Taming Chiral Quaternary Stereocenters via Remote H-Bonding Stereoinduction in Palladium-Catalyzed (3+2) Cycloadditions.

Ring-opening transformations of donor-acceptor (D-A) cyclopropanes enable the rapid assembly of complex molecules. However, the enantioselective formation of chiral quaternary stereocenters using substrates bearing two different acceptors remains a challenge. Herein, we describe the first palladium-catalyzed highly diastereo- and enantioselective (3+2) cycloaddition of vinyl cyclopropanes bearing two different electron-withdrawing groups, a subset of D-A cyclopropanes. The key to the success of this reaction is the remote stereoinduction through hydrogen bond from chiral ligands, which thereby addressed the aforementioned challenge. A variety of chiral five-membered heterocycles were produced in good yields and with high stereoselectivity (up to 99 % yields, 99 : 1 er and >19 : 1 dr). In-depth mechanistic investigations, including control experiments and theoretical calculations, revealed the origin of the stereoselectivity and the importance of H-bonding in stereocontrol.

Concise Total Synthesis of Salimabromide.

We achieved a concise total synthesis of salimabromide by using a novel intramolecular radical cyclization to simultaneously construct the unique benzo-fused [4.3.1] carbon skeleton and the vicinal quaternary stereocenters. Other notable transformations include a tandem Michael/Mukaiyama aldol reaction to introduce most of the molecule's structural elements, along with hidden information for late-stage transformations, an intriguing tandem oxidative cyclization of a diene to form the bridged butyrolactone and enone moieties spontaneously, and a highly enantioselective hydrogenation of a cycloheptenone derivative (97% ee) that paved the way for the asymmetric synthesis of salimabromide.

Concise Enantioselective Total Synthesis of Daphenylline Enabled by an Intramolecular Oxidative Dearomatization.

Daphenylline is a structurally unique member of the triterpenoid Daphniphyllum natural alkaloids, which exhibit intriguing biological activities. Six total syntheses have been reported, five of which utilize aromatization approaches. Herein, we report a concise protecting-group-free total synthesis by means of a novel intramolecular oxidative dearomatization reaction, which concurrently generates the critical seven-membered ring and the quaternary-containing vicinal stereocenters. Other notable transformations include a tandem reductive amination/amidation double cyclization reaction, to assemble the cage-like architecture, and installation of the other two chiral stereocenters via a highly enantioselective rhodium-catalyzed challenging hydrogenation of the diene intermediate (90% e.e.) and an unprecedented remote acid-directed Mukaiyama-Michael reaction of the complex benzofused cyclohexanone (13:1 d.r.).

Enantioselective Addition-Alkylation of α,ß-Unsaturated Carbonyls via Bisguanidinium Silicate Ion Pair Catalysis.

Silicon hydrides, alkynylsilanes, and alkoxylsilanes were activated by fluoride in the presence of bisguanidinium catalyst to form hypervalent silicate ion pairs. These activated silicates undergo 1,4-additions with chromones, coumarins, and α-cyanocinnamic esters generating enolsilicate intermediates, for a consequent stereoselective alkylation reaction. The reduction-alkylation reaction proceeded under mild conditions using polymethylhydrosiloxane, a cheap and environmentally friendly hydride source. The addition-alkylation reactions with alkynylsilanes and alkoxylsilanes resulted in the construction of two vicinal chiral carbon centers with excellent enantioselectivities and diastereoselectivities (up to 99% ee, >99:1 dr). Density functional theory calculations and experimental NMR studies revealed that penta-coordinated silicates are crucial intermediates.

Optically Active Flavaglines-Inspired Molecules by a Palladium-Catalyzed Decarboxylative Dearomative Asymmetric Allylic Alkylation.

With the aid of a class of newly discovered Trost-type bisphosphine ligands bearing a chiral cycloalkane framework, the Pd-catalyzed decarboxylative dearomative asymmetric allylic alkylation (AAA) of benzofurans was achieved with high efficiency [0.2-1.0 mol% Pd2(dba)3/L], good generality, and high enantioselectivity (>30 examples, 82-99% yield and 90-96% ee). Moreover, a diversity-oriented synthesis (DOS) of previously unreachable flavaglines is disclosed. It features a reliable and scalable sequence of the freshly developed Tsuji-Trost-Stoltz AAA, a Wacker-Grubbs-Stoltz oxidation, an intra-benzoin condensation, and a conjugate addition, which allows the efficient construction of the challenging and compact cyclopenta[b]benzofuran scaffold with contiguous stereocenters. This strategy offers a new avenue for developing flavagline-based drugs.

