Organocatalytic Enantioselective Methodologies for the Synthesis of Spirooxindoles

3-Alkylideneindolones are particularly good electrophiles, especially toward Michael additions, and therefore constitute excellent starting materials for the synthesis of spirooxindoles by multiple bond-forming approaches. The general strategy of the cascade reactions consists of an initial Michael reaction followed by a nucleophilic addition of the in situ formed enolate intermediate to various electrophiles. In the last years, several electrophilic partners with different scaffolds that lead to formal cyclizations, such as [3+2] cycloadditions [8a], Diels-Alder reactions [8b], and cyclopropanation [8c], have been used to afford a plethora of new spirooxindole scaffolds with excellent stereocontrol. 

A similar approach was developed by Gong and coworkers, inspired by the Nazarov reaction [14]. The reaction started with the conjugate addition of a Nazarov 

Under optimized reaction conditions, spirocyclopropanes were obtained in good yields and enantioselectivities. Moreover, the researchers expanded the substrate scope of the reaction by synthesizing a spironitrocyclopropane with 

Wang and coworkers made a similar approach using isocyanoesters [25]. The reaction was catalyzed by bifunctional tertiary amine-thiourea catalysts and afforded the pyrrolidinyl spirooxindoles in good yields and excellent enantioselectivities but low diastereoselectivities. Later, Yan and coworkers developed a similar reaction involving the three-component cascade reaction of isatin, isocyanoesters, and malononitrile [26]. First, the Knoevenagel reaction between isatin and malononitrile afforded the 

Two complementary thia-Michael/aldol [28] and Michael/aldol [29] strategies from alkylideneindolones involving either a bifunctional tertiary amine-thiourea or the J0rgensen-Hayashi catalyst I have also been proposed contemporaneously. 

---