Sadphos as Adaptive Ligands in Asymmetric Palladium Catalysis.

ConspectusPalladium catalysis, as one of the most important strategies in asymmetric synthesis, has continuously attracted the attention of organic chemists. With the development of chiral ligands, increasingly challenging reactions and substantial progress in asymmetric catalysis are being realized.Since 2014, we have focused on exploiting a series of sulfinamide phosphine ligands called "Sadphos," including Ming-Phos, Xu-Phos, Xiao-Phos, Xiang-Phos, TY-Phos, PC-Phos, GF-Phos, and WJ-Phos. These ligands can be easily prepared in two to four steps using commercial materials. These new types of ligands have shown remarkable performance in transition-metal-catalyzed reactions, especially in Pd-catalyzed transformations. X-ray diffraction analysis, mechanistic studies, and density functional theory calculations have revealed that Sadphos ligands can coordinate with the Pd0 and PdII species in the Pd0/P, Pd0/P,S, or PdII/P,O modes.This Account summarizes our recent efforts toward palladium-catalyzed enantioselective reactions using Sadphos ligands. These ligands were found to be privileged and very crucial to promote the reactions by increasing the reactivity and enantioselectivity. Ming-Phos is an effective ligand in Pd-catalyzed asymmetric coupling and intramolecular Heck reactions, providing highly enantioselective trisubstituted allenes, axially chiral anilides, gem-diarylmethine silanes, and disubstituted dihydroisoquinolinones. Incorporation of an electron-rich cyclohexyl group in the phosphine moiety afforded Xu-Phos, which showed a unique effect in a series of asymmetric transformations, including reductive Heck, dearomative Mizoroki-Heck, tandem Heck/Suzuki coupling, carboiodination, carboamination, and cross-coupling reactions. Using a similar strategy, our group synthesized more electron-rich TY-Phos and Xiang-Phos ligands bearing t-butyl and 1-adamantyl group at P atoms, respectively. Regarding stereoelectronic features, these two characteristic ligands were the best choice to satisfy the requirements of the palladium-catalyzed fluoroarylation of gem-difluoroalkenes, intermolecular α-arylation of aldehydes, carboetherification of alkenyl oximes, and carboheterofunctionalization of 2,3-dihydrofurans. Compared with the aforementioned Sadphos ligands, the attractive features of Xiao-Phos, including high nucleophilicity originating from the CH2PPh2 group and the ortho-substituent effect at the side of the aryl ring, are presumably responsible for its efficiency. The Pd/Xiao-Phos catalyst system shows good performance in a series of cross-coupling reactions of secondary phosphine oxides, affording P-stereogenic products bearing multiple types of molecular skeletons. The modification of the basic Sadphos backbone by introducing a xanthene skeleton motivated us to design and synthesize monophosphines, named PC-Phos and GF-Phos. PC-Phos is effective in various reactions, including arylation of sulfenate anions, denitrogenative cyclization of benzotriazoles, and dearomatization of indoles. The practicability of GF-Phos was validated in the Pd-catalyzed asymmetric three-component coupling of N-tosylhydrazones, aryl halides, and terminal alkynes, as well as in the cross-coupling of N-tosylhydrazones and vinyl iodides with pendent amines. In addition, ferrocene-derived WJ-Phos was employed in the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction, affording axially chiral biaryl monophosphine oxides in excellent enantiomeric excesses.

Recent advances in Pd-catalyzed asymmetric cyclization reactions.

Over the past few decades, there have been major developments in transition metal-catalyzed asymmetric cyclization reactions, enabling the convenient access to a wide spectrum of structurally diverse chiral carbo- and hetero-cycles, common skeletons found in fine chemicals, natural products, pharmaceuticals, agrochemicals, and materials. In particular, a plethora of enantioselective cyclization reactions have been promoted by chiral palladium catalysts owing to their outstanding features. This review aims to collect the latest advancements in enantioselective palladium-catalyzed cyclization reactions over the past eleven years, and it is organized into thirteen sections depending on the different types of transformations involved.

Ascites-derived hsa-miR-181a-5p serves as a prognostic marker for gastric cancer-associated malignant ascites.

