Selective recognition between aromatics and aliphatics by cage-shaped borates supported by a machine learning approach.

Selective recognition between hydrocarbon moieties is a longstanding issue. Although we developed a π-pocket Lewis acid catalyst with high selectivity for aromatic aldehydes over aliphatic ones, a general strategy for catalyst design remains elusive. As an approach that transfers the molecular recognition based on multiple cooperative non-covalent interactions within the π-pocket to a rational catalyst design, herein, we demonstrate Lewis acid catalysts showing improved selectivity through the support of an ensemble algorithm with random forest, Ada Boost, and XG Boost as a machine learning (ML) approach. Using 7963 explanatory variables extracted from model hetero-Diels-Alder reactions, the ensemble algorithm predicted the chemoselectivity of unlearned catalysts. Experiments confirmed the prediction. The proposed catalyst shows the highest selective recognition, reminiscing enzymatic catalytic activity. Additionally, a SHapley Additive exPlanations (SHAP) method suggested that the selectivity originates from the polarizability and three-dimensional size of the catalyst. This insight leads to rational design guidelines for Lewis acid catalysts with dispersion forces.

Sequential C-F Bond Transformation of the Difluoromethylene Unit in Perfluoroalkyl Groups: A Combination of Fine-Tuned Phenothiazine Photoredox Catalyst and Lewis Acid.

A sequential process via photoredox catalysis and Lewis acid mediation for C-F bond transformation of the CF2 unit in perfluoroalkyl groups has been achieved to transform perfluoroalkylarenes into complex fluoroalkylated compounds. A phenothiazine-based photocatalyst promotes the defluoroaminoxylation of perfluoroalkylarenes with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) under visible light irradiation, affording the corresponding aminoxylated products. These products undergo a further defluorinative transformation with various organosilicon reagents mediated by AlCl3 to provide highly functionalized perfluoroalkyl alcohols. Our novel phenothiazine catalyst works efficiently in the defluoroaminoxylation. Transient absorption spectroscopy revealed that the catalyst regeneration step is crucial for the photocatalytic aminoxylation.

Synthesis and Characterization of Dibenzothieno[a,f]pentalenes Enabling Large Antiaromaticity and Moderate Open-Shell Character through a Small Energy Barrier for Bond-Shift Valence Tautomerization.

Experimental and theoretical rationalization of bond-shift valence tautomerization, characterized by double-well potential surfaces, is one of the most challenging topics of study among the rich electronic properties of antiaromatic molecules. Although the pseudo-Jahn-Teller effect (PJTE) is an essential effect to provide attractive characteristics of 4nπ systems, an understanding of the structure-property relationship derived from the PJTE for planar 4nπ electron systems is still in its infancy. Herein, we describe the synthesis and characterization of two regioisomers of the thiophene-fused diareno[a,f]pentalenes 6 and 7. The magnetic and optoelectronic properties characterize these sulfur-doped diareno[a,f]pentalenes as open-shell antiaromatic molecules, in sharp contrast to the closed-shell antiaromatic systems of 3 and 5, in which these main cores consist of the same number of π electrons as 6 and 7. Notably, thiophene-fused 6b and 7b showed pronounced antiaromaticity, the strongest among the previous systems, as well as moderate open-shell characteristics. Our experimental and theoretical investigations concluded that these properties of 6b and 7b are derived from the small energy barrier Ea‡ for the bond-shift valence tautomerization. The energy profile of the single crystal of 6b showed the temperature-dependent structural variations assigned to the dynamic mutual exchange between the two Cs-symmetric structures, which was also supported by changes in the chemical shifts of variable-temperature 1H NMR spectra in the solution phase. Both experimental and computational results revealed the importance of introducing heteroaromatic rings into 4nπ systems for controlling the PJTE and manifesting the antiaromatic and open-shell natures originating from the high-symmetric structure. The findings of this study advance the understanding of antiaromaticity characterized by the PJTE by controlling the energy barrier for bond-shift valence tautomerizations, potentially leading to the rational design of optoelectronic devices based on novel antiaromatic molecules possessing the strong contributions of their high-symmetric geometries.

