(3R,7S)-12-Hydroxy-jasmonoyl-l-isoleucine is the genuine bioactive stereoisomer of a jasmonate metabolite in Arabidopsis thaliana.

The oxylipin plant hormone (3R,7S)-jasmonoyl-l-isoleucine [or (+)-7-iso-jasmonoyl-l-isoleucine, JA-Ile] is widely recognized as a plant defense hormone against pathogens and chewing insects. The metabolism of JA-Ile into 12-OH-JA-Ile and 12-COOH-JA-Ile is the central mechanism for the inactivation of JA signaling. Recently, 12-OH-JA-Ile was reported to function as a ligand for the JA-Ile co-receptor COI1-JAZ. However, in previous studies, '12-OH-JA-Ile' used was a mixture of four stereoisomers, the naturally occurring cis-isomer (3R,7S)-12-OH-JA-Ile and the trans-isomer (3R,7R)-12-OH-JA-Ile, and the unnatural cis-isomer (3S,7R)-12-OH-JA-Ile and the trans-isomer (3S,7S)-12-OH-JA-Ile. Thus, the genuine bioactive form of 12-OH-JA-Ile has not yet been identified. In the present study, we prepared pure stereoisomers of 12-OH-JA-Ile and identified (3R,7S)-12-OH-JA-Ile as the naturally occurring bioactive form of 12-OH-JA-Ile and found that it binds to COI1-JAZ9 as effectively as (3R,7S)-JA-Ile. In addition, we revealed that the unnatural trans-isomer (3S,7S)-12-OH-JA-l-Ile functions as another bioactive isomer. The pure (3R,7S)-12-OH-JA-Ile causes partial JA-responsive gene expression without affecting the expression of JAZ8/10, which is involved in the negative feedback regulation of JA-signaling. Thus, (3R,7S)-12-OH-JA-Ile could cause weak and sustainable expression of certain JA-responsive genes until the catabolism of (3R,7S)-12-OH-JA-Ile into (3R,7S)-12-COOH-JA-Ile occurs. The use of chemically pure (3R,7S)-12-OH-JA-Ile confirmed the genuine biological activities of '12-OH-JA-Ile' by excluding the possible effects of other stereoisomers. A chemical supply of pure (3R,7S)-12-OH-JA-Ile with an exact bioactivity profile will enable further detailed studies of the unique role of 12-OH-JA-Ile in planta.

Carboiodanation of Arynes: Organoiodine(III) Compounds as Nucleophilic Organometalloids.

Organic iodine(III) compounds represent the most widely used hypervalent halogen compounds in organic synthesis, where they typically perform the role of an electrophile or oxidant to functionalize electron-rich or -nucleophilic organic compounds. In contrast to this convention, we discovered their unique reactivity as organometallic-like nucleophiles toward arynes. Equipped with diverse transferable ligands and supported by a tethered spectator ligand, the organoiodine(III) compounds undergo addition across the electrophilic C-C triple bond of arynes while retaining the trivalency of the iodine center. This carboiodanation reaction can forge a variety of aryl-alkynyl, aryl-alkenyl, and aryl-(hetero)aryl bonds along with the concurrent formation of an aryl-iodine(III) bond under mild conditions. The newly formed aryl-iodine(III) bond serves as a versatile linchpin for downstream transformations, particularly as an electrophilic reaction site. The amphoteric nature of the iodine(III) group as a metalloid and a leaving group in this sequence enables the flexible and expedient synthesis of extended π-conjugated molecules and privileged biarylphosphine ligands, where all of the iodine(III)-containing compounds can be handled as air- and thermally stable materials.

Copper-Catalyzed Intramolecular Olefinic C(sp2)-H Amidation for the Synthesis of γ-Alkylidene-γ-lactams.

Herein, we report the copper-catalyzed dehydrogenative C(sp2)-N bond formation of 4-pentenamides via nitrogen-centered radicals. This reaction provides a straightforward and efficient preparation method for γ-alkylidene-γ-lactams. Notably, we could controllably synthesize α,ß-unsaturated- or α,ß-saturated-γ-alkylidene-γ-lactams depending on the reaction conditions.

Iron-Catalyzed Biomimetic Dimerization of Tryptophan-Containing Peptides.

