天然产物Luxenchalcone的全合成

Vol. 34高等学校化学学报No.122013年12月CHEMICAL J0OURNAL OF CHINESE UNIVERSITIES2734 ~ 2737doi: 10. 7503/cjcn20130306天然产物Luxenchalcone的全合成张应鹏，张伟娜，杨云裳，乔明(兰州理工大学石油化工学院，兰州730050)摘要以对羟基苯甲 醛和2 ,4-二羟基苯乙酮为起始原料,经过甲氧甲基化、溴代、Ulmann反应、羟醛缩合和脱保护等反应,完成了天然产物双查尔酮Luxenchalcone的全合成,关键步骤为Ulmann反应,重要中间体和目标产物的化学结构经'H NMR, "C NMR和ESI-MS等表征确认.关键词Luxenchalcone; Ullmann 反应;双查尔酮;全合成中图分类号0625. 1文献标志码A查尔酮及其衍生物(芳香醛酮经羟醛缩合后的产物1.21)是- -类重要的有机合成和药物合成中间体[94].研究[5.61 发现,查尔酮具有活血、消肿、止痛、止血和抗癌等多种生物活性,双查尔酮类化合物也因具有多种药理活性[7-10]而被广泛研究(1"1-14]. Luxenchalcone[4 ,2',4'-Trihydroxychalcone-(3-04")-2”,4"-dihydroxychalcone]是2004年由Carvalho等[15]首次从巴西东南部的灌木Luxemburgia octandra 中提取得到的具有药理活性的化合物.2007 年，Danie 等[|6]报道了该化合物对HT-29, NCL-H460, RXF-393, MCF-7和0VCAR-3这5种人体癌细胞有积极的抑制作用.本文以对羟基苯甲醛和2,4-二羟基苯乙酮为起始原料，经溴代、甲氧基甲基化、Ullumann 反应、羟醛缩合和脱保护等反应对该化合物进行了首次全合成1实验部分1.1试剂与仪器XRC-1型显微熔点仪(四川大学科学仪器厂); Bruker Avance 400型核磁共振仪(TMS为内标，CDCl3或DMSO-d,作溶剂); Esquire 6000型液相色谱/质谱联用仪(Bruker公司);柱层析用硅胶(100 ~200目,青岛海洋化工厂).2,4-二羟基苯乙酮(分析纯,连云港达瑞化工有限公司);对羟基苯甲醛(分析纯,天津光复精细化工有限公司);碳酸铯和碘化亚铜[分析纯，阿拉丁试剂(上海)有限公司];其它所用试剂均为分析纯或化学纯.1.2实验过程目标化合物的合成路线如Scheme 1所示.1.2.14-(4-甲基-1 ,3-二氧戊环基2-基)苯酚(1)的合成参考文献[17]方法, 得到乳状液体(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,计算值):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 羟基苯甲醛(2)的合成参考 文献[ 18]方法,加入对羟基苯甲醛610 mg(50 mmol),得到白色结晶(2) 8.5g,收率85%, m. p. 124~128 C(文献值[8): 122 ~124 C).收稿日期: 2013-04-03.中国煤化工基金项目:甘肃省自然科学基金(批准号: 3ZS062 B25-017)资助MHCNMHG联系人简介:张应鹏，男，博士,副教授,主要从事生物有机化学研究E mail:ingengzhang@ 126. com.No.12张应鹏等:夭然产物Luxenchalcone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-羟 基苯甲醛(3)的合成在100 mL三口烧瓶中加入334 mg(2 mmol)对羟基苯甲醛、401 mg(2 mmol)化合物2、1313 mg(4 mmol)碳酸铯和30 mL DMF,搅拌,待固体溶解后加入80 mg碘化亚铜，氮气保护下于150 C回流反应12 h,再加人20 mL 2mol/L的稀盐酸溶液,加热回流5 h,再用乙酸乙酯萃取(20 mLx3),有机层用饱和氯化钠溶液洗涤,无水硫酸镁干燥.过滤,蒸除溶剂，经硅胶柱层析纯化[洗脱剂V(乙酸乙酯): V(石油醚)= 1:12], 得到褐色固体(3) 350 mg,m. p. 133~135 C(文献值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)合成参考文献[20]方法, 得到褐色液体(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,计算值): 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)的制备参考文献[20]方法， 得到无色液体(5),收率97%.ESI-MS, m/z: 240. 2(文献值[21]: 240. 0).1.2.6 4,2' ,4' ,2”" ,4"-五甲氧甲氧基(3-04 ")双查尔酮的合成(中国煤化工，得到黄色固体(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高等学校化学学报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计算值): C 65.41(66.74), H5.70(5. 79), 0 28. 39(28. 46); ESI-MS, m/z: 730. 1.1.2.7 Luxenchalcone 的合成参考文献[22]方法， 得到黄色晶体238 mg, m. p. 169~171 C(天然产物值'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]*.以上数据与天然产物[15]基本相符.2结果与讨论目标化合物的结构有一定的对称性,根据反合成分析可知，合成目标化合物的关键在于中间体3的合成，得到中间体3后,经羟醛缩合反应即可得到目标化合物中间体3可由化合物1与化合物2通过Ulmann反应得到;化合物1依据文献[17 ,18]方法制备;化合物2依据文献[19]方法制备;化合物5依据文献[ 20]方法制备;化合物3经由Ullmann反应得到，反应以碘化亚铜为催化剂、碳酸铯为碱在DMF溶剂中进行,得到关键中间体化合物3.化合物3与保护的苯乙酮羟醛缩合得到化合物6,再在酸性条件下脱去MOMO保护剂，以总产率18%完成了Luxenchalcone 的全合成，产物经'H NMR,"C NMR和ESI-MS表征与天然产物基本- -致.参.考文献[ 1 ] MasesaneI. 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Chinese Unierities, 2004, 25(2), 292- 293(张应鹏，李瀛,薛吉军,吴疆.高等学校化学学报, 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( 张应鵬,陈宇涛,杨.云裳，关晓高等学校化学学报, 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)中国煤化工MHCNMHG.