Total Synthesis of N-hydroxy Cyclic Peptide: Talarolide A

This chapter reports the successful synthesis of talarolide A (1), a natural product exhibiting a unique hydroxamate H-bond bridge, through a carefully designed solid-phase approach. By systematically selecting the disconnection site, we synthesized a protected linear precursor, which was then sequentially deprotected and cyclized. We discovered that the order of deprotection and cyclization was critical: precyclization of the unprotected peptide facilitated the correct conformational folding essential for achieving the natural product's structure. This approach not only yielded talarolide A but also revealed a noncanonical atropisomer (atrop-talarolide A 5), providing new insights into the role of hydroxamate H-bond bridging in atropisomerism among nonribosomal peptide synthetase (NRPS)-derived cyclic peptides.