Solid-phase synthesis of a cyclodepsipeptide: cotransin.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Peptide Chemistry

Background:

• Cyclic depsipeptides, like cotransin, exhibit promising pharmacological activities.
• Solid-phase synthesis is a crucial technique for producing complex peptides.
• Challenges in solid-phase synthesis include diketopiperazine formation and epimerization.

Purpose of the Study:

• To achieve the first solid-phase synthesis of cotransin.
• To develop efficient and epimerization-free cyclization conditions.
• To explore novel protection/deprotection strategies in peptide synthesis.

Main Methods:

• Solid-phase peptide synthesis utilizing optimized coupling reagents.
• Fmoc/Bsmoc orthogonal protection system with novel deprotection conditions.
• Cyclization in solution initiated from the C-terminal lactic acid residue.
• Use of tetrabutylammonium fluoride (TBAF) or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) for Fmoc removal.

Main Results:

• Successful solid-phase synthesis of cotransin was achieved.
• Diketopiperazine formation was suppressed by strategic Fmoc removal.
• Fast and epimerization-free cyclization was accomplished by starting from C-terminal lactic acid.
• Novel orthogonal conditions for the Fmoc/Bsmoc system were established.
• Unexpected nucleophilic properties of DBU in this context were observed.

Conclusions:

• The developed solid-phase synthesis provides a viable route to cotransin.
• The findings offer new insights into controlling side reactions in cyclic depsipeptide synthesis.
• This methodology can be applied to the synthesis of other complex cyclic peptides with pharmacological potential.