CN1174103C - 黑曲霉菌株选择性拆分制备手性取代芳基环氧乙烷类化合物及其二醇的方法 - Google Patents
黑曲霉菌株选择性拆分制备手性取代芳基环氧乙烷类化合物及其二醇的方法 Download PDFInfo
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Abstract
本发明是涉及一种黑曲霉菌株(Asperillus niger CGMCC 0496)对映选择性拆分取代芳基类环氧乙烷底物生成光学活性的手性环氧与二醇化合物的方法。用此反应可以不经分离直接通过化学方法进行手性拆分,一步合成具有R-构型的光学活性二醇化合物,光学活性二醇在合成手性药物具有重大的应用价值。特别是在合成是α-或β-肾上腺受体激动剂或拮抗剂。这是一类广泛运用于治疗:高血压、心绞痛、焦虑、支气管炎等心血管疾病与肺病的手性药物。
Description
技术领域
本发明涉及一种微生物催化剂在不对称水解取代芳基环氧乙烷类底物中的用途。即用黑曲霉菌株对映选择性拆分取代芳基环氧乙烷类底物的方法,制备手性取代芳基环氧乙烷类化合物及其二醇的方法。
技术背景
具有光学活性的取代芳基环氧乙烷类化合物及其对应的二醇化物在农药、医药和精细化工等方面具有极高的应用价值。目前光学活性药物主要集中在治疗心血管,中枢神经***疾病,抗病毒以及抗肿瘤疾病上。其中在治疗心血管类疾病的药物中β-受体阻滞剂上具有R构型的苯乙二醇类化合物是一类重要的合成中间体。其S构型的取代芳基环氧乙烷类底物也可以通过简单的化学催化生成同样具有R构型的苯乙二醇类化合物。(M.Cleij;A.Archelas;R.Furstoss J.Org.Chem.1999,64,5029-5035)这二步可以不经分离直接在同一反应器内进行(I.V.Archer;D.J.Leak;D.A.Widdowson Tetrahedron Letter 1996,37,8819-8822)。由于最终所得大部分二醇产物可以通过重结晶法进行纯化。因此运用本方法合成光学活性苯乙二醇类化合物具有高效快速,后处理方便等优点。用化学方法合成手性苯乙二醇类化合物1,2-二醇主要为有Sharpless不对称双羟化制备手性1,2-二醇,使用salen-Co(II)的复合物对1,2-环氧进行不对称水解,它们对底物都有一定的限止(1.Johnson,R.A.;Sharpless,K.B.in:Catalytic Asymmetric Synthesis,Ed.:Ojima,I.,Verlag Chemie,NewYork,1993,p.103.2.Kolb,H.C.,van Nieuwenhze,M.S.;Sharpless,K.B.Chem.Rev.1994,94,2483.3.Katsuki,T.J.Synth.Org.Chem.Jpn.1995,53,940.4.Jacobsen,E.S.;Kakiuchi,F.;Fonsler,R.G.;Larrow J.F.;Tokunaga,M.Tetrahedron Lett.1997,38,773.5.Larrow,J.F.;Schauss,S.E.;Jacobsen,E.N.J.Am.Chem.Soc.1996,50,249.)(外,由于β-受体阻滞剂这一类心血管药物往往需要长期服用,这就需要在合成中尽量不使用有害试剂如:重金属离子等。而使用化学催化法必须使用含有重金属离子的手性催化剂。
使用微生物转化法催化不对称水解1,2-环氧的报道目前不多。主要为法国的R.Furstoss小组与K.Farber小组(1.Chen,X.J.;Archelas,A.;Furstoss,R.J.Org.Chem.1993,58,5528.2.Mischitz,M.;Kroutil,W.;Wandel,U.;Faber,K.Tetrahedron:Asymmetry,1995,6(6),1261.)。李祖义等人发明黑曲霉菌株(Asperillus niger CGMCC 0496)、培养方法及其用途(CN00127451.1),培养所得新鲜菌体可以贮存在0-4℃下5天活力无明显变。
至今,建立一个完整的催化不对称水解取代芳基环氧乙烷类底物以得到具有光学活性的环氧与二醇的反应条件与方法仍是手性合成研究的重点之一。
发明内容
本发明目的是提供一种用黑曲霉菌体内的环氧水解酶不对称水解取代芳基环氧乙烷类底物的反应体系与方法。
本发明的方法是用具有环氧水解酶的黑曲霉菌本(Asperillus niger CGMCC 0496)催化取代芳基环氧乙烷类化合物不对称水解,制备手性取代芳基环氧乙烷类化合物及其手性二醇的方法。
所述的取代芳基环氧乙烷类化合物底物具有以下结构:
,其中Ar为苯基、萘基或吡啶基,R1或R2=H、C1-4的烷基、NO2、CF3、CN或X,X=F、Cl、Br或I。
在本发明的方法中在pH=5.0-9.50的磷酸缓冲溶液和助溶剂中,上述的取代芳基环氧乙烷类化合物和黑曲霉菌体(湿)(Asperillus niger CGMCC 0496)重量比为500∶1-20∶1时,底物在反应器中的浓度为0.1g/L至20g/L,推荐pH=7.5-8.5,反应温度20-35℃下,反应时间0.01-120小时。
采用本发明的方法,菌体(湿)与底物的重量比推荐为200∶1至50∶1,底物在反应器中的浓度推荐为1g/L至5g/L。底物溶解在缓冲溶液过程中推荐使用的助溶剂为N,N-二甲基甲酰胺(DMF)。推荐反应温度25-27℃,推荐反应时间0.2-3小时。通过快速过滤菌体终止反应。
用此反应可以不经分离直接通过化学方法进行手性拆分,一步合成具有R-构型的光学活性二醇化合物,光学活性二醇在合成手性药物具有重大的应用价值。特别是在合成是α-或β-肾上腺受体激动剂或拮抗剂。 这是一类广泛运用于治疗:高血压、心绞痛、焦虑、支气管炎等心血管疾病与肺病的手性药物。
具体实施方式
通过下述实施例将有助于理解本发明,但并不限制本发明的内容。
实施例1对单取代的环氧苯乙烷类底物的对映选择性拆分
取新鲜培养的黑曲霉CGMCC 0496湿菌体10g(相当于1.6克干菌体)或20g投入100ml磷酸缓冲体系(PH=8),水浴并控制温度在25-26℃,加入200mg或100mg取代芳基环氧乙烷类底物,机械搅拌(800转/分钟),用TLC跟踪反应进程。当反应进行到如表上所示时间时,过滤除去菌体(菌体用乙酸乙酯浸泡12小时)反应液用NaCl进行饱和,用乙酸乙酯萃取3次,合并有机层。除去溶剂用1∶20至1∶4(乙酸乙酯∶石油醚)进行快速柱层析得(S)-构型的剩余环氧;再改用1∶3至1∶1(乙酸乙酯∶石油醚)得(R)-构型的二醇产物。
反应情况列于下表:
上述反应式中,(S)-1-16为手性环氧化合物,(R)-17-32为手性双醇化合物。其中,1.R1=p-NO2,2.R1=m-NO2,3.R1=o-NO2,4.R1=p-F,5.R1=p-Cl,6.R1=m-Cl,7.R1=o-Cl,8.R1=p-Br,9.R1=m-Br,10.R1=o-Br,11.R1=p-I,12.R1=p-CH3,13.R1=p-CH3CH2,14.R1=H,15.R1=o-CF3,16.R1=p-CN,17.R1=p-NO2,18.R1=m-NO2,19.R1=o-NO2,20.R1=p-F,21.R1=p-Cl,22.R1=m-Cl,23.R1=o-Cl,24.R1=p-Br,25.R1=m-Br,26.R1=o-Br,27.R1=p-I,28.R1=p-CH3,29.R1=p-CH3CH2,30.R1=H,31.R1=o-CF3,32.R1=p-CN。
表1.