Cage-Shaped Phosphites Having C3 -Symmetric Chiral Environment: Steric Control of Lewis Basicity and Application as Chiral Ligands in Rhodium-Catalyzed Conjugate Additions.

Designing chiral ligands with an axial symmetry higher than C2 -rotational symmetry is one of the most crucial approaches to improving enantioselectivity in asymmetric synthesis. Herein, C3 -symmetric chiral cage-shaped phosphites are reported. Their Lewis basicity and chiral environment are precisely controlled by the tethered group. The cage-shaped phosphites successfully worked as chiral ligands in Rh-catalyzed asymmetric conjugate additions, realizing acceptable yields with excellent enantioselectivity, and were used to synthesize a pharmacologically important molecule.

Synthesis and Characterization of Hexafluorocyclopentane-Bridged Bisbutatrienes as Models for Longer Cumulenes: Various Transformations for the Construction of π-Conjugated Frameworks.

Cumulenes have attracted considerable attention due to their unique structural and electronic properties. Despite their high potential for constructing condensed π-conjugated molecules, the synthetic utility of longer cumulenes remains to be established owing to their inherently high reactivity. Conjugated bisbutatrienes having two cumulene moieties linked by a spacer as a mimic of a longer cumulene were evaluated. Here, the synthesis and characterization of hexafluorocyclopentane-bridged bisbutatrienes are described. These bisbutatrienes underwent various cyclizations, to construct the unique π-extended frameworks inaccessible by other methodologies. The bisbutatrienes were converted into fulvenes, pentalene, germacycle, and benzocyclobutene under various conditions. Furthermore, a cyclooctatetraene derivative was synthesized by a one-step dimerization of the bisbutatriene.

Lipopolysaccharide Priming Exacerbates Anaphylatoxin C5a-Induced Anaphylaxis in Mice.

Anaphylaxis is a serious allergic or hypersensitivity reaction with a sudden onset that can be life-threatening or fatal. Previous studies have highlighted two pathways of anaphylaxis in mice. One is the classical immunoglobulin E (IgE)-mediated pathway that involves mast cells and histamine. The other is an alternative IgG-mediated pathway that involves basophils, monocytes/macrophages, neutrophils, and the platelet-activating factor (PAF). However, little is known about the mechanism by which complement anaphylatoxins contribute to the induction of anaphylaxis. Infection is a cofactor that potentially amplifies the risk of anaphylaxis. Here, we showed that priming with a lipopolysaccharide (LPS), which mimics bacterial infection, exacerbates anaphylatoxin C5a-induced anaphylaxis in mice. LPS plus C5a-induced anaphylaxis was mediated by histamine and lipid mediators, especially PAF. Cell depletion experiments demonstrated that LPS plus C5a-induced anaphylaxis depended on monocytes/macrophages, basophils, and neutrophils. These results suggest that C5a is a potent inducer of anaphylaxis in bacterial infections. Remarkably, the molecular and cellular mediators of LPS plus C5a-induced anaphylaxis are mostly shared with IgE- and IgG-mediated anaphylaxis. Therefore, combined inhibition of histamine and PAF may be beneficial as a second-line treatment for severe anaphylaxis.

Plasma levels and urinary excretion of protein Z in patients with urolithiasis.

