Carbene-Catalyzed Asymmetric Acetalization to Access Chiral 3-Aryloxyphthalides

Abstract

Chiral acetals, particularly aryloxyacetals, are pivotal intermediates in organic synthesis, pharmaceuticals, and natural product synthesis. Aryloxyacetals have been utilized as chiral aldehyde equivalents in the total synthesis of biologically significant natural products. However, achieving high enantiocontrol in the synthesis of aryloxyphthalides remains a significant challenge due to side reactions and racemic product formation. Herein, we report a novel N-heterocyclic carbene (NHC)-catalyzed enantioselective synthesis of aryloxyphthalides from phthalaldehyde and phenols. Our methodology demonstrates broad substrate scope, providing up to 98% enantioselectivity with excellent yields. This strategy offers a practical solution for the enantioselective synthesis of aryloxyphthalides, expanding the utility of chiral acetals in asymmetric synthesis. The development of optically pure aryloxyphthalides may further benefit the synthesis of complex natural products containing phthalide moieties.

Keywords: Aryloxy phthalides; Asymmetric acetalization; Enantioselectivity; N‐Heterocyclic carbenes.