Controllable Skeletal and Peripheral Editing of Pyrroles with Vinylcarbenes.

The skeletal editing of azaarenes through insertion, deletion, or swapping of single atoms has recently gained considerable momentum in chemical synthesis. Here, we describe a practical skeletal editing strategy using vinylcarbenes in situ generated from trifluoromethyl vinyl N-triftosylhydrazones, leading to the first dearomative skeletal editing of pyrroles through carbon-atom insertion. Furthermore, depending on the used catalyst and substrate, three types of peripheral editing reactions of pyrroles are also disclosed: α- or γ-selective C-H insertion, and [3+2] cycloaddition. These controllable molecular editing reactions provide a powerful platform for accessing medicinally relevant CF3-containing N-heterocyclic frameworks, such as 2,5-dihydropyridines, piperidines, azabicyclo[3.3.0]octadienes, and allylated pyrroles from readily available pyrroles. Mechanistic insights from experiments and density functional theory (DFT) calculations shed light on the origin of substrate- or catalyst-controlled chemo- and regioselectivity as well as the reaction mechanism.

Tunable molecular editing of indoles with fluoroalkyl carbenes.

Building molecular complexity from simple feedstocks through precise peripheral and skeletal modifications is central to modern organic synthesis. Nevertheless, a controllable strategy through which both the core skeleton and the periphery of an aromatic heterocycle can be modified with a common substrate remains elusive, despite its potential to maximize structural diversity and applications. Here we report a carbene-initiated chemodivergent molecular editing of indoles that allows both skeletal and peripheral editing by trapping an electrophilic fluoroalkyl carbene generated in situ from fluoroalkyl N-triftosylhydrazones. A variety of fluorine-containing N-heterocyclic scaffolds have been efficiently achieved through tunable chemoselective editing reactions at the skeleton or periphery of indoles, including one-carbon insertion, C3 gem-difluoroolefination, tandem cyclopropanation and N1 gem-difluoroolefination, and cyclopropanation. The power of this chemodivergent molecular editing strategy has been highlighted through the modification of the skeleton or periphery of natural products in a controllable and chemoselective manner. The reaction mechanism and origins of the chemo- and regioselectivity have been probed by both experimental and theoretical methods.

Oscillatory shear stress-mediated aberrant O-GlcNAc SIRT3 accelerates glycocalyx inflammatory injury via LKB1/p47phox/Hyal2 signaling.

Glycocalyx coating on endothelial surface layer helps to sense shear forces and maintain endothelial function. However, the underlying mechanism of endothelial glycocalyx degradation upon disordered shear stress stimulation is not fully understood. SIRT3, a major NAD+-dependent protein deacetylases, is required for protein stability during vascular homeostasis and partly involved in atherosclerotic process. While few studies showed that SIRT3 is responsible for endothelial glycocalyx homeostasis under shear stress, the underlying mechanisms remain largely unknown. Here, we demonstrated that oscillatory shear stress (OSS) induces glycocalyx injury by activating LKB1/p47phox/Hyal2 axis both in vivo and in vitro. And O-GlcNAc modification served to prolong SIRT3 deacetylase activity and stabilized p47/Hyal2 complex. OSS could decrease SIRT3 O-GlcNAcylation to activate LKB1, further accelerated endothelial glycocalyx injury in inflammatory microenvironment. SIRT3Ser329 mutation or inhibition of SIRT3 O-GlcNAcylation strongly promoted glycocalyx degradation. On the contrary, overexpression of SIRT3 reverse glycocalyx damage upon OSS treatment. Together, our findings indicated that targeting O-GlcNAcylation of SIRT3 could prevent and/or treat diseases whereby glycocalyx injured.

Rh-Catalyzed [2,3]-Sigmatropic Rearrangement of Alkynyl Carbenes with Allyl Sulfides to Access Sulfide-Substituted 1,5-Enynes.

This study describes the development of Rh-catalyzed [2,3]-sigmatropic rearrangement of alkynyl carbenes with allyl sulfides. The protocol exhibits equitable functional group tolerance and allows the formation of a variety of synthetically valuable sulfide-substituted 1,5-enyne products. To the best of our knowledge, this is the first example of [2,3]-sigmatropic rearrangement of alkynyl carbenes. DFT analysis supports the involvement of rhodium carbene generation, sulfonium ylides formation, and [2,3]-sigmatropic rearrangement pathway.

