Intramolecular Hosomi-Sakurai Reaction for the Synthesis of Benzoxasiloles.

A Lewis acid-catalyzed intramolecular Hosomi-Sakurai reaction of o-(allylsilyl)benzaldehyde/ketone has been developed. The reaction proceeds through simultaneous C-Si bond cleavage and C-C bond reconstruction. This protocol provides a rapid approach for the synthesis of allyl-substituted benzoxasiloles under mild conditions.

MUC4 O-GlcNAcylation Regulates the Epithelial Phenotype in Conjunctival Epithelial Cells.

In the present study, our aim was to explore the role of MUC4 in IL-4-stimulated conjunctival epithelial cells and the underlying mechanisms. Human recombinant IL-4 was employed in human conjunctival epithelial cells (HConEpic) cells, and MUC4 shRNA (sh-MUC4) was constructed to explore the functional role of MUC4. The protein level of MUC4, O-GlcNAc transferase (OGT), O-GlcNAc hydrolase (OGA), zonula occludens 1 (ZO-1), gap junction protein beta 2 (GJB2), claudin-8 (CLDN8), and E-cadherin were detected by Western blot in HConEpic cells, the interaction between MUC4 and OGT/OGA was assessed by co-immunoprecipitation (IP) and Western blot in 293T cells. Our results showed that IL-4 significantly up-regulated MUC4 and OGT protein levels in HConEpic cells, while down-regulated OGA protein level. Also, IL-4 down-regulated ZO-1, GJB2, CLDN8, and E-cadherin protein levels in HConEpic cells, while which was markedly reversed by sh-MUC4. Additionally, OGT inhibitor significantly reduced MUC4 protein level, and elevated ZO-1, GJB2, CLDN8, and E-cadherin protein levels in HConEpic cells, while OGA inhibitor resulted in the opposite results. Furthermore, in addition to the interaction between OGT/OGA and MUC4, Co-IP and Western blot also revealed the alteration of MUC4 O-GlcNAcylation in 293T cells treated with OGT/OGA inhibitor. Above findings suggested that OGT/OGA inhibitor regulated MUC4 protein level by affecting MUC4 O-GlcNAcylation to regulate ZO-1, GJB2, CLDN8, and E-cadherin protein levels in HConEpic cells, which was achieved via inhibiting the interaction between OGT/OGA and MUC4. This study may provide a better understanding of the pathogenesis of allergic conjunctivitis (AC).

Effect of GnRH Active Immunisation on Reproductive Performance of Male Sprague Dawley Rats.

To investigate the effect of active immunisation with gonadotropin-releasing hormone (GnRH) on the reproductive function in male Sprague Dawley (SD) rats, 24 42-day-old rats were randomly assigned to treatment with GnRH6-MAP, GnRH-OVA, a surgical castration group, and a blank control group. Each rat in the treatment groups was intramuscularly injected at 6, 8, and 10 weeks of age. The serum concentrations of testosterone (T), follicle-stimulating hormone (FSH), luteinising hormone (LH), and anti-GnRH antibodies were determined using enzyme-linked immunosorbent assays. The results showed that active immunisation with recombinant GnRH6-MBP and GnRH-OVA significantly increased the serum levels of anti-GnRH antibodies and reduced the serum concentrations of testosterone compared to the black control. Eight weeks after immunisation, the rats' testes were surgically removed for morphological evaluation, showing atrophy of the convoluted vasculature, relative emptying of the lumen, and insignificant differentiation of spermatogonial cells, which were increased in weight and volume compared with the blank control group. These findings indicated that active immunisation with GnRH can lead to testicular atrophy and reduce gonadal hormone concentrations, suggesting that GnRH is a highly effective immunogen.

Copper-Catalyzed Asymmetric Synthesis of Silicon-Stereogenic Benzoxasiloles.

A Cu-catalyzed asymmetric synthesis of silicon-stereogenic benzoxasiloles has been realized via intramolecular Si-O coupling of [2-(hydroxymethyl)phenyl]silanes. Cu(I)/difluorphos is found to be an efficient catalytic system for enantioselective Si-C bond cleavage and Si-O bond formation. In addition, kinetic resolution of racemic substituted [2-(hydroxymethyl)phenyl]silanes using Cu(I)/ PyrOx (pyridine-oxazoline ligands) as the catalytic system is developed to afford carbon- and silicon-stereogenic benzoxasiloles. Ring-opening reactions of chiral benzoxasiloles with organolithiums and Grignard reagents yield various enantioenriched functionalized tetraorganosilanes.

