不对称Mannich反应合成手性1,3,4-噻二唑丙二酸酯衍生物  

Synthesis of Chiral Malonate Derivatives Containing 1,3,4-Thiadiazole Moiety by Asymmetric Mannich Reaction

作　　者：朱芸莹 柏松 吴琴[1] ZHU Yun-ying;BAI Song;WU Qin(School of Chemical Engineering,Guizhou Institute of Technology,Guiyang 550003,Guizhou,China;KeyLaboratory of Green Pesticide and Agricultural Bioengineering,Ministry of Education,Guizhou University,Guiyang 550025,Guizhou,China)

机构地区：[1]贵州理工学院化学工程学院,贵州贵阳550003 [2]贵州大学绿色农药与农业生物工程教育部重点实验室,贵州贵阳550025

出　　处：《精细化工》2019年第7期1494-1500,共7页Fine Chemicals

基　　金：贵州省教育厅青年科技人才成长项目(黔教合KY字[2018]251);贵州省科技计划项目(黔科合平台人才[2017]5789);贵州大学绿色农药实验室开放基金资助项目(2018GDGP0102);贵州省自然科学基金(黔科合基础[2017]1066);贵州理工学院高层次人才启动基金

摘　　要：以金鸡纳碱衍生物为催化剂,采用不对称Mannich反应,在催化剂3-((3,5-二(三氟甲基)苯基)氨基)-4-(((1S)-6-甲氧基喹啉-4-基)((1S,4S,5R)-5-乙烯基奎宁-2-基)甲基)氨基)-3-环丁烯-1,2-二酮(Ⅴe)摩尔分数为10%,溶剂为甲苯,温度为60℃的最佳反应条件下一锅法合成了9个手性含1,3,4-噻二唑的丙二酸酯衍生物(Ⅳa^i),具有较高的收率(70%~89%)和优异的对映选择性(e.e.值最高>99%)。生物活性测试结果表明:该类衍生物对烟草花叶病毒具有一定的活性,其中,手性化合物(–)-Ⅳf〔(–)-二乙基-2-((3,4-二氯苯基)((5-(2,4-二氯苯基)-1,3,4-噻二唑-2-基)氨基)甲基)丙二酸酯〕的治疗活性和保护活性分别为50.8%和42.6%,与对照商品化药剂病毒唑相当。Nine chiral malonate derivatives containing 1,3,4-thiadiazole moiety(Ⅳa^i)were synthesized by one-pot asymmetric Mannich reaction using cinchona alkaloid squaramide catalyst.High yields(70%~89%)and excellent enantioselectivities[up to>99%,enantiomeric excess(e.e.)]were obtained in toluene in the presence of 10 mol%catalyst 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((1 S)-(6-methoxyquinolin-4-yl)((1 S,4 S,5 R)-5-vinylquinuclidin-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione(Ⅴe)at 60℃which were the optimum reaction conditions.The bioassay results showed that these derivatives possessed good activities against tobacco mosaic virus(TMV).Especially,chiral compound(-)-Ⅳf exhibited high curative and protective activities against TMV in vivo(50.8%and 42.6%,respectively),equivalent to that of commercially available antiviral agent ribavirin.

关 键 词：丙二酸酯衍生物 不对称Mannich反应 抗病毒活性 精细化工中间体 

分 类 号：O626[理学—有机化学]