Ent-Pimaranes isolated from Flickingeria fimbriata and their acetylcholinesterase inhibitory activities.

Two new and six known ent-pimaranes were isolated from Flickingeria fimbriata. One of them possesses a rare carbon skeleton. It is the first time such a compound with this specific carbon skeleton has been isolated from a natural source. The structure and absolute configuration were determined by NMR, MS, and X-ray diffraction analysis. The biosynthetic pathway of the rare skeleton was proposed and suggested a new pathway for these nor-ent-pimarane analogues. All isolated compounds were screened for inhibitory activity against acetylcholinesterase (AChE). The compound 4 exhibits potent inhibitory effect on AChE with the 50% inhibitory concentration (IC50) being 5.8 µM, which is close to that of the positive control (Huperzine A). This is the first report about inhibitory activity on AChE of ent-pimaranes.

Access to thiazoline and spiro[indoline-3,3'-thiophene] scaffolds via a formal [3 + 2] annulation reaction of crotonate-derived sulfur ylides and ß-ketothioamides.

A formal [3 + 2] annulation reaction of crotonate-derived sulfur ylides and ß-ketothioamides (KTAs) was successfully developed to produce good-to-excellent yields of thiazoline and spiro[indoline-3,3'-thiophene] scaffolds. This transformation is a powerful tool for the synthesis of thiazoline and spiro[indoline-3,3'-thiophene] scaffolds due to its mild reaction conditions, easily accessible starting materials, and broad substrate scope. A large-scale reaction was carried out to ensure the practical applicability of this methodology. Finally, the plausible mechanistic pathway of the developed methodology was investigated.

Profiling aromatic constituents of Chimonanthus nitens Oliv. leaf granule using mass spectrometry.

RATIONALE: The chemical constituents of Chinese patent medicine are usually different from those of crude medicine because of specific preparation processes. Chimonanthus nitens Oliv. leaf granule is widely used for prevention against COVID-19 in China. However, no research has been reported on the chemical constituents of the granule and their variation during the preparation process. METHODS: Fragmentation patterns of reference compounds were investigated using electrospray ionization mass spectrometry, and the new gas-phase reaction was demonstrated by electronic and steric effects and calculated chemistry. Then, a strategy based on new fragmentation patterns was used to profile aromatic constituents. In addition, based on untargeted metabolomics analytical workflow, a comparison was made on the chemical constituents of the leaf and granule. RESULTS: New fragmentation patterns related to two competing reactions, ring-opening and ring-closing reactions for coumarin, have been proposed and investigated in depth. The newly established diagnostic ion at m/z 81.0331 worked strongly in the assignment of OH-7 and substituent at C-8 of coumarin. McLafferty rearrangement occurring in coumarin glycoside while sugar group locating at C-4 was first observed, and new diagnostic ions at m/z 147.0440, 119.0488, and 91.0543 were constructed. CONCLUSIONS: Aromatic constituents of the granule were first profiled. A total of 114 aromatic compounds were identified; of these 85 compounds were identified first. Kaempferol-7-O-neohesperidoside and its homologues were mostly enriched in the granule. Considering their reported bioactivities, these analogues possibly contribute greatly to clinical efficacy. Our results provided a new fragmentation theory for coumarins and a new material basis for the quality control of the granule.

Palladium-Catalyzed Chemo- and Regioselective C-H Bond Functionalization of Phenols with 1,3-Dienes.

Chemo- and site-selective functionalization of phenols offers a rapid strategy for the synthesis of phenol derivatives with diverse structures. Herein, we report a Pd-catalyzed regioselective C-H bond allylic alkylation of phenols with 1,3-dienes, which has precision reactivity at the ortho C-H bond of 2-naphthols, 1-naphthols, and electron-rich phenols. The reaction is accelerated by a diphosphine ligand, does not need any other additive, and features broad substrate scope and good chemo- and regioselectivity. In addition, we have also investigated the asymmetric variant, and the product could be achieved in up to 55% ee.

Intracranial peak pressure as a predictor for perioperative mortality after spontaneous intracerebral hemorrhage evacuation and decompressive craniectomy.

