Modular assembly of chiral nitrogen-bridged rings achieved by palladium-catalyzed diastereoselective and enantioselective cascade cyclization reactions

(Press-News.org) The research team led by Hanmin Huang and Bangkui Yu at the University of Science and Technology of China developed a palladium-catalyzed diastereoselective and enantioselective cascade cyclization strategy, achieving the modular synthesis of chiral nitrogen-bridged ring skeletons. Using readily available salicylaldehyde and aminodiene as starting materials, and based on the team's previously developed strategy of "in-situ generation of three-membered ring palladium active intermediates from aldehydes and amines," the bridged oxazole bicyclic compounds were constructed with high diastereoselectivity through a continuous cyclization process. This method exhibits excellent substrate universality, providing an efficient and precise route for synthesizing drug molecules with complex three-dimensional structures. The article was published as an open access Communication in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:

Bridged heterocyclic compounds possess unique three-dimensional topological structures and excellent biological activities, making them a promising backbone for drug development. However, despite their significant potential, the synthesis of these compounds—especially those with high enantioselectivity—remains fraught with challenges. This is primarily due to the inherent topological strain and conformational constraints during bridge ring formation, which impose extremely high requirements on reaction efficiency. Traditionally, the construction of chiral bridged rings relies on pre-fabricated cyclic precursors, achieved through strategies such as asymmetric cycloaddition or cascade cyclization. These methods are often limited by the scarcity of substrates and the limited structural diversity. Therefore, developing a novel strategy that uses readily available acyclic building blocks as direct raw materials to efficiently and selectively construct chiral bridged ring frameworks has significant synthetic implications and broad application prospects.

Against this backdrop, the team developed a palladium-catalyzed asymmetric cascade cyclization reaction of aminodienes and salicylaldehyde by utilizing a reaction strategy that generates active intermediates of three-membered ring palladium in situ from amines and aldehydes. This enabled the asymmetric synthesis of nitrogen-bridged ring compounds.

Highlights of this article:

1. Strategy Innovation: A highly efficient synthetic strategy based on palladium-catalyzed tandem cyclization was developed. Using readily available salicylaldehyde and aminodiene as raw materials, a chiral bridged oxazole bicyclic skeleton was directly constructed, overcoming the dependence of traditional methods on prefunctionalized cyclic precursors and significantly improving the synthetic efficiency.
2. Excellent stereoselectivity: The reaction achieves excellent stereoselectivity control under mild conditions, with enantioselectivity up to 96% and high diastereoselectivity, providing a reliable method for the precise construction of chiral molecules with complex three-dimensional structures.
3. Good substrate universality: This strategy shows good compatibility with salicylaldehyde and aminodiene with different substituents, and can efficiently prepare structurally diverse bridged heterocyclic compounds, expanding the chemical space of such advantageous skeletons.
4. Skeleton transformation and drug-directed synthesis: Through a clever chiral transfer strategy, the bridged ring skeleton was successfully transformed into a spirocyclic structure with potential biological activity, providing a new approach for the asymmetric synthesis of lead compounds for central nervous system drugs.
5. Flexible subsequent derivatization: The study further demonstrated the diverse derivatization capabilities of the carbon-carbon double bonds in the obtained bridged ring products, which can be smoothly transformed by epoxidation, hydroboration-oxidation, etc., highlighting the practical value of this method in the late-stage modification and directed synthesis of complex molecules.

Summary and Outlook:

In summary, this study developed a highly efficient palladium-catalyzed cascade cyclization strategy using three-membered ring palladium complexes as leading-complexes , successfully achieving highly stereoselective construction of chiral-bridged oxazole bicyclic skeletons. This method not only boasts excellent yields and precise enantioselectivity control but also exhibits good substrate universality and synthetic practicality, providing a new approach for the modular and diverse synthesis of chiral bridged ring compounds. Looking ahead, the reaction mechanism and stereocontrol model revealed by this strategy can provide important theoretical basis for designing more efficient and universal catalytic systems. It is anticipated that this method will be further applied to challenging total synthesis of natural products and the discovery of drug lead compounds, accelerating the construction of chiral molecular libraries rich in three-dimensional structures, thereby providing powerful synthetic tools and material foundations for the development of innovative drugs.

The research findings were published as a Communication in CCS Chemistry. Professor Hanmin Huang and Associate Research Fellow Bangkui Yu from the University of Science and Technology of China are the corresponding authors, and doctoral student Haocheng Zhang is the first author. This research was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, and the Natural Science Foundation of Anhui Province.

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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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