Perinatal exposure to bisphenol A causes a disturbance of neurotransmitter metabolic pathways in female mouse offspring: A focus on the tryptophan and dopamine pathways.

Perinatal exposure to bisphenol A (BPA) contributes to neurological disorders in offspring, but the underlying mechanisms are still poorly understood. The abnormal release of neuroactive metabolites in the tryptophan (TRP) and dopamine (DA) pathways is considered to be closely associated with some disorders. Thus, in this study, TRP and DA pathways in adult female mouse offspring were investigated when the pregnant mice were given either vehicle or BPA (2, 10, or 100 µg/kg/d) from day 6 of gestation until weaning. Then, the serum and brain samples of offspring were collected at 3, 6 and 9 months, and 12 neuroactive metabolites in the TRP and DA pathways were detected. The results showed that, in the TRP pathway, TRP levels decreased, whereas kynurenine (KYN) levels and TRP turnover increased in the brain. In the serum, TRP, KYN and 5-hydroxytryptamine (5-HT) levels decreased significantly. For the DA pathway, DA and DA metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA), reduced significantly in the brain and serum. DA turnover decreased dramatically in the brain but enhanced in the serum. The disturbance of these two metabolic pathways might be one of the potential mechanisms of BPA-induced neuropsychiatric disorders.

Massive haemoptysis from right middle lobe bronchus managed by customized silicon stents.

Massive haemoptysis is life-threatening. Management options include pharmacological treatment, bronchial artery embolization, surgical resection, and bronchoscopic interventions. As an alternative treatment method of controlling haemoptysis, endobronchial stent insertion has been performed in several pulmonary carcinoma patients. We presented an 89-year-old bronchiectasis patient who developed massive haemoptysis from the right middle lobe bronchus. Haemoptysis was not controlled by both pharmacological treatment and bronchial artery embolization. Two customized silicone stents with the one in the right middle lobe bronchus and another in the right intermediate bronchus were used to manage haemoptysis. One month after stents implantation, the stent inside the right intermediate bronchus was removed, another stent was left in the right middle lobe bronchus to continue occluding the bleeding passageway. Haemoptysis did not occur after silicon stents deployment. This may be the first case of receiving straight silicon stent implantation to manage massive haemoptysis from the right middle lobe bronchus.

A sensitive method for the determination of the gender difference of neuroactive metabolites in tryptophan and dopamine pathways in mouse serum and brain by UHPLC-MS/MS.

Tryptophan (TRP) and dopamine (DA) pathways are of great importance for their related pathology and physiology. In the present study, a new reliable and sensitive analytical method was developed and validated for 12 neuroactive metabolites in TRP and DA pathways in mouse serum and brain by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method exhibited good sensitivity as the lower limit of detections ranged from 0.10 to 0.50 ng/ml and the lower limit of quantifications ranged from 0.20 to 2.00 ng/ml by derivatization with dansyl chloride (DNS-Cl) following solid phase extraction (SPE) on C18 cartridges. Good linearity (R2 > 0.99), intra-day precision (<9.8% in serum and <8.8% in brain), inter-day precision (<8.9% in serum and <8.5% in brain) and accuracy (90.3%-110.3% in serum and 86.5%-114.0% in brain) were obtained. The method was successfully applied in measuring 12 neuroactive metabolites in TRP and DA pathways in serum and brain samples of male and female mice to explore the differences between genders. As a result, DA and the turnover of DA to 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxtryptamine (5-HT) to TRP and 5-hydroxyindole acetic acid (5-HIAA) to 5-HT in the serum and norepinephrine (NE) in the brain were significantly different between genders.

Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies.

The 'neurotrophic sesquiterpenes' refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other 'cage convulsant' compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.

Optimized ultra performance liquid chromatography tandem high resolution mass spectrometry method for the quantification of paraquat in plasma and urine.

