β-欖香烯烴基硒醚的一鍋法合成

2008年第28卷有機化學(xué)vl.28.2008第8期,1428~1432Chinese Joumal of Organic ChemistryNo.8,1428~1432·研究論文·β-欖香烯烴基硒醚的一鍋法合成尹紅星“張殊佳鄭學(xué)仿*b楊蘭義(大連大學(xué)環(huán)境與化學(xué)工程學(xué)院大連116622)大連大學(xué)遼寧省生物有機化學(xué)重點(diǎn)實(shí)驗室大連1162)摘要常溫下將硒用N2HH2O還原后與鹵代烴反應得到對稱(chēng)二硒醚,不經(jīng)分離直接用NaBH還原,再與13-氟B欖香烯作用得到β-欖香烯烴基硎醚.此一鍋法操作簡(jiǎn)便、條件溫和、反應快速而且產(chǎn)率較髙,是合成不對稱(chēng)硒醚的一種簡(jiǎn)便實(shí)用的方法.對化合物g的初步生物活性實(shí)驗表明其具有顯著(zhù)的抗氧化作用關(guān)健詞β欖香烯;不對稱(chēng)硒醚;一鍋法;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欖香烯是從中藥溫莪術(shù)中分離出來(lái)的一種有效物的抗癌成分,以其為主要成分的欖香烯乳劑已批量生有關(guān)不對稱(chēng)硒醚的合成,傳統方法基本上都是從對產(chǎn)并廣泛應用于臨床.以B欖香烯為先導化合物,對其稱(chēng)二硒醚出發(fā),斷開(kāi)SeSe鍵,再與另一種鹵代烴反應進(jìn)行結構修飾,深入研究其構效關(guān)系,對進(jìn)一步進(jìn)行分而得到46如果從單質(zhì)硒出發(fā),則必須先合成、分子設計,尋找具有高效、低毒的抗腫瘤新藥具有重要的離得到對稱(chēng)二硒醚,才能進(jìn)行下一步反應.步驟較多,理論和現實(shí)意義,硒是人體必需的微量元素,具有顯著(zhù)操作繁瑣,需要花費較長(cháng)時(shí)間.盡管以前偶爾有文獻報的抗腫瘤1、抗氧化等多種生物活性,故我們設想將硒道從單質(zhì)硒出發(fā)一鍋法合成不對稱(chēng)硒醚,但都存在著(zhù)需和B欖香烯相結合,在不破壞尸欖香烯骨架結構的前提要嚴格控制反應溫度以及時(shí)間過(guò)長(cháng)等缺點(diǎn).本文下,合成B欖香烯烴基硒醚類(lèi)化合物,使分子中既保持在以前研究的基礎上,采用了一種新的一鍋法成功地合欖香烯的基本骨架,又含有硒這一新的活性基團,這樣成了B-欖香烯烴基不對稱(chēng)硒醚 Scheme1).與傳統方法有可能增加作用靶點(diǎn),促使其活性疊加或提高,從而發(fā)相比,具有操作簡(jiǎn)便、條件溫和、反應快速、產(chǎn)率較高現活性更高的藥物,同時(shí)為進(jìn)一步的分子設計提供實(shí)驗等依據.另外也有可能發(fā)現新的具有抗氧化等活性的藥中國煤化工CNMHG.e-mAil:dlxfzheng@163.comReceived January 24, 2008; revised March 11, 2008: accepted April 10, 2008國家自然科學(xué)基金(No20271010)、遼寧省優(yōu)秀人才培養計劃(No.Rc0410)和遼寧省高校創(chuàng )新團隊(No.2006T002)資助項目No 8尹紅星等:β欖香烯烴基硒醚的一鍋法合成14293351254, found335.1262β-欖香烯丙基硒醚(b):無(wú)色油狀物;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實(shí)驗部分2965,2925,2851,1635,1434,1418,1373,1279,1185,1011, 909, 890 cm HRMS-ESI calcd for Cl8H3oSe(M+1.1儀器和試劑Na):349.1410, found349.1412紅外光譜用 Nicolet ft-IR型紅外光譜儀;核磁共振β-欖香烯丁基硒醚(c):淺黃色油狀物;"HNMR用 Bruker Av500核磁共振儀(用CDCl3作溶劑,除了 a(CDCl2.500MHz):0.91(,J=7.35Hz,3H,CH3),1.01的硒譜以Me2Se為內標外,其余以TMS為內標);高分s,3HCH,1.36~1.70(m,10HCH2),171(s,3H,CH3),辨質(zhì)譜用 Bruker A PeXⅡ高分辨質(zhì)譜儀;柱層析用硅膠204(dd,J=4.l,11.85Hz,1H,CH),2.20~2.26(m,IH,(200~300目)由青島海洋化工廠(chǎng)生產(chǎn);薄層硅膠板CH,248〔,J=7.5H,2H,CH2),3.25(s,2H,CH2),(GF254)由煙臺康必諾化學(xué)試劑廠(chǎng)生產(chǎn).