Synthesis and structure-activity relationship of violaceoid D, a cytotoxic alkylated phenol isolated from Aspergillus violaceofuscus Gasperini.

The enantioselective synthesis of violaceoid D, a cytotoxic phenolic compound isolated from the culture broth of Aspergillus violaceofuscus Gasperini, was achieved. The total synthesis involves stereoselective construction of the stereogenic center of violaceoid D via Sharpless asymmetric dihydroxylation, followed by Smiles rearrangement. The absolute configuration of natural violaceoid D was determined to be R from the specific rotation value. Synthesized violaceoid D and its analogs were evaluated for cytotoxicity against two human cancer cell lines, Jurkat and HCT116. Because the enantiomer of violaceoid D showed no cytotoxicity, it is plausible that violaceoid D binds selectively to specific target molecules, such as proteins in the cancer cells.

Synthesis and structure-activity relationship of kujigamberol B, a dinorlabdane diterpenoid isolated from an ancient Kuji amber.

The versatile methodology was developed for synthesizing kujigamberol B, a dinorlabdane diterpenoid isolated from the methanol extract of Kuji amber. A highly efficient intramolecular cyclization is followed by a Sonogashira-coupling reaction during the total synthesis. The synthesized compounds were evaluated for the growth-restoring activity against the mutant yeast (zds1Δ erg3Δ pdr1Δ pdr3Δ) and for the degranulation of RBL-2H3 cells. We found that in both activities, primary alcohol and secondary alcohol analogs are as active as kujigamberol B.

Disproof of the Proposed Structures of Bradyoxetin, a Putative Bradyrhizobium japonicum Signaling Molecule, and HMCP, a Putative Ralstonia solanacearum Quorum-Sensing Molecule.

First, we revisited the reported NMR data of bradyoxetin, a putative cell density factor of Bradyrhizobium japonicum, and found some inconsistencies in the proposed structure. To elucidate the correct structure, we synthesized model oxetane compounds and confirmed that the NMR data of the synthetic compounds did not match those of the reported bradyoxetin. After reinterpreting the reported NMR data, we concluded that bradyoxetin must be chloramphenicol. Next, some derivatives of 2-hydroxy-4-((methylamino)(phenyl)methyl)cyclopentanone (HMCP), which is a putative quorum-sensing molecule of Ralstonia solanacearum, were synthesized. The NMR spectra of the synthesized compounds were completely different from those of the reported natural products. Based on theoretical studies, including the estimation of 1H and 13C NMR chemical shifts using density functional theory calculations, we confirmed the correctness of the structure of the synthesized compound. These results strongly suggest that the proposed structure of HMCP could be incorrect.

Synthetic and Biological Studies of Juglorubin and Related Naphthoquinones.

Juglorubin, juglorescein, and juglocombins A/B are naturally occurring naphthoquinone dimers isolated from Streptomyces sp. These dimers are proposed to be biogenetically derived from juglomycin C, a monomeric naphthoquinone isolated from the same Streptomyces sp. In this study, the dimerization of a juglomycin C derivative, a key step in the total syntheses of these natural products, was investigated. Juglorubin was synthesized from the minor product of the dimerization via the formation of the juglocombin A/B stereoisomers. A mechanism for the dimerization reaction as well as a plausible biosynthetic pathway to obtain juglorubin from juglomycin C are proposed. Furthermore, the antibacterial and cytotoxic activities of five synthetic compounds were evaluated. Among the compounds tested in this study, 1'-O-methyljuglocombin B dimethyl ester and juglomycin C exhibited antibacterial activity against Bacillus subtilis. 1'-O-Methyljuglocombin B dimethyl ester and juglomycin C showed cytotoxicity against human colon carcinoma HCT116 cells and human leukemia HL-60 cells. 1'-O-Methyljuglocombin B dimethyl ester exhibited cytotoxicity against human normal MRC-5 cells as strong as that against human cancer cells. In contrast, juglomycin C was less toxic against normal MRC-5 cells, indicating a significant selectivity toward cancer cells.

Mechanistic Study on Aryl-Exchange Reaction of Diaryl-λ3-iodane with Aryl Iodide.

