Diastereo‐ and Enantioselective Synthesis of Chiral Pyrrolidine‐Fused Spirooxindoles via Organocatalytic [3+2] 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Maleimides

Abstract

In the presence of a Cinchona alkaloid‐based squaramide organocatalyst, the [3+2] cycloaddition of isatin‐derived azomethine ylides with maleimides proceeded readily, thus delivering the desired pyrrolidine‐fused spirooxindoles in 61–89% yields with >20:1 dr and 12 to >99 % ee. The absolute configuration of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione was unambiguously determined by means of X‐ray single crystal structure analysis. The reaction mechanism was hypothesized to account for the enantioselective formation of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione.magnified image

Synthesis of Functionalized 3-Spiro[cyclopropa[a]pyrrolizine]- and 3-Spiro[3-azabicyclo[3.1.0]hexane]oxindoles from Cyclopropenes and Azomethine Ylides via [3 + 2]-Cycloaddition

“…In order to further expand the usability of this reaction, we tried to apply benzylamine as one more amine component for the in situ azomethine ylide generation . Initially, a three-component reaction of isatin derivative 2b , benzylamine ( 11A ), and cyclopropene 1b was conducted in dichloromethane at room temperature.…”

Organocatalytic Asymmetric Michael/Cyclization Cascade Reaction of 3‐Isothiocyanato Oxindoles with Maleimides for the Efficient Construction of Pyrrolidonyl Spirooxindoles

“…Since then, 3‐isothiocyanato‐oxindoles have been used for the synthesis of various functionalized spirooxindoles. Although many synthetic strategies have been developed, leading to spirooxindoles with great diastereo‐ and enantioselectivity, to the best of our knowledge, to date there are still few enantioselective syntheses of pyrrolidonyl spirooxindoles bearing a disubstituted succinimide . In this paper, we disclose the results of our research into the asymmetric synthesis of a class of spirooxindoles based on Michael/cyclization cascade reactions of 3‐isothiocyanato‐oxindoles with maleimides catalyzed by bifunctional cinchona‐derived squaramides.…”

Enantioselective Synthesis of CF3‐Containing 3,2’‐Pyrrolidinyl Spirooxindoles and Dispirooxindoles via Thiourea‐Catalyzed Domino Michael/Mannich [3+2] Cycloaddition Reactions

“…[1] Accordingly, a variety of enantioselective catalytic strategies for the construction of the 3,2'-pyrrolidinyl spirooxindole framework have been devised over the past decade. [2] However, of particular note in this regard are only a handful of reported methods for the asymmetric synthesis of 3,2'pyrrolidinyl spirooxindole scaffold with four contiguous stereocenters, including two adjacent spiro quaternary stereogenic centers assembled in one ring structure, [3] despite their prevalence as core structural motifs in a wide range of biological molecules (Figure 1b). [4] This is mainly ascribed to the challenges in constructing such intriguing molecular structure with multiple adjacent stereogenic centers including two vicinal spiro quaternary chiral centers.…”