Details of a Researcher - Miyamoto, Kazunori

Papers - Miyamoto, Kazunori

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Kenta Koyamada, Kazunori Miyamoto, Masanobu Uchiyama

Nature Synthesis 3 ( 9 ) 1083 - 1090 2024.09

Research paper (scientific journal), Corresponding author, Accepted

For over a century, scientists have been fascinated by the unique electronic, structural and bonding properties of the three isomers of benzyne, a highly reactive organic intermediate derived from benzene by removing two hydrogen atoms. Although o- and p-benzynes have been extensively studied following the establishment of reliable synthetic methods to prepare them, m-benzyne in the ground state has remained experimentally inaccessible. We report herein the room-temperature and atmospheric-pressure synthesis of m-benzyne in solution. Experimental and theoretical investigations revealed that owing to the inner bond inside the benzene ring between C1 and C3 atoms, m-benzyne behaves as a potent electrophile with a Mayr’s electrophilicity parameter E of around −2 but shows weak free-radical character. The bonding appears similar to the inverted σ-bond, the so-called charge-shift bond, in [1.1.1]propellane. By utilizing the unique bonding character of m-benzyne, we established halogenations and C–N and C–C coupling reactions, as well as a successive m-benzyne generation and trapping sequence that provides access to 1,3,5-trisubstituted benzenes. (Figure presented.)

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Transition-Metal-Free Thioboration of Terminal Alkynes

Taro Matsuyama, Hiroshi Ishida, Chao Wang, Kazunori Miyamoto, Masaya Nakajima, Naoyuki Toriumi, Yuki Nagashima, Masanobu Uchiyama

JACS Au (American Chemical Society (ACS)) 4 ( 12 ) 4927 - 4933 2024

Research paper (scientific journal), Accepted, ISSN 2691-3704

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Dearomative triple elementalization of quinolines driven by visible light

Shiho Ishigaki, Yuki Nagashima, Daiki Yukimori, Jin Tanaka, Takashi Matsumoto, Kazunori Miyamoto, Masanobu Uchiyama, Ken Tanaka

Nature Communications 14 ( 1 ) 2023.12

Research paper (scientific journal), Accepted

Organoboron and organosilicon compounds are used not only as synthetic building blocks but also as functional materials and pharmaceuticals, and compounds with multiple boryl and silyl groups are beginning to be used for these purposes. Especially in drug discovery, methodology providing easy stereoselective access to aliphatic nitrogen heterocycles bearing multiple boryl or silyl groups from readily available aromatic nitrogen heterocycles would be attractive. However, such transformations remain challenging, and available reactions have been mostly limited to dearomative hydroboration or hydrosilylation reactions. Here, we report the dearomative triple elementalization (carbo-sila-boration) of quinolines via the addition of organolithium followed by photo-boosted silaboration, affording the desired products with complete chemo-, regio-, and stereoselectivity. The reaction proceeds via the formation of silyl radicals instead of silyl anions. We also present preliminary studies to illustrate the potential of silaboration products as synthetic platforms.

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Mechanistic Analysis of Stereodivergent Nitroalkane Cyclopropanation Catalyzed by Nonheme Iron Enzymes

Richiro Ushimaru, Lide Cha, Shotaro Shimo, Xiaojun Li, Jared C. Paris, Takahiro Mori, Kazunori Miyamoto, Lindsay Coffer, Masanobu Uchiyama, Yisong Guo, Wei-chen Chang, Ikuro Abe

