In the ever-evolving landscape of chemical synthesis, the precision construction of functional molecules has become a crucial focal point for advancements across pharmaceuticals, materials science, and chemical biology. Among the diverse toolkit available to chemists, the sulfur fluoride exchange (SuFEx) click chemistry has emerged as a remarkable approach, known for its robustness and reliability in forming sulfur(VI)–fluoride bonds. Despite its growing popularity, the challenge in steering SuFEx towards asymmetric syntheses—especially those that deliver chiral sulfur(VI)-centered sulfonimidoyl fluorides—has limited its broader application in enantioselective molecular design. Now, a groundbreaking study by Li, N., Lian, SY., Wei, T., and colleagues sets a new landmark by unveiling a catalytic asymmetric protocol that successfully surmounts these limitations, opening new vistas in chiral SuFEx chemistry.
The crux of this breakthrough lies in the development of a catalytic enantioselective chlorine-fluorine (Cl–F) exchange reaction. This strategy cleverly harnesses racemic sulfonimidoyl chlorides as substrates to construct optically active, chiral sulfonimidoyl fluorides. The significance here is profound: chiral sulfonimidoyl fluorides serve as versatile building blocks in SuFEx reactions, enabling the modular and stereospecific incorporation of chiral sulfur(VI) functionalities into diverse molecular scaffolds. This development tackles a longstanding barrier, where the intense steric congestion around sulfur centers has traditionally impeded asymmetric transformations, especially those entailing sulfonimidoyl transfer.
The methodology’s elegance is reflected in its catalytic conditions that facilitate the dynamic kinetic asymmetric transformation (DyKAT) of the sulfonimidoyl chloride substrates. Through this process, the enantiomeric composition of the substrate undergoes selective epimerization in the presence of the catalyst, steering the reaction towards one predominant enantiomer in the product. Mechanistic elucidation disclosed a fascinating dichotomy where a two-catalyst-bound pentacoordinate sulfur intermediate plays a pivotal role. This hypervalent sulfur species acts as the nexus for the sulfur-configuration epimerization during the catalytic cycle, effectively allowing the dynamic resolution of racemic precursors into enantioenriched products.
Central to the mechanistic pathways are transient O-sulfonimidoyl ester pyridinium cation intermediates. Covalent organocatalysis enables the formation of these intermediates, which are instrumental in facilitating the nucleophilic substitution at sulfur necessary for the high-fidelity Cl–F exchange. This stepwise strategy ensures not only the stereochemical integrity of the sulfur center but also the efficient catalytic turnover essential for practical synthetic applications. The finely balanced interplay between catalyst design and mechanistic finesse underpins the high enantioselectivity and yield observed in these transformations.
Beyond synthetic prowess, this catalytic framework exhibits remarkable versatility. The optically active sulfonimidoyl fluorides produced via this method serve as robust connectable units that undergo subsequent stereospecific SuFEx reactions with a variety of nucleophiles. Importantly, substrates bearing carbon-centered, nitrogen-centered, and oxygen-centered nucleophiles can be appended, paving the way to a plethora of functional chiral sulfonimidoyl derivatives including azides, sulfonimidamides, and esters. This modularity greatly expands the toolbox available for assembling molecules with precise three-dimensional architectures, a trait highly coveted in drug development and advanced materials synthesis.
The study not only brings to light an enabling synthetic tool but also contributes significantly to the fundamental understanding of sulfur(VI) chemistry. The concept of dynamic sulfur-centered epimerization mediated by coordinated catalysts challenges traditional notions of configurational stability at pentacoordinate sulfur and demonstrates how subtle catalyst interactions can manipulate stereochemical outcomes. Such insights are invaluable, potentially translating to other realms of organosulfur chemistry where control over stereochemistry is critical.
Moreover, the implications for medicinal chemistry are compelling. Sulfonimidoyl moieties have garnered increasing attention for their potential as bioisosteres of sulfonamides, which are prevalent in many drug molecules. Enabling access to enantioenriched sulfonimidoyl fluorides with high stereochemical precision unlocks avenues for crafting chiral sulfonimidoyl-containing pharmaceuticals with tunable biological properties and increased metabolic stability. The ability to finely control stereochemistry at sulfur could, therefore, represent a new frontier in rational drug design.
