Stereoconvergent and Enantioselective Synthesis of Z-Homoallylic Alcohols via Nickel-Catalyzed Reductive Coupling of Z/E-1,3-Dienes with Aldehydes.

Stereoconvergent reactions enable the transformation of mixed stereoisomers into well-defined, chiral products─a crucial strategy for handling Z/E-mixed olefins, which are common but challenging substrates in organic synthesis. Herein, we report a stereoconvergent and highly enantioselective method for synthesizing Z-homoallylic alcohols via the nickel-catalyzed reductive coupling of Z/E-mixed 1,3-dienes with aldehydes. This process is enabled by an N-heterocyclic carbene ligand characterized by C2-symmetric backbone chirality and bulky 2,6-diisopropyl N-aryl substituents. Our method achieves excellent stereocontrol over both enantioselectivity and Z-selectivity in a single step, producing chiral Z-homoallylic alcohols that are valuable in natural products and pharmaceuticals.

Regioselective and Enantioselective Nickel-Catalyzed Intermolecular Reductive Coupling of Aliphatic Alkenes with Imines.

Unactivated aliphatic alkenes are particularly desirable as starting materials because they are readily accessible in large quantities, but the enantioselective intermolecular reductive coupling of unactivated alkenes with imines is challenging. In this paper, we report a method for nickel-catalyzed intermolecular reductive coupling reactions between aliphatic alkenes and imines to yield chiral amines with excellent enantioselectivities and good linear selectivities. The reaction conditions are compatible with a broad range of aliphatic alkenes, including those derived from bioactive molecules. The success of this method can be attributed to the use of newly developed monodentate chiral spiro phosphine ligands.

Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydroaminoalkylation of Unactivated Alkenes.

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % Vbur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Multimodal non-invasive evaluation in MRI-negative epilepsy patients.

Presurgical evaluation is still challenging for MRI-negative epilepsy patients. As non-invasive modalities are the easiest acceptable and economic methods in determining the epileptogenic zone, we analyzed the localization value of common non-invasive methods in MRI-negative epilepsy patients. In this study, we included epilepsy patients undergoing presurgical evaluation with presurgical negative MRI. MRI post-processing was performed using a Morphometric Analysis Program (MAP) on T1-weighted volumetric MRI. The relationship between MAP, magnetoencephalography (MEG), scalp electroencephalogram (EEG), and seizure outcomes was analyzed to figure out the localization value of different non-invasive methods. Eighty-six patients were included in this study. Complete resection of the MAP-positive regions or the MEG-positive regions was positively associated with seizure freedom (p = 0.028 and 0.007, respectively). When an area is co-localized by MAP and MEG, the resection of the area was significantly associated with seizure freedom (p = 0.006). However, neither the EEG lateralization nor the EEG localization showed statistical association with the surgical outcome (p = 0.683 and 0.505, respectively). In conclusion, scalp EEG had a limited role in presurgical localization and predicting seizure outcome, combining MAP and MEG results can significantly improve the localization of epileptogenic lesions and have a positive association with seizure-free outcome. PLAIN LANGUAGE SUMMARY: Due to the lack of obvious structure abnormalities on neuroimaging examinations, the identification of epilepsy lesions in MRI-negative epilepsy patients can be difficult. In this study, we intended to use non-invasive examinations to explore the potential epileptic lesions in MRI-negative epilepsy patients and to determine the results accuracy by comparing the neuroimaging results with the epilepsy surgery outcomes. A total of 86 epilepsy patients without obvious structure lesions on MRI were included, and we found that the combinations of different non-invasive examinations and neuroimaging post-processing methods are significantly associated with the seizure freedom results of epilepsy surgery.

miRNA profiling of granulosa cell-derived exosomes reveals their role in promoting follicle development.