Journal of the American Chemical Society 145 ( 44 ) 24210 - 24217 2023.11

Research paper (scientific journal), Accepted, ISSN 00027863

BelL and HrmJ are α-ketoglutarate-dependent nonheme iron enzymes that catalyze the oxidative cyclization of 6-nitronorleucine, resulting in the formation of two diastereomeric 3-(2-nitrocyclopropyl)alanine (Ncpa) products containing trans-cyclopropane rings with (1′R,2′R) and (1′S,2′S) configurations, respectively. Herein, we investigate the catalytic mechanism and stereodivergency of the cyclopropanases. The results suggest that the nitroalkane moiety of the substrate is first deprotonated to produce the nitronate form. Spectroscopic analyses and biochemical assays with substrates and analogues indicate that an iron(IV)-oxo species abstracts proS-H from C4 to initiate intramolecular C-C bond formation. A hydroxylation intermediate is unlikely to be involved in the cyclopropanation reaction. Additionally, a genome mining approach is employed to discover new homologues that perform the cyclopropanation of 6-nitronorleucine to generate cis-configured Ncpa products with (1′R,2′S) or (1′S,2′R) stereochemistries. Sequence and structure comparisons of these cyclopropanases enable us to determine the amino acid residues critical for controlling the stereoselectivity of cyclopropanation.

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Total Biosynthesis of Melleolides from Basidiomycota Fungi: Mechanistic Analysis of the Multifunctional GMC Oxidase Mld7

Fukaya M., Nagamine S., Ozaki T., Liu Y., Ozeki M., Matsuyama T., Miyamoto K., Kawagishi H., Uchiyama M., Oikawa H., Minami A.

Angewandte Chemie - International Edition 62 ( 44 ) 2023.10

Research paper (scientific journal), Accepted, ISSN 14337851

Mushroom terpenoids are biologically and chemically diverse fungal metabolites. Among them, melleolides are representative sesquiterpenoids with a characteristic protoilludane skeleton. In this study, we applied a recently established hot spot knock-in method to elucidate the biosynthetic pathway leading to 1α-hydroxymelleolide. The biosynthesis of the sesquiterpene core involves the cytochrome P450 catalyzing stepwise hydroxylation of the Δ6-protoilludene framework and a stereochemical inversion process at the C5 position catalyzed by short-chain dehydrogenase/reductase family proteins. The highlight of the biosynthesis is that the flavoprotein Mld7 catalyzes an oxidation-triggered double-bond shift accompanying dehydration and acyl-group-assisted substitution with two different nucleophiles at the C6 position to afford the Δ7-protoilludene derivatives, such as melleolide and armillarivin. The complex reaction mechanism was proposed by DFT calculations. Of particular importance is that product distribution is regulated by interaction with the cell membrane.

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Structural and Mechanistic Insights into the C–C Bond-Forming Rearrangement Reaction Catalyzed by Heterodimeric Hinokiresinol Synthase

Richiro Ushimaru, Yiling Ding, Takahiro Mori, Kazunori Miyamoto, Masanobu Uchiyama, Ikuro Abe

Journal of the American Chemical Society 145 ( 40 ) 21966 - 21973 2023.10

Research paper (scientific journal), Accepted, ISSN 00027863

Hinokiresinol synthase (HRS) from Asparagus officinalis consists of two subunits, α and β, and catalyzes an unusual decarboxylative rearrangement reaction of 4-coumaryl 4-coumarate to generate (Z)-hinokiresinol with complete stereoselectivity. Herein, we describe the mechanism of rearrangement catalysis and the role played by the heterodimeric HRS, through structural and computational analyses. Our results suggest that the HRS reaction is unlikely to proceed via the previously hypothesized Claisen rearrangement mechanism. Instead, we propose that the 4-coumaryl 4-coumarate substrate is first cleaved into coumarate and an extended p-quinone methide, which then recombine to generate a new C-C bond. These processes are facilitated by proton transfers mediated by the basic residues (α-Lys164, α-Arg169, β-Lys168, and β-Arg173) in the cavity at the heterodimer interface. The active site residues, α-Asp165, β-Asp169, β-Trp17, β-Met136, and β-Ala171, play crucial roles in controlling the regioselectivity of the coupling between the fragmented intermediates as well as the stereoselectivity of the decarboxylation step, leading to the formation of the (Z)-hinokiresinol product.

