Taizo Ono

Dedication: Dedicated to dear colleague and friend, Professor Volodymyr Brovarets – a true wizard of heterocyclic chemistry whose brilliance, kindness, and passion inspired us all. You left us far too soon, but your warmth and legacy will live on in our hearts and in every reaction we run. We miss you deeply. The development of sustainable and efficient synthetic methodologies for complex molecular architectures remains a cornerstone of modern organic chemistry. This paper reviews the recent advancements in multicomponent reactions (MCRs) facilitated by innovative magnetic nanocatalysts, including Fe3O4@CS@Ag, γ-Fe2O3@HAp-Ag, Ag/CdO/Fe3O4@MWCNTs, and Ag/Fe3O4/ZnO@MWCNT. These heterogeneous systems have demonstrated exceptional catalytic efficacy in the streamlined synthesis of diverse heterocyclic scaffolds, such as hexahydroquinolines, highly functionalized tetrahydropyridines, triazinopyrrolothiazepines, and oxazolopyrazoloazepines. A significant focus is placed on the transition from traditional three-component couplings to more sophisticated five- and six-component transformations involving aromatic aldehydes, anilines, and 1,3-dicarbonyl building blocks. Furthermore, the strategic incorporation of fluorine and trifluoromethyl groups is highlighted as a vital tool for enhancing the pharmacological profiles of the resulting bioactive derivatives. In alignment with green chemistry principles, these magnetic catalytic systems offer the distinct advantage of rapid recovery via external magnetic fields, high atom economy, and the use of environmentally benign media such as water or ionic liquids at ambient temperatures. The recyclability of these catalysts, maintaining high yields over multiple consecutive cycles, underscores their potential for industrial scalability. This review concludes with a critical assessment of future directions, including the development of enantioselective MCRs and the application of advanced spectroscopic techniques to elucidate metal-support synergistic mechanisms.

Children exposed to war experience severe neurodevelopmental disruption from the combined effects of chronic stress, malnutrition, environmental toxins, and psychological trauma during critical windows of brain development. These overlapping insults impair synapto­ge­nesis, myelination, and the maturation of stress‑regulation circuits, creating long‑term risks for cognitive deficits, emotional dysregulation, and reduced educational and social outcomes. Nutritional biochemistry, neurochemistry, and molecular medicine offer evidence‑based strategies to protect the developing brain under these extreme conditions and to mitigate the biological consequences of trauma. Key micronutrients—such as iron, iodine, zinc, and magnesium—along with long‑chain omega‑3 fatty acids and enzymatic cofactors essential for neurotransmitter synthesis, can stabilize the hypothalamic–pituitary–adrenal axis, reduce neuroinflammation, support mitochondrial function, and preserve synaptic plasticity. Advances in formulation chemistry now enable stable, low‑cost, field‑deployable pediatric supplements that remain viable despite disrupted supply chains, limited refrigeration, and damaged infrastructure. In parallel, portable chemical sensors and rapid analytical platforms can detect heavy metals, explosive residues, and other neurotoxic contaminants in water and soil, preventing secondary exposure that further threatens vulnerable developing nervous systems. By elucidating the molecular pathways of trauma—including cortisol dysregulation, oxidative stress, excitotoxicity, and impaired neuroplasticity—chemistry provides rational targets for timely intervention and guides the design of protective strategies suited for conflict zones. While chemistry cannot end war, it can meaningfully preserve cognitive potential, psychological resilience, and the possibility of healthy development in the youngest victims of armed conflict.

D-Amino acids (D-AAs) have become indispensable building blocks in modern peptide drug design. Although relatively rare in higher organisms, D-AAs are widely utilized in nature, particularly in bacterial peptidoglycans and microbial antimicrobial peptides, where they confer proteolytic stability and unique biological activities. Inspired by these natural strategies, medicinal chemists have successfully incorporated D-Aas into synthetic peptides to overcome the inherent limitations of conventional peptide therapeutics, such as rapid enzymatic degradation and poor bioavailability. The incorporation of D-AAs offers several key advantages, including dramatically enhanced proteolytic resistance, prolonged plasma half-life, reduced immunogenicity, and improved receptor selectivity. These properties have enabled the development of clinically successful drugs across multiple therapeutic areas. Prominent examples include the early antibiotic gramicidin D (1955), the immunosuppre­ssive agent cyclo­sporine, D-penicillamine, daptomycin, etelcalcetide, difelikefalin, and voclo­sporin. These compounds illustrate the transformative impact of D-AAs on peptide pharmacology and their expanding role in treating infectious diseases, autoimmune disorders, nephrological conditions, and beyond. This review highlights the strategic importance of D-AAs in pharmaceutical design, their natural occurrence, clinical applications, and major advances in synthetic methodologies, with particular emphasis on the versatile Ni(II) Schiff base complex approach for the preparation of tailor-made D-AAs. The evolution of D-AA-containing pharmaceuticals demonstrates how stereochemical engineering continues to drive innovation in peptide drug discovery and development.

