The Same Sadphos, A Different 2025!
Created on Today
The research team led by Professor Junliang Zhang at Fudan University has consistently dedicated itself to the design, development, and application research of novel chiral phosphine ligands within the Sadphos library, injecting new vitality into the field of chiral catalysis through innovation. The standout performance of Sadphos ligands is attributed to their comprehensive advantages: in synthesis, they feature readily available starting materials, low cost, and ease of modification, significantly lowering the barrier to application; structurally, they combine non-C2 symmetry, rigidity with flexibility, a balance of hard and soft donor properties, and versatile coordination modes, safeguarding catalytic performance; in application, they exhibit excellent performance in various transition metal catalyses (Pd, Au, Cu, Ag, Rh, Ni, Co, Ir) and organocatalysis. As commercially available chiral ligands, they have already facilitated numerous research groups domestically and internationally in achieving prolific outcomes.
Looking back to 2014, adhering to the innovative concepts of "non-C2 symmetry, rigidity with flexibility, and synergistic multi-coordination atoms," Professor Junliang Zhang's group officially embarked on the research and development of Sadphos ligands. As a novel class of chiral tert-butylsulfinamide-based phosphine ligands/catalysts with independent intellectual property rights, they are truly "versatile tools" in organic synthesis, equipped with an "all-round buff": diverse and readily modifiable structures, facile gram-scale preparation, and compatibility with over 50 types of asymmetric reactions across 8 categories of metal catalysis (e.g., Au, Cu, Pd) and organocatalysis, empowering efficient scientific breakthroughs! The nomenclature itself contains thoughtful design and expectation: "Sadphos" derives from the abbreviations of its common structural units "Sulfinamide" and "Phosphine," and embodies a gentle promise: Sadphos never makes you sad! Now officially named "赛德福仕" in Chinese, it wishes every user the joy of breakthrough and a sense of full accomplishment on their research journey.
Over the past year, nurtured by the research community, Sadphos has steadily grown, demonstrating exceptional catalytic activity and chiral induction capabilities in asymmetric copper catalysis, palladium catalysis, nickel catalysis, and organocatalytic reactions. More notably, Sadphos is gradually expanding its application boundaries, showing promise in the field of machine learning, opening new possibilities for cross-disciplinary integration! This push specially summarizes the latest application achievements of Sadphos ligands, witnessing each breakthrough and growth on the scientific path. This includes remarkable efforts from domestic peers: the research group of Researcher Ying Xia at Sichuan University, the teams of Professor Renrong Liu and Associate Professor Longlong Xi at Qingdao University, the team of Researcher Xin Hong at Zhejiang University, the team of Associate Professor Lei Wang at Yangzhou University, etc., who have delved deep into their fields and achieved new progress; as well as collaborative explorations between Professor Zhang Junliang's team and other teams: the team of Academic院士 Yundong Wu at Peking University Shenzhen Graduate School, the team of Professor Min Zhou at Yunnan Minzu University, the teams of Professor Yingwu Lin and Associate Professor Huamin Wang at University of South China, pooling efforts to explore new frontiers. These research teams have all relied on the Sadphos family of ligands to tackle challenges and meticulously develop their dedicated reaction systems, achieving a series of significant scientific advances, jointly propelling related research fields forward with synergistic force!
- Cu/Ming-Phos Catalyzed Enantioselective Alkenylation of Sulfinamides In targeted cancer therapies such as Antibody-Drug Conjugates (ADCs), vinyl sulfones and their derivatives are commonly used active warheads. However, nitrogen-containing analogues with S(IV)/S(VI) stereocenters (e.g., alkenyl sulfinamides) have been understudied due to the lack of efficient asymmetric catalytic synthesis methods. Existing syntheses of sulfur-chiral compounds mostly focus on aromatic and aliphatic fragments, making alkenyl structures containing sulfur stereocenters difficult to prepare. Professor Junliang Zhang's team, employing Ming-Phos ligand, developed a copper-catalyzed enantioselective alkenylation reaction, efficiently synthesizing alkenyl sulfinamides from alkenyl boronic esters and sulfinamides [1]. The method exhibits good functional group tolerance, accommodating various substituents and biologically relevant substrates. The products can be transformed into diverse S(IV)/S(VI) derivatives. DFT calculations indicate a preference for migratory insertion into the S=O bond, and hydrogen-bonding interactions between the ligand and substrate are key to high enantioselectivity (Figure 1).
