Asymmetric Construction of Bispiro[oxindole-pyrrolidine-rhodanine]s via Squaramide-Catalyzed Domino Michael/Mannich [3 + 2] Cycloaddition of Rhodanine Derivatives with N-(2,2,2-Trifluoroethyl)isatin Ketimines

Abstract

Squaramide-catalyzed asymmetric domino Michael/Mannich [3 + 2] cycloaddition reaction between rhodanine derivatives and N-(2,2,2-trifluoroethyl)isatin ketimines has been developed to synthesize various bispiro[oxindole-pyrrolidine-rhodanine]s with good to excellent yields (up to 99%) and excellent stereoselectivities (up to >99% ee and >99:1 dr). The biologically active rhodanine, oxindole, and pyrrolidine moieties were embedded in these novel bispirocyclic products, which will provide some support for the enrichment of chiral heterocyclic compound databases with potential medical value.

Recent Advances in Squaramide‐Catalyzed Asymmetric Mannich Reactions

“…This umpolung cross-coupling Mannich reaction provided another strategy for constructing diamine compounds. In 2018, our group [49] reported the domino Michael/ Mannich cascade reaction of N-2,2,2-trifluoroethyl isatin ketimine 53 with rhodanine 55 catalyzed by squaramide catalyst C6 to afford the novel bispiro [oxindole-pyrrolidine-rhodanine]s 56 bearing four stereocenters in excellent yields (65-99%) with excellent enantio-and diastereoselectivities (86:14-> 99:1 dr, 57-> 99% ee) (Scheme 23). It's worth noting that a host of different substituted substrates 53 and 55 were tolerated well in this reaction and the desired products have three bioactive moieties including a CF 3 group.…”

Recent Advances in the Construction of Trifluoromethyl‐Containing Spirooxindoles through Cycloaddition Reactions

“…In 2018, Du's group used rhodanine derivatives (Scheme 4, c); In 2019, Du's group used arylidene azlactones (Scheme 4, d); in 2019, Yan's group used N-2,2,2-trifluoroethylisatin ketimines and aurones (Scheme 4, e) to construct certain chiral spirooxindoles, respectively. [11][12][13] The spirooxindoles obtained from Du's methodology in 2019 (Scheme 4, d) were not stable and could be easily converted into hydrolysates by the treatment of HCl. In 2019, Yan's group reported a catalytic asymmetric cyclization of N-2,2,2-trifluoroethylisatin ketimines and α,β-unsaturated pyrazolones and Cinchona alkaloid-derived squaramide C-6 was adopted to be the best chiral catalyst in the reaction (Scheme 4, f).…”

“…Similarly, Cinchona alkaloid‐derived squaramide C‐5 were adopted in the catalytic asymmetric cyclizations with N ‐2,2,2‐trifluoroethylisatin ketimines. In 2018, Du's group used rhodanine derivatives (Scheme , c); In 2019, Du's group used arylidene azlactones (Scheme , d); in 2019, Yan's group used N ‐2,2,2‐trifluoroethylisatin ketimines and aurones (Scheme , e) to construct certain chiral spirooxindoles, respectively . The spirooxindoles obtained from Du's methodology in 2019 (Scheme , d) were not stable and could be easily converted into hydrolysates by the treatment of HCl.…”

Phase‐Transfer Catalytic Strategy: Rapid Synthesis of Spiro‐Fused Heterocycles, Integrated with Four Pharmacophores‐Succinimide, Pyrrolidine, Oxindole, and Trifluoromethyl Group

“…N ‐2,2,2‐trifluoroethylisatin ketimine is a type of versatile reagent that it could act as nucleophile [12] or azomethine ylide precursor [13] in organic synthesis. Since it was firstly utilized in organocatalytic 1,3‐dipolar [3+2] cycloaddition with α,β‐unsaturated aldehydes for the formation of CF 3 ‐substituted spiropyrrolidinyl‐2,3′‐oxindoles by Wang′s group, [14] many kinds of canonical electron‐deficient alkenes had been employed as variants to react with this synthon, delivering large amount of more structurally diverse trifluoromethyl spiropyrrolidinyl‐2,3′‐oxindoles, such as nitroalkenes, [15] 3‐alkenyl‐5‐arylfuran‐2(3 H )‐ones, [16] 3‐alkylideneoxindoles, [17] α,β‐unsaturated ketone, [18] arylidene azlactone, [19] 5‐alkylidenerhodanine, [20] 5‐alkylidenethiazolones„ [21] barbiturate‐based olefin, [22] aurone olefin, [23] 4‐alkylidenepyrazolinones, [24] 2,3‐dioxopyrrolidine, [25] cyclic 2,4‐dienones [26] . However, these seminal studies all suffered from long reaction time, and this insuperable defect impeded their potential applications in the medicinal industry because of the high production costs.…”