Skeletal Editing of (Hetero)Arenes Using Carbenes.

(Hetero)arenes continue to prove their indispensability in pharmaceuticals, materials science, and synthetic chemistry. As such, the controllable modification of biologically significant (hetero)arenes towards diverse more-potent complex molecular scaffolds through peripheral and skeletal editing has been considered a challenging goal in synthetic organic chemistry. Despite many excellent reviews on peripheral editing (i. e., C-H functionalization) of (hetero)arenes, their skeletal editings via single atom insertion, deletion, or transmutations have received less attention in the review literature. In this review, we systematically summarize the state-of-the-art skeletal editing reactions of (hetero)arenes using carbenes, with a focus on general mechanistic considerations and their applications in natural product syntheses. The potential opportunities and inherent challenges encountered while developing these strategies are also highlighted.

Stereoselective Synthesis of trans-Stilbenes through Silver-Catalyzed Self-Coupling of N-Triftosylhydrazones: An Experimental and Theoretical Study.

A silver-mediated homocoupling of N-triftosylhydrazones for the construction of trans-stilbenes has been presented. This protocol is characterized by its suitability for both inter- and intramolecular reactions, operational simplicity, high efficiency with excellent stereoselectivity, broad substrate scope, and good functional group tolerance. A plausible mechanism involving nucleophilic attack of in situ generated sulfonium ylides on silver carbene was proposed on the basis of experimental results and DFT calculations, which further indicates that π-π stacking interactions play a dominant role in stereoselectivity control.

High temporal waveform fidelity stimulated Brillouin scattering phase conjugate mirror using Novec-7500.

A high temporal waveform fidelity stimulated Brillouin scattering phase conjugate mirror (SBS-PCM) with high energy efficiency, based on a novel medium, Novec-7500, is proposed and practically achieved in this study. A theoretical analysis reveals that the temporal-domain waveform distortion is caused by the inherent pulse duration compression effect of the SBS, and this undesirable phenomenon can be significantly suppressed by decreasing the compression coefficient (CC afterwards), which is defined as the gain coefficient divided by the phonon lifetime, which coefficient and is identified as the key parameter for high waveform-fidelity in SBS-PCM. The feasibility of this approach was demonstrated experimentally, in which a reflected pulse with waveform symmetry equals to the pump and an average pulse duration of 0.974 τp (τp is the duration of pump) with an energy efficiency of over 90% was achieved using Novec-7500.

Site-Selective C-H Allylation of Alkanes: Facile Access to Allylic Quaternary sp3 -Carbon Centers.

The construction of allylic quaternary sp3 -carbon centers has long been a formidable challenge in transition-metal-catalyzed alkyl-allyl coupling reactions due to the severe steric hindrance. Herein, we report an effective carbene strategy that employs well-defined vinyl-N-triftosylhydrazones as a versatile allylating reagent to enable direct assembly of these medicinally desirable structural elements from low-cost alkane feedstocks. The reaction exhibited excellent site selectivity for tertiary C-H bonds, broad scope (>60 examples and >20 : 1:0 r. r.) and good efficiency, even on a gram-scale, making it a convenient alternative to the well-known Trost-Tsuji allylation reaction for the formation of alkyl-allyl bonds. Combined experimental and computational studies were employed to unravel the mechanism and origin of site- and chemoselectivity of the reaction.

Motivation, self-efficacy, perception, curiosity, and barriers toward medical research among undergraduates in China.

Medical research is important to scientific progress and medical education. Institutions worldwide have sought to increase student involvement in research such as clinician-scientists training programs, while little is known about how medical undergraduates perceive research. A cross-sectional study was conducted in Chongqing Medical University, Chongqing, China, with first-fourth year undergraduates. An online, anonymous, and self-rating 5-point Likert questionnaire was conducted to investigate medical undergraduates' demographic characteristics and assess motivation, self-efficacy, perception, curiosity, and barriers regarding medical research. Content validity was checked with experts and face validity was checked for clarity and understanding of the questionnaire. The Cronbach's alpha coefficient of the questions ranged from 0.813 to 0.879. A total of 3273 medical undergraduates were surveyed, and 86.62% (2835) participants (male 962, female 1873) were identified as effective. Males scored higher than females on self-efficacy (p < 0.001), perception (p = 0.017), and curiosity (p < 0.001), and lower on barriers (p < 0.001). The second year students are at the peak of their perception (p = 0.006) and lowest barrier scores (p = 0.003). Students with scientific research experience scored higher in motivation (p = 0.002), self-efficacy (p < 0.001), perception (p < 0.001), and curiosity (p < 0.001). Lack of proper mentoring opportunity (86.2%) and knowledge (84.5%) were the main barriers in conducting research. Even though they have a positive perspective, only a few undergraduates enrolled in research. Medical universities should encourage faculties to supervise and guide undergraduates' projects, and provide feasible solutions for students to learn scientific knowledge and skills. It is vital to build a research-oriented environment and academic atmosphere.

