Synthetic approaches to novel, Triazole-containing Oligonucleotide analogues
Tazioli, Lia Ashley Maria
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The work reported in this thesis focuses on the development of synthetic approaches to prepare novel triazole-containing nucleic acid (TCNA) monomers for subsequent incorporation into oligomers. The triazole moiety was designed to be prepared using “click chemistry”. Initial studies involved development of viable synthetic pathways for preparation of both the required azide component, derived from L-serine methyl ester and the nucleobase-containing alkyne component. The azide has been successfully synthesised from either protected or unprotected L-serine methyl ester by direct diazotransfer employing the novel ‘diazo donor’, imidazole-1-sulfonyl azide 152. Synthesis of the four protected nucleobase-containing alkyne components has been achieved in overall yields ranging from 55-89%. The key step involved alkylation of the appropriately protected nucleobase with propargyl bromide. A series of model ‘click’ reactions were performed in which it was found that the best yields of triazole products were obtained using CuSO4·5H2O and sodium ascorbate in a 1:2 ratio. These conditions have been applied to the ‘click’ reaction employing the thymine alkyne component 161 and L-serine derived azide 158 to afford the desired thymine-derivatised triazole product 246 in a 44% yield. Preliminary studies into converting the resulting triazole compound into the required phosphoramidite thyminyl TCNA monomer 252 have been undertaken.