Background
Peptides play a crucial role in the development of functional molecules such as pharmaceuticals; however, their poor absorption and low proteolytic stability limit their applications. To overcome these drawbacks, a wide range of peptidomimetics has been developed in which the peptide bond is replaced by alternative structural motifs.
Among these, triazolamers (1,2,3-triazole-based peptidomimetics) have emerged as promising scaffolds for bioactive compounds. While 1,4-disubstituted and 1,5-disubstituted triazoles are well established, the development of aminotriazolamers―where amino acid side chains are connected through aminotriazole units―represents a new frontier for creating nonpeptidic foldamers with unique higher-order structures.
Research Results
In this study, we developed a synthetic strategy for 4- and 5-aminotriazolamers by assembling three amino acid-derived modules (glycine, leucine, and phenylalanine). The synthesis was accomplished through iterative electrophilic ethynylation using triisopropylsilyl ethynylbenziodoxolone (TIPS-EBX), followed by transition-metal-catalyzed azide-alkyne cycloaddition (AAC).
Specifically, copper-catalyzed AAC (CuAAC) selectively afforded the 4-aminotriazole framework, whereas ruthenium-catalyzed AAC (RuAAC) was employed to construct the 5-aminotriazole skeleton. Subsequent deprotection and cyclization furnished a cyclic 4-aminotriazolamer (a 15-membered lactam) and a cyclic 5-aminotriazolamer (a 13-membered lactam), respectively (Scheme 1).
X-ray crystallographic analysis revealed that these cyclic aminotriazolamers form unique porous structures in the solid state. The 4-aminotriazolamer adopts a right-handed helical architecture, generating pores of approximately 3 Å in diameter, stabilized by amide hydrogen bonds and multiple weak intermolecular interactions. In contrast, the 5-aminotriazolamer assembles into a tubular structure with a pore diameter of approximately 5 Å (Figure 1).
The distinct structural characteristics of 4- and 5-aminotriazoles―analogous to trans- and cis-amide conformations―position these aminotriazolamers in a chemical space clearly differentiated from conventional peptides and triazolamers, thereby offering new opportunities for molecular design and drug discovery.
Research Grant
This research was supported by JSPS KAKENHI Grant Numbers 19K06977 and 22K06530 and Grants for Research from SIS (The Society of Iodine Science), OGAWA Science and Technology Foundation, Takeda Science Foundation, Suzuken Memorial Foundation, and COMIT Collaborative Research 2023.
Article information and publications
This work was carried out at the Laboratory of Pharmaceutical Synthetic Chemistry, Gifu Pharmaceutical University (Chihiro Muraki, Ryosuke Tomono, Ryusei Uozumi, Associate Professor Norihiro Tada, and Professor Akichika Itoh), in collaboration with Rigaku Corporation (Yoshiki Kiyota). The results were published in The Journal of Organic Chemistry.
Highlights in this study
- Development of 4- and 5-aminotriazolamers as a new class of nonpeptidic foldamers.
- Application of iterative electrophilic ethynylation using hypervalent iodine reagents combined with regioselective AAC.
- X-ray crystallographic analysis revealed distinct helical and tubular porous structures in the solid state.
- These scaffolds occupy a unique chemical space, potentially mimicking trans- and cis-peptide bonds with extended bond distances.
Article information
Journal name: The Journal of Organic Chemistry
Article title: Synthesis of 4- and 5-Aminotriazolamers via Iterative Electrophilic Ethynylation and Azide−Alkyne Cycloaddition
Author list: Chihiro Muraki, Ryosuke Tomono, Ryusei Uozumi, Norihiro Tada*, Yoshiki Kiyota, and Akichika Itoh*
Volume and number: Vol. 90, Issue 47
Page: 16794-16799
DOI: 10.1021/acs.joc.5c02149
https://pubs.acs.org/doi/10.1021/acs.joc.5c02149
Lab name
Laboratory of Pharmaceutical Synthetic Chemistry
https://www.gifu-pu.ac.jp/lab/gousei/