Study On The Catalytic Promiscuity, Tandem Reaction And Modulation Of Hydrolase

Enzyme plays more and more important role in organic synthesis as the development of the enzymatic reaction. The discovery of new catalytic ability of enzyme, modulation of the enzymatic reaction and the tandem reaction synthetic strategy based on the enzymatic reaction attracts the research interest of chemists.Lipase was firstly found to catalyze the Markovnikov addition to form nitrogen-carbon bond in organic media. After screening the enzyme sources, reaction media, reaction temperature and the structure of substrates, lipase M from Mucor javanicus (MJML) catalyzed the Markovnikov addition of imidazoles and pyrimidines to vinyl esters successfully. A series of N-heterocycle derivatives were synthesized. The control experiments demonstrated that the active site of MJML was responsible for the enzymatic Michael addition reaction. The mechanism for the Markovnikov addition reaction catalyzed by MJML was proposed.A single lipase-catalyzed one-pot, three-component reaction was established successfully. Through the optimization of enzyme and reaction media, CAL-B catalyzed the three-component reaction of imidazole,2-methylimidazole and 4-methylimidazole with aldehyde and ester in t-butyl methyl ether, while lipase PS was able to promote the three-component reaction of 4-nitro-imidazole in DMSO.Small organic molecular could catalyze the Michael addition and Markovnikov addition of N-heterocycles. The influence of the structure and usage of catalyst, addition donor and acceptor was investigated. The experiment results demonstrated that N-eterocycles the showed higher catalytic ability to Michael addition than Markovnikov addition.A new strategy for the synthesis of drug derivatives was developed by combining Markovnikov addition with acylation procedure. The N-heterocyclic mono-vinyl esters were prepared from Markovnikov addition azoles and pyrimidine to divinyl esters catalyzed by N-methylimidazole, followed enzymatic reaction with drugs. A series of drug derivatives containing N-heterocycles were successfully obtained with high regioselectivity.The influence of additives on the enzymatic reaction was investigated. The results showed that 10%[BMIM]BF4 could improve the reaction rate. And a better result was obtained by adding 10% N-methylimidazole. It was found that PGA could catalyze esterification by adding N-methylimidazole. The control experiments demonstrated that the cooperation of additive and the active site of PGA was responsible for the catalytic action. The influence of additive on the structure of enzymes was investigated by IR and AutoDock simulation. High efficient enzymatic reactions were achieved by modulation of additives.In this thesis,99 compounds were synthesized including 21 Markovnikov adducts, 25 Michael adducts,20 compounds from three-component reaction and 33 drug derivatives. These compounds were characterized by 1H NMR, 13C NMR, FTIR and ESI-MS and 58 compounds have been confirmed to be new compounds.