Chemical Aspect of Displacive-Type Ferroaxial Phase Transition from Perspective of Second-Order Jahn-Teller Effect: NASICON Systems as an Example.

Ferroaxial order, characterized by a rotational arrangement of electric dipoles, attracts increasing attention in terms of a new family of ferroic orders. However, there has been no chemical guideline for exploring crystalline materials showing ferroaxial order, namely ferroaxial materials. Here, we present a chemical guideline grounded in staggered polyhedral connectivity, which we propose as a structural prerequisite for ferroaxial order, and the second-order Jahn-Teller (SOJT) theory extended from molecular orbitals to electronic band structures. Na-superionic conductors (NASICON) including NaM2(PO4)3 (M = early-transition or post-transition metal) are identified as potential ferroaxial materials because of their staggered structures composed of MO6 octahedra and PO4 tetrahedra. However, ferroaxial phase transitions hardly occur in some of the NASICON systems, which offers a platform to uncover a hidden factor playing an important role in driving this system into ferroaxial states. Our first-principles calculations demonstrate that a ferroaxial phase transition in NASICON systems occurs only when SOJT interaction is symmetrically allowed, that is, energy-lowering chemical bonds are formed as a consequence of the distortion. Our proposals would be not limited to NASICON systems but applicable to a variety of compounds and provide new insight into the exploration of displacive-type ferroaxial materials.

C-F Transformations of Benzotrifluorides by the Activation of Ortho-Hydrosilyl Group.

Single C-F transformations of aromatic trifluoromethyl compounds are challenging issues due to the strong C-F bond. We have recently developed selective methods for single C-F transformations such as allylation of o-hydrosilyl-substituted benzotrifluorides through the hydride abstraction with trityl cations. Single C-F thiolation and azidation of o-(hydrosilyl)benzotrifluorides were achieved using trityl sulfides and trityl azide catalyzed by Yb(OTf)3 . Treatment of o-(hydrosilyl)benzotrifluorides with trityl chloride resulted in single C-F chlorination. The resulting fluorosilyl group served in further transformations including protonation, halogenation, and Hiyama cross-coupling with C-Si cleavage. We also synthesized benzyl fluorides by LiAlH4 -reduction of the resulting fluorosilanes and further C-F transformations. These methods enabled us to prepare a broad range of organofluorines from simple benzotrifluorides through C-F and C-Si transformations.

Facile synthesis of sulfinate esters from aryl iodides via direct oxidation of thioesters.

A practical method to synthesize sulfinate esters from aryl iodides is disclosed. Direct oxidation of thioesters prepared by copper-catalyzed C-S formation of aryl iodides realized the efficient synthesis of sulfinate esters. Due to the good accessibility of aryl iodides, a wide variety of sulfinate esters were prepared from easily available starting materials such as carboxylic acids and anilines.

Topochemical Synthesis of LiCoF3 with a High-Temperature LiNbO3-Type Structure.

A novel perovskite fluoride, LixCoF3, which has an exceptionally low tolerance factor (0.81), has been synthesized via low-temperature lithium intercalation into a distorted ReO3-type fluoride CoF3 using organolithium reagents. Interestingly, this reaction is completed within 15 min at room temperature. Synchrotron X-ray diffractometry and optical second harmonic generation at room temperature have revealed that this compound shows a high-temperature LiNbO3-type structure (space group: R3̅c) involving Li-Co antisite defects and A-site splitting along the c direction. A-site splitting is consistent with the prediction based on hybrid Hartree-Fock density functional theory calculations. Co-L2,3 edge X-ray absorption spectroscopy, as well as bond valence sum analysis, has verified the divalent oxidation state of Co ions in the lithiated phase, suggesting that its composition is close to LiCoF3 (x ≈ 1). This compound exhibits a paramagnetic-to-antiferromagnetic transition at 36 K on cooling, accompanied by weak ferromagnetic ordering. The synthetic route based on low-temperature lithiation of metal fluorides host paves the way for obtaining a new LiNbO3-type fluoride family.

Modular synthesis of triazoles from 2-azidoacrylamides having a nucleophilic amino group.