To explore whether granulosa cell (GC)-derived exosomes (GC-Exos) and follicular fluid-derived exosomes (FF-Exos) have functional similarities in follicle development and to establish relevant experiments to validate whether GC-Exos could serve as a potential substitute for follicular fluid-derived exosomes to improve folliculogenesis. GC-Exos were characterized. MicroRNA (miRNA) profiles of exosomes from human GCs and follicular fluid were analyzed in depth. The signature was associated with folliculogenesis, such as phosphatidylinositol 3 kinases-protein kinase B signal pathway, mammalian target of rapamycin signal pathway, mitogen-activated protein kinase signal pathway, Wnt signal pathway, and cyclic adenosine monophosphate signal pathway. A total of five prominent miRNAs were found to regulate the above five signaling pathways. These miRNAs include miRNA-486-5p, miRNA-10b-5p, miRNA-100-5p, miRNA-99a-5p, and miRNA-21-5p. The exosomes from GCs and follicular fluid were investigated to explore the effect on folliculogenesis by injecting exosomes into older mice. The proportion of follicles at each stage is counted to help us understand folliculogenesis. Exosomes derived from GCs were isolated successfully. miRNA profiles demonstrated a remarkable overlap between the miRNA profiles of FF-Exos and GC-Exos. The shared miRNA signature exhibited a positive influence on follicle development and activation. Furthermore, exosomes derived from GCs and follicular fluid promoted folliculogenesis in older female mice. Exosomes derived from GCs had similar miRNA profiles and follicle-promoting functions as follicular fluid exosomes. Consequently, GC-Exos are promising for replacing FF-Exos and developing new commercial reagents to improve female fertility.

Asymmetric Synthesis of Cyclopamine, a Hedgehog (Hh) Signaling Pathway Inhibitor.

Cyclopamine is a teratogenic steroidal alkaloid, which inhibits the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor. Suppression of Hh signaling with synthetic small molecules has been pursued as a therapeutic approach for the treatment of cancer. We report herein the asymmetric synthesis of cyclopamine based on a two-stage relay strategy. Stage-I: total synthesis of veratramine through a convergent approach, wherein a crucial photoinduced excited-state Nazarov reaction was applied to construct the basic [6-6-5-6] skeleton of C-nor-D-homo-steroid. Stage-II: conversion of veratramine to cyclopamine was achieved through a sequence of chemo-selective redox manipulations.

Practical synthesis of allylic amines via nickel-catalysed multicomponent coupling of alkenes, aldehydes, and amides.

Molecules with an allylic amine motif provide access to important building blocks and versatile applications of biologically relevant chemical space. The need for diverse allylic amines requires the development of increasingly general and modular multicomponent reactions for allylic amine synthesis. Herein, we report an efficient catalytic multicomponent coupling reaction of simple alkenes, aldehydes, and amides by combining nickel catalysis and Lewis acid catalysis, thus providing a practical, environmentally friendly, and modular protocol to build architecturally complex and functionally diverse allylic amines in a single step. The method is remarkably simple, shows broad functional-group tolerance, and facilitates the synthesis of drug-like allylic amines that are not readily accessible by other methods. The utilization of accessible starting materials and inexpensive Ni(ii) salt as the alternative precatalyst offers a significant practical advantage. In addition, the practicality of the process was also demonstrated in an efficient, gram-scale preparation of the prostaglandin agonist.

Diastereodivergent and Enantioselective Synthesis of Homoallylic Alcohols via Nickel-Catalyzed Borylative Coupling of 1,3-Dienes with Aldehydes.

We present the first enantioselective nickel-catalyzed borylative coupling of 1,3-dienes with aldehydes, providing an efficient route to highly valuable homoallylic alcohols in a single step. The reaction involves the 1,4-carboboration of dienes, leading to the formation of C-C and C-B bonds accompanied by the construction of two continuous stereogenic centers. Enabled by a chiral spiro phosphine-oxazoline nickel complex, this transformation yields products with exceptional diastereoselectivity, E-selectivity, and enantioselectivity. The diastereoselectivity of the reaction can be controlled by employing either (Z)-1,3-dienes or (E)-1,3-dienes.

SUMO2/3 promotes the progression and oxaliplatin resistance of colorectal cancer through facilitating the SUMOylation at Ku80-K307.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is typically treated with the FOLFOX regimen (folinic acid, 5-fluorouracil, and oxaliplatin). However, oxaliplatin resistance remains a serious clinical problem. In the present study, we found that SUMO2/3 was overexpressed in CRC tissues and exogenous overexpression of SUMO2/3 promoted CRC cell proliferation, extension, and invasion and positively regulated the cell cycle. In contrast, SUMO2/3 gene knockdowns inhibited migration and repressed cell viability in vitro and in vivo. In addition, we found that SUMO2/3 was recruited to the cell nucleus and suppressed oxaliplatin-induced apoptosis of CRC cells. Moreover, Ku80, a DNA-binding protein essential for the repair of DNA double-strand breaks, was confirmed to bind with SUMO2/3. Notably, Ku80 undergoes SUMOylation at K307 by SUMO2/3 and this correlated with apoptosis in CRC cells suffering oxaliplatin stress. Collectively, we found that SUMO2/3 plays a specific role in CRC tumorigenesis and acts through Ku80 SUMOylation which is linked with the development of CRC-oxaliplatin resistance.

