Amide C-N bonds activation by A new variant of bifunctional N-heterocyclic carbene

Yuxing Cai; Yuxin Zhao; Kai Tang; Hong Zhang; Xueling Mo; Jiean Chen; Yong Huang

doi:10.1038/s41467-024-44756-8

Amide C-N bonds activation by A new variant of bifunctional N-heterocyclic carbene

Nat Commun. 2024 Jan 12;15(1):496. doi: 10.1038/s41467-024-44756-8.

Authors

Yuxing Cai^#^{1

2}, Yuxin Zhao^#³, Kai Tang², Hong Zhang², Xueling Mo², Jiean Chen⁴, Yong Huang⁵

Affiliations

¹ State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, 518055, Shenzhen, China.
² Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, 518118, Shenzhen, China.
³ Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China.
⁴ Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, 518118, Shenzhen, China. chenja@szbl.ac.cn.
⁵ Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China. yonghuang@ust.hk.

^# Contributed equally.

Abstract

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C-N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation.