Nanoscale and chiral metal-organic frameworks for asymmetric reactions in water: bridging Lewis acid catalysis and biological systems.

Nowadays, stereoselective control over the sheer variety of chemical transformations benefits from the multipotency of chiral Lewis acids. Their use under biocompatible conditions has long posed a challenge because profuse amounts of biogenic nucleophiles readily deactivate them. To bridge the gap between chiral Lewis acid catalysis and biocompatible chemistry, the conversion of UiO(BPY)-type nanosized metal-organic frameworks (NMOFs) into chiral variants was herein exemplified. The combination of an elongated 2,2'-bipyridyl linker and scandium salt with a hydrophobic anion proved essential to implement traits such as robustness, biocompatibility, and catalytic activity. The catalyst could construct sufficiently hydrophobic environments sequestered within the framework, catalyzing asymmetric ring-opening reactions of meso-epoxide with low catalyst loading to afford ß-amino acid alcohols in high yield (up to >99%) with high enantioselectivity (up to 88%). Most impressively, it exhibited a tolerance to the ex vivo poisoning of chiral Lewis acid catalysis by biogenic nucleophiles in sharp contrast to conventional water-compatible Lewis acids.

Direct Aromatic Nitrosation Using 2-Methoxyethyl Nitrite as a NO Cation Source.

This work presents an acid-free method for aromatic nitrosation using 2-methoxyethyl nitrite (MOE-ONO). While originally developed as a NOx radical source in our group, we demonstrate the utility of MOE-ONO as a NO cation source for aromatic electrophilic nitrosation. This method successfully nitrosates phenols, naphthols, and other pronucleophiles, completely suppressing undesired nitration by NOx radicals. Notably, it enables nitrosation of acid-sensitive substrates, which has been difficult to achieve with existing protocols.

A highly efficient catalytic method for the synthesis of phosphite diesters.

In contrast to conventional methods that rely on stoichiometric activation of phosphonylating reagents, we have developed a highly efficient catalytic method for the synthesis of phosphite diesters using a readily available phosphonylation reagent and alcohols with environmentally benign Zn(ii) catalysts. Two alcohols could be introduced consecutively on the P center with release of trifluoroethanol as the sole byproduct, without any additive, under mild conditions. The products could be oxidized smoothly to access phosphate triesters. A range of alcohols, including sterically demanding and highly functionalized alcohols such as carbohydrates and nucleosides, can be applied in this reaction.

Efficient Radical-Mediated Intermolecular α-Alkylation Reactions of Carbonyl Compounds with Nonactivated Alkenes.

Alkylation reactions are fundamental carbon-carbon bond-forming reactions in synthetic organic chemistry. Among them, intermolecular α-alkylation reactions of carbonyl compounds with alkenes are important because they are more atom-economical than the equivalent processes using alkyl halides. However, intermolecular reactions with nonactivated alkenes such as 1-hexene, which can allow the use of a wide range of valuable substrates, have been considered to be very challenging for a long time. In this review, radical-mediated intermolecular α-alkylation reactions of carbonyl compounds with nonactivated alkenes are discussed. The examples are grouped into three types of reactions: peroxide-mediated reactions, metal-oxidant-mediated reactions, and photoactivated reactions. Photoredox-catalyzed alkylation reactions under visible-light irradiation are discussed as a particularly promising recent hot topic. This review provides brief history and new prospects on the α-alkylation process with nonactivated alkenes using α-carbonyl radical species.

Changes in long-term care insurance revenue among service providers during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has impacted peoples' health-related behaviors, especially those of older adults, who have restricted their activities in order to avoid contact with others. Moreover, the pandemic has caused concerns in long-term care insurance (LTCI) providers regarding management and financial issues. This study aimed to examine the changes in revenues among LTCI service providers in Japan during the pandemic and analyze its impact on different types of services. METHODS: In this study, we used anonymized data from "Kaipoke," a management support platform for older adult care operators provided by SMS Co., Ltd. Kaipoke provides management support services to more than 27,400 care service offices nationwide and has been introduced in many home-care support offices. The data used in this study were extracted from care plans created by care managers on the Kaipoke platform. To examine the impact of the pandemic, an interrupted time-series analysis was conducted in which the date of the beginning of the pandemic was set as the prior independent variable. RESULTS: The participating providers were care management providers (n = 5,767), home-visit care providers (n = 3,506), home-visit nursing providers (n = 971), and adult day care providers (n = 4,650). The results revealed that LTCI revenues decreased significantly for care management providers, home-visit nursing providers, and adult day care providers after the COVID-19 pandemic began. The largest decrease was an average base of USD - 1668.8 in adult day care. CONCLUSION: The decrease in revenue among adult day care providers was particularly concerning in terms of the sustainability of their business. This decrease in revenue may have made it difficult to retain personnel, and staff may have needed to be laid off as a result. Although this study has limitations, it may provide useful suggestions for countermeasures in such scenarios, in addition to support conducted measures.

