In recent years, we disclosed that the N-alkoxyanilines underwent [1,3]-alkoxy rearrangement by the action of NHC-ligated cationic copper catalysts. The rearrangement reactions afforded the corresponding ortho-aminophenol derivatives with high compatibility of functional groups, such as bromo, iodo, methoxycarbonyl, and trifluoromethyl groups. The rearrangement reactions were applicable to polyarenes, such as naphthalenes and phenanthlenes and benzene ring of heteroarenes, such as indoles. Since directed C-H oxygenation reactions of 1-naphthylamine derivatives generally occurs at the peri position, the present rearrangement reactions are regarded as a complementary approach to ortho-aminonaphthol derivatives. To our surprise, N-methoxyanilines, which have alkyl and electron-rich aryl groups at the ortho position, underwent domino rearrangement reactions, including [1,3]-rearrangement of the methoxy group to the substituted ortho position followed by [1,2]-rearrangement of the ortho substituent to the meta position. The present rearrangement reactions are quite efficient to generate functionalized ortho-quinol imines, which have been rarely utilized in organic synthesis due to poor accessibility. The reactions of the N-methoxyanilines, which have an electron-donating group at the ortho position, with carbon nucleophiles, such as 1-methylindole, 1,3,5-trimethoxybenzene, and dimethyl malonate, proceeds via [1,3]-methoxy rearrangement followed by Michael addition to the in-situ generated ortho-quinol imines. Moreover, the Cu-catalyzed [1,3]-alkoxy rearrangement / Diels-Alder cascade reactions between the N-methoxyanilines and olefins afforded the corresponding bicyclic compounds in good yields with excellent stereoselectivity.

Industrially-produced chlorosilanes are cheap and abundant silicon feedstocks. To obtain various useful organosilicon compounds directly from these chlorosilanes, classical nucleophilic substitution reactions (Kipping method) with reactive organometallic reagents such as Grignard reagents and organolithium are often employed. In contrast, their direct catalytic transformation into beneficial organosilicon compounds remains challenging due to difficulty in cleaving the strong Si-Cl bond(s). To address this issue, we hypothesized that the activation of chlorosilanes with transition metal catalysts could be achieved with the cooperative assistance of Lewis acids by stabilizing the transition state or products. We initially developed Ni-catalyzed silyl-Heck reaction of chlorosilanes and styrenes. The aid of trimethylaluminum dramatically assisted silyl-Heck reaction to afford the corresponding alkenylsilanes. Successively, we also achieved the Ni-catalyzed cross-coupling reaction of chlorosilanes with trialkylaluminum species. Interestingly, the selective monoalkylation of dichlorosilanes was achieved to form various monochrolosilanes with a variety of alkyl substituents, which are useful raw materials for silicones. To further broaden the scope of this cross-coupling reaction, we then developed Pd-catalyzed cross-coupling reaction of chlorosilanes with dimethylaluminum chloride. The broader generality of di-, tri- and tetrachlorosilanes was revealed in the selective methylation to provide the corresponding methylmonochlorosilanes. Finally, we demonstrated computational study on the activation of Si-Cl bond by the cooperation of palladium and aluminum Lewis acid.

Synthetic organic chemistry is a core technology of drug discovery, but combined with in silico technology which consists of molecular modeling and/or informatics using computational methods, it can be expected to accelerate drug discovery research and increase the success rate for developing a new drug. However, in silico technology cannot create new drugs by itself, and its integration with organic chemistry is necessary. In this paper, we describe drug discovery research that effectively integrates organic chemistry and in silico technology to develop synthetic strategies and efficiently create a novel lead compound or in vivo tool.

The first study is a drug discovery research for renin inhibitors. We applied a fragment-based approach to discover high-quality hit compounds through comprehensive analysis of virtual library and high throughput library synthesis. The subsequent rational structure-based drug design approach focusing on hotspots enhanced the renin inhibitory activity dramatically and then discovered a novel lead compound with moderate bioavailability in rats. The second study is a drug discovery research for O-GlcNAcase (OGA) inhibitors. We identified a potent compound by virtual screening and optimized the hit chemical series utilizing a docking model, pocket analysis, and molecular dynamics (MD) to improve ligand lipophilicity efficiency (LLE), which resulted in a novel OGA inhibitor demonstrating the increase of O-GlcNAcylated protein level in cells with suitable pharmaceutical properties and brain permeability.

These studies provided not only high-quality lead compounds but also essential information that can be used to strategically promote drug discovery research to both synthetic organic chemists and computational chemists.

