Introduction of fluorine atom(s) into an organic framework is one of the common strategies in life science field due to its unique properties. Therefore, fluorine atom(s) can be found in many bioactive compounds including medicinal drugs. Considering chiral environment in nature, the development of efficient fluorination to construct chiral fluorine-containing compounds is an important subject. In this context, we have studied the development of asymmetric fluorofunctionalization of alkenes and deraomative fluorination of aromatic compounds using a newly designed phase-transfer catalysts. In 2015, we reported the first successful example of asymmetric fluorolactonization using a hydroxy-carboxylate catalyst. Based on the mechanistic studies of the fluorolactonization, we were able to create a dianionic phase-transfer catalyst with more efficient catalytic activity. The dianionic phase-transfer catalyst was found to promote asymmetric 6-endo-fluorocyclization and deprotonative fluorination of simple cyclic and acyclic allylic amides, asymmetric fluorocyclization of ene-oximes, and dearomatizing fluorinations of indoles, 2-naphthols, and resorcinols. According to the mechanistic studies using allylic amides, the active catalytic species switches depending on the substitution pattern of allylic amides, which would result in the reversal of the face-selectivity. Thus, an active aggregate of the catalyst/Selectfluor ion pair promotes the reaction of γ,γ-disubstituted allylic amides, while a monomer complex would be active for γ-monosubstituted substrates.

Catalytic intramolecular hydrofunctionalizations of acyclic alkenes and alkynes are desired methods for the construction of pharmaceutically important heterocycles with 100% atom efficiencies. Although electrophilic activation of alkenes and alkynes in the presence of Lewis basic hydroxy and amino groups can cause the reactions, those of monoalkyl- and 1,2-dialkyl-substituted alkenes and alkynes called unactivated alkenes and alkynes are difficult owing to their inherent reactivity. Herein, we introduce several transition metal-free novel catalytic systems for the intramolecular hydrofunctionalization of such unactivated alkenes and alkynes; iodine-silane catalytic system for the hydroalkoxylation of unactivated alkenes, Brønsted acid-silane and iodine-silane catalytic systems for the hydrofunctionalization/reduction of unactivated alkynes, and boron catalytic systems for double hydrofunctionalization reactions of unactivated alkynes. A novel active species, iodophenylsilane (PhSiH₂I) efficiently catalyzes the intramolecular hydroalkoxylation of unactivated alkenes in the iodine-silane catalytic system. A super strong Brønsted acid catalyst can activate unactivated alkynes in the presence of silane to cause the hydrofunctionalization/reduction. Tris(pentafluorophenyl)borane [B(C₆F₅)₃] chemoselectively activates unactivated alkynes in the presence of allylsilane to cause the intramolecular hydrofunctionalization/hydro-allylation. In addition, tris(pentafluorophenyl)borane hydrate [B(C₆F₅)₃·nH₂O] reacts with trime-thylsilylcyanide to form H⁺[NCB(C₆F₅)₃]^-, which catalyzes the intramolecular hydroalkoxylation/hydrocyanation of unactivated alkynes. These catalytic methods enable the rapid construction of multiply-substituted oxygen-or nitrogen-containing heterocycles.

Intermolecular oxidative cross-coupling of enolate species is a useful reaction for the direct synthesis of unsymmetrical 1,4-dicarbonyl compounds. 1,4-Dicarbonyl compounds are important not only as structures found in natural products, pharmaceuticals, and their synthetic intermediates, but also as building blocks for the construction of heterocyclic compounds. The difficulty in the oxidative cross-coupling lies in the cross-selectivity. The key point is how to suppress undesired homo-coupling. Since the cross-coupling must proceed between nucleophilic species in contrast to the commonly used nucleophile-electrophile coupling, some elaboration is required to achieve this. The author focused on the fact that the reactivity of the enolate anion changes depending on the metallic counter-cation. Specifically, we discovered that a combination of boron and silicon for the counter-cation of enolate clarifies the role of the two enolate species, and leads to the selective oxidative cross-coupling. This article summarizes our studies on the oxidative cross-coupling between boron and silicon enolates by oxovanadium(V) oxidant.

Epigenetic mechanisms, including DNA methylation, histone acetylation, and histone methylation, are crucial for regulating cellular functions, cellular differentiation, and developmental changes in organisms. These mechanisms also play key roles in the pathogenesis of various diseases. Conventional drug discovery studies in the field of epigenetics have focused mainly on specific enzymes such as histone deacetylases. However, there has been increasing interest in small molecules targeting the multiprotein enzyme/transcription factor complexes responsible for the epigenetic control of gene expression. Herein, we describe our researches on small molecules that manipulate the epigenetic complexes. The small molecules we identified exhibit significant anticancer activities by inactivating the functions of the specific epigenetic complexes through distinct mechanisms. These small molecules targeting the complexes are expected to expand the potential of drug discovery studies.

Antimicrobial resistance (AMR) raises a difficult challenge in achieving universal health coverage. Antibiotic-resistant Streptococcus pneumoniae strains may cause infections that fail to respond to antimicrobial therapy. Clindamycin, an orally active derivative of natural lincomycin, is effective against Gram-positive bacteria including S. pneumoniae, but is not active enough against resistant bacteria of S. pneumoniae possessing constitutive erm gene. Novel chemical modifications of lincomycin at the C-6 and C-7 positions were exhaustively performed to explore useful derivatives which are effective against resistant S. pneumoniae with erm gene. Two groups among them exhibited potent activities against resistant S. pneumoniae with erm gene. The first group was 7(S)-S-1,3,4-thiadiazole derivatives and the second group was 7(S)-S-phenyl derivatives. Several derivatives in the second group exhibited potent in vitro activities against 60 clinical isolates of S. pneumoniae including susceptible strains and resistant strains with erm and/or mef genes, and two of them exhibited strong therapeutic effects in rat in vivo models.

Talatisamine (1), isolated from an Aconitum species, is a C19-diterpenoid alkaloid that selectively inhibits K⁺ channel and exhibits an antiarrhythmic effect. The structure of 1 is quite unique, consisting of the intricately fused 6/7/5/6/6/5-membered hexacyclic ring system with five oxygen functionalities and twelve contiguous stereocenters. Both the intriguing structure and biological activities have attracted the attention of organic chemists. In this short review, recent total syntheses of 1 by Inoue and Reisman groups are discussed with focusing on synthetic strategy.