单甲基化表没食子儿茶素没食子酸酯的化学合成
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摘要
表没食子儿茶素没食子酸酯(EGCG)经甲基化后在抗过敏、降血脂等方面具有更高的生物活性。但茶叶中甲基化EGCG含量较低,为进一步研究其生物活性,本文对其半合成路线进行了优化。先以EGCG为原料制得五苄基化的表没食子儿茶素(EGC),然后将没食子酸丙酯经4-甲氧基苯甲醛二甲缩醛保护,甲基化,脱保护,苄基化,水解得到3,4-二苄氧基-5-甲氧基苯甲酸,再与苄基化EGC酯化和脱苄基得到表没食子儿茶素3-O-甲基没食子酸酯(3″-Me-EGCG);同样将没食子酸丙酯经全乙酰化、选择性甲基化、脱除乙酰基、苄基化、水解得到3,5-二苄氧基-4-甲氧基苯甲酸,再与苄基化EGC酯化和脱苄基得到表没食子儿茶素4-O-甲基没食子酸酯(4″-Me-EGCG);总产率分别为53%和57%。
(-)-Epigallocatechin 3-O-methyl gallate(3″-Me-EGCG)and(-)-epigallocatechin 4-O-methyl gallate(4″-Me-EGCG),minor natural compounds of green tea polyphenol,exihibit antiallergic and hypolipidemic activity.In this study,semisynthetic methods of 3″-Me-EGCG and 4″-Me-EGCG were modifidied to investigate their biological activity.The key intermedite pentabenzylated epigallocatechin(EGC)was prepared by benzylation of epigallocatechin gallate(EGCG)and hydrolysis of perbenzylated EGCG.Protection of propyl gallate by 4-methoxybenzaldehyde dimethyl acetal with subsequent methylation,deprotection,benzylation,and hydrolysis produced 3,4-bis(benzyloxy)-5-methoxybenzoic acid.This acid was then reacted with pentabenzylated EGC to afford an ester which was debenzylated to provide 3″-Me-EGCG;Acetylation of propyl gallate with subsequent selective methylation,removal of acetyl,benzylation,and hydrolysis gave 3,5-bis(benzyloxy)-4-methoxybenzoic acid,which was reacted with penbenzylated EGC to get another ester which was debenzylated to obtain 4″-Me-EGCG.The total yields of 3″-Me-EGCG and 4″-Me-EGCG were 53%and 57%,respectively.
(-)-Epigallocatechin 3-O-methyl gallate(3″-Me-EGCG)and(-)-epigallocatechin 4-O-methyl gallate(4″-Me-EGCG),minor natural compounds of green tea polyphenol,exihibit antiallergic and hypolipidemic activity.In this study,semisynthetic methods of 3″-Me-EGCG and 4″-Me-EGCG were modifidied to investigate their biological activity.The key intermedite pentabenzylated epigallocatechin(EGC)was prepared by benzylation of epigallocatechin gallate(EGCG)and hydrolysis of perbenzylated EGCG.Protection of propyl gallate by 4-methoxybenzaldehyde dimethyl acetal with subsequent methylation,deprotection,benzylation,and hydrolysis produced 3,4-bis(benzyloxy)-5-methoxybenzoic acid.This acid was then reacted with pentabenzylated EGC to afford an ester which was debenzylated to provide 3″-Me-EGCG;Acetylation of propyl gallate with subsequent selective methylation,removal of acetyl,benzylation,and hydrolysis gave 3,5-bis(benzyloxy)-4-methoxybenzoic acid,which was reacted with penbenzylated EGC to get another ester which was debenzylated to obtain 4″-Me-EGCG.The total yields of 3″-Me-EGCG and 4″-Me-EGCG were 53%and 57%,respectively.
引文
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[12] Saijo N,Masaya A,Yagi K.Novel Function of rare catechin,epigallocatechin-3-(3″-O-Methyl)gallate,against cold injury in primary rat hepatocytes[J].Journal of Bioscience and Bioengineering,2003,96(6):559-563.
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[14] Kawase M,Wang R,Shiomi T,et al.Antioxidative activity of(-)-epigallocatechin-3-(3″-O-methyl)gallate isolated from fresh tea leaf and preliminary results on its biological activity[J].Bioscience,Biotechnology,and Biochemistry,2000,64(10):2218-2220.
[15] Chiu F L,Lin J K.HPLC analysis of naturally occurring methylated catechins,3″-and 4″-methyl-epigallocatechin gallate,in various fresh tea leaves and commercial teas and their potent inhibitory effects on inducible nitric oxide synthase in macrophages[J].Journal of Agricultural and Food Chemistry,2005,53(18):7035-7042.
[16] Kurita I,Maeda-Yamamoto M,Tachibana H,et al.Antihypertensive effect of benifuuki tea containing O-Methylated EGCG[J].Journal of Agricultural and Food Chemistry,2010,58(3):1903-1908.
[17] Wan S B,Ping D Q,Chan T H.Regiospecific and enantioselective synthesis of methylated metabolites of tea catechins[J].Tetrahedron,2006,62(25):5897-5904.
[18] Aihara Y,Yoshida A,Furuta T,et al.Regioselective synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl(Ns)protecting group[J].Bioorganic and Medicinal Chemistry Letters,2009,19(15):4171-4174.
[19] Lai R,Zhao W,Huang Y,et al.The synthesis of methylated epigallocatechin gallate[J].Chemistry of Natural Compounds,2015,51(3):472-475.
[20] Chan T H,Chan,K F,Zhao Y,et al.Synthesis of(±)-5’-methoxyhydnocarpin-D,an inhibitor of the Staphylococcus aureus multidrug resistance pump[J].Tetrahedron,2005,61(16):4149-4156.