底物a 时间 手性环氧化合物 二醇产物
编号 (分钟) 编号b 产率, ee,% 编号c 产率, ee,%
% %
(±)-1 109 (S)-1 42 94 (R)-16 45 95
(±)-2 140 (S)-2 45 55 (R)-17 48 66
(±)-3* 68 (S)-3 34 98 (R)-18 38 >99
(±)-4 32 (S)-4 24 41 (R)-19 33 74
(±)-5 60 (S)-5 32 95 (R)-20 46 85
(±)-6 24 (S)-6 47 28 (R)-21 40 74
(±)-7 45 (S)-7 17 47 (R)-22 37 84
(±)-7* 44 (S)-7 22 94 (R)-22 30 84
(±)-8 40 (S)-8 30 >99 (R)-23 43 86
(±)-9 38 (S)-9 43 35 (R)-24 43 70
(±)-10 65 (S)- 22 >99 (R)-25 46 80
10
(±)-11 52 (S)- 25 97 (R)-26 39 72
11
(±)-12 43 (S)- 45 70 (R)-27 43 63
12
(±)-13 41 (S)- 29 63 (R)-28 41 70
13
(±)-14 215 (S)- 15 75 (R)-29 36 52
14
(±)-15* 126 (S)- 34 98 (R)-30 31 82
15
a:大部分反应中底物与菌体的用量为200mg底物每10g菌体。有*的反应中底物与菌体的用量为200mg底物每10g菌体。
上述化合物分析结果如下:
上述化合物分析结果如下:
(S)-(+)-2-(4-硝基苯基)-环氧乙烷(S)-1淡黄色固体mp.73-75℃;94%ee,[α]D 25+35.0(c1.20,CHCl3);1HNMR(300MHz,CDCl3):δ2.78(dd,1H,J=5.5,2.5Hz),3.23(dd,1H,J=5.5,4.1Hz),3.96(dd,1H,J=4.1,2.5Hz),8.22,7.46(AB,4H,J=8.7Hz);IR:νmax 1610,1530,1410,1350,855cm-1;MSm/z(rel.intensity):166([M+1]+,2),165(M+,3),164(6),148(47),118(68),91(30),89(100),77(12),65(21),63(47),51(21).
(S)-(+)-2-(3-硝基苯基)-环氧乙烷(S)-2黄色液体;57%ee,[α]D 18+2.5(c2.8,CHCl3),1H NMR(300MHz,CDCl3):δ2.80(dd,1H,J1=4.8Hz,J2=2.4Hz),3.22(dd,1H,J1=4.2Hz,J2=0.9Hz),3.97(dd,1H,J1=3.9Hz,J2=1.2Hz),7.40-7.75(m,2H),8.02-8.24(m,2H);IR:νmax 3113,2995,1517,1343,1301,1042,983,887,789,741cm-1;MSm/z(rel.intensity):165(M+,18),150(32),136(68),120(25),105(17),90(100),77(22),74(12),65(52),63(59).
(S)-(-)-2-(2-硝基苯基)-环氧乙烷(S)-3.
黄色固体;mp.51-52℃;98% ee,[α]D 19.5-107.2(c=1.7;CHCl3)1HNMR(300MHz,CDCl3,TMS):δ2.67(dd,1H,J1=5.4Hz,J2=2.4Hz),3.30(dd,1H,J1=5.4Hz,J2=4.2Hz),4.48(dd,1H,J1=4.5Hz,J2=3.0Hz)7.40-7.55(m,1H),7.58-7.75(m,2H),8.15(dd,1H,J1=8.1Hz,J2=1.2Hz).IR:νmax3150,2997,1532,1353,1254,899,859,809,737,684cm-1;MSm/z(rel.intensity):165(M+,0.3),149(2),135(21),105(10),104(10),91(79),89(21)79(71),77(100).
(S)-(+)-2-(4-氟代苯基)-环氧乙烷(S)-4无色液体;41%ee;[α]D 27+7.0(c1.9,CHCl3);MSm/z(rel.intensity):139(M+1,0.92),138(M+,13),110(13),109(100),107(11),83(22),81(4).1H NMR(300MHz,CDCl3,TMS):δ2.75(dd,1H,J1=5.4Hz,J2=2.5Hz),3.13(dd,1H,J1=5.3Hz,J2=4.1Hz),3.84(dd,1H,J1=3.9Hz,J2=2.7Hz),6.90-7.12(m,2H),7.14-7.35(m,2H).IR:νmax3055,2995,2926,1608,1514,1479,1383,1222,1157,1015,988,882,836,820cm-1.
(S)-(+)-2-(4-氯代苯基)-环氧乙烷(S)-5.
液体;95%ee;[α]D 27+18.7(c1.8,CHCl3);MSm/z(rel.intensity):156,154(M+1,2,8),155,153(M+,3,7),138(3),125(40),119(39),91(29),89(100),63(34),50(17);1H NMR(300MHz,CDCl3,TMS):δ2.74(dd,1H,J1=5.4Hz,J2=2.4Hz),3.13(dd,1H,J1=5.4Hz,J2=4.2Hz),3.82(dd.1H,J1=4.2Hz,J2=2.4Hz),7.10-7.21(m,2H),7.26-7.35(m,2H);IR:νmax3054,2992,2920,1602,1496,1478,1417,1381,1199,1090,1015,987,879,831,769cm-1.
(S)-(+)-2-(3-氯代苯基)-环氧乙烷(S)-6.
液体:28%ee;[α]D 27+3.6(c 1.0,CHCl3);MSm/z(rel.intensity):157,155(M+1,0.8,1.4),156,154(M+,10,24),141(15),139(14),125(50),111(11),91(56),89(100);1H NMR(300MHz,CDCl3,TMS):δ2.79(dd,1H,J1=5.3Hz,J2=2.4Hz),3.17(dd,1H,J1=J2=4.8Hz),3.86(dd,1H,J1=J2=2.8Hz),7.16-7.62(m,4H);IR:νmax 3059,2993,1602,1575,1481,1435,1386,1079,999,880,823,692cm-1.
(S)-(+)-2-(2-氯代苯基)-环氧乙烷(S)-7.
液体;94%ee;[α]D 23+48.3(c1.2,CHCl3);MS m/z(rel.intensity):156,154(M+,4,16),155,153(M+-1,10,23),134(9),124(28),119(75),91(33),89(100),63(17);1H NMR(300 MHz,CDCl3,TMS):δ2.65(dd,1H,J1=5.9Hz,J2=3.6Hz),3.19(dd,1H,J1=5.3Hz,J2=4.2Hz),4.21(dd,1H,J1=J2=3.3Hz),7.10-7.50(m,4H);IR:νmax 3061,2993,1699,1593,1482,1442,1383,1249,1121,1053,1035,880,755cm-1.(S)-(+)-2-(4-溴代苯基)-环氧乙烷(S)-8.
