Nucleoside Reverse Transcriptase Inhibitors (NRTIs) became the first class of FDA approved drugs for the treatment of HIV in 1987, upon the release of zidovudine (AZT). Lacking a 3´-hydroxyl moiety means that once incorporated into the growing RNA chain by the viral enzyme reverse transcriptase, no further nucleosides may be added on, leading to chain termination. The main problems attributed to NRTIs are associated toxicities and development of viral resistance, thus there is a constant need for new therapy options.1 4´-Thionucleosides have long been of interest to researchers for their ability to act as bioisosteres of cell-native nucleosides. Although none have made it to market, several have exhibited promising antiviral activity.2-4 We aim to synthesise and test several novel 4´- thionucleosides for biological activity. Using methodology published by Young et al. we have adapted and optimised their strategy to build the 4´-thiosugar core of our molecules.5 Important steps have included the incorporation of sulfur into the molecule’s scaffold, and our discovery of a microwave-based green-approach to the Krapcho decarboxylation of a thiolactone-type species. The key step in the overall synthesis of our 4´-thionucleosides is a Vorbrüggen-type glycosylation, with which we initially encountered difficulties. In this presentation we will outline our synthetic approach and process optimization strategies.