In addition to drug discovery, the method offers promising prospects in the realm of chemical biology and molecular labeling. The sulfur(VI)-centered chiral motifs generated by this catalytic permutation could be exploited as bioorthogonal ligation handles, facilitating the site-selective modification of biomolecules. Because SuFEx reactions are known for their mild and biofriendly conditions, introducing chiral SuFEx arms with high enantiopurity could significantly improve the specificity and efficiency of bioconjugation strategies in live-cell contexts or proteomic studies.
Another exciting aspect is the catalytic approach’s operational simplicity and scalability. The use of readily accessible racemic sulfonimidoyl chlorides combined with catalytic organocatalysts circumvents the need for laborious resolution or chiral auxiliary approaches, making this method practical for large-scale synthetic campaigns. This accessibility enhances its appeal for both academic research and industrial applications, where enantioselectivity, robustness, and cost-efficiency are paramount.
Furthermore, this work addresses a critical gap in asymmetric sulfur fluoride exchange chemistry, which hitherto lacked general catalytic methods for chiral sulfonimidoyl transfer. By establishing a modular and general platform, the authors have effectively created a new paradigm that merges click chemistry’s efficiency with three-dimensional stereochemical sophistication—a feat that inspires rethinking the potential and scope of SuFEx as an asymmetric synthesis tool.
The catalytic system’s finely tuned design, exploiting covalent organocatalysis to generate reactive pyridinium cation intermediates, highlights the ingenuity behind harnessing subtle sulfur chemistry to orchestrate stereoselective transformations. This strategy’s mechanistic traversal from a racemic chlorinated precursor to a stereodefined fluorinated product exemplifies the innovative bridging of classical and contemporary synthetic concepts.
Equally notable is the comprehensive mechanistic groundwork supporting the experimental findings. Detailed studies including intermediate characterization and catalytic cycle analyses substantiate the proposed DyKAT process and validate the central role of the pentacoordinate sulfur intermediate. These insights not only underscore the reaction’s sophistication but provide a blueprint for rational catalyst and reaction design in similar sulfur-centered enantioselective transformations.
Looking forward, the platform’s adaptability to diverse nucleophilic partners and the potential to tailor the molecular complexity introduced via the chiral sulfonimidoyl arm promises expanding horizons. Applications envisaged include stereochemically defined polymers, gating systems, and advanced materials featuring sulfonimidoyl functionalities with tuned electronic and steric environments.
In conclusion, the catalytic asymmetric Cl–F exchange reaction pioneered in this work marks a transformative advance in the field of SuFEx chemistry. By bridging the gap between racemic sulfonimidoyl chlorides and enantioenriched sulfonimidoyl fluorides, this approach not only enriches the synthetic toolbox but also sets a precedent for controlling stereochemistry at sulfur centers. The ramifications for asymmetric synthesis, drug design, biomolecular conjugation, and beyond are profound, reasserting the centrality of innovative catalytic strategies in pushing the boundaries of chemical science.
With this study, Li and colleagues have showcased how precision catalysis and mechanistic insight can conspire to unlock new dimensions in click chemistry and sulfur chemistry. It is a compelling exemplification of how thoughtful molecular engineering can surmount steric and stereochemical challenges, delivering powerful synthetic capabilities with broad-reaching impact across fundamental and applied chemical sciences.
Subject of Research: Catalytic asymmetric sulfonimidoyl transfer enabling stereoselective construction of chiral sulfonimidoyl fluorides and derivatives via dynamic kinetic asymmetric transformation.
Article Title: Catalytic asymmetric sulfonimidoyl transfer to access chiral sulfonimidoyl fluorides and related derivatives.
Article References:
Li, N., Lian, SY., Wei, T. et al. Catalytic asymmetric sulfonimidoyl transfer to access chiral sulfonimidoyl fluorides and related derivatives. Nat. Chem. (2026). https://doi.org/10.1038/s41557-026-02071-3
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