Aromatic skeletons are typically considered resistant to cleavage due to their high aromatic stabilization energy as well as strong bonds between adjacent endocyclic atoms. While exocyclic functionalizations of aromatic compounds have garnered significant attention, endocyclic modifications of aromatic cores—achieved through partial disassembly of the cyclic skeletons followed by ring reconstruction—have received less focus. Here, we detail our endeavors to establish ‘aromatic metamorphosis’, wherein common aromatic compounds like thiophenes, benzofurans, and indoles are transformed into distinct ring systems in a multi-step strategy or ideally a one-step transformation. Aromatic metamorphosis challenges conventional notions in organic chemistry and introduces a revolutionary approach to organic synthesis. It opens up new avenues for the synthesis of intriguing heterocycles that were previously challenging to synthesize and for the generation of chemical libraries enriched with endocyclic diversity.

The positron emission tomography (PET) is one of the imaging technologies that allows for visualization of the behavior of a bioactive compound labeled with a positron emission nuclide, generally called a PET probe. To date, many (radio) chemists have developed various methods to introduce a short-lived PET nuclide, such as carbon-11 or fluorine-18, and expanded the available range of chemical structures of small molecular-based PET probes. However, the number of useful PET probes for life science research is still limited. This is mainly due to the insufficient range of available radiolabeling reactions, limiting the synthesizable chemical structures of PET probes. Furthermore, the densely functionalized complex structure of the compounds in interest impedes the preparation of radiolabeling precursors. To address these issues, we have proposed two strategies; one is the molecular renovation strategy that enables expeditious preparation of labeling precursors, and the other is the mimic strategy for designing a radiolabelable chemical structure for PET probe development. This account describes these two concepts and our recent efforts to realize them by developing various borylations and radiolabeling reactions.

As alternative strategy to transition metal-catalyzed cross-coupling, unimolecular fragment coupling (UFC) is defined as the reaction format, in which the atom(s) in the middle of the molecule is extruded, and the remaining fragments are coupled. UFC is a potentially powerful strategy, as the starting materials are readily available through well-established methods, and the key bond formation event proceeds in an intramolecular manner, thereby allowing for high chemo- and stereoselectivity. Herein, we overview UFC reactions of ketones, esters, amides and acylsilanes with the elimination of carbon monoxide, carbon dioxide, isocyanate and oxygen atom.

Structural modifications of anti-malarial artemisinins have traditionally focused on the lactone (D-ring) as the sole modifiable functional group. Our research group has developed two de novo synthetic processes capable of rapidly synthesizing tetracyclic peroxides with a wide range of skeletal and stereochemical variations. The first approach features the concise synthesis and diversification of structural motifs inspired by highly oxygenated sesquiterpenes recognized for their biological activities against infectious diseases. This divergent synthetic approach, accomplished within five to seven-step sequence, successfully provided appropriately functionalized and skeletally diverse sesqueiterpene-like scaffolds, involving systematic variations of stereochemical relationships at the sp³ ring-junctions. Lead generation for human African sleeping sickness, along with the elucidation of the pharmacophore, provided a proof-of-concept of our synthetic campaign. The second-generation approach focused on the expeditious and customizable access to the anti-malarial pharmacophore by installation of an amino nitrogen at the C6 position, akin to “point mutation”. This molecular design presented a completely distinct retrosynthetic disconnection and enabled the most efficient fully synthetic access to the tetracyclic scaffold, achieved in just four steps. This modular catalytic asymmetric synthesis allowed generation of substitutional variations at three sites (N6, C9, and C3). The 6-aza-artemisinins exhibited promising in vivo anti-malarial activities, surpassing the efficacy of artemisinin. These findings overturned the prevailing belief that the cyclohexane moiety (C-ring) of artemisinins merely serves as a structural unit. Instead, it became evident that the piperidine ring, with an unnatural substituent on the N6 nitrogen, played a pivotal functional role within the anti-malarial pharmacophore. These molecular design and modular synthetic strategies have facilitated the rapid and flexible de novo synthesis of sp³-rich pharmacophores relevant to natural products, overcoming limitations associated with semi-synthetic and engineered biosynthetic approaches.

