RÉSUMÉ
Efficiently mixing highly viscous liquids in microfluidic systems is appealing for green chemistry such as chemical synthesis and catalysis, but it is a long-standing challenge owing to the unfavorable diffusion kinetics. In this work, a new strategy is explored for mixing viscous droplets by harnessing a peculiar Leidenfrost state, where the substrate temperature is above the boiling point of the liquid without apparent liquid evaporation. Compared to the control experiment where the droplet stays at a similar temperature but in the contact boiling regime, the mixing time can be reduced significantly. Moreover, it is demonstrated that the liquid mixing originates from the chaotic convection flow in the Leidenfrost droplet, characterized by the internal vortex motion evidenced by the microscale visualization. A correlation between mixing time and droplet volume is also proposed, showing a good agreement with experimental results. It is further shown that Leidenfrost droplets can be used to synthesize nanoparticles of the desired morphology, and it is anticipated that this simple and scalable fabrication approach will find applications in the biological, pharmaceutical, and chemical industries.
RÉSUMÉ
Dual-atom catalysts (DACs) have been proposed to break the limitation of single-atom catalysts (SACs) in the synergistic activation of multiple molecules and intermediates, offering an additional degree of freedom for catalytic regulation. However, it remains a challenge to synthesize DACs with high uniformity, atomic accuracy, and satisfactory loadings. Herein, we report a facile cascade synthetic strategy for DAC via precise electrostatic interaction control and neighboring vacancy construction. We synthesized well-defined, uniformly dispersed dual Fe sites which were connected by two nitrogen bonds (denoted as Fe-N2-Fe). The as-synthesized DAC exhibited superior catalytic performances towards oxygen reduction reaction, including good half-wave potential (0.91â V), high kinetic current density (21.66â mA cm-2), and perfect durability. Theoretical calculation revealed that the DAC structure effectively tunes the oxygen adsorption configuration and decreases the cleavage barrier, thereby improving the catalytic kinetics. The DAC-based zinc-air batteries exhibited impressive power densities of 169.8 and 52.18â mW cm-2 at 25 °C and -40 °C, which is 1.7 and 2.0 times higher than those based on Pt/C+Ir/C, respectively. We also demonstrated the universality of our strategy in synthesizing other M-N2-M DACs (M=Co, Cu, Ru, Pd, Pt, and Au), facilitating the construction of a DAC library for different catalytic applications.
RÉSUMÉ
A palladium-catalyzed decarboxylative asymmetric [4 + 2] annulation of methyleneindolinones with a zwitterionic oxo-1,4-dipole intermediate was successfully developed to access spirocyclic oxindoles bearing two vicinal stereocenters in good yields with high diastereoselectivities and enantioselectivities. This strategy features a broad substrate scope (28 examples), allowing for efficient scale-up. Further selective transformation of the product and preliminary mechanistic studies were conducted.
RÉSUMÉ
16ß-Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16ß-methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability-oriented strategy toward the unified stereoselective synthesis of 16ß-methylcorticoids in 12.6-14.0 % overall yield from commercially available 9α-hydroxyandrost-4-ene-3,17-dione (9α-OH-AD). In this approach, the chiral C16ß-Me and C17α-OH groups of the corticosteroid D ring were installed via a substrate-controlled diastereo- and enantioselective Mn-catalyzed oxidation-reduction hydration of Δ4,9(11),16 -triene-3,20-dione. The C1-C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3-ketosteroid-Δ1 -dehydrogenase (MK4-KstD)-catalyzed regioselective Δ1 -dehydrogenation of Δ4,9(11) -diene-3,21-dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.
