Total Synthesis of Talarolide A and <i>atrop</i>-Talarolide A: Hydroxamate H-Bond Bridge Stabilization of Cyclic Peptide Conformers Invokes Non-Canonical Atropisomerism

Abstract

The first total synthesis of the Australian marine tunicate fungus-derived cyclic peptide talarolide A (1) has confirmed the structure previously proposed on the basis of spectroscopic and chemical analyses and re-affirmed the importance of the unique hydroxamate H-bond bridge in ring conformer stabilization. The unexpected co-synthesis of atrop-talarolide A (8) revealed, for the first time, that hydroxamate H-bond bridging in the talarolide framework invokes non-canonical atropisomerism and that talarolides A (1), C (3), and D (4) all exist naturally as atropisomers. These discoveries raise the intriguing prospect that comparable functionalisation of other cyclic peptides, including those with commercial value, could provide ready access to new “unnatural atropisomeric” chemical space, with new and/or improved chemical and biological properties.

Keywords

• talarolide A
• total synthesis
• atropisomerism
• cyclic peptide
• conformer stabilization
• hydroxamate H-bond bridge