BACKGROUND: Peritoneal carcinomatosis was the main reason leading to gastric cancer (GC)-related death. We aimed to explore the roles of dysregulated microRNAs (miRNAs) and related immune regulation activities in GC-associated malignant ascites. METHODS: GSE126399 were downloaded from GEO database. Differentially expressed miRNAs in GC ascites samples was firstly screened, and critical miRNAs were further investigated by LASSO (least absolute shrinkage and selection operator) logistic regression and random forest (RF) algorithm. Receiver operating characteristic of critical miRNAs was also constructed. Moreover, functional analysis, immune cell infiltration associated with differentially expressed mRNAs were further analyzed. After selecting key modules by weighted gene co-expression network analysis, mRNAs related with survival performance and transcription factor (TF)-miRNA-mRNA network were constructed. RESULTS: Hsa-miR-181b-5p was confirmed as critical differentially expressed miRNAs in GC ascites. Then, the tumor samples were divided into high- and low- expression groups divided by mean expression levels of hsa-miR-181b-5p, and subjects with high hsa-miR-181b-5p levels had better survival outcomes. In total, 197 differentially expressed mRNAs associated with hsa-miR-181b-5p levels were obtained, and these mRNAs were mainly enriched in muscle activity and vascular smooth muscle contraction. Hsa-miR-181b-5 was positively related with activated CD4 T cells and negatively related with eosinophil. 17 mRNAs were selected as mRNAs significantly related with prognosis of GC, such as PDK4 and RAMP1. Finally, 75 TF-miRNA-mRNA relationships were obtained, including 15 TFs, hsa-miR-181b-5p, and five mRNAs. CONCLUSION: Our data suggest that the differentially expressed hsa-miR-181b-5p in ascites samples of GC patients may be a valuable prognostic marker and a potential target for therapeutic intervention, which should be validated in the near future.

Pd-Catalyzed Asymmetric Larock Indole Synthesis to Access Axially Chiral N-Arylindoles.

Larock indole synthesis is one of the most straightforward and efficient methods for the synthesis of indoles; however, there has been no asymmetric version yet for the construction of indole-based axially chiral N-arylindoles since its initial report in 1991. Herein we report the first example of an asymmetric Larock indole synthesis by employing a chiral sulfinamide phosphine (SadPhos) ligand (Ming-Phos) with palladium. It allows rapid construction of a wide range of axially chiral N-arylindole compounds in good yields up to 98:2 er. The application of this unique chiral scaffold as an organocatalyst is promising. Furthermore, a kinetic study has revealed that the alkyne migratory insertion is the rate-determining step, which has been proven by the density functional theory (DFT) calculations. Additionally, DFT studies also suggest that the N-C dihedral difference caused by the steric hindrance of the ligand contributes to enantioselectivity control.

Catalytic Asymmetric Synthesis of Sulfinamides via Cu-Catalyzed Asymmetric Addition of Aryl Boroxines to Sulfinylamines.

The application of sulfinamides has been witnessed in medicinal and agrochemistry with employment in asymmetric transformations. However, methods for their asymmetric catalytic synthesis have rarely been explored. Herein, the catalytic enantioselective addition of aryl boroxines to sulfinylamines via Cu catalyst and the newly developed Xuphos ligand were reported. A series of chiral aryl sulfinamides can be readily accessed in one step. This protocol enables the stereospecific transformation of sulfinamides to sulfonimidoyl fluorides, sulfonimidamides, and sulfonimidate esters. DFT calculations have revealed the reaction pathway, and the migratory insertion is the enantio-determining step. The noncovalent interaction between the oxygen atom of sulfinylamines and the C-H bonds in the ligand is crucial for enantioselectivity control.

Ligand-Controlled, Nickel-Catalyzed Stereodivergent Construction of 1,3-Nonadjacent Stereocenters.

In contrast to the asymmetric synthesis of molecules with a single stereocenter or 1,2-adjacent stereocenters, the simultaneous construction of acyclic 1,3-nonadjacent stereocenters via a single catalyst in an enantioselective and diastereoselective manner remains a formidable challenge. Here, we demonstrate the enantioselective and diastereodivergent construction of 1,3-nonadjacent stereocenters through Ni-catalyzed reductive cyclization/cross-coupling of alkene-tethered aryl bromides and α-bromoamides, which represents the major remaining stereochemical challenge of cyclization/difunctionalization of alkenes. Using Ming-Phos as ligand, a diverse set of oxindoles containing 1,3-nonadjacent stereocenters were obtained with high levels of enantio- and diastereoselectivity. Mechanistic experiments and density functional theory calculations indicate that magnesium salt plays a key role in controlling the diastereoselectivity. Furthermore, another set of complementary stereoisomeric products were constructed from the same set of starting materials using Ph-Phox as ligand.