Sujet(s)
Béclométasone , Clobétasol , Humains , Clobétasol/usage thérapeutique , Bétaméthasone/usage thérapeutique , Stéroïdes , Hormones corticosurrénaliennesRÉSUMÉ
Objective: This study aims to explore the experiences and consequences of taste alterations in patients undergoing HSCT, how they respond to these changes, and the factors that influence their responses. Methods: In this descriptive qualitative study, face-to-face semi-structured individual interviews were conducted with 31 patients undergoing HSCT in a comprehensive hospital in Hubei, China. The interview data were transcribed and analyzed using Colaizzi's seven-step analysis. The Symptom Management Theory was applied to design the study and identify key themes. Results: Three key themes were identified from the theory: (1) the complexity and diversity of taste experiences; (2) coping strategies; and (3) the multifaceted challenges of coping. Taste alterations in HSCT patients were characterized by diversity and dynamism. Patients employed three distinct coping styles in response to taste alterations: active coping, reluctant submission, and passive coping. These coping styles were influenced by various factors, including the specific treatment modalities of HSCT, individual patient characteristics, and the healthcare environment. Conclusions: The experience of taste alterations among HSCT patients is intricate and varied, and the importance of addressing this symptom can easily be underestimated. Management of taste alterations is influenced by multiple factors. Nursing staff should give careful attention to taste alterations in HSCT survivors, enhance their expertise in managing taste alterations, provide robust health education, conduct regular screening and assessments, and formulate individualized intervention plans to assist patients in actively and effectively managing taste alterations.
RÉSUMÉ
BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) commonly have coexisting comorbidities that contribute to higher exacerbation frequency, poorer health status, and increased all-cause mortality; however, there are only a few studies available on the sex discrepancy in the comorbidity distribution and outcomes among COPD patients, and there is limited information about the discrepancy in all-cause mortality between men and women. METHODS: Based on data from the U.S. National Health and Nutrition Examination Survey conducted between 2007 and 2012, we compared participants aged 40-79 years with spirometry-defined COPD to compare the prevalence of comorbidities between men and women. The survival of the subjects was documented, and the sex discrepancy was determined using Kaplan-Meier analysis. Comorbidities and all-cause mortality were analyzed by using a Cox proportional hazards model to determine their strength of association in different sex groups. RESULTS: Compared to men, women had a significantly higher prevalence of asthma (OR 1.93, 95% CI 1.46 to 2.57, p < 0.001) and arthritis (OR 1.77, 95% CI 1.39 to 2.24, p < 0.001). Women had a significantly lower prevalence of coronary heart disease (OR 0.48, 95% CI 0.27 to 0.87, p = 0.015) and gout (OR 0.42, 95% CI 0.25 to 0.67, p = 0.001). Kaplan-Meier analysis revealed that compared with that of the female group, the survival rate of the male group was significantly lower (p < 0.001). Among men, the presence of anemia (HR 2.38, [95% CI 1.52-3.73], p < 0.001), gout (HR 1.55, [95% CI 1.04-2.30], p = 0.029) and congestive heart failure comorbidities (HR 1.85, [95% CI 1.12-3.04] p = 0.016) was associated with a higher risk of mortality; among women, the presence of anemia (HR 2.21, [95% CI 1.17-4.20], p = 0.015) and stroke (HR 2.04, [95% CI 1.07-3.88], p = 0.031) comorbidities was associated with a higher risk of mortality after adjusting for age, race/Hispanic status, BMI, smoking status, FEV1% predicted and prevalent comorbidities. CONCLUSIONS: COPD-related comorbidities and all-cause mortality were discrepant between men and women, and men had poorer survival than women in the nationally representative data that were analyzed.
Sujet(s)
Anémie , Goutte , Broncho-pneumopathie chronique obstructive , Humains , Femelle , Mâle , Enquêtes nutritionnelles , Caractères sexuels , Comorbidité , Anémie/épidémiologie , Anémie/complications , Goutte/complications , Goutte/épidémiologie , Facteurs de risqueRÉSUMÉ
OBJECTIVES: This study aimed to determine the epidemiological and genetic features of human metapneumovirus (HMPV) infection in children in southern China, and the effect of meteorological factors on infection. METHODS: 14,817 children (≤14 years) with acute respiratory tract infections from 2010 to 2019 were examined for HMPV and other respiratory viruses by real-time quantitative polymerase chain reaction. Full-length F gene of 54 positive samples were sequenced and subjected to phylogenetic analysis. The correlation between the HMPV-positive rate and meteorological factors was analyzed by linear regression analysis. RESULTS: HMPV was detected in 524 (3.5%) children, who were mostly younger than 1 year. The seasonal peak of HMPV prevalence mainly occurred in spring. Respiratory syncytial virus was the most common virus coinfected with HMPV (5.3%). Phylogenetic analysis revealed that the sequenced HMPV strains belonged to four sublineages, including A2b (1.9%), A2c (31.5%), B1 (50.0%), and B2 (16.7%). After adjusting for all meteorological factors, sunshine duration was inversely correlated with the HMPV-positive rate. CONCLUSION: HMPV is an important respiratory pathogen that causes acute respiratory tract infections in children in southern China, particularly in children ≤5 years old. The prevalence peak of HMPV in this area appeared in spring, and the predominant subtype was B1. Meteorological factors, especially long sunshine duration, might decrease the HMPV prevalence.
