Background
Thiols, which are found in proteins essential for life processes as well as in numerous pharmaceuticals, play a crucial role in biomolecular labeling and derivatization owing to their high reactivity. In particular, thioalkynes obtained through thiol alkynylation have attracted significant attention because they serve as key entry points for "click reactions," enabling the efficient connection of diverse molecular units.
However, conventional alkynylation reactions typically require bases, transition-metal catalysts, or basic buffer solutions, which limits their applicability to sensitive biomolecules and drug molecules. Therefore, the development of a thiol alkynylation method that proceeds smoothly under neutral conditions has been highly desired.
Research Results
In this study, we used a uniquely designed and developed highly reactive hypervalent iodine alkynylating agent, triisopropylsilyl diynylbenziodoxolone (TIPS-diyne-BX), and discovered that the reaction proceeds in a short time with an extremely simple operation of simply mixing the reaction mixture at room temperature, without the need for any external base addition.
Using this method, we have successfully introduced diyne structures into complex compounds rich in functional groups, such as the amino acid cysteine, thiosugar derivatives, and even the antihypertensive drug captopril (Scheme 1).
To elucidate the origin of the high reactivity of TIPS-diyne-BX under base-free conditions, density functional theory (DFT) calculations were performed on TIPS-diyne-BX and related reagents. These studies revealed that TIPS-diyne-BX possesses a relatively low LUMO energy and that the hypervalent iodine center exhibits the highest δ⁺ character among the examined reagents. In addition, the reduced δ⁻ character at the α-carbon suggests that both thiol coordination to the hypervalent iodine center and the subsequent nucleophilic addition to the α-carbon are efficiently promoted (Figures 1 and 2).
The resulting 1,3-butadiynyl sulfides obtained by this method can undergo further transformations. For example, two consecutive azide-alkyne cycloaddition reactions enable access to structurally unique tripeptide analogues. In addition, the successful synthesis of cyclobutene derivatives via [2+2] cycloaddition reactions has also been demonstrated.
This methodology allows derivatization of pharmaceuticals and natural products while retaining their intrinsic functions and is therefore expected to become a powerful tool in next-generation drug discovery and chemical biology research.
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 conducted as a collaborative study involving the Laboratory of Pharmaceutical Synthetic Chemistry at Gifu Pharmaceutical University (Ryusei Uozumi, Takuto Naito, Hiroyoshi Esaki, Associate Professor Norihiro Tada, and Professor Akichika Itoh) and the Department of Chemistry at Hyogo Medical University (Associate Professor Hiroyoshi Esaki). The results were published in Organic & Biomolecular Chemistry, a journal issued by the Royal Society of Chemistry (UK).
The paper was also selected for the Back Front Cover of the journal.
Highlights in this study
- A hypervalent iodine reagent enables molecular transformation through an extremely simple operation.
- Cysteine derivatives and drug molecules can be efficiently derivatized.
- The obtained products serve as versatile platforms for further functionalization via click reactions.
Article information
Journal name: Organic & Biomolecular Chemistry
Article title: External base-free electrophilic diynylation of thiols with diynyl benziodoxolone
Author list: Ryusei Uozumi, Takuto Naito, Hiroyoshi Esaki, Norihiro Tada*, and Akichika Itoh*
Volume and number: Vol. 23
Page: 10045-1050
DOI: 10.1039/d5ob01384d
https://pubs.rsc.org/en/content/articlelanding/2025/ob/d5ob01384d
Lab name
Laboratory of Pharmaceutical Synthetic Chemistry
https://www.gifu-pu.ac.jp/lab/gousei/