Chemoselective carbene insertion into the N-H bonds of NH3·H2O.

The conversion of inexpensive aqueous ammonia (NH3·H2O) into value-added primary amines by N-H insertion persists as a longstanding challenge in chemistry because of the tendency of Lewis basic ammonia (NH3) to bind and inhibit metal catalysts. Herein, we report a chemoselective carbene N-H insertion of NH3·H2O using a TpBr3Ag-catalyzed two-phase system. Coordination by a homoscorpionate TpBr3 ligand renders silver compatible with NH3 and H2O and enables the generation of electrophilic silver carbene. Water promotes subsequent [1,2]-proton shift to generate N-H insertion products with high chemoselectivity. The result of the reaction is the coupling of an inorganic nitrogen source with either diazo compounds or N-triftosylhydrazones to produce useful primary amines. Further investigations elucidate the reaction mechanism and the origin of chemoselectivity.

Transition-metal-free azide insertion of N-triftosylhydrazones using a non-metallic azide source.

Benzylic azides, an important class of active organic synthons, were synthesized in high yields from the easily accessible N-triftosylhydrazones with stable TMSN3 under mild conditions. The reaction features high efficiency and excellent functional group tolerance, as illustrated by gram-scale synthesis and the synthesis of drug-like molecules. Mechanistic studies reveal that azidation occurs at the electron-deficient diazo-carbon via the elimination of N2 by an azide ion.

Rh-Catalyzed Coupling Reactions of Fluoroalkyl N-Sulfonylhydrazones with Azides Leading to α-Trifluoroethylated Imines.

Herein we describe the pioneering Rh-catalyzed coupling reactions of a fluoroalkyl carbene with azides to access α-trifluoroethylated imines, where fluoroalkyl N-sulfonylhydrazones are used as fluoroalkyl diazo surrogates. Remarkably, using TMSN3 as the N source, two C-N bond formation products were obtained. Furthermore, the α-trifluoroethylated imine products could be easily reduced to the corresponding N-trifluoroethylated anilines. Experimental results and theoretical calculations justify a stepwise reaction pathway involving the formation of rhodium carbene, the addition of HN3, and C═N bond formation.

Synthesis of gem-Disulfonyl Enamines via an Iminyl-Radical-Mediated Formal 1,3-HAT/Radical Coupling Cascade.

We herein report the first example of an iminyl-radical-mediated formal 1,3-HAT/radical coupling cascade of vinyl azides leading to the synthesis of tetrasubstituted gem-disulfonyl enamines. It is possible to employ a variety of vinyl azides and sulfinate salt coupling elements without sacrificing effectiveness and scalability. The combination of experimental studies and DFT calculations showed that this reaction proceeds via a radical addition/formal 1,3-HAT/radical coupling mechanism.

N-Triftosylhydrazones: A New Chapter for Diazo-Based Carbene Chemistry.

