{"id":37,"date":"2024-02-09T11:09:15","date_gmt":"2024-02-09T02:09:15","guid":{"rendered":"https:\/\/www.lbb.iir.isct.ac.jp\/MedOrgChem\/?page_id=37"},"modified":"2026-04-10T23:55:08","modified_gmt":"2026-04-10T14:55:08","slug":"research-en","status":"publish","type":"page","link":"https:\/\/www.lbb.iir.isct.ac.jp\/MedOrgChem\/research-en\/","title":{"rendered":"Research"},"content":{"rendered":"\n

Research<\/h2>\n\n\n\n

Organic synthetic chemistry is a highly attractive field that enables the precise construction of target molecules by controlling chemical reactions. This molecular construction technology underpins not only the creation of pharmaceuticals, but also a wide range of fields, including drug delivery and biomaterials, thereby linking basic research to diverse applied research areas.<\/p>\n\n\n\n

In our laboratory, we aim to fully realize a fundamental appeal of organic synthetic chemistry: the ability to create desired molecules as desired. To achieve this, we develop original reactions and catalysts that enable such molecular construction to be achieved efficiently and selectively. Building on these foundational technologies, we further extend our research to the precise structural transformation of biomolecules such as peptides and proteins, with the goal of creating new molecular transformation methods that contribute to drug discovery, drug delivery, and biomaterials development. Leveraging experience in process chemistry in the pharmaceutical industry, we also strive to refine these approaches into practical methodologies and reagents that can be conveniently applied in the pharmaceutical industry. We welcome students who are eager to pursue research grounded in organic synthesis and expanding into the life sciences and pharmaceutical sciences.<\/p>\n\n\n\n

Development of New Reagents for the Modular Synthesis of Disulfides<\/h3>\n\n\n\n

Disulfides, consisting of two sulfur atoms linked together, are important structural motifs found not only in a variety of biologically active natural products, but also in drug delivery as cleavable linkers in vivo, in peptide drug discovery, and in materials science exploiting their redox properties. However, the construction of unsymmetrical disulfides bearing different substituents has been challenging.<\/p>\n\n\n

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Our laboratory has recently developed a novel modular disulfide reagent bearing two distinct leaving groups that can be selectively transformed under different conditions. In this system, the amino leaving group is selectively activated under acidic conditions via protonation, whereas the intrinsically electron-deficient imide moiety reacts under neutral or basic conditions. By combining these orthogonal transformations, a wide variety of unsymmetrical disulfides can be synthesized in a short sequence. This reagent is a highly stable, easy-to-handle solid with high reactivity, and its commercialization by a chemical supplier is currently under consideration.<\/p>\n\n\n\n

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This platform enables diverse transformations at both sulfur atoms, and we have successfully synthesized a broad range of disulfides, including various heterocycle-containing disulfides, oligopeptides bearing disulfide units, and multifunctional disulfides.<\/p>\n\n\n

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We are currently developing new reagents with enhanced reactivity, stereoselectivity, and expanded reactivity beyond electrophilic transformations, as well as reagents applicable to the synthesis of polysulfides containing multiple sulfur atoms. In addition, we are exploring the use of disulfides as cleavable linker motifs in drug delivery.<\/p>\n\n\n\n

Related Publications<\/h5>\n\n\n\n

Angew. Chem., Int. Ed.<\/em> 2023<\/strong>, 62<\/em>, e202219156.
Org. Chem. Front. <\/em>2026<\/strong>, 13, <\/em>1299.
J. Org. Chem. <\/em>2026<\/strong>, 91<\/em>, 1817.
Chem. Sci. <\/em>2025<\/strong>, 16<\/em>, 2777.
Org. Lett.<\/em>2024<\/strong>, 26<\/em>, 438.<\/p>\n\n\n\n

Development of Site-Selective Peptide Modification Methods<\/h3>\n\n\n\n
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Peptides are the fundamental units that constitute proteins and play an essential role in the regulation of biological processes, while also showing great potential as biomaterials. However, because peptides contain multiple nucleophilic sites, achieving site-selective transformation at a desired position remains challenging. Our laboratory aims to develop new molecular transformation methods to address this challenge.<\/p>\n\n\n