液体;>99%ee;[α]D 23+13.9(c1.2,CHCl3);MS:m/z(rel.intensity%):200,198(M+,4),199,197(M-1,3),169(14),119(41),89(100),63(36);1H NMR(300MHz,CDCl3,TMS):δ2.73(dd,1H,J1=5.4Hz,J2=2.7Hz),3.13(dd,1H,J1=5.1Hz,J2=3.6Hz),3.81(dd,1H,J1=3.9Hz,J2=2.4Hz),7.05-7.18(m,2H),7.40-7.48(m,2H);IR:νmax3051,2991,2919,1595,1490,1415,1378,1101,1073,1011,987,878,828cm-1.
(S)-(+)-2-(3-溴代苯基)-环氧乙烷(S)-9.
液体;35%ee;[α]D 27+4.0(c1.1,CHCl3);MSm/z(rel.intensity):200,198(M+,23,23),199,197(M+-1,32,32),169(27),141(16),119(67),91(60),89(100);1H NMR(300MHz,CDCl3,TMS):δ2.77(dd,1H,J1=5.4Hz,J2=2.5Hz),3.15(dd,1H,J1=5.4Hz,J2=4.1Hz),3.81(dd,1H,J1=4.0Hz,J2=2.5Hz),7.10-7.50(m,4H);IR:νmax 3057,2992,1600,1571,1478,1385,1369,1201,1070,997,877,786,691cm-1.
(S)-(+)-2-(2-溴代苯基)-环氧乙烷(S)-10.
液体;>99%ee;[α]D 18+68.7(c1.1,CHCl3);MSm/z(rel.intensity):200,198(M+,17,18),199,197(M+-1,16,15),185(1),171(9),169(10),141(1),120(7),119(84),91(63),90(41),89(100);1HNMR(300MHz,CD3COCD3,TMS):δ2.64(dd,1H,J1=5.9Hz,J2=2.6Hz),3.18(dd,1H,J1=5.9Hz,J2=4.1Hz),4.15(dd,1H,J1=4.1Hz,J2=2.6Hz)7.08-7.38(m,3H),7.54(dd,1H,J1=7.9Hz,J2=1.1Hz);IR:νmax3055,2991,2916,1569,1472,1440,1381,1248,1045,1026,879,753cm-1.
(S)-(+)-2-(4-碘代苯基)-环氧乙烷(S)-11.
液体;97%ee;[α]D 26+25.1(c1.0,CHCl3);MSm/z(rel.intensity):247(M+1,10),246(M+,53),245(36),233(19),230(10),217(53),127(6),119(75),91(69),90(54),89(75);1H NMR(300MHz,CDCl3,TMS):δ2.74(dd,1H,J1=5.4 Hz,J2=2.6Hz),3.13(dd,1H,J1=5.3Hz,J2=2.6Hz),2.80(dd,1H,J1=3.8Hz,J2=2.5Hz),6.90-7.05(m,2H),7.60-7.78(m,2H);IR:νmax 3053,2990,1589,1474,1413,1377,1056,1006,876,825,792cm-1.
(S)-(+)-2-(4-甲基苯基)-环氧乙烷(S)-12.
液体;70%ee;[α]D 16+19.5(c1.2,CHCl3);MS:m/z(rel.intensity%):235(M+1,3),134(M+,2),121(100),91(42),77(24),65(12),51(6);1H NMR(300MHz,CDCl3,TMS):δ2.34(s,3H),2.80(dd,1H,J1=5.4Hz,J2=2.7Hz),3.13(dd,1H,J1=5.7Hz,J2=4.2Hz),3.83(dd,1H,J1=3.9Hz,J2=2.4Hz),7.10-7.20(m,4H);IR:νmax 3051,2988,2922,1519,1477,1386,1131,1255,1199,1109,986,881,818cm-1.
(S)-(+)-2-(4-乙基苯基)-环氧乙烷(S)-13.
液体;63%ee;[α]D 16+18.4(c1.4,CHCl3);MSm/z(rel.intensity):149(M+1,4),148(M+,14),131(5),119(62),117(11),115(5),104(9),91(21),77(7);1H NMR(300 MHz,CDCl3,TMS):δ1.23(t,3H,J=7.6Hz),5.30(q,2H,J=7.6Hz),2.80(dd,1H,J1=5.5Hz,J2=2.6Hz),3.13(dd,1H,J1=J2=4.7Hz),3.83(dd,1H,J1=4.0Hz,J2=2.5Hz)7.02-7.25(m,4H);IR:νmax 3057,2967,2874,1908,1617,1519,1384,1255,1128,987,881,834cm-1.
(S)-(-)-2-苯基-环氧乙烷(S)-14.
液体;75%ee;MSm/z(rel.intensity):122(M+2,15),121(M+1,43),120(M+,20),105(100),91(68),77(88);1H NMR(300MHz,CDCl3,TMS):δ2.67(dd,1H,J1=5.7Hz,J2=2.7Hz),3.15(dd,1H,J1=5.4Hz,J2=3.9Hz),3.86(dd,1H,J1=3.9Hz,J2=2.7Hz)7.15-7.45(m,4H);IR:νmax3040,2991,2913,1608,1497,1477,1453,1390,1254,1202,985,877,759,699cm-1.
(S)-(+)-2-((2-三氟甲基苯基)-环氧乙烷(S)-15.
液体;98%ee;[α]D 21+35.4(c0.2,CHCl3);MSm/z(rel.intensity):188(M+,16),187(51),174(33),173(75),159(39),157(30),138(27),119(100),108(25),95(11);1H NMR(300MHz,CDCl3,TMS):δ2.63(dd,1H,J1=6.0Hz,J2=2.7Hz),3.18(dd,1H,J1=5.1Hz,J2=4.5Hz),3.83(dd,1H,J1=J2=1.8Hz)7.20-7.85(m,4H);IR:νmax1655,1606,1458,1316,1168,1121,1060,1035,887,769cm-1.
(S)-(+)-2-((4-腈基苯基)-环氧乙烷(S)-16.
白色固体;mp38-39℃;98%ee;[α]D 25+37.6(c1.99,CHCl3);MSm/z(rel.intensity):145(M+,12);1H NMR(300MHz,CDCl3,TMS):δ2.76(dd,1H,J1=5.5Hz,J2=2.4Hz),3.20(dd,1H,J1=5.4Hz,J2=4.2Hz),3.90(dd,1H,J1=4.0Hz,J2=2.5Hz)7.20-7.85(m,4H);13C-NMR;δ51.5(C1和C2)111.7(CN);118.6;126.1;132.2;143.3(C-Ar)
(R)-(-)-1-(4-硝基苯基)-1,2-乙二醇(R)-17.
