Construction of Vicinal Tetrasubstituted Stereogenic Centers via a Mannich‐Type Organocatalyzed Addition of Δ²‐Pyrrolin‐4‐ones to Isatin Imines

Abstract

Racemic D 2 -pyrrolin-4-ones (i. e. 4-pyrrolones), easily available in two steps from Nprotected a-amino acids, undergo organocatalysed asymmetric Mannich-type addition to isatin-derived ketimines to furnish the non-racemic oxindole-D 2pyrrolin-4-one adducts, stereoselectively (up to 96% ee, dr ! 15:1). The oxindole-pyrrolone products feature vicinal tetrasubstituted carbon stereocenters. The developed protocol has a broad substrate scope and tolerates diverse substituents at position C-5 in 4-pyrrolones and at positions N-1 and C-5/7 in isatin imines.

Double Spirocyclization of Arylidene-Δ2-Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles

“…Bis-spiroheterocyclic oxindoles containing oxazolone, thiazolidinone, pyrazolone, pyrimidinedione, and pyrrolone structural motifs. In continuation of our research on the implementation of pyrrolone derivatives in asymmetric organocatalyzed transformations [67][68][69][70], we herein report a successful application of the arylidene-∆ 2 -pyrrolin-4-ones [71] 1 for the enantioselective construction of oxindolethiopyrolidinone-∆ 2 -pyrrolin-4-one bis-spiroheterocycles 3 (Scheme 1).…”

“…In continuation of our research on the implementation of pyrrolone derivatives in asymmetric organocatalyzed transformations [67][68][69][70], we herein report a successful application of the arylidene-Δ 2 -pyrrolin-4-ones [71] 1 for the enantioselective construction of oxindole-thiopyrolidinone-Δ 2pyrrolin-4-one bis-spiroheterocycles 3 (Scheme 1). For the construction of bis-spiroheterocyclic thiopyrrolidinone-spirooxindoles with 3-isothiocyanato oxindoles, arylidene or (functionalized) alkylidene (hetero)cyclic Michael acceptors have been applied.…”

Recent Advances in Squaramide‐Catalyzed Asymmetric Mannich Reactions

“…An enantioselective Mannich reaction of pyrrol‐4‐ones 41 derived from glutamic acid to isatin ketimines 37 catalyzed by cyclohexane‐1,2‐diamine‐derived squaramide catalyst C5 was developed by Grošelj group [44] (Scheme 18). The desired products 42 bearing two vicinal tetrasubstituted stereocenters were smoothly obtained in moderate to high yields (47–99%) with excellent enantioselectivities (80–96% ee) and good to excellent diastereoselectivities (15:1–>33:1 dr).…”

Mechanistic Insights into Annulation of Arylidene‐Δ2‐Pyrrolin‐4‐Ones by Cinchona Squaramide‐Based Organocatalysts

“…Organocatalyzed annulation of either acyclic or (hetero)cyclic Michael acceptors with malononitrile is a convenient approach for the stereoselective synthesis of amino‐cyano‐substituted 4 H ‐pyran heterocycles and their fused analogues [31–34] . The pyrrolone (Δ 2 ‐pyrrolin‐4‐one) structural motif, although featured in several natural products and bioactive molecules, [35–40] has seldom been employed as a substrate in organocatalyzed transformations [17,30,41–46] . Herein, a successful application of arylidene‐Δ 2 ‐pyrrolin‐4‐ones [17,45] 1 in the annulation with malononitrile for the enantioselective construction of dihydropyrano[3,2‐ b ]pyrroles 3 and 4 , along with detailed mechanistic investigations, is disclosed.…”