A novel strategy for the solid-phase synthesis of cyclic lipodepsipeptides

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Peptide Chemistry

Background:

• Fusaricidin A is a cyclic lipodepsipeptide antibiotic with significant antimicrobial properties.
• Developing efficient synthetic routes for complex cyclic peptides is crucial for drug discovery.
• Solid-phase synthesis offers advantages in constructing complex peptide structures.

Purpose of the Study:

• To develop a rapid and efficient Fmoc solid-phase synthesis for a cyclic lipodepsipeptide analogue of fusaricidin A.
• To establish a robust method for forming the depsipeptide bond and achieving head-to-tail cyclization.
• To overcome challenges such as O→N acyl shift during synthesis.

Main Methods:

• Utilized Fmoc (9-fluorenylmethoxycarbonyl) solid-phase synthesis.
• Employed side-chain attachment of the first amino acid to the resin.
• Incorporated four quasi-orthogonal protecting groups for selective removal.
• Performed stepwise synthesis of the linear peptide analogue.
• Attached the lipid tail and formed the depsipeptide bond prior to cyclization.
• Achieved on-resin head-to-tail cyclization.

Main Results:

• Successfully synthesized a cyclic lipodepsipeptide analogue of fusaricidin A.
• Demonstrated an efficient and rapid synthetic process.
• Successfully avoided the undesired O→N acyl shift by strategic timing of lipid tail incorporation and cyclization.
• Validated the use of four quasi-orthogonal protecting groups in the synthesis.

Conclusions:

• The developed Fmoc solid-phase synthesis is a viable and efficient method for constructing cyclic lipodepsipeptide analogues.
• The strategy effectively prevents O→N acyl shift, enhancing the yield and purity of the target molecule.
• This approach provides a valuable tool for the synthesis of fusaricidin A analogues and related compounds.