The bicyclic 3H-isobenzofuran-1-one skeleton, commonly known as the phthalide scaffold I, is characterized by the fusion of a g-lactone with a benzene core (Figure ). A range of compounds bearing the phthalide structure are found within natural products and are known to have significant and varied biological activities. For example, n-butyl phthalide is marketed as an anti-platelet drug, with the (S)-enantiomer more effective than its enantiomer. Phthalide, and in particular its 3-substituted derivatives, are also widely recognised as valuable starting materials in organic synthesis, and have been particularly used for the synthesis of naphthalene and naphthacene natural products. 3-Hydroxyphthalide II reversibly ring-opens to generate 2-formylbenzoic acid, with the cyclised form favoured in most solvents. A range of 3-hydroxyphthalides are natural products and possess significant bioactivity. For example, hyphodermin B contains a C(3)-hydroxyl substituent, while tetrasubstituted 3-hydroxyphthalide natural products such as corollosporine and Danshenspiroketallactone also show biological activity (Figure ). Significantly, 3-hydroxyphthalide ester derivatives are also of widespread interest. For example, Luterosin is a natural product that displays ichthyotoxic activity, while ester derivatives of 3-hydroxyphthalide have been widely investigated as prodrugs of the corresponding carboxylic acid. In this area, marketed prodrugs of acylated 3-hydroxyphthalide compounds such as Talmetacin and Talampicillin [1e] have been described. Given their significance, catalytic methods capable of preparing enantiopure tri-substituted 3hydroxyphthalide esters have been investigated, although methods that allow the effective preparation of the corresponding tetra-substituted phthalide ester analogues are a recognised synthetic challenge. Within this area the configurational lability of the 3hydroxyphtalide unit (through ring-opening and ring-closure) has been exploited as a key testing ground for the development of dynamic kinetic resolution (DKR) processes (Figure ). The current state-of-the-art in this area has been described by Chi and co-workers, who demonstrated an oxidative NHC catalysed enantioselective acylative DKR of 3-hydroxyphthalides with excellent enantioselectivity (up to 98:2 er) although a stoichiometric oxidant (3,3′,5,5′-tetra-tert-butyldiphenoquinone, DQ) is required. Further work by Zhang and co-workers demonstrated the use of imidazole derivative Cy-DPI 2 in the DKR of 3-hydroxyphthalide derivatives, generating ester products with excellent enantioselectivity (up to >99:1 er). The widely recognized remaining challenge in the area of acylative DKR is to develop effective processes for the preparation of A. Phthalide and 3-hydroxyphthalide derivatives enantioenriched tetra-substituted ester analogues from lactols. In the preceding manuscript the isothiourea (2S,3R)-HyperBTM was shown to promote the DKR of tetra-substituted morpholinone and benzoxazinone lactols to generate the corresponding lactol esters in highly enantioenriched form. In this manuscript (Figure ), the application of isothiourea-mediated enantioselective acylative DKR to tetra-substituted 3-hydroxyphthalide derivatives is reported. The scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields (up to 99% yield, 99:1 er) observed across a broad range of substrate derivatives. To the best of our knowledge, the only previous examples of such a protocol were demonstrated as part of Chi's work, elegantly demonstrating the feasibility of this process but with only moderate to good enantioselectivity observed (up to 86:14 er, 7 examples). Results and Discussion: Optimisation: The proposed DKR process was initially developed using the acylation of 3-methyl-3-hydroxyphthalide 4 as a model substrate to generate the corresponding tetrasubstituted ester (Table ). Treatment of 4 with the isothiourea (2S,3R)-HyperBTM 3 (5 mol%), isobutyric anhydride (1.5 equiv.), i-Pr2NEt (1.5 equiv.) in toluene gave a 57% yield of 7 in 65:35 er (entry 1). Variation of the solvent showed that higher enantioselectivity was observed in chlorinated solvents (CH2Cl2 or CHCl3), giving 7 in 88% yield and 83:17 er (entries 3-4). Variation of the base equivalents showed that the base was necessary for optimal reactivity, although the stoichiometry could be reduced (to 1.0 equiv.) without detriment to yield or selectivity (entries 4-6). Alternative bases (lutidine and K2CO3) showed marginally improved enantioselectivity at room temperature (entries 7 and 8), with -20 ˚C proving optimal, giving ester 7 in 73% isolated yield and 93:7 er (entries 9 and 10). Application of these conditions to a small range of alternative substrates (R = Et 5, Ph 6) indicated that the nature of the C(3)-substituent at the carbinol centre has a profound impact upon both rate of product formation and product enantioselectivity (~20% conversion at -20˚C, see SI for details). For example, incorporation of a C(3)ethyl substituent resulted in improved yield and selectivity compared to the C(3)-methyl substituted derivative at rt or 0 ˚C (entries 11 and 12), giving ester 8 in 70% yield and 94:6 er. The introduction of an aromatic C(3)-Ph substituent at the carbinol centre 6 resulted in only moderate yield but high enantioselectivity at room temperature (entry 13). Increasing the reaction temperature to 50 ˚C led to improved conversion while maintaining enantioselectivity, giving 9 in 82% yield and 94:6 er (entry 14).