5696
[59]Tang,Z.;Yang,Z.-H.;Chen,X.-H.;Cun,L.-F.;Mi,A.-Q.;Jiang,Y.-Z.;Gong,L.-Z.J.Am.Chem.Soc.,2005,127,9285-9289
[60]Yan Zhou and Zixing ShanTetrahedron:Asymmetry,2006,17,1671-1677
[61]Guo,H.-M.;Cun,L.-F.;Gong,L.-Z.;Mi,A.-Q.;Jiang,Y.-Z.Chem.Commun.2005,