Construction of thioglycoside bonds via an asymmetric organocatalyzed sulfa-Michael/aldol reaction: access to 4'-thionucleosides.

Thioglycoside bond formation via an asymmetric sulfa-Michael/aldol reaction of (E)-ß-nucleobase acrylketones and 1,4-dithiane-2,5-diol has been achieved with a cinchona alkaloid-derived bifunctional squaramide chiral catalyst. Diverse purine, benzimidazole, and imidazole substrates are well tolerated and generate 4'-thionucleoside derivatives containing three contiguous stereogenic centers with excellent results (30 examples, up to 97% yield, >20 : 1 dr and up to 99% ee). Moreover, the novel strategy provides an efficient and convenient synthetic route to construct chiral 4'-thionucleosides.

Reconfigurable Micro/Nano-Optical Devices Based on Phase Transitions: From Materials, Mechanisms to Applications.

In recent years, numerous efforts have been devoted to exploring innovative micro/nano-optical devices (MNODs) with reconfigurable functionality, which is highly significant because of the progressively increasing requirements for next-generation photonic systems. Fortunately, phase change materials (PCMs) provide an extremely competitive pathway to achieve this goal. The phase transitions induce significant changes to materials in optical, electrical properties or shapes, triggering great research interests in applying PCMs to reconfigurable micro/nano-optical devices (RMNODs). More specifically, the PCMs-based RMNODs can interact with incident light in on-demand or adaptive manners and thus realize unique functions. In this review, RMNODs based on phase transitions are systematically summarized and comprehensively overviewed from materials, phase change mechanisms to applications. The reconfigurable optical devices consisting of three kinds of typical PCMs are emphatically introduced, including chalcogenides, transition metal oxides, and shape memory alloys, highlighting the reversible state switch and dramatic contrast of optical responses along with designated utilities generated by phase transition. Finally, a comprehensive summary of the whole content is given, discussing the challenge and outlooking the potential development of the PCMs-based RMNODs in the future.

Cough flows as a criterion for decannulation of autonomously breathing patients with tracheostomy tubes.

BACKGROUND: Adequate cough or exsufflation flow can indicate an option for safe tracheostomy decannulation to noninvasive management. Cough peak flow via the upper airways with the tube capped is an outcome predictor for decannulation readiness in patients with neuromuscular impairment. However, this threshold value is typically measured with tracheotomy tube removed, which is not acceptable culturally in China. The aim of this study was to assess the feasibility and safety of using cough flow measured with tracheostomy tube and speaking valve (CFSV) > 100 L/min as a cutoff value for decannulation. STUDY DESIGN: Prospective observational study conducted between January 2019 and September 2022 in a tertiary rehabilitation hospital. METHODS: Patients with prolonged tracheostomy tube placement were referred for screening. Each patient was assessed using a standardized tracheostomy decannulation protocol, in which CFSV greater than 100 L/min indicated that the patients' cough ability was sufficient for decannulation. Patients whose CFSV matched the threshold value and other protocol criteria were decannulated, and the reintubation and mortality rates were followed-up for 6 months. RESULTS: A total of 218 patients were screened and 193 patients were included. A total of 105 patients underwent decannulation, 103 patients were decannulated successfully, and 2 patients decannulated failure, required reinsertion of the tracheostomy tube within 48 h (failure rate 1.9%). Three patients required reinsertion or translaryngeal intubation within 6 months. CONCLUSIONS: CFSV greater than 100 L/min could be a reliable threshold value for successful decannulation in patients with various primary diseases with a tracheostomy tube. TRIAL REGISTRATION: This observational study was not registered online.

Ruthenium(II)-Catalyzed [4 + 2] Electro-Oxidative Annulation of C6-Arylpurines/Purine Nucleosides.

A sustainable pathway for the synthesis of tetracyclic purinium salts via ruthenium-catalyzed electro-oxidative annulation of C6-arylpurine nucleosides with alkynes without a stoichiometric metal oxidant has been developed. The protocol described herein exhibits high regioselectivity, broad scope, and wide functional group tolerance, allowing efficient coupling of various biologically important molecules including acyclic, ribosyl, arabinosyl, and deoxyribosyl purine nucleoside derivatives. A novel purinoisoquinolinium-coordinated ruthenium(0) sandwich intermediate has been isolated, crystallographically characterized, and electrochemically analyzed, offering direct mechanistic insight.

