In conclusion, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted 3-hydroxyphthalide derivatives is reported using (2S,3R)-HyperBTM (5 mol%) as the catalyst (>40 examples in total). The scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields (up to 99%, 99:1 er) observed across a broad range of substrate derivatives. Aliphatic and aromatic substitution is tolerated at C(3)-, as well as substitution of the aromatic core. A diverse range of anhydrides, including those derived from bioactive and pharmaceutically relevant acids, can be used as the acyl donor in this catalytic process, allowing the preparation of a tetra-substituted C(3)-t-Bu analogue of the known prodrug Talmetacin in 97:3 er. The high levels of enantioselectivity observed in this DKR process has been rationalised through DFT computation, with a heteroatom O•••isothiouronium interaction identified as being key to high enantiodiscrimination in this process. Ongoing work from within our laboratory is aimed at developing further effective DKR processes using isothioureas as catalysts alongside developing an understanding of alternative recognition motifs that can give rise to enantioselectivity in such processes.