Biomimetic oxidative dimerization of tryptophan derivatives in aqueous media with oxygen as a bulk oxidant catalyzed by an iron octacarboxy phthalocyanine complex was established. The discovery of the extremely active iron catalyst enables aerobic enzyme-mimetic oxidation to be performed in a flask. This method was applicable to the oxidative dimerization of a wide range of tryptophan derivatives, including various dipeptides and oligopeptides, with remarkable functional-group tolerance without the protection of the amino acid residues. Furthermore, oxidative dimerization of tryptophan derivatives bearing dioxopiperazine units enabled the convergent total synthesis of five natural pyrroloindole compounds and unnatural congeners. The established chemical method provides facile access to a broad range of dimerized peptides with a unique scaffold to link two turn structures, which will serve as a powerful tool to create new small- and medium-sized-molecules as drug candidates.

Development of an Internal Calibration Algorithm for Ultrahigh-Resolution Mass Spectra of Dissolved Organic Matter.

In order to obtain a spectrum with high mass accuracy, an internal calibration of Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) is inevitable. This in turn is critical for subsequent data processing and is generally performed using the commercial instrument software DataAnalysis in the benchmark calibration mode. However, no methodological study has systemically addressed the automated internal calibration of FTICR-MS spectra for dissolved organic matter (DOM) from different sources such as terrestrial and aquatic environments. In this study, a new piecewise algorithm, FTMSCalibrate, was developed to automatically calibrate FTICR-MS spectra in both positive and negative ion modes. FTMSCalibrate was found to reproduce 91.7% ± 4.4% (referred to as the true positive ratio) of the chemical formulas obtained by calibration using manual DataAnalysis. In addition to significantly reducing the mass error, FTMSCalibrate is more accurate in terms of the molecular formula assignment for low m/z peaks than Formularity and MFAssignR. FTMSCalibrate was compatible with deprotonated ions for FTICR-MS spectra in the negative ion mode as well as protonated and adduct ions, including Na- and K-adducts, for FTICR-MS spectra in the positive ion mode. These results suggest that FTMSCalibrate publicly available herein is a robust alternative for the internal calibration of FTICR-MS spectra during postdata processing and will facilitate DOM analysis by FTICR-MS.

Formula Assignment Algorithm for Deuterium-Labeled Ultrahigh-Resolution Mass Spectrometry: Implications of the Formation Mechanism of Halogenated Disinfection Byproducts.

Ultrahigh-resolution mass spectrometry (UHR-MS) coupled with isotope labeling has attracted significant attention in elucidating the mechanisms of the transformation of dissolved organic matter (DOM). Herein, we developed a novel formula assignment algorithm based on deuterium (D)-labeled UHR-MS, namely, FTMSDeu, for the first time. This algorithm was employed to determine the precursor molecules of halogenated disinfection byproducts (Xn-DBPs) and to evaluate the relative contribution of electrophilic addition and substitution reactions in Xn-DBP formation according to the H/D exchange of DOM molecules. Further, tandem mass spectrometry with homologous-based network analysis was used to validate the formula assignment accuracy of FTMSDeu in the identification of iodinated disinfection byproducts. Electrophilic substitution accounted for 82-98, 71-89, and 43-45% of the formation for Cl-, Br-, and I-containing Xn-DBPs, respectively, indicating the dominant role of the electrophilic substitution in chlorinated disinfection byproducts with low Br and I concentrations. The absence of putative precursors in some Xn-DBPs also suggests that Xn-DBP formation includes secondary reactions (e.g., oxidation and hydrolysis) in addition to the electrophilic addition and/or substitution of halogens. These findings highlight the significance of isotopically labeled UHR-MS techniques in revealing the transformation of DOM in natural and engineered systems.

Enantiodivergent One-Pot Synthesis of Axially Chiral Biaryls Using Organocatalyst-Mediated Enantioselective Domino Reaction and Central-to-Axial Chirality Conversion.

Enantiodivergent one-pot synthesis of biaryls was developed using a catalytic amount of a single chiral source. A domino organocatalyst-mediated enantioselective Michael reaction and aldol condensation provided centrally chiral dihydronaphthalenes with excellent enantioselectivity, from which an enantiodivergent chirality conversion from central-to-axial chirality was achieved. Both enantiomers of biaryls were obtained with excellent enantioselectivity. All transformations can be conducted in a single reaction vessel. A plausible reaction mechanism for the enantiodivergence is proposed.

