Structural Conversion of Supramolecular Assembly in Solution by Thermally Induced Intramolecular Electron Transfer of [Co2 Fe2 ] Complex.

Invited for the cover of this issue is the group of Masayuki Nihei at the University of Tsukuba. The image depicts the electron transfer-triggered structural conversion of the supramolecular assembly of a [Co2 Fe2 ] complex between reverse vesicles and entangled one-dimensional chains. Read the full text of the article at 10.1002/chem.202300954.

Structural Conversion of Supramolecular Assembly in Solution by Thermally Induced Intramolecular Electron Transfer of [Co2 Fe2 ] Complex.

Combining metal complexes with amphiphilic molecules leads to a wide variety of functional self-assembled nanostructures. Metal complexes exhibiting spin transitions can be good candidates as the trigger to cause structural conversion of such assembly because they respond to various external stimuli. In this work, we studied a structural conversion of a supramolecular assembly containing a [Co2 Fe2 ] complex through a thermally induced electron transfer-coupled spin transition (ETCST). With an amphiphilic anion, the [Co2 Fe2 ] complex formed reverse vesicles in solution and showed thermal ETCST. In contrast, thermal ETCST in the presence of a bridging hydrogen-bond donor caused structural conversion from the reverse vesicle structure to entangled one-dimensional chains through hydrogen bond formation.

Construction of Thienothiophene and Thienofuran Ring Systems via Ring Expansion of Difluorothiiranes Generated from Dithioesters.

The reaction of aryl thiophene-2-carbodithioates or thiophene-3-carbodithioates with difluorocarbene generated from BrCF2CO2Li/molecular sieves 4A produced arylsulfanylated 2,2-difluoro-3-thienylthiiranes. In the presence of lithium ion, the thiirane intermediates underwent ring expansion followed by HF elimination, leading to fluorinated thieno[3,2-b]thiophenes or thieno[2,3-b]thiophenes. The reactions of the oxygen analogues, aryl furancarbodithioates, also proceeded to afford the corresponding thieno[3,2-b]furans. Intramolecular fluorine substitution in the produced arylsulfanyl(fluoro)thienofurans allowed for another thiophene ring construction, leading to the synthesis of fused pentacyclic thienothienofurans.

Chemical Modification of Phage-Displayed Helix-Loop-Helix Peptides to Construct Kinase-Focused Libraries.

Conformationally constrained peptides hold promise as molecular tools in chemical biology and as a new modality in drug discovery. The construction and screening of a target-focused library could be a promising approach for the generation of de novo ligands or inhibitors against target proteins. Here, we have prepared a protein kinase-focused library by chemically modifying helix-loop-helix (HLH) peptides displayed on phage and subsequently tethered to adenosine. The library was screened against aurora kinase A (AurA). The selected HLH peptide Bip-3 retained the α-helical structure and bound to AurA with a KD value of 13.7 µM. Bip-3 and the adenosine-tethered peptide Bip-3-Adc provided IC50 values of 103 µM and 7.7 µM, respectively, suggesting that Bip-3-Adc bivalently inhibited AurA. In addition, the selectivity of Bip-3-Adc to several protein kinases was tested, and was highest against AurA. These results demonstrate that chemical modification can enable the construction of a kinase-focused library of phage-displayed HLH peptides.

Facile Synthesis of Thienoacenes via Transition-Metal-Free Ladderization.

Herein, we report a facile transition-metal-free approach to sulfur-containing heteroacenes from fluorinated oligophenylenes. Unlike most existing methods, the presented approach is not restricted to simple dibenzothiophene derivatives and thus appears to be a useful tool for the synthesis of extended sulfur-containing heteroacenes. The incorporation of sulfur is unambiguously preprogrammed via the positions of fluorines in the precursors, allowing the selective synthesis of extended thienoacenes with up to 96% yield.

Transition-metal free synthesis of N-aryl carbazoles and their extended analogs.

Herein, we describe a facile synthesis of N-arylated carbazoles via ladderization of fluorinated oligophenylenes. The reaction consists of two subsequent nucleophilic substitutions triggered by an electronic transfer from dimsyl anions. The reaction allows the effective one-pot formation of at least six C-N bonds with pronounced selectivity to the C-F bond placement.

Catalyst-Free Synthesis of O-Heteroacenes by Ladderization of Fluorinated Oligophenylenes.

A novel catalyst-free approach to benzoannulated oxygen-containing heterocycles from fluorinated oligophenylenes is reported. Unlike existing methods, the presented reaction does not require an oxygen-containing precursor and relies on an external oxygen source, potassium tert-butoxide, which serves as an O2- synthon. The radical nature of the reaction facilitates nucleophilic substitution even in the presence of strong electron-donating groups and enables de-tert-butylation required for the complete annulation. Also demonstrated is the applicability of the method to introduce five-, six-, and seven-membered rings containing oxygen, whereas multiple annulations also open up a short synthetic path to ladder-type O-heteroacenes and oligodibenzofurans.

Intramolecular Electron Transfers in a Series of [Co2Fe2] Tetranuclear Complexes.