Cobalt(II)-Catalyzed Enantioselective Propargyl Claisen Rearrangement: Access to Allenyl-Substituted Quaternary ß-Ketoesters.

Highly enantioselective propargyl Claisen rearrangement of O-propargyl ß-ketoesters was achieved under 2.5 mol % of the chiral cobalt complex as the catalyst under mild reaction conditions. With Co(OTf)2 as the Lewis acid and C1-symmetric imidazoline-pyrroloimidazolone pyridine as the ligand, diverse chiral allenyl-substituted all-carbon quaternary ß-ketoesters were obtained in good yields (up to 97% yield) and high enantioselectivities (up to 98% ee).

Reversal of Enantioselectivity for the Desymmetrization of meso-1,2-Diols Catalyzed by Pyridine-N-oxides.

The desymmetrization of meso-vic-diols with a reversal of enantioselectivity catalyzed by chiral pyridine-N-oxides with l-proline as a single source of chirality is reported. With chiral 3-substituted ArPNO C2c and 2-substituted 4-(dimethylamino)pyridine-N-oxide C3b as catalysts, a wide range of monoesters were obtained with satisfactory results with a complete and controlled switch in stereoselectivity (up to 97:3 and 1:99 er). Chiral six-membered carbocyclic uracil nucleosides were generated with excellent enantioselectivities after derivatization. A series of control experiments and density functional theory (DFT) calculations supported that the reaction proceeded in a bifunctional activated manner, where the N-oxide groups and N-H proton of the amides were vital for catalytic reactivity and stereocontrol. The DFT calculation also supported the distance-directed switching of enantioselectivity, in which the l-prolinamide moiety moved from the C3 to C2 position on the pyridine ring, resulting in the H-bond interaction between the amide N-H and OH group of meso-vic-diol also shifted from one hydroxyl group to another.

ArPNO-Catalyzed Acylative Dynamic Kinetic Resolution of 3-Hydroxyphthalides: Access to Enantioenriched Phthalidyl Esters.

A chiral 4-aryl-pyridine-N-oxide nucleophilic organocatalyst was used to synthesize chiral phthalidyl ester prodrugs by the acylative dynamic kinetic resolution process. By using the 3,5-dimethylphenyl-derived ArPNO catalyst, the phthalidyl esters were obtained in up to 97% yield with 97% ee at room temperature. Two phthalidyl esters of prodrugs, talosalate and talmetacin, were generated. By control experiments and density functional theory calculations, an acyl transfer mechanism was proposed.

Dearomative [4 + 2] Annulation of Electron-Poor N-Heteroarenes with Azoalkenes for Access to Polycyclic Tetrahydro-1,2,4-triazines.

A direct dearomative [4 + 2] annulation of electron-poor N-heteroarenes with azoalkenes generated in situ from α-halogeno hydrazones was developed under mild conditions. Accordingly, a series of fused polycyclic tetrahydro-1,2,4-triazines with potential biological activity were obtained in up to 96% yield. Various α-halogeno hydrazones and N-heteroarenes, such as pyridines, quinolines, isoquinolines, phenanthridine, and benzothiazole, were tolerated by this reaction. The general applicability of this method was shown by upscale synthesis and product derivatization.

Design of C1-symmetric tridentate ligands for enantioselective dearomative [3 + 2] annulation of indoles with aminocyclopropanes.

Chiral polycyclic indolines are widely present in natural products and have become the focus of extensive synthetic efforts. Here, we show the catalytic asymmetric dearomative [3 + 2] annulation of indoles with donor-acceptor aminocyclopropanes to construct tricyclic indolines. Key to the success of the reaction is the rational design of C1-symmetric bifunctional tridentate imidazoline-pyrroloimidazolone pyridine ligand. Under 5 mol% of Ni(OTf)2-ligand complex, diverse tricyclic indolines containing cyclopentamine moieties are obtained in good chemoselectivities, high diastereoselectivities, and excellent enantioselectivities. An unusual cis-configuration ligand is superior to the trans-configuration ligand and the corresponding C2-symmetric tridentate nitrogen ligands in the annulation reaction. Mechanistic studies by control experiments and density functional theory calculations reveal a dual activation manner, where Ni(II) complex activates the aminocyclopropane via coordination with the geminal diester, and imidazolidine NH forms a H-bond with the succinimide moiety.