- Pd/Ming-Phos Catalyzed Asymmetric Narasaka-Heck Cyclization/Suzuki Coupling Cascade Reaction Nitrogen-containing heterocycles are core structures in numerous bioactive molecules and drugs. The asymmetric synthesis of pyrroline derivatives is a hot topic in organic catalysis. Transition-metal-catalyzed intramolecular 1,2-carboamination is an effective method for constructing N-heterocycles, among which the Narasaka-Heck cyclization is widely applicable. However, its radical reaction nature makes enantioselective control challenging, and there is currently no general method for constructing chiral aryl-functionalized pyrrolines. Professor Junliang Zhang's team developed a palladium/Ming-Phos catalyzed asymmetric Narasaka-Heck cyclization/Suzuki coupling cascade reaction. Using oxime esters and boronic acids as substrates, it enables the efficient synthesis of pyrroline derivatives containing quaternary carbon stereocenters [2] (Figure 2). This method offers good functional group tolerance, excellent yield, and enantioselectivity, providing a new strategy for chiral N-heterocycle synthesis.
- Pd/Xu-Phos Catalyzed Asymmetric Carbene Cross-Coupling Reaction Axially chiral alkylidenecyclobutanes are important building blocks in bioactive molecules and synthetic chemistry. However, their asymmetric synthesis is highly challenging due to the rigidity and ring strain of the four-membered ring. Existing methods rely on specific substrates, limiting their application. Transition-metal-catalyzed carbene coupling reactions are efficient strategies for constructing carbon-carbon bonds, with N-tosylhydrazones being reliable carbene precursors. The research team of Researcher Ying Xia at Sichuan University developed a palladium/Xu-Phos catalyzed asymmetric carbene cross-coupling reaction. Using N-tosylhydrazones derived from cyclobutanecarboxaldehyde and aryl bromides, and through enantioselective migratory insertion and central-to-axial chirality transfer β-H elimination, it efficiently synthesizes axially chiral alkylidenecyclobutanes. Furthermore, both enantiomers can be obtained by selecting cis/trans substrates [3] (Figure 3).
- Pd/Xu-Phos Catalyzed Asymmetric Cascade Carboetherification Reaction Palladium-catalyzed carbofunctionalization of alkenes is an efficient method for constructing heterocyclic compounds. However, asymmetric carboetherification reactions and the enantioselective synthesis of bis-heterocyclic compounds remain challenging. Bis-heterocyclic skeletons are widely used in drug and bioactive molecule design, making the development of efficient synthetic strategies highly significant. The team of Associate Professor Lei Wang at Yangzhou University, using Xu-Phos as the ligand, achieved efficient construction of isoxazoline-linked methylenedihydrobenzofuran and methyleneindole bis-heterocyclic skeletons via enantioselective palladium-catalyzed cascade carboetherification of β,γ-unsaturated oxime derivatives [4] (Figure 4). This method features good functional group tolerance, broad substrate scope, and high chemoselectivity and enantioselectivity, providing a practical tool for synthesizing complex chiral structures.
- Pd/Xu-Phos Catalyzed Asymmetric Cascade Heck/Tsuji-Trost Reaction For decades, palladium-catalyzed enantioselective cascade Heck/cross-coupling reactions have been powerful tools in organic synthesis. However, asymmetric Heck/cross-coupling cascade reactions involving highly flexible vinyl halide substrates remain challenging. These substrates have flexible conformations, making it difficult to control regioselectivity, diastereoselectivity, and enantioselectivity. Moreover, the stereodetermining step in traditional reactions relies on Tsuji-Trost nucleophilic attack. Professor Junliang Zhang's team, in collaboration with Professor Min Zhou's team at Yunnan Minzu University and leveraging the Xu-Phos ligand from the Sadphos family, developed a palladium-catalyzed asymmetric cascade Heck/Tsuji-Trost reaction between highly flexible vinyl halides and 1,3-dienes. Using Heck insertion as the stereodetermining step, it achieves high chemo-, regio-, and enantioselectivity [5] (Figure 5). This reaction efficiently synthesizes chiral cyclic isoprenoid compounds rich in sp3-hybridized carbons, providing a modular platform for the synthesis of natural product and pharmaceutical intermediates.
