Asymmetric Synthesis of Spirooxindole Lactones by Ammonium-tethered Chiral Organocatalysts catalyzed Michael Addition/Cyclization of 3- hydroxyoxindoles with α,β-unsaturated Aldehydes

The ammonium-tethered pyrrolidine-based organocatalyst catalyzed asymmetric Michael addition/cyclization reaction of α,β-unsaturated aldehydes with 3-hydroxyoxindole in aqueous media was developed, giving the spirooxidole lactones in high yields with high enantioselectivities. Background: The asymmetric Michael addition/cyclization reaction of 3-hydroxyoxindoles with α,β- unsaturated aldehydes is an important method for the synthesis of chiral spirooxindole derivatives, which are found in a wide range of biologically active natural products and pharmaceutical agents. Objective: Organocatalyzed asymmetric Michael addition/cyclization reactions are one of the most powerful and effective approaches for the construction of complex molecules from relatively simple starting materials. However, a major problem associated with these organocatalytic system is that high catalyst loading and organic solvents are required. In the present work, our objective was to develop a water-compatible organocatalyst that aimed at lowering catalyst loading and being active in an aqueous system. Methods: In a typical experiment, To a solution of catalyst 2a (0.008 mmol) and PhCO2H (0.096 mmol) in 0.5 mL of a mixture solvent iPrOH/H2O (1:3) was added α,β-unsaturated aldehyde (0.4 mmol) and 3-hydroxyoxindole (0.8 mmol). The reaction mixture was proceeded at room temperature for 16 hours, and then was extracted with 10 mL dichloromethane to give the cyclized hemiacetal, which was subjected to the direct oxidation with pyridinium chlorochromate (PCC, 1.2 mmol) for 16 hours to give the desired spirooxindole lactones. Results: The reactions successfully gave spirooxindole lactones in high to excellent yields (81-95%) with moderate to excellent enantioselectivities (up to 99% ee). However, the diastereoselectivities were poor ranging from 1:1.1 to 1:2.3. Conclusion: The asymmetric Michael addition/cyclization reaction of α,β-unsaturated aldehydes with 3-hydroxyoxindole using ammonium-tethered pyrrolidine-based organocatalyst has been developed. The reaction was performed in aqueous media with low catalyst loading (2 mol%) and provided the spirooxidole lactones in high yields (81-95%) with high enantioselectivities (ee: up to 99%).