ELFN1-AS1 promotes GDF15-mediated immune escape of colorectal cancer from NK cells by facilitating GCN5 and SND1 association.

The ability of colorectal cancer (CRC) cells to escape from natural killer (NK) cell immune surveillance leads to anti-tumor treatment failure. The long non-coding RNA (lncRNA) ELFN1-AS1 is aberrantly expressed in multiple tumors suggesting a role as an oncogene in cancer development. However, whether ELFN1-AS1 regulates immune surveillance in CRC is unclear. Here, we determined that ELFN1-AS1 enhanced the ability of CRC cells to escape from NK cell surveillance in vitro and in vivo. In addition, we confirmed that ELFN1-AS1 in CRC cells attenuated the activity of NK cell by down-regulating NKG2D and GZMB via the GDF15/JNK pathway. Furthermore, mechanistic investigations demonstrated that ELFN1-AS1 enhanced the interaction between the GCN5 and SND1 protein and this influenced H3k9ac enrichment at the GDF15 promotor to stimulate GDF15 production in CRC cells. Taken together, our findings indicate that ELFN1-AS1 in CRC cells suppresses NK cell cytotoxicity and ELFN1-AS1 is a potential therapeutic target for CRC.

Nickel-Catalyzed Desymmetric Reductive Cyclization/Coupling of 1,6-Dienes: An Enantioselective Approach to Chiral Tertiary Alcohol.

We have developed a nickel-catalyzed desymmetric reductive cyclization/coupling of 1,6-dienes. The reaction provides an efficient method for constructing a chiral tertiary alcohol and a quaternary stereocenter by a single operation. The method has excellent diastereoselectivity and high enantioselectivity, a broad substrate scope, as well as good tolerance of functional groups. Preliminary mechanism studies show that alkyl nickel(I) species are involved in the reaction.

Nickel-Catalyzed Intramolecular Hydroalkenylation of Imines.

A ligand-enabled nickel-catalyzed intramolecular hydroalkenylation of imines with unactivated alkenes has been developed. A variety of five- and six-membered cyclic allylic amines were synthesized in high yields. The use of both wide-bite-angle diphosphine ligand and Brønsted acid is crucial for realizing the reaction. Preliminary investigation of the asymmetric intramolecular hydroalkenylation of imines shows promising potential for the application of the method in the synthesis of enantio-enriched cyclic allylic amines.

Nickel-Catalyzed Desymmetrizing Cyclization of 1,6-Dienes to Construct Quaternary Stereocenters.

A highly enantioselective and diastereoselective nickel-catalyzed desymmetrizing cyclization of 1,6-dienes was developed by using chiral spiro phosphoramidite ligands. The reaction provides a new atom- and step-economical approach to chiral spiro lactones and analogues bearing a quaternary stereocenter.

Application of Enhanced Recovery After Surgery in Perioperative Period of Tympanoplasty and Mastoidectomy.

INTRODUCTION: Enhanced recovery after surgery (ERAS) protocols are a series of perioperative care to optimize preoperative preparation, prevent postoperative complications, minimize stress, and speedup recovery. Tympanoplasty and mastoidectomy are common surgical procedures for chronic suppurative otitis media. OBJECTIVE: To compare the efficacy and safety between ERAS and conventional recovery after surgery in the perioperative period of chronic suppurative otitis media. METHODS: From April 2018 to February 2019, a total of 84 patients scheduled for tympanoplasty and/or mastoidectomy due to chronic suppurative otitis media were involved and randomly divided into the ERAS group and the control group. The patients' preoperative anxiety, postoperative pain, and comfort level were determined by comparing the results of Self-Rating Anxiety Scale (SAS), Visual Analog Scale (VAS) and General Comfort Questionnaire (GCQ). The postoperative complications, postoperative hospital stay, and hospitalization cost were calculated. RESULTS: The ERAS group showed a lower SAS score (30 [28-31.5] vs 35 [30-43], P < .05], a higher GCQ score (88 [84-100] vs 83 [78.25-92.25], P < .05), and a lower VAS score (0 [0-0] vs 1 [0-2], P < .05] after surgery. No significant difference (P > .05) was observed between the ERAS group and the control group in postoperative complications, postoperative hospitalization time, and hospitalization cost, respectively. CONCLUSION: Enhanced recovery after surgery can reduce pain and improve comfort in the perioperative period of chronic suppurative otitis media.