Assembling methods using 2-azidoacrylamides having a nucleophilic amino group are disclosed. Divergent transformations of the amine-type trivalent platform were accomplished with a wide variety of electrophiles to obtain a broad range of 2-azidoacrylamides involving a fluorosulfonyl group-containing trivalent platform. Consecutive click conjugations including triazole formation, thiol-ene-type 1,4-addition, and SuFEx reactions realized the efficient assembly of easily available simple modules.

HaloTag-based conjugation of proteins to barcoding-oligonucleotides.

Highly sensitive protein quantification enables the detection of a small number of protein molecules that serve as markers/triggers for various biological phenomena, such as cancer. Here, we describe the development of a highly sensitive protein quantification system called HaloTag protein barcoding. The method involves covalent linking of a target protein to a unique molecule counting oligonucleotide at a 1:1 conjugation ratio based on an azido-cycloalkyne click reaction. The sensitivity of the HaloTag-based barcoding was remarkably higher than that of a conventional luciferase assay. The HaloTag system was successfully validated by analyzing a set of protein-protein interactions, with the identification rate of 44% protein interactions between positive reference pairs reported in the literature. Desmoglein 3, the target antigen of pemphigus vulgaris, an IgG-mediated autoimmune blistering disease, was used in a HaloTag protein barcode assay to detect the anti-DSG3 antibody. The dynamic range of the assay was over 104-times wider than that of a conventional enzyme-linked immunosorbent assay (ELISA). The technology was used to detect anti-DSG3 antibody in patient samples with much higher sensitivity compared to conventional ELISA. Our detection system, with its superior sensitivity, enables earlier detection of diseases possibly allowing the initiation of care/treatment at an early disease stage.

Electronic Origin of Non-Zone-Center Phonon Condensation: Octahedral Rotation as a Case Study.

Unstable zone-boundary phonon modes drive atomic displacements linked to a rich array of properties. Yet, the electronic origin of the instability remains to be clearly explained. In this Letter, we propose that bonding interaction between Bloch states belonging to different wave vectors leads to such instability via the pseudo- or second-order Jahn-Teller effect. Our first-principles calculations and representation theory-based analyses show that rotations of anion coordinated octahedra, an archetypal example of zone-boundary phonon condensations, are induced by this bonding mechanism. The proposed mechanism is universal to any non-zone-center phonon condensations and could offer a general approach to understanding the origin of structural phase transitions in crystals.

Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface.

Prostaglandin E receptor EP4, a G-protein-coupled receptor, is involved in disorders such as cancer and autoimmune disease. Here, we report the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution. The structure reveals that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain. Functional and docking studies demonstrate that the natural agonist PGE2 binds in a similar manner. This structural information also provides insight into the ligand entry pathway from the membrane bilayer to the EP4 binding pocket. Furthermore, the structure reveals that the antibody allosterically affects the ligand binding of EP4. These results should facilitate the design of new therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.

Synthesis of Azidoanilines by the Buchwald-Hartwig Amination.

We report a Buchwald-Hartwig amination compatible with azido functionality. Treatment of azidoaryl iodides and amines with fourth-generation Buchwald precatalyst coordinated by CPhos and sodium tert-butoxide in 1,4-dioxane at 50 °C afforded the corresponding azidoanilines while leaving the azido groups intact. The method showed a broad substrate scope and was applicable to the synthesis of diazido compounds as photoaffinity probe candidates of pharmaceutical amines and multiazido platform molecules.

A novel yellow fluorescent protein of recombinant apoPholasin with dehydrocoelenterazine.

Pholasin is classified as a photoprotein and comprises apoPholasin (an apoprotein of pholasin) and an unknown prosthetic group as the light-emitting source. The luminescence reaction of pholasin is triggered by reactive oxygen species. Recombinant apoPholasin was recently expressed as a fusion protein of glutathione S-transferase (GST-apoPholasin) and purified from E. coli cells. By incubating non-fluorescent dehydrocoelenterazine (dCTZ, dehydrogenated form of CTZ) with GST-apoPholasin, the complex of GST-apoPholasin and dCTZ (GST-apoPholasin/dCTZ complex) was formed immediately and showed bright yellow fluorescence (λmax = 539 nm, excited at 430 nm). Unexpectedly, the fluorescent chromophore of the GST-apoPholasin/dCTZ complex was identified as non-fluorescent dCTZ. The luminescence intensity of the GST-apoPholasin/dCTZ complex was increased in a catalase-H2O2 system, but not in sodium hypochlorite.