Enantioselective Synthesis of Isoindolinone by Palladium-Catalyzed Aminoalkynylation of O-Phenyl Hydroxamic Ethers with Alkynes.

A highly efficient palladium-catalyzed asymmetric tandem aza-Heck/Sonogashira coupling reaction of O-phenyl hydroxamic ethers with terminal alkynes is described. This protocol enables versatile access to challenging chiral isoindolinone derivatives bearing a quaternary stereogenic center. The palladium-catalyzed aminoalkynylation reaction shows broad functional group tolerance and allows the straightforward preparation of isoindolinones with high efficiency and excellent enantioselectivity under mild conditions. DFT calculations were performed to disclose the reaction mechanism and the origins of the enantioselectivity.

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes.

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94-99% ee has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings. The obtained O-BCHeps are promising bioisosteres for ortho-substituted benzenes.

Boosting Bulk Oxygen Transport with Accessible Electrode Nanostructure in Low Pt Loading PEMFCs.

Despite the high potential for reducing carbon emissions and contributing to the future of energy utilization, polymer electrolyte membrane fuel cells (PEMFCs) face challenges such as high costs and sluggish oxygen transport in cathode catalyst layers (CCLs). In this study, the impact of pore size distribution on bulk oxygen transport behavior is explored by introducing nano calcium carbonate of varying particle sizes for pore-forming. Physicochemical characterizations for are employed to examine the electrode structure, while in situ electrochemical measurements are used to scrutinize bulk oxygen transport resistance, effective oxygen diffusivity ( D O 2 eff $D_{{{\mathrm{O}}}_2}^{{\mathrm{eff}}}$ ) and fuel cell performance. Additionally, the CCLs are constructed with aid of Lattice Boltzmann method (LBM) simulations and D O 2 eff $D_{{{\mathrm{O}}}_2}^{{\mathrm{eff}}}$ for CCLs with different pore size distribution are calculated. The findings reveal that D O 2 eff $D_{{{\mathrm{O}}}_2}^{{\mathrm{eff}}}$ initially increases and then decreases as the most probable pore size increases. A "sphere-pipe" model is proposed to describe practical bulk oxygen transport in CCLs, highlighting the significant role of not only the pore size of secondary pores but also the number of primary pores in bulk oxygen transport.

Recent Advances in Palladium-Catalyzed Asymmetric Heck/Tsuji-Trost Reactions of 1,n-Dienes.

Transition-metal catalyzed tandem asymmetric reactions were powerful tools to access various chiral compounds. Many strategies have been developed for the coupling of 1,n-dienes with aryl halides via a tandem Heck/Tsuji-Trost process. However, the control of regio- and stereo-chemistry remains a challenging task. This minireview details the recent advances in the field of asymmetric Heck/Tsuji-Trost reactions catalyzed by palladium complex, which have opened new opportunities and expanded our understanding in this area of research in recent years.

Enantioselective Arylation of Sulfenamides to Access Sulfilimines Enabled by Palladium Catalysis.

Sulfur-containing functional groups have garnered considerable attention owing to their frequent occurrence in ligands, pharmaceuticals and insecticides. However, enantioselective synthesis of sulfilimines, particularly diaryl sulfilimines remains a challenging and long-standing goal. Herein we report a highly enantio- and chemoselective cross-coupling of sulfenamides with aryl electrophiles to construct diverse S(IV) stereocenters by Pd catalysis. Bisphosphine ligands bearing sulfinamide groups were crucial for attaining high reactivity and selectivity. This strategy offers a general, modular and divergent platform for rapid synthesis of chiral sulfilimines and sulfoximines that are otherwise difficult to access. Furthermore, the origins of the high chemoselectivity and enantioselectivity were extensively investigated using density functional theory calculations.