BACKGROUND: An optimal intracranial pressure (ICP) management target is not well defined in patients with spontaneous intracerebral hemorrhage. The aim of this study was to explore the association between perioperative ICP monitoring parameters and mortality of patients with spontaneous intracerebral hematoma undergoing emergency hematoma removal and decompressive craniectomy (DC), to provide evidence for a target-oriented ICP management. METHODS: The clinical and radiological features of 176 consecutive patients with spontaneous intracerebral hemorrhage that underwent emergent hematoma evacuation and DC were reviewed. The Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) scores were assessed 2 weeks after surgery. Multivariate logistic regression analysis was performed to identify predictors for perioperative death. RESULTS: Forty-four cases (25.0%) were assigned to the ICP group. In patients with an ICP monitor, the median peak ICP value was 25.5 mmHg; 50% of them had a peak ICP value of more than 25 mmHg. The median duration of ICP > 25 mmHg was 2 days. Without a target-specific ICP management, the mortality at 2 weeks after surgery was similar between patients with or without an ICP monitor (27.3% versus 18.2%, p = 0.20). In multivariable analysis, the peak ICP value (OR 1.11, 95% CI 1.004-1.234, p = 0.04) was significantly associated with perioperative death in the ICP group. The area under ROC curve of peak ICP value was 0.78 (95%CI 0.62-0.94) for predicting mortality, with a cut-off value of 31 mmHg. CONCLUSION: Compared with a persistent hyperintracranial pressure, a high ICP peak value might provide a better prediction for the mortality of patients with spontaneous intracerebral hemorrhage evacuation and DC, suggesting a tailored ICP management protocol to decrease ICP peak value.

Investigation of fragmentation pathways of norpimarane diterpenoids by mass spectrometry combined with computational chemistry.

RATIONALE: Norpimarane diterpenes possess plentiful bioactivities and are widely distributed in herbs, such as Flickingeria fimbriata. Rapid characterization of these natural products in complicated plant extracts is of great importance, and electrospray ionization tandem mass spectrometry is a powerful tool for chemical constituent profiling. However, limited researches on their fragmentation mechanisms seriously hinder identification via mass spectrometry. METHODS: Three norpimarane diterpenes isolated from F. fimbriata via multiple types of column chromatography served as reference compounds, and collision-induced dissociation experiments were performed on them with a series of variable collision energies. Plausible fragmentation pathways were proposed based on product ions. To further validate the fragmentation mechanisms, the proton affinity and product ion energy were simulated by density functional theory at the B3LYP/6-31+G(d, p) level. RESULTS: Three main cleavage reactions induced skeleton breakage and resulted in characteristic ions, methyl (CH3 -20) migration, hydrogen arrangement and Retro-Diels-Alder reaction, among which methyl migration was firstly proposed for pimarane diterpenes. A series of common diagnostic ions were identified, such as m/z 133.1012, 121.1012, 119.0805 and 107.0855. Additionally, the constructed fragmentation mechanisms were successfully applied for fragment ion rationalization of previously reported isopimarane diterpenes. CONCLUSIONS: Fragmentation mechanisms of norpimarane diterpenes have been uncovered. Carbocation located at the C ring tends to result in methyl (CH3 -20) migration which has been rarely reported before. This characteristic dissociation reaction allows multiple diagnostic ions to be rationalized and aids in rationalizing fragmentation patterns of other diterpenes. The uncovered mechanisms also shed light on rapid identification of norpimarane diterpenes.

Iodine-Modified Pd Catalysts Promote the Bifunctional Catalytic Synthesis of 2,5-Hexanedione from C6 Furan Aldehydes.

Currently, low intimacy between hydrogenation sites and acidic sites causes unsatisfactory catalytic activity and selectivity for the synthesis of 2,5-hexanedione from C6 furan aldehydes (5-methylfurfural, 5-hydroxymethylfurfural). Herein, iodine(I) modification of Pd-supported catalysts (such as PdI/Al2 O3 and PdI/SiO2 ) was investigated to modulate the hydrogenation sites and acidic sites. Unlike Pd catalysts that produced 71.4 % yield of 2-hydroxymethyl-5-methyl tetrahydrofuran via an overhydrogenation route of 5-methylfurfural, PdI catalysts showed a high efficiency for 2,5-hexanedione with 93.7 % yield by a hydrogenative ring-opening route. More importantly, the selective synthesis of 2,5-hexanedione from 5-hydroxymethylfurfural with a high yield of 50.2 % by the hydrogenolysis and subsequent ring-opening route was reported for the first time. I-modified Pd nanoparticles produced in-situ hydrogen spillover, which promoted the selective C=O hydrogenation and ring-opening steps by regulating the adsorption configuration of the reactants and the transformation of Lewis to Brønsted acidity, respectively.

Direct Synthesis of 5-Methylfurfural from d-Fructose by Iodide-Mediated Transfer Hydrogenation.