黄色固体;mp.89-90℃;94%ee;[α]D 25-19.5(c1.0,EtOH);1H NMR(300MHz,CD3COCD3):δ3.45(br s,2H),3.58(dd,1H,J=11.1,6.7Hz),3.66(dd,1H,J=11.1,4.9Hz),4.85(dd,1H,J=6.7,4.9Hz),8.18,7.69(AB,4H,J=8.7Hz);IR:νmax 3250,1600,1510,1410,1350,1100,1060,850,800,720 cm-1;MS m/z(rel.intensity):184([M+1]+;100),182(2)166(17),152(63),136(26),122(16),106(43),94(35),91(11),78(44).
(R)-(-)-1-(3-硝基苯基)-1,2-乙二醇(R)-18.
黄色固体;mp.76-77℃;79%ee,[α]D 25-13.9(c1.6,EtOH);1H NMR(300MHz,CD3COCD3):δ3.40(br s,2H),3.70-3.50(m,2H),4.87(dd,1H,J1=J2=5.7Hz),7.61(t,1H,J=8.2Hz),7.83(d,1H,J=7.5Hz),8.10(d,1H,J=8.2Hz),8.28(s,1H);MSm/z(rel.intensity):184([M+1]+,5.1),166(70),152(100),136(34.4),105(60),91(16),77(52);IR:νmax3300,1520,1340,1070,1030,860,800,720cm-1.
(R)-(+)-1-(2-硝基苯基)-1,2-乙二醇(R)-19.
淡黄色固体;mp.108-109℃;>99%ee,[α]D 19.5+53.4(c=1.1;EtOH);1H NMR(300MHz,CD3COCD3):δ3.45(br s,2H),3.60(dd,1H,J=11.1,7.0Hz),3.74(dd,1H,J=11.1,4.0Hz),5.28(dd,1H,J=7.0,4.0Hz),7.53(t,1H,J=7.8Hz),7.73(t,1H,J=7.8Hz),7.91-7.86(m,2H);IR:νmax 3250,1610,1530,1065,825,795,750,700cm-1;MSm/z(rel.intensity):184([M+1]+,1.1),166(21),152(88),135(52),104(100),91(54),79(69),77(88).
(R)-(-)-1-(4-氟代苯基)-1,2-乙二醇(R)-20.
白色固体;mp55-56℃,74%ee;[α]D 24-23.5(c1.5,EtOH);MSm/z(rel.intensity):156(M+,2),140(3),139(47),126(6),125(100),123(15),121(5),119(4),109(9),107(4),95(26),91(3),77(38),70(4);1H NMR(300MHz,CD3COCD3,TMS):δ3.29(s,2H),3.45-3.78(m,2H),4.70-4.83(m,1H),7.02-7.20(m,2H),7.22-7.54(m,2H);IR:νmax3207,2934,2878,1608,1512,1470,1245,1234,1105,1086,1033,891,831cm-1.
(R)-(+)-1-(4-氯代苯基)-1,2-乙二醇(R)-21.
白色固体;mp83-84℃;95%ee;[α]D 27+18.7(c1.8,CHCl3);MS:m/z(rel.intensity%):172(M+,2),155(11),141(86),113(26),89(8),77(100),51(21);1H NMR(300MHz,CD3COCD3,TMS):δ3.13(bs,2H),3.52(dd,1H,J1=10.9Hz,J2=7.4Hz),3.60(dd,1H,J1=11.0Hz,J2=4.6Hz),4.71(dd,1H,J1=11.9Hz,J2=4.5Hz),7.30-7.40(m,2H),7.40-7.50(m,2H);IR:νmax 3310,2977,2939,2879,1596,1490,1457,1341,1110,1085,1031,1015,890,823cm-1.
(R)-(-)-1-(3-氯代苯基)-1,2-乙二醇(R)-22.
液体;74%ee;[α]D 24-15.8(c1.1,EtOH);MSm/z(rel.intensity):175,173(M+1,0.38,1.09),174,172(M+,3.65,11.65),143(25),141(80),139(4),125(2),115(10),113(33),105(4),89(4),77(100);1HNMR(300MHz,CD3COCD3,TMS:δ2.92(s,2H),3.59(dd,1H,J1=11.2Hz,J2=8.1Hz),3.73(dd,1H,J1=11.2Hz,J2=2.6Hz),4.76(dd,1H,J1=7.8Hz,J2=2.8Hz)7.01-7.28(m,3H),7.35(s,1H);IR:νmax 3369,2926,2878,1599,1575,1479,1431,1197,1102,1077,1029,786,693cm-1.
(R)-(-)-1-(2-氯代苯基)-1,2-乙二醇(R)-23.
白色固体;mp99-100℃;84%ee;[α]D 23-50.4(c1.7,EtOH);MSm/z(rel.intensity):172(M+,1.8),143(38),141(100),113(24),77(70);1NMR(300 MHz,CD3COCD3,TMS):δ3.39(dd,1H,J1=11.2Hz,J2=7.8Hz),3.46(bs,2H),3.69(dd,1H,J1=11.2Hz,J2=3.0Hz),5.12(dd,1H,J1=7.8Hz,J2=3.0Hz),7.61-7.29(m,4H);IR:νmax3300,1635,1440,1070,1040,760cm-1.
(R)-(-)-1-(4-溴代苯基)-1,2-乙二醇(R)-24.
白色固体;mp104-105℃;86%ee;[α]D 23-41.4(c1.2,EtOH);MSm/z(rel.intensity):218,216)(M+,3,3),187(71),185(83),159(16),157(19),77(100),51(18);1H NMR(300MHz,CD3COCD3,TMS)δ3.26(bs,2H),3.53(dd,1H,J1=11.4Hz,J2=7.5Hz),3.61(dd,1H,J1=11.1Hz,J2=4.8Hz),4.70(dd,1H,J1=7.5Hz,J2=4.8Hz),7.20-7.38(m,2H),7.40-7.60(m,2H);IR:νmax 3051,2991,2919,1595,1490,1073,1011,828cm-1.
(R)-(-)-1-(3-溴代苯基)-1,2-乙二醇(R)-25.
液体;70%ee;[α]D 23-8.5(c1.2,EtOH);MS:m/z(rel.intensity%):218,216(M+,8),191(22),187(70),185(74),157(34),117(7),105(12),81(21),77(100);1H NMR(300MHz,CDCl3,TMS):δ3.50-2.80(bs,2H),3.58-3.85(m,2H),4.74(dd,1H,J1=8.2Hz,J2=3.3Hz),7.12-7.52(m,3H),7.55(s,1H);IR:νmax 3260,2918,1656,1594,1569,1415,1193,1111,1068,1057,1022,995,906,779,695 cm-1.
(R)-(-)-1-(2-溴代苯基)-1,2-乙二醇(R)-26.
白色固体;mp118-119℃80%ee;[α]D 18-24.8(c1.3,EtOH);MSm/z(rel.intensity):219,217(M+1,0.3,0.2),218,216(M+,2,2),201(2),199(2),188(7),187(72),185(76),159(15),157(19),155(3),137(3),119(3),107(2),105(11),91(5),89(6),78(44),77(100);1HNMR(300MHz,CD3COCD3,TMS):δ3.29(s,2H),3.42(dd,1H,J1=11.2Hz,J2=7.9Hz),3.74(dd,1H,J1=11.2Hz,J2=3.1Hz),5.07(dd,1H,J1=7.9Hz,J2=3.1Hz)7.20(ddd,1H,J1=J2=7.7Hz,J3=1.8Hz),7.39(ddd,1H,J1=J2=7.4Hz,J3=1.2Hz),7.54(ddd,1H,J1=J2=8.0Hz,J3=1.2Hz),7.66(dd,1H,J1=7.8Hz,J2=1.6Hz);IR:νmax 3276,2923,1589,1568,1467,1431,1363,1193,1127,1093,1069,1023,953,898,836,756cm-1.