A simple, sensitive and specific ultra performance liquid chromatography coupled to electrospray tandem high resolution mass spectrometry (UPLC-ESI-HRMS/MS) method has been developed and validated for quantification of paraquat in plasma and urine. The sample preparation was carried out by one-step protein precipitation with acetonitrile. The paraquat was separated with a HILIC column in 10min. Detection was performed using Q Exactive Orbitrap mass spectrometer by Targeted-MS/MS scan mode. Methodological parameters, such as ammonium formate concentration, formic acid concentration, spray voltage, capillary temperature, heater temperature and normalized collision energy were optimized to achieve the highest sensitivity. The calibration curve was linear over the concentration range of LOQ-1000ng/mL. LOD was 0.1 and 0.3ng/mL, LOQ was 0.3 and 0.8ng/mL for urine and plasma, respectively. The intra- and inter-day precisions were <7.97% and 4.78% for plasma and urine. The accuracies were within the range 93.51-100.90%. The plasma and urine matrices had negligible relative matrix effect in this study. This method was successfully applied to determine paraquat concentration in plasma samples with hemoperfusion from 5 suspected paraquat poisoning patients.

Synthesis of (+)-7,20-Diisocyanoadociane and Liver-Stage Antiplasmodial Activity of the Isocyanoterpene Class.

7,20-Diisocyanoadociane, a scarce marine metabolite with potent antimalarial activity, was synthesized as a single enantiomer in 13 steps from simple building blocks (17 linear steps). Chemical synthesis enabled identification of isocyanoterpene antiplasmodial activity against liver-stage parasites, which suggested that inhibition of heme detoxification does not exclusively underlie the mechanism of action of this class.

Simultaneous quantification of neuroactive dopamine serotonin and kynurenine pathway metabolites in gender-specific youth urine by ultra performance liquid chromatography tandem high resolution mass spectrometry.

Neuroactive metabolites in dopamine, serotonin and kynurenine metabolic pathways play key roles in several physiological processes and their imbalances have been implicated in the pathophysiology of a wide range of disorders. The association of these metabolites' alterations with various pathologies has raised interest in analytical methods for accurate quantification in biological fluids. However, simultaneous measurement of various neuroactive metabolites represents great challenges due to their trace level, high polarity and instability. In this study, an analytical method was developed and validated for accurately quantifying 12 neuroactive metabolites covering three metabolic pathways in youth urine by ultra performance liquid chromatography coupled to electrospray tandem high resolution mass spectrometry (UPLC-ESI-HRMS/MS). The strategy of dansyl chloride derivatization followed by solid phase extraction on C18 cartridges were employed to reduce matrix interference and improve the extraction efficiency. The reverse phase chromatographic separation was achieved with a gradient elution program in 20 min. The high resolution mass spectrometer (Q Exactive) was employed, with confirmation and quantification by Target-MS/MS scan mode. Youth urine samples collected from 100 healthy volunteers (Female:Male=1:1) were analyzed to explore the differences in metabolite profile and their turnover between genders. The results demonstrated that the UPLC-ESI-HRMS/MS method is sensitive and robust, suitable for monitoring a large panel of metabolites and for discovering new biomarkers in the medical fields.

Paleo-soraphens: chemical total syntheses and biological studies.

The soraphens are natural products that exhibit a molecular structure different from what would have been expected by following its polyketidal assembly line. The most significant differences are the presence of a hemiketal instead of a trisubstituted double bond and a double bond at C9 and C10 where a saturated carbon chain was expected. We were interested in the biological activity of the soraphens with architectures as described by the polyketide synthase since we hypothesized that these modifications reflect the evolutionary optimization of the soraphens. Herein we describe four additional derivatives of the so-called paleo-soraphens and their biological profiling to provide a picture of the hypothetical evolutionary optimization of this family of natural products. The syntheses required a unified and convergent strategy and their biological profiling was performed with the aid of impedance measurements. The results of these biological experiments are consistent with the proposed evolutionary optimization of the soraphens.

An eight-step gram-scale synthesis of (-)-jiadifenolide.

Development of a biologically active secondary metabolite into a useful medicine requires continuous access to meaningful quantities of material. Although any chemical synthesis is broadly useful for its versatility, identification of a synthesis route that can be economically scaled represents a greater challenge. Here we report a concise synthesis of the neurotrophic trace metabolite (-)-jiadifenolide and its production on a gram-scale. The brevity of the route and the structural similarity of a key intermediate to many potent Illicium terpenes make chemical synthesis the unquestionable method for accessing and modifying these potential therapeutics.

