The first total synthesis and structural determination of antibiotics K1115 B1s (alnumycins)

K1115 B₁, isolated from the broth of Streptomyces species, was found to be a mixture of stereoisomers. Authors synthesized all stereoisomers of K1115 B₁ by convergent synthesis coupling a rhamnose derivative, an isobenzofuranone, and a chiral tetraol. Comparison of ¹H NMR spectra and optical rotations made it clear that the absolute structures of K1115 B_1α (the major isomer) and K1115 B_1β (the minor isomer) were (1R, 17S)- and (1R, 17R)-configurations, respectively. The optical rotations of the stereoisomers revealed that alnumycin, reported as the identical structure with K1115 B₁, might be another mixture of stereoisomers.     

Diverse reactivities of aromaticity-unsaturation coexisted metalladithiolene rings

This review paper summarizes the reactivities of metal dithiolene complexes based on the ‘coexistence of aromaticity and unsaturation’ in the five-membered metallacycle, the so-called metalladithiolene ring (MS₂C₂). The 16-electron [LM(dithiolene)] (LM = CpM^III, Cp*M^III, (C₆R₆)M^II) complexes are coordinatively unsaturated and usually show M-S centered cycloaddition reactions with nucleophiles (e.g. diazoalkanes, organic azides, quadricyclane) and electrophiles (e.g. tetracyanoethylene oxide, activated acetylene). The resulting metalladithiolene cycloadducts, which have three-membered M-S-C or M-S-N rings, further react with protic acids or PR₃ to undergo the ring-opening reactions involving the M-C bond, M-S bond or M-N bond cleavages. Furthermore, diverse adduct dissociations are observed by thermal, photochemical or electrochemical redox reactions. Such reactions normally produce the original [LM(dithiolene)] complexes (non-adduct) and the eliminated fragments. Among them, the Co-S centered imido adduct [CpCo(dithiolene)(NR)] (R = Ts, Ms) reacted under thermal conditions in the presence of PR₃ to undergo the intramolecular imido migration reaction to the Cp ligand, giving [(C₅H₄-NHR)Co(dithiolene)] complexes. The M-S centered multinuclear cluster complexes are obtained by the reaction of [LM(dithiolene)] with low valent M(CO)_n complexes. The square-planar bis(dithiolene) complexes [M(dithiolene)₂]⁰ (M = Ni, Pd, Pt) or tris(dithiolene) complexes [M(dithiolene)₃]⁰ yield cycloaddition products with olefins. These reactions are due to ligand centered reactions made possible by a molecular orbital overlap between dithiolene LUMO and olefin HOMO. Similar ligand centered adducts are obtained by the reaction of dianionic [M(dithiolene)₂]²⁻ with haloalkanes or dihaloalkanes. Also these adducts of bis(dithiolene) complex are dissociated photochemically and electrochemically. This paper also describes the reactivities of organometallic o-carborane dithiolate complexes, which are generally formulated as [LM(S₂C₂B₁₀H₁₀)] (LM = CpCo, Cp*Rh, Cp*Ir, (p-cymene)Ru and (p-cymene)Os). Diverse addition reactions are reported; in particular, the reaction with acetylene involves B-H bond activation in the carborane moiety.     

Mass balance method for purity assay of phthalic acid esters: development of primary reference materials as traceability sources in the Japan Calibration Service System

Purity assay of high-purity materials (HPMs) of phthalic acid esters (PAEs) was carried out by means of a mass balance method. In this method, chromatographic methods such as gas chromatography-flame ionization detector (GC-FID) and/or high-performance liquid chromatography (HPLC) in combination with other methods such as Karl-Fischer (KF) titration and vacuum evaporation (VE) were applied. The sum of the impurities estimated by these methods allowed the estimation of the purity of the main component by difference. Seven PAEs with varying side chain structures and levels of impurities were analysed on a systematic way in which impurities were classified into several groups in terms of their abundance, availability of qualitative information and availability of authentic compounds, etc. The absolute quantity of each impurity was determined by GC-FID and/or HPLC based on the calibration made by the authentic compounds of impurities whenever available. The purities in mass fraction of these PAEs were certified at the National Metrology Institute of Japan (NMIJ), and the PAEs were registered as primary reference materials playing an essential role in linking the metrological traceability of the Japan Calibration Service System (JCSS) to the International System of Units (SI).     

Linear polystyrene-stabilized PdO nanoparticle-catalyzed Mizoroki-Heck reactions in water

Linear polystyrene-stabilized PdO nanoparticles (PS-PdONPs) were prepared by thermal decomposition of Pd(OAc)(2) in the presence of polystyrene. X-ray diffraction (XRD) and transmission electron microscopy (TEM) indicated the production of PdO nanoparticles. The loading of palladium was determined by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). PS-PdONPs exhibited high catalytic activity for Mizoroki-Heck reactions under air in water and could be recycled without loss of activity.     

