Thiourea-Catalyzed Domino Michael–Mannich [3+2] Cycloadditions: A Strategy for the Asymmetric Synthesis of 3,3′-Pyrrolidinyl-dispirooxindoles

Abstract

The asymmetric synthesis of trifluoromethylated 3,3′-pyrrolidinyl-dispirooxindole derivatives with four contiguous stereogenic centers, including two vicinal spiro-stereocenters, is described. Employing a bifunctional thiourea catalyst, a domino Michael–Mannich [3+2] cycloaddition occurs readily between isatin ketimines and isatin-derived enoates with good yields and very high stereoselectivities, providing a direct entry to the title compounds of potential medical value.

Stereoselective Domino Reactions in the Synthesis of Spiro Compounds

“…78 A strategy for the asymmetric synthesis of trifluoromethylated 3,3′-pyrrolidinyl-dispirooxindole derivatives 365 with four contiguous stereogenic centers, including two vicinal spirostereocenters, was described by Enders and coworkers. 79 Isatin ketimines 366 and isatin-derived enoates 283 was employed in the domino Michael/Mannich/[3+2] cycloaddition catalyzed by a bifunctional thiourea 367 to provide the products with good yields and very high stereoselectivities (Scheme 66). The gramscale reaction demonstrated the practical utility and robustness of the methodology, making it possible to obtain the desired product, whose absolute configuration was determined by X-ray crystallography.…”

Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems

“…The first report on the organocatalytic synthesis of trifluoromethylated 3,3'-pyrrolidinyl-dispirooxindoles was by Enders and coworkers in 2017. [100] A domino Michael-Mannich [3 + 2] cycloaddition reaction between isatin ketimines 94 and isatin-derived enoates 95 provided the complex substances 96 with good yields and very high stereoselectivities in a single synthetic step (Figure 32). A range of substituents could be used without affecting the results much.…”

“…Organocatalytic synthesis of trifluoromethylated 3,3'-pyrrolidinyldispirooxindoles. [100] Figure 33. Synthesis of CF 3 -containing 3,2'-pyrrolidinyl spirooxindoles and dispirooxindoles.…”

Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry

“…A bifunctional pyrrolidine-thiourea was applied by Tang and co-workers to the diastereo-and enantioselective Michael additions of cyclohexanone to alkyl and aryl nitroolefins [189]. In a study by Enders and co-workers, tertiary amines (piperidine and pyrrolidine derivatives) were found the best option for domino Michael-Mannich cycloadditions [190]. Chen's group prepared a series of chiral catalysts, including thioureas, using a chloramphenicol base skeleton, and used them in asymmetric transformations [191][192][193].…”

“…Thiourea-based multivalent organocatalysts offer a great opportunity for preparation of substituted spiro-chroman structures, as exemplified by Michael-acetylation-cascade reaction of 2-oxocyclohexanecarbaldehyde derivatives (Scheme 31) [212]. [187][188][189][190][191][192][193].…”