In 2025, seven fluorine-containing anticancer agents received approval from the US Food and Drug Administration, underscoring the continued and growing impact of strategic fluorination in modern oncology drug design. These newly authorized therapies represent a diverse portfolio spanning a broad spectrum of malignancies, molecular targets, and innovative mechanisms of action, further validating fluorine’s unique ability to enhance drug performance. Sunvozertinib (Zegfrovy®) was approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring specific EGFR mutations. The combination of defactinib and avutometinib (Avmapki®) provides a much-needed targeted option for patients with KRAS-mutated recurrent low-grade serous ovarian cancer, addressing a historically challenging disease setting. Imlunestrant (Inluriyo®) offers a next-ge­neration selective estrogen receptor degrader (SERD) as an effective endocrine therapy for estrogen receptor-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Ziftomenib (Komzifti®) enables precision therapy for adults with relapsed or refractory (AML) carrying susceptible NPM1 mutations, representing a signi­ficant advancement in targeted hematologic oncology.Datopotamab deruxtecan (Datroway®), a novel TROP2-directed antibody–drug conjugate (ADC) with a topoisomerase I inhibitor payload, expands treatment options for previously treated hormone receptor-positive, HER2-negative metastatic breast cancer and for certain TKI-experienced NSCLC populations. Taletrectinib (Ibtrozi®), a potent next-generation ROS1 tyrosine kinase inhibitor, received approval for ROS1-­positive NSCLC in both TKI-naïve and TKI-experienced patients, offering improved central ner­vous system penetration and activity against resistant mutations.Collectively, these seven agents vividly illustrate the remarkable versatility of fluorine incorporation in enhancing molecular potency, metabolic stability, binding selectivity, and overall pharmacokinetic performance across vastly different therapeutic modalities — from small-molecule kinase inhibitors and degraders to complex antibody–drug conjugates. The strategic placement of fluorine atoms or fluorinated groups in these molecules often leads to improved lipophilicity, stronger target engagement, reduced clearance, and better safety profiles.For each compound, we provide a comprehensive integrated discussion covering its discovery history, detailed biological me­chanism of action, primary therapeutic applications, recommended clinical administration and dosing regimens, the specific role of fluorination in optimizing its pharmacological and physicochemical properties, as well as the detailed chemical synthesis routes employed in its industrial-scale production.

Fluorine-containing heterocycles occupy a central position in pharmaceutical, agroche­mical, and materials science due to their unique physicochemical properties and broad functional relevance. The pursuit of efficient and sustainable synthetic methodologies has catalyzed the emergence of photochemistry as a compelling alternative to conventional thermal, acid–base, or redox-based approaches. Indeed, many of the transformations highlighted in this review would be unattainable under traditional reaction conditions, underscoring the distinctive reactivity enabled by light-driven processes. This review surveys key advances over the past decade in the photochemical synthesis of fluorinated heterocyclic compounds. It begins with an overview of fundamental photoche­mical principles and the most commonly employed photocatalysts. The discussion then proceeds to categorize reactions into unimolecular, bimolecular, and trimolecular classes. Unimolecular (intramolecular) reactions typically involve the cyclization of strategically designed substrates capable of forming heterocyclic frameworks upon photoactivation. Unimolecular (intramolecular) reactions represent the most prevalent class, wherein two distinct components contribute complementary fragments to construct the target heterocycle. Trimolecular (three-component) photochemical reactions, by contrast, are exceedingly rare due to the inherent mechanistic, kinetic, and spatial constraints associated with three-body interactions under photochemical conditions. For each transformation discussed, we detail the photocatalyst employed, the irradiation source, reaction conditions, and the specific fluorination pattern introduced. Photochemistry redefines light not merely as an energy source but as a precise and sustainable reagent—unlocking synthetic pathways with elegance, selectivity, and minimal environmental impact. This work aims to serve as a comprehensive resource for researchers and practitioners seeking to harness photochemical strategies for the synthesis of fluorinated heterocycles, with an emphasis on catalytic efficiency, structural diversity, and ecological responsibility.

1-Substituted-2,2,2-trifluoroethylamines have emerged as structurally distinct and pharmacologically potent motifs in modern drug design, contributing to enhanced metabolic stability, target selectivity, and bioactivity across various therapeutic classes. This review provides a comprehensive account of their catalytic enantioselective synthesis, encompassing chiral auxiliary-based methods and a wide array of asymmetric catalytic strategies — including hydrogenation, [1,3]-proton shift reactions, nucleophilic additions, and cycloadditions. Emphasis is placed on the stereochemical outcomes achieved with ruthenium, palladium, phosphoric acid, borane, and squaramide-based catalysts, many of which routinely deliver an enantiomeric excess (ee) exceeding 90–99%. Despite these advances, the phenomenon of self-disproportionation of enantiomers (SDE) remains critically underreported, casting doubt on the veracity of ee values in the literature. This review highlights the pronounced SDE behavior of fluorinated amines and underscores the need for rigorous stereochemical validation. By integrating synthetic innovation with epistemic scrutiny, this work aims to guide future research toward more reliable, efficient, and stereochemically sound methodologies for the synthesis of fluorinated amine derivatives.