Herein, a robust catalytic system was developed for the green synthesis of 5-methylfurfural (5-MF) by iodide-mediated transfer hydrogenation. Around 50 % of 5-MF was yielded from d-fructose within 7.5 min using NaI as the catalyst and formic acid as both the hydrogen source and co-catalyst. The catalytic system was used for six consecutive cycles without any decrease in the yield. Various starch and raw biomass could be used as promising starting materials for 5-MF synthesis with moderate yields, and the productivity of 5-MF from corn starch reached 103 mmol gcat -1 h-1 , which is comparable with the best result from l-rhamnose. Moreover, the co-production of 5-MF and furfural from raw biomass makes this methodology more competitive than other routes.

Two New Alkaloids from Fuzi and Their Metabolites Study.

Former study suggests alkaloids from herbs of Aconitum genus plants possess excellent bioactivities, which exert great value for related deeper chemical constituent investigation. Herein, chemical isolation was performed and four alkaloids were isolated from Fuzi, of which two were new ones, and the other two were reported NMR data for the first time. Their chemical structures were identified by NMR data, high resolution MS, UV and IR analysis. Additionally, the MS fragmentation patterns were explored, formerly, that of hetisane alkaloid was rarely reported, and fragmentation mechanism of the diagnostic ion was proposed. Based on these fragment pathway, metabolites and metabolic pathways of four compounds were investigated in rat liver microsomes using UPLC-Q/TOF-MS, and dehydrogenation product was firstly found from metabolites of hetisane alkaloid.

The global profiling of alkaloids in Aconitum stapfianum and analysis of detoxification material basis against Fuzi.

Aconitum alkaloids are versatile in chemical structures and are well known for their bioactivity and toxicity. Cases of analogs with closely similar structures or positional isomers are widespread in herbs of the Aconitum genus. It is still challenging to rapidly identify unknown compounds via mass spectrometry, especially positional isomers. Herein, to profile the alkaloids of Aconitum stapfianum that possess bioactivity against intoxication by the lateral root of Aconitum carmichaelii (Fuzi), a strategy was developed by carefully determining the fragmentation pathways of authentic standards. A series of rules was summarized and involved charge site effects, hydrogen bonding effects, competitive channels between charge-remote reactions and charge migration reactions, and fragment patterns exhibiting a "diamond shape". Accordingly, a total of 124 alkaloids in A. stapfianum were tentatively characterized, including 85 potential new compounds and 24 sets of isomers. On the other hand, to explore the material basis of detoxification, a chemical constituent comparison was made between A. stapfianum and Fuzi, and principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were performed to identify markers that were different between the two . In total, 25 characteristic markers were identified to discriminate between these two herbal medicines, of which 14 compounds were specific for A. stapfianum and most of them were characteristic for a para-substituted benzoic acid ester at C-14.

[Application of continuous monitoring of intracranial pressure and brain oxygen partial pressure in the treatment of patients with severe craniocerebral injury].