Discrete cyanide-bridged Co-Fe multinuclear complexes can be considered as functional units of bulk Co-Fe Prussian blue analogues, and they have been recognized as a new class of switching molecules in the last decade. The switching property of the cyanide-bridged Co-Fe complexes is based on intramolecular electron transfers between Co and Fe ions, and we herein refer to this phenomenon as an electron transfer-coupled spin transition (ETCST). Although there have been numerous reports on the complexes exhibiting ETCST behavior, the systematic study of the substituent effects on the thermal ETCST equilibrium in solution has not been reported yet, and the rational control of the equilibrium temperature remains challenging. We report here the syntheses and thermal ETCST behavior both in the solid state and solution for a series of tetranuclear [Co2Fe2] complexes, [Co2Fe2(CN)6(L1)2(L2)4]X2 (L1 and L2: tri- and bidentate capping ligands for Fe and Co ions, X: counteranions). All complexes showed thermal ETCST equilibrium between high-spin ([(hs-CoII)2(ls-FeIII)2]) and low-spin ([(ls-CoIII)2(ls-FeII)2]) states in butyronitrile, and the equilibrium temperatures (T1/2) showed systematic shifts by chemical modifications and chemical stimuli. The T1/2 values were correlated with the redox potential differences (ΔE) of the Fe and Co ions in the constituent units, and the larger ΔE values led to the lower T1/2. The present result suggests that the thermal ETCST behavior in solution can be rationally designed by considering the redox potentials of the constituent molecules.

Establishment of an Evaluation Method for Gene Silencing by Serial Pulmonary Administration of siRNA and pDNA Powders: Naked siRNA Inhalation Powder Suppresses Luciferase Gene Expression in the Lung.

In order to evaluate the in vivo effect of inhaled formulations, it is a gold standard to create a lung metastasis model by intravenously injecting cancer cells into an animal. Because the cancer grows from the blood vessel side, there is a possibility of underestimating the effect of an inhaled formulation administered to the lung epithelium side. In addition, the metastasis model has disadvantages in terms of preparation time and expense. The present study aimed to establish a new method to evaluate the effect of an inhaled small interfering RNA (siRNA) formulation that is more correct, more rapid, and less expensive. We investigated whether siRNA can suppress gene expression of plasmid DNA (pDNA) by serial pulmonary administration of siRNA and pDNA powders prepared by spray-freeze-drying. We revealed that formulations of dry siRNA powder significantly suppressed gene expression of pDNA powder compared with a control group with no siRNA. Naked siRNA inhalation powder with no vector showed the suppression of gene expression equivalent to that of an siRNA-polyethyleneimine complex without damaging tissues. These results show that the present method is suitable for evaluating the gene-silencing effect of inhaled siRNA powders.

Solid-State Hydrogen-Bond Alterations in a [Co2 Fe2 ] Complex with Bifunctional Hydrogen-Bonding Donors.

A hydrogen-bonding donor-acceptor system, [Co2 Fe2 (bpy*)4 (CN)6 (tp*)2 ](PF6 )2 ⋅2ABA⋅4BN⋅2PE (1 solv ), was prepared by co-crystallization of an external stimuli-responsive cyanide-bridged tetranuclear [Co2 Fe2 ] complex and bifunctional hydrogen-bonding donors, p-aminobenzoic acid. Compound 1 solv exhibited a gradual electron-transfer-coupled spin transition (ETCST), and the removal of solvent molecules led to an abrupt thermal ETCST behavior with increased transition temperature. X-ray structural analysis revealed that the modification of ETCST was caused by a significant alteration of a hydrogen-bonding mode between the tetranuclear [Co2 Fe2 ]2+ cations and ABA molecules. Variable temperature IR measurements indicated that the desolvated form, 1 desolv , showed dynamic alteration of hydrogen-bonding interactions coupled with thermal ETCST behavior. These results suggested that the tetranuclear [Co2 Fe2 ] complex shows solid-state modulations of hydrogen-bond strengths by external stimuli.

Synthesis of Sulfanylated Difluoroalkenes: Electrophilic Difluoromethylidenation of Dithioesters with Difluorocarbene.

Electrophilic difluoromethylidenation of dithioesters was achieved in high yields via the reaction with difluorocarbene. When aryl or alkyl dithiocarboxylates were treated with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in the presence of 5 mol % of a Proton Sponge catalyst, the in situ generated difluorocarbene reacted with the dithioesters to afford 2-sulfanylated 1,1-difluoro-1-alkenes via difluorothiiranes. This reaction can be considered as an electrophilic counterpart of the Wittig-type difluoromethylidenation of carbonyl compounds with nucleophilic difluoromethylene ylides.

Regioselective Synthesis of α-Fluorinated Cyclopentenones by Organocatalytic Difluorocyclopropanation and Fluorine-Directed and Fluorine-Activated Nazarov Cyclization.

Silyl dienol ethers, prepared from α,ß-unsaturated ketones, underwent proton sponge-catalyzed difluorocyclopropanation with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in a regioselective manner, leading to 1,1-difluoro-2-siloxy-2-vinylcyclopropanes in good yields. The cyclopropanes thus obtained were in turn subjected to fluoride-ion-catalyzed ring opening to afford 1-fluorovinyl vinyl ketones (i.e., Nazarov precursors). Treatment of the precursors with Me3 Si+ B(OTf)4- regioselectively promoted the Nazarov cyclization, the rate and regioselectivity of which were drastically enhanced by the fluoro substituent, which thus facilitated efficient synthesis of biologically promising α-fluorocyclopentenone derivatives.