Because of its hyper-leaving ability, as well as its strong oxidizing ability, diaryl(triflato)-λ3-iodane transfers one of the aryl groups to iodoarenes simply upon gentle heating (>85 °C) in nonpolar solvents. We have performed an in-depth mechanistic study of this unusual aryl transfer reaction. A combination of experimental (product analysis, kinetic study, and substituent effects) and density functional theoretical approaches revealed that the reaction proceeds through a concerted bimolecular transition state, in which ipso-carbon binds loosely to both iodine centers. We also evaluated electronic effects on the thermodynamic stability of diaryl-λ3-iodanes.

Transition Metal-Free trans-Selective Alkynylboration of Alkynes.

We report the first transition metal-free and trans-selective alkynylboration reaction of alkynes. This unprecedented carboboration reaction is enabled by pseudo-intramolecular activation of alkynylboronates using propargylic alcohols. The carboboration affords 4-alkynyl-1,2-oxaborol-2(5H)-ols, which are not only versatile building blocks but also exhibit strong violet-blue fluorescence emission.

Direct Hydroxylation and Amination of Arenes via Deprotonative Cupration.

Deprotonative directed ortho cupration of aromatic/heteroaromatic C-H bond and subsequent oxidation with t-BuOOH furnished functionalized phenols in high yields with high regio- and chemoselectivity. DFT calculations revealed that this hydroxylation reaction proceeds via a copper (I → III → I) redox mechanism. Application of this reaction to aromatic C-H amination using BnONH2 efficiently afforded the corresponding primary anilines. These reactions show broad scope and good functional group compatibility. Catalytic versions of these transformations are also demonstrated.

Cross-Coupling of Organolithium with Ethers or Aryl Ammonium Salts by C-O or C-N Bond Cleavage.

Various aryl-, alkenyl-, and/or alkyllithium species reacted smoothly with aryl and/or benzyl ethers with cleavage of the inert C-O bond to afford cross-coupled products, catalyzed by commercially available [Ni(cod)2 ] (cod=1,5-cyclooctadiene) catalysts with N-heterocyclic carbene (NHC) ligands. Furthermore, the coupling reaction between the aryllithium compounds and aryl ammonium salts proceeded under mild conditions with C-N bond cleavage in the presence of a [Pd(PPh3 )2 Cl2 ] catalyst. These methods enable selective sequential functionalizations of arenes having both C-N and C-O bonds in one pot.

Rhodium-Catalyzed (Perfluoroalkyl)olefination of Acetanilides Leading to Perfluoroalkylated Aromatics.

We have developed an efficient Rh-catalyzed (perfluoroalkyl)olefination reaction of acetanilides, which provides a versatile synthetic entry to a range of perfluoroalkylated compounds.

Gold-Catalyzed Cyclization of Alkyne Alcohols: Regioselective Construction of Functionalized 6,6- and 6,7-Bicyclic Ethers.

We describe an efficient regioselective formation of six-/seven-membered cyclic ethers based on gold-catalyzed intramolecular hydroalkoxylation. Sequential gold-catalyzed cyclization and palladium-catalyzed cross-coupling reactions afforded 6,6-bicyclic ethers, while reversing the reaction sequence (cross-coupling then cyclization) afforded 6,7-bicyclic ethers. This methodology should provide access to a range of functional polycyclic ethers.

Organoaluminum-mediated direct cross-coupling reactions.

We present a direct cross-coupling reaction between arylaluminum compounds (ArAlMe2 ⋅LiCl) and organic halides RX (R=aryl, alkenyl, alkynyl; X=I, Br, and Cl) without any external catalyst. The reaction takes place smoothly, simply upon heating, thereby enabling the efficient and chemo-/stereoselective formation of biaryl, alkene, and alkyne coupling products with broad functional group compatibility.

Consideration on the Intergenerational Ethics on Uranium Waste Disposal.

