Intermolecular Buchwald-Hartwig Reactions for Enantioselective Synthesis of Diverse Atropisomers: Rerouting the C-N Forming Mechanism to Substrate Oxygen-Assisted Reductive Elimination.

Axially chiral biaryls featuring a C-N axis are important functional molecules in diverse fields. The asymmetric Buchwald-Hartwig reaction represents a powerful strategy for these targets. Previous studies, however, have been predominantly restricted to intramolecular atroposelective coupling, likely due to the steric and entropic effects in the reductive elimination of Pd(II) species with sterically congested aryl and nitrogen groups. We now report two intermolecular Buchwald-Hartwig coupling systems of bulky NH lactams and halohydrocarbons enabled by rerouting the mechanism of C-N reductive elimination to one that accommodates sterically challenging substrates. Both atroposelective coupling systems exhibited functional group tolerance, excellent enantioselectivity, and high Z selectivity (if applicable), affording C-N atropisomeric biaryl and olefins through de novo construction of a C-N chiral axis. Experimental and computational studies were performed to elucidate the mechanism, and the switch of the reaction pathways is traced to the steric effect (ortho substituent) of the aryl halide substrate. A bulky 2,6-disubstituted aryl halide reorients the proximal lactamide ligand to its unusual O-ligation mode. With the amide oxygen participation, this intermediate undergoes C-N reductive elimination with an accessible barrier through a five-membered ring transition state, a pathway as well as a chiral induction mode that has been much underexplored in asymmetric catalysis.

Rhodium(I)-Catalyzed Asymmetric Hydroarylative Cyclization of 1,6-Diynes to Access Atropisomerically Labile Chiral Dienes.

Axially chiral open-chained olefins are an underexplored class of atropisomers, whose enantioselective synthesis represents a daunting challenge due to their relatively low racemization barrier. We herein report rhodium(I)-catalyzed hydroarylative cyclization of 1,6-diynes with three distinct classes of arenes, enabling highly enantioselective synthesis of a broad range of axially chiral 1,3-dienes that are conformationally labile (ΔG≠ (rac)=26.6-28.0 kcal/mol). The coupling reactions in each category proceeded with excellent enantioselectivity, regioselectivity, and Z/E selectivity under mild reaction conditions. Computational studies of the coupling of quinoline N-oxide system reveal that the reaction proceeds via initial oxidative cyclization of the 1,6-diyne to give a rhodacyclic intermediate, followed by σ-bond metathesis between the arene C-H bond and the Rh-C(vinyl) bond, with subsequent C-C reductive elimination being enantio-determining and turnover-limiting. The DFT-established mechanism is consistent with the experimental studies. The coupled products of quinoline N-oxides undergo facile visible light-induced intramolecular oxygen-atom transfer, affording chiral epoxides with complete axial-to-central chirality transfer.

Rhodium-Catalyzed Enantioselective Formal [4+1] Cyclization of Benzyl Alcohols and Benzaldimines: Facile Access to Silicon-Stereogenic Heterocycles.

The carbon-to-silicon switch in formation of bioactive sila-heterocycles with a silicon-stereogenic center has garnered significant interest in drug discovery. However, metal-catalyzed synthesis of such scaffolds is still in its infancy. Herein, a rhodium-catalyzed enantioselective formal [4+1] cyclization of benzyl alcohols and benzaldimines has been realized by enantioselective difunctionalization of a secondary silane reagent, affording chiral-at-silicon cyclic silyl ethers and sila-isoindolines, respectively. Mechanistic studies reveal a dual role of the rhodium-hydride catalyst. The coupling system proceeds via rhodium-catalyzed enantio-determining dehydrogenative OH silylation of the benzyl alcohol or hydrosilylation of the imine to give an enantioenriched silyl ether or silazane intermediate, respectively. The same rhodium catalyst also enables subsequent intramolecular cyclative C-H silylation directed by the pendent Si-H group. Experimental and DFT studies have been conducted to explore the mechanism of the OH bond silylation of benzyl alcohol, where the Si-O reductive elimination from a Rh(III) hydride intermediate has been established as the enantiodetermining step.