Cu-Catalyzed N-Arylation of Prolinamides: Access to Enantioenriched DMAP Analogues and Its Application in Black Rearrangement.

A CuI-catalyzed C-N coupling reaction of 3-bromo-DMAP with l-prolinamides was conducted at 80 °C in 12-16 h, where the prolinamide's structure had an accelerating effect on the Ullmann-type reaction. This reaction was used to construct chiral 3-amino DMAP catalysts. Furthermore, enantioenriched DMAP analogue C8 was applied in an asymmetric Black rearrangement of 2-benzofuranylcarbonates, affording 3,3-disubstituted benzofuran-2-ones in up to 96% yield and 97% ee.

Substrate-Dependent Regioselectivity: Pd/PTC Cooperatively Catalyzed Domino Heck/Allylation of Allenamides with α-Carbon of Carbonyl Compounds.

A Pd/phase-transfer catalyst cooperatively catalyzed domino Heck/allylation reaction is first reported, which represents interesting substrate-dependent regioselectivity. Under the same conditions, Ts-protected N-(2-iodophenyl)allenamides produced only linear allylation products, while Cbz, Ac, or Boc-protected N-(2-iodophenyl)allenamides and N-(2-iodobenzoyl)allenamides with various compounds generated branch allylation products with an exocylic C═C bond and two vicinal stereocenters. Up-scale syntheses and diverse fused cyclization transformations of products were then carried out. The enantioselective version for the domino process was studied.

Highly Chemoselective Synthesis of Purino[3,2-c]oxazoles via the Asymmetric Dearomative [3+2] Cycloaddition of Purines with Donor-Acceptor Oxiranes.

A Ni(II)/bisoxazoline-catalyzed asymmetric dearomative [3+2] cycloaddition of substituted purines with donor-acceptor oxiranes was developed. This reaction, which proceeds via highly chemoselective C-C bond cleavage of the oxiranes, accesses chiral purino[3,2-c]oxazole compounds (≤99% ee after enrichment via crystallization). The electronic effects of the purine ring determine the reactivity of the substrate. The general applicability of this method was illustrated by gram-scale synthesis, the diverse transformations of the product, and the promising biological activities of selected derivatives.

Efficacy and Safety of Remimazolam Besylate Combined with Alfentanil in Painless Gastroscopy: A Randomized, Single-Blind, Parallel Controlled Study.

Background: The efficacy and adverse reactions of remimazolam besylate (RB) in combination with alfentanil in patients with painless gastroscopy remain unclear. Objective: The aim of the study is to observe the efficacy and adverse reactions of RB in combination with alfentanil in patients with painless gastroscopy RB. Methods: All patients were randomly divided into two groups: RB combined with the alfentanil group (research group) and propofol combined with the alfentanil group (control group). After full oxygen inhalation and electrocardiographic monitoring, the research group was given 10 µg/Kg alfentanil + RB 0.2 mg/kg intravenously, and the control group was given 10 µg/Kg alfentanil + propofol 1.5 mg/kg. If there is a clinical need, the research group was given 2.5 mg/additional RB, whereas the control group was treated with an additional 0.5 mg/kg propofol. Main outcome measures were as follows: The vital endpoints including diachronic changes in heart rate (HR), blood pressure (BP), respiratory rate (RR), blood oxygen saturation (SPO2), end-expiratory carbon dioxide (etCO2), IPI, modified observer's assessment of alert/sedation (MOAA/S), time-related endpoints, perioperative adverse events, endoscopy, and anesthesiologist satisfaction, and 24-hour follow-up of adverse reactions, IPI scores, and satisfaction were recorded. Results: The HR and BP of the patients in the research group and the control group decreased, with a greater decrease in the control group, and the difference was statistically significant (p < 0.05). The values of RR, PETCO2, and IPI in the research group and the control group decreased to the lowest at 2-3 min but the decrease in the control group was more significant. Furthermore, there was no significant difference in the time from the completion of administration to 4 minutes of IPI and the total examination time, but the awakening time in the research group was slightly longer than that in the control group, and the difference was statistically significant (p < 0.05). The incidences of respiratory depression and hypotension during the operation were shown to be markedly smaller in the investigation relative to the control team, and the difference was statistically significant (p < 0.05), whereas the occurrence of cough, movements, and singultus was more common in the investigations, and the difference was statistically significant (p < 0.05). The results of the 24-hour follow-up showed that the adverse reactions such as nausea, dizziness, fatigue, abdominal pain, and abdominal distension were much less frequent in the study team, and the difference was statistically significant (p < 0.05), and the patient satisfaction was higher than in the control group, and the difference was statistically significant (p < 0.05). The regression results showed that age, sedative, and total dose of analgesia had significant effects on the results, and the covariance coefficient of sedative was 1.57 of IPI score in the research group higher than that of the control group. Conclusions: RB combined with alfentanil can provide safe and effective sedation for patients undergoing painless gastroscopy. Compared with propofol, RB and alfentanil for injection can avoid large hemodynamic fluctuations and deep sedation, and have fewer adverse reactions. However, the cases involved in this study are all from a single-center data, which requires further multicenter research and conformation.

