Solid phase library synthesis of cyclic depsipeptides: aurilide and aurilide analogues

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Cyclic depsipeptides like aurilide are complex natural products with potential biological activities.
• Developing efficient synthetic routes is crucial for accessing these compounds and their analogues for further study.

Purpose of the Study:

• To describe a solid-phase combinatorial synthesis approach for aurilide and related analogues.
• To establish an optimized and efficient method for generating a library of aurilide derivatives.

Main Methods:

• Solid-phase synthesis utilizing trityl linker-functionalized SynPhase Crowns and Fmoc strategy for peptide assembly.
• Optimization of tetrapeptide assembly via parallel synthesis and liquid chromatography-mass spectrometry (LC/MS) analysis.
• Coupling of aliphatic moiety to solid-supported peptide, followed by deprotection, cleavage, and macrocyclization under high dilution conditions.

Main Results:

• Aurilide (1) was synthesized in 11% overall yield after deprotection and macrocyclization.
• A combinatorial library of aurilide derivatives (4) was successfully synthesized using a similar protocol and the TranSort technique.
• The described method provides a viable route for generating diverse cyclic depsipeptide analogues.

Conclusions:

• The developed solid-phase combinatorial synthesis is effective for producing aurilide and its analogues.
• This approach facilitates the generation of compound libraries for exploring structure-activity relationships.
• The methodology offers a platform for discovering novel cyclic depsipeptide-based therapeutics.