β-榄香烯烃基硒醚的一锅法合成

2008年第28卷有机化学vl.28.2008第8期,1428~1432Chinese Joumal of Organic ChemistryNo.8,1428~1432·研究论文·β-榄香烯烃基硒醚的一锅法合成尹红星“张殊佳郑学仿*b杨兰义(大连大学环境与化学工程学院大连116622)大连大学辽宁省生物有机化学重点实验室大连1162)摘要常温下将硒用N2HH2O还原后与卤代烃反应得到对称二硒醚,不经分离直接用NaBH还原,再与13-氟B榄香烯作用得到β-榄香烯烃基硎醚.此一锅法操作简便、条件温和、反应快速而且产率较髙,是合成不对称硒醚的一种简便实用的方法.对化合物g的初步生物活性实验表明其具有显著的抗氧化作用关健词β榄香烯;不对称硒醚;一锅法;抗氧化作用One-Pot Synthesis of B-Elemene-13-yl Alkyl SelenidesYIN, Hong-Xing ZHANG, Shu-Jia. ZHENG, Xue-Fang*YANG, Lan-YiC College of Environment and Chemical Engineering, Dalian University, Dalian 116622)c Liaoning Key Laboratory of Bioorganic Chemistry, Dalian University, Dalian 116622Abstract A convenient and efficient procedure is described for the preparation of B-elemene-13-yl alkylselenides by treatment of selenium with N2H4H2O/R/NaBH413-chloro-p-elemene sequentially in one-potat room temperature. This method has several advantages such as simple operation, short reaction time, mildconditions and high yields. It also provides a convenient and efficient way to the synthesis of unsymmetricaldialkyl selenides. The preliminary bioassay showed that product g exhibited notable antioxidation activity.Keywords B-elemene; unsymmetrical selenide; one-pot procedure; antioxidationβ榄香烯是从中药温莪术中分离出来的一种有效物的抗癌成分,以其为主要成分的榄香烯乳剂已批量生有关不对称硒醚的合成,传统方法基本上都是从对产并广泛应用于临床.以B榄香烯为先导化合物,对其称二硒醚出发,断开SeSe键,再与另一种卤代烃反应进行结构修饰,深入研究其构效关系,对进一步进行分而得到46如果从单质硒出发,则必须先合成、分子设计,寻找具有高效、低毒的抗肿瘤新药具有重要的离得到对称二硒醚,才能进行下一步反应.步骤较多,理论和现实意义,硒是人体必需的微量元素,具有显著操作繁琐,需要花费较长时间.尽管以前偶尔有文献报的抗肿瘤1、抗氧化等多种生物活性,故我们设想将硒道从单质硒出发一锅法合成不对称硒醚,但都存在着需和B榄香烯相结合,在不破坏尸榄香烯骨架结构的前提要严格控制反应温度以及时间过长等缺点.本文下,合成B榄香烯烃基硒醚类化合物,使分子中既保持在以前研究的基础上,采用了一种新的一锅法成功地合榄香烯的基本骨架,又含有硒这一新的活性基团,这样成了B-榄香烯烃基不对称硒醚 Scheme1).与传统方法有可能增加作用靶点,促使其活性叠加或提高,从而发相比,具有操作简便、条件温和、反应快速、产率较高现活性更高的药物,同时为进一步的分子设计提供实验等依据.另外也有可能发现新的具有抗氧化等活性的药中国煤化工CNMHG.e-mAil:dlxfzheng@163.comReceived January 24, 2008; revised March 11, 2008: accepted April 10, 2008国家自然科学基金(No20271010)、辽宁省优秀人才培养计划(No.Rc0410)和辽宁省高校创新团队(No.2006T002)资助项目No 8尹红星等:β榄香烯烃基硒醚的一锅法合成14293351254, found335.1262β-榄香烯丙基硒醚(b):无色油状物;HNMR()N2H4H2O, NaOH/DMF(CDCl3,500MHz)098(t,J=73Hz,3H,CH3),1.01(,RSe Na()RX:(ii)NaBH43H,CH3),142~1.69(m,8H,CH2),1.71(s,3H,CH3y)204(dd,J=4.15,11.8Hz,1H,CH),220~2.26(m,1H,cH,247(t,J=74Hz,2H,CH2),3.24(s,2H,CH2),2),582(dd,J=10.95,174Hz,IH,=CH);C NMR(CDCI3, 125 MHz)8: 14.6, 