Electrochemical reduction of azido nucleosides: Mechanism and synthetic and analytical applications

Abstract

The mechanism of electrochemical reduction, in aqueous media, of the 3′- and 5′-azido derivatives of thymidine, uridine and 5-halogenouridines was elucidated from the electrochemical properties of these compounds when subjected to dc, DPP and ac polarography, and cyclic voltammetry. All of them undergo 2-electron reduction of the azido group to the corresponding amino derivatives in virtually quantitative yield. Those with a C(5) halogeno substituent undergo an additional 2-electron reduction of the CX bond (X = halogen), the ease of reduction decreasing in the order I > Br > Cl > F. The polarographic p K a values for protonation of the azido groups, and associated E 1 2 potentials, were dependent on the site of substitution of the azido group on the pentose ring. All the compounds, with exception of the 5-iodo analogues, exhibited high surface activity, confirmed by ac polarography. This surface activity accounted for the shift in the potential for catalytic hydrogen evolution to more positive values with E in the range 60–250 mV, depending on pH, and more marked for the 5′-azido isomers. Electrochemical reduction is shown to be the method of choice for preparative one-step syntheses of sugar-substituted amino nucleosides from the now widely available azido nucleosides. It is also a convenient procedure for monitoring the levels of chemotherapeutically active azido nucleosides (such as AZT) in physiological fluids of patients undergoing treatment for AIDS, with a lower detection limit of 1 × 10 −8 M.