American Chemical Society (ACS) Acta Medica Okayama 0163-3864 2025 First Total Synthesis of the Kikai Island Polybrominated C3′–N1 Bisindole Alkaloid by a Directed Metalation Strategy EN Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The first total synthesis of one out of four Kikai Island polybrominated C3′–N1 bisindole alkaloids from red alga Laurencia brongniartii is described. The key steps involve both dehydration of trans-hemiaminal and a C2′-methylthiolation of bisindole using dimethyl disulfide through directed metalation, followed by C3-methylthiolation using a N-SMe succinimide reagent. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1359-7345 61 68 2025 Revisiting 3-azidoindoles: overcoming the trade-off challenges between stability and reactivity of in situ-generated azidoindoles 12801 12804 EN Shota Asai School of Pharmacy, Shujitsu University Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University A concise protocol based on the E2 reaction of indoline hemiaminals for accessing 3-azidoindoles is reported. In contrast to previous methods that require in situ generation by hypervalent iodine reagents, our protocol allows for the isolation of a variety of 3-azidoindoles upon a mild reaction for a short reaction time at room temperature. The obtained 3-azidoindoles are reasonably reactive, bench-stable and easy to handle. These findings could be used as a starting point for various reactions, including Huisgen reaction, [3+2] cycloaddition, phosphoramidation, and cine-substitution with the release of N2. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1477-0520 23 2025 One-pot synthesis of trans-2,3-diaminoindolines through 2,3-diamination of electrophilic indolines 6699 6703 EN Yuito Kobori Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Despite recent advances in the synthesis of 2,3-diaminoindole derivatives, construction of 2,3-diaminoindolines, whose two amine moieties on each molecule differ from one another has yet to be achieved. In this work, we developed a concise one-pot protocol for differentiated diamination involving reacting a C2,C3-electrophilic indole reagent with amines to access a variety of previously inaccessible 2,3-diaminoindolines. Furthermore, the synthetic utility of this protocol was demonstrated by a successful gram-scale reaction and further transformation of the 2,3-diaminoindolines. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2193-5807 14 7 2025 2-Hydroxy-3-(Pyrrolidin-1-yl)-Indolines: A Platform for Accessing Decorated Deaminokynurenines Enabled by a Double Tautomeric Control e202500439 EN Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University In this study we introduce indoline hemiaminals as phenacyl bromide surrogates for the synthesis of deaminokynurenine derivatives through cyclic-linear tautomeric intermediates. The reaction proceeds through a tandem process involving the ring opening of indoline hemiaminals, generating transient acyclic aldehydes which are then trapped with in situ generated enolate species. Our protocol overcomes traditional dilemma in production of polar-mismatch 1,4-dicarbonyl compounds by utilizing a transient highly electrophilic linear aldehyde and late-stage transposition of carbonyl moiety. The synthetic utility of our transformation was demonstrated by follow-up transformations, including the first total synthesis of quinoline-2,4-dione alkaloid. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2624-8549 7 2 2025 Molecular Iodine-Catalyzed Synthesis of 3,3-Disubstituted Isatins: Total Synthesis of Indole Alkaloid, 3,3-Dimethoxy-2-oxindole 43 EN Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shota Asai School of Pharmacy, Shujitsu University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 3,3-Dialkoxy-2-oxindoles are prevalent in natural products and exhibit unique biological activities. Among them, acyclic alkoxy analogues show instability in acidic conditions, making access to acyclic isatin ketals highly challenging. Conventional methods for the synthesis of 3,3-dialkoxy-2-oxindoles usually require strongly acidic and harsh reaction conditions, resulting in a low overall efficiency. Herein, we report on an acid- and metal-free protocol for the synthesis of 3,3-dialkoxy-2-oxindoles from isatins through an iodine-catalyzed ketalization. This photochemical protocol does not require the use of any specific reagents such as metal catalysts. Furthermore, the total synthesis of an unprecedented 2-oxindole alkaloid bearing 3,3-dimethoxy moiety is achieved. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2193-5807 14 2 2024 Potassium tert-Butoxide-Mediated Ring-Opening of Indolines: Concise Synthesis of 2-Vinylanilines e202400552 EN Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shota Asai School of Pharmacy, Shujitsu University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University A concise and metal-free procedure has been developed for the synthesis of 2-vinylanilines. Reactions of indolines with tert-BuOK in DMSO afford the decorated 2-vinylanilines in yields up to 92 %. In addition, the 2, or 3-substituted indolines could be converted to trisubstituted alkenes. Also, the protocol can be scaled to afford gram quantities of the decorated 2-vinylanilines. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1477-0520 22 36 2024 Indoline hemiaminals: a platform for accessing anthranilic acid derivatives through oxidative deformylation 7343 7348 EN Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuito Kobori Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Shota Asai School of Pharmacy, Shujitsu University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 2-Aminobenzoyl chlorides possess both a nucleophilic nitrogen atom and an electrophilic carbonyl group, and thus selective acylation of nucleophiles is challenging; self-dimerization and sluggish reactions occur. Herein, we introduce a new synthetic protocol using 2-aminobenzoyl surrogates, allowing concise entry to decorated 2-aminobenzoyl derivatives in the absence of transition metals, acid chlorides, and specific reagents. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2624-8549 6 4 2024 Azidoindolines―From Synthesis to Application: A Review 556 580 EN Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Azide-containing compounds, organic azides, showcases a variety of reactivities, making them highly convenient and chameleonic intermediates. An indoline derivative has been proven to be of great significance in drug discovery due to its sp3-rich property. In this context, it is interesting to perform such vigorous azidation on medicinal-relevant indoles/indolines, resulting in the production of sp3-rich azidoindolines. The potential biological activity, in combination with the sp3-rich indoline bearing the azido moiety, makes azidoindolines an attractive synthetic target for medicinal and synthetic chemists. This review describes recent advances in the synthesis and application of azidoindolines: (1) iodine-mediated azidations, (2) metal-catalyzed azidations, (3) electrochemical azidations, (4) photochemical azidations, (5) azidation using a combination of an oxidant and an azide source, and (6) nucleophilic azidation. No potential conflict of interest relevant to this article was reported.

American Chemical Society (ACS) Acta Medica Okayama 0022-3263 89 14 2024 Formal One Carbon Deletion of Indoline Hemiaminals under Tautomeric Control to Access 2-Aminobenzyl Compounds 10349 10354 EN Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Unprecedented tert-BuOK-mediated one carbon deletion of indoline hemiaminals has been achieved. This novel protocol provides an efficient synthetic tool for the construction of 2-aminobenzyl compounds with high chemoselectivity. In addition, functionalized 2-aminobenzyl compounds are difficult to make, for which few limited means of access currently exist. The key to success is the use of in situ generated Heyns rearrangement products (α-amino carbonyl compounds) as precursors for formal one carbon deletion. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1359-7345 60 52 2024 Switchable synthesis of 3-aminoindolines and 2′-aminoarylacetic acids using Grignard reagents and 3-azido-2-hydroxyindolines 6615 6618 EN Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The switchable synthesis of 3-aminoindolines and 2′-aminoaryl acetic acids from the same substrates, 3-azido-2-hydroxyindolines, was developed through denitrogenative electrophilic amination of Grignard reagents. The key to success is the serendipitous discovery that the reaction conditions, including solvents and reaction temperature, can affect the chemoselectivity. It is noteworthy that isotope-labeling experiments revealed the occurrence of the aziridine intermediate in the production of 2′-aminoaryl acetic acids. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1477-0520 22 9 2024 Synthetic strategies for the construction of C3–N1′ bisindoles 1756 1764 EN Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University C3–N1′ bisindoles are unique structures, and the construction of these structures has drawn much attention. However, their synthesis still presents significant challenges that limit the functional group compatibility. This minireview summarizes the recent progress in the methodology for constructing C3–N1′ bisindoles. There are two approaches for access to C3–N1′ bisindoles: (1) direct approaches including reverse polarity techniques. (2) Stepwise approaches using designed and prefunctionalized substrates enable further functionalization by additional reactions to facilitate access to the target products. I believe that this review will allow its readers to develop novel approaches for the synthesis of C3–N1′ bisindoles. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0947-6539 30 11 2024 On Demand Synthesis of C3－N1’ Bisindoles by a Formal Umpolung Strategy: First Total Synthesis of (±)‐Rivularin A e202302963 EN Keisuke Tokushige Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University In this work, a straightforward synthesis of C3－N1’ bisindolines is achieved by a formal umpolung strategy. The protocols were tolerant of a wide variety of substituents on the indole and indoline ring. In addition, the C3－N1’ bisindolines could be converted to C3－N1’ indole-indolines and C3－N1’-bisindoles. Also, we have successfully synthesized (±)-rivularin A through a biomimetic late-stage tribromination as a key step. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 2624-8549 5 4 2023 Total Synthesis of the Proposed Structure of Indolyl 1,2-Propanediol Alkaloid, 1-(1H-Indol-3-yloxy)propan-2-ol 2772 2784 EN Momoko Kimata Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The first total synthesis of the proposed structure of unprecedented indolyl derivative bearing 1,2-propanediol moiety is described. Isomerization of 3-alkoxyindolines through indolenium intermediates was the key step in the total synthesis. H-1, C-13-NMR, IR, and HRMS spectra of the synthetic compound drastically differed to those of the originally reported structure, which suggests the natural product requires revision. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1434-193X 27 4 2023 Concise Synthesis of Thiazolo[4,5-b]indoles via Ring Switch/Cyclization Sequences e202301130 EN Koji Yamada Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido Tetsu Tsubogo Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido Hikaru Kanazawa Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido Sayaka Ishizuka Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido Koutaro Ohyama Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido Masaki Kaida Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The unexpected reactions of indoline hemiaminals affords 2,5-diaryl-4-hydroxythiazolines through a thioamidation/ring switch sequence. The key to success of this transformation is to use a thioamide as a thiazoline precursor under transient tautomeric control. This transformation features mild reaction conditions and good yields with broad functional group tolerance (17 examples, up to 99 % yield). Further transformations of the thiazolines provide a direct entry to dihydrothiazolo[4,5-b]indoles and thiazolo[4,5-b]indoles. No potential conflict of interest relevant to this article was reported.

American Chemical Society (ACS) Acta Medica Okayama 0022-3263 88 14 2023 Oxytrofalcatin Puzzle: Total Synthesis and Structural Revision of Oxytrofalcatins B and C 9920 9926 EN Kazuma Sugitate Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ibuki Takahashi Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 0610293, Japan Koji Yamada Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University The previously reported structures of oxytrofalcatins B and C possess a benzoyl indole core. However, following synthesis and NMR comparison of both the proposed structure and the synthesized oxazole, we have revised the structure of oxytrofalcatins B and C as oxazoles. The synthetic route developed herein can further our understanding of the biosynthetic pathways that govern the production of natural 2,5-diaryloxazoles. No potential conflict of interest relevant to this article was reported.

