Royal Society of Chemistry (RSC) Acta Medica Okayama 2633-0679 7 1 2026 Programmable synthesis of alkaloidal frameworks integrating Michael acceptor generates covalent probes for targeting POLE3 in HBV replication 105 119 EN Nobuto Kaneko Department of Chemistry, Graduate School of Science, The University of Tokyo Misao Himeno Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo Yuhi Kobayashi Department of Chemistry, Graduate School of Science, The University of Tokyo Ryo Tanifuji Department of Chemistry, Graduate School of Science, The University of Tokyo Hiroki Kubota Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology Haruki Mizoguchi Graduate School of Natural Science and Technology, Okayama University Makoto Muroi Centre for Sustainable Resource Science, RIKEN Takehiro Suzuki Centre for Sustainable Resource Science, RIKEN Masaya Sugiyama Department of Viral Pathogenesis and Control, National Institute of Global Health and Medicine, Japan Institute for Health Security Naoshi Dohmae Centre for Sustainable Resource Science, RIKEN Hiroyuki Osada Centre for Sustainable Resource Science, RIKEN Taketomo Kido Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo Atsushi Miyajima Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo Hiroki Oguri Department of Chemistry, Graduate School of Science, The University of Tokyo The growing need for effective HBV treatments and lead compounds with novel mechanisms prompted us to explore synthetic strategies for generating skeletally diverse alkaloidal Michael acceptors. Our approach uniquely embeds Michael acceptors directly within multicyclic alkaloid-inspired frameworks, exploiting the azepinoindole scaffold—a privileged structure in indole alkaloids. A single-step assembly between the versatile intermediate 13 with methyl propiolate 14 or its derivatives enabled the rapid and divergent synthesis of six alkaloidal Michael acceptors (15–20). This strategy facilitated systematic diversification of three-dimensional functional group arrangements and precise tuning of the electronic and steric properties of the embedded α,β-unsaturated carbonyl moieties. The optimal hit 15 inhibited hepatitis B surface antigen (HBsAg) production with an IC50 of 2.48 μM and significantly reduced levels of covalently closed circular DNA (cccDNA), the master template of HBV. Unlike existing nucleoside/nucleotide-based anti-HBV drugs that primarily inhibit reverse transcription, the alkaloidal Michael acceptor 15 suppressed both cccDNA and relaxed circular DNA (rcDNA) levels, suggesting a potential pathway toward a functional HBV cure. Our study also streamlined the target identification by leveraging the covalent binding properties of the Michael acceptors and the operational simplicity of biotin- or fluorescent-tag attachment via a pre-installed alkyne moiety. Competitive pull-down experiments identified several potential target proteins, involving DNA polymerase epsilon subunit 3 (POLE3). Notably, the alkaloidal Michael acceptor 15 was demonstrated to covalently modify Cys51 in POLE3, providing new insights into virus–host interactions and opening novel avenues for targeted anti-HBV therapies. This approach represents a significant advance beyond traditional screening methods and underscores the potential of skeletally diverse alkaloidal Michael acceptors in antiviral drug development. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1433-7851 2025 Development of a Vinylated Cyclic Allene: A Fleeting Strained Diene for the Diels–Alder Reaction e202510319 EN Haruki Mizoguchi Graduate School of Environmental, Life, Natural Science and Technology, Okayama University Takumi Obata Graduate School of Environmental, Life, Natural Science and Technology, Okayama University Taiki Hirai Graduate School of Environmental, Life, Natural Science and Technology, Okayama University Manaka Komatsu Graduate School of Environmental, Life, Natural Science and Technology, Okayama University Akira Sakakura Graduate School of Environmental, Life, Natural Science and Technology, Okayama University Fleeting molecules possessing strained multiple bonds are important components in organic synthesis due to their ability to undergo various chemical reactions driven by the release of strain energy. Although the use of strained π-bonds as 2π components, represented by dienophiles in Diels–Alder reactions, has been well studied, “the strained diene (4π component) approach” for molecular construction remains underexplored. Herein, we report the design of a vinyl cyclic allene (1-vinyl-1,2-cyclohexadiene) as a highly reactive strained diene and the development of its Diels–Alder reactions. Experimental and computational studies of vinyl cyclic allenes revealed that this diene system undergoes cycloaddition with dienophiles regio- and stereoselectively under mild reaction conditions. These studies also provide insight into the reactivity and selectivity of the system. The strained diene approach enables the convergent construction of polycyclic molecules through bond disconnections distinct from conventional retrosynthetic analysis, thus offering an efficient strategy for the assembly of functional molecules. No potential conflict of interest relevant to this article was reported.

