In the ever-evolving realm of asymmetric synthesis, the capacity to construct multiple stereocenters in a stereodivergent manner represents a zenith of synthetic achievement. Stereodivergent strategies are highly coveted, especially when tackling molecules bearing non-adjacent stereocenters, a feature that complicates the synthetic landscape and challenges conventional methodologies. Recent advances have now illuminated a pathway to overcome these hurdles through an innovative application of chain walking mechanisms in nickel-catalyzed migratory hydroalkylation reactions.
The groundbreaking work, recently published by Ju, G., Yan, X., Bai, H., and colleagues, reveals the elegant stereodivergent construction of acyclic 1,n-non-adjacent stereocenters (where n equals 3 or 4) using trisubstituted alkenes as substrates. This represents a monumental leap in asymmetric catalysis, a domain where the creation of spatially distant stereocenters in a controlled and predictable fashion has proven elusive. The researchers’ successful deployment of a chain walking strategy in this context marks a transformative moment in how stereocenters can be organized and manipulated remotely, enlarging the scope of accessible chiral architectures.
At the heart of this innovation lies the nickel-catalyzed migratory hydroalkylation reaction. Nickel catalysis has garnered significant attention in recent years due to its unique electronic versatility and ability to mediate complex bond-forming processes under mild conditions. The team’s approach harnesses these capabilities to orchestrate a migration of the catalytic center along the carbon chain, effectively “walking” from the original alkene site to remote α-C(sp³)–H sites adjacent to nitrogen atoms. This migration enables site-selective installation of alkyl groups, thus constructing stereogenic centers that are strategically spaced along the molecule.
The strategy is particularly noteworthy because it allows the simultaneous creation of two stereocenters in an acyclic framework, one located α- to a nitrogen substituent and the other at a distal γ- or δ-position bearing all-alkyl substituents. Traditionally, accessing such non-adjacent stereocenters with precise stereochemical control has been fraught with difficulties due to limited control over remote functionalities and stereochemical relay. However, the chain walking mechanism employed here overcomes these barriers by exploiting the dynamic flux of the metal along the carbon backbone to achieve both regio- and stereocontrol.
One of the most compelling aspects of this work is its stereodivergent nature. Typically, achieving stereochemical diversity in molecules with multiple stereocenters requires different catalysts, reagents, or reaction conditions. In contrast, this nickel-catalyzed platform allows access to all four possible stereoisomers from a single catalytic system. By judiciously selecting the olefin geometry (cis or trans) and tuning the chiral ligand environment, the researchers can finely control the enantiomeric and diastereomeric outcomes of the reaction. Such exquisite stereochemical precision under a uniform catalytic regime highlights the system’s remarkable versatility and operational simplicity.
The implications of this work extend well beyond the synthetic novelty. Chiral amines bearing multiple stereocenters are ubiquitous motifs within pharmaceuticals, agrochemicals, and complex natural products. The ability to selectively and efficiently generate these motifs with full stereochemical fidelity opens new avenues for the rapid assembly of complex bioactive molecules and medicinal scaffolds that previously required lengthy and less efficient synthetic routes. This approach holds promise for accelerating drug discovery programs by enabling swift exploration of stereochemical space.
From a mechanistic standpoint, the phenomenon of chain walking involves iterative β-hydride elimination and reinsertion steps, facilitating the migration of the nickel center along the alkyl chain. This catalytic flux contrasts with static catalytic systems where bond formation is localized at the olefinic position. The researchers exploited this unique dynamic to shift the nickel catalyst several carbons away from the original double bond, maneuvering toward α-C(sp³)–H bonds adjacent to nitrogen where the alkylation takes place. Such mechanistic ingenuity highlights the evolving understanding of transition metal catalysis beyond traditional paradigms.
The study meticulously examines the stereochemical outcomes by integrating comprehensive ligand design and olefin substrate variation. Through the application of chiral ligands with distinct stereochemical configurations, the team demonstrates control not only over enantioselectivity but also diastereoselectivity. This control is crucial when dealing with acyclic systems, which often suffer from conformational flexibility and diminished stereocontrol compared to cyclic frameworks. The authors’ success in overcoming these challenges further underscores the robustness of their catalytic strategy.
Beyond the immediate synthetic toolkit, this research underscores the importance of chain walking as a conceptual and practical tool in organic synthesis. Previously, chain walking strategies were often limited to specific transformations or constrained by substrate scope. Here, the integration of migratory hydroalkylation introduces a broader, more generalizable approach to remotely functionalize complex molecules. This transformation is both mild and operationally simple, which should ease its adoption across academic and industrial laboratories.
The adoption of nickel catalysis as the core reactive platform offers additional benefits. Nickel’s relative abundance and lower cost compared to precious metals like palladium or rhodium make this methodology attractive for large-scale and sustainable synthesis. Moreover, the mild reaction conditions preserve sensitive functional groups, expanding the range of compatible substrates and thus the chemical diversity accessible through this protocol.
This platform’s capacity to systematically explore all stereoisomeric permutations also greatly facilitates stereochemical studies and the development of stereochemistry-dependent biological activity. Medicinal chemists can now generate full stereochemical libraries with relative ease, enabling detailed evaluations of structure-activity relationships (SAR) and accelerating lead optimization cycles. Consequently, this technology is poised to become a linchpin in stereochemically complex molecule synthesis.
The work also invites future exploration into expanding the scope beyond trisubstituted alkenes and nitrogen-adjacent α-C(sp³)–H bonds. It is conceivable that related migratory functionalizations could target other remote C–H bonds or more complex substitution patterns, heralding the advent of chain walking-enabled stereocontrolled syntheses of an even broader palette of scaffolds. Strategic ligand innovations and deeper mechanistic insights will undoubtedly catalyze such developments.
In conclusion, the stereodivergent construction of acyclic non-adjacent stereocenters via nickel-catalyzed migratory hydroalkylation represents a seminal advance in asymmetric catalysis and synthetic efficiency. By leveraging the power of chain walking and precise ligand control, this methodology bridges longstanding gaps in stereochemical construction within acyclic frameworks. It affirms the untapped potential of nickel catalysis coupled with migratory functionalization strategies to deliver molecules of high complexity and stereochemical richness with relative ease.
As the synthetic community digests this innovation, the significance of combining catalyst design, mechanistic understanding, and stereochemical strategy comes sharply into focus. This work not only sets new standards for asymmetric catalysis but also highlights a versatile platform that resonates across chemical synthesis, medicinal chemistry, and process development. The streamlining of complex molecule assembly through such advances is poised to profoundly impact future directions in chemical research and industry alike.
The collective achievements portrayed herein illuminate an inspiring pathway whereby catalytic migration and stereochemical orchestration converge, redefining how chemists approach the fabrication of stereochemically intricate molecules. Undoubtedly, this pioneering method will catalyze a wave of innovation in the synthesis of chiral amines and beyond, marking a milestone in the chemistry of stereodivergent synthesis.
Subject of Research: Asymmetric Synthesis, Stereodivergent Construction, Chain Walking Catalysis, Migratory Hydroalkylation, Nickel Catalysis, Remote C(sp3)–H Functionalization
Article Title: Stereodivergent construction of non-adjacent stereocentres via migratory functionalization of alkenes
Article References:
Ju, G., Yan, X., Bai, H. et al. Stereodivergent construction of non-adjacent stereocentres via migratory functionalization of alkenes. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01994-7
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41557-025-01994-7
