Studies on Oxidative Couplings in H-Phosphonate Chemistry

In this thesis oxidative coupling of H-phosphonate and H phosphonothioate diesters with different alcohols and amines are presented. Since the reactions with alcohols previously have been particularly unfavourable due to competing side reactions, a modified protocol leading to high coupling yields of structurally diverse hydroxylic components was developed. The phosphorylation reaction was studied using 31P NMR spectroscopy and for the first time the previously only postulated reactive intermediate involved in these reactions was observed. The use of iodine in combination with a bulky chlorosilane in pyridine was found to have a profound effect on both the suppression of side reactions and the rate of the oxidative couplings, and led to a clean formation of phosphorylated products in high yields. This synthetic protocol was then extended to include coupling reactions with bis-functional reagents containing hexamethylene linkers to provide handles for derivatisations of oligonucleotides. A synthetic protocol consisting of the stereospecific oxidative coupling of amines with H-phosphonate diesters to produce phosphoroamidates was designed in such a way that it permitted control of the stereochemical outcome of the reactions. Based on a silylation-mediated reaction utilising phenyl H phosphonothioate monoester as a thiophosphonyl transferring agent, a method was developed and used for the preparation of H-phosphonothioate building blocks for the synthesis of DNA analogues.