Synthesis of Stoichiometric SrTiO3 and Its Carrier Doping from Air-Stable Bimetallic Complexes.

We demonstrate the synthesis of perovskite oxide SrTiO3 with ideal cation stoichiometry and homogeneous La doping using air-stable Sr-Ti and La-Ti bimetallic peroxo complexes with a 1:1 cation ratio. Phase-pure SrTiO3, La2Ti2O7, and LaTiO3 were successfully synthesized by thermal decomposition of those complexes. La-doped SrTiO3 was obtained by mixing the Sr-Ti and La-Ti complexes in an acid solution, followed by thermal decomposition. La-doped SrTiO3 showed systematic chemical trends in the lattice constant and electrical conduction. Not only those bulk polycrystals but also cation-stoichiometric SrTiO3 epitaxial thin films were grown with an atomically flat surface from the Sr-Ti complex.

Temperature-Dependent Low-Frequency Vibrations of Thiamine Crystal Containing Hydrated Ions.

Low-frequency vibrations of crystalline molecules are very sensitive to the local environment in which the molecules, for example, hydrated ions captured in crystals, find themselves. We present low-temperature X-ray crystallographic measurements on the harvested thiamine crystal containing hydrated ions and its temperature-dependent terahertz spectra and synchrotron infrared microspectra. It is found from the X-ray structure that the hydrated ions and hydration water are in a similar environment to liquid, although those are captured in crystals. The vibrationally resolved THz spectra of two states in the present organic crystals containing hydrated ions are well explained by the difference in the hydrogen-bonded pattern. Peak assignments were performed based on highly accurate first-principles calculations incorporating relativistic effects and dispersion corrections. The temperature dependences are observed for the vibrations around the chloride ions and hydration water due to the loose binding of chloride ions, the bond elongation with increasing temperature, and the cleavage of weak hydrogen bonds.

Simple amino silyl ether organocatalyst for asymmetric hetero Diels-Alder reaction of isatins with enones.

New two catalysts component system comprising of a primary ß-amino silyl ethers as an organocatalyst and N-protected amino acids as a co-catalyst put together worked as an efficient organocatalyst system in the hetero Diels-Alder reaction of isatins with enones affording the chiral spirooxindole-tetrahydropyranones in good chemical yields and stereoselectivities (up to 94%, up to dr 78:22., up to 85% ee).

Semipinacol rearrangement of a bicyclo[7.2.0]undecane framework into a bicyclo[6.3.0]undecane skeleton: a model study on the biosynthesis of seiridiasteriscane A.

Seiridiasteriscane A is an asteriscane-type sesquiterpenoid bearing a trans-fused bicyclo[6.3.0]undecane skeleton. Although its biosynthesis has been proposed to involve a semipinacol rearrangement of a putative intermediary acetate bearing a bicyclo[7.2.0]undecane ring system (presumably derived from coisolated pestalotiopsin M) followed by epimerization of the resulting cis-fused seiridiasteriscane B, such a type of semipinacol rearrangement has never been reported so far. Our model study revealed that a 1-hydroxybicyclo[7.2.0]undecan-2-yl acetate underwent a smooth and stereospecific semipinacol rearrangement with the assistance of Et2AlCl to give the corresponding bicyclo[6.3.0]undecane-9-one. In addition, the resulting cis-fused 5,8-bicyclic ketone was partially epimerized to the corresponding trans-fused ketone by prolonged adsorption onto a silica gel plate. These results may support a recently proposed biosynthetic pathway of seiridiasteriscane A.

Development and Application of a High-Precision Algorithm for Nontarget Identification of Organohalogens Based on Ultrahigh-Resolution Mass Spectrometry.