Asymmetric organocatalytic reactions have made significant advancements in recent years. They are cost-effective, safe, and easy to handle, making them a focal point in the realm of green chemistry. These reactions are actively utilized in the total synthesis of natural product. However, when dealing with multifunctional substrates for natural product synthesis, there are instances where conventional methods are not applicable, requiring reoptimization. In this paper, I describe an asymmetric organocatalytic reaction that we have developed for the comprehensive total synthesis of specific natural product we have targeted. We have successfully developed asymmetric organocatalytic formal aza [3+3] cycloaddition reactions for the total synthesis of quinine and silicine, both of which possess multi-substituted piperidine rings. Additionally, we have established a dihydropyran ring construction reaction through an enantioselective, anti-selective Michael addition/Fukuyama reduction cascade to prepare secologanin, a pivotal biosynthetic intermediate in the monoterpenoid indole alkaloid biosynthesis. Moreover, I have introduced a trienamine-mediated asymmetric Diels-Alder reaction, utilizing dihydropyridones as substrates, for the total synthesis of Lycopodium alkaloids featuring decahydroquinoline rings. By incorporating these asymmetric reactions with secondary amine-type organocatalysts into our total synthesis approach, we efficiently constructed chiral carbon centers and the natural product scaffolds. All total syntheses were completed in relatively short steps and in high yields.

Natural product chemistry has entered a mature phase, where the total synthesis of a variety of natural products has been achieved and can then promote structure-activity relationship studies and chemical biology research. However, bioorganic and chemical biological researches on natural products that are challenging to synthesize because of the large sizes and the structural complexities, are currently at a standstill. We have been working on the mystery of aplyronine A for almost 30 years from its isolation in 1993 to the present day and have clarified the mechanism of actions to a certain extent. In this article, we introduce our research to create ‘useful molecules’ based on aplyronine A as medicinal chemistry and chemical biology tools, which evolve further aplyronine A. Thus, we designed and synthesized aplyronine A-swinholide A hybrid 5, which consists of the macrolactone part of aplyronine A (1) and the side chain part of swinholide A (4). Hybrid 5 retained not only a strong actin-depolymerizing activity but also a potent cytotoxicity, which is much stronger than that of aplyronine A-mycalolide B hybrid (3) reported previously. In addition, hybrid 5 induces protein-protein interactions between actin and tubulin in the same manner as aplyronine A. These results showed that the substitution patterns and configurations at C24-C26 positions in the side chain are essential for the strong cytotoxicity of aplyronine A-type compound. Furthermore, we conducted the structure-activity relationship studies about the amino acid moiety at C7 using hybrid 5 and found that the methoxy group of the trimethylserine ester group is important for potent cytotoxicity. In addition, comparing the side chain analogs of aplyronine A and swinholide A, we clarified that the side chain analog of swinholide A had a weaker actin-depolymerizing activity than that of aplyronine A. These studies have provided important findings into the mechanism of cytotoxicity of the “molecular glue” between two major cytoskeletons, actin and tubulin.

Natural products are attractive drug lead compounds. But rarely can natural products be used as-is as drugs, often requiring chemical modifications. Chemical modifications of structurally complex natural products are difficult due to multistep synthesis, complexity of purification operation and determination of those structures. To overcome this difficulty, we have a developed structural optimization process accelerating natural product drug discovery. This process contains parallel synthesis of a large number of analogues using chemoselective and clean reactions and in situ evaluation of biological activities, thereby simplifying the synthetic operations and providing seamless access to biological activity evaluation. Here, we describe our studies on the optimization of natural products exhibiting antibacterial activity, MraY inhibitory natural products and polymyxin. In the MraY inhibitory natural products study, a library of a series of natural products was synthesized and evaluated simultaneously for enzyme inhibitory activity and antibacterial activity to rapidly obtain analogues with high antibacterial activity. In the polymyxin study, analogues overcoming resistance were obtained by combining peptide scanning and library synthesis. This structural optimization process can be applied to a variety of natural products and is particularly powerful in cases, where it is difficult to design rational analogues, and we hope that it will lead to the creation of innovative new drugs based on natural products.

Biological methane oxidation stands as an exceptionally coveted method for transforming natural gas into a liquid state, meeting the burgeoning demands for fuel and chemical feedstock while concurrently alleviating the potent greenhouse effects associated with methane emissions. The longstanding presumption, owing to the absence of naturally occurring hemoenzymes capable of catalyzing methane-to-methanol conversion, posited that hemoenzymes, including cytochrome P450s (P450s), were inept at facilitating the oxidative conversion of methane. In a groundbreaking revelation, we now report the catalytic oxidation of methane by wild-type P450BM3, achieved without resorting to any mutagenesis, under the influence of chemically evolved dummy substrates (decoy molecules) at high-pressure methane conditions of 10 MPa. Our comprehensive investigations unfold a compelling narrative wherein methane undergoes catalytic conversion into methanol at ambient temperatures, showcasing a remarkable total turnover number of 4.0±0.4. This discovery not only challenges the previously held beliefs regarding the catalytic potential of hemoenzymes but also opens new avenues for advancing our understanding of methane transformation processes. In essence, this breakthrough holds promise for addressing the dual imperatives of sustainable energy production and environmental stewardship, marking a pivotal stride in the ongoing quest for innovative solutions to pressing global challenges.

