The Chemical And Enzymatic Synthesis,Biological Activity Of Coumarins And Their Derivatives

Coumarins are widely distributed in nature and had many biological activities,such as antiphlogosis, the resistance of oedema, anti-cancer, antineoplastic and improving immunity, antioxidant, moving oxygen-free radicals, protecting liver cells.In this paper, 4- methyl-7-hydroxyl coumarins and a series of Mannich bases and other amines derivatives have been synthesized through nucleophilic substitution, Fries rearrangement, Baeyer-Villiger rearrangement, Claisen rearrangement, and Mannich reaction. In order to improve the activities of coumarins and the application in medicine, cosmetic, biology, materials, a series of long chain fatty acids acylated coumarin glycoside esters have been synthesized by enzyme catalytic esterification.Coumarins were synthesized using throresorcinol and ethyl acetoacetate as starting materials and sulfuric acid as catalyst. Then, eight kinds of new compounds1a-1h were synthesized through the Mannich reaction of coumarin, formaldehyde and the ring and chain secondary amine(such as, di-n-propylamine, dimethylamine,4-hydroxy piperidine, etc) under the condition of microwave(600W, 80oC). The effect of different secondary amine, microwave heating and conventional oil bath heating on synthesis was different. By using microwave heating, the reaction time was short and the conversion rate was high.A series of 4-methyl-7-butoxy coumarin amine compounds 3a-3g were synthesized through the reaction of the 4-methyl-7-hydroxyl coumarin, Br(CH2)n Br,the ring and chain secondary amine. In the process,we found that the smaller the steric hindrance, the more the electronics group, the easier the synthesis was, the increasing of temperature was beneficial to the chemical reaction rate and the reaction yield.However, too high temperature would cause side effects and decrease reaction yield.4-methyl-5-isoamyl alkenyl-8-hydroxy-7-methoxy coumarin, which has similar structure with Osthole, was synthesized through esterification reaction, methylation reaction, isoamyl alkenyl reaction, Fries rearrangement, Baeyer-Villiger rearrangement,Claisen rearrangement, etc. We discussed the effect of different solvents and temperature on the rearrangement and study the inhibitory activity of coumarins on Hela cell.The results showed compound 9 had good inhibitory activity on Hela cell.A series of novel coumarin glycoside esters 12a-12 i were synthesized through the acylation reaction of 4-methylcoumarin-7-O-?-D-glucoside(11) with various long chain fatty acids catalyzed by lipase in organic medium. The acylation occurred regioselectively at the 6?-OH of glycosyl moiety. The enzymatic synthesis wereoptimized to achieve 54%-70% yield, using Novozym 435( 10 mg/m L) in acetone and pyridine as solvent(v/v, 9:1), molar ratio of 10:1(acyl donor/coumarin glycoside),temperature of 40-50?for 96 h. 9 kinds of new compounds have been confirmed by1 H NMR, 13 C NMR, IR and MS techniques.The thesis synthesizes thirty-one compounds. Among them, twenty-nine are new compounds, and their structures have been confirmed by1 H NMR,13 C NMR, IR and MS.