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. 2024 Jun 10;14(26):18453-18458.
doi: 10.1039/d4ra02252a. eCollection 2024 Jun 6.

N-heterocyclic carbene catalyzed [2 + 3] annulation reaction for the synthesis of trifluoroethyl 3,2'-spirooxindole γ-lactam

Yiru Pu  1 , Maolin Wang  2 , Wanrong Tian  1 , Xian Ge  1 , Dikai Zhu  3 , Chuanqi Wang  1 , Yingjie Zeng  1 , Feiyan Tao  3 , Yun Deng  1 , Jun Lu  1   4
Affiliations

N-heterocyclic carbene catalyzed [2 + 3] annulation reaction for the synthesis of trifluoroethyl 3,2'-spirooxindole γ-lactam

Yiru Pu et al. RSC Adv. .

Abstract

Asymmetric catalytic processes promoted by N-heterocyclic carbenes (NHCs) hold great potential for the sustainable preparation of chiral molecules. However, catalyzing the reactions by manipulating the reactive intermediates is challenging. We report herein that the known NHC-catalyzed [3 + 2] annulation reaction between ketimine and enal can also be turned into a [2 + 3] annulation reaction for the highly enantioselective direct synthesis of trifluoroethyl 3,2'-spirooxindole γ-lactams (4) through timely catalysis of the intermediates. DFT calculations revealed that this transformation included the key step of the nucleophilic attack of the Breslow intermediate M2 derived from NHC and enal (2) to the unattacked ketimine (1). Our study demonstrates that it is possible to tune the desired selectivities through the dynamic catalysts of the reactive intermediates.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthesis of γ-lactam.
Fig. 1
Fig. 1. Postulated mechanism for the NHC-catalyzed [2 + 3] annulation reaction based on DFT calculations. (a). Energy profiles of detailed mechanistic processes. (b). Transition-state structures of the enantioselectivity-determining step.
Scheme 2
Scheme 2. Synthetic applications. (a). Gram-scale experiment. (b). Synthetic transformations of (3S, 3′R)-4l.
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