論文 - 高尾　賢一

Synthesis of Tetrahydro-β-carbolines via Cascade Sigmatropic Rearrangements

Oka D., Ohtsuka T., Takao K.i., Ogura A.

Advanced Synthesis and Catalysis 367 （ 3 ）  2025年02月

ISSN  16154150

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We have developed a synthesis for tetrahydro-β-carbolines involving cascade sigmatropic rearrangements. The substrates were conveniently prepared from parent anilines via a [2,3]-sigmatropic rearrangement and cyanomethylation. Silver-mediated decyanation afforded the corresponding iminium cation, which underwent a cascade consisting of an aza-Cope rearrangement, an aza-oxa-Cope rearrangement, an aromatization, and a Pictet-Spengler reaction, and tetrahydro-β-carbolines were obtained as the single product. The reaction involved seven bond scissions and four bond formations and was triggered by a single reagent.

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Synthetic Studies of Polycyclic Polyprenylated Acylphloroglucinols: Asymmetric Construction of a Cyclohexanone Moiety

Nanataki S., Aoki D., Onozawa H., Akiya T., Okuyama G., Abo K., Yoshida K., Ogura A., Takao K.I.

Synlett 36 （ 10 ） 1375 - 1378 2025年

ISSN  09365214

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As a common intermediate for polycyclic polyprenylated acylphloroglucinols (PPAPs), we successfully synthesized a cyclohexanone moiety that contains two adjacent stereocenters, one of which is a quaternary carbon. Our synthetic strategy relied on an asymmetric Claisen rearrangement using Oppolzer's camphorsultam and a regioselective Dieckmann condensation.

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Antiproliferative activities through accelerating autophagic flux by basidalin and its analogs in human cancer cells

Matagawa T., Sasazawa Y., Agui K., Fujimaki M., Kawano S., Ogura A., Takao K.i., Igarashi M., Simizu S.

Bioorganic and Medicinal Chemistry Letters （Bioorganic and Medicinal Chemistry Letters）  104 2024年05月

ISSN  0960894X

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Basidalin, isolated from the basidiomycete Leucoagaricus naucina, has previously demonstrated antibacterial and antitumor properties against murine cancer cells in vivo, but its effects on human cancer cells remain unknown. In this study, we found that basidalin possesses antiproliferative activity against human cancer cell lines. To elucidate the antiproliferative mechanism of basidalin, we focused on autophagy. Treatment with basidalin led to an increase in LC3-II expression level, and accelerated autophagic flux through an mTOR-independent pathway. Moreover, according to the structure–activity relationship analysis—including newly synthesized basidalin analogs—the formyl group, not the amino group, contributes to the antiproliferative activities of basidalin against human cancer cells. Additionally, the antiproliferative activity of basidalin analogs was strongly correlated with autophagy-inducing activity, indicating that basidalin exhibits antiproliferative activity through autophagy induction. These data suggest that basidalin, characterized by its ability to upregulate autophagic flux, emerges as a novel anticancer drug.

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Open system massive synthesis of narrow-band blue and green fluorescent graphene quantum dots and their application in water sensing

Ochi Y., Otani A., Katakami R., Ogura A., Takao K.I., Iso Y., Isobe T.

Journal of Materials Chemistry C （Journal of Materials Chemistry C）  12 （ 18 ） 6548 - 6558 2024年04月