Maitotoxin (MTX) is a ladder-shaped polyether produced by the dinoflagellate Gambierdiscus toxicus. MTX comprises of 32 cyclic ethers and 98 stereogenic centers with the molecular weight of 3422. The molecule can be divided in two parts, hydrophobic (northern hemisphere) and hydrophilic (southern hemisphere) regions. MTX elicits potent acute toxicity and Ca²⁺ influx activity. The unique giant structure and potent biological activity of MTX has attracted great deal of interest among synthetic chemists. During the course of our structure-activity relationship studies based on chemical synthesis of partial structure of MTX, we synthesized the C'D'E'F' and WXYZA'B'C' ring systems corresponding to partial structures of the hydrophobic region of MTX, and found that they inhibited MTX-induced Ca²⁺ influx with IC₅₀ values of 59µM and 30µM, respectively. With the expectation that a more extended partial structure would inhibit MTX-induced Ca²⁺ influx in a more potent manner, the WXYZA'B'C'D'E'F' ring corresponding to the hydrophobic region was synthesized. We have developed a convergent method for synthesizing ladder-shaped polyethers via α-cyano ethers, therefore we planned to synthesize the WXYZA'B'C'D'E'F' ring from the WXYZ ring and the C'D'E'F' ring systems via construction of the A'B' ring system. The C'D'E'F' ring was synthesized from the E' ring via successive construction of the D' and C' rings by using SmI₂ induced reductive cyclization, and Suzuki-Miyaura coupling to introduce a side chain, and Pd catalyzed cyclization to construct the F' ring. The WXYZ ring was synthesized from the W and Z rings via aldehyde-alkyne coupling, cyclodehydration, ring-expansion of a six-membered ring ketone to a seven-membered one, and methylation of an O, S-acetal. The WXYZ ring aldehyde and the C'D'E'F' ring diol was combined by acetal formation, and regioselective opening of the resulting seven-membered ring acetal afforded an α-cyano ether. Reduction of the nitrile followed by Grignard reaction afforded a diene, which was subjected to ring closing metathesis to furnish eight-membered cyclic ether. Oxidation of the secondary alcohol followed by base induced epimerization afforded an enone corresponding to the B' ring. Although reductive etherification of a methyl acetal to construct the A' ring was unsuccessful giving an undesired diastereomer at C117, that via radial reduction of an O, S-acetal resulted in the formation of the desired one. Introduction of the terminal olefin via Wittig reaction afforded the WXYZA'B'C'D'E'F' ring in 16 steps. The molecular weight of the synthesized compound is 1140, and the longest linear sequence from commercially available starting material is 53 steps with 104 total steps. Although a number of synthetic studies on partial structure of MTX have been reported, this is the first example of the synthesis of the WXYZA'B'C'D'E'F' ring segment of MTX. The NMR data for the synthetic compound are in good accordance with those for the natural product except for the W ring terminus due to the structure difference from MTX. Contrary to our expectation, the WXYZA'B'C'D'E'F' ring segment did not inhibit MTX-induced Ca²⁺ influx, presumably due to its poor solubility in aqueous media. These results provide potential clues to understanding the mode of action of MTX, and will aid in the design of biologically active molecules based on the partial structure of the natural product.

Gas storage and separation are closely related to various aspects of human society, such as the alleviation of greenhouse effect, promoting clean energy, and controlling harmful gases. In particular, hydrogen has been enthusiastically researched as a clean energy source that emits no greenhouse gases. Therefore, there are requirements for safe methods to manufacture, store, and transport hydrogen. Conventionally, hydrogen storage materials are metal hydrides and metal amides that react violently with moisture, and their usage environments are limited by the extreme conditions required for hydrogen gas generation. Metal-organic frameworks (PCP/MOFs) are porous coordination materials that are composed of organic ligands and metal ions. Because of their ability to efficiently adsorb small molecules, PCP/MOFs have potential applications in e.g., gas adsorption, catalysis, as well as energy storage and conversion. Functionalization and modification of the organic ligands to construct new MOFs are fascinating and significant areas in crystal engineering owing to the potential applications of the resulting materials. We describe the synthesis and gas-adsorption properties of novel MOFs using the functionalized organic ligands.

Herqulines are small alkaloids with highly distorted structures that are synthesized from two tyrosine molecules. Between December 2018 and January 2019, the excellent total syntheses of herqulines B and C were reported by the groups of Wood, Baran, and Schindler. In 2022, the group of Han reported the synthesis of 1-hydroxyherquline A; however, the total synthesis of herquline A has not yet been achieved. In this short review, we will give an overview of the studies reported to date that focused on the syntheses of the herquline family.