Vol. 34高等學(xué)?；瘜W(xué)學(xué)報(bào)No.122013年12月CHEMICAL J0OURNAL OF CHINESE UNIVERSITIES2734 ~ 2737doi: 10. 7503/cjcn20130306天然產(chǎn)物L(fēng)uxenchalcone的全合成張應(yīng)鵬，張偉娜，楊云裳，喬明(蘭州理工大學(xué)石油化工學(xué)院，蘭州730050)摘要以對(duì)羥基苯甲 醛和2 ,4-二羥基苯乙酮為起始原料,經(jīng)過(guò)甲氧甲基化、溴代、Ulmann反應(yīng)、羥醛縮合和脫保護(hù)等反應(yīng),完成了天然產(chǎn)物雙查爾酮Luxenchalcone的全合成,關(guān)鍵步驟為Ulmann反應(yīng),重要中間體和目標(biāo)產(chǎn)物的化學(xué)結(jié)構(gòu)經(jīng)'H NMR, "C NMR和ESI-MS等表征確認(rèn).關(guān)鍵詞Luxenchalcone; Ullmann 反應(yīng);雙查爾酮;全合成中圖分類號(hào)0625. 1文獻(xiàn)標(biāo)志碼A查爾酮及其衍生物(芳香醛酮經(jīng)羥醛縮合后的產(chǎn)物1.21)是- -類重要的有機(jī)合成和藥物合成中間體[94].研究[5.61 發(fā)現(xiàn),查爾酮具有活血、消腫、止痛、止血和抗癌等多種生物活性,雙查爾酮類化合物也因具有多種藥理活性[7-10]而被廣泛研究(1"1-14]. Luxenchalcone[4 ,2',4'-Trihydroxychalcone-(3-04")-2”,4"-dihydroxychalcone]是2004年由Carvalho等[15]首次從巴西東南部的灌木Luxemburgia octandra 中提取得到的具有藥理活性的化合物.2007 年，Danie 等[|6]報(bào)道了該化合物對(duì)HT-29, NCL-H460, RXF-393, MCF-7和0VCAR-3這5種人體癌細(xì)胞有積極的抑制作用.本文以對(duì)羥基苯甲醛和2,4-二羥基苯乙酮為起始原料，經(jīng)溴代、甲氧基甲基化、Ullumann 反應(yīng)、羥醛縮合和脫保護(hù)等反應(yīng)對(duì)該化合物進(jìn)行了首次全合成1實(shí)驗(yàn)部分1.1試劑與儀器XRC-1型顯微熔點(diǎn)儀(四川大學(xué)科學(xué)儀器廠); Bruker Avance 400型核磁共振儀(TMS為內(nèi)標(biāo)，CDCl3或DMSO-d,作溶劑); Esquire 6000型液相色譜/質(zhì)譜聯(lián)用儀(Bruker公司);柱層析用硅膠(100 ~200目,青島海洋化工廠).2,4-二羥基苯乙酮(分析純,連云港達(dá)瑞化工有限公司);對(duì)羥基苯甲醛(分析純,天津光復(fù)精細(xì)化工有限公司);碳酸銫和碘化亞銅[分析純，阿拉丁試劑(上海)有限公司];其它所用試劑均為分析純或化學(xué)純.1.2實(shí)驗(yàn)過(guò)程目標(biāo)化合物的合成路線如Scheme 1所示.1.2.14-(4-甲基-1 ,3-二氧戊環(huán)基2-基)苯酚(1)的合成參考文獻(xiàn)[17]方法, 得到乳狀液體(1),收率72%, [a]5 =-30. 23°(c=0.12, CHClz). 'H NMR(400 MHz, CDCl3), 8: 1. 34(d, J=3. 13 Hz, 3H,CH), 3. 47 ~3.59(m, 1H, H1), 4.01 ~4.21(m, 1H, H1'), 4. 22 ~4.37(m, 1H, H2), 5.77(s, 1H,0CHPh), 6.85(d, J=8.02 Hz, 2H, ArH), 7.25(d, J=8. 02 Hz, 2H, ArH); BC NMR( 100 MHz,CDCI,), 8: 158.4, 128.9, 127.6, 116.1, 103.5, 73.7, 71.2, 18. 6;元素分析(%, CrH2O,計(jì)算值):C 66.31(66. 65), H6. 65(6.71), 0 26.29(26. 64); ESI-MS, m/z: 180. 2.1.2.23-澳4 羥基苯甲醛(2)的合成參考 文獻(xiàn)[ 18]方法,加入對(duì)羥基苯甲醛610 mg(50 mmol),得到白色結(jié)晶(2) 8.5g,收率85%, m. p. 124~128 C(文獻(xiàn)值[8): 122 ~124 C).收稿日期: 2013-04-03.