O-Allylhydroxyamine: A Bifunctional Olefin for Construction of Axially and Centrally Chiral Amino Alcohols via Asymmetric Carboamidation.

Difunctionalization of olefins offers an attractive approach to access complex chiral structures. Reported herein is the design of N-protected O-allylhydroxyamines as bifunctional olefins that undergo catalytic asymmetric 1,2-carboamidation with three classes of (hetero)arenes to afford chiral amino alcohols via C-H activation. The C═C bond in O-allylhydroxyamine is activated by the intramolecular electrophilic amidating moiety as well as a migrating directing group. The asymmetric carboamidation reaction pattern depends on the nature of the (hetero)arene reagent. Simple achiral (hetero)arenes reacted to give centrally chiral ß-amino alcohols in excellent enantioselectivity. The employment of axially prochiral or axially racemic heteroarenes afforded amino alcohols with both axial and central chirality in excellent enantio- and diastereoselectivity. In the case of axially racemic heteroarenes, the coupling follows a kinetic resolution pattern with an s-factor of up to >600. A nitrene-based reaction mechanism has been suggested based on experimental studies, and a unique mode of induction of enantio- and diastereoselectivity has been proposed. Applications of the amino alcohol products have been demonstrated.

Sigma-Bond Metathesis as an Unusual Asymmetric Induction Step in Rhodium-Catalyzed Enantiodivergent Synthesis of C-N Axially Chiral Biaryls.

Mechanistic understanding of asymmetric induction plays a crucial role in designing new catalytic asymmetric reactions. Reported herein is atroposelective access to C-N axially chiral isoquinolones via rhodium-catalyzed C-H activation of N-alkoxy benzamides and annulation with imidoyl sulfoxonium ylides. The coupling system proceeded with excellent functional group tolerance, and different conditions were identified to afford one or the other enantiomeric product each in excellent enantioselectivity for a representative class of the sulfoxonium ylide reagent, thus making both enantiomers readily available using the same catalyst. Experimental and computational studies revealed a pathway of C-H alkylation and enantio-determining formal nucleophilic substitution-C-N cyclization that is mediated by the rhodium catalyst via σ-bond metathesis as the asymmetric induction mechanism. Computational studies indicated that the solvent-dependent enatiodivergence originated from different levels of σ-bond metathesis mediated by neutral versus cationic rhodium species.

Synthesis of Bridged Cycloisoxazoline Scaffolds via Rhodium-Catalyzed Coupling of Nitrones with Cyclic Carbonate.

Bridged isoxazolidines were synthesized via Rh(III)-catalyzed C-H allylation of α-aryl nitrones with 5-methylene-1,3-dioxan-2-one. The nitrone group serves as a directing group and 1,3-dipole in the C-H activation/[3 + 2] cycloaddition cascade, exhibiting excellent chemo- and stereoselectivity along with good functional group compatibility. The resulting skeletal structure was conveniently modified to produce a range of important chemical frameworks, and the protocol was applied to biologically active molecules.

A near-infrared fluorescent probe for in situ imaging of SO2 flux in drug-induced liver injury.

Sulfur dioxide (SO2) has been widely applied as an important additive in various foods and drugs due to its antioxidant, antiseptic and bleaching properties. SO2 in living organisms plays a key biological role as an antioxidant in a variety of life activities. However, abnormal levels of SO2 in both food and living organisms could cause harm and even serious illness, such as diseases related to the respiratory and cardiovascular systems and cancers. Therefore, it is of great practical significance to accurately determine the level of SO2 in food and organisms. In this work, we synthesized a novel near-infrared ratiometric fluorescent probe (NTO) using xanthene and benzopyran as the matrix for the detection of SO2. NTO demonstrates a rapid response (within 8 s), high selectivity, excellent sensitivity (LOD = 3.64 µM) and a long emission wavelength (800 nm), which could be applied to SO2 monitoring in a complex environment. NTO showed a high recovery (90%-110%) of SO2 in food samples such as beer and rock sugar. The results of HeLa cell experiments indicate that NTO has excellent fluorescence labeling ability for SO2 in endoexogenous-sulfide metabolism. In addition, we applied it to mice with acetaminophen (APAP)-induced acute liver injury and observed changes in SO2 during liver injury. Based on these results, we believe that this will provide a convenient visual tool for the detection of the SO2 content in food safety and biomedicine.

