A groundbreaking advancement in the realm of asymmetric synthesis has emerged from the collaboration of leading chemists across prestigious Chinese institutions. The team, comprising Xin Li from Nankai University, Wei Zhang from Sichuan University, and Hanliang Zheng from Zhejiang Normal University, has successfully unveiled a novel, environmentally friendly catalytic approach that harnesses visible light to achieve the deracemization of α-aryl cyclic ketones. This innovative methodology melds photocatalysis, hydrogen atom transfer (HAT), and chiral phosphoric acid (CPA) catalysis in a highly synergistic fashion, providing unprecedented access to enantiomerically enriched α-aryl cyclic ketones, which are pivotal scaffolds in medicinal chemistry and natural product synthesis.
Traditional approaches to synthesizing chiral α-aryl ketones have long grappled with challenges, especially when targeting tertiary centers due to the propensity of the carbonyl α-carbon to racemize and the inherent complexity associated with ketone structures. Previous synthetic routes have heavily relied on transition metal catalysis or base-promoted enolate chemistry for asymmetric α-arylation, yet these methods often falter in effectively introducing chirality at the tertiary α-aryl site with high enantioselectivity. The current research confronts this void by leveraging a unique visible-light-driven deracemization process, effectively flipping the paradigm from traditional asymmetric synthesis to an atom-economical racemization strategy that converts racemic mixtures into single enantiomers.
At the heart of this transformative process is a finely orchestrated catalytic cycle initiated by visible light excitation of a photosensitizer. This event triggers a proton-coupled electron transfer (PCET) with aryl thiols, generating highly reactive sulfur radicals. These radicals then engage in hydrogen atom transfer steps, enabling the cleavage and reformation of bonds pivotal to the racemization process. Concurrently, the chiral phosphoric acid catalyst instigates an asymmetric keto-enol tautomerization, fundamentally tilting the equilibrium toward the formation of enantioenriched products. This triple-catalysis system elegantly aligns radical chemistry with stereoselective catalysis to reach transformations hitherto deemed arduous or unattainable under mild and environmentally benign conditions.
Mechanistic insights into this reaction paradigm stem from a suite of painstakingly conducted experimental studies complemented by advanced density functional theory (DFT) computations. These investigations highlight the subtle yet profound influence of conformational changes within the chiral phosphoric acid catalyst, particularly how its structural distortion in less favorable transition states plays a crucial role in dictating enantioselectivity. This nuanced understanding not only underpins the mechanistic rationale but also charts a pathway for rational catalyst design to further optimize such photocatalytic asymmetric processes.
A salient aspect of this methodology lies in the multifunctionality of the aryl thiol catalyst. It plays a dual role—as a Brønsted acid and as a HAT reagent—thereby streamlining the catalytic cycle without necessitating additional additives or reagents. This dual functionality enhances the reaction’s efficiency and obviates complications commonly associated with the use of stoichiometric or excess reagents, reassuring its potential scalability and application in industrial settings.
Moreover, the system showcases remarkable substrate versatility and robust functional group tolerance, even accommodating challenging electron-deficient α-aryl ketones that traditionally evade such transformations. This broadens the scope toward more structurally diverse and pharmacologically relevant molecules, enhancing the utility of this deracemization approach in complex molecule syntheses, including late-stage functionalizations.
The implications of this study transcend the immediate synthesis of chiral α-aryl cyclic ketones. By exemplifying a green and mild operational framework that couples visible-light photochemistry with strategic catalytic synergy, it paves the way for developing a new generation of racemization protocols tailored for other classes of substrates and structural motifs. Consequently, this strategy could profoundly impact drug discovery pipelines by facilitating access to optically pure intermediates critical for bioactive molecule construction.
In comparison to prior art, including the seminal work of the Meggers group that utilized chiral rhodium photocatalysts for the deracemization of acyclic α-aryl ketones, this platform distinguishes itself by circumventing the need for stoichiometric amine donors and benefiting from operational simplicity and wider substrate applicability, especially towards cyclic structures. Such improvements attest to the strategic innovation embedded in the current catalytic triad.
The publication of these findings as an open-access article in CCS Chemistry—the flagship journal of the Chinese Chemical Society—underscores the significant scientific value and potential impact of the research within the global chemical community. It aligns with ongoing efforts to promote sustainable and efficient synthetic methodologies that embrace the principles of green chemistry.
Looking forward, the research team anticipates that this catalytic blueprint will inspire analogous visible-light-driven racemization strategies applicable to a wider array of complex molecules, amplifying the reach of photocatalytic asymmetric transformations. The method’s mild nature, combined with its mechanistic robustness, makes it an attractive candidate for integration into automated synthetic platforms and high-throughput screening workflows.
This pioneering work was made possible through substantial support from several prestigious funding bodies including the National Key Research and Development Program of China, the National Natural Science Foundation of China, provincial science and technology departments, and esteemed research laboratories dedicated to green material synthesis. The convergence of multidisciplinary expertise within this collaborative network exemplifies the modern scientific ethos of open innovation.
In summation, the visible light-driven deracemization of α-aryl cyclic ketones via a synergistic catalytic system exemplifies an auspicious convergence of radical photochemistry and asymmetric catalysis. It not only furnishes a practical route to enantiomerically enriched ketones but also charts a roadmap for future endeavors in sustainable, atom-economical asymmetric synthesis, underscoring the transformative potential of light as a clean energy source for complex molecular construction.
Subject of Research:
Not applicable
Article Title:
Visible Light-Driven Deracemization of α-Aryl Ketones by Synergistic Aryl Thiol and Chiral Phosphoric Acid Catalysis
News Publication Date:
7-Jan-2026
Web References:
https://www.chinesechemsoc.org/journal/ccschem
http://dx.doi.org/10.31635/ccschem.025.202506718
Image Credits:
CCS Chemistry
Keywords
Photocatalysis