PURPOSE OF REVIEW: This review provides insights into resolving intergenerational issues related to the disposal of waste containing high amounts of uranium (uranium waste), from which distant future generations will have higher health risks than the current generation. RECENT FINDINGS: Uranium (half-life: 4.5 billion years) produces various progeny radionuclides through radioactive decay over the long term, and its radioactivity, as the sum of its contributions, continues to increase for more than 100,000 years. In contrast to high-level radioactive wastes, protective measures, such as attenuation of radiation and confinement of radionuclides from the disposal facility, cannot work effectively for uranium waste. Thus, additional considerations from the perspective of intergenerational ethics are needed in the strategy for uranium waste disposal. The current generation, which has benefited from the use and disposal of uranium waste, is responsible for protecting future generations from the potential risk of buried uranium beyond the lifetime of a disposal facility. Fulfilling this responsibility means making more creative efforts to convey critical information on buried materials to the distant future to ensure that future generations can properly take measures to reduce the harm by themselves in response to changing circumstances including people's values.

Isolation, structural determination, and antiviral activities of a novel alanine-conjugated polyketide from Talaromyces sp.

Antiviral agents are highly sought after. In this study, a novel alkylated decalin-type polyketide, alaspelunin, was isolated from the culture broth of the fungus Talaromyces speluncarum FMR 16671, and its structure was determined using spectroscopic analyses (1D/2D NMR and MS). The compound was condensed with alanine, and its absolute configuration was determined using Marfey's method. Furthermore, the antiviral activity of alaspelunin against various viruses was evaluated, and it was found to be effective against both severe acute respiratory syndrome coronavirus 2 and pseudorabies (Aujeszky's disease) virus, a pathogen affecting pigs. Our results suggest that this compound is a potential broad-spectrum antiviral agent.

Synthesis of Carlactone Derivatives to Develop a Novel Inhibitor of Strigolactone Biosynthesis.

Strigolactones (SLs), phytohormones that inhibit shoot branching in plants, promote the germination of root-parasitic plants, such as Striga spp. and Orobanche spp., which drastically reduces the crop yield. Therefore, reducing SL production via chemical treatment may increase the crop yield. To design specific inhibitors, it is valid to utilize the substrate structure of the target proteins as lead compounds. In this study, we focused on Os900, a rice enzyme that oxidizes the SL precursor carlactone (CL) to 4-deoxyorobanchol (4DO), and synthesized 10 CL derivatives. The effects of the synthesized CL derivatives on SL biosynthesis were evaluated by the Os900 enzyme assay in vitro and by measuring 4DO levels in rice root exudates. We identified some CL derivatives that inhibited SL biosynthesis in vitro and in vivo.

Isolation, structural determination, and antiviral activities of metabolites from vanitaracin A-producing Talaromyces sp.

Vanitaracin A, an anti-hepatitis B virus polyketide, has been previously isolated from Talaromyces sp. In the present study, we searched for novel compounds in the culture broth obtained from a vanitaracin A-producing fungus under various conditions. Three novel compounds (vanitaracin C, vanitaraphilone A, and 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde) were isolated, and their structures were determined using spectroscopic methods (1D/2D NMR and MS). In addition, the antiviral spectrum of vanitaracin A was examined by measuring its antiviral activities against rabies virus, Borna disease virus 1, and bovine leukemia virus. This compound exhibited antiviral activity against bovine leukemia virus, which is the causative agent of enzootic bovine leukosis. The anti-bovine leukemia virus effects of other compounds isolated from the vanitaracin A-producing fungus, namely, vanitaracins B and C, vanitaraphilone A, and 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde, were also evaluated. Vanitaracin B, vanitaraphilone A and 2-hydroxy-4-(hydroxymethyl)-6-methylbenzaldehyde were also found to exhibit activity against bovine leukemia virus. These findings reveal the broad-spectrum antiviral activity of the vanitaracin scaffold and suggest several candidates for the development of anti-bovine leukemia virus drugs.

Numerical reproduction of the seasonal variation in dissolved uranium in Lake Biwa.

