Study On Asymmetric Synthesis Of Purine Nucleoside Anti - HCV Active Compounds With Five - Carbocyclic

Nature is asymmetrical, and the most substants for construction of organisms’ life possess chiral center, such as amino acids and enzymes. In the interpretation of life, the asymmetric molecules caused the phenomenon of chiral recognition. People, a special group in nature, possess diffrient physiological differences with other organisms. Therefore, the chiral drug for human is very important and the best evidence is the tragedy of thalidomide in the last century in Europe.HCV, a kind of hepatitis, is popular in the world, which can cause liver chronic inflammation, necrosis and fibrosis. Furthermore, some patients can be transformed into liver cirrhosis and hepatocellular carcinoma (HCC). At present, the clinical drug for the treatment of hepatitis C is IFN, IFN and ribavirin combination therapy. However, the inadequacy of interferon and ribavirin is low efficiency (40-50%), long cycle of treatment and greater side effects. Therefore, efficient drug for HCV is important for treatment of hepatitis C. The main purpose of this paper is to explore the asymmetric synthesis of purine nucleoside structure contating chiral five member ring for activity of anti-HCV.In this dissertation, based on the cheaper2-azabicyclo [2,21] g-5-allyl-3-ketone material, the synthesis strategy of enzymatic kinetic resolution was used as key step for the synthesis of chiral compound24. The major results included:1. The method for kinetic resolution of compound23was established by the Bacillus subtilis enzyme (Y=46%, dr>99%).2. Under potassium permanganate/pyridine oxidative condition, the high diasteroselective method for the preparation of compound30was explored by self-induced asymmetric dihydroxylation (Y=80%, dr>99:1)。 3. The key chiral intermediate15was convenient preparation using the strategy of regiosenective reduction.(Y=68%, dr>99:1).4. The method for synthesis of purine nucleoside fragment was explored. In addition, a convenient approach for preparation of compound34and35was established with high stereoselectivity (dr>99:1).5. Furthermore, a synthetic process for preparation of tripeptide48for100gram scale was achieved.