OBJECTIVES: Protein Z (PZ) is a γ-carboxyglutamic acid protein present in plasma that is involved in blood coagulation. Detailed analysis of urinary stones from patients with urolithiasis has revealed that PZ is often found in urinary stones composed of calcium oxalate monohydrate. In this study, we compared blood and urinary PZ concentrations between healthy individuals and patients with urolithiasis. METHODS: Plasma and urine were collected from healthy individuals and patients with urolithiasis who provided informed consent. PZ was detected as a urinary stone matrix protein in some of the patients. PZ was quantified by ELISA, creatinine was measured by the enzymatic method, and the total protein concentration was measured by the Bradford method. RESULTS: The plasma PZ level was 2.54 ± 1.02 µg/mL in healthy individuals and that in urolithiasis patients classified by stone history were from 1.16 ± 0.77 to 3.73 ± 1.09 µg/mL, which was not significantly different. The urinary excretion of PZ (PZ/creatinine) was also not different in patients with urolithiasis and in healthy individuals (from 54.1 ± 40.9 to 95.4 ± 69.4 ng/mg vs. 73.3 ± 36.0 ng/mg). A positive correlation was found between the plasma PZ level and creatinine-corrected urinary PZ concentration (r = 0.46). CONCLUSIONS: Both the plasma level and urinary excretion of PZ in urolithiasis patients were not significantly different with normal individuals. PZ detected in urinary stones as a matrix protein is thought to be incorporated into urinary stones regardless of blood and urine levels of PZ.

Bis-periazulene (Cyclohepta[def]fluorene) as a Nonalternant Isomer of Pyrene: Synthesis and Characterization of Its Triaryl Derivatives.

Bis-periazulene (cyclohepta[def]fluorene), which is an unknown pyrene isomer, was synthesized as kinetically protected forms. Its triaryl derivatives 1c-e exhibited the superimposed electronic structures of peripheral, polarized, and open-shell π-conjugated systems. In contrast to previous theoretical predictions, bis-periazulene derivatives were in the singlet ground state. Changing an aryl group controlled the energy gap between the lowest singlet-triplet states.

Carboboration-Driven Generation of a Silylium Ion for Vinylic C-F Bond Functionalization by B(C6 F5 )3 Catalysis.

Strong main-group Lewis acids such as silylium ions are known to effectively promote heterolytic C(sp3 )-F bond cleavage. However, carrying out the C(sp2 )-F bond transformation of vinylic C-F bonds has remained an unmet challenge. Herein, we describe our development of a new and simple strategy for vinylic C-F bond transformation of α-fluorostyrenes with silyl ketene acetals catalyzed by B(C6 F5 )3 under mild conditions. Our theoretical calculations revealed that a stabilized silylium ion, which is generated from silyl ketene acetals by carboboration, cleaves the C-F bond of α-fluorostyrenes. A comparative study of α-chloro or bromostyrenes demonstrated that our reaction can be applied only to α-fluorostyrenes because the strong silicon-fluorine affinity facilitates an intramolecular interaction of silylium ions with fluorine atom to cleave the C-F bond. A broad range of α-fluorostyrenes as well as a range of silyl ketene acetals underwent this C-F bond transformation.

Synthesis of Cage-Shaped Borates Bearing Pyrenylmethyl Groups: Efficient Lewis Acid Catalyst for Photoactivated Glycosylations Driven by Intramolecular Excimer Formation.

We describe the synthesis and characterization of a photoactivated boron-based Lewis acid catalyst based on a cage-shaped triphenolic ligand with three pyrenylmethyl moieties. The obtained cage-shaped borate functioned as a photoactivated Lewis acid catalyst thanks to the flexible three pyrenylmethyl moieties. The deformation of the cage-shaped scaffold driven by intramolecular excimer formations of the pyrenes is a critical factor in realizing the photoactivation. Mannich-type reactions and glycosylations significantly were accelerated under 370 nm light irradiations. It is noteworthy that various glycosyl fluorides, which are not easily activated in photocatalytic systems due to their high C-F bond stability, are activated by the photoimproved catalytic activity of the catalyst.

Lewis Acid-Catalyzed Diastereoselective C-C Bond Insertion of Diazo Esters into Secondary Benzylic Halides for the Synthesis of α,ß-Diaryl-ß-haloesters.