(R)-(-)-1-(4-碘代苯基)-1,2-乙二醇(R)-27.
白色固体;mp120-121℃ 72%ee;[α]D 27-17.7(c1.1,EtOH);MSm/z(rel.intensity):265(M+1,3),264(M+,30),234(13),233(100),205(3),141(11),127(3),107(25),105(21),79(25),78(99);1H NMR(300MHz,CD3COCD3,TMS):δ3.25(s,2H),3.52(dd,1H,J1=11.0Hz,J2=7.6Hz),3.61(dd,1H,J1=11.2Hz,J2=4.2Hz),4.70(dd,1H,J1=7.6Hz,J2=4.3Hz),7.20,7.66(AB,4H,J=8.1Hz);IR:νmax 3369,2923,1586,1484,1396,1092,1066,1034,1023,1006,895,832,821,523cm-1.
(R)-(-)-1-(4-甲基苯基)-1,2-乙二醇(R)-28.
白色固体;mp68-69℃;63%ee;[α]D 27-48.1(c1.1,EtOH);MSm/z(rel.intensity):152(M+2.4),135(11),121(100),105(5),93(45),77(25),65(6);1H NMR(300MHz,CD3COCD3,TMS):δ2.32(s,3H),3.18(bs,2H),3.50(dd,1H,J1=11.1Hz,J2=8.1Hz),3.60(dd,1H,J1=11.1Hz,J2=4.2Hz),4.68(dd,1H,J1=7.8Hz,J2=4.2Hz),7.14,7.28(AB,4H,J=7.8Hz);IR:νax 3264,2921,2863,1515,1347,1097,1070,1033,900,849,819cm-1.
(R)-(-)-1-(4-乙基苯基)-1,2-乙二醇(R)-29.
白色固体;mp64-65℃,;70%ee;[α]D 23-23.8(c1.2,EtOH);MSm/z(rel.intensity):166(M+,0.16),165(2),155(1),149(100),136(3),135(51),133(7),131(64),120(4),105(6),91(20),79(39);1H NMR(300MHz,CD3COCD3,TMS):δ1.23(t,3H,J=5.2Hz),2.65(q,2H,J=7.6Hz)2.74-3.15(bs,2H),3.60-3.78(m,2H),4.78(dd,1H,J1=8.0Hz,J2=3.5Hz),7.20,7.26(AB,4H,J=8.1Hz);IR:νmax 3259,2959,2921,2867,1513,1456,1358,1097,1072,1050,1031,900,849,831cm-1.
(R)-1-(-)-苯基-1,2-乙二醇(R)-30.
白色固体;mp:66-67℃;52%ee;MS:m/z(rel.intensity%):138(M+,3),121(11),107(100),79(85),77(65),63(4),51(14);1H NMR(300MHz,CDCl3,TMS)δ2.92(bs,2H),3.56-3.81(m,2H),4.82(dd,1H,J1=8.1Hz,J2=3.3Hz),7.26-7.50(m,5H);IR:νmax 3203,3061,3030,2934,1469,1448,1343,1228,1101,1089,1054,887,833,760,748,699cm-1.
(R)-(-)-1-((2-三氟甲基苯基)-1,2-乙二醇(R)-31.
白色固体;mp66-67℃;82%ee;[α]D 21-38.4(c0.5,EtOH);MS:m/z(rel.intensity%):206(M+,4),175(44),173(25),155(100),145(18),127(55);1H NMR(300MHz,CD3COCD3,TMS):δ):δ3.18(bs,2H),3.48(dd,1H,J1=11.4Hz,J2=8.1Hz),3.54(dd,1H,J1=11.1Hz,J2=3.0Hz),5.10(dd,1H,J1=8.1Hz,J2=1.5Hz),7.40-7.56(m,1H),7.58-7.78(m,2H),7.82-7.98(m,1H);IR:νmax 3323,2939,2877,1610,1586,1456,1316,1164,1110,1025,770,755,667cm-1.
(R)-(-)-1-((4-腈基苯基)-1,2-乙二醇(R)-32.
白色固体;mp78-79℃;82%ee;[α]D 21-19.8(c0.5,EtOH);MS:m/z(rel.intensity%):163(M+,4);1H NMR(300MHz,CD3COCD3,TMS):δ):δ3.51-+3.65(m,2H),3.93(t,1H,OH,J=6.0Hz),4.65(d,1H,OH,J=4.0Hz),4.75-4.83(m,1H),7.62,8.11(AB,4H,J=8.8Hz).13C-NMRδ:68.4,74.5,123.8,128.2,146.3,151.6
实施例2对双取代的环氧苯乙烷类
底物的对映选择性拆分
取新鲜培养的黑曲霉CGMCC 0496湿菌体10g投入100ml磷酸缓冲体系(PH=8),水浴并控制温度在25-26℃,加入200mg或100mg双取代环氧乙烷类底物,机械搅拌(800转/分钟),用TLC跟踪反应进程。当反应进行到如表上所示时间时,过滤除去菌体(菌体用乙酸乙酯浸泡12小时)反应液用NaCl进行饱合,用乙酸乙酯萃取3次,合并有机层。除去溶剂用1∶20(乙酸乙酯∶石油醚)进行快速柱层析得(S)-构型的剩余环氧;再改用1∶3(乙酸乙酯∶石油醚)得(R)-构型的二醇产物。反应情况如下表:
表2.
编 取代基位 反应时 手性环 手性环氧 二醇产物 二醇产
号 置 间(分 氧化合物 化合物的 (产率(%)) 物的ee.
钟) (产率 ee.值 值
(%))
33 2,3-二氯 122 (S)-31a 95% (R)-31b 84%
(27) (34)
34 2,4-二氯 23 (S)-32a >99% (R)-32b 95%
(15) (26)
35 2,5-二氯 73 (S)-33a 58% (R)-33b 95%
(40) (39)
36 2,6-二氯 3小时后无明显水解
37 3,4-二氯 46 (S)-35a 63% (R)-35b 90%
(40) (37)
38 2,4-二甲 20 (S)-38a 98% (R)-38b 96%
基 (37) (36)
39 3,5-二氯 3小时后无明显水解
a:所有反应中菌体与底物的重量比为15g湿菌体加入200mg底物。
上述化合物分析结果如下:
(S)-(+)-2-(2,3-二氯代苯基)-环氧乙烷;(+)-33aColorless oil;e.e.=95%;[α]D 18.5+55.9(c0.6,CHCl3);MSm/z(rel.intensity):193,191,189(M+1,1.0,6.1,18.2),192,190,188(M+,7,19,19),155(55),153(56),127(11),125(65),123(100),111(8),89(22);1H NMR(300MHz,CDCl3,TMS):δ2.63(dd,1H,J1=5.7Hz,J2=2.7Hz),3.21(dd,1H,J1=6.0Hz,J2=4.2Hz),4.20(dd,1H,J1=4.2Hz,J2=2.7Hz),7.16-7.35(m,2H),7.36-7.50(m,1H);IR:νmax 3067,2992,1425,1116,1047,889,781cm-1;元素分析(计算值:C:50.83%;H:3.20%;Cl:37.51%) 分析值:C,50.87%;H,3.26%;Cl,37.61%.
