不对称Mannich反应合成手性1,3,4-噻二唑丙二酸酯衍生物
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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.
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.
引文
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[3]Polkam N,Rayam P,Anireddy J S,et al.Synthesis,in vitro anticancer and antimycobacterial evaluation of new 5-(2,5-dimethoxyphenyl)-1,3,4-thiadiazole-2-amino derivatives[J].Bioorganic and Medicinal Chemistry Letters,2015,25(7):1398-1402.
[4]Hu Y,Li C Y,Wang X M,et al.1,3,4-Thiadiazole:synthesis,reactions,and applications in medicinal,agricultural,and materials chemistry[J].Chemical Reviews,2014,45(31):5572-5610.
[5]Guan P,Wang L,Hou X,et al.Improved antiproliferative activity of1,3,4-thiadiazole-containing histone deacetylase(HDAC)inhibitors by introduction of the heteroaromatic surface recognition motif[J].Bioorganic and Medicinal Chemistry,2014,22(21):5766-5775.
[6]Schenone S,Brullo C,Bruno O,et al.New 1,3,4-thiadiazole derivatives endowed with analgesic and anti-inflammatory activities[J].Bioorganic and Medicinal Chemistry,2005,14(6):1698-1705
[7]Eckelbarger J D,Parker M H,Yap M C H,et al.Synthesis and biological activity of a new class of insecticides:the N-(5-aryl-1,3,4-thiadiazol-2-yl)amides[J].Pest Management Science,2016,73(4):761-773.
[8]Yu P,Hu J,Zhou T Y,et al.Synthesis,insecticidal evaluation of novel 1,3,4-thiadiazole chrysanthemamide derivatives formed by an EDCI/HOBt condensation[J].Journal of Chemical Research,2011,35(12):703-706.
[9]Alwan W S,Karpoormath R,Palkar M B,et al.Novel imidazo[2,1-b]-1,3,4-thiadiazoles as promising antifungal agents against clinical isolate of cryptococcus neoformans[J].European Journal of Medicinal Chemistry,2015,95:514-525.
[10]Liu F,Luo X Q,Song B A,et al.Synthesis and antifungal activity of novel sulfoxide derivatives containing trimethoxyphenyl substituted1,3,4-thiadiazole and 1,3,4-oxadiazole moiety[J].Bioorganic and Medicinal Chemistry,2008,16(7):3632-3640.
[11]Chen C J,Song B A,Yang S,et al.Synthesis and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole and5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives[J].Bioorganic and Medicinal Chemistry,2007,15(12):3981-3989.
[12]Gan X H,Hu D Y,Chen Z,et al.Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates[J].Bioorganic and Medicinal Chemistry Letters,2017,27:4298-4301.
[13]Wu W N,Tai A Q,Chen Q,et al.Synthesis and antiviral bioactivity of novel 2-substituted methlthio-5-(4-amino-2-methylpyrimidin-5-yl)-1,3,4-thiadiazole derivatives[J].Journal of Heterocyclic Chemistry,2015,53:2243-2246.
[14]Zhang K K,Liang X P,He M,et al.One-pot synthesis of novel chiralβ-amino acid derivatives by enantioselective Mannich reactions catalyzed by squaramide cinchona alkaloids[J].Molecules,2013,18(6):6142-6152.
[15]Williams A.Opportunities for chiral agrochemicals[J].Pest Science,1996,46(1):3-9.
[16]Massey M P R,Tandy M J.Challenges and frustrations in the separation and analysis of chiral agrochemicals[J].Chirality,1994,6(2):63-71.
[17]Sekhon B S.Chiral pesticides[J].Journal of Pesticide Science,2009,34(1):1-12.
[18]Yang M C,Peng C,Huang H,et al.Organocatalytic asymmetric synthesis of spiro-oxindole piperidine derivatives that reduce cancer cell proliferation by inhibiting MDM2-p53 interaction[J].Organic Letters,2017,19(24):6752-6755.
[19]Han X,Zhou H B,Dong C.Applications of chiral squaramides:from asymmetric organocatalysis to biologically active compounds[J].The Chemical Record,2016,16(2):897-906.
[20]Liu B Y,Zhao D S,Xu D Q,et al.Amide ionic liquids(AILs)/L-proline synergistic catalyzed asymmetric Mannich reactions[J].Chemical Research in Chinese Universities,2007,23(2):163-168.
[21]Bai S,Liu S,Zhu Y Y,et al.Asymmetric synthesis and antiviral activity of novel chiral amino-pyrimidine derivatives[J].Tetrahedron Letters,2018,59:3179-3183.
[22]Bai S,Liu S,Zhu Y Y,et al.Antiviral bioactivity of chiralβ-amino acid ester derivatives synthesized through a one-pot,solvent-free asymmetric mannich reaction[J].Synlett,2018,29(22):1921-1925.
[23]Bai S,Liu S,Zhu Y Y,et al.Cinchona alkaloid thiourea-catalyzed one-pot synthesis and bioselective activities ofβ-amino acid ester derivatives containing a pyrimidine moiety[J].Heterocycles,2018,96(8):1383-1397.