ISSN  20507526

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Graphene quantum dots (GQDs) are environmentally friendly fluorescent carbon-based nanomaterials. However, there is no report on the massive synthesis of GQDs with narrow-band fluorescence and a high photoluminescence quantum yield (PLQY) using a simple liquid-phase method under atmospheric conditions. In this study, GQDs were successfully synthesized in ∼100% product yield by heating phloroglucinol (PG) with Na3PO4·12H2O in 1,2-pentanediol at 180 °C for 6 h in an open system with air flow, followed by dialysis purification. The high product yield was attributed to the addition of Na3PO4·12H2O as a base catalyst, which promoted the dehydration-condensation reaction between PG molecules. The dispersion of PG derived GQDs (PG-GQDs) in ethanol resulted in blue fluorescence with a full width at half maximum of 32 nm and a PLQY of 54%. Further purification of PG-GQDs by silica gel column chromatography improved the PLQY to 75%. Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, and X-ray photoelectron spectroscopy confirmed that dehydration-condensation reactions occurred not only between PGs but also between GQDs and 1,2-pentanediol. The binding of 1,2-pentanediol to the edges of GQDs suppressed the stacking of GQDs and prevented concentration quenching, resulting in a high PLQY. PG-GQDs exhibited negative fluorescence solvatochromism, i.e., the fluorescence wavelength blue-shifted with increasing solvent polarity. Dispersion of PG-GQDs in N-methyl-2-pyrrolidone (MP) resulted in green fluorescence with a PLQY of 96%. Dispersion of PG-GQDs in water resulted in blue fluorescence and a low PLQY of 6% at pH 7, while the PLQY was more than 50% at pH ≥ 11. Using these properties, the sensing of water (pH 13) in MP was investigated. The results showed that as the water content was increased from 0% to 100%, the fluorescence color gradually changed from green to blue and the fluorescence wavelength continuously shifted from 514 nm to 466 nm, indicating their applicability in water sensing.

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Red-light-mediated Barton decarboxylation reaction and one-pot wavelength-selective transformations

Yamamoto H., Yamaoka K., Shinohara A., Shibata K., Takao K.I., Ogura A.

Chemical Science （Chemical Science）  14 （ 40 ） 11243 - 11250 2023年09月

ISSN  20416520

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In organic chemistry, selecting mild conditions for transformations and saving energy are increasingly important for achieving sustainable development goals. Herein, we describe a red-light-mediated Barton decarboxylation using readily available red-light-emitting diodes as the energy source and zinc tetraphenylporphyrin as the catalyst, avoiding explosive or hazardous reagents or external heating. Mechanistic studies suggest that the reaction probably proceeds via Dexter energy transfer between the activated catalyst and the Barton ester. Furthermore, a one-pot wavelength-selective reaction within the visible light range is developed in combination with a blue-light-mediated photoredox reaction, demonstrating the compatibility of two photochemical transformations based on mechanistic differences. This one-pot process expands the limits of the decarboxylative Giese reaction beyond polarity matching.

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Open system synthesis of narrow-bandwidth red-fluorescent carbon quantum dots with a function of multi-metal ion sensing

Katakami R., Sato K., Ogura A., Takao K.I., Iso Y., Isobe T.

Journal of Materials Chemistry C （Journal of Materials Chemistry C）  11 （ 12 ） 4143 - 4152 2023年03月

ISSN  2050-7526

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Carbon quantum dots (CQDs) are environmentally friendly phosphors. However, there have been few reports on red-emitting CQDs with narrow-bandwidths, all of which were synthesized via solvothermal methods using autoclaves. Here, red-emitting CQDs were synthesized from 4,6-diaminoresorcinol dihydrochloride (DAR), which is an aromatic compound with electron-donating hydroxy and amino groups. The synthesis involved heating at 180 °C for 6 h in a high-boiling-point 1,2-pentanediol solvent in an open system without using autoclaves and catalysts. The DAR-derived-CQDs in ethanol exhibited red photoluminescence with a 0.14 eV full width at half-maximum that was comparable to that of narrow-bandwidth blue-fluorescent phloroglucinol (PG)-derived-CQDs. The red emission was attributed to a weakened quantum-size effect and electron-donating NH2 groups. The hydroxy groups of PG-derived-CQDs interacted with Al3+ and Fe3+ ions, resulting in fluorescence quenching. DAR-derived-CQDs have hydroxy and amino groups, which facilitate the fluorescence quenching for Al3+, Fe3+, Cu2+, and Pb2+ ions.

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Synthesis of Indoles via Sigmatropic Rearrangements and Olefin Isomerization

Uchida T., Saito R., Takao K.i., Ogura A.

Advanced Synthesis and Catalysis （Advanced Synthesis and Catalysis）  366 （ 3 ） 465 - 472 2023年

ISSN  16154150

　概要を見る

Indoles are important heterocycles in pharmaceuticals and agrochemicals, and their atom-economical synthesis is needed. Herein, we describe the synthesis of indoles using sigmatropic rearrangements. The N-allylaniline was oxidized by environmentally benign hydrogen peroxide, and spontaneous [2,3]-Meisenheimer rearrangement gave N-allyloxyaniline. Subsequent treatment with a ruthenium catalyst afforded N-vinyloxyaniline, which underwent [3,3]-sigmatropic rearrangement to give indoles, expelling water as the only byproduct. The whole sequence is free of quantitative salt byproducts, thereby avoiding aqueous work up and cutting off the inorganic waste.

