Published papers

© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Molecular arrangements of bowl-shaped molecules, corannulene and sumanene, in single-walled carbon nanotubes (SWCNTs) were investigated using high-resolution transmission microscopy and near-infrared photoluminescence spectroscopy. The results indicated that corannulenes are nested in SWCNTs with a random orientation, whereas sumanenes form stacked structures. The trends are consistent with the molecular orientations of corannulene and sumanene in single crystals.

© 2018 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Fatty acid monoesters of hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol] were synthesized in two steps from tyrosol (4-hydroxyphenylethanol) by successive Candida antarctica lipase B-catalyzed chemoselective acylation on the primary aliphatic hydroxy group over phenolic hydroxy group in tyrosol, and 2-iodoxybenzoic acid (IBX)-mediated hydroxylation adjacent to the remaining free phenolic hydroxy group. Examination of their suppression effects on nitric oxide production stimulated by lipopolysaccharides in RAW264.7 cells showed that hydroxytyrosol butyrate exhibited the highest inhibition (IC 50 7.0 μM) among the tested compounds.

© 2019 The Japan Institute of Heterocyclic Chemistry. Lipase-catalyzed site-selective deacetylation of 2,5-dimethylnaphthalene-l,4-diol diacetate was examined. With Candida antarctica lipase B, the suppressing effect of a methyl substituent at the peri-position of the a-naphthyl ester over that at the ortho-position was significant. This site-selectivity was in contrast to that of chemical hydrolysis reported to date. From the resulting monoacetate, mansonone F, a physiologically active heterocyclic orthoquinone, was synthesized in 38% yield in as few as three steps.

© 2019 The Japan Institute of Heterocyclic Chemistry. Candida antarctica lipase B-catalyzed deacetylation proceeded with high site-selectivity on the C-4′ acetyl group in apigenin triacetate to give apigenin 5,7-diacetate. Methylation of the liberated hydroxy group with the combination of trimethyloxonium tetrafluoroborate (Meerwein reagent) and 1,8-bis(dimethylamino)naphthalene (proton sponge) in CH2Cl2 proceeded in a quantitative manner to give the product methylated at the C-4′ hydroxy group (acacetin 5,7-diacetate). Even with the same precursor, a different methylation product at the C-7 hydroxy group (genkwanin 4′,5-diacetate) was obtained in 86% yield by applying iodomethane and Cs2CO3 in dimethyl sulfoxide (DMSO). The methylated products were deprotected to form acacetin and genkwanin. We inferred that the latter unexpected methylation was ascribable to the intermolecular migration of an acetyl group from C-7 to C-4′. DFT calculations indicated that the C-7 phenoxide ion was 12.6 kJ/mol more stable than the initially formed C-4′ phenoxide ion.

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3′,4′,7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3′,4′-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI 50 ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF, RI 50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 50 18 nm). Fluoro-substituted 5-fluoro-3′,4′,7-trimethoxyflavone (FTMF, RI 50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3′,4′-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

© 2020, © 2020 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Catathelasmols C, D, and E, which had been isolated from Catathelasma imperiale as inhibitors for 11-hydroxysteroid dehydrogenases, were comprehensively semisynthesized from commercially available D-glutamic acid. The key synthetic intermediate, (R)-pentane-1,2,5-triol, was site-selectively acetylated by treatment with vinyl acetate and Candida antarctica lipase B (Novozym 435) in tetrahydrofuran (THF) at 25°C to furnish 1,5-diacetate (catathelasmol E, quantitative). The acetylation occurred site-selectively on the primary alcohols at the C-1 and C-5 positions over the secondary alcohol at the C-2 position. Dichromic acid oxidation provided 2-oxopentane-1,5-diyl diacetate (catathelasmol C, 78%). Burkholderia cepacia lipase-catalyzed transesterification with methanol in THF at–5°C proceeded preferentially on the acetate at C-1 located adjacent to the C-2 carbonyl group over the other terminal acetate at the C-5 position. 5-Hydroxy-4-oxopentyl acetate (catathelasmol D) was obtained in 53% yield.

