The process of dephosphorylation of tyrosine residues in proteins is key to a number of cellular processes and is controlled by protein tyrosine phosphatases (PTPs). Misregulation of these phosphatase enzymes is implicated in a range of human disease states, including cancer, type 2 diabetes, and a number of autoimmune conditions. Many natural substrate mimetics - including those substituting oxygen for a non-hydrolysable difluoromethylene group - lack cell permeability as a result of the ionised phosphate group at physiological pH, and many compounds are not sufficiently phosphatase selective as a result of the highly conserved active site. As a result, the development of potent, cell-permeable and selective phosphatase inhibitors has been severely limited. In chapter one, synthetic strategies for the synthesis of model phosphonodiamidate prodrugs with a difluoromethylene moiety adjacent to phosphorus are explored. Through masking the charge of the phosphonic acid, the prodrugs should be cell permeable and should be activated intracellularly. Also reported is the synthesis of a number of novel compounds displaying diversity at the carbon adjacent to phosphorus, as well as a study analysing aromatic substituent effects on the reaction pathway. In chapter two, the amination conditions developed are applied to the synthesis of a series of novel prodrugs designed to target protein tyrosine phosphatase 1B (PTP1B). Chapter three shows the report of the preliminary biochemical and in vitro analysis of these novel prodrugs and the corresponding phosphonic acids. Finally, progress toward the synthesis of precursors of novel allylic phosphonate prodrugs incorporating an internal nucleophile that can activate in the presence of catalytic amounts of palladium is explored in chapter four.