We report a formal carbon-carbon (C-C) bond insertion via the reaction of secondary benzylic halides (fluorides, chlorides, and bromides) with α-diazo esters catalyzed by Lewis acid catalysts. Secondary benzylic halides underwent elongation to afford α,ß-diaryl-ß-haloesters diastereoselectively. Density functional theory calculation revealed that the present formal C-C bond insertion was the result of Lewis acid-promoted cleavage and the re-formation of a carbon-halogen bond and that the aryl-migration step determined the diastereoselectivity. Various diarylmethyl halides and α-diazo esters were applicable to this reaction system. In addition, ring expansion in cyclic benzylic chlorides was accomplished.

anti-Selective Borylstannylation of Alkynes with (o-Phenylenediaminato)borylstannanes by a Radical Mechanism.

We have achieved the first anti-borylstannylation of alkynes by using (o-phenylenediaminato)borylstannanes. This reaction afforded 1-boryl-2-stannylalkenes with excellent regio- and stereoselectivity by a radical mechanism. This anti-addition manner is in sharp contrast to the syn-selectivity obtained during transition metal-catalyzed borylstannylation. The mild radical conditions enabled a broad substrate scope, and various types of aromatic and aliphatic alkynes were applicable. The origin of regio- and stereoselectivity was elucidated by DFT calculation of the reaction mechanism. The application of the borylstannylation products to cross- or homocoupling reactions provided ready access to either triarylethenes or bisborylbutadienes.

Photoredox-Catalyzed C-F Bond Allylation of Perfluoroalkylarenes at the Benzylic Position.

Site-selective and direct C-F bond transformation of perfluoroalkylarenes was achieved with allylic stannanes via an iridium photoredox catalyst system. The present defluoroallylation proceeds exclusively at the benzylic position through perfluoroalkyl radicals generated by a single-electron transfer from an excited photoredox catalyst to perfluoroalkylarenes. A variety of perfluoroalkyl groups are applicable: linear perfluoroalkyl-substituted arenes such as Ar-nC4F9 and Ar-nC6F13 and heptafluoroisopropylarenes (Ar-CF(CF3)2) underwent site-selective defluoroallylation. DFT calculation studies revealed that the in situ generated Bu3SnF traps F- to prevent a retroreaction from the unstable perfluoroalkyl radical intermediate, and the radical intermediate favorably reacts with allylic stannanes. The synthesis of a bis(trifluoromethyl)methylene unit containing compound, which is an analog that is useful as a pharmaceutical agent for the prophylaxis or treatment of diabetes and inflammatory diseases, demonstrated the utility of this reaction.

Insertion of Diazo Esters into C-F Bonds toward Diastereoselective One-Carbon Elongation of Benzylic Fluorides: Unprecedented BF3 Catalysis with C-F Bond Cleavage and Re-formation.

Selective transformation of C-F bonds remains a significant goal in organic chemistry, but C-F insertion of a one-carbon-atom unit has never been established. Herein we report the BF3-catalyzed formal insertion of diazo esters as one-carbon-atom sources into C-F bonds to accomplish one-carbon elongation of benzylic fluorides. A DFT calculation study revealed that the BF3 catalyst could contribute to both C-F bond cleavage and re-formation. This elongation provided α-fluoro-α,ß-diaryl esters with a high level of diastereoselectivity. Various benzylic fluorides and diazo esters were applicable. The synthetic utility of this method was demonstrated by the synthesis of a fluoro analogue of a compound that is used as a transient receptor and potential canonical channel inhibitor.

Thymic stromal lymphopoietin contributes to protection of mice from Strongyloides venezuelensis infection by CD4+ T cell-dependent and -independent pathways.

