Synthesis Of Thiol Containing Chiral Acyclic Nucleoside Compounds By Asymmetric Michael Addition Reaction

Nucleoside compounds has a remarkable significance influence in biology,and there a plenty of nucleoside medicine on sale.Nucleoside compounds can directly affect the formation of RNA and protein in the human body,so it can affect the reproduction progress of cancer cells and the virus.So nucleoside drugs in the drug structure have a very important significance.Among all kinds of nucleoside compounds,acyclic nucleoside compounds are one of the big categories.Acyclic nucleoside means in the position of ribose substituted with other hydroxyl containing alkyl side chain of nucleosides in nucleoside structure.The traditional ways to synthesis acyclic nucleoside compounds has these plans: first,synthesis the hydroxyl side chain and connected it to the nucleobase;second synthesis the acyclic nucleoside through asymmetric induction reaction;third,synthesis the acyclic nucleoside through asymmetric catalyst reaction..The first two methods,due to the need for chiral side chain compounds,are greatly restricted.Based on previous studies of nucleosides and the investigation of documents,we found that there are no report on the synthesis of chiral pyrimidine acyclic nucleoside through asymmetric catalyst reaction.So we designed and synthesis a series of pyridine substrate and use the organic catalyst to catalysis the reaction with the thio acetic acid.Finally we synthesis a series of acyclic nucleoside compound that containing thio group.And we expect these compounds can have great anti-cancer or anti-virus activity.In this paper,we investigate the reaction between our pyrimidine substrate and thio acetic acid.We investigate the reaction through: investigation of catalysts;investigation of solvent;investigation of solvent temperature;and the investigation of additive and so on.And we carried out the expanding of the substrate Under the optimized condition.Finally we found: on the-20? temp,3% mol catalyst quantity;the solvent is ether and the 4A M.S as addictive.The reaction can happen with 99% yield and 99% ee.Then,we examine the universality of the reaction,We found that the reaction result decreases under the reaction condition,and we investigated the effect of substituent effect of pyrimidine and effect of ester group,and we found a better reaction condition,and expansion a variety of different types of substrate.We also culture a single crystal and got the absolute configuration of our product.In addition,after 2 steps reaction we synthesis a new acyclic nucleoside that containing thio group.In this paper,we present a new method for asymmetric synthesis of chiral acyclic nucleoside compounds,and developed a new method for the synthesis of acyclic nucleosides.