Reductive N-Alkylation of Amines with Ketones Using Heterogeneous Polysilane-Palladium Catalysts under Continuous-Flow Conditions.

This work reports a continuous-flow reductive N-alkylation of amines with ketones using molecular hydrogen. The reaction, performed with highly active polysilane-modified heterogeneous palladium catalysts, enables the efficient synthesis of diversely substituted amines under mild flow conditions. The developed catalyst exhibits sustained activity for 5 days (turnover number of >2400). Moreover, the utility of the method is demonstrated by the synthesis of a key intermediate of the active pharmaceutical ingredient teneligliptin.

Alteration of knee joint moment after anterior cruciate ligament reconstruction conditions in subjects with and without meniscal pathology.

BACKGROUND: The effects of anterior cruciate ligament (ACL) reconstruction on postoperative gait biomechanics remain controversial, and the influence of meniscus pathology on pre- and post-ACL reconstruction biomechanical changes has not yet been studied. Here, we aimed to clarify the difference in knee joint moment between pre- and post-ACL reconstruction conditions in subjects with and without meniscal pathology. METHODS: Twenty-four subjects with unilateral ACL reconstruction injuries participated in this study. A total of 13 of the subjects had concomitant meniscus injuries. Gait analysis was performed preoperatively and at 11 months postoperatively. Three-dimensional knee joint angles and moments were calculated based on motion-capture data. The total joint moment and contribution of individual moments during the stance phase were assessed. For statistical analysis, we compared pre- and postoperative alterations, and differences were assessed in subjects with and without meniscal pathology. RESULTS: Tibial rotation excursion was lower in subjects with meniscal pathology than in those with intact menisci postoperatively. An significant increase in the contribution of the knee flexion moment and a significant decrease in the contribution of the knee adduction moment postoperatively were observed in subjects with intact menisci. CONCLUSIONS: Patients with ACL injury showed different postoperative alterations in joint moments depending on the concomitant meniscal injury.

Development of Catalytic Enantioselective Mannich Reactions Using Esters.

Catalytic enantioselective Mannich reactions of simple nonactivated esters proceeded using a chiral potassium strong base catalyst prepared from a chiral bisoxazoline and potassium hexamethyldisilazide. Alkyl acetates, alkyl propionates, and an alkyl butyrate were employed as the simple esters, and the desired reactions proceeded smoothly to afford Mannich products in good to high yields with high enantioselectivities. One of the products was successfully employed in the asymmetric total synthesis of Maraviroc.

Water vs. Organic Solvents: Water-Controlled Divergent Reactivity of 2-Substituted Indoles.

Water is not a good solvent for most organic compounds, yet water can offer many benefits to some organic reactions, hence enriching organic chemistry. Herein, the unique divergent reactivity of 2-substituted indoles with ⋅NO sources is presented. The amount of water solvent was harnessed for a scalable, benign, and expedient synthesis of indolenine oximes, albeit with water's inability to dissolve the reactants. 2-Methoxyethyl nitrite, which has been tailored for reactions in water, empowered this protocol by enhancing the product selectivity. We further report on chemoselective transformations of the products that rely on their structural features. Our findings are expected to offer access to an underexplored chemical space. The platform is also applicable to oximinomalonate synthesis. Mechanistic studies revealed the important role of water in the reversal of stability between oxime and nitroso compounds, promoting the proton transfer.

Continuous-Flow Enantioselective Hydroacylations under Heterogeneous Chiral Rhodium Catalysts.

Transition metal-catalyzed enantioselective C-H bond functionalizations have become efficient methods for the synthesis of complex optically active molecules. Heterogeneous catalysts for this chemistry remain largely unexplored despite the advantages they offer in terms of ease of separation and reuse of catalysts. Herein, we report the development of heterogeneous chiral Rh catalysts for continuous-flow enantioselective hydroacylations. Heterogeneous catalysts could be prepared simply by mixing supports and Rh complexes. The prepared catalysts exhibited excellent activity and enantioselectivity affording optically active ketones in quantitative yields with 99 % ee's. Under the optimized reaction conditions, a turnover number >300 was achieved without the leaching of Rh species. The catalysts exhibited a wide substrate scope and in sequential-flow reactions with other heterogeneous catalysts, the syntheses of biologically active molecules and functional materials were demonstrated.