Type I Collagen-Adhesive and ROS-Scavenging Nanoreactors Enhanced Retinal Ganglion Cell Survival in an Experimental Optic Nerve Crush Model.

Traumatic optic neuropathy (TON) is a severe condition characterized by retinal ganglion cell (RGC) death, often leading to irreversible vision loss, and the death of RGCs is closely associated with oxidative stress. Unfortunately, effective treatment options for TON are lacking. To address this, catalase (CAT) is encapsulated in a tannic acid (TA)/poly(ethylenimine)-crosslinked hollow nanoreactor (CAT@PTP), which exhibited enhanced anchoring in the retina due to TA-collagen adhesion. The antioxidative activity of both CAT and TA synergistically eliminated reactive oxygen species (ROS) to save RGCs in the retina, thereby treating TON. In vitro experiments demonstrated that the nanoreactors preserve the enzymatic activity of CAT and exhibit high adhesion to type I collagen. The combination of CAT and TA-based nanoreactors enhanced ROS elimination while maintaining high biocompatibility. In an optic nerve crush rat model, CAT@PTP is effectively anchored to the retina via TA-collagen adhesion after a single vitreous injection, and RGCs are significantly preserved without adverse events. CAT@PTP exhibited a protective effect on retinal function. Given the abundance of collagen that exists in ocular tissues, these findings may contribute to the further application of this multifunctional nanoreactor in ocular diseases to improve therapeutic efficacy and reduce adverse effects.

Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy.

The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy. This was achieved by coassembling methoxy poly(ethylene glycol)-b-poly(caprolactone) with ketal-linked HF- and PTX-derived prodrugs. HF nanomedicine and PTX nanomedicine had excellent prodrug-nanocarrier compatibility and exhibited greatly improved pharmacokinetic profiles and high tumor accumulation. HF nanomedicine pretreatment restored stromal homeostasis and considerably facilitated the distribution of PTX nanomedicine and its penetration into carcinoma cells, leading to positive modulation of the infiltration of cytotoxic T cells and significant regression of tumor growth in two PDAC models. Our nanomedicine-based stromal remodeling strategy appears promising for treating desmoplastic malignancies.

Rhodium-Catalyzed Enantioselective 1,4-Oxyamination of Conjugated gem-Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones.

The incorporation of fluorine atoms in organics improves their bioactivity and lipophilicity. Catalytic functionalization of gem-difluorodienes represents one of the most straightforward approaches to access fluorinated alkenes. In contrast to the regular 1,3-dienes that undergo diverse asymmetric di/hydrofunctionalizations, the regio- and enantioselective oxyamination of gem-difluorodienes remains untouched. Herein, we report asymmetric 1,4-oxyamination of gem-difluorodiene by chiral rhodium-catalyzed three-component coupling with readily available carboxylic acid and dioxazolone, affording gem-difluorinated 1,4-amino alcohol derivatives. Our asymmetric protocol exhibits high 1,4-regio- and enantioselectivity with utility in the late-stage modification of pharmaceuticals and natural products. Stoichiometric experiments provide evidences for the π-allylrhodium pathway. Related oxyamination was also realized when trifluoroethanol was used as an oxygen nucleophile.

Prevalence and distribution of human papillomavirus (HPV) in Luoyang city of Henan province during 2015-2021 and the genetic variability of HPV16 and 52.

