C–H bonds are ubiquitous and abundant in organic molecules. If C–H bonds could be directly converted to desired functional groups in a chemo‐, site‐, and stereoselective manner, C–H functionalization ...would be a strong and useful tool for organic synthesis. Recent developments in catalytic and enzymatic chemistry have achieved highly sustainable and selective nitrene C–H insertion. Initially, C–H amination was inspired by model studies on enzymatic oxidation and used iminoiodinanes, nitrogen analogs of iodosobenzene, as nitrene precursors. Transition‐metal/iminoiodinane systems are well studied and established. These systems can directly introduce sulfonamide groups with excellent stereoselectivity, albeit with co‐production of iodobenzene as waste material. Fortunately, the atom economics of this methodology were improved by introducing highly sustainable nitrene sources such as azide compounds and 1,2,4‐dioxazol‐5‐one derivatives. In this review, we present the details of these developments with respect to their catalysts and nitrene sources.
Transition‐metal‐catalyzed C–H bond amination through nitrene transfer is a straightforward method to provide chiral aminated compounds. This minireview focuses on recent strategies for the asymmetric C–H amination towards enantioenriched products with several nitrogen sources cataylzed by small molecule complexes or artificial metalloenzymes.
The diverse biological activities of tocopherols and their analogs have inspired considerable interest in the development of routes for their efficient asymmetric synthesis. Here, we report that ...chiral ammonium hypoiodite salts catalyze highly chemo- and enantioselective oxidative cyclization of γ-(2-hydroxyphenyl)ketones to 2-acyl chromans bearing a quaternary stereocenter, which serve as productive synthetic intermediates for tocopherols. Raman spectroscopic analysis of a solution of tetrabutylammonium iodide and tert-butyl hydroperoxide revealed the in situ generation of the hypoiodite salt as an unstable catalytic active species and triiodide salt as a stable inert species. A high-performance catalytic oxidation system (turnover number of ∼200) has been achieved through reversible equilibration between hypoiodite and triiodide in the presence of potassium carbonate base. We anticipate that these findings will open further prospects for the development of high-turnover redox organocatalysis.
Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction. Senescent T cells, defined as CD4
CD44
CD62L
PD-1
CD153
cells, accumulate in visceral adipose tissues (VAT) ...in obese individuals. Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with Alhydrogel (CD153-Alum) or CpG oligodeoxynucleotide (ODN) 1585 (CD153-CpG) and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10-11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of CD153-CpG-vaccinated mice, accompanied by glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the CD153-CpG-vaccinated mice successfully reduced the number of senescent T cells. The CD153-CpG vaccine is an optional tool for senolytic therapy.
Predicting the whole process of a chemical reaction while solving kinetic equations presents an opportunity to realize an on-the-fly kinetic simulation that directly discovers chemical reactions with ...their product yields. Such a simulation avoids the combinatorial explosion of reaction patterns to be examined by narrowing the search space based on the kinetic analysis of the reaction path network, and would open a new paradigm beyond the conventional two-step approach, which requires a reaction path network prior to performing a kinetic simulation. The authors addressed this issue and developed a practical method by combining the artificial force induced reaction method with the rate constant matrix contraction method. Two algorithms are available for this purpose: a forward mode with reactants as the input and a backward mode with products as the input. This article first numerically verifies these modes for known reactions and then demonstrates their application to the actual reaction discovery. Finally, the challenges of this method and the prospects for ab initio reaction discovery are discussed.
Quantum chemical calculations have been used in the development of synthetic methodologies to analyze the reaction mechanisms of the developed reactions. Their ability to estimate chemical reaction ...pathways, including transition state energies and connected equilibria, has led researchers to embrace their use in predicting unknown reactions. This perspective highlights strategies that leverage quantum chemical calculations for the prediction of reactions in the discovery of new methodologies. Selected examples demonstrate how computation has driven the development of unknown reactions, catalyst design, and the exploration of synthetic routes to complex molecules prior to often laborious, costly, and time-consuming experimental investigations.
This perspective showcases how quantum chemical calculations drive predictive strategies to explore unknown reactions, catalysts, and synthetic routes toward complex molecules in synthetic methodology development.