Photoinduced Efficient Catalytic α-Alkylation Reactions of Active Methylene and Methine Compounds with Nonactivated Alkenes.

In catalytic α-alkylation reactions of carbonyl compounds, although SN2-type substitution reactions of enolates with alkyl halides are a conventional methodology, addition reactions with alkenes are more desirable because of their atom-economical character; however, reactions with nonactivated alkenes are challenging. Here, we developed highly efficient catalytic α-alkylation reactions of active methylene and methine compounds with nonactivated alkenes such as 1-decene using an organophotocatalyst and lithium thiophenoxide as a Lewis acid/Brønsted base/hydrogen atom transfer (HAT) multifunctional catalyst under blue-light irradiation. The reaction was also performed with a higher degree of efficiency under a continuous-flow system to obtain the products in multigram scales. The present reaction system enables highly efficient and practical α-alkylation reactions of active methylene and methine compounds to be achieved.

Highly enantioselective hydroxymethylation of unmodified α-substituted aryl ketones in water.

Catalytic asymmetric direct-type aldol reactions of ketones with aldehydes are a perennial puzzle for organic chemists. Notwithstanding the emergence of a myriad of chiral catalysts to address the inherent reversibility of the aldol products, a general method to access acyclic α-chiral ketones from prochiral aryl ketones has remained an unmet synthetic challenge. The approach outlined herein is fundamentally different to that used in conventional catalysis, which typically commences with an α-proton abstraction by a Brønsted base. The use of a chiral 2,2'-bipyridine scandium complex enabled the hydroxymethylation of propiophenone to be run under base-free conditions, which avails effectual suppression of hydrolytic deactivation of the Lewis acid catalyst. Intriguingly, the use of water as a reaction medium had an overriding effect on the progress of the reaction. The sagacious selection of sodium dodecyl sulfate and lithium dodecyl sulfate as surfactants allowed a variety of propiophenone derivatives to react in a highly enantioselective manner.

Aluminium-catalysed synthesis of aryl enol ethers from phenols and dimethyl ketals.

We report an environmentally friendly, aluminium-catalysed, halide- and transition metal-free method for the synthesis of aryl enol ethers from phenols and dimethyl ketals that involves ketal exchange driven by the removal of methanol. The obtained aryl enol ethers were transformed into the corresponding diaryl ethers by Pd/C-catalysed dehydrogenation or DDQ oxidation.

Heterogeneous Single-Atom Zinc on Nitrogen-Doped Carbon Catalyzed Electrochemical Allylation of Imines.

Organometallic reagents are effective for carbon-carbon bond formation; however, consumption of stoichiometric amounts of metals is problematic. We developed electrochemical allylation reactions of imines catalyzed by nitrogen-doped carbon-supported single-atom zinc, which were fixed on a cathode to afford a range of homoallylic amines efficiently. The system could suppress generation of metallic waste, and the catalyst electrode showed advantages over bulk zinc in terms of activity and robustness. An electrochemical flow reaction was also successfully performed to produce the homoallylic amine continuously with minimum amounts of waste.

Chlamydial Infection-Dependent Synthesis of Sphingomyelin as a Novel Anti-Chlamydial Target of Ceramide Mimetic Compounds.

The obligate intracellular bacterium Chlamydia trachomatis is the major causative agent of bacterial sexually transmitted diseases worldwide. In infected cells, the ceramide transport protein (CERT) is recruited to inclusions, where C. trachomatis replicates using host-synthesized ceramide. The ceramide is converted to sphingomyelin (SM) by a chlamydial infection-dependent SM synthesis (cidSM-synthesis) pathway, which occurs even in the absence of the SM synthases (SMS)-1 and -2 of host cells. The ceramide mimetic compound (1R,3S)-HPA-12 and the nonmimetic compound E16A, both of which are potent inhibitors of CERT, repressed the proliferation of C. trachomatis in HeLa cells. Unexpectedly, (1R,3R)-HPA-12, a ceramide mimetic compound that lacks CERT inhibitory activity, also exhibited potent anti-chlamydial activity. Using endogenous SMS-knockout mutant HeLa cells, we revealed that (1R,3R)-HPA-12 mildly inhibited cidSM-synthesis. In addition, LC-MS analysis revealed that (1R,3R)-HPA-12 is converted to a phosphocholine-conjugated metabolite in an infection-dependent manner. Imaging analysis with a fluorescent analog of ceramide suggested that cidSM-synthesis occurs in the bacterial bodies and/or inclusions. Collectively, these results suggested that (1R,3R)-HPA-12 exerts its anti-chlamydia activity not only as an inhibitor of cidSM-synthesis, but also via putative toxic effects of its phosphocholine adduct, which is most likely produced by the cidSM-synthesis route.