Synthesis of Diverse Aromatic Ketones through C-F Cleavage of Trifluoromethyl Group.

An efficient synthetic method of aromatic ketones through C-F cleavage of trifluoromethyl group is disclosed. The high functional group tolerance of the transformation and the remarkable stability of trifluoromethyl group in various reactions enabled multi-substituted aromatic ketone synthesis in an efficient route involving useful transformations such as ortho-lithiation, aryne chemistry, and cross-couplings.

Functionalization of a Single C-F Bond of Trifluoromethylarenes Assisted by an ortho-Silyl Group Using a Trityl-Based All-in-One Reagent with Ytterbium Triflate Catalyst.

Catalytic thiolation and azidation of a single C-F bond of trifluoromethylarenes were achieved assisted by an ortho-silyl group with all-in-one reagents to generate a trityl cation and nucleophiles. The reactions catalyzed by ytterbium triflate efficiently afforded a wide variety of difluoromethylenes avoiding the further C-F bond cleavage, by virtue of the mild conditions without the generation of a Brønsted acid.

Consecutive Aryne Generation Strategy for the Synthesis of 1,3-Diarylpyrazoles.

An efficient method for the synthesis of diverse 1,3-diarylpyrazoles via consecutive aryne generation has been developed. The bisaryne precursors bearing o-iodo- and o-silylaryl triflate moieties were prepared by sequential Suzuki-Miyaura and Chan-Lam-Evans cross-coupling reactions. The selective generation of the first aryne triggered by a silylmethyl Grignard reagent followed by the second aryne generation mediated by a fluoride ion allowed for the synthesis of diverse multisubstituted 1,3-diarylpyrazoles in a modular synthetic manner with various arynophiles.

Sequential conjugation methods based on triazole formation and related reactions using azides.

The recent remarkable progress in azide chemistry has realized sequential conjugation methods with selective 1,2,3-triazole formation. On the basis of the diverse reactivities of azides and azidophiles, including terminal alkynes and cyclooctynes, various selective reactions to furnish triazoles and a wide range of platform molecules, such as diynes, diazides, triynes, and triazides, have been developed so far for bis- and tris(triazole) syntheses. This review highlights recent transformations involving selective triazole formation, allowing the efficient preparation of unsymmetric bis- and tris(triazole)s using diverse platform molecules.

Effect of Ammonia on Methane Hydrate Stability under High-Pressure and High-Temperature Conditions.

High-pressure experiments were conducted to investigate the stability and phase transition of methane hydrate (MH) in the water-methane-ammonia system at room-to-high temperatures employing Raman spectroscopy and synchrotron X-ray powder diffraction, in combination with an externally heated diamond anvil cell. The results revealed that, at room temperature, MH undergoes phase transitions from MH-I to MH-II at ∼1.0 GPa and from MH-II to MH-III at ∼2.0 GPa. These transition behaviors are consistent with those in the water-methane system, which indicates that ammonia has a negligible effect on a series of phase transitions of MH. Contrarily, a sequential in situ Raman spectroscopy revealed that ammonia affects the stability of MH-III under high pressure and high temperature: the dissociation temperature of MH-III was more than 10 K lower in the water-methane-ammonia system than in the water-methane system. These findings aid in improving the internal structural models of icy bodies and estimating the origin of their atmospheric methane.

Structural evolution of methane hydrate under pressures up to 134 GPa.

High-pressure experiments were performed to understand the structural evolution of methane hydrate (MH) up to 134 GPa using x-ray powder diffraction (XRD) and Raman spectroscopy with diamond anvil cells. XRD revealed the distinct changes in the diffraction lines of MH owing to phase transition from a guest-ordered state phase [MH-III(GOS)] to a new high-pressure phase (MH-IV) at 33.8-57.7 GPa. MH-IV was found to be stable up to at least 134 GPa without decomposition into solid methane and high-pressure ices. Raman spectroscopy showed the splits in the C-H vibration modes ν3 and ν1 of guest methane molecules in filled-ice Ih (MH-III) at 12.7 GPa and 28.6 GPa, respectively. These splits are caused by orientational ordering of guest methane molecules contained in the hydrate structure, as observed in a previous study. These results suggest that the structural evolution of the filled-ice structure of MH is caused by successive orientational ordering of guest methane molecules, thereby inducing changes in the host framework formed by water molecules.

Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice.

Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS. The oral administration of this compound, named ALGERNON (altered generation of neurons), restored NSC proliferation in murine models of DS and increased the number of newborn neurons. Moreover, administration of ALGERNON to pregnant dams rescued aberrant cortical formation in DS mouse embryos and prevented the development of abnormal behaviors in DS offspring. These data suggest that the neurogenic phenotype of DS can be prevented by ALGERNON prenatal therapy.

Hybrid Improper Ferroelectricity in (Sr,Ca)3Sn2O7 and Beyond: Universal Relationship between Ferroelectric Transition Temperature and Tolerance Factor in n = 2 Ruddlesden-Popper Phases.

Hybrid improper ferroelectricity, which utilizes nonpolar but ubiquitous rotational/tilting distortions to create polarization, offers an attractive route to the discovery of new ferroelectric and multiferroic materials because its activity derives from geometric rather than electronic origins. Design approaches blending group theory and first principles can be utilized to explore the crystal symmetries of ferroelectric ground states, but in general, they do not make accurate predictions for some important parameters of ferroelectrics, such as Curie temperature ( TC). Here, we establish a predictive and quantitative relationship between TC and the Goldschmidt tolerance factor, t, by employing n = 2 Ruddlesden-Popper (RP) A3B2O7 as a prototypical example of hybrid improper ferroelectrics. The focus is placed on an RP system, (Sr1- xCa x)3Sn2O7 ( x = 0, 0.1, and 0.2), which allows for the investigation of the purely geometric (ionic size) effect on ferroelectric transitions, due to the absence of the second-order Jahn-Teller active (d0 and 6s2) cations that often lead to ferroelectric distortions through electronic mechanisms. We observe a ferroelectric-to-paraelectric transition with TC = 410 K for Sr3Sn2O7. We also find that the TC increases linearly up to 800 K upon increasing the Ca2+ content, i.e., upon decreasing the value of t. Remarkably, this linear relationship is applicable to the suite of all known A3B2O7 hybrid improper ferroelectrics, indicating that the  TC correlates with the simple crystal chemistry descriptor, t, based on the ionic size mismatch. This study provides a predictive guideline for estimating the TC of a given material, which would complement the convergent group-theoretical and first-principles design approach.

Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia.

Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by missplicing of exon 20, resulting from an intronic mutation in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene encoding IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1). A newly established splicing reporter assay allowed us to visualize pathogenic splicing in cells and to screen small chemicals for the ability to correct the aberrant splicing of IKBKAP. Using this splicing reporter, we screened our chemical libraries and identified a compound, rectifier of aberrant splicing (RECTAS), that rectifies the aberrant IKBKAP splicing in cells from patients with FD. Here, we found that the levels of modified uridine at the wobble position in cytoplasmic tRNAs are reduced in cells from patients with FD and that treatment with RECTAS increases the expression of IKAP and recovers the tRNA modifications. These findings suggest that the missplicing of IKBKAP results in reduced tRNA modifications in patients with FD and that RECTAS is a promising therapeutic drug candidate for FD.

Construction of Condensed Polycyclic Aromatic Frameworks through Intramolecular Cycloaddition Reactions Involving Arynes Bearing an Internal Alkyne Moiety.

Facile synthetic methods for condensed polycyclic aromatic compounds via aryne intermediates are reported. The generation of arynes bearing a (3-arylpropargyl)oxy group from the corresponding o-iodoaryl triflate-type precursors efficiently afforded arene-fused oxaacenaphthene derivatives, which were formed through intramolecular [2+4] cycloaddition. Extending the method to the generation of arynes bearing a 1,3-diyne moiety led to a continuous generation of naphthalyne intermediate through the hexadehydro Diels-Alder reaction involving the aryne triple bond. This novel type of aryne-relay chemistry enabled the synthesis of a unique aminoarylated oxaacenaphthene derivative and highly ring-fused anthracene derivatives.