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Asymmetric Synthesis of Cyclopentene Compounds Containing All-Carbon Quaternary Stereocenters by (3 + 2) Cycloaddition and Its Application in the Formal Synthesis of (R)-(-)-Puraquinonic Acid

Oga M., Takamatsu Y., Ogura A., Takao K.I.

Journal of Organic Chemistry （Journal of Organic Chemistry）  87 （ 13 ） 8788 - 8795 2022年07月

ISSN  00223263

　概要を見る

A highly stereoselective (3 + 2) cycloaddition for the asymmetric synthesis of versatile cyclopentene compounds containing all-carbon quaternary stereocenters was developed. The phosphine-catalyzed reactions of alkynoates with α-alkylated electron-deficient alkenes bearing Oppolzer's camphorsultam showed high to excellent diastereoselectivities and perfect regioselectivities. The usefulness of this reaction was demonstrated in the concise formal synthesis of (R)-(-)-puraquinonic acid.

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Elucidation of structure-activity relationship of humulanolides and identification of humulanolide analog as a novel HSP90 inhibitor

Saegusa J., Osada Y., Miura K., Sasazawa Y., Ogura A., Takao K.i., Simizu S.

Bioorganic and Medicinal Chemistry Letters （Bioorganic and Medicinal Chemistry Letters）  60 2022年03月

ISSN  0960894X

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Humulanolides are natural products isolated from Asteriscus, and the isolation and total synthesis of many types of humulanolides have been reported. In this study, we evaluated anti-proliferative activity of twelve humulanolides against various human cancer cell lines and found that humulanolide analog E, which was newly designed and synthesized, exhibited the highest anti-proliferative activity. Structure-activity relationship analysis revealed that α,β-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. To identify molecular targets of humulanolide analog E, we investigated various cell-based and in vitro assays. Treatment with humulanolide analog E against human fibrosarcoma HT1080 cells increased the expression level of HSP70 protein and decreased the levels of AKT and CDK4, which are HSP90 client proteins. Moreover, humulanolide analog E inhibited refolding of denatured luciferase protein via suppression of HSP90 activity in vitro. These results suggest that humulanolide analog E possesses the anti-proliferative activity against human cancer cells by inhibiting HSP90 functions.

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Development of TfOH-Catalyzed Spirocyclization by Intramolecular Friedel-Crafts-type 1,4-Addition: Application to the Total Synthesis of the Unusual Proaporphine Alkaloid (±)-Misrametine

Yoshida K., Hidaka A., Fukami Y., Fujino Y., Imaizumi Y., Takao K.i., Kitagaki S.

Chemistry - A European Journal （Chemistry - A European Journal）  28 （ 60 ）  2022年

ISSN  09476539

　概要を見る

An effective method was developed for TfOH-catalyzed construction of spiroindanes and spirotetralines containing an all-carbon quaternary stereocenter. Intramolecular Friedel-Crafts-type 1,4-addition of the substrates which were di- or trimethoxybenzene and 2-cyclohexenone linked by an alkyl chain proceeded smoothly in the presence of 30 mol % of TfOH. A variety of spiroindanes and spirotetralines were obtained with moderate to excellent yield by this method. The reaction was successfully applied in the first total synthesis of the unusual proaporphine alkaloid (±)-misrametine, which included the gram-scale spirocyclization and selective O-demethylation used KCN in DMSO condition as key steps.

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Asymmetric Diels–Alder reaction between furans and propiolates

Ogura A., Ito T., Moriya K., Horigome H., Takao K.i.

Tetrahedron Letters （Tetrahedron Letters）  72 2021年05月

ISSN  00404039

　概要を見る

We report the first asymmetric Diels–Alder reaction between furan and propiolates. Propiolate, a dienophile, was equipped with an Evans’ auxiliary and a sulfonyl group to control and facilitate diastereoselective cycloaddition. Treatment with furan as a diene and aluminium Lewis acid afforded a 7-oxabicyclo[2.2.1]heptadiene skeleton diastereoselectively. The origin of diastereoselectivity can be explained by chelation of aluminium center to carbonyl groups and oxygen of furan. Friedel–Crafts-type products were obtained when pyrrole was used as diene.

