Access to chiral spiroketals via catalytic enantioselective halogenation of racemic olefinic hemiketals

Abstract

Chiral spiroketals are privileged structural motifs that widely appear in natural products, pharmaceutical agents, and chiral catalysts. Nevertheless, catalytic asymmetric methods for synthesizing chiral spiroketals remain scarce. Here, we report an asymmetric catalytic halogenation of racemic olefinic hemiketals to synthesize chiral halo-spiroketals. The approach utilizes a cross-assembled bifunctional catalyst system that integrates a chiral phosphoric acid with an achiral quinoline base. Optimization of the reaction was accomplished mainly by modifying the cost-effective achiral quinoline. The reaction mechanism is characterized by a dynamic kinetic resolution of hemiketal and a diastereoselective bromocyclization, underscoring the critical function of the achiral quinoline base throughout both phases of the catalytic process. The chiral halo-spiroketals are important intermediates for the synthesis of chiral spiroketal phosphine ligands, which can be applied in various asymmetric catalytic reactions. The halogen substituents in the spiroketal phosphine ligands enable late-stage modifications that aid in the selection of suitable ligands for particular reactions.