BACKGROUND: Persistent high-risk Human papillomavirus (HPV) subtypes infection has been implicated as a causative of cervical cancer. Distribution and genotypes of HPV infection among females and their variations would assist in the formulation of preventive strategy for cervical cancer. The purpose of the present study is to investigate the prevalence of HPV among females in central China. METHODS: The distribution and genotypes of HPV among 9943 females attending the gynecological examinations in central of China during 2015-2021 were investigated. HPV genotypes were detected using a commercial kit. Nucleotides sequences of L1, E6 and E7 genes in HPV16 or HPV52 positive samples collected in 2021 were amplified by polymerase chain reaction (PCR). Variations of L1, E6 and E7 in HPV16 and HPV52 were gained by sequencing and compared with the reference sequence. Sublineages of HPV16 and HPV52 were determined by the construction of phylogenetic tree based on L1 gene. RESULTS: The overall prevalence of HPV infection was 22.81%, with the infection rate of high-risk human papillomavirus (HR-HPV) was 19.02% and low-risk human papillomavirus (LR-HPV) was 6.40%. The most top five genotypes of HPV infection were HPV16 (7.49%), HPV52 (3.04%), HPV58 (2.36%), HPV18 (1.65%) and HPV51 (1.61%). Plots of the age-infection rate showed that the single HPV, multiple HPV, HR-HPV, LR-HPV infection revealed the same tendency with two peaks of HPV infection were observed among females aged ≤ 20 year-old and 60-65 year-old. The predominant sublineage of HPV16 was A1 and B2 for HPV52. For HPV16, The most prevalent mutations were T266A (27/27) and N181T (7/27) for L1, D32E for E6 and S63F for E7 in HPV16. For HPV52, all of the nucleotide changes were synonymous mutation in L1 (except L5S) and E7 genes. The K93R mutation was observed in most HPV52 E6 protein. CONCLUSIONS: The present study provides basic information about the distribution, genotypes and variations of HPV among females population in Henan province, which would assist in the formulation of preventive strategies and improvements of diagnostic probe and vaccine for HPV in this region.

Long non-coding RNA maternally expressed 3 (MEG3) regulates isoflurane-induced cognitive dysfunction by targeting miR-7-5p.

This study aimed to investigate the role and mechanism of long non-coding RNA maternally expressed gene 3 (MEG3) in cognitive dysfunction induced by isoflurane (ISO). Morrier water maze analysis was performed to evaluate the cognitive function of rats. Modified modified neurological severity score (mNSS) scores were assessed for neurological damage. The levels of MEG3 in hippocampal tissues of rats and hippocampal neuron cell lines HT22 were examined by reverse transcription-quantitative polymerase chain reaction (qRT-PCR). Moreover, the cell viability and apoptosis were assessed by the Cell Counting Kit-8 (CCK-8) and flow cytometry assay. Indicators of inflammation and oxidative stress were determined using enzyme-linked immunosorbent assay (ELISA) and commercial assay kits. Relationship between MEG3 and microRNA (miR)-7-5p was verified by the dual-luciferase reporter gene assay. MEG3 was increased in hippocampal tissues and HT22 after ISO treatment (p < 0.05). MEG3 downregulation alleviated the increase in neurological severity score and cognitive dysfunction caused by ISO treatment (p < 0.05). In vitro, MEG3 downregulation alleviates the decrease in cell activity and increased apoptosis induced by ISO. What's more, MEG3 reduction eliminated activation of neuroinflammation and oxidative stress promoted by ISO treatment in rats and HT22 (p < 0.05). MEG3 was confirmed to specifically bind to miR-7-5p. Inhibition of miR-7-5p eliminated the alleviating effects of MEG3 downregulation on cognitive dysfunction caused by ISO treatment. Decreased MEG3 alleviates cognitive dysfunction caused by ISO by targeting miR-7-5p and play a neuroprotective effect. We present a strategy for MEG3 as a potential target for brain protection during anesthesia.

Rhodium-Catalyzed Atroposelective Access to Axially Chiral Olefins via C-H Bond Activation and Directing Group Migration.