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Glycothermally Synthesized Carbon Dots with Narrow-Bandwidth and Color-Tunable Solvatochromic Fluorescence for Wide-Color-Gamut Displays

Yoshinaga T., Shinoda M., Iso Y., Isobe T., Ogura A., Takao K.I.

ACS Omega （ACS Omega）  6 （ 2 ） 1741 - 1750 2021年01月

ISSN  2470-1343

　概要を見る

Fluorescent carbon dots (CDs) represent a promising eco-friendly next-generation phosphor. However, most CDs exhibit broad photoluminescence (PL) spectra [full width at half-maximum (fwhm) over 60 nm]; few works on CDs with sharp PL spectra (fwhm less than 40 nm) have been reported. In addition, their syntheses and color tuning require harsh conditions of high temperatures, long reaction times, and high pressures with catalysts. Here, we successfully prepared narrow-bandwidth emissive CDs (fwhm of 27-40 nm) from phloroglucinol in a glycol solvent of 1,2-pentanediol at temperatures as low as 180 °C for a reaction duration of as short as 6 h under ambient conditions without any catalysts via an open reaction system in which dehydration and condensation reactions among phloroglucinol molecules were enhanced. We shifted the emission peak from 463 to 511 nm by selecting seven kinds of solvents with different polarities, that is, emission colors could be tuned from blue to green by taking advantage of fluorescence solvatochromism. The CD-dispersed polymer films showed a similar solvatochromic behavior and sharp PL spectra, verifying the feasibility of applying the CDs to displays with a wide color gamut.

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Diaryliodonium Salt-Based Synthesis of N-Alkoxyindolines and Further Insights into the Ishikawa Indole Synthesis

Shibata K., Takao K.I., Ogura A.

Journal of Organic Chemistry （Journal of Organic Chemistry）  86 （ 15 ） 10067 - 10087 2021年

ISSN  00223263

　概要を見る

A diaryliodonium salt-based strategy enabled the first systematic synthesis of rarely accessible N-alkoxyindoles. Mechanistic analyses suggested that the reaction likely involves reductive elimination of iodobenzene from iodaoxazepine via a four-membered transition state, followed by Meisenheimer rearrangement. Substrates with N-carbamate protection afforded indole in a manner similar to that of the Ishikawa indole synthesis. Preinstallation of a stannyl group as an iodonium salt precursor greatly expanded the substrate scope, and further mechanistic insights are discussed.

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The stereoselective construction of all-carbon quaternary stereocenters by allylations and its application to synthetic studies of natural products

Sakama A., Ogura A., Yoshida K., Takao K.I.

Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry （Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry）  78 （ 11 ） 1039 - 1047 2020年11月

ISSN  00379980

　概要を見る

© 2020 Society of Synthetic Organic Chemistry. All rights reserved. The synthesis of organic compounds containing all.. carbon quaternary stereocenters through the addition of allylmetals to aldehydes is still a challenge. In this account we describe two methods to achieve this transformation stereoselectively: One involves the zinc-mediated Barbier-type allylation and the other allylboration of a sugar.. derived aldehyde. These methods were applied to the total synthesis of (+)-vibsanin A, and the synthesis of the tricyclic core of (-)-callophycoic acid A.

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Enantioselective Organocatalytic Construction of Spirochroman Derivatives

Yoshida K., Inoue H., Oji Y., Suzuki H., Takao K.I.

Journal of Organic Chemistry （Journal of Organic Chemistry）  85 （ 15 ） 10189 - 10197 2020年08月

ISSN  00223263

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Copyright © 2020 American Chemical Society. Highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. Intramolecular oxy-Michael addition was catalyzed with a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivities of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

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Red-Light-Mediated Barton-McCombie Reaction

Ogura Akihiro, Ichii Naoki, Shibata Kouhei, Takao Ken-ichi

BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN （Bulletin of the Chemical Society of Japan）  93 （ 7 ） 936 - 941 2020年07月

ISSN  0009-2673

　概要を見る

© 2020 Chemical Society of Japan. All rights reserved. A red-light-mediated BartonMcCombie reaction is described, in which chlorophyll a is used as a photocatalyst and tris(trimethylsilyl)silane or Hantzsch ester is used as the hydrogen source. The reaction can be performed with a set of easily available equipment and reagents, and a variety of linear and cyclic xanthates could be applied. In contrast to the traditional conditions, the reaction does not involve toxic organotin or an explosive radical initiator. The reaction mechanism was analyzed both by experiments and computation, and it was suggested that the radical chain mechanism initiated by excitation of complex followed by charge transfer is likely to be operative.

