Harnessing molecular motion for asymmetry–nitrogen inversion as a springboard for stereoselective C–H functionalization

Abstract

The asymmetric construction of nitrogen stereocenters is notoriously difficult due to rapid nitrogen inversion. Zhang and co-workers now showcase a Pd-catalyzed enantioselective C-H activation strategy that turns this inversion into an advantage, delivering stable chiral azepines with high enantioselectivity. Coincidentally, almost at the same time, Shi and co-workers reported a similar C-H alkylation reaction. Beyond methodology, the products serve as promising scaffolds for asymmetric catalysis and chiroptical materials, bridging synthesis and function. This Perspective discusses how their works not only provide a powerful synthetic method but also open a new avenue for constructing heteroatom stereocenters by harnessing, rather than suppressing, molecular dynamics. Here, nitrogen inversion is deliberately exploited as a dynamic feature that enables enantioselective C-H functionalization, rather than being suppressed as a stereochemical liability.

Keywords

Nitrogen stereocenters / Pd-catalyzed / enantioselective C-H activation

Acknowledgements

GPT-5 was used solely for language editing and polishing. The authors take full responsibility for the integrity, accuracy, and originality of the content.

Authors contribution

Guan CY: Investigation, writing-original draft, writing-review & editing. Mei GJ: Conceptualization, funding acquisition, supervision, writing-review & editing.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

We acknowledge the financial support from the National Natural Science Foundation of China (22371265 and 22208302), Natural Science Foundation of Henan Province (232301420047), and the project of State Key Laboratory of Green Pesticide, Guizhou Medical University (GPLKF202507).

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