Catalytic Synthesis of Silanols by Hydroxylation of Hydrosilanes: From Chemoselectivity to Enantioselectivity.

As a crucial class of functional molecules in organosilicon chemistry, silanols are found valuable applications in the fields of modern science and will be a potentially powerful framework for biologically active compounds or functional materials. It has witnessed an increasing demand for non-natural organosilanols, as well as the progress in the synthesis of these structural features. From the classic preparative methods to the catalytic selective oxidation of hydrosilanes, electrochemical hydrolysis of hydrosilanes, and then the construction of the most challenging silicon-stereogenic silanols. This review summarized the progress in the catalyzed synthesis of silanols via hydroxylation of hydrosilanes in the last decade, with a particular emphasis on the latest elegant developments in the desymmetrization strategy for the enantioselective synthesis of silicon-stereogenic silanols from dihydrosilanes.

Disilane-bridged architectures: an emerging class of molecular materials.

Disilanes are organosilicon compounds that contain saturated Si-Si bonds. The structural characteristics of Si-Si single bonds resemble those of C-C single bonds, but their electronic structure is more similar to that of C[double bond, length as m-dash]C double bonds, as Si-Si bonds have a higher HOMO energy level. These organosilicon compounds feature unique intramolecular σ electron delocalization, low ionization potentials, polarizable electronic structure, and σ-π interaction. It has been demonstrated that the employment of disilane units (Si-Si) is a versatile and effective approach for finely adjusting the photophysical properties of organic materials in both solution and solid states. In this review, we present and discuss the structure, properties, and relationships of novel σ-π-conjugated hybrid architectures with saturated Si-Si σ bonds. The application of disilane-bridged σ-conjugated compounds as optoelectronic materials, multifunctional solid-state emitters, CPL, and non-linear optical and stimuli-responsive materials is also reviewed.

Rhodium-Catalyzed Hydrolytic Cleavage of the Silicon-Carbon Bond of Silacyclobutanes to Access Silanols.

Herein, we report the first rhodium-catalyzed hydrolytic cleavage of the silicon-carbon bond in silacyclobutanes using water as the reactant. A series of silacyclobutanes could be employed in this reaction in the presence of the Rh/BINAP complex, resulting in the corresponding silanols in good yields. Additionally, a chiral 1,1,4,4-tetraaryl-2,3-O-isopropylidene-l-threitol-derived phosphoramidite ligand could be used in this reaction to yield Si-stereogenic silanol with promising enantioselectivity.

Solvent-Dependent Rhodium-Catalyzed Divergent Hydrofunctionalization of Trifluoromethylalkenes.

We report a rhodium-catalyzed anti-Markovnikov regioselective hydrosilylation of trifluoromethylalkenes with substituted silanes giving various α-trifluoromethyl-ß-silanes in good to excellent yields. The hydrogenation products were obtained via the same key intermediate treated with methanol as a protic solvent. Both transformations had a broad functional tolerance and were expected to facilitate the construction of complex α-trifluoromethyl compounds.

Palladium- and nickel-catalyzed cascade enantioselective ring-opening/coupling reactions of cyclobutanones.

The chemistry of small ring compounds is an intriguing subject in organic chemistry. As the smallest stable cyclic aliphatic ketones, cyclobutanones have garnered tremendous attention owing to their intrinsic high reactivity such as transition-metal catalyzed C-C bond cleavage. In this context, transition-metal catalyzed formal cycloaddition of cyclobutanones via a "cut and sew" strategy has gained marvelous advances. In contrast, an alternative reaction paradigm, i.e., transition-metal catalyzed ring-opening reactions of cyclobutanones, is still underdeveloped. This feature article aims to summarize our efforts in developing enantioselective palladium-catalyzed ring-opening/coupling reactions and recently emerging nickel-catalyzed ring-opening/reductive coupling reactions of cyclobutanones with a tethered aryl halide. The possible mechanisms are briefly showcased and the advantages and limitations of each strategy as well as their synthetic applications in the synthesis of natural products or bioactive compounds are presented.

Lewis Base-Catalyzed Trifluoromethylsulfinylation of Allylic Alcohols: Stability-Oriented Divergent Synthesis.