N-Alkylated cyclic peptides are an attractive modality for targeting intracellular PPI, but the lack of a sufficient synthetic method has prevented progress in the development of this modality. We have established a versatile and durable method for synthesizing highly N-alkylated drug-like cyclic peptides. This is the first reported method for synthesizing such peptides in parallel with a high success rate and acceptable purity, without the need for sequence-specific optimizations. In this study, we addressed three key challenges in setting up reaction conditions: (1) diketopiperazine (DKP) formation as a side reaction during Fmoc removal, (2) insufficient amide bond formation due to the steric hindrance of the N-Me amino acid, and (3) the instability of N-Me rich peptides under acidic conditions. Using this newly established method, we successfully synthesized thousands of cyclic peptides, greatly enhancing our understanding of their drug-likeness and enabling us to innovate the whole drug discovery process, from hit generation to lead optimization. Consequently, we discovered the clinical cyclic peptide LUNA18 (RAS inhibitor), demonstrating the value of cyclic peptides as a middle-size molecule modality.

Lipopolysaccharide, an outer membrane component of Gram-negative bacteria, is known as a representative immune activator, and its active principle is the terminal glycolipid, lipid A. LPS is thus a potential adjuvant candidate. However, canonical Escherichia coli LPS is known as an endotoxin, since it can induce lethal sepsis due to hyperinflammatory immune response. Therefore, to apply them as adjuvants, it is necessary to structurally modify LPS and lipid A to minimize their toxic effects while maintaining their adjuvant effects.

Chemical ecology research considers the various life phenomena that occur between organisms as molecular interactions, and has developed mainly focusing on plants. Recently, as a new trend, we hypothesized that LPS and lipid A mediate the bacterial-host chemical ecology and regulate various biological phenomena in the host, especially immunity. We also predicted that parasitic and symbiotic bacteria that inhabit their host would have a low-toxicity immunomodulator due to chemical structural modifications in LPS as a result of co-evolution with the host (molecular evolution). To confirm these hypotheses and apply the lipid As to low-toxicity and safe adjuvants, we developed research on the chemical synthesis and functional evaluation of their lipid As. In this paper, chemical synthesis of lipid A, the structure-activity relationship of lipid A and its potential as a vaccine adjuvant are discussed.

The long-term goal of our research is to develop the working tools and methodologies that will form the foundation of “Therapeutic In Vivo Synthetic Chemistry”. The main benefit of this approach is that synthetic transformations can be directly performed at target regions within the body to generate molecules that elicit localized biological effects. This method should largely circumvent off-target binding and instability issues associated with current drug administration techniques. In these years, we have engaged this topic through the usage of glycosylated artificial metalloenzymes, where the primary aim is to exploit the chemoselectivity of embedded, non-natural transition metal catalysts for the synthesis/release of bioactive molecules. Thus, we developed the albumin-based artificial metalloenzymes with various transition metal complexes, of which metals are efficiently protected inside the hydrophobic pocket of albumin, hence various transition metal-catalyzed transformation could be now possible in cells, mice, or even plants. These catalysts show quite high catalytic activity in the presence of 20 mM of glutathione and even in the whole blood. Furthermore, by conjugating the glycans on the albumin surface as a targeting vector, we successfully carried the artificial metalloenzymes to the cancer regions in mice through “glycan pattern recognition”, and synthesized the anti-cancer drugs for the first time as the true meaning of “catalytically” in mice, to disturb the cancer onset and growth. Our molecular technique is quite powerful; Just a single intravenous injection of the glycosylated artificial metalloenzyme and substrates (starting compounds) led to efficient metal-catalyzed drug synthesis leading to efficient cancer treatment. Since our technology is well targeting, non-invasive, without risk of immunogenicity, non-toxicity, and high efficiency of in vivo drug synthesis, we must point out that our technology could be a possible method to apply to the patients for disease treatment in a hospital, as we indeed have been actively investigating with the companies.