欖香烯由中國4.59~493(m,6H,=CH2),5.82(dd,J=10.9,1745Hz科學(xué)院大連化學(xué)物理研究所提供;所用其它試劑均為市H,=CH;"cNMR(CDCl,125MHz)13.6,16.7,售分析純.13氯B欖香烯參照文獻14]制備23.1,23.7,24.8,27.7,29.1,32.4,33.7,39.9,40.0,41.9,12β-欖香烯烴基硒醚類(lèi)化合物的合成52.8,1099,110.1,1122,1477,150.3,1508;IR(film)v向一裝有磁力攪拌裝置的三頸瓶中加入048(53079,2952,2851,1635,1434,1414,1373,1259,1185,mmo)Se粉、0.3g(75mmol)NaOH固體和10mh1004, 906, 890 cm- HRMS-ESI caled for CIgH3 Se(M+DMF,氮氣保護.緩慢滴入含有NHH2O1.5mmo的Na):363.1567, found3631574.DMF溶液5mL,室溫攪拌15min,然后緩慢加入鹵代B欖香烯異戊基硒醚(d):淺黃色油狀物;HNMR烴5mmol.攪拌1h后,加入NaBH40.57g(15mmol)(CDCl,500MHz):0.89(d,J=6.6Hz,6H,CH3),1.01反應劇烈,大量氣泡產(chǎn)生,15min后,再緩慢滴加13.(s.3cH,143-170im,9cHch,1.n1(s.3H氯欖香烯19g(5ml),繼續室溫反應1h抽濾,cH1,204,J=40,119 Hz, IH, CH.2.20-22(m石油醚萃取(5mL×3)合并有機相,用水(20m對有HcH.248(J=,7H,2H,CH),326(.3H,cCH),機相洗1次,分出有機相,無(wú)水Na2SO4干燥.減壓蒸去59~492(m,6H,=CH2),582(dd,J=10.9,174H,溶劑,粗產(chǎn)品用柱色譜分離200~300目硅膠石油醚H,=CH;"cMMR(CDCl125MHz):167,21.8,洗脫)提純223,24.8,27.7,28.6,29.0,33.7,394,39.8,40.0,41.9,β欖香烯乙基硒醚(a):無(wú)色油狀物;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欖香烯環(huán)己基硒醚(e):無(wú)色油狀物;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中國煤化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有機化學(xué)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欖香烯庚基硒醚(:無(wú)色油狀物;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欖香烯芐基硒醚①:無(wú)色油狀物;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欖香烯硒代乙醇(g):無(wú)色油狀物;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結果與討論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總結了一鍋法合成β欖香烯烴基硒醚的反應結276,27.7,29.0,33.7,39.8,399,419,528,60.9,110.0,果.整個(gè)過(guò)程一直是在室溫下進(jìn)行,共需2~3h.選用110.122,1476,1502,1503;R(im)v:3:8307,了10種鹵代烴,得到目標產(chǎn)物a~的總產(chǎn)率為74%~2972,2925,2858,1723,1642,1447,1415,1373,127387%,產(chǎn)物均經(jīng)R,HNMR,CNMR以及HRMS確認1185,104,101,908,890cm-l; HRMS- ESI calcd for其中產(chǎn)物a還經(jīng)硒譜確認C1H2sOSe(M+Na):351.1203, found35112192.1鹵代烴的加入順序對產(chǎn)率的影響欖香烯硒代乙酸乙酯(h)無(wú)色油狀物;HMMR我們對本方法中鹵代烴和13氯欖香烯的加入次(CDCl.500MHz)b:lol(s,3H,CH3,128(tJ=7.15序進(jìn)行了研究.結果發(fā)現,必須是先加入鹵代烴,后加H3HCH),144-1.69(m6HcH.1.71(,3HcH),入13-氯P欖香烯,否則目標產(chǎn)物的產(chǎn)率會(huì )大幅降低(表203(dd,J=405,141CH,2.18~2.20(m,ⅢH2,Enry1ws2,3vs4).