Practical methods have been established for the synthesis of multifunctional N-heterocyclic carbenes (NHCs) via the introduction of substituents on either the nitrogen atom(s) or the backbone of the NHCs. However, their use has been mainly limited to acting as multidentate ligands for metal complexes. Herein, results of our recent studies on the synthesis and application of N-phosphine oxide-substituted imidazolylidenes (PoxIms) as novel type of multifunctional NHCs are discussed. PoxIms were used not only as a mono-/bi-dentate ligand for mono-/bi-metallic complexes, but also as an external stimuli-responsive Lewis base for achievement of the frustration revival strategy as well as a reagent for the direct phosphinoylation of CO₂ and carbonyl compounds. These results manifest the pioneering role of PoxIms as a multifunctional multipurpose NHC.

The cross-coupling reaction employing organosilicon compounds is one of the most important carbon-carbon bond-forming reactions. This reaction usually proceeds in the presence of a palladium catalyst and a base such as fluoride anion. Due to many advantages in the silicon-based cross-coupling reaction, this transformation has attracted much attention for the past decades. Especially, organo(trialkyl)silanes are characterized by robustness, low toxicity, good solubility, and easy handling. There properties are ideal for synthesis of bioactive agents and organofunctional materials such as π-electron conjugated molecules. However, these organo(trialkyl)silanes are difficult to be employed in the cross-coupling reactions, most probably because of their exceeding robustness. Thus, a practical method to use them for cross-coupling nucleophiles has been a long-standing challenging research target. We have developed the copper-catalyzed cross-coupling using heteroaryl(trialkyl)silanes or aryl(trialkyl)silanes having an electron-withdrawing substituent on the reacting aryl ring with aryl halides or alkyl halides. This method allows us to construct a variety of biaryls and teraryls. Moreover, the concept of the trialkylsilyl-based cross-coupling is applicable to the formation of a carbon-nitrogen bond. N-Trimethylsilyl-amines underwent the cross-coupling with aryl halides catalyzed by a palladium or a nickel catalyst with a base. The present article describes the concept of reaction design and the details of the experimental outcomes.

Cyclization reactions oriented toward synthetic diversity using propargylic alcohols have been developed by employing difference of valence of gold catalysts. Thus, strategic use of oxophilic (hard) gold(III) and π-philic (soft) gold(I) catalysts provides access to two types of cyclic ethers/piperidines from propargylic alcohols via intramolecular reactions. Treatments of propargylic alcohols with an oxophilic gold(III) catalyst (AuBr₃) result in cyclization to furnish cyclic ethers/piperidines/azepane bearing an acetylenic moiety, due to activation of the propargylic hydroxyl group by coordination of gold(III). On the other hand, similar treatments of propargylic alcohols with a π-philic gold(I) catalyst (Ph₃PAuNTf₂) induce Meyer-Schuster rearrangement, triggered by activation of the triple bond by coordination of gold(I), to afford α,β-unsaturated ketones, which undergo intramolecular oxa-/aza-Michael addition to give cyclic ethers/piperidines/azepanes having a carbonyl group. Expanding this strategy of intramolecular reactions to intermolecular reactions, synthesis of oxazoles/dihydropyrans from propargylic alcohols with amides/dicarbonyl compounds was achieved via gold(III)-catalyzed propargylic substitution and cycloisomerization. In addition, synthesis of 1,3-diarylindenes was achieved via dehydrative Friedel-Crafts reaction followed by Nazarov-type cyclization from propargylic alcohols with aromatic rings by gold(III)-catalyst.

Amphidinol 3 (AM3), a secondary metabolite isolated from the dinoflagellate Amphidinium krebsi, elicits potent antifungal and hemolytic activities. Although the absolute configuration of AM3 was determined by instrumental analysis in combination with degradation of the natural product and chemical correlation in 1999, it was a daunting task, because of the presence of a number of stereogenic centers are located on the acyclic chain and limited availability from natural sources. During the course of our synthetic studies to confirm the structure, the absolute configuration of AM3 was revised. Based on the structure revised in 2018, the first total synthesis of AM3 has been achieved via assemblage of the C1-C29 and the C30-C52 sections by Suzuki-Miyaura coupling, followed by Julia-Kocienski olefination with the C53-C67 section. The spectral data for the synthetic specimen were in agreement with those for the natural product including the sign and magnitude of the specific rotation and antifungal activity, revealing its true structure after more than twenty years since its first discovery. This article describes all the process to prepare the segments and to assemble the segments in the total synthesis of AM3.

Radiation diagnostics and therapeutics are promising to be effective for cancer medicine. In radiodiagnosis, PET is widely used to quantitatively visualize the locations and levels of radiotracer accumulation with high sensitivity. In radiotherapy, in particular, α-emission therapy based on radioimmunoconjugate has attracted attention as a potent cancer therapeutics because radiation of α-particles can damage targeted cancer tissue within a few cell diameters, thereby minimizing damage of other normal tissues. In a few decades, many researchers have devoted much effort to development of radiolabeled cancer-targeting molecules. However, there are few examples of radiolabeled molecules clinically utilized for cancer diagnosis and therapy due to few effective and practical methods for labeling of biofunctional molecule, especially protein and antibody. So far, we have developed an invasive and effective labeling method for protein based on RIKEN click reaction. We have recently developed practical labeling method by using two click reactions, which comprised of strain-promoted [3+2] cyclization for introduction of functional group to unsaturated aldehyde and RIKEN click reaction for protein labeling, named as double click reaction. By utilizing this double click reaction, we established a practical synthetic protocol of gallium-68-labeled cyclic RGDyK peptide, which was applied for PET imaging, from elution of gallium-68 to synthesis of gallium-68-labeled cyclic RGDyK peptide. Furthermore, we developed one-pot three-component double clicks, which conducted tetrazine ligation and RIKEN click reaction as highly reactive click reaction under mild conditions. On the basis of the one-pot three-component double clicks, we accomplished highly effective and practical synthesis of radioimmunoconjugates labeled with copper-67 as β^--emitter and with astatine-211 as α-emitter. In addition, we also succeeded in evaluation of α-emission cancer therapeutic efficacy of the astatine-211-labeled trastuzumab on the A431 cells-xenograft mice.

Natural products have contributed to development of medicine for a long time. The structures and bioactivities of natural products often exceed the human knowledge and imagination. We have developed target protein-oriented natural products isolation methods to quick find bioactive compounds from natural resources (compounds mixture). This review summarizes our recent results including protein beads methods and protein plate method for neural stem cells differentiation activators and new cancer drug candidates. Isolated compounds accelerated neural stem cells differentiation and/or showed cytotoxicity against cancer cells. Syntheses of isolated compounds were also described. As protein binding ability tightly related bioactivity, protein based natural products isolation would be a powerful way to find new candidate of medicines.

Mono N-protected amino acid (MPAA), as a bidentate ligand of padum, has been used in carbon-hydrogen bond activation, because it strongly accelerates concerted metalation deprotonation (CMD) step to easily cleave carbon(sp³)-hydrogen bond. This mini-review describes the recent progress in carbon(sp³)-hydrogen activation using MPAA ligands.