A novel strategy is demonstrated for Lewis base-activated trifluoromethylsulfinylation of allylic alcohols. Controllable synthesis of structurally varied allylic trifluoromethanesulfones via sigmatropic rearrangements was performed, and trifluoromethanesulfinate esters were achieved. This metal-free, catalytic divergent transformation features good functional group tolerance and late-stage modification of bioactive molecules. Mechanistic studies suggested that Lewis bases interact with N-(trifluoromethylsulfinyl)phthalimide to generate an ion pair adduct followed by O-trifluoromethylsulfinylation with allylic alcohols.

An unusual autocatalysis with an air-stable Pd complex to promote enantioselective synthesis of Si-stereogenic enynes.

Given the powerful potential of chiral-at-silicon chemistry, enantioselective synthesis of Si-stereogenic centers has attracted substantial research interest in recent years. However, the catalytic asymmetric synthesis of Si-stereogenic organosilicon compounds remains an appealing venture and is a challenging subject because of the difficulty in achieving high reactivity and stereoselectivity for "silicon-center" transformations. Herein, we disclose a highly enantioselective palladium-catalyzed hydrosilylation of 1,3-diynes with dihydrosilanes, which enables the facile preparation of Si-stereogenic enynes and an enyne-linked chiral polymer (polyenyne) in good yields and excellent ees (up to >99%) by desymmetrization. The unusual stereoselectivity in this reaction is achieved by precisely controlling the steric hindrance and electronic effect of the newly developed chiral ligands, resulting in a wide range of chiral silanes and a Si-containing polymer bearing a Si-stereogenic center which is otherwise difficult to access. The key to the high enantioselectivity relies on catalyst aggregation-induced non-covalent interaction, which exerts a remarkably positive influence on the Si-H bond activation and enhancement of enantioselectivity, in which the palladium/P-ligand complex was proved to be air-stable and moisture-insensitive in this reaction.

Transition-metal free C-N bond formation from alkyl iodides and diazonium salts via halogen-atom transfer.

Construction of C-N bond continues to be one part of the most significant goals in organic chemistry because of the universal applications of amines in pharmaceuticals, materials and agrochemicals. However, E2 elimination through classic SN2 substitution of alkyl halides lead to generation of alkenes as major side-products. Thus, formation of a challenging C(sp3)-N bond especially on tertiary carbon center remains highly desirable. Herein, we present a practical alternative to prepare primary, secondary and tertiary alkyl amines with high efficiency between alkyl iodides and easily accessible diazonium salts. This robust transformation only employs Cs2CO3 promoting halogen-atom transfer (XAT) process under transition-metal-free reaction conditions, thus providing a rapid method to assemble diverse C(sp3)-N bonds. Moreover, diazonium salts served as alkyl radical initiator and amination reagent in the reaction. Mechanism studies suggest this reaction undergo through halogen-atom transfer process to generate active alkyl radical which couples with diazonium cations to furnish final products.

Rhodium-Catalyzed Dynamic Kinetic Asymmetric Hydrosilylation to Access Silicon-Stereogenic Center.

Strategies on the construction of enantiomerically pure silicon-stereogenic silanes generally relies on desymmetrization of prochiral and symmetric substrates. However, dynamic kinetic asymmetric transformations of organosilicon compounds have remained underdeveloped and unforeseen owing to a lack of an effective method for deracemization of the static silicon stereocenters. Here we report the first Rh-catalyzed dynamic kinetic asymmetric intramolecular hydrosilylation (DyKAH) with "silicon-centered" racemic hydrosilanes that enables the facile preparation of silicon-stereogenic benzosiloles in good yields and excellent enantioselectivities. The special rhodium catalyst controlled by non-diastereopure-type mixed phosphine-phosphoramidite ligand with axial chirality and multiple stereocenters can induce enantioselectivity efficiently in this novel DyKAH reaction. Density functional theory (DFT) calculations suggest that the amide moiety in chiral ligand plays important role in facilitating the SN 2 substitution of chloride ion to realize the chiral inversion of silicon center.

Administration of USP7 inhibitor P22077 inhibited cardiac hypertrophy and remodeling in Ang II-induced hypertensive mice.