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Mechanistic Investigation of the Degradation Pathways of α–β/α–α Bridged Epipolythiodioxopiperazines (ETPs)

Daiki Kurita, Hajime Sato, Kazunori Miyamoto, Masanobu Uchiyama

The Journal of Organic Chemistry 88 ( 17 ) 12797 - 12801 2023.09

Research paper (scientific journal), Accepted, ISSN 00223263

Epipolythiodioxopiperazines (ETPs) make up a class of biologically active fungal metabolites with a transannular disulfide bridge. In this work, we used DFT calculations to examine in detail the degradation (desulfurization) pathways of α-β/α-α bridged ETPs. The chemical stability of ETPs is influenced by the type of sulfur bridge, the structural features, and the storage conditions. Our results suggest appropriate protection of the phenolic OH of ETPs would improve various pharmaceutically relevant properties, including bioavailability.

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Catalytic stereoselective synthesis of doubly, triply and quadruply twisted aromatic belts

Nogami J., Hashizume D., Nagashima Y., Miyamoto K., Uchiyama M., Tanaka K.

Nature Synthesis 2 ( 9 ) 888 - 897 2023.09

Twisted aromatic belt molecules provide unique topologies and complex chiralities for nanocarbon materials. However, a synthetic method for aromatic belts with multiple twists remains elusive. Here we report the catalytic and stereoselective synthesis of doubly, triply and quadruply twisted aromatic belts (up to e.r. = 98:2) via rhodium(I)-catalysed asymmetric [2 + 2 + 2] cycloadditions. The hybrid substrate design, consisting of curved metaphenylene units and linear paraphenylene units, overcomes the hurdles of conventional methods, that is, large twist strain and unravelling of twists during belt formation, allowing the coexistence of multiple P- and M-twists in a single belt molecule. Three-dimensional structures of the multiply twisted aromatic belts were confirmed by X-ray crystallography, revealing that their topology depends on the sequence of P- and M-twists. Decomposition analysis of the linking number (Lk) shows that the twisting number (Tw) of the triply twisted Möbius belt is Tw = 2.45, among the highest Tw found for twisted conjugated macrocycles. Analysis of the electron density of delocalized bonds reveals that the electronic structure has unique Lk-dependent topologies, such as a catenane and a trefoil knot. [Figure not available: see fulltext.].

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A Switchable Near-Infrared-Absorbing Dye Based on Redox-Bistable Benzitetraazaporphyrin

Yanagi S., Matsumoto A., Toriumi N., Tanaka Y., Miyamoto K., Muranaka A., Uchiyama M.

Angewandte Chemie - International Edition 62 ( 11 ) 2023.03

Research paper (scientific journal), Accepted, ISSN 14337851

Activatable near-infrared (NIR) dyes responsive to external stimuli are used in medical and other applications. Here, we describe the design and synthesis of bench-stable 18π- and 20π-electron benzitetraazaporphyrins (BzTAPs) possessing redox-switchable NIR properties. X-Ray, NMR, and UV/Visible-NIR analyses revealed that 20π-electron BzTAP 1 exhibits NIR absorption and antiaromaticity with a paratropic ring-current, while 18π-electron BzTAP 2 shows weakly aromatic character with NIR inertness. Notably, the NIR-silent BzTAP 2 was readily converted to the NIR-active BzTAP 1 in the presence of mild reducing agents such as amine. The intense NIR absorption band of BzTAP 1 is in sharp contrast to the very weak absorption bands of previously reported antiaromatic porphyrinoids. Molecular orbital analysis revealed that symmetry-lowering perturbation of the 20π-electron porphyrinoid skeleton enables the HOMO–LUMO transition of 1 to be electric-dipole-allowed. BzTAPs are expected to be useful for constructing activatable NIR probes working in reductive environments.