ROYAL SOC CHEMISTRY Acta Medica Okayama 2041-6520 13 2022 Annulative coupling of vinylboronic esters: aryne-triggered 1,2-metallate rearrangement 9580 9585 EN Haruki Mizoguchi Graduate School of Natural Science and Technology, Okayama University Hidetoshi Kamada Graduate School of Natural Science and Technology, Okayama University Kazuki Morimoto Graduate School of Natural Science and Technology, Okayama University Ryuji Yoshida Graduate School of Natural Science and Technology, Okayama University Akira Sakakura Graduate School of Natural Science and Technology, Okayama University A stereoselective annulative coupling of a vinylboronic ester ate-complex with arynes producing cyclic borinic esters has been developed. An annulation reaction that proceeded through the formation of two C-C bonds and a C-B bond was realized by exploiting a 1,2-metallate rearrangement of boronate triggered by the addition of a vinyl group to the strained triple bond of an aryne. The generated aryl anion would then cyclize to a boron atom to complete the annulation cascade. The annulated borinic ester could be converted to boronic acids and their derivatives by oxidation, halogenation, and cross-coupling. Particularly, halogenation and Suzuki-Miyaura coupling proceeded in a site-selective fashion and produced highly substituted alkylboronic acid derivatives. No potential conflict of interest relevant to this article was reported.

American Chemical Society Acta Medica Okayama 0022-3263 85 2 2019 Formal Total Synthesis of Manzacidin B via Sequential Diastereodivergent Henry Reaction 798 805 EN Yuya Araki Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Natsumi Miyoshi Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Kazuki Morimoto Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Takayuki Kudoh Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Haruki Mizoguchi Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University Akira Sakakura Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University A formal total synthesis of manzacidin B is described. beta,beta-Disubstituted gamma-hydroxy-beta-aminoalcohol, the key structure of manzacidin B, is stereoselectively constructed via sequential Henry reactions. By taking advantage of noncovalent interactions, such as intramolecular hydrogen bonding and chelation, we could diastereodivergently control the stereoselectivity of the Henry reaction. No potential conflict of interest relevant to this article was reported.

American Chemical Society Acta Medica Okayama 1523-7060 21 7 2019 Thioureas as Highly Active Catalysts for Biomimetic Bromocyclization of Geranyl Derivatives 2073 2076 EN Miyuki Terazaki Graduate School of Natural Science and Technology, Okayama University Kei-ichi Shiomoto Graduate School of Natural Science and Technology, Okayama University Haruki Mizoguchi Graduate School of Natural Science and Technology, Okayama University Akira Sakakura Graduate School of Natural Science and Technology, Okayama University Thioureas bearing electron-deficient aryl groups show high catalytic activity in the biomimetic bromocyclization of geranyl derivatives. The reaction of geranyl derivatives with N-bromosuccinimide (NBS) proceeds rapidly in CH2Cl2 to give the corresponding bromocyclization products in high yields as a ca. 1:1 mixture of endo- and exo-isomers. The reactivity of geranyl derivatives highly depends on the terminal substituent: electron-donating substituents increase the reactivity, while electron-withdrawing substituents decrease the reactivity. No potential conflict of interest relevant to this article was reported.

Georg Thieme Verlag Acta Medica Okayama 0936-5214 30 15 2019 Dipeptide-Derived Chiral Tri- or Diammonium Salt-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition Reaction of Nitrones with a- (Acyloxy)acroleins 1835 1839 EN Chihiro Kidou Graduate School of Natural Science and Technology, Okayama University Haruki Mizoguchi  Graduate School of Natural Science and Technology, Okayama University Tatsuo Nehira Graduate School of Integrated Sciences for Life, Hiroshima University Akira Sakakura Graduate School of Natural Science and Technology, Okayama University Organoammonium salts of dipeptide-derived chiral tri-amines or diamines with TfOH catalyzed the enantioselective 1,3-dipolar cycloaddition reactions of alpha-acyloxyacroleins with nitrones to give the corresponding adducts in good yields (up to 96%) and with high diastereo- and enantioselectivities (up to 89% ee). Although alpha-(p-methoxybenzoyloxy)acrolein is rather unstable under the reaction conditions, alpha-(3-pyrroline-1-carbonyloxy)acrolein is stable enough to be smoothly converted into the corresponding adducts with the aid of the chiral organoammonium salt catalysts. No potential conflict of interest relevant to this article was reported.