Peptides are essential molecules in drug discovery, but they have drawbacks such as low stability in vivo and insufficient membrane permeability. Therefore, peptidomimetics with various modifications of peptide structures have been developed to improve metabolic stability and membrane permeability in vivo and create molecules with new higher-order structures. For example, peptoids with a substituent on the nitrogen atom of the amide bond and β-peptides composed of β-amino acids are known. Peptide analogs with further structural changes have also been synthesized, and triazolamers have been developed in which the amide bond is replaced with a triazole. Triazolamers can be used to create a vast number of molecules comprehensively by combining substituents, just like peptides, and some molecules that exhibit biological activity have been found. This way, if we can comprehensively synthesize peptide analogs with new structures, it is believed to contribute to creating functional molecules such as medicines. In our laboratory, we have succeeded in synthesizing diynyl benziodoxolone with a diyne protected by a triisopropylsilyl group as a ligand (TIPS-diyne-BX) and have achieved the synthesis of ynamides with complex structural substituents by using copper-catalyzed diynylation of sulfonamides and terminal alkyne-selective azide-alkyne cycloaddition (Chem. Commun., 2023, 59, 450-453).
In this study, we synthesized the tripeptide analogs with aminobitriazole skeletons through amino acid-derived TIPS diynamides by diynylation of sulfonamides derived from amino acids and ynamide-selective azide-alkyne cycloaddition and terminal alkyne-selective azide-alkyne cycloaddition (Scheme 1).
To realize this synthesis method, it was necessary to establish the electrophilic diynylation of amino acid-derived sulfonamides in the first step, and the reaction proceeded in high yields using an electron-rich phenanthroline ligand. In addition, the ynamide site-selective azide-alkyne cycloaddition reaction in the second step proceeded in good yields by using a ruthenium or rhodium catalyst.
The synthesized aminobitriazole is bonded at the amino group site of the amino acid, so it has a three-dimensional structure that is significantly different from peptides, which are connected by an amide bond at the amino and carboxyl groups. It was revealed that it is a compound with an interesting three-dimensional structure with N-C axial chirality between the sulfonamide and triazole ring.
This work 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, and COMIT Collaborative Research 2023.
Article information
Journal name : The Journal of Organic Chemistry
Article title : Modular Synthesis of Tripeptide Analogs with an Aminobitriazole Skeleton Using Diynyl Benziodoxolone as a Trivalent Platform
Author list : Takashi Kano, Ryusei Uozumi, Toshifumi Maruyama, Norihiro Tada,* and Akichika Itoh*
Volume and number : Vol. 89, No. 16
Page : 11761-11765
DOI: 10.1021/acs.joc.4c00999
Lab name
Laboratory of Pharmaceutical Synthetic Chemistry
https://www.gifu-pu.ac.jp/lab/gousei/