- Pd/Xu-Phos Catalyzed Asymmetric Intramolecular C-H Arylation Reaction Sulfoximines are important active pharmacophores in pharmaceuticals and agrochemicals. Sulfoximines containing S(VI) chiral centers possess excellent physicochemical and biological activities. However, their asymmetric synthesis remains a challenge in organocatalysis. Existing methods rely on chiral starting materials or have limited catalytic strategies, lacking efficient methods for synthesizing structurally diverse derivatives. Professor Junliang Zhang's team developed a Pd/Ag dual-catalyzed enantioselective intramolecular C-H arylation reaction. Using Xu-Phos as the chiral ligand and identifying Pd-G3/Ag2CO3 as the optimal catalytic system, they achieved efficient construction of sulfur-chiral sulfoximines [6] (Figure 6). This method exhibits broad functional group tolerance and excellent enantioselectivity, is compatible with natural product derivatives, and allows for gram-scale preparation. DFT calculations confirmed that Ag2CO3 can form a Pd-Ag heterodimeric transition state, enhancing enantioselectivity control. The resulting chiral sulfoximines can be converted into novel YW-Phos chiral monophosphine ligands, which show good catalytic performance in Pd- and Au-catalyzed asymmetric reactions.
- Pd/Xu-Phos Catalyzed Asymmetric Cascade Heck/Intermolecular Heteroarylation Reaction Asymmetric cascade Heck/C-H functionalization is an important strategy for activating inert C-H bonds and efficiently constructing heterocycles containing quaternary carbon centers. Its domino-type carbopalladation and C-H functionalization sequence can efficiently build multiple chemical bonds in one pot. Professor Junliang Zhang's team developed a palladium/Xu-Phos catalyzed enantioselective cascade Heck/intermolecular direct heteroarylation reaction of unactivated alkenes with heteroarenes. Under mild conditions, it conveniently synthesizes bis-heterocyclic compounds containing valuable all-carbon quaternary stereocenters with excellent yield and enantioselectivity (7) (Figure 7). Diversified transformations of the products further validate the synthetic utility of this strategy, providing a new method for the efficient construction of complex chiral heterocycles.
- Pd/PC-Phos Catalyzed Asymmetric Suzuki-Miyaura Cross-Coupling Reaction Pillararenes have wide applications in biomedicine, materials science, and other fields. Chiral pillar[5]arenes are particularly valuable in enantioselective host-guest recognition, chiral sensing, etc. Traditional methods for obtaining chiral pillararenes rely on resolving agents or chiral HPLC separation. Asymmetric catalytic synthesis still faces challenges. The teams of Professor Renrong Liu and Associate Professor Longlong Xi at Qingdao University developed a palladium-catalyzed asymmetric extended-side-arm Suzuki-Miyaura cross-coupling strategy. Using PC-Phos ligand, they achieved the efficient synthesis of inherently chiral pillar[5]arenes with excellent product yield and enantioselectivity [8] (Figure 8). This method is applicable to various arylboronic acids, 2-arylvinylboronic acids, and multi-OTf substituted substrates, synthesizing 49 structurally diverse chiral pillar[5]arenes. Their photophysical and chiroptical properties indicate potential for multidisciplinary applications.
- Pd/PC-Phos Catalyzed Asymmetric Three-Component Reaction Triarylmethanes are important structural units in natural products, drug discovery, and materials science. Chiral triarylmethanes have attracted significant attention due to their unique three-dimensional structures. Existing enantioselective synthesis methods mostly rely on pre-constructed skeletons, facing challenges in synthesizing non-functionalized triarylmethanes. Professor Junliang Zhang's team, in collaboration with Academician Yundong Wu's team at Peking University Shenzhen Graduate School, developed a modular, enantioselective strategy. Using aldehyde-derived hydrazones, aryl halides, and aryl nucleophiles as starting materials, a one-pot cascade reaction catalyzed by Pd/PC-Phos simultaneously forms two C-C bonds, efficiently synthesizing chiral triarylmethanes 9 (Figure 9). This method transfers the enantioselectivity-determining step to the transition metal-carbene migratory insertion process, overcoming the limitations of traditional methods. Furthermore, both enantiomers can be conveniently obtained by switching aryl fragments, demonstrating excellent step economy and functional group tolerance.