The role of botulinum toxin type A related axon transport in neuropathic pain induced by chronic constriction injury.

Background: The mechanism of peripheral axon transport in neuropathic pain is still unclear. Chemokine ligand 13 (CXCL13) and its receptor (C-X-C chemokine receptor type 5, CXCR5) as well as GABA transporter 1 (GAT-1) play an important role in the development of pain. The aim of this study was to explore the axonal transport of CXCL13/CXCR5 and GAT-1 with the aid of the analgesic effect of botulinum toxin type A (BTX-A) in rats. Methods: Chronic constriction injury (CCI) rat models were established. BTX-A was administered to rats through subcutaneous injection in the hind paw. The pain behaviors in CCI rats were measured by paw withdrawal threshold and paw withdrawal latencies. The levels of CXCL13/CXCR5 and GAT-1 were measured by western blots. Results: The subcutaneous injection of BTX-A relieved the mechanical allodynia and heat hyperalgesia induced by CCI surgery and reversed the overexpression of CXCL13/CXCR5 and GAT-1 in the spinal cord, dorsal root ganglia (DRG), sciatic nerve, and plantar skin in CCI rats. After 10 mmol/L colchicine blocked the axon transport of sciatic nerve, the inhibitory effect of BTX-A disappeared, and the levels of CXCL13/CXCR5 and GAT-1 in the spinal cord and DRG were reduced in CCI rats. Conclusions: BTX-A regulated the levels of CXCL13/CXCR5 and GAT-1 in the spine and DRG through axonal transport. Chemokines (such as CXCL13) may be transported from the injury site to the spine or DRG through axonal transport. Axon molecular transport may be a target to enhance pain management in neuropathic pain.

ArPNO-catalyzed acylative kinetic resolution of tertiary alcohols: access to 3-hydroxy-3-substituted oxindoles.

Bifunctional chiral 4-aryl-pyridine-N-oxides (ArPNO) were reported for the acylative kinetic resolution of 3-hydroxy-3-substituted oxindoles, where the oxygen acts as the nucleophilic site. Using less sterically hindered acetic anhydride, both the recovered tertiary heterocyclic alcohols and the ester products exhibited good to excellent results with s-factors up to 167. Control experiments supported the dual activation manner, where the N-oxide group and N-H proton in ArPNO were crucial for high selectivity and enhanced catalytic reactivity. Compared with the extensively used chiral NHC, isochalcogenourea, and DMAP catalysts, we found that chiral ArPNO were also efficient organocatalysts in the kinetic resolution of tertiary alcohols.

Tracheostomy decannulation protocol in patients with prolonged tracheostomy referred to a rehabilitation hospital: a prospective cohort study.