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Total Synthesis of Natural Products Using Intramolecular Nozaki-Hiyama-Takai-Kishi Reactions

Takao K.I., Ogura A., Yoshida K., Simizu S.

Synlett （Synlett）  31 （ 5 ） 421 - 433 2020年03月

ISSN  09365214

　概要を見る

© 2020 Georg Thieme Verlag. All rights reserved. In this Account, we describe our studies on the total synthesis of several natural products using intramolecular Nozaki-Hiyama-Takai-Kishi (NHTK) reactions. In each synthesis, an NHTK reaction is used to efficiently construct a medium-sized ring. These examples demonstrate the utility of the intramolecular NHTK reaction in natural product synthesis. 1 Introduction 2 Total Synthesis of (+)-Pestalotiopsin A 3 Total Synthesis of (+)-Cytosporolide A 4 Total Synthesis of (+)-Vibsanin A 5 Total Syntheses of (+)-Aquatolide and Related Humulanolides 6 Conclusion.

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Stereoselective Synthesis of the Tricyclic Core of (-)-Callophycoic Acid A

Sakama A., Kameshima R., Motohashi Y., Sumida W., Unno Y., Yoshida K., Ogura A., Takao K.I.

Journal of Organic Chemistry （Journal of Organic Chemistry）  85 （ 5 ） 3245 - 3264 2020年03月

ISSN  00223263

　概要を見る

Copyright © 2020 American Chemical Society. Two stereocontrolled routes to the tricyclic core of (-)-callophycoic acid A are described. Our synthetic strategy relied on stereoselective allylboration using a new allylboronate reagent to construct the all-carbon quaternary stereocenter in the core, followed by efficient radical cyclization or palladium-catalyzed reductive cyclization to form its multisubstituted cyclohexane ring. The tetrahydrooxepin ring was constructed by intramolecular etheration. This study provides the first method for the stereoselective synthesis of the characteristic tricyclic skeleton of callophycoic acids.

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Identification of vibsanin A analog as a novel HSP90 inhibitor

Miura K., Matsuki W., Ogura A., Takao K., Simizu S.

Bioorganic and Medicinal Chemistry （Bioorganic and Medicinal Chemistry）  28 （ 2 ）  2020年01月

ISSN  09680896

　概要を見る

© 2019 Elsevier Ltd Vibsanin A is the first natural product isolated from Viburnum awabuki and has several biological activities. We have reported that a vibsanin A analog, obtained from process of total synthesis of vibsanin A, has anti-proliferative activity against human cancer cell lines. In this study, we evaluated anti-proliferative effect of the vibsanin A analogs against various human cancer cell lines and examined molecular target of the analog in human cells. Among the vibsanin A analogs, vibsanin A analog C (VAC) showed anti-proliferative effect against various cancer cell lines, and the anti-proliferative activity was strongest among the vibsanin A analogs. Additionally, VAC fluctuated amounts of HSP90-related proteins in cells and inhibited HSP90-mediated protein refolding of luciferase in vitro. These results suggest that the anti-proliferative activity of VAC is due to HSP90 inhibition, and VAC has a potential as novel anti-cancer drug as HSP90 inhibitor.

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Recent advances in the total synthesis of clavilactones

Ogura A., Takao K.I.

Heterocycles （Heterocycles）  100 （ 9 ） 1355 - 1370 2020年

ISSN  03855414

　概要を見る

© 2020 The Japan Institute of Heterocyclic Chemistry – Clavilactones are meroterpenoids containing a 10-membered carbocycle fused to an α,β-epoxy-γ-lactone and a hydroquinone or benzoquinone. This review describes the total synthesis of clavilactones achieved by four research groups, focusing on their innovative synthetic strategies.

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