Studies On The Synthesis Of Nucleoside Polyphosphates

Nucleoside polyphosphates are a large group of naturally occurring compounds, including nucleoside5’-diphosphates, nucleoside5’-triphosphates, nucleoside diphosphate sugars, and dinucleoside polyphosphates. The physiologically active dinucleoside polyphosphates are present in human and other mammalian species and known as intra-and extracellular regulators of many important biological processes, dinucleoside polyphosphates have a myriad of applications in a great variety of biological and medicinal research. Currently, there is still no efficient and practical methods for the synthesis of dinucleoside polyphosphates.The current thesis focuses on development of novel synthetic methodologies for dinucleoside polyphosphates on the basis of H-phosphonate method and P(V)-N activation strategy, respectively. The detailed research contents are described as follow.1) In the study of the H-phosphonate method for the synthesis of symmetrical P1,P2-dinucleoside-5’,5’-diphosphates, nucleoside5’-H-phosphonate monoesters were converted into silylated phosphite and oxidized with iodine to generate reactive pyridinium phosphoramidates. Upon the key sequential hydrolysis, six symmetrical P1,P2-dinucleoside-5’,5’-diphosphates were obained in high yields. The reaction path was detemined with the observation of reactive P1,P2,P3-trinucleoside-5’-triphosphate intermediate in31P NMR tracing experiments.2) The triphosphates and homodinucleotides of2’,3’-dideoxynucleosides (ddNs) were efficiently synthesized from the corresponding nucleoside H-phosphonate monoesters via the reactive pyridinium phosphoramidate intermediates. The result of the31P NMR tracing experiment confirmed the existence of P1,P2,P3-trinucleoside-5’-triphosphate intermediate and reaction path proposed. Moreover, addition of3equiv. of pyrophosphate could effectively increase the yield of ddN triphosphates.3) An efficient P(V)-N activation method based on nucleoside 5’-phosphoropiperidates/4,5-dicyanoimidazole (DCI) system was developed for the synthesis of dinucleoside polyphosphates and their analogs. The detailed reaction conditions such as the amount of DCI activator, ratio of reactants, solvent, and temperature were systematically optimized for different types of nucleophiles based on their unique chemical properties.