Hypertension is one of the common causes of pathological cardiac hypertrophy and a major risk for morbidity and mortality of cardiovascular diseases worldwide. Ubiquitin-Specific Protease 7 (USP7), the first identified deubiquitinating enzymes, participated in a variety of biological processes, such as cell proliferation, DNA damage response, tumourigenesis, and apoptosis. However, its role and mechanism in cardiac remodeling remain unclear. Here, our data indicated that USP7 expression was increased during Ang II-induced cardiac hypertrophy and remodeling in mice and humans with heart failure, while the administration of its inhibitor p22077 attenuated cardiac hypertrophy, cardiac fibrosis, inflammation, and oxidase stress. Mechanistically, the administration of p22077 inhibited the multiple signaling pathways, including AKT/ERK, TGF-ß/SMAD2/Collagen I/Collagen III, NF-κB/NLRP3, and NAPDH oxidases (NOX2 and NOX4). Taken together, these findings demonstrate that USP7 may be a new therapeutic target for hypertrophic remodeling and HF.

Palladium-Catalyzed Transient Chirality Transfer and Atroposelective C-H Functionalization to Access Quaternary Stereocenters.

Although palladium-catalyzed asymmetric C-H functionalization and Heck reactions represents one of the most important synthetic strategies for the construction of quaternary stereocenters, developing the enantioselective version of PdII -catalyzed carbopalladation-initiated cascade reactions still remains a formidable challenge. Herein, an unprecedent enantioselective [3+2] annulation of oxime ethers and alkynes has been developed, providing both spiro and nonspiro indenes bearing all-carbon quaternary stereocenters in good yields (up to 98 %) with excellent enantioselectivities (up to >99 % ee). This annulation is accomplished by merging the PdII -catalyzed atroposelective C-H activation/double carbopalladation and the transient axial-to-central chirality transfer process, constituting the first successful example of catalytic chirality transfer strategy involving axially chiral styrene intermediate.

3-Alkyl-2-pyridyl Directing Group-Enabled C2 Selective C-H Silylation of Indoles and Pyrroles via an Iridium Catalyst.

An iridium-catalyzed, directing group-enabled site selective intra- and intermolecular silylation of indoles and pyrroles with hydrosilanes has been developed under ligand-free conditions. Fine-tuning of the removable 3-alkyl-2-pyridyl directing group was found to be crucial for achieving high yields for C2-silylated indole and pyrrole products. Moreover, the scalability was demonstrated, and further transformations of the silylation products were achieved.

Siloxane-Based Organosilicon Materials in Electrochemical Energy Storage Devices.

Siloxane-based molecular material, by virtue of its unique chemical structure, thermal and electrochemical properties, has triggered tremendous research interest and sparked a revolution for energy storage in the past years. Siloxanes and their analogues are generally demonstrated to be more environmentally friendly, durable, and safer when employed to reconstruct the nano-micro surface structure of electrodes, separators, and their interfaces with electrolytes. To better understand the recent and comprehensive achievement of siloxane-based materials in energy storage, a systematic summary is necessary to provide important clues, aiming at achieving better electrochemical properties. In this Minireview, siloxane materials are presented comprehensively and systematically in terms of molecule design, functionality, and unique superiority for lithium-ion batteries and supercapacitors. The challenges, perspectives, and future directions of siloxane-based organosilicon materials are put forward for higher performance and wider application in electrochemical energy storage devices.

Atropisomers with Axial and Point Chirality: Synthesis and Applications.

Enantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.

Application of aromatic amide-derived atropisomers as chiral solvating agents for discrimination of optically active mandelic acid derivatives in 1 H nuclear magnetic resonance spectroscopy.

Non-biaryl atropisomers and their stereochemistry have attracted much attentions in the past years. However, application of the non-biaryl atropisomers as chiral solvating agents is yet to be explored. In this work, four aromatic amide-derived atropisomeric phosphine ligands (hosts) were used as chiral solvating agents to recognize various mandelic acid derivatives (guests) in 1 H nuclear magnetic resonance (NMR) spectroscopy. It is found that chiral center configurations of the four hosts have different effects on the enantiorecognition to the used guests. In addition, the host and guest interaction was further investigated by determination of the host-guest complex stoichiometry using the Job's method and density functional theory calculation, respectively. Moreover, chiral analysis accuracy of these hosts was evaluated through relationship between enantiomeric excess values of 4-chloromandelic acid provided by NMR and gravimetry, respectively.