α-Bromocarbonyl compounds are excellent reagents due to several key features: 1) they generate reactive α-radical species upon reaction with copper catalysts, 2) they can serve as precursors for tertiary alkyl groups, 3) they enable the development of various organic reactions for introducing a fourth substituent onto the α-carbon atom, and 4) they offer the opportunity to investigate steric effects in radical reactions through the transformations they facilitate. This study examines the reactions that proceed when these radical precursors are used as chiral starting materials. The results demonstrate that chiral α-bromocarbonyl compounds react with tertiary alkyl alcohols, cesium fluoride, and terminal alkynes while maintaining stereochemistry. In reactions with alcohols, aziridinones are formed in situ, and the reaction proceeds with stereoretention through two consecutive S_N2 reactions. On the other hand, fluorination and alkynylation reactions proceed in the presence of a copper catalyst, suggesting a metal-mediated stereospecific process.

Here we describe our syntheses of polycyclic natural products, including daphenylline, huperzine R, kopsone, and melognine, in which intramolecular cycloadditions of nitrogen-containing 1,3-dipoles played crucial roles in the construction of the cyclic skeletons. Cycloadditions of azomethine ylides resulted in the formation of pyrrolidine rings, which are incorporated into the structures of the target molecules. Cycloadditions of a nitrile oxide or of nitrones formed an isoxazoline or isoxazolidines, respectively, which could be utilized as a β-hydroxyimine or as 1,3-aminoalcohols after cleavage of the N-O bond of the heterocycles.

Plants have evolved sophisticated defense mechanisms to counter biotic and abiotic stresses, such as pathogen infection and environmental challenges. Among these, phytoalexins—low molecular-weight antimicrobial secondary metabolites induced in response to stress—are essential for plant immunity. This account summarizes over 25 years of synthetic and bioorganic chemical research on rice and maize phytoalexins conducted by our group, highlighting the contribution of organic synthesis in elucidating their structures and biosynthetic pathways.

Development of γ-position-selective bond formation reactions of β-ketocarbonyl derivatives catalyzed by amine-based catalyst systems and reaction-based mechanistic analyses of the regioselective reactions are discussed. The reactions developed include enantioselective γ-position-selective Mannich reactions of β-ketoesters, β-ketophosphonates, and other β-ketocarbonyl derivatives to afford δ-amino β-ketocarbonyl derivatives and γ-position-selective formal aldol condensation reactions of β-ketophosphonates to afford γ,δ-unsaturated β-ketophosphonates. By harnessing the dynamics of the reversible formation of the enamines and/or the α-position-reacted products of β-ketocarbonyl derivatives, γ-position-selective bond formation reactions of β-ketocarbonyl derivatives under aminocatalysis were enabled.

Spirocyclic and bridged polycyclic systems are common in bioactive molecules such as natural products and therapeutic agents. Accordingly, they have attracted attention in drug discovery as valuable “drug-like” templates. We have developed a series of visible-light-mediated radical dearomatization reactions using N-(2-phenyl)benzoyl amino acid derivatives as unified precursors for the construction of such frameworks. Mild photoredox conditions enabled radical dearomatization, leading to efficient formation of spirocyclohexadiene scaffolds. Further exploration revealed that electron-deficient biphenyl substrates underwent a radical cascade involving dearomatization, 1,4-hydrogen atom transfer, and [4+2] cycloaddition to afford bicyclo[2.2.2]octene skeletons. The spirocyclohexadiene formation strategy was successfully applied to the first total synthesis of zephycarinatines C and D, Amaryllidaceae alkaloids bearing a 6,6-spirocyclic core with multiple stereocenters. Our studies highlight the utility of visible-light-mediated radical dearomatization as a powerful and modular approach to access complex, bioactive molecular architectures from simple aromatic feedstocks.

The selective cleavage of carbon-oxygen (C-O) and carbon-nitrogen (C-N) bonds remains a fundamental transformation in organic synthesis, offering a versatile platform for constructing new chemical bonds. In particular, homogeneous transition metal catalysis has enabled highly selective reductive cleavage of ethereal C-O bonds under mild conditions, providing new strategies for both small molecule functionalisation and polymer degradation. Meanwhile, recent advances have extended this approach to more challenging C-N bonds. This review highlights recent advances in the development of homogeneous catalysis for the reductive cleavage of C-O and C-N bonds alongside their mechanistic insights. Additionally, emerging applications in the valorisation of polymers such as lignin and epoxy resins highlight the broader impact of reductive cleavage of C-O bonds.

In recent years, the development of nucleic acid therapeutics has gained considerable traction, with the aim of controlling the expression of disease-related genes. In particular, numerous small interfering RNA (siRNA) drugs that act through the RNA interference (RNAi) mechanism have been developed. Growing attention has also been directed toward strategies that inhibit microRNAs (miRNAs), which endogenously mediate RNAi. Both approaches involve nucleic acid drugs that modulate the RNA-induced silencing complex (RISC)—the central effector of RNAi—to control disease-related gene expression through either gene silencing or restoration. To improve the design of nucleic acid therapeutics, artificial nucleic acids have been employed to enhance enzymatic stability and target RNA recognition. Although ribose-based artificial nucleic acids have been widely adopted, researchers have also begun exploring alternatives with chemical structures that differ substantially from those of the ribose type, especially to achieve greater enzymatic resistance. Against this backdrop, we have focused on non-ribose type acyclic artificial nucleic acids with amino-acid-based backbones, serinol nucleic acid (SNA) and acyclic L-threoninol nucleic acid (L-aTNA), and have explored their use in designing nucleic acid therapeutics. This account describes designs for both siRNA and antisense oligonucleotides against miRNA (anti-miRNA), which are referred to as AMOs. The unique properties of these acyclic nucleic acids are highlighted, along with an introduction to research on siRNA designs aimed at regulating strand selection during RISC assembly—a key strategy for minimizing off-target effects. This account also includes the design and mechanism of action for our AMO. A key limitation of acyclic artificial nucleic acids is also addressed, with a chemical strategy proposed to overcome it. Ultimately, this review suggests that the unique chemical properties of acyclic artificial nucleic acids may enable the next generation of highly stable and selective nucleic acid therapeutics, paving the way for more effective and safer clinical applications.

Frustrated Lewis Pairs (FLPs) have been widely utilized as useful reagents and catalysts in organic synthesis. Recently, Frustrated Radical Pairs (FRPs), which refer to radical or radical ion variants of FLPs, have also emerged as promising reactive species for molecular transformations through mechanistic investigations in FLP chemistry. This article summarizes our recent findings on photo-promoted transformations of unreactive bonds and molecules utilizing intramolecular phosphine-borane FLPs, highlighting the novel reactivity and synthetic utility of the photochemically generated FRPs.

A connection between chirality-induced spin selectivity (CISS) and organic synthesis has been explored. CISS refers to the effect of chiral molecules on electron spin, in which the spin polarization of electrons becomes aligned parallel or antiparallel to their velocity while tunneling through the chiral medium. Symmetry aspects of CISS have been discussed to rationalize enantioselectivity induced by spin polarization, a phenomenon verified by spintronics experiments using an organic chiral superconductor. Extending this concept, enantioselectivity has also been demonstrated in helical nanowires and electrochemical processes.