Brominated and/or chlorinated organic compounds (referred to as organohalogens) are frequently detected in natural and engineered environments. However, ultrahigh-resolution mass spectrometry (UHR-MS)-based nontargeted identification of organohalogens remains challenging because of the coexistence of a vast number of halogenated and nonhalogenated organic molecules. In this study, a new algorithm, namely, the NOMDBP code, was developed to simultaneously identify organohalogens and non-organohalogens from the UHR-MS spectra of natural and engineered waters. In addition to isotopic patterns, for the first time, three optional filter rules [i.e., selection for minimum nonoxygen heteroatoms, inspection of the presence of newly formed halogenated disinfection byproducts (Xn-DBPs), and of their precursors] were incorporated into our code, which can accurately identify DBP-associated peaks and further elucidate Xn-DBP generation and transformation mechanisms. The formula assignment ratio against 2815 previously reported organohalogens, and their 11,583 isotopologues exceeded 97%. Application of our algorithm to disinfected natural organic matter indicated that oxygen-containing Xn-DBP species accounted for a majority of the Xn-DBPs. Furthermore, brominated Xn-DBPs (Br-DBPs) were characterized by a higher degree of unsaturation compared to chlorinated Xn-DBPs. In addition to electrophilic substitution and electrophilic addition reactions, the decomposition/transformation pathway was found to be another important mechanism in Br-DBP formation. The results of this study highlight the superior potential of our code for the efficient detection of yet unknown organohalogens (including organohalogens bearing nonoxygen heteroatoms) in a nontargeted manner and for the identification of their generation mechanism occurring during the disinfection process.

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step.

Invited for the cover of this issue is the group of Yujiro Hayashi at the University of Tohoku University. The image depicts the spinning motion of a figure skater, which illustrates the transformation of the chiral information investigated in this work. Read the full text of the article at 10.1002/chem.201905814.

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step.

The pot-economical, highly enantioselective synthesis of axially chiral biaryls was developed by using one-pot organocatalyst-mediated domino and aromatization reactions as key steps. The axial information of the precursor, which also has central chirality, was completely inverted in the final biaryls. The inversion of the axial information occurred in the conversion of the central chirality to the axial chirality of an oxidative aromatization step.

Gear Slippage in Molecular Bevel Gears Bridged with a Group 14 Element.

Ditriptycilmethanes are known as molecular bevel gears because the two triptycil groups show correlated rotation. In this report, molecular bevel gears bridged with a group 14 element, bis(methyltriptycil)X (X = SiH2, GeH2, GeF2), were synthesized, and their gearing properties were investigated. Gear slippage, that is an error in gear rotation, is observed in high-temperature solutions of molecular bevel gears. Heavy atom derivatives undergo gear slippage more easily due to the long bond lengths and wide angles between the two triptycil units and the bridging group 14 element. Activation energies of gear slippages were estimated by temperature-dependent NMR spectroscopy and DFT calculations, and theoretical thermodynamic parameters for gear slippage were found to be in excellent agreement with experimental values. The results indicate that theoretical calculations for gear rotation in molecular bevel gears can accurately reproduce experimental phenomena.

Kinetic Stabilization of Carbazole Nitroxides by Inclusion in a Macrocage and Their Electron Spin Resonance Characterization.

Some nitroxides, for example, tetramethylpyridiniumoxide, are known as stable radicals; however, carbazole nitroxide is less stable. The kinetic stabilization of labile radicals by introduction of bulky substituents is usually effective to investigate intrinsic properties of the molecule because of small electronic perturbation induced by the substituents. In this study, macrocage molecules with a carbazole nitroxide connected by covalent bonds were newly designed as kinetically stabilized carbazole nitroxides. The nitroxides were prepared and characterized by electron spin resonance spectroscopy. The caged nitroxides presented long half-lives (∼50 h) by kinetic analysis.

The thermodynamic properties and molecular dynamics of [Li+@C60](PF6-) associated with structural phase transitions.

Calorimetric and terahertz-far-infrared (THz-FIR) spectroscopic and infrared (IR) spectroscopic measurements were conducted for [Li+@C60](PF6-) at temperatures between 1.8 and 395 K. [Li+@C60](PF6-) underwent a structural phase transition at around 360 K accompanied by the orientational order-disorder transition of Li+@C60 and PF6-. The transition occurred in a step-wise manner. The total transition entropy (ΔtrsS) of 40.1 ± 0.4 J K-1 mol-1 was smaller than that of the orientational order-disorder transition in a pristine C60 crystal (ΔtrsS = 45.4 ± 0.5 J K-1 mol-1). Thus, the orientational disorder of Li+@C60 in the high-temperature phase of [Li+@C60](PF6-) was much less excited than that of the pristine C60 owing to the Coulombic interactions, which stabilized the ionic crystal lattice of [Li+@C60](PF6-). At T < 100 K, upon cooling, Li+ ions were trapped in two pockets on the inner surface of C60, and no phase transition was observed. Finally, the Li+ ions achieved a complete order at 24 K through antiferroelectric transition. The ΔtrsS value of 4.6 ± 0.4 J K-1 mol-1 was slightly smaller than R ln 2 = 5.76 J K-1 mol-1 expected for the two-site order-disorder transition. The extent of the Li+ motion in the C60 cage was related to the selection rule in the THz-FIR and IR spectroscopy of the C60 internal vibrations, because a C60 cage should be polarized by the Li+ ion. It is shown that the local symmetry of the caged molecule can be modified by the rotational or hopping motion of the encaged ions.

