Ryosuke Masuda

Abstract The catalytic selenium redox chemistry of iodothyronine deiodinases (DIOs) has remained largely speculative because the proposed oxidized selenium intermediates have never been connected through direct chemical transformations. Herein, we examine the chemical feasibility of the proposed DIO selenium redox cycle using isolable DIO-inspired selenopeptide models encapsulated within molecular-cradle frameworks. The reaction of a cradled selenocysteine selenol (Sec−SeH) with a thyroxine derivative produced the corresponding selenocysteine selenenyl iodide (Sec−SeI) together with the outer-ring-deiodinated product, providing the first direct chemical demonstration of the proposed initial oxidation step in a selenocysteine-containing system. Isolated Sec−SeI underwent trapping by cysteine thiols to form selenenyl sulfides, hydrolysis to selenenic acid (Sec−SeOH), including the DIO1-inspired species reported here for the first time, and reductive conversion back to Sec−SeH through the selenenyl sulfide. These reactions establish the chemical competence of several key selenium transformations proposed for the DIO catalytic cycle. Propylthiouracil (PTU) rapidly trapped Sec−SeI under basic conditions, whereas the corresponding selenenyl sulfides were unreactive, indicating that oxidized selenium species preceding Se−S resolution are more plausible PTU targets than the resolved selenenyl sulfides. These findings provide a molecular-level experimental framework for evaluating the proposed elementary steps in DIO catalysis and inhibition.

Although dearomatization of benzene converts flat molecules into three-dimensional (3D) frameworks, the stability of the benzene ring makes this transformation difficult. Main-group compounds that achieve it are typically highly reactive low-valent species or contain weak multiple bonds and usually require elaborate design. Thioketones engage an adjacent aryl ring only with strongly electron-poor partners or fused arenes, and the products rearomatize. Whether a simple, isolable main-group functional group can dearomatize a non-fused benzene ring under mild conditions has remained unclear so far. Here, we introduce a substituent-based strategy that switches on this reactivity, i.e., thioketones bearing a σ-donating silyl or germyl group dearomatize their own benzene rings at room temperature without the need for metals, light, or redox reagents. Whereas conventional thioketones are inert toward alkenes under identical conditions, these compounds, including the first structurally characterized silyl-thioketone and the first isolable germyl-thioketones, undergo cascade cycloadditions with alkenes and alkynes to give air-stable 3D frameworks. Rather than strengthening frontier-orbital interactions, the group-14 substituent polarizes the C═S bond and renders bond formation highly asynchronous, thus markedly reducing the distortion required to disrupt the aromatic ring. These results establish main-group substitution as a design strategy for unlocking latent dearomative reactivity under mild conditions.

Abstract Selenoamides have been recognized as attractive chemical species in various fields; however, derivatives bearing a third heteroatom that can serve as a second reactive center remain limited. In this highlight review, we summarize recent advances regarding the synthesis, structural characterization, and reactivity of selenocarbamoyl compounds that bear main-group substituents such as silyl, germyl, and phosphino groups. Particular emphasis is placed on our recent results pertaining to (selenocarbamoyl)phosphines, which exhibit ambident reactivity at 2 principal sites, i.e. the phosphorus and selenium atoms.

ABSTRACT Despite more than half a century of research on selenoproteins, the central catalytic intermediate, selenocysteine selenenic acid (Sec–SeOH), has remained experimentally elusive. Its isolation has long been impeded by its presumed instability and propensity for thermal deselenation. Here, we report the first isolable Sec–SeOH at ambient temperature. This relies on a bioinspired design of a selenopeptide sequence encapsulated within a protective cradle, together with an oxidant‐free route from the corresponding selenenyl iodides (Sec–SeI), enabling x‐ray structural analysis and chemical characterization. The isolated Sec–SeOH shows unexpected resistance to β‐elimination to dehydroalanine (DHA). Oxidation experiments combined with theoretical calculations demonstrate that conversion to DHA proceeds preferentially via overoxidation to the seleninic acid (Sec–SeO ₂ H), for which β‐elimination is substantially more favorable. Reactivity profiling further highlights the pronounced electrophilicity of Sec–SeOH toward biologically and pharmacologically relevant nucleophiles. These findings redefine the stability–reactivity landscape of Sec–SeOH and provide a foundation for strategies aimed at preventing selenoprotein inactivation. Beyond defining an isolable Sec–SeOH model, the work provides a molecular‐level rationale for how selenoproteins can combine high selenium‐centered reactivity with resistance to irreversible oxidative self‐inactivation.