Fe-Doped ZnO/Reduced Graphene Oxide Nanocomposite with Synergic Enhanced Gas Sensing Performance for the Effective Detection of Formaldehyde.

Here, we report the synthesis of Fe-doped ZnO/reduced graphene oxide (rGO) nanocomposites for gas sensing applications via a one-pot hydrothermal process. A wide range of characterization techniques were used to confirm the successful fabrication of the nanocomposite material and to determine the surface area, the structural and morphological properties, the chemical composition, and the purity of the samples, such as Brunauer-Emmett-Teller, X-ray diffraction, Fourier transform infrared, Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, UV-vis spectroscopy, and X-ray photoelectron spectroscopy techniques. The gas sensing performance to formaldehyde was studied thoroughly in a temperature-controlled test chamber. Compared to that of the bare ZnO and ZnO/rGO nanocomposites, the as-prepared 5 atom % Fe-doped ZnO/rGO nanocomposites presented significantly enhanced gas sensing performance to formaldehyde at relatively low temperatures. Whereas most formaldehyde sensors operate at 150 °C and can detect as low as 100 ppm concentrations, the presented sensor can detect 5 ppm formaldehyde at 120 °C. Its fast response-recovery time, high stability, and high selectivity make it an ideal sensor; however, it can exhibit degenerative gas sensing performance at elevated relative humidity. The enhanced gas sensing mechanism was explained as the synergic effect of rGO and Fe doping. The results demonstrate that Fe doping and decorating the nanocomposite with rGO are promising approaches for achieving a superior gas sensing performance for the development of ZnO gas sensors for the detection of formaldehyde.

Stereoselective synthesis of medium lactams enabled by metal-free hydroalkoxylation/stereospecific [1,3]-rearrangement.

Rearrangement reactions have attracted considerable interest over the past decades due to their high bond-forming efficiency and atom economy in the construction of complex organic architectures. In contrast to the well-established [3,3]-rearrangement, [1,3] O-to-C rearrangement has been far less vigorously investigated, and stereospecific [1,3]-rearrangement is extremely rare. Here, we report a metal-free intramolecular hydroalkoxylation/[1,3]-rearrangement, leading to the practical and atom-economical assembly of various valuable medium-sized lactams with wide substrate scope and excellent diastereoselectivity. Moreover, such an asymmetric cascade cyclization has also been realized by chiral Brønsted acid-catalyzed kinetic resolution. In addition, biological tests reveal that some of these medium-sized lactams displayed their bioactivity as antitumor agents against melanoma cells, esophageal cancer cells and breast cancer cells. A mechanistic rationale for the reaction is further supported by control experiments and theoretical calculations.

Alkenyl Exchange of Allylamines via Nickel(0)-Catalyzed C-C Bond Cleavage.

A functional group exchange reaction between allylamines and alkenes via nickel-catalyzed C-C bond cleavage and formation was developed. This reaction provides a novel protocol, which does not require the use of unstable imine substrates, for the synthesis of allylamines, which are widely used in the production of fine chemicals, pharmaceuticals, and agrochemicals.

Nickel-catalyzed hydroalkylation and hydroalkenylation of 1,3-dienes with hydrazones.

Transition-metal-catalyzed hydrofunctionalization of 1,3-dienes is a useful and atom-economical method for constructing allylic compounds. Although substantial progress on hydroalkylation of dienes with stabilized carbon nucleophiles has been made, hydroalkylation of dienes with unstabilized carbon nucleophiles has remained a challenge. In this article, we report a protocol for nickel-catalyzed hydroalkylation of dienes with hydrazones, which serve as equivalents of alkyl carbon nucleophiles. In addition, we developed a protocol for hydroalkenylation of dienes with α,ß-unsaturated hydrazones, providing a new method for the synthesis of 1,4-dienes. These hydroalkylation and hydroalkenylation reactions feature mild conditions and a wide substrate scope, and the utility of the reaction products is demonstrated by the preparation of an activator of soluble guanylate cyclase.

Nickel(0)-catalyzed linear-selective hydroarylation of unactivated alkenes and styrenes with aryl boronic acids.

Herein, we describe the first linear-selective hydroarylation reaction of unactivated alkenes and styrenes with aryl boronic acids, which was achieved by introducing a directing group on the alkenes. This efficient, scalable reaction serves as a method for modular assembly of structurally diverse alkyl arenes, including γ-aryl butyric acid derivatives, which are widely utilized as chemical building blocks for the synthesis of various drugs and other biologically active compounds.