16.7235,248,261,27.7,29.1,33.7,399,40.0,41.9,528109.9,110.1,112.2,147.7,150.2,150.8;IR(film)v:3079,1实验部分2965,2925,2851,1635,1434,1418,1373,1279,1185,1011, 909, 890 cm HRMS-ESI calcd for Cl8H3oSe(M+1.1仪器和试剂Na):349.1410, found349.1412红外光谱用 Nicolet ft-IR型红外光谱仪;核磁共振β-榄香烯丁基硒醚(c):浅黄色油状物;"HNMR用 Bruker Av500核磁共振仪(用CDCl3作溶剂,除了 a(CDCl2.500MHz):0.91(,J=7.35Hz,3H,CH3),1.01的硒谱以Me2Se为内标外,其余以TMS为内标);高分s,3HCH,1.36~1.70(m,10HCH2),171(s,3H,CH3),辨质谱用 Bruker A PeXⅡ高分辨质谱仪;柱层析用硅胶204(dd,J=4.l,11.85Hz,1H,CH),2.20~2.26(m,IH,(200~300目)由青岛海洋化工厂生产;薄层硅胶板CH,248〔,J=7.5H,2H,CH2),3.25(s,2H,CH2),(GF254)由烟台康必诺化学试剂厂生产.榄香烯由中国4.59~493(m,6H,=CH2),5.82(dd,J=10.9,1745Hz科学院大连化学物理研究所提供;所用其它试剂均为市H,=CH;"cNMR(CDCl,125MHz)13.6,16.7,售分析纯.13氯B榄香烯参照文献14]制备23.1,23.7,24.8,27.7,29.1,32.4,33.7,39.9,40.0,41.9,12β-榄香烯烃基硒醚类化合物的合成52.8,1099,110.1,1122,1477,150.3,1508;IR(film)v向一装有磁力搅拌装置的三颈瓶中加入048(53079,2952,2851,1635,1434,1414,1373,1259,1185,mmo)Se粉、0.3g(75mmol)NaOH固体和10mh1004, 906, 890 cm- HRMS-ESI caled for CIgH3 Se(M+DMF,氮气保护.缓慢滴入含有NHH2O1.5mmo的Na):363.1567, found3631574.DMF溶液5mL,室温搅拌15min,然后缓慢加入卤代B榄香烯异戊基硒醚(d):浅黄色油状物;HNMR烃5mmol.搅拌1h后,加入NaBH40.57g(15mmol)(CDCl,500MHz):0.89(d,J=6.6Hz,6H,CH3),1.01反应剧烈,大量气泡产生,15min后,再缓慢滴加13.(s.3cH,143-170im,9cHch,1.n1(s.3H氯榄香烯19g(5ml),继续室温反应1h抽滤,cH1,204,J=40,119 Hz, IH, CH.2.20-22(m石油醚萃取(5mL×3)合并有机相,用水(20m对有HcH.248(J=,7H,2H,CH),326(.3H,cCH),机相洗1次,分出有机相,无水Na2SO4干燥.减压蒸去59~492(m,6H,=CH2),582(dd,J=10.9,174H,溶剂,粗产品用柱色谱分离200~300目硅胶石油醚H,=CH;"cMMR(CDCl125MHz):167,21.8,洗脱)提纯223,24.8,27.7,28.6,29.0,33.7,394,39.8,40.0,41.9,β榄香烯乙基硒醚(a):无色油状物;HNMR52.8,109.9,110.1,112.2,1477,150.2,150.7;IR(film)v(CDCl3,500MH)1.01(s,3H,CH,1,37(J=75z,3079,2972,2925,2844,1635,1447,1414,1373,1252,3H,CH3),143~1.70(m,6H,CH2),I7I(s,3H,CH3),1185, 1011, 907, 897 cm HRMS-ESI caled for C2ohuSe2.04(dd,J=4.2,8Hz,1H,CH),220~2.26(m,IH,(M+Na):377.1723, found371738.CH),249(q,J=75Hz,2H,CH2),3.25(8,2H,CH2)β榄香烯环己基硒醚(e):无色油状物;HNMR4.59~4.93(m,6H,=CH2),5.82(dd,J=109,174Hz(CDCl3500MHz):1.01(s,3H,CH3),125~1.69(m,IH, =CH); C NMR(CDCl3, 125 MHz)& 15.4, 16.6,14H,CH2),1.71(s,3H,CH3),1.98~2.01(m,2H,CH2),172,248,27.6,288,33.6,398,400,41.8,527,109.9,2.04中国煤化T22-24(m晶110.0,1122,147.7,150.2,150.6; Se nmr(CDCl3,95(s,2H,CH2),4.59~MHz,Me2Se)b:163.52;IR(film)v:3079,2965,2918493CNMHG10.95. 