Synthesis and Stereochemical Revision of the Aromatic Polyketide NFAT-133.

NFAT-133, isolated from Streptomyces sp., is an immunosuppressive, antidiabetic, and antitrypanosomal aromatic polyketide with three contiguous stereocenters. The first enantioselective total synthesis of the proposed structure of NFAT-133 [(10R,11R,12S)-1] and its C10 epimer [(10S,11R,12S)-1] was achieved from a known aromatic ester (5) by a 10-step sequence that featured chiral auxiliary-directed asymmetric alkylation and the Evans asymmetric aldol reaction as the chirality-inducing steps. The 1H and 13C NMR data as well as the specific rotation value of natural NFAT-133 were not identical to those of the proposed structure, but were in good agreement with those of its C10 epimer. This led us to conclude that the absolute configuration of NFAT-133 should be revised to 10S, 11R, and 12S.

Competent Route to Unsymmetric Dimer Architectures: Total Syntheses of (-)-Lycodine and (-)-Complanadines†A and B, and Evaluation of Their Neurite Outgrowth Activities.

Valuable synthetic routes to the Lycopodium alkaloid lycodine (1) and its unsymmetric dimers, complanadines A (4) and B (5), have been developed. Regioselective construction of the bicyclo[3.3.1]nonane core structure of lycodine was achieved by a remote functionality-controlled Diels-Alder reaction and subsequent intramolecular Mizoroki-Heck reaction. A key coupling reaction of the lycodine units, pyridine N-oxide (66) and aryl bromide (65), through C-H arylation at the C1 position of 66 provided the unsymmetric dimer structure at a late stage of the synthesis. This strategy greatly simplified the construction of the dimeric architecture and functionalization. Complanadines A (4) and B (5) were synthesized by adjusting the oxidation level of the bipyridine mono-N-oxide (67). The diverse utility of this common intermediate (67) suggests a possible biosynthetic pathway of complanadines in Nature. Both enantiomers of lycodine (1) and complanadines A (4) and B (5) were prepared in sufficient quantities for biological evaluation. The effect on neuron differentiation of PC-12 cells upon treatment with culture medium, in which human astrocytoma cells had been cultured in the presence of 1, 4, or 5 was evaluated.

Regioregular Phthalocyanines Substituted with Bulky Donors at Non-Peripheral Positions.

Three regioregular phthalocyanines (1-3) were synthesized selectively by the cyclic tetramerization of phthalonitriles bearing a bulky diarylamine substituent at the next position of nitrile. The steric repulsion at the tetramerization of bulky phthalonitriles allowed for the selective formation of regioregular phthalocyanines as confirmed by NMR and single crystal X-ray structural analyses. The absorption spectrum of 1 substituted with di(4-tert-butylphenyl)amine groups at the non-peripheral positions showed a non-split Q-band at 764 nm, which was redshifted by 83 nm compared with that of metal free phthalocyanine (H2 Pc). The TD-DFT calculation and electrochemical studies prove that the substitution of diarylamine groups at the α-positions effectively destabilizes the HOMO energy level, which causes a large redshift of the Q-band. Moreover, 1 can generate a one-electron oxidation species through chemical oxidation. The Q-band position of 2 bearing 4,4'-dimetoxyphenylamine units was further shifted by 10 nm compared with that of 1. In addition, 3 having carbazole units showed a small redshift of the Q-band relative to H2 Pc. The hole-mobility of 2 in thin film was determined to be 1.1×10-5  cm V-1 s-1 by using a space charge limited current method. A perovskite solar cell employing 2 as a hole-transporting layer gave an efficiency of 5.1 % under standard global 100 Wcm-2 AM 1.5 G illumination.