Systematic reaction path exploration revealed the entire mechanism of Knowles's light‐promoted catalytic intramolecular hydroamination. Bond formation/cleavage competes with single electron transfer ...(SET) between the catalyst and substrate. These processes are described by adiabatic processes through transition states in an electronic state and non‐radiative transitions through the seam of crossings (SX) between different electronic states. This study determined the energetically favorable SET path by introducing a practical computational model representing SET as non‐adiabatic transitions via SXs between substrate's potential energy surfaces for different charge states adjusted based on the catalyst's redox potential. Calculations showed that the reduction and proton shuttle process proceeded concertedly. Also, the relative importance of SET paths (giving the product and leading back to the reactant) varies depending on the catalyst's redox potential, affecting the yield.
Systematic exploration of reaction paths based on quantum chemical calculations revealed the entire mechanism of Knowles's light‐promoted catalytic intramolecular hydroamination via radical processes. The energetically favorable reaction path was determined based on the reaction path searches and the SX geometry searches. The present calculations showed that the reduction and proton transfer proceed concertedly.
Herein, we developed a Ru(II)(BPGA) complex that could be used to catalyze chemo- and site-selective C-H oxidation. The described ruthenium complex was designed by replacing one pyridyl group on ...tris(2-pyridylmethyl)amine with an electron-donating amide ligand that was critical for promoting this type of reaction. More importantly, higher reactivities and better chemo-, and site-selectivities were observed for reactions using the cis-ruthenium complex rather than the trans-one. This reaction could be used to convert sterically less hindered methyne and/or methylene C-H bonds of a various organic substrates, including natural products, into valuable alcohol or ketone products.
The aim of this study is to understand adaptive immunity to SARS-CoV-2 through the analysis of B cell epitope and neutralizing activity in coronavirus disease 2019 (COVID-19) patients. We obtained ...serum from forty-three COVID-19 patients from patients in the intensive care unit of Osaka University Hospital (n = 12) and in Osaka City Juso Hospital (n = 31). Most individuals revealed neutralizing activity against SARS-CoV-2 assessed by a pseudotype virus-neutralizing assay. The antibody production against the spike glycoprotein (S protein) or receptor-binding domain (RBD) of SARS-CoV-2 was elevated, with large individual differences, as assessed by ELISA. We observed the correlation between neutralizing antibody titer and IgG, but not IgM, antibody titer of COVID-19 patients. In the analysis of the predicted the linear B cell epitopes, hot spots in the N-terminal domain of the S protein were observed in the serum from patients in the intensive care unit of Osaka University Hospital. Overall, the analysis of antibody production and B cell epitopes of the S protein from patient serum may provide a novel target for the vaccine development against SARS-CoV-2.
Background: Although aberrant proliferation and activation of lung fibroblasts are implicated in the initiation and progression of idiopathic pulmonary fibrosis (IPF), the underlying mechanisms are ...not well characterized. Numerous microRNAs (miRNAs) have been implicated in this process; however, miRNAs derived from exosomes and the relevance of such miRNAs to fibroblast-to-myofibroblast differentiation are not well understood. In this study, we attempted to identify exosome-derived miRNAs relevant to fibrosis development. Methods: Using miRNA array analysis, we profiled exosome-derived miRNA expression in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. After validating a selected miRNA by quantitative reverse-transcription polymerase chain reaction, its effect on fibroblast-to-myofibroblast differentiation was investigated in human lung fibroblasts. Furthermore, we determined the role of the selected miRNA in an in vivo model of pulmonary fibrosis. Results: MiRNA array analysis revealed that miR-22 expression was increased by up to 2 fold on day 7 after bleomycin treatment compared with that in vehicle-treated mice. In vitro, miR-22 transfection suppressed TGF-β1-induced α-SMA expression. This was mediated via inhibition of the ERK1/2 pathway. Baseline α-SMA expression was increased upon miR-22 inhibitor transfection. Furthermore, miR-22 negatively regulated connective tissue growth factor expression in the presence of TGF-β1. In vivo, administration of a miR-22 mimic on day 10 after bleomycin challenge ameliorated pulmonary fibrosis lesions accompanied by decreased α-SMA expression in the model mice. Conclusions: Exosomal miR-22 modulates fibroblast-to-myofibroblast differentiation. The present findings warrant further study, which could shed light on miR-22 as a novel therapeutic target in IPF.
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