Sujet(s)
Metapneumovirus , Infections à Paramyxoviridae , Infections de l'appareil respiratoire , Enfant , Humains , Nourrisson , Enfant d'âge préscolaire , Metapneumovirus/génétique , Études rétrospectives , Épidémiologie moléculaire , Phylogenèse , Infections à Paramyxoviridae/épidémiologie , Infections de l'appareil respiratoire/épidémiologie , Chine/épidémiologie , Concepts météorologiquesRÉSUMÉ
In alkaline seawater electrolysis, the oxygen evolution reaction (OER) is greatly suppressed by the occurrence of electrode corrosion due to the formation of hypochlorite. Herein, a catalyst consisting of MoC nanowires modified with NiFe alloy nanoparticles (NiFe/MoC) on nickel foam (NF) is prepared. The optimized catalyst can deliver a large current density of 500â mA cm-2 at a very low overpotential of 366â mV in alkaline seawater, respectively, outperforming commercial IrO2 . Remarkably, an electrolyzer assembled with NiFe/MoC/NF as the anode and NiMoN/NF as the cathode only requires 1.77â V to drive a current density of 500â mA cm-2 for alkaline seawater electrolysis, as well as excellent stability. Theory calculation indicates that the initial activity of NiFe/MoC is attributed to increased electrical conductivity and decreased energy barrier for OER due to the introduction of Fe. We find that the change of the catalyst in the composition occurred after the stability test; however, the reconstructed catalyst has an energy barrier close to that of the pristine one, which is responsible for its excellent long-term stability. Our findings provide an efficient way to construct high-performance OER catalysts for alkaline seawater splitting.
RÉSUMÉ
Endometriosis is diagnosed by laparoscopic surgery. The availability of biomarkers can help understand the pathophysiology and aid in the diagnosis of the condition. In this context, this review aimed to examine levels of expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are increased amongst patients with endometriosis and if they can serve as a potential biomarker. PubMed, CENTRAL, Scopus, Web of Science, and Embase databases were searched for studies comparing BDNF or NGF levels amongst endometriosis patients and controls. Data were pooled for serum and tissue levels of BDNF and NGF. Ten fulfilled the inclusion criteria. On comparing BDNF levels, it was noted that endometrial tissue had significantly higher expression of BDNF levels as compared to controls (SMD: 1.73 95% CI: 0.64, 2.82 I2 = 89%). Similarly, the meta-analysis found significantly higher serum levels of BDNF in endometriosis patients as compared to controls (SMD: 1.66 95% CI: 0.73, 2.59 I2 = 95%). Pooled analysis showed significantly increased levels of NGF in endometrial tissue as compared to controls (SMD: 4.15 95% CI: 0.11, 8.18 I2 = 98%) but with unstable results on sensitivity analysis. Only one study showed higher levels of NGF in serum amongst endometriosis patients. Limited data shows higher expression of BDNF in endometrial lesions and increased serum levels of BDNF in endometriosis patients. Similar results were noted for NGF but with very scarce data. Further research is needed to establish BDNF and NGF as suitable biomarkers for the disease.
