Enantioselective Synthesis of 3-Hydroxy Oxindoles via NHC-Catalyzed [2 + 2] Cycloaddition

Abstract

Chiral 3-hydroxy-3-substituted oxindoles represent privileged heterocyclic cores ubiquitous in pharmaceuticals, lead compounds, and bioactive natural products. Despite the establishment of numerous synthetic methodologies for the asymmetric construction of 3-hydroxy-3-substituted oxindoles, the enantioselective construction of such frameworks bearing multiple stereogenic centers under mild conditions remains challenging. Most existing approaches require transition-metal catalysts, harsh reaction conditions, or prefunctionalized starting materials, which limit their practical utility. In recent years, N-heterocyclic carbenes (NHCs) have emerged as powerful and efficient organic catalysts in an expanding range of asymmetric transformations. Many novel activation modes, including the generation of acyl azoliums and enolates, have been developed using NHCs as key organocatalysts. Consequently, diverse functional and biologically active molecules have been constructed via NHC-catalyzed reactions. Among these intermediates, enolate intermediates play a pivotal role in NHC catalysis and are widely utilized as two-carbon (2C) synthons in [2 + 4] cycloadditions to construct heterocyclic compounds. However, exploiting alternative [2 + n] annulation modes, particularly [2 + 2] cycloadditions, remains of considerable scientific interest and practical relevance due to the potential for generating strained β-lactone intermediates that can be further elaborated. Herein, we report an NHC-catalyzed enantio- and diastereoselective [2 + 2] cycloaddition/ring-opening sequence that provides quick and efficient access to structurally diverse 3-substituted-3-hydroxyoxindoles bearing two chiral centers. The reaction tolerates a broad scope of substrates, affording the products in generally moderate to excellent yields with good optical purities. Moreover, the reaction is scalable to a 10-fold loading, delivering the target product in 84% isolated yield with 96 : 4 er and >20 : 1 dr. Notably, the obtained products can undergo diverse further derivatizations without erosion of stereoselectivity, underscoring their utility as chiral building blocks. We proposed a plausible reaction mechanism involving the formation of an NHC-bound enolate followed by a stereoselective [2 + 2] cycloaddition to generate a spirocyclic β-lactone intermediate, which then undergoes ring opening. Key intermediates were detected by HRMS and NMR, providing solid evidence for the proposed pathway.