Over recent decades, N-sulfonylhydrazones have attracted significant attention in academic and industrial contexts owing to their ease of preparation, versatile reactivity, high stability, and practicality. In particular, the use of N-sulfonylhydrazones as precursors for diazo compounds has paved the way for innovative and original organic reactions that are otherwise difficult to achieve. Three key developments are noteworthy in the history of N-sulfonylhydrazone chemistry: (1) Bamford and Stevens initially disclosed the application of N-tosylhydrazones as a diazo source in 1952; (2) Aggarwal and co-workers investigated N-tosylhydrazone salts as diazo precursors for sulfur ylide-mediated asymmetric epoxidation and aziridination in 2001; and (3) Barluenga, Valdés and co-workers first reported Pd-catalyzed cross-coupling reactions with N-tosylhydrazones in 2007, thus introducing the direct use of N-tosylhydrazones in carbene transfer reactions. In the past 2 decades, the synthetic exploration of N-sulfonylhydrazones in carbene chemistry has increased remarkably. N-Tosylhydrazones are the most commonly used N-sulfonylhydrazones, but they are not easy to decompose and normally need relatively high temperatures (e.g., 90-110 °C). Temperature, as a key reaction parameter, has a significant influence on the selectivity and scope of organic reactions, especially the enantioselectivity. Aggarwal and co-workers have addressed this issue by using N-tosylhydrazone salts and achieved a limited number of asymmetric organic reactions, but the method is greatly limited because the salts must be freshly prepared or stored in the dark at -20 °C prior to use. Hence, easily decomposable N-sulfonylhydrazones, especially those capable of decomposing at low temperature, should open up new opportunities for the development of N-sulfonylhydrazone chemistry. Since 2014, our group has worked toward this goal and eventually identified N-2-(trifluoromethyl)benzenesulfonylhydrazone (i.e., N-triftosylhydrazone) as an efficient diazo surrogate that can decompose at temperatures as low as -40 °C. This allowed us to carry out a range of challenging synthetic transformations and to broaden the applications of some known reactions of great relevance.In this Account, we report our achievements in the application of N-triftosylhydrazones in carbene chemistry. On the basis of the reaction types, such applications can be categorized as (i) C(sp3)-H insertion reactions, (ii) defluorinative reactions of fluoroalkyl N-triftosylhydrazones, (iii) cycloaddition reactions with alkenes and alkynes, and (iv) asymmetric reactions. Additional applications in Doyle-Kirmse rearrangements and cross-coupling with isocyanides (ours) and benzyl chlorides (from the group of Xia) are also summarized in this Account concerning miscellaneous reactions. In terms of reaction efficiency, selectivity, and functional group tolerance, N-triftosylhydrazones are generally superior to traditional N-tosylhydrazones because of their easy decomposition. Mechanistic investigations by theoretical calculations provide insights into both the reaction mechanisms and the origin of selectivity. We hope that this Account will inspire broad interest and promote new progress in the synthetic exploration of easily decomposable N-sulfonylhydrazones.

Quarter acoustic period pulse compression using stimulated Brillouin scattering in PF-5060.

The pulse duration of the near quarter-acoustic period (τa) is demonstrated in transient stimulated Brillouin scattering (SBS) pulse compression by the suppressing Stokes trailing-edge broadening at high intensities. A theoretical analysis reveals that the difficulty in attaining the transient compression limit is caused by the broadening of the Stokes trailing edge owing to insufficient pump depletion, and this undesirable phenomenon can be significantly suppressed by a high SBS gain coefficient. An average pulse duration of ∼1.05 τa was experimentally achieved in transient compression with a high-energy efficiency of over 30%. Benefiting from energy back conversion, compression below the transient SBS limit (< τa) also occurred when the pump peak power was increased to 150 MW.

Silver-catalyzed site-selective C(sp3)-H benzylation of ethers with N-triftosylhydrazones.

The insertion of carbenes into the α-C-H bonds of ethers represents one of the most powerful approaches to access polysubstituted α-branched ethers. However, intermolecular carbene insertions remain challenging, since current approaches are generally limited to the use of toxic and potentially explosive α-diazocarbonyl compounds. We now report a silver-catalyzed α-C-H benzylation of ethers using bench-stable N-triftosylhydrazones as safe and convenient carbene precursors. This approach is well suited for both inter- and intramolecular insertions to deliver medicinally relevant homobenzylic ethers and 5-8-membered oxacycles in good yields. The synthetic utility of this strategy is demonstrated by its easy scalability, broad scope with valuable functional groups, high regioselectivity, and late-stage functionalization of complex oxygen-containing molecules. The relative reactivities of different types of silver carbenes and C-H bonds were also investigated by experments and DFT calculations.

Diagnostic efficacy of FibroScan for liver inflammation in patients with chronic hepatitis B: a single-center study with 1185 liver biopsies as controls.