When animals are infected with helminthic parasites, resistant hosts mount type II helper T (Th2) immune responses to expel worms. Recent studies have clearly shown that epithelial cell-derived cytokines contribute to the induction of Th2 immune responses. Here we demonstrate the role of endogenous thymic stromal lymphopoietin (TSLP) for protection against Strongyloides venezuelensis (S. venezuelensis) infection, utilizing TSLP receptor-deficient Crlf2-/- mice. The number of eggs per gram of feces (EPG) and worm burden were significantly higher in Crlf2-/- mice than in wild type (WT) mice. S. venezuelensis infection induced Tslp mRNA expression in the skin, lung, and intestine and also facilitated the accumulation of mast cells in the intestine in a TSLP-dependent manner. Furthermore, CD4+ T cells from S. venezuelensis-infected Crlf2-/- mice showed diminished capacity to produce Th2 cytokines in the early stage of infection. Finally, CD4+ cell-depleted Crlf2-/- mice still showed higher EPG counts and worm burden than CD4+ cell-depleted WT mice, indicating that TSLP contributes to protecting mice against S. venezuelensis infection in both CD4+ T cell-dependent and -independent manners.

Indium-Catalyzed C-F Bond Transformation through Oxymetalation/ß-Fluorine Elimination to Access Fluorinated Isocoumarins.

Fluorinated heterocycles have attracted much attention in the pharmaceutical and agrochemical industries. Many strategies have already been developed to achieve the synthesis of fluorinated heterocycles. Formidable challenges remain, however, in the synthesis of fluorinated isocoumarin derivatives that are among the most alluring structural motifs. Herein, the indium-catalyzed C-F bond transformation of 2-(2,2-difluorovinyl) benzoates is reported, which are readily accessible compounds, to give a diverse array of fluorinated isocoumarins. The present reaction proceeds smoothly using inexpensive reagents: a catalytic amount of indium salt in the presence of zinc salt. A theoretical calculation of potential energy profiles showed that the reaction consists of oxymetalation with the elimination of alkyl halide and the ß-fluorine elimination.

Indium-Catalyzed C-F Bond Transformation through Oxymetalation/ß-Fluorine Elimination to Access Fluorinated Isocoumarins.

Invited for the cover of this issue are Yoshihiro Nishimoto, Makoto Yasuda and co-workers at Osaka University and MOLSIS Inc.. The image depicts the crafting of a gladiator's shield to represent the reaction reported in this work. Read the full text of the article at 10.1002/chem.202100672.

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

Invited for the cover of this issue are Kensuke Suzuki, Yoshihiro Nishimoto and Makoto Yasuda from Osaka University. The image depicts a circus trapeze act, with different elements of the picture representing components of the borylation reaction reported in this work. Read the full text of the article at 10.1002/chem.202004692.

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

(o-Phenylenediamino)borylstannanes were newly synthesized to achieve radical boryl substitutions of a variety of alkyl radical precursors. Dehalogenative, deaminative, decharcogenative, and decarboxylative borylations proceeded in the presence of a radical initiator to give the corresponding organic boron compounds. Radical clock experiments and computational studies have provided insights into the mechanism of the homolytic substitution (SH 2) of the borylstannanes with alkyl radical intermediates. DFT calculation disclosed that the phenylenediamino structure lowered the LUMO level including the vacant p-orbital on the boron atom to enhance the reactivity to alkyl radicals in SH 2. Moreover, C(sp3 )-H borylation of THF was accomplished using the triplet state of xanthone.

Synthesis of (Z)-ß-(Carbonylamino)alkenylindium through Regioselective anti-Carboindation of Ynamides and Its Transformation to Multisubstituted Enamides.

The regioselective anti-carboindation of ynamides by using InBr3 and silylated nucleophiles was developed to synthesize (Z)-ß-(carbonylamino)alkenylindiums. The X-ray crystallographic analysis of an alkenylindium suggested that the reaction proceeded in an anti-addition fashion. In contrast to reported syn-carbometalations of ynamides by using organometallics, a cooperation of InBr3 and silylated nucleophiles to ynamides achieved an anti-addition, which was supported by DFT calculations. The scope of substrates included various ynamides and silylated nucleophiles, such as silyl ketene acetals and silyl ketene imines. The transformation of synthesized alkenylindiums by iodination, radical coupling, and Pd-catalyzed cross-coupling successfully afforded trisubstituted enamines with high regio- and stereoselectivities.