The seasonal variation in dissolved uranium (DU) concentrations in the epilimnion of Lake Biwa, the largest lake in Japan, was successfully reproduced by geochemical calculations. The DU in Lake Biwa's epilimnion was calculated using an ion-exchange-equilibrium model. The model used the water-DU simple mixing based on monthly observations of water sources (river water, rainwater, evaporation, and groundwater) and thermocline depths from previous studies (Mochizuki et al. (2016)), the adsorbed uranium (AU) on the soil surface based on work by Saito et al. (2021), and the chemical equilibrium of major chemical species such as H, C, and Ca. The total uranium (TU = AU + DU), which determines the peak DU level in summer, and cation-exchange capacity of the soil surface (CECZp), which determines the DU decrease in winter, were optimized by reproducing the DU measurements. The DU value calculated by PHREEQC with the ion-exchange-equilibrium model can be expressed as the sum of three dissolved chemical species (DUeq), which constitute on average 97% of the DU calculated by PHREEQC. DUeq values were decomposed and the contribution of each factor was ranked by comparing their seasonal variabilities. The complexation equilibrium had the greatest variability and was proportional to the reciprocal of the cube of hydrogen ions. This indicates that the seasonal variation in DU is caused mainly by variation in pH. The peak in the DU observations lagged behind the peak in the pH observations by approximately 1 month. However, DUeq did not reproduce this peak delay. Therefore, we assumed that when DU fails to reach the ion-exchange equilibrium concentration and the peak delay occurs, it follows a first-order reaction, and the rate coefficient is determined by the reproducibility of the DU measurements. The DUlim, as the adsorption/desorption rate-limited DU, improved the reproducibility of the DU and the delay after the pH peak. This implies that the delay of the DU peak after the pH peak represents the lag from equilibrium to a first-order rate reaction caused by the soil uranium adsorption/desorption rate.

Synthesis and antifungal activity of the proposed structure of a volatile compound isolated from the edible mushroom Hypsizygus marmoreus.

We synthesized the proposed structure of an antifungal compound detected in the culture broth of the edible mushroom Hypsizygus marmoreus. Using the Evans aldol and Abiko-Masamune aldol reactions as the key steps, we synthesized all of the stereoisomers of the compound with high stereoselectivity. The GC retention times and the fragmentation patterns in the mass spectra of the synthesized isomers did not match those of the natural product. Therefore, this result may imply that it is necessary to reisolate the natural product and reconsider its structure. All of the synthesized isomers were found to exhibit antifungal activity against the phytopathogenic fungus Alternaria brassicicola. Due to their simple structures, the obtained isomers could be lead compounds for new pesticides.

Numerical reproduction of dissolved U concentrations in a PO4-treated column study of Hanford 300 area sediment using a simple ion exchange and immobile domain model.

We succeeded at numerical reproduction of dissolved U concentrations from column experiments with PO4-treated Hanford 300 Area sediment using a simple ion exchange and immobile domain model. The time-series curves of dissolved U concentrations under various Darcy flow rate conditions were reproduced by the numerical model in the present study through optimization of the following parameters: the mass of U in mobile domain (on surface soil connected to the stream) to fit the starting U concentration at the column exit, and the rest of the total U was left as precipitation in immobile domain (isolated in deep soil); the mixing ratio between immobile and mobile domains, to fit the final recovering curve of concentration; and the cation exchange capacity (CECZp) and equilibrium constant (kZp) of the exchange reaction of UO22+ and H+ on simulated soil surface (Zp), to fit the transient equilibrium concentration, forming the bed of the bathtub curve. Numerical setting of no U in immobile domain or no mixing between immobile and mobile domains caused all U flushed out of the column exit, and setting of no CEC on Zp, formed no transient equilibrium concentration. The ion exchange immobile domain model is so common that it has become a standard process in the general-purpose geochemical program Phreeqc. Optimization of this model led to the development of the model presented here, which was capable of explaining the fluctuations in dissolved U concentration well and reproducing column experiments under various conditions.

Regio- and stereocontrol in rhenium-catalyzed transposition of allylic alcohols.

A hydroxyl group-directed, highly regio- and stereoselective transposition of allylic alcohols based on rhenium catalysis has been developed. The method is suitable for a direct isomerization of acetals into the thermodynamically preferred isomer as long as one of the hydroxyl groups is allylic. This method will expand the scope of rhenium-catalyzed alcohol transpositions for complex molecule synthesis.

[Reaction Development Utilizing the Features of Chemical Elements and Synthesis of Marine Natural Products].

Marine natural products and biologically active compounds often contain cyclic ether units. Thus, regio- and stereoselective construction of these structures has long been a topic of interest in organic synthesis. This review summarizes new synthetic approaches to polycyclic ether natural products utilizing the features of chemical elements.