Sujet(s)
Endométriose , Femelle , Humains , Facteur neurotrophique dérivé du cerveau , Facteur de croissance nerveuse , Bases de données factuellesRÉSUMÉ
Graphene nanoribbons (GNRs) are widely recognized as intriguing building blocks for high-performance electronics and catalysis owing to their unique width-dependent bandgap and ample lone pair electrons on both sides of GNR, respectively, over the graphene nanosheet counterpart. However, it remains challenging to mass-produce kilogram-scale GNRs to render their practical applications. More importantly, the ability to intercalate nanofillers of interest within GNR enables in-situ large-scale dispersion and retains structural stability and properties of nanofillers for enhanced energy conversion and storage. This, however, has yet to be largely explored. Herein, we report a rapid, low-cost freezing-rolling-capillary compression strategy to yield GNRs at a kilogram scale with tunable interlayer spacing for situating a set of functional nanomaterials for electrochemical energy conversion and storage. Specifically, GNRs are created by sequential freezing, rolling, and capillary compression of large-sized graphene oxide nanosheets in liquid nitrogen, followed by pyrolysis. The interlayer spacing of GNRs can be conveniently regulated by tuning the amount of nanofillers of different dimensions added. As such, heteroatoms; metal single atoms; and 0D, 1D, and 2D nanomaterials can be readily in-situ intercalated into the GNR matrix, producing a rich variety of functional nanofiller-dispersed GNR nanocomposites. They manifest promising performance in electrocatalysis, battery, and supercapacitor due to excellent electronic conductivity, catalytic activity, and structural stability of the resulting GNR nanocomposites. The freezing-rolling-capillary compression strategy is facile, robust, and generalizable. It renders the creation of versatile GNR-derived nanocomposites with adjustable interlay spacing of GNR, thereby underpinning future advances in electronics and clean energy applications.
RÉSUMÉ
Spirodiphosphines have been successfully applied in various asymmetric catalytic transformations. However, controlling the coordinating conformations by the direct displacement of the spiro atom remains elusive. Herein, we report the application of Si-centered spirodiphosphine (Si-SDP) ligands in the enantioselective hydrosilylation/cyclization of 1,6-enynes. The Si-SDPs showed superior reactivity to existing C2-symmetric diphosphines, allowing the generation of a range of chiral pyrrolidines with high yields and enantioselectivity (up to 96% yield and 92% ee) at room temperature with low catalyst loading. The mechanistic observations were consistent with the modified Chalk-Harrod mechanism, and the high reactivity of Si-SDPs was further leveraged for the room-temperature Rh-catalyzed hydrosilylation of alkynes.
RÉSUMÉ
Aflatoxin B1 (AFB1) and zearalenone (ZEN) cause serious damage to mammals, but few studies have investigated the impacts of these toxins on pregnant and lactating mammals. This study investigated the effects of ZEN on AFB1-induced intestinal and ovarian toxicity in pregnant and lactating rats. Based on the results, AFB1 reduces the digestion, absorption, and antioxidant capacity in the intestine, increases intestinal mucosal permeability, destroys intestinal mechanical barriers, and increases pathogenic bacteria' relative abundances. Simultaneously, ZEN can exacerbate the intestinal injury caused by AFB1. The intestines of the offspring were also damaged, but the damage was less severe than that observed for the dams. While AFB1 activates various signalling pathways in the ovary and affects genes related to endoplasmic reticulum stress, apoptosis, and inflammation, ZEN may exacerbate or antagonize the AFB1 toxicity on gene expression in the ovary through key node genes and abnormally expressed genes. Our study found that mycotoxins can not only directly damage the ovaries and affect gene expression in the ovaries but can also impact ovarian health by disrupting intestinal microbes. Mycotoxins are an important environmental pathogenic factor for intestinal and ovarian disease in pregnancy and lactation mammals.
Sujet(s)
Mycotoxines , Trichothécènes , Zéaralénone , Animaux , Rats , Grossesse , Femelle , Zéaralénone/toxicité , Trichothécènes/toxicité , Aflatoxine B1/toxicité , Ovaire , Lactation , Intestins , MammifèresRÉSUMÉ
Cytoskeleton has been reported to play an essential role in facilitating the viral life cycle. However, whether the host can exert its antiviral effects by modulating the cytoskeleton is not fully understood. In this study, we identified that host factor DUSP5 was upregulated after dengue virus (DENV) infection. In addition, we demonstrated that overexpression of DUSP5 remarkably inhibited DENV replication. Conversely, the depletion of DUSP5 led to an increase in viral replication. Moreover, DUSP5 was found to restrain viral entry into host cells by suppressing F-actin rearrangement via negatively regulating the ERK-MLCK-Myosin IIB signaling axis. Depletion of dephosphorylase activity of DUSP5 abolished its above inhibitory effects. Furthermore, we also revealed that DUSP5 exhibited broad-spectrum antiviral effects against DENV and Zika virus. Taken together, our studies identified DUSP5 as a key host defense factor against viral infection and uncovered an intriguing mechanism by which the host exerts its antiviral effects through targeting cytoskeleton rearrangement.
