Enantioselective [3 + 2] Cycloaddition of Spirocyclopropyloxindoles with 2-(phthalimido)acrylates: Access to Spirocyclopentaneoxindoles

Abstract

Chiral spirocyclopentane oxindoles represent privileged scaffolds in bioactive compounds, motivating the development of efficient stereoselective synthetic methods. Traditional [3 + 2] cycloadditions of spirocyclopropyl oxindoles are largely limited to internal alkenes, while terminal alkenes remain underexplored owing to higher reactivity and stereocontrol challenges. Herein, we report the first palladium-catalyzed asymmetric [3 + 2] cycloaddition of spirocyclopropyl oxindoles with 2-(phthalimido)acrylate derivatives. This protocol affords 21 spirocyclopentane oxindole derivatives in up to 99% yield with 99% ee. Further post-functionalization and single-crystal X-ray diffraction analysis demonstrated the synthetic utility and unambiguously assigned the absolute configuration. In addition, a plausible mechanism involving this transformation to form three distinct diastereomers is proposed. This work represents the first asymmetric [3 + 2] cycloaddition of spirocyclopropyl oxindoles with amino acid-based terminal alkenes, providing an efficient, stereocontrolled route to diverse chiral spirocyclopentane oxindoles.