BACKGROUND: The aim of the study was to assess the feasibility of a standardized tracheostomy decannulation protocol in patients with prolonged tracheostomy referred to a rehabilitation hospital. METHODS: This prospective cohort study recruited conscious patients with prolonged tracheostomy who were referred to the pulmonary rehabilitation department of a tertiary rehabilitation hospital between January 2019 and December 2021. A pulmonary rehabilitation team used a standardized tracheostomy decannulation protocol developed by the authors. The primary outcome was the success rate of decannulation. Secondary outcomes included decannulation time from referral and reintubation rate after a follow-up of 3 months. RESULTS: Of the 115 patients referred for weaning from mechanical ventilation and tracheostomy decannulation over the study period, 80.0% (92/115) were finally evaluated for tracheostomy decannulation. The mean time of tracheostomy in patients transferred to our department was 70.6 days. After assessment by a multidisciplinary team, 57 patients met all the decannulation indications and underwent decannulation. Fifty-six cases were successful, and 1 case was intubated again. The median time to decannulation after referral was 42.7 days. Reintubation after a follow-up of 3 months did not occur in any patients. CONCLUSIONS: A standardized tracheostomy decannulation protocol implemented by a pulmonary rehabilitation team is associated with successful tracheostomy decannulation in patients with prolonged tracheostomy. Not every tracheostomy patient must undergo upper airway endoscopy before decannulation. Tolerance of speaking valve continuously for 4 h can be used as an alternative means for tube occlusion. A swallow assessment was used to evaluate the feeding mode and did not affect the final decision to decannulate. TRIAL REGISTRATION: 2018bkky-121.

Highly Diastereoselective Synthesis of Oxindoles Containing Vicinal Quaternary and Tertiary Stereocenters by a Domino Heck/Decarboxylative Alkynylation Sequence.

A palladium-catalyzed domino Heck/decarboxylative alkynylation reaction of trisubstituted alkenes or enamines is reported. For two different types of substrates, the current domino reaction employing different solvents and bases led to 3,3-disubstituted oxindoles and hydropyrimidinyl spirooxindoles containing vicinal quaternary and tertiary stereocenters in moderate to good yields, respectively. The general applicability of this method was shown by gram-scale syntheses and diverse transformations of the reaction products. The enantioselective version for this domino process was also studied.

Rhodium(III)-Catalyzed Synthesis of Diverse Fluorescent Polycyclic Purinium Salts from 6-Arylpurine Nucleosides and Alkynes.

Described herein is an efficient strategy for assembling a new library of functionalized polycyclic purinium salts with a wide range of anions through RhIII-catalyzed C-H activation/annulation of 6-arylpurine nucleosides with alkynes under mild reaction conditions. The resulting products displayed tunable photoluminescence covering most of the visible spectrum. Mechanistic insights delineated the rhodium catalyst's mode of action. A purinoisoquinolinium-coordinated rhodium(I) sandwich complex was well characterized and identified as the key intermediate.

Fe-BPsalan Complex-Catalyzed Asymmetric [4 + 2] Cycloaddition of Cyclopentadiene with α,ß-Unsaturated Heterocycles.

An efficient iron-catalyzed asymmetric [4 + 2] cycloaddition of cyclopentadiene with α,ß-unsaturated acyl imidazoles or 2-cinnamoylisoindoline-1,3-dione derivatives was developed to afford the addition products in high yield and selectivity. Interestingly, the absolute structures of the addition products were controlled by the auxiliaries via different coordination modes with the same type of catalyst.

Rational Design of Chiral Tridentate Ligands: Bifunctional Cobalt(II) Complex/Hydrogen Bond for Enantioselective Michael Reactions.

Bifunctional chiral tridentate bis(pyrroloimidazolone)pyridine (PyBPI) ligands have been designed, synthesized, and applied in an asymmetric Michael addition. With a 0.05 mol % PyBPI-Co(II) complex, ß,γ-unsaturated α-keto esters reacted with 4-hydroxycoumarin to give the adducts in 93-99% yields and 90-97% ee. Experiments and DFT calculations supported the dual activation manner, in which the tridentate ligand coordinated with Co(II) to activate the keto ester, and the hydroxyl and carbonyl groups in PyBPI interacted with 4-hydroxycoumarin via two different H bonds.