Sujet(s)
Virus de la dengue , Dengue , Infection par le virus Zika , Virus Zika , Humains , Réplication virale , Cytosquelette , Antiviraux/pharmacologie , Dengue/traitement médicamenteux , Dual-specificity phosphatases/génétique , Dual-specificity phosphatases/pharmacologieRÉSUMÉ
The ability to construct metal single-atom catalysts (SACs) asymmetrically coordinated with organic heteroatoms represents an important endeavor toward developing high-performance catalysts over symmetrically coordinated counterparts. Moreover, it is of key importance in creating supporting matrix with porous architecture for situating SACs as it greatly impacts the mass diffusion and transport of electrolyte. Herein, we report the crafting of Fe single atoms with asymmetrically coordinated nitrogen (N) and phosphorus (P) atoms scaffolded by rationally designed mesoporous carbon nanospheres (MCNs) with spoke-like nanochannels for boosting ring-opening reaction of epoxide to produce an array of pharmacologically important ß-amino alcohols. Notably, interfacial defects in MCN derived from the use of sacrificial template create abundant unpaired electrons, thereby stably anchoring N and P atoms and in turn Fe atoms on MCN. Importantly, the introduction of P atom promotes the symmetry-breaking of common four N-coordinated Fe sites, resulting in the Fe-N3P sites on MCN (denoted Fe-N3P-MCN) with an asymmetric electronic configuration and thus superior catalytic capability. As such, the Fe-N3P-MCN catalysts manifest a high catalytic activity for ring-opening reaction of epoxide (97% yield) over the Fe-N3P docked on nonporous carbon surface (91%) as well as the sole Fe-N4 SACs grounded on the same MCN support (89%). Density functional theory calculations reveal that Fe-N3P SAC lowers the activation barrier for the C-O bond cleavage and the C-N bond formation, thus accelerating the ring-opening of epoxide. Our study provides fundamental and practical insights into developing advanced catalysts in a simple and controllable manner for multistep organic reactions.
RÉSUMÉ
Food and feed are frequently co-contaminated with aflatoxin B1 (AFB1) and zearalenone (ZEN). This study investigated the effects of ZEN on the AFB1-induced liver and mammary gland toxicity in pregnant and lactating rats. AFB1 and ZEN co-exposure inhibited the growth of rats and caused oxidative stress and inflammatory responses in the liver and mammary gland. Compared with the AFB1-only group, damage was aggravated in the AFB1 + 10 mg/kg ZEN group, and the AFB1 + 1 mg/kg ZEN group showed a reduction in some metrics. The metabolomic results of the mammary gland showed that metabolite changes were mainly in lipid, amino acid, and glucose metabolism. Compared with the AFB1 + 0 mg/kg ZEN group, the AFB1 + 1 mg/kg ZEN group had the most metabolite changes. Moreover, AFB1 and ZEN co-exposure reduced the levels of sex hormones and RNA m6A methylation in the mammary gland. We speculate that ZEN affects the toxicity of AFB1 to the liver and mammary gland by interfering with the function of sex hormones, regulating cell proliferation and metabolic processes.
Sujet(s)
Zéaralénone , Aflatoxine B1/toxicité , Acides aminés , Animaux , Femelle , Glucose , Lactation , Lipides , Foie , Grossesse , ARN , Rats , Zéaralénone/toxicitéRÉSUMÉ
The first systematic study of ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) on aryl α-chloro ß-keto esters was performed, and 15 structurally diverse chiral anti-aryl α-chloro ß-hydroxy esters were synthesized in 74-98% isolated yields, along with moderate-to-excellent diastereoselectivity (up to >99 : 1 dr) and good-to-excellent enantioselectivity (mostly >99% ee). LfSDR1-catalyzed complete reduction of 100 g L-1 of substrate 6b at a ten-gram scale was achieved with a continuous fed-batch strategy, affording anti-(2S,3S)-1b, the key intermediate of diltiazem, in a record-breaking space-time yield of 96 g L-1 d-1. An eight-step synthesis of diltiazem, clentiazem, and siratiazem was accomplished in 32-45% overall yields, featuring this versatile biocatalytic reduction reaction as well as an efficient, green chlorination reaction in flow.