[Two Cases of Emphysematous Pyelonephritis Successfully Treated by Transurethral Catheterization].

Emphysematous pyelonephritis (EPN) is a severe necrotic urinary tract infection accompanied by retention of gas in the kidney and areas around it. Formerly, emergency nephrectomy was the primary treatment, but the trend is shifting to treatment with maximum conservation of the kidney. In this report, two cases of EPN successfully treated by transurethral drainage are presented. The first case was in a 63-year-old woman with a history of poorly controlled diabetes. She arrived at the hospital by ambulance with primary symptoms of vomiting and trembling of the hands, and computed tomography (CT) revealed gas in the right renal calix. The second case was in a 61-year-old woman who arrived by ambulance with difficulty of body movement as the primary symptom, and CT revealed a calculus in the right ureter accompanied by right hydronephrosis and retention of gas in the right renal pelvis and right upper ureter. Both patients were diagnosed with EPN and treated by transurethral drainage rather than percutaneous drainage or nephrectomy because of their poor general condition. The treatment was successful. Along with percutaneous drainage, transurethral drainage is considered to be an option of surgical treatment for EPN.

The Stat3 inhibitor F0648-0027 is a potential therapeutic against rheumatoid arthritis.

Rheumatoid arthritis (RA) is a disease characterized by chronic joint inflammation, pain and joint destruction, leading to alteration in activities of daily living, yet pathological mechanisms underlying the condition are not fully clarified. To date, various therapeutic agents have been developed as RA therapy including DMARDs and/or biological agents that target inflammatory cytokines or inhibit JAK. Here we asked whether inhibiting signal transducer and activator of transcription 3 (Stat3) activity would antagonize RA. Stat3 forms dimers when activated and undergoes nuclear translocalization; thus we screened approximately 4.9 million small compounds as potential blockers of protein-protein interactions required for Stat3 dimerization using in silico screening. We identified 15 as strong candidates as potential blockers of protein-protein interactions required for Stat3 dimerization using in silico screening from those compounds. Four of the 15 significantly inhibited expression of IL-6 and RANKL, both of which are direct targets of Stat3, induced by IL-6. Among four, one compound, F0648-0027, significantly inhibited arthritis development without apparent adverse effects in vivo in collagen-induced arthritis model mice. F0648-0027 also significantly blocked Stat3 phosphorylation and nuclear localization following IL-6 stimulation of fibroblasts. These data suggest that Stat3 is a target for collagen-induced arthritis in mice, and that F0648-0027 could serve as a therapeutic reagent against comparable conditions in humans.

Development of Metal-Free, Trifluoromethanesulfonic Acid-Immobilized Nitrogen-Doped Carbon Catalysts for Povarov Reactions.

A metal-free, heterogeneous acid catalyst, trifluoromethanesulfonic acid-immobilized nitrogen-doped carbon catalyst, was developed for Povarov reactions. This catalyst exhibited excellent catalytic activity, achieving high turnover frequency (>400 h-1) and good cis-selectivity of the desired 1,2,3,4-tetrahydroquinoline products. The reaction had a broad substrate scope, and the multicomponent Povarov reaction proceeded smoothly with readily accessible aldehydes and anilines. The heterogeneity and reusability of this catalytic system were confirmed. The catalyst was characterized by spectroscopic and microscopic analysis studies.

Effect of Activation Methods of Molecular Sieves on Ketimine Synthesis.

Although the use of molecular sieves for imine synthesis is a common protocol, there have been no comprehensive studies on heat-drying methods. This can be crucial for reproducibility. It was found that molecular sieve 5A dried at 160 °C for 5 h under vacuum efficiently promoted the condensation of various ketones and amines to afford even relatively bulky ketimines. Several control experiments and analyses revealed that only a small amount of Brønsted acid sites was important for the activity, rather than dehydration ability. Other types of molecular sieves could be utilized for the reaction after treatment with water followed by heat drying. A continuous-flow acetalization reaction of alcohols using the activated molecular sieve 5A was also demonstrated.