OBJECTIVE: To investigate the effects of continuous monitoring intracranial pressure (ICP) and brain oxygen partial pressure (PbtO2) on the prognosis of patients with severe craniocerebral injury. METHODS: A prospective randomized controlled trial was conducted. Seventy patients with severe craniocerebral injury with a Glasgow coma score (GCS) 4-8 admitted to the neurosurgical intensive care unit (NICU) of the People's Hospital of Inner Mongolia Autonomous Region from January 2017 to May 2020 were enrolled, and they were divided into ICP monitoring group and ICP+PbtO2 monitoring group by random number table. Patients in ICP monitoring group received ICP monitoring and were given traditional treatment of controlling ICP and cerebral perfusion pressure (CPP), the therapeutic target was ICP < 20 mmHg (1 mmHg = 0.133 kPa) and CPP > 60 mmHg. Patients in ICP+PbtO2 monitoring group were given ICP and PbtO2 monitoring at the same time, and oxygen flow was adjusted on the basis of controlling ICP and CPP to maintain the PbtO2 > 20 mmHg, and the therapeutic target of ICP and CPP was the same as the ICP monitoring group. ICP and PbtO2 values were recorded during monitoring in the two groups, the results of CPP, GCS and arterial blood gas analysis were recorded, and the prognosis at 3 months and 6 months after injury was compared by Glasgow outcome scale (GOS) score between the two groups. GOS score > 3 was considered as good prognosis. Kaplan-Meier survival curve was drawn, and the 3-month and 6-month cumulative survival rates of the two groups were analyzed. Linear regression analysis was used to further evaluate the relationship between PbtO2 and GOS score. RESULTS: Finally, a total of 70 patients with severe craniocerebral injury were enrolled in the analysis, 34 patients received ICP combined with PbtO2 monitoring and guided therapy, and 36 patients received ICP monitoring alone. The average ICP of ICP+PbtO2 monitoring group was significantly lower than that of ICP monitoring group (mmHg: 13.4±3.2 vs. 18.2±8.3, P < 0.01). Although the CPP in both groups was great than 60 mmHg, the average CPP of ICP+PbtO2 monitoring group was significantly higher than that of ICP monitoring group (mmHg: 82.1±10.5 vs. 74.5±11.6, P < 0.01). No significant difference was found in average GCS score or arterial partial pressure of carbon dioxide (PaCO2) between the ICP+PbtO2 monitoring group and ICP monitoring group [GCS score: 5.3±2.3 vs. 5.2±2.2, PaCO2 (mmHg): 33.5±4.8 vs. 32.6±5.2, both P > 0.05]. The average arterial partial pressure of oxygen (PaO2) of ICP+PbtO2 monitoring group was obviously higher than that of ICP monitoring group (mmHg: 228.4±93.6 vs. 167.3±81.2, P < 0.01). Compared with the ICP monitoring group, the good outcome rates of 3 months and 6 months after injury in the ICP+PbtO2 monitoring group were significantly higher (3 months: 67.6% vs. 38.9%, 6 months: 70.6% vs. 41.7%, both P < 0.05). Kaplan-Meier survival curve showed that the 3-month and 6-month cumulative survival rates of ICP+PbtO2 monitoring group were significantly higher than those of ICP monitoring group (3 months: 85.3% vs. 61.1%, Log-Rank test: χ2 = 5.171, P = 0.023; 6 months: 79.4% vs. 55.6%, Log-Rank test: χ2 = 4.511, P = 0.034). Linear regression analysis showed that PbtO2 was significantly correlated with GOS score at 3 months and 6 months after injury in patients with severe craniocerebral injury (r values were 0.951 and 0.933, both P < 0.01). CONCLUSIONS: PbtO2 compared with ICP monitoring guiding therapy is valuable in improving the prognosis of patients with severe craniocerebral injury. It can improve the prognosis at 3-6 months after injury.

Domino Annulation Reaction of Sulfur Ylides and Morita-Baylis-Hillman Carbonates of Isatins: Synthesis of Oxospiro[bicyclo[3.1.0]hexane-6,3'-indolin] Scaffolds.

A sequential [3 + 2]/[2 + 1] annulation domino reaction of crotonate-derived sulfur ylides and Morita-Baylis-Hillman carbonates of isatins for the construction of oxospiro[bicyclo[3.1.0]hexane-6,3'-indolin] scaffolds in moderate to good yields with almost 1:1 diastereoselectivity has been developed. Mild reaction conditions and readily accessible starting materials as well as excellent functional group compatibility render this transformation a powerful tool for the synthesis of spirocyclopropyloxindoles. A gram-scale synthetic procedure was also successfully carried out and a plausible reaction mechanism could be proposed.

A formal [3 + 2] annulation reaction of propargyl sulfonium compounds and N-ylides: access to pyrrolo[2,1-a]quinolines, pyrrolo[2,1-a]phthalazines and indolizines.

A sequential [3 + 2] annulation of prop-2-ynylsulfonium salt and N-ylides was developed, leading to the formation of a series of pyrrolo[2,1-a]quinolines, pyrrolo[2,1-a]phthalazines and indolizines. The protocol featured the simultaneous one-pot formation of three new C-C bonds in moderate yields under mild conditions. In this reaction, the prop-2-ynylsulfonium salts acted as the C2 synthons and sulfide served as the leaving group. The resultant products could serve as useful precursors for the synthesis of diverse chemical compounds.

Study on the bio-oil characterization and heavy metals distribution during the aqueous phase recycling in the hydrothermal liquefaction of As-enriched Pteris vittata L.

