Thiol-Epoxy Click Chemistry: Neutral Quaternary Phosphonium-Promoted Weak Catalysis for Alkylation of Thiols
The thiol-involved ring-opening reaction of epoxides plays a critical role in organic synthesis and life sciences. However, achieving efficient, precise, and green thiolysis of epoxides under mild conditions remains a significant challenge, and the application in thiol-targeted alkylation in biologi...
Saved in:
| Main Author: | |
|---|---|
| Other Authors: | , , , , , , , , |
| Published: |
2025
|
| Subjects: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | The thiol-involved ring-opening reaction of epoxides plays a critical role in organic synthesis and life sciences. However, achieving efficient, precise, and green thiolysis of epoxides under mild conditions remains a significant challenge, and the application in thiol-targeted alkylation in biological scenarios is even more restricted by harsh reaction conditions and a narrow substrate scope. Herein, we present a straightforward thiol-epoxy click chemistry that was catalyzed by neutral phosphonium salts under ambient conditions in solvent-free or aqueous systems. The protocol exhibits excellent orthogonality and substrate compatibility, achieving near-quantitative conversion of both common and more challenging substrates, including sterically hindered steroidal epoxides, tetrasubstituted epoxides, drug precursors, cysteine, and a thiosugar, into β-hydroxy thioethers. Moreover, the method demonstrated scalability to 10-<i>g</i>-scale synthesis with consistent efficiency and enabled catalyst recycling over seven cycles. Density functional theory (DFT) calculations reveal a synergistic catalytic process in which the phosphonium ion coordinates with the epoxide, while Cl<sup>–</sup> assists in thiol deprotonation. By eliminating the use of toxic reagents, transition metals, and harsh acidic or basic conditions, this method provides a green platform for drug synthesis, peptide conjugations, biomolecular modifications, etc. that leverage thiol alkylation as a pathway. This work validates the feasibility of “weak catalysis” in advancing sustainable organic chemistry and life sciences. |
|---|