- Pd/PC-Phos Catalyzed Asymmetric Hydrophosphonylation Reaction Chiral organophosphorus compounds are important motifs in bioactive molecules and chiral ligands. The synthesis of α-chiral alkylphosphorus compounds is particularly significant. Existing methods mostly rely on chiral auxiliaries or are only applicable to activated alkenes. The asymmetric hydrophosphonylation of simple styrenes faces challenges in regioselectivity and enantioselectivity control. Professor Junliang Zhang's team developed a palladium-catalyzed, ligand-controlled regioselective asymmetric hydrophosphonylation of styrenes. Using PC-Phos as the ligand affords Markovnikov products with high selectivity (>95:5 rr, 92% ee), while switching to rac-BINAP predominantly yields anti-Markovnikov products, with good functional group tolerance [10] (Figure 10). Deuterium labeling experiments and DFT calculations indicate that migratory insertion is the enantioselectivity-determining step. The O-H hydrogen bonding between the phosphonate and ligand is a key interaction, and both migratory insertion and reductive elimination jointly regulate regioselectivity.
- Ni/Xiao-Phos Catalyzed Asymmetric Suzuki-Miyaura Cross-Coupling Reaction Catalyst design is often limited by the complex structure-activity relationship and data scarcity. Traditional methods struggle to meet cutting-edge synthetic needs. Machine learning offers new pathways for catalyst development, but predictive performance is limited in low-data scenarios. The research team of Researcher Xin Hong at Zhejiang University, based on the mechanistic similarity between Pd and Ni catalysis, proposed a transfer learning strategy. By integrating abundant Pd-catalysis literature data with limited Ni/Sadphos catalysis experimental data, they built a model to predict novel chiral ligands [11] (Figure 11). This successfully achieved the first Ni-catalyzed asymmetric Suzuki-Miyaura cross-coupling reaction, predicting that the Xiao-Phos ligand would give 93% ee. The reaction also features a broad substrate scope and allows for gram-scale synthesis. DFT calculations validated the reaction mechanism, providing a new paradigm for the rational design of catalysts in low-data scenarios.
- A Comprehensive Resource for Exploring Chiral Ligand Chemical Space Traditional chiral ligand discovery relies on chemists' experience, which is time-consuming and prone to bias. Data science offers systematic methods for ligand design. Chiral Sadphos ligands have attracted attention due to their multiple coordination sites and excellent catalytic activity. However, the high cost of DFT calculations hinders their large-scale screening. Researcher Shuang Yu constructed a library containing 890 reported Sadphos molecules. Using the xTB method, 76 physico-organic descriptors were generated, covering backbone, phosphorus atoms, and molecular properties [12] (Figure 12). Employing dimensionality reduction and clustering techniques, a representative subset of ligands was screened. Validated on small datasets, this approach can rapidly identify key features related to catalytic performance, providing support for the efficient discovery of high-performance catalysts.
- Sadphos-Catalyzed Asymmetric Sequential [3+2]/[3+2] Dearomative Annulation Reaction Dearomative reactions are efficient means to construct complex three-dimensional structures. Phosphine-catalyzed asymmetric dearomative reactions have garnered attention for synthesizing cyclic molecules with multiple stereocenters, but successful examples are limited. Cyclopentane-fused polycyclic skeletons with consecutive stereocenters are key pharmacophores in many bioactive natural products, making their efficient synthesis highly significant. In collaboration with Professor Yingwu Lin and Associate Professor Huamin Wang at University of South China, Professor Junliang Zhang's team, using Sadphos as the catalyst, developed a phosphine-catalyzed asymmetric sequential [3+2]/[3+2] dearomative annulation reaction of 4-nitroisoxazoles with allenoates. Under mild conditions, isoxazoline-fused bicyclo[3.3.0]octene derivatives were synthesized [13] (Figure 13). This method has a broad substrate scope and also achieved gram-scale synthesis and diversified transformations of the products, providing an efficient synthetic route for such chiral polycyclic skeletons containing quaternary stereocenters.
