Novel synthetic pathways for the preparation ofProTides as potential therapeutic agents

The phosphoroamidate (ProTide) approach is a prodrug technology aimed to \ncircumvent metabolic bottlenecks in the activation of nucleoside-based drugs and \noptimise their intracellular delivery. The tremendous importance of the ProTide approach \nis highlighted by the approval of Sofosbuvir (Sovaldi®, HCV infections) and tenofovir \nalafenamide fumarate (TAF, Vemlidy®, HIV and HBV infections). A great deal of \nsuccess is also demonstrated by many other compounds adopting this technology either \nin clinical trials or preclinical evaluations as antiviral and anticancer agents. Given the \ngreat impact of phosphor(n)oamidate nucleoside prodrugs in the antiviral arena and \nbeyond, the application of this technology has grown dramatically. \nSeveral procedures are present in the literature for the preparation of \nphosphoroamidate prodrugs of nucleosides. However, an efficient and inexpensive \ndiastereoselective synthesis to prepare ProTides as single diastereoisomers is missing. \nAdditionally, the phosphonoamidate cognate class, one of the most significant groups of \nantiviral drugs, presents many synthetic challenges. Recent literature reported the \nsynthesis of novel acyclic nucleoside backbones including the phosphonate derivatives \nbearing a double bond in the aliphatic chain. However, the methodologies described for \nthe preparation of ProTides on alkenyl acyclic nucleosides are scarce and inefficient. \nBeside phosphoroamidates and phosphonoamidates, many difficulties can also be \nencountered in the preparation of modified unnatural nucleosides and related prodrugs. \nOne of them is the ProTide of 2’-deoxy-O6-methylguanosine to be tested for \nmitochondrial DNA depletion syndrome. \nIn this context, the research discussed in this thesis is focused on addressing the \nsynthetic problems related to unnatural nucleosides and their ProTides. This thesis aims \nto explore novel methodologies for the preparation of both phosphoroamidate and \nphosphonoamidate prodrugs of biologically relevant nucleosides in order to give easy \naccess to novel ProTides to be evaluated for their potential therapeutic acti