The hydrothermal liquefaction (HTL) of As enriched Pteris vittata L. (PVL, hyper-accumulator biomass) was performed with the recycled aqueous phase as reaction medium, aiming to dispose the biomass with high water content and produce high-quality bio-oil. After three times of aqueous phase recycling at 275 °C, 30 min, the bio-oil yield increased to 30.32% from 21.54% and the higher heating value (HHV, 28.51 MJ/kg) of the bio-oil was higher than that of the bio-oil from HTL with pure water (26.80 MJ/kg). The main compounds detected in bio-oils were phenols, ketones, hydrocarbons, and aldehydes. Acetic acid (17.21-24.77 mg/mL) was dominant in the aqueous phases, resulting in the low pH (4.31-4.89). The heavy metals (Cu, Pb, Zn, Cd) mainly remained in bio-char whereas As was transferred to aqueous phase. Thus, HTL by aqueous phase recycling could be a promising way for PVL treatment to obtain high-quality bio-oil and arsenic recovery.

[4 + 2]-Annulation of Prop-2-ynylsulfonium Salts and Isatoic Anhydrides: Access to 3-Methylthio-4-quinolones.

An unparalleled [4 + 2]-annulation of prop-2-ynylsulfonium salts with isatoic anhydrides was developed, affording a series of 4-quinolones with a alkylthio group in medium to good yields under mild conditions. In this reaction type, the prop-2-ynylsulfonium salt serves as a C2 synthon and sulfide does not act as a leaving group, providing facile access to organosulfur compounds. The resulting quinolone products could be further transformed to a diverse range of synthetically useful compounds.

Construct indeno[1,2-b]oxepine or cis-cyclopropylacrylate by sulfur ylides.

For the first time, the [4 + 3] or [2 + 1] annulation of crotonate-derived sulfur ylides with arylidenemalononitrile or arylidene-1H-indene-1,3(2H)-dione is reported using Na2CO3 as the base. This protocol is advantageous as it does not require prior preparation of arylidenemalononitrile or arylidene-1H-indene-1,3(2H)-dione substrates, due to the independent participation of the base in the two reactions. This mild, operationally multicomponent process can be employed for the transformation of a wide variety of commercially available aldehydes into the corresponding indeno[1,2-b]oxepine or cyclopropyl acrylate core in moderate to excellent yields under mild conditions.

Mechanistic study of a one-step catalytic conversion of fructose to 2,5-dimethyltetrahydrofuran.

Carbohydrates, such as fructose, can be fully dehydroxylated to 2,5-dimethyltetrahydrofuran (DMTHF), a valuable chemical and potential gasoline substitute, by the use of a dual catalytic system consisting of HI and RhX(3) (X=Cl, I). A mechanistic study has been carried out to understand the roles that both acid and metal play in the reaction. HI serves a two-fold purpose: HI acts as a dehydration agent (loss of 3 H(2)O) in the initial step of the reaction, and as a reducing agent for the conjugated carbinol group in a subsequent step. I(2) is formed in the reduction step and metal-catalyzed hydrogenation reforms HI. The rhodium catalyst, in addition to catalyzing the reaction of iodine with hydrogen, functions as a hydrogenation catalyst for C=O and C=C bonds. A general mechanistic scheme for the overall reaction is proposed based on identification of intermediates, independent reactions of the intermediates, and deuterium labeling studies.

Selective reduction of biomass by hydriodic acid and its in situ regeneration from iodine by metal/hydrogen.

HI returns: Hydroiodic acid is a highly selective reducing reagent for a wide variety of substrates. Its application is limited by the formation of iodine and the difficulty in reconverting that iodione back to HI in situ. We report the facile conversion of I(2) to HI by metal-catalyzed hydrogenation in the presence of water, and demonstrate the utility of this process in the conversion of fructose to 5-methyfurfural and glycerol to 2-iodopropane.

One-step catalytic transformation of carbohydrates and cellulosic biomass to 2,5-dimethyltetrahydrofuran for liquid fuels.

Existing technologies to produce liquid fuels from biomass are typically energy-intensive, multistep processes. Many of these processes use edible biomass as starting material. Carbohydrates, such as mono- and polysaccharides and cellulose, typically constitute 50-80% of plant biomass. Herein, we report that hexose from a wide range of biomass-derived carbohydrates, cellulose, and even raw lignocellulose (e.g., corn stover) can be converted into 2,5-dimethyltetrahydrofuran (DMTHF) in one step, in good yields and under mild conditions in water. Under the same conditions, 2-methyltetrahydrofuran is formed from pentose. The reaction employs a soluble rhodium catalyst, dihydrogen, and HI/HCl+NaI. The catalytic system is robust and can be recycled repeatedly without loss of activity. DMTHF is superior to ethanol and has many of the desirable properties currently found in typical petroleum-derived transportation fuels.