Musashino University, Faculty of Pharmacy武蔵野大学薬学部― 91 ―Four-membered heterocycles are in high demand within modern drug discovery, owing to their ability to confer advantageous properties on target molecules. Despite significant efforts from the synthetic chemistry community, there remains an imperative for simple, innovative methods to integrate these motifs into molecular designs. In this study, we introduce a cycloisomerization approach to synthesize oxetane and azetidine rings through metal hydride hydrogen atom transfer combined with radical polar crossover. This process, which is both enthalpically and entropically challenging, offers a novel pathway for creating polysubstituted four-membered heterocycles. The reaction is mild, functional-group tolerant, and has a wide substrate scope, including spirostructures—key motifs in drug discovery. We further expand the utility of this method by demonstrating the synthesis of various four-membered heterocyclic compounds through product derivatization. Additionally, we elucidate the reaction mechanism, particularly the formation of the four-membered ring, using deuterium labeling experiments and density functional theory (DFT) studies.Abstractはじめに四員環複素環は，その独特な化学的性質と生物活性のために，創薬の分野で極めて重要な役割を果たしている1)．それらの構造は，標的分子に対して独自の結合様式や選択性を示し，結果として創薬における有望なケミカルスペースを提供することにつながる．しかし，これらの四員環複素環を効率的に合成する方法は限られており，特にオキセタンとアゼチジン環の構築は，合成化学において依然として大きな課題となっている．環状エーテル構造であるオキセタンはgem-ジメチル基やカルボニル基の生物学的等価体として知られている（図１）．MHAT/RPC反応による創薬ケミカルスペースの開拓Exploring chemical space of drug design by MHAT/RPC reaction重久 浩樹Hiroki Shigehisa
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