References
- Y. Yuan, L. Pan, Y. Han, X. Tian, W. Ye, J. Zhang,* J. Yang* Enantioselective Alkenylation of Sulfinylamines via Copper/Sadphos for the Synthesis of Alkenyl Sulfinamides. CCS Chem.2025, DOI: 10.31635/ccschem.025.202505937.
- W. Ye, K. Cao, Z. Ye, S. Qi, J. Yang,* J. Zhang* Enantioselective Palladium-Catalyzed Cascade Narasaka-Heck Cyclization/Suzuki Coupling Reaction. ACS Catal.2025, 15, 2516.
- X. Ning, T. Zhao, Y. Zhu, B. Liu, X. Yan,* Y. Xia* Enantioselective Synthesis of Axially Chiral Alkylidenecyclobutanes via Palladium-Catalyzed N-Tosylhydrazone-Based Carbene Coupling. J. Am. Chem. Soc.2025, 147, 16773.
- L. Wang,* Y. He, H. Li, S. Wu, X. Deng, W. Jiang, L. Zhou, G. Zhang Enantioselective Palladium-Catalyzed Domino Carboetherification Reaction:Access to Isoxazoline-Linked Bis-Heterocycles. Org. Lett.2025, 27, 7518.
- L.-Z. Zhang, P.-C. Zhang, Q. Wang, M. Zhou,* J. Zhang* Enantioselective Heck/Tsuji-Trost reaction of flexible vinylic halides with 1,3-dienes. Nat. Commun.2025, 16, 930.
- Y. Xia, B. Xu, Z. Zhang,* J. Zhang* Pd/Ag dual-catalyzed asymmetric synthesis of sulfur-stereogenic sulfoximines via enantioselective intramolecular C-H arylation. Green Synth. Catal.DOI: org/10.1016/j.gresc.2025.06.004.
- K. Dong, C. Fang, Z. Li, B. Xu, Z. Zhang,* J. Zhang* Palladium/Xu-Phos-Catalyzed Enantioselective Cascade Heck/Intermolecular Direct Heteroarylation Reaction. Chin. J. Chem.2025, 43, 2199.
- T.-R. Luan, C. Sun, Y.-L. Tian, Y.-K. Jiang, L.-L. Xi, R.-R. Liu, Enantioselective construction of inherently chiral pillar[5]arenes via palladium-catalysed Suzuki-Miyaura cross-coupling. Nat. Commun.2025, 16, 2370.
- S. Zhu, B. Xiao, M. Huang, Y. Wu, T.-Y. Sun,* J. Yang,* Y.-D. Wu,* J. Zhang* Pd/SadPhos Enabled Modular and Enantioselective Assembly of Triarylmethanes. J. Am. Chem. Soc.2025, 147, 45210.
- C. Ma, X. Wang, T. Soós, J. Zhang, J. YangNat Commun, 2025, 16, 5436.
- X.-Y. Xu, L.-G. Liu, L.-C. Xu, S.-Q. Zhang,* X. Hong* Transfer Learning-Enabled Ligand Prediction for Ni-Catalyzed Atroposelective Suzuki-Miyaura Cross-Coupling Based on Mechanistic Similarity: Leveraging Pd Knowledge for Ni Discovery. J. Am. Chem. Soc.2025, 147, 15318.
- S. Yu* SadPhos Library: A Comprehensive Resource for Exploring Chiral Ligand Chemical Space. Chem Asian J.2025, 20, e202500023.
- H. Wang,* H.-D. Xie, J.-L. Ding, Y. Xie, Y.-W. Lin,* J. Zhang* Phosphine-Catalyzed Asymmetric Dearomative Annulation of 4-Nitroisoxazoles with Allenoates: Construction of Isoxazoline Fused Bicyclo[3.3.0]octenes. Org. Lett.2025, 27, 6812.