© 2020, © 2020 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Hot water extraction of D-arabinofuranosylvitexin from the raw leaves of commercially available Basella alba “Tsurumurasaki” and subsequent acidic hydrolysis was improved to be a procedure using a high-pressure steam sterilizer to afford vitexin. The amount was estimated to be 14.1 mg from 1 g of dry weight of the raw leaves, whose recovery was calculated to be 95% based on the estimated content of D-arabinofuranosylvitexin in B. alba raw leaves. The product was dehydratively cyclized between hydroxy groups on the carbohydrate and flavone skeletons under modified Mitsunobu reaction conditions in N,N-dimethylformamide to give chafuroside B, which is known to be a bioactive Oolong tea polyphenol. Through these transformations, 10.2 mg of chafuroside B could be semisynthesized from 1 g of dry weight of the raw leaves, and the efficiency was improved compared to that from the extraction from Oolong tea (3.4 μg from 1 g of dry weight).

This journal is © The Royal Society of Chemistry. A stepwise dehydrogenative cross-coupling method was developed for the formation of sterically hindered Csp3-Csp3 bonds. Intramolecular dehydrogenative O-alkylation of a β-ketoester by 2,3-dichloro-5,6-dicyano-p-benzoquinone to form an oxolane followed by Lewis acid-catalyzed [1,3]-rearrangement furnished the sesquiterpene arylmethylcyclopentane skeleton. The formal syntheses of herbertane-type β-herbertenol, cuparane-type enokipodins A and B were also achieved.

© 2020 Wiley-VCH GmbH Interconversion of atropisomers of chiral 3,3’-di-tert-butyl-9,9’-bicarbazole linked by a single N−N bond was analyzed by DFT calculations and experiments. The calculations revealed that the trans transition state has a lower energy for the interconversion than the cis transition state. The lowest transition state of interconversion between natural dixiamycins A and B containing a 9,9’-bicarbazole structure was found to be the trans transition state. The calculations also indicated that degradation through N−N bond cleavage was faster than racemization. Atropisomeric enantiomers of 3,3’-di-tert-butyl-9,9’-bicarbazole were resolved by chiral HPLC for the first time, and then racemization and N−N bond cleavage were investigated by heating experiments, showing that racemization did not take place below the degradation temperature.

© 2020 Wiley-VCH GmbH Herein, we report a C−S cross-coupling reaction between alkyl thiols or aryl thiols and ortho-substituted arylboronic acids that proceeds in the presence of an inexpensive and ligand-free NiCl2 ⋅ 6H2O salt and N-methylmorpholine, a weak base, at 25 °C in air. The presence of coordinating and electron-withdrawing groups at the ortho-position of the arylboronic acids played a crucial role in determining the efficiency of the reaction. X-ray crystallographic analysis revealed that the [NiCl2(DMF)2(H2O)2] complex was formed in-situ. The complex is an excellent precursor of the active nickel species. The reaction offers an extremely mild and operationally convenient method to access a wide variety of alkyl aryl sulfides and diaryl sulfides without using expensive transition metals, such as palladium, gold, and rhodium, and specialized and expensive ligands.

© 2020 The Japan Institute of Heterocyclic Chemistry. The syntheses of indirubin (76% yield), 6-bromoindirubin (82% yield), and 6-bromoindirubin-3′-oxime (78% yield in two steps) were achieved via the lipase-triggered aldol condensation between isatins and an indoxyl anion in tetrahydrofuran under anhydrous and anaerobic conditions as the key step. The aldol donor was generated in situ by Burkholderia cepacia lipase (Amano PS-IM)-catalyzed deacetylation of commercially available and stable indoxyl acetate in the presence of triethylamine and with 2-propanol as the transesterification reagent. The scale-up of the presently developed reactions is easier than that in the previously reported chemical aldol condensations, because of the simplicity of the isolation procedure and suppression of the oxidative byproduct formation from indoxyl acetate.

© 2021 The Authors. Published by Wiley-VCH GmbH Dearomative heterocyclic [4+2] cycloaddition between the N-(2,4-dinitrophenyl)pyridinium ion of nicotinamide and an enol ether was analyzed by Density Functional Theory (DFT) calculations. The calculation revealed that the reaction undergoes stepwise bond formation rather than occurring in a concerted manner. The experimental products were found to be both kinetically and thermodynamically favored. The calculated transition states and intermediate suggested that the high diastereoselectivity is derived from the electrostatic interaction between the 2-nitro group of the pyridinium ion and the hydrogen of the enol ether.

© 2021 Wiley-VCH GmbH The total synthesis of dehydroantofine was achieved by employing a novel, regioselective, azahetero Diels–Alder reaction of easily accessible 3,5-dichloro-2H-1,4-oxazin-2-one with 14 a as a key step. Furthermore, it is demonstrated that dehydroantofine is a promising candidate as a new antimalarial agent in a biological assay with chloroquine-resistant Plasmodium falciparum.