[21] Zhu J,Chastanet J,Beugelmans R.Selective hydroxy group protection of gallic acid[J].Synthetic Communications,1996,26(13):2479-2486.
[2] Leong D J,Choudhury M,Hanstein R,et al.Green tea polyphenol treatment is chondroprotective,anti-inflammatory and palliative in amouse post-traumatic osteoarthritis model[J].Arthritis Research&Therapy,2014,16(6):508.
[3] Tipoe G L,Leung T M,Liong E C,et al.Epigallocatechin-3-gallate(EGCG)reduces liver inflammation,oxidative stress and fibrosis in carbon tetrachloride(CCl4)-induced liver injury in mice[J].Toxicology,2010,273:45-52.
[4]伍妍俊,汪小钢,宛晓春.甲基化EGCG的研究现状及展望[J].茶叶科学,2010,30(6):407-413.Wu Y J,Wang X G,Wan X C.Present studies and the research prospects on the methylated EGCG[J].Chaye Kexue,2010,30(6):407-413.
[5] Saijo R.Isolation and chemical structures of two new catechins from fresh tea leaf[J].Agricultural and Biological Chemistry,1982,46(7):1969-1970.
[6] Sano M,Suzuki M,Miyase T,et al.Novel antiallergic catechin derivatives isolated from Oolong tea[J].Journal of Agricultural and Food Chemistry,1999,47(5):1906-1910.
[7] Amarowicz R,Shahidi F.Presence of two forms of methylated(-)-epigallocatechin-3-gallate in green tea[J].Molecular Nutrition and Food Research,2003,47(1):21-23.
[8] a.吕海鹏,林智,谭俊峰,等.茶叶中的EGCG3″Me研究[J].食品与发酵工业,2008,34(10):22-25.Lv H P,Lin Z,Tan J F,et al.Study on EGCG3″Me in Tea[J].Food And Fermentation Industries,2008,34(10):22-25.b.吕海鹏,谭俊峰,林智.茶树种质资源EGCG3″Me含量及其变化规律研究[J].茶叶科学,2006(4):310-314.Lv H P,Lin Z,Tan J F.Study on the content of EGCG3″Me in different tea germplasms and its changes[J].Chaye Kexue,2006,26(4):310-314.
[9] Maeda-Yamamoto M,Nagai H,Asai K,et al.Changes in epigallocatechin-3-O-(3-O-methyl gallate and strictinin contents of tea(Camellia sinensis L.)cultivar‘Benifuki’in various degrees of maturity and leaf order[J].Food Science and Technology Research,2004,10(2):186-190.
[10] Maeda-Yamamoto M,Ema K,Shibuichi I.In vitro and in vivo anti-allergic effects of‘Benifuuki’green tea containing O-methylated catechin and ginger extract enhancement[J].Cytotechnology,2007(55):135-142.
[11] Maeda-Yamamoto M,Ema K,Monobe M,et al.The efficacy of early treatment of seasonal allergic rhinitis with Benifuuki green tea containing O-methylated catechin before pollen exposure:an open randomized[J].Allergology International,2009(58):437-444.
[12] Saijo N,Masaya A,Yagi K.Novel Function of rare catechin,epigallocatechin-3-(3″-O-Methyl)gallate,against cold injury in primary rat hepatocytes[J].Journal of Bioscience and Bioengineering,2003,96(6):559-563.
[13] Suzuki M,Yoshino K,Maeda-Yamamoto M,et al.Inhibitory effects of tea catechins and O-methylated derivatives of(-)-epigallocatechin-3-O-gallate on mouse type IV allergy[J].Journal of Agricultural and Food Chemistry,2000,48(11):5649-5653.
[14] Kawase M,Wang R,Shiomi T,et al.Antioxidative activity of(-)-epigallocatechin-3-(3″-O-methyl)gallate isolated from fresh tea leaf and preliminary results on its biological activity[J].Bioscience,Biotechnology,and Biochemistry,2000,64(10):2218-2220.
[15] Chiu F L,Lin J K.HPLC analysis of naturally occurring methylated catechins,3″-and 4″-methyl-epigallocatechin gallate,in various fresh tea leaves and commercial teas and their potent inhibitory effects on inducible nitric oxide synthase in macrophages[J].Journal of Agricultural and Food Chemistry,2005,53(18):7035-7042.
[16] Kurita I,Maeda-Yamamoto M,Tachibana H,et al.Antihypertensive effect of benifuuki tea containing O-Methylated EGCG[J].Journal of Agricultural and Food Chemistry,2010,58(3):1903-1908.
[17] Wan S B,Ping D Q,Chan T H.Regiospecific and enantioselective synthesis of methylated metabolites of tea catechins[J].Tetrahedron,2006,62(25):5897-5904.
[18] Aihara Y,Yoshida A,Furuta T,et al.Regioselective synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl(Ns)protecting group[J].Bioorganic and Medicinal Chemistry Letters,2009,19(15):4171-4174.
[19] Lai R,Zhao W,Huang Y,et al.The synthesis of methylated epigallocatechin gallate[J].Chemistry of Natural Compounds,2015,51(3):472-475.
[20] Chan T H,Chan,K F,Zhao Y,et al.Synthesis of(±)-5’-methoxyhydnocarpin-D,an inhibitor of the Staphylococcus aureus multidrug resistance pump[J].Tetrahedron,2005,61(16):4149-4156.
[21] Zhu J,Chastanet J,Beugelmans R.Selective hydroxy group protection of gallic acid[J].Synthetic Communications,1996,26(13):2479-2486.