Ryosuke Masuda

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.

The synthesis, structural characterization in the solid state, and reactivity of a selenazolidine and a six-membered-ring derivative, i.e., a 1,3-tetrahydroselenazine, that contain a C6F5 substituent are reported. The first crystallographic characterization of a 1,3-tetrahydroselenazine was accomplished by means of single-crystal X-ray diffraction analysis. Despite the structural analogy to C6F5-substituted imidazolidines, these selenium-containing heterocycles exhibit pronounced thermal stability and high resistance toward the formation of the corresponding (amino)(seleno)carbenes, highlighting fundamentally different reactivity patterns between imidazolidines and selenazolidines.

Although various types of selenoamides have already been developed, examples of derivatives bearing a third heteroatom that acts as a second reactive center have remained limited so far. Recently, we reported the synthesis, structure, and fundamental reactivity of (selenocarbamoyl)phosphines, which exhibit ambident reactivity at two principal sites, i.e., the phosphorus and selenium atoms, in reactions with electrophiles. Herein, we report the synthesis of the first crystalline (phosphino)(seleno)iminium salt from a (selenocarbamoyl)phosphine, as well as the double-functionalization of (selenocarbamoyl)phosphines. Notably, the critical importance of the selenium atom for chalcogen-selective methylation was corroborated by a combined experimental and theoretical comparison with its sulfur analogue. Furthermore, the transition-metal complex of a (selenocarbamoyl)phosphine, whose phosphorus and selenium atoms were modified to give the phosphine selenide and the palladium complex, was obtained as a double-functionalized product.