A class of nonlocal coupled semilinear parabolic system with nonlocal boundaries.

We investigate the positive solutions of the semilinear parabolic system with coupled nonlinear nonlocal sources subject to weighted nonlocal Dirichlet boundary conditions. The blow-up and global existence criteria are obtained.

The vinylogous Mukaiyama aldol reaction (VMAR) in natural product synthesis.

The vinylogous Mukaiyama aldol reaction (VMAR) allows efficient access to larger segments for complex natural product synthesis, primarily polyketides, through the construction of vicinal hydroxyl and methyl groups as well as di and tri-substituted double bonds in one single operation. In this review, we will highlight stereoselective protocols that have been used in natural product synthesis and cluster them into the four groups that can be obtained from different silyl ketene acetals or enol ethers. At the beginning, an overview on different stereoselective VMARs is presented; disregarding their applications in total syntheses.

Synthesis and biological evaluation of paleo-soraphens.

Synthesis can provide molecules such as paleo-soraphens A and B that are genetically encoded but not obtained from the natural source. Although it is unclear whether this is part of an evolutionary process or the consequence of the chemical synthesis, the biological evaluation of these genetically encoded natural products can shed light on how natural products are structurally optimized with respect to their biological profile.

Enantioselective conjugate addition of oximes to trisubstituted ß-nitroacrylates: an organocatalytic approach to ß(2,2)-amino acid derivatives.

A highly enantioselective organocatalytic intermolecular conjugate addition of oximes to ß-nitroacrylates has been developed. The highly functionalized adducts obtained are valuable precursors for asymmetric synthesis, as demonstrated by the synthesis of ß(2,2)-amino acids and oxazolidin-2-ones.

In vivo differentiation of magnetically labeled mesenchymal stem cells into hepatocytes for cell therapy to repair damaged liver.

OBJECTIVES: It was unclear whether systemically administered mesenchymal stem cells (MSCs) labeled with magnetic nanoparticles can transdifferentiate into hepatocytes. In the present study, we built a new in vivo murine model for monitoring the transdifferentiation of magnetically labeled green fluorescent protein (GFP) positive MSCs into albumin-positive hepatocytes, under the carbon tetrachloride (CCl4) induced persistent liver damage. We also tracked magnetically labeled MSCs by using magnetic resonance imaging (MRI) in vivo. MATERIALS AND METHODS: Among the liver damage groups, magnetically labeled GFP-positive MSCs (group A), GFP-positive MSCs (group B), and saline alone (group C) were intravenously injected. In control groups without CCl4 administration magnetically labeled GFP-positive MSCs (group D) were infused, whereas nothing was given in group E. MRI examinations were performed 24 hours and 4 weeks after cell injection in group A, B, and C. Liver-to-muscle contrast-to-noise ratios on T2*-weighted MR images were measured. At 4 weeks, 3 serum biologic liver function markers were analyzed, and mice in all groups were killed for histologic examination. RESULTS: The results showed that migration of transplanted magnetic labeled cells to the liver was successfully documented with in vivo MRI. Serum liver function markers were changed for all liver damage groups than nondamage control groups (P < 0.05), but still insignificant compared with group C (P > 0.05). Hematoxylin and eosin and Masson staining confirmed the presence of liver damage and hepatic fibrosis in group A, B, and C. Positive Prussian blue stained cells were highly correlated with GFP-positive cells in group A with an average matching rate of 95%. In group D, no iron-GFP-positive cells can be found in the liver. Albumin was expressed in (34% ± 6%) and (35% ± 7%) of GFP-positive cells in group A and B, respectively, and there was no significant difference between the 2 groups. CONCLUSIONS: Our data demonstrate that magnetic labeling technique synchronized well in GFP expressing MSCs and did not interfere with the transdifferentiation process and amending function of MSCs in vivo. Both magnetically labeled and unlabeled MSCs appeared to have the potential to differentiate into hepatocytes.

Enantioselective Michael reactions of beta, beta-disubstituted nitroalkenes: a new approach to beta(2,2)-amino acids with hetero-quaternary stereocenters.

An atom-economic organocatalytic asymmetric Michael reaction of alpha,beta,beta-trisubstituted olefins has been successfully developed. The reaction exhibits excellent enantioselectivities under low loading of catalysts, and the conjugate addition products are valuable for the synthesis of novel beta(2,2)-amino acids and beta-peptides.