Novel Synthetic Methodologies For Phosphate-masked Nucleoside Prodrugs And Nucleoside Diphosphate Sugars

Phosphorylated nucleoside compounds and their derivatives have important applications in biology and medicinal research. Phosphate-masked nucleoside prodrugs can improve pharmacokinetic properties of nucleoside drugs and enhance their antiviral activity. On the other hand, nucleoside diphosphate sugars (NDP-sugars) are the natural glycosyl donors in the biosynthesis of glycosyl compounds in cells. In recent years, the chemoenzymatic methods based on glycosyltransferases and NDP-sugars have been extenstively applied in oligosaccharide synthesis and the development of novel antibiotics. However, general and high-yielding methods for the synthesis of these two types of compounds are still an unsolved problem.This thesis focuses on development of novel synthetic methodologies for nucleoside phosphoramidates and their derivatives via the H-phosphonamidate intermediates and nucleoside diphosphate sugar via the P(V)-N activation strategy. The main research work is described as follow.1. A series of amino acid methyl ester H-phosphonamidates of AZT and d4T were prepared in excellent yields from the controlled tandem substitution reactions on PCl3with pyridine as a suitable base. The properties of these H-phosphonamidates were studied.2. An efficient and convenient method for the synthesis of nucleoside5’-phosphoramidates and heteroatom-substituted phosphoramidates via the oxidation of H-phosphonamidates has been developed. The oxidization with iodine, sulfur, and selenium afforded nucleoside5’-phosphoramidates, thiophosphoramidates, and selenophosphoramidates in high yields.3. A novel approach for the preparation of sugar-1-phosphates via glycosyl-l-H-phosphonates has been developed. Phosphitylation of acetyl-protected sugars with triimidazolyl phosphite (PIm3), oxidation upon silylation, and final deprotection afforded sugar-1-phosphates in excellent yields.4. An improved P(V)-N activation strategy based on nucleoside5’-phosphoropiperidates/4,5-dicyanoimidazole (DCI) system has been developed for the synthesis of NDP-sugars. The detailed reaction conditions such as the amount of DCI activator, ratio of reactants, and temperature were systematically optimized.