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A Switchable Near‐Infrared‐Absorbing Dye Based on Redox‐Bistable Benzitetraazaporphyrin

Shunsuke Yanagi, Akihisa Matsumoto, Naoyuki Toriumi, Yusuke Tanaka, Kazunori Miyamoto, Atsuya Muranaka, Masanobu Uchiyama

Angewandte Chemie 2023.03

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Synthesis, Characterization, and Reaction of Hypervalent Organo-λ3-bromanes and Chloranes

Miyamoto Kazunori, Uchiyama Masanobu, Ochiai Masahito

Journal of Synthetic Organic Chemistry, Japan (The Society of Synthetic Organic Chemistry, Japan) 81 ( 5 ) 416 - 427 2023

ISSN 00379980

Hypervalent organoiodine(III/V) reagents (λ3-/λ5-iodane) have enjoyed widespread application as oxidant/electrophile in synthetic organic chemistry. In contrast, the development of the chemistry of hypervalent organo-λ3-bromane and λ3-chlorane is still just beginning. We have developed a versatile, high-yield synthesis of λ3-chloranes and λ3-bromanes through the reaction of various haloarenes/chloroalkenes with readily prepared arenediazonium tetrakis(pentafluorophenyl)borate under mild conditions. The improved accessibility enabled us to investigate the unique physico-chemical characters and unprecedented reactivity of these hypervalent organo-λ3-haloganes (e.g. onium structure, enhanced electrophilicity, etc.). The leaving group ability of λ3-haloganyl groups was also evaluated as it governs the rate of a variety of chemical transformations.

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Cycloisomerization of enynones by aluminum halides: construction of bicyclo[3.1.0]hexanes by introducing halides

Daisuke Sato, Akira Tsubouchi, Yuichiro Watanabe, Keiichi Noguchi, Kazunori Miyamoto, Masanobu Uchiyama, Akio Saito

Organic Chemistry Frontiers 10 ( 5 ) 1112 - 1118 2022.12

ISSN 20524110

Alkyne π-bond activation by transition metal complexes has been well studied for cycloisomerization of enynes into bicyclo[3.1.0]hexanes, which can allow the introduction of carbon and oxygen functional groups concomitant with the construction of the core structures. However, the cycloisomerization of enynones through the activation of carbonyl groups into bicyclo[3.1.0]hexanes has not been achieved. Herein, we report the aluminum halide-mediated cycloisomerization of 7-en-2-ynones into halogenated bicyclo[3.1.0]hexanes.

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Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes

Toranosuke Iida, Junichiro Kanazawa, Tadafumi Matsunaga, Kazunori Miyamoto, Keiichi Hirano, Masanobu Uchiyama

Journal of the American Chemical Society 144 ( 48 ) 21848 - 21852 2022.12

ISSN 00027863

There is increasing interest in replacement of the planar aromatic rings of drug candidates with three-dimensional caged scaffolds in order to improve the physical properties, but bioisosteres of meta-substituted benzenes have remained elusive. We focused on the bicyclo[3.1.1]heptane (BCH) scaffold as a novel bioisostere of meta-substituted benzenes, anticipating that [3.1.1]propellane (2) would be a versatile precursor of diversely functionalized BCHs. Here, we describe a practical preparative method for [3.1.1]propellane from newly developed 1,5-diiodobicyclo[3.1.1]heptane (1), as well as difunctionalization reactions of 2 leading to functionalized BCHs. We also report postfunctionalization reactions of these products.