Palladium/TY-Phos-Catalyzed Asymmetric Heck/Tsuji-Trost Reaction of o-Bromophenols with 1,3-Dienes.

2,3-Dihydrobenzofurans are crucial building blocks in the synthesis of natural products and pharmaceutical molecules. However, their asymmetric synthesis has been a long-standing formidable challenge so far. In this work, we developed a highly enantioselective Pd/TY-Phos-catalyzed Heck/Tsuji-Trost reaction of o-bromophenols with various 1,3-dienes, allowing expedient access to chiral substituted 2,3-dihydrobenzofurans. This reaction features excellent regio- and enantiocontrol, high functional group tolerance, and easy scalability. More importantly, the demonstration of this method as a highly valuable tool for the construction of optically pure natural products (R)-tremetone and fomannoxin is highlighted.

Lithium-Mediated Ammonia Electrosynthesis with Ether-Based Electrolytes.

Ammonia is of great importance in fertilizer production and chemical synthesis. It can also potentially serve as a carbon-free energy carrier for a future hydrogen economy. Motivated by a worldwide effort to lower carbon emissions, ammonia synthesis by lithium-mediated electrochemical nitrogen reduction (LiNR) has been considered as a promising alternative to the Haber-Bosch process. A significant performance improvement in LiNR has been achieved in recent years by exploration of favorable lithium salt and proton donor for the electrolyte recipe, but the solvent study is still in its infancy. In this work, a systematic investigation on ether-based solvents toward LiNR is conducted. The assessments of solvent candidates are built on their conductivity, parasitic reactions, product distribution, and faradaic efficiency. Notably, dimethoxyethane gives the lowest potential loss among the investigated systems, while tetrahydrofuran achieves an outstanding faradaic efficiency of 58.5 ± 6.1% at an ambient pressure. We found that solvent molecules impact the above characteristics by dictating the solvation configurations of conductive ions and inducing the formation of solid electrolyte interphase with different compositions. This study highlights the importance of solvents in the LiNR process and advances the electrolyte optimization for better performance.

Enantiodivergent Hydrogenation of Exocyclic α,ß-Unsaturated Lactams Enabled by Switching the N-Chirality of Iridium Catalyst.

Central chirality is an important chiral element used in the design of chiral ligands and catalysts. Mostly, the attention of organic chemists is focused on developing of chiral ligands with stable stereogenic centers. However, the N-chirality in chiral ligand design has been rarely explored due to its flexibility. Here we demonstrate the design, synthesis, and application of a class of simple P,N-ligands with flexible N-chirality and their derived iridium complexes with fixed N-chiral stereocenters. Both fixed configurations of the N-stereocenter of the iridium complexes could be selectively formed from the same chiral ligand. This pair of diastereoisomeric iridium complexes showed good performance in the enantiodivergent asymmetric hydrogenation of exocyclic α,ß-unsaturated lactams. The N-H group plays an impressive role in catalytic activity. Computational studies emphasized the importance of N-chirality and N-H group.

Palladium/PC-Phos-Catalyzed Asymmetric Heck/Tsuji-Trost Reactions of Amino-Tethered 1,3-Cyclohexadiene with Aryl and Alkenyl Halides.

Chiral perhydroindoles are found in a number of natural products and biologically active compounds. Therefore, the development of new asymmetric methodology for rapid access to this core is of high importance. Herein, we reported a highly regio- and diastereo-selective palladium/PC-Phos-catalyzed asymmetric Heck/Tsuji-Trost reactions of readily available amino tethered 1,3-cyclohexadienes with aryl and alkenyl halides, delivering various functionalized chiral hexahydroindoles in good yields with high enantioselectivity. The application of this reaction to the concise synthesis of (-)-α-Lycorane was demonstrated. DFT computation results indicate that the difference in ΔEdis of two migration insertion transition states determines the enantioselectivity of the reaction.

Enantioselective Synthesis of Dihydropyrazoles by Palladium/Xu-Phos-Catalyzed Alleneamination of ß,γ-Unsaturated Hydrazones with Propargylic Acetates.

