Carbene-catalyzed kinetic resolution of bispirooxindoles: selective lactam amidation and access to challenging chiral scaffolds

• Published in: Organic chemistry frontiers an international journal of organic chemistry 2023-02, Vol.10 (5), p.1230-1236
• Main Authors: Pu, Yiru, Zuo, Yi, Ling, Jie, Li, Meimei, Huang, Hui, Zhang, Chaozheng, Yang, Jirui, Deng, Yun, Wang, Maolin, Lu, Jun
• Format: Article
• Language: English
• Subjects: Acylation; Amides; Biological activity; Carbenes; Chirality; Density functional theory; Enantiomers; Organic chemistry; Reaction mechanisms; Stereoselectivity
• ISSN: 2052-4110; 2052-4110
• DOI: 10.1039/d2qo01724e

Despite kinetic resolution (KR) via N-heterocyclic carbene (NHC)-catalyzed acylation minimizing any competitive racemic background reactions, the KR of NHC-activated lactam amidation is mostly uninvestigated. Enantioenriched bispirooxindoles bearing multichiral quaternary stereocenters have important applications in chemical and medical fields, but their enantioselective synthesis remains extremely challenging. Described herein is an unprecedented strategy for realizing NHC-catalyzed atroposelective amidation of lactams on racemic bispirooxindoles with enals, providing high to excellent yields and stereoselectivities and superior KR performances (S-factor >500). Density functional theory calculations of the reaction mechanism and the origin of the enantioselectivity indicated steric repulsion between oxindole and trimethylphenyl to be responsible for the stereoselectivity. Given the utmost importance of chirality for bioactivity and the widespread presence of spirocyclic structures in pharmaceutical molecules, we expect that our reaction pattern results will significantly expand the applications of NHCs in KR and for future drug discovery purposes.