Fudan University Zhang Junliang / Zhang Zhanming Team, Nat. Commun.: New Applications of Sadphos-Ming-Phos
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Asymmetric Synthesis of Heteroatom-Bridged [3.2.1]Octane Scaffolds via Enantioselective β-H Elimination Reaction
Fudan University Zhang Junliang / Zhang Zhanming Team, Nat. Commun.: New Applications of Sadphos-Ming-Phos
Nature Communicationshttps://doi.org/10.1038/s41467-026-69960-6
Article in Press
Heteroatom-bridged [3.2.1]octane (tropane) scaffolds are important structural motifs in synthetic and medicinal chemistry. Their derivatives, specifically 3-aryl tropanes, hold significant value in the treatment of neuropsychiatric disorders and the development of monoamine transporter ligands. However, methods for the asymmetric synthesis of chiral 3-aryl tropanes are scarce, with traditional strategies suffering from drawbacks such as lengthy procedures, harsh conditions, and low enantioselectivity. Simultaneously, the stereoselective control of β-H elimination is a persistent challenge in asymmetric catalysis. In cases involving two potential β-H elimination sites, it is necessary to concurrently control the diastereoselectivity of migratory insertion and the enantioselectivity of β-H elimination—a feat not yet reported. To address these challenges, the team of Prof. Junliang Zhang and Prof. Zhan-Ming Zhang at Fudan University has recently developed a Pd/Ming-Phos-catalyzed enantioselective β-H elimination reaction, using inexpensive tropinone as the starting material. This method enables the efficient construction of chiral tropane and oxa-tropane skeletons. Through rational design and modification of the Ming-Phos ligand, a precise chiral pocket was constructed leveraging hydrogen-bonding interactions, successfully overcoming the stereocontrol难题 presented by the dual β-H elimination sites. The reaction exhibits excellent functional group tolerance, accommodating various aryl bromides, heterocycles, and other substrates, and is amenable to scale-up synthesis. This methodology has been successfully applied to the asymmetric total synthesis of therapeutic agents for Alzheimer's disease and monoamine transporter ligands, significantly reducing costs and simplifying synthetic steps. The products also show potential for anticancer drug development. Furthermore, mechanistic studies clarified that carbene formation is the rate-determining step, and the irreversibility of the β-H elimination is crucial for maintaining high enantioselectivity, providing important mechanistic insights for related asymmetric catalysis research.
Condition Screening
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Substrate Scope
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Highlights of the Ming-Phos ligand used in this reaction:
- Precise Dual Stereoselectivity Control: The Ming-Phos ligand forms hydrogen bonds with the substrate. Rational modifications, such as the introduction of an ortho-methoxy group, enable the construction of a precise chiral pocket. This allows for simultaneous control over the diastereoselectivity of migratory insertion and the enantioselectivity of β-H elimination, breaking the limitation of traditional methods that rely solely on substrate control.
- Broad Functional Group Compatibility: After complexation with palladium, it demonstrates excellent catalytic performance. It is compatible with aryl bromides bearing various substituents at different positions, heterocycles, benzannulated systems, and other diverse substrates, stably affording target products in 60%–87% yield and 87%–94% ee.
- High Practical Application Value: Relying on the catalytic system featuring this ligand, the asymmetric total synthesis of an Alzheimer's disease drug and a monoamine transporter ligand was successfully achieved, significantly reducing costs. The products also exhibit anticancer potential, providing a new strategy for chiral tropane synthesis and drug research and development.
To support related research, Anhui Cat-Lab has made the Ming-Phos Ligand Kit available and offers custom synthesis services. We sincerely welcome inquiries and collaboration!
Publication Details
Authors: Chao Fang, Junpeng Ai, Quanpu Wang, Bing Xu, Junliang Zhang* & Zhan-Ming Zhang*
Title: Asymmetric synthesis of Heteroatom-bridged [3.2.1]Octane scaffolds via enantioselective β-H elimination reaction
DOI: 10.1038/s41467-026-69960-6
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