17.45 HZ, IH2851,1629,144,4144.1373,1232,119,1004,909,890=CH);"CNMR(CDCl,125MH)b16,7,24.8,259,cm, HRMS-ESI calcd for CIH2seM+Na):269.27,281,3,344390,399,40,421,528,1430有机化学Vl.28,20081083,1099,1122,1477,1503,1514;IR(flm)v3086,2H,=CH2),5.82(dd,J=10.95,1745Hz,1H,=CH)2958,2918,2864,1642,1474,1416,1373,1185,1011,5.90(d,J=99,174Hz,1H,=cH;"cNMR(CDCl909,890cm; HRMS-ESI calcd for C2H4Se(M+Na'):125MH2)b:16.7,24.8,260,277,287,337,39.8,40.0,3891723, found389.1726.422,52.8,109.9,1106,112.2,1163,135.1,147.6,150.2,B榄香烯庚基硒醚(:无色油状物;HNMR1506;R(flm)v:3086,2965,20925,2851,1642,144CDCl2500MH):0.88(J=675Hz,3H,CH3),1.011414,1373,1185,1011,909,890cm; HRMS-ESI calcd(s,3H,CH3),1,25~170(m,16H,CH2),171(s,3H,CH3), for CigH23Se(M+Na'):347.1254, found347.1258204(dd,J=4.15,11.9Hz,IH,cH),2.20~2.26(m,IH,B榄香烯苄基硒醚①:无色油状物;HMMRCH,2.48(tJ=7.5Hz,2H,CH2),3.20(s,2H,CH2),(CDCl3,500MHz):101(s,3H,CH3),1.4l~1.65(m,4.59~493(m,6H,=CH2),582(dd,J=10.9,174H,6H,CH2),L.71(s,3H,CH3),2.00(dd,J=4.l5,11.2Hz1H,=CH;"cMMR(CDC3,125MH)b:141,167,1H,CH,215~2.20(m,1H,CH,3.19(s,2H,CH),3.70226,240,24.8,27.7,289,29.1,300,303,31.8,33.7,(s,2H,CH2),4.58~491(m,6H,=CH2),58l(dd,J=399,400,41.9,52.8,109,4,110.1,1122,147.7,150.2,114,17.1H,H,=CH),717~7.28(m,SH,PhH);"C150.8;IR(flm)v:3079,2965,2918,2851,1629,14l4,NMR( CDCl3,125MHz):16.7,24.8,274,27.6,297,454,1373,1179,1011,910,890cm;HRMS- ESI calcd337,39.8,400,421,528,1099,10,7,1122,1267,for C22H3gSe(M+Na): 405 2036, found 405.20321285,1290,1394,147.6,150.2,150.5;IR(flm)v3079,B榄香烯硒代乙醇(g):无色油状物;HNMR3029,2972,2918,2858,1635,1595,1494,144,414CDC,500MHz)b:1.01(s,3H,CH,14~1.69(m,1373,1185,1011,909,890,755,6956H,CH2),171(s,3H,CH3),204(dd,J=42,155H, calcd for C2H3Se(M+Na'):397.410, found39714l51H,CH,220~2.25(m,IH,CH),2.70(t,J=62Hz,2H,CH2),3.26(s,2H,CH2),373(tJ=6.15Hz,2H,CH2),2结果与讨论4.59~4.92(m,6H,=CH2),582(dd,J=10.05,174HH,=CH2);C NMR(CDCI3, 125 MHz)8:16.7, 24.8表1总结了一锅法合成β榄香烯烃基硒醚的反应结276,27.7,29.0,33.7,39.8,399,419,528,60.9,110.0,果.整个过程一直是在室温下进行,共需2~3h.选用110.122,1476,1502,1503;R(im)v:3:8307,了10种卤代烃,得到目标产物a~的总产率为74%~2972,2925,2858,1723,1642,1447,1415,1373,127387%,产物均经R,HNMR,CNMR以及HRMS确认1185,104,101,908,890cm-l; HRMS- ESI calcd for其中产物a还经硒谱确认C1H2sOSe(M+Na):351.1203, found35112192.1卤代烃的加入顺序对产率的影响榄香烯硒代乙酸乙酯(h)无色油状物;HMMR我们对本方法中卤代烃和13氯榄香烯的加入次(CDCl.500MHz)b:lol(s,3H,CH3,128(tJ=7.15序进行了研究.结果发现,必须是先加入卤代烃,后加H3HCH),144-1.69(m6HcH.1.71(,3HcH),入13-氯P榄香烯,否则目标产物的产率会大幅降低(表203(dd,J=405,141CH,2.18~2.20(m,ⅢH2,Enry1ws2,3vs4).