A research team led by Professor Wang Chao from the College of Chemistry at Tianjin Normal University (TNU), in collaboration with Professor Huang Genping from Tianjin University, has published a paper titled "Stereodivergent construction of non-adjacent stereocenters via migratory functionalization of alkenes" in Nature Chemistry. This milestone represents the first time TNU has served as the primary corresponding affiliation for a research article in a Nature family journal.

The stereocontrolled synthesis of chiral molecules remains one of the fundamental challenges in modern organic and medicinal chemistry. Particularly, the precise construction of multiple stereocenters separated by distant positions (1,3- or 1,4-relationships) within a single reaction system has long been considered a significant challenge in the international scientific community. Conventional approaches typically rely on the synergistic effects of two distinct chiral catalysts, yet often suffer from system complexity and limited selectivity.

Addressing this challenge, Professor Wang Chao's team innovatively developed a nickel-catalyzed asymmetric migratory alkylation system based on achain-walking strategy. This system enables the precise and controllable construction of remote non-adjacent stereocenters in acyclic molecules under single catalytic conditions. By modulating substrate geometry (E/Z) and chiral ligand configuration (R/S), the research team successfully obtained all four stereoisomers of the target compounds, achieving stereodivergent synthesis. The method demonstrates exceptional regioselectivity, enantioselectivity, and diastereoselectivity (>99:1 r.r., >20:1 d.r., up to 99% e.e.).

Notably, through combined experimental and density functional theory (DFT) calculations, the study systematically revealed the fundamental mechanism of remote chiral induction during the chain-walking process, clarifying the molecular origin of stereocontrol in the multi-step migration reaction. This discovery not only enriches the understanding oftransition-metal chain-walking chemistry but also provides new insights and tools for future precise stereocontrol in more complex molecular frameworks.

At the application level, this catalytic system efficiently synthesizes various pharmaceutical structural modifiers and chiral functional molecules. For instance, the team demonstrated its utility in the streamlined synthesis of the anti-anxiety drug candidate imagabalin hydrochloride, significantly shortening the original multi-step route and greatly enhancing the efficiency of pharmaceutical construction.

The research was supported by the National Natural Science Foundation of China, the Tianjin Natural Science Foundation, and research programs from TNU.

Article information:

https://www.nature.com/articles/s41557-025-01994-7

Nat. Chem. 2025, DOI: 10.1038/s41557-025-01994-7

By He Jierui