為探明其原因,我們先合成并分CH,3.08(s,2H,CH2),343(s,2HCH),417(9,J=7.15離得到β欖香烯二硒醚k產(chǎn)率達到90%左右H,2H,CH2),459~4.92(m,6H,=CH2),5.82(d,J=k:黃色油狀,HNMR(CIDCl3,500MHz)b:101(s,6H,1105173Hz,IH,=CH; C NMR(CDCI3,125MH)樂(lè )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欖香烯烯丙基硒醚():無(wú)色油狀物; H NMR Coh63.76,H6.20].而用(CDCl3. 500 MHz)8:3H,CH3),1.43~1.70(m,NaB中國煤化工一步反應時(shí),產(chǎn)率卻6H,CH2),171(s,3H,CH3,203(ddJ=3.85,12H,1H,不足CNMHG為B欖香烯分子的空CH),218223(m,IH,CH,3.11(s,2H,CH2),3.22(s,間位阻太大,阻止了SeSe鍵的斷裂,故而導致目標化2H,CH),4.59~4.93(m,6H,=CH,5.04~505(m,合物產(chǎn)率降低.為了驗證這一事實(shí),我們采用其他鹵代No 8尹紅星等:B欖香烯烴基硒醚的一鍋法合成1431表1一鍋法合成欖香烯烴基硒醚Table 1 One-pot synthesis of B-elemene-13-yl alkyl selenidesCompoundrtl00℃Bromoethane1-Bromobutane8161-Bromoheptane792-Chloroethanol980877488485烴代替13-氯-β-欖香烯,結果發(fā)現,改變鹵代烴的加入24生物活性順序并未明顯改變目標產(chǎn)物的產(chǎn)率(表2,Enty5ws6,7以產(chǎn)物B欖香烯硒代乙醇g為代表進(jìn)行了初步的抗8).氧化活性測試.將空白低密度脂蛋白(nLDL組)用5表2鹵代烴加入順序對反應產(chǎn)率的影響molL CuSO4水溶液氧化修飾( blank control組),然后Table 2 Influence of added sequence of alkyl halides on the向 blank control組中分別加入無(wú)水乙醇( alcohol control組)和不同濃度g的無(wú)水乙醇溶液,測定以上各組中丙二RX1 Bromoethane13 Chloro-B-elemene、d/%醛MDA)含量MDA是LDL的氧化產(chǎn)物其含量越小,RX2 13-Chloro-B-elemene Bromoethane說(shuō)明氧化作用越弱,抗氧化作用越強.研究結果表明:3 2-Chloroethanol13-Chloro-B-elemene 83nDL用CuSo4氧化修飾后,MDA含量大幅增加.而隨4 13-Chloro-B-elemene 2-Chloroethanol著(zhù)g的加入,MDA含量明顯降低,說(shuō)明β欖香烯硒代5 Bromoethane1-Bromobutane86醇對LDL的氧化具有顯著(zhù)的抑制作用,而且抗氧化活7 2-Chloroethanol iso-Amyl iso-Amyl bromide 83性同底物濃度呈正相關(guān)(圖1).抗氧化作用是抗腫瘤的2-Chloroethanol重要機制之-12,還與心血管疾病、腫瘤、糖尿病、白4加入順序均為先Rx,后R2X.內障等多種疾病的預防和治療有著(zhù)極其密切的聯(lián)系22反應溫度對產(chǎn)率的影響期望本研究可以拓寬β欖香烯類(lèi)藥物的藥用研究領(lǐng)域,我們還研究了溫度對產(chǎn)率的影響.在實(shí)驗中,我們其它產(chǎn)物的抗氧化及抗腫瘤活性正在測試中分別采用室溫,60,100℃進(jìn)行了對照實(shí)驗,發(fā)現升高溫度對產(chǎn)率并無(wú)明顯影響,而對于一些低沸點(diǎn)的鹵代烴來(lái)說(shuō),較高的溫度反而使產(chǎn)率有所降低(表1).因此本實(shí)驗采用室溫最適宜,而且還大大簡(jiǎn)化了操作過(guò)程23反應機理在堿性環(huán)境中,水合肼通過(guò)電子轉移將Se還原為Se(Eqs.1,2),然后Se和鹵代烴發(fā)生親核取代得到對稱(chēng)二硒醚緊接著(zhù)對稱(chēng)二硒醚在NaBH4作用下SeSe鍵發(fā)生斷裂得到硒負離子(Fq3),最后硒負離子與nLDL blank alcohol 10 20 40 80Control Seμgm)13-氯欖香烯(13- chloro- B-elemene)作用得到目標產(chǎn)物-欖香烯烴基硒醚.圖1欖香烯硒代乙醇(SE的抗氧化作用m YH中國煤化工elemene-Se-ethanol (Se)N2H4 H2ON2+4e+5H2OCNMHG(3) ReferencesI Wang, G. 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