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A combined DFT-predictive and experimental exploration of the sensitivity towards nucleofuge variation in zwitterionic intermediates relating to mechanistic models for unimolecular chemical generation and trapping of free C2 and alternative bimolecular pathways involving no free C2

Henry S. Rzepa, Miki Arita, Kazunori Miyamoto, Masanobu Uchiyama

Physical Chemistry Chemical Physics 24 ( 42 ) 25816 - 25821 2022.10

ISSN 14639076

Following the recent report of the chemical generation and trapping at room temperatures of C2, generated from an alkynyl phenyl iodonium salt, a computational analysis had indicated that both unimolecular fragmentation and bimolecular substitution mechanisms for the process could be envisaged. Here a combined theoretical and experimental analysis explores how the energetics of these mechanisms and resulting experimental products respond to variation in the nucleofuge. When the phenyl iodonium nucleofuge is replaced by pyridinium, trapping products are again obtained, which we conclude favours a bimolecular mechanism involving no free C2. Trapped products in greater yield were also observed using dibenzothiophenium as the nucleofuge in both condensed solution phase and most significantly in a two-flask room temperature experiment in which a volatile species, presumed to be C2, is transferred and trapped in a second flask. The energetics of the unimolecular fragmentation process producing C2 are predicted to be too high to correspond to a facile thermal reaction, which means that an experimental/theoretical dichotomy remains to be explained.

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Diamond-rich crystalline nanosheets seeded with a Langmuir monolayer of arachidic acid on water

Toshihiko Tanaka, Yasuhiro F. Miura, Tetsuya Aoyama, Kazunori Miyamoto, Yoshiya Akagi, Masanobu Uchiyama, Eiji Osawa

RSC Advances 12 ( 41 ) 26575 - 26579 2022.09

The enigmatic self-assembling ability of nanodiamond (ND) particles has been discovered herein. Diamond-rich crystalline nanosheets with thickness of approximately ∼25 nm were grown from a Langmuir monolayer of arachidic acid (AA) at the interface between air and a dilute aqueous ND solution. Their fine rectangular shapes with uniform uniaxial birefringence indicate appreciable crystallinity, thus supporting that they are hydrated colloidal crystals of homogeneous ND particles.

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In Situ Generation of N-Triflylimino-λ3-iodanes: Application to Imidation of Phosphines and Catalytic α-Amidation of 1,3-Dicarbonyl Compounds

Shun Sunagawa, Fumiya Morisaki, Takafumi Baba, Akira Tsubouchi, Akira Yoshimura, Kazunori Miyamoto, Masanobu Uchiyama, Akio Saito

Organic Letters 24 ( 28 ) 5230 - 5234 2022.07

ISSN 15237060

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Synthesis of Cyclophenacene‐ and Chiral‐Type Cyclophenylene–Naphthylene Belts

Juntaro Nogami, Yuki Nagashima, Kazunori Miyamoto, Haruki Sugiyama, Yusuke Tanaka, Hidehiro Uekusa, Atsuya Muranaka, Masanobu Uchiyama, Ken Tanaka

Angewandte Chemie International Edition (Wiley) 61 ( 15 ) 2022.04

ISSN 14337851

We report the synthesis of a [20]cyclophenacene-type cyclophenylene-naphthylene (CPN) belt and the enantioselective synthesis of chiral-type CPN belts (up to >99 % ee) by the cationic rhodium(I)-catalyzed intramolecular [2+2+2] cycloaddition of naphthalene-embedded cyclic polyynes. The synthesis of a depth-expanded CPN belt was also attempted, but the final intramolecular [2+2+2] cycloaddition was unsuccessful. Theoretical calculations clarified that the reactivity depends on the stability of the transition state in the initial oxidative cycloaddition step which is subject to molecular strain. The cylindrical structures of these CPN belts were confirmed by X-ray crystallographic analyses. As a result of π-extension through the introduction of naphthalenes in the chiral-type CPN belts, the anisotropy dissymmetry factors of electronic circular dichroism and circularly polarized luminescence are amplified compared with the corresponding zigzag-type chiral cyclophenylene belts.

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Improvement in aqueous solubility of achiral symmetric cyclofenil by modification to a chiral asymmetric analog

Morimoto J., Miyamoto K., Ichikawa Y., Uchiyama M., Makishima M., Hashimoto Y., Ishikawa M.