Dedication: Dedicated with admiration and gratitude to Professor Giuseppe Resnati on his 70th birthday, for his pioneering and enduring contributions to fluorine chemistry and the art of noncovalent bonding. The 1,3-proton shift reaction has emerged as a highly convenient, scalable, and synthetically practical strategy for accessing fluorinated amines and amino acids - structural motifs that play a pivotal role in the design of contemporary pharmaceuticals and agrochemicals. This transformation typically proceeds via a biomimetic reductive amination of fluorinated carbonyl compounds, wherein a benzylamine derivative functions dually as the nitrogen source and as a formal reducing agent. Over the past decade, substantial progress has been achieved in this domain, particularly through the strategic use of 1,3-azaallylic anion intermediates in reactions with a broad array of electrophiles. A notable advancement involves the adoption of 2,2-diphenylglycine as a synthetically advantageous alternative to the conventionally employed diphenylmethylamine. In this review, we underscore the benefits of this modification and examine its application across reactions with diverse electrophilic partners, including aldehydes, imines, and allyl alcohol-derived species, enabling the synthesis of vicinal amino alcohols, vicinal diamines, homoallylamines, and α-methylene-γ-amino acids

Fluorine-containing heterocycles play a crucial role in the pharmaceutical, agrochemical, and materials industries. The pursuit of effective and sustainable synthesis methods has dri­ven the development of electrochemistry as a compelling alternative to conventional chemical transformations. Among these approaches, electrochemistry has emerged as a particularly promising technique for orchestrating multibond-forming processes under mild, environmentally benign conditions. This review highlights key advances over the past decade in the electrochemical synthesis of fluorinated heterocyclic compounds, encompassing bimolecular, trimolecular, and tetramolecular reactions. Emphasis is placed on multicomponent cascade strategies, radical-mediated couplings, and oxidant-free cyclizations that afford broad functional group tolerance and fluorine incorporation flexibility. Collectively, this work serves as a resource for researchers developing next-generation sustainable synthetic platforms tailored to fluorinated heterocycles with diverse structural and biological profiles.

α-Aminocyclopropanecarboxylic acid (ACC) and its derivatives are widely distributed in the plant kingdom, fulfilling diverse roles ranging from regulation of plant life cycles to defensive mechanisms. The sterically constrained structure of ACC has proven invaluable in the design of numerous drugs, particularly hepatitis C virus (HCV) NS3/4A protease inhibitors. Indeed, ACC has been instrumental in the development of multiple generations of potent HCV treatments, with ongoing efforts focused on further improvements and refinements. The inherent steric constraints of these derivatives present a significant challenge for their synthesis, especially in enantiomerically pure form. This article provides a comprehensive overview of synthetic methodologies reported in the literature for the preparation of ACC and its derivatives. The synthetic strategies discussed herein are organized based on key transformations, including dialkylation of nucleophilic glycine equivalents, cyclopropanation of carbenoid glycine equivalents, and addition reactions to dehydroamino acids. Particular emphasis is placed on asymmetric approaches that enable the preparation of these tailor-made amino acids in enantiomerically pure form. Furthermore, aspects of Self-Disproportionation of Enantiomers (SDE) relevant to enantioselective catalysis are highlighted. By compiling these methodologies, we aim to provide a comprehensive resource and a source of inspiration for researchers in synthetic and medicinal chemistry, as well as drug discovery.

Amino acids are fundamental to virtually every aspect of biological science and healthcare ser­ving as the cornerstone of molecular structure and function. Research has now expanded beyond naturally occurring amino acids to tailor-made derivatives enabling precise control over biological pro­cesses and unlocking new functionalities unattainable with standard amino acids and peptides. One of the most exciting advancements is the development of fluorine-containing amino acids which integrate the powerful pharmacological effects of fluorine with the structural adaptability of amino acid frameworks. This review explores the synthesis of fluorinated amino acids bearing unsaturated residues—a highly valuable and distinct subgroup within the broader class of fluorinated amino acids. These specialized molecules feature fluorine directly bonded to sp2-hybridized carbon atoms, effectively replicating the electronic properties of aromatic substitution without relying on an aromatic system. The olefinic placement of fluorine enhances molecular stability and imparts specific steric, geometric, chemical, and biological characteristics critical for drug design and bioactive compound development. The synthetic strategies presented herein are organized around key transformations, including α alkylation of amino acids, side chain elaboration, introduction of amino and/or carboxylic functionalities, and the generation of unsaturation within fluoro-amino acid cores. By compiling these methodologies we aim to provide a comprehensive resource and a source of inspiration for researchers engaged in synthetic and medicinal chemistry, drug discovery, and organofluorine chemistry.