Photocatalytic hydrogen atom transfer achieves reverse thermodynamic olefin position isomerization of α,β-dehydroamino acids

Professor Pan Xu's research group at Southeast University reported a photocatalytic hydrogen atom transfer (HAT) strategy, successfully achieving the deconjugated olefin isomerization reaction of α,β-dehydroamino acids. This resulted in the efficient synthesis of β,γ-dehydroamino acids, which are difficult to prepare using traditional methods, under mild conditions. The reaction uses decatungstate (TBADT) as a photocatalyst, selectively extracting the γ-C–H bond of the substrate under 390 nm illumination to form a delocalized allylic radical. Subsequently, through hydrogen atom transfer and tautomerism steps, the reaction drives the reverse thermodynamic double bond isomerization. This method exhibits good substrate applicability, excellent (E)-selectivity, and 100% atom economy, providing a new route for the synthesis of β,γ-dehydroamino acids and their derivatives, and showing significant application potential in medicinal chemistry and natural product modification. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background Information:
Reverse thermodynamic olefin repositional isomerization is a significant challenge in synthetic chemistry, capable of converting readily available regioisomers into thermodynamically less stable but synthetically valuable non-conjugated analogs, thereby expanding the chemical space. Traditional thermodynamic methods can only drive reactions toward more stable products, while photochemistry, with its excited-state energy input, has the potential to drive "uphill" reactions. In the deconjugation isomerization of α,β-unsaturated carbonyl compounds, the classical photochemical pathway relies on the 1,5-hydrogen atom transfer initiated by direct photoexcitation of the substrate. However, this mechanism is limited by geometric requirements, cannot be applied to conformationally locked trans substrates, and often suffers from poor stereoselectivity. Therefore, developing a catalytic strategy that overcomes these limitations, operates under mild conditions, and is universally applicable has become an urgent need in this field.

Highlights of the Article:
This study proposed and realized photo-mediated hydrogen atom transfer (HAT) catalytically driven deconjugated olefin positional isomerization, with key features including:
1. Mechanism Breakthrough: By abandoning the 1,5-HAT pathway required for direct excitation of traditional substrates, the catalyst selectively captures γ-hydrogen through photoexcitation, thus successfully solving the long-standing problem of the inability of trans conformation substrates to react.
2. Broad Substrate Applicability: The reaction is applicable not only to linear and cyclic α,β-dehydroamino acids, but also to a variety of functional groups such as chlorine, ester, hydroxyl, benzylic, and tertiary C-H bonds.
3. High Stereoselectivity: The β,γ-olefin bonds of the product are mainly formed in the (E)- configuration, and the original chiral center is basically maintained during the reaction without racemization.
4. High Practicality of Synthesis: It has been successfully applied to the concise synthesis of a variety of natural β,γ-dehydroamino acids (such as MVG, AVG, Δ-APA, etc.), demonstrating the great potential of this method in the late-stage modification of complex bioactive molecules.

Summary and Outlook:
This study developed a highly efficient, mild, and widely applicable photocatalytic deconjugated isomerization strategy, providing a new approach for the synthesis of β,γ-dehydroamino acids. This method not only overcomes the mechanistic limitations of traditional photochemical pathways but also demonstrates excellent functional group compatibility and ease of operation (catalytic system, visible light driven), providing a powerful tool for the late-stage modification and structural diversity of complex bioactive molecules. In the future, this catalytic mode is expected to be further extended to other types of olefin isomerization reactions.

This research was published as a Research Article in CCS Chemistry. Professor Pan Xu of the School of Chemistry and Chemical Engineering at Southeast University is the corresponding author, and Master's student Zhuoyuan Yang is the first author. This research was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province, the Jiangsu Distinguished Professor Program, and the Startup Fund of Southeast University. Furthermore, the authors thank Professor Shangqian Zhu and Dr. Pengcheng Zhao of the School of Chemistry and Chemical Engineering at Southeast University for their guidance and assistance in the in-situ infrared spectroscopy measurements.

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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/.