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Benzophenone-Based Phenylogous Peptide Linkage via Friedel-Crafts Acylation
Hao Wu1, Yuko Otani1, Ying Zhou1
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Organic Letters
|October 18, 2025
Summary
Researchers developed a new method to create diverse peptide backbones by replacing amide bonds with phenylogous amide linkages. This novel approach expands possibilities for drug discovery and peptide design.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Peptide Chemistry
Background:
- Conventional peptide synthesis relies on amide bonds, limiting structural diversity.
- Exploring non-natural linkages is crucial for advancing peptide-based therapeutics and materials.
Purpose of the Study:
- To introduce a novel method for diversifying peptide backbones.
- To explore the synthesis and utility of phenylogous (vinylogous) amide linkages in peptides.
Main Methods:
- Utilized Friedel-Crafts acylation to form phenylogous amide bonds using benzophenone units.
- Optimized reaction conditions involving acidic catalysis and low temperatures.
- Applied the method to synthesize modified di- and tetrapeptides.
Main Results:
- Successfully replaced conventional amide bonds with phenylogous amide linkages.
- Demonstrated broad substrate compatibility for the reaction.
- Showcased the ability to perform further transformations, such as Beckmann rearrangement, to revert to amide bonds.
Conclusions:
- The developed strategy effectively expands peptide structural diversity.
- This method offers new avenues for drug discovery and the design of non-natural peptide architectures.
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