The palladium-catalyzed asymmetric carboamination reaction is one of the most significant transformations in organic chemistry. Herein, we report the first palladium-catalyzed asymmetric alleneamination of ß,γ-unsaturated hydrazones with propargylic acetates. This protocol enables the efficient installation of various multisubstituted allene groups onto dihydropyrazoles in good yields with excellent enantioselectivities. The chiral sulfinamide phosphine ligand Xu-5 exhibits highly efficient stereoselective control in this protocol. The salient features of this reaction include the readily available starting materials, a broad substrate scope, an easy scale-up, mild reaction conditions and versatile transformations.

Catalytic Asymmetric Axially Chiral Allenyl C-P Bond Formation.

Chiral organophosphorous compounds are very important in catalysis, organic syntheses, and medicinal chemistry. However, catalytic enantioselective protocols for the axially chiral allenyl phosphorus compounds have never been reported. Herein, a palladium-catalyzed enantioselective carbon-phosphorus bond formation reaction affording axially chiral allenyl phosphonates has been developed. The reaction enjoys high yields and ees accommodating a wide range of functional groups. Mechanistic studies have unveiled an overwhelming kinetic resolution process.

PC-Phos Enabled Catalytic Palladium-heteroallyl Asymmetric Cycloaddition.

Asymmetric cycloaddition reactions are the most powerful tool to the expeditious construction of enantioenriched cyclic motifs in organic chemistry. In sharp contrast to well-developed cycloaddition reactions via the palladium-trimethylenemethane (Pd-TMM) intermediate, hetero (3 + 2) cycloadditions of the heteroallyl cations remain rare, largely due to their thermally forbidden nature. To the best of our knowledge, there is no example of asymmetric version leading to enantioenriched heterocycles reported so far. Herein we enabled the first example of catalytic asymmetric (3 + 2) cycloaddition of electrophilic palladium-heteroallyl zwitterion intermediate (Pd-OTMM or Pd-NTMM) with cyclic or acyclic 1,3-dienes via a pathway terminated with C-N or C-O bond formation, delivering the highly substituted or fused pyrrolidine and tetrahydrofuran rings in high yields with excellent regio-, diastereo-, and enantioselectivity. Engineering the PC-Phos, one of the chiral sulfinamide phosphine (Sadphos) type ligands, by introducing the di-tert-butyl or/and 3,5-difluorophenyl group is a vital component in achieving excellent catalytic reactivity and enantioselectivity.

Pd/Ming-Phos-Catalyzed Asymmetric Three-Component Arylsilylation of N-Sulfonylhydrazones: Enantioselective Synthesis of gem-Diarylmethine Silanes.

A Pd-catalyzed enantioselective three-component reaction of N-sulfonylhydrazones, aryl bromides, and silylboronic esters is developed, enabling the synthesis of chiral gem-diarylmethine silanes in high enantioselectivity with the use of a newly identified Ming-Phos. Compared with N-tosyl, the more easily decomposed N-mesitylsulfonyl is more suitable as the masking group of electron-rich hydrazone to improve the reaction efficiency. The reaction features a broad scope concerning both coupling partners, high enantioselectivity, and mild reaction conditions. The ready access to enantiomers and utility of this catalytic method are also presented.

Probing the Effect of Rigidity on the Cellular Uptake of Core-Shell Nanoparticles: Stiffness Effects are Size Dependent.

Nanoparticles are well established vectors for the delivery of a wide range of biomedically relevant cargoes. Numerous studies have investigated the impact of size, shape, charge, and surface functionality of nanoparticles on mammalian cellular uptake. Rigidity has been studied to a far lesser extent, and its effects are still unclear. Here, the importance of this property, and its interplay with particle size, is systematically explored using a library of core-shell spherical PEGylated nanoparticles synthesized by RAFT emulsion polymerization. Rigidity of these particles is controlled by altering the intrinsic glass transition temperature of their constituting polymers. Three polymeric core rigidities are tested: hard, medium, and soft using two particle sizes, 50 and 100 nm diameters. Cellular uptake studies indicate that softer particles are taken up faster and threefold more than harder nanoparticles with the larger 100 nm particles. In addition, the study indicates major differences in the cellular uptake pathway, with harder particles being internalized through clathrin- and caveolae-mediated endocytosis as well as macropinocytosis, while softer particles are taken up bycaveolae- and non-receptormediated endocytosis. However, 50 nm derivatives do not show any appreciable differences in uptake efficiency, suggesting that rigidity as a parameter in the biological regime may be size dependent.