Published papers

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.

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.

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.

With the increasing importance of fluorine to medicinal chemistry and other areas, methods to access various fluorinated compounds are needed. Herein, we report the synthesis of difluoropropargyl vinyl ethers from ketones and aldehydes using difluoropropargyl bromide dicobalt complexes. We applied difluoropropargyl vinyl ethers to the synthesis of difluorodienone or difluoroallene under thermal conditions and trifluoro-pyran under acid-catalyzed conditions.

Spiroviolene is a spirocyclic triquinane diterpene produced by Streptomyces violens. Recently, a biosynthetic pathway that includes secondary carbocation intermediates and a complicated concerted skeletal rearrangement was proposed for spiroviolene, based upon careful labeling experiments. On the basis of density functional theory (DFT) calculations, we propose a revised pathway for spiroviolene biosynthesis, involving a multistep carbocation cascade that bypasses the formation of unstable secondary carbocations by breaking the adjacent C–C bond to form a more stable tertiary carbocation (IM3) and by Wagner–Meerwein 1,2-methyl rearrangement (IM7).

The bicyclo[1.1.1]pentane (BCP) scaffold is useful in medicinal chemistry, and many protocols are available for synthesizing BCP derivatives from [1.1.1]propellane. Here, we report (1) the α-cyclodextrin (α-CD) encapsulation of BCP derivatives, affording a stable, readily storable material from which BCPs can be easily and quantitatively recovered and (2) new and simple protocols for deiodination reaction of 1,3-diiodo BCP to afford [1.1.1]propellane in protic/aprotic/polar/non-polar solvents. The combination of these methodologies enables simple, on-demand preparation of [1.1.1]propellane in various solvents under mild conditions from α-CD capsules containing 1,3-diiodo BCP.

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.

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.].

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.

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.

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.

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.)

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.

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.

We present a new type of elementoboration reaction, the thioboration of terminal alkynes. This method enables highly controllable regio-/stereo-/chemoselective cis- and trans-thioboration on demand, affording synthetically versatile and densely functionalized vinyl boron/vinyl sulfide derivatives in a straightforward manner without the need for a transition-metal catalyst.