(S)-(+)-2-(2,4-二氯代苯基)-环氧乙烷;(±)-34a
液体;e.e.>99%;[α]D 23+31.4(c 1.7,CHCl3);Colorless oil;MSm/z(rel.intensity):193,191,189(M+1,0.2,1.4,2.2),192,190,188(M+3,15,23),163(12),161(68),159(100),127(10),125(46),123(45),99(7),89(29);1H NMR(300MHz,CDCl3,TMS):δ2.63(dd,1H,J1=5.5Hz,J2=2.3Hz),3.19(dd,1H,J1=5.9Hz,J2=4.3Hz),4.15(dd,1H,J1=4.1Hz,J2=2.6Hz),7.05-7.30(m,2H),7.37(d,1H,J=2.0Hz);IR:νmax3060,2993,1480,1100,1052,880,825cm-1;元素分析(计算值:C:50.83%;H:3.20%;Cl:37.51%) 分析值:C,50.91%;H,3.20%;Cl,37.60%.
(S)-(+)-2-(2,5-二氯代苯基)-环氧乙烷;(±)-35a
液体;e.e.=58%;[α]D 16 16.2(c1.1,CHCl3);Colorless oil;MSm/z(rel.intensity):193,191,189(M+1,0.4,2.6,8.9),192,190,188(M+,3,13,20),155(31),153(91),127(10),125(62),124(12),123(100),109(5),89(18);1H NMR(300MHz,CDCl3,TMS):δ2.64(dd,1H,J1=5.4Hz,J2=2.4Hz),3.19(dd,1H,J1=6.6Hz,J2=4.8Hz),4.15(dd,1H,J1=3.9 Hz,J2=2.7 Hz),7.05-7.30(m,3H);IR∶νmax 3064,2995,1464,1094,1052,813cm-1.元素分析(计算值:C:50.83%;H:3.20%;Cl:37.51%) 分析值:C,50.60%;H,3.24%;Cl,37.46%.
(S)-(+)-2-(3,4-二氯代苯基)-环氧乙烷;(±)-37a
液体;e.e.=63%;[α]D 19 15.3(c0.5,CHCl3);Colorless oil;MSm/z(rel.intensity):193,191,189(M+1,0.2,4.6,16.5),192,190,188(M+,3,11,16),161(23),159(37),155(30),153(71),127(11),123(100),118(2),109(5),89(12);1H NMR(300MHz,CDCl3,TMS):δ2.74(dd,1H,J1=5.4Hz,J2=2.4Hz),3.15(dd,1H,J1=5.1Hz,J2=4.2Hz),3.82(dd,1H,J1=3.9Hz,J2=3.0Hz),7.12(dd,1H,J1=8.4Hz,J2=2.1Hz),7.35-7.55(m,2H);IR:νmax 3058,2921,1470,1371,1133,1031,882,821cm-1;元素分析(计算值:C:50.83%;H:3.20%;Cl:37.51%)分析值:C,50.58%;H,3.21%;Cl,37.55%.
(S)-(+)-2-(3,4-二甲基苯基)-环氧乙烷;(±)-38a
液体;e.e.=98%;[α]D 19 35.4(c0.5,CHCl3);MSm/z(rel.intensity):148(M+,15)m 1H NMR(300MHz,CDCl3,TMS):δ2.30(s,3H),2.34(s,3H),2.65(dd,1H),3.10(dd,1H,),3.90(dd,1H),6.95-7.10(m,3H);13C-NMRδ19.1,25.5,50.5,50.6,51.0,124.6,127.2,131.1,133.3,136.6,137.7.
(R)-(-)-1-(2,3-二氯代苯基)-1,2-乙二醇;(-)-33b
白色固体;e.e.=84%;mp.126-127℃;[α]D 18.5-52.7(c1.4,EtOH);MS:m/z(rel.intensity%):210,208,206(M+,0.0,0.6,1.7),189(7),179(11),177(65),175(100),153(3),149(23),147(35),113(22),111(65),89(3);1H NMR(300MHz,CD3COCD3,TMS)δ3.25(bs,2H),3.49(dd,1H,J1=11.4Hz,J2=7.5Hz),3.76(dd,1H,J1=11.1Hz,J2=3.0Hz),5.17(dd,1H,J1=7.5 Hz,J2=3.3Hz),7.35-7.45(m,1H),7.47-7.58(m,1H),7.60-7.75(m,1H);IR:νmax3366,3223,2945,1452,1419,1401,1180,1100,1070,1041,860,782cm-1;元素分析(计算值:C:46.41%;H:3.89%;Cl:34.24%) 分析值:C,46.24%;H,4.04%;Cl,34.27%.
(R)-(-)-1-(2,4-二氯代苯基)-1,2-乙二醇;(-)-34b
白色固体;e.e.=95%;mp.77-78℃;[α]D 23-62.5(c 1.6,EtOH);MS:m/z(rel.intensity%):179,177,175(M+-CH2OH,10,62,100),149(10),147(16),139(5),113(22),111(68),89(3);1H NMR(300MHz,CD3COCD3,TMS)1H NMR(300MHz,CD3OCD3,TMS):δ3.26(bs,2H),3.46(dd,1H,J1=11.3Hz,J2=7.3Hz),3.71(dd,1H,J1=11.3Hz,J2=3.3Hz),5.09(dd,1H,J1=7.4Hz,J2=3.4Hz),7.30-7.45(m,2H),7.66(d,1H,J=8.4Hz);IR:νmax 3253,2961,2943,1590,1559,1466,1375,1349,1270,1190,1093,1062,1046,1025,869,819,778cm-1;元素分析(计算值:C:46.41%;H:3.89%;Cl:34.24%)分析值:C,46.52%;H,4.11%;Cl,34.29%.
(R)-(-)-1-(2,5-二氯代苯基)-1,2-乙二醇;(-)-35b
白色固体;e.e.=95%;mp.59-60℃;[α]D 13-52.1(c1.4,EtOH);MS:m/z(rel.intensity%):210,208,206(M+,1.3,8.1,12.6),179(10),177(61),175(100),149(19),147(32),141(5),139(6),113(25),111(75),75(27);1H NMR(300MHz,CD3COCD3,TMS)δ3.28(bs,2H),3.49(dd,1H,J1=11.1Hz,J2=7.2Hz),3.76(dd,1H,J1=11.1Hz,J2=3.0Hz),5.11(dd,1H,J1=6.9Hz,J2=2.7Hz),7.35-7.45(m,2H),7.47-7.58(m,1H);IR:νmax 3293,3191,2923 1462,1191,1104,1093,1037,1023,900,811cm-1;元素分析(计算值:C:46.41%;H:3.89%;Cl:34.24%)分析值:C,46.42%;H,3.85%;Cl,34.15%.
