Visible light-driven deracemization of α-aryl ketones synergistically catalyzed by thiophenols and chiral phosphoric acid

(Press-News.org) A collaborative research team comprised of Xin Li from Nankai University, Wei Zhang from Sichuan University, and Hanliang Zheng from Zhejiang Normal University developed a green and efficient photo-redox/hydrogen atom transfer (HAT)/chiral phosphoric acid (CPA) synergistic catalytic strategy to achieve the deracemization of α-aryl cyclic ketones, successfully synthesizing a series of chiral α-aryl cyclic ketones (Figure 1). The reaction generates a sulfur radical via a proton-coupled electron transfer (PCET) process between an excited-state photosensitizer and a thiophenol, followed by hydrogen atom transfer and single-electron reduction to form a key enol intermediate. Finally, an asymmetric keto-enol tautomerism occurs under chiral phosphoric acid catalysis, achieving deracemization. A series of mechanistic experiments and density functional theory (DFT) calculations support the above reaction pathway and further reveal that conformational distortion of the chiral catalyst in the unfavorable transition state is a key factor in regulating the enantioselectivity of the reaction. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:

Chiral α-aryl ketones are fundamental structural units and important building blocks in the synthesis of many pharmaceutical, bioactive molecules, and natural products (Figure 2a). Over the past few decades, direct asymmetric α-arylation reactions based on transition metal catalysis and base-promoted enol anion chemistry have become a powerful strategy for constructing such chiral skeletons. However, due to the tendency of the carbonyl α-carbon atom to undergo racemization and the inherent structural complexity of ketones, achieving the enantioselective synthesis of tertiary α-aryl ketones remains extremely challenging. Therefore, developing novel catalytic strategies for the efficient construction of chiral α-aryl ketones is of significant research importance.

Deracematization reactions can directly convert racemic substrates into single enantiomeric products, theoretically achieving 100% atom economy, and are therefore considered an ideal strategy for constructing chiral molecules. Notably, the Meggers group previously reported a highly efficient photoinduced deracematization reaction of α-aryl ketones, using a chiral rhodium catalyst that simultaneously functions as a photocatalyst and a chiral Lewis acid catalyst (Figure 2b). However, this system still has certain limitations in terms of practicality: the reaction requires an equivalent amount of amine as an electron donor and a HAT reagent, and it is only applicable to the deracematization of acyclic α-aryl ketones.

Highlights of this article:

This study achieved efficient and highly enantioselective synthesis of chiral α-aryl cyclic ketones through visible light photocatalysis-driven racemization, with the main advantages being:

1. Under alkaline conditions, transition metal-catalyzed α-arylation reactions of ketones typically struggle to achieve highly enantioselective construction of tertiary α-aryl stereocenters. This method utilizes a photocatalyst, a hydrogen atom transfer catalyst, and a chiral phosphoric acid catalyst co-catalyzed (Figure 2c) to achieve the construction of chiral α-aryl cyclic ketones under visible light irradiation .
2. Thiophenols play a dual role in this reaction: acting as both a Brønsted acid and a HAT catalyst to activate carbonyl compounds.
3. The reaction conditions are mild, exhibiting good functional group compatibility and broad substrate universality, and successfully solving the problem that electron-deficient substrates are difficult to participate in deracemization reactions (Figure 3).

Summary and Outlook:

This study develops a green, efficient, and mild visible-light-driven racemization strategy, providing a new approach for the synthesis of chiral α-aryl cyclic ketones. This method demonstrates good substrate applicability and functional group compatibility, offering a powerful tool for the racemization of complex bioactive molecules. This synergistic catalytic system holds promise for future applications in more visible-light-driven racemization reactions.

This research was published as a Research Article in CCS Chemistry. Professor Xin Li from the College of Chemistry, Nankai University, Associate Research Fellow Wei Zhang from the West China School of Public Health (West China Fourth Hospital), Sichuan University, and Professor Hanliang Zheng from the College of Chemistry and Materials Science, Zhejiang Normal University are the co-corresponding authors. Yue Zhang, a doctoral student at the College of Chemistry, Nankai University, is the first author. We sincerely thank the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Sichuan Provincial Department of Science and Technology, the Tianjin Municipal Science and Technology Bureau, the Haihe Laboratory for Green Creation and Manufacturing of Materials, and Sichuan University for their funding support.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.

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