New Applications of Sadphos Ming-Phos Ligands
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Research Background
The chiral gem-diaryl motif is a core scaffold in numerous natural products and drug molecules. The γ,γ-diaryl carbonyl skeleton, in particular, plays a key role in the synthesis of pharmaceuticals such as integrin receptor inhibitors and the antidepressant sertraline. However, its efficient asymmetric synthesis has long been a persistent challenge in organic synthesis. Existing methods mostly rely on chiral precursors or multi-step synthetic routes, and also suffer from narrow substrate scope, moderate enantioselectivity, and limited practicality. Addressing this, the collaborative research team of Professor Junliang Zhang (Fudan University) and Academician Yundong Wu (Peking University Shenzhen Graduate School) has recently developed the first example of a palladium/Ming-Phos catalyzed asymmetric three-component reaction. This reaction employs readily available N-sulfonylhydrazones, aryl halides, and cyclopropanols as substrates, enabling the efficient one-pot construction of chiral γ,γ-diaryl carbonyl skeletons. The method features excellent functional group tolerance, affording the target products in good to excellent yields with high enantioselectivity. Furthermore, the enantiomers of the products can be accessed by exchanging the aryl moieties of the aryl halide and the N-tosylhydrazone. Through Density Functional Theory (DFT) calculations, Academician Wu's team clarified that the oxidative addition of the aryl halide is the rate-determining step, while the carbene formation process is the enantio-determining step. Moreover, multiple stabilizing chelating C-H···Pd interactions between the catalytic system and the substrates are key to achieving high enantioselectivity.
Condition Screening
Substrate Scope
Product Derivatization and Kinetic Experiments
Highlights of the Ming-Phos Ligand Used in This Reaction
- Precise Stereocontrol: As a classic ligand from the Sadphos family, Ming-Phos, through its non-C₂ symmetric structure, forms a unique coordination environment with the palladium center. Combined with the hydrogen-bonding capability of its sulfinamide group, it constructs a well-defined chiral pocket. In this Pd-catalyzed multicomponent reaction, it effectively distinguishes the stereochemical orientation of the carbene intermediate, enabling high enantiocontrol and providing core support for the efficient construction of chiral γ,γ-diaryl ketone scaffolds.
- Excellent Catalytic Activity and Generality: The combination of this ligand with the palladium catalyst exhibits extremely high catalytic efficiency, completing the three-component reaction in good to excellent yields. Simultaneously, Ming-Phos demonstrates outstanding functional group tolerance, accommodating various substituted aryl halides, N-sulfonylhydrazones, and cyclopropanol derivatives. Substrates bearing either electron-donating or -withdrawing groups, as well as heterocyclic substrates, are smoothly converted, significantly expanding the applicability of the reaction.
- Clear Mechanistic Insight and Scientific Value: Combined experimental and DFT calculation studies confirm that the Ming-Phos ligand can modulate the energy of reaction intermediates through stabilizing chelating C-H···Pd interactions. This clarifies the key mechanism where oxidative addition of the aryl halide is the rate-determining step, and carbene formation is the enantio-determining step. This synergistic "ligand-metal-substrate" interaction mechanism not only explains the origin of the high selectivity but also provides an important theoretical basis for the rational design of future ligands based on the Ming-Phos scaffold and the development of novel asymmetric catalytic reactions.
- Practical Scalability and Application Potential: The ligand system supports gram-scale reactions, and the products can undergo various subsequent transformations, such as carbonyl reduction and arene derivatization, with good retention of chirality. Furthermore, Ming-Phos has already demonstrated application value in the synthesis of drug molecules (e.g., intermediates related to integrin receptor inhibitors) and chiral materials. Its simple synthesis and controllable cost further enhance the potential for industrialization and research translation of this catalytic strategy.
To support related research, Anhui Kaitai Laibo now offers over 100 Ming-Phos chiral ligands with different structures. Below are some representative products:
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Publication Details
Authors: Bin Yang,# Jiahao Chen,# Bo Xiao,# Shanshan Li, Tian-Yu Sun,* Junfeng Yang,* Yun-Dong Wu,* and Junliang Zhang*
Title: Enantioselective Synthesis of γ,γ-Diaryl Ketones Enabled by Pd-Catalyzed Multicomponent Reaction of N-Sulfonylhydrazones
DOI: 10.1021/acscatal.5c08986
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