BACKGROUND: Noninvasive diagnostic technologies that can dynamically monitor changes in liver inflammation are highly important for the management of chronic hepatitis B (CHB) patients and thus warrant further exploration. This study assessed the diagnostic efficacy of FibroScan for liver inflammation in CHB patients. METHODS: A total of 1185 patients were selected, and ultrasound-guided liver biopsy was performed within 1 month after the FibroScan test. The liver stiffness measurement (LSM), the reliability criteria (IQR/M) of LSM, the quality of liver biopsy (complete portal area, PA), and the liver inflammation grades were the main observation items of this study. With liver biopsy as the control, the diagnostic efficacy of FibroScan for liver inflammation in CHB patients was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: The grade of liver inflammation was positively correlated with the stage of fibrosis (rho = 0.829, P < 0.001). Different grades of inflammation will have significant rise in LSM values within the same fibrosis stage, and LSM values were positively correlated with liver inflammation grade and fibrosis stage, and the rho is 0.579 and 0.593 respectively (P < 0.001). Significant differences in the LSM of FibroScan were observed among different grades of liver inflammation (P < 0.0001). Liver biopsy (PA > 10) served as the control, and the cutoff point and the area under ROC curves (AUCs) of the LSMs for different inflammation grades were as follows: G2, 8.6 kPa, 0.775; G3 9.8 kPa, 0.818; and G4, 11.0 kPa; 0.832. With LSM cutoff values of 8.6 kPa, 9.8 kPa and 11.0 kPa, FibroScan showed certain diagnostic value for CHB patients with G2, G3 and G4 liver inflammation, especially those with G4 inflammation. CONCLUSIONS: The grade of liver inflammation was positively correlated with the stage of fibrosis, different grades of inflammation will have significant rise in LSM values within the same fibrosis stage. In addition to liver fibrosis, FibroScan could evaluate liver inflammation in CHB patients in a noninvasive manner.

The azidosulfonylation of terminal alkynes leading to ß-azidovinyl sulfones.

We report herein the first example of the N3 radical-mediated azidosulfonylation of alkynes, affording the ß-azidovinyl sulfone products with a broad substrate scope, excellent functional group compatibility, and high yield. DFT calculations suggest that the mechanism of the reaction proceeds through an unprecedented sequential N3 radical addition and sulfonyl radical coupling pathway.

Fluorocyclization of Allyl Alcohols and Amines to Access 3-Functionalized Oxetanes and Azetidines.

An efficient method to prepare 3-functionalized oxetanes and azetidines has been realized by fluorocyclization of readily available 2-azidoallyl/2-alkoxyallyl alcohols and amines. Notably, this is the first example applying the fluorocyclization strategy to construct four-membered heterocycles. The pendant electron-donating group (-N3 or -OR) plays a crucial role in polarizing the C═C double bond and facilitating the cyclization process, as verified by DFT and experimental studies.

Clinical efficacy of "ICE-FIRE" ablation for non-paroxysmal atrial fibrillation.

PURPOSE: Catheter ablation is less successful for non-paroxysmal atrial fibrillation (NPAF) according to numerous follow-up studies. The choice of ablation strategy for patients with NPAF remains controversial. The objective of the study was to explore the clinical efficacy of the "ICE-FIRE" ablation. METHODS: Ninety NPAF patients were enrolled. Patients were randomly divided into RF (treated with circumferential pulmonary vein isolation (CPVI) and additional substrate modification by radiofrequency ablation) group and I-F (treated with CPVI by cryoablation and additional substrate modification by radiofrequency ablation) group. After CPVI and cardioversion to sinus rhythm, high-density mapping was performed. Eight-one of 90 participants restored to sinus rhythm. Seventy-four of 81 NPAF patients showed low-voltage zone. Substrates with low-voltage zone were targeted for further modification. Participants were followed at baseline, 3, 6, 9, and 12 months after the initial ablation. RESULTS: The I-F group shared more X-ray exposure (I-F, 264.4 ± 97.4 mGy; RF, 224.9 ± 62.0 mGy; P = 0.039) and less duration of the procedure (I-F, 150.3 ± 27.5 min; RF, 174.2 ± 38.5 min; P = 0.003) compared to RF group. The freedom from atrial arrhythmia recurrence at 12 months post-ablation was similar between the RF and I-F groups (RF, 57.1%; I-F, 71.8%; P = 0.197). However, I-F group experienced lower rehospitalization rate of AF recurrence (RF, 42.9%; I-F, 20.5%; P = 0.038). CONCLUSIONS: In NPAF patients requiring substrate mapping and modification, the "ICE-FIRE" ablation demonstrated non-inferior clinical efficacy and lower rehospitalization rate of AF recurrence when compared with pure radiofrequency ablation strategy.