増田 涼介

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.

A palladium-catalyzed and photoinduced coupling reaction between acylsilanes and allylic alcohol derivatives based on the reactions of nucleophilic siloxycarbenes, generated via the light-induced isomerization of the corresponding aroyl-, heteroaroyl-, alkenoyl-, or alkanolysilanes, with electrophilic π-allylpalladium complexes was developed. The dual activation by light and Pd(0) enables the coupling to proceed at temperatures below ambient temperature with a broad substrate scope and high functional-group tolerance.

Crystalline (selenocarbamoyl)phosphines, which exhibited dual reactivity on two principal sites, i.e., on the phosphorus and the selenium atoms, were synthesized.

Although much attention has been paid to chemical elucidation of the catalytic cycle of glutathione peroxidase (GPx), it has been hampered by instability of selenocysteine selenenic acid (Sec–SeOH) intermediates. In this study, not only chemical processes of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of a Sec–SeOH to the corresponding five-membered ring selenenyl amide were demonstrated experimentally by utilizing selenopeptide model systems in which reactive intermediates can be stabilized by a nano-sized molecular cradle. The resulting cyclic selenenyl amide exhibited higher durability under oxidative conditions than in the state of a Sec–SeOH, corroborating its role as the protective form of GPx. The cyclization of Sec–SeOHs of the Sec-Gly-Thr and Sec-Gly-Lys models, which mimic the catalytic site of isozymes GPx1 and GPx4, respectively, was found to proceed at lower temperature than in the Sec-Gly-Gly model, which corresponds to the generalized form of the tripeptides in the catalytic site of GPx. The role of the hydrogen-bond accepting moieties in the cyclization process was elucidated by DFT calculation. It was indicated that, if the selenocysteine centers are incorporated in appropriate microenvironments, the bypass mechanism can function efficiently.

Although selenocysteine selenenic acids (Sec–SeOHs) have been recognized as key intermediates in the catalytic cycle of glutathione peroxidase (GPx), examples of the direct observation of Sec–SeOH in either protein or small-molecule systems have remained elusive so far, mostly due to their instability. Here, we report the first direct spectroscopic (1H and 77Se NMR) evidence for the formation of Sec–SeOH in small-molecule selenocysteine and selenopeptide model systems with a cradle-type protective group. The catalytic cycle of GPx was investigated using NMR-observable Sec–SeOH models. All the hitherto proposed chemical processes, i.e., not only those of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of Sec–SeOH to the corresponding five-membered ring selenenyl amide, were examined in a stepwise manner.