Axially chiral open-chain olefins represent an underexplored class of chiral platform. In this report, two classes of tetrasubstituted axially chiral acyclic olefins have been accessed in excellent enantioselectivity and regioselectivity via C-H activation of (hetero)arenes assisted by a migratable directing group en route to coupling with sterically hindered alkynes. The coupling of indoles bearing an N-aminocarbonyl directing group afforded C-N axially chiral acrylamides with the assistance of a racemic zinc carboxylate additive. DFT studies suggest a ß-nitrogen elimination-reinsertion pathway for the directing group migration. Meanwhile, the employment of N-phenoxycarboxamide delivered C-C axially chiral enamides via migration of the oxidizing directing group. Experiments suggest that in both cases the (hetero)arene substrate adopts a well-defined orientation during the C-H activation, which in turn determines the disposition of the alkyne in migratory insertion. Synthetic applications of representative chiral olefins are demonstrated.

A retrospective cohort study on prevalence of postoperative complications in comminuted patellar fractures: comparisons among stabilized with Cannulated-Screw, Kirschner-Wire, or Ring-Pin Tension Bands.

BACKGROUND: Displaced patellar fractures are commonly treated with open reduction and fixation with several different types of tension-band (TB) constructs. The main objective of this study was to compare the prevalence of postoperative complications after surgical stabilization of comminuted patellar fractures with either a modified Kirschner-wire tension band (MKTB), a cannulated-screw tension band (CSTB), or a ring-pin tension band (RPTB). METHODS: We conducted a retrospective and consecutive cohort study of comminuted patellar fractures (n = 334) stabilized using a TB construct. Postoperative premature loss of reduction, infection, and skin breakdown were compared according to the type of TB constructs received (MKTB, CSTB, or RPTB). The rate of implant removal due to symptomatic hardware was also evaluated. RESULTS: Fixation failure rate was significantly different among the groups (P = 0.013), with failure rates of 4.7% observed in the MKTB group,14.5% in the CSTB group, and 4.9% in the RPTB group. Skin breakdown and infection were not significantly different among the groups (Ps > 0.05). Due to symptomatic hardware, 40.5% of the patients in the MKTB group, 22.9% in the CSTB group, and 24.3% in the RPTB group underwent implant removal (P = 0.004). After adjusting for age, gender, comorbidities, number of supplementary screws/K-wires, and use of cerclage cables, multivariate regression analysis revealed that CSTB contributed to a 2.08-times greater risk of fixation failure compared to RPTB, while MKTB and RPTB were similar in risk of failure. In addition, it was found that patients who underwent MKTB fixation were more than twice as likely to undergo implant removal for symptomatic hardware compared with RPTB (odds ratio = 2.11, 95% CI = 1.20 to 3.72; P = 0.010). CONCLUSIONS: RPTB have advantage over MKTB and CSTB fixation in terms of symptomatic hardware and premature failure, respectively. LEVEL OF EVIDENCE: Therapeutic Level III.

Neuroprotective effect of miR-212-5p on isoflurane-induced cognitive dysfunction by inhibiting neuroinflammation.

BACKGROUND: Isoflurane is a commonly used inhalation anesthetic in the clinic, which can induce cognitive dysfunction and neuroinflammation. miR-212-5p has been demonstrated to be involved in the neuronal system and play vital roles in memory formation. Its function in the learning and memory impairment and neuroinflammation induced by isoflurane was investigated in this study. METHODS: Cognitive dysfunction rat models were established by 3% isoflurane inhalation. The neurological function was evaluated by the modified Neurological Severity Scale. The learning and memory ability of rats was assessed by the Morris water maze test. The expression level of miR-212-5p was analyzed by RT-qPCR, and the protein levels of proinflammatory cytokines were detected by ELISA. RESULTS: Isoflurane induced cognitive dysfunction in rats with the neurological scores and the escape latency increased, and time spent in the target quadrant decreased. The protein levels of IL-1ß, IL-6, and TNF-α were increased in isoflurane treated rats. miR-212-5p was downregulated in cognitive impairment rats. The upregulation of miR-212-5p by the agomir injection decreased the neurological scores of rats and increased the learning and memory ability of impaired rats. Moreover, the neuroinflammation was inhibited by the overexpression of miR-212-5p. CONCLUSION: miR-212-5p showed a neuroprotective effect in isoflurane-induced cognitive dysfunction rats by inhibiting neuroinflammation.

