Powles, Nicholas, Atherton, John H. and Page, Michael I. (2012) Reactive intermediates in the H-phosphonate synthesis of oligonucleotides. Organic and Biomolecular Chemistry, 10 (30). pp. 5940-5947. ISSN 1477-0539

The formation of H-phosphonate diesters is an important step in the synthesis of oligonucleotides. Using diphenylchlorophosphate as the activator for the coupling step is often accompanied by side reactions as a result of self ‘capping’ and other reactions of the reactive intermediate. In the absence of base, the activation of ethyl H-phosphonate with diphenylchlorophosphate probably occurs through the intermediate formation of bis diethyl pyro-di-H-phosphonate rather than the expected diphenyl ethyl pyro-H-phosphonate. Pyridine acts as a nucleophilic catalyst converting diphenylchlorophosphate to its pyridinium adduct. Several side and unwanted reactions are quantified so that conditions to minimise these can be identified.