MDPI AG Acta Medica Okayama 1422-0067 24 5 2023 Revisiting Cryptocyanine Dye, NK-4, as an Old and New Drug: Review and Future Perspectives 4411 EN Shihui Liu Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Toshihiko Matsuo Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University NK-4 plays a key role in the treatment of various diseases, such as in hay fever to expect anti-allergic effects, in bacterial infections and gum abscesses to expect anti-inflammatory effects, in scratches, cuts, and mouth sores from bites inside the mouth for enhanced wound healing, in herpes simplex virus (HSV)-1 infections for antiviral effects, and in peripheral nerve disease that causes tingling pain and numbness in hands and feet, while NK-4 is used also to expect antioxidative and neuroprotective effects. We review all therapeutic directions for the cyanine dye NK-4, as well as the pharmacological mechanism of NK-4 in animal models of related diseases. Currently, NK-4, which is sold as an over-the-counter drug in drugstores, is approved for treating allergic diseases, loss of appetite, sleepiness, anemia, peripheral neuropathy, acute suppurative diseases, wounds, heat injuries, frostbite, and tinea pedis in Japan. The therapeutic effects of NK-4’s antioxidant and neuroprotective properties in animal models are now under development, and we hope to apply these pharmacological effects of NK-4 to the treatment of more diseases. All experimental data suggest that different kinds of utility of NK-4 in the treatment of diseases can be developed based on the various pharmacological properties of NK-4. It is expected that NK-4 could be developed in more therapeutic strategies to treat many types of diseases, such as neurodegenerative and retinal degenerative diseases. No potential conflict of interest relevant to this article was reported.

American Chemical Society (ACS) Acta Medica Okayama 0163-3864 85 8 2022 First Total Synthesis of Reassigned Echinosulfonic Acid D 2122 2125 EN Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ren Nakajima Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Echinosulfonic acid D, a sponge metabolite whose structure was recently reassigned, was synthesized for the first time. The key step is the double indolization of dimethylbarbituric acid using the umpolung indole reagent, followed by a hydrolysis/decarboxylation/esterification sequence. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 0947-6539 28 37 2022 Indole Editing Enabled by HFIP‐Mediated Ring‐Switch Reactions of 3‐Amino‐2‐Hydroxyindolines e202201113 EN Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaho Shimizu Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University We found the novel reactivity of hemiaminal as a precursor for indole editing at the multi-site. The HFIP-promoted indole editing of indoline hemiaminals affords 2-arylindoles through a ring-switch sequence. The key to success of this transformation is to use a cyclic hemiaminal as an a-amino aldehyde surrogate under transient tautomeric control. This transformation features mild reaction conditions and good yields with broad functional group tolerance. The utility of this transformation is presented through the one-pot protocol and the synthesis of isocryptolepine. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 2052-4129 9 7 2022 Synthesis of 2-monosubstituted indolin-3-ones by cine-substitution of 3-azido-2-methoxyindolines 1897 1903 EN Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University We report herein a formal cine-substitution/hydrolysis of 3-azidoindoles generated from 3-azido-2-methoxyindolines (AZINs). This protocol enables the introduction of various carboxylic acids and alcohols into indolin-3-ones at the C2-position, affording 2-monoacyloxy or alkoxy indolin-3-ones. No potential conflict of interest relevant to this article was reported.

Royal Society of Chemistry (RSC) Acta Medica Okayama 1359-7345 57 2021 cis-3-Azido-2-methoxyindolines as safe and stable precursors to overcome the instability of fleeting 3-azidoindoles 13381 13384 EN Toshiki Yamashiro Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takumi Abe Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masaru Tanioka School of Pharmaceutical Sciences, Aichi Gakuin University Shinichiro Kamino School of Pharmaceutical Sciences, Aichi Gakuin University Daisuke Sawada Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Use of 3-azidoindoles in organic synthesis remains a difficult task owing to their instabilities. Herein, we report a general and concise approach for tackling this problem by using 3-azidoindole surrogates. The surrogates are bench-stable, presumably due to the observed intramolecular O-N-beta bonding. The resultant fleeting intermediates undergo capturing in situ to afford 3-substitued indoles through formal ipso-substitution of the azide group by nucleophiles. In these investigations, we found that the fleeting 3-azidoindoles show a C3-electrophilic character for the first time. No potential conflict of interest relevant to this article was reported.