© The Author(s) 2020. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry. Caffeic acid β-phenethyl ester (CAPE), an antioxidative bioactive catechol isolated from propolis, was semisynthesized from chlorogenic acid and related compounds in an extract of raw (unroasted) Robusta coffee (Coffea canephora) beans in 5 steps and a total yield of 31%. Oxidative degradation of the intermediates and target molecule was prevented by alkaline hydrolysis of the chlorogenic acids in the presence of sodium dithionite (Na2S2O4) and deprotection of the catecholic diacetate precursor by Candida antarctica lipase B-mediated transesterification as the final step.

© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry. Prunetin (4',5-dihydroxy-7-methoxyisoflavone) was semisynthesized in 8 steps from readily available naringenin in 26% total yield. The key reaction was chemoenzymatic sequential deacetylation to 6'-acetoxy-2',4″-dihydroxy-4'-methoxychalcone, the in situ-formed precursor for thallium(III) nitrate-mediated oxidative rearrangement.

Electric switches are one of the most fundamental electric circuitries. Recent developments in single-molecule techniques allow us to study various electric-switching phenomena on the single-molecule scale. In this study, the switch of the current through a single molecule of a biphenothiazine derivative was investigated using the break junction technique. The biphenothiazine derivative undergoes acid-base reaction-induced electronic modulation due to the reversible structural transformation between a closed shell and an open shell, resulting in a change in the electronic gap and effective tunneling barrier height. We succeeded in controlling the single-molecule electric conductivity of the biphenothiazine derivative wired to two Au electrodes by allowing the reaction to proceed reversibly on the electrode.

The 1,2-rearrangement of o-quinols has been a long-standing unsolved problem since 1958. Although the rearrangement is expected to be useful for syntheses of catechol derivatives, it is hampered by many competing reactions and has not been developed as a useful methodology. Here, we succeeded in settling this problem by a first systematic thorough investigation, establishing the 1,2-rearrangement as a cascade reaction with a retro Diels-Alder reaction from o-quinol dimers. This is a useful strategy for syntheses of substituted catechols used as synthetic building blocks for bioactive compounds and material molecules. o-Quinol dimers were synthesized by improved oxidative hydroxylation of substituted phenols followed by spontaneous Diels-Alder reaction. The dimers then underwent the retro Diels-Alder reaction to regenerate the o-quinols followed by 1,2-rearrangement under neutral heating conditions at an appropriate temperature depending on the migratory substituent, furnishing substituted catechols in good yields. The competing reactions such as an elimination of a substituent or α-ketol rearrangement were minimized by controlling the reaction temperature.

The 1H-2-benzopyran-5,8-dione structure was synthesized by a cascade reaction through Michael addition, elimination of HBr, and O-alkylation between a dibromobenzoquinone derivative and β-ketoesters under basic conditions. The reaction using potassium carbonate and 18-crown-6 in THF was the best condition, giving 1H-2-benzopyran-5,8-dione derivatives in good yields. The UV-vis absorption spectrum and cyclic voltammogram of the synthesized 1H-2-benzopyran-5,8-dione derivative were measured, clarifying the photophysical and redox properties.

Metabolically stable C-glycosides are an essential family of compounds in bioactive natural products, therapeutic agents, and biological probes. For their application, development of synthetic methods by connecting glycosides and aglycons with strict stereocontrol at the anomeric carbon, as well as with high functional-group compatibility and environmental compatibility is a pivotal issue. Although Suzuki–Miyaura-type C(sp3)−C(sp2) cross-coupling using glycosyl boronates is a potential candidate for the construction of C-glycosides, neither the cross-coupling itself nor the facile synthesis of the coupling precursor, glycosyl boronates, have been achieved to date. Herein, it was succeeded to develop a copper-catalyzed stereoselective one-step borylation of glycosyl bromides to glycosyl boronates and palladium-catalyzed stereospecific cross-coupling of β-glycosyl borates with aryl bromides to give aryl β-C-glycosides, in which the β-configuration of the anomeric carbon of the glycosyl trifluoroborates is stereoretentively transferred to that of the resulting aryl C-glycosides.

We developed a one-step synthesis of acylborons from both readily available acyl chlorides and bis(pinacolato)diboron through copper(I)-catalyzed borylation. Under the reaction conditions using tBuOLi, polystyrene-supported triphenylphosphine as a copper ligand was found to promote the borylation of acyl chlorides while suppressing alcoholysis. This method enables the facile synthesis of potassium acyltrifluoroborates.