中國(guó)煤化工基金項(xiàng)目:甘肅省自然科學(xué)基金(批準(zhǔn)號(hào): 3ZS062 B25-017)資助MHCNMHG聯(lián)系人簡(jiǎn)介:張應(yīng)鵬，男，博士,副教授,主要從事生物有機(jī)化學(xué)研究E mail:ingengzhang@ 126. com.No.12張應(yīng)鵬等:夭然產(chǎn)物L(fēng)uxenchalcone的全合成2735)HOH-Br1,2-Propanedol, NaHSO4CHCl, Br:Benzene, 100 C, reflux40 C, refux,6.5hlCHO1H1+2Cul/Cs,CO,2 mol/L HCI, refux.MOMOCI acetone.150 C, reflux, 15 h5h0HC57 C, rflux, 1.5hOHC4MOMO、HO、MOMOCI acetone57 C, reflux, 1.5hOH 0MOMOOMOM+5KOH, CHsOHNz protect, 20 C,24h88 OMOM_0HHO~HCL, CH,OHReflux, 5.5 hOH 8r -OtOFLuxenchaloneScheme 1 Total synthesis of Luxenchalcone1.2.3 3-(3-甲酰基苯氧基)4-羥 基苯甲醛(3)的合成在100 mL三口燒瓶中加入334 mg(2 mmol)對(duì)羥基苯甲醛、401 mg(2 mmol)化合物2、1313 mg(4 mmol)碳酸銫和30 mL DMF,攪拌,待固體溶解后加入80 mg碘化亞銅，氮?dú)獗Ｗo(hù)下于150 C回流反應(yīng)12 h,再加人20 mL 2mol/L的稀鹽酸溶液,加熱回流5 h,再用乙酸乙酯萃取(20 mLx3),有機(jī)層用飽和氯化鈉溶液洗滌,無(wú)水硫酸鎂干燥.過(guò)濾,蒸除溶劑，經(jīng)硅膠柱層析純化[洗脫劑V(乙酸乙酯): V(石油醚)= 1:12], 得到褐色固體(3) 350 mg,m. p. 133~135 C(文獻(xiàn)值19]: 135~136 C),收率74%.1.2.4 3-(3-甲酰基苯氧基)4-( 甲氧基甲氧基)苯甲醛(4)合成參考文獻(xiàn)[20]方法, 得到褐色液體(4) 242 mg,收率84%. 'H NMR(400 MHz, DMS0-d6), 8: 9. 83(s, 1H, CHO), 9. 82(s, 1H, CHO),8.07(d, 1H, J=2.0 Hz, 3-H), 7.82(dd, 2H, J=8.4, 1.6 Hz, 2', 6'-H), 7.85(d, 2H, J=8.4 Hz,4, 5-H), 7.25(dd, 2H,J=8.4, 1.6 Hz, 3',5'-H),5.24(s, 2H, CH2), 3.53(s, 3H, CH,); Bc NMR(100 MHz, DMSO-d), 8: 192.0(C=0)， 190.7(C=0)， 160.0, 153.5, 147.3, 134.7, 134.3,132.5, 126.6, 120.7, 118.3, 116.7, 98.0, 55. 5;元素分析(%, C1H40,計(jì)算值): C 66.31(67.13),H4.65(4.93), 0 27.29(27.94); ESI-MS, m/z: 286. 2.1.2.5 2,4-二(甲 氧甲氧基)苯乙酮(5)的制備參考文獻(xiàn)[20]方法， 得到無(wú)色液體(5),收率97%.ESI-MS, m/z: 240. 2(文獻(xiàn)值[21]: 240. 0).1.2.6 4,2' ,4' ,2”" ,4"-五甲氧甲氧基(3-04 ")雙查爾酮的合成(中國(guó)煤化工，得到黃色固體(6) 295 mg, m. p. 95~97 C,收率43 %. 'H NMR(400 MTYHCNMHGd, 1H,J=7.7 Hz, 6-H), 8.34(d, 2H, J=8.8 Hz, 6', 6"-H), 8.01(d, 2H,J=15.4 Hz, β, β'-H), 7. 85(dd,.2736高等學(xué)?；瘜W(xué)學(xué)報(bào)Vol. 342H, J=8.8,2.1 Hz,2", 6".H), 7. 84(1H, brs, 2-H), 7.77(d, 2H, J=15.4 Hz, a, ax'-H), 7. 65(1H,d, J=7.7 Hz, 5-H), 7.28(d, 2H, J=8.8 Hz, 3", 5"-H), 6. 64(2H, dd, J=8.8,2.4 Hz, 5', 5"-H),6.58(d, 2H,J=2.4 Hz, 3', 3"-H), 5. 32(s, 10H, 5xCH2), 3. 42(s, 15H, 5xCH,); "C NMR(100.MHz, DMSO-d), 8: 194.4(C=0), 191.3(C=0), 165. 6(4'), 165. 6(4”), 160.9(2'), 160.9(2"), 157.3(4"), 147.7(4), 146. 8(3), 143. 8(β), 143. 8(β'), 132. 5(6'), 131.8(1"), 132.5(1),129.8(6"), 128.9(2")，128.9(6")，124.2(6), 122.7(a)，122.7(a'), 122. 1(1'), 122. 