Sujet(s)
Diltiazem , Esters , Diltiazem/analogues et dérivés , StéréoisomérieRÉSUMÉ
Invited for the cover of this issue are Dang Cheng, Fener Chen and co-workers at Fudan University. The image depicts six-step continuous-flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid in a desktop microchemical plant. Read the full text of the article at 10.1002/chem.202201420.
Sujet(s)
Diclofenac , HumainsRÉSUMÉ
Interstitial cystitis (IC) is a bladder syndrome of unclear etiology with no generally accepted treatment. Growing evidence suggest that periostin (POSTN) is an important homeostatic component in the tissue repair and regeneration in adulthood, but its function in urinary bladder regeneration is still unknown. Here we investigate whether POSTN is involved in bladder tissue repair in a cyclophosphamide (CYP)-induced interstitial cystitis model. POSTN is primarily expressed in bladder stroma (detrusor smooth muscle and lamina propria) and upregulated in response to CYP-induced injury. POSTN deficiency resulted in more severe hematuria, aggravated edema of the bladder, and delayed umbrella cell recovery. Besides, less proliferative urothelial cells (labeled by pHH3, Ki67, and EdU) and lower expression of Krt14 (a urothelial stem cell marker) were detected in POSTN-/- mice post CYP exposure, indicating a limited urothelial regeneration. Further investigations revealed that POSTN could induce Wnt4 upregulation and activate AKT signaling, which together activates ß-catenin signaling to drive urothelial stem cell proliferation. In addition, POSTN can promote resident macrophage proliferation and polarization to a pro-regenerative (M2) phenotype, which favors urothelial regeneration. Furthermore, we generated injectable P-GelMA granular hydrogel as a biomaterial carrier to deliver recombinant POSTN into the bladder, which could increase urothelial stem cells number, decrease umbrella cells exfoliation, and hence alleviate hematuria in a CYP-induced interstitial cystitis model. In summary, our findings identify a pivotal role of POSTN in bladder urothelial regeneration and suggest that intravesical biomaterials-assisted POSTN delivery may be an efficacious treatment for interstitial cystitis.
Sujet(s)
Cystite interstitielle , Cystite , Animaux , Prolifération cellulaire , Cyclophosphamide/effets indésirables , Cyclophosphamide/métabolisme , Cystite/induit chimiquement , Cystite/génétique , Cystite/métabolisme , Cystite interstitielle/métabolisme , Hématurie/métabolisme , Macrophages/métabolisme , Souris , Vessie urinaireRÉSUMÉ
Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) as over-the-counter (OTC) medication for the treatment of inflammatory diseases. Herein, the development of an intensified six-step continuous flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid is described. A challenging and unprecedented etherification/Smiles rearrangement cascade of 2-chloro-N-phenylacetamide and 2,6-dichlorophenol into hydroxyacetyldiphenylamine operated with the precise control of reaction conditions in continuous flow was realized as the key step in this multistep synthetic chemistry. The undesired amide hydrolysis in Smiles rearrangement was addressed and the extra installation of N-chloroacetyl group in current industrial batch mode was avoided. Diclofenac sodium was obtained in 63 % isolated yield with an average yield of above 90 % for each step in a total residence time of 205â min.
Sujet(s)
Anti-inflammatoires non stéroïdiens , DiclofenacRÉSUMÉ
Continuous flow synthetic technologies had been widely applied in the total synthesis in the past few decades. Fully continuous flow synthesis is still extremely focused on multi-step synthesis of complex natural pharmaceutical molecules. Thus, the development of fully continuous flow total synthesis of natural products is in demand but challenging. Herein, we demonstrated the first fully continuous flow approach towards asymmetric total synthesis of natural tetrahydroprotoberberine alkaloids, (-)-isocanadine, (-)-tetrahydropseudocoptisine, (-)-stylopine and (-)-nandinine. This method features a concise linear sequence involving four chemical transformations and three on-line work-up processing in an integrated flow platform, without any intermediate purification. The overall yield and enantioselectivity of this four-step continuous flow chemistry were up to 50 % and 92 %ee, respectively, in a total residence time of 32.5â min, corresponding to a throughput of 145â mg/h.