Scientific Reports 11 ( 1 ) 2021.12

Decreasing the partition coefficient (LogP) by the introduction of a hydrophilic group is the conventional approach for improving the aqueous solubility of drug candidates, but is not always effective. Since melting point is related to aqueous solubility, we and other groups have developed alternative strategies to improve solubility by means of chemical modification to weaken intermolecular interaction in the solid state, thereby lowering the melting point and increasing the solubility. Here, we show that converting the symmetrical molecular structure of the clinically used estrogen receptor (ER) antagonist cyclofenil (1) into asymmetrical form by introducing an alkyl group enhances the aqueous solubility. Among the synthesized analogs, the chiral methylated analog (R)-4c shows the highest solubility, being 3.6-fold more soluble than 1 even though its hydrophobicity is increased by the methylation. Furthermore, (R)-4c also showed higher membrane permeability than 1, while retaining a comparable metabolic rate, and equivalent biological activity of the active forms (R)-13a to 2. Further validation of this strategy using lead compounds having symmetric structures is expected.

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Stereodivergent Nitrocyclopropane Formation during Biosynthesis of Belactosins and Hormaomycins

Shotaro Shimo, Richiro Ushimaru, Alicia Engelbrecht, Mei Harada, Kazunori Miyamoto, Andreas Kulik, Masanobu Uchiyama, Leonard Kaysser, Ikuro Abe

Journal of the American Chemical Society (American Chemical Society ({ACS})) 143 ( 44 ) 18413 - 18418 2021.11

ISSN 00027863

Belactosins and hormaomycins are peptide natural products containing 3-(2-aminocyclopropyl)alanine and 3-(2-nitrocyclopropyl)alanine residues, respectively, with opposite stereoconfigurations of the cyclopropane ring. Herein we demonstrate that the heme oxygenase-like enzymes BelK and HrmI catalyze the N-oxygenation of l-lysine to generate 6-nitronorleucine. The nonheme iron enzymes BelL and HrmJ then cyclize the nitroalkane moiety to the nitrocyclopropane ring with the desired stereochemistry found in the corresponding natural products. We also show that both cyclopropanases remove the 4-proS-H of 6-nitronorleucine during the cyclization, establishing the inversion and retention of the configuration at C4 during the BelL and HrmJ reactions, respectively. This study reveals the unique strategy for stereocontrolled cyclopropane synthesis in nature.

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Molecular and Computational Bases for Spirofuranone Formation in Setosusin Biosynthesis

Xingxing Wei, Taro Matsuyama, Hajime Sato, Dexiu Yan, Pui Man Chan, Kazunori Miyamoto, Masanobu Uchiyama, Yudai Matsuda

Journal of the American Chemical Society (American Chemical Society ({ACS})) 143 ( 42 ) 17708 - 17715 2021.10

ISSN 00027863

The 3(2H)-furanone unit is observed in many biologically active natural products, as represented by the antifungal medication griseofulvin. Setosusin (1) is a fungal meroditerpenoid featuring a unique spiro-fused 3(2H)-furanone moiety; however, the biosynthetic basis for spirofuranone formation has not been investigated since its isolation. Therefore, in this study we identified the biosynthetic gene cluster of 1 in the fungus Aspergillus duricaulis CBS 481.65 and elucidated its biosynthetic pathway by heterologous reconstitution of related enzyme activities in Aspergillus oryzae. To understand the reaction mechanism to afford spirofuranone, we subsequently performed a series of in vivo and in vitro isotope-incorporation experiments and theoretical calculations. The results indicated that SetF, the cytochrome P450 enzyme that is critical for spirofuranone synthesis, not only performs the epoxidation of the polyketide portion of the substrate but also facilitates the protonation-initiated structural rearrangement to yield 1. Finally, a mutagenesis experiment using SetF identified Lys303 as one of the potential catalytic residues that are important for spirofuranone synthesis.

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