Synthesis of a new pyridine-stretched nucleoside

Abstract

Synthetic oligonucleotides have potential, clinical usefulness for controlling gene expression at the DNA level. Inhibition of gene expression at the DNA level can be achieved by using triplex-forming oligonucleotides (TFOs). Existing TFOs have their limitations therefore there is a need to develop synthetic analogues that address this problem. This thesis describes a viable synthetic route for new pyridine-stretched nucleosides of diaminopurine (strD) and proposals for guanine (strG). These new bases are intended for incorporation into pyridine-stretched oligonucleotides (PSOs) for planned evaluation as potential new, antigene TFOs. 1’-Chloro-2’-deoxy-3’,5’-di-O-toluoyl-c.-D-erythro-pentofuranose 4, which has proved to be a good reagent for the synthesis of 2’-deoxyribonucleosides, was synthesized in three steps from 2’-deoxyribose. Compound 4 was reacted with the cesium salt of 4(5)-nitroimidazole 5 giving four different isomers (6-9), which were identified by NMR. The glycosylation reaction was optimized by using the different solvents and different temperatures to maximize the yield of 1-(2'-Deoxy-3',5'-di-O-toluoyl-o/B-D-erythro-pentofuranosyl)-5-nitroimidazole 6. The nitro nucleoside 6 was hydrogenated with 5% Pd/C to give the amino derivative 10, which was unstable on attempted isolation. To avoid the decomposition, amino derivative 10 was formed in situ and was reacted immediately on C-addition with ethoxymethylene malononitrile (EMMN) to give 11. Despite repeated attempts this reaction was consistently low yielding. Cyclisation of 11 gave the pyridine ring and deprotection of the sugar in the same step gave 12 in high yield. Neutralization with citric acid was very important to maintain the product yield (84%). Finally, cyclisation of nucleoside 12 with guanidine gave strD. The highest yield (45%) was obtained using methanol at 145 °C in a steel bomb. The structures of all compounds were fully supported by their spectroscopic properties. Potentially viable routes to strG are proposed.

Date of Award	2002
Original language	English
Awarding Institution	Aston University
Supervisor	William Fraser (Supervisor)