为探明其原因,我们先合成并分CH,3.08(s,2H,CH2),343(s,2HCH),417(9,J=7.15离得到β榄香烯二硒醚k产率达到90%左右H,2H,CH2),459~4.92(m,6H,=CH2),5.82(d,J=k:黄色油状,HNMR(CIDCl3,500MHz)b:101(s,6H,1105173Hz,IH,=CH; C NMR(CDCI3,125MH)乐CH),143~168(m,12H,CH2),1.71(s,6H,CH),2.0414.2,167,221,248,277,30.5,337,398,39.9,42.0,(dd,J=3.95,12.05H,2H,CH,2.l8~2.21(m,2H,CH),528,611,110.0,11.1,1122,147.5,1493,150.l,1717;3.20(s,4H,CH2),4.59~4.95(m,12H,=CH2)5.82(dIR(fm)v3079,2932,2864,1743,1635,1434,1414,J=11,17.35Hz,2H,=CH);"cNMR(CDCl3,1251380,1259,1098,1031,906,890cm; HRMS-ESI caled MHz))b:167,24.8,27.7,29,4,337,39.9,400,42,3,52.9,for CioH3oO2 Se(M+Na): 393 1309, found 393. 1301099,110.6,1122,147.6,150.2,150.7.Anal. calcd for榄香烯烯丙基硒醚():无色油状物; H NMR Coh63.76,H6.20].而用(CDCl3. 500 MHz)8:3H,CH3),1.43~1.70(m,NaB中国煤化工一步反应时,产率却6H,CH2),171(s,3H,CH3,203(ddJ=3.85,12H,1H,不足CNMHG为B榄香烯分子的空CH),218223(m,IH,CH,3.11(s,2H,CH2),3.22(s,间位阻太大,阻止了SeSe键的断裂,故而导致目标化2H,CH),4.59~4.93(m,6H,=CH,5.04~505(m,合物产率降低.为了验证这一事实,我们采用其他卤代No 8尹红星等:B榄香烯烃基硒醚的一锅法合成1431表1一锅法合成榄香烯烃基硒醚Table 1 One-pot synthesis of B-elemene-13-yl alkyl selenidesCompoundrtl00℃Bromoethane1-Bromobutane8161-Bromoheptane792-Chloroethanol980877488485烃代替13-氯-β-榄香烯,结果发现,改变卤代烃的加入24生物活性顺序并未明显改变目标产物的产率(表2,Enty5ws6,7以产物B榄香烯硒代乙醇g为代表进行了初步的抗8).氧化活性测试.将空白低密度脂蛋白(nLDL组)用5表2卤代烃加入顺序对反应产率的影响molL CuSO4水溶液氧化修饰( blank control组),然后Table 2 Influence of added sequence of alkyl halides on the向 blank control组中分别加入无水乙醇( alcohol control组)和不同浓度g的无水乙醇溶液,测定以上各组中丙二RX1 Bromoethane13 Chloro-B-elemene、d/%醛MDA)含量MDA是LDL的氧化产物其含量越小,RX2 13-Chloro-B-elemene Bromoethane说明氧化作用越弱,抗氧化作用越强.研究结果表明:3 2-Chloroethanol13-Chloro-B-elemene 83nDL用CuSo4氧化修饰后,MDA含量大幅增加.而随4 13-Chloro-B-elemene 2-Chloroethanol着g的加入,MDA含量明显降低,说明β榄香烯硒代5 Bromoethane1-Bromobutane86醇对LDL的氧化具有显著的抑制作用,而且抗氧化活7 2-Chloroethanol iso-Amyl iso-Amyl bromide 83性同底物浓度呈正相关(图1).抗氧化作用是抗肿瘤的2-Chloroethanol重要机制之-12,还与心血管疾病、肿瘤、糖尿病、白4加入顺序均为先Rx,后R2X.内障等多种疾病的预防和治疗有着极其密切的联系22反应温度对产率的影响期望本研究可以拓宽β榄香烯类药物的药用研究领域,我们还研究了温度对产率的影响.在实验中,我们其它产物的抗氧化及抗肿瘤活性正在测试中分别采用室温,60,100℃进行了对照实验,发现升高温度对产率并无明显影响,而对于一些低沸点的卤代烃来说,较高的温度反而使产率有所降低(表1).因此本实验采用室温最适宜,而且还大大简化了操作过程23反应机理在碱性环境中,水合肼通过电子转移将Se还原为Se(Eqs.1,2),然后Se和卤代烃发生亲核取代得到对称二硒醚紧接着对称二硒醚在NaBH4作用下SeSe键发生断裂得到硒负离子(Fq3),最后硒负离子与nLDL blank alcohol 10 20 40 80Control Seμgm)13-氯榄香烯(13- chloro- B-elemene)作用得到目标产物-榄香烯烃基硒醚.图1榄香烯硒代乙醇(SE的抗氧化作用m YH中国煤化工elemene-Se-ethanol (Se)N2H4 H2ON2+4e+5H2OCNMHG(3) ReferencesI Wang, G. 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