Enantioselective Synthesis of Tetra‐substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution

A general and highly enantioselective method for the preparation of tetra‐substituted 3‐hydroxyphthalide esters via isothiourea‐catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)‐HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3‐hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)‐, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl‐isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.