(R)-(-)-1-(3,4-二氯代苯基)-1,2-乙二醇;(-)-37b
液体;e.e.=90%;[α]D 19-14.2(c1.2,EtOH);MS:m/z(rel.intensity%):210,208,206(M+,0.0,2.4,3.8),189(4),179(11),177(64),175(100),171(7),149(22),147(38),141(3),113(25),111(75),75(18);1H NMR(300MHz,CD3COCD3,TMS)δ3.27(bs,2H),3.57(dd,1H,J1=11.1Hz,J2=6.9Hz),3.63(dd,1H,J1=11.4Hz,J2=5.1Hz),4.73(dd,1H,J1=6.9Hz,J2=4.8Hz),7.37(dd,1H,J1=8.1Hz,J2=1.8Hz),7.51(d,1H,J=8.4Hz),7.60(d,1H,J=1.8Hz);IR:νmax 3369,2929,1469,1392,1084,1031,822cm-1;元素分析(计算值:C:46.41%;H:3.89%;Cl:34.24%)分析值:C,46.56%;H,4.15%;Cl,34.32%.
(R)-(-)-1-(3,4-二 甲基苯基)-1,2-乙二醇;(-)-38b
白色固体;mp.64-65℃;[α]D 25-71.2(c 1.2,EtOH);MS:m/z(rel.intensity%):166(M+,15);1H NMR(300MHz,CD3COCD3,TMS)δ2.30(s,6H),2.71(s,1H),2.90(s,1H),3.55-3.75(m,2H),5.02(dd,1H),6.90-7.10(m,2H),7.35(d,1H).13C-NMR δ18.9,20.9,66.9,71.3,125.6,126.9,131.2,134.7,135.5,137.4;IR:νmax 3263,3020,2931,1261,1087,1026,796cm-1.
实施例3对具有多环芳烃取代的环氧乙烷
类化合物的对映选择性拆分
取新鲜培养的黑曲霉CGMCC 0496湿菌体10g投入100mL磷酸缓冲体系(PH=8),水浴并控制温度在24-26℃,加入200mg或100mg萘基环氧乙烷类底物(溶于2mLDMF),机械搅拌(800转/分钟),用TLC跟踪反应进程。当反应进行到如表上所示时间时,过滤除去菌体(菌体用乙酸乙酯浸泡12小时)反应液用NaCl进行饱合,用乙酸乙酯萃取3次,合并有机层。除去溶剂用1∶10(乙酸乙酯∶石油醚)进行快速柱层析得(S)-构型的剩余环氧;再改用1∶1(乙酸乙酯∶石油醚)得(R)-构型的二醇产物。
反应情况列于下表:
R1=H;α-(±)-40 R1=H;α-(±)40a R1=H;α-(±)-40b
R1=7-Cl;α-(±)-41 R1=7-Cl;α-(±)-41a R1=7-Cl;α-(±)-41b
R1=H;β-(±)-42 R1=H;β-(±)-42a R1=H;β-(±)-42b
表3
底物 底物/菌体 反应时间 手性环氧 手性环 二醇产率 二醇
编号 化合物 氧化合 % e.e.值
产率% 物e.e.值
α-(±)- 210mg/10g 36min ((S)-40a) 32%(S) ((R)-40b) 94%(R)
40 33 19
α-(±)- 140mg/10g 37min ((S)-40a) 80%(S) ((R)-40b) 87%(R)
40 32 44
α-(±)- 140mg/10g 37min ((S)-41a) 82%(S) ((R)-41b) 85%(R)
41 38 40
β-(±)-42 210mg/10g 117min ((S)-41b) 43%(S) ((R)-42b) 85%(R)
48 47
β-(±)-42 140mg/10g 106min ((S)-41b) 60%(S) ((R)-42b) 78%(R)
45 37
上述化合物分析结果如下:
(S)-(+)-2-(1-萘基)-环氧乙烷;(S)-40a
液体:e.e.=32%;[α]D 16 28.6(c2.3,CHCl3);MSm/z(rel.intensity):171(M+1,4),170(M+,27),142(24),141(100),139(15),115(34).1H NMR(90MHz,CCl4,TMS):δ2.6(dd,1H,J1=9Hz,J2=4Hz),3.2(dd,1H,J1=9Hz,J2=6Hz),4.3(dd,1H,J1=J2=3Hz),7.3-8.4(m,7H).IR:νmax 3052,2989,1597,1515,1017,974,884,800cm-1.
(S)-(+)-2-(1-(7-氯代)-萘基)-环氧乙烷;(S)-41a
白色固体;mp40-41℃;e.e.=82%;[α]D 15 48.6(c0.2,CHCl3);MSm/z(rel.intensity):204(M+,21);1H NMR(90MHz,CCl4,TMS):δ2.6(dd,1H,J1=9Hz,J2=3.5Hz),3.2(dd,1H,J1=9Hz,J2=5.5Hz),4.3(dd,1H,J1=J2=3.5Hz),7.3-8.4(m,6H).元素分析(计算值:C:70.43%;H:4.43%;Cl:17.32%;)分析值:C:70.34%;H:4.40%;Cl:17.38%。
(S)-(-)-2-(2-萘基)-环氧乙烷;(S)-42a
白色固体;mp=57-58℃;e.e.=43%;[α]D 16-7.1(c 1.2,CHCl3);MSm/z(rel.intensity):171(M+1,12),170(M+,48),169(36),154(17),149(10),141(100),139(57),127(11),122(14),115(25).1H NMR(90MHz,CCl4,TMS):δ2.7(dd,1H,J1=6Hz,J2=2.5Hz),3.1(dd,1H,J1=J2=6Hz),3.9(dd,1H,J1=J2=3Hz),6.9-7.8(m,7H).IR:νmax 3055,2993,160 1,1509,1336,893,846,822,742cm-1.
(R)-(-)-2-(1-萘基)-乙二醇;(R)-40b
白色固体;mp=118-119℃;e.e.=94%;[α]D 16-61.7(c2.3,EtOH);MSm/z(rel.intensity):189(M+1,3),188(M+,20),169(1),157(94),129(100),77(7);1H NMR(300MHz,CD3COCD3,TMS):δ3.26(bs,2H),3.65-3.84(m,2H),4.94(dd,1H,J1=7.6Hz,J2=4.3Hz),7.45-8.04(m,7H);IR:νmax 3252,3158,2930,1596,1509,1375,1108,1066,1041cm-1.
(R)-(-)-2-(1-(7-氯代)-萘基)-乙二醇;(R)-41b
白色固体;mp=124-125℃;e.e.=85%;[α]D 16-60.4(c0.3,EtOH);MSm/z(rel.intensity):222(M+,3);1H NMR(300MHz,CD3COCD3,TMS):δ3.20(bs,2H),3.55-3.80(m,2H),4.92(dd,1H),7.45-8.04(m,6H);元素分析(计算值:C:64.73%;H:4.98%;Cl:15.92%;)分析值:C:64.77%;H:5.01%;Cl:15.38%。
(R)-(-)-2-(2-萘基)-乙二醇;(R)-42b
白色固体;mp=126-127℃;e.e.=85%;[α]D 18-32.3(c0.5,EtOH);;MSm/z(rel.intensity):189(M+1,7),188(M+,41),157(100),129(97),127(45),102(4),77(5).1H NMR(300MHz,CD3COCD3,TMS):δ3.26(s,2H),3.64(dd,1H,J1=11.1Hz,J2=7.7Hz),3.73(dd,1H,J1=10.9Hz,J2=6.6Hz),4.90(dd,1H,J1=7.6Hz,J2=4.3Hz),7.32-7.58(m,3H),7.82-8.01(m,4H).IR:νmax 3199,3052,2936,2874,1600,1469,1093,1045,1037,903,856,820,742cm-1.