Twofold C-H Activation-Based Enantio- and Diastereoselective C-H Arylation Using Diarylacetylenes as Rare Arylating Reagents.

C-H bond activation has been established as an attractive strategy to access axially chiral biaryls, and the most straightforward method is direct C-H arylation of arenes. However, the arylating source has been limited to several classes of reactive and bulky reagents. Reported herein is rhodium-catalyzed 1:2 coupling of diarylphosphinic amides and diarylacetylenes for enantio- and diastereoselective construction of biaryls with both central and axial chirality. This twofold C-H activation reaction stays contrast to the previously explored Miura-Satoh type 1:2 coupling of arenes and alkynes in terms of chemoselectivity and proceeded under mild conditions with the alkyne acting as a rare arylating reagent. Both C-H activation events are stereo-determining and are under catalyst control, with the 2nd C-H activation being diastereo-determining in a remote fashion. Analysis of the stereochemistry of the major and side products suggests moderate enantioselectivity of the initial C-H activation-desymmetrization process. However, the minor (R) rhodium vinyl intermediate is consumed more readily in undesired protonolysis, eventually resulting in high enantio- and diastereoselectivity of the major product.

Rhodium-Catalyzed Atroposelective Construction of Indoles via C-H Bond Activation.

Reported herein is the rhodium(III)-catalyzed C-H activation of anilines bearing an N-isoquinolyl directing group for oxidative [3+2] annulation with four classes of internal alkynes, leading to atroposelective indole synthesis via dynamic kinetic annulation with C-N reductive elimination constituting the stereo-determining step. This reaction proceeds under mild conditions with high regio- and enantioselectivity and functional group compatibility.

Rhodium-Catalyzed Enantioselective Synthesis of ß-Amino Alcohols via Desymmetrization of gem-Dimethyl Groups.

Desymmetrization of gem-dimethyl groups en route to the rhodium(III)-catalyzed enantioselective sp3 C-H amidation is reported. Synthetically important ß-amino alcohol derivatives were accessed in moderate to good yields and high enantioselectivity. The high enantioselectivity is enabled by an appropriate oxime directing group, sterically biased gem-groups in the C-H substrate, and high reactivity of the amidating reagent.

Rhodium-Catalyzed C-H Activation-Based Construction of Axially and Centrally Chiral Indenes through Two Discrete Insertions.

Reported herein is asymmetric [3+2] annulation of arylnitrones with different classes of alkynes catalyzed by chiral rhodium(III) complexes, with the nitrone acting as an electrophilic directing group. Three classes of chiral indenes/indenones have been effectively constructed, depending on the nature of the substrates. The coupling system features mild reaction conditions, excellent enantioselectivity, and high atom-economy. In particular, the coupling of N-benzylnitrones and different classes of sterically hindered alkynes afforded C-C or C-N atropochiral pentatomic biaryls with a C-centered point-chirality in excellent enantio- and diastereoselectivity (45 examples, average 95.6 % ee). These chiral center and axis are disposed in a distal fashion and they are constructed via two distinct migratory insertions that are stereo-determining and are under catalyst control.

Access to [4,3,1]-Bridged Carbocycles via Rhodium(III)-Catalyzed C-H Activation of 2-Arylindoles and Annulation with Quinone Monoacetals.

Reported herein is the Rh(III)-catalyzed annulation of N-unprotected 2-arylindoles with quinone monoacetals for the straightforward synthesis of [4,3,1]-bridged carbocycles with exclusive C(3) selectivity. Mechanistic studies, particularly deuterium-labeling experiments, suggest that the coupling likely proceeds via two-fold C-H activation with two-fold migratory insertion into the enone moieties.