A membrane-modulated chemoenzymatic dynamic kinetic resolution for the synthesis of chiral phthalidyl esters

Abstract

Abstract Chemoenzymatic dynamic kinetic resolution (DKR) offers a powerful bridge between chemocatalysis and biocatalysis for the preparation of chiral molecules. However, its broader application has been limited by the incompatibility between racemization and resolution catalysts, where mutual interference often compromises catalytic activity and/or enantioselectivity. Here, we introduce a membrane-modulated strategy that circumvents the mandatory requirement for strict rate matching, offering a significant conceptual advance in the design of chemoenzymatic DKR systems. By spatially separating racemization and resolution while enabling their collaborative operation within a two-stage, two-step process, this approach dramatically enhances the typically low efficiency of conventional DKR, allowing the efficient synthesis of tetra-substituted 3-hydroxyphthalide esters that are challenging to access by traditional methods, and greatly expanding the scope of chiral phthalide preparation. This membrane-modulated strategy not only streamlines the typically laborious optimization required in conventional DKR for developing an alternative chemoenzymatic DKR approach but also provides a useful platform with the potential for pharmaceutical synthesis.