Alkene isomerization/enamide-ene and diene metathesis for the construction of indoles, quinolines, benzofurans and chromenes with a chiral cyclopropane substituent

A synthetic method for bicyclic heterocycles, such as indole, benzofuran and chromene derivatives bearing a chiral cyclopropane at the 2-position, was established using isomerization of a terminal olefin and enamide-ene or diene metathesis. This route can also be applied to chiral 2-cyclopropylquinoline synthesis (both cis and trans).     

A tandem reaction of organozinc reagent prepared from palladium-catalyzed umpolung method: diastereoselective formation of cyclohexene derivatives bearing three adjacent stereocenters

In the presence of a palladium catalyst, treatment of γ-acyloxy-α,β-unsaturated ketone with bis(iodozincio)methane caused umpolung of π-allylpalladium to give a zinc dienolate. Thus formed zinc species afforded a cyclohexene derivative via a self-condensation reaction. It is noteworthy that the three adjacent stereogenic centers were created in a single process with quite high diastereoselectivity.     

Cu-mediated chemoselective trifluoromethylation of benzyl bromides using shelf-stable electrophilic trifluoromethylating reagents

Copper-mediated chemoselective trifluoromethylation at the benzylic position by the use of shelf-stable electrophilic trifluoromethylating reagents 3 in good to high yields under mild conditions is described for the first time. The generality of this trifluoromethylation for a wide variety of benzyl bromides facilitates the rapid creation of structural diversity of medicinal candidates in drug discovery.     

Diastereoselective hydroformylation of 2,5-cyclohexadienyl-1-carbinols with catalytic amounts of a reversibly bound directing group

A phosphinite plays a role as a reversibly bound directing group for the regio- and diastereoselective hydroformylation of 2,5-cyclohexadienyl-1-carbinols. Of the two alkene functions only one was functionalized through hydroformylation to form a synthetically attractive quaternary carbon center leaving the second alkene function for potential further functionalization.     

Use of ultra-performance liquid chromatography/time-of-flight mass spectrometry with nozzle-skimmer fragmentation for comprehensive quantitative analysis of secondary metabolites in Arabidopsis thaliana

This study sought to develop techniques for LC/MS-based metabolomics and to verify that an MS/MS spectral tag (MS2T) could be used in practical secondary metabolite profiling. The retention time (RT), precursor ions, and fragment ions generated by nozzle-skimmer fragmentation were determined using ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC/TOF-MS) and compared with the MS2T. A standard mix was analyzed with UPLC/TOF-MS under the same conditions as were used to construct the MS2T. The difference in RT for the standards was less than 0.15 min and the average RSD was about 2.8%, suggesting that the analysis was highly repeatable. Both precursor ions and fragment ions were observed when the cone voltage was 75 V. Experimental data and fragmentation pattern in the MS2T annotation list were highly similar. Wild-type and cas-1 mutant Arabidopsis thaliana samples treated with an elicitor were analyzed using UPLC/TOF-MS. Sixty-five peaks were successfully annotated. Fragment ions were observed with nozzle-skimmer fragmentation in 50 of 65 (77%) peaks. The reliability of annotation may have increased as a result of fragment ions. Results of multivariate analysis suggested that cas-1 was related to induction of the biosynthesis of these flavonoids. The devised method facilitated practical secondary metabolite profiling.     

Use of the MALDI BioTyper system with MALDI–TOF mass spectrometry for rapid identification of microorganisms

In a clinical diagnosis microbiology laboratory, the current method of identifying bacterial isolates is based mainly on phenotypic characteristics, for example growth pattern on different media, colony morphology, Gram stain, and various biochemical reactions. These techniques collectively enable great accuracy in identifying most bacterial isolates, but are costly and time-consuming. In our clinical microbiology laboratory, we prospectively assessed the ability of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI–TOF MS) to identify bacterial strains that were routinely isolated from clinical samples. Bacterial colonies obtained from a total of 468 strains of 92 bacterial species isolated at the Department of Clinical Laboratory at Chiba University were directly placed on target MALDI plates followed by addition of CHCA matrix solution. The plates were then subjected to MALDI–TOF MS measurement and the microorganisms were identified by pattern matching with the libraries in the BioTyper 2.0 software. Identification success at the species and genus levels was 91.7% (429/468) and 97.0% (454/468), respectively. MALDI–TOF MS is a rapid, simple, and high-throughput proteomic technique for identification of a variety of bacterial species. Because colony-to-colony differences and effects of culture duration on the results are minimal, it can be implemented in a conventional laboratory setting. Although for some pathogens, preanalytical processes should be refined, and the current database should be improved to obtain more accurate results, the MALDI–TOF MS based method performs, in general, as well as conventional methods and is a promising technology in clinical laboratories.