1(1"),120.0(5")，120.0(3"), 118. 1(2), 117.0(5), 110.0(5'), 110.0(S"), 103.9(3'), 103.9(3"),97. 9~97.4(0CH20), 55.4(0CH3);元素分析(%, C.H203計(jì)算值): C 65.41(66.74), H5.70(5. 79), 0 28. 39(28. 46); ESI-MS, m/z: 730. 1.1.2.7 Luxenchalcone 的合成參考文獻(xiàn)[22]方法， 得到黃色晶體238 mg, m. p. 169~171 C(天然產(chǎn)物值'5): 172 C),收率95%. 'H NMR(400 MHz, DMSO-d}), 8: 13. 6(2H, brs, 0H), 11. 0(2H,brs, 0H), 10.7(1H, brs, 0H), 8.23(d, 1H, J=9.0 Hz, 6-H ), 8.22(d, 2H, J=8.8 Hz, 6' ,6"-H),7. 95(brs, 1H, 2-H), 7. 85(d, 2H, J=15.4 Hz, β, β'-H), 7.72(d, 1H, J=7.7 Hz, 5-H), 7.71(d,2H, J=15.4 Hz, a, a'-H), 7.70(dd, 2H, J=8.8, 2.1 Hz, 2", 6"-H), 7.01(d, 2H, J=8.4 Hz,5', 5"-H), 6. 42(dd, 2H, J=8.4, 2.2 Hz, 3", 5"-H), 6. 29(d, 2H, J=2.2 Hz, 3', 3"-H); 3C NMR(100 MHz, DMSO-d), 8: 203.1(C=0), 193.3(C=0), 167.6(4'), 167. 6(4"), 166. 6(2'),166. 6(2"), 157.9(4"), 155.2(4), 143. 9(3), 143. 9(β), 143. 9(β'), 134. 9(6"), 134.7(6'), 134.2(1"), 133. 6(2"), 132.5(6"), 130.6(1), 129.5(6), 128.3(2), 120. 0(5), 117.5(x), 117.5(a'),114.5(1'), 11.6(3"), 11.6(5"), 110.9(1")，109.2(5')， 109. 1(5"), 103. 8(3'), 103. 8 (3");ESI-MS, m/z: 509. 1[M-H]*.以上數(shù)據(jù)與天然產(chǎn)物[15]基本相符.2結(jié)果與討論目標(biāo)化合物的結(jié)構(gòu)有一定的對(duì)稱性,根據(jù)反合成分析可知，合成目標(biāo)化合物的關(guān)鍵在于中間體3的合成，得到中間體3后,經(jīng)羥醛縮合反應(yīng)即可得到目標(biāo)化合物中間體3可由化合物1與化合物2通過(guò)Ulmann反應(yīng)得到;化合物1依據(jù)文獻(xiàn)[17 ,18]方法制備;化合物2依據(jù)文獻(xiàn)[19]方法制備;化合物5依據(jù)文獻(xiàn)[ 20]方法制備;化合物3經(jīng)由Ullmann反應(yīng)得到，反應(yīng)以碘化亞銅為催化劑、碳酸銫為堿在DMF溶劑中進(jìn)行,得到關(guān)鍵中間體化合物3.化合物3與保護(hù)的苯乙酮羥醛縮合得到化合物6,再在酸性條件下脫去MOMO保護(hù)劑，以總產(chǎn)率18%完成了Luxenchalcone 的全合成，產(chǎn)物經(jīng)'H NMR,"C NMR和ESI-MS表征與天然產(chǎn)物基本- -致.參.考文獻(xiàn)[ 1 ] MasesaneI. 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Pharmacal. Res. , 2012, 35(12), 2117- -2125MihigoS. 0. , Mammo w. , Bezabih M. , Andrae Marobela K., Abeguz B. M.中國(guó)煤化工7), 2464- -2473 .[12] ReddyM. V. B., ChenS. Ss.,LinM. L., ChanH. H, KuoP. C., WuT. s:YHC N M H G(12), 1549-1554[13] Sagrera G.. Berucci A, Vazquez A, Seoane G., Bioorg. Med. Chem. , 2011, 19(10), 3060- -3073.No. 12張應(yīng)鵬等:天然產(chǎn)物L(fēng)uxenchalcone的全合成2737[14] GurungS. K., KimS. B., Park H, Arch. Pharmacal. Res. , 2010, 33(12), 1919- -1926[15] MarioCC., CassiaC. F. A, KedmaG. s. s., MarcosN. E, AlceniA. W,J. Braz. Chem. Soc. , 2004, 15(1), 146-149[16] JulianaF. s. D., CassiaC. F. A., Ivana C., AdrianaB. R., MarioG. C., Indian J. Pharnacal. , 2007, 39(4), 184- -186[17] LuoZ. C., Wang Q. , Chemical World, 2010, 51(11), 675- 677(羅志臣, 王勤.