Total Synthesis of N-hydroxy Cyclic Peptide: Talarolide A

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Talarolide A is a natural product with a unique hydroxamate H-bond bridge.
• Nonribosomal peptide synthetase (NRPS)-derived cyclic peptides can exhibit complex structures and atropisomerism.

Purpose of the Study:

• To report the successful synthesis of talarolide A via a solid-phase approach.
• To investigate the critical factors influencing the conformational folding and cyclization process.
• To explore the role of hydroxamate H-bond bridging in atropisomerism.

Main Methods:

• Solid-phase synthesis of a protected linear precursor.
• Systematic selection of disconnection sites for precursor synthesis.
• Sequential deprotection and cyclization strategies.
• Analysis of conformational folding and atropisomer formation.

Main Results:

• Successful synthesis of talarolide A (1).
• Identification of a critical order for deprotection and cyclization steps, enabling correct conformational folding.
• Discovery of a noncanonical atropisomer, atrop-talarolide A (5).

Conclusions:

• The developed solid-phase approach is effective for synthesizing talarolide A.
• Hydroxamate H-bond bridging plays a significant role in atropisomerism within NRPS-derived cyclic peptides.
• The findings provide new insights into the structural diversity and formation of cyclic peptides.