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Dithiane-Alkyne Metathesis Enables Trp(C2)-Alkene-Cross-Linked Cyclic Peptides
Liang Li1, Xiaomeng Gong1, Guohong Tang1
1School of Pharmacy and State Key Laboratory of Natural Product Chemistry, Lanzhou University, Lanzhou 730000, P. R. China.
Organic Letters
|February 10, 2026
Summary
We developed a new indium-catalyzed reaction for creating cyclic peptides. This efficient method, dithiane-alkyne metathesis (DAM), produces diverse, E-selective Trp(C2)-alkene-cross-linked macrocycles from linear precursors.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Peptide Chemistry
Background:
- Cyclic peptides are valuable scaffolds in drug discovery, offering a blend of rigidity and diversity.
- Developing efficient methods for synthesizing complex cyclic peptides is crucial for advancing drug development.
Purpose of the Study:
- To introduce a novel indium(III)-catalyzed intramolecular dithiane-alkyne metathesis (DAM) reaction.
- To demonstrate the utility of DAM for constructing Trp(C2)-alkene-cross-linked cyclic peptides.
Main Methods:
- Indium(III)-catalyzed intramolecular dithiane-alkyne metathesis (DAM).
- Transformation of linear peptide precursors into cyclic peptide macrocycles.
- Characterization of the resulting cyclic peptides for structure and selectivity.
Main Results:
- Efficient synthesis of Trp(C2)-alkene-cross-linked cyclic peptides.
- Exclusive E-selectivity in the macrocycle formation.
- Broad substrate scope, high atom economy, and operational simplicity of the DAM protocol.
Conclusions:
- Dithiane-alkyne metathesis (DAM) is a mechanistically distinct and practical peptide stapling strategy.
- This method enables the efficient construction of diverse cyclic peptide macrocycles.
- The developed protocol holds significant promise for drug discovery applications.
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