化學(xué)世界, 2010, 51(11),675- 677)[18] QiuC. R.,J Weifang Unieriy, 2003, 3(4), 26- 31(邱國(guó)榮. 濰坊學(xué)院學(xué)報(bào), 2003, 3(4),26- -31)[19] BickI. R. C., BremnerJ. B., Wiriyachitra P. , Tetrahedron Le. , 1971, 12(50), 4795- 4797[20] ZhangY. P.,LiY., XueJ. J, WuJ., Chem. J. Chinese Unierities, 2004, 25(2), 292- 293(張應(yīng)鵬，李瀛,薛吉軍,吳疆.高等學(xué)校化學(xué)學(xué)報(bào), 2004, 25(2), 292--293)[21] RaoC. V., Swamy B. N. , Chandregowda V., Reddy C., Eur. J. Med. Chem. , 2009, 44(5), 2239- -2245[22] ZhangY. P., ChenY. r, YangY. s., GuanX., Chem. J Chinese Univerities, 2010, 31(7), 1342- 1345( 張應(yīng)鵬,陳宇濤,楊.云裳，關(guān)曉高等學(xué)校化學(xué)學(xué)報(bào), 2010, 31(7), 1342-1345)Total Synthesis of Natural Product LuxenchalconeZHANC Ying-Peng* , ZHANC Wei-Na, YANG Yun Shang, QIA0 Ming(School of Petrochemical Enginering , Lanzhou University of Technology, Lanzhou 730050, China)Abstract Luxenchalcone was first isolated from the leaves of Luxemburgia octandra in 2004 by Brazilchemists. In 2007 this compound was proved to have significant cytotoxicity on HT-29 colon adenocarcinoma,NCI-H460 non-small cell lung carcinoma, MCF-7 breast cancer cell, OVCAR-3 ovarian adenocarcinoma cellsand RXF -393 renal cell carcinoma. But the natural compound has not been synthesized in the literature. Inorder to synthesize Luxenchalcone , based on the natural product symmetry, the key step was UIlmann reac-tion, and then the natural product was easily to obtain by aldo condensation. In this work, Luxenchalcone wassynthesized by methoxymethylation, bromination, Ulamnn reaction, aldo condention, deprotective groupfrom 2,4-bibydroxyacetophone and 4-hydroxybenzaldehyde in 18% overyield. The structure of Luxenchalconeand intermediates were confirmned by 'H NMR, "C NMR and ESI-MS. The synthesis of this compound maybegives some vital significance to find lead compounds.Keywords Luxenchalcone; Ulmann reaction; Bichalcone ; Total synthesis(Ed.: P, H, N, K)中國(guó)煤化工MHCNMHG.