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Recently, we developed a new methodology that enables selective molecular conjugation exclusively at the N-terminus, which is typically present only once. This method allows the installation of two functional molecules onto the N-terminus and proceeds with very high efficiency even for long-chain peptides. In addition, by using dehydroalanine, which can be selectively generated from various amino acid residues such as serine and cysteine, we have established a method for the precise ligation of two peptides.<\/p>\n\n\n

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We are currently developing new site-selective peptide ligation reactions that are not limited to the N-terminus. We are also pursuing advanced applications such as functional modification of proteins. Furthermore, we are working on the development of multifunctional materials that take advantage of the ability to readily integrate two functional peptide components.<\/p>\n\n\n\n

Related Publications<\/h5>\n\n\n\n

Angew. Chem., Int. Ed.<\/em> 2024<\/strong>, 63<\/em>, e202320012.
Org. Chem. Front. <\/em>2026<\/strong>, 13<\/em>, 1317.<\/p>\n\n\n\n

Development of Stereoselective Reactions and Their Application to Foundational Technologies for Drug Discovery<\/h3>\n\n\n\n

Amino acids possess chirality, which plays an important role in molecular recognition in biological systems. Peptides and proteins, which are assemblies of amino acids, also contain numerous stereogenic centers. In our laboratory, we pursue not only the asymmetric synthesis of unnatural amino acids based on azomethine ylides, but also the development of asymmetric reactions targeting peptides.<\/p>\n\n\n\n

In particular, we focus on stereocontrol at the late stages of peptide synthesis. Recently, we revealed that asymmetric reactions of dehydroalanine residues in peptides proceed with high selectivity and that, by selecting an appropriate chiral ligand, either stereoisomer can be selectively constructed regardless of side-chain effects.<\/p>\n\n\n

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By contrast, abundant knowledge has been accumulated for asymmetric reactions of amino acids, those targeting peptides remain underdeveloped. In this research, we aim to expand the knowledge obtained in amino acid chemistry to peptide chemistry by using computational science as a bridge<\/a> and to pioneer new asymmetric reactions. Currently, we focus primarily on the development of asymmetric reactions useful for amino acid and peptide chemistry, but we will continue to extend this work to a broader range of molecular transformations.<\/p>\n\n\n\n

Related Publications<\/h5>\n\n\n\n

Peptide-related:
Org. Chem. Front. <\/em>2026<\/strong>, 13<\/em>, 1317.<\/p>\n\n\n\n

Amino acid-related:
Org. Lett<\/em>. 2024<\/strong>, 26<\/em>, 1880.
Chem. Eur. J. <\/em>2023<\/strong>, 29<\/em>, e202302609.
J. Org. Chem. <\/em>2023<\/strong>, 88<\/em>, 924.
Chem. Asian J. <\/em>2022<\/strong>,17<\/em>, e202200239.
J. Org. Chem. <\/em>2021<\/strong>, 86<\/em>, 14586.
J. Org. Chem. <\/em>2020<\/strong>,85<\/em>, 8142.
Eur. J. Org. Chem.<\/em> 2019<\/strong>, 4561.<\/p>\n\n\n\n

Development of Practical Reagents Applicable to the Industrial Production of Pharmaceuticals<\/h3>\n\n\n\n

In pharmaceutical development, even when a highly active compound is identified, it cannot reach the market unless it can be produced industrially in a stable and cost-effective manner. In recent years, the increasing complexity of drug structures and the emergence of new modalities have renewed recognition of the importance of industrial manufacturing. Through my experience in the pharmaceutical industry, I have seen many candidate compounds abandoned because their production costs were incompatible with drug pricing. From this perspective, we believe that developing reagents that enable the simple and cost-effective introduction of valuable functional groups can enhance their utility in drug discovery.<\/p>\n\n\n

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In our laboratory, in addition to developing such useful reagents, we aim to refine the disulfide-forming reactions and peptide modification reactions described above into robust methodologies suitable for scale-up processes. To date, we have successfully developed organosulfur reagents, including disulfide reagents, and a disulfide reagent is scheduled to be marketed. By creating an environment in which these reagents are readily accessible to many reseachers, we hope to further enhance the utility of the corresponding functional groups. Looking ahead, we aim to expand our repertoire of reagents beyond sulfur-based systems. Ultimately, we hope that these reagents and methodologies will find practical use in pharmaceutical development.<\/p>\n","protected":false},"excerpt":{"rendered":"

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