实施例4对吡啶环氧乙烷类底物
的对映选择性拆分
取新鲜培养的黑曲霉CGMCC 0496湿菌体20g投入100ml磷酸缓冲体系(PH=8),水浴并控制温度在25-26℃,加入200mg吡啶环氧乙烷类底物,机械搅拌(800转/分钟),用TLC跟踪反应进程。当反应进行到如表上所示时间时,过滤除去菌体(菌体用乙酸乙酯浸泡12小时)反应液用NaCl进行饱合,用乙酸乙酯萃取3次,合并有机层。除去溶剂用1∶20(乙酸乙酯∶石油醚)进行快速柱层析得(S)-构型的剩余环氧;再改用1∶3(乙酸乙酯∶石油醚)得(R)-构型的二醇产物。反应情况如下表:
环氧位 反应时 环氧产 环氧ee 二醇 产二醇ee置 间 率 值 率 值(±)-43 205分钟 31;((S)- 98(S) 38;((R)- 50(R)
43a) 43b)(±)-44 226分钟 28;((S)- 95(S) 41;((R)- 48(R)
44a) 44b)(±)-45 198分钟 32;((S)- 97(S) 39;((R)- 52(R)
45a) 45b)
上述化合物分析结果如下:
(S)-(+)-2-吡啶环氧乙烷;(S)-43a
液体:e.e.=98%;[α]D 19 13.8(c2.3,CHCl3);MS/z(rel.intensity):121(M+,26).1H NMR(250MHz,CDCl3,TMS):δ2.78(dd,1H,J1=5Hz,J2=2.5Hz),2.99(dd,1H,J1=5Hz,J2=3.5Hz),3.84(dd,1H,J1=2.5Hz,J2=3.75Hz),7.02-7.08(m,2H),7.50(t,1H);8.39(d,1H,J=5Hz).13C-NMR:δ50.38,52.81,119.69,123.12,136.82,149.39,157.18.
(S)-(+)-3-吡啶环氧乙烷;(S)-44a
液体:e.e.=95%;[α]D 19 18.8(c1.3,CHCl3);MSm/z(rel.intensity):121(M+,26).1H NMR(250MHz,CDCl3,TMS):δ2.83(dd,1H,J1=5.3Hz,J2=2.51Hz),3.20(dd,1H,J1=5.26Hz,J2=4.1Hz),3.90(dd,1H,J1=3.87Hz,J2=2.7Hz),7.25-7.31(m,1H),7.52-7.57(m,1H),8.55-8.59(m, 2H).13C-NMR:δ50.38,51.1,123.46,132.73,147.88,149.62.
(S)-(+)-4-吡啶环氧乙烷;(s)-45a
液体:e.e.=97%;[α]D 19 28.0(c1.1,CHCl3);MSm/z(rel.intensity):121(M+,26).1H NMR(250MHz,CDCl3,TMS):δ2.77(dd,1H,J1=5.6Hz,J2=2.5Hz),3.20(dd,1H,J1=5.6Hz,J2=4.2Hz),3.85(dd,1H,J1=4.0Hz,J2=2.5Hz),7.21(dd,1H,J1=4.5Hz,J2=1.5Hz);8.58(d,2H,J=5.7Hz).13C-NMR:δ50.95,51.33,120.36,146.96,149.93.
(R)-(-)-2-吡啶乙二醇;(R)-43b
白色固体;mp=89-90℃;e.e.=50%;[α]D 16-32.4(c1.1,EtOH);MSm/z(rel.intensity):139(M+,17);1H NMR(250MHz,CD3COCD3,TMS):δ3.64(dd,1H,J1=10.8Hz,J2=5.6Hz),3.82(dd,1H,J1=11.3Hz,J2=6.1Hz),3.97-3.94(m,1H,OH),4.66(d,1H,J=4.95Hz),4.77-4.73(m,1H),7.28-7.24(m,1H),7.56(d,1H,J=7.8Hz);7.82-7.75(m,1H);8.51(d,1H,J=4.5Hz);13C-NMR:δ67.81,75.06,121.59,123.07,137.32,149.12,162.57.
(R)-(-)-3-吡啶乙二醇;(R)-44b
白色固体;e.e.=48%;[α]D 16-22.4(c1.0,EtOH);MSm/z(rel.intensity):139(M+,14);1H NMR(250MHz,CD3COCD3,TMS):δ3.69-3.58(m,2H);4.10(s,1H,OH),4.66(s,1H,OH),4.8-4.78(m,1H),7.34(dd,1H,J1=7.86Hz,J2=4.75Hz),7.81-7.77(m,1H),8.60-8.44(m,2H).13C-NMR:δ68.45,73.16,123.91,134.63,139.00,149.07,149.28.
(R)-(-)-3-吡啶乙二醇;(R)-45b
白色固体;mp71-73℃;e.e.=52%;[α]D 16-10.9(c0.8,EtOH);MSm/z(rel.intensity):139(M+,10);1H NMR(250MHz,CD3COCD3,TMS):δ3.67-3.58(m,2H);4.03(s,1H,OH),4.66(s,1H,OH),4.74(s,1H),7.40-7.37(m,2H),8.52-8.49(m,2H).13C-NMR:δ68.22,73.96,122.27,150.13,152.59.
Claims (5)
1.一种由黑曲霉(Asperillus niger CGMCC 0496)菌体产生的环氧水解酶不对称催化水解取代芳基环氧乙烷类化合物生成具有光学活性的环氧化合物与手性二醇产物的方法,在20-35℃下和pH=5.0-9.50的0.01-0.3M的磷酸缓冲溶液及助溶剂N,N-二甲基甲酰胺中,湿的黑曲霉菌体与芳基环氧乙烷类化合物重量比是20~500∶1,催化反应时间0.01~120小时,所述的芳基环氧乙烷类化合物的结构式为
其中Ar=苯基、萘基或吡啶基,R1或R2=H、C1-4的烷基、NO2、CN、CF3或X,X=F、Cl、Br或I,终止反应并提取分离光学活性的环氧化合物和手性二醇产物,所述的光学活性的环氧化合物的绝对构型是S构型,结构式为
所述的手性二醇的绝对构型是R构型,结构式为
2.如权利要求1所述的方法,其特征是所述的反应时间为0.2~3小时。
3.如权利要求1所述的方法,其特征是所述的湿的黑曲霉菌体与芳基环氧乙烷类化合物重量比是50~200∶1。
4.如权利要求1所述的方法,其特征是所述的芳基环氧乙烷类化合物在反应器中的浓度为0.1g/L至20g/L。
5.如权利要求1所述的方法,其特征是通过快速过滤菌体终止反应。
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