Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts

Abstract

Bench-stable 3,3-difluoroallyl sulfonium salts (DFASs), featuring tunable activity and their editable C-β and gem-difluoroallyl group, proved to be versatile fluoroalkylating reagents for site-selective S-gem-difluoroallylation of cysteine residues in unprotected peptides. The reaction proceeds with high efficiency under mild conditions (ambient temperature and aqueous and weak basic conditions). Various protected/unprotected peptides, especially bioactive peptides, are site-selectively S-gem-difluoroallylated. The newly added gem-difluoroallyl group and other functional groups derived from C-β of DFASs are poised for ligation with bio-functional groups through click and radical chemistry. This stepwise “doubly orthogonal” modification of peptides enables the construction of bioconjugates with enhanced complexity and functionality. This proof of principle is successfully applied to construct a peptide–saccharide–biotin chimeric bioconjugate, indicating its great potential application in medicinal chemistry and chemical biology.

Graphical abstract: Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts

Supplementary files

Article information

Article type
Edge Article
Submitted
23 Apr 2024
Accepted
20 May 2024
First published
22 May 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024, Advance Article

Site-selective S-gem-difluoroallylation of unprotected peptides with 3,3-difluoroallyl sulfonium salts

J. Ren, M. Zhou, X. Feng, H. Zhao, X. Fu and X. Zhang, Chem. Sci., 2024, Advance Article , DOI: 10.1039/D4SC02681K

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