start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue=1 article-no= start-page=105 end-page=119 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Programmable synthesis of alkaloidal frameworks integrating Michael acceptor generates covalent probes for targeting POLE3 in HBV replication en-subtitle= kn-subtitle= en-abstract= kn-abstract=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 ,-unsaturated carbonyl moieties. The optimal hit 15 inhibited hepatitis B surface antigen (HBsAg) production with an IC50 of 2.48 M 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. en-copyright= kn-copyright= en-aut-name=KanekoNobuto en-aut-sei=Kaneko en-aut-mei=Nobuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HimenoMisao en-aut-sei=Himeno en-aut-mei=Misao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KobayashiYuhi en-aut-sei=Kobayashi en-aut-mei=Yuhi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanifujiRyo en-aut-sei=Tanifuji en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KubotaHiroki en-aut-sei=Kubota en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MizoguchiHaruki en-aut-sei=Mizoguchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MuroiMakoto en-aut-sei=Muroi en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SuzukiTakehiro en-aut-sei=Suzuki en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SugiyamaMasaya en-aut-sei=Sugiyama en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=DohmaeNaoshi en-aut-sei=Dohmae en-aut-mei=Naoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OsadaHiroyuki en-aut-sei=Osada en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KidoTaketomo en-aut-sei=Kido en-aut-mei=Taketomo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MiyajimaAtsushi en-aut-sei=Miyajima en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OguriHiroki en-aut-sei=Oguri en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= affil-num=2 en-affil=Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=3 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= affil-num=4 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= affil-num=5 en-affil=Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology kn-affil= affil-num=6 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=8 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=9 en-affil=Department of Viral Pathogenesis and Control, National Institute of Global Health and Medicine, Japan Institute for Health Security kn-affil= affil-num=10 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=11 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=12 en-affil=Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo kn-affil= affil-num=13 en-affil=Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo kn-affil= affil-num=14 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=e202510319 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250626 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Development of a Vinylated Cyclic Allene: A Fleeting Strained Diene for the Diels?Alder Reaction en-subtitle= kn-subtitle= en-abstract= kn-abstract=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 -bonds as 2 components, represented by dienophiles in Diels?Alder reactions, has been well studied, gthe strained diene (4 component) approachh 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. en-copyright= kn-copyright= en-aut-name=MizoguchiHaruki en-aut-sei=Mizoguchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ObataTakumi en-aut-sei=Obata en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HiraiTaiki en-aut-sei=Hirai en-aut-mei=Taiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KomatsuManaka en-aut-sei=Komatsu en-aut-mei=Manaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SakakuraAkira en-aut-sei=Sakakura en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=Activation strain model kn-keyword=Activation strain model en-keyword=Carbocycles kn-keyword=Carbocycles en-keyword=Diels?Alder reaction kn-keyword=Diels?Alder reaction en-keyword=Strained diene kn-keyword=Strained diene en-keyword=Vinylated cyclic allene kn-keyword=Vinylated cyclic allene END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=9580 end-page=9585 dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220725 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Annulative coupling of vinylboronic esters: aryne-triggered 1,2-metallate rearrangement en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=MizoguchiHaruki en-aut-sei=Mizoguchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KamadaHidetoshi en-aut-sei=Kamada en-aut-mei=Hidetoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MorimotoKazuki en-aut-sei=Morimoto en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YoshidaRyuji en-aut-sei=Yoshida en-aut-mei=Ryuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SakakuraAkira en-aut-sei=Sakakura en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=85 cd-vols= no-issue=2 article-no= start-page=798 end-page=805 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20191218 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Formal Total Synthesis of Manzacidin B via Sequential Diastereodivergent Henry Reaction en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=ArakiYuya en-aut-sei=Araki en-aut-mei=Yuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyoshiNatsumi en-aut-sei=Miyoshi en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MorimotoKazuki en-aut-sei=Morimoto en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KudohTakayuki en-aut-sei=Kudoh en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MizoguchiHaruki en-aut-sei=Mizoguchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SakakuraAkira en-aut-sei=Sakakura en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=7 article-no= start-page=2073 end-page=2076 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190312 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Thioureas as Highly Active Catalysts for Biomimetic Bromocyclization of Geranyl Derivatives en-subtitle= kn-subtitle= en-abstract= kn-abstract= 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. en-copyright= kn-copyright= en-aut-name=TerazakiMiyuki en-aut-sei=Terazaki en-aut-mei=Miyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShiomotoKei-ichi en-aut-sei=Shiomoto en-aut-mei=Kei-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MizoguchiHaruki en-aut-sei=Mizoguchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakakuraAkira en-aut-sei=Sakakura en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=15 article-no= start-page=1835 end-page=1839 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190917 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Enantioselective 1,3-Dipolar Cycloaddition Reaction of Nitrones with -(Acyloxy)acroleins Catalyzed by Dipeptide-Derived Chiral Tri- or Diammonium Salts kn-title=Dipeptide-Derived Chiral Tri- or Diammonium Salt-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition Reaction of Nitrones with a- (Acyloxy)acroleins en-subtitle= kn-subtitle= en-abstract= kn-abstract= 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. en-copyright= kn-copyright= en-aut-name=KidouChihiro en-aut-sei=Kidou en-aut-mei=Chihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Mizoguchi?Haruki en-aut-sei=Mizoguchi? en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NehiraTatsuo en-aut-sei=Nehira en-aut-mei=Tatsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakakuraAkira en-aut-sei=Sakakura en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Integrated Sciences for Life, Hiroshima University kn-affil= affil-num=4 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=acyloxyacroleins kn-keyword=acyloxyacroleins en-keyword=1,3-dipolar cycloaddition kn-keyword=1,3-dipolar cycloaddition en-keyword=isoxazolidines kn-keyword=isoxazolidines en-keyword=nitrones kn-keyword=nitrones en-keyword=organocatalysis kn-keyword=organocatalysis en-keyword=asymmetric catalysis kn-keyword=asymmetric catalysis END